Chemoenzymatic synthesis of antiviral carbocyclic nucleosides: Asymmetric hydrolysis of meso-3,5-bis(acetoxymethyl)cyclopentenes using Rhizopus delemar lipase

Article abstract of DOI:10.1021/jo9608230

7-Substituted norbornadienes were stereoselectively converted into the meso-3,5-bis(acetoxymethyl)cyclopentenes by a three-step sequence of ozonolysis, reduction, and acetylation. Rhizopus delemar lipase (RDL)-catalyzed asymmetric hydrolysis of meso-3,5-bis(acetoxymethyl)cyclopentenes afforded the monoalcohols of high enantiomeric purities (> 95% ee) in good yields (64-95%). The obtained monoalcohols 11 and 14 could be applied for the synthesis of antiviral carbocyclic nucleosides (-)-carbovir and (-)-BCA.

Full text of DOI:10.1021/jo9608230

6952
J . Org. Chem. 1996, 61, 6952-6957
Ch em oen zym a tic Syn th esis of An tivir a l Ca r bocyclic Nu cleosid es:
Asym m etr ic Hyd r olysis of
m eso-3,5-Bis(a cetoxym eth yl)cyclop en ten es Usin g Rh izopu s
d elem a r Lip a se
Masakazu Tanaka,* Yoshihiko Norimine,1 Toshiaki Fujita, and Hiroshi Suemune
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-82, J apan
Kiyoshi Sakai*
Kyushu Women’s University, 1-1 J iyugaoka, Yahata-nishi, Kitakyushu 807, J apan
Received May 6, 1996X
7-Substituted norbornadienes were stereoselectively converted into the meso-3,5-bis(acetoxymethyl)-
cyclopentenes by a three-step sequence of ozonolysis, reduction, and acetylation. Rhizopus delemar
lipase (RDL)-catalyzed asymmetric hydrolysis of meso-3,5-bis(acetoxymethyl)cyclopentenes afforded
the monoalcohols of high enantiomeric purities (>95% ee) in good yields (64-95%). The obtained
monoalcohols 11 and 14 could be applied for the synthesis of antiviral carbocyclic nucleosides (-)-
carbovir and (-)-BCA.
In tr od u ction
We have previously reported the effective synthesis of
a carbocyclic nucleoside, (-)-aristeromycin.6 This success
in synthesis of an optically active carbocyclic nucleoside
using Rhizopus delemar lipase (RDL)7,8 prompted us to
further studies on the generality and ability of RDL for
asymmetric hydrolysis of various meso-compounds and
synthesis of carbocyclic nucleosides. In this paper, we
report that meso-3,5-bis(acetoxymethyl)cyclopentenes with
the bulky substituent at the C4-position could be easily
prepared from 7-substituted norbornadiene, and these
compounds were further hydrolyzed by RDL to the
monoalcohols in an enantioselective manner. The opti-
cally active alcohols obtained could be converted into the
anti-HIV active carbocyclic nucleosides, (-)-carbovir and
(-)-BCA.
Recently, the synthesis of nucleoside analogs has been
the focus of extensive study in the fields of organic and
medicinal chemistry because of the strong biological
activities displayed by some of them as antiviral and
antitumor drugs. The finding that nucleosides, such as
3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxycytidine
(ddC), and 2′,3′-dideoxyinosine (ddI), are potentially
effective therapeutic agents for the treatment of the
acquired immune deficiency syndrome (AIDS) has trig-
gered explosive developments in the modifications of both
the heterocyclic base and the sugar moiety of nucleo-
sides.2 The replacement of the oxygen in the furanose
ring by a carbon atom is of particular interest since the
resulting carbocyclic nucleosides possess greater chemical
stability against acid and metabolic stability against the
enzymes that cleave the glycosidic linkage of conventional
nucleosides.3 Much attention is being paid to the unsat-
urated derivatives such as (-)-carbovir4 and (1′R,4′S,5′S)-
(-)-9-[4′,5′-bis(hydroxymethyl)cyclopent-2′-en-1′-yl]-9H-
adenine (BCA)5 for their anti-HIV activity which is
comparable to that of AZT. The realization that the
biological activity only resides in one nucleoside enanti-
omer, and the increasing demand for new drug sub-
stances to be enantiomerically pure, have made the
design and synthesis of optically active carbocyclic nu-
cleosides important targets of study.
Resu lts a n d Discu ssion
P r ep a r a tion of Su bstr a tes. 7-tert-Butoxynorborna-
diene (1)9 is used as a starting material because it is
readily accessible. Compound 1 could be readily con-
verted to the diacetates 2a and 2b in the ratio of 5.0
(trans,trans) to 1.0 (cis,cis), via a three-step sequence: [(i)
O3/MeOH-CH2Cl2/-78 °C; (ii) NaBH4/0 °C; (iii) Ac2O/
pyridine]. These two products could be easily separated
by silica gel column chromatography. It was expected
that the less hindered olefin was attacked by ozone to
give trans,trans-diacetate 2a ,9b preferentially. Stereo-
chemistry of the products was determined by examina-
1
tion of NOESY H NMR spectra of 2a and 2b. In the
X Abstract published in Advance ACS Abstracts, September 15, 1996.
(1) Research Fellow of the J apan Society for the Promotion of
Science.
(2) (a) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745. (b)
J effries, D. Chem. Ind. 1993, 746.
(3) (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.
(b) J enkins, G. N.; Turner, N. J . Chem. Soc. Rev. 1995, 169. (c) Katagiri,
N; Kaneko, C. Tanpakushitsu Kakusan Koso 1995, 40, 1219. (d)
Wachtmeister, J .; Classon, B.; Samuelsson, B.; Kvarnstru¨m, I. Tetra-
hedron 1995, 51, 2029.
spectrum of 2a , NOEs were observed between the ace-
toxymethylene protons [δ: 4.06 (d, J ) 6.3 Hz, 4 H)] and
the methine proton-Ha [δ: 3.85 (br s, 1 H)]. However, in
the NOESY spectrum of 2b, the NOEs were not observed
between the acetoxymethylene protons [δ: 3.97 (dd, J )
7.3, 10.9 Hz, 2 H), 4.27 (dd, J ) 5.0, 10.9 Hz, 2 H)] and
(4) (a) Vince, R.; Brownell, J . Biochem. Biophys. Res. Commun. 1990,
168, 912. (b) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17. (c) Evans,
C. T.; Roberts, S. M.; Shoberu, K. A.; Sutherland, A. G. J . Chem. Soc.,
Chem. Commun. 1992, 589. (d) Handa, S.; Earlam, G. J .; Geary, P. J .;
Hawes, J . E.; Phillips, G. T.; Pryce, R. J .; Ryback, G.; Shears, J . H. J .
