Efficient and selective synthesis of S,R,R,S,R,S-4,6,8,10,16,18- hexamethyldocosane via zr-catalyzed asymmetric carboalumination of alkenes ZACA reaction

Article abstract of DOI:10.1021/ol703056u

S,R,R,S,R,S-4,6,8,10,16,18-Hexamethyldocosane 1 was synthesized in 11% yield in 11 steps in the longest linear sequence from ≥98% pure S-β-citronellal and 6 additional steps for the preparation of 11 in 23% yield from propene. Five of the six asymmetric c

Full text of DOI:10.1021/ol703056u

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1099-1101
Efficient and Selective Synthesis of
(S,R,R,S,R,S)-4,6,8,10,16,18-Hexamethyl-
docosane via Zr-Catalyzed Asymmetric
Carboalumination of Alkenes (ZACA
Reaction)
Gangguo Zhu, Bo Liang, and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
negishi@purdue.edu
Received December 19, 2007
ABSTRACT
(S,R,R,S,R,S)-4,6,8,10,16,18-Hexamethyldocosane (1) was synthesized in 11% yield in 11 steps in the longest linear sequence from
(S)- -citronellal and 6 additional steps for the preparation of 11 in 23% yield from propene. Five of the six asymmetric carbon centers were
generated catalytically and stereoselectively by the ZACA reaction (5 times), one lipase-catalyzed acetylation, and two chromatographic operations.
g98% pure
â
(S,R,R,S,R,S)-4,6,8,10,16,18-Hexamethyldocosane (1) was
isolated from the cuticula of the cane beetle Antitrogus
parVulus by Kitching and co-workers1 and shown by them
to incorporate a rare anti-anti-anti-4,6,8,10-methyl tetrad
along with a more usual syn-methyl diad.2 On the basis of
the deduced stereochemistry, Breit3 and then Burgess4
reported total syntheses of this hydrocarbon, which estab-
lished the 4S,6R,8R,10S,16R,18S absolute configuration of
1. Our recent development of an efficient and enantio-face
selective ZACA route5,6 to deoxypolypropionates, which has
been shown to favor the syn relationship between two
neighboring methyl groups,6a-6c vis-a`-vis the unusual anti-
anti-anti configuration found in 1 prompted us to attempt
the synthesis of 1 by the ZACA route, in part, for exploring
its scope and limitations. It should be clearly noted that
(5) ZACA stands for Zr-catalyced asymmetric carboalumination of
alkenes. For the discovery and early development of the ZACA reaction,
see: (a) Kondakov, D.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 10771-
10772. (b) Kondakov, D.; Negishi, E. J. Am. Chem. Soc. 1996, 118, 1577-
1578. (c) Huo, S.; Negishi, E. Org. Lett. 2001, 3, 3253-3256. (d) Huo, S.;
Shi, J.; Negishi. E. Angew. Chem., Int. Ed. 2002, 41, 2141-2143.
(6) For applications of the ZACA reaction to asymmetric syntheses of
natural products, see: (a) Negishi, E.; Tan, Z.; Liang, B.; Novak, T. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5782-5787. (b) Tan, Z.; Negishi, E.
Angew. Chem., Int. Ed. 2004, 43, 2911-2914. (c) Magnin-Lachaux, M.;
Tan, Z.; Liang, B.; Negishi, E. Org. Lett. 2004, 6, 1425-1427. (d) Novak,
T.; Tan, Z.; Liang, B.; Negishi, E. J. Am. Chem. Soc. 2005, 127, 2838-
2839. (e) Liang, B.; Novak, T.; Tan, Z.; Negishi, E. J. Am. Chem. Soc.
2006, 128, 2770-2771. (f) Tan, Z.; Liang, B.; Huo, S.; Shi, J.; Negishi, E.
Tetrahedron: Asymmetry 2006, 17, 512-515. (g) Huang, Z.; Tan, Z.;
Novak, T.; Zhu, T.; Negishi, E. AdV. Synth. Catal. 2007, 349, 539-545.
(h) Zhu, G.; Negishi, E. Org. Lett. 2007, 9, 2771-2774. (i) Liang, B.;
Negishi, E. Org. Lett. 2008, 10, 193-195.
(1) (a) 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. (b) 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.
(2) For a recent overview of deoxypolypropionates, see: Hanessian, S.;
Giroux, S.; Mascitti, V. Synthesis 2006, 1057-1076.
(3) (a) Herber, C.; Breit, B. Angew. Chem., Int. Ed. 2005, 44, 5267-
5269. (b) Herber, C.; Breit, B. Eur. J. Org. Chem. 2007, 3512-3519. (c)
For a related methodological study, see: Breit, B. Angew. Chem., Int. Ed.
1998, 37, 525-527.
(4) (a) Zhou, J.; Zhu, Y.; Burgess, K. Org. Lett. 2007, 9, 1391-1393.
(b) For a related methodological study, see: Zhou, J.; Burgess, K. Angew.
Chem., Int. Ed. 2007, 46, 1129-1131.
10.1021/ol703056u CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/15/2008

