Rigid Dipeptide Surrogates: Syntheses of Enantiopure Quinolizidinone and Pyrroloazepinone Amino Acids from a Common Diaminodicarboxylate Precursor

Article abstract of DOI:10.1021/jo991766o

A versatile and practical approach for synthesizing azabicyclo[X.Y.0]alkane amino acids of different ring sizes from a common diaminodicarboxylate precursor has been developed as a means for mimicking different peptide conformations. (2S,9S)-1-tert-Butyl 10-benzyl 5-oxo-2-[-N-(PhF)amino] 9-[N-(BOC)amino]dec-4-enedioate (18) was first prepared in 83% yield by the Horner-Wadsworth-Emmons olefination of N-(PhF)aspartate β-aldehyde 8 with pyroglutamate-derived β-keto phosphonate 12 (PhF = 9-phenylfluoren-9-yl). The practicality of this approach for making azabicyclo-[X.Y.0]alkane amino acids was then illustrated by the first synthesis of enantiopure quinolizidin-2-one amino acid 6 in seven steps and 40% overall yield from L-pyroglutamic acid. Hydrogenation of δ-keto α,ω-diaminosebacate 18, followed by lactam cyclization and protection, gave quinolizidin-2-one amino acid 6 as a single diastereomer. The versatility of this approach was next demonstrated by the synthesis of both ring-fusion isomers of pyrroloazepin-2-one amino acid 6 in 11 steps and 13% overall yield from pyroglutamic acid. Hydride reduction of 18, followed by methanesulfonate displacement, gave 5-alkylproline 22. Protective group manipulations, lactam cyclization, and removal of the ester group afforded readily separable pyrroloazepinone amino acids (7S)- and (7R)-7 in a 1:2 diastereomeric ratio. By introducing two new azabicycloalkane amino acids using our olefination approach, we have expanded the diversity of these important heterocycles for studying the conformational requirements for peptide biological activity.

Full text of DOI:10.1021/jo991766o

J . Org. Chem. 2000, 65, 2163-2171
2163
Rigid Dip ep tid e Su r r oga tes: Syn th eses of En a n tiop u r e
Qu in olizid in on e a n d P yr r oloa zep in on e Am in o Acid s fr om a
Com m on Dia m in od ica r boxyla te P r ecu r sor
Francis Gosselin 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 November 12, 1999
A versatile and practical approach for synthesizing azabicyclo[X.Y.0]alkane amino acids of different
ring sizes from a common diaminodicarboxylate precursor has been developed as a means for
mimicking different peptide conformations. (2S,9S)-1-tert-Butyl 10-benzyl 5-oxo-2-[N-(PhF)amino]
9-[N-(BOC)amino]dec-4-enedioate (18) was first prepared in 83% yield by the Horner-Wadsworth-
Emmons olefination of N-(PhF)aspartate â-aldehyde 8 with pyroglutamate-derived â-keto phos-
phonate 12 (PhF ) 9-phenylfluoren-9-yl). The practicality of this approach for making azabicyclo-
[X.Y.0]alkane amino acids was then illustrated by the first synthesis of enantiopure quinolizidin-
2-one amino acid 6 in seven steps and 40% overall yield from L-pyroglutamic acid. Hydrogenation
of δ-keto R,ω-diaminosebacate 18, followed by lactam cyclization and protection, gave quinolizidin-
2-one amino acid 6 as a single diastereomer. The versatility of this approach was next demonstrated
by the synthesis of both ring-fusion isomers of pyrroloazepin-2-one amino acid 6 in 11 steps and
13% overall yield from pyroglutamic acid. Hydride reduction of 18, followed by methanesulfonate
displacement, gave 5-alkylproline 22. Protective group manipulations, lactam cyclization, and
removal of the ester group afforded readily separable pyrroloazepinone amino acids (7S)- and (7R)-7
in a 1:2 diastereomeric ratio. By introducing two new azabicycloalkane amino acids using our
olefination approach, we have expanded the diversity of these important heterocycles for studying
the conformational requirements for peptide biological activity.
In tr od u ction
handles using combinatorial techniques.1,3 Their close
structural relationship to the pyrrolizidine, indolizidine,
and quinolizidine alkaloids suggests the use of the related
azabicyclo[X.Y.0]alkane amino acids as scaffolds for
generating libraries of lead compounds that may possess
similar biological activities as members of these large
classes of alkaloids.4
The biologically active conformation of a flexible pep-
tide may be elucidated by using structural constraints
to rigidify its backbone and side-chain geometries. For
this endeavor, azabicyclo[X.Y.0]alkane amino acids have
been used as rigid dipeptide surrogates that constrain
three backbone dihedral angles within a fused bicyclic
framework. Incorporation of these heterocyclic amino
acids into a peptide can provide a better understanding
of the spatial requirements for its biological activity.1,2
Furthermore, these conformationally constrained dipep-
tide surrogates can serve as geometrically defined plat-
forms onto which a variety of pharmacophores may be
attached by modification of the amino and carboxylate
Ideally, the azabicycloalkane ring system should be
formed unambiguously, with stereocontrol and the ability
to append functional groups onto different positions of
the heterocycle in order to mimic the side-chains of the
common amino acids. Among the strategies for synthe-
sizing azabicyclo[X.Y.0]alkane amino acid, methods based
on N-acyl iminium ion cyclization as well as the conden-
sation between a cysteine derivative and an amino acid
ω-aldehyde have to date been the most successful for
providing a variety of ring-systems.5 Inability to control
the stereochemistry of the ring-fusion center as well as
low yields during the synthesis of alkyl-substituted
analogues have, however, been drawbacks encountered
(1) Reviewed in 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.
(2) Some recent syntheses of azabicyclo[X.Y.0]alkane amino acids
that have appeared since the writing of refs 1 and 9 include (a)
Lindemann, U.; Wessig, P. J . Inf. Rec. Mater. 1998, 24, 441. (b) Geyer,
A.; Bockelmann, D.; Weissenbach, K.; Fischer, H. Tetrahedron Lett.
1999, 40, 477. Recent examples of the use of azabicycloalkane amino
acids to explore bioactive peptides include the following: (c) Interleu-
kin-1â-converting-enzyme: Karanewski, D. S.; Bai, X.; Linton, S. D.;
Krebs, J . F.; Wu, J .; Pham, B.; Tomaselli, K. J . Bioorg. Med. Chem.
Lett. 1998, 8, 2757. (d) Farnesyl transferase: Liu, R.; Dong, D. L.-Y.;
Sherlock, R.; Nestler, H. P.; Gennari, C.; Mielgo, A.; Scolastico, C.
Bioorg. Med. Chem. Lett. 1999, 9, 847. (e) Zinc finger of human YY1
protein: Viles, J . H.; Patel, S. U.; Mitchell, J . B. O.; Moody, C. M.;
J ustice, D. E.; Uppenbrink, J .; Doyle, P. M.; Harris, C. J .; Sadler, P.
J .; Thornton, J . M. J . Mol. Biol. 1998, 279, 973. (f) Calcitonin-gene-
(3) Alternative examples of scaffolds for peptide mimicry and
combinatorial chemistry include (a) Hirschmann, R.; Nicolaou, K. C.;
Pietranico, S.; Salvino, J .; Leahy, E. M.; Sprengeler, P. A.; Furst, G.;
Smith, A. B., III; Strader, C. D.; Cascieri, M. A.; Candelore, M. R.;
Donaldson, C.; Vale, W.; Maechler, L. J . Am. Chem. Soc. 1992, 114,
9217. (b) Hirschmann, R.; Sprengeler, P. A.; Kawasaki, T.; Leahy, J .
W.; Shakespeare, W. C.; Smith A. B., III. J . Am. Chem. Soc. 1992,
114, 9699. (c) Barry, J . F.; Davis, A. P.; Nieves Pe´rez-Payan, M.;
Elsegood, M. R. J .; J ackson, R. F. W.; Gennari. C.; Piarulli, U.; Gude,
M. Tetrahedron Lett. 1999, 40, 2849.
(4) Recent reviews include: (a) Michael, J . P. Nat. Prod. Rep. 1997,
14, 21. (b) Ohmiya, S.; Saito, K.; Murakoshi, I. In The Alkaloids;
Cordell, G. A., Ed.; Acad. Press: New York, 1995; Vol. 47, pp 1-114.
For additional examples see ref 1 in ref 10a below.
related-peptide8-37: Wisskirchen, F. M.; Doyle, P. M.; Gough, S. L.;
Harris, C. J .; Marshall, I. Br. J . Pharmacol. 1999, 126, 1163. For
additional examples see ref 2 in ref 9 below.
(5) For examples see refs 17, 19, 23, 26 and 41-49 in ref 1 above.
10.1021/jo991766o CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/16/2000

2164 J . Org. Chem., Vol. 65, No. 7, 2000
Gosselin and Lubell
Sch em e 1. Olefin a tion 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
Sch em e 2. Syn th esis of Dia m in od ica r boxyla tes
by Olefin a tion of Am in o Ald eh yd es w ith
Dia m in od ica r boxyla te-Der ived
â-Ketop h osp h on a tes.