Chem. Soc., Chem. Commun. 1994, 1885.
(5) (a) Katagiri, N.; Toyota, A.; Shiraishi, T.; Sato, H.; Kaneko, C.
Tetrahedron Lett. 1992, 33, 3507. (b) Katagiri, N.; Nomura, M.; Sato,
H.; Kaneko, C.; Yusa, K.; Tsuruo, T. J . Med. Chem. 1992, 35, 1882.
(6) Tanaka, M.; Yoshioka, M.; Sakai, K. J . Chem. Soc., Chem.
Commun. 1992, 1454.
(7) Suemune, H.; Okano, K.; Akita, H.; Sakai, K. Chem. Pharm. Bull.
1987, 35, 1741.
(8) Tanaka, M.; Yoshioka, M.; Sakai, K. Tetrahedron: Asymmetry
1993, 4, 981.
(9) (a) Baumgarten, H. E. Org. Synth. 1973, 5, 151. (b) Cheikh, A.
B.; Craine, L. E.; Recher, S. G.; Zemlicka, J . J . Org. Chem. 1988, 53,
929.
S0022-3263(96)00823-7 CCC: $12.00 © 1996 American Chemical Society

Synthesis of Antiviral Carbocyclic Nucleosides
J . Org. Chem., Vol. 61, No. 20, 1996 6953
Sch em e 1a
Ta ble 1. En zym a tic Hyd r olysis of m eso-Su bstr a tes
a
In practice, a mixture of meso-diacetates 2a and 2b (5:1) was
used for RDL-catalyzed asymmetric hydrolysis on gram scale.
Purification by silica gel column chromatography gave the enan-
tiomerically pure monoalcohol (-)-11 in 78% yield (>99% ee). b The
specific rotations of all monoalcohols show minus signs.
a
Reagents: (i) O3; (ii) NaBH4; (iii) Ac2O/pyridine; (iv) K2CO3/
MeOH; (v) LiAlH4; (vi) MOMCl.
tert-butoxy and phenyl groups could be hydrolyzed by
RDL, or not. It was also interesting to note the position
at which the acetate could be hydrolyzed by RDL in the
case of triacetate 5.
the methine proton-Hb [δ: 4.48 (t, J ) 8.7 Hz, 1 H)].
These observations clearly indicated the stereochemistry
of 2a as trans,trans and that of 2b as cis,cis. Solvolysis
of 2a with K2CO3 in MeOH gave the diol 3 in 90% yield.
7-Acetoxy- and 7-phenylnorbornadienes (4 and 6) were
prepared from 1 via Story’s methods.10,11 These 7-sub-
stituted norbornadienes were stereoselectively converted
into the triacetate 5 and the diacetate 7 via a similar
The results of enzymatic hydrolyses using three kinds
of lipases are summarized in Table 1. The enantiomeric
excess (% ee) of the hydrolyzed products was determined
1
by H NMR spectra after conversion into the correspond-
ing Mosher’s esters [(+)-MTPA esters].13 Compound 2b
could not be hydrolyzed by these three enzymes because
the cis-oriented bulky tert-butoxy substituent hindered
the enzymes from approaching the acetyl functions.
However, hydrolysis of the other substrates by these
enzymes proceeded satisfactorily. In the cases of
Pseudomonas fluorescens lipase (PFL)-14,15 and porcine
pancreatic lipase (PPL)-catalyzed hydrolyses, the ee’s of
the alcohols obtained were low or moderate (16-87% ee),
except for that of monoalcohol (11, entry 3 and 4). Sicsic
et al.16 reported the differentiation of the acetyl groups
separated by three carbon atoms in cyclopentene moieties
was not easily achieved by the previously known hydro-
lytic enzymes. On the other hand, RDL-catalyzed hy-
drolysis of all the substrates afforded monoalcohols of
high enantiomeric excess in good yields (64-95%).
It was notable that, in entry 1, the hydrolyzed product
1
three-step sequence. In the NOESY H NMR spectra,
the NOEs were observed between the acetoxymethylene
protons [δ: 4.11 (dd, J ) 5.6, 11.0 Hz, 2 H), 4.19 (dd, J
) 6.6, 11.0 Hz, 2 H)] and the methine proton [δ: 5.00 (t,
J ) 3.0 Hz, 1 H)] in the case of 5, and also the NOEs
were observed between the acetoxymethylene protons
[δ: 4.12 (dd, J ) 6.3, 10.9 Hz, 2 H), 4.05 (dd, J ) 5.9,
10.9 Hz, 2 H)] and the methine proton [δ: 2.76 (t, J )
7.1 Hz, 1 H)] in the case of 7. For the synthesis of (-)-
BCA, the substrate 10 was also prepared from 1. Com-
pound 1 was converted to carboxylic acid 8 according to
Klumpp’s methods,12 which could be converted to 7-sub-
stituted norbornadiene 9 by the reduction of carboxylic
acid with LiAlH4 followed by protection of the alcohol
with MOMCl. Compound 9 was similarly converted into
diacetate 10. The stereochemistry of 10 was determined
as trans,trans, because the NOEs were observed between
the MOM oxymethylene protons [δ: 3.56 (d, J ) 6.6 Hz,
2 H)] and the methine protons-Hc [δ: 2.84 (dd, J ) 5.9,
1
11 was obtained in 95% yield with >99% ee.17 The H
NMR spectra of (+)-MTPA13 ester derived from (()-11
showed the methoxy proton signal at δ 3.53 (m, 1.5 H)
and 3.55 (m, 1.5 H), while the corresponding signal from
(-)-11 was observed at δ 3.53 (m, 3 H), only. In the case
of triacetate 5, the acetyl function of the secondary
alcohol at the C4-position of cyclopentene was not
hydrolyzed; however, that of the primary alcohol was
1
11.2 Hz, 2 H] in the NOESY H NMR spectrum.
En zym a tic Hyd r olysis. We previously reported the
asymmetric hydrolysis of meso-1,3-bis(acetoxymethyl)-
cyclopentane derivatives using RDL.7,8 The box-type
active site model of RDL has been proposed to explained
the enantioselectivities and the absolute configurations
of the products. According to this model, it was antici-
pated that other substrates would be converted to chiral,
enantiomerically pure monoalcohols. It was especially
interesting whether meso-substrates with the bulky
substituents at the C4-position of cyclopentene such as
(13) (a) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969,
34, 2543. (b) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95,
512.
(14) (a) Xie, Z.-F. Tetrahedron: Asymmetry 1991, 2, 733. (b) Sue-
mune, H. Yakugaku Zasshi 1992, 112, 432.
(15) Pseudomonas fluorescens lipase (PFL) has been reclassified as
P. cepacia lipase (PCL). However, we use the former name for the sake
of uniformity with previous results.
