Cycloadditions of Ketenes Generated in the Wolff Rearrangement. Stereoselective Synthesis of Aminoalkyl-Substituted β-Lactams from α-Amino Acids

Article abstract of DOI:10.1021/jo9705069

Diazo ketones 1-16, derived from suitable protected amino acids (Ala, Leu, Val, Ile, Tie, Phe, Pro, Orn, Lys, Ser, and Thr), have been photochemically rearranged, leading to the corresponding ketene intermediates. They were trapped with N-benzylbenzaldimine 17 to give β-lactams 18-33 in up to 90% yield. In these cycloadditions, two of the four possible diastereoisomers were formed exclusively. The selectivity ranged from 60:40 to 93:7 and the bulkiness of the parent amino acid side chain is the governing factor. The relative configuration was proved by three X-ray crystal structures. The diastereoselectivity in these reactions is also influenced by the use of chiral N-phenethylbenzaldimines 34 and 35. With regard to a projected deprotection of the lactam-nitrogen, N-allyl- (49) and N-(p-methoxybenzyl)benzaldimme (44) were used in this reaction. This led to the N-allyl β-lactams 50 and 51 in 62 and 56% yield, respectively, and to the p-methoxybenzyl-substituted β-lactams 45 and 46 (50 and 72% yield). The p-methoxybenzyl group on the valine-derived β-lactam 45a can be cleaved with potassium peroxodisulfate in 63% yield.

Full text of DOI:10.1021/jo9705069

J . Org. Chem. 1997, 62, 5873-5883
5873
Cycloa d d ition s of Keten es Gen er a ted in th e Wolff Rea r r a n gem en t.
Ster eoselective Syn th esis of Am in oa lk yl-Su bstitu ted â-La cta m s
fr om r-Am in o Acid s†
J oachim Podlech* and Michael R. Linder‡
Institut fu¨r Organische Chemie und Isotopenforschung der Universita¨t Stuttgart, D-70569 Stuttgart,
Germany
Received March 19, 1997X
Diazo ketones 1-16, derived from suitable protected amino acids (Ala, Leu, Val, Ile, Tle, Phe, Pro,
Orn, Lys, Ser, and Thr), have been photochemically rearranged, leading to the corresponding ketene
intermediates. They were trapped with N-benzylbenzaldimine 17 to give â-lactams 18-33 in up
to 90% yield. In these cycloadditions, two of the four possible diastereoisomers were formed
exclusively. The selectivity ranged from 60:40 to 93:7 and the bulkiness of the parent amino acid
side chain is the governing factor. The relative configuration was proved by three X-ray crystal
structures. The diastereoselectivity in these reactions is also influenced by the use of chiral
N-phenethylbenzaldimines 34 and 35. With regard to a projected deprotection of the lactam-
nitrogen, N-allyl- (49) and N-(p-methoxybenzyl)benzaldimine (44) were used in this reaction. This
led to the N-allyl â-lactams 50 and 51 in 62 and 56% yield, respectively, and to the p-methoxybenzyl-
substituted â-lactams 45 and 46 (50 and 72% yield). The p-methoxybenzyl group on the valine-
derived â-lactam 45a can be cleaved with potassium peroxodisulfate in 63% yield.
In tr od u ction
reaction of ketenes (Staudinger reaction)7 or ester eno-
lates8 (which are ketene equivalents) with an imine is
one of the most straightforward reaction sequences for
the preparation of â-lactams,9 the trans-substitution is
sometimes hard to achieve. The use of ketenes (mostly
generated from acid chlorides) in the cycloaddition with
imines usually gives rise to cis-substituted ring systems
(vide infra), whereas employing ester enolates often leads
to a mixture of cis- and trans-substituted products.
â-Lactam antibiotics have been sucessfully used in the
treatment of infectious diseases for many years.1 Despite
the plethora of compounds bearing a â-lactam moiety
which have already been synthesized and tested, there
is still a need for new compounds of this kind2 due to the
increasing restistance of bacterial strains to certain types
of antibiotics.3
Thienamycin, a broad-spectrum antibiotic of the car-
bapenem series, is effective against almost all kinds of
bacteria.1 In addition, it is stable1 with respect to the
lactamase present in the bacteria which would lead to a
ring-opening of the â-lactam moiety.4 In thienamycin, a
hydroxyalkyl group is attached to C-3 of the trans-
substituted â-lactam ring. â-Lactams which bear an
aminoalkyl instead of a hydroxyalkyl group in position
C-3 are also of interest. Merck has patented some
aminoethyl-substituted â-lactams,5 and a method to
prepare similar compounds via the cycloaddition of ester
enolates has been published recently.6 Although the
The Arndt-Eistert reaction sequence is a well-estab-
lished protocol for the homologation of carboxylic acids.10
In the second step of this reaction, the Wolff rearrange-
ment,11 a ketene is formed as an intermediate which
cannot usually be isolated. It reacts with a nucleophile
present in the reaction mixture to form the corresponding
carboxylic acid derivatives. This reaction sequence was
used by Balenovic´ et al. in the late 1950s for the
preparation of enantiopure â-amino acids starting from
appropriately protected R-amino acids.12 They employed
water, alcohols, and amines as nucleophiles and obtained
â-amino acids, esters, and amides, respectively. Seebach
and co-workers used amino acid,13 peptide,14 sugar,13,15
and nucleoside derivatives15 as nucleophiles to produce
† This paper is dedicated to Dieter Seebach on the occasion of his
60th birthday.
