Straightforward asymmetric entry to highly functionalized medium-sized rings fused to β-lactams via chemo- and stereocontrolled divergent radical cyclization of Baylis-Hillman adducts derived from 4-oxoazetidine-2-carbaldehydes

Article abstract of DOI:10.1021/jo005715z

DABCO promoted reactions of various activated vinyl systems with optically pure 4-oxoazetidine-2-carbaldehydes 1 gave rise to Baylis - Hillman adducts 3 with excellent syn stereoselectivities, without detectable racemization. Products 3 are used for the asymmetric preparation of unusual 2-azetidinones fused to medium-sized rings via chemo- and stereocontrolled divergent radical cyclization. The formation of bicyclic β-lactams 4 - 6 could be rationalized through a tandem radical Michael addition/endo cyclization or a tandem radical addition/Michael addition, depending on the electronic nature of the radical promoter.

Full text of DOI:10.1021/jo005715z

1612
J . Org. Chem. 2001, 66, 1612-1620
Str a igh tfor w a r d Asym m etr ic En tr y to High ly F u n ction a lized
Med iu m -Sized Rin gs F u sed to â-La cta m s via Ch em o- a n d
Ster eocon tr olled Diver gen t Ra d ica l Cycliza tion of Ba ylis-Hillm a n
Ad d u cts Der ived fr om 4-Oxoa zetid in e-2-ca r ba ld eh yd es†
Benito Alcaide,* Pedro Almendros, and Cristina Aragoncillo
Departamento de Quı´mica Orga´nica I, Facultad de Qu´ımica,
Universidad Complutense 28040-Madrid, Spain
alcaideb@eucmax.sim.ucm.es
Received November 2, 2000
DABCO promoted reactions of various activated vinyl systems with optically pure 4-oxoazetidine-
2-carbaldehydes 1 gave rise to Baylis-Hillman adducts 3 with excellent syn stereoselectivities,
without detectable racemization. Products 3 are used for the asymmetric preparation of unusual
2-azetidinones fused to medium-sized rings via chemo- and stereocontrolled divergent radical
cyclization. The formation of bicyclic â-lactams 4-6 could be rationalized through a tandem radical
Michael addition/endo cyclization or a tandem radical addition/Michael addition, depending on the
electronic nature of the radical promoter.
In tr od u ction
having the 2-azetidinone ring as common feature, which
will both target the PBPs and overcome the defense
mechanisms of the bacteria.5 Besides, the ever-growing
new applications of 2-azetidinones in fields ranging from
enzyme inhibition6 to the use of these products as
starting materials to develop new synthetic methodolo-
gies, has triggered a renewed interest in the building of
new bi- and polycyclic â-lactam systems in an attempt
to move away from the classical â-lactam antibiotic
structures.7
The Baylis-Hillman reaction, an emerging carbon-
carbon bond forming reaction for the preparation of a
â-hydroxy-R-methylene ketone, nitrile, ester, etc., in-
volves an activated alkene and a carbon electrophile in
the presence of a suitable catalyst (particularly a tertiary
amine).1 This fascinating reaction has many of the basic
properties that an efficient synthetic method should have,
e.g., it is selective, economical in atom count, requires
mild conditions, and provides densely funtionalized
products.2 However, the reaction suffers from two major
drawbacks, namely, its slow reaction rate and limited
scope of substrates. On the other hand, the interest in
free radical reactions applied to synthetic problems
continues to advance, and these reactions have been used
successfully for a growing number of synthetic targets,
being a powerful tool in the synthesis of five- and six-
membered carbocycles and heterocycles.3 This wide re-
search has been fostered by its operational simplicity and
its tolerance to substrate functionalization. Furthermore,
by a combination of stereoelectronic and molecular orbital
effects, radical cyclizations occur, in general, with high
degrees of both regio- and stereocontrol.
(3) For leading references, see: (a) Bowman, W. R.; Bridge, C. F.;
Brookes, P. J . Chem. Soc., Pekin Trans. 1 2000, 1. (b) Mart´ınez-Grau,
A.; Marco-Contelles, J . Chem. Soc. Rev. 1998, 27, 155. (c) Aldabbagh,
F.; Bowman, W. R. Contemp. Org. Synth. 1997, 261. (d) Rousseau, G.;
Homsi, F. Chem. Soc. Rev. 1997, 26, 453. (e) Fallis, A. B.; Brinza, I.
M. Tetrahedron 1997, 53, 17543. (f) Curran, D. P.; Porter, N. A.; Giese,
B. In Stereochemistry of Radical Reactions; VCH Publishers: New
York, 1996. (g) Malacria, M. Chem. Rev. 1996, 96, 289. (h) Giese, B.;
Kopping, B.; Go¨bel, T.; Dickhaut, J .; Thoma, G.; Kulicke, K. J .; Trach,
F. Org. React. 1996, 48, 301-856. (i) Fossey, J .; Lefort, D.; Sorba, J .
Free Radicals in Organic Chemistry; J ohn Wiley & Sons: New York,
1995. (j) Barton, D. H. R.; Parekh, S. I. Half a Century of Free Radical
Chemistry; Cambridge University Press: Cambridge, 1993. (k) Moth-
erwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic
Synthesis; Academic Press: London, 1992. (l) Curran, D. P. In
Comprehesive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford,
1992; Vol 4, Chapter 4.2. (m) J asperse, C. P.; Curran, D. P.; Fevig, T.
L. Chem. Rev. 1991, 91, 1237. (n) Curran, D. P. M. Synthesis 1988,
417 and 489.
(4) See, for example: (a) D´ıaz, N.; Sua´rez, D.; Merz, K. M. M., J r.
J . Am. Chem. Soc. 2000, 122, 4197. (b) Page, M. I. Chem. Commun.
1998, 1609. (c) Niccolai, D.; Tarsi, L.; Thomas, R. J . Chem. Commun.
1997, 2333. (d) Hook, V. Chem. Br. 1997, 33, 34. (e) Spratt, B. G.
Science 1994, 264, 388. (f) Davies, J . Science 1994, 264, 375.
(5) For reviews on this subject, see: (a) Lednicer, D. The Organic
Chemistry of Drug Synthesis; Wiley: New York, 1995; Vol. 5. (b)
Southgate, R. Contemp. Org. Synth. 1994, 1, 417. (c) Southgate, R.;
Branch, C.; Coulton, S.; Hunt, E. In Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products; Lukacs, G.,
Ed.; Springer: Berlin, 1993; Vol. 2, p 621. (d) Ojima, I. The Organic
Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: New York, 1993, 197.
(e) The Chemistry of â-Lactams; Page, M. I., Ed.; Chapman and Hall:
London, 1992. (f) Marchand-Brynaert, J .; Ghosez, L. Recent Progress
in the Chemical Synthesis of Antibiotics; Lukas, G., Ohno, M., Eds.;
Springer-Verlag: Berlin, 1990; p.727. (g) Southgate, R.; Elson, S. In
Progress in the Chemistry of Organic Natural Products; Herz, W.,
Grisebach, H., Kirby, G. W., Tamm, C., Eds.; Springer: Vienna, 1985;
Vol. 47, p1. (h) Manhas, M. S.; Bose, A. K. â-Lactams: Natural and
Synthetic; Wiley: New York, 1971; Part 1.
Due to the increased resistance of bacteria to common
â-lactam antibiotics,4 there has been much effort ex-
pended in recent years to prepare new structural types
* To whom correspondence should be addressed.
† Dedicated to Prof. J ose´ Elguero on the occasion of his 65th
birthday.
(1) For reviews, see: (a) Langer, P. Angew. Chem., Int. Ed. 2000,
39, 3049. (b) Ciganek, E. Org. React. 1997, 51, 201. (c) Basavaiah, D.;
Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001. (d) Drewes, S. E.;
Roos, G. H. P.; Thomas, R. J . Tetrahedron 1988, 44, 4653. (e) Hoffmann,
H. M. R.; Rabe, J . Angew. Chem., Int. Ed. Engl. 1985, 24, 4653.
(2) For very recent, selected examples, see: (a) Trost, B. T.; Tsui,
H.-C.; Toste, F. D. J . Am. Chem. Soc. 2000, 122, 3534. (b) Yang, K.-S.;
Chen, K. Org. Lett. 2000, 2, 729. (c) Kim, J . N.; Lee, K. Y.; Kim, H. S.;
Kim, T. Y. Org. Lett. 2000, 2, 343. (d) Mikami, K.; Okubo, Y. Synlett
2000, 491. (e) Basavaiah, D.; Muthukumaran, K.; Sreenivasulu, B.
Synthesis 2000, 545. (f) Basavaiah, D.; Hyma, R. S.; Muthukumaran,
K.; Kumaragurubaran, N. Synthesis 2000, 217. (g) Li, G.; Wei, H.-X.;
Gao, J . J .; Caputo, T. D. Tetrahedron Lett. 2000, 41, 1. (h) Kaye, P. T.;
Nokanda, X. W. J . Chem. Soc., Perkin Trans. 1 2000, 1331.
10.1021/jo005715z CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/02/2001

Cyclization of Baylis-Hillman Adducts
J . Org. Chem., Vol. 66, No. 5, 2001 1613
Sch em e 1
Continuing with our work on the synthesis and syn-
thetic applications of chiral, functionalized 2-azetidino-
nes,8 we wish to report now full details of a straightfor-
ward synthesis of unusual, chiral nonracemic bicyclic
â-lactams via combination of Baylis-Hillman reaction of
4-oxoazetidine-2-carbaldehydes with free-radical chem-
istry.9
Resu lts a n d Discu ssion
The starting substrates, 4-oxoazetidine-2-carbalde-
hydes 1, were prepared in optically pure form using
standard methodology.8a Enantiopure 2-azetidinones 2
were obtained from imines of (R)-2,3-O-isopropylidenepro-
panal, through Staudinger reaction with the correspond-
ing acid chlorides in the presence of Et3N as single cis
enantiomers.10 Standard acetonide hydrolysis to provide
diols, followed by oxidative cleavage, smoothly formed
4-oxoazetidine-2-carbaldehydes 1 in excellent yields
(Scheme 1).
The Baylis-Hillman reaction using nonracemic pro-
tected R-amino aldehydes has been attempted with
limited success, due to partial racemization of the chiral
aldehyde by DABCO after prolongate exposure times11a
or due to poor diastereoselection.11b,c To our delight,
Baylis-Hillman adducts 3a -i can be prepared, almost
as single diastereoisomers, by the DABCO promoted
reaction of various activated vinyl systems with the
appropriate 4-oxoazetidine-2-carbaldehyde 1, and per-
forming the experiment in acetonitrile at -20 °C. How-
ever, when the reaction was carried out at ambient
temperature maintaining the molar ratio of reagents
(aldehyde/DABCO/alkene ) 1:1:10), partial epimerization
together with some unreacted aldehyde were observed.
