Asymmetric synthesis of the C3α fragment of 5,6-dihydro-α-pyrone nonpeptidic HIV-1 protease inhibitors

Full text of DOI:10.1021/jo990278d

4980
J . Org. Chem. 1999, 64, 4980-4984
ing these potential interactions with the enzyme would
result in an increase in HIV protease inhibitory activity.
The targetted analogues all possessed the same absolute
configuration at the C3R side chain position, and some
analogues contained an additional chiral center at C-6
of the dihydropyrone ring (2, R1 * R2). Three dihydro-
pyrone compounds (e.g., 2a -c) of this class were consid-
ered as potential third generation candidates, and just
recently 2c7-10 was selected for clinical trials. To facilitate
the synthesis of analogues, as well as to explore prepara-
tive scale syntheses of a potential drug candidate, we
embarked upon an effort to streamline the synthesis of
these substituted dihydropyrones.
Asym m etr ic Syn th esis of th e C3r F r a gm en t
of 5,6-Dih yd r o-r-p yr on e Non p ep tid ic HIV-1
P r otea se In h ibitor s
Donna L. Romero,* Peter R. Manninen,
Fusen Han,† and Arthur G. Romero*
Medicinal Chemistry Research and Structural, Analytical &
Medicinal Chemistry, Pharmacia & Upjohn,
Kalamazoo, Michigan 49001
Received February 16, 1999
One promising strategy for the treatment of HIV
infection is the administration of drugs that inhibit the
virally encoded protease.1 The most extensively studied
inhibitors have been peptidomimetic compounds that
contain transition-state inserts instead of the usual
dipeptidic cleavage sites found in the substrates of HIV
protease.2 These types of compounds generally suffer
from low oral bioavailability and rapid excretion. Exten-
sive structure-activity relationship (SAR) studies in
concert with structure-based design have led to the
synthesis of inhibitors with reduced peptidic nature and
correspondingly greater oral bioavailability. Several of
these compounds have recently been approved by the
FDA as therapeutic agents for the treatment of HIV
infection. Previous reports from Pharmacia & Upjohn
describe the identification of phenprocoumon (1) as a
nonpeptidic lead HIV protease inhibitor.3 Subsequent
iterative cycles of structure-based design led to the
discovery of three generations of clinical candidates.4
The third generation candidate was derived from a
series of analogues of a 5,6-dihydro-4-hydroxy-2-pyrone
template (e.g., 2).5 This template was attractive for
exploring the steric and electronic requirements of the
active site because of the ability of a C-6 disubstituted
dihydropyrone to fill the S2 and S2′ pockets6 of the HIV
protease enzyme active site. It was thought that exploit-
Retrosynthetic analysis of 2 led to â-ketoester 3,
because conversion of â-ketoesters to dihydropyrones is
well precedented (Scheme 1).11,12 Because we were seek-
ing a route amenable to large scale synthesis, we were
pleased to note that this retrosynthetic analysis would
likely allow for introduction of the stereogenic center at
C3R by an efficient catalytic asymmetric hydrogenation
of a substituted acrylic acid such as 5 or 6. To examine
this possibility, 713 was subjected to Ru(II)(R)-BINAP-
(OAc)2-catalyzed hydrogenation (Scheme 2).14 Although
7 possessed an aromatic nitro group, which is ordinarily
highly sensitive to catalytic hydrogenation conditions, we
were optimistic that the homogeneous Ru catalyst would
provide the needed chemoselectivity owing to the antici-
† Structural, Analytical & Medicinal Chemistry.
(1) (a) Blundell, T. L.; Lapatto, R.; Wilderspin, A. F.; Hemmings, A.
M.; Hobart, P. M.; Danley, D. E.; Whittle, P. J . Trends Biol. Sci. 1990,
15, 425-430. (b) Kempf, D. J .; Sham, H. L. Curr. Pharm. Res. 1996,
2, 225-246.
(2) (a) Robins, T.; Plattner, J . J . AIDS 1993, 6, 162-170. (b)
Thaisrivongs, S. Chapter 14. HIV Protease Inhibitors. Annu. Rep. Med.
Chem. 1994, 29, 133-144.
(3) Thaisrivongs, S.; Tomich, P. K.; Watenpaugh, K. D.; Chong, K.-
T.; Howe, W. J .; Yang, C.-P.; Strohbach, J . W.; Turner, S. R.; McGrath,
J . P.; Bohanon, M. J .; Lynne, J . C.; Mulichak, A. M.; Spinelli, P. A.;
Hinshaw, R. R.; Pagano, P. J .; Moon, J . G.; Ruwart, M. J .; Wilkinson,
K. F.; Rush, B. D.; Zipp, G. L.; Dalga, R. J .; Schwende, F. J .; Howard,
G. M.; Padbury, G. E.; Toth, L. N.; Zhao, Z.; Koeplinger, K. A.; Kakuk,
T. J .; Cole, S. L.; Zaya, R. M.; Piper, R. C.; J effrey, P. J . Med. Chem.
1994, 37, 3200-3204.
(4) Skulnick, H. I.; J ohnson, P. D.; Howe, W. J .; Tomich, P. K.;
Chong, K.-T.; Watenpaugh, K. D.; J anakiraman, M. N.; Dolak, L. A.;
McGrath, J . P.; Lynn, J . C.; Horng, M.-M.; Hinshaw, R. R.; Zipp, G.
