6784 J . Org. Chem., Vol. 66, No. 20, 2001
Mase et al.
is treated with 3 equiv of NaOH and extracted with
heptane. The organic phase, containing free dicyclohexy-
lamine, is removed, and the remaining aqueous solution
of the sodium salt of 2 (an extra 2 equiv of base) is treated
with 3 in CH3CN. The excess NaOH neutralizes two
equiv of acid from 3, and the mixture is treated with
HOBT and EDC. The resulting homogeneous mixture is
stirred for 16 h at ambient temperature to produce 1 in
80-85% yield after extractive workup and i-PrOAc/n-
heptane crystallization (eq 9).
novel zinc-MAEP complex was demonstrated to catalyze
a selective lithium enolate Michael reaction (which was
itself inactivated by MAEP) to produce the desired adduct
with high diastereoselectivity (this finding is in contrast
to the usual case where a transition-metal catalytically
activates inactive Zn-containing organometallics), (3)
Deoxofluor/BF3‚OEt2 was demonstrated as a highly ef-
ficient and selective reagent for the conversion of func-
tionalized ketones to their corresponding geminally
difluorinated derivatives (this reagent proved to be
superior to DAST in suppression of vinyl fluoride side
product formation), (4) n-Bu3MgLi was shown to be a
highly effective reagent for selective metal-halogen
exchange of 2,6-dihalopyridines and obviated the need
for cryogenic reaction conditions (as required with the
alkyllithium reagents). This approach should be widely
applicable to other aryl or vinyl halides. This work
enabled us to provide multi-kilograms of highly pure bulk
drug without the use of chromatographic purification.
Con clu sion
A highly efficient and convergent synthesis of drug
candidate 1 was accomplished in excellent overall yield.
The synthesis is highlighted by the following transforma-
tions: (1) a triisopropyl orthoformate-induced acetaliza-
tion was used as an alternative to the usual azeotropic
approach to give the desired mandelic acid derived
dioxolane with unprecedented stereoselectivity, (2) a
Exp er im en ta l Section
Aceta l F or m a tion : (2R,5R)-2-ter t-Bu tyl-5-p h en yl-1,3-
d ioxola n -4-on e (7). A slurry of (R)-mandelic acid (6) (7.00
kg) in toluene (70 L) was treated with triisopropyl orthofor-
mate (10.51 kg) added dropwise at 24 °C. The batch was stirred
at 24 °C for 2 h, until NMR monitoring showed a ratio of 15:6
of 82:18). Toluene (70 L) was added (to 170 L total volume),
and the batch was distilled maintaining a constant volume of
170 L by gradual addition of toluene. NMR analysis showed
complete consumption of 6 at this time. The batch was
concentrated to 70 L at 16 °C under vacuum. Gas chromato-
graphic analysis showed <1.5% of i-PrOH. p-Toluenesulfonic
acid (6 mol %, 525 g) and a solution of pivalaldehyde (5151 g)
in toluene (35 L) were added at 25-28 °C over a period of 50
min, and the reaction mixture was stirred at 28 °C for 30 min.
After confirming the completion of the reaction, by HPLC
analysis, the batch was diluted with toluene (90 L) to 200 L
and was washed with 5% aqueous sodium bicarbonate solution
(70 L) and 30% aqueous NaCl solution. The organic layer was
concentrated in vacuo to a minimum stirrable volume, n-
heptane was added (50 L), and the batch was further concen-
trated to a volume of 25 L. The same procedure was repeated
three times to switch the solvent to n-heptane. The resulting
slurry was filtered, washed with n-heptane (2 × 25 L), and
dried under reduced pressure to give the desired compound 7
(9.3 kg, 92% yield, 98.8% purity).5,53
Mich a el Ad d ition : (2R,5R)-2-ter t-Bu tyl-5-[(1R)-4-oxo-
2-cyclop en tyl]-5-p h en yl-1,3-d ioxola n -4-on e (17). A 3000
mL three-neck flask was equipped with mechanical stirrer and
temperature probe. Dimethoxyethane (DME, 350 mL) and 18
(176 mL) were mixed at room temperature and cooled to -20
°C. A solution of LDA (2.0 M, 159 mL) was added over 10 min
while keeping the temperature below -10 °C. The resulting
solution was cooled to -20 °C, and a solution of 7 (50.0 g) in
DME (470 mL, heating to 35 °C is required for complete
dissolution) was added dropwise over 45 min while keeping
the temperature below -15 °C. The resulting solution was
allowed to stand for 15 min at -15 °C. The ZnCl2-MAEP
complex 19 (20.9 g) and toluene (820 mL) were added sequen-
tially. The temperature was raised to 0 °C, and the mixture
was allowed to stand for 2 h. The reaction mixture was then
cooled to -78 °C, and a solution of 2-cyclopenten-1-one (20.9
mL) in toluene (82 mL) was added dropwise over 50 min while
(45) Yang, B. H.; Buchwald, S. L. J . Organomet. Chem. 1999, 576,
125-146. (b) Hartwig, J . F. Angew. Chem., Int. Ed. 1998, 37, 2046-
2067. (c) Wolfe, J . P.; Wagaw, S.; Marcoux, J .-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805-818. (d) Hartwig, J . F. Acc. Chem. Res. 1998,
31, 852-860. (e) Hartwig, J . F. Synlett. 1997, 329-340.
