Regioselective enolization and alkylation of 4-oxo-N-(9-phenylfluoren-9-yl)proline: Synthesis of enantiopure proline-valine and hydroxyproline-valine chimeras

Article abstract of DOI:10.1021/jo9514984

The regioselective enolization of 4-oxo-N-(9-phenylfluoren-9-yl)proline benzyl ester (5) followed by alkylation with different alkyl halides has been used to synthesize a variety of β-alkylproline derivatives. In particular, enolization of 5 with 400 mol % of KN(SiMe₃)₂ and alkylation with iodomethane provided 3,3-dimethyl-4-oxo-N-(9-phenylfluoren-9-yl)proline benzyl ester (7a) in excellent yield. Subsequent hydride reduction of ketone 7a and protecting group exchange by hydrogenation in the presence of di-tert-butyl dicarbonate provided enantiopure (2S,4R)- and (2S,-4S)-3,3-dimethyl-4-hydroxy-N-(BOC)prolines 2. Hydroxyproline-valine chimeras (2S,4R)- and (2S,4S)-2 are each synthesized from hydroxyproline in six steps and 27% respective overall yield. Deoxygenation of 3,3-dimethyl-4-hydroxy-N-(9-phenylfluoren-9-yl)proline benzyl esters 9 via their conversion to xanthates 10 followed by tributylstannane-mediated reduction provided 3,3-dimethyl-N-(9-phenylfluoren-9-yl)proline benzyl ester (11) in excellent yield. Hydrogenation of 11 with Pearlman's catalyst in the presence of di-tert-butyl dicarbonate then furnished (2S)-3,3-dimethyl-N-(BOC)proline (1) in the last step of an eight-step synthesis (41% overall yield) from hydroxyproline. Both proline-valine and hydroxyproline-valine chimeras 1 and 2 were designed to serve as tools for studying the conformational requirements of biologically active peptides.

Full text of DOI:10.1021/jo9514984

202
J . Org. Chem. 1996, 61, 202-209
Regioselective En oliza tion a n d Alk yla tion of
4-Oxo-N-(9-p h en ylflu or en -9-yl)p r olin e: Syn th esis of En a n tiop u r e
P r olin e-Va lin e a n d Hyd r oxyp r olin e-Va lin e Ch im er a s
Raman Sharma and William D. Lubell*
De´partement de chimie, Universite´ de Montre´al, C. P. 6128, Succursale Centre Ville,
Montre´al, Que´bec, Canada H3C 3J 7
Received August 11, 1995X
The regioselective enolization of 4-oxo-N-(9-phenylfluoren-9-yl)proline benzyl ester (5) followed by
alkylation with different alkyl halides has been used to synthesize a variety of â-alkylproline
derivatives. In particular, enolization of 5 with 400 mol % of KN(SiMe3)2 and alkylation with
iodomethane provided 3,3-dimethyl-4-oxo-N-(9-phenylfluoren-9-yl)proline benzyl ester (7a ) in
excellent yield. Subsequent hydride reduction of ketone 7a and protecting group exchange by
hydrogenation in the presence of di-tert-butyl dicarbonate provided enantiopure (2S,4R)- and (2S,-
4S)-3,3-dimethyl-4-hydroxy-N-(BOC)prolines 2. Hydroxyproline-valine chimeras (2S,4R)- and
(2S,4S)-2 are each synthesized from hydroxyproline in six steps and 27% respective overall yield.
Deoxygenation of 3,3-dimethyl-4-hydroxy-N-(9-phenylfluoren-9-yl)proline benzyl esters 9 via their
conversion to xanthates 10 followed by tributylstannane-mediated reduction provided 3,3-dimethyl-
N-(9-phenylfluoren-9-yl)proline benzyl ester (11) in excellent yield. Hydrogenation of 11 with
Pearlman’s catalyst in the presence of di-tert-butyl dicarbonate then furnished (2S)-3,3-dimethyl-
N-(BOC)proline (1) in the last step of an eight-step synthesis (41% overall yield) from hydroxyproline.
Both proline-valine and hydroxyproline-valine chimeras 1 and 2 were designed to serve as tools
for studying the conformational requirements of biologically active peptides.
In tr od u ction
â-alkylprolines that combine amino acid side-chain func-
tionality with proline conformational rigidity. Replace-
ment of the natural amino acids in peptides for such
proline-amino acid chimeras has led to better under-
standing of the bioactive conformations of cholecystoki-
nin,2 angiotensin II,3 bradykinin,4 and opioid peptides.5
Furthermore, such â-alkylproline analogues have served
in the development of enzyme inhibitors,6 as well as
peptidomimetics exhibiting improved bioactivity and
greater metabolic stability.3-5
Proline analogues possessing the characteristics of
other amino acids are important tools for studying the
spatial requirements for receptor affinity and biological
activity of natural amino acids1 and peptides.2-6 For
example, the geometric relationship of the side-chain
group to the peptide backbone can be explored using
X Abstract published in Advance ACS Abstracts, December 15, 1995.
(1) Syntheses and uses of 3-carboxyproline, a proline-aspartate
chimera, are described in (a) Baldwin, J . E.; Adlington, R. M.; Gollins,
D. W.; Godfrey, C. R. A. Tetrahedron 1995, 51, 5169. (b) Cotton, R.;
J ohnstone, A. N. C.; North, M. Tetrahedron Lett. 1994, 35, 8859. (c)
Humphrey, J . M.; Bridges, R. J .; Hart, J . A.; Chamberlin, A. R. J . Org.
Chem. 1994, 59, 2467. (d) Hashimoto, K.; Yamamoto, O.; Horikawa,
M.; Ohfune, Y.; Shirahama, H. Bioorg. Med. Chem. Lett. 1994, 4, 1851.
(e) Sasaki, N. A.; Pauly, R.; Fontaine, C.; Chiaroni, A.; Riche, C.; Potier,
P. Tetrahedron Lett. 1994, 35, 241. Syntheses and uses of proline-
glutamate chimeras,4-carboxyproline, and trans-2-carboxy-3-pyrro-
lidineacetic acid are described in the following: (f) Bridges, R. J .;
Stanley, M. S.; Anderson, M. W.; Cotman, C. W.; Chamberlin, A. R. J .
Med. Chem. 1991, 34, 717. (g) Moss, W. O.; J ones, A. C.; Wisedale, R.;
Mahon, M. F.; Molloy, K. C.; Bradbury, R. H.; Hales, N. J .; Gallagher,
T. J . Chem. Soc., Perkin Trans. 1 1992, 2615. (h) Tsai, C.; Schneider,
J . A.; Lehmann, J . Neurosci. Lett. 1988, 92, 298. (i) Langlois, N.;
Andriamialisoa, R. Z. Tetrahedron Lett. 1991, 32, 3057. (j) Yoo, S.-E.;
Lee, S.-H.; Kim, N.-J . Tetrahedron Lett. 1988, 29, 2195. (k) Sato, T.;
Matsubayashi, K.-I.; Yamamoto, K.; Ishikawa, H.; Ishibashi, H.; Ikeda,
M. Heterocycles 1995, 40, 261. Synthesis of 4-(carboxymethyl)proline,
a proline-R-aminoadipic acid chimera, is presented in: (l) Pellicciari,
R.; Arenare, L.; De Caprariis, P.; Natalini, B.; Marinozzi, M.; Galli, A.
J . Chem. Soc., Perkin Trans. 1 1995, 1251. Synthesis of 4-(guanidi-
nomethyl)proline, a proline-arginine chimera, is presented in: (m)
Webb, T. R.; Eigenbrot, C. J . Org. Chem. 1991, 56, 3009. Syntheses of
3-phenylproline, a proline-phenylalanine chimera, are presented in:
(n) Chung, J . Y. L.; Wasicak, J . T.; Arnold, W. A.; May, C. S.; Nadzan,
A. M.; Holladay, M. W. J . Org. Chem. 1990, 55, 270. (o) Herdeis, C.;
Hubmann, H. P.; Lotter, H. Tetrahedron: Asymmetry 1994, 5, 351.
(p) Belokon’, Y. N.; Bulychev, A. G.; Pavlov, V. A.; Fedorova, E. B.;
Tsyryapkin, V. A.; Bakhmutov, V. A.; Belikov, V. M. J . Chem. Soc.,
Perkin Trans. 1 1988, 2075. (q) Sarges, R.; Tretter, J . R. J . Org. Chem.
1974, 39, 1710. Syntheses of 3-methylproline, a proline-valine chi-
mera, are reported in ref 25 as well as: (r) Kanemasa, S.; Tatsukawa,
A.; Wada, E. J . Org. Chem. 1991, 56, 2875. (s) Mauger, A. B. J . Org.
Chem. 1981, 46, 1032. (t) Esch, P. M.; Hiemstra, H.; de Boer, R. F.;
Speckamp, W. N. Tetrahedron 1992, 48, 4659. Syntheses of proline-
norleucine and proline-methionine chimeras are respectively pre-
sented in refs 2a and 2c.
