Synthesis of sulfur-containing olefinic peptide mimetic farnesyl transferase inhibitors using the Nozaki-Hiyama-Kishi reaction and cuprate S(N)2' displacements

Article abstract of DOI:10.1021/jo981892c

Syntheses of the potent sulfur-containing tetrapeptide mimetic farnesyl transferase inhibitors B956 (22) and B957 (23) are described. The two double bonds in 22 and 23 were constructed by application of iterative NHK and cuprate S(N)2' reactions. Normal syn NHK reaction and substrate-dependent syn and anti-S(N)2' diastereoselectivities accompanied by exclusive E-olefin selectivity were observed for the first NHK iteration (1 → 4). In the second iteration, unexpected epimerization and a strong preference for syn diastereoselectivity was observed for the NHK reaction (5b → 7a + 9a) while an unusual Z-olefin was observed for the S(N)2' reaction (7b → 11). Deprotection conditions were optimized to ensure high purity and yield of the final aminothiol compounds.

Full text of DOI:10.1021/jo981892c

242
J . Org. Chem. 1999, 64, 242-251
Syn th esis of Su lfu r -Con ta in in g Olefin ic P ep tid e Mim etic F a r n esyl
Tr a n sfer a se In h ibitor s Usin g th e Noza k i-Hiya m a -Kish i Rea ction
a n d Cu p r a te SN2′ Disp la cem en ts
Hu Yang,† Xiaoning C. Sheng,† Edmund M. Harrington,† Karen Ackermann,‡
Ana Maria Garcia,‡ and Michael D. Lewis*,†
Eisai Research Institute, 4 Corporate Drive, Andover, Massachusetts 01810
Received September 17, 1998
Syntheses of the potent sulfur-containing tetrapeptide mimetic farnesyl transferase inhibitors B956
(22) and B957 (23) are described. The two double bonds in 22 and 23 were constructed by application
of iterative NHK and cuprate SN2′ reactions. Normal syn NHK reaction and substrate-dependent
syn and anti-SN2′ diastereoselectivities accompanied by exclusive E-olefin selectivity were observed
for the first NHK iteration (1 f 4). In the second iteration, unexpected epimerization and a strong
preference for syn diastereoselectivity was observed for the NHK reaction (5b f 7a + 9a ) while an
unusual Z-olefin was observed for the SN2′ reaction (7b f 11). Deprotection conditions were
optimized to ensure high purity and yield of the final aminothiol compounds.
In tr od u ction
Interest in targeting FT inhibition lead us to consider
developing peptidomimetics based upon CAAX tetrapep-
tides. We and others have hypothesized that the nature
of the two interior residues of the CAAX peptides,
typically bulky hydrophobic residues, served to confer a
bent or turn configuration to the inhibitors.8,9 Isosteric
replacement of the interior peptide bonds with olefins
might serve to increase the hydrophobic nature of the
Farnesyl transferase (FT) covalently attaches the
farnesyl group of farnesyl pyrophosphate (FPP) to a
cysteine thiol of its protein substrate.1,2 FT is one of three
known isoprenyl-protein transfer enzymes; the remaining
two, geranylgeranyl transferases I and II (GGT-I, GGT-
II), transfer a geranylgeranyl group to their respective
substrates.3 FT and GGT-I share consensus recognition
elements in their respective target proteins: the putative
C-terminal CA1A2X box sequence. Interest in these
enzymes has arisen out of the unique nature of the lipid
modifications they mediate and the importance of their
protein substrates in critical cellular processes such as
growth regulation, signaling, and intracellular transport.
One substrate in particular, the small G protein ras,4 has
generated an enormous amount of interest in FT. Inhibi-
tion of oncogenic ras function through inhibition of ras
posttranslational farnesylation offers the potential for a
novel, rational mechanistic approach to anticancer therapy.
Many groups have reported on the successful in vitro and
in vivo inhibition of ras farnesylation with CAAX-derived
peptides1,5 and peptidomimetics.6 At least two agents
have been reported to be under clinical study.7
(5) (a) Leftheris, K.; Kline, T.; Natarajan, S.; DeVirgilio, M. K.; Cho,
Y. H.; Pluscec, J .; Ricca, C.; Robinson, S.; Seizinger, B. R.; Manne, V.;
Meyers, C. A. Bioorg., Med. Chem. Lett. 1994, 4, 887. (b) Clerc, F. F.;
Guitton, J . D.; Fromage, N.; Lelievre, Y.; Duchesne, M.; Tocque, B.;
J amessurcouf, E.; Commercon, A.; Becquart, J . Ibid. 1995, 5, 1779.
(6) (a) Garcia, A. M.; Rowell, C.; Ackermann, K.; Kowalczyk, J . J .;
Lewis, M. D. J . Biol. Chem. 1993, 268, 18415. (b) Kohl, N. E.; Mosser,
S. D.; deSolms, S. J .; Giuliani, E. A.; Pompliano, D. L.; Graham, S. L.;
Smith, R. L.; Scolnick, E. M.; Oliff, A.; Gibbs, J . B. Science 1993, 260,
1934. (c) J ames, G. L.; Goldstein, J . L.; Brown, M. S.; Rawson, T. E.;
Somers, T.; McDowell, R. S.; Crowley, C. W.; Lucas, B. K.; Levinson,
A. D.; Marsters, J . C., J r. Science 1993, 260, 1937. (d) Nigam, M.;
Seong, C. M.; Qian, Y.; Hamilton, A. D.; Sebti, S. M. J . Biol. Chem.
1993, 268, 20695. (e) Cox, A. D.; Garcia, A. M.; Westwick, J . K.;
Kowalczyk, J , J .; Lewis, M. D.; Brenner, D. A.; Der, C. J . J . Biol. Chem.
1994, 269, 19203. (f) Harrington, E. M.; Kowalczyk, J . J .; Pinnow, S.
L.; Ackermann, K.; Garcia, A. M.; Lewis, M. D. Bioorg., Med. Chem.
Lett. 1994, 4, 2775. (g) 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. (h) Graham, S. L.; deSolms, S.; Guiliani, E. A.; Kohl, N. E.; Mosser,
S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Breslin, M. J .; Deana,
A. A.; Garksy, V. M.; Scholz, T. H.; Gibbs, J . B.; Smith, R. L. J . Med.
Chem. 1994, 37, 725. (i) Qian, Y.; Blaskovich, M. A.; Saleem, M.; Seong,
C. M.; Wathen, S. P.; Hamilton, A. W.; Sebti, S. M. J . Biol. Chem. 1994,
269, 12410. (j) Kowalczyk, J . J .; Ackermann, K.; Garcia, A. M.; Lewis,
M. D. Bioorg., Med. Chem. Lett. 1995, 5, 3073.
(7) (a) Liu M.; Lee, S.; Yaremko, B.; Chen, J .; Dell, J .; Nielsen, L.;
Lipari, P.; Ferrari, E.; Malkowski, M.; Bryant, M. S.; Njoroge, F. G.;
Taveras, A. G.; Doll, R. J .; Kirschmeieri, P.; Nemeir, A. A.; Kelly, J .;
Remiszewski, S.; Mallams, A. K.; Afonso, A., Hollinger, F. P.; Cooper,
A. B.; Liu Y.-T.; Rane, D.; Girijavallabhan, V.; Ganguly, A. K.; Bishop,
W. R. Proceedings of the American Association for Cancer Research
89th Annual Meeting, March 28-April 1, 1998, New Orleans, LA,
abstract no. 1848. (b) Zujewski, J .; Horak, I. D.; Woestenborghs, R.;
Chiao, J .; Cusack, G.; Kohler, D.; Kremer, A. B.; Cowan, K. H. Ibid.
Abstract no. 1848.
(8) See ref 6c, above, and Stradley S. J .; Rizo J .; Gierasch L. M.
Biochemistry 1993, 32, 12586.
(9) Conversely, evidence supporting the binding of tetrapeptides and
peptidomimetics in extended conformations has been reported: see refs
6i and (b) Dunten, P.; Kammlott, U.; Crowther, R.; Weber, D.; Palermo,
R.; Birktoft, J . Biochemistry 1998, 37, 7907.
† Department of Chemistry.
‡ Department of Biology.
(1) (a) Reiss, Y.; Goldstein, J . L.; Seabra, M. C.; Casey, P. J .; Brown,
M. S. Cell 1990, 62, 81. (b) Reiss, Y.; Stradley, S. J .; Gierasch, L. M.;
Brown, M. S.; Goldstein, J . L. Proc. Natl. Acad. Sci U.S.A. 1991, 88,
732. (c) Moores, S. L.; Schaber, M. D.; Mosser, S. D.; Rands, E.; O’Hara,
M. B.; Garsky, V. M.; Marshall, M. S.; Pompliano, D. L.; Gibbs, J . B.
J . Biol. Chem. 1991, 266, 14603. (d) Goldstein, J . L.; Brown, M. S.;
Stradley, S. J .; Reiss, Y.; Gierasch, L. Ibid. 1991, 266, 15575.
(2) (a) Manne, V.; Roberts, D.; Tobin, A.; O’Rourke, E.; De Virgilio,
M.; Meyers, C.; Ahmed, N.; Kurz, B.; Resh, M.; Kung, H.-F.; Barbacid,
M. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 7541. (b) Chen, W.-J .;
Moomaw, J . F.; Overton, L.; Kost, T. A.; Casey, P. J . J . Biol. Chem.
1993, 268, 9675.
(3) (a) Yoshida, Y.; Kawata, M.; Katayama, M.; Horiuchi, H.; Kita,
Y.; Takai, Y. Biochem. and Biophys. Res. Communun. 1991, 175, 720.
(b) Casey, P. J .; Thissen, J . A.; Moomaw, J . F. Proc. Natl. Acad. Sci.
U.S.A. 1991, 88, 8631. (c) Seabra, M. C.; Goldstein, J . L.; Su¨dhof, T.
C.; Brown, M. S. J . Biol. Chem. 1992, 267, 14497. (d) Moomaw, J . F.;
Casey, P. J . Ibid. 1992, 267, 17438.
(4) (a) Barbacid, M. Annu. Rev. Biochem. 1987, 56, 779. (b) Hancock,
J . F.; Magee, A. I.; Childs, J . E.; Marshall, C. J . Cell 1989, 57, 1167.
10.1021/jo981892c CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/10/1998

Farnesyl Transferase Inhibitors
J . Org. Chem., Vol. 64, No. 1, 1999 243
Sch em e 1a
inner portion of the molecule and further stabilize such
bent conformations. In addition, it was shown that
replacement of the proteolytically unstable N-terminal
amide bonds in tetrapeptide inhibitors was necessary to
demonstrate inhibition of FT function in whole cells.10
Substitution of the amide bonds with olefins would
represent an attractive means to achieve proteolytic
stability.11 While this approach is not novel, it has been
underutilized within the context of sulfur-containing
amino acids characteristic of the FT tetrapeptide inhibi-
tors. The presence of sulfur sharply limits the extent to
which oxidative conditions may be utilized to prepare
these materials and presented a challenge for the devel-
opment of inhibitors. Novel chemistry is required to
prepare such materials within this constraint.
