Rigid Dipeptide Mimics: Synthesis of Enantiopure 5- And 7-Benzyl and 5,7-Dibenzyl Indolizidinone Amino Acids via Enolization and Alkylation of δ-Oxo α,ω-Di-[N-(9-(9-phenylfluorenyl))amino]azelate Esters

Article abstract of DOI:10.1021/jo980596x

Azabicyclo[X.Y.0]alkane amino acids are tools for constructing mimics of peptide structure and templates for generating combinatorial libraries for drug discovery. Our methodology for synthesizing these conformationally rigid dipeptides has been elaborated such that alkyl groups can be appended onto the heterocycle to generate mimics of peptide backbone and side-chain structure. Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/ketone alkylation/ reductive amination/lactam cyclization sequence that furnished alkyl-branched azabicyclo[4.3.0]-alkane amino acid. Enantiopure 5-benzyl-, 7-benzyl-, and 5,7-dibenzylindolizidinone amino acids 2-4 were stereoselectively synthesized via efficient reaction sequences featuring the alkylation of di-tert-butyl α,ω-di-[N-(PhF)amino]azelate δ-ketone 5. A variety of alkyl halides were readily added to the enolate of ketone 5 to provide mono- and dialkylated ketones 6 and 7. Hydride additions to 6 and 7, methanesulfonations, and intramolecular S_N2 displacements by the PhF amine gave 5-alkylprolines that were converted by lactam cyclizations into 7- and 5-benzyl-, as well as 5,7-dibenzyl-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylate methyl esters 10, 11, and 14. Epimerization of the alkyl-branched stereocenter via an iminium-enaminium equilibrium proved effective for controlling diastereoselectivity in reductive aminations with 6 and 7 in order to furnish 5-alkylprolines that were similarly converted to 7- benzyl- and 5,7-dibenzylindolizidinone N-(BOC)amino esters 10 and 14. Ester hydrolysis with hydroxide ion and potassium trimethylsilanolate then gave enantiopure indolizidinone amino acids 2-4. Epimerization at C-9 of benzylindolizidinone amino esters was also used to provide alternative diastereomers of 10, 11, and 14. This practical methodology for introducing side-chain groups onto the heterocycle with regioselective and diastereoselective control is designed to enhance the use of alkyl-branched azabicycloalkane amino acids for the exploration of conformation-activity relationships of various biologically active peptides.

Full text of DOI:10.1021/jo980596x

J . Org. Chem. 1998, 63, 5937-5949
5937
Rigid Dip ep tid e Mim ics: Syn th esis of En a n tiop u r e 5- a n d 7-Ben zyl
a n d 5,7-Diben zyl In d olizid in on e Am in o Acid s via En oliza tion a n d
Alk yla tion of δ-Oxo r,ω-Di-[N-(9-(9-p h en ylflu or en yl))a m in o]a zela te
Ester s
Felix Polyak 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 April 1, 1998
Azabicyclo[X.Y.0]alkane amino acids are tools for constructing mimics of peptide structure and
templates for generating combinatorial libraries for drug discovery. Our methodology for synthesiz-
ing these conformationally rigid dipeptides has been elaborated such that alkyl groups can be
appended onto the heterocycle to generate mimics of peptide backbone and side-chain structure.
Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/ketone alkylation/
reductive amination/lactam cyclization sequence that furnished alkyl-branched azabicyclo[4.3.0]-
alkane amino acid. Enantiopure 5-benzyl-, 7-benzyl-, and 5,7-dibenzylindolizidinone amino acids
2-4 were stereoselectively synthesized via efficient reaction sequences featuring the alkylation of
di-tert-butyl R,ω-di-[N-(PhF)amino]azelate δ-ketone 5. A variety of alkyl halides were readily added
to the enolate of ketone 5 to provide mono- and dialkylated ketones 6 and 7. Hydride additions to
6 and 7, methanesulfonations, and intramolecular SN2 displacements by the PhF amine gave
5-alkylprolines that were converted by lactam cyclizations into 7- and 5-benzyl-, as well as 5,7-
dibenzyl-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylate methyl esters 10, 11, and
14. Epimerization of the alkyl-branched stereocenter via an iminium-enaminium equilibrium
proved effective for controlling diastereoselectivity in reductive aminations with 6 and 7 in order
to furnish 5-alkylprolines that were similarly converted to 7- benzyl- and 5,7-dibenzylindolizidinone
N-(BOC)amino esters 10 and 14. Ester hydrolysis with hydroxide ion and potassium trimethyl-
silanolate then gave enantiopure indolizidinone amino acids 2-4. Epimerization at C-9 of
benzylindolizidinone amino esters was also used to provide alternative diastereomers of 10, 11,
and 14. This practical methodology for introducing side-chain groups onto the heterocycle with
regioselective and diastereoselective control is designed to enhance the use of alkyl-branched
azabicycloalkane amino acids for the exploration of conformation-activity relationships of various
biologically active peptides.
In tr od u ction
technology is particularly necessary for appending side
chains onto these heterocycle systems in order to gener-
ate mimics of both peptide backbone and side-chain
properties. Since alkyl-branched azabicycloalkane amino
acids have typically been prepared in the course of
investigations of specific targets,1 the current state of the
art for their synthesis has usually involved multiple step
sequences that provide a single alkyl-substituted frame-
work in low overall yield. Because the future investiga-
tion of biologically relevant peptides can be advanced
through routine employment of alkyl-branched azabicy-
cloalkane amino acids, more proficient means are needed
for obtaining a series of these dipeptide mimics from
common intermediates via efficient reaction sequences.
The spatial requirements for protein chemistry and
biology may be explored through the employment of
azabicyclo[X.Y.0]alkane amino acids as building blocks
for the construction of conformationally rigid surrogates
of peptide structures.1,2 These unique dipeptide ana-
logues can be used to restrain the backbone geometry and
side-chain conformations of the native peptide in order
to probe and elucidate structure-activity relationships.1,2
Furthermore, because these scaffolds possess spatially
defined amine and carboxylate handles suitable for
functionalization by combinatorial technology, azabicyclo-
[X.Y.0]alkane amino acids can also serve as inputs for
generating libraries on which different pharmacophores
are systematically displayed for studying recognition
events in medicinal chemistry.1,3
Striving to develop such a versatile process for syn-
thesizing azabicyclo[X.Y.0]alkane amino acid, we have
introduced a Claisen condensation/reductive amination/
lactam cyclization sequence to stereoselectively furnish
these important targets.4,5 Employment of different N-(9-
(9-phenylfluorenyl))aminodicarboxylates (Scheme 1, PhF
) 9-(9-phenylfluorenyl)), such as glutamate, aspartate,
and longer aminodicarboxylates, in this scheme is de-
signed to provide azabicycloalkane amino acid having a
variety of heterocyclic ring sizes. Stereocontrol is at-
tained at the ring-fusion and along the peptide backbone
Concurrent with increasing applications of these novel
tools for studying peptide structure has grown a necessity
for practical methodology for the stereocontrolled syn-
thesis of azabicyclo[X.Y.0]alkane amino acid. Efficient
(1) For
a review, see: Hanessian, S.; McNaughton-Smith, G.;
Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789. We have
adopted the nomenclature and ring system numbering used in this
reference in order to maintain clarity and consistency when comparing
these different heterocyclic systems.
S0022-3263(98)00596-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/05/1998

5938 J . Org. Chem., Vol. 63, No. 17, 1998
Polyak and Lubell
Sch em e 1. Gen er a l Ap p r oa ch for Syn th esizin g Alk yl-Br a n ch ed Aza bicyclo[X.Y.0]a lk a n e Am in o Acid s
by employing L- and D-aminodicarboxylates to induce
diastereoselectivity during the reductive amination reac-
tion. By specifically employing inexpensive glutamic acid
as chiral educt, we have developed an efficient synthesis
of enantiopure indolizidinone amino acid 1 that gives
access to all of the possible stereoisomers of this interest-
ing dipeptide mimic (Figure 1).4,5
We have now elaborated our approach such that a
variety of side chains may be added to the heterocycle
via stereoselective alkylations of a common N-(PhF)-
amino ketone intermediate (Scheme 1). Focusing on the
benzyl side chain because of the significance of phenyl-
alanine in biologically active peptides,6-8 we have dem-
onstrated the power of this strategy by furnishing three
novel C-benzylated indolizidinone amino acid scaffolds
(2) Some recent syntheses of azabicyclo[X. Y.0]alkane amino acids
that have appeared since the writing of ref 1 include the following:
(a) Lenman, M. M.; Lewis, A.; Gani, D. J . Chem. Soc., Perkin Trans.
1 1997, 2297. (b) Kim, H.-Ok; Lum, C.; Lee, M. S. Tetrahedron Lett.
1997, 38, 4935. (c) Kim, H.-Ok; Kahn, M. Tetrahedron Lett. 1997, 38,
6483. (d) Siddiqui, M. A.; Pre´ville, P.; Tarazi, M.; Warder, S. E.; Eby,
P.; Gorseth, E.; Puumala, K.; DiMaio, J . Tetrahedron Lett. 1997, 38,
8807. (e) Colombo, L.; Di Giacomo, M.; Brusotti, G.; Sardone, N.;
Angiolini, M.; Belvisi, L.; Maffioli, S.; Manzoni, L.; Scolastico, C.
Tetrahedron 1998, 54, 5325. Recent examples of the use of azabicyclo-
[X. Y.0]alkane amino acids in peptide mimicry include the following:
(f) (Rvâ3-receptor binders) Tran, T.-A.; Mattern, R.-H.; Zhu, Q.; Good-
man, M. Bioorg. Med. Chem. Lett. 1997, 7, 997. (g) Haubner, R.;
Finsinger, D.; Kessler, H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1374.
(h) (gramicidin S analogues) Andreu, D.; Ruiz, S.; Carren˜o, C.; Alsina,
J .; Albericio, F.; J ime´nez, M. A.; de la Figuera, N.; Herranz, R.; Garcı´a-
Lo´pez, M. T.; Gonza´lez-Mun˜iz, R. J . Am. Chem. Soc. 1997, 119, 10579.
(i) (thrombin inhibitors) Salimbeni, A.; Paleari, F.; Canevotti, R.;
Criscuoli, M.; Lippi, A.; Angiolini, M.; Belvisi, L.; Scolastico, C.;
Colombo, L. Bioorg. Med. Chem. Lett. 1997, 7, 2205. (j) (dopamine
receptor modulators) Baures, P. W.; Ojala, W. H.; Costain, W. J .; Ott,
M. C.; Pradhan, A.; Gleason, W. B.; Mishra, R. K.; J ohnson, R. L. J .
Med. Chem. 1997, 40, 3594. (k) (dual metalloprotease inhibitors) Robl,
J . A.; Sun, C.-Q.; Stevenson, J .; Ryono, D. E.; Simpkins, L. M.;
Cimarutsi, M. P.; Dejneka, T.; Slusarchyk, W. A.; Chao, S.; Stratton,
L.; Misra, R. N.; Bednarz, M. S.; Asaad, M. M.; Cheung, H. S.; Abboa-
Offei, B. E.; Smith, P. L.; Mathers, P. D.; Fox, M.; Schaeffer, T. R.;
Seymour, A. A.; Trippodo, N. C. J . Med. Chem. 1997, 40, 1570. (l)
(interleukin-1â-converting enzyme inhibitors) Dolle, R. E.; Prasad, C.
V. C.; Prouty, C. P.; Salvino, J . M.; Awad, M. M. A.; Schmidt, S. J .;
Hoyer, D.; Ross, T. M.; Graybill, T. L.; Speier, G. J .; Uhl, J .; Miller, B.
E.; Helaszek, C. T.; Ator, M. A. J . Med. Chem. 1997, 40, 1941.
(3) For lead references on the use of templates for combinatorial
chemistry, see: Falorni, M.; Giacomelli, G.; Nieddu, F.; Taddei, M.
Tetrahedron Lett. 1997, 38, 4663 and refs 3-7 therein.
F igu r e 1. Indolizidinone, 5- and 7-benzylindolizidinone, and
5,7-dibenzylindolizidinone amino acids 1-4.
(Figure 1). Enantiopure 5-benzyl-, 7-benzyl-, and 5,7-
dibenzyl indolizidinone amino acids 2-4 were selectively
synthesized via a sequence featuring alkylation of di-tert-
butyl R,ω-di-[N-(PhF)amino]azelate δ-ketone 5, cycliza-
tion to an alkylproline, and subsequent lactam formation.
Employing conditions that proved effective for the
preparation of the parent indolizidinone amino acid 1,4
we have observed that alkyl substituents exhibited
interesting effects during conversions of ketones 6 and 7
into alkylproline intermediates. Remarkable regioselec-
tivity resulted from intramolecular displacements of
methanesulfonates that were obtained from reduction of
ketones 6 and 7 and activation of their respective
alcohols. Epimerization of the alkyl-branched stereo-
center via an iminium ion-enaminium ion equilibrium
proved an effective means for controlling diastereoselec-
tivity in the reductive amination of 4-benzyl ketones 6
to 4,5-dialkylproline intermediates. Furthermore, we
found that epimerization at C-9 of benzylindolizidinone
amino esters can be used to expand diversity by providing
alternative diastereomeric frameworks.
(4) Lombart, H.-G.; Lubell, W. D. J . Org. Chem. 1996, 61, 9437.
(5) (a) Lombart, H.-G.; Lubell, W. D. J . Org. Chem. 1994, 59, 6147.
(b) Lombart, H.-G.; Lubell, W. D. In Peptides 1994 (Proceedings of the
23rd European Peptide Symposium); Maia, H. L. S., Maia, Ed.;
ESCOM: Leiden, The Netherlands, 1995; p 696.
(6) For numerous examples of bioactive peptides possessing phen-
ylalanine see: Schmidt, G. Top. Curr. Chem. 1986, 136, 109. For
additional examples see refs 1-6 in ref 8b below.
One important practical aspect highlighted by our
research was the capacity to transform selectively the
major product from diastereoselective alkylation of ke-

