Cyclopropane-derived peptidomimetics. Design, synthesis, and evaluation of novel enkephalin analogues

Article abstract of DOI:10.1021/jo991288h

It is known that peptide mimics containing trans-substituted cyclopropanes stabilize extended conformations of oligopeptides, and molecular modeling studies now suggest that the corresponding cis- cyclopropane dipeptide isosteres could stabilize a reverse turn. To begin to assess this possibility, a series of cis-substituted cyclopropanes were incorporated as replacements of the Gly²-Gly³ and Phe⁴-Leu⁵ dipeptide subunits in Leu-enkephalin (H₂N-Tyr-Gly-Gly-Phe-Leu-OH), which is believed to bind to opiod receptors in a conformation containing a β-turn. General methods for the synthesis of the cyclopropane-containing dipeptide isosteres -XaaΨ[COcpCO]Yaa- and -XaaΨ[NHcpNH]Yaa-were developed by a sequence that featured the enantioselective cyclization of allylic diazoacetates catalyzed by the chiral rhodium complexes Rh₂[(5S)-MEPY]₄ and Rh₂[(5R)-MEPY]₄. A useful modification of the Weinreb amidation procedure was applied to the opening of the intermediate lactones with dipeptides, and a novel method for the synthesis of substituted diaminocyclopropanes was also developed. The Leu-enkephalin analogues were tested in a panel of binding and functional assays, and although those derivatives containing cyclopropane replacements of the Gly²-Gly³ exhibited low micromolar affinity for the μ- receptor, analogues containing such replacements for the Phe⁴-Leu⁵ subunit did not bind with significant affinity to any of the opiod receptors. These results are discussed.

Full text of DOI:10.1021/jo991288h

J . Org. Chem. 2000, 65, 1305-1318
1305
Cyclop r op a n e-Der ived P ep tid om im etics. Design , Syn th esis, a n d
Eva lu a tion of Novel En k ep h a lin An a logu es
Stephen F. Martin,* Michael P. Dwyer, Benoˆıt Hartmann, and Kyle S. Knight
Department of Chemistry and Biochemistry, The University of Texas, Austin, Texas 78712
Received August 12, 1999
It is known that peptide mimics containing trans-substituted cyclopropanes stabilize extended
conformations of oligopeptides, and molecular modeling studies now suggest that the corresponding
cis-cyclopropane dipeptide isosteres could stabilize a reverse turn. To begin to assess this possibility,
a series of cis-substituted cyclopropanes were incorporated as replacements of the Gly2-Gly3 and
Phe4-Leu5 dipeptide subunits in Leu-enkephalin (H2N-Tyr-Gly-Gly-Phe-Leu-OH), which is believed
to bind to opiod receptors in a conformation containing a â-turn. General methods for the synthesis
of the cyclopropane-containing dipeptide isosteres -XaaΨ[COcpCO]Yaa- and -XaaΨ[NHcpNH]Yaa-
were developed by a sequence that featured the enantioselective cyclization of allylic diazoacetates
catalyzed by the chiral rhodium complexes Rh2[(5S)-MEPY]4 and Rh2[(5R)-MEPY]4. A useful
modification of the Weinreb amidation procedure was applied to the opening of the intermediate
lactones with dipeptides, and a novel method for the synthesis of substituted diaminocyclopropanes
was also developed. The Leu-enkephalin analogues were tested in a panel of binding and functional
assays, and although those derivatives containing cyclopropane replacements of the Gly2-Gly3
exhibited low micromolar affinity for the µ-receptor, analogues containing such replacements for
the Phe4-Leu5 subunit did not bind with significant affinity to any of the opiod receptors. These
results are discussed.
In tr od u ction
few that also are capable of orientating the amino acid
side chains, which provide crucial sites for recognition,
specificity, and binding. Thus, there is a need for peptide
mimics that preorganize the peptide backbone and the
side chains in the biologically active conformation of the
native peptide.3
The ability to design small molecules that contain the
key structural and functional elements of biologically
active peptides is a central goal in drug discovery.
However, a major challenge in this area is the ability to
define the biologically active conformation, or the bound
structure, of the peptide. Strategies for elucidating this
structure typically involve introducing conformational
restraints at specific sites of the peptide.1 The solution
structures of the constrained analogues can then be
determined and correlated with binding and biological
activity in an iterative process that ultimately provides
insights regarding the bound conformation of the peptide.
Most conformationally restricted replacements of peptide
secondary structure imitate a turn or helix, but there
have been several reports of mimics that enforce extended
structures.2 Most known peptide replacements have been
designed only to constrain the backbone, and there are
Toward identifying peptide replacements that would
satisfy the above criteria and serve as useful tools to help
elucidate the biologically active conformation of oligopep-
tides, we launched a program to evaluate the cyclopro-
panes 2 (-XaaΨ[COcpCO]Yaa-), and 3 (-XaaΨ[NHcpNH]-
Yaa-) as novel mimics of the dipeptide 1.4-8 The cyclopro-
pane ring in 2 incorporates the R-carbon, the nitrogen,
and the â-carbon of the amino acid Yaa, whereas the
cyclopropane in 3 replaces the R-carbon, the carbonyl
carbon, and the â-carbon atom of Yaa. Preliminary
molecular modeling studies to identify low-energy con-
formations of 2 and 3 indicated that when the backbone
substituents were trans, the φ- or ψ-angle would be
locked, and a local â-strand structure, a motif commonly
(1) For leading reviews, see: (a) Spatola, A. F. In Chemistry and
Biochemistry of Amino Acids, Peptides, and Proteins; Weinstein, B.,
Ed; Marcel Dekker: New York 1983; Vol. 7, pp 267-357. (b) Hruby,
B. J .; Al-Obeidi, F.; Kazmierski, W. Biochem. J . 1990, 268, 249-262.
(c) Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bo¨s, M.; Cook, C. M.; Fry,
D. C.; Graves, B. J .; Hatada, M.; Hill, D. E.; Kahn, M.; Madison, V. S.;
Ruisiecki, V. K.; Sarabu, R.; Sepinwall, J .; Vincent, G. P.; Voss, M. E.
J . Med. Chem. 1993, 36, 3039-3049. (d) Giannis, A.; Kolter, T. Angew.
Chem., Int. Ed. Eng. 1993, 32, 1244-1267. (e) Gante, J . Angew. Chem.,
Int. Ed. Eng. 1994, 33, 1699-1720. (f) Hanessian, S.; McNaughton-
Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 38, 12789-
12854. (g) Goodman, M.; Zhang, J . Chemtracts-Org. Chem. 1997, 10,
629-645.
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G. L. Biopolymer 1997, 43, 191-217. (b) Hruby, V. J .; Li, G.; Haskell-
Luevano, C.; Shenderovich, M. Biopolymer 1997, 43, 219-266.
(4) Martin, S. F.; Austin, R. E.; Oalmann, C. J . Tetrahedron Lett.
1990, 31, 4731-4734.
(5) (a) Martin, S. F.; Austin, R. E.; Oalmann, C. J .; Baker, W. R.;
Condon, S. L.; DeLara, E.; Rosenberg, S. H.; Spina, K. P.; Stein, H.
H.; Cohen, J .; Kleinert, H. D. J . Med. Chem. 1992, 35, 1710-1721. (b)
Baker, W. R.; J ae, H.-S.; Martin, S. F.; Condon, S. L.; Stein, H. H.;
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S. V.; Topol, I. A. J . Med. Chem. 1998, 41, 1581-1597. (b) Hillier, M.
C.; Martin, S. F. In Methods in Molecular Medicine: Vol. 30, Peptido-
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Press: Totowa, N. J ., 1999; pp 397-406.
(2) 2. For example, see: (a) Hagihara, M.; Anthony, N. J .; Stout, T.
J .; Clardy, J .; Schreiber, S. L. J . Am. Chem. Soc. 1992, 114, 6568-
6570. (b) Smith, A. B., III; Guzman, M. C.; Sprengeler, P. A.; Keenan,
T. P.; Holcomb, R. C.; Wood, J . L.; Carroll, P. J .; Hirschmann, R. J .
Am. Chem. Soc. 1994, 116, 9947-9962. (c) Chen, L.; Trilles, R. V.
Tetrahedron Lett. 1995, 36, 8715-8718. (d) Boumendjel, A.; Roberts,
J . C.; Hu, E.; Pallai, P. V.; Rebek, J r., J . J . Org. Chem. 1996, 61, 4434-
4438. (e) J anetka, J . W.; Raman, P.; Satyshur, K.; Flentke, G. R.; Rich,
D. H. J . Am. Chem. Soc. 1997, 119, 441-442.
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3521-3532.
(8) Martin, S. F.; Hom, R. K. Tetrahedron Lett. 1999, 40, 2887-
2890.
10.1021/jo991288h CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/09/2000

1306 J . Org. Chem., Vol. 65, No. 5, 2000
Martin et al.
found in inhibitors bound to enzyme active sites,9 would
be preferred. Similar modeling studies of the isomers of
2 and 3 in which the backbone substituents were cis
suggested that such replacements might enforce a reverse
turn, such as a â-turn.10 However, because of steric
interactions between the side chains, extended structures
were also observed as local minima. Depending upon the
stereochemistry at the cyclopropyl carbons bearing R2 in
2 and 3, this side chain may occupy a spatial position
relative to the backbone that approximates ø1-angles in
1 of gauche(-) (-60°), gauche(+) (+60°), or anti ((180°).
The aforementioned studies established the underlying
efficacy of cyclopropanes related to 2 and 3 as structural
tools and isosteric mimics of dipeptide arrays in cases
where the pseudopeptide is known to bind in an ex-
tended, â-strand conformation. However, we were inter-
ested in exploring the possibility that positioning the
backbone substituents in a cis-orientation might locally
stabilize a reverse turn. Inasmuch as enkephalins appear
to bind to opiod receptors in a turned conformation (vide
infra), it occurred to us that preparing and evaluating
the biological activities of Leu-enkephalin analogues
containing cis-2 and cis-3 mimics would present an
opportunity to determine whether such replacements
enforced their biologically active conformation. We now
present the results of these investigations.
Resu lts a n d Discu ssion
Design of Novel En k ep h a lin An a logu es. Determin-
ing the three-dimensional structures of enkephalins,
H2N-Tyr-Gly-Gly-Phe-Leu(Met)-OH, bound to the µ- and
δ-opioid receptors has been the focus of numerous
investigations.13,14 Conformationally constrained enkepha-
lin derivatives have been identified that are highly potent
and selective,15 and an analysis of these and other reports
suggests that a 5f2 â-turn might be an important
structural motif in the biologically active conformation
of these important neuropeptides.16 On the basis of
modeling studies, we reasoned that replacing the Gly2-
Gly3 and the Phe4-Leu5 subunits with cis-GlyΨ[COcpCO]-
As proof of the concept, we first introduced truncated
analogues of tr a n s-2 into a number of potent pseudopep-
tide inhibitors of renin.5 We have since incorporated
replacements related to 2 and 3 in inhibitors of HIV-1
protease6 and matrix metalloproteinases,7,11 and others
have used such cyclopropane-derived mimics in non-
peptide fibrinogen receptor antagonists.12 We verified the
predicted structural properties of peptide replacements
related to 2 in our study of HIV-1 protease inhibitors
wherein compounds 4 and 5, which contain two cyclo-
propane replacements, were found to be subnanomolar
inhibitors of HIV-1 protease that were equipotent with
flexible analogues. The solution structure of 4 was
determined by NMR, and the structure of the complex
of 5 bound to HIV-1 protease was established by X-ray
crystallography. Except at two terminal benzyl groups,
the solution conformation of 4 was nearly identical to the
enzyme-bound structures of 5 and other closely related,
flexible HIV-1 protease inhibitors. Thus, the two cyclo-
propane rings in 4 and 5 stabilize extended structures
in solution that correspond closely to the biologically
active conformations of 4 and 5 as well as more flexible
ligands.
(13) For leading references to conformational calculations of the
enkephalins, see: (a) Montcalm, T.; Cui, W.; Zhao, H.; Guarnieri, F.;
Wilson, S. R. J . Mol. Struct. (THEOCHEM) 1994, 308, 37-51. (b) Koca,
J .; Carlsen, P. H. J . J . Mol. Struct. (THEOCHEM) 1995, 337, 17-24.
(14) For reviews, see: (a) Schiller, P. W. In The Peptides: Analysis,
Synthesis, Biology. Vol. 6. Opioid Peptides: Biology, Chemistry and
Genetics; Udenfriend, S.; Meienhofer, J ., Eds.; Academic Press: New
York, 1984; pp 219-268. (b) Hansen, P. E.; Morgan, B. A. In The
Peptides: Analysis, Synthesis, Biology. Vol. 6. Opioid Peptides: Biology,
Chemistry and Genetics; Udenfriend, S.; Meienhofer, J ., Eds.; Academic
Press: New York, 1984; pp 269-321.
(15) 57. (a) Hruby, V. J .; Pettit, B. M. In Computer Aided Drug
Design; Perun, T., Probst, C., Eds.; Dekker: New York, 1989; pp 406-
460. (b) Hruby, V. J .; Toth, G.; Gehrig, C. A.; Kao, L.-F.; Knapp, R.;
Lui, G. K.; Yamamura, H. I.; Kramer, T. H.; Davis, P.; Burks, T. F. J .
Med. Chem. 1991, 34, 1823-1830. (c) Kazmierski, W. M.; Yamamura,
H. I.; Hruby, V. J . J . Am. Chem. Soc. 1991, 113, 2275-2283. (d)
Schiller, P. W.; Weltrowska, G.; Nguyen, T. M.-D.; Lemieux, C.; Chung,
N. N.; Marsden, B. J .; Wilkes, B. C. J . Med. Chem. 1991, 34, 3125-
3132. (e) Schiller, P. W.; Weltrowska, G.; Nguyen, T. M.-D.; Wilkes,
B. C.; Chung, N. N.; Lemieux, C. J . Med. Chem. 1993, 36, 3182-3187.
(f) Lomize, A. L.; Flippen-Anderson, J . L.; George, C.; Mosberg, H. I.
J . Am. Chem. Soc. 1994, 116, 429-436. (g) Mosberg, H. I.; Lomize, A.
L.; Wang, C.; Kroona, H.; Heyl, D. L.; Sobczyk-Kojiro, K.; Ma, W.;
Mousigian, C.; Porreca, F. J . Med. Chem. 1994, 37, 4371-4383. (h)
Mosberg, H. I.; Omnaas, J . R.; Lomize, A. L.; Heyl, D. L.; Nordan, I.;
Mousigian, C.; Davis, P.; Porreca, F. J . Med. Chem. 1994, 37, 4384-
4391. (i) Flippen-Anderson, J . L.; Hruby, V. J .; Collins, N.; George, C.;
Cudney, B. J . Am. Chem. Soc. 1994, 116, 7523-7531. (j) Collins, N.;
Flippen-Anderson, J . L.; Haaseth, R. C.; Deschamps, J . R.; George,
C.; Ko¨ver, K.; Hruby, V. J . J . Am. Chem. Soc. 1996, 118, 2143-2152.
(16) (a) Currie, B. L.; Krstenansky, J . L.; Lin, Z.-L.; Ungwitayatorn,
J .; Lee, Y.-H.; del Rosario-Chow, M.; Sheu, W.-S.; J ohnson, M. E.
Tetrahedron 1993, 49, 3489-3500. (b) Su, T.; Nakanishi, H.; Xue, L.;
Chen, B.; Tuladhar, S.; J ohnson, M. E.; Kahn, M. BioMed. Chem. Lett.
1993, 3, 835-840.
(9) For a review, see: Babine, R. E.; Bender, S. L. Chem. Rev. 1997,
97, 1359-1472.
(10) Ball, J . B.; Hughes, R. A.; Alewood, P. F.; Andrews, P. R.
Tetrahedron 1993, 49, 3467-3478.
(11) (a) Kennedy, A. L. Masters Thesis, The University of Texas at
Austin, 1996. (b) Frey, R. R. Masters Thesis, The University of Texas
at Austin, 1998. (c) Gaul, C. Masters Thesis, The University of Texas
at Austin, 1998.
(12) Bovy, P. R.; Tjoeng, F. S.; Rico, J . G.; Rogers, T. E.; Lindmark,
R. J .; Zablocki, J . A.; Garland, R. B.; McMackins, D. E.; Dayringer,
H.; Toth, M. V.; Zupec, M. E.; Rao, S.; Panzer-Knodle, S. G.; Nicholson,
N. S.; Salyers, A.; Taite, B. B.; Herin, M.; Miyano, M.; Feigen, L. P.;
Adams, S. P. Bioorg. Med. Chem. 1994, 2, 881-895.

