Highly efficient and enantioselective synthesis of carbocyclic nucleoside analogs using selective early transition metal catalysis

Full text of DOI:10.1021/jo961241l

J . Org. Chem. 1996, 61, 7963-7966
7963
High ly Efficien t a n d En a n tioselective
Syn th esis of Ca r bocyclic Nu cleosid e
An a logs Usin g Selective Ea r ly Tr a n sition
Meta l Ca ta lysis
Luis E. Mart´ınez,1 William A. Nugent,*,2 and
Eric N. J acobsen*,1
Harvard University, Department of Chemistry and
Chemical Biology, Cambridge, Massachusetts 02138, and
DuPont Central Research & Development,
Wilmington, Delaware 19880
F igu r e 1.
Received J uly 2, 1996
The development of synthetic routes to carbocyclic
nucleoside analogs has attracted considerable attention,
due partly to the interesting biological activity of these
compounds and also to the persistent challenges associ-
ated with constructing substituted 5-membered car-
bocycles with defined relative and absolute stereochem-
istry.3 Particularly noteworthy members of this class of
compounds include the naturally-occurring carbocyclic
adenosine analog (-)-aristeromycin (1), the biosynthesis4
and biological activity5 of which have been subject to
recent intensive scrutiny; the related natural product (-)-
3′-deoxyaristeromycin (2);6 (-)-carbovir (3), a selective
inhibitor of HIV reverse transcriptase in vitro;7 and the
structurally related (-)-1592U89 succinate (4), which has
been reported to have a higher oral bioavailability than
carbovir and is currently in clinical trials for the treat-
ment of HIV infection (Figure 1).8
F igu r e 2.
F igu r e 3.
generated in situ by the combination of WOCl4 and 2,6-
dibromophenol, is a useful and inexpensive catalyst for
the ring-closing metathesis (RCM) of acyclic dienes to
afford 5- and 6-membered cyclic compounds.9 The (sa-
len)Cr complex 6 has been identified as a catalyst for the
asymmetric ring-opening (ARO) of meso and racemic
epoxides by TMSN3,10 with particularly high enantio-
selectivity displayed for the opening of epoxides fused to
5-membered rings. The sequential application of these
two catalytic transformations, along with an intermedi-
ary epoxidation reaction, could constitute an efficient
method for the conversion of simple dienes to cyclic 1,2-
amino alcohols wherein a new C-C bond has been
constructed and two contiguous stereogenic centers have
been established with high relative and absolute control
(Figure 3). In this paper, the power of this strategy is
illustrated in the efficient synthesis of key intermediates
leading to the carbocylic nucleoside analog structures
outlined in Figure 1.
The key intermediate epoxide 10 needed for this
synthetic approach was obtained in four steps from
commercially available diethyl diallylmalonate (Scheme
1). Decarboxylation followed by RCM with catalyst 5
under previously reported conditions9 produced the 3-cy-
clopentenecarboxylic ester 8 in 61% overall yield after
distillation. Epoxidation of 8 was effected with m-
chloroperoxybenzoic acid (m-CPBA), providing a 3:1
mixture of anti- and syn-isomers.11 The pure anti-
epoxide 9 was isolated in 70% yield after chromatogra-
Our two groups recently uncovered effective catalysts
for the highly selective synthesis and manipulation of
5-membered cyclic structures (Figure 2). Complex 5,
(1) Harvard University.
(2) DuPont Central Research & Development.
(3) For recent reviews, see: (a) Borthwick, A. D.; Biggadike, K.
Tetrahedron 1992, 48, 571. (b) Huryn, D. M.; Okabe, M. Chem. Rev.
1992, 92, 1745. Asymmetric synthesis: (c) Trost, B. M.; Stenkamp,
D.; Pulley, S. R. Chem. Eur. J . 1995, 1, 568. (d) Campbell J . A.; Lee,
W. K.; Rapoport, H. J . Org. Chem. 1995, 60, 4602. (e) Park, K. H.;
Rapoport, H. J . Org. Chem. 1994, 59, 394. (f) Csuk, R.; Do¨rr, P.
Tetrahedron 1995, 51, 5789. (g) 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., Perkin Trans. 1 1994, 1885. (h) Nokami, J .; Matsuura,
H.; Nakasima, K.; Shibata, S. Chem. Lett. 1994, 1071.
