Improved synthesis of (2S,5S)-5-tert-butylproline

Article abstract of DOI:10.1016/S0040-4020(01)00535-X

(2S,5S)-N-Boc-5-tert-butylproline (1) was synthesized by an improved procedure featuring the conversion of (2S)-1-tert-butyldimethylsiloxy-2-N-(PhF)amino-5-oxo-6,6-dimethylheptane (16) into its corresponding imino alcohol followed by directed hydride deli

Full text of DOI:10.1016/S0040-4020(01)00535-X

TETRAHEDRON
Pergamon
Tetrahedron 57 +2001) 6439±6446
Improved synthesis of ꢀ2S,5S)-5-tert-butylproline
p
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Liliane Halab, Laurent Belec and William D. Lubell
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Departement de Chimie, Universite de Montreal, C.P. 6182, Succursale Centre Ville, Montreal, Quebec, Canada H3C 3J7
We dedicate this work to our colleague Professor Stephen Hanessian on the occasion of his entering into his golden years
Received 7 February 2001; revised 11 April 2001; accepted 26 April 2001
AbstractÐ+2S,5S)-N-Boc-5-tert-butylproline +1) was synthesized by an improved procedure featuring the conversion of +2S)-1-tert-butyl-
dimethylsiloxy-2-N-+PhF)amino-5-oxo-6,6-dimethylheptane +16) into its corresponding imino alcohol followed by directed hydride delivery
to reduce the imine functionality with a 95:5 diastereoselectivity. Ketone 16 was obtained from methyl 2-N-+PhF)amino-5-oxo-6,6-dimethyl-
heptanoate +13), a previously reported precursor for the synthesis of +2S,5R)-5-tert-butylproline, by reduction to its corresponding diol,
selective protection of the primary alcohol and oxidation of the secondary alcohol. This route provided +2S,5S)-N-Boc-5-tert-butylproline +1)
of .96% enantiomeric purity suitable for peptide chemistry in 39% overall yield from ketone 13. q 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
shown to adopt helical conformations by X-ray analysis and
NMRspectroscopy.
7
Related long synthetic peptides
containing at least one Aib residue among 5±20 residues
have been shown by X-ray analysis to adopt predominantly
helical geometry.8 Type III b-turn conformations have been
observed by X-ray crystallography to be stabilized when
Aib residues were introduced into shorter peptides
composed of 2±4 amino acids.4 a,a-Dialkylglycines
containing larger a-alkyl substituents, such as a,a-diethyl-
glycine +Deg), a,a-di-n-propylglycine +Dpg), a,a-di-n-
butylglycine +Dbg), a,a-diphenylglycine +DFg) and a,a-
dibenzylglycine +Dbzg), have favored fully extended C5
structures in peptides characterized by 1808 f- and c-di-
hedral angles and intramolecular H-bonds between the
Amino acids possessing alkyl substituents have emerged as
important tools for controlling peptide conformation.
Because their steric interactions can restrict the motion
about the backbone and side-chain dihedral angles within
a peptide, alkyl-substituted amino acids may promote
particular peptide secondary structures.1±34 Although the
steric bulk of the alkyl-substituted amino acid may interfere
with binding and alter biological activity of a peptide
analog, the structure±activity relationships of peptides
possessing such alkyl-substituted amino acids have in
some cases provided a better understanding of the biologic-
ally active conformation responsible for receptor recog-
nition and signal transduction. Furthermore, the hydro-
phobic nature of the alkyl substituent may enhance af®nity
of conformations that favor antagonist activity at the
receptor.2,3
Among the acyclic amino acids, a,a-dialkylglycines, such
as a-aminoisobutyric acid +Aib), exert signi®cant con-
straints on the backbone dihedral angles in a peptide4
+Fig. 1) and many approaches for their stereoselective
synthesis have been reported.5 Replacement of the a-proton
in an alanine residue with a methyl substituent restricts the
f- and c-torsion angles to regions that correspond to right-
and left-handed a-helices and 310-helix geometry as demon-
strated by computational analysis.6 Naturally-occurring
Aib-rich peptide antibiotics, peptaibols which produce
voltage-gated ion channels in lipid membranes, have been
Keywords: steric effects; 5-tert-butylproline; trans-diastereomer; directed
hydride addition; prolinol; imine; prolinal.
p
Corresponding author. Tel.: 1514-343-7339; fax: 1514-343-7586;
e-mail: lubell@CHIMIE.UMontreal.CA
Figure 1. Representative examples of a-, b- and g-alkyl substituted acyclic
a-amino acids.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+01)00535-X

6440
L. Halabet al. / Tetrahedron 57 .2001) 6439±6446
Among cyclic amino acids, azetidine-2-carboxylic acids,
prolines and pipecolates possessing alkyl substituents have
been synthesized and introduced into peptides.1,2,21±38 In
prolyl peptides, alkyl substituents can in¯uence the ring
puckering, the c-dihedral angle and the N-terminal amide
equilibrium of the proline residue. For example, in N-acetyl
a-methylproline N0-methylamide, only the trans-amide
isomer was observed by NMRspectroscopy in CDCl and
3
in water +Fig. 2).23 Several b-substituted azetidine-2-
carboxylates, prolines and pipecolates have been synthe-
sized to serve as amino acid chimeras in which the func-
tional groups of the amino acid side-chain are combined
with the conformational restrictions characteristic of the
cyclic amino acid residue.22a,24,35±37 Chimeras with proline
bodies have been used to study the relationship of side-chain
geometry to bioactivity in biologically active peptides
such as angiotensin II, bradykinin, morphiceptin, and
cholecystokinin.24 Although b-substituents exhibited little
effect on the populations of the prolyl amide isomers, they
have in¯uenced the proline c-dihedral angle as well as the
energy barrier for amide isomerization. In the case of
N-acetyl b-methylproline N0-methylamides, the cis-b-
methyl substituent imposed steric interactions that restricted
the c dihedral angle and prevented formation of a g-turn
Figure 2. Representative examples of a-, b-, g- and d-alkyl substituted
cyclic a-amino acids.
