A convenient synthesis of chiral β3-amino acids

Article abstract of DOI:10.1055/s-2002-35608

A novel method for the synthesis of chiral β³-amino acids is developed where the acid functionality was built by oxidative cleavage of an α-allylic group that was introduced by Evans' asymmetric alkylation of an appropriate acid substrate and the amino part came from the amide of the original carboxyl group following a modified Hofmann rearrangement reaction.

Full text of DOI:10.1055/s-2002-35608

LETTER
2039
3
A Convenient Synthesis of Chiral -Amino Acids
3
S
ynthesis of Ch
u
iral -Amin
s
oAcids har K. Chakraborty,* Animesh Ghosh
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)7160387; E-mail: chakraborty@iict.ap.nic.in; E-mail: chakraborty@iict.res.in
Received 7 September 2002
equally well with both alkyl- and aryl-substituted com-
pounds and can be applied to prepare both D- and L-iso-
mers.
Abstract: A novel method for the synthesis of chiral 3-amino ac-
ids is developed where the acid functionality was built by oxidative
cleavage of an -allylic group that was introduced by Evans’ asym-
metric alkylation of an appropriate acid substrate and the amino part
came from the amide of the original carboxyl group following a
modified Hofmann rearrangement reaction.
The salient features of this route are: (a) the carboxyl
group of the final amino acids was obtained by oxidative
cleavage of an -allyl group that was introduced in the -
position of the corresponding carboxylic substrate by
Evans’ alkylation method;5 (b) the original carboxyl
group was converted to an amide that was transformed
into the amino group by a modified Hofmann rearrange-
ment reaction6 (Scheme 1).
Key words: -amino acids, Hofmann rearrangement, oxazolidi-
none, Evans’ reaction
While there are many forms of amino acids, all of the im-
portant amino acids found in living organisms are -ami-
no acids. However, peptides from -amino acids are
physiologically unstable due to their cleavage by pro-
teolytic enzymes. This problem can be tackled by intro-
ducing unnatural components, like -amino acids, in the
peptides.1 Development of several biologically active -
peptides have already been reported.2 Syntheses of these
-peptide based compounds depend largely on the effi-
cient construction of the unusual -amino acid compo-
nents.3,4 In this paper, we describe a new method for the
stereoselective synthesis of 3-amino acids that works
The synthesis started with the chiral oxazolidinone 1.
Treatment of 1 with NaHMDS in THF provided the
enolate that was stereoselectively alkylated with allyl bro-
mide following Evans’ method5 to furnish the -allyl-
substituted intermediate 27 with excellent diastereoselec-
tivity.8 Removal of the chiral auxiliary9 using LiOH–H2O2
led to the formation of an acid 37 that was transformed into
its amide 4 in the next step by the mixed anhydride meth-
od.10 Treatment of 3 with ethyl chloroformate in the pres-
ence of Et3N gave an intermediate mixed anhydride,
which was treated in situ with NH4OH to provide amide
Bn
Bn
i
ii
iii
O
O
N
N
OH
R
R
R
O
O
O
O
O
2
3
1
a: R = Ph; b: R = Me; c: R = (CH3)2CH; d: R = C8H17; e: R = C16H33
CO2Me
CO2Me
CO2H
vi
iv
v
NH2
NH2
R
R
NHBoc
R
R
NHBoc
O
O
7
6
5
4
Scheme 1 Synthesis of 3-amino acids. Reagents and conditions: (i) NaHMDS (1.5 equiv), THF, 78 °C, 1 h; followed by allyl bromide (4.0
equiv), 78 °C to r.t., 1 h; then 45 °C, 4 h (65% for 1a, 73% for 1b, 60% for 1c, 71% for 1d, 70% for 1e). (ii) LiOH (2.0 equiv), aq H2O2 (30%,
6.0 equiv), THF–H2O (3:1, 0.05 M concd.), 0 °C to r.t., 5 h (91% for 2a, 84% for 2b, 87% for 2c, 92% for 2d, 95% for 2e). (iii) Et3N (1.1 equiv),
ClCO2Et (1.1 equiv), THF, 20 °C, 0.5 h; then aq NH4OH (25%, 5.0 equiv), 0 °C, 1.5 h (94% for 3a, 91% for 3b, 94% for 3c, 92% for 3d, 96%
for 3e). (iv) 1) RuCl3 3H2O (0.001 equiv), NaIO4 (4.0 equiv), CCl4–CH3CN–H2O (1:1:1.5), 0 °C to r.t., 1 h; 2) ethereal CH2N2, 0 °C (57% for
4a, 61% for 4b, 63% for 4c, 58% for 4d, 49% for 4e). (v) PhI(CF3CO2)2 (1.2 equiv), CH3CN:H2O (1:1), r.t., 2.5 h; then Boc2O (2.0 equiv), Et3N
(4.0 equiv), 0 °C, 1 h (68% for 5a, 70% for 5b, 66% for 5c, 68% for 5d, 61% for 5e). (vi) LiOH (4.0 equiv), MeOH–THF–H2O (1:1.5:1), 0 °C
to r.t., 1 h (92% for 6a, 90% for 6b, 89% for 6c, 93% for 6d, 92% for 6e).
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2039,2040,ftx,en;G26302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

