Asymmetric synthesis of unusual fused tricyclic β-lactam structures via aza-cycloadditions/ring closing metathesis

Article abstract of DOI:10.1021/jo026112l

Conveniently substituted bis-β-lactams, pyrrolidinyl-β-lactams, and piperidinyl-β-lactams undergo ring-closing methatesis using Grubbs' carbene, Cl₂(Cy₃P)₂Ru=CHPh, to give medium-sized rings fused to bis-2-azetidinone, pyrrolidinyl-2-azetidinone, or piperidinyl-2-azetidinone systems. The diolefinic cyclization precursors can be obtained from optically pure 4-oxoazetidine-2-carbaldehydes bearing an extra alkene tether at position 1 or 3 of the β-lactam ring via [2 + 2] cycloaddition of imino 2-azetidinones, N-metalated azometine ylide [3 + 2] cycloaddition, and subsequent N-acylation of the pyrrolidinyl nitrogen atom, or through aza-Diels-Alder cycloaddition of 2-azetidinone-tethered imines. Under standard reaction conditions, the combination of cycloaddition reactions of 2-azetidinone-tethered imines with ring-closing methatesis offers an asymmetric entry to a variety of unusual fused tricyclic 2-azetidinones bearing two bridgehead nitrogen atoms.

Full text of DOI:10.1021/jo026112l

Asym m etr ic Syn th esis of Un u su a l F u sed Tr icyclic â-La cta m
Str u ctu r es via Aza -Cycloa d d ition s/Rin g Closin g Meta th esis
Benito Alcaide,*,† Pedro Almendros,*,‡ J ose M. Alonso,† and Mar´ıa C. Redondo†
Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense,
28040-Madrid, Spain, and Instituto de Quı´mica Orga´nica General, CSIC, J uan de la Cierva 3,
28006-Madrid, Spain
alcaideb@quim.ucm.es; iqoa392@iqog.csic.es
Received J une 28, 2002
Conveniently substituted bis-â-lactams, pyrrolidinyl-â-lactams, and piperidinyl-â-lactams undergo
ring-closing methatesis using Grubbs’ carbene, Cl2(Cy3P)2RudCHPh, to give medium-sized rings
fused to bis-2-azetidinone, pyrrolidinyl-2-azetidinone, or piperidinyl-2-azetidinone systems. The
diolefinic cyclization precursors can be obtained from optically pure 4-oxoazetidine-2-carbaldehydes
bearing an extra alkene tether at position 1 or 3 of the â-lactam ring via [2 + 2] cycloaddition of
imino 2-azetidinones, N-metalated azometine ylide [3 + 2] cycloaddition, and subsequent N-acylation
of the pyrrolidinyl nitrogen atom, or through aza-Diels-Alder cycloaddition of 2-azetidinone-tethered
imines. Under standard reaction conditions, the combination of cycloaddition reactions of 2-azeti-
dinone-tethered imines with ring-closing methatesis offers an asymmetric entry to a variety of
unusual fused tricyclic 2-azetidinones bearing two bridgehead nitrogen atoms.
In tr od u ction
synthetic antibacterial agents featuring good resistance
to â-lactamases and dehydropeptidases.2 In addition, the
ever-growing new applications of 2-azetidinones in fields
ranging from enzyme inhibition3 to the use of these
products as starting materials to develop new synthetic
methodologies4 has triggered a renewed interest in the
building of new polycyclic â-lactam systems in an attempt
to move away from the classical â-lactam antibiotic
structures.5 On the other hand, ring-closing metathesis
(RCM) has recently emerged as a powerful tool for the
formation of a variety of ring systems.6 Ring sizes from
five through to complex macrocycles have been synthe-
sized. However, the complexity and functional group
tolerance of substrates in this process need to be further
investigated to expand its applicability in organic syn-
theses. Although many investigations have been made
in this field into various types of dienes, there are a
limited number of reports on the use of â-lactam building
blocks for the metathesis, with only Barret, Holmes, and
â-Lactam antibiotics account for 50% of the total
antibiotic market of the world. The extensive use of
common â-lactam antibiotics such as penicillins and
cephalosporins in medicine has resulted in an increasing
number of resistant strains of bacteria through mutation
and â-lactamase gene transfer.1 There has, therefore,
been much effort expended in recent years to prepare new
structural types having the 2-azetidinone ring as a
common feature, which will overcome the defense mech-
anisms of the bacteria. Tricyclic â-lactam antibiotics,
generally referred to as trinems, are a new class of
† Universidad Complutense.
‡ CSIC.
(1) See, for example: (a) Sandanayaka, V. P.; Prashad, A. S. Curr.
Med. Chem. 2002, 9, 1145. (b) Ritter, T. K.; Wong, C.-H. Angew. Chem.,
Int. Ed. 2001, 40, 3508. (c) D´ıaz, N.; Sua´rez, D.; Merz, K. M. M., J r. J .
Am. Chem. Soc. 2000, 122, 4197. (d) Page, M. I. Chem. Commun. 1998,
1609. (e) Niccolai, D.; Tarsi, L.; Thomas, R. J . Chem. Commun. 1997,
2333. (f) Hook, V. Chem. Br. 1997, 33, 34. (g) Spratt, B. G. Science
1994, 264, 388. (h) Davies, J . Science 1994, 264, 375.
(2) For selected references, see: (a) Kanno, O.; Kawamoto, I.
Tetrahedron 2000, 56, 5639. (b) Hanessian, S.; Reddy, B. Tetrahedron
1999, 55, 3427. (c) Biondi, S.; Pecunioso, A.; Busi, F.; Contini, S. A.;
Donati, D.; Maffeis, M.; Pizzi, D. A.; Rossi, L.; Rossi, T.; Sabbatine, F.
M. Tetrahedron 2000, 56, 5649. (d) Ghiron, C.; Rossi, T. The Chemistry
of Trinems. In Targets in Heterocyclic Systems-Chemistry and Proper-
ties; Attanasi, O. A., Spinelli, D., Eds.; Societa Chimica Italiana: Rome,
1997; Vol. 1, pp 161-186. (e) Ngo, J .; Castan˜er, J . Drugs Future 1996,
21, 1238.
(3) (a) Page, M. I.; Laws, A. P. Tetrahedron 2000, 56, 5631. (b)
Bonneau, P. R.; Hasani, F.; Plouffe, C.; Malenfant, E.; LaPlante, S.
R.; Guse, I.; Ogilvie, W. W.; Plante, R.; Davidson, W. C.; Hopkins, J .
L.; Morelock, M. M.; Cordingley, M. G.; Deziel, R. J . Am. Chem. Soc.
1999, 121, 2965. (c) Vaccaro, W. D.; Davis, H. R., J r. Bioorg. Med.
Chem. Lett. 1998, 8, 313. (d) 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. (e) Han, W.
T.; Trehan, A. K.; Wright, J . J . K.; Federici, M. E.; Seiler, S. M.;
Meanwell, N. A. Bioorg. Med. Chem. 1995, 3, 1123.
(4) For reviews, see: (a) Alcaide, B.; Almendros, P. Chem. Soc. Rev.
2001, 30, 226. (b) Alcaide, B.; Almendros, P. Org. Prep. Proced. Int.