Rigid Dipeptide Mimics
Ta ble 1. Alk yla tion of Keton e 5
J . Org. Chem., Vol. 63, No. 17, 1998 5939
products using proton NMR spectroscopy and integration
of the tert-butyl ester singlets which appeared at distinct
chemical shifts (Table 2). Stereochemical assignments
were made on the basis of analogy with benzylated
ketones 6a and 7a which were characterized as described
below. Mass recoveries were typically excellent; however,
the reported isolated yields were lower than the amounts
for conversion due to the difficulties of achieving complete
separation of diastereomers by column chromatography
and the exclusion of mixed fractions in the overall yields.
Initially, conditions that proved successful for the
regioselective alkylations of N-(PhF)amino ketones were
employed with 5 on small scale (100 mg, Table 1).9 In a
typical experiment, a solution of 5 in THF at -78 °C was
converted into its enolate with potassium bis(trimethyl-
silyl)amide (KHMDS) and then treated with 1,3-dimeth-
yl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and an
alkyl halide for 1-2 h before aqueous workup. The
conversion of 5 to alkylated material usually ranged from
63 to 95%, except in the reaction with isopropyl iodide
which gave lower conversion (28%). Diastereoselectivity
was typically low with these conditions. When the
counterion was changed from potassium to sodium
similar reactivity and selectivity were observed; switch-
ing to lithium retarded the rate of alkylation. In the
reaction of the potassium enolate of 5 with benzyl
bromide, we found that the ratio of mono- versus dialky-
lated product could be controlled by varying the stoichi-
ometry of base. Higher diastereoselectivities and better
conversions were obtained on larger scale in the absence
of DMPU by allowing the reaction mixture to warm from
-78 °C up to -10 °C after the addition of the alkyl halide
(Table 1).
Silylenol ether 8 was prepared in order to study the
geometry of the enolate formed under the conditions
described above. Exposure of ketone 5 to KHMDS in
tone 5, 4-benzyl ketone (4R)-6a , into three different
indolizidinone amino acids, (3S,6S,7S,9S)-2, (3S,6S,
7R,9S)-2 and (3S,5R,6R,9S)-3 (Figure 1), via reagent
control in sequences featuring methanesulfonate dis-
placement and reductive amination. These features,
combined with the versatility of the alkylation reaction
for introducing a variety of side-chain groups onto the
heterocycle, all illustrate the potential of this practical
methodology for the synthesis of enantiopure 5-, 7-, and
5,7-alkyl-branched azabicyclo[4.3.0]alkane amino acids
for use as building blocks for peptide mimicry and
templates for combinatorial chemistry.
(7) (a) The synthesis of a 2-oxo-3-amino-4-benzyl-1-azabicyclo[4.3.0]-
nonane-9-carboxylic acid analogue that serves as a model antagonist
of the tachykinin NK-2 receptor is reported in: Hanessian, S.; Ronan,
B.; Laoui, A. Bioorg. Med. Chem. Lett. 1994, 4, 1397. (b) Hanessian,
S.; McNaughton-Smith, G. Bioorg. Med. Chem. Lett. 1996, 6, 1567. (c)
The synthesis of a 2-oxo-3-amino-3-benzyl-1-azabicyclo[4.3.0]nonane-
9-carboxylic acid analogue is reported in: Colombo, L.; Di Giacomo,
M.; Scolastico, C.; Manzoni, L.; Belvisi, L.; Molteni, V. Tetrahedron
Lett. 1995, 36, 625.
(8) Representative examples of constrained phenylalanine mimics
include the following: (a) Gibson (ne´e Thomas), S. E.; Guillo, N.;
Middleton, R. J .; Thuilliez, A.; Tozer, M. J . J . Chem. Soc., Perkin Trans.
1 1997, 447. (b) Collot, V.; Schmitt, M.; Marwah, A. K.; Norberg, B.;
Bourguignon, J .-J . Tetrahedron Lett. 1997, 38, 8033. (c) Kazmierski,
W. M.; Urbanczyk-Lipkowska, Z.; Hruby, V. J . J . Org. Chem. 1994,
59, 1789. (d) Cativiela, C.; D´ıaz-de-Villegas, M. D.; Avenoza, A.;
Peregrina, J . M. Tetrahedron 1993, 49, 10987. (e) de Laszlo, S. E.;
Bush, B. L.; Doyle, J . J .; Greenlee, W. J .; Hangauer, D. G.; Halgren,
T. A.; Lynch, R. J .; Schorn, T. W.; Siegl, P. K. S. J . Med. Chem. 1992,
35, 833. (f) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J . Am.
Chem. Soc. 1983, 105, 5390. (g) 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. (h) Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahedron:
Asymmetry 1994, 5, 351. (i) 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. (j) Sarges, R.; Tretter,
J . R. J . Org. Chem. 1974, 39, 1710. (k) Semple, J . E.; Minami, N. K.;
Tamura, S. Y.; Brunck, T. K.; Nutt, R. F.; Ripka, W. C. Bioorg. Med.
Chem. Lett. 1997, 7, 2421. (l) Pasto´, M.; Moyano, A.; Perica`s, M. A.;
Riera, A. J . Org. Chem. 1997, 62, 8425. (m) Ku¨hn, C.; Lindeberg, G.;
Gogoll, A.; Hallberg, A.; Schmidt, B. Tetrahedron 1997, 53, 12497. (n)
Liao, S.; Shenderovich, M. D.; Lin, J .; Hruby, V. J . Tetrahedron 1997,
53, 16645. (o) Van Betsbrugge, J .; Van Den Nest, W.; Verheyden, P.;
Tourwe´, D. Tetrahedron 1998, 54, 1753.
Resu lts a n d Discu ssion
Alk yla tion of (2S,8S)-Di-ter t-bu tyl 5-Oxo-2,8-d i-[N-
(P h F )a m in o]a zela te (5). Alkylation of (2S,8S)-di-tert-
butyl 5-oxo-2,8-di-[N-(PhF)amino]azelate ((2S,8S)-5) was
studied using various alkyl halides in order to open a
general route for making alkyl-branched indolizidinone
amino acids. Crystalline diaminoazelate δ-ketone 5 was
synthesized in >30 mmol scale in five steps and >50%
overall yield from L-glutamic acid via our reported route
featuring the Claisen condensation of N-(PhF)glutamate,
followed by hydrolysis and decarboxylation of the result-
ing â-keto ester.4 The alkylation of azelate 5 was first
explored with benzyl bromide, and similar conditions
were then employed with a variety of alkyl halides (Table
1). Reaction conversion, the diastereomeric ratio of
alkylated product 6, and formation of dialkylated product
7 were ascertained by analysis of the crude reaction
(9) (a) Lubell, W. D.; Rapoport, H. J . Am. Chem. Soc. 1988, 110,
7447. (b) Lubell, W. D.; J amison, T. F.; Rapoport, H. J . Org. Chem.
1990, 55, 3511. (c) Sharma, R.; Lubell, W. D. J . Org. Chem. 1996, 61,
202. (d) Gill, P.; Lubell, W. D. J . Org. Chem. 1995, 60, 2658.

5940 J . Org. Chem., Vol. 63, No. 17, 1998
Ta ble 2. Ch em ica l Sh ifts (δ) of ter t-Bu tyl Ester Sin glets of 6 a n d 7
Polyak and Lubell
R
(4S)-6
(4R)-6
(4R,6R)-7
(4R,6S)-7
a
b
c
d
e
PhCH2-
1.05, 1.17
1.16, 1.22
1.17, 1.22
1.20, 1.23
1.18, 1.22
1.13, 1.15
1.14, 1.19
1.15, 1.21
1.18, 1.22
1.15, 1.20
1.11
1.17
1.20
1.20
1.08, 1.11
CH2dCHCH2-
H3CO2CCH2-
H3C-
1.17, 1.25
CH3CH2-
Sch em e 2. Syn th esis of Silylen ol Eth er s 8
diastereoselectivity in the cyclization of simple δ-hydroxy
R,â-diaminoazelate,4 we explored this reaction sequence
to convert C-benzylated ketones 6a into their respective
indolizidinone amino esters. Since alkyl substituents can
promote ring formation by steric interactions,10 which
may favor cyclization to form substituted prolines pos-
sessing 4-benzyl substituents, we considered that 7-ben-
zylindolizidinone amino esters 10 and 5-benzylindoliz-
idinone amino esters 11 might be formed by the influences
of the benzyl substituent and stereochemistry in the
displacement reaction.
All four diastereomeric alcohols 9 were therefore
synthesized by independent reductions of ketones (4S)-
and (4R)-6a using sodium borohydride in ethanol to
obtain low diastereoselectivity (Scheme 4). Sodium boro-
hydride reduction of (4R)-6a gave a 2:1 mixture of
(4R,5R)- and (4R,5S)-9 alcohols that were separated by
chromatography. Similar reduction of (4S)-6a yielded an
inseparable 1:1 mixture of alcohols (4S,5S)- and (4S,5R)-
9, that was directly used in the subsequent reaction
sequence. Attempts to reduce ketone (4R)-6a diastereo-
selectively led to the discovery that sodium cyanoboro-
hydride in ethanol with a catalytic amount of acetic acid
gave a 5:1 ratio of (4R,5S)- and (4R,5R)-9.
Sch em e 3. Ep im er iza tion of Alk yl-Br a n ch ed
Keton e (4R)-6a
5-Alkylproline intermediates were readily obtained by
alcohol activation with methanesulfonyl chloride, tri-
ethylamine, and DMAP in dichloromethane, followed by
intramolecular substitution on heating the solvent at a
reflux. Cyclization of (4R,5S)-9 occurred at higher tem-
perature and required heating in boiling toluene. In all
cases, each alcohol provided a single 5-alkylproline that
was directly converted to the fully protected indolizidi-
none amino acid by tert-butyl ester and PhF group
solvolysis with TFA, esterification with methanol and
thionyl chloride, lactam cyclization on stirring with
triethylamine in dichloromethane, and N-acylation with
di-tert-butyl dicarbonate. 7-Benzylindolizidinone amino
esters (6R,7S)- and (6S,7S)-10 were easily separated by
chromatography on silica gel after their formation via
cyclization of the 1:1 mixture of alcohols (4S,5S)- and
(4S,5R)-9.
In total, three different 7-benzylindolizidinone amino
ester diastereomers 10 and one 5-benzylindolizidinone
amino ester 11 were selectively synthesized by this
process. Cyclizations with (4S,5R)- and (4R,5R)-9 gave
4-substituted cis-5-alkylproline diastereomers that were
respectively converted to 7-benzylindolizidinone amino
esters (6S,7S)- and (6S,7R)-10 in 56% and 48% overall
yields from their respective alcohols 9. Cyclization with
(4S,5S)-9 gave the 4-substituted 5-alkylproline trans-
diastereomer, that was converted to (6R,7S)-10 in 36%
overall yield from 9, which indicated that the steric
effects from the 4S-benzyl group were significant enough
to promote a transition state providing the trans- rather
than the cis-5-alkylproline diastereomer. On the other
THF at -78 °C for 2 h followed by addition of tert-
butyldimethysilyl chloride furnished enol ether 8 as a 1:1
mixture of E:Z isomers (Scheme 2). Although the isomers
were not separable by chromatography, spectral analysis
confirmed their structure by revealing vinyl protons for
each isomer as triplets at 4.48 and 4.52 ppm, as well as
two sets of vinyl carbons at δ ) 102.2, 103.5, 151.8, and
153.2 ppm.
Epimerization of benzyl ketone (4R)-6a was also ex-
amined in order to augment the amount of the minor
diastereomer. Treatment of ketone (4R)-6a with KH-
MDS in THF at -78 °C for 2 h followed by addition of
methanol furnished a 1.3:1 mixture of (4S)- and (4R)-6a
(Scheme 3). Thus, although (4S)-6a was isolated as the
minor diastereomer from the alkylation reaction, epimer-
ization of the major diastereomer was successfully used
to augment the quantity of this isomer.
Syn th esis of 7- an d 5-Ben zylin dolizidin on e Am in o
Ester s 10 a n d 11 by Meth a n esu lfon a te Disp la ce-
m en ts. In the preparation of indolizidinone amino acid
1, hydride reduction of δ-oxo azelate 5, methanesulfo-
nylation, and SN2 displacement by the phenylfluorenyl-
amines proved to be an effective method for synthesizing
5-alkylproline intermediates.4 Specific formation of the
cis-5-alkylproline diastereomer from symmetrical di-tert-
butyl δ-hydroxy-R,ω-di-[N-(PhF)amino]azelate was a note-
worthy outcome that required the attack of each of the
two amines 50% of the time in the SN2 displacement of
the methanesulfonate. This diastereospecificity indicated
a significant difference in the energy of the transition
states leading to the favored cis- over the trans-5-
alkylproline diastereomer. In light of the excellent cis-
(10) (a) For a review, see: Sammes, P. G.; Weller, D. J . Synthesis
1995, 1205. (b) Parrill, A. L.; Dolata, D. P. Tetrahedron Lett. 1994, 35,
7319.

