Catalytic enantioselective Cr-Mediated propargylation: application to halichondrin synthesis

Article abstract of DOI:10.1021/ol9016595

A catalytic enantioselective propargylation In the presence of 10 mol % of Cr catalyst prepared from Cr(III) bromide and (R)-sulfonamide E furnishes homopropargyl alcohol 8 In 78% yield with 90% ee. Coupled with the workup based on Amano-llpase, this meth

Full text of DOI:10.1021/ol9016595

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4520-4523
Catalytic Enantioselective Cr-Mediated
Propargylation: Application to
Halichondrin Synthesis
Songbai Liu, Joseph T. Kim, Cheng-Guo Dong, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford
Street, Cambridge, Massachusetts 02138
kishi@chemistry.harVard.edu
Received July 21, 2009
ABSTRACT
A catalytic enantioselective propargylation in the presence of 10 mol % of Cr catalyst prepared from Cr(III) bromide and (R)-sulfonamide E
furnishes homopropargyl alcohol 8 in 78% yield with 90% ee. Coupled with the workup based on Amano-lipase, this method provides a
practical synthesis of optically pure 8 on a multigram scale. With maintenance of its optical purity, 8 has been converted to 1b, the C14-C19
building block of halichondrins and E7389, in two steps.
In the first-generation synthesis of halichondrin B, we
synthesized the C14-C26 building block from 2-deoxy-
L-arabinose diethyl thioacetal 4,5-acetonide in 17 steps
in approximately 20% overall yield (Scheme 1).1,2 This
synthesis used three C-C bond-forming reactions highlighted
in Scheme 1. Although lengthy, it served well for not only
the first-generation total synthesis of the halichondrins but
also the discovery and development of E7389.1,3 For the past
several years, we have been exploring a new synthetic route,
resulting in a concise and stereoselective synthesis of the
same building block. The new synthesis relied on three
catalytic asymmetric Cr-mediated couplings in a consecutive
manner (Scheme 1).4 With one chromatographic separation,
the new synthesis provides us with a stereochemically
homogeneous C14-C26 building block in six steps from
(t-Bu)(Ph)2SiO(CH2)3CHO.
We were pleased with the new synthesis in terms of
the overall yield and stereoselectivity, except for the
catalyst loading for the C19-C20 coupling (Scheme 2).
This bond was formed via a catalytic asymmetric Ni/Cr-
mediated coupling of 1a with 2 in the presence of the Cr
catalyst derived from (R)-sulfonamide A, with a useful
level of stereoselectivity (dr ) 22:1). However, this
(3) For discovery and development of E7389, see ref 5 in ref 2.
(4) For reviews on Cr-mediated carbon-carbon bond-forming reactions,
see: (a) Saccomano, N. A. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, p 173. (b)
Fu¨rstner, A. Chem. ReV. 1999, 99, 991. (c) Wessjohann, L. A.; Scheid, G.
Synthesis 1999, 1. (d) Takai, K.; Nozaki, H. Proc. Jpn. Acad. Ser. B 2000,
76, 123. (e) Hargaden, G. C.; Guiry, P. J. AdV. Synth. Catal. 2007, 349,
2407.
(5) Kim, D.-S.; Dong, C.-G.; Kim, J. T.; Guo, H.; Huang, J.; Tiseni,
P. S.; Kishi, Y. Submitted for publication.
(6) (a) Kurosu, M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126,
12248. (b) Zhang, Z.; Huang, J.; Ma, B.; Kishi, Y. Org. Lett. 2008, 10,
3073.
(1) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.;
Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am.
Chem. Soc. 1992, 114, 3162
(2) For isolation and synthesis on the halichondrins, see refs 1-
the preceding paper: Yang, Y.-R.; Kim, D.-S.; Kishi, Y. Org. Lett. 2009,
11, (DOI 10.1021/ol9016589)
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Originally, we planned to synthesize 1b from the vinyl
iodide alcohol 6, readily available via a catalytic enantio-
selective Co/Cr-mediated 2-haloallylation (Scheme 3).6
Scheme 1. Structure of Halichondrin B and C-C Bond-Forming
Sites in the Synthesis of C14-C26 Building Block. Panel I:
First-Generation Synthesis Using Three C-C Bond-Forming
Reactions Indicated.1 Panel II: New Synthesis Using Three
Catalytic Asymmetric Cr-Mediated Coupling Reactions Indicated5
Scheme 3. Attempted SN2 OH f Cl Substitution
However, we soon realized that the SN2 OH f Cl substitu-
tion is accompanied with partial racemization under various
conditions tested (Scheme 3). No literature precedent related
to the observed partial racemization was found.7 However,
because the corresponding homoallyl alcohols are known to
maintain the optical purity in the SN2 OH f Cl substitution,7
we speculated that the observed partial racemization might be
due to formation of the (partial) carbocation C stabilized via
participation of the lone pair electron of iodine. For this reason,
we modified the original plan to perform the SN2 OH f Cl
substitution on homopropargyl alcohol 8 (Scheme 4).
