Synthesis of enantiopure α,α-disubstituted amino acids from the asymmetric strecker reaction products of aldehydes

Article abstract of DOI:10.1021/ol0061891

(equation presented) Treatment of the enolates of 4 generated from the asymmetric Strecker reaction products with alkyl halides or aldehydes provided the corresponding functionalized products with high diastereoselectivity. Deprotection of these products

Full text of DOI:10.1021/ol0061891

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2515-2517
Synthesis of Enantiopure
r,r-Disubstituted Amino Acids from the
Asymmetric Strecker Reaction Products
of Aldehydes
,†
Dawei Ma* and Ke Ding‡
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, 354 Fenglin Lu, Shanghai 200032, China,
and Department of Chemistry, Fudan UniVersity, Shanghai 200433, China
madw@pub.sioc.ac.cn
Received June 11, 2000
ABSTRACT
Treatment of the enolates of 4 generated from the asymmetric Strecker reaction products with alkyl halides or aldehydes provided the
corresponding functionalized products with high diastereoselectivity. Deprotection of these products afforded the corresponding enantiopure
r,r-dialkyl amino acids.
The asymmetric synthesis of R,R-disubstituted amino acids
continues to challenge an ever growing group of chemists.1-10
The driving force behind much of this work is based on their
remarkable pharmacological and conformational properties.1
One of the most popular emerging methods1-10 is dia-
(5) By Sharpless epoxidation or dihydroxylation: (a) Shao, H.; Rueter,
J. K.; Goodman, M. J. Org. Chem. 1998, 63, 5240. (b) Hatakeyama, S.;
Fukuyama, H.; Mukugi, Y.; Irie, H. Tetrahedron Lett. 1996, 37, 4047.
(6) By asymmetric Strecker reactions: (a) Ma, D.; Tang, G.; Tian, H.
Tetrahedron Lett. 1999, 40, 5753 (published erratum appeared in Tetra-
hedron Lett. 1999, 40, 9385). (b) Ma, D.; Tian, H. Zou, G. J. Org. Chem.
1999, 64, 120. (c) Ohfune, Y.; Moon, S.; Horikama, M. Pure Appl. Chem.
1996, 68, 645. (d) Ohfune, Y.; Horikawa, M. J. Synth. Org. Chem. Jpn.
1997, 55, 982. (e) Cordi, A. A.; Lacoste, J.-M.; Borgne, F. L.; Herve, Y.;
Vaysse-Ludot, L.; Descombes, J.-J. Courchay, C.; Laubie, M.; Verbeuren,
T. J. J. Med. Chem. 1997, 40, 2931, and references therein.
(7) Through chiral sulfinamides: (a) Hua, D. H.; Miao, S.; Chen, J.;
Iguchi, S. J. Org. Chem. 1991, 56, 4. (b) Bravo, P.; Crucianelli, M.; Vergani,
B.; Zanda, M. Tetrahedron Lett. 1998, 39, 7771.
† Shanghai Institute of Organic Chemistry.
‡ Fudan University.
(1) For reviews, see (a) Cativiela, M. D.; Diaz-De-Villegas, M. D.
Tetrahedron: Asymmetry 1998, 9, 3517. (b) Wirth, T. Angew. Chem., Int.
Ed. Engl. 1997, 36, 225. (c) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2708. (d) Williams, R. M.; Hendrix, J. A.
Chem. ReV. 1992, 92, 889.
(2) By alkylation of acyclic chiral esters: (a) Badorrey, R.; Cativiela,
C.; Diaz-de-Villegas, M. D.; Galvez, J. A.; Lapena, Y. Tetrahedron:
Asymmetry 1997, 8, 311. (b) Berkowitz, D. B.; Smith, M. K. J. Org. Chem.
1995, 60, 1233.
(3) By self-regeneration of stereogenic center strategy: (a) Schollkopf,
U. Pure Appl. Chem. 1983, 55, 1799. (b) Hsiao, Y.; Hegedus, L. S. J. Org.
Chem. 1997, 62, 3586. (c) Zhang, L.; Finn, J. M. J. Org. Chem. 1995, 60,
5719. (d) Smith, A. B.; Benowitz, A. B.; Favor, D. A.; Sprengeler, P. A.;
Hirschmann, R. Tetrahedron Lett. 1997, 38, 3809. (e) Acton, J. J.; Jones,
A. B. Tetrahedron Lett. 1996, 37, 4319. (f) Chinchilla, R.; Falvello, L. R.;
Galindo, N.; Najera, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 995. (g)
Juaristi, E.; Lopez-Ruiz, H.; Madrigal, D.; Ramirez-Quiros, Y.; Escalante,
J. J. Org. Chem. 1998, 63, 4706.
(8) By chiral memory strategy: (a) Fuji, K.; Kawabata, T. Chem. Eur.
J. 1998, 4, 373. (b) Ferey, V.; Toupet, L.; Gall, T. L.; Mioskowski, C.
Angew. Chem. Int. Ed. Engl. 1996, 35, 430.
(9) By chiral phase transfer catalysts: (a) Lygo, B.; Crosby, J.; Peterson,
J. A. Tetrahedron Lett. 1999, 40, 8671. (b) Belokon, Y. N.; Kochetkov, K.
A.; Churkina, T. D.; Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.;
Parmar, V. S.; Kumar, R.; Kagan, H. B. Tetrahedron: Asymmetry 1998, 9,
851.
(10) By rearrangement reactions: (a) Frutos, R. P.; Spero, D. M.
Tetrahedron Lett. 1998, 39, 2475. (b) Imogai, H.; Petit, Y.; Larcheveque,
M. Tetrahedron Lett. 1996, 37, 2573.
(4) By enzymatic resolution: Spero, D. M.; Kapadia, S. R. J. Org. Chem.
1996, 61, 7398.
10.1021/ol0061891 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/08/2000

