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The Journal of Organic Chemistry
 
J Org Chem. 2017 January 6; 82(1): 57–75.
Published online 2016 December 22. doi:  10.1021/acs.joc.6b02053
PMCID: PMC5224347

Diastereoselective Synthesis of Highly Substituted Tetrahydrofurans by Pd-Catalyzed Tandem Oxidative Cyclization–Redox Relay Reactions Controlled by Intramolecular Hydrogen Bonding

Abstract

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Palladium-catalyzed oxidative cyclization of alkenols provides a convenient entry into cyclic ethers but typically proceeds with little or no diastereoselectivity for cyclization of trisubstituted olefins to form tetrahydrofurans due to the similar energies of competing 5-membered transition-state conformations. Herein, a new variant of this reaction has been developed in which a PdCl2/1,4-benzoquinone catalyst system coupled with introduction of a hydrogen-bond acceptor in the substrate enhances both diastereoselectivity and reactivity. Cyclization occurs with 5-exo Markovnikov regioselectivity. Mechanistic and computational studies support an anti-oxypalladation pathway in which intramolecular hydrogen bonding increases the nucleophilicity of the alcohol and enforces conformational constraints that enhance diastereoselectivity. The cyclization is followed by a tandem redox-relay process that provides versatile side-chain functionalities for further derivatization.

Introduction

Highly substituted tetrahydrofurans are found in myriad natural products with diverse biological activities (Figure Figure11).1 Among these are the macrocyclic norcembrenoids,2 isolated from Sinularia soft corals and exemplified by the first identified family member, norcembrenolide (5-episinuleptolide),2a,2b which inhibits production of the proinflammatory cytokine tumor necrosis factor-α.2i The plakortin family of polyketides,3 isolated from Plakortis marine sponges, includes plakortone D,3a an activator of a Ca2+-pumping ATPase involved in proper cardiac relaxation, and plakortether A,3e which exhibits selective cytotoxicity against a macrophage-like cell line. Other examples include squalene-derived polyethers such as venustratriol,4 an antiviral natural product isolated from Laurencia red algae, and aplysqualenol A,5 a potent antitumor and antiviral agent isolated from the Laurencia-consuming Caribbean sea slug Aplysia dactylomela.

Figure 1
Natural products containing 1,1,4-trisubstituted tetrahydrofuran motifs.

A variety of methods have been developed for the synthesis of THFs.6 Intramolecular oxypalladation of alkenols,7,8 pioneered by Hosokawa and co-workers,9 is a particularly powerful method for the construction of such oxygen heterocycles. Semmelhack later demonstrated that the resulting palladium–alkyl intermediate can be trapped with carbon monoxide in methanol to provide ester products (Figure Figure22).10 Indeed, plakortone natural products have been synthesized using this approach via oxidative cyclization of tertiary alcohols onto 1,2-disubstituted olefins to form the THF ring with subsequent carbonylative lactonization to form the fused ring system.11 However, in the converse approach, Semmelhack found that cyclization of secondary alcohols onto 1,1-disubstituted olefins resulted, after carbonylation, in a 1:1 mixture of diastereomers. This was attributed to similar energies of the two competing 5-membered ring reactive conformations.10

Figure 2
Models of diastereocontrol in intramolecular oxypalladations of alkenols to form 1,1,4-trisubstituted tetrahydrofurans.

We became interested in this problem in the context of our ongoing program on the synthesis of libraries based on underrepresented scaffolds from natural products.12 Herein, we report a novel variant of this Pd-catalyzed oxidative cyclization in which intramolecular hydrogen bonding provides increased diastereoselectivity (up to 7:1 dr) in the conversion of trisubstituted alkenols to 1,1,4-trisubstituted THFs. The resulting Pd–alkyl intermediate then undergoes a tandem redox-relay reaction,13 leading to synthetically useful side chain functionalities. A rationale for the observed diastereoselectivity is proposed based on mechanistic studies and computational modeling. The reaction accommodates a variety of substituent patterns and chelating functionalities.

Results and Discussion

Reaction Discovery, Optimization, and Scope

In the course of exploratory studies of metal-catalyzed cyclizations of alkenols to access oxygen heterocycles, we discovered that Pd(OAc)2/Cu(OAc)2-mediated oxidative cyclization9 of alkenediol 1 provided 1,1,4-trisubstituted THF 2a with modest but non-zero 2:1 diastereoselectivity (Table 1, entry 1). Based on this unexpected result, we investigated other copper co-oxidants, but all led to either lower yields or decomposition of starting material (data not shown). Interestingly, use of a PdCl2/CuCl2 catalyst system led instead to 6-endo cyclization product 3 (entry 2). Returning to Pd(OAc)2, we found that 1,4-benzoquinone (BQ) was also an effective co-oxidant (entry 3), while use of Pd(TFA)2/BQ resulted in a much lower yield (entry 4). Strikingly, the combination of PdCl2 and BQ resulted in increased 6:1 diastereoselectivity, a dramatic shift in reactivity, with aldehyde 2b isolated in excellent yield (entry 5). The diastereomers were inseparable, but the stereochemical configuration of the major diastereomer was assigned by extensive 1D and 2D NMR analysis.16 Notably, none of the expected β-hydride elimination product 2a was observed. Formation of an aldehyde (2b) side chain, rather than an alkene (2a), in the product suggested that the initial oxidative cyclization was followed by a tandem redox-relay process (vide infra).

Table 1
Discovery and Optimization of Diastereoselective Tandem Oxidative Cyclization–Redox Relay Reactiona

Addition of catalytic pyridine, which has been shown to increase catalytic efficiency in Wacker oxidations,14 completely inhibited the reaction (entry 6). Pd(PPh3)2Cl2 was also ineffective as a catalyst, resulting in no reaction (entry 7). No reaction was observed in the absence of 1,4-benzoquinone as a co-oxidant, even with stoichiometric PdCl2 (entry 8). Evaluation of other solvents (entries 9–13) identified THF and toluene as the most effective with respect to both diastereoselectivity and yield.

With these conditions in hand, we next investigated the scope of the tandem oxidative cyclization–redox relay reaction. Reactions of other substituted alcohols revealed that diastereoselectivity correlated positively with the steric bulk of the cyclizing alcohol (t-Bu > Ph > isopropenyl > n-Bu > Me) (Table 2, entries 1–4, and Table 1, entry 5), reaching 7:1 dr for the tert-butyl-substituted substrate 4d. Ester-substituted diol 4e also underwent efficient cyclization, albeit with diminished 2:1 diastereoselectivity (entry 5). A triol substrate 4f also cyclized to the corresponding THF with complete regioselectivity over tetrahydropyran formation (entry 6), although again with lower 2:1 diastereoselectivity (cf. entry 4). Notably, tertiary alcohols 4g and 4h were unreactive at 25 °C but underwent efficient oxidative cyclizations at 60 °C (entries 7 and 8). Variation in chain length for the distal (noncyclizing) alcohol led to somewhat decreased diastereoselectivies and yields (entries 9 and 10). Taken together, the observed decreases in diastereoselectivity in the presence of competing coordinating functionalities and with alternative chain lengths are suggestive of a role for the distal alcohol in transition-state organization.

Table 2
Scope of the Diastereoselective Tandem Oxidative Cyclization–Redox Relay Reactiona

Role of the Distal Alcohol on Diastereoselectivity and Reactivity

To gain further insights into the possible role of the distal alcohol in the reaction, we investigated substrates with related distal functionalities (Table 3). When the alcohol was capped as a TBS ether in substrate 6, no reaction took place under our standard reaction conditions or upon heating to 60 °C (entry 1), consistent with a role for the distal alcohol in promoting the reaction. Further heating to 80 °C in 1,4-dioxane led to substrate decomposition to form a complex mixture. In contrast, when Hosokawa’s original Pd(OAc)2/Cu(OAc)2 catalyst system was employed at 25 °C, the cyclization product 7 was isolated in 2:1 dr (entry 2), identical to the result obtained with the parent diol substrate 1 (Table 1, entry 1). This suggests that the distal alcohol does not impact reactivity or diastereoselectivity under Hosokawa’s classical oxidative cyclization conditions.9 When the distal alcohol was capped as a methyl ether in 8, the PdCl2/BQ reaction did proceed at 60 °C to form aldehyde 3 in modest yield and diastereoselectivity (Table 2, entry 3). We posit that the side-chain aldehyde is formed as a result of the subsequent redox relay process rather than via initial demethylation of the substrate 8 to reform diol 1 (vide infra). Ester, carboxylic acid, and Weinreb amide directing groups in 911, respectively, were also effective under PdCl2/BQ catalysis at 60 °C, yielding the corresponding α,β-unsaturated ester, acid, and amide products 1214, respectively (entries 4 and 5), albeit with modest diastereoselectivities.

Table 3
Effects of Distal Functionalities on the Diastereoselective Tandem Oxidative Cyclization–Redox Relay Reactiona,b

Mechanistic Studies via Deuterium-Labeling Experiments

We next evaluated structural isomers of the parent alkene diol substrate 1 in the reaction (Figure Figure33). The isomeric diol 15, in which the phenyl substituent is moved to the noncyclizing side chain bearing the distal alcohol, also underwent efficient cyclization with 5-exo Markovnikov regioselectivity to give phenyl ketone 16. To probe the mechanism of the redox-relay process, we carried out the same reaction with the corresponding deuterium-labeled substrate 17. Complete deuterium transfer to the α-carbon of the ketone in 18 was observed, consistent with a processive Pd–H migration mechanism leading directly to the carbonyl product rather than initial formation of an enol product followed by spontaneous tautomerization (vide infra).13b,13c

Figure 3
Deuterium-labeling experiment to probe mechanism of side-chain carbonyl formation.

Other PdCl2-catalyzed oxypalladations have been shown to proceed via both syn- and anti-oxypalladation pathways.15 To differentiate between these two possibilities, we synthesized deuterium-labeled substrates 19a and 19b and subjected them to PdCl2/BQ-catalyzed cyclization at 60 °C to yield THFs 23a and 23b, respectively, as single diastereomers (Figure Figure44 and Figure S1).16 Relative stereochemical configurations were assigned by hydrogenolytic cleavage of the THF ring and conversion to cyclic acetals 24a and 24b, followed by 1H NMR analysis of coupling constants and NOE interactions (Figure S2 and Figure S3).16 This confirmed that the α-deuterium (adjacent to the THF ring) and C1-methyl group were syn in 23a and anti in 23b, consistent with the intermediacy of anti-oxypalladation intermediates 20a and 20b. In contrast, if a syn-oxypalladation mechanism were operative, the α-deuterium and C1-methyl group would be anti in 23a and syn in 23b, consistent with a syn relationship between the methyl group and the palladium in intermediate (cf. 20).

Figure 4
Deuterium-labeling experiments to differentiate between syn- and anti-oxypalladation mechanisms.

Computational Studies

The experimental results strongly suggest a role of the distal functionality in enhancing both reactivity and diastereoselectivity in the reaction. Moreover, inclusion of other potentially competing functionalities as solvent (Table 1, entries 11–13) or in the substrate (Table 2, entries 5 and 6, and Table 3, entries 4–6) leads to reduced diastereoselectivity. Thus, we considered two possible mechanistic hypotheses for a role of the distal hydroxyl functionality in organizing the transition state, leading to the unusual diastereoselectivity of this intramolecular oxypalladation (Figure Figure55). In one scenario, the distal functionality engages in an intramolecular hydrogen-bonding interaction with the cyclizing alcohol to organize the anti-oxypalladation transition state 25 (pathway A). Ess and co-workers have reported similar hydrogen-bonding interactions in AuI- and PdII-catalyzed intramolecular cyclizations of allylic alcohols.17 Alternatively, the distal functionality could chelate the Pd to organize the transition state 26 (pathway B). This chelation effect has been proposed to rationalize chirality transfer in oxypalladation reactions,18 although experimental studies on a redox-relay Heck reaction13f have excluded chelation of the Pd. In both cases, 5-exo Markovnikov oxidative cyclization would be followed by a redox-relay process that, based on the deuterium-labeling experiment above (Figure Figure33), terminates with β-hydride elimination across the terminal C–O bond to form the observed aldehyde products (2b or 5) directly.13b,13d

Figure 5
Proposed models for organization of anti-oxypalladation transition state by intramolecular hydrogen bonding (pathway A) or Pd chelation (pathway B) by the distal (noncyclizing) alcohol followed by tandem redox-relay reaction to generate an aldehyde side-chain functionality. ...

To evaluate these mechanistic hypotheses, we carried out computational studies of the two putative reaction pathways by calculating the stereodifferentiating (diastereomeric) transition structures for the cyclization of alkene diol substrate 4a at the M06/LanL2DZ+f/6-31g(d,p) level of theory.16,19 For the Pd chelation model (26), attempts to locate transition structures for the direct attack of the cyclizing alcohol on the π-coordinated palladium were not successful. This suggests that the free hydroxyl group is not sufficiently nucleophilic to attack the Pd–olefin complex under these conditions. In agreement with previous work,13d,13f this indicates that the distal (noncyclizing) alcohol does not chelate Pd. In contrast, in the hydrogen-bonding model (25), we were able to locate the transition structures 25a and 25b (Figure Figure66). Here, the distal hydroxyl group activates the cyclizing alcohol by an intramolecular hydrogen bond that increases the nucleophilicity of the hydroxyl group by partial deprotonation. It is noteworthy that, in contrast to the work of Ess and co-workers,17 no dehydrative elimination is observed in our system. This is consistent with the experimental finding that elimination of the Pd from the carbon chain is disfavored compared to the chain-walking redox-relay process (Figure Figure33). It has been shown previously in redox-relay–Heck reactions13b,13d that elimination is highly endergonic due to the instability of Pd bound to an electron-withdrawing ligand, suggesting a possible role for the BQ in controlling reactivity in our system. With the elimination pathways energetically unfavorable, the distal alcohol is converted into an aldehyde after a series of β-hydride elimination and reinsertion chain-walking steps.13b

Figure 6
Stereodifferentiating transition structures 25a and 25b for the cyclization of 4a (Ln = Cl2(BQ)) with bond distances in Å.

Consistent with the experimentally observed 2:1 dr for oxidative cyclization of 4a (Table 2, entry 1), transition structure 25a, which leads to the anti-1,4-diastereomer 5a, was calculated to be 0.5 kcal/mol lower in free energy than the diastereomeric transition structure 25b.19 Importantly, these calculated structures provide insights into the structural origin of the observed diastereoselectivity. In the favored transition structure 25a, the methyl group α to the cyclizing alcohol is in a pseudoequatorial orientation relative to the forming five-membered ring. In contrast, this α-methyl group is an unfavorable pseudoaxial position in transition structure 25b, inducing a 1,3-diaxial steric repulsion between the α-methyl group and an axial hydrogen atom. This is in agreement with the observation that diastereoselectivity increases as the size of this substituent increases (Table 2, entries 1–4). Nevertheless, the effect is modest due to the relatively small steric differences between the equatorial and axial positions in five-membered rings.20

Conclusion

Several features of this unusually diastereoselective tandem oxidative cyclization–redox relay reaction are notable. In particular, the choice of catalyst is critical to the outcome of the reaction. First, under PdCl2/BQ catalysis herein, a hydrogen-bond accepting distal functionality is required for the oxidative cyclization reaction to proceed (Table 3, entry 1). In contrast, reaction with Hosokawa’s classical Pd(OAc)2/Cu(OAc)2 catalyst system does not require a distal hydrogen-bonding functionality (Table 3, entry 2).

Second, under PdCl2/BQ catalysis, diastereoselectivity of the oxidative cyclization is dependent upon tether length (Table 2, entries 9 and 10) and the electronics of the distal functional group (Table 3). This suggests that the distal functionality plays a critical role in organizing the transition state, as supported by our computational modeling studies (Figure Figure66). In contrast, under Pd(OAc)2/Cu(OAc)2 catalysis, the distal functionality does not appear to impact diastereoselectivity (Table 1, entry 1, vs Table 3, entry 2). This suggests that the 2:1 dr observed for oxidative cyclization of both 1 and 6 represents the inherent diastereoselectivity of the isolated THF-forming portion of the substrate. The 6:1 dr observed for oxidative cyclization of 1 under PdCl2/BQ catalysis then indicates the increased diastereoselectivity attributable to the distal functionality.

Third, PdCl2/BQ catalysis herein leads to aldehyde (or α,β-unsaturated carboxylate derivative) side chains via a putative tandem redox-relay process that follows the oxidative cyclization reaction.13 In contrast, under Pd(OAc)2/Cu(OAc)2 catalysis, the tandem redox-relay process does not take place, and vicinal olefin side chains are formed via immediate β-hydride elimination of the initial alkyl-Pd intermediate (Table 1, entry 1 vs entry 5). The lack of reinsertion of Pd–H across the olefin in the latter case suggests rapid dissociation of the Pd–olefin complex and short lifetime of the resulting Pd–H species.15 This may be due to differences between the Pd ligands in these two catalyst systems.

In conclusion, we have developed a novel variant of the classical Pd-catalyzed oxidative cyclization of alkenols in which use of a PdCl2/BQ catalyst system and introduction of a distal hydrogen-bonding functionality into the substrate dramatically change the course of the reaction. The oxidative cyclization reaction proceeds via an anti-oxypalladation mechanism with 5-exo Markovnikov regioselectivity and a tandem redox-relay process converts distal side chain alcohols to aldehydes or ketones that are poised for further functionalization. In this tandem reaction, the distal hydrogen-bonding functionality enhances both reactivity and diastereoselectivity, and computational modeling studies suggest that this results from introduction of specific conformational constraints in the transition state. While the absolute diastereoselectivity of these reactions ranges from moderate to high depending on substrate structure, this transition-state organization increases diastereoselectivity well above the intrinsic levels observed under classical Hosokawa conditions that are not influenced by intramolecular hydrogen bonding. Further investigations of the scope and mechanism of this reaction, particularly the role of catalyst structure, and applications to natural product and library synthesis are ongoing.

Experimental Section

General Methods

All reactions were performed in flame-dried glassware under positive Ar pressure with magnetic stirring unless otherwise noted. Solvents were degassed with Ar and purified on a solvent drying system as described21 unless otherwise indicated. Liquid reagents and solutions were transferred through rubber septa via syringes flushed with Ar prior to use. Cold baths were generated as follows: 0 °C, wet ice/water; −78 °C, dry ice/acetone.

NMR spectra were recorded on a 500 MHz NMR or 600 MHz NMR with a DCH CryoProbe at 24 °C in CDCl3 unless otherwise indicated. Chemical shifts are expressed in ppm relative to TMS (1H, 0 ppm) or solvent signals: CDCl3 (13C, 77.0 ppm); coupling constants are expressed in hertz. High-resolution mass spectra were obtained at the MSKCC Analytical Core Facility on an LC-TOF-MS by electrospray ionization (ESI).

Compounds not cited explicitly in the main text are numbered from S1 below. Detailed synthetic schemes are shown in Figures S8–S25.

