A novel enantioselective alkylation and its application to the synthesis of an anticancer agent

Article abstract of DOI:10.1021/jo034380t

A novel enantioselective alkylation of double benzylic substrates with secondary electrophiles is reported. A simple norephedrine-based chiral ligand was synthesized that gives alkylation product in 95% yield and 95% ee. A unique water effect on the enantioselectivity was unveiled. Good to excellent ee values were obtained with a number of double benzylic substrates and secondary electrophiles. This novel reaction has been applied to the synthesis of a promising anticancer agent.

Full text of DOI:10.1021/jo034380t

A Novel En a n tioselective Alk yla tion a n d
Its Ap p lica tion to th e Syn th esis of a n
An tica n cer Agen t
Shen-Chun Kuo, Frank Chen, Donald Hou,
Agnes Kim-Meade, Charles Bernard, J inchu Liu,
Stacy Levy, and George G. Wu*
Chemical Process Research and Development,
Schering-Plough Research Institute, 1011 Morris Avenue,
Union, New J ersey 07083
george.wu@spcorp.com
Received March 24, 2003
F IGURE 1. Retrosynthetic analysis.
selective alklylation.4,5 These reported methods can be
divided into two types: those using a covalently bonded
chiral auxiliary4 and those using a noncovalently bonded
chiral mediator.5 We focused our attention on the straight-
forward chiral mediator-promoted alkylation. Most of the
chiral mediator-promoted alkylation substrates reported
bear a carbonyl-like group such as ketone, imine, and
hydrazone. There are few examples of chiral mediator-
promoted enantioselective alkylation of anions generated
from benzylic compounds.6 Those reported benzylic ex-
amples gave moderate yield and low ee values. Moreover,
only primary electrophiles were used for the alkylation.
For the preparation of 2a , we have developed a zinc-
promoted selective reduction of ketone 3 as shown in
Scheme 1.7 The three halogen substituents in ketone 3
remained essentially intact under the mild conditions.
The precursor ketone 3 was prepared from a Grignard-
promoted selective acylation.8 We initially reduced ke-
tone 3 to an alcohol in 80% ee with CBS reagent.9
Attempts to convert the alcohol to a related leaving group
followed by displacement with a nucleophile resulted in
racemization of the chiral center. We therefore turned
our effort to an alternative alkylation approach shown
in Scheme 2.
Abstr a ct: A novel enantioselective alkylation of double
benzylic substrates with secondary electrophiles is reported.
A simple norephedrine-based chiral ligand was synthesized
that gives alkylation product in 95% yield and 95% ee. A
unique water effect on the enantioselectivity was unveiled.
Good to excellent ee values were obtained with a number of
double benzylic substrates and secondary electrophiles. This
novel reaction has been applied to the synthesis of a
promising anticancer agent.
Lonafarnib (Sch 66336) is a potent farnesyl protein
transferase inhibitor (FPTI) and is currently in clinical
trial for the treatment of several types of cancer. FPT is
a key enzyme that facilitates the signal transduction
during cell proliferation.1 Therefore, inhibition of FPT
stops the progression of tumor cells.2 These important
clinical indications have stimulated research interests in
developing synthetic routes. Several racemic syntheses
were used for the initial supply of drug substance.3 Those
syntheses have more than 19 steps with poor yield.
Furthermore, the late stage resolution resulted in more
than 50% yield loss and the wrong enantiomer was very
difficult to racemize. These shortcomings and the re-
quirement of a large quantity of drug substance for
clinical studies prompted our effort toward an efficient
process. We now report the first example of an enantio-
selective alkylation of double benzylic substrates with
secondary electrophiles and its application to the syn-
thesis of Lonafarnib.
First, we studied the racemic alkylation with substrate
2a . Among the leaving groups (mesylate, brosylate,
nosylate, and iodide) tested, mesylate was found to be
the best for this alkylation. LDA was found to be an
We envisioned, as a key step, an enantioselective
alkylation for the formation of the benzylic chiral center
starting from a tricycle 2a and piperidine mesylate 1
shown in Figure 1. Various synthetic methods have been
reported for carbon-carbon bond formation via enantio-
(4) (a) Evans, D. A., et al. Encyclopedia of Reagents for Organic
Synthesis; Wiley: Chichester, UK, 1995; Vol. 1, p 345. (b) Gant, T. G.;
Meyers, A. I. Tetrahedron 1994, 50, 2297. (c) Evans, D. A.; Ennis, M.
