Asymmetric intermolecular conjugate addition of amino acid derivatives via memory of chirality: Total synthesis of manzacidin A

Article abstract of DOI:10.1021/ol303568f

Asymmetric intermolecular conjugate addition of α-amino acid derivatives with 4 via memory of chirality has been developed. The reactions proceeded in up to 98% ee with retention of configuration at the newly formed tetrasubstituted carbon center when R = Me. The product (R = Me) was transformed into manzacidin A.

Full text of DOI:10.1021/ol303568f

ORGANIC
LETTERS
2013
Vol. 15, No. 4
864–867
Asymmetric Intermolecular Conjugate
Addition of Amino Acid Derivatives
via Memory of Chirality: Total Synthesis
of Manzacidin A
Tomoyuki Yoshimura, Tomohiko Kinoshita, Hiroyasu Yoshioka, and
Takeo Kawabata*
Institute for Chemical Research, Kyoto University, Uji 611-0011, Japan
kawabata@scl.kyoto-u.ac.jp
Received December 30, 2012
ABSTRACT
Asymmetric intermolecular conjugate addition of R-amino acid derivatives with 4 via memory of chirality has been developed. The reactions
proceeded in up to 98% ee with retention of configuration at the newly formed tetrasubstituted carbon center when R = Me. The product (R = Me)
was transformed into manzacidin A.
R,R-Disubstituted R-amino acids have been recognized
They have also been frequently found as structural sub-
units in biologically active natural products.2 Several
excellent methods have been reported for the asymmetric
synthesis of R,R-disubstituted R-amino acid derivatives.3
We have reported asymmetric syntheses of them by direct
alkylation of R-amino acid derivatives, via memory of
chirality, without the use of external chiral sources such as
chiral catalysts or chiral auxiliaries.4,5 The reactions have
been proposed to proceed via axially chiral enolate inter-
mediates A (Scheme 1).4,5a,5c Recently, we reported asym-
metric aldol reactions of R-amino acid derivatives via memory
of chirality.6 This strategy for asymmetric synthesis is also
applicable to intramolecular alkylation,7,8 intramolecular
acyl migration,9 and intramolecular conjugate addition.10
as useful building blocks in the field of medicinal chemistry.1
(1) (a) Boyle, S.; Guard, S.; Higginbottm, M.; Horwell, D. C.;
Howson, W.; McKnight, A. T.; Martin, K.; Pritchard, M. C.; O’Toole,
J.; Raphy, J.; Rees, D. C.; Roberts, E.; Watling, K. J.; Woodruff, G. N.;
Hughes, J. Bioorg. Med. Chem. 1994, 2, 357–370. (b) Ilies, M.; Costanzo,
L. D.; Dowling, D. P.; Thorn, K. J.; Christianson, D. W. J. Med. Chem.
2011, 54, 5432–5443.
(2) For a review on the total synthesis of natural products containing
a tert-alkylamino hydroxyl carboxylic acid substructure, see: Kang,
S. H.; Kang, S. Y.; Lee, H.-S.; Buglass, A. J. Chem. Rev. 2005, 105,
4537–4558.
(3) For a review, see: Vogt, H.; Braese, S. Org. Biomol. Chem. 2007, 5,
406–430.
(4) Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem., Int.
Ed. 2000, 39, 2155–2157.
(5) For reviews on asymmetric synthesis via memory of chirality, see:
(a) Kawabata, T.; Fuji, K. Top. Stereochem. 2003, 23, 175–205. (b) Zhao,
H.; Hsu, D. C.; Carlier, P. R. Synthesis 2005, 1–16. (c) Patil, N. T.
Chem.;Asian J. 2012, 7, 2189–2194. For recent reports related to the
memory of chirality, see: (d) Mondal, S.; Nechab, M.; Vanthuyne, N.;
Bertrand, M. P. Chem. Commun. 2012, 48, 2549–2551. (e) Mai, T. T.;
Viswambharan, B.; Gori, D.; Kouklovsky, C.; Alezra, V. J. Org. Chem.
