Diastereoselective arylithium addition to an α-trifluoromethyl imine. Practical synthesis of a potent cathepsin K inhibitor

Article abstract of DOI:10.1021/jo052430j

A practical, chromatography-free synthesis of potent cathepsin K inhibitor 1 is described. The addition of 4-bromophenyllithium to an α- trifluoromethylimine derived from commercially available (S)-leucinol was accomplished in a highly diastereoselective

Full text of DOI:10.1021/jo052430j

osteoclasts,3 the cells that are responsible for bone resorption.
Because of this unique and selective cellular distribution, it is
believed that cathepsin K plays a key role in the osteoclast-
mediated degradation of bone matrix. It has also been reported
that cathepsin K can attack the collagen of adult human bone,
which constitutes 90% of the organic matrix in bone.4 It is
postulated that molecules capable of selectively inhibiting
cathepsin K may serve as useful therapeutic agents against
diseases such as osteoporosis and other bone disorders involving
excessive bone loss.
As part of an ongoing drug discovery program at our
laboratories, compound 15 was identified as a highly potent and
selective inhibitor of cathepsin K. To enable further study of
the pharmacological properties of 1, we sought a scaleable
chromatography-free synthesis suitable for the preparation of
this compound in multigram quantities. A notable feature of 1
is the chiral, nonbasic R-trifluoromethylbenzylamine moiety
(pKa ∼ 1.5). Stereoselective methods for the synthesis of
perfluoroalkylamines have been the subject of recent reviews,6
and several approaches were envisioned to achieve the synthesis
of 1. However, we were particularly interested in exploring
synthetic routes from (S)-leucine derivatives given their com-
mercial availability and the possibility of using the stereocenter
to install the R-trifluoromethylamine center of 1 in a diaste-
reoselective manner.
Diastereoselective Arylithium Addition to an
r-Trifluoromethyl Imine. Practical Synthesis of a
Potent Cathepsin K Inhibitor
Ame´lie Roy,†,* Francis Gosselin,† Paul D. O’Shea,† and
Cheng-y. Chen‡
Department of Process Research, Merck Frosst Centre for
Therapeutic Research, 16711 Trans Canada Highway,
Kirkland, Que´bec H9H 3L1, Canada, and Department of
Process Research, Merck Research Laboratories,
Post Office Box 2000, Rahway, New Jersey 07065
amelie_roy@merck.com
ReceiVed NoVember 24, 2005
Our retrosynthetic analysis of 1 is illustrated in Scheme 1.
We envisioned that the key (S)-R-trifluoromethylamine stereo-
center could be set via diastereoselective addition of 4-bro-
mophenyllithium to imine 4. Subsequent Suzuki cross-coupling
followed by sulfur and carbon oxidations would afford biaryl
acid 8. Amide coupling with commercially available aminoac-
etonitrile hydrochloride would complete the synthesis of 1.
The condensation of (S)-leucinol 2 with trifluoroacetaldehyde
methyl hemiacetal 3 in toluene in the presence of a catalytic
amount of pyridinium p-toluenesulfonate (PPTS) with the
azeotropic removal of water/MeOH did not yield the desired
imine 4. Instead oxazolidine 5 was obtained as an ∼2:1 mixture
A practical, chromatography-free synthesis of potent cathe-
psin K inhibitor 1 is described. The addition of 4-bromophe-
nyllithium to an R-trifluoromethylimine derived from com-
mercially available (S)-leucinol was accomplished in a highly
diastereoselective manner (97.6% de, 91% yield). Subsequent
Suzuki cross-coupling afforded biaryl 7. Oxidation of the
alcohol and sulfide functionalities led to the formation of
carboxylic acid 8. Crystallization of 7 and acid 8 as its
dicyclohexylamine salt gave excellent impurity rejection. The
final amide coupling with commercially available aminoac-
etonitrile hydrochloride afforded 1 in excellent purity
(99.6A% by HPLC, 100% de, <3 ppm Pd, W, Cr).
(3) (a) Bromme, D.; Okamoto, K.; Wang, B. B.; Biroc, S. J. Biol. Chem.
1996, 271, 2126. (b) Bossard, M. J.; Tomaszek, T. A.; Thompson, S. K.;
Amegadzie, B. Y.; Hanning, C. R.; Jones, C.; Kurdyla, J. T.; McNulty, D.
E.; Drake, F. H.; Gowen, M.; Levy, M. A. J. Biol. Chem. 1996, 271, 12517.
