Stereospecific synthesis of polyfunctionalized carbacephams induced by titanocene(III) chloride

Article abstract of DOI:10.1021/jo026524u

Enantiomerically pure N-substituted epoxyalkene-2-azetidinones reacted with titanocene monochloride to give stereospecifically polyfunctionalized bicyclic β-lactams. Four isomeric epoxyaldehydes 2 reacted with TiCp₂- Cl to give exclusively the respective carbacephams 7 while under the same reaction conditions the epoxyesters 1, which are more hindered for an intramolecular addition, gave the cyclization products 6 (only two isomers) and/or the elimination products 5 (all isomers).

Full text of DOI:10.1021/jo026524u

SCHEME 1a
Ster eosp ecific Syn th esis of
P olyfu n ction a lized Ca r ba cep h a m s In d u ced
by Tita n ocen e(III) Ch lor id e
Gema Ruano, J usto Martia´n˜ez, Manuel Grande,* and
J osefa Anaya
Departamento de Quı´mica Orga´nica, Universidad de
Salamanca, E-37008 Salamanca, Spain
mgrande@usal.es
Received October 4, 2002
Ab st r a ct : Enantiomerically pure N-substituted epoxyal-
kene-2-azetidinones reacted with titanocene monochloride
to give stereospecifically polyfunctionalized bicyclic â-lac-
tams. Four isomeric epoxyaldehydes 2 reacted with TiCp2-
Cl to give exclusively the respective carbacephams 7 while
under the same reaction conditions the epoxyesters 1, which
are more hindered for an intramolecular addition, gave the
cyclization products 6 (only two isomers) and/or the elimina-
tion products 5 (all isomers).
a
Reagents and conditions: (a) PhI(CF3CO2)2/NaHCO3/85:15
CH3CN/H2O, rt; (b) Ph3PdCH-CO2Me, THF, rt; (c) m-CPBA,
In a previous paper1 on the TiCp2Cl-promoted reduc-
tive ring opening via single electron transfer2 of enan-
tiomerically pure epoxy-monobactams, we described the
cyclization by 1,4 addition of benzyl radicals to a conju-
gated γ-lactone and by 1,2 addition to an amide and a
lactone carbonyl functional group. These last additions
were not described previously in the literature. To extend
the application of these reactions and to compare the
reactivity of the generated benzyl radicals on the conju-
gated alkenes, amides, and aldehydes,2c we report here
the results obtained by reaction of enantiomerically pure
epoxides 1 and 2 (Scheme 1)3 with TiCp2Cl.
CH2Cl2, rt; (d) O3, CH2Cl2, -78 °C; Me2S, rt.
enantiomerically pure epoxides 1 and 2. Deprotection of
dithioacetal groups with [bis(trifluoroacetoxy)iodo]ben-
zene yielded the aldehydes 4, which were used without
further purification in the next steps. Wittig reactions
on the crude aldehydes 4a and 4b afforded in good yields
the respective conjugated alkenes 5a and 5b and the
regioselective epoxidation of the styryl group with m-
CPBA followed by chromatography of the reaction prod-
ucts afforded the pure epoxides 1a a (35%; [R]25 ) +56)
D
and 1a b (42%; [R]25 ) +54) from 5a and 1b a (40%;
D
The readily available cis-2-azetidinones 3a and 3b4,5
(Scheme 1) were used as starting material to prepare the
[R]25 ) -33) and 1bb (49%; [R]25 ) -21) from 5b.
D
D
The instability of aldehyde functions to basic and acidic
reaction media6 prevents the direct conversion of the
crude reaction products 4a and 4b into the respective
epoxides 2a a to 2bb. However, the ozonolysis of each one
of the pure epoxides 1 proceeded with very good yields
to give the respective enantiomerically pure epoxyalde-
hydes 2a a (100%; [R]25D ) +52), 2a b (85%; [R]25D ) +27),
2ba (100%; [R]25 ) +22), and 2bb (90%; [R]25 ) -29).
* To whom correspondence should be addressed. Phone: (+34)
923294482. Fax: (+34) 923294574.
(1) Ruano, G.; Grande, M.; Anaya, J . J . Org. Chem. 2002, 67, 8243-
8245.