The configuration of the asymmetric A2 R center in a
previously reported series of monosubstituted straight
chain alkyl carbon-linked tetrapeptide mimetics was
demonstrated to be important in determining the FT/
GGT-I specificity of the inhibitors.12 It was intriguing to
speculate that it might be possible to manipulate the
enzymatic specificity further in the stereochemically
defined environment of the proposed olefin-derived mi-
metics by adjusting the substitution and configuration
at the asymmetric R center of A2. Selectivity of FT over
GGT-I may be critical with respect to the toxicity of the
inhibitors and/or their ability to completely inhibit the
processing of specific forms of ras, which in the presence
of FT inhibitors may be alternatively processed through
GGT-I.13 Such manipulations might be accessible through
a general, well-characterized synthetic route for the
construction of olefinic peptide mimetics. With these
objectives in mind, we set out to investigate syntheses
of bis-olefin mimetics of the prototype FT tetrapeptide
inhibitor, CVFM.
a
(a) (2Z)-3-Iodoacrylate, CrCl2, Ni(COD)2, THF, rt, 65%; (b)
TBSOTf, CH2Cl2, TEA, 64%; (c) TBAF, HOAc, THF, quant; (d)
MsCl, TEA, CH2Cl2, 0 °C, 94%; (e) CuCN, i-PrMgCl, THF,
BF3OEt2, 0 °C; 2c or 3c, -78 °C, ∼90%; (f) DIBAL, hexanes, PhMe,
rt, 97%; (g) (COCl)2, DMSO, CH2Cl2, -60 °C; 5a or 5b; TEA; 91-
95%.
Resu lts a n d Discu ssion s
A general method for the construction of olefinic
peptide isosteres is the SN2′ reaction of organometallic
reagents RCu(CN)MgX‚BF3 with γ-(mesyloxy)-R,â-enoates
as reported by Ibuka, Fujii, and Yamamoto.14 The pre-
cursor alcoholic enoates are in turn derived from the
treatment of amino acid aldehydes with vinyl Grignard
reagents, followed by ozonolysis and reaction with (car-
bomethoxymethyl)triphenylphosphorane. Although this
sequence is tolerant of many functional groups, the
presence of sulfur in the proposed bis-olefinic CVFM
mimetics such as B957 (23) necessitated using a modified
approach.
lates react very well under these conditions to afford
γ-hydroxyenoate products.16 Reaction with aldehydes
derived from amino acids would permit the convenient
preparation of the Yamamoto SN2′ substrate precursors.
Thus, methyl (2Z)-3-iodoacrylate was reacted with
aldehyde 117 under modified NHK conditions to afford a
∼1:2.5 ratio of the desired adducts 2a and 3a in a
combined yield of 55-65% (Scheme 1). Although modest,
this product ratio is consistent with the nonchelating
preference usually observed under these conditions. The
configuration of 3a was confirmed by an NOE experiment
on a bicyclic derivative.18 It was not possible to repro-
The Nozaki-Hiyama-Kishi (NHK) reaction has been
shown to be a very tolerant method for the construction
of carbon-carbon bonds in the presence of reactive and
oxidatively sensitive functionality.15 Moreover, â-iodoacry-
(15) For recent work on the catalytic NHK reaction and general
leading references for this extremely versatile reaction see Fu¨rstner,
A.; Shi, N. J . Am. Chem. Soc. 1996, 118, 12349.
(16) Schreiber, S. L.; Meyers, H. V. J . Am. Chem. Soc. 1988, 110,
5198.
(17) Duthaler, R. O. Angew. Chem., Int. Ed. Engl. 1991, 30, 705.
(18) Silylated alcohol 3b was treated with (a) LAH, THF, 0 °C; (b)
NaH, MeI, THF; (c) TBAF, HOAc, THF; (d) NaH, DMF to afford the
following bicyclic compound 30 which exhibited an NOE between the
indicated protons.
(10) See ref 6a above.
(11) See for example (a) Wipf, P.; Fritch, P. C. J . Org. Chem. 1994,
59, 4875. (b) Wipf, P.; Henninger, T. C. Ibid. 1997, 62, 1586 and
references contained therein.
(12) See ref 6f above.
(13) (a) Rowell, C. A.; Kowalczyk, J . J .; Lewis, M. D.; Garcia, A. M.
J . Biol. Chem. 1997, 272, 14093. (b) Whyte, D. B.; Kirschmeier, P.;
Hockenberry, T. N.; Nunezoliva, I.; J ames, L.; Catino, J . J .; Bishop,
W. R.; Pai, J . K. ibid 1997, 272, 14459.
(14) (a) Ibuka, T.; Tanaka, M.; Nemoto, H.; Yamamoto, Y. Tetrahe-
dron 1989, 45, 435. (b) Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N.;
Oguchi, Y.; Uyehara, T.; Yamamoto, Y. J . Org. Chem. 1991, 56, 4370.
(c) Ibuka, T.; Taga, T.; Habashita, H.; Nakai, K.; Tamara, H.; Fujii,
N.; Chounan, Y.; Nemoto, H.; Yamamoto, Y. J . Org. Chem. 1993, 58,
1207.

244 J . Org. Chem., Vol. 64, No. 1, 1999
Yang et al.
Sch em e 2a
ducibly achieve chromatographic baseline separation of
alcohols 2a or 3a with any degree of efficiency. Conse-
quently, for the purpose of establishing the course of the
succeeding SN2′ reaction, alcohols 2a and 3a were
converted to their tert-butyldimethylsilyl ethers 2b and
3b, the diastereomers separated, and then individually
desilylated. Mesylation of alcohol 2a or 3a followed by
treatment with the reagent formed from the addition of
BF3OEt2 to a mixture of i-PrMgBr and CuCN afforded
an excellent yield of diastereomeric SN2′ products 4 in
approximate ratios of 4.4:1 and 1:2.4 syn:anti directions
of reagent attack, respectively. In both cases, proceeding
from either 2c or 3c, the configuration of the newly
transposed stereogenic center was predominantly (R).
This configuration was confirmed by later X-ray analyses
of two compounds derived from 4 (7a and 12, see below).
In routine practice it was convenient to forego the
silylation, carry forward a mixture of 2a and 3a , and to
separate the diastereomers after DIBAL reduction to the
corresponding allylic alcohols 5a and 5b. The observed
stereoselectivity is analogous to the SN2′ displacement
reported for the related serine-derived series and repre-
sents in the case of mesylate 2c, a substrate-dependent
shift of the normal direction of reagent attack from anti
to syn.14c This phenomenon is seen with substrates
possessing bulky substitution around the reacting olefin,
in this case represented by the N-BOC dimethylthiazo-
lidine ring which exerts its steric bulk in a manner
similar to its oxygen counterpart. DIBAL reduction of 4
followed by oxidation afforded access to either the
predominant (2R)-diastereomer 5b or its minor (2S)-
isomer 6b. Unfortunately it was not possible to directly
hydrolyze methyl ester 4 without decomposition, presum-
ably due to the steric hindrance of the R-isopropyl
substituent.
a
(a) (2Z)-3-Iodoacrylate, CrCl2, Ni(COD)2, THF, rt, 68-79%; (b)
Dess-Martin reagent, 4 Å mol sieves, t-BuOH; CH2Cl2; (c) NaBH4,
MeOH, 0 °C; (d) MsCl, TEA, CH2Cl2, 77-86%.
To establish the second olefin, aldehydes 5b and 6b
were separately and iteratively treated with (2Z)-3-
iodoacrylate under the same modified NHK reaction
conditions (Scheme 2). Interestingly, although the dia-
stereomeric product ratios appeared similar, ∼6:1 for
reaction with 5b and ∼4:1 for reaction with 6b, the
product composition indicated a differing course of reac-
tion for these two diastereomers. Aldehyde 6b reacts to
afford the expected major syn alcohol 9a and its minor
anti diastereomer 10a . However, NHK reaction of (2Z)-
3-iodoacrylate with aldehyde 5b predominantly afforded
the expected syn isomer 7a and the epimerized syn
diastereomer 9a . None of the expected anti diastereomer
8a could be detected by HPLC analysis of the crude
reaction product from 5b and no similar epimerized
product was detected in reactions using 6b. To confirm
these stereochemical assignments, an authentic sample
of diastereomer 8a was prepared by oxidation of 7a
followed by stereorandom reduction of the resulting
enone. Final confirmation of structure for 7a was ob-
tained by X-ray crystallographic analysis (Figure 1). It
is remarkable that the dimethylthiazolidine ring exerts
such a substantial influence across the E olefin on the
relative configuration of the isopropyl-bearing stereo-
center during the course of the NHK reaction.
F igu r e 1.
reaction while major isomer 11 possessed a Z-olefin, a
somewhat unusual SN2′ reaction product. Confirmation
of the configuration of the newly generated stereogenic
benzyl center was performed both by a short sequence
of chemical degradation and subsequent correlation with
known materials,19 and by X-ray crystallographic analy-
Syn adduct 7a was mesylated to provide 7b which was
subjected to SN2′ displacement with the reagent derived
from BnMgCl, CuCN, and BF3OEt2 (Scheme 3). As
expected, two products were obtained from this reaction
in a ratio of ∼2:1. Remarkably, minor isomer 14 was the
expected E-olefinic product arising from the anti SN2′
(19) Successive reaction of 11 with (a) LAH; b) NaH, BnBr; (c) O3,
MeOH; (d) NaBH4 afforded isolation of (S)-2-[(phenylmethoxy)methyl]-
3-benzenepropanol, [R]D ) -27° (c 0.25, CHCl3). Similar treatment of
15 afforded isolation of the (R) enantiomer, [R]D ) +24° (c 0.95, CHCl3).
(R)-2-[(Phenylmethoxy)methyl]-3-benzenepropanol has a reported opti-
cal rotation of +33.1° (c 1.32, CHCl3) by Aebi, J . D.; Sutter, M. A.;
Wasmuth, D.; Seebach, D. Liebigs Ann. Chem. 1983, 12, 2114.

Farnesyl Transferase Inhibitors
J . Org. Chem., Vol. 64, No. 1, 1999 245
Sch em e 3a
Sch em e 4a
a
(a) CuCN, BnMgCl, THF, -20 °C to rt; 7b, -78 °C, 89%; (b)
LiOH, H2O, dioxane, ∼85%.
a
(a) HCl‚H2NMetOMe, NMM, HOBt, 1-[3-(dimethylamino)Pro-
sis of 12. In contrast to the first SN2′ reaction, syn reagent
attack was not observed. Hydrolysis of methyl ester 11
afforded both the expected product 12 and small quanti-
ties of a material assigned the structure of the epimerized
product 13 in a ratio of 27:1. However, identical hydroly-
sis conditions applied to 14 yielded a 2:1 ratio of the
corresponding mixture of expected 15 and the proposed
epimerized 16. Interestingly, when the mesylate 9b was
subjected to the SN2′ displacement with the same benzyl
copper mixture, an even higher Z-olefin selectivity (g6.8:
1) was observed, affording a compound assigned the
structure of 17 by presumed exclusive anti attack of the
reagent (Scheme 5).
pyl]-3-ethylcarbodiimide Hydrochloride, DMF, 100%; (b) LiOH,
H2O, dioxane, 80%; (c) MeO2CSCl, NaOAc, HOAc, H2O, DMF, 97%;
(d) HCl, EtOAc, 0 °C, 71%; (e) Me3P, THF, H2O, TFA, 100%.
Sch em e 5a
a
(a) CuCN, BnMgCl, THF, -20 °C to rt, -78 °C, 83%.
The synthesis of B956 (22) was completed in a straight-
forward manner as depicted in Scheme 4. Although the
individual transformations for deprotection of the cys-
teine-like functionality are not novel, the precise se-
quence was critical to the preparation of final products
in high yields and in >95% purity. B957 (23) was
prepared uneventfully from 15 in an analogous manner
to B956 (15 f 24 f 25 f 26 f 27 f 23). For both
compounds, the deblock sequence was equally effective
if the hydrolysis step (Scheme 4, step b) was omitted,
permitting access to both B956 and B957 methyl esters
of high purity. The methyl esters are of biological utility
as prodrugs of B956 and B957 for cell-based and in vivo
experiments.
It is difficult to speculate on the basis for the formation
of the Z-olefin in 11 and 19. An examination of the solid-
state structure of 7a (Figure 1) reveals that the protons
attached to carbon atoms 3 and 4 are gauche aligned,
exhibiting a narrow dihedral angle of only 37.9°. Packing
forces might be the major factors responsible for this
orientation in the solid state. However, its appearance
in the solid state predicts that this bent conformation is
at least readily accessible, if not actually favored in the
solution phase.