Rigid Dipeptide Mimics
J . Org. Chem., Vol. 63, No. 17, 1998 5941
Sch em e 4. Syn th esis of 5- a n d 7-Ben zylin d olizid in on e Am in o Ester s 10 a n d 11 via Meth a n esu lfon a te
Disp la cem en ts
hand, the cyclization with (4R,5S)-9 provided the less-
substituted 5-alkylproline cis-diastereomer that was
converted to 5-benzylindolizidinone amino ester (5R,6R)-
11 in 59% overall yield from 9, which illustrated that the
steric effects from the (4R)-benzyl group did not perturb
the transition state favoring cis-5-alkylproline diastere-
omer. Thus, stereochemistry at the alkyl-branched
4-position influenced significantly the transition state for
SN2 displacement of the (5S)-methanesulfonate. The
remarkable formation of only one 5-alkylproline from
each diaminoazelate alcohol 9 implicates the importance
of steric and stereochemical forces in the methane-
sulfonate displacements and underlines the power of this
technique for selective generation of alkyl-branched
azabicyclo[4.3.0]alkane ring systems.
Syn th esis of 7-Ben zylin d olizid in on e Am in o Ester
10 by Red u ctive Am in a tion . 7-Benzylindolizidinone
amino ester 10 was also synthesized using the reductive
amination/lactam cyclization strategy that had previously
been developed for the synthesis of indolizidinone amino
acid 1.4 A solution of 6a in 10:1 EtOH:AcOH was treated
with palladium-on-carbon under hydrogen atmosphere
until TLC analysis showed complete disappearance of
starting ketone. Hydrolysis of the tert-butyl esters with
acid, esterification with MeOH and SOCl2, lactam forma-
tion with Et3N in dichloromethane, and protection with
di-tert-butyl dicarbonate gave N-(BOC)amino 7-benzylin-
dolizidinone ester 10 which was purified by column
chromatography.
formed instead of the 5-alkyl counterparts. Both steric
promotion of ring formation,10 as well as the formation
of a more substituted enamine intermediate11 during the
reductive amination can account for the production of 4,5-
dialkylprolines that lead to 7-alkylindolizidinones 10.
Furthermore, only 5-alkylproline cis-diastereomers, which
yielded concave bicyclic ring systems, were isolated from
hydrogenation of amino ketone 6a at high hydrogen
pressure. This result was consistent with the outcome
of reductive amination of symmetrical (2S,8S)-di-tert-
butyl 5-oxo-2,8-di-[N-(PhF)amino]azelate ((2S,8S)-5) at
high hydrogen pressure to form predominantly the
concave indolizidinone system.4 The steric bulk of the
tert-butyl ester has previously been found to shield
effectively one face of the dehydroproline intermediate
such that cis-5-alkylprolines were the major products
isolated from reductive amination of ordinary 5-keto
esters.12
Finally, epimerization of the alkyl branched chiral
center occurred via iminium ion-enaminium ion tau-
tomerization during hydrogenation in the reductive ami-
nation, such that the reaction with pure (4S)- or (4R)-
diastereomer 6a and palladium-on-carbon at 9 atm of
hydrogen in a 9:1 EtOH:AcOH solution, followed by
lactam cyclization and protection, resulted in 5:1 to 8:1
ratios of (3S,6S,7S,9S)- and (3S,6S,7R,9S)-10 (Table 3).
At 1 atm of hydrogen under the same conditions, the
(11) Shainyan, B. A.; Mirskova, A. N. Russ. Chem. Rev. 1979, 48,
107.
We noted several aspects of this reductive amination
reaction that provided (3S,6S,7R,9S)- and (3S,6S,7S,9S)-
10 from hydrogenation of diastereomerically pure 6a . In
the first place, 7-alkylindolizidinone amino esters were
(12) (a) Beausoleil, E.; L’Archeveˆque, B.; Be´lec, L.; Atfani, M.; Lubell,
W. D. J . Org. Chem. 1996, 61, 9447. (b) Ibrahim, H. H.; Lubell, W. D.
J . Org. Chem. 1993, 58, 6438. (c) Ho, T. L.; Gopalan, B.; Nestor, J . J .
J r. J . Org. Chem. 1986, 51, 2405. (d) Fushiya, S.; Chiba, H.; Otsubo,
A.; Nozoe, S. Chem. Lett. 1987, 2229.

5942 J . Org. Chem., Vol. 63, No. 17, 1998
Polyak and Lubell
Ta ble 3. Syn th esis of 10 via Red u ctive Am in a tion of 6a
ium ions and diastereoselective cycloadditions of azome-
thine ylides.16b,17
Syn th esis of 5,7-Diben zylin d olizid in on e Am in o
Ester 14. With successful means in hand for making 7-
and 5-benzylindolizidinone amino esters 10 and 11, we
next investigated both the mesylate displacement and the
reductive amination approaches with dibenzylazelate
(4R,6R)-7a in order to synthesize 5,7-dibenzylindolizidi-
none amino ester 14 (Scheme 5). Symmetrical alcohol
(4R,6R)-12 was prepared in excellent yield by hydride
reduction of ketone (4R,6R)-7a using sodium borohydride
in ethanol. Methanesulfonylation of 12 using the condi-
tions described above and heating in toluene furnished
the cis-5-alkylproline intermediate which was converted
to (5R,6S,7R)-5,7-dibenzylindolizidinone amino ester 14
in an overall yield of 26% from 12. The same (5R,6S,7R)-
5,7-dibenzylindolizidinone isomer 14 was also isolated as
the only product in 20% overall yield from the reductive
amination/lactam cyclization procedure using (4R,6R)-
7a and hydrogenation at 9 atm with palladium-on-
carbon.
Hyd r olysis a n d Ep im er iza tion of 5- a n d 7-Ben zyl-
a n d 5,7-Diben zylin d olizid in on e Am in o Ester s. N-
(BOC)amino 7- and 5-benzylindolizidinone acids 2 and 3
as well as N-(BOC)amino 5,7-dibenzylindolizidinone acid
4 were synthesized via hydrolysis of their respective
esters 10, 11, and 14 using conditions previously devel-
oped to generate (3S,6S,9S)-N-(BOC)amino indolizidi-
none acid (Table 4).4 Quantitative hydrolysis was achieved
using LiOH in dioxane; however, in certain cases, epimer-
ization of the C-9 center competed with ester hydrolysis
and afforded mixtures of (9S)- and (9R)-diastereomeric
acids. For example, treatment of (3S,6S,7R,9S)-N-(BOC)-
amino 7-benzylindolizidinone ester (3S,6S,7R,9S)-10 with
200 mol % LiOH furnished a 3:2 mixture of (9S)- and
(9R)-2. Exposure of (3S,5R,6S,7R,9S)-N-(BOC)amino
5,7-dibenzylindolizidinone ester (3S,5R,6S,7R,9S)-14 to
similar conditions gave a 55:45 mixture of (9S)- and (9R)-
4. Ester hydrolysis without epimerization was achieved
by employing potassium trimethylsilanolate in ether
which furnished pure (3S,5R,6S,7R,9S)-4 from its respec-
tive ester 14.12a,b Similarly, treatment of ester (3S,6S,
7R,9S)-10 with 200 mol % KOSiMe3 in ether gave pure
(9S)-2 in excellent yield without epimerization.
isolated yield of 10
substrate
H2 atm
(6S,7S)-10
(6S,7R)-10
(4R)-6a
(4R)-6a
(4S)-6a
(4S)-6a
9
1
9
1
53
36
49
31
10
24
6
21
reductive amination of pure (4S)- or (4R)-diastereomer
6a followed by conversion to indolizidinone ester pro-
duced a 1.5:1 ratio of (3S,6S,7S,9S)- and (3S,6S,7R,9S)-
10.
The observed stereoselectivity of the hydrogenation at
high pressure may be explained by a mechanism that
implicates iminium ion-enaminium ion tautomerization
as illustrated in Figure 2.13,14 Among the possible
intermediates leading to the hydrogenation transition
state, the one labeled B may minimize the pseudo-1,3-
diaxial interactions between the carboxylate and the
4-benzyl substituent by placing only the smallest sub-
stituent in an axial orientation. As mentioned above, cis-
5-alkylprolines are produced from hydrogenation at high
pressure due to the steric effects of the tert-butyl ester
shielding attack of the upper face of the imine.12 Relief
of A1,2 strain between the 4- and 5-position substituents
in B would result from the catalyst delivering hydrogen
to the underside of the imine.15 Steric interactions
between the tert-butyl ester and the 4-benzyl substituent
most probably disfavor the (4R)-benzyl iminium inter-
mediates that reduce to form the more congested
(2S,4R,5S)-4,5-dialkylproline and furnish the minor
(3S,6S,7R,9S)-7-benzylindolizidinone diastereomer 10
(Figure 2). At lower hydrogen pressure, reduced dia-
stereoselectivity may be the consequence of competing
palladium-catalyzed isomerization which leads to the
minor (3S,6S,7R,9S)-diastereomer 10.16 Since the dia-
stereoselectivity in the reductive amination of 6a may
also be observed in the hydrogenation of simpler γ-alkyl
δ-oxo R-amino esters, this process exhibits potential as
a complementary alternative to other approaches for
synthesizing enantiopure 4,5-substituted prolinates, such
as the addition of organocopper reagents to N-acylimin-
Since epimerization of esters 10, 11, and 14 can provide
a means for generating benzylindolizidinone scaffolds
having alternative configurations, we investigated condi-
tions to transform (3S,6S,7S,9S)-N-(BOC)amino 7-ben-
zylindolizidinone ester (3S,6S,7S,9S)-10 into its corre-
sponding (3S,6S,7S,9R)-10 diastereomer. Epimerization
of ester 10 was accomplished using KHMDS (200 mol %)
in THF at -50 °C followed by an aqueous quench.4
A
(13) Our process is related to the use of imine-enamine tautomer-
ization for achieving diastereoselective Michael addition reactions. For
example, see: (a) J abin, I.; Revial, G.; Tomas, A.; Lemoine, P.; Pfau,
M. Tetrahedron: Asymmetry 1995, 6, 1795 and refs 1 and 2 therein.
For a review, see: (b) d’Angelo, J .; Desmae¨le, D.; Dumas, F.; Guingant,
A. Tetrahedron: Asymmetry 1992, 3, 459.
(14) Our process is also related to hydride additions to six-membered
iminium ions, the stereochemical course of which has been discussed
in the following: (a) Hart, D. J .; Leroy, V. Tetrahedron 1995, 51, 5757
and refs 4 and 19 therein. (b) Maruoka, K.; Miyazaki, T.; Ando, M.;
Matsumura, Y.; Sakane, S.; Hattori, K.; Yamamoto, H. J . Am. Chem.
Soc. 1983, 105, 2831.
(15) (a) J ohnson, F. Chem. Rev. 1968, 68, 375. (b) Narula, A. S.
Tetrahedron Lett. 1981, 22, 2017.
(16) (a) Rylander, P. N. Catalytic Hydrogenation in Organic Syn-
theses; Academic Press: New York, 1979; p 32. (b) To further probe
the mechanism of this reductive amination reaction as well as to test
the generality of this method, we are presently examining alternative
hydrogenation conditions and simpler substrates.
separable 3:1 mixture of (9R)- and (9S)-10 was isolated
from this reaction.
En a n tiom er ic P u r ity a n d Ster eoch em ica l Assign -
m en ts of 7- a n d 5-Ben zyl- a n d 5,7-Diben zylin d oliz-
id in on e Am in o Ester s 10, 11, a n d 14. The enantio-
meric purity of (3S,6S,7S,9S)-10 produced from 5 via the
alkylation/reductive amination/lactam cyclization se-
quence was determined after conversion to (1′R)- and
(1′S)-N-R-methylbenzylureas 15 (Scheme 6). Trifluoro-
acetic acid in CH2Cl2 removed quantitatively the N-BOC
(17) (a) Collado, I.; Ezquerra, J .; Pedregal, C. J . Org. Chem. 1995,
60, 5011 and refs therein. (b) Galley, G.; Liebscher, J .; Pa¨tzel, M. J .
Org. Chem. 1995, 60, 5005 and refs therein.

