Enzymatic resolution of aminocyclopentenols as precursors to D- and L- carbocyclic nucleosides

Article abstract of DOI:10.1021/jo972265a

Racemic cis-4-aminocyclopent-2-en-1-ols were synthesized in three steps utilizing hetero Diels-Alder chemistry. Starting from suitably protected hydroxylamines, oxidization with sodium periodate and trapping with cyclopentadiene afforded cycloadducts (±)-5a-d. The N-O bond of the cycloadducts was reduced with Mo(CO)₆ to afford (±)-cis-4-aminocyclopent- 2-en-1-ols (±)-6a-d. These compounds, or their corresponding acetates, were kinetically resolved by enzymatic acetylation of hydrolysis, respectively. Enzymatic acetylation of cis-N-(benzylcarbamoyl)-4-aminocylopent-2-enol [(±)-6a] with Candida antarctica B lipase and Pseudomonas species lipase gave the corresponding acetate (-)-7a in 90% and 92% ee, respectively, after 40% conversion. Enzymatic hydrolysis of cis-N-acetyl-4-aminocyclopent-2-enol 1-O-acetate (±)-7d with electric eel acetylcholine esterase was successful in providing both cis-N-acetyl-4-aminocyclopent-2-enols (+)-6d and (+)-7d in 92% ee (99% ee after a single recrystallizaton) after 40% conversion. Further synthetic transformation of these resolved synthetic building blocks and derivatives are also reported.

Full text of DOI:10.1021/jo972265a

J . Org. Chem. 1998, 63, 3357-3363
3357
En zym a tic Resolu tion of Am in ocyclop en ten ols a s P r ecu r sor s to
D- a n d L-Ca r bocyclic Nu cleosid es
Mark J . Mulvihill, J ennifer L. Gage, and Marvin J . Miller*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556
Received December 15, 1997
Racemic cis-4-aminocyclopent-2-en-1-ols were synthesized in three steps utilizing hetero Diels-
Alder chemistry. Starting from suitably protected hydroxylamines, oxidization with sodium
periodate and trapping with cyclopentadiene afforded cycloadducts (()-5a -d . The N-O bond of
the cycloadducts was reduced with Mo(CO)6 to afford (()-cis-4-aminocyclopent-2-en-1-ols (()-6a -
d . These compounds, or their corresponding acetates, were kinetically resolved by enzymatic
acetylation or hydrolysis, respectively. Enzymatic acetylation of cis-N-(benzylcarbamoyl)-4-
aminocyclopent-2-enol [(()-6a ] with Candida antarctica B lipase and Pseudomonas species lipase
gave the corresponding acetate (-)-7a in 90% and 92% ee, respectively, after 40% conversion.
Enzymatic hydrolysis of cis-N-acetyl-4-aminocyclopent-2-enol 1-O-acetate (()-7d with electric eel
acetylcholine esterase was successful in providing both cis-N-acetyl-4-aminocyclopent-2-enols (+)-
6d and (+)-7d in 92% ee (99% ee after a single recrystallization) after 40% conversion. Further
synthetic transformations of these resolved synthetic building blocks and derivatives are also
reported.
In tr od u ction
syntheses of L-nucleosides,7 the enantiomers of naturally
occurring D-nucleosides, we recognized the need for a
concise, inexpensive route to 4-aminocyclopent-2-enol
precursors. These compounds could serve as chiral
building blocks for D- and L-4-hydroxymethyl carbocyclic
nucleosides as well as for structurally diverse carbocyclic
nucleosides6a and aminocyclopentenol natural products.8
Enantiomerically pure 4-aminocyclopent-2-enols were
envisioned to be derived through an enzymatic route,
which would alleviate the need for a chiral auxiliary (one
for each enantiomer) as well as the need for cleavage of
that auxiliary, resulting in improved atom efficiency.
Also, utilization of a biocatalyst provides direct and
immediate access to each enantiomer. Resolution of
racemic cis-4-aminocyclopent-2-enol (()-1 would afford
both enantiopure 4-aminocyclopent-2-enol derivatives (1
and 2) in an enantiodivergent synthesis (Scheme 1).
Herein, we report a successful enantiodivergent syn-
thesis of 4-aminocyclopent-2-enols that can serve as
building blocks for D- and L-carbocyclic nucleosides.
Nucleosides have proven to be a functionally diverse
class of compounds with a wide range of biological
activity.1 Several structural modifications have been
applied to their basic framework, including the replace-
ment of the furanose oxygen with a methylene unit,
creating a new class of compounds termed carbocyclic
nucleosides.2 These cyclopentane versions of nucleosides
have in some cases proven to be more biologically
effective than their furanose counterparts due to in-
creased resistance to enzymatic and hydrolytic degrada-
tion.3 Several approaches toward the synthesis of opti-
cally active carbocyclic nucleosides have been reported
over the past decade.2,4 Many involve the production of
typical 5′-(hydroxymethyl)cyclopentane derivatives, such
as aristeromycin and carbovir5 and, therefore, do not
allow access to structurally diverse carbocyclic nucleo-
sides such as the polyoxins and nikkomycins.6
With recent reports in the literature describing the
Resu lts a n d Discu ssion
* To whom correspondence should be addressed. Tel.: (219) 631-
7571. Fax: (219) 631-6652. E-mail: Marvin.J .Miller.2@nd.edu.
(1) For reviews, see: (a) Chu, C. K., Baker, D. C., Eds. Nucleosides
and Nucleotides as Antitumor and Antiviral Agents: Plenum Press:
New York, 1993. (b) Townsend, L. B., Ed. Chemistry of Nucleosides
and Nucleotides; Plenum Press: New York, 1988.
Several substrates for kinetic enzymatic resolution
were prepared for both enzymatic acetylation and hy-
drolytic reactions (Scheme 2). Benzyl carbamate (()-6a
(2) For reviews on carbocyclic nucleoside chemistry, see: (a) Borth-
wick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571. (b) Agrofoglio,
L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl, R. A.;
Guedj, R. Tetrahedron 1994, 50, 10611. (c) Mansour, T. S.; Storer, R.
Curr. Pharm. Des. 1997, 3, 227. (d) Marquez, V. E. In Advances in
Antiviral Drug Design; De Clercq, E., Ed.; J AI Press Inc.: Greenwich,
CT, 1996; Vol. 2, p 89.
(6) (a) Zhang, D.; Miller, M. J . J . Org. Chem. 1998, 63, 755. (b)
Dondoni, A.; J unquera, F.; Merchan, R. L.; Merino, P.; Tejero, T.
Tetrahedron Lett. 1994, 35, 9439 and references therein. (c) Baum-
gartner, H.; Marschner, C.; Pucher, R.; Singer, M.; Griengl, H.
Tetrahedron Lett. 1992, 33, 6443. (d) Aggarwal, V. K.; Monteiro, N.;
Tarver, G. J .; Lindell, S. D. J . Org. Chem. 1996, 61, 1192.