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 65, No. 5, 2000 1307
Ala- and cis-PheΨ[NHcpNH]Leu- isosteres, respectively,
might stabilize such a reverse turn via geometric con-
straints alone. Consequently, the pseudopeptides 7-9,
which are analogues of Leu-enkephalin methyl ester (6),
were selected as the primary targets for synthesis.
Because it is likely that different conformations of Leu-
enkephalin bind to the several types of opiod receptors,
we postulated that altering the stereochemistry on the
dipeptide replacement might eventuate in receptor se-
lectivity. Pseudopeptides 10 and 11 were thus identified
as additional targets for synthesis. The flexible analogues
12-14 were prepared as controls, as they are functionally
more closely related to 7-11 than Leu-enkephalin itself.
there are potent linear enkephalin analogues that cannot
form hydrogen bond-stabilized 5f2 turns.17 Thus, sta-
bilization of the putative â-turn by an intramolecular
hydrogen-bond is not itself essential for high-affinity
binding to opiod receptors. Despite this argumentation,
replacing the Gly2-Gly3 amide bond was not without
potential risk, as this linkage has been shown to play a
role in determining enkephalin activity.18 The orientation
of phenyl group on the Phe4 residue in ø-space was also
known to be important as documented in studies involv-
ing enkephalins that contain dehydrophenylalanine4 and
cyclopropylphenylalanine4 replacements.19 Inasmuch as
the phenyl group in 8 and 9 is constrained in an anti
conformation, these enkephalin analogues might not be
expected to bind strongly to the δ-receptor, where the
gauche(-) orientation is known to be critical.15b On the
other hand, compounds 8 and 9 might probe whether an
anti orientation of the phenyl group was important for
binding to other receptors.
Syn th esis of En k ep h a lin An a logu es. One of the
significant challenges associated with the syntheses of
pseudopeptides related to 7-11 was the design of a
general entry to the dipeptide isosteres 2 and 3 that
originated with non-amino acid precursors. To address
this problem, we developed a stereoselective approach to
cyclopropanes having the various substitution patterns
found in 2 and 3 by a sequence of reactions that featured
the enantioselective, intramolecular cyclopropanations of
allylic diazoacetates, a construction that has been pio-
neered in our laboratories.20,21 In the event, the synthesis
of the enkephalin analogue 7 commenced with heating
the diazo ester 15 in the presence of the chiral rhodium
catalyst Rh2[(5S)-MEPY]4 to give 16 as the major product
(g94% ee; >95% de) (Scheme 1).21 Ozonolysis of the
double bond of 16 and reductive workup with sodium
borohydride gave an intermediate alcohol that was
converted in two steps (50% overall yield from 16) into
the azide 17, which incorporates the essential functional
and stereochemical features present in the cis-GlyΨ-
[COcpCO]Ala- isostere.
The most direct tactic for elaborating the C-terminus
of the pseudopeptide 7 would involve N-acylation of the
H-Phe-Leu-OH dipeptide with the lactone 17. However,
at the outset of these investigations there were no known
methods for achieving this useful transformation. We
then discovered that cyclopropyl lactones related to 17
could be opened with amino acids and oligopeptides by a
modification of the Weinreb amidation protocol,7,22,23 and
we recently extended this reaction to the preparation
(17) Spatola, A. F.; Saneii, H.; Edwards, J . V.; Bettag, A. L.; Anwer,
M. K.; Rowell, P.; Browne, B.; Lahti, R.; von Voigtlander, P. Life Sci.
1986, 38, 1243-1249.
(18) Roubini, E.; Laufer, R.; Gilon, C.; Selinger, Z.; Roques, B. P.;
Chorev, M. J . Med. Chem. 1991, 34, 2430-2438.
(19) (a) Shimohigashi, Y.; English, M. L.; Stammer, C. H.; Costa,
T. Biochem. Biophys. Res. Commun. 1982, 104, 583-590. (b) Kimura,
H.; Stammer, C. H.; Shimohigashi, Y.; Lin, C. R.; Stewart, J . Biochem.
Biophys. Res. Commun. 1983, 115, 112-115. (c) Shimohigashi, Y.;
Costa, T.; Nitz, T. J .; Chen, C. H.; Stammer, C. H. Biochem. Biophys.
Res. Commun. 1984, 121, 966-972.
In the context of evaluating cis-cyclopropane replace-
ments related to 2 and 3, it is important to recognize that
the enkephalin analogues 7-10 differ in some significant
ways from Leu-enkephalin. Although each of these
compounds contains geometric constraints that might
stabilize a turned structure, they also lack one or more
of the natural amide linkages that would presumably be
involved in the intramolecular hydrogen bond between
the Gly2 and Leu5 residues. Whether the loss of this
hydrogen-bond would ultimately be detrimental to recep-
tor binding affinity cannot be predicted a priori, because
(20) (a) Doyle, M. P.; Pieters, R. J .; Martin, S. F.; Austin, R. E.;
Oalmann, C. J .; Mu¨ller, P. J . Am. Chem. Soc. 1991, 113, 1423-1424.
(b) Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.; Dyatkin, A.
B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C. J .; Pieters,
R. J .; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.;
Martin, S. F. J . Am. Chem. Soc. 1995, 117, 5763-5775.
(21) Martin, S. F.; Spaller, M. R.; Liras, S.; Hartmann, B. J . Am.
Chem. Soc. 1994, 116, 4493-4494.
(22) (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 4171-4174. (b) Sibi, M. P. Org. Prep. Proc. Int. 1993 25, 15-40.

1308 J . Org. Chem., Vol. 65, No. 5, 2000
Martin et al.
Sch em e 1
Sch em e 2
Sch em e 3
dipeptides.24 Following this precedent, 17 was allowed
to react with H-Phe-Leu-OH in the presence of Me3Al (3
equiv) in refluxing dichloroethane followed by esterifi-
cation of the intermediate acid with diazomethane to
furnish 18 in 60% overall yield. Reduction of the azide
function afforded 19, which was transformed into the
enkephalin analogue 7 in 67% yield by standard peptide
coupling (HOBt, EDC) with Boc-Tyr-OH and acid-
catalyzed deprotection. This route to 7 is both efficient
and concise, requiring only 10 steps from commercially
available starting materials.
The diastereoisomeric enkephalin analogue 10, in
which the cis-GlyΨ[COcpCO]Ala- replacement is enan-
tiomeric with that present in 7, was prepared by a
sequence of reactions identical to those shown in Scheme
1, except that Rh2[(5R)-MEPY]4 was used as the catalyst
to effect enantioselective cyclization of 15 to give 20, the
enantiomer of 16 (Scheme 2).
The synthesis of the trans-GlyΨ[COcpCO]Ala- dipep-
tide replacement 26 required a stereochemical inversion
at the C-terminal cyclopropyl carbon prior to its incor-
poration into 11 (Scheme 3). The lactone ring of the vinyl
cyclopropane 20 was first opened by MeONHMe in the
presence of Me3Al, and after protection of the secondary
hydroxyl group as a silyl ether, the stereocenter R to the
hydroxamide group was epimerized using strong base to
afford 23 in 48% yield overall yield from 20. If the
intermediate alcohol was not protected prior to epimer-
ization, relactonization to return the starting lactone 20
was a significant side reaction. The subsequent trans-
formation of 23 into the azide 24 proceeded in 60% overall
yield following protocols previously developed for the
syntheses of 17 and 21 (Schemes 1 and 2). Hydrolysis of
the hydroxamide moiety in 24 followed by deprotection
of the secondary hydroxyl group furnished 25. The azide
was then reduced by catalytic hydrogenation in the
presence of (Boc)2O to give the protected dipeptide
isostere 26 in 63% overall yield from 24. The final
conversion of 26 into the enkephalin analogue 11 was
achieved in 36% overall yield by sequential couplings
with Phe-Leu-OMe and Boc-Tyr-OH according to stand-
ard protocols in peptide chemistry.
The syntheses of mimics of the general type 3 pre-
sented a somewhat greater challenge because of the
known tendency of amino- and diaminocyclopropanes to
undergo facile ring-opening reactions.25 However, N-
acylated aminocyclopropanes are much less inclined to
suffer such deleterious side reactions. We were able to
exploit the stabilizing effect derived from this N-acylation
in the design of a novel approach to substituted diamino-
cyclopropanes as exemplified by the preparation of the
protected cis-PheΨ[NHcpNH]Leu- isostere 34, which was
then incorporated in the enkephalin analogue 8 (Scheme
4).
(25) For example, see: (a) Schroff, C. C.; Stewart, W. S.; Uhm, S.
J .; Wheeler, J . W. J . Org. Chem. 1971, 36, 3356-3361. (b) Cannon, J .
G.; Garst, J . E. J . Org. Chem. 1975, 40, 182-184. (c) Paulini, K.;
Reissig, H.-R. Liebigs Ann. Chem. 1991, 455-461. (d) Paulini, K.;
Reissig, H.-U. Liebigs Ann. Chem. 1994, 549-554. See also: (e) Von
Der Saal, W.; Quast, H. J . Org. Chem. 1995, 60, 4024-4029.
(23) For an independent report of a related process, see: Hanko,
R.; Rabe, K.; Dally, R.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1991,
30, 1690-1693.
(24) Martin, S. F.; Dwyer, M. P.; Lynch, C. L. Tetrahedron Lett.
1998, 39, 1517-1520.

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 65, No. 5, 2000 1309
Sch em e 4
Oxidation of the primary alcohol in 32 with RuCl3/NaIO4
afforded the desired acid 33 (85% yield).28
When 33 was subjected to modified Curtius conditions
using diphenyl phosphorazidate in the presence of allyl
alcohol,29 the carbamate 34 was produced, albeit in
variable yields (40-75%), together with recovered start-
ing material. However, 34 could be prepared in 85% yield
from the acid 33 via a stepwise Curtius procedure that
featured preparation of the intermediate azide by activa-
tion of the acid as a mixed anhydride.30 The tactic that
was invented for appending the N-terminal Tyr-Gly-Gly
tripeptide moiety was inspired by an elegant trans-
acylation procedure first developed by Hiemstra and
Speckamp.31 In a modification of this procedure, the Alloc
carbamate 34 was allowed to react with the preformed
HOBt ester of Boc-Tyr(O-t-Bu)-Gly-Gly-OH, which was
generated in situ by the action of HOBt and DCC,32 in
the presence of Pd(PPh3)4 and Bu3SnH to deliver 35 in
78% yield. Global deprotection of 35 with CF3CO2H then
gave 8 in 90% yield.
The methods required for the synthesis of the bis-
cyclopropane pseudopeptide 9 were now established, and
two of the key intermediates 17 and 34 needed for this
endeavor were already in hand. The lactone 17 was first
converted into the ester 37 (70% yield) by acid-catalyzed
methanolysis followed by protection of the secondary
alcohol as its silyl ether (Scheme 5). Catalytic reduction
of the azido group in 37 gave an intermediate amine that
was coupled with a suitably protected tyrosine; subse-
quent hydrolysis of the C-terminal methyl ester afforded
the acid 38 in 70% overall yield. The carboxylic acid in
38 was preactivated as its HOBt ester and allowed to
react with 34 in the presence of Pd(PPh3)4 and Bu3SnH
according to our modified Hiemstra-Speckamp protocol
to furnish 39 in 75% yield. Although the tert-butyl groups
in 39 could not be cleanly removed under standard acidic
conditions (CF3COH/CH2Cl2, 4 N HCl/dioxane, etc.),
treatment of 39 with excess trimethylsilyliodide in
CH3CN delivered 9 in 85% yield.33
It remained to prepare the flexible analogues 12-14
that would serve as controls in the biological evaluation
of 7-11. The synthesis of 12 commenced with opening
the lactone ring of the known azide 4034 with the H-Phe-
Leu-OH dipeptide in the presence of Me3Al according to
our modification of the Weinreb amidation;7,24 esterifi-
cation of the resulting acid with diazomethane then
provided 41 in 63% yield (Scheme 6). Catalytic reduction
of the azide functionality followed by coupling the inter-
mediate amine with Boc-Tyr-OH and global deprotection
We had previously prepared the cyclopropyl lactone 28
by the Rh2[(5S)-MEPY]4-catalyzed cyclization of the diazo
ester 27 in 77% yield and 65% ee,20 and it was not
necessary to increase the enantiomeric purity of 28, as
the unwanted enantiomer was easily removed at a later
stage (vide infra). Thus, treatment of 28 with hydrazine
followed by reaction of the resultant hydrazide with
nitrous acid gave an intermediate hydroxy isocyanate
that cyclized spontaneously to provide the urethane 29
in 83% overall yield. Base-induced hydrolysis of 29 then
furnished the amino alcohol 30 (90% yield). The leucine
fragment was then introduced by the N-alkylation of 30
with the triflate 31, which was prepared from 5(R)-
methyl oxopentanote26 (Tf2O, 2,6-lutidine, 25 min at 0
°C). The inseparable mixture (5:1) of secondary amines
thus obtained was treated directly with Boc2O to give a
readily separable mixture of 32 (46% overall yield)
together with its diastereoisomer 36 (9% overall yield).27
(27) For related reactions, see: (a) Chapman, K. T.; Kopka, I. E.;
Durette, P. L.; Esser, C. K.; Lanza, T. J .; Izquierdo-Martin, M.;
Niedzwiecki, L.; Chang, B.; Harrison, R. K.; Kuo, D. W.; Lin, T.-Y.;
Stein, R. L.; Hagmann, W. K. J . Med. Chem. 1993, 36, 4293-4301. (b)
Bird, J .; De Mello, R. C.; Harper, G. P.; Hunter, D. J .; Karran, E. H.;
Markwell, R. E.; Miles-Williams, A. J .; Rahman, S. S.; Ward, R. W. J .
Med. Chem. 1994, 37, 158-169.
(28) (a) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K.
B. J . Org. Chem. 1981, 46, 3936-3938. See also: (b) Godier-Marc, E.;
Aitken, D. J .; Husson, H.-P. Tetrahedron Lett. 1997, 38, 4065-4068.
(29) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30,
2151-2157.
(30) Kaiser, C.; Weinstock, J . Org. Synth. 1988, 6, 910-913.
(31) Roos, E. C.; Bernabe, P.; Hiemstra, H, Speckamp, W. N.;
Kaptein, B.; Boesten, W. H. J . J . Org. Chem. 1995, 60, 1733-1740.
(32) Bower, J . D.; Guest, K. P.; Morgan, B. A. J . Chem. Soc., Perkin
1 1976, 2488-2492.
(33) Lott, R. S.; Chauhan, V. S.; Stammer, C. H. J . Chem. Soc.,
Chem. Commun. 1979, 495-496.
(34) Olsen, R. K.; Bhat, K. L.; Wardle, R. B.; Hennen, W. J .; Kini,
G. D. J . Org. Chem. 1985, 50, 896-899.
(26) Kolasa, T.; Miller, M. J . J . Org. Chem. 1987, 52, 4978-4984.