process required 20 mol % of the catalyst to maintain an
acceptable level of coupling rate. We speculated that the
poor catalyst loading might be attributed to the fact that
one of the OdS bonds of the sulfate group present in the
nucleophile 1a could coordinate to the Cr metal, cf. B in
Scheme 2, thereby slowing or shutting down the coupling.
Scheme 2.
New Synthesis of C14-C23 Building Block 3a
Among a number of methods reported for synthesis of
chiral homopropargyl alcohols,8,9 we were interested in a
catalytic enantioselective Cr-mediated propargylation of an
aldehyde with a propargyl halide, primarily because of the
directness of preparation. The work by Inoue and Nakada is
most relevant to the proposed catalytic enantioselective Cr-
(7) No literature example was found for the i f ii transformation where
X is I, Br, Cl, SR, and OR. To the contrary, examples are known to
demonstrate no racemization where X is H; for example, see: Clapp, C. H.;
Grandizio, A. M.; Yang, Y.; Kagey, M.; Turner, D.; Bicker, A.; Muskardin,
D. Biochemistry 2002, 41, 11504.
a Note that the SN2-cyclization of the C20-OH to the C17 carbon takes
place in situ.
(8) Carbonyl propargylations with allenylmetal reagents are well
established to synthesize chiral homopropargyl alcohols. For general reviews,
see, for example: (a) Denmark, S. D.; Fu, J. Chem. ReV. 2003, 103, 2763.
(b) Marshall, J. A.; Gung, B. W.; Grachan, M. L. In Modern Allene
Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim,
2004; Vol. 1, p 493. (c) Gung, B. W. Org. React. 2004, 64, 1. (d) Marshall,
J. A. J. Org. Chem. 2007, 72, 8153. Also see: Patman, R. L.; Williams,
V. M.; Bower, J. F.; Krische, M. J. Angew. Chem., Int. Ed. 2008, 47, 5220,
and references cited therein.
This notion encouraged us to study the Ni/Cr-mediated
coupling with the nucleophile bearing no OdS or OdC
bond, such as the chloride 1b. Experimentally, it was
found that the efficiency of Cr-mediated coupling, i.e.,
coupling rate and catalyst loading, was noticeably im-
proved in the 1b series (catalyst loading: e10 mol %)
over the 1a series (catalyst loading: g20 mol %),
while the same level of the asymmetric induction was
maintained.5
(9) For enantioselective propargylations with a propargyl halide in the
presence of low-valent metal, see: (a) Bandini, M.; Cozzi, P. G.; Umani-
Ronchi, A. Polyhedron 2000, 19, 537. (b) Bandini, M.; Cozzi, P. G.;
Melchiorre, P.; Tino, R.; Umani-Ronchi, A. Tetrahedron Asymmetry 2001,
12, 1063. (c) Loh, T.-P.; Lin, M.-J.; Tan, K.-L. Tetrahedron Lett. 2003,
44, 507.
Org. Lett., Vol. 11, No. 20, 2009
4521

or comparable with, that of (R)-sulfonamide D.13 Among
them, (R)-sulfonamide E was found to be the best ligand in
terms of the asymmetric induction, although the coupling
yield was modest (65%). In order to improve the coupling
efficiency, we then attempted various modifications on the
coupling conditions used for allylation/2-haloallylation and
eventually found that addition of LiCl significantly improves
the coupling yield. The mechanistic explanation for the LiCl
effect is not clear at this time. However, we should note that
addition of LiCl slightly slows down the coupling rate.
With this modification, it is now possible to prepare 8 in
approximately 80% yield with 90% ee in a multigram scale
with excellent reproducibility (Scheme 4).14 It is worthwhile
adding that sulfonamide E can be recovered in at least 50%
yield (80% before recrystallization) by simple operation.
To reveal the scope and limitation, we studied the catalytic
asymmetric propargylation on representative aliphatic and
aromatic aldehydes in the presence of the Cr catalysts (10
mol %) derived from two sulfonamides D and E (Table 1).
