Direct asymmetric intramolecular alkylation of β-alkoxy-α-amino esters via memory of chirality

Article abstract of DOI:10.1021/ol801213c

(Chemical Equation Presented) The intramolecular α-alkylation of β-alkoxy-α-amino esters derived from L-serine proceeded predominantly over β-elimination. When β-alkoxy-α-amino esters were treated with powdered CsOH in DMSO at 20 °C, α-alkoxymethyl cyclic

Full text of DOI:10.1021/ol801213c

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3883-3886
Direct Asymmetric Intramolecular
Alkylation of ꢀ-Alkoxy-r-amino Esters
via Memory of Chirality
Katsuhiko Moriyama, Hiroki Sakai, and Takeo Kawabata*
Institute for Chemical Research, Kyoto UniVersity, Uji, Kyoto 611-0011, Japan
kawabata@scl.kyoto-u.ac.jp
Received June 22, 2008
ABSTRACT
The intramolecular r-alkylation of ꢀ-alkoxy-r-amino esters derived from L-serine proceeded predominantly over ꢀ-elimination. When ꢀ-alkoxy-
r-amino esters were treated with powdered CsOH in DMSO at 20 °C, r-alkoxymethyl cyclic amino esters were obtained in up to 94% ee.
Optically active THF amino acids were synthesized for the first time by the present method.
R-Substituted serine derivatives are important building blocks
for the synthesis of biologically active natural products such
as sphingofungin-E,1 lactacystin,2 salinosporamide A,3 dysi-
betaine,4 kaitocephalin,5 neooxazolomycin,6 and so on. The
most straightforward synthesis of optically active R-substi-
tuted serines might involve the R-alkylation of protected
serine derivatives (Scheme 1, path a). However, this has
Scheme 1
(1) (a) Zweerink, M. M.; Edison, A. M.; Wells, G. B.; Pinto, W.; Lester,
R. L. J. Biol. Chem. 1992, 267, 25032. (b) Horn, W. S.; Smith, J. L.; Bills,
G. F.; Raghoobar, S. L.; Helms, G. L.; Kurtz, M. B.; Marrinan, J. A.;
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Toyama, R.; Chiba, K.; Hoshino, Y.; Okumoto, T. J. Antibiot. 1994, 47,
208.
never been achieved due to expected racemization during
enolate formation and/or concomitant ꢀ-elimination7 (Scheme
(2) (a) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi,
R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44, 113. (b) Omura, S.;
Matsuzaki, K.; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita, S.; Nakagawa,
A. J. Antibiot. 1991, 44, 117. (c) Fenteany, G.; Standaert, R. F.; Lane, W. S.;
Choi, S.; Corey, E. J.; Schreiber, S. L. Science 1995, 268, 726–731. (d)
Conner, E. M.; Brand, S.; Davis, J. M.; Laroux, F. S.; Palombella, V. J.;
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1999, 274, 22123. (f) Soucy, F.; Grenier, L.; Behnke, M. L.; Destree, A. T.;
McCormack, T. A.; Adams, J.; Plamondon, L. J. Am. Chem. Soc. 1999,
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81, 163.
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Katayama, C.; Iwadare, S.; Shizuri, Y.; Mitomo, R.; Nakano, F.; Matsuzaki,
A. Tetrahedron Lett. 1985, 26, 1073. (b) Wang, Z.; Moloney, M. G.
Tetrahedron Lett. 2002, 43, 9629. (c) Alezra, V.; Bonin, M.; Micouin, L.;
Husson, H.-P. Tetrahedron Lett. 2001, 42, 2111–2113. (d) Jime´nez-Ose´s,
G.; Aydillo, C.; Busto, J. H.; Zurbano, M. M.; Peregrina, J. M.; Avenoza,
A. J. Org. Chem. 2007, 72, 5399–5402. (e) Brunner, M.; Koskinen, A. M. P.
Tetrahedron Lett. 2004, 45, 3063–3065. (f) Aydillo, C.; Jime´nez-Ose´s, G.;
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10.1021/ol801213c CCC: $40.75
Published on Web 08/13/2008
2008 American Chemical Society

1, path b). To avoid these problems, cyclic analogues with
chiral auxiliaries such as 1-3 have been used to prepare
optically active R-substituted serine derivatives.8 We report
here the direct asymmetric synthesis of R-substituted serine
derivatives by intramolecular alkylation of ꢀ-alkoxy-R-amino
esters derived from L-serine via memory of chirality.
