Tandem Ireland-Claisen rearrangement ring-closing alkene metathesis in the construction of bicyclic β-lactam carboxylic esters

Article abstract of DOI:10.1021/jo991932s

4-Alkenyl-2-azetidinone systems were converted to the corresponding ethyl 2-[4-alkenyl-2-oxo-1azetidinyl]-4-pentenoates. In addition, 4-(2- propenyl-1-oxy)-, 4-(2-propenyl-1-thio)-, 4-[N-(2-propenyl)(4- toluenesulfonyl)]- and (3S,4R)-4-(2-propenyl)-3-[(1R)-1-(tert- butyldimethylsilyloxy)ethyl]-azetidin2-one were converted into β-lactam dienes via sequential N-alkylation, Ireland-Claisen ester enolate rearrangement and esterification. Ring-closing metathesis using the Schrock [(CF₃)₂MeCO]₂-Mo(=CHCMe₂Ph)(=NC₆H₃-2,6-iso-Pr₂) (1) or Grubbs Cl₂(Cy₃P)₂Ru=CHPh (2) carbenes gave a series of [5.2.0] and [6.2.0] bicycles. Subsequent elaboration of the analogous (2R*,7R,8S)-tert-butyl 8- [(1R)(tert-butyldimethylsilyloxy)ethyl]-1-aza-9-oxobicyclo[5.2.0]non-4-ene-2- carboxylate (15), via selenation and desilylation, gave (+)-(2S, 7R, 8S)- tert-butyl 8-[(1R)-hydroxyethyl]-1-aza-9-oxobicyclo[5.2.0]nona-2,4-diene-2- carboxylate (18), a novel type of bicyclic β-lactam. Diels-Alder cycloaddition further afforded tetracyclic systems exemplified by tert-butyl (1R,4S,5R,7S)-4-[(1R)-1-hydroxyethyl]-3,9,11-trioxo-10-phenyl-2,8,10,12- tetraazatetracyclo[5.5.2.^2,50^8,12]tetradec-13-ene-1-carboxylate (19).

Full text of DOI:10.1021/jo991932s

3716
J . Org. Chem. 2000, 65, 3716-3721
Ta n d em Ir ela n d -Cla isen Rea r r a n gem en t Rin g-Closin g Alk en e
Meta th esis in th e Con str u ction of Bicyclic â-La cta m Ca r boxylic
Ester s
Anthony G. M. Barrett,*,† Mahmood Ahmed,† Simon P. Baker,† Simon P. D. Baugh,†
D. Christopher Braddock,† Panayiotis A. Procopiou,*,‡ Andrew J . P. White,† and
David J . Williams†
Department of Chemistry, Imperial College of Science, Technology and Medicine, South Kensington,
London, UK SW7 2AY, and Department of Medicinal Chemistry, GlaxoWellcome Research and
Development Ltd, Gunnels Wood Road, Stevenage, Hertfordshire, UK SG1 2NY
Received December 17, 1999
4-Alkenyl-2-azetidinone systems were converted to the corresponding ethyl 2-[4-alkenyl-2-oxo-1-
azetidinyl]-4-pentenoates. In addition, 4-(2-propenyl-1-oxy)-, 4-(2-propenyl-1-thio)-, 4-[N-(2-propenyl)-
(4-toluenesulfonyl)]- and (3S,4R)-4-(2-propenyl)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-azetidin-
2-one were converted into â-lactam dienes via sequential N-alkylation, Ireland-Claisen ester enolate
rearrangement and esterification. Ring-closing metathesis using the Schrock [(CF3)2MeCO]2-
Mo(dCHCMe2Ph)(dNC6H3-2,6-iso-Pr2) (1) or Grubbs Cl2(Cy3P)2RudCHPh (2) carbenes gave a series
of [5.2.0] and [6.2.0] bicycles. Subsequent elaboration of the analogous (2R*,7R,8S)-tert-butyl 8-[(1R)-
(tert-butyldimethylsilyloxy)ethyl]-1-aza-9-oxobicyclo[5.2.0]non-4-ene-2-carboxylate (15), via selena-
tion and desilylation, gave (+)-(2S,7R,8S)-tert-butyl 8-[(1R)-hydroxyethyl]-1-aza-9-oxobicyclo[5.2.0]-
nona-2,4-diene-2-carboxylate (18), a novel type of bicyclic â-lactam. Diels-Alder cycloaddition further
afforded tetracyclic systems exemplified by tert-butyl (1R,4S,5R,7S)-4-[(1R)-1-hydroxyethyl]-3,9,-
11-trioxo-10-phenyl-2,8,10,12-tetraazatetracyclo[5.5.2.0.2,508,12]tetradec-13-ene-1-carboxylate (19).
The rapid espousal of ring-closing metathesis by syn-
While these results clearly established that polyfunc-
tional â-lactam dienes were excellent substrates for
metathesis, the reactions were not appropriate for the
synthesis of bioactive â-lactam carboxylic acids. For this
metathetic approach to find utility in the generation of
novel drug candidates, it is essential that it be capable
of installing a carboxylic acid motif adjacent to the lactam
nitrogen. Herein we disclose methods for incorporating
the requisite framework via Ireland-Claisen rearrange-
ment13 and subsequent alkene metathesis. Such a strat-
egy has recently been shown to be versatile for the
synthesis of cyclohexenes, dihydropyrans, tetrahydro-
pyridines, and related heterocycles.14-16 Furthermore, we
disclose a novel type of bicyclo[5.2.0]dienes, derived from
the aforementioned systems, which was elaborated by
Diels-Alder cycloaddition to tetracyclic â-lactam sys-
tems.
thetic organic chemists, following the introduction of well-
defined molybdenum 11 and ruthenium catalysts 2,2 is
remarkable.3,4 Such atom economic cyclization reactions
have found application in the synthesis of carbocyclic,
heterocyclic, and macrocyclic arrays.5-10 Recently, we
reported the use of ring-closing metathesis in the as-
sembly of simple bicyclic â-lactams,11 and extended the
reaction to related enyne and dienyne â-lactam systems.12
Resu lts a n d Discu ssion
† Imperial College of Science, Technology and Medicine.
‡ GlaxoWellcome Research and Development Ltd.
(1) Schrock, R. R.; Murdzek, J . S.; Bazan, G. C.; Robbins, J .; Dimare,
M.; O’Reagan, M. J . Am. Chem. Soc. 1990, 112, 3875-3886.
(2) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041.
(3) Armstrong, S. K. J . Chem. Soc., Perkin Trans. 1 1998, 371-388.
(4) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(5) Chang, S.; Grubbs, R. H. J . Org. Chem. 1998, 63, 864-866.
(6) Peters, J . U.; Blechert, S. Chem. Commun. 1997, 1983-1984.
(7) Clark, J . S.; Kettle, J . G. Tetrahedron Lett. 1997, 38, 127-130.
(8) Fu¨rstner, A.; Mu¨ller, T. Synlett 1997, 1010-1012.