1. Synthesis of Diol Substrates

1a. Synthesis of Ester Intermediate S4 and Aldehyde Intermediate S6

tert-Butyl(pent-4-en-1-yloxy)diphenylsilane (S1)

In a 250 mL round-bottom flask, 4-penten-1-ol (6.00 mL, 58.1 mmol) and imidazole (7.90 g, 116 mmol, 2 equiv) were dissolved in CH2Cl2 (100 mL), and the solution was cooled to 0 °C. TBDPSCl (58.1 mL, 15.1 mmol, 1 equiv) was added slowly with stirring. The solution was allowed to warm to rt and stirred until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (100 mL), extracted with CH2Cl2 (3 × 50 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product S1 as a colorless oil (17.1 g, 91%) that was carried onto the next step without further purification. IR (neat) (cm–1): 2929, 2857, 2337, 2271, 1671, 1015, 821, 737, 700, 614. 1H NMR (600 MHz): δ 7.70–7.64 (m, 4H), 7.44–7.35 (m, 6H), 5.83–5.77 (m, 1H), 5.03–4.91 (m, 2H), 3.67 (t, J = 6.4 Hz, 2H), 2.15 (q, J = 6.4, 2H), 1.66 (quint, J = 6.4, 2H), 1.05 (s, 1H). 13C NMR (151 MHz): δ 138.5, 135.6, 134.0, 129.5, 127.6, 114.5, 63.2, 31.78, 30.0, 26.8, 19.2. HRMS (ESI): m/z calcd for (C21H29OSi [M + H]+) 325.1988, found 325.1985.

4-((tert-Butyldiphenylsilyl)oxy)butanal (S2)

In a 500 mL round-bottom flask, alkene S1 (16.0 g, 49.3 mmol) was dissolved in CH2Cl2 (150 mL), and the solution was cooled to −78 °C. Ozone was bubbled through the solution until the blue color was persistent. The stream of ozone was replaced with oxygen until the blue color dissipated, and then the reaction was quenched with zinc powder (16.0 g, 246 mmol, 5 equiv) in acetic acid (50 mL), allowed to slowly warm to rt, and stirred overnight. The solution was concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded aldehyde S2 (15.3 g, 46.7 mmol, 95%) as a colorless oil. IR (neat) (cm–1): 2936, 2862, 1729, 1431, 1112, 944, 826, 743, 706, 616. 1H NMR (600 MHz): δ 9.79 (s, 1H), 7.65 (d, J = 6.5 Hz, 4H), 7.46–7.33 (m, 6H), 3.69 (t, J = 6.0 Hz, 4H), 2.55 (t, J = 1.7 Hz, 2H), 1.89 (quint., J = 6.0 Hz, 2H), 1.04 (s, 15H). 13C NMR (151 MHz): δ 202.5, 135.5, 133.5, 129.7, 127.7, 62.9, 40.7, 26.8, 25.2, 19.2. HRMS (ESI): m/z calcd for (C20H27O2Si [M + H]+) 327.1780, found 327.1769.

6-((tert-Butyldiphenylsilyl)oxy)-2-methylhex-1-en-3-ol (S3)

In a 500 mL round-bottom flask, aldehyde S2 (15.3 g, 49.3 mmol) was dissolved in THF (100 mL), and the solution was cooled to 0 °C. Isopropenylmagnesium bromide (1.0 M in THF, 93.5 mL, 46.7 mmol, 1 equiv) was added slowly via an addition funnel. Once addition was complete, the cooling bath was removed, and the solution was allowed to stir at rt until complete conversion had occurred as judged by TLC. The mixture was recooled to 0 °C and quenched with 1 M HCl (100 mL). The mixture was extracted with Et2O (3 × 50 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded allylic alcohol S3 (16.1 g, 43.7 mmol, 93%) as a yellow oil. IR (neat) (cm–1): 3690–3147, 2936, 2862, 1431, 1111, 1001, 741, 704, 616. 1H NMR (600 MHz): δ 7.69–7.63 (m, 4H), 7.43–7.33 (m, 6H), 4.94 (s, 1H), 4.83 (s, 1H), 4.06 (t, J = 6.4 Hz, 1H), 3.73–3.59 (m, 2H), 2.20 (s, 1H), 1.72 (s, 3H), 1.67–1.55 (m, 4H), 1.06 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 147.4, 135.5, 133.7, 129.6, 127.6, 110.9, 75.5, 63.9, 31.7, 28.5, 26.8, 19.2, 17.7. HRMS (ESI): m/z calcd for (C23H33O2Si [M + H]+) 369.2250, found 369.2242.

Ethyl (E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyloct-4-enoate (S4)

In a 50 mL round-bottom flask, allylic alcohol S3 (3.00 g, 8.14 mmol), triethyl orthoacetate (15 mL), and propionic acid (60 μL, 0.81 mmol, 0.1 equiv) were added. The flask was equipped with a distillation head and heated to 140 °C, during which time ethanol was collected. Heating was continued at this temperature until complete conversion had occurred as judged by TLC. The mixture was cooled to rt and quenched with 1 M HCl (25 mL). The mixture was extracted with Et2O (3 × 50 mL), washed with 1 M NaOH (10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded ester S4 (3.25 g, 91%) as a colorless oil. IR (neat) (cm–1): 2956, 2858, 1735, 1445, 1428, 1156, 822, 737, 701, 649. 1H NMR (600 MHz): δ 7.67 (d, J = 6.5 Hz, 4H), 7.45–7.33 (m, 6H), 5.12 (t, J = 1.4 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 2.37 (t, J = 6.1 Hz, 2H), 2.30–2.24 (m, 2H), 2.07 (q, J = 7.4 Hz, 2H), 1.64–1.55 (m, 5H), 1.24 (t, J = 7.1 Hz, 3H), 1.05 (s, 9H). 13C NMR (151 MHz): δ 173.5, 135.5, 134.0, 133.7, 129.5, 127.6, 124.8, 63.3, 60.2, 34.7, 33.2, 32.6, 26.8, 24.1, 19.2, 15.9, 14.3. HRMS (ESI): m/z calcd for (C27H39O3Si [M + H]+) 439.2668, found 439.2663.

(E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyloct-4-en-1-ol (S5)

In a 250 mL round-bottom flask, ester S4 (2.00 g, 4.56 mmol) was dissolved in THF (50 mL), and the solution was cooled to 0 °C. LiAlH4 (173 mg, 4.56 mmol, 1 equiv) was added slowly and the solution stirred at 0 °C until complete conversion had occurred as judged by TLC. The mixture was carefully quenched with 1 M HCl (25 mL). The mixture was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S5 (1.80 g, 4.53 mmol, 99%) as a colorless oil. IR (neat) (cm–1): 3702–3114, 2933, 2858, 1589, 1470, 1428, 1107, 821, 737, 701, 612. 1H NMR (600 MHz): δ 7.70–7.64 (m, 4H), 7.45–7.34 (m, 6H), 5.14 (t, J = 7.3 Hz, 1H), 3.65 (t, J = 6.4 Hz, 2H), 3.61 (t, J = 6.5 Hz, 2H), 2.08 (q, J = 7.4 Hz, 2H), 2.04 (t, J = 7.3, 2H), 1.69–1.58 (m, 5H), 1.27 (s, 3H), 1.05 (s, 9H). 13C NMR (151 MHz): δ 135.6, 135.0, 134.1, 129.5, 127.6, 124.6, 63.4, 62.8, 35.9, 32.7, 30.7, 26.8, 24.2, 19.2, 15.8. HRMS (ESI): m/z calcd for (C25H37O2Si [M + H]+) 397.2563, found 397.2558.

(E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyloct-4-enal (S6)

In a 250 mL round-bottom flask, alcohol S5 (1.85 g, 4.66 mmol) was dissolved in CH2Cl2 (100 mL), and PCC (2.01 g, 9.33 mmol, 2 equiv) was added. The solution was stirred at rt until complete conversion had occurred as judged by TLC. The mixture was filtered through a pad of silica with hexane/EtOAc 9:1 and concentrated by rotary evaporation to afford aldehyde S6 (1.42 g, 3.60 mmol, 77%) as a colorless oil. IR (neat) (cm–1): 2931, 2858, 1725, 1427, 1106, 822, 738, 701, 612. 1H NMR (600 MHz): δ 9.73 (t, J = 1.9 Hz, 1H), 7.69–7.64 (m, 4H), 7.44–7.34 (m, 6H), 5.12 (t, J = 7.3 Hz, 1H), 3.64 (t, J = 6.3 Hz, 2H), 2.48 (td, J = 7.6, 1.9 Hz, 2H), 2.29 (t, J = 7.6 Hz, 2H), 2.08 (q, J = 7.3 Hz, 2H), 1.62–1.55 (m, 5H), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 202.7, 135.6, 134.0, 133.3, 129.5, 127.6, 125.2, 63.3, 42.2, 32.5, 31.8, 26.8, 24.2, 19.2, 16.0. HRMS (ESI): m/z calcd for (C25H34O2NaSi [M + Na]+) 417.2226, found 417.2212.

1b. Synthesis of Diol Substrates 1 and 4a-d from Aldehyde Intermediate S6

(E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1-phenyloct-4-en-1-ol (S7)

In a 25 mL round-bottom flask, aldehyde S6 (200 mg, 0.51 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. PhMgBr (1.0 M in THF, 0.61 mL, 0.61 mmol, 1.2 equiv) was added dropwise with stirring. Once addition was complete, the solution was allowed to warm to rt, and stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded benzylic alcohol S7 (211 mg, 0.45 mmol, 88%) as a colorless oil. IR (neat) (cm–1): 3683–3118, 3068, 2931, 2857, 1427, 1106, 821, 737, 699, 612. 1H NMR (600 MHz): δ 7.68–7.64 (m, 4H), 7.42–7.30 (m, 11H), 5.12 (t, J = 7.0 Hz, 1H), 4.62 (dd, J = 7.8, 5.3 Hz, 1H), 3.65 (t, J = 6.4 Hz, 2H), 2.11–2.04 (m, 3H), 2.02–1.95 (m, 1H), 1.91–1.81 (m, 1H), 1.81–1.74 (m, 1H), 1.62–1.55 (m, 5H), 1.05 (s, 9H). 13C NMR (151 MHz): δ 144.7, 135.5, 134.9, 134.0, 129.5, 128.4, 127.5, 127.4, 125.9, 124.6, 74.3, 63.4, 37.2, 35.9, 32.6, 26.8, 24.1, 19.2, 16.0. HRMS (ESI): m/z calcd for (C31H40O2NaSi [M + Na]+) 495.2695, found 495.2681.

(E)-4-Methyl-1-phenyloct-4-ene-1,8-diol (1)

In a 10 mL round-bottom flask, protected alcohol S7 (200 mg, 0.42 mmol) was dissolved in THF (4 mL) at rt. TBAF (1.0 M in THF, 0.85 mL, 0.85 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 1 (96 mg, 0.41 mmol, 97%) as a colorless oil. IR (neat) (cm–1): 3715–3092, 2932, 2864, 1720, 1496, 1059, 1033, 765, 703. 1H NMR (600 MHz): δ 7.29–7.24 (m, 4H), 7.22–7.18 (m, 1H), 5.10 (t, J = 7.0, 1H), 4.56 (dd, J = 7.8, 5.3 Hz, 1H), 3.54 (t, J = 6.5 Hz, 2H), 2.08–1.90 (m, 1H), 1.85–1.78 (m, 1H), 1.77–1.70 (m, 1H), 1.57–1.49 (m, 5H). 13C NMR (151 MHz): δ 144.8, 135.4, 128.4, 127.5, 125.9, 124.3, 74.3, 62.7, 37.2, 36.0, 32.7, 24.3, 16.0. HRMS (ESI): m/z calcd for (C14H20O2Na [M + Na]+) 243.1361, found 243.1363.

(E)-9-((tert-Butyldiphenylsilyl)oxy)-5-methylnon-5-en-2-ol (S8)

In a 25 mL round-bottom flask, aldehyde S6 (100 mg, 0.25 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. MeMgBr (1.0 M in THF, 0.30 mL, 0.30 mmol, 1.2 equiv) was added dropwise with stirring. Once addition was complete, the solution was allowed to warm to rt, and stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S8 (102 mg, 0.25 mmol, 98%) as a colorless oil. IR (neat) (cm–1): 3660–3131, 2930, 2858, 1469, 1427, 1106, 821, 735, 700, 612. 1H NMR (600 MHz): δ 7.67 (d, J = 6.8 Hz 4H), 7.44–7.34 (m, 6H), 5.15 (t, J = 7.3 Hz, 1H), 3.76 (q, J = 6.2 Hz, 1H), 3.65 (t, J = 6.3 Hz, 2H), 2.12–1.98 (m, 4H), 1.63–1.67 (m, 4H), 1.56–1.47 (m, 1H), 1.18 (d, J = 6.2 Hz, 3H), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 135.6, 135.3, 134.1, 129.5, 127.6, 124.4, 68.0, 63.4, 37.3, 36.1, 32.7, 26.8, 24.2, 23.4, 19.2, 15.9. HRMS (ESI): m/z calcd for (C26H39O2Si [M + H]+) 411.2719, found 411.2719.

(E)-5-Methylnon-4-ene-1,8-diol (4a)

In a 10 mL round-bottom flask, protected alcohol S8 (75 mg, 0.18 mmol) was dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.37 mL, 0.37 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 4a (29 mg, 0.17 mmol, 92%) as a colorless oil. IR (neat) (cm–1): 3667–3095, 2967, 2933, 2886, 1452, 1378, 1132, 1061, 737. 1H NMR (600 MHz): δ 5.20–5.18 (m, 1H), 3.78 (sextet, J = 6.2 Hz, 1H), 3.63 (t, J = 6.5 Hz, 2H), 2.14–2.01 (m, 4H), 1.92 (s, 2H), 1.66–1.50 (m, 7H), 1.19 (d, J = 6.2 Hz, 3H). 13C NMR (151 MHz): δ 135.7, 124.2, 68.0, 62.6, 37.2, 36.1, 32.6, 24.3, 23.4, 15.9. HRMS (ESI): m/z calcd for (C10H20O2Na [M + Na]+) 195.1361, found 195.1357.

(E)-12-((tert-Butyldiphenylsilyl)oxy)-8-methyldodec-8-en-5-ol (S9)

In a 25 mL round-bottom flask, aldehyde S6 (100 mg, 0.25 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. nBuLi (2.5 M in hexanes, 0.12 mL, 0.30 mmol, 1.2 equiv) was added dropwise with stirring. Once addition was complete, the solution was allowed to warm to rt, and stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S9 (108 mg, 0.24 mmol, 94%) as a colorless oil. IR (neat) (cm–1): 3683–3120, 2930, 2858, 1428, 1106, 1004, 822, 701, 612. 1H NMR (600 MHz): δ 7.69–7.65 (m, 4H), 7.44–7.33 (m, 6H), 5.15 (t, J = 7.1 Hz, 1H), 3.66 (t, J = 6.3 Hz, 2H), 3.60–3.54 (m, 1H), 2.16–1.98 (m, 4H), 1.65–1.52 (m, 7H), 1.52–1.37 (m, 3H), 1.37–1.24 (m, 3H), 1.05 (s, 9H), 0.91 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ 135.9, 135.5, 135.4, 134.1, 129.5, 127.6, 71.9, 63.4, 37.1, 36.0, 35.4, 32.7, 27.8, 26.8, 24.2, 22.8, 19.2, 15.9, 14.1. HRMS (ESI): m/z calcd for (C29H45O2Si [M + H]+) 453.3189, found 453.3180.

(E)-5-Methyldodec-4-ene-1,8-diol (4b)

In a 10 mL round-bottom flask, protected alcohol S9 (100 mg, 0.22 mmol) was dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.44 mL, 0.44 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 4b (29 mg, 0.17 mmol, 92%) as a colorless oil. IR (neat) (cm–1): 3686–3076, 2860, 1378, 1055. 1H NMR (600 MHz): δ 5.21 (t, J = 7.2 Hz, 1H), 3.65 (t, J = 6.5 Hz, 2H), 3.61–3.55 (m, 1H), 2.19–2.02 (m, 4H), 1.65–1.55 (m, 7H), 1.54–1.37 (m, 3H), 1.37–1.27 (m, 3H), 0.91 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz): δ 135.9, 124.1, 71.9, 62.7, 37.2, 36.0, 35.4, 32.7, 27.8, 24.3, 22.8, 16.0, 14.1. HRMS (ESI): m/z calcd for (C13H26O2Na [M + Na]+) 237.1831, found 237.1828.

(E)-10-((tert-Butyldiphenylsilyl)oxy)-2,6-dimethyldeca-1,6-dien-3-ol (S10)

In a 25 mL round-bottom flask, aldehyde S6 (100 mg, 0.25 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. Isopropenylmagnesium bromide (0.5 M in THF, 0.61 mL, 0.30 mmol, 1.2 equiv) was added dropwise with stirring. Once addition was complete, the solution was allowed to warm to rt, and stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded allylic alcohol S10 (98 mg, 0.22 mmol, 88%) as a colorless oil. IR (neat) (cm–1): 3660–3157, 2932, 2858, 1380, 1106, 899, 822, 736, 701, 612. 1H NMR (600 MHz): δ 7.68–7.65 (m, 4H), 7.43–7.35 (m, 6H), 5.14 (t, J = 7.2, 1H), 4.93 (s, 1H), 4.84 (s, 1H), 4.03 (dd, J = 7.4, 5.5 Hz, 1H), 3.65 (t, J = 6.4 Hz, 2H), 2.08 (q, J = 7.5 Hz, 2H), 2.06–2.01 (m, 1H), 2.01–1.94 (m, 1H), 1.72 (t, J = 1.2 Hz, 3H), 1.65–1.56 (m, 7H), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 147.5, 135.6, 135.0, 134.1, 129.5, 127.6, 124.5, 111.0, 75.7, 63.4, 35.7, 33.2, 32.7, 26.8, 24.2, 19.2, 17.6, 16.0. HRMS (ESI): m/z calcd for (C28H40O2SiNa [M + Na]+) 459.2695, found 459.2710.

(E)-5,9-Dimethyldeca-4,9-diene-1,8-diol (4c)

In a 10 mL round-bottom flask, protected alcohol S10 (100 mg, 0.23 mmol) was dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.46 mL, 0.46 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 4c (40 mg, 0.20 mmol, 88%) as a colorless oil. IR (neat) (cm–1): 3667–3128, 2937, 2866, 1444, 1375, 1058, 899, 732. 1H NMR (600 MHz): δ 5.20 (t, J = 7.1 Hz, 1H), 4.94 (s, 1H), 4.84 (s, 1H), 4.04 (t, J = 6.2 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 2.11–2.04 (m, 3H), 2.03–1.96 (m, 1H), 1.73 (s, 3H), 1.71–1.57 (m, 7H). 13C NMR (151 MHz, CDCl3): δ 147.5, 135.5, 124.2, 111.0, 75.6, 62.7, 35.7, 33.1, 32.7, 24.3, 17.6, 16.0. HRMS (ESI): m/z calcd for (C12H22O2Na [M + Na]+) 221.1517, found 221.1524.

(E)-10-((tert-Butyldiphenylsilyl)oxy)-2,2,6-trimethyldec-6-en-3-ol (S11)

In a 25 mL round-bottom flask, aldehyde S6 (100 mg, 0.25 mmol) was dissolved in THF (5 mL) and the solution was cooled to 0 °C. tBuMgBr (1.6 M in THF, 0.19 mL, 0.30 mmol, 1.2 equiv) was added dropwise with stirring. Once addition was complete, the solution was allowed to warm to rt, and stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S11 (109 mg, 0.24 mmol, 95%) as a colorless oil. IR (neat) (cm–1): 3677–3211, 1471, 1428, 1107, 822, 737, 701, 612. 1H NMR (600 MHz): δ 7.67 (d, J = 6.5 Hz, 4H), 7.44–7.34 (m, 6H), 5.18 (t, J = 6.4 Hz, 1H), 3.66 (t, J = 6.3 Hz, 2H), 3.16 (d, J = 10.5 Hz, 1H), 2.24–2.19 (m, 1H), 2.09 (q, J = 7.4 Hz, 2H), 2.05–1.97 (m, 1H), 1.66–1.53 (m, 7H), 1.38–1.29 (m, 1H), 1.05 (s, 9H), 0.89 (s, 9H). 13C NMR (151 MHz): δ 135.6, 135.5, 134.1, 129.5, 127.5, 124.5, 79.6, 63.4, 37.2, 34.9, 32.7, 29.5, 26.8, 25.7, 24.2, 19.2, 15.9. HRMS (ESI): m/z calcd for (C29H45O2Si [M + H]+) 453.3189, found 453.3184.