D.; Mathre, D. J . J . Am. Chem. Soc. 1982, 104, 1737.
(5) (a) For a review see: O’Donnell, M. J . Alchim. Acta 2001, 34, 3.
(b) Serino, C.; Stehle, N.; Park, Y. S.; Florio, S.; Beak, P. J . Org. Chem.
1999, 64, 1160. (c) Corey, E. J .; Bo, Y.; Busch-Peterson, J . J . Am. Chem.
Soc. 1998, 120, 13000 and references therein. (e) Hoppe, I.; Marsch,
M.; Harms, K.; Boche, G.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1995,
34, 3419. (f) Sato, D.; Kawasaki, H.; Shimado, I.; Arata, Y.; Okamura,
K.; Date, T.; Koga, K. Tetrahedron 1997, 53, 7191. (g) Koga, K. Pure
Appl. Chem. 1994, 66, 1487. (h) Tomiok, K.; Shindo, M.; Koga, K. Chem.
Pharm. Bull. 1989, 37, 1120. (i) Dolling, U.-H.; Davis, P.; Grabowski,
E. J . J . Am. Chem. Soc. 1984, 106, 446.
(6) (a) Nozaki, H.; Aratani, T.; Toraya, T.; Noyori, R. Tetrahedron
1971, 27, 905. (b) Papasergio, R. I.; Skelton, B. W.; Twiss, P.; White,
A. H.; Raston, C. L. J . Chem. Soc., Dalton Trans. 1990, 1161.
(7) Yamamura, S.; Hirata, Y. J . Chem. Soc. 1968, 2887.
(8) (a) Poirier, M.; Chen, F.; Bernard, C.; Wong, Y.; Wu, G. Org.
Lett. 2001, 3, 3795. (b) Wu, G.; Wong, Y.; Poirier, M. Org. Lett. 1999,
1, 745.
(1) Barbcid, M. Annu. Rev. Biochem. 1987, 56, 779.
(2) Leonard, D. M. J . Med. Chem. 1997, 40, 2971.
(3) (a) Njoroge, F. G.; Taveras, A. G.; Kelly, J .; Remiszewski, S.;
Mallams, A.; Wolin, R.; Afonso, A.; Cooper, A. B.; Rane, D. F.; Liu, Y.;
Wong, J .; Vibulbhan, B.; Pinto, P.; Deskus, J .; Alvarez, C. S.; del
Rosario, J .; Connolly, M.; Wang, J .; Desai, J .; Rossman, R. R.; Bishop,
W. R.; Patton, R.; Wang, L.; Kirschmeier, P.; Bryant, M. S.; Nomeir,
A. A.; Lin, C. C.; Liu, M.; McPhail, A.; Doll, R. J .; Girijavallabhan, V.;
Ganguly, A. K. J . Med. Chem. 1998, 41, 4890. (b) Njoroge, F. G.;
Vibulbhan, B.; Wong, J . K.; White, S. K.; Wong, S.; Carruthers, N. I.;
Kaminski, J . J .; Doll, R.; Girijavallabhan, V.; Ganguly, A. K. Org. Lett.
1999, 1, 1371. (c) Morgan, B.; Zaks, A.; Dodds, D.; Liu, J .; J ain, R.;
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10.1021/jo034380t CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/10/2003
4984
J . Org. Chem. 2003, 68, 4984-4987

TABLE 1. Nor ep h ed r in e-Ba sed Med ia tor s
SCHEME 1. Red u ction of 3 to 2a
SCHEME 2
TABLE 2. Effect of Wa ter on th e En a n tioselectivity
entry
6d , equiv
water, equiv
ee, %
yield, %
1
2
3
1.8
1.8
1.8
0.0
0.7
1.0
55
85
95
50
92
95
richer the electron density on the aromatic ring the better
the ee and (2) meta substitution is better than ortho. The
rationally designed mediator, 6d , gave up to 88% ee.