Scheme 2
enolate intermediate A with a racemization barrier of ∼15.5
kcal/mol was proposed. On the basis of this barrier, the chiral
enolate was thought to undergo rapid cyclization within 10-3
s after its generation to give the cyclized products in 99%
ee. The extremely rapid intramolecular alkylation was
expected to underlie the high asymmetric induction at 20
°C because competitive racemization of the chiral enolate
was minimized. The high reactivity of the enolates generated
with KOH in DMSO prompted us to apply this method to
the asymmetric intramolecular alkylation of ꢀ-alkoxy-R-
amino esters. We had expected that the ꢀ-alkoxy enolates
generated from ꢀ-alkoxy-R-amino esters and KOH in DMSO
might undergo asymmetric cyclization predominantly over
ꢀ-elimination due to the high rate of intramolecular alkylation
(Scheme 1, k1 > k2).
We have developed a direct method for the asymmetric
R-alkylation of R-amino acid derivatives without the aid of
external chiral sources such as chiral auxiliaries or chiral
catalysts, i.e., memory of chirality.9 The inter- and intramo-
lecular R-alkylation of R-amino acid derivatives proceeded
in up to 98% ee via axially chiral enolate intermediates,
where enolate formation was performed at low temperatures
such as -78 to -60 °C to maintain the enantiomeric purity
of the chiral enolate.10 Recently, we reported that asymmetric
cyclization via memory of chirality could proceed with high
enantioselectivity even at 20 °C when powdered KOH in
DMSO was used as a base (Scheme 2).11 The axially chiral
We chose compounds 4 derived from L-serine as a
substrate and examined the asymmetric cyclization of 4
(Table 1). Treatment of 4 with powdered KOH in DMSO at
20 °C for 60 min gave, as expected, cyclization product 6
predominantly in 97% yield (entry 2). The product resulting
from ꢀ-elimination was not observed. Since the enantiose-
lectivity of the cyclization was moderate (75% ee), the
conditions for asymmetric cyclization of 4 were further
examined. Treatment of 4 with powdered NaOH, RbOH, or
CsOH in DMSO at 20 °C gave 6 in 85%, 93%, or 91% yield
and in 67%, 69%, or 77% ee, respectively (entries 1, 3, and
4). While the use of powdered CsOH in DMF at -20 °C
gave 6 in a slightly improved ee of 83%, this required a
long reaction time and promoted ꢀ-elimination (11%) (entries
4 vs 5). The use of iodide 5 instead of bromide 4 increased
the enantioselectivity of the asymmetric cyclization (entries
2 vs 7, 4 vs 8). Treatment of 5 with powdered CsOH in
DMSO at 20 °C gave 6 in 86% ee and 84% yield (entry 8).
The increase in the enantioselectivity of cyclization of the
iodides could be ascribed to their increased rates of cycliza-
tion. Similar effects of leaving groups on asymmetric
alkylation via memory of chirality have been reported by
Carlier and co-workers.12 The use of potassium hexameth-
yldisilazide (KHMDS) also gave cyclization product 6 in
high yield (96%) albeit in low enantioselectivity (34% ee)
(entry 6).
(7) (a) Shigematsu, N.; Kayakiri, N.; Okada, S.; Tanaka, H. Chem.