From our previous work in this field,12 and in view of
their ready accessibility from commercially available
precursors, â-lactams 3a -c were chosen. Reaction with
ethyl glyoxalate followed by acetylation gave the corre-
sponding acetates 5a -c, which underwent smooth C-
allylation with allyltrimethylsilane and boron trifluoride
etherate to give dienes 6a -c as approximately 1:1
mixtures of diastereoisomers (Scheme 1). Attempts to
(9) Morehead, A.; Grubbs, R. Chem. Commun. 1998, 275-276.
(10) Ahmed, M.; Barrett, A. G. M.; Beall, J . C.; Braddock, D. C.;
Flack, K.; Gibson, V. C.; Procopiou, P. A.; Salter, M. M. Tetrahedron
1999, 55, 3219-3232.
(11) Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles, M. R.;
Marshall, E. L.; Procopiou, P. A. Chem. Commun. 1997, 155-156.
(12) Barrett, A. G. M.; Baugh, S. P. D.; Braddock, D. C.; Flack, K.;
Gibson, V. C.; Giles, M. R.; Marshall, E. L.; Procopiou, P. A.; White,
A. J . P.; Williams, D. J . J . Org. Chem. 1998, 63, 7893-7907.
(13) Ireland, R. E.; Wipf, P.; Armstrong, J . D. J . Org. Chem. 1991,
56, 650-657.
(14) Picoul, W.; Urchegui, R.; Haudrechy, A.; Langlois, Y. Tetrahe-
dron Lett. 1999, 40, 4797-4800.
(15) Burke, S. D.; Ng, R. A.; Morrison, J . A.; Alberti, M. J . J . Org.
Chem. 1998, 63, 3160-3161.
(16) Miller, J . F.; Termin, A.; Koch, K.; Piscopio, A. D. J . Org. Chem.
1998, 63, 3158-3159.
10.1021/jo991932s CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/16/2000

Construction of Bicyclic â-Lactam Carboxylic Esters
J . Org. Chem., Vol. 65, No. 12, 2000 3717
Ta ble 1. Rin g-Closin g Meta th esis of Dien es 6a -c, 9d -g
Sch em e 1
Sch em e 2
a
All reactions performed in CH2Cl2 (0.05 M) under nitrogen for
12 h with 20 mol % ruthenium carbene 2 unless otherwise stated.
b
Combined yield of separated chromatographed diastereoisomers.
c 5 mol % molybdenum carbene 1 employed. Figure in parenthe-
d
ses denotes isolated yield after further addition of 5 mol %
molybdenum carbene 1. e Inseparable mixture of diastereoisomers.
f All substrate consumed within 1 h.
extend the protocol to generate heteroatom 4-substituted
lactams were unsuccessful. This is presumably due to
competing endocyclic iminium ion formation. These
problems were not alleviated by recourse to other Lewis
acidic catalysts, including trimethylsilyl trifluoromethane-
sulfonate and titanium tetrachloride, nor by modifying
the nature of the leaving group (p-nitrobenzoate, trifluo-
romethanesulfonate, methanesulfonate). Therefore, it
was necessary to develop an alternative approach to avoid
these limitations.
We considered that such dienes could alternatively be
prepared via Ireland-Claisen rearrangement13 of silyl
ketene acetals derived from allyl esters 7d -g. Thus,
alkylation of â-lactams 3d -g with allyl bromoacetate
furnished the Ireland-Claisen precursors 7d -g (Scheme
2). Much to our delight, following the conditions of
Baldwin and co-workers17 the corresponding silyl ketene
acetals underwent smooth rearrangement affording the
carboxylic acids 8d -g in excellent yield. Gratifyingly, the
reaction proved to be perfectly amenable to scale-up, the
rearrangement reactions being conducted on up to a 20
g scale. As in the case of the allylation reactions, the
carboxylic acids 8d -g were formed as inseparable 1:1
mixtures of diastereoisomers.
p-nitrobenzyl esters 9d -g. Attempted ring-closing me-
tathesis of vinyl azetidinone 6a (Table 1, entry 1) failed
to provide any ring-closed adducts, as expected on the
basis of previous investigations.12 However, both dia-
stereoisomers of dienes 6b and 9g underwent clean ring-
closing metathesis in the presence of the ruthenium
carbene 2 to provide the homocarbacephems 10b and 10g
in excellent yields (entries 2, 7). Eight-membered ring
closures leading to â-lactams 10d and 10f proceeded
equally smoothly in the presence of catalyst 2 (entries 4,
6). The two diastereoisomers of diene 6c were found to
cyclize at substantially different rates, giving â-lactams
10c as a 2:1 mixture of diastereoisomers. This rate
difference is thought to arise from the relative orientation
of the ester functionality in the diastereoisomeric transi-
tion states leading to the ring-closed adducts.12 Treat-
ment of thiadiene 9e with the ruthenium carbene 2
resulted in immediate catalyst decomposition; however,
the use of the molybdenum carbene 1 (5 mol %) resulted
in rapid cyclization (2 h) to provide thioalkene 10e as a
single diastereoisomer. The remaining uncyclized dia-
stereoisomer 9e underwent slow metathesis (24 h) with
additional molybdenum carbene 1 (5 mol %). The relative
Though these products presented no inherent func-
tional group incompatibility issues in metathesis reac-
tions mediated by catalyst 2, carboxylic acids 8d -g had
only limited solubility in chloroform or dichloromethane,
the optimal solvents for metathesis using carbenes 1 or
2, and were directly converted into the corresponding
1
positions in the H NMR spectra of the protons R to the
ester, in concert with X-ray crystallography of desilylated
(2R)-11g, provided the necessary information for the
assignment of their structures. The utility of the above
method for the preparation of compounds with potential
biological activity was demonstrated by the saponification
of ester 10b to provide the bicyclic â-lactam carboxylic
acid 11b in 72% yield.
(17) Baldwin, J . E.; Bradley, M.; Turner, N. J .; Adlington, R. M.;
Pitt, A. R.; Sheridan, H. Tetrahedron 1991, 47, 8203-8222.

3718 J . Org. Chem., Vol. 65, No. 12, 2000
Barrett et al.
Sch em e 3
Sch em e 4
conversion to diene 18.19 It was always our hope that the
ester could be cleaved under the necessarily mild condi-
tions required to maintain the integrity of the diene
motif. Trifluoroacetic acid, although routinely used for
such operations, was viewed to be unduly harsh in our
circumstances, directing our attention to the procedure
of Torii and co-workers,20 who demonstrated the removal
of â-lactam tert-butyl esters by using neat phenol. This
cleavage is believed to be mediated by proton relay
through a hydrogen-bonded phenolic matrix. This was
indeed found to be a suitable method in this case,
although it was observed that, on larger scale, the rate
of reaction could be significantly increased by the addition
of trace amounts of trifluoroacetic acid, without signifi-
cantly deleterious effect, acid 12 being obtained in 65%
yield.
We also had occasion to investigate the synthesis of
[5.2.0] bicyclic diene systems, exemplified by 12. Thus,
ester 10g was allowed to react with LDA and phenyl-
selenyl bromide in THF in an attempt to furnish 13. The
With a route to such endocyclic dienes established, it
seemed wise to probe their suitability in Diels-Alder
reactions (Scheme 4). To this end, ester 18 was allowed
to react with 4-phenyl-1,2,4-triazoline-3,5-dione, affording
the cycloadduct 19 in high diastereoselectivity (endo:exo
> 20:1).