(7) (a) Lin, T.; Luo, M.; Liu, M.; Zhu, Y.; Gullen, E.; Dutschman,
G.; Cheng, Y. J . Med. Chem. 1996, 39, 1757. (b) Wang, P.; Agrofoglio,
L.; Newton, M.; Chu, C. Tetrahedron Lett. 1997, 38, 4207. (c) Chen,
S. H.; Li, X.; Li J .; Niu, C.; Carmichael, E.; Doyle, T. W. J . Org. Chem.
1997, 62, 3449. (d) Gould, J . H. M.; Mann, J . Nucleosides Nucleotides
1997, 16, 193.
(8) (a) Trost, B. M.; Van Vranken, D. L. J . Am. Chem. Soc. 1993,
115, 444. (b) Nishimura, Y.; Umezawa, Y.; Adachi, H.; Kondo, S.;
Takeuchi, T. J . Org. Chem. 1996, 61, 480. (c) Ganem, B.; King, B. J .
Am. Chem. Soc. 1991, 113, 5089. (d) Ledford, B. E.; Carreira, E. M.
J . Am. Chem. Soc. 1995, 117, 11811.
(3) Marquez, V. E.; Lim, M. I. Med. Res. Rev. 1986, 6, 1.
(4) (a) Ritter, A. R.; Miller, M. J . J . Org. Chem. 1994, 59, 4602. (b)
Zhang, D.; Su¨ling, C.; Miller, M. J . J . Org. Chem. 1998, 63, 885. (c)
Trost, B. M. Acc. Chem. Res. 1996, 29, 355. (d) Sicsic, S.; Ikbal, M.;
Goffic, F. Tetrahedron Lett. 1987, 28, 1887. (e) Dorr, P.; Csuk, R.
Terahedron: Asymmetry 1994, 5, 269.
(5) (a) Boyer, S. J .; Leahy, J . W. J . Org. Chem. 1997, 62, 3976. (b)
Tanimori, S.; Tsubota, M. H.; Nakayama, M. Synth. Commun. 1997,
27, 2371. (c) J ones, M. F.; Myers, P. L.; Pobertson, C. A.; Storer, R.;
Williamson, C. J . Chem. Soc., Perkin Trans. 1 1991, 2479.
S0022-3263(97)02265-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/28/1998

3358 J . Org. Chem., Vol. 63, No. 10, 1998
Mulvihill et al.
Sch em e 1
with a large number of enzymes in order to find an
appropriate biocatalyst for kinetic resolution of allylic
alcohols (()-6a and (()-6b. A screening kit11 containing
25 lipases was utilized for the determination of substrate
compatibility with alcohol (()-6a . Vinyl acetate was used
as the acetylation reagent with CH2Cl2 as the solvent.
Of the 25 lipases examined, several were found to
successfully acetylate alcohol (()-6a , and on the basis of
commercial availability, four of these enzymes were
selected for further testing: Mucor meihei, Candida
rugosa, Candida antarctica A, and Candida antarctica
B. M. meihei lipase was found not to catalyze the
formation of allylic acetate 7a on a larger scale even
under “forcing” conditions (mg enzyme:mg substrate 1:2;
18 equiv of vinyl acetate). C. rugosa and C. antarctica
A lipases were found to catalyze substrate turnover, but
were sluggish. C. antarctica B lipase, however, was
found to produce allylic acetate (-)-7a after 39% conver-
sion of starting material (()-6a (Scheme 3, Table 1). The
resulting allylic acetate (-)-7a was hydrolyzed (K2CO3)
and derivatized with (S)-(+)-R-methoxy-R-(trifluoro-
methyl)phenylacetyl chloride for Mosher ester analysis
(HPLC).12 Thus, allylic acetate (-)-7a was found to be
of 90% ee. The E value for C. antarctica B was calculated
to be 34.13 This E value indicates that the acetylation is
selective enough for production of an enantiopure 4-ami-
nocyclopent-2-enol but would require recrystallization of
the acetylation product to increase the % ee. The
absolute configuration of (-)-7a was determined by
comparison of the optical rotation to that of a sample with
known configuration.14a
Sch em e 2
N-Boc-protected aminocyclopentenol derivative (()-6b
was screened as a substrate for enzymatic kinetic resolu-
tion by acetylation with a kit containing eight lipases.15
Isopropenyl acetate was used as the acetylation reagent
with CH2Cl2 as solvent. It was found that two enzymes
accepted (()-6b as a substrate; Burkholderia species
lipase and Candida antarctica B lipase. A larger scale
was prepared in two steps from benzyl N-hydroxycar-
bamate (4a ) in 41% yield. tert-Butyl carbamate (()-6b
was prepared in three steps from hydroxylamine hydro-
chloride in 45% overall yield according to literature
procedures.4b Thus, the N-protected hydroxylamines
(4a ,b) were oxidized with sodium periodate to the tran-
sient acylnitroso species in the presence of cyclopenta-
diene to form the corresponding hetero Diels-Alder
cycloadducts (5a ,b).9 Subsequent N-O bond reduction10
with Mo(CO)6 in MeCN-H2O provided (()-6a and (()-
6b suitable for enzymatic kinetic resolution by acetyla-
tion. Two other substrates were designed to have higher
solubility in aqueous media, which would allow for
enzymatic resolution by esterase-catalyzed hydrolysis.
Thus, methyl carbamate (()-7c and acetamide (()-7d
were synthesized by a slightly modified method (com-
pared to the synthesis of carbamates (()-6a and (()-6b)
to enable efficient production of these water-soluble
compounds (Scheme 2). Thus, hydroxylamine was pro-
tected as methylcarbamate 4c and acetamide 4d and
then oxidized and trapped with cyclopentadiene in situ
to yield cycloadducts (()-5c and (()-5d , respectively, in
one-pot, two-step reactions. N-O bond reduction of the
cycloadducts, followed by acetylation, gave methyl car-
bamate (()-7c and acetamide (()-7d in 80% and 92%
overall yields, respectively, in four steps.
(11) ChiroScreen-TE, Altus Biologics, Inc.
(12) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(13) The E value was calculated with the program “Selectivity”
available at www-orgc.tu-graz.ac.at/programs/enantio/mac/selectiv.hqx.
See: (a) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am.
Chem. Soc. 1982, 104, 7294. (b) Chen, C. S.; Wu, S.-H.; Girdaukas,
G.; Sih, C. J . J . Am. Chem. Soc. 1987, 109, 2812.
(14) (a) The absolute stereochemistry of acetate (-)-7a was deter-
mined by comparison of the optical rotations of this compound as well
as its solvolysis product, alcohol (+)-6a , to samples of known config-
uration synthesized from an intermediate in the Edman degradation
sequence as shown below. Acetamide (-)-7d was also synthesized by
this method; [R]24 ) -24.5 (c 0.33, CHCl3). See: Vogt, P. F.; Hansel,
D
J .-G.; Miller, M. J . Tetrahedron Lett. 1997, 38, 2803. (b) Synthesis
of (-)-7b from (-)-7d (Scheme 6) gave a standard for determination
of the configuration of acetate (-)-7b derived from enzymatic resolution
of (()-6b. Methyl carbamate (+)-6c obtained from enzymatic hydroly-
sis was transformed to acetate (-)-7b by the synthetic route shown in
Scheme 6 in order to determine its absolute configuration.
