Synthesis of (S,R,R,S,R,S)-4,6,8,10,16,18-hexamethyldocosane from antitrogus parvulus via diastereoselective hydrogenations

Article abstract of DOI:10.1021/ol070298z

Figure presented The hydrocarbon 1 was prepared via a series of catalyst-controlled diastereoselective hydrogenations beginning with fragments derived from the Roche ester.

Full text of DOI:10.1021/ol070298z

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1391-1393
Synthesis of (S,R,R,S,R,S)-4,6,8,10,16,18-
Hexamethyldocosane from Antitrogus
parvulus via Diastereoselective
Hydrogenations
Jianguang Zhou, Ye Zhu, and Kevin Burgess*
Texas A & M UniVersity, Chemistry Department, P.O. Box 30012,
College Station, Texas 77842
burgess@tamu.edu
Received February 5, 2007
ABSTRACT
The hydrocarbon 1 was prepared via a series of catalyst-controlled diastereoselective hydrogenations beginning with fragments derived from
the Roche ester.
Kitching and co-workers isolated hydrocarbon 1 (see Ab-
stract) from female Australian melolonthine beetles.1,2 The
larvae of these insects are apparently significant pests,
attacking sugar cane crops in that region.
Definitive elucidation of the structure emerged from a
synthesis by Breit et al.3 that built on work Kitching had
done to eliminate many stereochemical possibilities. Kitch-
ing’s group reported that the “Western fragment” (as drawn
above) had anti,anti,anti relative stereochemistry and that
the Eastern part had syn stereochemistry. They made several
epimers of 1 in this process, but via routes based on existing
methodologies that are not readily amenable to making all
stereoisomers. Thus, the relative configurations of the
Western and Eastern fragments and the absolute configura-
tion of the whole molecule were not established. Breit was
then able to make the particular anti,anti,anti/syn stereoiso-
mer shown and proved that it corresponded to the natural
product.
Breit’s synthesis featured a methodology developed in his
laboratory.4 Briefly, it is an iterative approach beginning with
the Roche ester to prepare two deoxypolyketide fragments.
The essential feature of the iteration sequence is that organo-
cuprates are prepared from Roche ester derived fragments,
and these are added to an optically pure allylic ester formed
from (2-diphenylphosphino)benzenoic acid. This particular
ester directs a syn-SN2′ displacement. Other steps in the itera-
tion are reductive ozonolysis and conversion of the product
alcohol into an organoiodide, ready for the next cycle.
We saw a synthesis of the hydrocarbon 1 as an opportunity
to test our catalyst-controlled diastereoselective hydrogena-
(1) Fletcher, M. T.; Chow, S.; Lambert, L. K.; Gallagher, O. P.; Cribb,
B. W.; Allsopp, P. G.; Moore, C. J.; Kitching, W. Org. Lett. 2003, 5, 5083-
5086.
(2) Chow, S.; Fletcher, M. T.; Lambert, L. K.; Gallagher, O. P.; Moore,
C. J.; Cribb, B. W.; Allsopp, P. G.; Kitching, W. J. Org. Chem. 2005, 70,
1808-1827.
(3) Herber, C.; Breit, B. Angew. Chem., Int. Ed. 2005, 44, 5267-5269.
(4) Breit, B.; Herber, C. Angew. Chem., Int. Ed. 2004, 43, 3790-3792.
10.1021/ol070298z CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/06/2007

