Preliminary studies on a novel synthesis of β-amino acids: stereocontrolled transformation of d- and l-glyceraldehyde into 3-amino-2-(2′,2′-dimethyl-1′,3′-dioxolan- 4′-yl)propanoic acids

Article abstract of DOI:10.1016/j.tetasy.2006.11.037

A stereocontrolled synthesis of the methyl ester of (2S)-3-amino-2-((4′S)-2′,2′-dimethyl-1′,3′ -dioxolan-4′-yl)propanoic acid from d-glyceraldehyde is described for the first time. This method involves the stereoselective Michael addition of the lithium s

Full text of DOI:10.1016/j.tetasy.2006.11.037

Tetrahedron: Asymmetry 17 (2006) 3063–3066
Preliminary studies on a novel synthesis of b-amino acids:
stereocontrolled transformation of D- and L-glyceraldehyde into
3-amino-2-(20,20-dimethyl-10,30-dioxolan-40-yl)propanoic acids
*
´
´
´
´
´
Fernando Fernandez, Jose M. Otero, Juan C. Estevez and Ramon J. Estevez
Departamento de Quı´mica Orga´nica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Received 13 October 2006; accepted 24 November 2006
Abstract—A stereocontrolled synthesis of the methyl ester of (2S)-3-amino-2-((40S)-20,20-dimethyl-10,30-dioxolan-40-yl)propanoic acid
from D-glyceraldehyde is described for the first time. This method involves the stereoselective Michael addition of the lithium salt of
tris(phenylthio)methane to (S)-2,2-dimethyl-4-((E)-2-nitrovinyl)-1,3-dioxolane followed by hydrolysis of the resulting (4S)-2,2-
dimethyl-4-((20S)-30-nitro-10,10,10-tris(phenylthio)propan-20-yl)-1,3-dioxolane to (2S)-methyl 2-((40S)-20,20-dimethyl-10,30-dioxolan-40-
yl)-3-nitropropanoate, which was finally reduced to the target compound. A similarly stereocontrolled transformation of L-glyceralde-
hyde into (2R)-methyl 3-amino-2-((40R)-20,20-dimethyl-10,30-dioxolan-40-yl)propanoate is also described.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
activity.2b,5 Moreover, these b-peptides can adopt novel
and unique folding patterns.3
The biological functions and pharmacological limitations
of natural peptides have, in recent years, prompted intense
work on the preparation of analogues resulting from the
replacement of one or more a-amino acids by unnatural
and rare amino acids. The resulting compounds have
become increasingly important due to the significant bio-
logical activities that have been observed.1,2 The best
candidates for such replacements are b-amino acids, mainly
because their oligomers do not exhibit the pharmacological
limitations of natural peptides due to their resistance to
enzymatic degradation and their tendency to be more rigid
than a-peptides.3 Accordingly, there has recently been a
great deal of interest in the enantioselective synthesis of
b-amino acids. However, while there are numerous routes
to achiral b2-amino acids, their EPC synthesis is currently
the subject of many investigations.4 Research efforts in this
field are due to the importance of these compounds. In fact,
it has been shown that when b2-amino acids are included in
peptides or in naturally occurring compounds, they lead to
entities that, in some cases, show cytotoxic or antiviral
Nitroolefins are powerful Michael acceptors that have re-
ceived considerable attention due to their special chemical
properties.6 These compounds are readily attacked by a
wide range of nucleophiles to produce nitroalkanes bearing
a stereogenic centre at the 2-position, a fact that makes
them powerful tools for the construction of C–C bonds
by addition of organometallics to the electron-deficient
double bond. Following the addition reaction, the nitro
group can be transformed into a diverse range of function-
alities (amines, oximes, ketones, carboxylic acids, etc.) to
provide a wide range of chemical compounds. This versa-
tile chemical protocol has recently been applied to the
enantioselective preparation of b2-amino acids by the addi-
tion of organometallics to 3-nitropropenoates7 and to 3,3-
dialkoxy-1-nitroprop-1-enes8 with asymmetric catalysis,
followed by the reduction of the resulting 2-substituted 3-
nitro derivatives and the subsequent generation of their
respective carboxylic acid moieties. A variant of this strat-
egy involves conjugate addition of organometallics to opti-
cally active nitroalkenes, such as 2,2-dimethyl-4-[(E)-2-
nitrovinyl]-1,3-dioxolanes. These compounds are synthetic
equivalents of nitroacrylates and have proven to be versa-
tile precursors for the synthesis of enantiopure b-amino
acids, in which the nitro group is again a precursor for
*
Corresponding author. Tel.: +34 981 563100; fax: +34 981 591014;
e-mail: qorjec@usc.es
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.037

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F. Ferna´ndez et al. / Tetrahedron: Asymmetry 17 (2006) 3063–3066
the amino functionality and the dioxolanyl side chain pro-
vides the carboxylic acid moiety by glycol cleavage.9
(Fig. 1).13 The stereoselectivity is due to the dioxolane sub-
unit of the nitroolefin 2a, which only allows attack by the
bulky tris(phenylthio)methyl anion on the less hindered
face of the double bond. Deprotection of the masked car-
boxyl group of 3a by treatment with HgO and BF3ÆOEt2
was followed by the reduction of the resulting b-nitro ester
4a to the desired b-amino ester 5a by catalytic hydrogena-
tion with Pd–C. Freshly isolated 5a was subjected to pep-
tide coupling with benzyloxycarbonylglycine, TBTU and
DIPEA to give the expected dipeptide 6a. This compound
was reacted with barium hydroxide and the resulting car-
boxylic acid was directly coupled with methoxycarbonyl-
glycine in the presence of HATU and DIPEA to give
tripeptide 7a.