Among the many routes developed for synthesizing
proline-amino acid chimeras,1-7 few approaches provide
general access to enantiopure â-alkylprolines in quanti-
(2) (a) Holladay, M. W.; Lin, C. W.; May, C. S.; Garvey, D. S.; Witte,
D. G.; Miller, T. R.; Wolfram, C. A. W.; Nadzan, A. M. J . Med. Chem.
1991, 34, 457. (b) Tilley, J . W.; Danho, W.; Madison, V.; Fry, D.;
Swistok, J .; Makofske, R.; Michalewsky, J .; Schwartz, A.; Weatherford,
S.; Triscari, J .; Nelson, D. J . Med. Chem. 1992, 35, 4249. (c) Kolodziej,
S. A.; Nikiforovich, G. V.; Skeean, R.; Lignon, M.-F.; Martinez, J .;
Marshall, G. R. J . Med. Chem. 1995, 38, 137.
(3) (a) Marshall, G. R. Tetrahedron 1993, 49, 3547. (b) Plucinska,
K.; Kataoka, T.; Yodo, M.; Cody, W. L.; He, J . X.; Humblet, C.; Lu, G.
H.; Lunney, E.; Major, T. C.; Panek, R. L.; Schelkun, P.; Skeean, R.;
Marshall, G. R. J . Med. Chem. 1993, 36, 1902.
(4) Kaczmarek, K.; Li, K.-M.; Skeean, R.; Dooley, D.; Humblet, C.;
Lunney, E.; Marshall, G. R. In Peptides: Chemistry, Structure and
Biology; Hodges, R. S., Smith, J . A., Eds.; ESCOM Science Publishers
B.V.: Leiden, The Netherlands, 1994; p 687.
(5) (a) Mosberg, H. I.; Kroona, H. B. J . Med. Chem. 1992, 35, 4498.
(b) Mosberg, H. I.; Lomize, A. L.; Wang, C.; Kroona, H.; Heyl, D. L.;
Sobczyk-Kojiro, K.; Ma, W.; Mousigian, C.; Porreca, F. J . Med. Chem.
1994, 37, 4371. (c) Nelson, R. D.; Gottlieb, D. I.; Balasubramanian, T.
M.; Marshall, G. R. In Opioid Peptides: Medicinal Chemistry, NIDA
Research Monograph 69; Rapaka, R. S. R. S.; Barnett, G.; Hawks, R.
L., Eds.; 1986, p 204.
(6) The use of â-alkylprolines in collagenase inhibitors is reported
in: (a) Ghose, A. K.; Logan, M. E.; Treasurywala, A. M.; Wang, H.;
Wahl, R. C.; Tomczuk, B. E.; Gowravaram, M. R.; J aeger, E. P.;
Wendoloski, J . J . J . Am. Chem. Soc. 1995, 117, 4671. The use of
â-alkylprolines in collagen proline hydroxylase inhibitors is reported
in: (b) Hutton, J . J ., J r.; Marglin, A.; Witkop, B.; Kurtz, J .; Berger,
A.; Udenfriend, S. Arch. Biochem. Biophys. 1968, 125, 779.
(7) See ref 1. Synthetic methods for preparing racemic 3-alkylpro-
lines have been reviewed in: (a) Mauger, A. B.; Witkop, B. Chem. Rev.
1966, 66, 47. (b) Moss, W. O.; Bradbury, R. H.; Hales, N. J .; Gallagher,
T. Tetrahedron Lett. 1990, 31, 5653.
0022-3263/96/1961-0202$12.00/0 © 1996 American Chemical Society

Proline-Valine and Hydroxyproline-Valine Chimeras
J . Org. Chem., Vol. 61, No. 1, 1996 203
Sch em e 1. Syn th esis of 4-Oxo-N-(P h F l)p r olin e
Ben zyl Ester (5)
F igu r e 1. Design of a proline-valine chimera.
carboxylic acid (Dtc) which has been used extensively in
conformational analyses of biologically active peptides.11-13
For example, Dtc has been incorporated into angiotensin
II agonists and antagonists,11 as well as potent chole-
cystokinin-A receptor agonists.2b Lately, Dtc has found
application in the design of potent peptide-based HIV
protease inhibitors.12 In these peptide analogues, steric
interactions between the â-methyl substituents and the
R-carboxylate restrict the ψ-dihedral angle of the Dtc
residue, which can not adopt a seven member γ-turn
conformation.13 Since added conformational rigidity as
well as metabolic stability should result from replace-
ment of the thiazolidine sulfur with carbon, we synthe-
sized 3,3-dimethylproline 1 and 3,3-dimethyl-4-hydroxy-
proline 2 that do not possess the masked aldehyde in Dtc.
We are currently studying proline-valine chimeras 1 and
2 in order to determine the influence of the â-substituents
on the geometries and barriers to rotation about the ω-
and ψ-dihedral angles of prolyl and hydroxyprolyl resi-
dues in peptides.10b
F igu r e 2. â,â-Dimethylproline derivatives.
ties suitable for incorporation into peptides. In order to
furnish a variety of â-alkylprolines from an inexpensive
source of chirality, we selected for use 4-hydroxy-L-proline
as described in a previous synthesis of a proline-
norleucine chimera.2a We have found that regioselective
enolization and alkylation of a hydroxyproline-derived
amino ketone is an effective way of preparing enan-
tiopure â-alkylproline analogues. We recently com-
municated the application of this reaction in the synthe-
sis of unique kainic acid derivatives.8 In this paper, we
now present details of the alkylation chemistry as well
as syntheses of â,â-dimethylprolines 1 and 2.
As part of a greater program to examine the influence
of steric bulk on the conformation of prolyl residues in
peptides, we are preparing various alkylproline deriva-
tives. We first reported methodology for synthesizing
5-alkylprolines9 and observed that steric repulsion be-
tween 5-alkyl and N-acyl substituents can disfavor the
trans-rotamer and greatly increase the cis-rotamer popu-
lation of the amide N-terminal to 5-alkylprolines that
possess bulky 5-position substituents such as a tert-butyl
group.9b With our methodology for synthesizing 5-alkyl-
prolines in hand, we next pursued a complementary
approach for synthesizing 3-alkylprolines in order to
study the influence of â-alkyl substituents on the geom-
etry of the prolyl ψ-dihedral angle and C-terminal
residues.10
Resu lts a n d Discu ssion
Syn th esis, En oliza tion , a n d Alk yla tion of 4-Oxo-
N-(P h F l)p r olin e Ben zyl Ester (5). Our method for
synthesizing â-alkylproline derivatives begins with (2S,-
4R)-hydroxyproline as a chiral educt that is converted
in three steps to 4-oxoprolinate 5. Regioselective eno-
lization of this amino ketone and subsequent C-alkylation
is the key step for synthesizing â-alkylproline derivatives.
For this purpose, the proline nitrogen was protected with
the 9-phenylfluoren-9-yl group (PhFl, Scheme 1), which
prevents racemization during enolization and alkylation
of R-amino ketones.14 J udicious employment of a benzyl
ester at the R-carboxylate allowed for one-pot O- and
N-deprotection as well as N-protecting group shuffles via
hydrogenolysis in the presence of di-tert-butyl dicarbon-
In this paper, we report the syntheses of enantiopure
proline-valine and hydroxyproline-valine chimeras 1
and 2 (Figures 1 and 2). These â,â-dialkylprolines share
a structural similarity with 5,5-dimethylthiazolidine-4-
(8) Gill, P.; Lubell, W. D. J . Org. Chem. 1995, 60, 2658.
(9) (a) Ibrahim, H. H.; Lubell, W. D. J . Org. Chem. 1993, 58, 6438.
(b) Ibrahim, H. H.; Beausoleil, E.; Atfani, M.; Lubell, W. D. In
Peptides: Chemistry, Structure and Biology; Hodges, R. S., Smith, J .
A., Eds.; ESCOM Science Publishers B.V.: Leiden, The Netherlands,
1994; p 307. (c) Lombart, H.-G.; Lubell, W. D. J . Org. Chem. 1994, 59,
6147. (d) Lombart, H.-G.; Lubell, W. D. In Peptides 1994 (Proceedings
of the 23rd European Peptide Symposium); Maia, H. L. S., Ed.;
ESCOM: Leiden, The Netherlands, 1995; p 696. (e) Lombart, H.-G.;
Lubell, W. D. In Peptides: Chemistry, Structure and Biology; Kaumaya,
P. T. P., Hodges, R. S., Eds.; ESCOM Scientific Publishers B.V.:
Leiden, The Netherlands, 1995, in press.
(11) Samanen, J .; Narindray, D.; Cash, T.; Brandeis, E.; Adams, W.,
J r.; Yellin, T.; Eggleston, D.; DeBrosse, C.; Regoli, D. J . Med. Chem.
1989, 32, 466.
