Nuclear analogs of p-lactam antibiotics. XIX.' Syntheses of racemic and enantiomeric p-nitrobenzyl carbapen-2-em-3-carboxylates

Y ~ s u . ~ . s c c u UEDA.' CI-IRISTOPI-IEIZ E. DAMAS. A N D V I V I A N N E VINET Br.isrol LtrDortr~ot.ie.s oj' Crrr~trcltr, 100 It~tlrr.srritrl Bo~rler~crr~tl. Ctrrrtlitcc~. P .Q . , Crrt~crclcr JSli IJ I

Rcccivcd March 1 . 1983

Y,\svrsUc;U UEDA. CHRISTOPHER E. DAMAS. and VIVIANNE VINET. Can. J . Chcm. 61, 2257 (1983). Raccmic and cnantiorncric 1,-nitrobcnzyl carbapcn-2-em-3-carhoxylatcs 3 . 3c1. and 3h wcrc prcparccl starting from incxpcn-

sivc sorbic acid through the kcy intcrmcdiatcs. azctidinonc cstcrs 4, thus establishing a total synthesis of the p-nitrobcnzyl cstcr of a natural product SQ 27,860. Optical I-csolution was achieved readily on azctidinonc rncnthyl cstcrs. 12. The absolute configurations wcrc also established.

YASUTSUGU UEDA. CHRISTOI'HER E. DAMAS ct V I V I A N N E VINET. Can. J . Chcrn. 61, 2257 (1983). On a prCparC Ics carbapcncrnc-2 carboxylatcs-3 dc 11-nitrobcnzylc racdmiqucs ct Cnantiomcrcs 3 , 3tr ct 31) cn partant d'un

rCactif pcu coitcux, I'acidc sorbiquc, ct cn passant par dcs intcrmCdiaircs clds, dcs cstcrs dc I'azdtidinonc 4; on n tlonc rdalisd ainsi unc synthbsc totalc dc I'cstcr p-nitrobcnzylc clu produit naturcl SQ 27,860. On a facilc~ncnt cffcctuC la r6solution dcs antipodes optiqucs dcs csters rncnthyliqucs dc I'nzCtidinonc 12 ct on a Cgalcrnent Ctabli Ics configurations absolucs.

[Traduit par Ic journal]

In our previous paper (1) we reported a silnple route to (2)-7-alkylthiocarbapen-2-eni-3-carboxylat 1 (R = S-alkyl).

~ C O ~ M ~ - q c 0 2 ~ e

starting from inexpensive sorbic acid via an intermediate 4 0 H 0 (R = PNB). Now we wish to describe the versatility of inter- C 0 2 P N B

mediates 4 by preparing racelnic and enantiomeric carba- 4 R=Me 5 penems 3 , 30 , and 3 6 from 4 (R = Me, I-menthyl). Although raceniic carbapen-2-em-3-carboxylic acid esters 2 and 3 have /'

ONB = -CH2 9 NO^

PNB = -CH

been reported (2-5), their enantioliiers have not been prepared in pure form.' The Squibb scientists (7) recently isolated a simple carbapenem antibiotic S Q 27,860 as the p-nitrobenzyl ester, from bacterial sources, which was found to be (+)-p-nitrobenzyl carbapen-2-eni-3-carboxylate. 'Therefore, a part of this report represents a total sysnthesis of the p- nitrobenzyl ester of the natural product from sorbic acid.

Racemic parent carbapen-7-em-3-carboxylate 3 was synthe- sized by the well-established method (3, 8) , originated by Woodward and co-workers , from our key intermediate 4 (R = Me). Condensation of 3 (R = Me) (1) with p-nitrobenzyl gly-

' For Part XVlll of this series, sec rcf. I. ' ~ u t h o r to whom corrcspondcncc should bc addrcsscd. ' ~ h c Bcccharn group dcscribcs thc preparation of cnantiorncric

carbapcncm csters 30 and 3 b in thcir recent patcnt application (6). but thcir method is curnbcrsornc and. furthcrrnorc, thc enantiomcric puri- tics are low.

oxylate hydrate gave carbinolamides 5 as a diastereoliieric niix- ture which was converted to chloro-compounds 6 by thionyl chloride and pyridine. Treatment of 6 with triphenylphosphine and 2,6-lutidine provided phosphorane 7 in 64% overall yield from 4 (R = Me) as yellowish crystals. Ozonolysis of 7 in CHIC12 in the presence of trifluoroacetic acid (8c) , followed by reduction of the ozonide with diniethyl sulfide, then regen- eration of the phosphorane with NaHC03, yielded aldehyde 8 which spontaneously cyclized at 35"-40°C to give racemic carbapenem ester 3 as yellowish crystals (mp 153.5"- 155°C) in 60% yield (Scheme 1). This material had spectroscopic properties ( 'Hmr, ir) consistent with data reported by Bateson et 01. (36). Preparation of carbapenem salt 2 (R = K , Na) was attempted by hydrogenolysis (H,/Pd-C, phosphate buffer) of 3 . Although the presence of 2 (R = K , Na) was detected in the crude, dilute solution by the uv spectrum (h,,,,,,l,l,, -762 nm), it was not possible to isolate it, due to the instability of the molecule (2. 36, 5 , 17).

Bearing a carboxylic acid ester group in the molecule, the

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CAN. 1. CHERI. VOL. 61. 1983

intermediate 4 provides a possibility of preparing optically active parent carbapenem carboxylates 3cr and 3b. Instead of a methyl ester, an optically active ester grouping such as I- menthyl ester could be introduced into the intermediate 4 , producing a mixture of two diastereomers. This could make resolution of the racemate possible. After the resolution is achieved, this ester moiety is removed from the molecule to prepare optically active carbapenems.'

We found that although optical resolution on the inter- mediate 4 (R = I-rnenthyl) was possible, it was performed more conveniently on azetidinone menthyl ester 12.