Rigid Dipeptide Mimics
J . Org. Chem., Vol. 63, No. 17, 1998 5943
F igu r e 2. Mechanism of the reductive amination of 6a .
Sch em e 5. Syn th esis of
5,7-Diben zylqu in d olizid in on e Am in o Ester 14
followed by acylation with either (R)- or (S)-R-methyl-
benzyl isocyanate in THF with triethylamine. Measure-
ment of the diastereomeric methyl ester singlets at 3.71
and 3.79 ppm in CDCl3 and at 3.36 and 3.42 ppm in C6D6
1
by 400 MHz H NMR spectroscopy demonstrated 16 to
be of >99% diastereomeric excess.
The high diastereomeric purity of ureas 15 and 16
indicate that both routes, via reductive amination and
via methanesulfonate displacement, provide enantiopure
material. Hence, alkyl-branched intermediates 6 and 7,
benzylindolizidinone amino acid analogues 2-4, and
esters 10, 11, and 14 are all presumed to be of >99%
enantiomeric purity.
The position and relative stereochemistry of the ben-
zylated carbons in indolizidinone N-(BOC)amino esters
10, 11, and 14 were conveniently determined by two-
dimensional NMR experiments because the majority of
the signals for each of the ring protons was well resolved
at distinct chemical shifts (Table 5). The point of union
between the benzyl group and the indolizidinone hetero-
cycle was first established by systematic assignment of
each of the ring protons in the COSY spectrum. For
example, in the COSY spectrum of (3S,6S,7S,9S)-10, the
presence of the benzyl substituent at the 7-position was
confirmed by the coupling between the benzyl methylene
protons at 2.7 and 2.8 ppm with the C7 proton at 2.3 ppm.
Subsequently, the relative stereochemistry of the stereo-
centers at the 5-, 6-, and 7-positions was assigned by
analysis of NOESY and ROESY spectra of 10, 11, and
14. The various two-dimensional NMR spectra as well
as the observed nuclear Overhauser effects that were
used to assign the relative stereochemistry at the ring-
fusion and alkyl-branched stereocenters of 10, 11, and
14, all are illustrated in the Supporting Information. The
stereochemical assignments made for the 5- and 7-posi-
protecting group, and the TFA salt was acylated with
either (R)- or (S)-R-methylbenzyl isocyanate in THF with
triethylamine.4 Measurement of the diastereomeric meth-
yl ester singlets at 3.67 and 3.70 ppm in CDCl3 and at
3.28 and 3.38 in C6D6 by 400 MHz 1H NMR spectroscopy
demonstrated 15 to be of >99% diastereomeric excess.
The enantiomeric purity of (5R,6S,7R)-14, synthesized
from 5 via the alkylation/methanesulfonate displacement/
lactam cyclization sequence was determined in a similar
fasion (Scheme 6). N-R-Methylbenzylureas 16 were
prepared by BOC group solvolysis with TFA in CH2Cl2

5944 J . Org. Chem., Vol. 63, No. 17, 1998
Ta ble 4. Syn th esis of Am in o Acid s 2-4 by Ester Hyd r olysis
Polyak and Lubell
acid
ester
base
solvent
(9S):(9R)
yield (%)
88
(3S,6S,7S,9S)-10
(3S,6S,7R,9S)-10
(3S,6S,7R,9S)-10
(3S,6R,7S,9S)-10
(3S,5R,6R,9S)-11
(3S,5R,6S,7R,9S)-14
(3S,5R,6S,7R,9S)-14
2 N LiOH
2 N LiOH
KOSiMe3
2 N LiOH
2 N LiOH
2 N LiOH
KOSiMe3
dioxane
dioxane
Et2O
dioxane
dioxane
dioxane
Et2O
99:1a
60:40
99:1a
95:5
2
2
2
2
3
4
4
77
83
73
99:1a
55:45
99:1a
83
a(9R)-Isomer was not detected.
Sch em e 6. En a n tiom er ic P u r ity of
7-Ben zylin d olizid in on e a n d 5,7-Diben zyl-
in d olizid in on e Am in o Ester s 10 a n d 14 a n d
Ep im er iza tion of Ester 10
type II′ â-turn. For comparison, we have listed in Table
6 the values for 10 with those observed in the crystal
structures of the corresponding methyl ester of indoliz-
idinone amino acid (3S,6S,9S)-1, and a (3S,6R,9S)-6-
thiaindolizidinone â-turn dipeptide analogue,19 as well
as the values for an ideal type II′ â-turn20 and an ideal
inverse γ-turn conformation.21
Con clu sion
We have developed a practical method for synthesizing
alkyl-branched azabicyclo[X.Y.0]alkane amino acids from
R-aminodicarboxylates as inexpensive chiral educts. Alky-
lation of readily accessible (2S,8S)-di-tert-butyl 5-oxo-2,8-
di-[N-(PhF)amino]azelate (5) permits a variety of sub-
stituents to be appended onto both linear and heterocycle
dipeptide surrogates in order to mimic different amino
acid side chains. Illustrating our method by the synthe-
sis of 5- and 7-benzyl as well as 5,7-dibenzylindolizidi-
none amino acids 2-4, we have prepared five new
azabicyclo[X.Y.0]alkane amino acid scaffolds via efficient
sequences featuring reductive aminations, methane-
sulfonate displacements, and lactam cyclizations. Be-
cause our routes are amenable to other amino acid side
chains, and because the use of alternative R-aminodicar-
boxylates may furnish azabicyclo[X.Y.0]alkanes of vari-
ous ring sizes, our methodology offers a versatile means
for constructing these important tools for studying the
spatial requirements for protein chemistry and biology.
tions of 10, 11, and 14 were then used to deduce the
relative stereochemistry at the benzyl branched 4- and
6-positions of ketones 6a and 7a based on the fact that
no epimerization happened during the reaction sequences
featuring methanesulfonate displacements. The stere-
ochemistries of alcohols 9 were similarly deduced from
the assignments made for the ring-fusion 6-positions of
10, 11, and 14 based on the actuality that the methane-
sulfonate displacements occurred with complete inversion
of stereochemistry during this SN2 reaction.
Crystallization of (3S,6R,7S,9S)-methyl 2-oxo-3-N-
(BOC)amino-7-benzyl-1-azabicyclo[4.3.0]nonane-9-car-
boxylate ((3S,6R,7S,9S)-10) from 1:1 EtOAc:hexane and
X-ray crystallographic analysis confirmed the NMR as-
signments (Figure 3).18 In the crystal structure of
(3S,6R,7S,9S)-benzylindolizidinone 10, the dihedral angles
of the backbone atoms constrained inside the heterocycle
resemble the values of the central residues in an ideal
Exp er im en ta l Section
Gen er a l. Unless otherwise, noted all reactions were run
under nitrogen atmosphere and distilled solvents were trans-
ferred by syringe. Tetrahydrofuran (THF) and ether were
distilled from sodium/benzophenone immediately before use;
1,1,1,3,3,3-hexamethyldisilazane and CH2Cl2 were distilled
from CaH; CHCl3 was from P2O5; triethylamine (Et3N) was
distilled from BaO. Final reaction mixture solutions were
dried over Na2SO4. Melting points are uncorrected. Mass
spectral data, HRMS and MS (EI and FAB), were obtained by
the Universite´ de Montre´al Mass Spectrometry facility. Unless
otherwise noted, 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 tetrameth-
ylsilane ((CH3)4Si), CHCl3, and C6H6; coupling constants (J )
are reported in hertz. Chemical shifts of PhF aromatic carbons
are not reported for the 13C NMR spectra. Analytical thin-
layer chromatography (TLC) was performed by using aluminum-
backed silica plates coated with a 0.2 mm thickness of silica
gel 60 F254 (Merck). Chromatography was performed using
Kieselgel 60 (230-400 mesh).
(18) The structure of 10 was solved at l’Universite´ de Montre´al X-ray
facility using direct methods (SHELXS 96) and refined with SHELXL
96: C22H30N2O5; Mr ) 402.48; monoclinic, colorless crystal; space group
P21; unit cell dimensions (Å) a ) 5.928(2), b ) 10.207(3), c ) 17.964(7);
â ) 93.45(3)°; volume of unit cell (Å3) 1085.0(6); Z ) 2; R1 ) 0.0599 for
I > 2 σ(I), wR2 ) 0.1507 for all data; GOF ) 0.860. The author has
deposited the atomic coordinates for the structure of 10 with the
Cambridge Crystallographic Data Center. The coordinates can be
obtained, on request, from the Cambridge Crystallographic Data
Center, 12 Union Road, Cambridge, CB2 1EZ, U.K.
Gen er a l P r oced u r e for th e Alk yla tion of (2S, 8S)-Di-
ter t-bu tyl 5-Oxo-2,8-d i-[N-(P h F )a m in o]a zela te (5). A -78
(19) Nagai, U.; Sato, K.; Nakamura, R.; Kato, R. Tetrahedron 1993,
49, 3577.
(20) Ball, J . B.; Alewood, P. F. J . Mol. Recogn. 1990, 3, 55.
(21) Madison, V.; Kopple, K. D. J . Am. Chem. Soc. 1980, 102, 4855.

