A New Access to the 6,8-Dioxabicyclo[3.2.1]octane Ring System Using a Three-Component Reaction: Enantioselective Synthesis of (+)-iso-exo-Brevicomin

Abstract

The combination of a catalytic hetero-Diels-Alder-­allylboration sequence and a ruthenium-catalyzed isomerization of an allylic alcohol moiety as key steps open a new route for the asymmetric synthesis of 6,8-dioxabicyclo[3.2.1]octane subunits. The application of this strategy to the synthesis of (+)-iso-exo-brevi­comin is also reported.

natural product - asymmetric catalysis - cycloaddition - boron - redox isomerization

References and Notes

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General Procedure and Selected Characterization Data
To a stirred solution of 3 (0.3 mmol) in CH₂Cl₂ (3 mL) at 0 ˚C was added BF₃˙OEt₂ (0.33 mmol). After 10 min, the resulting solution was warmed to r.t. and stirred for 90 min (excepted in the case of 3d). The reaction mixture was quenched with sat. aq NaHCO₃ (1 mL), and the aqueous phase was extracted with Et₂O (2 × 2 mL). The combined organic phases were washed with brine, dried over MgSO₄, filtrated, and concentrated under reduced pressure. Compounds 4 were purified by flash chromatography on silica gel (210-400 mesh).
Compound 4d was obtained as a colorless oil (95%). [α]_D ^²5 +33.5 (c 1.75, CH₂Cl₂). ^¹H NMR (300 MHz, CDCl₃): δ = 1.03 (s, 9 H), 1.91-1.97 (m, 1 H), 2.33-2.42 (m, 1 H), 4.26 (d, 1 H, J = 8.4 Hz), 4.44 (d, 1 H, J = 8.8 Hz), 4.47 (d, 1 H, J = 4.9 Hz), 5.50-5.52 (m, 1 H), 5.60-5.63 (m, 1 H), 5.98-6.04 (m, 1 H), 7.20-7.28 (m, 7 H), 7.35-7.49 (m, 6 H), 7.66-7.71 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 19.4, 26.9, 33.8, 72.0, 75.0, 88.7, 100.9, 124.3, 127.4, 127.5, 127.6, 127.7, 128.0, 128.9, 129.7, 129.8, 133.0, 134.0, 135.9, 136.0, 141.4. Anal. Calcd for C₂₉H₃₂O₃Si: C, 76.28; H, 7.06. Found: C, 76.35; H, 7.01.

<A NAME="RG34409ST-12">12</A>

Compound 8 was obtained as colorless oil (87%). [α]_D ^²5 +20.3 (c 1.30, CH₂Cl₂). ^¹H NMR (300 MHz, CDCl₃): δ = 1.03 (s, 9 H), 1.45-1.88 (m, 4 H), 2.29 (br s, 1 H), 3.60-3.63 (m, 1 H), 4.04 (d, 1 H, J = 7.3 Hz), 4.20-4.25 (m, 1 H), 4.49 (d, 1 H, J = 7.3 Hz), 5.32 (br s, 1 H), 7.21-7.33 (m, 7 H), 7.35-7.48 (m, 6 H), 7.61-7.69 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 19.4, 23.8, 26.8, 26.9, 66.7, 76.1, 77.2, 78.9, 81.5, 102.5, 127.4, 127.6, 127.8, 128.1, 129.6, 129.8, 133.1, 133.8, 135.9, 136.0, 140.9. Anal. Calcd for C₂₉H₃₄O₄Si: C, 73.38; H, 7.22. Found: C, 73.37; H, 7.11.

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The ee was measured by GC analysis using a chiral stationary phase (Varian WCOT Fused Silica 25 × 0.25 mm coated CP Chirasil-dex CB DF = 0.25).

<A NAME="RG34409ST-16A">16a</A> Using isomerization of allylic alcohols, see: Ito M. Kitahara S. Ikariya T. J. Am. Chem. Soc.  2005,  127:  6172 

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1-Phenylpropan-1-one can be obtained from the corresponding allylic alcohol in 97% yield with only 2 mol% of [RuCp*(MeCN)₃][PF₆] in toluene at r.t. These new conditions represent an improvement of the previously described process with this catalyst.

<A NAME="RG34409ST-20">20</A>

Characterization Data for Key Synthetic Intermediates
Compound 3e was obtained from 1 in 70% yield as a colorless oil. [α]_D ^²5 +72 (c 0.59, CH₂Cl₂). ^¹H NMR (300 MHz, CDCl₃): δ = 1.18-1.25 (m, 6 H), 2.19-2.22 (m, 2 H), 2.72 (br s, 1 H), 3.53 (dq, 1 H, J = 7.1, 9.3 Hz), 3.69-3.72 (m, 1 H), 3.96 (dq, 1 H, J = 7.1, 9.3 Hz), 3.98-4.03 (m, 1 H), 4.72 (dd, 1 H, J = 4.8, 6.1 Hz), 5.60-5.63 (m, 1 H), 5.78-5.80 (m, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 15.2, 18.6, 31.1, 64.4, 69.6, 78.8, 98.5, 124.9, 126.1. HRMS (EI): m/z [M -˙OCH₂CH₃]⁺ calcd for C₇H₁₁O₂: 127.0759; found: 127.0755.
Compound 12 was obtained as colorless oil (mixture of diastereomers, 63%). ^¹H NMR (300 MHz, CDCl₃): δ = 1.20 (d, 3 H, J = 5.9 Hz), 1.35-1.70 (m, 6 H), 1.81 (br s, 1 H), 2.68 (br s, 1 H), 3.40-3.43 (m, 2 H), 4.09-4.12 (m, 1 H), 4.43 (d, 1 H, J = 11.5 Hz), 4.68 (d, 1 H, J = 11.5 Hz), 5.11 (dd, 1 H, J = 1.2, 10.4 Hz), 5.23 (d, 1 H, J = 17.2 Hz), 5.88 (ddd, 1 H, J = 6.2, 10.4, 17.2 Hz), 7.26-7.43 (m, 5 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 15.5, 21.3, 21.4, 32.5, 32.6, 36.9, 71.0, 73.0, 73.1, 74.8, 74.9, 78.3, 78.4, 114.5, 114.6, 127.7, 127.8, 128.5, 138.3, 141.1, 141.2. ESI-HRMS: m/z [M + Na]⁺ calcd for C₁₆H₂₄O₃Na: 287.1623; found: 287.1623.
(+)-Iso-exo-brevicomin was obtained as a colorless oil (highly volatile, 60%): [α]_D ^²5 +53 (c 0.3, CHCl₃); lit.^¹4d [α]_D +54 (c 0.5, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 0.96 (t, 3 H, J = 7.9 Hz), 1.18 (d, 3 H, J = 6.5 Hz), 1.43-1.95 (m, 8 H), 4.06 (br s, 1 H), 4.22 (q, 1 H, J = 6.5 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 7.3, 17.1, 21.6, 28.0, 30.6, 33.5, 75.5, 79.9, 109.5. Anal. Calcd for C₉H₁₆O₂: C, 69.19; H, 10.32. Found: C, 69.27; H, 10.41.

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