The diastereomeric mixture 12 was prepared following the method used for the preparation of methyl ester 4 (R = Me) ( I ), starting from sorbic acid (9) and optically active /-menthol (Scheme 2). Thus, esterification of sorbic acid (9) with I- menthol gave I-menthyl sorbate (10) which was isomerized to I-menthyl 3,s-hexadienoate (11) in 95% yield by kinetic pro- tonation of the enolate generated from 10 with lithium di-

"A similar approach has been used by Pfaendler et al. (9) in the preparation of enantiomcric penem-3-carboxylic acids.

isopropylamide in THF-HMPA. Cycloaddition of chloro- sulfonyl isocyanate (10) to this conjugated diene 11. followed by a reductive work-up ( I I ) , yielded two diastereomeric azeti- dinones 12 in 54% yield. These two diastereomers were readily separated by crystallization to give 12a and 1211 in 28% and 21% yield respectively. This facile resolution of the racemic modification depends on different solubilities of these two diastereomers in EtzO. One crystallization from Et20 was enough to obtain one diastereomer 120 (mp 120"- 125°C) in a reasonably pure form. The other diastereomer 120 (mp 75"-78"C), which was more soluble in Et20, crystallized from the mother liquor by addition of pentane in the cold. In both cases. their mp and optical rotation did not change significantly by further recrystallization. Upon isomerization of the carbon-carbon double bond with 1,4-diazabicyclo[2.2.2]- octane (DABCO) in CHICN as described before ( l ) , each diastereomer 12a and 120 gave 4a and 40 in good yield.

The independent transformation of the two diastereomers 4a and 40 into the optically active p-nitrobenzyl (5R)-carbapen- 2-em-3-carboxylate (30): mp 123"-124°C: [ale $127.5" ( C 1.0, CH,C12), and its SS-enantiomer 30: mp 122"-124°C;

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UEDA ET AL.

[a],,- 1 10.8" ( c 1 .O, CH2CI,), was achieved through phos- phoranes 130 and 130 (Schenie 2) by the same method used for the racetnic series. These enantioniers had 'Hmr and ir spectra identical to the racemic material. Determination of en- antiomeric p~trities by 'Hmr spectroscopic means was at- tempted using a chiral shift reagent (12). Examination of 'Hmr spectra of raceniic and each enantionieric material obtainecl revealecl that Eu(dcm), (120) caused separation of a doublet (a part of an AB quartet) for one of the niethylene protons of tlie 12-nitrobenzyl group into two sets of the doublet. The one in 3 a appeared ;~t~slLghtly lower field than the one in 3 0 , AAS being 0.07 ppm. Any peaks which correspond to 3 0 were not de- tected in the ' H ~ I spectrum of the enantionier obtained with [a],, of + 127.5". The isomer with [a]l, - 110.8° showed the major peaks corresponding to the enantionier 3 0 and ;I trace of peaks froni the enantiomer 3 n . indicating some cont;lmination of 3~1 (ca. 10%). Because of the noise associated with these spectra, accurate measurements were not obtained. None- theless we believe that one of the isomers, 3 a , was prepared with high enantiomeric purity.

The I-menthyl group,which served for raceniate resolution, was removed at the last stage of the sequence (see Scheme 2). Combined with the fact that the resolution was achieved at an earlier stage, this provided the possibility of yielding a better optical purity of each final enantionier, because fi~rther en- richment is possible at each step (e .g. 4) .

The absolute configurations were established as conlpounds 1 2 0 , 4 ~ 1 , 1 3 a , and 3~1 (R-series) and compounds 12u, 4 0 , 1 3 0 , and 3 0 (S-series) by two-step conversion of 4 ~ 1 and 4 0 to 1 5 a , [a],, -67.5" ( c 1.0, CH,Cl,), ant1 150 , [ a ] D +36.6" ( c 1.0, CH2Cl2) respectively (Schenie 3). This conversion involved protection of the p-lactam by te1.t-butyldimethylsilyl chloride and triethylamine in DMF and subsequent oxidation of the double bond by potassium perrnanganate under phase transfer conditions (13). The acid 1 5 ~ 1 was correlated to the one ob- tained, [aID -80.3" (c 1.0, CH?CI,). by permanganate oxida- tion of allylazetidinone 16' whose absolute configuration was known. Consequently, the absolute configuration of the p- nitrobenzyl ester of S Q 27,860, having an optical rotation [a]l," of + 104" (7) was determined to be (5R)-p-nitrobenzyl carbapen-2-em-3-carboxylate ( 3 ~ ) .

Since racemic carbapenem ester 3 has been used as an inter-

his compound was derived from a natural product. penicillin. A highly stereoselective conversion of 6ol-bromopenicillanic acid to op- tically active allylazetidinonc 16 is reported in Part XVII of this series. We thank Dr. A. Martel for the procedures of this conversion.

mediate in tlie preparation of 6-unsubstituted analogs of oli- vanic acid (6, 14), the synthesis of the (5R)-isomer 3 ~ 1 , de- scribed here, provides a useful and practical entry to the natural enantioniers of 6-unsubstituted carbapenem antibiotics.

In summary, we have described the syntheses of racemic and enantionieric carbapen-2-eni-3-carboxylates starting from in- expensive sorbic acid. The compounds 4 were found to be very versatile intermediates in the synthesis of carbapenenis.

Experimental Melting points were cletcrmined on a Gallcnkamp melting point

apparatus and arc not corrected. The infrared spectra wcrc recordcd on a Perkin-Elmer 267 grating infrared spcctronictcr. The 'H nuclear magnetic resonance spcctra wcrc taken with either a Varian EM-360 (60 MHz) or a Vorian CF7-20 (80 MHz) nmr spectrorncter. Tetra- metliylsilane was used as an internal standard ant1 chemical shifts arc reported in parts per million (6) relative to the internal standard. The ultraviolet spcctra were recorded on an Unicam SP8-100 uv spcc- trophotomcter. Optical rotations were me;tsurcd with a Perkin-Elnicr Model 141 polarimetes. Tetrahydrofuran was freshly distilled from lithium aluminum hydride. Anhydrous tliethyl ether (Fisher) was uscd without further treatment. All other solvents were reagent grade and had been stored over molecular sieves before use. n-Butyllithium (n-BuLi) in hexane and tris[d,d-dicampholylmethanato]europium ( I l l ) ( E u ( d ~ r n ) ~ ) were purchased from Alfa Products and uscd as such. Triethylamine and diisopropylaminc were distilled from CaH? and stored over NaOH. p-Nitrobenzyl glyoxylate hydrate (15) was pre- pared from di-p-nitrobenzyl fumarate by ozonolysis (CH.CI,, -78°C) followetl by reduction with dimethylsulfidc ( 16). Analytical thin layer chromatography (tlc) was contlucted on precoatetl plates (Silica Gel 60F-254, Merck). Preparative layer chrornatography (plc) was per- formed on silica gel plates prepared from Silica Gel 60GF-254 (E. Merck). Column chromatography was carried out on Silica Gel 60 (70-230 mesh, E. Merck). 'The analyses were performed by Micro- Tech Laboratories, Skokie. Illinois, U.S.A.