Low-temperature NMR experiments, which freeze out
the higher order complexity introduced by the carbox-
amate rotamers, lend support to a similar conformation
being favored in solution. The value of J 3-4 as measured
1
from the H NMR spectrum of 7a at -60 °C is about 1
20
Hz while that of J 4-5 is 8.4 and 9.2 Hz for the two
rotamers. That compound 9a may prefer a similar
conformation is indicated by the similarity of its coupling
constants when obtained under similar conditions (J 3-4
) 2.9, 3.8 Hz and J 4-5 ) 10.3, 9.9 Hz, respectively, for
the two rotamers). In contrast to 7a and 9a , 8a and 10a
exhibit a different pattern of coupling constants: J 3-4
∼
J 4-5 ∼ 1 Hz for either rotamers of 8a , while J 3-4 ∼ 1 Hz
and J 4-5 ) 2.0 Hz for one rotamer of 10a , and J 3-4
J 4-5 ) 4.1 Hz for the other rotamer.
)
The unexpected stability of these bent conformations
potentially rationalize the origin of the surprising ap-
(20) The dihedral angle for H-C4-C5-H from the X-ray structure
of 7a is 182.8°.

246 J . Org. Chem., Vol. 64, No. 1, 1999
Yang et al.
indicated that starting material had been consumed. The
reaction mixture was removed from the drybox, quenched by
addition of 30 mL of satd NH4Cl and 30 mL of CHCl3, and
then stirred overnight. The aqueous layer was extracted 3 ×
CHCl3, and the combined organic layers were dried with
anhydrous Na2SO4, filtered, concentrated, and purified by FC
eluting with a stepwise gradient of 25% EtOAc:hexanes to 66%
EtOAc:hexanes. A mixture of butenoates 2a and 3a (652 mg,
65%) was obtained as an oily white solid.
pearances of the Z-olefinic products. Additionally, it is
also possible that this conformation is reinforced in the
SN2′ displacement transition state due to stabilization
of the incipient positive charge on the mesylate-bearing
carbon by electron donation from the ∆6,7 double bond.
Such electron donation would tend to reinforce the bent
configuration to bring the participating centers into the
closest possible proximity.
B956 and B957 were tested in an in vitro enzymatic
isoprenyl transferase assays. Both compounds were
potent inhibitors of FT (IC50’s of 27 and 19 nM, respect-
ively).6a,21 As predicted from the previous studies,12 B957
exhibited a marked 11-fold selectivity for FT over GGT I
while B956 was essentially nonselective. This difference
in enzyme specificity for two such similar structures has
already proven useful in elucidating alternative ras
processing pathways in cells.13a It is tempting to struc-
turally rationalize this selectivity on the basis of calcu-
lated binding interactions with the enzyme. However, the
active site of the available FT structure22 is distorted by
the presence of a bound oligopeptide from another
molecule of FT and the absence of the FPP cosubstrate.
Such calculations must await the release of coordinates
derived from more relevant FT structures,23 and ideally,
similar structures of GGT as well.
The present work confirms the accessibility of olefinic
peptide mimetics even when operating with synthetically
restrictive cysteine-containing peptide leads. Use of the
NHK reaction followed by the Yamamoto SN2′ displace-
ment should prove of widespread utility in the prepara-
tion of olefinic peptide mimetics of other biologically
interesting peptides. Such methodology widens the po-
tential use of olefinic isosteres and increases the pos-
sibility of their incorporation into pharmaceuticals of
importance.
Data for representative mixture of 2a and 3a : 1H NMR
(CDCl3) δ: 6.99 bd (J ) 14.0 Hz, â), 6.96 dd (J ) 5.6, 15.6 Hz,
R), 6.17 dd (J ) 1.7, 15.5 Hz, â), 6.13 dd (J ) 1.0, 15.4 Hz, R),
4.65 s (â), 4.61 t (J ) 6.6 Hz, R), 4.50 bs (â), 4.48 t (J ) 6.7 Hz,
R), 3.75 s (â), 3.74 s (R), 3.15 dd (J ) 6.2, 12.4 Hz), 2.91 d (J
) 12.3 Hz, â), 2.71 d (J ) 12.5 Hz, R), 1.76 s, 1.74 s, 1.44 s.
Separation of alcohols 2a and 3a was typically performed
as follows: 690 mg (2.08 mmol) of a mixture of 2a and 3a was
dissolved in 6 mL of CH2Cl2 at 0 °C and 548 µL (3.94 mmol) of
TEA and 574 µL (2.50 mmol) of TBSOTf were added. The
resulting solution was allowed to warm to rt and stirred for
20 min. The CH2Cl2 was removed by rotary evaporation and
the residue dissolved in EtOAc and washed successively with
satd NH4Cl, satd NaHCO3, and brine. Concentration followed
by FC, eluting with 1:10 EtOAc:hexanes, afforded 140 mg of
pure 2b, 130 mg of mixed fractions, and 321 mg of 3b for a
combined recovery of 64%. A typical desilylation was ac-
complished by stirring a solution of 84 mg of silyl ether 2b
(0.189 mmol), 11 µL HOAc (0.192 mmol), and 386 µL (0.386
mmol) of a 1 M solution of TBAF in THF in 2 mL of THF for
1 h. The THF was removed by rotary evaporation, and the
residue was dissolved in EtOAc and washed once with water.
The organic layer was dried over Na2SO4, filtered, evaporated,
and the crude oily residue was purified by FC, eluting with
20% EtOAc:hexanes to afford 45 mg 100% of the pure alcohol
diastereomer 2a .
Data for 2a : 1H NMR (CD3OD, -20 °C) δ: 7.01 dd (J )
6.1, 15.5 Hz, major rotamer), 6.97 dd (J ) 6.3, 15.3 Hz, minor
rotamer), 6.03 dd (J ) 1.6, 15.7 Hz, major), 5.93 dd (J ) 1.2,
15.7 Hz, minor rotamer), 4.45 m, 4.37 dd (J ) 5.1, 8.7 Hz,
minor), 4.27 dd (J ) 4.9, 9.2, major), 3.73 s (major), 3.68 s
(minor), 3.24 dd (J ) 5.3, 13.2 Hz), 3.21 dd (J ) 5.1, 12.2 Hz),
3.10 dd (J ) 11.8 Hz), 3.05 d (J ) 13 Hz, minor), 1.80 s (major),
1.78 s (minor), 1.76 s (major), 1.73 s (minor), 1.43 s (minor),
1.41 s (major); 13C NMR (CD3OD) δ: 168.6, 149.9, 149.8, 120.6,
82.1, 79.5, 71.4, 69.7, 52.1, 52.0, 28.73, 28.66, 27.6; IR (neat)
Exp er im en ta l Section
Gen er a l. Starting materials and solvents were purchased
from commercial sources and used without further purification
unless otherwise noted. Analytical normal phase HPLC was
conducted using 5 mm × 10 cm Waters Nova-Pak 6 µM silica
column eluting with a linear gradient of 100% hexane to 100%
ethyl acetate. Analytical reverse phase HPLC was conducted
using a 5 mm × 10 cm Waters Nova-Pak 6 µM HRC18 column
eluting with a linear gradient of 0-100% A to B over 30 min
(A: 0.15% TFA, 5% MeCN in H2O; B: 0.15% TFA in MeCN).
Preparative reverse phase HPLC was conducted using the
analytical reverse phase elution system and either one or two
40 mm × 10 cm Waters 6 µM HRC18 cartridges. All NMR
data was collected at either 400 or 500 MHz for proton and
100 or 125 MHz for carbon.
Meth yl (2E,4S)-4-Hyd r oxy-4-[(5R)-N-[(ter t-bu tyloxy)-
ca r bon yl]-2,2-d im eth yl-4-th ia zolid in yl]-2-bu ten oa te (2a )
a n d Its (4R)-Isom er (3a ). At rt, in an N2-filled drybox, 742
mg (3.03 mmol) aldehyde 1 was dissolved in 31 mL of THF,
followed by successive addition of 2.00 g (9.08 mmol) of (2Z)-
3-iodoacrylate,16 1.12 g (9.09 mmol) CrCl2, and 12.5 mg (0.045
mmol) Ni(COD)2. A slight exotherm developed and the reaction
mixture changed color from pale green to rusty brown after
the addition of the Ni(COD)2. The resulting mixture was
stirred for 2 d at which point TLC (25% EtOAc:hexanes)
ν cm-1: 3455, 1724, 1696, 1657; [R]20 ) -57.9 (c ) 0.00458,
D
CHCl3); LRMS (FAB+) m/z: 354, 276, 254, 232, 216; HRMS
calcd for C15H25NO5S [M + Na]+ 354.1351, found 354.1337.
Data for 3a : 1H NMR (CD3OD) δ: 7.18 dd (J ) 5.2, 15.6
Hz), 5.98 dd (J ) 2.0, 15.5 Hz), 4.72 bm, 4.47 bm, 3.73 s, 3.19
dd (J ) 6.7, 12.7 Hz), 2.92 d (J ) 13.0 Hz), 1.74 s, 1.73 s, 1.50
s; 13C NMR (CD3OD) δ: 168.5, 150.9, 121.6, 121.4, 82.2, 73.4,
72.7, 69.6, 69.0, 52.3, 52.2, 52.1, 52.0, 31.4, 30.5, 29.8, 28.7;
IR (neat) ν cm-1: 3444, 1726, 1696; [R]20D ) -25.5 (c ) 0.0168,
CHCl3); LRMS (FAB+) m/z: 354, 276, 232, 216; HRMS calcd
for C15H25NO5S [M + Na]+ 354.1351, found 354.1358.
Data for 2b: 1H NMR (CDCl3) δ: 7.14 dd (J ) 3.7, 15.1 Hz),
5.92 d (J ) 15.1 Hz), 4.86 br s, 4.39 br s, 3.73 s, 3.05 dd (J )
7.3, 11.4 Hz), 2.97 m, 1.68-1.71 m, 1.48 s, 0.89 s, 0.097 s, 0.042
s; 13C NMR (CDCl3) δ: 167.6, 149.9, 149.2, 120.0, 81.3, 73.5,
70.8, 69.4, 68.3, 52.19, 52.15, 52.10, 30.9, 29.2, 28.9, 27.0, 26.6,
26.4, 18.7, -3.4, -4.1; IR (neat) ν cm-1: 1727, 1687; [R]20
)
D
-121.0 (c ) 0.0834, CHCl3); LRMS (FAB+) m/z: 468, 346, 216;
HRMS calcd for C21H39NO5SSi [M + Na]+ 468.2216, found
468.2236.
Data for 3b: 1H NMR (CDCl3) δ: 6.77 br m, 5.71-5.79 br
m, 4.29-4.39 br m, 4.14 br m, 3.55 br m, 2.94 dd (J ) 5.5,
11.9 Hz), 1.83 br m, 1.57-1.63 br m, 1.27 s, 0.76 s; 13C NMR
(CDCl3) δ: 166.0, 152.8, 151.8, 148.9, 120.9, 120.5, 80.2, 72.7,
71.1, 69.6, 68.0, 67.3, 51.1, 51.0, 31.3, 30.4, 29.9, 29.0, 28.7,
28.4, 27.9, 25.5, 25.4, 22.317.7, 13.8, -4.33, -5.04; IR (neat),
(21) In vitro human tumor growth inhibition and in vivo human
tumor xenotransplant growth suppression has been previously reported
for B956: Nagasu, T.; Yoshimatsu, K.; Rowell, C.; Lewis, M. D.; Garcia,
A. M. Cancer Res. 1995, 55, 5310.
(22) Park, H.-W.; Boduluri, S. R.; Moomaw, J . F.; Casey, P. J .; Beese,
L. S Science 1997, 275, 1800.
ν cm-1: 1728, 1694; [R]20 ) -21.6 (c ) 0.108, CHCl3); LRMS
D
(FAB+) m/z: 468, 446, 346, 216; HRMS calcd for C21H39NO5SSi
[M + Na]+ 468.2216, found 468.2206.
