Enantioselective Synthesis of 4-Acetylaminocyclopent-2-en-1-ols from Tricyclo[5.2.1.02,6]decenyl Enaminones. Precursors for 5′-Norcarbocyclic Nucleosides and Related Antiviral Compounds

Article abstract of DOI:10.1021/jo982498h

An efficient synthesis of both (1S,4R) and (1R,4S)-4-N-acetylamino-1-benzoylcyclopent-2-enes 33 has been accomplished starting from enantiopure 5-(1′-phenylethylamino)-endo-tricyclo[5.2.1.0 ^2,6]-deca-4,8-dien-3-ones 14 and 15. N-Acetylation of both 15 and 14 followed by single electron-transfer reduction using lithium in liquid ammonia afforded diastereomeric mixtures of β-amino ketones 26 and 27 and of ent-26 and ent-27 in high yields and with high diastereoselectivity. In this reduction process, the enaminone double bond is reduced with the concomitant removal of the α-methylbenzyl group as the chiral auxiliary. Thermolysis of the respective diastereomic mixtures of 26 and 27 in the gas phase (FVT) or in solution afforded 4-N-acetylaminocyclopent-2-ene-1-ones 30 in high optical and chemical yields. Acidic hydrolysis of (+)-30 gave (R)-(+)-4-aminocyclopentenone 31 as its hydrochloride. Stereoselective reduction of 30 using sodium borohydride and cerium chloride heptahydrate furnished amido alcohol 32, which was isolated and characterized as its benzoyl derivative 33.

Full text of DOI:10.1021/jo982498h

J . Org. Chem. 1999, 64, 3635-3641
3635
En a n tioselective Syn th esis of 4-Acetyla m in ocyclop en t-2-en -1-ols
fr om Tr icyclo[5.2.1.02,6]d ecen yl En a m in on es. P r ecu r sor s for
5′-Nor ca r bocyclic Nu cleosid es a n d Rela ted An tivir a l Com p ou n d s
Namakkal G. Ramesh, Antonius J . H. Klunder,* and Binne Zwanenburg*
Department of Organic Chemistry, NSR Center for Molecular Structure, Design and Synthesis,
University of Nijmegen, Toernooiveld, 6525 ED Nijmegen, The Netherlands
Received December 23, 1998
An efficient synthesis of both (1S,4R) and (1R,4S)-4-N-acetylamino-1-benzoylcyclopent-2-enes 33
has been accomplished starting from enantiopure 5-(1′-phenylethylamino)-endo-tricyclo[5.2.1.02,6]-
deca-4,8-dien-3-ones 14 and 15. N-Acetylation of both 15 and 14 followed by single electron-transfer
reduction using lithium in liquid ammonia afforded diastereomeric mixtures of â-amino ketones
26 and 27 and of ent-26 and ent-27 in high yields and with high diastereoselectivity. In this reduction
process, the enaminone double bond is reduced with the concomitant removal of the R-methylbenzyl
group as the chiral auxiliary. Thermolysis of the respective diastereomic mixtures of 26 and 27 in
the gas phase (FVT) or in solution afforded 4-N-acetylaminocyclopent-2-ene-1-ones 30 in high optical
and chemical yields. Acidic hydrolysis of (+)-30 gave (R)-(+)-4-aminocyclopentenone 31 as its
hydrochloride. Stereoselective reduction of 30 using sodium borohydride and cerium chloride
heptahydrate furnished amido alcohol 32, which was isolated and characterized as its benzoyl
derivative 33.
In tr od u ction
With the discovery that carbocyclic nucleosides exhibit
pronounced antiviral activities,1 recent years have wit-
nessed an upsurge in research related to the synthesis
of these compounds and their analogues. Naturally
occurring carbocyclic nucleosides such as aristeromycin
(1), obtained from Streptomycis citricolor,2 and neplanocin
A (2), isolated from Actinoplanacea ampullariella,3 all
display significant biological activity (Figure 1). However,
the antiviral potential of aristeromycin4 has been limited
by its cytotoxicity, which arises from the biological
consequences of its 5′-triphosphate metabolite.5 Nepl-
anocin A (2) has been found to exhibit antileukemic
activity, and it is less toxic.3 Carbovir (3)6 and 1592U89
(4)7 are synthetic carbocyclic nucleosides that also have
interesting antiviral activities. Recently, Schneller and
co-workers reported that 5′-noraristeromycin (5),8 which
is a desmethylene analogue of 1, shows similar antiviral
F igu r e 1.
activity but without significant cytotoxicity. Since then,
the synthesis of 5′-noraristeromycin9 and various ana-
logues of 5′-norcarbocyclic nucleosides have been reported
and their biological activities evaluated.10
Basic building blocks for the synthesis of these 5′-
norcarbocyclic nucleosides constitute suitably substituted
aminocyclopentenols 6 (Figure 2).11 General approaches
* To whom correspondence should be addressed. Tel:+ 31 24
3653159. Fax: + 31 24 3652929. E-mail: zwanenb@sci.kun.nl.
(1) For recent reviews on carbocyclic nucleosides and their synthesis,
see: (a) Crimmins, M. T. Tetrahedron 1998, 54, 9229. (b) Mansour, T.
S.; Storer, R. Curr. Pharm. Des. 1997, 3, 227. (c) Marquez, V. E. In
Advances in Antiviral Drug Design; De Clercq, E., Ed.; J AI Press Inc.:
Greenwich, CT, 1996; Vol. 2, p 89. (d) Agrofoglio, L.; Suhas, E.; Farese,
A.; Condom, R.; Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron
1994, 50, 10611. (e) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992,
48, 571.
(2) Kusaka, T.; Yamamato, H.; Shibata, M.; Muroi, M.; Hicki, T.;
Mizuno, K. J . Antibiot. 1968, 21, 255.
(3) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.;
Otani, M. J . Antibiot. 1981, 34, 359.
(4) (a) De Clercq, E. Biochem. Pharmacol. 1987, 36, 2567. (b) Cools,
M.; De Clercq, E. Biochem. Pharmacol. 1989, 38, 1061.
(5) (a) Shealy, Y. F.; Clayton, J . D. J . Pharm. Sci. 1973, 62, 858. (b)
Wolfe, M. S.; Borchardt, R. T. J . Med. Chem. 1991, 34, 1521.
(6) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17.
(7) For a recent synthesis: Crimmins, M. T.; King, B. W. J . Org.
Chem. 1996, 61, 4192.
(9) Merlo, V.; Reece, F. J .; Roberts, S. M.; Gregson, M.; Storer, R. J .
Chem. Soc., Perkin Trans. 1 1993, 1717.
(10) (a) Ghosh, A.; Ritter, A. R.; Miller, M. J . J . Org. Chem. 1995,
60, 5808. (b) Ghosh, A.; Miller, M. J . Tetrahedron Lett. 1995, 36, 6399.