(4) (a) J enkins, G. N. Chem. Soc. Rev. 1995, 169. (b) Hill, J . M.;
J enkins, G. N.; Rush, C. P.; Turner, N. J .; Willetts, A. J .; Buss, A. D.;
Dawson, M. J .; Rudd, B. A. M. J . Am. Chem. Soc. 1995, 117, 5391.
(5) (a) Mayers, D. L.; Mikovits, J . A.; J oshi, B.; Hewlett, I. K.;
Estrada, J . S.; Wolfe, A. D.; Garcia, G. E.; Doctor, B. P.; Burke, D. S.;
Gordon, R. K.; Lane, J . R.; Chiang, P. K. Proc Natl. Acad. Sci. U.S.A.
1995, 92, 215. (b) Mizutani, Y.; Masuoka, S.; Imoto, M.; Kawada, M.;
Umezawa, K. Biochem. Biophys. Res. Commun. 1995, 207, 69. (c) Wolfe,
M. S.; Lee, Y.; Bartlett, W. J .; Borcherding, D. R.; Borchardt, R. T. J .
Med. Chem. 1992, 35, 1782. (d) Herdewijn, P.; Balzarial, J .; De Clercq,
E.; Vanderhaegbe, H. J . Med. Chem. 1985, 28, 1385.
(6) (a) Agrofoglio, L.; Condom, R.; Guedj, R. Challand, R.; Selway,
J . Tetrahedron Lett. 1993, 34, 6271. (b) Palmer, C. F.; Parry, K. P.;
Roberts, S. M. . Chem. Soc., Perkin Trans. 1 1991, 484. (c) Shealy, Y.
F.; O’Dell, C. A.; Arnett, G. J . Med. Chem. 1987, 30, 1090. (d)
Hronowski, L. J . J .; Szarek, W. A. Can. J . Chem. 1986, 64, 1620.
(7) (a) Miller, W. H.; Daluge, S. M.; Garvey, E. P.; Hopkins, S.;
Reardon, J . E.; Boyd, F. L.; Miller, R. L. J . Biol. Chem. 1992, 267,
21220. (b) Mahony, W. B.; Domin, B. A.; Daluge, S. M.; Miller, W. H.;
Zimmerman, T. P. J . Biol. Chem. 1992, 267, 19792. (c) Orr, D. C.;
Figueiredo, H. T.; Mo, C. L.; Penn, C. R.; Cameron, J . M. J . Biol. Chem.
1992, 267, 4177. (d) Vince, R.; Brownell, J . Biochem. Biophys. Res.
Commun. 1990, 168, 912. (e) Vince, R.; Hua, M. J . Med. Chem. 1990,
33, 17.
(8) (a) Kimberlin, D. W.; Coen, D. M.; Biron, K. K.; Cohen, J . I.;
Lamb, R. A.; McKinlay, M.; Emini, E. A.; Whitley, R. J . Antiviral Res.
1995, 26, 369. (b) Good, S. S.; Daluge, S. M.; Ching, S. V.; Ayers, K.
M.; Mahony, W. B.; Faletto, M. B.; Domin, B. A.; Owens, B. S.; Dornsife,
R. E.; McDowell, J . A.; LaFon, S. W.; Symonds, W. T. Antiviral Res.
1995, 26, A229.
(9) Nugent, W. A.; Feldman, J .; Calabrese, J . C. J . Am. Chem. Soc.
1995, 117, 8992.
(10) (a) Mart´ınez, L. E.; Leighton, J . L.; Carsten, D. H.; J acobsen,
E. N. J . Am. Chem. Soc. 1995, 117, 5897. (b) Larrow, J . F.; Schaus, S.
E.; J acobsen, E. N. J . Am. Chem. Soc. 1996, 118, 7420.
(11) For epoxidation of related compounds, see: (a) Agrofoglio, L.;
Condom, R.; Guedj, R. Tetrahedron Lett. 1992, 33, 5503. (b) Norman,
M. H.; Almond, M. R.; Reitter, B. E.; Rahim, S. G. Synth. Commun.
1992, 22, 3197.