(23) Long, S. B.; Casey, P. J .; Beese, L. S. Biochemistry 1998, 37,
9612 and ref 9b, above.

Farnesyl Transferase Inhibitors
J . Org. Chem., Vol. 64, No. 1, 1999 247
Met h yl
(2E,4S)-4-(Met h a n su lfon yloxy)-4-[(5R)-N-
to afford 8.5 g (68%) of 5a and 3.6 g 29%) of 6a (ratio 2.3:1,
total yield 97%). Diastereomeric ratios in the crude product
could be directly determined by reverse phase HPLC. Com-
pound 4 derived from pure 2c afforded 5a and 6a in a ratio of
2.4:1; for compound 4 derived from pure 3c, a ratio of 4.4:1
was obtained.
[(ter t-bu tyloxy)ca r bon yl]-2,2-d im eth yl-4-th ia zolid in yl]-
2-bu ten oa te (2c) a n d Its (4R)-Isom er (3c). To a solution of
43 mg alcohol 2a (0.130 mmol) in 1.5 mL of CH2Cl2 cooled to
0 °C was added 33 µL of triethylamine (0.24 mmol) followed
by dropwise addition of 17 µL of methanesulfonyl chloride (0.22
mmol). The mixture was stirred for 5 min at 0 °C, the ice bath
was removed, and the mixture was stirred an additional 15
min at ambient temperature. CH2Cl2 was removed by rotary
evaporation and the residue dissolved in EtOAc, washed twice
with water, once with brine, dried over Na2SO4, filtered,
concentrated and purified by FC to afford 53 mg (94%) of the
desired mesylate 2c as an oil. Mesylate 3c was prepared in
an similar manner from alcohol 3a .
Data for 5a : 1H NMR (CDCl3) δ: 5.67 dd (J ) 6.3, 15.3 Hz),
5.39 dd (J ) 9.3, 15.2 Hz), 4.83 bm, 3.65 m, 3.31 t (J ) 10.1
Hz), 3.26 dd (J ) 6.1, 11.7 Hz), 2.58 (J ) 11.7 Hz), 1.99 m,
1.77 bs, 1.74 s, 1.43 s, 0.89 d (J ) 6.7 Hz), 0.85 d (J ) 6.7 Hz);
13C NMR (CDCl3) δ: 152.5, 131.3, 80.3, 64.9, 63.8, 51.9, 33.2,
28.6, 28.3, 20.7, 19.4; IR (neat) ν cm-1: 3452, 1692; [R]20
)
D
-64.4 (c ) 0.0854, CHCl3); LRMS (FAB+) m/z: 352, 330, 274,
230; HRMS calcd for C17H31NO3S [M + Na]+ 352.1922, found
352.1941.
Data for 2c: 1H NMR (CD3OD) δ: 6.95 dd (J ) 7.7, 15.7
Hz), 6.14 bm, 5.44 t (J ) 7.5 Hz), 4.60 bm, 3.74 bs, 3.28 dd (J
) 5.5, 13.0 Hz), 3.11 s, 3.00 bd (J ) 12.0 Hz). 1.78 bs, 1.76 bs,
1.44 s; 13C NMR (CD3OD) δ: 166.8, 142.9, 124.4, 79.9, 78.3,
69.8, 67.9, 56.1, 52.5, 39.5, 32.5, 28.9; IR (neat), ν cm-1: 1725,
Data for 6a : 1H NMR (CDCl3) δ: 5.62 dd (J ) 7.1, 15.2 Hz),
5.33 m, 4.73 bm, 3.64 dt (J ) 5.4, 15.2 Hz), 3.32 t (J ) 10.4
Hz), 3.36 dd (J ) 6.2, 11.8 Hz), 1.98 m, 1.73 bs, 1.43 s, 0.88 d
(J ) 6.7), 0.84 d (J ) 6.7 Hz); 13C NMR (CDCl3) δ: 133.3, 80.4,
80.0, 63.7, 52.6, 33.1, 30.0, 29.6, 28.8, 28.4, 20.7, 20.1; IR (neat)
ν cm-1: 3443, 1693; [R]20D ) -62.8 (c ) 0.00916, CHCl3); LRMS
(FAB+) m/z: 352, 330, 274, 230; HRMS calcd for C17H31NO3S
[M + Na]+ 352.1922, found 352.1915.
1692; [R]20 ) - 167 (c ) 0.0043, CHCl3); LRMS (FAB+) m/z:
D
432, 310, 280, 258, 214; HRMS calcd for C16H27NO7S2 [M +
Na]+ 432.1127, found 432.1118.
Data for 3c: 1H NMR (CD3OD) δ: 7.12 dd (J ) 6.5, 16.0
Hz), 6.08 dd (J ) 1.2, 15.7 Hz), 5.59 bm, 4.68 bm, 3.76 s, 3.33
m, 3.14 bs, 2.9 bs, 1.75 s, 1.73 s, 1.52 s; 13C NMR (CD3OD) δ:
167.3, 143.6, 125.5, 99.5, 82.8, 80.9, 71.5, 67.0, 52.5, 52.4, 39.1,
39.0, 30.9, 30.1, 28.64, 28.59; IR (neat) ν cm-1: 1728, 1694;
(2R,3E)-2-Isopr opyl-4-[(5R)-N-[(ter t-bu tyloxy)car bon yl]-
2,2-d im eth yl-4-th ia zolid in yl]-3-bu ten a l (5b). A solution of
659 µL (7.55 mmol) of oxalyl chloride in 30 mL of CH2Cl2 was
cooled to -60 °C and 1.15 mL (16.2 mmol) of DMSO added
dropwise. A solution of 1.77 g (5.39 mmol) of 5a in 20 mL of
CH2Cl2 was added dropwise and the reaction mixture allowed
to stir for 10 min after the addition was completed at which
point the mixture had become cloudy. TEA (3.00 mL, 21.57
mmol) was added dropwise and the mixture warmed to rt. The
reaction became homogeneous after the TEA had been com-
pletely added, but became cloudy again upon warming to rt.
Satd NH4Cl (50 mL) was added, the resulting two-phase
mixture was extracted with CH2Cl2, and the combined extracts
were dried over Na2SO4, filtered, and concentrated to 1.9 g of
a yellow oil. After purification by FC, eluting with 1:10 EtOAc:
hexanes, 1.60 g (91%) of 5b was obtained as a clear oil.
1H NMR (CDCl3) δ: 9.58 d (J ) 2.8 Hz), 5.75 dd (J ) 7.1,
15.3 Hz), 5.61 bm, 4.84 bm, 3.27 dd (J ) 6.1, 11.8 Hz), 2.72
bm, 2.57 d (J ) 11.8 Hz), 2.13 m, 1.76 s, 1.44 s, 0.95 d (J ) 6.6
Hz), 0.91 d (J ) 6.3 Hz); 13C NMR (CDCl3) δ: 202.3, 152.4,
135.6, 125.5, 80.3, 65.1, 63.0, 33.5, 29.9, 28.6, 28.5, 28.4, 20.9,
19.5; IR (neat) ν cm-1: 1726, 1692; [R]20D ) - 86.1 (c ) 0.0544,
CHCl3); LRMS (FAB+) m/z: 681, 350, 321, 294, 228; HRMS
calcd for C17H29NO3S [M + Na]+ 350.1766, found 352.1781.
(2R,3E)-2-Isopr opyl-4-[(5R)-N-[(ter t-bu tyloxy)car bon yl]-
2,2-d im eth yl-4-th ia zolid in yl]-3-bu ten a l (6b). Using the
above conditions for the conversion of 5a to 5b, 2.04 g (6.19
mmol) of 6a was oxidized to yield 1.93 g (95%) of 6b. 1H NMR
(CDCl3) δ: 9.57 d (J ) 2.8 Hz), 5.75 dd (J ) 6.8, 15.5 Hz),
5.58 bm, 4.82 bm, 3.28 dd (J ) 6.2, 11.8 Hz), 2.72 m, 2.58 d (J
) 11.8 Hz), 2.12 m, 1.78 bs, 1.75 s, 0.95 d (J ) 6.7 Hz), 0.89 d
(J ) 6.8 Hz); 13C NMR (CDCl3) δ: 201.7, 152.2, 135.0, 125.3,
80.1, 65.0, 62.3, 33.2, 30.5, 29.9, 29.2, 28.4, 28.3, 20.7, 19.3;
[R]20 ) -36.3 (c ) 0.0199, CHCl3); LRMS (FAB+) m/z: 432,
D
310, 280, 258; HRMS calcd for C16H27NO7S2 [M + Na]+,
432.1127, found 432.1132.
Met h yl (2R/S,3E)-2-Isop r op yl-4-[(5R)-N-[(ter t-b u t yl-
oxy)ca r bon yl]-2,2-d im eth yl-4-th ia zolid in yl]-3-bu ten oa te
(4). A stock solution was prepared as follows: to a suspension
of 360 mg (4.0 mmol) CuCN in 40 mL of THF cooled to 0 °C
was added dropwise 2.0 mL (4.0 mmol) of a 2 M solution of
i-PrMgCl in THF. After the addition was complete, the mixture
was stirred for an additional 2 h and recooled to -78 °C, and
then BF3OEt2 (492 µL, 4.0 mmol) was added dropwise. Either
mesylate 2c (50 mg, 0.122 mmol) or 3c (56 mg, 0.137 mmol)
dissolved in 2.0 mL of THF was added to 6 mL of the above
stock solution at -78 °C. The resulting mixture was stirred
for an additional 30 min at which point TLC (20% ethyl
acetate-hexanes) indicated complete disappearance of the
starting mesylate. The reactions were quenched with ∼ 3 mL
of 1:1 satd NH4Cl:NH4OH and the mixture allowed to warm
to ambient temperature and stirred overnight. The resulting
mixture was extracted with ethyl acetate, washed with water
and brine, dried over Na2SO4, filtered, and concentrated. The
crude products were purified by FC eluting with 10% ethyl
acetate-hexanes. Diastereomeric mixtures of esters 4 were
obtained as clear oils (40 mg, 92%, from 2c; 43 mg, 88%, from
3c). Diastereomeric product ratios were most conveniently
determined after subsequent reduction. Using analogous
conditions on a 22 g scale, a mixture of 2c and 3c obtained
directly from mesylation of an unseparated mixture of 2a and
2b could be converted to 4 in 93% yield.
1H NMR (CDCl3) δ: 5.66 m, 4.78 bm, 3.66 s, 3.25 dd (J )
5.6, 11.6 Hz, (2S)-4), 3.24 dd (J ) 5.9, 11.7 Hz, (2R)-4), 2.66
m, 2.57 d (J ) 11.7 Hz, (2S)-4), 2.55 d (J ) 11.8 Hz, (2R)-4),
1.96 b sept (J ) 6.7 Hz), 1.77 s, 1.74 s, 1.42 s ((2R)-4), 1.41 s
((2S)-4), 0.89 d (J ) 6.5 Hz, (2R)-4), 0.87 d (J ) 8.0 Hz), 0.85
d (J ) 6.5 Hz, (2S)-4).
