Cyclopropane-derived peptidomimetics, design, synthesis, and evaluation of novel Ras farnesyltransferase inhibitors

Article abstract of DOI:10.1021/jo001257i

Trisubstituted cyclopropanes have previously been established as rigid replacements of dipeptide arrays in several biological systems. Toward further evaluating the utility of these dipeptide mimics in the design of novel CA₁A₂X-based inhibitors of Ras farnesyltransferase (FTase), the conformationally constrained, diastereomeric pseudopeptides CAbuψ[COcpCO]FM 7-9, the flexible analogue CAbuψ[CHOHCH₂]FM (10), and the tetrapeptide CAbuFM (6) were prepared. The orientations of the two peptide backbone substituents and the phenyl group on the cyclopropane rings in 7-9 were specifically designed to probe selected topological features of the hydrophobic binding pocket of the A₂ subsite of FTase. The syntheses of the requisite trisubstituted cyclopropane carboxylic acid 22 and the diastereomeric cyclopropyl lactones 32a,b featured diastereoselective intramolecular cyclopropanations of chiral allylic diazoacetates and a new method for introducing side chains onto the C-terminal amino acid of cyclopropane-derived dipeptide replacements via the opening of an N-Boc-aziridine with an organocuprate. These cyclopropane intermediates were then converted into the targeted FTase inhibitors 7-9 by standard peptide coupling techniques. The pseudopeptides 7-9 were found to be competitive inhibitors of Ras FTase with IC₅₀s of 1055 nM for 7, 760 nM for 8, and 7200 nM for 9. The flexible analogue 10 of these constrained inhibitors exhibited a IC₅₀ of 320 nM and hence was slightly more potent than 7 and 8. All of these pseudopeptides were less potent than the tetrapeptide parent CAbuFM (6), which had an IC₅₀ of 38 nM. Because 7 and 8 are approximately equipotent, it appears that the orientation of the peptide backbone substituents on the cyclopropane rings in 7 and 8 do not have any significant effect on binding affinity and that multiple binding modes are possible without significant changes in affinity. On the other hand, this flexibility does not extend to the orientation of the side chain of the A₂ residue as 7 and 8 were both nearly i order of magnitude more potent than 9. Comparison of the relative potencies of 6 and 10 suggests that the amide linkage between the A₁ and the A₂ residues of CA₁A₂X-derived FTase inhibitors is important.

Full text of DOI:10.1021/jo001257i

J . Org. Chem. 2001, 66, 1657-1671
1657
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 Ra s F a r n esyltr a n sfer a se In h ibitor s
Michael C. Hillier, J ames P. Davidson, and Stephen F. Martin*
Department of Chemistry and Biochemistry and The Institute of Cellular and Molecular Biology,
The University of Texas, Austin, Texas 78712
sfmartin@mail.utexas.edu
Received August 18, 2000
Trisubstituted cyclopropanes have previously been established as rigid replacements of dipeptide
arrays in several biological systems. Toward further evaluating the utility of these dipeptide mimics
in the design of novel CA1A2X-based inhibitors of Ras farnesyltransferase (FTase), the conforma-
tionally constrained, diastereomeric pseudopeptides CAbuΨ[COcpCO]FM 7-9, the flexible analogue
CAbuΨ[CHOHCH2]FM (10), and the tetrapeptide CAbuFM (6) were prepared. The orientations of
the two peptide backbone substituents and the phenyl group on the cyclopropane rings in 7-9
were specifically designed to probe selected topological features of the hydrophobic binding pocket
of the A2 subsite of FTase. The syntheses of the requisite trisubstituted cyclopropane carboxylic
acid 22 and the diastereomeric cyclopropyl lactones 32a ,b featured diastereoselective intramolecular
cyclopropanations of chiral allylic diazoacetates and a new method for introducing side chains onto
the C-terminal amino acid of cyclopropane-derived dipeptide replacements via the opening of an
N-Boc-aziridine with an organocuprate. These cyclopropane intermediates were then converted
into the targeted FTase inhibitors 7-9 by standard peptide coupling techniques. The pseudopeptides
7-9 were found to be competitive inhibitors of Ras FTase with IC50s of 1055 nM for 7, 760 nM for
8, and 7200 nM for 9. The flexible analogue 10 of these constrained inhibitors exhibited a IC50 of
320 nM and hence was slightly more potent than 7 and 8. All of these pseudopeptides were less
potent than the tetrapeptide parent CAbuFM (6), which had an IC50 of 38 nM. Because 7 and 8 are
approximately equipotent, it appears that the orientation of the peptide backbone substituents on
the cyclopropane rings in 7 and 8 do not have any significant effect on binding affinity and that
multiple binding modes are possible without significant changes in affinity. On the other hand,
this flexibility does not extend to the orientation of the side chain of the A2 residue as 7 and 8 were
both nearly 1 order of magnitude more potent than 9. Comparison of the relative potencies of 6
and 10 suggests that the amide linkage between the A1 and the A2 residues of CA1A2X-derived
FTase inhibitors is important.
In tr od u ction
organization, and few are capable of orienting the amino
acid side chains, which contribute critical recognition
elements for binding and specificity. Thus, there is a
general need for peptide replacements that predictably
constrain both the peptide backbone and the side chains
in orientations that correspond to the biologically active
conformation, or the bound structure, of the peptide.
Toward this end, we invented a novel class of cyclo-
propane-derived peptide isosteres related to 2.3,4 These
dipeptide mimics differ from the traditional peptide bond
replacements in that the cyclopropane ring in 2 replaces
the nitrogen and R-carbon atoms in the peptide backbone
of the dipeptide 1 as well as the â-carbon of the amino
acid (Yaa). Hence, we have modified the usual abbrevia-
tion for designating simple peptide bond replacements
and use the formulation -Xaaψ[COcpCO]Yaa- to indi-
cate the presence of a cyclopropane ring as a subunit in
these dipeptide mimics. When the cyclopropane substit-
uents corresponding to the peptide chain on 2 are trans,
the backbone φ angle is locked to enforce a local â-strand
conformation, an important secondary structural element
The development of conformationally constrained mim-
ics of peptide secondary structure is central to the process
of mutating small, biologically active peptides into non-
peptidic substances that have comparable or enhanced
binding affinity for the same enzyme active site or
macromolecular receptor.1 Most such replacements have
been designed to imitate or initiate turns or helices, but
several have been reported that stabilize extended struc-
tures.2 A survey of the vast majority of peptide mimics
reveals that most are dedicated to controlling backbone
(1) For some recent reviews of peptide mimics, see: (a) Giannis, A.;
Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244-1267. (b)
Gante, J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1699-1720. (c)
Schneider, J . P.; Kelly, J . W. Chem. Rev. 1995, 95, 2169-2187. (d)
Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D.
Tetrahedron 1997, 38, 12789-12854. (e) Goodman, M.; Zhang, J .
ChemtractssOrg. Chem. 1997, 10, 629-645.
(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 ., J r. 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.
(3) Martin, S. F.; Austin, R. E.; Oalmann, C. J . Tetrahedron Lett.
1990, 31, 4731-4734.
(4) Martin, S. F.; Hom, R. K. Tetrahedron Lett. 1999, 40, 2887-
2890.
10.1021/jo001257i CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/02/2001

1658 J . Org. Chem., Vol. 66, No. 5, 2001
Hillier et al.
found in proteins and numerous inhibitors bound at
enzyme active sites.5 In the corresponding cis-isomer, a
reverse turn may be initiated. Depending on the stereo-
chemistry at the cyclopropyl carbon bearing R2 in 2, this
side chain may be positioned relative to the backbone in
orientations that approximate ø1 angles in 1 of gauche(-)
(-60°) or gauche(+) (+60°). Of these two orientations,
the gauche(-) conformation is more commonly encoun-
tered in oligo and polypeptides than the sterically more
congested gauche(+) conformation.6
the enzyme-bound structures of selected pseudopeptides,
we were intrigued by the possibility that these replace-
ments might be used as tools to probe the topology of the
bound conformation of peptide-derived inhibitors of other
biologically important proteins. In this context, we be-
came interested in Ras farnesyltransferase (FTase), a 21
kD G-protein that catalyzes the farnesylation of a cys-
teine residue at the C-terminus of Ras proteins, the
critical step in the posttranslational modification of Ras
that leads to translocation of Ras to the membrane. If
Ras farnesylation is blocked, oncogenic Ras proteins do
not acquire their transforming ability, so the development
of potent inhibitors of FTase has emerged as an impor-
tant strategy for discovery of potential anticancer agents.12
Many inhibitors of FTase are based upon the C-terminal
tetrapeptide Cys-Val-Ile-Leu, CVIL, of the H-Ras p21
substrate, and such compounds are commonly referred
to as CA1A2X mimetics. The middle two amino acids A1A2
are typically hydrophobic residues with X usually being
Met. Numerous derivatives of the tetrapeptide Cys-Val-
Phe-Met, CVFM (5), have been found to be potent
inhibitors of FTase, several of which cause complete
tumor regression in vivo.12
To establish the efficacy of dipeptide replacements
related to 2, we developed methods for their enantiose-
lective synthesis and then introduced them into a number
of biologically active pseudopeptides, including inhibitors
of renin, HIV-1 protease, and matrix metalloproteinases
as well as enkephalin analogues.7-10 Others have used
such cyclopropane-derived mimics in non-peptide fibrino-
gen receptor antagonists.11 The predicted structural
properties of these rigid replacements were verified in a
significant study in which truncated analogues of 2 were
incorporated in conformationally restricted inhibitors of
HIV-1 protease. For example, the two pseudopeptides 3
and 4, which contain two cyclopropane replacements,
were subnanomolar inhibitors.8 The structure of 3 in
solution was determined by NMR, and the structure of
the complex of 4 bound to HIV-1 protease was established
by X-ray crystallography. Except at two terminal benzyl
groups, the solution conformation of 3 was nearly identi-
cal to the enzyme-bound structures of 4 and other closely
related flexible HIV-1 protease inhibitors. Thus, the two
cyclopropane rings in 3 and 4 stabilize an extended,
â-strand conformation in solution that corresponds with
high fidelity to their biologically active conformation.
Having established that isosteric replacements related
to 2 mimicked secondary structural elements found in
Central to the design of novel ligands as FTase
inhibitors is knowledge of their bound conformation, and
there are various studies that suggest such inhibitors
may bind to the active site in extended and turn-like
conformations.13,14 Perhaps most informative are the
detailed insights emanating from recent X-ray crystal-
(12) For reviews, see: (a) Scholten, J . D.; Zimmerman, K.; Oxender,
M.; Sebolt-Leopold, J .; Gowan, R.; Leonard, D.; Hupe, D. J . Bioorg.
Med. Chem. 1996, 4, 1537-1543. (b) Qian, Y.; Sebti, S. M.; Hamilton,
A. D. Biopolymers 1997, 43, 25-41. (c) Leonard, D. M. J . Med. Chem.
1997, 40, 2972-2990.
(13) For example, see: (a) Nigam, M.; Seong, C.-M.; Qian, Y.;
Hamilton, A. D.; Sebti, S. M. J . Biol. Chem. 1994, 268, 20695-20698.
(b) Qian, Y.; Blaskovich, M. A.; Saleem, M.; Seong, C. M.; Wathen, S.
P.; Hamilton, A. D.; Sebti, S. M. J . Biol. Chem. 1994, 269, 12410-
12413. (c) Qian, Y.; Vogt, A.; Sebti, S.; Hamilton, A. J . Med. Chem.
1996, 39, 217-223. (d) Williams, T. M.; Ciccarone, T. M.; MacTough,
S. C.; Bock, R. L.; Conner, M. W.; Davide, J . P.; Hamilton, K.; Koblan,
K. S.; Kohl, N. E.; Kral, A. M.; Mosser, S. D.; Omer, C. A.; Pompliano,
D. L.; Rands, E.; Schaber, M. D.; Shah, D.; Wilson, F. R.; Gibbs, J . B.;
Graham, S. L.; Hartman, G. D.; Oliff, A. I.; Smit, R. L. J . Med. Chem.
1996, 39, 1345-1348. (e) Burns, C.; Guitton, J .; Baudoin, B.; Lelievre,
Y.; Duchesne, M.; Parker, F.; Fromage, N.; Commercon, A. J . Med.
Chem. 1997, 40, 1763-1767. (f) Dinsmore, C.; Williams, T.; Hamilton,
K.; O’Neill, T.; Rands, E.; Koblan, K.; Kohl, N.; Gibbs, J .; Graham, S.;
Hartman, G.; Oliff, A. Bioorg. Med. Chem. Lett. 1997, 10, 11345-1348.
(g) Byk, G.; Lelievre, Y.; Duchesne, M.; Clerc, F.; Scherman, D.;
Guitton, J . D. Bioorg. Med. Chem. 1997, 5, 115-124.
(14) For example, see: (a) Stradley, S. J .; Rizo, J .; Gierasch, L. M.
Biochemistry 1993, 32, 12586-12590. (b) J ames, G. L.; Goldstein, J .
L.; Brown, M. S.; Rawson, T. E.; Somers, T. C.; McDowell, R. S.;
Crowley, G. W.; Lucas, B. K.; Levinson, A. D.; Marsters, J . C. Science
1993, 260, 1937-1942. (c) Marsters, J . C., J r.; McDowell, R. S.;
Reynolds, M. E.; Oare, D. A.; Somers, T. C.; Stanley, M. S.; Rawson,
T. E.; Struble, M. E.; Burdick, D. J .; Chan, K. S.; Duarte, C. M.; Paris,
K. J .; Tom, J . Y. K.; Wan, D. T.; Xue, Y.; Burnier, J . P. Bioorg. Med.
Chem. 1994, 2, 949-957. (d) Koblan, K. S.; Culberson, J . C. Desolms,
S. J .; Giuliani, E. A.; Mosser, S. D.; Omer, C. A.; Pitzenberger, S. M.;
Bogusky, M. J . Protein Science 1995, 4, 681-688. (e) Liu, R.; Dong, D.
L.-Y.; Sherlock, R.; Nestler, H. P.; Genarri, C.; Mieglo, A.; Scolastico,
C. Bioorg. Med. Chem. Lett. 1999, 9, 847-852. (f) O’Connell, C. E.;
Ackermann, K.; Rowell, C. A.; Garcia, A. M.; Lewis, M. D.; Schwartz,
C. E. Bioorg. Med. Chem. Lett. 1999, 9, 2095-2100.
(5) For a review, see: Babine, R. E.; Bender, S. L. Chem. Rev. 1997,
97, 1359-1472.
(6) Hruby, V. J .; Li, G.; Haskell-Luevano, C.; Shenderovich, M.
Biopolymers 1994, 42, 219-266.
(7) (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.;
Cohen, J .; Kleinert, H. D. BioMed. Chem. Lett. 1992, 2, 1405-1410.
(8) (a) Martin, S. F.; Dorsey, G. O.; Gane, T. H.; Hillier, M. C.;
Kessler, H.; Baur, M.; Matha¨, B.; Erickson, J . W.; Bhat, N.; Munshi,
S.; Gulnik, 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, Peptidomimetics Protocols; Kazmierski, W. M.,Walker, J . M., Eds.;
Humana Press: Totowa, NJ , 1999; pp 397-406.
(9) Martin, S. F.; Oalmann, C. J .; Liras, S. Tetrahedron 1993, 49,
3521-3532.
(10) (a) Dwyer, M. P.; Martin, S. F. In Methods in Molecular
Medicine: Vol. 30, Peptidomimetics Protocols; Kazmierski, W. M.,
Walker, J . M., Eds.; Humana Press: Totowa, NJ , 1999; pp 407-416.
(b) Martin, S. F.; Dwyer, M. P.; Hartmann, B.; Knight, K. S. J . Org.
Chem. 2000, 65, 1305-1318.
(11) 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. 66, No. 5, 2001 1659
lographic studies that were not available at the time the
present work was initiated. In the ternary complex of
N-acetyl-Cys-Val-Ile-selenoMet-COOH, R-hydroxyfarne-
sylphosphonic acid, and FTase, the tetrapeptide was
found to bind in an extended conformation.15 Because of
the conformational changes that occur on complexation
of this CVIM analogue, the authors noted that there may
be alternate inhibitor binding modes for inhibitors related
to CVFM, which have an aromatic residue rather than
isoleucine at the A2 position. More recent structural work
with complexes of other CVIM and farnesyl pyrophos-
phate analogues with rat FTase reveals that the peptides
can bind in either an extended or a â-turn conformation
depending upon whether the enzyme contains the active
site zinc ion that coordinates with the SH group of the
C-terminal cysteine.16
to induce a turn in the chain. As in 7, the orientation of
the phenyl group in 8 is gauche(-). The pseudopeptide
9 was selected to assess the consequence upon binding
affinity of placing the phenyl group in a gauche(+)
orientation. The route to 7 was not readily amenable to
the syntheses of epimers of 7 in which the stereochem-
istry of the cyclopropylcarbinol was the same as in 8 and
9 or in which the configuration at the carbon bearing the
phenyl group was inverted. It was necessary to prepare
the pseudopeptide 10 as a flexible control to provide a
better measure of the specific effects of introducing the
rigid -AbuΨ[COcpCO]Phe- replacement because the
A1-A2 amide bond of 6 in the CVFM analogues 7-9 is
replaced with a constrained hydroxyethylene moiety. In
each of the pseudopeptides 7-10, the carbonyl group of
the A2 residue, which forms a hydrogen bond to Arg202â
of rat FTase and is important for biological activity,15,16,18
is retained.
In h ibitor Design a n d Syn th esis
Id en tifica tion of Ta r get CVF M (5) An a logu es.
Although it was not evident at the outset of our studies
whether peptide-derived FTase inhibitors bound prefer-
entially in extended or turn-like conformations, it was
known that the orientation of the phenyl group on the
Phe residue played an important role in determining the
potency of CVFM derivatives.17 Hence, to probe selected
topographical requirements about the Phe subunit of
such inhibitors, we decided to examine conformationally
constrained CVFM analogues containing extended and
turn-like replacements 2 (R2 ) Ph) at the A1 and A2
subsites. Based upon synthetic considerations, we se-
lected the tetrapeptide sequence 6, CAbuFM, as the
template for designing cyclopropane-containing ana-
logues of CVFM (5). The replacement of valine in the
CVFM parent 5 with R-aminobutyric acid, Abu, in 6 was
not anticipated to be deleterious because previous work
had shown that a number of hydrophobic residues may
be introduced at the A1 position of CVFM derivatives
without significant changes in binding affinity.18,19
Incorporation of an -AbuΨ[COcpCO]Phe- as the
dipeptide replacement 2 at the A1 and A2 subsites of 6
led to a number of potential pseudopeptide analogues of
6. However, we selected compounds 7-9 as the initial
targets of our inquiry because they would be readily
accessible and they seemed most likely to mimic the
biologically active conformation of 6. The cyclopropane
ring in 7 was predicted to stabilize a local extended
conformation while orienting the phenyl group in ap-
proximately a gauche(-) orientation. In 8 and 9, the cis
relationship of the backbone substituents was anticipated
Syn th eses of Cyclop r op a n e-Der ived P seu d op ep -
tid es 7-9. The first task to be addressed in the synthesis
of the pseudopeptide 7 was the preparation of the syn
allylic diazoester 16. Following literature precedent,20 we
found addition of lithium phenylacetylide added to 11 in
THF containing hexamethylphosphorus triamide (HMPT)
proceeded without racemization to give a mixture (9:1)
of 12 (74% yield) together with lesser amounts of the anti
isomer 13 (8%) (Scheme 1). HMPT was employed to
enhance “nonchelation”-controlled addition,21 although
we found 18-crown-6 could be used in place of HMPT to
give similar product ratios.20a To establish the relative
stereochemistry of 12 and 13, they were converted into
their respective acetonides ((i) Amberlyst/H+, MeOH; (ii)
2,2-dimethoxypropane, pyridinium p-toluenesulfonate) 14
(15) Strickland, C. L.; Windsor, W. T.; Syto, R.; Wang, L.; Bond, R.;
Wu, J .; Schwartz, J .; Le, H. V.; Beese, L. S.; Weber, P. C. Biochemistry
1998, 37, 16601-16611.
(16) Long, S. B.; Casey, P. J .; Beese, L. S. Structure 2000, 8, 209-
222.
(17) Leftheris, K.; Kline, T.; Vite, G. D.; H., C. Y.; Bhide, R.; Patel,
D. V.; M., P. M.; Schmidt, R. J .; Weller, H. N.; Andahazy, M. L.;
Carboni, J . M.; Gullo-Brown, J . L.; Lee, F. Y. F.; Ricca, C.; Rose, W.
C.; Yan, N.; Barbacid, M.; Hunt, J . T.; Meyers, C. A.; Seizinger, B. R.;
Zahler, R.; Manne, V. J . Med. Chem. 1996, 39, 224-236.
(18) Leftheris, K.; Kline, T.; Natarajan, S.; DeVirgilio, M. K.; Cho,
Y. H.; Plusec, J .; Ricca, C.; Robinson, S.; Seizinger, B. R.; Manne, V.;
Meyers, C. A. Bioorg. Med. Chem. Lett. 1994, 4, 887-892.
(19) (a) Graham, S. L.; deSolms, S. J .; Giuliani, E. A.; Kohl, N. E.;
Mosser, S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Breslin, M. J .;
Deana, A. A.; Garsky, V. M.; Scholz, T. H.; Gibbs, J . B.; Smith, R. L.
J . Med. Chem. 1994, 37, 725-732. (b) Wallace, A.; Koblan, K. S.;
Hamilton, K.; Marquis-Omer, D. J .; Millier, P. J .; Mosser, S. D.; Omer,
C. A.; Schaber, M. D.; Cortese, R.; Oliff, A.; Gibbs, J . B.; Pessi, A. J .
Biol. Chem. 1996, 271, 31306-31311.
(20) (a) Herold, P. Helv. Chem. Acta 1988, 71, 354-362. (b) Garner,
P.; Park, J . M. In Organic Synthesis; Meyers, A. I., Ed.; J ohn Wiley &
Sons: New York, 1991; Vol. 69, pp 18-28.
(21) (a) Reetz, M. T.; Hu¨llmann, M. J . Chem. Soc., Chem. Commun.
1986, 1600-1602. (b) Mulzer, J .; Angermann, A. Tetrahedron Lett.
1983, 24, 2843-2845.