We carried out a study in order to test the effect of the
amount of catalyst on the conversion rate, finding that
the process can be significantly accelerated on increasing
the amount of catalyst (DABCO), without detectable
racemization (see Table). There is not a significant sol-
vent (acetonitrile, tetrahydrofuran or dichloromethane)
effect in the observed diastereoselectivity. High diaste-
reoselectivity was generally observed when different
aldehydes were used. However, enhancing solvent polar-
ity slightly improved the yield, with the best yield
obtained in acetonitrile, which became the solvent of
choice.
(6) For selected references, see: (a) Mascaretti, O. A.; Boschetti, C.
E.; Danelon, G. O.; Mata, E. G.; Roveri, O. A. Curr. Med. Chem. 1995,
1, 441. (b) Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14,
127. (c) Vaccaro, W. D.; Davis, H. R., J r. Bioorg. Med. Chem. Lett. 1998,
8, 313. (d) Vaccaro, W. D.; Sher, R.; Davis, H. R., J r. Bioorg. Med. Chem.
Lett. 1998, 8, 35. (e) Burnett, D. A. Tetrahedron Lett. 1994, 35, 7339.
(f) Borthwick, A. D.; Weingarte, G.; Haley, T. M.; Tomaszewski, M.;
Wang, W.; Hu, Z.; Bedard, J .; J in, H.; Yuen, L.; Mansour, T. S. Bioorg.
Med. Chem. Lett. 1998, 8, 365. (g) Ogilvie, W.; Bailey, M.; Poupart,
M.-A.; Abraham, A.; Bhavsar, P.; Bonneau, P.; Bordeleau, J .; Bousquet,
Y.; Chabot, C.; Duceppe, J .-S.; Fazal, G.; Goulet, S.; Grand-Maitre, C.;
Guse, I.; Halmos, T.; Lavallee, P.; Leach, M.; Malefant, E.; O’Meara,
J .; Plante, R.; Plouffe, C.; Poirier, M.; Soucy, F.; Yoakim, C.; Deziel, R.
J . Med. Chem. 1997, 40, 4113.
Placing a bulky group, such as p-methoxyphenyl at N1,
decreased the efficiency of the addition, making now the
C4-epimerization of the â-lactam a competitive process
with the Baylis-Hillman reaction. It is possible that the
carbaldehyde moiety is now less accessible to the acti-
vated olefin due to steric effects. However, the bulkiness
of the 3-phenoxy substituent on the â-lactam ring may
play a role in ensuring the high selectivity of this process,
while less demanding groups dropped the diastereose-
lectivity. In fact, when a methoxy group was used instead,
the stereoselectivity was lowered (entry 12, Table 1).
Fortunately, diastereomeric Baylis-Hillman adducts
syn-3 and anti-3 could be separated by flash chromatog-
raphy. The observed stereochemistry might be tentatively
explained by the Felkin-Anh model, through an anti-
Felkin addition. The large substituent (the aminogroup
of the four-membered ring) is assumed to be arranged
perpendicularly to the carbonyl group. The activated
olefin may attack the CdO bond in the most favored
conformation, explaining the preference for the syn-
configured products (Figure 1).
(7) For an exhaustive revision of cyclization methodologies to
prepare bicyclic â-lactams, see: (a) Kant, J .; Walker, D. G. In The
Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: New York,
1993; Chapter 3. For selected recent examples building bicyclic
â-lactams, see: (b) Alcaide, B.; Rodr´ıguez-Campos, I. M.; Rodr´ıguez-
Lo´pez, J .; Rodr´ıguez-Vicente, A. J . Org. Chem. 1999, 64, 5377. (c) Hwu,
J . R.; Hakimelahi, S.; Moosavi-Movahedi, A. A.; Tsay, S.-C. Chem.s
Eur. J . 1999, 5, 2705. (d) Maison, W.; Kosten, M.; Charpy, A.;
Kintscher-Langenhagen, J .; Schlemminger, I.; Lu¨tzen, A.; Westerhoff,
O.; Martens, J . Eur. J . Org. Chem. 1999, 2433. (e) Banfi, L.; Guanti,
G.; Basso, A. Eur. J . Org. Chem. 2000, 939. (f) J ensen, M. S.; Yang,
C.; Hsiao, Y.; Rivera, N.; Wells, K. M.; Chung, J . Y. L.; Yasuda, N.;
Hughes, D. L.; Reider, P. J . Org. Lett. 2000, 2, 1081.
(8) (a) Alcaide, B.; Almendros, P.; Salgado, N. R. J . Org. Chem. 2000,
65, 3310. (b) Alcaide, B.; Almendros, P.; Alonso, J . M.; Aly, M. F. Chem.
Commun. 2000, 485. (c) Alcaide, B.; Sa´ez, E. Tetrahedron Lett. 2000,
41, 1647. (d) Alcaide, B.; Almendros, P.; Salgado, N. R.; Rodr´ıguez-
Vicente, A. J . Org. Chem. 2000, 65, 4453. (e) Alcaide, B.; Aly, M. F.;
Rodr´ıguez, C.; Rodr´ıguez-Vicente, A. J . Org. Chem. 2000, 65, 3453. (f)
Alcaide, B.; Almendros, P.; Aragoncillo, C. Org. Lett. 2000, 2, 1411.
(g) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Commun. 2000,
757.
(9) For a preliminary communication of a part of this work, see:
Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Commun. 1999, 1913.
(10) The cis-selectivity observed for compounds 2 was expected
according to the current model for the Staudinger reaction. (a) Arrieta,
A.; Lecea, B.; Coss´ıo, F. P. J . Org. Chem. 1998, 63, 5869. (b) Cossio, F.
P.; Arrieta, A.; Lecea, B.; Ugalde, J . M. J . Am. Chem. Soc. 1994, 116,
2085. (c) Hegedus, L. S.; Montgomery, J .; Narukawa, Y.; Snustad, D.
C. J . Am. Chem. Soc. 1991, 113, 5784. (d) Palomo, C.; Aizpurua, J .
M.; Mielgo, A.; Linden, A. J . Org. Chem. 1996, 61, 9186. This model
accounts for a 3R,4S stereochemistry for D-glyceraldehyde derived
2-azetidinones. For an experimental study on the synthesis of 2-aze-
tidinones derived from D- and L-glyceraldehyde acetonide imines,
see: (e) Niu, Ch.; Miller, M. J . Tetrahedron Lett. 1995, 36, 497. (f)
Hubschwerelen, C.; Schmid, G. Helv. Chim. Acta 1983, 66, 2206. (g)
Welch, J . T.; Araki, K.; Kawecki, R.; Wichtowski, J . A. J . Org. Chem.
1993, 58, 2454. (h) Wagle, D. R.; Garai, C.; Chiang, J .; Monteleone,
M. G.; Kurys, B. E.; Strohmeyer, T. W.; Hedge, V. R.; Manhas, M. S.;
Bose, A. K. J . Org. Chem. 1988, 53, 4227 and references therein.
In view of the importance of ring structures in es-
sentially all classes of natural products, numerous com-
binations of reactions have therefore been exploited to
construct mono- and polycyclic derivatives. Among the
various available options, such as cycloaddition reactions,
(11) (a) Drewes, S. E.; Khan, A. A.; Rowland, K. Synth. Commun.
1993, 23, 183. (b) Nayak, S. K.; Thijs, L.; Zwanenburg, B. Tetrahedron
Lett. 1999, 40, 981. (c) Manickum, T.; Roos, G. Synth. Commun. 1991,
21, 2269.

1614 J . Org. Chem., Vol. 66, No. 5, 2001
Ta ble 1. Ster eoselective Ba ylis-Hillm a n Rea ction of 4-oxoa zetid in e-2-ca r ba ld eh yd es 1a
Alcaide et al.
DABCO
(mol %)
entry
aldehyde
R1
R2
EWG
t (h)
adduct
d.r.b
yield (%)c
1
2
3
4
5
6
7
8
9
(+)-1a
(+)-1a
(+)-1a
(+)-1a
(+)-1a
(+)-1a
(+)-1b
(+)-1c
(+)-1d
(+)-1e
(+)-1f
(+)-1g
2-propenyl
2-propenyl
2-propenyl
2-propenyl
2-propenyl
2-propenyl
3-butenyl
2-propynyl
3-butynyl
4-pentynyl
5-hexynyl
2-propenyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
COCH3
COCH3
COCH3
COCH3
CN
COOCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
10
20
50
96
32
24
(+)-3a
(+)-3a
(+)-3a
(+)-3a
(+)-3b
(+)-3c
(+)-3d
(+)-3e
(+)-3f
(+)-3g
(+)-3h
(+)-3i
99:1
99:1
99:1
99:1
93:7
99:1
99:1
96:4
99:1
99:1
99:1
81:19
80
80
80
80
84
58
72
78
67
60
60
71
100
100
100
100
100
100
100
100
100
17
192
120
72
72
24
48
24
144
10
11
12
a
b
All reactions were carried out on 1 mmol scale. PMP ) 4-MeOC6H4. The ratio was determined by integration of well-resolved signals
in the 1H NMR spectra of the crude reaction mixtures before purification. c Yield of pure, isolated product with correct analytical and
spectral data.
sociated with the formation of medium-sized rings using
free radical methodology are widely appreciated. Even
the formation of seven-membered rings in the 7-exo-trig
mode is likely to be unsuccessful in most cases (at 25 °C,
k 7exo < 7 × 10-1 s-1). However, several authors were able
to prepare seven-membered rings by radical cyclization
on substrates having only a limited degree of freedom,
including â-lactam-tethered haloalkenes or alkynes15,16
and arylbridged compounds.17 The formation of rings with
F igu r e 1. Model to explain the observed stereochemistry by
delivery of the activated olefin to the less hindered face.
more than seven atoms have unfavorable rates because
the addition step is often too slow to allow it to compete
successfully with other pathways open to the radical
intermediate. In stannane-based chemistry for example,
premature hydrogen abstraction from the organotin
hydride is difficult to avoid. Nevertheless, Gibson has
reported the radical cyclization of aryl radicals onto R,â-
unsaturated amino esters to give eight- and nine-mem-
bered ring benzocyclic R-aminoesters which have the
nitrogen atom in the ring,18a and Pattenden has studied
this methodology of cyclization for the synthesis of eight-
membered bicyclic lactones.18b
Subjection of any organic molecule to a high enough
temperature in the gas phase results in the formation of
free radicals. When the molecule contains bonds with
dissociation energies from 20 to 40 Kcal mol-1, cleavage
can be caused in the liquid phase. The dissociation energy
of the PhCH2-H bond is 88 Kcal mol-1, so the generation
of the benzylic radical is an unexpected process via
heating at usual temperatures.19 To our surprise, Baylis-
Hillman adduct (+)-3a , on heating in toluene, p-xylene,
or mesitylene in a sealed tube at 210 °C,20 formed as
single isomers the bicyclic products 4a -c, which were
ring transformations, and cyclization reactions, the latter
are probably the most commonly used because of the
number of possible initiators and terminators. But not
every ring size is accessible with the same ease. Cycliza-
tion processes generally fail when applied to the con-
struction of medium-sized rings, because of enthalpic
(increasing strain in the transition state) and entropic
influences (probability of the chain ends meeting).12
However there are a few notable exceptions, such as the
rapidly emerging metathesis reaction.13 Indirect routes
(ionic- and radical-based ring expansions and fragmenta-
tions) are often needed to access such structures.14
Unlike intermolecular C-C bond formation involving
radical additions to activated (usually electrophilic) ole-
fins, clean bimolecular additions to simple alkenes are
not generally easy to accomplish using common radical
processes. Although construction of five- and six-mem-
bered rings has received much attention, problems as-
(12) (a) Galli, L.; Mandolini, L. Eur. J . Org. Chem. 2000, 3117. (b)
Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(13) For some recent reviews on olefin metathesis, see: (a) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3012. (b) Maier, M. E. Angew.