2001, 33, 315. (c) Alcaide, B.; Almendros, P. Synlett 2002, 381. (d)
Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Oiarbide, M. Synlett 2001,
1813. (e) Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Oiarbide, M. Amino
Acids 1999, 16, 321. (f) Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997,
26, 377. (g) Ojima, I. Adv. Asym. Synth. 1995, 1, 95. (h) Manhas, M.
S.; Wagle, D. R.; Chiang, J .; Bose, A. K. Heterocycles 1988, 27, 1755.
(5) For a recent review on bi- and tricyclic-â-lactams with nonclas-
sical structure, see: Alcaide, B.; Almendros, P. Curr. Org. Chem. 2002,
6, 245.
(6) For some recent reviews on olefin metathesis, see: (a) Grubbs,
R. H.; Trnka, T. M. Acc. Chem. Res. 2001, 34, 18. (b) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012. (c) Buchmeiser, M. R. Chem.
Rev. 2000, 100, 1565. (d) Fu¨rstner, A. Synlett 1999, 1523. (e) Wright,
D. L. Curr. Org. Chem. 1999, 3, 211. (f) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (g) Armstrong, S. K. J . Chem. Soc., Perkin
Trans. 1 1998, 371. (h) Schuster, M.; Blechert, S. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2036.
10.1021/jo026112l CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/18/2003
1426
J . Org. Chem. 2003, 68, 1426-1432

Synthesis of Unusual Fused Tricyclic â-Lactam Structures
TABLE 1. Syn th esis of P yr r olid in yl-â-la cta m s 4 a n d 5
aldehyde
R1
R2
R3
R4
products
4/5 ratioa
yield 4/5b (%)
(+)-1a
(+)-1a
(+)-1a
(+)-1b
(+)-1b
(+)-1c
(+)-1d
Me
Me
Me
Me
Me
Me
2-propenyl
2-propenyl
2-propenyl
3-butenyl
3-butenyl
4-pentenyl
PMP
H
H
H
(+)-4a /(+)-5a
(+)-4b/(+)-5b
(+)-4c/(+)-5c
(+)-4d /(+)-5d
(+)-4e/(+)-5e
(+)-4f/(+)-5f
(+)-4gc
65:35
66:34
60:40
69:31
64:36
59:41
c
34/18
49/25
45/30
36/16
42/24
47/33
51d
Me
Me
H
Me
Me
Me
CO2Me
H
H
H
H
2-propenyl
a
The ratio was determined by integration of well-resolved signals in the 1H NMR spectra of the crude reaction mixtures before
purification.PMP ) 4-MeOC6H4. Yield of pure, isolated product with correct analytical and spectral data. c The 1H NMR spectrum of
b
the crude mixture showed mainly (+)-4g together with two other minor isomers accounting, respectively, for 9% and 4% of the products
d
formed. Additional fractions containing the major cycloadduct together with traces of the minor isomers were isolated after column
chromatography, accounting for an overall 69% yield.
Genet having recently reported the construction of bicy-
clic â-lactams, mainly in racemic form.7 However, no
efforts have been published to construct the tricyclic
â-lactam skeleton via RCM. In connection with our
ongoing project directed toward the synthesis of poten-
tially bioactive products through â-lactams,8 in this
paper, we present a novel concept for the asymmetric
synthesis of unusual fused tricyclic 2-azetidinones, which
is based on a [2 + 2], [3 + 2], or [4 + 2] aza-cycloaddition
reaction and a ring-closing metathesis sequence.9
small-sized heterocycle, incorporation should be facili-
tated by aza-cycloadditions. Thus, C4,C4′-bis-â-lactams
(+)-2a and (+)-2b were prepared from aldehyde (+)-1a
by a two-step route.10 Treatment with allylamine followed
by ketene-imine cyclization directly provided the diene
bis-â-lactam (+)-2a (81%) as a single diastereoisomer.
Similarly, the bis-â-lactam (+)-2b was achieved in 77%
yield using homoallylamine and further methoxyacetyl
chloride-triethylamine treatment (Scheme 1).
SCHEME 1
Resu lts a n d Discu ssion
Cycloaddition precursors, alkenyl-4-oxoazetidine-2-car-
baldehydes 1a -d , were prepared using standard meth-
odology.8 The diolefinic metathesis precursors were ob-
tained in optically pure form in a straightforward fashion
from 2-azetidinone-tethered imines. Depending on the
desired ring size of the central ring, our approach
required the introduction of alkene functionality at either
the â-lactam ring or at the nitrogen atom of the four-,
five-, and six-membered heterocycles. In addition, this
The requisite dienes 6 should be again available from
alkenyl-4-oxoazetidine-2-carbaldehydes 1. Treatment of
aldehydes 1 with various R-amino esters in the presence
of 4 Å molecular sieves provided the corresponding
aliphatic aldimines 3. These were obtained in quantita-
tive yields and were used in the next step without further
purification. 1,3-Dipolar cycloaddition of 2-azetidinone-
tethered azomethine ylides was achieved at room tem-
perature via metal ion catalysis to afford with moderate
diastereoselectivity and in useful to good yields (80-52%)
mixtures of cycloadducts 4 and 5 (see Table 1) having
an alkene tether at the C3 or N1 positions of the
2-azetidinone ring, as we previously reported for alanine
(glycine)-derived iminoesters bearing a N-(4-methoxyphe-
nyl) unit at the â-lactam ring.11 Fortunately, in all cases
(7) (a) Barrett, A. G. M.; Ahmed, M.; Baker, S. P.; Baugh, S. P. D.;
Braddock, D. C.; Procopiou, P. A.; White, A. J . P.; Willians D. J . J .
Org. Chem. 2000, 65, 3716. (b) Barrett, A. G. M.; Baugh, S. P. D.;
Braddock, D. C.; Flack, K.; Gibson, V. C.; Giles, M. R.; Marshall, E.
L.; Procopiou, P. A.; White, A. J . P.; Willians D. J . J . Org. Chem. 1998,
63, 7893. (c) Barrett, A. G. M.; Baugh, S. P. D.; Braddock, D. C.; Flack,
K.; Gibson, V. C.; Procopiou, P. A. Chem. Commun. 1997, 1375. (d)
Tarling, C. A.; Holmes, A. B.; Markwell, R. E.; Pearson, N. D. J . Chem.
Soc., Perkin Trans. 1 1999, 1695. (e) Duboc, R.; He´naut, C.; Savignac,
M.; Genet, J .-P.; Bhatnagar, N. Tetrahedron Lett. 2001, 42, 2461.
(8) See, for instance: (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.
Chem. Eur. J . 2002, 8, 1719. (b) Alcaide, B.; Almendros, P.; Rodr´ıguez-
Acebes, R. J . Org. Chem. 2002, 67, 1925. (c) Alcaide, B.; Almendros,
P.; Aragoncillo, C.; Rodr´ıguez-Acebes, R. J . Org. Chem. 2001, 66, 5208.
(d) Alcaide, B.; Almendros, P.; Aragoncillo, C. J . Org. Chem. 2001, 66,
1612. (e) Alcaide, B.; Almendros, P.; Alonso, J . M.; Aly, M. F. Org. Lett.