(c) Ritter, A. R.; Miller, M. J . J . Org. Chem. 1994, 59, 4602. (d) Wu,
Y.; Woster, P. M. J . Med. Chem. 1992, 35, 3196. (e) Merlo, V.; Roberts,
S. M.; Storer, R.; Bethell, R. C. J . Chem. Soc., Perkin Trans. 1 1994,
1477. (f) Coe, D. M.; Roberts, S. M.; Storer, R. J . Chem. Soc., Perkin
Trans. 1 1992, 2695. (g) Coe, D. M.; Garafalo, A.; Roberts, S. M.; Storer,
R.; Thorpe, A. J . J . Chem. Soc., Perkin Trans. 1 1994, 3061. (h) Drake,
A. F.; Garafalo, A.; Hillmann, J . M. L.; Merlo, V.; McCague, R.; Roberts,
S. M. J . Chem. Soc., Perkin Trans. 1 1996, 2739. (i) Gooding, H.;
Roberts, S. M.; Storer, R. J . Chem. Soc., Perkin Trans. 1 1994, 1891.
(j) Seley, K. L.; Schneller, S. W. J . Org. Chem. 1997, 62, 5645.
(8) (a) Siddiqi, S. M.; Chen, X.; Schneller, S. W.; Ikeda, S.; Snoeck,
R.; Andrei, G.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1994, 37,
551. (b) Patil, S. D.; Schneller, S. W. J . Med. Chem. 1992, 35, 3372.
10.1021/jo982498h CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/29/1999

3636 J . Org. Chem., Vol. 64, No. 10, 1999
Ramesh et al.
Sch em e 1
F igu r e 2.
to 6 involve (a) the cycloaddition of appropriate nitroso
compounds with cyclopentadiene followed by hydroly-
sis,8b,10a,b,11b,c,e,f (b) the displacement of hydroxy group or
its derivatives in mono- or diprotected 1,4-dihydroxycy-
clopent-2-ene by an amino8a,10d,j or azido11g function, (c)
opening of epoxy cyclopentene by purine bases,9 and (d)
rearrangement of 4-amino substituted cyclopentene
oxide.11a In recent years, we12 and others13,14 have dem-
onstrated that the endo-tricyclo[5.2.1.02,6]deca-4,8-dien-
3-one system 7 is a highly useful synthon for a wide range
of naturally occurring cyclopentanoids and other phar-
macologically important structures. Recently, we re-
ported on the asymmetric desymmetrization of pseudo-
meso-5-hydroxy-endo-tricyclodecadienone 8 by chiral
amines affording the readily separable diastereomeric
tricyclic enaminones 9 and 9′ in excellent yields.15 These
tricyclic enaminones are attractive chirons as they could
provide a convenient entry to the enantioselective syn-
thesis of aminocyclopentenols 6 applying the cyclorever-
sion methodogy as depicted in Scheme 1. Selective 1,4-
reduction of 9 would give â-aminoketone 10, which on [4
+ 2]-cycloreversion gives access to the valuable γ-ami-
nocyclopentenones 11. These γ-aminocyclopentenones,
although reported in some specific cases as precursors
in the synthesis of prostanoids,16 carbanucleosides, an-
tiviral dipeptide isosteres,17 and thienamycin,18 have so
far not been extensively studied, clearly due to the lack
of a general and efficient access to these compounds. The
present routes to this class of compounds involve the
oxidation of amino alcohols17-19 and the nucleophilic 1,4-
addition of amines to suitably functionalized 4-hydroxy-
cyclopentenones.20,21 Subsequent carbonyl reduction in 11
would afford the desired aminocyclopentenols 6. Alter-
natively, 1,2-reduction of the enaminone system in 9 may
lead to tricyclic enamines 12, which, then, in a second
regioselective reduction step can be converted into tri-
cyclic amino alcohols 13, which on cycloreversion are ex-
pected to give aminocyclopentenols 6. In this paper, we
disclose a general and enantioselective synthesis of γ-
aminocyclopentenones 11 including the parent amino
compound (11, R, R′) H), which so far had not been pre-
pared, and their stereo- and regioselective reduction to
cis-amino alcohols 6, starting from appropriately sub-
situted homochiral tricyclic enaminones 9 and 9′, essen-
tially following the strategy as depicted in Scheme 1.22
Resu lts a n d Discu ssion
N-R-Methylbenzyl-substituted tricyclic enaminones 14
and 15 were selected as the most appropriate substrates
to test the synthetic strategy shown in Scheme 1 because
(i) both diastereomers are readily available from γ-hy-
droxytricyclodecadienone (8) in optically pure form15 and
(ii) the chiral auxiliary, namely the R-methylbenzyl
group, can in principle be reductively removed, consider-
ably enhancing the synthetic potential of this methodol-
ogy. The first step in our synthetic approach requires a
chemo- and regioselective reduction of either the C4-C5
enaminone double bond or the C3-ketone function in 14
and 15. A wide range of hydride reagents was employed
to effect this conversion,23 but none of them proved
successful. The conventional reagents either refused to
reduce the enaminone moiety in 14 and 15 at all or, if
reduction had occurred, a mixture of inseparable com-
pounds was obtained. In some cases, parent endo-tricyclo-
[5.2.1.02,6]deca-4,8-dien-3-one (17) was isolated from 14,
indicating the intermediacy of â-amino ketone 16 (Figure
3), which under the reaction conditions is apparently not
(11) For recent synthesis on aminocyclopentenol derivatives see: (a)
Brien, P. O.; Towers, T. D.; Voith, M. Tetrahedron Lett. 1998, 39, 8175.
(b) Mulvihill, M. J .; Gage, J . L.; Miller, M. J . J . Org. Chem. 1998, 63,
3357. (c) Zhang, D.; Suling, C.; Miller, M. J . J . Org. Chem. 1998, 63,
885. (d) ref 10j. (e) Ranganathan, S.; George, K. S. Tetrahedron 1997,
53, 3347. (f) Vogt, P. F.; Hansel, J .-G.; Miller, M. J . Tetrahedron Lett.
1997, 38, 2803. (g) Trost, B. M.; Stenkamp. D.; Pulley, S. R Chem.
Eur. J . 1995, 1, 568.
(12) Klunder, A. J . H.; Zwanenburg, B. In Gas-Phase Reactions in
Organic Synthesis; Valle´e, Y., Ed.; Gordon and Breach Science Publ.:
Amsterdam, 1997; p 107.
(13) For a recent synthesis of tricyclodecadienone, see: Knol, J .;
Feringa, B. L. Tetrahedron Lett. 1997, 38, 2527.
(14) (a) Kanada, R. M.; Taniguchi, T.; Ogasawara, K. J . Chem. Soc.,
Chem. Commun. 1998, 1755. (b) Ogasawara, K. J . Synth. Org. Chem.
J pn. 1996, 54, 15. (c) Ogasawara, K. Pure. Appl. Chem. 1994, 66, 2119.
