Stereoselective synthesis of furo[2,3-c]pyridine pyrimidine thioethers, a new class of potent HIV-1 non-nucleoside reverse transcriptase inhibitors

Article abstract of DOI:10.1021/jo9810359

An efficient stereoselective total synthesis of the furo[2,3-c]pyridine thiopyrimidine HIV-1 reverse transcriptase inhibitors, PNU-142721 and PNU- 109886, has been developed. A convergent approach was utilized, providing direct access to the desired (S)-configuration of the molecule by making use of the alkylation of 4-amino-6-chloro-2-thiopyrimidine with the appropriate (R)-1-chloroethyl furo[2,3-c]pyridine intermediates. The successful preparation makes use of an efficient enzymatic kinetic resolution of the key 1-hydroxyethyl furo[2,3-c]pyridine intermediates to establish stereochemical control of the respective stereogenic centers. In addition, a workable asymmetric reduction strategy was developed for the synthesis of PNU-109886. Prudent reagent selection for the chlorination required for the final coupling reactions allowed for maintenance of the stereochemical integrity of the target compounds. Structural assignment of the absolute configuration of PNU-142721 and PNU-109886 as the (S)-enantiomer was confirmed by X-ray crystallographic analysis.

Full text of DOI:10.1021/jo9810359

J . Org. Chem. 1998, 63, 7851-7859
7851
Ster eoselective Syn th esis of F u r o[2,3-c]p yr id in e P yr im id in e
Th ioeth er s, A New Cla ss of P oten t HIV-1 Non -n u cleosid e Rever se
Tr a n scr ip ta se In h ibitor s
Donn G. Wishka, David R. Graber, Eric P. Seest, Lester A. Dolak, Fusen Han,
William Watt, and J oel Morris*
Medicinal Chemistry and Structural, Analytical & Medicinal Chemistry Research, Pharmacia & Upjohn,
Inc., Kalamazoo, Michigan 49001
Received J une 1, 1998
An efficient stereoselective total synthesis of the furo[2,3-c]pyridine thiopyrimidine HIV-1 reverse
transcriptase inhibitors, PNU-142721 and PNU-109886, has been developed. A convergent approach
was utilized, providing direct access to the desired (S)-configuration of the molecule by making
use of the alkylation of 4-amino-6-chloro-2-thiopyrimidine with the appropriate (R)-1-chloroethyl
furo[2,3-c]pyridine intermediates. The successful preparation makes use of an efficient enzymatic
kinetic resolution of the key 1-hydroxyethyl furo[2,3-c]pyridine intermediates to establish stereo-
chemical control of the respective stereogenic centers. In addition, a workable asymmetric reduction
strategy was developed for the synthesis of PNU-109886. Prudent reagent selection for the
chlorination required for the final coupling reactions allowed for maintenance of the stereochemical
integrity of the target compounds. Structural assignment of the absolute configuration of PNU-
142721 and PNU-109886 as the (S)-enantiomer was confirmed by X-ray crystallographic analysis.
The search for new and more potent nonnucleoside
reverse transcriptase inhibitors (NNRTIs) targeting drug-
resistant variants of HIV-1 of specific genotypes has led
to the discovery of the furo[2,3-c]pyridine thiopyrimidine
ethers.1,2 A major outcome of an intensive evaluation of
this class of NNRTIs has been the recent selection of
PNU-142721 as a candidate for clinical development for
the treatment of HIV infection and AIDS.3 PNU-142721
offers a significantly improved profile relative to the
currently marketed NNRTI, delavirdine. In addition to
being 50 times more potent against a laboratory strain
of wild type HIV-1, PNU-142721 is extremely potent
against variant virus selected for by delavirdine and
other NNRTIs.4 Another member of this class of current
interest is the corresponding 3-methyl furopyridine de-
rivative, PNU-109886, which displays increased potency
against variant virus conferring the Y181C mutation.1,5
However, PNU-109886 is characterized by a somewhat
less favorable pharmacokinetic profile in the rat relative
to PNU-142721.1
An examination of the SAR associated with the furo-
pyridine pyrimidine thioether NNRTIs led to the conclu-
sion that incorporation of the methyl group on the carbon
adjacent to the sulfur has an extremely positive effect
on the antiviral potency of these derivatives.1 Moreover,
it was apparent that this effect is stereoselective, with
the broad antiviral activity associated primarily with the
(S)-enantiomer. PNU-142721, whose structural (S)-
configuration was determined by X-ray crystallographic
analysis, was found to be at least 100 times more potent
than the corresponding (R)-enantiomer against variant
virus selected for by the NNRTI L-697,661.3
PNU-142721 was originally prepared as its racemate
and was resolved using preparative chiral HPLC.3 In
support of a more thorough preclinical evaluation of
PNU-142721, as well as PNU-109886, we required the
development of a general stereoselective synthesis of this
class of NNRTIs. A concise retrosynthetic analysis for
the preparation of PNU-142721 and PNU-109886 speci-
fied for the alkylation of thiopyrimidine 3 with the (R)-
1-chloroethyl furopyridine intermediates 1 and 2 (eq 1).
(1) Morris, J . Nonnucleoside reverse transcriptase inhibitors for the
treatment of AIDS. Book of Abstracts, 213th National Meeting of the
American Chemical Society, San Francisco, CA, April 13-17 1997,
BIOC-056.
(2) Nugent, R. A.; Wishka, D. G.; Cleek, G. J .; Graber, D. R.;
Schalachter, S. T.; Murphy, M. J .; Morris, J .; Thomas, R. C. Prepara-
tion of 2-pyrimidino alkyl ethers and thioethers as inhibitors of viral
reverse transcriptase. WO/9635678.
(3) Wishka, D. G.; Graber, D. R.; Kopta, L. A.; Olmsted, R. A.; Friis,
J . M.; Hosley, J . D.; Adams, W. J .; Seest, E. P.; Castle, T. M.; Dolak,
L. A.; Keiser, B. J .; Yagi, Y.; J eganathan, A.; Schlachter, S. T.; Murphy,
M. J .; Cleek, G. J .; Nugent, R. A.; Poppe, S. M.; Swaney, S. M.; Han,
F.; Watt, W.; White, W. L.; Poel, T. J .; Thomas, R. C.; Voorman, R. L.;
Stefanski, K. J .; Stehle, R. G.; Tarpley W. G.; Morris, J . J . Med. Chem.
1998, 41, 1357-1360.
(4) (a) Dueweke, T. J .; Pushkarskaya, T.; Poppe, S. M.; Swaney, S.
M.; Zhao, J . Q.; Chen, I. S. Y.; Stevenson, M.; Tarpley, W. G. Proc.
Natl. Acad. Sci. U.S.A. 1993, 90, 4713-4717. (b) Fan, N.; Evans, D.
B.; Rank, K. B.; Thomas, R. C.; Tarpley, W. G.; Sharma, S. K. FEBS
Lett. 1995, 359, 233-8.
(5) Carroll, S. S.; Olsen, D. B.; Bennett, C. D.; Gotlib, L.; Graham,
D. J .; Condra, J . H.; Stern, A. M.; Shafer, J . A.; Kuo, L. C. J . Biol.
Chem. 1993, 268, 276-81.
This convergent approach, expected to proceed with
inversion of configuration at the key stereogenic center,
provided direct access to the desired (S)-configuration of
the molecule. Herein, we present our synthetic studies
in this area, culminating in a stereoselective total
10.1021/jo9810359 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/07/1998

7852 J . Org. Chem., Vol. 63, No. 22, 1998
Wishka et al.
Sch em e 1
Sch em e 3
Sch em e 2
7 afforded 8,8 which was cleanly iodinated to give the
4-iodo derivative 9 in 60% overall yield. Alternatively,
7 was first iodinated to produce 10, as a prerequisite for
the direct introduction of the 1-hydroxyethyl side chain.
Initial deprotonation of the pyridyl alcohol of 10 with LiH
then allowed for the subsequent lithium-halogen ex-
change with nBuLi and quenching with acetaldehyde to
afford 11 in 62% yield. Finally, iodination of 11 produced
the 1-hydroxyethyl pyridine intermediate 12.
The o-hydroxy iodide functionality of 9 and 12 provided
ready access to the construction of the unsubstituted
fused furan ring of PNU-142721 (Scheme 3). Palladium-
copper cross-coupling reactions of 9 and 12 with TMS-
acetylene afforded 92% and 81% yields of the 4-acetylenic
pyridines 13 and 14, respectively.9 Cyclization of 14
utilizing the CuI catalysis conditions reported by Houpis
produced the desired furopyridine 17 in 86% yield.10
Alternatively, 13 was cyclized in a fashion similar to give
the 5-(hydroxymethyl)furopyridine 15 (80%). A one-
carbon homologation of the side chain of 15 was ac-
complished by initial Swern oxidation11 to aldehyde 16,
followed by treatment with CH3MgBr, to afford 17 in 76%
overall yield. The chloro substituent of 17 was readily
removed under transfer hydrogenolysis conditions, pro-
ducing a 77% recovery of the desired racemic furopyridine
intermediate 18.
synthesis of PNU-109886 and the clinical candidate
PNU-142721.
Resu lts a n d Discu ssion
Th iop yr im id in e Syn th esis. The required thiopyrim-
idine 3 was synthesized in four steps starting with 4,6-
dihydroxy-2-thiopyrimidine (4) by variation of the meth-
odology described by d’Atri (Scheme 1).6 Protection of
the 2-thiol of 4 with a p-methoxybenzyl group provided
5, which upon subsequent (bis)chlorination with POCl3
and monoamination gave the 4-amino-6-chloro derivative
6 in good yield. Deprotection of 6 with CH3SO3H afforded
3 which was isolated and utilized as its methanesulfonate
salt.
