(1S,2R)-[(benzyloxy)methyl]cyclopent-3-enol. A versatile synthon for the preparation of 4',1'a-methano- and 1',1'a-methanocarbocyclic nucleosides

Full text of DOI:10.1021/jo962124t

4870
J . Org. Chem. 1997, 62, 4870-4873
Sch em e 1
(1S,2R)-[(Ben zyloxy)m eth yl]cyclop en t-3-en ol.
A Ver sa tile Syn th on for th e P r ep a r a tion of
4′,1′a -Meth a n o- a n d
1′,1′a -Meth a n oca r bocyclic Nu cleosid es
Abdallah Ezzitouni, Pamela Russ, and
Victor E. Marquez*
Laboratory of Medicinal Chemistry, Division of Basic
Sciences, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland 20892
Received November 13, 1996
In tr od u ction
4′,1′a-Methanocarbocyclic thymidine (1, Scheme 1) is
a recently discovered potent anti-herpes virus agent that
showed better in vitro activity against HSV-1 and HSV-2
than acyclovir.1 The structurally related and conforma-
tionally distinct 1′,1′a-methanocarbocyclic thymidine (2),
however, was totally devoid of antiviral activity.1,2 We
have recently suggested that the difference between 1
and 2 might be related to their antipodal pseudosugar
conformation imposed by the rigid bicyclo[3.1.0]hexane
system.1 In the case of 1, the conformation of the
pseudosugar mimics that of a 2′-deoxysugar locked in the
northern hemisphere of the pseudorotational cycle,
whereas in 2 the pseudosugar mimics a 2′-deoxysugar
locked in the southern hemisphere.3
Sch em e 2
In an effort to prepare additional quantities of 1 for
further biological testing, we decided to investigate an
alternative approach to the already published meth-
ods.1,4,5 These methods begin with the same chiral
cyclopentenone precursor 3 (Scheme 1) that was first
employed for the synthesis of neplanocin A (4).6 In these
methodologies, a two-step deoxygenation protocol to
remove the extra hydroxyl group was necessary, and
thus, the development of a method that circumvented
these steps was desirable. For that reason, we considered
the possibility of using the readily accessible cyclopen-
tenol synthon, (1S,2R)-2-[(benzyloxy)methyl]cyclopent-3-
enol (5), as a starting material for the preparation of 1
and other 4′,1′a-methanocarbanucleosides. Compound 5
was developed by Roberts et al.7,8 for the synthesis of 2′-
deoxycarbanucleosides, and recently, we have utilized it
for the synthesis of 1′,1′a-methano carbocyclic nucleo-
sides, including 2.2 If successful, the same homochiral
compound could then serve as a common precursor to
both series of conformationally locked nucleosides.
(1) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.; Wang,
J .; Wagner, R. W.; Matteucci, M. D. J . Med. Chem. 1996, 39, 3739.
(2) Ezzitouni, A.; Marquez, V. E. J . Chem. Soc., Perkin Trans. 1, in
press.
(3) Saenger, W. in Principles of Nucleic Acid Structure;
Springer-Verlag: New York, 1984; pp 51-104. The concept of pseu-
dorotation was introduced and applied for the first time to substituted
furanoses by: Altona, C.; Sundaralingam, M. J . Am. Chem. Soc. 1972,
94, 8205.
(4) Altmann, K.-H.; Kesselring, R.; Francotte, E.; Rihs, G. Tetrahe-
dron Lett. 1994, 35, 2331.
(5) Siddiqui, M. A.; Ford, H., J r.; George, C.; Marquez, V. E.
Nucleosides Nucleotides 1996, 15, 235.
(6) Marquez, V. E.; Lim, M.-I.; Tseng, C. K.-H.; Markovac, A.; Priest,
M. A.; Khan, M. S.; Kaskar, B. J . Org. Chem. 1988, 53, 5709.
(7) Biggadike, K.; Borthwick, A. D.; Exall, A. M.; Kirk, B. E.; Roberts,
S. M.; Youds, P.; Slawin, A. M. Z.; Williams, D. J . J . Chem. Soc., Chem.
Commun. 1987, 255.
(8) Biggadike, K.; Borthwick, A. D.; Evans, D.; Exall, A. M.; Kirk,
B. E.; Roberts, S. M.; Stephenson, L.; Youds, P. J . Chem. Soc., Perkin
Trans. 1 1988, 549.