L.; Ruwart, M. J .; Schwende, F. J .; Zhong, W.-Z.; Padbury, G. E.; Dalga,
R. J .; Shiou, L.; Possert, P. L.; Rush, B. D.; Wilkinson, K. F.; Howard,
G. M.; Toth, L. N.; Williams, M. G.; Kakuk, T. J .; Cole, S. L.; Zaya, R.
M.; Lovasz, K. D.; Morris, J . K.; Romines, K. R.; Thaisrivongs, S.;
Aristoff, P. A. J . Med. Chem. 1995, 38, 4968-4971.
(7) Thaisrivongs, S.; Skulnick, H. I.; Turner, S. R.; Strohbach, J .
W.; Tommasi, R. A.; J ohnson, P. D.; Aristoff, P. A.; J udge, T. M.;
Gammill, R. B.; Morris, J . K.; Romines, K. R.; Chrusciel, R. A.;
Hinshaw, R. R.; Chong, K.-T.; Tarpley, W. G.; Poppe, S. M.; Slade, D.
E.; Lynne, J . C.; Horng, M.-M.; Tomich, P. K.; Seest, E. P.; Dolak, L.
A.; Howe, W. J .; Howard, G. M.; Schwende, F. J .; Toth, L. N.; Padbury,
G. E.; Wilson, G. J .; Shiou, L.; Zipp, G. L.; Wilkinson, K. G.; Rush, B.
D.; Ruwart, M. J .; Koeplinger, K. A.; Zhao, Z.; Cole, S.; Zaya, R. M.;
Kakuk, T. J .; J anakiraman, M. N.; Watenpaugh, K. D. J . Med. Chem.
1996, 39, 4349-4353.
(8) This route took advantage of chemistry previously developed for
the synthesis of the first generation clinical candidate: J udge, T. M.;
Phillips, B.; Morris, J . K.; Lovasz, K. D.; Romines, K. R.; Luke, G. P.;
Tulinsky, J .; Tustin, J . M.; Chrusciel, R. A.; Dolak, L. A.; Seest, E. P.;
Mizsak, S. A.; Watt, W.; Morris, J .; Gammill, R. B.; Vandervelde, S.
L. J . Am. Chem. Soc. 1997, 119, 3627-3628.
(9) J udge, R. M.; Phillips, G.; Morris, J . K.; Lovasz, K. D.; Romines,
K. R.; Luke, G. P.; Tulinsky, J . M.; Tustin, J . M.; Chrusciel, R. A.;
Dolak, L. A.; Mizsak, S. A.; Watt, W.; Morris, J .; Vander Velde, S. L.;
Strohbach, J . W.; Gammill, R. B. J . Am. Chem. Soc. 1997, 119, 3627-
3628.
(10) Fors, K. S.; Gage, J . R.; Heier, R. F.; Kelly, R. C.; Perrault, W.
R.; Wicnienski, N. J . Org. Chem. 1998, 63, 7348-7356.
(11) Huckin, S. N.; Weiler, L. Tetrahedron Lett. 1971, 50, 4835-
4838.
(5) Thaisrivongs, S.; Romero, D. L.; Tommasi, R. A.; J anakiraman,
M. N.; Strohbach, J . W.; Turner, S. R.; Biles, C.; Morge, R. A.; J ohnson,
P. D.; Aristoff, P. A.; Tomich, P. K.; Lynn, J . C.; Horng, M.-M.; Chong,
K.-T.; Hinshaw, R. R.; Howe, W. J .; Finzel, B. C.; Watenpaugh, K. D.
J . Med. Chem. 1996, 39, 4630-4642.
(6) Sn and Sn′ refer to the nomenclature for enzyme binding pockets
as described in Schechter, I.; Berger, A. Biochem. Biophys. Res.
Commun. 1967, 27, 157-162.
(12) Peterson, J . R.; Winter, T. J .; Miller, C. P. Synth. Comm. 1988,
18(9), 949-963.
10.1021/jo990278d CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/06/1999

Notes
J . Org. Chem., Vol. 64, No. 13, 1999 4981
Sch em e 1. Retr osyn th etic An a lysis
Sch em e 3. Ap p r oa ch es To Obta in
Ster eoch em ica lly P u r e 12
Sch em e 2. F ir st Asym m etr ic Hyd r ogen a tion
Attem p t
Sch em e 4. F in a l Syn th etic Rou te To Obta in
Op tica lly P u r e 17
pated relatively poor coordinating ability of the nitro
group. Indeed, hydrogenation of 7 at 40 psi cleanly
afforded carboxylic acid 8 with no trace of other products
by HPLC analysis; however, 8 was obtained in very poor
optical yield (6% ee). Furthermore, although it has been
demonstrated that the hydrogen pressure can exert a
large influence on the optical yield for certain substituted
acrylic acids,15 only a slight improvement (16% ee) was
found when the reaction was repeated using 1800 psi
hydrogen pressure.16
At this point, we decided to pursue the asymmetric
hydrogenation of the geometrical isomer of the acrylic
acid. To prepare 10 (Scheme 3), the roles of the coupling
partners were reversed. Methyl propionyl acetate (9) was
cleanly converted to enol triflate 10,17 which smoothly
underwent Pd(0)-catalyzed coupling with 1118 to provide
stereochemically pure 12 in an overall yield of 72% from
9. Although this procedure worked well, it relied on the
relatively costly and hazardous triflic anhydride, which
was undesirable for large scale synthesis. A search for
an alternative to enol triflate 10 led to a straightforward
procedure for the stereoselective trans addition of H-I
to alkynoates.19 Simply stirring ethyl pent-2-ynoate (13)
with lithium iodide in acetic acid at 70 °C for 5 h afforded
an 88% yield of Z-alkenyliodide 1420 (Scheme 4). This
iodoalkene reacted cleanly with 11 under Pd(0) catalysis
to afford 12 in 79% yield on a multigram scale.21 Careful
dibenzylation of the aniline nitrogen followed by saponi-
fication of the ester gave crystalline 15 in 89% yield.