stereolective functionallization of an enantiopure R-amino
acids via a nonracemic enolate.3 However, this method is
restricted by the lack of enantiopure R-amino acids. On the
other hand, although asymmetric Strecker reactions starting
with chiral amines have been successfully used in synthesiz-
ing chiral R-monosubstituted R-amino acids from aldehydes
with good diastereoselectivity (Scheme 1),11 this reaction’s
Scheme 2
Scheme 1
the diastereoselectivity of over 200:1 as detected by HPLC.
Its stereochemistry was assigned by its single-crystal X-ray
analysis in which the 5-n-propyl group is cis to the 3-phenyl
group. This result indicated that the configuration of 5-posi-
tion is R.
Encouraged by this result, we tested several different
electrophiles and substrates, and the results are summarized
in Table 1. Other alkyl halides such as benzyl bromide and
capability to afford chiral R,R-disubstituted R-amino acids
from ketones is still limited because of the low reactivity of
ketones and low diastereoselectivity of the products.6 Our
idea is to combine these two methods to prepare enantiopure
R,R-disubstituted amino acids as shown in Scheme 1. The
asymmetric Strecker reaction products of an aldehyde could
be converted into lactone A under the conditions indicated
in Scheme 1, which can serve as a nonracemic enolate upon
the treatment of a suitable base. The reactions of this enolate
with various electrophiles would provide functionalized
products B. If the diastereoselectivity in this step was good
we would be able to obtain enantiopure R,R-disubstituted
amino acids after deprotection of B.
Table 1. Diastereoselective Functionallization of 412
With this idea in mind, we prepared the lactone 1a as a
mixture of two diastereomers from butyraldehyde according
to the known procedure except for using KCN instead of
TMSCN and cyclization of the resultant ester under refluxing
in toluene.11 Initially, direct alkylation of 1a with methyl
bromoacetate mediated by NaHMDS was attempted and it
was found that two diastereomers 2 (45%) and 3 (14%) were
formed (Scheme 2). To improve the diastereoselectivity, we
tried to modify the structure of 1a. Thus it was converted
into 4a by treatment with benzyl bromide and potassium
carbonate in DMF. As we expected, the alkylation of 4a with
methyl bromoacetate provided a single diastereomer 5a, with
entry
substrate
electrophile
product
yield (%)a
1
2
3
4
5
6
7
4a
4b
4b
4b
4b
4a
4a
BrCH2CO2Me
BnBr
EtI
n-PrCHO
BrCH2CO2Me
BnBr
5a
5b
5c
5d
5e
5f
76
90
50
80b
87
85
85b
CH3CHO
5g
a Isolated yield. b Based on 50% starting material recovery.
ethyl iodide were found to be suitable for functionallization
of 4 and gave the corresponding alkylation products in similar
diastereoselectivities (entries 2-3, 5-6). When aldehydes
were used as the electrophiles, the reaction gave two isomers
and the ratio for them ranged from 8:1 to 10:1 (entries 4
and 7). By recrystallization the pure major isomer 5d or 5g
was obtained. To determine the stereochemistry of two
(11) (a) Chakraborty, T. K.; Reddy, G. V.; Hussain, K. A. Tetrahedron
Lett. 1991, 32, 7597. (b) Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V.
Tetrahedron 1995, 51, 9179.
(12) Typical Procedure for Functionalization of 4. A solution of 4 (5
mmol) in DME-THF (1:1, 1 mL) was cooled to -78 °C under argon before
NaHMDS in THF (6 mmol) was added over 15 min. The stirring was
continued for 1 h and then benzyl bromide (6 mmol) was added. After the
reaction was completed as monitored by TLC, ether workup followed by
chromatography afforded 5.
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Org. Lett., Vol. 2, No. 16, 2000

