Catalytic, efficient, and syn-selective construction of deoxypolypropionates and other chiral compounds via Zr-catalyzed asymmetric carboalumination of allyl alcohol

Article abstract of DOI:10.1021/ja0530974

An efficient, syn-selective, all catalytic asymmetric protocol for the synthesis of α,ω-diheterofunctional deoxypolypropionates via Zr-catalyzed asymmetric carboalumination (ZACA reaction) was developed. The success of the method critically hinges on the

Full text of DOI:10.1021/ja0530974

Published on Web 02/07/2006
Catalytic, Efficient, and syn-Selective Construction of Deoxypolypropionates
and Other Chiral Compounds via Zr-Catalyzed Asymmetric Carboalumination
of Allyl Alcohol
Bo Liang, Tibor Novak, Ze Tan, and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
Received May 11, 2005; E-mail: negishi@purdue.edu
Scheme 1
Herein reported is an all-catalytic syn-selective asymmetric
protocol for the synthesis of deoxypolypropionates, especially those
that are R,ω-diheterofunctional, and other chiral compounds. The
crucial transformation involves a novel “one-pot” conversion of
inexpensive allyl alcohol to TBS-protected (R)- or (S)-3-iodo-2-
methyl-1-propanol (1)1 via (i) Zr-catalyzed asymmetric carboalu-
mination2 (ZACA reaction hereafter), (ii) in situ iodinolysis, and
(iii) in situ protection with tBuMe2SiCl. The entire one-pot reaction
proceeds to give either R or S isomer of 1 in 82% isolated yield by
using (-)- or (+)-(NMI)2ZrCl2,3 respectively. (R)- or (S)-3-Iodo-
Scheme 2 a,b
2-methyl-1-propanol (2) can also be readily isolated, and its Mosher
ester analysis has indicated its enantiomeric purity to be 91% (or
82% ee). Treatment of (S)-2 with vinyl acetate in THF-H2O in
the presence of Amano PS lipase (32 mg/mmol of 2)4 at 23 °C for
8.5 h readily improved the stereoisomeric purity to 98% ee (68%
recovery at 25% conversion). It was also practical to convert (R)-2
of 82% ee into its acetate of 98% ee in 68% recovery (75%
conversion) by using the same procedure. The results discussed
above are summarized in Scheme 1.
For the synthesis of deoxypolypropionates and other chiral
compounds containing two or more asymmetric carbon centers,
crudely isolated 1 may be used without purification for the synthesis
of isomerically pure compounds, as reported earlier1,5 and further
Scheme 3
elaborated later in this paper. In addition to the Pd-catalyzed
vinylation of 1 to give 3 in 87 or 71% in two steps from allyl
alcohol, several additional Pd-catalyzed cross-coupling reactions7
with differently substituted alkenyl, aryl, trimethylsilylethynyl (to
give 4), benzyl, and acyl halides have been achieved in high yields,
as shown in Scheme 2. No stereoisomerization has been detected
in these transformations.
Behind all these favorable results are numerous unsatisfactory
reactions, of which the following are worth mentioning. (1)
Iodinolysis of the in situ generated isoalkylalane leading to the
corresponding 2-methyl-4-alken-1-ols of about 75% ee.9 It then
occurred to us that the unsubstituted and symmetrical parent 1,4-
pentadiene could undergo facile racemization via cyclic intra-
molecular carbometalation to generate an unstable and achiral
cyclobutylcarbinylmetal derivative 6.10 Accordingly, (1E,4E)-1,5-
dideuterio-1,4-pentadiene (ca. 80-85% D incorporation) was
prepared and subjected to the ZACA reaction. Scrambling of only
the D atom of that vinyl group which participated in the ZACA
reaction was observed to a considerable extent, and it was more or
less evenly distributed at C1 and C3, even though the starting diene
was only 80-85% dideuterated and 13C NMR analysis of C1 was
not very accurate due to signal overlapping. It is nevertheless
unmistakably clear that the ZACA reaction is accompanied by a
skeletal rearrangement that is consistent with the mechanism
proposed in Scheme 4.
synthesis of 1 and 2 in high yields was a crucial finding since neither
oxidation nor protonolysis of the isoalkylalane intermediate would
lead to chiral products. To avoid the loss of chirality, TBS- or
TBDPS-protected allyl alcohol was initially used. The four-step
synthesis of 3 shown in eq 1 of Scheme 3 is not only cumbersome
but of lower stereoselectivity (74-75% ee), suggesting that the Me2-
AlO group in the allylic position (Scheme 1) must exert a minor
but unmistakably favorable effect on stereoselectivity. (2) Attempts
to prepare 3 via one-pot ZACA-Pd-catalyzed vinylation6 of allyl
alcohol without going through iodinolysis and zincation have thus
far failed to yield useful results. (3) Also attempted was a one-step
synthesis of 2-methyl-4-penten-1-ol (5) from 1,4-pentadiene. The
use of a 5-fold excess of 1,4-pentadiene in the ZACA reaction with
Me3Al and either (+)- or (-)-(NMI)2ZrCl2 followed by oxidation
with O2 did produce 5 in 80% yield based on Me3Al. To our
surprise, however, it was found to be 0% ee,8 even though several
other 1,4-diene derivatives had reacted normally to produce the
Although some promising routes to deoxypolypropionates and
other related chiral compounds via catalytic asymmetric C-C bond
9
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J. AM. CHEM. SOC. 2006, 128, 2770-2771
10.1021/ja0530974 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
Scheme 7
Although the ZACA reaction by itself has failed to provide
convenient routes to enantiomerically pure chiral compounds of
g98-99% ee containing just one asymmetric carbon atom, the
ZACA-lipase-catalyzed acetylation tandem protocol (Scheme 1) has
now provided a convenient solution to this pending issue, as
exemplified by the synthesis of g98% pure 13, which can serve as
a potential intermediate for the synthesis of callystatin A (14),20
from (S)-2 of 98% ee in 49% yield over six steps (Scheme 7).21
Scheme 5
Acknowledgment. We dedicate this paper to the memory of
Professor Herbert C. Brown. We thank the National Institutes of
Health (GM 36792), the National Science Foundation (CHE-
0309613), and Purdue University for financial support.
Scheme 6 a
Supporting Information Available: Detailed experimental pro-
cedures and compound characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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missing piece for rounding out the development of the ZACA-
based all-catalytic asymmetric method for the synthesis of deoxy-
polypropionates and many other related chiral organic compounds
developed over the past several years.5,6,16,17 Since the ZACA
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(syn/anti ) 13/1) than anti-selective (anti/syn ) 8/1),1 the new
protocol herein reported nicely complements an anti-selective
styrene-based protocol reported recently.6
To demonstrate its synthetic utility, a key intermediate 7 in a
recently reported synthesis18b of doliculide (8)18 preparable via 91
and a major acid component of a preen-gland wax of the graylag
goose, Anser anser, that is, all-(R)-2,4,6,8-tetramethyldecanoic acid
(10),19 were chosen, and their syntheses were performed as
summarized in Schemes 5 and 6, respectively. In our previously
reported partially catalytic synthesis of 9,1 methyl (S)-3-hydroxy-
2-methylpropionate was converted to 9 in 11.5% yield over eight
steps and two chromatographic operations. The same compound 9
(dr ) 43/1, >99% ee) can now be prepared in mere four isolation
steps and one chromatographic purification from allyl alcohol in
25% overall yield (Scheme 5).
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vinylation followed by the third (+)-ZACA reaction and oxidation
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to give a 12/1.3/1 diastereomeric mixture in 20% yield from 3.
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