(E)-5,9,9-Trimethyldec-4-ene-1,8-diol (4d)

In a 10 mL round-bottom flask, protected alcohol S11 (100 mg, 0.22 mmol) was dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.44 mL, 0.44 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 4d (37 mg, 0.17 mmol, 78%) as a colorless oil. IR (neat) (cm–1): 3673–3092, 2951, 2889, 1711, 1445, 1364, 1062, 1010, 911, 733. 1H NMR (600 MHz): δ 5.27–5.19 (m, 1H), 3.65 (dt, J = 79.9, 6.5 Hz, 2H), 3.17 (d, J = 9.0 Hz, 1H), 2.28–2.21 (m, 1H), 2.13–2.01 (m, 3H), 1.68–1.60 (m, 6H), 1.51 (s, 1H), 1.42 (s, 1H), 1.38–1.30 (m, 1H), 0.90 (s 9H). 13C NMR (151 MHz): δ 135.9, 124.2, 79.6, 62.5, 37.2, 34.9, 32.7, 29.5, 25.8, 24.3, 15.9. HRMS (ESI): m/z calcd for (C13H26O2Na [M + H]+) 237.1831, found 237.1832.

1c. Synthesis of Diol Substrate 4e from Aldehyde intermediate S6

Ethyl (E)-10-((tert-Butyldiphenylsilyl)oxy)-3-hydroxy-6-methyldec-6-enoate (S12)

In a 25 mL round-bottom flask, LDA was freshly prepared in THF (2 mL) at 0 °C from diisopropylamine (54 μL, 0.38 mmol, 1.5 equiv) and nBuLi (2.5 M in hexane, 0.15 mL, 0.38 mmol, 1.5 equiv). The flask was cooled to −78 °C, and EtOAc (50 μL, 0.38 mmol, 2 equiv) as a solution in THF (0.5 mL) was added dropwise with stirring. The solution was stirred at −78 °C for 30 min, and aldehyde S6 (100 mg, 0.25 mmol) was added as a solution in THF (1 mL). Stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched at −78 °C with the addition of satd aq NH4Cl (5 mL). The mixture was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded S12 (120 mg, 0.25 mmol, 98%) as a yellow oil. IR (neat) (cm–1): 3712–3113, 2932, 2858, 1723, 1427, 1185, 1106, 821, 734, 701, 612. 1H NMR (600 MHz): δ 7.67 (d, J = 6.6 Hz, 4H), 7.45–7.33 (m, 6H), 5.14 (t, 7.2 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4,00–3.95 (m, 1H), 3.65 (t, J = 6.2 Hz, 2H), 2.99 (s, 1H), 2.49 (dd, J = 16.3, 3.3 Hz, 1H), 2.41 (dd, J = 16.3, 8.9 Hz, 1H), 2.18–2.00 (m, 4H), 1.63–1.55 (m, 6H), 1.55–1.48 (m, 1H), 1.27 (t, J = 7.2 Hz, 2H), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 173.0, 135.5, 134.8, 134.0, 129.5, 127.6, 124.6, 67.8, 63.4, 60.6, 41.3, 35.6, 34.7, 32.7, 26.8, 24.2, 19.2, 15.9, 14.2. HRMS (ESI): m/z calcd for (C29H42O4NaSi [M + H]+) 505.2750, found 505.2746.

Ethyl (E)-3,10-Dihydroxy-6-methyldec-6-enoate (4e)

In a 10 mL round-bottom flask, protected alcohol S12 (75 mg, 0.16 mmol) was dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.31 mL, 0.31 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 4e (33 mg, 0.14 mmol, 86%) as a colorless oil. IR (neat) (cm–1): 3640–3131, 2931, 1721, 1375, 1299, 1185, 1156, 1031, 879, 731. 1H NMR (600 MHz): δ 5.20 (t, J = 7.3 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.03–3.94 (m, 1H), 3.64 (t, J = 6.5 Hz, 2H), 3.03 (s, 1H), 2.55–2.37 (m, 2H), 2.18–2.11 (m, 1H), 2.08 (q, J = 7.0 Hz, 3H), 1.67–1.59 (m, 7H), 1.58–1.49 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz): δ 173.0, 135.2, 124.4, 67.7, 62.6, 60.7, 41.3, 35.6, 34.6, 32.6, 24.3, 15.9, 14.2. HRMS (ESI): m/z calcd for (C13H24O4Na [M + Na]+) 267.1572, found 267.1568.

1d. Synthesis of Triol Substrate 4f from Geranyl Bromide

Dimethyl (E)-2-(3,7-Dimethylocta-2,6-dien-1-yl)malonate (S13)

In a 100 mL round-bottom flask, K2CO3 (2.55 g, 18.4 mmol, 2 equiv) was added, followed by a solution of geranyl bromide (2.00 g, 9.21 mmol) dissolved in DMF (40 mL). Dimethyl malonate (1.27 mL, 11.1 mmol, 1.2 equiv) was added and the solution stirred at rt until complete conversion had occurred as judged by TLC. The mixture was diluted with H2O (50 mL) and extracted with Et2O (3 × 20 mL). The combined organic layers were washed with H2O (2 × 20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded diester S13 (1.86 g, 6.93 mmol, 75%) as a yellow oil. IR (neat) (cm–1): 2956, 2917, 1737, 1437, 1338, 1272, 1237, 1201, 1150, 1026, 687. 1H NMR (600 MHz): δ 5.06 (q, J = 6.7 Hz, 2H), 3.73 (s, 6H), 3.38 (t, J = 7.7 Hz, 1H), 2.61 (t, J = 7.5 Hz, 2H), 2.04 (t, 2H), 1.98 (d, J = 6.2 Hz, 1H), 1.67 (s, 3H), 1.63 (s, 3H), 1.59 (s, 3H). 13C NMR (151 MHz): δ 169.6, 166.9, 138.7, 131.5, 124.0, 119.4, 52.6, 52.4, 51.9, 41.1, 39.7, 27.6, 26.5, 25.7, 17.7, 16.0. HRMS (ESI): m/z calcd for (C15H24O4Na [M + Na]+) 291.1572, found 291.1521.

Methyl (E)-5,9-Dimethyldeca-4,8-dienoate (S14)

In a 50 mL round-bottom flask, LiCl (750 mg, 17.7 mmol, 5 equiv) was added, followed by a solution of diester S13 (950 mg, 3.54 mmol) dissolved in DMSO (15 mL). The solution was heated to 150 °C until complete conversion had occurred as judged by TLC. The mixture was diluted with H2O (20 mL) and extracted with Et2O (3 × 20 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded ester S14 (725 mg, 3.45 mmol, 97%) as a yellow oil. IR (neat) (cm–1): 2919, 1739, 1437, 1162. 1H NMR (500 MHz): δ 5.14–5.03 (m, 2H), 3.67 (s, 3H), 2.38–2.28 (m, 4H), 2.11–2.02 (m, 2H), 1.98 (t, J = 8.9 Hz, 2H), 1.68 (s, 3H), 1.62 (s, 3H), 1.60 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 173.8, 136.7, 131.4, 124.1, 122.2, 51.4, 39.6, 34.3, 26.6, 25.6, 23.5, 17.7, 15.9. HRMS (ESI): m/z calcd for (C13H22O2Na [M + Na]+) 233.1517, found 233.1515.

(E)-5,9-Dimethyldeca-4,8-dien-1-ol (S15)

In a 100 mL round-bottom flask, ester S14 (700 mg, 3.33 mmol) was dissolved in THF (50 mL), and the solution was cooled to 0 °C. LiAlH4 (126 mg, 3.33 mmol, 1 equiv) was added slowly and the solution stirred at 0 °C until complete conversion had occurred as judged by TLC. The mixture was carefully quenched with 1 M HCl (25 mL). The mixture was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded S15 (580 mg, 3.18 mmol, 96%) as a colorless oil. IR (neat) (cm–1): 3699–3125, 2924, 1723, 1449, 1379, 1055, 909, 732. 1H NMR (600 MHz): δ 5.14 (t, J = 6.4 Hz, 1H), 5.09 (t, J = 5.8 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 2.12–2.04 (m, 4H), 1.99 (d, J = 6.3 Hz, 2H), 1.68 (s, 3H), 1.65–1.59 (m, 8H). 13C NMR (151 MHz): δ 135.8, 131.4, 124.3, 123.8, 68.0, 62.7, 39.7, 32.7, 26.6, 25.7, 25.7, 25.6, 24.3, 17.7, 16.0. HRMS (ESI): m/z calcd for (C12H23O [M + H]+) 183.1749, found 183.1751.

(S,E)-5,9-Dimethyldec-4-ene-1,8,9-triol (4f)

In a 100 mL round-bottom flask, diene S15 (500 mg, 2.74 mmol) was dissolved in t-BuOH/H2O (1:1, 50 mL), and the solution was cooled to 0 °C. AD mix-α (3.85 g, 1.4 g/mol) was added, and the solution was stirred at 0 °C until complete conversion had occurred as judged by TLC. The reaction was diluted with H2O (50 mL) and extracted with Et2O (3 × 25 mL), and the organic layers were pooled washed with 10% HCl (10 mL), brine (10 mL), and dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded 4f (220 mg, 1.02 mmol, 37%) as a colorless oil. IR (neat) (cm–1): 3682–3112, 2932, 2858, 1739, 1384, 1108, 821, 737, 700, 612. 1H NMR (600 MHz): δ 5.24 (d, J = 6.8 Hz, 1H), 3.66 (t, J = 6.5 Hz, 2H), 3.38–3.32 (m, 1H), 2.30–2.21 (m, 2H), 2.14–2.03 (m, 4H), 1.70–1.55 (m, 8H), 1.47–1.36 (m, 1H), 1.21 (s, 3H), 1.16 (s, 3H). 13C NMR (151 MHz): δ 124.6, 78.2, 73.0, 62.7, 36.8, 32.6, 29.6, 26.4, 24.3, 23.2, 15.9. HRMS (ESI): m/z calcd for (C12H24O3Na [M + Na]+) 239.1623, found 239.1615.

1e. Synthesis of Diol Substrates 4g,h from Ester Intermediate S4

(E)-9-((tert-Butyldiphenylsilyl)oxy)-2,5-dimethylnon-5-en-2-ol (S16)

In a 25 mL round-bottom flask, ester S4 (200 mg, 0.46 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. MeMgBr (1.0 M in THF, 1.00 mL, 1.00 mmol, 2.2 equiv) was added dropwise with stirring. Once addition was complete, the solution was allowed to warm to rt, and stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S16 (110 mg, 0.45 mmol, 98%) as a colorless oil. IR (neat) (cm–1): 3695–3115, 2965, 2936, 2862, 1473, 1431, 1110, 912, 826, 736, 705, 616. 1H NMR (600 MHz): δ 7.67 (d, J = 6.8 Hz, 4H), 7.45–7.33 (m, 6H), 5.15 (d, J = 5.7 Hz, 1H), 3.65 (t, J = 6.3 Hz, 2H), 2.11–1.99 (m, 4H), 1.64–1.57 (m, 5H), 1.57–1.51 (m, 2H), 1.34 (s, 1H), 1.22 (s, 8H), 1.05 (d, J = 2.2 Hz, 9H). 13C NMR (151 MHz): δ 135.7, 135.6, 129.5, 127.6, 124.1, 71.1, 63.4, 42.0, 34.4, 32.6, 29.2, 26.8, 24.2, 19.2, 16.1. HRMS (ESI): m/z calcd for (C27H41O2Si [M + H]+) 425.2876, found 425.2876.

(E)-5,8-Dimethylnon-4-ene-1,8-diol (4g)

In a 10 mL round-bottom flask, protected alcohol S22 (180 mg, 0.42 mmol) was dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.85 mL, 0.85 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 4g (55 mg, 0.30 mmol, 69%) as a colorless oil. IR (neat) (cm–1): 3727–3067, 2884, 1657, 1321, 1189, 1123, 1060, 966, 925. 1H NMR (600 MHz): δ 5.20 (t, J = 7.2 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 2.13–2.04 (m, 4H), 1.64 (s, 3H), 1.63–1.60 (m, 2H), 1.60–1.55 (m, 2H), 1.23 (s, 6H). 13C NMR (151 MHz, CDCl3): δ 136.2, 123.8, 71.1, 62.6, 41.9, 34.5, 32.7, 29.2, 24.3, 16.1. HRMS (ESI): m/z calcd for (C11H22O2Na [M + Na]+) 209.1517, found 209.1518.

(E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1,1-diphenyloct-4-en-1-ol (S17)

In a 25 mL round-bottom flask, ester S4 (200 mg, 0.45 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. PhMgBr (1.0 M in THF, 1.00 mL, 1.00 mmol, 2.2 equiv) was added dropwise with stirring. Once addition was complete, the solution was allowed to warm to rt, and stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S17 (220 mg, 0.40 mmol, 88%) as a colorless oil. IR (neat) (cm–1): 3712–3254, 3068, 2931, 2858, 1592, 1187, 1107, 1003, 909, 822, 733, 698, 612. 1H NMR (600 MHz): δ 7.69–7.63 (m, 4H), 7.46–7.23 (m, 14H), 7.26–7.18 (m, 2H), 5.08 (d, J = 7.1 Hz, 1H), 3.64 (t, J = 6.4 Hz, 2H), 2.39–2.34 (m, 2H), 2.06 (d, J = 7.4 Hz, 2H), 2.00–1.94 (m, 2H), 1.60 (s, 3H), 1.59–1.54 (m, 2H), 1.04 (s, 9H). 13C NMR (151 MHz): δ 147.0, 135.5, 134.0, 129.5, 128.1, 127.5, 126.7, 125.9, 124.5, 78.5, 63.3, 40.0, 33.9, 32.6, 26.8, 24.2, 19.2, 16.2. HRMS (ESI): m/z calcd for (C37H44O2SiNa [M + Na]+) 571.3008, found 571.3000.

(E)-4-Methyl-1,1-diphenyloct-4-ene-1,8-diol (4h)

In a 10 mL round-bottom flask, protected alcohol S17 (200 mg, 0.36 mmol) was dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.73 mL, 0.73 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 4h (85 mg, 0.27 mmol, 75%) as a colorless oil. IR (neat) (cm–1): 3709–3128, 2934, 2862, 1717, 1492, 1447, 1057, 1032, 944, 698. 1H NMR (600 MHz): δ 7.42 (d, J = 6.6 Hz, 4H), 7.31 (t, J = 7.0 Hz, 4H), 7.22 (t, J = 7.3 Hz, 2H), 5.14 (t, J = 7.2 1H), 3.63 (t, J = 6.5 Hz, 2H), 2.43–2.36 (m, 2H), 2.06 (q, J = 7.3 Hz, 2H), 1.99 (dd, J = 9.9, 6.2 Hz, 2H), 1.65–1.56 (m, 5H). 13C NMR (151 MHz): δ 146.9, 136.1, 128.1, 126.8, 126.0, 124.2, 78.5, 62.6, 40.0, 34.0, 32.6, 24.2, 16.2. HRMS (ESI): m/z calcd for (C21H26O2Na [M + Na]+) 333.1831, found 333.1840.

1f. Synthesis of Diol Substrate 4i from 3-Buten-1-ol

(But-3-en-1-yloxy)(tert-butyl)diphenylsilane (S18)

In a 250 mL round-bottom flask, 3-buten-1-ol (1.00 g, 13.9 mmol) and imidazole (944 mg, 13.9 mmol, 2 equiv) were dissolved in CH2Cl2 (15 mL), and the solution was cooled to 0 °C. TBDPSCl (3.60 mL, 13.9 mmol, 1 equiv) was added slowly with stirring. The solution was allowed to warm to rt and stirred until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (10 mL) and extracted with CH2Cl2 (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil (4.24 g, 98%) that was taken onto the next step without further purification. IR (neat) (cm–1): 2928, 2361, 1558, 1427, 1105, 822, 737, 700, 613. 1H NMR (600 MHz): δ 7.76–7.62 (m, 4H), 7.48–7.31 (m, 6H), 5.91–5.76 (m, 1H), 5.10–4.97 (m, 2H), 3.71 (t, J = 6.7 Hz, 2H), 2.32 (q, J = 7.1, 6.3 Hz, 2H), 1.05 (s, 9H). 13C NMR (151 MHz): δ 135.6, 135.4, 133.9, 129.5, 127.6, 116.3, 63.5, 37.2, 26.8, 19.2. HRMS (ESI): m/z calcd for (C20H27OSi [M + H]+) 311.1831, found 311.1821.

3-((tert-Butyldiphenylsilyl)oxy)propanal (S19)

In a 250 mL round-bottom flask, alkene S18 (1.50 g, 4.83 mmol) was dissolved in CH2Cl2 (50 mL), and the solution was cooled to −78 °C. Ozone was bubbled through the solution until the blue color was persistent. The stream of ozone was replaced with oxygen until the blue color dissipated, and then the reaction was quenched with triphenylphosphine (1.58 g, 6.04 mmol, 1.25 equiv), allowed to slowly warm to rt, and stirred for 0.5 h. The solution was concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded aldehyde S19 (1.40 g, 4.48 mmol, 92%) as a colorless oil. IR (neat) (cm–1): 2959, 2934, 2724, 1729, 1470, 1426, 1095, 824, 745, 702, 613. 1H NMR (600 MHz): δ 9.81 (t, J = 2.2 Hz, 1H), 7.69–7.63 (m, 4H), 7.47–7.36 (m, 6H), 4.02 (t, J = 6.0 Hz, 2H), 2.60 (td, J = 6.0, 2.2 Hz, 2H), 1.04 (s, 9H). 13C NMR (151 MHz): δ 201.9, 135.5, 133.2, 129.8, 127.7, 58.3, 46.4, 26.7, 19.1. HRMS (ESI): m/z calcd for (C19H24O2NaSi [M + H]+) 335.1443, found 335.1447.

5-((tert-Butyldiphenylsilyl)oxy)-2-methylpent-1-en-3-ol (S20)

In a 25 mL round-bottom flask, aldehyde S19 (1.00 g, 3.20 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. Isopropenylmagnesium bromide (1.0 M in THF, 6.40 mL, 3.20 mmol, 1 equiv) was added slowly. Once the addition was complete, the cooling bath was removed, and the solution was stirred at rt until complete conversion had occurred as judged by TLC. The mixture was recooled to 0 °C and quenched with 1 M HCl (10 mL). The mixture was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded allylic alcohol S20 (1.10 g, 3.10 mmol, 96%) as a yellow oil. IR (neat) (cm–1): 3699–3144, 3053, 2937, 2779, 1720, 1431, 1111, 873, 743 706, 648. 1H NMR (600 MHz): δ 7.68 (d, J = 7.0 Hz, 4H), 7.49–7.34 (m, 6H), 5.05 (s, 1H), 4.86 (s, 1H), 4.34 (dd, J = 7.1, 4.6 Hz, 1H), 3.91–3.85 (m, 1H), 3.81 (d, J = 3.2 Hz, 1H), 3.22 (s, 1H), 1.83–1.77 (m, 2H), 1.72 (s, 3H), 1.06 (s, 9H). 13C NMR (151 MHz): δ 147.0, 135.5, 133.0, 129.8, 127.7, 110.5, 74.8, 62.8, 36.8, 26.8, 19.0, 18.3. HRMS (ESI): m/z calcd for (C22H31O2Si [M + H]+) 355.2093, found 355.2083.