(d) Garland, R. B.; Miyano, M.; Pireh, D.; Clare, M.; Finnegan, P. M.;
Swenton, L. J . Org. Chem. 1990, 55, 5854. (e) Liu, Z.-Y.; He, L.; Zheng,
H. Synlett 1993, 191.
(15) Bakkeren, F. J . A. D.; Ramesh, N. G.; De Groot, D.; Klunder,
A. J . H.; Zwanenburg, B. Tetrahedron Lett. 1996, 37, 8003.
(16) (a) Tolstikov, G. A.; Ismailov, S. A.; Prishchepova, E. V.;
Khalilov, L. M.; Shitikova, O. V.; Miftakhov, M. S. Zh. Org. Khim. 1991,
27, 2534; Chem. Abstr. 1992, 117, 89997. (b) Freimanis, J .; Bolaldere,
R.; Lola, D.; Turovskii, I. V.; Gavars, M. Zh. Org. Khim. 1990, 26, 2114;
Chem. Abstr. 1991, 115, 207700.
(17) Thompson, W. J .; Vacca, J . P.; Huff, J . R.; Lyle, T. A.; Young,
S. D.; Hungate, R. W.; Britcher, S. F.; Ghosh, A. K. Eur. Pat. Appl. EP
434,365; Chem. Abstr. 1992, 116, 256051.
(19) (a) Ranganathan, D.; Ranganathan, S.; Rao, C. B. Tetrahedron
1981, 37, 637. (b) Ranganathan, D.; Ranganathan, S.; Rao, C. B.;
Raman, K. Tetrahedron 1981, 37, 629.
(20) Minamii, M. J pn. Kokai Tokkyo Koho J P 6205,940; Chem. Abstr.
1987, 107, 175556.
(21) (a) West, F. G.; Gunawardena, G. U. J . Org. Chem. 1993, 58,
2402. (b) Bokaldere, R.; Lola, D.; Freimanis, J . Latv. PSR Zinat. Akad.
Vestis, Kim Ser. 1987, 3, 359; Chem. Abstr. 1988, 108, 149937. (c)
Minai, M.; Katsura, T. Ger. Offen. DE 3217904; Chem. Abstr. 1982,
98, 106859.
(18) Morley, A. D.; Hollinshead, D. M.; Procter, G. Tetrahedron Lett.
1990, 31, 1047.
(22) For a preliminary communication, see: Ramesh, N. G.; Klunder,
A. J . H.; Zwanenburg, B. Tetrahedron Lett. 1998, 39, 1429.

Synthesis of 4-Acetylaminocyclopent-2-en-1-ols
J . Org. Chem., Vol. 64, No. 10, 1999 3637
Sch em e 3
F igu r e 3.
Sch em e 2a
The next step in our route to aminocyclopentenols 6 is
the regioselective reduction of the remaining C4-C5
enamine double bond (Scheme 1). The susceptibility of
the norbornene C8-C9 double bond toward catalytic
hydrogenation necessitates the temporary protection of
this double bond in order to allow selective hydrogenation
of the enamine double bond. An elegant protection
involves the use of the endo configuration of the C3-
hydroxyl function. Ogasawara et al.25 have shown for
related tricyclic endo-alcohols that halogenation of 20 or
21 using N-halosuccinimides may lead to the cyclic ethers
22 and 23, respectively, by intramolecular attack of the
endo-alcohol function at the intermediate halonium ion.
Regeneration of the original double bond is eventually
accomplished by reductive halogen elimination using
activated zinc. Whereas in the literature N-bromosuc-
cinimide (NBS) worked well for the parent endo-3-
hydroxy-endo-tricyclo[5.2.1.02,6]deca-4,8-diene, the hy-
droxy enamines 20 and 21 only gave complex mixtures
of halogenated products, even at -78 °C. In contrast,
N-iodosuccinimide (NIS) proved to be an efficient and
successful halogenating reagent and led to the iodo ethers
22 and 23 in excellent yields of 94% and 89%, respectively
(Scheme 4). Attempted hydrogenation26 of the iodo ether
23 with a variety of catalysts did not lead to any
reduction of the enamine double bond. Surprisingly, both
the enamine double bond and the R-methylbenzyl group
proved inert to hydrogenation even after prolonged
reaction times. Use of Pd/C or Pd(OH)2 as catalysts
resulted in the cleavage of the allylic carbon-oxygen
bond, giving rise to the trans iodo alcohol 24 as the only
product. On the contrary, Raney nickel afforded a single
product 25 arising from deiodination (Scheme 4). The
strategy outlined in the bottom line in Scheme 1, leading
to aminocyclopentenols 6, was abandoned because of the
failure of the iodo ether 23 to give the desired reduction.
a
Key: (a) NaH, CH3COCl, THF, 89%.
stable but immediately undergoes elimination of the
â-amino functionality.
The reluctance of the enaminone moiety in 14 and 15
to undergo hydride reduction under relatively mild
conditions may be attributed to its pronounced π-delo-
calization, which decreases its electrophilicity in such a
manner that rather harsh reduction conditions are nec-
essary leading to nonselective reactions. We hypothesized
that the introduction of an electron-withdrawing group
on nitrogen might possibly circumvent this problem. For
this purpose, N-acetyl derivatives 18 and 19 were pre-
pared by acetylation of 14 and 15, respectively, using
sodium hydride and acetyl chloride in THF (Scheme 2).
Hyd r id e Red u ction of N-Acetyl En a m in on es 18
a n d 19. Selective reduction of 18 and 19 was attempted
again with a variety of reducing agents. In some cases
the lability of the N-acetyl group interfered with the
reduction method. Thus, the use of sodium borohydride
in MeOH led to complete removal of the amide bond in
18 or 19 to give the original enaminones 14 or 15,
respectively. The use of more reactive metal hydrides
appeared rather unselective and led, among other reac-
tion pathways, to reduction of the acetamide function,
producing mixtures of compounds. The use of metal
hydrides therefore seemed unsuited for selective 1,2- or
1,4-reduction of enaminones 18 and 19. Brown and co-
workers24 reported that 9-BBN was an ideal reagent for
the selective reduction of ketone carbonyls in the pres-
ence of a wide variety of other functional groups. When
this reagent was applied to enaminones 18 and 19, a
highly selective 1,2-reduction took place to give the
respective endo-alcohols 20 and 21 as single compounds,
in 83% and 92% yield, respectively (Scheme 3).
Sin gle Electr on -Tr a n sfer Red u ction of N-Acetyl
En a m in on es 18 a n d 19. An attractive alternative con-
jugated reduction of enones involves the use of alkali and
alkaline earth metals in liquid ammonia,27 which accord-
ingly was attempted for 18 and 19. Upon treatment of
diastereomerically pure 19 with lithium in liquid am-
(23) For the reduction of enaminones using various reagents, see:
(a) Cimarelli, C.; Palmieri, G. J . Org. Chem. 1996, 61, 5557. (b) Comins,
D. L.; LaMunyon, D. H. Tetrahedron Lett. 1989, 30, 5053. (c) Michael,
J . P.; Parsons, A. S.; Hunter, R. Tetrahedron Lett. 1989, 30, 4879. (d)
Imhof, R.; Kyburz, E.; Daly, J . J . J . Med. Chem. 1984, 27, 165. (e)
Nikiforov, T.; Stanchev, S.; Milenkov, B.; Dimitrov, V. Heterocycles
1986, 24, 1825. (f) Schuda, P. F.; Ebner, C. B.; Morgan, M. T.