(2) (a) Nugent, W. A.; RajanBabu, T. V. J . Am. Chem. Soc. 1994,
116, 986-997. (b) Gansa¨uer, A.; Pierobon, M.; Bluhm, H. Angew.
Chem., Int. Ed. 1998, 37, 101-103. (c) Ferna´ndez-Mateos, A.; Mart´ın
de la Nava, E.; Pascual Coca, G.; Ramos Silvo, A.; Rubio Gonza´lez, R.
Org. Lett. 1999, 1, 607-609. (d) Gansa¨uer, A.; Bluhm, H. Chem. Rev.
2000, 100, 2771-2788. (f) Li, J . J . Tetrahedron 2001, 57, 1-24. (e)
Gansa¨uer, A.; Pierobon, M.; Bluhm, H. Angew. Chem., Int. Ed. 2002,
41, 3206-3208.
(3) The stereodescriptors R and â refers to the substituents below
and above to the reference plane of the 2-azetidinone ring as it is
depicted (IUPAC. Pure Appl. Chem. 1995, 67, 1307-1375).
(4) The cis-monobactams 3a and 3b were the only cyclization
D
D
The structure of the epoxy-â-lactams 1 and 2 was
deduced from one- and two-dimensional NMR data,
including COSY and HMQC experiments; however, it
was not possible to assign the C-5 and C-6 configurations
for these 2-azetidinones from the 1H NMR data. The
configurations depicted in Scheme 1 were deduced, as will
be discussed below, from the configurational assignments
of the cyclization products obtained from these epoxides
(Table 1).
products obtained as
a 1:2.1 mixture by Staudinger reaction of
methoxyacetyl chloride with the imine produced from D-glucosamine
and trans-cinnamaldehyde in the presence of Et3N. No trans diaster-
eomeric 2-azetidinone was detected. The absolute configuration of these
compounds was deduced from their [R]D data by comparison with the
1′,1′-dithyanyl derivative 3â,4â-disubstituted-2-azetidinone ([R]25D -102
(c 1.0, CHCl3)) of known absolute configuration established by X-ray
crystallography.5
(5) (a) Barton, D. H. R.; Gateau-Olesker, A.; Anaya-Mateos, J .;
Cle´ophax, J .; Gero, S. D.; Chiaroni, A.; Riche, C. J . Chem. Soc., Perkin
Trans. 1 1990, 3211-3212. (b) Chiaroni, A.; Riche, C.; Anaya, J .;
Gateau-Olesker, A.; Gero, S. D.; Hernando, J . I. M. Acta Crystallogr.
1994, C50, 1470-1480. (c) Anaya, J .; Gero, S. D.; Grande, M.;
Hernando, J . I. M.; Laso, N. M. Bioorg. Med. Chem. 1999, 7, 837-
850.
To explore the reactivity of the epoxides 1 and 2 with
titanocene (III) monochloride, a THF solution of each
pure epoxide (1.0 mmol) was added at room temperature
(6) These aldehydes are very labile because of the acidity of the
R-proton H-2′. The chromatographic grade silica gel is acidic enough
to induce instantly the formation of the unsaturated aldehyde if not
treated previously with TEA.1
10.1021/jo026524u CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/30/2003
2024
J . Org. Chem. 2003, 68, 2024-2027

F IGURE 1. Proposed conformations for the carbacephams 6 and 7 and their precursors.
TABLE 1. Rea ction of Ep oxid es 1 a n d 2 w ith TiCp 2Cla
In these cases, the deoxygenated monobactams 5a or 5b
were isolated in 60 and 77% yield, respectively (entry 4,
Table 1), and no cyclization product was observed.
On the contrary, all four isomeric epoxyaldehydes 2
under the above reaction conditions reacted with ti-
tanocene(III) chloride in the same way (entries 4-8,
Table 1). In these cases, the reactions proceeded to give
exclusively in a stereospecific manner the cyclization
products, the respective bicyclic â-lactams 7, with moder-
ate yields (50-65%).