Subjecting 15 to 0.5% Ru(II)(R)-BINAP catalyst at 40 psi
hydrogen pressure afforded 16 in a 95:5 (R)/(S) enantio-
meric ratio, upgraded to >99% optical purity by a single
recrystallization (87% chemical yield on a 53 g scale).16
(13) Compound 7 was synthesized from commercially available ethyl
3-nitrobenzoyl acetate, which was converted to the (Z)-enolphosphate
under kinetic conditions with sodium hydride and chlorodiethyl
phosphate according to the method of Weiler and Sum (Can. J . Chem.
1979, 57, 1431-1441). This reaction afforded a 94% yield of stereo-
chemically pure enolphosphate. Pd-catalyzed cross-coupling reaction
of the enol phosphate with diethylzinc provided stereochemically pure
7 in 85% yield after saponification to the ester and crystallization
(multigram scale).
(14) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori, R. J .
Org. Chem. 1987, 52, 3174-3176. The hydrogenation complex was
prepared according to Kitamura, M.; Tokunaga, M.; Noyori, R. J . Org.
Chem. 1992, 57, 4053-5054. More recently we have had success with
other acrylic acids using an alternative and more readily prepared
BINAP-ruthenium(II) catalyst: Mashima, K.; Kusano, K.; Ohta, T.;
Noyori, T.; Takaya, H. J . Chem. Soc., Chem. Commun. 1989, 1208-
1210.
(15) Noyori, R. Asymmetric Catalysis in Organic Synthesis; J ohn
Wiley & Sons: New York, 1994; pp 32-33.
(16) The % ee was determined by reducing the carboxylic acid to
the alcohol with borane methyl sulfide and analyzing the alcohol by
HPLC using a Chiracel OD-H column (2-propanol/hexane). No attempt
was made to determine the absolute configuration of the major isomer
of 8.
(17) Attempts to couple the (Z)-enolphosphate prepared from 9 with
the arylzinc reagent 11 were unsuccessful because 11 reacted slug-
gishly under Pd(0)-catalyzed cross-coupling conditions and the reaction
could not be driven to completion. Cu(I) catalysis with copper(I)
bromide (1:1) left the enol phosphate unchanged.
(18) Prepared in situ from the commercially available Grignard
reagent (Aldrich) and ZnCl2.
(19) A report indicating that nonterminal alkynes were poor sub-
strates: Ma, S.; Lu, X. J . Chem. Soc., Chem. Commun. 1990, 1643-
1644. A subsequent report that nonterminal alkynes did indeed work
well: Marek, I.; Allexakis, A.; Normant, J . F. Tetrahedron Lett. 1991,
32, 5329-5332.
(20) Stable after several months of storage.
(21) An example of an arylzinc reacting with an alkenyliodide under
Pd(0) catalysis: Tucker, C.; Majid, T. N.; Knochel, P. J . Am. Chem.
Soc. 1992, 114, 3983-3985.

4982 J . Org. Chem., Vol. 64, No. 13, 1999
Notes
Sch em e 5. Con ver sion of 17 to 2a (P NU-140135)
was prepared in five steps from optically pure ester 17
in 23% yield, resulting in a 12% overall yield of 2a from
commercially available 13 (unoptimized).
Con clu sion
A synthetic process that affords HIV protease inhibitor
2a (PNU-140135) in 11 steps and 12% overall yield from
commercially available material was developed. The
synthesis relied on an efficient asymmetric hydrogenation
of a stereochemically pure â-substituted (Z)-cinnamic acid
to set the C3R stereocenter. This methodology is poten-
tially useful in the search for an economical route to the
clinical candidate PNU-140690, which contains the iden-
tical C3R substitution.
Exp er im en ta l Section
All reactions were run under an atmosphere of nitrogen,
unless otherwise indicated. Methyl 2-pentynoate was obtained
from Farchan Chemical Co.; methyl propionyl acetate, 3-[bis-
(trimethylsilyl)amino]phenylmagnesium chloride, and etheral
anhydrous zinc chloride were obtained from Aldrich Chemical
Co.; bis(triphenylphosphine)palladium chloride and anhydrous
zinc chloride were obtained from Strem Chemical Co.; and (R)-
BINAP was obtained from T.C.I.
