Stereochemical diversity in asymmetric cyclization via memory of chirality

Article abstract of DOI:10.1021/ja0670761

An enantiodivergent asymmetric cyclization of N-Boc-N-ω-bromoalkyl-α-amino acid derivatives has been developed. With potassium amide bases in DMF, cyclization proceeds with retention of configuration, while inversion of configuration was observed with lit

Full text of DOI:10.1021/ja0670761

Published on Web 11/09/2006
Stereochemical Diversity in Asymmetric Cyclization via Memory of Chirality
Takeo Kawabata,* Seiji Matsuda, Shimpei Kawakami, Daiki Monguchi, and Katsuhiko Moriyama
Institute for Chemical Research, Kyoto UniVersity, Uji, Kyoto 611-0011, Japan
Received October 3, 2006; E-mail: kawabata@scl.kyoto-u.ac.jp
Scheme 1. Stereochemical Diversity in Asymmetric Cyclization
The enantioselective construction of a chiral tetrasubstituted
stereocenter is one of the most challenging tasks in current synthetic
organic chemistry.1 We have developed a direct method for the
enantioselective construction of R,R-disubstituted R-amino acids
from R-amino acids via memory of chirality.2,3 Under these
conditions, R-methylation of N-tert-butoxycarbonyl(Boc)-N-meth-
oxymethyl(MOM)-R-amino acid derivatives takes place in up to
93% ee without the aid of external chiral sources such as chiral
auxiliaries or chiral catalysts.4 This protocol has been applied to
the asymmetric cyclization for straightforward synthesis of cyclic
amino acids with a tetrasubstituted stereocenter from R-amino
acids.5 We further developed a method for the asymmetric
construction of highly substituted nitrogen heterocycles via the
intramolecular conjugate addition of chiral enolates generated from
R-amino acids.6 We report here stereochemical diversity in asym-
metric cyclization as shown in Scheme 1. This provides a novel
access to both enantiomers of nitrogen heterocycles with a
tetrasubstituted stereocenter of high enantiomeric purity from readily
available L-R-amino acids.
A chiral nonracemic enolate A with a chiral C-N axis has been
proposed as the crucial intermediate for the asymmetric transforma-
tion via memory of chirality.2,4-6 Experimental evidence for A
involves the observation that R-alkylation of I and II gave racemic
products, respectively, under the standard conditions for asymmetric
alkylation via memory of chirality because the enolates generated
from these derivatives cannot be axially chiral along the C-N
axis.4,5
Table 1. Effects of Base and Solvent on the Stereochemical
Course for the Asymmetric Cyclization of 1
entry
basea
solvent
temp, time (h)
2, yield (%)
2, eeb (%)
1c
2c
3c
4c
5
6
7
8
9
KHMDSd
KHMDSd
KHMDSd
LHMDSe
LHMDSe
LTMPf
DMF
THF
toluene
DMF
THF
THF
THF
toluene
THF
-60 °C, 0.5
-78 °C, 0.5
-78 °C, 2
-60 °C, 0.5
-60 °C, 1
-60 °C, 1
20 °C, 0.5
20 °C, 0.5
20 °C, 0.5
94
92
92
60
10
73
93
90
69
98 (S)
89 (S)
47 (S)
77 (S)
14 (R)
41 (R)
91 (R)
77 (R)
82 (R)
LTMPf
LTMPf
LDA
a Reactions were run using 1.2 equiv of base. b Determined by HPLC
analysis. The letter in parentheses indicates the absolute configuration. For
determination of the absolute configuration, see ref 5. c Data quoted from
ref 5. d Potassium hexamethyldisilazide. e Lithium hexamethyldisilazide.
f Lithium 2,2,6,6-tetramethylpiperidide.
Scheme 2. A Hypothetical Scheme for Stereochemical Course of
Asymmetric Cyclization
We have reported that treatment of 1 with potassium hexa-
methyldisilazide (KHMDS) in DMF at -60 °C gave 2 in 98% ee
with retention of configuration (Table 1, entry 1).5 A rationale for
the stereochemical course is shown in Scheme 2. A conformation
search of 1 gives two stable conformers A and B.5 Deprotonation
of conformer A with KHMDS, where the C(R)-H bond is eclipsed
with the N-C(CH2CH2CH2Br) bond, via transition state X would
give an enantiomerically enriched enolate C with a chiral C-N
axis, which undergoes intramolecular alkylation to give 2 with a
total retention of configuration. Deprotonation of conformer B,
where the C(R)-H bond is eclipsed with the N-C(Boc) bond, to
give ent-C seems unfavorable because of the steric interaction
between KHMDS and the Boc group. This hypothesis is consistent
with the observed solvent effects, since deprotonation of B via
chelation of the Boc-carbonyl group with potassium cation (transi-
tion state Y) becomes more significant in less coordinative solvents,
resulting in decreased enantioselectivity (entries 1-3). This ob-
servation prompted us to investigate another hypothesis that
enforcing chelation by the use of a lithium cation should make
transition state Y dominant and give the product with inversion of
configuration. According to this hypothesis, we investigated the
asymmetric cyclization of 1 with lithium amide bases (entries 4-9).