Two approaches in the search for an appropriate
enzyme for the kinetic resolution by acetylation were
pursued. The first approach involved wide screening
(9) For a review on acylnitroso hetero-Diels-Alder reactions, see:
Vogt, P. F.; Miller, M. J . Tetrahedron 1998, 54, 1317.
(10) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351.
(15) Chirazyme Lipases and Esterases Screening Kit; Boehringer
Mannheim.

Enzymatic Resolution of Aminocyclopentenols
J . Org. Chem., Vol. 63, No. 10, 1998 3359
Ta ble 1. Kin etic En zym a tic Resolu tion s
substrate
enzyme
product
% conversion
%eea
E
Acetylation Reactions
(()-6a
(()-6a
(()-6b
(()-6b
C. antarctica B lipase
Pseudomonas sp. lipase
Burkholderia sp. lipase
C. antarctica B lipase
(-)-7a
(-)-7a
(-)-7b
(-)-7b
39
40
39
40
90
92
55
81
34
44.9
4.8
16.3
Hydrolysis Reactions
(+)-6c
(()-7c
(()-7d
electric eel acetylcholine esterase
electric eel acetylcholine esterase
50
40
72
92
15.6
44.9
(+)-6d
a
Before recrystallization.
Sch em e 3
Sch em e 4
reaction with isopropenyl acetate in tert-butyl methyl
ether (MTBE) with Burkholderia sp. afforded acetate (-)-
7b in 55% ee after 39% conversion (% ee determined by
Mosher ester analysis; 19F NMR).14b Acetylation cata-
lyzed by C. antarctica B lipase under the same conditions
afforded acetate (-)-7b in 81% ee after 40% conversion.
The second approach utilized in locating an appropriate
enzyme involved literature searching for analogous sub-
strates that have been resolved enzymatically.16 Enzy-
matic resolution of cyclopentene diol derivatives is well-
known in the literature, but resolution of amino-
cyclopentenols is not as prevalent.17 Pseudomonas sp.
lipase has been shown to provide resolution of cyclopen-
tene alcohols.18 The similarities between such alcohols
and alcohol (()-6a led us to attempt kinetic resolution
by similar methodology using Pseudomonas sp. lipase.
Thus, alcohol (()-6a was reacted with vinyl acetate in
dichloromethane in the presence of Pseudomonas sp.
lipase (Scheme 3, Table 1). After 6 h, 40% of alcohol (()-
6a had been transformed into the corresponding allylic
acetate (-)-7a . The resulting allylic acetate (-)-7a was
determined to be of 92% ee (determined by Mosher ester
analysis; HPLC; calcd E ) 44.9).14a A disadvantage of
the use of this enzyme was the large enzyme-to-substrate
ratio needed (mg enzyme:mg substrate 1:4.7), which
may make large-scale synthesis impractical.
resolved by this enzyme and should result in enantiose-
lective recognition. Thus, acetate (()-7c was subjected
to EEAC in 1.45 M NaH2PO4, pH 6.9 buffer (Scheme 3,
Table 1); after 50% conversion, alcohol (+)-6c was formed
in 72% ee (Mosher ester analysis; 19F NMR) with an E
value of 15.6.14b With such a low E value for this reaction,
it appears that although acetate (()-7c is a good sub-
strate for EEAC, the enzyme is not enantioselective in
its choice of substrates.20
Acetate (()-7d (0.15 g, 0.82 mmol) was subjected to
EEAC (0.20 mg, 100 units) in 1.45 M NaH2PO4, pH 6.9
buffer, upon which 40% of the allylic acetate had been
hydrolyzed to the alcohol in 9 h. Alcohol (+)-6d was
found to be of 92% ee (Mosher ester analysis) with an E
value of 44.9 (Scheme 3, Table 1).14a This reaction was
conducted on a larger scale in which 4 g of acetate (()-
7d was resolved by EEAC (1.1 mg; 500 units) in 49 h
(Scheme 4). Alcohol (+)-6d was found to be of 92% ee
(Mosher ester analysis; 99% ee after a single recrystal-
lization (EtOAc/hexanes)). The remaining enantiomeri-
cally enriched acetamide 7d was then resubjected to
EEAC, and after a 20% conversion the unreacted allylic
acetate was isolated, saponified to the alcohol, and
1
derivatized to its Mosher ester. Analysis by H and 19F
Electric eel acetylcholinesterase (EEAC), an enzyme
that has high specificity for cyclopentene diacetates, was
chosen for enzymatic hydrolysis of water-soluble acetates
(()-7c and (()-7d .19 It was reasoned that both of these
compounds could resemble the meso diacetates previously
NMR showed 92% ee of (+)-N-acetyl-4-aminocyclopent-
2-enol 1-O-acetate (+)-7d . A greater than 99% ee of (+)-
7d could be achieved through a single recrystallization
(EtOAc/hexanes).
With these results in hand, we attempted to remove
the Cbz and acetamide protecting groups from com-
pounds 7a and 7d in order to gain entry into carbocyclic
nucleoside syntheses. Cbz groups are normally removed
under hydrogenation conditions, which would not be
(16) For a review on enzymatic approaches to enantiomerically pure
chiral building blocks, see: (a) Santaniello, E.; Ferraboschi, P.; Grisenti,
P.; Manzocchi, A. Chem. Rev. 1992, 92, 1071. (b) Boland, W.; Frobl,
C.; Lorenz, M. Synthesis 1991, 1049.
(17) Ba¨ckvall, J . E.; Gatti R.; Schink, H. E. Synthesis 1993, 343.
(18) (a) Hsu, S. H.; Wu, S. S.; Wang, Y. F. Tetrahedron Lett. 1990,
31, 6403. (b) Theil, F.; Ballschuh, S. Tetrahedron: Asymmetry 1996,
7, 3565.
(20) Acetate (()-7a was subjected to EEAC in aqueous buffer;
apparently, insolubility of the substrate prevented hydrolysis from
occurring even after addition of 10% MeOH or 10% EtOH (4 days
reaction time).
(19) Deardorff, D. R.; Windham, C. Q.; Craney, C. L. Org. Syn. 1995,
73, 25.

3360 J . Org. Chem., Vol. 63, No. 10, 1998
Mulvihill et al.
Sch em e 5
(()-6b in 67% yield from (()-7a . Enantiomerically pure
amino alcohol 10, from (-)-7d , was also reprotected as
the Boc-carbamate followed by subsequent O-acetylation
to afford acetate (-)-7b in 92% yield for the three steps.
Acetate (-)-7b may be more suitable for carbocyclic
nucleoside syntheses that require a more easily removed
N-protecting group, such as the Boc carbamate moiety,
as well as provide an allylic acetate for Pd(0)-catalyzed4c
nucleophilic additions. Alternatively, reaction of the
enantiomerically pure intermediate amino alcohol 10,
from either (+)-6d or (-)-7d , with an appropriate het-
erocyclic moiety26 would give direct entry to both D- and
L-carbocyclic nucleoside syntheses.