One of the issues associated with the reaction with both
quinine and 6d was the inconsistency of ee values
obtained from run to run. We first suspected that water
was detrimental to the LDA reaction. Counter-intuitively,
a consistently lower range of ee values was observed
when moisture was vigorously excluded from the system.
To follow up on this unexpected observation, we then
spiked different amounts of water to the reaction mixture
prior to the addition of a second equivalent of LDA. To
our delight, water had a pronounced positive effect on
the ee as shown in Table 2. The higher the water contents
the better the ee with an optimum being 1.0 equiv. The
same trend was also true for the yield. With added water,
95% ee was consistently achieved with either 6d or
quinine. The added water was compensated by an equal
equivalent of LDA. Interestingly, addition of solid LiOH,
B(OH)3, MeOH, and AcOH had no effect on the ee. The
mechanism is under further investigation.
A number of substrates and electrophiles were sub-
jected to the chiral alkylation with either 6d or quinine
and their results are listed in Table 3. The following
points are worth noting. (1) The positive water effect has
been observed for all reactions.( 2) Good to excellent ee
values were achieved for all the substrates. (3) This
alkylation worked well for such a relatively symmetric
substrate as des-10 bromo analogue, 2b, (entries 7 and
8). (4) The substituent at the 4-position of the electrophile
has a distinct effect on the ee.
To complete the reaction, the alkylated product 4a was
hydrolyzed in situ and crystallized as N-acetyl-L-phenyl-
alanine salt, further enhancing the ee to >98%. Both
quinine and 6d can be readily recovered and recycled
without loss of ee. The commercially available quinine
was used for scale-up. After some practical modifications,
this novel chiral alkylation was scaled up to a 33 kg batch
size, producing more than 200 kg of 4-salt in 99% ee and
80% isolated yield. To complete the synthesis, 4-salt was
coupled with N-Boc-piperidine-4-acetic acid followed by
removal of the Boc and formation of the urea to give
Lonafarnib in excellent overall yield as outlined in
Scheme 3.
effective base.10 Reaction in THF generated only 15% of
the alkylated product. Elimination of the mesylate was
found to be the major pathway. Substitution of toluene,
a lesser polar solvent, for THF minimized the elimination
and increased the yield of alkylated product from 15%
to 85%. This is not surprising as more polar solvents favor
elimination.
With the success of racemic alkylation, we then studied
its chiral version by screening commercially available
chiral mediators. To test our secondary electrophiles, a
general procedure was developed. Thus, to a mixture of
1a , 2a , and a chiral mediator in toluene was added LDA
until a purple color was observed. Addition of a second
equivalent of LDA completed the alkylation. The first
equivalent of LDA neutralizes the alcohol in the mediator
while the second one deprotonates the substrate. The ee
of 4a was determined by chiral HPLC. Over 40 com-
mercially available mediators were screened and some
selected results are summarized in Scheme 2. Sparteine
did not give any chiral induction while D-valine sulfona-
mide produced 4a in 15% ee. Cinchonidine induced
20-30% ee; however, its methoxy derivatives, quinine
and hydroquinine, gave up to 85% ee. Apparently, the
extra methoxy on the quinoline moiety exerts great
influence on the enantioselectivity.
To improve the ee, we designed some mediators. On
the basis of the results in Scheme 2, we postulated a
three-point interaction between 2a and quinine. The
alkoxy and the bridgehead nitrogen are the first two sites
to chelate with lithium. The third point of interaction
comes from the π-stacking between the quinoline moiety
and the pyridine ring in 2a . The presence of an electron-
donating methoxy group enriches the electron density on
the aromatic ring and therefore enhances the π-stacking
effect. Norephedrine was selected as the starting material
for its easy derivatization. Both secondary and tertiary
amines were prepared and tested as shown in Table 1.
The ee values of 4a with tertiary amines only ranged
from 13 to 28%. The use of secondary amines produced
much better ee values. Table 1 also indicates that (1) the
In summary, we have developed a novel enantioselec-
tive alkylation of benzylic derivatives with secondary
(10) Villani, F. J .; Daniels, P. J .; Ellis, C. A.; Mann, T. A.; Wang,
K.; Wefer, E. A. J . Med Chem. 1972, 15, 750.