The proposed structures for the carbacephams 6 and
7 were deduced mainly from MS and NMR data, includ-
ing NOE and two-dimensional experiments. The relative
configurations trans-3,4,5-substituted in carbacephams7
7a b and 7bb or cis-3,4-trans-4,5-substituted in 6a b, 6ba ,
7a a , and 7ba were deduced from the vicinal coupling
constants between the hydrogen atoms of the six-
membered ring (Table 2).8
The 1H NMR data reported in Table 2 are in agreement
with the conformations shown in Figure 1 for each one
of the seven bicyclic â-lactams,9 and the NOE observed
in the compounds 6 and 7 also support these conforma-
tions. Consequently, as the configurations for C-2, C-6,
and C-7 were known from the starting materials 3,4 we
propose the following absolute configurations for the
synthesized carbacephams: 2S,3R,4R,5S,6S,7R for 6a b
and 7a b; 2S,3S,4S,5R,6R,7S for 6ba ; 2S,3R,4S,5R,6S,7R
for 7a a ; 2S,3R,4S,5R,6R,7S for 7ba and 2S,3R,4R,5S,-
6R,7S for 7bb.
a
In parentheses: isolated yield after column chromatography.
to a green solution of TiCp2Cl, generated “in situ” from
TiCp2Cl2 (2.2 mmol) and zinc (6.6 mmol) in THF.2a
The reactions of 1a b and 1ba with titanocene(III)
chloride proceeded in a similar way to give a mixture of
two products in 75% yield (entries 2 and 3, Table 1). In
these reactions the major component was the expected
cyclization product, the respective bicyclic â-lactam 6, and
the minor component was the elimination product, the
alkene 5. Different results were obtained when the
isomers 1a a and 1bb were used as the starting material.
(7) The numbering of the carbacepham system is given according
to the IUPAC rules (Pure Appl. Chem. 1995, 67, 1307-1375).
(8) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C. Tetrahedron
1980, 36, 2783-2792.
(9) The nomenclature for the six-membered ring conformation is
given as proposed by Schwarz. Schwarz, J . C. P. J . Chem. Soc., Chem.
Commun. 1973, 505-508.
J . Org. Chem, Vol. 68, No. 5, 2003 2025

TABLE 2. Selected 1H NMR Da ta on Com p ou n d s 6 a n d 7
compd
H-2
H-3
H-4
H-5
H-6
J 2,3
J 3,4
J 4,5
J 5.6
J 6,7
J 2,1′
J 3,1′′
6a b
6ba
7a a
7a b
7ba
7bb
3.91 dd
3.78 dd
3.93 br s
4.34 dd
3.25 dd
3.90 dd
2.61 ddt
2.85 m
3.59 dd
3.14 dd
2.82 br s
3.30 dd
2.73 dd
3.69 dd
4.39 dd
4.37 dd
4.66 dddb
4.02 dd
4.68 dd
4.37 dd
3.77 dd
3.38 dd
4.33 dd
3.87 dd
3.53 dd
3.78 dd
4.6
3.6
1.0
6.8
0.5
9.8
4.1
3.6
1.1
10.8
0.4
5.9
11.4
11.5
3.5
10.4
11.2
3.5
9.8
8.2
7.9
8.6
8.0
2.1
4.1
4.3
4.8
4.2
4.4
4.9
4.8
3.8
4.2, 4.2
3.4, 8.0
4.25 dta
4.06 dt
1.2
8.8
8.4
3.98 m
4.59 dddc
a
b
c
J 3,OH ) 1.0. J 5,OH ) 2.9. J 3,OH ) 0.9.
SCHEME 2. P ossible Rea ction Mech a n ism for th e
F or m a tion of Com p ou n d s 5, 6, a n d 7
Likewise, the stereospecific cyclization of the epoxyal-
dehydes 2 to form the carbacephams 7a a to 7bb may be
explained assuming for the starting epoxides the con-
formers P 5, P 6, P 7, and P 8 (Figure 1). In these cases,
the smaller size of the aldehyde functional group in 2 as
compared with the acrylate group in the epoxides 1
allows an easier approach of the benzyl radical I to the
electrophile Csp2-1′ for yielding the cyclization products,
as confirmed by the observed results.
Thus, the four isomeric epoxyaldehydes 2 reacted with
TiCp2Cl and gave exclusively the respective carbaceph-
ams. The epoxyesters 1 are too crowded, and their
intermediate benzylic radicals progress under the same
reaction conditions to the cyclization products 6 (only two
isomers) and to the elimination products 5 (all isomers).