2001, 3, 3781. (f) Alcaide, B.; Pardo, C.; Rodr´ıguez-Ranera, C.;
Rodr´ıguez-Vicente, A. Org. Lett. 2001, 3, 4205. (g) Alcaide, B.; Almen-
dros, P.; Aragoncillo, C. Chem. Eur. J . 2002, 8, 3646.
(10) Alcaide, B.; Mart´ın-Cantalejo, Y.; Pe´rez-Castells, J .; Sierra, M.
A. J . Org. Chem. 1996, 61, 9156.
(9) For a preliminary communication of a part of this work, see:
Alcaide, B.; Almendros, P.; Alonso, J . M.; Aly, M. F.; Redondo, M. C.
Synlett 2001, 773.
(11) (a) Alcaide, B.; Almendros, P.; Alonso, J . M.; Aly, M. F. J . Org.
Chem. 2001, 66, 1351. (b) Alcaide, B.; Almendros, P.; Alonso, J . M.;
Aly, M. F. Chem. Commun. 2000, 485.
J . Org. Chem, Vol. 68, No. 4, 2003 1427

Alcaide et al.
the major isomers 4 could be easily separated by flash
chromatography from the diastereomeric cycloadducts 5.
Finally, the N-acylation reaction of the pyrrolidinyl
nitrogen atom on cycloadducts 4 was effective to obtain
dienic substrates 6 in good yields (Scheme 2).
In view of the particular disposition of a variety of
dienes to undergo ring-closing metathesis reactions, we
sought to apply this methodology to our novel 2-azetidi-
none-tethered diene substrates 2, 6, and 8 for the
synthesis of unusual fused tricyclic â-lactams bearing two
bridgehead nitrogen atoms. The use of this approach in
the synthesis of tricyclic 2-azetidinones has not been
hitherto applied. The extraordinary functional group
tolerance of the ruthenium-based catalyst Cl2(Cy3P)2Rud
CHPh coupled with its commercial availability makes it
the catalyst of choice. Our objective was the synthesis of
tricyclic â-lactam structures containing various medium-
sized central rings and four-, five- and six-membered
distal rings. Treatment of dienes 2, 6, and 8 with Grubbs’
catalyst under smooth ring-closing metathesis conditions
(5 mol %, CH2Cl2, 25 °C), analogous to those described
for bicyclic â-lactams,7 did not furnish the desired tri-
cycles. The majority of the reaction mixture was com-
posed of unreacted dienes. While the reasons for this lack
of cyclization were not definitively established, we at-
tributed the low reactivity of the structures 2, 6, and 8
to either the ring strain inherent to the fused tricyclic
products or kinetic problems associated with its forma-
tion. Finally, we found that dienic substrates 2, 6, and 8
require more vigorous conditions for ring closure. It is
believed that high temperature is favorable for rotation
about the single bond connecting the two rings, and a
“cis”-like conformation is probably necessary for cycliza-
tion. Among the various solvents and conditions tested,
we found that toluene at reflux temperature gave the best
yields of tricyclic-â-lactams containing medium-sized
central rings. Grubbs’ catalyst is known to be moderately
thermally unstable, and the decomposition would inhibit
productive metathesis.13 To circumvent this problem,
Grubbs’ carbene was added in small portions every 20
min (5 mol % is the overall amount of all the portions).
Thus, the catalytic species is continuously being renewed
by fresh Grubbs’ carbene. Exposure of dienes 2, 6, and 8
to the ruthenium catalyst Cl2(Cy3P)2RudCHPh under our
standard cyclization conditions (5 mol % catalyst, 0.03
M, toluene, 110 °C) resulted in clean formation of the
tricycles 10-12 in moderate to good yields (31-69%)
(Schemes 4-6). It should be mentioned that minor
SCHEME 2
To further expand the scope of substrates to submit to
RCM, we thought of the piperidine-â-lactam moiety, in
which the four- or five-membered azaheterocycle is
replaced by a piperidine residue. The aza Diels-Alder
reaction of N-alkenyl-2-azetidinone-tethered propenyl-
imines with Danishefsky’s diene provided the required
precursors.12 To activate the imine, we used 20% molar
zinc iodide as Lewis acid catalyst. Cycloaddition took
place at low temperature to give mixtures of diastereoi-
somers 7 with modest diastereoselectivity in favor of the
anti isomer, but it could not be separated from the minor
syn isomer. Fortunately, L-Selectride reduction of the
alkene moiety at the six-membered ring is a convenient
way to obtain the desired dienes. Thus, the diastereo-
meric adducts 8 and 9 were easily separated by gravity
flow chromatography after L-Selectride treatment (Scheme
3).
SCHEME 3
SCHEME 4
cycloadducts 9 as well as the N-acylated derivatives of
minor cycloadducts 5 did not undergo RCM. Thus, for a
successful RCM a structural condition must be satisfied
in the starting dienes, namely, a relative anti stereo-
chemistry at the single bond connecting the two hetero-
cyclic rings. As has been outlined recently, ligand modi-
fication in Grubbs’ carbene improves their excellent
application profile even further.14 Metathesis of some
compounds 2, 6, and 8 was effected with the second-
(12) Alcaide, B.; Almendros, P.; Alonso, J . M.; Aly, M. F., Torres,
M. R. Synlett 2001, 1531.
(13) Ulman, M.; Grubbs, R. H. J . Org. Chem. 1999, 64, 7202.
1428 J . Org. Chem., Vol. 68, No. 4, 2003

Synthesis of Unusual Fused Tricyclic â-Lactam Structures
SCHEME 5
the stereogenic centers at the four-, five-, and six-
membered rings remained unaltered during the trans-
formation of dienic compounds 2, 6, and 8 into tricyclic
products 10-12. The stereochemistry of fused tricyclic
2-azetidinones 10-12 was deduced by qualitative homo-
nuclear NOE difference spectra. Taking into account that
dienes 2, 6, and 8 could be cyclized, the stereochemistry
for compounds 2, 6, and 8 was inmediately deduced by
comparison with the NOE results of the tricyclic systems.
Furthermore, the stereochemistry of metathesis precur-
sors 2, 6, and 8 was assigned on the basis of our previous
results for related cycloaddition products.10-12
Con clu sion s
The combination of [2 + 2], [3 + 2], or [4 + 2]
cycloaddition of imines and ring-closing metathesis has
been shown as a useful synthetic tool for the asymmetric
synthesis of unusual fused tricyclic 2-azetidinones bear-
ing two bridgehead nitrogen atoms. A range of substrates
was examined, and tricyclic â-lactams containing eight,
nine, and 10 medium-sized central rings and four-, five-,
and six-membered distal rings were prepared. In addition
to the novelty of this sequential strategy, this methodol-
ogy is very versatile with the possibility of obtaining a
variety of conveniently functionalized tricyclic â-lactams
just by changing the substituents in readily available
starting materials. The method offers the possibility of
a future application to different chiral building blocks
other than 2-azetidinones, and we believe this finding
could open a new way for the design and asymmetric syn-
thesis of fused heterocycles. Other aspects of this chem-
istry are currently under investigation in our laboratory.
