Toward synthesis of alpha-alkyl amino glycines (A3G), new amino acid surrogates.

Article abstract of DOI:10.1021/jo020154s

A general method giving access to protected alpha-alkyl amino glycines (A3G) 4 from the previously described precursor alpha-isopropylthioglycine 1 is described. In the presence of N-bromosuccinimide, displacement of the thiol by a large variety of amines afforded the corresponding racemic amino acid mimics. The efficiency of the reaction was strongly dependent on the protective groups of the nucleophile used in the condensation.

Full text of DOI:10.1021/jo020154s

SCHEME 1
Tow a r d Syn th esis of r-Alk yl Am in o
Glycin es (A3G), New Am in o Acid
Su r r oga tes
Lo¨ıc Yaouancq, Lo¨ıc Rene´,†
Marie-Elise Tran Huu Dau, and Bernard Badet*
Institut de Chimie des Substances Naturelles,
CNRS-UPR2301, 91198 Gif-sur-Yvette, France
badet@icsn.cnrs-gif.fr
Received March 7, 2002
investigated. For instance, replacement of the R hydroxyl
function (Scheme 1, X ) OH) by an alkoxy (X ) OR) or
alkylthio (X ) SR) group could be performed under acidic
conditions.7,9,10 Access to R-aminoglycine (Scheme 1,
X ) NH2) was then accomplished by displacement of the
alkylthio group by alkylamines with the help of mercuric
salts.9,11 Reduction of R-azidoglycine12 directly accessible
from the hydroxyl function using diphenylphosphoryl
azide also leads to R-aminoglycine. Alternatively, R-hy-
droxyglycine could be converted into the corresponding
acetate, which was displaced by nucleophiles such as
thiols13 or amines.14 An interesting application is the
addition of enantiopure R-amino acid esters to R-halogly-
cine-containing peptides, which yields the corresponding
modified oligopeptides with remarkable stereoselectiv-
ity.16 Further improvement in the access to R-heterosub-
stituted glycines was obtained by way of a three-
component reaction using amide (or carbamate) and
glyoxylic acid in the presence of benzotriazole or pro-
pane-2 thiol to give R-benzotriazolyl- or R-isopropylth-
ioglycine. The benzotriazolyl or isopropylthio accessory
group can then be directly displaced by ammonia15 or
carbamates17 to afford R-amino or R-acylamino glycines,
respectively.
As a result of the presence of a geminal diamine
function, the stability of R-alkylamino glycines 4 (Scheme
2) is generally restricted to very particular cases. It has
been previously demonstrated that acylation of only one
of the nitrogens (R1, R3, or R4) allows isolation of the
corresponding compound.9,15 We previously reported that
incorporation of R-aminoglycine within a peptide se-
quence could be automated17 using the fully protected
Boc, Fmoc amino glycine 4 (R1 ) Boc, R3 ) Fmoc, R2 )
R4 ) H) as the smallest of the protected basic amino
acids. This unique compound, which allowed interesting
applications after incorporation into peptide sequences
and further acylation,18-20 has also been obtained as a
Abstr a ct: A general method giving access to protected
R-alkyl amino glycines (A3G) 4 from the previously described
precursor R-isopropylthioglycine 1 is described. In the pres-
ence of N-bromosuccinimide, displacement of the thiol by a
large variety of amines afforded the corresponding racemic
amino acid mimics. The efficiency of the reaction was
strongly dependent on the protective groups of the nucleo-
phile used in the condensation.
Nonnatural amino acids and amino acid mimics have
become increasingly important in the discovery of phar-
macologically active peptides and peptidomimetics. In
this respect, a large variety of strategies for the synthesis
of new amino acid isosteres has appeared with the coming
of age of combinatorial chemistry.1 An interesting ap-
proach is the synthesis of R-substituted glycines in which
the CR-substituent is replaced by a heteroatom, leading
to a variety of side chains and thereby increasing the
molecular diversity of these amino acid analogues.