Chem., Int. Ed. 2000, 39, 2073. (c) Fu¨rstner, A. Synlett 1999, 1523.
(d) Wright, D. L. Curr. Org. Chem. 1999, 3, 211. (e) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (f) Shuster, M.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (g) Grubbs, R. H.; Miller,
S. J .; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(14) For selected references, see: (a) Kirsch, V.; Wolff, C.; Na¨ther,
C.; Tochtermann, W. Eur. J . Org. Chem. 2000, 99, 1741. (b) Mehta,
G.; Singh, V. Chem. Rev. 1999, 99, 881. (c) Boivin, J .; Pothier, J .;
Ramos, L.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 9239. (d) Dowd, P.;
Zhang, W. Chem. Rev. 1993, 93, 2091. (e) Hesse, M. Ring Enlargement
in Organic Chemistry; VCH: Weinheim, 1991. (f) Wovkulich, P. M. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol 1, pp 843-899. (g) Grob, C. A.
Angew. Chem., Int. Ed. Engl. 1969, 8, 535.
(15) (a) Knight, J .; Parsons, P. J . J . Chem. Soc., Perkin Trans. 1
1987, 1237. (b) Knight, J .; Parsons, P. J .; Southgate, R. J . Chem. Soc.,
Chem. Commun. 1 1986, 78.
(16) (a) Bachi, M. D. In Recent Advances in the Chemistry of
â-Lactam Antibiotics; Bentley, P. H., Southgate, R., Eds.; Special
Publication No. 70; Royal Society of Chemistry: London, 1989; Ch. 6.
(b) Bachi, M. D.; Frolow, F.; Hoornaert, C. J . Org. Chem. 1983, 48,
1841.
(17) (a) Beck, A. L.; Mascal, M.; Moody, C. J .; Slawin, A. M. Z.;
Williams, D. J .; Coates, W. J . J . Chem. Soc., Perkin Trans. 1 1992,
797. (b) Mathvink, R.; Boger, D. L. J . Org. Chem. 1988, 53, 3377.
(18) (a) Gibson, S. E.; Guillo, N.; Tozer, M. J . Chem. Commun. 1
1997, 637. (b) Blake, A. J .; Hollingworth, G. J .; Pattenden, G. Synlett
1996, 643.

Cyclization of Baylis-Hillman Adducts
J . Org. Chem., Vol. 66, No. 5, 2001 1615
Sch em e 2
Sch em e 4
5, 1,2-diarylethanes were isolated as byproducts in all
cases. These products may be formed by recombination
of the initially generated benzylic radicals.
Sch em e 3
In view of the particular disposition of 1,5- and 1,6-
enyne-2-azetidinones to undergo 5-exo and 6-exo tin-
promoted radical cyclization,21 we examined the appli-
cability of this methodology to our novel Baylis-Hillman
1,ω-enyne substrates 3e-h for the synthesis of less
common bicyclic â-lactams. This approach in the prepa-
ration of seven-membered or larger sized rings has not
been hitherto applied.22 The extraordinary synthetic
potential of Baylis-Hillman adducts 3 is illustrated by
a dramatic change in the chemoselectivity when the
bicyclic â-lactam (+)-6a was smoothly formed as the
exclusive product from compound (+)-3e, in nearly
quantitative yield as crude product. The tin-promoted
radical reaction was also useful in the conversion of the
homologous 1,4-tethered enynes (+)-3f and (+)-3g into
the corresponding bicyclic systems (+)-6b and (+)-6c with
similar efficiency and selectivity. Compounds 6a -c were
exclusively obtained as single Z- or E-isomers. The
triphenyltin group in the final products represents a very
useful handle since it provides an entry into the excep-
tionally rich chemistry of tin. In addition, PhSH reacted
in boiling benzene with â-lactams 3e-g in the presence
of a catalitic amount of AIBN as initiator under an inert
atmosphere, delivering in good yields the corresponding
phenylthiovinyl derivatives 6d -f as mixtures of Z/ E-
isomers (Scheme 4). Fortunately, in all cases the isomeric
products Z-6d -f and E-6d -f could be easily separated
by gravity flow chromatography, wherein the major
isomer was usually the less polar compound. It should
be noted that reactions were carried out under standard
dilution conditions and did not require the use of high
dilution techniques. Efforts to promote this process on
substrate (+)-3h failed, even by conducting the experi-
ment with very low concentrations of both the Baylis-
Hillman adduct (+)-3h and Bu3SnH and slow addition
of reagents, such as syringe pump addition. In this case
the radical addition to the triple bond occurs, but the rate
of hydrogen-atom transfer to unclyclized radicals is faster
than the further Michael addition required for achieving
the then-membered fused bicycle.
isolated in modest yields (37-45%); the use of chloroben-
zene or anisole as solvents gave unaltered starting
material. Variation of Baylis-Hillman adduct was ex-
amined. Dienes 3b, 3c, and 3i by heating in toluene or
p-xylene suffer as well this novel thermally induced
reaction (Scheme 2). The COMe substituent gave the best
match of diastereoselectivity. Changing the EWG to
COOMe saw the lowest diastereoselectivity.
When enyne (+)-3e was used instead of diene (+)-3a
the reaction proceeded in the same manner, giving
product (+)-5d in good yield (60%). Furthermore, thermal
treatment of enyne (+)-3f with toluene or p-xylene gave
the eight-membered cycles (+)-5e and (+)-5f in reason-
able yields. Interestingly, the use of benzyl alcohol
allowed us to obtain the hemicetal derivative (+)-5b
(Scheme 3). Although this latter compound was isolated
in low yield (20%), this is an interesting case because
three new chiral centers are generated in a straightfor-
ward and highly stereoselective manner. The use of ethyl
benzene instead of benzyl alcohol furnished a mixture of
two products (+)-5c (50:50) which were identified as
epimers at the benzylic carbon center. Compounds 5 were
obtained as single diastereomers except (+)-5c, derived
from ethylbenzene. However, attempts to promote such
a thermal reaction on substrate (+)-3g failed, and
complex reaction mixtures were isolated in all cases.
When a catalytic amount of hydroquinone was added, the
reaction rate was considerably reduced and the product
yield fell dramatically. This fact confirms that a radical
reaction is involved. Also, together with compounds 4 and
Formation of bicyclic â-lactams 4, 5, and 6 can be
explained in terms of a competition between a tandem
radical Michael addition/endo cyclization and a tandem
radical addition/Michael addition, depending on the
(19) For a review on formation of free radicals by thermal cleavage,
see: (a) Brown, R. F. C. Pyrolytic Methods in Organic Chemistry;
Academic Press: New York, 1980; pp. 44-61. For a summary of
methods of radical formation, see: (b) Giese, B. Radicals in Organic
Synthesis: Formation of Carbon-Carbon Bonds; Pergamon Press:
Elmsford, New York, 1986; pp 267-281.
(20) One of the reviewers has suggested that the generation of a
benzylic radical is unlikely by simple heating in toluene or other
aromatic compounds. For this reviewer, a much more likely scenario
is that traces of oxygen serve to generate the benzylic radicals.
(21) Representative examples: Cyclizations using R3SnH: Stork,
G.; Mook, R., J r. J . Am. Chem. Soc. 1987, 109, 2829. J anardhanam,
S.; Balakumar, A.; Rajagopalan, K. J . Chem. Soc., Perkin Trans. 1
1994, 551. Cyclizations using sulfur- and phosphorus-centered radi-
cals: Brumwell, J . E.; Simpkins, N. S.; Terret, N. K. Tetrahedron 1994,
50, 13533.

1616 J . Org. Chem., Vol. 66, No. 5, 2001
Alcaide et al.
Sch em e 5. Mech a n istic exp la n a tion for th e
for m a tion of bicyclic â-la cta m s 4-6
F igu r e 2. Model to rationalize the 1,2-stereoinduction on
radical reactions.
Sch em e 6
electronic nature of the radical promoter (Scheme 5). It
is known that nucleophilic radicals react more rapidly
with electron poor alkenes than with electron rich al-
kenes or alkynes, and conversely, electrophilic radicals
react more rapidly with electron rich alkenes than elec-
tron poor alkenes.3l In our case, Baylis-Hillman adducts
3 may react through two different pathways to give the
bicyclic systems. The more nucleophilic benzylic radical
would favor formation of compounds 4 and 5 through
pathway A, while the more electrophilic radicals, such
as PhS‚ and Ph3Sn‚, should promote formation of com-
pounds 6 through pathway B. Alternatively, the differ-
ences in reactivity between the benzylic and the thiyl and
stannyl radicals, respectively, could be explained by other
considerations. Thus, for the thiyl and stannyl radicals
the initial addition to the double bond is fast but
reversible. Since the cyclization is a slow reaction, it
cannot compete with fragmentation. However, the addi-
tion to the triple bond is irreversible, and therefore only
products deriving from addition to the triple bond are
isolated. Addition of the benzylic radical to the double
bond of course is not reversible.