SCHEME 6
Exp er im en ta l Section
generation 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene
(Im)-substituted ruthenium-based catalyst ImCl2Cy3-
PRudCHPh, obtaining results similar to those observed
with Grubbs’ carbene. Because the second-generation
Grubbs’ catalyst neither accelerated the reaction rate or
improved the yield of tricycles 10-12, we chose the less
expensive first-generation Grubbs’ carbene for our study.
Interestingly, in the Grubbs’ carbene promoted reaction
of compounds (+)-8b and (+)-8c together with the RCM
products (+)-12b and (+)-12c we isolated N-deallylation
products. Results of this novel method toward catalytic
N-deallylation of tertiary amines by using Grubbs’ car-
bene will be published independently.8e
1H NMR analysis of the reaction mixtures showed a
single isomer for compounds 10-12 in all cases. Not
unexpectedly, only the cis-olefin was formed for eight-
and nine-membered rings (compounds 10a -b, 11a -e,
(+)-11g, and 12a ,b), while for the 10-membered diazoni-
nones (+)-11f and (+)-12c only the trans-olefin was
obtained.15 Importantly, the stereochemical integrity of
Gen er a l Meth od s. General experimental data and proce-
dures have been previously reported.8 NMR spectra were
recorded in CDCl3 solutions, except when 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.
Gen er a l P r oced u r e for th e Syn th esis of C4,C4′-Bis-â-
la cta m s 2. A suspension of 4-oxoazetidine-2-carbaldehyde (+)-
1a (308 mg, 1.82 mmol), the appropriate amine (2.73 mmol),
and MgSO4 (1.75 g, 14.6 mmol) in anhydrous dichloromethane
(25 mL) was stirred at room temperature overnight. Then, the
mixture was filtered, and the solvent was removed under
reduced pressure. Further purification was not necessary, and
the resulting imino â-lactams were used as such. Phenoxy-
acetyl chloride (469 mg, 2.75 mmol) in anhydrous dichlo-
romethane (5 mL) was added dropwise via syringe to a solution
of the corresponding imine and Et3N (555 mg, 5.49 mmol) in
dichloromethane (30 mL), at 0 °C under argon. The resulting
mixture was allowed to warm to room temperature and was
stirred for 16 h. The crude mixture was diluted with CH2Cl2
(20 mL) and washed with saturated NaHCO3 (2 × 5 mL) and
brine (5 mL). The organic layer was dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue eluting with ethyl acetate/hexanes mixtures gave
analytically pure compounds 2. Spectroscopic and analytical
data for some representative forms of 2 follow.16
(14) (a) Morgan, J . P.; Morrill, C.; Grubbs, R. H. Org. Lett. 2002, 4,
67. (b) Fu¨rstner, A.; Guth, O.; Du¨ffels, A.; Seidel, G.; Liebl, M.; Gabor,
B.; Mynott, R. Chem. Eur. J . 2001, 7, 4811. (c) Fu¨rstner, A.; Acker-
mann, L.; Gabor, B.; Goddard, R.; Lehmann, C. W.; Mynott, R.; Stelzer,
F.; Thiel, O. R. Chem. Eur. J . 2001, 7, 3236. (d) Fu¨rstner, A.; Thiel, O.
R.; Ackermann, L.; Schanz, H.-J .; Nolan, S. J . Org. Chem. 2000, 65,
2204.
(15) Since it is known that the J value for trans-olefins is ap-
proximately 12-18 Hz while for cis-olefins its is approximately 7-11
Hz, the geometry of the double bond could be determined. In addition,
NOE experiments were performed to confirm these assignments.
(16) Full spectroscopic and analytical data for compounds not
included in this Experimental Section are described in the Supporting
Information.
J . Org. Chem, Vol. 68, No. 4, 2003 1429

Alcaide et al.
C4,C4′-Bis-2-a zetid in on e (+)-2a . From 156 mg (2.73
mmol) of allylamine, after column chromatography eluting
with ethyl acetate/hexanes (1:1), 500 mg (81%) of the com-
pound (+)-2a was obtained: colorless oil; [R]D ) +15.5 (c 1.0,
4.08 (m, 2H), 4.30 (d, 1H, J ) 4.8 Hz), 5.18 (m, 4H), 5.23 (m,
2H); 13C NMR (CDCl3) δ 177.5, 177.3, 174.0, 167.8, 132.2,
117.8, 83.3, 66.9, 60.5, 59.1, 58.3, 55.2, 52.8, 52.1, 52.0, 49.0,
43.8, 21.5; IR (CHCl3, cm-1) ν 3336, 1734; MS (CI), m/z 399
(M+ + 1, 100), 398 (M+, 33). Anal. Calcd for C18H26N2O8: C,
54.26; H, 6.58; N, 7.03. Found: C, 54.19; H, 6.59; N, 7.01.
Cycloa d d u ct (+)-5c: colorless oil; [R]D ) +24.1 (c 1.0,
CHCl3); 1H NMR (CDCl3) δ 1.28 (s, 3H), 3.57 (m, 4H), 3.66 (s,
3H), 3.71 (m, 4H), 3.79 (s, 3H), 3.85 (d, 1H, J ) 5.1 Hz), 4.02
(m, 3H), 4.46 (d, 1H, J ) 4.9 Hz), 5.22 (m, 2H), 5.78 (m, 1H);
13C NMR (CDCl3) δ 174.1, 171.9, 171.5, 167.2, 131.9, 117.9,
84.2, 66.7, 59.1, 59.0, 57.1, 54.5, 52.8, 52.1, 51.9, 48.9, 43.0,
1
CHCl3); H NMR δ 3.52 (s, 3H), 3.86 (m, 2H), 4.18 (m, 4H),
4.59 (d, 1H, J ) 5.1 Hz), 5.16 (m, 4H), 5.31 (d, 1H, J ) 5.1
Hz), 5.77 (m, 2H), 7.04 (m, 2H), 7.31 (m, 3H); 13C NMR δ 167.6,
165.9, 157.2, 131.5, 129.8, 122.7, 118.3, 118.1, 115.7, 83.5, 80.5,
59.3, 56.5, 56.2, 44.4, 44.0; IR (CHCl3, cm-1) ν 1765, 1750; MS
(CI), m/z 343 (M+ + 1, 100), 342 (M+, 11). Anal. Calcd for
C19H22N2O4: C, 66.65; H, 6.48; N, 8.18. Found: C, 66.72; H,
6.44; N, 8.16.
Gen er a l P r oced u r e for th e Syn th esis of Cycloa d d u cts
4 a n d 5. A solution of the appropriate 4-azetidinone-2-
carbaldehyde 1 (1.00 mmol) in anhydrous dichloromethane (7
mL) was added dropwise to a stirred solution of 4 Å molecular
sieves (2.0 g) and the corresponding R-amino ester (1.50 mmol)
in dichloromethane (3 mL) at room temperature. After being
stirred for 2 h at room temperature, the mixture was filtered
through a plug of Celite. The solvent was removed under
reduced pressure giving in quantitative yield imines 3. The
crude product was used for the next step without any further
purification.