As illustrated in Scheme 2, syn-elimination of the
intermediate selenoxides 7a ,b generated from 5 could in
theory proceed in two directions, giving the allylic azide
(path A) or the vinyl azide (path B), respectively. Ret-
rosynthetically, path A should provide access to the 4′,1′a-
methanocarbanucleoside series, whereas path B would
lead to the 1′,1′a-methanocarbanucleoside series, after
performing hydroxyl-directed cyclopropanations on each
olefin. The preferred pathway for the syn-elimination
would be determined by the ease of abstraction of the
hydrogens (Ha vs Hb), the stability of the five-membered
Ei transition state, and the stability of the resulting
S0022-3263(96)02124-X This article not subject to U.S. Copyright. Published 1997 by the American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 14, 1997 4871
Sch em e 3
Sch em e 4
(6b). However, a better yield was obtained with the more
sterically demanding tert-butyldiphenylsilyl group (87%
yield after column chromatography). On the other hand,
1
the H NMR spectrum of 7b was more diagnostic due to
the isolated appearance of the H-3 signal as nearly
symmetric triplet at δ 3.15 (J ≈ 9 Hz). The tert-
butyldiphenylsilyl ether was ultimately preferred because
it allowed the selective liberation of the 1-hydroxyl moiety
required for the hydroxyl-directed cyclopropanation step
(vide infra). Subsequently, the in situ oxidation of the
phenylselenide group in 7a triggered the anticipated syn-
elimination, giving almost exclusively the allylic azide
8a with only an observable trace of the alternate vinyl
azide. In the case of 7b, the isolated yield of the allylic
azide 8b was lower, and several unidentified side prod-
ucts were detected (see the Experimental Section). Such
overwhelming preference for the abstraction of Ha
(Schemes 2 and 4) over Hb was intriguing; however, there
is precedent in the literature for the predominance of the
allylic azide under similar oxidative eliminations.9,10
The allylic azide 8a was efficiently reduced (Scheme
3), and the resulting carbocyclic amine 9a was protected
as the phthalimide derivative 10a before removing of the
tert-butyldiphenylsilyl group. Complete protection of the
amine was necessary to allow the allylic hydroxyl group
in 11 to direct the course of cyclopropanation in the
succeeding Simmons-Smith reaction. Indeed, we have
shown previously that in the identical system an acyl-
NH group takes precedence over a hydroxyl group in
directing delivery of the incoming methylene group in the
Simmons-Smith reaction.11 Therefore, after full protec-
tion of the amine, the allylic alcohol was able to control
delivery of the methylene group, and compound 12 was
obtained exclusively in 96% yield following column chro-
matography. Hydrazinolysis of the phthalimido group
afforded the required bicyclo[3.1.0]hexane amine 13,
which was used without further purification for the
construction of the base.
olefin, among other factors.9 Experimentally, the allylic
azide (path A) overwhelmingly predominated over the
vinyl azide (path B), despite the inductive polarization
associated with the azido group, which could have
facilitated removal of Hb. Therefore, since we already
have used compound 5 for the effective synthesis of the
1′,1′a-methanocarbanucleoside series,2 we now wish to
report the use of the same precursor for the synthesis of
the antipodal 4′,1′a-methanocarbanucleosides by capital-
izing on the regioselectivity of the syn-elimination of the
selenoxide intermediates 7a ,b (path A). As an illustra-
tion, the synthetic method for the preparation of the
biologically important thymidine analogue 1 is herein
described.
Discu ssion
The successful completion of the synthesis of 1 accord-
ing to path A (Scheme 2) required the regio and stereo-
selective generation of the trans-3-(phenylselenyl)-
4-azidocyclopentane intermediate 7a ,b (Scheme 3). Re-
markably, azido-phenylselenylation of protected olefin 5
(6a or 6b ) proceeded with complete stereochemical
control, possibly due to the preferred pseudoequatorial
disposition of both substituents in the cyclopentene ring,
which biased formation of the episelenonium intermedi-
ate from the bottom face of the ring to give a stable
chairlike transition-state intermediate (Scheme 4). Re-
gioselective opening of the episelenonium ion was fol-
lowed by azide attack at the carbon atom farthest from
the (benzyloxy)methyl group to give the desired com-
pounds 7a and 7b. Equal stereo- and regioselectivity was
achieved when the 1-hydroxyl group was protected either
as a tert-butyldiphenylsilyl ether (6a ) or as a benzyl ether
Pyrimidine bases are normally prepared by reacting
the corresponding amine with 3-methoxy-2-methylacry-
loyl isocyanate.12 Use of this reagent, however, would
have required reprotection of the alcohol function in 13.
