Asymmetric carbonyl migration of α-amino acid derivatives via memory of chirality

Article abstract of DOI:10.1055/s-0030-1259324

N-tert-Butoxycarbonylcarbamates of α-amino acid derivatives underwent asymmetric carbonyl migration by treatment with KHMDS in DMF to give α-amino acid derivatives with an additional ester group at the newly formed tetrasubstituted carbon center in up to 99% ee. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259324

LETTER
543
Asymmetric Carbonyl Migration of a-Amino Acid Derivatives via Memory
of Chirality
Asymmetric
C
u
arbonyl Mig
m
ration iteru Teraoka,a Kaoru Fuji,a Orhan Ozturk,b Tomoyuki Yoshimura,b Takeo Kawabata*b
a
Faculty of Pharmacy, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
Fax +81(774)383197; E-mail: kawabata@scl.kyoto-u.ac.jp
b
Received 4 December 2010
CO2Et
N
CO2Et
Abstract: N-tert-Butoxycarbonylcarbamates of a-amino acid de-
rivatives underwent asymmetric carbonyl migration by treatment
with KHMDS in DMF to give a-amino acid derivatives with an ad-
ditional ester group at the newly formed tetrasubstituted carbon cen-
ter in up to 99% ee.
R
KHMDS, DMF
or KOH, DMSO
R
N
Br
Boc
Boc
retention
up to 99% ee
Key words: amino acids, chirality, stereoselectivity, tetrasubstituted
carbon, carbonyl migration
OK
Br
EtO
N
Boc
R
We have studied asymmetric alkylation and conjugate ad-
dition via memory of chirality.1–5 This asymmetric trans-
formation was proposed to proceed via axially chiral
enolate intermediates without the need of external chiral
sources such as chiral auxiliaries or chiral catalysts. For
the generation of the axially chiral enolates, the choice of
the nitrogen substituents is critically important. For exam-
ple, treatment of N-tert-butoxycarbonyl-N-w-bromoalkyl
a-amino acid derivatives (tert-butoxycarbonyl = Boc)
with bases generates axially chiral enolates, which under-
go intramolecular alkylation to give amino acid deriva-
tives with a tetrasubstituted carbon center in up to 99% ee
(Scheme 1).2 In the course of our studies on chemistry of
axially chiral enolates, we found that N-tert-butoxycarbo-
nylcarbamates of a-amino acid derivatives underwent
asymmetric carbonyl migration to give a-amino acid de-
rivatives with an additional ester group at the newly
formed tetrasubstituted carbon in up to 99% ee
(Scheme 2). Here, we describe the preliminary aspects of
the present asymmetric transformation and its stere-
ochemical course.
Scheme 1 Our previous work on asymmetric alkylation via an axi-
ally chiral enolate intermediate
R1
R2
CO2Bn
O
R1
CO2Bn
KHMDS
DMF
R2HN
N
Ot-Bu
CO2t-Bu
O
O
inversion
up to 99% ee
Scheme 2 Present work on asymmetric carbonyl migration via me-
mory of chirality
CO2Bn
O
i) allyl bromide, i-Pr2NEt Ph
Ph
CO2Bn
N
ii) (Boc)2O (1.2 equiv)
DMAP (0.1 equiv)
MeCN, r.t., 30 min
Ot-Bu
NH3+ TsO-
O
O
1
71%
Scheme 3 Preparation of N-tert-butoxycarbonylcarbamate derivati-
ve 1
Basel and Hassner reported that N-tert-butoxycarbonyl-
carbamates are the labile intermeditaes for the formation
of N-Boc derivatives, however, they could be isolated by
tretament of amines with (Boc)2O and 4-dimethylami-
nopyridine (DMAP) in MeCN at 0 °C for one to five min-
utes.6 According to this procedure, N-allyl-N-tert-
butoxycarbonylcarbamate derivative 1 was prepared from
phenylalanine benzyl ester in 71% yield (Scheme 3).
Compound 1 is stable after six months at –18 °C (in a
freezer), while the corresponding ethyl ester was labile
and suffered from some decomposition to give the corre-
sponding Boc derivative within a week even at –18 °C.