1310 J . Org. Chem., Vol. 65, No. 5, 2000
Martin et al.
Sch em e 5
Sch em e 7
Ta ble 1. Biologica l Activities of Con str a in ed a n d
F lexible Leu -en k ep h a lin An a logu es
Ki, (nM)
IC50 (nM)
MVD(δ)
compound
Leu-enkephalin 22
[3H]DAMGO [3H]Cl-DPDPE GPI(µ)
2
87
7
6
7
8
9
10
11
12
13
14
3.9 ( 1.1
1355 ( 263
>10000
10.6 ( 3.0
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
167 ( 14 87 ( 15
640 ( 241 4261 ( 921
NAa
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
>10000
1344 ( 367
2159 ( 95
1367 ( 111
1194 ( 539
438 ( 230
a
NA ) not active up to 10000 nM.
The binding affinities, which were calculated as Kis,36 of
these compounds to the µ- and δ-opiate receptors were
determined by their ability to displace the radioligands
[3H]DAMGO and [3H]Cl-DPDPE, respectively, from crude
guinea pig brain membranes; concentrations of the test
compounds were varied from 10-5 to 10-10 nM. The opiate
agonist potentials of the test compounds were then
determined using electrically stimulated guinea pig ileum
(GPI) and mouse vas deferens (MVD) muscle prepara-
tions.37-39 The tissues were stimulated and treated with
the test compounds, and the inhibition of the muscle
contraction was measured at different concentrations to
obtain a concentration-response curve. The IC50 in these
assays was defined as the concentration of the agonist
that caused 50% inhibition of the electrically induced
contractions. The results obtained for the radioligand
binding assays as well as the GPI and MVD bioassays
are summarized in Table 1.
As measured by their Kis, the cyclopropane-containing
pseudopeptides 7, 10, and 11 as well as the flexible
controls 12-14 exhibited low micromolar binding affinity
for the µ-receptor and virtually no affinity for the
δ-receptor, whereas the cyclopropane-containing pseudo-
peptides 8 and 9 had no observable affinity for either
opioid receptor. In the functional assays, only 7 exhibited
weak agonist activity for the µ- and δ-receptors as
measured by the experimental IC50s. The ratio of the IC50
Sch em e 6
afforded 12 in 58% yield from 41. The enantiomeric
analogue 13 was synthesized in an identical fashion from
the enantiomer of 40, which was prepared from L-
glutamic acid.
The synthesis of methyl analogue 14 was initiated by
methylation of the known lactone 4235 to give a mixture
(8:1) of diastereomers 43 and 44 in 75% overall yield
(Scheme 7). When the enolate generated from this
mixture was kinetically protonated, a new mixture (43:
44 ) 1:6) was produced from which the desired cis isomer
44 was isolated as the major product (65% yield).
Removal of the trityl group from 44 under acidic condi-
tions followed by introduction of the azido function led
to 45 in 59% overall yield. The subsequent transforma-
tion of 45 into 14 follows from the analogous sequence of
reactions set forth in Scheme 6 for the preparation of 12.
Biologica l Da ta for En k ep h a lin Mim etics. The
cyclopropane-based enkephalin analogues 7-11 together
with the flexible controls 12-14 and Leu-enkephalin
methyl ester (6) were submitted to the National Institute
for Drug Abuse (NIDA) for biological evaluation in a
standard panel of receptor binding and functional assays.
(36) Cheng, Y. C.; Prusoff, W. H. Biochem. Pharmacol. 1973, 22,
3099-3108.
(37) Paton, W. D. M.; Vizi, E. S. Br. J . Pharmacol. 1969, 35, 10-
29.
(38) Hughes, J .; Kosterlitz, H. W.; Leslie, F. M. Br. J . Pharmcol.
1975, 53, 371-381.
(39) Ronai, A. Z.; Graf, L.; Szekely, J . I.; Dunai-Kovacs, Z.; Bajusz,
S. FEBS Lett. 1977, 74, 182-184.
(35) Takano, S.; Yonaga, M.; Ogasawara, K. Synthesis 1981, 265-
266.

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 65, No. 5, 2000 1311
values obtained for opiate agonists in the GPI and MVD
assays is a common indicator of µ- or δ-receptor selectiv-
ity, and the ratio for IC50(MVD)/IC50(GPI) of 6.7 for 7
shows a reasonable preference for the µ-receptor. Inter-
estingly, the methyl ester of Leu-enkephalin (6) exhibited
the opposite selectivity and with a slight preference for
the δ-receptor.
The weak µ-receptor binding and the lack of δ-receptor
binding of the constrained Leu-enkephalin analogues
7-11 suggest that these molecules do not embody those
structural features that are important for binding to the
µ- and δ-opioid receptors. We were aware of the risks
associated with replacing the enkephalin Gly2-Gly3 dipep-
tide with the -GlyΨ[COcpCO]Ala- isostere in 7, 10, and
11, because it had been previously shown that the amide
bond between Gly2 and Gly3 was important for biological
activity.18 Other substitutions of the Gly2-Gly3 dipeptide
have also yielded relatively inactive compounds.40 Thus,
the comparable biological activities of 7, 10 and 11 and
the flexible controls 12-14 further demonstrate that
there is little tolerance for significant structural and
functional modifications of the Gly2-Gly3 amide.
Although pseudopeptides bearing Gly2-Gly3 replace-
ments retained some affinity for the µ-receptor, analogues
8 and 9, which contain the cis-PheΨ[NHcpNH]Leu-
replacement for the Phe4-Leu5 dipeptide, displayed no
measurable binding affinity for either the µ- or the
δ-opioid receptors. The orientation of the phenyl group
at Phe4 is known to be important for binding to these
receptors.19 For example, a gauche(-) orientation of Phe4
appears to be required for optimal interaction with the
δ-opiod receptor.15b Thus, one plausible explanation for
the observed lack of activity of 8 and 9 is that the phenyl
group in these pseudopeptides, which is fixed in an anti
conformation in ø1-space, is not properly oriented for
interaction with the receptor. Other factors contributing
to the lack of activity could be the basic nature of the
aminocyclopropyl moiety (pKa ) 9.1)41 in 8 and 9 and/or
the loss of the Leu5 amide N-H that helps stabilize a
â-turn via an intramolecular hydrogen bond. In this latter
context, however, it should be noted that there are
replacements of the Phe4-Leu/Met5 amide bond that give
enkephalin analogues having potencies comparable to
those of the appropriate reference compounds.42
to the preparation of rigid analogues of other pseudo-
peptides. For example, an effective technique for opening
lactones directly with dipeptides in the presence of AlMe3
was developed, and tactics for preparing substituted
diaminocyclopropanes were discovered. These studies
show that the cis-GlyΨ[COcpCO]Ala- and cis-PheΨ-
[NHcpNH]Leu- replacements that were introduced in the
pseudopeptides 7-11 do not adequately mimic the req-
uisite structural and functional features at the Gly2-Gly3
and the Phe4-Leu5 subsites in any of the biologically
active conformations of Leu-enkephalin at opiod recep-
tors. Although the Gly2-Gly3 linkage and the orientation
of the phenyl group are clearly important, it is premature
to make further conclusions regarding the significance
of these experiments because structural information
regarding what geometric constraints are imposed by the
cis-GlyΨ[COcpCO]Ala- and cis-PheΨ[NHcpNH]Leu- re-
placements is presently lacking. Preliminary NMR work
shows there is some local order about the cyclopropane
rings in 7-11, but the remaining sections of the mol-
ecules are flexible with no apparent ordered structure.
NMR studies to establish the solution structures of
pseudopeptides containing the dipeptide isosteres 2 and
3 and additional studies in which these novel replace-
ments are incorporated in other biologically active pep-
tides are in progress, and the results of these investiga-
tions will be reported in due course.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, solvents and reagents
were reagent grade and used without purification. Tetrahy-
drofuran (THF) was distilled from potassium/benzophenone
ketyl under nitrogen, and dichloromethane (CH2Cl2) was
distilled from calcium hydride prior to use. Reactions involving
air or moisture sensitive reagents or intermediates were
performed under an inert atmosphere of argon in glassware
that had been oven- or flame-dried. Melting points are uncor-
rected. Infrared (IR) spectra were recorded either neat on
sodium chloride plates or as solutions in CHCl3 as indicated
and are reported in wavenumbers (cm-1) referenced to the
1601.8 cm-1 absorption of a polystyrene film. 1H and 13C NMR
spectra were obtained as solutions in CDCl3 unless otherwise
indicated, and chemical shifts are reported in parts per million
(ppm, δ) downfield from the internal standard Me4Si (TMS).
Coupling constants are reported in hertz (Hz). Spectral split-
ting patterns are designated as s, singlet; br, broad; d, doublet;
t, triplet; q, quartet; m, multiplet; and comp, complex mul-
tiplet. Flash chromatography was performed using Merck
silica gel 60 (230-400 mesh ASTM). Percent yields are given
for compounds that were g95% pure as judged by NMR.
Gen er a l P r oced u r e for P r ep a r in g Allylic Dia zoa ce-
ta tes. The p-toluenesulfonyl hydrazone of glyoxylic chloride
was added to a solution of the alcohol in dry CH2Cl2 (0.20 M)
at 0 °C, whereupon N,N-dimethylaniline (1.10 equiv) was
added. After the mixture was stirred at 0 °C for 15 min, Et3N
(5.13 equiv) was added slowly. The resulting dark suspension
was stirred for 15 min at 0 °C and then for 30 min at room
temperature, whereupon an equal volume of water was added.
The reaction mixture was extracted with CH2Cl2 (3 × 1
volume), and the combined organic fractions were dried
(MgSO4) and concentrated under reduced pressure. The crude
diazoester thus obtained was purified by flash chromatography
using either hexane/EtOAc or pentane/Et2O mixtures (ratios
given) to furnish pure allylic diazoacetates as yellow oils.
1,4-P en ta d ien yl-3-d ia zoa ceta te (15). The crude product
was purified by flash chromatography eluting with pentane/
Et2O (20:1) to provide 1.19 g (65%) of a yellow liquid: 1H NMR
(CDCl3) δ 5.91-5.78 (comp, 3 H), 5.34-5.23 (comp, 4 H), 4.79
(s, 1 H); 13C NMR δ 165.8, 134.9, 117.5, 75.3, 46.3; IR (CHCl3)
Con clu sion s
A series of conformationally constrained analogues of
Leu-enkephalin that contain the novel cyclopropane di-
peptide mimics 2 (-GlyΨ[COcpCO]Ala-) and 3 (-PheΨ-
[NHcpNH]Leu-) were prepared and evaluated for biologi-
cal activity. A number of concise and efficient protocols
were developed for the enantioselective syntheses of these
dipeptide isosteres, and these methods may be applied
(40) (a) Belanger, P. C.; Dufresne, C.; Scheigetz, J .; Young, R. N.;
Springer, J . P.; Dmitrienko, G. I. Can J . Chem. 1982, 60, 1019-1029.
(b) Belanger, P. C.; Dufresne, C. Can. J . Chem. 1986, 64, 1514-1520.
(c) Claridge, T. D. W.; Hulme, C.; Kelly, R. J .; Lee, V.; Nash, I. A.;
Schofield, C. J . Biorg. Med. Chem. Lett. 1996, 6, 485-490. (d) von
Roedern, E. G.; Lohof, E.; Hessler, G.; Hoffman, M.; Kessler, H. J . Am.
Chem. Soc. 1996, 118, 10156-10167.
(41) Christensen, J . J .; Izatt, R. M.; Wrathall, D. P.; Hansen, L. D.
J . Chem. Soc. (A) 1969, 1212-1223.
(42) Morley, J . S.; Dutta, A. S. Structure-Activity Relationships of
Opiod Peptides. In Opioid Peptides: Medicinal Chemistry; NIDA
Monograph 69; Rapaka, R. S.; Barnett, G.; Hawks, R. L., Eds., 1986;
p 42-64.
ν 2116, 1692 cm-1
.