(6) Watanabe, T.; Yoshimura, T.; Kawakami, S.; Sasamori, T.;
Tokitoh, N.; Kawabata, T. Chem. Commun. 2012, 48, 5346–5348.
(7) (a) Kawabata, T.; Kawakami, S.; Majumdar, S. J. Am. Chem.
Soc. 2003, 125, 13012–13013. (b) Kawabata, T.; Matsuda, S.; Kawaka-
mi, S.; Monguchi, D.; Moriyama, K. J. Am. Chem. Soc. 2006, 128,
15394–15395. (c) Kawabata, T.; Moriyama, K.; Kawakami, S.; Tsubaki,
K. J. Am. Chem. Soc. 2008, 130, 4153–4157.
ꢀ
2012, 77, 8797–8801. (f) Fletcher, S. P.; Sola, J.; Holt, D.; Brown, R. A.;
Clayden, J. Beilstein J. Org. Chem. 2011, 7, 1304–1309. (g) MacLellan,
P.; Clayden, J. Chem. Commun. 2011, 47, 3395–3397. (h) Nechab, M.;
Campolo, D.; Maury, J.; Perfetti, P.; Vanthuyne, N.; Siri, D.; Bertrand,
M. P. J. Am. Chem. Soc. 2010, 132, 14742–14744. (i) Wanyoike, G. N.;
Matsumura, Y.; Kuriyama, M.; Onomura, O. Heterocycles 2010, 80,
1177–1185. (j) Branca, M.; Pena, S.; Guillot, R.; Gori, D.; Alezra, V.;
Kouklovsky, C. J. Am. Chem. Soc. 2009, 131, 10711–10718.
(8) Asymmetric synthesis of β-lactams by the intramolecular alkyl-
ation via memory of chirality has been reported. See: (a) Gerona-
ꢀ
Navarro, G.; Bonache, M. A.; Hernz, R.; Garcı
~
M. A.; Cativiela, C.; Garcı
´
a-Lopez, M. T.;
ꢀ
Gonzalez-Muniz, R. J. Org. Chem. 2001, 66, 3538–3547. (b) Bonache,
ꢀ ꢀ ~
´
a-Lopez, M. T.; Gonzalez-Muniz, R. Tetra-
hedron Lett. 2006, 47, 5883–5887.
r
10.1021/ol303568f
Published on Web 01/25/2013
2013 American Chemical Society

On the other hand, intermolecular conjugate addition
reactions via memory of chirality have yet to be devel-
oped. Here we report highly enantioselective intermole-
cular conjugate addition reactions of R-amino acid
derivatives via memory of chirality. This method provides
a concise access to a new class of glutamic acid derivatives
with a tetrasubstituted carbon center. The diastereomeric
products obtained by this method were transformed to
manzacidin A and ent-manzacidin C, members of the
biologically active bromopyrrole class of alkaloids
(Figure 1).11
Scheme 2. An Expected Stereochemical Course for Asymmetric
Intermolecular Reactions of Axially Chiral Enolates Generated
from L-Alanine
was examined. N-tert-butoxycarbonyl(Boc)-N-methoxy-
methyl(MOM)-alanine benzyl ester (3) was chosen as a
substrate according to our previous results from the asym-
metric reactions of the corresponding L-phenylalanine
derivatives.4,5a,5c,6 Attempted asymmetric conjugate addi-
tion of 3 with Michael acceptors such as ethyl acrylate or
acrylonitrile under various conditions resulted in the low
yields and/or low enantioselectivity (data not shown). By
further screening of Michael acceptors, 4 was found sui-
table for the purpose. We first examined potassium hex-
amethyldisilazide (KHMDS) in toluene/THF (4:1) as a
base, because this base/solvent system was critical for high
enantioselectivity and yield in the asymmetric methylation
of amino acid derivatives 1 via an axially chiral enolate
(Scheme 1, R ¼ Me).4 Since the alanine-derived axially
chiral enolate was expected to be readily racemized, a solu-
tion of 3 and 4 was added slowly to a solution of KHMDS
(Table 1, entry 1, procedure I) in order to minimize race-
mization of the chiral enolate during the course of inter-
molecular conjugate addition. Under these conditions, the
axially chiral enolate was expected to react with the Michael
acceptor immediately after its generation. A 1:1 diaste-