stereogenic centers in this coupling reaction, the alcohol 5d
was recrystallized to give a single crystal. X-ray analysis
showed that the configuration of 5d was 3R,5S,1′S (Scheme
2). This stereochemistry was quite surprising, because in
compound 5a the configuration of the 5-position was R!
Obviously, the reason for this difference was that different
electrophiles were employed. These results promoted us to
check the stereochemistry of 5b, 5c, and 5f that were
generated by alkylation with simple alkyl halides. We
decided to solve this problem by conversion of 5b to the
known amino acid 6. Thus, treatment of 5b with aqueous
NaOH opened the lactone ring. The generated sodium salt
was neutralized with HCl before being deprotected by Pd/
C-catalyzed hydrogenation (40 atm and 40 °C) to give the
crude amino acid, which was purified with Dowex-50W to
afford 6 ([R]19 -22.2 (c 2.8, H2O), lit. [R]25 -22 (c 1.0,
Figure 1. Asymmetric induction of the enolates C derived from
4.
phile from the backside of the benzyl group and give the
(3R,5S)-product. However, as mentioned above, when so-
dium enolates of 4 attacked methyl bromoacetate, the
coupling products had (3R,5R)-configuration. The reason for
this exception is not clear, but one possible explanation is
that this stereochemistry might come from some chelation
between the ester moiety of methyl bromoacetate and sodium
enolates.
According to the procedure for preparing 6 from 5b, the
lactone 5a was transformed into (R)-R-methylaspartic acid
in 72% yield (Scheme 3). From the functionalized products
R,R-disubstituted amino acids could be obtained in another
manner as demonstrated by the conversion of 5g to 8.
Refluxing of 5g in 6 N HCl to open the lactone ring followed
by Pd/C-catalyzed hydrogenation to cleavage the benzyl
groups afforded 8 in 80% yield.
D
D
H2O) for (S)-R-methylphenylalanine) in 62% yield (Scheme
3). This result implied that the quarternary carbon in 5b, 5c,
and 5f might have S-form configuration.
Scheme 3
In conclusion, we have developed a five-step method to
synthesize R,R-diasubstituted amino acids from aldehydes,
using chiral phenylglycinol as a chiral auxiliary. The key
step is the diastereoselective functionalization of the lactones
4 with some highly reactive electrophiles. This method is
suitable for preparing enantiopure R-dialkyl amino acids,
especially R-alkyl aspartic acids and R,R-disubstituted
analogues of serine and threine.
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (grant 29725205) and Qiu Shi Science & Technolo-
gies Foundation for their financial support.
At this stage we concluded that when sodium enolates of
4 reacted with aldehydes or some simple alkyl halides, the
(3R,5S)-products were formed. This stereochemistry could
be explained by Figure 1. When 4 was used as a substrate,
the generated enolate would prefer the conformation C, in
which the N-benzyl group and the phenyl group are trans to
each other. This enolate would attack favorably the electro-
Supporting Information Available: Experimental details
for the synthesis and product characterizations and X-ray
structures of 5a and 5d. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0061891
Org. Lett., Vol. 2, No. 16, 2000
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