p-Nitr.oDer1~~1 [4-(3-c~nr.l1c~r~1etIzo,rj~-2-~r-o~er~-l-~l)nzetidirt-2-ort-l-~l] 1zydr.o.vytrc.etcrres (5)

A mixture of 4-(3-carbometlioxy-2-propen-1-y1)-2-azetidinone (4, R = Me) ( 1 ) (3.19 g, 18.9 mmol) and p-nitrobenzyl glyoxyl:~te hydrate (4.72 g, 20.8 mmol) in benzene (200 rnL) was heated at reflux with a Dean-Stark trap for 3 h. Evaporation of the solvent gilve 8.08 g of the title compound 5 as yellow foam; R, 0.37 (EtzO-EtOAc 1 : I); ir (neat) v,,,.,,: 3400 (OH). 1750 (br, p-lactam and ester), 1725 (conj. ester), 1660 (C=C), 1520. and 1350 (NO2) crn ' ; ' ~ m r (CDC13, 60 MHz) 6: 2.3-2.9 (2H, m, I"-H). 2.65 (IH, dd, J = 15 and 3 Hz, 3'-H;,), 3.12 (IH, dd. J = 15 and 5 Hz, 3'-H,), 3.72 (3H, s, -C02Me), 3.95 ( 1 H, m, 4'-H), 4.97 ( 1 H, br. -OH), 5.33 (2H, s, -C02CH2Ar), 5.48 ( IH, br, 1-H), 5.85 ( l H, d, J = 16 Hz, 3"-H), 6.6-7.2 ( lH, m, 2'-H), 7.55 (2H, d, J = 9 Hz. ArH's), and 8.20 (2H,

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2260 C A N . J . Cl-IEivl. \

d. J = 9 Hz. ArH's) ppm. This crudc material was used in thc next stcp without any purification.

p-Nitro1)etr:yl [4-(.3-c~orho11~etIro.v~-2-1~ro~~e1r-I-~l)o~etitli1~-2-o11-l-~~l] e~hlot.otrc~rttrtc.~ ( 6 )

To a stirrctl solution of crutlc p-nitrobcnzyl [4-(3-carbomcthoxy- 2-propcn- I-yl)azctitlin-?-on- I-yl]liyclroxyacctatcs (5) (8.08 g) anel pyridinc (2.14 mL) in THF (I90 mL) was adrlcci, at - I5'C to -200C. thionyl chloridc ( 1.66 mL) ovcr a pcriod of 5 min unilcr an atmosplicrc of nitrogen. l'hc niixturc was stirrcd for 20 rnin at - 15'C. Aftcr filtration of whitc prccipitatcs and washing thc prccipitatcs with bcn- zcnc, tlic filtratc oncl washings wcrc conlbincd ancl cvaporntcd to dryncss. Thc rcsid~lc. cxtractccl with bcnzcnc, was trc21tcd with Norit and evaporation of thc solvcnt gavc 6.64 g (16.7 mmol. crudc yicld 88.6% basccl on 4. R = Mc) of tlic titlc compounds 6 as a cruclc oil: R, 0.72 (EtzO-EtOAc 1 : I); is (ncat) u,,,;,,: 1770 (br. p-lactam and estcr), 1660 (C=C), 1525, and 1355 (NO?) crn ' : 'Hmr (CDCIs, 60 MHz) 6: 2.2-3.4 (4H, m, 3'-H's and 1"-H's), 3.73 (3H. s. -C02Mc). 4.2 ( IH. rn. 4'-H). 5.35 (2H, s, -C02CH2Ar). 5.88 ( IH, d, J = 16 Hz, 3"-H), 6.23 (IH. s, I-H), 6.5-7.2 ( IH, m , 3"-H), 7.55 (2H, d, J = 9 Hz, ArH's). ant1 8.26 (2H, d . J = 9 HZ, ArH's) ppni. This crudc niatcrial was uscd in the ncxt reaction without furthcr purification.

p-Nitrohetizxl [4-(3-t~trt~bn1tietl1o,1-~-2-~~1~o~~1~11-I-~l)n~etitlit1-2-o,r-I-yI] t r i / ~ l ~ e t l y l ~ ~ h o . s ~ ~ l ~ o ~ ~ t ~ ~ ~ ~ I i t I e ~ ~ e t t c t t t e (7)

To a stirrctl solution of crudc p-rlitrobcnzyl [4-(3-c:~rbomethoxy- 2-propcn- I -yl)a7.cticlin-2-on- I-yl]chloroacctatcs (6) (6.60 g. 16.6 mmol) and triphcnylphosphinc (4.78 g, 18.3 mmol) in dioxanc (166

