A stereocontrolled, convergent synthesis of hydroxyethylene dipeptide isosteres

Article abstract of DOI:10.1021/jo970579s

A simple, convergent, and stereoselective synthesis of hydroxyethylene dipeptide isosteres 1 and 2 from scalemic α-hydroxy esters has been developed. The method is short (six steps), efficient (?15-25% overall), and highly diastereoselective (86-94% de) and enantioselective (>95% ee).

Full text of DOI:10.1021/jo970579s

6240
J . Org. Chem. 1997, 62, 6240-6244
A Ster eocon tr olled , Con ver gen t Syn th esis of Hyd r oxyeth ylen e
Dip ep tid e Isoster es
J unhua Tao and Robert V. Hoffman*
Department of Chemistry and Biochemistry, New Mexico State University,
Las Cruces, New Mexico 88003-0001
Received March 31, 1997X
A simple, convergent, and stereoselective synthesis of hydroxyethylene dipeptide isosteres 1 and 2
from scalemic R-hydroxy esters has been developed. The method is short (six steps), efficient (≈15-
25% overall), and highly diastereoselective (86-94% de) and enantioselective (>95% ee).
In tr od u ction
For the past two decades there has been an ever
increasing interest in the use of enzyme inhibitors as
therapeutic agents.1 Since proteases are known to medi-
ate a wide variety of disease states, protease inhibitors
have become common starting points for drug discovery
efforts related to those diseases.2 A recurring design
element in protease inhibitors is replacement of the
scissile amide bond in a substrate peptide with another
functional group. The resulting peptide isostere can bind
strongly in the active site of the protease, but hydrolysis
(and thus release and turnover) is not possible, thus
inhibiting the normal function of the protease.2
F igu r e 1. Hydroxyethylene isosteric replacement.
common. However, the stereocontrolled synthesis of both
2R and 2S diastereomers is desirable for the study of
structure-activity relationships7 and in the preparation
of several potential HIV-1 protease inhibitors.8
Inhibitors of aspartate proteases have been of particu-
lar interest recently, since the aspartate protease renin
is involved in the regulation of blood pressure,3 and the
aspartate protease HIV-1 protease plays a crucial role
in the replication cycle of the AIDS virus.4 Replacement
of the scissile amide bond with a hydroxyethylene group
is a common structural motif in aspartate protease
inhibitors (Figure 1). The hydroxyl group serves as a
mimic for the tetrahedral intermediate of proteolysis and
is bound tightly in the active site, but the hydroxyeth-
ylene group is incapable of hydrolytic cleavage.2a
A synthesis of hydroxyethylene peptide isosteres must
focus on the dipeptide core which is a 2-alkyl-4-hydroxy-
5-amino acid derivative. Moreover the control of stere-
ochemistry at three stereogenic centers is a central
requirement of any preparative method. The 4S,5S
stereochemistry5 is generally preferred in hydroxyethyl-
ene peptide isostere inhibitors of aspartate proteases.2a,6
The chiral center at C-2 may be either the 2R (1) or 2S
(2) configuration. The 2R configuration in 1 has the same
stereochemical disposition as the alkyl group of the
natural peptide (containing an L-amino acid) and is most
A second prerequisite of synthetic methodology for the
preparation of 1 and 2 is the latitude to incorporate a
wide range of R2 groups at C-2. The use of R1 and R2
groups not commonly found in amino acids can lead to
increased intrinsic inhibitory potency and improved
antiviral activity.9
Beginning with the pioneering work of Szelke10 and
Rich11 in 1983, a number of approaches have been
reported for the synthesis of 1. The most common
approach is to construct the 3,4-carbon-carbon bond by
reacting an N-protected amino aldehyde with a homoeno-
late equivalent.12 The alkyl group at C-2 is installed by
an alkylation of an intermediate lactone in a stereospe-
cific trans fashion (Scheme 1).
A less common approach to 1 is to construct the 2,3-
carbon-carbon bond by the reaction of a two-carbon
fragment with amino ketones,13 R-amino epoxides,14
R-hydroxy-â-amino aldehydes,15 or 4-amino-3-keto phos-
X Abstract published in Advance ACS Abstracts, August 15, 1997.
(1) Sandler, M.; Smith, H. J . Design of Enzyme Inhibitors as Drugs;
Oxford Press: Oxford, U.K., 1989.
(2) (a) Rich, D. H. Peptidase Inhibitors. In Comprehensive Medicinal
Chemistry; Sammes, P. G., Ed.; Pergamon Press: Oxford, U.K., 1990;
pp 391-441. (b) Gante, J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(3) Peach, M. J . Physiol. Rev. 1977, 57, 313.
(4) (a) Kramer, R. A.; Schaber, M. D.; Skalka, A. M.; Ganguly, K.;
Wong-Staal, F.; Reddy, E. P. Science 1986, 231, 1580. (b) Kohl, N. E.;
Emini, E. A.; Schleis, W. A.; Davis, L. J .; Heimbach, J . C.; Dixon, R.
A.; Scolnik, E. M.; Sigal, I. S. Proc. Natl. Acad. Sci. U.S.A. 1988, 85,
4686.
