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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Org Chem. Author manuscript; available in PMC 2010 December 4.
Published in final edited form as:
PMCID: PMC2787704

Improved Method for the Synthesis of β-Carbonyl Silyl-1,3-Dithianes by the Double Conjugate Addition of 1,3-Dithiol to Propargylic Carbonyl Compounds


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Base-mediated double conjugate addition of 1,3-propane dithiol to various silylated propargylic aldehydes and ketones allows for an efficient and scalable synthesis of β-carbonyl silyl-1,3-dithianes.

Polyketide-based natural products show a tremendous variety of biological activity and structural diversity, and thus the development of new synthetic methods for their efficient syntheses has been a highly pursued goal in organic chemistry.1 Most general and effective methods for the construction of typical polyketide motifs include an aldol reaction between enolates and aldehydes,2 asymmetric allylation and crotylation of aldehydes,3 and opening of epoxides with 2-lithiodithianes.4 In our plan to develop a modular approach for the construction of polyketides, we

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desired to take advantage of the capacity of olefin metathesis.5 Thus, allylation or a crotylation product derived from bifunctional aldehyde 1 can be directly joined with another polyketide motif without any functional group manipulation. Also, it was envisioned that these processes could be further streamlined by a tandem allylation (crotylation)-epoxide opening via 1,4-Brook rearrangement, further improving the economy of polyketide synthesis (Eq 1). Such a streamlined synthesis can also be envisaged for the corresponding ketones 2 via an asymmetric aldol,6 Evans-Tishchenko reduction7 and anion relay chemistry (ARC)4 sequence (Eq 2). The effectiveness of this concept was amply demonstrated in our recent formal synthesis of cochleamycin A (Scheme 1),8 where, triethylsilyldithiane aldehyde 1 was converted to the β-hydroxy dithiane by Leighton's asymmetric allylation.9 A subsequent alkylation with bromoacetaldehyde dimethylacetal under basic conditions in the presence of HMPA afforded a product, which later takes part in a tandem enyne RCM to afford an advanced intermediate in the formal synthesis of cochleamycin A.

Through this streamlined sequence, various polyketide motifs are expected to be synthesized in an unusually effective manner, which, however, is contingent upon a secure supply of carbonyl compounds 1 and 2 (Scheme 2) containing γ,3-dithiane and trialkylsilyl moieties.

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Conceptually, two general approaches (Path A and B) to these compounds are envisioned, and along these lines, several procedures10,11,12,13 were already reported in the literature. From the standpoint of substrate scope and functional group tolerance,11,12 the latter involving a double Michael addition of 1,3-propanedithiol to α,β-acetylenic aldehydes and ketones seems to be most attractive. However, the isolation of a silylated hemiacetal by Ley and coworkers under their base-mediated conjugate addition to silyl-substituted propargylic aldehydes (Eq 3) calls for an alternative procedure for silyl-substituted acetylenic aldehydes. Herein, we report on the development of a general, efficient and scalable method for the synthesis of β-carbonyl silyl-1,3-dithianes (1 and 2) carrying various silyl groups.

It was expected that the aldehyde 4 and ketone 6 could be garnered via formylation14 or acylation15 of the corresponding silyl acetylides. However, this route gave poor yields when lithium acetylide and silyl chlorides were employed.16 An alternative approach involves the silylation of the lithium acetylide of the commercially available THP protected propargyl alcohol, deprotection of the THP group generating alcohols 3a–k with PPTS, and their oxidation with IBX. This three step sequence afforded aldehydes 4a–k in good to excellent overall yields (Table 1).17 Other oxidation protocols such as Swern,18 Parikh-Doering19 or PCC oxidation led to much lower yields. Since triethylsilylacetylene is readily available at low price, the corresponding aldehyde 4b (entry 2) was synthesized according to our initial plan involving formylation of the lithium acetylide.

Table 1
Synthesis of silyl substituted propargylic aldehydesa
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Silyl-substituted methyl propargylic ketones 6a–j were also obtained in good to excellent yields by the silylation of commercially available TMS protected 3-butyn-2-ol,20 followed by desilylation with 1 M HCl, and MnO2 oxidation21 of the precursor allylic alcohols 5a–j (Table 2).

