Cycloadditions of cephalosporins. A comprehensive study of the reaction of cephalosporin triflates with olefins, acetylenes, and dienes to form [2 + 2] and [4 + 2] adducts

4998

J . Org. Chem. 1997, 62, 4998-5016

Cycloa d d ition s of Cep h a losp or in s. A Com p r eh en sive Stu d y of th e

Rea ction of Cep h a losp or in Tr ifla tes w ith Olefin s, Acetylen es, a n d

Dien es To F or m [2 + 2] a n d [4 + 2] Ad d u cts

Richard L. Elliott,*^,†Neville H. Nicholson,^†Fiona E. Peaker,^†Andrew K. Takle,^†

Christine M. Richardson,^†J ohn W. Tyler,^‡J anet White,^‡Michael J . Pearson,^†

Drake S. Eggleston,^§and R. Curtis Haltiwanger^§

SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (North), Third Avenue,

Harlow, Essex, CM19 5AW, U.K.

Received J anuary 30, 1997^X

Novel polycyclic cephalosporins are formed by the reaction of cephalosporin triflates with various

unsaturated compounds in the presence of Hunigs base. 2,3-Fused cyclobutane and cyclobutene

cephems are obtained with olefins and acetylenes, respectively, whereas [4 + 2] cycloadducts are

obtained with furan. The reaction has been rationalized by invoking the intermediacy of a strained

6-membered cyclic allene. The allene undergoes an orbital symmetry allowed concerted 2_s+ 2_a

π

cycloaddition with olefins and acetylenes and a 4_s+ _π2_scycloaddition with furan. The regiochem-

π

istry of the [2 + 2] cycloadducts is independent of the substitution of the unsaturated component

and of the oxidation state of the cephalosporin sulfur atom. However in the case of the [4 + 2]

adducts, the sulfur oxidation state determines the regiochemistry of the addition. Carbacepha-

losporins also participate in this reaction with olefins but require a stronger base such as DBU.

Thus the reaction described provides a facile, one-step procedure for the production of a rich variety

of novel polycyclic cephalosporins.

Sch em e 1^a

In tr od u ction

Since the introduction of third-generation cephalospor-

ins (e.g., cefotaxime 1) there has been considerable

interest in finding replacements for the metabolically

unstable acetoxy group at C-3. Numerous modifications

have been achieved by replacing the acetoxy group with

a variety of nitrogen heterocycles and sulfur-based nu-

cleophiles.¹However, there are also several examples of

carbon substituents at C-3 demonstrating that a leaving

group at C-3 is not essential for antimicrobial activity.²

a

TFP ) tri(2-furyl)phosphine, NMP ) N-methylpyrrolidone,

pMB ) p-methoxybenzyl.

the cephem nucleus gave dramatically superior oral

absorption in mice when dosed as prodrug esters, al-

though the antibacterial activities of the sodium salts

were not as potent as the C-3-lactonyl compounds.⁵

Farina and others have developed organometallic

methodologies for the formation of carbon-carbon bonds

at C-3 of cephalosporins.⁶The Stille coupling of the

readily accessible triflates (4)⁷with stannanes has been

particularly successful for the introduction of unsaturated

substituents at C-3 (Scheme 1). Although the introduc-

tion of sp³-based substituents is generally not successful

using the Stille coupling conditions, the reaction of

organocuprates with the triflates (4) provides an alterna-

tive approach to alkyl substituents.⁸

Recently Burton and co-workers reported on the syn-

thesis and antimicrobial activity of C-3 lactonyl (2) and

C-3 cyclic ether (3) cephalosporins.³They demonstrated

that a lactone functionality retained cefotaxime-like

activity and hoped that this would circumvent the

problem of metabolism. Burton discovered that the

introduction of C-3 cyclic ethers, groups known to confer

good activity when attached to the C-2 of penems,⁴onto

We wished to investigate alternative methods for the

introduction of the tetrahydrofuryl group onto the C-3

of the cephem nucleus via the triflates (4) with the

ultimate goal of achieving the reaction stereoselectively.

Treatment of the triflate 4a with (2-tetrahydrofuryl)tri-

^†Department of Medicinal Chemistry.

^‡Department of Analytical Sciences.

^§Department of Physical and Structural Chemistry (King of Prussia,

Pennsylvania, 19406).

^XAbstract published in Advance ACS Abstracts, J uly 1, 1997.

(1) Du¨rckheimer, W.; Blumbach, J .; Lattrell, R.; Scheunemann, K.

H. Angew. Chem., Int. Ed. Engl. 1985, 24, 180.

(2) Kukolja, S.; Chauvette R. R. In Chemistry and Biology of

â-Lactam Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic

Press: New York, 1982; Vol. 1, pp 93-198.

(5) Bateson, J . H.; Burton, G.; Fell, S. C. M.; Smulders H. C. J .

Antibiot. 1994, 47, 253.

(6) Farina, V.; Kant, J . Synlett 1994, 565, and references cited

therein.

(7) Farina, V.; Baker, S. R.; Hauck, S. I. J . Org. Chem. 1989, 54,

4962.

(8) Kant, J . J . Org. Chem. 1993, 58, 2296.

(3) Bateson, J . H.; Burton, G.; Fell, S. C. M. Biorg. Med. Chem. Lett.

1993, 3, 2219.

(4) Ishiguro, M.; Iwata, H.; Nakatsuka, T.; Tanaka, R.; Maeda, Y.;

Nishihara, T.; Noguchi, T. J . Antibiot. 1988, 41, 1685.

Cycloadditions of Cephalosporins

J . Org. Chem., Vol. 62, No. 15, 1997 4999

Sch em e 2

Sch em e 5

Sch em e 3

An alternative approach for the introduction of a

dihydrofuryl group appeared to be the asymmetric Heck

reaction.¹¹If applied to the cephalosporin triflate 4b, the

expected dihydrofuran 14 would now have the double

Sch em e 4

bond out of conjugation and therefore be more amenable

to reduction. However this reaction took a totally

unexpected course. Rather than the expected dihydro-

furan 14, two 2,3-fused polycyclic cephalosporins (15 and

16) were formed¹²(Scheme 5). We postulated that a

cyclic allene intermediate was involved in the reaction,

which underwent cycloaddition with the unsaturated

component. We have reported on our initial findings,¹³

and now report in full further investigations regarding

the scope and mechanism of this remarkable reaction.

Resu lts a n d Discu ssion

n-butylstannane⁹under palladium catalysis led to the

unwanted transfer of a butyl group to give 6 after an

extended reaction time (Scheme 2), whereas the unsatur-

ated stannane 7 underwent a facile Stille coupling to give

8. However we were unable to reduce the dihydrofuryl

double bond. Attempts to deprotect 8 to the correspond-

ing acid instead led to formation of a spiroacetal lactone

(9) (Scheme 3).¹⁰

Treatment of the triflate 4b with 2,3-dihydrofuran in

N-methylpyrrolidone under conditions suitable for the

asymmetric Heck reaction (ⁱPr₂NEt, catalytic Pd(OAc)₂,

(R)-BINAP) gave rise to a mixture of two isomeric

products in 73% yield in a ratio of 1.8:1. Detailed NMR

studies showed the products to be the fused cyclobutane

adducts 15 and 16 and not the expected Heck product

14. We subsequently discovered that the reaction could

The tetrahydrofuryl group was successfully introduced

at C-3 using the cuprate 10 (derived from (2-tetrahydro-

furyl)tri-n-butylstannane). In addition to the desired ∆³-

cephem 11, a considerable amount of the ∆²isomer 12

was obtained (Scheme 4). The 3-n-butyl analogues 13

and 6 were also obtained as a mixture of ∆²and ∆³

isomers. These resulted from the presence of excess

n-butyllithium in the preparation of the tetrahydrofu-

rylcuprate. A potential solution to this problem would

be the use of dialkylmagnesiocuprates (Normant’s cu-

prates). These are less basic in nature than lithiocu-

prates and are reported by Kant to afford pure ∆³

products.⁸

(11) Hayashi, T.; Kubo, A.; Ozawa, F. Pure Appl. Chem. 1992, 64,

421. Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. For a Heck

reaction on carbapenems, see: Nishi, K.; Narukawa, Y.; Onoue, H.

Tetrahedron Lett. 1996, 37, 2987.

(12) Conventional cephalsporin numbering has been used when

referring to the bicyclic cephalosporin nucleus (see compound 4b), and

systematic nomenclature has been used for the cycloadducts (see

compounds 15, 19, and 95). R-Substituents are projected into the page

while â-substituents are oriented out of the page.

(13) Elliott, R. L.; Takle, A. K.; Tyler, J . W.; White, J . J . Org. Chem.

1993, 58, 6954. Elliott, R. L.; Nicholson, N. H.; Peaker, F. E.; Takle,

A. K.; Tyler, J . W.; White, J . J . Org. Chem. 1994, 59, 1606. Burton,

G.; Elliott, R. L. (SmithKline Beecham plc) PCT Pat. Appl. WO

9318044, 16 Sept 1993; Chem. Abstr. 1994, 121, 57222. Burton, G.;

Bateson, J . H.; Elliott, R. L.; Fell, S. C. M. (SmithKline Beecham plc)

PCT Pat. Appl. WO 9400457, 6 J an 1994; Chem. Abstr. 1994, 120,

191424. Elliott, R. L.; Nicholson, N. H.; Takle, A. K. (SmithKline

Beecham plc) PCT Pat. Appl. WO 9421633, 29 Sept 1994; Chem. Abstr.

1995, 122, 31202. For other examples of polycyclic â-lactams, see: Niu

C.; Pettersson T.; Miller M. J . J . Org. Chem. 1996, 61, 1014 and

references therein.

(9) Sawyer, J . S.; Kucerovy, A.; Macdonald, T. L.; McGarvey, G. J .

J . Am. Chem. Soc. 1988, 110, 842.

(10) Bateson, J . H.; Burton, G.; Elsmere, S. A.; Elliott, R. L. Synlett

1994, 152.

5000 J . Org. Chem., Vol. 62, No. 15, 1997

Elliott et al.

cycloaddition reaction occurred faster with trans-2-butene

than with the cis isomer (k_rel) 25:1). A competition

reaction with cis-2-pentene (containing 0.9% trans) and

trans-2-pentene also showed a k_relof 22.7:1 (trans:cis) by

integration of the NMR signals in the crude product. This

strongly suggested a rate enhancement for the trans

isomer over the cis. 5-Membered monocyclic olefins gave

two isomeric products, with the fourth ring in the R- and

â-orientations (Scheme 5 and entry 10), while the 6-mem-

bered monocyclic olefins gave products with the fourth

ring exclusively on the R-face (entries 11 and 18). Benzo-

fused 5-membered cyclic dienes also gave exclusive

products with the benzo-fused rings on the R-face and

the nonaromatic atom attached to position 4 (entries 19,

20, 21, and 22).

The novel polycyclic ring structures of these cepha-

1

losporin derivatives made unambiguous H NMR assign-

F igu r e 1. Observed NOEs.

ment difficult. Therefore extensive ¹H and ¹³C NMR

studies were undertaken on several key compounds in

order to fully elucidate their structures and define the

stereochemistry. The 4-membered rings formed in this

cycloaddition reaction were found to exhibit characteristic

cross-ring ⁴J _H,Hcouplings. In order to distinguish the cis

and trans couplings, NOE difference experiments were

performed (Figure 1).

In 26 strong NOEs were observed from H-6 to H-8 and

to H-4R and also from Me-5R to H-6 and to H-4R. Since

H-8 is known to be on the R-face of the molecule, H-6,

H-4R, and Me-5R must also be R-oriented. This was

supported by the large NOE from Me-5â to H-4â alone,

be performed in CH₂Cl₂and in the absence of any

transition metal catalyst without affecting product yield

or ratio (Scheme 5). The products 15 and 16 were most

conveniently separated by silica gel chromatography after

oxidation to the sulfoxides 17 and 18. Reduction back

to the respective sulfides was achieved with PCl₃in DMF.

The reaction of the triflates 4 with olefins in the

presence of a base to give fused cyclobutane products has

proved to be extremely general (Table 1). In many cases

the cyclobutane was obtained as a single isomer. The

yields and purities of the products were often improved

by the use of a large excess of the olefin.

which therefore confirmed both to be â-oriented. The

The most facile cycloadditions in terms of highest yields

and utilizing only 1-5 equiv of olefin occurred with the

electron rich olefins (entries 12, 13, 14, 15, and 18) and

styrene (entry 4). In general the monosubstituted olefins

with conjugated π-systems gave mixtures of isomers with

the substituents in the 5R- and 5â-positions (entries 4,

16, and 17) whereas the monosubstituted olefins with no

extended π-system gave single isomers with the substitu-

ent in the 5â-position (entries 2, 12, 13, 15, 23, 24, and

30). 1,1-Disubstituted olefins also gave products with the

substituents in the 5-position together with 3-substituted

ceph-2-ems (entries 5 and 6). 1,1-Diphenylethylene,

however, gave two isomeric products (entry 31) which

have the 6-H in the R- (60) and â-positions (61). The two

isomers were readily identified in the mixture by ¹H

NMR. Particularly diagnostic was H-8 which appeared

at 3.82 ppm in 61 and at 5.02 ppm in 60. In an attempt

to effect separation of the isomers, the mixture was

oxidized with m-CPBA. This resulted in the isolation of

only one product, the 6R-H isomer; the yield indicated

that the 6â-H isomer must have isomerized to the 6R-H

under the reaction conditions. Subsequent reduction

gave the pure 6R-H isomer (60). Symmetrical trans-

disubstituted olefins gave single products with the sub-

stituents at the 4R- and 5â-positions (entries 7 and 9);

in unsymmetrical trans-olefins the electron rich substitu-

ent was found at the 5â-position in the product (entry

25). trans-2-Pentene gave two products with the sub-

stituents still occupying the 4R- and 5â-positions (entry

29). Acyclic cis-olefins gave predominantly the product

with the substituents on the R-face (entries 8, 26, and

28). The products from cis-2-butene (entry 8) contained

34% of 29, the exclusive product from trans-2-butene

(entry 7). GC analysis of the cis-2-butene used showed

the presence of 2.1% of the trans isomer. Thus 29 could

be accounted for in two ways. Either a C-4-C-5 bond

rotation occurred in some reaction intermediate or the

4

cross-ring coupling constants were measured to be J _4R,6

-

4

(cis) ) 1.3 Hz and J _4â,6(trans) ) 2.7 Hz. In 29 there were

strong NOEs from H-6 to H-8, H-5R, and Me-4R and also

3

from H-4â to Me-5â. The coupling constants were J _5R,6

4

) 9.5 Hz, ³J _4â,5R) 2.9 Hz, and J _4â,6) 3.2 Hz. The NMR

assignment of the stereochemistry of the products from

olefins was confirmed by single-crystal X-ray diffraction

analysis of the 5â-SPh derivative 62¹⁴(Figure 2).

In one isomer (15) of the dihydrofuran reaction (Scheme

5) there is a large NOE between H-9 and H-11, confirm-

ing the R-orientation of H-9. Unfortunately, the proxim-

ity of the resonances H-9 (4.12 ppm), H-4 (4.15 ppm), and

H-6R (4.18 ppm) prevented determination of the tetrahy-

drofuran ring stereochemistry from the NOE data.

However H-9 exhibited a 3.1 Hz coupling to both H-4 and

H-8, indicating that both were trans to H-9, and thus the

tetrahydrofuryl ring was R-oriented. In the correspond-

ing sulfoxide (17) an additional NOE was observed

between H-9 (3.69 ppm) and H-6R (3.96 ppm) confirming

the R-orientation of the tetrahydrofuryl ring. In the

second isomer (16) strong NOEs were observed between

H-9 and H-11 confirming the R-orientation of H-9. The

coupling constant between H-8 and H-9 was 6.5 Hz, and

that between H-9 and H-4 was small (<0.5 Hz). These

values are indicative of a cis relationship between H-4,

H-8, and H-9. There was reduced spectral crowding in

the corresponding sulfoxide (18), and a weak NOE was

observed between H-4 and H-9; but no NOE was observed

between H-6 and H-9. These results indicated that the

tetrahydrofuryl ring was oriented to the â-face.

A study of the effect of solvents and bases on the

reaction of triflate 4b with 2,3-dihydrofuran was under-

(14) The author has deposited atomic coordinates for 62 and 86 with

the Cambridge Crystallographic Data Centre. The coordinates can be

obtained, on request, from the Director, Cambridge Crystallographic

Data Centre, 12 Union Road, Cambridge, CB2 1EZ, U.K.

Cycloadditions of Cephalosporins

J . Org. Chem., Vol. 62, No. 15, 1997 5001

Ta ble 1. Rea ction of Tr ifla tes 4b or 4c w ith Olefin s^a

5002 J . Org. Chem., Vol. 62, No. 15, 1997

Elliott et al.

Ta ble 1 (Con tin u ed )

Cycloadditions of Cephalosporins

J . Org. Chem., Vol. 62, No. 15, 1997 5003

Ta ble 1 (Con tin u ed )

a

i

b

Reaction conditions: triflate 4b or 4c (1 equiv), olefin, Pr₂NEt (1 equiv), CH₂Cl₂, 15 min. Ethylene passed into EtOAc solution of

4b. ^cThe benzamide derivative was used to simplify the NMR spectrum of the products. Gas condensed into solution at -30 °C.

d

Ta ble 2. Effect of Ba ses on th e Rea ction of Tr ifla te 4b

w ith 2,3-Dih yd r ofu r a n ^a

base

time, h

yield,^b%

ⁱPr₂NEt

DBU

0.25

3

73

31

NEt₃

2,6-lutidine

K₂CO₃

0.5

24

18

36

58^c

92^c

d

a

Reaction carried out at room temperature, ratio 4b:2,3-

dihydrofuran:ⁱPr₂NEt ) 1:5:1. Isolated yield after workup and

b

chromatography. ^cVery little product observed by TLC after 0.5

d

h. 2 equiv of K₂CO₃used.

particularly advantageous for the reaction with ethylene,

when the gas was bubbled through a dilute solution of

i

the triflate (4b) in EtOAc during slow addition of Pr₂-

NEt. ⁱPr₂NEt was routinely used as the base of choice.

Bases with pK_avalues higher than that of ⁱPr₂NEt (e.g.,

DBU) or less hindered bases (e.g., NEt₃) gave lower

yields, Table 2, while bases with lower pK_avalues (e.g.,

2,6-lutidine) gave longer reaction times and also lower

yields. Bases with even lower pK_avalues failed to react,

allowing recovery of the triflate. The use of K₂CO₃gave

superior yields to those of ⁱPr₂NEt, but the reactions were

much slower. The isomer ratio of the products did not

alter significantly on changing the solvent or the base.

The existence of 6-membered cyclic allenes as inter-

mediates which undergo cycloaddition reactions is well

documented.¹⁵It is therefore proposed that the cepha-

losporin triflate eliminates triflic acid on treatment with

base to form the allene (63). This allene is then trapped

by olefins in a cycloaddition reaction. The polarized

nature of the allene in 63, having electron-donating

sulfur and the electron-withdrawing ester substituents,

F igu r e 2. ORTEP view of 62 (the 5â-SPh product from 4b

and phenyl vinyl sulfide).

i

taken. In the presence of 1 equiv of Pr₂NEt at room

temperature, acetone and CH₂Cl₂gave rapid reactions

in 61 and 73% yields, respectively, whereas DMF and

EtOH gave poorer yields (16 and 30%). Interestingly,

however, EtOAc and THF gave much slower reactions,

requiring ca. 1 h for complete disappearance of triflate

(TLC monitoring) in 56 and 71% yields, respectively.

Although CH₂Cl₂was routinely used as solvent the

(15) Harnos, S.; Tivakornpannarai, S.; Waali, E. E. Tetrahedron Lett.

1986, 27, 3701. Christl, M.; Braun, M. Chem. Ber. 1989, 122, 1939.

Christl, M.; Braun, M.; Mu¨ller, G. Angew. Chem., Int. Ed. Engl. 1992,

31, 473. Angus, R. O., J r.; Schmidt, M. W.; J ohnson, R. P. J . Am. Chem.

Soc. 1985, 107, 532. Bottini, A. T.; Hilton, L. L.; Plott, J . Tetrahedron

1975, 31, 1997. Su¨tbeyaz, Y.; Ceylan, M.; Sec¸en, H. J . Chem. Res.,

Synop. 1993, 293. J amart-Gre´goire, B.; Mercier-Girardot, S.; Ianelli,

S.; Nardelli, M.; Caube`re, P. Tetrahedron 1995, 51, 1973.

i

lifetime of the triflate in the presence of Pr₂NEt was

relatively short. The use of EtOAc as solvent was

5004 J . Org. Chem., Vol. 62, No. 15, 1997

Elliott et al.