* To whom correspondence should be adressed. Phone: +711-685-
4286. Fax: +711-685-4269. E-mail: joachim.podlech@po.uni-stutt-
gart.de.
‡ Part of the diploma thesis of M.R.L., Universita¨t Stuttgart, 1997.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) (a) Gra¨fe, U. Biochemie der Antibiotika; Spektrum Akademischer
Verlag: Heidelberg, 1992; p 359 f. (b) J ones, R. N.; Barry, A. L.;
Thornsberry, C. J . Antimicrob. Chemother. 1989, 24 (Suppl. A), 9-29.
(2) Chu, D. T. W.; Plattner, J .; Katz, L. J . Med. Chem. 1996, 39,
3853-3874.
(8) (a) Hart, D. J .; Ha, D.-C. Chem. Rev. 1989, 89, 1447-1465. (b)
Brown, M. J . Heterocycles 1989, 29, 2225-2244.
(9) Ternansky, R. J .; Morin, J . M., J r. in ref 7, pp 257-293.
(10) (a) Arndt, F.; Eistert, B.; Partale, W. Ber. Dtsch. Chem. Ges.
1927, 60, 1364-1370. (b) Ye, T.; McKervey, M. A. Chem. Rev. 1994,
94, 1091-1160.
(3) The Chemistry of â-Lactams; Page, M. I., Ed.; Blackie Academic
& Professional: London, 1992.
(4) Wiley, S. G. in ref 3, p 198-228.
(5) For example: (a) Merck Inc., Patent DE 2751624, 1977; Chem.
Abstr. 90; 203858. See also: (b) Corbett, D. F.; Coulton, S.; Southgate,
R. J . Chem. Soc., Perkin Trans. 1 1982, 12, 3011-3016. (c) Corbett,
D. F.; Coulton, S.; Southgate, R. Tetrahedron Lett. 1983, 24, 5543-
5546.
(6) Alcaide, B.; Esteban, G.; Mart´ın-Cantalejo, Y.; Plumet, J .;
Rodr´ıguez-Lo´pez, J .; Monge, A.; Pe´rez-Garc´ıa, V. J . Org. Chem. 1994,
59, 7994-8002.
(7) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH: New York, 1993, p 295-368.
(11) Meier, H.; Zeller, K.-P. Angew. Chem. Int. Ed. Engl. 1975, 14,
32-43.
(12) (a) Balenovic´, K.; J ambresˇic´, I.; Gasˇpert, B.; Cerar, D. Recl.
Trav. Chim. Pays-Bas 1956, 75, 1252-1258. (b) Balenovic´, K.; Sˇtimac,
N. Croat. Chem. Acta 1957, 29, 153 and references cited therein.
(13) Podlech, J .; Seebach, D. Liebigs Ann. Chem. 1995, 1217-1228.
(14) Podlech, J .; Seebach, D. Angew. Chem. Int. Ed. Engl. 1995, 34,
471-472.
S0022-3263(97)00506-9 CCC: $14.00 © 1997 American Chemical Society

5874 J . Org. Chem., Vol. 62, No. 17, 1997
Podlech and Linder
Sch em e 1
Sch em e 2a
the corresponding biomolecules linked to a â-amino acid
(Scheme 1).16
a
For specification of the substituents, see Table 1.