(5) The S stereochemical designation may change to R for certain
side chains because of Cahn-Ingold-Prelog priority rules, but the
stereochemical orientation of the side chain would be the same.
(6) It has been found that extended binding regions can alter the S
preference in HIV-1 protease and potentially other proteases as well.
Rich, D. H.; Sun, C.-Q.; Vara Prasad, J . V. N.; Pathiasseril, A.; Toth,
M. V.; Marshall, G. R.; Clare, M.; Mueller, R. A.; Houseman, K. J . Med.
Chem. 1991, 34, 1222.
(7) Dreyer, G. B.; Metcalf, B. W.; Tomaszek, T. A., J r.; Carr, T. J .;
Chandler, A. C., III; Hyland, L.; Farkhoury, S. A.; Magaad, V. W.;
Moore, M. L.; Strickler, J . E.; Debouk, C.; Meek, T. D. Proc. Natl. Acad.
Sci. U.S.A. 1989, 86, 9752.
(8) Kempf, D. J .; Norbeck, D. W.; Codacovi, L.; Wang, X. C.;
Kohlbrenner, W. F.; Wideburg, N. E.; Saldivar, A.; Craig-Kennard, A.;
Vasavanonda, S.; Clement, J . J .; Erickson J . in Recent Advances in
the Chemistry of Anti-Infective Agents; Bentley, P. H., Ed.; Royal Society
of Chemistry: Cambridge, 1993; pp 297-313.
(9) Danielmeier, K.; Schierle, K.; Steckhan, E. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2247 and references therein.
(10) Szelke, M.; J ones, M. D.; Atrash, B.; Hallet, A.; Leckie, B. J .
Proc. Am. Pept. Symp. 8th 1983, 579
(11) Rich, D. H.; Salituro, F. G.; Holliday, M. W. Proc. Am. Pept.
Symp. 8th 1983, 511.
S0022-3263(97)00579-3 CCC: $14.00 © 1997 American Chemical Society

Convergent Synthesis of Hydroxyethylene Dipeptide Isosteres
J . Org. Chem., Vol. 62, No. 18, 1997 6241
Sch em e 1
Sch em e 2
phonates16 which themselves were generally obtained
from R-amino aldehydes. Other approaches have utilized
a variety of starting materials including carbohydrates,17
acid chlorides,18 glutamic acid,19 and isovaleryl alde-
hyde.20 These methodologies often are long (>10 steps)
and thus inefficient, sometimes have poor diastereose-
lectivity, and are limited in the choice of side chains R1
and R2. In addition, virtually all of these syntheses
install the R2 group by alkylation of a lactone intermedi-
ate which occurs diastereoselectively to give 1. Few
preparations of the diastereomer 2 have been at-
tempted.18 An efficient and convergent synthesis of 1 and
2 has yet to be described.
Sch em e 3
We reported earlier that the alkylation of 4-amino-3-
keto esters with ethyl bromoacetate followed by decar-
boxylation produced 2-unsubstituted 5-amino-4-keto es-
ters.21 Subsequently we found that scalemic 2-triflyloxy
esters react with â-keto ester enolates to give 2-alkyl-4-
keto esters in high ee’s.22,23 These results provided a
simple entry into ketomethylene dipeptide isosteres,24 but
these could not be reduced to hydroxyethylene dipeptide
isosteres with high diastereoselectivity.21
amine and hydroxyl groups of hydroxyethylene peptide
isosteres as demonstrated by Liotta.13a
By linking our scalemic triflate alkylation results with
the reduction studies of Reetz,25 we are pleased to
describe the first convergent synthesis of 1 and 2 which
is short, efficient, and highly stereoselective.
Resu lts a n d Discu ssion
Reetz reported that R-N,N-dibenzylamino ketones can
be reduced to the corresponding syn-vicinal amino alcohol
with high diastereoselectivity.25 This reduction method
gives the correct stereochemical relationship between the
The synthetic approach we have developed to 1 and 2
is shown in Scheme 2. As rewritten to emphasize the
more common 4S,5S-syn relationship of the amine and
hydroxyl groups, 1 is derived from reduction of keto ester
3, which in turn results from the chiral alkylation of the
enolate of â-keto ester 4 and a scalemic triflate 5 (R or
S). Both 4 and 5 ultimately come from R-hydroxy esters
which can be obtained optically pure from a variety of
sources.26
We previously disclosed an efficient three step synthe-
sis of 4-(N,N-dibenzylamino)-3-keto esters 4 from scale-
mic R-hydroxy esters (Scheme 3). This sequence gives
good overall yields (55-61%) with no detectable racem-
ization (>95% ee) and provides an extraordinarily short
route to statine derivatives.27
Keto esters 4 were converted to their enolates with
NaH and alkylated with scalemic 2-triflyloxy esters 5,
also prepared from R-hydroxy esters.24 Both R and S
enantiomers of 5 were used to demonstrate convergency.
The intermediate tricarbonyl derivatives 6 were treated
immediately with TFA to effect decarboxylation and give
ketomethylene peptide isosteres 3 in moderate yields for
the two steps (40-57%) (Scheme 4). For the various
combinations used, reaction of keto ester 4x with triflate
5y gives isostere 3xy.