Tetrahedron Lett. 1986, 27, 2567. (g) Weselowsky, V. W.; Moiseenkov,
A. M. Synthesis 1974, 58. (h) Borch, R. F.; Bernstein, M. D.; Durst, H.
D. J . Am. Chem. Soc. 1971, 93, 2897.
(24) Brown, H. C.; Krishnamurthy, S.; Yoon, N. M. J . Org. Chem.
1976, 41, 1778.
(25) (a) Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 1996, 37,
205. (b) Kamikubo, T.; Hiroya, K.; Ogasawara, K. Tetrahedron Lett.
1996, 37, 499.
(26) J ohnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Chem. Rev.
1985, 85, 129.
(27) Caine, D. Org. React. 1976, 23, 1.

3638 J . Org. Chem., Vol. 64, No. 10, 1999
Ramesh et al.
Sch em e 4
F igu r e 4.
Sch em e 6
at C5 preferentially occurs from the endo face, thus
positioning the â-amino group on the exo side of the
tricyclodecenyl system. Interestingly, the reduction of the
diastereomer 18 gave a similarly high yield of ent-26 and
ent-27, however strikingly, with a considerably lower
diastereoselectivity (de ) 76%)28 than observed for the
reduction of 19 (de ) 94%) (Scheme 5). This difference
in the diastereoselectivity shows that the chiral R-meth-
ylbenzyl group plays a role in the stereocontrol during
the protonation of the intermediate carbanion. As a
consequence, it follows that the reduction of the enone
moiety precedes the reductive removal of the R-methyl-
benzyl group (Scheme 6). If true, this sequence of
reduction steps also explains the ultimate preferential
protonation of the intermediate carbanionic interme-
diate from the sterically generally less accessible endo
face. In the intermediate dianion 28, the amino func-
tionality containing the bulky R-methylbenzyl group is
forced to move away from the endo face of the tricyclic
system due to considerable steric interaction with the
norbornene unit, thereby promoting protonation from the
endo face to form 29. Furthermore, the nature of the
proton donor as well as the order of addition of the
reagents seem to play an important role in the course of
the reaction. Among the various proton donors tried, viz.
water, ammonium chloride, t-BuOH, and triphenyl-
methane, only in the case of t-BuOH as the proton donor
was the reaction efficient in terms of both yield and
diastereoselectivity. With respect to the order of addi-
tion: lithium metal must be added to the mixture of the
enaminone, t-BuOH, THF, and liquid ammonia (see
Experimental Section). Changing the order of addition
resulted in much lower yields of the desired â-amino
ketones.
Sch em e 5
monia as the reducing agent and t-BuOH as the proton
donor, a diastereomeric mixture of â-amino ketones 26
and 27 was obtained in an excellent yield of 89% and
with a remarkably high diastereoselectivity (de ) 94%)28
(Scheme 5). This unexpected and facile reduction of the
enaminone double bond in 19 along with the concomitant
removal of the chiral auxiliary by lithium in liquid
ammonia is unprecedented. Even though removal of an
R-methylbenzyl group from a tertiary amide using lithium
in liquid ammonia has been reported,29 to our knowledge,
this is the first example wherein this method has been
used to simultaneously reduce an enaminone double bond
with the concurrent removal of an R-methylbenzyl group
at nitrogen. Apart from being novel, this method may be
general for the synthesis of optically active â-amino
ketones from enaminones.
Detailed NOESY studies unambiguously revealed the
exo stereochemistry of the N-acetyl amino group in the
major diastereomer 26. The H5 proton in 26 has a strong
NOE with one of the norbornene olefinic protons, pre-
sumably H8, and with H4b, but not with H4a (Figure 4).
In addition, the NH proton has a strong NOE with H4a
and H6. It is worth noting that despite the endo face being
sterically considerably hindered in 19, proton donation
Attempts to separate the diastereomers 26 and 27 by
chromatographic methods were not successful; hence, this
diastereomeric mixture (de 94%) was subjected to ther-
molysis in order to bring about the desired [4 + 2]
cycloreversion. The retro Diels-Alder reaction proceeded
smoothly both under static conditions in refluxing o-
chlorobenzene (o-DCB)30 as well as under dynamic condi-
tions, applying the flash vacuum thermolytic technique
(FVT)31 at 500 °C and 0.05 mbar to afford (R)-(+)-N-
acetyl-4-aminocyclopent-2-ene-1-one ((+)-30), [R]25
)
(28) The diastereomeric ratios were determined by GC analysis and
1H NMR (300 MHz).
D
(29) Webster, F. X.; Millar, J . G.; Silverstein, R. M. Tetrahedron Lett.
1986, 27, 4941.
(30) For an example of similar solution thermolysis, see ref 25b.

Synthesis of 4-Acetylaminocyclopent-2-en-1-ols
J . Org. Chem., Vol. 64, No. 10, 1999 3639
Sch em e 7
yield (88%), the product alcohol 32 could not be obtained
in an entirely pure form due to contamination with a very
small amount of some inorganic material. Removal of
these impurities was rather troublesome due to the high
polarity and therefore high solubility in water of amido
alcohol 32, which did not allow aqueous workup. In
addition, overlapping of the signals of H1 and H3 at δ 4.69
1
ppm in the H NMR spectrum of 32 (both in CDCl3 and
CD3OD) rendered it difficult to establish the relative
stereochemistry between the hydroxyl and amido func-
tionalities. These problems were readily overcome by
converting the alcohol 32 into its benzoate viz. (1S,4R)-
4-N-acetylamino-1-benzoyl-cyclopent-2-ene ((-)-33) (81%
yield), [R]20 ) -144° (c 0.5, CHCl3), by treatment with
D
Sch em e 8
benzoyl chloride in the presence triethylamine and a
catalytic amount of DMAP (Scheme 8). The NMR data
of the crystalline benzoyl derivative (-)-33 was consistent
with the literature values for structurally similar
compounds.11g The cis stereochemistry between the ac-
etamido and benzoyl groups was unequivocally confirmed
by detailed NOESY studies also.
In the same manner, (1R,4S)-4-N-acetylamino-1-ben-
zoyl-cyclopent-2-ene (ent-(+)-33) was obtained from di-
astereomer 18. Cycloreversion of a mixture of ent-26 and
ent-27 (de ) 76%), obtained by the single electron-
transfer reduction of diastereomer 18, applying both FVT
+89° (c 0.6, CHCl3), in 89% and 92% yield, respectively
(Scheme 7). In both cases, the enantiomeric excess
amounted to 94%,32 showing that under both thermolytic
conditions no racemization had occurred. The product
(+)-30 obtained from the FVT experiment was completely
chemically pure right away, however, the product ob-
tained from the solution thermolysis needed purification
by column chromatography. In contrast to what is
generally observed for static thermolysis reactions carried
out in boiling o-DCB, hardly any decomposition of the
produced acetamidocyclopentenone 30 was observed,
showing its thermal stability. Even more rewarding is
the observation that after thermolysis, cooling of the
mixture to room temperature resulted in spontaneous
crystallization on standing overnight to give N-acetami-
and solution thermolysis, afforded ent-(-)-30, [R]27
)
D
-72.5° (c 0.49, CHCl3),32 in 90% yield and with an ee of
76%. Crystallization from o-DCB, by allowing the reac-
tion mixture after solution thermolysis to stand at room
temperature overnight, led to ent-(-)-30 in 71% yield
with an enriched optical purity [ee ) 97%; [R]19 ) -92°
D
(c 0.48, CHCl3)]. Reduction of ent-(-)-30 using NaBH4/
CeCl3‚7H2O afforded alcohol ent-32 (87% yield), which on
benzoylation produced (1R,4S)-4-N-acetylamino-1-ben-
zoyl-cyclopent-2-ene (ent-(+)-33), [R]20D ) +142.5° (c 0.35,
CHCl3), in 77% yield and with ee ) 97%. The spectral
data of ent-(+)-33 were identical to those of (-)-33.
docyclopentenone (+)-30, [R]20 ) +93° (c ) 0.5, CHCl3),
D
in 80% yield and with an enriched ee of 98% (Scheme 7).