Table 2
Synthesis of silyl substituted propargylic ketonesa
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With these aldehydes and ketones 4 and 6 in hand, we attempted the addition of 1,3-propane dithiol using NaOMe as the base according to Ley's conditions.11c,12 As shown in Table 3, the desired dithiane aldehydes 1a and 1b with a trimethylsilyl (entry 1), and triethylsilyl group (entry 3) were obtained in 61 and 62% yields, respectively, whereas t-butyl dimethylsilyl-substituted aldehyde 1c (entry 2) was generated in only moderate yield (42%). Further, this procedure is unlikely to be amenable to a large scale synthesis due to the necessity of large amounts (0.05 M) of solvents, which is necessary to prevent the undesired intermolecular processes. Hence, we investigated the heterogenous conditions employing MgO and basic Al2O3 as reported by Knight11d and Ranu.1a Reactions with MgO purchased from Aldrich were very slow even with 10 eq. at room temperature; only 40% of desired dithiane formed for the triethylsilyl aldehyde after 24 h together with unreacted starting material. On the other hand, with 10 equivalents of basic alumina in CH2Cl2, dithiane 1b was obtained in 70% yield after 24 h (entry 7). Optimal yield was observed with 10 equivalents of basic Al2O3 in THF at 1 M concentration at room temperature. Under these conditions, substrate aldehydes 4b and 4c afforded dithianes 1b and 1c in 81 and 78% isolated yields, respectively (entries 9 and 10).

Table 3
Optimization of reaction conditions for the addition of dithiols to propargylic aldehydes
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Next, an optimization for the formation of 1,3-dithianes via the addition of dithiol to the propargylic ketones was carried out with ketone substrates 6f and 6g that contain vinyl dimethylsilyl and benzyldimethylsilyl groups, respectively (Table 4). As expected, the propargylic ketones were much less reactive towards conjugate addition: even the reaction with 30 equivalents of Al2O3 gave a 1:1 mixture of double and mono conjugate addition product for the benzyldimethylsilyl ketone 6g after 24 h at room temperature (entry 3). It was found that for these ketones, homogenous bases such as NaOMe, NaOEt and KOtBu were more efficient (entries 5–9); addition of 0.5 equivalents of KOtBu in tBuOH at 0 °C, followed by warming to room temperature over 3 h provided the best ratio of 6:2:7.

Table 4
Optimization of reaction conditions for the addition of dithiols to propargylic ketonesa
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After establishing these optimized reaction conditions, a range of aldehyde and ketone substrates was further examined (Table 5). Substrate aldehydes 4a–h provided excellent yields of the corresponding products 1a–h in the range of 48–93% yield (entries 1–8) under condition A (10 equiv. Al2O3, THF, 1.5 M). Gratifyingly, reactions on 5–6 g scale of triethylsilyl and TBS-propargyl aldehydes (4b and 4c) showed no diminution of yields, demonstrating the utility of these conditions. However, no conversions were observed even with 15 equivalents of Al2O3 for di-tert-butylsilyl (4k), t-butyl diphenylsilyl (4i), and triisopropyl (4j)-substituted aldehydes (entries 17–19).

Table 5
Dithiol additions to propargylic aldehydes and ketones
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Under condition B, ketones 6a–h afforded the corresponding 1,3-dithiane products 2a–h in good to excellent yields (entries 9–16), except for trimethylsilyl containing substrate 6a (entry 9). The poor yield (35%) for 2a is probably due to the instability of the trimethylsilyl group toward the alkoxide. Similar to the cases with the aldehydes, substrates 6i and 6j with sterically bulky silyl substituents showed either decomposition or no reaction (entries 20 and 21).

In conclusion, base-mediated conjugate addition of 1,3-dithiols to silyl-propargylic aldehydes and ketones allows for a versatile, efficient, and scalable approach towards the assembly of β-carbonyl silyl-1,3-dithianes.

Experimental Section

General procedure for dithiane aldehydes 1a–h

To a well-stirred solution of propargylic aldehydes (1 equiv) and 1,3-propanedithiol (1 equiv) in THF (1.5 M with respect to aldehyde) was added activated basic alumina (5–10 equiv, standard grade, ~150 mesh, 58 Å) in 10 portions, such that the temperature did not go above room temperature. After completion of the reaction (3–6 h, TLC), the reaction mixture was filtered through a short plug of Celite, followed by washing of the residue with DCM (2 × 50 mL). The filtrate and the washings were evaporated to give the crude product, which was purified by column chromatography (0–5% ethyl acetate in hexanes) to yield the aldehydes 1ah as a light yellow oil.

General procedure for dithiane ketones 6a–6h

To a well stirred solution of propargylic ketones (1.0 equiv) and 1,3-propanedithiol (1.0 equiv) in tBuOH (0.5 M with respect to ketone) was added KOtBu (0.5 equiv) at 0 °C and the reaction was maintained at that temperature for 1–2 h, following which it was warmed up to room temperature and kept there until the reaction was complete (TLC). The reaction was diluted with H2O and extracted with ether. The combined ether layers were washed with water and brine, dried over MgSO4, filtered, concentrated, and subjected to column chromatography (0–5% ethyl acetate in hexanes) to obtain the ketones 6a–h.

Supplementary Material



We thank UIC and the NIH (CA106673) for a partial support this work.


Supporting Information Available: General procedures and characterization data of new compounds. This material is available free of charge via the Internet at


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