Sch em e 6

presumably allows it to react with an electronically

diverse range of olefins. It is significant that there was

found to be a number of monosubstituted olefins that did

not successfully form cycloadducts. Examination of the

¹³C resonances of the terminal carbon of the olefins

revealed that the reactivity of the olefins fell into three

catagories: (a) δ_C< 120 ppm or (b) δ_C> 130 ppm where

successful reactions were achieved and the intermediate

region (c) δ_C120-130 ppm where no or very poor yields

of cycloadducts were observed (Table 3).

Ta ble 3. Olefin s Th a t Do Not F or m Cycloa d d u cts a n d

Th eir δ(¹³C) (dCH₂)

Vinylpyridines also failed to give any cycloadducts

despite falling in the predicted active region. However

in these cases it is assumed that the pyridine nitrogen

is preferentially reacting with the allene leading to

decomposition. When a competition reaction was per-

formed with a mixture of styrene and 4-vinylpyridine,

this also resulted in decomposition and no styrene

cycloadducts were observed.

F igu r e 3. Plot of log k_relvs σ.

A Hammett study was conducted for the reaction of

triflate 4b with substituted styrenes in the presence of

ⁱPr₂NEt (Scheme 6). A plot of relative rates (log k_rel) vs

Hammett’s σ-constants¹⁷gave a straight line with a

reaction constant (F) of -0.54 (Figure 3). This result

suggests that if the cycloaddition is the rate determining

step then there is little charge separation in the transi-

tion state.

Close inspection of the olefins used and their product

distributions (see Table 1) has enabled us to speculate

on the mechanism of this reaction leading to the proposal

that the reaction is essentially a concerted process. For

example, vinylcyclopropane (entry 3) gave a mixture of

isomers 21 and 22 whereas vinylcyclohexane (entry 30)

only gave one isomer (59). This result depicts the

π-character of the cyclopropane ring, thus giving both

isomers as observed when extended π-systems are present.

However this result effectively rules out a stepwise

biradical cycloaddition reaction (via intermediate 64) as

the cyclopropylcarbinyl radical has a very short lifetime

and would result in cyclopropane ring opening rather

than bond rotation followed by cyclobutane ring closure.¹⁶

Olefins with electron-donating or electron-withdrawing

substituents such as ethyl vinyl ether (entry 12) and

methyl acrylate (entry 17) both give rise to products

showing the same regiochemistry. Allyltrimethylsilane

(entry 23) forms a single isomeric product (50). These

results suggest that diionic intermediates are not in-

volved as different regiochemistries might be expected

for the electron-donating and -withdrawing olefins, and

with allyltrimethylsilane the silyl group would stabilize

a â-carbocation (65), allowing time for bond rotation to

occur before ring closure.

The most significant mechanistic result was that

obtained with cis-â-deuteriostyrene (68). Only two prod-

ucts (69 and 70) were obtained in which the deuterium

was cis to the phenyl group in both isomers as shown by

2

¹H, H, and ¹³C NMR spectroscopy. This indicates that

bond rotation does not occur in the reaction and that the

styrene is oriented in either of two directions as it

approaches the cephalosporin allene to account for the

two isomeric products (Scheme 7). This result contrasts

that obtained by Waali who showed that the reaction of

1,2-cyclohexadiene (72) with cis-â-deuteriostyrene (68) is

a stepwise diradical process in which bond rotation occurs

in the diradical intermediate as all four possible isomers

(73) are obtained¹⁵(Scheme 8). The Hammett F value

for the reaction of 72 with styrenes is +0.79.¹⁵

1,2-Dienes (e.g., 1,1-dimethylallene, Table 1, entry 27)

also undergo [2 + 2] reactions to form cyclobutanes.

However, this provided the only example observed so far

in which a cycloadduct was formed with the substituent

at the 4-position rather than the 5-position. The â-ori-

entation of H-6 in 55 was shown by an NOE to the amide

proton, while the UV spectrum (λ_max304 nm) and the

strong NOEs between H-6 and the H-5 protons rather

than the methyl groups confirmed the regiochemistry.

As allenes generally react at the central carbon, the

(16) Newcomb, M. Tetrahedron 1993, 49, 1151. Newcomb, M.; Glenn,

A. G. J . Am. Chem. Soc. 1989, 111, 275.

(17) Hansch, C.; Leo A.; Taft, R. W. Chem. Rev. 1991, 91, 165.

Cycloadditions of Cephalosporins

J . Org. Chem., Vol. 62, No. 15, 1997 5005

Sch em e 7

Sch em e 9

Sch em e 10

Sch em e 8

stituent at the C-5 position. Generally a single stereoi-

somer is formed; however, in some cases, especially when

extended π-systems are present, isomeric mixtures at C-6

are obtained (entries 1, 3, and 8). The structure and

stereochemistry of the products was again determined

by extensive NMR studies. Characteristically strong

NOEs were observed between H-6 and H-8 when the

former was on the R-face. Where two isomers were

formed the â-orientation of H-6 was shown by the

presence of an NOE between H-6 and the amide N-H.

The structures were once again confirmed by single-

crystal X-ray diffraction analysis of the p-bromobenzyl

ester 86 (Figure 4). As seen previously with ethylene, a

successful reaction with acetylene was achieved by bub-

bling the gas into a dilute solution of the triflate in EtOAc

i

during the slow addition of Pr₂NEt.

To further extend our investigations of the reaction of

the triflates 4 with unsaturated systems, we next turned

our attention to 1,3-dienes. With 1,3-butadiene an

unidentifiable mixture of products was obtained, but with

furan a product of [4 + 2] addition was formed (Scheme

9). Extensive NMR studies assigned the structure as 87,

the product of addition to the C-3-C-4 bond of the

cephalosporin. Unfortunately the stereochemistry of the

three new chiral centers could not be unambiguously

assigned by NMR and we were unable to grow crystals

suitable for X-ray studies. 1,3-Diphenylisobenzofuran

underwent a similar reaction to give 88. Cyclopentadiene

and 1,3-cyclohexadiene gave complex mixtures of prod-

ucts whose NMR spectra were consistent with the exist-

ence of both [2 + 2] and [4 + 2] cycloadducts; these

products were not characterized further.

Christl has also observed changes in regioselectivity

between [2 + 2] and [4 + 2] cycloadditions with 1-oxa-

2,3-cyclohexadiene (89).¹⁵While [2 + 2] cycloaddition

utilizes the 2,3-double bond to form the cyclobutane 90,

the [4 + 2] cycloaddition takes place at the less electron

rich 3,4-double bond to give 91 (Scheme 10). An analo-

gous change in regioselectivity is apparent with the

cephalosporin allene 63. These results enabled us to

propose that the minor products seen in the reaction with

1,1-disubstituted olefins (Table 1, entries 5 and 6) are

F igu r e 4. ORTEP view of 86 (the 6R-H product from 4b and

phenylacetylene as the p-bromobenzyl ester).

orientation of the ring formation probably supports a

concerted process occurring at the least sterically con-

gested double bond, since a radical or diion intermediate

would be expected to be stabilized by the dimethyl group.

The reaction of the triflate 4b with acetylenes has also

been investigated and shown to result in the formation

of fused cyclobutenes (Table 4). As with olefins, the

monosubstituted acetylenes gave products with the sub-

5006 J . Org. Chem., Vol. 62, No. 15, 1997

Ta ble 4. Rea ction of Tr ifla te 4b w ith Acetylen es^a

Elliott et al.

a,b

Reaction conditions as in Table 1.

Sch em e 11

Sch em e 12

the result of a 6-electron electrocyclic ene reaction on the

3,4-double bond of the allene (Scheme 11).

Having examined the generality of the unsaturated

component in this reaction, we then investigated modi-

fications at the cephalosporin nucleus. Peracid oxidation

of the triflate 4b gave rise to the 1â-sulfoxide 92.

As with the sulfide triflate 4b, the sulfoxide triflate

92 underwent cyclobutane formation with cis-â-deuteri-

ostyrene (68) with retention of relative stereochemistry

affording the isomeric cyclobutanes 93 and 94 (Scheme

12). However, with furan, although a [4 + 2] addition

product was again formed, the addition was now across

the 2,3-position of the cephalosporin nucleus to form 95.

Once again extensive NMR studies were required to

elucidate the structure of 95. A large NOE between the

C-7 and C-9 protons defined the C-9 stereochemistry,

and the orientation of the oxygen bridge was deduced

from the 4 Hz coupling observed between H-9 and

H-10. Molecular modeling studies predicted a dihe-

Cycloadditions of Cephalosporins

J . Org. Chem., Vol. 62, No. 15, 1997 5007

Ta ble 5. Rea ction of Tr ifla te 92 w ith F u r a n s a n d

P yr r oles^a

Sch em e 14

Sch em e 15

allene (63). In the case of the sulfide this is the 3,4

double bond, whereas in the sulfoxides the 2,3 double

bond is more electron deficient. Furthermore we propose

that the stereochemistry of the addition products is due

to the approach of the furan such that its oxygen atom

is on the opposite face of the allene to the sulf-

oxide oxygen, thus reducing the electrostatic repulsion

(Scheme 14).

a

Reaction conditions as in Table 1 (5 equiv diene used).

Sch em e 13

The carbacephalosporin triflate 103¹⁹was particularly

remarkable in its reaction with olefins (Scheme 15).

Under palladium-catalyzed, Heck type conditions, 103

reacted with 2,3-dihydrofuran in the presence of ⁱPr₂NEt

to give two diastereomers (104) as the result of a

conventional Heck reaction. However, in the presence

of the stronger base (DBU) and in the absence of a

palladium catalyst, 103 reacted with indene to give the

[2 + 2] cycloadduct 105. The products 106 and 107 were

obtained from the reaction of cis-â-deuteriostyrene (68)

and once again retained the relative stereochemistry of

the deuterium and the phenyl group, suggesting a

concerted cycloaddition onto a cyclic allene intermediate.

We believe that the requirement for a stronger base

reflects the relative acidities of the H-2 protons of the

carbacephem compared to that of the cephem nucleus.²⁰

dral angle of 46° between H-9 and H-10 for an R-oxygen

bridge and 91° for a â-oxygen bridge. This implies, from

the Karplus equation, that the coupling constant should

be approximately 4 Hz for an R-bridge and 0 Hz for a

â-bridge. A limited number of substituted furans also

underwent cycloaddition with 92 (Table 5). The cycload-

duct 98 was formed in 29% yield with N-Boc-pyrrole in

contrast to pyrrole or N-methylpyrrole which formed

products of direct displacement of the triflate.

The cephalosporin R-sulfoxide triflate 101 could be

prepared by N,N-dichlorourethane-mediated oxidation of

4b.¹⁸Triflate 101 also underwent reaction with furan

to yield the adduct 102 in 62% yield (Scheme 13). In this

case the newly formed chiral centers have the opposite

stereochemistry to that seen in 95.

Recently two other groups have postulated the inter-

mediacy of cephalosporin allenes to account for observed

products. Cainelli²¹described the formation of 3-chloro-

cephems from the 3-mesyloxy derivative in the presence

of a base. In this case the corresponding sulfoxide did

not undergo the reaction. Torii²²also proposed that the

We propose that the [4 + 2] cycloaddition occurs to the

more electron deficient double bond of the cephalosporin

(18) Ochiai, M.; Aki O.; Morimoto, A.; Okada, T. Tetrahedron Lett.

1972, 3241.

(19) Crowell, T. A.; Halliday, B. D.; McDonald J . H., III; Indelicato,

J . M.; Pasini, C. E.; Wu, E. C. Y. J . Med. Chem. 1989, 32, 2436. Evans,

D. A.; Sjogren, E. B. Tetrahedron Lett. 1985, 26, 3787. Bodurow, C.;

Carr, M. A. Tetrahedron Lett. 1989, 30, 4081.

(20) The rate difference between the chlorination of 3-hydroxycar-

bacephems and 3-hydroxycephems has been attributed to sulfur

neighboring group participation. Burks, J . E., J r.; Chelius, E. C.;

J ohnson, R. A. J . Org. Chem. 1994, 59, 5724.

(21) Cainelli, G.; Contento, M.; Panunzio, M.; Sandri, S.; Umani-

Ronchi, A.; Col, M. D. Synlett 1994, 243.

5008 J . Org. Chem., Vol. 62, No. 15, 1997

Elliott et al.

F igu r e 6. Schematic illustration of proposed approach of the

cephalsporin allene and styrene. Molecular orbitals shown as

calculated for the separate molecules.

bond. It could only react in a concerted manner with the

allene through a suprafacial-antarafacial type mecha-

nism. This would involve an antarafacial approach by

the olefin (Figure 6). The observed regioselectivity of the

cycloaddition is as explained with the larger orbital in

the HOMO interacting with the large LUMO orbital on

C-3 of the allene. The requirement for suprafacial-

antarafacial overlap between the reagent and the allene

also produces steric control at position 4 of the cyclobu-

tane product. Any substituent which was attached to the

reactive double-bond carbon with the greater HOMO

density will be attached to C-4 of the product and on the

R-face of the molecule.

F igu r e 5. LUMO of the cephalosporin derived allene using

PM3 (hydrogen atoms at C-7, R ) pMB). The positive lobe is

shown in dark grey and the negative lobe in light grey. The

molecular orbital surface is contoured at a value of 0.032 e/au.

copper(I) chloride mediated alkenylation of cephem tri-

flates with alkenyltributylstannes proceeds by the reac-

tion of a vinylcopper species with an allene to give

3-alkenyl-∆²-cephems.

Con clu sion

The formation of fused polycyclic cephalosporins from

the reaction of cephalosporin triflates with unsaturated

compounds and a base is a remarkable process. In this

paper we have described the results of our studies to

determine the scope and mechanism of this reaction.

These studies have suggested that the reaction proceeds

via the intermediacy of a 6-membered cyclic allene which

undergoes concerted 2_s+ 2_acycladditions with olefins

As previously stated 6-membered cyclic allenes have

been generated by a number of routes and trapped

through [2 + 2] and [4 + 2] cycloadducts. For 1,2-

cyclohexadiene the twisted allene structure (72) appears

to have the lowest energy. The [2 + 2] cycloadditions

onto 1,2-cyclohexadiene can all be rationalized by a

stepwise diradical mechanism.¹⁵However, we have

obtained products that would not be consistent with the

intermediacy of radicals or charged species. Our experi-

mental evidence suggests that the [2 + 2] cycloadducts

are obtained by a concerted _π2_s+ _π2_amechanism²³in

which the olefin approaches the cephalosporin allene in

an antarafacial manner.

In order to assess the relative stability of an allene

intermediate and attempt to rationalize the observed

chemoselectivity of selected reagents, we performed a

number of MO calculations.²⁴Model systems of putative

allenic, allynic, and dipolar intermediates were generated

and optimized using semiempirical MO methods. The

calculated geometries were consistent with an allene type

intermediate, with the cephem 2,3 and 3,4 bonds being

similar in length (1.311 and 1.326 Å). Of note was the

observation that the hydrogen at C-2 was oriented toward

the R-face, suggesting that olefin attack was more likely

from the â-face. Our results suggest that the reaction

occurs between the LUMO of the cephalosporin allene

63 (Figure 5) and the HOMO of the unsaturated compo-

nent. The HOMO of a simple dienophile, such as styrene,

is concentrated on the two carbons of the reactive double

π

and acetylenes and _π4_s+ 2_scycloadditions with cyclic

π

1,3-dienes. These extremely rapid reactions, which occur

under very mild conditions on readily available cepha-

losporin triflates, have produced numerous novel poly-

cyclic cephalosporins bearing a wide range of function-

ality. The potential utility of this reaction is enormous.

Indeed, a recent report has described the reaction of the

cephalosporin triflate with silyl enol ethers and si-

lylketene acetals. Subsequent fragmentation of the

cyclobutane ring resulted in the formation of a variety

of C3-substituted cephalosporins.²⁵Additional studies

from our laboratories have dealt with the introduction

of more biologically relevant amino substituents at the

cephalosporin C7 position. The results of these studies

will be reported at a later date.

Exp er im en ta l Section

Gen er a l Meth od s. The ¹H and ¹³C NMR spectra were

referenced to TMS and the ²H spectra referenced to CDCl₃

(7.28 ppm). Analytical TLC was performed on 0.25 mm silica

gel 60F plates. Purification of the products was carried out

using silica gel 60 (230-400 mesh) and the appropriate solvent

system. Cephalosporin triflates 4a -c were prepared by the

methodology described in ref 7. The carbacephem triflate was

prepared as described in ref 19.

(22) Tanaka, H.; Sumida, S.-i.; Torii, S. Tetrahedron Lett. 1996, 37,

5967.

(23) Woodward, R. B.; Hoffman, R. Angew. Chem., Int. Ed. Engl.

1969, 8, 781.

(24) SPARTAN Version 4.1, Wavefunction Inc., 18401 Von Karmen

Avenue, No. 370, Irvine, CA 92715, 1995.

(25) Kang, H-Y.; Lee, S. H.; Choi, K. I.; Koh, H. Y. Tetrahedron Lett.

1996, 37, 7549.

Cycloadditions of Cephalosporins

J . Org. Chem., Vol. 62, No. 15, 1997 5009

P r ep a r a tion of th e Cycloa d d u cts. Gen er a l P r oced u r e.

To a solution of triflate (4a -c) (1 equiv) and alkene or alkyne

(see Tables 1, 4, and 5) in CH₂Cl₂(30 mL per mmol) was added

ⁱPr₂NEt (1 equiv). After being stirred for 15 min, the mixture

was chromatographed to afford the cycloadducts.

55.3, 58.4, 61.1, 67.4, 70.8, 77.1, 114.0 (2C), 122.5, 127.1, 127.7,

129.1 (2C), 129.5 (2C), 130.6 (2C), 133.8, 140.7, 159.9, 160.1,

164.4, 171.3; mass spectrum m/z 506.1503, calcd for C₂₇H₂₆

-

N₂O₆S 506.1512.

P r ep a r a tion of 19. Ethylene was passed through

a

p -Met h oxyb en zyl

(4R,8R,9R,10S,11R,12R)-13-Oxo-

sintered glass bubbler into a solution of triflate 4b (0.50 g,

0.852 mmol) in EtOAc (500 mL) at room temperature while a

solution of ⁱPr₂NEt (0.15 mL, 0.852 mmol) in EtOAc (100 mL)

was added dropwise over 1.5 h. The mixture was stirred under

an ethylene atmosphere for a further 16 h and then concen-

trated. The residue was chromatographed to give p-methoxy-

benzyl (6S,8R,9R)-10-oxo-9-(phenylacetamido)-7-thia-1-aza-

tricyclo[6.2.0.0^3,6]dec-2-ene-2-carboxylate (19) (0.24 g, 60%): IR

(CH₂Cl₂) 1786, 1723, 1686 cm^-1; ¹H NMR (CDCl₃) δ 2.08 (dddd,

J ) 10.4, 9.4, 8.8, 8.2 Hz, 1H), 2.46 (dtd, J ) 10.4, 9.3, 3.2 Hz,

1H), 3.16 (dtd, J ) 15.8, 9.4, 1.6 Hz, 1H), 3.28 (ddt, J ) 15.8,

8.8, 3.0 Hz, 1H), 3.60 and 3.67 (ABq, J ) 16.1 Hz, 2H), 3.80

(s, 3H), 4.32 (dddd, J ) 9.3, 8.2, 2.8, 1.5 Hz, 1H), 4.94 (d, J )

5.0 Hz, 1H), 5.15 and 5.20 (ABq, J ) 11.9 Hz, 2H), 5.76 (dd, J

) 8.8, 5.0 Hz, 1H), 5.97 (d, J ) 8.8 Hz, 1H), 6.87 (d, J ) 8.7

Hz, 2H), 7.24-7.37 (m, 7H); mass spectrum m/z 464.1411,

calcd for C₂₅H₂₄N₂O₅S 464.1406.