F igu r e 1. Indolizidinone, quinolizidinone, and pyrroloazepi-
none amino acids 1-7 (ref 1).
with these two strategies. For example, condensations
Striving to expand the variety of heterocycles that can
between (R)-penicillamine and (S)-â-phenylcysteine with
be made by our approach, we introduced next an olefi-
nation entry for making a series of linear precursors for
R-methyl-N-phthalyl-L-glutamate were plagued by low
yields.6 N-Acyl iminium ion cyclizations have given access
azabicyclo[X.Y.0]alkane synthesis (Scheme 1).10 Employ-
to only one ring-fusion isomer in the synthesis of 5,7-
ing aspartic acid as an inexpensive chiral educt in this
fused pyrroloazepinone amino ester.7 In the same light,
olefination/reductive amination/lactam cyclization se-
although our Claisen condensation/alkylation/reductive
quence, we synthesized enantiopure indolizidin-9-one
amination/lactam cyclization strategy provided a stereo-
amino acid 5.10 We envisioned that alkylation and
conjugate addition to the R,â-unsaturated ketone inter-
mediate in the synthesis of amino acid 5 may be used to
selective method for synthesizing indolizidin-2-one amino
acid 1 and analogues 2-4 possessing amino acid side-
chains at the 5- and 7-positions (Figure 1),8,9 limitations
introduce side-chains onto this heterocycle.
in the Claisen condensation of aminodicarboxylates
Having employed the olefination strategy to selectively
restricted this method’s potential for generating a variety
join different amino dicarboxylates,10 we investigated
of ring-systems.10a
using the (E)-geometry of the resulting double bond to
direct the cyclization of the unsymmetrical R,ω-di-
(6) (a) Nagai, U.; Kato, R.; Sato, K.; Nakamura, R. Tetrahedron
aminodicarboxylate intermediate in order to regioselec-
1993, 49, 3577. (b) Nagai, U. Sato, K. In Peptides. Structure and
tively produce different azabicyclo[X.Y.0]alkanes. Our
Function. Proceedings of the 9th American Peptide Symposium, Deber,
investigation has now led to the synthesis of two azabi-
cycloalkane ring systems from a common linear olefin
precursor. Quinolizidin-2-one amino acid 6 and pyr-
roloazepin-2-one amino acid 7 both were prepared from
δ-keto R,ω-diaminosebacate 18 (Schemes 3-5). The
former, azabicyclo[4.4.0]alkane amino acid 6 had previ-
ously never been synthesized. Although the latter,
azabicyclo[5.3.0]alkane amino acid 7 had been made, only
the concave (7S)-isomer was produced because of confor-
mational preferences during a route involving an N-acyl
C. M., Hruby, V. J ., Kopple, K. D., Eds.; Pierce Chemical Company:
Rockford, 1985; p 465. (c) Nagai, U.; Kato, R. In Peptide Chemistry,
Structural Biology. Proceedings of the 11th American Peptide Sym-
posium, Rivier, J . E.; Marshall, G. R., Eds.; ESCOM Sci. Pub.: Leiden,
The Netherlands, 1989; p 653.
(7) Robl, J . A. Tetrahedron Lett. 1994, 35, 393.
(8) (a) Lombart, H.-G.; Lubell, W. D. J . Org. Chem. 1996, 61, 9437.
(b) Lombart, H.-G.; Lubell, W. D. J . Org. Chem. 1994, 59, 6147.
(9) Polyak, F.; Lubell, W. D. J . Org. Chem. 1998, 63, 3, 5937.
(10) (a) Gosselin, F.; Lubell, W. D. J . Org. Chem. 1998, 63, 7463.
(b) Gosselin, F.; Lubell, W. D. In Peptides 1998. Proceedings of the
25th European Peptide Symposium, Bajusz, S., Hudecz, F., Eds.;
Akade´mia Kiado´: Budapest, Hungary, 1998; p 660.

Rigid Dipeptide Surrogates
J . Org. Chem., Vol. 65, No. 7, 2000 2165
Sch em e 3. Syn th esis of δ-Keto
and 6-alkylpipecolate intermediates could be respectively
synthesized from R,â-unsaturated ketones 10 and 14, we
abandoned these approaches for preparing the 7,5- and
6,6-fused azabicycloalkanes because of difficulties en-
countered when trying to differentiate between the two
N-(PhF)amines as well as between the two carboxylate
functions.
r,ω-Dia m in oseba ca te 18
We envisioned that a single linear olefin precursor
could be used to synthesize both the 6,6- and 7,5-fused
ring systems, if its amino and carboxylate functions were
suitably protected. By employing a combination of N-
BOC- and N-PhF-amines and tert-butyl and benzyl
esters, we anticipated that acidic and hydrogenolytic
conditions could be respectively used to unmask one
member from each protected pair. Attention was thus
turned toward the synthesis of 1-tert-butyl 10-benzyl
5-oxo-2-[N-(PhF)amino]-9-[N-(BOC)amino]dec-4-enedio-
ate (18, Scheme 3).
Nucleophilic addition to N-carbamoyl pyroglutamate
derivatives had previously been used to synthesize â-ke-
tophosphonate.13,14 Regioselective addition of diethyl
methyl phosphonate to ethyl N-(BOC)pyroglutamate in
THF afforded (2S)-R-ethyl 2-N-(BOC)amino-5-oxo-6-(di-
ethylphosphonyl)hexanoate in 60% yield.14b In our route,
benzyl N-(BOC)pyroglutamate 16 was first obtained in
77% overall yield by alkylative esterification of pyro-
glutamic acid with benzyl bromide and N,N-diisopropyl-
ethylamine (DIEA) in CH2Cl2, followed by N-protection
using di-tert-butyl dicarbonate, DMAP, and Et3N, in CH3-
CN.15,16 By substituting benzyl bromide for the less
reactive chloride, we found that the alkylation was
complete in less than 24 h, instead of the previously
required 7 days.15 (2S)-R-Benzyl 2-N-(BOC)amino-5-oxo-
6-(dimethylphosphonyl)hexanoate (17) was then prepared
by the addition of the lithium anion of dimethyl meth-
ylphosphonate to benzyl N-(BOC)pyroglutamate 16 in
toluene in 74% yield.17 Earlier attempts to react this
nucleophile on pyroglutamate 16 using THF as solvent
gave lower yields (40-50%) of â-ketophosphonate 17.
The R,â-unsaturated ketone 18 was obtained by Hor-
ner-Wadsworth-Emmons olefination of N-(PhF)aspar-
tate â-aldehyde 8 with â-ketophosphonate 17.10 Initially,
longer times and high temperatures were required for
the olefination reaction when K2CO3 was used as base
alone as well as in the presence of 18-crown-6 (1,4,7,10,-
13,16-hexaoxacyclooctadecane). Because of the limited
stability of â-amino aldehyde 8 under these harsh condi-
tions, R,â-unsaturated ketone 18 was isolated in less than
30% yield. Alternatively, the use of Cs2CO3 as base in
Sch em e 4. Syn th esis of Qu in olizid in -2-on e Am in o
Acid 6
iminium ion cyclization,7 and because of the precursor
stereochemistry in a route featuring a radical cyclization
of an N-acyl acrylamide.11 Besides yielding the concave
isomer,7 our route has now, for the first time, furnished
the convex (7R)-isomer of pyrroloazepin-2-one amino acid
7.
Resu lts a n d Discu ssion
Dia m in od ica r boxyla te p r ecu r sor syn th esis was
initially investigated using different amino acid-derived
aldehydes in the Horner-Wadsworth-Emmons olefina-
tion (Schemes 2 and 3). For example, olefination of
N-(PhF)aspartate â-aldehyde 8 with N-(PhF)glutamate-
derived â-ketophosphonate 9 in acetonitrile with potas-
sium carbonate as base was initially found to provide R,â-
unsaturated ketone 10 in 78% yield.10a Similarly, the
reaction of configurationally stable N-(PhF)serinal 1112
with R-amino adipate-derived â-ketophosphonate 1210 in
acetonitrile with K2CO3 as base gave R,â-unsaturated
ketone 14 in 60% yield as described in the Supporting
Information. In both cases, only the (E)-olefin was formed
as confirmed by the large coupling constant (J ) 16.0
Hz) between the vinyl protons. Although 5-alkylproline
(13) The use of pyroglutamic acid in asymmetric synthesis has
recently been reviewed: Na´jera, C.; Yus, M. Tetrahedron Asymmetry
1999, 10, 2245.
(14) The addition of nucleophiles to N-carbamoyl pyroglutamates
is described in (a) Ohta, T.; Hosoi, A.; Kimura, T.; Nozoe, S. Chem.
Lett. 1987, 2091. (b) Ezquerra, J .; de Mendoza, J .; Pedregal, C.;
Ramirez, C. Tetrahedron Lett. 1992, 33, 5589. (c) Molina, M. T.; Valle,
C. D.; Escribano, A. M.; Ezquerra, J .; Pedregal, C. Tetrahedron, 1993,
49, 3801. (d) Ezquerra, J .; Rubio, A.; Pedregal, C.; Sanz, G.; Rodriguez,
J . H.; Garc´ıa Ruano, J . L. Tetrahedron Lett. 1993, 34, 4989. (e)
Ezquerra, J .; Pedregal, C.; Rubio, A.; Valenciano, J .; Garc´ıa, J . L.;
Alvarez-Builla, N. J .; Vaquero, J . J . Tetrahedron Lett. 1993, 34, 6317.