S0022-3263(96)01241-8 CCC: $12.00 © 1996 American Chemical Society

7964 J . Org. Chem., Vol. 61, No. 22, 1996
Notes
Sch em e 1
tive elimination of the resulting selenide proved effective
and afforded azido cyclopentene 14 in 81% yield. Syn-
thesis of the carbocyclic cores of (-)-carbovir (3) and (-)-
1592U89 (4) was provided by reduction of 14 to amine
15.14 Synthesis of the core structure of (-)-aristeromycin
(1) was achieved by a highly diastereoselective OsO4-
catalyzed dihydroxylation15 of 14 followed by azide reduc-
tion to provide amino diol 16 in 75% yield over two
steps.16
The approach to carbocyclic nucleoside analogs out-
lined herein is rendered efficient by virtue of the succes-
sive use of catalytic reactions that are not only highly-
selective and clean but also afford product with minimal
generation of waste byproducts. Application of these
early-transition metal-catalyzed reactions to a range of
other targets of synthetic and biological interest is under
active investigation in our laboratories.
Sch em e 2
Exp er im en ta l Section
3-Cyclop en ten eca r boxylic Acid , Eth yl Ester (8). The
reported procedure for the decarboxylation of diethyl diallyl-
malonate followed by ring-closing metathesis of the resulting
diene (7)9 was followed with minor modifications: A 500 mL
flask was charged with tungsten oxychloride (0.813 g, 2.38
mmol), 2,6-dibromophenol (1.20 g, 4.76 mmol), and toluene (25
mL), and the resulting mixture was heated to reflux for 1 h
under N2. Volatile materials were removed under reduced
pressure, and the solid residue was kept under vacuum for 30
min. The flask was then charged with dry toluene (160 mL),
tetraethyllead (1.54 g, 4.76 mmol), and 7 (22.0 g, 131.0 mmol),
and the mixture was heated at 90 °C for 1.5 h under N2. After
being cooled to room temperature, the mixture was filtered
through a 1 cm pad of silica and the silica pad was rinsed with
tert-butyl methyl ether (TBME) (300 mL). The organic layers
were combined and washed with 1% NaOH (2 × 300 mL), water
(2 × 200 mL), and saturated NH4Cl (200 mL). After drying
(MgSO4) and removal of the solvent under reduced pressure,
distillation (60-64 °C, 15 Torr) provided 8 (15.60 g, 85%) as a
colorless liquid: 1H NMR (CDCl3, 400 MHz) δ 5.66 (s, 2H), 4.15
(q, J ) 7.1 Hz, 2H), 3.10 (quin, J ) 8.3 Hz, 1H), 2.65 (d, J ) 7.8
Hz, 4H) 1.26 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
176.1, 128.9, 60.4, 41.5, 36.3, 14.2.
phy. Although molybdenum-catalyzed epoxidation of 8
with alkyl hydroperoxides provided superior diastereo-
selectivity (up to 12:1 anti/syn), competing decomposition
of the products resulted in diminished isolated yields of
the desired epoxide. Reduction of ester 9 with LiAlH4
and conversion to the tert-butyldimethylsilyl (TBS) ether
afforded 10 in high yield with no detectable epoxide-
opening.
Enantioselective ring opening of epoxide 10 with
TMSN3 catalyzed by (S,S)-6b proceeded quantitatively
to a single product, providing azido silyl ether 11 in 95%
yield and in 96% ee after purification by distillation
(Scheme 2).12 Hydrogenation of azido silyl ether 11 over
Lindlar’s catalyst provided the enantiomerically enriched
3′-deoxyaristeromycin precursor 12 in 93% yield.6c
Synthesis of the carbocyclic cores of compounds 1, 3,
and 4 required elimination of the TMS ether from 11.
Camphorsulfonic acid (CSA)-catalyzed selective removal
of the trimethylsilyl group was followed by tosylation of
the resultant secondary alcohol to produce activated
intermediate 13. Attempts to effect elimination directly
from 13 using a variety of Brønsted bases either failed
altogether or provided very poor yields of the desired
alkene 14. In contrast, nucleophilic tosylate displace-
ment by sodium phenyl selenide13 and subsequent oxida-
tr a n s-3,4-Ep oxycyclop en ten eca r boxylic Acid , Eth yl Es-
ter (9). To a cooled (0 °C) solution of cyclopentene ester 8 (17.10
g, 122.00 mmmol) in CH2Cl2 (260 mL), m-chloroperbenzoic acid
(27.54 g, 159.60 mmol) was added in three portions. The
reaction was allowed to warm to room teperature and after 4 h
filtered to remove the precipitated m-chlorobenzoic acid. The
solids were rinsed with CH2Cl2 (150 mL), and the combined
organic layers were then washed with saturated NaHCO3 (200
mL), 10% Na2SO3 (200 mL), and saturated NaHCO3 (200 mL).
