Enantioselective synthesis of the farnesyltransferase inhibitor, A-345665.0

Article abstract of DOI:10.1016/j.tetlet.2006.10.008

The stereoselective synthesis of A-345665.0 1, a novel farnesyl transferase inhibitor, is described. The key step involves a stereoselective addition of an imidazolyl Grignard reagent to aldehyde 8 in the presence of an external chiral auxiliary. Crystall

Full text of DOI:10.1016/j.tetlet.2006.10.008

Tetrahedron Letters 47 (2006) 8765–8768
Enantioselective synthesis of the farnesyltransferase inhibitor,
A-345665.0
Michael J. Rozema,* Michael Fickes, Maureen McLaughlin, Bridget Rohde
and Todd McDermott
GPRD Process Research and Development, R450, NCR8-1, Abbott, 1401 Sheridan Road, North Chicago, IL 60064-6285,
United States
Received 2 August 2006; revised 2 October 2006; accepted 2 October 2006
Available online 20 October 2006
Abstract—The stereoselective synthesis of A-345665.0 1, a novel farnesyl transferase inhibitor, is described. The key step involves a
stereoselective addition of an imidazolyl Grignard reagent to aldehyde 8 in the presence of an external chiral auxiliary. Crystalliza-
tion of the product as the dimeric zinc complex 12 facilitates the isolation of product in >98:2 er. The biaryl linkage is formed by the
use of a Suzuki coupling, employing boronic acid 4 prepared by the directed ortho-lithiation of benzonitrile 6. The overall yield for
the six step sequence is 21%.
Ó 2006 Elsevier Ltd. All rights reserved.
Mutation of the ras-oncogene regulating cell growth and
5
proliferation is implicated in up to 25% of human
N
cancers.1 After transcription of the protein and further
N
CN
OTf
N
B(OH)2
CN
activation by normal ras-protein activation processes
(cysteine–farnesylation, cleavage of a tripeptide and C-
terminal methylation), the mutated ras-protein derives
an uncontrolled cell growth and proliferation.2 One
strategy for the interruption of this process is by the
inhibition of the farnesylation process, which is medi-
ated by farnesyl transferase (FT). A-345665.0 (1)3 has
been identified as a FT inhibitor possessing excellent
potency, bioavailability and pharmacokinetics.4 Herein,
we disclose research into the preparation of A-345665.0.
N
N
2
N
I
O
4
O
Br
CN
A-345665.0 (1)
3
CN
Figure 1. Retrosynthetic analysis of A-345665.0.
Among the synthetic challenges presented by A-
345665.0 (1) are the biaryl formation and generation
of the stereogenic center. Choosing to construct the
biaryl through a Suzuki protocol and hoping to find a
method for the stereoselective addition of the imidazole
moiety to the aldehyde, retrosynthetic analysis (Fig. 1)
led us to iodoimidazole 2, benzylbromide 3, aldehyde/
boronic acid 4, and quinoline triflate 5 as the starting
materials.
Directed ortho metalation of arenes5 followed by trap-
ping the anion with a trialkyl boronate is a powerful
method for the generation of boronic acids. Recently,
Vedsø and co-workers6 found that by using a modifica-
tion of the method described by Martin and Krizan,7
arenes bearing sensitive electron-withdrawing groups
could be ortho metalated with LiTMP and trapped
in situ with triisopropylborate (B(OiPr)3) to produce,
after work-up, the corresponding boronic acid. We
found that by protecting commercially available 4-
cyanobenzaldehyde 6a as its diethyl acetal (Scheme 1),
the desired boronic acid 4 could be obtained by the reac-
tion of 6b with LiTMP in the presence of B(OiPr)3 at
ꢀ70 °C, followed by the acidic work-up. Suzuki
Keywords: Farnesyl-transferase inhibitor; FTI; Asymmetric addition;
Suzuki coupling; Palladium coupling.
*
Corresponding author. Tel.: +847 935 3490; fax: +847 938 2258;
e-mail: michael.rozema@abbott.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.008