(16) Mekrami, M.; Sicsic, S. Tetrahedron: Asymmetry 1992, 3, 431.
(17) Transesterification of the corresponding diol 3 by PFL in vinyl
acetate gave the optically active monoalcohol (+)-11 in 78% yield (95%
ee).
(10) Story, P. R. J . Org. Chem. 1961, 26, 287.
(11) Story, P. R.; Fahrenholtz, S. R. J . Org. Chem. 1963, 28, 1716.
(12) Klumpp, G. W.; Stapersma, J . Tetrahedron 1981, 37, 187.

6954 J . Org. Chem., Vol. 61, No. 20, 1996
Tanaka et al.
Sch em e 2a
regioselectively hydrolyzed by RDL to afford the alcohol
of high enantiomeric purity (12, 86% yield, 95% ee). The
substrate 7 with an aromatic substituent was also
hydrolyzed into the alcohol of high enantiomeric purity
(13, 64% yield, 95% ee),18,19 and diacetate 10 was ef-
ficiently hydrolyzed into the alcohol of high enantiomeric
excess (14, 95% yield, 95% ee).
Syn th esis of (-)-Ca r bovir . The obtained optically
active alcohol 11 in entry 1 was used for the formal
synthesis of (-)-carbovir,4 which is thought to be a
therapeutic candidate for the treatment of AIDS.2 Oxi-
dation of (-)-11 with J ones reagent, followed by Curtius
rearrangement with diphenyl phosphorazidate (DPPA)
afforded the carbamate 15. The carbamate 15 could be
converted to the alcohol 16b by deprotection of the tert-
butyl function, reductive removal of the secondary alcohol
function, and solvolysis of the acetate. Hydrolysis of
carbamate and coupling of the resultant amino alcohol
to 2-amino-4,6-dichloropyrimidine furnished the Roberts
intermediate 17.4c The absolute configuration of 17 was
determined to be 1′R,4′S by the comparison with the
reported specific rotation. This means that the absolute
configuration of (-)-11 is 3R,4R,5S. Thus, the formal
synthesis of (-)-carbovir was completed.
Syn th esis of (-)-BCA. The absolute configuration of
optically active alcohol (-)-14 was expected to be un-
desirable for the synthesis of (-)-BCA by our RDL
model.8 Therefore, compound (-)-14 was converted to
alcohol 18 which showed the opposite configuration by
protection of the alcohol with MOMCl and subsequent
deprotection of the acetyl function. Oxidation of the
alcohol function with PCC and then NaClO2, followed by
Curtius rearrangement with DPPA, afforded the car-
bamate 19. After deprotection of the methoxycarbonyl
group by basic hydrolysis, the obtained amine was
subjected to reaction with 5-amino-4,6-dichloropyrimidine
to give the pyrimidinylamino derivative 20. Ring closure
by treatment with triethyl orthoformate, followed by the
substitution of chlorine with ammonia in MeOH, afforded
the MOM protected (-)-BCA (21). Acidic deprotection
of 21 afforded (-)-BCA. The spectroscopic data of the
synthetic material were identical with those reported.5
The success in synthesis of (-)-BCA reveals the stereo-
chemistry of monoalcohol 14 obtained by enzymatic
hydrolysis to be (3S,4R,5R)-configuration.
a
Reagents: (i) J ones reagent; (ii) DPPA, Et3N and then MeOH;
(iii) TiCl4; (iv) PhOCSCl; (v) Bu3SnH, AIBN; (vi) K2CO3/MeOH;
(vii) KOH; (viii) 2-amino-4,6-dichloropyrimidine; (ix) MOMCl; (x)
PCC and then NaClO2; (xi) DPPA and then MeOH; (xii) 5-amino-
4,6-dichloropyrimidine; (xiii) HC(OEt)3; (xiv) NH3; (xv) HCl/MeOH.
Exp er im en ta l Section
1H NMR spectra were determined at 270 MHz. For O3
oxidation, an Ishii ozone generator (7800 V, O2 flow rate; 0.5
mL/min) was used. Chemicals were used as received unless
otherwise noted. Et2O was distilled from Na/benzophenone
before use. Benzene and CH2Cl2 were distilled from P2O5.
Vinyl acetate (monomer) was purchased from Tokyo Kasei
Corp. PPL (Type II) was purchased from Sigma Corp., RDL
(EC 3.1.1.3) was purchased from Seikagaku Kogyo Corp.
(J apan), PFL (Amano PS) was given by courtesy of Amano
Pharmaceutical Corp. (J apan), and all were used as received.
Norbornadiene derivatives 1, 4, 6, and 8 were prepared
according to Story’s and Klumpp’s methods.9-12
Con clu sion
It has become clear that the application of RDL to
hydrolysis of meso-4-substituted-3,5-bis(acetoxymethyl)-
cyclopentenes would be efficient for the preparation of
chiral building blocks in the synthesis of carbocyclic
nucleoside derivatives. The formal synthesis of (-)-
carbovir and the total synthesis of (-)-BCA have been
attained. The optically active alcohols obtained in Table
1 might be converted into the carbocyclic nucleoside
analogs by similar routes. Further studies on the
behavior of RDL, the synthesis of carbocyclic analogs, and
anti-HIV activities of these compounds are currently
under way.
(3R,4s,5S)-4-ter t-Bu toxy-3,5-bis(a cetoxym eth yl)cyclo-
p en ten e (2a ) a n d (3R,4r ,5S)-4-ter t-Bu toxy-3,5-bis(a ce-
toxym eth yl)cyclop en ten e (2b). Ozone gas was bubbled into
a solution of 1 (5.0 g, 30.5 mmol) in MeOH (70 mL) and CH2Cl2
(40 mL) at -78 °C, and the reaction was monitored by TLC.
NaBH4 (1.2 g, 30.5 mmol) was added portionwise to the
reaction mixture at -78 °C. After 1 h, the reaction mixture
was gradually warmed to 0 °C and neutralized with concd HCl
aqueous to pH 7.0. The solution was evaporated in vacuo to
leave an oily residue, which was dissolved in pyridine (50 mL)
and Ac2O (20 mL), and the whole was stirred overnight. The
reaction mixture was diluted with 5% aqueous HCl and
extracted with EtOAc. The EtOAc extract was successively
washed with 5% aqueous NaHCO3 and brine then dried.