Three different strategies have been developed for the
preparation of R-heterosubstituted glycines. The first
synthetic route (Scheme 1, route a) relies on the func-
tionalization of a protected glycine that can occur through
halooxazolone formation2 or by radical bromination,3-5
followed in both cases by nucleophilic halogen displace-
ment. A second alternative (Scheme 1, route b) involves
oxidative cleavage of serine- and threonine-containing
peptides, which directly affords acetoxyglycine-containing
molecules.6 The third synthetic route relies on the
condensation of an amide or carbamate (Scheme 1, route
c, R) R′′CO, R′′OCO) with glyoxylic acid to give the
corresponding N-acylated R-hydroxyglycine. Following
the initial reports by Ben-Ishai7 and Schouteeten8 the
synthetic possibilities of this reaction have been largely
(9) Bock, M. G.; Dipardo, R. M.; Freidinger, R. M. J . Org. Chem.
1986, 51, 3718.
(10) Ben-Ishai, D.; Altman, J .; Bernstein, Z. Tetrahedron 1977, 33,
1191.
† To whom this work is dedicated.
(1) Combinatorial Peptide & Nonpeptide Librairies; J ung, G., Ed.;
VCH: Weinheim, 1996.
(2) Chemiakine, M. M.; Tchaman, E. S.; Denisova, L. I.; Ravdel, G.
A.; Rodionow, W. J . Bull. Soc. Chim. Fr. 1959, 530.
(3) Kohn, H.; Sawhney, K. N.; LeGall, P.; Robertson, D. W.; Leander,
J . D. J . Med. Chem. 1991, 34, 2444.
(4) Easton, C. J .; Scharbillig, I. M.; Tan, E. W. Tetrahedron Lett.
1988, 29, 1565.
(5) (a) Lidvert, Z.; Gronowitz, S. Synthesis 1980, 322-324. (b) Kober,
R.; Steglich, W. Ann. Chem. 1983, 599.
(6) Apitz, G.; J a¨ger, M.; J aroch, S.; Kratzel, M.; Scha¨ffeler, L.;
Steglich, W. Tetrahedron Lett. 1993, 36, 8223.
(7) Zoller, U.; Ben-Ishai, D. Tetrahedron 1975, 31, 863.
(8) Schouteeten, A.; Christidis, Y.; Mattioda, G. Bull. Soc. Chim.
Fr. II 1978, 248.
(11) Bock, M. G.; Dipardo, R. M.; Evans, B. E.; Rittle, K. E.; Veber,
D. F.; Freidinger, R. M. Tetrahedron Lett. 1987, 28, 939.
(12) Schmidt, U.; Sta¨bler, S.; Lieberknecht, A. Synthesis 1994, 890.
(13) Kingsbury, W. D.; Boehm, J . C. Int. J . Peptide Protein Res. 1986,
27, 659.
(14) Hwang, S. Y.; Berges, D. A.; Taggart, J . J .; Gilvarg, C. J . Med.
Chem. 1989, 32, 694.
(15) Katrizky, A. R.; Urogdi, L.; Mayence, A. J . Org. Chem. 1990,
55, 2206.
(16) (a) Apitz, G.; J a¨ger, M.; J aroch, S.; Kratzel, M.; Scha¨ffeler L.;
Steglich, W. Tetrahedron 1993, 49, 8223. (b) Steglich, W.; J a¨ger, M.;
J aroch, S.; Zistler, P. Pure Appl. Chem. 1994, 66, 2167.
(17) Qasmi, D.; Rene´, L.; Badet, B. Tetrahedron Lett. 1993, 34, 3861.
10.1021/jo020154s CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/18/2002
5408
J . Org. Chem. 2002, 67, 5408-5411

SCHEME 2
single enantiomer by total synthesis from S-Cbz-serine
or by papain resolution of the corresponding ester or
amide.21 Access to R-amino glycine derivatives is there-
fore restricted to compounds bearing acylamino side
chains with the exception of a methyl amino group. We
therefore believe that the problem of a general access to
A3G remains unsolved.