It is not clear to us why the attack of the benzyl radical
takes place at only one of the faces (the Re face) of the
aldehyde. Perhaps a steric effect caused by the coordina-
tion of the carbonyl group with the reagent and/or with
the sugar residue could explain the observed face selec-
tivity.
From these results and those previously disclosed,1 we
conclude that the reaction of TiCp2Cl with enantiomeri-
cally pure N-substituted 4-epoxyalkene-2-azetidinones is
an efficient method for the stereospecific synthesis of very
important polycyclic â-lactam compounds. Efforts to
optimize the yields of the cyclization process are now
under study.
The reaction of the epoxy-â-lactams 1 and 2 upon
treatment with TiCp2Cl could be rationalized as shown
in Scheme 2. The benzyl radicals I generated by the
homolytic cleavage of the epoxides 1 and 2 can evolve
through the pathways a and b. The benzyl radicals I can
give the alkenes 5a and 5b after â-elimination of the
titanium-oxo moieties (pathway a)2 or progress through
pathway b, which implies the radical trapping by the
conjugate electrophilic double bond or by the aldehyde
carbonyl group for giving the carbacephams 6 or 7 after
acidic workup. In these experiments, no cyclization
products derived from the addition of the benzyl radicals
to the amide carbonyl functional group were observed.
The stereospecific formation of the bicyclic â-lactams
6 and 7 suggests that the epoxide ring opening and the
radical addition to C-1′ should be a concerted process with
configuration inversion at C-6. A conformational analy-
sis10 of the epoxy-â-lactams 1 and 2 induced us to consider
the conformers P 1 to P 8 (Figure 1) as the most appropri-
ate precursors of the respective bicyclic â-lactams. In
these conformers, the C-6-C-1′ distance and orientation
are the best suited for cyclization.
In the case of the epoxide 1a b, the benzyl radical I can
access the Re face more easily than the Si face of the
C-1′-conjugated alkene, as shown in the conformer P 2,
to give the 3R-substituted carbacephams 4a b. Similarly,
the best conformer of 1ba for a conjugate addition is P 3,
in which the radical C-6 is close to the Si face of the C-1′
giving rise to the 3â-substituted carbacepham 4ba . In
contrast, the conformations for the epoxides 1a a and 1bb
with a suitable distance C-6-C-1′ for cyclization (P 1 and
P 4) evidence severe crowding, mainly between the ox-
irane oxygen and the oxygen of the C-3 methoxyl group,
apart from the steric interactions between the sugar
residue with the â-lactam carbonyl group and the car-
boxylate-phenyl interactions. This could explain why no
cyclization products were observed in these cases.
Exp er im en ta l Section
P r ep a r a tion of Mon oba cta m s 3a a n d 3b.5c A solution of
3,4;5,6-di-O-isopropylidene-1,1-bis-ethylsulfanyl-D-glucosa-
mine (10.0 mmol) and trans-cinnamaldehyde (10.0 mmol) in
toluene was stirred at 110 °C for 4 h, and then the reaction
product was concentrated to dryness. To a solution of the crude
imine (10.0 mmol) and TEA (25 mmol) in dry toluene (100 mL)
was added methoxyacetyl chloride (15.0 mmol) in toluene (6.0
mL) dropwise under argon atmosphere. The mixture was stirred
at room temperature until the starting material disappeared (1
h). The reaction product was then poured onto a saturated NH4-
Cl solution at 0 °C, neutralized with acetic acid, extracted with
CH2Cl2, and washed with water (three times) and brine solution
(twice), and the organic layer was concentrated to dryness.
Purification by column chromatography (SiO2, hexane/ethyl
acetate mixtures) gave pure monobactams 3. For NMR data, see
the Supporting Information.
3a : isolated in 26% yield; Rf (8:2 hexane/ethyl acetate) 0.27;
[R]25 +79 (c 1.0, CHCl3); IR (neat) ν 1759, 1451, 1383, 1211,
D
1061 cm-1. Anal. Calcd for C28H41NO6S2: C, 60.95; H, 7.49; N,
2.54; S, 11.62. Found: C, 60.76; H, 7.53; N, 2.65; S, 11.63.