Removal of the solvent in vacuo gave an oily residue, which
was purified by column chromatography on silica gel. The
fraction eluted with 5% EtOAc in hexane afforded 2a (4.3 g,
50%) as a colorless oil, and the fraction eluted with 10% EtOAc
in hexane afforded 2b (0.9 g, 10%) as a colorless oil. 2a : IR
(18) (a) Monoalcohol (-)-13 was converted into 2-phenylcyclopen-
tane-1-methanol by hydrogenation (Pd-C, H2), oxidation (PCC), de-
carbonylation [RhCl(Ph3)3], and solvolysis (K2CO3/MeOH). By the
comparison of specific rotation of the synthetic sample; [R]33D -42.1 (c
0.45, MeOH) to the reported value;19 [R]23 -48.9 (c 1.20, MeOH), the
D
absolute configuration of (-)-13 was determined to be 3S,4R,5R.
(19) Fang, C.-L.; Suemune, H.; Sakai, K. J . Org. Chem. 1992, 57,
4300.
(neat) 1740 cm-1
) 6.3 Hz, 4 H), 3.85 (br s, 1 H), 2.89 (t, J ) 6.3 Hz, 2 H), 2.06
.
1H NMR (CDCl3) δ 5.69 (s, 2 H), 4.06 (d, J

Synthesis of Antiviral Carbocyclic Nucleosides
J . Org. Chem., Vol. 61, No. 20, 1996 6955
(s, 6 H), 1.23 (s, 9 H); 13C NMR (68 MHz, CDCl3) δ 170.9, 131.3,
75.6, 74.3, 65.3, 55.3, 28.7, 20.8; EIMS m/ z 284 (M+, 8), 229
(51), 228 (100), 224 (31), 211 (85); FAB(+)HRMS calcd for
C15H25O5 (M+ + H) 285.1702, found 285.1708.
monitored by TLC. When a spot of the diol appeared on TLC,
hydrolysis was terminated by extracting the mixture with
EtOAc. The EtOAc extract was dried over MgSO4 and then
concentrated in vacuo to leave an oily residue, which was
purified by column chromatography on silica gel.
1
2b: IR (neat) 1740 cm-1; H NMR (CDCl3) δ 5.79 (s, 2 H),
4.48 (t, J ) 8.7 Hz, 1 H), 4.27 (dd, J ) 5.0, 10.9 Hz, 2 H), 3.97
(dd, J ) 7.3, 10.9 Hz, 2 H), 2.87 (m, 2, H), 2.05 (s, 6 H), 1.19
(s, 9 H); 13C NMR (68 MHz, CDCl3) δ 171.0, 132.2, 73.9, 71.7,
(3R,4R,5S)-(-)-5-(Acetoxym eth yl)-4-ter t-bu toxy-3-(h y-
d r oxym eth yl)cyclop en ten e (11): colorless oil; [R]25 -25.2
D
(c 1.40, CHCl3); IR (neat) 3425, 1740 cm-1; 1H NMR (CDCl3) δ
5.71 (br s, 2 H), 4.09 (d, J ) 6.6 Hz, 2 H), 3.94 (br s, 1 H), 3.67
(m, 2 H), 2.90 (m, 1 H), 2.80 (m, 1 H), 2.06 (s, 3 H), 1.55 (br 1
H), 1.23 (s, 9 H). EIMS m/ z 242 (M+, 0.8), 227 (1), 224 (1),
186 (62), 182 (48), 169 (100); FAB(+)HRMS calcd for C13H23O4
(M+ + H) 243.1596, found 243.1602.
64.9, 47.4, 27.8, 21.1; FAB(+)HRMS calcd for C15H25O5 (M+
H) 285.1702, found 285.1704.
+
(3R,4s,5S)-4-ter t-Bu toxy-3,5-bis(h yd r oxym eth yl)cyclo-
p en ten e (3). A mixture of 2a (3.5 g, 12.3 mmol) and K2CO3
(1.7 g, 12.3 mmol) in MeOH (180 mL) was stirred at 0 °C for
8 h. The mixture was neutralized with 5% aqueous HCl,
extracted with EtOAc, and dried over MgSO4. Removal of the
solvent in vacuo gave an oily residue, which was purified by
column chromatography on silica gel. The fraction eluted with
50% EtOAc in hexane afforded 3 (2.4 g, 90%) as colorless
Tr a n sester ifica tion of 3. A suspension of diol 3 (500 mg,
2.50 mmol) and PFL (50 mg) in vinyl acetate (10 mL) was
stirred at room temperature for 72 h. PFL was removed by
the filtration, and the filtrate was concentrated in vacuo to
leave an oily residue, which was purified by column chroma-
tography on silica gel. The fraction eluted with 20% EtOAc
in hexane afforded (+)-11 (473 mg, 78%) as a colorless oil:
crystals: mp 97-99 °C (from hexane); IR (Nujol) 3320 cm-1
;
1H NMR (CDCl3) δ 5.70 (s, 2 H), 4.05 (br s, 1 H), 3.82 (dd, J )
3.9, 10.9 Hz, 2 H), 3.77 (dd, J ) 4.2, 10.9 Hz, 2 H), 3.25 (br, 2
H), 2.74 (m, 1 H), 1.23 (s, 9 H); 13C NMR (25 MHz, CDCl3) δ
132.0, 76.2, 73.8, 63.5, 58.2, 29.1; EIMS m/ z 201 (M+ + H, 1),
200 (M+, 2), 182 (19), 152 (61), 127 (100); FAB(+)HRMS calcd
for C11H21O3 (M+ + H) 201.1491, found 201.1487. Anal. Calcd
for C11H20O3: C, 65.97; H, 10.07. Found: C, 66.00; H, 10.03.
(3R,4s,5S)-4-Acetoxy-3,5-bis(a cetoxym eth yl)cyclop en -
ten e (5). 5 was prepared from compound 4 in a similar
manner to that described for the preparation of 2. Colorless
oil; IR (neat) 1740 cm-1; 1H NMR (CDCl3) δ 5.70 (s, 2 H), 5.00
(t, J ) 3.0 Hz, 1 H), 4.19 (dd, J ) 6.6, 11.0 Hz, 2 H), 4.11 (dd,
J ) 5.6, 11.0 Hz, 2 H), 3.01 (m, 2 H), 2.07 (s, 9 H); 13C NMR
(25 MHz, CDCl3) δ 170.8, 170.5, 130.9, 78.2, 64.7, 52.5, 21.1,
20.8; EIMS m/ z 271 (M+ + H, 3), 227 (1), 211 (4), 167 (9), 108
(100); FAB(+)HRMS calcd for C13H19O6 (M+ + H) 271.1182,
found 271.1177.
[R]22 +22.0 (c 1.21, CHCl3).
D
MTP A Ester of 11. The 270 MHz 1H NMR spectrum of
(+)-MTPA ester derived from the monoacetate (()-11 showed
the methoxy proton signals at δ 3.53 (m, 1.5 H) and 3.55 (m,
1.5 H), while the corresponding signal from (-)-11 was
observed at δ 3.53 (m, 3 H), and the corresponding signal from
(+)-11 was observed at δ 3.55 (m, 3 H), only.