12-(p h e n yla ce t a m id o)-7-oxa -10-t h ia -1-a za t e t r a cyclo-

[9.2.0.0^3,9.0^4,8]tr idec-2-en e-2-car boxylate 10-Oxide (17) an d

p-Meth oxyben zyl (4S,8S,9R,10S,11R,12R)-13-Oxo-12-(ph e-

n ylacetam ido)-7-oxa-10-th ia-1-azatetr acyclo[9.2.0.0.^3,9.0^4,8]-

tr id ec-2-en e-2-ca r boxyla te 10-Oxid e (18). A mixture of 15

and 16 was prepared from 4b and 2,3-dihydrofuran by the

general procedure in 73% yield (1.8:1): TLC R_f0.30 (15%

EtOAc in CH₂Cl₂). To a solution of the mixture of 15 and 16

(0.626 g, 1.236 mmol) in CH₂Cl₂(10 mL) at 0 °C was added a

solution of m-CPBA (1.236 mmol) in CH₂Cl₂(5 mL) dropwise

over 5 min. The reaction mixture was washed with dilute

NaHCO₃and water. The organic layer was dried (MgSO₄) and

evaporated to give the sulfoxides which were separated by

chromatography (50% EtOAc in CH₂Cl₂). (4R,8R) isom er

(17) (0.245 g, 39%): TLC R_f0.39 (50% EtOAc in CH₂Cl₂); mp

215 °C dec (EtOAc/CH₂Cl₂); IR (CH₂Cl₂) 1801, 1728, 1687 cm^-1

;

¹H NMR (CDCl₃) δ 2.05 (m, 2H), 3.61 and 3.65 (ABq, J ) 15.5

Hz, 2H), 3.69 (dt, J ) 1.9, 3.2 Hz, 1H), 3.80 (s, 3H), 3.96 (dt,

J ) 6.7, 9.6 Hz, 1H), 4.11 (m, 1H), 4.25 (ddd, J ) 9.6, 7.7, 3.1

Hz, 1H), 4.31 (dd, J ) 4.9, 1.9 Hz, 1H), 4.99 (dd, J ) 5.9, 3.2

Hz, 1H), 5.16 and 5.29 (ABq, J ) 11.9 Hz, 2H), 5.92 (dd, J )

9.7, 4.9 Hz, 1H), 6.60 (d, J ) 9.7 Hz 1H), 6.88 (d, J ) 8.7 Hz,

2H), 7.27-7.35 (m, 7H); ¹³C NMR (CDCl₃) δ 29.7, 43.5, 51.8,

55.3, 58.1, 61.5, 67.6, 69.2, 69.8, 74.9, 114.1 (2C), 124.0, 125.1,

127.1, 127.7, 129.2 (2C), 129.4 (2C), 130.5 (2C), 133.7, 159.7,

160.0, 163.7, 171.4. Anal. Calcd for C₂₇H₂₆N₂O₇S: C, 62.06;

H, 5.02; N, 5.36; S, 6.14. Found: C, 62.00; H, 5.00; N, 5.40; S,

6.28. (4S,8S) isom er (18) (0.165 g, 26%): TLC R_f0.32 (50%

Sp ectr a l Da ta for th e Cycloa d d u cts P r ep a r ed . The

General Procedure was followed unless indicated otherwise.

p-Meth oxyben zyl (5S,6S,8R,9R)-5-bu tyl-10-oxo-9-(p h e-

n yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]d ec-2-en e-2-

ca r boxyla te (20) (from 4b and 1-hexene): mp 160-161 °C;

IR (CH₂Cl₂) 1785, 1722, 1686 cm^-1; UV (EtOH) λ_max(ꢀ) 270

(11 200), 226 (17 900) nm; ¹H NMR (CDCl₃) δ 0.92 (t, J ) 7.2

Hz, 3H), 1.18-1.50 (m, 6H), 2.66 (dquintet, J ) 3.1, 8.4 Hz,

1H), 2.84 (dt, J ) 16.2, 3.1 Hz, 1H), 3.22 (dd, J ) 16.3, 9.2 Hz,

1H), 3.60 and 3.67 (ABq, J ) 16.1 Hz, 2H), 3.80 (s, 3H), 4.40

(dd, J ) 9.3, 1.8 Hz, 1H), 4.92 (d, J ) 4.9 Hz, 1H), 5.12 and

5.22 (ABq, J ) 11.9 Hz, 2H), 5.76 (dd, J ) 9.1, 4.9 Hz, 1H),

5.97 (d, J ) 9.1 Hz, 1H), 6.87 (d, J ) 8.6 Hz, 2H), 7.26-7.36

(m, 7H); ¹³C NMR (CDCl₃) δ 14.0, 22.6, 30.0, 30.6, 35.2, 36.4,

43.3, 44.0, 55.2, 58.2, 59.8, 66.9, 113.9 (2C), 120.9, 127.4, 127.6,

129.1 (2C), 129.5 (2C), 130.2 (2C), 133.7, 139.8, 159.7, 160.9,

164.0, 170.9. Anal. Calcd for C₂₉H₃₂N₂O₅S: C, 66.90; H, 6.20;

N, 5.38; S, 6.16. Found: C, 67.12; H, 5.78; N, 5.49; S, 5.74.

EtOAc in CH₂Cl₂); IR (CH₂Cl₂) 1800, 1729, 1688 cm^-^{1 1}H

;

NMR (CDCl₃) δ 1.81 (m, 1H), 2.61 (dd, J ) 12.8, 5.0 Hz, 1H),

3.57 and 3.61 (ABq, J ) 15.1 Hz, 2H), 3.66 (dd, J ) 6.5, 1.9

Hz, 1H), 3.80 (s, 3H), 4.02 (m, 1H), 4.09 (m, 1H), 4.13 (m, 1H),

4.38 (dd, J ) 4.8, 1.9 Hz, 1H), 5.15 (t, J ) 6.3 Hz, 1H), 5.23 (s,

2H), 5.89 (dd, J ) 9.8, 4.8 Hz, 1H), 6.78 (d, J ) 9.8 Hz, 1H),

6.89 (d, J ) 8.7 Hz, 2H), 7.27-7.34 (m, 7H); ¹³C NMR (CDCl₃)

δ 32.4, 43.4, 52.5, 55.4, 58.5, 60.0, 67.7, 70.7, 70.9, 79.5, 114.1

(2C), 123.3, 127.0, 127.5, 129.0 (2C), 129.3 (2C), 130.6 (2C),

133.7, 134.0, 159.3, 160.0, 164.1, 171.4; mass spectrum m/z

522.1472, calcd for C₂₇H₂₆N₂O₇S 522.1461.

p-Meth oxyben zyl (5S,6S,8R,9R)-5-Cyclop r op yl-10-oxo-

9-(p h en yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]d ec-2-

en e-2-ca r b oxyla t e (21) a n d p -Met h oxyb en zyl (5R,6S,-

8R,9R)-5-Cyclopr opyl-10-oxo-9-(ph en ylacetam ido)-7-th ia-

1-a za tr icyclo[6.2.0.0^3,6]d ec-2-en e-2-ca r boxyla te (22) (from

4b and vinylcyclopropane²⁶). The (5S) isomer 21 was eluted

first: IR (KBr) 1783, 1720, 1660, 1513 cm^-1; ¹H NMR (CDCl₃)

δ 0.13-0.22 (m, 2H), 0.48-0.59 (m, 2H), 0.92-1.02 (m, 1H),

1.99 (dq, J ) 8.9, 7.8 Hz, 1H), 2.80 (ddd, J ) 1.6, 9.0, 15.9 Hz,

1H), 3.35 (ddd, J ) 2.7, 8.0, 15.6 Hz, 1H), 3.61 and 3.68 (ABq,

J ) 16.4 Hz, 2H), 3.80 (s, 3H), 3.93 (ddd, J ) 1.4, 2.7, 8.0 Hz,

1H), 4.92 (d, J ) 4.9 Hz, 1H), 5.15 and 5.18 (ABq, J ) 12.0

Hz, 2H), 5.74 (dd, J ) 4.9, 8.8 Hz, 1H), 5.94 (d, J ) 8.9 Hz,

1H), 6.85-6.92 (m, 2H), 7.21-7.40 (m, 7H); mass spectrum

m/z 505 (MH⁺). (5R) isom er 22: IR (KBr) 1785, 1720, 1665,

p-Meth oxyben zyl (4R,8R,9R,11R,12R)-13-Oxo-12-(p h e-

n ylacetam ido)-7-oxa-10-th ia-1-azatetr acyclo[9.2.0.0^3,9.0^4,8]-

tr id ec-2-en e-2-ca r boxyla te (15). To a solution of sulfoxide

17 (0.22 g, 0.421 mmol) in DMF (6 mL) at -30 °C was added

PCl₃(74 µL, 0.85 mmol). The mixture was stirred at -30 °C

for 30 min and then added to a mixture of ice, water, and ethyl

acetate. The organic phase was washed with NaHCO₃, H₂O,

and brine, and then dried (MgSO₄) and evaporated. The

residue was chromatographed to give 15 (0.108 g, 50%): IR

1

(CH₂Cl₂) 1788, 1723, 1687 cm^-1; H NMR (CDCl₃) δ 1.96 (m,

1H), 2.08 (m, 1H), 3.59 and 3.64 (ABq, J ) 16.0 Hz, 2H), 3.79

(s, 3H), 3.99 (m, 1H), 4.12 (t, J ) 3.1 Hz, 1H), 4.15 (m, 1H),

4.18 (m, 1H), 4.56 (dd, J ) 5.8, 3.1 Hz, 1H), 4.90 (d, J ) 5.0

Hz, 1H), 5.12 and 5.25 (ABq, J ) 11.9 Hz, 2H), 5.75 (dd, J )

8.8, 5.0 Hz, 1H), 6.15 (d, J ) 8.8 Hz, 1H), 6.88 (d, J ) 8.7 Hz,

2H), 7.26-7.35 (m, 7H); ¹³C NMR (CDCl₃) δ 29.8, 43.3, 45.6,

50.4, 55.3, 58.1, 61.2, 67.3, 69.1, 79.1, 114.0 (2C), 122.7, 127.3,

127.8, 129.2 (2C), 129.5 (2C), 130.5 (2C), 133.8, 133.9, 159.9,

160.7, 164.3, 171.3; mass spectrum m/z 506.1513, calcd for

C₂₇H₂₆N₂O₆S 506.1512.

1

1514 cm^-1; H NMR (CDCl₃) δ 0.00-0.20 (m, 2H), 0.40-0.56

(m, 2H), 0.88-1.00 (m, 1H), 2.01 (dq, J ) 3.2, 9.3 Hz, 1H),

3.02 (dt, J ) 2.9, 16.2 Hz, 1H), 3.25 (ddd, J ) 1.2, 8.9, 16.4

Hz, 1H), 3.61 and 3.67 (ABq, J ) 16.1 Hz, 2H), 3.80 (s, 3H),

4.38 (ddd, J ) 1.2, 2.9, 9.2 Hz, 1H), 4.94 (d, J ) 4.9 Hz, 1H),

5.13 and 5.24 (ABq, J ) 12.0 Hz, 2H), 5.77 (dd, J ) 4.9, 9.0

Hz, 1H), 6.06 (d, J ) 9.0 Hz, 1H), 6.85-6.92 (m, 2H), 7.21-

7.40 (m, 7H); ¹³C NMR (CDCl₃) δ 3.9, 4.1, 12.5, 36.6, 40.7, 43.4,

45.2, 55.3, 58.3, 60.0, 67.0, 114.0 (2C), 120.8, 127.5, 127.7, 129.2

(2C), 129.5 (2C), 130.3 (2C), 133.8, 139.4, 159.8, 161.0, 164.2,

171.2. Anal. Calcd for C₂₈H₂₈N₂O₅S: C, 66.65; H, 5.59; N,

5.55. Found: C, 66.43; H, 5.62; N, 5.41.

p-Meth oxyben zyl (4S,8S,9R,11R,12R)-13-oxo-12-(p h e-

n ylacetam ido)-7-oxa-10-th ia-1-azatetr acyclo[9.2.0.0^3,9.0^4,8]-

tr id ec-2-en e-2-ca r boxyla te (16) (prepared from 18 by the

above procedure (48% yield)): IR (CH₂Cl₂) 1787, 1723, 1689

cm^-1; ¹H NMR (CDCl₃) δ 1.75 (m, 1H), 2.46 (dd, J ) 12.7, 4.6

Hz, 1H), 3.58 and 3.63 (ABq, J ) 15.9 Hz, 2H), 3.76 (m, 1H),

3.80 (s, 3H), 4.08 (m, 1H), 4.11 (m, 1H), 4.17 (d, 1H, J ) 6.5

Hz), 4.92 (dd, J ) 6.5, 5.2 Hz, 1H), 4.98 (d, J ) 5.0 Hz, 1H),

5.15 and 5.18 (ABq, J ) 11.9 Hz, 2H), 5.77 (dd, J ) 8.9, 5.0

Hz, 1H), 6.19 (d, J ) 8.9 Hz, 1H), 6.88 (d, J ) 8.7 Hz, 2H),

7.27-7.34 (m, 7H); ¹³C NMR (CDCl₃) δ 31.3, 43.2, 45.1, 51.3,

p-Meth oxyben zyl (5S,6S,8R,9R)-9-Ben za m id o-10-oxo-

5-p h en yl-7-t h ia -1-a za t r icyclo[6.2.0.0.^3,6]d ec-2-en e-2-ca r -

boxyla te (23) (from 4c and styrene). The (5S) isomer 23 was

eluted first: IR (CH₂Cl₂) 1787, 1724, 1677 cm^-^{1 1}H NMR

;

(CDCl₃) δ 3.33 (ddd, J ) 5.0, 9.2, 1.4 Hz, 1H), 3.56 (q, J ) 8.4

Hz, 1H), 3.80 (s + ddd, J ) 15.0, 8.0, 2.5 Hz, 4H), 4.41 (ddd J

(26) Tsunoda, T.; Hudlicky, T. Synlett 1990, 322.

5010 J . Org. Chem., Vol. 62, No. 15, 1997

Elliott et al.

) 7.9, 2.3, 1.4 Hz, 1H), 5.12 (d, J ) 4.9 Hz, 1H), 5.24 (ABq, J

) 11.9 Hz, 2H), 5.98 (dd, J ) 8.4, 4.9 Hz, 1H), 6.89 (d, J ) 8.6

Hz, 2H), 7.20-7.56 (m, 11H), 7.81 (d, J ) 7.0 Hz, 2H). Anal.

Calcd for C₃₀H₂₆N₂O₅S: C, 68.43; H, 4.98; N, 5.32; S, 6.09.

Found: C, 68.42; H, 4.98; N, 5.46; S, 6.12. The later-eluting

fractions contained the (5R) isomer 24 as a mixture comprising

27% 23. Da ta for 24: IR (CH₂Cl₂) 1786, 1724, 1676 cm^-1; ¹H

NMR (CDCl₃) δ 3.56 (dt, J ) 16.8, 3.3 Hz, 1H), 3.65 (dd, J )

16.9, 9.2 Hz, 1H), 3.80 (s, 3H), 4.01 (td, J ) 9.4, 4.0 Hz, 1H),

4.76 (ddd, J ) 9.8, 2.5, 1.2 Hz, 1H), 5.08 (J ) 5.0 Hz, 1H),

5.28 (ABq, J ) 12.0 Hz, 2H), 5.96 (dd, J ) 8.9, 5.0 Hz, 1H),

6.59 (d, J ) 8.7 Hz, 1H), 6.90 (d, J ) 8.5 Hz, 2H), 7.16-7.51

(m, 10H), 7.65 (d, J ) 8.5 Hz, 2H); mass spectrum m/z

526.1583, calcd for C₃₀H₂₆N₂O₅S 526.1562.

P r ep a r a tion of Cycloa d d u cts fr om cis-2-Bu ten e (from

4b and a mixture of cis-2-butene + 2.1% trans-2-butene by

the method described for the preparation of 26). An insepa-

rable mixture of 29, the (4R,5S) isomer 30, and the (4S,5R)

isomer 31 was obtained in 78% yield (ratio 34:8:58): ¹H NMR

(CDCl₃) (signals due to 31) δ 1.12 (d, J ) 7.5 Hz, 3H), 1.15 (d,

J ) 7.0 Hz, 3H), 2.47 (sextet, J ) 7.5 Hz, 1H), 3.97 (dd, J )

8.2, 3.0 Hz, 1H); signals due to 30, δ 0.93 (d, J ) 7.2 Hz), 2.67-

2.83 (m), 4.25 (d, J ) 9.2Hz).

p -Met h oxyb en zyl (4R,5R,6S,8R,9R)-4,5-d ip h en yl-10-

oxo-9-(p h en yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]-

d ec-2-en e-2-ca r boxyla te (32) (from 4b and trans-stilbene):

mp 167-168 °C; IR (CH₂Cl₂) 1788, 1724, 1687 cm^-1; UV

1

(EtOH) λ_max(ꢀ) 273 (12 400) nm; H NMR (CDCl₃) δ 3.50 and

3.60 (ABq, J ) 16.2 Hz, 2H), 3.76 (s, 3H), 3.89 (dd, J ) 9.9,

4.2 Hz, 1H), 4.83-4.89 (m, 2H), 5.03 (d, J ) 11.9 Hz and d, J

) 4.9Hz, 2H), 5.19 (d, J ) 11.8 Hz, 1H), 5.78-5.83 (m, 2H),

6.70 (d, J ) 8.7 Hz, 2H), 6.98-7.37 (m, 17H). Anal. Calcd

for C₃₇H₃₂N₂O₅S: C, 72.06; H, 5.23; N, 4.54; S, 5.20. Found:

C, 71.98; H, 5.18; N, 4.55; S, 4.87.

p -Met h oxyb en zyl (6S,8R,9R)-5,5-Dim et h yl-10-oxo-9-

(p h en yla cet a m id o)-7-t h ia -1-a za t r icyclo[6.2.0.0^3,6]d ec-2-

en e-2-ca r boxyla te (26). Isobutene (ca. 5 mL) was condensed

into a solution of triflate 4b (80 mg, 0.136 mmol) in CH₂Cl₂(8

mL) at -30 °C. ⁱPr₂NEt (24 µL, 0.136 mmol) was added and

the mixture allowed to warm to room temperature with

stirring over 30 min. The mixture was concentrated then

chromatographed. p-Methoxybenzyl (6R,7R)-3-(2-methyl-2-

propenyl)-7-(phenylacetamido)ceph-2-em-4-carboxylate (25) was

p-Meth oxyben zyl (4R,8S,9S,11R,12R)-13-Oxo-12-(p h e-

n ylacetam ido)-10-th ia-1-azatetr acyclo[9.2.0.0^3,9.0^4,8]tr idec-

2-en e-2-car boxylate (33) an d p-Meth oxyben zyl (4S,8R,9S,-

11R,12R)-13-Oxo-12-(p h e n yla ce t a m id o)-10-t h ia -1-a za -

t et r a cyclo[9.2.0.0^3,9.0^4,8]t r id ec-2-en e-2-ca r b oxyla t e (34)

(from 4b and cyclopentene). The earlier-eluting fractions

contained predominantly the (4R,8S) isomer 33: IR (CH₂Cl₂)

1785, 1719, 1685 cm^-1; ¹H NMR (CDCl₃) δ 1.35-1.48 (m, 1H),

1.50-1.69 (m, 4H), 2.25-2.29 (m, 1H), 3.13 (dtd, J ) 9.8, 6.8,

2.7 Hz, 1H), 3.60 and 3.66 (ABq, J ) 16.0 Hz, 2H), 3.79 (s,

3H), 3.86 (t, J ) 6.8Hz, 1H), 4.31 (d, J ) 9.8 Hz, 1H), 4.98 (d,

J ) 4.9 Hz, 1H), 5.12 and 5.19 (ABq, J ) 12.0 Hz, 2H), 5.74

(dd, J ) 9.0, 4.9 Hz, 1H), 6.00 (d, J ) 8.7Hz, 1H), 6.87 (d, J )

8.6 Hz, 2H), 7.25-7.37 (m, 7H); ¹³C NMR (CDCl₃) δ 26.8, 28.7,

31.9, 39.6, 42.6, 43.4, 50.5, 55.3, 58.3, 60.9, 67.1, 114.0 (2C),

121.1, 127.4, 127.7, 129.1 (2C), 129.5 (2C), 130.5 (2C), 133.8,

144.8, 159.8, 160.3, 164.1, 171.1; mass spectrum m/z 504.1729,

calcd for C₂₈H₂₈N₂O₅S 504.1719. The later-eluting fractions

contained predominantly the (4S,8R) isomer 34: IR (CH₂Cl₂)