To a solution of the appropriate imine 3 (1.00 mmol) in
anhydrous toluene (6 mL) were sequentially added silver
acetate (1.20 mmol), the corresponding dipolarophile (1.50
mmol), and triethylamine (1.20 mmol), and the reaction
mixture was stirred at room temperature for 40 h. Saturated
aqueous NH4Cl (1 mL) 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/triethylamine mixtures
gave analytically pure compounds 4 and 5.
P r ep a r a tion of Cycloa d d u cts (+)-4b a n d (+)-5b. From
400 mg (2.35 mmol) of the aldehyde (+)-1a and 364 mg (3.53
mmol) of alanine methyl ester, after column chromatography
eluting with ethyl acetate/hexanes (10:1 containing 10% of
triethylamine), were obtained 396 mg (49%) of the less polar
compound (+)-4b and 202 mg (25%) of the more polar
compound (+)-5b.
20.7; IR (CHCl3, cm-1) ν 3332, 1735; MS (CI), m/z 399 (M+
+
1, 100), 398 (M+, 21). Anal. Calcd for C18H26N2O8: C, 54.26;
H, 6.58; N, 7.03. Found: C, 54.34; H, 6.56; N, 7.02.
P r ep a r a tion of Cycloa d d u cts (+)-4d a n d (+)-5d . From
274 mg (1.64 mmol) of the aldehyde (+)-1b and 221 mg (2.45
mmol) of glycine methyl ester, after column chromatography
eluting with ethyl acetate/hexanes (3:1 containing 10% of
triethylamine), were obtained 162 mg (36%) of the less polar
compound (+)-4d and 71 mg (16%) of the more polar compound
(+)-5d .
Cycloa d d u ct (+)-4d : colorless oil; [R]D ) +40.7 (c 0.5,
1
CHCl3); H NMR (CDCl3) δ 2.30 (m, 4H), 3.17 (m, 1H), 3.35
(m, 2H), 3.53 (m, 1H), 3.58 (s, 3H), 3.69 (m, 4H), 3.79 (m, 4H),
4.36 (d, 1H, J ) 4.9 Hz), 5.07 (m, 2H), 5.77 (m, 1H); 13C NMR
(CDCl3) δ 173.9, 173.8, 167.9, 135.2, 117.1, 83.5, 63.8, 59.8,
59.5, 59.4, 52.3, 51.8, 45.6, 40.7, 34.4, 32.1; IR (CHCl3, cm-1
)
ν 3338, 1735; MS (CI), m/z 341 (M+ + 1, 100), 340 (M+, 25).
Anal. Calcd for C16H24N2O6: C, 56.46; H, 7.11; N, 8.23.
Found: C, 56.52; H, 7.09; N, 8.24.
Cycloa d d u ct (+)-5d : colorless oil; [R]D ) +75.0 (c 0.6,
1
CHCl3); H NMR (CDCl3) δ 2.35 (m, 4H), 3.02 (m, 1H), 3.13
(dd, 1H, J ) 7.3, 5.8 Hz), 3.39 (dd, 1H, J ) 8.5, 5.8 Hz), 3.52
(m, 1H), 3.58 (s, 3H), 3.68 and 3.75 (s, each 3H), 3.90 (m, 2H),
4.48 (d, 1H, J ) 5.1 Hz), 5.08 (m, 2H), 5.73 (m, 1H); 13C NMR
(CDCl3) δ 173.7, 173.2, 168.1, 134.7, 117.3, 83.7, 62.9, 59.2,
57.9, 57.7, 52.2, 51.9, 44.9, 40.2, 32.7, 32.3; IR (CHCl3, cm-1
)
ν 3340, 1737; MS (CI), m/z 341 (M+ + 1, 100), 340 (M+, 18).
Anal. Calcd for C16H24N2O6: C, 56.46; H, 7.11; N, 8.23.
Found: C, 56.38; H, 7.08; N, 8.25.
Cycloa d d u ct (+)-4b: colorless oil; [R]D ) +30.6 (c 0.7,
CHCl3); 1H NMR (C6D6) δ 1.18 (s, 3H), 1.49 (dd, 1H, J ) 13.8,
7.8 Hz), 2.56 (dd, 1H, J ) 13.8, 3.9 Hz), 3.04 (m, 1H), 3.20 (s,
3H), 3.32 (m, 4H), 3.40 (s, 3H), 3.53 (dd, 1H, J ) 8.4, 4.8 Hz),
3.82 (dd, 1H, J ) 15.6, 7.2 Hz), 4.05 (m, 2H), 5.10 (m, 2H),
5.64 (m, 1H); 13C NMR (CDCl3) δ 176.5, 173.6, 167.5, 131.9,
118.4, 83.6, 65.5, 62.0, 59.3, 58.9, 52.4, 51.5, 46.3, 43.6, 41.1,
Gen er a l P r oced u r e for th e N-Acyla tion of Cycloa d -
d u cts 4. Syn th esis of Dien es 6. Acryloyl chloride (1.3 mmol)
and triethylamine (1.3 mmol) were sequentially added drop-
wise to a stirred solution of the corresponding pyrrolidinyl-â-
lactam 4 (1.0 mmol), in dichloromethane (17 mL) at 0 °C, and
the mixture was stirred for 3 h. The organic phase was washed
with water (2 × 5 mL), dried (MgSO4), and concentrated under
reduced pressure. In some cases, chromatography of the
residue eluting with hexanes/ethyl acetate mixtures was
necessary to obtain analytically pure compounds 6. Spectro-
scopic and analytical data for some representative pure forms
of 6 follow.
27.4; IR (CHCl3, cm-1) ν 3334, 1736; MS (CI), m/z 341 (M+
+
1, 100), 340 (M+, 25). Anal. Calcd for C16H24N2O6: C, 56.46;
H, 7.11; N, 8.23. Found: C, 56.50; H, 7.07; N, 8.20.
Cycloa d d u ct (+)-5b: colorless oil; [R]D ) +56.8 (c 0.8,
1
CHCl3); H NMR (CD3OD) δ 1.29 (s, 3H), 1.85 (dd, 1H, J )
13.8, 7.5 Hz), 2.63 (dd, 1H, J ) 13.8, 1.5 Hz), 3.02 (td, 1H, J
) 8.1, 2.1 Hz), 3.49 (s, 3H), 3.54 (m, 4H), 3.65 (m, 4H), 3.93
(m, 2H), 4.53 (d, 1H, J ) 5.1 Hz), 5.12 (m, 2H), 5.72 (m, 1H);
13C NMR (CDCl3) δ 176.6, 173.5, 168.0, 132.6, 117.6, 84.2, 64.1,
61.6, 59.4, 58.6, 52.6, 51.9, 46.5, 43.5, 40.6, 28.1; IR (CHCl3,
cm-1) ν 3339, 1740; MS (CI), m/z 341 (M+ + 1, 100), 340 (M+,
17). Anal. Calcd for C16H24N2O6: C, 56.46; H, 7.11; N, 8.23.
Found: C, 56.39; H, 7.08; N, 8.27.