diastereoselective construction of deoxypolypropionates rely-
ing on pre-existing chiral centers7 gives predominantly syn
isomers and is hence not practical for the synthesis of anti
deoxypolypropionates, such as 1. Despite high yields and
enantioselectivity figures, the use of the stoichiometric
amounts of relatively expensive chiral reagents8 becomes
increasingly undesirable as the number of asymmetric carbon
centers in a molecule increases. With these considerations
in mind, a predominantly catalytic asymmetric synthesis of
1 has been devised as outlined in Schemes 1 and 2.
Scheme 2
Scheme 1
Scheme 3
For the preparation of the tetramethylundecane fragment,
we initially opted for a fully reagent-controlled protocol
involving four ZACA reactions to synthesize 2,4,6,8-tetra-
methyl-1-undecanol (13) from propene, as shown in Scheme
3. This synthesis did work very efficiently as planned.
However, the anticipated low diastereomeric ratios ranging
from 3.5/1 to 4.5/1 and the unfavorable chromatographic
recoveries of 47-54% for improving the diastereomeric ratio
to 40 or higher led to the total yield of 7% over 6 steps.
To alleviate the difficulty stemming from the generally
unfavorable construction of a series of three anti-1,3-
dimethylpropylidine moieties, the use of (S)-â-citronellal was
considered as a relatively inexpensive ($453/mol from TCI)
source of an enantiomerically pure (g98% S) monochiral
building block, which led to the synthesis of 6 (dr g98/2)
in 14% yield over 6 steps from (S)-â-citronellal (Scheme
1). By taking advantage of the facts that the starting (S)-â-
citronellal was g98% S and that 3 was the 2R isomer of a
2-methyl-substituted terminal alcohol, purification of 3 was
achieved by Amano PS lipase-catalyzed acetylation6g leading
to a considerably higher recovery of 74% than that observed
in the chromatographic purification (∼50% recovery). For
the syntheses of shorter syn-dimethylalkyl derivatives 9-11,
a fully catalytic and reagent-controlled enantio-face selective
ZACA route shown in Scheme 2 proved to be highly
efficient, even though there still exists considerable room
for improvement in both product yield and stereoselectivity.
With the two key intermediates 7 and 11 in hand as
isomerically pure compounds, the final assembly of the target
compound 1 was achieved in 85% in 2 steps via Wittig
olefination and catalytic hydrogenation with H2 over Pd/C
(Scheme 2). The desired product 1 thus obtained exhibited
(7) Hanessian, S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. J. Am. Chem.
Soc. 1990, 112, 5276-5290.
(8) (a) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R.
J. Am. Chem. Soc. 1990, 112, 5290-5313. (b) Abiko, A.; Masamune, S.
Tetrahedron Lett. 1996, 37, 1081-1084. (c) Myers, A. G.; Yang, B. H.;
Chen, H.; Mckinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc.
1997, 119, 6496-6511. (d) Myers, A. G.; Yang, B. H.; Chen, H.; Kopecky,
D. J. Synlett 1997, 457-459. (e) Birkbeck, A. A.; Enders, D. Tetrahedron
Lett. 1998, 39, 7823-7826. (f) Nicolos, E.; Russell, K. C.; Hruby, V. J. J.
Org. Chem. 1993, 58, 766-770. (g) Williams, D. R.; Turske, R. A. Org.
Lett. 2000, 2, 3217-3220.
1
23
the H and 13C NMR spectra as well as [R]D ) +10.9 (c,
1.5, CHCl3) that were in good agreement with those reported
previously.1,3,4
1100
Org. Lett., Vol. 10, No. 6, 2008