(12) Representative examples: (a) Ciapetti, P.; Taddei, M.; Ulivi,
P. Tetrahedron Lett. 1994, 35, 3183. (b) Konieczny, M. T.; Toma, P.
H.; Cushman, M. J . Org. Chem. 1993, 58, 4619. (c) J ones, D. M.;
Nilsson, B.; Szelke, M. J . Org. Chem. 1993, 58, 2286. (d) D’Aniello, F.;
Gehanne, S.; Taddei, M. Tetrahedron Lett. 1992, 33, 5621. (e) Thomp-
son, W. J .; Ball, R. G.; Darke, P. L.; Zugay, J . A.; Thies, J . E.
Tetrahedron Lett. 1992, 33, 2957. (f) Kano, S.;Yokomatsu, T.; Shibuya,
S. Tetrahedron Lett. 1991, 32, 233. (g) Fray, A. H.; Kaye, R. L.;
Kleinman, E. F. J . Org. Chem. 1986, 51, 4828. (h) Kempf, D. J . J . Org.
Chem. 1986, 51, 3921.
(13) (a) Lagu, B. R.; Liotta, D. C. Tetrahedron Lett. 1994, 35, 547.
(b) Radunz, H.-E.; Eierman, V.; Schneider, G.; Riethmuner, A. Tetra-
hedron 1991, 47, 1887.
(14) (a) Askin, D.; Wallace, M. A.; Vacca, J . P.; Reamer, R. A.;
Volante, R. P.; Shinkai, I. J . Org. Chem. 1992, 57, 2771 and references
therein. (b) Evans, B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J . P.;
Hirshfield, J .; Veber, P. F. J . Org. Chem. 1985, 50, 4615.
(15) (a) Dondoni, A.; Perrone, D.; Semola, M. T. J . Org. Chem. 1995,
60, 7927 and references therein. (b) Poss, M. A.; Reid, J . A. Tetrahedron
Lett. 1992, 33, 1411. (c) Boyd, S. A.; Mantei, R. A.; Hsiao, C.-N.; Baker,
W. R. J . Org. Chem. 1991, 56, 438.
(16) Plata, D. J .; Leanna, M. R.; Morton, H. E. Tetrahedron Lett.
1991, 32, 3623.
(17) (a) Chakraborty, T. K.; Gangakhedkar, K. K. Synth. Commun.
1996, 26, 2045 and references therein. (b) Ghosh, A. K.; McKee, S. P.;
Thompson, W. J . J . Org. Chem. 1991, 56, 6500. (c) Shiozaki, M.;
Kobayashi, Y. Tetrahedron 1991, 47, 2785.
The diastereoselectivity of the alkylation-decarboxyl-
ation is generally quite good, ranging from 86 to 94% de
(Table 1); moreover the diastereomers can easily be
separated by chromatography on silica gel. The lowest
de was found for the alkylation of 4d with triflate 5c
(18) Sakurai, M.; Hata, T.; Yabe, Y. Tetrahedron Lett. 1993, 34,
5939.
(19) Peyrat, J .-F.; Chaboche, C.; Figade`re, B.; Cave´, A. Tetrahedron
Lett. 1995, 36, 2757.
(20) Wuts, P. G. M.; Ritter, A. R.; Pruitt, L. E. J . Org. Chem. 1992,
57, 6696.
(21) Hoffman, R. V.; Kim, H.-O. Tetrahedron Lett. 1992, 33, 3579.
(22) Hoffman, R. V.; Kim, H.-O. Tetrahedron Lett. 1993, 34, 2051.
(23) Hoffman, R. V.; Kim, H.-O. J . Org. Chem. 1995, 60, 5107.
(24) Hoffman, R. V.; Tao, J .-H. Tetrahedron, submitted.
(25) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531 and
references therein.
(26) (a) Hoffman, R. V.; Kim, H.-O. Tetrahedron 1992, 48, 3007 and
references therein. (b) Xiang, Y. B.; Snow, K.; Belley, M. J . Org. Chem.
1993, 58, 993 and references therein.
(27) Hoffman, R. V.; Tao, J .-H. J . Org. Chem. 1997, 62, 2292.

6242 J . Org. Chem., Vol. 62, No. 18, 1997
Tao and Hoffman
Ta ble 2. Ster eoch em ica l Resu lts of th e P r ep a r a tion of
Hyd r oxyeth ylen e Dip ep tid e Isoster es 1 a n d 2 by th e
Red u ction of 3
Sch em e 4
entry
Product
Yield (%)a
de (%)b
1
3
4
6
2
5
1a a
1cb
1d c
1d a
2bd
2ee
89
80
90
91
80
84
>95
>95
>95
>95
>95
>95
a
Isolated yields of chromatographically pure diastereomers.