J . Org. Chem, Vol. 68, No. 12, 2003 4985

164 °C. 1H NMR (CDCl3) δ 8.38 (d, J ) 2.0 Hz, 1H), 7.46 (d, J
) 2.0 Hz, 1H), 7.44 (d, J ) 2.0 Hz, 1H), 7.14 (d, J ) 2.0 Hz, 1H),
4.45 (s, 2H), 3.10-3.20 (m, 4H). 13C NMR (CDCl3) δ 154.1, 148.5,
143.9, 141.7, 137.2, 135.8, 133.9, 131.6, 128.7, 125.5, 119.8, 41.7,
32.90, 32.7. Anal. Calcd for C14H10Br2ClN: C, 43.37; H, 2.58; N,
3.61; Br, 41.31; Cl, 9.17. Found: C, 43.33; H, 2.66; N, 3.69; Br,
41.06; Cl, 9.11.
TABLE 3. En a n tioselective Alk yla tion
Meth od A. En a n tioselective Alk yla tion w ith Qu in in e
a n d 1a to 4a . A mixture of 6.0 g (15.5 mmol) of the tricycle, 2a ,
and 5.0 g (17.9 mmol) of N-Boc-piperidine mesylate, 1a , in 25
mL of toluene was heated to 40 °C until all solid dissolved (30
min). The solution was cooled to 25 °C and transferred to another
flask containing 6.0 g (18.5 mmol) of quinine. To the resulting
mixture at 5-10 °C was added 1.5 M of LDA/monoTHF in
cyclohexane (ca. 13.4 mL, 20.1 mmol) until a red solution was
formed. To the red solution were sequentially added water (0.28
mL, 15.5 mmol) and 1.5 M of LDA/monoTHF (10.3 mL, 15.5
mmol). The reaction mixture was allowed to warm to between
14 and 18 °C. To the mixture at 14-18 °C was added the same
type of LDA (11.4 mL, 17.1 mmol) over a period of 3 h. The
reaction mixture was allowed to warm to between 20 and 25 °C
and agitated at this temperature for 18 h. The reaction was then
quenched by an addition of 36 mL of water. The precipitated
quinine was filtered and washed with 12 mL of toluene and 12
mL of water. The layers of the filtrate were separated and the
organic phase was washed with 24 mL of 7.6% sulfuric acid. The
toluene layer can be concentrate to give the N-Boc-protected
product, 4a , as a white solid (95% ee). Mp 172-174 °C. 1H NMR
(CDCl3) δ 8.31 (d, J ) 2.2 Hz, 1H), 7.40 (d, J ) 2.2 Hz, 1H), 7.36
(d, J ) 2.2 Hz, 1H), 7.00 (d, J ) 2.2 Hz, 1H), 4.76 (d, J ) 10.3
Hz, 1H), 3.94 (br s, 2H), 3.49 (td, J ) 14.0, 7.0 Hz, 1H), 3.13 (dt,
J ) 13.3, 4.3 Hz, 1H), 2.84 (tt, J ) 13.3, 4.3 Hz, 1H), 2.67 (dt, J
) 14.9, 4.5 Hz, 1H), 2.32 (br s, 2H), 2.22-2.05 (m, 1H), 1.30 (br
s, 9H), 1.25-1.05 (m, 3H). 13C NMR (CDCl3) δ 115.1, 154.7,
147.3, 142.6, 141.3, 137.4, 135.1, 132.9, 131.0, 129.1, 127.2, 118.8,
79.4, 58.2, 43.6, 42.0, 32.0, 31.7, 31.4, 30.3, 28.4. Anal. Calcd
for C24H27Br2ClN2O2: C, 50.51; H, 4.77; N, 4.91. Found: C, 50.50;
H, 4.73; N, 4.70.
SCHEME 3. Syn th esis of Lon a fa r n iba
In the total synthesis, the toluene layer was further processed
as following. To the toluene phase was added 36 mL of 20%
sulfuric acid while maintaining the temperature below 80 °C.