An alternative approach consisting of the addition of car-
boxyl-synthetic equivalents to electron-deficient nitro-
alkenes remains practically unexplored. To the best of our
knowledge, only one example has been described and this
involves an organocatalytic asymmetric addition of 2,4-
pentadione to nitroolefins.10 Following this addition, a
long reaction sequence is required to generate the carboxyl
function of the corresponding b-amino acids. Moreover,
the preparation of b-amino acids involving the addition
of a carboxyl-synthon equivalent to optically active nitro-
alkenes has not yet been described. We report here our pre-
liminary results on a novel synthesis of sugar b-amino
acids, illustrated by the diastereoselective transformation
of D-glyceraldehyde into the corresponding b-amino acid
ester 5a via (S)-2,2-dimethyl-4-((E)-2-nitrovinyl)-1,3-dioxo-
lane 2a. L-Glyceraldehyde was similarly converted into b-
amino acid ester 5b via b-nitro acid ester 4b. In our ap-
proach tris(phenylthio)methyl was used as a bulky car-
boxyl synthon.
On the other hand, nitroolefin 2b was easily obtained from
L-glyceraldehyde14 in a similar way to the preparation of
analogue 2a. As expected, reaction of 2b with the lithium
salt of tris(phenylthio)methane under the same conditions
as for 2a, gave compound 3b (90% yield) as the only stereo-
isomer. When compound 3b was subjected to the above
protocol, b-amino ester 5b (enantiomer of 5a) was formed
via b-nitro ester 4b (Scheme 2). Incorporation of this novel
b-amino acid 5b into tripeptide 7b via dipeptide 6b was car-
ried out using the same approach as for the preparation of
tripeptide 7a.
Reaction of the lithium salt of tris(phenylthio)methane
with nitroolefin 2a11 at ꢀ78 ꢁC gave stereoisomer 3a12 as
the only product (90% yield) (Scheme 1). The structure of
3a was unambiguously established by X-ray diffraction
2. Conclusion
In conclusion, we have reported here the preliminary results
on a novel synthesis of b-amino acids, which may prove to
be simpler and more efficient than previous approaches. The
route involves the Michael addition of lithium tris(phen-
ylthio)methane (a carboxyl synthetic equivalent) to nitro-
olefins, followed by removal of the carboxyl masking group
and reduction of the nitro group to the amino group. The
remarkable stereoselectivity achieved in the preparation of
the novel amino acids 5a and 5b suggests that this approach
will be of particular interest for the stereoselective prepara-
tion of b-amino acids derived from nitroethylenes bearing a
chiral substituent at the 2-position.
Work is currently in progress to extend this route to the
plethora of tetroses, pentoses and hexoses in order to pre-
Figure 1. X-ray structure of compound 3a.