Removal of the N-acetyl group was readily accom-
plished by hydrolysis of (+)-30 in 2 N HCl (aq) to yield
the hydrochloride salt of (R)-(+)-4-aminocyclopent-2-en-
Con clu sion s
We succeeded in an efficient enantioselective synthesis
of both enantiomers of 4-N-acetylaminocyclopent-2-en-
1-one 30 and 4-N-acetylamino-1-benzoylcyclopent-2-ene
33, starting from tricyclo[5.2.1.02,6]decenyl enaminones
14 and 15. Both enantiomers of 30 and 33 were ob-
tained in excellent overall chemical yields of 71% (three
steps) and 50% (five steps) and in almost enantiopure
form (ee g 97%). Both the γ-aminocyclopentenones 30,
31 and aminocyclopentenol derivatives 33 have great
potential as building blocks for 5′-norcarbocyclic nucleo-
sides as well as for related antiviral compounds. A key
step in our methodology is the concomitant electron-
transfer reduction of the enaminone double bond and the
reductive elimination of the N-R-methylbenzyl group in
enaminones 18 and 19. We have also demonstrated that
the regiochemistry of the reduction of N-acylated tri-
cyclic enaminones 18 and 19 can be directed by choosing
the appropriate reductive conditions. With 9-BBN, ex-
clusive 1,2-reduction of the C3-ketone function is ob-
served, whereas selective 1,4-reduction is achieved by
electron-transfer reduction with lithium in liquid am-
monia in the presence of t-BuOH. The generality of this
reductive procedure needs to be established for other
enaminones.
1-one ((+)-31), [R]22 ) +61.5° (c 0.5, MeOH), as a pale
D
yellow solid (Scheme 7). Unfortunately, attempts to
recrystallize this ammonium salt did not meet with
success. To establish the optical purity of (+)-31, it was
reconverted to the N-acetyl derivative (+)-30 by treat-
ment with acetic anhydride in the presence of triethyl-
amine (Scheme 7). After purification by column chroma-
tography, the isolated N-acetyl compound (+)-30 had
the same optical rotation as the original (+)-30, proving
that no racemization had occurred either during the
hydrolysis or during its reconversion to the N-acetyl
compound.
To complete the synthesis of cis-4-aminocyclopentenol
6, reduction of the carbonyl group in (+)-30 was next
attempted. While NaBH4 as such gave a mixture of
products, stereo- and regioselective reduction was con-
veniently achieved using NaBH4/CeCl3‚7H2O (Scheme 8).
Even though the reduction proceeded smoothly with high
(31) In our laboratory, this methodology has been successfully
applied for the synthesis of a variety of cyclopentanoid natural
products. For an illustrative example, see ref 12.
(32) The ee’s were determined by using chiral shift reagent
Eu(hfc)3 and integrating the separation of the signal due to the
â-olefinic proton.

3640 J . Org. Chem., Vol. 64, No. 10, 1999
Ramesh et al.
(1R,2S,3S,6R,7S,1′R)-5-N-Acetyl-(N-1′-p h en yleth yl)a m i-
n o-en d o-tr icyclo[5.2.1.02,6]d eca -4,8-d ien -3-ol (21). In the
same manner as described for the synthesis of alcohol 20, the
N-acetyl enaminone 19 underwent reduction with 9-BBN to
give alcohol 21 in 92% yield as a colorless viscous liquid: IR
3300, 1630 cm-1; 1H NMR δ 7.18-7.38 (m, 5H), 6.29 (dd, J )
5.6, 2.0 Hz, 1H), 5.93 (dd, J ) 5.6, 3.1 Hz, 1H), 5.60 (q, J )
7.1 Hz, 1H), 5.22 (s, 1H), 4.45 (t, J ) 7.1 Hz, 1H), 3.18 (dd, J
) 6.8, 3.3 Hz, 1H), 2.90 (m, 3H), 2.12 (s, 3H), 1.74 (d, J ) 7.1
Exp er im en ta l Section
Gen er a l Meth od s. All commercial solvents were distilled
according to standard procedures.33 All commercial chemicals
were purchased from Aldrich or Acros and were used as such.
Merck Kieselgel 60 F-254 silica gel plates were used for thin-
layer chromatography. Column chromatography was carried
out with EM Kieselgel 60 silica gel. Unless mentioned other-
wise, all H NMR and 13C NMR spectra were recorded at 300
and 75 MHz, respectively, in CDCl3. All IR measurements were
carried out in CHCl3 solution. Unless stated otherwise, all
mass spectra were recorded under EI conditions.
1
Hz, 3H), 1.60 (d, J ) 8.3 Hz, 1H), 1.40 (d, J ) 8.3 Hz, 1H); 13
C
NMR δ 170.0, 146.1, 140.0, 134.7, 134.2, 131.5, 127.9, 127.3,
126.9, 72.5, 54.7, 53.6, 52.9, 47.0, 44.3, 23.2, 17.8; MS m/z 309
(M+), 227, 204, 187, 139; HRMS calcd for C20H23NO2 309.1729,
found 309.1729.