With stable N-tert-butoxycarbonylcarbamate 1 in hand,
asymmetric carbonyl migration of 1 was examined
(Table 1). The reaction took place by treatment of 1 with
potassium hexamethyldisilazide (KHMDS) in various
solvents at 20 °C (entries 1–5). The extent of asymmetric
induction was strongly depended on the solvent polarity.
The highest ee (65% ee) was obtained in the reaction in
the most polar solvent, DMSO (entry 5). We then exam-
ined the reactions at lower temperatures (entries 6–8). The
reactions in toluene and THF were sluggish, and gave 2a
in low yields (26–33%) but in high ee (86–88% ee; entries
6 and 7). The best result was obtained in the reaction in
DMF. Treatment of 1 with 1.2 equivalents of KHMDS in
DMF for two hours at –60 °C gave the desired product 2a
in 99% ee and in 49% yield (entry 8). Use of excess
SYNLETT 2011, No. 4, pp 0543–0546
x
x.
x
x.
2
0
1
1
Advanced online publication: 13.01.2011
DOI: 10.1055/s-0030-1259324; Art ID: U10610ST
© Georg Thieme Verlag Stuttgart · New York

544
F. Teraoka et al.
LETTER
amount (2.4 equiv) of KHMDS did not improve the yield ylcarbamates (Table 2). Allyl amine 3a (R = Bn) was
of 2a (41% yield, 97% ee, entry 9). Use of other bases treated with 1.2 equivalents of (Boc)2O and 0.1 equivalent
such as NaHMDS, LiHMDS, or LiTMP diminished both of DMAP in DMF at room temperature for 30 minutes.
of the yield of carbonyl migration (5–31% yield) and After cooling to –60 °C, the reaction mixture was treated
enantioselectivity (85–87% ee; entries 10–12). The major with 1.5 equivalents of KHMDS at –60 °C for two hours
side path was the formation of the corresponding Boc de- to give 2a in 53% yield and 98% ee (entry 1). On the same
rivative of 1 resulting from decarboxylation. The product treatment, allyl amine derivative 3b (R = i-Pr) derived
2a obtained in these reactions had an R-configuration at from L-valine gave 2b (R = i-Pr) in 49% yield and 98% ee
the newly formed stereogenic center (vide infra), which (entry 2). Similarly, 2c (R = Me) was obtained in 64%
indicates that the migration took place with inversion of yield and 97% ee from 3c (R = Me) derived from L-ala-
the configuration in each case.
nine (entry 3).
Table 1 Optimization of the Conditions for Asymmetric Carbonyl
Table 2 One-Pot Procedure for 2a
Migration
i) (Boc)2O (1.2 equiv)
DMAP (0.1 equiv)
DMF, r.t., 30 min
CO2Bn
R
CO2Bn
R
CO2Bn
Ph
base (1.2 equiv)
solvent, 2 h
1
NH
CO2t-Bu
NH
NH CO2t-Bu
ii) KHMDS (1.5 equiv)
–60 °C, 3 h
2a
3
2
Entry Base
Solvent
Temp (°C) Yield (%) ee (%)
Entry
R
Yield (%)
ee (%)
98
1
KHMDSa
toluene
Et2O
20
20
64
49
50
73
68
26
33
49
41
30
31
5
10
18
26
38
65
88
86
99
97
87
85
87
1
2
3
Bn
i-Pr
Me
53
49
64
2
KHMDSa
KHMDSa
KHMDSa
KHMDSa
KHMDSa
KHMDSa
KHMDSa
KHMDSa
NaHMDSd
LiHMDSe
LiTMPf
98
3
THF
20
97
4
DMF
DMSO
toluene
THF
20
a The absolute configuration of 2b (R = i-Pr) and 2c (R = Me) was ten-
tatively assigned to be R according to the analogy to 2a (R = Bn).