1312 J . Org. Chem., Vol. 65, No. 5, 2000
Martin et al.
Gen er a l P r oced u r e for th e Cycliza tion of Dia zoa ce-
ta tes in th e P r esen ce of Rh 2[(5S)-MEP Y]4 a n d Rh 2[(5R)-
MEP Y]4. A solution of the diazo ester in dry CH2Cl2 (0.010
M) was added via syringe pump to a refluxing solution of the
chiral rhodium catalyst in CH2Cl2 (0.01 equiv, 1 × 10-4 M) over
a period of 12-18 h. The reaction was cooled to room temper-
ature, and the solvents were removed under reduced pressure.
The crude product was purified by flash chromatography
eluting with pentane/ether (ratios given).
Gen er a l P r oced u r e for Op en in g Cyclop r op yl La cton es
w ith P h e-Leu -OH. A solution of Me3Al in hexanes (2.0 M, 9
equiv) was added to a suspension of Phe-Leu-OH (3 equiv) in
CH2ClCH2Cl (0.24 M) at room temperature over 40 min, and
the resulting solution was stirred at room temperature for 45
min. A solution of the appropriate cyclopropyl lactone 17, 21,
40, or 45 (1 equiv) in CH2ClCH2Cl (0.12 M) was then added
dropwise over 20 min, and the reaction was heated at reflux
for 24 h. After cooling to 0 °C, 1 N HCl (2 vol) was carefully
added, and the mixture was extracted with CH2Cl2 (3 × 1
volume). The organic layers were combined, dried (Na2SO4),
and concentrated under reduced pressure. The crude pseudo-
tetrapeptides were purified by flash chromatography using
CH2Cl2/MeOH mixtures (ratio given) as eluant to afford the
pseudopeptide acids.
N-[(1S-(1r,2r,1′r))-2-(2′-Azid o)eth a n -1′-ol-cyclop r op a n -
1-oyl]-L-p h en yla la n in e-L-leu cin e was prepared in 60% yield
from 17 as a waxy white solid: CH2Cl2/MeOH (15:1); mp 146-
148 °C; 1H NMR (300 MHz, CD3OD) δ 7.30-7.20 (comp, 5 H),
4.75-4.69 (m, 1 H), 4.43-4.39 (m, 1 H), 3.52 (dt, J ) 4.7, 9.1
Hz, 1 H), 3.20 (dd, J ) 4.3, 14.1 Hz, 1 H), 2.80 (dd, J ) 11.1,
14.4 Hz, 1 H), 2.54 (d, J ) 4.9 Hz, 2 H), 1.62-1.70 (comp, 4
H), 1.18-1.15 (m, 1 H), 1.07-1.01 (m, 1 H), 0.99-0.96 (m, 1
H), 0.95 (d, J ) 6.0 Hz, 3 H), 0.92 (d, J ) 6.0 Hz, 3 H); 13C
NMR (75 MHz, CD3OD) δ 175.9, 174.0, 173.4, 138.4, 130.3,
129.5, 127.7, 70.1, 57.1, 55.8, 52.2, 41.7, 39.0, 25.9, 24.3, 23.4,
21.9, 20.1, 11.6; IR (Nujol) ν 3440, 3282, 2100, 1713, 1638, 1560
cm-1; mass spectrum (CI) m/z 432.2232 (C21H29N5O5 + H
requires 432.2247).
[1S -(1r,4r,5r)]-4-Vin yl-3-oxa b icyclo[3.1.0]h e xa n -2-
on e (16) was prepared in 90% yield from 15 and Rh2[(5S)-
MEPY]4. The crude cyclopropane was purified by flash chro-
matography eluting with pentane/ether (1:1). The enantiomeric
excess had previously been determined to be g94%:26 1H NMR
(300 MHz) δ 5.79-5.68 (m, 1 H), 5.29-5.16 (comp, 2 H), 4.95
(t, J ) 5.1 Hz, 1 H), 2.25-2.18 (m, 1 H), 2.03-1.97 (m, 1 H),
1.08-1.01 (m, 1 H), 0.82-0.78 (m, 1 H); 13C NMR (75 MHz) δ
175.2, 132.6, 117.6, 78.7, 20.6, 17.9, 8.7; IR (neat) ν 1770 cm-1
;
mass spectrum (CI) m/z 125.0605 (C7H8O2 + H requires
125.0602).
[1S-(1r,4r,5r)]-4-H yd r oxym et h yl-3-oxa b icyclo[3.1.0]-
h exa n -2-on e. Ozone was passed through a solution of 16 (0.57
g, 4.6 mmol) in MeOH/CH2Cl2 (3:1, 40 mL) at -78 °C until
the solution was blue. The excess ozone was removed by
purging with argon, whereupon NaBH4 (0.34 g, 9.2 mmol) was
added and the reaction stirred for 10 min at -78 °C. The
mixture was warmed to 0 °C and stirred for 30 min, and
saturated aqueous NH4Cl (10 mL) then was slowly added. The
volatiles were removed under reduced pressure, and the
resulting aqueous layer was extracted with CH2Cl2 (3 × 30
mL). The organic layers were combined and washed brine (1
× 25 mL). The organic layer was dried (MgSO4) and concen-
trated under reduced pressure, and the crude residue was
purified by flash chromatography using hexanes/EtOAc (1:3)
to afford 353 mg (60%) of the alcohol as a pale yellow oil: 1H
NMR (300 MHz) δ 4.76-4.69 (m, 1 H), 3.81-3.69 (m, 2 H),
3.58 (s, 1H), 2.30-2.22 (m, 1 H), 2.14-2.08 (m, 1 H), 1.19-
1.12 (m, 1 H), 1.08-1.04 (m, 1 H); 13C NMR (75 MHz) δ 176.0,
79.5, 62.2, 18.6, 17.3, 8.6; IR (CHCl3) ν 1770 cm-1; mass
spectrum (CI) m/z 129.0549 (C6H8O3 + H requires 129.0552),
111 (base).
[1S-(1r,4r,5r)]-4-Meth a n esu lfon ylm eth yl-3-oxa bicyclo-
[3.1.0]h exa n -2-on e. A solution of alcohol from the preceding
experiment (0.10 g, 0.78 mmol) in CH2Cl2 (4 mL), Et3N (0.16
mL, 1.2 mmol), and methanesulfonyl chloride (0.07 mL, 0.94
mmol) was stirred for 1 h at 0 °C. Saturated aqueous NaHCO3
(5 mL) was added, and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were washed
with 10% aqueous HCl (1 × 10 mL) and brine (1 × 10 mL).
The organic layer was dried (MgSO4) and concentrated under
reduced pressure, and the crude residue was purified by flash
chromatography eluting with hexanes/EtOAc (1:3) to afford
0.11 g (90%) of the mesylate as a pale yellow oil: 1H NMR
(300 MHz) δ 4.89-4.84 (m, 1 H), 4.38 (dd, J ) 4.3, 11.2 Hz, 1
H), 4.27 (dd, J ) 7.0, 11.2 Hz, 1 H), 3.07 (s, 3 H), 2.34-2.28
(m, 1 H), 2.22-2.16 (m, 1 H), 1.28-1.21 (m, 1 H), 1.05 (dd, J
) 4.7, 8.3 Hz, 1 H); 13C NMR (75 MHz) δ 174.5, 75.5, 68.4,
37.6, 18.2, 17.4, 8.8; IR (CHCl3) ν 1784, 1550 cm-1; mass
spectrum (CI) m/z 207.0332 (C7H10O5S + H requires 207.0327).
Gen er a l P r oced u r e for Ester ifica tion of Ca r bocyclic
Acid s w ith Dia zom eth a n e. An ethereal solution of CH2N2
was added to a solution of the carboxylic acid derivative until
a bright yellow color persisted. The excess CH2N2 was removed
by bubbling argon through the reaction mixture and the
solvent was removed under reduced pressure. The crude
residue was purified by flash chromatography using MeOH/
CH2Cl2 mixtures (ratio given) as the eluant to afford the
corresponding methyl esters.
N-[(1S-(1r,2r,1′r))-2-(2′-Azid o)eth a n -1′-ol-cyclop r op a n -
1-oyl]-L-p h en yla la n in e-L-leu cin e m et h yl est er (18) was
prepared in 95% yield from the corresponding acid as a clear
1
glassy solid: MeOH/CH2Cl2 (25:1); mp 115-117 °C; H NMR
(300 MHz, CD3OD) δ 7.30-7.21 (comp, 5 H), 4.75 (dd, J ) 4.4,
10.7 Hz, 1 H), 4.50-4.45 (m, 1 H), 3.69 (s, 3 H), 3.53 (dt, J )
4.5, 9.9 Hz, 1 H), 3.17 (dd, J ) 4.4, 14.0 Hz, 1 H), 2.81 (dd, J
) 10.5, 14.0 Hz, 1 H), 2.57 (d, J ) 4.9 Hz, 2 H), 1.73-1.59
(comp, 4 H), 1.18-1.12 (m, 1 H), 1.08-1.01 (m, 1 H), 0.99-
0.96 (m, 1 H), 0.94 (d, J ) 6.2 Hz, 3 H), 0.90 (d, J ) 6.2 Hz, 3
H); 13C NMR (75 MHz, CD3OD) δ 174.4, 174.0, 173.3, 138.6,
130.3, 129.5, 127.7, 70.0, 57.2, 55.7, 52.7, 52.2, 41.5, 39.0, 25.9,
24.4, 23.2, 21.9, 20.1, 11.5; IR (CHCl3) ν 3292, 2108, 1675, 1639,
1555 cm-1; mass spectrum (CI) m/z 446.2401 (C22H31N5O5
H requires 446.2403).
+
Gen er a l P r oced u r e for Red u ction of Azid es. A mixture
of azide (1 equiv) in MeOH (0.3 M) containing 10% Pd/C (cat.)
was stirred under H2 (1 atm) for 6-8 h. The reaction mixture
was filtered through a Celite pad, and the pad was washed
with MeOH (3 volumes). The combined filtrates were concen-
trated under reduced pressure, and the crude amines were
used without further purification.
[1S-(1r,4r,5r)]-4-Azidom eth yl-3-oxabicyclo[3.1.0]h exan -
2-on e (17). A mixture of the mesylate from the preceding
experiment (0.14 g, 0.67 mmol) and NaN3 (0.44 g, 6.7 mmol)
in DMF (3 mL) was heated at 65 °C for 12 h. After cooling to
room temperature, Et2O (20 mL) was added, and the solution
was washed with water (2 × 7 mL) and brine (1 × 7 mL). The
organic layer was dried (Na2SO4) and concentrated under
reduced pressure, and the crude residue was purified by flash
chromatography eluting with hexanes/EtOAc (1:1) to yield 0.15
g (90%) of 17 as a yellow oil: 1H NMR (300 MHz) δ 4.66 (dd,
J ) 5.3, 6.5 Hz, 1 H), 3.50-3.40 (m, 2 H), 2.28-2.21 (m, 1 H),
2.15-2.09 (m, 1 H), 1.18-1.13 (m, 1 H), 1.02-0.98 (m, 1 H);
13C NMR (75 MHz) δ 174.6, 76.8, 51.8, 19.1, 17.6, 8.7; IR
(CHCl3) ν 2109, 1778 cm-1; mass spectrum (CI) m/z 154.0612
(C6H7N3O2 + H requires 154.0617) (base).
N-[(1S-(1r,2r,1′r))-2-(2′-Am in o)eth an -1′-ol-cyclopr opan -
1-oyl]-L-p h en yla la n in e-L-leu cin e m et h yl est er (19) was
prepared in 90% yield from 18 as a pale yellow solid: mp 90-
1
93 °C; H NMR (300 MHz, CD3OD) δ 7.30-7.20 (comp, 5H),
4.74-4.69 (m, 1 H), 4.48-4.43 (m, 1 H), 3.68 (s, 3 H), 3.37-
3.33 (m, 1 H), 3.14 (dd, J ) 5.0, 14.0 Hz, 1 H), 2.84 (dd, J )
10.1, 14.0 Hz, 1 H), 2.25 (dd, J ) 8.0, 13.2 Hz, 1 H), 2.15 (dd,
J ) 3.7, 13.2 Hz, 1 H), 1.74-1.58 (comp, 4 H), 1.10-1.06 (comp,
2 H), 1.00-0.97 (m, 1 H), 0.94 (d, J ) 6.4 Hz, 3 H), 0.90 (d, J
) 6.4 Hz, 3 H); 13C NMR (75 MHz, CD3OD) δ 174.4, 174.0,
173.9, 138.6, 130.3, 129.5, 127.8, 71.5, 55.8, 52.7, 52.2, 49.3,
41.5, 39.0, 25.9, 25.2, 23.3, 21.9, 20.1, 11.1; IR (Nujol) ν 3298,
1744, 1636, 1560 cm-1; mass spectrum (CI) m/z 420.2495
(C22H33N2O5 + H requires 420.2498), 212 (base).

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 65, No. 5, 2000 1313
Gen er a l P r oced u r e for Cou p lin g P seu d otetr a p ep tid es
w ith Boc-Tyr -OH. To a solution of pseudotetrapeptide (1
equiv) in dry DMF (0.07 M) at 0 °C were added HOBt (3.2
equiv), Boc-Tyr-OH (1.2 equiv), and 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.2 equiv).
The mixture was allowed to warm to room temperature and
stir for 14 h. The solution was partitioned between EtOAc (2
volumes) and brine (1 volume), and the aqueous layer was
extracted with EtOAc (2 × 2 volumes). The combined organic
layers were washed with 10% citric acid (2 × 1 volume),
saturated aqueous NaHCO3 (2 × 1 volume), and brine (2 × 1
volume). The organic layer was dried (Na2SO4) and concen-
trated under reduced pressure, and the crude product was
purified by flash chromatography using CH2Cl2/MeOH mix-
tures (ratio given) as eluant to afford the desired pseudo-
pentapeptides.
[1R-(1r,2r,1′r)]-2-[1′-(ter t-Bu tyld im eth ylsiloxy)-2′-p r o-
p en yl]cyclop r op a n e-1-N-m et h oxy-N-m et h yl-ca r b oxa m -
id e. A solution of the alcohol from the previous experiment
(1.4 g, 7.6 mmol) in DMF (25 mL) containing imidazole (1.3 g,
19 mmol) and tert-butyldimethylsilyl chloride (1.7 g, 11 mmol)
was stirred for 12 h at room temperature, whereupon H2O (15
mL) was added. The aqueous layer was extracted with Et2O
(3 × 50 mL), and the organic layers were combined and washed
with 10% aqueous HCl (2 × 50 mL), saturated aqueous
NaHCO3 (2 × 50 mL), and brine (2 × 50 mL). The organic
layer was dried (Na2SO4) and concentrated under reduced
pressure, and the crude product was purified by flash chro-
matography eluting with hexanes/EtOAc (6:1) to afford 2.1 g
(93%) of the protected material as a pale yellow oil: 1H NMR
(300 MHz) δ 5.84-5.73 (m, 1 H), 5.09 (d, J ) 17.1 Hz, 1 H),
4.94 (d, J ) 10.3 Hz, 1 H), 3.70 (s, 3 H), 3.17 (s, 3 H), 2.30-
2.20 (br s, 1 H), 1.44-1.24 (comp, 2 H), 1.11-1.01 (m, 1 H),
0.90 (s, 9 H), 0.09 (s, 3 H), 0.05 (s, 3 H); 13C NMR (75 MHz) δ
172.5, 141.0, 113.0, 72.1, 61.5, 32.6, 26.4, 25.8, 18.1, 15.5, 12.1,
-4.4, -4.6; IR (neat) ν 2960, 1660 cm-1; mass spectrum (CI)
m/z 300.1995 (C15H30NO3Si + H requires 300.1995), 242 (base).
[1S-(1r,2â,1′â)]-2-[1′-(ter t-Bu tyld im eth ylsiloxy)]-2′-p r o-
p en ylcyclop r op a n e-1-N-m et h oxy-N-m et h ylca r b oxa m -
id e (23). A solution of sodium bis(trimethysilyl)amide in THF
(21 mL of a 1 M solution in THF, 21 mmol) was added dropwise
to a solution of the protected alcohol from the previous
experiment (2.0 g, 7.0 mmol) in THF (50 mL) at 0 °C. After
stirring for 4 h at 0 °C, saturated aqueous NH4Cl (35 mL) was
added, and the mixture was extracted with EtOAc (3 × 75 mL).
The combined organic fractions were washed with 10% aque-
ous HCl (2 × 60 mL) and brine (2 × 60 mL), dried (Na2SO4),
and concentrated under reduced pressure. The crude product
was purified by flash chromatography eluting with hexanes/
EtOAc (6:1) to afford 1.3 g (62%) of 23 as a pale yellow oil: 1H
NMR (300 MHz) δ 5.83-5.74 (m, 1 H), 5.16 (d, J ) 17.1 Hz, 1
H), 5.05 (d, J ) 10.3 Hz, 1 H), 4.13 (t, J ) 5.0 Hz, 1 H), 3.72
(s, 3 H), 3.18 (s, 3 H,), 2.16-2.14 (br s, 1 H), 1.59-1.51 (m, 1
H), 1.13-1.07 (m, 1 H), 0.98-0.91 (m, 1 H), 0.87 (s, 9 H), 0.04
(s, 3 H), 0.02 (s, 3 H); 13C NMR (75 MHz) δ 174.0, 140.1, 114.3,
72.3, 61.4, 32.4, 27.4, 25.6, 18.1, 13.7, 10.5, -4.4, -5.0; IR
(neat) ν 2960, 1660 cm-1; mass spectrum (CI) m/z 300.1986
(C15H29NO3Si + H requires 300.1995), 242 (base).
[1S-(1r,2â,1′â)]-2-[1′-(ter t-Bu tyld im eth ylsiloxy)]eth a n -
2′-ol-cyclop r op a n e -1-N -m e t h oxy-N -m e t h ylca r b oxa m -
id e. Ozone was bubbled through a solution of 23 (1.3 g, 4.4
mmol) in MeOH/CH2Cl2 (3:1, 300 mL) at -78 °C until a blue
endpoint was reached, whereupon the excess ozone was
removed with a stream of argon. After NaBH4 (1.7 g, 44 mmol)
was added, the reaction mixture was warmed to 0 °C and
stirred for 1.5 h. Saturated aqueous NH4Cl (150 mL) was
added, and the mixture was concentrated under reduced
pressure to approximately 30 mL. The aqueous phase was
extracted with CH2Cl2 (3 × 75 mL), and the combined organic
layers were washed with 10% aqueous HCl (1 × 60 mL) and
brine (1 × 60 mL). The organic layer was dried (MgSO4),
concentrated under reduced pressure, and the crude oil was
purified by flash chromatography eluting with hexanes/EtOAc
(3:1) to afford 1.1 g (80%) of the alcohol as a pale yellow oil:
1H NMR (300 MHz) δ 3.74 (s, 3 H), 3.63-3.50 (comp, 3 H),
3.19 (s, 3 H), 2.85-2.64 (br s, 1 H), 2.22-2.14 (m, 1 H), 1.62-
1.50 (m, 1 H), 1.16-1.08 (m, 1 H), 1.01-0.88 (m, 1 H), 0.89 (s,
9 H), 0.10 (s, 3 H), 0.06 (s, 3 H); 13C NMR (75 MHz) δ 173.8,
72.9, 66.8, 61.5, 32.5, 25.7, 24.3, 18.0, 13.8, 11.3, -4.5, -4.7;
IR (neat) ν 3440, 2960, 1730, 1630 cm-1; mass spectrum (CI)
m/z 304.1942 (C14H30NO4Si + H requires 304.1944), 172 (base).
[1S-(1r,2â,1′â)]-2-[1′-(ter t-Bu tyldim eth ylsiloxy)-2′-m eth -
a n esu lfon yl]eth ylcyclop r op a n e-1-N-m eth oxy-N-m eth yl-
ca r boxa m id e. A solution of alcohol (1.1 g, 3.6 mmol) in
CH2Cl2 (25 mL) containing Et3N (1.0 mL, 7.3 mmol) and
methanesulfonyl chloride (0.42 mL, 5.4 mmol) was stirred at
0 °C for 1 h, whereupon saturated aqueous NaHCO3 (15 mL)
was added. The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 40 mL). The combined organic
layers were washed with 10% aqueous HCl (2 × 50 mL) and
brine (2 × 50 mL). The organic layer was dried (MgSO4) and
N -[(1S -(1r,2r,1′r))-2-[2′-(N -(t er t -Bu t oxyca r b on yl)-L-
tyr osin e)a m in o]eth a n -1′-ol-cyclop r op a n -1-oyl]-L-p h en yl-
a la n in e-L-leu cin e m eth yl ester was prepared in 73% yield
from 19 as a white solid: CH2Cl2/MeOH (25:1); mp 130-132
°C; 1H NMR (300 MHz, CD3OD) δ 7.28-7.15 (comp, 5 H), 7.04
(d, J ) 8.4 Hz, 2 H), 6.70 (d, J ) 8.4 Hz, 2 H), 4.74-4.71 (m,
1 H), 4.47-4.45 (m, 1 H), 4.23-4.18 (m, 1 H), 3.67 (s, 3 H)
3.48-3.32 (m, 1 H), 3.16 (dd, J ) 5.6, 14.0 Hz, 1 H), 3.00 (dd,
J ) 5.8, 13.9 Hz, 2 H), 2.89 (dd, J ) 9.4, 13.9 Hz, 1 H), 2.70-
2.56 (m, 2 H), 1.70-1.56 (comp, 4 H), 1.36 (s, 9 H), 1.30-1.21
(m, 1 H), 1.19-0.97 (comp, 2 H), 0.93 (d, J ) 6.3 Hz, 3 H),
0.90 (d, J ) 6.3 Hz, 3 H)); 13C NMR (75 MHz, CD3OD) δ 175.4,
174.5, 174.3, 173.8, 157.6, 157.2, 138.4, 131.4, 130.3, 129.5,
129.3, 127.4, 116.2, 80.7, 69.5, 57.8, 55.8, 52.7, 52.2, 45.9, 41.5,
38.9, 38.5, 28.7, 25.9, 24.7, 23.3, 21.9, 20.3, 11.0; IR (CHCl3) ν
2995, 1735, 1685 cm-1; mass spectrum (CI) m/z 683.3640
(C36H50N4O9 + H requires 683.3656), 293 (base).
N -[(1S -(1r,2â,1′â))-2-[2′-(N -(t er t -Bu t oxyca r b on yl)-L-
tyr osin e)a m in o]eth a n -1′-ol-cyclop r op a n -1-oyl]-L-p h en yl-
a la n in e-L-leu cin e m eth yl ester was prepared by the general
coupling procedure in 68% yield from the corresponding
pseudotetrapeptide as an off-white solid: CH2Cl2/MeOH (25:
1); mp 105-107 °C; 1H NMR (300 MHz, CD3OD) δ 7.25-7.16
(comp, 5 H), 7.04 (d, J ) 8.4 Hz, 2 H), 6.70 (d, J ) 8.4 Hz, 2
H), 4.64 (dd, J ) 5.3, 8.9 Hz, 1 H), 4.45 (dd, J ) 5.7, 8.8 Hz,
1 H), 4.21-4.16 (m, 1 H), 3.68 (s, 3 H), 3.34-3.30 (m, 1 H),
3.19-3.14 (comp, 2 H), 3.01-2.84 (comp, 3 H), 2.77-2.63 (m,
1 H), 1.66-1.53 (comp, 4 H), 1.37 (s, 9 H), 1.19-1.03 (m, 1 H),
1.01-0.98 (m, 1 H), 0.93 (d, J ) 6.4 Hz, 3 H), 0.90 (d, J ) 6.4
Hz, 3 H), 0.90-0.85 (m, 1 H); 13C NMR (75 MHz, CD3OD) δ
174.9, 174.7, 174.4, 173.7, 157.7, 157.3, 138.5, 131.4, 130.5,
129.4, 129.3, 127.7, 116.3, 81.0, 72.8, 57.9, 55.8, 52.7, 52.2, 46.6,
41.5, 39.0, 38.5, 28.7, 25.9, 25.6, 23.3, 21.9, 19.6, 11.6; IR
(CHCl3) ν 3398, 2956, 1739, 1666 cm-1; mass spectrum (CI)
m/z 683.3663 (C36H50N4O9 + H requires 683.3656), 261 (base).
[1R-(1r,2r,1′r)]-(N-m eth oxy-N-m eth yl)-2-(2′-p r op en -1′-
ol)cyclop r op a n e-1-ca r boxa m id e. A solution of AlMe3 (19
mL of a 2.0 M solution in hexanes, 38.0 mmol) was added
dropwise over the course of 20 min to a suspension of N,O-
dimethylhydroxylamine hydrochloride (2.8 g, 29 mmol) in
CH2Cl2 (120 mL) at room temperature, and the resulting
homogeneous solution was stirred at room temperature for 30
min. A solution of 20 (1.2 g, 9.7 mmol) in CH2Cl2 (80 mL) was
then added dropwise, and the mixture was stirred overnight
at room temperature. The reaction mixture was cooled to 0
°C, and 10% aqueous HCl (100 mL) was slowly added. The
layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 200 mL). The organic layers were combined,
dried (Na2SO4), and concentrated under reduced pressure. The
crude oil was purified by flash chromatography eluting with
hexane/EtOAc (1:2) to afford 1.5 g (84%) of the amide/alcohol
as a pale yellow oil: 1H NMR (300 MHz) δ 5.84-5.73 (m, 1
H), 5.08 (d, J ) 17.1 Hz, 1 H), 4.95 (d, J ) 10.3 Hz, 1 H), 4.07
(t, J ) 6.3 Hz, 1 H), 3.63 (s, 3 H), 3.09 (s, 3 H), 2.20 (br s, 1 H),
1.39-1.29 (comp, 2 H), 1.03-0.97 (m, 1 H); 13C NMR (75 MHz)
δ 171.5, 139.9, 113.4, 69.7, 61.0, 32.0, 26.4, 14.9, 10.3; IR (neat)
ν 3425, 2980, 1640 cm-1; mass spectrum (CI) m/z 186.1131
(C9H15NO3 + H requires 186.1130), 168 (base).