I mL) was addcd 2.6-luticlinc (2. I2 niL) at room tcnipcraturc undcr a

I nitrogen atmosplicrc. Thc rnixturc was stirrcd (room temp.. N,) ovcr-

1 night (23 h). Thc prccipitatc was filtcrcd and wnslicd with dioxanc. Thc filtratc and washings wcrc combincd and cvaporatccl. Thc rcsi- duc, redissolvcd in EtOAc (100 mL). was washcd with I N HCI (20 mL X 2), saturatcd NaHCO, and tlicn brinc. dricd (N;llSO,), and cvaporatcd to givc 1 1.68 g of crutlc pliosplioranc. This was purificd by column clirom;~tograpliy (300 g, EtOAc) followccl by crys- tallization from EtOAc-Et,O to yicld 6.64 g (10.7 mmol, yicld 64.3%) of thc titlc compound 7 as light ycllow crystals: nip 172"- 173°C (rccrystallizctl from EtOAc); R1 0.40 (EtOAc): ir (film) u,,,;,,: 1745 (p-lactam), 1720 (conj. cstcr). 1660 (C=C), 1625 (cstcr). 1520, and 1350 (NO?) cm-"; ' ~ m r (CDCI,, 60 MHz) 6 : 3.70 (3H, s, -C02Me), 4.83, 5.17 (2H. 2s. -C02CH2Ar), 7.55 (15H, s, +H's). and 8.19 (2H, d , J = 10 Hz, ArH's) pp~ii, thc others arc not wcll resolved. Atlal. Calcd. for C,,H,,N,O,P: C 67.52. H 5.02. N 4.50; found: C 67.70, H 5.00, N 4.47.

(2)-p-Nitrobenzyl carbapen-2-em-3-carboO~~~It~te (3) To a stirred solution of p-nitrobenzyl [4-(3-carbomethoxy-2-pro-

pen- 1-yl)azetidin-2-on- I-yl]triphenylphosphoranylideneacetate (7) (1.24 g, 2.00 mmol) in CHIClz (40 mL) was added. at 0'-5'C, tri- fluoroacetic acid (2 mL), and the yellowish mixture was cooled to -78°C. A stream of ozone was introduced until the blue colour was retained, and the solution was stirred at -78OC for another 5 min. Nitrogen was passed through the solution to remove excess ozone and then dimethyl sulfide (2 mL) was added. After removing the cooling bath, the solution was stirred at 0"-5°C for 1 h. This mixture was

. . . washed with saturated NaHCO, (50 mL x 2) and then brine, dried (NazSO,), and evaporated in vacuo (bath temperature 35"-40°C). The residue was purified by column chromatography (30 g, EtOAc-hex I : I ) , followed by crystallization from CH2CI2-Et20 to give 343 mg (1.19 mmol, yield 59.5%) of the title compound 3 as yellowish crys-

I tals; mp 153.5"- 155°C; R, 0.35 (EtOAc-hex 1 : I); ir (film) v,,,;,,: 1780 (p-lactarn), 1730 (ester), 1520, and 1350 (NOz) cm- ' ; uv (EtOH) A,,,;,,: 267 nm (E 15 900); ' ~ m r (CDCI,. 80 MHz) 6: 2.72 ( IH, ddd,J,,,,, = 1 9 H z , J , _ , = 9 H z , J l - 2 = 3 HZ, I -HZ,) ,2 .98(IH,dd,

- J,,,,, = 17 HZ, Jh-srnr,,.. - 3 HZ, 6-H;,), 3.02 ( IH, ddd. Jg,,,, = 19 HZ, Jt-3 = 9.5 HZ, J,-2 = 3 HZ. 1-Hh), 3.54(lH, dd. J ,,,,, = 17 HZ, Jh-5 <.,., = 5.6 Hz, 6-H,), 4.3 ( IH, m, 5-H), 5.16-5.33-5.38-5.55 (2H, ABq, -C02CH,Ar), 6.58 (IH, t, J = 3 Hz, 2-H), 7.60 (2H, d, J =

8.8 Hz. ArH's). and 8.23 (2H. d , J = 8.8 Hz. ArH's) ppm; 'Hmr (3, 5 mg, and Eu(dcm)?, 25 rng, in CDCI,. 0.5 nlL; 80 MHz) 6: 5.98-6.15-6.26-6.43 (1H. ABq. -CO,CH,Ar in thc 5s-isomcr), 5.98-6 15-6.32-6.50 (IH. ABq. -CO?CH,Ar in tlic 5K-isomcr), 7.01 (t, J = 3 Hz, 2-H in thc 5R-isomcr), and 7.05 ( t . J = 3 Hz, 2-H in thc 5s-isomer) ppm. Atrtrl. calcti for C14Hl,N205. C 58.33, H 4.20. N 9.72; found: C 58.34, H 4.15, N 9.60.

(-)-Metrthyl 2,4-he.rtitlie1rot1te (10) A solution of 2.4-hcxadicnoic acid ( 1 12 g, 1.00 ~nol; sorbic acid).

I-menthol (172 g, I . I0 niol), and conccntratcd sulfuric acid (10.3 mL) in bcnzcnc (1.85 L) was hcatcd at rcflux witli a Dcari-Stark trap for 5 days. Thc mixturc was coolcd and basificd by slow addition of saturatcd NaHC03 (400 mL) with vigorous stirring. Thc organic laycr was scparatcd and further washed with saturatcd NaHCO, (2 X 400 mL). The aqueous layers wcrc conibincd and cxtractcd with EtOAc (400 mL). All organic layers wcrc combincd and washcd with brinc (2 X 500 mL), dried (Na2S0,), and cvaporatcd it1 iJtrcrro to obtain 191 g of amber oil. This was purified by a silica pad consisting of Mal- linckrodt silicic acid (I00 mcsh. 1.4 L) on top of Mcrck silica gcl 60 (70-230 mesh. 1.4 L), eluting with hcxancs and then 2 and 570 E L 0 in hcxanes to yicld 116.9 g (0.467 mol, yicld 46.7%) of thc titlc compound 10 as an oil; bp 112"- 114"C/0.3 Torr (lit. (17) bp 173"C/14 Torr); R, 0.42 (Et20-hcx I:9): [el: -83.5" (c. 0.60, CH2C12); ir (ncat) u,,,;,,: 1705 (cstcr), 1645, and 1620 (C=C) crn-I; ' ~ m r (CDC13, 60 MHz) 6: 0.77 (3H, d, J = 7 Hz, -Me), 0.90 (6H, d , J = 7 Hz. gem-Me). 0.8-2.2 (9H, ni, -CH, CHI-), 1.85 (3H. d, J = 4.5 Hz, 5-Me). 4.73 ( IH, td. J .,-., = 9 H z . J .,-, = 2 Hz,

I -CO~CH-), 5.6-6.2 (3H, m, olcfinic protons), and 7.0-7.45 ( IH. m, 5-H) ppm.