The reaction of aminoalkyl-substituted ketenes with
nucleophiles has been described in several publications,
including some reports on the synthesis of natural
products.17 Surprisingly, cycloadditions with ketenes
generated in the Wolff rearrangement have hardly been
investigated,18 and chiral ketenes have been reported
only once.19 In this paper, we present a diastereoselective
synthesis of trans-substituted â-lactams by the cycload-
dition of ketenes derived from easily accessible R-amino
acid derivatives. An aminoalkyl group at C-3 of the
products was introduced by way of the amino acid
derivatives employed.20
compounds was complete after 90 min even at lower
reaction temperatures. Nevertheless, it should be kept
in mind that the reaction times might be longer when
more concentrated solutions or weaker irradiation lamps
are used. No changes in yields and selectivities were
observed when the reaction was performed at 20, 2, and
-24 °C, respectively. When 4, 2, and 1.1 equiv imine
were used, again no significant difference in the yields
was observed. Besides diethyl ether, we tested pentane
as a solvent. This was unsuitable because the starting
materials were insoluble and no reaction occurred. tert-
Butyl methyl ether did not affect the selectivity, but the
yield decreased slightly due to additional side products.
Using a Durane filter instead of the quartz filter did not
change the selectivity or yield of the â-lactam products.
Therefore, all subsequent experiments were performed
with 1.5 equiv of the imine in diethyl ether with a quartz
filter at about -15 °C, except when otherwise noted.
Irradiation of the diazo ketones in the presence of the
imine 1723 gave rise to two of the four possible diastere-
oisomeric â-lactams 18-33. The ratios were determined
by HPLC analysis of the crude reaction mixtures. The
configuration of the products was established by 1H NMR
analysis. The coupling constants between the protons
at C-3 and C-4 is about 2 Hz, which gives strong evidence
for a 3,4-trans-substitution of the â-lactams (vide infra).
Assignment of the NMR spectra of the products and
comparision with three X-ray crystal structures of 20b,
21a , and 48 (vide infra) allowed the determination of the
relative configurations in all diastereoisomers. In the 1H
NMR spectra the coupling constant between H-3 and H-1′
in the isomers 18-33a is significantly smaller than in
18-33b.
The diastereoselectivity seems to be predominantly
influenced by the bulkiness of the parent amino acid side
chain. While primary substituents as in alanine, leucine,
phenylalanine, serine, ornithine, and lysine (entries 1,
2, 4, 9, and 11-14 in Table 1) gave poor selectivities of
about 70:30, the ratios are improved to better than
80:20 with secondary side chains (valine, isoleucine, and
threonine, entries 5-7, 15, and 16). The best results
were obtained when a tertiary side chain as in tert-
leucine is present (ratio 93:7, entry 8). The nature of the
carbamate protection group at the nitrogen seems to have
no significant influence (entries 1, 2 and 5, 6) on the
diaseteroselectivity of the reaction. The TBDMS protect-
ing group seems to be unsuitable (entries 15 and 16).
Yields drop significantly with this protecting group,
Resu lts a n d Discu ssion
The starting materials, the diazo ketones derived from
Boc-, Cbz-, Fmoc- [[(9-fluorenylmethyl)oxy]carbonyl], and
Pht- (phthaloyl) protected amino acids (Ala, Leu, Val, Ile,
Tle (tert-leucin), Phe, Pro, Orn, Lys, Ser, and Thr, 1-16),
were prepared according to known procedures.13 As a
starting point, we used the simple imine N-benzylben-
zaldimine (17), which is known to react well with ketenes
to form the corresponding â-lactams (Scheme 2 and Table
1). Nevertheless, when we stirred the diazo ketones with
catalytic silver benzoate in the presence of the imine, no
reaction occurred and the diazo ketone was recovered
quantitatively. Either the silver catalyst was complexed
by the imine, a problem that is known for bis-imines,21
or the imine is oxidized by the silver salt.22 As an obvious
alternative, the decomposition of the diazo ketones was
achieved by irradiation through a quartz filter and
monitoring by TLC. To enable a complete reaction with
the imine, the reaction mixture was stirred for an
additional 30 min. We tested several reaction conditions
in the rearrangement of the Cbz-valine-derived diazo
ketone 5: We found that the degradation of the diazo
(15) Guibourdenche, C.; Podlech, J .; Seebach, D. Liebigs Ann. Chem.
1996, 1121-1129.
(16) Matthews, J . L.; Braun, C.; Guibourdenche, C.; Overhand, M.;
Seebach, D. in Enantioselective Synthesis of â-Amino Acids; J uaristi,
E., Ed., Wiley-VCH: New York, 1997; pp 105-126.
(17) (a) Stork, G; Nakahara, Y.; Nakahara, Y.; Greenlee, W. J . J .
Am. Chem. Soc. 1978, 100, 7775-7777. (b) Cooper, J .; Gallagher, P.
T.; Knight, D. W. J . Chem. Soc., Chem. Comm. 1988, 509-510. (c)
Grieco, P. A.; Hon, Y. S.; Perez-Medrano, A. J . Am. Chem. Soc. 1988,
110, 1630-1631. (d) J efford, C. W.; Tang, Q.; Zaslona, A. J . Am. Chem.