Therefore, we chose to use carbamate 14,13,14 which
selectively reacted with the carbocyclic amine 13 to give
the intermediate acryloylurea 15 (Scheme 5). Acid-
catalyzed cyclization of 15 provided the protected thy-
(10) Denis, J . N.; Vicens, J .; Krief, A. Tetrahedron Lett. 1979, 2697.
(11) Russ, P.; Ezzitouni, A.; Marquez, V. E. Tetrahedron Lett. 1997,
38, 723.
(12) Shealy, Y. F; O’Dell, C. A. J . Heterocycl. Chem., 1976, 13, 1015.
(13) Wyatt, P. G.; Anslow, A. S.; Coomber, B. A.; Cousins, R. P. C.;
Evans, D. N.; Gilbert, V. S.; Humber, D. C.; Paternoster, I. L.; Sollis,
S. L.; Tapolczay, D. J .; Weingarten, G. G. Nucleosides Nucleotides 1995,
14, 2039.
(9) Kondo, N.; Fueno, H.; Fujimoto, H.; Makino, M.; Nakaoka, H.;
Aoki, I.; Uemura, S. J . Org. Chem. 1994, 59, 5254-5263.
(14) Shaw, G.; Warrener, R. W. J . Chem. Soc. 1958, 157.

4872 J . Org. Chem., Vol. 62, No. 14, 1997
Notes
tetrabutylammonium iodide (0.037 g, 0.10 mmol) and benzyl
bromide (0.36 mL, 3.04 mmol) were added. The reaction mixture
was stirred for 4.5 h after it was allowed to reach ambient
temperature. Volatiles were removed under reduced pressure,
and the crude material was purified by flash column chroma-
tography (silica gel, step gradient: hexane, 3% EtOAc/hexane,
and 5% EtOAc/hexane) to give 6b (0.206 g, 35%) as a colorless
liquid: 1H NMR (CDCl3) δ 7.40-7.20 (m, 10 H), 5.75 (m, 1 H),
5.65 (m, 1 H), 4.56 (s, 2 H), 4.51 (s, 2 H), 4.08 (irregular
quintuplet, 1 H), 3.45 (dd, J ) 9.2, 5.7 Hz, 1 H), 3.33 (dd, J )
9.2, 7.2 Hz, 1 H), 3.05 (br m, 1 H), 2.70 (m, 1 H), 2.42 (m, 2 H).
Anal. Calcd for C22H22O2‚0.25H2O: C, 80.37; H, 7.58. Found:
C, 80.15; H, 7.58.
Sch em e 5
(1S,2R,3S,4S)-1-O-(ter t-Bu t yld ip h en ylsilyl)-2-[(b en zyl-
oxy)m eth yl]-3-(p h en ylselen yl)-4-a zid ocyclop en ta n e (7a ).
Under an atomosphere of argon, phenylselenium chloride (2.31
g, 12.1 mmol) was added to a stirred solution of 6a (2.67 g, 6.04
mmol) in DMSO (75 mL) at room temperature. After the
reaction mixture appeared completely homogeneous, sodium
azide (1.57 g, 24.2 mmol) was added, and stirring was continued
overnight. The reaction mixture was poured into ether (150 mL),
and the organic layer was washed with water (3 × 100 mL),
dried (MgSO4), and concentrated under reduced pressure.
Purification by flash column chromatography (silica gel, 25%
benzene/hexane) gave 7a (3.34 g, 87%) as a viscous oil: IR (neat)
midine analogue 16, and following the removal of the
benzyl ether group, the intended target 1 was obtained.
The physical and spectral properties of this compound
were identical with those of an authentic sample.1,4
In summary, we have developed a new approach for
the preparation of the potent antiviral agent 4′,1′a-
methanocarbocyclic thymidine (1). The starting material
is the readily accessible chiral cyclopentenol 5, which also
serves as starting material for the synthesis of the
complementary 1′,1′a-methanocarbocyclic nucleoside se-
ries. The remarkable efficiency of the process appears
to depend on (a) the stereo- and regioselective azido-
phenylselenylation of protected olefin 5 (6a or 6b), (b)
the regiospecific syn-elimination of the transient sele-
noxide generated in situ from 7a or 7b, and (c) the
hydroxyl-directed cyclopropanation of 11 under Sim-
mons-Smith conditions after full protection of the amine
function. The resulting carbocyclic amine 13 obtained
by this method represents an advanced common inter-
mediate for the synthesis of 1 and other 4′,1′a-methano-
carbocyclic nucleosides.
