A convergent, scalable synthesis of HIV protease inhibitor PNU-140690

Article abstract of DOI:10.1021/jo9809229

PNU-140690, an inhibitor of the HIV protease enzyme undergoing clinical evaluation as a chemotherapeutic agent for treatment of AIDS, was synthesized by a convergent approach amenable to large-scale preparation in a pilot plant environment. The key step is the aldol addition of nitroaromatic ester (+)-8 to aldehyde 19e. The two stereocenters present in the target molecule were each set independently by resolution of enantiomers. Intermediates along the synthetic routes were chosen to maximize opportunities for isolation and purification by crystallization.

Full text of DOI:10.1021/jo9809229

7348
J . Org. Chem. 1998, 63, 7348-7356
A Con ver gen t, Sca la ble Syn th esis of HIV P r otea se In h ibitor
P NU-140690
Kristina S. Fors, J ames R. Gage,* Richard F. Heier, Robert C. Kelly, William R. Perrault, and
Nancy Wicnienski
Chemical Process Research & Preparations, 1510-91-2, Pharmacia & Upjohn Inc., 7000 Portage Road,
Kalamazoo, Michigan 49001
Received May 14, 1998
PNU-140690, an inhibitor of the HIV protease enzyme undergoing clinical evalution as a
chemotherapeutic agent for treatment of AIDS, was synthesized by a convergent approach amenable
to large-scale preparation in a pilot plant environment. The key step is the aldol addition of
nitroaromatic ester (+)-8 to aldehyde 19e. The two stereocenters present in the target molecule
were each set independently by resolution of enantiomers. Intermediates along the synthetic routes
were chosen to maximize opportunities for isolation and purification by crystallization.
Sch em e 1
In tr od u ction
PNU-140690 (1) is an inhibitor of the HIV protease
enzyme and is currently undergoing clinical trials for the
treatment of AIDS. This compound emerged from a
longstanding research program at Pharmacia & Upjohn
to identify effective small molecule inhibitors of the viral
protease enzyme.1 Several HIV protease inhibitors have
recently been approved for use by the FDA, all of which
are peptidomimetic compounds. PNU-140690 is the first
nonpeptide to possess comparable antiviral potency while
retaining useful pharmaceutical properties. In addition,
it retains useful activity against strains resistant to
ritonavir and cross-resistant to other protease inhibitors,
suggesting that PNU-140690 could be very valuable
when used in combination with a subset of these struc-
turally unrelated drugs.2
Availability of an efficient, scalable process for the
synthesis of PNU-140690 is vital to its successful clinical
development and commercialization. However, its struc-
ture and properties pose some unique difficulties. Fore-
most among these is the poor crystallinity of the target
molecule itself and other compounds containing the
tertiary alkoxy or acyloxy stereocenter at C6, restricting
opportunities for purification, isolation, and drying.
Other challenges include control of stereochemistry at
two widely separated asymmetric centers and instability
of the dihydropyrone core.
addition of an enolate represented by 2 with an electro-
philic partner 3 was required. In addition to the well-
known advantages of convergency, this strategy attracted
us because it offered the ability to set each stereocenter
independently, simplifying the control of diastereomeric
impurities.
Resu lts a n d Discu ssion
A classical resolution to set the C6 stereocenter, the
key feature of the projected electrophile 3, was planned
from the outset of this work. In keeping with our
strategy, racemic hydroxy acid 4 was chosen as the
resolution “substrate” (Scheme 2). The hydroxy acid
synthesis was originally performed in a single step by
addition of the dianion of acetic acid to 1-phenyl-3-
hexanone. However, yields were higher and more re-
producible when done in two steps. Thus, addition of the
ketone to a THF solution of the lithium enolate of ethyl
acetate while maintaining the temperature at or below
-30 °C afforded the ethyl ester 5 in nearly quantitative
yield. Higher temperatures resulted in recovery of un-
reacted 1-phenyl-3-hexanone. Isolation of 5 was un-
necessary; instead, after aqueous workup the unpurified
ester was directly subjected to saponification with sodium
hydroxide in methanol. Hydroxy acid (()-4 was isolated
by standard basic extraction and concentrated to a
viscous oil. It was not necessary to remove all of the
solvent before doing the resolution.
We planned a convergent approach relying on con-
struction of the C3-C4 bond of the dihydropyrone ring
(Scheme 1). In practice, a Claisen condensation or aldol
(1) (a) 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.; Lynn, 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.; Winkinson, K. F.; 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. (b) J udge, T. M.; Phillips, G.; Morris, J . K.;
Lovasz, K. D.; Romines, K. R.; Luke, G. P.; Tulinsky, J .; Tustin, J . M.;
Chrusciel, R. A.; Dolak, L. A.; Mizsak, S. A.; Watt, W. A.; Morris, J .;
VanderVelde, S. L.; Strohbach, J . W.; Gammill, R. B. J . Am. Chem.
Soc. 1997, 119, 3627-3628.
Resolution of (()-4 was achieved by crystallization with
norephedrine. Other chiral amines screened for this
(2) Chong, K.-T.; Pagano, P. J . Antimicrob. Agents Chemother. 1997,
41, 2367-2373.
S0022-3263(98)00922-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/30/1998

Synthesis of HIV Protease Inhibitor PNU-140690
J . Org. Chem., Vol. 63, No. 21, 1998 7349
Sch em e 2
Sch em e 3
Sch em e 4
purpose included R-methylbenzylamine, phenylglycinol,
ephedrine, and sparteine. (1R,2S)-Norephedrine crystal-
lized with the stereoisomer of 4 needed for PNU-140690
synthesis. This was determined first by chemical cor-
relation (vide infra) but was later confirmed by X-ray
structure determination of the diasteromeric salt 7. The
first set of conditions for the resolution consisted of
reaction of the racemate (10 mL/g in acetonitrile) with 1
equiv of norephedrine followed by two recrystallizations
from acetonitrile, affording the desired salt 6 in about
35% yield. However, the level of chiral purity was
inconsistent. Eventually, we determined that chiral
purity and filterability were much more reproducible
when the salt was formed from only 0.5 equiv of the
amine, albeit in lower yield. Almost all of the yield loss
was incurred during the salt formation; each recrystal-
lization from acetonitrile comes at the expense of only
1-2% yield. Solubility measurements of 6 and its
diastereomer 7 suggested that toluene and methylene
chloride might also be appropriate solvents for salt
formation. However, we were not able to form tractable
salts in either of these solvents. Efforts to improve the
yield by adjusting concentration and temperature during
the salt formation were marginally successful. While
colder temperature did increase the yield, enantiopurity
suffered. Decreasing the volume improved the yield
without sacrificing enantiomeric excess, but volumes
lower than 5 mL/g of (()-4 became unstirrable. In the
preferred variant of the procedure, the salt formation is
done at a concentration of 5 mL/g and 0 °C to maximize
yield and recrystallized twice at 7 mL/g and room
temperature to achieve the desired optical purity (>99:
1). (1R,2S)-Norephedrine recovered by standard acid/
base extraction techniques can be reused.
catalyzed addition of ethyl Grignard or ethyl zinc re-
agents to methyl 3-nitrocinnamate. We surmised that
the addition might be facilitated by an additional carboxy
group. Thus, we prepared dimethyl 3-nitrobenzalma-
lonate (9) by Knoevenagel condensation (Scheme 3). This
compound, indeed, was found to undergo Michael addi-
tion with a variety of copper reagents including the
Knochel reagent,3 copper-catalyzed Grignard addition,
and most simply and in highest yield with copper bromide
catalyzed addition of diethyl zinc, giving the racemic
malonate 10. Hydrolysis and concomitant decarboxyla-
tion readily produced the desired 3-(m-nitrophenyl)-
propionic acid 11, which in turn was converted to the
methyl ester 8 by Fischer esterification.
Attempts at resolution of the acid with a variety of chi-
ral amines resulted in only moderate yields of the dia-
stereomerically enriched salts. Wishing to rapidly obtain
samples of key coupling products derived from (R)-8, we
decided to separate the isomers4 by preparative chiral
column chromatography, and this was readily achieved
(Scheme 4). Once coupling of this material to the left-
hand portion of the molecule was successfully demon-
strated (see below), an alternative preparation of (+)-8
was sought. 1-(m-Nitrophenyl)propanol (12) is readily
available by reduction of the corresponding propiophe-
none. Acylation of this material with isopropenyl acetate
in the presence of Amano P30 lipase results in a nearly
quantitative conversion of the (R)-alcohol to its acetate,
leaving the nearly enantiomerically pure alcohol in close
to 50% weight yield (Scheme 5). These compounds were
readily separated chromatographically. Alcohol 14 was
converted to the mesylate and reacted with sodium
diethyl malonate to give the diester (+)-15. Hydrolysis-
decarboxylation and reesterification gave (+)-8.
Earlier syntheses of PNU-140690 have incorporated
the nitrogen substituent at the meta position of the
phenyl ring as a dibenzyl-protected aniline,1 as did an
early version of the aldol process described here. Because
of its susceptibility to oxidation, lack of crystallinity, and
the high mass of the protecting groups, we wanted to
replace the dibenzyl aniline moiety with another aniline
surrogate, preferably a nitro group. Toward this end, we
sought an efficient synthesis of (R)-8. In our first
approach to 8, we wished to pursue a Michael addition
to an unsaturated ester, but earlier work in our group
had shown that the nitro group inhibited the copper-
Of the reactions examined for formation of the key C3-
C4 bond, the more aggressive Claisen condensation
approach was plagued by two fundamental problems. The
first was reactivity: the presence of the tertiary â-hy-
droxyl group made preparation of active acylating agents
(3) (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 7. (b) J ubert,
C.; Knochel, P. J . Org. Chem. 1992, 57, 5431.