Ethyl (E)-7-((tert-Butyldiphenylsilyl)oxy)-4-methylhept-4-enoate (S21)

In a 25 mL round-bottom flask, allylic alcohol S20 (1.00 g, 2.82 mmol), triethyl orthoacetate (5 mL), and propionic acid (20 μL, 0.28 mmol, 0.1 equiv) were added. The flask was equipped with a distillation head and heated to 140 °C during which time ethanol was collected. Heating was continued at this temperature until complete conversion had occurred as judged by TLC. The mixture was cooled to rt and quenched with 1 M HCl (10 mL). The mixture was extracted with Et2O (3 × 10 mL), washed with 1 M NaOH (10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded ester S21 (820 mg, 68%) as a colorless oil. IR (neat) (cm–1): 2957, 2900, 1735, 1445, 1107, 701, 612. 1H NMR (600 MHz): δ 7.71–7.63 (m, 4H), 7.45–7.35 (m, 6H), 5.15 (t, J = 7.2 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.62 (t, J = 7.0 Hz, 2H), 2.37 (d, J = 7.2 Hz, 2H), 2.34–2.22 (m, 4H), 1.56 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.04 (h, 9H). 13C NMR (151 MHz): δ 173.5, 135.6, 135.3, 134.0, 129.5, 127.6, 121.2, 63.6, 60.2, 34.7, 33.1, 31.5, 26.8, 19.2, 16.0, 14.2. HRMS (ESI): m/z calcd for (C26H36O3NaSi [M + Na]+) 447.2331, found 447.2312.

(E)-7-((tert-Butyldiphenylsilyl)oxy)-4-methylhept-4-en-1-ol (S22)

In a 25 mL round-bottom flask, ester S21 (500 mg, 1.18 mmol) was dissolved in THF (10 mL), and the solution was cooled to 0 °C. LiAlH4 (45 mg, 1.18 mmol, 1 equiv) was added slowly and the solution stirred at 0 °C until complete conversion had occurred as judged by TLC. The mixture was carefully quenched with 1 M HCl (5 mL). The mixture was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S22 (405 mg, 1.06 mmol, 89%) as a colorless oil. IR (neat) (cm–1): 3670–3134, 2893, 2858, 1470, 1170, 1087, 821, 804, 735, 700, 611. 1H NMR (600 MHz, Chloroform-d) δ 7.70–7.65 (m, 4H), 7.44–7.34 (m, 6H), 5.17 (t, J = 6.7 Hz, 1H), 3.64 (t, J = 7.0 Hz, 2H), 3.59 (t, J = 6.5 Hz, 2H), 2.27 (q, J = 7.2 Hz, 2H), 2.04 (t, J = 7.4 Hz, 2H), 1.64 (quint, J = 6.7 Hz, 2H), 1.56 (s, 3H), 1.05 (s, 9H). 13C NMR (151 MHz): δ 136.6, 135.6, 134.0, 129.5, 127.6, 120.8, 63.7, 62.7, 36.0, 31.5, 30.7, 26.8, 19.2, 16.0. HRMS (ESI): m/z calcd for (C24H35O2Si [M + H]+) 383.2406, found 383.2422.

(E)-7-((tert-Butyldiphenylsilyl)oxy)-4-methylhept-4-enal (S23)

In a 25 mL round-bottom flask, alcohol S22 (250 mg, 0.65 mmol) was dissolved in CH2Cl2 (10 mL). PCC (140 mg, 0.65 mmol, 2 equiv) was added, and the solution was stirred at rt until complete conversion had occurred as judged by TLC. The mixture was filtered through a pad of silica with hexane/EtOAc 9:1 and concentrated by rotary evaporation to afford aldehyde S23 (225 mg, 0.59 mmol, 90%) as a colorless oil. IR (neat) (cm–1): 316, 3050, 2933, 2883, 1468, 1108, 1005, 858, 702, 647, 611. 1H NMR (600 MHz): δ 9.73 (t, J = 1.9 Hz, 1H), 7.67 (dd, J = 8.0, 1.5 Hz, 4H), 7.44–7.34 (m, 6H), 5.16 (td, J = 7.2, 1.3 Hz, 1H), 3.63 (t, J = 6.9 Hz, 2H), 2.48 (td, J = 7.6, 1.9 Hz, 2H), 2.32–2.23 (m, 4H), 1.57 (s, 3H), 1.04 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 202.5, 135.7, 134.9, 133.9, 129.5, 127.8, 121.6, 63.5, 42.2, 31.8, 31.5, 27.5, 26.8, 26.8, 19.2, 16.2. HRMS (ESI): m/z calcd for (C24H33O2Si [M + H]+) 381.2250, found 381.2234.

(E)-7-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1-phenylhept-4-en-1-ol (S24)

In a 25 mL round-bottom flask, aldehyde S23 (200 mg, 0.52 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. PhMgBr (1.0 M in THF, 0.66 mL, 0.66 mmol, 1.25 equiv) was added dropwise with stirring. Once addition was complete, the solution was allowed to warm to rt, and stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded S24 (220 mg, 0.47 mmol, 91%) as a colorless oil. IR (neat) (cm–1): 3735–3131, 3050, 2931, 2893, 1892, 1822, 1724, 1108, 1086, 701, 612. 1H NMR (600 MHz): δ 7.69–7.64 (m, 4H), 7.43–7.31 (m, 10H), 7.29–7.24 (m, 1H), 5.15 (t, J = 7.7, 6.8 Hz, 1H), 4.63 (t, J = 6.8, 6.0 Hz, 1H), 3.63 (t, J = 7.0 Hz, 2H), 2.26 (q, J = 7.1 Hz, 2H), 2.13–2.06 (m, 1H), 2.03–1.96 (m, 1H), 1.92–1.83 (m, 2H), 1.83–1.75 (m, 1H), 1.55 (s, 3H), 1.04 (s, 9H). 13C NMR (151 MHz): δ 144.7, 136.5, 135.6, 134.0, 129.5, 128.4, 127.6, 125.9, 120.9, 115.2, 74.3, 63.7, 37.1, 35.9, 31.5, 26.8, 19.2, 16.1. HRMS (ESI): m/z calcd for (C30H38O2NaSi [M + Na]+) 489.2539, found 489.2529.

(E)-4-Methyl-7-phenylhept-3-ene-1,7-diol (4i)

In a 10 mL round-bottom flask, protected alcohol S24 (150 mg, 0.33 mmol) was dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.66 mL, 0.66 mmol, 2 equiv) was added and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 4i (50 mg, 0.23 mmol, 69%) as a colorless oil. IR (neat) (cm–1): 3722–3124, 2936, 2863, 1812, 1491, 1059, 1025, 760, 700, 613. 1H NMR (600 MHz): δ 7.37–7.30 (m, 4H), 7.29–7.24 (m, 1H), 5.16 (t, J = 7.6 Hz, 1H), 4.63 (dd, J = 7.9, 5.1 Hz, 1H), 3.58 (t, J = 6.7, 5.6 Hz, 2H), 2.30–2.21 (m, 2H), 2.18–2.10 (m, 1H), 2.09–2.00 (m, 1H), 1.93–1.85 (m, 1H), 1.84–1.76 (m, 1H), 1.63 (s, 3H). 13C NMR (151 MHz): δ 144.8, 138.1, 128.4, 127.5, 125.9, 120.5, 74.2, 62.3, 37.1, 36.1, 31.4, 16.2. HRMS (ESI): m/z calcd for (C14H20O2Na [M + Na]+) 243.1361, found 243.1363.

1g. Synthesis of Diol Substrate 4j from 5-Hexen-1-ol

tert-Butyl(hex-5-en-1-yloxy)diphenylsilane (S25)

In a 250 mL round-bottom flask, 5-hexen-1-ol (1.00 g, 9.98 mmol) and imidazole (1.36 g, 20.0 mmol, 2 equiv) were dissolved in CH2Cl2 (10 mL), and the solution was cooled to 0 °C. TBDPSCl (2.60 mL, 9.98 mmol, 1 equiv) was added slowly with stirring. The solution was allowed to warm to rt and stirred until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (10 mL) and extracted with CH2Cl2 (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product S25 as a colorless oil (3.21 g, 95%) that was carried onto the next step without need for further purification. IR (neat) (cm–1): 2929, 2857, 2361, 2337, 1558, 1427, 1105, 822, 700, 614. 1H NMR (600 MHz): δ 7.70–7.64 (m, 4H), 7.44–7.34 (m, 6H), 5.79 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.01–4.89 (m, 2H), 3.66 (t, J = 6.4 Hz, 2H), 2.03 (t, J = 7.2 Hz, 2H), 1.58 (quint, J = 6.9 Hz, 2H), 1.46 (quint, J = 7.8 Hz, 2H), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 138.9, 135.6, 134.1, 129.5, 127.6, 114.3, 63.7, 33.5, 32.0, 26.8, 25.1, 19.2. HRMS (ESI): m/z calcd for (C22H31OSi [M + H]+) 339.2144, found 339.2132.

5-((tert-Butyldiphenylsilyl)oxy)pentanal (S26)

In a 250 mL round-bottom flask, alkene S25 (1.50 g, 4.43 mmol) was dissolved in CH2Cl2 (50 mL), and the solution was cooled to −78 °C. Ozone was bubbled through the solution until the blue color was persistent. The stream of ozone was replaced with oxygen until the blue color dissipated, then the reaction was quenched with triphenylphosphine (1.45 g, 5.54 mmol, 1.25 equiv), allowed to slowly warm to rt, and stirred for 0.5 h. The solution was concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded aldehyde S26 (1.38 g, 4.05 mmol, 91%) as a colorless oil. IR (neat) (cm–1): 2934, 2858, 2723, 1729, 1426, 1097, 1008, 702, 612. 1H NMR (600 MHz): δ 9.74 (t, J = 1.8 Hz, 1H), 7.66 (dd, J = 8.0, 1.5 Hz, 4H), 7.44–7.36 (m, 6H), 3.67 (t, J = 6.2 Hz, 2H), 2.41 (td, J = 7.4, 1.8 Hz, 2H), 1.73 (quint, J = 7.4 Hz, 2H), 1.62–1.56 (m, 2H), 1.05 (s, 9H). 13C NMR (151 MHz): δ 202.7, 135.5, 133.8, 129.6, 127.6, 127.6, 63.3, 43.5, 31.8, 26.8, 19.2, 18.5. HRMS (ESI): m/z calcd for (C21H28O2SiNa [M + Na]+) 363.1757, found 363.1795.

7-((tert-Butyldiphenylsilyl)oxy)-2-methylhept-1-en-3-ol (S27)

In a 25 mL round-bottom flask, aldehyde S26 (1.00 g, 2.94 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. Isopropenylmagnesium bromide (1.0 M in THF, 5.87 mL, 2.94 mmol, 1 equiv) was added slowly. Once addition was complete, the cooling bath was removed, and the solution was allowed to stir at rt until complete conversion had occurred as judged by TLC. The mixture was recooled to 0 °C and quenched with 1 M HCl (10 mL). The mixture was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded allylic alcohol S27 (1.12 g, 2.93 mmol, 99%) as a yellow oil. IR (neat) (cm–1): 3709–3167, 2933, 2859, 1710, 1469, 1427, 1107, 1000, 937, 898, 822, 739, 701, 612. 1H NMR (600 MHz): δ 7.66 (d, J = 6.8 Hz, 2H), 7.45–7.33 (m, 8H), 4.92 (s, 1H), 4.82 (s, 1H), 4.03 (t, J = 6.5 Hz, 1H), 3.66 (t, J = 6.5 Hz, 2H), 1.70 (s, 3H), 1.64–1.56 (m, 2H), 1.56–1.48 (m, 2H), 1.48–1.40 (m, 1H), 1.40–1.30 (m, 1H), 1.04 (s, 9H). 13C NMR (151 MHz): δ 147.5, 135.5, 134.02, 129.5, 127.6, 111.0, 75.9, 63.8, 34.6, 32.4, 26.8, 26.8, 21.8, 19.2, 17.4. HRMS (ESI): m/z calcd for (C24H34O2NaSi [M + Na]+) 405.2226, found 405.2217.

Ethyl (E)-9-((tert-Butyldiphenylsilyl)oxy)-4-methylnon-4-enoate (S28)

In a 25 mL round-bottom flask, allylic alcohol S27 (1.00 g, 2.61 mmol), triethyl orthoacetate (5 mL), and propionic acid (20 μL, 0.26 mmol, 0.1 equiv) were added. The flask was equipped with a distillation head and heated to 140 °C during which time ethanol was collected. Heating was continued at this temperature until complete conversion had occurred as judged by TLC. The mixture was cooled to rt and quenched with 1 M HCl (5 mL). The mixture was extracted with Et2O (3 × 5 mL), washed with 1 M NaOH (5 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded ester S28 (0.85 g, 1.88 mmol, 71%) as a colorless oil. IR (neat) (cm–1): 3051, 2929, 2857, 2775, 2337, 2270, 1735, 1372, 822, 667, 615. 1H NMR (600 MHz): δ 7.67 (dd, J = 8.0, 1.5 Hz, 4H), 7.44–7.34 (m, 6H), 5.16–5.11 (m, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.65 (t, J = 6.4 Hz, 2H), 2.41–2.37 (m, 2H), 2.29 (dd, J = 9.2, 6.4 Hz, 2H), 1.96 (q, J = 7.3 Hz, 2H), 1.58 (s, 3H), 1.58–1.51 (m, 2H), 1.44–1.36 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.04 (s, 9H). 13C NMR (151 MHz): δ 173.5, 135.5, 134.1, 133.3, 129.5, 127.6, 125.4, 63.8, 60.2, 34.7, 33.3, 32.1, 27.6, 26.8, 25.9, 19.2, 15.9, 14.3. HRMS (ESI): m/z calcd for (C28H40O3NaSi [M + H]+) 475.2644, found 475.2662.

(E)-9-((tert-Butyldiphenylsilyl)oxy)-4-methylnon-4-en-1-ol (S29)

In a 25 mL round-bottom flask, ester S28 (500 mg, 1.10 mmol) was dissolved in THF (10 mL), and the solution was cooled to 0 °C. LiAlH4 (42 mg, 1.10 mmol, 1 equiv) was added slowly and the solution stirred at 0 °C until complete conversion had occurred as judged by TLC. The mixture was carefully quenched with 1 M HCl (10 mL). The mixture was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S29 (410 mg, 0.99 mmol, 90%) as a colorless oil. IR (neat) (cm–1): 3667–3141, 2862, 2775, 1474, 1110, 805, 742, 704, 615. 1H NMR (600 MHz): δ 7.71–7.62 (m, 4H), 7.45–7.34 (m, 6H), 5.20–5.11 (m, 1H), 3.65 (t, J = 6.5 Hz, 2H), 3.64–3.60 (m, 2H), 2.10–2.02 (m, 2H), 1.97 (q, J = 7.3 Hz, 2H), 1.72–1.62 (m, 2H), 1.62–1.49 (m, 5H), 1.47–1.37 (m, 2H), 1.36 (s, 1H), 1.05 (s, 9H). 13C NMR (151 MHz): δ 135.6, 134.1, 129.5, 127.6, 127.6, 125.1, 63.8, 62.8, 36.0, 32.2, 30.7, 27.6, 26.9, 26.0, 19.2, 15.9. HRMS (ESI): m/z calcd for (C26H38O2SiNa [M + H]+) 433.2539, found 433.2531.

(E)-9-((tert-Butyldiphenylsilyl)oxy)-4-methylnon-4-enal (S30)

In a 25 mL round-bottom flask, alcohol S29 (250 mg, 0.61 mmol) was dissolved in CH2Cl2 (10 mL). PCC (262 mg, 1.22 mmol, 2 equiv) was added, and the solution was stirred at rt until complete conversion had occurred as judged by TLC. The mixture was filtered through a pad of silica with hexane/EtOAc 9:1 and concentrated by rotary evaporation to afford aldehyde S30 (220 mg, 0.54 mmol, 88%) as a colorless oil. IR (neat) (cm–1): 3070, 2931, 2858, 1725, 1388, 1107, 822, 738, 701. 1H NMR (600 MHz): δ 9.74 (s, 1H), 7.71–7.64 (m, 4H), 7.46–7.33 (m, 6H), 5.18–5.09 (m, 1H), 3.65 (t, J = 6.3 Hz, 2H), 2.50 (td, J = 7.5, 1.9 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 1.97 (q, J = 7.4 Hz, 2H), 1.58 (s, 3H), 1.55 (dd, J = 8.7, 6.3 Hz, 2H), 1.40 (quint, J = 7.6 Hz, 2H), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 202.7, 135.7, 134.1, 132.9, 129.5, 127.8, 125.7, 63.8, 42.2, 32.2, 31.8, 27.6, 26.9, 25.8, 19.2, 16.1. HRMS (ESI): m/z calcd for (C26H36O2NaSi [M + H]+) 431.2382, found 431.2390.

(E)-9-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1-phenylnon-4-en-1-ol (S31)

In a 25 mL round-bottom flask, aldehyde S30 (200 mg, 0.49 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. PhMgBr (1.0 M in THF, 0.61 mL, 0.61 mmol, 1.2 equiv) was added dropwise with stirring. Once addition was complete, the solution was allowed to warm to rt, and stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S31 (130 mg, 0.27 mmol, 54%) as a colorless oil. IR (neat) (cm–1): 3683–3183, 2930, 2857, 1454, 1428, 1107, 821, 737, 699. 1H NMR (600 MHz): δ 7.66 (d, J = 6.5 Hz, 4H), 7.44–7.31 (m, 10H), 7.29–7.24 (m, 1H), 5.15 (t, J = 7.3 Hz, 1H), 4.64 (dd, J = 7.8, 5.3 Hz, 1H), 3.65 (t, J = 6.4 Hz, 2H), 2.13–2.06 (m, 1H), 2.04–1.93 (m, 3H), 1.93–1.85 (m, 1H), 1.84–1.76 (m, 1H), 1.63–1.51 (m, 5H), 1.40 (dq, J = 9.9, 7.6 Hz, 2H), 1.04 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 144.7, 135.5, 134.6, 134.1, 129.5, 128.4, 127.6, 127.5, 125.9, 125.1, 74.3, 63.8, 37.2, 36.0, 32.2, 27.6, 26.9, 26.0, 19.2, 16.0. HRMS (ESI): m/z calcd for (C32H42O2NaSi [M + H]+) 509.2852, found 509.2862.

(E)-4-Methyl-1-phenylnon-4-ene-1,9-diol (4j)

In a 10 mL round-bottom flask, protected alcohol S31 (100 mg, 0.21 mmol) was dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.41 mL, 0.41 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 4j (40 mg, 0.16 mmol, 78%) as a colorless oil. IR (neat) (cm–1): 3677–3144, 3029, 2858, 1451, 1059, 911, 733, 699. 1H NMR (600 MHz): δ 7.37–7.33 (m, 4H), 7.30–7.27 (m, 1H), 5.17 (t, J = 7.1 Hz, 1H), 4.66 (dd, J = 7.9, 5.3 Hz, 1H), 3.63 (t, J = 6.6 Hz, 2H), 2.16–2.08 (m, 1H), 2.06–1.97 (m, 4H), 1.94–1.86 (m, 1H), 1.85–1.78 (m, 1H), 1.61 (s, 3H), 1.56 (quint, J = 8.5 Hz, 2H), 1.40 (quint, J = 10.1 Hz, 2H), 1.32 (s, 1H). 13C NMR (151 MHz): δ 144.7, 134.9, 128.4, 127.5, 125.9, 124.8, 74.4, 62.9, 37.2, 36.0, 32.3, 27.6, 25.9, 16.0. HRMS (ESI): m/z calcd for (C16H24O2Na [M + H]+) 271.1674, found 271.1667.