2200 (N3) cm-1 1H NMR (CDCl3) δ 7.70-7.10 (m, 20 H), 4.25
;
(m, 3 H), 3.98 (dd, J ) 15.5, 8.3 Hz, 1 H), 3.35 (dd, J ) 9.4, 3.9
Hz, 1 H), 3.15 (m, 2 H), 2.08 (m, 1 H), 1.95 (m, 1 H), 1.59 (m, 1
H), 1.05 (m, 9 H). Anal. Calcd for C29H34N3O2SeSi: C, 65.61;
H, 6.14; N, 6.56. Found: C, 65.49; H, 6.16; N, 6.52.
(1S ,2R ,3S ,4S )-1-O -B e n zy l-2-[(b e n zy lo x y )m e t h y l]-3-
(p h en ylselen yl)-4-a zid ocyclop en ta n e (7b). In the same
manner as described for 7a , a solution of 6b (0.200 g, 0.68 mmol)
in dry DMSO (10 mL) was treated with phenylselenium chloride
(0.260 g, 1.36 mmol) and NaN3 (0.177 g, 2.72 mmol). The crude
product was purified by flash column chromatography (silica gel,
step gradient: 25% benzene/hexane and 50% benzene/hexane)
to give 7b (0.231 g, 71%) as a pale orange liquid that was used
directly in the following step: 1H NMR (CDCl3) δ 7.40-7.20 (m,
10 H), 4.45 (s, 2 H), 4.38 (s, 2 H), 3.95 (m, 2 H), 3.55 (AB d, 2
H), 3.15 (t, J ) 9.0 Hz, 1 H), 2.10 (m, 2 H), 1.80 (m, 1 H).
(1S ,4S )-1-O-(t er t -Bu t yld ip h e n ylsilyl)-2-[(b e n zyloxy)-
m eth yl]-4-a zid ocyclop en t-2-en ol (8a ). A solution of 7a (4.23
g, 6.61 mmol) and sodium metaperiodate (2.83 g, 13.2 mmol) in
methanol:water (9:1) was stirred at room temperature for 36 h.
The reaction mixture was concentrated under reduced pressure,
and the residue was stirred with benzene. Removal of the
insolubles by filtration and concentration of the filtrate under
vacuum gave an orange oily residue. Purification by flash
column chromatography (silica gel, step gradient: hexane, 30%
benzene/hexane, and 50% benzene/hexane) afforded the desired
compound 8a (2.42 g, 76%) as a viscous oil: IR (neat) 3500 (OH),
Exp er im en ta l Section
All chemical reagents were commercially available. Reported
melting points are uncorrected. Column chromatography was
performed on silica gel 60, 230-400 mesh (E. Merk), and
analytical TLC was performed on Analtech Uniplates silica gel
GF. Infrared and 1H NMR spectra were recorded using standard
methods. Elemental analyses were performed by Atlantic
Microlab, Inc., Norcross, GA.