3a : isolated in 53% yield; Rf (8:2 hexane/ethyl acetate) 0.30;
mp 120-121 °C; [R]25 -118 (c 1.0, CHCl3); IR (KBr) ν 1765,
D
1495, 1381, 1213, 1067, 733 cm-1. Anal. Calcd for C28H41NO6S2:
C, 60.95; H, 7.49; N, 2.54; S, 11.62. Found: C, 60.98; H, 7.48; N,
2.71; S, 11.62.
(10) CS Chem3D Pro software (version 5.0, 1999, CambridgeSoft
Corp., 100 Cambridge Park Drive, Cambridge, MA 02140-2317) using
MM2 calculations.
2026 J . Org. Chem., Vol. 68, No. 5, 2003

Gen er a l P r oced u r e for th e P r ep a r a tion of Alk en es 5a
a n d 5b. To a solution of monobactams 3 (1.00 mmol) and
NaHCO3 (4.00 mmol) in 85:15 CH3CN/H2O (10.0 mL) was added
[bis(trifluoroacetoxy)iodo]benzene (1.50 mmol), and the mixture
was stirred at room temperature until the starting material
disappeared (20-30 min). The reaction product was then
concentrated to dryness, the crude reaction products 4a and 4b
2a b: obtained in 85% yield from 1a b (200 mg, 0.39 mmol); Rf
(45:55 hexane/ethyl acetate) 0.27; IR (neat) ν 1767, 1456, 1375,
1215, 1154, 1065, 845 cm-1; MS (FAB) m/z 462 (M+ + 1, 8), 404
(6), 307 (12), 189 (11), 154 (100), 136 (86), 91 (46); HRMS (FAB)
calcd for C24H32NO8 (M+ + 1) 462.2128, found 462.2161.
2ba : obtained in 100% yield from 1ba (210 mg, 0.41 mmol);
Rf (1:1 hexane/ethyl acetate) 0.27; IR (neat) ν 1761, 1456, 1381,
1215, 1154, 1067, 847 cm-1; MS (FAB) m/z 462 (M+ + 1,7), 434
(3), 404 (5), 376 (5), 307 (8), 154 (100), 91 (76); HRMS (FAB)
calcd for C24H32NO8 (M+ + 1) 462.2128, found 462.2144.
2bb: obtained in 90% yield from 1bb (520 mg, 1.00 mmol); Rf
(1:1 hexane/ethyl acetate) 0.20; IR (neat) ν 1759, 1458, 1373,
1215, 1154, 1069, 840 cm-1; MS (FAB) m/z (%) 462 (M+ + 1,
12), 434 (8), 404 (10), 376 (7), 286 (7), 143 (100), 91 (75). HRMS
(FAB) calcd for C24H32NO8 (M+ + 1) 462.2128, found 462.2138.
Gen er a l P r oced u r e for Red u ctive Op en in g of Ep oxid es
1 a n d 2. A solution of the epoxide 1 or 2 (1.00 mmol) in THF
(10.0 mL) was added to a green suspension of TiCp2Cl, generated
from TiCp2Cl2 (2.20 mmol) and Zn0 (6.60 mmol) in dry and
strictly deoxygenated THF (22.0 mL). The mixture was stirred
at room temperature until the starting material disappeared
(2-5 h) and then quenched with 10% v/v aqueous KH2PO4 (30.0
mL). The aqueous phase was separated and extracted with ethyl
acetate, and the organic combined extracts were filtered through
Celite, dried (Na2SO4), and concentrated in vacuo. Purification
by flash column chromatography on silica gel using hexane/ethyl
acetate mixtures as the eluent gave the products shown in Table
1. For NMR data, see Table 2 and the Supporting Information.
6a b: Rf (4:6 hexane/ethyl acetate) 0.25; mp 159 °C (hexane-
were solved in dry THF (15 mL), and then
a solution of
methoxycarbonylmethylenetriphenylphosphorane (2.2 mmol) in
THF (10.0 mL) was added dropwise under argon atmosphere.