5
20
6b
7b
8
–78
–78
–60
–60
–60
–60
–60
The absolute configuration of 2a was determined to be R
by its transformation into 5 (Scheme 4). The benzyl ester
of 2a was selectively transformed to its p-bromoanilide 4
by treatment with p-bromoaniline and potassium hydride
in 68% yield. Reduction of 4 with lithium aluminum hy-
dride followed by p-bromobenzoylation gave 5, which
showed [a]D +10.1 (c = 0.5, CHCl3). On the other hand,
known serine derivative (4S)-6 was prepared according to
the literature.7 (4S)-6 was transformed into (S)-5 accord-
ing to the procedure in Scheme 4, which showed an opti-
cal rotation identical to that obtained from 2a.
Accordingly, the absolute configuration of 2a obtained by
the carbonyl migration of 1 was determined to be R. This
indicates that the carbonyl migration of 1 proceeded with
inversion of configuration.
DMF
DMF
DMF
DMF
DMF
9c
10
11
12
a KHMDS = potassium hexamethyldisilazide.
b The reaction was run for 24 h.
c 2.4 equiv of KHMDS was used.
d NaHMDS = sodium hexamethyldisilazide.
e LiHMDS = lithium hexamethyldisilazide.
f LiTMP = lithium 2,2,6,6-tetramethylpiperidide.
The stereochemical course of the carbonyl migration of
(S)-1 into (R)-2a is shown in Scheme 6 based on our ratio-
nale for asymmetric cyclization of (S)-8 into (S)-9, which
proceeds with retention of configuration (Scheme 5).2
We then examined a one-step procedure for 2a and the an-
alogues in order to improve the overall yield of the carbo-
nyl migration and to avoid handling the labile N-tert-
butoxycarbonylcarbamate derivatives (Table 2). Since the
asymmetric migration proceeded in a stereospecific man-
ner in DMF at low temperature, preparation of the N-tert-
butoxycarbonylcarbamates was performed in DMF.
Quantitative formation of 1 was observed when N-allyl
amine 3a (R = Bn) was treated with (Boc)2O and DMAP
in DMF at room temperature for 15 minutes. Based on this
observation, a one-step procedure for 2 was successfully
developed using DMF as a common solvent both for the
formation of N-tert-butoxycarbonylcarbamates and for
carbonyl migration of the resulting N-tert-butoxycarbon-
A conformation search of (S)-8 gives the most stable con-
former A. Deprotonation of the C(a)–H bond, which is
oriented anti to the N–C(Boc) bond, is proposed to prefer-
entially occur to give enantiomerically enriched enolate C
with a chiral C–N axis, which undergoes intramolecular
alkylation to give (S)-9 with a total retention of configura-
tion.2 The stereochemical course was shown to be highly
dependent on the base and the solvent employed.2 Among
bases and solvents, a combination of KHMDS and DMF
gave cyclization products with retention of configuration
in the highest selectivity.2 By analogy, a possible rationale
Synlett 2011, No. 4, 543–546 © Thieme Stuttgart · New York

LETTER
Asymmetric Carbonyl Migration
545
O
H
O
H
p-bromoaniline
KH, THF
N
Ph
Br
N
Br
Ph
i) LiAlH4
2a
NH
ii) p-bromobenzoyl
chloride, Et3N
68%
NH CO2t-Bu
O
Br
O
5
4
59%
[α]D26 = + 10.1 (c 0.5, CHCl3)
H
N
Br
O
CO2Me
i) HCl, MeOH
ii) allyl bromide
i-Pr2NEt
4
p-bromoaniline
KH, THF
Ph
Boc
Ph
Boc
(S)-5
O
N
O
N
87%
[α]D26 = + 10.0 (c 0.1, CHCl3)
iii) p-bromobenzoyl
chloride, Et3N
t-Bu
(4S)-6
t-Bu
7
41%
Scheme 4 Selective transformation of the benzyl ester of 2a to an amide and the determination of the absolute configuration of 2a
CO2Et
Ph
CO2Et
Ph
Boc
KHMDS
N
N
Br
DMF, –60 °C
Boc
(S)-9
(S)-8
retention
Ot-Bu
O
Ot-Bu
O
O
O
O
OEt
O
O
Ph
OEt
OK
Ph
KHMDS
N
N
N
H
K
H
: N
Br
SiMe3
Br
Br
Me3Si
A
C