P r ep a r a tion of Cycloa d d u cts (+)-4c a n d (+)-5c. From
274 mg (1.64 mmol) of the aldehyde (+)-1a and 253 mg (2.45
mmol) of alanine methyl ester, after column chromatography
eluting with ethyl acetate/hexanes (7:1 containing 10% of
triethylamine), were obtained 290 mg (45%) of the less polar
compound (+)-4c and 193 mg (30%) of the more polar com-
pound (+)-5c.
Com p ou n d (+)-6a : pale yellow oil (100%); [R]D ) +20.2 (c
0.4, CHCl3); 1H NMR (CDCl3) δ 2.44 (m, 2H), 3.02 (m, 1H),
3.54 (s, 3H), 3.64 (m, 4H), 3.71 (s, 3H), 3.89 (dd, 1H, J ) 15.8,
5.7 Hz), 4.12 (dd, 1H, J ) 10.3, 5.2 Hz), 4.28 (d, 1H, J ) 5.2
Hz), 4.55 (dd, 1H, J ) 10.5, 8.3 Hz), 4.67 (dd, 1H, J ) 10.3,
6.9 Hz), 5.11 (m, 2H), 5.71 (m, 2H), 6.38 (m, 2H); 13C NMR
(CDCl3) δ 172.3, 170.8, 169.3, 165.4, 131.5, 130.7, 127.0, 117.8,
83.3, 59.7, 59.3, 58.5, 55.9, 52.7, 52.3, 45.9, 44.7, 31.1; IR
(CHCl3, cm-1) ν 1735, 1650; MS (CI), m/z 381 (M+ + 1, 100),
380 (M+, 17). Anal. Calcd for C18H24N2O7: C, 56.83; H, 6.36;
N, 7.36. Found: C, 56.90; H, 6.37; N, 7.34.
Com p ou n d (+)-6b: pale yellow oil (100%); [R]D ) +20.1
(c 1.0, CHCl3); 1H NMR δ 1.56 (s, 3H), 2.06 (dd, 1H, J ) 12.7,
6.0 Hz), 2.57 (dd, 1H, J ) 13.1, 12.9 Hz), 3.35 (m, 1H), 3.50 (s,
3H), 3.65 (m, 4H), 3.69 (s, 3H), 3.77 (m, 1H), 4.22 (m, 2H),
4.74 (dd, 1H, J ) 9.7, 6.9 Hz), 5.01 (m, 2H), 5.67 (m, 2H),
6.31 (m, 2H); 13C NMR δ 173.4, 170.6, 169.3, 164.1, 131.3,
128.9, 127.8, 117.1, 83.0, 65.8, 59.3, 59.1, 56.1, 52.7, 52.1, 44.4,
44.2, 39.7, 21.3; IR (CHCl3, cm-1) ν 1748, 1651; MS (CI), m/z
Cycloa d d u ct (+)-4c: colorless oil; [R]D ) +34.1 (c 0.8,
CHCl3); 1H NMR (CDCl3) δ 1.25 (s, 3H), 3.19 (d, 1H, J ) 10.2
Hz), 3.35 (dd, 1H, J ) 10.8, 9.3 Hz), 3.54 and 3.65 (s, each
3H), 3.67 (m, 1H), 3.68 and 3.78 (s, each 3H), 3.90 (m, 1H),
1430 J . Org. Chem., Vol. 68, No. 4, 2003

Synthesis of Unusual Fused Tricyclic â-Lactam Structures
395 (M+ + 1, 100), 391 (M+, 21). Anal. Calcd for C19H26N2O7:
C, 57.86; H, 6.64; N, 7.10. Found: C, 57.92; H, 6.68; N,
7.06.
Com p ou n d (+)-8a : colorless oil; [R]D ) +141.0 (c 0.3,
1
CHCl3); H NMR (CDCl3) δ 2.25 and 2.57 (m, each 2H), 3.17
and 3.43 (m, each 2H), 3.56 (m, 4H), 3.72 (dd, 1H, J ) 10.5,
4.6 Hz), 3.86 (dd, 1H, J ) 15.4, 7.3 Hz), 4.20 (ddt, 1H, J )
15.4, 4.4. 1.7 Hz), 4.45 (d, 1H, J ) 4.9 Hz), 5.18 (m, 4H), 5.77
(m, 2H); 13C NMR (CDCl3) δ 208.7, 167.9, 135.7, 132.5, 118.3,
118.1, 83.2, 62.0, 59.3, 56.0, 55.9, 46.6, 43.8, 39.3, 37.4; IR
(CHCl3, cm-1) ν 1742, 1715; MS (CI), m/z 279 (M+ + 1, 100),
278 (M+, 9). Anal. Calcd for C15H22N2O3: C, 64.73; H, 7.97; N,
10.06. Found: C, 64.79; H, 7.96; N, 10.08.
Com p ou n d (+)-6g: pale yellow oil (88%); [R]D ) +14.2 (c
0.6, CHCl3); 1H NMR (CDCl3) δ 1.55 (s, 3H), 2.14 (dd, 1H, J )
12.7, 5.9 Hz), 2.77 (t, 1H, J ) 13.2 Hz), 3.44 (m, 1H), 3.68 and
3.72 (s, each 3H), 3.85 (s, 3H), 4.01 (m, 2H), 4.48 (dd, 1H, J )
12.2, 5.4 Hz), 4.57 (d, 1H, J ) 5.4 Hz), 4.85 (dd, 1H, J ) 10.3,
7.3 Hz), 4.96 (dd, 1H, J ) 10.8, 5.4 Hz), 5.26 (m, 3H), 5.72
(dd, 1H, J ) 16.6, 1.9 Hz), 5.83 (m, 1H), 7.57 (m, 2H); 13C NMR
(CDCl3) δ 173.4, 171.6, 166.2, 164.8, 156.7, 133.3, 131.1, 128.6,
127.3, 119.8, 117.8, 113.9, 80.9, 72.2, 66.7, 60.4, 58.6, 55.4, 52.8,
52.2, 45.2, 40.9, 21.1; IR (CHCl3, cm-1) ν 3336, 1735; MS (CI),
m/z 486 (M+ + 1, 100), 485 (M+, 19). Anal. Calcd for
Com p ou n d (+)-9a : colorless oil; [R]D ) +33.5 (c 0.1,
1
CHCl3); H NMR (CDCl3) δ 2.35 and 2.81 (m, each 2H), 3.28
(m, 5H), 3.49 (m, 4H), 3.91 (t, 1H, J ) 5.3 Hz), 4.14 (m, 1H),
4.43 (t, 1H, J ) 5.2 Hz), 5.19 (m, 4H), 5.69 (m, 2H); 13C NMR
(CDCl3) δ 208.0, 168.4, 134.9, 131.5, 118.9, 118.2, 83.8, 59.7,
59.6, 58.1, 56.2, 48.7, 44.6, 41.2, 39.3; IR (CHCl3, cm-1) ν 1741,
1716; MS (CI), m/z 279 (M+ + 1, 100), 278 (M+, 12). Anal. Calcd
for C15H22N2O3: C, 64.73; H, 7.97; N, 10.06. Found: C, 64.65;
H, 7.96; N, 10.04.
C
25H29N2O8: C, 61.85; H, 6.02; N, 5.77. Found: C, 61.92; H,
6.01; N, 5.76.