Sch em e 6
Con clu sion s
cis-(()-4-Aminocyclopent-2-enol derivatives were ki-
netically resolved by several enzymes to afford com-
pounds of high enantiopurity. Selected enzymatic ex-
periments based on literature precedence and broad
screen testing of lipases were both useful approaches for
the determination of appropriate biocatalysts. From
these two approaches, amino alcohol (()-6a was enan-
tiomerically resolved to provide acetate (-)-7a in 90% and
92% ee with C. antarctica B and Pseudomonas sp.,
respectively. Also, acetate (()-7d was enzymatically
resolved with electric eel acetylcholinesterase to ef-
ficiently provide two enantiomerically pure N-acetyl
cyclopentenol derivatives (+)-6d and (+)-7d as precursors
in the enantiospecific syntheses of D- and L-carbocyclic
nucleosides.
compatible with the alkene moiety. Several methods
appeared to be compatible with both esters and alkenes,
but suitability of these methods for an allylic acetate
moiety was unknown. It was found that all three of the
reaction conditions tested (TMSI/CH3CN/0-5 °C,21 B-bro-
mocatecholborane/CH2Cl2,22 and TFA/rt) led to a rear-
ranged oxazolidinone product 8, although only TFA drove
the reaction to completion (Scheme 5). Oxazolidinone 8
was immediately derivatized to Boc-carbamate 9 in 75-
80% overall yield (via TFA). This rearrangement process
to form 8 is equally successful with either alcohol 6a or
its acetate derivative 7a . Oxazolidinones 8 and 9 have
been previously reported by Muxworthy and co-workers.23
Compound 8 was also produced by these authors via a
rearrangement reaction (35% yield) but under basic
conditions, therefore, presumably operating by a different
mechanism.24
Although both Lewis and Brønsted acids were found
to effect rearrangement of acetate (()-7a , Ba(OH)2 in
H2O/p-dioxane under refluxing conditions, conditions
used to cleave N-acetamides,25 was successful in removal
of the N-benzyloxycarbamoyl protecting group of (()-7a ,
as well as the N-acetamide of (-)-7d (Scheme 6). With-
out purification, the intermediate 4-aminocyclopent-2-
enol (10) was reprotected with a Boc group to give alcohol
Exp er im en ta l Section
Gen er a l Meth od s. 1H, 13C, and 19F NMR spectra were
recorded at 300, 75.4, and 282 MHz, respectively, in CDCl3
unless otherwise noted. R,R,R-Trifluorotoluene was used as
an internal standard for 19F NMR and was defined as 0.0 ppm.
In cases where both racemates and optically pure compounds
were synthesized, the racemates were used for full character-
ization (excepting polarimetry data); all optically pure samples
gave 1H NMR spectra that matched that of racemates. The
enzymes used in this study were obtained from the following
sources and had the following activity: Burkholderia sp. lipase,
Boehringer Mannheim, 225 U/mg; C. antarctica B lipase,
Boehringer Mannheim, 130 U/mg; Pseudomonas sp. lipase,
Sigma, 25 U/mg; electric eel acetylcholine esterase, Sigma, 263
U/mg. Instruments and general methods used have been
described previously.4a,27
Gen er a l P r oced u r e for Cycloa d d u ct N-O Bon d Re-
d u ction . A 15:1 CH3CN:H2O solution of cycloadduct was
charged with Mo(CO)6 (1.1 equiv) and refluxed under Ar until
the solution turned black. The heat was then removed and
the solution allowed to cool to room temperature. NaBH4 (1
equiv) was then added slowly (if the N-protecting group was
a carbamate, NaBH4 was not used), and the reaction was again
refluxed. When complete as determined by TLC analysis, the
mixture was concentrated in vacuo and the crude mixture was
purified by column chromatography.
(21) J ung, M. E.; Lyster, M. A. J . Chem. Soc., Chem. Commun. 1978,
315.
(22) Boeckman, R. K.; Potenza, J . C. Tetrahedron Lett. 1985, 26,
1411.
(23) Muxworthy, J . P.; Wilkinson, J . A.; Procter, G. Tetrahedron Lett.
1995, 36, 7539.
(24) Oxazolidinone 9 was reported23 to undergo Pd(0) coupling with
carbon nucleophiles (MeCOCH2Ts). We also found that 9 underwent
successful Pd(0) coupling with dimethyl malonate (90% yield) and
methyl nitroacetate (69% yield) and in one case underwent coupling
with Pd(II) (dimethyl malonate, 65% yield). Adenine coupling, how-
ever, was not successful under Pd(0)-coupling conditions, possibly
indicative of the equilibrium between the closed and open forms of the
urethane. This equilibrium has been previously reported with lactone
substrates: Aggarwal, V. K.; Monteiro, N.; Tarver, G. J .; Lindell, S.
D. J . Org. Chem. 1996, 61, 1192.
N-(Ben zyloxyca r bon yl)-2-oxa -3-a za bicyclo[2.2.1]h ep t-
5-en e [(()-5a ]. This compound was prepared by a modified
method as compared to that of Kirby et al.28 N-(Benzyloxy-
carbonyl)hydroxylamine (1.02 g, 6.1 mmol) was dissolved in
MeOH-H2O (3:1, 40 mL) and cooled to 0-5 °C. Freshly
distilled cyclopentadiene (1.4 mL, 17.4 mmol) and then NaIO4
(26) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17. (b) Shealy, Y.
F.; Clayton, J . D. J . Pharm. Sci. 1973, 62, 2311.
(27) Teng, M.; Miller, M. J . J . Am. Chem. Soc. 1993, 115, 548.
(28) Kirby, G. W.; McGuigan, H.; Mackinnon, J . W. M.; McLean,
D.; Sharma, R. P. J . Chem. Soc., Perkin Trans. 1 1985, 1437.
(25) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17.

Enzymatic Resolution of Aminocyclopentenols
J . Org. Chem., Vol. 63, No. 10, 1998 3361
(1.26 g, 5.9 mmol) were added, and the reaction was allowed
to warm to room temperature and stirred 2 h. The reaction
was cooled to 0-5 °C, more cyclopentadiene (1 mL, 12.5 mmol)
and NaIO4 (0.76 g, 3.5 mmol) were added, and the mixture
was stirred for 30 min. The mixture was concentrated in vacuo
to a slurry, H2O was added, and the solution was extracted
with EtOAc. The combined organic layers were washed with
saturated sodium thiosulfate, H2O, and brine, dried over
MgSO4, vacuum-filtered through Celite, and concentrated in
vacuo to a tan oil. Spectral data of the crude material was
consistent with that reported in the literature.28 This material
was used in the next reaction without further purification.
from that of Corrie30 and Ranganathan et al.31 NH2OH·HCl
(5.0 g, 72.0 mmol) was dissolved in EtOH (120 mL) and H2O
(60 mL) and cooled in an ice-water bath. NaHCO3 (12.1 g,
144 mmol) was added slowly, and after the mixture was stirred
for 15 min, Ac2O (6.8 mL, 72.0 mmol) was added. The reaction
was refluxed for 3 h (solution became homogeneous) and then
stirred overnight at room temperature. The pH of the reaction
was then adjusted from 7 to 5.5 by addition of 15% HCl.