(1S ,2R )-1-O-(t er t -Bu t yld ip h e n ylsilyl)-2-[(b e n zyloxy)-
m eth yl]cyclop en t-3-en ol (6a ). A stirred solution of (1S,2R)-
2-[(benzyloxy)methyl]cyclopent-3-enol (5, 2.2.4 g, 10.8 mmol) and
imidazole (1.61 g, 23.7 mmol) in dry DMF (30 mL) was treated
dropwise with tert-butyldiphenylsilyl chloride (3.1 mL, 11.9
mmol) at room temperature. After 14 h, the reaction mixture
was cooled over ice, treated with water (50 mL), and extracted
with CH2Cl2 (3 × 50 mL). The organic solution was washed with
saturated aqueous NaCl (2 × 50 mL), dried (MgSO4), and
concentrated under reduced pressure. Purification by flash
column chromatography (silica gel, 25% benzene/hexane) gave
6a (3.70 g, 76%) as a viscous oil: 1H NMR (CDCl3) δ 7.65-7.20
(m, 15 H), 5.62 (s, 2 H), 4.30 (s, 2 H), 4.25 (m, 1 H), 3.15 (dd, J
) 8.9, 3.4 Hz, 1 H), 3.02 (dd, J ) 8.9, 6.7 Hz, 1 H), 2.92 (m, 1
H), 2.42 (dd, J ) 15.5, 6.6 Hz, 1 H), 2.30 (dd, J ) 15.5, 3.8 Hz,
1 H), 1.10 (s, 9 H). Anal. Calcd for C29H34O2Si: C, 78.68; H,
7.74. Found: C, 78.44; H, 7.73.
2200 (N3) cm-1 1H NMR (CDCl3) δ 7.70-7.20 (m, 15 H), 5.80
;
(br s, 1 H), 5.00 (br t, 1 H), 4.45 (s, 2 H), 4.42 (m, 1 H), 4.10 (d,
J ) 14.4 Hz, 1 H), 3.90 (d, J ) 14.4 Hz, 1 H), 2.08 (ddd, J )
14.2, 7.3, 4.2 Hz, 1 H), 1.89 (ddd, J ) 14.2, 6.7, 2.8 Hz, 1 H),
1.03 (br s, 9 H). Anal. Calcd for C29H33N3O2Si: C, 72.01; H,
6.88; N, 8.69. Found: C, 71.98; H, 6.93; N, 8.63. A small amount
of a less polar compound was isolated and characterized by NMR
as (1R,2S)-1-O-(tert-butyldiphenylsilyl)-2-[(benzyloxy)methyl]-
4-azidocyclopent-3-enol: 1H NMR (CDCl3) δ 7.70-7.20 (m, 15
H), 5.65 (s, 1 H), 4.32 (s, 2 H), 4.25 (m, 1 H), 3.15 (dd, J ) 8.9,
5.4 Hz, 1 H), 3.02 (dd, J ) 8.9, 6.6 Hz, 1 H), 2.93 (m, 1 H), 2.42
(ddd, J ) 15.5, 6.6, 1.5 Hz, 1 H), 2.30 (dd, J ) 15.5, 3.8 Hz, 1
H), 1.03 (s, 9 H).
(1S,4S)-1-O-Ben zyl-2-[(ben zyloxy)m eth yl]-4-a zid ocyclo-
p en t-2-en ol (8b). In the same manner as described for 8a , a
mixture of 7b (0.214 g, 0.45 mmol) and sodium metaperiodate
(0.192 g, 0.90 mmol) in 10 mL of methanol:water (9:1) was
allowed to react. Purification by flash column chromatography
(silica gel, step gradient: 25% benzene/hexane, 50% benzene/
hexane, and 75% benzene/hexane) gave 8b (0.082 g, 54%) as a
pale yellow liquid. This reaction was not as clean as the previous
one and required a second purification under the same chro-
matographic conditions to afford 0.079 g (52%) of 8b as a
colorless liquid: 1H NMR (CDCl3) δ 7.40-7.20 (m, 10 H), 5.92
(br s, 1 H), 4.75 (br m, 1H), 4.55 (m, 4 H), 4.20 (s, 2 H), 2.25 (m,
1 H), 2.19 (m, 1 H). Anal. Calcd for C20H21N3O2: C, 71.62; H,
6.31; N, 12.53. Found: C, 71.68; H, 6.34; N, 12.56.
(1S,2R)-1-O-Ben zyl-2-[(b en zyloxy)m et h yl]cyclop en t -3-
en ol (6b). A stirred solution of (1S,2R)-2-[(benzyloxy)methyl-
]cyclopent-3-enol (5, 0.414 g, 2.03 mmol) in dry THF (8 mL) was
cooled to 0 °C under argon. Sodium hydride (0.122 g, 60%, 3.04
mmol) was immediately added, and after 15 min at 0 °C,

Notes
(1S ,4S )-1-O-(t er t -Bu t yld ip h e n ylsilyl)-2-[(b e n zyloxy)-
J . Org. Chem., Vol. 62, No. 14, 1997 4873
(silica gel, hexane:EtOAc 1:1) showed total disappearance of
starting material, complete hydrolysis required heating at 50
°C for 3.5 h. The reaction mixture was concentrated under
reduced pressure, dissolved in ethanol (3 × 50 mL), and
reconcentrated three times. Finally, the residue was triturated
with CHCl3 (3 × 50 mL), and the insolubles were discarded. The
chloroform solution was evaporated to dryness to give 13 (0.47
g, 100%) as a viscous oil. This crude product was used directly
in the following condensation step.
