With the cyclohexene in hand, we turned our attention to
construction of the right side cyclohexane ring and the
quaternary carbon center at C10. The carboxylic acid 10 was
transformed to the cyclization precursor 9 in 4 steps (Scheme
4). The SmI2-induced Barbier-type cyclization14 of 9 in the
Scheme 3. Diels-Alder Reaction Using the Lewis Acid
Scheme 4. Synthesis of Nitrile 22
in good yield. The mixture was equilibrated with NaOMe
in MeOH (0.08 M) to that of the two trans-esters 19 and
20. The desired ester 19 was hydrolyzed with complete
selectivity by the slow addition of 1 N HCl to the MeOH
solution at 0 °C to provide the easily separable mixture of
the desired carboxylic acid 10 and the unhydrolyzed ester
20 (10:20 ) 2:1). Separation of these two trans diastereomers
was essential for the total synthesis. After extensive studies,
we found the excellent method mentioned above.13
presence of HMPA occurred cleanly in excellent yield to
give the alcohol 21, which was oxidized with Dess-Martin
periodinane (DMP).15 To construct the quaternary carbon
center, the nitrile 22 was derived from ketone 8 with
p-toluenesulfonylmethyl isocyanide (TosMIC).7l,16 The nitrile
22 was next reduced to the aldehyde 23 (Scheme 5).17 The
alkylation of 23 with p-methoxybenzyl chloromethyl ether
2418 successfully afforded the PMB ether,19,20 which was
subjected to Wolff-Kishner conditions21 to afford the PMB
ether 25 as a single diastereomer. The PMB ether 25 was
(8) For a typical example, the intramolecular Diels-Alder reaction of
the (()-trienone 5 afforded a mixture of the (()-cis-decalins 6 and 7 in a
ratio of 89.7:10.3. Furthermore, the mixture of 6 and 7 was isomerized by
NaOMe in MeOH forming an inseparable mixture of the (()-trans-decalin
8 and 6 and 7 in a ratio of 42.7:47.2:10.1. See ref 7b.
(14) (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1993, 58, 7216–
7227. (b) Molander, G. A.; Harris, C. R. J. Org. Chem. 1997, 62, 2944–
2956. (c) Tamiya, H.; Goto, K.; Matsuda, F. Org. Lett. 2004, 6, 545–549.
(15) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
(16) Oldenziel, O. H.; van Leusen, A. M. Tetrahedron Lett. 1973, 14,
1357–1360
.
(17) Alkylation of 22 under various conditions resulted in low yield or
a complex mixture. See ref 7l.
(9) (a) Hodgson, D. M.; Foley, A. M.; Lovell, P. J. Synlett 1999, 744–
746. (b) Ru¨eger, H.; Stutz, S.; Spindler, F.; Maibaum, J. Tetrahedron Lett.
2000, 41, 10085–10089.
(18) (a) Benneche, T.; Strande, P.; Undheim, K. Synthesis 1983, 762–
763. (b) Go´mez, C.; Macia´, B.; Lillo, V. J.; Yus, M. Tetrahedron 2006,
62, 9832–9839.
(10) Wang, Y.; West, F. G. Synthesis 2002, 99–103.
(11) (a) Roush, W. R.; Barda, D. A. J. Am. Chem. Soc. 1997, 119, 7402–
7403. (b) Schu¨rer, S. C.; Blechert, S. Synlett 1999, 1879–1882. (c) Roush,
W. R.; Limberakis, C.; Kunz, R. K.; Barda, D. A. Org. Lett. 2002, 4, 1543–
1546.
(12) Among the solvents examined (xylene, toluene, benzene, and
CH2Cl2), xylene was found to be the best for yield.
(13) For example, treatment of 18 (four diastereomers) with NaOMe in
dilute MeOH solution (0.02 M) and neutralization with 1 N HCl afforded
a mixture of 19 and 20 without hydrolysis of the methyl ester moiety.
Attempted separation of 19 and 20 by silica gel chromatography failed.
(19) R-Alkylation of 23 took place from an equatorial orientation in a
completely stereoselective manner. For similar equatorial alkylations, see:
(a) Ireland, R. E.; Mander, L. N. J. Org. Chem. 1967, 32, 689–696. (b)
Ireland, R. E.; Mander, L. N. J. Org. Chem. 1969, 34, 142–152. (c)
Vishnumuthy, K.; Cheung, E.; Scheffer, J. R.; Scott, C. Org. Lett. 2002, 4,
1071–1074
.
(20) It was found that R-alkylation of 23 with MeI and t-BuOK and
Pinnick oxidation gave the 10-epimer of 26 as a sole stereoisomer, from
which 10-epi-10-isocyano-4-cadinene was synthesized following the same
synthetic scheme.
906
Org. Lett., Vol. 12, No. 5, 2010