1h. Synthesis of TBS-Protected Substrate 6

(E)-8-((tert-Butyldimethylsilyl)oxy)-4-methyl-1-phenyloct-4-en-1-ol (6)

In a 10 mL round-bottom flask, diol 1 (20 mg, 0.085 mmol) and imidazole (12 mg, 0.17 mmol, 2 equiv) were dissolved in CH2Cl2 (2 mL). The solution was cooled to 0 °C, and TBSCl (13 mg, 0.085 mmol, 1 equiv) was added. The solution was allowed to warm to rt and stirred until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (1 mL) and extracted with CH2Cl2 (3 × 1 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded TBS ether 6 (24 mg, 0.069 mmol, 80%) as a colorless oil. IR (neat): 3711–3103, 2933, 2858, 1602, 1450, 1254, 1059, 871, 835, 769, 699. 1H NMR (600 MHz): δ 7.32–7.27 (m, 4H), 7.25–7.19 (m, 1H), 5.12 (t, J = 7.2 Hz, 1H), 4.58 (dd, J = 7.8, 5.3 Hz, 1H), 3.55 (t, J = 6.5 Hz, 2H), 2.10–2.02 (m, 2H), 2.02–1.92 (m, 3H), 1.89–1.80 (m, 1H), 1.80–1.71 (m, 1H), 1.56 (s, 3H), 1.50 (q, J = 6.6 Hz, 2H), 0.85 (s, 9H), 0.00 (s, 6H). 13C NMR (151 MHz): δ 144.8, 134.9, 128.4, 127.4, 125.9, 124.6, 74.3, 62.7, 37.2, 35.9, 32.9, 26.0, 24.2, 18.3, 15.9, −5.3. HRMS (ESI): m/z calcd for (C12H22O3Na [M + Na]+) 237.1467, found 237.1476.

1i. Synthesis of Methyl Ether Substrate 8

(E)-8-Hydroxy-4-methyl-1-phenyloct-4-en-1-one (S32)

In a 10 mL round-bottom flask, diol 1 (75 mg, 0.320 mmol) was dissolved in CH2Cl2 (3 mL) at rt. MnO2 (690 mg, 8.0 mmol, 25 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The slurry was filtered through a pad of Celite, washed with CH2Cl2 (10 mL), and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded ketone S32 (63 mg, 0.074 mmol, 85%) as a colorless oil. IR (neat): 3695–3140, 2931, 1818, 1491, 1379, 909, 729. 1H NMR (600 MHz): δ 7.96 (dd, J = 7.1, 7.6 Hz, 2H), 7.56 (t, 1H), 7.47 (t, J = 7.7 Hz, 2H), 5.20 (tq, J = 7.2, 1.4 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 3.07 (t, J = 7.4 Hz, 2H), 2.42 (t, J = 7.9 Hz, 2H), 2.09 (q, J = 6.8 Hz, 2H), 1.68 (s, 3H), 1.60 (quint, J = 7.0 Hz, 2H). 13C NMR (151 MHz): δ 200.1, 136.9, 134.6, 133.0, 128.6, 128.1, 124.5, 62.6, 37.3, 34.0, 32.6, 24.3, 16.2. HRMS (ESI): m/z calcd for (C15H21O2 [M + H]+) 233.1542, found 233.1549.

(E)-8-Methoxy-4-methyl-1-phenyloct-4-en-1-one (S33)

In a 10 mL round-bottom flask, NaH (12 mg, 0.32 mmol, 1.5 equiv, as a 60% dispersion in oil) was suspended in THF (1 mL), and the solution was cooled to 0 °C. The alcohol S32 (50 mg, 0.22 mmol) was added as a solution in THF (1 mL); once addition was complete, stirring was continued for 15 min, iodomethane (26 μL, 0.43 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction was quenched by the addition of 10% HCl (1 mL) and extracted with Et2O (3 × 1 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded methyl ether S33 (42 mg, 0.17 mmol, 79%) as a colorless oil. IR (neat): 2923, 2857, 1685, 1597, 1448, 1357, 1289, 1203, 1117, 1037, 971, 742, 692. 1H NMR (400 MHz): δ 8.00–7.94 (m, 2H), 7.56 (ddt, J = 7.9, 6.9, 1.3 Hz, 1H), 7.50–7.43 (m, 2H), 5.18 (tq, J = 7.2, 1.4 Hz, 1H), 3.35 (t, J = 6.6 Hz, 2H), 3.32 (s, 3H), 3.10–3.02 (m, 2H), 2.48–2.38 (m, 2H), 2.11–2.01 (m, 2H), 1.67 (s, 3H), 1.63–1.57 (m, 2H). 13C NMR (125 MHz): δ 200.2, 137.0, 134.4, 132.9, 128.6, 128.1, 124.5, 72.2, 58.6, 37.4, 34.1, 29.6, 24.4, 16.1. HRMS (ESI): m/z calcd for (C16H23O2 [M + H]+) 247.1698, found 247.1703.

8-Methoxy-4-methyl-1-phenyloct-4-en-1-ol (8)

In a 10 mL round-bottom flask, ketone S33 (40 mg, 0.16 mmol) was dissolved in EtOH (2 mL) at rt. NaBH4 (6 mg, 0.16 mmol, 1 equiv) was added and the mixture stirred until complete conversion had occurred as judged by TLC. The reaction was quenched by the addition of 10% HCl (1 mL) and extracted with Et2O (3 × 1 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol 8 (36 mg, 0.14 mmol, 89%) as a colorless oil. IR (neat): 3720–3114, 2936, 2899, 1456, 1117, 1060, 1027, 775, 738, 699. 1H NMR (400 MHz): δ 7.38–7.31 (m, 4H), 7.30–7.26 (m, 1H), 5.16 (tq, J = 7.2, 1.3 Hz, 1H), 4.66 (dd, J = 7.8, 5.4 Hz, 1H), 3.35 (t, J = 6.5 Hz, 2H), 3.32 (s, 3H), 2.16–2.08 (m, 1H), 2.08–1.99 (m, 3H), 1.97 (s, 1H), 1.94–1.85 (m, 1H), 1.85–1.78 (m, 1H), 1.65–1.54 (m, 5H). 13C NMR (125 MHz): δ 144.7, 135.1, 128.4, 127.5, 125.9, 124.4, 74.3, 72.3, 58.6, 37.2, 36.0, 29.6, 24.4, 15.9. HRMS (ESI): m/z calcd for (C16H24O2Na [M + Na]+) 271.1674, found 271.1666.

1j. Synthesis of Ethyl Ester Substrate 9

(E)-5-Methyl-8-oxo-8-phenyloct-4-enoic Acid (S34)

In a 50 mL round-bottom flask, diol 1 (400 mg, 1.71 mmol) was dissolved in acetone (17 mL), and the solution was cooled to 0 °C. Jones reagent (1.19 mL, 3.58 mmol, 3.0 M) was added over a period of 10 min, until the orange color persisted. Excess reagent was destroyed by addition of i-PrOH (5 mL), as indicated by the reappearance of a deep green color. The reaction was quenched by the addition of 10% HCl (10 mL) and extracted with Et2O (3 × 20 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded acid S34 (360 mg, 1.46 mmol, 85%) as a colorless oil. IR (neat) (cm–1): 3705–3107, 2861, 1705, 1683, 1410, 1204, 911, 842, 690, 655. 1H NMR (600 MHz): δ 7.95 (d, J = 6.8 Hz, 6H), 7.56 (t, J = 6.8 Hz, 3H), 7.46 (t, J = 7.7 Hz, 2H), 5.18 (t, J = 6.7 Hz, 3H), 3.06 (dd, J = 8.4, 7.0 Hz, 2H), 2.40 (dd, J = 8.5, 6.6 Hz, 6H), 1.69 (s, 3H). 13C NMR (151 MHz): δ 200.0, 179.0, 136.9, 135.8, 133.0, 128.6, 128.0, 122.7, 37.2, 34.0, 33.9, 23.2, 16.2. HRMS (ESI): m/z calcd for (C15H19O3 [M + H]+) 247.1334, found 247.1325.

Ethyl (E)-5-Methyl-8-oxo-8-phenyloct-4-enoate (S35)

In a 10 mL round-bottom flask, acid S34 (100 mg, 0.41 mmol) was dissolved in benzene (4 mL) at rt. To this was added DMF (2 μL, 0.020 mmol, 5 mol %) followed by the dropwise addition of oxalyl chloride (35 μL, 0.41 mmol, 1 equiv) and the mixture stirred for 2 h. To this solution was added EtOH (47 μL, 0.81 mmol, 2 equiv) as a solution in pyridine (1 mL) and the solution stirred for 4 h. The reaction was quenched by the addition of 10% HCl (5 mL) and extracted with Et2O (3 × 2 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (hexanes/EtOAc 4:1) yielded ester S35 (102 mg, 0.37 mmol, 91%) as a colorless oil. IR (neat): 3065, 2984, 2917, 1735, 1688, 1601, 1451, 1374, 1295, 1268, 1205, 1100, 974, 746, 695. 1H NMR (600 MHz): δ 7.96 (d, J = 7.0 Hz, 2H), 7.56 (t, J = 7.0 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 5.20–5.14 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.10–3.02 (m, 2H), 2.41 (t, J = 7.8 Hz, 2H), 2.35–2.30 (m, 4H), 1.69 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz): δ 200.0, 173.3, 136.9, 135.4, 133.0, 128.6, 128.0, 123.0, 60.3, 37.3, 34.4, 33.9, 23.5, 16.2, 14.2. HRMS (ESI): m/z calcd for (C17H23O3 [M + H]+) 275.1647, found 275.1645.

Ethyl 8-Hydroxy-5-methyl-8-phenyloct-4-enoate (9)

In a 10 mL round-bottom flask, ketone S35 (40 mg, 0.15 mmol) was dissolved in EtOH (2 mL) at rt. NaBH4 (5.5 mg, 0.15 mmol, 1 equiv) was added and the mixture stirred until complete conversion had occurred as judged by TLC. The reaction was quenched by the addition of 10% HCl (1 mL) and extracted with Et2O (3 × 1 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (hexanes/EtOAc 2:1) yielded ester 9 (42 mg, 0.17 mmol, 83%) as a colorless oil. IR (neat) (cm–1): 3735–3131, 2980, 2915, 1731, 1450, 1374, 1181, 1035, 762, 701. 1H NMR (600 MHz): δ 7.37–7.31 (m, 4H), 7.31–7.24 (m, 1H), 5.16–5.10 (m, 1H), 4.63 (t, J = 6.8 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 2.36–2.27 (m, 4H), 2.13–2.06 (m, 2H), 2.05–1.97 (m, 1H), 1.88 (dddd, J = 13.6, 9.2, 7.8, 5.7 Hz, 1H), 1.79 (dddd, J = 13.6, 9.6, 6.2, 5.3 Hz, 1H), 1.62 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz): δ 173.4, 144.7, 136.2, 128.4, 127.5, 125.9, 122.8, 122.8, 74.2, 60.3, 37.1, 35.9, 34.4, 23.5, 16.0, 14.2. HRMS (ESI): m/z calcd for (C17H24O3Na [M + Na]+) 299.1623, found 299.1624.

1k. Synthesis of Carboxylic Acid Substrate 10

8-Hydroxy-5-methyl-8-phenyloct-4-enoic Acid (10)

In a 10 mL round-bottom flask, ketone S34 (50 mg, 0.20 mmol) was dissolved in EtOH (2 mL) at rt. NaBH4 (7.7 mg, 0.20 mmol, 1 equiv) was added and the mixture stirred until complete conversion had occurred as judged by TLC. The reaction was quenched by the addition of 10% HCl (1 mL) and extracted with Et2O (3 × 1 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (CH2Cl2/MeOH 9:1) yielded acid 10 (42 mg, 0.17 mmol, 83%) as a colorless oil. IR (neat) (cm–1): 3677–3118, 3030, 2934, 1707, 1450, 1409, 1267, 1200, 1059, 1014, 915, 763, 699. 1H NMR (600 MHz): δ 7.37–7.32 (m, 4H), 7.29–7.27 (m, 1H), 5.14 (t, J = 7.0 Hz, 1H), 4.64 (dd, J = 7.8, 5.3 Hz, 1H), 2.40–2.27 (m, 4H), 2.17–1.98 (m, 2H), 1.94–1.76 (m, 2H), 1.63 (s, 3H). 13C NMR (151 MHz): δ 178.4, 144.6, 136.5, 128.5, 127.6, 125.8, 122.5, 74.2, 37.0, 35.8, 34.0, 23.2, 16.0. HRMS (ESI): m/z calcd for (C15H19O3 [M + H]+) 247.1334, found 247.1329.

1l. Synthesis of Weinreb Amide Substrate 11

8-((tert-Butyldimethylsilyl)oxy)-N-methoxy-N,5-dimethyl-8-phenyloct-4-enamide (S36)

In a 10 mL round-bottom flask, acid S34 (100 mg, 0.41 mmol) was dissolved in benzene (4 mL) at rt. To this was added DMF (2 μL, 0.020 mmol, 5 mol %) followed by the dropwise addition of oxalyl chloride (35 μL, 0.41 mmol, 1 equiv) and the mixture stirred for 2 h. To this solution was added N,O-dimethylhydroxylamine hydrochloride (79 mg, 0.81 mmol, 2 equiv) followed by pyridine (1 mL) and the solution stirred for 4 h. The reaction was quenched by the addition of 10% HCl (5 mL) and extracted with Et2O (3 × 2 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (hexanes/EtOAc 4:1) yielded amide S36 (105 mg, 0.36 mmol, 89%) as a colorless oil. IR (neat) (cm–1): 2971, 2941, 1665, 1451, 1387, 1290, 1206, 1182, 1118, 1075, 998, 746, 696. 1H NMR (600 MHz): δ 7.98–7.94 (m, 2H), 7.58–7.54 (m, 1H), 7.47 (t, J = 7.6 Hz, 2H), 5.19 (t, J = 6.0 Hz, 1H), 4.62 (s, 3H), 3.51 (t, J = 6.6 Hz, 2H), 3.36 (s, 3H), 3.10–3.03 (m, 2H), 2.42 (t, J = 7.6 Hz, 2H), 2.08 (quintp, J = 6.9 Hz, 2H), 1.67 (s, 3H). 13C NMR (151 MHz): δ 200.1, 137.0, 134.4, 132.9, 128.6, 128.0, 124.4, 96.4, 67.3, 55.1, 37.4, 34.0, 29.7, 24.5, 16.2. HRMS (ESI): m/z calcd for (C17H24NO3 [M + H]+) 290.1756, found 290.1747.

8-Hydroxy-N-methoxy-N,5-dimethyl-8-phenyloct-4-enamide (11)

In a 10 mL round-bottom flask, ketone S36 (50 mg, 0.17 mmol) was dissolved in EtOH (2 mL) at rt. NaBH4 (6.5 mg, 0.17 mmol, 1 equiv) was added and the mixture stirred until complete conversion had occurred as judged by TLC. The reaction was quenched by the addition of 10% HCl (1 mL) and extracted with Et2O (3 × 1 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (hexanes/EtOAc 2:1) yielded amide 11 (38 mg, 0.13 mmol, 75%) as a colorless oil. IR (neat): 3712–3113, 2932, 2857, 1641, 1450, 1386, 1317, 1178, 1060, 993, 916, 761, 700. 1H NMR (400 MHz): δ 7.35 (d, J = 4.4 Hz, 4H), 7.31–7.24 (m, 1H), 5.19 (tq, J = 7.2, 1.3 Hz, 1H), 4.65 (dd, J = 7.9, 5.3 Hz, 1H), 3.67 (s, 3H), 3.17 (s, 3H), 2.45 (t, J = 7.6 Hz, 2H), 2.33 (q, J = 7.4 Hz, 2H), 2.15–2.08 (m, 1H), 2.07–1.99 (m, 1H), 1.94–1.85 (m, 1H), 1.86–1.77 (m, 1H), 1.64 (s, 3H). 13C NMR (125 MHz): δ 144.8, 135.8, 128.4, 127.5, 125.9, 123.5, 74.2, 61.2, 37.1, 35.9, 23.2, 16.0. HRMS (ESI): m/z calcd for (C17H25NO3Na [M + Na]+) 314.1732, found 314.1732.

1m. Synthesis of Diol Substrate 15

Methyl (E)-2-Benzoyl-5,9-dimethyldeca-4,8-dienoate (S37)

In a 250 mL round-bottom flask containing K2CO3 (12.7 g, 92.1 mmol, 2 equiv) was added geranyl bromide (10.00 g, 46.0 mmol) dissolved in DMF (100 mL). Ethyl benzoylacetate (11.1 mL, 57.6 mmol, 1.22 equiv) was added and the solution stirred at rt until complete conversion had occurred as judged by TLC. The mixture was diluted with H2O (100 mL) and extracted with Et2O (3 × 50 mL). The combined organic layers were washed with H2O (2 × 50 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded ester S37 (14.8 g, 45.0 mmol, 97%) as a colorless oil. IR (neat) (cm–1): 2966, 1740, 1438, 1162, 834. 1H NMR (600 MHz): δ 7.99 (d, J = 7.7 Hz, 2H), 7.62–7.55 (m, 1H), 7.47 (t, J = 7.8 Hz, 2H), 5.12 (d, J = 6.5 Hz, 1H), 5.03 (d, J = 6.5 Hz, 1H), 4.31 (t, J = 7.3 Hz, 1H), 4.14 (qd, J = 7.1, 2.2 Hz, 2H), 2.80–2.64 (m, 2H), 2.05–1.91 (m, 4H), 1.64 (s, 4H), 1.62 (s, 3H), 1.56 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz): δ 195.1, 169.7, 138.3, 136.4, 133.4, 131.5, 128.7, 128.6, 124.0, 120.0, 61.3, 54.5, 39.7, 27.7, 26.5, 25.6, 17.7, 16.1, 14.0. HRMS (ESI): m/z calcd for (C21H29O3 [M + H]+) 329.2117, found 329.2126.

(E)-5,9-Dimethyl-1-phenyldeca-4,8-dien-1-one (S38)22

In a 250 mL round-bottom flask containing LiCl (7.74 g, 183.0 mmol, 5 equiv) was added ester S37 (12.0 g, 36.6 mmol) dissolved in DMSO (100 mL). The solution was heated to 150 °C until complete conversion had occurred as judged by TLC. The mixture was diluted with H2O (100 mL) and extracted with Et2O (3 × 50 mL). The combined organic layers were washed with H2O (100 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded ketone S38 (8.58 g, 33.5 mmol, 92%) as a colorless oil. IR (neat) (cm–1): 2968, 2915, 1685, 1597, 1448, 1270, 1180, 975, 911, 733, 690. 1H NMR (600 MHz): δ 7.96 (d, J = 7.0 Hz, 2H), 7.55 (d, J = 7.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 5.19 (d, J = 7.1 Hz, 1H), 5.08 (d, J = 7.0 Hz, 1H), 3.00 (d, J = 8.3 Hz, 2H), 2.44 (q, J = 7.4 Hz, 2H), 2.06 (q, J = 7.3 Hz, 2H), 1.98 (d, J = 9.2 Hz, 2H), 1.67 (s, 3H), 1.63 (s, 3H), 1.59 (s, 3H). HRMS (ESI): m/z calcd for (C18H25O [M + H]+) 257.1900, found 257.1898.