The R-substituted â-oxy-radicals (types 7 and 8 in
Scheme 5) react preferentially via the transition states
I and II which minimize the steric repulsive interactions
between the â-lactam ring and the bulky aryl moiety. We
should like to note that the 1,2-asymmetric induction
observed during the radical process is favored by steric
reasons and it is consistent with the attack in the enolate
radicals occurring anti to the â-lactam ring attached to
the C-2 stereogenic center (Figure 2).23 The difference in
behavior between ethylbenzene and benzyl alcohol may
be due to the extent of coordination in the radical
involved in the reaction. It is possible that internal
hydrogen bonding between the ketonic oxygen atom and
the hydroxylic hydrogen atom from the benzylic moiety
gives rise to a rotationally restricted transition state,
generating a preferred conformation.24 The methyl group
from ethylbenzene does not have this ability of coordina-
tion with the ketone, involving two conformations with
the same energy.
To illustrate the value of these substrates, exocyclic
double bond thioderivatives 6d -f were ozonolyzed to
give seven-, eight- and nine-membered25 ketones 9a -c
(Scheme 6).
To test the reactivity of these polyfunctionalized sub-
strates, Swern oxidation was carried out in bicycle (+)-
5d providing diketone (-)-10a . Treatment of â-dicarbo-
nylic compound (-)-10a with hydrazine hydrate formed
product (+)-11a as single isomer (Scheme 7). This
transformation could be rationalized through a retro-
aldol reaction followed by a stereoselective protonation
of the enolate to the less hindered face.
Con figu r a tion a l Assign m en t for Bicyclic Sys-
tem s. The bicyclic structure (by DEPT, HETCOR, and
COSY) and the stereochemistry (by vicinal proton cou-
plings and NOE experiments) of compounds 4, 5, 6, and
11 were established by NMR mono- and two-dimensional
techniques. Taking into account that optically pure
Baylis-Hillman adducts 3 could be obtained and cy-
clized,26 the stereochemistry for compounds 3 was inme-
diately deduced by comparison with the NOE results of
(22) The only related example is by Parsons et al. and refers to the
cyclization of N-(2-bromo-2-propen-1-yl)-4-allyl-2-azetidinone to yield
a homocarbacephem derivative. See ref 15.
(23) For selected references on 1,2-asymmetric induction in radical
reactions, see for example: (a) Giese, B.; Damm, W.; Dickhaut, J .;
Wetterich, F.; Sun, S.; Curran, D. P. Tetrahedron Lett. 1991, 32, 6097.
(b) Damm, W.; Dickhaut, J .; Wetterich, F.; Giese, B. Tetrahedron Lett.
1993, 34, 431. (c) Renaud, P.; Bourquard, T. Synlett 1995, 1021. (d)
Giese, B.; Bulliard, M.; Dickhaut, J .; Halbach, R.; Hassler, C.; Hoff-
mann, U.; Hinzen, B.; Senn, M. Synlett 1995, 116.
(24) For the role of intramolecular hydrogen bonding in the stereo-
control of R-sulfinylated â-hydroxy-radicals see: Mase, N.; Watanabe,
Y.; Toru, T. Tetrahedron Lett. 1999, 40, 2797.
(25) The generation of nine-membered nitrogen heterocycles (azonines)
bearing defined constitutions and configurations is still a challenge in
organic synthesis. Furthermore, azonines are found as subunits in
natural and pharmaceutically important products. See: Evans, P. A.;
Holmes, A. B. Tetrahedron 1991, 47, 9131.

Cyclization of Baylis-Hillman Adducts
J . Org. Chem., Vol. 66, No. 5, 2001 1617
Sch em e 7
the bicyclic systems. Besides, the cis-stereochemistry of
the four-membered ring is set during the cyclization step
to form the 2-azetidinone ring, and it is transferred
unaltered during the further synthetic steps.27 NOE
irradiation of H6 (carbinolic hydrogen) on compound (+)-
4f resulted in enhancement of the signals corresponding
to H7 and CHHBn (12% and 9%, respectively), which is
consistent with a syn H6-H7/syn H6-CH2Bn relative
stereochemistry. Conversely, NOE enhancement (10%)
was observed on H6 upon irradiation of CHHBn. NOE
enhancements of 7% and 10% were observed on H6 and
H8, respectively, upon irradiation of H7, so confirming
this pattern. The syn H7-H8/syn H7-CH2CH2Ar relative
stereochemistry for compound (+)-5e was obvious on the
basis of NOE enhancements of the signals corresponding
to H8 and CHHCH2Ar (8% and 9%, respectively) upon
irradiation of H7. Furthermore, NOE irradiation of H8
resulted in a 7% enhancement of the signal corresponding
to H7. A NOE enhancement of 2% on H5 for compound
(+)-11b on irradiating the signal corresponding to H7 is
in good agreement with a syn-relative disposition be-
tween H5 and H7 (Figure 3). Analogous NOE enhance-
ments were observed for remaining compounds 4 and 5.
F igu r e 3. Selected NOE effects and stereochemistry of some
fused bicyclic â-lactams 4-6.
monocyclic â-lactams and a number of unusual bicyclic
â-lactams fused to medium rings. This methodology is
very versatile offering the possibility to obtain a variety
of conveniently functionalized bicyclic â-lactams just by
changing the substituents in readily available 4-oxoaze-
tidine-2-carbaldehydes, activated alkenes, or radical
precursors. In addition to the novelty of this strategy,
the method proved to be general and highly diastereo-
selective for the preparation up to nine-membered fused
rings, offering the possibility of a future application to
different chiral building blocks other than 2-azetidinones.
Other aspects of this chemistry are currently under
investigation in our laboratory.
Azetidinones 6 have a medium-sized ring bearing an
exocyclic double bond fused to the â-lactam. The stere-
ochemistry at the stereocenters in compounds 6 was
stablished by NOE studies, as shown in Figure 3 for
compounds (+)-Z-6a , (-)-Z-6d , and (+)-E-6d . The geom-
etry of the exocyclic double bond was assigned by
qualitative homonuclear NOE difference spectra as de-
picted in Figure 3 for compounds (+)-Z-6a , (-)-Z-6d , and
(+)-E-6d . Similar values of NOE enhancements for
compounds 6b-f were observed, in agreement with the
proposed stereochemistries.
Exp er im en ta l Section
Gen er a l. General experimental data and procedures have
been previously reported.8a NMR spectra were recorded in
CDCl3 solutions, except otherwise stated. Chemical shifts are
given in ppm relative to TMS (1H, 0.0 ppm) or CDCl3 (13C, 76.9
ppm). Specific rotation [R]D is given in deg per dm at 20 °C,
and the concentration (c) is expressed in g per 100 mL. All
commercially available compounds were used without further
purification. 4-Oxoazetidine-2-carbaldehydes (+)-1a and (+)-
1c and 2-azetidinones (+)-2a , (+)-2c, and (+)-2g were prepared
according to our previously reported procedures.8a
In conclusion, we have shown that combination of
Baylis-Hillman reaction and tandem radical addition/
cyclization sequences is an extremely useful synthetic tool
for the asymmetric synthesis of densely functionalized
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
3a -i. A solution of the appropriate 4-oxoazetidine-2-carbal-
dehyde 1 (0.20 mmol) in acetonitrile (2 mL) was added drop-
wise to a stirred solution of DABCO (22.4 mg, 0.20 mmol) in
acetonitrile (2 mL) at -20 °C. After 15 min, an activated olefin
(2.00 mmol) was added at -20 °C and the reaction mixture
was placed in a -20 °C freezer until complete disappearance
of the aldehyde (TLC). The mixture was concentrated under
reduced pressure. Chromatography of the residue eluting with
hexanes/ethyl acetate or ethyl acetate/dichloromethane mix-
tures gave analytically pure compounds 3. Spectroscopic and
analytical data for some representative forms of 3 follow.28
(26) Derivatizing the hydroxyesters 3 with (R)- and (S)-O-acetyl-
mandelic acids would allow assignment of the configuration at the
carbinolic stereocenter. However, sluggish and low yielding reactions
were observed. This behavior of the â-lactamic Baylis-Hillman adducts
is in sharp contrast with the good yields observed by us for related
O-acetylmandelates derived from homoallylic alcohols. See ref 8a.
(27) For clarity throughout this work, bicyclic systems have been
numbered according to the numeration used for trinems. Thus, the
four-membered ring nitrogen has been assigned the locator 1, and the
remaining positions have been numbered to place the higher number
on the amide carbonyl group.
(3R,4S)-4-[(R)-1-Hyd r oxy-2-m eth ylid en e-3-oxo-bu tyl]-
3-p h en oxy-1-(2-p r op en yl)-2-a zetid in on e, (+)-3a . From 249

1618 J . Org. Chem., Vol. 66, No. 5, 2001
Alcaide et al.
mg (1.08 mmol) of 4-oxoazetidine-2-carbaldehyde (+)-1a and
after 17 h at -20 °C, 260 mg (80%) of compound (+)-3a was
obtained as a colorless solid after purification by flash chro-
matography (dichloromethane/ethyl acetate, 9/1). Colorless
solid. Mp: 114-116 °C (hexanes/ethyl acetate). [R]D ) + 58.1
(c 0.4, CHCl3). 1H NMR: δ 1.79 (td, 2H, J ) 12.4, 6.8 Hz),
1.98 (t, 1H, J ) 2.7 Hz), 2.24 (td, 2H, J ) 6.8, 2.7 Hz), 2.39 (s,
3H), 3.15 (d, 1H, J ) 4.6 Hz), 3.27 and 3.56 (td, each 1H, J )
14.0, 7.8 Hz), 4.31 (dd, 1H, J ) 4.6, 3.7 Hz), 4.86 (m, 1H), 5.21
(d, 1H, J ) 4.9 Hz), 6.29 and 6.38 (d, each 1H, J ) 1.5 Hz),
7.05 (m, 3H), 7.31 (m, 2H). 13C NMR: δ 199.8, 165.9, 157.3,
146.4, 129.7, 128.9, 122.8, 115.8, 82.9, 80.6, 69.2, 68.8, 59.6,
41.1, 26.3, 26.1, 16.2. IR (CHCl3, cm-1): ν 3395, 3291, 1756,
1666. MS (CI), m/z: 329 (M+ + 2, 10), 328 (M+ + 1, 100). Anal.
Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C,
69.82; H, 6.32; N, 4.36.