Treatment of 1 with LHMDS in DMF gave (S)-2 with retention of
configuration in decreased enantioselectivity (entry 1 vs 4). The
use of LHMDS in a less coordinative solvent (THF) gave (R)-2
with inversion of configuration in 14% ee (entry 4 vs 5). Upon
treatment of 1 with LTMP in THF at -60 °C, (R)-2 was obtained
in 41% ee (entry 6). Surprisingly, the corresponding reaction at 20
°C gave (R)-2 in 91% ee and in 93% yield (entry 7).7 Against our
expectation, the use of toluene instead of THF did not increase the
enantioselectivity (entry 7 vs 8).8 Use of LDA also gave (R)-2 in
9
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J. AM. CHEM. SOC. 2006, 128, 15394-15395
10.1021/ja0670761 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantiodivergent Asymmetric Cyclizationa
Scheme 3. Enantiodivergent Intramolecular Conjugate Addition of
Chiral Enolates.
entry
substrate
base, solvent, temp
product
yield (%)
ee (%)b
1c
2
1
1
3
3
5
5
7
7
9
9
11
11
KHMDS, DMF, -60 °C
LTMP, THF, 20 °C
KHMDS, DMF, -60 °C
LTMP, THF, -20 °C
KHMDS, DMF, -60 °C
LTMP, THF, 20 °C
KHMDS, DMF, -60 °C
LTMP, THF, -20 °C
KHMDS, DMF, -60 °C
LTMP, THF, 0 °C
NaHMDS, THF, 20 °C
LHMDS, toluene, 0 °C
2
2
4
4
6
6
8
8
10
10
12
12
94
93
92
92
91
91
61
69
98
66
72
66
98 (S)
91 (R)
97 (S)
81 (R)
95 (R)
87 (S)
95 (R)
90 (S)
97 (S)
83 (R)
99 (R) d
94 (S) d
3c
4
5c
6
7c
8
9
In conclusion, we have developed an enantiodivergent asym-
metric cyclization of N-Boc-N-ω-bromoalkyl-R-amino acid deriva-
tives. With potassium or sodium amide bases in DMF or THF,
cyclization proceeds with retention of configuration, while inversion
of configuration was observed with lithium amide bases in THF or
toluene. Since high enantioselectivity was obtained in each
transformation, these methods provide a concise entry to both
enantiomers of cyclic amino acids with a tetrasubstituted stereo-
center from natural L-amino acids.9
10
11
12
a For experimental procedure, see Supporting Information. b The ee was
determined by HPLC analysis. The letter in parentheses indicates the
absolute configuration. For the determination of the absolute configuration,
see Supporting Information. c Data quoted from reference 5. d Notation
based on central chirality.
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research on Priority Areas “Advanced Molecular
Transformation of Carbon Resources” from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental procedures and
HPLC charts in Table 2; preparation and characterization of 9, 11, and
13; characterization of 10, 12, and 14; determination of the absolute
configuration of 4, 8, 10, and 12. This material is available free of
charge via the Internet at http://pubs.acs.org.
82% ee (entry 9), which is consistent with the hypoth-
esis.
The conditions for enantiodivergent cyclization have been applied
to various amino acid derivatives (Table 2). Five-membered
cyclization of 1, 3, and 5 with KHMDS in DMF at -60 °C gave
2, 4, and 6 in 98, 97, and 95% ee, respectively, with retention of
configuration (entries 1, 3, and 5). On the other hand, use of LTMP
in THF gave the cyclization products in 81∼91% ee with inversion
of configuration (entries 2, 4, and 6). Similar phenomena were
observed in four-membered cyclization. Treatment of 7 with
KHMDS in DMF at -60 °C gave 8 in 95% ee with retention of
configuration (entry 7), while that with LTMP at -20 °C gave 8
in 90% ee with inversion of configuration (entry 8). Four-membered
cyclization of methionine-derived analogue 9 showed similar
stereochemical results (entries 9 and 10). Five-membered spirocy-
clization showed somewhat different stereochemical behavior.
Treatment of 11 with KHMDS in DMF at -60 °C did not give 12,
due to the predominant â-elimination of HBr. Upon treatment of
11 with NaHMDS in THF at 20 °C, (R)-12 was obtained with
retention of configuration in 99% ee (entry 11). On the other hand,
treatment of 11 with LHMDS in toluene at 0 °C gave (S)-12 in
94% ee with inversion of configuration (entry 12).
The present protocol for enantiodivergent cyclization was applied
to intramolecuar conjugate addition of chiral enolates. We have
reported that treatment of 13 with KHMDS in DMF-THF (1:1) at
-78 °C gave 14 as a single diastereomer in 95% ee (Scheme 3,
(a)).6 The absolute configuration of 14 was tentatively assigned
based on the stereochemical course of asymmetric intramolecuar
conjugate addition via memory of chirality. Upon treatment with
LTMP in THF at 0 °C, 13 gave ent-14 as a single diastereomer in
91% ee. Thus, both enantioners of tetrahydroisoquinoline derivatives
with contiguous quarternary-tertiary stereocenters were readily
prepared from L-alanine.
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