The o-hydroxypyridyl iodide 12 also served as the
source for the corresponding 3-methylfuropyridine inter-
mediate necessary for the synthesis of PNU-109886
(Scheme 4). A rapid entry to the this ring system was
realized through initial allylation of 12 followed by
palladium acetate catalyzed cyclization of the resultant
allyloxypyridyl iodide 19 to provide a modest 29-36%
yield of 20.12 Subsequent hydrodechlorination of 20
afforded a 97% recovery of 21. A more efficient ring
closure of 19 was identified through the use of nBu3SnH
which provided an 88% yield of the corresponding 2,3-
F u r o[2,3-c]p yr id in e Syn th esis. Our synthetic strat-
egy served to complete the elaboration of the carbon
framework of the furo[2,3-c]pyridine entity prior to
establishment of the essential chirality in the side chain
of the molecule. Several routes directed toward construc-
tion of the furo[2,3-c]pyridine nucleus were examined
starting from two related functionally advanced pyridine
intermediates.7 The synthesis of these pyridine homo-
logues, 9 and 12, started from commercially available
2-chloro-3-hydroxypyridine (7) (Scheme 2). By blocking
access to the 2-position, the chloro substituent of 7 served
to direct subsequent electrophilic reactions of the pyridine
to the 6-position and was readily removed at a later stage
in the synthesis. Base-promoted hydroxymethylation of
(8) Baldo, M. A.; Chessa, G.; Marangoni, G.; Pitteri, B. Synthesis
1987, 720-723.
(9) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470.
(10) Houpis, I. N.; Choi, W. B.; Reider, P. J .; Molina, A.; Churchill,
H.; Lynch, J .; Volante, R. P. Tetrahedron Lett. 1994, 35, 9355-8.
(11) Mancuso, A. J .; Huang, S. L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482.
(6) d’Atri, G.; Gomarasca, P.; Resnati, G.; Tronconi, G.; Scolastico,
C.; Sirtori, C. R. J . Med. Chem. 1984, 27, 1621-1629.
(7) For
a review on furopyridine synthesis, see: Shiotani, S.
Heterocycles 1997, 975-1011.
(12) Larock, R. C.; Stinn, D. E. Tetrahedron Lett. 1988, 4687-4690.

Stereoselective Synthesis of Furo[2,3-c)-pyridine Thioethers
J . Org. Chem., Vol. 63, No. 22, 1998 7853
Sch em e 4
Sch em e 5
by the X-ray crystallographic analysis of its correspond-
ing (1S)-camphanic ester derivative 28.16
To realize maximum overall efficiency from the resolu-
tion process, methodology was examined to invert the
stereocenter of (R)-18. Mitsunobu treatment of (R)-18
with benzoic acid in the presence of Ph3P and diethyl
azodicarboxylate produced a 90% yield of benzoate 26.17
Subsequent hydrolysis of 26 with aqueous NaOH gave
(S)-18 in 94% yield. Analysis of the corresponding
acetate of (S)-18 showed the optical purity of this sample
to be 99% ee. Taking into account both the (S)-18 lots
obtained from the enzymatic resolution and that received
from the Mitsunobu inversion, the total amount of
resolved (S)-18 obtained through this process was 80%
of the theoretical yield. A similar sequence and analysis
was used for the resolution of the corresponding 3-
methylfuro[2,3-c]pyridine intermediate 21 to afford the
desired (S)-enantiomer in 87% overall yield (Scheme 5).
dihydrofuropyridine intermediate 22.13 Conversion of 22
to 21 was accomplished in three high-yielding steps.
Following hydrodechlorination of 22, acetylation of the
secondary alcohol affording 23 was required in order to
achieve a successful oxidation of the 2,3-dihydrofuran.
Thus, treatment of 23 with chloranil followed by acetate
removal upon workup produced a 90% yield of 21. The
use of DDQ for this oxidation proceeded in somewhat
lower yield due to complications realized during the
workup of the reaction. Although five steps were re-
quired, the latter route for the preparation of 21 from
19 proved to be more efficient considering both the higher
overall yield (77% vs 26%) and lack of chromatography
required for the purification of intermediates.
En zym a tic Resolu tion of F u r o[2,3-c]p yr id in es 18
a n d 21. Textbook resolution proved achievable by a
process employing the enzymatic esterification of the
furo[2,3-c]pyridine intermediates 18 and 21 (Scheme 5).14
Exposure of 18 to excess (2,2,2-trifluoroethyl)butyrate in
the presence of porcine pancreatic lipase (type II) for 9
days allowed for complete reaction affording a 44.5%
recovery of (S)-18 along with 46.5% of the (R)-butyric
ester 24.15 The enantiomeric purity of (S)-18 was estab-
lished as >99% ee by comparison of the chiral HPLC
analysis of its corresponding acetate derivative with an
independently prepared racemic sample. A similar chiral
HPLC analysis was performed for butyrate 24 (>99% ee).
Hydrolysis of 24 with aqueous NaOH afforded (R)-18 in
89% yield. The stereochemistry of (R)-18 was determined
Asym m etr ic Red u ction Rou te to F u r o[2,3-c]p yr -
id in e (S)-21. The hydroxyethyl substrates 20 and 22
served as sources of the methyl ketone intermediates
needed to examine a potential asymmetric reduction
strategy for the production of (S)-21 (Scheme 6). Swern
oxidation of 20 and 22 afforded methyl ketones 30 and
31 in 90% and 84% yields, respectively.11 Reduction of
30 with (-)-chlorodiisopinocampheylborane [(-)-Dip-Cl]
was carried out in THF at room temperature overnight.18
Following a prescribed oxidative workup, there was
obtained a 94% yield of alcohol (S)-20. Chiral HPLC
analysis and comparison of the corresponding acetate of
(S)-20 with an independently prepared racemic sample
showed the alcohol to be 92% ee. Recrystallization of this
material from Et2O/hexane provided a 78% recovery of
(S)-20 with >99% ee. The subsequent hydrodechlorina-
tion of (S)-20 under transfer hydrogenolysis conditions
(13) Shankaran, K.; Sloan, C. P.; Snieckus, V. Tetrahedron Lett.
1985, 6001-6004.
(14) For the recent optical resolution of 1-(2-pyridyl)ethanols by
lipase-catalyzed enantioselective acetylation, see: Uenishi, J .; Hiraoka,
T.; Hata, S.; Nishiwaki, K.; Yonemitsu, O. J . Org. Chem. 1998, 63,
2481-2487.
(16) ORTEP drawing of and atomic coordinate information for this
compound can be obtained from Supporting Information.
(17) Mitsunobu, O. Synthesis 1981, 1-28.
(18) (a) Brown, H. C.; Chandrasekharan, J .; Ramachandran, P. V.
J . Am. Chem. Soc. 1988, 110, 1539-1546. (b) Bolm, C.; Ewald, M.;
Felder, M.; Schlingloff, G. Chem Ber. 1992, 125, 1169-1190.
(15) Tanis, S. P.; Robinson, E. D.; McMills, M. C.; Watt, W. J . Am.
Chem. Soc. 1992, 114, 8349-8362.

7854 J . Org. Chem., Vol. 63, No. 22, 1998
Wishka et al.
Sch em e 6
but opposite rotation. Turning to the use of other
methods to accomplish this transformation, we saw some
improvement in the enantiopurity of the product chloride
(79% ee, 70% yield) through the use of the conditions of
Meyers and Collington (MsCl, LiCl).21 Fortunately, the
use of Ph3P/CCl4 resulted in a complete inversion of the
stereogenic center, providing chloride 2 in 75-89% yields
(>97% ee).22 Similar results were obtained for the
conversion of (S)-18 to chloride 1.
The alkylation of the mesylate salt of thiopyrimidine
3 with chlorides 1 and 2 was performed by initial
formation of the thiolate anion with 2 equiv of NaH in
DMF. With 1, an 89% initial chromatographed yield of
PNU-142721 was obtained with 97.6% ee. Recrystalli-
zation of this material afforded a final 64% recovery of
PNU-142721 that was determined to be >99% ee by
chiral HPLC analysis. Similar results of 61% yield (98%
ee) were obtained for the preparation of PNU-109886
from chloride 2. Definitive proof for the proposed out-
come of overall retention of configuration resulting from
the chlorination-alkylation sequence was afforded by
X-ray crystallographic analysis of the final products.
These determinations of absolute configuration by X-ray
provided confirmation of the (S)-configuration assign-
ment to the stereogenic centers of PNU-1427213 and
PNU-109886.16
Sch em e 7
Con clu sion
An efficient stereoselective synthesis of the furo[2,3-
c]pyridine thiopyrimidine HIV-1 RTIs, PNU-142721 and
PNU-109886, has been developed. The successful prepa-
ration makes use of an efficient enzymatic kinetic resolu-
tion of the key alcohol intermediates, 18 and 21, to
establish stereochemical control of their respective ste-
reogenic centers. In addition, a workable asymmetric
reduction strategy was examined for the synthesis of
PNU-109886. Prudent reagent selection for the chlorina-
tion reaction required for the coupling of (S)-18 and (S)-
21 with thiopyrimidine 3 allowed for maintenance of the
stereochemical integrity of the final products. Finally,
structural assignment of the absolute configuration of
PNU-142721 and PNU-109886 as the (S)-enantiomer was
confirmed by X-ray crystallographic analysis.
described for the racemic material afforded an 88% yield
of (S)-21 (>99% ee).
A related reduction of the 3-methyldihydrofuropyridine
derivative 31 with (-)-Dip-Cl afforded a 99% yield of (S)-
22. Analysis of the enantiopurity of this material was
complicated due to the formation of a diastereomeric
mixture. Conversion of (S)-22 to (S)-21 as outlined for
the corresponding racemic series (Scheme 4) proceeded
in 79% overall yield and with 89% ee.
Syn th esis of P NU-142721 a n d P NU-109886. The
synthetic plan for the coupling of (S)-18 and (S)-21 with
3 called for a double inversion process that included the
stereocontrolled chlorination of the hydroxyl group fol-
lowed by displacement with the thiopyrimidine anion. We
had previously examined the reaction of 4-ethyl-2-(1(S)-
hydroxyethyl)pyridine with SOCl2 which cleanly afforded
the inverted (R)-chloride in high yield (>99% ee).19 This
outcome was consistent with the classical reaction of
secondary alcohols with SOCl2 that produce chlorides
with inversion of configuration in the presence of pyridine
and chlorides with retention of configuration (SNi mech-
anism) in the absence of base.20 However, the corre-
sponding reaction of (S)-21 with SOCl2 with pyridine
proved to be more problematic, producing chloride 2 with
a modest 42% ee (70% yield) (Scheme 7). A related
transformation in the absence of pyridine with the
corresponding (R)-21 alcohol gave chloride with an equal
Exp er im en ta l Section
4-Am in o-6-ch lor o-2-th iop yr im id in e, Mesyla te Sa lt (3).