(E)-4-Methyl-8-oxo-8-phenyloct-4-enal (S39)23

In a 100 mL round-bottom flask, diene S38 (8.50 g, 33.2 mmol) was dissolved in CH2Cl2 (30 mL), and the solution was cooled to 0 °C. m-CPBA (77%, 8.17 g, 36.5 mmol, 1.2 equiv) was added, and the solution was stirred at 0 °C until complete conversion had occurred as judged by TLC. The mixture was quenched with satd aq Na2S2O3 (50 mL) and extracted with CH2Cl2 (3 × 20 mL). The organic fractions were pooled, washed with 1 M NaOH (20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude epoxide product as a colorless oil which was taken on to the next step without purification.

In a 250 mL round-bottom flask, the crude epoxide above was dissolved in THF/H2O (9:1, 100 mL) and cooled to 0 °C. NaIO4 (3.30 g, 19.9 mmol, 0.6 equiv) and HIO4 (7.00 g, 36.5 mmol, 1.1 equiv) was added, and the solution was warmed to rt and stirred until complete conversion had occurred as judged by TLC. The mixture was quenched with satd aq Na2S2O3 (50 mL) and extracted with Et2O (3 × 50 mL). The organic fractions were pooled, washed with 1 M NaOH (50 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a gray oil. Purification by silica flash chromatography (19:1 hexanes/EtOAc) yielded aldehyde S39 (5.05 g, 21.9 mmol, 66%) as a colorless oil. IR (neat) (cm–1): 2927, 2898, 2360, 2342, 1723, 1685, 1449, 1253, 1105, 837, 743, 691. 1H NMR (500 MHz): δ 9.75 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 7.2 Hz, 1H), 7.47 (t, J = 7.9 Hz, 2H), 5.23 (t, J = 7.2 Hz, 1H), 3.01 (t, J = 7.3 Hz, 2H), 2.52 (t, J = 7.9 Hz, 2H), 2.45 (q, J = 7.3 Hz, 2H), 2.33 (t, J = 7.5 Hz, 2H), 1.66 (s, 3H). 13C NMR (126 MHz): δ 202.4, 199.8, 137.0, 134.4, 133.0, 128.6, 128.0, 123.9, 42.1, 38.5, 31.7, 22.8, 16.1. HRMS (ESI): m/z calcd for (C15H18O2Na [M + Na]+) 253.1204, found 253.1204.

(E)-5-Methyl-1-phenyloct-4-ene-1,8-diol (15)

In a 50 mL round-bottom flask, keto aldehyde S39 (1.50 g, 6.51 mmol) was dissolved in EtOH (20 mL) at rt. NaBH4 (250 mg, 6.51 mmol, 1 equiv) was added and the mixture stirred until complete conversion had occurred as judged by TLC. The reaction was quenched by the addition of 10% HCl (10 mL) and extracted with Et2O (3 × 10 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (hexanes/EtOAc 2:1) yielded diol 15 (1.27 g, 5.42 mmol, 83%) as a colorless oil. IR (neat) (cm–1): 3722–3118, 2934, 1450, 1058, 915, 759, 699. 1H NMR (600 MHz): δ 7.31–7.24 (m, 4H), 7.23–7.17 (m, 1H), 5.11 (t, J = 6.0 Hz, 1H), 4.57 (dd, J = 7.9, 5.3 Hz, 1H), 3.55 (t, J = 6.5 Hz, 2H), 2.08–1.90 (m, 4H), 1.87–1.78 (m, 1H), 1.77–1.69 (m, 1H), 1.58–1.48 (m, 5H). 13C NMR (151 MHz): δ 144.8, 135.4, 128.4, 127.5, 125.9, 124.9, 74.3, 62.7, 37.2, 36.0, 32.7, 24.3, 16.0. HRMS (ESI): m/z calcd for (C15H22O2Na [M + H]+) 257.1517, found 257.1526.

1n. Synthesis of Carbinol Deuterium-Labeled Diol Substrate 17

(E)-8-Hydroxy-5-methyl-1-phenyloct-4-en-1-one (S40)

In a 25 mL round-bottom flask, diol 15 (200 mg, 0.85 mmol) was dissolved in CH2Cl2 (10 mL) at rt. MnO2 (3.71 g, 42.7 mmol, 50 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The slurry was filtered through a pad of Celite, washed with CH2Cl2 (50 mL), and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded ketone S40 (182 mg, 0.78 mmol, 91%) as a colorless oil. IR (neat) (cm–1): 3664–3141, 2936, 1681, 1448, 1273, 1203, 1052, 750, 690. 1H NMR (500 MHz): δ 7.97 (d, J = 7.1 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.48 (q, J = 7.6 Hz, 2H), 5.24 (t, J = 7.2 Hz, 1H), 3.63 (t, J = 6.3 Hz, 2H), 3.02 (t, J = 7.4 Hz, 2H), 2.45 (q, J = 7.4 Hz, 2H), 2.08 (t, J = 9.8 Hz, 2H), 1.79 (s, 1H), 1.76–1.65 (m, 5H). 13C NMR (126 MHz): δ 200.1, 137.0, 136.0, 133.0, 128.6, 128.0, 123.2, 62.6, 38.6, 35.9, 30.7, 22.9, 15.9. HRMS (ESI): m/z calcd for (C15H20O2Na [M + Na]+) 255.1361, found 255.1366.

(E)-5-Methyl-1-phenyloct-4-ene-1-d-1,8-diol (17)

In a 10 mL round-bottom flask, ketone S40 (50 mg, 0.22 mmol) was dissolved in EtOH (2 mL) at rt. NaBD4 (18 mg, 0.43 mmol, 2 equiv) was added and the mixture stirred until complete conversion had occurred as judged by TLC. The reaction was quenched by the addition of 10% HCl (1 mL) and extracted with Et2O (3 × 1 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (hexanes/EtOAc 2:1) yielded diol 17 (48 mg, 0.20 mmol, 95%) as a colorless oil. IR (neat) (cm–1): 3732–3102, 2932, 1447, 1059, 946, 759, 698. 1H NMR (600 MHz): δ 7.39–7.32 (m, 4H), 7.31–7.24 (m, 1H), 5.20 (t, J = 5.9 Hz, 1H), 3.62 (t, J = 6.5 Hz, 2H), 2.14–2.00 (m, 4H), 1.84 (quint, J = 7.5 Hz, 1H), 1.78–1.71 (m, 1H), 1.67 (hept, J = 6.1 Hz, 2H), 1.59 (s, 3H). 13C NMR (151 MHz): δ 144.6, 135.5, 128.4, 127.5, 125.9, 124.2, 73.8(t), 62.8, 38.8, 36.0, 30.7, 24.3, 15.9. HRMS (ESI): m/z calcd for (C15H21DO2Na [M + Na]+) 258.1580, found 258.1578.

2. Oxidative Cyclization–Redox Relay Reactions

2a. Representative Procedure for PdCl2/BQ Oxidative Cyclization–redox Relay

4-(2-Methyl-5-phenyltetrahydrofuran-2-yl)butanal (2b)

In a 5 mL round-bottom flask charged with PdCl2 (1.9 mg, 0.011 mmol, 0.05 equiv) and 1,4-benzoquinone (46.1 mg, 427 mmol, 2.0 equiv) dissolved in THF (1 mL) was added diol 1 (50 mg, 0.22 mmol) as a solution in THF (1 mL). The solution was then stirred at rt until complete conversion had occurred as judged by TLC. The reaction mixture was quenched by the addition of 5% NaOH (2 mL) and extracted with Et2O (3 × 1 mL). The organic layers were combined, washed with brine (1 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (hexanes/EtOAc 9:1) yielded tetrahydrofuran 2b (46 mg, 0.20 mmol, 93%) as a colorless oil. The stereochemical configuration of the major diastereomer was assigned based on 1D NOE (Figure S4) and 2D NOESY analyses.16

2b. Analytical Data for Alternative Products 2a and 3

(E)-4-(2-Methyl-5-phenyltetrahydrofuran-2-yl)but-3-en-1-ol (2a)

Prepared from diol 1 under the representative procedure above but with the alternative catalyst systems shown in Table 1. IR (neat) (cm–1): 3732–3130, 2966, 2929, 2869, 1684, 1493, 1371, 1290, 1203, 1041, 972, 748, 698. 1H NMR (600 MHz): δ 7.40–7.35 (m, 2H), 7.35–7.30 (m, 2H), 7.27–7.23 (m, 1H), 5.83–5.77 (m, 1H), 5.67 (dt, J = 15.5, 7.1 Hz, 1H), 5.05–4.97 (m, 1H), 3.68–3.55 (m, 2H), 2.36–2.27 (m, 2H), 2.10–2.01 (m, 2H), 1.95–1.87 (m, 2H), 1.44 (d, J = 7.5 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ 143.5, 139.8, 139.2, 128.3, 127.3, 126.0, 125.8, 123.6, 123.3, 83.0, 82.8, 80.7, 62.0, 38.6, 37.8, 35.7, 35.0, 34.8, 31.6, 27.5, 26.9, 22.7, 14.2. HRMS (ESI): m/z calcd for (C15H 20O2 [M + Na]+) 255.1361, found 255.1371.

3-(2-Methyltetrahydro-2H-pyran-2-yl)-1-phenylpropan-1-one (3)

Prepared from diol 1 under the representative procedure above, but with the alternative catalyst systems shown in Table 1. 1H NMR (600 MHz): δ 7.93 (d, J = 6.7 Hz, 1H), 7.51–7.46 (m, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.26 (quint, J = 7.5 Hz, 1H), 3.57 (dddd, J = 15.1, 11.4, 6.4, 4.4 Hz, 2H), 3.06–2.93 (m, 2H), 2.13 (ddd, J = 15.1, 9.9, 5.7 Hz, 1H), 1.69 (ddd, J = 14.4, 9.9, 6.0 Hz, 1H), 1.64–1.57 (m, 1H), 1.48–1.39 (m, 4H), 1.14 (s, 3H). 13C NMR (151 MHz): δ 200.7, 137.1, 132.9, 128.6, 128.1, 72.3, 61.7, 35.6, 32.7, 32.6, 30.3, 29.7, 25.8, 23.8, 19.3.

2c. Analytical Data for Tetrahydrofuran Products 2b, 5aj, 1214, 16, and 18

4-(2-Methyl-5-phenyltetrahydrofuran-2-yl)butanal (2b)

Prepared from diol 1 according to the procedure above. IR (neat) (cm–1): 2933, 2862, 1450, 1058, 1030, 699, 535. 1H NMR (600 MHz): δ 9.79 (t, J = 1.6 Hz, 1H), 7.38–7.30 (m, 4H), 7.26–7.20 (m, 1H), 4.96 (dd, J = 8.0, 6.4 Hz, 0.14H minor, C5-H), 4.91 (dd, J = 8.7, 5.8 Hz, 0.86H major, C5-H), 2.50 (t, J = 7.2 Hz, 2H), 2.33–2.26 (m, 1H), 2.00–1.87 (m, 2H), 1.87–1.82 (m, 1H), 1.82–1.72 (m, 2H), 1.71–1.59 (m, 2H), 1.35 (s, 3H). 13C NMR (151 MHz): δ 202.7, 143.3, 128.3, 127.2, 125.8, 83.2, 81.1, 44.3, 40.8, 37.6, 35.6, 26.9, 17.3. HRMS (ESI): m/z calcd for (C15H21O 2 [M + H]+) 233.1542, found 233.1545.

4-(2,5-Dimethyltetrahydrofuran-2-yl)butanal (5a)

Prepared from diol 4a according to the representative procedure above. IR (neat) (cm–1): 2970, 2879, 1712, 1451, 1377, 1282, 1114, 713. 1H NMR (600 MHz): δ 9.77 (t, J = 1.7 Hz, 1H), 4.11–4.05 (m, 0.29H minor, C5-H), 4.05–3.98 (m, 0.71H major, C5-H), 2.46 (t, J = 7.2 Hz, 2H), 2.02–1.95 (m, 1H), 1.83–1.75 (m, 1H), 1.75–1.64 (m, 2H), 1.57–1.44 (m, 4H), 1.23 (d, J = 6.0 Hz, 3H), 1.21 (s, 2H), 1.20 (s, 1H). 13C NMR (151 MHz, CDCl3) δ 202.7, 82.4, 75.0, 44.3, 40.8, 37.4, 33.8, 27.3, 21.8, 17.3. HRMS (ESI): m/z calcd for (C10H18O2 Na [M + Na] +) 193.1204, found 193.1195.

4-(5-Butyl-2-methyltetrahydrofuran-2-yl)butanal (5b)

Prepared from diol 4b according to the representative procedure above.

IR (neat) (cm–1): 2958, 2869, 1710, 1459, 1376, 1110, 1038, 884, 742. 1H NMR (600 MHz): δ 9.77 (t, J = 1.7 Hz, 1H), 3.96 (dd, J = 8.0, 6.4 Hz, 0.22H minor, C5-H), 3.85 (dq, J = 8.8, 6.1 Hz, 0.78H major, C5-H), 2.46 (t, J = 7.4 Hz, 2H), 1.99–1.92 (m, 1H), 1.82–1.73 (m, 1H), 1.72–1.66 (m, 2H), 1.66–1.56 (m, 3H), 1.56–1.44 (m, 2H), 1.44–1.37 (m, 1H), 1.37–1.23 (m, 4H), 1.19 (d, J = 2.7 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ 202.8, 82.0, 79.3, 44.3, 40.7, 37.1, 36.2, 31.8, 28.2, 27.1, 22.9, 17.3, 14.1. HRMS (ESI): m/z calcd for (C13H 25O2 [M + H]+) 213.1855, found 213.1848.

4-(2-Methyl-5-(prop-1-en-2-yl)tetrahydrofuran-2-yl)butanal (5c)

Prepared from diol 4c according to the representative procedure above. IR (neat) (cm–1): 2935, 2863, 1721, 1459, 1379, 1063, 902. 1H NMR (600 MHz): δ 9.78 (t, J = 1.7 Hz, 1H), 5.00 (s, 1H), 4.79 (s, 1H), 4.37 (t, J = 7.1 Hz, 0.79H major, C5-H), 4.32 (t, J = 7.3 Hz, 0.21H minor, C5-H), 2.47 (td, J = 7.3, 1.7 Hz, 2H), 2.11–1.99 (m, 1H), 1.87–1.78 (m, 1H), 1.78–1.66 (m, 4H), 1.64–1.50 (m, 5H), 1.28–1.17 (m, 3H). 13C NMR (151 MHz): δ 202.7, 145.7, 134.8, 110.2, 81.4, 44.3, 41.2, 37.0, 31.3, 25.8, 18.1, 17.4. HRMS (ESI): m/z calcd for (C12H 21O2 [M + H]+) 197.1542, found 197.1549.

4-(5-(tert-Butyl)-2-methyltetrahydrofuran-2-yl)butanal (5d)

Prepared from diol 4d according to the representative procedure above. IR (neat) (cm–1): 2967, 1723, 1458, 1371, 1313, 1261, 1135, 977, 883, 771, 703. 1H NMR (600 MHz): δ 9.78 (t, J = 1.8 Hz, 1H), 3.63 (dd, J = 7.9, 6.7 Hz, 0.12H minor, C5-H), 3.55 (dd, J = 8.9, 5.4 Hz, 0.88H major, C5-H), 2.47 (td, J = 7.3, 1.7 Hz, 2H), 1.81–1.58 (m, 6H), 1.59–1.44 (m, 2H), 1.15 (s, 3H), 0.86 (s, 9H). 13C NMR (151 MHz): δ 203.0, 87.3, 81.8, 44.3, 40.5, 37.2, 33.2, 26.7, 26.6, 25.9, 17.3. HRMS (ESI): m/z calcd for (C13H25O2 [M + H]+) 213.1855, found 213.1846.

Ethyl 2-(5-Methyl-5-(4-oxobutyl)tetrahydrofuran-2-yl)acetate (5e)

Prepared from diol 4e according to the representative procedure above. IR (neat) (cm–1): 2941, 1711, 1450, 1380, 1280, 1111, 1067, 1025, 703. 1H NMR (600 MHz): δ 9.77 (s, 1H), 4.35 (quint, J = 6.7 Hz, 0.37H minor, C5-H), 4.28 (dq, J = 8.1, 6.3 Hz, 0.63H major, C5-H), 4.14 (q, J = 7.1 Hz, 2H), 2.62 (ddd, J = 18.9, 15.1, 6.4 Hz, 1H), 2.51–2.38 (m, 3H), 2.22–2.04 (m, 1H), 1.90–1.77 (m, 1H), 1.77–1.65 (m, 5H), 1.59–1.42 (m, 1H), 1.32–1.23 (m, 3H), 1.21 (s, 2H), 1.20 (s, 1H). 13C NMR (151 MHz): δ 202.7, 171.3, 82.9, 75.1, 60.4, 44.2, 41.4, 40.5, 36.9, 31.7, 27.0, 17.2, 14.2. HRMS (ESI): m/z calcd for (C13H 22O4 Na [M + Na] +) 265.1416, found 265.1404.

4-((2S,5R)-5-(2-Hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)butanal (5f)

Prepared from diol 4f according to the representative procedure above. IR (neat) (cm–1): 3648–3154, 2972, 2871, 1727, 1463, 1378, 1064, 706. 1H NMR (600 MHz): δ 9.78 (t, J = 1.6 Hz, 1H), 3.79 (dd, J = 8.1, 6.6 Hz, 0.33H minor, C5-H), 3.74–3.69 (m, 0.67H major, C5-H), 2.48 (t, J = 7.4 Hz, 2H), 2.14 (s, 1H), 1.90–1.76 (m, 2H), 1.76–1.64 (m, 4H), 1.56–1.45 (m, 2H), 1.20 (s, 6H), 1.12 (s, 3H). 13C NMR (151 MHz): δ 202.7, 85.8, 82.8, 70.6, 44.2, 40.6, 37.4, 27.6, 26.5, 24.0, 17.2. HRMS (ESI): m/z calcd for (C12H22O3Na [M + Na] +) 237.1467, found 237.1476.

4-(2,5,5-Trimethyltetrahydrofuran-2-yl)butanal (5g)

Prepared from diol 4g according to the representative procedure above, but at a reaction temperature of 60 °C. IR (neat): 2973, 2360, 2337, 1714, 1652, 1451, 1269, 1188, 1039, 984, 749, 699. 1H NMR (600 MHz): δ 9.77 (t, J = 1.7 Hz, 1H), 2.45 (td, J = 7.3, 1.8 Hz, 2H), 1.94–1.83 (m, 2H), 1.83–1.74 (m, 2H), 1.75–1.65 (m, 2H), 1.59–1.43 (m, 2H), 1.26 (s, 3H), 1.21 (s, 6H). 13C NMR (151 MHz): δ 202.8, 82.9, 80.9, 44.3, 41.9, 38.5, 36.9, 29.9, 29.5, 27.5, 17.5. HRMS (ESI): m/z calcd for (C11H20O2Na [M + Na] +) 207.1361, found 207.1354.

4-(2-Methyl-5,5-diphenyltetrahydrofuran-2-yl)butanal (5h)

Prepared from diol 4h according to the representative procedure above, but at a reaction temperature of 60 °C. IR (neat) (cm–1): 3058, 2966, 2872, 1723, 1684, 1598, 1448, 1047, 1010, 699. 1H NMR (600 MHz): δ 9.71 (t, J = 1.7 Hz, 1H), 7.43 (d, J = 7.7 Hz, 4H), 7.30–7.23 (m, 4H), 7.17 (q, J = 7.3 Hz, 2H), 2.73–2.66 (m, 1H), 2.66–2.59 (m, 1H), 2.41 (q, J = 7.2 Hz, 2H), 1.89–1.76 (m, 3H), 1.73–1.63 (m, 1H), 1.59–1.47 (m, 2H), 1.28 (s, 3H). 13C NMR (151 MHz): δ 202.8, 148.0, 147.6, 128.0, 127.9, 126.5, 126.4, 125.8, 125.7, 88.0, 84.0, 44.2, 41.7, 38.6, 37.6, 26.4, 17.6. HRMS (ESI): m/z calcd for (C21H24O 2 Na [M + Na] +) 331.1674, found 331.1670.