(1S,2R,3S,6S,8R,9R,10R,1′R)-4-N-Acet yl-(N-1′-p h en yl-
eth yl)a m in o-9-iod o-7-oxa tetr a cyclo[6.3.0.02,6.03,10]u n d ec-
4-en e (23). To a solution of the alcohol 21 (192 mg, 0.62 mmol)
in CH2Cl2 (3 mL) cooled to -25 °C in a dry ice-acetone bath
was added N-iodosuccinimide (168 mg, 0.75 mmol). After 10
min, when TLC showed the absence of starting material, the
reaction was stopped, CH2Cl2 was removed, and the residue
was purified by column chromatography (hexane/EtOAc 1:1)
(1S,2R,6S,7R,1′R)-5-N-Acetyl-(N-1′-p h en yleth yl)a m in o-
en d o-tr icyclo[5.2.1.02,6]d eca -4,8-d ien -3-on e (18). To solu-
tion of the enaminone 1415 (530 mg, 2 mmol) in dry THF (15
mL) was added sodium hydride (60 mg, 2.5 mmol) at room
temperature. After stirring the reaction mixture was stirred
for 1 h, acetyl chloride (0.21 mL, 3 mmol) was added dropwise
over a period of 10 min. After the reaction mixture was stirred
for another 2 h at room temperature, it was carefully quenched
with water and extracted with CH2Cl2. The organic layer was
then washed with water, dried over anhydrous Na2SO4,
concentrated, and purified by column chromatography (hex-
ane/EtOAc 1:1) to afford 18 (522 mg, 85%) as a viscous yellow
to give iodo ether 23 (239 mg, 89%) as a colorless viscous
1
liquid: [R]19 ) -10° (c 0.78, CHCl3); IR 1640, 1620 cm-1; H
D
liquid: [R]20 ) -345° (c 1.25, CHCl3); IR 1690, 1680, 1670
NMR δ 7.20-7.40 (m, 5H), 5.71-5.80 (m, 2H), 4.81 (d, J )
5.0 Hz, 1H), 4.55 (dd, J ) 6.0, 2.9 Hz, 1H), 3.89 (d, J ) 2.5 Hz,
1H), 3.05 (dt, J ) 8.8, 5.7 Hz, 1H), 2.80 (dd, J ) 8.8, 3.8 Hz,
1H), 2.56 (m, 1H), 2.35 (d, J ) 11.0 Hz, 1H), 2.13 (s, 3H), 1.86
(d, J ) 11.0 Hz), 1.65 (d, J ) 7.1 Hz); 13C NMR δ 169.8, 145.9,
140.5, 131.7, 128.7, 127.2, 126.8, 92.1, 82.1, 54.1, 52.9, 49.9,
48.8, 47.4, 41.8, 32.8, 23.1, 17.5; MS m/z 435 (M+), 392, 331,
308, 204, 105; HRMS calcd for C20H22NO2I 435.0695, found
435.0698.
D
cm-1; 1H NMR δ 7.21-7.40 (m, 5H), 6.06 (dd, J ) 5.5, 2.8 Hz,
1H), 5.77-5.88 (m, 2H), 5.26 (s, 1H), 3.92 (m, 1H), 3.15 (broad
s, 1H), 2.90 (m, 1H), 2.45 (broad s, 1H), 2.28 (s, 3H), 1.70 (d,
J ) 7.1 Hz, 3H), 1.65 (d, J ) 8.5 Hz, 1H), 1.47 (d, J ) 8.5 Hz,
1H); 13C NMR δ 206.4, 171.9, 171.1, 140.2, 133.8, 132.1, 128.6,
127.3, 125.7, 123.8, 54.3, 52.5, 50.6, 49.4, 44.1, 44.0, 24.4, 16.1;
MS m/z 307 (M+), 279, 264, 199; HRMS calcd for C20H21NO2
307.1572, found 307.1573.
(1R,2S,6R,7S,8R,9R,1′R)-3-N-Acetyl-(N-1′-p h en yleth yl)-
a m in o-9-iod o-en d o-tr icyclo[5.2.1.02,6]d ec-3-en -8-ol (24). To
a solution of the iodo ether 23 (43.5 mg, 0.1 mmol) in MeOH
(3 mL) was added a catalytic amount of Pd/C or Pd(OH)2 and
the reaction mixture subjected to hydrogenation at room
temperature and atmospheric pressure. The progress of the
reaction was monitored by TLC. When TLC indicated the
disappearance of the starting material, hydrogenation was
stopped. The catalyst was filtered and the solvent removed.
Purification of the product by column chromatography (hexane/
EtOAc 1:1) afforded trans iodo alcohol 24 (24 mg, 52%) as a
(1R,2S,6R,7S,1′R)-5-N-Acetyl-(N-1′-ph en yleth yl)am in o-
en d o-tr icyclo[5.2.1.0.2,6]d eca -4,8-d ien -3-on e (19). In a simi-
lar way as described for the synthesis of 18 from 14, the
diastereomeric enaminone 15 afforded the N-acetyl derivative
19 in 89% yield as a yellow solid: mp 139-140 °C; [R]21
)
D
1
+447° (c 0.45, CHCl3); IR 1690, 1680, 1670 cm-1; H NMR δ
7.21-7.40 (m, 5H), 6.07 (dd, J ) 5.6, 2.9 Hz, 1H), 5.89 (dd, J
) 5.6, 2.9 Hz, 1H), 5.63 (q, J ) 7.0 Hz, 1H), 5.44 (s, 1H), 3.71
(dd, J ) 5.9, 4.2 Hz, 1H), 3.18 (broad s, 1H), 3.04 (broad s,
1H), 2.84 (dd, J ) 5.9, 4.8 Hz, 1H), 2.17 (s, 3H), 1.82 (d, J )
7.0 Hz, 3H) 1.76 (d, J ) 8.5 Hz, 1H), 1.58 (d, J ) 8.5 Hz, 1H);
13C NMR δ 206.2, 173.0, 170.8, 138.9, 134.1, 131.7, 128.3,
127.2, 126.1, 123.4, 55.5, 52.2, 50.8, 49.0, 44.6, 43.8, 24.6, 17.5;
MS m/z 307 (M+), 279, 264, 237, 199, 105, 43 HRMS calcd for
sticky solid: [R]18 ) +110° (c 0.25, CHCl3); IR 3500, 1640,
D
1620 cm-1; 1H NMR δ 7.19-7.40 (m, 5H), 5.50 (d, J ) 1.3 Hz,
1H), 5.31 (q, J ) 7.2 Hz, 1H), 4.79 (q, J ) 4.3 Hz, 1H), 4.03 (t,
J ) 3.4 Hz, 1H), 3.11 (m, 2H), 2.67 (m, 2H), 2.00-2.38 (m,
7H), 1.75 (d, J ) 7.1 Hz, 1H), 1.50-1.56 (m, 2H); 13C NMR δ
170.4, 140.6, 140.5, 130.8, 128.2, 126.8, 89.1, 55.5, 55.2, 52.2,
46.6, 40.2, 39.2, 32.0, 29.3, 23.3, 18.1; MS m/z 437 (M+), 394,
332, 105; HRMS calcd for C20H24NO2I 437.0852, found 437.0850.
(1S,2R,3R,6S,8S,10S,1′R)-4-N-Acet yl-(N-1′-p h en ylet h -
yl)a m in o-7-oxa tetr a cyclo[6.3.0.02,6.03,10]u n d ec-4-en e (25).
The reduction procedure was similar to that of the previous
experiment. Instead of Pd/C or Pd(OH)2, a catalytic amount
of Raney nickel was employed as the catalyst. The reaction
resulted in the formation of deiodinated product 25 (100%) as
C
20H21NO2 307.1572, found 307.1573.
(1S,2R,3R,6S,7R,1′R)-5-N-Acetyl-(N-1′-ph en yleth yl)am i-
n o-en d o-tr icyclo[5.2.1.02,6]d eca -4,8-d ien -3-ol (20). To a
flame-dried flask cooled under argon was added enaminone
18 (614 mg, 2 mmol), which was dissolved in dry THF (6 mL).