Scheme 5 A rationale for the stereochemical course of our previous work on asymmetric alkylation via an axially chiral enolate intermediate
for the stereochemical course for the transformation of While this is merely an explanation without experimental
(S)-1 into (R)-2a is shown in Scheme 6. Conformational proof, the tendency of the solvent effects on the stere-
search of 1 gives the most stable conformer B.8 Deproto- ochemical course of asymmetric migration of 1 (Table 1)
nation of the C(a)–H bond, which is oriented anti to the was parallel to that of asymmetric cyclization of (S)-8.2
N–C(N-tert-butoxycarbonylcarbamate) bond, with KH- The stereochemical result for the transformation of (S)-8
MDS would give enantiomerically enriched enolate D into (S)-9 (retention) seems opposite to that of (S)-1 into
with a chiral C–N axis, which undergoes carbonyl migra- (R)-2a (inversion), however, the stereochemical course of
tion to give (R)-2a with a total inversion of configuration. the deprotonation process with KHMDS is essentially
CO2Bn
O
Ph
CO2Bn
Ph
KHMDS
DMF, –60 °C
inversion
N
Ot-Bu
CO2t-Bu
NH
O
O
(R)-2a
(S)-1
Ot-Bu
O
Ot-Bu
O
O
O
O
O
O
O
O
O
OBn
O
O
Ph
OBn
OK
KHMDS
Ph
N
O
N
N
H
K
H
:
N
SiMe3
B
D
Me3Si
Scheme 6 A possible stereochemical course for the transformation of (S)-1 into (R)-2a
Synlett 2011, No. 4, 543–546 © Thieme Stuttgart · New York

546
F. Teraoka et al.
LETTER
1009; American Chemical Society: Washington DC, 2009,
31–56.
same for both cases in terms of the enantioselectivity
of the formation of the axially chiral enolates [i.e. the ab-
solute configuration (axial chirality) of C is same as that
of D].9
(6) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368.
(7) Brunner, M.; Saarenketo, P.; Straub, T.; Rissanen, K.;
Koskinen, A. M. P. Eur. J. Org. Chem. 2004, 3879.
(8) The most stable conformer B was generated by a molecular
modeling search (MCMM 50,000 steps) with OPLS 2005
force field and GB/SA solvation model for chloroform using
MacroModel (V. 9.0); see Supporting Information.
(9) The possibility that the present asymmetric migration
proceeds without the intervention of an axially chiral enolate
cannot be excluded. Alternative route may involve a
concerted SEi process. This route was excluded by the
experimental results in the case of asymmetric cyclization
shown in Scheme 5 (refs. 2a and 2c). By analogy, we assume
that the present asymmetric carbonyl migration would
proceed through an axially chiral enolate intermediate.
(10) (a) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2003,
125, 4050. (b) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am.
Chem. Soc. 2003, 125, 13368. (c) Shaw, S. A.; Aleman, P.;
Christy, J.; Kampf, J. W.; Va, P.; Vedejs, E. J. Am. Chem.
Soc. 2006, 128, 925.
In conclusion, we have developed asymmetric carbonyl
migration of the N-tert-butoxycarbonylcarbamates of a-
amino acid derivatives. This process provides a-amino
acid derivatives with an additional ester group at the new-
ly formed tetrasubstituted stereogenic center in a highly
enantioselective manner. Compounds with similar struc-
tural characteristics have been reported to be prepared by
catalytic C-acylation of lactone enolates10 or asymmetric
Sommelet–Hauser rearrangement.11 The present method
provides a unique and new entry to this class of amino
acid derivatives from readily available usual amino
acids.12
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(11) (a) Takayama, E.; Nanbara, S.; Nakai, T. Chem. Lett. 2006,
35, 478. (b) Takayama, E.; Kimura, H. Angew. Chem. Int.
Ed. 2007, 46, 8869.