m eth yl]-4-a m in ocyclop en t-2-en ol (9a ). A mixture of 8a (1.81
g, 3.77 mmol) and triphenylphosphine (2.45 g, 9.37 mmol) in 70
mL of wet THF (4% water) was refluxed for 4 h and then
concentrated under reduced pressure. The crude amine was first
purified by rapid flash column chromatography (silica gel) using
CHCl3 and a step gradient of MeOH/CHCl3 solutions (1% f 2%
f 5% MeOH). Pure amine 9a (1.54 g, 90%) was obtained as a
viscous oil after a second chromatography under the same
conditions: 1H NMR (CDCl3) δ 7.70-720 (m, 15 H), 5.78 (br s,
1 H), 5.00 (m, 1 H), 4.42 (s, 2 H), 4.05 (m, 2 H), 3.92 (d, J ) 13.5
Hz, 1 H), 2.13 (ddd, J ) 13.9, 7.3, 3.1 Hz, 1 H), 1.40-1.60 (m, 3
H), 1.03 (s, 9 H). Anal. Calcd for C29H35NO2Si‚0.3H2O: C, 75.22;
H, 7.74; N, 3.02. Found: C, 75.25; H, 7.71; N, 2.92.
(1S ,4S )-1-O-(t er t -Bu t yld ip h e n ylsilyl)-2-[(b e n zyloxy)-
m eth yl]-4-p h th a lim id ocyclop en t-2-en ol (10a ). Under an
atmosphere of argon, a mixture of 9a (0.87 g, 1.91 mmol) and
phthalic anhydride (0.84 g, 5.73 mmol) was heated in dry
pyridine (2 mL) at 90 °C for 2 h. Acetic anhydride (2 mL) was
added to the dark-colored reaction mixture, and heating was
continued for 2 h. The reaction mixture was cooled to room
temperature, reduced to dryness, dissolved in toluene (15 mL),
and reconcentrated. The residue was purified by flash column
chromatography (silica gel) using hexane and 10% EOAc/hexane
as eluants to give 10a (0.86 g, 77%) as a viscous oil: 1H NMR
(CDCl3) δ 7.80-7.20 (m, 19 H), 5.65 (br s, 1 H), 5.50-5.30 (m, 2
H), 4.45 (AB q, J ) 11.8 Hz, 2 H), 4.12 (d, J ) 14.3 Hz, 1 H),
4.00 (d, J ) 14.3 Hz, 1 H), 2.15 (t, J ) 5.8 Hz, 2 H), 1.05 (s, 9
H). Anal. Calcd for C37H37NO4Si: C, 75.61; H, 6.35; N, 2.38.
Found: C, 75.87; H, 6.51; N, 2.31.
N -(E t h oxyc a r b on yl)-(E )-2-(m e t h oxym e t h yle n e )p r o-
p a n a m id e (14). A solution of 3-methoxy-2-methylacryloyl
chloride (3.94 g, 29.3 mmol) in toluene (100 mL) was refluxed
with silver cyanate (6.62 g, 43.9 mmol) under argon for 1.5 h.
The solution was cooled and rapidly decanted from the silver
salt, which was washed three times with small portions of
toluene. The combined organic solution was reduced to dryness
under reduced pressure to give the isocyanate intermediate as
a solid. The solid was immediately dissolved in dry dioxane (100
mL) and stirred with ethanol (100 mL) at room temperature for
20 min. The reaction mixture was reduced to dryness and
purified by flash column chromatography (silica gel, step gradi-
ent: hexane, 25% EtOAc/hexane, 50% EtOAc/hexane, and
EtOAc) to give 14 (3.07 g, 56%) as a white solid: mp 95 °C
(begins to soften at 73 °C) (lit.14 mp 103 °C); 1H NMR (CDCl3) δ
1.30 (t, J ) 7.1 Hz, 3 H), 1.75 (s, 3 H), 3.82 (s, 3 H), 4.25 (q, J )
7.1 Hz, 2 H), 7.30 (s, 1 H), 7.40 (br s, 1 H). Anal. Calcd for
C8H3NO4‚0.1H2O: C, 50.87; H, 6.99; N, 7.42. Found: C, 50.75;
H, 6.93; N, 7.59.