amide hydrogen and carbonyl oxygen groups within the
same residue.9,10 1-Aminocycloalkane-1-carboxylic acids
of 3-, and 5- to 7-carbon ring-sizes have induced helical,
b-turn and g-turn conformations in peptides of 3±10
residues as observed in solution and in the solid state.10,11
b-Alkyl substituents can in¯uence signi®cantly the side-
chain dihedral angle and to some extent the backbone
geometry of amino acid residues in peptides. Several
b-methyl analogs of the naturally occurring amino acids
+Asp, Glu, His, Phe, Trp and Tyr) have been stereoselec-
tively synthesized for application in peptide mimics.12±14
For example, b-methylphenylalanine has been employed
to constrain the side-chain x1 dihedral angles in enkephalin
and somatostatin analogs.3,15 The steric effects of the
b-methyl group are contingent on stereochemistry.12,16 In
+2S,3R)-b-MePhe, the side-chain x1 dihedral angle adopted
the trans-conformer and in +2S,3S)-b-MePhe the gauche
+2) conformer was preferred +Fig. 1).15,16 g-Alkyl sub-
stituents may also in¯uence side-chain geometry of an
amino acid residue in a peptide. Although several g-alkyl
analogs of the naturally occurring amino acids have been
synthesized,17±19,26,56a their in¯uence on peptide confor-
mation and biology has been less thoroughly studied.
Their signi®cance to peptide biology has been illustrated
in an analog of the natural cyclic peptide cyclosporine,
where removal of the g-alkyl substituents from the
MeBmt residue caused a dramatic reduction in immuno-
suppressive activity +Fig. 1).20
23a
conformation +c<808) as observed by IRspectroscopy.
A similar effect was observed in N-acetyl b,b-dimethyl-
proline N0-methylamide; moreover, the presence of the
two methyl substituents in this proline-valine chimera was
shown to cause a nearly seven-fold reduction in the rate of
prolyl amide isomerization as demonstrated by magneti-
zation transfer experiments +Fig. 2).25 g-Alkylprolines
have been stereoselectively synthesized and used to prepare
proline oligomers because their ring substituents interact
minimally with the prolyl residue conformation.26±28 For
example, natural poly-proline type II geometry was adopted
by short oligomers composed of trans-4-+3-methylbutyl)-
prolines as observed by NMRspectroscopy.
28
On the
other hand, d-alkyl substituents can exhibit signi®cant steric
interactions that may disturb the preferred conformation
about the prolyl residue.1,2,29±34,38 For example, replacement
of proline by +2S,5R)-5-tert-butylproline in peptides
has increased the prolyl amide cis-isomer population,
diminished the barrier for prolyl amide isomerization and
favored the formation of type VI b-turns.2,30±33 In N-acetyl-
proline
N0-methylamides,
+2S,5S)-5-tert-butylproline
caused a greater increase in cis-isomer population relative
to its cis-diastereomer counterpart without in¯uencing the
barrier for amide isomerization relative to proline.30
In addition, N-acetyl-trans-5-tert-butylproline N0-methyl-
amide was shown by IRspectroscopy not to adopt a seven
member g-turn conformation, which was a favored confor-
mer for its natural proline and cis-diastereomer counterparts
in CHCl3.30
These examples demonstrate the ability of alkyl substituted
amino acids to reinforce and to disturb natural peptide second-
ary structures. Improved methods for synthesizing alkyl
substituted amino acids advance their use by making them
more readily accessible for peptide science. In our own work
with 5-tert-butylproline, we have until now focused primarily
on the +2S,5R)-diastereomer, because it can be synthesized
effectively via our high-yielding stereoselective sequence
featuring acylation of g-methyl N-+PhF)-l-glutamate
Figure 3. Iminium ion intermediates used in the synthesis of trans-5-tert-
butylproline.

L. Halabet al. / Tetrahedron 57 .2001) 6439±6446
6441
ation of the +2S,5R)-diastereomer. A similar approach had
been used previously for the synthesis of N-benzyl-2-cyano-
5-heptylpyrrolidine to afford a 3:1 mixture of trans:cis
diastereomers for the preparation of 2,5-dialkylpyrrolidines
found in ant venum.40 We prepared both iminium salt 5 and
its N-benzyl analog
6 by heating their respective
Figure 4. Prolyl lactam 3.
N-protected-+2S,5R)-5-tert-butylproline +1 and 4) with
POCl3 at 1008C +Scheme 1). Although the bulky tert-butyl
substituent was envisioned to direct attack towards the less
hindered face of the iminium salt to provide the trans-
isomer, the 2-cyano-5-tert-butylpyrrolidines +7 and 8)
were obtained with low diastereoselectivity. For example,
treatment of iminium salt 5 with KCN in isopropanol gave a
1:1 mixture of +2S,5R)- and +2R,5R)-2-cyano-5-tert-butyl-
pyrrolidines in 40% yield. This ratio remained unchanged
after attempts to equilibrate the mixture with silica gel in an
isooctane/EtOAc solution.40 Although the overall yield was
increased to 58% when TMSCN in THF was used in the
second step of the two step sequence, diastereomeric
2-cyano-5-tert-butylpyrrolidines 7 were obtained again
as a 1:1 mixture. The yield of the sequence could be
improved to 85% by employing N-+benzyl)proline 4;21
however, N-benzyl-2-cyano-5-tert-butylpyrrolidines +8)
were produced non-selectively as a 1:1.6 mixture of
diastereomers.