(-)-Metitlryl 3,5-l~ctrtrtlietlntrte (11) To a stirrcd solution of diisopropylaniinc (140 I ~ L , 1.01 mriiol) in

THF (2.4 L) was addcd at 0'-S°C, undcr a nitrogcn atniosphcre. n-butyllithium (500 mL, 2.02 M in hcxanc. 1.01 mol) ovcr a pcriod of 30 rnin. Aftcr stirring for 30 min. tlic light ycllow solution was coolcd to -75' to -78°C. A solution of licxanicthylphospliora1i1idc ( I80 mL, 1 .OO niol) in THF (I00 niL) was adclcd ovcr- a pcriod of 20 min. and thc rnixturc stirrcd for I h. To this rnixturc was addcd a solution of (-)-n~cnthyl 2.4-licxadicnoatc (10) (200 g, 0.80 mol) in THF (100 mL) during a 15 niin pcriod. and thc resulting dark red niixturc was stirred (-78"C, N,) for 2 h. This was pourcd into a solution of conccntratcd HCI (200 rnL) in watcr (800 mL) and cx- tracted with EtOAc (3 X 500 mL). Thc EtOAc cxtracts were washed with water (5 X 500 mL) and then brine (500 niL), dricd (Na2S0,), and evaporated it7 vtrclro to yicld 189.2 g (0.756 rnol. crudc yicld 94.5%) of the title compound 11 as an amber oil. This crudc oil was used in the subsequcnt reaction without any purification. An analytical sample was obtained by distillation followed by plc (Et2O-hex 1 :9); bp 95"-97"C/0.2 Torr; R, 0.52 (Et20-hex 1 :9); [a]:' -70.2" (c 1.0, CHzCIZ); ir (ncat) v,,,;,,: 1735 (ester), 1650, and 1605 (C=C) cm-I; 'Hmr (CDCI,, 60 MHz) 6: 0.77 (3H, d, J = 7 Hz, -Me), 0.90 (6H,

I d, J = 7 Hz, get,?-Me), 0.8-2.2 (9H. m, -CH- and --CHz-), 3.10 (2H, d, J = 6 Hz, 2-H's), 4.69 (IH, td, J ;,-;, = 9 Hz, I;,-, = 4 Hz, -C02--CH-), 5.0-5.4 (2H, n1, olefinic protons), and 5.7-6.7 (3H, m, olefinic protons) ppni. Atrtrl. calcd. for CI~HZ(,OZ: C 76.75. H 10.47; found: C 77.02. H 10.56.

4(S)- trtld 4 (R)-(3-ctrrbott~etitI~~lo.~y- I -pt.ol>etiyl)-2-azrticli1iot1es (12 a ntrtl 12 b)

To a stirred solution of crude (-)-mcnthyl 3.5-hexadienoate (11) (184.2 g. 0.737 mol) in CH2CI2 (2.3 L) was added at 0"-5" C. under a nitrogen atniosphcre, chlorosulfonyl isocyanate (72.0 niL. 0.819 mol) ovcr a period of 22 niin. Thc niixturc was stirrcd at room temperature for 24 h. This mixturc was added slowly to a nicchanical- ly stirrcd mixturc of sodium sulfite (460 g, 3.65 mol) in watcr (2.3 L) and CH2C12 (0.9 L) at 0"-5°C. During the addition, the mixture was adjusted to pH 7-9 by siniultancous addition of saturated NaHC03

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VOL h l . I9Si

p-Nirrob~rr:yl [4(S)- ( i -c~tr1~hor i1er1r l r~Io.~y--7- l~r~o~~r11- l -y l ) r r :er i t l i r1-2- I - - ] f / l l / l l O . ~ / ~ l O t l ~ l / t l l t l t t f l f (13 b)

The titlc cornpountl. 4.12 g (5.52 mmol. yicltl 68.0%. based on 46). was prepared as yellow foam from 4(S)-(3-c;1rbome11tIiy1c1xy-2- propcn- I-yl)-2-azctitlinonc (411) (2.93 g. 10.0 mmol) by the method dcscribctl above for tlic 4li-isomer, throu4i the corrcspontlin, '

s'l (7 Illtcr-

mediates: K, 0.47 (EtOAc-Et20 I : I ) : [a] , --0.2" (t. 1.3, CH,C12); ir (film) v,,,;,,: 1750 (p-luct;~m), 17 I5 (conj. cstcr), 1655 (C=C). 1630 (ester), 1420, and 1350 (NO?) cm ' : l ~ r i i ~ . (CDCIt, 60 MHz) 6: 0.75 (3H, d. J = 7 Hz. -Me). 0.88 (6H. (I . J = 7 Hz, gerrr-Me), 7.2-8.0 (17H, m. ArH's). ;uid 8.2 (2H, d. J = 9 Hz. ArH's) ppm, the rest arc not well rcsolvctl. Ailtrl. calcd. for C,,HJ7N207P: C 70.76. H 6.34, N 3.75; found: C 70.47. H 6.42. N 3.69.

p-Nifro1~~~11zyI 5(R)-ctirl~t1~~c~r1-2-err~-3-~~~1rl~o.~ylt1~~~ (3a) To a stirrcd solution of 1)-nitrobcnzyl [4(K)-(3-carbomenthyloxy-