(3R ,4R ,5S )-(-)-4-Ace t oxy-5-(a ce t oxym e t h yl)-3-(h y-
d r oxym eth yl)cyclop en ten e (12): colorless oil; [R]23D -88.14
(c 1.62, CHCl3); IR (neat) 3450, 1725 cm-1; 1H NMR (CDCl3) δ
5.68 (br s, 2 H) 4.97 (t, J ) 3.0 Hz, 1 H), 4.16 (dd, J ) 6.3,
11.0 Hz, 1 H), 4.10 (dd, J ) 5.6, 11.0 Hz, 1 H), 3.73 (dd, J )
4.3, 11.0 Hz, 1 H), 3.56 (dd, J ) 7.6, 11.0 Hz, 1 H), 3.10 (m, 1
H), 2.88 (m, 1 H), 2.70 (br, 1 H), 2.09 (s, 3 H), 2.06 (s, 3 H); 13
C
NMR (25 MHz, CDCl3) δ 171.8, 170.9, 131.4, 130.4, 79.3, 65.0,
64.1, 56.6, 52.4, 21.2, 20.8; EIMS m/ z 229 (M+ + H, 2), 211
(1), 169 (5), 155 (3), 138 (100); FAB(+)HRMS calcd for C11H17O5
(M+ + H) 229.1076, found 229.1073.
(3R,4r ,5S)-4-P h en yl-3,5-b is(a cet oxym et h yl)cyclop en -
ten e (7). Compound 7 was prepared from compound 6 in a
similar manner to that described for the preparation of 2.
MTP A Ester of 12. The 270 MHz 1H NMR spectrum of
(+)-MTPA ester derived from the monoacetate (()-12 showed
the methylene signals at δ 4.53 (dd, J ) 5.9, 10.9 Hz, 0.5 H),
4.43 (dd, J ) 6.3, 10.9 Hz, 0.5 H), 4.36 (dd, J ) 6.6, 10.9 Hz,
0.5 H), and 4.29 (dd, J ) 6.3, 10.9 Hz, 0.5 H), while the
corresponding signals from (-)-11 were observed at δ 4.43 (dd,
J ) 6.3, 10.9 Hz, 1 H) and 4.36 (dd, J ) 6.6, 10.9 Hz, 1 H),
only.
1
Colorless oil; IR (neat) 1740, 1600 cm-1; H NMR (CDCl3) δ
7.18-7.34 (m, 5 H), 5.78 (s, 2 H), 4.12 (dd, J ) 6.3, 10.9 Hz, 2
H), 4.05 (dd, J ) 5.9, 10.9 Hz, 2 H), 3.14 (m, 2 H), 2.76 (t, J )
7.1 Hz, 1 H), 1.95 (s, 6 H); 13C NMR (25 MHz, CDCl3) δ 170.9,
144.3, 131.9, 128.6, 127.6, 126.5, 66.5, 54.4, 51.2, 20.7; EIMS
m/ z 288 (M+, 3), 228 (2), 168 (100); FAB(+)HRMS calcd for
C17H21O4 (M+ + H) 289.1440, found 289.1446.
7-[(Meth oxym eth oxy)m eth yl]n or bor n a d ien e (9). A so-
lution of carboxylic acid 8 (1.95 g, 14.3 mmol) in Et2O (15 mL)
was added to the stirred suspension of LiAlH4 (550 mg, 14.5
mmol) in Et2O (150 mL) at 0 °C. After being stirred at room
temperature for 5 h, the reaction was quenched with wet Et2O
followed by filtered through Celite. The evaporation of filtrate
afforded the crude 7-(hydroxymethyl)norbornadiene as a color-
less oil, and this was used to the next step without purification.
MOMCl (1.42 mL, 18.6 mmol) was added dropwise to the
stirred mixture of above oily residue and diisopropylethyl-
amine (2.40 g, 18.6 mmol) in CH2Cl2 (60 mL) at 0 °C. After
being stirred overnight at room temperature, the reaction was
quenched with H2O, extracted with Et2O, and dried over
MgSO4. Removal of the solvent afforded 7-substituted nor-
bornadiene 9 (2.00 g, 84%) as a colorless oil: 1H NMR (CDCl3)
δ 6.85 (m, 2 H), 6.61 (m, 2 H), 4.54 (s, 2 H), 3.42 (d, J ) 7.1
Hz, 2 H), 3.40 (m, 2 H), 3.32 (s, 3 H), 2.78 (t, J ) 7.1 Hz, 1 H).
(3R,4r ,5S)-4-[(Met h oxym et h oxy)m et h yl]-3,5-b is(a ce-
toxym eth yl)cyclop en ten e (10). Compound 10 was prepared
from compound 9 in a similar manner to that described for
(3S,4R,5R)-(-)-5-(Acetoxym eth yl)-3-(h yd r oxym eth yl)-
4-p h en ylcyclop en ten e (13). colorless oil; [R]29 -28.25 (c
D
1.04, CHCl3); IR (neat) 3450, 1740 cm-1; H NMR (CDCl3) δ
1
7.18-7.34 (m, 5 H), 5.82 (m, 2 H), 4.13 (dd, J ) 6.3, 10.8 Hz,
1 H), 4.08 (dd, J ) 5.9, 10.8 Hz, 1 H), 3.70 (m, 1 H), 3.59 (m,
1 H), 3.15 (m, 1 H), 3.03 (m, 1 H), 2.84 (t, J ) 6.9 Hz, 1 H),
1.95 (s, 3 H), 1.34 (br, 1 H); 13C NMR (25 MHz, CDCl3) δ 171.1,
145.1, 132.6, 132.1, 128.6, 127.7, 126.4, 66.9, 65.0, 58.0, 54.5,
50.2, 20.7; EIMS m/ z 246 (M+, 2), 228 (1), 216 (3), 187 (15),
186 (100); FAB(+)HRMS calcd for C15H19O3 (M+ + H) 247.1334,
found 247.1344.
MTP A Ester of 13. The 270 MHz 1H NMR spectrum of
(+)-MTPA ester derived from the monoacetate (()-13 showed
the acetyl proton signals at δ 1.92 (s, 1.5 H) and 1.90 (s, 1.5
H), while the corresponding signal from (-)-13 was observed
at δ 1.90 (s, 3 H), only.