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Owen, K. L. J. Chem. Soc., Perkin Trans. 1 1996, 227–228. (d) Andrews,
M. D.; Brewster, A. G.; Moloney, M. G. Synlett 1996, 612–614. (e)
Andrews, M. D.; Brewster, A. G.; Crapnell, K. M.; Ibbett, A. J.; Jones, T.;
Moloney, M. G.; Prout, K.; Watkin, D. J. Chem. Soc., Perkin Trans. 1
1998, 223–235. (f) Alezra, V.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche,
C.; Husson, H.-P. Tetrahedron Lett. 2000, 41, 1737–1740. (g) Alezra, V.;
Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2001, 42, 2111–
2113. (h) Brunner, M.; Koskinen, A. M. P. Tetrahedron Lett. 2004, 45,
3063–3065. (i) Jime´nez-Ose´s, G.; Aydillo, C.; Busto, J. H.; Zurbano, M. M.;
Peregrina, J. M.; Avenoza, A. J. Org. Chem. 2007, 72, 5399–5402. (j)
Aydillo, C.; Jime´nez-Ose´s, G.; Busto, J. H.; Peregrina, J. M.; Zurbano,
M. M.; Avenoza, A. Chem. Eur. J. 2007, 13, 4840–4848.
(9) For reactions related to memory of chirality, see: (a) Beagley, B.;
Betts, M. J.; Pritchard, R. G.; Schofield, A.; Stoodley, R. J.; Vohra, S.
J. Chem. Soc., Chem. Commun. 1991, 924–925. (b) Kawabata, T.; Yahiro,
K.; Fuji, K. J. Am. Chem. Soc. 1991, 113, 9694–9696. (c) Betts, M. J.;
Pritchard, R. G.; Schofield, A.; Stoodley, R. J.; Vohra, S. J. Chem. Soc.,
Perkin Trans. 1 1999, 1067–1072. (d) Gerona-Navarro, G.; Bonache, M. A.;
Herranz, R.; Garc´ıa-Lo´pez, M. T.; Gonza´lez-Mun˜iz, R. J. Org. Chem. 2001,
66, 3538–3547. (e) Bonache, M. A.; Gerona-Navarro, G.; Mart´ın-Mart´ınez,
M.; Garc´ıa-Lo´pez, M. T.; Lo´pez, P.; Cativiela, C.; Gonza´lez-Mun˜iz, R.
Synlett 2003, 1007–1011. (f) Carlier, P. R.; Zhao, H.; DeGuzman, J.; Lam,
P. C.-H. J. Am. Chem. Soc. 2003, 125, 11482–11483. (g) Kawabata, T.;
Ozturk, O.; Suzuki, H.; Fuji, K. Synthesis 2003, 505–508. (h) Kawabata,
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Kawabata, T.; Matsuda, S.; Kawakami, S.; Monguchi, D.; Moriyama, K.
J. Am. Chem. Soc. 2006, 128, 15394–15395.
We next examined the effects of protective groups for the
ꢀ-hydroxy group of serine derivatives (Table 2). Upon
treatment with powdered CsOH in DMSO at 20 °C, methyl
ether 7 underwent intramolecular alkylation to give R-meth-
(10) (a) Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem.,
Int. Ed. 2000, 39, 2155–2157. (b) Kawabata, T.; Chen, J.; Suzuki, H.; Nagae,
Y.; Kinoshita, T.; Chancharunee, S.; Fuji, K. Org. Lett. 2000, 2, 3883–
3885. (c) Kawabata, T.; Kawakami, S.; Majumdar, S. J. Am. Chem. Soc.
2003, 125, 13012–13013. (d) Kawabata, T.; Kawakami, S.; Shimada, S.;
Fuji, K. Tetrahedron 2003, 59, 965–974. (e) Kawabata, T.; Majumdar, S.;
Tsubaki, K.; Monguchi, D. Org. Biomol. Chem. 2005, 3, 1609–1611. (f)
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Tetrahedron: Asymmetry 2005, 16, 2998–3002.