1314 J . Org. Chem., Vol. 65, No. 5, 2000
Martin et al.
concentrated under reduced pressure, and the crude residue
was purified by flash chromatography eluting with hexanes/
EtOAc (4:1) to afford 1.3 g (93%) of the mesylate as a pale
yellow oil: 1H NMR (300 MHz) δ 4.06 (dd, J ) 4.4, 10.2 Hz, 1
H), 3.97 (dd, J ) 6.5, 10.2 Hz, 1 H), 3.78-3.74 (m, 1 H), 3.64
(s, 3 H), 3.08 (s, 3 H), 2.92 (s, 3 H), 2.11-2.06 (br s, 1 H), 1.45-
1.41 (m, 1 H), 1.02-0.96 (m, 1 H), 0.89-0.81 (m, 1 H), 0.80 (s,
9 H), 0.01 (s, 6 H); 13C NMR (75 MHz) δ 173.3, 72.5, 69.7, 61.5,
37.3, 32.5, 25.6, 23.5, 18.0, 13.7 10.6, -4.5, -4.8; IR (neat) ν
2955, 1740, 1660 cm-1; mass spectrum (CI) m/z 382.1711 (base)
(C15H32NO6SiS + H requires 382.1720).
[1S -(1r,2â,1′â)]-2-[2′-Azid o -1′-(t er t -b u t y ld im e t h y l-
siloxy)]eth ylcyclopr opan e-1-N-m eth oxy-N-m eth ylcar box-
a m id e (24). A mixture of the mesylate (1.3 g, 3.4 mmol) in
DMF (25 mL) containing NaN3 (2.2 g, 34 mmol) was heated
to 65 °C for 12 h. The mixture was cooled to room temperature
and Et2O (150 mL) added. The mixture was filtered, and the
resulting filtrate was washed with water (2 × 60 mL) and brine
(2 × 60 mL). The organic layer was dried (Na2SO4) and
concentrated under reduced pressure, and the crude residue
was purified by flash chromatography using hexanes/EtOAc
(6:1) as eluant to yield 0.89 g (81%) of 24 as a yellow oil: 1H
NMR (300 MHz) δ 3.66 (s, 3 H), 3.66-3.59 (m, 1 H), 3.26 (dd,
J ) 3.9, 12.4 Hz, 1 H), 3.15 (dd, J ) 6.4, 12.4 Hz, 1 H), 3.12 (s,
3 H), 2.08-2.05 (br s, 1 H), 1.52-1.47 (m, 1 H), 1.09-1.04 (m,
1 H), 0.95-0.88 (m, 1 H), 0.83 (s, 3 H), 0.05 (s, 3 H), 0.02 (s, 3
H); 13C NMR (75 MHz) δ 173.4, 71.1, 61.5, 57.1, 32.4, 25.6,
24.8, 17.9, 13.9, 11.2, -4.7, -4.8; IR (neat) ν 2960, 2100, 1655,
1110, 830 cm-1; mass spectrum (CI) m/z 329.2009 (base)
(C14H28N3O3Si + H requires 329.2009).
[1S -(1r,2â,1′â)]-2-[2′-Azid o -1′-(t er t -b u t y ld im e t h y l-
siloxy)]eth ylcyclop r op yl-1-ca r boxylic Acid . Solid tert-
BuOK (2.4 g, 22 mmol) was slowly added to stirred solution
of 24 (0.89 g, 2.7 mmol) in THF (30 mL) containing H2O (98
µL, 5.4 mmol) at 0 °C. After 30 min, 10% aqueous HCl was
slowly added until pH 3, and the reaction mixture was
extracted with EtOAc (3 × 60 mL). The combined organic
layers were washed with brine (2 × 60 mL), dried (Na2SO4),
and concentrated under reduced pressure to yield 0.69 g (90%)
of the crude acid as a light yellow oil. The crude product was
judged to be >95% pure by 1H NMR and used without further
purification: 1H NMR (300 MHz) δ 9.85-9.55 (br s, 1 H), 3.62-
3.58 (m, 1 H), 3.32 (dd, J ) 4.4, 12.5 Hz, 1 H), 3.21 (dd, J )
5.9, 12.5 Hz, 1 H), 1.66-1.60 (m, 1 H), 1.57-1.52 (m, 1 H),
1.26-1.17 (m, 1 H), 1.10-1.03 (m, 1 H), 0.88 (s, 9 H), 0.09 (s,
3 H), 0.06 (s, 3 H); 13C NMR (75 MHz) δ 179.9, 71.0, 57.0, 26.1,
25.6, 17.9, 16.8, 12.3, -4.6, -4.7; IR (neat) ν 3500-2800, 2100,
1695 cm-1; mass spectrum (CI) m/z 286.1584 (C12H23N3O3Si
+ H requires 286.1587), 240 (base).
[1S-(1r,2â,1′â)]-2-(2′-Azid o)eth a n -1′-ol-cyclop r op a n e-1-
ca r boxylic Acid (25). A solution of the acid from the previous
experiment (0.69 g, 2.4 mmol) in CH2Cl2 (12 mL) containing
an excess of HF-pyridine (1.0 mL) was stirred for 12 h. Water
(6 mL) was added, and the aqueous phase was extracted with
EtOAc (3 × 15 mL). The combined organic fractions were
washed with brine (2 × 20 mL), dried (Na2SO4), and concen-
trated under reduced pressure to yield 0.33 g (81%) of 25 as a
light yellow oil. The crude product was judged to be >95% pure
by 1H NMR and was used without further purification: 1H
NMR (300 MHz) δ 8.30-7.45 (br s, 1 H), 3.53-3.36 (comp, 3
H), 1.67-1.60 (comp, 2 H), 1.28-1.22 (m, 1 H), 1.15-1.11 (m,
1 H); 13C NMR (75 MHz) δ 179.5, 70.9, 56.4, 25.4, 17.1, 12.3;
IR (neat) ν 3700-2720, 2100, 1695, 1080, 1030 cm-1; mass
spectrum (CI) m/z 172.0730 (C6H9N3O3 + H requires 172.0722),
154 (base).
flash chromatography eluting with hexanes/EtOAc (1:3) to
yield 0.11 g (87%) of 26 as a white solid: mp 118-120 °C; 1H
NMR (300 MHz) δ 5.04 (br s, 1 H), 3.47-3.36 (comp, 2 H),
3.21-3.14 (m, 1 H), 1.65-1.60 (m, 1 H), 1.58-1.53 (m, 1 H),
1.44 (s, 9 H) 1.25-1.20 (m, 1 H), 1.11-1.08 (m, 1 H); 13C NMR
(75 MHz) δ 179.1, 157.3, 80.2, 71.9, 46.4, 28.3, 25.8, 16.8, 12.3;
IR (Nujol) ν 3458, 2982, 1698 cm-1; mass spectrum (CI) m/z
246.1343 (C11H19O5N + H requires 246.1341), 172 (base).
N-[(1S-(1r,2â,1′â))-2-[2′-N-(ter t-Bu toxyca r bon yl)a m in o]-
e t h a n -1′-olcyclop r op a n -1-oyl]-L-p h e n yla la n in e -L-le u -
cin e Meth yl Ester . To solution of 26 (25 mg, 0.10 mmol) in
dry DMF (1.5 mL) containing HOBt (44 mg, 0.33 mmol) and
Phe-Leu-OMe (39 mg, 0.13 mmol) at -10 °C was added 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
(27 mg, 0.13 mmol) in one portion. The mixture was allowed
to warm to room temperature and stir for 12 h, whereupon
the solution was partitioned between EtOAc (7 mL) and brine
(3 mL). The aqueous layer was extracted EtOAc (2 × 7 mL),
and the combined organic layers were washed with 10% citric
acid (2 × 7 mL), saturated aqueous NaHCO3 (2 × 7 mL), and
brine (2 × 7 mL). The organic layer was dried (Na2SO4) and
concentrated under reduced pressure, and the crude residue
was purified by flash chromatography eluting with CH2Cl2/
MeOH (25:1) to yield 31 mg (60%) of the coupled product as a
white solid: mp 85-88 °C; 1H NMR (300 MHz, CD3OD) δ
7.29-7.19 (comp, 5 H), 6.45 (br s, 1 H), 4.67 (dd, J ) 5.5, 9.1
Hz, 1 H), 4.47-4.43 (m, 1 H), 3.67 (s, 3 H), 3.19-3.11 (comp,
3 H), 2.90-2.82 (comp, 2 H), 1.65-1.53 (comp, 4 H), 1.44 (s, 9
H), 1.18-1.13 (m, 1 H), 0.98-0.94 (m, 1 H), 0.93 (d, J ) 6.2
Hz, 3 H), 0.90 (d, J ) 6.2 Hz, 3 H), 0.88-0.84 (m, 1 H); 13C
NMR (75 MHz, CD3OD) δ 174.9, 174.3, 173.7, 158.5, 138.4,
130.4, 129.3, 127.6, 80.1, 73.2, 55.7, 52.6, 52.1, 47.5, 41.4, 39.1,
28.8, 25.8, 25.5, 23.3, 21.9, 19.6, 11.5; IR (CHCl3) ν 3424, 2960,
1740, 1682, 1510 cm-1; mass spectrum (CI) m/z 520.3018
(C27H41N3O7 + H requires 520.3023).
N-[(1S-(1r,2â,1′â))-2-(2′-Am in o)eth a n -1′-ol-cyclop r op a n -
1-oyl]-L-p h en yla la n in e-L-leu cin e Meth yl Ester . To a solu-
tion of the pseudopeptide from the preceding experiment (31
mg, 0.06 mmol) in CH2Cl2 (0.2 mL) at room temperature was
added TFA (0.2 mL) and the mixture was stirred for 30 min
at room temperature. The solvent was removed under reduced
pressure, and the crude residue was triturated with Et2O (3
× 2 mL) to yield light yellow solid. The residue was dissolved
in EtOAc (2 mL) and was washed with saturated aqueous
NaHCO3 (2 × 1 mL) and brine (1 × 1 mL). The organic layer
was dried (Na2SO4) and concentrated under reduced pressure
to afford 24 mg (95%) of amino pseudopeptide as an off-white
1
solid. This material was shown to be >95% pure by H NMR
and did not require further purification: mp 68-70 °C (dec);
1H NMR (300 MHz, CD3OD) δ 7.28-7.18 (comp, 5 H), 4.70-
4.65 (m, 1 H), 4.47-4.43 (m, 1 H), 3.68 (s, 3 H), 3.36-3.34 (m,
1 H), 3.16 (dd, J ) 5.3, 13.5 Hz, 1 H), 2.99-2.78 (comp, 3 H),
1.68-1.55 (comp, 4 H), 1.22-1.16 (m, 1 H), 1.04-0.98 (m, 1
H), 0.92 (d, J ) 6.3 Hz, 3 H), 0.90 (d, J ) 6.3 Hz, 3 H), 0.91-
0.88 (m, 1 H); 13C NMR (75 MHz, CD3OD) δ 174.9, 174.4, 173.8,
138.5, 130.4, 129.4, 127.1, 74.9, 55.7, 52.7, 52.2, 48.0, 41.5, 39.0,
25.9, 25.6, 23.3, 21.8, 19.6, 11.6; IR (Nujol) ν 3305, 1735, 1676,
1638, 1560 cm-1; mass spectrum (CI) m/z 420.2489 ((C22H33N5O5
+ H requires 420.2498).
[1S-(1r,2r,3â)]-2-H yd r oxym et h yl-3-p h en ylcyclop r o-
p a n e Hyd r a zid e. To a solution of 28 (0.50 g, 2.9 mmol) in
MeOH (10 mL) at room temperature was added hydrazine
monohydrate (0.83 mL, 17 mmol) over 10 min. The mixture
was stirred at room temperature for 12 h and was concentrated
under reduced pressure to yield 0.56 g (ca. 95%) of the crude
hydrazide as an off-white solid. This material was >95% pure
by 1H NMR and was used without further purification: mp
[1S-(1r,2â,1′â)]-2-[2′-N-(ter t-Bu t oxyca r b on yl)a m in o]-
eth a n -1′-ol-cyclop r op a n e-1-ca r boxylic Acid (26). A sus-
pension of Pd/C (5 mg) in dry EtOAc (1 mL) was degassed three
times and stirred under H2 (1 atm) for 1 h. A solution of 25
(90 mg, 0.53 mmol) and Boc2O (0.14 g, 0.63 mmol) in EtOAc
(1 mL) was added dropwise, and the resulting mixture was
stirred vigorously under H2 (1 atm) for 36 h. The solution was
filtered through a pad of Celite, which was washed with EtOAc
(7 mL). The filtrate was concentrated under reduced pressure
to yield a thick yellow oil. The crude residue was purified by
1
85-88 °C; H NMR (300 MHz, CD3OD) δ 7.27-7.23 (comp, 3
H), 7.18-7.11 (comp, 2 H), 3.94 (dd, J ) 6.1, 11.5 Hz, 1 H),
3.81 (dd, J ) 7.5, 11.5 Hz, 1 H), 2.57 (t, J ) 5.7 Hz, 1 H), 1.98
(dd, J ) 5.3, 9.1 Hz, 1 H), 1.91-1.83 (m, 1 H); 13C NMR (75
MHz, CD3OD) δ 172.6, 141.5, 129.4, 127.3, 60.3, 32.7, 29.0,
28.8; IR (Nujol) ν 3288, 1675, 1625, 1540, 1100, 1034 cm-1
;
mass spectrum (CI) m/z 207.1123 (C11H14N2O2 + H requires
207.1134).