Gen er a l P r oced u r e for th e Syn th esis of Cycloa d d u cts
7. A solution of allylamine (1.10 mmol) in dichloromethane (4
mL) was added dropwise to a stirred suspension of the
appropriate 4-azetidinone-2-carbaldehyde 1 (1.0 mmol) and
magnesium sulfate (1.50 mmol) in dichloromethane (100 mL)
at room temperature. After being stirred for 16 h at room
temperature, the mixture was filtered and the solvent was
removed under reduced pressure. The solvent was removed
under reduced pressure giving in quantitative yield the
corresponding imines. The crude product was used for next
step without any further purification.
A solution of the appropriate imine (1.0 mmol) in acetonitrile
(5 mL) was added dropwise to a stirred suspension of zinc
iodide (1.10 mmol) in acetonitrile (13 mL) at -20 °C. The
reaction mixture was stirred at -20 °C for 15 min, and then
Danishefsky’s diene (1.20 mmol) was added. After disappear-
ance of the imine (TLC), saturated aqueous NaHCO3 (1 mL)
was added, and the mixture was extracted with ethyl acetate
(3 × 20 mL). The combined organic extract was washed with
brine, dried (MgSO4) and concentrated under reduced pres-
sure. Chromatography of the residue eluting with ethyl
acetate/hexanes mixtures (containing 1% of triethylamine)
gave compounds 7. Spectroscopic and analytical data for some
representative forms of 7 follow.
Cycloa d d u ct 7a . From the allyl imine of aldehyde (+)-1a
(250 mg, 1.20 mmol), 248 mg (75%) of cycloadduct 7a , contain-
ing ca. 20% of its syn epimer, was obtained as a colorless oil:
1H NMR (CDCl3) δ 2.21 and 2.83 (m, each 1H), 3.49 (s, 2.4H),
3.57 (s, 0.6H), 3.96 (m, 4H), 4.21 (m, 1H), 4.43 (m, 1H), 4.93
(m, 1H), 5.19 (m, 4H), 5.69 (m, 2H), 6.90 (m, 1H); 13C NMR
(CDCl3) δ 190.5 (M), 189.9 (m), 168.5 (M), 168.4 (m), 152.1 (M
+ m), 133.4 (m), 133.0 (M), 130.8 (m), 130.5 (M), 119.7 (M),
119.3 (m), 118.7 (m), 118.6 (M), 98.5 (M + m), 82.9 (M), 82.6
(m), 59.4 (M), 58.6 (m), 58.3 (M), 56.5 (m), 56.1 (m), 54.9 (M),
54.3 (m), 53.1 (M), 44.9 (m), 44.4 (M), 37.6 (M), 37.2 (m); IR
(CHCl3, cm-1) ν 1740, 1705; MS (CI), m/z 277 (M+ + 1, 100),
276 (M+, 12).
Gen er a l P r oced u r e for th e Syn th esis of Dien es 8. A
cooled solution of L-Selectride (49 mg, 0.259 mmol) in tetrahy-
drofuran (0.259 mL) was added dropwise to a stirred solution
of the appropriate cycloadduct 7 (0.236 mmol) in tetrahydro-
furan (3.5 mL) at -78 °C, and the mixture was stirred for 1 h
at -78 °C. Saturated aqueous sodium hydrogen carbonate (0.5
mL) was added, and the mixture was allowed to warm to room
temperature, before being extracted with ethyl acetate. The
organic extract was washed with brine, dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue eluting with ethyl acetate/hexanes mixtures (contain-
ing 1% of triethylamine) gave analytically pure compounds 8
and 9.
Gen er a l P r oced u r e for th e RCM Rea ction . To a solution
protected from the sunlight of the corresponding dienes 2, 6,
and 8 (0.20 mmol) in anhydrous toluene (6 mL) was added in
portions Cl2(Cy3P)2RudCHPh (0.01 mmol) under argon. The
resulting mixture was heated at reflux until complete disap-
pearance of the starting material (TLC) and was concentrated
under reduced pressure. Chromatography of the residue
eluting with ethyl acetate/hexanes mixtures gave analytically
pure compounds 10-12.
Tr icyclic 2-Azetid in on e (+)-10b. From 80 mg (0.223
mmol) of diene (+)-2b was obtained 40 mg (54%) of compound
1
(+)-10b as a pale yellow oil: [R]D ) +36.0 (c 1.0, CHCl3); H
NMR (CDCl3) δ 2.36 (m, 2H), 3.09 (m, 1H), 3.39 (s, 3H), 3.73
(m, 2H), 4.12 (m, 3H), 4.56 (d, 1H, J ) 4.4 Hz), 5.30 (d, 1H, J
) 4.3 Hz), 5.71 (m, 2H), 7.05 (m, 3H), 7.18 (m, 2H); 13C NMR
(CDCl3) δ 166.2, 164.7, 157.5, 129.7, 129.6, 129.2, 122.6, 115.9,
83.2, 80.0, 59.7, 58.6, 58.3, 36.3, 36.1; IR (CHCl3, cm-1) ν 1762,
1753; MS (CI), m/z 329 (M+ + 1, 100), 328 (M+, 9). Anal. Calcd
for C18H20N2O4: C, 65.84; H, 6.14; N, 8.53. Found: C, 65.92;
H, 6.15; N, 8.51).
Tr icyclic 2-Azetid in on e (+)-11c. From 60 mg (0.135
mmol) of diene (-)-6c was obtained 32 mg (57%) of compound
(+)-11c as a yellow oil: [R]D ) +210.8 (c 0.3, CHCl3); 1H NMR
(CDCl3) δ 1.76 (s, 3H), 3.33 (m, 2H), 3.72 (s, 3H), 3.77 and
3.78 (s, each 3H), 4.11 (m, 2H), 4.22 (dd, 1H, J ) 10.2, 4.8
Hz), 4.60 (d, 1H, J ) 4.8 Hz), 4.84 (d, 1H, J ) 10.1 Hz), 6.15
(m, 2H); 13C NMR (CDCl3) δ 171.6, 170.8, 166.9, 166.8, 165.6,
129.3, 128.2, 83.1, 70.9, 62.5, 58.9, 58.4, 57.1, 52.9, 52.8, 52.7,
47.1, 36.5, 23.8; IR (CHCl3, cm-1) ν 1743, 1661; MS (CI), m/z
425 (M+ + 1, 100), 426 (M+, 15). Anal. Calcd for C19H24N2O9:
C, 53.77; H, 5.70; N, 6.60. Found: C, 53.85; H, 5.71; N, 6.59.
Tr icyclic 2-Azetid in on e (+)-11d . From 80 mg (0.221
mmol) of diene (+)-6d was obtained 43 mg (58%) of compound
(+)-11d as a pale brown oil: [R]D ) +145.8 (c 1.0, CHCl3); 1H
NMR (CDCl3) δ 2.39 (m, 4H), 3.08 (m, 1H), 3.49 (s, 3H), 3.64
(m, 5H), 3.79 (s, 3H), 4.13 (dd, 1H, J ) 10.2, 4.6 Hz), 4.25 (d,
1H, J ) 4.9 Hz), 4.55 (dd, 1H, J ) 10.5, 7.1 Hz), 4.64 (dd, 1H,
J ) 10.0, 8.5 Hz), 5.89 and 6.35 (m, each 1H); 13C NMR (CDCl3)
δ 172.5, 170.8, 168.8, 168.3, 132.9, 125.7, 83.0, 61.3, 58.7, 56.9,
52.6, 52.1, 45.6, 38.7, 31.5, 27.3; IR (CHCl3, cm-1) ν 1742, 1662;
MS (CI), m/z 367 (M+ + 1, 100), 366 (M+, 11). Anal. Calcd for
C
17H22N2O7: C, 55.73; H, 6.05; N, 7.65. Found: C, 55.80; H,
6.04; N, 7.63.