(12) (a) Holmes, D. S.; Bethell, R. C.; Hann, M. M.; Kitchin, J .;
Starkey, I. D.; Storer, R. Bioorg. Med. Chem. Lett. 1993, 3, 1485. (b)
Mimoto, T.; Kisanuki, S.; Takhashi, O.; Kiso, Y. Eur. Pat. Appl. EP
574,135; Chem. Abstr. 1994, 121, 301322r. (c) Kiso, Y.; Mimoto, T.;
Enomoto, H.; Kisanuki, S.; Moriwaki, H.; Kimura, T.; Hattori, N.;
Hayashi, H.; Takada, K.; Akaji, K.; Kageyama, S.; Mitsuya, H. In
Peptides 1994 (Proceedings of the 23rd European Peptide Symposium);
Maia, H. L. S., Ed.; ESCOM: Leiden, The Netherlands, 1995; p 71.
(13) Samanen, J .; Zuber, G.; Bean, J .; Eggleston, D.; Romoff, T.;
Kopple, K.; Saunders, M.; Regoli, D. Int. J . Pept. Protein Res. 1990,
35, 501.
(10) Conformational distributions of 3-methylproline derivatives
have been presented in: (a) Delaney, N. G.; Madison, V. J . Am. Chem.
Soc. 1982, 104, 6635. (b) Sharma, R.; Beausoleil, E.; Michnick, S.;
Lubell, W. D. manuscript in preparation.
(14) Lubell, W. D.; Rapoport, H. J . Am. Chem. Soc. 1988, 110, 7447.

204 J . Org. Chem., Vol. 61, No. 1, 1996
Sharma and Lubell
Ta ble 1. Alk yla tion of 4-Oxop r olin e 5
of 4-oxoproline derivatives had thus required formation
of an enamine and furnished 3-alkylproline product in
low to moderate yield, sometimes accompanied by bis-
alkylation.2a,21 Recently, alkylation of the silyl enol ether
of 4-oxo-N-(BOC)proline tert-butyl ester using fluoride ion
and tert-butyl bromoacetate also gave low yields of bis-
alkylated product.22
In our work, specific incorporation of deuterium at the
proline 3-position (δ ) 2.3 and 2.4 ppm) was observed
on treatment of the enolate of 5 with CD3OD. Enolization
of 5 was accomplished using lithium, sodium, and potas-
sium bis(trimethylsilyl)amide bases in THF at -78 °C.
The addition of alkyl halide to the enolate in THF without
cosolvant failed to yield product except in the case of
R-bromoacetate. Alkylation did occur once DMPU was
used as cosolvant,20c which was mixed with the base in
THF at 0 °C prior to the addition of ketone 5 at -78 °C.23
Decomposition with loss of the phenylfluorenyl group was
observed at temperatures above -40 °C,24 yet alkylation
with benzyl bromide was successfully performed at -55
°C. The extent of alkylation was usually controlled by
limiting the quantities of base and electrophile; however,
complete conversion to monoalkylated product without
dialkylation was difficult to achieve (Table 1). The
3-position stereochemistry in product 6 was assigned on
the basis of the size of the vicinal coupling constant
between the R- and â-protons as well as the chemical shift
of the â-methyl group in 6a .2a,25 We also observed that
the R-proton signals in the 3S-diastereomers appeared
downfield from those of the 3R-isomers.25 Although
hydroxylation of the enolate of 4-oxo-N-(PhFl)proline
methyl ester is reported to furnish only product with the
3-hydroxyl group cis to the R-carboxylate,19 alkylation of
benzyl ester 5 was less stereoselective. One-pot alkyla-
tion of 5 with excess base and excess electrophile gave
generally good yields of dialkylprolines 7. However, in
the case of benzyl bromide O-alkylation competed with
the second C-alkylation such that 3-benzyl 4-O-benzyl
enol ether 8 was obtained in 48% yield and a separable
3:1 mixture of 3,3-dibenzylproline 7h and (2S)-benzyl
∆3-N-(PhFl)proline 4-O-benzyl enol ether was isolated in
29% yield.26
ate and furnished the final products 1 and 2 as N-(BOC)-
amino acids suitable for peptide synthesis.
The synthesis of the amino ketone 4-oxo-N-(PhFl)-
proline benzyl ester (5) was best accomplished by a
sequence of esterification, phenylfluorenation, and oxida-
tion (Scheme 1).8 Treatment of (2S,4R)-hydroxyproline
with benzyl alcohol and stoichiometric p-toluenesulfonic
acid in benzene with azeotropic removal of water gave
hydroxyproline benzyl ester p-toluenesulfonate 3 in 98%
yield after crystallization.1m,15 Phenylfluorenation of 3
was performed according to the procedure for preparation
of N-(PhFl)serine methyl ester and gave 4-hydroxy-N-
(PhFl)proline benzyl ester (4) in 71% yield.16 The sec-
ondary alcohol of 4 was then oxidized with N-chlorosuc-
cinimide and methyl sulfide in toluene to furnish amino
ketone 5 as a crystalline solid in 87% yield.17 Alterna-
tively, oxidation of 4 with (COCl)2 and DMSO in dichlo-
romethane provided ketone 5 in good yield on a larger
scale.18 We now use this three-step synthesis to provide
20 g batches of crystalline 4-oxo-N-(PhFl)proline 5 with-
out chromatography in ∼50% overall yield from hydroxy-
proline.
The synthesis of 3,3-dimethyl-4-oxo-N-(PhFl)proline
benzyl ester (7a ) was accomplished from 5 using 400 mol
% of potassium bis(trimethylsilyl)amide and 1000 mol %
of iodomethane in a 3:1 THF:DMPU solution. These
conditions provided 3,3-dimethylproline 7a contaminated
with minor amounts of starting ketone 5 and 3-methyl-
proline 6a . Both 5 and 6a could be conveniently sepa-
(20) (a) Garst, M. E.; Bonfiglio, J . N.; Grudoski, D. A.; Marks, J .
Tetrahedron Lett. 1978, 2671. (b) Garst, M. E.; Bonfiglio, J . N.;
Grudoski, D. A.; Marks, J . J . Org. Chem. 1980, 45, 2307. (c) Giles, M.;
Hadley, M. S.; Gallagher, T. J . Chem. Soc., Chem. Commun. 1990,
1047 and ref 1 therein.
(21) Baldwin, J . E.; Rudolph, M. Tetrahedron Lett. 1994, 35, 6163.
(22) Barraclough, P.; Hudhomme, P.; Spray, C. A.; Young, D. W.
Tetrahedron 1995, 51, 4195.
Regioselective enolization and alkylation of N-(PhFl)-
amino ketone 5 provides mono- and bis-3-alkylprolines
6 and 7 in moderate to excellent yields (Table 1). Prior
to the use of 4-oxo-N-(PhFl)prolines,8,19 the enolization
of N-acyl- and N-alkyl-3-pyrrolidinones under thermo-
dynamically and kinetically controlled conditions was
shown to proceed predominantly but not specifically away
from the nitrogen-bearing carbon.20 Selective alkylation
(23) Snyder, L.; Meyers, A. I. J . Org. Chem. 1993, 58, 7507.
(24) A mechanism for PhFl loss is presented in: Lubell, W. D.,
Rapoport, H. J . Am. Chem. Soc. 1987, 109, 236.
(25) The chemical shifts and J 2,3 coupling constants from 1H NMR
spectra of 6 in CDCl3 are as follows: (3R)-6a , 3.32 (6 Hz); (3S)-6a ,
3.88 (8.5 Hz); (3S)-6b, 4.08 (8.3 Hz); (3R)-6c, 3.5 (4.3 Hz); (3R)-6d ,
3.52 (4.7 Hz); (3S)-6d , 3.84 (7.8 Hz). The use of J 2,3 coupling constants
in the assignment of the relative C2-C3 stereochemistry of 3-meth-
ylprolines is presented in: Mauger, A. B.; Irreverre, F.; Witkop, B. J .
Am. Chem. Soc. 1966, 88, 2019.
(15) Zervas, L.; Winitz, M.; Greenstein, J . P. J . Org. Chem. 1957,
22, 1515.
(16) Lubell, W.; Rapoport, H. J . Org. Chem. 1989, 54, 3824.
(17) Corey, E. J .; Kim, C. U. J . Am. Chem. Soc. 1972, 94, 7586.
(18) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480.
(19) Regioselective enolization of methyl δ-oxo-N-(PhFl)prolinate
and subsequent oxidation of the sodium enolate provides stereoselec-
tively a 3-hydroxyproline derivative, see: Blanco, M. J .; Sardina, F. J .
Tetrahedron Lett. 1994, 35, 8493.
(26) (2S)-Benzyl ∆3-N-(PhFl)proline 4-O-benzyl enol ether: 1H NMR
δ 3.77 (m, 1H), 3.94 (m, 1 H), 4.12 (ddd, 1 H, J ) 2, 5, 14), 4.38 (dd, 1
H, J ) 2, 4), 4.68 (d, 1 H, 11.6), 4.75 (d, 1 H, 11.6), 4.84 (d, 1 H, 12.4),
4.94 (d, 1 H, 12.4), 7.0-7.7 (m, 23 H); 13C NMR δ 55.5, 66, 67, 71.6,
77.1, 92.1, 158.1, 174.4.