MeOH (150 mL) and H2O (30 mL) were added followed by the
addition of freshly distilled cyclopentadiene (28 mL, 350.0
mmol). NaIO4 (15.0 g, 70 mmol) was dissolved in a minimal
amount of water (50 mL) and added to the reaction mixture.
The reaction was complete in 30 min as indicated by TLC
analysis. The mixture was concentrated in vacuo and the
slurry taken up into water and extracted with CH2Cl2. The
combined organics were dried over Na2SO4, vacuum-filtered
through Celite, and concentrated in vacuo to afford a light tan
oil. The product was not stable if heated during concentration.
Column chromatography (50% EtOAc-hexanes) afforded 9.7
g of cycloadduct (()-5d as a light tan oil in 99% yield. This
material was used in the next reaction without further
purification: 1H NMR δ 1.83 (bs, 1H), 1.86 (s, 1H), 1.98 (s,
3H), 5.28 (bs, 1H), 5.34 (bs, 1H), 6.37 (bs, 1H), 6.57 (bs, 1H);
HRMS (FAB) calcd for C7H10NO2 (M + 1) 140.0712, obsd
140.0697.
cis-N-Acet yl-4-a m in ocyclop en t -2-en ol [(()-6d ]. Cy-
cloadduct (()-5d was converted to the alcohol following the
general procedure for N-O bond reduction. Cycloadduct (()-
5d (1.0 g, 7.2 mmol) was reduced [Mo(CO)6 (2.28 g, 8.64 mmol),
NaBH4 (0.272 g, 7.2 mmol)]; column chromatography (2-8%
MeOH-CH2Cl2) afforded 870 mg of aminocylcopentenol (()-
6d as a yelow oil in 92% yield: 1H NMR δ 1.56 (ddd, J ) 3.3,
3.3, 14.4 Hz, 1H), 1.96 (s, 3H), 2.71 (ddd, J ) 7.5, 8.1, 14.4
Hz, 1H), 3.45 (bs, 1H), 4.72 (m, 2H), 5.83 (dd, J ) 1.5, 5.6 Hz,
1H), 6.01 (m, 1H), 6.23 (bs, 1H); 13C NMR δ 23.33, 40.83, 53.52,
74.97, 133.57, 136.47, 169.98; IR (neat) cm-1 3296, 3011, 1635;
HRMS (FAB) calcd for C7H12NO2 (M + 1) 142.0868, obsd
142.0882. Anal. Calcd for C9H13NO3: C, 59.56; H, 7.85; N,
9.92. Found: C, 59.39; H, 7.81; N, 9.90.
Gen er a l P r oced u r e for Acet yla t ion of N-P r ot ect ed
Am in ocyclop en ten ols. A CH2Cl2 solution of aminocyclo-
pentenol was charged with pyridine or triethylamine (6 equiv),
Ac2O (5 equiv), and (dimethylamino)pyridine (DMAP, 0.05
equiv) and stirred overnight under Ar at room temperature.
For water-insoluble products [(()-7a and (()-7b], the reaction
mixture was concentrated in vacuo, taken up in EtOAc,
washed with dilute aqueous HCl, H2O, and saturated aqueous
NaHCO3, dried over MgSO4, vacuum-filtered through Celite,
and concentrated in vacuo to give the crude product. For
water-soluble products [(()-7c and (()-7d ], the reaction
mixture was diluted with EtOAc and washed with 15% HCl
until no pyridine remained. The combined aqueous layers
were saturated with NaCl and back-extracted with EtOAc to
remove any product. The organic layers were combined,
washed with brine, dried over Na2SO4, filtered, and concen-
trated. The products were then purified as stated.
cis-N-(Ben zylcar bam oyl)-4-am in ocyclopen t-2-en ol [(()-
6a ]. Cycloadduct (()-5a was dissolved in MeCN-H2O (15:1,
40 mL); Mo(CO)6 (1.95 g, 7.4 mmol) was added, and the
mixture was refluxed for 2 h. The reaction mixture was then
concentrated in vacuo to a brown sludge, which was taken up
in EtOAc, dried over MgSO4, vacuum-filtered through Celite/
silica, and concentrated in vacuo. Column chromatography
(0-90% EtOAc-hexanes) provided 0.582 g of a white powder
in 41% yield for two steps: 1H NMR δ 1.55 (dt, J ) 3.3, 14.4,
1H), 2.72 (dt, J ) 8.1, 14.4, 1H), 3.07 (d, J ) 6.6, 1H), 4.49
(broad m, 1H), 4.67 (broad m, 1H), 5.07 (s, 2H), 5.22 (d, J )
8.4, 1H), 5.83 (dt, J ) 0.9, 5.4, 1H), 5.98 (d, J ) 5.4), 7.30-
7.36 (m, 5H); 13C NMR δ 41.09, 55.17, 66.65, 75.02, 128.04,
128.11, 128.48, 133.80, 136.29, 155.77; IR (KBr) cm-1 3319,
3062, 3032, 2892, 1682; HRMS (FAB) calcd for C13H16NO3 (M
+ 1) 234.1130, obsd 234.1107.
N-(Meth ylca r ba m oyl)-2-oxo-3-a za bicyclo[2.2.1]h ep t-5-
en e [(()-5c]. This compound was previously prepared by
Keck et al., although spectral data were not reported.29 NH2-
OH·HCl (5.22 g, 74.5 mmol) was dissolved in EtOH (60 mL)
and H2O (30 mL) and cooled in an ice-water bath. NaHCO3
(6.26 g, 74.5 mmol) was added slowly, and after the mixture
was stirred for 15 min, dimethylpyrocarbonate (8 mL, 74.5
mmol) was added. The reaction was refluxed for 3 h (solution
became homogeneous) and then stirred overnight at room
temperature. The pH of the reaction was then adjusted from
7 to 5.5 by addition of 15% HCl. MeOH (50 mL) and H2O (10
mL) were added followed by the addition of freshly distilled
cyclopentadiene (25 mL, 298.0 mmol). NaIO4 (16.0 g, 74.5
mmol) was dissolved in a minimal amount of water (10 mL)
and added to the reaction mixture. The reaction was complete
in 30 min as indicated by TLC analysis. The mixture was
concentrated in vacuo and the slurry taken up into water and
extracted with CH2Cl2. The combined organics were dried over
Na2SO4, vacuum-filtered through Celite, and concentrated in
vacuo to afford a tannish oil. The product was not stable if
heated during concentration. Column chromatography (50%
EtOAc-hexanes) afforded 11.5 g of cycloadduct (()-5c as a
light tan oil in 99% yield. This material was used in the next
reaction without further purification: 1H NMR δ 1.79 (d, J )
8.7 Hz, 1H), 2.03 (dt, J ) 2.1, 8.7 Hz, 1H), 3.75 (s, 3H), 5.05
(s, 1H), 6.42 (m, 1H), 6.47 (m, 1H); HRMS (FAB) calcd for
C7H10NO3 (M + 1) 156.0661, obsd 156.0657.