followed by ester hydrolysis, decarboxylation and reductive
amination.21 Less attention has been given to the +2S,5S)-
diastereomer because of drawbacks in its stereoselective
synthesis. For example, although good diastereoselectivity
was achieved in the hydride reduction of +2S)-5-tert-butyl-
D5-dehydroproline tri¯uoroacetate +2) to furnish the trans-
diastereomer, the iminium ion intermediate 2 proved to
be con®gurationally labile and racemized product was
obtained +Fig. 3).21 Although epimerization of the
+2S,5R)-diastereomer
of
N-benzyl-5-tert-butylproline
methyl ester could be used to provide enantiopure
+2R,5R)-diasereomer, only a 1:1 ratio of +2S)-:+2R)-isomers
was achieved under our best conditions: t-BuOK in t-BuOH
at 508C.21 Encouraged by our success in the use of +2S,5R)-
5-tert-butylproline in the synthesis of type VI b-turn
mimics,31,32 polyproline analogs33 and biologically active
derivatives of natural prolyl peptides such as oxytocin,2
we chose to explore the attributes of its +2S,5S)-dia-
stereomer for peptide mimicry. We present now an
improved synthesis of +2S,5S)-5-tert-butylproline that
provides enantiopure material +.96% ee) suitably protected
for peptide synthesis.
To improve diastereoselectivity, we investigated next the
addition of a tert-butylcopper reagent to prolyl iminium
ion 11 +Fig. 3). Less sterically bulky alkylcopper reagents,
possessing n-propyl, n-butyl, n-heptyl, phenyl, benzyl and
iso-propenyl substituents, have been reported to add dia-
stereoselectively to iminium ions to afford 5-alkylprolines
with the trans con®guration.41,42 Furthermore, the tert-
butylcopper reagent prepared from CuI and t-BuLi had
been reported to react quantitatively with benzoyl chloride
in dimethylsul®de at 2788C to afford phenyl tert-butyl-
ketone.43 Initially, N-Boc-5-methoxyproline benzyl ester
+10) was synthesized as a 2:3 mixture of diastereomers in
92% yield by reduction of N-Boc-pyroglutamate benzyl
ester44 +9) with LiEt3BH in THF followed by etheri®cation
of the aminal in MeOH with a catalytic amount of p-tolu-
enesulfonic acid +Scheme 2).45 Although several attempts to
add a tert-butylcopper reagent to 11 failed, in one experi-
ment, addition of a diastereomeric mixture of N-Boc-5-
methoxyproline benzyl ester +10) to a suspension of
t-BuLi, CuBr´SMe2 and BF3´OEt2 in THF at 2788C
provided protected 5-tert-butylproline 12 as a 1:4 mixture
2. Results and discussion
Several approaches were considered for the synthesis of
enantiopure trans-5-tert-butylproline. Because of limited
success in the epimerization of +2S,5R)- to +2R,5R)-N-
benzyl-5-tert-butylproline methyl ester, we examined
epimerization of its bicyclic lactam counterpart, proline 3
+Fig. 4). Although protonation with inversion of con®gu-
ration was considered for producing the trans-5-tert-butyl-
proline, computational analysis of the cis- and trans-lactam
diastereomers 3 indicated that the energy minimum for the
cis-isomer was 0.9 kcal/mol lower than that of its trans-
counterpart.39 Opting for a new strategy for synthesizing
trans-5-tert-butylproline, we examined the addition of
cyanide ion to iminium salt 5 obtained from decarboxyl-
Scheme 2. Synthesis of N-Boc-5-tert-butylproline via addition of tert-
butylcopper reagent.
Scheme 1. Synthesis of 2-cyano-5-tert-butylpyrrolidines 7 and 8.

6442
L. Halabet al. / Tetrahedron 57 .2001) 6439±6446
Figure 5. Proposed transition state for hydride addition to imine 19.
ratios.48 We pursued thus the synthesis and reduction of
+2S)-5-tert-butyl-D5-dehydroprolinol 19 in order to prepare
+2S,5S)-5-tert-butylproline.
The synthesis of +2S)-5-tert-butyl-D5-dehydroprolinol +19)
started with methyl 2-N-+PhF)amino-5-oxo-6,6-dimethyl-
heptanoate +13), an intermediate in the synthesis of
+2S,5R)-5-tert-butylproline derived from acylation of
g-methyl N-PhF-l-glutamate with pivaloyl chloride, ester
hydrolysis, decarboxylation and esteri®cation.21 Sodium
borohydride reduction of ketone 13 in a mixture of metha-
nol/tert-butanol at 608C gave 2-N-+PhF)amino-5-hydroxy-
6,6-dimethylheptanol 14 in 94% yield as a 1:1 mixture of
diastereomers +Scheme 3).49 1-tert-Butyldimethylsiloxy-2-
N-+PhF)amino-5-oxo-6,6-dimethylheptane 16 was then
synthesized in quantitative yield by selective protection of
the primary alcohol of diol 14 with tert-butyldimethysilyl
chloride, DIEA and DMAP in CH2Cl2 heated at a re¯ux,49
followed by oxidation of neopentyl alcohol 15 with tetra-
propylammonium perruthenate +TPAP) and N-methyl-
morpholine oxide in CH2Cl2.50 Earlier attempts failed to
oxidize the secondary alcohol of 15 to its corresponding
ketone 16 using DMSO and oxalyl chloride in dichloro-
methane,51 as well as using methylsul®de and N-chloro-
succinamide in toluene,52 and only starting material was
isolated after each reaction.
