Asymmetric synthesis of syn-(2R,3S)-and anti-(2S,3S)-ethyl diamino-3-phenylpropanoates from N-(benzylidene)-p-toluenesulfinamide and glycine enolates

Article abstract of DOI:10.1021/ol048981y

Addition of differentially N-protected glycine enolates to enantiopure sulfinimines affords syn- and anti-α,β-diamino esters with high diastereoselectivities and good yields.

Full text of DOI:10.1021/ol048981y

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2789-2792
Asymmetric Synthesis of syn-(2R,3S)-
and anti-(2S,3S)-Ethyl
Diamino-3-phenylpropanoates from
N-(Benzylidene)-p-toluenesulfinamide
and Glycine Enolates†
Franklin A. Davis* and Jianghe Deng
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received June 2, 2004
ABSTRACT
Addition of differentially N-protected glycine enolates to enantiopure sulfinimines affords syn- and anti-r,â-diamino esters with high
diastereoselectivities and good yields.
R,â-Diamino acids are important structural units found in
natural products, in peptides,l in peptide antibiotics,1,2 and
in medicinally valuable compounds.3,4 As such, a number
of methods, with varying degrees of efficiency, have been
devised for their preparation in enantiomerically pure form.5
Routes to optically active syn- and anti-R,â-diamino acids
generally begin with a suitably protected R- or â-amino
acid.6,7 The second amino group is then introduced by azide
displacement on derived aziridines, on mesylates, or on
hydroxyl groups under Mitsunobu conditions, followed by
reduction of the azide moiety.1,6,7 R,â-Diamino acids have
also been prepared by a catalytic aza-Henry reaction, which
involved the addition of alkyl nitro anions to imines.8,9
Benzophenone imines of glycine are reported to react with
certain N-sulfonyl imines, in the presence of catalytic chiral
copper(I) complexes, to give the syn R,â-diamino acids in
high ee.10 Viso and co-workers explored the 1,3-dipolar
cycloaddition of glycine iminoester enolates to sulfinimines
(N-sulfinyl imines) in the presence of BF3‚Et2O to give
N-sulfinylimidazolidines with good levels of diastereoselec-
tivity.11 This group recently devised a procedure to transform
the 1,3-imidazolidines into syn-R,â-diamino acids.5a
† This work is dedicated to Professor Amos B. Smith III, University of
Pennsylvania, on the occasion of his 60th birthday.
(1) For leading references, see: Luo, Y.; Blaskovich, M. A.; Lajoie, G.
A. J. Org. Chem. 1999, 64, 6106.
(2) (a) Khan, L. K.; Kuo, Y. H.; Haque. A.; Lambein, F. Acta Neurol.
Scand. 1995, 91, 506. (b) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58,
5176.
(3) Rane, D. F.; Girijavallabhan, V. M.; Ganguly, A. K.; Pike, R. E.;
Saksena, A. K.; McPhail, A. T. Tetrahedron Lett. 1993, 34, 3201.
(4) For a review on the chemistry of diamino acids, see: Lucet, D.; Le
Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580.
(5) For summaries of the existing literature of the syntheses of R,â-
diamino acids, see: (a) Viso, A.; de la Pradilla, R. F.; Lopez-Rodrigues,
M. L.; Garcia, A.; Flores, A.; Alonso, M. J Org. Chem. 2004, 69, 1542.
(b) Reference 1. (c) Soloshonok, V. A.; Avilov, D. V.; Kukhar, V. P.;
Meervelt, L. V.; Mischenko, N. Tetrahedron Lett. 1997, 38, 4671.
(6) Han, H.; Yoon, J.; Janda, K. D. J. Org. Chem. 1998, 63, 2045.
(7) Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Millican, N. L.;
Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2003,
1, 3780.
(8) For a review of the asymmetric catalytic aza-Henry reaction, see:
Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151.
(9) Kundsen, K. R.; Risagaard, T.; Nishiwaki, N.; Gothelf, K. V.;
Jorgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843.
(10) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jorgensen, K. A. J. Org.
Chem. 2003, 68, 2583.
10.1021/ol048981y CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/07/2004