1660 J . Org. Chem., Vol. 66, No. 5, 2001
Hillier et al.
Sch em e 1
Sch em e 2
only 25% yield, thus reflecting a “mis-matched” catalyst-
substrate interaction similar to that observed in previous
work.25 Cyclization of 16 in the presence of the achiral
catalyst Cu(TBS)2 also gave a mixture (3:1) of 17 and 18,
but in 84% combined yield. Thus, there is a clear
preference for the formation of the exo diastereomer 17
in the catalyzed, intramolecular cyclopropanations of 16.
Elaboration of the Abu side chain in 20 was then
accomplished by first converting the protected amino
alcohol side chain of 17 into the aziridine 19 via a three-
step sequence featuring a Mitsunobu cyclization;26 it was
not possible to cleave the N,O-acetal without concomitant
cleavage of the N-Boc group. Subsequent ring opening
of the intermediate aziridine with Gilman’s reagent
(Me2CuLi) then furnished the cyclopropyl dipeptide 20
in 81% overall yield from 17.27
Aluminum-mediated amidation of the lactone 20 ac-
cording to the Weinreb protocol,28 followed by protection
of the intermediate secondary alcohol provided 21 in 66%
overall yield (Scheme 2). Upon treatment with base under
modified Gassman conditions,29 21 underwent thermo-
dynamically driven epimerization at the cyclopropane
carbon bearing the amide function, and subsequent
hydrolysis of the amide proceeded spontaneously in situ
to afford the acid 22 in 95% yield. The peptide backbone
of 22 was now locally locked in the requisite extended
motif. The C-terminal end of the dipeptide replacement
22 was coupled with the methyl ester of L-methionine,
whereupon the N-terminus of the resultant tripeptide
was deprotected and coupled with the pentafluorophenol
ester of N-Boc-2,2-dimethylthiazolidine 2330 to give 24
and 15, and the vicinal coupling constants for the protons
at the two stereogenic centers were determined (14, J 1,2
) 9.3 Hz; 15, J 1,2 ) 2.9 Hz).20a The syn adduct 12 was
then reduced stereoselectively using P-2 Ni22 to provide
an intermediate Z-allylic alcohol that was converted into
the diazoester 16 (72% overall) by the procedure of Corey
and Myers.23 When 16 was heated in the presence of
Rh2[(5R)-MEPY]4,24 a mixture (8:1) of diastereomeric
cyclopropyl lactones 17 and 18, which were readily
separable, was obtained in 76% combined yield. Stereo-
chemical assignments were based on the established
trends that have been observed in the relative chemical
shifts of the proton Ha in the two isomers: Ha in an exo
isomer consistently appears upfield from Ha in the
corresponding endo isomer [e.g., δ(Ha) in 17 ) 4.26 ppm,
18 ) 4.71 ppm].25 If the cyclization of 16 was conducted
in the presence of the enantiomeric Rh2[(5S)-MEPY]4
catalyst, a mixture (3:1) of 17 and 18 was obtained in
(22) Marvell, E. N.; Li, T. Synthesis 1973, 457-468.
(23) Corey, E. J .; Myers, A. G. Tetrahedron Lett. 1984, 23, 3559-
3562.
(24) For a general procedure for the synthesis of both Rh2[(5R)-
MEPY]4 and Rh2[(5S)-MEPY]4, see: Doyle, M. P.; Winchester, W. R.;
Protopopova, M. N. In Organic Synthesis; Boeckman, R. K., Ed.; J ohn
Wiley & Sons: New York, 1995; Vol. 73, pp 13-24.
(25) (a) Martin, S. F.; Spaller, M. R.; Liras, S.; Hartmann, B. J . Am.
Chem. Soc. 1994, 116, 4493-4494. (b) Martin, S. F.; Hillier, M. C.
Tetrahedron Lett. 1998, 39, 2929-2932. (c) Martin, S. F.; Hillier, M.
C. J . Chin. Chem. Soc. 2000, 47, 41-55.
(26) (a) Ho, M.; Chung, J . K. K.; Tang, N. Tetrahedron Lett. 1993,
34, 6513-6516. (b) Cherney, R. J .; Wang, L. J . Org. Chem. 1996, 61,
2544-2546.
(27) Baldwin, J . E.; Farthing, C. N.; Russell, A. T.; Schofield, C. J .;
Spivey, A. C. Tetrahedron Lett. 1996, 37, 3761-3764.
(28) (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.
(29) Gassman, P. G.; Hodgson, P. K. G.; Balichunis, R. J . J . Am.
Chem. Soc. 1976, 98, 1276-1277.
(30) Kemp, D. S.; Carey, R. I. J . Org. Chem. 1989, 54, 3640-3646.

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 66, No. 5, 2001 1661
Sch em e 3
Sch em e 4
in 52% overall yield. Global deprotection of 24 delivered
the desired CVFM analogue 7 as its trifluoroacetate salt
in 61% yield after purification via reversed-phase HPLC.
Having thus prepared the extended CVFM analogue
7, we focused on the synthesis of the turn-like derivatives
8 and 9. Toward this end, it was necessary to employ
the two diastereoisomeric allylic diazoacetates 26a ,b,
which would be derived from the anti alcohol 13, as
substrates for the key intramolecular cyclopropanations.
In the event, when the addition of lithium phenylacetyl-
ide to the aldehyde 11 was performed in the presence of
ZnBr2,31 the reaction proceeded via a preferential chela-
tion-controlled mode to give the anti product 13 (80%
yield) together with lesser quantities of the syn product
12 (13%).20a Reduction of 13 with Red-Al gave 25a in 78%
yield,32 whereas hydrogenation of 13 using P-2 Ni22
provided the cis-alkene 25b in 87% yield (Scheme 3). The
allylic alcohols 25a ,b were then converted to their
corresponding diazoacetates 26a ,b as before in about 90%
yield.23 When 26a was heated in the presence of the
achiral catalyst Cu(TBS)2, a mixture (6:1) of 27a and 28a
was obtained in 84% combined yield. Similarly, when 26b
was heated in the presence of Cu(TBS)2, a mixture (8:1)
of 27b and 28b was obtained. The structural assignments
of the cyclized products were based on the observed
chemical shifts of the diagnostic proton Ha (vide supra),
intermediate aziridines 29a ,b (Scheme 4). The correct-
ness of previous stereochemical assignments were con-
firmed in part by an X-ray structure of the aziridine 29a .
Deprotection of the N-terminus of 30a ,b followed by
coupling the intermediate amines with the cysteine
derivative 3133 afforded the cyclopropyl lactone tripep-
tides 32a ,b in 98% and 80% yield, respectively. Hydroly-
sis of the lactone moieties of 32a ,b followed by esterifi-
cation and protection of the secondary alcohol, which was
necessary to prevent relactonization, gave 33a ,b (60%
and 79%). Whereas the saponification of 33a to give 34a
(64% yield) proceeded readily with 1 N NaOH in EtOH
at room temperature, hydrolysis of 33b required reflux-
ing with base in EtOH overnight to furnish 34b (47%
yield). Not only was the hydrolysis of 33b sluggish,
perhaps due to the steric influence of the phenyl group
proximal to the methyl ester, but it was also accompanied
by a significant amount of epimerization.34 The addition
of more base or use of extended heating times led only
to decreased yield and increased epimerization. Never-
theless, the final coupling of 34a ,b with the methyl ester
1
which typically appears upfield in the H NMR spectra
of the exo diastereomers: δ(Ha) in 27a ) 4.61 ppm, 27b
) 4.66 ppm; 28a ) 4.24 ppm, 28b ) 4.62 ppm.25b,c
Interestingly, use of the chiral catalysts Rh2[(5S or 5R)-
MEPY]4 did not greatly enhance the diastereomeric ratios
of the cyclopropyl lactone products.
The remaining steps in the conversion of 27a ,b into
the pseudopeptide 8 and 9 are similar to the reactions
developed for the synthesis of 7. Thus, the Abu side
chains in 30a ,b were elaborated from the protected amino
alcohol side chains in 27a ,b by ring opening of the
(31) Asami, M.; Kimura, R. Chem. Lett. 1985, 1221-1222.
(32) Denmark, S. E.; J ones, T. K. J . Org. Chem. 1982, 47, 4595-
4597.
(33) Kemp, D. S.; Carey, R. I. J . Org. Chem. 1989, 54, 3640-3646.
(34) The epimerized product could be separated from the desired
carboxylic acid 34b by silica gel chromatography.

1662 J . Org. Chem., Vol. 66, No. 5, 2001
Hillier et al.
Sch em e 5
Sch em e 6
of L-methionine delivered 35a ,b in 71% and 84% yield,
respectively. The deprotection and purification of the
protected pseudopeptides 35a ,b was conducted as before
to provide the desired turn-like CVFM analogues 8 and
9. However, it was necessary to use acetonitrile rather
than MeOH in the final stage of deprotecting the N,S-
acetal and during the purification procedure in order to
facilitate the azeotropic removal of water at lower tem-
peratures; the hydroxy acids 8 and 9 underwent rela-
tively facile lactonization on heating.
Syn th esis of Refer en ce Tetr a p ep tid e Der iva tives.
The parent tetrapeptide CAbuFM (6) was prepared in a
straightforward fashion using standard peptide coupling
procedures. Thus, the dipeptide 36, which was prepared
by condensing 23 with the methyl ester of L-ethylglycine,
and phenylalanyl methionine methyl ester, H-Phe-Met-
OMe, were joined by EDC/HOBt-mediated coupling to
give 36 in 67% yield (Scheme 5). Global deprotection of
37 followed by purification gave 6 as its trifluoroacetate
salt in 17% overall yield.
Ta ble 1. Biologica l Activities of 6-10 a s In h ibitor s
of F Ta se
a
inhibitor
IC50 (nM)
6
10
7
38
320
1055
760
8
9
7200
The synthesis of the hydroxyethylene derivative 10
commenced with the alkylation of (S)-pseudophedrine-
3-hydrocinnamide (38) with 1-bromo-2-pentene according
to the Myers protocol to provide 39 (93% yield) as
predominantly one diastereomer (14:1) according to chiral
HPLC analysis of the crude product mixture (Scheme
6).35 Bromolactonization of 39 afforded the R-bromo
lactone 40 together with several inseparable minor
isomers in 79% combined yield.36 Displacement of the
secondary bromide in 40 by NaN3 followed by reduction
of the azide gave an intermediate amine that was coupled
with 23 to deliver 41 as a single isomer in 57% overall
yield. Hydrolysis of the lactone ring in 41 gave a hydroxy
butyric acid derivative that was transformed into the
protected acid 42 by sequential treatment with TBDM-
SCl/imidazole/DMF and then glacial acetic acid/THF.37
Coupling of 42 with the methyl ester of L-methionine gave
the protected tetrapseudopeptide 43 in 82% yield. Depro-
tection of 43 to give 10 was achieved in a fashion similar
to that described for the preparation of 8 and 9.
Biologica l Activities of 6-10. The tetrapeptide 6 and
the derived pseudopeptides 7-10 were evaluated as
inhibitors of FTase in an in vitro assay that was
conducted at Rhoˆne-Poulenc Rorer. The assay employed
was based upon a previously described protocol that had
been modified to incorporate scintillation proximity assay
(SPA) techniques using streptavidin-coated SPA beads.38
The IC50 determinations are derived by measurement of
inhibition of farnesylation from 8-point serial dilution of
test compounds, and the results of these assays are
summarized in Table 1. The tetrapeptide template 6 that
a
The IC50 values were determined from a single assay by
measurement of inhibition of farnesylation from eight-point serial
dilution of 6-10.
was used as the basis for these studies is the most active
being approximately equipotent with CVFM itself.17
Compound 10, which is the flexible equivalent of the
constrained pseudopeptides 7-9, was about 8-fold less
potent than 6. Hence, the mere replacement of the A1-
A2 amide bond in 6 with a hydroxyethylene moiety as in
10 does not appear to be well tolerated. In the two
cyclopropane-derived pseudopeptides 7 and 8, the phenyl
ring is oriented trans to the C-terminus, and these
compounds were only 2-3-fold less active than 10.
However, compound 9, in which the phenyl ring is cis to
the C-terminus, is about 22 times less potent than 10.
The relatively small difference in biological activity
between the extended mimic 7 and the putative turn-
like mimic 8 raises two questions: (1) Do the cyclopro-
pane rings in these derivatives maintain the extended
and turn-like conformations as they were intended? (2)
Why are 7 and 8 essentially equipotent? To gain some
preliminary structural insights to address the first ques-
tion, 44, which has the same stereochemistry at each of
the stereogenic centers as those in the turn-like analogue
8, was prepared via a Weinreb amidation28 of 30a . The
X-ray structure of 44 (Figure 1b) reveals that the
hydrogen of the secondary hydroxyl group is not within
hydrogen bonding distance of the cis-amide carbonyl
group on the adjacent carbon of the cyclopropane ring.
Presumably the lack of this hydrogen bonding interaction