In conclusion, we have demonstrated the facile as-
sembly of bicyclic â-lactam carboxylic esters and hence
carboxylic acids via tandem Ireland-Claisen rearrange-
ment and subsequent alkene metathesis. It is clear that
this strategy represents a powerful and rapid entry into
novel pharmacologically interesting compounds.
Exp er im en ta l Section
Gen er a l. All reactions, except those using molybdenum
catalyst 1, were run in oven-dried glassware under a nitrogen
atmosphere. Reactions using molybdenum catalyst 1 were
performed in a glovebox under an argon atmosphere. THF and
Et2O were distilled from K/Ph2CO and Na/K/Ph2CO, respec-
tively. CH2Cl2, DMF, and NEt3 were distilled from CaH2.
Chromatographed refers to column chromatography per-
formed on BDH silica gel 60, 230-400 mesh ASTM. Concen-
trated refers to concentrated in vacuo. Analytical thin-layer
chromatography (TLC) was performed on precoated glass
backed plates (Merck Kieselgel 60 F254) and visualized with
ultraviolet light (254 nm) or potassium permanganate or
vanillin as appropriate.
yield of the corresponding selenide was disappointing
(21%), possibly explained in part by the relatively high
acidity of the benzylic protons giving rise to competitive
deprotonation. A change in protecting-group strategy was
required, and mindful of the probable instability of the
desired conjugated diene in strongly acidic media, it was
thought that the tert-butyl ester would satisfactorily
address both of these issues (Scheme 3). To this end, acid
8g was treated with O-tert-butyl trichloroacetimidate,
following the method of J ackson and co-workers,18 af-
fording ester 14 in 72% yield. Ring-closing metathesis
proceeded without incident to give â-lactam 15, which
was converted to selenide 16 by a modified protocol, in
which LiHMDS was used as base.
Our previously raised concerns over the instability
were in part assuaged by the decision to elaborate the
diene as late as possible in the synthesis. Thus, the tert-
butyldimethylsilyl group was removed, prior to oxidative
elimination of the selenide, by the action of HF‚pyridine
in acetonitrile, furnishing selenide 17 in 98% yield.
Elimination with hydrogen peroxide resulted in excellent
Molybdenum carbene 1 was prepared in-house,1 ruthenium
carbene 2 was purchased from Fluka, and (3R,4R)-4-acetoxy-
3-[(1R)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one was
kindly donated by GlaxoWellcome. 4-Ethenylazetidin-2-one
(3a ),21 4-(2-propenyl)azetidin-2-one (3b),22 4-(3-butenyl)azeti-
din-2-one (3c),22 4-(2-propenyl-1-oxy)azetidin-2-one (3d ),23 4-(2-
propenyl-1-thio)azetidin-2-one (3e),12 4-[N-(2-propenyl)-(4-
toluenesulfonamido)]azetidin-2-one (3f),24 (3S,4R)-4-(2-propenyl)-
3-[(1S)-1-hydroxyethyl]azetidin-2-one (3g),25 and ethyl 2-[4-(2-
(19) Barrett, A. G. M.; Head, J .; Smith, M. L.; Stock, N. S.; White,
A. J . P.; Williams, D. J . J . Org. Chem. 1999, 64, 6005-6018.
(20) Torii, S.; Tanaka, H.; Taniguchi, M.; Kameyama, Y.; Sasaoka,
M.; Shiroi, T.; Kikuchi, R.; Kawahara, I.; Shimabayashi, A.; Nagao, S.
J . Org. Chem. 1991, 56, 3633-3637.
(21) Hauser, F. M.; Ellenberger, S. R. Synthesis 1987, 324.
(22) Bateson, J . H.; Baxter, A. J . G.; Roberts, P. M.; Smale, T. C.;
Southgate, R. J . Chem. Soc., Perkin Trans. 1 1981, 3242-3249.
(23) Basak, A.; Khamrai, U. Synth. Commun. 1994, 24, 131-135.
(18) Armstrong, A.; Brackenridge, I.; J ackson, R. F. W.; Kirk, J . M.
Tetrahedron Lett. 1988, 29, 2483-2486.

Construction of Bicyclic â-Lactam Carboxylic Esters
J . Org. Chem., Vol. 65, No. 12, 2000 3719
propenyl)-2-oxo-1-azetidinyl]-2-hydroxyacetate (4b )12 allyl
bromoacetate26 were synthesized according to literature pro-
cedure with minor modifications where necessary.
Gen er a l P r oced u r e for th e P r ep a r a tion of La cta m s
4a -4c. The following procedure is representative:
tereoisomers (71 mg, 67%) as a colorless oil: Rf ) 0.21 (3:2
Et2O:hexanes); IR (thin film) 1757, 1740 cm -1; 1H NMR (270
MHz, CDCl3) δ 5.80 (m, 2H), 5.40-5.10 (m, 5H), 4.34 (m, 1H),
4.19 (q, 1H, J ) 7.2 Hz), 4.17 (q, 1H, J ) 7.2 Hz), 3.19 (dd,
0.5H, J ) 5.3, 14.8 Hz), 3.15 (dd, 0.5H, J ) 4.2, 15.2 Hz), 2.74-
2.51 (m, 3H), 1.27 (t, 1.5H, J ) 7.2 Hz), 1.26 (t, 1.5H, J ) 7.2
Hz); 13C NMR (67.5 MHz, CDCl3) δ 170.0, 169.9, 167.3, 167.0,
137.5, 136.8, 133.6, 133.3, 119.3, 118.4, 118.3, 61.55, 61.49,
54.8, 54.6, 53.9, 43.6, 43.5, 34.3, 33.2, 14.22, 14.18; MS(CI)
m/e 224 (M + H)+, 168, 156, 124, 120, 78, 73, 61, 44; HRMS-
(CI) calcd for C12H18NO3 (M + H)+ 224.1287, found 224.1280.
Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27. Found:
C, 64.43; H, 7.65; N, 6.15.