Soc. 1991, 113, 3513-3518. (e) Ikeda, Y.; Ikeda, D.; Kondo, S. J .
Antibiot. 1992, 45, 1677-1680. (f) Evans, D. A.; Miller, S. J .; Ennis,
M. D. J . Org. Chem. 1993, 58, 471-485.
(18) Backes, J . In Houben-Weyl, 4th ed.; Klamann, D., Ed.; Thi-
eme: Stuttgart, 1991; Vol. E16b, p 460.
(19) Elliot, J . E.; Khalaf, M. M.; J ephcote, V. J .; J ohn, D. I.; Williams,
D. J .; Allwood, B. L. J . Chem. Soc., Chem. Commun. 1986, 584-586.
(20) Podlech, J . Synlett 1996, 582-584.
(21) Hoyer, E.; Skopenko, V. V. Russ. J . Inorg. Chem. 1966, 11, 436-
(23) Investigations with imines not derived from benzaldehyde are
in progress. There appears to be no restriction on the use of imines
derived from aromatic and heteroaromatic aldehydes.
439.
(22) Hess, U.; Ziebig, M. Z. Chem. 1980, 20, 444.

Cycloadditions of Ketenes
J . Org. Chem., Vol. 62, No. 17, 1997 5875
Ta ble 1. Decom p osition of Am in o Acid Der ived Dia zo Keton es in th e P r esen ce of Im in e 17 Lea d in g to â-La cta m s (See
Sch em e 2)
diazo
ketone
yield
(%)
entry
PG1
PG2
R
amino acid
Ala
Ala
Ala
Leu
Val
Val
Ile
Tle
Phe
Pro
Orn(Cbz)
Orn(Boc)
Lys(Cbz)
Ser(Bn)
Thr(TBDMS)
Thr(TBDMS)
product
ratioa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Cbz
Boc
H
H
Me
Me
18
19
20
21
22
23
24
25
26
27
28
29
30
31b
32
33
71
70
54
89
89
79
90
88
58
63
73
70
71
63
45
37c
67:33
71:29
17:83
70:30
82:18
77:23
83:17
93:7
59:41
63:37
70:30
70:30
65:35
70:30
80:20
80:20d
Pht
Me
Cbz
Cbz
Fmoc
Cbz
Cbz
Cbz
Boc
Boc
Cbz
Boc
Boc
Cbz
Boc
H
H
H
H
H
H
iBu
iPr
iPr
sBu
tBu
Bn
-(CH2)3-
H
H
H
H
H
H
CbzNH(CH2)3
BocNH(CH2)3
CbzNH(CH2)4
BnOCH2
TBDMSOCH(CH3)
TBDMSOCH(CH3)
a
b
Ratio of diastereoisomers determined by HPLC. Diastereoisomers could not be separated; the experiment is not included in the
experimental section. c Isolated yield of 33a . Determined by 1H NMR spectroscopy.
d
Sch em e 3a
seemingly due to a partial decomposition of these com-
pounds on silica gel. This decomposition seems to be
faster for isomer 33b, since the ratio of 33a /b changes
from 80:20 before chromatography (determined by 1H
NMR spectroscopy) to better than 95:5 (no second isomer
detected) after filtrative chromatography. The diastere-
oisomeric ratio was inverted with the phthaloyl protect-
ing group (entry 3, ratio of 17:83). Unfortunately it is
not possible to prove the universal validity of this result,
since it is known that phthaloyl-protected amino acid
derivatives with a â-proton in the side chain rearrange
when irradiated,24 and therefore, no further examples
with a phthaloyl protection were investigated. Even the
a
diazo ketone derived from phthaloylphenylalanine (which
bears no â-proton) decomposes to an undefinable mixture
when irradiated in the presence of imine 17. The yields
in the cyclization reactions were better than 60%, except
for the phthaloyl protection (20, entry 3) and for the
threonine-derived diazo ketones 32 and 33 (entries 15
and 16). The good result for the Fmoc-protected diazo
ketone (6, entry 6) was quite astonishing, since this
protecting group might have been suspected to be sensi-
tive against irradiation. This result should be advanta-
geous for the possible use of these products in future solid
phase synthesis, in which Fmoc protection is most
commonly used.25 All diastereoisomeric mixtures except
for the serine-derived â-lactams 31a ,b (entry 14, experi-
ment is not included in the Experimental Section) were
separated by either flash column chromatography or by
MPLC (medium pressure liquid chromatography). The
best separation efficiency could be achieved with light
petroleum/isopropyl alcohol solvent systems, but in most
cases mixtures of light petroleum and ethyl acetate
mixtures gave sufficient separations.