(c) Tezuka, K.; Tezuka, Y.; Maejima, A.; Sato, T.; Nemoto, K.; Kamioka,
H.; Hakeda, Y.; Kumegawa, M. J. Biol. Chem. 1994, 269, 1106.
(4) Garnero, P.; Borel, O.; Byrjalsen, I.; Ferras, M.; Drake, F. H.;
McQueney, M. S.; Fogged, N. T. Delmas, P. D.; Delaisse, J. M. J. Biol.
Chem. 1998, 273, 32347.
(5) Li, C. S.; Descheˆnes, D.; Desmarais, S.; Falgueyret, J.-P.; Gauthier,
J. Y.; Kimmel, D. B.; Le´ger, S.; Masse´, F.; McKay, D. J.; Percival, M. D.;
Riendeau, D.; Rodan, S. B.; Somoza, J. R.; The´rien, M.; Truong, V.-L.;
Wesolowski, G.; Zamboni, R.; Black, W. C. Bioorg. Med. Chem. Lett. 2006,
16, 1985.
(6) (a) Enantiocontrolled Synthesis of Fluoro-Organic Compounds;
Soloshonok, V. A., Ed.; Wiley: Chichester, 1999. (b) Asymmetric Fluo-
roorganic Chemistry: Synthesis, Applications and Future Directions;
Ramachandran, P. V., Ed.; American Chemical Society; Washington, DC,
1999. (c) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42, 2436. (d)
Wang, Y.; Mosher, H. S. Tetrahedron Lett. 1991, 32, 987. (e) Abe, H.;
Amii, H.; Uneyama, K. Org. Lett. 2001, 3, 313. (f) Sakai, T.; Yan, F.;
Kashino, S.; Uneyama, K. Tetrahedron 1996, 52, 233. (g) Enders, D.;
Funabiki, K. Org. Lett. 2001, 3, 1575. (h) Soloshonok, V. A.; Avilov, D.
V.; Kukhar, V. P.; Van Meervelt, L.; Mischenki, N. Tetrahedron Lett. 1997,
38, 4671. (h) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001,
3, 2847. (i) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int.
Ed. 2001, 40, 589.
Osteoporosis is a disease characterized by low bone mass,
resulting in skeletal fragility and a greater risk of fracture. It is
known as the “silent disease”, as bone loss often progresses
over a number of years without showing any symptoms. In the
United States alone, 10 million individuals are reported to
already have osteoporosis and another 34 million are estimated
to have low bone mass, placing them at an increased risk for
osteoporosis. Each year, this disease is also responsible for more
than 1.5 million fractures.1 Cathepsin K, a member of the papain
superfamily of cysteine proteases and one of a growing number
of cysteinyl cathepsins (B, H, L, S, C, K, O, F, V, X, and W),2
has been shown to be abundantly and selectively expressed in
† Merck Frosst Centre for Therapeutic Research.
‡ Merck Research Laboratories.
(1) About Osteoporosis, Fast Facts Sheet; National Osteoporosis Founda-
tion: Washington, DC, October, 2004 (www.nof.org.).
(2) Drake, F. H.; Dodds, R. A.; James, I. E.; Connor, J. R.; Debouck,
C.; Richardson, S.; Lee-Rykaczewski, E.; Coleman, L.; Rieman, D.;
Barthlow, R.; Hastings, G.; Gowen, M. J. Biol. Chem. 1996, 271, 12511.
10.1021/jo052430j CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/03/2006
4320
J. Org. Chem. 2006, 71, 4320-4323

SCHEME 1. Retrosynthetic Analysis of 1
SCHEME 2. Organometallic Addition to O-TBDMS-Protected Imine 9a
a Reagents and conditions: (a) TBDMSCl, Et3N, DMAP (cat.), toluene, rt (77%); (b) trifluoroacetaldehyde methyl hemiacetal 3, ppts (cat.), toluene,
reflux (70%); (c) 1,4-dibromobenzene, n-BuLi, THF, -78 °C then 9 (94%, 31:1 dr).
of diastereomers in high yield, and imine 4 was never observed.
However, several groups have reported that the addition of
organometallic species to 1,3-oxazolidine mixtures bearing an
alkyl or aryl group at the 2-position gave the desired adducts
in moderate to excellent yields and diastereoselectivities.7 In
our case, a preliminary investigation of the addition of aryl-
lithium species at -78 °C to 2-trifluoromethyl-1,3-oxazolidine
5 gave good conversion to the desired adduct 6 but with no
diastereoselectivity. Indeed, a 2:1 mixture of adduct 6 was
obtained from a 2:1, nonseparable mixture of oxazolidine 5.