The resulting mixture was heated to 85 °C for 4 h to complete
the hydrolysis of the Boc group. After the mixture was cooled to
25 °C, 15.1 mL of 25% ammonium hydroxide was added. The
layers were separated. The organic layer was concentrated under
vacuum to 48 mL. To the concentrated mixture was added 114
mL of ethanol. The mixture was concentrated to a final volume
of 48 mL and was then cooled to between 20 and 25 °C. To the
resulting mixture was added 3 g of N-acetyl-L-phenylalanine
dissolved in 120 mL of ethanol. The mixture was concentrated
under vacuum to 48 mL. The concentrated batch was stirred at
70 °C for 1 h and cooled to room temperature. The precipitate
was filtered and washed with t-BuOMe/EtOH (1:1) and dried
at 55 °C under vacuum to give 10.5 g (80% yield, 98% ee) of
4-salt. The corresponding free base was obtained by dissolving
the salt in water, adjusting pH, and extracting with toluene.
Characterization of the free base. Mp 179-182 °C. 1H NMR
(CDCl3) δ 8.44 (d, J ) 2.2 Hz, 1H), 7.53 (d, J ) 2.2 Hz, 1H), 7.48
(d, J ) 2.2 Hz, 1H), 7.12 (d, J ) 2.2 Hz, 1H), 4.90 (d, J ) 10.3
Hz, 1H), 3.64 (td, J ) 13.9, 4.4 Hz, 1H), 3.27 (dt, J ) 17.4, 4.4
Hz, 1H), 3.15-2.90 (m, 3H), 2.79 (dt, J ) 14.8, 4.5 Hz, 1H), 2.49-
2.41 (m, 2H), 2.32-2.20 (m, 1H), 1.55-1.40 (m, 2H), 1.35-1.20
(m, 2H). 13C NMR (CDCl3) δ 155.8, 147.5, 142.9, 141.6, 138.0,
135.4, 133.1, 131.3, 129.4, 128.5, 127.6, 119.1, 59.2, 47.2, 47.0,
42.5, 33.3, 32.4, 32.1, 32.0. HRMS 470.9661 (MH+), calcd for
a
Reagents and conditions: (i) LDA/quinine/toluene; (ii)
H2SO4; (iii) N-Boc-piperidine acetic acid/HOBT/EDCl; (iv) HCl/
urea/NMP.
electrophiles. We have also designed and synthesized a
highly effective norephedrine-based mediator. In addi-
tion, we have discovered a unique water effect on the
enantioselectivity. With the novel alkylation, we have not
only achieved an 8-step synthesis of Lonafarnib but also
scaled up production in the plant.
Exp er im en ta l Section
Zin c Red u ction of Keton e 3 to 2a . To a mixture of the
tricyclic ketone 3 (200 g, 0.5 mol) and acetic anhydride (360 mL)
in THF (700 mL) at -25 °C were sequentially added zinc dust
(113 g, 1.7 mol) and trifluoroacetic acid (84 mL, 1.1mol) dropwise
over a 2-h period. The temperature of the mixture was slowly
raised to 18 °C over a period of 2 h and kept at 18 °C for 20 h.
A filter aid (Supercel) and toluene (200 mL) were added and
the mixture was filtered. The extra zinc and inorganic residue
were washed with toluene (40 mL). The filtrate and wash were
combined, and washed with water (1 L), 10% NaOH (160 L),
and water (1 L). After layer separation, the organic layer was
concentrated to 600 mL. 2-Butanol (1.6 L) was added to the
mixture, which was then concentrated to 600 mL under vacuum.
Again, 800 mL of 2-butanol was added and the mixture was
heated to reflux for 1 h. The mixture was cooled to between 0
and 5 °C and stirred for 4 h. The solid was filtrated and washed
with 400 mL of 2-butanol. The wet cake was dried under vacuum
at 70 °C to give 162 g (84%) of 2a as a crystalline solid. Mp 163-
C
19H20Br2ClN2 (MH+) 470.9661.