The intermediate 2 (or more likely 2′ whose lowest
unoccupied molecular orbital is 0.8 eV lower) further
reacts with the incoming nucleophile 3, which provides
the side chain of the amino acid equivalent. The one-pot
conversion 1 f 4 occurred smoothly over a few hours,
and the resulting adduct 4 was purified by silica gel
chromatography in order to remove (i) the di-isopropyl
disulfide, (ii) the starting carbamate R1NH2 and glyoxy-
late resulting from retrocondensation of iminium 2′ and,
(iii) the R-hydroxy glycine resulting from hydration of the
latter.
The irreversibility of the condensation affording 4Xx
was demonstrated in a particular case. Thus, the com-
position of a mixture of 4Ec and 0.5 equiv of anhydrous
HBr in THF at room temperature (i.e., under conditions
similar to the synthetic procedure) was followed by
reverse-phase chromatography over a period of 18 h;
under these conditions no decomposition of the compound
was observed as judged from the integration of the
corresponding 4Ec HPLC peak.
As demonstrated by the selected examples listed in
Table 1, the reaction allowed access to amino acid
analogues containing alkyl (entries 2 and 3), hydroxy-
alkyl (entry 5), alkylcarboxylates (entry 4), alkylamino
(entry 6), and aryl (entries 7 and 8) side chains. Within
these series virtually any analogue can be obtained.
Interestingly, the corresponding homologues, i.e., with
a shorter or a longer side chain, are easily accessible
(entries 3 and 6). Proline analogues have been previously
obtained directly from glyoxylic acid and the suitably
protected ethylenediamine.23 Access to histidine and
tryptophan analogues have not been possible because of
instability of the corresponding 4-aminoimidazole and
3-aminoindole. The yields are generally less affected by
the nature of the protecting groups of 1 (compare entries
2, 4, and 7) than by the nature of the nucleophile 3. For
instance, the rather constrained analogue 4Eg (entry 4)
was isolated with 60% yield, whereas the phenylalanine
mimic 4El (entry 7) was obtained with 15% yield. None
of the acetylated analogues 4Al, 4Bl, 4Am , or 4Bm could
be isolated following the procedure depicted in Scheme
2. The synthesis of compound 4Am was performed as
described in Scheme 3. Condensation of acetamide and
benzyl glyoxylate under the conditions described by
Schouteeten et al.8 afforded the corresponding R-hydroxy-
The strategy followed is shown in Scheme 2. The
numbering used throughout this study refers to the four
structures 1-4 of Scheme 2. The final compound 4Xx was
identified by two additional letters (Xx), a capital letter
referring to the substituents of the electrophilic precursor
(1X) and the lower case letter referring to the substitu-
ents brought by the nucleophile 3x. The three-component
condensation of amide/carbamate R1NH2, isopropyl mer-
captan, and glyoxylic acid (R2 ) H) according to refer-
ence22 gave the protected R-isopropylthio glycine deriva-
tives 1A, 1C, and 1E in good to excellent yields. The
corresponding esters could be obtained under similar
conditions starting from the corresponding benzyl or tert-
butyl glyoxylate. It was found, however, that the esters
1B, 1D, and 1F could be obtained more efficiently by
esterification of the acidic precursors with the desired
alcohol, conditions that we systematically used as de-
scribed in the experimental protocol. Displacement of
sulfur in 1 by amines, amides, or carbamates occurred
under very mild conditions (THF, 0 °C) in the presence
of N-bromosuccinimide. It was observed that condensa-
tion of stoichiometric amounts of 1 and 3 requires only
0.5 equiv of NBS. This suggests that NBS first generates
the bromosulfonium salt 2 (X ) Br), which decomposes
into 2′ with the simultaneous formation of isopropyl
sulfenyl bromide (i-PrSBr). The latter acts as a sulfeny-
lating agent on 1 to give 2 (X ) i-PrS), which decomposes
to the same iminium 2′ with simultaneous formation of
di-isopropyl disulfide. The presence of this disulfide was
indeed detected by comparison with an authentic sample
and was quantified to 100% by analytical HPLC, thereby
validating the proposed mechanism for the reaction of 1
with NBS.
(18) Rivier, J . E.; J iang, G.; Koerber, S. C.; Porter, J .; Simon, L.;
Craig, A. G.; Hoeger, C. A. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 2031.