1785, 1720, 1687cm^-1; ¹H NMR (CDCl₃) δ 1.56-1.94 (m, 6H),

2.85 (q, J ) 6.0 Hz, 1H), 3.59 and 3.06 (ABq, J ) 16.1 Hz,

2H), 3.77 (dd, J ) 5.0, 3.3 Hz, 1H), 3.79 (s, 3H), 3.86-3.91 (m,

1H), 4.88 (d, J ) 5.0 Hz, 1H), 5.11 and 5.23 (ABq, J ) 11.9

Hz, 2H), 5.74 (dd, J ) 8.8, 5.0 Hz, 1H), 6.06 (d, J ) 8.8 Hz,

1H), 6.86 (d, J ) 8.6 Hz, 2H), 7.25-7.35 (m, 7H); ¹³C NMR

(CDCl₃) δ 25.7, 30.7, 32.9, 43.4, 43.5, 43.7, 49.4, 55.3, 58.4,

61.4, 67.0, 114.0 (2C), 120.7, 127.5, 127.7, 129.2 (2C), 129.5

(2C), 130.5 (2C), 133.8, 140.7, 159.8, 160.9, 164.3, 171.2; mass

spectrum m/z 504.1719, calcd for C₂₈H₂₈N₂O₅S 504.1719.

eluted first (9 mg, 13%): IR (CH₂Cl₂) 1780, 1741, 1685 cm^-1

;

¹H NMR (CDCl₃) δ 1.57 (s, 3H), 2.69 and 2.87 (ABq, J ) 15.3

Hz, 2H), 3.60 and 3.67 (ABq, J ) 16.3 Hz, 2H), 3.82 (s, 3H),4.67

(s, 1H), 4.81 (s, 1H), 4.84 (s, 1H), 5.06 and 5.12 (ABq, J ) 11.8

Hz, 2H), 5.23 (d, J ) 4.0 Hz, 1H), 5.63 (dd, J ) 9.1, 4.0 Hz,

1H), 5.94 (s, 1H), 6.15 (d, J ) 9.1Hz, 1H), 6.89 (d, J ) 8.7 Hz,

2H), 7.23-7.37 (m, 7H); mass spectrum m/z 492 (M⁺). 26 (50

mg, 75%); IR (CH₂Cl₂) 1786, 1723, 1686 cm^-1; ¹H NMR (CDCl₃)

δ 1.04 (s, 3H), 1.33 (s, 3H), 2.85 (d, J ) 15.7 Hz, 1H), 2.97 (dd,

J ) 15.6, 2.5 Hz, 1H), 3.59 and 3.68 (ABq, J ) 16.1 Hz, 2H),

3.80 (s, 3H), 4.02 (dd, J ) 2.4, 1.2 Hz, 1H), 4.92 (d, J ) 4.9

Hz, 1H), 5.10 and 5.23 (ABq, J ) 12.0 Hz, 2H), 5.75 (dd, J )

8.9, 4.9 Hz, 1H), 6.04 (d, J ) 9.0 Hz, 1H), 6.87 (d, J ) 8.7 Hz,

2H), 7.19-7.36 (m, 7H); mass spectrum m/z 492.1715, calcd

for C₂₇H₂₈N₂O₅S 492.1719.

p-Meth oxyben zyl (6R,7R)-3-(1-Cycloh exen ylm eth yl)-7-

(p h en yla ceta m id o)cep h -2-em -4-ca r boxyla te (27) a n d p-

Meth oxyben zyl (6S,8R,9R)-10-Oxo-9-(p h en yla ceta m id o)-

7-t h ia -1-a za t r icyclo[6.2.0.0^3,6]d e c-2-e n e -5-sp ir ocyclo-

h exa n e-2-ca r boxyla te (28) (from 4b and methylenecyclo-

hexane). 27 was eluted first (21%): IR (CH₂Cl₂) 1778, 1740,

1684 cm^-^{1 1}H NMR (CDCl₃) δ 1.53-1.96 (m, 8H), 2.63 and

;

2.77 (ABq, J ) 15.1 Hz, 2H), 3.60 and 3.67 (ABq, J ) 16.2 Hz,

2H), 3.82 (s, 3H), 4.79 (s, 1H), 5.07 and 5.12 (ABq, J ) 11.8Hz,

2H), 5.21 (d, J ) 4.0 Hz, 1H), 5.39 (br s, 1H), 5.63 (dd, J )

9.1, 4.0 Hz, 1H), 5.88 (s, 1H), 6.14 (d, J ) 9.1 Hz, 1H), 6.89 (d,

J

) 8.7 Hz, 2H), 7.23-7.37 (m, 7H); mass spectrum m/z

p-Meth oxyben zyl (4S,9R,10S,12R,13R)-14-oxo-13-(p h e-

n yla cet a m id o)-11-t h ia -1-a za t et r a cyclo[10.2.0.0^3,10.0^4,9]-

t et r a d ec-2-en e-2-ca r b oxyla t e (35) (from 4b and cyclo-

532.2037, calcd for C₃₀H₃₂N₂O₅S 532.2032. 28 (47%); IR (CH₂-

Cl₂) 1785, 1721, 1688 cm^-1; ¹H NMR (CDCl₃) δ 1.42-1.65 (m,

10H), 2.74 (br d, J ) 16.3 Hz, 1H), 3.00 (dd, J ) 15.9, 2.8 Hz,

1H), 3.59 and 3.68 (ABq, J ) 16.1 Hz, 2H), 3.80 (s, 3H), 3.95

(dd, J ) 2.7, 1.0 Hz, 1H), 4.90 (d, J ) 4.9 Hz, 1H), 5.11 and

5.23 (ABq, J ) 12.0 Hz, 2H), 5.74 (dd, J ) 9.0, 4.9 Hz, 1H),

6.02 (d, J ) 8.9 Hz, 1H), 6.87 (d, J ) 8.7 Hz, 2H), 7.19-7.37

(m, 7H); mass spectrum m/z 532.2042, calcd for C₃₀H₃₂N₂O₅S

532.2032.

hexene): mp 234-236 °C; IR (CH₂Cl₂) 1784, 1718, 1685 cm^-1

;

¹H NMR (CDCl₃) δ 0.97-1.08 (m, 1H), 1.30-1.74 (m, 6H),

1.93-2.00 (m, 1H), 2.39 (br q, J ) 8.2 Hz, 1H), 3.47 (tdd, J )

9.3, 8.4, 2.6 Hz, 1H), 3.60 and 3.66 (ABq, J ) 16.3 Hz, 2H),

3.80 (s, 3H), 4.26 (dd, J ) 8.7, 2.6 Hz, 1H), 4.90 (d, J ) 4.9

Hz, 1H), 5.11 and 5.23 (ABq, J ) 11.9 Hz, 2H), 5.75 (dd, J )

8.9, 4.9 Hz, 1H), 5.98 (d, J ) 8.8 Hz, 1H), 6.86 (d, J ) 8.7 Hz,

2H), 7.25-7.37 (m, 7H); mass spectrum m/z 518.1882, calcd

for C₂₉H₃₀N₂O₅S 518.1875.

p -Met h oxyb en zyl (4S,5S,6S,8R,9R)-4,5-d im et h yl-10-

oxo-9-(p h en yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]-

d ec-2-en e-2-ca r boxyla te (29) (from 4b and trans-2-butene

by the method described for the preparation of 26): mp 172-

p-Meth oxyben zyl (5S,6R,8R,9R)-5-eth oxy-10-oxo-9-(ph e-

n yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]d ec-2-en e-2-

ca r boxyla te (36) (from 4b and ethyl vinyl ether): mp 181-

183 °C; IR (CH₂Cl₂) 1787, 1724, 1685 cm^-1; UV (EtOH) λ_max

1

173 °C; IR (CH₂Cl₂) 1786, 1721, 1687 cm^-1; H NMR (CDCl₃)

δ 1.03 (d, J ) 7.1 Hz, 3H), 1.25 (d, J ) 7.3 Hz, 3H), 2.41 (ddq,

J ) 9.5, 7.1, 3.0 Hz, 1H), 3.04 (ddq, J ) 7.3, 3.2, 3.0 Hz, 1H),

3.63 (ABq, J ) 16.0 Hz, 2H), 3.79 (s, 3H), 4.47 (dd, J ) 9.5,

3.2 Hz, 1H), 4.90 (d, J ) 4.9 Hz, 1H), 5.08 (d, J ) 11.9 Hz,

1H), 5.26 (d, J ) 11.9 Hz, 1H), 5.76 (dd, J ) 9.0, 4.9 Hz, 1H),

6.07 (d, J ) 9.0 Hz, 1H), 6.87 (d, J ) 8.7 Hz, 2H), 7.30 (m,

7H); ¹³C NMR (CDCl₃) δ 15.9, 17.9, 37.2, 43.1, 43.4, 47.0, 55.3,

58.3, 59.8, 67.0, 114.0 (2C), 121.7, 127.4, 127.7, 129.1 (2C),

129.5 (2C), 130.5 (2C), 133.8, 142.9, 159.8, 160.8, 164.2, 171.2.

Anal. Calcd for C₂₇H₂₈N₂O₅S: C, 65.84; H, 5.73; N, 5.68; S,

6.51. Found: C, 65.56; H, 5.49; N, 5.60; S, 6.22.

1

(ꢀ) 225 (17 600), 270 (10 700) nm; H NMR (CDCl₃) δ 1.20 (t,

J ) 7.0 Hz, 3H), 3.17 (dt, J ) 17.3, 2.3 Hz, 1H), 3.34 (dd, J )

17.3, 6.5 Hz, 1H), 3.39-3.48 (m, 2H), 3.60 and 3.66 (ABq, J )

16.0 Hz, 2H), 3.79 (s, 3H), 4.30 (dd, J ) 6.6, 2.7 Hz, 1H), 4.40

(td, J ) 6.6, 2.0 Hz, 1H), 4.94 (d, J ) 5.0 Hz, 1H), 5.12 and

5.21 (ABq, J ) 12.0 Hz, 2H), 5.76 (dd, J ) 8.9, 4.9 Hz, 1H),

6.08 (d, J ) 8.9 Hz, 1H), 6.86 (d, J ) 8.7 Hz, 2H), 7.26-7.35

(m, 7H); ¹³C NMR (CDCl₃) δ 15.2, 38.7, 43.5, 45.7, 55.4, 58.5,

60.5, 66.1, 67.2, 73.7, 114.2 (2C), 121.6, 127.6, 127.8, 129.3 (2C),

129.7 (2C), 130.5 (2C), 133.9, 137.5, 159.9, 160.9, 163.7, 171.4.

Cycloadditions of Cephalosporins

J . Org. Chem., Vol. 62, No. 15, 1997 5011

Anal. Calcd for C₂₇H₂₈N₂O₆S: C, 63.76; H, 5.55; N, 5.51; 6.30.

Found: C, 63.62; H, 5.31; N, 5.53; S, 6.30.

structure was solved by direct methods and refined with

anisotropic displacement parameters for non-hydrogen atoms.

The hydrogen atoms were included in idealized positions riding

on the atom to which they are attached with isotropic displace-

ment factors assigned as a constant (1.2) times U_eqof the

attached atom. The full-matrix least-squares refinement (on

p -Met h oxyb en zyl (5S,6R,8R,9R)-5-a cet oxy-10-oxo-9-

(p h en yla cet a m id o)-7-t h ia -1-a za t r icyclo[6.2.0.0^3,6]d ec-2-

en e-2-ca r boxyla te (37) (from 4b and vinyl acetate): mp 171-

172 °C; IR (CH₂Cl₂) 1789, 1741, 1684 cm^-1; UV (EtOH) λ_max

F

²) of 361 parameters converged (∆/σ_max) 0.00) to values of

1

(ꢀ) 267 (10 700), 225 (17 500) nm; H NMR (CDCl₃) δ 2.05 (s,

the conventional crystallographic residuals R ) 0.060 for 4117

observed data [I > 2σ(I)] and R ) 0.065 (wR2 ) 0.182) for all

4325 data.¹⁴

3H), 3.26 (ddd, J ) 17.4, 2.6, 1.7 Hz, 1H), 3.49 (dd, J ) 17.4,

6.5 Hz, 1H), 3.60 and 3.67 (ABq, J ) 16.3 Hz, 2H), 3.79 (s,

3H), 4.50 (dd, J ) 6.6, 2.6 Hz, 1H), 4.93 (d, J ) 5.0, 1H), 5.13

and 5.23 (ABq, J ) 11.9 Hz, 2H), 5.29 (td, J ) 6.6, 1.7 Hz,

1H), 5.79 (dd, J ) 9.1, 5.0 Hz, 1H), 5.96 (d, J ) 9.1 Hz, 1H),

6.87 (d, J ) 8.7 Hz, 2H), 7.24-7.37 (m, 7H); ¹³C NMR (CDCl₃)

δ 20.7, 38.0, 43.4, 45.3, 55.3, 58.3, 59.8, 67.3, 69.1, 114.0 (2C),

121.8, 127.3, 127.7, 129.2 (2C), 129.7 (2C), 130.4 (2C), 133.7,

135.2, 159.9, 160.6, 164.0, 170.8, 171.1. Anal. Calcd for

C₂₇H₂₆N₂O₇S: C, 62.06; H, 5.01; N, 5.36. Found: C, 61.99; H,

4.72; N, 5.35.

p-Meth oxyben zyl (5R,6R,8R,9R)-9-Ben za m id o-10-oxo-

5-(p h en ylth io)-7-th ia -1-a za tr icyclo[6.2.0.0.^3,6]d ec-2-en e-2-

ca r boxyla te (38) a n d p-Meth oxyben zyl (5S,6R,8R,9R)-9-

B e n z a m i d o -10-o x o -5-(p h e n y lt h i o )-7-t h i a -1-a z a t r i -

cyclo[6.2.0.0^3,6]d ec-2-en e-2-ca r boxyla te (39) (from 4c and

phenyl vinyl sulfide). The (5R) isomer 38 was eluted first: IR

(CH₂Cl₂) 1788, 1725, 1677 cm^-1; ¹H NMR (CDCl₃) δ 3.07-3.19

(m, 1H), 3.62-3.76 (m, 2H), 3.81 (s, 3H), 4.26-4.30 (m, 1H),

5.05 (d, J ) 4.9 Hz, 1H), 5.21 (s, 2H), 5.95 (dd, J ) 8.4, 4.9

Hz, 1H), 6.70 (d, J ) 8.4 Hz, 1H), 6.90 (d, J ) 8.7 Hz, 2H),

7.10-7.59 (m, 10H), 7.78 (d, J ) 7.0 Hz, 2H); ¹³C NMR (CDCl₃)

δ 39.4, 43.6, 48.9, 55.3, 58.9, 60.5, 67.3, 114.1 (2C), 120.4, 127.3

(3C), 128.2, 128.8 (2C), 129.4 (2C), 130.5 (2C), 132.4, 132.6 (2C),

132.8, 132.9, 133.1, 159.9, 160.8, 164.3, 167.4; mass spectrum

m/z 558.1281, calcd for C₃₀H₂₆N₂O₅S₂558.1283. (5S) isom er

39: IR (CH₂Cl₂) 1788, 1725, 1677 cm^-1; ¹H NMR (CDCl₃) δ 3.31

(dt, J ) 16.9, 3.0 Hz, 1H), 3.72 (ddd, J ) 16.9, 8.4, 1.2 Hz,

1H), 3.81 (s, 3H), 4.30 (td, J ) 8.4, 3.0 Hz, 1H), 4.86 (ddd, J )

8.4, 3.0, 1.2 Hz, 1H), 5.11 (d, J ) 5.0 Hz, 1H), 5.18 and 5.28

(ABq, J ) 12.0 Hz, 2H), 6.00 (dd, J ) 8.6, 5.0 Hz, 1H), 6.77 (d,

J ) 8.6 Hz, 1H), 6.88 (d, J ) 8.7 Hz, 2H), 7.16-7.58 (m, 10H),

7.77 (d, J ) 7.0 Hz, 2H); ¹³C NMR (CDCl₃) δ 39.0, 42.3, 46.3,

55.3, 58.9, 60.6, 67.2, 114.0 (2C), 122.2, 126.9, 127.3, 127.4 (2C),

128.7 (2C), 129.2 (2C), 129.4 (2C), 130.3 (2C), 132.3, 132.9,

134.9, 136.0, 159.8, 160.8, 163.8, 167.5; mass spectrum m/z

558.1293, calcd for C₃₀H₂₆N₂O₅S₂558.1283

p-Meth oxyben zyl (5S,6R,8R,9R)-10-Oxo-9-(p h en yla c-

etam ido)-5-(ph en ylth io)-7-th ia-1-azatr icyclo[6.2.0.0^3,6]dec-

2-en e-2-ca r boxyla te (62) (from 4b and phenyl vinyl sulfide)

(84%, 35:65 ratio). The later-eluting (5S) isomer 62 was

partially separated from the (5R) isomer by chromatography.

Crystallization from ethyl acetate and hexane gave crystals

of 62 suitable for X-ray diffraction analysis: mp 174-177 °C;

¹H NMR (CDCl₃) δ 3.23 (dt, J ) 17.0, 3.0 Hz, 1H), 3.51-3.72

(m, 3H), 3.80 (s, 3H), 4.26 (td, J ) 8.3, 3.0 Hz, 1H), 4.76 (dd,

J ) 8.3, 2.2 Hz, 1H), 4.90 (d, J ) 5.0 Hz, 1H), 5.13 and 5.23

(ABq, J ) 12.0 Hz, 2H), 5.76 (dd, J ) 8.9, 5.0 Hz, 1H), 6.06 (d,

J ) 8.9 Hz, 1H), 6.86 (d, J ) 8.7 Hz, 2H), 7.19-7.37 (m, 12H).

Anal. Calcd for C₃₁H₂₈N₂O₅S₂: C, 65.02; H, 4.93; N, 4.89; S,

11.20. Found: C, 65.67; H, 4.95; N, 5.16; S, 10.89.

X-r a y Str u ctu r e Deter m in a tion of 62. Light yellow

plates suitable for the collection of X-ray diffraction data were

obtained by recrystallization from a solution of 62 in ethyl

acetate and hexane. A crystal of dimensions 0.70 × 0.30 ×

0.02 mm was mounted on an Enraf Nonius CAD-4 diffracto-

meter and flash cooled in a stream of N₂gas to 223(2) K.

Intensity data were collected on the diffractometer using

graphite-monochromated Cu KR radiation and an ω-2θ vari-

able speed scan technique. Final cell constants, and other

information pertinent to data collection and refinement, were

as follows: space group, P2₁; unit cell dimensions, a ) 5.0900-

(10) Å, b ) 18.831(4) Å, c ) 14.422(3) Å, â ) 98.13(3)°, V )

1368.5(5) Å³; empirical formula, C₃₁H₂₈N₂O₅S₂; formula weight,

572.67 amu; Z ) 2; density (calc) ) 1.390 Mg m^-3; F(000) )

600; linear absorption coefficient µ(Cu K) ) 2.135 mm^-1; data

collection range 3.10 e θ e 62.47°, -5 e h e 1, -21 e k e 21,

-16 e l e 16; total number of reflections collected, 5084;

unique independent reflections, 4325 (R_int) 0.102). The

p-Meth oxyben zyl (5S,6R,8R,9R)-10-oxo-9-(p h en yla ce-

t a m id o )-5-(2-o x o p y r r o lid -1-y l)-7-t h ia -1-a za t r ic y c lo -

[6.2.0.0^3,6]d ec-2-en e-2-ca r b oxyla t e (40) (from 4b and

N-vinyl-2-pyrrolidone): IR (CH₂Cl₂) 1789, 1724, 1686 cm^-1; ¹H

NMR (CDCl₃) δ 1.80-1.98 (m, 2H), 2.34-2.39 (m, 2H), 3.31-

3.40 (m, 2H), 3.42 (dt, J ) 17.4, 2.8 Hz, 1H), 3.53 (dd, J )

17.2, 8.6 Hz, 1H), 3.61 and 3.68 (ABq, J ) 16.4 Hz, 2H), 3.80

(s, 3H), 4.52 (dd, J ) 8.0, 2.2 Hz, 1H), 4.98 (d, J ) 4.9 Hz,

1H), 5.07 (dt, J ) 8.4, 2.7 Hz, 1H), 5.15 and 5.22 (ABq, J )

12.0 Hz, 2H), 5.79-5.89 (m, 2H), 6.87 (d, J ) 8.5 Hz, 2H),

7.23-7.35 (m, 7H); mass spectrum m/z 547.1788, calcd for

C₂₉H₂₉N₃O₆S 547.1777.

p -Met h oxyb en zyl (5RS,6S,8R,9R)-5-Cya n o-10-oxo-9-

(p h en yla cet a m id o)-7-t h ia -1-a za t r icyclo[6.2.0.0^3,6]d ec-2-

en e-2-ca r boxyla tes (41 a n d 42) (from 4b and acrylonitrile).