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 65, No. 5, 2000 1315
[1S-(1r,6r,7â)]-2-Aza-3-oxo-7-ph en yl-4-oxabicyclo[4.1.0]-
h ep ta n e (29). To a suspension of the crude acyl hydrazide
(0.30 g, 1.5 mmol) in H2O/Et2O (1:1, 8 mL total) at 0 °C was
added NaNO2 (0.15 g, 2.3 mmol) portionwise. A solution of 6
N HCl (2.3 mmol) was then added dropwise. Upon completion
of the addition, the mixture was stirred for 30 min at 0 °C,
and cold CHCl3 (15 mL) was added. The layers were separated,
and the aqueous layer was extracted with CHCl3 (2 × 15 mL).
The organic layers were combined and washed with 5%
aqueous NaHCO3 (2 × 15 mL) and brine (2 × 15 mL). The
organic layer was dried (Na2SO4) and concentrated under
reduced pressure to half volume, whereupon a volume of
toluene (20 mL) was added. The remaining chloroform was
removed under reduced pressure, and an additional portion
of toluene (10 mL) was added. The reaction mixture was
heated at 80 °C for 14 h, whereupon the reaction mixture was
concentrated under reduced pressure, and the residual yellow
solid was purified by flash chromatography eluting with
hexanes/EtOAc (1:1.5) to yield 0.22 g (87%) of 29 as a white
solid: mp 163-165 °C; 1H NMR (300 MHz) δ 7.31-7.18 (comp,
3 H), 7.00 (d, J ) 7.2 Hz, 2 H), 6.61 (br s, 1 H), 4.78 (dd, J )
6.1, 11.9 Hz, 1 H), 4.28 (dd, J ) 4.5, 11.9 Hz, 1 H), 3.04 (dt, J
) 2.7, 8.9 Hz, 1 H), 2.20 (dd, J ) 3.2, 4.8 Hz, 1 H), 1.98-1.90
(m, 1 H); 13C NMR (75 MHz) δ 154.7, 138.1, 128.5, 126.5, 125.6,
68.2, 36.2, 32.6, 18.1; IR (CHCl3) ν 3431, 1716 cm-1; mass
spectrum (CI) m/z 190.0867 (C11H11NO2 + H requires 190.0868),
129 (base).
4.03 (dd, J ) 9.0, 11.0 Hz, 1 H), 3.81 (m, 1 H), 3.73 (s, 3 H),
3.57 (br s, 1 H), 3.04 (dd, J ) 4.4, 7.0 Hz, 1 H), 1.94 (br s, 1
H), 1.87 (ddd, J ) 5.6, 8.6, 14.3 Hz, 1 H), 1.80 (br s, 1 H),
1.75-1.70 (m, 1 H), 1.66-1.59 (m, 1 H), 1.47 (s, 9 H), 0.95 (d,
J ) 6.6 Hz, 3 H), 0.84 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz)
δ 172.9, 157.8, 139.4, 128.6, 126.3, 125.8, 82.1, 60.5, 60.4, 52.1,
44.8, 39.3, 33.4, 28.2, 26.2, 25.2, 23.0, 21.9; IR (CHCl3) ν 3449,
2960, 1742, 1676, cm-1; mass spectrum (CI) m/z 392.2445
(C22H33NO5 + H requires 392.2437).
For 36: yellow oil; 1H NMR (300 MHz) δ 7.29-7.16 (comp,
3 H), 7.05-7.01 (comp, 2 H), 4.05 (dd, J ) 3.0, 12.1 Hz, 1 H),
3.93 (dd, J ) 5.4, 12.1 Hz, 1 H), 3.71 (s, 3 H), 3.52-3.47 (m, 1
H), 3.08 (dd, J ) 4.1, 6.8 Hz, 1 H), 2.00-1.79 (comp, 4 H),
1.65-1.57 (m, 1 H), 1.44 (s, 9 H), 0.86 (d, J ) 6.6 Hz, 3 H),
0.69 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz) δ 171.7, 156.5,
139.2, 128.5, 126.3, 125.7, 82.1, 60.5, 60.1, 52.0, 46.0, 39.4, 35.0,
28.2, 27.0, 24.9, 23.2, 21.5; IR (CHCl3) ν 3455, 3030, 2960, 1743,
1674 cm-1; mass spectrum (CI) m/z 392.2437 (C22H33N1O5
H requires 392.2437), 320, 292 (base).
+
[1S-(1r,2r,3â)]-1-[N-(ter t-Bu t oxyca r b on yl)-L-leu cin e
m eth yl ester ]-2-ca r boxy-3-p h en ylcyclop r op a n e (33). To
a solution of 32 (0.16 g, 0.41 mmol) in CH3CN/CHCl3/H2O (1:
1:1.5; 12.5 mL total) at room temperature were added NaHCO3
(0.22 g, 2.7 mmol), NaIO4 (0.48 g, 2.3 mmol), and RuCl3 (9.0
mg, 0.041 mmol). The mixture was stirred vigorously for 30
min, whereupon an additional 0.1 equiv of RuCl3 (9.0 mg, 0.041
mmol) was added, and the mixture was stirred for 1 h. The
mixture was diluted with EtOAc (5 mL) and the aqueous layer
was adjusted to pH 4 with 10% aqueous HCl. The layers were
separated, and the aqueous layer was extracted with EtOAc
(2 × 7 mL). The organic layers were combined, washed with
brine (2 × 7 mL), dried (Na2SO4), and concentrated under
reduced pressure to yield a light yellow oil. The crude oil was
purified by flash chromatography eluting with hexane/EtOAc
(1:1) to yield 0.14 g (85%) of 33 as a pale yellow oil: 1H NMR
(300 MHz) δ 7.33-7.26 (comp, 3 H), 7.09 (d, J ) 6.8 Hz, 2 H),
4.40 (br s, 1 H), 3.76 (s, 3 H), 3.31 (br s, 1 H), 2.93 (app t, J )
5.5 Hz, 1 H), 2.40 (br s, 1 H), 1.89-1.76 (comp, 4 H), 1.45 (s,
9 H), 0.95 (d, J ) 6.4 Hz, 3 H), 0.87 (d, J ) 6.4 Hz, 3 H); 13C
NMR (75 MHz) δ 173.3, 173.1, 155.6, 137.1, 128.8, 127.3, 126.3,
81.7, 59.9, 52.4, 45.1, 38.9, 33.0, 31.8, 28.0, 25.3, 22.8, 22.0;
IR (CHCl3) ν 3500-3300, 2958, 1736, 1702 cm-1; mass
spectrum (CI) m/z 404.2074 (C22H31NO6-H requires 404.2073),
179 (base).
[1S-(1r,2r,3â)]-1-Am in o-2-h yd r oxym et h yl-3-p h en yl-
cyclop r op a n e (30). A solution of 29 (0.50 g, 0.030 mmol) in
dioxane/H2O (2:1, 18 mL total) containing Ba(OH)2‚8H2O (1.7
g, 0.060 mmol) was heated at reflux for 4 h. The mixture was
cooled to room temperature and filtered through a thin pad of
Celite and washed with CH2Cl2 (20 mL). The layers of filtrate
were separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 25 mL). The organic layers were combined, dried
(Na2SO4), and concentrated under reduced pressure to yield
0.41 g (90%) of 30 as a light yellow oil. This material was
shown to be >95% pure by 1H NMR and did not require further
purification: 1H NMR (300 MHz) δ 7.29-7.14 (comp, 3 H), 7.03
(d, J ) 7.4 Hz, 2 H), 4.20 (dd, J ) 2.6, 11.6 Hz, 1 H), 4.02 (dd,
J ) 4.9, 11.6 Hz, 1 H), 2.84 (dd, J ) 3.4, 7.2 Hz, 1 H), 2.23-
2.17 (m, 1 H), 1.38-1.33 (m, 1 H); 13C NMR (75 MHz) δ 141.4,
128.2, 125.8, 125.6, 59.9, 38.4, 29.4, 27.3; IR (CHCl3) ν 3440,
3029, 1534 cm-1; mass spectrum (CI) m/z 164.1075 (C10H13
NO + H requires 164.1075).
-
[1S-(1r,2r,3â)]-2-[(Allyloxyca r bon yl)a m in o]-1-[N-(ter t-
Bu toxyca r bon yl)-L-leu cin e m eth yl ester ]-3-p h en ylcyclo-
p r op a n e (34). To a solution of 33 (85 mg, 0.21 mmol) in
acetone/H2O (10:1; 0.5 mL total) at 0 °C were added Et3N (35
µL, 0.25 mmol) and EtO2CCl (26 mL, 0.27 mmol). The mixture
was stirred for 1 h, whereupon NaN3 (20 mg, 0.32 mmol) in
H2O (0.13 mL) was added dropwise. The mixture was stirred
for 1 h at 0 °C, and cold H2O (1 mL) and CH2Cl2 (2 mL) were
added and the layers separated. The aqueous layer was
extracted with CH2Cl2 (2 × 2 mL), and the organic layers were
combined. The organic layers were dried (MgSO4), anhydrous
toluene (2 mL) was added, and the mixture was concentrated
under reduced pressure. Allyl alcohol (0.5 mL) was added, and
the mixture was heated at reflux 12 h. The mixture was cooled
to room temperature and concentrated under reduced pressure
to yield a light yellow oil. The crude oil was purified by flash
chromatography eluting with hexanes/EtOAc (6:1) to yield 82
mg (85%) of 34 as clear oil: 1H NMR (300 MHz) δ 7.29-7.12
(comp, 5 H), 6.07 (br s, 1 H), 5.90 (ddd, J ) 5.7, 10.5, 16.2 Hz,
1 H), 5.27 (d, J ) 16.2 Hz, 1 H), 5.18 (d, J ) 10.5 Hz, 1 H),
4.57 (d, J ) 4.8 Hz, 2 H), 3.74 (s, 1 H), 3.45 (br s, 1 H), 2.96
(br s, 1 H), 2.21 (br s, 1 H), 1.90-1.70 (comp, 3 H), 1.65-1.55
(m, 1 H), 1.45 (s, 9 H), 0.90 (d, J ) 6.6 Hz, 3 H), 0.80 (d, J )
6.6 Hz, 3 H); 13C NMR (75 MHz) δ 173.7, 156.5, 156.4, 138.0,
133.0, 128.7, 126.6, 126.5, 117.6, 81.4, 65.6, 52.4, 38.9, 38.3,
[1S-(1r,2r,3â)]-1-[N-(ter t-Bu t oxyca r b on yl)-L-leu cin e
m eth yl ester ]-2-h yd r oxym eth yl-3-p h en ylcyclop r op a n e
(32) a n d [1R-(1r,2r,3â)]-1-[N-(ter t-Bu toxyca r bon yl)-L-leu -
cin e m eth yl ester ]-2-h yd r oxym eth yl-3-p h en ylcyclop r o-
p a n e (36). To a solution of 5(R)-methyl oxopentanoate26 (1.3
g, 9.2 mmol) in CH2Cl2 (12 mL) at 0 °C was added Tf2O (0.92
mL, 9.2 mmol) over the course of 5 min. The reaction mixture
was stirred for 10 min, and 2,6-lutidine (1.1 mL, 9.2 mmol)
was added dropwise. The mixture was stirred for an additional
10 min at 0 °C, whereupon i-Pr2NEt (1.6 mL, 9.8 mmol) and
30 (1.0 g, 6.1 mmol) in CH2Cl2 (12 mL) were added. The
mixture was allowed to warm to room temperature and was
stirred 12 h. The mixture was diluted with CH2Cl2 (10 mL),
and the organic layer was washed successively with water (1
× 15 mL), saturated aqueous NaHCO3 (1 × 15 mL), and brine
(1 × 15 mL). The organic layer was dried (Na2SO4) and
concentrated under reduced pressure to yield a bright yellow
oil. The crude oil was purified by flash chromatography eluting
with hexane/EtOAc (3:1) to yield 1.2 g (65%) of secondary
amines as an inseparable mixture (5:1) of diastereomers as a
clear oil. A solution of the diastereomeric amines (1.0 g, 3.4
mmol) and Boc2O (2.3 g, 10 mmol) in CH3CN (11 mL) was
stirred at room temperature for 36 h. An additional portion of
Boc2O (2.3 g, 10 mmol) was added, and the mixture was stirred
another 36 h. The solvent was removed under reduced pres-
sure to yield a light yellow oil. The crude oil was purified by
flash chromatography eluting with hexanes/EtOAc (6:1) to
yield 0.94 g (71%) of 32 and 0.19 g (14%) of 36.
28.1, 25.3, 23.0, 21.4; IR (CHCl3) ν 3685, 1717, 1693, 1537 cm-1
;
mass spectrum (CI) m/z 461.2652 (C25H36N2O6 + H requires
461.2652), 361 (base).
N-[1S-(1r,2r,3â)]-2-[N-(ter t-Bu toxycar bon yl)-L-tyr osin e-
t-bu tyl eth er -L-glycin e-L-glycin e]-3-p h en ylcyclop r op a n e-
1-N-(ter t-Bu toxyca r bon yl)-L-leu cin e Meth yl Ester (35).
For 32: pale yellow oil; 1H NMR (300 MHz) δ 7.30-7.26 (m,
2 H), 7.21-7.18 (m, 1 H), 7.05-7.02 (m, 2 H), 4.21 (br s, 1 H),