O
O
O
O
ii
i
O
iii
O
O
H
NO2
SPh
O
NO2
OMe
4a
NO2
O
PhS
O
1a
SPh
2a
3a
O
O
O
O
iv
v
O
O
vi
NHGlyCbz
NHGlyOMe
NH2
OMe
NHGlyCbz
OMe
O
O
O
7a
6a
5a
Scheme 1. Reagents and conditions: (i) (a) CH3NO2, KFÆ2H2O, iPrOH, rt, 14 h, 90% yield; (b) MsCl, Et3N, CH2Cl2, ꢀ20 ꢁC, 15 min, 94% yield. (ii)
(PhS)3CH, n-BuLi, THF, ꢀ78 ꢁC, 15 min, 90% yield. (iii) HgO, BF3ÆOEt2, MeOH/THF/H2O, rt, 48 h, 66% yield. (iv) H2, Pd–C, AcOEt, rt, 4 h, 68% yield.
(v) CbzGlyOH, TBTU, DIPEA, CH2Cl2, rt, 12 h, 62% yield. (vi) (a) Ba(OH)2Æ8H2O, THF/H2O, rt, 30 min, 90% yield; (b) MeOGlyHÆHCl, HATU,
DIPEA, CH2Cl2, rt, 12 h, 69% yield.

F. Ferna´ndez et al. / Tetrahedron: Asymmetry 17 (2006) 3063–3066
3065
O
O
O
O
ii
i
O
iii
O
O
H
NO2
SPh
O
NO2
OMe
4a
NO2
O
PhS
O
1a
SPh
2a
3a
O
O
O
O
iv
v
O
O
vi
NHGlyCbz
NHGlyOMe
NH2
OMe
NHGlyCbz
OMe
O
O
O
7a
6a
5a
Scheme 2. Reagents and conditions: (i) (a) CH3NO2, KFÆ2H2O, iPrOH, rt, 14 h, 87% yield; (b) MsCl, Et3N, CH2Cl2, ꢀ20 ꢁC, 15 min, 93% yield. (ii)
(PhS)3CH, n-BuLi, THF, ꢀ78 ꢁC, 15 min, 82% yield. (iii) HgO, BF3ÆOEt2, MeOH/THF/H2O, rt, 48 h, 69% yield. (iv) H2, Pd–C, AcOEt, rt, 4 h, 83% yield.
(v) CbzGlyOH, TBTU, DIPEA, CH2Cl2, rt, 12 h, 70% yield. (vi) (a) Ba(OH)2Æ8H2O, THF/H2O, rt, 30 min, 98% yield; (b) MeOGlyHÆHCl, HATU,
DIPEA, CH2Cl2, rt, 12 h, 64% yield.
O. In The Nitro Group in Organic Synthesis; Feuer, H., Ed.;
Organic Nitro Chemistry Series; Wiley-VCH, 2001, Chapter 3.
7. (a) Eilitz, U.; Lebmann, F.; Seidelmann, O.; Wendisch, V.
Tetrahedron: Asymmetry 2003, 14, 189; (b) Rimkus, A.;
Sewald, N. Org. Lett. 2003, 5, 79.
pare a wide range of novel sugar b-amino acids, including
polyhydroxylated cyclopentane and cyclohexane b-amino
acids, which could be of great interest for incorporation
into peptides. Our future plans also include the application
of this novel approach to b-amino acids to a wide range of
nitroolefins in order to explore its general applicability.
8. Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2003, 125, 3700.
9. Hubner, J.; Liebscher, J.; Pa¨tzel, M. Tetrahedron 2002, 58,
¨
10485.
Acknowledgements
10. Wan, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett. 2005,
21, 4713.
11. For the preparation of nitroelefin 2a from D-glyceraldehyde
see: (a) Kozikowski, A. P.; Li, C.-S. J. Org. Chem. 1985, 50,
778; (b) Mangione, M. I.; Suarez, A. G.; Spanevello, R. A.
Carbohydr. Res. 2005, 340, 149.
We thank the Spanish Ministry of Education and Science
´
for financial support and for a grant to Jose M. Otero,
and the Xunta de Galicia for a grant to Fernando
´
Fernandez.
12. All new compounds gave satisfactory spectroscopic and
analytical data. Selected physical and spectroscopic data are
27
1
References
as follows. Compound 3a: ½aꢁD ¼ ꢀ44:5 (c 1.05, CHCl3). H
NMR (CDCl3) d 1.19, 1.29 (2 · s, 6H, 2 · CH3), 3.31 (ddd,
0
0
0
0
0
1. For excellent reviews, see: (a) Gellman, S. H. Acc. Chem. Res.
1998, 31, 717; (b) Kirshenbaum, K.; Zuckermann, R. N.; Dill,
K. A. Curr. Opin. Struct. Biol. 1999, 9, 530; (c) Stigers, K. D.;
Soth, M. J.; Nowick, J. S. Curr. Opin. Chem. Biol. 1999, 3,
714; (d) Andrews, M. J. L.; Tabor, A. B. Tetrahedron 1999,
55, 11711; (e) Venkatraman, J.; Shankaramma, S. C.;
Balaram, P. Chem. Rev. 2001, 101, 3131.