3-(2-Methyl-5-phenyltetrahydrofuran-2-yl)propanal (5i)

Prepared from diol 4i according to the representative procedure above. IR (neat) (cm–1): 2934, 1713, 1685, 1450, 1281, 1114, 713. 1H NMR (600 MHz): δ 9.80 (dd, J = 2.2, 1.5 Hz, 1H), 7.34–7.30 (m, 4H), 7.26–7.22 (m, 1H), 4.96 (dd, J = 8.4, 6.2 Hz, 0.37H minor, C5-H), 4.85 (dd, J = 8.6, 6.1 Hz, 0.73H major, C5-H), 2.68–2.52 (m, 3H), 2.36–2.29 (m, 1H), 2.04–1.83 (m, 4H), 1.36 (s, 2H), 1.32 (s, 1H). 13C NMR (151 MHz): δ 202.4, 143.0, 128.3, 127.3, 125.8, 82.5, 81.0, 39.4, 37.5, 35.3, 33.3, 27.1. HRMS (ESI): m/z calcd for (C14H18O2 Na [M + Na] +) 241.1204, found 241.1204.

5-(2-Methyl-5-phenyltetrahydrofuran-2-yl)pentanal (5j)

Prepared from diol 4j according to the representative procedure above. IR (neat) (cm–1): 2945, 1707, 1279, 1175, 1113, 711. 1H NMR (600 MHz): δ 9.78 (t, J = 1.8 Hz, 1H), 7.38–7.29 (m, 4H), 7.25–7.20 (m, 1H), 4.95 (dd, J = 8.4, 6.1 Hz, 0.22H minor, C5-H), 4.90 (dd, J = 8.6, 5.8 Hz, 0.78H major, C5-H), 2.47 (td, J = 7.3, 1.7 Hz, 2H), 2.34–2.25 (m, 1H), 1.96–1.86 (m, 2H), 1.86–1.76 (m, 1H), 1.74–1.63 (m, 4H), 1.54–1.38 (m, 2H), 1.33 (s, 2.4H), 1.29 (s, 0.6H). 13C NMR (151 MHz): δ 202.8, 143.4, 128.3, 127.2, 125.8, 83.3, 81.1, 43.9, 41.4, 37.6, 35.6, 27.0, 24.2, 22.6. HRMS (ESI): m/z calcd for (C16H22O2 Na [M + Na] +) 269.1517, found 269.1520.

(E)-tert-Butyldimethyl((4-(2-methyl-5-phenyltetrahydrofuran-2-yl)but-3-en-1-yl)oxy)silane (7)

Prepared from TBS ether 6 under the representative procedure above, but with the alternative catalyst systems shown in Table 3. 1H NMR (600 MHz): δ 7.91 (d, J = 7.01 Hz, 0.6H), 7.50 (t, J = 6.64 Hz, 0.3H), 7.40 (t, J = 7.66, 0.6H), 7.34–7.29 (m, 1.5H), 7.26 (t, J = 7.25 Hz, 1.5H), 7.20–7.17 (m, 0.8H), 5.71–5.57 (m, 2H), 5.13 (t, J = 6.64 Hz, 0.28H minor, C5-H), 4.97–4.92 (m, 0.72H major, C5-H), 3.62–3.58 (m, 1.32H major, CH2OSi), 3.54 (t, J = 7.66 Hz, 0.68H minor, CH2OSi) 3.02–3.00 (m, 0.5H), 3.36 (t, J = 6.13 Hz, 0.5H), 2.28–2.21 (m, 2H), 2.01–1.96 (m, 1H), 1.94–1.91 (m, 0.4H), 1.87–1.79 (m, 1.5H), 1.49 (quint. J = 6.13 Hz, 0.6H), 1.39 (s, 0.80H minor, C1-Me), 1.35 (s, 2.20H major, C1-Me), 0.84 (s, 9H), 0.02 – −0.01 (m, 6H). 13C NMR (151 MHz): δ 1.43.8, 1.43.1, 1.38.25, 1.37.6, 137.0, 134.1, 132.9, 128.6, 128.2, 18.1, 127.2, 126.1, 125.8, 124.8, 124.2, 124.1, 83.1, 82.8, 80.7, 80.4, 63.1, 62.6, 38.6, 37.5, 36.0, 35.0, 34.1, 32.9, 27.4, 26.9, 26.0, 24.2, 18.4, 16.2, −5.2. HRMS (ESI): m/z calcd for (C21H35O2 [M + H]+) 346.2328, found 346.2331.

Ethyl (E)-4-(2-Methyl-5-phenyltetrahydrofuran-2-yl)but-2-enoate (12)

Prepared from hydroxy ester 9 according to the representative procedure above, but at a reaction temperature of 60 °C. Diastereomeric ratio of crude reaction product was 4:1, which increased to 10:1 following purification by silica gel chromatography. IR (neat): 3030, 2971, 2933, 2872, 1716, 1653, 1493, 1451, 1309, 1270, 1188, 1040, 985, 940, 749, 699. 1H NMR (600 MHz): δ 7.38–7.26 (m, 4H), 7.28–7.22 (m, 1H), 7.03 (dt, J = 15.5, 7.7 Hz, 1H), 5.91 (dt, J = 15.6, 1.4 Hz, 1H), 5.03–4.97 (m, 0.09H minor, C5-H), 4.95 (dd, J = 8.7, 5.9 Hz, 0.91H major, C5-H), 4.20 (q, J = 7.1 Hz, 2H), 2.58–2.48 (m, 2H), 2.37–2.26 (m, 1H), 2.02–1.80 (m, 3H), 1.38 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz): δ 166.4, 145.1, 143.0, 128.3, 127.3, 125.8, 124.1, 82.8, 81.3, 60.3, 44.3, 37.2, 35.4, 27.5, 14.3. HRMS (ESI): m/z calcd for (C17H22O3 Na [M + Na] +) 297.1467, found 297.1461.

(E)-4-(2-Methyl-5-phenyltetrahydrofuran-2-yl)but-2-enoic Acid (13)

Prepared from hydroxy acid 10 according to the representative procedure above, but at a reaction temperature of 60 °C. IR (neat): 3772–3131, 3031, 2971, 2874, 2821, 2360, 1695, 1651, 1451, 1279, 1216, 1040, 986, 941, 909, 748, 698. 1H NMR (600 MHz): δ 7.38–7.29 (m, 4H), 7.29–7.24 (m, 1H), 7.14 (dt, J = 15.5, 7.7 Hz, 3H), 5.93 (dt, J = 15.6, 1.4 Hz, 1H), 5.02–4.95 (m, 1H), 2.56 (dt, J = 7.6, 1.6 Hz, 2H), 2.37–2.26 (m, 1H), 2.02–1.84 (m, 3H), 1.38 (s, 2.03H major, C1-Me), 1.35 (s, 0.97H minor, C1-Me). 13C NMR (151 MHz): δ 170.9, 148.1, 142.9, 128.4, 127.4, 125.8, 123.3, 82.7, 81.4, 44.9, 37.3, 35.2, 27.5. HRMS (ESI): m/z calcd for (C15H 18O3 Na [M + H] +) 269.1154, found 269.1159.

(E)-N-Methoxy-N-methyl-4-(2-methyl-5-phenyltetrahydrofuran-2-yl)but-2-enamide (14)

Prepared from hydroxy Weinreb amide 11 according to the representative procedure above, but at a reaction temperature of 60 °C. The 2:1 dr was determined based on relative peak integrations of the NMe, OMe, and C1-Me groups. Resonances for the minor diastereomer were also observable, but not resolved, for C5-H and the amide side chain β-H. IR (neat) (cm–1): 2971, 2938, 1667, 1638, 1421, 1384, 1313, 1097, 1046, 1002, 705. 1H NMR (600 MHz): δ 7.39–7.30 (m, 4H), 7.26–7.21 (m, 1H), 7.09–7.00 (m, 1H), 6.51 (d, J = 15.3 Hz, 1H), 5.01–4.93 (m, 1H), 3.71 (s, 2.07H major, NMe), 3.70 (s, 0.93H minor, NMe), 3.26 (s, 2.03H major, OMe), 3.25 (s, 0.97H minor, OMe), 2.63–2.53 (m, 2H), 2.38–2.27 (m, 1H), 2.06–1.97 (m, 1H), 1.96–1.79 (m, 2H), 1.39 (s, 2.03H major, C1-Me), 1.36 (s, 0.97H minor, C1-Me). 13C NMR (151 MHz, CDCl3): δ 143.4, 143.0, 128.3, 127.2, 125.9, 125.8, 121.6, 83.0, 82.8, 81.3, 80.3, 61.7, 44.7, 36.9, 35.5, 27.7. HRMS (ESI): m/z calcd for (C17H24NO3 [M + H]+) 290.1756, found 290.1761.

4-(2-Methyltetrahydrofuran-2-yl)-1-phenylbutan-1-one (16)

Prepared from diol 15 according to the representative procedure above. IR (neat): 2925, 2856, 1686, 1452, 1376, 1105, 754, 700. 1H NMR (600 MHz): δ 7.96 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.9 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 3.84 (q, J = 7.8 Hz, 1H), 3.80 (q, J = 6.9 Hz, 1H), 3.00 (td, J = 7.1, 1.6 Hz, 2H), 1.98–1.86 (m, 2H), 1.84–1.74 (m, 3H), 1.70–1.52 (m, 3H), 1.21 (s, 3H). 13C NMR (151 MHz): δ 200.3, 137.0, 132.9, 128.6, 128.0, 82.5, 67.2, 40.7, 38.9, 36.6, 26.1, 25.7, 19.6. HRMS (ESI): m/z calcd for (C 15H21O2 [M + H]+) 233.1542, found 233.1546.

4-(2-Methyltetrahydrofuran-2-yl)-1-phenylbutan-1-one-2-d (18)

Prepared from diol 17 according to the representative procedure above. IR (neat): 2965, 2870, 1682, 1597, 1449, 1373, 1268, 1178, 1045, 744, 692. 1H NMR (600 MHz): δ 7.89 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 7.1 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 3.77 (q, J = 7.8 Hz, 1H), 3.72 (q, J = 7.3 Hz, 1H), 2.90 (qq, J = 6.1, 3.5, 2.9 Hz, 1H), 1.94–1.79 (m, 2H), 1.77–1.64 (m, 3H), 1.67–1.54 (m, 2H), 1.57–1.49 (m, 1H), 1.13 (s, 3H). 13C NMR (151 MHz): δ 200.4, 137.0, 132.9, 128.6, 128.0, 82.5, 67.2, 40.7, 38.7, 38.6, 38.4, 36.6, 26.1, 25.8, 19.5. HRMS (ESI): m/z calcd for (C15O2H20 D [M + H] +) 234.1604, found 234.1608.

3. Deuterium Labeling Experiments

3a. Singly Vinylic Deuterium-Labeled Diol Substrate 19a (→ 23a, 24a)

6-((tert-Butyldiphenylsilyl)oxy)-2-methylhex-1-en-3-one (S41)

In a 100 mL round-bottom flask, alcohol S3 (1.00 g, 2.71 mmol) was dissolved in CH2Cl2 (30 mL). PCC (1.17 g, 5.43 mmol, 2 equiv) was added and the solution was stirred at rt until complete conversion had occurred as judged by TLC. The mixture was filtered through a pad of silica with hexane/EtOAc 9:1 and concentrated by rotary evaporation to afford ketone S41 (0.95 g, 2.59 mmol, 95%) as a colorless oil. IR (neat) (cm–1): 3070, 3049, 3016, 2931, 2858, 1678, 1470, 1427, 1107, 964, 794, 738, 701. 1H NMR (600 MHz): δ 7.68–7.61 (m, 2H), 7.46–7.32 (m, 8H), 5.96 (s, 1H), 5.75 (s, 1H), 3.70 (t, J = 6.0 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 1.87 (s, 3H), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 201.9, 144.4, 135.5, 133.8, 129.6, 127.7, 124.5, 63.1, 33.8, 27.3, 26.8, 19.2, 17.7. HRMS (ESI): m/z calcd for (C23H30O2SiNa [M + Na]+) 389.1913, found 389.1908.

6-((tert-Butyldiphenylsilyl)oxy)-2-methylhex-1-en-3-d-3-ol (S42)

In a 25 mL round-bottom flask, ketone S41 (1.00 g, 2.73 mmol) was dissolved in MeOH (10 mL) at rt. CeCl3·7(H2O) (1.01 g, 2.73 mmol) was added with stirring, followed by NaBD4 (114 mg, 2.73 mmol, 1 equiv). The solution was stirred until complete conversion had occurred as judged by TLC. The reaction was quenched by the addition of 10% HCl (10 mL) and extracted with Et2O (3 × 10 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. Purification by silica flash chromatography (hexanes/EtOAc 4:1) yielded allylic alcohol S42 (780 mg, 2.11 mmol, 77%) as a colorless oil. 1H NMR (600 MHz): δ 7.69–7.64 (m, 2H), 7.45–7.40 (m, 4H), 7.40–7.35 (m, 4H), 4.95 (s, 1H), 4.84 (s, 1H), 3.71–3.65 (m, 2H), 1.72 (s, 5H), 1.67–1.54 (m, 4H), 1.05 (s, 9H). 13C NMR (151 MHz): δ 147.4, 135.6, 133.7, 129.6, 127.6, 111.0, 75.1(t), 63.9, 31.6, 28.5, 26.8, 19.2, 17.7. HRMS (ESI): m/z calcd for (C23H32DO2Si [M + H]+) 370.2311, found 370.2313.

Ethyl (E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyloct-4-enoate-5-d (S43)

In a 25 mL round-bottom flask, allylic alcohol S42 (780 mg, 2.11 mmol), triethyl orthoacetate (10 mL), and propionic acid (16 μL, 0.21 mmol, 0.1 equiv) were added. The flask was equipped with a distillation head and heated to 140 °C during which time ethanol was collected. Heating was continued at this temperature until complete conversion had occurred as judged by TLC. The mixture was cooled to rt and quenched with 1 M HCl (10 mL). The mixture was extracted with Et2O (3 × 10 mL), washed with 1 M NaOH (10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded ester S43 (750 mg, 80%) as a colorless oil. 1H NMR (600 MHz): δ 7.66 (d, J = 6.5 Hz, 2H), 7.44–7.34 (m, 8H), 4.11 (q, J = 7.1 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 2.39–2.34 (m, 2H), 2.28 (dd, J = 8.9, 6.2 Hz, 2H), 2.06 (t, J = 7.4 Hz, 2H), 1.67–1.50 (m, 5H), 1.24 (t, J = 7.2 Hz, 3H), 1.05 (s, 9H). 13C NMR (151 MHz): δ 173.5, 135.6, 134.8, 134.1, 129.5, 127.6, 124.5 (t), 63.3, 60.2, 34.6, 33.2, 32.3, 26.8, 24.0, 19.2, 15.9, 14.3. HRMS (ESI): m/z calcd for (C27H38DO3Si [M + H]+) 440.2731, found 440.2740.

(E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1,1-diphenyloct-4-en-5-d-1-ol (S44)

In a 25 mL round-bottom flask, ester S43 (750 mg, 1.71 mmol) was dissolved in THF (10 mL), and the solution was cooled to 0 °C. PhMgBr (1.0 M in THF, 3.75 mL, 3.75 mmol, 2.2 equiv) was added dropwise with stirring. Once addition was complete, the solution was allowed to warm to rt, and stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (10 mL), extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S44 (505 mg, 0.92 mmol, 54%) as a colorless oil. 1H NMR (600 MHz): δ 7.69–7.63 (m, 4H), 7.45–7.33 (m, 10H), 7.31 (dd, J = 8.4, 7.1 Hz, 4H), 7.22 (t, J = 8.1 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 2.39–2.34 (m, 2H), 2.09–2.01 (m, 2H), 1.99–1.93 (m, 2H), 1.58 (tq, 5H), 1.04 (s, 9H). 13C NMR (151 MHz): δ 147.0, 135.5, 134.8, 134.0, 129.5, 128.1, 127.6, 126.7, 126.0, 124.2 (t), 78.5, 63.4, 40.0, 34.0, 32.6, 26.8, 24.1, 19.2, 16.2. HRMS (ESI): m/z calcd for (C37H43DO2SiNa [M + Na]+) 572.3068, found 572.3071.

(E)-4-Methyl-1,1-diphenyloct-4-ene-5-d-1,8-diol (19a)

In a 10 mL round-bottom flask, protected alcohol S44 (425 mg, 0.77 mmol) was dissolved in THF (8 mL) at rt. TBAF (1.0 M in THF, 1.55 mL, 1.55 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 19a (220 mg, 0.71 mmol, 91%) as a colorless oil. 1H NMR (600 MHz): δ 7.41 (d, J = 8.1 Hz, 4H), 7.31 (t, J = 8.4 Hz, 4H), 7.22 (t, J = 7.3 Hz, 2H), 3.61 (t, J = 6.5 Hz, 2H), 2.45 (s, 1H), 2.42–2.35 (m, 2H), 2.05 (t, J = 7.4 Hz, 2H), 2.01–1.94 (m, 2H), 1.62 (s, 3H), 1.59 (quint, J = 7.3 Hz, 2H), 1.42 (s, 1H). 13C NMR (151 MHz): δ 146.9, 136.0, 128.1, 126.8, 125.9, 123.8 (t), 78.5, 62.6, 40.0, 33.9, 32.6, 24.1, 16.2. HRMS (ESI): m/z calcd for (C21H25DO2Na [M + Na]+) 334.1893, found 334.1890.

4-(2-Methyl-5,5-diphenyltetrahydrofuran-2-yl)butanal-4-d (23a)

Prepared from diol 19a according to the representative procedure in section 2a, but at a reaction temperature of 60 °C. 1H NMR (600 MHz): δ 9.70 (s, 1H), 7.43 (d, J = 8.3 Hz, 4H), 7.26 (ddd, J = 8.1, 7.1, 4.9 Hz, 4H), 7.20–7.09 (m, 2H), 2.73–2.57 (m, 2H), 2.39 (qd, J = 7.6, 6.8, 1.8 Hz, 2H), 1.88–1.74 (m, 3H), 1.70–1.62 (m, 1H), 1.48 (dd, J = 12.2, 4.6 Hz, 1H), 1.27 (s, 3H). 13C NMR (151 MHz): δ 202.7, 148.0, 147.6, 127.9, 127.9, 126.4, 126.4, 125.8, 125.7, 88.0, 83.9, 44.2, 41.2 (t), 38.6, 37.6, 26.3, 17.5. HRMS (ESI): m/z calcd for (C21H23DO2Na [M + Na]+) 332.1737, found 332.1741.

2-(3,3-Diphenylpropyl)-6-methoxy-2-methyltetrahydro-2H-pyran-3-d (24a)

In a 5 mL round-bottom flask, diphenyl THF 23a (10 mg, 0.032 mmol) was dissolved in MeOH (2 mL), and 10% Pd/C (100 mg) was added. The flask was placed in a Parr reactor, pressurized to 150 psi with H2, and stirred at rt for 12h. The mixture was filtered through a pad of Celite and washed with Et2O and the solvent removed under reduced pressure to afford the product as a mixture of α- and β-isomers. The isomers were separated by preparative TLC (benzene/EtOAc 99:1) to yield methoxytetrahydropyran α-24a (4.7 mg, 0.014 mmol) and β-24a (4.3 mg, 0.012 mmol, 85%) as a colorless oils.