(2R,3E)-2-Isopr opyl-4-[(5R)-N-[(ter t-bu tyloxy)car bon yl]-
2,2-d im eth yl-4-th ia zolid in yl]-3-bu ten ol (5a ) a n d Its (2S)-
Isom er (6a ). A 1 M solution of DIBAL in hexanes (76 mL, 76
mmol) was added to a solution of 13.6 g (38.0 mmol) of 4 in
250 mL of toluene stirring at room temperature. The reaction
mixture was stirred 15 min and then quenched by addition of
250 mL of satd sodium potassium tartrate. The resulting
heterogeneous mixture was stirred vigorously for 2 h at room
temperature and then diluted with 500 mL ethyl acetate, and
the organic layer was separated, washed with brine, dried over
Na2SO4, filtered through MgSO4, and concentrated. The
resulting crude mixture of alcohols was separated and purified
by FC, eluting with a 5-25% ethyl acetate-hexanes gradient
IR (neat) ν cm-1 1726, 1693; [R]20 ) -19.5 (c ) 0.0495,
:
D
CHCl3); LRMS (FAB+) m/z: 681, 350, 321, 294, 228, 176, 154;
HRMS calcd for C17H29NO3S [M + Na]+ 350.1766, found
350.1764.
Met h yl (2E,4R,5R,6E)-4-Hyd r oxy-5-isop r op yl-7-[(5R)-
N-[(ter t-bu tyloxy)car bon yl]-2,2-dim eth yl-4-th iazolidin yl]-
2,6-h ep ta d ien oa te (7a ) a n d Its (5S) Isom er (9a ). In an N2-
filled drybox, 2.10 g (17.08 mmol) of chromium dichloride was
added to a solution of 1.60 g (4.88 mmol) of 5b and 3.10 g (14.64
mmol) of (2Z)-3-iodoacrylate in 50 mL of THF followed by
addition of 20 mg (0.073 mmol) of Ni(COD)2 in one portion.
After stirring overnight, the reaction was removed from the
drybox and the THF removed under reduced pressure. The
residue was dissolved in a mixture of 35 mL of satd aq NH4Cl,
35 mL of CHCl3, and 5 mL of 10% aq Na2S2O3, and stirred for
1 h, and then the CHCl3 layer was separated. The CHCl3 layer
was washed further by stirring with satd aq NH4Cl and 10%
aq Na2S2O3 an additional two times. The aqueous layers were
combined and back extracted with CHCl3. The CHCl3 extracts

248 J . Org. Chem., Vol. 64, No. 1, 1999
Yang et al.
were combined, washed with brine, dried with Na2SO4, and
concentrated under reduced pressure to afford 3.95 g of a green
oily residue. The residue was chromatographed over silica gel
eluting with 1:3 ethyl acetate:hexanes to afford 1.60 g (79%)
of a 5.5:1 mixture of 7a and 9a as a yellow oil. The ratio was
determined by HPLC analysis on a C18 column eluting with
a gradient of 0-100% (phase A: 0.15% TFA, 5% MeCN in
H2O; phase B: 0.15% TFA in MeCN).
g mixture of two isomers, 9a and 10a , in 68% yield in a ratio
of 1.4:1 as determined by analytical reverse phase HPLC. Data
for 9a are identical to that reported above.
Data for 10a : 1H NMR (CDCl3) δ: 6.93 dd (J ) 5.5, 15.7
Hz), 6.05 dd (J ) 1.1, 15.5 Hz), 5.65 dd (J ) 7.0, 15.2 Hz),
5.51 m, 4.73 br s, 4.21 (t, J ) 6.2 Hz), 3.72 s, 3.25 dd (J ) 6.2,
11.9 Hz), 2.50-2.80 m, 1.93 m, 1.73 br s, 1.45 br s, 0.87 m;
13C NMR (CDCl3) δ: 166.8, 148.8, 121.1, 71.1, 55.5, 51.53,
51.49, 29.6, 28.4, 28.3, 27.8, 21.9; IR (neat) ν cm-1: 3474, 1725,
Data for 7a : 1H NMR (CDCl3) δ: 6.98 dd (J ) 4.7, 15.6 Hz),
6.02 dd (J ) 0.9, 15.6 Hz), 5.71 dd (J ) 6.4, 15.3 Hz), 5.31 m,
4.82 br s, 4.40 t (J ) 4.6 Hz), 3.71 s, 3.26 dd (J ) 6.1, 11.8
Hz), 2.55 d (J ) 11.7 Hz), 2.02 m, 1.74 br s, 1.43 br s, 0.95 d
(J ) 6.6 Hz), 0.88 d (J ) 6.3 Hz); 13C NMR (CDCl3) δ: 166.7,
148.0, 129.1, 121.2, 70.6, 56.2, 51.6, 50.1, 50.0, 49.8, 28.4, 28.2,
1693; [R]20 ) -57.0 (c ) 0.025, CHCl3); LRMS (FAB+) m/z:
D
436, 314; HRMS calcd for C21H35NO5S [M + Na]+ 436.2134,
found 436.2148.
Meth yl (2E,4R,5R,6E)-4-(Mesyloxy)-5-isop r op yl-7-[(5R)-
N-[(ter t-bu tyloxy)car bon yl]-2,2-dim eth yl-4-th iazolidin yl]-
2,6-h ep ta d ien oa te (7b). Triethylamine (22 mg, 0.218 mmol)
was added to a solution of 7a (30 mg, 0.0726 mmol) in 0.82
mL of CH2Cl2 cooled to 0 °C, followed by the dropwise addition
of 11.3 of µL methansulfonyl chloride (16.7 mg, 0.145 mmol).
The reaction mixture was stirred at 0 °C for 40 min and then
quenched by addition of a solution of satd aq ammonium
chloride. The mixture was extracted twice with CH2Cl2, the
combined extracts were washed with water and brine, dried
over anhydrous sodium sulfate, and the solvent was concen-
trated under reduced pressure. The residue was chromato-
graphed over 4 g of silica gel (eluting with 1:3.3 ethyl acetate:
hexanes) to provide 27 mg (77%) 7b as a colorless oil. 1H NMR
(CDCl3) δ: 6.82 dd (J ) 6.6, 15.7 Hz), 6.06 d (J ) 15.6 Hz),
5.71 dd (J ) 7.3, 15.2 Hz), 5.32 br s, 5.24 t (J ) 6.8 Hz), 4.81
br s, 3.73 s, 3.24 dd (J ) 6.0, 11.7 Hz), 2.99 s, 2.51 d (J ) 11.7
Hz), 2.25 dd (J ) 7.3, 15.8 Hz), 1.87 oct (J ) 6.5 Hz), 1.74 s,
1.43 s, 0.93 d (J ) 6.3 Hz), 0.89 d (J ) 6.5 Hz); 13C NMR
(CDCl3) δ: 166.4, 152.9, 143.9, 142.9, 124.8, 124.6, 81.7, 81.1,
80.8, 65.7, 54.9, 54.4, 52.6, 40.0, 33.5, 32.3, 31.4, 30.6, 29.6,
20.7; IR (neat) ν cm-1: 3460, 1725, 1692; [R]20 ) -71.1 (c )
D
0.0662, CHCl3); LRMS (FAB+) m/z: 436, 388, 314, 160, 109;
HRMS calcd for C21H35NO5S [M + Na]+ 436.2134, found
436.2138.
Data for 9a : 1H NMR (CDCl3) δ: 7.06 dd (J ) 4.1, 15.6 Hz),
6.11 d (J ) 15.5 Hz), 5.59 dd (J ) 6.3, 15.1 Hz), 5.21 br s,
4.65-4.85 br m, 4.41 s, 3.72 s, 3.21br s, 2.64 br s, 2.57 m, 2.05
m, 1.72 br s, 1.45 br s, 0.98 d (J ) 6.5 Hz), 0.86 br d (J ) 3.9
Hz); 13C NMR (CDCl3) δ: 166.8, 147.8, 135.2, 130.2, 121.5,
70.3, 66.5, 56.7, 51.56, 51.53, 51.47, 51.44, 33.0, 30.2, 29.7, 28.4,
28.3, 21.4, 20.5; IR (neat) ν cm-1: 3468, 1725, 1693; [R]20
)
D
-4.53 (c ) 0.0269, CHCl3); LRMS (FAB+) m/z: 436, 346, 314,
217, 176; HRMS calcd for C21H35NO5S [M + Na]+ 436.2134,
found 436.2114.
Meth yl (2E,4S,5R,6E)-4-Hyd r oxy-5-isop r op yl-7-[(5R)-N-
[(ter t-bu tyloxy)ca r bon yl]-2,2-d im eth yl-4-th ia zolid in yl]-
2,6-h ep ta d ien oa te (8a ). A suspension of the Dess-Martin
reagent24 (155 mg, 0.370 mmol), molecular sieves 4 Å (37 mg),
and tert-butyl alcohol (27 mg, 0.370 mmol) in CH2Cl2 (1.2 mL)
was stirred at room temperature for 0.5 h. To this suspension
was added a solution of 7a (51 mg, 0.123 mmol) in CH2Cl2
(0.8 mL) and the mixture stirred at room temperature for 15
min. After dilution with 50 mL of ethyl ether, the solid was
removed by centrifugation. The supernatant was then washed
with aq sodium thiosulfate, aq sodium bicarbonate, and brine,
dried over anhydrous sodium sulfate, and concentrated under
vacuum. The residue was chromatographed on silica gel
(eluting with 1:10 ethyl acetate:hexane) to afford the inter-
mediate ketone as a yellow oil (22 mg, 43%).
This oil (22 mg, 0.054 mmol) was dissolved in methanol (1
mL), cooled to 0 °C, and 2 mg (0.053 mmol) of sodium
borohydride was added. The solution was stirred for 0.5 h and
then concentrated under reduced pressure, and the resulting
residue was dissolved in ethyl acetate. The solution was
washed with 0.1 N HCl, water, and brine and then dried over
anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was chromatographed on silica gel
(eluting with 1:2 ethyl acetate:hexanes) to yield a colorless oil
(20 mg, 91%), which was a mixture of two diastereomers (1:
1). The two diastereomers were separated by reverse phase
HPLC to afford the starting diastereomer 7a and a new
compound 8a .
29.1, 28.8, 28.4, 23.4, 21.8, 21.7, 18.9, 14.8; IR (neat) ν cm-1
:
1727, 1690; [R]20D ) -56.0 (c ) 0.0223, CHCl3); LRMS (FAB+)
m/z: 514, 418, 362, 340, 296; HRMS calcd for C22H37NO7S2
[M + Na]+ 514.1909, found 514.1916.
Meth yl (2E,4S,5S,6E)-4-(Mesyloxy)-5-isop r op yl-7-[(5R)-
N-[(ter t-bu tyloxy)car bon yl]-2,2-dim eth yl-4-th iazolidin yl]-
2,6-h ep ta d ien oa te (9b). Alcohol 9a (12 mg, 0.0291 mmol) was
converted to mesylate 9b in 86% yield using the same
procedure as described above for the conversion of 7a to 7b.
1H NMR (CDCl3) δ: 6.84 dd (J ) 6.7, 15.7 Hz), 6.08 d (J )
15.8 Hz), 5.61 dd (J ) 5.5, 15.2 Hz), 5.29 br s, 5.22 t (J ) 6.7
Hz), 4.83 br s, 3.72 s, 3.24 dd (J ) 6.3, 11.8 Hz), 2.98 s, 2.50
d (J ) 11.8 Hz), 2.29 dd (J ) 8.6, 14.4 Hz), 1.91 oct (J ) 6.6
Hz), 1.73 s, 1.43 s, 0.93 d (J ) 6.2 Hz), 0.89 d (J ) 6.5 Hz); 13
C
NMR (CDCl3) δ: 166.4, 152.9, 143.0, 136.6, 135.5, 126.7, 125.9,
124.9, 81.0, 65.6, 64.7, 54.2, 52.5, 40.0, 34.1, 33.5, 32.3, 31.4,
30.1, 29.2, 29.1, 28.9, 28.8, 28.2, 23.3, 21.7, 18.5, 14.8; IR (neat)
ν cm-1: 1727, 1690; [R]20D ) -34.9 (c ) 0.0621, CHCl3); LRMS
(FAB+) m/z: 514, 418, 362, 261, 217; HRMS calcd for
C
22H37NO7S2 [M + Na]+ 514.1909, found 514.1906.