A solution of 4,6-dichloro-2-(4-methoxybenzyl)thiopyrimidine
(19.55 g, 64.9 mmol) in 391 mL of warm CH3CN was treated
with 391 mL of 29% NH4OH at 75 °C for 9 h and at 40 °C
overnight. The contents were cooled to room temperature,
filtered, and concentrated in vacuo. The white solid was
dissolved in EtOAc and washed once with a mixture of 50 mL
of water and 75 mL of saturated brine. The combined aqueous
layers were extracted once with EtOAc, and the combined
organics were dried over Na2SO4 and concentrated in vacuo.
The crude product was dissolved in refluxing Et2O plus a
minimum amount of EtOAc, diluted with hexane, and placed
in refrigerator to afford 15.0 g (82%) of 6. Mp: 118.5-119.5
°C; 1H NMR (CDCl3): δ 7.26 (d, J ) 8.7 Hz, 2H), 6.77 (d, J )
8.7 Hz, 2H), 6.07 (s, 1H), 4.93 (brs, 2H), 4.23 (s, 2H), 3.72 (s,
3H). Anal. Calcd for C12H12ClN3OS: C, 51.25; H, 4.27; N,
14.95; S, 11.39. Found: C, 51.38; H, 4.54; N, 14.41; S, 11.04.
(21) Collington, E. W.; Meyers, A. I. J . Org. Chem. 1971, 36, 3044-
3045.
(19) Graber, D. R.; Morris, J . Unpublished results.
(20) March, J . Advanced Organic Chemistry Reactions, Mechanisms,
and Structure, 3rd ed.; J ohn Wiley & Sons: New York, 1985; p 287.
(22) Weiss, R. G.; Snyder, E. I. J . Chem. Soc., Chem. Commun. 1968,
1358-1359.

Stereoselective Synthesis of Furo[2,3-c)-pyridine Thioethers
J . Org. Chem., Vol. 63, No. 22, 1998 7855
A suspension of 6 (10.0 g, 33.22 mmol) in 160 mL of CH2Cl2
at room temperature was treated with methanesulfonic acid
(31.89 g, 332.2 mmol). After 50 min, 1280 mL of Et2O was
added dropwise (slowly, at first) to precipitate the product as
a granular solid. The suspension was stirred overnight at
room temperature. The product was collected by filtration and
washed with Et2O to provide 8.62 g of 3. Mp: 166-167 °C;
HRMS: Calcd for C5H8ClN3O3S2: 160.9814. Found: 160.9822.
Anal. Calcd for C5H8ClN3O3S2 @4.94% H2O: C, 23.22; H, 3.16;
N, 16.25. Found: C, 23.48; H, 3.25; N, 15.70.
2-Ch lor o-3-h yd r oxy-6-(1-h yd r oxyet h yl)p yr id in e (11).
A suspension of LiH (2.5 g, 313 mmol) in 1000 mL of dry THF
was treated portionwise with 10 (80 g, 313 mmol) and stirred
for 1 h at 45 °C. The solution was cooled to room temperature
and then to -78 °C and was treated dropwise with nBuLi (205
mL, 329 mmol). The suspension was stirred for 1 h at -78
°C and was treated dropwise with acetaldehyde (35 mL, 626
mmol). The mixture was stirred for 1 h at -78 °C and was
allowed to slowly warm to -40 °C over 2 h and then to 0 °C.
The reaction was quenched with 300 mL of H2O, and the
aqueous layer was washed with 2 × 100 mL of Et2O. The pH
of the aqueous layer was adjusted to 3.5 with 10% HCl, and
the mixture was extracted with 4 × 100 mL of EtOAc followed
by 2 × 100 mL of 10% MeOH/CH2Cl2. The combined organics
were dried over MgSO4 and treated with 150 g of silica gel
(230-400 mesh), and the volatiles were removed in vacuo. The
plug was chromatographed over 600 g of silica gel, eluting with
4 L of 35% EtOAc/hexane, 1 L of 55% EtOAc/hexane, and
followed by 2 L of 80% EtOAc/hexane to provide an amber oil
which was crystallized from 150 mL of 2:1 CHCl3/hexane to
afford 33.8 g (62%) of 11 as a white solid. Mp: 89-92 °C, dec;
1H NMR (DMSO-d6): δ 1.10 (d, J ) 6.5 Hz, 3H), 4.40 (m, 1H),
5.10 (d, J ) 4.5 Hz, 1H), 7.12 (s, 2H), 10.27 (s, 1H); 13C NMR
(DMSO-d6): δ 24.0, 68.4, 119.6, 124.6, 136.2, 147.9, 156.0; IR:
3334, 2925, 2569, 1558 cm-1; HRMS: Calcd for C7H8ClNO2:
173.0244. Found: 173.0252.
2-Ch lor o-3-h yd r oxy-6-(h yd r oxym eth yl)p yr id in e (8). A
solution of 2-chloro-3-pyridinol (7) (20.0 g, 0.154 mol) and
NaHCO3 (19.5 g, 0.232 mol) in 150 mL of H2O was stirred at
room temperature for several minutes and heated to 90 °C.
After 5 min at 90 °C, the first of six unequal doses of 37%
formaldehyde (40.5 mL, 0.541 mol, 3.5 equiv) was added; 12
mL initially, 3 × 8 mL followed by 1 × 2.2 mL all at 90 min
intervals with the final 2.3 mL added after maintaining at 90
°C overnight (15 h). The reaction mixture was heated for an
additional 4 h after the last dosing. The mixture was cooled
to 0 °C, and 100 mL of crushed ice was added followed by 39
mL of 6 N HCl (to pH 1). The precipitated slurry was stirred
for 1.5 h at 0 °C. The undesired precipitated side product was
filtered off and washed once with 75 mL of ice-water. The
yellow filtrate was extracted seven times with EtOAc. The
organic extracts were dried with anydrous Na2SO4 and con-
centrated. Toluene was added, and the mixture was recon-
centrated to azeotrope any remaining water. The addition of
CH2Cl2 to suspend the material followed by reconcentration
afforded 8 as a pale yellow solid (19.93 g, 81%). Mp: 133.5-
135 °C; 1H NMR (DMSO-d6): δ 10.47 (brs, 1H), 7.38-7.19 (m,
2H), 5.33 (brs, 1H), 4.38 (s, 2H); 13C NMR (DMSO-d6): δ 63.7,
121.2, 124.9, 137.0, 148.5, 152.5; UV (λmax, ethanol): 225
2-Ch lor o-3-h yd r oxy-4-iod o-6-(1-h yd r oxye t h yl)p yr i-
d in e (12). A suspension of 11 (4.5 g, 23.6 mmol) in 70 mL of
H2O was treated successively with K2CO3 (6.5 g, 47.2 mmol)
and I2 (12.0 g, 47.2 mmol), and the reaction mixture was stirred
for 4 h at room temperature. The excess I2 was quenched with
saturated sodium thiosulfate, and the pH of the reaction
mixture was adjusted to 3 with 10% HCl. The solid was
collected, washed with H2O, and dissolved in EtOAc. The
organics were dried over MgSO4 and concentrated in vacuo.
The yellow solid was washed with CHCl3 and was dried to
provide 4.4 g (62%) of 12 as a white solid. Mp: 114-116 °C,
(7680), 288 (5930) nm; IR 3055, 3038, 2925, 2956, 1562 cm-1
.
MS: m/z(relative intensity %): 159 (41), 158 (42), 132 (31),
130 (100), 94 (34). Anal. Calcd for C6H6ClNO2: C, 45.16; H,
3.79; N, 8.78. Found: C, 44,88; H, 3.76; N, 8.57.
2-Ch lor o-3-h yd r oxy-6-(h yd r oxym e t h yl)-4-iod op yr i-
d in e (9). A mixture of 8 (11.6 g, 72.7 mmol) and NaHCO3
(18.3 g, 218 mmol) in 200 mL of H2O was stirred until
homogeneous, cooled to 0 °C, and treated with I2 (19.4 g, 76.3
mmol). The reaction was stirred over the weekend as the
cooling bath expired. The pH of the mixture was adjusted to
3 with 2 N NaHSO3, and the mixture was extracted with 4 ×
50 mL of EtOAc. The combined organics were dried over
anhydrous MgSO4 and were concentrated in vacuo to a yellow
solid. The crude solid was washed with EtOAc to provide 12.9
g (62%) of 9 as an off-white solid. The filtrate was concen-
trated to a small volume and was chromatographed over 250
g of silica gel (230-400 mesh) eluting with EtOAc/CH2Cl2/
hexane/HOAc 2.5:4.5:4:0.1 to afford an additional 2.4 g (12%)
1
dec; H NMR (DMSO-d6): δ 1.10 (d, J ) 6.5 Hz, 3H), 4.38 (q,
J ) 6.5 Hz, 1H), 5.22 (bs 1H), 7.59 (s, 1H), 10.2 (bs, 1H); 13C
NMR (DMSO-d6): δ 24.0, 68.1, 100.1, 129.6, 136.3, 148.1,
157.7; IR: 3078, 2926, 1669, 1537 cm-1; MS: [m/z](relative
intensity): [299](16). Anal. Calcd for C7H7ClINO2: C, 28.07;
H, 2.36; N, 4.68. Found: C, 27.96; H, 2.28; N, 4.55.
2-Ch lor o-3-h yd r oxy-6-(h yd r oxym eth yl)-4-[(tr im eth yl-
silyl)eth yn yl]p yr id in e (13). A mixture of 9 (13.9 g, 48.6
mmol), (trimethylsilyl)acetylene (9.6 mL, 68 mmol), bis(tri-
phenylphosphine)palladium dichloride (1.02 g, 1.46 mmol), and
CuI (139 mg, 0.73 mmol) in 80 mL of chloroform and 40 mL of
THF under N2 was treated with Et3N (21 mL, 151 mmol) and
was stirred for 3 h at room temperature. The reaction was
diluted with 200 mL of CHCl3 and was washed with 2 × 150
mL of 5% HCl. The combined aqueous layers were extracted
with 2 × 50 mL of CHCl3, and the combined organics were
washed with 100 mL of 50% saturated NaCl, dried over
anhydrous MgSO4, and concentrated in vacuo to an amber oil.