(2R*)-Eth yl 2-[(4S*)-4-Eth en yl-2-oxo-1-a zetid in yl]-2-h y-
d r oxya ceta te a n d (2S*)-Eth yl 2-[(4S*)-4-Eth en yl-2-oxo-
1-a zetid in yl]-2-h yd r oxya ceta te (4a ). 4-Ethenylazetidin-2-
one (0.155 g, 1.6 mmol, 1.0 equiv) was added to ethyl glyoxalate
(50% in PhMe; 0.35 mL, 1.8 mmol) in PhMe (6 mL), and the
solution was heated to reflux for 1 h. Ethyl glyoxalate (50%
in PhMe; 0.18 mL, 0.88 mmol) was added and the solution
heated to reflux for a further 15 h. The solution was allowed
to cool and was concentrated and chromatographed (3:2 Et2O:
hexanes) to give 4a as a mixture of diastereoisomers as a
colorless oil (0.25 g, 79%): Rf ) 0.39 (Et2O); IR (thin film) 3401,
1747 cm -1; 1H NMR (400 MHz, CDCl3) δ 5.89 (m, 0.5H), 5.72
(m, 0.5H), 5.41-5.15 (m, 3H), 4.26 (m, 4H), 3.19 (dd, 0.5H, J
) 5.6, 15.2 Hz), 3.19 (dd, 0.5H, J ) 5.4, 15.1 Hz), 2.74 (m,
1H), 1.30 (t, 1.5H, J ) 7.1 Hz), 1.28 (t, 1.5H, J ) 7.3 Hz); 13C
NMR (100 MHz, CDCl3) δ 168.9, 168.5, 167.1, 166.4, 136.1,
135.5, 120.0, 119.6, 72.1, 71.1, 62.9, 62.7, 53.4, 52.0, 44.1, 14.1,
13.9; MS(CI) m/e 416 (2M + NH4)+, 399 (2M + H)+, 217 (M +
NH4)+, 200 (M + H)+, 115, 73; HRMS(CI) calcd for C9H14NO4
Gen er a l P r oced u r e for th e P r ep a r a tion of La cta m s
7d -7g. The following procedure is representative:
2-P r op en yl 2-[2-Oxo-4-(2-p r op en yl-1-oxy)-1-a zetid in yl]-
a ceta te (7d ). Sodium hydride (60% mineral oil dispersion, 160
mg, 4.00 mmol, 1.1 equiv) was added to 3d (462 mg, 3.64 mmol,
1.0 equiv) in DMF (30 mL) at 0 °C. The mixture was stirred
for 2 min, prior to the addition of allyl bromoacetate (0.87 mL,
7.3 mmol, 2.0 equiv). The mixture was allowed to warm to
room temperature and was stirred for 2 h, after which time
the reaction was diluted with Et2O and quenched with H2O.
The organic layer was washed with H2O, dried (MgSO4), and
evaporated to dryness. Chromatography (2:3 Et2O:hexanes)
afforded 7d as a colorless oil (680 mg, 83%): Rf ) 0.18 (3:2
Et2O:hexanes); IR (thin film) 1771, 1747 cm -1; 1H NMR (300
MHz, CDCl3) δ 5.93 (m, 2H), 5.31 (m, 5H), 4.67 (d, 2H, J )
6.7 Hz), 4.11 (d, 2H, J ) 4.9 Hz), 3.80 (d, 1H, J ) 17.8 Hz),
3.18 (dd, 1H, J ) 3.5, 15.3 Hz), 2.94 (app d, 1H, J ) 15.2 Hz);
13C NMR (75 MHz, CDCl3) δ 167.9, 166.1, 133.7, 131.3, 119.2,
117.8, 81.7, 68.9, 66.1, 45.0, 41.4; MS(CI) m/e 243 (M + NH4)+,
226 (M + H)+, 185; HRMS(CI) calcd for C11H16NO4 (M + H)+
226.1079, found 226.1082. Anal. Calcd for C11H15NO4: C,
58.66; H, 6.71; N, 6.22. Found: C, 58.72; H, 6.72; N, 6.31.
Gen er a l p r oced u r e for th e p r ep a r a tion of la cta m s 8d-
8g. The following procedure is representative:
(M + H)+ 200.0923, found 200.0925. Anal. Calcd for C9H13
-
NO4: C, 54.26; H, 6.58; N, 7.03. Found: C, 54.27; H, 6.58; N,
6.96.
Gen er a l P r oced u r e for th e P r ep a r a tion of Aceta tes
5a -5c. The following procedure is representative:27
(2R*)-Eth yl 2-Acetoxy-2-[(4S*)-2-eth en yl-2-oxo-1-a ze-
t id in yl]a cet a t e a n d (2S*)-E t h yl 2-Acet oxy-2-[(4S*)-2-
eth en yl-2-oxo-1-a zetid in yl]a ceta te (5a ). Acetate 4a (0.40
g, 2.0 mmol, 1.0 equiv) was added to Ac2O (2.8 mL) in pyridine
(2 mL), and the solution was stirred at room temperature for
10 h. The solution was diluted with Et2O and washed with
saturated CuSO4 solution. The organic layer was dried (Mg-
SO4), concentrated, and chromatographed (3:2 Et2O:hexanes)
to give 5a as a mixture of diastereoisomers (0.35 g, 73%) as a
viscous liquid: Rf ) 0.61 (5:1 Et2O:hexanes); IR (thin film)
1780, 1759 cm -1; 1H NMR (400 MHz, CDCl3) δ 6.24 (s, 0.5H),
6.14 (s, 0.5H), 5.88 (m, 0.5H), 5.75 (m, 0.5H), 5.33 (m, 2H),
4.32-4.14 (m, 3H), 3.28 (dd, 0.5H, J ) 5.7, 15.4 Hz), 3.25 (dd,
0.5H, J ) 5.4, 15.3 Hz), 2.81 (m, 1H), 2.141 (s, 1.5H), 2.136 (s,
1.5H), 1.30 (t, 1.5H,_J ) 7.2 Hz), 1.28 (t, 1.5H J ) 7.1 Hz);
13C NMR (100 MHz, CDCl3) δ 169.5, 169.4, 166.7, 166.1,
164.32, 164.26, 135.6, 135.1, 120.2, 119.9, 72.00, 71.98, 62.6,
62.3, 54.3, 53.7, 44.8, 44.4, 20.6, 20.5, 14.0, 13.9; MS(CI) m/e
259 (M + NH4)+, 242 (M + H)+, 210, 199, 140, 115, 102; HRMS-
(CI) calcd for C11H16NO5 (M + H)+ 242.1028, found 242.1035.
Anal. Calcd for C11H15NO5: C, 54.77; H, 6.27; N, 5.81. Found:
C, 55.04; H, 6.38; N, 5.56.