Meth yl (2S,3Z,5S,6E)-2-(P h en ylm eth yl)-5-isop r op yl-7-
[(5R)-N-[(ter t-bu tyloxy)ca r bon yl]-2,2-d im eth yl-4-th ia zo-
lid in yl]-2,6-h ep ta d ien oa te (11) a n d Its (2R,3E,5S,6E)
Isom er (14). Using a procedure similar to the procedure for
the preparation of 17 from 9b, a mixture of 11 and 14 (25 mg,
89%, ratio 2.6:1) was obtained from SN2′ displacement reaction
of 28 mg of 7b (0.057 mmol). Separation of 11 and 14 was
performed by chromatography over silica gel (eluting with 1:20
ethyl acetate:hexanes).
Data for 8a : 1H NMR (CDCl3) δ: 6.93 dd (J ) 5.3, 15.6 Hz),
6.06 (d, J ) 15.7 Hz), 5.66 (dd, J ) 6.2 15.4 Hz), 5.47 (dd, J )
10.1, 15.0 Hz). 4.82 br s, 4.29 br s, 3.73 s, 3.26 (dd, J ) 6.2,
11.8 Hz), 2.57 m, 1.80-1.96 m, 1.75 br s, 1.44 br s, 0.80-0.97
m; 13C NMR (CD3OD) δ: 168.8, 154.2, 72.2, 56.7, 52.2, 29.7,
28.9, 27.5; IR (neat) ν cm-1: 1724, 1691; [R]20 ) -51.6 (c )
D
1
Data for 11: H NMR (CDCl3) δ: 7.22-7.26 m, 7.12-7.18
0.0058, CHCl3); LRMS (FAB+) m/z: 436, 406, 314, 217, 176;
HRMS calcd for C21H35NO5S [M + Na]+ 436.2134, found
436.2118.
m, 5.37-5.49 m, 4.70 br s, 3.57-3.64 m, 3.59 s, 3.20 dd (J )
6.0, 11.6 Hz), 3.02 dd (J ) 8.0, 13.6 Hz), 2.74 dd (J ) 6.8, 13.6
Hz), 2.68 dd (J ) 7.4, 9.0 Hz), 2.42 d (J ) 11.6 Hz), 1.74-1.77
m, 1.49-1.58 m, 1.42 s, 0.85 d (J ) 6.5 Hz), 0.81 d (J ) 6.7
Hz); 13C NMR (CD3OD) δ: 175.8, 154.1, 140.2, 135.5, 135.1,
134.6, 130.1, 129.6, 129.5, 128.6, 128.3, 127.7, 127.6, 66.8, 52.5,
52.4, 52.3, 52.2, 48.0, 47.8, 40.1, 34.4, 33.8, 30.2, 29.0, 28.9,
Meth yl (2E,4R,5S,6E)-4-Hyd r oxy-5-isop r op yl-7-[(5R)-N-
[(ter t-bu tyloxy)ca r bon yl]-2,2-d im eth yl-4-th ia zolid in yl]-
2,6-h ep ta d ien oa te (9a ) a n d Its (4S) Isom er (10a ). NHK
reaction of 6b with (2Z)-3-iodoacrylate was performed using
a procedure similar to that used to prepare 7a and 9a from
5b above. From 1.556 g of 6b (4.76 mmol) was obtained a 1.345
20.9, 20.7, 20.5; IR (neat) ν cm-1: 1738, 1694; [R]20 ) +17.6
D
(c ) 0.0647, CHCl3); LRMS (FAB+) m/z: 510, 388, 217; HRMS
calcd for C28H41NO4S [M + Na]+ 510.2654, found 510.2673.
Data for 14: 1H NMR (CDCl3) δ: 7.22-7.25 m, 7.11-7.18
m, 5.42-5.52 m, 5.38-5.40 m, 4.70 br s, 3.61 s, 3.23-3.31 m,
(24) (a) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(b) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899. (c) Meyer, S.
D.; Schreiber, S. L. Ibid. 1994, 59, 7549.

Farnesyl Transferase Inhibitors
J . Org. Chem., Vol. 64, No. 1, 1999 249
3.05 dd (J ) 7.7, 13.6 Hz), 2.78 dd (J ) 7.4, 13.6 Hz), 2.53 d (J
) 11.6 Hz), 2.39-2.41 m, 1.75-1.77 m, 1.50-1.58 m, 1.43 s,
0.77 d (J ) 6.7 Hz); 13C NMR (CD3OD) δ: 175.7, 153.9, 140.13,
140.09, 136.8, 134.1, 130.2, 129.5, 129.4, 128.8, 128.2, 127.5,
79.6, 66.7, 53.7, 52.5, 52.4, 52.35, 52.29, 39.9, 34.4, 33.6, 29.04,
magnesium chloride (0.122 mL, 0.244 mmol) was added
dropwise to a suspension of 22.0 mg of CuCN (0.244 mmol) in
1.2 mL of THF maintained under Ar atmosphere at - 20 °C.
After the addition was completed, the solution was gradually
warmed to rt and the color changed to dark brown at which
point it was cooled to -78 °C and 36 µL of BF3OEt2 (0.293
mol) was added. Next, a solution of 12 mg 9b (0.0244 mmol)
in 0.2 mL THF was added and the resulting mixture was
stirred for 20 min at -78 °C. The reaction was then quenched
by addition of a 2:1 solution of satd ammonium chloride and
ammonium hydroxide, warmed to room temperature, stirred
for 15 min, and then extracted three times with ethyl acetate.
The extracts were combined, washed with brine, dried over
anhydrous sodium sulfate and concentrated under reduced
pressure. The resulting residue was chromatographed over
silica, eluting with 1:20 ethyl acetate:hexanes to afford 10 mg
17 (83%) as a colorless oil. Compound 17 was contaminated
with a chromatographically inseparable related impurity to
the extent of 10-20% as estimated from the 1H NMR spec-
trum. This ratio was determined to be 6.8:1 by DIBAL
reduction of the mixture and subsequent analysis by RP-
HPLC. The impurity was tentatively assigned the structure
28.99, 20.9, 20.7, 20.5; IR (neat) ν cm-1: 1738, 1693; [R]20
)
D
- 67.8 (c ) 0.0979, CHCl3); LRMS (FAB+) m/z: 510, 388;
HRMS calcd for C28H41NO4S [M + Na]+ 510.2654, found
510.2668.
(2S,3Z,5S,6E)-2-(P h en ylm eth yl)-5-isop r op yl-7-[(5R)-N-
[(ter t-bu tyloxy)ca r bon yl]-2,2-d im eth yl-4-th ia zolid in yl]-
2,6-h ep ta d ien oic a cid (12) a n d Its (2R,3Z,5S,6E) Isom er
(13). A 2.0 M aqueous solution of lithium hydroxide (0.28 mL,
0.56 mmol) was added to a solution of 27 mg of 11 (0.055 mmol)
in 0.28 mL of dioxane. The mixture was stirred at rt for 23 h,
acidified with 0.6 mL of 1 N HCl (0.6 mmol), and then
extracted with ethyl acetate three times. The combined
extracts were washed with brine and dried over anhydrous
sodium sulfate, and the solvent was removed under reduced
pressure to yield 22 mg of a colorless oil (85%), which is a
mixture of 12 and 13 in the ratio of 27:1 as determined by
reverse phase HPLC. The separation of the two epimers could
be accomplished by preparative reverse phase HPLC using
similar conditions.
1
1
of the C.1 epimer on the basis of the H NMR data. H NMR
(CD3OD) δ: 7.22-7.26 m, 7.12-7.19 m, 5.31-5.56 m, 4.79 br
s, 3.25-3.41 m, 3.05 dd (J ) 7.1, 13.5 Hz), 2.77 dd (J ) 7.8,
13.7 Hz), 2.57 d (J ) 11.9 Hz), 2.41 q (J ) 7.1 Hz), 1.75-1.79
m, 0.78 d (J ) 6.9 Hz), 0.73 d (J ) 6.4 Hz); 13C NMR (CD3OD)
δ: 174.8, 153.0, 139.5, 134.4, 134.0, 129.7, 129.6, 129.0, 128.5,
127.8, 127.1, 127.0, 65.9, 52.3, 51.9, 48.1, 47.2, 39.6, 39.5, 34.2,
33.1, 32.9, 29.2, 29.1, 20.9, 20.6, 20.4; IR (neat) ν cm-1: 1738,
Data for 12: 1H NMR (CD3OD) δ: 7.21-7.25 m, 7.13-7.18
m, 5.38-5.51 m, 4.71 br s, 3.54-3.60 m, 3.25 dd (J ) 6.0, 11.8
Hz), 3.00 dd (J ) 7.8, 13.5 Hz), 2.72 dd (J ) 6.9, 13.4 Hz),
2.45 d (J ) 11.7 Hz), 1.73-1.76 m, 1.51-1.66 m, 1.43 s, 0.89
d (J ) 6.6 Hz), 0.85 d (J ) 6.7 Hz); 13C NMR (CD3OD) δ: 177.5,
154.1, 140.4, 135.1, 130.2, 129.5, 128.7, 127.5, 48.2, 40.2, 33.9,
32.9, 28.92, 28.87, 23.8, 20.7, 14.6; IR (neat) ν cm-1: 1734,
1693; [R]20 ) -149 (c ) 0.0517, CHCl3); LRMS (FAB+) m/z:
D
1694; [R]20 ) +24.0 (c ) 0.0101, CHCl3); LRMS (FAB+) m/z:
510, 388, 217; HRMS calcd for
510.2654, found 510.2649.
C
28H41NO4S [M + Na]+
D
496, 374; HRMS calcd for C27H39NO4S [M + Na]+ 496.2498,
found 496.2501.
Meth yl (2S,3Z,5S,6E)-2-(P h en ylm eth yl)-5-isop r op yl-7-
[(5R)-N-[(ter t-bu tyloxy)ca r bon yl]-2,2-d im eth yl-4-th ia zo-
lid in yl]-2,6-h ep ta d ien yl Meth ion in e (18). 4-Methylmor-
pholine (47 µL, 0.427 mmol) is added to a DMF (2.5 mL)
solution containing 126 mg of 12 (0.267 mmol), 80 mg of
methionine methyl ester hydrochloride (0.400 mmol), 58 mg
of 1-hydroxybenzotriazole hydrate (0.427 mmol), and 103 mg
of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochlo-
ride (0.534 mmol). The mixture was stirred at room temper-
ature for 16 h, diluted with 50 mL of ethyl acetate, and washed
with 2 × 50 mL of water and once with brine. The solvent
was removed under reduced pressure, and the residue was
chromatographed over silica, eluting with 1:4 ethyl acetate:
hexanes to afford 165 mg of 18 as a colorless oil (100%). 1H
NMR (CD3OD) δ: 8.25 d (J ) 8.2 Hz), 7.21-7.26 m, 7.16-
7.18 m, 5.67 dd (J ) 7.0, 15.2 Hz), 5.38-5.59 m, 4.79 br s,
4.46 m, 3.64 s, 3.60 m, 3.30 m, 2.90-2.94 m, 2.68 dd (J ) 5.2,
13.3 Hz), 2.52 d (J ) 11.8 Hz), 1.97 s, 1.83-2.06 m, 1.75-1.78
m, 1.64-1.72 m, 1.58 oct (J ) 7.0), 1.44 s, 0.93 d (J ) 6.3 Hz),
0.89 d (J ) 6.6 Hz); 13C NMR (CD3OD) δ: 176.0, 175.9, 173.6,
173.5, 154.1, 140.4, 135.2, 134.3, 130.34, 130.26, 129.57, 127.6,
52.9, 52.84, 52.75, 52.68, 52.36, 52.26, 40.9, 34.5, 33.7, 32.0,
30.8, 30.3, 29.0, 28.9, 20.8, 15.4, 15.2; IR (neat) ν cm-1: 1743,
Data for 13: 1H NMR (CD3OD) δ: 7.22-7.26 m, 7.13-7.19
m, 5.58 dd (J ) 7.0, 15.3 Hz), 5.35-5.47 m, 4.73 t (J ) 6.4
Hz), 3.53-3.59 m, 3.25 dd (J ) 6.0, 11.7 Hz), 3.06 dd, (J )
6.4, 13.3 Hz), 2.73 dd (J ) 8.3, 13.3 Hz), 2.52-2.58 m, 1.73-
1.75 m, 1.41 s, 1.25-1.34 m, 0.75 d (J ) 6.6 Hz), 0.60 d (J )
6.8 Hz); 13C NMR (CD3OD) δ: 177.4, 154.1, 140.5, 135.3, 134.4,
130.4, 130.3, 129.5, 128.6, 127.6, 81.3, 66.9, 48.1, 40.3, 34.2,
33.5, 28.91, 28.85, 20.7; IR (neat) ν cm-1: 1693; [R]20D ) -26.5
(c ) 0.0173, CHCl3); LRMS (FAB+) m/z: 496, 374; HRMS calcd
for C27H39NO4S [M + Na]+ 496.2498, found 496.2496.