E n a n t ioselect ive Alk yla t ion of 2b w it h Qu in in e a s a
Liga n d . Mehtod A was followed with 0.5 g of des-3-bromo 2b
analogue and 1a to give 4f in 80% ee. The alkylated product
was purified on a silica gel column, eluting with hexanes/EtOAc
(1:1), to give des-10-bromo 4f as a white solid. Mp 85-90 °C. 1H
NMR (CDCl3) δ 8.32 (d, J ) 2.0 Hz, 1H), 7.49 (s, 1H), 7.06 (d, J
) 2.0 Hz, 1H), 7.03 (dd, J ) 8.1, 2.1 Hz, 1H), 6.99 (d, J ) 8.1
Hz, 1H), 4.12-3.95 (m, 2H), 3.81 (d, J ) 10.2 Hz, 1H), 3.47-
4986 J . Org. Chem., Vol. 68, No. 12, 2003

3.15 (m, 2H), 2.90-2.70 (m, 2H), 2.58-2.35 (m, 2H), 2.25-2.08
(m, 1H), 1.36 (s, 9H), 1.35-1.00 (m, 3H).
57.3, 52.7, 15.8. Anal. Calcd for C19H25NO4: C, 68.86; H, 7.60;
N, 4.23. Found: C, 68.68; H, 7.74; N, 4.30.
E n a n t ioselect ive Alk yla t ion of 2c w it h Qu in in e a s a
Liga n d . Mehtod A was followed with 0.8 g of 2c and 1a to give
4g in 85% ee. The crude product was chromatographed on silica
gel, eluting with hexanes/EtOAC (4:1), to give 0.97 g (76%) of
4g as a white solid. Mp 80-85 °C. 1H NMR (CDCl3) δ 8.32 (d, J
) 3.8 Hz, 1 H), 7.39 (d, J ) 1.4 Hz, 1H), 7.29 (d, J ) 7.5 Hz,
1H), 7.05 (s, 1H), 7.00 (dd, J ) 7.5, 3.8 Hz, 1H), 4.85 (d, J )
10.3 Hz, 1H), 4.00 (br s, 2H), 3.58 (td, J ) 14.3, 2.6 Hz, 1H),
3.23-3.19 (m, 1H), 3.00-2.80 (m, 1H), 2.78-2.60 (m, 1H), 2.46
(br s, 2H), 2.35-2.15 (m, 2H), 1.36 (br s, 9H), 1.34-1.20 (m, 3H).
13C NMR (CDCl3) δ 156.8, 155.1, 146.8, 143.4, 139.7, 138.4,
133.6, 133.1, 131.2, 129.5, 127.6, 122.4, 79.7, 59.3, 42.6, 32.6,
32.5, 31.8, 30.8, 28.8. MS (MH+): 491. Calcd for C24H29BrClN2O2
(MH+): 491.
Con ver sion of 4-sa lt to 8. To a 500-mL flask were sequen-
tially charged 10 g (14.4 mmol) of 4-salt, 100 mL of toluene, 50
mL of 25% NaOH, and 100 mL of water. The resulting mixture
was agitated for 30 min and 1 g of Celite was added. The mixture
was filtered and washed with 10 mL of toluene. The layers were
separated and the organic layer was washed with 4 × 50 mL of
water. To the organic layer were added 40 mL of DMF, 0.20 g
(14.7 mmol) of 1-hydroxybenzotriazole (HOBT), 3.2 g (16.6 mmol)
of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide/HCl (EDCl/Cl),
and 4.0 g of 1-N-tert-butoxy-carbonylpiperidinyl-4-acetic acid.
The mixture was stirred at room temperature to completion
(about 18 h) as monitored by HPLC. To the reaction mixture
was added 50 mL of water and the layers were separated. The
organic layer was sequentially washed with 20 mL of 10% acetic
acid solution, 40 mL of water, 3% NaOH solution, 3 × 40 mL of
water, and 40 mL of brine. The organic layer was concentrated
to 60 mL and chromatographed on silica gel, eluting with EtOAc/
toluene (1:1). The fractions containing the product were com-
bined, concentrated, and treated with 3.5 g of activated basic
alumina. The mixture was filtered and washed with toluene.
The filtrate was concentrated and treated with EtOAc and
heptane to give after filtration 8.0 g (80%) of 8 as a solid. Mp
171-173 °C. 1H NMR (CDCl3) δ 8.44 (d, J ) 2.0 Hz, 1H), 7.55
(dd, J ) 5.0, 2.0 Hz, 1H), 7.49 (t, J ) 2.0 Hz, 1H), 4.89 (dd, J )
10.3, 3.5 Hz, 1H), 4.63-4.57 (m, 1H), 4.18-3.98 (m, 2H), 3.82
(t, J ) 12.7 Hz, 1H), 3.64 (tt, J ) 13.8, 3.6 Hz, 1H), 3.60 (dt, J
) 17.7, 4.3 Hz, 1H), 2.98 (tt, J ) 13.8, 3.6 Hz, 1H), 2.90-2.75
(m, 2H), 2.75-2.60 (m, 2H), 2.45-2.30 (m, 2H), 2.30-2.15 (m,
2H), 2.05-1.90 (m, 1H), 1.80-1.20 (m, 6H), 1.45 (s, 9H), 1.20-
1.05 (m, 2H).