α-24a. 1H NMR (600 MHz): δ 7.31–7.23 (m, 8H), 7.20–7.15 (m, 2H), 4.42 (dd, J = 6.2, 3.0 Hz, 1H), 3.84 (t, J = 7.8 Hz, 1H), 3.41 (s, 3H), 2.12 (q, J = 7.9 Hz, 2H), 1.75–1.69 (m, 1H), 1.69–1.60 (m, 2H), 1.52–1.46 (m, 1H), 1.46–1.36 (m, 2H), 1.25 (s, 3H). 13C NMR (151 MHz): δ 145.2, 144.9, 128.5, 127.8, 127.8, 126.1, 98.2, 74.5, 55.5, 51.9, 37.0, 35.0, 30.5 (t), 29.3, 26.6, 16.9. HRMS (ESI): m/z calcd for (C22H27DO2Na [M + Na]+) 348.2050, found 348.2061.

β-24a. 1H NMR (600 MHz): δ 7.31–7.22 (m, 8H), 7.16 (dddd, J = 8.3, 7.0, 4.0, 1.7 Hz, 2H), 4.53 (dd, J = 8.6, 2.5 Hz, 1H), 3.85 (t, J = 7.0 Hz, 1H), 3.40 (s, 3H), 2.23–2.07 (m, 2H), 1.71 (tq, J = 4.1, 3.4 Hz, 2H), 1.61 (ddt, J = 11.7, 8.6, 4.5 Hz 1H), 1.58–1.53 (m, 2H), 1.49 (ddd, J = 13.6, 12.0, 4.9 Hz, 1H), 1.32 (tt, J = 6.1, 4.0 Hz, 1H), 1.17 (s, 3H). 13C NMR (151 MHz): δ 145.4, 144.8, 128.4, 128.4, 127.9, 127.8, 126.1, 126.0, 98.3, 75.1, 55.6, 51.9, 42.2, 34.2 (t), 31.1, 29.4, 21.4, 18.1. HRMS (ESI): m/z calcd for (C22H27DO2Na [M + Na]+) 348.2050, found 348.2050.

3b. Doubly Allylic Deuterium-Labeled Diol Substrate 19b (→ 23b, 24b)

4-((tert-Butyldiphenylsilyl)oxy)butanal-2,2-d2 (S45).24

In a 10 mL round-bottom flask, aldehyde S2 (1.00 g, 3.06 mmol) was suspended in D2O (3 mL), and DMAP (37 mg, 0.306 mmol, 10 mol %) was added. The suspension was heated to 70 °C for 12 h. The reaction mixture was diluted with 1 M HCl (10 mL), extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a colorless oil. The product was purified by silica flash chromatography (9:1 hexanes/EtOAc) to yield diol S45 (0.99 g, 0.303 mmol, 99%) as a colorless oil. 1H NMR (600 MHz): δ 9.79 (s, 1H), 7.65 (d, J = 6.5 Hz, 2H), 7.45–7.34 (m, 8H), 3.69 (t, J = 6.0 Hz, 2H), 1.87 (t, J = 6.0 Hz, 2H), 1.04 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 202.8, 135.5, 134.8, 133.5, 129.7, 127.7, 127.7, 62.9, 40.0 (p), 26.8, 26.5, 25.1, 19.2. HRMS (ESI): m/z calcd for (C20H25D2O2Si [M + H]+) 329.1906, found 329.1912.

6-((tert-Butyldiphenylsilyl)oxy)-2-methylhex-1-en-4,4-d2-3-ol (S46)

In a 25 mL round-bottom flask, aldehyde S45 (950 mg, 2.89 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. Isopropenylmagnesium bromide (0.5 M in THF, 5.8 mL, 2.9 mmol, 1 equiv) was added slowly via syringe. Once addition of the Grignard was complete, the cooling bath was removed and the solution was allowed to stir at rt until complete conversion had occurred as judged by TLC. The mixture was recooled to 0 °C and quenched with 1 M HCl (10 mL). The mixture was extracted with Et2O (3 × 10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded allylic alcohol S46 (850 mg, 2.29 mmol, 79%) as a yellow oil. 1H NMR (600 MHz): δ 7.69–7.65 (m, 2H), 7.46–7.34 (m, 8H), 4.95 (s, 1H), 4.84 (s, 1H), 4.07 (s, 1H), 3.72–3.64 (m, 2H), 1.72 (s, 3H), 1.65–1.54 (m, 2H), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 147.5, 135.6, 135.5 134.8, 133.7, 129.6, 127.7, 110.9, 75.5, 63.9, 31.0(p), 28.3, 26.8, 26.5, 19.2, 17.7. HRMS (ESI): m/z calcd for (C23H31D2O2Si [M + H]+) 371.2375, found 371.2358.

Ethyl (E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyloct-4-enoate-6,6-d2 (S47)

In a 50 mL round-bottom flask, S46 (650 mg, 1.75 mmol), triethyl orthoacetate (5 mL), and propionic acid (13 μL, 0.18 mmol, 0.1 equiv) were added. The flask was equipped with a distillation head and heated to 140 °C during which time ethanol was collected. Heating was continued at this temperature until complete conversion had occurred as judged by TLC. The mixture was cooled to rt and quenched with 1 M HCl (10 mL). The mixture was extracted with Et2O (3 × 10 mL), washed with 1 M NaOH (10 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (9:1 hexanes/EtOAc) yielded ester S47 (470 mg, 61%) as a colorless oil. 1H NMR (600 MHz): δ 7.66 (d, J = 6.2 Hz, 2H), 7.43–7.32 (m, 8H), 5.12 (s, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 2.36 (q, J = 8.1 Hz, 2H), 2.28 (q, J = 7.6 Hz, 2H), 1.59 (s, 3H), 1.56 (t, J = 6.4 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.05 (s, 9H). 13C NMR (151 MHz): δ 173.5, 135.6, 134.1, 133.8, 129.5, 127.6, 127.6, 124.8, 63.3, 60.2, 34.7, 33.3, 32.5, 26.9, 23.5 (p), 19.2, 15.9, 14.3. HRMS (ESI): m/z calcd for (C27H37D2O3Si [M + H]+) 441.2794, found 441.2794.

(E)-8-((tert-Butyldiphenylsilyl)oxy)-4-methyl-1,1-diphenyloct-4-en-6,6-d2-1-ol (S48)

In a 25 mL round-bottom flask, ester S47 (200 mg, 0.45 mmol) was dissolved in THF (5 mL), and the solution was cooled to 0 °C. PhMgBr (1.0 M in THF, 1.00 mL, 1.00 mmol, 2.2 equiv) was added dropwise with stirring. Once addition was complete, the solution was allowed to warm to rt, and stirring was continued until complete conversion had occurred as judged by TLC. The mixture was quenched with 1 M HCl (5 mL), extracted with Et2O (3 × 5 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the crude product as a yellow oil. Purification by silica flash chromatography (4:1 hexanes/EtOAc) yielded alcohol S48 (75 mg, 0.14 mmol, 30%) as a colorless oil. 1H NMR (600 MHz): δ 7.70–7.62 (m, 2H), 7.43–7.38 (m, 8H), 7.37–7.33 (m, 4H), 7.31 (dd, J = 8.4, 7.1 Hz, 4H), 7.24–7.20 (m, 2H), 5.08 (s, 1H), 3.64 (t, J = 6.3 Hz, 2H), 2.40–2.34 (m, 2H), 2.32 (s, 1H), 2.00–1.93 (m, 2H), 1.60 (s, 3H), 1.56 (t, J = 6.4 Hz, 2H), 1.04 (s, 9H). 13C NMR (151 MHz): δ 147.0, 135.6, 135.5, 134.0, 129.5, 128.1, 127.6, 126.7, 126.0, 124.4, 78.5, 63.3, 40.0, 34.0, 32.4, 26.8, 23.5 (quint.), 19.2, 16.2. HRMS (ESI): m/z calcd for (C37H42D2O2SiNa [M + Na]+) 573.3134, found 573.3121.

(E)-4-Methyl-1,1-diphenyloct-4-ene-6,6-d2-1,8-diol (19b)

In a 10 mL round-bottom flask, protected alcohol S48 (75 mg, 0.14 mmol) was dissolved in THF (2 mL) at rt. TBAF (1.0 M in THF, 0.27 mL, 0.27 mmol, 2 equiv) was added, and the solution was stirred until complete conversion had occurred as judged by TLC. The reaction mixture was concentrated by rotary evaporation. Purification by silica flash chromatography (1:1 hexanes/EtOAc) yielded diol 19b (29 mg, 0.092 mmol, 68%) as a colorless oil. 1H NMR (600 MHz): δ 7.41 (d, J = 7.3 Hz, 3H), 7.30 (t, J = 7.3 Hz, 4H), 7.22 (t, J = 7.3 Hz, 2H), 5.12 (s, 1H), 3.60 (t, J = 6.5 Hz, 2H), 2.42–2.35 (m, 2H), 2.03–1.94 (m, 2H), 1.62 (d, J = 1.4 Hz, 3H), 1.57 (t, J = 6.6 Hz, 2H). 13C NMR (151 MHz): δ 147.0, 136.1, 128.2, 126.8, 126.0, 124.1, 78.5, 62.6, 40.1, 34.0, 32.4, 23.6 (p), 16.3. HRMS (ESI): m/z calcd for (C21H24D2O2Na [M + Na]+) 335.1956, found 335.1955.

4-(2-Methyl-5,5-diphenyltetrahydrofuran-2-yl)butanal-3,4-d2 (23b)

Prepared from diol 19b according to the representative procedure in section 2a, but at a reaction temperature of 60 °C. 1H NMR (600 MHz): δ 9.71 (s, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.26 (td, J = 7.6, 3.6 Hz, 4H), 7.17 (q, J = 7.3 Hz, 2H), 2.69 (dt, J = 13.3, 6.8 Hz, 1H), 2.63 (dt, J = 12.8, 7.3 Hz, 1H), 2.39 (t, J = 6.2 Hz, 2H), 1.90–1.76 (m, 2H), 1.66 (quint, J = 7.3 Hz, 1H), 1.54 (d, J = 12.2 Hz, 1H), 1.28 (s, 3H). 13C NMR (151 MHz): δ 202.7, 148.0, 147.6, 127.9, 126.5, 126.4, 125.8, 125.7, 88.0, 84.0, 44.1, 41.2 (t), 38.6, 37.6, 26.4, 17.2 (t). HRMS (ESI): m/z calcd for (C21H22D2O2Na [M + Na]+) 333.1797, found 333.1800.

2-(3,3-Diphenylpropyl)-6-methoxy-2-methyltetrahydro-2H-pyran-3,4-d2 (24b)

In a 5 mL round-bottom flask, diphenyl THF 23b (10 mg, 0.032 mmol) was dissolved in MeOH (2 mL) and 10% Pd/C (100 mg) was added. The flask was placed in a Parr reactor, pressurized to 150 psi with H2, and stirred at rt for 12 h. The mixture was filtered through a pad of Celite and washed with Et2O and the solvent removed under reduced pressure to afford the product as a mixture of α- and β-isomers. The isomers were separated by preparative TLC (benzene/EtOAc 99:1) to yield methoxytetrahydropyran α-24b (4.5 mg, 0.014 mmol) and β-24b (4.1 mg, 0.012 mmol, 85%) as a colorless oils.

α-24b. 1H NMR (600 MHz): δ 7.32–7.23 (m, 8H), 7.20–7.15 (m, 2H), 4.42 (dd, J = 6.3, 3.0 Hz, 1H), 3.84 (t, J = 7.8 Hz, 1H), 3.41 (s, 3H), 2.15–2.09 (m, 2H), 1.69–1.59 (m, 2H), 1.45 (s, 1H), 1.43–1.38 (m, 2H), 1.25 (s, 3H). 13C NMR (151 MHz): δ 145.2, 144.9, 128.5, 127.8, 126.1, 98.2, 74.5, 55.5, 51.9, 37.0, 34.5 (t), 30.4, 29.3, 26.6, 16.6 (t). HRMS (ESI): m/z calcd for (C22H26D2O2Na [M + Na]+) 349.2113, found 349.2114.

β-24b. 1H NMR (600 MHz): δ 7.31–7.22 (m, 8H), 7.20–7.12 (m, 2H), 4.53 (dd, J = 8.6, 2.6 Hz, 1H), 3.85 (t, J = 7.1 Hz, 1H), 3.40 (s, 3H), 2.23–2.07 (m, 2H), 1.72 (ddd, J = 12.7, 4.5, 2.6 Hz, 1H), 1.67 (q, J = 4.5 Hz, 1H), 1.57 (td, J = 13.5, 12.0 Hz, 2H), 1.49 (td, J = 13.6, 12.0 Hz, 1H), 1.36 (d, J = 4.4 Hz, 1H), 1.17 (s, 3H). 13C NMR (151 MHz): δ 145.4, 144.8, 128.4, 128.3, 127.9, 127.8, 126.1, 126.0, 98.3, 75.1, 55.6, 51.9, 42.2, 33.7 (t), 31.0, 29.4, 21.5, 17.7 (t). HRMS (ESI): m/z calcd for (C22H26D2O2Na [M + Na]+) 349.2113, found 349.2122.

3c. Synthesis of Unlabeled Cyclic Acetals 24-H3 for NMR Comparison

2-(3,3-Diphenylpropyl)-6-methoxy-2-methyltetrahydro-2H-pyran (24-H3)

In a 5 mL round-bottom flask, diphenyl THF, 5h (10 mg, 0.032 mmol) was dissolved in MeOH (2 mL), and 10% Pd/C (100 mg) was added. The flask was placed in a Parr reactor, pressurized to 150 psi with H2, and stirred at rt for 12h. The mixture was filtered through a pad of Celite and washed with Et2O and the solvent removed under reduced pressure to afford the product as a mixture of α- and β-isomers. The isomers were separated by preparative TLC (benzene/EtOAc 99:1) to yield methoxytetrahydropyran α-24-H3 (4.5 mg, 0.014 mmol) and β-24-H3 (4.0 mg, 0.012 mmol, 81%) as a colorless oils.

α-24-H3. IR (neat) (cm–1): 3060, 3026, 2935, 1736, 1599, 1493, 1451, 1373, 1261, 1225, 1202, 1156, 1123, 1066, 1034, 974, 914, 875, 802, 745, 700. 1H NMR (600 MHz): δ 7.31–7.23 (m, 8H), 7.21–7.15 (m, 2H), 4.42 (dd, J = 6.3, 3.0 Hz, 1H), 3.84 (t, J = 7.8 Hz, 1H), 3.41 (s, 3H), 2.12 (ddd, J = 10.1, 8.3, 7.1 Hz, 2H), 1.73 (dddd, J = 10.6, 8.9, 5.4, 3.5 Hz, 1H), 1.69–1.59 (m, 2H), 1.49 (tdt, J = 12.6, 8.0, 4.1 Hz, 1H), 1.45–1.38 (m, 2H), 1.32–1.21 (m, 5H). 13C NMR (151 MHz, CDCl3): δ 145.2, 144.9, 128.5, 127.8, 127.8, 126.1, 98.2, 74.6, 55.5, 51.9, 37.0, 35.0, 30.5, 29.3, 26.6, 17.0. HRMS (ESI): m/z calcd for (C22H28O2Na [M + Na]+) 347.1987, found 347.1972.

β-24-H3. IR (neat) (cm–1): 3060, 3026, 2942, 2872, 1736, 1674, 1599, 1493, 1451, 1377, 1263, 1229, 1160, 1119, 1079, 1033, 1004, 979, 909, 744, 701. 1H NMR (600 MHz): δ 7.30–7.21 (m, 8H), 7.16 (qd, J = 6.7, 3.2 Hz, 2H), 4.53 (dd, J = 8.5, 2.4 Hz, 1H), 3.85 (dd, J = 8.7, 7.0 Hz, 1H), 3.40 (s, 3H), 2.22–2.07 (m, 2H), 1.71 (tq, J = 13.1, 4.2 Hz, 2H), 1.67–1.60 (m, 1H), 1.57–1.53 (m, 2H), 1.49 (ddd, J = 13.6, 12.0, 4.9 Hz, 1H), 1.55 (ddd, J = 13.7, 11.9, 4.8 Hz, 2H), 1.17 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 145.4, 144.8, 128.4, 128.4, 127.9, 127.8, 126.1, 126.0, 98.3, 75.2, 55.6, 51.9, 42.2, 34.2, 31.1, 29.4, 21.5, 18.2. HRMS (ESI): m/z calcd for (C22H28O2Na [M + Na]+) 347.1987, found 347.1982.

4. Computational Studies

4a. Computational Methods

All calculations were performed using the M0625 functional implemented in Gaussian09.26 The Lanl2DZ27 (augmented with one f-function28) and 6-31G(d,p) basis sets were used for Pd and all other atoms, respectively. Frequency calculations at the same level of theory at the optimized geometries were carried out to confirm the stationary points as minima (zero imaginary frequencies) or transition states (one imaginary frequency) and provided the thermal corrections to the single-point energies. Single-point calculations using the SDD basis set for Pd and the 6-311++G(d,p) basis set for all other atoms and the SMD solvent model with the parameters for THF were used to account for solvent effects.

4b. Detailed Reaction Pathway for anti-oxypalladation of Diol Substrate 4a

We have calculated PdCl2 with two 1,4-benzoquinone molecules coordinating to Pd and found that the trans conformation is energetically favored (25a-Cat1: 6.0 kcal/mol; 25a-Cat2: 12.4 kcal/mol) (Figure Figure66 and Figure S5). The ligand-exchange step then forms 25a-INT1. This is a exothermic step, and 25a-INT1 is −14.7 kcal/mol lower in free energy than 25a-Cat1. The anti-oxypalladation step then takes place through 25a to form 25a-INT2 (−0.4 kcal/mol). The activation barrier is 8.7 kcal/mol, and diastereoselectivity is determined by the anti-oxypalladation transition structures.

4c. Transition Structures for anti-Oxypalladation of Diol Substrate 1

We have also calculated transition structures for the anti-oxypalladation step in the oxidative cyclization of phenyl-substituted diol 1 en route to tetrahydrofuran product 2b, as well as the tert-butyl substituted diol 4d en route to tetrahydrofuran product 5d. In the first system, the energy difference between 25a-Ph and 25b-Ph is 0.5 kcal/mol, favoring 25a-Ph that leads to the major diastereomer (Figure S6). Similary, in the second system, the energy difference between 25a-tBu and 25b-tBu is 0.6 kcal/mol, favoring 25a-tBu that leads to the major diastereomer (Figure S7).

Acknowledgments

We thank Dr. George Sukenick, Rong Wang, Dr. Sylvi Rusli, and Dr. Hiu Liu (MSKCC) for expert NMR and mass spectral support, Michaelyn Lux (MSKCC) for assistance with NMR spectra, and Gustavo Moura-Letts and Maria Chiriac (MSKCC) for helpful discussions. D.S.T. and J.L.B. gratefully acknowledge financial support from the NIH (P41 GM076267 to D.S.T., T32 CA062948-Gudas to J.L.B., P30 CA008748 to C. B. Thompson), William and Alice Goodwin and the Commonwealth Foundation for Cancer Research, and the MSKCC Experimental Therapeutics Center. O.W. and L.X. gratefully acknowledge financial support from the U.S. NSF (CHE1058075, CHE1565669), National Science Foundation of China (NSFC 21133002), Shenzhen Peacock Program (JCYJ20140509093817689), and Nanshan District (KC2014ZDZJ0026A).

Supporting Information Available

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.6b02053.

  • Complete experimental protocols and analytical data for all new compounds; details of computational methodology, including coordinates and energies for all described transition structures (PDF)

Notes

The authors declare no competing financial interest.

Supplementary Material

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