Asymmetric construction of quaternary carbon centers by sequential conjugate addition of lithium amide and in situ alkylation: Utility in the synthesis of (-)-aspidospermidine

Article abstract of DOI:10.1021/ol802759j

(Chemical Equation Presented) Chiral diether ligand-controlled asymmetric conjugate addition of a lithium amide to cyclopentenecarboxylate and subsequent in situ alkylation gave a chiral cyciopentane derivative bearing a quaternary carbon with high enanti

Full text of DOI:10.1021/ol802759j

ORGANIC
LETTERS
2009
Vol. 11, No. 3
653-655
Asymmetric Construction of Quaternary
Carbon Centers by Sequential
Conjugate Addition of Lithium Amide
and in Situ Alkylation: Utility in the
Synthesis of (-)-Aspidospermidine
Mayuko Suzuki, Yoshito Kawamoto, Takeo Sakai, Yasutomo Yamamoto, and
Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received November 29, 2008
ABSTRACT
Chiral diether ligand-controlled asymmetric conjugate addition of a lithium amide to cyclopentenecarboxylate and subsequent in situ alkylation
gave a chiral cyclopentane derivative bearing a quaternary carbon with high enantio- and diastereoselectivity. The cyclopentane derivative
was converted successfully to (-)-aspidospermidine.
Synthetically useful asymmetric nitrogen-carbon bond
formations that are otherwise difficult to accomplish have
been achieved through conjugate addition reactions of both
chiral1 and achiral2 lithium amides to enoates.3 Since the
resulting lithium enolate intermediate is a powerful nucleo-
phile, subsequent in situ alkylation is quite promising. Thus,
potentially, useful one-pot transformations to produce adja-
cent asymmetric carbon centers with concomitant installation
of vicinal N-C and C-C bonds could be achieved.4 Of
particular interest is the asymmetric construction of quater-
nary carbons in tandem fashion. Given our success in the
development of chiral diether-mediated asymmetric conjugate
additions of lithium arylmethyl- and allyltrialkylsilylamides,5
we envisioned a tandem asymmetric conjugate addition-
alkylation strategy for the construction of a quaternary carbon
center. Herein, we describe a highly efficient enantioselective
construction of a quaternary carbon center with up to 97%
ee and over 98% de and the use of the product in the
asymmetric total synthesis of (-)-aspidospermidine.
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10.1021/ol802759j CCC: $40.75
Published on Web 12/30/2008
2009 American Chemical Society

Table 1. Tandem Asymmetric Conjugate Addition-Alkylationa
Scheme 1. Conversion of 4 to 5 and 6
entry
R-X
4
yield (%)
ee (%)
de (%)
1
2
3
4
PhCH2Br
H2CdCHCH2Br
EtIb
4a
4b
4c
4d
90
93
94
93
97
95
95
95
>98
>98
>98
>98
MeI
a All reactions were performed using 2 (3 equiv), 1 (3.6 equiv), and 3
(1 equiv). In the alkylation step, R-X (2 equiv) was used in entries 1, 2,
and 4. b For ethylation, EtI (10 equiv) and HMPA (6 equiv) were used.
N-oxide, and thermal Cope elimination8 in THF at 60 °C in
84% overall yield (Scheme 1). We also obtained olefin 6
from 4a via N-methylation, m-CPBA oxidation, and Cope
elimination9 with dialuminium trioxide10 in 33% overall
yield.
We began our studies with allylation of the lithium enolate
intermediate generated by conjugate addition of lithium
N-mesitylmethyl-N-TMS-amide 2 to tert-butyl cyclopenten-
ecarboxylate 3 in the presence of C2-symmetric chiral diether
1 in toluene at -78 °C (Table 1, entry 2).5d Treatment of a
toluene solution of this lithium enolate with allyl bromide
did not yield the expected allylation product 4b (R )
CH2CHdCH2), but instead yielded the conjugate addition
product 4 (R ) H) with 96% ee. Upon addition of THF to
a toluene solution of the lithium enolate at -78 °C, the
allylation process proceeded at -40 °C for 1 h, giving the
desired product 4b as nearly a single diastereomer in 92%
yield. However, the enantioselectivity dropped to 90% ee.
We overcame this problem by additional stirring at -60 °C
for 1.5 h during the conjugate addition step (to complete
the asymmetric conjugate addition, before the addition of
THF, which accelerates the racemic conjugate addition
reaction), giving the allylation product 4b with 95% ee and
over 98% de in 93% yield.
Asymmetric conjugate addition of lithium allylamide 75c
to 3 and in situ benzylation gave 8, which was then treated
without purification with aq HF for protodesilylation to
provide 9 (Scheme 2). Olefin isomerization of 9 with
Wilkinson’s catalyst in aqueous acetonitrile at reflux and
simultaneous hydrolysis of the imine gave primary amine 5
in 90% yield. In this benzylation, we obtained 9 with 98%
ee in 55% yield, which is in stark contrast to 85% ee for the
protonation product in the conjugate addition of 7.5c Kinetic
enantioenrichment in the benzylation step may be responsible
for this high enantioselectivity. In fact, almost complete
C-allylation and C-methylation gave the corresponding
products with 85% ee in reasonably high yields of 88% and
94%, respectively.
C-Benzylation and C-methylation also proceeded satis-
factorily to give the corresponding quaternary carbon prod-
ucts 4a (R ) Bn) and 4d (R ) Me) with up to 97% ee as
nearly single diastereomers (entries 1 and 4). C-Ethylation
with ethyl iodide required the coaddition of HMPA to give
the product 4c6 (R ) Et) with 95% ee in 94% yield (entry 3).
Ready conversion of the secondary amine product to the
primary amine was demonstrated by successively treating
4a with NCS for N-chlorination (87%); N-dibutylamino-DBU
for elimination to the imine, and; hydroxylamine for tran-
soximation (51%, two steps). These successive reactions gave
the ꢀ-amino acid derivative 5 (Scheme 1).5d,7
Scheme 2
.
Asymmetric Conjugate Addition of Allylamine and
Benzylation
Elimination of the amino function of 5 to give olefin 6
was also performed by sequential N-dimethylation with
formalin-sodium cyanoborohydride, m-CPBA oxidation to
The asymmetric total synthesis of aspidospermidine 18 has
been considered to be a touchstone of the methodology for
(6) The stereochemistry of asymmetric conjugate addition has been
reported in ref 5b. The relative configuration of 4c was assigned by an
NOE experiment. Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi,
M.; Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 3796–3798.
(8) Grainger, R. S.; Patel, A. Chem. Commun. 2003, 1072–1073.
(9) Albini, A. Synthesis 1993, 263–277.
(7) Katoh, T.; Watanabe, T.; Nishitani, M.; Ozeki, M.; Kajimoto, T.;
(10) Brand, M.; Drewes, S. E.; Loizou, G.; Roos, G. H. P. Synth.
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Node, M. Tetrahedron Lett. 2008, 49, 598–600
.
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Org. Lett., Vol. 11, No. 3, 2009