An inseparable mixture of the (5S) (41) and (5R) (42) isomers

(ratio 1:2) was obtained: IR (KBr) 1787, 1724, 1674 cm^-1; ¹H

NMR (CDCl₃) δ 3.05-3.12 (m, 1H), 3.50-3.77 (m, 4H), 3.80

(s, 3H), 4.53-4.63 (m, 2H), 4.95 and 4.99 (2d, J ) 5.0 Hz, 1H),

5.16, 5.20 and 5.18 (ABq + s, J ) 12.0 Hz, 2H), 5.80 (2dd, J )

8.7, 5.0 Hz, 1H), 6.05 and 6.30 (2d, J ) 8.7 Hz, 1H), 6.88 (d, J

) 8.7 Hz, 2H), 7.24-7.41 (m, 7H); mass spectrum m/z 510

(MH⁺).

p-Meth oxyben zyl (5RS,6S,8R,9R)-5-(m eth oxycar bon yl)-

10-oxo-9-(ph en ylacetam ido)-7-th ia-1-azatr icyclo[6.2.0.0^3,6]-

d ec-2-en e-2-ca r boxyla tes (43 a n d 44) (from 4b and methyl

acrylate). An inseparable mixture of the (5S) (43) and (5R)

(44) isomers (ratio 2:3) was obtained: IR (CH₂Cl₂) 1786, 1728,

1686 cm^-1; ¹H NMR (CDCl₃) δ 3.10 (m, 0.4H), 3.33 (m, 0.6H),

3.67 (s, 1.8H), 3.70 (m, 4H), 3.75 (s, 1.2H), 3.79 (s, 3H), 4.58

(m, 1H), 4.94 (d, J ) 5.0 Hz, 0.6H), 4.97 (d, J ) 5.0 Hz, 0.4H),

5.17 (ABq, J ) 12.0 Hz, 0.8H), 5.19 (ABq, J ) 11.9 Hz, 1.2H),

5.77 (m, 1H), 6.06 (d, J ) 8.9 Hz, 1H), 6.87 (d, J ) 8.6 Hz,

2H), 7.22-7.39 (m, 7H); mass spectrum m/z 522.1482, calcd

for C₂₇H₂₆N₂O₇S 522.1461.

p-Meth oxyben zyl (4R,9R,10S,12R,13R)-14-oxo-13-(p h e-

nylacetamido)-8-oxa-11-thia-1-azatetracyclo[10.2.0.0^3,10.0^4,9]-

tetr a d ec-2-en e-2-ca r boxyla te (45) (from 4b and 3,4-dihy-

1

dro-2H-pyran): IR (CH₂

Cl₂) 1786, 1725, 1685 cm^-1; H NMR

(CDCl₃) δ 1.49-1.66 (m, 3H), 2.00-2.15 (m, 1H), 3.59 and 3.67

(ABq, J ) 16.0 Hz, 2H) and 3.60-3.74 (m, 3H), 3.80 (s, 3H),

4.10 (dd, J ) 7.3, 6.6 Hz, 1H), 4.67 (dd, J ) 6.6, 2.8 Hz, 1H),

4.94 (d, J ) 5.0 Hz, 1H), 5.10 and 5.24 (ABq, J ) 11.9 Hz,

2H), 5.76 (dd, J ) 9.0, 5.0 Hz, 1H), 6.09 (d, J ) 9.0 Hz, 1H),

6.88 (d, J ) 8.8 Hz, 2H), 7.24-7.39 (m, 7H); ¹³

C NMR (CDCl₃)

δ 22.1, 23.5, 42.7, 42.9, 43.4, 55.3, 57.8, 60.0, 62.9, 67.2, 70.0,

114.0 (2C), 122.1, 127.3, 127.8, 129.2 (2C), 129.5 (2C), 130.5

(2C), 133.7, 134.7, 159.9, 160.7, 164.3, 171.3; mass spectrum

m/z 520.1666, calcd for C₂₈H₂₈N₂O₆S 520.1668.

p -Met h oxyb en zyl

(4S,8S,9S,11R,12R)-13-oxo-12-

(p h en yla cet a m id o)-10-t h ia -1-a za -6,7-b en zot et r a cyclo-

[9.2.0.0^3,9.0^4,8]tr id eca 2,6-d ien e-2-ca r boxyla te (46) (from 4b

and indene): IR (KBr) 1781, 1730, 1650 cm^-^{1 1}H NMR

;

(DMSO-d₆) δ 3.18 (dd, J ) 17.6, 4.9 Hz, 1H), 3.30 (dd, J )

17.4, 10.3 Hz, 1H), 3.51 and 3.57 (ABq, J ) 14.0 Hz, 2H), 3.76

(s, 3H), 3.95 (dd, J ) 6.8, 5.7 Hz, 1H), 4.23-4.29 (m, 2H), 5.04

(d, J ) 5.0 Hz, 1H), 5.19 and 5.24 (ABq, J ) 11.9 Hz, 2H),

5.67 (dd, J ) 8.3, 5.0 Hz, 1H), 6.96 (d, J ) 8.6 Hz, 2H), 7.19-

7.33 (m, 9H), 7.40 (d, J ) 8.6 Hz, 2H), 9.08 (d, J ) 8.3 Hz,

1H); mass spectrum m/z 552.1730, calcd for C₃₂H₂₈N₂O₅S

552.1719.

p-Meth oxyben zyl (4S,8R,9S,11R,12R)-13-oxo-12-(p h e-

n yla cet a m id o)-5-oxa -10-t h ia -1-a za -6,7-ben zot et r a cyclo-

[9.2.0.0^3,9.0^4,8]tr id eca -2,6-d ien e-2-ca r boxyla te (47) (from 4b

1

and 2,3-benzofuran): IR (CH₂Cl₂) 1785, 1729, 1687 cm^-1; H

NMR (CDCl₃) δ 3.62 and 3.70 (ABq, J ) 16.3 Hz, 2H), 3.80 (s,

5012 J . Org. Chem., Vol. 62, No. 15, 1997

Elliott et al.

3H), 4.07 (dd, J ) 6.3, 4.7 Hz, 1H), 4.24 (dd, J ) 4.7, 1.7 Hz,

1H), 4.88 (d, J ) 5.0 Hz, 1H), 5.23 and 5.30 (ABq, J ) 11.9

Hz, 2H), 5.83 (dd, J ) 8.7, 5.0 Hz, 1H), 5.93 (d, J ) 8.9 Hz,

1H), 6.05 (dd, J ) 6.3, 1.7 Hz, 1H), 6.87-6.94 (m, 4H), 7.17-

7.39 (m, 9H); mass spectrum m/z 554 (M⁺).

the (4S)-methoxy-(5R)-phenyl compound 53 and the (5R)-

methoxy-(4R)-phenyl compound 54 was obtained (63%, 3.3:

1). 53 was obtained pure after recrystallization from EtOAc:

mp 191-196 °C; IR (KBr) 1789, 1714, 1656 cm^-1; UV (EtOH)

λ_max(ꢀ) 270 (13 000) nm; ¹H NMR (CDCl₃) δ 3.01 (s, 3H), 3.52

(dd, J ) 9.3, 6.0 Hz, 1H), 3.59 and 3.65 (ABq, J ) 16.2 Hz,

2H), 3.79 (s, 3H), 4.76 (dd, J ) 9.3, 1.7 Hz, 1H), 5.01 (d, J )

5.1 Hz, 1H), 5.12 (dd, J ) 8.9, 5.1 Hz, 1H), 5.20 and 5.26 (ABq,

J ) 11.8 Hz, 2H), 5.85 (dd, J ) 8.9, 5.1 Hz, 1H), 6.03 (d, J )

8.9 Hz, 1H), 6.87 (d, J ) 8.7 Hz, 2H), 7.23-7.37 (m, 12H); ¹³

NMR (CDCl₃) δ 43.3, 45.2, 49.8, 55.2, 57.5, 58.5, 60.1, 67.6,

82.2, 114.0 (2C), 123.3, 126.8, 127.4, 127.7, 128.0 (2C), 128.4

(2C), 129.2 (2C), 129.4 (2C), 130.7 (2C), 132.6, 133.5, 135.4,

160.0, 160.4, 164.7, 171.1. Anal. Calcd for C₃₂H₃₀N₂O₆S: C,

67.35; H, 5.30; N, 4.91; S, 5.62. Found: C, 67.35; H, 5.11; N,

5.00; S, 5.38.

p-Meth oxyben zyl (6S,8R,9R)-4-isop r op ylid en e-10-oxo-

9-(p h en yla cet a m id o)-7-t h ia -1-a za t r icyclo[6.2.0.0^3,6]d ec

2-en e-2-ca r boxyla te (55) (from 4b and 3,3-dimethylallene):

IR (CH₂Cl₂) 1778, 1717, 1684 cm^-1; UV (EtOH) λ_max(ꢀ) 304

(9100) nm; ¹H NMR (CDCl₃) δ 1.73 (s, 3H), 1.86 (t, J ) 1.8

Hz, 3H), 2.53 (ddqq, J ) 12.8, 5.2, 1.8, 1.4 Hz, 1H), 2.90 (ddqq,

J ) 12.8, 8.2, 1.8, 1.4 Hz, 1H), 3.52 (dd, J ) 8.2, 5.2 Hz, 1H),

3.65 (s, 2H), 3.79 (s, 3H), 5.07 (d, J ) 4.1 Hz, 1H), 5.16 (s,

2H), 5.37 (dd, J ) 8.2, 4.1 Hz, 1H), 6.47 (d, J ) 8.2 Hz, 1H),

6.87 (d, J ) 8.5 Hz, 2H), 7.25-7.35 (m, 7H); ¹³C NMR (CDCl₃)

δ 22.2, 23.6, 36.6, 36.8, 43.5, 55.3, 60.4, 62.4, 66.7, 114.0 (2C),

115.6, 127.5, 127.7, 128.4, 129.0 (2C), 129.7 (2C), 130.0 (2C),

134.3, 143.2, 156.7, 159.7, 161.6, 167.5, 171.2. Anal. Calcd

for C₂₈H₂₈N₂O₅S: C, 66.65; H, 5.59; N, 5.55; S, 6.35. Found

C, 66.37; H, 5.27; N, 5.39; S, 6.17.

p-Meth oxyben zyl (4S,5R,6S,8R,9R)-5-Eth yl-4-m eth yl-

10-oxo-9-(ph en ylacetam ido)-7-th ia-1-azatr icyclo[6.2.0.0^3,6]-

d ec-2-en e-2-ca r boxyla te (56b) (from 4b and cis-2-pentene

+ 0.9% trans-2-pentene). After chromatography a mixture of

the (4S)-ethyl-(5R)-methyl isomer 56a , 56b, the (4R)-ethyl-

(5S)-methyl isomer 57a , the (5S)-ethyl-(4R)-methyl isomer

57b, 58a , and 58b was obtained in 45% yield (ratio 46:41:3.6:

2.6:3.6:3.2). Crystallization from EtOAc gave 56b: ¹H NMR

(CDCl₃) δ 0.89 (t, J ) 7.3 Hz, 3H), 1.13 (d, J ) 7.5 Hz, 3H),

1.55 (quintet, J ) 7.3 Hz, 2H), 2.23 (quintet, J ) 8.1 Hz, 1H),

3.59 and 3.68 (ABq, J ) 16.1 Hz, 2H) and 3.65 (m, 1H), 3.80

(s, 3H), 3.94 (dd, J ) 8.3, 2.9 Hz, 1H), 4.89 (d, J ) 4.9 Hz,

1H), 5.11 and 5.25 (ABq, J ) 11.9 Hz, 2H), 5.75 (dd, J ) 8.8,

4.9 Hz, 1H), 5.98 (d, J ) 8.8 Hz, 1H), 6.87 (d, J ) 8.6 Hz, 2H),

7.25-7.36 (m, 7H). ¹H NMR signals assigned to 56a : δ 0.78

(t, J ) 7.4 Hz, 3H), 1.17 (d, J ) 7.0 Hz, 3H), 2.47 (sextet, J )

7.9 Hz, 1H). 57a : 4.28 (d, J ) 9.3 Hz). 57b: 4.20 (d, J ) 9.3

Hz).

p-Meth oxyben zyl (4S,8S,9S,11R,12R)-12-(p h en yla ceta -

m id o)-5,5,13-tr ioxo-5,10-d ith ia -1-a za -6,7-ben zotetr a cyclo-

[9.2.0.0^3,9.0^4,8]tr id eca 2,6-d ien e-2-ca r boxyla te (48) (from 4b

and thianaphthene 1,1-dioxide²⁷): mp 270 °C dec (CH₂Cl₂/

Et₂O); IR (CH₂Cl₂) 1798, 1734, 1690 cm^-1; UV (EtOH) λ_max(ꢀ)

278 (13 200) nm; ¹H NMR (DMSO-d₆) δ 3.51 and 3.56 (ABq, J

) 14.1 Hz, 2H), 3.76 (s, 3H), 4.39 (dd, J ) 5.6, 3.0 Hz, 1H),

4.65 (t, J ) 6.6 Hz, 1H), 5.14 (d, J ) 5.2 Hz, 1H), 5.25 and

5.31 (ABq, J ) 12.0 Hz, 2H), 5.38 (dd, J ) 7.5, 3.0 Hz, 1H),

5.77 (dd, J ) 8.2, 5.2 Hz, 1H), 6.93 (d, J ) 8.5 Hz, 2H), 7.22-

7.33 (m, 5H), 7.43 (d, J ) 8.5 Hz, 2H), 7.66 (t, J ) 7.5 Hz,

1H), 7.71 (d, J ) 7.6 Hz, 1H), 7.78 (t, J ) 7.5 Hz, 1H), 7.90 (d,

J ) 7.8 Hz, 1H), 9.14 (d, J ) 8.3 Hz, 1H). Anal. Calcd for

C₃₁H₂₆N₂O₇S₂: C, 61.78; H, 4.35; N, 4.65; S, 10.64. Found:

C, 61.84; H, 4.24; N, 4.69; S, 10.66.

C

p-Meth oxyben zyl (4S,8R,9S,11R,12R)-13-oxo-12-(p h e-

n yla ce t a m id o)-10-t h ia -1,5-d ia za -6,7-b e n zot e t r a cyclo-

[9.2.0.0^3,9.0^4,8]tr id eca 2,6-d ien e-2-ca r boxyla te (49) (from 4b

and 1-acetylindole): IR (KBr) 1777, 1713, 1669, 1650 cm^-1

;

¹H NMR (CDCl₃) δ 1.57 (s, 3H), 3.62 (d, J ) 16.3 Hz, 1H),

3.70 (d, J ) 16.3 Hz, 1H,), 3.81 (s, 3H), 3.98 (t, J ) 6.4 Hz,

1H), 4.32 (dd, J ) 6.4, 1.5 Hz), 4.88 (d, J ) 5.0 Hz, 1H), 5.18

(d, J ) 11.9 Hz, 1H), 5.33 (d, J ) 11.9 Hz, 1H), 5.82 (dd, J )

6.8, 1.6 Hz, 1H), 5.85 (dd, J ) 9.0, 5.0 Hz, 1H), 5.96 (d, J )

9.0 Hz, 1H), 6.89 (d, J ) 8.7 Hz, 2H), 7.05 (t, J ) 7.5 Hz, 1H),

7.18-7.42 (m, 10H); mass spectrum m/z (EI) 595 (M⁺).

p-Meth oxyben zyl (5R,6S,8R,9R)-10-oxo-9-(p h en yla ce-

ta m id o)-5-[(tr im eth ylsilyl)m eth yl]-7-th ia -1-a za tr icyclo-

[6.2.0.0^3,6]d ec-2-en e-2-ca r b oxyla t e (50) (from 4b and

1

allyltrimethylsilane): IR (CH₂Cl₂) 1786, 1719, 1685 cm^-1; H

NMR (CDCl₃) δ 0.00 (s, 9H), 0.61-0.72 (m, 2H), 2.78-2.86 (m,

2H), 3.28 (br dd, J ) 16.5, 9.5 Hz, 1H), 3.63 and 3.66 (ABq, J

) 16.0 Hz, 2H), 3.80 (s, 3H), 4.41 (ddd, J ) 9.0, 2.8, 1.2 Hz,

1H), 4.96 (d, J ) 4.9 Hz, 1H), 5.16 and 5.19 (ABq, J ) 12.6

Hz, 2H), 5.77 (dd, J ) 9.1, 4.9 Hz, 1H), 6.04 (d, J ) 9.1 Hz,

1H), 6.88 (d, J ) 8.7 Hz, 2H), 7.27-7.37 (m, 7H); mass

spectrum m/z 550.1950, calcd for C₂₉H₃₄N₂O₅SSi 550.1958.

p-Meth oxyben zyl (5R,6S,8R,9R)-5-(h yd r oxym eth yl)-10-

oxo-9-(p h en yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]-

d ec-2-en e-2-ca r boxyla te (51) (from 4b and allyl alcohol): IR

(CH₂Cl₂) 1787, 1722, 1687 cm^-1; ¹H NMR (CDCl₃) δ 2.83-2.95

(m, 1H), 2.96 (dt, J ) 16.8, 3.0 Hz, 1H), 3.22 (ddd, J ) 16.2,

8.9, 1.2 Hz, 1H), 3.58 and 3.65 (ABq, J ) 15.7 Hz, 2H), 3.65

(d, J ) 7.2 Hz, 2H), 3.79 (s, 3H), 4.41-4.45 (m, 1H), 4.92 (d, J

) 5.0 Hz, 1H), 5.11 and 5.23 (ABq, J ) 12.0 Hz, 2H), 5.76 (dd,

J ) 8.9, 5.0 Hz, 1H), 6.32 (d, J ) 8.9 Hz, 1H), 6.86 (d, J ) 8.6

Hz, 2H), 7.16-7.34 (m, 7H); mass spectrum m/z 494.1528,

calcd for C₂₆H₂₆N₂O₆S 494.1512.

p-Meth oxyben zyl (4S,5S,6S,8R,9R)-5-Eth yl-4-m eth yl-

10-oxo-9-(ph en ylacetam ido)-7-th ia-1-azatr icyclo[6.2.0.0^3,6]-

d ec-2-en e-2-ca r boxyla te (58b) (from 4b and trans-2-pen-

tene). After chromatography a mixture comprising the (4S)-

ethyl-(5S)-methyl isomer 58a and 58b (68%, 1.4:1 ratio) was

obtained. 58b was obtained pure after crystallization from

EtOAc/hexane: mp 158-159 °C; IR (CH₂Cl₂) 1786, 1719, 1685

cm^-1; ¹H NMR (CDCl₃) δ 0.86 (t, J ) 7.3 Hz, 3H), 1.25 (d, J )

7.3 Hz, 3H), 1.29-1.49 (m, 2H), 2.14-2.25 (m, 1H), 3.10 (qt, J

) 7.2, 3.3 Hz, 1H), 3.60 and 3.69 (ABq, J ) 16.1 Hz, 2H), 3.80

(s, 3H), 4.50 (dd, J ) 9.6, 3.3 Hz, 1H), 4.89 (d, J ) 4.9 Hz,

1H), 5.08 and 5.29 (ABq, J ) 11.9 Hz, 2H), 5.76 (dd, J ) 9.1,

4.9 Hz, 1H), 5.98 (d, J ) 9.2 Hz, 1H), 6.87 (d, J ) 8.7 Hz, 2H),

7.26-7.37 (m, 7H). Anal. Calcd for C₂₈H₃₀N₂O₅S: C, 66.38;

H, 5.97; N, 5.53; S, 6.33. Found: C, 66.40; H, 5.97; N, 5.65; S,

6.30. ¹H NMR signals assigned to 58a in the mixture of 58a

and 58b: δ 1.03 (d, J ) 7.1 Hz), 1.56-1.64 (m), 2.41-2.54 (m),

2.85-2.94 (m), 4.40 (dd, J ) 9.5, 3.1 Hz), 4.91 (d, J ) 4.9 Hz).

p-Met h oxyb en zyl (5R,6S,8R,9R)-5-cycloh exyl-10-oxo-

9-(p h en yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]d ec-2-

en e-2-ca r boxyla te (59) (from 4b and vinylcyclohexane): IR

p-Meth oxyben zyl (4R,5S,6R,8R,9R)-4-acetyl-5-m eth oxy-

10-oxo-9-(ph en ylacetam ido)-7-th ia-1-azatr icyclo[6.2.0.0^3,6]-

d ec-2-en e-2-ca r b oxyla t e (52) (from 4b and trans-4-

methoxy-3-buten-2-one): IR (CH₂Cl₂) 1791, 1714, 1689 cm^-1

;

UV (EtOH) λ_max(ꢀ) 273 (10 200) nm; ¹H NMR (DMSO-d₆) δ

2.09 (s, 3H), 3.31 (s, 3H), 3.49 and 3.56 (ABq, J ) 13.9 Hz,

2H), 3.75 (s, 3H), 4.30 (dd, J ) 2.8, 2.2 Hz, 1H), 4.50 (dd, J )

7.2, 1.9 Hz, 1H), 4.59 (dd, J ) 7.3, 3.1 Hz, 1H), 5.13 (d, J )

5.1 Hz, 1H), 5.19 (s, 2H), 5.74 (dd, J ) 8.5, 5.0 Hz, 1H), 6.93

(d, J ) 8.6 Hz, 2H), 7.20-7.31 (m, 5H), 7.34 (d, J ) 8.6 Hz,

2H), 9.13 (d, J ) 8.5 Hz, 1H); ¹³C NMR (DMSO-d₆) δ 28.7,

41.5, 44.5, 55.1, 56.9, 58.3, 60.2, 62.1, 66.5, 77.5, 113.8 (2C),

122.1, 126.4, 127.2, 128.2 (2C), 129.0 (2C), 130.2 (2C), 133.9,

135.8, 159.3, 160.0, 164.5, 171.0, 202.1. Anal. Calcd for

C₂₈H₂₈N₂O₇S: C, 62.67; H, 5.26; N, 5.22; S, 5.98. Found: C,

62.40; H, 5.32; N, 5.17; S, 5.77.

p-Meth oxyben zyl (4S,5R,6S,8R,9R)-4-Meth oxy-10-oxo-

5-p h e n y l-9-(p h e n y la c e t a m id o )-7-t h ia -1-a za t r ic y c lo -

[6.2.0.0^3,6]d ec-2-en e-2-ca r boxyla te (53) (from 4b and cis-â-

methoxystyrene). After chromatography a mixture comprising

(KBr) 1786, 1704, 1657 cm^-^{1 1}H NMR (CDCl₃) δ 0.68-1.80

;

(m, 11H), 2.37 (dq, J ) 4.0, 9.2 Hz, 1H), 3.03 (dt, J ) 3.5, 16.9

Hz, 1H), 3.12 (ddd, J ) 1.1, 9.1, 16.7 Hz, 1H), 3.61 and 3.69

(ABq, J ) 16.2 Hz, 2H), 3.78 (s, 3H), 4.41 (ddd, J ) 1.2, 2.7,

9.5 Hz, 1H), 4.87 (d, J ) 4.9 Hz, 1H), 5.11 and 5.24 (ABq, J )

12 Hz, 2H), 5.77 (dd, J ) 4.9, 9.2 Hz, 1H), 5.97 (d, J ) 9.2 Hz,

(27) Bordwell, F. G.; Lampert, B. B.; McKellin, W. H. J . Am. Chem.