Scheme 3. Synthesis of ketone 16.
of diastereomers in 32% yield.46 Because we could not later
reproduce this result, we abandoned this approach involving
tert-butylcopper reagents which were known to be sensitive
to variations in reaction solvent and temperature.43
The less than satisfactory results we obtained in nucleo-
philic additions of cyanide ion and tert-butylcopper reagents
respectively to iminium salts 5 and 11 +Fig. 3) made us
reconsider our published strategy for synthesizing +2S,5S)-
5-tert-butylproline with a signi®cant modi®cation. As
mentioned, we found previously that hydride reduction of
iminium acid 2 provided trans-5-tert-butylproline dia-
stereoselectively with signi®cant racemization due to the
con®gurational lability of this intermediate under the acidic
conditions for its production.21 Attempts to circumvent
racemization by using its more con®gurationally stable
amide counterpart resulted in lower diastereoselectivity.21
Reduction of the carboxylate to its respective alcohol has
now been investigated as a means to alleviate the problem of
racemization and to install an effective site for metal
hydride coordination in order to direct iminium ion reduc-
tion to afford the trans-diastereomer. b-Hydroxy ketones
have been reported to reduce diastereoselectively using
tetramethylammonium triacetoxyborohydride to provide
anti diols by directed intramolecular hydride delivery.47
Furthermore, reduction of imino alcohols under similar con-
ditions have been reported to produce predominantly trans-
2-hydroxymethyl-5-alkylpyrrolidines possessing 5-methyl
and 5-n-nonyl substituents in 83:17 and 70:30 respective
Concurrent deprotection of the silyl ether and PhF groups
with formation of the iminium salt 17 was achieved on
heating ketone 16 with anisole in a 1:3 TFA/CH2Cl2 solu-
tion at a re¯ux for 70 h +Scheme 4). Because tri¯uoroacetate
17 +Fig. 3) was volatile, the acidic counter ion was
exchanged with p-toluenesulfonic acid as monitored by
comparison of the integrations for the tert-butyl and methyl
singlets respectively at 1.35 and 2.36 ppm in the proton
NMRspectrum in CDCl 3. On larger scale, p-TsOH
+100 mol%) was added at the start of the reaction to ketone
16 and anisole in 25% TFA/CH2Cl2 and the conversion to 18
was complete after 18 h. The con®gurational stability of
Scheme 4. Synthesis of prolinol 21.

L. Halabet al. / Tetrahedron 57 .2001) 6439±6446
6443
cations, such as those found in the dolastatins,57 to study
relationships between their amide isomer geometry and
bioactivity.
The enantiomeric purity of +2S,5S)-5-tert-butylproline +1)
was determined as described previously.21 Formation of dia-
stereomeric a-methylbenzylamides was ®rst performed on
coupling +R)- and +S)-methylbenzylamine to +2S,5S)-1 using
TBTU in acetonitrile, then the Boc group was removed with
TFA in CH2Cl2.21 Integration of the tert-butyl singlets
+1.055 and 1.065 ppm) in the proton 600 MHz NMRspectra
in CD3OD revealed the amides to be of a .98:2 diastereo-
meric ratio. Hence, +2S,5S)-5-tert-butylproline is presumed
to be of .96% enantiomeric purity.
Scheme 5. Oxidation of 21 to +2S,5S)-N-Boc-5-tert-butylproline.
In conclusion, we have developed an ef®cient synthesis of
+2S,5S)-5-tert-butylproline. Starting from methyl 2-N-
+PhF)amino-5-oxo-6,6-dimethylheptanoate +13), a precur-
sor of +2S,5R)-5-tert-butylproline, +2S,5S)-N-Boc-5-tert-
butylproline was obtained in 39% overall yield and .96%
enantiomeric purity via directed hydride addition to imine
19. With an effective means for producing +2S,5S)-5-tert-
butylproline in hand, we are now exploring its introduction
into peptides in order to study the in¯uence of this stereo-
isomer on peptide conformation and biology.
iminium salt 18 was demonstrated by measuring the speci®c
rotation of 18 after treatments with 25% TFA/CH2Cl2 at
re¯ux for 18, 24, 48 and 72 h. Because the speci®c rotation
value of 18 remained unchanged after these treatments,
iminium salt 18 was concluded to be con®gurationally
stable under these acidic conditions.
+2S,5S)-N-Boc-5-tert-butylprolinol +21) was obtained from
p-toluenesulfonate 18 by a sequence commencing with
liberation of imine 19 on washing with aqueous potassium
carbonate, imine reduction with sodium triacetoxyboro-
hydride in toluene at 1008C and N-acylation with di-tert-
butyldicarbonate in acetonitrile +Scheme 4). Alcohol 21 was
obtained in 68% overall yield from ketone 16 as a .95:5
diastereomeric mixture on small scale. Lower diastereo-
selectivity +87:13 trans/cis) was obtained when p-toluene-
sulfonate 18 was reduced under the same conditions. On
larger scale, the diastereomeric N-+Boc)amino alcohols
were separated by chromatography and +2S,5S)- and
+2S,5R)-21 were isolated in 39% and 5% respective overall
yield from ketone 16. The predominant trans-isomer is
proposed to result from a transition state involving coordi-
nation of the borohydride by the alcohol and intramolecular
hydride delivery to the si face of the iminium ion +Fig.
5).47,48 For comparison, an authentic sample of the minor
alcohol isomer +2S,5R)-21 was synthesized by reduction of
acid +2S,5R)-1 using borane in THF.53
3. Experimental
3.1. General
Unless otherwise noted, all reactions were run under a nitro-
gen atmosphere and distilled solvents were transferred by
syringe. Dichloromethane was distilled over P2O5, THF was
distilled over sodium/benzophenone, toluene was distilled
over sodium and DIEA was distilled over ninhydrin and
CaH2. Final reaction mixture solutions were dried over
Na2SO4. Chromatography was on 230±400 mesh silica
gel, and TLC was on aluminium-backed silica plates.
