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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 October 16.
Published in final edited form as:
PMCID: PMC2759854
NIHMSID: NIHMS146289

Regio- and Stereoselective Indium Triflate-Mediated Nucleophilic Ring-Opening Reactions of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene and [2.2.2]oct-5-ene Systems

Abstract

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Indium triflate-mediated nucleophilic ring-opening reactions of 3-aza-2-oxabicyclo[2.2.1]hept-5-ene and [2.2.2]oct-5-ene systems with alcohols and water were investigated. Reactions of [2.2.1] bicyclic systems gave anti-1,2-, anti-1,4- and syn-1,4-ring opened products with moderate to excellent regio- and stereoselectivity. When [2.2.2] bicyclic systems were subjected to similar reaction conditions, only anti-1,2 and anti-1,4-ring opened products were obtained.

Nitroso cycloadducts obtained from hetero Diels–Alder (HDA) reactions, such as 3-aza-2-oxabicyclo[2.2.1]hept-5-enes and [2.2.2]oct-5-enes (14), are valuable synthetic intermediates for the construction of a variety of biologically interesting molecules (Scheme 1). 1 The chemistry of acylnitroso cycloadduct 1 has revealed several modes of ring-opening reactions to introduce different functionalities with defined stereo- and regiochemistries.26 Commonly employed strategies involve N–O bond reductive cleavage to form syn-1,4 aminocyclopentenols,2 and C–O bond cleavage through metal-mediated reactions in the presence of nucleophiles or electrophiles.35 Recently, stereoselective nitroso HDA reactions using iminonitroso agents have attracted more attention because they facilitate generation of enantiopure 3-aza-2-oxa-bicyclic compounds such as 3 and 4 in a single step.1b,7 We also successfully utilized iminonitroso Diles– Alder reactions for the derivatization and functionalization of diene-containing natural products for modular enhancement of Nature's diversity (MEND).8 While extensive chemistry has been developed from reactions of acylnitroso agents, elaborations of heteroaryl nitroso adducts such as 3 and 4 have been less explored and are mainly limited to reductive cleavage of the N–O bond.7 To the best of our knowledge, Lewis acid-mediated ring-opening reactions of iminonitroso cycloadducts have not been disclosed in the literature despite their potential synthetic value. Herein, we report recent advances in this area that expand the versatility of Lewis acid-mediated nucleophilic ring-opening reactions to a range of 3-aza-2-oxabicyclo[2.2.1]hept-5-enes 3 and [2.2.2]oct-5-enes 4.

SCHEME 1
Syntheses of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene and [2.2.2]oct-5-ene, and 8-Aza-7-oxabicyclo[4.2.2]dec-9-ene Systems

To begin our investigation, [2.2.1], [2.2.2] and [4.2.2] bicyclic systems 3a–d, 4a–c and 5a were prepared by HDA reactions between the corresponding nitroso agents9 and dienes (Scheme 1). Cycloadduct 3a, as a model substrate, was then reacted with various Lewis acids in the presence of MeOH at room temperature (Table 1). While a variety of Lewis acids (0.5 equiv), including FeCl3, CuCl2 and CuSO4, induced the ring-opening reactions of 3a to form anti-1,2-, anti-1,4- and syn-1,4-disubstituted products 6a, 7a, and 8a, respectively, only low to moderate yields were obtained (entries 1–10). Subsequent screening revealed that reaction with 0.5 equiv of indium triflate (In(OTf)3) provided the best yield (92%) of a 2.4:3.7:1 ratio of anti-1,2-:anti-1,4-:syn-1,4-products (6a:7a:8a) within 1 h (entry 11). The anti-1,2-product 6a was isolated cleanly after silica gel chromatography, and its structure was determined by 1D and 2D NMR studies (COSY, HETCOR). The regio- and stereochemistry of the generally inseparable anti-1,4- and syn-1,4-products (7a and 8a) were assigned using comparison of the coupling pattern of the C(5) methylene protons. 10 A plausible mechanism indicated that two major products, 6a and 7a, were results of indirect and direct nucleophilic displacement of the oxygen, respectively (Scheme 2, path A and B), though a competitive open cation process might also account for the mixed stereoselectivity and formation of the minor syn-1,4 product (8a). Variation of the amount of In(OTf)3 used in the reaction was then explored. Increasing the amount of In(OTf)3 to 1.0 equiv gave the products in a similar yield but with slightly compromised stereoselectivity (entry 12). Low conversions were observed when 0.2 and 0.1 equiv of In(OTf)3 were employed even when the reaction time was prolonged (entries 13–14). Thus, we selected 0.5 equiv of In(OTf)3 for further studies of the Lewis acid-mediated ring-openings of additional substrates.