Meth yl (Z)-3-Tr iflu or om eth ylsu lfon yloxy-2-p en ten oa te
(10). A three neck flask was fitted with an overhead stirrer, and
DME or toluene (500 mL) was added to sodium hydride (7.080
g of a 60% dispersion in oil, 177.1 mmol) that had been washed
with pentane (2×). This slurry was cooled to 0 °C, and methyl
3-oxopentoate (20.19 g, 161.0 mmol) was added over 10 min, with
hydrogen gas evolution. The resulting slurry was cooled to -30
°C, and trifluoromethanesulfonic anhydride (50.0 g, 177 mmol)
was added by syringe. Stirring was continued for 30 min, at
which point the slurry was allowed to warm to 25 °C and stir
overnight. Optionally, the slurry could be filtered through
diatomaceous earth before extractive workup. The slurry was
cooled to 0 °C, diluted with aqueous sodium bicarbonate, and
extracted with MTBE. The organic layer was washed with water
(2×) and brine and dried over sodium sulfate. Solvent removal
at 40 °C afforded 27.1 g (103 mmol, 64% yield) of a dark liquid,
pure by NMR and HPLC, which was carried forward without
further purification. An aliquot was shown to be unchanged by
stirring overnight with aqueous sodium bicarbonate, showing
it to be hydrolytically stable; likewise, storage for several days
at 25 °C also resulted in no change. 1H NMR (CDCl3): δ 1.16 (t,
3H, 7 Hz), 2.44 (q, 2H, 7 Hz), 3.78 (s, 3H), 5.77 (s, 1H). IR (thin
film): 1738, 1684, 1427, 1298 cm-1. HRMS calcd for C7H9F3O5-
S: 262.0123, found 262.0110.
The absolute configuration of 16 was determined by X-ray
diffraction analysis of the hydrogen bromide salt. With
enantiomerically pure 17 possessing the requisite C3R
stereochemistry in hand, we turned our attention to
devising a method for incorporating this intermediate
into the dihydropyrone ring.
Careful acylation of 17 via deprotonation with LDA
and addition to excess acetyl chloride afforded 18 in 78%
yield (Scheme 5). Treatment of the â-ketoester with
sodium hydride followed by n-butyllithium formed the
dianion, which was quenched with 3-heptanone to pro-
vide 19 in 61% yield. Lactonization was attempted using
standard conditions of 0.1 N sodium hydroxide but
afforded the desired dihydropyrone 20 in dismal yields
(17-21%). A variety of other bases, such as potassium
t-butoxide, sodium carbonate, potassium carbonate, so-
dium methoxide, and sodium hexamethyldisilazide, in
various solvents and at various temperatures, were
examined, but all favored the retro-aldol product 18
rather than hydrolysis and lactonization of the dihydro-
pyrone. Because this cyclization worked well in a model
system lacking the bis(benzyl)amine substitutent on the
C3R phenyl ring, we hypothesized that the benzylamine
protecting groups were in some way sterically inhibiting
lactonization. Fortunately, removal of the benzyl protect-
ing groups allowed lactonization to proceed uneventfully.
Thus, treatment of 21 with 0.1 N sodium hydroxide
provided dihydropyrone 22 in 77% yield. Finally, treat-
ment of aniline 22 with sulfonyl chloride 234 provided
2a (PNU-140135) in 69% yield. Thus, PNU-140135 (2a )
Eth yl (Z)-3-Iod op en ten oa te (14). Lithium iodide (39.0 g,
291 mmol) was placed in a flask with ethyl 2-pentynoate (33.1
g, 263 mmol) and fitted with a mechanical stirrer. Acetic acid
(30 mL) was added, and the slurry was heated to 70 °C with
stirring. After 5 h, analysis by HPLC indicated that no starting
material remained and that a single new peak was present. The
slurry was cooled, water and ether were added, and the mixture
was extracted. The organic layer was washed with water (3X),
saturated aqueous sodium bicarbonate, and brine. Solvent
removal afforded a liquid that was pure by 1H NMR analysis.
The liquid was filtered through a plug of silica gel with ethyl
acetate/hexane (5:95), and the solvent was removed to afford 58.8
g of a clear liquid (88%), pure by HPLC analysis. The liquid was
stored at 25 °C for three months with no noticeable decomposi-
1
tion. H NMR (300 MHz, CDCl3): δ 6.32 (s, 1H), 4.02 (q, 2H, 7
Hz), 2.74 (q, 2H, 7 Hz), 1.27 (t, 3H, 7 Hz), 1.15 (t, 3H, 7 Hz). IR
(thin film): 1731, 1666, 1437, 1370 cm-1. HRMS calcd for
C7H11O2I: 266.0919, found 266.0921. Anal. Calcd for C7H11O2I:
C, 33.09; H, 4.36. Found: C, 32.77; H, 4.27.