Proline-Valine and Hydroxyproline-Valine Chimeras
J . Org. Chem., Vol. 61, No. 1, 1996 205
rated from dimethylproline 7a by taking advantage of
their different solubilities in solutions of EtOAc in
hexanes. In this way, the more soluble 5 and 6a were
removed and 3,3-dimethyl-4-oxoproline 7a was obtained
as a crystalline solid in 82% yield. 3-Methylproline 6a
could also be resubmitted to alkylation with iodomethane
in order to yield additional 3,3-dimethylproline 7a .
Syn th esis of Hyd r oxyp r olin e-Va lin e Ch im er a s 2.
3,3,-Dimethyl-4-hydroxy-N-(PhFl)proline (9) was ob-
tained in excellent yield from the reduction of amino
ketone 7a with ordinary hydride reagents, albeit with
low diastereoselectivity (Scheme 2). Reduction with
NaBH4 in MeOH at 0 °C provided quantitatively a 3:2
mixture of 4R:4S diastereomers 9. On the other hand,
LiAlH4 in THF gave a 1:2 mixture of (4R)-9:(4S)-9 in 90%
yield. Diastereomeric alcohols 9 were readily separated
by chromatography on silica gel.
F igu r e 3. ORTEP drawing of (4R)-3,3-dimethyl-4-hydroxy-
N-(PhFl)proline benzyl ester ((4R)-9). Nonhydrogen atoms are
represented by ellipsoids corresponding to 40% probability.
Hydrogen atoms are represented by spheres of arbitrary size.
Sch em e 2. Syn th esis of Hyd r oxyp r olin e-Va lin e
Ch im er a s 2
The stereochemistry at the alcohol 4-position was
assigned initially on the basis of chemical shift data for
the hydroxyl group proton of 9 in CDCl3. In the 1H NMR
spectrum of cis-diastereomer (4S)-9, the signal of the
alcohol proton is observed downfield at 4.0 ppm due to a
hydrogen bond with the ester carbonyl. The alcohol
proton signal of trans-diastereomer (4R)-9 appears at 1.5
ppm. This assignment was confirmed by X-ray analysis
of crystals of alcohol (4R)-9 that were grown from
methanol.27 We note again that in the crystal structure
of (4R)-9 (Figure 3) the R-proton and the R-ester carbonyl
are almost coplanar. Such an arrangement has been
observed previously in the X-ray analyses of R-N-(PhFl)-
amino esters and acids,28 as well as R-N-benzyl-N-(PhFl)-
amino esters.1c This coplanar geometry has also been
suggested to contribute to the configurational stability
of R-N-(PhFl)amino carbonyl compounds, because R-depro-
tonation from this arrangement is stereoelectronically
less favored than from an orthogonal geometry.1c
Hydroxyproline-valine chimeras, (4R)- and (4S)-3,3-
dimethyl-4-hydroxy-N-(BOC)prolines ((4R)- and (4S)-2),
were produced respectively in excellent yield from hy-
drogenation of (4R)- and (4S)-3,3-dimethyl-4-hydroxy-N-
(PhFl)proline benzyl esters (9). In THF, hydrogenation
of 9 at 5 atm of H2 with catalytic palladium-on-carbon
in the presence of di-tert-butyl dicarbonate caused depro-
tection of the amino and carboxylate groups and subse-
quent acylation of the amine such that pure 2 was
obtained after filtration of the catalyst and removal of
the hydrocarbon side product by trituration. In MeOH,
the same reaction on (4S)-9 occurred with acylation of
the alcohol and gave mostly (4S)-4-O-BOC-2 that was
characterized as its N′-methyl amide.29
as well as displace secondary alcohol 9 using various
conditions were confounded by the steric effects of the
adjacent gem-dimethyl center.2a,30,31 However, xanthates
(4R)- and (4S)-10 were prepared in quantitative yield
Syn th esis a n d En a n tiom er ic P u r ity of P r olin e-
Va lin e Ch im er a 1. We next explored the deoxygenation
of alcohols 9 in order to furnish (2S)-3,3-dimethyl-N-
(PhFl)proline 11 (Scheme 3). Early attempts to acylate
(29) (2S,4S)-3,3-Dimethyl-4-O-(tert-butyloxycarbonyloxy)-N-(BOC)-
proline N’-methylamide was obtained from treatment of a mixture of
(4S)-2 and (4S)-4-O-BOC-2 with methylamine hydrochloride, triethyl-
amine, and TBTU in acetonitrile followed by purification on silica gel
using EtOAc in hexane as eluant: 1H NMR δ 1.0 (s, 3 H), 1.15 (s, 3
H), 1.38 (s, 9 H), 1.41 (s, 9 H), 2.78 (d, 3 H, J ) 5), 3.65 (br m, 1 H),
3.75 (dd, 1 H, J ) 4.6, 12.6), 3.8 (br s, 1 H), 4.72 (dd, 1 H, J ) 4.6, 1.7),
6.1 (br m, 1 H); 13C NMR δ 18.2, 25.7, 27.6, 27.9, 28.2, 45.6, 50.9, 70.4,
80.9, 81.2, 82.5, 152.5, 154.4, 171.2; HRMS calcd for C18H33N2O6 (MH+)
373.2339, found 373.2354.
(27) The structure of (4R)-9 was solved at l’Universite´ de Montre´al
X-ray facility using direct methods (SHELXS 86). The author has
deposited the atomic coordinates for the structure of (4R)-9 with the
Cambridge Crystallographic Data Center. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, U.K.
(30) Volante, R. P. Tetrahedron Lett. 1981, 22, 3119.
(31) Robins, M. J .; Wilson, J . S.; Hansske, F. J . Am. Chem. Soc.
1983, 105, 4059.
(28) Atfani, M.; Lubell, W. D. J . Org. Chem. 1995, 60, 3184.

206 J . Org. Chem., Vol. 61, No. 1, 1996
Sharma and Lubell
Sch em e 3. Syn th esis a n d En a n tiom er ic P u r ity of P r olin e-Va lin e Ch im er a 1
from alcohols (4R)- and (4S)-9 by acylation of the sodium
alkoxide with carbon disulfide in THF and subsequent
alkylation with iodomethane.32 At first, xanthate (4R)-
10 was reduced with tributylstannane and AIBN as
radical initiator in refluxing toluene.33 Chromatography
gave (2S)-3,3-dimethyl-N-(PhFl)proline 11 in 57% yield
accompanied by a more polar side product, which was
later determined to be hemithiol acetal (4R)-12 (13%). A
notable improvement in the xanthate reduction was
obtained by switching to refluxing xylene.33 This change
decreased significantly the formation of hemithiol acetal
12 and gave excellent yield (91%) of dimethylproline 11.
The enantiomeric purity of dimethylproline 1 was
ascertained via its conversion to R-methylbenzylamides
14 and examination of the diastereomers by 1H NMR
(Scheme 3). Both (R)- and (S)-R-methylbenzylamine were
coupled to proline (2S)-1 in high yield using benzotriazol-
1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate in ac-
etonitrile.36 Integration of the diastereomeric â-methyl
group singlets (δ ) 0.81, 1.03) in CD3OD showed amide
(1′S)-14 to be of 97% diastereomeric purity. Since (S)-
R-methylbenzylamine of 99% ee was used in the coupling
step, dimethylproline (2S)-1 as well as 4-hydroxy-3,3-
dimethylprolines (2S,4R)- and (2S,4S)-2 all are deter-
mined to be of 98% enantiomeric purity.
The structure of 12 was initially assigned on consid-
eration of its molecular ion and 1H,1H and 1H,13C cor-
relation spectra.34 Additional structural proof came from
treatment of 12 with citric acid in methanol which caused
hydrolysis of the hemithiol acetal, returning alcohol (4R)-
9. Alkylation of 12 with sodium hydride and io-
domethane in THF furnished (methylthio)methyl ether
13 in 84% yield. Finally, a sample exhibiting an identical
Rf value as 13 was synthesized for comparison by
alkylation of the sodium alkoxide of (4R)-9 with chlo-
romethyl methyl sulfide.
Con clu sion
Regioselective enolization and alkylation of 4-oxo-N-
(9-phenylfluoren-9-yl)proline benzyl ester (5) lays the
foundation for building a variety of enantiopure â-alkyl-
prolines and â-alkyl-γ-hydroxyprolines. Starting from
(2S,4R)-hydroxyproline as an inexpensive source of chiral-
ity, we have demonstrated the utility of this method by
synthesizing enantiopure (2S)-3,3-dimethyl-N-(BOC)pro-
line (1) in eight steps with 41% overall yield, as well as
(2S,4R)- and (2S,4S)-3,3-dimethyl-4-hydroxy-N-(BOC)-
prolines ((2S,4R)- and (2S,4S)-2) in six steps with 27%
respective overall yields. Because our strategy can be
elaborated to furnish other â-alkylproline and â-alkyl-
γ-hydroxyproline analogues possessing diverse side-chain
functions, potential exists for the synthesis of an assort-
ment of amino acid chimeras for studying the spatial
requirements of various biologically active amino acids
and peptides.