3884
Org. Lett., Vol. 10, No. 17, 2008

Table 1. Asymmetric Cyclization of O-Benzyl Serine Derivatives 4 and 5a
entry
substrate
X
base (mol equiv)
solvent
DMSO
DMSO
DMSO
DMSO
DMF
temp (°C)
time (min)
yield (%)
ee (%)d
1
2
3
4
5
6
7
8
9
4
4
4
4
4
4
5
5
5
5
Br
Br
Br
Br
Br
Br
I
I
I
I
NaOHb (3.0)
KOHb (3.0)
RbOHb (1.5)
CsOHb (1.5)
CsOHb (1.5)
KHMDS (1.5)
KOHb (3.0)
CsOHb (1.5)
CsOHb (1.5)
CsOHb (1.5)
20
20
20
60
60
20
20
1080
30
30
30
30
420
85
97
93
91
83c
96
91
84
88
88
67
75
69
77
83
34
82
86
83
81
20
-20
-78
20
20
20
THF
DMSO
DMSO
1%H2O in DMSO
DMF
10
-20
a Reactions were carried out with a substrate concentration of 0.1 M. b Powdered metal hydroxide was used. c A product resulting from ꢀ-elimination
was also obtained in 11% yield. d Ee of the corresponding N-benzoate determined by HPLC analysis. (S)-Isomer was obtained in each run. For the determination
of the absolute configuration, see the Supporting Information.
oxymethyl proline 8 in 82% ee and 75% yield (entry 2).
Methoxymethyl (MOM) ether 9 underwent cyclization with
an efficiency similar to that of methyl ether 7 (72% yield
and 82% ee, entry 3). tert-Butyldiphenylsilyl (TBDPS) ether
11 underwent asymmetric cyclization to give R-substituted
proline 12 in 88% ee, but in only 13% yield due to the
predominant ꢀ-elimination (58%) (entry 4). The use of
4-methoxybenzyl (PMB) and tert-butyl (tBu) ethers 13 and
15 in asymmetric cyclization gave R-substituted prolines 14
and 16 with increased enantioselectivities of 92% and 93%,
respectively (entries 5 and 6). The four- and six-membered
cyclization of ꢀ-alkoxy-R-amino esters was performed.
Treatment of t-Bu ethers 17 and 19 with powdered CsOH
in DMSO at 20 °C gave R-substituted azetidine 18and
Scheme 3
Table 2. Asymmetric Cyclization of Serine Derivativesa
R-substituted piperidine 20 in 92% or 94% ee, respectively
(entries 7 and 8). The stereochemical course of the five-
membered cyclization was retention in all cases (entries
1-6). R-Substituted proline 16 obtained by the present
method was converted into R-hydroxymethyl pyrroglutamate
23, a common key intermediate for the synthesis of lacta-
cystin,2 dysibetaine,4 and kaitocephalin.5 Ethyl ester 16 (93%
ee) was converted into methyl ester 21 in 97% yield via
hydrolysis followed by methylation of the resulting carboxy-
lic acid. Ruthenium-promoted oxidation13 of N-Boc amine
21 into amide 22 followed by removal of the Boc group gave
23 in 95% yield (Scheme 3).
time
yield
entry substrate
R
n
(min) product (%) eeb (%)
1
2
3
4
5
6
7
8
5
7
9
11
13
15
17
19
Bn
3
3
3
3
3
3
2
4
60
10
30
10
30
30
20
60
6
8
84
75
72
86c (S)
82d (S)
82d (S)
Me
MOM
TBDPS
PMB
tBu
tBu
tBu
10
12
14
16
18
20
13e 88d (S)
88
89
74
77
92d (S)
93d (S)
92f
94c
The present method for the direct asymmetric intramo-
lecular alkylation of ꢀ-alkoxy-R-amino esters was applied
to the asymmetric synthesis of THF amino acids. THF amino
a Reactions were carried out with a substrate concentration of 0.1 M.
Powdered CsOH was used. b Ee was determined by HPLC analysis. A letter
in parentheses indicates the absolute configuration. c Ee of the corresponding
N-benzoate. d Ee of N-(benzoyl)-R-(hydroxymethyl)proline ethyl ester
derived from the cyclization product. e A product resulting from ꢀ-elimina-
tion was also obtained in 58% yield. f Ee of ethyl N-(benzoyl)-R-
(hydroxymethyl)azetidine-2-carboxylate derived from 18.
(13) (a) Bettoni, G.; Carbonara, G.; Franchini, C.; Tortorella, V.
Tetrahedron 1981, 37, 4159–4164. (b) Perrone, R.; Bettoni, G.; Tortorella,
V. Synthesis 1976, 598–600. (c) Tanaka, K.; Yoshifuji, S.; Nitta, Y. Chem.
Pharm. Bull. 1986, 3879–3884.