1316 J . Org. Chem., Vol. 65, No. 5, 2000
Martin et al.
To a solution of Boc-Tyr(O-t-Bu)-Gly-Gly-OH (25 mg, 0.056
mmol) in CH2Cl2 (1 mL) at room temperature were added
HOBt (8.0 mg, 0.056 mmol) and DCC (12 mg, 0.56 mmol). The
mixture was stirred for 1 h at room temperature, whereupon
it was transferred via syringe to a flask charged with 34 (20
mg, 0.043 mmol). Pd(PPh3)4 (10 mg, 8.7 × 10-3 mmol) and
Bu3SnH (13 µL, 0.047 mmol) were added, and the resulting
mixture was stirred at room temperature for 6 h, filtered, and
concentrated under reduced pressure to yield a bright yellow
semisolid. The crude product was purified by flash chroma-
tography eluting with CH2Cl2/MeOH (25:1) to afford 27 mg
(78%) of 35 as a clear glass: 1H NMR (500 MHz, CD3OD) δ
7.29 (t, J ) 7.2 Hz, 2 H), 7.23-7.14 (m, 1 H), 7.15-7.10 (comp,
2 H), 7.14 (d, J ) 8.4 Hz, 2 H), 6.80 (d, J ) 8.4 Hz, 2 H), 4.26
(dd, J ) 5.4, 8.6 Hz, 1 H), 4.11-3.90 (comp, 4 H), 3.78 (s, 3
H), 3.79-3.71 (br s, 1 H), 3.11 (dd, J ) 5.8, 13.9 Hz, 1 H), 2.96
(app t, J ) 5.8 Hz, 1 H), 2.80 (dd, J ) 9.2, 13.9 Hz, 1 H), 2.37
(br s, 1 H), 1.87-1.77 (comp, 2 H), 1.61-1.57 (m, 1 H), 1.45 (s,
9 H), 1.36-1.30 (m, 1 H), 1.34 (s, 9 H), 1.29 (s, 9 H), 0.91 (d,
J ) 6.6 Hz, 3 H), 0.76 (d, J ) 6.6 Hz, 3 H); 13C NMR (125
MHz, CD3OD) δ 177.0, 174.8, 171.8, 158.0, 157.8, 155.3, 139.3,
133.7, 130.9, 129.7, 127.8, 127.3, 125.2, 82.7, 80.8, 79.5, 57.8,
53.6, 43.7, 43.6, 39.2, 38.7, 38.3, 34.7, 31.0, 29.2, 28.7, 28.6,
1 H), 4.46 (dd, J ) 5.7, 9.5 Hz, 1 H), 4.07 (dd, J ) 6.6, 8.0 Hz,
1 H), 3.66 (s, 3 H) 3.56-3.53 (m, 1 H), 3.38-3.34 (m, 1 H),
3.27-3.15 (comp, 3 H), 3.14-2.85 (comp, 2 H), 1.74-1.57
(comp, 5 H), 1.05-1.00 (m, 2 H), 0.95 (d, J ) 6.6 Hz, 3 H),
0.89 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz, CD3OD) δ 174.5,
174.0, 169.9, 158.3, 138.4, 131.6, 130.3, 129.6, 127.8, 126.1,
116.8, 69.2, 56.2, 56.0, 52.7, 52.3, 46.2, 41.6, 39.0, 38.0, 25.8,
24.9, 23.3, 22.0, 20.5, 10.4; IR (Nujol) ν 2998, 1730, 1690 cm-1
;
mass spectrum (CI) m/z 583.3119 (C31H42N4O7 + H requires
583.3132), 294 (base).
N-[(1S-(1r,2â,1′â))-2-[2′-(L-Tyr osin e)a m in o]eth a n -1′-ol-
cyclop r op a n -1-oyl]-L-p h en yla la n in e-L-leu cin e m eth yl es-
ter (11) was prepared in 93% yield from the protected
pseudopeptide as an off-white solid: mp 118-121 °C; 1H NMR
(300 MHz, CD3OD) δ 7.28-7.16 (comp, 5 H), 7.09 (d, J ) 8.6
Hz, 2 H), 6.77 (d, J ) 8.6 Hz, 2 H), 4.71-4.66 (m, 1 H), 4.47-
4.42 (m, 1 H), 3.99 (t, J ) 6.8 Hz, 1 H), 3.69 (s, 3 H), 3.40 (dd,
J ) 4.0, 13.6 Hz, 1 H), 3.21-3.09 (comp, 3 H), 3.00-2.81 (comp,
3 H), 1.68-1.55 (comp, 4 H), 1.20-1.13 (m, 1 H), 1.02-0.96
(m, 1 H), 0.93 (d, J ) 6.4 Hz, 3 H), 0.90 (d, J ) 6.4 Hz, 3 H),
0.88-0.82 (m, 1 H); 13C NMR (75 MHz, CD3OD) δ 175.0, 174.5,
173.8, 169.9, 158.3, 138.5, 131.6, 130.4, 129.4, 127.7, 126.0,
116.9, 72.7, 56.0, 52.7, 52.2, 46.5, 41.3, 39.0, 37.9, 25.9, 25.7,
26.5, 23.3; IR (CHCl3) ν 3428, 3013, 2930, 1735, 1690 cm-1
;
23.3, 21.8, 19.8, 11.5; IR (Nujol) ν 3420, 2960, 1730, 1678 cm-1
;
mass spectrum (CI) m/z 810.4653 (C43H64N5O10 requires
810.4653).
mass spectrum (CI) m/z 583.3118 (C31H42N4O7 + H requires
583.3132), 212 (base).
Gen er al P r ocedu r e for Depr otectin g P seu dopen tapep-
tid es to 7, 8, 10-14. To a solution of the pseudopentapeptide
(1 equiv) in CH2Cl2 (0.1 M) at room temperature was added
TFA (10 equiv), and the mixture was stirred at room temper-
ature for 30 min to 2 h. The solvent was removed under
reduced pressure, and the crude residue was triturated with
Et2O (3 × 1 volume) to yield a light yellow solid that was
dissolved in EtOAc (2 volumes). The organic layer was washed
with saturated aqueous NaHCO3 (2 × 1 volume) and brine (2
× 1 volume). The organic layer was dried (Na2SO4) and
concentrated under reduced pressure, and the resulting prod-
uct was recrystallized from MeOH/Et2O.
N-[5-(L-Tyr osin e)a m in o-(4S)-h yd r oxy]p en t a n -1-oyl-L-
p h en yla la n in e-L-leu cin e m eth yl ester (12) was prepared
in 89% yield from the protected pseudopeptide as a crystalline
solid: mp 81-83 °C; 1H NMR (300 MHz, CD3OD) δ 7.33-7.17
(comp, 5 H), 7.02 (d, J ) 8.4 Hz, 2 H), 6.70 (d, J ) 8.4 Hz, 2
H), 4.66 (dd, J ) 5.6, 9.2 Hz, 1 H), 4.44 (dd, J ) 6.0, 8.2 Hz,
1 H), 3.67 (s, 3 H), 3.50 (dd, J ) 6.8, 13.5 Hz, 1 H), 3.47-3.44
(m, 1 H), 3.18-3.03 (comp, 2 H), 2.93-2.81 (comp, 2 H), 2.71
(dd, J ) 7.4 Hz, 13.5 Hz, 1 H), 2.31-2.17 (comp, 2 H), 1.69-
1.44 (comp, 5 H), 0.93 (d, J ) 6.2 Hz, 3 H), 0.89 (d, J ) 6.2 Hz,
3 H); 13C NMR (75 MHz, CD3OD) δ 175.7, 174.4, 173.8, 157.4,
138.5, 131.4, 130.3, 129.4, 129.2, 127.7, 116.4, 70.6, 57.8, 55.7,
52.7, 52.2, 46.0, 41.5, 38.9, 32.9, 31.3, 25.9, 23.3, 21.9; IR
(Nujol) ν 1647, 1550 cm-1; mass spectrum (CI) m/z 571.3133
(C30H42N4O7 + H requires 571.3132), 293 (base).
N-[(1S-(1r,2r,1′r))-2-[2′-(L-Tyr osin e)a m in o]eth a n -1′-ol-
cyclop r op a n -1-oyl]-L-p h en yla la n in e-L-leu cin e m eth yl es-
ter (7) was prepared in 92% yield from the protected pseudo-
1
peptide as an off-white solid: mp 120-122 °C; H NMR (300
N-[5-(L-Tyr osin e)a m in o-(4R)-h yd r oxy]p en ta n -1-oyl-L-
p h en yla la n in e-L-leu cin e m eth yl ester (13) was prepared
in 90% yield from the protected pseudopeptide as a chalky
solid: mp 79-81 °C; 1H NMR (300 MHz, CD3OD) δ 7.26-7.17
(comp, 5 H), 7.02 (d, J ) 8.2 Hz, 2 H), 6.71 (d, J ) 8.2 Hz, 2
H), 4.65 (dd, J ) 5.4, 9.2 Hz, 1 H), 4.45 (dd, J ) 6.1, 7.9 Hz,
1 H), 3.67 (s, 3 H), 3.55-3.44 (comp, 2 H), 3.18-3.07 (comp, 2
H), 2.93-2.72 (comp, 3 H), 2.23 (t, J ) 7.5 Hz, 2 H), 1.69-
1.44 (comp, 5 H), 0.93 (d, J ) 6.1 Hz, 3 H), 0.89 (d, J ) 6.1 Hz,
3 H); 13C NMR (75 MHz, CD3OD) δ 176.3, 175.6, 174.4, 173.9,
157.4, 138.5, 131.4, 130.3, 129.4, 129.1, 127.7, 116.4, 70.5, 57.7,
52.7, 52.2, 45.9, 41.5, 41.0, 38.9, 32.8, 31.3, 25.9, 23.3, 21.9;
IR (Nujol) ν 1736, 1643, 1536 cm-1; mass spectrum (CI) m/z
571.3133 (C30H42N4O7 + H requires 571.3132), 293 (base).
N-[5-(L-Tyr osin e)am in o-(4R)-h ydr oxy-(3R)-m eth yl]pen -
ta n -1-oyl-L-p h en yla la n in e-L-leu cin e m eth yl ester (14)
was prepared in 92% yield from the protected pseudopeptide
as a light yellow solid: mp 68-70 °C; 1H NMR (300 MHz,
CD3OD) δ 8.37 (d, J ) 8.0 Hz, 1 H), 7.99 (d, J ) 8.2 Hz, 1 H),
7.37-7.15 (comp, 5 H), 7.09 (d, J ) 8.4 Hz, 1 H), 6.78 (d, J )
8.4 Hz, 1 H), 4.67 (dd, J ) 5.4, 9.1 Hz, 1 H), 4.52-4.41 (m, 1
H), 3.99-3.94 (m, 1 H), 3.67 (s, 3 H), 3.48-3.42 (m, 1 H), 3.16
(dd, J ) 5.7, 14.1 Hz, 1 H), 3.11-3.01 (comp, 3 H), 2.90 (dd, J
) 8.2, 13.4 Hz, 1 H), 2.87 (dd, J ) 9.6, 14.1 Hz, 1 H), 2.47 (q,
J ) 7.1 Hz, 1 H), 1.69-1.55 (comp, 4 H), 1.51-1.45 (m, 1 H),
1.37-1.33 (comp, 2 H), 1.03 (d, J ) 6.8 Hz, 3 H), 0.93 (d, J )
6.4 Hz, 3 H), 0.90 (d, J ) 6.4 Hz, 1 H); 13C NMR (75 MHz,
CD3OD) δ 179.2, 174.3, 173.8, 170.0, 158.3, 138.5, 131.5, 130.4,
129.4, 127.7, 126.1, 116.9, 68.7, 56.1, 55.5, 52.7, 52.2, 49.6, 46.4,
41.5, 39.2, 38.7, 38.1, 38.0, 25.9, 23.2, 21.8, 17.7; IR (Nujol) ν
3540, 2940, 1731, 1695 cm-1; mass spectrum (CI) m/z 585.3276
(C31H44N4O7 + H requires 585.3288).
MHz, CD3OD) δ 7.32-7.18 (comp, 5 H), 7.09 (d, J ) 8.5 Hz, 2
H), 6.78 (d, J ) 8.5 Hz, 2 H), 4.64-4.59 (m, 1 H), 4.49-4.46
(m, 1 H), 4.11 (app t, J ) 7.1 Hz, 1 H), 3.66 (s, 3 H) 3.55-3.53
(m, 1 H), 3.38-3.34 (m, 1 H), 3.20-3.12 (comp, 3 H), 2.97-
2.85 (comp, 2 H), 1.74-1.55 (comp, 4 H), 1.05-1.00 (comp, 2
H), 0.93 (d, J ) 6.5 Hz, 3 H), 0.93-0.89 (m, 1 H), 0.89 (d, J )
6.5 Hz, 3 H); 13C NMR (75 MHz, CD3OD) δ 176.6, 174.3, 173.9,
173.8, 157.4, 131.4, 130.4, 129.5, 129.4, 127.8, 116.3, 69.5, 57.8,
55.9, 52.7, 52.2, 45.9, 41.6, 41.2, 38.9, 25.9, 24.9, 23.2, 21.9,
20.3, 11.0; IR (Nujol) ν 2998, 1730, 1690 cm-1; mass spectrum
(CI) m/z 583.3119 (C31H42N4O7 + H) requires 583.3132), 294
(base).
N-[1S-(1r,2r,3â)]-2-(L-Tyr osin e-L-glycin e-L-glycin e)-3-
p h en ylcyclop r op a n e-1-L-leu cin e m eth yl ester (8) was
prepared in 90% yield from the protected pseudopeptide as a
1
white solid: mp 101-103 °C; H NMR (300 MHz, CD3OD) δ
7.30-7.14 (comp, 5 H), 7.09 (d, J ) 8.4 Hz, 2 H), 6.76 (d, J )
8.4 Hz, 2 H), 4.07-4.00 (comp, 3 H), 3.92-3.83 (comp, 3 H),
3.72 (s, 3 H), 3.14 (dd, J ) 6.4, 14.6 Hz, 1 H), 3.11 (dd, J )
4.6, 6.6 Hz, 1 H), 2.96 (dd, J ) 8.0, 14.6 Hz, 1 H), 2.82 (dd, J
) 4.6, 6.1 Hz, 1 H), 1.77-1.70 (comp, 2 H), 1.66-1.61 (comp,
2 H), 0.95 (d, J ) 6.3 Hz, 3 H), 0.93 (d, J ) 6.3 Hz, 3 H); 13C
NMR (75 MHz, CD3OD) δ 176.0, 175.0, 172.8, 170.0, 155.7,
139.3, 133.7, 130.9, 129.7, 127.8, 127.3, 125.2, 57.8, 53.6, 46.7,
43.6, 39.2, 38.7, 38.3, 34.7, 31.0, 26.5, 23.3 ; IR (Nujol) ν 3028,
2950, 1730, 1665 cm-1; mass spectrum (CI) m/z 554.2987
(C29H39N5O6 + H requires 554.2979).
N-[(1R-(1r,2r,1′r))-2-[2′-(L-Tyr osin e)a m in o]eth a n -1′-ol-
cyclop r op a n -1-oyl]-L-p h en yla la n in e-L-leu cin e m eth yl es-
ter (10) was prepared in 90% yield from the protected
pseudopeptide as an off-white solid: mp 106-108 °C; 1H NMR
(300 MHz, CD3OD) δ 7.37-7.20 (comp, 5 H), 7.09 (d, J ) 8.6
Hz, 2 H), 6.76 (d, J ) 8.6 Hz, 2 H), 4.63 (dd, J ) 5.7, 8.8 Hz,
[(1S-(1r,2r,1′r))-2-[2′-Azido-1′-(ter t-Bu tyldim eth ylsiloxy)]-
eth yl-cyclop r op a n e-1-ca r boxylic Acid Meth yl Ester (37).