(3S,4R,5R)-5-(Acet oxym et h yl)-3-(h yd r oxym et h yl)-4-
[(m eth oxym eth oxy)m eth yl]cyclop en ten e (14): colorless
oil; [R]24 -52.11 (c 1.04, CHCl3); IR (neat) 3450, 1735 cm-1
;
D
1H NMR (CDCl3) δ 5.65 (m, 2 H), 4.67 (br s, 2 H), 4.12 (dd, J
) 6.6, 11.0 Hz, 1 H), 4.06 (dd, J ) 6.3, 11.0 Hz, 1 H), 3.70 (m,
2 H), 3.45 (m, 2 H), 3.39 (s, 3 H), 2.78 (m, 2 H), 2.62 (m, 1 H),
2.07 (s, 3 H), 2.02 (m, 1 H). FDMS m/ z 245 (M+ + H, 29),
214 (100); FAB(+)HRMS calcd for C12H21O5 (M+ + H) 245.1389,
found 245.1399.
the preparation of 2. Colorless oil; IR (neat) 1740 cm-1 1H
;
NMR (CDCl3) δ 5.68 (s, 2 H), 4.63 (s, 2 H), 4.12 (dd, J ) 6.3,
10.6 Hz, 2 H), 4.03 (dd, J ) 5.9, 10.6 Hz, 2 H), 3.56 (d, J ) 6.6
Hz, 2 H), 3.37 (s, 3 H), 2.84 (dd, J ) 5.9, 11.2 Hz, 2 H), 2.06 (s,
6 H), 2.02 (m, 1 H); FAB(+)HRMS calcd for C14H23O6 (M+
H) 287.1495, found 287.1498.
+
MTP A Ester of 14. 270 MHz 1H NMR spectrum of (+)-
MTPA ester derived from the monoacetate (()-14 showed the
methyl proton signals at δ 3.333 (s, 1.5 H) and 3.328 (s, 1.5
H), while the corresponding signals from (-)-14 was observed
at δ 3.328 (s, 3 H), only.
En zym a tic Hyd r olysis of Meso Com p ou n d s. Gen er a l
Meth od s. A suspension of substrate (100 mg) and enzyme
(10 mg) in acetone (0.1 mL) and 0.1 M phosphate buffer (10
mL, pH 7.0) was stirred at 30 °C, and the reaction was

6956 J . Org. Chem., Vol. 61, No. 20, 1996
Tanaka et al.
(3S,4S,5S)-5-(Acet oxym et h yl)-4-ter t-b u t oxy-3-[(m et h -
oxyca r bon yl)a m in o]cyclop en ten e (15). J ones reagent was
added dropwise to the stirred solution of monoacetate 11 (1.60
g, 6.61 mmol) in acetone (20 mL) at 0 °C until the reaction
mixture show red-purple color. After being stirred for 1 h, the
reaction mixture was diluted with brine, extracted with EtOAc,
and dried over MgSO4. Removal of the solvent afforded the
crude carboxylic acid, which was used to the next reaction
without purification. Diphenyl phosphorazidate (DPPA, 1.42
mL, 6.61 mmol) and Et3N (0.92 mL, 6.61 mmol) in benzene
(10 mL) were added to the stirred solution of above acid in
benzene (10 mL). The reaction mixture was refluxed for 3 h,
MeOH (0.50 mL) was added, and the mixture was refluxed
for 9 h. After removal of the solvent, the residue was diluted
with EtOAc and washed with 5% aqueous HCl, water, 5%
aqueous NaHCO3, and brine, successively. Organic layer was
dried over MgSO4. Removal of the solvent afforded the oily
residue, which was purified by column chromatography on
silica gel (20% EtOAc in hexane) to give 15 (941 mg, 50%) as
the solution was refluxed for 24 h. After removal of the
solvent, the residue was diluted with H2O, extracted with
EtOAc and dried over MgSO4. After removal of the solvent,
the residue, 2-amino-4,6-dichloropyrimidine (125 mg, 0.76
mmol), and diisopropylethylamine (0.6 mL) in n-BuOH (3 mL)
were refluxed for 14 h. The mixture was diluted with H2O,
extracted with CH2Cl2, and dried over MgSO4. After removal
of the solvent, the residue was purified by column chroma-
tography on silica gel (10% MeOH in CHCl3) to give 17 (42
mg , 45%) as white foam: mp 48-51 °C (lit.4c 49-53 °C); [R]22
D
-29.2 (c 0.50, MeOH), [lit.4c [R]24 -35 (c 1, MeOH)]; IR
D
(CHCl3) 3450, 1590, 1110 cm-1; H NMR (CDCl3) δ 5.85 (s, 2
1
H), 5.78 (s, 1 H), 5.23 (br, 1 H), 4.93 (br s, 2 H), 4.85 (br, 1 H),
3.69 (dd, J ) 3.9, 10.5 Hz, 1 H), 3.61 (dd, J ) 4.4, 10.5 Hz, 1
H), 2.90 (m, 1 H), 2.53 (dt, J ) 8.5, 13.7 Hz, 1 H), 1.85 (br 1
H), 1.50 (dt, J ) 3.9, 13.7 Hz, 1 H); FAB(+)HRMS calcd for
C10H14N4O1Cl1 (M+ + H) 241.0856, found 241.0851.
(3R ,4S ,5S )-3-(H y d r o x y m e t h y l)-4,5-b is [(m e t h o x y -
m eth oxy)m eth yl]cyclop en ten e (18). MOMCl (0.17 mL, 2.2
mmol) was added to a stirred solution of monoacetate 14 (414
mg, 1.70 mmol) and diisopropylethylamine (285 mg, 2.2 mmol)
in CH2Cl2 (30 mL) at 0 °C, and the mixture was stirred
overnight. The reaction was quenched with H2O, extracted
with EtOAc, and dried over MgSO4. Removal of the solvent
in vacuo gave an oily residue. A mixture of this residue and
K2CO3 (225 mg, 1.63 mmol) in MeOH (10 mL) was stirred at
room temperature for 2 h. K2CO3 was filtered off, and the
filtrate was concentrated in vacuo to leave an oily residue,
which was purified by column chromatography on silica gel
a colorless oil: [R]22 -34.5 (c 2.70, CHCl3); IR (neat) 3340,
D
1
1720 (br) cm-1; H NMR (CDCl3) δ 5.75 (m, 2 H), 4.70 (m, 1
H), 4.56 (m, 1 H), 4.12 (dd, J ) 5.3, 11.2 Hz, 1 H), 4.08 (dd, J
) 5.0, 11.2 Hz, 1 H), 3.78 (br s, 1 H), 3.67 (br s, 3 H), 2.81 (br,
1 H), 2.08 (s, 3 H), 1.23 (s, 9 H); FAB(+)HRMS calcd for
C20H28N1O5 (M+ + H) 286.1654, found 286.1649.