Determined by 1H NMR, only one diastereomer observed.
b
Sch em e 6
Ta ble 1. Ster eoch em ica l Resu lts of th e P r ep a r a tion of
Ketom eth ylen e Dip ep tid e Isoster es 3
sumed for the reduction of 3. Although the chiral center
at C-2 could influence the reduction stereochemistry, the
data suggest this is not the case. Only a single diaste-
reomer is observed in the reduction. Thus the alkyl
group at C-2 must either completely reverse the syn
diastereoselectivity known for R-dibenzylamino ketones
or have no observable effect. Since it is unlikely that a
chiral center two atoms away from the carbonyl group
would completely reverse the stereochemical control
effected by the bulky dibenzylamino group vicinal to the
carbonyl group, the assumption of syn stereochemistry
in 1 is a sound one. Because R-R-hydroxy esters were
used as starting materials, the stereochemistry in 3 is
5S and consequently syn reduction products 1 and 2 both
have the 4S,5S stereochemistry common in hydroxyeth-
ylene dipeptide isosteres.
entry
product
yield (%)a
de (%)b
ee (%)c
1
2
3
4
5
6
3a a
3cb
3d c
3d a
3bd
3ee
50
46
40
42
57
46
94
90
70
94
86
90
>95
>95
>95
>95
>95
>95
a
Isolated yields of chromatographed mixtures of diastereomers.
Determined by 1H NMR of the mixture of diastereomers in
b
corroboration with chromatographic separation. c Determined by
chiral LIS study using Eu(hfc)3 on separated major diastereomer.
Sch em e 5
Solely for demonstration purposes, the N,N-dibenzyl
protecting group was removed and converted to the Boc
group, 7, in a one-pot procedure (Scheme 6).29 No
attempts were made to optimize the yields of 7. N-Boc-
protected hydroxyethylene dipeptide isosteres 7 tend to
lactonize during removal of the Boc group under acidic
conditions; thus Boc protection is not very useful for these
compounds.11c,13 This protecting group interchange sim-
ply shows that N,N-dibenzyl groups provide good or-
thogonal protection for 7 and they can be removed
readily.
There are several points that should be noted. First,
the starting R-hydroxy esters are available commercially,
from amino acids, or from a variety of other sources.26
Thus the structure of R1 and R2 and the chirality of the
product are not restricted to those available in amino acid
precursors. Furthermore the methodology is convergent
so that diastereomers epimeric at C-2 can be produced
from a single precursor.
Second, the diastereoselectivity of the process is gener-
ally good (86-94% de) and the enantioselectivity is very
high (>95% ee); thus good stereocontrol can be exerted
at three chiral centers. This control is based on clean
stereochemical inversion in the alkylation of 4 by scale-
mic triflate 523 and by highly diastereoselective syn
reduction of 3.13a,25
Third, differential reactivity is used to create the
functional groupings in 1 and 2 without the need for
extensive protection-deprotection schemes. This con-
tributes to the overall efficiency of the method.
(entry 3) which has a branched chain next to the triflate
leaving group. In this sterically hindered case the
reaction time was increased to 48 h. In each case the
major diastereomer of 3 was separated and examined by
the chiral shift reagent Eu(hfc)3. Within the limits of
NMR detection only one enantiomer was present (>95%
ee), indicating that no epimerization at C-5 takes place
during the reaction sequence.28
Reduction of the major diastereomers of amino ketones
3 with sodium borohydride in absolute methanol gave
N,N-dibenzyl-protected hydroxyethylene dipeptide isos-
teres 1a a , 1cb, 1d c, 1d a , and 2bd , 2ee in good yields
and excellent diastereoselectivity (Scheme 5, Table 2).
Only a single diastereomer was observed in the 1H NMR
spectrum, indicating both that the reduction is highly
stereoselective (>95%) and that no epimerization at C-2
or C-5 occurs.
From previous studies it is known that the reduction
of N,N-dibenzylamino ketones takes place with syn
stereochemistry,13a,25 and syn stereochemistry was as-
(28) For calibrating the LIS method to determine enantioselectivity,
racemic 4a was prepared and converted to racemic 3a a which was
examined by the LIS reagent.
(29) Bajwa, J . S. Tetrahedron Lett. 1992, 33, 2955.

Convergent Synthesis of Hydroxyethylene Dipeptide Isosteres
J . Org. Chem., Vol. 62, No. 18, 1997 6243
NMR δ 0.82 (d, 3H, J ) 8.1 Hz), 0.86 (d, 3H, J ) 5.4 Hz),
0.82-1.69 (set of m, 16H), 2.63-2.82 (set of m, 3H), 3.33 (dd,
1H, J ) 4.8, 6.7 Hz), 3.53 (d, 2H, J ) 13.8 Hz), 3.62 (s, 3H),
3.65 (d, 2H, J ) 13.8 Hz), 7.31 (m, 10H); 13C NMR δ 22.7, 26.7,
27.0, 31.0, 33.6, 34.1, 35.1, 38.8, 41.7, 43.6, 52.0, 54.9, 63.5,
127.6, 128.8, 129.1, 129.4, 140.0, 176.8, 210.3; FTIR (neat)
In summary, a simple, convergent, and stereoselective
synthesis of hydroxyethylene dipeptide isosteres 1 and
2 from scalemic R-hydroxy esters has been developed. The
method is short (six steps from R-hydroxy esters), efficient
(≈15-25% overall), and highly diastereoselective (86-
94% de) and enantioselective (>95% ee).
1744, 1716 cm-1
. Anal. Calcd for C31H43O3N: C, 77.95; H,
9.07; N, 2.93. Found: C, 78.06; H, 8.81; N, 2.98.