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 66, No. 5, 2001 1663
extended conformers for each that can bridge this 12 Å
distance. Three-dimensional structures for 7-9 were then
generated using the extracted structure of the bound
CVIM analogue as a template for the peptide backbones
of 7-9. These structures were then locally minimized and
modeled back into the active site so that the Cys thiol
group and the C-terminal carboxyl group of 7-9 make
the necessary contacts with the enzyme. Although the
phenyl ring in both 7 and 8 may be oriented so that it
occupies part of the isoleucine binding pocket of FTase,
it is not possible to place the phenyl ring of 9 in this
hydrophobic pocket while positioning the backbone in the
active site cleft. Thus, while the relative orientation of
the backbone substituents on the cyclopropane rings of
7-9 does not appear to have a significant effect on
binding affinity, the position of the phenyl ring relative
to the backbone is critical. This observation is consistent
with the report of Leftheris who examined a series of Phe
constrained FTase inhibitors and found that changes in
the orientation of the phenyl group in CA1A2X-based
pseudopeptides had dramatic effects upon their relative
potencies.17
F igu r e 1. (a) Line drawing of 44. (b) Chem 3D representation
of the X-ray structure of 44 showing orientation of backbone
and amide and hydroxyl functional groups.
coupled with unfavorable steric interactions between the
N-terminal and C-terminal side chains conspire to pro-
vide a three-dimensional structure in which the backbone
substituents are directed away from each another in an
extended conformation rather than the desired turn-like
array. The turn in the backbone chain is thus localized
only about the cyclopropane ring itself, and the remain-
der of the molecule is free to adopt a number of confor-
mations with an extended one being favored, at least in
the solid state. However, this extended array might result
from intermolecular packing forces that override any
intramolecular interactions, so it is not possible to
extrapolate this structure to the preferred conformation
of 44 in solution.
To examine whether the cis-substituted cyclopropane
found in compounds related to 44 and 8 might stabilize
a turn-like structure in solution, an NMR study of 45,
which was prepared by reaction of 35a with neat CF3-
CO2H, was conducted in DMSO-d6. No NOE interactions
between the protected cysteine and methionine residues
that flank the cyclopropane ring in 45 could be detected;
only intraresidue contacts were observed. Hence, while
in DMSO-d6 there does not appear to be a significant
concentration of a turn-like structure in solution, this
study does not exclude the possibility that a more turn-
like structure of 45 might exist in an aqueous medium.
Con clu sion s
Compounds 6-10 were prepared as novel CA1A2X-
based inhibitors of Ras farnesyltransferase to probe the
topological features of the hydrophobic binding pocket of
the A2 subsite. During the course of these synthetic
studies, a novel method was developed for elaborating
the C-terminal residue of cyclopropane-derived dipeptide
replacements via the regioselective opening of aziridines
with organocuprates. The cyclopropane-derived pseudopep-
tides 7-9 were designed as conformationally constrained
derivatives of the tetrapeptide CAbuFM (6) by substitut-
ing the cyclopropane replacement -AbuΨ[COcpCO]Phe-
for Abu-Phe. Compound 10, which is the flexible analogue
of 7-9, served as the pseudopeptide benchmark for 6,
although direct comparison of the relative potencies of 6
and 10 suggests that replacing the A1-A2 amide linkage
with a S-hydroxyethylene moiety is not well tolerated.
In the FTase inhibitor 7, the backbone substituents are
trans, whereas these substituents in 8 and 9 are cis. The
orientation of the phenyl group relative to the C-terminus
of the pseudopeptide in 7 and 8 is positioned in an
orientation that mimics a gauche(-) ø1-angle very dif-
ferent from the gauche(+) orientation approximated in
9.
The constrained pseudopeptides 7 and 8 are nearly
equipotent inhibitors of FTase suggesting that the rela-
tive orientations of the peptide backbone substituents on
the cyclopropane rings in 7 and 8 does not have a
significant effect on binding affinity, presumably because
of some flexibility in the FTase peptide binding pocket.
However, changes in the orientation of the phenyl ring
are not tolerated as evidenced by the fact that 7 and 8
were both nearly 1 order of magnitude more potent than
9. The comparable biological activities of 7 and 8 coupled
with the structural studies of 44 and 45 suggest that the
Inasmuch as the available structural data for com-
pounds related to 8 do not support a turn-like conforma-
tion, 7 and 8 have comparable biological activity pre-
sumably because they can adopt similar, three-dimensional
structures at the active site of FTase. The X-ray structure
of the ternary complex of FTase with a CVIM derivative
and R-hydroxyfarnesylphosphonic acid offers an op-
portunity to evaluate this hypothesis.15 In this structure,
there is an approximate 12 Å separation between the Cys
thiol group, which associates with the zinc ion, and the
C-terminal methionine carboxyl function that forms a salt
bridge with Gln167R of the enzyme. Preliminary model-
ing of 7 and 8, and hence 9, revealed a number of
(35) Myers, A. G.; Gleason, J . L. In Organic Synthesis; Martin, S.
F., Ed.; J ohn Wiley & Sons: New York, 1999; Vol. 76, pp 57-76.
(36) Dragovich, P. S.; Prins, T. J .; Zhou, R. J . Org. Chem. 1997, 62,
7872-7876.
(37) Evans, B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J . P.;
Hirshfield, J .; Veber, D. F. J . Org. Chem. 1985, 50, 4615-4625.
(38) Roskoski, R., J r.; Ritchie, P.; Gahn, L. G. Anal. Biochem. 1994,
222, 275-280.

1664 J . Org. Chem., Vol. 66, No. 5, 2001
Hillier et al.
(CI) m/z 332.1857 (C19H25NO4 + H requires 332.1862), 276,
258 (base), 232, 218, 200, 156.
cis-relationship of the backbone substituents on the
cyclopropane rings of these compounds does not appear
to enforce turn-like conformations. Whether other cis-
substituted dipeptide replacements related to 2 might
stabilize such conformations must be ascertained by
further experimentation. Indeed, other applications of
cyclopropane-derived dipeptide isosteres are under in-
vestigation, and these results will be reported in due
course.
cis-[4S,4(1′R)]-4-(1′-Hyd r oxy-3′-p h en yl-2′-p r op en yl)-2,2-
d im eth yloxa zolid in e-3-ca r boxylic Acid ter t-Bu tyl Ester .
To a green suspension of Ni(OAc)2‚4H2O (1.25 g, 5.03 mmol)
in anhydrous EtOH (25 mL) was added 1 M NaBH4 in 0.1 N
NaOH/EtOH (5.0 mL, 5.0 mmol). The resulting black suspen-
sion was stirred for 45 min, whereupon the flask was attached
to a hydrogenator and flushed with H2. Ethylenediamine (0.67
mL, 10.0 mmol) was added followed by the alcohol 12 (5 g,
15.09 mmol) in anhydrous EtOH (7 mL), and the reaction was
stirred until the appropriate amount of H2 had been taken up.
The suspension was poured into Et2O/pentane (300 mL, 1:1)
and filtered through a bed of Fluorosil. The filtrate was
concentrated, and the residue was purified by flash chroma-
tography eluting with EtOAc/hexanes (1:3) to give 4.38 g (87%)
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, solvents and
reagents were reagent grade and used without purification.
Tetrahydrofuran (THF) was distilled from potassium/ben-
zophenone ketyl under nitrogen, and dichloromethane (CH2-
Cl2) 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 uncorrected. 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 internal standard Me4Si
(TMS). Coupling constants are reported in hertz (Hz). Spectral
splitting patterns are designated as follows: s, singlet; br,
broad; d, doublet; t, triplet; q, quartet; m, multiplet; and comp,
complex multiplet. Flash chromatography was performed
using Merck silica gel 60 (230-400 mesh ASTM).39 Percent
yields are given for compounds that were g95% pure as judged
by NMR.
1
of allylic alcohol as a light yellow syrup: H NMR (500 MHz,
DMSO-d6, 85 °C) δ 7.36-7.21 (comp, 5 H), 6.50 (d, J ) 11.8
Hz, 1 H), 5.70 (dd, J ) 9.6, 11.8 Hz, 1 H), 4.53 (dd, J ) 6.0,
9.6 Hz, 1 H), 4.03 (d, J ) 6.8 Hz, 1 H), 3.86-3.82 (m, 2 H),
1.40 (s, 9 H), 1.39 (s, 3 H), 1.22 (s, 3 H); 13C NMR (125 MHz,
DMSO-d6, 85 °C) δ 151.4, 136.2, 132.8, 129.9, 128.1, 127.6,
126.4, 92.9, 78.6, 66.1, 63.5, 60.6, 27.6, 25.7, 23.6; IR (neat) ν
3426, 2978, 1695, 1391, 1255, 1172, 1102, 1046 cm-1; mass
spectrum (CI) m/z 334.2021 (C19H27NO4 + H requires 334.2018),
260, 234, 220, 202.
cis-[4S,4(1′R)]-4-[1′-Dia zoa cetic a cid (3′-p h en yl-2′-p r o-
p en yl) ester ]-2,2-d im eth yloxa zolid in e-3-ca r boxylic Acid
ter t-Bu tyl Ester (16). To an ice-cooled solution of the above
allylic alchohol (490 mg, 1.47 mmol) were added the p-
toluenesulfonyl hydrazone of glyoxylic acid chloride (645 mg,
2.47 mmol) and N,N-dimethylaniline (3.2 mL, 2.5 mmol). After
15 min, Et3N (1.1 mL, 8.1 mmol) was added, and the orange
slurry was stirred for 10 min at 0 °C and for 15 min at room
temperature. The solvent was removed under reduced pressure
and the residue dissolved in EtOAc/hexanes (1:3, 20 mL) and
washed once with 20% saturated aqueous Citric acid (5 mL).
The organics were dried (MgSO4), and concentrated, and the
crude orange residue was purified via flash chromatography
eluting with EtOAc (1:5) to give 516 mg (87%) of 16 as a yellow
oil: 1H NMR (300 MHz, DMSO-d6, rotamers) δ 7.60-7.20
(comp, 5 H), 6.64 (t, J ) 12.2 Hz, 1 H), 6.15-6.13 (m, 1 H),
5.62-5.49 (m, 1 H), 4.67 (br s, 1 H), 4.19 (br s, rotamer a, 0.5
H), 4.01 (m, rotamer b, 0.5 H), 3.91 (br s, 2 H), 1.60-1.05
(comp, 15 H); 13C NMR (75 MHz, DMSO-d6, rotamers) δ 152.7,
151.7, 135.9, 134.0, 133.8, 128.8, 128.5, 127.5, 126.8, 94.6, 93.9,
80.3, 71.0, 70.3, 64.0, 59.2, 46.3, 28.3, 28.1, 26.4, 25.5, 24.3,
23.2; IR (CDCl3) ν 3085, 2979, 2936, 2880, 2112, 1704, 1391,
1242, 1175, 1081 cm-1; mass spectrum (CI) m/z 402.2030
(C21H27N3O5 + H requires 402.2029), 316, 302, 288, 274, 260,
246, 230, 216, 202 (base).
ter t-Bu tyl-(4S,1′R)- a n d -(4S,1′S)-2,2-d im eth yl-4-(1′-h y-
dr oxy-3′-ph en yl-2′-pr opyn yl)oxazolidin e-3-car boxylate (12
a n d 13). To a solution of phenylacetylene (3.8 mL, 34.6 mmol)
in THF (160 mL) at -78 °C was added with stirring 1.4 M
n-BuLi in hexanes (28 mL, 38.2 mmol). After 1 h, 18-crown-6
(12.6 g, 47.6 mmol) was added in one portion, and the resulting
brown slurry was stirred for 10 min. The aldehyde 11 (5.45 g,
23.8 mmol) in THF (10 mL) was added slowly over 15 min,
whereupon the slurry became dark red in color. This mixture
was stirred at -78 °C for 2 h, and a saturated solution of NH4-
Cl (100 mL) was added. The cooling bath was removed, and
the slurry was stirred until it reached rt. Water (25 mL) was
added, and the mixture was extracted with ether (2 × 100 mL).
The combined organics were washed with 1 N HCl (40 mL)
and brine (40 mL), dried (MgSO4), and concentrated under
reduced pressure. The crude product was purified by flash
chromatography eluting with a gradient of 15% EtOAc/hexanes
then 30% EtOAc/hexanes to give 6.0 g (76%) of 12 and 0.7 g
(8%) of 13.
tr a n s-[4S,4(1′S)]-4-(1′-Hyd r oxy-3′-p h en yl-2′-p r op en yl)-
2,2-d im eth yloxzolid in e-3-ca r boxylic Acid ter t-Bu tyl Es-
ter (25a ). To a solution of Red-Al (0.94 mL, 3.28 mmol) in
anhydrous Et2O (2 mL) at 0 °C was added a solution of 13
(680 mg, 2.05 mmol) in Et2O (0.6 mL) dropwise. After 10 min,
the cooling bath was removed, and the reaction was stirred at
room temperature for 45 min. A saturated solution of NH4Cl
(0.7 mL) was slowly added (Caution! very exothermic). The
resulting white slurry was diluted with Et2O (5 mL), 1 N
NaOH (1 mL), and water (1 mL), and the layers were
separated. The aqueous phase was re-extracted with Et2O (2
× 5 mL), and the combined organics were dried (MgSO4) and
concentrated. The residue was purified via silica gel chroma-
tography eluting with 30% EtOAc/hexanes to afford 532 mg
(78%) of 25a as clear oil: 1H NMR (500 MHz, DMSO-d6, 85
°C) δ 7.37-7.20 (comp, 5 H), 6.52 (d J ) 15.9 Hz, 1 H), 6.22
(dd, J ) 6.9, 15.9 Hz, 1 H), 4.97 (d, J ) 4.5 Hz, 1 H), 4.59-
4.56 (m, 1 H), 4.05 (dd, J ) 2.0, 9.2 Hz, 1 H), 4.00-3.98 (m, 1
H) 3.91 (dd, J ) 6.6, 9.1 Hz, 1 H) 1.46 (s, 6 H), 1.39 (s, 9 H);
13C NMR (125 MHz, DMSO-d6, 85 °C) δ 151.3, 136.6, 130.0,
129.3 128.1, 126.7, 93.1, 78.8, 69.8, 62.5, 60.7, 27.7, 25.6, 23.2;
1
For 12: H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.41-7.34
(comp, 5 H), 5.47 (d, J ) 6.4 Hz, 1 H), 4.73 (dd, J ) 3.4, 6.4
Hz, 1 H), 4.13-3.99 (comp, 2 H), 3.01 (s, 1 H), 1.52 (s, 3 H),
1.46 (s, 3 H), 1.42 (s, 9 H); 13C NMR (125 MHz, DMSO-d6, 85
°C) δ 151.4, 130.8, 128.0, 127.9, 122.1, 93.4, 89.6, 83.9, 78.9,
63.6, 61.1, 60.9, 27.6, 25.8; IR (neat) ν 3437, 2979, 1686, 1392,
1366, 1173, 1068 cm-1; mass spectrum (CI) m/z 332.1862
(C19H25NO4 + H requires 332.1862), 276, 258 (base), 232, 218,
156.
1
For 13: H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.40-7.34
(comp, 5 H), 5.55 (br s, 1 H), 4.92 (d, J ) 4.4 Hz, 1 H), 4.17
(dd, J ) 3.0, 9.0 Hz, 1 H), 4.02 (dd, J ) 6.7, 9.0 Hz, 1 H), 3.97-
3.94 (m, 1 H), 1.54 (s, 3 H), 1.44-1.42 (comp, 12 H); 13C NMR
(125 MHz, DMSO-d6, 85 °C) δ 151.4, 130.7, 128.1, 127.9, 122.2,
93.5, 89.3, 83.9, 79.1, 63.6, 61.2, 60.5, 27.7, 25.8; IR (neat) ν
3427, 2977, 1686, 1393, 1366, 1171, 1056 cm-1; mass spectrum
IR (neat) ν 3424, 2978, 1694, 1390, 1255, 1172, 1100 cm-1
;
mass spectrum (CI) m/z 334.2014 (C19H27NO4 + H requires
(39) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
334.2018), 316, 260 (base), 216, 202.