(f) Van Betsbrugge, J .; Van Den Nest, W.; Verheyden, P.; Tourwe´, D.
Tetrahedron 1998, 54, 1753.
(15) August, R. A.; Khan, J . A.; Moody, C. M.; Young, D. W. J . Chem.
Soc. Perkin. Trans. 1 1995, 507.
(16) (a) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983,
48, 2424. (b) Grehn, L.; Gunnarsson, K.; Ragnarsson, U. Acta Chem.
Scand., Ser. B 1986, 40, 745.
(11) Colombo, L.; Di Giacomo, M.; Belvisi, L.; Manzoni, L.; Scolastico,
C.; Salimbeni, A. Gazz. Chim. Ital. 1996, 126, 543.
(12) Lubell, W. D.; Rapoport, H. J . Org. Chem. 1989, 54, 3824.
(17) Corey, E. J .; Kwiatkowski, G. T. J . Am. Chem. Soc. 1966, 88,
5654.

2166 J . Org. Chem., Vol. 65, No. 7, 2000
Sch em e 5. Syn th esis of P yr r oloa zep in -2-on e Am in o Acid 7
Gosselin and Lubell
CH3CN cleanly afforded 18 in 83% yield after 4-5 h at
room temperature. No decomposition of the aldehyde to
tert-butyl N-(PhF)-5-azapenta-2,4-dienoate18a was ob-
served under these conditions. The (E)-double bond
geometry was confirmed by the J ) 16.0 Hz coupling
constant between the vinyl protons in R,â-unsaturated
ketone 18.
ester were simultaneously removed with HCl gas in CH2-
Cl2. The amino acid hydrochloride was acylated with
9-fluorenylmethyloxycarbonyl hydroxysuccinimide (Fmoc-
OSu), in the presence of NaHCO3 in a solution of acetone
and water.23 Quinolizidinone N-(Fmoc)amino acid 6 was
finally obtained in 86% yield after column chromatogra-
phy.
Qu in olizid in -2-on e a m in o a cid syn th esis was stud-
ied using a reductive amination approach to selectively
unmask the N-(PhF)amine and furnish the 6-alkylpipe-
colate. Previously, we had shown that δ- and ꢀ-keto
R-amino esters can be effectively converted to their
respective 5-alkylprolines and 6-alkylpipecolates by cata-
lytic hydrogenation with high diastereoselectivity.8-10,18,19
In the case of (2S, 9S)-1-tert-butyl 10-benzyl 5-oxo-2-[N-
(PhF)amino] 9-[N-(BOC)amino]dec-4-enedioate (18,
Scheme 4), treatment with palladium-on-carbon in an
i-PrOH:THF solution at 6 atm of hydrogen caused
reduction of the double bond, hydrogenolysis of the benzyl
ester and the PhF group, imine formation, and reduction
from the less-hindered face of the imine to afford pipe-
colate 19 as a single diastereomer. After filtration to
remove the catalyst, the crude pipecolate mixture was
then treated with diphenylphosphoryl azide (DPPA)20 in
CH2Cl2 in the presence of DIEA and provided crystalline
azabicycloalkane N-(BOC)amino ester 20 in >99% yield
from ketone 18 after chromatography.
P yr r oloa zep in -2-on e a m in o a cid syn th esis was
next pursued using the same olefin precursor 18. As
mentioned, the concave (7S)-isomer of pyrroloazepin-2-
one amino acid 7 had been previously synthesized by an
N-acyl iminium ion cyclization from an allylglycine
dipeptide precursor,7 as well as by an intramolecular
radical-mediated cyclization of a 5-alkylproline deriva-
tive.11 This 7,5-fused azabicycloalkane amino acid and
its 4-thiapyrroloazepin-10-one counterpart have been
used as D-Ala-Pro mimics in the preparation of potent
angiotensin-converting-enzyme inhibitors.24,25 Further-
more, this constrained dipeptide surrogate has been
shown to stabilize preferentially γ-turn conformations in
short peptides.26
Previously, we have shown that methanesulfonate
displacements can be effectively used for synthesizing the
proline ring in indolizidin-2-one amino acid and its 5- and
7-benzyl, and 5,7-dibenzyl derivatives.8a,9 Intramolecular
attack of N-(PhF)amine onto secondary methanesulfonates
(21) Wellings, D. E.; Atherton, E. Solid-Phase Peptide Synthesis.
In Methods in Enzymology; Fields, G. B., Ed.; Acad. Press: New York,
1997; Vol. 289, p 44.
Because of the growing importance of Fmoc-based
solid-phase peptide synthesis, 6,6-fused azabicycloalkane
N-(BOC)amino ester 20 was converted into its Fmoc
derivative.21,22 First, the BOC group and the tert-butyl
(22) (a) Carpino, L. A.; Han, G. Y. J . Am. Chem. Soc. 1970, 92, 5748.
(b) Carpino, L. A.; Han, G. Y. J . Org. Chem. 1972, 37, 3405.
(23) (a) Lapatsanis, L.; Milias, G.; Froussios, K.; Kolovos, M.
Synthesis 1983, 671. (b) Sigler, G. F.; Fuller, W. D.; Chutuverdi, N.
C.; Goodman, M.; Verlander, M. Biopolymers 1983, 22, 2157.
(24) Robl, J . A.; Sun, C.-Q.; Stevenson, J .; Ryono, D. E.; Simpkins,
D. E.; Cimarusti, 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.
(25) Wyvratt, M. J .; Patchett, A. A. Med. Res. Rev. 1985, 5, 483.
(26) (a) Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico,
C. Eur. J . Org. Chem. 1999, 389. (b) Gennari, C.; Mielgo, A.; Potenza,
D.; Scolastico, C.; Piarulli, U.; Manzoni, L. Eur. J . Org. Chem. 1999,
379.
(18) (a) Swarbrick, M. E.; Gosselin, F.; Lubell, W. D. J . Org. Chem.
1999, 64, 1993. (b) Gosselin, F.; Swarbrick, M. E.; Lubell, W. D. In
Peptides 1998. Proceedings of the 25th European Peptide Symposium,
Bajusz, S., Hudecz, F., Eds.; Akade´mia Kiado´: Budapest, Hungary,
1998; p 688.
(19) (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) For prior articles see refs 15s and
15t in ref 19a above.
(20) Shioiri, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc. 1972,
94, 6203.

Rigid Dipeptide Surrogates
J . Org. Chem., Vol. 65, No. 7, 2000 2167
has provided excellent yields of 5-alkylprolines by what
appears to be a selective SN2 process in these cases. To
examine the methanesulfonate displacement for making
the proline in the pyrroloazepin-2-one amino acid, ketone
18 was first transformed into its corresponding allylic
alcohol by reduction with sodium borohydride in the
presence of cerium trichloride in MeOH:THF to provide
21 as a 1:1 mixture of diastereomers in 86% yield
(Scheme 5).27 Treatment of the alcohol with methane-
sulfonyl chloride and triethylamine in CH2Cl2, afforded
cyclization to 5-alkylprolines 22 in 91% yield. The (E)-
olefin geometry of alcohol 21 excluded the attack of the
N-(PhF)amine onto the methanesulfonate such that
exclusive cyclization of the N-(BOC)amine occurred.
5-Alkylproline 22 was obtained as a 2:1 mixture of 5R:
5S diastereomers as indicated by measurements of the
tert-butyl ester singlets in the 1H NMR spectra of
analogues 23 and 24. The enhanced stereochemical ratio
relative to starting allylic alcohol 21 was ascribed to SN1-
type cyclization, presumably due to ionization of the
methanesulfonates under the reactions conditions. As
previously noted in a related synthesis of (-)-pyrrolidine-
2,5-dicarboxylic acid,28 the conformation of the allylic
cation intermediate may have contributed to the enrich-
ment of the 5R diastereomer of proline 22.
Prior to the key lactam cyclization, the protecting
groups were exchanged. First, the N-(PhF)amine and
benzyl ester of 22 were cleaved with concurrent double
bond reduction by catalytic hydrogenation in a THF/
methanol solution. N-Acylation with Fmoc-OSu in an
acetone/water solution gave prolines 23 in 81% overall
yield from 22. Alkylative esterification with allyl iodide
in CH3CN heated at a reflux afforded ester 24 in 86%
yield. Simultaneous removal of the BOC group and tert-
butyl ester with HCl in CH2Cl2 then gave amino acid
hydrochloride 25.