(19) Cervini, L.; Theobald, P.; Corrigan, A.; Craig, A. G.; Rivier, C.;
Vale, W.; Rivier, J . J . Med. Chem. 1999, 42, 761.
(20) Kirby, D. A.; Wang, W.; Gershenhorn, M. C.; Rivier, J . E.
Peptides 1998, 10, 1679.
(21) Sypniewski, M.; Penke, B.; Simon, L.; Rivier, J . J . Org. Chem.
2000, 65, 6595.
(22) Rene´, L.; Badet, B. Synth. Commun. 1996, 26, 3237.
(23) Rene´, L.; Yaouancq, L.; Badet, B. Tetrahedron Lett. 1998, 39,
2569.
J . Org. Chem, Vol. 67, No. 15, 2002 5409

TABLE 1. Ch em ica l Yield s of Isola ted A3G (see a lso
Sch em e 2)
MHz, and the chemical shifts are reported with respect to the
residual solvent used. Melting points were determined using a
capillary apparatus. Low-resolution mass spectra were acquired
in ESI, FAB or IC modes whereas high-resolution spectra were
acquired in ESI or IC.
entry
1
mimic of
R1
R2
R3
R4
yield, %
alanine
4Ea 22
leucine
4Cc
Fmoc
H
Boc H
82
Syn th esis of P r otected r-Isop r op ylth ioglycin e Der iva -
tives 1. 2-Aceta m id o 2-Isop r op ylth io Acetic Acid , Ac-Gly-
(S-iP r )-OH (1A). Acetamide (30 g, 0.5 mol), isopropanethiol (100
mL, 1.07 mol), 50% aqueous glyoxylic acid (75 mL, 0.6 mol), and
p-toluenesulfonic acid (PTSA, 0.7 g) were stirred in toluene (500
mL) under reflux in a Dean-Stark apparatus until no water
was extracted. Crystallization from heptane/ethyl acetate gave
2
Cbz
H
Boc i-Pr
48
45
80
45
44
20
4Dc
Cbz
t-Bu Boc i-Pr
4Db
Cbz
t-Bu
H
i-Pr
4Ec
4F c
4Ed
Fmoc
Fmoc Bn
Fmoc
H
Boc i-Pr
Boc i-Pr
Cbz i-Pr
H
1
1A (78.0 g, 81%), mp 135 °C. H NMR (300 MHz, DMSO-d6): δ
3
4
isoleucine
4Be
1.33 (d, J ) 6.6 Hz, 3H), 1.35 (d, J ) 6.6 Hz, 3H), 1.99 (s, 3H),
3.2 (h, J ) 6.6 Hz, 1H), 5.45 (d, J ) 8.8 Hz, 1H), 8.75 (d, J ) 8.8
Hz, 1H), 12.9 (bs, 1H). 13C NMR (75 MHz, DMSO-d6): δ 22.72,
23.58, 24.10, 35.31, 53.24, 169.48, 170.74. MS (IC, isobutane):
m/z 192 [M + H]+. Anal. Calcd for C7H13NO3S: C, 43.96; H, 6.85;
N, 7.32. Found: C, 43.81; H, 6.83; N, 7.37.
Ac
Ac
Bn
Bn
Me Et
74
89
4Bfa
Et
Et
glutamate
4Eg
4Cg
Fmoc
Cbz
H
H
Boc CH2CO2-tBu
Boc CH2CO2-tBu
61
53
5
6
serine
4Eh
lysine
4Ei
2-Aceta m id o 2-Isop r op ylth io Acetic Acid Ben zyl Ester ,
Ac-Gly(S-iP r )-OBn (1B). To 1A (38.24 g, 0.2 mol), benzyl
alcohol (23.71 g, 0.22 mol), and DMAP (1.00 g, 0.008 mol) in
THF (400 mL) at 0 °C was added DCC (45.38 g, 0.22 mol). DCU
was removed by filtration after 12 h, and the solvent was
removed under vacuum. Flash chromatography (heptane/EtOAc,
1/1) gave 1B (31.5 g, 56%), mp 40 °C. 1H NMR (300 MHz, DMSO-
d6): δ 1.26 (d, J ) 6.6 Hz, 3H), 1.29 (d, J ) 6.6 Hz, 3H), 1.99 (s,
3H), 3.19 (h, J ) 6.6 Hz, 1H), 5.29 (s, 2H), 5.58 (d, J ) 7.9 Hz,
1H), 7.47 (bs, 5H), 8.95 (bd, J ) 7.9 Hz, 1H). 13C NMR (75 MHz;
DMSO-d6): δ 22.88, 23.78, 24.24, 35.83, 53.40, 67.24, 128.56,
128.78, 128.86, 136.29; 169.56, 169.89. MS (ESI): m/z 304 [M +
Na]+. HRMS (IC, isobutane): calc for C14H20NO3S [M + H]+
282.1163, obsd 282.1159.