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 66, No. 5, 2001 1665
1
tr a n s-[4S,4(1′S)]-4-[1′-Dia zoa cetic a cid (3′-p h en yl-2′-
p r op en yl) est er ]-2,2-d im et h yloxa zolid in e-3-ca r boxylic
Acid ter t-Bu tyl Ester (26a ). Prepared in 90% yield as a
yellow oil from 25a by the procedure described for 16: 1H NMR
(500 MHz, DMSO-d6, rotamers) δ 7.40-7.00 (comp, 5 H), 6.72-
6.61 (m, 1 H), 6.24-6.21 (m, 1 H), 5.92-5.84 (m, 1 H), 4.77-
3.90 (m, 3 H), 1.65-1.25 (comp, 15 H); 13C NMR (125 MHz,
DMSO-d6, rotamers) δ 155.2, 136.5, 135.7, 134.0, 133.8, 133.7,
129.7, 128.6, 128.4, 128.1, 128.0, 127.4, 126.4, 126.0, 123.7,
98.5, 93.5, 79.4, 77.9, 73.3, 70.9, 63.6, 63.2, 47.4, 45.9, 29.0,
28.0, 25.5, 22.6, 19.0; IR (CDCl3) ν 2978, 2112, 1702, 1376,
1238, 1174, 1092 cm-1; mass spectrum (CI) m/z 402.2027
(C21H27N3O5 + H requires 402.2029), 316, 276, 260 (base), 220,
202.
cis-[4S,4(1′S)]-4-(1′-Hyd r oxy-3′-p h en yl-2′-p r op en yl)-2,2-
d im eth yloxa zolid in e-3-ca r boxylic Acid ter t-Bu tyl Ester
(25b). Prepared in 87% as a white solid after recrystallization
from EtOAc/hexanes from 13 by the same procedure described
for the semi-hydrogenation of 12: mp 97-99 °C; 1H NMR (500
MHz, DMSO-d6; 85 °C) δ 7.33-7.22 (comp, 5 H), 6.58 (d, J )
11.8 Hz, 1 H), 5.73 (dd, J ) 10.0, 11.8 Hz, 1 H), 4.86-4.14 (m,
2 H), 4.15 (d, J ) 9.1 Hz, 1 H), 3.00-2.48 (comp, 2 H), 1.47 (s,
3 H), 1.39 (s, 3 H), 1.28 (br s, 9 H); 13C NMR (125 MHz, DMSO-
d6, 85 °C) δ 151.3, 136.3, 131.3, 130.8, 128.0, 127.5, 126.4, 93.0,
78.6, 64.4, 62.4, 60.8, 27.4, 25.8, 22.9; IR (CDCl3) ν 3440, 2977,
1666, 1390, 1255, 1172, 1062 cm-1; mass spectrum (CI) m/z
334.2024 (C19H27NO4 + H requires 334.2018), 316, 278, 260,
220, 202.
°C; H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.32-7.13 (comp,
5 H), 4.62 (d, J ) 4.7 Hz, 1 H), 4.17 (app t, J ) 4.7 Hz, 1 H),
4.01 (dd, J ) 6.1, 9.7 Hz, 1 H), 3.95 (dd, J ) 1.5, 9.7 Hz, 1 H),
2.66 (dd, J ) 4.2, 5.8 Hz, 1 H), 2.46-2.43 (comp, 2 H), 1.54 (s,
3 H), 1.47 (s, 3 H), 1.45 (s, 9 H); 13C NMR (125 MHz, DMSO-
d6, 85 °C) δ 173.1, 151.7, 137.3, 128.0, 126.3, 93.5, 80.1, 79.5,
63.4, 58.5, 27.5, 27.3, 26.3, 23.0; IR (CDCl3) ν 2980, 1760, 1694,
1365, 1365, 1259, 1176, 1078 cm-1; mass spectrum (CI) m/z
374.1963 (C21H27NO5 + H requires 374.1967), 318 (base), 302,
274, 260, 200, 174, 144.
[1R,4S,5S,6R,4(4′S)]-4′-(4-Oxo-3-oxa -6-p h en ylb icyclo-
[3.1.0]h ex-2-yl)-2′,2′-d im et h yloxa zolid in e-3′-ca r b oxylic
Acid ter t-Bu tyl Ester (27b). Obtained in 67% yield from 26b
via Cu(TBS)2-catalyzed cyclization per the general procedure
described above. This isomer was isolated via flash chroma-
tography eluting with EtOAc/hexanes (1:3) as a white solid
after recrystallization from EtOAc/hexanes: mp 177-179 °C;
1H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.36-7.24 (comp, 5
H), 4.24 (dd, J ) 4.4 Hz, 1 H), 4.11 (dd, J ) 4.8, 5.0 Hz, 1 H),
4.00 (dd, J ) 6.3, 9.7 Hz, 1 H), 3.91 (dd, J ) 1.4, 9.7 Hz, 1 H),
2.85 (app t, J ) 8.5 Hz, 1 H), 2.72 (dd, J ) 6.1, 8.1 Hz, 1 H),
2.63 (dd, J ) 6.1, 8.3 Hz, 1 H), 1.53 (s, 3 H), 1.44 (s, 3 H), 1.42
(s, 9 H); 13C NMR (125 MHz, DMSO-d6, 85 °C) δ 172.9, 151.4,
133.0, 128.7, 128.1, 126.9, 93.6, 79.4, 75.7, 63.2, 58.0, 27.43,
26.1, 24.9, 24.4, 23.4, 22.7; IR (CDCl3) ν 2982, 1770, 1694, 1366,
1258, 1172, 1085 cm-1; mass spectrum (CI) m/z 374.1973
(C21H27NO5 + H requires 374.1967).
[1S ,4R ,5R ,6S ,4(1′S )]-[2′-H yd r oxy-1′-(4-oxo-3-oxa -6-
p h en ylbicyclo[3.1.0]h ex-2-yl)eth yl]ca r ba m ic Acid ter t-
Bu tyl Ester . Compound 17 (869 mg, 2.32 mmol) was dissolved
in THF (11 mL) containing concentrated aqueous HCl (1.6 mL)
and triethylsilane (370 µL, 2.32 mmol), and the mixture was
heated at 70 °C for 6 h. The solvent was removed under
reduced pressure, and the crude residue was dissolved in
acetonitrile (10 mL). Et3N (0.4 mL, 2.55 mmol) and Boc2O (757
mg, 3.48 mmol) were added, and the mixture was stirred
overnight at room temperature. The solvent was removed
under reduced pressure, and the crude brown residue was
purified by silica gel chromatography eluting with 60% EtOAc/
hexanes to afford 720 mg (93%) of amino alcohol as a white
cis-[4S,4(1′S)]-4-[1′-Dia zoa cetic a cid (3′-p h en yl-2′-p r o-
p en yl) ester ]-2,2-d im eth yloxa zolid in e-3-ca r boxylic Acid
ter t-Bu tyl Ester (26b). Prepared from 25b by the same
procedure described for 16 in 90% yield as a yellow oil: 1H
NMR (500 MHz, toluene-d8) δ 7.34-6.96 (comp, 5 H), 6.55 (d,
J ) 11.8 Hz, 1 H), 6.39 (dd, J ) 5.1, 10.2 Hz, 1 H), 5.70 (dd,
J ) 10.6, 10.8 Hz, 1 H), 4.00 (m, 2 H), 3.95 (d, J ) 9.4 Hz, 1
H), 3.63 (dd, J ) 6.4, 9.4 Hz, 1 H), 1.65 (s, 3 H), 1.41 (s, 3 H),
1.30 (s, 9 H); 13C NMR (125 MHz, toluene-d8) δ 164.9, 152.3,
137.7, 129.3, 128.8, 127.8, 126.2, 125.5, 80.1, 70.4, 64.0, 60.0,
45.6, 28.6, 23.7, 20.9; IR (CDCl3) ν 2978, 2111, 1698, 1376,
1173 cm-1; mass spectrum (CI) m/z 402.2024 (C21H27N3O5
H), 316, 260 (base), 202.
+
1
powdery solid: mp 168-170 °C; H NMR (300 MHz, MeOD-
Gen er a l Meth od for th e Cyclop r op a n a tion of 16 a n d
26a ,b. To a refluxing solution of Rh2[(5R)-MEPY]2 (0.01 equiv)
in CH2Cl2 (0.05 M) was added a solution of the diazoester (1
equiv) in CH2Cl2 (0.05 M) via syringe pump over 16-20 h.
Alternatively, a solution of Cu(TBS)2 (0.02 equiv) in toluene
(0.05 M) was added a solution of the diazoester (1 equiv) in
toluene (0.05 M) via syringe pump over 16-20 h. The reaction
was cooled to room temperature, volatiles were removed under
reduced pressure, and the residue was purified by flash
chromatography and recrystallization if necessary.
[1S,4S,5R,6S,4(4′S)]-4′-(4-Oxo-3-oxa -6-p h en ylb icyclo-
[3.1.0]h ex-2-yl)-2′,2′-d im et h yloxa zolid in e-3′-ca r b oxylic
Acid ter t-Bu tyl Ester (17). Obtained in 67% yield from 16
via Rh2[(5R)-MEPY]2-catalyzed cyclization as per the general
procedure described above. This isomer was purified via flash
chromatography eluting with EtOAc/hexanes (1:3) to give 17
as a white solid after recrystallization from EtOAc/hexanes:
mp 165-168 °C; 1H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.36-
7.24 (comp, 5 H), 4.26 (d, J ) 4.5 Hz, 1 H), 4.11 (ddd, J ) 1.9,
4.5, 6.3 Hz, 1 H), 4.00 (dd, J ) 6.3, 9.6 Hz, 1 H), 3.85 (dd, J )
1.9, 9.6 Hz, 1 H), 2.86 (app t, J ) 8.5 Hz, 1 H), 2.68-2.62
(comp, 2 H), 1.46 (s, 3 H), 1.44 (s, 3 H), 1.41 (s, 9 H); 13C NMR
(125 MHz, DMSO-d6, 85 °C) δ 172.9, 151.2, 133.0, 128.7, 128.2,
127.0, 93.3, 78.4, 75.2, 27.6, 25.7, 25.3, 25.0, 23.3, 23.1; IR
(CDCl3) ν 2979, 2935, 1770, 1694, 1366, 1169 cm-1; mass
spectrum (CI) m/z 275.1300 (C16H18O4 + H requires 275.1283),
259, 217, 199, 171.
d3) δ 7.89-7.24 (comp, 5 H), 4.25 (d, J ) 6.4 Hz, 1 H), 3.78
(ddd, J ) 5.0, 5.2, 11.4 Hz, 1 H), 3.63-3.61 (m, 2 H), 2.86 (app
t, J ) 8.4 Hz, 1 H), 2.69-2.58 (comp, 2 H), 1.45 (s, 9 H); 13C
NMR (75 MHz, MeOD-d3) δ 176. 7, 158.1, 134.5, 130.6, 129.8,
128.7, 80.6, 77.7, 61.4, 56.2, 28.7, 27.4, 26.7, 25.1; IR (IR card)
ν 3382, 2981, 1766, 1682, 1416, 1367, 1169, 982 cm-1; mass
spectrum (CI) m/z 333.1563 (C18H22NO5 + H requires 333.1576),
315, 280 (base), 236.
[1R ,4S ,5S ,6S ,4(1′S )]-[2′-H yd r oxy-1′-(4-oxo-3-oxa -6-
p h en ylbicyclo[3.1.0]h ex-2-yl)eth yl]ca r ba m ic Acid ter t-
Bu tyl Ester . A solution containing 27a (3.2 g, 8.5 mmol),
triethylsilane (1.4 mL, 8.5 mmol), and 4 N HCl in dioxane (10
mL) was stirred for 1 h. The solvent was removed under
reduced pressure, and the crude product was dissolved in CH3-
CN (20 mL). Et3N (1.7 mL, 9.4 mmol) and Boc2O (2.5 g, 11.3
mmol) were added, and the mixture was stirred at room
temperature for 12 h. Solvent was removed under reduced
pressure, and the residue was purified via silica gel chroma-
tography eluting with EtOAc/hexanes (1:1) to give 2.61 g of
the amino alcohol (92%) as a colorless solid: mp 55-56 °C;
1H NMR (300 MHz, MeOD-d3) δ 7.33-7.02 (comp, 5 H), 5.07
(d, J ) 8.9 Hz, 1 H), 4.79 (s, 1 H), 4.13-4.03 (m, 1 H), 3.84-
3.69 (m, 2 H), 2.72-2.28 (m, 2 H), 2.29 (d, J ) 4.3 Hz, 1 H),
1.46 (s, 9 H); 13C NMR (300 MHz, MeOD-d3) δ 174.6, 156.3,
136.8, 128.7, 127.2, 125.9, 81.1, 80.3, 62.1, 54.8, 28.2, 27.4; IR
(CDCl3) ν 3333, 2977, 1754, 1693, 1500, 1366, 1171 cm-1; mass
spectrum (CI) m/z 334.1648 (C18H23NO5 + H requires 334.1654),
318, 306, 278 (base), 262, 234, 216, 190, 173.
[1R,4S,5S,6S,4(4′S)]-4′-(4-Oxo-3-oxa -6-p h en ylb icyclo-
[3.1.0]h ex-2-yl)-2′,2′-d im et h yloxa zolid in e-3′-ca r b oxylic
Acid ter t-Bu tyl Ester (27a ). Obtained in 71% yield via the
Cu(TBS)2-catalyzed cyclization of 26a per the general proce-
dure described above. This isomer was isolated via flash
chromatography eluting with EtOAc/hexanes (1:3) as a white
solid after recrystallization from EtOAc/hexanes: mp 170-172
[1R ,4S ,5S ,6R ,4(1′S )]-[2′-H yd r oxy-1′-(4-oxo-3-oxa -6-
p h en ylbicyclo[3.1.0]h ex-2-yl)eth yl]ca r ba m ic Acid ter t-
Bu tyl Ester . Prepared in 83% yield as a clear oil after
purification by flash chromatography (EtOAc/hexanes: 1:1)
from 27b by the preceding procedure: 1H NMR (500 MHz,
DMSO-d6, 85 °C) δ 7.35-7.25 (comp, 5 H), 6.33 (br s, 1 H),