Proline-valine chimera 3,3-dimethyl-N-(BOC)proline
(1) was obtained from hydrogenation of (2S)-3,3-dimethyl-
N-(PhFl)proline benzyl ester (11) in the presence of di-
tert-butyl dicarbonate. Low yields of 1 were obtained
when palladium-on-carbon was used as catalyst in the
hydrogenation of 11 in THF under 5 atm of H2. The
major side product from hydrogenation under these
conditions was (2S)-3,3-dimethyl-N-(BOC)proline benzyl
ester which was obtained as the sole product from the
same conditions in methanol.35 An excellent yield (95%)
of proline-valine chimera 1 was obtained upon switching
to palladium-hydroxide-on-carbon as catalyst under the
above conditions in THF.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted all reactions were run
under a nitrogen atmosphere and distilled solvents were
transferred by syringe. Tetrahydrofuran (THF) was distilled
from sodium/benzophenone immediately before use. CH3CN,
CH2Cl2, Et3N, and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU) were distilled from CaH2. MeOH was
distilled from Mg(OCH3)2. Toluene and xylene were distilled
from sodium. CS2 was distilled from P2O5. Final reaction
mixture solutions were dried over Na2SO4. Chromatography
(32) Roberts, J . D.; Sauer, C. W. J . Am. Chem. Soc. 1949, 71, 3925.
(33) Reviewed in: Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413.
(34) Barton, D. H. R.; Crich, D.; Lo¨bberding, A.; Zard, S. Z.
Tetrahedron 1986, 42, 2329.
(35) (2S)-3,3-Dimethyl-N-(BOC)proline benzyl ester: 1H NMR δ 0.97
(s, 3 H), 1.12 (s, 3 H), 1.3 (s, 6.3 H), 1.42 (s, 2.7 H), 1.6 (m, 1 H), 1.84
(m, 1 H), 3.45 (m, 1 H), 3.6 (m, 1 H), 3.89 (s, 0.7 H), 3.98 (s, 0.3 H), 5.2
(m, 2 H), 7.37 (m, 5 H); 13C NMR δ (23.57) 23.62, (27.7) 27.8, 28.1 (28.3),
37.2 (38), (41.5) 42.5, 44.8 (45.1), 66.4, (68.7) 69.2, (79.7) 79.8, 128.3,
128.5, 128.6, 135.5, 154, 171.9; FAB MS m/e 334 [MH]+, 278, 234, 198
[M - CO2CH2Ph]+ 142 (100).
(36) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahe-
dron Lett. 1989, 30, 1927.

Proline-Valine and Hydroxyproline-Valine Chimeras
J . Org. Chem., Vol. 61, No. 1, 1996 207
was on 230-400 mesh silica gel. TLC on aluminum-backed
silica plates. Melting points are uncorrected. Mass spectral
data, HRMS (EI & FAB), were obtained by the Regional Center
for Mass Spectroscopy at the Universite´ de Montre´al. 1H NMR
(300/400 MHz) and 13C NMR (75/100 MHz) spectra were
recorded in CDCl3. Chemical shifts are reported in ppm (δ
units) downfield of internal tetramethylsilane ((CH3)4Si), and
coupling constants are given in hertz. Chemical shifts for
aromatic carbons are not reported. The chemical shifts for the
carbons of minor rotamers are reported in parentheses.
(2S,4R)-4-H yd r oxyp r olin e b en zyl est er p -t olu en e-
su lfon a te (3) was obtained as a white crystalline solid in 98%
yield by treatment of (2S,4R)-4-hydroxyproline (25 g) according
to the procedure for the preparation of (2S,4S)-4-hydroxy-
proline benzyl ester p-toluenesulfonate:1m mp 127-129 °C;
4.38 (d, 1 H, J ) 12.5), 4.55 (d, 1 H, J ) 12.5), 4.96 (m, 2 H),
5.55 (m, 1 H), 7.1-7.7 (m, 18 H); 13C NMR δ 33.6, 52.2, 55.4,
62.9, 66.1, 75.5, 117.7, 172.5, 212.9.
(2S,3R)-3-Ben zyl-4-oxo-N-(P h F l)p r olin e b en zyl est er
(6d ) was isolated as a mixture of diastereomers in 24% yield:
1H NMR δ 2.64 (dd, 1 H, J ) 8.5, 13.3), 2.76 (m, 1 H), 2.9 (dd,
1 H, J ) 4.5, 13.3), 3.35 (d, 1 H, J ) 17.8), 3.52 (d, 1 H, J )
4.7), 3.83 (d, 1 H, J ) 17.8), 4.2 (d, 1 H, J ) 12.5), 4.3 (d, 1 H,
J ) 12.5), 6.9-7.7 (m, 23 H); 13C NMR δ 34.9, 54.2, 55.6, 63,
66, 75.5, 172.3, 212.9; HRMS calcd for C38H32NO3 (MH+)
550.2382, found 550.2404. (2S,3S)-3-Ben zyl-4-oxo-N-(P h -
F l)p r olin e ben zyl ester (6d ): 1H NMR δ 2.07 (dd, 1 H, J )
9.1, 14.8), 2.94 (m, 1 H), 3.04 (dd, 1 H, J ) 4.5, 14.9), 3.62 (dd,
1 H, J ) 1, 17.5), 3.84 (d, 1 H, J ) 7.8), 3.9 (d, 1 H, J ) 17.5),
4.5 (d, 1 H, J ) 12.5), 4.55 (d, 1 H, J ) 12.5), 6.9-7.7 (m, 23
H).
[R]22 -19.4° (c 1.18, H2O); 1H NMR (D2O with DOH as
D
reference δ ) 4.8) δ 2.2 (ddd, 1 H, J ) 4, 10, 14), 2.3 (s, 3 H),
2.3 (ddt, 1 H, J ) 2, 8, 14), 3.3 (dt, 1 H, J ) 2, 12.6), 3.44 (dd,
1 H, J ) 3.6, 12.6), 4.62 (m, 1 H), 4.66 (dd, 1 H, J ) 8, 10.6),
5.2 (d, 1 H, J ) 12), 5.27 (d, 1 H, J ) 12), 7.34 (d, 2 H, J ) 8),
7.4 (m, 5 H), 7.6 (d, 2 H, J ) 8); 13C NMR (D2O with CH3OH
as reference δ ) 49) 16, 32.2, 44.4, 53.6, 64.2, 64.9, 120.9, 124,
124.3, 124.4, 124.9, 130, 135.3, 137.6, 164.9.
(2S,4R)-4-H yd r oxy-N-(P h F l)p r olin e b en zyl est er (4)
was synthesized from (2S,4R)-4-hydroxyproline benzyl ester
p-toluenesulfonate (3, 11.79 g, 30 mmol) using the procedure
for the preparation of N-PhFl-L-serine methyl ester.16 Puri-
fication by filtration through a column of silica gel using an
eluant of EtOAc followed by recrystallization from EtOAc/
hexane provided 4 (9.81 g, 71%): mp 151-152 °C; [R]22D 54.8°
(c 1.16, CHCl3); 1H NMR δ 1.5 (br s, 1 H), 1.78 (ddd, 1 H, J )
6, 9, 13), 1.97 (dt, 1 H, J ) 5.5, 13), 2.93 (dd, 1 H, J ) 5, 10),
3.38 (dd, 1 H, J ) 5, 9), 3.6 (dd, 1 H, J ) 5.5, 10), 4.5 (m, 1 H),
4.54 (d, 1 H, J ) 12.4), 4.8 (d, 1 H, J ) 12.4), 7.1-7.8 (m, 18
H); 13C NMR δ 39.8, 56.6, 59.4, 66, 70.1, 76.2, 175.4; HRMS
calcd for C31H28NO3 (MH+) 462.2069, found 462.2093.
(2S)-3,3-Bis(et h oxyca r b on ylm et h yl)-4-oxo-N-(P h F l)-
p r olin e ben zyl ester (7f) (52%): [R]22 -204.9° (c 0.82,
D
CHCl3); 1H NMR δ 1.02 (t, 3 H, J ) 7.2), 1.27 (t, 3 H, J ) 7.2),
2.24 (d, 1 H, J ) 18), 2.83 (d, 1 H, J ) 18), 3.04 (d, 1 H, J )
14), 3.1 (d, 1 H, J ) 14), 3.8 (m, 3 H), 3.96, (s, 1 H), 4.12 (m,
4 H), 4.39 (d, 1 H, J ) 12), 7-7.7 (m, 18 H); 13C NMR δ 13.7,
14.1, 33.7, 39.1, 52.1, 52.3, 60.4, 60.9, 65.9, 66.2, 74.3, 169.8,
170.2, 170.3, 211.2; HRMS calcd for C39H38NO7 (MH+) 632.2648,
found 632.2672.