Mass spectral data, HRMS +EI and FAB), were obtained
Â
Â
by the Universite de Montreal Mass Spectroscopy facility.
1H and 13C NMRexperiments were performed on Brucker
ARX400 and av400 spectrometers. The chemical shifts
are reported in ppm +d units) down®eld of internal tetra-
methylsilane ++CH3)4Si). Coupling constants are in Hertz.
Aromatic carbon resonances for PhF groups are not
reported.
+2S,5S)-N-Boc-5-tert-butylproline was produced by two
different oxidation procedures. Direct oxidation of alcohol
21 to acid +2S,5S)-1 was accomplished in 86% yield using
ruthenium trichloride and sodium periodate in a solvent
mixture of 2:2:3 CCl4/CH3CN/H2O +Scheme 5).54 On
larger scale, alcohol 21 was oxidized to the corresponding
acid in 84% yield using 2,2,6,6-tetramethyl-1-piperidinyl-
oxy +TEMPO), sodium chlorite and sodium hypochlorite in
a sodium phosphate buffered acetonitrile solution.55 Alter-
natively, oxidation of 21 to the prolinal 22 was achieved
using TPAP and N-methylmorpholine oxide in CH2Cl2.50
Subsequent oxidation to the corresponding acid was then
performed using NaClO2 in 1:1 CH3CN/t-BuOH to provide
+2S,5S)-1 in 45% overall yield from the two step process.56
Because no epimerization was observed after puri®cation
of aldehyde 22 on silica gel nor during conversion to acid
1, prolinal 22 is an attractive intermediate for synthesizing
analogs of prolyl residues having C-terminal modi®-
3.1.1. ꢀ2S,5RS)-2-N-ꢀPhF)Amino-5-hydroxy-6,6-dimethyl-
heptanol ꢀ14). A solution of ketone 13 +3.16 g, 7.16 mmol)
in a mixture of tert-butanol +200 mL) and MeOH +12 mL)
was treated with NaBH4 +0.812 g, 300 mol%), stirred at
608C for 4 h, cooled to room temperature and diluted with
water +150 mL). The mixture was extracted with EtOAc
+3£150 mL) and the organic phase was washed with
brine, dried and evaporated to a residue that was puri®ed
by chromatography on silica gel using 25% EtOAc in
hexane as eluant. Evaporation of the collected fractions
furnished a 1:1 mixture of diastereomers 14 +2.80 g, 94%
yield) as a white foam: H NMR+CDCl ) d 0.79 +s, 9H),
1
3
0.83 +s, 9H), 0.98 +m, 2H), 1.18±1.28 +m, 4H), 1.48 +m, 2H),
2.13±2.20 +m, 2H), 2.27 +br s, 2H), 2.77±3.12 +m, 6H),
7.19±7.43 +m, 22H), 7.67±7.74 +m, 4H); 13C NMR

6444
L. Halabet al. / Tetrahedron 57 .2001) 6439±6446
+CDCl3) d 25.5, 25.6, 27.5 +2C), 30.8, 31.4, 34.7, 34.8, 53.5,
54.0, 63.7, 64.0, 72.5, 72.6, 79.3, 79.9; HRMS calcd for
C28H34O2N +MH1) 416.2589, found 416.2602.
sulfonate 18 +4.08 mmol) was dissolved in CHCl3 +40 mL),
washed with a saturated aqueous solution of K2CO3
+30 mL), dried and evaporated to imine 19: [a]20
145.98 +c 0.4, MeOH); H NMR+CD OD) d 1.18 +s, 9H),
ˆ
D
1
3
3.1.2.
ꢀ2S,5RS)-1-tert-Butyldimethylsiloxy-2-N-ꢀPhF)-
1.78 +m, 1H), 2.00 +m, 1H), 2.62 +m, 1H), 2.71 +m, 1H), 3.54
+dd, 1H, Jˆ5.6, 11.1 Hz), 3.69 +dd, 1H, Jˆ4.3, 11.1 Hz),
amino-5-hydroxy-6,6-dimethylheptane ꢀ15). A solution
of diol 14 +2.74 g, 6.6 mmol) in CH2Cl2 +70 mL) was treated
with DIEA +4.6 mL, 26.4 mmol), DMAP +0.08 g,
0.66 mmol) and TBDMSCl +1.99 g, 13.2 mmol). The
mixture was heated at a re¯ux for 6 h when complete
consumption of the starting alcohol +Rfˆ0.18, 30% EtOAc
in hexane) was observed by TLC. The solution was evapo-
rated to a residue that was dissolved in EtOAc +100 mL) and
washed with 0.1 M HCl +100 mL) and brine, dried and
evaporated to a residue that was puri®ed by chromatography
on silica gel using 5% EtOAc in hexane as eluant. The
4.06 +m, 1H); 13C NMR+CD OD) d 26.0, 28.7, 34.7, 37.1,
3
65.7, 74.8, 189.3. Imine 19 +4.08 mmol) was dissolved in
toluene +40 mL), treated with NaHB+OAc)3 +1.30 g,
6.12 mmol) and heated at a re¯ux for 18 h. The solution
was cooled, treated with HCl +4 mL, 2 M) and evaporated
