Asymmetric Cyclization via Memory of Chirality: A Concise Access to Cyclic Amino Acids with a Quaternary Stereocenter

Article abstract of DOI:10.1021/ja0378299

N-(ω-Bromoalkyl)-amino acid derivatives, readily prepared from natural α-amino acids, gave cyclic amino acids with a quaternary stereocenter by treatment with potassium hexamethyldisilazaide in DMF. The chirality of parent amino acids was almost completely preserved during an enolate-formation and cyclization process, giving aza-cyclic amino acids in up to 98% ee in retention of configuration. This method is applicable to the asymmetric synthesis of azetidine, pyrrolidine, piperidine, and azepane derivatives. The asymmetric cyclization seems to proceed via an axially chiral enolate intermediate and not through a concerted S_Ei process. Copyright

Full text of DOI:10.1021/ja0378299

Published on Web 10/04/2003
Asymmetric Cyclization via Memory of Chirality: A Concise Access to Cyclic
Amino Acids with a Quaternary Stereocenter
Takeo Kawabata,* Shimpei Kawakami, and Swapan Majumdar
Institute for Chemical Research, Kyoto UniVersity, Uji, Kyoto 611-0011, Japan
Received August 8, 2003; E-mail: kawabata@scl.kyoto-u.ac.jp
Scheme 1. Strategy for Asymmetric Cyclization
Table 1. Asymmetric Cyclization of 1
Cyclic amino acids are of increasing interest in the life-science
industry.1 Incorporation of these compounds into peptides induces
conformational constraint, and it provides an important tool for
studying the relationships between peptide conformation and
biological activity and for probing biological processes including
protein folding.2 Cyclic amino acids are useful building blocks for
natural product synthesis3 and are also key structural units of
catalysts for enantioselective synthesis.4 Cyclic amino acids with
a quaternary stereocenter constitute a new class of nonnatural amino
acids with an even more constrained conformation. The lack of
availability of these unusual amino acids from natural sources
necessitates the development of efficient methods for their synthe-
sis.5 The simplest and ideal access to these molecules seems to
involve direct intramolecular alkylation of R-amino acid derivatives
as shown in Scheme 1. However, such a route has rarely been
examined, probably because of the anticipated production of racemic
products due to a loss of chirality during the enolization step. In a
pioneering work in this field by Stoodley, the intramolecular
reaction of an axially chiral enolate with an electrophilic diazo group
gave 1,4,5-triazabicyclo-3-nonenes with retention of configuration.6
Recently, enantioselective â-lactam synthesis has been reported on
the basis of the memory effect of chirality of the parent amino
acids, albeit with a moderate enantiomeric excess.7 We report here
a simple and efficient method for asymmetric cyclization of amino
acid derivatives according to the strategy in Scheme 1. This provides
a novel access to a variety of aza-cyclic amino acids with a
quaternary stereocenter of high enantiomeric purity.
c
entry
basea
solvent
temp, time
2, yield (%)
2b, ee (%)
1
2
3
4
5
KHMDSd
KHMDSd
KHMDSd
LHMDSe
LTMPf
THF
-78 °C, 30 min
-78 °C, 2 h
-60 °C, 30 min
-60 °C, 30 min
-60 °C, 30 min
92
92
94
60
∼0
89
47
98
77
toluene
DMF
DMF
DMF
a 1.2 equiv of base was used. b The (S)-isomer was obtained in every
entry. See the Supporting Information. c Determined by HPLC analysis.
d Potassium hexamethyldisilazide. e Lithium hexamethyldisilazide. f Lithium
2,2,6,6-tetramethylpiperidide.
Table 2. Enantioselective Synthesis of Aza-cyclic Amino Acid
Derivatives with a Quaternary Stereocentera
To preserve chirality during enolate formation and subsequent
C-C bond formation, the choice of the protecting group on the
nitrogen of R-amino acids is critical.8,9 According to our previous
results on the intermolecular alkylation of R-amino acid derivatives,
where the N-tert-butoxycarbonyl (Boc) group is essential for the
generation of a chiral nonracemic enolate intermediate,8 N-Boc-
N-(3-bromopropyl)-phenylalanine derivative 1 was designed as a
substrate for asymmetric cyclization. Substrate 1 was readily
prepared from (S)-phenylalanine ethyl ester through N-alkylation
with 3-bromo-1-propanol, introduction of a Boc group to the
nitrogen, and conversion of the hydroxy group into bromine in 63%
overall yield without loss of enantiomeric purity (>99% ee).
The conditions for enantioselective cyclization of 1 were
examined (Table 1). Treatment of 1 with potassium hexamethyl-
disilazide (KHMDS) in THF at -78 °C gave R-benzylproline 2 in
89% ee and 92% yield. Whereas the corresponding reaction in
toluene gave 2 in 47% ee, the reaction of 1 in DMF gave 2 in 98%
ee and 94% yield with retention of configuration (entries 2 and 3).
Lithium amide bases such as lithium hexamethyldisilazide or lithium
2,2,6,6-tetramethylpiperidide gave worse results (entries 4 and 5).
Asymmetric cyclization via enantioselective intramolecular C-C
bond formation was examined with various amino acid derivatives
(Table 2). Treatment of tyrosine derivative 3 simply with KHMDS
in DMF at -60 °C for 30 min gave R-(4-ethoxyphenyl)methyl-
entry
substrate
n
R
product
yield (%)
ee (%)b
1
2
3
4
5
6
7
8
9d
1c
3
5
7
9
11
13c
15c
15c
3
3
3
3
3
2
4
5
5
PhCH2
2
4
6
8
10
12
14
16
16
94
95
92
78
91
61
84
31e
61f
98 (S)
97
97
94
95 (R)
95
97
83 (S)
72 (S)
4-EtO-C6H4-CH2
MeSCH2CH2
Me2CH
CH3
PhCH2
PhCH2
PhCH2
PhCH2
a A solution of substrate (0.25 mmol) in dry DMF (2.4 mL) was treated
with 1.2 mol equiv of KHMDS (0.50 M in THF) for 30 min at -60 °C,
