Synthesis of the Optically Active Bicyclo[4.2.1]nonane Segment of Mediterraneols

Abstract

An efficient method was established for the synthesis of the optically active bicyclo[4.2.1]nonane segment of mediterraneols using diastereoselective sequential Michael reaction and then retro-aldol reaction.

Key words

antitumor agents - marine natural products - sequential Michael additions - bicyclic compounds - retro-aldol reactions

References

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• Recent examples:
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1

Present address: Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan, Fax[phone]; E-mail: [e-mail].

7

α,β-Unsaturated esters 6 and 8 were prepared from diol a [16] as shown in Scheme [5] :

Scheme 5 Reagents and conditions: For 6: A. TBDMS-Cl, Et₃N, DMAP, CH₂Cl₂, r.t., 78% (based on SM recovered); B. i) DMSO, (COCl)₂, Et₃N, CH₂Cl₂, -78 °C, ii) Ph₃P=C(CH₃)CO₂Et, benzene, r.t., 60% (2 steps). For 8: A. TBDPS-Cl, Et₃N, DMAP, CH₂Cl₂, r.t., 79% (based on SM recovered); B. i) DMSO, (COCl)₂, Et₃N, CH₂Cl₂, -78 °C, ii) Ph₃P=C(CH₃)CO₂Et, benzene, r.t., 63% (2 steps).

8

α,β-Unsaturated ester 10 was obtained from p-bromobenzoate b [17] as shown in Scheme [6] :

Scheme 6 Reagents and conditions: A. i) Acetone, H₂SO₄, benzene, 0 °C to r.t., 97%, ii) K₂CO₃, EtOH, r.t., 81%; B. i) DMSO, (COCl)₂, Et₃N, CH₂Cl₂, -78 °C, ii) Ph₃P=C(CH₃)CO₂Et, benzene, r.t., 54% (2 steps).

9

The stereochemistry of 11a was determined based on chemical correlation with 5a, whose stereochemistry was previously elucidated. [6b] Bicyclo[2.2.1]heptane derivative 11a was converted to aldehyde 13, [α]_D -52.4 (c 0.33, CHCl₃) (Scheme [2] ), whose spectral data and sign of optical rotation were found identical to aldehyde 13, [α]_D -54.6 (c 0.29, CHCl₃), which was converted from 5a as shown in Scheme [7] :

Scheme 7 Reagents and conditions: A. i) DIBALH, THF, -78 °C, ii) Bn-Br, NaH, THF-DMF, r.t., 93% (2 steps); B. i) HOAc-H₂O (4:1), 60 °C, 91% (based on SM recovered), ii) NaIO₄, MeOH-H₂O, r.t., 85%.

11

Numbering of compounds is accordance with that of mediterraneol.

15

1: Colorless solid: mp 142-145 °C. Anal. Calcd for C₁₂H₁₆O₃: C, 69.21; H, 7.74. Found: C, 69.25; H, 7.85. IR (CHCl₃): ν_max 2950, 1745, 1720, 1695, 1618 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 3.79 (1 H, d, J = 14.4 Hz), 3.44 (1 H, dt, J = 14.4, 1.1 Hz), 2.96 (1 H, d, J = 8.6 Hz), 2.82 (1 H, dd, J = 19.9, 8.6 Hz), 2.70 (1 H, d, J = 16.4 Hz), 2.64 (1 H, d, J = 16.4 Hz), 2.58 (1 H, dd, J = 19.9, 0.9 Hz), 1.11 (3 H, s), 1.10 (3 H, s), 1.05 (3 H, s).