Soc. 1949, 71, 1702.

Cycloadditions of Cephalosporins

J . Org. Chem., Vol. 62, No. 15, 1997 5013

1H), 6.83-6.91 (m, 2H), 7.20-7.40 (m, 7H); mass spectrum

m/z 546 (M⁺).

Hz, 2H), 5.88 (dd, J ) 8.1, 4.8 Hz, 1H), 6.75 (d, J ) 8.0 Hz,

1H), 6.89 (d, J ) 1.3 Hz, 1H), 6.90 (d, J ) 8.9 Hz, 2H), 7.24-

7.50 (m, 12H); ¹³C NMR (CDCl₃) δ 43.0, 43.8, 55.3, 60.1, 63.2,

67.1, 113.7, 114.0 (2C), 126.6 (2C), 127.5, 127.6, 128.2, 129.0

(2C), 129.1 (2C), 129.4 (2C), 130.3 (2C), 130.7, 131.1, 133.8,

134.4, 152.6, 159.8, 161.4, 163.9, 171.8. Anal. Calcd for

C₃₁H₂₆N₂O₅S: C, 69.13; H, 4.87; N, 5.20; S, 5.95. Found: C,

69.03; H, 4.63; N, 5.27; S, 5.97. (6R) isom er 78: mp 98-101

°C; IR (CH₂Cl₂) 1782, 1718, 1684 cm^-1; UV (EtOH) λ_max(ꢀ) 341

(22 300) nm; ¹H NMR (CDCl₃) δ 3.70 (s, 2H), 3.80 (s, 3H), 4.82

(s, 1H), 4.71 and 4.92 (ABq, J ) 12.1 Hz, 2H), 5.34 (dd, J )

8.1, 4.1 Hz, 1H), 5.61 (d, J ) 4.1 Hz, 1H), 6.55 (s, 1H), 6.87 (d,

J ) 8.6 Hz, 2H), 7.14 (d, J ) 8.1 Hz, 1H), 7.17-7.46 (m, 12H);

¹³C NMR (CDCl₃) δ 43.0, 43.7, 55.5, 60.0, 66.8, 71.3, 112.7,

114.2 (2C), 125.3, 127.5, 127.7, 127.8 (2C), 129.1 (2C), 129.3

(2C), 129.8 (2C), 130.0 (2C), 130.1, 132.0, 134.8, 154.0, 157.7,

159.9, 162.4, 168.8, 171.5. Anal. Found: C, 69.29; H, 4.87;

N, 5.11; S, 5.79.

p -Met h oxyb en zyl (6S,8R,9R)-5,5-Dip h en yl-10-oxo-9-

(p h en yla cet a m id o)-7-t h ia -1-a za t r icyclo[6.2.0.0^3,6]d ec-2-

en e-2-ca r boxyla te (60) (from 4b and 1,1-diphenylethylene).

After chromatography a mixture of 60 and the (6R) isomer 61

(77%, 58:42 ratio) was obtained. This mixture was treated

with m-CPBA by the method described for the preparation of

17/18. This gave, after chromatography, a single sulfoxide in

66% yield. Reduction with PCl₃by the method described for

the reduction of 17 gave 60 as the sole isomer in 75% yield.

1

Spectral data for 60: IR (CH₂Cl₂) 1788, 1726, 1684 cm^-1; H

NMR (CDCl₃) δ 3.49 and 3.58 (ABq, J ) 16.4 Hz, 2H), 3.62

(dd, J ) 16.4, 0.6 Hz, 1H), 3.81 (s, 3H), 4.31 (dd, J ) 16.3, 2.6

Hz, 1H), 4.98 (dd, J ) 2.3, 0.8 Hz, 1H), 5.02 (d, J ) 4.9 Hz,

1H), 5.24 and 5.32 (ABq, J ) 12.0 Hz, 2H), 5.72 (dd, J ) 8.9,

4.8 Hz, 1H), 5.87 (d, J ) 8.9 Hz, 1H), 6.91 (d, J ) 8.7 Hz, 2H),

7.04-7.37 (m, 17H); mass spectrum m/z 616.2035, calcd for

C₃₇H₃₂N₂O₅S 616.2032. ¹H NMR signals assigned to 61 in the

original mixture of 60 and 61: δ 3.51 (d, J ) 15.5 Hz, 1H),

3.82 (obscured by s at 3.81; but observed in a COSY experi-

ment), 4.16 (dd, J ) 15.5, 1.5 Hz, 1H), 4.89 (brs, 1H), 5.46

(dd, J ) 9.3, 4.5 Hz, 1H), 6.17 (d, J ) 9.3 Hz, 1H).

p -Met h oxyb en zyl (6R,8R,9R)-5-(h yd r oxym et h yl)-10-

oxo-9-(p h en yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]-

d eca -2,4-d ien e-2-ca r boxyla te (79) (from 4b and propargyl

alcohol): mp 190-197 °C; IR (KBr) 1776, 1709, 1660 cm^-1

;

UV (EtOH) λ_max(ꢀ) 299 (15 700)nm; ¹H NMR (DMSO-d₆) δ 3.48

and 3.54 (ABq, J ) 14.0 Hz, 2H), 3.76 (s, 3H), 4.26 and 4.33

(ABq, J ) 17.6 Hz, 2H), 4.47 (d, J ) 1.0 Hz, 1H), 5.01 (d, J )

4.9 Hz, 1H), 5.18 and 5.22 (ABq, J ) 12.0 Hz, 2H), 5.84 (dd, J

) 8.4, 4.9 Hz, 1H), 6.57 (d, J ) 1.2 Hz, 1H), 6.94 (d, J ) 8.7

Hz, 2H), 7.20-7.31 (m, 5H), 7.37 (d, J ) 8.7 Hz, 2H), 9.06 (d,

J ) 8.4 Hz, 1H). Anal. Calcd for C₂₆H₂₄N₂O₆S: C, 63.40; H,

4.91; N, 5.69; S, 6.51. Found: C, 63.42, H, 4.88; N, 5.81; S,

6.80.

p-Meth oxyben zyl (6S,8R,9R)-10-Oxo-9-(p h en yla ceta -

m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]d eca -2,4-d ien e-2-ca r -

boxyla te (74) a n d p-Meth oxyben zyl (6R,8R,9R)-10-Oxo-

9-(p h en yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]d eca -

2,4-d ien e-2-ca r boxyla te (75). Acetylene, passed successively

through a cold trap at -78 °C and then traps containing

concentrated H₂SO₄and soda lime, was bubbled through a

sintered glass tube into a solution of triflate 4b (1.0 g, 1.7

mmol) in EtOAc (500 mL) at room temperature while a

p-Meth oxyben zyl (6R,8R,9R)-5-br om om eth yl-10-oxo-9-

(p h en yla cet a m id o)-7-t h ia -1-a za t r icyclo[6.2.0.0^3,6]d eca -

2,4-d ien e-2-ca r b oxyla t e (80) (from 4b and propargyl

bromide): IR (CH₂Cl₂) 1790, 1723, 1688 cm^-1; ¹H NMR (CDCl₃)

δ 3.60 and 3.68 (ABq, J ) 16.1 Hz, 2H), 3.81 (s, 3H), 4.12 and

4.17 (ABq, J ) 12.7 Hz, 2H), 4.34 (d, J ) 0.7 Hz, 1H), 4.87 (d,

J ) 4.6 Hz, 1H), 5.17 and 5.25 (ABq, J ) 11.9 Hz, 2H), 5.93

(dd, J ) 8.7, 4.5 Hz, 1H), 5.99 (d, J ) 8.7 Hz, 1H), 6.68 (s,

1H), 6.88 (d, J ) 8.7 Hz, 2H), 7.24-7.39 (m, 7H). Anal. Calcd

for C₂₆H₂₃N₂BrO₅S: C, 56.22; H, 4.17; N, 5.04. Found: C,

56.42; H, 4.21; N, 5.11.

p-Meth oxyben zyl (6R,8R,9R)-5-eth oxy-10-oxo-9-(p h e-

n yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]d eca -2,4-d i-

en e-2-ca r boxyla te (81) (from 4b and ethoxyacetylene): IR

(CH₂Cl₂) 1782, 1733, 1685 cm^-1; ¹H NMR (CDCl₃) δ 1.41 (t, J

) 7.2 Hz, 3H), 3.59 (d, J ) 16.1 Hz, 1H), 3.67 (d, J ) 16.1 Hz,

1H), 3.80 (s, 3H), 4.10 (q, J ) 7.2 Hz, 2H), 4.37 (d, J ) 1.2 Hz,

1H), 4.82 (d, J ) 4.6 Hz, 1H), 5.15 (d, J ) 12.0 Hz, 1H), 5.24

(d, J ) 12.0 Hz, 1H), 5.54 (d, J ) 1.0 Hz, 1H), 5.88 (dd, J )

8.5, 4.6 Hz, 1H), 6.02 (d, J ) 8.5 Hz, 1H), 6.87 (d, J ) 8.7 Hz,

2H), 7.24-7.39 (m, 7H); mass spectrum m/z 506.1513, calcd

for C₂₇H₂₆N₂O₆S 506.1512.

i

solution of Pr₂NEt (0.30 mL, 1.7 mmol) in EtOAc (100 mL)

was added dropwise over 1.5 h. The mixture was stoppered

and stirred for a further 16 h and then concentrated. The

residue was chromatographed to give two isomers: 74 (63mg,

8%) and 75 (267 mg, 34%). The (6S) isomer 74 was eluted

1

first: mp 197 °C dec; IR (CH₂Cl₂) 1787, 1723, 1686 cm^-1; H

NMR (CDCl₃) δ 3.60 and 3.68 (ABq, J ) 16.2 Hz, 2H), 3.80 (s,

3H), 4.26 (t, J ) 1.2 Hz, 1H), 4.82 (d, J ) 4.9 Hz, 1H), 5.18

and 5.25 (ABq, J ) 11.9 Hz, 2H), 5.96 (dd, J ) 8.7, 4.9 Hz,

1H), 6.07 (d, J ) 8.8 Hz, 1H), 6.73 (dd, J ) 2.3, 1.3 Hz, 1H),

6.79 (dd, J ) 2.1, 0.9 Hz, 1H), 6.88 (d, J ) 8.7 Hz, 2H), 7.23-

7.36 (m, 7H). Anal. Calcd for C₂₅H₂₂N₂O₅S: C, 64.92; H, 4.79,

N, 6.06; S, 6.93. Found: C, 64.92; H, 4.75; N, 6.07; S, 6.65.

(6R) isom er 75: IR (CH₂Cl₂) 1782, 1725, 1684 cm^-1; ¹H NMR

(CDCl₃) δ 3.65 (s, 2H), 3.80 (s, 3H), 4.42 (s, 1H), 5.11 and 5.17

(ABq, J ) 12.0 Hz, 2H), 5.24 (dd, J ) 8.0, 4.1 Hz), 5.70 (d, J

) 4.1 Hz, 1H), 6.34 (d, J ) 2.4 Hz, 1H), 6.57 (dd, J ) 2.3, 0.4

Hz, 1H), 6.73 (d, J ) 8.0 Hz, 1H), 6.88 (d, J ) 8.7 Hz, 2H),

7.26-7.34 (m, 7H); ¹³C NMR (CDCl₃) δ 43.5, 44.1, 55.4, 59.8,

67.0, 73.5, 114.1 (2C), 114.3, 127.48, 127.51, 129.1 (2C), 129.6

(2C), 130.2 (2C), 134.3, 136.5, 147.7, 155.9, 159.9, 162.0, 166.3,

171.3; mass spectrum m/z 463 (MH⁺).

p -Met h oxyb en zyl (6R,8R,9R)-10-oxo-9-(p h en yla cet a -

m ido)-5-(tr im eth ylsilyl)-7-th ia-1-azatr icyclo[6.2.0.0^3,6]deca-

2,4-d ien e-2-ca r boxyla te (82) (from 4b and (trimethylsilyl)-

p-Meth oxyben zyl (6S,8R,9R)-5-bu tyl-10-oxo-9-(p h en y-

la ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]d eca -2,4-d ien e-

2-ca r boxyla te (76) (from 4b and 1-hexyne): mp 196-198 °C;

acetylene): IR (CH₂Cl₂) 1787, 1720, 1687 cm^-^{1 1}H NMR

;

1

IR (CH₂Cl₂) 1786, 1717, 1684 cm^-1; H NMR (CDCl₃) δ 0.94

(CDCl₃) δ 0.18 (s, 9H), 3.59 and 3.67 (ABq, J ) 16.1 Hz, 2H),

3.80 (s, 3H), 4.23 (s, 1H), 4.80 (d, J ) 4.2 Hz, 1H), 5.18 and

5.26 (ABq, J ) 12.0 Hz, 2H), 5.90-5.96 (m, 2H), 6.88 (d, J )

8.5 Hz, 2H), 7.05 (s, 1H), 7.25-7.35 (m, 7H); mass spectrum

m/z 534.1650, calcd for C₂₈H₃₀N₂O₅SSi 534.1645.

(t, J ) 7.3 Hz, 3H), 1.37 (sextet, J ) 7.3 Hz, 2H), 1.50 (quintet,

J ) 7.2 Hz, 2H), 2.39 (t, J ) 7.4 Hz, 2H), 3.63 (ABq, J ) 16.1

Hz, 2H), 3.80 (s, 3H), 4.19 (s, 1H), 4.81 (d, J ) 4.8 Hz, 1H),

5.20 (ABq, J ) 12.0 Hz, 2H), 5.89 (dd, J ) 8.5, 4.8 Hz, 1H),

5.99 (d, J ) 8.4 Hz, 1H), 6.47 (s, 1H), 6.88 (d, J ) 8.5 Hz, 2H),

7.25-7.34 (m, 7H). Anal. Calcd for C₂₉H₃₀N₂O₅S: C, 67.16;

H, 5.83; N, 5.40; S, 6.18. Found: C, 67.00; H, 5.75; N, 5.49; S,

5.98.

p-Meth oxyben zyl (6S,8R,9R)-5-(Meth oxyca r bon yl)-10-

oxo-9-(p h en yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]-

d eca -2,4-d ien e-2-ca r boxyla te (84) (from 4b and methyl

propiolate). The (6R) isomer 83 was eluted first: IR (CH₂Cl₂)

1

p-Meth oxyben zyl (6S,8R,9R)-10-Oxo-5-p h en yl-9-(p h e-

n yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]d eca -2,4-d i-

en e-2-ca r boxyla te (77) a n d p-Meth oxyben zyl (6R,8R,9R)-

10-O x o -5-p h e n y l-9-(p h e n y la c e t a m id o )-7-t h ia -1-a za -

tr icyclo[6.2.0.0^3,6]d eca -2,4-d ien e-2-ca r boxyla te (78) (from

4b and phenylacetylene). The (6S) isomer 77 was eluted

first: mp 240 °C dec; IR (CH₂Cl₂) 1787, 1720, 1688 cm^-1; UV

1792, 1721, 1684 cm^-1; H NMR (CDCl₃) δ 3.60 (d, J ) 16.3

Hz, 1H), 3.66 (d, J ) 16.3 Hz, 1H), 3.81 (s, 3H), 3.82 (s, 3H),

4.39 (s, 1H), 4.88 (d, J ) 4.4 Hz, 1H), 5.20 (d, J ) 11.9 Hz,

1H), 5.26 (d, J ) 11.9 Hz, 1H), 5.99 (m, 2H), 6.89 (d, J ) 4.8

Hz, 2H), 7.20 (s, 1H), 7.24-7.35 (m, 7H); mass spectrum m/z

520.1310, calcd for C₂₇H₂₄N₂O₇S 520.1304. (6S) isom er 84:

1

IR (CH₂Cl₂) 1783, 1724, 1678 cm^-1; H NMR (CDCl₃) δ 3.67

1

(EtOH) λ_max(ꢀ) 350 (23 900) nm; H NMR (CDCl₃) δ 3.59 and

(d, J ) 16.5 Hz, 1H), 3.74 (d, J ) 16.5 Hz, 1H), 3.82 (s, 3H),

3.86 (s, 3H), 4.43 (s, 1H), 5.13 (d, J ) 11.3 Hz, 1H), 5.19 (m,

1H), 5.20 (d, J ) 11.3 Hz, 1H), 5.67 (d, J ) 4.1 Hz, 1H), 6.17

3.63 (ABq, J ) 15.8 Hz, 2H), 3.81 (s, 3H), 4.60 (d, J ) 1.1 Hz,

1H), 4.98 (d, J ) 4.6 Hz, 1H), 5.21 and 5.28 (ABq, J ) 11.9

5014 J . Org. Chem., Vol. 62, No. 15, 1997

Elliott et al.

(d, J ) 7.8 Hz, 1H), 6.86 (s, 1H), 6.90 (d, J ) 8.7 Hz, 2H),

7.26-7.41 (m, 7H); mass spectrum m/z 520.1310, calcd for

C₂₇H₂₄N₂O₇S 520.1304.