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M. J. Rozema et al. / Tetrahedron Letters 47 (2006) 8765–8768
B(OH)2
CN
CN
ii
H
H
70 %
X
O
iv
N
O
6a X = O
6b X = (OEt)2
i
4
CN
+
90%
H
iii
N
N
94%
8
OH
OTf
7
5
Scheme 1. Reagents and conditions: (i) triethyl orthoformate, ethanol, reflux; (ii) LiTMP, B(O-iPr)3, THF, ꢀ60 °C; (iii) Tf2O, pyr, ꢀ5 °C and (iv)
KF, toluence/methanol, cat. Pd(OAc)2, cat. biphenyl-2-dicyclohexyl-phosphane, 68 °C.
coupling of boronic acid 4 with quinoline triflate 5 (pre-
pared from commercially available hydroxyquinoline 7)
was accomplished with catalytic Pd(OAc)2 using biphen-
yl-2-yl-dicyclohexyl-phosphane8 as the ligand and
afforded aldehyde 8. With the aldehyde in hand, the ste-
reoselective addition of an imidazolyl moiety was
investigated.
by the addition of 3-methyl-3H-imidazol-4-yl magne-
sium chloride,12 produced a reagent that delivered the
imidazolyl moiety to aldehyde 8 in an 85% HPLC yield,
80% ee and without Cannizzaro side products. The
selectivity was not greatly affected by temperature
(84% ee at ꢀ40 °C, 70% ee at 0 °C). The chiral purity16
of the product was further enhanced through its isol-
ation as a 2:1:1 complex of alcohol 9:zinc:sulfonamide
(12).17,18 The isolation of complex 12 (69% yield from
8) from ethanol afforded alcohol 9 in a 98% ee after
decomplexation by partitioning 12 between CH2Cl2
and aqueous NaOH.
The enantioselective additions of alkyl9 and to a lesser
extent arylzinc10 reagents to carbonyl compounds con-
stitute a powerful method for the construction of chiral
secondary alcohols. We felt, however, that the presence
of heteroatoms would disrupt the highly ordered coordi-
nation complex needed to effect high levels of stereo-
selection. Guided by the work of chemists from Merck
and Dupont on the stereoselective synthesis of Efavir-
nez,11 we explored the external chiral auxiliary approach
for the addition of organometallic reagents to aldehyde
8 (Eq. 1). Starting with 5-iodo-1-methyl-1H-imidazole,
the corresponding Grignard12 or organozinc13 reagent
could be prepared. The additions of chiral auxiliaries
to the imidazolyl metallic reagent, with and without var-
ious additives, were explored to effect the stereoselective
addition to aldehyde 8 (Table 1). The use of 1-phenyl-2-
pyrrolidin-1-yl-propan-1-ol (10) under a variety of
conditions afforded alcohol 9 in moderate enantiomeric
excesses (34–60%) and in variable yields (41–80%).
Aldehyde 8, was prone to undergo a Cannizzaro14
disproportionation to the corresponding primary alco-
hol and acid, and these products were seen in the crude
reaction mixtures.
N
CN
SO2CF3
N
Zn
N
N
2
OH
N
SO2CF3
12
The exact nature of the imidazolyl Grignard reagent was
not determined, however, its use for the addition of the
imidazolyl moiety could be extended to other aldehydes,
Table 1. Enantioselective additions to 8
Entry
MetX
Ligand
Additive
HPLC
Ee
yield (%)
(%)
N
1
2
3
ZnI
ZnI
ZnI
10
10
10
BuLi
None
Me2Zn,
trifluoroethanol
Me2Zn,
40
62
81
60
55
34
N
O
N
N
MetX
CN
CN
N
H
N
4
5
MgCl
MgCl
10
11
41
85
56
80
See Table
for details
trifluoroethanol
Me2Zn
OH
8
9
OH
NHSO2CF3
NHSO2CF3
ð1Þ
Bis-sulfonamide 1115 has also proven to be an effective
ligand for the stereoselective addition of organozinc
reagents to carbonyl compounds. We found that the
treatment of 11 with dimethylzinc in CH2Cl2 followed
N
10
11