Rigid Dipeptide Mimics
J . Org. Chem., Vol. 63, No. 17, 1998 5945
F igu r e 3. ORTEP view of indolizidinone methyl ester
(3S,6R,7S,9S)-10. Ellipsoids are drawn at 40% probability
level. Hydrogens are represented by spheres of arbitrary size.18
Ta ble 6. Com p a r ison of th e Dih ed r a l An gles fr om
Aza bicycloa lk a n e X-r a y Da ta a n d Id ea l P ep tid e Tu r n s
entry
ψ
φ
7-benzylindolizidinone (3S,6R,7S,9S)-10
indolizidinone (3S,6S,9S)-14
-147°
-176°
-161°
-120°
-56°
-78°
-69°
-80°
-80°
(3S,6R,9S)-6-thiaindolizidinone19
Type II′ â-turn i + 1 and i + 2 residues20
inverse γ-turn i + 2 residue21
°C solution of 5 (100 mg, 0.12 mmol, 100 mol %) in THF (1
mL) was treated with a 0.5 M solution of KHMDS in toluene,
stirred for 30 min, and treated with DMPU (0.3 mL) and alkyl
halide (170 mol %). After 1-2 h of stirring at -78 °C, the
reaction mixture was partitioned between EtOAc (15 mL) and
1 M NaH2PO4 (15 mL). The aqueous layer was extracted with
EtOAc (15 mL), and the combined organic layers were washed
with brine, dried, and evaporated to a crude residue that was
first analyzed by proton NMR spectroscopy and later chro-
matographed on silica gel using an eluant of hexane to 1:10
hexane:dichloromethane.
(2S,4R,8S)-Di-ter t-bu tyl 5-oxo-4-ben zyl-2,8-d i-[N-(P h F )-
a m in o]a zela te ((2S,4R,8S)-6a ): [R]D20 -178.5 (c 1.07, CHCl3);
1H NMR δ 1.13 (s, 9 H), 1.15 (s, 9 H), 1.37 (m, 1 H), 1.50 (m,
2 H), 1.80 (m, 1 H), 2.27 (m, 1 H), 2.37 (m, 2 H), 2.47 (m, 2 H),
2.58 (dd, 1 H, J ) 13.6, 8.5), 2.90 (bs, 2 H), 3.11 (m, 1 H), 7.05
(m, 2 H), 7.1-7.4 (m, 25 H), 7.65 (m, 4 H); 13C NMR δ 27.8,
27.9, 28.4, 29.0, 36.6, 38.1, 39.8, 49.4, 54.3, 55.1, 72.9, 72.9,
80.6, 80.8, 175.0, 175.0, 213.2; HRMS calcd for C62H63O5N2
(MH+) 915.4737, found 915.4707.
(2S,4S,8S)-Di-ter t-bu tyl 5-oxo-4-ben zyl-2,8-d i-[N-(P h F )-
a m in o]a zela te ((2S,4S,8S)-6a ): [R]D20 -202.4 (c 0.77, CHCl3);
1H NMR δ 1.09 (s, 9 H), 1.17 (s, 9 H), 1.52 (m, 2 H), 1.76 (m,
1 H), 1.90 (m, 1 H), 2.03 (ddd, 1 H, J ) 5.3, 11.6, 16.8), 2.37
(m, 2 H), 2.51 (t, 1 H, J ) 5.0), 2.69 (m, 2 H), 2.95 (ddd, 1 H,
J ) 4.2, 11.6, 16.8), 3.1 (bs, 2 H), 7.03 (d, 2 H, J ) 7.0), 7.1-
7.5 (m, 25 H), 7.7 (m, 4 H); 13C NMR δ 27.7, 27.9, 29.0, 36.6,
38.6, 40.6, 50.1, 55.0, 55.2, 72.9, 73.7, 80.6, 80.8, 174.4, 175.2,
213.2; HRMS calcd for C62H63O5N2 (MH+) 915.4737, found
915.4716.
(2S,4R,6R,8S)-Di-ter t-bu tyl 5-oxo-4,6-d iben zyl-2,8-d i-
[N-(P h F )a m in o]a zela te ((2S,4R,6R,8S)-7a ): [R]D20 -93.9 (c
1.73, CHCl3); 1H NMR δ 1.03 (m, 2 H), 1.11 (s, 18 H), 1.15 (m,
2 H), 2.36 (m, 4 H), 2.45 (dd, 2 H, J ) 9.6, 3.1), 3.05 (bs, 2 H),
3.26 (m, 2 H), 6.95 (m, 4 H), 7.1-7.4 (m, 28 H), 7.68 (m, 4 H);
13C NMR δ 27.8, 35.2, 35.7, 48.8, 53.9, 72.8, 80.5, 175.2, 214.1;
HRMS calcd for C69H69O5N2 (MH+) 1005.5206, found 1005.5188.
(2S,4S,6R,8S)-Di-ter t-b u t yl 5-oxo-4,6-d ib en zyl-2,8-d i-
[N-(P h F )a m in o]a zela te ((2S,4S,6R,8S)-7a ): [R]D20 -125.3 (c
0.95, CHCl3); 1H NMR δ 1.05 (m, 1 H), 1.08 (s, 9 H), 1.11 (s, 9
H), 1.25 (t, 1 H, J ) 7.2), 1.33 (m, 1 H), 1.52 (m, 1 H), 1.86 (m,
1 H), 1.96 (m, 1 H), 2.19 (m, 2 H), 2.29 (m, 1 H), 2.45 (dd, 1 H,
J ) 9.5, 2.6), 2.55 (dd, 1 H, J ) 13.7, 7.2), 2.67 (dd, 1 H, J )
7.3, 4.8), 2.87 (m, 1 H), 3.18 (m, 1 H), 6.72 (m, 2H), 6.93 (m, 2
H), 7.1-7.7 (m, 32 H); 13C NMR δ 27.8, 27.8, 31.6, 35.3, 35.7,
36.1, 36.5, 48.2, 49.5, 54.2, 54.9, 72.8, 73.5, 80.4, 80.8, 174.5,
175.0, 213.5; HRMS calcd for C69H69O5N2 (MH+) 1005.5206,
found 1005.5178.

5946 J . Org. Chem., Vol. 63, No. 17, 1998
Polyak and Lubell
(2S,4R,8S)-Di-ter t-b u t yl 5-oxo-4-a llyl-2,8-d i-[N-(P h F )-
a m in o]a zela te ((2S,4R,8S)-6b): [R]D -74.0 (c 1.5, CHCl3);
analyzed by proton NMR spectroscopy. Integration of the tert-
butyl ester singlets indicated a 7:1:0.5 ratio of (4R)-6a :(4S)-
6a :(4R,6R)-7a as well as trace amounts of starting ketone 5.
The residue was then chromatographed on silica gel (30 g per
1 g of residue) using a gradient of hexane to 1:10 hexane:
dichloromethane. The collected fractions were combined into
four portions: first an impure mix of (4R,6R)-7a and (4S)-6a
(370 mg); second a 3.5:1 (4R)-6a :(4S)-6a mixture (580 mg,
27%); third a 9:1 (4R)-6a :(4S)-6a mixture (400 mg, 18%); fourth
pure (4R)-6a (950 mg, 43%).
Ep im er iza tion of (2S,4R,8S)-Di-ter t-bu tyl 5-Oxo-4-ben -
zyl-2,8-d i-[N-(P h F )a m in o]a zela te ((2S,4R,8S)-6a ). A -78
°C solution of (2S,4R,8S)-di-tert-butyl 5-oxo-4-benzyl-2,8-di-
[N-(PhF)amino]azelate ((2S,4R,8S)-6a , 20 mg, 0.022 mmol, 100
mol %) in THF (1 mL) was treated with a 0.5 M solution of
KHMDS in toluene (0.1 mL, 0.05 mmol, 227 mol %), stirred
for 30 min, and quenched with CD3OD (30 µL). After 1 h of
stirring at -78 °C, the reaction mixture was partitioned
between EtOAc (5 mL) and 1 M NaH2PO4 (5 mL). The
aqueous layer was extracted with EtOAc (5 mL), and the
combined organic layers were washed with brine, dried, and
evaporated to a residue that was analyzed by proton NMR
spectroscopy and showed a 1:1.3 ratio of the two pairs of
diastereomeric tert-butyl singlets at 1.13 and 1.15 ppm ((4R)-
6a ) and 1.09 and 1.17 ppm ((4S)-6a ).
(2S,4S,5RS,8S)-Di-ter t-bu tyl 4-Ben zyl-5-h yd r oxy-2,8-d i-
[N-(P h F )a m in o]a zela te ((2S,4S,5RS,8S)-9). A solution of
(4S)-6a (300 mg, 0.33 mmol) in EtOH (15 mL) was treated
with NaBH4 (40 mg, 1 mmol, 300 mol %), stirred for 4 h at
room temperature, and diluted with water (5 mL). The volume
was reduced using a rotary evaporator, and the remaining
volume was extracted with EtOAc (2 × 15 mL). The combined
organic phases were washed with brine, dried, and evaporated
to a residue which was shown by proton NMR analysis to
contain a 1:1 mixture of (5R)- and (5S)-alcohols 9 that were
used in the subsequent reactions as a mixture without further
purification: 1H NMR δ 1.07 (s, 9 H), 1.12 (s, 9 H), 1.18 (s, 9
H), 1.22 (s, 9 H), 1.32-1.95 (m, 16 H), 2.19 (dd, 1 H), 2.30 (dd,
1 H), 2.52-2.80 (m, 6 H), 3.22-3.30 (m, 1 H), 3.38-3.47 (m, 1
H), 7.08-7.75 (m, 62 H).
(2S,4R,5S,8S)- a n d (2S,4R,5R,8S)-Di-ter t-bu tyl 4-ben -
zyl-5-hydroxy-2,8-di-[N-(P hF)amino]azelates ((2S,4R,5S,8S)-
a n d (2S,4R,5R,8S)-9) were prepared using the protocol as
described for the reduction of ketone (4S)-6a . Analysis of the
crude residue by proton NMR spectroscopy showed a 2:1 ratio
of 5R:5S diastereomeric alcohols 9 which were separated by
chromatography on silica gel using a gradient of pure CH2Cl2
to 94:6 CH2Cl2:EtOAc. The first compound to elute was
(4R,5S)-9 (100 mg, 35%): [R]D20 -113.5 (c 0.4, CHCl3); 1H NMR
δ 1.09 (s, 9 H), 1.22 (s, 9 H), 1.26-1.80 (m, 7 H), 1.94 (bs, 1
H), 2.22-2.28 (m, 1 H), 2.34-2.36 (m, 2 H), 2.62-2.72 (m, 1
H), 3.39-3.40 (m, 1 H), 6.85 (d, 2 H, J ) 6.9), 7.08-7.53 (m,
25 H), 7.66-7.71 (m, 4 H); 13C NMR δ 27.7, 27.9, 29.3, 32.5,
34.4, 36.8, 42.5, 55.8, 56.4, 72.0, 73.0, 73.1, 80.4, 80.6, 175.1,
175.3; HRMS calcd for C62H65N2O5 (MH+) 917.4893, found
917.4869.
20
1H NMR δ 1.14 (s, 9 H), 1.19 (s, 9 H), 1.35 (m, 1 H), 1.65 (m,
3 H), 1.75 (m, 2 H), 2.35 (m, 1 H), 2.48 (m, 2 H), 2.65 (m, 1 H),
2.87 (m, 1 H), 4.86 (m, 2 H), 5.49 (m, 1 H), 6.0 (bs, 1 H), 6.7
(bs, 1 H), 7.2-7.4 (m, 22 H), 7.67 (d, 4 H, J ) 7.4); 13C NMR
δ 27.8, 27.8, 29.1, 35.1, 36.0, 38.6, 47.4, 54.1, 55.3, 72.9, 73.0,
80.7, 175.0, 175.3, 212.8; HRMS calcd for C58H61O5N2 (MH+)
865.4581, found 865.4609. (2S,4S,8S)-Di-tert-butyl 5-oxo-4-
allyl-2,8-di-[N-(PhF)amino]azelate ((2S,4S,8S)-6b) was isolated
as a 3:1 mixture with the bis-alkylated product 7b.
(2S,4R,8S)-Di-ter t-b u t yl 5-oxo-4-m et h yloxyca r bon yl-
m eth yl-2,8-d i-[N-(P h F )a m in o]a zela te ((2S,4R,8S)-6c) was
isolated and characterized as a 4:1 mixture with (2S,4S,8S)-
6c. Spectral data for the major product (2S,4R,8S)-6c are as
follows: 1H NMR δ 1.20 (s, 9 H), 1.26 (s, 9 H), 1.51-1.61 (m,
2 H), 1.62-1.70 (m, 1 H), 1.72-1.88 (m, 1 H), 2.36 (dd, 2 H, J
) 10.8, 17.1), 2.52-2.64 (m, 2 H), 2.84-2.94 (m, 1 H), 3.20 (d,
1 H, J ) 7.9), 3.26 (d, 1 H, J ) 9.8), 3.40 (t, 1 H, J ) 9.9), 3.67
(s, 3 H), 7.11-7.53 (m, 22 H), 7.72 (m, 4 H); 13C NMR δ 27.7,
27.9, 29.2, 33.6, 36.3, 38.2, 43.3, 51.4, 53.6, 55.4, 72.8, 73.0,
80.7, 81.1, 172.3, 175.0, 175.1, 212.4; HRMS calcd for
C
58H61O7N2 (MH+) 897.4479, found 897.4504.
(2S,4R,8S)-Di-ter t-bu tyl 5-oxo-4-m eth yl-2,8-d i-[N-(P h -
F )a m in o]a zela te ((2S,4R,8S)-6d ) was isolated as a 9:1
mixture with (2S,4R,6R,8S)-7d . Spectral data for the major
product (2S,4R,8S)-6d are as follows: 1H NMR δ 0.61 (d, 3 H,
J ) 6.9), 1.17 (s, 9 H), 1.21 (s, 9 H), 1.64-1.76 (m, 3 H), 2.39-
2.42 (m, 2 H), 2.44 (dd, 1 H, J ) 3.2, 10.4), 2.51 (dd, 1 H, J )
4.9, 7.5), 2.64-2.73 (m, 1 H), 2.82-2.88 (m, 1 H), 7.18-7.70
(m, 26 H); 13C NMR δ 15.6, 27.8, 27.9, 29.5, 37.2, 38.1, 42.6,
54.0, 55.4, 72.8, 73.1, 77.2, 80.6, 80.7, 175.1, 175.5, 213.9.
(2S,4S,6R,8S)-Di-ter t-bu tyl 5-oxo-4,6-d im eth yl-2,8-d i-
20
[N-(P h F )a m in o]a zela te ((2S,4S,6R,8S)-7d ): [R]D -160.7
1
(c 0.3, CHCl3); H NMR δ 0.42 (d, 3 H, J ) 6.9), 0.95 (d, 3 H,
J ) 6.9), 1.17 (s, 9 H), 1.25 (s, 9 H), 1.46 (m, 2 H), 1.78 (dt, 2
H, J ) 13.3, 1.2), 1.94 (m, 1 H), 2.36 (dd, 1 H, J ) 11.4, 2.4),
2.61 (dd, 1 H, J ) 7.0, 4.6), 2.66 (q, 1 H, J ) 6.8), 3.11 (bs, 2
H), 7.1-7.5 (m. 22 H), 7.75 (m, 4 H); 13C NMR δ 14.1, 14.8,
27.9, 28.0, 29.7, 37.7, 39.3, 40.9, 53.5, 55.0, 72.8, 73.5, 77.2,
80.6, 80.8, 174.8, 175.7, 216.8; HRMS calcd for C57H61O5N2
(MH+) 853.4581, found 853.4548.
(2S,4S,8S)-Di-ter t-bu tyl 5-oxo-4-eth yl-2,8-d i-[N-(P h F )-
a m in o]a zela te ((2S,4S,8S)-6e): [R]D20 -111.7 (c 1.2, CHCl3);
1H NMR δ 0.75 (t, 3 H, J ) 7.4), 1.18 (s, 9 H), 1.22 (s, 9 H),
1.27 (m, 1 H), 1.42 (m, 2 H), 1.68 (m, 2 H), 1.88 (m, 1 H), 2.22
(ddd, 1 H, J ) 4.6, 11.3, 18.0), 2.39 (m, 1 H), 2.43 (dd, 1 H, J
) 4.3, 8.5), 2.50 (t, 1 H, J ) 5.5), 2.80 (ddd, 1 H, J ) 4.8, 11.7,
18.0), 3.20 (bs, 2 H), 7.1-7.4 (m, 22 H), 7.65 (m, 4 H); 13C NMR
δ 11.6, 25.3, 27.9, 29.1, 36.5, 39.5, 49.5, 55.1, 55.4, 72.9, 73.4,
76.7, 80.7, 80.8, 174.8, 175.2, 213.3; HRMS calcd for C57H61O5N2
(MH+) 853.4581, found 853.4565.
(2S,4R,8S)-Di-ter t-bu tyl 5-oxo-4-eth yl-2,8-d i-[N-(P h F )-
20
a m in o]a zela te ((2S,4R,8S)-6e): [R]D -97.5 (c 1.4, CHCl3);
1H NMR δ 0.66 (t, 3 H, J ) 7.3), 1.01 (m, 1 H), 1.15 (s, 9 H),
1.20 (s, 9 H), 1.31 (m, 2 H), 1.66 (m, 3 H), 2.40 (m, 1 H), 2.42
(dd, 1 H, J ) 4.2, 10.2), 2.49 (dd, 1 H, J ) 4.7, 7.5), 2.62 (m,
1 H), 2.72 (m, 1 H), 3.22 (bs, 2 H), 7.1-7.4 (m, 22 H), 7.67 (m,
4 H); 13C NMR δ 11.2, 23.7, 27.8, 27.9, 29.3, 36.3, 38.5, 49.3,
54.2, 55.3, 72.9, 73.0, 80.7, 80.7, 175.1, 175.4, 213.6; HRMS
calcd for C57H61O5N2 (MH+) 853.4581, found 853.4556.
The next compound to elute was (4R,5R)-9 (180 mg, 61%):
20
1
[R]D -133.6 (c 1.4, CHCl3); H NMR δ 1.03 (s, 9 H), 1.23 (s,
9 H), 1.34-1.40 (m, 2 H), 1.50-1.72 (m, 6 H), 2.04-2.06 (m, 1
H), 2.11 (dd, 1 H, J ) 14.5, 9.5), 2.60 (bs, 1 H), 2.66 (dd, 1 H,
J ) 13.2, 6.2), 3.35-3.38 (m, 1 H), 6.74 (d, 2 H, J ) 7.0), 7.05-
7.47 (m, 25 H), 7.65-7.73 (m, 4 H); 13C NMR δ 27.7, 27.9, 30.7,
31.4, 36.3, 37.5, 42.6, 55.9, 56.9, 72.9, 73.1, 73.5, 77.2, 80.3,
80.7, 175.1, 175.2; HRMS calcd for C62H65N2O5 (MH+) 917.4893,
found 917.4915.
(2S,4R,8S)- a n d (2S,4S,8S)-Di-ter t-bu tyl 5-Oxo-4-ben -
zyl-2,8-d i-[N-(P h F )a m in o]a zela te ((2S,4R,8S)- a n d (2S,4S,
8S)-6a ). A solution of 5 (2.0 g, 2.4 mmol) in 7 mL of THF was
cooled to -78 °C and treated with a 0.5 M solution of KHMDS
in toluene (7.8 mL, 3.9 mmol, 160 mol %) dropwise over 30
min. The reaction mixture was stirred for 30 min at -78 °C,
and benzyl bromide (1.71 mL, 14.4 mmol, 600 mol %) was
added dropwise over 30 min. The reaction mixture was stirred
for 1 h at -78 °C and allowed to warm to -10 °C over 45 min.
The reaction mixture was stirred an additional 1 h at -10 °C
and partitioned between EtOAc (15 mL) and 1 M NaH2PO4
(15 mL), and the separated aqueous layer was extracted with
EtOAc (2 × 30 mL). The combined organic layers were washed
with brine, dried, and evaporated to a residue that was
(2S,4R,5R,8S)- a n d (2S,4R,5S,8S)-Di-ter t-bu tyl 5-Hy-
droxy-4-benzyl-2,8-di-[N-(P hF)amino]azelate ((2S,4R,5R,8S)-
a n d (2S,4R,5S,8S)-9) by Na CNBH 3 Red u ction of 6a .
A
solution of ketone (4R)-6a (300 mg, 0.33 mmol) in ethanol (10
mL) was cooled to -78 °C and treated with NaCNBH3 (16.5
mg, 0.263 mmol, 300 mol %) in one portion, followed by several
drops of acetic acid. The reaction mixture was stirred for 6 h
at -78 °C, allowed to warm to room temperature over 45 min,
diluted with water (5 mL), concentrated under vacuum, and
extracted with EtOAc (2 × 15 mL). The combined organic