Th er m a lly-In d u ced Rea ction s betw een Ba ylis-Hill-
m a n Ad d u cts 3 a n d Rea gen ts bea r in g a Ben zylic-Typ e
Hyd r ogen . Gen er a l P r oced u r e for th e Syn th esis of
Bicycles 4a -g a n d 5a -f. A solution of the corresponding
Baylis-Hillman adduct 3 (0.20 mmol) in the appropriate
benzylic solvent (10 mL) was heated in a sealed tube at 210
°C for 3 h. The reaction mixture was allowed to cool to room
temperature, the solvent was removed under reduced pressure,
and after purification by flash chromatography bicycles 4 and
5 were obtained.
Bicycle (+)-4b. From 111.3 mg (0.368 mmol) of Baylis-
Hillman adduct (+)-3a , 68 mg (45%) of compound (+)-4b was
obtained as a colorless solid after purification by flash chro-
matography (hexanes/ethyl acetate, 4/6). Colorless solid. Mp:
83-85 °C (hexanes/ethyl acetate). [R]D ) +50.9 (c 1.6, CHCl3).
1H NMR: δ 1.33 (m, 1H), 1.68 (td, 1H, J ) 13.2, 3.7 Hz), 2.02
(m, 3 H), 2.19 (td, 1H, J ) 12.7, 3.7 Hz), 2.22 (s, 3H), 2.31 (s,
3H), 2.36 (td, 1H, J ) 13.4, 5.0 Hz), 2.57 (td, 1H, J ) 12.2, 5.2
Hz), 2.69 (s, 1H), 3.45 (m, 2H), 4.31 (d, 1H, J ) 4.6 Hz), 4.52
(m, 1 H), 5.19 (d, 1H, J ) 4.6 Hz), 7.06 (m, 5 H), 7.17 (d, 2H,
J ) 8.5 Hz), 7.35 (t, 2H, J ) 8.5 Hz). 13C NMR: δ 211.9, 165.2,
157.2, 138.3, 135.6, 129.8, 129.2, 128.1, 123.1, 116.2, 80.4, 66.7,
60.1, 57.6, 42.8, 38.2, 32.8, 30.2, 25.6, 22.6, 21.0. IR (KBr,
cm-1): ν 3332, 1753, 1709. MS (EI), m/z: 409 (M+ + 2, 36),
408 (M+ + 1, 100). Anal. Calcd for C25H29NO4: C, 73.69; H,
7.17; N, 3.44. Found: C, 73.56; H, 7.13; N, 3.51.
1
(c 0.9, CHCl3). H NMR: δ 2.35 (s, 3H), 3.14 (d, 1H, J ) 4.6
Hz), 3.65 (dd, 1H, J ) 15.4, 7.5 Hz), 4.24 (m, 1H), 4.31 (d, 1H,
J ) 4.9 Hz), 4.86 (m, 1H), 5.19 (m, 2H), 5.23 (d, 1H, J ) 4.9
Hz), 5.70 (m, 1H), 6.26 (s, 1H), 6.37 (d, 1H, J ) 1.5 Hz), 7.05
(m, 3H), 7.31 (m, 2H). 13C NMR: δ 199.6, 165.7, 157.2, 146.6,
131.3, 129.7, 128.6, 122.8, 119.0, 115.8, 80.7, 68.5, 58.9, 44.1,
26.2. IR (KBr, cm-1): ν 3431, 1763, 1665. MS (EI), m/z: 302
(M+ + 1, 54), 301 (M+, 6), 60 (100). Anal. Calcd for C17H19
-
NO4: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.50; H, 6.55; N,
4.55.
(3R,4S)-4-[(R)-2-Cya n o-1-h yd r oxy-2-p r op en yl]-3-p h e-
n oxy-1-(2-p r op en yl)-2-a zetid in on e, (+)-syn -3b. From 341
mg (1.47 mmol) of 4-oxoazetidine-2-carbaldehyde (+)-1a and
after 192 h at -20 °C, 327 mg (78%) of compound (+)-syn-3b
was obtained as a colorless solid after purification by flash
chromatography (hexanes/ethyl acetate, 3/2). Colorless solid.
Mp: 78-80 °C (hexanes/ethyl acetate). [R]D ) + 68.3 (c 0.7,
1
CHCl3). H NMR: δ 3.15 (d, 1H, J ) 3.4 Hz), 3.71 (dd, 1H, J
) 15.4, 7.0 Hz), 4.20 (dd, 1H, J ) 15.9, 4.9 Hz), 4.32 (t, 1H, J
) 4.4 Hz), 4.65 (bs, 1H), 5.29 (m, 2H), 5.32 (d, 1H, J ) 4.4
Hz), 5.79 (m, 1H), 6.12 (s, 1H), 6.29 (d, 1H, J ) 1.5 Hz), 7.08
(m, 3H), 7.33 (m, 2H). 13C NMR: δ 165.5, 156.9, 132.5, 130.9,
129.8, 123.1, 122.6, 119.7, 116.6, 115.9, 80.7, 69.6, 58.6, 44.4.
IR (KBr, cm-1): ν 3430, 2230, 1759. MS (CI), m/z: 285 (M+
+
1, 100), 284 (M+, 36). Anal. Calcd for C16H16N2O3: C, 67.69;
H, 5.67; N, 9.85. Found: C, 67.59; H, 5.81; N, 9.73.
(3R,4S)-4-[(R)-2-Car boxym eth yl-1-h ydr oxy-2-pr open yl]-
3-p h en oxy-1-(2-p r op en yl)-2-a zetid in on e, (+)-3c. From 362
mg (1.56 mmol) of 4-oxoazetidine-2-carbaldehyde (+)-1a and
after 120 h at -20 °C, 289 mg (58%) of compound (+)-3c was
obtained as a colorless solid after purification by flash chro-
matography (hexanes/ethyl acetate, 2/1). Colorless solid. Mp:
120-122 °C (hexanes/ethyl acetate). [R]D ) + 71.5 (c 0.8,
Bicycle (+)-4c. From 53.7 mg (0.178 mmol) of Baylis-
Hillman adduct (+)-3a , 28 mg (38%) of compound (+)-4c was
obtained as a colorless solid after purification by flash chro-
matography (hexanes/ethyl acetate, 1/1). Colorless solid. Mp:
116-117 °C (hexanes/ethyl acetate). [R]D ) +55.3 (c 0.6,
1
CHCl3). H NMR: δ 3.14 (d, 1H, J ) 4.6 Hz), 3.65 (dd, 1H, J
) 15.4, 7.8 Hz), 3.78 (s, 3H), 4.22 (ddt, 1H, J ) 15.4, 4.9, 1.5
Hz), 4.36 (dd, 1H, J ) 4.9, 3.4 Hz), 4.83 (m, 1H), 5.15 (dq, 1H,
J ) 10.9, 1.5 Hz), 5.22 (m, 1H), 5.23 (d, 1H, J ) 4.9 Hz), 5.69
(m, 1H), 6.15 (t, 1H, J ) 1.7 Hz), 6.39 (t, 1H, J ) 1.5 Hz), 7.06
(m, 3H), 7.31 (m, 2H). 13C NMR: δ 166.4, 165.8, 157.3, 138.6,
131.2, 129.8, 127.9, 122.9, 119.4, 116.0, 80.9, 69.1, 58.7, 52.1,
44.3. IR (KBr, cm-1): ν 3428, 1759, 1672. MS (EI), m/z: 317
(M+ + 1, 100), 316 (M+, 17). Anal. Calcd for C17H19NO5: C,
64.34; H, 6.03; N, 4.41. Found: C, 64.40; H, 5.91; N, 4.51.
(3R,4S)-4-[(R)-1-Hyd r oxy-2-m eth ylid en e-3-oxo-bu tyl]-
3-p h en oxy-1-(2-p r op yn yl)-2-a zetid in on e, (+)-syn -3e. From
109.8 mg (0.48 mmol) of 4-oxoazetidine-2-carbaldehyde (+)-
1c and after 72 h at -20 °C, 107 mg (75%) of compound (+)-
syn-3e was obtained as a colorless solid after purification by
flash chromatography (dichloromethane/ethyl acetate, 9/1).
Colorless solid. Mp: 116-118 °C (hexanes/ethyl acetate). [R]D
1
CHCl3). H NMR: δ 1.35 (m, 3H), 1.67 (td, 1H, J ) 12.9, 3.9
Hz), 1.99 (m, 3H), 2.13 (td, 1H, J ) 13.2, 3.7 Hz), 2.24 (s, 3H),
2.28 (s, 6H), 2.73 (d, 1H, J ) 2.2 Hz), 3.45 (m, 2H), 4.32 (d,
1H, J ) 4.4 Hz), 4.52 (d, 1H, J ) 2.9 Hz), 5.21 (d, 1H, J ) 4.4
Hz), 6.79 (m, 3H), 7.11 (m, 3H), 7.34 (m, 2H). 13C NMR: δ
211.9, 165.1, 157.2, 141.3, 137.9, 129.8, 127.7, 126.0, 123.1,
116.2, 80.4, 66.7, 60.0, 57.5, 42.7, 38.1, 32.8, 30.4, 25.6, 22.6,
21.2. IR (KBr, cm-1): ν 3330, 1750, 1704. MS (CI), m/z: 422
(M+ + 1, 100), 421 (M+ + 1, 50). Anal. Calcd for C26H31NO4:
C, 74.08; H, 7.41; N, 3.32. Found: C, 74.16; H, 7.33; N, 3.48.
Bicycle (+)-4d . From 55.8 mg (0.196 mmol) of Baylis-
Hillman adduct (+)-syn-3b, 27 mg (37%) of compound syn-4d ,
containing ca. 15% of its anti-4d epimer, was obtained as a
colorless oil after purification by flash chromatography (hex-
anes/ethyl acetate, 3/1). Colorless solid. Mp: 145-147 °C
(hexanes/ethyl acetate). [R]D ) +62.3 (c 0.7, CHCl3). 1H NMR:
δ 1.99 (m, 4H), 2.22 (m, 2H), 2.77 (d, 1H, J ) 2.9 Hz), 2.85 (t,
2H, J ) 8.0 Hz), 3.49 (m, 2H), 4.18 (d, 1H, J ) 2.9 Hz), 4.48
(d, 1H, J ) 4.9 Hz), 5.28 (d, 1H, J ) 4.9 Hz), 7.15 (m, 7H),
7.34 (m, 3H). 13C NMR: δ 164.9, 156.8, 140.4, 129.9, 128.6,
128.4, 126.4, 123.4, 121.4, 116.1, 80.1, 69.4, 57.5, 46.9, 42.7,
38.5, 32.3, 31.6, 22.3. IR (KBr, cm-1): ν 3340, 2250, 1746. MS
(EI), m/z: 377 (M+ + 1, 36), 421 (M+ + 1, 100). Anal. Calcd for
1
) + 89.1 (c 0.8, CHCl3). H NMR: δ 2.26 (t, 1H, J ) 2.5 Hz),
2.40 (s, 3H), 3.22 (d, 1H, J ) 4.4 Hz), 3.78 and 4.45 (dd, each
1H, J ) 17.6, 2.5 Hz), 4.42 (dd, 1H, J ) 4.9, 2.9 Hz), 4.91 (m,
1H), 5.23 (d, 1H, J ) 5.1 Hz), 6.29 and 6.37 (d, each 1H, J )
1.5 Hz), 7.06 (m, 3H), 7.31 (m, 2H). 13C NMR: δ 199.4, 164.9,
157.0, 146.4, 129.6, 128.2, 122.8, 115.7, 80.8, 75.9, 73.1, 68.1,
58.4, 31.2. IR (KBr, cm-1): ν 3393, 3292, 1755, 1665. MS (CI),
m/z: 301 (M+ + 2, 17), 300 (M+ + 1, 100). Anal. Calcd for
C
17H17NO4: C, 68.22; H, 5.72; N, 4.68. Found: C, 68.12; H,
7.83; N, 4.76.