Meth yl (Z)-3-(3-Am in op h en yl)p en ten oa te (12). Meth od
1. A flask containing bis(triphenylphosphine)palladium chloride
(3 mol %, 6.42 g) and triphenylphosphine (3 mol %, 2.4 g) was
flushed with nitrogen. THF (200 mL) was added, and the slurry
was cooled to 0 °C. DIBAL-H (6 mol %, 18.3 mL of a 1.0 M

Notes
J . Org. Chem., Vol. 64, No. 13, 1999 4983
toluene solution) was slowly added. The cold bath was removed,
and the dark slurry was allowed to stir for 30 min to generate
the palladium(0) catalyst. During this time, 3-[bis(trimethyl-
silyl)amino]phenylmagnesium chloride (1.2 equiv, 366 mL of a
1.0 M THF solution) was added at 0 °C to an ether solution of
anhydrous zinc chloride (1.2 equiv, 366 mL of a 1.0 M solution),
and a white slurry formed. Methyl (Z)-3-trifluoromethylsulfon-
yloxypentenoate (10) (1.0 equiv, 80.5 g, 307 mmol) was added
to the arylzinc slurry followed by cannula transfer of the
palladium catalyst. The reaction was allowed to stir at 0 °C, and
the ice was allowed to melt. After a total of 1 h at 25 °C, the
reaction was cooled to 0 °C, and 2 N aqueous hydrochloric acid
(300 mL) was carefully added, followed by water (1 L). MTBE
was added, and the reaction was partitioned. The organic layer
was back-extracted with additional water. The aqueous layers
were combined and washed with MTBE, and then concentrated
ammonium hydroxide was added followed by MTBE. Filtration
through diatomateous earth at this point circumvents a potential
emulsion problem. The solvent mixture was partitioned, and the
organic layer was washed with water (2×) and brine. Drying
over sodium sulfate and solvent removal afforded the product
as a liquid in 46.2 g crude yield (225 mmol, 73%), contaminated
only by a trace amount of aniline, as judged by HPLC and 1H
NMR analysis. This material was carried on as is. An analytical
sample was purified by chromatography with ethyl acetate/
(S)-3-(3-N,N-Diben zyla m in op h en yl)p en ta n oic Acid (16).
All solvents were sparged with argon before use. Compound 15
(53.0 g, 143 mmol) was placed in a large Parr bottle, flushed
with nitrogen, and diluted with methanol (300 mL). Freshly
prepared [(R)-BINAP]ruthenium acetate (0.005 equiv) was added
by syringe as a methanol (50 mL)/THF (10 mL) solution. The
Parr bottle was repeatly flushed with hydrogen and then allowed
to shake under a 40 psi (2.7 atm) atmosphere of hydrogen.
Careful removal of an aliquot after 3 d showed the reduction to
be complete (1H NMR analysis). The solvent was removed in
vacuo, at which point the residue solidified. Reduction of a
sample to the alcohol with borane methyl sulfide, followed by
examination by chiral HPLC on a Chiracel OD-H column (2.5%
2-propanol/hexane) showed the product to be a 95:5 ratio of
enantiomers. Cyclohexane, acetonitrile, and acetic acid were all
judged to be suitable recrystallation solvents to upgrade the
optical purity; recrystallization from acetic acid (35 mL)/water
(10 mL) afforded 47.0 g (124 mmol, 87% yield) of pure 16, as
judged by reverse phase HPLC, 1H NMR, and examination of
the alcohol by chiral column HPLC (vide supra); mp 120 °C,
[R]25 ) +11° (c ) 0.904, CH3OH). X-ray diffraction analysis of
D
the HBr salt (crystallized from CH3OH) showed the product to
be the (S)-enantiomer. 1H NMR (CDCl3): δ 0.69 (t, 3H, 7 Hz),
1.48 (m, 1H), 1.61 (m, 1H), 2.53 (d, 2H, 7 Hz), 2.83 (m, 1H), 4.62
(s, 4H), 6.52, (d, 1H, 8 Hz), 6.53, (s, 1H), 6.58 (d, 2H, 8 Hz), 7.09
(t, 1H, 8 Hz), 7.33-7.22 (m, 10H), 11.4 (bs, 1H). IR (mineral
oil): 2710, 1700, 1600 cm-1. MS (m/e): 373, 296, 283, 223. Anal.
Calcd for C25H27NO2: C, 80.40; H, 7.29; N, 3.75. Found: C, 80.57;
H, 7.46; N, 3.71.
(S)-Meth yl 3-(3-N,N-Diben zyla m in op h en yl)p en ta n oa te
(17). Thionyl chloride (20.0 g, 169 mmol) was added dropwise
to methanol (220 mL) at 0 °C. The ice bath was removed, 16
(42.0 g, 113 mmol) was added, and the solution was allowed to
stand overnight. The solvent was removed in vacuo, and the
residue was placed in a separatory funnel with MTBE and water.
Concentrated ammonium hydroxide was added, and the mixture
was extracted. The organic layer was washed with water and
brine and dried over sodium sulfate, and the solvent was
1
hexane (25:75). H NMR (CDCl3): δ 1.04 (t, 3H, 7 Hz), 2.41 (q,
2H, 7 Hz), 3.46 (s, 3H), 5.83 (s, 1H), 6.48 (s, 1H), 6.53 (d, 1H, 7
Hz), 6.62 (d, 1H, 7 Hz), 7.14 (d, 1H, 7 Hz). IR (thin film): 1721,
1602 cm-1. Anal. Calcd for C12H15NO2: C, 70.21; H, 7.37; N, 6.83.
Found: C, 70.21; H, 7.37; N, 6.78.
Eth yl (Z)-3-(3-Am in op h en yl)p en ten oa te (12). Meth od 2.