Rigid Dipeptide Mimics
J . Org. Chem., Vol. 63, No. 17, 1998 5947
layers were washed with brine, dried, and evaporated to a
residue which was analyzed to be a 1:5 mixture of (5R)- and
(5S)-9 by integration of the tert-butyl ester singlets in the NMR
spectrum. The residue was chromatographed on silica gel (30
g per 1 g of residue) using a gradient of CH2Cl2 to 94:6 CH2Cl2:
EtOAc. The collected fractions were combined into three
portions: first (5R)-9 (8 mg, 10%); second a 1:7 (5R)-9:(5S)-9
mixture (22 mg, 28%); third (5S)-9 (45 mg, 56%).
139.4, 155.6, 169.4, 172.1; HRMS calcd for C22H30N2O5 (MH+)
403.2233, found 403.2212
(3S,6R,7S,9S)-Meth yl 2-Oxo-3-N-(BOC)a m in o-7-ben zyl-
1-a za bicyclo[4.3.0]n on a n e-9-ca r boxyla te ((3S,6R,7S,9S)-
10) was obtained from 400 mg of a 1:1 mixture of (4S,5S)- and
20
(4S,5R)-9 in 19% (37%) overall yield: mp 177-179 °C; [R]D
-86.7 (c 0.86, CHCl3); 13C NMR δ 23.2, 28.3, 28.7, 31.8, 33.8,
42.2, 52.1, 52.3, 56.3, 63.0, 79.6, 126.5, 128.7, 128.9, 139.0,
168.5, 172.7; HRMS calcd for C22H30N2O5 (MH+) 403.2233,
found 403.2216.
(2S,4R,6R,8S)-Di-ter t-bu tyl 4,6-Diben zyl-5-h yd r oxy-2,8-
d i-[N-(P h F )a m in o]a zela te ((2S,4R,6R,8S)-12) was synthe-
sized from dibenzyl ketone 7a using the procedure described
for the sodium borohydride reduction of ketone (4S)-6a and
stirring the mixture overnight before dilution with water. The
crude alcohol 12 (280 mg, 95%) was used in subsequent
reactions without further purification. A crystalline sample
(3S,5R,6R,9S)-Meth yl 2-oxo-3-N-(BOC)a m in o-5-ben zyl-
1-a za bicyclo[4.3.0]n on a n e-9-ca r boxyla te ((3S,5R,6R,9S)-
11) was obtained from 190 mg of (4R,5S)-9 in 59% overall
yield: [R]D 17.7 (c 1.63, CHCl3); 13C NMR δ 28.3, 28.9, 31.6,
20
34.2, 40.0, 40.7, 49.4, 52.3, 58.0, 61.8, 79.5, 126.4, 128.5, 129.0,
138.9, 155.7, 169.3, 172.2; HRMS calcd for C22H30N2O5 (MH+)
403.2233, found 403.2216.
20
of 12 was obtained from EtOH: mp 118-119 °C; [R]D -62.5
1
(c 0.4, CHCl3); H NMR δ 1.03 (s, 9 H), 1.08 (s, 9 H), 1.30-
(3S,5R,6S,7R,9S)-Met h yl 2-oxo-3-N-(BOC)a m in o-5,7-
dibenzyl-1-azabicyclo[4.3.0]nonane-9-carboxylate ((3S,5R,6S,
7R,9S)-14) was obtained from 280 mg of alcohol 12 in 26%
overall yield: [R]D20 37.3 (c 0.64, CHCl3); 13C NMR δ 28.3, 30.8,
32.7, 33.1, 33.8, 40.1, 41.4, 49.7, 52.3, 56.6, 65.2, 79.7, 126.3,
126.7, 128.5, 128.6, 128.7, 128.8, 128.9, 129.2, 138.6, 139.4,
1.38 (m, 1 H), 1.42-1.54 (m, 2 H), 1.78 (bs, 1 H), 1.82-1.98
(m, 2 H), 2.02-2.16 (m, 2 H), 2.38 (s, 2 H), 2.63 (dd, 1 H, J )
5.3, 3.5), 2.74-2.77 (m, 2 H), 3.26 (dd, 1 H, J ) 7.5, 0.5), 6.62-
6.64 (m, 2 H), 6.98-7.40 (m, 30 H), 7.53-7.73 (m, 4 H); 13C
NMR δ 27.7, 27.8, 34.3, 36.2, 37.4, 37.2, 38.6, 40.5, 55.2, 56.4,
72.9, 73.0, 77.2, 80.1, 80.2, 175.3, 175.5; HRMS calcd for
C
29H36N2O5 (MH+)
C
69H71N2O5 (MH+) 1007.5363, found 1007.5389.
155.6, 169.7, 172.0; HRMS calcd for
493.2702, found 493.2698.
Gen er a l P r oced u r e for th e Syn th esis of 5- a n d 7-Ben -
Gen er a l P r oced u r e for th e Syn th esis of 7-Ben zyl a n d
5,7-Diben zylin d olizid in on e Am in o Ester s 10 a n d 14 via
Red u ctive Am in a tion . Hydrogenation was performed by
stirring a solution of azelate 6a or 7a (0.5 mmol, 100 mol %)
in anhydrous EtOH (30 mL) and AcOH (3 mL) with palladium-
on-carbon (10 wt %) under hydrogen atmosphere for 24 h. The
mixture was filtered onto Celite and washed with EtOH (30
mL). The combined organic solution was evaporated to
dryness and the residue was triturated with hexane (3 × 10
mL). The remaining solid was used without additional
purification.
zyl a n d 5,7-Diben zylin d olizid in on e Am in o Ester s 10, 11,
a n d 14 via Meth a n esu lfon a te Disp la cem en t. Methane-
sulfonylation and SN2 displacement were performed by treat-
ing a magnetically stirred, 0 °C solution of alcohol 9 or 12 (0.2-
0.3 mmol, 100 mol %) in CH2Cl2 (5 mL) with methanesulfonyl
chloride (200 mol %), DMAP (10 mol %), and Et3N (300 mol
%). The solution was stirred for 1 h, at 0 °C, the ice bath was
removed, and the mixture was stirred an additional 1 h at
room temperature and heated at a reflux for 24 h (in the cases
of alcohols (4R,5S)-9 and (4R,6R)-12, the reaction was carried
out in boiling toluene instead of CH2Cl2). The solution was
allowed to cool to room temperature and partitioned between
EtOAc (15 mL) and water (5 mL). The organic layer was
washed with 2 N HCl (3 mL), 5% NaHCO3 (3 mL), and water
(3 mL), dried, and evaporated. The crude reaction product was
used without further purification.
The tert-butyl esters and PhF groups were solvolyzed by
dissolving the crude reaction product in a 10% solution of TFA
in CH2Cl2 (15 mL) and stirring the solution at room temper-
ature for 48 h. Evaporation gave a residue which was
triturated with hexane (3 × 10 mL) to furnish a solid that was
used without further purification.
Esterification was performed on treatment of the crude
reaction product in MeOH at -5 °C with SOCl2 (300 mol %).
The reaction mixture was stirred at -5 °C for 1 h, then at
room temperature for 1 h, and at 50 °C for 2 h. Evaporation
of the volatiles gave a crude residue which was subsequently
used without further purification.
The tert-butyl esters were solvolyzed by dissolving the crude
product in a 10% solution of TFA in CH2Cl2 (50 mL) and
stirring overnight. Evaporation of the volatiles gave a residue
which was used without further purification.
Esterification, lactam cyclization and nitrogen protection
commenced by treatment of the residue in MeOH (20 mL) at
-5 °C with SOCl2 (300 mol %). The solution was stirred at
-5 °C for 1 h, at room temperature for 1 h, and at 50 °C for 2
h and then evaporated. The solid was dissolved in CH2Cl2 (15
mL), treated with Et3N (500 mol %), stirred at room temper-
ature for 24 h, treated with di-tert-butyl dicarbonate (500 mol
%), and stirred at room temperature for 2 h. The reaction
mixture was diluted with CH2Cl2 (15 mL), washed with a 1 M
solution of NaH2PO4 (5 mL) and brine (5 mL), dried, and
evaporated. The residue was chromatographed with 3:2
hexanes: EtOAc as eluant. Yields of (3S,6S,7S,9S)- and
(3S,6S,7R,9S)-methyl
2-oxo-3-N-(BOC)amino-7-benzyl-1-
azabicyclo[4.3.0]nonane-9-carboxylate ((3S,6S,7S,9S)- and
(3S,6S,7R,9S)-10) obtained from hydrogenation of (4R)- and
(4S)-6a at 1 and 9 atm of hydrogen are reported in Table 3.
(3S,5R,6S,7R,9S)-Methyl 2-oxo-3-N-(BOC)amino-5,7-dibenzyl-
1-azabicyclo[4.3.0]nonane-9-carboxylate ((3S,5R,6S,7R,9S)-14)
was obtained in 20% overall yield from 280 mg of ketone 7a .
Gen er a l P r oced u r e for th e Hyd r olysis of Meth yl
Ester s 10, 11, a n d 14 w ith LiOH. A 0.012 M solution of
indolizidinone amino ester 10, 11, or 14 (100 mol %) in dioxane
(2 mL) was treated with 2 M LiOH (200 mol %), stirred at
room temperature for 4 h, and partitioned between EtOAc (5
mL) and 1 M NaH2PO4 (5 mL). The aqueous layer was
extracted with EtOAc (5 mL), and the combined organic layers
were washed with brine, dried, and evaporated. The crude
reaction mixtures were analyzed by proton NMR spectroscopy.
Chromatography with 20:1 EtOAc:AcOH as eluant and evapo-
ration of the collected fractions gave the pure indolizidinone
amino acid.
Lactam cyclization and amine protection involved the treat-
ment of the reaction product in CH2Cl2 (15 mL) with Et3N (500
mol %) for 24 h at room temperature, followed by addition of
(BOC)2O (500 mol %) and additional stirring at room temper-
ature for 2h. The mixture was diluted with CH2Cl2 (15 mL),
washed with a 1 M solution of NaH2PO4 (5 mL) and brine (5
mL), dried, and evaporated. The residue was chromato-
graphed using 40:60 hexanes:EtOAc as eluant. Evaporation
of the collected fraction gave the indolizidinone amino ester.
(3S,6S,7S,9S)-Meth yl 2-oxo-3-N-(BOC)a m in o-7-ben zyl-
1-a za bicyclo[4.3.0]n on a n e-9-ca r boxyla te ((3S,6S,7S,9S)-
10) was obtained in 23% (55%) overall yield from 400 mg of a
20
1:1 mixture of (4S,5S)- and (4S,5R)-9: [R]D -3.6 (c 1.69,
CHCl3); 13C NMR δ 25.9, 27.9, 28.3, 35.0, 38.2, 47.0, 50.0, 52.3,
57.4, 60.9, 79.4, 128.6, 128.7, 138.7, 155.6, 169.1, 172.0; HRMS
calcd for C22H30N2O5 (MH+) 403.2233, found 403.2216.
(3S,6S,7R,9S)-Meth yl 2-oxo-3-N-(BOC)a m in o-7-ben zyl-
1-a za bicyclo[4.3.0]n on a n e-9-ca r boxyla te ((3S,6S,7R,9S)-
10) was obtained from 180 mg of (4R,5R)-9 in 48% overall
yield: [R]D 20 27.4 (c 0.95, CHCl3); 13C NMR δ 21.4, 26.4, 28.3,
32.8, 34.2, 42.4, 50.2, 52.4, 58.0, 58.7, 79.6, 126.4, 128.6, 128.7,
(3S ,6S ,7S ,9S )-2-O x o -3-N -(B O C )a m in o -7-b e n zy l-1-
a za bicyclo[4.3.0]n on a n e-9-ca r boxylic a cid ((3S,6S,7S,9S)-
20
1
2): 88% yield; [R]D -5.9 (c 2.0, CHCl3); H NMR δ 1.44 (s, 9
H), 1.48-1.49 (m, 1 H), 1.71-1.72 (m, 1 H), 1.86-1.92 (m, 1