cis-N-(Ben zylcar bam oyl)-4-am in ocyclopen t-2-en ol 1-O-
Aceta te [(()-7a ]. To provide a standard for enzymatic assays;
following the general procedure for acetylation, alcohol (()-
6a (0.327 g, 1.4 mmol) was acetylated [Ac2O (0.16 mL, 1.7
mmol), triethylamine (1 mL, 7.2 mmol), DMAP (∼2 mg)] to
give 0.43 g of a pale yellow solid in quantitative yield: 1H NMR
δ 1.56 (dt, J ) 4.2, 15, 1H), 2.02 (s, 3H), 2.82 (overlapping dt,
J ) 7.8, 14.4, 1H), 4.73 (br s, 1H), 5.02 (d, J ) 8.4, 1H), 5.10
(s, 2H), 5.51-5.53 (m, 1H), 5.94 (d, J ) 5.7, 1H), 5.98 (d, J )
5.7, 1H), 7.27-7.36 (s, 5H); 13C NMR δ 21.10, 38.46, 54.81,
66.79, 77.32, 128.16, 128.50, 132.46, 136.61, 136.53, 155.42,
170.53; IR (KBr) cm-1 3315, 3068, 3037, 2953, 1734, 1687;
HRMS (FAB) calcd for C15H17NO4 (M + 1) 276.1236, obsd
276.1239.
cis-N-(Meth ylcar bam oyl)-4-am in ocyclopen t-2-en ol [(()-
6c]. Cycloadduct (()-5c was converted to the alcohol following
the general procedure for N-O bond reduction. Cycloadduct
(()-5c (1.0 g, 6.45 mmol) was reduced [Mo(CO)6 (2.04 g, 7.74
mmol), CH3CN (20 mL), H2O (1 mL)]; column chromatography
(2-4% MeOH-CH2Cl2) afforded 800 mg of aminocylcopentenol
(()-6c as a yelow oil in 80% yield: 1H NMR δ 1.56 (m, 1H),
2.74 (ddd, J ) 7.5, 8.1, 14.4 Hz, 1H), 3.07 (bs, 1H), 3.66 (s,
3H), 4.48 (m, 1H), 4.69 (m, 1H), 5.16 (bs, 1H), 5.84 (m, 1H),
6.00 (m, 1H); 13C NMR δ 40.87, 51.90, 54.90, 74.76, 133.76,
136.02, 156.46; IR (neat) cm-1 3336, 3064, 2951, 1700, 1540;
HRMS (FAB) calcd for C7H12NO3 (M + 1) 158.0817, obsd
158.0829.
N-Acetyl-2-oxo-3-a za bicyclo[2.2.1]h ep t-5-en e [(()-5d ].
This compound was prepared by a synthetic route different
(30) Corrie, J . E. T.; Kirby, G. W.; Mackinnon, J . W. M. J . Chem.
Soc., Perkin Trans. 1 1985, 883.
(31) Ranganathan, D.; Ranganathan, S.; Rao, C. B.; Raman, K.
Tetrahedron 1981, 37, 629.
(29) Keck, G. E.; Fleming, S.; Nickell, D.; Weider, P. Synth.
Commun. 1979, 9, 281 and references therein.

3362 J . Org. Chem., Vol. 63, No. 10, 1998
Mulvihill et al.
cis-N-(Meth ylcar bam oyl)-4-am in ocyclopen t-2-en ol 1-O-
Aceta te [(()-7c]. Following the general procedure for acetyl-
ation, alcohol (()-6c (0.370 g, 2.36 mmol) was acetylated [Ac2O
(0.67 mL, 7.08 mmol), pyridine (0.76 mL, 9.44 mmol), DMAP
(5 mg, 0.0460]; column chromatography (60% hexanes-EtOAc)
afforded 471 mg (quantitative) of methyl carbamate (()-7c as
a white solid (recrystallized from EtOAc-hexanes): mp 62-
63 °C; 1H NMR δ 1.53 (ddd, J ) 4.2, 4.2, 14.7 Hz, 1H), 2.05 (s,
3H), 2.82 (m, 1H), 3.68 (s, 3H), 4.75 (bs, 2H), 5.54 (m, 1H),
5.98 (m, 1H); 13C NMR δ 21.05, 38.46, 52.04, 54.74, 77.29,
132.34, 136.54, 156.10, 170.49; IR (KBr) cm-1 2952, 1726, 1530;
HRMS (FAB) calcd for C9H14NO4 (M + 1) 200.0923, obsd
200.0923.
cis-N-Acetyl-4-a m in ocyclop en t-2-en ol 1-O-Aceta te [(()-
7d ]. Following the general procedure for acetylation, alcohol
(()-6d (0.550 g, 3.9 mmol) was acetylated [Ac2O (1.84 mL, 19.5
mmol), pyridine (1.9 mL, 23.4 mmol), DMAP (5 mg, 0.046
mmol)]; column chromatography (80% EtOAc-hexanes) af-
forded 700 mg of acetamide (()-7d as a white solid in 98%
yield (recrystallized from EtOAc-hexanes): mp 103-104 °C;
1H NMR δ 1.53 (ddd, 3.9, 3.9, 14.7 Hz, 1H), 2.84 (ddd, J ) 7.8,
7.8, 14.7 Hz, 1H), 1.99 (s, 3H), 2.05 (s, 3H), 4.98 (m, 1H), 5.55
(m, 1H), 5.66 (bs, 1H), 5.99 (m, 2H); 13C NMR δ 21.08, 23.17,
38.16, 52.88, 77.49, 132.42, 136.48, 169.25, 170.44; IR (KBr)
cm-1 3438, 2986, 1732, 1666, 1509; HRMS (FAB) calcd for
C9H14NO3 (M + 1) 184.0974, obsd 184.0974.
En zym e Scr een in g of (()-6a w ith Altu s Ch ir oScr een -
TE Kit. The directions contained within the kit were followed.
Gen er a l P r oced u r e for E n zym a t ic R esolu t ion s b y
Acetyla tion . The alcohol to be kinetically resolved was
dissolved in the appropriate solvent; the enzyme and the
acetylation reagent were added. The flask was sealed, and
the mixture was stirred at room temperature with initial
qualitative monitoring by TLC and quantitative monitoring
by 1H NMR or by HPLC. After the % conversion reported,
the reaction was filtered through silica to remove the enzyme
and concentrated in vacuo.
Gen er a l P r oced u r e for Ch em ica l Solvolysis of Ace-
ta tes. Acetate (0.04 mmol) was dissolved in MeOH (∼2 mL),
and K2CO3 (∼5 mg) was added. The reaction was stirred at
room temperature for 3.5 h, at which time no starting material
remained as determined by TLC. The reaction mixture was
concentrated in vacuo, taken up in 10% MeOH-CHCl3 (EtOAc
for less polar saponification products), and washed with H2O
and brine. The solution was dried over MgSO4, vacuum-
filtered through Celite, and concentrated in vacuo.
Gen er a l P r oced u r e for Syn th esis of Mosh er Ester s.
The alcohol (0.038 mmol, crude) was placed in a flask, purged
with Ar, and then dissolved in CH2Cl2 (dry, 2 mL). DMAP
(15 mg, 0.12 mmol) and (S)-(+)-methoxy-R-(trifluoromethyl)-
phenylacetyl chloride (0.010 mL, 0.05 mmol) were added, and
the reaction was stirred for 30 min at room temperature. TLC
analysis indicated that no starting material remained. The
mixture was concentrated in vacuo, and the residue was taken
up in EtOAc, washed with H2O and saturated NaHCO3, dried
over MgSO4, vacuum-filtered through Celite, and concentrated
in vacuo.