Lactam cyclization of 25 using either azabenzotria-
zolyl-1,1,3,3-tetramethylaminium hexafluorophosphate
(HATU)29,30 or benzotriazolyl-1,1,3,3-tetramethylaminium
tetrafluoroborate (TBTU)30,31 with DIEA in CH2Cl2 gave
N-(Fmoc)-azabicycloalkane amino esters 26 in yields
ranging between 50 and 60%.32,33 Although TBTU gave
essentially the same amount of conversion to lactam 26,
we found that the coupling reaction with HATU pro-
ceeded with an enhanced cyclization rate and yielded
product of better purity.29 Pyrroloazepin-2-one N-(Fmoc)-
amino esters 26 were isolated as a 2:1 mixture of
diastereomers that were easily separated by chromatog-
raphy on silica gel. Pyrroloazepin-2-one N-(Fmoc)amino
acids (7S)-7 and (7R)-7 were finally synthesized by
palladium-catalyzed hydrostannolytic cleavage of their
respective allyl esters (7R)-26 and (7S)-26 on treatment
with Pd(PPh3)2Cl2 and nBu3SnH in a CH2Cl2/AcOH
solution at room temperature in yields of 88% and 99%
after chromatography.34
Rela tive ster eoch em istr y at the ring-fusion center
of the new azabicycloalkane amino acids was confirmed
by spectroscopic and crystallographic methods. Because
quinolizidin-2-one N-(BOC)amino ester (3S,6R,10S)-20
was prepared by a reductive amination sequence, we
assigned the stereochemistry of its ring-fusion carbon
initially based on analogy with N-(BOC)amino indolizi-
din-9-one acid (2S,6R,8S)-5 and 6-alkylpipecolates.10,18
Since hydrogenation of R-tert-butyl δ-oxo-R-N-(PhF)-
amino ester produced 6-alkylpipecolates with high se-
lectivity in favor of the cis-diastereomer, we presumed
that the reductive amination with amino ketone 18
proceeded to form cis-6-alkylpipecolate (2S,6R,2′S)-19.
Crystals of (3S,6R,10S)-tert-butyl 2-oxo-3-N-(BOC)amino-
1-azabicyclo[4.4.0]decane-10-carboxylate (20) were later
obtained from an EtOAc/hexanes solution. Subsequently,
X-ray crystallographic analysis confirmed our hypothesis
and indicated formation of the concave isomer (Figure
2).35
With both (7S)- and (7R)-pyrroloazepin-2-one N-(Fmoc)-
amino acids (7S)-7 and (7R)-7 in hand, a series of two-
dimensional NMR experiments were performed in order
to assign the relative stereochemistry at the ring-fusion.
First, the protons within the peptide backbone and at
the ring-fusion of each isomer were identified using their
COSY spectra. The stereochemistry at the ring-fusion
was next determined by NOESY experiments (Figure 3).
Transfer of magnetization was observed between the
ring-fusion C-7 proton (3.86 ppm) and the backbone
protons at C-3 (4.40 ppm) and C-10 (4.70 ppm) in the
case of the (7S)-7 minor diastereomer. By comparison,
nuclear Overhauser effects were observed between the
C-7 proton (3.70 ppm) and carbamate N-H (6.08 ppm)
in the case of the (7R)-7 major diastereomer.
En a n tiom er ic p u r ity of quinolizidin-2-one amino
ester (3S,6R,10S)-20, produced from the reductive ami-
nation/lactam cyclization sequence on ketone 18, was
determined after conversion to diastereomeric (1′R)- and
(32) In our hands, onium salt based coupling reagents were superior
to all other methods. Earlier attempts provided lower yields of the
desired seven-membered lactams using (a) catecholborane: Collum,
D. B.; Chen, S.-C.; Ganem, B. J . Org. Chem. 1978, 43, 439, as well as
peptide coupling reagents such as the following: (b) Carbodiimides:
Sheehan, J . C.; Hess, G. P. J . Am. Chem. Soc. 1955, 77, 1067. (c) (1-
Azabenzotriazolyloxy)tris(dimethylamino)phosphonium hexafluoro-
phosphate (BOP): Castro, B.; Dormoy, J . R.; Evin, G.; Selve, C.
Tetrahedron Lett. 1975, 14, 1219. (d) Bis(2-oxo-3-oxazolidinyl)phos-
phinic chloride (BOP-Cl): Tung, R. D.; Rich, D. H. J . Am. Chem. Soc.
1985, 107, 4342. (e) Diphenylphosphoryl azide (DPPA): see ref 20. For
a discussion on the use of peptide coupling agents in synthesis, see (f)
Humphrey, J . M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243.
(33) In comparison, formation of the seven-membered lactam by
iminium ion cyclization and by radical-mediated cyclization went
respectively in 79% and 42-61% yields, as discussed in refs 7 and 11.
(34) (a) Dangles, O.; Guibe´, F.; Balavoine, G.; Lavielle, S.; Marquet,
A. J . Org. Chem. 1987, 52, 4984. (b) Loffet, A.; Zhang, H. X. Int. J .
Pept. Protein Res. 1993, 42, 346.
(27) (a) Luche, J .-L. J . Am. Chem. Soc. 1978, 100, 2226. (b) Luche,
J .-L.; Rodriguez-Hahn, L.; Crabbe´, P. J . Chem. Soc., Chem. Commun.
1978, 601. (c) The diastereomeric ratio of allylic alcohol 21 was
determined by 1H NMR of its O-acetyl derivative, prepared by treating
21 with Ac2O in DMAP-pyridine at room temperature for 30 min; 1H
NMR δ 1.18 (s, 4.5 H), 1.19 (s, 4.5 H), 1.45 (s, 9 H), 1.50-1.68 (m, 3
H), 1.86 (m, 1 H), 2.02 (s, 1.5 H), 2.03 (s, 1.5 H), 2.12 (m, 2 H), 2.60 (m,
1 H), 4.35 (bm, 1 H), 5.05-5.28 (m, 3 H), 5.30-5.38 (m, 1 H), 5.63-
5.69 (m, 1 H), 7.16-7.43 (m, 16 H), 7.66-7.69 (m, 2 H).
(28) For a related observation and an example of cyclization of a
N-(Cbz)amine onto an allylic methanesulfonate see ref 14a above.
(29) Carpino, L. A. J . Am. Chem. Soc. 1993, 115, 4397.
(30) The crystal structures of HBTU, the corresponding PF6 salt,
and HATU indicate that these reagents exist in the form of aminium
salts: Abdelmoty, I.; Albericio, F.; Carpino, L. A.; Foxman, B. M.; Kates,
S. A. Lett. Pept. Sci. 1994, 1, 52.
(35) The structure of 20 was solved at the Universite´ de Montre´al
X-ray facility using direct methods (SHELXS96) and refined with
NRCVAX and SHELXL96: C19H32N2O5; Mr ) 368.46; monoclinic,
colorless crystal; space group P21; unit cell dimensions (Å) a ) 9.773
(3), b ) 10.201 (9), c ) 11.064 (3), â ) 105.01 (2)°; volume of unit cell
(Å3) 1065.4 (10); Z ) 2; R1 ) 0.04 for I > 2 σ(I), wR2 ) 0.12 for all
data; GOF ) 1.065. The author has deposited the atomic coordinates
for the structure of 20 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.
(31) Knorr, R.; Trzreciak, A.; Bannwarth, W.; Gillessen, D. Tetra-
hedron Lett. 1989, 30, 1927

2168 J . Org. Chem., Vol. 65, No. 7, 2000
Gosselin and Lubell
Ta ble 1. 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
entry
ψ, deg φ, deg
(3S,6R,10S)-3-N-(BOC)amino quinolizidin-
2-one-10-carboxylate 20
-163
+48
-34
-78
(2S,6R,8S)-8-N-(BOC)amino indolizidin-9-
-141
one-2-carboxylate 510
(3S,6S,9S)-3-N-(BOC)amino indolizidin-2-one- -176
9-carboxylate 18
Ba ck -Bon e Con for m a tion were illustrated on com-
parison of the dihedral angles of indolizidin-2-one, in-
dolizidin-9-one, and quinolizidin-2-one N-(BOC)amino
esters 1, 5, and 20 in the solid-state (Table 1). Because
they possess the same relative stereochemistry, signifi-
cant differences in the internal ψ and φ dihedral angles
from the X-ray data of 1, 5, and 20 indicate that ring-
size has a profound effect on conformation. Our data also
indicates that a variety of azabicycloalkane amino acids
of different ring-size may be used to mimic a compre-
hensive spectrum of peptide conformations. Because
structure-activity relationship studies have already
shown that peptides possessing γ-, δ-, and ꢀ-lactams can
differ in bioactivity,36 the application of a series of
azabicycloalkane amino acids toward the study of biologi-
cally relevant peptides should provide detailed pictures
of the conformational requirements for activity.
F igu r e 2. ORTEP view of N-(BOC)amino quinolizidin-2-one
tert-butyl ester (3S,6R,10S)-20. Ellipsoids drawn at 40%
probability level. Hydrogens represented by spheres of arbi-
trary size.35
Con clu sion
F igu r e 3. Observed diagnostic NOE’s in NOESY experiments.