M. J. Rozema et al. / Tetrahedron Letters 47 (2006) 8765–8768
8767
4. Tong, Y.; Lin, N.-H.; Wang, L.; Hasvold, L.; Wang, W.;
Leonard, N.; Li, T.; Li, Q.; Cohen, J.; Gu, W.-Z.; Zhang,
H.; Stoll, V.; Bauch, J.; Marsh, K.; Rosenberg, S. H.;
Sham, H. L. Bioorg. Med. Chem. Lett. 2003, 13, 1571.
5. Anctil, E. J.-G.; Snieckus, V. J. Organomet. Chem. 2002,
653, 150, and the references cited therein.
CN
OMe
CN
N
N
N
N
OH
OH
OH
13, 81% ee
14, 89% ee
15, 0% ee
´
6. Kristensen, J.; Lysen, M.; Vedsø, P.; Begtrup, M. Org.
Figure 2.
Lett. 2001, 3, 1435; See also Caron, S.; Hawkins, J. M.
J. Org. Chem. 1998, 63, 2054; and Cailly, T.; Fabis, F.;
Bouillon, A.; Lemaˆıtre, S.; Sopkova, J.; de Santos, O.;
Rault, S. Synlett 2006, 53.
such as 4-cyanobenzaldehyde and p-anisaldehyde to
produce secondary alcohols 13 and 14, respectively.
Unfortunately, other Grignard reagents (PhMgBr) when
used under these conditions gave racemic product 15
(Fig. 2).
7. Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105,
6155.
8. Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999,
38, 2413.
9. For reviews see: (a) Soai, K.; Niwa, S. Chem. Rev. 1992,
92, 833; (b) Noyori, R.; Kitamura, M. Angew. Chem., Int.
Ed. Engl. 1991, 30, 49.
With the chiral alcohol in hand, the ether was
constructed (equation 2) by the alkylation of 9 with
benzylbromide 12 to afford the farnesyltransferase
inhibitor A-345665.0 (1).
10. For a review see: Bolm, C.; Hildebrand, J. P.; Muniz, K.;
˜
Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284.
11. (a) Choudhury, A.; Moore, J. R.; Pierce, M. E.; Fortunak,
J. M.; Valvis, I.; Confalone, P. N. Org. Process Res. Dev.
2003, 7, 324; (b) Thompson, A.; Corley, E. G.; Hunting-
ton, M. F.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36,
8937; (c) Pierce, M. E.; Parsons, R. L., Jr.; Radesca, L. A.;
Lo, Y. S.; Silverman, S.; Moore, J. R.; Islam, Q.;
Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.; Luo,
C.; Morgan, S. J.; Davis, W. P.; Confalone, P. N.; Chen,
C.-Y.; Tillyer, R. D.; Frey, L.; Tan, L.; Xu, F.; Zhao, D.;
Thompson, A. S.; Corley, E. G.; Grabowski, E. J. J.;
Reamer, R.; Reider, P. J. J. Org. Chem. 1998, 63, 8536.
12. (a) Holden, K. G.; Mattson, M. N.; Cha, K. H.;
Rapoport, H. J. Org. Chem. 2002, 67, 5913; (b) Panosyan,
F. B.; Still, I. W. J. Can. J. Chem. 2001, 79, 1110; (c) Burm,
B. E. A.; Blokker, P.; Jongmans, E.; van Kampen, E.;
Wanner, M. J.; Koomen, G.-J. Heterocycles 2001, 55,
495.
13. (a) Yeh, M. C. P.; Knochel, P. Tetrahedron Lett. 1988, 29,
2395; (b) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert,
J. J. Org. Chem. 1988, 53, 2392.
14. (a) Cannizzaro, S. Annuals 1853, 88, 129; (b) Geissman, T.
A. Org. React. 1944, 2, 94; For a current synthetic example
see (c) Abaee, M. S.; Sharifi, R.; Mojtahedi, M. M. Org.
Lett. 2005, 7, 5893.
15. (a) Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron
Lett. 1989, 30, 1657; (b) Rozema, M. J.; AchyuthaRao, S.;
Knochel, P. J. Org. Chem. 1992, 57, 1956.
N
CN
N
N
i
ii, iii
CN
N
12
69%
O
50%
H
1
O
8
CN
Reagents and conditions: (i) see Ref. 18; (ii) aq NaOH, CH2Cl2; (iii)
LiHMDS, 4-cyanobenzyl bromide, Bu4NI (10 mol %), DMF, 0 ºC.
ð2Þ
In summary, we have developed a short and selective
synthesis of A-345665.0. It is highlighted by the forma-
tion of a chiral secondary alcohol through the enantio-
selective addition of a imidazolyl Grigand reagent to
an aldehyde using an external chiral auxiliary.
16. Chiral purity determined by chromatography on Chir-
alpak AD (hexane:ethanol).
Acknowledgments
17. We have seen similar complexes between the imidazolyl
moiety and zinc salts: Rozema, M. J.; Kruger, A. W.;
Rohde, B. D.; Shelat, B.; Bhagavatula, L.; Tien, J. T.;
Zhang, W.; Henry, R. F. Tetrahedron 2005, 61, 4419; See
also Comprehensive Coordination Chemistry; Wilkinson,
G., Ed.; Pergamon Press: Oxford, 1987; Vol. 5, p 925.
18. General procedure for 12: A solution of PhMgBr (1.0 M in
THF, 37.0 mL, 37.0 mmol) was added at ꢀ10 °C to a
We thank Mike Fitzgerald for the development of
the method for separation of enantiomers of the
A-345665.0 and Howard Morton for his helpful discus-
sions. We also thank Vincent Stoll for X-ray crystallo-
graphic analysis of A-345665.0 (1).
solution
of
5-iodo-1-methyl-1H-imidazole
(8.3 g,
References and notes
40.0 mmol) in CH2Cl2 (100 mL) and the resulting mixture
stirred at ꢀ10 °C for an additional 45 min. In a separate
reaction vessel, a solution of dimethylzinc (2 M in toluene,
20.0 mL, 40.0 mmol) was added to a solution of N,N0-
((1R,2R)-cyclohexane-1,2-diyl)bis(1,1,1-trifluoromethane-
sulfonamide) (11) (15.0 g, 39.7 mmol) in CH2Cl2 (50 mL)
at an ambient temperature. After an additional 45 min,
THF (50 mL) was added. The resulting solution of zinc
sulfonamide was added to the imidazolyl Grignard
reagent, and after stirring the resulting mixture at
ꢀ10 °C for 1 h, aldehyde 8 (5.2 g, 20.1 mmol) was added
1. Bos, J. L. In Molecular Genetics in Cancer Diagnosis;
Cossman, J., Ed.; Elsevier Scientific: USA, 1990; p 273.
2. Prendergast, G. C.; Rane, N. Exp. Opin. Invest. Drugs
2001, 10, 2105.
3. The absolute stereochemistry of A-345665.0 (1) was
established through an X-ray crystallographic structure
of 1 bound to the active site of farnesyl transferase,
Vincent Stoll, R46Y, AP10, Global Pharmaceutical R&D,
Abbott, 100 Abbott Park Road, Abbott Park, IL 60064-
6101, private communication.