(46) (a) Vedejs, E.; Trapencieris, P.; Suna, E. J . Org. Chem. 1999,
64, 6724-6729. (b) Lindley, J . Tetrahedron 1984, 40, 1433-1456. (c)
Paine, A. J . J . Am. Chem. Soc. 1987, 109, 1496-1502. (d) Ott, H.;
Hardtmann, G.; Denzer, M.; Frey, A. J .; Gogerty, J . H.; Leslie, G. H.;
Trapold, J . H. J . Med. Chem. 1968, 11, 777-787.
(47) Hori, K.; Mori, M. J . Am. Chem. Soc. 1998, 120, 7651-7652.
(48) (a) Wolfe, J . P.; A° hman, J .; Sadighi, J . P.; Singer, R. A.;
Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367-6370. (b) Mann, G.;
Hartwig, J . F.; Driver, M. S.; Ferna´ndez, -R. C. J . Am. Chem. Soc.
1998, 120, 827-828. (c) J aime-Figueroa, S.; Liu, Y.; Muchowski, J .
M.; Putman, D. G. Tetrahedron Lett, 1998, 39, 1313-1316. (d) Hartwig,
J . F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman,
L. M. J . Org. Chem. 1999, 64, 5575-5580.
(49) Use of allylamine or diallylamine as a surrogate was abandoned
due to sluggish cleavage and its toxicity. For the deallylations: see
(a) Garro-Helion, F.; Merzouk, A.; Guibe´, F. J . Org. Chem. 1993, 58,
6109-6113. (b) Lemaire-Audoire, S.; Savignac, M.; Dupuis, C.; Geneˆt,
J . P. Bull. Chim. Soc. Fr. 1995, 132, 1157-1166. (c) Lemaire-Audoire,
S.; Savignac, M.; Geneˆt, J . P.; Bernard, J .-M. Tetrahedron Lett. 1995,
36, 1267-1270. (d) Honda, M.; Morita, H.; Nagakura, I. J . Org. Chem.
1997, 62, 8932-8936. (e) Alonso, E.; Ramon, D. J .; Yus, M. Tetra-
hedron. 1997, 53, 14355-14366.
(50) Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster,
B. S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer, R. A.;
Tschaen, D. M.; Verhoeven, T. R.; Reider, P. J . J . Org. Chem. 1994,
59, 6391-6394.
(51) Alternatively, amine moiety 3 could also be prepared from
commercially available 2-amino-6-bromopyridine (40). Conversion to
pivalamide 41 (quantitative) and metal-halogen exchange with i-
PrMgCl followed by quenching with DMF provided the aldehyde 42
(87-90%). Reductive amination with N-acyl-protected piperidine 35b
gave 43 which was readily deprotected in the presence of acid to furnish
the desired tris-HCl salt amine coupling partner 3 (86%).
(52) Mach, R. H.; Luedtke, R. R.; Unsworth, C. D.; Boundy, V. A.;
Nowak, P. A.; Scripko, J . G.; Elder, S. T.; J ackson, J . R.; Hoffman, P.
L.; Evora, P. H.; Rao, A. V.; Molinoff, P. B.; Childers, S. R.; Ehren-
kaufer, R. L. J . Med. Chem. 1993, 36, 3707-3720.
(53) All spectral data (1H, 13C NMR, IR, HR-MS, elemental analysis,
melting point and optical rotation) obtained were identical with those
of authentic samples.