Exp er im en ta l Section
Diben zyl-Ser (Bzl)Ψ[COCH2](2S,5S)Va l-OMe, 3d c: yield
40% (based on 4d ) of a colorless oil that had de 70% on the
basis of flash chromatography (hexane:ether ) 85:10 to 80:
15). The major diastereomer had ee 95%: [R]25D +21.5 (c 1.36,
CHCl3); 1H NMR δ 0.87(d, 6H, J ) 5.9 Hz), 1.90 (m, 1H), 2.86
(dd, 1H, J ) 3.3, 15.2 Hz), 2.66 (m, 1H), 3.25 (dd, 1H, J )
10.8, 15.2 Hz), 3.59 (t, 1H, J ) 6.1 Hz), 3.64 (s, 3H), 3.69 (d,
2H, J ) 13.6 Hz), 3.80 (d, 2H, J ) 13.6 Hz), 3.88 (d, 2H, J )
6.1 Hz), 4.46 (d, 1H, J ) 12.0 Hz), 4.54 (d, 2H, J ) 12.0 Hz),
7.32 (m, 15H); 13C NMR δ 19.7, 20.2, 30.0, 40.3, 45.9, 51.4,
54.9, 65.1, 67.0, 73.5, 127.1, 127.7, 128.3, 129.0, 138.1, 139.5,
175.3, 209.9; FTIR (neat) 1739, 1721 cm-1. Anal. Calcd for
C31H37O4N: C, 76.36; H, 7.65; N, 2.87. Found: C, 76.11; H,
7.89; N, 2.87.
Infrared spectra were taken as neat liquids or as KBr
pellets. 1H NMR and 13C NMR spectra were recorded at 200
and 50 MHz, respectively, in CDCl3. Thin-layer chromatog-
raphy was performed on silica gel 60 F254 plates from EM
reagents and visualized by UV irradiation and/or iodine.
Analytical HPLC was performed with the indicated solvent
systems and flow rates on 8 mm × 25 mm cm silica gel
columns using UV detection. Preparative thin-layer chroma-
tography was performed on silica gel 60 F254 plates from EM
reagents and visualized by UV irradiation. Flash chromatog-
raphy was performed using silica gel 60 (230-400 mesh).
Tetrahydrofuran was distilled from benzophenone ketyl. Other
solvents were HPLC grade and were used without further
purification. Starting materials were purchased from Aldrich,
Sigma, or Novabiochem and used as received. Elemental
analyses were carried out by M-H-W laboratories, Phoenix,
AZ.
Diben zyl-NvaΨ[COCH2](2S,5S)P h e-OMe, 3ee: yield 46%
(based on 4e) of a colorless oil that had de 90% on the basis of
flash chromatography (hexane:ether ) 85:10). The major
diastereomer had ee 95%: [R]25 +57.5 (c 3.94, CHCl3); 1H
D
NMR δ 0.85 (t, 3H, J ) 7.2 Hz), 1.14-1.71 (set of m, 4H), 2.63
(m, 3H), 3.03 (m, 2H), 3.17 (dd, 3H, J ) 4.4, 8.0 Hz), 3.45 (d,
2H, J ) 13.6 Hz), 3.56 (d, 2H, J ) 13.6 Hz), 3.61 (s, 3H), 7.24
(m, 15H); 13C NMR δ 14.6, 20.7, 25.5, 28.2, 38.2, 42.2, 52.2,
54.9, 65.8, 127.1, 127.6, 128.7, 129.0, 129.1, 139.1, 139.8, 175.6,
The synthesis of 3-oxo esters 4 and triflates 5 has been
reported previously.27
N,N-Dib en zyl-P h e Ψ[COCH 2](2R,5S)Nva -OMe, 3a a .
Gen er a l P r oced u r e. A solution of 3-oxo ester 4a (970 mg,
2.19 mmol) in THF (10 mL) was added dropwise to a stirred
suspension of NaH (92.0 mg of 60% in oil, 2.30 mmol) in dry
THF (30 mL) at 0 °C under nitrogen. The mixture was stirred
for 10 min. A solution of triflate 5a (607 mg, 2.30 mmol) in
dichloromethane (10 mL) was added dropwise to the gray
suspension. The resulting mixture was stirred at room tem-
perature for 24 h and then quenched with 1 N HCl (50 mL)
and extracted with ethyl acetate (3 × 50 mL). The organic
extracts were combined, washed with brine (100 mL), dried
210.3; FTIR (neat) 1734, 1716 cm-1
.
Anal. Calcd for
C30H35O3N: C, 78.74; H, 7.71; N, 3.06. Found: C, 78.88; H,
7.86; N, 3.16.