(2R*)-2-[(4R*)-2-Oxo-4-(2-pr open yl-1-oxy)-1-a zetid in yl]-
4-p en ten oic a cid a n d (2S*)-2-[(4R*)-2-Oxo-4-(2-p r op en yl-
1-oxy)-1-a zetid in yl]-4-p en ten oic a cid (8d ). A freshly pre-
pared solution of lithium hexamethyldisilazide in THF (2.0
mL, 0.93 mmol, 1.0 equiv) was added to 7d (210 mg, 0.93
mmol, 1.0 equiv) in THF (4 mL) at -78 °C over 10 min. The
mixture was stirred for a further 15 min, prior to the addition
of Me3SiCl (0.118 mL, 0.93 mmol, 1.0 equiv). The solution was
heated at reflux for 4 h and cooled to 0 °C. MeOH (10 mL)
was added dropwise over 10 min and the resultant solution
was evaporated to dryness to give 8d as an off-white paste
(200 mg, 95%), which was used without further purification:
Rf ) 0.10 (1:4 MeOH: CHCl3); IR (thin film) 3455, 1743, 1625
cm -1; MS(CI) m/e 243 (M + NH4)+, 226 (M + H)+, 185, 114,
92, 73, 59; HRMS(CI) calcd for C11H16NO4 (M + H)+ 226.1079,
found 226.1089.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dien es 6a -
6c. The following procedure is representative:
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 4-Nit r o-
ben zyl Ester s 9d -9g. The following procedure is representa-
tive:
(2R*)-E t h yl 2-[(4S*)-4-E t h en yl-2-oxo-1-a zet id in yl]-4-
p en ten oa te a n d (2S*)-Eth yl 2-[(4S*)-4-Eth en yl-2-oxo-1-
a zetid in yl]-4-p en ten oa te (6a ). Allyltrimethylsilane (0.27
mL, 2.4 mmol, 5.0 equiv) was added to 5a (0.115 g, 0.475 mmol,
1.0 equiv) in CH2Cl2 (2 mL). The solution was cooled to 0 °C,
and BF3‚OEt2 (0.21 mL, 1.7 mmol, 3.5 equiv) was added and
the mixture allowed to warm to room temperature, at which
point it was stirred for 16 h. The solution was diluted with
Et2O and quenched with saturated aqueous NaHCO3. The
organic layer was dried (MgSO4), concentrated, and chromato-
graphed (3:2 Et2O:hexanes) to give 6a as a mixture of dias-
(2R*)-4-Nit r ob en zyl 2-[(4R*)-2-Oxo-4-(2-p r op en yl-1-
oxy)-1-a zetid in yl]-4-p en ten oa te a n d (2S*)-4-Nitr oben zyl
2-[(4R*)-2-Oxo-4-(2-p r op en yl-1-oxy)-1-a zetid in yl]-4-p en -
ten oa te (9d ). K2CO3 (81 mg, 0.59 mmol, 1.5 equiv), p-
n
nitrobenzyl bromide (169 mg, 0.782 mmol, 2.0 equiv) and Bu4I
(cat.) were added to 8d (88 mg, 0.39 mmol, 1.0 equiv) in DMF
(4 mL). The mixture was stirred for 12 h, prior to dilution with
Et2O and H2O. The organic layer was washed with H2O, dried
(MgSO4), and evaporated to dryness. Chromatography (1:4
Et2O:hexanes) gave 9d (120 mg, 85%) as a colorless oil: Rf )
(24) Campbell, M. M.; Connarty, B. P. Heterocycles 1982, 19, 1853-
1854.
1
0.72 (Et2O); IR (thin film) 1767, 1747, 1523 cm -1; H NMR
(400 MHz, CDCl3) δ 8.22 (m, 2H), 7.51 (dd, 2H, J ) 2.1, 8.9
Hz), 5.83 (m, 2H), 5.32-5.08 (m, 7H), 4.43 (dd, 0.5H, J ) 6.9,
8.1 Hz), 4.31 (dd, 0.5H, J ) 6.7, 8.8 Hz), 4.03 (m, 1H), 3.07
(dd, 0.5H, J ) 3.7, 6.0 Hz), 3.02 (dd, 0.5H, J ) 3.9, 6.0 Hz),
2.90 (t, 0.5H, J ) 1.9 Hz), 2.84 (t, 0.5H, J ) 1.9 Hz), 2.71 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 169.8, 166.5, 142.7,
134.0, 133.9, 133.4, 133.1, 129.0, 128.8, 127.4, 124.3, 124.2,
124.1, 119.4, 119.1, 118.1, 117.9, 82.3, 81.2, 68.7, 66.2, 66.1,
(25) Hanessian, S.; Desilets, D.; Bennani, Y. L. J . Org. Chem. 1990,
55, 3098-3103. During these investigations, an excellent alternative
method was disclosed: Kang, S. K.; Baik, T. G.; J iao, X. H.; Lee, K. J .;
Lee, C. H. Synlett 1999, 447-449.
(26) Clarke, H. T. J . Chem. Soc. 1910, 97, 416-429.
(27) During these investigations an alternative esterification pro-
cedure was disclosed and employed, with comparable results: Proco-
piou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G. G. A. J . Org. Chem.
1998, 63, 2342-2347.

3720 J . Org. Chem., Vol. 65, No. 12, 2000
Barrett et al.
54.6, 54.5, 45.1, 44.7, 35.2, 33.5; MS(CI) m/e 378 (M + NH4)+,
361 (M + H)+, 320, 303, 261, 243, 226, 122; HRMS(CI) calcd
for C18H21N2O6 (M + H)+ 361.1400, found 361.1396.
Gen er a l P r oced u r e for th e Rin g-Closin g Meta th esis
of Dien es 10b-10g. Carbene 1 or 2 was added to the
corresponding diene (30-50 mg) in CH2Cl2 (2 mL) (Table 1).
The mixture was allowed to stir for 12 h prior to destruction
of the catalyst by exposure to air. The mixture was evaporated
and chromatographed.
solved by direct methods, and the non-hydrogen atoms were
refined anisotropically using full matrix least-squares based
on F2 to give R1 ) 0.043, wR2 ) 0.114 for 1619 independent
observed reflections [|Fo| > 4σ(|Fo|), 2θ e 128°] and 240
parameters. The assignment of the absolute chirality of the 2
center as R was by internal reference to the already known
1R, 7R, and 8S centers. (2S)-11g: Rf ) 0.10 (Et2O); [R]19
)
D
-2.6 (c 0.50, CHCl3); IR (thin film) 3432, 1738, 1522 cm -1; 1H
NMR (400 MHz, CDCl3) δ 8.22 (d, 2H, J ) 8.6 Hz), 7.50 (d,
2H, J ) 8.4 Hz), 5.65 (m, 1H), 5.55 (m, 1H), 5.31 (d, 1H, J )
13.3 Hz), 5.21 (d, 1H, J ) 13.3 Hz), 4.54 (t, 1H, J ) 4.0 Hz),
4.24 (m, 1H), 4.12 (m, 1H), 2.88 (dd, 1H, J ) 2.0, 5.4 Hz), 2.76
(m, 2H), 2.49 (m, 2H), 1.81 (broad s, 1H), 1.30 (d, 3H, J ) 6.3
Hz); 13C NMR (100 MHz, CDCl3) δ 169.9, 166.2, 147.8, 142.6,
130.5, 128.4, 124.6, 123.8, 65.8, 64.8, 62.3, 54.9, 53.1, 35.0, 26.9,
21.5; MS(CI) m/e 378 (M + NH4)+, 361 (M + H)+, 277, 257,
240; HRMS(CI) calcd for C18H21N2O6 (M + H)+ 361.1400, found
361.1396.
(2R*,7R*)-Eth yl 1-Aza -9-oxobicyclo[5.2.0]n on -4-en e-2-
car boxylate an d (2S*,7R*)-Eth yl 1-Aza-9-oxobicyclo[5.2.0]-
n on -4-en e-2-ca r boxyla te (10b): Separable diastereoisomers
both as colorless oils (combined yield 92%): (2R*,7R*)-10b:
Rf ) 0.41 (Et2O); IR (thin film) 1742 cm -1; 1H NMR (400 MHz,
CDCl3) δ 5.94 (m, 1H), 5.83 (m, 1H), 4.63 (t, 1H, J ) 4.4 Hz),
4.19 (m, 2H), 3.90 (m, 1H), 3.11 (dd, 1H, J ) 4.8, 14.6 Hz),
2.67 (m, 3H), 2.49 (dd, 1H, J ) 3.1, 7.8, 15.8 Hz), 2.40 (m,
1H), 1.27 (t, 3H, J ) 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ
165.7, 165.8, 131.1, 128.7, 61.4, 51.1, 49.1, 43.2, 33.5, 30.0, 14.2;
MS(CI) m/e 227 (M + NH4)+, 210 (M + H)+, 136; HRMS(CI)
calcd for C11H16NO3 (M + H)+ 210.1130, found 210.1126.