-2-propcn- l -yl)azctidin-2-on- l -yl]triphcnylphospIior;11~ylic1~1i~~1cctatc (130) (747 mg, 1 .OO rnrnol) in CHIC12 (20 mL) was addcd at 0"-5°C trifluoroacctic acid (2 rnL) and the resulting ycllow solution was cooled to -78'C. A stream of ozonc was introduced until the blue colour was rctaincd and the mixture was stirred at -78°C for another 5 min. Nitrogcn was bubbled through tlic solution to remove cxccss ozonc and thcn dimcthyl sulfidc (1.5 mL) was addctl. After removing the cooling bath, thc mixture was stirrcd at 0"-5°C for I 11 and washcd successively with saturated NaHCO, (50 mL X 2) and brinc. The organic layer was dried (Na2S0,) and evaporated iir 1,ncrro (bath tem- perature 35"-40°C) to yicld a crude oil. This was purified by column chromatography (30 g, EtzO) to give 197 mg (0.683 rnmol. yicld 68.3%) of the titlc compound 30 as a yellow solid. An analytical sample was obtained, by rccrystallization From CH2CI2-Et20, as whitc crystals: mp 123"- 124°C; R, 0.35 (EtOAc-hex I : I); [a]:' + 127.5" ( c l .O, CH2C12); ir (film) v,,,,,: 1780 (p-lactnm), 1725 (cstcr), 1520, and 1350 (NO?) em- '; uv (EtOH) A,,,.,,: 267 nrn (E 14 800): 'Hmr (CDCI?, 80 MHz) 6: 2.72 (IH. ddd, J ,,,,, = 19 Hz. J l _ 5 = 9 Hz, JI-2 = 3 HZ. I-H;,), 2.98 ( IH, dd, J ,,,,, = 17 HZ. J,,-5 ,,<,,, ,> = 3.3 HZ, 6-HD), 3.02 ( l H . ddd, J,,,,, = 19 HZ, = 9 HZ, J I - 2 = 3 HZ, I-HI,). 3.54 ( IH, dd, J ,,,,, = 17 Hz. J h-5 = 5.5 HZ. 6-H,,), 4.3 (IH. In, 5-H,,). 5.16-5.33-5.38-5.55 (2H. ABq, -C02CH2Ar), 6.58 ( I H, t, J = 3 Hz. 2-H), 7.60 12H, d, J = 8.8 Hz, ArH's), and 8.23 (2H, d, J = 8.8 Hz. ArH's) ppm: 'Hmr (3tr. 5 mg, and Eu(dcm),, 25 mg, in CDC1,. 0.5 mL; 80 MHz) 6: 5.98-6.15-6.32-6.49 (2H, ABq, -C02CHIAr), and 7.01 ( IH, t . J = 3 Hz, 2-H) ppm. Airtrl. calcd. for C l ~ H I ~ N Z 0 5 : C 58.33, H 4.20, N 9.72; found: C 58.37, H 4.18, N 9.72.

p-Nifrobei~zyl 5-(S)-cc1rD~pei1-2-ern-3-ctrr~l)o.vyI(11e (3 b) The crudc titlc compound was obtaincd from 1)-nitrobcnzyl [4(S)-

(3-carbomenthyloxy-2-propen- l -y l)azetidin-2-on- I-y1]t1-iphenylphos- phoranylidcneacetate (136) (747 mg, l .OO mniol) by the method dc- scribed for the SR-isomcr. This material was purified by column chromatography (20 g, EtOAc-hex 1 : 1 ) to yicld 182 my (0.791 mmol, yicld 79.1%) of mcnthyl glyoxylatc hydrate as whitc solid: mp 78"-81°C (EtzO-pentanc); R, 0.75 (EtOAc-hex I : I): [a]:' -77.0" (C l .O, CH,C12); ir (film) v,,,.,: 3420 (OH) and 1740 (cster) em- ' : and 197 mg (0.683 mmol, yield 68.3%) of the titlc compound as a whitc solid; mp 122"- 124°C (rccrystallizcd from CH,Cl2-Et,O); Rr 0.35 (EtOAc-hex 1 : 1); [a]:' - 110.8" (C 1 .O, CH2CIZ); ir (film) v,,,.,,: 1780 (p-lactam), 1730 (ester), 1520, and 1350 (NO,) c m - ' ; uv (EtOH) A,,,,,: 267 nm (E 15 600); 'Hmr (CDC13. 80 MHz) 6 : 2.73 ( I H , ddd, J,,,,,= 19Hz, J , _ , = 9 H z . J l - z = 3 H z . I-H;,), 2.98 ( l H , d d , J ,,,,, - - 17 H z . 5 ~ 5 , ~ ~ ,,,., = 3 HZ, 6-H,). 3.03 (IH. ddd, J ,,,,, = 19 HZ, J I - 5

= 9.5 Hz, Jl-2 = 3 HZ. I-H,), 3.55 ( l H , d d , J ,,,,, = 17 Hz.Jb-5 <.,\ = 5.5 Hz, 6-H,,), 4.3 ( IH, m, 5-H,), 5.16-5.34-5.38-5.56 (2H, ABq, -COzCH?Ar), 6.59 ( IH, t, J = 3 Hz, 2-H), 7.60 (2H. d, J = 8.8 Hz, ArH's), and 8.23 (2H, d , J = 8.8 Hz, ArH's) ppm; 'Hmr (30, 5 mg, and Eu(dcm),, 25 mg, in CDCI,, 0.5 niL; 80 MHz) 6: 5.98-6.15-6.27-6.45 (2H, ABq, -C02CHIAr), 6.34 (a part of the

ABq in the SR-isomer). anel 7.05 ( IH. t. J = 3 Hz. 2-H) ppm. Ar~rrl. calcd. for CI,HI2N2Oi: C 58.33. H 4.20, N 0.72: Sound: C 58.08. H 4.26, N 9.93.