(4) The assignment of stereochemistry was achieved by correlation
of the (+)-isomer with (R)-3-[m-(dibenzylamino)phenyl]propanoic acid
methyl ester. This material had previously been converted to PNU-
140690.

7350 J . Org. Chem., Vol. 63, No. 21, 1998
Fors et al.
Sch em e 5
An aldol process addresses both the reactivity and
product acidity problems encountered in the attempted
direct acylation chemistry. These benefits come at the
price of having to adjust the oxidation state sometime
after coupling the two halves of the molecule. The
aldehydes 19 required for this study were prepared by
derivatization of both the acid and alcohol functional
groups of acid (R)-4, reduction of the resulting ester to
the primary alcohol with diisobutylaluminum hydride,
and tetramethylpiperidinyloxy radical (TEMPO) cata-
lyzed sodium hypochlorite oxidation9 to the aldehyde.
This protocol and several variations thereof were used
without success to make derivatives protected by a silyl
ether as in 16. However, chloromethyl ethers reacted
readily under standard conditions, and the benzyloxy-
methyl- (BOM), methoxymethyl- (MOM), [2-(trimethyl-
silyl)ethoxy]methyl- (SEM), and (methoxyethoxy)methyl-
(MEM) ether derivatives were prepared in this manner.
Attempts to prepare the corresponding allyl or benzyl eth-
ers failed. Curiously, with oxymethyl esters it was not
possible to stop the reduction reactions at the aldehyde
oxidation step even at -78 °C, a process that worked well
with the corresponding ethyl ester compounds.
Sch em e 6
Unfortunately for our purposes, none of the aldehydes
19a -d are crystalline, nor are the ester and alcohol
intermediates used in their preparation. The aldehydes
themselves also displayed a tendency to self-condense
during silica gel chromatography, the extent of dimer-
ization related both to the bulkiness of the protecting
group and residence time on the column. In general, it
was not possible to remove the dimer once formed from
the aldehyde because of the similarities of polarity
between the two. The presence of varying amounts of
dimer in samples of aldehyde made accurate determina-
tion of the yield in and optimization of the subsequent
aldol reactions very difficult.
The [(p-phenylphenyl)oxy]methyl (POM) ether was in-
vented to induce crystallinity in the aldehyde and thereby
solve the purification problem. Of all the attempted
protections or derivatizations of the tertiary alcohol in
4, only base-promoted reactions with alkoxymethyl chlo-
rides have worked well. To the extent that crystallinity
might be expected to be related to the melting point of
the alkoxy group employed, 4-phenylphenol (mp 165-
167 °C) was selected for incorporation into a new protect-
ing group.10 The previously unknown 1-(chloromethoxy)-
4-phenylbenzene (POMCl) was synthesized in 74% yield
from p-chlorothiophenol according to a literature method
as shown below (Scheme 7).11
Derivatization of 4 with POMCl required more strin-
gent conditions than those used for reaction with simpler
alkoxymethyl chlorides. Esterification proceeded readily,
but protection of the tertiary hydroxy group required
reaction with an excess of POMCl and diisopropylethyl-
amine for 5 h in refluxing toluene. Under these condi-
tions, POMCl slowly decomposes to 4-phenylphenol and
bis(4-phenylphenoxy)methane. Bases examined for this
such as the acid chloride very difficult because of the
possibility of elimination or retroaldol. The most suc-
cessful acylating agent was the thiophenyl ester 165
(Scheme 6), which could be prepared by reacting the acid
with carbonyldiimidazole and thiophenol followed by
silylation.6 However, this electrophile is not synthetically
useful in this situation because of the second and more
difficult problem: the acidity of the product â-keto esters.
The enolate quenching byproduct limited conversion to
50%. Additional base served only to deprotonate the
thioester, thus deactivating it as an electrophile. In
principle, the conversion problem could be avoided by
acylating a substituted malonate derivative instead of a
simple enolate, but doing so exacerbated the reactivity
problem. The problem might also be solved by acylating
with electrophiles that would be expected to form stable
tetrahedral intermediates (N-methoxy-N-methylamides7
or acyl cyanides8), but these either lacked sufficient
reactivity or proved unstable.
(8) Hunig, S.; Schaller, R. Angew. Chem., Int. Ed. Engl. 1982, 21,
36-49.
(9) Hewitt, B. D. PCT Int. Appl. WO 9516698 A1, 1994; Chem. Abstr.
1994, 123, 314263.
(5) Damon, R. E.; Luo, T.; Schlessinger, R. H. Tetrahedron Lett.
1976, 32, 2749.
(6) Gais, H. J . Angew. Chem., Int. Ed. Engl. 1977, 16, 244.
(7) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3816. (b) Levin, J . I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
12, 989-993.
(10) Other noncrystalline aryloxyethers have been used as protecting
groups for tertiary alcohols. See: (a) Masaki, Y.; Iwata, I.; Mukai, I.;
Oda, H.; Nagashima, H. Chem. Lett. 1989, 659-662. (b) Loubinoux,
B.; Coudert, G.; Guillaumet, G. Tetrahedron Lett. 1981, 22, 1973-1976.
(11) Benneche, T.; Undheim, K. Acta Chem. Scand. 1983, B37, 93-
96.

Synthesis of HIV Protease Inhibitor PNU-140690
J . Org. Chem., Vol. 63, No. 21, 1998 7351
Sch em e 7
Sch em e 8
reaction included potassium carbonate, triethylamine,
tributylamine, diethylaniline, dimethylaniline, pyridine,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), molecular sieves,
and no base at all, but all were inferior to diisopropyl-
ethylamine. The crude product could be precipitated
from the reaction mixture by addition of methanol. The
major contaminant was the diphenoxymethane impurity,
which was conveniently removed by filtration in the next
step.
Reduction of ester 17e with diisobutylaluminum hy-
dride in toluene as above proceeded smoothly. No other
reducing agents were examined. Excess reagent was
quenched with acetone, and the aluminum salts were
removed by extraction with aqueous citric acid. After a
sodium hydroxide wash to remove the 4-phenylphenol
byproduct of the reduction, alcohol 18e was crystallized
from methylene chloride/hexane. The bleach/TEMPO
oxidation also proceeded as expected. The crude product
solution was subjected to a filtration through magnesol.
Displacement of methylene chloride with hexane resulted
in crystallization of the desired aldehyde 19e (mp 47.0-
48.5 °C) in an analytically pure state. Thus, use of the
POM protecting group allowed for preparation, purifica-
tion, and isolation of a suitably functionalized aldehyde
without chromatography. Aldehyde 19e could also be
stored for weeks without any evidence of dimerization
or other degradation.
With the two coupling partners in hand, we turned to
the crucial aldol addition reaction. Enolization of ester
(+)-8 with lithium diisopropylamide in tetrahydrofuran
solution led to formation of a dark brown color, and the
subsequent reaction with aldehyde 19a resulted in low
conversion to the desired aldol adducts and significant
dimerization of the aldehyde. Supposing that the un-
satisfactory result was due to electron transfer from the
amide base to the nitroaromatic, we chose to attempt
enolization with the weaker base, and less effective one-
electron reductant, lithium hexamethyldisilazide. The
yield rose to 76%. Interestingly, at this time a paper by
Black appeared reporting the metalation of 2,4-difluo-
ronitrobenzene.12 In this study, hexamethyldisilazide
bases, especially with sodium or potassium counterion,
were far superior to lithium diisopropylamide, which
again was prone to one-electron-transfer reactions. Ap-
plication of sodium hexamethyldisilazide to our system
resulted in a slight increase in yield relative to the
lithium case.
As discussed above, full optimization and accurate
yield measurement for the aldol reaction were hindered
at first by lack of aldehyde purity. With the availability
of POM-protected aldehyde 19e, application of our best
conditions afforded aldols 20 as a mixture of four dia-
stereomers in 90% yield (Scheme 8). The mixture could
be carried directly into the next reaction after an aqueous
workup. Attempted reaction at -25 °C instead of -80
°C resulted in extensive aldehyde decomposition from
dimerization and loss of the POM group.
Pyridinium chlorochromate (PCC) on basic alumina
and the Swern oxidation were investigated for conversion
of the aldols to â-keto esters in an earlier version of this
chemistry. PCC was chosen because it does not require
low temperature, is operationally simpler, and does not
generate odor. Application to aldols 20 resulted in
quantitative conversion to â-keto ester 21 as a mixture
of two diastereomers (epimers at the labile C3 center).
After removal of the chromium salts by filtration through
magnesol, the unpurified product was carried directly
into the next reaction, acidic hydrolysis of the POM
protecting group. This was accomplished by treatment
with sulfuric acid in THF/methanol solution at room
temperature.13 It is notable that these conditions do not
result in appreciable elimination of the tertiary alcohol
to form a mixture of unsaturated ketones, a facile
decomposition pathway seen with many of the intermedi-
ates described in this paper. Once again, the unpurified
product 22 could be carried into the next reaction
following an aqueous workup to remove the 4-phenylphe-
nol byproduct.
Saponification of ester 22 leads directly to the lacton-
ized intermediate 23. Cyclization appears to occur
spontaneously under the basic reaction conditions as
(12) Black, W. C.; Guay, B.; Scheuermeyer, F. J . Org. Chem. 1997,
62, 758-760.
(13) Shih, T.; Thomas, L.; Wyvratt, M. J . J . Org. Chem. 1987, 52,
2029-2033.