We have expanded the diversity of azabicyclo[X.Y.0]-
alkane amino acids by application of our olefination entry
to synthesize their linear precursors. By taking advan-
tage of the olefin geometry to direct the reductive
amination and methanesulfonate displacement cycliza-
tions on a common diaminodicarboxylate intermediate,
two new ring systems of different sizes were prepared
for the first time. Enantiopure (3S,6R,10S)-quinolizidin-
2-one amino acid 6 was assembled in 7 steps and 40%
overall yield from pyroglutamic acid. Convex (3S,7R,10S)-
pyrroloazepin-2-one amino acid 7 was prepared as a 2:1
diastereomeric mixture with its previously synthesized
concave counterpart in 11 steps and 13% overall yield
from pyroglutamic acid.38 Stereocontrol was achieved
during the syntheses of 6 and 7 by selectively joining
inexpensive aminodicarboxylate starting materials. More-
over, our approach is well poised for the introduction of
side-chains onto the heterocycle framework through
functionalization of the pyroglutamate and â-amino
aldehyde precursors, as well as by conjugate additions
and alkylations on the R,â-unsaturated ketone interme-
diate (Scheme 1). Our strategy now provides a series of
azabicycloalkane amino acids for systematic mimicry of
the backbone and side-chain conformations of biologically
relevant peptides.
Sch em e 6. En a n tiom er ic P u r ity of
Qu in olizid in -2-on e Am in o Ester 20
(1′S)-N-R-methylbenzylureas 28 by analysis using NMR
spectroscopy (Scheme 6). Hydrogen chloride in methanol
removed both the N-BOC and tert-butyl ester protecting
groups and esterified the acid intermediate to quantita-
tively furnish methyl ester hydrochloride 27. Acylation
of 27 with either (R)- or (S)-R-methylbenzyl isocyanate
and triethylamine in THF heated at a reflux gave
R-methylbenzylureas 28 which were directly examined
after evaporation of the volatiles. Measurement of the
diastereomeric methyl ester singlets at 3.70 and 3.65 ppm
in CDCl3 by 400 MHz 1H NMR spectroscopy demon-
strated 28 to be of >99% in diastereomeric ratio. Hence
diaminodicarboxylate 18, N-(BOC)amino quinolizidin-2-
one ester 20, and its respective acid 6, all are presumed
to be of >99% enantiomeric purity. Because concurrent
racemization of both stereocenters in ketone precursor
18 is very unlikely under the reaction conditions of the
methanesulfonate displacement sequence, N-(Fmoc)-
amino pyrroloazepinone-2-one acids 7 are also assumed
to be of >99% enantiomeric purity.
(36) Freidinger, R. M. In Peptides: Synthesis, Structure, Function.
Proceedings of the 7th American Peptide Symposium, Rich, D. H.,
Gross, E., Eds., Pierce Chemical Company: Rockford, 1981; p 673.
(37) Andreu, D.; Ruiz, S.; Carren˜o, C.; Alsina, J .; Albericio, F.;
J ime´nez, M. A.; de la Figuera, N.; Herranz, R.; Garc´ıa-Lo´pez, M. T.;
Gonza´lez-Mun˜iz, R. J . Am. Chem. Soc. 1997, 119, 10579.
(38) By comparison, the iminium ion cyclization route required 11
steps and provided N-phthalyl pyrroloazepinone methyl ester in 23%
overall yield from the more advanced intermediates N-phthalyl-L-
allylglycine and N-phthalyl γ-benzyl glutamate. The radical cyclization
based strategy took seven steps and provided N-acetyl pyrroloazepi-
none tert-butyl ester in 16-24% overall yield from the advanced
intermediate (2S,5S)-diethyl N-benzylpyrrolidine 2,5-dicarboxylate.
In flu en ces of Heter ocycle Rin g-Size on P ep tid e

Rigid Dipeptide Surrogates
Exp er im en ta l Section
J . Org. Chem., Vol. 65, No. 7, 2000 2169
1 H), 2.62-2.78 (m, 2 H), 3.04 (s, 1 H), 3.09 (s, 1 H), 3.66 (m,
1 H), 3.75 (d, 5 H, J ) 11.2), 4.28 (dd, 1 H, J ) 4.7, 8.1), 5.13
(d, 1 H, J ) 12.3), 5.18 (d, 1 H, J ) 12.3), 5.48 (bd, 1 H, J )
8.1), 7.34 (s, 5 H); 13C NMR (keto-enol mixture) δ 27.7, 28.2,
39.7, 40.4, 41.7, 52.7, 52.8, 52.9, 53.4, 62.1, 66.9, 79.7, 135.3,
155.5, 172.0, 200.6. HRMS calcd for C20H31NO8P [M + H]:
444.1787, found: 444.1802.
Gen er a l. Unless otherwise noted all reactions were run
under nitrogen atmosphere, and distilled solvents were trans-
ferred by syringe. Tetrahydrofuran (THF) was distilled from
sodium/benzophenone immediately before use; toluene was
distilled from sodium; CH2Cl2 was distilled from P2O5; com-
mercial anhydrous CH3CN was used without further purifica-
tion; triethylamine (Et3N) was distilled from BaO; N,N-
diisopropylethylamine [Et(i-Pr)2N, DIEA] was distilled from
CaH2 and ninhydrin. 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
(2S,9S)-1-ter t-Bu tyl 10-Ben zyl 5-Oxo-2-[N-(P h F )a m in o]
9-[N-(BOC)a m in o]d ec-4-en ed ioa te (18). To a stirred solu-
tion of â-keto phosphonate 17 (1.02 g, 2.3 mmol) and N-(PhF)-
aspartate aldehyde 8 (950 mg, 2.3 mmol, 100 mol %, prepared
according to refs 10 and 18a) in CH3CN (20 mL) was added
Cs2CO3 (899 mg, 2.76 mmol, 120 mol %). The mixture was
stirred at room temperature for 4-5 h, quenched with aqueous
NaH2PO4 (20 mL, 1 M), and diluted with EtOAc (25 mL). The
aqueous layer was saturated with solid NaCl and extracted
with EtOAc until TLC of the organic layer showed no UV-
active material. The combined organic layers were washed
with 10 mL of brine, dried, and evaporated to a solid residue
that was chromatographed using a gradient of 10-50% EtOAc
in hexanes as eluant. Evaporation of the collected fractions
gave ketone 18 as a white crystalline solid: 1.39 g, 83%; mp
144-145 °C; TLC Rf ) 0.40 (1:4 EtOAc:hexanes); [R]20D -81.8
1
otherwise noted, IR spectra were recorded in mineral oil; H
NMR (300/400 MHz) and 13C NMR (75/100 MHz) spectra were
recorded in CDCl3. IR bands are reported in reciprocal
centimeters (cm-1). Chemical shifts are reported in ppm (δ
units) downfield of internal tetramethylsilane ((CH3)4Si), or
residual CHCl3; coupling constants are reported in hertz.
Chemical shifts of the vinyl carbons in 18 and 21 and of PhF
aromatic carbons are not reported in 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), visualized with UV light,
ninhydrin solution, and ceric ammonium molybdate solution.
Chromatography was performed using Kieselgel 60 (230-400
mesh).
1
(c 1.0, CHCl3); IR (cm-1): 3359, 1736, 1709, 1678. H NMR δ
1.20 (s, 9 H), 1.44 (s, 9 H), 1.96-2.04 (m, 1 H), 2.14-2.20 (m,
1 H), 2.22-2.36 (m, 1 H), 2.52-2.72 (m, 3 H), 3.21 (bs, 1 H),
4.37 (dd, 1 H, J ) 5.2, 7.6), 5.14 (d, 1 H, J ) 12.3), 5.20 (d, 1
H, J ) 12.3), 5.28 (d, 1 H, J ) 7.9), 5.99 (d, 1 H, J ) 16.0),
6.69 (dt, 1 H, J ) 7.4, 16.0), 7.19-7.43 (m, 16 H), 7.67-7.71
(m, 2 H); 13C NMR δ 26.6, 28.0, 28.5, 35.8, 39.1, 53.4, 55.7,
67.3, 73.1, 80.1, 81.4, 155.6, 172.4, 174.1, 198.7. HRMS calcd
for C45H51N2O7 [M + H]: 731.3696, found: 731.3676. Anal.
Calcd for C45H50N2O7: C, 73.95; H, 6.90; N, 3.83. Found: C,
73.90; H, 7.10; N, 3.84.