(2R,3E,5S,6E)-2-(P h en ylm eth yl)-5-isop r op yl-7-[(5R)-N-
[(ter t-bu tyloxy)ca r bon yl]-2,2-d im eth yl-4-th ia zolid in yl]-
2,6-h ep ta d ien oic Acid (15) a n d Its (2S,3E,5S,6E) Isom er
(16). Methyl ester 14 (2.847 g, 5.846 mmol) was hydrolyzed
as for 11 above to afford a mixture of 15 and 16 in a ratio of
1:1. The separation of a 276 mg portion of the crude product
by reverse phase HPLC afforded pure 15 (92 mg, 33%) and 16
(145 mg, 53%) and the remaining material in mixed fractions.
Data for 15: 1H NMR (CD3OD) δ: 7.21-7.24 m, 7.13-7.16
m, 5.41-5.48 m, 4.78 br s, 3.22-3.32 m, 3.03 dd (J ) 7.4, 13.6
Hz), 2.76 dd (J ) 7.7, 13.5 Hz), 2.55 d (J ) 11.8 Hz), 2.43-
2.44 m, 1.75-1.76 m, 1.54 (oct, J ) 6.7 Hz), 1.45 s, 0.81 d (J
) 6.7 Hz), 0.79 d (J ) 6.3 Hz); 13C NMR (CD3OD) δ: 177.6,
154.1, 140.5, 136.6, 134.3, 130.4, 130.3, 129.5, 129.4, 129.3,
127.5, 53.79, 53.84, 52.7, 40.0, 33.7, 29.04, 28.98, 20.9, 20.6;
IR (neat) ν cm-1: 1735, 1706, 1694; [R]20D ) -83.1 (c ) 0.0637,
CHCl3). LRMS (FAB+) m/z: 496, 374; HRMS calcd for
1691; [R]20 ) +51.6 (c ) 0.0452, CHCl3); LRMS (FAB+) m/z:
D
642, 520; HRMS calcd for C33H50N2O5S2 [M + Na]+ 641.3059,
found 641.3058.
(2S,3Z,5S,6E)-2-P h en ylm et h yl-5-isop r op yl-7-[(5R)-N-
[(ter t-bu tyloxy)ca r bon yl]-2,2-d im eth yl-4-th ia zolid in yl]-
2,6-h ep ta d ien yl m eth ion in e (19). A 1 M solution of lithium
hydroxide (1.0 mL, 1.0 mmol) was added to a solution of 50
mg of 17 (0.081 mmol) in 1.0 mL of dioxane. The mixture was
stirred at room temperature for 1 h and then acidified by
addition of 1 N hydrochloric acid. The mixture was extracted
with ethyl acetate and then washed with brine, dried over
anhydrous sodium sulfate, and concentrated under vacuum.
The residue was purified by reverse phase HPLC to yield 39
C
27H39NO4S [M + Na]+ 496.2498, found 496.2502.
Data for 16: 1H NMR (CD3OD) δ: 7.21-7.25 m, 7.14-7.19
m, 5.37-5.56 m, 4.79 br s, 3.24-3.29 m, 3.05 dd (J ) 7.3, 13.7
Hz), 2.77 dd (J ) 8.2, 13.7 Hz), 2.56 d (J ) 11.4 Hz), 2.42 q (J
) 7.3 Hz), 1.77 s, 1.75 s,, 1.52 oct (J ) 6.9 Hz), 1.44 s, 0.78 d
(J ) 6.9 Hz), 0.73 d (J ) 6.9 Hz); 13C NMR (CD3OD) δ: 177.7,
154.2, 140.4, 136.5, 130.4, 130.3, 129.52, 129.48, 129.45,
129.24, 52.84, 40.1, 33.7, 29.0, 28.9, 20.8, 20.6; IR (neat) ν cm-1
:
1733, 1696; [R]20D ) -10.2 (c ) 0.112, CHCl3). LRMS (FAB+)
m/z: 496, 374; HRMS calcd for C27H39NO4S [M + Na]+
496.2498, found 496.2515.
mg of 19 as a colorless oil (80%). H NMR (CD3OD) δ: 8.11 d
1
(J ) 8.2 Hz), 7.23-7.27 m, 7.15-7.19 m, 5.67 dd (J ) 15.1,
6.9 Hz), 5.59 t (J ) 10.5 Hz), 5.50-5.54 br m, 5.42 t (J ) 10.5
Hz), 4.79 br m, 4.43 dd (J ) 9.2, 4.1 Hz), 3.62 dt (J ) 5.0, 10.1
Hz), 3.29 dd (J ) 11.9, 6.0 Hz), 2.92 m, 2.70 dd (J ) 13.3, 5.5
Hz), 2.52 d (J ) 11.4 Hz), 1.99-2.08 m, 1.98 s, 1.84-1.98 m,
Meth yl (2S,3Z,5R,6E)-2-(P h en ylm eth yl)-5-isop r op yl-7-
[(5R)-N-[(ter t-bu tyloxy)ca r bon yl]-2,2-d im eth yl-4-th ia zo-
lid in yl]-2,6-h ep ta d ien oa te (17). A 2.0 M solution of benzyl-

250 J . Org. Chem., Vol. 64, No. 1, 1999
Yang et al.
1.76-1.79 m, 1.66-1.75 m, 1.58 oct (J ) 6.9), 1.45 s, 0.93 d (J
) 6.4 Hz), 0.89 d (J ) 6.9 Hz); 13C NMR (CD3OD) δ: 176.08,
175.99, 174.8, 154.1, 140.5, 135.2, 134.4, 130.4, 130.3, 129.6,
127.6, 81.3, 66.8, 52.4, 52.3, 40.9, 34.5, 33.8, 32.3, 30.9, 30.1,
Meth yl (2R,3E,5S,6E)-2-(P h en ylm eth yl)-5-isop r op yl-7-
[(5R)-N-[(ter t-bu tyloxy)ca r bon yl]-2,2-d im eth yl-4-th ia zo-
lid in yl]-2,6-h ep ta d ien yl Meth ion in e (24). Compound 24
(64 mg) was obtained from 65 mg of 15 (0.137 mmol) using
the procedure described above for the preparation of 18 from
12. After additional purification by reverse phase HPLC, 58
29.0, 28.9, 20.8, 15.2; IR (neat) ν cm-1: 1734, 1691, 1653; [R]20
D
) +43.9 (c ) 0.0368, CHCl3); LRMS (FAB+) m/z: 642, 520;
HRMS calcd for C32H48N2O5S2 [M + Na]+ 627.2902, found
627.2907.
1
mg pure of 24 was obtained (68%). H NMR (CD3OD) δ: 8.30
d (J ) 7.8 Hz), 7.22-7.26 m, 7.13-7.17 m, 5.43-5.56 m, 4.79
br m, 4.49-4.53 m, 3.64 s, 3.27-3.32 m, 2.90-2.94 m, 3.05 dd
(J ) 7.8, 13.7 Hz), 2.73 dd (J ) 7.3, 13.7 Hz), 2.56 d (J ) 11.9),
2.34-2.49 m, 2.02-2.10 m, 2.04 s, 1.81-1.93 m, 1.76-1.77 m,
1.54 oct (J ) 6.9), 1.46 s, 0.86 d (J ) 6.9 Hz), 0.83 d (J ) 6.4
Hz); 13C NMR (CD3OD) δ: 176.5, 173.7, 154.1, 140.6, 136.2,
134.6, 130.43, 130.29, 129.46, 129.36, 129.39, 127.31, 66.9,
54.02, 53.96, 53.5, 52.9, 52.83, 52.75, 52.62, 52.52, 39.7, 34.3,
33.8, 32.0, 31.2, 30.9, 29.0, 28.9, 20.9, 20.6, 15.4; IR (neat) ν
(2S,3Z,5S,6E,8R)-2-(P h en ylm eth yl)-5-isop r op yl-8-(ter t-
bu tyloxyca r bon yla m in o)-9-(ca r bom eth oxysu lfen ylth io)-
2,6-n on a d ien yl Meth ion in e (20). To a solution of 38 mg of
19 (0.063 mmol) and 17 mg of sodium acetate hydrate (0.125
mmol) in 0.6 mL of a 8:1:0.5 mixture of acetic acid:DMF:water
at 0 °C was added 12 mg of methoxycarbonylsulfenyl chloride
(0.094 mmol). The solution was stirred for 15 min during which
period it was allowed to warm to room temperature. The
solution was concentrated under vacuum, and the residue was
chromatographed using reverse phase HPLC to yield 40 mg
cm-1: 1745, 1691, 1647; [R]20 ) -62.8 (c ) 0.0532, CHCl3);
D
LRMS (FAB+) m/z: 641, 519; HRMS calcd for C33H50N2O5S2
[M + Na]+ 641.3059, found 641.3041.
1
20 as a colorless oil (97%). H NMR (CD3OD) δ: 8.09 d (J )
(2R,3E,5S,6E)-2-(P h en ylm eth yl)-5-isop r op yl-7-[(5R)-N-
[(ter t-bu tyloxy)ca r bon yl]-2,2-d im eth yl-4-th ia zolid in yl]-
2,6-h ep ta d ien yl Meth ion in e (25). Acid 25 (49 mg, 86%) was
obtained from 58 mg of 24 (0.094 mmol) using the procedure
8.2 Hz), 7.22-7.27 m, 7.15-7.19 m, 5.58 t (J ) 10.1 Hz), 5.55
m, 5.41 t (J ) 10.5 Hz), 5.34 dd (J ) 15.1, 6.4 Hz), 4.43-4.47
m, 4.24 br q (J ) 6.4 Hz), 3.88 s, 3.57 m, 2.84-2.96 m, 2.73 dd
(J ) 13.3, 6.0 Hz), 2.00-2.13 m, 2.00 s, 1.91-1.99 m, 1.69-
1.77 m, 1.59 oct (J ) 6.9 Hz), 1.43 s, 0.90 d (J ) 6.9 Hz), 0.87
d (J ) 6.9 Hz); 13C NMR (CD3OD) δ: 176.1, 174.8, 171.4, 157.6,
140.5, 135.5, 134.0, 130.4, 130.3, 129.8, 129.6, 129.5, 127.6,
80.4, 56.3, 56.2, 53.1, 52.4, 52.4, 45.4, 40.9, 33.7, 32.3, 31.0,
28.92, 28.88, 20.8, 20.6, 15.2; IR (neat) ν cm-1: 1733, 1654;
1
described above for the preparation of 19. H NMR (CD3OD)
δ: 7.21-7.24 m, 7.13-7.18 m, 5.44-5.49 m, 4.77 br m, 4.51
dd (J ) 4.6, 9.6 Hz), 3.27-3.31 m, 3.06 dd (J ) 13.7, 6.9 Hz),
2.74 dd (J ) 7.8, 13.7 Hz), 2.55 d (J ) 11.9), 2.37-2.51 m,
2.05-2.14 m, 2.05 s, 1.88-1.95 m, 1.76 m, 1.55 oct (J ) 6.9
Hz), 1.45 s, 0.77-0.85 m; 13C NMR (CD3OD) δ: 176.5, 175.0,
154.1, 140.7, 136.3, 134.5, 130.4, 129.5, 129.3, 127.3, 81.4, 66.9,
53.97, 53.92, 53.50, 52.5, 52.3, 39.6, 34.3, 33.8, 32.4, 31.3, 29.0,
[R]20 ) +92.4 (c ) 0.0343, CHCl3); LRMS (FAB+) m/z: 677,
D
599, 440; HRMS calcd for C31H46N2O7S3 [M + Na]+ 677.2365,
found 677.2359.