SCHEME 2
Proposed Mechanism for Formation of 6a and 7a in the Lewis Acid-Mediated Nucleophilic Ring-Opening Reaction of 3a
TABLE 1
Lewis Acid-Mediated Nucleophilic Ring-Opening Reaction of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene 3a with MeOH Using Different Lewis Acids

The ability to control the stereochemical outcome of the In(OTf)3-mediated ring-opening reactions was further investigated by adding cosolvents to MeOH (Table 2). Use of DCM or toluene as cosolvents in a 1:1 ratio with MeOH gave the products in yields similar to those obtained when MeOH was used alone, but the stereoselectivity decreased slightly (entries 1–3). The use of 1,4-dioxane or THF as cosolvents increased the relative amounts of anti-1,4- and syn-1,4-products (entries 4–5). This preference was enhanced by increasing the amount of THF in the reactions (entries 5–9). Reduction of the amount of MeOH to only 2 equiv in THF led to a 0.3:1.9:1 ratio of anti-1,2-:anti-1,4-:syn-1,4-products (6a:7a:8a) in moderate yield (45%, entry 9).

TABLE 2
Effects of Cosolvent on In(OTf)3-Mediated Nucleophilic Ring-Opening Reaction of 3a with MeOH

In an effort to determine the scope of this ring-opening chemistry, we expanded the studies to include reactions of variously substituted 3-aza-2-oxabicyclo[2.2.1]hept-5-ene systems 3a–d with a series of alcohols (Table 3). When 3a was used, separate reactions with each of the aliphatic alcohols gave the ring-opened products in good to excellent yields (entries 1–3). The preference for the formation of anti-1,4-products was enhanced by increasing the size of nucleophile. For example, use of tert-butanol gave a 90% yield of a 1.7:5:1 ratio of anti-1,2-:anti-1,4-:syn-1,4-products (6c:7c:8c) (entry 3). Addition of THF to tert-butanol slightly increased the ratio of 1,4-products (entry 4). Similar reactivity and stereoselectivity were noted when 3b was treated with different alcohols under conditions used in the studies of 3a (entries 5–7). While only moderate conversions for the ring-opening reactions of 3c were obtained, improved stereoselectivity favoring the formation of anti-1,2- and anti-1,4-products was observed (entries 8–10). The reaction of cycloadduct 3d with MeOH gave a 93% yield of a 1.4:4:1 ratio of anti-1,2-:anti-1,4-:syn-1,4-products (6j:7j:8j); however, the yields dropped when bulkier alcohols such as 2-propanol and tert-butanol were used (entries 11–13). In all ring-opening reactions of 3d, the preference for anti-1,4-products (7j–l) was much more noticeable than with substrates 3a–c (entries 11–13). In order to give compounds more compatible for eventually further elaboration, reactions of 3a with benzyl alcohol and allyl alcohol were perfomed, generating a mixture of anti-1,2-:anti-1,4-:syn-1,4-products in 73% and 57% yields, respectively, with anti-1,4-compounds (7m and 7n) as the major products (entries 14–15).