The mixture was stirred at room temperature until the starting
material disappeared and then was poured into a cold am-
monium chloride solution, extracted twice with ethyl acetate,
and concentrated to dryness. Purification by column chroma-
tography (SiO2, 70% hexanes-ethyl acetate) gave the alkenes
5. For NMR data, see the Supporting Information.
5a . Compound 5a was isolated in 93% yield from the mono-
bactam 3a (1.10 g, 2.00 mmol) and also in 72% and 25% yield
from the epoxy-â-lactams 1a a and 1a b by reductive opening of
the epoxides (see below): Rf (6:4 hexane/ethyl acetate) 0.25;
[R]25 +158 (c 1.0, CHCl3); IR (neat) ν 1761, 1732, 1661, 1495,
D
1383, 1212, 1069, 970, 847, 754, 735 cm1; MS (FAB) m/z 502
(M+ + 1, 13), 444 (10), 386 (6), 284 (25), 143 (100), 101 (44);
HRMS (FAB) calcd for C27H36NO8 (M+ + 1) 502.2441, found
502.2475.
5b. Compound 5b was isolated in 94% yield from 3b (1.12 g,
2.03 mmol) and also in 23% and 77% yields from the epoxy-â-
lactams 1ba and 1bb, respectively, by reductive opening of the
epoxides (see below): Rf (6:4 hexane/ethyl acetate) 0.30; [R]25
D
CH2Cl2); [R]25 +11 (c 1.0, CHCl3); IR (KBr) ν 3439, 1748, 1454,
D
-75 (c 1.0, CHCl3); IR (neat) ν 1765, 1726, 1661, 1451, 1383,
1213, 1071, 972, 847 cm1; MS (FAB) m/z 502 (M+ + 1, 8), 444
(12), 386 (5), 284 (30), 143 (100), 101 (50); HRMS (FAB) calcd
for C27H36NO8 (M+ + 1) 502.2441, found 502.2416.
1377, 1260, 1211, 1103, 1070, 847 cm-1; MS (FAB) m/z 520
(M+ + 1, 48), 434 (23), 376 (8), 290 (42), 143 (38), 87 (100); HRMS
(FAB) calcd for C27H38NO9 (M+ + 1) 520.2545, found 520.2542.
6ba : Rf (1:1 hexane/ethyl acetate) 0.25; [R]25 -41 (c 1.0,
D
Gen er a l P r oced u r e for th e Ep oxid a tion of 5. To a solution
of alkene 5 (1.00 mmol) in anhydrous CH2Cl2 (10.0 mL) was
added m-CPBA (1.20 mmol), and the mixture was stirred at room
temperature until the starting material disappeared. The reac-
tion mixture was diluted in CH2Cl2, washed with a solution of
sodium bicarbonate and water, dried over anhydrous Na2SO4,
and evaporated to dryness. The epoxidation of 5a (520 mg, 1.04
mmol) for 15 h with m-CPBA (207 mg, 1.20 mmol) gave after
column chromatography (7:3 hexane/ethyl acetate) the epoxides
1a a (187 mg, 35%) and 1a b (225 mg, 42%). Likewise, the
epoxidation of 5b (1.00 g, 2.00 mmol) for 15 h with m-CPBA
(413 mg, 2.39 mmol) gave after column chromatography (7:3
hexane/ethyl acetate) the epoxides 1ba (413 mg, 40%) and 1bb
(507 mg, 49%). For NMR data, see the Supporting Information.
1a a : Rf (6:4 hexane/ethyl acetate) 0.28; IR (neat) ν 1761, 1728,
1456, 1383, 1213, 1155, 1071, 914, 847, 733 cm1; HRMS (FAB)
calcd for C27H36NO9 (M+ + 1) 518.2390, found 518.2388.
1a b: Rf (6:4 hexane/ethyl acetate) 0.30; mp 98 °C (hexane/
CH2Cl2); IR (KBr) ν 1763, 1728, 1456, 1379, 1215, 1155, 1067,
912, 847, 735 cm1; HRMS (FAB) calcd for C27H36NO9 (M+ + 1)
518.2390, found 518.2335.
CHCl3); mp 176 °C (hexane-CH2Cl2); IR (KBr) ν 3464, 1748,
1454, 1373, 1223, 1169, 1067, 841 cm-1; MS (FAB) m/z 520
(M+ + 1, 5) 307 (16), 154 (100), 107 (23), 69 (25); HRMS (FAB)
calcd for C27H38NO9 (M+ + 1) 520.2545, found 520.2542.