When Grignard reagents were employed, the reaction only took
place at higher temperature (0 °C), and many byproducts were
formed. In an analogous manner, the use of BF3‚OEt2 has been
reported to promote the nucleophilic addition of aryl species to
chiral 2-trifluoromethyl-1,3-oxazolidine through the correspond-
ing trifluoromethyl-iminium ion.8 When oxazolidine 5 was
submitted to a variety of such reaction conditions, disappoint-
ingly low conversion or decomposition of the reaction mixture
was observed, along with no diastereoselectivity.
On the basis of our observed results, we postulated that the
highly electron-withdrawing CF3 group at the 2-position of 5
greatly enhances the electrophilicity of the imine carbon, thus,
greatly shifting the equilibrium completely to the oxazolidine
tautomer. We reasoned that installing a protecting group (PG)
on the oxygen of (S)-leucinol would prevent the ring closure
and thus enable preparation of the desired imine. A diastereo-
selective aryl addition to this imine would give access to the
key 1-aryl-2,2,2-trifluoroethylamine intermediate 6 after depro-
tection. Thus, tert-butyldimethylsilyl (TBDMS) was employed
as a PG, and the subsequent reaction of the protected adduct
with trifluoroacetaldehyde methyl hemiacetal 3 furnished imine
1
9 in high yield as a single geometric E isomer by H NMR
(Scheme 2). The addition of 4-bromophenyllithium in THF at
-78 °C cleanly and reproducibly provided adduct 10 in 94%
yield and with 94% de (determined by HPLC) in favor of the
desired (S,S)-diastereomer. The diastereoselectivity was similar
in THF, THF/toluene, or MTBE. Confident that this approach
would rapidly give us access to 1, we began the development
of a process suitable for a multigram-scale synthesis.
(7) Although this strategy works well with nonfluorinated alkyl or aryl
groups at the 2-position,7a-c lower selectivities have been reported in the
case of 2-trifluoromethyl-1,3-oxazolidines, unless the diastereomeric ox-
azolidines are separated by column chromatography prior to addition of
the organometallic species.7d,e (a) Takahashi, H.; Chida, Y.; Yoshii, T.;
Suzuki, T.; Yanaura, S. Chem. Pharm. Bull. 1986, 34, 2071. (b) Wu, M.-
J.; Pridgen, L. N. J. Org. Chem. 1991, 56, 1340. (c) Pridgen, L. N.;
Mokhallalati, M. K.; Wu, M.-J. J. Org. Chem. 1992, 57, 1237. (d)
Higashiyama, K.; Ishii, A.; Mikami, K. Synlett 1997, 1381. (e) Higashiyama,
K.; Ishii, A.; Miyamoto, F.; Mikami, K. Tetrahedron Lett. 1998, 39, 1199.
(8) Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T. Tetrahedron
Lett. 2002, 43, 2827.
A number of groups were evaluated for the protection of the
(S)-leucinol alcohol. An initial screen indicated that TBDMS
and trimethylsilyl protection gave mixtures of N- and O-
protected products. However, using chlorotriethylsilane (TESCl)
only O-protection was observed. Thus, 250 g of (S)-leucinol 2
was O-protected using TESCl in toluene with Et3N and a
catalytic amount of DMAP (Scheme 3). Et3N‚HCl was removed
by filtration, and the toluene solution was used directly for the
imine formation. In general, good results were obtained by
J. Org. Chem, Vol. 71, No. 11, 2006 4321

SCHEME 3. Large-Scale Diastereoselective Synthesis of 1a
a Reagents and conditions: (a) TESCl, Et3N, DMAP (cat), toluene, rt (100%); (b) trifluoroacetaldehyde methyl hemiacetal 3, DMAP‚HCl, toluene, reflux
(80%); (c) 1,4-dibromobenzene, n-BuLi, THF, -78 °C then 12 (91%, 97.6% de); (d) TFA, THF/H2O, 0 °C to room temperature (88%, 97.6% de); (e)
4-(methylthio)phenylboronic acid, Pd(OAc)2, PPh3, Na2CO3, n-PrOH/H2O, 90 °C (78%, 100% de); (f) 30% H2O2, Na2WO4‚2H2O (cat.), Bu4NHSO4, toluene,
rt (94%); (g) H5IO6, CrO3 (cat.), CH3CN, 5 °C (79%); (h) aminoacetonitrile‚HCl, HATU, Et3N, DMF, 0 °C (79%).