7352 J . Org. Chem., Vol. 63, No. 21, 1998
Fors et al.
liquids or solutions were transferred via syringe or polypro-
pylene cannula. Organic solutions were concentrated by rotary
evaporation at ∼80 mmHg and less than 60 °C except where
noted.
indicated by our failure to detect any intermediates by
TLC or HPLC. That the reaction is truly a saponification
followed by cyclization rather than direct lactonization
of the hydroxy ester is suggested by the inability of
potassium tert-butoxide to mediate the closure. Use of
sodium hydroxide in THF,14 conditions used successfully
for several related substrates, resulted in unexpectedly
high levels of decarboxylation to form an open-chain
ketone. Use of an alcoholic medium led to improvement,
but there was little difference over the series methanol-
ethanol-2-propanol. After extensive experimentation,
reaction with 1.5-2 equiv of sodium hydroxide in metha-
nol at 0 °C was found to produce the optimal yield of
lactone 23. The reaction takes 3 days to go to completion
at this temperature, but the value of this late intermedi-
ate provides justification. Upon completion, neutral
species are removed by hexane extraction, the pH of the
aqueous methanol layer is adjusted, and the product is
extracted into methylene chloride. Upon concentration
and addition of diethyl ether, analytically pure 23
crystallizes in 75% yield. Lactone 23 is the first crystal-
line intermediate since aldehyde 19e; its efficient puri-
fication by crystallization is significant in light of the four
synthetic steps performed. Comparison of NMR spectra
recorded in different solvents reveals that the proportions
of 23 existing in the enol tautomer shown and the
mixture of diastereomeric C3 keto tautomers varies, with
a tendency to exist as the enol in protic media.
Hydrogenation of nitroaromatic 23 under mild condi-
tions quantitatively gives aniline 24, the previously
reported penultimate intermediate. Intersection with
this intermediate conclusively proves the C6 stereochem-
istry obtained from the resolution of (()-4. It is worthy
of note that application of the same sulfonylation and
purification conditions afforded a 78% yield of analyti-
cally pure 1. This yield is by far the highest yet attained
for this step, roughly 20% above what was routinely
achieved earlier when intermediates were not chromato-
graphically purified. Much of this improvement is at-
tributable to the high-quality 24 derived from this new
route.
NMR spectra were recorded at 300 and 75 MHz for 1H and
13C, respectively, in CDCl3 unless otherwise noted. Multiplici-
ties for 13C experiments are reported on the basis of DEPT
data. Melting points were determined in unsealed capillary
tubes and are uncorrected. Elemental analysis and high-
resolution mass spectra (HRMS) and optical rotations were
obtained from Pharmacia and Upjohn Physical and Analytical
Chemistry. The following HPLC method was used: stationary
phase, 4.6 X 250 mm Zorbax RX C-8 column; mobile phase A
) acetonitrile; mobile phase B ) water; gradient from 50:50
A:B to 100:0 A:B over 15 min; flow rate ) 2.0 mL/min; UV
detection at 254 nm.
Eth yl 3-Hyd r oxy-3-(2-p h en yleth yl)h exa n oa te (5). To
a solution of diisopropylamine (32.2 mL, 230 mmol) in THF
(240 mL) cooled to -58 °C was added 2.63 M n-butyllithium
in hexane (87.4 mL, 230 mmol) over 1 h. Ethyl acetate (21.4
mL, 220 mmol) was then added and the reaction mixture
stirred for 1 h, during which time the reaction mixture was
cooled to -70 °C. 1-Phenylhexan-3-one (35.2 g, 200 mmol) was
added slowly over 30 min and the reaction mixture stirred cold
for 1 h. The mixture was quenched with aqueous ammonium
chloride (100 mL) and warmed to room temperature. The
product was extracted into methyl tert-butyl ether, dried over
MgSO4, and concentrated to give 53.41 g (98%) of 5 as an oil:
TLC Rf ) 0.71 (30% EtOAc/hexanes); 1H NMR δ 7.28-7.12
(m, 5H), 4.13 (q, 2H, J ) 7.1 Hz), 3.60 (s, 1H), 2.73-2.63 (m,
2H), 2.50 (s, 2H), 1.83-1.77 (m, 2H), 1.58-1.53 (m, 2H), 1.41-
1.36 (m, 2H), 1.24 (t, 3H, J ) 7.1 Hz), 0.93 (t, 3H, J ) 7.2 Hz);
13C NMR δ 173.0 (s), 143.2 (s), 128.5 (d), 128.4 (d), 128.3 (d),
128.1 (d), 125.8 (d), 72.8 (s), 60.6 (t), 42.9 (t), 41.3 (t), 30.1 (t),
17.0 (t), 14.6 (q), 14.2 (q); MS (CI, NH3) m/z (relative intensity)
282 (100), 264 (63). Anal. Calcd for C16H24O3: C, 72.69; H,
9.15. Found: C, 72.69; H, 9.41.
3-Hyd r oxy-3-(2-p h en yleth yl)h exa n oic Acid ((()-4). Es-
ter 5 (200 mmol) was dissolved in methanol (423 mL), and 2
M aqueous NaOH (150 mL, 300 mmol) was added. The
reaction mixture was stirred at room-temperature overnight.
Methanol was removed in vacuo and the remaining solution
acidified with 4 M aqueous HCl. This was extracted into
methyl tert-butyl ether, dried over MgSO4, and concentrated
to give 44.51 g (94%) of (()-4 as a yellow oil: TLC Rf ) 0.10
(30% EtOAc/hexanes); 1H NMR δ 7.43-7.13 (m, 5H), 2.77-
2.62 (m, 2H), 2.06 (s, 2H), 1.87-1.76 (m, 2H), 1.63-1.57 (m,
2H), 1.45-1.31 (m, 2H), 0.93 (t, 3H, J ) 7.2 Hz); 13C NMR δ
176.9 (s), 141.9 (s), 128.4 (d), 128.3 (d), 125.9 (d), 73.4 (s), 42.7
(t), 41.4 (t), 40.9 (t), 31.9 (t), 17.0 (t), 14.5 (q); MS (CI, NH3)
m/z (relative intensity) 254 (100), 236 (28). Anal. Calcd for
Con clu sion
A convergent route for preparation of PNU-140690 (1)
amenable to scale-up has been developed. The new route
sets each of the two stereocenters present in the final
target separately, allowing for easy control over the level
of diastereomeric impurities. It uses relatively cheap raw
materials and reagents that do not pose severe hazards
for large-scale manufacture, although an evaluation of
toxicity associated with POMCl must still be investigated.
Notable features include a resolution to set the stereo-
chemistry of the tertiary hydroxyl group at C6, develop-
ment of a new (aryloxy)methyl ether protecting group for
alcohols useful for inducing crystallinity, successful eno-
lization of ester 8 containing an aryl nitro group, and
identification of a crystalline advanced intermediate 23.
C
14H20O3: C, 71.16; H, 8.53. Found: C, 71.22; H, 8.68.
(R)-3-Hydr oxy-3-(2-ph en yleth yl)h exan oic Acid, (1R,2S)-
Nor ep h ed r in e Sa lt (6). Hydroxy acid (()-4 (2.83 g, 11.97)
was dissolved in acetonitrile (15 mL). (1R,2S)-(-)-Norephe-
drine (910 mg, 5.99 mmol, 0.5 equiv) was added and the
mixture stirred overnight at room temperature. After ap-
proximately 1 h, crystals began to precipitate. The slurry was
cooled to 0 °C for 1 h before filtering to collect the crude salt.
The solids were washed with 9 mL of cold acetonitrile to give
1.53 g (33%, 92% ee) of crude 6 as white crystalline solids.
The solids were slurried in acetonitrile (21 mL) and heated to
70 °C for 30 min. The resulting solution was gradually cooled
to room temperature as the product precipitated. After 2 h
at room temperature, the product was collected by vacuum
filtration and washed with acetonitrile (21 mL). The recrys-
tallization from acetonitrile was repeated to yield 1.25 g (27%,
98% ee by chiral HPLC analysis) of white crystalline 6: mp
Exp er im en ta l Section
1
113-117 °C; H NMR (MeOH) δ 7.41-7.08 (m, 10H), 5.18 (s,
Gen er a l P r oced u r es. All reagents were commercially
obtained and used as received unless otherwise noted. All
nonaqueous reactions were performed in dry glassware under
an atmosphere of dry nitrogen. Air- and moisture-sensitive
5H), 4.98 (d,1H, J ) 3.2 Hz), 3.15 (m, 1H), 2.65-2.60 (m, 2H),
2.34 (s, 2H), 1.79-1.73 (m, 2H), 1.56-1.52 (m, 2H), 1.43-1.37
(m, 2H), 1.06 (d, 2H, J ) 6.7 Hz), 0.92 (t, 3H, J ) 7.1 Hz); 13
C
NMR (MeOH) δ 181.4 (s),144.6 (s), 142.2 (s), 130.2-129.3 (d),
127.6 (d), 127.1 (d), 74.5 (s), 73.9 (s), 54.0 (d), 46.4 (t), 43.6 (t),
43.4 (t), 31.9 (t), 31.9 (t), 18.6 (t), 15.7 (q), 12.9 (q); MS (CI,
(14) Peterson, J . R.; Miller, C. P. Synth. Commun. 1988, 18, 949.

Synthesis of HIV Protease Inhibitor PNU-140690
J . Org. Chem., Vol. 63, No. 21, 1998 7353
NH3) m/z (relative intensity) 388 (25), 254 (30), 236 (7), 152
EtOAc/hexane); 1H NMR δ 0.80 (t, 3H), 1.56-1.83 (m, 2H),
2.55-2.75 (m, 2H), 3.05-3.2 (m, 1H), 3.57 (s, 3H), 7.4-7.55
(m, 2H), 8.03-8.12 (m, 2H).