Fmoc
H
Boc OBoc
60
Fmoc
Cbz
Fmoc
Fmoc
H
H
H
H
Boc (CH2)3NHBoc
Boc (CH2)3NHBoc
Boc (CH2)2NHBoc
Boc (CH2)4NHBoc
37
40
40
30
4Ci
4Eja
4Ek a
phenylalanine
4El
7
Fmoc
Ac
Ac
H
Bn
H
Boc Ph
15
20
20
4Bm b
4Am b
tyrosine
4En
H
H
Ph
Ph
8
Fmoc
Cbz
H
H
Boc PhOBoc
PhOBoc
22
12
4Cn
,
a
Homologous to the amino acid. b Derivative obtained according
2-[N-Ben zyloxyca r bon yl]a m in o 2-Isop r op ylth io Acetic
Acid , Cbz-Gly(S-iP r )-OH (1C). Benzylcarbamate (7.5 g, 0.05
mol), isopropanethiol (10 mL, 0.107 mol), 50% aqueous glyoxylic
acid (7.5 mL, 0.06 mol), and PTSA (0.15 g) in toluene (50 mL)
were stirred under reflux in a Dean-Stark apparatus until no
water was extracted. The toluene was removed under vacuum,
and the residue was crystallized in heptane/EtOAc to afford 1C
to Scheme 3.
SCHEME 3
(13 g, 90%), mp 83 °C (lit.8 82-84 °C). Anal. Calcd for C13H17
-
NO4S: C, 55.11; H, 6.05; N, 4.94. Found: C, 54.92; H, 5.91; N,
4.87.
2-[N-Ben zyloxyca r bon yl]a m in o 2-Isop r op ylth io Acetic
Acid ter t-Bu tyl Ester , Cbz-Gly(S-iP r )-OtBu (1D). To 1C
(10.00 g, 0.035 mol) dissolved in THF (100 mL) containing tert-
butanol (3.68 mL, 0.039mol) was added DCC (8.01 g, 0.039 mol)
at 0 °C. After 12 h DCU was removed by filtration. Flash
chromatography of the oily residue (heptane/EtOAc, 8/2) gave
1
1D (4.46 g 37%). H NMR (250 MHz, CDCl3): δ 1.33 (d, J ) 7.2
Hz, 3H), 1.35 (d, J ) 7.2 Hz, 3H), 1.49 (s, 9H), 3.22 (hept, J )
7.2 Hz, 1H), 5.08 (d, J ) 12.0 Hz, 1H), 5.20 (d, J ) 12 Hz, 1H),
5.23 (d, J ) 8.5 Hz, 1H), 6.05 (d, J ) 8.5 Hz, 1H), 7.36 (bs, 5H).
13C NMR (62.5 MHz, CDCl3): δ 23.43, 24.10, 27.86, 36.13, 56.10,
67.22, 82.99, 128.17, 128.53, 136.06, 154.80, 168.35. MS (ESI):
m/z 339.8 [M + H]+, 361.8 [M + Na]+, 701.0 [2M + Na]+. HRMS
(IC, isobutane) calcd for C17H26NO4S [M + H]+ 340.1582, obsd
340.1553.