(2S)-Ben zyl N-(BOC)-p yr oglu ta m a te (16). A solution of
pyroglutamic acid (5.0 g, 38.75 mmol) and DIEA (13.5 mL, 77.5
mmol, 200 mol %) in CH2Cl2 (200 mL) was treated with benzyl
bromide (18.5 mL, 155 mmol, 400 mol %), heated at a reflux
for 12-24 h, cooled to room temperature, and washed with
aqueous NaH2PO4 (50 mL, 1 M). The aqueous layer was
extracted with CH2Cl2 (2 × 25 mL), and the combined organic
layers were washed with brine (50 mL), dried, filtered, and
evaporated. The crude product (HRMS calcd for C12H14NO3 [M
+ H]: 220.0974, found: 220.0967) was then dissolved in a
solution of CH3CN (100 mL) and Et3N (5.4 mL, 100 mol %),
treated with (BOC)2O (16.9 g, 200 mol %) and DMAP (473 mg,
10 mol %), and stirred at room temperature overnight. The
colored mixture was washed with NaH2PO4 (50 mL, 1 M) and
brine (50 mL), dried, filtered, and evaporated to a colored
viscous solid that was filtered through a plug of silica gel using
1:1 EtOAc in hexanes as eluant. The collected fractions were
evaporated to provide pyroglutamate 16 as a colorless crystal-
line solid: 9.56 g, 77%; mp 69-70 °C (lit. 57-59 °C;14f 72-74
(3S,6R,10S)-ter t-Bu t yl 2-Oxo-3-N-(BOC)a m in o-1-a za -
bicyclo[4.4.0]d eca n e-10-ca r boxyla te (20). A solution of
ketone 18 (1.46 g, 2.0 mmol) in THF (30 mL) and i-PrOH (20
mL) was transferred into a hydrogenation apparatus and
treated with palladium-on-carbon (200 mg, 10 wt %). The
pressure bottle was filled, vented, and refilled four times with
6 atm of H2. The reaction mixture was stirred for 18 h and
filtered onto a plug of diatomaceous earth (Celite) that was
washed thoroughly with MeOH. Evaporation of the volatiles
gave crude pipecolate 19 (HRMS calcd for C19H35N2O6 [M +
H]: 387.2495, found: 387.2507) that was dissolved in CH2Cl2
(50 mL), cooled to 0 °C, treated with DIEA (698 µL, 4 mmol,
200 mol %) and diphenylphosphoryl azide (862 µL, 4 mmol,
200 mol %), stirred for 30 min, warmed to room temperature,
and left to stir for 16 h. Evaporation of the volatiles and
chromatography of the residue using 0-100% EtOAc in
hexanes as eluant gave quinolizidin-2-one amino ester 20 as
a clear oil that crystallized on standing: 736 mg, 99%, mp
°C15); TLC Rf ) 0.19 (1:4 EtOAc:hexanes); [R]20 -37.8 (c 1.0,
D
CHCl3) (lit.15 [R]25 -35.0 (c 0.98, CHCl3); IR (cm-1): 1782,
D
1
1739, 1702. H NMR δ 1.42 (s, 9 H), 1.95-2.59 (m, 4 H), 4.64
(m, 1 H), 5.20 (s, 2 H), 7.36 (m, 5 H); 13C NMR δ 21.7, 27.9,
31.3, 59.1, 67.5, 83.8, 128.7, 128.8, 128.9, 135.2, 149.4, 171.3,
173.4. HRMS calcd for C17H22NO5 [M + H]: 320.1498, found:
320.1508. Anal. Calcd for C17H21NO5: C, 63.94; H, 6.63; N,
4.39. Found: C, 63.96; H, 6.94; N, 4.43.
115-117 °C; TLC Rf ) 0.47 (1:1 EtOAc:hexanes); [R]20 -1.6
D
1
(c 1.0, CHCl3); IR (cm-1): 3346, 1721, 1708, 1657. H NMR δ
1.33 (s, 9 H), 1.35 (s, 9 H), 1.26-1.75 (m, 7 H), 1.80-1.93 (m,
3 H), 2.24-2.30 (m, 1 H), 3.38-3.45 (m, 1 H), 3.99-4.05 (m, 1
H), 4.19-4.22 (dd, 1 H, J ) 5.7, 5.8), 5.50 (bs, 1 H); 13C NMR
δ 18.8, 24.3, 25.3, 27.4, 27.9, 28.0, 28.3, 29.1, 50.7, 52.7, 55.3,
79.3, 81.1, 155.6, 170.6. HRMS calcd for C19H33N2O5 [M + H]:
369.2390, found: 369.2403. Anal. Calcd for C19H32N2O5: C,
61.93; H, 8.75; N, 7.60. Found: C, 61.85; H, 9.04; N, 7.51.
(3S,6R,10S)-2-Oxo-3-N-(Fm oc)am in o-1-azabicyclo[4.4.0]-
d eca n e-10-ca r boxyla te (6). A solution of N-(BOC)amino-1-
azabicyclo[4.4.0]decane-10-carboxylate 20 (350 mg, 0.95 mmol)
in CH2Cl2 (15 mL) at 0 °C was treated with HCl bubbles for
60 min, when TLC showed complete disappearance of the
starting material. The volatiles were evaporated to give the
crude hydrochloride as a white solid, that was dried under
vacuum, dissolved in water (5 mL), treated with solid NaHCO3
(160 mg, 1.9 mmol, 200 mol %), stirred for 10 min, and treated
with a solution of Fmoc-OSu (320 mg, 0.95 mmol, 100 mol %)
in acetone (10 mL). The mixture was stirred for 3 h at room
temperature, acidified with H3PO4 to pH 4, and extracted with
EtOAc until TLC of the aqueous layer showed no UV-active
material. The combined organic layers were evaporated to a
(2S)-r-Ben zyl 2-N-(BOC)Am in o-5-oxo-6-(dim eth ylph os-
p h on yl)h exa n oa te (17). A -78 °C solution of dimethyl
methyl phosphonate (360 µL, 3.3 mmol, 105 mol %) in toluene
(40 mL) was treated with n-butyllithium (2.53 mL, 3.3 mmol,
105 mol %, 1.3 M in hexanes), stirred for 20 min at -78 °C,
and transferred by cannula dropwise over 60 min into a -78
°C solution of (2S)-benzyl N-(BOC)pyroglutamate (16, 1.0 g,
3.1 mmol) in toluene (30 mL). The solution was stirred for 1
h, warmed to room temperature over 30 min, quenched with
aqueous NaH2PO4 (20 mL, 1 M), and diluted with EtOAc (50
mL). The aqueous layer was separated, saturated with solid
NaCl, and extracted with EtOAc until TLC of the organic layer
showed no material that stained with ceric ammonium mo-
lybdate. The combined organic layers were washed with brine,
dried, and evaporated to a residue that was chromatographed
using 10-100% EtOAc in hexanes as eluant to afford a
colorless oil that crystallized (17, 1.02 g, 74%): mp 81-83 °C;
TLC Rf ) 0.26 (EtOAc); [R]D -4.8 (c 1.0, CHCl3); IR (cm-1):
20
1
3542, 1738, 1736, 1701, 1621. H NMR (keto-enol mixture) δ
1.37 (s, 2 H), 1.42 (s, 7 H), 1.88-1.98 (m, 1 H), 2.14-2.18 (m,

2170 J . Org. Chem., Vol. 65, No. 7, 2000
Gosselin and Lubell
residue that was chromatographed using 0-70% EtOAc in
hexanes containing 2% AcOH as eluant. Evaporation of the
collected fractions gave N-(Fmoc)amino acid 6 as a white
as a 2:1 diastereomeric mixture: 1.05 g, 81%, white foam, TLC
Rf ) 0.30 (EtOAc + 1% AcOH); H NMR δ 1.25-1.55 (bm, 4
1
H), 1.44 (s, 3 H), 1.48 (s, 6 H), 1.50 (s, 9 H), 1.58-1.71 (bm, 2
H), 1.84-1.99 (bm, 2 H), 2.03-2.33 (bm, 2 H), 3.80-4.10 (m,
1 H), 4.04-4.58 (bm, 5 H), 5.14 (bd, 0.2 H, J ) 7.4), 5.53 (bd,
0.4 H, J ) 7.6), 5.68 (bd, 0.2 H, J ) 8.0), 6.12 (bs, 0.2 H), 7.14-
7.78 (m, 8 H); 13C NMR δ 22.3, 25.1, 25.3, 25.5, 28.1, 28.4,
28.5, 28.6, 29.1, 32.6, 32.8, 33.6, 33.9, 46.4, 47.3, 53.4, 54.3,
54.4, 58.0, 59.4, 59.6, 60.0, 67.5, 73.0, 80.1, 80.4, 80.8, 82.2,
151.7, 154.1, 155.7, 156.1, 156.3, 168.8, 172.1, 177.2. HRMS
calcd for C34H44N2O8Na [M + Na]: 631.2996, found: 631.3039.