(100); [R]25 +16° (c 1.0, MeOH). Anal. Calcd for C23H33NO4:
D
C, 71.29; H, 8.53; N, 3.61. Found: C, 70.99; H, 8.68; N, 3.62.
Dim eth yl (3-Nitr oben za l)m a lon a te (9). 3-Nitrobenzal-
dehyde (75.5 g, 0.50 mol) and dimethyl malonate (70.0 g, 0.53
mol) were added to toluene (200 mL) and cyclohexane (150
mL). The mixture was treated with benzoic acid (2.0 g, 0.017
mol) and piperidine (2.5 mL, 2.15 g, 0.025 mol) and then heated
under reflux, collecting the evolved water in a Dean-Stark
trap. After 5.5 h, 8.8 mL (0.49 mol) of water was collected.
The reaction was then cooled to room temperature and allowed
to stand for 16 h. The resultant crystals were collected and
washed with methanol, giving dimethyl (3-nitrobenzal)ma-
lonate (9) (86.5 g, mp 98.5-99.4 °C). The filtrate and washings
from these crystals were concentrated and crystallized from
methanol, giving additional dimethyl (3-nitrobenzal)malonate
(21.1 g): TLC Rf ) 0.34 (20% EtOAc/hexane); 1H NMR δ 3.88
(s, 3H), 3.90 (s, 3H), 7.59 (t, 1H), 7.73 (br d, 1H), 7.79 (s, 1H),
8.26 (br d,1H), 8.31 (br s, 1H); IR (drift) 1722, 1535 cm-1; UV
Ch ir a l Sep a r a tion of 3-(3-Nitr op h en yl)p en ta n oic Acid
Meth yl Ester ((()-8) to (R)-3-(3-Nitr op h en yl)p en ta n oic
Acid Meth yl Ester ((+)-8) a n d (S)-3-(3-Nitr op h en yl)-
p en ta n oic Acid Meth yl Ester ((-)-8). Aliquots (5.0 mL of
60 mg/mL) of (()-8 in the mobile phase were injected onto a
50 × 30 cm (R,R)Whelk-O 1 column (Regis Technologies). The
mobile of 10% 2-propanol in heptane was pumped at 50 mL/
min at 30 °C, and the eluted products were monitored at 260
nm. Resolution was incomplete after a single pass through
the column. The leading and tailing edges of the material
eluting from 28 to 40 min was collected and the central portion
recycled. Automated iteration of this allowed the processing
of 0.25 g/h of racemate. In this manner, (()-8 (27.94 g) was
resolved to the less polar isomer (-)-8 (12.1 g, [R]25 -20.1°)
D
and the more polar isomer (+)-8 (13.1 g, [R]25D +18.6°). These
materials were found to have 99% and 98.2% ee, respectively,
as determined below.
λmax 262 nm (25200, 95% EtOH). Anal. Calcd for C12H11NO6:
C, 54.34; H, 4.18; N, 5.28. Found: C, 54.23; H, 4.18; N, 5.27.
(+)-Dim eth yl 1-[1-(3-Nitr oph en yl)pr opyl]m alon ate ((+)-
10). Dimethyl (3-nitrobenzal)malonate (9) (105.6 g, 0.399 mol)
was dissolved in dry THF (525 mL) and the solution treated
with cuprous bromide methyl sulfide (16.3 g, 0.05 mol) and
cooled to -10 °C under a nitrogen atmosphere. To this was
added (1 h) diethylzinc in hexane (1 M, 450 mL, 0.45 mol).
After 2 h, the solution was treated dropwise with saturated
aqueous ammonium chloride (250 mL). The reaction was then
poured into ethyl acetate and extracted with hydrochloric acid
(1 N) and saturated aqueous sodium chloride. The ethyl
acetate solution was dried (sodium sulfate) and concentrated
under vacuum to give dimethyl 1-(3-nitrophenyl)propylma-
lonate ((+)-10) (113.9 g). A sample of this material was
recrystallized from methanol (mp 84.6-84.9° C): TLC Rf )
0.38 (20% EtOAc/hexane); 1H NMR δ 0.735 (t, 3H), 1.6-1.9
(m, 2H), 3.42 (dt, 1H), 3.47 (s, 3H), 3.71 (d, 1H), 3.79 (s, 3H),
7.48 (t, 1H), 7.55 (br d, 1H), 7.79 (s, 1H), 8.11 (br d, 1H); IR
(drift) 1723, 1528 cm-1; UV λmax 262 nm (8010, 95% EtOH).
Anal. Calcd for C14H17NO6: C, 56.94; H, 5.80; N, 4.74.
Found: C, 56.92; H, 5.82; N, 4.78.
The retention times were 18.9 and 20.5 min for the enan-
tiomers when the racemate was injected onto a 0.46 × 25 cm
(R,R)Whelk-O 1 column (Regis Technologies) eluted with 10%
2-propanol in heptane (V/V) at 0.5 mL/min while being
observed at 260 nm, ambient temperature.
3-(3-Nitr op h en yl)p en ta n oic Acid ((+)-11) a n d Its Cy-
cloh exyla m in e Sa lt by Hyd r olysis of (R)-3-(3-Nitr op h e-
n yl)p en ta n oic Acid Meth yl Ester ((+)-8). (R)-3-(3-Nitro-
phenyl)pentanoic acid methyl ester ((+)-8) (1.15 g, 4.84 mmol)
was treated with methanol (25 mL) and 1 N sodium hydroxide
(7.2 mL, 7.2 mmol) and the solution stirred for 18 h. The
reaction was then concentrated under vacuum and the residue
partitioned between ethyl acetate and 1 N hydrochloric acid.
The organic layer was dried (sodium sulfate) and evaporated
under vacuum to give 3-(3-nitrophenyl)pentanoic acid ((+)-11)
(1.074 g): [R]25 ) +22.7°; [R]25 ) +23.7° (MeOH, c ) 1.0)
D
578
3-(3-nitrophenyl)pentanoic acid ((+)-11) (1.074 g) was dis-
solved in ethyl acetate and treated with cyclohexylamine (0.55
mL). The crystals of 3-(3-nitrophenyl)pentanoic acid cyclo-
hexylamine salt (1.446 g) was collected by filtration: mp 145-7
°C; [R]25 ) +12.8° (MeOH, c ) 1.0)
578
3-(3-Nitr op h en yl)p en ta n oic Acid ((()-11) a n d Its Cy-
cloh exyla m in e Sa lt. Dimethyl 1-(3-nitrophenyl)propylma-
lonate ((()-10) (97 g, 0.331 mol) was treated with 1 N
hydrochloric acid (1 L) and the mixture stirred vigorously and
heated under reflux (19 h). The reaction was then cooled and
extracted two times with methylene chloride. The combined
methylene chloride solutions were dried (sodium sulfate) and
concentrated under vacuum, leaving 3-(3-nitrophenyl)pen-
tanoic acid (()-11 (71.38 g) as a pale brown solid: TLC Rf )
0.10 (20% EtOAc/hexane); 1H NMR δ 0.804 (t, 3H), 1.57-1.88
(m, 2H), 2.56-2.80 (m, 2H), 3.5-3.2 (m, 1H), 7.4-7.55 (m, 2H),
7.97-8.12 (m, 2H); IR (drift) 3090, 3078, 3045, 2967, 2932,
1709, 1528, cm-1; UV λmax 263 nm (7760, 95% EtOH). Anal.
Calcd for C11H13NO4: C, 59.19; H, 5.87; N, 6.28. Found: C,
58.97; H, 5.85; N, 6.23.
R esolu t ion of (()-1-(3-Nit r op h en yl)p r op a n ol (12) b y
Con ver sion to (S)-1-(3-Nitrophenyl)propanol (13) and (R)-
1-(3-Nitr op h en yl)p r op a n ol Aceta te (14). Celite-supported
PS-30 lipase (Amano, 24 g) and isopropenyl acetate (22.00 mL,
0.20 mol) was added to (()-1-(3-nitrophenyl)propanol (12,
24.00 g, 0.13 mol) in MTBE (240 mL). The mixture was stirred
at 20-25 °C for 2 days. At the end of this time, the catalyst
was removed by filtration, the catalyst cake washed with ether,
and the mixture concentrated under reduced pressure to give
an acetate-alcohol mixture. Separation of the mixture by
silica gel chromatography gave 14 (13.03 g) and 13 (10.7 g).
Data for 14: 1H NMR δ 0.91-0.96 (t, 3 H), 1.75-1.87 (m, 2
H), 2.04 (br s, 1 H), 4.72-4.76 (t, 1 H), 7.48-7.53 (t, 1 H), 7.66-
7.69 (d, 1 H), 8.10-8.13 (m, 1 H), 8.20-8.21 (m, 1 H); [R]25
D
+68.7° (EtOH, c ) 1). Data for 13: [R]25 -33.0° (EtOH, c )
D
The solid was dissolved in ethyl acetate and the solution
treated with cyclohexylamine (31.7 g, 0.32 mol). After the
solution was allowed to stand for 16 h, the crystals of 3-(3-
nitrophenyl)pentanoic acid cyclohexylamine salt were collected
(96.13 g, mp 143.8-144.6° C): IR (drift) 2937, 1632, 1528,
1380, cm-1; UV λmax 264 nm (7690, MeOH). Anal. Calcd for
1).