Not surprisingly, it was found that the Cr catalyst derived
from E performs well for aliphatic aldehydes with no
R-substituent (see entries 1-3). Interestingly, unlike the
2-haloallylations,6b the Cr catalysts derived from both E and
D recognize the chirality of the ꢀ-methyl group present in
(S)- and (R)-citronellals (entries 4a,b and 5a,b). For R-sub-
stituted aliphatic aldehydes, the Cr catalyst derived from D
gives a better result than the catalyst from E (entries 6 and
7). Overall, the Cr catalysts derived from E and D match
well with aliphatic aldehydes. However, their performance
on benzaldehyde and trans-cinnamaldehyde is slightly lower
than, or comparable with, that by Nakada’s catalyst (entries
8 and 9).10
In order to use the reported catalytic asymmetric reaction
for the preparative purposes, it is important to have a practical
means to enrich the optical purity of 8. To achieve this goal,
we took two different approaches. First, we attempted to
convert 8 into a crystalline derivative suitable for fractional
recrystallization, but with no significant success.15 Second,
we tested use of Amano lipase to discriminate 8 from its
enantiomer at either esterification or saponification. Eventu-
ally, it was found that the acetate derived from only (S)-8 is
hydrolyzed by Amano lipase PS-800 to furnish optically pure
(S)-8, readily separable from the remaining acetate via
filtration through a silica gel plug. Amano lipase PS-800 was
found to be equally effective for the crude acetate directly
prepared from the crude product obtained in the catalytic
enantioselective Cr-mediated propargylation. Thus, the step
of lipase-based optical purity enrichment was coupled with
the workup of the catalytic enantioselective Cr-mediated
Scheme 4. New Synthesis of C14-C19 Building Block
mediated propargylation; with use of carbazole-based ligands,
they demonstrated that the catalytic enantioselective Cr-
mediated propargylation is a valuable synthetic method.10
We were encouraged with their propargylation of hex-
anal because of its structural similarity to the aldehyde 5.
However, we wished to improve its overall efficiency (55%
yield; 58% ee). In particular, considering a possible mecha-
nistic similarity between Cr-mediated propargylation and
allylation/2-haloallylation, we were anxious to test the
sulfonamide ligand developed for catalytic enantioselective
Cr-mediated 2-haloallylation and allylation in this laboratory.6b
In the presence of the Cr catalyst prepared from CrBr3
and the (R)-sulfonamide D (Scheme 4),6b catalytic enanti-
oselective propargylation of 5 with propargyl bromide (7)
proceeded smoothly to furnish 8 in 83% yield with 87% ee.
1
The optical purity of 8 was estimated from a H NMR
analysis of its Mosher ester, and on the basis of the previous
examples,6 the absolute configuration was predicted as
indicated and then confirmed by a chemical correlation with
the authentic sample prepared via a different route.11
As shown for the allylation/2-haloallylation, this reaction
was easy to scale up. Unlike the allylation/2-haloallylation,
however, the asymmetric induction of this process varied
between 80% and 87%. Despite extensive efforts, we were
unable to establish an experimental protocol to reproducibly
perform the coupling at the level of 87% ee. Under this
circumstance, we shifted our focus to search for a new
sulfonamide ligand.
(12) Guo, H.; Dong, C.-G.; Kim, D.-S.; Urabe, D.; Wang, J.; Kim, J. T.;
Liu, X.; Sasaki, T.; Kishi, Y. Submitted for publication.
Using the ligand-optimization strategy recently devel-
oped,12 we searched for an alternative ligand within the pool
of chiral sulfonamides, whose performance is better than,
(13) These included the following sulfonamides: R1 ) t-Bu/R2 ) 3,5-
(CF3)2Ph//R3 ) (OMe)3 (er ) 20:1, 65% yield); R1 ) t-Bu/R2
)
3,5-(CF3)2Ph/R3 ) OPh (er ) 17:1, 68% yield); R1 ) t-Bu/R2 ) 3,5-
(CF3)2Ph/R3 ) OMe (er ) 15:1, 65% yield); R1 ) t-Bu/R2 ) 3,5-(Cl)2Ph/
R3 ) (OMe)3 (er ) 15:1, 73% yield); R1 ) t-Bu/R2 ) 3,5-(Cl)2Ph/R3 ) F
(er ) 11:1, 80% yield); R1 ) t-Bu/R2 ) 3,5-(CF3)2Ph/R3 ) F (er ) 11:1,
80% yield).