(2S*,7R*)-10b: Rf ) 0.10 (Et2O); IR (thin film) 1742 cm -1; 1H
NMR (400 MHz, CDCl3) δ 5.67 (m, 1H), 5.57 (m, 1H), 4.41 (t,
1H, J ) 4.0 Hz), 4.20 (2H, q, J ) 7.1 Hz), 4.05 (m, 1H), 3.05
(dd, 1H, J ) 4.7, 14.6 Hz), 2.75-2.44 (m, 5H), 1.25 (t, 3H J )
7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 170.1, 165.7, 130.3,
124.7, 61.5, 55.1, 50.2, 41.8, 35.3, 27.1, 14.1; MS(CI) m/e 436
(2M + NH4)+, 419 (2M + H)+, 227 (M + NH4)+, 210 (M + H)+,
The crystallographic data for (2R)-11g has been deposited
with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC-143691. Copies of the data
can be obtained free of charge on application to The Director,
CCDC, 12 Union Road, Cambridge CB12 1EZ, U.K. (Fax: 44+-
(1223)336-033. E-mail: teched@chemcrys.cam.ac.uk.)
(2R)-ter t-Bu tyl 2-{(3S,4R)-3-[(1R)-(ter t-Bu tyld im eth yl-
silyloxy)ethyl]-2-oxo-4-(2-propenyl)-1-azetidinyl}-4-pentenoate
a n d (2S)-ter t-Bu tyl 2-{(3S,4R)-3-[(1R)-(ter t-Bu tyld im eth -
ylsilyloxy)eth yl]-2-oxo-4-(2-pr open yl)-1-azetidin yl}-4-pen -
ten oa te (14). A solution of O-tert-butyl trichloroacetimidate
(0.63 mL, 3.6 mmol, 2.0 equiv) in cyclohexane (3 mL) was
added to 8g (652 mg, 1.77 mmol, 1.0 equiv) in CH2Cl2 (2.2 mL).
BF3‚OEt2 (35 µL) was then added, and the mixture was stirred
at room temperature for 6 h. Solid NaHCO3 (500 mg) was
added prior to filtration of the mixture through a short plug
of silica. Evaporation to dryness gave 14 as a colorless oil as
168, 136, 94; HRMS(CI) calcd for
210.1130, found 210.1132.
C
11H16NO3 (M + H)+
(2R*,7R*)-1-Aza -9-oxobicyclo[5.2.0]n on -4-en e-2-ca r box-
ylic Acid (11b). Aqueous NaOH (0.25M; 1.34 mL, 0.33 mmol,
1.2 equiv) was added dropwise to (2R*, 7R*)-10b (58.3 mg,
0.279 mmol, 1.0 equiv) in THF (2.5 mL) at 0 °C. The mixture
was stirred for 0.5 h, diluted with saturated aqueous NaCl
and CH2Cl2, and acidified to pH 2. The organic layer was
separated, and the aqueous solution was twice extracted with
CH2Cl2. The combined organic layers were washed with
saturated aqueous NaCl, dried (MgSO4) and evaporated to
dryness. Chromatography (1:4 MeOH:CHCl3) yielded 11b (37
mg, 72%): Rf ) 0.18 (1:4 MeOH:CHCl3); IR (thin film) 3485,
a mixture of inseparable diastereoisomers (554 mg, 75%): Rf
-1
) 0.53 (60:40 Et2O:hexanes); IR (thin film) 1758, 1737 cm
;
1H NMR (270 MHz, CDCl3) δ 5.77 (m, 2H), 5.12 (m, 4H), 4.20
(m, 1H), 4.08 (m, 1H), 3.85 (m, 0.5H), 3.65 (m, 0.5H), 2.76 (dd,
0.5H, J ) 2.1, 6.8 Hz), 2.74 (dd, 0.5H, J ) 2.3, 6.1 Hz), 2.58
(m, 3H), 2.31 (m, 1H), 1.45 (s, 4.5H), 1.44 (s, 4.5H), 1.21 (d,
1.5H, J ) 6.7 Hz), 1.18 (d, 1.5H, J ) 6.2 Hz), 0.86 (s, 4.5H),
0.85 (s, 4.5H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (67.5, CDCl3)
δ 168.9, 168.4, 167.5, 167.3, 133.7, 133.6, 117.9, 81.9, 81.8, 66.5,
66.0, 62.3, 56.0, 55.2, 54.9, 38.2, 38.0, 36.2, 33.6, 27.91, 27.86,
26.1, 25.7, 22.8, 17.8, -4.5, -4.8; MS(CI) m/e 424 (M + H)+,
1
1730 cm -1; H NMR (300 MHz, CDCl3) δ 5.97 (m, 1H), 5.87
(m, 1H), 4.56 (t, J ) 4.6 Hz), 3.88 (m, 1H), 3.06 (dd, 1H, J )
4.7, 14.7 Hz), 2.67 (m, 3H), 2.47 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 172.9, 168.6, 132.2, 130.0, 52.7, 50.8, 43.3, 34.0, 30.5;
MS(CI) m/e 199 (M + NH4)+, 182 (M + H)+, 61, 44; HRMS(CI)
calcd for C9H12NO3 (M + H)+ 182.0817, found 182.0819.
(+)-(2R,7R,8S)-4-Nit r ob en zyl 1-Aza -8-[(1R)-h yd r oxy-
eth yl]-9-oxobicyclo[5.2.0]n on -4-en e-2-car boxylate an d (-)-
(2S,7R,8S)-4-Nitr oben zyl 1-Aza -8-[(1R)-h yd r oxyeth yl]-9-
oxob icyclo[5.2.0]n on -4-en e-2-ca r b oxyla t e (11g). N,N′-
Diisopropylethylamine trihydrofluoride (49.8 mg, 0.263 mmol,
1.25 equiv) was added to 10g (100 mg, 0.211 mmol, 1.0 equiv)
in N-methyl-2-pyrrolidinone (0.2 mL). The mixture was stirred
at room temperature for 4 d, at which point saturated aqueous
NaHCO3 was added. The mixture was extracted with EtOAc,
and the combined organic layers were washed with saturated
NaCl, dried (MgSO4), and evaporated to dryness. Chromatog-
raphy (Et2O) yielded separable diastereoisomers of 11g (59 mg,
366, 310, 282, 159, 95, 73, 57, 41; HRMS(CI) calcd for C23H42
-
NO4Si (M + H)+ 424.2883, found 424.2879.