(2S)-3,3-Dia llyl-4-oxo-N-(P h F l)p r olin e ben zyl ester (7g)
1
(69%): [R]22 -89.4° (c 0.62, CHCl3); H NMR δ 1.8 (dd, 1 H,
D
J ) 7, 15), 2.3 (ddd, 1 H, J ) 1, 7.8, 15), 2.53 (dd, 1 H, J ) 8.5,
14.1), 2.75 (dd, 1 H, J ) 6.2, 14.1), 3.55 (s, 1 H), 3.76 (dd, 1 H,
J ) 1.4, 17.1), 4.1 (dd, 1 H, J ) 0.8, 17.1), 4.3 (s, 2 H), 4.8 (d,
1 H, J ) 18), 4.85 (d, 1 H, J ) 10), 5.14 (d, 1 H, J ) 17.3), 5.16
(d, 1 H, J ) 10), 5.55 (m, 1 H), 5.74 (m, 1 H), 7.0-7.8 (m, 18
H); 13C NMR δ 33.3, 38.5, 53.1, 55.2, 65.9, 66.7, 74.3, 118.6,
119, 170.9, 213.6; HRMS calcd for C37H34NO3 (MH+) 540.2539,
found 540.2575.
(2S)-3,3-Diben zyl-4-oxo-N-(P h F l)p r olin e ben zyl ester
1
(2S)-4-Oxo-N-(P h F l)p r olin e Ben zyl Ester (5). A suspen-
sion of N-chlorosuccinimide (5.03 g, 38 mmol) in toluene (50
mL) was cooled to 0 °C, treated with methyl sulfide (3.3 mL,
45 mmol), stirred 20 min, and cooled to -20 °C. A solution of
hydroxyproline benzyl ester 4 (6.92 g, 15 mmol) in toluene (40
mL) and CH2Cl2 (5 mL) was then added to the cooled solution.
The mixture was stirred for 3 h, treated with triethylamine
(5.25 mL, 38 mmol), and allowed to warm to rt with continued
stirring. Water (100 mL) was added, and the mixture was
extracted with EtOAc (3 × 40 mL). The organic extractions
were combined, washed with brine, dried, and evaporated to
a residue. The residue was chromatographed on silica gel
using 10% EtOAc in hexane. Evaporation of the collected
fractions gave 5.97 g (87%) of 5 as a white solid: mp 106-108
(7h ): [R]22 -171° (c 0.3, CHCl3); H NMR δ 2.5 (d, 1 H, J )
D
15.4), 3 (d, 1 H, J ) 15.4), 3.07 (d, 1 H, J ) 14), 3.12 (d, 1 H,
J ) 14), 3.65 (d, 1 H, J ) 17.4), 3.92 (s, 1 H), 4.07 (d, 1 H, J
) 17.4), 4.23 (d, 1 H, J ) 12.6), 4.3 (d, 1 H, J ) 12.6), 6.9-7.7
(m, 28 H); 13C NMR δ 37, 41, 54, 58, 65.9, 67.4, 74.8, 170.6,
213.2; HRMS calcd for C45H38NO3 (MH+) 640.2852, found
640.2819.
(2S)-Ben zyl 3-ben zyl-∆3-N-(P h F l)p r olin e 4-O-ben zyl
en ol eth er (8) (48%): [R]22D 7.6° (c 1, CHCl3); 1H NMR δ 2.89
(d, 1 H, J ) 15.3), 3.45 (d, 1 H, J ) 15.3), 3.78 (s, 1 H), 3.8 (m,
1 H), 4.25 (dd, 1 H, J ) 5, 14), 4.64 (d, 1 H, J ) 12.2), 4.67 (d,
1 H, J ) 12.3), 4.8 (d, 1 H, J ) 12.2), 4.84 (d, 1 H, J ) 12.3),
6.7-7.7 (m, 28 H); 13C NMR δ 29.4, 53.6, 65.9, 68.3, 71.3, 77.2,
111.2, 151, 173.9; HRMS calcd for C45H38NO3 (MH+) 640.2852,
found 640.2833.
°C; [R]22 -32.6° (c 1.16, CHCl3); 1H NMR δ 2.3 (dd, 1 H, J )
D
3.2, 18.2), 2.4 (dd, 1 H, J ) 8.4, 18.2), 3.5 (d, 1 H, J ) 18), 3.81
(d, 1 H, J ) 18), 3.82 (dd, 1 H, J ) 3.2, 8.4), 4.67 (d, 1 H,
12.4), 4.74 (d, 1 H, J ) 12.4), 7.1-7.7 (m, 18 H); 13C NMR δ
(2S)-3,3-Dim eth yl-4-oxo-N-(P h F l)p r olin e Ben zyl Ester
(7a ). A mechanically stirred solution of KN(SiMe3)2 (64 mL,
0.5 M in toluene, 32 mmol) at 0 °C was treated with 31 mL of
DMPU, stirred 10 min, cooled to -78 °C, and treated with a
-78 °C solution of (2S)-4-oxo-N-(PhFl)proline benzyl ester (5,
3.76 g, 8 mmol) in 60 mL of THF. The solution was stirred 1
h, treated with iodomethane (5 mL, 80 mmol), and stirred 4.5
h, and the reaction was quenched with 1 M KH2PO4 (50 mL).
The mixture was extracted with EtOAc (3 × 50 mL), and the
combined organic extractions were washed with H2O (3 × 25
mL) and brine (25 mL), dried, and evaporated to a solid. The
solid was suspended in a solution of 15% EtOAc in hexanes
(10 mL), stirred 5 min, and decanted. The solid was resubmit-
ted to this process four additional times and then four times
using 10% EtOAc in hexanes (15 mL). The solid was dried
41.4, 55.6, 58.3, 66.3, 76.4, 172.5, 213; HRMS calcd for C31H26
-
NO3 (MH+) 460.1913, found 460.1926.
Alk yla tion of 4-Oxo-N-(P h F l)p r olin e ben zyl ester (5)
was performed according to the general procedure for the
alkylation of amino ketones as described in ref 14 using the
conditions presented in Table 1. Chromatography with EtOAc
in hexanes as eluant provided 3-alkylprolines 6-8.
(2S,3R)- a n d (2S,3S)-3-Meth yl-4-oxo-N-(P h F l)p r olin e
Ben zyl Ester (6a ). Spectral characterization of 6a was
performed on a 56:44 mixture of diastereomers: 1H NMR δ
0.8 (d, 3 H, J ) 7.1), 1.0 (d, 3 H, J ) 7.3), 2.6 (m, 2 H), 3.32 (d,
1 H, J ) 6), 3.38 (d, 1 H, J ) 18), 3.62 (d, 1 H, J ) 17.8), 3.81
(d, 1 H, J ) 18), 3.87 (d, 1 H, J ) 17.8), 3.88 (d, 1 H, J ) 8.5),
4.36 (d, 1 H, J ) 12.5), 4.53 (d, 1 H, J ) 12.4), 4.62 (d, 1 H, J
) 12.5), 4.64 (d, 1 H, J ) 12.4), 7.1-7.7 (m, 18 H); 13C NMR
δ 8.4, 13.3, 46.1, 47.7, 54.2, 55.5, 63.4, 65.9, 66, 66.2, 75.4, 75.7,
171.3, 172.5, 213.8, 214.4; HRMS calcd for C32H28NO3 (MH+)
474.2069, found 474.2043.
under high vacuum, giving pure 7a (3.24 g, 82%): mp 195-
1
197 °C; [R]22 -254° (c 0.87, CHCl3); H NMR δ 0.78 (s, 3 H),
D
1.32 (s, 3 H), 3.46 (s, 1 H), 3.75 (d, 1 H, J ) 17), 4.03 (d, 1 H,
J ) 17), 4.27 (d, 1 H, J ) 12.4), 4.4 (d, 1 H, J ) 12.4), 7.0-7.7
(m, 18 H); 13C NMR δ 17.4, 25.5, 49, 52.7, 65.8, 69.3, 74.3,
171.7, 216; HRMS calcd for C33H30NO3 (MH+) 488.2226, found
488.2211.