2. (a) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1; (b)
Reinelt, S.; Marti, M.; Dedier, S.; Reitinger, T.; Folkers, G.;
de Castro, J. A.; Rognan, D. J. Biol. Chem. 2001, 276, 24525.
3. For a recent review on b-peptides, see: Cheng, R. P.;
Gellman, S. H.; DeGrado, W. Chem. Rev. 2001, 101, 3219,
which includes references to work by the Seebach and
Gellman groups—the most active in this field.
J2 ;3 ¼ 8:0 Hz; J2 ;4 ¼ 5:8 Hz; J2 ;3 ¼ 2:0 Hz, 1H, H-20), 3.47
(dd, J5,5 = 8.5 Hz, J5,4 = 6.8 Hz, 1H, H-5), 4.12 (dd, J5,5
=
0
0
8.5 Hz, J5,4 = 6.3 Hz, 1H, H-5), 4.65 (dd, J3 ;3
¼
15:0 Hz; J3 ;2 ¼ 9:0 Hz, 1H, H-30), 4.68–4.76 (m, 1H, H-4),
0
0
4.87 (dd, J3 ;3 ¼ 15:0 Hz; J3 ;2 ¼ 2:0 Hz, 1H, H-30), 7.30–
7.47 (m, 9H, 9 · Ar–H); 7.64–7.70 (m, 6H, 6 · Ar–H). 13C
NMR (CDCl3) d 24.65, 25.05, 48.74, 70.69, 73.40, 73.75,
77.00, 108.76, 128.65, 129.70, 130.16, 135.97. MS (CI) m/z
(%) 514 (MH+, 2); 498 (1); 456 (1); 438 (2); 404 (88); 111
0
0
0
0
26
(100). Compound 4a: ½aꢁD ¼ ꢀ23:2 (c 1.23, CHCl3). 1H
NMR (CDCl3) d 1.33, 1.42 (2 · s, 6H, 2 · CH3), 3.22 (dt,
0
J2,3 = 8.0 Hz, J2,3 = 3.9 Hz, J2;4 ¼ 3:9 Hz, 1H, H-2), 3.77 (s,
0
0
0
0
3H, OCH3); 3.91 (dd, J5 ;5 ¼ 8:7 Hz; J5 ;4 ¼ 5:2 Hz, 1H, H-
50); 4.21 (dd, J5 ;5 ¼ 8:7 Hz; J5 ;4 ¼ 6:0 Hz, 1H, H-50); 4.29–
4.37 (m, 1H, H-40); 4.75 (dd, J3,3 = 15.0 Hz, J3,2 = 3.9 Hz,
1H, H-3); 4.87 (dd, J3,3 = 15.0 Hz, J3,2 = 8.0 Hz, 1H, H-3).
13C NMR (CDCl3) d 24.55, 26.11, 46.90, 52.35, 68.04, 72.23,
72.80, 109.62, 169.75. MS (CI) m/z (%) = 234 (MH+, 42), 218
0
0
0
0
4. For a recent review on b2-amino acids, see: (a) Lelais, G.;
Seebach, D. Biopolymers 2004, 76, 2006; See also: (b)
Beddow, J. E.; Davies, S. G.; Smith, A. D.; Russell, A. J.
Chem. Commun. 2004, 2778; (c) Sammis, G. M.; Jacobsen, E.
N. J. Am. Chem. Soc. 2003, 125, 4442; (d) Davies, H. M. L.;
Venkataramani, C. Angew. Chem., Int. Ed. 2002, 41, 2197; (e)
Bower, F.; Roshan, J.-J.; Williams, A.; Williams, M. J. J.
J. Chem. Soc., Perkin Trans. 1 1997, 1411.
5. (a) Lew, R. A.; Boulos, E.; Stewart, K. M.; Perlmutter, P.;
Harte, M. F.; Bond, S.; Aguilar, M. I.; Smith, A. I. J. Pept.
Sci. 2000, 9, 440; (b) Abele, S.; Vo¨gtli, K.; Seebach, D. Helv.
Chim. Acta 1999, 82, 1539.