5948 J . Org. Chem., Vol. 63, No. 17, 1998
Polyak and Lubell
H), 2.27-2.40 (m, 3 H), 2.73 (d, 2 H, J ) 6.3), 3.30-3.42 (m,
1 H), 4.14-4.26 (m, 1 H), 4.53 (d, 1 H, J ) 8.9), 5.48 (d, 1 H,
J ) 5.5), 7.13 (d, 2 H, J ) 7.0), 7.21-7.32 (m, 3 H); 13C NMR
δ 25.7, 26.9, 28.3, 34.1, 38.0, 46.9, 50.0, 58.3, 61.4, 79.9, 126.7,
128.7, 128.8, 131.9, 138.4, 155.7, 171.3, 172.8; HRMS calcd
for C21H28N2O5 (MH+) 389.2076, found 389.2062.
brine, dried, and evaporated to an oil (28 mg, 93% of a 1:3
ratio of (3S,6S,7S,9S)-10:(3S,6S,7S,9R)-10 as determined by
1H NMR) that was chromatographed using a gradient of
hexane to 1:1 hexane:EtOAc as eluant. Evaporation of the
collected fractions gave (3S,6S,7S,9S)-10 followed by (3S,6S,7
S,9R)-Methyl 2-oxo-3-N-(BOC)amino-7-benzyl-1-azabicyclo-
20
(3S,6R,7S,9S)-2-Oxo-3-N-(BOC)a m in o-7-b en zyl-1-a za -
bicyclo[4.3.0]n on a n e-9-ca r boxylic a cid ((3S,6R,7S,9S)-2):
[4.3.0]nonane-9-carboxylate ((3S,6S,7S,9R)-10: [R]D 33.2 (c
1.0, CHCl3); 13C NMR δ 25.2, 26.9, 28.3, 34.7, 38.1, 48.4, 50.3,
52.4, 57.8, 61.4, 79.6, 126.6, 128.7, 128.8, 138.8, 155.7, 168.9,
172.1; HRMS calcd for C28H35N2O5 (MH+) 479.2546, found
479.2558.
20
1
83% yield; [R]D -33.9 (c 0.38, CHCl3); H NMR δ 1.46 (s, 9
H), 1.78-1.87 (m, 2 H), 2.00-2.16 (m, 3 H), 2.39 (dd, 1 H, J )
8.3, 6.9), 2.52-2.68 (m, 1 H), 2.82 (dd, 1 H, J ) 13.3, 5.5), 3.42-
3.50 (m, 1 H), 4.12-4.33 (m, 1 H), 4.56 (d, 1 H, J ) 8.5), 5.37
(bs, 1 H), 7.15-7.33 (m, 5 H); 13C NMR δ 23.3, 25.8, 28.3, 29.7,
30.4, 33.9, 41.4, 57.7, 63.2, 77.2, 126.6, 128.7, 128.8, 138.6,
En a n tiom er ic P u r ity of (3S,6S,7S,9S)-Meth yl 2-Oxo-
3-N-(BOC)a m in o-7-b en zyl-1-a za b icyclo[4.3.0]n on a n e-9-
ca r boxyla te ((3S,6S,7S,9S)-10). A solution of (3S,6S,7S,9S)-
10 (10 mg, 0.025 mmol) in CH2Cl2 (1 mL) was treated with
TFA (0.5 mL) and stirred for 4 h at room temperature. The
volatiles were removed under vacuum. The residue was
dissolved in THF (1 mL), treated with either (R)- or (S)-R-
methylbenzyl isocyanate (7.3 mg, 0.05 mmol, 200 mol %) and
Et3N (7 µL, 0.05 mmol, 200 mol %), and heated at a reflux for
3 h. After cooling, the volatiles were removed under vacuum
and the residue was directly examined by NMR. The limits
of detection were determined by measuring the diastereomeric
methyl ester singlets at 3.67 and 3.70 ppm in CDCl3 and 3.28
and 3.38 in C6D6 in the 400 MHz 1H NMR spectra. Less than
1% of the other diastereomer was detected in the spectra for
ureas (1′S)- and (1′R)-15. Purification by chromatography
using a gradient of pure hexane to pure EtOAc as eluant gave
15 having the following spectra.
Ur ea (1′R)-15: 1H NMR δ 1.46 (d, 3 H, J ) 6.8), 1.50-1.60
(m, 2 H), 1.82-1.93 (m, 1 H), 1.94 (dd, 1 H, J ) 12.5, 9.2),
2.05 (dd, 1 H, J ) 12.8, 6.1), 2.24-2.37 (m, 2 H), 2.65 (dd, 1
H, J ) 13.7, 8.1), 2.76 (dd, 1 H, J ) 13.4, 6.3), 3.32-3.38 (m,
1 H), 3.70 (s, 3 H), 4.20 (dd, 1 H, J ) 5.4, 2.5), 4.41 (d, 1 H, J
) 9.0), 4.83 (q, 1 H, J ) 6.9), 5.11 (d, 1 H, J ) 7.1), 5.51 (d, 1
H, J ) 5.5), 7.12 (d, 2 H, J ) 7.1), 7.20-7.34 (m, 8 H); 1H
NMR δ (C6D6) 1.18-1.21 (m, 1 H), 1.23 (d, 3 H, J ) 6.8), 1.27-
1.51 (m, 2 H), 1.71 (dd, 1 H, J ) 13.2, 6.3), 1 97-2.06 (m, 1
H), 2.12-2.20 (m, 1 H), 2.25 (dd, 1 H, J ) 13.5, 7.9), 2.37 (dd,
1 H, J ) 13.7, 6.4), 2.87-2.93 (m, 1 H), 3.38 (s, 3 H), 4.02-
4.12 (m, 1 H), 4.17 (d, 1 H, J ) 9.2), 4.76-4.78 (m, 1 H), 4.98
(bs, 1 H), 5.50 (d, 1 H, J ) 0.8), 6.61 (d, 1 H, J ) 3.4), 6.86 (d,
2 H, J ) 6.9), 6.98-7.36 (m, 8H).
Ur ea (1′S)-15: 1H NMR δ 1.45 (d, 3 H, J ) 6.8), 1.53-1.63
(m, 2 H), 1.74-1.78 (m, 1 H), 1.94 (dd, 1 H, J ) 12.8, 8.8),
2.05 (dd, 1 H, J ) 10.8, 6.0), 2.25-2.36 (m, 2 H), 2.65 (dd, 1
H, J ) 13.8, 7.8), 2.76 (dd, 1 H, J ) 13.7, 6.5), 3.34-3.39 (m,
1 H), 3.67 (s, 3 H), 4.25 (dd, 1 H, J ) 5.5, 2.3), 4.42 (d, 1 H, J
) 9.0), 4.83 (q, 1 H, J ) 7.0), 5.10 (d, 1 H, J ) 7.2), 5.51 (d, 1
H, J ) 5.3), 7.12 (d, 2 H, J ) 7.0), 7.21-7.33 (m, 8 H); 1H
NMR δ (C6D6): 1.29 (d, 3 H, J ) 6.9), 1.30-1.55 (m, 3 H),
1.65 (dd, 1 H, J ) 12.9, 6.1), 1.93-2.05 (m, 1 H), 2.12-2.24
(m, 2 H), 2.31 (dd, 1 H, J ) 13.4, 7.5), 2.78-2.83 (m, 1 H),
3.28 (s, 3 H), 4.19 (d, 1 H, J ) 9.2), 4.27 (dd, 1 H, J ) 15.9,
6.6), 4.91 (q, 1 H, J ) 7.3), 5.20 (bs, 1 H), 5.71 (d, 1 H, J )
3.2), 6.40 (d, 1 H, J ) 1.4), 6.84 (d, 2 H, J ) 6.9), 6.99-7.24
(m, 8 H).
156.0, 170.8, 173.4; HRMS calcd for
389.2076, found 389.2088.
C
21H29N2O5 (MH+)
(3S,5R,6R,9S)-2-Oxo-3-N-(BOC)a m in o-5-b en zyl-1-a za -
bicyclo[4.3.0]n on a n e-9-ca r boxylic a cid ((3S,5R,6R,9S)-3):
20
1
73% yield; [R]D 18.0 (c 0.7, CHCl3); H NMR δ 1.45 (s, 9 H),
1.47-1.71 (m, 2 H), 1.96-2.06 (m, 2 H), 2.11-2.18 (m, 2 H),
2.39 (dd, 1 H, J ) 8.3, 6.9), 2.52-2.68 (m, 1 H), 2.82 (dd, 1 H,
J ) 13.3, 5.5), 3.42-3.50 (m, 1 H), 4.12-4.33 (m, 1 H), 4.56
(d, 1 H, J ) 8.5), 5.37 (bs, 1 H), 7.15-7.33 (m, 5 H); 13C NMR
δ 27.6, 28.3, 29.7, 31.7, 34.1, 39.8, 40.7, 49.4, 59.2, 62.6, 80.1,
126.6, 128.6, 129.0, 138.5, 155.6, 171.6; HRMS calcd for
C
21H29N2O5 (MH+) 389.2076, found 389.2068.
(3S,5R,6S,7R,9S)-2-Oxo-3-N-(BOC)a m in o-5,7-d iben zyl-
1-a za bicyclo[4.3.0]n on a n e-9-ca r boxylic Acid ((3S,5R,6S,
7R,9S)-4). Methyl ester 14 (10 mg, 0.02 mmol) in 5 mL of
Et2O was treated with KOSiMe3 (2.9 mg, 0.022 mmol), stirred
for 10 h at room temperature, treated with another portion
(2.9 mg) of KOSiMe3, and stirred overnight. The reaction
solution was concentrated under reduced pressure. Water (10
mL) was added, and the pH was adjusted to pH ≈ 2 using
citric acid. After 10 min of stirring, the solution was saturated
with NaCl and extracted with EtOAc (2 × 10 mL). The organic
solutions were combined and purified by filtration through
silica gel using 20:1 EtOAc:AcOH as eluant. Evaporation of
20
the collected fractions gave 8 mg (83%) of acid 4: [R]D 52.1
1
(c 1.0, CHCl3); H NMR δ 1.45 (s, 9 H), 1.72 (q, 1 H, J ) 8.3),
1.92-2.14 (m, 3 H), 2.19-2.60 (m, 3 H), 2.65-2.93 (m, 3 H),
3.72 (dd, 1 H, J ) 13.3, 5.5), 4.08-4.19 (m, 1 H), 4.52 (t, 1 H,
J ) 8.5), 5.37 (bs, 1 H), 6.90 (bs, 1 H), 7.15-7.33 (m, 10 H);
13C NMR δ 28.3, 29.7, 30.2, 33.2, 33.7, 35.4, 40.4, 57.3, 68.2,
74.6, 126.6, 126.9, 128.7, 128.8, 128.9, 129.2, 138.1, 138.4,
156.2, 172.8; HRMS calcd for C28H35N2O5 (MH+) 479.2546,
found 479.2558.
(3S,6S,7R,9S)-2-Oxo-3-N-(BOC)a m in o-7-b en zyl-1-a za -
bicyclo[4.3.0]n on a n e-9-ca r boxylic a cid ((3S,6S,7R,9S)-2)
was formed as a 60:40 mixture with (3S,6S,7R,9R)-2 using the
LiOH conditions for hydrolysis. Pure (3S,6S,7R,9S)-2 was
isolated from treatment of 0.01 mmol of (3S,6S,7R,9S)-10 with
one portion of KOSiMe3 (0.02 mmol, 200 mol %) in ether under
the conditions described above for acid 4. Extraction with
Et2O, drying, evaporation, and filtration through silica gel
using 20:1 EtOAc:AcOH as eluant gave 30 mg (77%) of acid
20
(3S,6S,7R,9S)-2: mp 179-181 °C; [R]D 98.0 (c 2.1, CHCl3);
1H NMR δ 1.44 (s, 9 H), 1.78-1.96 (m, 2 H), 1.99-2.11 (m, 3
H), 2.16 (dd, 1 H, J ) 1.6, 13.7), 2.36-2.46 (m, 1 H), 2.53-
2.59 (m, 1 H), 2.85 (dd, 1 H, J ) 4.7, 13.5), 4.00 (dd, 1 H, J )
5.0, 11.1), 4.12-4.31 (m, 1 H), 4.53 (t, 1 H, J ) 9.0), 5.60 (bs,
1 H), 7.14 (dd, 2 H, J ) 6.8, 8.4), 7.17-7.34 (m, 3 H), 7.70 (bs,
1 H); 13C NMR δ 20.6, 23.3, 28.3, 31.1, 33.8, 41.9, 51.8, 57.2,
63.1, 80.8, 126.5, 128.7, 128.9, 138.8, 156.4, 173.9, 176.3;
HRMS calcd for C21H29N2O5 (MH+) 389.2076, found 389.2088.
(3S,6S,7S,9R)-Meth yl 2-Oxo-3-N-(BOC)a m in o-7-ben zyl-
1-a za bicyclo[4.3.0]n on a n e-9-ca r boxyla te ((3S,6S,7S,9R)-
10) Via Ep im er iza tion of (3S,6S,7S,9S)-10. A solution of
KN(SiMe3)2 (0.3 mL, 0.15 mmol, 200 mol %, 1 M in toluene)
was added over 15 min to a -50 °C solution of (3S,6S,7S,9S)-
10 (30 mg, 0.07 mmol, 100 mol %) in THF (1 mL). The reaction
mixture was stirred for 1 h at -50 °C followed by 1 h at -20
°C and then partitioned between EtOAc (5 mL) and 1 M NaH2-
PO4 (5 mL). The aqueous phase was extracted with EtOAc (2
× 5 mL). The organic layers were combined, washed with
En a n tiom er ic p u r ity of (3S,5R,6S,7R,9S)-Meth yl 2-oxo-
3-N-(BOC)a m in o-5,7-d iben zyl-1-a za bicyclo[4.3.0]n on a n e-
9-ca r boxyla te ((3S,5R,6S,7R,9S)-14) was determined on 3
mg samples of 14 in a similar manner as described for 10
above. The limits of detection were determined on the crude
residue by measuring the diastereomeric methyl ester singlets
at 3.71 and 3.79 ppm in CDCl3 as well as 3.36 and 3.42 ppm
1
in C6D6 in the 400 MHz H NMR. Less then 1% of the other
diastereomer was detected in the spectra for ureas (1′S)- and
(1′R)-16. Purification by chromatography using a gradient of
pure hexane to pure EtOAc as eluant gave 16 having the
following spectra.
Ur ea (1′R)-16: 1H NMR δ 1.46 (d, 3 H, J ) 6.9), 1.61 (m, 2
H), 1.77 (d, 1 H, J ) 13.9), 1.88-2.08 (m, 4 H), 2.31-2.37 (m,
2 H), 2.46 (t, 1 H, J ) 13.4), 2.65 (dd, 1 H, J ) 8.3, 13.9), 2.72
(dd, 1 H, J ) 3.4, 13.1), 2.89 (dd, 1 H, J ) 13.5, 6.7), 3.55 (dd,
1 H, J ) 10.0, 5.2), 3.79 (s, 3 H), 4.31-4.35 (m, 2 H), 4.84 (t,

