C O M M U N I C A T I O N S
Scheme 3. Synthesis of iso-Cladospolide Ba
rotation, [R]23D -87.5 (c 0.25, MeOH aq.) {lit.13a [R]D -90 (c 0.23,
MeOH)}, and spectral data for synthetic 21a matched the data
reported for the natural material.13a,c,d Additionally, 21b was
prepared by an analogous route from 23 and ent-24, and the
spectroscopic data were indistinguishable from 21a within experi-
mental error. The optical rotation, [R]23 -60.4 (c 0.23, distilled
D
MeOH), matched the literature value for recently isolated material
{lit.13e [R]D -61 (c 16.6, MeOH)}. Both diastereomers appear to
be natural products that are structurally related to known macrolides,
and 21b should be referred to as 11-epi-iso-cladospolide B.
In summary, an efficient preparation of synthetically useful
intermediates in high ee from a mixture of the cyclic carbonates
dl- and meso-1,2-divinylethylene carbonate has been developed
whereby two different modes of asymmetric induction give the same
product in excellent ee. This process, combined with ring-closing
and cross-metathesis, provides rapid access to a wide range of useful
synthons from the feedstock chemical acrolein. Further studies to
understand the mechanism and the broad utility of the products
will be the subjects of future reports.
a Conditions: (i) Acryloyl chloride, DMAP, Et3N, CH2Cl2, 71%; (ii) 10
mol % of Grubbs 2nd generation catalyst (27), CH2Cl2, 70%; (iii) CAN,
CH3CN/H2O, 70%; (iv) 24 (5 equiv), 27 (10 mol %), CH2Cl2, 73%; (v)
PhSH, Et3N (5 mol %), CH2Cl2, 77%; (vi) oxone, MeOH/H2O, 82%; (vii)
H2, 10% Pd/C; (viii) DBU, CH2Cl2, 82% (2 steps).
improved the ratio from 1.5:1 to 7.5:1 (entries 1 and 6) and also gave
1911 in higher yield. When the catalyst loading, equivalents of 18,
and temperature were lowered, 19 was isolated in 64% yield (theo-
retical max 75%) with 98% ee in a 12:1 ratio with 20 (entry 7).
Under the optimized conditions (Table 3, entry 7), (R,R)-2 could
be reisolated from the reaction mixture, and although differences
are observed, the same mechanism (Scheme 2) is proposed to be
operative. Appearance of the linear products 17 and 20 is likely
due to matched nucleophilic addition to π-allylpalladium complex
13. Additional evidence of this was obtained by assignment of the
absolute stereochemistry. While racemic material failed to separate
on a variety of chiral stationary phase HPLC columns, both the
configuration and ee could be determined by NMR.12 After
conversion to the O-methyl mandalate ester, the major product was
determined to be of the S configuration and the ee was 60%. These
data are also consistent with the proposed mechanism. The principal
difference between the phenol and phthalimide reactions is the
solubility of the nucleophile. Phthalimide is only partially soluble,
while the phenols completely dissolve under the reaction conditions.
With phthalimide, proper balance is achieved, but the higher
concentration of phenol present increases the rate of nucleophilic
addition relative to equilibration of the π-complexes and leads to
a less regioselective reaction.
The impetus for developing this chemistry was for application
to the synthesis of natural products containing 1,2-amino alcohols
or 1,2-diols, two relatively simple structures being the proposed
structures of iso-cladospolide B 21a,b.13 The stereochemistry of
iso-cladospolide B (21a) was originally postulated to be analogous
to that of the macrolide cladospolide B,13c,d but recent reports
indicate a discrepancy as 21b was proposed based on NMR studies
of material isolated from a marine fungus culture of a different
source and by analogy to pandangolides 1 and 1a of known
stereochemistry that were also isolated.13e
Acknowledgment. We thank the National Science Foundation
and National Institutes of Health for their generous support of our
programs. A.A. is supported by an NIH postdoctoral fellowship.
Mass spectra were provided by the Mass Spectrometry Regional
Center of the University of CaliforniasSan Francisco, supported
by the NIH Division of Research Resources.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
References
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Our strategy relies on a union of two fragments of defined
stereochemistry to establish both the absolute and relative config-
uration. To this end, the alcohol 19 was acylated with acryloyl
chloride, and ring-closing metathesis (RCM) provided 22 (Scheme
3). Deprotection and cross-metathesis (CM) with the olefin 2414
assembled the carbon framework in good yield.
Chemoselective reduction of the allylic olefin proved more
difficult than anticipated and required that the butenolide olefin be
protected. Conjugate addition of thiophenol and oxidation of the
resultant sulfide to the sulfone followed by hydrogenation and
elimination provided 21a in 52% yield over four steps. The optical
(14) Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem. Soc., Perkin Trans. 1
2000, 2385.
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