(10) Inoue, M.; Nakada, M. Org. Lett. 2004, 6, 2977.
(11) Chiral homopropargyl alcohol 8 was synthesized via addition of
TMS-acetylene anion to chiral epoxide obtained through Jacobsen’s
hydrolytic kinetic resolution of racemic epoxide: Tokunaga, M.; Larrow,
J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936.
(14) For details, see the Supporting Information.
(15) Propargyl alcohol derivatives, including 4-acetylphenylurethane,
were tested.
4522
Org. Lett., Vol. 11, No. 20, 2009

Table 1. Catalytic Asymmetric Cr-Mediated Propargylationsa
entry
R1
sulfonamide
yieldb (%)
ee or dec (%)
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
8a
8b
9a
9b
-CH2CH2CH2OTBDPS
E
D
E
D
E
D
E
D
E
D
E
D
E
D
E
D
E
D
78
85
82
81
91
94
70
81
73
86
67
88
55
75
80
92
84
89
90
83
81
67
89
72
93
93
80
84
78
90
92
73
46
73
51
70
-CH2CH2CH2CH2Me
-CH2CH2C6H5
-CH2CH(Me)CH2CH2CHdC(Me)2-S
-CH2CH(Me)CH2CH2CHdC(Me)2-R
-(CH2)6-c
-C(Me)3
-C6H5
-CHdCHC6H5-E
a All reactions were performed with CrBr3 (10 mol %) and D or E (11 mol %) at 0 °C. On the basis of the previous examples,6 the absolute configuration
of the major product was predicted as indicated and confirmed from the 1H NMR analysis of Mosher esters. b Yields based on chromatographically isolated
c
1
products. Ee and de were estimated by H NMR analysis of its Mosher ester. For details, see the Supporting Information.
propargylation to furnish optically pure (S)-8 in 73% overall
yield from 5 (5 g scale).16 Overall, the catalytic enantiose-
lective Cr-mediated propargylation provides us with a
practical and scalable synthesis of (S)-8.14
In summary, we have reported a catalytic enantioselective
Cr-mediated propargylation in the presence of 10 mol % of
Cr catalyst prepared from Cr(III) bromide and (R)-sulfon-
amide E to furnish homopropargyl alcohol 8 in 78% isolated
yield with 90% ee. Coupled with the workup based on
Amano lipase, this method provides us with a practical route
to obtain optically pure (S)-8 in 73% overall yield from 5 in
a multigram scale. (S)-8 is then transformed to optically pure
1b, the C14-C19 building block of halichondrins and E7389.
With optically pure homopropargyl alcohol (S)-8 in hand,
we studied the SN2 OH f Cl substitution, which was
uneventfully achieved on treatment with trichloroacetamide
and triphenylphosphine.17 Upon treatment with 9-iodo-9-
borabicyco[3.3.1]nonane (B-iodo-9-BBN),18 the terminal
acetylene in 9 was cleanly converted to the corresponding
vinyl iodide 1b. As mentioned previously, our concern was
the optical purity of 1b obtained from (S)-8. Among several
methods studied, HPLC analyses on a chiral column of the
4-acetylphenyl urethane of 1b gave the most reliable result.19
With this method, we demonstrated no detectable loss of
the optical purity in the process of 8 f 9 f 1b.
Acknowledgment. Financial support from the National
Institutes of Health (CA 22215) and Eisai Research Institute
is gratefully acknowledged.
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL9016595
(16) Amano lipase PS-800 was found effective to obtain the optically
pure (S)-8 (42% isolated yield) from the racemic homopropargyl acetate,14
prepared via propargylation of 5 in the presence of 1 mol % of 3,3′-dimethyl-
2,2′-dipyridyl-Cr(III) complex, followed by acetylation: Namba, K.; Wang,
J.; Cui, S.; Kishi, Y. Org. Lett. 2005, 7, 5421.
(19) The optical purity of 1b was determined via HPLC analysis (OJ-H
chiral column) of 4-acetylphenylurethane iii prepared from 1b. For details,
see the Supporting Information.
(17) Pluempanupat, W.; Chavasiri, W. Tetrahedron Lett. 2006, 47, 6821.
(18) (a) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett.
1983, 24, 731. For a review, see: Suzuki, A. ReV. Heteroatom Chem. 1997,
17, 271.
Org. Lett., Vol. 11, No. 20, 2009
4523