Con ver sion of 8 to Lon a fa r n ib. To a 250-mL flask were
added 7.07 g (10.2 mmol) of 8 and 35 mL of ethanol. To the above
solution was added slowly 42 mL of 3 N HCl while maintaining
the temperature below 25 °C with an ice bath. The mixture was
stirred at room temperature for about 6 h to complete the
hydrolysis. The reaction mixture was concentrated under vacuum
to about 35 mL. To the concentrated mixture was added 17.5
mL of 1-methyl-2-pyrrolidinone and the pH was carefully
adjusted to 9 with 3 N NaOH. To the resulting mixture was
added 28.0 g of urea. The mixture was heated to 110 °C for about
10 h and cooled to 50 °C. The pH of the reaction mixture was
adjusted to 6 with 3 N HCl. The precipitate was filtered and
washed with 140 mL of water to give after drying 5.44 g (84%)
of Lonafarnib. Mp 222-223 °C. δ 1H NMR (CDCl3) 8.38 (d, J )
2.2 Hz, 1H), 7.48 (dd, J ) 4.8, 2.0 Hz, 1H), 7.43 (d, J ) 2.0 Hz,
1H), 7.08 (d, J ) 2.2 Hz, 1H), 4.82 (dd, J ) 10.3, 4.2 Hz, 1H),
4.53 (t, J ) 7.4 Hz, 1H), 4.34 (s, 2H), 3.90-3.70 (m, 3H), 3.55
(tt, J ) 13.8, 4.3 Hz, 1H), 3.20 (dt, J ) 17.6, 4.2 Hz, 1H), 2.95-
2.82 (m, 1H), 2.80-2.70 (m, 4H), 2.37-2.30 (m, 2H), 2.20-2.15
(m, 2H), 2.00-1.95 (m, 1H), 1.70 (d, J ) 12.8 Hz, 2H), 1.48-
1.00 (m, 6H). 13C NMR (CDCl3, two rotamers) 169.5, 158.3, 155.1,
155.0, 146.8, 144.1, 144.1, 137.8, 137.7, 136.3, 136.2, 132.4, 130.4,
129.8, 129.7, 126.7, 126.7, 118.8, 58.3, 58.2, 45.4, 45.3, 43.9, 41.4,
41.2, 40.8, 39.0, 38.9, 33.1, 32.7, 32.0, 31.8, 31.4, 31.3, 30.8, 30.6.
Anal. Calcd for C27H31Br2ClN4O2: C, 50.76; H, 4.89; N, 8.77.
Found C, 50.84; H, 4.77; N, 8.73.
En a n tioselective Alk yla tion w ith Qu in in e to 4b, 4c, a n d
4d . These alkylation products were all converted to the free
amine 4 for charaterization.
Alk yla tion w ith Cycloh exyl Mesyla te w ith Qu in in e to
4e. Mehtod A was followed and 4e was isolated with silica gel
column, eluting with hexanes/ethyl acetate (1:1) to give the
alkylated product as a white solid in 65% ee. Mp 165-167 °C.
1H NMR (CDCl3) δ 8.36 (d, J ) 2.2 Hz, 1H), 7.44 (dd, J ) 2.2,
1.1 Hz, 1H), 7.03 (d, J ) 2.2 Hz, 1H), 4.77 (d, J ) 10.3 Hz, 1H),
3.59 (td, J ) 13.2, 4.5 Hz, 1H), 3.34 (dt, J ) 17.4, 4.5 Hz, 1H),
2.88 (td, J ) 13.2, 4.7 Hz, 1H), 2.69 (dt, J ) 14.8, 4.7 Hz, 1H),
2.12-2.04 (m, 1H), 1.70-1.23 (m, 4H), 1.22-0.95 (m, 6H). 13C
NMR (CDCl3) δ 156.5, 147.5, 142.9, 141.6, 138.8, 135.4, 133.0,
131.2, 129.4, 127.6, 119.0, 59.3, 43.9, 32.7, 32.3, 32.0, 31.8, 27.0,
26.8, 26.5. MS (MH+): 468. Calcd for C20H21Br2ClN (MH+): 468.