(3R,5S)-5-(Acetoxym eth yl)-3-[(m eth oxyca r bon yl)a m i-
n o]cyclop en ten e (16a ). TiCl4 (0.11 mL, 1.0 mmol) was
added dropwise to the stirred solution of 15 (273 mg, 0.96
mmol) in CH2Cl2 (25 mL) at 0 °C. After being stirred for 30
min at 0 °C, the reaction was quenched with 5% aqueous
NaHCO3 and extracted with EtOAc. The organic layer was
washed with brine and dried over MgSO4. Removal of the
solvent afforded the crude alcohol as a colorless oil. Phenyl
chlorothionoformate (0.14 mL, 1.0 mmol) was added to the
solution of the above crude alcohol and DMAP (3 mg) in
pyridine (1 mL) and acetonitrile (2 mL) at 0 °C. After being
stirred for 12 h, the reaction was quenched with 5% aqueous
HCl and extracted with EtOAc. The organic layer was washed
with 5% aqueous NaHCO3 and brine and dried over MgSO4.
Removal of the organic solvent gave crude thiocarbonate ester.
n-Bu3SnH (0.40 mL, 1.5 mmol) was added dropwise to the
refluxing mixture of AIBN (16 mg, 0.10 mmol) and the above
thiocarbonate ester in benzene (17 mL). After being refluxed
for 8 h, KF (88 mg, 1.5 mmol) was added, and the mixture
was stirred for 30 min at room temperature. The mixture was
washed with brine and dried over MgSO4. After removal of
the solvent, the residue was purified by column chromatog-
raphy on silica gel (25% EtOAc in hexane) to give 16a (188
to give 18 (354 mg, 85%) as a colorless oil; [R]22 + 50.15 (c
D
1.30, CHCl3); ΙR (neat) 3450 cm-1; 1H NMR (CDCl3) δ 5.71 (m,
1 H), 5.61 (m, 1 H), 4.67 (s, 2 H), 4.63 (s, 2 H), 3.75 (m, 2 H),
3.40-3.60 (m, 4 H), 3.38 (s, 3 H), 3.36 (s, 3 H), 2.93 (m, 1 H),
2.78 (m, 1 H), 2.68 (m, 1 H), 2.07 (m, 1 H); FDMS m/ z 247
(M+ + H, 42), 216 (100); FAB(+)HRMS calcd for C12H23O5 (M+
+ H) 247.1545, found 247.1552.
(3R,4S,5S)-4,5-Bis[(m eth oxym eth oxy)m eth yl]-3-[(m eth -
oxyca r bon yl)a m in o]cyclop en ten e (19). PCC (400 mg, 2.32
mmol) was added to a stirred solution of 18 (315 mg, 1.28
mmol) in CH2Cl2 (10 mL). After being stirred for 5 h, the
mixture was diluted with Et2O, and then black solid was
filtered off using a florisil short column. After evaporation of
Et2O, the residue, 2-methyl-2-butene (500 mg), and NaH2PO4
(200 mg) were dissolved in H2O (3 mL) and t-BuOH (11 mL).
NaClO2 (500 mg, 85%, 4.70 mmol) was added to this stirred
solution at 0 °C. After being stirred for 1 h, 1 N aqueous HCl
was added to the solution to acidify the reaction mixture to
pH 5-7 at 0 °C. The mixture was extracted with CH2Cl2 and
organic layer was dried over Na2SO4. After removal of the
solvent, the residue was dissolved in benzene (7 mL), and a
solution of DPPA (400 mg, 1.45 mmol) and Et3N (160 mg, 1.58
mmol) in benzene (2 mL) was added. The mixture was
refluxed for 1 h, MeOH (10 mL) was added, and the solution
was refluxed for 3 days. The solvent was removed in vacuo,
and the residue was diluted with EtOAc. The organic layer
was washed with 5% aqueous HCl, water, 5% aqueous
NaHCO3, and brine, successively. Organic layer was dried
over MgSO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel (30% EtOAc
mg, 92%) as a colorless oil; [R]17 -41.9 (c 1.47, CHCl3); IR
D
(neat) 3350, 1720 (br) cm-1; 1H NMR (CDCl3) δ 5.79 (m, 2 H),
4.77 (br s, 2 H), 4.08 (dd, J ) 5.9, 10.9 Hz, 1 H), 3.99 (dd, J )
5.6, 10.9 Hz, 1 H), 3.67 (br s, 3 H), 2.94 (m, 1 H), 2.56 (m, 1
H), 2.07 (s, 3 H), 1.30 (m, 1 H); FAB(+)HRMS calcd for
C10H16N1O4 (M+ + H) 214.1079, found 214.1073.
(3R,5S)-5-(Hyd r oxym eth yl)-3-[(m eth oxyca r bon yl)a m i-
n o]cyclop en ten e (16b). A mixture of 16a (124 mg, 0.58
mmol) and K2CO3 (50 mg, 0.36 mmol) in MeOH (4 mL) was
stirred at 0 °C for 5 h. After removal of methanol, the residue
was diluted with brine, neutralized with 10% aqueous HCl,
and extracted with EtOAc. Removal of the solvent in vacuo
gave an oily residue, which was purified by column chroma-
tography on silica gel. The fraction eluted with 20% EtOAc
in hexane afforded 16b (85 mg, 85%) as colorless crystals: mp
in hexane) to give 19 (179 mg , 48%) as a colorless oil: [R]22
D
+13.59 (c 1.30, CHCl3); ΙR (neat) 3350, 1720 cm-1; H NMR
1
(CDCl3) δ 5.78 (m, 1 H), 5.72 (m, 1 H), 5.02 (br, 1 H), 4.65 (s,
2 H), 4.63 (s, 2 H), 4.58 (m, 1 H), 3.66 (s, 3 H), 3.50-3.65 (m,
4 H), 3.38 (s, 3 H), 3.35 (s, 3 H), 2.73 (br, 1 H), 2.00 (m, 1 H);
FAB(+)HRMS calcd for C13H24N1O6 (M+ + H) 290.1603, found
290.1598.
(1′R,4′S,5′R)-5-Am in o-4-[[4′,5′-b is[(m et h oxym et h oxy)-
m e t h yl]cyclop e n t -2′-e n -1′-yl]a m in o]-6-ch lor op yr im i-
d in e (20). KOH (2.5 g, 44.6 mmol) in H2O (15 mL) was added
to a stirred solution of carbamate 19 (144 mg, 0.50 mmol) in
MeOH (10 mL), and the solution was refluxed for 12 h. After
removal of the solvent, the residue was diluted with H2O,
extracted with EtOAc, and dried over MgSO4. After removal
of the solvent, the residue was dissolved in n-BuOH (6 mL).