TABLE 3
In(OTf)3-Mediated Nucleophilic Ring-Opening Reactions of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene 3a–d with Different Alcohols

The In(OTf)3-mediated ring-opening reactions with 3-aza-2-oxabicyclo[2.2.2]oct-5-ene systems 4a–b were also investigated. The results are summarized in Table 4. Because of the decreased ring strain of the [2.2.2] substrates relative to the [2.2.1] substrates, we anticipated that the ring-opening reactions would be slower. However, reaction with [2.2.2] bicyclic compound 4a in MeOH with 0.5 equiv of In(OTf)3 at room temperature still occurred, generating a 35% yield of a 1:1 ratio of anti-1,2-:anti-1,4-products (9a:10a) after prolonged reaction (24 h, entry 1). Interestingly, no syn-1,4-product 11a was detected, which further supported the proposed reaction mechanism as shown in Scheme 2. Compounds 9a and 10a were readily separable by column chromatography, and their regio- and stereochemistries were determined by 1D and 2D NMR experiments.11 Use of excess In(OTf)3 (1.5 equiv) increased the yield significantly, as expected; however the reaction still required 24 h (entry 2). Meanwhile, we were pleased to find that at elevated temperature (70 °C) the nucleophilic ring-opening reaction of 4a with 0.5 equiv of In(OTf)3 was complete within 2 h, forming products in 92% yield without loss of stereoselectivity (entry 3). Similar results were obtained when 2-propanol and tert-butanol were used (entries 4–5). Although only moderate yields were observed when 4b was treated with various alcohols, the exclusive selectivity for anti-1,2- and anti-1,4-products remained (entries 6–8). Again when benzyl alcohol and allyl alcohol were used, ring-opening reactions of 4a afforded anti-1,2- and anti-1,4-products in moderate to good yields (entries 9–10). In contrast, the ring-opening reaction with [4.2.2] bicyclic cycloadduct 5a derived from cyclooctadiene failed, even with the use of excess In(OTf)3 and at 70 °C (entry 11). Clearly, ring strain of substrates is important for the Lewis acid-mediated ring-opening reactions to occur.

TABLE 4
In(OTf)3-Mediated Nucleophilic Ring-Opening Reactions of 3-Aza-2-oxabicyclo[2.2.2]oct-5-ene 4a–b with Different Alcohols

Ring-opening reactions with other, non-alcohol nucleophiles, were also briefly studied. Attempted Lewis acid-mediated reactions with amines generated complex mixtures. However, use of water in mixed solvent systems was effective in the In(OTf)3-mediated ring-opening reactions (Table 5). Reaction of 3a with 0.5 equiv of In(OTf)3 in 1:1 water:THF at room temperature gave a 45% yield of a 1:6.7:1 ratio of anti-1,2-:anti-1,4-:syn-1,4-products (12a:13a:14a) with anti-1,4-product 13a as the major product (entry 1). [2.2.2] Bicyclic system 4a again required elevated temperature (70 °C) to induce reaction but generated only anti-1,2- and anti-1,4-products (12b and 13b) in moderate yield (51%, entry 2). Compared to the typical N–O bond cleavage reactions of nitroso cycloadducts which can only form single syn-1,4 amino alcohol products, the methodology presented here allows generation of 1,2 or 1,4-hydroxyamino cyclopentenols and cyclohexenols with some control of regio- and stereochemistry. Moreover, subsequent N-O bond reduction can provide the corresponding amino alcohol compounds.12

TABLE 5
In(OTf)3-Mediated Nucleophilic Ring-Opening Reactions of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene 3a and [2.2.2]oct-5-ene 4a with Water

We also conducted an emperiment with cycloadduct 3a under Brønsted acid conditions.13 Thus, treatment of 3a with 3 equiv of 6 N HCl in dioxane for 2 h at 0 °C afforded a 40% yield of a 1:1.6:3 ratio of anti-1,2-:anti-1,4-:syn-1,4-products (12a:13a:14a) (Scheme 3). This result indicated that Brønsted acid (HCl in this case) is sufficient enough to induce the ring-opening reaction without need for metal chelation.