The procedure used above for the enol triflate was applied to 14
(5.20 g, 19.6 mmol), except that it was necessary to reflux the
THF solution, and afforded 3.00 g (15.6 mmol, 80%) of the title
compound. 1H NMR (CDCl3): δ 1.04 (t, 3H, 7 Hz), 1.26 (t, 3H, 7
Hz), 2.41 (q, 2H, 7 Hz), 4.19 (q, 2H, 7 Hz), 5.83 (s, 1H), 6.48 (s,
1H), 6.53 (d, 1H, 7 Hz), 6.62 (d, 1H, 7 Hz), 7.14 (d, 1H, 7 Hz). IR
(thin film): 1723, 1600 cm-1. Anal. Calcd for C13H17NO2: C,
71.41; H, 7.81; N, 6.39. Found: C, 71.57; H, 8.13; N, 6.12.
removed in vacuo to afford a liquid (42 g, 96% yield). [R]25
)
D
+16° (c ) 0.994, CH3OH). 1H NMR (CDCl3): δ 0.69 (t, 3H, 7
Hz), 1.48 (m, 1H), 1.55 (m, 1H), 2.50 (d, 2H, 7 Hz), 2.83 (m, 1H),
3.57 (s, 3H), 4.62 (s, 4H), 6.51 (d, 1H, 8 Hz), 6.53 (s, 1H), 6.58
(d, 1H, 8 Hz), 7.08 (t, 1H, 8 Hz), 7.34-7.16 (m, 10H). IR (thin
film): 1737, 1600, 1494 cm-1. HRMS calcd for C26H29NO2:
387.2198, found 387.2203. Anal. Calcd for C26H29NO2: C, 80.59;
H, 7.54; N, 3.61. Found: C, 80.42; H, 7.41; N, 3.65.
Meth yl (Z)-3-(3-N,N-Diben zyla m in op h en yl)p en ten oa te.
Compound 12 (77.0 g, 375 mmol) was dissolved in acetonitrile
(500 mL) with diisopropylethylamine (131 mL) and cooled to 0
°C. Benzylbromide (2.1 equiv, 94.1 mL) was added, and the
solution was stirred overnight. When HPLC analysis ascertained
that all of the primary and secondary amines were consumed,
the solution was cooled to 0 °C, and a solution of 25% aqueous
trimethylamine was added to scavenge the excess benzylbro-
mide. After 60 min at 25 °C, the solution was diluted with MTBE
and washed with saturated aqueous ammonium hydroxide and
water. The organic layer was washed with water (2×) and brine.
Drying over sodium sulfate and solvent removal afforded a
liquid, which was filtered through a plug of silica gel with ethyl
acetate/hexane (15:85). Solvent removal afforded 128 g (334
(S)-Meth yl 2-[1-(3-Bis(p h en ylm eth yl)a m in op h en yl)p r o-
p yl] Acetoa ceta te (18). To a mixture of 14.77 g (38.16 mmol)
of 17 in 100 mL of freshly distilled THF at -78 °C under nitrogen
was added 21.0 mL of 2.0 M lithium diisopropyl amide via
syringe over 1 min. After stirring for 10 minutes, this mixture
(anion solution) was added to a solution of 26.0 mL of acetyl
chloride in 100 mL of freshly distilled THF stirring at -78 °C
under nitrogen via cannula, followed by THF rinse (60 mL) over
9 min. This mixture was then allowed to stir for 3 min and then
allowed to stir at 0 °C. After 2 min at 0 °C, 200 mL of ice-cold
water was added. The mixture was stirred for 6 min and then
poured into 200 mL of saturated aqueous sodium bicarbonate,
and the resulting layers were separated. The organic layer was
washed with saturated aqueous sodium bicarbonate. The pH of
the aqueous layer was adjusted from 1 to 8 with solid sodium
bicarbonate, and then the aqueous layer was extracted with
ethyl acetate (3×). All of the organic layers were then combined,
dried (MgSO4), and concentrated in vacuo to provide 21.66 g of
crude material as a yellow oil. The crude was taken up into a
mixture of methylene chloride and hexane and placed on a 36
cm × 5.5 cm, 40-63 µm silica MPLC column and eluted with
ethyl acetate in hexane (1 L each 2%, 4%, 6%, 8%, 10%, 12%,
20%). Collection of 40 mL fractions provided 12.76 g (78% yield)
of 18 as a light yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.33
(m, 4 H), 7.25 (m, 6 H), 7.08 (t, J ) 8.0 Hz, 1H), 6.61 (m, 1 H),
6.53 (m, 2 H), 4.62 (s, 4 H), 3.72 (m, 3.5 H), 3.40 (s, 0.5 H), 3.10
(m, 1 H), 2.25 (s, 0.5 H), 1.80 (s, 2.5 H), 1.62 (m, 1 H), 1.43 (m,
1 H), 0.63 (m, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 11.90, 12.07,
27.16, 27.78, 30.07, 30.12, 47.77, 48.20, 52.47, 52.78, 54.75, 54.93,
66.55, 67.10, 111.87, 111.97, 113.47, 113.56, 117.00, 127.17,
127.24, 127.28, 127.32, 128.96, 129.02, 129.48, 129.78, 139.01,
1
mmol, 89%) of pure product. H NMR (CDCl3): δ 0.95 (t, 3H, 7
Hz), 2.31 (q, 2H, 7 Hz), 3.52 (s, 3H), 4.61 (s, 1H), 6.49 (d, 1H, 8
Hz), 6.51 (s, 1H), 6.68 (d, 1H, 7 Hz), 7.14 (t, 1H, 8 Hz), 7.34-
7.23 (m, 11 H). IR (thin film): 1728, 1640, 1598 cm-1. Anal. Calcd
for C26H27NO2: C, 81.00; H, 7.06; N, 3.64. Found: C, 80.68; H,
6.85; N, 3.50.
(Z)-3-(3-N,N-Diben zyla m in op h en yl)p en ten oic Acid (15).