The crude material was chromatographed over 350 g of silica
gel (230-400 mesh), eluting with 35% EtOAc/hexane to afford
11.4 g (92%) of 13 as a golden solid. Mp: 97-98 °C; 1H NMR
(DMSO-d6): δ 0.28 (s, 9H), 4.63 (s, 2H), 7.24 (s, 1H); 13C NMR
(DMSO-d6): δ -0.4, 63.8, 96.1, 107.4, 119.7, 122.4, 137.4,
147.8, 150.8; IR: 3151, 2924, 1602, 1464 cm-1; MS: [m/z]-
(relative intensity): [255](25). Anal. Calcd for C11H14ClNO2-
Si: C, 51.66; H, 5.52; N, 5.48. Found: C, 51.39; H, 5.41; N,
5.37.
1
of pure 9. Mp: 147-149 °C; H NMR (DMSO-d6): δ 4.38 (s,
2H), 7.73 (s, 1H), 10.35 (s, 1H); IR: 3156, 2925, 1541, 1455,
1361, 1248 cm-1; MS: [m/z](relative intensity): [285](80). Anal.
Calcd for C6H5ClINO2: C, 25.25; H, 1.77; N, 4.91. Found: C,
25.06 H, 1.81; N, 4.92.
2-Ch lor o-3-h yd r oxy-6-iod o-p yr id in e (10). A solution of
2-chloro-3-pyridinol (7) (60 g, 0.46 mole) was dissolved in 700
mL of H2O containing K2CO3 (220 g, 1.6 mol) was treated with
I2 (141 g, 0.56 mol) and stirred for 4 h at room temperature.
The excess I2 was quenched with saturated sodium thiosulfate,
and the pH of the mixture was adjusted to 2 with 12 N HCl.
The mixture was extracted with 3 × 250 mL of EtOAc, and
the combined organics were dried over MgSO4 and were
concentrated in vacuo. The crude yellow solid was recrystal-
lized from 150 mL of EtOAc and 700 mL of heptane to give 69
g (58%) of 10 as a crystalline solid. The mother liquor was
concentrated to a yellow solid which was recrystallized from
60 mL of EtOAc and 370 mL of heptane to provide 15.5 g (13%)
of additional 10. Mp: 142-143 °C; 1H NMR (DMSO-d6): δ
6.90 (d, J ) 8 Hz, 1H), 7.43 (d, J ) 8 Hz, 1H), 10.87 (bs, 1H);
13C NMR (DMSO-d6): δ 100.7, 126.5, 134.5, 137.6, 150.2; IR:
3056, 2925, 1554, 1289, 1226 cm-1; MS: [m/z](relative inten-
sity): [255](80). Anal. Calcd for C5H3ClINO: C, 23.51; H,
1.18; N, 5.48. Found: C, 23.44; H, 1.22; N, 5.39.
2-Ch lor o-3-h yd r oxy-6-(1-h yd r oxyeth yl)-4-[(tr im eth yl-
silyl)eth yn yl]p yr id in e (14). Following the procedure for the
preparation of 13, starting with 5.99 g (20 mmol) of 12, there
was synthesized 4.35 g (81%) of 14 as a pale yellow solid.
1
Mp: 97-98 °C; H NMR (CDCl3, TMS): δ 0.20 (s, 9H), 1.39
(d, J ) 6.5 Hz, 3H), 2.77 (bs, 1H), 4.71 (q, J ) 6.5 Hz, 1H),
6.07 (bs, 1H), 7.16 (s, 1H); 13C NMR (CDCl3): δ -2, 23.8, 68.8,
96.2, 107.0, 119.6, 121.3, 137.1, 147.6, 154.8; IR: 3155, 2924,
2162, 1598, 1461 cm-1; HRMS: Calcd for C12H16ClNO2Si:
269.0639. Found: 269.0639. Anal. Calcd for C12H16ClNO2Si

7856 J . Org. Chem., Vol. 63, No. 22, 1998
Wishka et al.
@ 0.18% water found: C, 53.32; H, 5.99; N, 5.18. Found: C,
52.85; H, 5.99; N, 5.02.
intensity): [197](3). Anal. Calcd for C9H8ClNO2: C, 54.70;
H, 4.08; N, 7.09. Found: C, 54.46; H, 4.01; N, 7.04.
5-(1-Hyd r oxyeth yl)fu r o[2,3-c]p yr id in e (18). A solution
of 17 (3.95 g, 20 mmol) in 110 mL of MeOH containing 20%
Pd(OH)2 on carbon (1 g) under N2 was treated with cyclohexene
(19.8 mL, 200 mmol) followed by 2 N NaOH (15 mL, 30 mmol),
and the reaction was refluxed for 3.5 h. The mixture was
cooled and filtered through Celite, and the filter cake was
washed well with fresh MeOH. The filtrate was concentrated
in vacuo to a yellow paste. The residue was partitioned
between 50 mL of water and 4 × 25 mL of CH2Cl2, and the
organics were dried over K2CO3 and were concentrated in
vacuo to a pale oil (3.16 g). The crude material was chromato-
graphed over 125 g of silica gel (230-400 mesh), eluting with
60% EtOAC/hexane to give 2.52 g (77%) of 18 as a pale oil. 1H
NMR (CDCl3, TMS): δ 1.55 (d, J ) 6.5 Hz, 3H), 4.19 (bs, 1H),
5.01 (q, J ) 6.5 Hz, 1H), 6.78 (d, J ) 2 Hz, 1H), 7.56 (s, 1H),
7.76 (d, J ) 2 Hz, 1H), 8.76 (s, 1H); 13C NMR (CDCl3): δ 24.7,
69.6, 106.1, 111.8, 132.0, 135.0, 148.8, 151.4, 156.5; IR: 3355,
7-Ch lor o-5-(h yd r oxym et h yl)fu r o[2,3-c]p yr id in e (15).
13 (11.4 g, 44.6 mmol) was combined with CuI (424 mg, 2.23
mmol) in 60 mL of EtOH and 60 mL of Et3N and was warmed
to 75 °C for 3 h. The reaction mixture was treated with
DARCO, diluted with 60 mL of MeOH, and refluxed for 20
min. The mixture was cooled and filtered through Celite. The
filtrate was treated with 25 mL of saturated NaHCO3 and 25
mL of 2 N NaOH (50 mmol) and stirred overnight at room
temperature. The volatiles were removed in vacuo, and the
residue was partitioned between 250 mL of 50% saturated
NaCl and 4 × 75 mL of CH2Cl2. The combined organics were
dried over anhydrous K2CO3 and were concentrated in vacuo
to give a crude tan solid. The crude material was chromato-
graphed over 300 g of silica gel (230-400 mesh) eluting with
40% EtOAc/hexane to afford 6.6 g (80%) of 15 as a white solid.
1
Mp: 102-103 °C; H NMR (CDCl3): δ 3.37 (bs, 1H), 4.79 (s,
2H), 6.82 (d, J ) 2 Hz, 1H), 7.51 (s, 1H), 7.79 (d, J ) 2 Hz,
1H); 13C NMR (CDCl3): δ 64.6, 107.1, 112.5, 133.1, 136.8,
146.9, 149.3, 153.1; IR: 3312, 3099, 2924, 1611, 1572, 1444
cm-1; MS: [m/z](relative intensity): [183](53). Anal. Calcd
for C8H6ClNO2: C, 52.34; H, 3.29; N, 7.63. Found: C, 52.27;
H, 3.23; N, 7.57.
2973, 1614, 1465, 1280 cm-1
163.0633. Found: 163.0646.
. HRMS: Calcd for C9H9NO2:
3-(Allyloxy)-2-ch lor o-6-(1-h yd r oxyet h yl)-4-iod op yr i-
d in e (19). A suspension of 60% NaH (1.2 g, 30 mmol) (washed
with 3 × 10 mL of hexane) in 48 mL of dry DMF at 0 °C was
treated portionwise with 12 (8.98 g, 30 mmol). The mixture
was stirred for 1 h at room temperature and treated with allyl
bromide (2.9 mL, 33 mmol), and the reaction was stirred for 4
h. The mixture was diluted with 150 mL of EtOAc, washed
with 4 × 25 mL of 50% saturated 1:1 NaCl/NaHCO3, and dried
over anhydrous MgSO4/K2CO3. The dried organics were
concentrated in vacuo to a solid which was washed with
hexane to give 9.52 g (93%) of 19 as a white solid. Mp: 89-
91 °C; 1H NMR (CDCl3, TMS): δ 1.49 (d, J ) 6.6 Hz, 3H),
2.87 (bs, 1H), 4.56 (m, 2H), 4.82 (q, J ) 6.6 Hz, 1H), 5.32 (m,
1H), 5.45 (m, 1H), 6.16 (m, 1H), 7.73 (m, 1H); 13C NMR
(CDCl3): 24.0, 68.6, 74.4, 105.6, 119.5, 129.6, 132.4, 143.5,
150.5, 159.8; IR 3157, 2928, 1561, 1523 cm-1; MS: [m/z]-
7-Ch lor o-5-for m ylfu r o[2,3-c]p yr id in e (16). A solution of
oxalyl chloride (831 µL, 9.5 mmol) in 30 mL of CH2Cl2 under
N2 at -60 °C was treated with DMSO (1.34 mL, 18.9 mmol)
in 5 mL of CH2Cl2 and stirred for 20 min. The solution was
treated with 15 (1.5 g, 8.2 mmol) in 2 × 5 mL of CH2Cl2 at
-60 °C, was stirred for 20 min, and was treated with Et3N
(5.83 mL, 41.8 mmol). The reaction was diluted with 50 mL
of CH2Cl2 and was washed with 100 mL of 1:1 saturated NaCl/
5% HCl. The organics were dried over anhydrous MgSO4 and
concentrated in vacuo to give 1.5 g of a crude off-white solid.
The crude material was chromatographed over 60 g of silica
gel (230-400 mesh), eluting with 25% EtOAc/hexane to
provide 1.42 g (95%) of 16. Mp: 140-142 °C; 1H NMR
(CDCl3): δ 7.03 (d, J ) 2 Hz, 1H), 7.92 (d, J ) 2 Hz, 1H), 8.23
(s, 1H), 10.09 (s, 1H);13C NMR (CDCl3): δ 108.2, 115.2, 134.8,
(relative intensity): [339](44). Anal. Calcd for
C10H11-
ClINO2: C, 35.37; H, 3.26; N, 4.12. Found: C, 35.11; H, 3.03;
N, 3.98.
