Asymmetric construction of three contiguous stereogenic centers by conjugate addition-alkylation of lithium ester enolate

Article abstract of DOI:10.1021/ol900447n

A chiral ligand- and lithium amide-assisted asymmetric conjugate addition of lithium enolate of propionate to cyclopentenecarboxylate gave the corresponding lithium enolate, whose allylation gave the key intermediate of the marine alkaloid halichlorine as

Full text of DOI:10.1021/ol900447n

ORGANIC
LETTERS
2009
Vol. 11, No. 9
2007-2009
Asymmetric Construction of Three
Contiguous Stereogenic Centers by
Conjugate Addition-Alkylation of
Lithium Ester Enolate
Yasutomo Yamamoto, Yorinobu Yasuda, Hiroyuki Nasu, and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received March 3, 2009
ABSTRACT
A chiral ligand- and lithium amide-assisted asymmetric conjugate addition of lithium enolate of propionate to cyclopentenecarboxylate gave
the corresponding lithium enolate, whose allylation gave the key intermediate of the marine alkaloid halichlorine as a single diastereomer with
moderate enantioselectivity.
Efficient construction of contiguous stereogenic centers is a
challenging pursuit in organic synthesis.1 An asymmetric
conjugate addition-alkylation sequence is a powerful method
that installs two new C-C bonds and multiple stereocenters in
a single operation.2,3 Lithium enolates are useful in this
context. We recently reported a highly enantioselective
conjugate addition of lithium ester enolate to acyclic enoates
assisted by a chiral diether ligand and lithium amide, giving
synthetically useful functionalized 1,5-diesters.4 We describe
herein the asymmetric construction of three contiguous
stereogenic centers by a tandem conjugate addition-alkylation
reaction of lithium ester enolate of propionate and its
application to the synthesis of azaspirobicyclic core of the
marine alkaloid halichlorine (1), isolated from the marine
sponge Halichondria okadai Kadota in 1996 by Uemura and
co-workers (Figure 1).5 The related natural products, pinnaic
Figure 1. Halichlorine (1), pinnaic acid (2), and tauropinnaic acid
(1) (a) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1–21. (b) Enders,
D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570–
1581. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134–7186. (d) Ramo´n, D. J.; Yus, M. Angew. Chem.,
Int. Ed. 2005, 44, 1602–1634. (e) Nicolaou, K. C.; Montagnon, T.; Snyder,
S. A. Chem. Commun. 2003, 551–564. (f) Tietze, L. F. Chem. ReV. 1996,
96, 115–136.
(3).
acid (2) and tauropinnaic acid (3), were also isolated by the
same research group from the Okinawan bivalve Pinna
10.1021/ol900447n CCC: $40.75
Published on Web 04/08/2009
 2009 American Chemical Society