The organic phase was dried (MgSO4), filtered, and concentrated
1
to give 20.5 g of a clear liquid identified by H NMR to be a 3:1
mixture of 9 and its cis diastereomer; purification by flash
chromatography provided 9 in pure form (13.43 g, 70.5%): TLC
Rf ) 0.27-0.28 (1:4 EtOAc:hexanes); 1H NMR (CDCl3, 400 MHz)
δ 4.10 (q, J ) 7.1 Hz, 2H), 3.50 (s, 2H),2.62 (m, 1H), 2.32 (dd, J
) 14.1, 8.0 Hz, 2H), 1.86 (dd, J ) 14.0, 9.8 Hz, 2H), 1.22 (t, J )
7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 174.6, 60.3, 55.9, 37.2,
30.9, 13.9; exact mass (EI) calcd for (C8H12O3)+ 156.0786, found
156.0791.
tr a n s-4-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-1,2-ep oxycy-
clop en ta n e (10). Under N2, LiAlH4 (36.2 mL, 36.2 mmol, 1 M
in THF) was added in two portions to a cooled (-78 °C) solution
of 9 (11.04 g, 70.70 mmol) in dry THF (500 mL). After 4.5 h,
the solution was warmed to 0 °C and quenched by the method
(12) Complex 2b catalyzes the ring opening of epoxides by TMSN3
with the same enantioselectivity as chloride complex 2a ; however, the
use of azide complex 2b avoids the production of minor amounts of a
chloride addition side product observed when catalyst 2a is used:
Leighton, J . L.; J acobsen, E. N. J . Org. Chem. 1996, 61, 389.
(13) (a) Liotta, D.; Sunay, U.; Santiesteban, H.; Markiewicz, W. J .
Org. Chem. 1981, 46, 2601. (b) Dowd, P.; Kennedy, P. Synth. Commun.
1981, 935.
(14) For the conversion of 15 to carbovir, see ref 7e.
(15) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
23, 1973.
(16) For the conversion of 16 to aristeromycin, see: Arita, M.;
Adachi, K.; Ito, Y.; Sawai, H.; Ohno, M. J . Am. Chem. Soc. 1983, 105,
4049.

Notes
J . Org. Chem., Vol. 61, No. 22, 1996 7965
of Fieser17 (1.4 mL of H2O, 1.4 mL of 15% NaOH, and 4.1 mL of
H2O). The solution was allowed to warm to room temperature
and filtered through a 1 cm pad of Celite. The Celite pad was
washed with hot EtOAc (300 mL), and the combined filtrates
were concentrated to give a clear oil (7.82 g, 97%).
and saturated NH4Cl (2 × 100 mL). The aqueous layers were
combined and extracted with CH2Cl2 (2 × 100 mL). The organic
extracts were combined and washed with saturated NH4Cl (2
× 100 mL). The organic layers were combined, dried (MgSO4),
and concentrated under reduced pressure, and flash chroma-
tography of the residue provided 15 (19.62 g, 81%) as a colorless
oil: 1H NMR (CDCl3, 400 MHz) δ 7.81 (d, J ) 8.6 Hz, 2H), 7.36
(d, J ) 8.6 Hz, 2H), 4.59 (ddd, J ) 5.0, 5.0, and 5.0 Hz, 1H),
3.88 (ddd, J ) 7.6, 7.6, 4.9 Hz, 1H), 3.46 (dd, J ) 5.2, 2.0 Hz,
2H), 2.46 (s, 3H), 2.33 (m, 1H), 2.13 (ddd, J ) 13.6, 8.1, 7.9 Hz,
1H), 1.83 (m, 2H), 1.42 (ddd, J ) 13.6, 8.0, 7.8 Hz, 1H), 0.87 (s,
9H), 0.01 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 145.0, 130.0,
129.9, 127.9, 85.7, 66.0, 65.5, 37.2, 33.2, 31.3, 25.9, 21.7, 18.2,
-5.5; exact mass (FAB, m-nitrobenzylalcohol + NaI) calcd for
(C19H31O4N3SiS + Na)+ 448.1704, found 448.1702.