2040
T. K. Chakraborty, A. Ghosh
LETTER
1999, 64, 12. (j) Myers, J. K.; Jacobsen, E. N. J. Am. Chem.
Soc. 1999, 121, 8959. (k) Evans, D. A.; Wu, L. D.; Wiener,
J. J. M.; Johnson, J. S.; Ripin, D. H. B.; Tedrow, J. S. J. Org.
Chem. 1999, 64, 6411. (l) Prabhakaran, E. N.; Iqbal, J. J.
Org. Chem. 1999, 64, 3339. (m) Guichard, G.; Abele, S.;
Seebach, D. Helv. Chim. Acta 1998, 81, 187. (n) Kunz, H.;
Burgard, A.; Schanzenbach, D. Angew. Chem., Int. Ed. Engl.
1997, 36, 386. (o) Enders, D.; Wahl, H.; Bettray, W. Angew.
Chem. Int., Ed. Engl. 1995, 34, 455.
4. With the amide in hand, the step was now set to carry
out the oxidative cleavage of the double bond. Treatment
of 4 with NaIO4 in the presence of catalytic amount of
RuCl3 3H2O in CH3CN–CCl4–H2O (1:1:1.5) gave the ex-
pected acid that was esterified after aqueous work-up with
CH2N2 to furnish methyl ester 5. Next, the crucial Hof-
mann rearrangement reaction6 was performed on 5 via
treatment
with
[bis(trifluoroacetoxy)iodo]benzene
(4) (a) It is not possible to list here all the references on the
synthesis of -amino acids. However, searches in http://
www.sciencedirect.com under ‘synthesis of -amino acids’
and ‘amino acids’ in http://pubs.acs.org and http://
www.wiley-vch.de/publish/en/journals/search/ will give
detailed lists of most of the references. (b) For earlier
references on the synthesis of -amino acids see:
Enantioselective Synthesis of -Amino Acids; Juaristi, E.,
Ed.; Wiley-VCH: New York, 1997.
[PhI(CF3COO)2] in CH3CN–H2O (1:1) to provide the cor-
responding amine that was treated in situ with Boc2O and
Et3N to furnish the N-Boc-protected methyl ester of the
expected -amino acid 67 in excellent overall yields.
Compound 6a on saponification with LiOH gave Boc-D-
26
3-HPhg-OH 7a that showed rotation, [ ]D
42.5 (c
26
0.75, EtOH), matching the reported value [ ]D
42.2.11
(5) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737.
In conclusion, an excellent method for the synthesis of
3-amino acids is developed that will find useful applica-
tions in the preparation of many unusual -amino acids in
either enantiomeric form starting from an appropriate
chiral oxazolidinone. While L-phenylalanine based ox-
azolidone 1 gives D-amino acids as shown in this paper, its
D-isomer can be similarly used to prepare the correspond-
ing L- -amino acids. Further work is in progress.
(6) (a) Yu, C.; Jiang, Y.; Liu, B.; Hu, L. Tetrahedron Lett. 2001,
42, 1449. (b) Huang, X.; Seid, M.; Keillor, J. W. J. Org.
Chem. 1997, 62, 7495. (c) Zhang, L.; Kauffman, G. S.;
Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. (d) Waki,
M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266.
(7) All new compounds were characterized by IR, NMR and
mass spectroscopic studies. Representative experimental
procedures for the key steps: Synthesis of 2a: To a stirred
solution of 1a (2.5 g, 8.47 mmol) in anhyd THF (20 mL) at
78 °C, NaHMDS (6.35 mL, 2 M solution in THF, 12.7
mmol) was added and stirring was continued at the same
temperature for 1 h. Next, allyl bromide (2.93 mL, 33.88
mmol) was added to the reaction mixture and the
temperature was slowly raised to 45 °C over a period of 45
minutes. After stirring for 4 h at 45 °C, the reaction mixture
was quenched with saturated NH4Cl solution and allowed to
warm up to room temperature. It was extracted with EtOAc
(2 50 mL), the extracts were combined, washed with brine,
dried (Na2SO4) and concentrated in vacuo. Purification by
column chromatography (SiO2, 12.5% EtOAc in petroleum
ether as eluant) furnished the major isomer 2a (1.84 g, 65%)
as a syrup.
Acknowledgement
The authors wish to thank CSIR, New Delhi for research fellowship
(A. G.).
References
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Synlett 2002, No. 12, 2039–2040 ISSN 0936-5214 © Thieme Stuttgart · New York