Scheme 1
Table 1. Reaction of Glycine Enolates with
(S)-(+)-N-(Benzylidene)-p-toluenesulfinamide (2) at -78 °C
R,â-diamino ester
conditions
(isomer ratio)a
% isolated yieldb
entry
glycine
1
base/equiv/solvent
1
2
3
4
5
6
7
8
9
LDA/1.6/THF
LDA/5.0/THF
(+)-3 (20:3:2:4) 30c
(20:3:2:3) 68
LDA/5.0/Et2O
LiHMDS/5.0/THF
NaHMDS/5.0/THF
KHMDS/5.0/THF
LDA/1.1/THF
(20:4:3:0) 50
(20:2:2:4) 65
(20:7:6:7) 80c
(20:3:10:6) 76c
(-)-6 (10:0:5:3) 36
(100:0:2:2) 89
(10:0:4:3) 34
5
LDA/1.6/THF
LDA/2.0/THF
a Estimated from the 1H NMR of the crude reaction mixture by
monitoring the C(3) and NH protons. b Isolated yield of the pure major
diastereoisomer. c Conversion yield, isomers not separated.
Glycine ester derivatives are valuable building blocks for
the preparation of amino acids via the alkylation and Michael
additions of the derived enolates.12 Therefore, the diastereo-
selective addition of glycine ester enolates to enantiopure
sulfinimines13 appeared to us to be a potentially attractive
method for the asymmetric synthesis of R,â-diamino acids
because two stereogenic centers could be created in a single
operation. Furthermore, there was the possibility that both
the syn and anti isomers could be created from a single
sulfinimine precursor. We describe here the realization of
this objective in concise, highly diastereoselective asym-
metric syntheses of syn-(2R,3S)- and anti-(2S,3S)-diamino-
3-phenylpropanoates from a benzaldehyde-derived sulfin-
imine. These diamino acids have been considered to be
analogues of the Taxol side chain and provide a way to
improve the water solubility of this antitumor compound.14
syn-Ethyl Diamino-3-phenylpropanonate. The lithium
enolate of ethyl (dibenzylamino)acetate (1) was prepared at
-78 °C by treatment with the appropriate base and allowed
to react at this temperature with (S)-(+)-N-(benzylidene)-p-
toluenesulfinamide (2) (Scheme 1).15 The formation of four
diastereoisomers are possible on the addition of the enolate
anti-Ethyl Diamino-3-phenylpropanoate. Addition of the
lithium enolate of N-(diphenylmethylene)glycine ethyl ester
(5) to (S)-(+)-2 gave the anti isomer ethyl (2S,3S)-(-)-anti-
2,3-diamino-3-phenylpropanonate (6) (Scheme 2). The op-
Scheme 2
1
of 1 to 2, and H NMR of the crude reaction mixtures
indicated the presence of all four isomers (Table 1, entries
1-6). Best results were observed using 5.0 equiv of the
lithium enolate of 1 generated from LDA or LiHMDS as
shown in Table 1. Quenching and chromatographic workup
afforded the major syn adduct (+)-3 in 68% isolated yield
(Table 1, entry 2). Subsequent treatment of (+)-3 with TFA/
EtOH to remove the sulfinyl auxiliary and hydrogenation
over Pd(OH)2 afforded ethyl (2R,3S)-(-)-syn-2,3-diamino-
3-phenylpropanonate (4) in 61% yield for the two steps
(Scheme 1). The absolute stereochemistry of 4 was estab-
lished by converting it into a product of known absolute
configuration as will be subsequently discussed.
timum conditions for the synthesis of (+)-6 required 1.6
equiv of the lithium enolate, which resulted in the formation
of a single isomer that was isolated in 89% yield (Table 1,
entry 8). Interestingly, when 1.1 or 2.0 equiv of the enolate,
respectively, were employed, the diastereoselectivity and
yield were significantly reduced (Table 1, entries 7 and 9).
Concomitant removal of the N-sulfinyl group and hydrolysis
of the imine was accomplished on treatment of (+)-6 with
TFA/EtOH affording the diamino ester (+)-7 in 80% yield
(Scheme 2). The absolute stereochemistry of (+)-7 was
(13) For reviews on the chemistry of sulfinimines, see: (a) Zhou, P.;
Chen, B.-C.; Davis, F. A. In AdVances in Sulfur Chemistry; Rayner, C. M.,
Ed.; JAI Press: Stamford, CT, 2000; Vol. 2, pp 249-282. (b) Davis, F.
A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13. (c) Ellman, J. A.;
Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (d) Zhou, P.;
Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, in press.
(14) Lee, S.-H.; Yoon, J.; Chung, S.-H.; Lee, Y.-S. Tetrahedron 2001,
57, 2139.
(11) (a) Viso, A.; de la Pradilla, R. F.; Lopez-Rodrigues, M. L.; Garcia,
A.; Alonso, M.; Guerrero-Strachan, C.; Flores, A. Synlett 1999, 1543. (b)
Viso, A.; de la Pradilla, R. F.; Lopez-Rodrigues, M. L.; Garcia, A.; Tortosa,
M. Synlett 2002, 755. (c) Viso, A.; de la Pradilla, R. F.; M. L.; Garcia, A.;
Guerrero-Strachan, C.; Alonso, M.; Tortosa, M.; Flores, A.; Martinez-Ripoll,
M.; Fonseca, I.; Andre, I.; Rodrigues, A. Chem. Eur. J. 2003, 9, 2867.
(12) For reviews on the application of imines of glycine esters in the
asymmetric synthesis of amino acids, see: (a) O’Donnell, M. J. Aldrichim.
Acta 2001, 34, 3. (b) Soloshonok, V. A. Curr. Org. Chem. 2002, 6, 341.
(15) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang. T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
2790
Org. Lett., Vol. 6, No. 16, 2004