(d), 130.1 (d), 131.1 (d), 131.1 (s), 133.9 (s), 138.5 (d), 160.0

(s), 160.3 (s), 167.0 (s), 170.8 (s); mass spectrum m/z 504.1369,

calcd for C₂₇H₂₄N₂O₆S 504.1355.

p-Meth oxyben zyl (5R,6R)-1,10-d ip h en yl-4-oxo-5-(p h e-

n ylacetam ido)-13-oxa-7-th ia-3-azatetr acyclo[8.2.1.0^2,9.0^3,6]-

t r id eca -8,11-d ien e-2-ca r b oxyla t e (88) (from 4b and 1,3-

p -Met h oxyb en zyl (6S,8R,9R)-4,5-d im et h yl-10-oxo-9-

(p h en yla cet a m id o)-7-t h ia -1-a za t r icyclo[6.2.0.0^3,6]d eca -

2,4-d ien e-2-ca r boxyla te (85) (from 4b and 2-butyne): IR

(CH₂Cl₂) 1783, 1716, 1684 cm^-1; UV (EtOH) λ_max(ꢀ) 298

(12 400) nm; ¹H NMR (CDCl₃) δ 1.79 (s, 3H), 1.97 (s, 3H), 3.59

and 3.65 (ABq, J ) 16.1 Hz, 2H), 3.79 (s, 3H), 4.07 (brs, 1H),

4.79 (d, J ) 4.8 Hz, 1H), 5.17 and 5.23 (ABq, J ) 11.8 Hz,

2H), 5.89 (dd, J ) 8.6, 4.8 Hz, 1H), 6.06 (d, J ) 8.6 Hz, 1H),

6.86 (d, J ) 8.5 Hz, 2H), 7.24-7.34 (m, 7H); ¹³C NMR (CDCl₃)

δ 12.5, 13.2, 43.3, 45.6, 55.3, 59.8, 62.3, 67.1, 111.8, 113.9 (2C),

127.4, 127.7, 129.2 (2C), 129.5 (2C), 130.8 (2C), 133.7, 135.4,

142.5, 149.1, 159.9, 161.4, 164.6, 171.2; mass spectrum m/z

490.1562, calcd for C₂₇H₂₆N₂O₅S 490.1562.

diphenylisobenzofuran): IR (CH₂Cl₂) 1778, 1733, 1687 cm^-1

;

¹H NMR (CDCl₃) δ 3.47 (d, J ) 15.7 Hz, 1H), 3.54 (d, J ) 15.7

Hz, 1H), 3.81 (s, 3H), 4.70 (d, J ) 11.9 Hz, 1H), 4.83 (d, J )

4.3 Hz, 1H), 4.85 (d, J ) 11.9 Hz, 1H), 5.37 (dd, J ) 8.6, 4.1

Hz, 1H), 5.81 (d, J ) 8.6 Hz, 1H), 6.11 (s, 1H), 6.78 (d, J ) 8.7

Hz, 2H), 7.01 (d, J ) 8.7 Hz, 2H), 7.15 (m, 3H), 7.21-7.30 (m,

5H), 7.37-7.41 (m, 3H), 7.47-7.51 (m, 3H), 7.60 (d, J ) 7.5

Hz, 1H), 7.83-7.90 (m, 4H); mass spectrum m/z 706.2145,

calcd for C₄₃

H₃₄N₂O₆S 706.2138.

p-Meth oxyben zyl (1S,6R,7R)-1-Oxo-7-(p h en yla ceta m i-

d o)-3-[(t r iflu or om et h a n esu lfon yl)oxy]cep h -3-em -4-ca r -

boxyla te (92). To an ice-cooled solution of triflate 4b (0.25

g, 0.43 mmol) in CH₂Cl₂(5 mL) was added a solution of

m-CPBA (0.106 g, 0.43 mmol) in CH₂Cl₂(1 mL). The mixture

was stirred at room temperature for 30 min, then diluted with

CH₂Cl₂, washed with NaHCO₃, dried (MgSO₄), and concen-

trated. The residue was crystallized to give 92 (0.202 g,

80%): mp 148-150 °C (CH₂Cl₂/Et₂O); IR (CH₂Cl₂) 1793, 1735,

1648 cm^-1; ¹H NMR (CDCl₃) δ 3.46 (dd, J ) 18.5, 1.6 Hz, 1H),

3.62 (ABq, J ) 15.6 Hz, 2H), 3.81 (3H, s), 3.87 (d, J ) 18.5

Hz, 1H), 4.53 (dd, J ) 4.8, 1.4 Hz, 1H), 5.20 (d, J ) 11.7 Hz,

1H), 5.36 (d, J ) 11.7 Hz, 1H), 6.06 (dd, J ) 9.8, 4.8 Hz, 1H),

6.65 (d, J ) 9.8 Hz, 1H), 6.89 (d, J ) 8.7 Hz, 2H), 7.25-7.36

(m, 7H); mass spectrum m/z 603 (MH⁺).

p -Br om ob en zyl (6S,8R,9R)-10-Oxo-5-p h en yl-9-(p h en -

ylacetam ido)-7-th ia-1-azatr icyclo[6.2.0.0^3,6]deca-2,4-dien e-

2-ca r boxyla te (86). To a mixture of 77 and 78 (0.397 g, 0.737

mmol) in anisole (2 mL) at 0 °C was added TFA (4 mL). The

mixture was stirred at 0 °C for 5 min and then evaporated

under reduced pressure. Toluene was added to the residue,

and it was evaporated under reduced pressure. The residue

was dissolved in DMF (5 mL). p-Bromobenzyl bromide (0.32

g, 1.28 mmol) and K₂CO₃(0.24 g, 1.73 mmol) were added, and

the mixture stirred at room temperature for 1.5 h. Water (50

mL) was added, and the mixture was extracted with EtOAc

(100 mL). The organic extract was washed with water and

brine, dried (MgSO₄), filtered and concentrated. The (6S)

isomer 86 (0.116 g, 27%) was separated from the (6R) isomer

(0.184g, 42%) by chromatography: IR (KBr) 1777, 1708, 1650

p -Met h oxyb en zyl (1S,6R,7R,8S,9R,10R)-5,8-d ioxo-6-

(p h e n y la c e t a m i d o )-13-o x a -8-t h i a -4-a z a t e t r a c y c lo -

[8.2.1.0^2,9.0^4,7]tr id eca -2,11-d ien e-3-ca r boxyla te (95) (from

92 and furan): mp 202-203 °C (acetone); IR (CH₂Cl₂) 1801,

1725, 1689 cm^-1; ¹H NMR (CDCl₃) δ 3.41 (dd, J ) 3.9, 1.6 Hz,

1H), 3.56 (d, J ) 15.4 Hz, 1H), 3.63 (d, J ) 15.4 Hz, 1H), 3.81

(s, 3H), 4.41 (dd, J ) 4.8, 1.6 Hz, 1H), 5.24 (s, 2H), 5.39 (dt, J

) 3.9, 1.1 Hz, 1H), 5.89 (brd, J ) 2.6 Hz, 1H), 5.96 (dd, J )

9.7, 4.8 Hz, 1H), 6.27 (dd, J ) 5.7, 1.6 Hz, 1H), 6.47 (dd, J )

5.7, 2.0 Hz, 1H,), 6.54 (d, J ) 9.7 Hz, 1H), 6.90 (d, J ) 8.7 Hz,

2H,), 7.22-7.33 (m, 5H), 7.36 (d, J ) 8.7 Hz, 2H); ¹³C NMR

(CDCl₃) δ 43.6 (t), 55.6 (q), 57.7 (d), 57.9 (d), 68.3 (t), 70.4 (d),

79.4 (d), 81.4 (d), 114.4 (d), 122.4 (s), 127.0 (s), 127.8 (d), 129.1

(s), 129.3 (d), 129.5 (d), 130.9 (d), 131.2 (d), 134.0 (s), 135.4

(d), 160.1 (s), 160.3 (s), 164.5 (s), 171.5 (s); mass spectrum m/z

521 (MH⁺). Anal. Calcd for C₂₇H₂₄N₂O₇S: C, 62.30; H, 4.65;

N, 5.38; S, 6.16. Found: C, 62.18; H, 4.68; N, 5.28; S, 6.09.

p-Meth oxyben zyl (1S,6R,7R,8S,9R,10S)-10-a cetyl-5,8-

dioxo-6-(ph en ylacetam ido)-13-oxa-8-th ia-4-azatetr acyclo-

[8.2.1.0^2,9.0^4,7]tr id eca -2,11-d ien e-3-ca r boxyla te (96) (from

cm^-^{1 1}H NMR (CDCl₃) δ 3.60 and 3.68 (ABq, J ) 16.3 Hz,

;

2H), 4.63 (d, J ) 1.2 Hz, 1H), 5.00 (d, J ) 4.5 Hz, 1H), 5.21

and 5.30 (ABq, J ) 12.4 Hz, 2H), 5.90-5.99 (m, 2H), 6.90 (d,

J ) 1.0 Hz, 1H), 7.26-7.52 (m, 14H); mass spectrum m/z

586.0560, calcd for C₃₀H₂₃⁷⁹BrN₂O₄S 586.0562.

X-r a y Str u ctu r e Deter m in a tion of 86. Light yellow

plates suitable for the collection of X-ray diffraction data were

obtained by recrystallization from a solution of 86 in ethyl

acetate and methanol. A crystal of dimensions 0.30 × 0.25 ×

0.02 mm was mounted on an Enraf Nonius CAD-4 diffracto-

meter and flash cooled in a stream of N₂gas to 223(2) K.

Intensity data were collected on the diffractometer using

graphite-monochromated Cu KR radiation and an ω-2θ vari-

able speed scan technique. Final cell constants, and other

information pertinent to data collection and refinement, were

as follows: space group P2₁; unit cell dimensions, a ) 4.5760-

(10) Å, b ) 12.727(3) Å, c ) 22.942(5) Å, â ) 93.29(3)°, V )

1333.9(5) Å³; empirical formula, C₃₀H₂₃BrN₂O₄S; formula

weight, 587.47; Z ) 2; density (calc) ) 1.463 Mg m^-3; F(000)

Cl₂) 1803, 1721, 1693 cm^-1; ¹H

) 600; linear absorption coefficient µ(Cu K) ) 3.155 mm^-1

;

92 and 2-acetylfuran): IR (CH₂

) δ 2.38 (s, 3H), 3.31 (d, J ) 1.5 Hz, 1H), 3.60 (br

data collection range 1.93 e θ e 62.44°, -5 e h e 1, 0 e k e

14, -23 e l e 26; total number of reflections collected, 2548;

unique independent reflections, 2223 (R_int) 0.092). The

structure was solved by direct methods and refined with

anisotropic displacement parameters for non-hydrogen atoms.

The hydrogen atoms were included in idealized positions riding

on the atom to which they are attached with isotropic displace-

ment factors assigned as a constant (1.2) times U_eqof the

attached atom. The full-matrix least-squares refinement (on

NMR (CDCl₃

s, 2H), 3.81 (s, 3H), 4.40 (dd, J ) 4.9, 1.5 Hz, 1H), 5.25 (s,

2H), 5.98 (d, J ) 1.9 Hz, 1H), 5.99 (dd, J ) 9.8, 4.9 Hz, 1H),

6.20 (d, J ) 5.4 Hz, 1H), 6.49 (d, J ) 9.8 Hz, 1H), 6.60 (dd, J

) 5.4, 1.8 Hz, 1H), 6.90 (m, 2H), 7.24-7.38 (m, 7H); mass

spectrum m/z 563 (MH

⁺).

p -Met h oxyb en zyl (1S,6R,7R,8S,9R,10R)-11-[(d im et h -

ylam in o)car bon yl]-5,8-dioxo-6-(ph en ylacetam ido)-13-oxa-

8-th ia -4-a za tetr a cyclo[8.2.1.0^2,9.0^4,7]tr id eca -2,11-d ien e-3-

ca r boxyla te (97) (from 92 and N,N-dimethyl-3-furamide): IR

(KBr) 1795, 1716, 1675 cm^-1; ¹H NMR (CDCl₃) δ 3.03 (s, 3H),

3.10 (s, 3H), 3.50 (dd, J ) 4.0, 1.2 Hz, 1H), 3.57 (s, 2H), 3.80

(s, 3H), 4.45 (dd, J ) 5.0, 1.5 Hz, 1H), 5.24 (s, 2H), 5.73 (dd, J

) 3.9, 0.9 Hz, 1H), 5.99 (dd, J ) 10.0, 5.3 Hz, 1H), 6.03 (d, J

) 1.4 Hz, 1H), 6.56 (d, J ) 10.0 Hz, 1H), 6.60 (d, J ) 2.0 Hz,

1H), 6.89 (d, J ) 8.7 Hz, 2H), 7.23-7.38 (m, 7H); mass

spectrum m/z 592 (MH⁺).

F

²) of 384 parameters converged (∆/σ_max) 0.20) to values of

the conventional crystallographic residuals R ) 0.054 for 2072

observed data [I > 2σ(I)] and R ) 0.058 (wR2 ) 0.149) for all

2223 data.¹⁴

p-Meth oxyben zyl (5R,6R)-4-oxo-5-(p h en yla ceta m id o)-

13-oxa -7-t h ia -3-a za t et r a cyclo[8.2.1.0^2,9.0^3,6]t r id eca -8,11-

d ien e-2-ca r boxyla te (87) (from 4b and furan): IR (CH₂Cl₂)

1777, 1739, 1686 cm^-1; ¹H NMR (CDCl₃) δ 3.57 (ABq, J ) 15.9

Hz, 2H), 3.80 (s, 3H), 4.77 (dd, J ) 4.0, 1.0 Hz, 1H), 5.11 (d, J

) 11.9 Hz, 1H), 5.21 (d, J ) 11.9 Hz, 1H), 5.28 (dt, J ) 1.9,

1.0 Hz, 1H), 5.32 (dd, J ) 8.6, 4.0 Hz, 1H), 5.67 (dt, J ) 1.8,

1.0 Hz, 1H), 5.96 (d, J ) 8.6 Hz, 1H), 6.07 (q, J ) 1.0 Hz, 1H),

6.43 (dd, J ) 5.6, 1.8 Hz, 1H), 6.47 (dd, J ) 5.6, 1.7 Hz, 1H),

6.88 (d, J ) 8.7 Hz, 2H), 7.22-7.36 (m, 7H); ¹³C NMR (CDCl₃)

δ 43.3 (t), 55.3 (q), 56.4 (d), 59.7 (d), 64.5 (s), 68.1 (t), 81.7 (d),

83.0 (d), 113.4 (d), 114.2 (d), 127.1 (s), 127.6 (d), 129.0 (d), 129.5

p -Met h oxyb en zyl (1S,6R,7R,8S,9R,10R)-13-(ter t-b u -

t oxyca r b on yl)-5,8-d ioxo-6-(p h en yla cet a m id o)-8-t h ia -4,-

13-d ia za tetr a cyclo[8.2.1.0^2,9.0^4,7]tr id eca -2,11-d ien e-3-ca r -

boxyla te (98) (from 92 and N-Boc-pyrrole): IR (CH₂Cl₂) 1801,

1

1718, 1700 cm^-1; H NMR (CDCl₃) δ 1.40 (s, 9H), 3.39 (dd, J

) 3.4, 1.6 Hz, 1H), 3.60 (ABq, J ) 15.4 Hz, 2H), 3.80 (s, 3H),

4.41 (dd, J ) 4.8, 1.6 Hz, 1H), 5.14 (dd, J ) 3.4, 1.7 Hz, 1H),

5.25 (s, 2H), 5.69 (brs, 1H), 5.94 (dd, J ) 9.7, 4.8 Hz, 1H), 6.24

Cycloadditions of Cephalosporins

J . Org. Chem., Vol. 62, No. 15, 1997 5015

(dd, J ) 5.6, 2.1 Hz, 1H), 6.41 (dd, J ) 5.6, 2.6 Hz, 1H), 6.53

(d, J ) 9.7 Hz, 1H), 6.90 (d, J ) 8.7 Hz, 2H), 7.23-7.35 (m,

5H), 7.36 (d, J ) 8.7 Hz, 2H); ¹³C NMR (CDCl₃) δ 28.5 (q),

43.70 (t), 55.6 (q), 57.9 (d), 58.0 (d), 61.8 (d), 64.2 (d), 68.4 (t),

70.3 (d), 82.2 (s), 114.4 (d), 122.7 (s), 127.1 (s), 127.7 (d), 129.4

(d), 129.6 (d), 129.7 (s), 131.0 (d), 131.5 (d), 134.0 (s), 135.3

(d), 153.9 (s), 160.2 (s), 160.3 (s), 164.5 (s), 171.5 (s); mass

spectrum m/z 637 (MNH₄⁺).

1649cm^-1; UV (EtOH) λ_max(ꢀ) 268 (13 100) nm; ¹H NMR

(CDCl₃) δ 3.51 (t, J ) 8.1 Hz, 1H), 3.61 and 3.67 (ABq, J )

16.1 Hz, 2H), 3.73 (dd, J ) 8.3, 2.5 Hz, 1H), 3.79 (s, 3H), 4.36

(dd, J ) 8.1, 2.6 Hz, 1H), 4.99 (d, J ) 5.0Hz, 1H), 5.18 and

5.23 (ABq, J ) 11.9 Hz, 2H), 5.78 (ABq, J ) 8.7, 4.9 Hz, 2H),

6.10 (d, J ) 8.7 Hz, 1H), 6.88 (d, J ) 8.7 Hz, 2H), 7.20-7.38

(m, 12H); ¹³C NMR (CDCl₃) δ 38.2 (t, J ) 20.4 Hz), 43.1, 43.4,

47.4, 55.4, 58.5, 60.4, 67.2, 114.1 (2C), 120.3, 126.2 (2C), 127.42,

127.44, 127.8, 128.9 (2C), 129.3 (2C), 129.6 (2C), 130.5 (2C),

133.8, 135.2, 141.0, 159.9, 161.1, 164.3, 171.3; ²H NMR (CHCl₃)

δ 3.32; mass spectrum m/z 542 (MH⁺). 70: mp 185-186 °C

(EtOAc); IR (KBr) 1779, 1717, 1654 cm^-1; UV (EtOH) λ_max(ꢀ)

p-Meth oxyben zyl (1S,6R,7R)-1-oxo-7-(p h en yla ceta m i-

d o)-3-(2-p yr r olyl)cep h -3-em -4-ca r boxyla te (99) (from 92

1

and pyrrole): IR (CH₂Cl₂) 1792, 1696 cm^-1; H NMR (CDCl₃)

δ 3.61 (dd, J ) 17.9, 1.5 Hz, 1H), 3.62 (m, 2H), 3.81 (s, 3H),

4.27 (d, J ) 17.9 Hz, 1H), 4.55 (dd, J ) 4.6, 1.5 Hz, 1H), 5.23

(ABq, J ) 11.8 Hz, 2H,), 5.97 (dd, J ) 10.0, 4.6 Hz, 1H), 6.26

(m, 1H), 6.45 (m, 1H), 6.77 (d, J ) 10.0 Hz, 1H), 6.90 (m, 3H),

7.34 (m, 7H), 11.32 (br s, 1H); ¹³C NMR (CDCl₃/methanol-d₄)

δ 42.6 (t), 46.7 (t), 58.1 (d), 55.0 (q), 66.9 (d), 68.4 (t), 109.8

(d), 112.5 (d), 113.7 (d), 116.7* and 116.8* (s), 117.3 (s), 121.4*

and 121.5* (d), 126.3 (s), 126.5 (s), 127.1 (d), 128.6 (d), 129.0

(d), 130.5 (d), 133.8 (s), 159.7 (s), 163.2 (s), 164.1 (s), 172.0 (s),

* signals split due to incomplete H-D exchange; mass spec-

trum m/z 520 (MH⁺).

p-Meth oxyben zyl (1S,6R,7R)-1-oxo-7-(p h en yla ceta m i-

do)-3-[2-(N-m eth ylpyr r olyl)]ceph -3-em -4-car boxylate (100)

(from 92 and N-methylpyrrole): IR (CH₂Cl₂) 1798, 1728, 1689

cm^-1; ¹H NMR (CDCl₃) δ 3.22 (dd, J ) 18.7, 1.8 Hz, 1H), 3.27

(s, 3H), 3.61 (d, J ) 15.5 Hz, 1H), 3.68 (d, J ) 15.5 Hz, 1H),

3.77 (d, J ) 19 Hz, 1H), 3.80 (s, 3H), 4.52 (dd, J ) 4.8, 1.6 Hz,

1H), 5.00 (s, 2H), 5.99 (dd, J ) 3.7, 1.8 Hz, 1H), 6.09 (dd, J )

3.7, 2.7 Hz, 1H), 6.13 (dd, J ) 9.9, 4.7 Hz, 1H), 6.57 (dd, J )

2.6, 1.8 Hz, 1H), 6.74 (d, J ) 9.9 Hz, 1H), 6.82 (d, J ) 8.7 Hz,

2H), 7.08 (d, J ) 8.7 Hz, 2H), 7.27-7.40 (m, 5H); ¹³C NMR

(CDCl₃) δ 34.0 (q), 43.6 (t), 49.1 (t), 55.3 (q), 59.8 (d), 67.1 (d),

68.0 (t), 108.3 (d), 110.2 (d), 113.7 (s), 113.8 (d), 124.3 (d), 126.6

(s), 127.3 (s), 127.7 (d), 129.1 (d), 129.4 (d), 130.8 (d), 133.7

(s), 159.9 (s), 161.1 (s), 164.1 (s), 171.2 (s); mass spectrum m/z

533.1620, calcd for C₂₈H₂₇N₃O₆S 533.1620. Anal. Calcd for

C₂₈H₂₇N₃O₆S: C, 63.03; H, 5.10; N, 7.87. Found: C, 62.64; H,

5.15; N, 7.96.