reomeric mixture of 5a and 5b was obtained in a combined
yield of 68%. The obtained diastereomer 5b showed 82%
ee (entry 1). Use of NaHMDS or LDA in toluene/THF
(4:1) resulted in the lower enantioselectivity (63% ee for
5a) or low yield (25%), respectively (entries 2 and 3). The
solvent effects of the reactions using KHMDS as a base
were then examined. We had anticipated that use of
solvents with low coordinating ability such as toluene
would elongate the half-life of racemization of the chiral
enolates, but reduce the reactivity of the enolates toward
electrophiles due to the higher aggregation state. On the
other hand, the use of solvents with high coordinating
ability such as THF or DMF would shorten the half-life
of racemization of the chiral enolates while enhancing the
reactivity of the enolates due to the lower aggregation
state.6 Therefore, the screening of solvents in the asym-
metric reactions of chiral enolate intermediates seemed
critical. The reaction of 3 and 4 with KHMDS in toluene
gave a 1:1 diastereomeric mixture of 5a and 5b in a
combined yield of 75%, and 92% ee and 92% ee, respec-
tively (entry 4). In contrast, the reaction in THF gave 5 in
Figure 1. Manzacidin A and ent-mazacidin C.
Scheme 1. Asymmetric Methylation via Axially Chiral Enolate A
We first focused on the asymmetric conjugate addition
of alanine derivatives, since these Michael adducts were
expected to be useful intermediates for the synthesis of
manzacidin A. However, we anticipated difficulty in the
asymmetric intermolecular reactions of alanine derivatives
via memory of chirality, because of the shorter half-life of
racemization of enolate B, derived from L-alanine, than
enolate A derived from L-phenylalanine (Scheme 2).12
Since the asymmetric reaction of B with an electrophile
competes with its own racemization, high enantioselectiv-
ity of the reaction is expected only when the reaction of B
with electrophiles proceeds more rapidly than its racemi-
zation (Scheme 2).
With the above assumption in mind, the asymmetric
intermolecular conjugate addition of alanine derivatives
(9) Teraoka, F.; Fuji, K.; Ozturk, O.; Yoshimura, T.; Kawabata, T.
Synlett 2011, 543–546.
(10) (a) Kawabata, T.; Majumdar, S.; Tsubaki, K.; Monguchi, D.
Org. Biomol. Chem. 2005, 3, 1609–1611. (b) Yoshimura, T.; Takuwa, M.;
Tomohara, K.; Uyama, M.; Hayashi, K.; Yang, P.; Hyakutake, R.;
Sasamori, T.; Tokitoh, N.; Kawabata, T. Chem.;Eur. J. 2012, 18,
15330–15336.
(11) Kobayashi, J.; Kanda, F.; Ishibashi, M.; Shigemori, H. J. Org.
Chem. 1991, 56, 4574–4576.
(12) The half-life of racemization of N-tert-butoxylcarbonyl-N-
methoxymethyl alanine ethyl ester was experimentally determined to
be ca. 1 h at ꢀ78 °C in toluene/THF (4:1), while that of the enolate
derived from the corresponding phenylalanine derivative has been
reported to be 22 h (ref 4).
Org. Lett., Vol. 15, No. 4, 2013
865

a quantitative yield with lower enantioselectivity (74% ee)
(entry 5). The increase of the ee in the reaction in entry 4
and increase in the yield of the reaction in entry 5 could be
attributed to the longer half-life of racemization in to-
luene and enhanced reactivity of the chiral enolate inter-
mediate in THF, respectively. While the use of toluene/
DMF (1:1) as a solvent slightly improved both the diastereo-
selectivity (5a:5b = 1:2) and enantioselectivity (5a: 91%
ee, 5b: 94% ee), it diminished the yield (31%; entry 6).