to a residue that was dissolved in MeOH, ®ltered and evapo-
rated to furnish +2S,5S)-5-tert-butylproline hydrochloride
+20): H NMR+CD OD) d 1.18 +s, 9H), 1.75 +m, 1H),
1
3
2.00 +m, 1H), 2.64 +m, 2H), 3.16 +m, 1H), 3.55 +dd, 1H,
Jˆ5.6, 11.1 Hz), 3.70 +dd, 1H, Jˆ4.4, 11.1 Hz), 4.06 +m,
1H). The hydrochloride 20 was dissolved in CH3CN
+30 mL), treated with K2CO3 +1.60 g, 11.3 mmol) and di-
tert-butyldicarbonate +2.40 g, 11.3 mmol). After 18 h, the
mixture was treated with K2CO3 +0.538 g, 3.8 mmol) and
di-tert-butyldicarbonate +0.799 g, 3.8 mmol) and stirred for
2 h when complete consumption of the amine was observed
by TLC +Rfˆ0.17, 10% MeOH in CHCl3). Evaporation of
the volatiles gave a residue that was puri®ed by chroma-
tography on silica gel using a gradient of 0±20% EtOAc in
hexane as eluant. First to elute was +2S,5R)-21 +45.9 mg, 5%
yield) which exhibited the same spectral and physical char-
acteristics as material synthesized as described below. Last
alcohol 15, an oil +3.50 g, 99% yield) was obtained as a
1:1 mixture of diastereomers: H NMR+CDCl ) d 20.09
1
3
+t, 12H, Jˆ7.9 Hz), 0.84 +s, 18H), 0.85 +s, 9H), 0.89 +s, 9H),
1.03±1.10 +m, 2H), 1.25 +m, 4H), 1.42±1.52 +m, 2H), 2.12
+m, 1H), 2.20 +m, 1H), 2.70 +br s, 2H), 2.88 +dd, 3H, Jˆ4.9,
9.6 Hz), 3.00 +m, 4H), 3.22 +dd, 1H, Jˆ5.2, 9.9 Hz), 7.18±
7.47 +m, 22H), 7.67±7.71 +m, 4H); 13C NMR+CDCl ) d
3
25.7, 25.6, 25.5, 25.4, 18.2 +2C), 25.7, 25.8, 27.3, 27.8,
30.7, 32.1, 34.7, 34.8, 53.8, 54.6, 65.4 +2C), 72.5, 72.7, 79.6,
80.2; HRMS calcd for C34H47O2NSi +MH1) 530.3455,
found 530.3445.
3.1.3. ꢀ2S)-1-tert-Butyldimethylsiloxy-2-N-ꢀPhF)amino-
5-oxo-6,6-dimethylheptane ꢀ16). A solution of diol 15
+3.50 g, 6.6 mmol) and N-methylmorpholine oxide +1.54 g,
to elute was +2S,5S)-21 +375 mg, 39% yield): [a]20 ˆ24.98
D
1
+c 1.05, CHCl3); H NMR+CDCl ) d 0.90 +s, 9H), 1.48 +s,
3
9H), 1.53 +m, 1H), 1.74 +m, 1H), 1.85 +m, 1H), 2.10 +m, 1H),
3.68 +m, 1H), 3.75 +m, 1H), 3.85 +m, 1H), 3.89 +dd, 1H,
Ê
13.2 mmol) in CH2Cl2 +66 mL) over powdered 4 A molecu-
lar sieves +4.0 g) was treated with tetrapropylammonium
perruthenate +0.23 g, 10 mol%) at room temperature, stirred
for 3 h and ®ltered through a pad of silica gel using 5%
EtOAc in hexanes as eluant. Evaporation of the ®ltrate
Jˆ1.5, 8.8 Hz), 5.00 +br s, 1H); 13C NMR+CDCl ) d 25.2,
3
28.1, 28.2, 28.8, 29.9, 63.2, 67.5, 80.7, 211.0; HRMS calcd
for C14H28O3N +MH1) 258.2069, found 258.2075.
gave ketone 16 +3.44 g, 99% yield) as an oil: [a]20
ˆ
3.1.6. ꢀ2S,5R)-N-Boc-5-tert-butylprolinol ꢀ21). A solution
of +2S,5R)-1 +50.8 mg, 0.19 mmol) in THF +0.4 mL) was
added to a solution of BH3´SMe2 +46mL, 0.46 mmol) in
THF +0.4 mL). The mixture was stirred and heated at a
re¯ux for 18 h. The excess BH3 was destroyed by addition
of MeOH +0.2 mL) and the solvent was removed by
evaporation. The residue was puri®ed by chromatography
on silica gel using a gradient of 0±20% EtOAc in hexane as
eluant. Evaporation of the collected fractions provided
D
1
2115.38 +c 0.36, CHCl3); H NMR+CDCl ) d 20.07 +d,
3
6H, Jˆ8.8 Hz), 0.87 +s, 9H), 1.16 +s, 9H), 1.41±1.48 +m,
1H), 1.53±1.62 +m, 1H), 2.16 +m, 1H), 2.40 +m, 1H), 2.42
+m, 2H), 2.98 +dd, 1H, Jˆ5.3, 9.8 Hz), 3.11 +dd, 1H, Jˆ3.7,
9.9 Hz), 7.21±7.48 +m, 11H), 7.70±7.74 +m, 2H); 13C NMR
+CDCl3) d 25.6, 25.5, 18.2, 25.8, 26.5, 28.5, 33.6, 43.9,
53.5, 65.5, 72.5, 216.3; HRMS calcd for C34H45O2NSi
+MH1) 528.3298, found 528.3288.
+2S,5R)-21 +40 mg, 83% yield) as an oil: [a]20 ˆ28.28 +c
D
3.1.4. ꢀ2S)-5-tert-Butyl-D5-dehydroprolinol p-toluene-
sulfonate ꢀ18). Ketone 16 +2.15 g, 4.08 mmol) was treated
with 25% TFA in CH2Cl2 +41 mL), anisole +2.2 mL,
20.4 mmol) and p-TsOH +0.776 g, 4.08 mmol), heated at a
re¯ux for 18 h, cooled to room temperature and evaporated.
