debenzylation to furnish alcohol 8 as a single stereoisomer
(NMR) in 95% yield. NOE studies revealed the cis diaste-
reomer of the alcohol as the predominant product.
Scheme 1
Our original intention was to simultaneously convert the
cyclopentanone into a six-membered ring while forming the
second ring using the intramolecular Schmidt reaction
developed in these laboratories.11 To accomplish this, a
modified Mitsunobu reaction on 8 afforded azide 9; no
epimerization was apparent in this step (Scheme 3).12 When
Scheme 3
1). In the present case, this would require a conjugate
reduction/alkylation sequence, in contrast to the conjugate
addition/trapping protocol more commonly associated with
such enones.4,6 In addition, an efficient ring adjustment
sequence would also be required. Herein, we report the
successful application of this strategy to lasubine alkaloid
synthesis.
The TIPS-protected 4-(S)-(-)-hydroxy-2-cyclopentenone
(4) was synthesized according to literature procedures
established for the known TBS derivative.7 The change of
protecting group was necessitated by the lability of the TBS
group in a later Lewis acid-promoted step (see below).
Reductive alkylation of 4 using platinum divinyltetramethyl
disiloxane complex (Karstedt’s catalyst) in the presence of
triethylsilane afforded enol ether 5 as a single regioisomer
in 96% yield (Scheme 2).6 Mukaiyama aldol reaction of 5
9 was subjected to the standard Schmidt reaction conditions
(TFA, BF3‚OEt2, or TiCl4 in CH2Cl2 at room temperature),
no reaction was observed. Eventually, it was found that
treatment with TiCl4 in refluxing CH2Cl2 reluctantly afforded
lactams 3a and 3b in a 1:1.3 ratio. Treatment of the
diastereomerically pure 2-(4′-chlorobutyl) analogue of 9
resulted in complete epimerization at the R stereogenic
center, which suggested that the formation of isomers 3a
and 3b resulted from Lewis acid-promoted enolization and
epimerization prior to the nitrogen insertion step (which has
been shown to be stereoselective11).
Scheme 2
To avoid this Lewis acid-promoted epimerization, alterna-
tive ring expansion routes were considered. We have recently
identified the photochemical rearrangement of endocyclic
nitrones as an alternative to the intramolecular Schmidt
reaction.13,14 We hypothesized that such a reaction may
proceed without epimerization because Lewis or protic acids
are not required. Thus, alcohol 8 was converted into the bis-
benzyloxylcarbonyl (Cbz)-protected hydroxylamine 10 under
modified Mitsunobu conditions (Scheme 4).15 Subsequent
(7) (a) Leighton, J. L.; Jacobsen, E. N. J. Org. Chem. 1996, 61, 389-
390. (b) Deardorff, D. R.; Windham, C. Q.; Craney, C. L. Org. Synth. 1996,
7325-35. (c) Myers, A. G.; Hammond, M.; Wu, Y. Tetrahedron Lett. 1996,
37, 3083-3086.
(8) Hashimoto, M.; Kan, T.; Yanagiya, M.; Shirahama, H.; Matsumoto,
T. Tetrahedron Lett. 1987, 28, 5665-5668.
(9) Chow, K.; Danishefsky, S. J. J. Org. Chem. 1989, 54, 6016-6018.
(10) (a) Suzuki, M.; Kawagishi, T.; Suzuki, T.; Noyori, R. Tetrahedron
Lett. 1982, 234057-4060. (b) Suzuki, M.; Yanagisawa, A.; Noyori, R.
Tetrahedron Lett. 1984, 25, 1383-1386.
(11) Milligan, G. L.; Mossman, C. J.; Aube´, J. J. Am. Chem. Soc. 1995,
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(12) Viaud, M. C.; Rollin, P. Synthesis 1990, 130-132.
(13) Smith, B. T.; Wendt, J. A.; Aube´, J. Org. Lett. 2002, 4, 2577-
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(14) Zeng, Y.; Smith, B. T.; Hershberger, J.; Aube´, J. J. Org. Chem.
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(15) Knight, D. W.; Leese, M. P. Tetrahedron Lett. 2001, 42, 2593-
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with aldehyde 68 followed by dehydration afforded the E
enone 7 in 57% overall yield.9,10 Catalytic hydrogenation of
7 with 10% Pd/C in ethanol resulted in reduction as well as
(5) (a) Elliott, J. D.; Hetmanski, M.; Palfreyman, M. N.; Purcell, N.;
Stoodley, R. J. Tetrahedron Lett. 1983, 24, 965-968. (b) Essig, S.;
Scheffold, R. Chimia 1991, 45, 30-32. (c) Forsyth, C. J.; Clardy, J. J. Am.
Chem. Soc. 1988, 110, 5911-5912. (d) Jaroszewski, J. W.; Olafsdottir, E.
S.; Cornett, C.; Schaumburg, K. Acta Chem. Scand. B 1987, B41, 410-
421. (e) Nagaoka, H.; Miyaoka, H.; Yamada, Y. Tetrahedron Lett. 1990,
31, 1573-1576.
(6) Johnson, C. R.; Raheja, R. K. J. Org. Chem. 1994, 59, 2287-2288.
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