(2R,7R,8S)-ter t-Bu tyl 1-Aza -8-[(1R)-(ter t-bu tyld im eth -
ylsilyloxy)eth yl]-9-oxobicyclo[5.2.0]n on -4-en e-2-ca r boxy-
la t e a n d (2S,7R,8S)-ter t-Bu t yl 1-Aza -8-[(1R)-(ter t-b u t -
yldimethylsilyloxy)ethyl]-9-oxobicyclo[5.2.0]non-4-ene-2-car-
boxyla te (15): from 14 following the general procedure for
ring-closing metathesis; colorless oil as a mixture of insepa-
rable diastereoisomers (97%): Rf ) 0.41 (3:2 Et2O:hexanes);
IR (thin film) 1757 cm -1; 1H NMR (270 MHz, CDCl3) δ 5.98-
5.58 (m, 2H), 4.50 (t, 0.5H, J ) 4.3 Hz), 4.27 (t, 0.5H, J ) 3.9
Hz), 4.22-4.03 (m, 1H), 3.80 (1H, dq, J ) 2.1, 9.9 Hz), 2.77
(dd, 0.5H, J ) 2.1, 7.7 Hz), 2.75 (m, 0.5H), 2.64-2.38 (m, 4H),
1.43 (s, 4.5H), 1.42 (s, 4.5H), 1.25 (d, 1.5H, J ) 6.0 Hz), 1.19
(d, 1.5H, J ) 6.2 Hz), 0.86 (s, 4.5H), 0.85 (s, 4.5H), 0.06 (s,
3H), 0.05 (s, 3H); 13C NMR (67.5 MHz, CDCl3) δ 169.0, 168.4,
166.0, 165.9, 130.9, 130.2, 128.4, 124.7, 81.5, 66.7, 64.9, 64.2,
62.4, 55.3, 53.1, 52.4, 51.0, 34.9, 32.9, 30.1, 27.9, 27.8, 27.0,
25.7, 25.6, 22.5, 22.4, 17.8, -4.2, -4.9, -5.2; MS(CI) m/e 396
77%): (2R)-11g: Rf ) 0.20 (Et2O); [R]19 ) +84.0 (c 0.50,
D
CHCl3); IR (thin film) 3447, 1737, 1522 cm -1; H NMR (400
1
MHz, CDCl3) δ 8.23 (m, 2H), 7.52 (d, 2H, J ) 8.7 Hz), 5.94 (m,
1H), 5.77 (m, 1H), 5.25 (s, 2H), 4.72 (t, 1H, J ) 4.5 Hz), 4.16
(m, 1H), 3.87 (m, 1H), 2.91 (dd, 1H, J ) 2.0, 6.0 Hz), 2.68 (m,
2H), 2.48 (m, 2H), 1.83 (broad s, 1H), 1.30 (d, 3H, J ) 6.3 Hz);
13C NMR (100 MHz, CDCl3) δ 169.3, 166.3, 147.8, 142.4, 131.5,
128.5, 128.2, 123.9, 65.6, 65.4, 63.6, 52.4, 51.0, 33.1, 29.7, 21.5;
MS(CI) m/e 378 (M + NH4)+, 361 (M + H)+, 156, 124, 61;
HRMS(CI) calcd for C18H21N2O6 (M + H)+ 361.1400, found
361.1413. Crystal data for (2R)-11g: C18H20N2O6, M ) 360.4,
orthorhombic, P212121 (no. 19), a ) 7.240(1) Å, b ) 8.937(2) Å,
(M + H)+, 340, 282, 90, 73, 57; HRMS(CI) calcd for C21H38
NO4Si (M + H)+ 396.257, found 396.2571.
-
(2R*,7R,8S)- ter t-Bu t yl 1-Aza -8-[(1R)-(ter t-b u t yld i-
m eth ylsilyloxy)eth yl]-9-oxo-2-ph en ylselen ylbicyclo[5.2.0]-
n on -4-en e-2-ca r boxyla te (16). A freshly prepared solution
of LiHMDS (0.5 M in THF, 4.93 mL) was added to 15 (481
mg, 1,12 mmol, 1.0 equiv) in THF (11 mL) at -78 °C. The
temperature was raised to -50 °C, maintained for 0.5 h, and
lowered to -78 °C, at which time a solution of phenylselenyl
bromide (580 mg, 2.46 mmol, 2.2 equiv) in THF (8 mL) was
c ) 27.838(2) Å, V ) 1801.2(2) Å3, Z ) 4, Dc ) 1.329 g cm-3
,
µ(Cu KR) ) 8.44 cm-1, F(000) ) 760, T ) 293 K; clear blocks,
1.00 × 1.00 × 1.00 mm, Siemens P4/PC diffractometer,
ω-scans, 1765 independent reflections. The structure was

Construction of Bicyclic â-Lactam Carboxylic Esters
J . Org. Chem., Vol. 65, No. 12, 2000 3721
added. The mixture was allowed to warm to room temperature
and was quenched with saturated NH4Cl. Et2O was added to
the solution, and the organic layer was dried (MgSO4) and
evaporated to dryness. Chromatography (1:4 Et2O:hexanes)
afforded 16 as a colorless oil as a mixture of inseparable
(+)-(7R,8S)-1-Aza -8-[(1R)-h yd r oxyeth yl]-9-oxobicyclo-
[5.2.0]n on -2,4-d ien e-2-ca r boxylic Acid (12). Phenol (350
mg) was added to 18 (35 mg, 0.12 mmol, 1.0 equiv) and the
mixture was heated to 40 °C, melting the phenol, at which
point TFA (1µL) was added. The mixture was heated at 60 °C
for 6 h. After cooling to room temperature, the phenol was
removed by vacuum sublimation (∼0.5 mbar). Chromatogra-
phy (1:4 MeOH:CHCl3) afforded 12 (17 mg, 65%): Rf ) 0.20
diastereoisomers (451 mg, 71%): Rf ) 0.68 (3:2 Et2O:hexanes);
-1
IR (thin film) 1762, 1723, 1652 cm
;
1H NMR (300 MHz,
CDCl3) δ 7.75 (m, 2H), 7.46-7.32 (m, 3H), 5.55 (m, 2H), 3.62
(ddd, 1H, J ) 1.3, 4.8, 9.0 Hz), 3.52 (m, 1H), 3.01 (dt, 1H, J )
3.0, 16.1 Hz), 2.84 (dd, 1H, J ) 8.6, 16.0 Hz), 2.55 (dd, 1H, J
) 1.7, 8.2 Hz), 2.38 (broad s, 2H), 1.46 (s, 9H), 1.23 (d, 1H, J
) 6.1 Hz), 0.86 (s, 9H), 0.03 (s, 3H), -0.03 (s, 3H); 13C NMR
(67.5 MHz, CDCl3) δ 168.1, 164.6, 138.9, 130.2, 129.6, 129.2,
128.8, 127.6, 124.7, 82.8, 67.5, 63.5, 62.8, 55.7, 36.5, 36.0, 27.8,
25.8, 25.6, 22.5, 17.9, -4.1, -4.6; MS(FAB) m/e 552 (M + H)+,
338; HRMS(FAB) calcd for C27H42NO4SeSi (M + H)+ 552.2050,
found 552.2048. Anal. Calcd for C27H41NO4SeSi: C, 58.89; H,
7.50; N, 2.54. Found: C, 58.92; H, 7.38; N, 2.48.