In summary, (S,R,R,S,R,S)-4,6,8,10,16,18-hexamethyl-
docosane (1) was synthesized in 11% yield in 11 steps in
the longest linear sequence from g98% pure (S)-â-citronellal.
Additionally, the preparation of 11 in 26% yield over 6 steps
from propene was required, making the total number of steps
17. Five of the six asymmetric carbon centers were generated
in a catalytic and enantio-face selective manner using the
ZACA reaction. In addition to the use of one lipase-catalyzed
acetylation, just two ordinary chromatographic purifications
were used to obtain the five asymmetric carbon centers with
the correct absolute configurations as stereoisomerically pure
chiral moieties. This predominantly catalytic and enantio-
face selective ZACA-based synthesis of 1 is highly efficient.
However, its cost-turnover factor needs to be further
investigated and improved. Most critically, relatively low
product yields stemming largely from the modest enantio-
face selectivity in the ZACA reaction must be improved
mainly through catalyst optimization, and such efforts are
currently in progress.
At the end of this report, brief comments on the two
previous syntheses of 13,4 might be in order. In Breit’s high-
yielding synthesis, 1 was obtained in astounding 34% yield
from the Me ester of (S)-2-methyl-3-hydroxypropionic acid,
so-called (S)-“Roche ester”, in 13 steps in the longest linear
sequence via Cu-catalyzed cross-coupling of the triflate of
2,4,6,8-tetramethyl-1-undecanol with the Grignard reagent
derived from 1-bromo-5,7-dimethylundecane, which was
prepared in 8 steps also from (S)-“Roche ester”. The four
other asymmetric carbon centers were established off the
main synthetic sequences in 3 to 4 steps each. Thus, the total
number of synthetic steps must be at least 31. Its major
drawback is the stoichiometric use of relatively expensive
“Roche ester” twice and surprisingly expensive o-diphe-
nylphosphinobenzoic acid ($9,000/mol, Aldrich) four times
for the introduction of all six asymmetric carbon centers. In
this respect, catalytic asymmetric hydrogenation used in
Burgess’ synthesis of 14 is a fundamentally promising
method, provided that the cost-turnover factor can be made
realistically attractive. Although it is somewhat difficult to
collect all pertinent details from the Burgess reports,4 it can
be discerned that the overall number of synthetic steps must
exceed 30. Another fundamentally promising catalytic method
involving a Cu-catalyzed asymmetric conjugated addition that
has been applied to the synthesis of deoxypolypropionates9
(but not to that of 1) is also noteworthy, although its cost-
turnover number profile appears to require further improve-
ment as in the other cases.
Acknowledgment. We thank the National Institutes of
Health (GM 36792) and Purdue University for support of
this research. We also thank Mr. Zhihong Huang for his
assistance in the manuscript preparation.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra of the isolated pure
compuonds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL703056U
(9) Des Mazery, R.; Pullez, M.; Lo´pez, F.; Harutyunyan, R.; Minnard,
A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966-9967.
Org. Lett., Vol. 10, No. 6, 2008
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