1666 J . Org. Chem., Vol. 66, No. 5, 2001
Hillier et al.
4.51 (dd, J ) 5.0, 5.1 Hz, 1 H), 4.23 (d, J ) 3.7 Hz, 1 H), 3.75
(ddd, J ) 3.7, 5.0, 6.0 Hz, 1 H), 3.44 (dd, J ) 5.0, 10.9 Hz, 1
H), 3.43 (dd, J ) 5.9, 10.9 Hz, 1 H), 2.77 (dd, J ) 8.2, 8.6 Hz,
1 H), 2.69 (ddd, J ) 0.7, 6.0, 8.2 Hz, 1 H), 2.52 (ddd, J ) 1.0,
6.0, 8.6 Hz, 1 H), 1.40 (s, 9 H); 13C NMR (125 MHz, DMSO-d6,
85 °C) δ 173.2, 155.2, 133.3, 128.8, 128.0, 126.7, 77.7, 75.6,
59.6, 55.0, 27.7, 25.2, 24.9, 23.2; IR (CDCl3) ν 3372, 1755, 1690,
spectrum m/z 332.1863 (C19H25NO4 + H requires 332.1862),
304, 276 (base), 260, 243, 232, 215.
[1R,4S,5S,6S,4(1′S)]-1′-(4-Oxo-3-oxa -6-p h en ylb icyclo-
[3.1.0]h ex-2-yl)p r op yl-1′-ca r ba m ic Acid ter t-Bu tyl Ester
(30a ). Prepared in 93% yield as a white solid from 29a
according to the procedure described for 20: mp 181-182 °C;
1H NMR (300 MHz) δ 7.32-7.01 (comp, 5 H), 4.57 (s, 1 H),
4.46 (d, J ) 9.4 Hz, 1 H), 3.84 (m, 1 H), 2.70 (dd, J ) 4.5, 5.3
Hz, 1 H), 2.26 (d, J ) 4.5 Hz, 2 H), 1.67-1.57 (m, 2 H), 1.46
(s, 9 H), 1.01 (t, J ) 7.4 Hz, 3 H); 13C NMR (75 MHz) δ 174.7,
156.2, 137.1, 127.2, 126.0, 82.7, 79.3, 55.5, 29.7, 28.6, 28.3, 28.2,
27.7, 25.1, 10.6; IR (CDCl3) ν 3338, 2970, 2934, 1776, 1704,
1515, 1165 cm-1; mass spectrum (CI) m/z 334.1647 (C18H23
NO5 + H requires 334.1654), 310, 278 (base), 234.
-
[1R,4S,5S,6S,4(1′S)]-1′-(4-Oxo-3-oxa -6-p h en ylb icyclo-
[3.1.0]h ex-2-yl)a zir id in e-1-ca r boxylic Acid ter t-Bu tyl Es-
ter (19). DEAD (135 µL, 0.86 mmol) was added dropwise to
an ice-cold solution of the corresponding amino alcohol (142
mg, 0.43 mmol) and PPh3 (173 mg, 0.66 mmol) in THF (6 mL).
The cooling bath was removed, and the orange solution was
stirred at room temperature for 3.5 h, whereupon the solvent
was removed under reduced pressure. The crude orange oily
product was purified via flash chromatography eluting with
EtOAc/hexanes (1:3) to give 99 mg (74%) of 19 as a clear oil:
1H NMR (300 MHz) δ 7.33-7.26 (comp, 5 H), 3.66 (d, J ) 8.0
Hz, 1 H), 2.86-2.83 (m, 2 H), 2.67 (dd, J ) 7.1, 7.5 Hz, 1 H),
2.61 (ddd, J ) 3.4, 5.9, 8.0 Hz), 2.39 (d, J ) 5.9 Hz, 1 H), 2.13
(d, J ) 3.4 Hz, 1 H), 1.49 (s, 9 H); 13C NMR (75 MHz) δ 173.5,
161.2, 132.3, 129.3, 128.8, 127.8, 81.9, 77.7, 38.6, 30.7, 27.8,
27.1, 26.4, 23.7; IR (CDCl3) ν 3427, 1770, 1716, 1643, 1308,
1153 cm-1, mass spectrum (CI) m/z 316.1544 (C18H21NO4 + H
requires 316.1589), 288, 260 (base), 244, 216, 198, 172, 155.
[1R,4S,5S,6S,4(1′S)]-1′-(4-Oxo-3-oxa -6-p h en ylb icyclo-
[3.1.0]h ex-2-yl)a zir id in e-1-ca r boxylic Acid ter t-Bu tyl Es-
ter (29a ). Prepared in 91% yield as clear crystalline plates
from the corresponding amino alcohol by same procedure
described for 19: mp 115-117 °C; 1H NMR (300 MHz) δ 7.34-
7.05 (comp, 5 H), 4.72 (d, J ) 3.0 Hz, 1 H), 2.72 (dt, J ) 3.0,
6.0 Hz, 1 H), 2.60 (dd, J ) 4.0, 6.0 Hz, 1 H), 2.37-2.31 (comp,
4 H), 1.47 (s, 9 H); 13C NMR (75 MHz) δ 173.8, 161.7, 136.9,
128.7, 127.2, 126.0, 81.8, 38.6, 28.5, 28.3, 27.9, 27.8, 26.9; IR
(CDCl3) ν 2979, 1780, 1721, 1301, 1160 cm-1; mass spectrum
(CI) m/z 316.1530 (C18H21N4 + H requires 316.1549), 300, 288,
260, 216 (base), 199, 187, 170, 155, 143.
[1R,4S,5S,6S,4(1′S)]-1′-(4-Oxo-3-oxa -6-p h en ylb icyclo-
[3.1.0]h ex-2-yl)a zir id in e-1-ca r boxylic Acid ter t-Bu tyl Es-
ter (29b). Prepared in 95% yield from the corresponding amino
alcohol by the procedure described for 19: mp 119-120 °C;
1H NMR (300 MHz) δ 7.36-7.26 (comp, 5 H), 4.32 (d, J ) 3.1
Hz, 1 H), 2.78 (dd, J ) 8.3, 8.5 Hz, 1 H), 2.70 (comp, 3 H),
1.37 (d, J ) 6.3, 1 H), 1.35 (dd, J ) 3.5, 3.7 Hz, 1 H), 1.45 (s,
9 H); 13C NMR (75 MHz) δ 173.6, 161.6, 132.6, 129.1, 128.7,
127.6, 81.4, 73.4, 38.6, 27.7, 27.6, 26.0, 25.7, 23.4; IR (CDCl3)
ν 2980, 1770, 1721, 1306, 1160 cm-1; mass spectrum (CI) m/z
316.1549 (C18H21NO4 + H requires 316.1549), 260, 216 (base),
199.
[1S,4R,5R,6S,4(1′S)]-1′-(4-Oxo-3-oxa -6-p h en ylb icyclo-
[3.1.0]h ex-2-yl)p r op yl-1′-ca r ba m ic Acid ter t-Bu tyl Ester
(20). A solution of 1.43 M MeLi in Et2O (120 µL, 0.172 mmol)
was added to a slurry of CuBr‚DMS (18 mg, 0.086 mmol) in
Et2O (1.3 mL) at 0 °C to give a clear solution. A solution of 19
(14 mg, 0.043 mmol) in CH2Cl2 (200 µL) was then added
dropwise. The resulting yellow slurry was stirred for 5 min at
0 °C and then for 5 min at room temperature, whereupon
saturated NH4Cl (0.5 mL) containing saturated NH4OH (1
drop) was added. Et2O (25 mL) and H2O (5 mL) were then
added and the layers separated. The aqueous layer was
extracted with additional Et2O (2 × 10 mL), the combined
organics were dried (MgSO4) and concentrated, and the residue
was purified via flash chromatography eluting with EtOAc/
hexanes (1:4) to give 13 mg (90%) of 20 as a white solid: mp
181-182 °C; 1H NMR (300 MHz) δ 7.37-7.27 (comp, 5 H), 4.55
(d, J ) 9.7 Hz, 1 H), 4.07 (d, J ) 4.9 Hz, 1 H), 3.76-3.68 (m,
1 H), 2.78 (dd, J ) 8.1, 9.0 Hz, 1 H), 2.60 (ddd, J ) 0.9, 6.0,
9.0 Hz, 1 H), 2.48 (dd, J ) 6.0, 8.1 Hz, 1 H), 1.81-1.70 (m, 1
H), 1.43 (s, 9 H), 1.39-1.22 (m, 1 H), 0.96 (t, J ) 7.4 Hz, 3 H);
13C NMR (75 MHz) δ 174.0, 155.7, 132.4, 129.4, 128.9, 127.8,
79.8, 79.2, 55.4, 28.3, 26.5, 26.2, 24.0, 22.5, 10.1; IR (neat) ν
3386, 2977, 1758, 1693, 1513, 1366, 1173, 975 cm-1; mass
1514, 1174 cm-1; mass spectrum (CI) m/z 332.1868 (C19H25
-
NO4 + H requires 332.1862), 316, 304, 276 (base), 260, 232,
215.
[1R,4S,5S,6S,4(1′S)]-1′-(4-Oxo-3-oxa -6-p h en ylb icyclo-
[3.1.0]h ex-2-yl)p r op yl-1′-ca r ba m ic Acid ter t-Bu tyl Ester
(30b ). Prepared in 93% yield as a white solid from 29b
according to the same procedure described for 20: mp 116-
118 °C; 1H NMR (300 MHz) δ 7.33-7.21 (comp, 5 H), 4.47 (d,
J ) 9.5 Hz, 1 H), 4.10 (d, J ) 0.6 Hz, 1 H), 3.79 (ddd, J ) 0.6,
6.2, 8.7 Hz, 1 H), 2.67 (d, J ) 7.7 Hz, 1 H), 2.66 (d, J ) 7.1 Hz,
1 H), 2.50 (dd, J ) 7.1, 7.7 Hz, 1 H), 1.51-1.40 (m, 2 H), 1.41
(s, 9 H), 0.87 (t, J ) 7.4 Hz, 3 H); 13C NMR (75 MHz) δ 174.6,
156.3, 132.9, 129.3, 129.0, 128.9, 127.7, 79.7, 79.0, 55.5, 28.3,
26.5, 25.6, 25.2, 23.9, 10.4; IR (CDCl3) ν 3334, 2971, 1764, 1698,
1522, 1173 cm-1; mass spectrum (CI) m/z 332.1871 (C19H25
NO4 + H requires 332.1861), 332 (base), 308, 276.
-
[1R,2R,3S,2(1′R,2′S)]-2-(1′-Hydr oxy-2′-car bam ic acid ter t-
b u t yl est er )b u t yl-3-p h en ylcyclop r op a n e-1-N-m et h oxy-
m eth yla m id e. To a slurry of HCl‚HN(Me)OMe (1.15 g, 11.7
mmol) in CH2Cl2 (50 mL) under argon at 0 °C was added 2.0
M AlMe3 in toluene (6.85 mL, 13.7 mmol). This clear solution
was stirred at 0 °C for 10 min, whereupon the cooling bath
was removed. Compound 20 (649 mg, 1.96 mmol) in CH2Cl2
(16 mL) was added, and the solution was stirred for 12 h. A
solution of aqueous sodium phosphate dibasic (6 mL) was
added, and the resulting suspension was dissolved in CHCl3
(50 mL) and filtered through a bed of Celite. The filtrate was
dried (MgSO4) and concentrated, and the residue was purified
by column chromatography eluting with 60% EtOAc in hex-
anes to afford 511 mg (66%) of the hydroxy amide as a clear
1
oil that solidified upon standing: mp 103-106 °C; H NMR
(500 MHz, DMSO-d6, 85 °C) δ 7.27-7.16 (comp, 5 H), 5.44 (br
s, 1 H), 3.82 (dd, J ) 5.0, 10.0 Hz, 1 H), 3.67 (s, 3 H), 3.46
(ddd, J ) 5.0, 9.3, 14.0 Hz, 1 H), 3.14 (s, 3 H), 2.68 (dd, J )
9.5, 10.5 Hz, 1 H), 2.52 (dd, J ) 9.0, 9.5 Hz, 1 H), 1.78 (app q,
J ) 9.2 Hz, 1 H), 1.63 (m, 1 H), 1.41 (d, J ) 2.0 Hz, 1 H), 1.38
(s, 9 H), 1.35-1.29 (m, 1 H), 0.80 (t, J ) 7.4 Hz, 3 H); 13C
NMR (125 MHz, DMSO-d6, 85 °C) δ 173.0, 155.4, 136.0, 129.2,
127.7, 125.9, 77.22, 68.8, 60.9, 56.5, 28.1, 27.7, 22.1, 20.5, 10.6;
IR (neat) ν 3433, 2971, 1710, 1633, 1499, 1454, 1391, 1365,
1172 cm-1; mass spectrum (CI) m/z 393.2381 (C21H32N2O5
H requires 393.2389), 393, 337 (base), 319, 234.
+
[1R,2R,3S,2(1′R,2′S)]-2-(1′-ter t-Bu tyldim eth ylsilan yloxy-
2′-ca r ba m ic a cid ter t-bu tyl ester )bu tyl-3-p h en ylcyclo-
p r op a n e-1-N-m eth oxym eth yla m id e (21). To a solution of
the hydroxy amide (84 mg, 0.21 mmol) from the preceding
reaction in CH2Cl2 (1 mL) at -78 °C were added 2,6-lutidine
(50 µL, 0.43 mmol) and TBDMSOTf (79 µL, 0.34 mmol). The
solution was stirred for 4 h at -78 °C, whereupon H2O (100
µL) was added, and the solution was allowed to warm to room
temperature. CHCl3 (10 mL) was added, and the solution was
dried (Na2SO4), filtered, and concentrated. The residue was
purified via column chromatography eluting with EtOAc/
hexanes (1:10) to give 105 mg (99%) of 21 as a light yellow oil:
1H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.30-7.12 (comp, 5
H), 5.03 (dd, J ) 3.3, 9.5 Hz), 4.88 (br s, 1 H), 3.60 (s, 3 H),
3.31-3.28 (m, 1 H), 3.00 (s, 3 H), 2.69 (app t, J ) 9.8 Hz, 1 H),
2.61 (dd, J ) 8.7, 9.8 Hz, 1 H), 1.73 (ddd, J ) 8.7, 9.5, 9.8 Hz,
1 H), 1.72-1.65 (m, 1 H), 1.43-1.35 (m, 1 H), 1.35 (s, 9 H),
0.89 (s, 9 H), 0.80 (t, J ) 7.4 Hz, 1 H), 0.11 (s, 3 H), 0.04 (s, 3
H); 13C NMR (125 MHz, DMSO-d6, 85 °C) δ 170.0, 154.7, 136.0,
129.5, 127.6, 125.8, 77.4, 68.2, 61.0, 55.9, 32.2, 30.1, 28.4, 28.1,
27.9, 25.9, 25.4, 20.8, 20.1, 18.0, 10.8, -4.1, -5.1; IR (neat) ν

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 66, No. 5, 2001 1667
2931, 1717, 1660, 1498, 1497, 1251, 1171, 1094, 836 cm-1; mass
spectrum (CI) m/z 507.3258 (C27H46N2O5Si + H requires
507.3254), 491, 449, 433, 375, 348, 319 (base).
1.51 (m, 1 H), 1.33 (s, 9 H), 0.78 (t, J ) 7.4 Hz, 3 H); 13C NMR
(125 MHz, DMSO-d6, 85 °C) δ 171.7, 171.2, 169.2, 151.3, 136.4,
127.9, 127.5, 125.6, 79.3, 70.4, 69.5, 66.2, 54.3, 51.2, 51.0, 30.8,
30.2, 29.9, 29.3, 28.9, 28.8, 27.7, 27.5, 24.2, 21.5, 14.2, 10.0;
IR (CDCl3) ν 3305, 2974, 2932, 1742, 1658, 1530, 1445, 1347,
1168, 757 cm-1; mass spectrum (CI) m/z 638.2931 (C31H47N3O7S2
+ H requires 638.2934), 621, 591, 567, 538 (base), 302, 246,
231, 203, 161, 117.
[1S,2R,3S,2(1′R,2′S)]-2-(1′-ter t-Bu tyldim eth ylsilan yloxy-
2′-ca r ba m ic a cid ter t-bu tyl ester )bu tyl-3-p h en ylcyclo-
p r op a n e-1-ca r boxylic Acid (22). To a solution of 21 (48 mg,
0.10 mmol) in Et2O (1 mL) at 0 °C was added solid KOtBu (64
mg, 0.57 mmol) in one portion. The solution was stirred for 2
h at 0 °C, whereupon H2O (40 µL) was added. This biphasic
mixture was diluted with EtOAc (5 mL) and washed once with
saturated aqueous citric acid (0.5 mL). The organic layer was
separated, dried (MgSO4), and concentrated, and the crude
product was purified by flash chromatography eluting with
20% EtOAc/hexanes to afford 43 mg (97%) of 22 as a clear oil:
1H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.31-7.14 (comp, 5
H), 6.09 (d, J ) 8.8 Hz, 1 H), 3.15 (comp, 2 H), 2.61 (dd, J )
5.4, 9.8 Hz, 1 H), 2.12 (dd, J ) 4.3, 5.2 Hz, 1 H), 1.95-1.91
(m, 1 H), 1.33 (s, 9 H), 1.22-0.87 (comp, 2 H), 0.84 (s, 9 H),
0.56 (t, J ) 7.4 Hz, 3 H), 0.07 (s, 3 H), 0.02 (s, 3 H); 13C NMR
(125 MHz, DMSO-d6, 85 °C) δ 178.5, 174.1, 155.2, 136.0, 128.2,
127.9, 126.5, 99.4, 77.1, 71.6, 56.1, 32.1, 31.2, 28.2, 25.7, 24.1,
22.6, 17.7, 10.7, -4.3, -4.6; IR (neat) ν 3248, 2930, 1707, 1651,
1462, 1405, 1255, 1172, 1097, 836, 773 cm-1; mass spectrum
(CI) m/z 464.2827 (C25H41NO5Si + H requires 464.2832), 408,
350 313, 276 (base).
[1R,4S,5S,6S,4(1′S)]-4-[1′-L-Am in o[ter t-bu tyl (N-(S)-d i-
m et h ylt h ia zolid in e)ca r b a m a t e]et h yl-6-p h en yl-3-oxa b i-
cyclo[3.1.0]h exa n -2-on e (32a ). The lactone 30a (170 mg, 0.52
mmol) was taken up in 4 N HCl/dioxane (6 mL) and stirred
with heating for 30 min. Excess HCl was removed by bubbling
a stream of argon through the solvent, and the mixture was
then concentrated in vacuo. The crude oily residue was
triturated with Et2O (2×) and dried in vacuo to give the
deprotected amine salt. This material was taken up in CH2-
Cl2 (4 mL) and DMF (0.4 mL), treated with Et3N (72 µL, 0.73
mmol), and cooled to 0 °C. HOBt (70 mg, 0.52 mmol) and 31
(136 mg, 0.52 mmol) were then added, and the reaction was
stirred for 3 h. The mixture was filtered, and the filtrate was
washed with 0.1 N HCl (2 × 5 mL), brine (1 × 5 mL), saturated
aqueous NaHCO3 (2 × 5 mL), and again with brine (1 × 5
mL). The organic layer was dried (MgSO4), the solvent was
removed in vacuo, and the crude oily product was purified via
flash chromatography eluting with EtOAc/hexanes (1:3) to give
[1S,2R,3S,2(1′R,2′S)]-2-(1′-ter t-Bu tyldim eth ylsilan yloxy-
2′-ca r ba m ic a cid ter t-bu tyl ester )bu tyl-3-p h en ylcyclo-
p r op a n e-1-ca r boxyl-L-m eth ion in e Meth yl Ester . A solu-
tion of the acid 22 (204 mg, 0.44 mmol) and HOBt (190 mg,
1.41 mmol) in DMF (3.4 mL) was cooled to -10 °C (NaCl/ice)
and stirred for 20 min. In a separate flask was prepared
MetOMe via treatment of a solution of HCl‚MetOMe (176 mg,
0.88 mmol) in DMF (1 mL) with Et3N (124 µL, 0.88 mmol).
The amine component was then transferred to the acid solution
via syringe, EDC (135 mg, 0.70 mmol) was added, and the
reaction was stirred at room temperature overnight. The
solution was partitioned between EtOAc (9 mL), brine (4 mL)
and saturated citric acid (4 mL). The layers were separated,
and the organic phase was washed with saturated NaHCO3
(4 mL) and brine (4 mL), dried (MgSO4), and concentrated
under reduced pressure. The crude yellow product was purified
via flash chromatography eluting with EtOAc/hexanes (1:3)
to afford 233 mg (87%) of the tripeptide as a white solid: mp
61-64 °C; 1H NMR (500 MHz, DMSO-d6, 85 °C) δ 8.44 (d, J )
7.8 Hz, 1 H), 7.32-7.19 (comp, 5 H), 5.22 (br s, 1 H), 4.48 (dt,
J ) 3.2, 5.5 Hz, 1 H), 3.62 (s, 3 H), 3.27 (dd, J ) 3.9, 9.9 Hz,
1 H), 3.13-3.06 (m, 1 H), 2.57-2.42 (comp, 3 H), 2.05 (s, 3 H),
2.02-1.83 (comp, 2 H), 1.32 (s, 9 H), 1.26-1.19 (m, 2 H), 0.86
1
240 mg (98%) of 32a as an oil: H NMR (300 MHz) δ 7.30-
7.01 (comp, 5 H), 6.26 (br s, 1 H), 4.88 (d, J ) 6.4 Hz, 1 H),
4.59 (s, 1 H), 4.24 (dd, J ) 7.9, 14.9 Hz, 1 H), 3.32 (dd J ) 6.8,
12.4 Hz, 1 H), 3.18 (d, J ) 12.4 Hz, 1 H), 2.57 (dd, J ) 4.0, 6.0
Hz, 1 H), 2.37 (br s, 1 H), 2.23 (dd, J ) 3.2, 3.6 Hz, 1 H), 1.83
(s, 3 H), 1.80 (s, 3 H), 1.76-1.59 (m, 1 H), 1.51 (s, 9 H), 1.02 (t,
J ) 7.4 Hz, 3 H); 13C NMR (75 MHz) δ 174.2, 171.9, 153.4,
137.1, 128.6, 127.0, 126.1, 82.3, 82.1, 77.2, 71.2, 67.7, 54.2, 30.9,
29.5, 28.9, 28.7, 28.6, 28.4, 27.5, 24.9, 10.5; IR (CDCl3) ν 3317,
2973, 1765, 1693, 1528, 1367, 1172 cm-1; mass spectrum (CI)
m/z 474.2191 (C25H33N2O5S requires 474.2188), 447, 419, 403,
375, 301, 171.
[1R,4S,5S,6R,4(1′S)]-4-[1′-L-Am in o-[ter t-b u t yl-(N-(S)-
d im e t h y lt h ia zo lid in e )c a r b a m a t e ]e t h y l-6-p h e n y l-3-
oxa bicyclo[3.1.0]h exa n -2-on e (32b). Prepared in 80% yield
as a white solid from 30b according to the procedure described
1
for 32a : mp 159-161 °C; H NMR (500 MHz, DMSO-d6, 85
°C) δ 7.47 (d, J ) 8.2 Hz, 1 H), 7.34-7.25 (comp, 5 H), 4.79 (d,
J ) 3.2, 7.0 Hz, 1 H), 4.12 (d, J ) 2.5 Hz, 1 H), 4.02-3.97 (m,
1 H), 3.33 (dd, J ) 7.0, 12.1 Hz), 2.95 (dd, J ) 3.2, 12.1 Hz, 1
H), 2.77 (dd, J ) 8.2, 8.5 Hz, 1 H), 2.57 (dd, J ) 6.1, 8.2 Hz,
1 H), 2.50 (dd, J ) 6.1, 8.5 Hz, 1 H), 1.80 (s, 3 H), 1.75 (s, 3
H), 1.56-1.40 (m, 2 H), 1.39 (s, 9 H), 0.87 (t, J ) 7.4 Hz, 3 H);
13C NMR (125 MHz, DMSO-d6, 85 °C) δ 173.2, 170.2, 151.4,
133.2, 128.8, 128.0, 126.8, 79.1, 77.8, 70.4, 65.9, 53.0, 30.7, 29.3,
27.8, 27.6, 25.4, 24.9, 23.4, 22.7, 9.9; IR (CDCl3) ν 3424, 2972,
1766, 1674, 1346, 1172 cm-1; mass spectrum (CI) m/z 475.2254
(C25H34N2O5S + H requires 475.2267), 419, 375, 225.
(s, 9 H), 0.66 (t, J ) 7.3 H, 3 H), 0.11 (s, 3 H), 0.06 (s, 3 H); 13
C
NMR (125 MHz, DMSO-d6, 85 °C) δ 172.5, 171.5, 155.2, 136.85,
128.1, 128.0, 126.3, 77.0, 71.5, 56.1, 52.0, 50.8, 30.7, 30.5, 29.4,
28.2, 25.8, 24.6, 22.5, 17.7, 14.4, 10.7, -4.3, -4.6; IR (CDCl3)
ν 3304, 2956, 1722, 1680, 1650, 1538, 1499, 1355, 1255, 1171
cm-1; mass spectrum (CI) m/z 609.3388 (C31H52N2O6SiS + H
requires 609.3394), 537, 509, 495, 451, 421 (base), 232, 117.
[1R,2R,3S,2(1′R,2′S)]-2-[2′-Am in o[ter t-b u t yl (N-L-d i-
m e t h y lt h ia zo lid in e )c a r b a m a t e ]-1′-h y d r o x y ]b u t y l-3-
p h en ylcyclop r op a n e-1-ca r boxyl-L-m eth ion in e Meth yl
Ester (24). The tripeptide (152 mg, 0.25 mmol) from the
preceding experiment in 4 N HCl in dioxane (2 mL) was stirred
at room temperature for 30 min, whereupon solvent was
removed under reduced pressure. The crude deprotected
material was dissolved in THF (2 mL) containing Et3N (30 mg,
0.3 mmol), 23 (28 mg, 0.74 mmol) was added, and the reaction
was stirred overnight at room temperature. Solvent was
removed under reduced pressure, and the crude residue was
purified via flash chromatography eluting with EtOAc/hexanes
(1:1) to afford 96 mg (60%) of 24 as a pale yellow oil: 1H NMR
(500 MHz, DMSO-d6, 85 °C) δ 8.25 (d, J ) 7.4 Hz, 1 H), 7.28-
7.16 (comp, 5 H), 6.89 (d, J ) 8.6 Hz, 1 H), 4.59 (dd, J ) 2.7,
7.1 Hz, 1 H), 4.46-4.44 (m, 1 H), 3.63 (s, 3 H), 3.52-3.49 (m,
1 H), 3.25 (dd, J ) 7.1, 12.0 Hz, 1 H), 3.05 (dd, J ) 3.8, 8.3
Hz, 1 H), 2.91 (dd, J ) 2.7, 12.0 Hz, 1 H), 2.57-2.48 (comp, 3
H), 2.29 (app t, J ) 5.3 Hz, 1 H), 2.07 (s, 3 H), 2.04-1.90 (comp,
3 H), 1.76 (s, 3 H), 1.75-1.71 (m, 1 H), 1.71 (s, 3 H), 1.54-
[1R,4S,5S,6S,4(1′S)]-2-[2′-Am in o[ter t-b u t yl (N-(S)-d i-
m et h ylt h ia zolid in e)ca r b a m a t e]-1′-ter t-b u t yld im et h yl-
sila n yloxy]bu tyl-3-p h en ylcyclop r op a n e 1-Meth yl Ester
(33a ). To a solution of 32a (156 mg, 0.33 mmol) in EtOH (2
mL) was added 1 N NaOH (0.49 mL, 0.49 mmol), and the
reaction was stirred for 1 h, whereupon solvent was removed
in vacuo. The crude solid residue was dissolved in H2O (5 mL),
and the solution was acidified by addition of 1 N NaHSO4 (0.5
mL, 0.5 mmol). The resultant white slurry was extracted with
EtOAc (3 × 5 mL), and the combined organic layers were dried
(MgSO4) and concentrated. The residue was dissolved in
MeOH (3 mL), and a solution of CH2N2 in Et2O was added
using a flame polished pipet until a yellow endpoint was
observed. The excess CH2N2 was removed by bubbling argon
through the solution through a flame-polished pipet. The
solvent was removed via rotary evaporation, and the crude
hydroxy ester product was dissolved in CH2Cl2 (2.5 mL). The
solution was cooled to -78 °C under argon, and 2,6-lutidine
(77 µL, 0.66 mmol) and TBDMSOTf (114 µL, 0.50 mmol) were
added. The reaction was stirred for 1 h at -78 °C and 1 h at
-20 °C, whereupon saturated NaHCO3 (1 mL) was added. The