(2R*,7R,8S)-ter t-Bu tyl 1-Aza -8-[(1R)-h yd r oxyeth yl]-9-
oxo-2-p h en ylselen ylb icyclo[5.2.0]n on -4-en e-2-ca r b oxy-
la te (17). An excess of HF‚pyridine (150µL) was added to 16
(1.21 g, 2.15 mmol, 1.0 equiv) in MeCN (14 mL). The mixture
was stirred for 3 h at room temperature prior to the addition
of saturated NaHCO3. The mixture was washed with EtOAc,
and the combined organic layers were dried (MgSO4) and
evaporated to dryness. Chromatography (4:1 Et2O:hexanes)
afforded 17 as a colorless oil (920 mg, 98%): Rf ) 0.31 (Et2O);
IR (thin film) 1746, 1652 cm -1; 1H NMR (300 MHz, CDCl3) δ
7.78 (m, 2H), 7.56 (m, 3H), 5.56 (m, 2H), 3.84 (ddd, 1H, J )
1.7, 4.9, 10.0 Hz), 3.74 (m, 1H), 3.03 (dt, 1H, J ) 2.6, 16.2
Hz), 2.88 (dd, 1H, J ) 8.2, 16.2 Hz), 2.61 (dd, 1H, J ) 7.0, 6.6
Hz), 2.47 (m, 2H), 1.64 (broad s, 1H), 1.46 (s, 9H), 1.24 (d, 3H,
J ) 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 168.0, 164.9, 138.7,
130.0, 129.6, 128.8, 124.7, 82.9, 65.81, 65.76, 63.6, 62.2, 54.8,
36.6, 35.9, 27.8, 21.5, 15.2; MS(FAB) m/e 438 (M + H)+, 394,
338, 224; HRMS(FAB) calcd for C21H28NO4Se (M + H)+
438.1184, found 438.1184.
(1:4 MeOH: CHCl3); [R]18 ) +95.4 (c 0.70, MeOH); IR (thin
D
film) 3373, 1727, 1636, 1574 cm -1; H NMR (400 MHz, CD3-
1
OD) δ 6.38 (d, 1H, J ) 8.3 Hz), 6.17 (m, 1H), 5.97 (m, 1H),
4.20 (m, 1H), 3.59 (m, 1H), 2.96 (ddd, 1H, J ) 2.0, 8.2, 16.3
Hz), 2.81 (dd, 1H, J ) 2.2, 6.1 Hz), 2.57 (tq, 1H, J ) 2.9, 9.2,
10.4 Hz), 1.30 (d, 3H, J ) 6.4 Hz); 13C NMR (100 MHz, CD3-
OD) δ 172.6, 168.3, 136.2, 133.7, 124.8, 118.4, 66.2, 64.3, 52.7,
38.1, 21.9.
ter t-Bu tyl (1R,4S,5R,7S)-4-[(1R)-1-h yd r oxyeth yl]-3,9,11-
tr ioxo-10-ph en yl-2,8,10,12-tetr aazatetr acyclo[5.5.2.02,5.08,12]-
tetr adec-13-en e-1-car boxylate (19). 4-Phenyl-1,2,4-triazoline-
3,5-dione (24.2 mg, 0.138 mmol, 1.5 equiv) was added to 18
(27 mg, 92 µmol, 1.0 equiv) in PhMe (2 mL). The mixture was
stirred at room temperature for 6 h. Concentration to dryness
and purification by column chromatography (Et2O) gave 19
(36 mg, 83%): Rf ) 0.33 (EtOAc); IR (thin film) 3373, 1727
1
cm -1; H NMR (400 MHz, CD3OD) δ 7.45 (m, 5H), 6.75 (dd,
1H, J ) 7.2, 9.0 Hz), 6.34 (1H, d, J ) 8.8 Hz, 1H), 5.21 (m,
1H), 3.98 (m, 1H), 3.63 (m, 1H), 2.70 (dd, 1H, J ) 1.8, 7.2 Hz),
2.54 (ddd, 1H, J ) Hz), 2.20 (m, 1H), 1.56 (s, 9H), 1.25 (s, 3H),
1.23 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 167.2, 163.2, 151.9,
151.3, 132.5, 131.0, 130.1, 129.7, 128.7, 127.4, 86.2, 73.2, 66.9,
64.8, 51.7, 51.2, 37.9, 28.0, 21.9; MS(FAB) m/e 455 (M + H)+,
399, 290, 176, 166, 152, 135, 120, 109, 97, 91, 83, 77, 69, 55;
HRMS(FAB) calcd for C23H27N4O6 (M + H)+ 455.1931, found
455.1926.
Ack n ow led gm en t. We thank GlaxoWellcome Re-
search and Development Ltd for the most generous
endowment (to A.G.M.B.), and for CASE grants (to M.A.
and S.P.D.B.), the Wolfson Foundation for establishing
the Wolfson Center for Organic Chemistry in Medical
Science at Imperial College, and the Engineering and
Physical Science Research Council for studentships (to
M.A., S.P.D.B. and S.P.B).
(+)-(7R,8S)-ter t-Bu tyl 1-Aza -8-[(1R)-h yd r oxyeth yl]-9-
oxobicyclo[5.2.0]n on a -2,4-d ien e-2-ca r boxyla te (18). Py-
ridine (0.34 mL, 4.2 mmol, 2.0 equiv) was added to 17 (0.92 g,
2.1 mmol, 1.0 equiv) in CH2Cl2 (22 mL). The solution was
cooled to -78 °C, and aqueous hydrogen peroxide (20%v/v, 5.88
M; 1.8 mL) was added. After the mixture was allowed to warm
to room temperature over 2 h, the reaction was diluted with
Et2O, washed with H2O, dried (MgSO4), and evaporated to
dryness. Chromatography (1:4 Et2O:hexanes) yielded 18 as a
pale yellow oil (556 mg, 90%): Rf ) 0.26 (Et2O); [R]19D ) +266.0
(c 1.00, CHCl3); IR (thin film) 3448, 1744 cm -1; 1H NMR (300
MHz, CDCl3) δ 6.04 (m, 3H), 4.34 (m, 1H), 3.57 (dt, 1H, J )
2.3, 8.9 Hz), 2.96 (ddd, 1H, J ) 2.3, 7.9, 15.7 Hz), 2.81 (dd,
1H, J ) 2.6, 5.8 Hz), 2.53 (ddt, 1H, J ) 3.0, 8.9, 20.5 Hz), 1.80
(broad s, 1H), 1.53 (s, 9H), 1.37 (d, 3H, J ) 6.3 Hz); 13C NMR
(67.5 MHz, CDCl3) δ 164.2, 162.2, 134.5, 129.9, 123.8, 116.1,
82.4, 65.3, 50.5, 37.6, 27.9, 21.6, 15.3; MS(FAB) m/e 280 (M +
H)+, 240, 224, 120; HRMS(FAB) calcd for C15H22NO4 (M + H)+
280.1544, found 280.1549.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and 13C NMR spectra of 4c, 9d -f, 10b-g, 11b, 11g, 12, 14-
15 and 17-19, NOE measurements on 19, and X-ray crystal-
lographic data for (2R)-11g and full characterization data for
4b, 5b and 5c, 6b and 6c, 7e-7g, 8e-8g, 9e-9g, and 10c-
10g. This material is published free of charge via the Internet
at http://pubs.acs.org.
J O991932S