(1R,4S)-1-Azid o-4-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-2-
cyclop en ten e (14). A solution of sodium hydride (0.0056 g,
0.23 mmol) and diphenyl diselenide (0.037 g, 0.12 mmol) in dry
THF (3 mL) was allowed to reflux under N2. After 3 h, HMPA
(0.52 g, 0.30 mmol) and 13 (0.067 g, 0.16 mmol) were added,
and reflux was resumed under N2. When TLC analysis indicated
complete consumption of the starting material (4.5 h), the
reaction was cooled to room temperature, and pyridine (55 µL,
0.68 mmol) and 30% H2O2 (0.13 mL) were added to the solution.
After 10 h, the reaction was diluted with TBME (15 mL) and
washed with H2O (15 mL) and saturated NaHCO3 (3 × 10 mL).
The organic layer was dried (MgSO4) and concentrated, and flash
chromatography of the oil provided 14 (0.032 g, 81%): 1H NMR
(CDCl3, 400 MHz) δ 6.03 (ddd, J ) 5.6, 3.7, 1.9 Hz, 1H), 5.78
(ddd J ) 5.6, 4.2, 2.1 Hz, 1H), 4.36 (m, 1H), 3.54 (dd, J ) 2.0,
6.9 Hz, 2H), 2.86 (m, 1H), 2.39 (ddd J ) 14.1, 8.3, 5.9 Hz, 1H),
1.53 (ddd, J ) 14.1, 9.9, 4.9 Hz, 1H), 0.89 (s, 9H), 0.05 (s, 6H);
13C NMR (CDCl3, 100 MHz) δ 137.9, 129.7, 66.8, 66.7, 47.8, 32.8,
25.9, 18.4, -5.3; exact mass (CI) calcd for (C12H23N3OSi + NH4)+
271.1956, found 271.1959.
(1R,4S)-1-Am in o-4-[(ter t-bu tyld im eth ylsiloxy)m eth yl]-2-
cyclop en ten e (15). Under N2, LiAlH4 (0.88 mL, 0.88 mmol, 1
M in THF) was added to a cooled (0 °C) solution of 14 (0.20 g,
0.79 mmol) in dry Et2O (5 mL). When TLC analysis indicated
complete consumption of the starting material (1 h), the solution
was quenched by the method of Fieser17 (0.4 mL of H2O, 0.4 mL
of 15% NaOH, and 1 mL of H2O). The solution was allowed to
warm to room temperature and filtered through a 1 cm pad of
silica, and the silica pad was washed with hot EtOAc (100 mL).
The combined filtrates were concentrated to give 15 (0.70 g, 88%)
as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 5.72 (dddd, J )
1.7, 5.6, 4.4, 8.2 Hz, 2H), 3.91 (ddd, J ) 1.5, 5.4, 7.9 Hz, 1H),
3.54 (ddd, J ) 5.8, 9.8, 19.1 Hz, 2H), 2.76 (m, 1H), 2.40 (ddd, J
) 5.2, 8.2, 13.4 Hz, 1H), 1.12 (ddd, J ) 5.6, 5.6, 13.3 Hz, 1H),
0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 137.0,
133.2, 66.9, 57.8, 47.9, 37.8, 26.0, 18.5, -5.2; exact mass (CI,
cool probe) calcd for (C6H11N3O + NH4)+ 159.1246, found
159.1242.
(1R ,2S ,3R ,4R )-2,3-Dih yd r oxy-4-[(t er t -b u t yld im e t h yl-
siloxy)m eth yl]-1-cyclop en ta n a m in e (16). A solution of N-
methylmorpholine N-oxide (89 µL, 0.51 mmol, 60% in H2O) and
osmium tetraoxide (16 µL, 0.0024 mmol, 0.15 M in H2O) was
added to a cooled (0 °C) solution of 14 (0.062 g, 0.245 mmol) in
1:1 THF/acetone (2.2 mL). When TLC analysis indicated
complete consumption of the starting olefin (22 h), the reaction
was diluted with CH2Cl2 (20 mL) and washed with 10% Na2-
SO3 (20 mL) and NH4Cl (20 mL). The aqueous layers were
combined and extracted with CH2Cl2 (2 × 20 mL). The organic
layers were combined, dried (MgSO4), and concentrated, and
purification by flash chromatography (1:1 EtOAc:hexanes) pro-
vided a yellow oil (0.061 g, 86%).