En zym a tic Resolu tion of Alcoh ol (()-6a by Acetyla -
tion . (1) Alcohol (()-6a (28.2 mg, 0.12 mmol) was reacted in
CH2Cl2 (0.5 mL) with C. antarctica B lipase (5.2 mg) and vinyl
acetate (0.04 mL, 0.43 mmol) with monitoring by HPLC (8%
i-PrOH-hexanes; tR acetate ) 2.8 min; tR alcohol ) 5.1 min).
The reaction was terminated after 31 h and 39% conversion.
Preparative radial chromatography (25-75% EtOAc-hexanes)
provided acetate (-)-7a (9.1 mg), [R]22D ) -9.7 (c 0.33, CHCl3).
The hydrolysis product (K2CO3/MeOH) was purified by column
chromatography (25-75% EtOAc-hexanes), [R]24D ) +64.9 (c
0.205, CHCl3). The Mosher ester was synthesized and ana-
lyzed by HPLC; 1% i-PrOH-hexanes tR ) 14.48 min (major),
tR ) 14.87 (minor); major/minor 21:1 or 90% ee. These peaks
matched that of the Mosher ester made from a racemic sample
of alcohol (()-6a and (S)-(+)-methoxy-R-(trifluoromethyl)-
phenylacetyl chloride.
acetate (0.125 mL, 1.36 mmol) with monitoring by HPLC (see
above conditions). The reaction was terminated after 6 h and
40% conversion. Column chromatography (20-33% EtOAc-
hexanes) provided 40 mg of pure acetate. The acetate was
hydrolyzed and the Mosher ester synthesized and analyzed
by HPLC (as above); major/minor 23:1 or 92% ee.
En zym e Scr een in g of (()-6b w ith Boeh r in ger Lip a se
Kit. The amounts of enzymes used in this experiment are as
follows: (L-1) 6.7 mg, (L-2) 2.9 mg, (L-3) 13.4 mg, (L-4) 4.1
mg, (L-5) 8.5 mg, (L-6) 7.2 mg, (L-7) 18 mg, (L-8) 38 mg. Each
enzyme was added to a 20 mL scintillation vial containing a
stir bar. Alcohol (()-6b (53 mg, 0.27 mmol) was dissolved in
CH2Cl2 (17 mL); 2 mL of this solution was added to each vial
(0.03 mmol of alcohol per vial). Isopropenyl acetate (2 drops)
was added to each vial. The vials were capped and magneti-
cally stirred at room temperature. The reactions were moni-
tored at 1, 11, 18.5, and 35 h by TLC (50% EtOAc-hexanes)
with comparison to an authentic sample of the racemic
product. Burkholderia sp. (L-1) and C. antarctica B (L-2)
lipases were found to produce significant amounts of acetylated
products after 18.5-36 h.
En zym a tic Resolu tion of Alcoh ol (()-6b by Acetyla -
tion . (1) Alcohol (()-6b (62 mg, 0.314 mmol) was acetylated
in MTBE (2.5 mL) with Burkholderia sp. lipase (9.3 mg) and
isopropenyl acetate (0.14 mL, 1.27 mmol) with monitoring by
1H NMR. The reaction was terminated after 5.3 h and 39%
conversion. Preparative radial chromatography with 50%
EtOAc-hexanes provided 23.1 mg of pure acetate (more
acetate also isolated as a mixture), [R]23 ) -14.94 (c 0.46,
D
CHCl3). The acetate was hydrolyzed and the Mosher ester
synthesized: 19F NMR δ -8.82 (s), -8.76 (s); 3.47:1 ratio;
therefore, 77.6% pure or 55% ee. These peaks matched that
of the Mosher ester made from a racemic sample of alcohol
(()-6b and (S)-(+)-methoxy-R-(trifluoromethyl)phenylacetyl
chloride.
(2) Alcohol (()-6b (47.1 mg, 0.24 mmol) was acetylated in
MTBE (1.5 mL) with C. antarctica B lipase (9.7 mg) and
isopropenyl acetate (0.15 mL, 1.4 mmol) with monitoring by
1H NMR. The reaction was terminated after 21 h and 40%
conversion. Preparative radial chromatography (35-50%
EtOAc-hexanes) provided 19.9 mg of pure acetate, [R]22
)
D
-22.6 (c 0.40, CHCl3). The acetate was hydrolyzed and the
Mosher ester was synthesized: 19F NMR δ -8.82 (s), -8.76
(s); 9.5:1 ratio; therefore, 81% ee.
Hyd r olytic En zym a tic Resolu tion of (()-6c. Methyl
carbamate (()-6c (0.163 g, 0.82 mmol) was dissolved in MeOH
(minimum amount) and hydrolyzed with EEAC (250 units) in
NaH2PO4 buffer solution.32 After 3.5 h (50% conversion by
HPLC) the reaction was terminated by removal of the solvent.
The remaining slurry was extracted with 2:1 MeOH-EtOAc.
The organic layers were combined and concentrated to a white
solid. Column chromatography (5-8% MeOH-CH2Cl2) af-
forded 0.65 g (49%) of alcohol (+)-6c and 0.75 g (45%) of acetate
(+)-7c. Alcohol 6c: [R]22 ) +66.4 (c 0.13, CHCl3). Acetate
D
7c: [R]24 ) +50.0 (c 0.24, CHCl3). Mosher ester analysis of
D
(+)-6c was conducted by 19F NMR: δ -8.73 (s), -8.78 (s);
6.14:1 ratio; therefore, 72% ee. These peaks matched that of
the Mosher ester made from a racemic sample of alcohol (()-
6c and (S)-(+)-methoxy-R-(trifluoromethyl)phenylacetyl chlo-
ride.
Hyd r olytic En zym a tic Resolu tion of (()-7d . Acetate
(()-7d (3.40 g, 18.56 mmol) was dissolved in MeOH (minimum
amount) and hydrolyzed with electric eel acetylcholinesterase
(500 units) in NaH2PO4 buffer solution.32 After 49 h (40%
conversion by HPLC), the reaction was concentrated to a
slurry. The remaining slurry was extracted with 2:1 MeOH-
EtOAc. The organic layers were combined and concentrated
to a white solid. Column chromatography (5-8% MeOH-CH2-
(32) The buffer was prepared by dissolution of 100 g of sodium
dihydrogen phosphate monohydrate into 200 mL of distilled water. The
pH of the solution was adjusted to 6.9 with the addition of concentrated
sodium hydroxide solution, and then the solution was diluted to a final
volume of 500 mL.