Yet, the use of THF/DMF (1:1) improved the diastereo-
selectivity (5a:5b = 1:2), enantioselectivity (5a: 93% ee,
5b: 93% ee), and the yield (83%), compared to the use of
toluene/THF (4:1) (entry 1 vs 7). The optimal results
were obtained by modification of the reaction procedure
(procedure II). Slow addition of KHMDS to a mixture of
3 and 4 in THF/DMF (1:1) gave a 1:2 diastereomeric
mixture of 5a and 5b in a quantitative yield and 97% ee
and 97% ee, respectively (entry 8). The corresponding
gram-scale reaction took place smoothly to give a repro-
ducible result (entry 9). The importance of the reaction
procedure was confirmed by comparison with our pre-
vious procedure for asymmetric methylation of 1 via
memory of chirality.4 A solution of 3 in THF/DMF
(1:1) was treated with KHMDS for 30 min before addi-
tion of 4, giving 5a and 5b in 70% yield and in 22% ee and
22% ee, respectively (entry 11). This indicates significant
racemization of the chiral enolate derived from alanine
derivative 3 during the initial 30 min. The absolute and
relative configurations of 5a and 5b were determined by
their conversion to manzacidin A and ent-manzacidin C,
respectively (Scheme 3). The transformation indicated
that the intermolecular conjugate addition proceeded with
retention of configuration at the newly formed tetrasub-
stituted carbon center. We have recently observed that the
ee of β-lactam formation by a related intramolecular con-
jugate addition process decreased following a prolonged
reaction time, due to the reversibility of the conjugated
addition process.10b In order to assess the reversibility of
the present asymmetric conjugate addition, the effect of a
prolonged reaction time was investigated after the addi-
tion of KHMDS. Stirring for 120 min (cf. 10 min in entry 8,
procedure II) after the addition of KHMDS to a solution
of 3 and 4 in THF/DMF (1:1) resulted in the formation of
5b with an ee comparable to that in entry 8 (entry 8 vs 10).
This suggests that the conjugate addition process of the
chiral enolate to Michael acceptor 4 is irreversible.
Intermolecular conjugate addition reactions of various
N-Boc-N-MOM-R-amino acid derivatives 6ꢀ9 with4 were
performed (Table 2). Reaction of phenylalanine-derived 6
with4 proceeded smoothly in 20 min at ꢀ78°C togivea 3:2
diastereomeric mixture of 10a and 10b in a quantitative
combined yield and 97% ee and 97% ee, respectively (entry 1).
The reaction of L-valine-derived 7 with 4 was sluggish
at ꢀ78 °C, and it proceeded at ꢀ40 °C to give 11a as a
Table 1. Search for the Conditions of Asymmetric Intermolecular Conjugate Additiona
base
ee of 5a
(%)e,f
ee of 5b
(%)e,g
entry
(1.2 equiv)
solvent
procedureb
yield
5a:5bc,d
i
1
KHMDSh
NaHMDSj
LDA
toluene/THF (4:1)
toluene/THF (4:1)
toluene/THF (4:1)
toluene
I
68%
1:1
1:1
1:1
1:1
1:1
1:2
1:2
1:2
1:2
1:2
1:2
ꢀ
82
i
2
I
quant
25%
63
ꢀ
i
i
3
I
ꢀ
ꢀ
4
KHMDSk
KHMDSh
KHMDSk
KHMDSh
KHMDSh
KHMDSh
KHMDSh
KHMDSh
I
75%
92
74
91
93
97
97
92
i
5
THF
I
quant
31%
ꢀ
6
toluene/DMF (1:1)
THF/DMF (1:1)
THF/DMF (1:1)
THF/DMF (1:1)
THF/DMF (1:1)
THF/DMF (1:1)
I
94
93
97
98
97
22
7
I
83%
8
II
II
IIm
III
quant
98%
9l
10
11
i
90%
ꢀ
70%
22
a All reactions were run at substrate concentration of 0.1 M. b I: A solution of 3 (0.25 mmol) and 4 (2.0 equiv) was added to a solution of the base (1.2
equiv) during a period of 60 or 15 min for entries 1, 4, 6, and 7 or entries 2, 3, and 5, respectively, at ꢀ78 °C. The resulting mixture was stirred at the same
temperature for 10 min. II: A KHMDS solution (1.2 equiv) was added to a solution of 3 (0.25 mmol) and 4 (2.0 equiv) during a period of 35 min at ꢀ78 °C.