(2S,6RS,9S)-Allyl 5-[4′-[N-(F m oc)Am in o]-4′-(ter t-b u t -
yloxyca r bon yl)bu tyl]-N-(BOC)p r olin a te (24). A solution
of acid 23 (357 mg, 0.60 mmol) in CH3CN (12 mL) was treated
with allyl iodide (108 µL, 2.4 mmol, 400 mol %) and DIEA (210
µL, 1.2 mmol, 200 mol %), heated at a reflux for 3 h, cooled to
room temperature, and evaporated to dryness. The crude
residue was chromatographed using a gradient of 0-30%
EtOAc in hexanes as eluant. Evaporation of the collected
fractions gave 24 as a 2:1 diastereomeric mixture: 334 mg,
86%, white foam, TLC Rf ) 0.37 (1:4 EtOAc:hexanes); 1H NMR
δ 1.17-1.50 (m, 4 H), 1.37 (s, 3 H), 1.41 (s, 6 H), 1.43 (s, 9 H),
1.57-1.59 (bm, 2 H), 1.66-1.97 (bm, 3 H), 2.15 (bm, 1 H),
3.75-4.05 (bm, 1 H), 4.15-4.49 (bm, 5 H), 4.49-4.62 (bm, 2
H), 5.23 (bm, 2 H), 5.61 (bm, 0.6 H), 5.73 (bm, 0.3 H), 5.86 (m,
1 H), 7.23-7.26 (m, 2 H), 7.31-7.33 (m, 2 H), 7.55-7.57 (m, 2
H), 7.68-7.70 (m, 2 H); 13C NMR δ 22.1, 24.9, 25.2, 27.3, 27.4,
27.9, 28.2, 28.3, 28.9, 32.3, 32.5, 33.4, 47.1, 53.4, 54.1, 54.2,
54.8, 57.5, 57.6, 57.8, 59.3, 59.6, 65.3, 65.5, 66.8, 79.5, 79.7,
79.8, 81.5, 81.7, 81.9, 153.7, 154.2, 155.3, 155.8, 156.0, 171.7,
171.8, 172.5, 172.7. HRMS calcd for C37H48N2O8Na [M + Na]:
671.3308, found: 671.3333.
foam: 356 mg, 86% TLC Rf ) 0.27 (EtOAc + 1% AcOH); [R]20
D
-5.2 (c 1.0, CHCl3); IR (cm-1): 3290, 1717, 1648. H NMR δ
1
1.50-1.80 (bm, 6 H), 2.02-2.09 (bm, 2 H), 2.34-2.39 (bm, 1
H), 3.52 (bs, 1 H), 4.25 (m, 1 H), 4.31 (m, 1 H), 4.34 (m, 1 H),
6.35 (bd, 1 H, J ) 6.0), 7.18-7.78 (m, 8 H), 10.04 (bs, 1 H); 13
C
NMR δ 19.4, 24.4, 25.0, 27.0, 29.3, 47.1, 51.1, 54.0, 55.9, 67.1,
119.9, 125.3, 127.1, 127.7, 128.2, 129.0, 137.8, 141.2, 143.8,
144.0, 156.4, 171.2, 174.9, 176.2. HRMS calcd for C25H27N2O5
[M + H]: 435.1920, found: 435.1938.
(2S,6RS,9S)-1-ter t-Bu t yl 10-Ben zyl 5-H yd r oxy-2-[N-
(P h F )a m in o]-9-[N-(BOC)a m in o]d ec-4-en ed ioa te (21). A
solution of ketone 18 (2.0 g, 2.72 mmol) in MeOH (20 mL) and
THF (20 mL) was treated with CeCl3‚7H2O (1.12 g, 110 mol
%) and stirred for 10 min. Solid NaBH4 (255 mg, 6.8 mmol,
250 mol %) was added, and the solution was stirred for 10 min,
quenched with aqueous NaH2PO4 (15 mL, 1 M), and diluted
with EtOAc (25 mL). The layers were separated, and the
aqueous layer was extracted with EtOAc (2 × 50 mL). The
combined organic layers were washed with brine, dried, and
evaporated to a residue that was chromatographed using
0-50% EtOAc in hexanes as eluant. Evaporation of the
collected fractions gave allylic alcohol 21 as a 1:1 mixture of
diastereomers: 1.71 g, 86%, white foam; TLC Rf ) 0.58 (1:1
EtOAc:hexanes); 1H NMR δ 1.17 (s, 9 H), 1.42 (s, 9 H), 1.46-
1.55 (m, 2 H), 1.57-1.99 (m, 2 H), 2.07-2.11 (bm, 3 H), 2.57
(ddd, 1 H, J ) 3.0, 6.0, 12.1), 3.09 (bs, 1 H), 3.98 (m, 1 H),
4.35 (bm, 1 H), 5.05-5.20 (m, 2 H), 5.23-5.44 (m, 2 H), 5.56-
5.66 (m, 1 H), 7.14-7.19 (m, 7 H), 7.21-7.28 (m, 9 H), 7.30-
7.42 (m, 1 H), 7.63-7.66 (m, 1 H); 13C NMR δ 28.0, 28.4, 32.7,
38.5, 38.6, 53.6, 56.2, 56.3, 65.1, 67.0, 72.0, 72.2, 73.1, 80.0,
80.8, 155.6, 172.7, 174.6. HRMS calcd for C45H53N2O7 [M +
H]: 733.3853, found: 733.3869.
(3S,7S,10S)- a n d (3S,6R,10S)-2-Oxo-3-N-(F m oc)a m in o-
1-a za bicyclo[5.3.0]d eca n e-10-ca r boxyla te (22). A solution
of allyl ester 24 (793 mg, 1.25 mmol) in CH2Cl2 (40 mL) at 0
°C was treated with HCl bubbles for 1.5 h. The solution was
stirred for 1.5 h at 0 °C, warmed to room temperature over 30
min, and evaporated to dryness. Hydrochloride 25 was ob-
tained as a white glassy solid: HRMS calcd for C28H33N2O6
[M + H]: 493.2339, found: 493.2330. A solution of hydrochlo-
ride 25 (439 mg, 0.83 mmol) in CH2Cl2 (200 mL) was treated
with azabenzotriazolyl-1,1,3,3-tetramethylaminium hexafluo-
rophosphate (HATU, 631 mg, 1.66 mmol, 200 mol %) and DIEA
(433 µL, 2.49 mmol, 300 mol %). The solution was stirred for
3 h at room temperature. The volatiles were evaporated, and
the residue was chromatographed using 0-50% EtOAc in
hexanes as eluant. First to elute was concave (3S,7S,10S)-26:
65 mg, 17%, white foam, TLC Rf ) 0.32 (1:1 EtOAc:hexanes);
TLC Rf ) 0.58 (4:1 EtOAc:hexanes); [R]20D -37.8 (c 0.5, CHCl3);
1H NMR δ 1.61-1.90 (m, 5 H), 2.01-2.13 (m, 4 H), 2.23-2.31
(m, 1 H), 3.86 (m, 1 H), 4.22 (t, 1 H, J ) 7.2), 4.31 (dd, 1 H, J
) 5.0, 6.1), 4.34 (d, 2 H, J ) 7.3), 4.66 (d, 2 H, J ) 5.9), 4.67-
4.70 (m, 1 H), 5.33 (m, 2 H), 5.97 (m, 1 H), 6.25 (d, 1 H, J )
5.9), 7.26-7.42 (m, 4 H), 7.60 (d, 2 H, J ) 7.4), 7.76 (d, 2 H, J
) 7.5); 13C NMR δ 27.8, 31.8, 33.1, 34.4, 47.3, 55.0, 59.4, 60.7,
66.0, 67.1, 118.9, 120.1, 125.4, 127.2, 127.8, 131.9, 141.4, 144.1,
144.2, 155.7, 171.3, 171.8. HRMS calcd for C28H31N2O5 [M +
H]: 475.2233, found: 475.2245.
Next to elute was convex (3S,7R,10S)-26: 129 mg, 33%,
white foam; TLC Rf ) 0.19 (1:1 EtOAc:hexanes); TLC Rf )
0.45 (4:1 EtOAc:hexanes); [R]20D -54.6 (c 0.5, CHCl3); 1H NMR
δ 1.59-1.84 (m, 4 H), 1.97-2.11 (m, 5 H), 2.27 (m, 1 H), 3.78
(m, 1 H), 4.22 (t, 1 H, J ) 7.0), 4.30 (bs, 1 H), 4.35 (d, 2 H, J
) 6.5), 4.59-4.65 (bm, 3 H), 5.30 (m, 2 H), 5.93 (m, 1 H), 6.01
(bs, 1 H), 7.25-7.40 (m, 4 H), 7.61 (d, 2 H, J ) 7.4), 7.75 (d, 2
H, J ) 7.5); 13C NMR δ 23.2, 26.7, 28.5, 34.3, 47.3, 53.3, 59.8,
61.3, 65.8, 67.0, 118.6, 120.1, 125.3, 127.2, 127.8, 132.0, 141.4,
144.0, 144.1, 156.1, 170.4, 172.3. HRMS calcd for C28H31N2O5
[M + H]: 475.2233, found: 475.2245.
(2S,6RS,9S)-Ben zyl 5-[4′-[N-(P h F )a m in o]-4′-(ter t-b u t -
yloxyca r bon yl)bu t-1-en yl]-N-(BOC)p r olin a te (22). A solu-
tion of allylic alcohol 21 (1.71 g, 2.3 mmol) in CH2Cl2 (30 mL)
at 0 °C was treated with Et3N (2.26 mL, 16.3 mmol, 700 mol
%) and methanesulfonyl chloride (1.06 mL, 13.6 mmol, 580
mol %). The stirred mixture was left to warm to room
temperature for 20 h and evaporated to dryness, and the
residue was chromatographed using a gradient of 0-20%
EtOAc in hexanes as eluant. Evaporation of the collected
fractions gave a 2:1 diastereomeric mixture of prolines 22 (1.53
1
g, 91%, white foam): TLC Rf ) 0.57 (1:4 EtOAc:hexanes); H
NMR δ 1.21 (s, 3 H), 1.23 (s, 4 H), 1.24 (s, 2 H), 1.32 (s, 1H),
1.41 (s, 2 H), 1.49 (s, 3 H), 1.50 (s, 3 H), 1.55-2.26 (m, 6 H),
2.66 (m, 1 H), 3.13 (bs, 1 H), 4.27-4.49 (m, 1 H), 5.15 (m, 2
H), 5.32 (m, 1 H), 5.45 (m, 1 H), 7.13-7.26 (m, 7 H), 7.31-
7.49 (m, 9 H), 7.66-7.74 (m, 2 H); 13C NMR δ 27.4, 27.5, 27.9,
28.3, 28.4, 29.3, 29.5, 30.1, 31.7, 34.3, 34.4, 38.3, 38.5, 52.2,
53.1, 55.7, 56.0, 58.3, 58.7, 59.0, 59.2, 59.5, 59.6, 59.9, 62.0,
62.2, 66.5, 66.6, 66.8, 67.0, 72.96, 73.0, 76.3, 77.4, 79.7, 80.0,
80.4, 80.7, 153.3, 154.4, 155.3, 172.2, 172.5, 172.8, 174.2, 174.3.