Scheme 3
Scheme 4
evoked to explain this stereochemical preference. The 1,3-
dipolar cycloaddition of glycine iminoester enolates to
sulfinimines, reported by Viso et al. and that leads to syn-
R,â-diamino esters, falls into the latter category.11
Nearly exclusive Re face addition was observed for
reaction of the enolates derived from 1 and 5 to (S)-(+)-2
resulting in the S-configuration at C-3 (Table 1). These results
are in accord with the six-membered chelate chairlike
transition state model (Scheme 4). The syn/anti diastereo-
selectivity at C-2, which is dependent on the protecting group
on the glycine nitrogen atom, can be readily interpreted in
terms of the geometry of the enolate. We suggest that the
syn/anti selectivity can be explained if 1 and 5 adopt the
(E)- and (Z)-enolate geometries, respectively, in transition
states TS-1 and TS-2 (Scheme 4).20 Intramolecular chelation
is expected to favor the (Z)-geometry in (Z)-5.21,22 Garcia
Ruano et al. used related arguments to explain the diaste-
reoselectivity of the addition of dienolates to sulfinimines
that affords syn- and anti-R-alkyl â-amino esters.23
In summary, new methodology has been introduced for
the concise asymmetric synthesis of diamino acids, key
structural units in natural products, and other biologically
active materials. Our procedure calls for the addition of
glycine enolates of ethyl (dibenzylamino)acetate (1) and
N-(diphenylmethylene)glycine ethyl acetate (5) to enan-
tiopure sulfinimine (S)-(+)-2. The resulting syn- and anti-
R,â-diamino esters are produced in good yield and excellent
diastereoselectivity. A mechanistic hypothesis involving the
determined by transforming it into a product of known
configuration, as discussed in the next section.
Determination of Product Absolute Configuration. The
absolute configurations of syn- and anti-4 and -7 were
determined as outlined in Scheme 3. Heating 4 and 7 with
carbonyl diimidazole (8) afforded the corresponding imida-
zolidin-2-ones 9 and 10 in 62-66% yield. The C-4, C-5
proton- coupling constants of 5 Hz for 9 and 9 Hz for 10
are consistent with their trans and cis relationship, respec-
tively.14 Finally, reduction of the carbethoxy groups with
NaBH4 gave the corresponding alcohols (-)-11 and (+)-
12, which were prepared previously by Rossi and co-workers
in an unequivocal manner.16
Mechanism. The absolute stereochemistry of the product
resulting from the addition of organometallic reagents (CN,
enolates, Grignard reagents) to sulfinimines is controlled by
the N-sulfinyl group and predicted by a six-membered
chairlike transition state.13 The opposite sense of stereoin-
duction is observed for the addition of benzyl Grignards,17
R-metallo phosphonates,18 and chloromethyl phosphonate
anions19 to sulfinimines and steric arguments have been
(19) (a) Davis, F. A.; McCoull, W. Org. Lett. 1999, 1, 1053. (b) Davis,
F. A.; McCoull, W. Tetrahedron Lett. 1999, 40, 249. (c) Davis, F. A.; Wu,
Y.; Yan, H.; McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68, 2410.
(d) Davis, F. A.; Ramaachandar, T.; Wu, Y. J. Org. Chem. 2003, 68, 6894.
(20) Under kinetically controlled conditions, the lithium enolate of 1 has
been determined to have the E-geometry. See: Guanti, G.; Banfi, L.;
Narisano, E.; Scolastico, C.; Tetrahedron 1988, 44, 3671.
(21) Ezquerra, J.; Pedregal, P.; Merino, I.; Florez, J.; Barluenga, J.;
Garcia-Granda, S.; Llorca, M.-A. J. Org. Chem. 1999, 64, 6554.
(22) Instead of reacting with the sulfinimine as the five membered
1-oxaallylanion (Z)-5 it could also react as the six-membered 2-azaallylanion.
See: Ezquerra, J.; Pedregeal, C.; Merino, I.; Florez, J.; Barluenga, J.; Garcia-
Granda, S.; Llorca, M.-A. J. Org. Chem. 1999, 64, 6554.
(16) Rossi, F. M.; Powers, E. T.; Yoon, R.; Rosenberg, L.; Meinwald,
J. Tetrahedron 1996, 52, 10279.
(17) (a) Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396. (b)
Bravo, P.; Crucianelli, M.; Vergani, B.; Zanda, M. Tetrahedron Lett. 1998,
39, 7771.
(18) Mikolajczyk, M.; Lyzwa, P.; Drabowicz, J.; Wieczorek, M. W.;
Blaszczyk, J. J. Chem. Soc., Chem. Commun. 1996, 1503.
(23) Garcia Ruano, J. L.; Fernandez, I.; del Prado-Catala, M.; Hermoso,
J. A.; Sanz-Apaaricio, J.; Martinez-Ripoll, M. J. Org. Chem. 1998, 63, 7157.
Org. Lett., Vol. 6, No. 16, 2004
2791

addition of the (E)- and (Z)-enolates of 1 and 5, respectively,
to 2 via a six-membered chairlike transition state is proposed.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by a grant
from the National Institute of General Medicinal Sciences
(NIGMS 57870).
OL048981Y
2792
Org. Lett., Vol. 6, No. 16, 2004