Methyl (Z)-3-(3-N,N-dibenzylaminophenyl)pentenoate (110 g,
286 mmol) was added to a solution of sodium hydroxide (45 g)
in water (400 mL), methanol (400 mL), and THF (300 mL). This
was stirred at 25 °C overnight and then heated to reflux for 2
h. The solvent was removed in vacuo, and water was added (500
mL). The solution was cooled in an ice bath, acidified to pH 6
with 6 N aqueous hydrochloric acid, and extracted with MTBE.
The organic layer was washed with water and brine. Drying over
sodium sulfate and solvent removal afforded 106 g (285 mmol,
100%) of a crystalline solid (mp 130 °C), pure by HPLC and 1H
NMR. 1H NMR (CDCl3): δ 0.960 (t, 3H, 7 Hz), 2.34 (q, 2H, 7
Hz), 4.60 (s, 4H), 5.75 (s, 1H), 6.50 (m, 2H), 6.68 (d, 1H, 8 Hz),
7.32-7.11 (m, 11 H), 10.5 (bs, 1H). IR (Nujol): 1695, 1671, 1600
cm-1. HRMS calcd for C25H25NO2: 371.1885, found 371.1885.
Anal. Calcd for C25H25NO2‚HCl: C, 73.45; H, 6.40; N, 3.77.
Found: C, 73.45; H, 6.40; N, 3.63.

4984 J . Org. Chem., Vol. 64, No. 13, 1999
Notes
139.10, 141.61, 141.96, 149.54, 168.93, 169.73, 202.89, 203.20.
IR (mull): 1740 (s), 1715 (m), 1596 (s) cm-1. MS (EI) m/z (rel
intensity): 429 (M+, 94), 352 (11), 338 (9), 222 (10), 208 (7). Anal.
Calcd for C28H31NO3: C, 78.29; H, 7.27; N, 3.26. Found: C, 78.22;
(6.67 mmol) of amine intermediate in 50 mL of THF and 170
mL of 0.1 N sodium hydroxide was stirred at room temperature
for 4.5 h. It was then stirred at 0 °C for 20 min, and 25 mL of 1
N hydrochloric acid was added. The mixture became cloudy and
then homogeneous again. The mixture was stirred at room
temperature for 30 min, and then the pH was adjusted from 3
to 7 with solid sodium bicarbonate. The mixture became cloudy
white while the pH was adjusted. The mixture was then
partitioned between ethyl acetate (200 mL) and brine (150 mL).
The resulting layers were separated, and the aqueous layer was
extracted with additional ethyl acetate. The combined ethyl
acetate layers were dried (MgSO4) and concentrated in vacuo
to provide 1.70 g (77% crude yield) of the title compound as a
H, 7.28; N, 3.40. [R]25 ) +32° (c ) 0.8844, MeOH).
D
(S)-Meth yl 2-[1-(3-Bis(m eth ylp h en yl)a m in op h en yl)p r o-
p yl]-5-h yd r oxy-3-oxo-5-p r op yl Octoa te (19). To a mixture of
5.68 g (13.2 mmol) of 18 in 35.0 mL of freshly distilled THF
under nitrogen was added 895 mg (22.4 mmol) of 60 wt % sodium
hydride. Only slight effervescence was noticed. The mixture was
heated to 45 °C for 5 h, cooled to 0 °C, and stirred for 20 min.
Then, 10.0 mL of 1.6 M n-butyllithium (16 mmol) was added
over 2 min, providing a reddish brown mixture. This mixture
was then stirred for 30 min at 0 °C. The mixture was cooled to
-78 °C, and after 7 min, 3.80 mL (27.2 mmol) of 4-heptanone
was added. After the mixture stirred for 18 min at -78 °C, it
was warmed to 0 °C. After 25 min, the color had changed to
yellow, and the mixture was slowly quenched with 10 mL of ice
water. The mixture was then partitioned between brine and
ethyl acetate. The resulting layers were separated, and the
aqueous layer was extracted with additional ethyl acetate. The
combined ethyl acetate layers were dried (MgSO4) and concen-
trated in vacuo to provide 8.46 g of crude yellow oil. The crude
was dissolved in methylene chloride, placed upon a 36 cm × 5.5
cm, 40-63 µm silica MPLC column, and eluted with ethyl
acetate in hexane (1 L each 2%, 4%, 6%, 8%, 10%, 12%, 20%).
Collection of 50 mL fractions provided 4.38 g (61% yield) of the
foam. IR (mull): 2660 (b), 1606 (s), 1531, 1493 cm-1 1H NMR
.
(300 MHz, MeOH-d4): δ 6.95 (t, J ) 7.7 Hz, 1 H), 6.80 (s, 1 H),
6.73 (d, J ) 7.7 Hz, 1 H), 6.51 (dd, J ) 1.2, 7.8 Hz, 1 H), 3.91
(dd, J ) 6.6, 9.5 Hz, 1 H), 2.54 (s, 2 H), 2.19 (m, 1 H), 1.96 (m,
1 H), 1.62 (m, 4 H), 1.32 (m, 4 H), 0.89 (m, 9 H). MS (EI) m/z
(rel intensity): 331 (M+, 96), 202 (30), 192 (32), 191 (68), 174
(53). HRMS (EI) calcd for C20H29NO3: 331.2147, found 331.2153.
Anal. Calcd for C20H29NO3: C, 72.47; H, 8.82; N, 4.23. Found:
C, 72.48; H, 8.98; N, 4.03.