SCHEME 3
Brønsted Acid-Mediated Ring-Opening Reaction of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene 3a under Aqueous Conditions

In summary, we have demonstrated that a variety of 3-aza-2-oxabicyclo[2.2.1]hept-5-ene and [2.2.2]oct-5-ene systems can be solvolytically ring-opened under In(OTf)3 catalyzed conditions. The regio- and stereoselectivity of the products obtained depends on the cosolvents and/or the size of the nucleophiles. Only anti-1,2- and anti-1,4-alkoxy hydroxyamino disubstituted cyclohexene products were obtained from [2.2.2] bicyclic systems. Extensions to addtional studies related to natural product functionalization and derivatization are in progress and will be reported in due course.

Experimental Section

General Procedure A for In(OTf)3-Mediated Nucleophilic Ring-Opening Reactions of 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene with Alcohols

A solution of cycloadduct 3 (0.39 mmol) in alcohol (3 mL) was treated at rt with anhydrous In(OTf)3 (0.19 mmol) and stirred under Ar for 1 h to 7 h until 3 was consumed. (The reaction was warmed to 30 °C when tert-butanol was used). The mixture was concentrated in vacuo to a slurry, then water (3 mL) and EtOAc (5 mL) were added and separated. The aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography.

General Procedure B for In(OTf)3-Mediated Nucleophilic Ring-Opening Reactions of 3-Aza-2-oxabicyclo[2.2.2]oct-5-ene with Alcohols

A solution of cycloadduct 4 (0.39 mmol) in alcohol (3 mL) was treated at rt with anhydrous In(OTf)3 (0.19 mmol) and quickly heated to 70 °C or 80 °C. The reaction mixture was stirred under Ar for 1 to 6 h until 4 was consumed. The mixture was cooled to rt and concentrated in vacuo to a slurry, then water (3 mL) and EtOAc (5 mL) were added and separated. The aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography.

All product ratios were determined by 1H NMR spectroscopy of the crude reaction mixtures.

anti-1-(N-(5-Bromo)-2-pyridinyl-N-hydroxyamino)-2-methoxycyclopent-3-ene (6a)

clear oil; IR (neat, cm−1) 3427, 3020, 1521, 1424, 1216, 1045; 1H NMR (500 MHz, DMSO-d6) δ 9.44 (s, 1 H), 8.25 (m, 1 H), 7.80 (dd, J = 8.9, 2.4 Hz, 1 H), 7.05 (dd, J = 8.9, 0.6 Hz, 1 H), 5.91 (m, 1 H), 5.84 (m, 1 H), 5.03-4.99 (m, 1 H), 4.65 (br m, 1 H), 3.22 (s, 3 H), 2.48–2.42 (m, 1 H), 2.34–2.28 (m, 1 H);13C NMR (125 MHz, DMSO-d6) δ 161.6, 147.5, 140.0, 133.3, 130.2, 111.1, 108.9, 87.0, 65.3, 55.7, 31.9; HRMS (ESI) [M + H]+ calcd for C11H14BrN2O2 285.0233, found 285.0231.

anti-1-(N-(5-Bromo)-2-pyridinyl-N-hydroxyamino)-4-methoxycyclopent-2-ene (7a)

clear oil; IR (neat, cm−1) 3407, 3019, 1579, 1458, 1364, 1216, 1091; 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1 H), 8.25 (dd, J = 2.6, 0.6 Hz, 1 H), 7.79 (dd, J = 9.0, 2.6 Hz, 1 H), 7.01 (dd, J = 9.0, 0.6 Hz, 1 H), 6.10 (m, 1 H), 5.87 (m, 1 H), 5.69 (br m, 1 H), 4.52 (br m, 1 H), 3.21 (s, 3 H), 2.05 (ddd, J = 13.8, 7.2, 3.8 Hz, 1 H), 1.80 (ddd, J = 13.8, 8.2, 3.4 Hz, 1 H); 13C NMR (125 MHz, DMSO-d6) δ 161.7, 147.4, 140.0, 134.8, 134.3, 111.4, 109.0, 84.7, 65.2, 55.5, 32.1; HRMS (ESI) [M + H]+ calcd for C11H14BrN2O2 285.0233, found 285.0205.