1668 J . Org. Chem., Vol. 66, No. 5, 2001
Hillier et al.
reaction was warmed to room temperature and diluted with
CH2Cl2 (4 mL). This layers were separated, and the organic
phase was dried (MgSO4) and concentrated. The residue was
purified via flash chromatography eluting with EtOAc/hexanes
(1:5) to give 123 mg (60%) of 33a as an oil and 42 mg (27%) of
the lactone 31a : 1H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.24-
7.14 (comp, 5 H), 6.72 (d, J ) 8.8 Hz, 1 H), 4.66 (dd, J ) 2.6,
7.0 Hz, 1 H), 4.14 (dd, J ) 1.8, 8.5 Hz, 1 H), 3.88 (ddd, J )
1.8, 5.9, 8.5 Hz, 1 H), 3.67 (s, 3 H), 3.20 (dd, J ) 7.0, 12.0 Hz,
1 H), 2.86 (dd, J ) 2.6, 12.0 Hz, 1 H), 2.45 (dd, J ) 5.2, 7.3
Hz, 1 H), 2.01 (dd, J ) 5.2, 8.7 Hz, 1 H), 1.89 (ddd, J ) 7.3,
8.5, 8.7 Hz, 1 H), 1.74 (s, 3 H), 1.73 (s, 3 H), 1.63-1.58 (m, 1
H), 1.49-1.43 (m, 1 H), 1.36 (s, 9 H), 0.94-0.86 (comp, 12 H),
0.07 (s, 3 H), 0.04 (s, 3 H); 13C NMR (125 MHz, DMSO-d6, 85
°C) δ 171.0, 169.3, 151.8, 138.1, 127.6, 126.4, 125.9, 79.8, 70.5,
68.9, 66.4, 55.4, 50.9, 40.0, 34.0, 30.0, 29.0, 28.6, 28.227.5, 27.2,
25.4, 25.3, 25.0, 24.3, 17.3, 10.0, -5.1, -5.4; IR (CDCl3) ν 3428,
2932, 1680, 1501, 1452, 1342, 1170, 1060, 840 cm-1; mass
spectrum (CI) m/z 621.3386 (C32H52N2O6SiS + H requires
621.3386), 605, 565, 521, 489, 433.
via flash chromatography eluting with EtOAc (gradient: 1:3
to 1:1) to give 15 mg (47%) of 34b as a pale yellow oil: 1H NMR
(500 MHz, DMSO-d6, 85 °C) δ 12.0 (br s, 1 H), 7.35-7.17
(comp, 5 H), 6.51 (d, J ) 9.6 Hz, 1 H), 4.74 (dd, J ) 1.0, 9.7
Hz, 1 H), 4.71 (dd, J ) 1.7, 7.2 Hz, 1 H), 3.89 (m, 1 H), 3.38
(dd, J ) 7.2, 12.2 Hz, 1 H), 3.00 (dd, J ) 1.7, 12.2 Hz, 1 H),
2.53 (dd, J ) 9.6, 9.9 Hz, 1 H), 2.08 (dd, J ) 8.3, 9.6 Hz, 1 H),
1.83 (s, 3 H), 1.70 (ddd, J ) 8.3, 9.7, 9.9 Hz, 1 H), 1.75 (s, 3
H), 1.46-1.39 (m, 1 H), 1.43 (s, 9 H), 0.90 (s, 9 H), 0.73 (t, J )
7.4 Hz, 3 H), 0.08 (s, 3 H), 0.07 (s, 3 H); 13C NMR (125 MHz,
DMSO-d6, 85 °C) δ 171.4, 169.6, 151.8, 134.8, 129.3, 127.1,
125.7, 80.1, 70.7, 67.2, 66.8, 54.3, 30.3, 29.6, 28.4, 28.2, 27.5,
25.7, 25.3, 22.8, 17.8, 9.7, -4.5, -5.4; IR (CDCl3) ν 2932, 1704,
1634, 1520, 1338, 1116 cm-1; mass spectrum (FAB) m/z
607.3231 (C31H50N2O6SiS + requires 607.3237), 551, 507, 419,
375 (base).
[1R,4S,5S,6S,4(1′S)]-2-[2′-Am in o[ter t-b u t yl (N-(S)-d i-
m et h ylt h ia zolid in e)ca r b a m a t e]-1′-ter t-b u t yld im et h yl-
silan yloxy]bu tyl-3-ph en ylcyclopr opan e-1-car boxyl-L-cys-
t ein e Met h yl E st er (35a ). A solution of 34a (50 mg, 0.08
mmol), HCl‚MetOMe (17 mg, 0.08 mmol), and HOBt (11 mg,
0.08 mmol) in CH2Cl2 (1 mL) and DMF (0.1 mL) was cooled to
0 °C, whereupon Et3N (11 µL, 0.08 mmol) and DCC (17 mg,
0.08 mmol) were added. The reaction was stirred for 3 d at
room temperature, and the solids were removed by filtration.
The filtrate was concentrated under reduced pressure, and the
residue was dissolved in EtOAc (3 mL). The solution was cooled
to 0 °C, and the solids were removed by vacuum filtration. The
combined filtrates were washed with 0.1 N HCl (1 × 1 mL),
H2O (1 mL) and brine (1 × 1 mL). The organic layer was then
dried (MgSO4) and concentrated, and the residue was purified
via flash chromatography eluting with EtOAc/hexanes (1:1)
to give 44 mg (71%) of 35a as an oil: 1H NMR (500 MHz,
DMSO-d6, 85 °C) δ 8.40 (d, J ) 7.4 Hz, 1 H), 7.24-7.12 (comp,
5 H), 6.63 (d, J ) 9.1 Hz, 1 H), 4.62 (dd, J ) 2.3, 6.9 Hz, 1 H),
4.25-4.39 (comp, 2 H), 3.86 (ddd, J ) 1.3, 8.1, 8.7 Hz, 1 H),
3.65 (s, 3 H), 3.17 (dd, J ) 6.9, 12.0 Hz, 1 H), 2.86 (dd, J )
2.3, 12.0 Hz, 1 H), 2.54 (dd, J ) 7.3, 7.7 Hz, 1 H), 2.30 (dd, J
) 5.2. 7.0 Hz, 1 H), 2.10 (ddd, J ) 5.2, 7.7, 8.5 Hz, 1 H), 2.06
(s, 3 H), 1.99-1.87 (m, 2 H), 1.78-1.71 (m, 1 H), 1.74 (s, 3 H),
1.73 (s, 3 H), 1.56-1.43 (m, 2 H), 1.36 (s, 9 H), 0.90 (s, 9 H),
0.88 (t, J ) 7.4 Hz, 3 H), 0.06 (s, 3 H), 0.04 (s, 3 H); 13C NMR
(125 MHz, DMSO-d6, 85 °C) δ 171.6, 170.4, 169.1, 151.8, 139.3,
127.5, 126.3, 125.5, 79.8, 70.5, 68.2, 66.5, 55.4, 51.2, 51.1, 33.6,
30.0, 29.3, 28.6, 28.3, 28.2, 27.7, 27.5, 25.5, 24.9, 17.4, 14.0,
9.9, 0.7, -4.6, -5.5; IR (CDCl3) ν 2932, 1743, 1657, 1514, 1343,
1167 cm-1; mass spectrum (CI) m/z 752.3790 (C37H61N3O7SiS2
+ H requires 752.3798), 694, 652, 620, 450, 307, 225.
[1R,4S,5S,6R,4(1′S)]-2-[2′-Am in o[ter t-b u t yl (N-(S)-d i-
m eth ylth ia zolid in e)ca r ba m a te]-1′-ter t-bu tyld im eth ylsi-
lanyloxy]butyl-3-phenylcyclopropane-1-carboxyl-L-cysteine
Meth yl Ester (35b). Prepared as a pale yellow oil in 84% yield
from 34b according to the procedure described for 35a : 1H
NMR (500 MHz, DMSO-d6, 85 °C) δ 8.43 (d, J ) 7.4 Hz, 1 H),
7.39-7.12 (comp, 5 H), 6.48 (d, J ) 9.6 Hz, 1 H), 4.85 (d, J )
9.4 Hz, 1 H), 4.72 (dd, J ) 1.6, 7.2 Hz, 1 H), 4.38 (ddd, J )
5.4, 8.0, 8.0 Hz, 1 H), 3.87 (ddd, J ) 7.6, 9.4, 9.4 Hz, 1 H),
3.58 (s, 3 H), 3.99 (dd, J ) 7.2, 12.2 Hz, 1 H), 3.03 (dd, J )
1.6, 12.2 Hz, 1 H), 2.55-2.45 (m, 2 H), 2.40 (dd, J ) 9.7, 9.8
Hz, 1 H), 2.16 (dd, J ) 8.5, 9.3 Hz, 1 H), 2.04 (s, 3 H), 1.20-
1.86 (m, 1 H), 1.83 (s, 3 H), 1.76 (s, 3 H), 1.71 (ddd, J ) 8.5,
9.8, 9.8 Hz, 1 H), 1.43 (s, 9 H), 1.40-1.30 (m, 1 H), 0.87 (s, 9
H), 0.67 (t, J ) 7.4 Hz, 3 H), 0.05 (s, 3 H), 0.02 (s, 3 H); 13C
NMR (125 MHz, DMSO-d6, 85 °C) δ 171.7, 169.9, 169.6, 151.8,
134.9, 129.8, 126.7, 125.3, 80.0, 70.8, 67.0, 66.9, 54.2, 51.1, 50.9,
30.3, 30.2, 29.4, 29.3, 28.3, 28.2, 27.5, 26.7, 25.8, 25.3, 22.8,
17.7, 14.0, 9.6, -4.5, -5.4; IR (CDCl3) ν 3280, 2956, 2930, 2854,
1745, 1655, 1515, 1343, 1254, 1164, 1056 cm-1; mass spectrum
(CI) m/z 752.3803 (C37H61N3O7SiS2 + H requires 752.3798),
736, 694, 620.
[1R,4S,5S,6R,4(1′S)]-2-[2′-Am in o-[ter t-b u t yl(N-(S)-d i-
m et h ylt h ia zolid in e)ca r b a m a t e]-1′-ter t-b u t yld im et h yl-
sila n yloxy]bu tyl-3-p h en ylcyclop r op a n e 1-Meth yl Ester
(33b). Prepared in 79% yield as an oil from 32b according to
1
the procedure described for 33a : H NMR (500 MHz, DMSO-
d6, 85 °C) δ 7.30-7.18 (comp, 5 H), 6.53 (d, J ) 9.5 Hz, 1 H),
4.72 (dd, J ) 1.8, 7.2 Hz, 1 H), 4.66 (dd, J ) 0.9, 9.7 Hz, 1 H),
3.94 (m, 1 H), 3.57 (s, 3 H), 3.38 (dd, J ) 7.2, 12.2 Hz, 1 H),
3.01 (dd, J ) 1.8, 12.2 Hz, 1 H), 2.61 (dd, J ) 9.4, 9.8 Hz, 1
H), 2.19 (dd, J ) 8.4, 9.4 Hz, 1 H), 1.86 (ddd, J ) 8.4, 9.8, 9.8
Hz, 1 H), 1.47-1.39 (m, 1 H), 1.42 (s, 9 H), 0.89 (s, 9 H), 0.75
(t, J ) 7.4 Hz, 3 H), 0.08 (s, 3 H), 0.01 (s, 3 H); 13C NMR (125
MHz, DMSO-d6, 85 °C) δ 170.3, 169.7, 151.9, 134.2, 129.3,
127.2, 125.8, 80.1, 70.7, 67.3, 66.8, 54.2, 50.6, 30.2, 30.0, 28.4,
28.2, 28.1, 27.5, 25.6, 25.3, 22.6, 17.6, 9.7, -4.8, -5.3; IR
(CDCl3) ν 3424, 2958, 2932, 2858, 1730, 1672, 1510, 1337, 1164
cm-1; mass spectrum (CI) m/z 621.3400 (C32H52N2O6SiS + H
requires 621.3394), 589, 565, 489, 433.
[1R,4S,5S,6S,4(1′S)]-2-[2′-Am in o[ter t-b u t yl (N-(S)-d i-
m et h ylt h ia zolid in e)ca r b a m a t e]-1′-ter t-b u t yld im et h yl-
silan yloxy]bu tyl-3-ph en ylcyclopr opan e-1-car boxylic Acid
(34a ). A solution of 33a (80 mg, 0.13 mmol) in EtOH (0.9 mL)
containing 1 N NaOH (0.2 mL, 0.2 mmol) was stirred for 1 h
at room temperature, and then the solvent was removed under
reduced pressure. The residue was dissolved in H2O (2 mL),
and the resulting solution was acidified with 1 N NaHSO4 (0.21
mL, 0.21 mmol). The mixture was with EtOAc (3 × 1 mL),
the combined organic layers were dried (MgSO4) and concen-
trated, and the crude product was purified via flash chroma-
tography eluting with EtOAc/hexanes (1:3) to give 50 mg (64%)
of 34a as an oil: 1H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.24-
7.13 (comp, 5 H), 6.69 (d, J ) 9.0 Hz, 1 H), 4.65 (dd, J ) 2.5,
7.0 Hz, 1 H), 4.21 (dd, J ) 1.8, 8.4 Hz, 1 H), 3.88 (ddd, J )
1.8, 8.3, 10.1 Hz, 1 H), 3.20 (dd, J ) 7.0, 12.0 Hz, 1 H), 2.86
(dd, J ) 2.5, 12.0 Hz, 1 H), 2.39 (dd, J ) 5.2, 7.2 Hz, 1 H),
1.90 (dd, J ) 5.2, 8.7 Hz, 1 H), 1.83 (ddd, J ) 7.2, 8.4, 8.7 Hz,
1 H), 1.74 (s, 3 H), 1.73 (s, 3 H), 1.62-1.55 (m, 1 H), 1.50-
1.45 (m, 1 H), 1.36 (s, 9 H), 0.91 (s, 9 H), 0.89 (t, J ) 7.4 Hz,
3 H), 0.10 (s, 3 H), 0.08 (s, 3 H); 13C NMR (125 MHz, DMSO-
d6, 85 °C) δ 171.9, 169.2, 151.8, 127.7, 126.4, 125.7, 79.8, 70.5,
68.9, 66.4, 55.4, 33.5, 29.9, 28.6, 27.6, 25.5, 25.3, 24.6, 17.4,
9.9, -4.7, -5.4; IR (CDCl3) ν 3431, 2933, 1694, 1651, 1340,
1167 cm-1; mass spectrum (CI) m/z 607.3231 (C31H50N2O6SiS
+ H requires 607.3237), 551, 507, 419, 375 (base), 171.
[1R,4S,5S,6R,4(1′S)]-2-[2′-Am in o[ter t-b u t yl (N-(S)-d i-
m et h ylt h ia zolid in e)ca r b a m a t e]-1′-ter t-b u t yld im et h yl-
silan yloxy]bu tyl-3-ph en ylcyclopr opan e-1-car boxylic Acid
(34b). A solution of 33b (34 mg, 0.054 mmol) in EtOH (0.5
mL) containing 1 N NaOH (162 µL, 0.162 mmol) was heated
at reflux overnight. The solvent was removed under reduced
pressure, and the residue was dissolved in H2O (2 mL). The
solution was acidified with excess 1 N HCl (170 µL, 0.170
mmol), and the resulting mixture was extracted with EtOAc
(3 × 1 mL). The combined organic layers were dried (MgSO4)
and concentrated, and the crude product mixture was purified
N-Boc-L-d im et h ylt h ia zolid in e-L-et h ylglycin e Met h yl
Ester . A mixture of HCl‚AbuOMe (108 mg, 0.70 mmol), Et3N
(98 µL, 0.70 mmol), and the pentaflourophenol ester of N-Boc-
L-dimethylthiazolidine (433 mg, 1.05 mmol) in THF (3 mL) was
stirred for 23 h at room temperature. The solvent was removed