N-tcrt-h~rfyltli111c~tI1yI.~iIyl-l(R)-(3-c~trrOori1er1tI1yIt~.vy-2-~~ro~~er1- I -!I)-?- trzetitlirror~e (14a)

To a stirrcd solution of 4(R)-(3-carbomcnthyloxy-2-propcn-1-yI)- 2-azctidinone (40) (1.91 g. 6.52 rnrnol) and rerr-butyldinicthylsilyl chloride (1.11 g. 7.37 mrnol) in dimcthylt'ormamidc (20 mL) was addcd at 0°C untlcr a nitrogen atmosphere tricthylaminc (1.04 mL. 7.5 mmol), causing whitc precipitation. ?'he mixture was stirrcd at room temperature overnight ( I8 h). and thcn diluted with watcr (100 mL) and Et20 (65 niL). After shaking. the separated orgi~nic laycr was washed with watcr (80 mL X 3) , then brinc, tlrictl (Na2S0.,), and evaporated to 2.56 g of an oil. This was crystallized from pcntanc at O°C, yielding 2.10 g (5. I5 mrnol, yicld 79.0%) of tlic titlc compound 14a as off-white c~ystals: mp 80.5"-81.5"C; R, 0.54 (EtOAc-hex 1 :4); [a]:' - 1 16.0' (c 1 .O. CH2CIZ): ir (film) v,,,;,,: 1750 (p-lactam), 17 15 (conj. cstcr), and 1655 (C=C) cni - I : ' ~ m r (CDCI,, 80 MHz) 6: 0.23 (3H, s, Si-Me), 0.25 (3H, s, Si-Me), 0.76 (3H, d. J = 7 Hz, -Me), 0.89 (6H, d. J = 7 Hz, geril-Me), 0.96 (9H. s , Si-tBu), 2.64 ( 1 H, dd. J,,,,, = 15 HZ, Jj_.r, ,,,,,, , = 3 HZ. 3-H,,), 3. 19 ( IH, tld, J ,,,, , = 15 Hz. J,_,,-,, = 5 Hz, 3-H,,). 3.65 ( IH, m. 4-H,,). 4.75 ( I H , td, J ;,-, = 10 HZ, J:,-, = 4 HZ, -CO,CH-), 5.85 ( I H, dt. Jz,_l, = 15.7 Hz. J,,L = 1.4 Hz, 3'-H). and 6.83 (IH. dt. J2.-,. = 15.7 Hz, J2 ._ ,. = 7 Hz, 2'-H) ppln. Anal. cnlcd. for CZ3H,,NO,Si: C 67.76. H 10.14. N 3.44: found: C 67.85, H 10.07. N 3.76.

N-tcrt-l~~1f~~lrlirr1~~tI1~I.riI~l-4( S)-(3-c.~rbori1er1fI1ylo,ry-.3-1)ro1~~1- 1-).I)-?- a:efirlitrot~e (14b)

Thc crude titlc compound (9.0 g) was prepared as an oil from 4(S)-(3-carbomcnthyloxy-2-propen-I-yl)-2-azctidinonc (41)) (6.70 g, 22.87 mmol) by tlic method described for the 4(R)-isomer. This was purified by column chromatography (270 g, EtOAc-hcx 1.4) to ob- tain 8.10 g (19.9 mmol, yicld 87.0%) of the titlc cornpountl 14B as a colourlcss oil: R, 0.54 (EtOAc-hex 1.4) ; [a]:' +9.0° (c. l .O. CH2CII): ir (neat) v,,,;,,: 1750 (p-lactam), 17 15 (conj. cster). and 1655 IC=C) c m ' : ' ~ m r (CDCI?, 80 MHz) 6: 0.22 (3H, s, Si-Mc), 0.24 (3H, s, Si-Me), 0.75 (3H, d. J = 7 Hz, -Me). 0.88 (6H, d , J = 7 Hz. geiif-Me), 0.95 (9H, s, Si-f Bu), 2.63 ( IH, dd. J ,,,,, = 15 Hz, J,-,r,c,,,r = 3 Hz, 3-H,,), 3.18 ( IH, dd, J ,,,,, = 15 Hz. Ji-, ,,, = 5 Hz. 3-Hp), 3.6 ( IH, m, 4-H,,), 4.74 ( IH, td, J .,-,, = 10 Hz, J .,-, = 4 Hz, -CO?CH-), 5.85 ( IH, dt, J3,-2, = 15.7 HZ, J,,- 1 . = 1.4 HZ, 3'-H), and 6.82 (IH, td. JZ.-?, = 15.7 HZ. Jz._l , = 7 Hz, 2'-H.

N - t e r t - D u f y l r l i i i 1 e t / 1 y l s i l y l - 3 ( S ) - ~ (15a) (a) Froiii cori~po~rrrd 14a A suspension of potassium permanganatc (474 rng, 3.00 mrnol) in

watcr (5 mL) was vigorously stirred for 10 min and cooled to 5"- 10°C while tolucne (2 mL), tctrabutylammonium bromide (50 mg), and a solution of N-rer1-butyldimcthyIsilyl-4(R)-(3-carbomcnthyloxy-2- propen-I-yl)-2-azetidinonc (14n) (408 mg, l .OO mmol) in EtOAc (3 mL) were addcd successively. The mixture was stirrcd at room tcm- perature for 1 h and then thc reaction was qucnched by successive addition of a solution of sodium bisulfite (937 mg) in watcr (9 mL), EtOAc (10 mL). and thcn 3 N HCI (3 mL). The organic laycr was collcctcd and the aqueous laycr cxtracted with EtOAc. All organic layers were combined, washed with brine, dried (Na2S0,), and evap- orated to obtain 507 mg of a crude gum. This was purified by column chromatography (30 g, acctonc-tolucne I : I ) to yicld 123 mg (0.505 mmol, yicld 50.5%) of thc titlc compound 150 as an amorphous solid;

7 I mp 100"- 105°C; R,- 0 .4 (acetone-toluene I : 1 . clongatcd spot); [a], -67.5" (c 1.0, CH2C12); ir (film) v,,,;,,: 2500-3500 (br, -C02H), 1730 (p-lactam), and 1680 (-C02H) c ~ n - ' ; 'Hmr (CDCI3, 80 MHz) 6: 0.22 (3H, s, Si-Me), 0.25 (3H, s , Si-Mc), 0.95 (9H. s, Si-rBu), 2.50 ( I H , dd, J ,,,,, = 16 HZ, J l ,_, = 9.8 HZ, -CH-C02H), 2.79 ( IH, dd, J ,,,,, = 15.7 Hz, J,_, ,,,,,,, = 2.8 Hz), 2.93 (1H. dd, J ,,,,, = 16 HZ, Jl.-, = 4.1 Hz, -CH-COZH), 3.33 ( I H , dd, J ,,,,, = 15.7 HZ, J ,-.,,.,, = 5.3 Hz, 3-H,), 3.9 ( IH, m, 4-H,), and 6.25 (br, -C02H) ppm.