Org. Lett., Vol. 10, No. 17, 2008
3885

Table 3. Asymmetric Synthesis of THF Amino Acids from L-Serinea
entry
substrate
R
baseb (mol equiv)
time (min)
product
yield (%)c
ee (%)d
1
2
3
4
24
24
24
26
MOM
MOM
MOM
MEM
KOH (3.0)
RbOH (1.5)
CsOH (1.5)
CsOH (1.5)
120
30
30
25
25
25
27
58 (19)
55 (23)
58 (17)
57 (20)
81
85
86
84
30
a Reactions were carried out with a substrate concentration of 0.1 M. b Powdered metal hydroxide was used. c Numbers in parentheses indicate the
percent yield of the product resulting from ꢀ-elimination. d Ee of the corresponding N-benzoate determined by HPLC analysis.
acids are a new class of amino acids that are useful for
searching conformationally restricted peptides with biological
activity.14 Racemic THF amino acids have been synthesized
by Walker and co-workers via the cyclization of silyl enol
ethers derived from homoserine,15 and also by Ko¨nig and
co-workers via the diastereoselective intramolecular aldol
reaction of the sulfonium salts of methionine derivatives.16
To the best of our knowledge, however, there has been no
report on the synthesis of optically active THF amino acids.
We report here the first asymmetric synthesis of THF amino
acids via the direct intramolecular alkylation of serine
derivatives. The precursors 24 and 26 were prepared from
L-serine. The conditions for the asymmetric cyclization of
24 and 26 were examined (Table 3). Treatment of N-MOM
derivative 24 with powdered KOH in DMSO for 120 min at
20 °C gave the desired THF amino acid with a tetrasubsti-
tuted carbon center 25 in 81% ee and 58% yield with
concomitant ꢀ-elimination (19%) (entry 1). The use of
powdered RbOH and CsOH instead of KOH slightly
improved the enantioselectivity of the asymmetric cyclization
to give 25 in 85% ee and 86% ee, respectively (entries 2
and 3). N-Boc-N-methoxyethoxymethyl (MEM) derivative
26 showed reactivity similar to that of 24 (entry 4). Treatment
of 26 with powdered CsOH in DMSO at 20 °C gave THF
amino acid 27 in 57% yield and 84% ee (entry 4). In the
asymmetric cyclization of 24 and 26, significant ꢀ-elimina-
tion (17-23%) was observed (entries 1-4). This suggests
that intramolecular alkylation with C(R) side chains may
proceed slower than that with N side chains.
In conclusion, we have developed a direct asymmetric
intramolecular alkylation of ꢀ-alkoxy-R-amino esters. This
method provides a convenient entry to optically active
R-substituted serine derivatives from readily available L-
serine. Optically active THF amino acids were also prepared
for the first time by the present method.
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 Education, Culture, Sports, Science and Technol-
ogy, Japan.
(14) (a) Ward, P.; Ewan, G. B.; Jordan, C. C.; Ireland, S. J.; Hagan,
R. M.; Brown, J. J. Med. Chem. 1990, 33, 1848–1851. (b) Hruby, V. J.;
Agnes, R. S. Biopolym. Pept. Sci. 1999, 51, 391–410. (c) Bisang, C.; Weber,
C.; Inglis, J.; Schiffer, C. A.; van Gunsteren, W. F.; Jelesarov, I.; Bosshard,
H. R.; Robinson, J. J. Am. Chem. Soc. 1995, 117, 7904–7915. (d)
Nikiforovich, S. D.; Sharma, S. D.; Hadley, M. E.; Hruby, V. J. Biopolymers
1998, 46, 155–167.
Supporting Information Available: Experimental pro-
cedure and characterization data of componds 4-27 and
determination of the absolute configuration of 6, 8, 10, 12,
14, and 16. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Walker, D. M.; Logusch, E. W. Tetrahedron Lett. 1989, 30, 1181–
1184.
(16) Maity, P.; Zabel, M.; Ko¨nig, B. J. Org. Chem. 2007, 72, 8046–
8053.
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