Imidazole (10.26 g, 150 mmol) and tert-butyldimethylsilyl
chloride (11.47 g, 76.1 mmol) were added to a solution of the oil
(7.82 g) in CH2Cl2 (120 mL). When TLC analysis indicated
complete consumption of the starting material, the reaction was
diluted with CH2Cl2 (150 mL) and the solution was washed with
saturated NaHCO3 (3 × 200 mL). The aqueous layers were
combined and extracted with CH2Cl2 (3 × 150 mL); the organic
layers were combined, washed with saturated NH4Cl (3 × 200
mL), dried (MgSO4), and concentrated in vacuo. Purification by
flash chromatography provided 12 (14.28 g, 91%) as a clear
liquid: TLC Rf ) 0.43 (1:9 EtOAc:hexanes); 1H NMR (CDCl3,
400 MHz) δ 3.52 (d, J ) 5.2 Hz, 2H), 3.44 (s, 2H), 2.04 (dd, J )
13.5, 7.6 Hz, 2H), 1.94 (m, 1H), 1.46 (dd, J ) 13.6, 9.1 Hz, 2H),
0.86 (s, 9H), 0.004 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 64.7,
57.2, 35.4, 30.6, 25.9, 18.3, -5.4; exact mass (EI) calcd for
(C12H24O2Si)+ 228.1546, found 228.1552.
(1R,2R,4S)-4-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-2-a zid o-
1-(tr im eth ylsiloxy)cyclop en ta n e (11). To a solution of (S,S)-
6b (0.94 g, 1.32 mmol) in 20 mL of dry Et2O was added epoxide
10 (12.1 g, 53.0 mmol) under N2. After 15 min, TMSN3 (9.14 g,
79.3 mmol) was added, and the resulting brown solution was
stirred at room temperature for 24 h. The reaction mixture was
concentrated in vacuo, and the residue was filtered through a 3
cm pad of silica gel with 1:4 EtOAc/hexane (150 mL). The
filtrate was concentrated and purified by distillation (115-117
°C, 2 Torr) to provide 11 (17.1 g, 94%, 96% ee). Use of the above
procedure with catalyst 6a provided 11 in 91% yield and 96%
ee. 1H NMR (CDCl3, 400 MHz) δ 3.98 (ddd, J ) 6.8, 6.8, and
6.8 Hz, 1H), 3.61 (ddd, J ) 9.0, 7.2 and 6.6 Hz, 1H), 3.46 (d, J
) 5.5 Hz, 2H), 2.28 (m, 1H), 2.07 (ddd, J ) 13.2, 8.0, 7.7 Hz,
1H), 1.75-1.60 (m, 2H), 1.33 (ddd, J ) 13.2, 8.7, 8.9 Hz, 1H),
0.89 (s, 9H), 0.13 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3, 100
MHz) δ 77.3, 68.5, 66.5, 36.2, 35.3, 31.1, 26.0, 18.3, 0.03, -5.4;
exact mass (CI, NH3) calcd for (C15H33N3O2Si2 + H) 344.2190,
found 344.2191.