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 65, No. 5, 2000 1317
A solution of 17 (0.25 g, 1.6 mmol) in MeOH (10 mL) containing
concentrated HCl (5 drops) was stirred for 12 h at room
temperature. After cooling to 0 °C, saturated aqueous NaHCO3
was added until pH 8 and the mixture was concentrated under
reduced pressure to remove the volatiles. The resulting aque-
ous layer mixture was then extracted with EtOAc (3 × 7 mL),
and the organic layers were combined. The organic layer was
then washed with brine (2 × 5 mL), dried (MgSO4), and
concentrated under reduced pressure to yield 0.24 g of a yellow
oil. To a solution of the crude oil (0.24 g, 1.3 mmol) in DMF (3
mL) were added imidazole (0.18 g, 2.6 mmol) and TBDMSCl
(0.26 g, 1.7 mmol), and the solution was stirred for 12 h at
room temperature. Et2O (10 mL) was added, and the organic
layer was washed with H2O (2 × 4 mL) and brine (2 × 4 mL).
The organic layer was dried (MgSO4) and concentrated under
reduced pressure, and the crude oil was purified by flash
chromatography eluting with hexanes/EtOAc (10:1) to afford
0.33 g (70% over two steps) of 37 as a light yellow oil: 1H NMR
(300 MHz) δ 3.92-3.86 (m, 1 H), 3.68 (s, 3 H), 3.22 (dd, J )
4.1, 12.5 Hz, 1 H), 3.05 (dd, J ) 5.2, 12.5 Hz, 1 H), 1.81 (dt, J
) 5.9, 8.0 Hz, 1 H), 1.46 (p, J ) 6.4 Hz, 1 H), 1.21-1.12 (comp,
2 H), 0.91 (s, 9 H), 0.12 (s, 6 H); 13C NMR (75 MHz) δ 173.2,
70.8, 57.3, 51.9, 25.8, 24.8, 18.1, 18.0, 13.6, -4.2, -4.7; IR
(CHCl3) ν 2954, 2104, 1722 cm-1; mass spectrum (CI)
m/z 300.1742 (C13H25N3O3Si + H requires 300.1743), 168
(base).
N-[(1S-(1r,2r,1′r))-2-[(2′-[N-(ter t-Bu toxyca r bon yl)-L-ty-
r osin e]a m in o)-1′-(ter t-bu tyld im eth ylsiloxy)]eth yl-cyclo-
p r op a n e-1-ca r boxylic Acid Meth yl Ester . To a solution of
37 (0.12 g, 0.40 mmol) in MeOH (2 mL) was added 10% Pd/C
(10 mg (cat.)) and the mixture was stirred under H2 (1 atm).
The reaction mixture was stirred vigorously for 1 h and was
then filtered through a Celite pad. The Celite pad was washed
with MeOH (2 mL), and the filtrate was concentrated under
reduced pressure to yield a light yellow oil. The oil was
dissolved in DMF (2 mL) and was cannulated into a solution
of Boc-Tyr(O-t-Bu)-OH (0.18 g, 0.52 mmol) and HOBt (0.17 g,
1.3 mmol) in DMF (2 mL) at 0 °C. EDCI (0.11 g, 0.52 mmol)
was added in one portion, and the mixture was stirred at room
temperature for 16 h. The mixture was diluted with EtOAc (5
mL) and brine (2 mL), and the layers were separated. The
aqueous layer was extracted with EtOAc (2 × 5 mL), and the
organic layers were combined. The organic layer was washed
with 10% citric acid (2 × 5 mL), saturated aqueous NaHCO3
(2 × 5 mL), and brine (2 × 5 mL). The organic layer was dried
(Na2SO4) and concentrated under reduced pressure, and the
crude oil was purified by flash chromatography eluting with
hexane/EtOAc (4:1) to yield 0.18 g (78%) of ester as a light
yellow oil: 1H NMR (300 MHz) δ 7.07 (d, J ) 8.4 Hz, 2 H),
6.89 (d, J ) 8.4 Hz, 2 H), 6.19 (br s, 1 H), 4.99 (d, J ) 8.6 Hz,
1 H), 4.60-4.50 (m, 1 H), 4.28 (m, 1 H), 3.78 (p, J ) 5.8 Hz, 1
H), 3.71 (s, 3 H), 3.35-3.27 (comp, 2 H), 3.13-2.82 (comp, 5
H), 1.75 (q, J ) 6.2 Hz, 1 H), 1.37 (s, 9 H), 1.31 (s, 9 H), 1.28-
1.12 (m, 1 H), 1.13-1.07 (comp, 2 H), 0.87 (s, 9 H), 0.08 (s, 3
H), 0.04 (s, 3 H); 13C NMR (75 MHz) δ 173.1, 171.1, 155.3,
154.4, 131.5, 129.7, 124.0, 80.0, 78.2, 69.9, 56.1, 52.0, 45.2, 37.9,
28.9, 28.3, 25.8, 24.6, 18.3, 18.0, 13.5, -4.0, -4.7; IR (CHCl3)
ν 3433, 2930, 1720, 1674, 1505 cm-1; mass spectrum (CI)
m/z 593.3616 (C31H52N2O7Si + H requires 593.3622), 537
(base).
to be >95% pure by 1H NMR and did not require further
1
purification: mp 124-126 °C; H NMR (300 MHz) δ 7.06 (d,
J ) 8.4 Hz, 2 H), 6.92 (d, J ) 8.4 Hz, 2 H), 5.82-5.77 (m, 1
H), 5.24 (d, J ) 9.5 Hz, 1 H), 4.30-4.22 (m, 1 H), 3.65-3.58
(m, 1 H), 3.54-3.45 (m, 1 H), 2.94 (d, J ) 7.4 Hz, 2 H), 2.90-
2.85 (m, 1 H), 1.76 (dt, J ) 5.9, 7.8 Hz, 1 H), 1.40 (s, 9 H), 1.33
(s, 9 H), 1.29-1.20 (m, 1 H), 1.14-1.00 (comp, 2 H), 0.88 (s, 9
H), 0.09 (s, 9 H); 13C NMR (75 MHz) δ 174.2, 171.3, 156.7,
154.4, 131.4, 129.7, 124.5, 81.1, 78.5, 69.8, 55.9, 46.2, 38.6, 28.9,
28.3, 25.8, 18.1, 17.9, 12.2, -4.3, -4.7; IR (CHCl3) ν 3433, 2930,
1717, 1673, 1506 cm-1; mass spectrum (CI) m/z 579.3465
(C30H50N2O7Si + H requires 579.3466).
Bis-Cyclop r op a n e Ad d u ct (39). To a solution of 38 (50
mg, 0.085 mmol) in CH2Cl2 (0.5 mL) at room temperature were
added HOBt (11 mg, 0.085 mmol) and DCC (18 mg, 0.085
mmol). The mixture was stirred for 1 h at room temperature,
whereupon it was transferred via syringe to a flask charged
with 34 (30 mg, 0.065 mmol) in CH2Cl2 (0.5 mL). Pd(PPh3)4
(15 mg, 0.013 mmol) and Bu3SnH (19 µL, 0.072 mmol) were
added, and the resulting mixture was stirred at room tem-
perature for 3 h. The mixture was filtered and concentrated
under reduced pressure to yield a bright yellow semisolid. The
crude product was purified by flash chromatography eluting
with hexane/EtOAc (4:1) to afford 46 mg (75%) of 39 as a clear
glass: mp 112-114 °C; 1H NMR (500 MHz, CD3OD) δ 7.29
(app t, J ) 7.4 Hz, 3 H), 7.21-7.18 (comp, 2 H), 7.10 (d, J )
8.2 Hz, 2 H), 6.86 (d, J ) 8.2 Hz, 1 H), 4.50 (br s, 1 H), 4.24
(dd, J ) 5.0, 9.4 Hz, 1 H), 3.93 (ddd, J ) 3.4, 5.4, 8.9 Hz, 1 H),
3.77 (s, 3 H), 3.71 (br s, 1 H), 3.37 (dt, J ) 6.4, 13.5 Hz, 1 H),
3.16-3.02 (comp, 2 H), 2.95 (br s, 1 H), 2.73 (dd, J ) 9.6, 13.4
Hz, 1 H), 2.44 (br s, 1 H), 1.90-1.82 (comp, 2 H), 1.70-1.63
(comp, 3 H), 1.43 (s, 9 H), 1.32 (s, 9 H), 1.31-1.25 (m, 1 H),
1.28 (s, 9 H), 1.20-1.14 (m, 1 H), 1.06-1.03 (m, 1 H), 0.95 (d,
J ) 6.4 Hz, 3 H), 0.91 (s, 9 H), 0.81 (d, J ) 6.4 Hz, 3 H), 0.12
(s, 3 H), 0.08 (s, 3 H); 13C NMR (125 MHz, CD3OD) δ 174.0,
157.5, 155.2, 139.6, 134.0, 130.9, 129.6, 127.7, 127.5, 125.1,
82.5, 80.6, 79.4, 71.4, 57.6, 53.3, 46.5, 39.1, 38.7, 31.6, 29.2,
28.7, 28.5, 26.6, 26.5, 25.3, 23.3, 21.8, 21.3, 18.9, 13.0, -3.7,
-4.4; IR (CHCl3) ν 3349, 2930, 1735, 1680, 1674, 1505 cm-1
;
mass spectrum (FAB) m/z 973.5714 (C51H80N4O10
S + H
requires 937.5722).
En k ep h a lin An a logu e (9). To a solution of 39 (20 mg,
0.021 mmol) and NaI (19 mg, 0.13 mmol) in dry CH3CN (0.25
mL) at room temperature was added freshly distilled TMSCl
(0.14 mL, 0.10 mmol). The mixture was stirred for 1 h,
whereupon the mixture was quenched with MeOH (1 mL) and
concentrated under reduced pressure. The crude residue was
diluted with EtOAc (1 mL) and washed with saturated sodium
thiosulfate (2 × 0.5 mL). The organic layer was dried (Na2SO4)
and concentrated under reduced pressure to yield 10 mg (85%)
of 9 as a white solid: mp 110-112 °C; 1H NMR (500 MHz,
d6-DMSO) δ 7.96 (d, J ) 4.2 Hz, 1 H), 7.74 (app t, J ) 5.4 Hz,
1 H), 7.22-7.20 (comp, 2 H), 7.14-7.11 (m, 1 H), 7.08-7.04
(comp, 2 H), 6.97 (d, J ) 8.4 Hz, 2 H), 6.64 (d, J ) 8.4 Hz, 2
H), 3.58 (s, 3 H), 3.56-3.49 (m, 1 H), 3.33-3.30 (m, 1 H), 3.19-
3.14 (m, 1 H), 2.98-2.92 (comp, 2 H), 2.85 (dd, J ) 4.2, 13.5
Hz, 1 H), 2.44 (dd, J ) 5.1, 13.5 Hz, 1 H), 2.42 (m, 1 H), 1.88
(app t, J ) 4.8 Hz, 1 H), 1.74-1.64 (comp, 3 H), 1.47-1.43 (m,
1 H), 1.22 (br s, 1 H), 1.13-1.07 (m, 1 H), 0.99-0.95 (m, 1 H),
0.87 (d, J ) 6.6 Hz, 3 H), 0.86 (d, J ) 6.6 Hz, 3 H), 0.84-0.81
(m, 1 H); 13C NMR (125 MHz, d6-DMSO) δ 175.4, 173.8, 171.9,
155.7, 140.4, 130.1, 128.5, 128.1, 126.1, 125.5, 114.9, 67.3, 59.1,
56.1, 51.4, 44.5, 42.4, 41.0, 37.6, 31.0, 28.7, 24.3, 23.8, 22.6,
22.1, 19.0, 9.8; IR (CHCl3) ν 3015, 1725, 1675 cm-1; mass
spectrum m/z (CI) 567.3202 (C31H42N4O6 + H requires 567.3183)
(base).
N-[1S-(1r,2r,1′r)]-2-[(2′-[N-(ter t-Bu toxyca r bon yl)-L-ty-
r osin e]a m in o)-1′-(ter t-bu tyld im eth ylsiloxy)]eth yl-cyclo-
p r op a n e-1-ca r boxylic Acid (38). To a solution of methyl
ester (0.15 g, 0.26 mmol) in EtOH (1.7 mL) at 0 °C was added
dropwise a 1 M solution of NaOH (0.34 mL). The mixture was
stirred at 0 °C for 2 h and then at room temperature for an
additional 12 h. The mixture was concentrated under reduced
pressure, and the resulting semisolid was dissolved in H2O (1
mL); EtOAc (2 mL) was added. The pH of the aqueous layer
was carefully adjusted to ca. 4 with 5% aqueous KHSO4, and
the layers were separated. The aqueous layer was extracted
with EtOAc (2 × 2 mL), and the organic layers were combined.
The organic layer was washed with brine (2 × 3 mL), dried
(Na2SO4), and concentrated under reduced pressure to yield
0.14 g (90%) of 38 as a clear glass. This material was shown
Ack n ow led gm en t. We wish to thank the National
Institutes of Health, the Robert A. Welch Foundation,
the Texas Advanced Technology Program, and the
Alexander von Humboldt Foundation (S.F.M.) for their
generous support of this work. We are also grateful to
Dr. David McCann (NIDA) for arranging for the in vitro
opiate receptor binding and functional activity assays

1318 J . Org. Chem., Vol. 65, No. 5, 2000
Martin et al.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and complete characterization (1H and 13C NMR and
IR spectra and mass spectral data) for new compounds not
included in the Experimental Section. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
to be conducted at SRI International (Menlo Park, CA)
by Drs. Lawrence Toll and Ilona Berzetei-Gurske with
the support of NIDA contract number N01DA-4-8307.
We also thank Dr. Matthias Baur (Technische Univer-
sita¨t Mu¨nchen) and Mr. Greg Pitzer (University of
Texas) for conducting preliminary NMR studies and
Professor Horst Kessler (Technische Universita¨t Mu¨n-
chen) for helpful discussions.
J O991288H