Efficient Synthesis of Anastrephin via the Allylic Substitution for Quaternary Carbon Construction

Abstract

Lactone-moiety-attached 2-cyclohexylideneethyl picolinate was prepared through the OH-directed epoxidation (98% ds) of (R)-3-methylcyclohex-2-en-1-ol (99% ee), Horner–Wadsworth–Emmons olefination, conversion to the allylic moiety, and epoxide ring opening with Et₂AlCH₂CO₂ t-Bu. The allylic substitution of the picolinate with Me₂CuMgBr·MgBr₂ furnished a quaternary carbon center with 92% ds. Finally, the lactonization of the product, the tert-butyl ester of the seco acid, under acidic conditions, afforded (–)-anastrephin.

Key words

anastrephin - quaternary carbon - asymmetric synthesis - allylic substitution - copper reagent - picolinate

• References and Notes

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• 16 Anastrephin (1) prepared from (E)-5 (95% ee): [α]_D ²¹ –39 (c 0.37, hexane) and mp 91.5–93.0 °C. Compare ref. 3b [α]_D ²⁶ –45.1 (c 0.51, hexane) and mp 88.0–89.5 °C; ref. 3a [α]_D ²³.⁵ –50.4 (c 0.25, hexane) and mp 91.0–91.5 °C; ref. 1h [α]_D +48.8 (hexane) and mp 94–95 °C for ent-1. Since the [α]_D value of epianastrephin (2) is larger than 1 {[α]_D ²⁸ –72.5 (c 0.57, hexane)}, contamination of 2 in 1 might be a reason for the reported larger [α]_D value of 1. The copy of the ¹H NMR spectrum of 1 attached in their Supporting Information is contaminated with 2.^3b
• 17 This conformer is supported by ¹H NMR analysis: Conformer C, J _Ha–Hb = 1.6 Hz, J _Hb–Hd = 0 Hz; conformer A, J _Ha–Hc = J _Hc–Hd = 0 Hz.
• 18 Lit.^3a 0.28% yield, 23 steps, 23% ds (46% ds and 50% ds in the two steps) from geraniol; lit.^3b 0.16% yield, 31 steps, 33% ds (53% and 63% ds in the two steps) from glucose; lit.^3c 0.89% yield, 27 steps, 47% ds (75% and 63% ds in the two steps) from geraniol.
• 19 A solution of 5b (E/Z = 47:53, 284 mg, 0.76 mmol) in THF (2 mL) was added to a mixture of MeMgBr (0.97 M in THF, 2.60 mL, 2.52 mmol), CuBr·Me₂S (235 mg, 1.14 mmol) and ZnI₂ (392 mg, 1.23 mmol) in THF (1 mL) at –40 °C. The resulting mixture was warmed to r.t. and stirred overnight to afford olefin 6b (105 mg, 51%, 92% ds) after chromatographic purification. ¹H NMR (400 MHz, CDCl₃): δ = 1.00 (s, 3 H), 1.08 (s, 3 H), 1.27–1.35 (m, 1 H), 1.39–1.46 (m, 1 H), 1.45 (s, 9 H), 1.50–1.60 (m, 2 H), 1.73 (br s, 1 H), 1.77–1.86 (m, 2 H), 1.95 (dd, J = 6.0, 4.8 Hz, 1 H), 2.31 (dd, J = 16.4, 4.8 Hz, 1 H), 2.45 (dd, J = 16.4, 6.4 Hz, 1 H), 5.00 (dd, J = 17.6, 1.2 Hz, 1 H), 5.03 (dd, J = 11.2, 0.8 Hz, 1 H), 5.88 (ddd, J = 17.6, 11.2, 0.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.2 (–), 22.1 (+), 28.1 (+), 30.1 (+), 31.8 (–), 37.5 (–), 41.1 (–), 43.2 (–), 53.9 (+), 73.0 (–), 80.4 (–), 112.5 (–), 142.2 (+), 174.8 (–). The diastereoselectivity of 6b was determined by integration of the key signals in the ¹H NMR [δ = 5.88 (ddd) for 6b and δ = 5.71 (dd) for the diastereomer].