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UEDA FT i\L 2263

(b) F~.orii c.ar~rpol~~ltl 16 6. J . H. BATESON and P. M. R o B E R . ~ ~ . (Bcccham Pharmaccuticals). Thc titlc compo~lnd 15tr (97 mg, 0.40 mmol. yicld 40%) was Europcan Patcnt Applic;ltion 0 008 888 (1980); Chcm. Absts. 94,

pscparctl as whitc foam from N-tr1~t-butyltlinictl1ylsilyl-4(R)-a1l~l-2- P3917f (1981). azctitlinonc (16) (2241112. 1.00mmol) by the rnctliod tlcscsibctl abovc; 7 . W. L. PARKER, M. L. RATHNUM, J . S. WELLS. JR . . W. H. R, 0 .4 (ncctonc-tolucnc I : I , clonpatcd spot); [a]:' -80.3' (c I .O. TREJO, P. A. PRINCIPE, and R. B. SYKES. J. Antibiot. 35. 653 CHZCI,). Thc 'Hms (CDCI,. 80 MHz) and ir (film) spectra wcsc (1982). identical with those obtained from 14n. 8. ( ( 2 ) R. SC,\RTAZZINI. H. PETER, H. BICKEL. K. HEUSI.ER. and

N-tcrt-hrrr~~lrlir11e~I1~I.sil~l-3(R)-c~trr/~o.v~~i~~~tl1~l-2-ci:~~tidir~or~e (15b) The titlc compountl 156 (5.07 mg. 2.08 niniol. yicld 69.3%) was

obtainctl as off-whitc foam from N-ter.t-butyltli11ict11ylsilyl-4(S)-(3- carborncnthyloxy-2-propcn- I -yl)-2-azctidinonc ( 14b) ( 1.223 g. 3.00 mlnol) by tlic mctliotl tlcscribcd abovc for thc 4s-isomer; R, 0.4 (acctonc-tolucnc I : I . clongatcd spot); [a]:' +36.b0 (c 1.0, CH2CI2). Thc ' ~ m r (CDC13, 80 MHz) ancl i r (Film) spcctra wcrc identical with thosc of thc 4s-isonicr.

R. B. WOODWARD. HcIv. Chiln. Acta, 55,408 (1972); ( h ) R. B. WOO~)WARD. K. HEUSLER. 1. EKNEST. K. BCRRI , R. J. F R I A R Y . F. HAVIV, W. OPPOLOZEII, R. PI\IONI, K . SYHORA, R. WEKGER. and J. K . WHITESELL. Nouv. J. Chini. 1, 85 (1977); ( c ) 1. ERNEST, J. GOSTELI, C. W. GREENGRASS, W. HOLICK. D. E. J I \ ~ K M I \ N , H. R. PFAENDLER. ant1 R. B. wOoDw~\l<D. J. Am. Chcm. Soc. 100, 8214 (1978).

9 . H. R. PFAENDLER. J. GOSTELI, and R. B. WOODWAIID. J. Am. Clicm. Soc. 101. 6306 (1979).

10. ( ( I ) J . K . RASMUSSEN and A. HASSNER. Chcm. Rcv. 76. 389 Acknowledgeme~its (1976); ( h ) W. A. SZI\BO. Aldricliin~ica Acta. 10, 23 (1977).

W e would like to thank Professor B. Belleau of McGill I I. T. DURST ant1 M. J. O'SULLIVAN. J. Org. Chcm. 35. 2043 University and Dr. M . MCnard for their interest in this work. ( 1970).

W e also thank Mr. G. Lacasse for 80 MHz 'Hmr spectra. 12. ((1) G . R. SULLIVAN. 111 Topics in stcrcocliemistry. Vol. 10. Etliretl by E. L. Elicl and N. L. Allinpcr. lntcrscicncc - John

1. Y. UEDA. C. E. DAMAS, and B. BELLEAU. Can. J . Chcln. 61. 1996 (1983).

2. L. D. CAMA and B. G. CIHRISTENSEN. J. Am. Chcm. Soc. 100, 8006 ( 1978).

3. ((1) A. J. G. BAXTER, K. H. DICKINSON. P. M. ROBERTS, T. C . SMALL. and R. SOUTHGATE. J . Chern. Soc. Clicln. Commun. 236 (1979); (0) J. H. BATESON. A. J. G. BAXTER. P. M. ROBERTS, T. C. SMALL, and R. SOUTHGKI'E. J. Chcm. Soc. Pcrkin Trans. 1 , 3242 (1981).

4. H. ONOUE. M. NARISADA. S. UYEO, H. MATSUMURA, K. OKADA. T . YANO. and W. NAGAT,\. Tctraliedron Lett. 3867 (1979).

5. H. R. PFAENDLER. J. GOSTELI. R. B. WOODWARI). and G. RIHS. J. Am. Chcm. Soc. 103. 4526 (1981).

Wiley and Sons. Ncw York. 1978. pp. 288-329: (0) M. D. MCCREARY, D. W. LEWIS, D. L. WERNICK, and G. M. WIHITE- SIDES. J. Am. Chcrn. Soc. 96. 1038 (1974).

13. A. W. HERRIOTT and D. PICKER. Tctrahcdron Lctt. 15 1 1 (1974). 14. M. J. BASKER, J . H. BATESON, A . J. G. BAXI'ER, R. J.

PONSFORD. P. M. ROBERTS. R. SOUTHGATE, T. C. S ~ I A L E , and J. SMITH. J . Antibiot. 34. 1224 (1981).

15. E. G. BRAIN, A. J . EGLINGTON, J . H. C. NAYLER. N. F. OSBORNE, R. SOUTHG~ITE. and P. M. TOLLIDAY. J. Chcm. Soc. Pcrkin Trans. I , 2479 (1977).

16. M. MENARD and A. MARTEL.. (Bristol-Myers Co.). U.S. Patcnt 4,282,150 (1981).

17. H. RUPE. Justus Licbigs Ann. Chcm. 327, 157 (1903).

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