C
23H24N2O3: C, 73.38; H, 6.43; N, 7.44. Found: C, 73.48; H,
(3R,4S)-4-[(R)-1-Hyd r oxy-2-m eth ylid en e-3-oxo-bu tyl]-
1-(4-p en tyn yl)-3-p h en oxy-2-a zetid in on e, (+)-3g. From 123
mg (0.478 mmol) of 4-oxoazetidine-2-carbaldehyde (+)-1e and
after 48 h at -20 °C, 93 mg (60%) of compound (+)-3g was
obtained as a colorless oil after purification by flash chroma-
tography (dichloromethane/ethyl acetate, 9/1). [R]D ) + 71.8
6.35; N, 7.38.
Bicycle (+)-4e. From 60 mg (0.189 mmol) of Baylis-
Hillman adduct (+)-3c, 43 mg (56%) of compound syn-4e,
containing ca. 15% of its anti-4e epimer was obtained as a
colorless oil after purification by flash chromatography (hex-
anes/ethyl acetate, 1/2). Colorless oil. [R]D ) +71.7 (c 0.6,
1
CHCl3). H NMR: δ 1.57 (m, 2H), 1.87 (m, 2H), 2.23 (m, 2H),
(28) Full spectroscopic and analytical data for compounds not
included in this Experimental Section are described in the Supporting
Information.
2.43 (td, 1H, J ) 11.5, 4.9 Hz), 2.60 (td, 1H, J ) 11.5, 5.5 Hz),
2.84 (d, 1H, J ) 2.7 Hz), 3.41 (dd, 2H, J ) 9.8, 2.5 Hz), 3.74

Cyclization of Baylis-Hillman Adducts
J . Org. Chem., Vol. 66, No. 5, 2001 1619
(s, 3H), 4.31 (d, 1H, J ) 4.6 Hz), 4.47 (d, 1H, J ) 2.7 Hz), 5.20
(d, 1H, J ) 4.6 Hz), 7.15 (m, 7H), 7.29 (m, 3H). 13C NMR: δ
175.0, 165.1, 157.2, 141.4, 129.8, 128.4, 128.3, 125.9, 123.1,
116.1, 80.1, 68.2, 57.6, 54.9, 51.9, 42.9, 39.3, 32.2, 31.1, 22.6.
IR (CHCl3, cm-1): ν 3336, 1747, 1710. MS (CI), m/z: 410 (M+
+ 1, 26), 409 (M+ + 1, 26). Anal. Calcd for C24H27NO5: C, 70.40;
H, 6.65; N, 3.42. Found: C, 70.26; H, 6.55; N, 3.48.
2.32 (s, 3H), 2.59 (m, 2H), 2.82 (s, 1H), 3.30 (dt, 1H, J ) 13.2,
3.4 Hz), 3.64 (td, 1H, J ) 13.2, 2.4 Hz), 4.53 (s, 1 H), 4.70 (d,
1H, J ) 5.4 Hz), 5.19 (d, 1H, J ) 5.4 Hz), 5.65 (d, 1H, J )
11.5 Hz), 5.88 (dt, 1H, J ) 11.5, 7.3 Hz), 7.07 (m, 5 H), 7.15
(d, 2H, J ) 7.8 Hz), 7.34 (dd, 2H, J ) 8.3, 7.3 Hz). 13C NMR:
δ 211.1, 167.3, 157.2, 137.8, 135.7, 134.7, 129.9, 129.7, 129.2,
128.1, 123.1, 116.3, 79.6, 70.5, 59.7, 57.9, 43.2, 39.5, 29.7, 26.8,
25.3, 20.9. IR (KBr, cm-1): ν 3421, 1751, 1711. MS (EI), m/z:
420 (M+ + 1, 34), 419 (M+, 100). Anal. Calcd for C26H29NO4:
C, 74.44; H, 6.97; N, 3.34. Found: C, 74.56; H, 7.09; N, 3.24.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
6a -c. A solution of the appropriate Baylis-Hillman adduct 3
(0.40 mmol), triphenyltin hydride (0.60 mmol), and AIBN (cat.)
in benzene (35 mL) was heated at reflux temperature until
complete disappearance of starting material (TLC). The reac-
tion mixture was allowed to cool to room temperature, the sol-
vent was removed under reduced pressure, and vinylstannanes
6a -c were obtained. The crude product can be purified by
flash chromatography on deactivated silica gel using hexanes/
ethyl acetate (1:1 containing 1% of triethylamine) as an eluent.
Bicycle (+)-Z-6b. From 54 mg (0.172 mmol) of Baylis-
Hillman adduct (+)-3f, 103 mg (90%) of compound (+)-Z-6b
was obtained as a colorless oil. [R]D ) + 25.4 (c 0.8, CHCl3).
1H NMR: δ 2.36 (s, 3H), 2.52 (m, 1H), 2.64 (bs, 1H), 2.87 (m,
2H), 3.24 (m, 2H), 3.62 (m, 2H), 4.35 (bs, 1H), 4.36 (d, 1H, J )
4.6 Hz), 5.07 (d, 1H, J ) 4.6 Hz), 6.05 (s, 1H), 7.09 (m, 6H),
7.35 (m, 8H), 7.60 (m, 6H). 13C NMR: δ 209.4, 165.4, 157.1,
156.3, 138.2, 136.7, 136.4, 129.6, 129.1, 128.6, 122.7, 115.7,
81.0, 66.6, 58.7, 56.5, 39.2, 37.1, 33.9, 29.5. IR (CHCl3, cm-1):
ν 3522, 1771, 1756. MS (EI), m/z: 587 (M+ - 77, 24), 77 (100).
Anal. Calcd for C36H35NO4Sn: C, 65.08; H, 5.31; N, 2.11; Sn,
17.86. Found: C, 65.20; H, 5.39; N, 2.14; Sn, 17.76.
Bicycle (+)-Z-6c. From 81 mg (0.1247 mmol) of Baylis-
Hillman adduct (+)-3g, 134 mg (80%) of compound (+)-Z-6c
was obtained as a colorless solid. Colorless solid. Mp: 72-74
°C (hexanes/ethyl acetate). [R]D ) + 88.6 (c 0.8, CHCl3). 1H
NMR: δ 1.68 and 1.98 (m, each 1H), 2.32 (s, 3H), 2.69 (m,
3H), 2.95 (d, 1H, J ) 2.5 Hz), 2.99 (dd, 1H, J ) 14.4, 11.0 Hz),
3.22 (td, 1H, J ) 10.7, 3.4 Hz), 3.97 (dd, 1H, J ) 15.6, 6.8 Hz),
4.43 (d, 1H, J ) 9.3 Hz), 4.59 (d, 1H, J ) 5.0 Hz), 5.19 (d, 1H,
J ) 5.0 Hz), 6.35 (s, 1H), 7.09 (m, 3H), 7.37 (m, 11H), 7.56 (m,
6H). 13C NMR: δ 209.5, 165.6, 161.7, 157.1, 138.3, 136.8, 129.8,
129.3, 128.8, 126.0, 123.2, 116.2, 81.8, 71.3, 59.6, 42.7, 41.5,
34.3, 31.1, 30.6. IR (CHCl3, cm-1): ν 3520, 1770, 1755. MS (EI),
m/z: 601 (M+ - 77, 42), 77 (100). Anal. Calcd for C37H37NO4Sn:
C, 65.61; H, 5.50; N, 2.06; Sn, 17.50. Found: C, 65.73; H, 5.43;
N, 2.10; Sn, 17.42.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
6d -f. A solution of the appropriate Baylis-Hillman adduct 3
(0.40 mmol), benzenethiol (0.60 mmol), and AIBN (cat.) in
benzene (35 mL) was heated at reflux temperature until
complete disappearance of starting material (TLC). The reac-
tion mixture was allowed to cool to room temperature, the
solvent was removed under reduced pressure, and after
purification by gravity flow chromatography, bicycles 6d -f
were obtained as isomerically pure products.
Rea ction of En yn e (+)-syn -3e a n d Ben zen eth iol. From
130 mg (0.434 mmol) of Baylis-Hillman adduct (+)-syn-3e,
and after chromatography eluting with ethyl acetate/hexanes
(3.5:6.5), 47 mg (26%) of the less polar compound (+)-E-6d and
68 mg (39%) of the more polar compound (-)-Z-6d were
obtained.
Bicycle (+)-E-6d . Colorless solid. Mp: 120-122 °C (hex-
anes/ethyl acetate). [R]D ) +9.6 (c 1.0, CHCl3). 1H NMR: δ
2.40 (s, 3H), 2.87 (dd, 1H, J ) 14.2, 5.6 Hz), 2.89 (d, 1H, J )
2.4 Hz), 3.05 (dd, 1H, J ) 14.2, 5.6 Hz), 3.29 (td, 1H, J ) 5.6,
2.4 Hz), 3.82 (d, 1H, J ) 13.7 Hz), 4.30 (s, 1 H), 4.34 (dd, 1H,
J ) 14.1, 1.5 Hz), 4.62 (d, 1H, J ) 4.9 Hz), 5.27 (dd, 1H, J )
4.6, 1.5 Hz), 6.31 (s, 1 H), 7.10 (m, 4H), 7.31 (m, 6H). 13C
NMR: δ 208.9, 164.8, 156.9, 134.6, 131.4, 129.9, 129.8, 129.2,
127.2, 123.2, 115.9, 80.8, 66.9, 58.9, 54.5, 50.1, 30.4, 28.9. IR
(KBr, cm-1): ν 3431, 1747, 1712. MS (CI), m/z: 410 (M+ + 1,
100), 409 (M+, 50). Anal. Calcd for C23H23NSO4: C, 67.46; H,
5.66; N, 3.42; S, 7.83. Found: C, 67.57; H, 5.56; N, 3.38; S,
7.90.