8768
M. J. Rozema et al. / Tetrahedron Letters 47 (2006) 8765–8768
and the reaction allowed to proceed for 1 h. After an
6H) 6.05 (d, J = 5.15 Hz, 2H) 6.44 (d, J = 5.52 Hz, 2H)
6.72 (s, 2H) 7.56–7.81 (m, 10H) 7.98 (s, 2H) 8.13 (dd,
J = 8.09, 1.47 Hz, 2H) 8.48 (dd, J = 8.46, 1.84 Hz, 2H)
8.86 (dd, J = 4.04, 1.84 Hz, 2H) ppm. 13C NMR
(75.5 MHz, DMSO-d6) d 24.3, 31.1, 32.7, 38.7, 38.9,
39.2, 39.5, 39.8, 40.1, 40.3, 62.1, 64.8, 112.3, 118.1, 118.4,
121.8, 122.4, 125.6, 125.9, 126.1, 128.0, 129.4, 130.4, 132.6,
135.0, 136.4, 136.9, 140.3, 143.2, 145.2, 146.4, 150.52 ppm.
Anal. Calcd. for C50H42F6N10O6S2Zn–H2O, C, 52.66; H,
3.89; F, 10.00; N, 12.2; S, 5.62; found C, 52.39; H, 3.80; F,
10.08; N,12.24; S, 6.13.
aqueous work-up (5% aqueous NH4OAc, 10% MeOH in
CH2Cl2), the organic layer was concentrated in vacuo. The
resulting residue was suspended in EtOH (50 mL),
warmed to 50 °C, and the suspension stirred for 8 h. After
cooling to ambient temperature, the solid was collected,
washed with EtOH (10 mL), and dried in a vacuum oven
at 50 °C to yield 8.25 g (4.67 g of alcohol 9 by HPLC
1
analysis versus a standard (69% yield)) of complex 12. H
NMR (300 MHz, DMSO-d6) d 1.08–1.26 (m, 4H) 1.55–
1.66 (m, 2H) 2.28–2.41 (m, 2H) 2.90–3.00 (m, 2H) 3.73 (s,