The reaction mixture was cooled to 0 °C. A 0.5 M solution of
9-BBN in THF (6 mL, 3 mmol) was injected dropwise. The
reaction mixture was stirred at 0 °C for 4 h and then at room
temperature for 2 h. Excess 9-BBN was quenched by adding
MeOH. The reaction mixture was then concentrated in a rotary
evaporator. The resulting residue was dissolved in EtOAc, and
ethanolamine was added. The precipitate formed was sepa-
rated. The EtOAc layer was concentrated and the product
purified by column chromatography (hexane/EtOAc 1:3) to
afford the alcohol 20 (512 mg, 83%) as a colorless viscous
liquid: IR 3300, 1630 cm-1; 1H NMR δ 7.20-7.40 (m, 5H), 6.23
(dd, J ) 5.4, 2.8 Hz, 1H), 6.02 (q, J ) 7.4 Hz, 1H), 5.84 (dd, J
) 5.6, 3.1 Hz, 1H), 5.31 (d, J ) 1.8 Hz, 1H), 4.69 (m, 1H), 3.00-
(m, 2H), 2.87 (broad s, 1H), 2.17 (s, 3H), 1.80 (broad s, 1H),
1.53 (d, J ) 7.2 Hz, 3H), 1.36 (d, J ) 8.2 Hz, 1H), 1.29 (d, J )
9.0 Hz, 1H), 1.12 (d, J ) 8.2 Hz, 1H); 13C NMR δ 170.3, 145.4,
142.1, 134.4, 134.2, 130.9, 128.1, 127.1, 126.9, 72.5, 54.6, 52.9,
50.1, 47.3, 46.3, 44.4, 23.1, 16.1; MS m/z 309 (M+), 227, 204,
187, 139; HRMS calcd for C20H23NO2 309.1729, found 309.1729.
a white solid: mp 85-86 °C; [R]20 ) +49.2° (c 0.32 CHCl3);
D
IR 1640, 1620 cm-1; 1H NMR δ 7.20-7.35 (m, 5H), 5.64-5.79
(m, 2H), 4.60 (dd, J ) 6.1, 2.8 Hz, 1H), 4.41 (dd, J ) 7.5, 5.1
Hz, 1H), 2.99 (m, 1H), 2.73 (dd, J ) 7.6, 3.3 Hz, 1H), 2.53 (t,
J ) 5.0 Hz, 1H), 2.13 (s, 3H), 1.68 (d, J ) 7.1 Hz, 3H), 1.25-
1.61 (m, 5H); 13C NMR δ 169.8, 147.2, 140.8, 131.0, 128.0,
127.3, 127.0, 81.8, 54.8, 52.8, 51.0, 47.0, 42.2, 39.2, 36.5, 23.1,
17.3; MS m/z 309(M+), 266, 206, 105; HRMS calcd for C20H23
-
NO2 309.17288, found 309.17290.
(1R ,2S ,5R ,6R ,7S )-5-N -Ac e t y la m in o -en d o-t r ic y c lo -
[5.2.1.02,6]d ec-8-en e-3-on e (26) a n d (1R,2S,5S,6R,7S)-5-N-
Acetyla m in o-en d o-tr icyclo[5.2.1.02,6]d ec-8-en e-3-on e (27).
A 500 mL three-necked flask containing an ammonia inlet, a
dropping funnel, and a KOH guard tube, cooled to -78 °C (dry
ice-acetone bath), was charged with liquid ammonia (150 mL).
N-Acetyl enaminone 19 (921 mg, 3 mmol) dissolved in THF (3
mL) was added dropwise followed by the addition of t-BuOH
(33) Perrin, D. D.; Armarego, W. L. F. In Purification of Laboratory
Chemicals; Pergamon Press: New York, 1988.

Synthesis of 4-Acetylaminocyclopent-2-en-1-ols
J . Org. Chem., Vol. 64, No. 10, 1999 3641
(888 mg, 12 mmol) in THF (2 mL). Freshly cut fine pieces of
lithium (168 mg, 24 mmol) were added to this mixture under
vigorous stirring. After some time (5-10 min), the reaction
mixture became completely blue. The reaction mixture was
stirred at -78 °C until all the blue color had disappeared. The
cooling bath was then removed and the ammonia evaporated
using a water bath. The residue was dissolved in a minimum
amount of water and extracted with CH2Cl2. The organic layer
was dried over anhydrous Na2SO4, filtered, and concentrated.
Purification over column chromatography (EtOAc/MeOH 20:
1) afforded an inseparable diastereomeric mixture of â-amino
ketones 26 and 27 (550 mg, 89%) as a colorless viscous oil.
The diastereomeric ratio was 97:3 as determined by GC as well
as by the 1H NMR spectrum: [R]25D ) +145.5° (c 0.95, CHCl3);
IR 3420, 1730, 1660 cm-1; 1H NMR δ (for major diastereomer
26) 6.26 (m, 2H), 6.12 (dd, J ) 5.6, 2.8 Hz, 1H), 3.86 (m, 1H),
3.22 (m, 2H), 3.05 (m, 1H), 2.86 (m, 1H), 2.42 (dd, J ) 19.1,
9.0 Hz, 1H), 2.13 (ddd, J ) 19.1, 5.2, 1.6 Hz, 1H), 1.99 (s, 3H),
1.57 (d, J ) 8.3 Hz, 1H), 1.40 (d, J ) 8.3 Hz, 1H); 13C NMR (δ
for major diastereomer 26) δ 218.6, 169.5, 136.2, 134.7, 54.9,
52.1, 50.9, 48.55, 48.51, 46.9, 46.6, 23.1; MS m/z 205 (M+), 177,
147, 140, 66; HRMS calcd for C12H15NO2 205.1103, found
205.1104.
185 °C) followed by crystallization from the reaction mixture
gave ent-30 in 71% yield and with an enriched ee of 97%, [R]19
D
) -92° (c 0.48, CHCl3).
(R)-(+)-4-Am in ocyclop en t -2-en -1-on e H yd r och lor id e
(31). A solution of (+)-30 in 2 N HCl (3 mL) was heated at
100 °C for 3 h. The reaction mixture was then cooled and the
solution evaporated to dryness in a rotary evaporator to yield
(R)-(+)-4-aminocyclopent-2-en-1-one hydrochloride 31 as a pale
yellow solid in quantitative yield. The solid did not melt but
1
decomposed above 170 °C: [R]20 ) +61.5° (c 0.5, MeOH); H
D
NMR (CD3OD) δ 7.70 (dd, J ) 5.7, 2.4 Hz, 1H), 6.50 (dd, J )
5.7, 1.7 Hz, 1H), 4.58 (m, 1H), 2.86 (dd, J ) 18.7, 6.8 Hz, 1H),
2.35 (dd, J ) 18.7, 2.4 Hz, 1H); 13C NMR (CD3OD) δ 205.8,
158.8, 139.2, 51.6, 39.7; MS m/z 97(M+ - HCl), 69, 38(H37Cl),
36(H35Cl); FAB (m-nitrobenzyl alcohol) 98 (M+ - Cl), 81;
HRMS calcd for C5H7NO (M+- HCl) 97.052 76, found 97.052 87.