Bicycle (+)-4f. From 57.9 mg (0.242 mmol) of Baylis-
Hillman adduct (+)-syn-3i, 54 mg (43%) of compound (+)-4f
was obtained as a colorless oil after purification by flash
chromatography (hexanes/ethyl acetate, 1/2). [R]D ) +66.9 (c
1
1.0, CHCl3). H NMR: δ 1.26 (m, 1H), 1.66 (td, 1H, J ) 13.4,
3.9 Hz), 1.96 (m, 3H), 2.21 (s, 3H, CH3), 2.24 (m, 1H), 2.36
(td, 1H, J ) 13.9, 5.4 Hz), 2.68 (td, 1H, J ) 12.2, 4.8 Hz), 3.07
(d, 1H, J ) 2.2 Hz), 3.38 (m, 2H), 3.67 (s, 3H), 4.13 (d, 1H, J
) 4.6 Hz), 4.42 (s, 1H), 4.51 (d, 1H, J ) 4.6 Hz), 7.19 (m, 5H).
13C NMR: δ 211.9, 166.6, 141.5, 128.5, 128.3, 126.0, 82.9, 66.7,
59.9, 59.7, 57.1, 42.4, 38.1, 32.8, 30.7, 29.7, 25.5, 22.6. IR
(CHCl3, cm-1): ν 3336, 1752, 1708. MS (CI), m/z: 332 (M+
+
1, 100), 331 (M+, 36). Anal. Calcd for C19H25NO4: C, 68.85; H,
7.61; N, 4.23. Found: C, 68.97; H, 7.43; N, 4.13.
Bicycle (+)-5a . From 56.6 mg (0.189 mmol) of Baylis-
Hillman adduct (+)-syn-3e, 30 mg (40%) of compound (+)-5a
was obtained as a colorless solid after purification by flash
chromatography (hexanes/ethyl acetate, 1/1). Colorless solid.
Mp: 130-132 °C (hexanes/ethyl acetate). [R]D ) +60.5 (c 1.0,
CHCl3). 1H NMR: δ 1.96 (td, 1H, J ) 13.2, 3.7 Hz), 2.25 (s,
3H), 2.42 (dd, 1H, J ) 12.2, 3.7 Hz), 2.50 (dd, 1H, J ) 13.4,
4.9 Hz), 2.60 (d, 1H, J ) 1.5 Hz), 2.66 (td, 1H, J ) 12.5, 4.6
Hz), 3.71 (dd, 1H, J ) 19.3, 1.5 Hz), 4.29 (d, 1H, J ) 4.6 Hz),
4.55 (dd, 1H, J ) 19.3, 5.1 Hz), 4.64 (s, 1H), 5.29 (dd, 1H, J )
4.4, 1.5 Hz), 5.59 (d, 1H, J ) 12.7 Hz), 5.71 (ddd, 1H, J ) 12.9,
4.9, 2.7 Hz). 13C NMR: δ 209.0, 164.7, 157.1, 141.0, 130.3,
129.8, 128.5, 128.3, 126.2, 125.4, 123.2, 116.2, 82.2, 68.1, 62.2,
58.6, 41.2, 39.7, 30.4, 27.8. IR (KBr, cm-1): ν 3332, 1745, 1704.
MS (EI), m/z: 392 (M+ + 1, 11), 391 (M+, 100). Anal. Calcd for
C
24H25NO4: C, 73.64; H, 6.44; N, 3.58. Found: C, 73.76; H,
6.60; N, 3.50.
Bicycle (+)-5b. From 52 mg (0.173 mmol) of Baylis-
Hillman adduct (+)-syn-3e, 14 mg (20%) of compound (+)-5b
was obtained as a colorless oil after purification by flash
chromatography (hexanes/ethyl acetate, 1/1). [R]D ) +62.3 (c
1
1.0, CHCl3). H NMR: δ 1.71 (s, 3H), 2.59 (dd, 1H, J ) 12.9,
10.5 Hz), 2.75 (dd, 1H, J ) 12.9, 6.6 Hz), 3.60 (m, 1H), 4.49
(d, 1H, J ) 4.4 Hz), 4.66 (m, 4H), 5.24 (dd, 1H, J ) 10.5, 6.6
Hz), 5.29 (dd, 1H, J ) 4.4, 1.5 Hz), 5.61 (m, 1H), 5.77 (ddd,
1H, J ) 12.9, 5.4, 2.2 Hz), 7.01 (m, 3H), 7.17 (m, 3H), 7.24 (m,
1H), 7.32 (m, 3H). 13C NMR: δ 164.9, 157.1, 141.7, 130.4,
129.8, 128.4, 127.6, 127.3, 127.2, 126.7, 125.3, 122.9, 115.7,
81.9, 79.8, 77.2, 71.9, 63.5, 62.0, 58.5, 46.9, 41.8, 20.7. IR
(CHCl3, cm-1): ν 3330, 1743. MS (CI), m/z: 408 (M+ + 1, 100),
407 (M+, 22). Anal. Calcd for C24H25NO5: C, 70.75; H, 6.18;
N, 3.44. Found: C, 70.63; H, 6.23; N, 3.46.
Bicycle (+)-5d . From 60 mg (0.20 mmol) of Baylis-Hillman
adduct (+)-syn-3e, 49 mg (60%) of compound (+)-5d was
obtained as a colorless oil after purification by flash chroma-
tography (hexanes/ethyl acetate, 1/1). [R]D ) +52.4 (c 0.9,
CHCl3). 1H NMR: δ 1.93 (m, 1H), 2.24 (s, 3H), 2.31 (s, 3H),
2.36 (dd, 1H, J ) 11.9, 4.2 Hz), 2.48 (dd, 1H, J ) 13.4, 4.9
Hz), 2.60 (td, 1H, J ) 16.1, 4.9 Hz), 2.68 (bs, 1H), 3.70 (dq,
1H, J ) 19.0, 2.0 Hz), 4.29 (d, 1H, J ) 4.6 Hz), 4.54 (dq, 1H,
J ) 19.0, 5.0 Hz), 4.63 (s, 1 H), 5.28 (dd, 1H, J ) 4.6, 1.5 Hz),
5.58 (d, 1H, J ) 13.0 Hz), 5.70 (ddd, 1H, J ) 13.0, 5.1, 2.9
Hz), 7.10 (m, 7 H), 7.36 (m, 2 H). 13C NMR: δ 209.2, 164.9,
157.3, 138.1, 135.8, 130.5, 130.0, 129.4, 128.3, 125.5, 123.3,
116.4, 82.3, 68.2, 62.4, 58.7, 41.4, 40.0, 30.1, 28.0, 21.1. IR
(CHCl3, cm-1): ν 3328, 1770, 1760. MS (CI), m/z: 406 (M+
+
1, 100), 405 (M+, 42). Anal. Calcd for C25H27NO4: C, 74.05; H,
6.71; N, 3.45. Found: C, 74.36; H, 6.57; N, 3.74.
Bicycle (+)-5f. From 64 mg (0.205 mmol) of Baylis-
Hillman adduct (+)-3f, 46 mg (53%) of compound (+)-5f was
obtained as a colorless solid after purification by flash chro-
matography (hexanes/ethyl acetate, 4/6). Colorless solid. Mp:
142-143 °C (hexanes/ethyl acetate). [R]D ) +62.3 (c 1.3,
1
CHCl3). H NMR: δ 1.41 (m, 2H), 1.96 (m, 2H), 2.23 (s, 3H),

1620 J . Org. Chem., Vol. 66, No. 5, 2001
Alcaide et al.
Bicycle (-)-Z-6d . Colorless solid. Mp: 128-130 °C (hex-
1H, J ) 7.8 Hz, PhO), 7.31 (m, 3H, PhO). 13C NMR: δ 205.6,
165.8, 157.3, 129.7, 122.9, 116.7, 114.0, 79.0, 74.7, 55.0, 54.5,
34.1, 32.4, 30.6, 19.8. IR (CHCl3, cm-1): ν 3440, 1750, 1714,
1710. MS (CI), m/z: 332 (M+ + 1, 100), 332 (M+, 20). Anal.
Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C,
65.44; H, 6.49; N, 4.21.
Sw er n Oxid a tion of Alcoh ols (+)-5d . P r oced u r e for th e
P r ep a r a tion of â-Dik eton e (-)-10a . A solution of dimethyl
sulfoxide (23.1 mg, 0.296 mmol) in dichloromethane (100 µL)
was added dropwise to a stirred solution of oxalyl chloride (18.7
mg, 0.147 mmol) in dichloromethane (165 µL) at -78 °C. After
20 min, a solution of the alcohol (+)-5d (0.123 mmol) in
dichloromethane (300 µL) was added and the mixture was
stirred for 3 h at -78 °C. Triethylamine (95 µL) was added at
-78 °C, and the mixture was allowed to warm to room
temperature. Water (350 µL) was added and the mixture was
partitioned between dichloromethane and water. The organic
extract was washed with brine, dried (MgSO4), and concen-
trated under reduced pressure. Chromatography of the residue
eluting with ethyl acetate/hexanes mixtures gave diketone (-)-
10a .
1
anes/ethyl acetate). [R]D ) -190.6 (c 1.0, CHCl3). H NMR: δ
2.26 (s, 3H), 2.90 (dd, 1H, J ) 14.6, 4.6 Hz), 3.06 (dd, 1H, J )
14.6, 4.1 Hz), 3.11 (bs, 1H) 3.18 (dd, 1H, J ) 7.8, 4.4 Hz), 4.16
(dd, 1H, J ) 15.6, 1.5 Hz), 4.32 (d, 1H, J ) 15.6 Hz), 4.41 (d,
1H, J ) 2.9 Hz), 4.52 (dd, 1H, J ) 4.9, 1.0 Hz), 5.29 (dd, 1H,
J ) 4.9, 1.5 Hz), 6.18 (d, 1H, J ) 1.0 Hz), 7.11 (m, 3H), 7.32
(m, 7H). 13C NMR: δ 208.2, 165.2, 156.9, 135.1, 132.9, 129.9,
129.4, 129.2, 127.0, 126.2, 123.3, 116.0, 81.0, 66.4, 59.1, 56.2,
43.9, 32.2, 29.2. IR (KBr, cm-1): ν 3436, 1750, 1710. MS (CI),
m/z: 410 (M+ + 1, 100), 409 (M+, 42). Anal. Calcd for C23H23
-
NSO4: C, 67.46; H, 5.66; N, 3.42; S, 7.83. Found: C, 67.58; H,
5.78; N, 3.30; S, 7.73.