136.2, 146.9, 150.0, 150.0, 191.3; IR: 2924, 1713, 1407 cm-1
;
7-Ch lor o-5-(1-h yd r oxyet h yl)-3-m et h ylfu r o[2,3-c]p yr i-
d in e (20). A combination 19 (9.52 g, 28 mmol) with nBu4NCl
(10.6 g, 38 mmol), sodium formate (2.4 g, 35 mmol), Na2CO3
(8.9 g, 84 mmol), and Pd(OAc)2 (367 mg, 1.6 mmol) in 60 mL
of DMF was warmed to 60 °C for 2 h. The mixture was diluted
with 150 mL of EtOAC and extracted with 4 × 50 mL of 50%
saturated NaCl. The organics were dried over K2CO3 and were
concentrated in vacuo to a dark oil. The crude oil was taken
up in 60 mL of MeOH, was refluxed with Darco for 10 min,
and was filtered through Celite. The filtrate was concentrated
in vacuo to a crude dark oil which was chromatographed over
150 g of silica gel (230-400 mesh), eluting with 25% EtOAc/
hexane to give 1.71 g (29%) of 20 as a pale yellow solid. Mp:
67-68 °C; 1H NMR (CDCl3, TMS): δ 1.55 (d, J ) 6.6 hz, 3H),
2.24 (s, 3H), 3.56 (bs, 1H), 4.96 (q, J ) 6.5 Hz, 1H), 7.49 (s,
1H), 7.57 (m, 1H); 13C NMR (CDCl3): 7.9, 24.5, 69.6, 109.7,
116.8, 132.5, 138.2, 145.7, 146.9, 156.9; IR 3293, 2925, 1441
cm-1; MS: [m/z](relative intensity): [211](4), [196](100). Anal.
Calcd for C10H10ClNO2: C, 56.75; H, 4.76; N, 6.62. Found: C,
56.54; H, 4.79; N, 6.52.
MS: [m/z](relative intensity): [181](47). Anal. Calcd for C8H4-
ClNO2: C, 52.92; H, 2.22; N, 7.71. Found: C, 52.72; H, 2.37;
N, 7.63.
7-Ch lor o-5-(1-h yd r oxyet h yl)fu r o[2,3-c]p yr id in e (17).
Method A: A combination of 14 (25.3 g, 94.1 mmol) and CuI
(896 mg, 4.7 mmol) in 300 mL of 1:1 absolute EtOH/ Et3N was
stirred at 75 °C for 2.5 h, was diluted with 2 N NaOH (94 mL,
188 mmol), and was stirred for 1.5 h at 75 °C. The reaction
was diluted with 150 mL of MeOH, was treated with 5 g of
DARCO, and was refluxed for 20 min. The DARCO was
removed by filtration through Celite, and the filtrate was
concentrated in vacuo to a small volume. The residue was
partitioned between 100 mL of saturated NaCl and 4 × 60
mL of CH2Cl2. The combined organics were washed with 2 ×
60 mL of 1:1 saturated NaCl/saturated disodium EDTA, were
dried over anhydrous MgSO4, and were concentrated in vacuo
to an amber oil. The crude material was chromatographed
over 600 g of silica gel (230-400 mesh), eluting with 38%
EtOAc/hexane to afford 15.9 g (86%) of 17 as a pale yellow
solid. Method B: A solution of 16 (6.47 g, 35.6 mmol) in 105
mL of THF and 155 mL of Et2O under N2 was treated dropwise
with methylmagnesium bromide (18 mL, 53.4 mmol, 3 M in
Et2O) at room temperature and was warmed to reflux for 2 h.
The reaction was cooled to 0 °C and was quenched with 150
mL of 5% HCl. The aqueous layer was washed with 2 × 50
mL of CH2Cl2, and the combined organics were dried over
anhydrous MgSO4. The organics were concentrated in vacuo.
The yellow oil was chromatographed over 300 g of silica gel
(230-400 mesh), eluting with 50% EtOAc/hexane, to afford
7-Ch lor o-2,3-d ih yd r o-5-(1-h yd r oxyeth yl)-3-m eth ylfu r o-
[2,3-c]p yr id in e (22). A solution of 19 (40 g, 117.8 mmol) in
260 mL of benzene under N2 was combined with N,N′-azobis-
(isobutyrylnitrile) (1.94 g, 11.8 mmol). The solution was
warmed to reflux and was treated rapidly dropwise with tri-
n-butyltin hydride (34.2 mL, 127.2 mmol) in 60 mL of dry
benzene. The reaction was stirred for 1 h at reflux, was cooled,
and the benzene was removed in vacuo. The residue was
chromatographed over 750 g of silica gel (230-400 mesh),
eluting with 4 L of 10% EtOAc/hexane (including a 2 L
forerun), 2 L of 20% EtOAc/hexane, followed by 3 L of 35%
EtOAc/hexane to afford 22.2 g (88%) of 22 as a pale yellow oil.
1H NMR (CDCl3, TMS): δ 1.37 (d, J ) 7 Hz, 3H), 1.48 (d, J )
6.5 Hz, 3H), 2.91 (bs, 1H), 3.65 (bs, 1H), 4.24 (t, J ) 8.8 Hz,
1
5.65 g (80%) of 17. Mp: 71-73 °C; H NMR (CDCl3): δ 1.56
(d, J ) 6.5 Hz, 3H), 4.96 (q, J ) 6.5 Hz, 1H), 6.84 (d, J ) 2
Hz,1H), 7.51 (s, 1H), 7.81 (d, J ) 2 Hz, 1H); 13C NMR
(CDCl3): δ 24.4, 69.5, 107.2, 111.3, 132.8, 136.8, 146.8, 149.2,
157.3; IR: 3205, 2925, 1611, 1572 cm-1. MS: [m/z](relative
1H), 4.83 (m, 2H), 7.12 (m, 1H); IR 3386, 2971, 1571 cm-1
;

Stereoselective Synthesis of Furo[2,3-c)-pyridine Thioethers
J . Org. Chem., Vol. 63, No. 22, 1998 7857
MS: Calcd for C10H12NO2: 213.0557. Found: 213.0555. Anal.
Calcd for C10H12NO2 @0.87% H2O: C, 55.46; H, 6.15; N, 6.47.
Found: C, 55.46; H, 5.63; N, 6.45.
MS: [m/z](relative intensity): [177](3), [162](100). Anal.
Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C,
67.65; H, 6.38; N, 7.85.
2,3-Dih yd r o-5-(1-a cetoxyeth yl)-3-m eth ylfu r o[2,3-c]p yr -
id in e (23). A solution of 22 (26 g, 122 mmol) in 200 mL of
MeOH was treated with 5.5 g DARCO and was refluxed for
20 min. The mixture was filtered through Celite, and the filter
cake was washed with MeOH. The filtrate was concentrated
in vacuo to give 25 g of a pale oil. The oil was dissolved in
160 mL of absolute EtOH, was treated with 5.5 g of 20% Pd-
(OH)2 on carbon, and was diluted with 60 mL (120 mmol) of 2
N aqueous NaOH. The mixture was hydrogenated at 22 psi
for 20 h. The catalyst was removed by filtration, and the filter
cake was washed with fresh absolute EtOH. The filtrate was
concentrated in vacuo to a pasty residue and was partitioned
between 1 × 200 mL of 50% saturated NaHCO3 and 4 × 100
mL of CH2Cl2. The organics were dried over K2CO3 and were
concentrated in vacuo to provide 20.1 g (93%) of 5-(1-hydroxy-
ethyl)-2,3-dihydro-3-methylfuro[2,3-c]pyridine as a pale yellow
oil. 1H NMR (CDCl3, TMS): δ 1.36 (m, 3H), 1.48 (m, 3H), 3.56
(m, 1H), 4.05 (bs, 1H), 4.13 (m, 1H), 4.86 (t, J ) 9 Hz, 1H),
4.87 (q, J ) 6.4 Hz, 1H), 7.15 (s, 1H), 8.03 (s, 1H); IR 3368,
2970, 1584, 1488, 1273, 1231, 1118, 959 cm-1; MS: Calcd for
(-)-(S)-5-(1-Hyd r oxyeth yl)fu r o[2,3-c]p yr id in e ((S)-18)
a n d (+)-(R)-5-(1-bu tyr yloxy)fu r o[2,3-c]p yr id in e (24).
A
combination of 18 (11.3 g, 69.4 mmol), porcine pancreatic lipase
type (II) (16.5 g), and 2,2,2 trifluoroethyl butyrate (41.8 mL,
227 mmol) in 226 mL of Et2O under N2 was stirred for 9 days
at room temperature. The mixture was filtered to remove the
enzyme, and the filter cake was washed well with Et2O. The
filtrate was concentrated in vacuo to a pale oil. The residue
was azeotroped with 3 × 200 mL of toluene and placed under
high vacuum at 40 °C for 3 h. The crude material was
chromatographed over 300 g of silica gel (230-400 mesh),
eluting with 60% EtOAc/hexane to provide 7.53 g (46.5%) of
24 as a pale oil and 5.03 g, (44.5%) of (-)-(S)-18 as an off-
1
white solid. Data for 24: [R]D
)
+84.0° (c ) 0.62, CHCl3); H
NMR (CDCl3, TMS): δ 0.94 (t, J ) 7.4 Hz, 3H), 1.61-1.74 (m,
5H), 2.36 (m, 2H), 6.04 (q, J ) 6.6 Hz, 1H), 6.79 (m, 1H), 7.59
(s, 1H), 7.75 (d, J ) 2.1 Hz, 1H), 8.85 (s, 1H); 13C NMR
(CDCl3): δ 13.6, 18.5, 21.2, 36.4, 72.7, 106.3, 113.2, 133.0,
134.9, 148.8, 151.5, 153.1, 173.0; IR 2968, 1735, 1611, 1466
cm-1; MS: [m/z](relative intensity): [233](2), [162](100). Anal.
Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C,
66.63; H, 6.39; N, 6.03. Chiral HPLC (0.46 × 25 cm (R,R)
Whelk-O1; 1.0 mL/min; 20% 2-propanol in hexane; retention
time (R)-isomer: 11.7 min, (S)-isomer: 8.2 min) indicated the
butyrate to be 99.9% ee. Data for (-)-(S)-18: Mp: 59-61 °C;
[R]D ) -35.8° (c ) 0.5, CHCl3); 1H NMR (CDCl3, TMS): δ 1.58
(d, J ) 6.5 Hz, 3H), 4.24 (bs, 1H), 5.07 (q, J ) 6.5 Hz, 1H),
6.84 (m, 1H), 7.61 (s, 1H), 7.84 (d, J ) 2.1 Hz, 1H), 8.84 (s,
1H); IR: 3111, 2926, 1612, 1465 cm-1; MS: [m/z](relative
intensity): [163](2), [148](100). Anal. Calcd for C9H9NO2: C,
66.25; H, 5.56; N, 8.58. Found: C, 66.13; H, 5.45; N, 8.54. A
50 mg sample of (S)-18 was converted to the corresponding
acetate ([R]D ) -102.2° (c ) 0.5, CHCl3); 1H NMR (CDCl3,
TMS): δ 8.86 (m, 1H), 7.76 (d, J ) 2.1 Hz, 1H), 7.60 (m, 1H),
6.80 (m, 1H), 6.03 (q, J ) 6.6 Hz, 1H), 2.12 (s, 3H), 1.64 (d, J
) 6.5 Hz, 3H). Anal. Calcd for C11H11NO3: C, 64.38; H, 5.40;
N, 6.82. Found: C, 64.05; H, 5.59; N, 6.74) with Ac2O/pyridine.
Chiral HPLC (0.46 × 25 cm (R,R) Whelk-O1; 1.0 mL/min; 10%
2-propanol in hexane; retention time (S)-isomer: 12.1 min, (R)-
isomer: 17.9 min) indicated the acetate to be 99% ee.
C
C
10H13NO2: 179.0946. Found: 179.0949. Anal. Calcd for
10H13NO2 @2.01% H2O: C, 65.67; H, 7.39; N, 7.66. Found:
C, 66.11; H, 7.10; N, 7.66. A solution of of 5-(1-hydroxyethyl)-
2,3-dihydro-3-methylfuro[2,3-c]pyridine (20.1 g, 112 mmol) in
112 mL of pyridine under N2 was treated with acetic anhydride
(31.2 mL, 336 mmol) and was stirred overnight at room
temperature. The pyridine was removed in vacuo, and the
residue was taken up in 200 mL of EtOAc. The solution was
stirred vigorously for 1 h with 200 mL of saturated NaHCO3
containing 35 g of solid NaHCO3. The organic layer was
extracted with 4 × 100 mL of 50% saturated NaCl, dried over
anhydrous MgSO4, and concentrated in vacuo to give 24.8 g
(quant) of 23 as a pale oil. 1H NMR (CDCl3, TMS): δ 1.36 (m,
3H), 1.58 (m, 3H), 2.11 (m, 3H), 3.57 (m, 1H), 4.14 (t, J ) 8.4
Hz, 1H), 4.75 (t, J ) 8.4 Hz, 1H), 5.89 (q, J ) 6.5 Hz, 1H),
7.18 (m, 1H), 8.12 (s, 1H); IR 2980, 1739 cm-1; HRMS: Calcd
for C12H15NO3: 221.1052. Found: 221.1054.
5-(1-Hyd r oxyeth yl)-3-m eth ylfu r o[2,3-c]p yr id in e (21).
Method A: A combination of 20 (1.71 g, 8.1 mmol) and 20%
Pd(OH)2 on carbon (1.71 g) in 24 mL of absolute EtOH under
N2 was treated with 1,4 cyclohexadiene (7.6 mL, 81 mmol),
and the reaction was warmed to reflux for 2 h. The mixture
was filtered through Celite, and the cake was washed well with
fresh MeOH. The filtrate was concentrated in vacuo, and the
residue was partitioned between 50 mL of saturated NaHCO3
and 4 × 25 mL of CH2Cl2. The combined organics were dried
over K2CO3 and were concentrated in vacuo to provide 1.39 g
(97%) of 21 as a colorless oil which crystallized on standing.
Method B: A solution of 23 (24.3 g, 110 mmol) and 2,3,5,6-
tetrachlorobenzoquinone (29.6 g, 120.4 mmol) in 500 mL of
dioxane under N2 was warmed to a gentle reflux for 24 h. The
reaction was cooled to room temperature and was filtered, and
the filter cake was washed well with EtOAc. The filtrate was
concentrated in vacuo to a reddish brown slurry which was
diluted with 100 mL of dioxane and filtered, and the filter cake
was washed with Et2O. The filtrate was concentrated to a
brown oil, was diluted with 500 mL of MeOH followed by 185
mL (370 mmol) of 2 N NaOH, and the reaction was stirred for
1 h at room temperature. The MeOH was removed in vacuo,
the aqueous residue was diluted with 300 mL of H2O, and the
mixture was extracted with 4 × 100 mL of CH2Cl2. The
combined organics were backwashed with 2 × 100 mL of 1 N
NaOH, dried over K2CO3, and concentrated in vacuo to a
greenish oil. The oil was dissolved in 200 mL of MeOH and
was refluxed with DARCO for 20 min. The mixture was
filtered through Celite, the filter cake was washed well with
MeOH, and the filtrate was concentrated in vacuo to provide
18.4 g (94%) of 21. Mp: 56-58 °C; 1H NMR (CDCl3, TMS): δ
1.57 (d, J ) 6.5 Hz, 3H), 2.26 (s, 3H), 3.68 (bs, 1H), 5.03 (q, J
) 6.5 Hz, 1H), 7.49 (s, 1H), 7.55 (m, 1H), 8.72 (m, 1H); 13C
NMR (CDCl3): δ 7.6, 24.7, 69.5, 110.1, 115.4, 131.8, 136.5,
(-)-(S )-5-(1-H yd r oxye t h yl)-3-m e t h ylfu r o[2,3-c]p yr i-
d in e ((S)-21) a n d (+)-(R)-5-(1-bu tyr yloxyeth yl)-3-m eth -
ylfu r o[2,3-c]p yr id in e (25). A solution of 21 (2.54 g, 14.35
mmol) in 50 mL of Et2O at room temperature was treated with
2,2,2-trifluoroethyl butyrate (9.76 g, 57.40 mmol) and porcine
pancreatic lipase, type II (3.71 g) and stirred for 7 days. The
contents were diluted with 40 mL of Et2O plus 3 g of Celite,
filtered through a pad of Celite (12 g), and washed thoroughly
with Et2O. The filtrate was concentrated in vacuo, and the
residue was chromatographed over 70 g of silica gel (230-400
mesh), eluting with acetone-CH2Cl2 (1:5), to yield 1.81 g (51%)
of 25 and 1.28 g (50%) of (-)-(S)-21. Data for 25: [R]D ) +
76.5° (c ) 1.50, CHCl3); 1H NMR (CDCl3,TMS): δ 8.78 (s, 1H),
7.50 (s, 2H), 6.04 (q, J ) 6.6 Hz, 1H), 2.35 (t, J ) 7.4 Hz, 2H),
2.23 (s, 3H), 1.72-1.57 (m, 2H), 1.64 (d, J ) 4.6 Hz, 3H), 0.92
(t, J ) 7.4 Hz, 3H); HRMS: Calcd for C14H17NO3: 247.1208.
Found: 247.1213. Anal. Calcd for C14H17NO3: C, 68.02; H,
6.88; N, 5.67. Found: C, 67.98; H, 6.97; N, 6.19. Chiral HPLC
(0.46 × 25 cm (R,R) Whelk-O1; 1.0 mL/min; 15% 2-propanol
in hexane; retention time (R)-isomer: 11.4 min, (S)-isomer:
6.7 min) indicated the butyrate to be 99.9% ee. Data for (S)-
21: Mp: 76-78 °C; [R]D ) - 40.8° (c ) 0.865, CHCl3); 1H NMR
(CDCl3,TMS): δ 8.69 (s, 1H), 7.51 (s, 1H), 7.46 (s, 1H), 5.00
(q, J ) 6.5 Hz, 1H), 2.23 (s, 3H), 1.55 (d, J ) 6.5 Hz, 3H);
HRMS: Calcd for C10H11NO2 - H: 176.0712. Found: 176.0709.
A 17 mg sample of (S)-21 was converted to the corresponding
1
acetate ([R]D ) -90.4° (c ) 0.575, CHCl3); H NMR (CDCl3,-
TMS): δ 8.78 (s, 1H), 7.51 (m, 2H), 6.03 (q, J ) 6.6 Hz, 1H),
2.25 (s, 3H), 2.12 (s, 3H), 1.64 (d, J ) 6.5 Hz, 3H); HRMS:
Calcd for C12H13NO3: 219.0895. Found: 219.0891) with acetic
anhydride/pyridine. Chiral HPLC (0.46 × 25 cm (R,R) Whelk-
O1; 1.0 mL/min; 15% 2-propanol in hexane; retention time (S)-
145.3, 151.7, 156.0; IR 3208, 2925, 1621, 1589, 1457 cm-1
;

7858 J . Org. Chem., Vol. 63, No. 22, 1998
Wishka et al.
isomer: 8.3 min, (R)-isomer: 13.5 min) indicated the acetate
to be 99% ee.
1588, 1462 cm-1. HRMS: Calcd for C10H11NO2 - H: 176.0712.
Found: 176.0711. Anal. Calcd for C10H11NO2: C, 67.78; H,
6.26; N, 7.90. Found: C, 67.77; H, 6.24; N, 8.11.
(+)-(R)-5-(1-Hyd r oxyeth yl)fu r o[2,3-c]p yr id in e ((R)-18).
A solution of 24 (7.5 g, 32.2 mmol) in 88 mL of MeOH was
treated with 2 N NaOH (35.4 mL, 70.8 mmol) and was stirred
for 1 h. The volatiles were removed in vacuo, and the residue
was partitioned between 25 mL of CH2Cl2 and 100 mL of H2O.
The insoluble material was removed by filtration through
Celite. The aqueous layer was extracted with 3 × 25 mL of
CH2Cl2. The combined organics were dried over K2CO3 and
were concentrated in vacuo to give 4.68 g (89%) of (R)-18 as a
white solid. Mp: 60-61 °C; [R]D ) + 37.0° (c ) 0.56, CHCl3);
1H NMR (CDCl3, TMS): δ 1.55 (d, J ) 6.5 Hz, 3H), 4.25 (bs,
1H), 5.01 (q, J ) 6.5 Hz, 1H), 6.81 (m, 1H), 7.55 (s, 1H), 7.78
(d, J ) 2.1 Hz, 1H), 8.80 (s, 1H); IR 3111, 2928, 1613, 1464
cm-1. Anal. Calcd for C9H9NO2: C, 66.25; H, 5.56; N, 8.58.