(S)-1-(3-Nitr op h en yl)p r op a n ol Mesyla te. Diisopropyl-
ethylamine (1.07 g, 8.3 mmol) was added to a mixture of (S)-
1-(3-nitrophenyl)propanol (14, 1 g, 5.5 mmol) in methylene
chloride (20 mL). The mixture was cooled to -20 °C, and
methanesulfonyl chloride (0.69 g, 6.02 mmol) was added. The
reaction was held at -20 °C for 10 min and then held at 0 °C
for 40 min. The reaction was diluted with methylene chloride,
sodium bicarbonate (5%) was added, and the phases were
separated. The methylene chloride was evaporated to give the
title compound, which was used directly in the following step:
C
11H13NO4.C6H13N: C, 63.33; H, 8.13; N, 8.69. Found: C,
63.42; H, 8.12; N, 8.63.
(+)-3-(3-Nitr oph en yl)pen tan oic Acid Meth yl Ester ((+)-
8). To a solution of (()-3-(3-nitrophenyl)pentanoic acid (11,
30.21 g, 135 mmol) in methanol (250 mL) was added concen-
trated sulfuric acid (0.6 mL). The resulting mixture was
heated to reflux for 3 h. Upon cooling, the mixture was
partitioned between ethyl acetate and sodium bicarbonate (5%
aqueous). The aqueous layer was separated and back-
extracted with two additional portions of ethyl acetate. The
combined organic phases were washed with saturated aqueous
sodium chloride, dried over sodium sulfate, filtered, and
concentrated to give the title compound: TLC Rf ) 0.54 (20%
[R]25 -79.9° (ethanol, c ) 1); TLC Rf ) 0.19 (20% EtOAc/
D
hexane); 1H NMR δ 0.96-1.01 (t, 3 H), 1.88-2.17 (m, 2 H),
2.89 (s, 3 H), 5.54-5.59 (t, 1 H), 7.57-7.62 (t, 1 H), 7.70-7.73
(d, 1 H), 8.20-8.24 (m, 2 H).
(R)-Dieth yl 1-[1-(3-Nitr op h en yl)p r op yl]m a lon a te (15).
A solution of sodium ethoxide (1.0 M) was prepared by
dissolving sodium metal (1.27 g, 0.055 mol) in absolute ethanol
(55 mL). Diethyl malonate (8.84 g, 0.055 mol) was added to

7354 J . Org. Chem., Vol. 63, No. 21, 1998
Fors et al.
the above solution at 0 °C. (S)-1-(3-Nitrophenyl)propanol
mesylate (1.43 g, 5.5 mmol) was added dropwise to the above
solution of sodium malonate (6.4 mL, 6.4 mmol) at -20 °C.
After 2 h at 20-25 °C, an additional aliquot of sodium
malonate (5 mL, 5.0 mmol) was added to the reaction and then
stirred overnight at 20-25 °C. The reaction was concentrated
and partitioned between ethyl acetate and hydrochloric acid
(1 N). The organic phase was separated and the solvent
removed to give crude product that was chromatographed
(silica gel; ethyl acetate/hexane, 10/90) to give the title
83.2%): mp 99-101 °C; TLC Rf ) 0.64 (10% EtOAc/hexanes);
1
HPLC tR ) 9.67 min; H NMR δ 7.55-6.99 (m, 13H), 5.44 (s,
2H); 13C NMR δ 156.0 (s), 140.5 (s), 135.3 (s), 133.5 (s), 132.1
(d), 129.2 (d), 128.8 (d), 128.2 (d), 126.9 (d), 126.8 (d), 116.3
(d), 73.2 (t); MS (CI, NH3) m/z (relative intensity) 328 (3.8),
326 (8.1), 200 (100). Anal. Calcd for C19H15ClOS: C, 69.82;
H, 4.63. Found: C, 69.73; H, 4.59.
1-(Ch lor om eth oxy)-4-p h en ylben zen e. To a solution of
the mixed S,O-acetal prepared above (176.45 g, 539.9 mmol)
in methylene chloride (750 mL) at 21 °C was added a solution
of sulfuryl chloride (73.32 g, 543.2 mmol, 1.01 equiv) in
methylene chloride (150 mL) while a temperature <23 °C was
maintained over 8 min. The mixture was stirred at 20 °C for
11 min and then cooled to 3 °C. A solution of cyclohexene (60.7
mL, 599 mmol, 1.11 equiv) in methylene chloride (100 mL)
was added over 10 min at 3-5 °C and then warmed to 19 °C
and stirred 10 min. The solution was concentrated to 600 mL
total volume, and hexanes (500 mL) was added. The solution
was concentrated to 500 mL, and hexanes (300 mL) was added.
The resultant slurry was concentrated to 500 mL and pentane
(1.3 l) added. The slurry was cooled to -50 °C and the
precipitate collected by vacuum filtration, washed with -30
°C pentane (700 mL), and dried to give a beige solid (115.28
g). A portion (110.34 g) was dissolved in methylene chloride
(200 mL). Hexanes (1 L) was added and the mixture concen-
trated to 949 g. Hexanes (200 mL) was added and the mixture
concentrated to 589 g. Hexanes (500 mL) was added, the
slurry cooled to -30 °C, and the precipitate collected by
vacuum filtration, washed with hexanes (300 mL), and dried
to give the title compound (POMCl) as a gray solid (100.66 g,
89.0%): mp 67-70 °C; TLC Rf ) 0.68 (8% EtOAc/hexanes);
compound: [R]25 +19.4° (EtOH, c ) 1); TLC Rf ) 0.48 (20%
D
1
EtOAc/hexane); H NMR (CDCl3, TMS) δ 0.70-0.75 (t, 3 H),
0.96-1.00 (t, 3 H), 1.27-1.32 (t, 3 H), 1.56-1.88 (m, 2 H),
3.37-3.45 (d of t, 1 H), 3.65-3.69 (d, 1 H), 3.86-3.96 (m, 2
H), 4.21-4.28 (q, 2 H), 7.44-7.49 (m, 1 H), 7.54-7.57 (m, 1
H), 8.08-8.11 (m, 2 H).
3-(3-Nitr op h en yl)p en ta n oic Acid ((+)-11) a n d Its Cy-
cloh exyla m in e Sa lt fr om Ma lon a te 15. [1-(3-Nitrophenyl)-
propyl]malonate (+)-15 (0.73 g, 2.26 mmol) was refluxed in 6
N HCl (10 mL) for 18 h. The reaction was cooled and extracted
with EtOAc. The EtOAc layer was washed with water,
separated, and evaporated to give 3-(3-nitrophenyl)pentanoic
acid ((+)-11) (0.51 g) as a clear oil: [R]25 +13.3° (MeOH, c )
D
1
1); TLC Rf ) 0.48 (2/20/80 AcOH/EtOAc/hexane); H NMR δ
0.78-0.83 (t, 3 H), 1.59-1.82 (m, 2 H), 2.59-2.78 (d of q, 2
H), 3.07-3.17 (m, 1 H), 7.44-7.54 (m, 2 H), 8.04-8.10 (m, 2
H). 3-(3-Nitrophenyl)pentanoic acid ((+)-11) (0.3 g, 1.34 mmol)
was dissolved in EtOAc (3 mL) and treated with cyclohexyl-
amine (0.14 g, 1.41 mmol). The resulting crystals were filtered
and rinsed with EtOAc to give 3-(3-nitrophenyl)pentanoic acid
cyclohexylamine salt (0.306 g): mp 145-8 °C; [R]25 +11.8°;
D
[R]25 +12.4° (MeOH, c ) 1.02); IR (mull) 1636, 1550, 1348,
HPLC rt ) 6.45 min; H NMR δ 7.80-7.13 (m, 9H), 5.89 (s,
1
578
cm-1. Anal. Calcd for C11H13NO4‚C6H13N: C, 63.33; H, 8.13;
2H); 13C NMR δ 155.0 (s), 140.3 (s), 136.5 (s), 128.8 (d), 128.4
(d), 127.1 (d), 126.9 (d), 116.4 (d), 77.2 (t); HRMS (EI+) calcd
for C13H11ClO 218.0498, found 218.0493.
N, 8.69. Found: C, 63.09; H, 7.88; N, 8.57.
(4-P h en ylp h en oxy)(4-ch lor oth iop h en oxy)m eth a n e. To
a slurry of paraformaldehyde (36.24 g, 1.21 mol, 1.58 equiv)
in toluene (243 mL) at 22 °C was added aqueous hydrobromic
acid (48.5 wt %, 652 mL, 5.86 mol, 7.68 equiv) with an
endotherm to 18 °C. The resultant biphasic solution was
warmed to 40 °C, and a solution of 4-chlorothiophenol (138.81
g, 0.960 mol, 1.26 equiv) in toluene (116 mL) was added over
0.5 h while the temperature was maintained at 40-43 °C and
rinsed in with toluene (50 mL). The mixture was then warmed
to 50 °C and stirred for 1 h. The mixture was cooled to 10 °C,
the phases were separated, and the aqueous layer was washed
with toluene (250 mL) The combined organics were treated
with ice-water (500 mL) and hexanes (350 mL), and the
phases were separated. The aqueous was then washed with
toluene (200 mL), and the combined organics were dried on
MgSO4 and concentrated to give the crude bromomethyl
thioether (268.01 g): 1H NMR δ 7.43 (d, 2H, J ) 8.4 Hz), 7.34
(d, 2H, J ) 8.7 Hz), 4.79 (s, 2H); 13C NMR δ 134.4 (s), 132.1
(d), 131.8 (s), 129.5 (d), 37.3 (t); HRMS (EI+) calcd for C7H6-
BrClS 235.9063, found 235.9063.