2-[N-F lu or en ylm eth oxyca r bon yl]a m in o 2-isop r op ylth io
a cetic a cid , F m oc-Gly(S-iP r )-OH (1E) was synthesized as
described.22 Anal. Calcd for C20H21NO4S: C, 64.67; H, 5.70; N,
3.77. Found: C, 64.52; H, 5.75; N, 3.99.
glycine isolated as a solid in 30% yield. Displacement of
its acetyl derivative 5 with aniline occurred in almost
quantitative yield to provide 4Bm , which was saponified
with a stoichiometric amount of sodium hydroxide in
dioxane to give 4Am .
In summary, this report describes the first general
access to racemic, orthogonally protected R-alkylamino
glycines, which are new interesting building blocks for
the synthesis of peptidomimetics. The synthesis of such
A3G-containing peptide mimics is currently under in-
vestigation.
2-[N-F lu or en ylm eth oxyca r bon yl]a m in o 2-isop r op ylth io
a cet ic a cid b en zyl est er , F m oc-Gly(S-iP r )-OBn (1F ) was
synthesized in 70% yield using the same protocol as for 1B. Mp
1
102 °C. H NMR (250 MHz, CDCl3): δ 1.32 (d, J ) 6.7 Hz, 3H),
Exp er im en ta l Section
1.36 (d, J ) 6.7 Hz, 3H), 3.21 (hept, J ) 6.7 Hz, 1H), 4.24 (t, J
) 7.0 Hz, 1H), 4.46 (d, J ) 7.0 Hz, 1H), 5.22 (d, J ) 12.2 Hz,
1H), 5.29 (d, J ) 12.2 Hz, 1H), 5.50 (d, J ) 9.2 Hz, 1H), 5.87 (d,
J ) 9.2 Hz, 1H), 7.32 (t, J ) 7.3 Hz, 2H), 7.39 (bs, 5H), 7.43 (t,
J ) 7.4 Hz, 2H), 7.61 (d, J ) 7.3 Hz, 2H), 7.78 (d, J ) 7.4 Hz,
2H).13C NMR (62.5 MHz, CDCl3): δ 23.20, 23.81, 36.04, 46.94,
55.37, 67.19, 67.60, 76.50, 77.00, 77.53, 119.90, 124.92, 126.97,
127.64, 128.11, 128.42, 134.82, 141.17, 143.45, 143.58, 154.71,
Gen er a l Meth od s. All solvents used were purified according
to standard procedures. NBS was crystallized from acetic acid,
dried in vacuo, and stored under vacuum over P2O5. Flash
chromatography was performed using silica (60 A C.C 35-70
µm). Boc-protected amines were visualized with ninhydrin and
sulfur-containing compounds with aniline followed by bromine
treatment. 1H and 13C NMR were recorded at 200, 250, or 300
5410 J . Org. Chem., Vol. 67, No. 15, 2002

169.10. HRMS (ESI) calcd for C27H27NO4SNa [M + Na]+
484.1558, obsd 484.1566.
mL, 73 mmol) was stirred for 16 h under argon. The solid
resulting from evaporation was crystallized from EtOAc/pentane
to afford 5.4 g (96%) of white powder, mp 145.5 °C. 1H NMR
(200 MHz, CDCl3): δ 2.00 (s, 3H), 4.93 (d, J ) 7.2 Hz, 1H), 5.32
(s, 2H), 6.02 (t, J ) 8.1 Hz, 1H), 6.17 (d, J ) 8.1 Hz, 1H), 6.69-
7.33 (m, 5H), 7.42 (bs, 5H). 13C NMR (75 MHz, CDCl3): δ 23.50,
60.49, 68.25, 114.10, 119.62, 128.35, 128.72, 128.78, 129.60,
135.50, 144.1, 170.50. MS (ESI): m/z 321 [M + Na]+, 337 [M +
K]+, 619.3 [2M + Na]+. Calcd for C17H19N2O3 [M + H]+ 299.1475,
obsd 299.1461.
2-Aceta m id o 2-An ilin o Acetic Acid Sod iu m Sa lt Ac-Gly-
(NH-P h )-ONa (4Am ). Compound 4Bm (1 g, 3.35 mmol) in
dioxane (100 mL) was stirred with 0.5 N NaOH (6.6 mL, 3.3
mmol) for 16 h. The residue was dissolved in water (100 mL),
and the aqueous phase was washed with EtOAc (2 × 20 mL).