The ee of the ethylation product 4c (95% ee) was increased
to >99% ee in 85% recovery by recrystallization of its
hydrochloride from ethyl acetate. Successive methylation of
the hydrochloride salt of 4c, N-oxidation with m-CPBA, and
Cope elimination with Al2O3 in tert-butyl alcohol14 gave
olefin 11 in 65% yield along with 12 (11%) and 13 (11%).
Lithium aluminum hydride reduction of ester 11 to alcohol
14, TPAP oxidation to the aldehyde, Wittig olefination for
one-carbon elongation, hydrolysis to the aldehyde, and
sodium borohydride reduction gave alcohol 15 in 79% yield
(five steps from 11). These steps should be carefully carried
out because the products all have low boiling points and can
easily be distilled off. Oxidative cleavage of olefin 15 with
osmium tetroxide and sodium metaperiodate yielded a lactol,
which was then oxidized to δ-lactone 16, bearing three
differently oxidized oxygen functionalities15 in 85% yield.
Amide formation with lactone 16 and tryptamine in n-butyl
alcohol at reflux gave 17 in 75% yield. The remaining
transformations were a modification of the Harley-Mason’s
protocol. Sulfuric acid treatment of 17 induced Pictet-Spengler
cyclization. Simultaneous rearrangement occurred at reflux
for 2.5 h. Lithium aluminum hydride reduction in THF at
reflux for 1.5 h completed the synthesis of (-)-aspidosper-
midine 18 in 37% yield.16
Scheme 3. Total Synthesis of (-)-Aspidospermidine 18
In summary, we have developed an efficient method for
constructing a chiral quaternary carbon by tandem asym-
metric conjugate addition of a lithium amide to an enoate
and its subsequent in situ alkylation. Total synthesis of (-)-
aspidospermidine was successfully demonstrated as a touch-
stone of the strategic application of the asymmetric conjugate
amination-alkylation protocol.
the asymmetric construction of quaternary carbons.11,12 The
utility of the quaternary carbon product 4 was demonstrated
by the asymmetric total synthesis of (-)-18 (Scheme 3).13
(11) Reviews of total synthesis: (a) Saxton, J. E. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol. 51, Chapter 1.
(b) Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998, 327–340, and references
therein.
Acknowledgment. This research was partially supported
by a Grant-in-Aid for Young Scientists (B), a Grant-in-Aid
for Scientific Research in Priority Areas “Advanced Molec-
ular Transformations of Carbon Resources”, a Grant-in-Aid
for Scientific Research (A), and the Targeted Proteins
Research Program of the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. T.S. acknowledges
a JSPS fellowship.
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Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802759J
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