unless otherwise mentioned. b The ee was determined by HPLC analysis.
The letter in the parentheses indicates the absolute configuration. See the
Supporting Information. c >99% ee. d The reaction was run for 2 h. e 15
(70% ee) was recovered in 52% yield. f 15 (54% ee) was recovered in 17%
yield.
proline derivative 4 in 97% ee and 95% yield (entry 2). Methionine
and valine derivative 5 and 7 gave R-substituted prolines 6 and 8
in 97% and 94% ee, respectively, by the same treatment (entries 3
and 4). Cyclization of alanine derivatives 9 via intramolecular
alkylation also proceeded in a highly enantioselective manner (95%
ee, entry 5). This is in contrast to the corresponding intermolecular
9
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J. AM. CHEM. SOC. 2003, 125, 13012-13013
10.1021/ja0378299 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. A Possible Mechanism for Asymmetric Cyclization
In conclusion, we have shown asymmetric cyclization of N-Boc-
N-ω-bromoalkyl-R-amino acid derivatives, where the chirality of
the parent amino acids is preserved to a high extent during enolate
formation and the subsequent C-C bond formation. Because of
the simplicity of the operation and wide applicability, this method
could provide useful access to nonnatural aza-cyclic amino acids
with a quaternary stereocenter from natural R-amino acids.
Acknowledgment. We thank Japan Society for the Promotion
of Science (JSPS) for financial support to S.M. (P02393).
Supporting Information Available: Experimental procedures and
characterization (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
reaction where the enantioselectivity in R-alkylation of an alanine
derivative is much lower than that with phenylalanine, tyrosine,
and valine derivatives.10 The enantioselective construction of four-,
six-, and seven-membered cyclic amino acids is also achieved by
this protocol. Treatment of 11, 13, or 15 with KHMDS in DMF at
-60 °C for 30 min gave azetidine (12), piperidine (14), or azepane
derivative (16) in 95%, 97%, or 83% ee, respectively (entries 6-8).
The stereochemical course of the cyclization of 1, 9, and 15 was
retention in each case.
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A possible mechanism for the asymmetric cyclization is shown
in Scheme 2. A conformational search of 1 gives two stable
conformers A and B.11 Deprotonation of conformer A with
KHMDS, where the C(R)-H bond is eclipsed with the N-C(CH2-
CH2CH2Br) bond, would give an enantiomerically enriched enolate
C with a chiral C-N axis,8b 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 due to
the steric interaction between KHMDS and the Boc group. This
hypothesis is consistent with the observed solvent effects, because
deprotonation of B via chelation of the Boc-carbonyl group with
potassium cation becomes more significant in a less coordinative
solvent such as toluene, resulting in decreased enantioselectivity
(Table 1, entries 1-3). An alternative mechanism may be a
concerted SEi process. Although we cannot exclude this possibility
at this time, we prefer the mechanism involving a chiral enolate
intermediate shown in Scheme 2 for several reasons. Enantiose-
lectivity in seven-membered ring formation depends on the reaction
time (Table 2, entries 8 and 9). This seems to be due to partial
racemization of a chiral enolate intermediate during relatively slow
seven-membered-ring cyclization. The ee of the recovered 15
indicates time-dependent racemization of the intermediary enolate
(Table 1, footnotes e and f).12
(9) For example, R-methylation of N-Boc-N-methyl phenylalanine derivatives
proceeds in up to 82% ee, while that of the corresponding N-formyl-N-
methyl derivative gives a racemic product; see ref 8a.
(10) Whereas R-methylation of N-Boc-N-methoxymethyl(MOM)-phenylalanine,
-tyrosine, and -valine derivatives proceeds in 81%, 79%, and 87% ee,
respectively (ref 8b), R-allylation of N-Boc-N-MOM-alanine derivative
proceeds in 33% ee (unpublished data). The low ee in the reaction of an
alanine derivative seems to be at least in part due to rapid racemization
of the chiral enolate intermediate during intermolecular alkylation. On
the other hand, the loss of enantiomeric purity of the chiral enolate is
minimized during rapid five-membered intramolecular alkylation, and it
gives 10 with high enantiomeric excess.
(11) The stable conformers A and B of 1 were generated by a molecular
modeling search with AMBER* force field with the GB/SA solvation
model for water using MacroModel V 6.0. The difference in potential
energies between A and B is estimated to be 0.1 kcal/mol. A PM3
calculation with a polarized continuum model (water, ꢀ ) 78.4) also gave
stable structures similar to A and B: (a) Still, W. C.; Tempczyk, A.;
Hawley, R. C.; Hendrickson, T. J. Am. Chem. Soc. 1990, 112, 6127-
6129; (b) J. Comput. Chem. 1991, 12, 620.
Support for this mechanism was obtained by the reaction of 17.
Upon cyclization by the standard procedure, 17 gave racemic-18.
This indicates the critical importance of a chiral enolate intermediate
for the asymmetric induction, because the enolate generated from
17 cannot be axially chiral along the C-N axis.
(12) The observed solvent effects in entries 1-3 of Table 1 seem not compatible
with the general features of a concerted SEi process. It has been reported
that a higher extent of inversion of stereochemistry is observed with more
polar solvents in SE2 reactions. See: Fukuto, J. M.; Jensen, F. R. Acc.
Chem. Res. 1983, 16, 177-184.
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