[3r(R)]-N-[3-[1-5,6-Dih yd r o-6,6-d ip r op yl-4-h yd r oxy-2-
oxo-2H-p yr a n -3-yl]p r op yl]p h en yl-5-tr iflu r or m eth yl)-2-p yr -
id in esu lfon a m id e (2a ). To a mixture of 534 mg (1.61 mmol)
of 22 (crude) in 20 mL of methylene chloride and 0.26 mL (3.21
mmol) of pyridine at 0 °C was added 415 mg (1.69 mmol) of
5-trifluoromethyl pyridine-2-sulfonyl chloride (23) as a solid all
at once. After 2 h, the mixture was added to 10 mL of 1 N
hydrochloric acid. The resulting layers were separated, and the
aqueous layer was extracted with additional methylene chloride
(3×). The combined organic layers were dried (MgSO4) and
concentrated in vacuo to provide 860 mg of crude as a dark oil.
The crude was taken up into methylene chloride, placed upon a
24 cm × 2.5 cm, 40-63 µm silica MPLC column, and eluted with
ethyl acetate in hexane (250 mL each 2%, 4%, 6%, 8%, 10%, 15%,
20%, 25%, 30%, 40%). Collection of 25 mL fractions provided
600 mg of 2a as colorless oil (69%). Upon reconcentration from
methylene chloride (2×) a tan foam was obtained. 1H NMR (300
MHz, MeOH-d4): δ 8.98 (s, 1 H), 8.26 (d, J ) 8.2 Hz, 1 H), 8.05
(d, J ) 8.2 Hz, 1 H), 7.20 (s, 1 H), 7.03 (m, 2 H), 6.92 (m, 1 H),
3.90 (m, 1 H), 2.53 (s, 2 H), 2.08 (m, 1 H), 1.86 (m, 1 H), 1.58 (m,
4 H), 1.26 (m, 4 H), 0.83 (m, 9 H). IR (mull): 1641 (m), 1608
(m), 1595 (m) cm-1. MS (EI) m/z (rel intensity): 540 (M+, 33),
401 (57), 383 (77), 343 (40), 197 (40), 174 (51), 146 (54), 145 (75).
Anal. Calcd for C26H31F3N2O5S: C, 57.77; H, 5.78; N, 5.18.
1
title compound as a colorless oil. H NMR (300 MHz, CDCl3): δ
7.28 (m, 10 H), 7.06 (m, 1 H), 6.50 (m, 3 H), 4.61 (s, 4 H), 3.73
(m, 2.6 H), 3.44 (s, 0.5 H), 3.39 (s, 1.4 H), 3.24 (s, 0.5 H), 3.12
(m, 1 H), 2.73 (d, J ) 18 Hz, 0.5 H), 2.65 (d, J ) 18 Hz, 0.5 H),
2.39 (d, J ) 18.0 Hz, 1 H), 2.18 (d, J ) 18.0 Hz, 1 H), 1.56-1.11
(m, 10 H), 0.860 (m, 6 H), 0.61 (m, 3 H). MS (EI) m/z (rel
intensity): 543 (M+, 34), 544 (13), 429 (15), 328 (10), 314 (10).
Anal. Calcd for C35H45NO4: C, 77.31; H, 8.34; N, 2.58. Found:
C, 77.32; H, 8.31; N, 2.76.
(S)-Met h yl 2-[1-(3-Am in op h en yl)p r op yl]-5-h yd r oxy-3-
oxo-5-p r op yl Octoa te (21). A mixture of 4.38 g (8.07 mmol) of
20 and 722 mg of 10% palladium on carbon in 50 mL of 20%
methanol in ethyl acetate was shaken on the Parr under
hydrogen (30 psi) for 5 h. The mixture was then evacuated, filled
with nitrogen (3×), and filtered over Celite. The filtrate was
concentrated in vacuo to provide 2.65 g (90%) of the title
compound. 1H NMR (300 MHz, MeOD): δ 7.02 (m, 1 H), 6.55
(m, 3 H), 4.00 (m, 1 H), 3.72 (s, 2 H), 3.38 (s, 1 H), 3.09 (m, 1 H),
2.77 (d, J ) 16.6 Hz, 0.5 H), 2.70 (d, J ) 16.6 Hz, 0.5 H), 2.55
(d, J ) 17.8 Hz, 1 H), 2.32 (d, J ) 17.9 Hz, 1 H), 1.62-1.06 (m,
10 H), 0.89 (m, 3 H), 0.73 (m, 6 H). MS (EI) m/z (rel intensity):
363 (M+, 45), 270 (66), 206 (20), 202 (16), 174 (36). HRMS (EI)
calcd for C21H33NO4: 363.2409, found 363.2402. Anal. Calcd for
C21H33NO4: C, 69.39; H, 9.15; N, 3.85. Found: C, 69.30; H, 9.21;
N, 4.04.
Found: C, 57.67; H, 5.80; N, 5.19. [R]25 ) +28° (c ) 0.8397,
D
MeOH).
Su p p or tin g In for m a tion Ava ila ble: Ortep drawing and
tables of X-ray data for compound 16. This material is
available free of charge via the Internet at http://pubs.acs.org.
[3r(R)]-3-[1-(3-Am in op h en yl)p r op yl]-5,6-d ih yd r o-6,6-d i-
p r op yl-4-h yd r oxy-2H-p yr a n -2-on e (22). A mixture of 2.42 g
J O990278D