Tr icyclic 2-Azetid in on e (+)-11f. From 67 mg (0.158
mmol) of diene (+)-6f was obtained 22 mg (35%) of compound
1
(+)-11f as a pale brown oil: [R]D ) +92.1 (c 0.2, CHCl3); H
NMR (CDCl3) δ 1.64 (s, 3H), 2.13 (dd, 1H, J ) 12.7, 6.4 Hz),
2.33 (m, 2H), 2.65 (t, 1H, J ) 13.2 Hz), 2.83 (m, 1H), 3.32 (m,
2H), 3.56 (s, 3H), 3.72 and 3.79 (s, each 3H), 4.24 (m, 1H),
4.76 (dd, 1H, J ) 9.3, 6.8 Hz), 5.35 (m, 1H), 5.48 (m, 1H), 5.69
(m, 1H), 6.42 (d, 1H, J ) 17.1 Hz), 6.57 (dd, 1H, J ) 17.1, 10.3
Hz); 13C NMR (CDCl3) δ 173.8, 171.2, 169.8, 164.2, 128.4,
127.9, 83.2, 66.7, 59.95, 59.6, 56.9, 53.2, 52.6, 44.7, 42.4, 40.2,
P r ep a r a tion of Com p ou n d s (+)-8a a n d (+)-9a . From 100
mg (0.36 mmol) of the cycloadduct 7a , after column chroma-
tography eluting with ethyl acetate/hexanes (2:1 containing
1% of triethylamine), 60 mg (68%) of the less polar compound
(+)-8a and 14 mg (16%) of the more polar compound (+)-9a
were obtained.
J . Org. Chem, Vol. 68, No. 4, 2003 1431

Alcaide et al.
31.1, 21.8, 18.4; IR (CHCl3, cm-1) ν 1744, 1664; MS (CI), m/z
395 (M+ + 1, 100), 394 (M+, 14). Anal. Calcd for C19H26N2O7:
C, 57.86; H, 6.64; N, 7.10. Found: C, 57.94; H, 6.66; N, 7.08.
Tr icyclic 2-Azetid in on e (+)-11g. From 45 mg (0.093
mmol) of diene (+)-6g was obtained 15 mg (35%) of compound
(+)-11g as a pale yellow oil: [R]D ) +214.1 (c 0.8, CHCl3); 1H
NMR (CDCl3) δ 1.48 (s, 3H), 2.09 (dd, 1H, J ) 12.5, 4.6 Hz),
2.71 (dd, 1H, J ) 13.2, 12.9 Hz), 3.48 (m, 1H), 3.66 (s, 3H),
3.67 (s, 3H), 3.78 (s, 3H), 4.09 (m, 1H), 4.38 (m, 1H), 4.54 (d,
1H, J ) 4.1 Hz), 4.91 (m, 2H), 5.67 (d, 1H, J ) 16.7 Hz), 6.31
(dd, 1H, J ) 16.4, 10.1 Hz); 13C NMR (CDCl3) δ 174.6, 173.0,
166.8, 165.1, 157.0, 132.7, 128.1, 127.0, 120.1, 114.2, 82.3, 77.4,
67.0, 60.9, 58.8, 55.8, 53.2, 52.6, 45.5, 41.8, 22.2; IR (CHCl3,
cm-1) ν 1744, 1660; MS (CI), m/z 459 (M+ + 1, 100), 458 (M+,
11). Anal. Calcd for C23H26N2O8: C, 60.26; H, 5.72; N, 6.11.
Found: C, 60.34; H, 5.70; N, 6.14.
Tr icyclic 2-Azetid in on e (+)-12c. From 50 mg (0.171
mmol) of diene (+)-8c were obtained 15 mg (33%) of the less
polar compound (+)-12c and the corresponding more polar
N-deallylation product: colorless oil; [R]D ) +191.0 (c 0.2,
1
CHCl3); H NMR (CDCl3) δ 2.26 (m, 8H), 3.05 (m, 4H), 3.34
(m, 1H), 3.48 (s, 3H),3.49 (m, 3H), 4.35 (d, 1H, J ) 5.0 Hz),
5.61 and 5.79 (m, each 1H); 13C NMR (CDCl3) δ 211.0, 170.8,
137.1, 128.8, 83.2, 77.0, 62.9, 59.6, 59.2, 47.3, 41.3, 37.9, 30.1,
28.1, 25.7; IR (CHCl3, cm-1) ν 1740, 1712; MS (CI), m/z 279
(M+ + 1, 100), 278 (M+, 10). Anal. Calcd for C15H22N2O3: C,
64.73; H, 7.97; N, 10.06. Found: C, 64.80; H, 7.98; N, 10.04.
Ack n ow led gm en t. Support for this work by the
DGI-MCYT (Project No. BQU2000-0645) is gratefully
acknowledged. J .M.A. and M.C.R. thank the UCM and
MEC, respectively, for predoctoral grants.
Tr icyclic 2-Azetid in on e (+)-12a . From 60 mg (0.216
mmol) of diene (+)-8a was obtained 28 mg (53%) of compound
1
(+)-12a as a pale brown oil: [R]D ) +96.7 (c 0.3, CHCl3); H
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for compounds (+)-2b, (+)-4a , (+)-4e-g, (+)-
5a , (+)-5e, (+)-5f, (-)-6c, (+)-6d -f, 7b, 7c, (+)-8b, (+)-8c, (+)-
9b, (+)-10a , (+)-11a , (+)-11b, (+)-11e, and (+)-12b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
NMR (CDCl3) δ 1.55 (dd, 1H, J ) 14.6, 10.2 Hz), 1.70 (m, 2H),
2.10 and 2.30 (m, each 2H), 2.71 (m, 3H), 3.02 (s, 3H), 3.23
(dd, 1H, J ) 14.2, 6.8 Hz), 3.57 (d, 1H, J ) 4.4 Hz), 3.69 (dd,
1H, J ) 14.2, 6.4 Hz), 5.01 (m, 2H); 13C NMR (CDCl3) δ 207.7,
166.4, 132.2, 123.8, 82.0, 61.1, 59.8, 58.9, 53.5, 51.3, 40.6, 39.7,
36.6; IR (CHCl3, cm-1) ν 1744, 1716; MS (CI), m/z 251 (M+
+
1, 100), 250 (M+, 9). Anal. Calcd for C13H18N2O3: C, 62.38; H,
7.25; N, 11.19. Found: C, 62.31; H, 7.24; N, 11.21.
J O026112L
1432 J . Org. Chem., Vol. 68, No. 4, 2003