1

273 (11 100) nm; H NMR (CDCl₃) δ 3.47 and 3.54 (ABq, J )

16.1 Hz, 2H), 3.59 (d, J ) 9.7 Hz, 1H), 3.79 (s, 3H), 3.97 (t, J

) 9.7 Hz, 1H), 4.68 (dd, J ) 9.7, 0.9 Hz, 1H), 4.95 (d, J ) 4.9

Hz, 1H), 5.19 and 5.29 (ABq, J ) 12.0 Hz, 2H), 5.71 (dd, J )

9.1 and 4.9 Hz, 1H), 5.82 (d, J ) 9.1 Hz, 1H), 6.88 (d, J ) 8.7

Hz, 2H), 7.07-7.35 (m, 12H); ¹³C NMR (CDCl₃) δ 36.3 (t, J )

20.9 Hz), 40.0, 43.3, 46.4, 55.4, 58.4, 60.5, 67.3, 114.1 (2C),

120.6, 127.4 (2C), 127.67, 127.73 (2C), 128.6 (2C), 129.1 (2C),

129.5 (2C), 130.4 (2C), 133.6, 138.0, 138.4, 159.9, 160.9, 164.1,

171.2; ²H NMR (CHCl₃) δ 3.55; mass spectrum m/z 542 (MH⁺).

p-Meth oxyben zyl (4S,5S,6S,7S,8R,9R)-[4-²H₁]-7,10-Di-

oxo-5-p h en yl-9-(p h en yla ceta m id o)-7-th ia -1-a za tr icyclo-

[6.2.0.0^3,6]d ec-2-en e-2-ca r boxyla te (93) a n d p-Meth oxy-

ben zyl (4R,5R,6S,7S,8R,9R)-[4-²H₁]-7,10-Dioxo-5-p h en yl-

9-(p h en yla ceta m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]d ec-2-

en e-2-ca r boxyla te (94) (from 92 and cis-â-deuteriostyrene)

(43%, 1:1 ratio). The earlier-eluting fractions contained

predominantly the (4S,5S) isomer 93: ¹H NMR (CDCl₃) δ 3.60

and 3.66 (ABq, J ) 15.4 Hz, 2H), 3.66 (dd, J ) 8.3, 2.1 Hz,

1H), 3.79 (s, 3H), 3.93 (t, J ) 8.2 Hz, 1H), 4.00 (dt, J ) 8.4,

1.9 Hz, 1H), 4.37 (dd, J ) 4.9, 1.7 Hz, 1H), 5.20 and 5.25 (ABq,

J ) 11.8 Hz, 2H), 5.96 (dd, J ) 9.7, 4.9 Hz, 1H), 6.65 (1H, d,

J ) 9.7 Hz), 6.89 (d, J ) 8.7 Hz, 2H), 7.15-7.39 (m, 12H); ²H

NMR (CHCl₃) δ 3.38. The later-eluting fractions contained

predominantly the (4R,5R) isomer 94: ¹H NMR (CDCl₃) δ 3.41

and 3.47 (ABq, J ) 15.2 Hz, 2H), 3.60 (brd, J ) 10.7 Hz, 1H),

3.79 (s, 3H), 4.05 (dt, J ) 10.0, 1.5 Hz, 1H), 4.29 (t, J ) 10.1

Hz, 1H), 4.35 (dd, J ) 4.9, 1.8 Hz, 1H), 5.23 and 5.31 (ABq, J

) 11.9 Hz, 2H), 5.84 (dd, J ) 9.8, 4.9 Hz, 1H), 6.51 (d, J ) 9.8

Hz, 1H), 6.89 (d, J ) 8.7 Hz, 2H), 7.15-7.39 (m, 12H); ¹³C

NMR (CDCl₃) δ 35.3 (m), 40.6, 42.9, 55.2, 58.2, 60.6, 67.4, 70.7,

114.0 (2C), 122.2, 127.1, 127.2, 127.6, 127.9 (2C), 128.5 (2C),

128.9 (2C), 129.3 (2C), 130.1, 130.4 (2C), 133.9, 135.5, 159.9

(2C), 163.6, 171.2; ²H NMR (CHCl₃) δ 3.76; mass spectrum

m/z 557 (M⁺).

p-Meth oxyben zyl (1R,6R,7R)-1-Oxo-7-(p h en yla ceta m i-

d o)-3-[(t r iflu or om et h a n esu lfon yl)oxy]cep h -3-em -4-ca r -

boxyla te (101). To a solution of triflate 4b (2.0 g, 3.4 mmol)

in a mixture of THF (50 mL) and water (2 mL) was added

N,N-dichlorourethane (0.54 g, 3.4 mmol). After being stirred

for 45 min, the mixture was concentrated, and the residue was

taken up in EtOAc, washed twice with water, and dried

(MgSO₄). Purification by chromatography and trituration from

Et₂O gave 101 (0.675 g, 33%): mp 74-75 °C (CH₂Cl₂/hexane);

p -Met h oxyb en zyl (4S,5R,6S,8R,9S)-[4-²H ₁]-10-Oxo-5-

p h en yl-9-(p h en yla ceta m id o)-1-a za tr icyclo[6.2.0.0^3,6]d ec-

2-en e-2-ca r boxyla te (106) a n d p-Meth oxyben zyl (4R,5S,-

6S,8R,9S)-[4-²H₁]-10-Oxo-5-p h en yl-9-(p h en yla ceta m id o)-

1-a za tr icyclo[6.2.0.0^3,6]d ec-2-en e-2-ca r boxyla te (107). To

a solution of triflate 103 (30 mg, 0.0528 mmol) and cis-â-

deuteriostyrene (0.12 mL, 0.80 mmol) in CH₂Cl₂(2 mL) was

added a solution of DBU (8 µL, 0.0528 mmol) in CH₂Cl₂(0.5

mL). After being stirred at room temperature for 1 h, the

mixture was chromatographed to give the products 106 and

107 (5.4 mg, 20%) as a 1:1 mixture: IR (CH₂Cl₂) 1772, 1720,

1

IR (CH₂Cl₂) 1808, 1736, 1681 cm^-1; H NMR (CDCl₃) δ 3.54

(d, J ) 16.4 Hz, 1H), 3.66 (s, 2H), 3.80 (s, 3H), 4.38 (d, J )

16.4 Hz, 1H), 4.55 (d, J ) 4.9 Hz, 1H), 5.19 (dd, J ) 7.5, 4.9

Hz, 1H), 5.22 (d, J ) 11.7 Hz, 1H), 5.32 (d, J ) 11.7 Hz, 1H),

6.28 (d, J ) 7.5 Hz, 1H), 6.88 (d, J ) 8.7 Hz, 2H), 7.34 (m,

7H). Anal. Calcd for C₂₄H₂₁F₃N₂O₉S₂: C, 47.84; H, 3.51; N,

4.65; S, 10.64. Found: C, 47.97; H, 3.47; N, 4.64; S, 10.84.

p -Met h oxyb en zyl (1R,6R,7R,8R,9S,10S)-5,8-d ioxo-6-

(p h e n y la c e t a m i d o )-13-o x a -8-t h i a -4-a z a t e t r a c y c lo -

[8.2.1.0^2,9.0^4,7]tr id eca -2,11-d ien e-3-ca r boxyla te (102) (from

101 and furan): IR (CH₂Cl₂) 1796, 1724, 1670 cm^-1; ¹H NMR

(CDCl₃) δ 3.63 (s, 2H), 3.81 (s, 3H), 4.09 (d, J ) 5.0 Hz, 1H),

4.43 (d, J ) 3.5 Hz, 1H), 4.79 (dd, J ) 7.1, 5.0 Hz, 1H), 5.17

(d, J ) 11.9 Hz, 1H), 5.26 (d, J ) 11.9 Hz, 1H,), 5.27 (ddd, J

) 3.7, 1.7, 0.8 Hz, 1H,), 6.17 (dd, J ) 2.0, 0.8 Hz, 1H), 6.30

(dd, J ) 5.6, 2.0 Hz, 1H), 6.37 (d, J ) 7.1 Hz, 1H), 6.68 (dd, J

) 5.6, 1.7 Hz, 1H), 6.90 (d, J ) 8.7 Hz, 2H), 7.25-7.40 (m,

7H); mass spectrum (NOBA-Na) m/z 543 (MNa⁺).

1680 cm^-^{1 1}H NMR (CDCl₃) δ 0.33 (q, J ) 11.7 Hz, 0.5H),

;

1.02 (q, J ) 11.4 Hz, 0.5H), 1.46 (ddd, J ) 12.4, 6.7, 3.5 Hz,

0.5H), 2.10 (ddd, J ) 12.3, 6.3, 3.5 Hz, 0.5H), 3.07-3.19 (m,

1H), 3.42-3.51 (m + ABq, J ) 16.2 Hz, 2H), 3.58 and 3.63

(ABq, J ) 15.7 Hz, 1H), 3.78-3.86 (m, 5H), 5.12 (t, J ) 5.7

Hz, 0.5H), 5.16 and 5.22 (ABq, J ) 12.0 Hz, 1H), 5.19 (t, J )

5.9 Hz, 0.5H), 5.19 and 5.26 (ABq, J ) 12.0 Hz, 1H), 5.54 (d,

J ) 6.3 Hz, 0.5H), 5.93 (d, J ) 6.0 Hz, 0.5H), 6.87 (d, J ) 8.6

Hz, 2H), 6.95 (brd, J ) 8.0 Hz, 1H), 7.09 (brd, J ) 7.8 Hz,

p -Met h oxyb en zyl (4S,5S,6S,8R,9R)-[4-²H ₁]-10-Oxo-5-

ph en yl-9-(ph en ylacetam ido)-7-th ia-1-azatr icyclo[6.2.0.0^3,6]-

d ec-2-en e-2-ca r b oxyla t e (69) a n d p -Met h oxyb en zyl

(4R,5R,6S,8R,9R)-[4-²H₁]-10-Oxo-5-ph en yl-9-(ph en ylaceta-

m id o)-7-th ia -1-a za tr icyclo[6.2.0.0^3,6]d ec-2-en e (70) (from

4b and cis-â-deuteriostyrene²⁸) (69%, 1:1 ratio). 69 was eluted

first: mp 211-212 °C (EtOAc); IR (KBr) 1785, 1705, 1677,

2

1H), 7.16-7.36 (m, 10H); H NMR (CHCl₃) δ 3.20 and 3.30;

mass spectrum m/z 523 (MH⁺).

p-Meth oxyben zyl (4S,8R,9S,11R,12S)-13-Oxo-12-(p h e-

n yla cet a m id o)-1-a za -6,7-b en zot et r a cyclo[9.2.0.0^3,9.0^4,8]-

tr id eca -2,6-d ien e-2-ca r boxyla te (105). To a solution of

triflate 103 (0.203 g, 0.357 mmol) and indene (0.63 mL, 5.40

mmol) in CH₂Cl₂(8 mL) was added a solution of DBU (54 µL,

0.36 mmol) in CH₂Cl₂(2 mL). After being stirred at room

temperature for 1 h, the mixture was chromatographed to give

(28) Dolbier, W. R., J r.; Wicks, G. E. J . Am. Chem. Soc. 1985, 107,

3626.

5016 J . Org. Chem., Vol. 62, No. 15, 1997

Elliott et al.

105 (0.101 g, 53%): mp 241-242 °C (CH₂Cl₂/EtOAc); IR (CH₂-

Cl₂) 1770, 1719, 1684 cm^-1; UV (EtOH) λ_max(ꢀ) 275 (9600) nm;

¹H NMR (CDCl₃) δ 1.07 (brq, J ) 11.6 Hz, 1H), 2.05 (ddd, J )

12.3, 6.7, 3.4 Hz, 1H), 2.91-3.02 (m, 1H), 3.23 and 3.30 (dABq,

J ) 17.3, 10.1, 6.1 Hz, 2H), 3.50 (brt, J ) 6.2 Hz, 1H), 3.59

and 3.66 (ABq, J ) 16.1 Hz, 2H), 3.68-3.76 (m, 1H), 3.80 (s,

3H), 4.04-4.13 (m, 1H), 5.13 and 5.26 (ABq, J ) 12.0 Hz, 2H),

5.18 (brt, J ) 5.5 Hz, 1H), 6.03 (d, J ) 6.1 Hz, 1H), 6.88 (d, J

) 8.7 Hz, 2H), 7.15-7.39 (m, 11H). Anal. Calcd for

C₃₃H₃₀N₂O₅: C, 74.14; H, 5.66; N, 5.24; m/z M 534.2155.

Found: C, 73.56; H, 5.68; N, 5.30; M⁺534.2155.

treated with m-CPBA and the resulting ∆³-sulfoxide reduced

with PCl₃by the procedure described for the preparation of

15 to give the title compound 11 as a 1:1 mixture of diaster-

1

eomers: IR (KBr) 1780, 1723, 1663 cm^-1; H NMR (CDCl₃) δ

1.23-1.96 (m, 2.5H), 2.21-2.32 (m, 0.5H), 2.99-3.92 (m, 6H),

4.84 (dd, J ) 9.1, 6.7 Hz, 0.5H), 4.95 (d, J ) 4.8 Hz, 1H), 5.01

(brt, J ) 8.0 Hz, 0.5H), 5.76 and 5.85 (2dd, J ) 8.9, 4.8 Hz,

1H), 6.01 and 6.08 (2d, J ) 8.9 Hz, 1H), 6.86 and 6.94 (2s,

1H), 7.26-7.38 (m, 15H); mass spectrum m/z 554 (M⁺).

Exa m p le of a Rea ction of Tr ifla te 4a w ith (2-Tetr a h y-

d r ofu r yl)tr i-n -bu tylsta n n a n e u n d er P d Ca ta lysis. F or -

m a tion of 3-n -Bu tylcep h -3-em (6). To a solution of triflate

4a (100 mg, 0.158 mmol) in N-methylpyrrolidone (1 mL) was

added (2-tetrahydrofuryl)tri-n-butylstannane (67 mg, 0.186

mmol), (MeCN)₂PdCl₂(8 mg), and ZnCl₂(0.336 mL, 1 M

solution in Et₂O). The mixture was stirred at room temper-

ature for 2 days and then partitioned between EtOAc and

water, and the organic phase was washed with water and

brine, dried (MgSO₄), and evaporated. The residue was

chromatographed to give diphenylmethyl (6R,7S)-3-n-butyl-

7-(phenylacetamido)ceph-3-em-4-carboxylate (6) (23 mg,

25%): ¹H NMR (CDCl₃) δ 0.80 (t, J ) 6.9 Hz, 3H), 1.14-1.45

(m, 4H), 2.21-2.50 (m, 2H), 3.17 and 3.38 (ABq, J ) 18.0 Hz,

2H), 3.61 and 3.69 (ABq, J ) 16.2 Hz, 2H), 4.94 (d, J ) 4.6

Hz, 1H), 5.76 (dd, J ) 8.9, 4.7 Hz, 1H), 6.11 (d, J ) 8.9 Hz,

1H), 6.92 (s, 1H), 7.26-7.38 (m, 15H); mass spectrum m/z 540

(M⁺).

p -Met h oxyb en zyl (6R,7S)-3-(2,5-Dih yd r ofu r -2-yl)-7-

(p h en yla ceta m id o)-1-ca r ba -1-d eth ia cep h -3-em -4-ca r box-

yla te (104). To a stirred solution of triflate 103 (20 mg, 0.035

mmol) and 2,3-dihydrofuran (13.3 µL, 0.176 mmol) in benzene

(0.5 mL) were added Pd(OAc)₂(0.4 mg), 1,1′-bis(diphenylphos-

i

phino)ferrocene (2.0 mg), and Pr₂NEt (6.1 µL, 0.035 mmol).

The reaction mixture was heated at 45 °C for 24 h. Chroma-

tography gave the product 104 (16.4 mg, 96%) as a mixture of

diastereomers (1:1): IR (CH₂Cl₂) 1769, 1720, 1683 cm^-^{1 1}H

;

NMR (CDCl₃) δ 1.00-1.17 and 1.17-1.32 (2m, 1H), 1.86-2.53

(m, 3H), 3.58 (s, 2H), 3.69-3.81 and 3.79 (m+s, 4H), 4.67-

4.70 (m, 2H), 5.16-5.27 (m, 3H), 5.55 (dd, J ) 6.0, 1.7 Hz,

0.5H), 5.71 (dd, J ) 5.5, 2.4 Hz, 0.5H), 5.96-6.00 (m, 1.5H),

6.07-6.18 (m, 1.5H), 6.86 (d, J ) 8.7 Hz, 2H), 7.16-7.35 (m,

7H); mass spectrum m/z 511 (MNa⁺).

Dip h en ylm eth yl (6R,7R)-7-(P h en yla ceta m id o)-3-(2-tet-

r a h yd r ofu r yl)cep h -3-em -4-ca r boxyla te (11). To a solution

of (2-tetrahydrofuryl)tri-n-butylstannane⁹(3.0 g, 8.3 mmol) in

THF (20 mL) at -78 °C was added n-butyllithium (6.23 mL,

9.97 mmol, 1.6 M solution in hexanes). After 15 min this

solution was transferred via a cannula to a suspension of

copper(I) bromide-dimethyl sulfide complex in a mixture of

dimethyl sulfide (15 mL) and THF (30 mL) at -78 °C. The

dark brown mixture was stirred for 30 min at -78 °C and then

transferred via a cannula to a solution of triflate 4a (1.9 g,

3.0 mmol) in a mixture of N-methylpyrrolidone (20 mL) and

THF (50 mL) at -78 °C. The mixture was stirred at -78 °C

for 1 h and then quenched by the addition of saturated NH₄-

Cl. The mixture was allowed to warm to room temperature.

The aqueous layer was extracted with EtOAc. The organic

phase was washed with water and brine, dried (MgSO₄), and

evaporated. The 3-butyl compounds (0.403 g, 25%), as a 3.3:1

mixture of ∆²- and ∆³-cephems 13 and 6, were separated from

the 3-(2-tetrahydrofuryl) products (1.014 g, 61%) as a 1.2:1

mixture of ∆²- and ∆³-cephems 12 and 11 by chromatography.

Kin etic Stu d ies. To the individual styrenes (10 equiv) and

i

triflate 4b (10 mg, 0.017 mmol) in CH₂Cl₂was added Pr₂NEt

(3 µL, 0.017 mmol). After being stirred for 10 min, the reaction

mixture was analyzed by HPLC (eluent 15%MeCN in CH₂-

Cl₂, detection at 270 nm). Competitive reactions were per-

formed as above but with a mixture of 4-methoxystyrene (10

equiv) and another styrene (10 equiv). Only the later-eluting

isomer of the 4-methoxystyrene product and the earlier-eluting

isomer of the other styrene product were resolved. The

information on the product isomer ratios of the individual

reactions allowed the determination of the total product ratios.

The relative rates of reactions were determined by the

formula: k_rel) k_X/k_OMe) P_X/P_OMe, where X is the other

substituted styrene and P_X/P_OMeis the product ratio.

Su p p or tin g In for m a tion Ava ila ble: ¹H, ²H, and ¹³C

NMR spectra of selected compounds (77 pages). This material

is contained in libraries on microfiche, immediately follows this

article in the microfilm version of the journal, and can be

ordered from the ACS; see any current masthead page for

ordering information.

1

Cep h -2-em 13: H NMR (CDCl₃) δ 0.81 (t, J ) 7.1 Hz, 3H),

1.10-1.50 (m, 4H), 1.92-2.12 (m, 2H), 3.63 (s, 2H), 4.87 (s,

1H), 5.21 (d, J ) 4.0 Hz, 1H), 5.62 (dd, J ) 9.1, 4.0 Hz, 1H),

5.87 (d, J ) 0.9 Hz, 1H), 6.16 (d, J ) 9.1 Hz, 1H), 6.87 (s, 1H),

7.26-7.42 (m, 15H). The 3-(2-tetrahydrofuryl) products were

J O970176S

Article Doi

Cycloadditions of cephalosporins. A comprehensive study of the reaction of cephalosporin triflates with olefins, acetylenes, and dienes to form [2 + 2] and [4 + 2] adducts

DOI: 10.1021/jo970176s

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