Diben zyl-Ser (Bzl)Ψ[COCH2](2R,5S)Nva-OMe, 3da: yield
42% (based on 4d ) of a colorless oil that had de 94% on the
basis of flash chromatography (hexane:ether ) 85:10 to 75:
20). The major diastereomer had ee 95%: [R]25D -12.2 (c 1.10,
CHCl3); 1H NMR δ 0.87 (t, 3H, J ) 7.2 Hz), 1.26 (m, 2H), 1.40
(m, 2H), 2.41 (dd, 1H, J ) 4.1, 18.1 Hz), 2.77 (m, 1H), 3.18
(dd, 1H, J ) 9.5, 18.1 Hz), 3.58 (t, 1H, J ) 6.1 Hz), 3.63 (s,
3H), 3.68 (d, 2H, J ) 13.6 Hz), 3.80 (d, 2H, J ) 13.6 Hz), 3.88
(d, 2H, J ) 6.1 Hz), 4.45 (d, 1H, J ) 11.8 Hz), 4.53 (d, 1H, J
) 11.8 Hz), 7.32 (m, 15H); 13C NMR δ 14.3, 20.7, 34.7, 40.1,
43.7, 52.0, 55.5, 65.5, 67.4, 74.0, 127.6, 128.2, 128.8, 129.5,
138.5, 140.0, 176.5, 209.7; FTIR (neat) 1746, 1726 cm-1. Anal.
Calcd for C31H37O4N: C, 76.36; H, 7.65; N, 2.87. Found: C,
76.32; H, 7.72; N, 2.86.
(MgSO4), passed through
a short pad of silica gel, and
concentrated to provide a pale yellow oil. Without further
purification, the above oil was dissolved in dichloromethane
(10 mL) and treated with TFA (3.2 mL) at room temperature
for 24 h. After dilution with dichloromethane (50 mL), the
resulting solution was washed with saturated NaHCO3 (2 ×
50 mL), brine (50 mL), dried (MgSO4), and concentrated to
provide 3a a as a colorless oil (500 mg, 50% based on 4a ) after
purification by flash chromatography (hexane:ether ) 85:10).
Product 3a a had 94% de on the basis of the separated
Diben zyl-P h eΨ[CHOHCH 2](2R,4S,5S)Nva -OMe, 1a a .
Gen er a l P r od ed u r e. Oxo ester 3a a (100 mg, 0.22 mmol) was
dissolved in dry methanol (5.0 mL).30 The resulting solution
was cooled to -20 °C and treated with NaBH4 (17.0 mg, 0.44
mmol). The reaction was monitored by TLC. After 4.0 h, the
solution was quenched with H2O (100 mL), extracted by ether
(3 × 100 mL), washed by brine (100 mL), dried (MgSO4), and
concentrated to provide 1a a as a colorless oil (90.0 mg, 89%
based on 3a a ) after purification by flash chromatography
1
diastereomers in corroboration with the H NMR of the crude
product. The major diastereomer had ee > 95% by a chiral
LIS study using Eu(hfc)3 in comparison with
a racemic
sample: [R]25D -83.0 (c 0.40, CHCl3); 1H NMR δ 0.81 (t, 3H, J
) 7.0 Hz), 1.18-1.43 (set of m, 4H), 2.09 (m, 1H), 2.66 (m,
1H), 2.90 (m, 1H), 3.20 (m, 2H), 3.54 (m, 1H), 3.60 (d, 2H, J )
13.6 Hz), 3.59 (s, 3H), 3.80 (d, 2H, J ) 13.6 Hz), 7.35 (m, 15H);
13C NMR δ 13.5, 19.9, 29.3, 33.7, 39.3, 43.2, 51.2, 54.1, 67.5,
125.8, 127.0, 128.1, 128.7, 129.3, 138.9,175.5, 196.6; FTIR
(neat) 1738, 1719 cm-1. Anal. Calcd for C30H35O3N: C, 78.78;
H, 7.71; N, 3.06. Found: C, 78.92; H, 7.59; N, 3.14.
1
(hexane:ether ) 85:15 to 80:25): de >95% on the basis of H
NMR; [R]25 -8.36 (c 2.44, CHCl3); 1H NMR δ 0.86 (t, 3H, J )
D
7.0 Hz), 1.21 (m, 2H), 1.47 (m, 4H), 2.47 (m, 1H), 2.80 (m, 2H),
3.05 (m, 1H), 3.36 (d, 2H, J ) 13.4 Hz), 3.56 (s, 3H), 3.59 (m,
Diben zyl-Leu Ψ[COCH2](2S,5S)Ch a-OMe, 3bd: yield 57%
1H), 3.90 (d, 2H, J ) 13.4 Hz), 4.21 (s, 1H), 7.24 (m, 15H); 13
C
(based on 4b) of a colorless oil that had de 86% on the basis of
NMR δ 14.0, 20.4, 32.3, 34.1, 37.0, 42.2, 51.4, 54.0, 64.1, 68.7,
126.3, 127.3, 128.5, 129.0, 129.4, 138.8, 140.3, 171.2; FTIR
(neat) 3426, 1738 cm-1. Anal. Calcd for C30H37O3N: C, 78.40;
H, 8.11; N, 3.05. Found: C, 78.75; H, 8.16; N, 3.06.