(1S,4R)-4-N-Acetyla m in ocyclop en t-2-en -1-ol (32) a n d
Its Ben zoyl Der iva tive (33). To a solution of 30 (125 mg,
0.9 mmol) in MeOH (3 mL) was added CeCl3‚7H2O (336 mg,
0.9 mmol) and the mixture stirred at room temperature for 1
h. The reaction mixture was then cooled to -78 °C, and NaBH4
(76 mg, 2 mmol) was added as such in one portion. Progress
of the reaction was monitored by TLC. When TLC indicated
the complete consumption of the starting material, the reaction
was stopped, the solvent removed, and the product im-
mediately purified by column chromatography (EtOAc/MeOH
20:1) to give 32 (108 mg, 88%) as a viscous oil: IR 3420, 3360,
(1S ,2R ,5S ,6S ,7R )-5-N -Ac e t y la m in o -en d o-t r ic y c lo -
[5.2.1.02,6]d ec-8-en e-3-on e (en t-26) a n d (1S,2R,5R,6S,7R)-
5-N -Ace t yla m in o-en d o-t r icyclo[5.2.1.02,6]d e c-8-e n e -3-
on e (en t-27). Following the same procedure as above, a
diastereomeric mixture of ent-26 and ent-27 was obtained from
the enaminone 20 in 85% yield and with a diastereomeric ratio
of 88:12. The spectral data of the major enantiomer ent-26 were
1670, 1650 cm-1 1H NMR (CD3OD) δ 5.94 (dt, J ) 7.4, 1.8
;
Hz, 1H), 5.80 (dt, J ) 7.1, 1.6 Hz, 1H), 4.69 (m, 2H), 2.71 (dt,
J ) 13.5, 7.5 Hz, 1H), 1.92 (s, 3H), 1.39 (dt, J ) 13.5, 5.5 Hz,
1H); 13C NMR δ 172.5, 137.5, 134.3, 75.7, 54.5, 41.9, 22.6; MS
m/z 141(M+), 124, 98; HRMS calcd for C7H11NO2 141.078 98,
found 141.078 93.
identical with those of 26: [R]23 ) -137.6° (c 1.0, CHCl3).
D
(R)-(+)-4-N-Acetyla m in ocyclop en t-2-en e-1-on e 30. By
F la sh Va cu u m Th er m olysis. The diastereomeric mixture of
â-amino ketones 26 and 27 (92 mg, 0.45 mmol; de ) 94%) was
subjected to flash vacuum thermolysis at 500 °C and 0.05
mbar. The product was collected on a coldfinger cooled with
dry ice/acetone. When all the starting material had been
consumed, the thermolysis was stopped. The product collected
on the coldfinger was removed by dissolving it in CH2Cl2.
Removal of the solvent gave pure (+)-30 in 92% yield (ee 94%)
as a white solid: mp 107-108 °C; [R]25D ) +89° (c 0.61, CHCl3);
Since the product obtained was not entirely pure, it was
immediately benzoylated. To a solution of alcohol 32 (108 mg,
0.79 mmol) in CH2Cl2 (5 mL), cooled to 0 °C in an ice bath
were added Et3N (0.25 mL, 2 mmol) and DMAP (10 mg). After
the reaction mixture was stirred for 15 min, benzoyl chloride
(0.13 mL, 1 mmol) was added. After 2 h, TLC showed the
reaction to be complete, and it was stopped. The solvent was
removed and the product purified by column chromatography
(hexane/EtOAc 1:1) to yield 33 (156 mg, 81%) as a white
1
IR 3420, 1720, 1680, 1670 cm-1; H NMR δ 7.55 (dd, J ) 5.6,
2.4 Hz, 1H), 6.38 (bs, 1H), 6.23 (dd, J ) 5.6, 1.7 Hz, 1H), 5.24
(m, 1H), 2.84 (dd, J ) 18.7, 6.8 Hz, 1H), 2.16 (dd, J ) 18.8,
2.5 Hz, 1H), 2.00 (s, 3H); 13C NMR δ 206.7, 169.9, 162.2, 135.2.,
49.6, 41.7, 23.0; HRMS calcd for C7H9NO2 139.06333, found
139.06336. Anal. Calcd for C7H9NO2: C, 60.42; H, 6.52; N,
10.07. Found: C, 60.66; H, 6.30; N, 9.88.
crystalline material: mp 138 °C, ee 98%; [R]20 ) -144° (c
D
0.5, CHCl3); IR 3420, 1710, 1670 cm-1
;
1H NMR δ 8.02 (m,
2H), 7.40-7.60 (m, 3H), 6.00-6.18 (m, 2H), 5.79 (m, 1H), 5.65
(m, 1H), 5.04 (m, 1H), 2.98 (dt, J ) 14.6, 7.7 Hz, 1H); 2.00 (s,
3H), 1.69 (dt, J ) 14.6, 4.1 Hz, 1H); 13C NMR δ 169.2, 166.0,
136.7, 133.0, 132.6, 130.1, 129.5, 128.3, 78.2, 53.0, 38.4, 23.3;
MS(CI) m/z 246 (MH+, very weak), 187, 152, 124, 105; HRMS
calcd for C12H11O2 (M+ - NHAc) 187.0759, found 187.0758.
Anal. Calcd. for C14H15NO3: C, 68.56; H, 6.10; N, 5.71.
Found: C, 68.08; H, 6.05; N, 5.70.
By Solu tion Th er m olysis. A solution of the â-amino
ketones 26 and 27 (205 mg, 1 mmol; de 94%) in o-dichloroben-
zene (5 mL) was refluxed in an oil bath at 185 °C. The progress
of the reaction was monitored by TLC. When TLC indicated
the absence of starting material, refluxing was stopped.
Removal of the solvent and purification by column chroma-
tography (EtOAc/MeOH 20:1) afforded (+)-30 in 89% yield and
(1R,4S)-4-N-Acetylam in o-1-ben zoylcyclopen t-2-en e (en t-
33). Using the same procedure as above and starting from ent-
30 (ee ) 97%), ent-33 was obtained in 77% yield and with an
with an ee of 94%, [R]25 ) +89° (c 1, CHCl3). On the other
D
ee of 97%: [R]20 ) +142.5° (c 0.35, CHCl3).
hand, cooling the reaction mixture overnight led to crystal-
D
lization yielding (+)-30 in 80% yield and with an enriched ee
of 98%, [R]20 ) +93° (c 0.48, CHCl3).
1
D
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
(S)-(-)-4-N-Acetyla m in ocyclop en t-2-en -1-on e (en t-30).
(S)-(-)-4-(N)-Acetylaminocyclopent-2-en-1-one (ent-30) was
obtained from a diastereomeric mixture of ent-26 and ent-27
(de 76%), both by FVT as well as solution thermolysis. Flash
vacuum thermolysis (500 °C, 0.05 mbar) afforded ent-30 in 90%
and 13C NMR spectra for compounds 18-20, 23, 25, (26 + 27),
(en t-26 + en t-27), 30, 31, 33, 13C NMR spectrum for compound
24, and 2D-NOESY spectra for compounds (26 + 27) and 33.
This material is available free of charge via the Internet at
http://pubs.acs.org.
yield and with an ee of 76%, [R]27 ) -72.5° (c 0.49, CHCl3),
D
while solution thermolysis in o-dichlorobenzene (refluxing at
J O982498H