The resulting mixture was stirred at the same temperature for 10 min. III: A KHMDS (1.2 equiv) solution was added to a solution of 3 (0.29 mmol) in
THF/DMF during a period of 5 min at ꢀ78 °C, and the mixture was stirred at the same temperature for 30 min. A solution of 4 (2.0 equiv) was added to
the solution, and the resulting mixture was stirred for 10 min. c Diastereomeric ratio was determined by 1H NMR of the diastereomeric mixture (see
Supporting Information). d The relative configuration was determined by NOESY spectrum (see Supporting Information). e Enantiomeric excess was
determined by HPLC analysis with a chiral stationaryphase (see SupportingInformation). f Absolute configuration was determined by the conversion to
ent-manzacidin C (see text). g Absolute configuration was determined after the conversion to manzacidin A (see text). h A KHMDS solution in THF (0.5 M)
was used. The solvent ratio shown in the table indicates the final solvent ratio. i Not determined. j A NaHMDS solution in THF (1.85 M) was used. The
solvent ratio shown in the table indicates the final solvent ratio. k A KHMDS solution in toluene (0.5 M) was used. The solvent ratio shown in the table
indicates the final solvent ratio. l A 3.4 mmol scale reaction. m After the addition of KHMDS, the solution was stirred for 120 min at ꢀ78 °C.
866
Org. Lett., Vol. 15, No. 4, 2013

anhydride to give alcohol 16b in 72% yield. Protection of
the primary alcohol and hydrogenolysis of the Cbz group,
followed by treatment with NCS and DBU, gave 17b in
74% yield. Global deprotection of 17b under acidic
conditions followed by esterification with 4-bromo-2-
trichloroacetylpyrrole13a gave manzacidin A in 44% yield,
[R]20D = ꢀ24.2 (c 0.7, MeOH) {lit.11[R]27D = ꢀ28 (c 0.67,
MeOH), lit.13a[R]27D =ꢀ22.4 (c0.52, MeOH)}. The spectral
data of synthetic manzacidin A were identical to those of
the natural product. ent-Manzacidin C was obtained
from 14a by a similar route to that shown in Scheme 3.
The spectral data of synthetic ent-manzacidin C were
identical to those of the natural product except for the
sign of the optical rotation.
Table 2. Asymmetric Intermolecular Conjugate Addition of
Amino Acid Derivatives 6ꢀ9 with 4a
time
(h)
product
(yield)
ee (%)e,f
entry
R
a:bbꢀd
a, b
1
PhCH2 (6)
i-Pr (7)
0.3
24
2
10 (quant)
11 (50%)
3:2
1:0
1:2
1:2
97, 97
87
2g
3
i-Bu (8)
12 (62%)
13 (quant)
97, 97
91, 92
4
MeS(CH2)2 (9)
0.2
a Reactions were run in 0.39, 0.26, 0.34, and 0.52 mmol scale for
entries 1, 2, 3, and 4, respectively, at substrate concentration of 0.1 M.
b A KHMDS solution (1.2 equiv, 0.5 M in THF) was added to a solution
of 6ꢀ9 and 4 (2.0 equiv) in THF/DMF during a period of 50, 30, or
25 min for entries 1, 2 and 3, or 4, respectively at ꢀ78 °C (final ratio of
THF/DMF = 1:1). The resulting mixture was stirred at ꢀ78 °C for the
time indicated in the table. c See footnote c in Table 1. d See footnote d in
Table 1. e See footnote e in Table 1. f Absolute configuration was
tentatively assigned by analogy with 5a and 5b. g Run at ꢀ40 °C.