To a solution of 4-phenylphenol (129.91 g, 0.763 mol, 1.00
equiv) in DMF (400 mL) at -10 °C was added a solution of
potassium tert-butoxide in THF (20 wt %, 429.40 g, 0.765 mol,
1.00 equiv) followed by THF (50 mL), while a temperature of
<5 °C was maintained. The solution was concentrated to 557
g net weight and DMF (33 mL) added followed by the crude
bromomethyl thioether prepared above with a free exotherm
from 22 to 70 °C. The crude PNU-174652 was rinsed in with
DMF (50 mL) and the resultant slurry stirred at 80 °C for 0.5
h. The mixture was cooled to 22 °C, and hexanes (400 mL)
followed by water (500 mL) was added. The precipitate was
collected by vacuum filtration, washed with water (1500 mL)
and methanol (300 mL), and dried in a nitrogen stream to give
a solid (251.25 g). This was dissolved in methylene chloride
(1 L) and dried on MgSO4, washing with methylene chloride
(200 mL). A constant volume concentration (1300-1800 mL)
was then performed while a total of 1.35 L methanol was
added, and the final amount was 1344 g net weight. The
resultant precipitate was collected at room temperature by
vacuum filtration, washed with methanol (1 L), and dried at
65 °C under vacuum to give the mixed S,O-acetal (207.63 g,
(R)-(4-P h en ylp h en oxy)m eth yl 3-(2-P h en yleth yl)-3-[(4-
p h en ylp h en oxy)m eth oxy]h exa n oa te (17e). To a slurry of
6 (25.04 g, 64.62 mmol) in water (185 mL) and MTBE (185
mL) at room temperature was added aqueous hydrochloric acid
(37.5 wt %, 7.51 g, 77.24 mmol, 1.20 equiv), and the pH was
adjusted from 8.04 to 1.30. The phases were separated, and
the aqueous phase was washed with MTBE (185 mL). The
organics were dried on MgSO4 and concentrated to an oil
(18.39). To the oil were then added toluene (77 mL), N,N-
diisopropylethylamine (96 mL, 551 mmol, 8.53 equiv), and
PNU-174222E (71.88 g, 328.68 mmol, 5.09 equiv). The
mixture was then warmed to 110 °C and stirred at 110-117
°C for 5 h. The mixture was cooled to 65 °C and methanol
(800 mL) added. The resultant slurry was cooled to -30 °C
and the product collected by vacuum filtration, washed with
methanol (200 mL), and dried to afford crude 17e (49.86 g,
56.5 wt % by HPLC, 72.6% yield). An analytical sample was
obtained by chromatography (ethyl acetate/hexanes) followed
by crystallization: mp 104.0-105.5 °C; TLC Rf ) 0.50 (15%
1
EtOAc/hexanes); HPLC tR ) 13.8 min; H NMR δ 7.51-7.04
(m, 23 H), 5.78 (s, 2H), 5.32 (s, 2H), 2.75 (s, 2H), 2.64-2.58
(m, 2H), 2.03-1.97 (m, 2H), 1.78-1.72 (m, 2H), 1.41-1.28 (m,
2H), 0.86 (t, 3H, J ) 7.2 Hz); 13C NMR δ 169.4 (s), 157.1 (s),
156.1 (s), 142.0 (s), 140.7 (s), 140.4 (s), 135.9 (s), 134.6 (s), 128.8
(d), 128.7 (d), 128.4 (d), 128.3 (d), 128.1 (d), 127.0 (d), 126.8
(d), 126.7 (d), 125.8 (d), 116.1 (d), 87.3 (t), 85.2 (t), 80.4 (s),
41.2 (t), 38.8 (t), 38.6 (t), 29.7 (t), 16.7 (t), 14.4 (q); MS (CI,
NH3) m/z (relative intensity) 618 (19), 266 (100); [R]25 -4 (C
D
1.0, CH2Cl2). Anal. Calcd for C40H40O5: C, 79.97; H, 6.71.
Found: C, 79.64; H, 6.58.
(R)-3-(2-P h en yleth yl)-3-[(4-p h en ylp h en oxy)m eth oxy]-
h exa n ol (18e). To a slurry of crude 17e (56.5 wt %, 49.32 g,
46.38 mmol) in toluene (500 mL) was added a solution of
diisobutylaluminum hydride in toluene (1.52 M, 85 mL, 129.2
mmol, 2.79 equiv) while a temperature of -20 °C was
maintained. The mixture was slowly warmed to 1 °C over 2.5
h and then stirred for 0.5 h. Acetone (8.0 mL, 108.5 mmol,
2.34 equiv) was added and the mixture cannulated into an 18
°C solution of citric acid monohydrate (136 g, 647.2 mmol, 14.0
equiv) in water (433 mL) with controlled exotherm to 28 °C,

Synthesis of HIV Protease Inhibitor PNU-140690
J . Org. Chem., Vol. 63, No. 21, 1998 7355
rinsing with toluene (100 mL). The mixture was stirred at
room temperature for 1.5 h, and the insolubles were removed
by vacuum filtration, washing with toluene. The phases were
separated in the filtrate, and the aqueous phase was washed
with toluene (2 × 300 mL). The organics were dried on MgSO4
and then washed with aqueous sodium hydroxide (0.5 M, 2 ×
500 mL). The organics were concentrated to 137 g net weight,
and methanol (250 mL) was added. The resultant slurry was
concentrated to 212 g net weight, and methanol (250 mL) was
added. The mixture was again concentrated to 253 g and
methanol (250 mL) added. The slurry was cooled to -60 °C,
and the insolubles were removed by filtration. The filtrate
was concentrated 60 g net weight, hexanes (500 mL) added,
and the mixture concentrated to 22 g net weight. Hexanes
(500 mL) was added and the mixture again concentrated to
40 g net weight. Methylene chloride (25 mL) was added
followed by a slow addition of hexanes (500 mL) and pentane
(250 mL) with cooling to -55 °C. The product was collected
by vacuum filtration, washed with pentane (200 mL), and dried
in a nitrogen stream to give a white solid (16.03 g, 91.1 wt %
PNU-174306 by HPLC, 77.8% yield). An analytical sample
was obtained by chromatography (ethyl acetate/hexanes) fol-
lowed by crystallization (methylene chloride/hexanes): mp 49-
53 °C; TLC Rf ) 0.14 (15% EtOAc/hexanes); HPLC tR ) 9.18
min while a temperature of -80 to -85 °C was maintained.
The resultant brown solution was then warmed to -74 °C and
stirred at -74 to -76 °C for 18 min. The mixture was cooled
to -90 °C, a solution of 19e (6.50 g, 16.147 mmol, 1.013 equiv)
in THF was added over 10 min while a temperature of -85 to
-90 °C was maintained and rinsed in with THF (20 mL). The
mixture was then warmed to -71 °C and saturated aqueous
ammonium chloride solution (90 mL) added, followed by water
(90 mL) and MTBE (90 mL), and the mixture warmed to room
temperature. The phases were separated, and the aqueous
phase was washed with MTBE (90 mL). The extracts were
dried on MgSO4 and concentrated to an oil (11.57 g, 79.0 wt
% PNU-174698 by HPLC, 89.7% yield). An analytical sample
was obtained by chromatography (ethyl acetate/hexanes): TLC
Rf ) 0.16, 0.24 (10% EtOAc/hexanes); HPLC tR ) 12.52, 12.68,
12.97 min; MS (electrospray, NaOAc) m/z (relative intensity)
662.5 (100). Anal. Calcd for C39H45NO7: C, 73.21; H, 7.09;
N, 2.19. Found: C, 73.22; H, 7.47; N, 1.99.
(3R,7R)-4-Ca r bom eth oxy-3-(3-n itr op h en yl)-7-(2-p h en -
yleth yl)-7-[(4-ph en ylph en oxy)m eth oxy]decan -5-on e (Mix-
tu r e of Dia ster eom er s a t C-4) (21). A solution of 20 (11.12
g, 79.0 wt %, 13.73 mmol) in methylene chloride (530 mL) was
added to a ground mixture of pyridinium chlorochromate
(16.099 g, 74.685 mmol, 5.44 equiv), sodium acetate (6.984 g,
85.14 mmol, 6.20 equiv), and Florisil (5.181 g) while a
temperature of <11 °C was maintained. The mixture was
warmed to 21 °C and stirred at room temperature for 20 h.
The resultant brown slurry was filtered through magnesol
(47.7 g) and rinsed with methylene chloride (375 mL). The
filtrate was concentrated to an oil (10.38 g, 83.7 wt % PNU-
174699 by HPLC, 99.2% yield). An analytical sample was
obtained by chromatography (ethyl acetate/hexanes): TLC Rf
) 0.34 (10% EtOAc/hexanes); HPLC tR ) 13.02,13.23 min; 1H
NMR δ 8.05-8.01 (m, 3H), 7.60-7.00 (m, 15H), 5.37 (s, 2H),
5.21 (q, 2H, J ) 6.0 Hz), 4.03 (d, 1H, J ) 10.8 Hz), 3.94 (d,
1H, J ) 10.8 Hz), 3.75 (s, 1.5 H), 3.58-3.43 (m, 1H), 3.39 (s,
1.5H), 2.96 (d, 2H, J ) 3.9 Hz), 2.78-1.37 (m, 7H), 1.20 (t,
1.5H, J ) 7.2 Hz), 0.91 (t, 1.5H, J ) 7.5 Hz), 0.71-0.61 (m,
3H); 13C NMR δ 200.9 (s), 200.6 (s), 168.3 (s), 167.8 (s), 157.1
(s), 157.1 (s), 148.4 (s), 148.3 (s), 143.6 (s), 143.3 (s), 142.0 (s),
141.9 (s), 140.7 (s), 140.7 (s), 135.3 (d), 135.0 (d), 134.8 (s),
129.4 (d), 129.2 (d), 128.8 (d), 128.5 (d), 128.4 (d), 128.2 (d),
126.8 (d), 125.9 (d), 125.8 (d), 123.0 (d), 122.8 (d), 122.04 (d),
122.0 (d), 116.2 (d), 87.1 (t), 86.9 (t), 80.9 (s), 80.4 (s), 66.3 (d),
65.9 (d), 52.8 (q), 52.4 (q), 49.0 (t), 48.6 (t), 46.3 (d), 46.2 (d),
38.7 (t), 38.5 (t), 38.4 (t), 38.0 (t), 30.1 (t), 29.5 (t), 26.9 (t),
26.7 (t), 16.6 (t), 16.4 (t), 14.4 (q), 14.2 (q), 11.8 (q), 11.6 (q);
MS (CI, NH3) m/z (relative intensity) 656 (2.8), 655 (6.1), 136
(100). Anal. Calcd for C29H43NO7: C, 73.45; H, 6.80; N, 2.20.