Meth od B. En a n tioselective Alk yla tion w ith Nor ep h e-
d r in -Ba sed Liga n d 6d to 4a . The tricyclic methylene com-
pound 2a (50 g, 0.13 mol), trimethoxybenzyl-norephedrine ligand
6d (77 g in 436 mL of toluene solution, 1.8 equiv), and N-Boc
piperidine mesylate 1a (43.2 g, 1.2 equiv) were dissolved in
toluene (1 L). To the mixture at between 0 and 5 °C were
sequentially added lithium diisopropyl amide mono(tetrahydro-
furan) solution (1.5 M in cyclohexane) (155 mL, 1.8 equiv) in 20
min and water (2.3 mL, 1 equiv) over 10 min. The remaining
LDA (172 mL, 2 equiv) was added slowly over 4 to 5 h at between
15 and 20 °C. The reaction mixture was stirred at 25 °C for
another 4 h as monitored by HPLC. Once the reaction is
completed, 1 N hydrochloric acid (1.2 L) was added to precipitate
the chiral inducing ligand as hydrochloric acid salt. The solid
was filtered and the layers were separated. The organic layer
was concentrated and the residue was separated on a silica gel
column to give 4a (95% yield and 95% ee) as a solid. Without
addition of the water into the reaction mixture the ee ranged
from 50 to 88%.
P r ep a r a tion of Nor ep h ed er in e-Ba sed Liga n d 6d . A
mixture of (1R,2S)-(-)-norephedrine (100 g) and 3,4,5-trimeth-
oxybenzaldehyde (143 g) was dissolved in ethanol (1 L). The
resulting solution was brought to a gentle reflux for 4-5 h. The
reaction mixture was then cooled with an ice batch, and sodium
borohydride (37 g) was added protionwise. The reaction mixture
was stirred at room temperature overnight. Once reduction was
completed, excess sodium borohydride was destroyed by adding
water (25 mL). The organic solvent was evaporated and the
product was extracted with ethyl acetate. The organic layer was
concentrated to give a colorless oil. The oil was dissolved in 400
mL of ethanol. To the resulting solution was added slowly
aqueous hydrobromic acid (48%, 73 mL). The precipitate was
stirred at room temperature for 1 h and filtered to give crude
6d as HBr salt. The crude salt was recrystallized in a mixture
of methanol/diethyl ether (12:1). The recrystallized salt was
converted to a free base with diluted aqueous sodium hydroxide.
The free base was extracted with toluene. The toluene was then
removed to give 114 g of 6d (87%) as a colorless oil. 1H NMR
(CDCl3) δ 7.25-7.33 (m, 5H), 6.56 (s, 2H), 4.80 (d, J ) 3.8 Hz,
1H), 3.86 (s, 6H), 3.84 (s, 3H), 3.82 (s, 2H), 3.00 (qd, J ) 6.5, 3.8
Hz, 1H), 0.89 (d, J ) 6.5 Hz, 1H). 13C NMR (CDCl3) δ 154.3,
142.2, 139.0, 136.4, 129.1, 128.2, 127.10, 106.0, 74.4, 62.0, 59.1,
Ack n ow led gm en t. We thank Mr. Zhixing Ding, Dr.
Mingsheng Huang, J ie Xie, and Ms. J acqueline Klug for
their help on this project and Drs. Doris Schumacher
and Michael Mitchell for their support and proof-reading
of the manuscript.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 2a ,b,c, 4a , 4, 4-salt, 4e,f,g,
5a ,b,c, 6a ,b,c,d ,e, 8, and Lonafarnib and a chiral HPLC
chromatogram for 4a . This material is available free of charge
via the Internet at http://pubs.acs.org.
J O034380T
J . Org. Chem, Vol. 68, No. 12, 2003 4987