Found: C, 66.46; H, 5.55; N, 8.70.
(+)-(R)-5-(1-H yd r oxyet h yl)-3-m et h ylfu r o[2,3-c]p yr i-
d in e ((R)-21). Following the procedure for the preparation
of (R)-18, starting with 10.8 g (43.7 mmol) of 25, there was
synthesized 6.94 g (90%) of (R)-21 as a tan solid. Mp: 78-79
°C; [R]D ) + 40.6° (c ) 0.515, CHCl3); 1H NMR (CDCl3,TMS):
δ 8.66 (s, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 4.95 (q, J ) 6.4 Hz,
1H), 3.77 (brs, 1H), 2.19 (s, 3H), 1.50 (d, J ) 6.4 Hz, 3H); IR
3316, 1615, 1588 cm-1. Anal. Calcd for C10H11NO2: C, 67.78;
H, 6.26; N, 7.90. Found: C, 67.74; H, 6.16; N, 7.95.
5-(1-Acetyl)-7-ch lor o-3-m eth ylfu r o[2,3-c]p yr id in e (30).
To a solution of oxalyl chloride (0.93 mL, 10.90 mmol) in 45
mL of CH2Cl2 at -60 °C was added dimethyl sulfoxide (1.54
mL, 21.80 mmol) in 5 mL of CH2Cl2 dropwise over a 7 min
period. After 30 min, a solution of 20 (2.00 g, 9.48 mmol) in 8
mL of CH2Cl2 was added dropwise to the mixture at -60 °C
over a 19 min period. An additional 5 mL of CH2Cl2 was added
to facilitate stirring. After 15 min, Et3N (6.6 mL, 47.4 mmol)
was added dropwise at -60 °C. After stirring for 1 h at -60
°C, the cooling bath was removed and the reaction was allowed
to warm to room temperature. After 1.5 h, the mixture was
poured into 50 mL of 50% saturated NaCl and extracted 2×
with EtOAc. The combined organics were concentrated, and
the mixture (2.0 g) was chromatographed on 200 g of silica
gel, eluting with 5% EtOAc/hexane to afford 1.78 g (90%) of
30. Recrystallization from ether provided an analytical sample.
Mp: 115-117 °C; 1H NMR (CDCl3, TMS): δ 8.23 (s, 1H), 7.62
(s, 1H), 2.74 (s, 3H), 2.27 (s, 3H); 13C NMR (CDCl3): δ 198.5,
149.8, 147.2, 145.9, 137.6, 132.8, 117.7, 113.7, 26.2, 7.8; IR:
2924, 1695, 1687, 1407, 1322, 1250 cm-1
10H8NClO2: C, 57.29; H, 3.85; N, 6.68. Found: C, 57.37; H,
3.90; N, 6.80.
. Anal. Calcd for
C
5-(1-Acetyl)-7-ch lor o-2,3-d ih yd r o-3-m eth ylfu r o[2,3-c]-
p yr id in e (31). Following the procedure for the preparation
of 30, starting with 27.9 g (130 mmol) of 22, there was
synthesized 23.2 g (84%) of 31. Mp: 88-89 °C; 1H NMR
(CDCl3, TMS): δ 7.87 (s, 1H), 4.90 (t, J ) 9.2 Hz, 1H), 4.31
(dd, J ) 7.5, 9.1 Hz, 1H), 3.68 (m, 1H), 2.64 (s, 3H), 1.38 (d, J
) 6.9 Hz, 3H); 13C NMR (CDCl3): δ 197.7, 156.0, 147.3, 143.6,
131.0, 117.6, 80.0, 36.8, 25.7, 18.8; IR 2926, 1686, 1587, 1476,
1290 cm-1. Anal. Calcd for C10H10NClO2: C, 56.75; H, 4.76;
N, 6.62. Found: C, 56.76; H, 4.83; N, 6.63.
(+)-(S)-5-[1-(Ben zoyloxy)eth yl]fu r o[2,3-c]p yr id in e (26).
A combination of (R)-18 (4.68 g, 28.7 mmol), benzoic acid (3.86
g, 31.6 mmol), and Ph3P (8.29 g, 31.6 mmol) in 125 mL of dry
THF under N2 was treated dropwise (moderate add rate, allow
some exotherm) with diethyl azodicarboxylate (4.98 mL, 31.6
mmol), and the reaction was stirred for 1.5 h at room
temperature. The volatiles were removed in vacuo, the oily
residue was diluted successively with equal volumes of Et2O
and hexane, and the white solid was collected by filtration.
The filtrate was concentrated in vacuo to an amber oil. The
crude material was chromatographed over 250 g of silica gel
(230-400 mesh), eluting with 20% EtOAc/hexane to give 6.87
g (90%) of 26. [R]D ) +52.7° (c ) 0.67, CHCl3); 1H NMR
(CDCl3, TMS): δ 1.79 (d, J ) 6.7 Hz, 3H), 6.32 (q, J ) 6.7 Hz,
1H), 6.80 (m, 1H), 7.41-7.48 (m, 2H), 7.52-7.60 (m, 1H), 7.71
(-)-(S)-7-Ch lor o-5-(1-h yd r oxyeth yl)-3-m eth ylfu r o[2,3-
c]p yr id in e ((S)-20). To a suspension of 30 (1.64 g, 7.85 mmol)
in 15 mL of THF at -30 °C was added a solution of (-)-
chlorodiisopinocampheylborane [(-)-DipCl] (5.42 g, 16.90 mmol)
in 15 mL of THF dropwise over a 22 min period. After 5 min,
the reaction temperature was adjusted to -18 °C and the
mixture was stirred at -18 °C for 4 h and at room temperature
overnight. The reaction mixture was cooled to -18 °C, and a
mixture of 14 mL of saturated NaHCO3 and 4 mL of 30% H2O2
was added over a 30 min period. The mixture was stirred at
room temperature for 1 h, diluted with EtOAc, and washed
with 2 × 50 mL of saturated NaHCO3 and 1 × 50 mL of
saturated NaCl. The organics were dried with anhydrous Na2-
SO4 and concentrated to give 6.08 g of a golden oil. Chroma-
tography on 140 g of silica gel (230-400 mesh), eluting with
25% EtOAc/hexane gave 1.56 g (94%) of (S)-20 as a white solid
[chiral HPLC of the prepared acetate of (S)-20 as compared
to that of the corresponding racemate shows the material to
be 92% ee]. Recrystallization of 1.30 g of the chromatographed
sample from ether/hexane afforded 1.02 g of white crystals
(Chiral HPLC (0.46 × 25 cm (R,R) Whelk-O1; 0.5 mL/min; 50%
2-propanol in hexane (0.05% TEA); retention time (S)-isomer:
10.3 min, (R)-isomer: 14.6 min) of the corresponding acetate
[optical rotation: [R]D ) -92.9° (c ) 2.54, CHCl3)] indicated
>99% ee). Mp: 99-100 °C; [R]D ) -26.2° (c ) 1.33, CHCl3);
1H NMR (CDCl3, TMS): δ 7.56 (s, 1H), 7.43 (s, 1H), 4.97 (q, J
) 6.3 Hz, 1H), 3.37 (d, J ) 5.2 Hz, 1H, OH), 2.23 (s, 3H), 1.54
(d, J ) 6.5 Hz, 3H); 13C NMR (CDCl3): 156.9, 147.0, 145.7,
138.2, 132.6, 116.5, 109.7, 69.6, 24.5, 7.9; IR 3262, 3178, 1617,
(s, 1H), 7.76 (d, J ) 2.1 Hz, 1H), 8.12 (m, 2H), 8.95 (s, 1H); 13
C
NMR (CDCl3): δ 21.3, 73.6, 106.3, 113.2, 128.4, 128.4, 129.8,
130.1, 130.3, 130.5, 133.0, 135.1, 149.0, 151.6, 152.0, 165.9,
170.2; IR 3062, 1718, 1466, 1450 cm-1; HRMS: Calcd for
C
16H13NO3: 267.0895. Found: 267.0903.
(+)-(S)-5-[1-(Ben zoyloxy)eth yl]-3-m eth ylfu r o[2,3-c]p yr -
id in e (27). Following the procedure for the preparation of 26,
starting with 3.9 g (22 mmol) of (R)-21, there was synthesized
5.57 g (90%) of 27. [R]D ) +55.6° (c ) 0.59, CHCl3); 1H NMR
(CDCl3,TMS): δ 8.79 (s, 1H), 8.13 (s, 1H), 8.11 (s, 1H), 7.63-
7.38 (m, 5H), 6.30 (q, J ) 6.6 Hz, 1H), 2.22 (s, 3H), 1.78 (d, J
) 6.6 Hz, 3H); IR 1717 cm-1; HRMS: Calcd for C17H15NO3:
281.1047. Found: 281.1052.
(-)-(S)-5-(1-Hyd r oxyeth yl)fu r o[2,3-c]p yr id in e ((S)-18).
A solution of 26 (6.87 g, 25.7 mmol) in 88 mL of MeOH was
treated with 2 N sodium hydroxide (28.3 mL, 56.6 mmol), and
the reaction was stirred for 2 h at room temperature. The
volatiles were removed in vacuo, and the residue was parti-
tioned between 50 mL of H2O and 4 × 25 mL of CH2Cl2. The
organics were dried over anhydrous K2CO3 and were concen-
trated in vacuo to an amber oil. The crude material was
chromatographed over 150 g of silica gel (230-400 mesh),
eluting with 65% EtOAc/hexane to afford 3.96 g (94%) of (S)-
18 as a white solid. Mp: 60-61 °C; [R]D ) -35.3° (c ) 0.51,
CHCl3). 1H NMR (CDCl3, TMS): δ 1.56 (d, J ) 6.5 Hz, 3H),
4.10 (bs, 1H), 5.03 (q, J ) 6.5 Hz, 1H), 6.82 (m, 1H), 7.57 (s,
1H), 7.81 (d, J ) 2.1 Hz, 1H), 8.81 (s, 1H).
1588, 1558, 1459 cm-1
. Anal. Calcd for C10H10NClO2: C,
56.75; H, 4.76; N, 6.62. Found: C, 56.57; H, 5.11; N, 6.61.