flash chromatography (hexane:ether ) 85:10). The major
1
diastereomer had ee > 95%; [R]25 +55.5 (c 0.81, CHCl3); H
D
NMR δ 0.79 (d, 3H, J ) 6.4 Hz), 0.82 (d, 3H, J ) 7.6 Hz),
0.86-1.72 (set of m, 16H), 2.52-2.90 (set of m, 3H), 3.30 (dd,
1H, J ) 4.5, 6.8 Hz), 3.52 (d, 2H, J ) 13.6 Hz), 3.62 (s, 3H),
3.69 (d, 2H, J ) 13.6 Hz), 7.31 (m, 10H); 13C NMR δ 22.4, 23.0,
25.3, 26.2, 27.8, 31.9, 33.2, 37.4, 39.6, 43.0, 51.6, 54.5,
63.7,127.1,128.3, 128.7, 128.9, 139.5, 176.4, 209.8; FTIR (neat)
Dib en zyl-Ch a Ψ[CH OH CH 2](2R,4S,5S)Leu -OMe, 1cb :
yield 80% (based on 3cb) of a colorless oil after flash chroma-
tography (hexane:ether ) 85:10 to 75:20); de >95%; [R]25
D
1
+23.8 (c 0.504, CHCl3); H NMR δ 0.84 (d, 3H, J ) 5.9 Hz),
1741, 1721 cm-1
. Anal. Calcd for C31H43O3N: C, 77.95; H,
0.87 (d, 3H, J ) 6.2 Hz), 0.91-1.83 (set of m, 18H), 2.44 (m,
1H), 2.48 (m, 1H), 2.79 (m, 1H), 3.26 (m, 1H), 3.42 (d, 2H, J )
9.07; N, 2.93. Found: C, 77.78; H, 9.19; N, 2.78.
Diben zyl-Ch aΨ[COCH2](2R,5S)Leu -OMe, 3cb: yield 46%
(based on 4c) of a colorless oil that had de 90% on the basis of
(30) Distilled from absolute methanol using Mg turnings and iodine.
Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals;
Pergamon Press: Oxford, U.K., 1988; p 217.
flash chromatography (hexane:ether ) 85:10). The major
1
diastereomer had ee > 95%; [R]25 -40.8 (c 0.80, CHCl3); H
D

6244 J . Org. Chem., Vol. 62, No. 18, 1997
Tao and Hoffman
13.5 Hz), 3.64 (s, 3H), 3.79 (d, 2H, J ) 13.5Hz), 4.52 (br, 1H),
7.26 (m, 10H); 13C NMR δ 22.4, 23.5, 26.7, 34.3, 36.7, 38.2,
40.8, 43.4, 51.8, 54.4, 54.8, 60.9, 69.6, 127.6, 128.9, 129.5, 139.6,
1.21-1.87 (set of m, 6H), 2.38 (m, 1H), 2.77 (m, 2H), 2.87 (m,
1H), 3.42 (d, 2H, J ) 13.3 Hz), 3.52 (s, 3H), 3.73 (m, 1H), 3.82
(d, 2H, J ) 13.3 Hz), 4.40 (br, 1H), 7.24 (m, 15H); 13C NMR δ
14.7, 22.4, 28.4, 36.6, 39.5, 44.0, 51.4, 54.0, 63.2, 68.6, 126.3,
126.8, 127.2, 128.4, 129.0, 138.9, 176.2; FTIR (neat) 3416, 1738
cm-1. Anal. Calcd for C30H37O3N: C, 78.40; H, 8.11; N, 3.05.
Found: C, 78.63; H, 8.20; N, 3.05.
177.8; FTIR (neat) 3446, 1735 cm-1
.
Anal. Calcd for
C31H45O3N: C, 77.62; H, 9.46; N, 2.92. Found: C, 77.80; H,
9.31; N, 2.95.
Dib e n zyl-Se r (Bzl)Ψ[CH OH CH 2](2S ,4S ,5S )Va l-OMe ,
1d c: yield 90% (based on 3d c) of a colorless oil after flash
chromatography (hexane:ether ) 75:20); de >95%; [R]25D -24.5
(c 0.714, CHCl3);1H NMR δ 0.84 (d, 3H, J ) 4.0 Hz), 0.86 (d,
3H, J ) 2.6 Hz), 1.64 (m, 2H), 1.82 (m, 1H), 2.37 (m, 1H), 2.68
(m, 1H), 3.52 (d, 2H, J ) 13.3 Hz), 3.59 (s, 3H), 3.68 (m, 1H),
3.69 (d, 2H, J ) 4.1 Hz), 3.95 (d, 2H, J ) 13.3 Hz), 4.50 (d,
1H, J ) 12.0 Hz), 4.57 (d, 1H, J ) 12.0 Hz) 7.25-7.37 (m,
15H); 13C NMR δ 18.5, 19.8, 29.4, 32.9, 47.9, 50.4, 53.9, 61.6,
65.8, 72.7, 126.4, 127.0, 127.7, 128.4, 137.3, 138.4, 175.6; FTIR
(neat) 3436, 1735 cm-1. Anal. Calcd for C31H39O4N: C, 76.04;
H, 8.03; N, 2.86. Found: C, 76.16; H, 8.23; N, 2.89.