28.9, 20.9, 20.6, 15.4; IR (neat) ν cm-1: 1735, 1691; [R]20
)
D
(2S,3Z,5S,6E,8R)-2-(P h en ylm eth yl)-5-isopr opyl-8-am in o-
9-(ca r bom eth oxysu lfen ylth io)-2,6-n on a d ien yl m eth ion -
in e (21). Dry HCl gas was bubbled for 1 min through a
solution of 40 mg of 20 (0.061 mmol) in 10 mL of ethyl acetate
maintained at 0 °C. The solution was stirred for 15 min
further, during which period it was allowed to warm to the
room temperature and then concentrated under reduced
pressure. The residue was purified by reverse phase HPLC to
afford 29 mg of the trifluoroacetate salt 21, obtained as a
-64.7 (c ) 0.0455, CHCl3); LRMS (FAB+) m/z: 627, 505, 470;
HRMS calcd for C32H48N2O5S2 [M + Na]+ 627.2902, found
627.2885.
(2R,3E,5S,6E,8R)-2-P h en ylm et h yl-5-isop r op yl-8-[(N-
ter t-bu tyloxy)car bon ylam in o]-9-(car bom eth oxysu lfen ylth -
io)-2,6-n on a d ien yl Meth ion in e (26). Compound 26 (49 mg,
92%) was obtained from 48 mg of 25 (0.080 mmol) using the
1
procedure described above for the preparation of 20. H NMR
(CD3OD) δ: 7.22-7.25 m, 7.13-7.18 m, 5.53 ddd (J ) 15.1,
7.3, 0.9 Hz), 5.45 dd (J ) 15.1, 8.2 Hz), 5.38 dd (J ) 15.6, 7.8
Hz), 5.15 ddd (J ) 15.6, 6.4, 0.9 Hz), 4.77 br m, 4.52 dd (J )
4.6, 9.6 Hz, 4.21 br q, (J ) 6.4 Hz), 3.90 s, 3.27-3.32 m, 3.06
dd (J ) 13.7, 6.9 Hz), 2.83-2.91 m, 2.75 dd (J ) 13.7, 8.7 Hz),
2.47-2.53 m, 2.39-2.44 m, 2.55 d (J ) 11.9 Hz), 2.10-2.12
m, 2.05 s, 1.90-1.95 m, 1.57 oct (J ) 6.4), 0.81 d (J ) 1.4 Hz),
0.79 d (J ) 0.9 Hz); 13C NMR (CD3OD) δ: 176.6, 175.1, 171.4,
157.6, 140.7, 135.7, 135.3, 130.8, 130.4, 129.5, 129.4, 127.3,
80.4, 56.4, 56.3, 56.2, 53.74, 53.68, 53.50, 53.10, 52.5, 52.3, 45.4,
39.5, 33.6, 32.4, 31.3, 31.0, 29.0, 28.9, 20.6, 20.5, 15.4; IR (neat)
1
colorless oil (71%). H NMR (CD3OD) δ: 8.10 d (J ) 8.2 Hz),
7.26-7.29 m, 7.17-7.20 m, 5.85 dd (J ) 15.6, 7.8 Hz), 5.66 t
(J ) 10.5 Hz), 5.38-5.44 m, 4.44-4.48 m, 3.88-3.94 m, 3.93
s, 3.59 td (J ) 9.6, 6.4 Hz), 3.06 d (J ) 6.9 Hz), 2.94-3.00 m,
2.73 dd (J ) 13.3, 6.0 Hz), 2.01-2.15 m, 2.00 s, 1.92-1.99 m,
1.70-1.78 m, 1.66 oct (J ) 6.9), 0.94 d (J ) 6.9 Hz), 0.90 d (J
) 6.4 Hz); 13C NMR (CD3OD) δ: 176.0, 175.9, 174.8, 171.7,
141.6, 140.4, 133.0, 130.5, 130.3, 129.7, 129.6, 127.7, 124.7,
57.0, 56.8, 53.4, 53.3, 52.5, 52.4, 43.2, 41.1, 33.6, 32.3, 31.0,
20.83, 20.86, 20.4, 15.2; IR (neat) ν cm-1: 1669; [R]20D ) +136
(c ) 0.0318, MeOH); LRMS (FAB+) m/z: 577, 555; HRMS
calcd for C26H38N2O5S3 [M + Na]+ 577.1841, found 577.1825.
ν cm-1: 1735, 1649; [R]20 ) -9.1 (c ) 0.0427, CHCl3); LRMS
D
(FAB+) m/z: 677, 599, 555; HRMS calcd for C31H46N2O7S3 [M
+ Na]+ 677.2365, found 677.2369.
(2S,3Z,5S,6E,8R)-2-(P h en ylm eth yl)-5-isopr opyl-8-am in o-
9-m er ca p to-2,6-n on a d ien yl m eth ion in e, B956 (22). A 1 M
solution of trimethylphosphine (0.12 mL, 0.12 mmol) was
added to a solution of 29 mg 21 (0.0434 mmol) in 0.4 mL of
20:1:1 THF:H2O:trifluoroacetic acid at room temperature. The
solution was stirred at room temperature for 1 h and then
concentrated under reduced pressure and purified by reverse
phase HPLC. After evaporation of the HPLC eluent under
vacuum, the residue was dissolved in 10:1 H2O:acetonitrile and
then lyophilized to afford 25 mg 22 (100%) as a white powder.
1H NMR (CD3OD) δ: 8.09 d (J ) 8.2 Hz), 7.22-7.29 m, 7.16-
7.20 m, 5.80 dd (J ) 15.6, 7.8 Hz), 5.65 t (J ) 10.5 Hz), 5.43
t (J ) 10.5 Hz), 5.35-5.39 m, 4.44-4.48 m, 3.88-3.94 m, 3.81
q (J ) 6.4 Hz), 3.59 td (J ) 9.6, 6.4 Hz), 2.94-3.00 m, 2.80 dd
(J ) 14.2, 6.0 Hz), 2.70-2.75 m, 2.01-2.16 m, 2.01 s, 1.92-
2.00 m, 1.70-1.77 m, 1.66 oct (J ) 6.9 Hz), 0.94 d (J ) 6.9
Hz), 0.91 d (J ) 6.4 Hz); 13C NMR (CD3OD) δ: 175.9, 174.8,
141.13, 141.09, 140.4, 133.2, 130.4, 129.6, 129.7, 127.8, 125.2,
56.4, 52.4, 41.0, 33.6, 32.3, 31.0, 28.4, 20.8, 20.5, 15.2; IR (neat)
(2R,3E,5S,6E,8R)-2-(P h en ylm eth yl)-5-isopr opyl-8-am in o-
9-(ca r bom eth oxysu lfen ylth io)-2,6-n on a d ien yl Meth ion -
in e (27). Compound 27 (36 mg, 72%) was obtained from 49
mg of 26 (0.075 mmol) using the procedure described above
1
for the preparation of 21. H NMR (CD3OD) δ: 7.20-7.25 m,
7.14-7.18 m, 5.88 dd (J ) 15.6, 8.2 Hz), 5.43-5.53 m, 5.34
ddd (J ) 15.6, 8.2, 0.9 Hz), 4.50 dd (J ) 4.6, 9.6 Hz), 3.90-
3.96 m, 3.94 s, 3.30-3.35 m, 3.02-3.11 m, 2.76 dd (J ) 13.7,
8.2 Hz), 2.46-2.55 m, 2.37-2.43 m, 2.05-2.15 m, 2.05 s, 1.88-
1.94 m, 1.63 oct (J ) 6.4), 0.83 d (J ) 5.0 Hz), 0.83 d (J ) 4.6
Hz); 13C NMR (CD3OD) δ: 176.5, 175.0, 171.8, 141.5, 141.4,
140.6, 134.6, 131.5, 130.4, 130.3, 129.5, 129.4, 127.5, 127.3,
125.4, 57.0, 56.9, 56.7, 54.0, 53.9, 53.5, 53.3, 52.5, 43.3, 43.2,
39.5, 33.5, 33.4, 32.3, 31.3, 20.6, 20.4, 15.3; IR (neat) ν cm-1
:
1718, 1668; [R]20D ) +20.0 (c ) 0.0364, CHCl3); LRMS (FAB+)
m/z: 577, 555, 159; HRMS calcd for C26H38N2O5S3 [M + Na]+
577.1841, found 577.1844.
(2R,3E,5S,6E,8R)-2-(P h en ylm eth yl)-5-isopr opyl-8-am in o-
9-m er ca p to-2,6-n on a d ien yl Meth ion in e, B957 (23). B957
(23, 30 mg, 96%) was obtained from 36 mg of 27 (0.0539 mmol)
using the procedure described above for the preparation of 22.
ν cm-1
:
1670, 1636; [R]20 ) +96.8 (c ) 0.00935, MeOH);
D
LRMS (FAB+) m/z: 487, 465; HRMS calcd for C24H36N2O3S2
[M + Na]+ 487.2065, found 487.2083.

Farnesyl Transferase Inhibitors
J . Org. Chem., Vol. 64, No. 1, 1999 251
1H NMR (CD3OD) δ: 8.26 d (J ) 8.2 Hz), 7.20-7.26 m, 7.14-
7.19 m, 5.82 dd (J ) 15.6, 8.2 Hz), 5.44-5.54 m, 5.33 ddd (J
) 15.6, 7.8, 0.9 Hz), 4.48-4.52 m, 3.82 q (J ) 6.4 Hz), 3.29-
3.35 m, 3.07 dd (J ) 13.7, 6.9 Hz), 2.71-2.83 m, 2.37-2.43 m,
2.06-2.15 m, 2.06 s, 1.88-2.04 m, 1.63 oct (J ) 6.9 Hz), 0.84
d (J ) 4.1 Hz), 0.83 d (J ) 4.1 Hz); 13C NMR (CD3OD) δ: 176.5,
175.0, 141.0, 140.9, 140.6, 134.8, 131.4, 130.4, 130.3, 129.5,
127.5, 126.0, 125.9, 56.6, 56.5, 54.0, 53.9, 53.3, 52.5, 39.5, 33.4,
32.2, 31.3, 28.5, 28.4, 28.3, 20.6, 20.4, 17.3, 15.3; [R]20D ) -41.4
(c ) 0.00959, CH3OH); LRMS (FAB+) m/z: 487; HRMS calcd
for C24H36N2O3S2 [M + Na]+ 487.2065 found 487.2059.
Ms. Megumi Ikemori of Eisai’s Tsukuba Research
Laboratories for obtaining the X-ray crystallographic
data for 7a and 12.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR for com-
pounds 1-3 and 5-27 and 13C NMR spectra for compounds
1, 2a , 2b, 3, 5-7, and 9-27; complete X-ray data for 7a and
12 (89 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Ack n ow led gm en t. The authors are deeply indebted
to Dr. Takatoshi Kawai, Dr. Yoshiyuki Kawakami, and
J O981892C