References and Notes
(12) One-Pot Procedure for 2a (Table 2): A solution of Boc2O
(105 mg, 0.48 mmol) in DMF (1.0 mL) was added to a
solution of 3 (R = Bn; 120 mg, 0.40 mmol) and DMAP (5.0
mg, 0.04 mmol) in DMF (4.1 mL) at r.t. After being stirred
for 30 min, the mixture was cooled to –60 °C, KHMDS (0.47
M in THF solution, 1.3 mL, 0.60 mmol) was added dropwise
to the mixture. The reaction mixture was stirred at –60 °C for
3 h and then poured into sat. aq NH4Cl and extracted with
EtOAc. The combined organic layers were washed with sat.
aq NaHCO3 and brine, dried over Na2SO4, filtered and
evaporated in vacuo. The residue was purified by preparative
TLC (SiO2, hexane–EtOAc = 9:1) to give (R)-2a (82 mg,
53%, 98% ee) as a colorless oil.
(1) For asymmetric intermolecular alkylation via memory of
chirality, see: (a) Kawabata, T.; Yahiro, K.; Fuji, K. J. Am.
Chem. Soc. 1991, 113, 9694. (b) Kawabata, T.; Wirth, T.;
Yahiro, K.; Suzuki, H.; Fuji, K. J. Am. Chem. Soc. 1994,
116, 10809. (c) Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji,
K. Angew. Chem. Int. Ed. 2000, 39, 2155.
(2) For asymmetric intramolecular alkylation via memory of
chirality, see: (a) Kawabata, T.; Kawakami, S.; Majumdar,
S. J. Am. Chem. Soc. 2003, 125, 13012. (b) Kawabata, T.;
Matsuda, S.; Kawakami, S.; Monguchi, D.; Moriyama, K.
J. Am. Chem. Soc. 2006, 128, 15394. (c) Kawabata, T.;
Moriyama, K.; Kawakami, S.; Tsubaki, K. J. Am. Chem.
Soc. 2008, 130, 4153.
(3) For asymmetric intramolecular conjugate addition via
memory of chirality, see: Kawabata, T.; Majuumdar, S.;
Tsubaki, K.; Monguchi, D. Org. Biomol. Chem. 2005, 3,
1609.
(4) For Dieckmann condensation via memory of chirality, see:
Watanabe, T.; Kawabata, T. Heterocycles 2008, 76, 1593.
(5) For recent reviews on asymmetric synthesis via memory of
chirality see: (a) Kawabata, T.; Fuji, K. Top. Stereochem.
2003, 53, 175. (b) Zhao, H.; Hsu, D.; Carlier, P. R. Synthesis
2005, 1. (c) Kawabata, T. Asymmetric Synthesis and
Application of a-Amino Acids, ACS Symposium Series
HPLC conditions: Daicel Chiralpak OJ-H; hexane–i-PrOH,
9:1; flow 0.5 mL/min; tR = 8.4 (R), tR = 9.9 (S); [a]D25 +2.6
(c = 2.1, CDCl3). 1H NMR (600 MHz, CDCl3): d = 7.33–7.38
(m, 5 H), 7.17–7.24 (m, 5 H), 5.91 (ddt, J = 15.1, 9.6, 5.5 Hz,
1 H), 5.20 (d, J = 15.1 Hz, 1 H), 5.16 (ABq, JAB = 12.3 Hz,
Dn = 10.6 Hz, 2 H), 5.08 (d, J = 9.6 Hz, 1 H), 3.22–3.29 (m,
1 H), 3.26 (ABq, JAB = 14.4 Hz, Dn = 18.4 Hz, 2 H), 3.19 (dd,
J = 13.1, 5.5 Hz, 1 H), 1.29 (s, 9 H). 13C NMR (150 MHz,
CDCl3): d = 170.1, 168.5, 135.9, 135.7, 135.2, 130.3, 128.9,
128.53, 128.49, 127.9, 126.8, 116.1, 82.6, 70.8, 67.1, 45.9,
36.8, 27.7. IR (CDCl3): 1728, 1456, 1369, 1190, 1151 cm–1.
ESI–MS (+): m/z = 418 [M + Na], 340, 278, 204. HRMS:
m/z calcd for C24H29NO4Na: 418.1994; found: 418.1953.
Synlett 2011, No. 4, 543–546 © Thieme Stuttgart · New York

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