5-Amino-4,6-dichloropyrimidine (85 mg, 0.52 mmol) and Et3N
(1 mL, 7.2 mmol) were added to this solution. The mixture
80-82 °C; [R]22 -17.2 (c 1.04, MeOH); ΙR (KBr) 3450, 3250,
D
1
1700 cm-1; H NMR (CDCl3) δ 5.80 (m, 2 H), 5.11 (br, 1 H),
4.73 (br, 1 H), 3.66 (br s, 3 H), 3.59 (m, 2 H), 2.83 (m, 1 H),
2.49 (dt, J ) 8.5, 13.9 Hz, 1 H), 1.76 (br s, 1 H), 1.43 (dt, J )
4.2, 13.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 156.3, 134.2,
133.7, 64.7, 56.3, 51.9, 46.8, 34.5; FAB(+)HRMS calcd for
C8H14N1O3 (M+ + H) 172.0974, found 172.1004. Anal. Calcd
for C8H13N1O3: C, 56.13; H, 7.65; N, 8.18. Found: C, 56.13;
H, 7.71; N, 7.91.
(1′R,4′S)-2-Am in o-4-[(4′-(h yd r oxym eth yl)cyclop en t-2′-
en -1′-yl)a m in o]-6-ch lor op yr im id in e (17). KOH (50 mg, 0.9
mmol) in H2O (1 mL) was added to a stirred solution of
carbamate 16b (65 mg, 0.38 mmol) in MeOH (0.5 mL), and

Synthesis of Antiviral Carbocyclic Nucleosides
J . Org. Chem., Vol. 61, No. 20, 1996 6957
was refluxed for 2 days, solvent was evaporated, and the
residue was purified by column chromatography on silica gel
(70% EtOAc in hexane) to give 20 (102 mg , 57%) as a colorless
oil: [R]28D -84.12 (c 0.91, CHCl3); IR (neat) 3350 cm-1; 1H NMR
(CDCl3) δ 8.05 (s, 1 H), 5.83 (m, 2 H), 5.49 (br d, J ) 8.6 Hz,
1 H), 5.05 (br d, J ) 8.6 Hz, 1 H), 4.68 (s, 2 H), 4.65 (s, 2 H),
3.55-3.75 (m, 4 H), 3.42 (br s, 2 H), 3.37 (s, 3 H), 3.36 (s, 3 H),
2.78 (br, 1 H), 2.17 (m, 1 H); FAB(+)HRMS calcd for
C15H24O4N4Cl1 (M+ + H) 359.1486, found 359.1483.
purified by ion-exchange resin (0.1 N NH3/H2O) and recrystal-
lized from MeOH to give (-)-BCA (11 mg, 95%) as colorless
crystals: mp 207-209 °C dec; [R]28 -24.0 (c 0.20, MeOH),
D
lit.5a [R]20 -29.0 (c 0.3, MeOH); IR (KBr) 3450, 3350, 3120
D
(br), 1680, 1660, 1610, 1570, 1450 (br) cm-1; 1H NMR (DMSO-
d6) δ 8.13 (s, 1 H), 8.06 (s, 1 H), 7.21 (br s, 2 H), 6.06 (m, 1 H),
5.78 (m, 1 H), 5.42 (m, 1 H), 4.84 (br s, 1 H), 3.60 (d, J ) 5.9
Hz, 2 H), 3.57 (dd, J ) 5.3, 10.7 Hz, 1 H), 3.51 (dd, J ) 5.6,
10.7 Hz, 1 H), 2.71 (m, 1 H), 2.22 (dddd, J ) 5.6, 5.6, 5.6 and
5.6, 1 H); 13C NMR (125 MHz, DMSO-d6) δ 155.9, 152.1, 149.3,
139.1, 137.4, 129.0, 119.0, 63.6, 62.31, 62.27, 51.3, 50.8;
FAB(+)HRMS calcd for C12H16N5O2 (M+ + H) 262.1304, found
262.1309.
MOM P r otected BCA (21). Concentrated HCl (0.5 mL)
was added to a solution of amine 20 (30 mg, 0.084 mmol) in
triethyl orthoformate (1 mL) at 0 °C. After being stirred at
room temperature for 24 h, solid NaHCO3 (50 mg) was added
to the reaction mixture. After removal of the solvent, the
residue was dissolved in MeOH (freshly distilled, 4 mL) and
cooled to -20 °C. This solution in sealed tube was bubbled
with NH3 gas for 10 min, and the whole was warmed to 45 °C
in sealed tube. After being stirred at 45-50 °C in sealed tube
for 2 days, the reaction mixture was evaporated and the
residue was purified by column chromatography on silica gel
(from 50% EtOAc in hexane to 10% MeOH in EtOAc) to give
Ack n ow led gm en t. This work was partly supported
by the Yamanouchi Pharmaceutical Co. Award in
Synthetic Organic Chemistry, J apan. We thank Amano
Pharmaceutical Co., Ltd., for kindly providing lipases.
We also wish to thank Dr. Ryuichi Isobe, Mr. Yoshitsugu
Tanaka, and Ms. Yasuko Soeda for the measurement
of MS and NMR spectra.
the 21 (21.6 mg, 74%) as a colorless oil: [R]25 -1.85 (c 0.70,
D
CHCl3); IR (neat) 3350 cm-1; 1H NMR (CDCl3) δ 8.34 (s, 1 H),
7.97 (s, 1 H), 6.13 (m, 1 H), 5.98 (br s, 2 H), 5.82 (m, 1 H), 5.64
(m, 1 H), 4.66 (s, 2 H), 4.65 (s, 2 H), 3.78 (d, J ) 5.6 Hz, 2 H),
3.73 (dd, J ) 4.9, 9.6 Hz, 1 H), 3.63 (dd, J ) 5.3, 9.6 Hz, 1 H),
3.38 (s, 3 H), 3.34 (s, 3 H), 2.97 (m, 1 H), 2.41 (dddd, J ) 5.6,
5.6, 5.6 and 5.6 Hz, 1 H); 13C NMR (68 MHz, CDCl3) δ 155.5,
152.9, 150.0, 139.3, 137.8, 129.2, 119.6, 96.7, 96.6, 69.4, 68.6,
62.3, 55.4, 55.3, 50.2, 48.8; FAB(+)HRMS calcd for C16H24N5O4
(M+ + H) 350.1828, found 350.1805.
(-)-BCA. Concentrated HCl (0.25 mL) was added dropwise
to the solution of MOM protected (-)-BCA (16 mg, 0.046 mmol)
in MeOH (3 mL) at 0 °C. After being stirred overnight at room
temperature, the solution was evaporated and the residue was
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR spectra of all new compounds, partial H NMR spectra
1
of MTPA esters for the determination of ee, 13C NMR spectra
of compounds 2a , 2b, 3, 5, 7, 12, 13, 16b, 21, and (-)-BCA,
and a synthetic scheme for the determination of absolute
configuration of monoalcohol 13 (35 pages). This material is
contained in libraries 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 O9608230