The residue was digested with MeOH +5 mL) and then tritu-
rated with hexane +3£5 mL) to furnish the iminium salt 18
as an oil that was used without further puri®cation:
0.16, CHCl3); 1H NMR+CDCl 3) d 0.89 +s, 9H), 1.48 +s, 9H),
1.81 +m, 3H), 2.01 +m, 1H), 3.67 +m, 2H), 3.81 +m, 1H), 3.98
+m, 1H), 5.50 +br s, 1H); 13C NMR+CDCl ) d 26.4, 28.1,
28.7, 35.9, 63.3, 68.2, 81.4, 159.8.
3
3.1.7. ꢀ2S,5S)-N-Boc-5-tert-butylproline ꢀ2S,5S)-1 from
direct oxidation of ꢀ2S,5S)-21 with RuCl3. A solution of
prolinol +2S,5S)-21 +15.7 mg, 65 mmol) in 2:2:3 CCl4/
CH3CN/H2O +1 mL) was treated with NaIO4 +57 mg,
267 mmol) and RuCl3 +0.8 mg, 2 mmol) at room temperature
and stirred for 90 min. The mixture was partitioned between
water +1 mL) and CH2Cl2 +10 mL) and the aqueous phase
was extracted with CH2Cl2 +3£2 mL). The combined
organic layers were washed with brine, dried and evapo-
rated to a residue that was puri®ed by chromatography on
silica gel using an initial gradient of 0±75% EtOAc in
hexane followed by 80±90% EtOAc in hexane containing
[a]20 ˆ134.78 +c 0.6, MeOH); H NMR+CD OD) d 1.35
1
D
3
+s, 9H), 2.28 +m, 2H), 2.36 +s, 3H), 3.00 +m, 1H), 3.16 +m,
1H), 3.66 +d, 1H, Jˆ11.9 Hz), 4.30 +d, 1H, Jˆ12.4 Hz), 4.60
+m, 1H), 7.18 +d, 2H, Jˆ7.98 Hz), 7.38 +br s, 1H), 7.73 +d,
2H, Jˆ7.99 Hz); 13C NMR+CD 3OD) d 20.3, 22.2, 26.4, 35.0,
37.3, 61.6, 69.1, 125.9, 128.9, 140.8, 142.7, 205.0; HRMS
calcd for C9H18ON +MH1) 156.1388, found 156.1381.
3.1.5. ꢀ2S,5S)-N-Boc-5-tert-butylprolinol ꢀ21). p-Toluene-

L. Halabet al. / Tetrahedron 57 .2001) 6439±6446
6445
Â
2. Belec, L.; Slaninova, J.; Lubell, W. D. J. Med. Chem. 2000,
Â
0.5% AcOH as eluant to furnish +2S,5S)-1 +15.2 mg, 86%
yield) as an oil: [a]20 ˆ238.18 +c 0.7, MeOH).
43, 1448±1455.
D
3. Huang, Z.; He, Y.-B.; Raynor, K.; Tallent, M.; Reisine, T.;
Goodman, M. J. Am. Chem. Soc. 1992, 114, 9390±9401.
4. Prasad, B. V.; Balaram, P. CRC Crit. Rev. Biochem. 1984, 16,
307±347.
3.1.8. ꢀ2S,5S)-N-Boc-5-tert-butylproline ꢀ2S,5S)-1 from
direct oxidation of ꢀ2S,5S)-21 with TEMPO. A solution
of +2S,5S)-21 +0.172 g, 0.67 mmoL) in a mixture of CH3CN
+3.3 mL) and sodium phosphate buffer +0.67 M, pHˆ6±7,
2.7 mL) was treated with TEMPO +10 mol%, 10.4 mg), a
solution of NaClO2 +0.121 g, 1.3 mmol) in H2O +0.66 mL)
and a solution of NaOCl +0.1 mL, 2 mol%) in H2O
+0.33 mL). After stirring at 358C for 18 h, the mixture was
cooled, partitioned between 0.1 M HCl +10 mL) and EtOAc
+10 mL) and the aqueous phase was extracted with EtOAc
+3£10 mL). The organic layers were combined, washed
with brine, dried and evaporated to a residue that was
puri®ed by chromatography on silica gel using a gradient
of 5±90% EtOAc in hexane as eluant. Evaporation of the
collected fractions gave +2S,5S)-1 +152 mg, 84%) as an oil:
[a]20 ˆ238.58 +c 0.7, MeOH). lit.21 [a]20 ˆ216.38 +c 0.7,
5. +a) Reviewed in: Seebach, D.; Sting, A. R.; Hoffman, M.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2708±2748.
+b) Berkowitz, D. B.; McFadden, J. M.; Sloss, M. K. J. Org.
Chem. 2000, 65, 2907±2918 and Refs. 10 and 11.
6. Marshall, G. R.; Hodgkin, E. E.; Langs, D. A.; Smith, G. D.;
Zabrocki, J.; Leplawy, M. T. Proc. Natl Acad. Sci. USA 1990,
87, 487±491.
7. +a) Chandrasekhar, K.; Das, M. K.; Kumar, A.; Balaram, P.
Int. J. Pept. Protein Res. 1988, 32, 167±174. +b) Fox, Jr., R. O.;
Richards, F. M. Nature 1992, 300, 325±330.
8. Karle, I. L.; Balaram, P. Biochemistry 1990, 29, 6747±6756.
9. +a) Benedetti, E.; Barone, V.; Bavoso, A.; Di Blasio, B.; Lelj,
F.; Pavone, V.; Pedone, C.; Bonora, G. M.; Toniolo, C.;
Leplawy, M. T.; Kaczmarek, K.; Redlinski, A. Biopolymers
1988, 27, 357±371. +b) Di Blasio, B.; Pavone, C.; Lombardi,
A.; Pedone, C.; Benedetti, E. Biopolymers 1993, 33, 1037±
1049.