SCHEME 4
heating compound 11 in toluene with azeotropic removal of
water/MeOH in the presence of a catalytic amount of acid.
Interestingly, a cleaner reaction was obtained using residual
DMAP‚HCl in the toluene solution in place of PPTS. We also
found that the order of operations had an influence on the yield
of imine 12. Indeed, adding hemiacetal 3 over 30 min to a
refluxing solution of O-TES-leucinol 11 and DMAP‚HCl in
toluene prevented the formation of impurities and reproducibly
afforded imine 12 in 80% yield over two steps.
An investigation of the halogen-metal exchange of 1,4-
dibromobenzene indicated that the formation of 4,4′-dibromo-
biphenyl became significant when the n-BuLi addition time and
age time after addition was greater than 30 min. Moreover,
thorough degassing of the reaction mixture was required prior
to the addition of n-BuLi to reduce the formation of oxidation
byproducts.9 The addition of 4-bromophenyllithium to imine
12 at -78 °C in THF proceeded smoothly and afforded clean
aryl bromide 13 in 91% yield and 97.6% de.10 It is noteworthy
that similar diastereoselectivities were observed using O-
TBDMS-, O-TES-, or O-Me-protected leucinol, suggesting that
the diastereoselectivity is not influenced by the size or the
complexing ability of the PG. Indeed, our results support the
hypothesis that the nucleophile attacks the imine face flanked
by the CH2OPG group, rather than the larger i-Bu group. A
number of conditions were investigated for the deprotection of
TES ether 13. The best results were obtained using 1.2 equiv
of TFA in THF/H2O from 0 °C to room temperature. Using
this protocol, compound 13 was deprotected to yield alcohol 6
in 88% yield and 97.6% de. Interestingly, we observed that if
the TFA was not quenched with a base prior to the workup,
significant amounts (∼20%) of TES-protected adduct 13 were
recovered, presumably due to reprotection during the workup.
(10) Further improvements have been made to the diastereoselective
organometallic addition sequence and are described in the following
reference: Gosselin, F.; Roy, A.; O’Shea, P. D.; Chen, C.-y.; Volante, R.
D. Org. Lett. 2004, 6, 641.
(9) Bromophenol was identified and characterized as one of the impuri-
ties.
4322 J. Org. Chem., Vol. 71, No. 11, 2006

The use of aqueous NaOH as a quenching agent eliminated this
side reaction.
isopropyl acetate and heptane to give 1 in 79% yield and
excellent purity (99.6A% by HPLC, <3 ppm Pd, W, Cr).
In conclusion, the discovery of a highly diastereoselective
addition of 4-bromophenyllithium to imine 12 derived from
commercially available (S)-leucinol allowed the rapid develop-
ment of a scaleable synthesis of a potent and selective cathepsin
K inhibitor. Crystallization of biphenyl adduct 7 and acid 8 as
its DCHA salt gave excellent impurity rejection, and no
chromatography was required in the process. Thus, 1 was
prepared in 9 steps and with a 31% overall yield.
4-(Methylthio)phenylboronic acid was prepared in 93% yield
via halogen-metal exchange of 4-bromothioanisole in THF at
-70 °C followed by quenching with triisopropyl borate. Among
many conditions investigated for the Suzuki cross-coupling, the
most effective protocol involved the use of Pd(OAc)2 (2.5 mol
%), PPh3 (7.5 mol %), and Na2CO3 (2.7 equiv) as a base in
n-propanol/water. After an aqueous workup, biaryl 7 was
crystallized as a tan solid in 78% yield, with complete rejection
of the undesired diastereomer. Initial attempts to oxidize sulfide
7 to sulfone 14 using OXONE were not successful, leading to
decomposition of the starting sulfide. However, the oxidation
proceeded smoothly at room temperature using 1 mol % Na2-
WO4‚2H2O in the presence of H2O2 in toluene under phase-
transfer catalysis conditions to furnish sulfone 14 in excellent
yield (94%).11 Oxidation of the primary alcohol to the corre-
sponding carboxylic acid 8 was performed with H5IO6 in the
presence of a catalytic amount of CrO3. Initial attempts using
published conditions12 (2.5 equiv of H5IO6, 1.2 mol % CrO3,
wet CH3CN, 0-5 °C) gave complete consumption of starting
material, however, a low yield (∼60%) of acid 8 was obtained.