7a a : Rf (3:7 hexane/ethyl acetate) 0.29; [R]25 +70 (c 1.4,
D
CHCl3); IR (neat) ν 3488, 1759, 1456, 1381, 1215, 1067, 914, 845,
753 cm-1; MS (FAB) m/z 464 (M+ + 1, 2), 434 (2), 307 (14), 154
(100), 91 (36); HRMS (FAB) calcd for C24H34NO8 (M+ + 1)
464.2284, found 464.2248.
7a b: Rf (3.7 hexane/ethyl acetate) 0.25; [R]25 +48 (c 1.1,
D
CHCl3); IR (neat) ν 3457, 1757, 1454, 1383, 1215, 1154, 1065,
845 cm-1; MS (FAB) m/z 464 (M+ + 1, 3), 307 (11), 154 (100), 91
(44); HRMS (FAB) calcd for C24H34NO8 (M+ + 1) 464.2284, found
464.2297.
7ba : Rf (3:7 hexane/ethyl acetate) 0.29; [R]25 +10 (c 0.6,
D
CHCl3); IR (neat) ν 3474, 1755, 1454, 1381, 1256, 1213, 1152,
1065, 847 cm-1; MS (FAB) m/z 464 (M+ + 1, 8), 391 (22), 279
(5), 149 (100), 113 (27), 91 (18); HRMS (FAB) calcd for C24H34
-
NO8 (M+ + 1) 464.2284, found 464.2303.
7bb: Rf (3:7 hexane/ethyl acetate) 0.25; [R]25D +19 (c 6, CHCl3);
IR (neat) ν 3489, 1761, 1454, 1373, 1215, 1154, 1067, 840 cm-1
;
1ba : Rf (7:3 hexane/ethyl acetate) 0.30; IR (neat) ν 1761, 1730,
1456, 1381, 1215, 1160, 1071, 916, 849 cm1; MS (FAB) m/z 518
(M+ + 1, 1), 460 (3), 307 (15), 154 (100), 107 (20), 77 (21); HRMS
(FAB) calcd for C27H36NO9 (M+ + 1) 518.2390, found 518.2421.
1bb: Rf (7:3 hexane/ethyl acetate) 0.25; IR (neat) ν 1761, 1732,
MS (FAB) m/z 464 (M+ + 1, 6), 391 (8), 307 (9), 154 (100), 91
(60); HRMS (FAB) calcd for C24H34NO8 (M+ + 1) 464.2284, found
464.2301.
Ack n ow led gm en t. Financial support for this work
from the Ministerio de Educacio´n y Ciencia of Spain
(PB98-0282) and the J unta de Castilla y Leo´n (SA15/
00B) is gratefully acknowledged. We thank the Minis-
terio de Educacio´n y Ciencia of Spain for the grants to
G.R. and J .M.
1455, 1373, 1213, 1154, 1071 cm1; HRMS (FAB) calcd for C27H36
-
NO9 (M+ + 1) 518.2390, found 518.2333.
Gen er a l P r oced u r e for th e Ozon olysis of 1. A solution of
epoxide 1 (1.00 mmol) in anhydrous CH2Cl2 (20.0 mL) was cooled
to -78 °C, and ozone was bubbled through it until the solution
had a permanent blue coloration. Dimethyl sulfide (2.0 mL) was
added, and the solution was brought to room temperature and
stirred for 30 min. Evaporation of solvent under reduced
pressure gave the pure epoxides 2. For NMR data, see the
Supporting Information.
2a a : obtained in 100% yield from 1a a (187 mg, 0.36 mmol);
Rf (45:55 hexane/ethyl acetate) 0.2; IR (neat) ν 1763, 1458, 1375,
1215, 1154, 1065, 847, 731 cm-1; MS (FAB) m/z 462 (M+ + 1,
11), 434 (6), 404 (8), 346 (5), 286 (9), 143 (100), 91 (73).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
data of 1, 2, 3, and 5-7 as well as 1H NMR and two-
dimensional (COSY and/or HMQC) spectra of carbacephams
6 and 7 are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O026524U
J . Org. Chem, Vol. 68, No. 5, 2003 2027