Dib en zyl-Ser (Bzl)Ψ[CH OH CH 2](2R,4S,5S)Nva -OMe,
1d a : yield 91% (based on 3d a ) of a colorless oil after flash
chromatography (hexane:ether ) 75:20); de >95%; [R]25D +36.0
(c 0.644, CHCl3);1H NMR δ 0.86 (t, 3H, J ) 7.1 Hz), 1.25 (m,
2H), 1.51 (m, 4H), 2.67 (m, 3H), 3.53 (d, 3H, J ) 13.5 Hz),
3.60 (s, 3H), 3.68 (d, 2H, J ) 5.1 Hz), 3.95 (d, 2H, J ) 13.5
Hz), 4.13 (br, 1H), 4.49 (d, 1H, J ) 11.8 Hz), 4.57 (d, 1H, J )
11.8 Hz), 7.25-7.37 (m, 15H); 13C NMR δ 14.0, 20.4, 33.8, 36.3,
41.9, 51.4, 54.5, 62.5, 65.2, 66.4, 73.4, 127.2, 127.6, 128.4, 129.2,
138.1, 139.0, 177.2; FTIR (neat) 3436,1731 cm-1. Anal. Calcd
for C31H39O4N: C, 76.04; H, 8.03; N, 2.86;. Found: C, 76.16;
H, 8.12; N, 2.91.
Boc-P h eΨ[CHOHCH2](2R,4S,5S)Nva -OMe, 7a a . Gen -
er a l P r oced u r e. To a solution of dibenzyl ester 1a a (170 mg,
0.37 mmol) and (Boc)2O (163 mg, 0.74 mmol) in absolute
ethanol (2.5 mL) under an N2 atmosphere was added 10%
Pd-C (340 mg) followed by 1,4-cyclohexadiene (0.75 mL, 7.5
mmol); 36 h later, the mixture was filtered through Celite and
concentrated to provide 7a a as a colorless oil (87 mg, 67%
based on 1a a ) after flash chromatography (hexane:ether ) 75:
1
20 to 60:40): [R]25 -32.9 (c 0.705, CHCL3); H NMR δ 0.84
D
(t, 3H, J ) 6.6 Hz), 1.23-1.40 (set of m, 6H), 1.46 (s, 9H),1.87
(m, 1H), 2.34 (m, 1H), 2.71 (dd, 1H, J ) 9.4, 11.0 Hz), 3.05
(br, 1H), 3.60 (s, 3H), 3.76 (m, 1H), 3.97 (m, 1H), 5.16 (br, 1H),
7.27 (m, 5H); 13C NMR δ 14.3, 20.7, 22.1, 29.0, 35.0, 35.8, 43.0,
52.0, 63.5, 79.4, 80.7, 127.0, 129.0, 130.0, 138.5, 153.6, 177.0;
FTIR (neat) 3495, 1736, 1701 cm-1
.
Boc-Ser (Bzl)Ψ[CH OH CH 2](2R,4S,5S)Nva -OMe, 7d a :
yield 56% (based on 1d a ) of a colorless oil after flash chroma-
tography (hexane:ether ) 75:20 to 60:40); [R]25D +3.13 (c 0.575,
CHCl3);1H NMR δ 0.90 (t, 3H, J ) 6.8 Hz), 1.25-1.53 (set of
m, 6H), 1.45 (s, 9H), 2.52 (m, 1H), 3.40 (m, 1H), 3.64 (s, 3H),
3.70 (d, 2H, J ) 11.2 Hz), 4.24 (m, 2H), 4.54 (s, 2H), 5.12 (br,
1H), 7.32 (m, 5H); 13C NMR δ 13.8, 20.4, 28.4, 34.8, 35.4, 42.7,
51.5, 60.6, 70.0, 73.2, 78.2, 80.4, 127.6, 128.4, 129.6, 138.1,
Dib en zyl-Leu Ψ[CH OH CH 2](2S,4S,5S)Ch a -OMe, 2b d :
153.2, 176.8; FTIR (neat) 3495, 1736, 1701 cm-1
.
yield 80% (based on 3bd ) of a colorless oil after flash chroma-
tography (hexane:ether ) 85:10 to 75:20): de >95%; [R]25
D
1
Ack n ow led gm en t. The authors thank the National
Science Foundation (CHE 9520431) for financial support
of this work.
-5.18 (c 0.580, CHCl3); H NMR δ 0.95 (d, 6H, J ) 6.4 Hz),
1.50-1.82 (set of m, 18H), 2.44 (m, 1H), 2.83 (m, 1H), 3.28
(m, 1H), 3.42 (d, 2H, J ) 13.4 Hz), 3.65 (s, 3H), 3.81 (d, 2H, J
) 13.4 Hz), 4.49 (br, 1H), 7.26 (m, 10H); 13C NMR δ 23.5, 26.6,
27.0, 33.2, 33.9, 36.0, 38.2, 40.0, 41.8, 51.8, 54.4, 61.8, 69.6.
Su p p or tin g In for m a tion Ava ila ble: The 1H spectra of
N-Boc-protected hydroxyethylene dipeptide isosteres 6a a and
6d a (2 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
127.6, 128.9, 129.5, 139.5, 177.9; FTIR (neat) 3396, 1736 cm-1
.
Anal. Calcd for C31H45O3N: C, 77.62; H, 9.46; N, 2.92.
Found: C, 77.80; H, 9.41; N, 2.94.
Dib en zyl-Nva Ψ[CH OH CH 2](2S,4S,5S)P h e-OMe, 2ee:
yield 84% (based on 3ee) of a colorless oil after flash chroma-
tography (hexane:ether ) 85:10 to 75:20); de >95%; [R]25
D
1
-8.76 (c 0.685, CHCl3); H NMR δ 0.94 (t, 3H, J ) 7.0 Hz),
J O970579S