(2S,3R)-3-Allyl-4-oxo-N-(P h F l)p r olin e ben zyl ester (6c)
was isolated as a >6:1 mixture of diastereomers in 54% yield:
1H NMR δ 2.14 (m, 1 H), 2.34 (m, 1 H), 2.47 (m, 1 H), 3.48
(dd, 1 H, J ) 1, 18), 3.5 (d, 1 H, J ) 4.3), 3.88 (d, 1 H, J ) 18),
(2S,4R)- a n d (2S,4S)-3,3-Dim eth yl-4-h yd r oxy-N-(P h F l)-
p r olin e Ben zyl Ester s ((2S,4R)- a n d (2S,4S)-9) fr om
Red u ction w ith Na BH4. A solution of (2S)-3,3-dimethyl-4-

208 J . Org. Chem., Vol. 61, No. 1, 1996
Sharma and Lubell
oxo-N-(PhFl)proline benzyl ester (7a , 2.13 g, 4.37 mmol) in 70
mL of THF was added to a 0 °C suspension of NaBH4 (662
mg, 17.5 mmol) in MeOH (40 mL), and the mixture was stirred
3.5 h. A second portion of NaBH4 (332 mg, 8.7 mmol) was
added, and the mixture was stirred an additional 2 h. The
mixture was poured into a solution of 1 M KH2PO4 (100 mL)
and extracted with EtOAc (4 × 50 mL), and the combined
organic extractions were washed with brine (3 × 50 mL), dried,
and evaporated to a solid that was purified by chromatography
on silica gel using 15% EtOAc in hexane as eluant. First to
3.26 (dd, 1 H, J ) 5.4, 10.4), 3.98 (dd, 1 H, J ) 6, 10.5), 4.61
(d, 1 H, J ) 12.3), 4.79 (d, 1 H, J ) 12.3), 5.75 (t, 1 H, J )
5.7), 7.0-7.8 (m, 18 H); 13C NMR δ 19, 22.2, 22.6, 44.8, 50.5,
66, 69.9, 75.8, 87.4, 173.1, 215.2. Xa n th a te (2S,4S)-10 was
also prepared quantitatively from (2S,4S)-9 according to the
procedure described above: [R]22D 203° (c 0.4, CHCl3); 1H NMR
δ 0.73 (s, 3 H), 0.87 (s, 3 H), 2.59 (s, 3 H), 2.77 (s, 1 H), 3.47
(dd, 1 H, J ) 4.8, 11.6), 3.72 (dd, 1 H, J ) 5.7, 11.6), 4.63 (d,
1 H, J ) 12.3), 4.82 (d, 1 H, J ) 12.3), 5.4 (t, 1 H, J ) 5),
7.0-7.8 (m, 18 H); 13C NMR δ 18.7, 19, 27.1, 45.3, 51.9, 66,
69.8, 76.4, 88, 173.1, 215.4; HRMS calcd for C35H34NO3S2
(MH+) 580.1980, found 580.2011.
elute was (2S,4S)-9 (0.8 g, 38%): mp 173-174 °C; [R]22 177°
D
1
(c 1.1, CHCl3); H NMR δ 0.5 (s, 3 H), 0.82 (s, 3 H), 2.63 (s, 1
H), 3.33 (dd, 1 H, J ) 3.4, 9.7), 3.45 (d, 1 H, J ) 9.7), 3.5 (br
s, 1 H), 4.03 (br d, 1 H), 4.55 (d, 1 H, J ) 12), 4.94 (d, 1 H, J
) 12), 7.0-7.8 (18 H); 13C NMR δ 19.1, 27.1, 46.2, 54.7, 66.9,
69.2, 75.3, 79.8, 177.3; HRMS calcd for C33H32NO3 (MH+)
A solution of xanthate (2S,4R)-10 (51 mg, 0.09 mmol), AIBN
(1-2 mg), and tri-n-butylstannane (0.05 mL, 0.2 mmol) in 2
mL of xylene was submitted to a bubbling of N2 gas for 20
min. The solution was then transferred over 10 min into
refluxing xylene (3 mL). The solution was heated at a reflux
for 1 h when TLC showed complete consumption of the starting
xanthate. The xylene was then removed by distillation under
high vacuum, and the residue was purified by chromatography
on silica gel using 4% EtOAc in hexanes as eluant. First to
elute was (2S)-3,3-dimethyl-N-(PhFl)proline benzyl ester ((2S)-
490.2382, found 490.2408. Next to elute was (2S,4R)-9 (1.31
1
g, 61%): mp 193-194 °C; [R]22 211° (c 1.1, CHCl3); H NMR
D
δ 0.5 (s, 3 H), 0.78 (s, 3 H), 1.5 (br s, 1 H), 2.76 (s, 1 H), 2.98
(t, 1 H, J ) 8.5), 3.6 (dd, 1 H, J ) 6.5, 8.5), 4.18 (t, 1 H, J )
6.5), 4.65 (d, 1 H, J ) 12.2), 4.86 (d, 1 H, J ) 12.2), 7.0-7.8
(18 H); 13C NMR δ 20.4, 21.9, 44, 52.1, 66, 70, 75.6, 76.2, 174.6;
HRMS calcd for C33H32NO3 (MH+) 490.2382, found 490.2368.
(2S,4R)- a n d (2S,4S)-9 fr om r ed u ction w ith LiAlH4. A
solution of 7a (620 mg, 1.27 mmol) in 12 mL of THF at -78
°C was treated with LiAlH4 (48 mg, 1.26 mmol) and stirred
30 min, and the reaction was quenched with a solution of 1 M
KH2PO4 (20 mL). The mixture was allowed to warm to rt and
extracted with EtOAc (3 × 25 mL). The combined organic
extractions were washed with water (2 × 20 mL) and brine,
dried, and evaporated to a solid that was purified by chroma-
tography as described above to provide 358 mg (58%) of
(2S,4S)-9 and 201 mg (32%) of (2S,4R)-9.
11, 38 mg, 91%): mp 131-132 °C; [R]22 161° (c 1, CHCl3); 1H
D
NMR δ 0.55 (s, 3 H), 0.78 (s, 3 H), 1.4 (ddd, 1 H, J ) 3, 6, 9),
1.87 (ddd, 1 H, J ) 7, 10, 12), 2.6 (s, 1 H), 3.11 (dt, 1 H, J )
6, 9), 3.37 (ddd, 1 H, J ) 3, 7, 9), 4.63 (d, 1 H, J ) 12), 4.83 (d,
1 H, J ) 12), 7.0-7.8 (m, 18 H); 13C NMR δ 24.4, 27.7, 38.9,
42.3, 46.9, 65.8, 70.4, 76, 175.2; HRMS calcd for C33H32NO2
(MH+) 474.2433, found 474.2394. Next to elute was hemithiol
acetal 12 (2 mg, 4%): 1H NMR δ 0.47 (s, 3 H), 0.77 (s, 3 H),
2.04 (t, 1 H, J ) 9.3), 2.68 (s, 1 H), 2.96 (t, 1 H, J ) 8.3), 3.65
(dd, 1 H, J ) 6.5, 8), 4.08 (dd, 1 H, J ) 6.5, 8.5), 4.62 (d, 1 H,
J ) 12.1), 4.66 (dd, 1 H, J ) 9.4, 11.1), 4.77 (dd, 1 H, J ) 9.3,
11.1), 4.84 (d, 1 H, J ) 12.2), 7.0-7.8 (m, 18 H); 13C NMR δ
21.3, 22, 43.4, 49.5, 66.1, 67.6, 69.7, 75.5, 81.1, 174.5; FAB MS
m/e 536 [MH]+, 400 [M - CO2CH2Ph], 241 (100); HRMS calcd
for C34H34NO3S (MH+) 536.2260, found 536.2233. When
xanthates (2S,4S)- and (2S,4R)-10 were reduced in refluxing
toluene, 11 was obtained in 81% and 57% respective yields.
(2S)-3,3-Dim eth yl-N-(BOC)p r olin e ((2S)-1). A solution
of (2S)-3,3-dimethyl-N-(PhFl)proline benzyl esters ((2S)-11,
107 mg, 0.23 mmol) and di-tert-butyl dicarbonate (67 mg, 0.31
mmol) in 10 mL of THF was treated with palladium-hydroxide-
on-carbon (32 mg, 20 wt % in Pd), and the mixture was stirred
under 5 atm of hydrogen for 25 h. The catalyst was removed
by filtration on Celite and washed with THF (4 × 10 mL) and
1:1 THF:MeOH (2 × 10 mL), and the combined organic phase
was evaporated to a residue that was purified by chromatog-
raphy on silica gel. Initially an eluant of 10% EtOAc in hexane
was used to elute the 9-phenylfluorene; afterward N-(BOC)-
amino acid 1 was eluted from the column using 5% acetic acid
in EtOAc. Evaporation of the ninhydrin positive fractions
(visualized on TLC after treatment with TFA vapors) gave
(2S ,4R )-3,3-D im e t h y l-4-h y d r o x y -N -(B O C )p r o lin e
((2S,4R)-2). A solution of (2S,4R)-3,3-dimethyl-4-hydroxy-N-
(PhFl)proline benzyl ester ((2S,4R)-9, 574 mg, 1.2 mmol) and
di-tert-butyl dicarbonate (670 mg, 2.6 mmol) in 35 mL of THF
was treated with palladium-on-carbon (70 mg, 10 wt %), and
the mixture was stirred under 5 atm of hydrogen for 48 h.