(1R ,2S ,4S ,5S )-1-[(B e n zy lo x y )m e t h y l]-2-h y d r o x y -4-
[(3-m e t h o x y -2-m e t h y la c r y lo y l)u r e i d o ]b i c y lo [3.1.0]-
h exa n e (15). A stirred solution of the carbocyclic amine 13
(0.141 g, 0.605 mmol) and 14 (0.113 g, 0.605 mmol) in dry
dioxane (10 mL) was heated to 100 °C under argon for 3 h. The
reaction mixture was evaporated to dryness under reduced
pressure, and the residue was purified by flash column chro-
matography (silica gel, packed with hexane and eluted with
EtOAc) to give 15 (0.108 g, 50%) as a hygroscopic foam: 1H NMR
(CDCl3) δ 8.81 (d, J ) 7.0 Hz, 1 H), 8.28 (s, 1 H), 7.40-720 (m,
6 H), 4.73 (t, J ) 8.4 Hz, 1 H), 4.55 (AB q, J ) 12.1 Hz, 2 H),
4.20 (t, J ) 6.7 Hz, 1 H), 3.83 (s, 3 H), 3.81 (d, J ) 9.8 Hz, 1 H),
3.41 (d, J ) 9.8 Hz, 1 H), 2.30 (br s, 1 H), 2.00 (dd, J ) 14.3, 7.6
Hz, 1 H), 1.75 (s, 3 H), 1.51 (m, 1 H), 1.38 (dd, J ) 8.3, 3.6 Hz,
1 H), 0.92 (br t, J ≈ 4.7 Hz, 1 H), 0.60 (distorted triplet, 1 H).
Anal. Calcd for C20H26N2O5‚0.2H2O: C, 63.62; H, 6.92; N, 7.42.
Found: C, 63.86; H, 7.22; N, 7.17.
(1S,4S)-2-[(Ben zyloxy)m eth yl]-4-p h th a lim id ocyclop en t-
2-en ol (11). Under an atmosphere of argon, a stirred solution
of 10a (0.985 g, 1.61 mmol) in dry acetonitrile (50 mL) was
treated with triethylamine trihydrofluoride (98%, 1.6 mL) and
refluxed overnight. After the mixture was cooled to room
temperature, water (50 mL) was added, and stirring was
continued for 0.5 h. The reaction mixture was reduced to
dryness, dissolved in toluene (50 mL), and reconcentrated. The
residue was purified by flash chromatography (silica gel) using
hexane and EtOAc. The product was eluted with EtOAc to give
1
11 (0.505 g, 90%) as a solid: mp 94-95 °C; H NMR (CDCl3) δ
7.90-7.20 (m, 9 H), 5.70 (br s, 1 H), 5.55 (m, 1 H), 5.30 (m, 1 H),
4.55 (AB q, J ) 11.7 Hz, 2 H), 4.29 (br AB m, 2 H), 2.55 (ddd, J
) 14.2, 7.25, 4.1 Hz, 1 H), 2.27 (ddd, J ) 14.2, 8.7, 3.4 Hz, 1 H).
Anal. Calcd for C21H19NO4: C, 72.19; H, 5.48; N, 4.01. Found:
C, 72.09; H, 5.56; N, 3.97.
(1R,2S,4S,5S)-1-[(Ben zyloxy)m eth yl]-2-h ydr oxy-4-[5-m eth -
yl-2,4-(1H,3H)-dioxopyr im idin -1-yl]bicyclo[3.1.0]h exan e (16).
In a Teflon-capped vial, compound 15 (0.028 g, 0.079 mmol) was
dissolved in a mixture of ethanol (0.6 mL) and 2 N H2SO4 (0.6
mL) and heated in a heating block at 93 °C for 3.5 h. The
ethanol was removed under reduced pressure, and the aqueous
solution was neutralized to pH 6 with 1 N NaOH. Following
neutralization, the solution was reduced to dryness, and the
residue was dissolved in CHCl3, dried (MgSO4), and concentrated
under reduced pressure to give 16 (0.019 g, 76%) as a white
powder that was recrystallized from EtOAc/hexane: mp 192-
193 °C; 1H NMR (CDCl3) δ 8.60 (s, 1 H), 7.70 (s, 1 H), 7.40-730
(m, 5 H), 5.00 (d, J ) 7.2 Hz, 1 H), 4.87 (t, J ) 8.5 Hz, 1 H), 4.55
(AB q, J ) 11.5 Hz, 2 H), 4.08 (d, J )10.0 Hz, 1 H), 3.25 (d, J )
10.0 Hz, 1 H), 1.98 (dd, J ) 15.2, 8.2 Hz, 1 H), 1.70 (m, 1 H),
1.58 (br s, 1 H), 1.52 (s, 3 H), 1.36 (dd, J ) 8.6, 3.7 Hz, 1 H),
0.93 (dd, J ) 5.9, 3.9 Hz, 1 H), 0.71 (distorted triplet, 1 H). Anal.