tion methodology for syntheses of deoxypolyketide chirons.
Figure 1 outlines the approach that was envisaged.
Scheme 1. Synthesis of the Eastern Part of 1, i.e., Chiron 3
Figure 1. Conceptual synthesis of 1 from two C11 chains derived
from catalyst-controlled diastereoselective hydrogenations.
Comprehensive details of our catalyst-controlled diaste-
reoselective hydrogenation methodology have been pub-
lished.5,6 In the work described here, it was only necessary
to use catalyst L-2.7,8
heterogeneous hydrogenation, deprotection, and iodination
sequence shown in converting the alcohol 6 to the iodide 9
were straightforward transformations. The last step, alkylation
of a ketophosphonate dianion, is also known,9 if not so
widely applied.
The challenge in this sequence was avoiding epimerization
at the aldehyde stage. This was not a problem for the
approach in Scheme 1, but it was for another approach that
was abandoned for this reason (see Supporting Information).
The Western part of 1, derived from aldehyde 4, contains
a stereochemical tetrad. Our hydrogenation methodology had
established a route to the anti,anti-stereochemical triad 10,5
so one further iteration was needed. Thus, alcohol 10 was
converted to the ester 11. Then, the material was reduced
using L-2, and the crude material was reduced to the alcohol
using DIBAL-H for ease of separation. Product 12 was
obtained in 80% yield as one stereoisomer to within the limits
of our GC detection after one chromatographic separation.
The remaining oxidation, Wittig, heterogeneous hydrogena-
tion, and deprotection steps gave the alcohol 14 (Scheme
2).
Hydrogenation of 5 in the first step of Scheme 1 reiterates
one of the several reactions we have used to prepare chiron
6. This reaction is catalyst controlled, but there is a significant
“substrate vector”,5 and the Z-allylic alcohol was used to
optimize this. Crude material formed in this step had a 34:
1.0 (via GC, throughout this paper) syn/anti diastereomeric
ratio, and 93% yield of 120:1.0 syn/anti product was obtained
after one chromatography. The Swern oxidation, Wittig,
(5) Zhou, J.; Burgess, K. Angew. Chem., Int. Ed. 2007, 46, 1129-1131.
(6) Zhou, J.; Ogle, J. W.; Fan, Y.; Banphavichit, V.; Zhu, Y.; Burgess,
K. J. Am. Chem. Soc. 2007, submitted.
(7) Perry, M. C.; Burgess, K. Tetrahedron: Asymmetry 2003, 14, 951-
961.
(8) Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.; Reibenspies, J.
H.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 113-123.
(9) Grieco, P. A.; Pogonowski, C. S. J. Am. Chem. Soc. 1973, 95, 3071-
3072.
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Org. Lett., Vol. 9, No. 7, 2007

Scheme 2. Synthesis of the Western Part of 1, i.e., Precursor
to Chiron 4
Scheme 3. Completion of the Synthesis of 1
As a synthesis of compound 1, the work described here is
a very direct and convergent approach that uses only the
two enantiomers of the Roche ester as starting materials.
Further, it demonstrates that catalyst-controlled diastereo-
selective hydrogenation routes to deoxypolyketides have
practical synthetic value. We feel that research on asymmetric
hydrogenations of largely unfunctionalized alkenes is moving
on from simple substrates13-15 to ones that give useful chirons
for organic synthesis.
Synthesis of the target molecule 1 from the alcohol 14,
via the aldehyde 4, and the phosphonate 3 was accomplished
as in Scheme 3. The Horner-Wadsworth-Emmons cou-
pling10 and heterogeneous hydrogenation steps were routine.
Milder variants of the final Wolff-Kischner reduction were
attempted briefly,11 but the reductive modification gave better
results.12
Acknowledgment. Financial support for this work was
provided by The National Science Foundation (CHE-
0456449) and The Robert A. Welch Foundation. We thank
Dr. Shane Tichy and the TAMU/LBMS-Applications Labo-
ratory for MS support and the NMR Laboratory at Texas
A&M University, supported by a grant from the National
Science Foundation (DBI-9970232) and the Texas A&M
University System.
Proton and 13C NMR spectra of the synthetic product 1
were essentially identical to those reported by both Kitching
and Breit. Further, the optical rotation value for the synthetic
material {[R]23D +12.1 (c 0.80, CHCl3)} compares well with
the value reported by Breit for natural material obtained from
Supporting Information Available: Experimental pro-
cedures and characterization data for the new compounds
reported. This material is available free of charge via the
Internet at http://pubs.acs.org.
Kitching {[R]20 +10.7 (c 0.44, CHCl3)}. Thus, we are
D
confident that the relative and absolute configurations of
product 1 match with those reports.
OL070298Z
(10) Paterson, I.; Yeung, K. S.; Smaill, J. B. Synlett 1993, 774-776.
(11) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 5436-
5445.
(12) Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J. Am. Chem.
Soc. 1973, 95, 3662-3668.
(13) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998,
37, 2897-2899.
(14) Kallstrom, K.; Hedberg, C.; Brandt, P.; Bayer, A.; Andersson, P.
G. J. Am. Chem. Soc. 2004, 126, 14308-14309.
(15) Cui, X.; Burgess, K. Chem. ReV. 2005, 105, 3272-3296.
Org. Lett., Vol. 9, No. 7, 2007
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