(2) Alcohol (()-6a (75 mg, 0.374 mmol) was reacted in CH2-
Cl2 (1.0 mL) with Pseudomonas sp. lipase (8 mg) and vinyl

Enzymatic Resolution of Aminocyclopentenols
J . Org. Chem., Vol. 63, No. 10, 1998 3363
Cl2) afforded 1.0 g of alcohol (+)-6d and 2.06 g of enantiomeri-
ci s-N -(t er t -B u t y lc a r b a m o y l)-4-a m in o c y c lo p e n t -2-
en ol [(()-6b] fr om (()-7a . Acetate (()-7a (0.35 g, 1.27 mmol)
was dissolved in p-dioxane-H2O (1:1, 24 mL) and Ba-
(OH)2·8H2O (1.5 g, 4.8 mmol) was added. The mixture was
refluxed for 55 h and then cooled to room temperature. The
reaction was neutralized with solid CO2 to pH 6-7 and then
gravity-filtered and concentrated in vacuo to an oil. The oil
was taken up in absolute EtOH, gravity-filtered, and concen-
trated in vacuo.
cally enriched acetate (+)-7d : [R]22 ) +25.66 (c 0.38,
D
CHCl3).
Enantiomerically enriched acetate 7d (2.0 g, 10.92 mmol)
was subjected to the same conditions (25 mL 1.45 M NaH2-
PO4 buffer, 38 mL H2O, 1000 units EEAC, and 5 mg NaN3)
for 7 h (20% conversion). The reaction was worked up and
chromatographed as described above to afford 1.60 g of
diacetate (+)-7d and 0.30 g of (()-6d . Alcohol (+)-6d : Mosher
ester analysis of (+)-6d : 19F NMR δ -8.24 (s), -8.11 (s); 96:4
ratio; therefore, 92% ee. These peaks matched that of the
Mosher ester made from a racemic sample of alcohol (()-6d
and (S)-(+)-methoxy-R-(trifluoromethyl)phenylacetyl chloride.
Acetate (+)-7d was solvolyzed (MeOH, K2CO3) to alcohol (-)-
The crude 4-aminocyclopent-2-enol was dissolved in THF
(20 mL) and then NaHCO3 (0.26 g, 3.8 mmol) and Boc2O (0.45
g, 2.1 mmol) were added and the mixture was stirred at room
temperature for 9 h. More NaHCO3 (0.2 g, 2.9 mmol) and
Boc2O (0.28 g, 1.3 mmol) were added, and the mixture was
stirred for an additional 3 h. The mixture was concentrated
in vacuo, taken up in EtOAc, and washed with saturated
aqueous NH4Cl, H2O, saturated aqueous NaHCO3, and brine.
The solution was dried over MgSO4, vacuum-filtered through
Celite/silica, and concentrated in vacuo. Preparative radial
chromatography gave 0.14 g of (()-6b in 67% yield based on
recovered starting material [(()-7a ]; 57 mg. Spectral data
were consistent with literature values.4b
6d , [R]24 ) -90.0 (c 0.10, CHCl3). Alcohol (-)-6d was
D
converted to its Mosher ester: 19F NMR δ -8.12 (s), -8.24
(s); 96:4 ratio; therefore, 92% ee. Alcohol (-)-6d was recrystal-
lized (EtOAc/hexanes) and then converted to its Mosher ester.
19F NMR analysis of the Mosher ester indicated >99% purity
of a single isomer; therefore, 99% ee.
1-(ter t-Bu tylca r ba m oyl)cyclop en t-4-en o-syn -3a ,6a -ox-
a zolid in -2-on e (9). Alcohol (()-6a (1.13 g, 4.8 mmol) was
dissolved in trifluoroacetic acid (10-12 mL). The reaction
evolved a slight amount of heat during which time it was
briefly cooled and the reaction turned dark brown. After being
stirred at room temperature for 30 min, no starting material
remained as determined by TLC (50% hexanes-EtOAc).
Toluene-EtOAc (1:1) was added, and the mixture was con-
centrated in vacuo. This procedure was repeated several
times. The crude, brown oil was stored at 0 °C overnight.
Crystallization of a portion of oxazolidinone 8 occurred, giving
colorless crystals that were collected on a Hirsch funnel and
rinsed with toluene-hexanes, mp 118-121 °C. These crystals
were recombined with the crude oil and taken on to the next
synthetic step.
ci s-N -(t er t -B u t y lc a r b a m o y l)-4-a m in o c y c lo p e n t -2-
en ol 1-O-Aceta te [(-)-7b] fr om (-)-7d . Acetamide (-)-7d
(0.814 g, 4.44 mmol) was dissolved in saturated aqueous Ba-
(OH)2 (37 mL) and refluxed for 26.5 h. The reaction was then
worked up as above. The crude 4-aminocyclopentenol was
protected with an N-Boc group as above for (()-6b from (()-
7a . Acetylation according to the general procedure described
above followed by column chromatography (0-40% EtOAc-
hexanes) gave 0.9805 g of a white solid in 92% yield. Spectral
data were consistent with literature values,6a [R]23 ) -16.7
D
(c 0.59, CHCl3).
The crude oxazolidinone 8 was dissolved in CH2Cl2 (dry, ∼40
mL) under Ar. Triethylamine (∼3 mL) was added, and the
mixture was cooled over an ice bath. Boc2O (1.6 g, 7.3 mmol)
and DMAP (∼5 mg) were added, and then the mixture was
allowed to warm to room temperature. After 3.5 h, starting
material remained as determined by TLC (100% EtOAc).
Triethylamine (1.5 mL) was added, and the mixture was
stirred for 22 h; TLC indicated that starting material still
remained. Boc2O (1.65 g, 7.6 mmol) was added, and the
reaction was stirred at room temperature for an additional 22.5
h. The mixture was then concentrated in vacuo. The residue
was taken up in EtOAc and washed with saturated aqueous
NaHCO3, water, and brine. The solution was dried over
MgSO4, vacuum filtered through Celite and silica, and con-
centrated in vacuo to a brown oil. Column chromatography
(0-75% EtOAc-hexanes) provided 0.803 g of a light yellow
solid in 76% overall yield: 1H NMR δ 1.40 (br s, 10H), 2.49 (d
of quintets, J ) 2.4, 18.3, 1H), 2.77 (ddt, J ) 2.4, 6.9, 18.6,
1H), 4.63 (t, J ) 8.0, 1H), 5.27 (d, J ) 8.1, 1H), 5.69-5.74 (m,
1H), 5.98 (dd, J ) 2.1, 5.7, 1H); 13C NMR δ 27.52, 40.11, 55.86,
81.13, 83.13, 127.26, 136.37, 148.89, 151.54; IR (KBr) cm-1
Ack n ow led gm en t. We gratefully acknowledge the
NIH (AI 30988) for partial support of this research and
the Lizzadro Magnetic Resonance Research Center at
Notre Dame for NMR facilities, as well as Dr. B. Boggess
and N. Sevova for mass spectrometry facilities. M. J .
Mulvihill also appreciated support from the University
of Notre Dame in the form of Nieuwland and Lubrizol
fellowships. The authors would like to acknowledge Dr.
Paul F. Vogt for assistance in determining absolute
configurations, Dr. Milton Zmijewski at Eli Lilly and
Co. for helpful suggestions, and Maureen Wickham for
assistance with the manuscript.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra (16 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.
3005, 2976, 2937, 1814, 1710; HRMS (FAB) calcd for C11H16
-
NO4 (M + 1) 226.1079, obsd 226.1098.
J O972265A