syn-1-(N-(5-Bromo)-2-pyridinyl-N-hydroxyamino)-4-methoxycyclopent-2-ene (8a)

clear oil; IR (neat, cm−1) 3407, 3019, 1579, 1458, 1364, 1216, 1091; 1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1 H), 8.23 (dd, J = 2.6, 0.6 Hz, 1 H), 7.79 (m, 1 H), 7.02 (dd, J = 9.0, 0.6 Hz, 1 H), 6.01 (m, 1 H), 5.84 (m, 1 H), 5.45 (m, 1 H), 4.33–4.30 (m, 1 H), 3.23 (s, 3 H), 2.40 (ddd, J = 12.8, 7.6, 7.6 Hz, 1 H), 1.68 (ddd, J = 12.8, 6.6, 6.6 Hz, 1 H); 13C NMR (125 MHz, DMSO-d6) δ 161.4, 147.4, 140.1, 133.9, 133.4, 111.1, 108.8, 83.2, 63.6, 55.3, 31.6; HRMS (ESI) [M + H]+ calcd for C11H14BrN2O2 285.0233, found 285.0205.

anti-1-(N-(5-Bromo)-2-pyridinyl-N-hydroxyamino)-2-methoxycyclohex-3-ene (9a)

yellowish oil; IR (neat, cm−1) 3416, 3020, 1520, 1421, 1363, 1216, 1090; 1H NMR (600 MHz, DMSO-d6) δ 9.22 (s, 1 H), 8.19 (dd, J = 2.5, 0.4 Hz, 1 H), 7.75 (dd, J = 9.0, 2.5 Hz, 1 H), 7.01 (dd, J = 9.0, 0.4 Hz, 1 H), 5.76 (m, 1 H), 5.70 (m, 1 H), 4.53 (ddd, J = 12.3, 9.0, 3.2 Hz, 1 H), 4.24–4.21 (m, 1 H), 3.18 (s, 3 H), 2.09 (br m, 2 H), 1.84–1.77 (m, 1 H), 1.57–1.55 (m, 1 H); 13C NMR (150 MHz, DMSO-d6) δ 161.7, 147.2, 139.7, 128.8, 127.6, 110.3, 107.8, 74.6, 58.9, 54.7, 24.8, 23.6; HRMS (ESI) [M + Na]+ calcd for C12H15BrN2NaO2 321.0208, found 321.0209.

anti-1-(N-(5-Bromo)-2-pyridinyl-N-hydroxyamino)-4-methoxycyclohex-2-ene (10a)

white glass; IR (neat, cm−1) 3406, 3020, 1521, 1424, 1216, 1046; 1H NMR (600 MHz, DMSO-d6) δ 9.19 (s, 1 H), 8.23 (dd, J = 2.6, 0.6 Hz, 1 H), 7.79 (dd, J = 8.8, 2.6 Hz, 1 H), 7.02 (dd, J = 8.8, 0.6 Hz, 1 H), 5.87–5.84 (m, 1 H), 5.61–5.59 (m, 1 H), 5.06 (m, 1 H), 3.84 (m, 1 H), 3.25 (s, 3 H), 2.14 (br m, 1 H), 1.78–1.74 (m, 2 H), 1.44–1.37 (m, 1 H); 13C NMR (150 MHz, DMSO-d6) δ 161.2, 147.4, 140.0, 131.6, 130.4, 111.1, 108.7, 74.7, 56.3, 54.8, 27.8, 22.5; HRMS (ESI) [M + H]+ calcd for C12H16BrN2O2 299.0388, found 299.0390.

Supplementary Material

1_si_001

Acknowledgement

We thank Cara Cesario for initial related studies and helpful discussions, Dr. Jaroslav Zajicek for 2D NMR assistance and Nonka Sevova for mass spectroscopic analyses. We acknowledge The University of Notre Dame and NIH (GM 075885) for support of this work.

Footnotes

Supporting Information Available: General methods, experimental details, characterization data and copies of 1H, 13C and 2D NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

References

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