D
D
MeOH); spectroscopic values for +2S,5S)-1 were identical
with those reported in Ref. 21.
3.1.9. ꢀ2S,5S)-N-Boc-5-tert-butylproline ꢀ2S,5S)-1 via
prolinal 22. Prolinol +2S,5S)-21 +12 mg, 50 mmol) was
oxidized to aldehyde 22 in 74% yield using the same con-
ditions described for the oxidation of alcohol 15 to ketone
10. Toniolo, C.; Benedetti, E. Macromolecules 1991, 24, 4004±
4009.
11. +a) Burgess, K.; Ho, K.-K.; Pettitt, B. M. J. Am. Chem. Soc.
1995, 117, 54±65. +b) Paradisi, M. P.; Torrini, I.; Zecchini,
G. P.; Lucente, G.; Gavuzzo, E.; Mazza, F.; Pochetti, G.
Tetrahedron 1995, 51, 2379±2386. +c) Prasad, S.; Roa,
R. B.; Balaram, P. Biopolymers 1995, 35, 11±20. +d) Toniolo,
C.; Crisma, M.; Formaggio, F.; Benedetti, E.; Santini, A.;
Iacovino, R.; Saviano, M.; Di Blasio, B.; Pedone, C.;
Kamphuis, J. Biopolymers 1997, 40, 519±522.
1
16: minor carbamate isomers are reported in brackets, H
NMR+CDCl ) d [0.90 +s, 2.2H)] 0.92 +s, 6.8H), 1.41 +s,
3
5.6H) [1.47 +s, 3.2H)], 1.86 +m, 3H), 2.26 +m, 1H), [3.88
+br s, 0.39H)] 4.03 +br s, 0.60H), 4.17 +d, 0.64H, Jˆ8.1 Hz)
[4.25 +br s, 0.28H), 9.43 +d, 0.55H, Jˆ2.7 Hz). Aldehyde 22
+9.5 mg, 37 mmol) was dissolved in 1:1 CH3CN/t-BuOH
+1 mL) and treated with a solution of NaClO2 +45 mg,
500 mmol) and NaH2PO4 +54 mg, 450 mmol) in H2O
+0.25 mL). After 2 h, more NaClO2 +50 mg) was added,
the reaction was stirred for 30 min and another portion of
NaClO2 +50 mg) was added. After stirring for 30 min, the
mixture was partitioned between ether +3 mL) and H3PO4
+2 mL, 1 M). The aqueous phase was extracted with Et2O
+3£3 mL). The combined organic layers were washed with
brine, dried and evaporated to a residue that was puri®ed by
chromatography on silica gel using the same conditions
reported above. Evaporation of the collected fractions
12. Reviewed in: Hruby, V. J.; Li, G.; Haskell-Luevano, C.;
Shenderovich, M. Biopolymers 1997, 43, 219±266.
13. Wang, S.; Tang, X.; Hruby, V. J. Tetrahedron Lett. 2000, 41,
1307±1310.
14. Hanessian, S.; Margarita, R.; Hall, A.; Luo, X. Tetrahedron
Lett. 1998, 39, 5883±5886.
15. Hruby, V. J.; Toth, G.; Gehrig, C. A.; Kao, L. F.; Knapp, R.;
Lui, G. K.; Yamamura, H. I.; Kramer, T. H.; Davies, P.; Burks,
T. F. J. Med. Chem. 1991, 34, 1823±1830.
16. Gomez-Catalan, J.; Perez, J. J.; Jimenez, A. I.; Cativiela, C.
J. Pept. Sci. 1999, 5, 251±262.
gave +2S,5S)-1 +6.1 mg, 61% yield) as an oil: [a]20
ˆ
D
237.18 +c 0.5, MeOH), lit.21 [a]20 ˆ216.38 +c 0.7,
17. Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39,
5887±5890.
D
MeOH); spectroscopic values for +2S,5S)-1 were identical
with those reported in Ref. 21
18. Baldwin, J. E.; North, M.; Flinn, A.; Moloney, M. G.
Tetrahedron 1989, 45, 1453±1464 and 1465±1474.
19. Del Bosco, M.; Johnstone, A. N. C.; Bazza, G.; Lopatriello, S.;
North, M. Tetrahedron 1995, 51, 8545±8554.
Acknowledgements
20. Wenger, R. M. Angew. Chem., Int. Ed. Engl. 1985, 24, 77±85.
Ã
Â
21. Beausoleil, E.; L'Archeveque, B.; Belec, L.; Atfani, M.;
Lubell, W. D. J. Org. Chem. 1996, 61, 9447±9454 and Refs.
15 and 16 therein.
This research was supported in part by the Natural Sciences
and Engineering Research Council of Canada and the
Â
Á
Â
Ministere de l'Education du Quebec. We are grateful for a
gift of g-methylglutamate from NSC Technologies. We
thank Christian Tornùe for providing useful lead references.
22. +a) Swarbrick, M. E.; Gosselin, F.; Lubell, W. D. J. Org.
Chem. 1999, 64, 1993±2002 and Refs. 17±22 therein.
+b) Swarbrick, M. E.; Lubell, W. D. Chirality 2000, 12,
366±373.
23. +a) Delaney, N. G.; Madison, V. J. Am. Chem. Soc. 1982, 104,
6635±6641. +b) Overberger, C. G.; Jon, Y. S. J. Polym. Sci.,
Polym. Chem. Ed. 1977, 15, 1413±1421.
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