Evaporation of water afforded 0.55 g (2.64 mmol, 79%) of a white
solid. 1H NMR (200 MHz, D2O): δ 1.92 (s, 3H), 5.43 (s,1H), 6.74-
7.27 (m, 5H). 13C NMR (50 MHz, pyridine-d5): δ 22.08, 64.80,
113.04, 116.64, 128.4, 145.92, 173.76, 176.88. MS (ESI): m/z 209
[M + H]+. HRMS (ESI) calcd for C20H22N4O6Na [2M - 2H +
Na]- 437.1437, obsd 437.1434.
Gen er a l P r otocol for Syn th esis of A3G, 4. To a cooled
solution (0 °C) of 1 (1 mmol) in dry THF (15 mL) under argon
was rapidly added NBS (90 mgs, 0.51 mmol). After 30 min at 0
°C, 3 (1 mmol except for b, e, f where 2 mmol were used) was
added, and the solution was stirred for 12 h. The resulting yellow
oil was purified on silica gel (from heptane/EtOAc, 1/1 to
heptane/EtOAc/AcOH, 1/1/0.05 or with CH2Cl2/EtOAc, 8/2 in the
case of b, e, f, m ) to afford 4 (Table 1). Spectral data are given
in Supporting Information.
2-Aceta m id o 2-Acetoxy Acetic Acid Ben zyl Ester Ac-Gly-
(OAc)-OBn (5). Benzyl glyoxylate (100 mL in 50% MTBE, 0.45
mol), acetamide (13 g, 0.22 mol), and PTSA (1 g) were refluxed
for 4 days in anhydrous THF (500 mL) in the presence of 3 Å
molecular sieves. The solid residue from evaporation was
triturated in Et2O to give 14.2 g (0.064 mol, 29%) of N-acetyl
R-hydroxy benzylglycinate, mp 107.5 °C. 1H NMR (200 MHz,
DMSO-d6): δ 1.97 (s, 3H), 5.26 (s, 2H), 5.64 (d, J ) 8.9 Hz, 1H),
6.74 (d, J ) 8.9 Hz, 1H), 7.48 (m, 5H), 8.96 (d, J ) 8.9 Hz, 1H).
13C NMR (75 MHz, DMSO-d6); 22.42, 65.98, 71.15, 127.82,
128.02, 128.17, 128.34, 135.73, 169.27, 169.76. MS (ESI): m/z
246.15 [M + Na]+, 224.01 [M + H]+.
Ack n ow led gm en t. We are much indebted to Clari-
ant s.a. (France) for a generous gift of glyoxylic deriva-
tives. We thank Drs. P. Durand and J . Thierry for
helpful discussions and Dr. R. Dodd for improving the
quality of the manuscript.
This hydroxy derivative (10 g, 0.045 mol) in CH2Cl2 (180 mL)
and pyridine (148 mL, 1.83 mol) was acetylated during 24 h with
Ac2O (224 mL, 2.37 mol). The crude residue was crystallized from
a mixture of pentane/ether 90/10 to give 9 g (76%) of white solid,
1
mp 142 °C. H NMR (250 MHz, CDCL3): δ 2.06 (s, 3H), 2.08 (s,
3H), 5.22 (s, 2H), 6.30 (d, J ) 9.1 Hz, 1H), 6.9 (d, J ) 9.1 Hz,
1H), 7.35 (m, 5H). 13C NMR (75 MHz, DMSO-d6): δ 22.17, 59.75,
66.42, 127.66, 127.98, 128.32, 135.60, 145.59, 169.02, 169.57. MS
(ESI): m/z 288.2 [M + Na]+.
2-Aceta m id o 2-An ilin o Acetic Acid Ben zyl Ester Ac-Gly-
(NH-P h )-OBn (4Bm ). Compound 5 (5 g, 18.86 mmol) in DMF
(150 mL) containing aniline (1.93 g, 20.74 mmol) and TEA (5.32
Su p p or tin g In for m a tion Ava ila ble: Spectral data of all
the new A3Gs 4Xx synthesized according to the general
protocol described above. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O020154S
J . Org. Chem, Vol. 67, No. 15, 2002 5411