muricata.6 Their complex spirobicyclic structures and sig-
nificant biological properties, including selective inhibition
of the induction of vascular cell adhesion molecule-1
(halichlorine) and inhibition of a cytosolic phospholipase
cPLA2 (pinnaic and tauropinnaic acids), are of interest to
synthetic chemists.7 Asymmetric8 and racemic9 total syn-
theses of 1-3 have been reported by some research groups.
Efficient construction of the characteristic structural feature,
an azaspirobicyclic core, is key for the synthesis of these
alkaloids.10,11
Table 1. Tandem Asymmetric Conjugate Addition-Alkylationa
Our synthetic strategy begins with the addition of the
lithium enolate 4 of propionate to cyclopentenecarboxylate
5 that would proceed by keeping the methyl group of 4 away
from the cyclopentene moiety of 5 to give enolate 6, whose
allylation was expected to proceed trans to the introduced
propionate, giving adduct 7 with three contiguous stereogenic
centers of 1.12 Subsequent Curtius rearrangement and reduc-
tion of the ester groups would give the synthetic precursor
8 of 1, as reported by Danishefsky’s group (Scheme 1).8a-c,13
entry
lithium amide
yield/%
ee/%
de/%
1b
2
3
none
i-Pr2NLi
i-Pr(c-Hex)NLi
(c-Hex)2NLi
54
57
74
50
37
56
64
50
>98
>98
>98
>98
4
a Enolate 4 was prepared from the corresponding ester and lithium amide.
All reactions were performed using 4 (1.3 equiv), 9 (1.7 equiv), and LiNR2
(1.3 eqiv). In the alkylation step, allyl bromide (4 equiv) and HMPA (4
equiv) were used. b Asymmetric conjugate addition was performed at -50
°C for 1 h and -40 °C for 4 h. The alkylation step was performed at -40
to 0 °C for 5 h.
Scheme 1. Synthetic Strategy
with greater than 99% ee in 72% yield. Curtius rearrangement
of 10 with DPPA (diphenylphosphoryl azide) gave isocy-
anate,15 which was inert to a nucleophilic addition of t-BuOH
under refluxing conditions. The addition of TMSCl16 was
effective to give Boc-amide 11 in 93% yield from 7 in two
steps. Reduction of the ester group with NaBH4 in DMSO
followed by protection with TBDPSCl gave the established
intermediate 8.13 The stereochemistry of 8 was confirmed
by spectroscopic data and the specific rotation of 12, which
(5) Kuramoto, M.; Tong, C.; Yamada, K.; Chiba, T.; Hayashi, Y.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3867–3870.
(6) Tong, C.; Kuramoto, M.; Otani, Y.; Shikano, M.; Yazawa, K.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3871–3874.
(7) Clive, D. L. J.; Yu, M.; Wang, J.; Yeh, V. S. C.; Kang, S. Chem.
ReV. 2005, 105, 4483–4514.
(8) Halichlorine: (a) Trauner, D.; Schwarz, J. B.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 1999, 38, 3542–3545. Pinnaic acid: (b) Carson,
M. W.; Kim, G.; Hentemann, M. F.; Trauner, D.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2001, 40, 4450–4452. (c) Carson, M. W.; Kim, G.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4453–4456. (d) Wu,
H.; Zhang, H.; Zhao, G. Tetrahedron 2007, 63, 6454–6461. (e) Xu, S.;
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2004, 101, 12079–12084. (b) Hayakawa, I.; Arimoto, H.; Uemura, D.
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The lithium ester enolate 4 was prepared by R-deproto-
nation of 2,4-dimethylpentan-3-yl propionate with LDA, and
(Z)-enolate was expected to be predominantly generated.14
The addition of 4 to 5 in THF proceeded smoothly, and after
alkylation, the addition product 7 was obtained in 74% yield
as a single diastereomer. The asymmetric reaction in the
presence of chiral ligand 9 in toluene was not efficient and
gave 7 in only 37% ee. The lithium amide-assisted asym-
metric conjugate addition of 4 to 5 in the presence of i-Pr(c-
Hex)NLi (lithium N-isopropyl-N-cyclohexylamide) and ligand
9 proceeded even at -78 °C and gave addition product 7
with 64% ee in 74% yield (Table 1).4
(10) Recent studies: (a) Hurley, P. B.; Dake, G. R. J. Org. Chem. 2008,
73, 4131–4138. (b) Keck, G. E.; Heumann, S. A. Org. Lett. 2008, 10, 4783–
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Production of carboxylic acid with TFA and optical
resolution by (S)-1-phenethylamine gave carboxylic acid 10
(12) Pilli’s group also reported a tandem Michael addition-enolate
alkylation strategy for racemic synthetic studies of halichlorine: de Sousa,
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2008
Org. Lett., Vol. 11, No. 9, 2009

was prepared by hydroboration of 8 followed by the Suzuki
coupling reaction, to be opposite that of natural halichlorine
(Scheme 2).13
Scheme 3. Construction of the Tricyclic Core of Halichlorine
Scheme 2. Formal Synthesis of (-)-Halichlorine
asymmetric conjugate addition of a lithium enolate to an
enoate and subsequent in situ alkylation. Formal synthesis
and construction of the tricyclic core of halichlorine suc-
cessfully exemplified the strategic application of the asym-
metric conjugate addition-alkylation protocol.
Next, we studied the construction of the tricyclic core
structure of halichlorine 1 (Scheme 3). Hydroboration and a
Suzuki coupling reaction of 8 with dienyl iodide 13, followed
by removal of the Boc group, gave cyclized product 14 in
74% yield in two steps. The next stage was amide formation
between the secondary amine and the ester moiety. Heating
of 14 in refluxing toluene did not give the desired amide
and resulted in recovery of the starting material. After
reduction of the double bond of 14, we again tried the amide
formation. Treatment of 15 with NaOEt in EtOH did not
give the desired lactam 16; instead, monosaponification
proceeded. KOH treatment also gave monosaponificated
product, and subsequent condensation of the amine with the
carboxylic acid gave lactam 16 with a tricyclic core of
halichlorine.
Acknowledgment. This research was partially supported
by a Grant-in-Aid for Young Scientist (B) from JSPS, a
Grant-in-Aid for Scientific Research on Priority Areas
“Advanced Molecular Transformations of Carbon Re-
sources”, a Grant-in-Aid for Scientific Research (A) from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan, and “Targeted Proteins Research Pro-
gram” from Japan Science and Technology Agency.
Supporting Information Available: Experimental details
and characterization data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
In summary, we developed an efficient method of con-
structing three contiguous chiral stereocenters by tandem
OL900447N
Org. Lett., Vol. 11, No. 9, 2009
2009