Rea ction of En yn e (+)-3g a n d Ben zen eth iol. From 82
mg (0.250 mmol) of Baylis-Hillman adduct (+)-3g, and after
chromatography eluting with ethyl acetate/hexanes (1:1), 45
mg (45%) of the less polar compound (+)-E-6f and 19 mg (19%)
of the more polar compound (+)-Z-6f were obtained.
Bicycle (+)-E-6f. Colorless solid. Mp: 114-116 °C (hex-
1
anes/ethyl acetate). [R]D ) +111.6 (c 1.0, CHCl3). H NMR: δ
1.85 (m, 1Η), 2.11 (m, 2Η), 2.34 (s, 3H), 2.45 (d, 2H, J ) 7.6
Hz), 2.87 (m, 1H), 3.03 (bs, 1H), 3.13 (dd, 1H, J ) 14.9, 11.0
Hz), 3.22 (m, 1H), 4.23 (dd, 1H, J ) 14.9, 5.4 Hz), 4.34 (m,
1H), 4.37 (d, 1H, J ) 4.9 Hz), 5.26 (d, 1H, J ) 4.9 Hz), 6.26 (s,
1H), 7.07 (t, 1H, J ) 7.3 Hz), 7.11 (d, 2H, J ) 7.8 Hz), 7.31
(m, 7H). 13C NMR: δ 209.7, 165.7, 157.0, 140.6, 135.4, 129.8,
129.2, 126.9, 123.2, 123.1, 116.2, 82.0, 71.4, 59.3, 52.9, 41.8,
38.2, 31.4, 31.0, 28.0. IR (CHCl3, cm-1): ν 3426, 1740, 1706.
MS (CI), m/z: 438 (M+ + 1, 100), 437 (M+, 38). Anal. Calcd for
Com p ou n d (-)-10a . From 50 mg (0.123 mmol) of alcohol
(+)-5d , 35 mg (70%) of diketone (-)-10a was obtained as a
pale yellow oil after purification by chromatography (ethyl
1
acetate/hexanes, 2/1). [R]D ) -3.5 (c 0.6, CHCl3). H NMR: δ
2.20 (s, 3H), 2.29 (s, 3H), 2.32 (m, 2H), 2.56 (m, 2H) 3.79 (dd,
1H, J ) 19.3, 2.9 Hz), 4.66 (d, 1H, J ) 5.1 Hz), 4.68 (dt, 1H,
J ) 19.5, 2.7 Hz), 5.54 (dd, 1H, J ) 7.7, 1.8 Hz), 5.83 (ddd,
1H, J ) 12.2, 4.0, 2.7 Hz), 6.16 (ddd, 1H, J ) 12.2, 2.7, 1.7
Hz), 7.05 (m, 6H), 7.29 (m, 3H). 13C NMR: δ 203.9, 202.2,
164.5, 156.9, 137.4, 135.7, 129.6, 129.2, 128.0, 126.5, 125.0,
123.1, 116.1, 84.3, 70.2, 65.3, 40.9, 36.3, 30.3, 27.6, 20.9. IR
C
25H27NSO4: C, 68.63; H, 6.22; N, 3.20; S, 7.33. Found: C,
68.53; H, 6.14; N, 3.12; S, 7.23.
Bicycle (+)-Z-6f. Colorless solid. Mp: 124-125 °C (hexanes/
1
(CHCl3, cm-1): ν 1770, 1760, 1745. MS (CI), m/z: 404 (M+
+
ethyl acetate). [R]D ) +144.1 (c 1.0, CHCl3). H NMR: δ 1.69
1, 100), 403 (M+, 44). Anal. Calcd for C25H25NO4: C, 74.42; H,
6.25; N, 3.47. Found: C, 74.32; H, 6.37; N, 3.55.
(m, 3Η), 2.16 (m, 2Η), 2.36 (s, 3H), 2.83 (dd, 1H, J ) 15.6,
12.3 Hz), 2.92 (bs, 1H), 3.25 (m, 2H), 4.11 (m, 1H), 4.14 (d,
1H, J ) 4.9 Hz), 4.38 (d, 1H, J ) 9.5 Hz), 5.14 (d, 1H, J ) 4.9
Hz), 6.21 (s, 1H), 7.05 (m, 3H), 7.30 (m, 7H). 13C NMR: δ 209.6,
165.9, 156.9, 141.5, 135.6, 129.7, 129.3, 128.5, 126.7, 123.1,
123.0, 116.0, 81.7, 71.0, 59.5, 52.3, 41.3, 33.7, 32.2, 30.7, 29.7.
IR (CHCl3, cm-1): ν 3432, 1738, 1708. MS (CI), m/z: 438 (M+
+ 1, 100), 437 (M+, 44). Anal. Calcd for C25H27NSO4: C, 68.63;
H, 6.22; N, 3.20; S, 7.33. Found: C, 68.76; H, 6.12; N, 3.26; S,
7.41.
Retr o-Ald ol Rea ction of â-Dik eton e (-)-10a . P r oce-
d u r e for th e P r ep a r a tion of Com p ou n d (+)-11a . Hydra-
zine hydrate (5.1 mg, 0.16 mmol) was added to a stirred
solution of diketone (-)-10a (58 mg, 0.144 mmol) in tetrahy-
drofuran (750 µL), and the mixture was refluxed for 4 h. The
reaction mixture was allowed to cool to room temperature, then
water (400 µL) was added and the mixture was extracted with
ethyl acetate (3 × 2 mL). The organic extract was washed with
brine, dried (MgSO4), and concentrated under reduced pres-
sure. Chromatography of the residue gave compound (+)-11a .
Com p ou n d (+)-11a . From 58 mg (0.144 mmol) of diketone
(-)-10a , 29 mg (55%) of compound (+)-11a was obtained as a
colorless oil after purification by chromatography (ethyl acetate/
Ozon olysis of P h en ylth iovin yl Der iva tives 6d -f. Gen -
er a l P r oced u r e. Ozonolyzed air was bubbled through a
solution of the bicycles 6d -f (0.18 mmol) in dichloromethane
(3 mL) at -78 °C for 30 min. Air was then blown through the
solution for 10 min, and dimethyl sulfide (112 mg, 1.80 mmol)
was added. The reaction was allowed to warm to room
temperature, and the solvent was removed under reduced
pressure and after purification by flash chromatography,
ketones 9a -c were obtained.
1
hexanes, 1/1). [R]D ) +280.3 (c 0.9, CHCl3). H NMR: δ 1.92
(m, 1H), 2.43 (m, 1H), 2.50 (s, 3H), 2.73 (m, 2H) 3.87 (m, 1H),
4.37 (m, 1H), 4.79 (d, 1H, J ) 4.9 Hz), 4.96 (dq, 1H, J ) 18.5,
2.9 Hz), 5.43 (m, 1H), 5.69 (dd, 1H, J ) 4.9, 1.0 Hz), 5.81 (m,
1H), 7.23 (m, 6H), 7.49 (m, 3H). 13C NMR: δ 201.7, 165.2,
156.9, 138.7, 135.4, 129.6, 129.0, 128.2, 127.2, 125.7, 122.9,
115.8, 83.7, 65.2, 47.5, 41.0, 32.8, 31.7, 20.9. IR (CHCl3, cm-1):
ν 1768, 1750. MS (EI), m/z: 362 (M+ + 1, 18), 361 (M+, 100).
Anal. Calcd for C23H23NO3: C, 76.43; H, 6.41; N, 3.88. Found:
C, 76.31; H, 6.37; N, 3.96.
Com p ou n d (+)-9b. From 77 mg (0.182 mmol) of phenyl-
thiovinyl derivative 6e, 40 mg (70%) of compound (+)-9b was
obtained as a colorless solid after purification by chromatog-
raphy (ethyl acetate/hexanes, 2/1). Mp: 218-219 °C (hexanes/
1
ethyl acetate). [R]D ) +50.1 (c 1.0, CH3COCH3). H NMR: δ
2.20 (s, 3H), 2.44 (m, 1H), 2.64 (dd, 1H, J ) 14.1, 10.7 Hz),
3.05 (m, 1H), 3.86 (m, 4H), 4.72 (m, 2H), 5.35 (d, 1H, J ) 4.9
Hz), 5.49 (bs, 1H), 7.07 (m, 3H), 7.34 (m, 2H). 13C NMR: δ
205.8, 190.2, 166.3, 158.4, 130.4, 122.7, 116.1, 81.4, 73.3, 59.8,
55.6, 39.4, 37.0, 34.9, 30.1. IR (CHCl3, cm-1): ν 3442, 1750,
1722, 1710. MS (CI), m/z: 318 (M+ + 1, 100), 317 (M+, 20).
Anal. Calcd for C17H19NO5: C, 64.34; H, 6.03; N, 4.41. Found:
C, 64.48; H, 6.13; N, 4.35.
Ack n ow led gm en t. Support for this work by the
DGI-MCYT (Project BQU2000-0645) is gratefully ac-
knowledged. C. Aragoncillo thanks the Comunidad
Auto´noma de Madrid for a fellowship.
Com p ou n d (+)-9c. From 41 mg (0.101 mmol) of phenyl-
thiovinyl derivative 6f, 17 mg (50%) of compound (+)-9c was
obtained as a colorless solid after purification by chromatog-
raphy (ethyl acetate/hexanes, 3/1). Colorless solid. Mp: 113-
114 °C (hexanes/ethyl acetate). [R]D ) +101.4 (c 1.1, CHCl3).
1H NMR: δ 1.90 (m, 5H), 1.98 (s, 3H), 2.42 (m, 2H), 3.46 (dd,
1H, J ) 13.7, 10.3 Hz), 3.65 (m, 1H), 3.78 (dd, 1H, J ) 13.2,
7.3 Hz), 3.91 (dd, 1H, J ) 7.8, 4.9 Hz), 5.05 (d, 1H, J ) 4.9
Hz), 5.19 (t, 1H, J ) 6.4 Hz), 7.07 (t, 1H, J ) 7.3 Hz), 7.2 (d,
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for compounds (+)-1b, (+)-1d -g, (+)-2b, (+)-
2d -f, (+)-3d , (+)-3f, (+)-3h , (+)-syn-3i, (+)-anti-3i, (+)-4a , (+)-
4g, (+)-5c, (+)-5e, (+)-6a , (+)-6e, and (+)-9a , as well as
general experimental procedures for compounds 1a -g and
2a -g. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O005715Z