Rigid Dipeptide Mimics
J . Org. Chem., Vol. 63, No. 17, 1998 5949
1 H, J ) 6.9), 5.0 (d, 1 H, J ) 4.8), 5.45 (bs, 1 H), 6.9 (d, 2 H,
J ) 7.0), 7.15-7.36 (m, 10 H).
thanked for helpful suggestions and work to optimize
reaction conditions. Ms. Bunda Hin is acknowledged for
preliminary research on the alkylation of ketone 5. The
crystal structure analysis of compound 10 was per-
formed by Francine Be´langer-Garie´py at l’Universite´ de
Montre´al X-ray facility. We are grateful for a loan of
Pd/C from J ohnson Matthey PLC. We are grateful for a
gift of γ-methyl glutamate from NSC Technologies.
Ur ea (1′S)-16: 1H NMR δ 1.4 (d, 3 H, J ) 6.9), 1.53 (m, 2
H), 1.81 (dd, 1 H, J ) 15.4, 1.4), 1.91-2.10 (m, 4 H), 2.33-
2.39 (m, 1 H), 2.46-2.57 (m, 2 H), 2.70 (dd, 1 H, J ) 8.0, 13.9),
2.81 (dd, 1 H, J ) 4.0, 13.2), 2.94 (dd, 1 H, J ) 13.8, 5.6), 3.60
(dd, 1 H, J ) 10.0, 4.7), 3.71 (s, 3H), 4.32-4.37 (m, 2 H), 4.90
(t, 1 H, J ) 6.9), 5.01 (d, 1 H, J ) 4.8), 5.63 (bs, 1 H), 6.9 (d,
2 H, J ) 7.0), 7.17-7.34 (m, 10 H).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 2-4, 6, 7, 9-12, and 14; 1H NMR spectra of 15 and
16; COSY and NOESY/ROESY spectra of 10, 11 and 14; and
crystallographic data for 10 (68 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.
Ack n ow led gm en t. This research was supported in
part by the Natural Sciences and Engineering Research
Council of Canada, the Ministe`re de l’EÄ ducation du
Que´bec, and ICAgen Inc. W.D.L. thanks Bio-Me´ga/
Boehringer Ingelheim Recherche Inc. for a Young
Investigator Award. We thank Sylvie Bilodeau and Dr.
M. T. Phan Viet of the Regional High-Field NMR
Laboratory for their assistance in establishing the
configurations of esters 10, 11, and 14. Mr. Zhe Feng is
J O980596X