Calcd for C19H22N2O4: C, 66.65; H, 6.48; N, 8.18. Found:
C,66.72; H, 6.49; N, 8.11.
(1R,2S,4S,5S)-1-[(Ben zyloxy)m eth yl]-2-h ydr oxy-4-ph th al-
im id o-bicyclo[3.1.0]h exa n e (12). A stirred solution of 11
(0.657 g, 1.88 mmol) in dry CH2Cl2 (20 mL) was cooled over an
ice/salt bath and treated dropwise with an Et2Zn solution in
hexane (1 M, 2.1 mL). After the addition, the reaction mixture
was stirred for 15 min. Separately, CH2I2 (0.350 mL, 4.2 mmol)
was dissolved in dry CH2Cl2 (10 mL), and 5 mL of this solution
was added rapidly to the reaction mixture. After 5 min,
additional Et2Zn/hexane (2.1 mL) was added dropwise followed
by the remaining 5 mL of the CH2I2 solution. The reaction
mixture was stirred cold for about 10 h and then gradually
allowed to reach room temperature as the bath warmed over-
night. The reaction mixture was again cooled over ice and
poured into 40 mL of aqueous saturated NH4Cl. Extraction with
EtOAc followed (3 × 50 mL), and the combined organic extract
was washed twice with aqueous saturated NH4Cl, dried (Mg-
SO4), filtered, and concentrated to dryness under reduced
pressure. Purification by flash column chromatography (silica
gel, step gradient: hexane, 25% EtOAc/hexane and 50% EtOAc/
hexane) afforded a pure fraction of 12 (0.660 g, 96%) as a viscous
oil (Note: the Rf values of starting material and product are
identical in different mixtures of hexane/EtOAc): 1H NMR
(CDCl3) δ 7.85-720 (m, 9 H), 5.15 (t, J ) 8.1 Hz, 1 H), 4.75 (d,
J ) 8.3 Hz, 1 H), 4.60 (AB q, J ) 12 Hz, 2 H), 4.28 (d, J ) 9.3
Hz, 1 H), 3.29 (d, J ) 9.3 Hz, 1 H), 2.15 (dd, J ) 15.0, 8.4 Hz, 1
H), 1.82 (dd, J ) 15.0, 7.7 Hz, 1 H), 1.28 (dd, J ) 8.4, 3.9 Hz, 1
H), 0.97 (br t, J ≈ 4.5 Hz, 1 H), 0.75 (dd, J ) 8.3, 5.8 Hz, 1 H).
Anal. Calcd for C22H21NO4‚0.3H2O: C, 71.64; H, 5.90; N, 3.80.
Found: C, 71.46; H, 5.72; N, 3.75.
(1R,2S,4S,5S)-1-(Hyd r oxym eth yl)-2-h yd r oxy-4-[5-m eth -
yl-2,4-(1H,3H)-dioxopyr im idin -1-yl]bicyclo[3.1.0]h exan e (1).
To a stirred suspension of Pd black (0.134 g) in MeOH (10 mL)
was added a solution of 16 (0.096 g, 0.282 mmol) in MeOH (5
mL). Formic acid (96%, 0.34 mL) was added, and the reaction
mixture was stirred at 50 °C for 1 h. The reaction mixture was
filtered through Celite, concentrated under reduced pressure,
and vacuum dried overnight to give a white solid. Recrystalli-
zation from 2-propanol/Et2O gave 1 (0.066 g, 93%) as a white
crystalline solid: mp 235-236 °C; [R]25D ) +47.5° (c 0.16, MeOH)
[lit.1 [R]25 ) +47° (c 0.28, MeOH)]. The rest of the spectral
D
(1R ,2S ,4S ,5S )-1-[(B e n zy lo x y )m e t h y l]-2-h y d r o x y -4-
a m in obicyclo[3.1.0]h exa n e (13). A solution of 12 (0.728 g, 2
mmol) was dissolved in 150 mL of 0.2 M methanolic hydrazine
and stirred at room temperature for 30 min. Although TLC
properties exactly matched those reported earlier for the identi-
cal compound synthesized by a different method.
J O962124T