The catalyst was removed by filtration on Celite and washed
with MeOH (3 × 10 mL) and THF (2 × 10 mL), and the
combined organic phase was evaporated to a solid. The solid
was triturated with hexane (20 mL), recovered by aid of a
centrifuge, and treated in the same manner with five ad-
ditional volumes of hexane (20 mL), providing (2S,4R)-2 (283
mg, 93%): mp 253-255 °C; [R]22 8.14° (c 1.2, CH3OH); 1H
D
NMR δ (CD3OD) 0.91 (s, 3 H), 1.06 (s, 3 H), 1.34 (s, 6.2 H),
1.38 (s, 2.8 H), 3.22 (m, 1 H), 3.63 (dd, 1 H, J ) 5.7, 11.1), 3.83
(m, 1 H), 3.85 (s, 1 H); 13C NMR δ (CD3OD) 19.9, (20.9) 21, 27
(27.2), (43.6) 44.5, 51.2 (51.4), (67.5) 67.9, 75.2 (75.6), (79.8)
80.1, 154.7 (155), (173) 173.4; HRMS calcd for C12H22NO5
(MH+) 260.1498, found 260.1478.
(2S ,4S )-3,3-D i m e t h y l-4-h y d r o x y -N -(B O C )p r o li n e
((2S,4S)-2) was prepared in 92% yield from (2S,4S)-9 (250 mg,
0.5 mmol) by the same procedure as described for (2S,4R)-2:
mp 173-175 °C; [R]22D -16.1° (c 1.4, CH3OH); 1H NMR δ (CD3-
OD) 0.94 (s, 3 H), 1.11 (s, 3 H), 1.35 (s, 6.4 H), 1.39 (s, 2.6 H),
3.24 (m, 1 H), 3.65 (dd, 1 H, J ) 6.3, 10.8), 3.73 (q, 1 H, J )
6), 3.8 (s, 1 H); 13C NMR δ (CD3OD) 19.4 (19.5), 28.3 (28.5),
30.2 (30.4), (47) 47.6, 54.3 (55), (70.8) 71.4, 79.1 (79.9), (83.2)
83.5, 157.8 (158.1), (176.6) 176.9; HRMS calcd for C12H22NO5
(MH+) 260.1498, found 260.1487.
(2S)-3,3-Dim eth yl-N-(P h F l)p r olin e Ben zyl Ester ((2S)-
11). A solution of (2S,4R)-3,3-dimethyl-4-hydroxy-N-(PhFl)-
proline benzyl ester ((2S,4R)-9, 350 mg, 0.72 mmol) in THF
(5 mL) was added to a suspension of NaH (114 mg, 2.86 mmol,
60% by weight which was prewashed with 10 mL of THF) in
5 mL of THF at 0 °C. The suspension was stirred for 30 min
and treated with 5 mL of CS2. The mixture was stirred 1 h at
0 °C, treated with iodomethane (0.44 mL, 7.2 mmol), stirred
overnight at 4 °C, evaporated, and partitioned between EtOAc
(50 mL) and H2O (10 mL). The organic phase was washed
with brine (10 mL), dried, and chromatographed on silica gel
using 10% EtOAc in hexane as eluant. Evaporation of the
collected fractions provided xa n th a te (2S,4R)-10 (100%): 1H
NMR δ 0.84 (s, 3 H), 0.92 (s, 3 H), 2.46 (s, 3 H), 3.0 (s, 1 H),
(2S)-1 (52 mg, 95%): mp 130-131 °C; [R]22 9.5° (c 1, CHCl3);
D
1H NMR δ 1.1 (s, 3 H), 1.2 (s, 3 H), 1.42 (s, 6.2 H), 1.46 (s, 2.8
H), 1.64 (m, 1 H), 1.89 (m, 1 H), 3.49 (m, 1 H), 3.6 (m, 1 H),
3.84 (s, 0.75 H), 3.94 (s, 0.25 H); 13C NMR δ 23.6, 27.8, 28.2
(28.3), 37.3 (38), (41.3) 42.3, 44.8 (45.1), 69.1, (80.1) 80.3, 154.2
(154.8), (177) 177.8; MS m/e 244 [MH]+, 188, 142 (100); HRMS
calcd for C12H22NO4 (MH+) 244.1549, found 244.1556.
(2S,4R)-Ben zyl 3,3-Dim eth yl-N-(P h F l)p r olin a te 4-(Me-
th ylth io)m eth yl Eth er ((2S,4R)-13). A solution of hemithiol
acetal (2S,4R)-12 (14 mg, 0.026 mmol) in 0.5 mL of THF was
treated first with K2CO3 (4 mg, 0.03 mmol) and then with
iodomethane (10 µL, 0.16 mmol). The mixture was stirred
overnight at rt and then filtered through a pad of silica gel
with THF as eluant. Evaporation gave 12 mg (84%) of
(methylthio)methyl ether (2S,4R)-13: 1H NMR δ 0.49 (s, 3 H),
0.77 (s, 3 H), 2.09 (s, 3 H), 2.69 (s, 1 H), 2.96 (t, 1 H, J ) 8.3),
3.63 (dd, 1 H, J ) 6.5, 8), 4.13 (dd, 1 H, J ) 6.5, 8.5), 4.52 (d,
1 H, J ) 11.3), 4.6 (d, 1 H, J ) 11.3), 4.63 (d, 1 H, J ) 12.3),
4.83 (d, 1 H, J ) 12.3), 7.0-7.8 (m, 18 H); 13C NMR δ 13.8,
21.3, 22.1, 43.5, 49.4, 65.9, 69.9, 75, 75.5, 80.7, 174.3.
En a n tiom er ic P u r ity of (2S)-3,3-Dim eth yl-N-(BOC)-
p r olin e ((2S)-1). A room temperature solution of (2S)-3,3-
dimethyl-N-(BOC)proline ((2S)-1, 5 mg, 0.02 mmol) and either

Proline-Valine and Hydroxyproline-Valine Chimeras
J . Org. Chem., Vol. 61, No. 1, 1996 209
(R)- or (S)-R-methylbenzylamine (3 µL, 0.02 mmol) in 0.5 mL
of acetonitrile was treated with benzotriazol-1-yl-1,1,3,3-
tetramethyluronium tetrafluoroborate (7 mg, 0.02 mmol) and
stirred 12 h when TLC showed complete disappearance of the
starting acid. The reaction mixture was partitioned between
brine (0.7 mL) and EtOAc (3 mL), and the organic layer was
washed with H2O (2 × 3 mL), dried, filtered, and evaporated
to a residue (7 mg) that was directly examined by 1H NMR.
When (S)-R-methylbenzylamine of 99% diastereomeric purity
was used, examination of the â-methyl singlets in the 1H NMR
in CD3OD demonstrated (S)-14 to be of 97% diastereomeric
purity. Hence, (2S)-1 is determined to be of 98% enantiomeric
purity.
H), 7.1-7.4 (m, 5 H), 8.4 (br d, 1 H); HRMS calcd for
C20H31N2O3 (MH+) 347.2335, found 347.2347.
Ack n ow led gm en t. This research was supported in
part by the Natural Sciences and Engineering Research
Council of Canada and the Ministe`re de l’EÄ ducation du
Que´bec. The crystal structure analysis of (4R)-9 was
performed by Francine Be´langer-Garie´py at l’Universite´
de Montre´al X-ray facility. W.D.L. thanks Bio-Me´ga/
Boehringer Ingelheim Recherche Inc. for a Young
Investigator Award. We gratefully acknowledge a loan
of Pd/C from J ohnson Matthey PLC.
(1′S,2S)-3,3-Dim et h yl-N-(BOC)p r olin e
N′-r-m et h yl-
ben zyla m id e ((S)-14): 1H NMR δ (CD3OD) 0.81 (s, 3 H), 1.08
(s, 3 H), 1.39 (s, 9 H), 1.46 (d, 3 H, J ) 7.1), 1.52 (m, 1 H), 1.84
(m, 1 H), 3.33 (m, 1 H), 3.54 (m, 1 H), 3.73 (s, 1 H), 5.0 (m, 1
H), 7.1-7.4 (m, 5 H), 8.4 (br d, 1 H); HRMS calcd for
C20H31N2O3 (MH+) 347.2335, found 347.2333.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
and DEPT spectra of 1-14 and 1H,1H COSY and 1H,13
C
HETCOR spectra of 12 (65 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.
(1′R,2S)-3,3-Dim et h yl-N-(BOC)p r olin e N′-r-m et h yl-
ben zyla m id e ((R)-14): 1H NMR δ (CD3OD) 1.03 (s, 3 H), 1.11
(s, 3 H), 1.19 (s, 9 H), 1.43 (d, 3 H, J ) 7), 1.57 (m, 1 H), 1.93
(m, 1 H), 3.35 (m, 1 H), 3.56 (m, 1 H), 3.72 (s, 1 H), 5.04 (m, 1
J O9514984