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 66, No. 5, 2001 1669
under reduced pressure, and the crude product was purified
via flash chromatography eluting with EtOAc/hexanes (1:3)
to give 241 mg (96%) of the dipeptide ester as a clear oil: H
to 0 °C. A solution of the (E)-1-bromo-2-pentene (500 mg, 3.36
mmol) in THF (1 mL) was added, and the reaction was stirred
for 2 h at 0 °C. The reaction was partitioned between saturated
aqueous NH4Cl (50 mL) and EtOAc/hexanes (1:1, 100 mL). The
layers were separated, and the organic phase was dried
(MgSO4) and concentrated. The residue was purified via flash
chromatography eluting with EtOAc/hexanes (1:3) to give 756
mg (93%) of 39 as an oil. The diastereomeric product ratio was
determined to be 14:1 by chiral HPLC (Daicel OD column,
i-PrOH/hexanes (1:10), retention time (rt) 39 ) 24.3 min, room
temperature diast-39 ) 27.1 min): 1H NMR (500 MHz, DMSO-
d6, 85 °C, rotamers) δ 7.29-7.10 (comp, 10 H), 5.47-5.32
(comp, 2 H), 5.1-4.9 (m, 1 H), 4.63-4.45 (m, 2 H), 3.8 (br s, 1
H), 3.02 (s, 3 H), 2.97-2.58 (comp, 3 H), 2.27-1.92 (comp, 4
H), 0.97-0.45 (comp, 5 H); 13C NMR (125 MHz, DMSO-d6, 85
°C, rotamers) δ 174.1, 174.0, 142.8, 139.7, 132.9, 132.8, 132.1,
128.4, 128.3, 127.6, 127.5, 127.2, 126.7, 126.3, 125.8, 125.3,
73.7, 73.5, 56.8, 54.5, 42.8, 42.6,37.8, 37.5, 35.0, 34.7, 30.6, 30.5,
29.6, 29.3, 26.5, 24.4, 24.3, 29.6, 19.4, 134.0, 13.4, 13.2, 13.1;
IR (CDCl3) ν 3028, 2963, 1614, 1494, 1454, 1408 cm-1; mass
spectrum m/z 366.2424 (C25H31NO2 + H requires 366.2433),
348, 258.
1
NMR (300 MHz) δ 4.78 (br s, 1 H), 4.61-4.57 (m, 1 H), 3.75
(s, 3 H), 3.75 (br s, 2 H), 2.05-1.85 (m, 1 H), 1.89 (s, 3 H), 1.80
(s, 3 H), 1.80-1.65 (m, 1 H), 1.48 (s, 9 H), 0.94 (t, J ) 7.4 Hz,
3 H); 13C NMR (75 MHz) δ 172.3, 170.3, 153.5, 81.6, 71.0, 67.3,
53.4, 52.2, 30.6, 29.1, 28.6, 28.2, 25.6, 9.1; IR (CDCl3) ν 3425,
3323, 2974, 2935, 1743, 1703, 1517, 1348, 1169 cm-1; mass
spectrum (CI) m/z 360.1707 (C16H27N2O5S requires 360.1719),
305 (base) 261, 250, 222.
N-Boc-L-d im eth ylth ia zolid in e-L-eth ylglycin e Ca r box-
ylic Acid (36). To a solution of the ester from the previous
experiment (207 mg, 0.57 mmol) in EtOH (3.8 mL) at 0 °C
was added 1 N NaOH (0.74 mL, 0.74 mmol). This mixture was
then stirred at room temperature for 24 h, whereupon the
solvent was concentrated under reduced pressure. The crude
product was dissolved in H2O (5 mL), the solution was acidified
to pH 3 by addition of saturated aqueous KHSO4, and the
mixture was extracted with EtOAc (3 × 3 mL). The combined
organics were dried (MgSO4) and concentrated to give 185 mg
1
(94%) of the acid which was g95% pure by H NMR and used
without further purification: mp 76-77 °C; 1H NMR (300
MHz, MeOD-d3) δ 9.12 (br s, 1 H), 7.00 (br s, 1 H), 4.80 (br s,
1 H), 4.59 (dt, J ) 5.8, 12.6 Hz, 1 H), 3.33-3.18 (m, 2 H), 2.06-
1.83 (m, 2 H), 1.89 (s, 3 H), 1.79 (s, 3 H), 1.46 (s, 9 H), 0.95 (t,
J ) 7.4 Hz, 3 H); 13C NMR (75 MHz, MeOD-d3) δ 175.1, 171.3,
153.5, 81.9, 71.0, 67.2, 53.3, 30.6, 28.8. 28.7, 28.1, 25.2, 9.0;
IR (CDCl3) ν 3409, 3306, 2975, 1704, 1666, 1535, 1367, 1166
cm-1; mass spectrum (CI) m/z 347.1638 (C15H26N2O5S + H
requires 347.1640), 319, 291, 275, 247.
(1′R,3R,5S)-3-Ben zyl-5-(1′-br om op r op yl)d ih yd r ofu r a n -
2-on e (40). N-Bromosuccinimide (670 mg, 3.76 mmol) was
added in portions to a solution of 39 (1.25 g, 3.42 mmol) in a
mixture (4:1) of THF/H2O (20 mL) containing glacial acetic acid
(1 mL, 17.1 mmol) at 0 °C. The resulting solution was stirred
for 1 h at 0 °C and then heated under reflux for 4 h. The
reaction was cooled to room temperature, and a mixture of
saturated NaHCO3 (40 mL) was added. The mixture was
extracted with EtOAc/hexanes (1:1, 3 × 40 mL), and the
combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified via
flash chromatography eluting with EtOAc/hexanes (1:7) to
provide 807 mg (79%) of an inseparable mixture of 40 as a
pale yellow oil that was contaminated with varying amounts
(4-13%) of a diastereomeric lactone. For 40: 1H NMR (300
MHz) δ 7.35-7.18 (comp, 5 H), 4.29 (ddd, J ) 5.2, 7.1, 7.9 Hz,
1 H), 3.94 (ddd, J ) 3.6, 7.1, 9.2 Hz, 1 H), 3.17 (dd, J ) 4.5,
13.6 Hz, 1 H), 3.05 (dddd, J ) 4.5, 7.0, 8.8, 9.4 Hz, 1 H), 2.82
(dd, J ) 8.8, 13.6), 2.27 (ddd, J ) 5.2, 9.4, 13.6 Hz, 1 H), 2.16
(ddd, J ) 7.0, 7.9, 13.6 Hz, 1 H), 1.96 (ddq, J ) 3.6, 7.3, 14.6
Hz, 1 H), 1.73 (ddq, J ) 7.3, 9.2, 14.6 Hz, 1 H), 1.04 (t, J ) 7.3
Hz, 3 H); 13C NMR (75 MHz) δ 177.8, 137.8, 128.9, 128.7, 126.9,
79.3, 59.3, 41.0, 36.8, 30.7, 27.8, 11.5; IR (CDCl3) ν 2970, 1774,
1454, 1171, 1020 cm-1; mass spectrum (CI) m/z 297.0493
(C14H17O2Br + H requires 297.0490), 217, 199, 171, 148.
(1′S,3R,5S)-5-(1′-Azid op r op yl)-3-ben zyld ih yd r ofu r a n -
2-on e. A suspension of sodium azide (114 mg, 1.75 mmol) and
40 (260 mg, 0.87 mmol) in DMF (3 mL) was heated at 50 °C
overnight. The mixture was cooled to room temperature and
partitioned between H2O (8 mL) and a mixture (1:1) of EtOAc/
hexanes (16 mL). The layers were separated, and the organic
phase was dried (MgSO4) and concentrated under reduced
pressure. The residue was purified via flash chromatography
eluting with EtOAc/hexanes (1:10) to give 159 mg (70%) of the
desired azide as a light yellow oil that was contaminated with
about 5% of an inseparable and unidentified isomer: 1H NMR
(300 MHz) δ 7.35-7.19 (comp, 5 H), 4.28 (ddd, J ) 3.9, 5.1,
9.0 Hz, 1 H), 3.22-3.15 (comp, 2 H), 3.09 (ddd, J ) 4.7, 8.0,
9.0 Hz), 2.79 (dd, J ) 9.0, 13.6 Hz, 1 H), 2.10 (ddq, J ) 5.0,
9.0, 14.5 Hz, 1 H), 1.68 (ddq, J ) 7.4, 7.4, 14.5 Hz, 1 H), 1.02
(t, J ) 7.4 Hz, 3 H); 13C NMR (75 MHz) δ 177.9, 137.9, 128.9,
128.8, 128.7, 126.9, 126.8, 78.4, 76.6, 66.4, 65.8, 40.7, 36.9, 29.9,
N-Boc-L-d im et h ylt h ia zolid in e-L-et h ylglycin e-L-p h en -
yla la n in e-L-m et h ion in e Met h yl E st er (37). N-Boc-phen-
ylalaninemethionine methyl ester (42 mg, 0.10 mmol) was
dissolved in 4 N HCl in dioxane (0.8 mL), and the solution
was heated for about 5 min. The solvent was removed under
reduced pressure, and the oily residue was dissolved in DMF
(500 µL). Et3N (14 µL, 0.10 mmol) was added, and the solution
cooled to about -5 to -10 °C in an ice-salt bath. The acid
from the preceding experiment (33 mg, 0.10 mmol), HOBt (44
mg, 0.33 mmol), and EDC (24 mg, 0.12 mmol) were then added
sequentially, and the resulting mixture was stirred overnight
at room temperature. The reaction was then partitioned
between EtOAc (2 mL), brine (1 mL), and saturated citric acid
(1 mL), and the layers were separated. The organic phase was
washed with saturated NaHCO3 (1 mL) and brine (1 mL), dried
(MgSO4), and concentrated. The residue was purified via flash
chromatography eluting with EtOAc/hexanes (1:1) to afford
41 mg (67%) of 37 as a white solid: mp 133-136 °C; 1H NMR
(500 MHz, DMSO-d6; 85 °C) δ 8.03 (d, J ) 7.5 Hz, 1 H), 7.83
(d, J ) 8.1 Hz, 1 H), 7.39 (d, J ) 7.6 Hz, 1 H), 7.24-7.15 (comp,
5 H), 4.66 (dd, J ) 3.1, 7.1 Hz, 1 H), 4.62-4.58 (m, 1 H), 4.44-
4.40 (m, 1 H), 4.24-4.20 (m, 1 H), 3.63 (s, 3 H), 3.28 (dd, J )
7.1, 12.1 Hz, 1 H), 3.04 (dd, J ) 5.5, 14.1 Hz, 1 H), 2.93 (dd, J
) 3.1, 12.1 Hz, 1 H), 2.86 (dd, J ) 8.4, 14.1 Hz, 1 H), 2.50-
2.43 (m, 2 H), 2.04 (s, 3 H), 2.02-1.95 (m, 1 H), 1.89 (ddq, J )
5.7, 8.4, 14.2 Hz, 1 H), 1.79 (s, 3 H), 1.73 (s, 3 H), 1.71-1.67
(m, 1 H), 1.58-1.53 (m, 1 H), 1.35 (s, 9 H), 0.81 (t, J ) 7.4 Hz,
3 H); 13C NMR (125 MHz, DMSO-d6, 85 °C) δ 171.1, 170.4,
169.3, 169.3, 151.3, 128.6, 127.5, 125.7, 79.4, 70.4, 66.1, 53.3,
53.2, 53.1, 51.2, 50.7, 50.6, 37.0, 30.6, 30.5, 30.0, 29.2, 28.8,
27.6, 27.5, 25.0, 14.2, 8.9; IR (CDCl3) ν 3319, 3284, 2974, 2932,
1746, 1704, 1641, 1538, 1353, 1173 cm-1; mass spectrum (CI)
m/z 639.2868 (C30H46N4O7S2 + H requires 639.2886), 591, 539
(base), 476, 420, 376, 311, 272, 229, 201.
23.5, 10.5; IR (CDCl3) ν 2968, 2931, 2105, 1775, 1152 cm-1
;
tr a n s-(1′S,2S,2′S)-2-Ben zylh ep t -4-en oic Acid (2′-H y-
d r oxy-1′-m eth yl-2′-p h en yleth yl)m eth yl Am id e (39). A so-
lution of 2.46 M n-BuLi (1.9 mL, 4.7 mmol) in hexane was
added to a solution diisopropylamine (0.7 mL, 5.0 mmol) and
LiCl (664 mg, 15.7 mmol) in THF (26 mL) at -78 °C. The
reaction was stirred at -78 °C for 30 min, warmed to 0 °C for
5 min, and re-cooled to -78 °C. An ice-cooled solution of 38
(665 mg, 2.24 mmol) in THF was added via a cannula over 3
min. The reaction was stirred for 1 h at -78 °C, warmed to 0
°C for 15 min, to room temperature for 5 min, and re-cooled
mass spectrum (CI) m/z 260.1398 (C14H17N3O2 + H requires
260.1399), 232, 177, 131.
(1′S,3R,5S)-[1-[4′-Ben zyl-5-oxotetr a h yd r ofu r a n -2′-yl]-1-
[8′S -(t er t -b u t y lo x y c a r b o n y l)d im e t h y lt h ia zo lid in e ]-
eth yl]ca r boxa m id e (41). A suspension of the azide (58 mg,
0.22 mmol) from the previous reaction and 10% Pd/C in dry
MeOH (1.2 mL) was stirred under an atmosphere of H2 (1 atm)
for 4 h, whereupon the catalyst was removed by filtration
through a plug of Celite. The filtrate was concentrated under
reduced pressure, and the resultant crude amine was dissolved