Found: C, 73.11; H, 6.61; N, 2.26.
(3R,7R)-4-Ca r bom eth oxy-7-h yd r oxy-3-(3-n itr op h en yl)-
7-(2-p h en yleth yl)d eca n -5-on e (Mixtu r e of Dia ster eom er s
a t C-4) (22). To a solution of 21 (9.14 g, 83.7 wt %, 11.995
mmol) in THF (20 mL) at 23 °C was added a solution of sulfuric
acid in methanol (0.524 M, 20 mL, 10.48 mmol, 0.87 equiv).
The solution was allowed to stand at 23 °C for 22 h, and then
a solution of sodium bicarbonate (3.52 g, 41.90 mmol, 3.49
equiv) in water (50 mL) was added, followed by MTBE (50 mL).
The phases were separated, and the aqueous phase was
washed with MTBE (30 mL). The combined organics were
washed with aqueous sodium hydroxide (0.5 M, 2 × 50 mL)
at 5 °C and then water (2 × 10 mL), then twice with a mixture
of saturated aqueous ammonium chloride (15 mL) and water
(35 mL). The organics were dried on magnesium sulfate and
concentrated to an oil (6.29 g, 73.3 wt % PNU-173900 by
HPLC, 84.4%). An analytical sample was obtained by chro-
matography (ethyl acetate/hexanes): TLC Rf ) 0.39 (25%
EtOAc/hexanes); HPLC tR ) 8.15, 8.50 min; 1H NMR δ 8.15-
7.85 (m, 3H), 7.48-7.01 (m, 6H), 3.99 (d, 1H, J ) 11.1 Hz),
3.92 (d, 1H, J ) 10.8 Hz), 3.78 (s, 1.5H), 3.50-3.39 (m, 5H),
3.38 (s, 1.5H), 3.32-1.21 (m, 8H), 0.95 (t, 1.5H, J ) 7.1 Hz),
0.82 (t, 1.5H, J ) 7.1 Hz), 0.74-0.67 (m, 3H); 13C NMR δ 205.2
(s), 205.0 (s), 168.0 (s), 167.5 (s), 148.4 (s), 143.1 (s), 142.0 (s),
142.0 (s), 135.2 (d), 135.0 (d), 129.5 (d), 129.3 (d), 128.5 (d),
128.4 (d), 128.3 (d), 128.2 (d), 125.9 (d), 122.8 (d), 122.6 (d),
1
min; H NMR δ 7.56-7.07 (m, 14H), 5.36 (s, 2H), 3.76-3.74
(m, 2H), 2.63-2.58 (m, 2H), 1.94-1.88 (m, 5H), 1.70-1.65 (m,
2H), 1.38-1.30 (m, 2H), 0.93 (t, 3H, J ) 7.2); 13C NMR δ 157.05
(s), 142.25 (s), 140.73 (s), 134.68 (s), 128.70 (d), 128.42 (d),
128.29 (d), 128.2 (d), 126.8 (d), 125.9 (d), 116.1 (d), 87.1 (t),
81.9 (s), 58.9 (t), 38.8 (t), 38.6 (t), 38.2 (t), 29.9 (t), 17.0 (t),
14.6 (q); MS (CI, NH3) m/z (relative intensity) 422 (9.9), 252
(100); [R]25 +6 (C 1.0, CH2Cl2). Anal. Calcd for C27H32O3:
D
C, 80.16; H, 7.97. Found: C, 80.06; H, 7.86.
(R)-3-(2-P h en yleth yl)-3-[(4-p h en ylp h en oxy)m eth oxy]-
h exa n a l (19e). To a solution of crude 18e (91.1 wt %, 15.40
g, 34.68 mmol) in methylene chloride (47 mL) at 0 °C was
added a solution of potassium bromide (0.4057 g, 3.409 mmol,
0.098 equiv) and sodium bicarbonate (1.557 g, 18.53 mmol, 0.53
equiv) in water (20.5 mL) followed by 4-hydroxy-2,2,6,6-
tetramethylpiperidinyloxy, free radical (0.3060 g, 1.776 mmol,
0.051 equiv). Aqueous sodium hypochlorite (13.4 wt %/vol,
26.6 mL, 47.88 mmol, 1.38 equiv) was then added by syringe
pump over 1 h while a temperature of 1-5 °C was maintained.
A solution of sodium thiosulfate pentahydrate (0.5182 g, 2.088
mmol, 0.0602 equiv) in water (14 mL) was then added. The
phases were separated at 0 °C, and the aqueous phase was
washed with 2 × 50 mL of methylene chloride. The organics
were immediately filtered through magnesol (50.25 g) and
rinsed through with methylene chloride (400 mL). The
extracts were concentrated to an oil (30 g), and hexanes (500
mL) was added. The mixture was concentrated to 250 g net
weight, and hexanes (100 mL) was added. The mixture was
concentrated to 186 g net weight, and pentane (300 mL) was
added. The resultant slurry was cooled to -50 °C and the
product collected by vacuum filtration, washed with -50 °C
pentane (100 mL), and dried to give a white solid, analytically
pure as PNU-174305 (13.77 g, 98.6%): mp 47.0-48.5 °C; TLC
Rf ) 0.41 (10% EtOAc/hexanes); HPLC tR ) 10.95 min; 1H
NMR δ 9.79 (t, 1H, J ) 2.7 Hz), 7.53 (t, 4H, J ) 7.5 Hz), 7.40
(t, 2H, J ) 7.5 Hz), 7.26 (t, 2H, J ) 8.1 Hz), 7.20-7.08 (m,
5H), 5.40 (s, 2H), 2.67 (t, 2H, J ) 2.1 Hz), 2.65-2.56 (m, 2H),
1.99 (t, 2H, J ) 8.4 Hz), 1.76 (t, 2H, J ) 8.7 Hz), 1.38 (bq, 2H,
J ) 6.6 Hz), 0.93 (t, 3H, J ) 7.2 Hz); 13C NMR δ 201.8 (d),
156.9 (s), 141.7 (s), 140.7 (s), 134.8 (s), 128.7 (d), 128.5 (d),
128.3 (d), 128.2 (d), 126.8 (d), 126.0 (d), 116.0 (d), 87.2 (t), 80.4
(s), 50.1 (t), 39.2 (t), 39.1 (t), 29.7 (t), 16.9 (t), 14.5 (q); MS (CI,
NH3) m/z (relative intensity) 420 (3.5), 220 (100); [R]25 +14
D
(c 1.0, CH2Cl2). Anal. Calcd for C27H30O3: C, 80.56; H, 7.51;
N, 0.00. Found: C, 80.59; H, 7.69; N, 0.08.
(3R,7R)-4-Ca r bom eth oxy-3-(3-n itr op h en yl)-7-(2-p h en -
yleth yl)-7-[(4-p h en ylp h en oxy)m eth oxy]d eca n -5-ol (Mix-
tu r e of Dia ster eom er s a t C-4 a n d C-5) (P NU-174698 (20)).
To a solution of (R)-8 (3.78 g, 15.932 mmol) in THF (55 mL)
at -80 °C was added a solution of sodium hexamethyldisilazide
in THF (0.935 M, 17.5 mL, 16.36 mmol, 1.027 equiv) over 7

7356 J . Org. Chem., Vol. 63, No. 21, 1998
Fors et al.
122.2 (d), 73.8 (s), 73.5 (s), 66.6 (d), 66.4 (d), 52.9 (q), 52.5 (q),
50.8 (t), 50.6 (t), 46.3 (d), 46.2 (d), 41.6 (t), 41.0 (t), 40.8 (t),
30.0 (t), 29.6 (t), 27.0 (t), 17.1 (t), 16.9 (t), 14.6 (q), 14.4 (q),
11.7 (q), 11.5 (q); MS (CI, NH3) m/z (relative intensity 474 (2.1),
473 (7.8), 194 (100). Anal. Calcd for C26H33NO6: C, 68.55; H,
7.30; N, 3.08. Found: C, 68.36; H, 7.31; N, 3.34.
mL, 750 mmol, 2.69 equiv) was sparged chlorine gas (60 g,
846 mmol, 3.0 equiv) while a temperature of 0-5 °C was
maintained. Methylene chloride (363 mL) was added, and the
phases were separated at 0 °C. The aqueous phase was
washed with methylene chloride (181.5 mL), and the combined
organics were washed with water (2 × 300 mL) at 0-5 °C.