(1R,2R,4S)-4-[(ter t-Bu tyldim eth ylsiloxy)m eth yl]-2-am in o-
1-(tr im eth ylsiloxy)cyclop en ta n e (12). A 10 mL flask con-
taining 0.0053 g of palladium on calcium carbonate (Lindlar
catalyst, 6.3%) and a solution of 11 (0.08 g, 0.232 mmol) in EtOH
(4 mL) was stirred at room temperature under a H2 atmosphere
(1 atm). When TLC analysis indicated complete consumption
of the starting azide, the hydrogen atmosphere was displaced
by N2, the reaction was filtered through a 1 cm pad of Celite,
and the filtrate was concentrated, providing 12 (0.70 g, 95%) as
a clear yellow liquid: 1H NMR (CDCl3, 400 MHz) δ 3.62 (ddd, J
) 7.0, 7.0, and 7.0 Hz, 1H), 3.46 (d, J ) 5.4 Hz, 2H), 3.00 (ddd,
J ) 9.4, 6.9, 6.0 Hz, 1H), 2.23 (m, 1H), 2.02 (ddd, J ) 12.8, 8.4,
and 7.2 Hz, 1H), 1.74 (ddd, J ) 12.9, 7.2, and 5.5 Hz, 1H), 1.58
(ddd, J ) 13.2, 9.9, 7.2 Hz, 1H), 1.08 (ddd, J ) 12.7, 9.3, 8.5 Hz,
1H), 0.89 (s, 9H), 0.11 (s, 9H), 0.03 (s, 6H); 13C NMR (CDCl3,
100 MHz) δ 80.7, 67.0, 60.0, 36.1, 35.3, 34.5, 26.0, 18.4, 0.3, -5.3;
exact mass (EI) calcd for C19H18N4O3Na 373.1277; found 373.1276.
(1R,2R,4S)-4-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-2-a zid o-
1-[(p-tolu en esu lfon yl)oxy]cyclop en ta n e (13). (1S)-(+)-10-
camphorsulfonic acid (0.264 g, 1.14 mmol) was added to a cooled
(0 °C) solution of 11 (19.56 g, 56.92 mmol) in MeOH (190 mL).
When TLC analysis indicated complete consumption of the
starting material (∼10 min), the reaction was quenched by the
addition of Et3N (1 mL), diluted with EtOAc (200 mL), and
washed with saturated NaHCO3 (200 mL) and H2O (2 × 200
mL). The aqueous layers were combined and extracted with
EtOAc (2 × 200 mL). All the organic layers were combined,
washed with saturated NH4Cl (200 mL), dried (MgSO4), and
concentrated in vacuo.
Under N2, LiAlH4 (232 µL, 0.232 mmol, 1 M in THF) was
added to a cooled (0 °C) solution of the oil (0.061 g, 0.211 mmol)
in dry Et2O (1.3 mL). When TLC analysis indicated complete
consumption of the starting material (1 h), the solution was
quenched by the method of Fieser17 (9 µL of H2O, 9 µL of 15%
NaOH, and 27 µL of H2O). The solution was allowed to warm
to room temperature and filtered through a 1 cm pad of Celite.
The Celite pad was washed with hot EtOAc (50 mL), and the
combined filtrates were concentrated to give 16 (0.048 g, 87%)
as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 3.97 (dd, J ) 5.0,
10.0 Hz, 1H), 3.75 (dd, J ) 4.0, 9.9 Hz, 1H), 3.68 (dd, J ) 5.8,
11.5 Hz, 1H), 3.61 (dd, J ) 5.6, 11.1 Hz, 1H), 3.55 (ddd, J ) 6.1,
To a cooled (0 °C) solution of the residue in CH2Cl2 (75 mL)
and pyridine (15 mL) was added p-toluenesulfonyl chloride (17.2
g, 90.2 mmol), and the mixture was allowed to warm to room
temperature. When TLC analysis indicated complete consump-
tion of the starting alcohol, the reaction was diluted with CH2-
Cl2 (100 mL) and washed with saturated NaHCO3 (2 × 100 mL)
(17) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; J ohn
Wiley and Sons: New York, 1967; Vol. 1, p 584.

7966 J . Org. Chem., Vol. 61, No. 22, 1996
Notes
6.1, 3.6 Hz, 1H), 2.08-2.14 (m, 2H), 1.02 (m, 1H), 0.89 (s, 9H),
0.06 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 77.1, 74.9, 65.4, 65.0,
44.7, 28.9, 25.9, 18.3, -5.5; exact mass (FAB, m-nitrobenzyl
alcohol + NaI) calcd for (C12H27O3NSi + H)+ 262.1838, found
262.1839.
Dr. J . L. Leighton and Ms. T. C. Chin for preliminary
experimental work, Dr. D. Taber for providing the
procedure to synthesize compound 7, and the Ford
Foundation for a graduate fellowship to L.E.M.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM-43214). We thank
J O961241L