HRMS calcd for
715.3735.
C45H51N2O6 [M + H]: 715.3747, found:
(2S,6RS,9S)-5-[4′-[N-(F m oc)a m in o]-4′-(ter t-b u t yloxy-
ca r bon yl)bu tyl]-N-(BOC)p r olin e (23). A solution of prolines
22 (1.53 g, 2.14 mmol) in THF (15 mL) and MeOH (15 mL)
was transferred into a hydrogenation apparatus and treated
with palladium-on-carbon (153 mg, 10 wt %). The pressure
bottle was filled, vented, and refilled four times with 6 atm of
H2. The reaction mixture was stirred for 16 h and filtered onto
a
plug of diatomaceous earth (Celite) that was washed
thoroughly with MeOH. Evaporation of the volatiles gave a
crude residue that was dissolved in acetone (12 mL) and water
(5 mL), treated with solid NaHCO3 (180 mg, 2.14 mmol, 100
mol %) and Fmoc-OSu (721 mg, 2.14 mmol, 100 mol %), stirred
for 2-3 h, acidified with solid citric acid to pH 4, saturated
with solid NaCl, and extracted with CH2Cl2 (3 × 25 mL). The
combined organic layers were washed with brine, dried, and
evaporated to a residue that was chromatographed using a
gradient of 20-100% EtOAc in hexanes containing 1% AcOH
as eluant. Evaporation of the collected fractions gave acid 23
(3S,7S,10S)-2-Oxo-3-N-(Fm oc)am in o-1-azabicyclo[5.3.0]-
d eca n e-10-ca r boxylic a cid ((7S)-7). A solution of (3S,7S,-
10S)-26 (60 mg, 0.126 mmol) in CH2Cl2 (2 mL) and AcOH (18
µL, 0.315 mmol, 250 mol %) was degassed by bubbling nitrogen
for 5-10 min and then treated with Pd(PPh3)2Cl2 (4 mol %)
and n-Bu3SnH (68 µL, 0.252 mmol, 200 mol %). The mixture

Rigid Dipeptide Surrogates
J . Org. Chem., Vol. 65, No. 7, 2000 2171
was stirred at room temperature for 1-2 min, when gas
evolution was complete and the color of the solution changed
from yellow to amber, and then it was evaporated to dryness.
Chromatography of the residue using a gradient of 50-100%
EtOAc in hexanes containing 1% AcOH and evaporation of the
reflux for 3 h, cooled, and evaporated to residue that was
directly examined by proton NMR. The limits of detection were
determined by measuring the diastereomeric methyl ester
singlets at 3.71 and 3.65 ppm in CDCl3 in the 400 MHz 1H
NMR spectrum. Less than 1% of the (1′R)-diastereomer was
detected in the spectrum for the (1′S)-urea 28. Purification by
chromatography using a gradient of pure hexanes to pure
EtOAc as eluant gave ureas 28 having the following spectra.
Ur ea (1′R)-28: 1H NMR δ 1.45 (d, 3 H, J ) 6.8), 1.46-1.69
(m, 4 H), 1.70-1.80 (m, 1 H), 1.81-2.05 (m, 4 H), 2.35 (m, 1
H), 3.50 (m, 1 H), 3.71 (s, 3 H), 4.15 (dd, 1 H, J ) 5.3, 7.2),
4.25 (m, 1 H), 4.83 (bm, 1 H), 5.27 (bs, 1 H), 5.59 (bs, 1 H),
7.19-7.34 (m, 5 H); HRMS calcd for C20H28N3O4 [M + H]:
374.2080, found: 374.2077.
collected fractions gave (7S)-7 as a foam: 54 mg, 99%; TLC Rf
1
) 0.38 (1% AcOH in EtOAc); [R]20 -54.0 (c 0.3, CHCl3); H
D
NMR δ 1.54-1.68 (m, 2 H), 1.83-1.85 (m, 3 H), 1.98-2.08 (m,
3 H), 2.11-2.35 (m, 2 H), 3.86 (m, 1 H), 4.21 (dd, 1 H, J ) 7.1,
7.3), 4.35 (bd, 3 H, J ) 7.5), 4.70 (d, 1 H, J ) 7.7), 6.21 (d, 1
H, J ) 6.2), 7.29-7.41 (m, 4 H), 7.60 (d, 2 H, J ) 7.3), 7.76 (d,
2 H, J ) 7.5); 13C NMR δ 26.8, 27.4, 31.3, 32.9, 34.2, 47.0,
54.6, 59.5, 66.9, 119.9, 125.1, 126.9, 127.6, 141.1, 143.7, 143.8,
155.5, 172.4, 174.7. HRMS calcd for C25H27N2O5 [M + H]:
435.1920, found: 435.1929.
Ur ea (1′S)-28: 1H NMR δ 1.45 (d, 3 H, J ) 6.9), 1.51-1.59
(m, 2 H), 1.62-1.76 (m, 4 H), 1.81-2.06 (m, 3 H), 2.31 (m, 1
H), 3.51 (bd, 1 H, J ) 4.9), 3.65 (s, 3 H), 4.14 (dd, 1 H, J ) 5.3,
7.0), 4.34 (dd, 1 H, J ) 6.0, 8.8), 4.88 (bs, 1 H), 5.37 (bs, 1 H),
5.69 (bs, 1 H), 7.20-7.40 (m, 5 H); HRMS calcd for C20H28N3O4
[M + H]: 374.2080, found: 374.2077.
(3S,7R,10S)-2-Oxo-3-N-(Fm oc)am in o-1-azabicyclo[5.3.0]-
d eca n e-10-ca r boxylic a cid ((7R)-7) was prepared using the
same procedure as described for (3S,7S,10S)-26 using (3S,7R,-
10S)-26 (123 mg, 0.259 mmol). Evaporation of the collected
fractions gave (7R)-7 as a foam: 98 mg, 88%; TLC Rf ) 0.19
1
(1% AcOH in EtOAc); [R]20 -40.0 (c 0.3, CHCl3); H NMR δ
D
Ack n ow led gm en t. This research was supported in
part by the Natural Sciences and Engineering Research
Council (NSERC) of Canada, and the Ministe`re de
l’EÄ ducation du Que´bec. The crystal structure analysis
of compound 20 was performed by Francine Be´langer-
Garie´py at l’Universite´ de Montre´al X-ray facility. F.G.
thanks both NSERC and FCAR for Ph.D. Scholarships
(97-00). We are grateful for a loan of Pd/C from J ohnson
Matthey PLC.
1.57-2.29 (bm, 10 H), 3.69 (bm, 1 H), 4.21 (t, 1 H, J ) 6.8),
4.31-4.35 (bm, 3 H), 4.58 (t, 1 H, J ) 7.9), 6.08 (bs, 1 H), 7.25-
7.46 (m, 4 H), 7.60 (d, 2 H, J ) 7.3), 7.73 (d, 2 H, J ) 7.4); 13
C
NMR δ 23.0, 26.4, 28.4, 34.2, 47.3, 53.8, 59.7, 61.6, 67.1, 120.1,
125.4, 127.3, 127.8, 141.4, 144.0, 144.1, 156.3, 171.3, 176.0.
HRMS calcd for
435.1929.
C25H27N2O5 [M + H]: 435.1920, found:
En a n tiom er ic P u r ity of (3S,6R,10S)-ter t-Bu tyl 2-Oxo-
3-N-(BOC)a m in o-1-a za bicyclo[4.4.0]d eca n e-10-ca r boxy-
la te ((3S,6R,10S)-20). A solution of (3S,6R,10S)-20 (8.1 mg)
in MeOH (5 mL) at 0 °C was treated with SOCl2 (100 µL),
stirred for 2.5 h at room temperature when TLC (100% EtOAc)
showed complete disappearance of the starting material 20.
The volatiles were removed under vacuum, and the hydro-
chloride 27 was dissolved in THF (1 mL), treated with either
(R)- or (S)-R-methylbenzylisocyanate (7.4 µL, 0.05 mmol, 200
mol %) and Et3N (7.4 µL, 0.05 mmol, 200 mol %), heated at a
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
1
tails for the preparation of 14, H and 13C NMR spectra of 6,
7, 17, 21, 22, 24, 26, 28, and crystallographic data for 20. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O991766O