The organics were dried on Na2SO4, filtered, and rinsed
through with methylene chloride (62 mL) at 0 °C. A sample
of this solution (125 g) was washed with aqueous sodium
metabisulfite (5 wt %/vol, 62.5 mL) and water (62.5 mL), dried
over Na2SO4, filtered, and stored at -70 °C for use in the next
step.
[3r(R),6R]-5,6-Dih yd r o-4-h yd r oxy-3-[1-(3-n itr op h en yl)-
pr opyl]-6-[1-(2-ph en yl)eth yl]-6-pr opyl-2H-pyr an -2-on e (23).
A 4 °C solution of aqueous sodium hydroxide (1 M, 11.4 mL,
11.4 mmol, 1.89 equiv) in methanol (35 mL) was added to crude
22 (73.3 wt %, 3.740 g, 6.018 mmol) and rinsed in with
methanol (45 mL) while a temperature of <5 °C was main-
tained. The mixture was vigorously stirred to dissolve the
majority of the crude oil and then moderately stirred at 0-5
°C for 67 h. The mixture was cooled to -5 °C and hexanes
(90 mL) added. The phases were separated at <5 °C, and the
organic phase was washed at <5 °C with a mixture of
methanol (50 mL) and water (7 mL). The pH of the combined
aqueous was adjusted from 12.55 to 6.24 at <5 °C with acetic
acid (1.52 g, 25.31 mmol, 4.21 equiv). The aqueous was
concentrated, extracted with methylene chloride (2 × 40 mL),
dried on MgSO4, and concentrated to give a crude oil (3.98 g).
To a sample of the crude oil (0.401 g) was added diethyl ether
(1.0 mL). The resultant slurry was cooled to -30 °C and the
precipitate collected by vacuum filtration, washed with cold
diethyl ether, and dried in a nitrogen stream to give a white
solid, analytically pure as 23 (0.176 g, 75.1%): TLC Rf ) 0.49
(50% EtOAc/hexanes); HPLC tR ) 6.93 min; 1H NMR (1:1
CDCl3/CD3OD) δ 8.08 (s, 1H), 7.80 (d, 1H, J ) 8.4 Hz), 7.56
(d, 1H, J ) 7.8 Hz), 7.22 (t, 1H, J ) 8.1 Hz), 7.07-6.88 (m,
5H), 3.98 (dd, 1H, J ) 6.9, 9.3 Hz), 3.33-3.30 (m, 1H), 2.50-
2.37 (m, 4H), 1.92-1.70 (m, 3H), 1.58-1.50 (m, 2H), 1.22-
1.14 (m, 2H), 0.76 (t, 3H, J ) 7.2 Hz), 0.72 (t, 3H, J ) 7.5 Hz);
13C NMR (1:1 CDCl3/CD3OD) δ 169.1 (s), 166.7 (s), 148.7 (s),
147.8 (s), 142.0 (s), 135.3 (d), 129.2 (d), 129.0 (d), 128.7 (d),
126.6 (d), 123.5 (d), 121.2 (d), 105.1 (s), 81.4 (s), 42.6 (d), 40.4
(t), 40.1 (t), 36.8 (t), 30.4 (t), 25.0 (t), 17.4 (t), 14.5 (q), 13.0 (q);
[R-(R*,R*)]-N-[3-[1-[5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-(2-
p h en ylet h yl)-6-p r op yl-2H -p yr a n -3-yl]p r op yl]p h en yl]-5-
(tr iflu or om eth yl)-2-p yr id in esu lfon a m id e (1). To a solu-
tion of crude 24 (0.555 g, 1.378 mmol) in methylene chloride
(3.10 mL), DMSO (0.100 mL, 1.409 mmol, 1.02 equiv), and
pyridine (0.56 mL, 6.92 mmol, 5.02 equiv) was added the crude
solution of 5-(trifluoromethyl)-2-pyridinesulfonyl chloride in
methylene chloride prepared above (5.23 mL, ∼2.3 mmol based
on thiol, ∼1.7 equiv) at -25 to -30 °C over 2 h, titrating with
the sulfonyl chloride solution to an HPLC endpoint of 1.4
area% residual 24. Aqueous hydrochloric acid (1 M, 6.2 mL,
6.2 mmol, 4.50 equiv) and ethyl acetate (5.2 mL) were added
and the phases separated. The aqueous was washed with
methylene chloride (10 mL), and the combined organics were
dried on magnesium sulfate and concentrated to an oil. This
oil was loaded on a 9.76 g silica gel column packed with 10%
ethyl acetate in hexanes and the product eluted with the
following ethyl acetate in hexanes mixtures (50 mL 10%, 100
mL 20%, 100 mL 30%, and 50 mL 40%). The eluent was
combined and concentrated to an oil with an ethyl acetate
chase. Ethyl acetate (5.2 mL) was added and the product
precipitated by slow addition of heptane (15 mL). The result-
ant slurry was cooled to -30 °C and the precipitate collected
by vacuum filtration, washed with a -30 °C mixture of ethyl
acetate (1 mL) and heptane (4 mL), and dried in a nitrogen
stream to give a white solid (0.6431 g, 77.4%, 97.10 wt % PNU-
140690): mp ) 86-89 °C; TLC Rf ) 0.66 (50% EtOAc/
hexanes);1H NMR (CD3OD) δ 8.94 (s, 1H), 8.19 (d, 1H, J )
8.3 Hz), 8.02 (d, 1H, J ) 8.2 Hz), 7.25-6.97 (m, 9H), 3.93 (t,
1H, J ) 9.0 Hz), 2.68-2.52 (m, 4H), 2.15-2.09 (m, 1H), 1.96-
1.64 (m, 4H), 1.33 (q, 2H, J ) 7.9 Hz), 0.88 (t, 3H, J ) 7.1
Hz), 0.83 (t, 3H, J ) 7.3 Hz); 13C NMR (CD3OD) δ 169.9 (s),
167.0 (s), 161.6 (s), 148.1 (d), 147.6 (s), 142.8 (s), 137.7 (s), 137.0
(d), 130.1 (qs, J ) 33 Hz), 129.5 (d), 129.3 (d), 127.0 (d), 126.1
(d), 124.2 (d), 122.6 (d), 120.3 (d), 106.2 (s), 81.9 (s), 43.6 (d),
40.5 (t), 40.5 (t), 37.4 (t), 30.9 (t), 25.8 (t), 17.9 (t), 14.7 (q),
13.3 (q); MS (CI, NH3) m/z (relative intensity) 621 (1.7), 620
(5.4), 603 (3.4), 148 (100); IR (mull) 1596, 1359, 720 cm-1. Anal.
Calcd for C31H33N2O5S: C, 61.78; H, 5.52; N, 4.65. Found: C,
61.47; H, 5.56; N, 4.58.
MS (CI, NH3) m/z (relative intensity) 441 (100); [R]25 +48 (c
D
1.0, CH3CN). Anal. Calcd for C25H29NO5: C, 70.90; H, 6.90;
N, 3.31. Found: C, 70.61; H, 6.91; N, 3.26.
[3r(R),6R]-3-[1-(3-Am in op h en yl)p r op yl]-5,6-d ih yd r o-4-
h yd r oxy-6-[1-(2-p h en yl)et h yl]-6-p r op yl-2H-p yr a n -2-on e
(24). To a solution of 23 (0.6993 g, 1.651 mmol) in THF (50
mL) was added 5% Pd/C (50% water wet, 0.2574 g, 0.06048
mmol, 0.0366 equiv) and the mixture hydrogenated at 50 psi
on a Parr shaker for 21 h. Celite (2.07 g) was added and the
catalyst removed by vacuum filtration and rinsed with THF.
The filtrate was concentrated to a white foam (0.665 g, 102.3%
crude yield): TLC Rf ) 0.45 (50% EtOAc/hexanes); HPLC tR
1
) 5.18 min; H NMR (CD3OD) δ 7.25-7.07 (m, 5H), 6.95 (t,
1H, J ) 7.7 Hz), 6.81-6.75 (m, 2H), 6.52 (bd, 1H, J ) 5.8 Hz),
3.95 (dd, 1H, J ) 6.7, 9.5 Hz), 2.65-2.21 (m, 4H), 2.20-2.03
(m, 1H), 2.02-1.65 (m, 5H), 1.40-1.33 (m, 3H), 0.89 (t, 6H, J
) 7.2 Hz); 13C NMR (CD3OD) δ 170.3 (s), 167.4 (s), 147.4 (s),
142.9 (s), 129.5 (d), 129.3 (d), 126.9 (d), 119.9 (d), 116.9 (d),
114.4 (d), 106.3 (s), 81.7 (s), 43.6 (d), 40.8 (t), 40.5 (t), 37.6 (t),
30.9 (t), 25.9 (t), 17.9 (t), 14.7 (q), 13.4 (q); MS (CI, NH3) m/z
Ack n ow led gm en t. Les Dolak and Eric Seest did the
preparative chiral HPLC to separate (+)-8 from its
enantiomer. The lipase resolution of 12 was developed
by J ohn Sih. Brad Hewitt, Desiree Quizon-Colquitt,
Holly Little, Azhwarsamy J eganathan, and Allen Scott
provided information from related studies and shared
in many helpful discussions.
(relative intensity) 411 (100), 394 (89); [R]25 +28 (c 1.0, CH3-
D
OH). Anal. Calcd for C25H31NO3: C, 76.30; H, 7.94; N, 3.56.
Found: C, 76.13; H, 7.90; N, 3.38.
5-(Tr iflu or om eth yl)-2-p yr id in esu lfon yl Ch lor id e. To
a well-agitated slurry of 5-(trifluoromethyl)-2-pyridinethiol
(50.00 g, 279.1 mmol) in aqueous hydrochloric acid (1 M, 750
J O9809229