7-Ch lor o-2,3-d ih yd r o-5-(1(S)-h yd r oxyeth yl)-3-m eth yl-
fu r o[2,3-c]p yr id in e ((S)-22). Following the procedure for the
preparation of (S)-20, starting with 7.2 g (34 mmol) of 31, there
was synthesized 7.2 g (99%) of (S)-22. 1H NMR (CDCl3,
TMS): δ 7.09 (m, 1H), 4.78 (m, 2H), 4.18 (t, J ) 8 Hz, 1H),
3.63 (m, 1H), 1.45 (d, J ) 6.3 Hz, 3H), 1.34 (d, J ) 6.8 Hz,
3H); 13C NMR (CDCl3): δ 156.7, 151.7, 144.5, 130.5, 114.5,
79.2, 69.2, 37.3, 24.2, 18.6; IR 3385, 2972, 1571 cm-1. HRMS:
Calcd for C10H12ClNO2: 213.0556. Found: 213.0550.
(-)-(S )-5-(1-H yd r oxye t h yl)-3-m e t h ylfu r o[2,3-c]p yr i-
d in e ((S)-21). Following the procedure for the preparation
of (S)-18, starting with 9.86 g (35 mmol) of 27, there was
synthesized 5.67 g (91%) of (S)-21. Mp: 78-79 °C; [R]D
)
1
-41.2° (c ) 0.505, CHCl3); H NMR (CDCl3, TMS): 8.73 (m,
1H), 7.55 (m, 1H), 7.49 (s, 1H), 5.03 (q, J ) 6.5 Hz, 1H), 3.91
(bs, 1H), 2.25 (s, 3H), 1.56 (d, J ) 6.4 Hz, 3H); IR: 3317, 1615,

Stereoselective Synthesis of Furo[2,3-c)-pyridine Thioethers
J . Org. Chem., Vol. 63, No. 22, 1998 7859
(+)-(R)-5-(1-Ch lor oeth yl)fu r o[2,3-c]p yr id in e (1). A so-
lution of (S)-18 (9.0 g, 55.2 mmol) in 35 mL of CHCl3 under
N2 was treated with Ph3P (28.9 g, 110.3 mmol) followed by
CCl4 (106 mL, 1.10 mol), and the reaction was stirred for 24 h
at room temperature. The solution was diluted with 35 mL
of hexane and stirred for 30 min, and the white precipitate
was removed by filtration. The filter cake was washed with
100 mL of 20% Et2O/hexane, and the filtrate was concentrated
to a small volume (not to dryness). The residue was chro-
matographed over 350 g of silica gel (230-400 mesh), eluting
with 15% EtOAc/hexane to afford 8.48 g (83%) of 1 as a low
melting off-white solid. Chiral HPLC analysis (0.46 × 25 cm,
Chiralcel OD-H, 0.5 mL/min; 2% 2-propanol in hexane; reten-
tion time (R)-isomer: 14.2 min, (S)-isomer: 12.9 min) indicated
CH2Cl2 and was chromatographed over 450 g of silica gel (230-
400 mesh), eluting with 45% EtOAc/hexane to give 11.05 g
(89%) of P NU-142721 as a white solid. Chiral HPLC analysis
(0.46 × 25 cm, Chiralcel OD-H; 0.5 mL/min; 25% 2-propanol/
hexanes; retention time (S)-isomer: 13.5 min, (R)-isomer: 12.1
min) indicated 97.6% ee. Recrystallization from EtOAc af-
forded 7.92 g (64%, 99% ee) of P NU-142721. Mp: 169-170.5
1
°C; [R]D ) -334° (c ) 0.68, CHCl3); H NMR (DMSO-d6): δ
1.70 (d, J ) 7 Hz, 3H), 5.11 (q, J ) 6.9 Hz, 1H), 6.15 (s, 1H),
7.00 (m, 1H), 7.30 (bs, 2H), 7.78 (d, J ) 1 Hz, 1H), 8.20 (d, J
) 2.1 Hz, 1H), 8.88 (s, 1H); IR 3458, 3114, 2925, 1637, 1572,
1529, 1465, 1282, 1116 cm-1; MS: [m/z](relative intensity):
[306](10), [273](69), [146](100). Anal. Calcd for C13H11Cl N4
OS: C, 50.90; H, 3.61; N, 18.26. Found: C, 51.16; H, 3.54; N,
18.11.
1
97% ee. Mp: 36-38 °C; [R]D ) +73.0° (c ) 0.47, CHCl3); H
NMR (CDCl3, TMS): δ 1.93 (d, J ) 6.8 Hz, 3H), 5.28 (q, J )
6.8 Hz, 1H), 6.80 (m, 1H), 7.72 (m, 1H), 7.77 (d, J ) 2.1 Hz,
1H), 8.83 (s, 1H); 13C NMR (CDCl3): δ 25.5, 59.2, 106.3, 113.7,
132.9, 135.1, 149.0, 151.5, 153.7; IR 2928, 1610, 1466, 1304,
1193 cm-1; MS: [m/z](relative intensity): [181](4), [146](100).
Anal. Calcd for C9H8ClNO: C, 59.52; H, 4.44; N, 7.71.
Found: C, 59.33; H, 4.41; N, 7.62.
(-)-(S)-6-ch lor o-2-[[1-(3-m eth ylfu r o[2,3-c]p yr id in -5-yl)-
eth yl]th io]-4-p yr im id in a m in e (P NU-109886). A suspen-
sion of NaH (1.25 g, 0.0522 mol, 60% oil dispersion) in 80 mL
of DMF at 16 °C was treated with 4-amino-6-chloro-2-mer-
captopyrimidine mesylate salt (3) (6.71 g, 0.0261 mol), and the
reaction mixture was stirred for 15 min. The cooling bath was
removed, and the contents were stirred at room temperature
for 1.5 h. A solution of 2 (4.86 g, 0.0249 mol) in 15 mL of DMF
was added (plus a 10 mL rinse). The reaction mixture was
allowed to stir at room temperature for 5 days. The contents
were poured into ice-water and extracted two times with
Et2O. The combined organic fractions were dried with anhy-
drous Na2SO4 and concentrated at reduced pressure. Chro-
matography over 350 g of silica gel, eluting with EtOAc/hexane
(2:3) and then (1:1), provided 6.55 g (82%) of P NU-109886.
Recrystallization from methyl tert-butyl ether-methylene
chloride-ethyl acetate afforded 4.83 g (61%) of analytical
material. Chiral HPLC analysis (0.46 × 25 cm, Chiralcel OD-
H; 0.5 mL/min; 25% 2-propanol/ hexanes; retention time (S)-
isomer: 12.1 min, (R)-isomer: 16.8 min) indicated 98% ee.
Mp: 156-157 °C; [R]D ) -270.3° (c ) 0.620, CHCl3); 1H NMR
(CDCl3): δ 8.81 (s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.30 (brs,
2H), 6.15 (q, J ) 7.0 Hz, 1H), 2.19 (s, 3H), 1.71 (d, J ) 7.0 Hz,
3H); IR 2925, 1644, 1572, 1537, 1465, 829 cm-1; MS: m/z
(relative intensity %): M+ 320 (9), 287 (75), 160 (100). Anal.
Calcd for C14H13ClN4OS: C, 52.42; H, 4.06; N, 17.47. Found:
C, 52.41; H, 4.06; N, 17.31.
(+)-(R )-5-(1-C h lo r o e t h y l)-3-m e t h y lfu r o [2,3-c]p yr i-
d in e (2). A solution of (S)-21 (5.57 g, 31.4 mmol) and Ph3P
(16.5 g, 62.8 mmol) in 20 mL of CHCl3 at 0 °C was treated
with 60 mL of CCl4 (0.628 mol), and the reaction was stirred
at room temperature for 48 h. The mixture was diluted with
20 mL of hexane and filtered. The filtrate was concentrated
in vacuo, and the material was chromatographed over 210 g
of silica gel (230-400 mesh), eluting with 20% EtOAc/hexanes
to give 5.45 g (89%) of 2. Chiral HPLC analysis (0.46 × 25
cm, Chiralpak AD, 0.25 mL/min; 5% EtOH in hexane; reten-
tion time (R)-isomer: 22.0 min, (S)-isomer: 23.4 min) of a
sample from a previous run, having an optical rotation of [R]D
) +68.4° (c ) 1.53, CHCl3), indicated >97% ee. Data for 2:
Optical rotation: [R]D ) +65.7° (c ) 0.49, CHCl3). 1H NMR
(CDCl3, TMS): δ 8.75 (m, 1H), 7.53 (m, 1H), 7.26 (s, 1H), 5.30
(q, J ) 6.8 Hz, 1H), 2.25 (s, 3H), 1.94 (d, J ) 6.8 Hz, 3H); IR
1463, 1313, 1193, 1089 cm-1
. Anal. Calcd for C10H10ClNO:
C, 61.38; H, 5.12; N, 7.16. Found: C, 60.94; H, 5.04; N, 7.06.
(-)-(S)-6-Ch lor o-2-[[1-(fu r o[2,3-c]pyr idin -5-yl)eth yl]th io]-
4-p yr im id in a m in e (P NU-142721). A suspension of 60%
NaH (3.5 g, 87.5 mmol, washed with 3 × 7 mL of hexane) in
75 mL of dry DMF under N2 at 0 °C was treated portionwise
with 4-amino-6-chloro-2-mercaptopyrimidine mesylate salt (3)
(10.9 g, 42.3 mmol) and was stirred for 1 h at room temper-
ature. The reaction mixture was treated dropwise with 1 (7.4
g, 40.6 mmol) in 1 × 20 mL of DMF (5 mL rinse) and the
mixture was stirred for 5 days at room temperature. The
mixture was poured into 400 mL of EtOAc, washed with 4 ×
100 mL of 50% saturated NaCl, and was dried over anhydrous
K2CO3/MgSO4. The dried organics were concentrated in vacuo
to an amber oil. The crude material was diluted with acetone/
Su p p or tin g In for m a tion Ava ila ble: Full experimental
and spectroscopic data for 5, 6, 28, 29, (S)-21 (from (S)-20 and
(S)-22), 1H NMR for 11, 18, (S)-21, 23, 26, 27, and ORTEP
drawings and atomic coordinate information for 28, 29, and
P NU-109886 (27 pages). This material is contained in librar-
ies on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O9810359