Scheme 3. Total Synthesis of Manzacidin A
single diastereomer in 50% yield and 87% ee (entry 2).
The reactions of leucine-derived 8 and methionine-de-
rived 9 with 4 took place at ꢀ78 °C to give 12 and 13,
respectively, in 91ꢀ97% ee (entries 3 and 4).
Michael adducts 5a and 5b were transformed into ent-
manzacidin C and manzacidin A, respectively11,13 (Scheme 3).
Treatment of a diastereomeric mixture of 5a (97% ee) and
5b (98% ee) with 4 M HCl in ethyl acetate followed by
regioselective introduction of an N-Boc group gave 14a
and 14b in 32% and 48% yield, respectively as a diaste-
reomerically pure form.14 The pyrimidine ring was formed
via an iminium intermediate generated from the N-MOM
group under acidic conditions. Hydrogenolysis of the
benzyl ester of 14b followed by N-benzyloxycarbonyla-
tion gave 15b in 97% yield. Chemoselective reduction of
the carboxyl group of 15b was accomplished via its mixed
In summary, we have developed a method for asym-
metric intermolecular conjugate addition of R-amino acid
derivatives via memory of chirality and achieved total
syntheses of manzacidin A and ent-manzacidin C. The
Michael adducts obtained by the present method will
provide chiral building blocks for the synthesis of the
manzacidin family and the related natural products.2 The
Michael adducts may also have potential utilities in the
field of medicinal chemistry because they provide a new
class of glutamic acid derivatives.15
(13) For total syntheses of manzacidin A, see: (a) Namba, K.;
Shinada, T.; Teramoto, T.; Ohfune, Y. J. Am. Chem. Soc. 2000, 122,
10708–10709. (b) Wehn, P. M.; Du Bois, J. J. Am. Chem. Soc. 2002, 124,
12950–12951. (c) Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem.
Soc. 2006, 128, 2174–2175. (d) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 3928–3930. (e) Sibi, M. P.; Stanley, L. M.; Soeta, T. Org.
Lett. 2007, 9, 1553–1556. (f) Hashimoto, T.; Maruoka, K. Org. Biomol.
Chem. 2008, 6, 829–835. (g) Ichikawa, Y.; Okumura, K.; Matsuda, Y.;
Hasegawa, T.; Nakamura, M.; Fujimoto, A.; Masuda, T.; Nakano, K.;
Kotsuki, H. Org. Biomol. Chem. 2012, 10, 614–622. (h) Ohfune, Y.; Oe,
K.; Namba, K.; Shinada, T. Heterocyles 2012, 85, 2617–2649.
Acknowledgment. We are grateful to Watanabe Chem-
ical Industries, LTD. for the generous supply of the amino
acid derivatives. This work was supported by a Grant-
in-Aid for Young Scientists (B) (23790010) to T.Y.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Attempted epimerization at the C(4) position of 14a was un-
successful under the basic conditions using DBU or KOt-Bu.
(15) (a) O’Neal, R. M.; Chen, G.-H.; Reynolds, C. S.; Meghal, S. K.;
Koeppe, R. E. Biochem. J. 1968, 106, 699–706. (b) Thomas, H. A.; Ling,
N.; Wei, E. T.; Berree, F.; Cobas, A.; Rapoport, H. J. Pharmcol. Exp.
Ther. 1993, 267, 1321–1326. (c) Gumpena, R.; Kishor, C.; Ganji, R. J.;
Addlagatta, A. ChemMedChem 2011, 6, 1971–1976.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
867