1670 J . Org. Chem., Vol. 66, No. 5, 2001
Hillier et al.
in THF (1.1 mL). Diisopropylethylamine (38 µL, 0.22 mmol)
and BocDMTOPfp (90 mg, 0.22 mmol) were added, and the
reaction was stirred overnight at room temperature. The
solvent was removed under reduced pressure, and the crude
oily product was purified via flash chromatography eluting
with EtOAc/hexanes (1:1) to give 85 mg (81%) of pure 41 as a
white foam: 1H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.30-7.19
(comp, 6 H), 4.74 (dd, J ) 2.9, 7.0 Hz, 1 H), 4.43 (ddd, J ) 3.6,
5.3, 8.3 Hz, 1 H), 3.81 (ddd, J ) 3.6, 5.0, 9.1), 3.30 (dd, J )
7.0, 12.1 Hz, 1 H), 3.01 (dd, J ) 5.0, 13.8 Hz, 1 H), 2.91 (dddd,
J ) 5.0, 7.4, 9.2, 9.7 Hz, 1 H), 2.88 (dd, J ) 2.9, 12.1 Hz, 1 H),
2.73 (dd, J ) 9.2, 13.8 Hz, 1 H), 2.04 (ddd, J ) 5.3, 9.7, 13.2
Hz, 1 H), 1.98 (ddd, J ) 7.4, 8.3, 13.2 Hz, 1 H), 1.76 (s, 3 H),
1.73 (s, 3 H), 1.56 (ddd, J ) 5.0, 7.4, 13.8 Hz, 1 H), 1.45 (ddd,
J ) 7.4, 9.1, 13.8 Hz, 1 H), 1.38 (s, 9 H), 0.88 (t, J ) 7.4 Hz,
3 H); 13C NMR (125 MHz, DMSO-d6, 85 °C) δ 177.4, 170.1,
151.5, 138.1, 128.3, 127.8, 125.9, 79.3, 78.6, 70.3, 66.1, 52.8,
35.7, 30.5, 29.2, 28.7, 27.7, 27.6, 23.7, 9.8; IR (CDCl3) ν 3310,
2972, 2933, 1770, 1662, 1345, 1166 cm-1; mass spectrum (CI)
m/z 476.2333 (C25H36N2O5S requires 476.2345), 449, 421, 405,
377.
Hz, 1 H), 7.26-7.15 (comp, 5 H), 6.69 (d, J ) 8.9 Hz, 1 H),
4.70 (dd, J ) 2.6, 7.0 Hz, 1 H), 4.36 (ddd, J ) 5.5, 9.1, 9.1 Hz,
1 H), 3.68 (ddd, J ) 2.0, 5.0, 7.2, 9.0 Hz, 1 H), 3.63 (ddd, J )
2.0 Hz, 6.0, 6.0 Hz, 1 H), 3.60 (s, 3 H), 3.31 (dd, J ) 7.1, 12.1
Hz, 1 H), 3.07 (dd, J ) 2.6, 12.1 Hz), 2.93 (dd, J ) 6.8, 13.8
Hz, 1 H), 2.71 (dddd, J ) 6.8, 6.8, 7.4, 8.0 Hz, 1 H), 2.58 (dd,
J ) 7.4, 13.8 Hz, 1 H), 2.48 (m, 1 H), 2.04 (s, 3 H), 2.00-1.85
(m, 2 H), 1.81 (dddd, J ) 5.8, 8.0, 13.8 Hz), 1.78 (s, 3 H), 1.74
(s, 3 H), 1.46-1.29 (comp, 3 H), 1.40 (s, 9 H), 0.85 (s, 9 H),
0.85 (t, J ) 7.4 Hz, 3 H), 0.03 (s, 3 H), 0.03 (s, 3 H); 13C NMR
(125 MHz, DMSO-d6, 85 °C) δ 173.6, 171.5, 169.6, 151.6, 139.1,
128.3, 127.5, 125.4, 79.6, 71.3, 70.4, 66.4, 53.8, 51.1, 50.8, 43.4,
38.1, 35.0, 30.5, 30.3, 29.4, 28.7, 28.0, 27.6, 25.4, 23.2, 17.2,
14.1, 10.2, -4.9, -5.1; IR (CDCl3) ν 3421, 3316, 2929, 2853,
1743, 1657, 1518, 1340, 1166 cm-1; mass spectrum (CI) m/z
754.3948 (C37H63N3O7SiS2 + H requires 754.3955), 698, 654,
452, 225.
L-Cyst ein e-L-et h ylglycin e-L-p h en yla la n in e-L-m et h io-
n in eca r boxylic Acid Tr iflu or oa ceta te Sa lt (6). To a solu-
tion of 24 (56 mg, 0.088 mmol) in MeOH (2.5 mL) and THF
(1.3 mL) was added 1 M LiOH (110 µL, 0.110 mmol), and the
mixture was stirred for 18 h at room temperature. The solvent
was removed, and the crude product was dissolved in H2O (1.0
mL). The solution was acidified with 1 N HCl (110 µL) and
extracted with EtOAc (3 × 1 mL). The combined EtOAc layers
were dried (MgSO4) and concentrated to give 45 mg (82%) of
crude N-Boc acid that was dissolved in CF3CO2H/CH2Cl2
(4:1.3 mL), and the solution was stirred for 2 h under argon.
The solvent was removed, and the crude acetonide was
triturated with Et2O/pentane (1:1, 2 × 1 mL). The solid residue
was dissolved in a mixture of MeOH/H2O (67 mL; 67 mL), and
the solvents were removed under reduced pressure (bath
temperature 50 °C). This process was repeated twice to
complete the hydrolysis of the N-terminal N,S-acetal, and the
crude product was purified by reverse phase chromatography
[HPLC tR 6min (25% CH3CN/74.9% H2O/0.1% CF3CO2H)] to
(2R,4S,5R)-5-[L-(ter t-Bu tyloxyca r bon yl)d im eth ylth ia -
zolid in eca r boxa m id e]-4-[(ter t-bu tyld im eth ysilyl)oxy-2-
(p h en ylm eth yl)]h ep ta n oic Acid (42). The lactone 41 (343
mg, 0.72 mmol) was dissolved in a mixture (2:1) of dioxane/
H2O (6 mL), and 1 N NaOH (0.8 mL, 0.8 mmol) was added.
The reaction was stirred for 2 h at room temperature, and
solvent was concentrated to one-half its original volume under
reduced pressure. The resulting solution was acidified with 1
N NaHSO4 (10 mL), and the mixture was extracted with
EtOAc (3 × 5 mL). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure, and the
crude hydroxy acid was dissolved in DMF (5 mL) under argon.
Imidazole (466 mg, 6.84 mmol) and TBSCl (543 mg, 3.60 mmol)
were added, and the reaction was stirred overnight at room
temperature. MeOH (1 mL) was added, and the reaction was
stirred for an additional 1 h, whereupon the solvent was
removed under reduced pressure. The resulting solution was
poured into ice-cold H2O (50 mL), and the mixture acidified
to pH 3 by addition of 1 N NaHSO4 (30 mL). This mixture
was extracted with Et2O (3 × 50 mL), and the combined
organic extracts were dried (MgSO4) and concentrated. The
crude product was purified via flash chromatography eluting
with EtOAc/hexanes (1:1) to afford 321 mg (73%) of 42 as a
1
give 7 mg (17%) of 6 as an oil: H NMR (500 MHz, MeOD-d3)
δ 7.26-7.15 (comp, 5 H), 4.65 (dd, J ) 5.6, 8.4 Hz, 1 H), 4.53
(dd, J ) 4.5, 9.2 Hz, 1 H), 4.25 (dd, J ) 5.6, 8.4 Hz), 4.00 (t, J
) 5.8 Hz, 1 H), 3.15 (dd, J ) 5.6, 14.0 Hz, 1 H), 2.93 (dd, J )
8.6, 14.0 Hz, 1 H), 2.94 (d, J ) 5.9 Hz, 2 H), 2.54 (ddd, J )
5.2, 8.8, 13.6 Hz, 1 H), 2.47 (ddd, J ) 7.3, 8.5, 13.6 Hz, 1 H),
2.16-2.09 (m, 1 H), 2.07 (s, 3 H), 1.98-1.90 (m, 1 H), 1.78
(ddq, J ) 5.7, 7.4, 13.4 Hz, 1 H), 1.63 (ddq, J ) 7.4, 8.4, 13.8
Hz, 1 H), 0.92 (t, J ) 7.4 Hz, 3 H); 13C NMR (125 MHz, MeOD-
d3) δ 174.6, 173.4, 173.3, 168.3, 138.2, 130.4, 129.4, 127.8, 56.5,
56.4, 55.8, 52.6, 38.8, 32.3, 31.1, 26.6, 26.5, 15.2, 10.7; mass
spectrum (FAB) m/z 485.1895 (C21H32N4O5S2 requires 485.1892),
460, 307, 289, 220, 205.
[1R,2R,3S,2(1′R,2′S)]-2-[2′-(Am in o-L-cystein e)-1′-h ydr oxy-
butyl]-3-phenylcyclopropyl-1-carboxyl-L-methioninecarbox-
ylic Acid Tr iflu or oa ceta te Sa lt (7). Prepared as an oil in
61% yield from 24 according to the procedure described for 6
[HPLC tR 5 min (40% MeOH/59.9% H2O/0.1% CF3CO2H)]: 1H
NMR (500 MHz, MeOD-d3) δ 7.35-7.14 (comp, 5 H), 4.59 (dd,
J ) 4.6, 9.0 Hz, 1 H), 3.96 (dd, J ) 5.1, 6.1 Hz, 1 H), 3.78 (dt,
J ) 4.2, 9.8 Hz, 1 H), 3.16 (dd, J ) 3.8, 8.8 Hz, 1 H), 2.92 (dd,
J ) 5.1, 6.1 Hz, 2 H), 2.70 (dd, J ) 5.1, 9.3 Hz, 1 H), 2.67-
2.55 (m, 2 H), 2.50 (app t, J ) 5.1 Hz, 1 H), 2.19-2.12 (m, 1
H), 2.10 (s, 3 H), 2.08-1.96 (m, 1 H), 1.87 (app t, J ) 5.1, 9.3
Hz, 1 H), 1.43-1.30 (m, 2 H), 0.78 (t, J ) 7.4 Hz, 3 H); 13C
NMR (125 MHz, MeOD-d3) δ 175.2, 174.9, 168.2, 137.6, 129.6,
129.5, 127.7, 58.3, 57.4, 55.9, 53.1, 53.0, 52.6, 32.4, 31.7, 31.2,
26.9, 25.6, 23.4, 15.2, 11.1; mass spectrum (FAB) m/z 484.1952
(C22H34N3O5S2 requires 484.1940), 460, 443, 409, 391, 363, 329,
307.
1
clear oil: H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.27 (comp,
5 H), 6.82 (d, J ) 9.0 Hz, 1 H), 4.69 (dd, J ) 3.2, 7.1 Hz, 1 H),
3.75 (ddd, J ) 2.5, 4.7, H), 3.67 (dddd, J ) 2.5, 4.6, 7.3, 9.0
Hz, 1 H), 3.29 (dd, J ) 7.1, 12.1 Hz, 1 H), 3.01-2.98 (m, 1 H),
2.88 (dd, J ) 9.8, 15.9 Hz, 1 H), 2.72-2.67 (comp, 2 H), 1.81-
1.78 (m, 1 H), 1.51 (ddd, J ) 4.6, 7.4, 13.7 Hz, 1 H), 1.47-1.42
(m, 1 H), 1.40 (s, 9 H), 1.30 (ddd, J ) 7.4, 7.4, 13.7 Hz, 1 H),
0.86 (s, 9 H), 0.85 (t, J ) 7.4 Hz, 3 H), 0.06 (s, 3 H), 0.04 (s, 3
H); 13C NMR (125 MHz, DMSO-d6, 85 °C) δ 175.2, 169.6, 151.5,
138.8, 128.2, 127.6, 125.6, 79.5, 70.8, 70.5, 66.2, 53.9, 42.8,
37.l9, 34.6, 32.8, 30.4, 28.7, 28.0, 27.6, 25.4, 22.3, 17.2, 10.3,
-5.0, -5.1; IR (CDCl3) ν 2931, 1709, 1342, 1254, 1167, 1065
cm-1; mass spectrum (FAB) m/z 609.3400 (C31H50N2O6SiS +
H requires 609.3394), 553, 509 (base), 491, 451, 377.
(2R,4S,5R)-1-(L-Meth ion in e m eth yl ester )-5-[L-(ter t-bu -
t yloxyca r b on yl)d im et h ylt h ia zolid in eca r b oxa m id e]-4-
[(ter t-b u t yld im et h ysilyl)oxy-2-(p h en ylm et h yl)]h ep t a n -
a m id e (43). A solution of the acid 42 (93 mg, 0.15 mmol), the
hydrochloride salt of methionine methyl ester (32 mg, 0.16
mmol), and HOBt (22 mg, 0.16 mmol) in a mixture (10:1) of
CH2Cl2/DMF (550 µL) was cooled to 0 °C, and Et3N (22 µL,
0.16 mmol) was added. After 5 min, DCC (33 mg, 0.16 mmol)
was added, and the reaction was stirred overnight at room
temperature. The precipitated solids were removed by filtra-
tion, and the filtrate was concentrated under reduced pressure.
The residue was dissolved in EtOAc and cooled to 0 °C. The
precipitated solids were again removed again by filtration, and
the filtrate was concentrated under reduced pressure. The
crude product was purified via flash chromatography eluting
with EtOAc/hexanes (1:4) to give 94 mg (82%) of 43 as a white
foam: 1H NMR (500 MHz, DMSO-d6, 85 °C) δ 7.78 (d, J ) 7.5
[1R,2S,3S,2(1′S,2′S)]-2-[2′-(Am in o-L-cystein e)-1′-h ydr oxy-
b u t y l]-3-p h e n y lc y c lo p r o p a n e -1-c a r b o x y l-L -m e t h io -
n in eca r boxylic Acid Tr iflu or oa ceta te Sa lt (8). Prepared
as an oil in 40% yield from 35a according to the procedure
described for 6, except that acetonitrile was substituted for
methanol for hydrolysis of the N,S-acetal and for purification
of the product by reversed-phase chromatography [HPLC tR 6
1
min (45% MeCN/54.9% H2O/0.1% CF3CO2H)]: H NMR (500
MHz, MeOD-d3) δ 7.29-7.12 (comp, 5 H), 4.57 (dd, J ) 4.7,

Cyclopropane-Derived Peptidomimetics
J . Org. Chem., Vol. 66, No. 5, 2001 1671
9.0 Hz, 1 H), 3.98 (dd, J ) 4.9, 6.7 Hz, 1 H), 3.94-3.88 (comp,
2 H), 2.90 (dd, J ) 4.9, 14.8 Hz, 1 H), 2.80 (dd, J ) 6.7, 14.7
Hz, 1 H), 2.65-2.54 (comp, 3 H), 2.19 (dd, J ) 5.1, 9.0 Hz, 1
H), 2.19-2.12 (m, 1 H), 2.09 (s, 3 H), 2.02-1.95 (m, 1 H), 1.76
(app t, J ) 6.5, 9.0 Hz, 1 H), 1.69 (ddd, J ) 5.1, 7.4, 13.8 Hz,
1 H), 1.51 (ddd, J ) 7.4, 8.9, 13.8 Hz, 1 H), 0.93 (t, J ) 7.4 Hz,
3 H); 13C NMR (125 MHz, MeOD-d3) δ 175.3, 173.1, 168.2,
141.0, 129.6, 127.5, 127.4, 70.9, 57.9, 56.0, 53.1, 35.4, 32.4, 31.2,
30.1, 30.0, 26.7, 25.8, 23.8, 15.2, 10.9; mass spectrum (FAB)
m/z 484.1937 (C22H34N3O5S2 requires 484.1940), 466, 460, 381,
307, 289, 266.
7.8, 13.0 Hz, 1 H), 2.53-2.39 (m, 2 H), 2.14-2.07 (m, 1 H),
2.06 (s, 3 H), 1.98-1.92 (m, 1 H), 1.73-1.40 (comp, 5 H), 0.90
(t, J ) 7.4 Hz, 3 H); 13C NMR (125 MHz, MeOD-d3) δ 177.9,
174.9, 168.5, 140.6, 130.2, 129.5, 127.4, 70.9, 57.6, 56.2, 52.7,
46.2, 40.4, 36.8, 31.9, 31.3, 27.0, 25.0, 15.1, 11.1; mass
spectrum (FAB) m/z (disulfide dimer) 969.3948 (C44H68N6O10S4
+ H requires 969.3958), 820, 671, 468. 434, 337, 285, 234, 216
(base).
Biologica l Assa ys. Compounds 6-10 were evaluated as
inhibitors of purified recombinant human farnesyl transferase
using an assay similar to a previously described protocol that
had been modified to incorporate scintillation proximity assay
(SPA) techniques with streptavidin-coated SPA beads.38 Briefly,
to an assay buffer containing the appropriate test compound,
25 nM biotinylated Tri-b Ala fragment (171-188) of Ki-Ras,
and 55 nM tritiated farnesyl pyrophosphate was added purified
recombinant human farnesyl transferase (final concentration
45 pg/well). The reaction was allowed to proceed for 30 min at
room temperature and transferred to a streptavidin coated 96-
well plate. The plate was washed, and the residual radioactiv-
ity was quantified. The IC50 determinations were determined
using regression analysis by measuring inhibition of farnesy-
lation from 8-point serial dilution of test compounds over a
1000-fold concentration range.
[1R,2S,3R,2(1′S,2′S)]-2-[2′-(Am in o-L-cystein e)-1′-h ydr oxy-
b u t y l]-3-p h e n y lc y c lo p r o p a n e -1-c a r b o x y l-L -m e t h io -
n in eca r boxylic Acid Tr iflu or oa ceta te Sa lt (9). Prepared
as a viscous oil in 11% yield from 35b according to the
procedure described for 6, except that acetonitrile was substi-
tuted for methanol for hydrolysis of the N,S-acetal and for
purification of the product by reversed-phase chromatography
1
[HPLC tR 6 min (45% MeCN/54.9% H2O/0.1% CF3CO2H)]: H
NMR (500 MHz, MeOD-d3) δ 7.36-7.15 (comp, 5 H), 4.59 (dd,
J ) 4.7, 9.2 Hz, 1 H), 4.08 (dd, J ) 4.8, 6.7 Hz, 1 H), 3.98-
3.95 (m, 1 H), 3.80 (dd, J ) 2.2, 10.2 Hz, 1 H), 3.10 (dd, J )
4.8, 14.8 Hz, 1 H), 3.01 (dd, J ) 6.7, 14.8 Hz, 1 H), 2.66 (dd, J
) 9.4, 9.6 Hz, 1 H), 2.64-2.51 (m, 2 H), 2.23 (dd, J ) 8.4, 9.4
Hz, 1 H), 2.21-2.12 (m, 1 H), 2.08 (s, 3 H), 2.03-1.97 (m, 1
H), 1.73 (ddd, J ) 2.2, 8.4, 9.6 Hz, 1 H), 1.52-1.37 (m, 2 H),
0.69 (t, J ) 7.4 Hz, 3 H); 13C NMR (125 MHz, MeOD-d3) δ
175.0, 173.5, 168.5, 136.5, 131.1, 129.9, 129.1, 127.5, 68.9, 56.7,
56.1, 52.9, 32.1, 31.3, 29.1, 28.6, 26.7, 26.2, 25.1, 15.2, 10.9;
mass spectrum (FAB) m/z 485.2031 (C22H34N3O5S2 + H
requires 485.2018), 466, 366, 278, 207.
Ack n ow led gm en t. We wish to thank the National
Institutes of Health and the Robert A. Welch Founda-
tion for their generous support of this work. We thank
Dr. Vincent Lynch (Department of Chemistry and
Biochemistry, The University of Texas) for performing
the X-ray analyses of 29a and 44. We are also grateful
to Drs. Christopher Burns and Richard Harrison and
Ms. Sarah E. Malmstrom (Rhoˆne-Poulenc Rorer, Col-
legeville, PA 19426) for performing the enzyme assays.
(2R,4S,5R)-1-(L-Meth ion in e)-5-[L-(ter t-bu tyloxyca r bo-
n yl)d im et h ylt h ia zolid in eca r b oxa m id e]-4-[(ter t-b u t yl-
d im eth ysilyl)oxy-2-(p h en ylm eth yl)h ep ta n a m id e Tr iflu o-
r oa ceta te Sa lt (10). Prepared from 43 in 57% yield as an oil
using the procedure described for preparing 6, except that
acetonitrile was substituted for methanol for hydrolysis of the
N,S-acetal and for purification of the product by reverse phase
chromatography [HPLC tR 10 min (30% MeCN/69.9% H2O/
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of all new compounds and experimental procedures
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.
1
0.1% CF3CO2H)]: H NMR (500 MHz, MeOD-d3) δ 7.27-7.15
(comp, 5 H), 4.45 (dd, J ) 4.7, 9.4 Hz, 1 H), 3.93 (dd, J ) 4.6,
7.4 Hz, 1 H), 3.68 (ddd, J ) 2.9, 4.9, 9.2 Hz, 1 H), 3.54 (dt, J
) 2.6, 10.6 Hz, 1 H), 2.98 (dd, J ) 6.8, 13.0 Hz, 1 H), 2.94-
2.87 (m, 2 H), 2.80 (dd, J ) 7.5, 14.7 Hz, 1 H), 2.63 (dd, J )
J O001257I