27
(23), 175 (100), 129 (9). Compound 6a: ½aꢁD ¼ ꢀ14:7 (c 1.20,
1
CHCl3). H NMR (CDCl3) d 1.33, 1.41 (2 · s, 6H, 2 · CH3),
2.65–2.75 (m, 1H, H-2), 3.60–3.69 (m, 2H, H-3 + H-3), 3.71
0
0
0
0
(s, 3H, OCH3), 3.77 (dd, J5 ;5 ¼ 8:5 Hz; J5 ;4 ¼ 6:0 Hz, 1H,
H-50), 3.85 (2 · d, JH,H = 5.8 Hz, JH,H = 5.8 Hz, 2H,
0
0
0
0
CH2Gly), 4.12 (dd, J5 ;5 ¼ 8:5 Hz; J5 ;4 ¼ 6:3 Hz, 1H, H-
50), 4.29–4.37 (m, 1H, H-40), 5.13 (s, 2H, CH2Ph), 5.34 (br s,
1H, NH), 6.58 (br s, 1H, NH), 7.32–7.38 (m, 5H, 5 · Ar–H).
13C NMR (CDCl3) d 24.92, 26.30, 38.07, 44.27, 48.56, 51.98,
66.87, 67.80, 74.51, 109.41, 127.86, 127.88, 128.02, 128.33,
135.96, 156.46, 169.14, 171.95. MS (CI) m/z (%) = 395 (MH+,
6. (a) Barret, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86,
751; (b) Nitroalkanes and Nitroalkenes in Synthesis; Barret,
A. G. M., Ed.; Tetrahedron Symp. 1990, 46, 7313; (c) Noboru,

3066
F. Ferna´ndez et al. / Tetrahedron: Asymmetry 17 (2006) 3063–3066
100), 379 (35), 319 (87), 261 (13), 91 (62). Compound 7a:
Road, Cambridge CB2 1EZ, UK [fax: (+44)1223 336 033;
e-mail: deposit@ccdc.cam.ac.uk]. Crystallographic data for
3a. C26H27NO4S3, M = 513.67, T = 100(2) K. Orthorhombic,
27
½aꢁD ¼ ꢀ15:8 (c 2.30, CHCl3). 1H NMR (CDCl3) d 1.34, 1.47
(2 · s, 6H, 2 · CH3), 2.68–2.79 (m, 1H, H-2), 3.18–3.20 (m,
1H, H-3), 3.67–3.74 (m, 1H, H-3), 3.71 (s, 3H, OCH3), 3.77 (s,
2H, CH2Gly), 3.85–4.07 (m, 3H, H-50 + CH2Gly), 4.13–4.35
(m, 2H, H-40 + H-50), 5.09 (s, 2H, CH2Ph), 5.79 (br s, 1H,
NH), 7.13 (br s, 2H, 2 · NH), 7.31–7.39 (m, 5H, 5 · Ar–H).
13C NMR (CDCl3) d 25.21, 26.72, 39.42, 41.07, 44.61, 49.52,
52.44, 67.13, 67.65, 74.87, 109.41, 128.00, 128.20, 128.47,
136.02, 147.38, 167.10, 169.52, 169.78. MS (CI) m/z (%) 452
(MH+, 21), 436 (15), 376 (100), 328 (18), 268 (66), 91 (97).
space group P212121 with a = 10.5316(19), b = 12.851(2),
3
˚
˚
c = 17.959(3) A, a = 90ꢁ, b = 90ꢁ, c = 90ꢁ, V = 2430.6(8) A ,
Dc (Z = 4) = 1.404 Mg/m3. F(000) = 1080, absorbtion coef-
ficient = 0.339 mmꢀ1. Data were obtained on an Smart-
CCD-1000 BRUKER diffractometer (graphite crystal mono-
˚
chromator, k = 0.71073 A) using the x = 2h scan method;
absorption corrections were applied. Refinement, with aniso-
tropic displacement parameters applied to each of the
13. Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as Supplementary
Publication No. CCDC 624162 (3a). Copies of the data can
be obtained free of charge on application to CCDC, 12 Union
nonhydrogen atoms, was by full-matrix least squares
P
on F2 (SHELXL-93) using all data; wR2 ¼ ½ð wðF 2o ꢀ
P
2
2 1=2
F 2cÞ = wðF 2oÞ ꢁ
.
14. L-Glyceraldehyde was obtained as stated in: Hubschwerlen,
C. Synthesis 1986, 962.