A closer examination of the reaction indicated that 2-aryl-2,2,2-
trifluoroethylamine 16 was formed in significant quantity,
presumably through oxidative cleavage of amino-alcohol 14
under the reaction conditions (Scheme 4). Increasing the quantity
of oxidant to 5 equiv and conducting the oxidation in anhydrous
CH3CN minimized formation of 16 (10%), which could be
readily rejected in the workup, and increased the yield to 79%
for acid 8. Moreover, no N-oxide product was seen under any
oxidation conditions. Purification of the acid was achieved by
crystallization of the dicyclohexylamine (DCHA) salt from
isopropyl acetate.
Experimental Section
[(1S)-1-(4-Bromophenyl)-2,2,2-trifluoroethyl]-((1S)-3-methyl-
1-triethylsilanyloxymethylbutyl)amine (13). A 22-L 4-neck round-
bottom flask equipped with a mechanical stirrer, a thermocouple,
an addition funnel, and a N2 inlet/outlet was charged with THF (6
L). 1,4-Dibromobenzene (439 g, 1.86 mol) was added in one
portion, followed by additional THF (1.5 L). The mixture was
degassed by bubbling N2 through the solution for about 15 min.
The mixture was then cooled to -74 °C using a MeOH/dry ice
bath, and n-BuLi (1.6 M hexanes, 1.12 L, 1.79 mol) was added
over 25 min via the addition funnel. The white slurry was aged at
-74 °C for 15 min. Imine 4 (463.40 g, 1.49 mol) in THF (1.2 L)
was then added over 45 min to the reaction mixture while keeping
the temperature below -70 °C. The reaction mixture was stirred
at -75 °C for 1 h. The mixture was quenched by the addition of
saturated aqueous NH4Cl (2 L) at -75 °C, followed by water (2
L), and the mixture was warmed to 20-25 °C. The batch was
transferred to a 50-L extractor. Toluene (10 L) was added, and after
agitation, the layers were cut. The organic layer was washed with
water (2 L) and concentrated under reduced pressure (<40 °C).
The residue was flushed with toluene (4 L) to give an orange oil
containing the desired bromide (700 g at 91 wt % in toluene )
637 g, 91% yield, 97.6% de). 1H NMR (500 MHz, CDCl3) δ 7.48
(d, 2H, J ) 8.4 Hz), 7.25 (d, 2H, J ) 8.3 Hz), 4.19 (m, 1H), 3.56
(dd, 1H, J1 ) 3.7 Hz, J2 ) 10.0 Hz), 3.35 (dd, 1H, J1 ) 7.3 Hz,
J2 ) 9.9 Hz), 2.56 (m, 1H), 2.23 (br s, 1H), 1.57 (m, 1H), 1.21 (m,
2H), 0.89 (t, 9H, J ) 7.9 Hz), 0.86 (d, 3H, J ) 6.6 Hz), 0.78 (d,
3H, J ) 6.6 Hz), 0.53 (q, 6H, J ) 7.9 Hz); 13C NMR (125 MHz,
CDCl3) δ 134.3, 131.7, 130.1, 125.3 (q, J ) 281 Hz), 122.8, 65.2,
61.4 (q, J ) 29 Hz), 54.8, 40.6, 24.9, 23.2, 22.6, 6.6, 4.3; HRMS
calcd for C20H33BrF3NOSi, 467.1467; found, 468.1544 [M + 1];
Several coupling reagents were screened for the final amide
coupling. While CDI did not afford any of the desired product,
EDC‚HCl showed complete conversion but with a maximum
yield of 60%. Similarly, PyBOP gave good conversion but led
to the formation of an impurity that proved difficult to remove.
The amide coupling was finally performed with HATU and Et3N
in DMF at 0 °C, without necessitating the protection of the less-
nucleophilic R-trifluoromethylamine. After a sodium bicarbonate
quench and extractive workup, the product was crystallized from
IR (CDCl3, cm-1) 2961, 2914, 2880, 1262, 1173, 907, 730; [R]20
D
+39.0 (c ) 10.5, CHCl3). Anal. Calcd for C20H33BrF3NOSi: C,
51.28; H, 7.10; N, 2.99. Found: C, 51.55; H, 6.90; N, 2.89.
Supporting Information Available: Experimental procedures
and characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.-Q.; Noyori, R. Tetra-
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JO052430J
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