For specification of the substituents, see Table 2.
diazo ketone 7 led to an improvement to 86:14 (39a /b)
with the (S)-imine 35 and to a decrease to 73:27 (38a /b)
with (R)-imine 34 (cf. the result with the achiral imine
17 f 24a /b, 83:17). When the alanine-derived diazo
ketone 2 was used, the influence was much more signifi-
cant: improvement from 71:29 (19a /b) to 88:12 (37a /b)
with (S)-imine 35 and a decrease to 55:45 (36a /b) with
(R)-imine 34 was observed.
Sometimes the N-benzyl protection, which was intro-
duced to optimize the reaction conditions, is disadvanta-
geous, since this protecting group is hard to remove.27
Therefore, we tried cycloadditions with N-trimethylsilyl-
(40),28 N-sulfonyl- (41),29 and N-bis(trimethylsilyl)methyl-
substituted imines (42).30 However, no â-lactams were
isolated with these imines. When the oxidatively remov-
able p-methoxyphenyl group (PMP)31 was introduced
with the corresponding imine 43, a partial cleavage of
the PMP group seemed to occur under our reaction
conditions and this led to no isolable product. When we
used the related p-methoxybenzyl (PMB) substituted
imine 44,32 no cleavage was observed: starting with the
The stereoselectivity in these reactions may be ad-
ditionally controlled by the use of a chiral imine (Scheme
3 and Table 2). When (R)- or (S)-N-phenethylbenzaldi-
mine (34, 35) were used, a match-mismatch interaction
was observed.26 The elaboration of the isoleucine-derived
(27) Wild, H. in ref 3, pp 1-48.
(28) Iimori, T.; Takahashi, Y.; Izawa, T.; Kobayashi, S.; Ohno, M.
J . Am. Chem. Soc. 1983, 105, 1659-1660.
(29) Tanner, D.; Somfai, P. Tetrahedron 1988, 44, 619-624.
(30) Palomo, C.; Aizpuruna, J . M.; Legido, M.; Galarza, R.; Dey, P.
M.; Dunogue`s, J .; Picard, J . P.; Ricci, A.; Seconi, G. Angew. Chem. Int.
Ed. Engl. 1996, 35, 1239-1241.
(24) (a) Griesbeck, A.; Henz, A.; Peters, K.; Peters, E.-M.; von
Schnering, H. G. Angew. Chem. Int. Ed. Engl. 1995, 34, 474. (b)
Griesbeck, A. G.; Mauder, H. Angew. Chem. Int. Ed. Engl. 1992, 31,
73.
(25) Atherton, E.; Sheppard, R. C. Solid Phase Peptide Synthesis;
IRL Press: Oxford, 1989.
(31) (a) Fukuyama, T.; Frank, R. K.; J ewell, C. F. J . Am. Chem.
Soc. 1980, 102, 2122-2123. (b) Kronenthal, D. R.; Han, C. Y.; Taylor,
M. K. J . Org. Chem. 1982, 47, 2765-2768.
(26) Masamune, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew.
Chem. Int. Ed. Engl. 1985, 24, 1-30.
(32) Yamaura, M.; Suzuki, T.; Hashimoto, H.; Yoshimura, J .;
Okamoto, T.; Shin, C.-g. Bull. Chem. Soc. J pn. 1985, 58, 1413-1420.

5876 J . Org. Chem., Vol. 62, No. 17, 1997
Podlech and Linder
Ta ble 2. Decom p osition of Dia zok eton es in th e P r esen ce of Ch ir a l Im in es (See Sch em e 3)
diazo
ketone
amino
acid
configuration
of imine
yield
(%)
entry
PG
R
R1
R2
imine
product
ratio
1
2
3
4
5
6
2
2
2
7
7
7
Boc
Boc
Boc
Cbz
Cbz
Cbz
Me
Me
Me
sBu
sBu
sBu
Ala
Ala
Ala
Ile
Ile
Ile
Me
H
H
Me
H
H
H
H
Me
H
H
34
17
35
34
17
35
(R)
36
19
37
38
24
39
72
70
88
72
90
56
55:45
71:29
88:12
73:27
83:17
86:14
(S)
(R)
Me
(S)
to no cleavage of the PMB group.34 Subsequent repro-
tection of â-lactam 47 with tert-butyl pyrocarbonate
(Boc2O)35 gave rise to the Boc-protected â-lactam 48 (67%
yield) whose structure could be unambiguously deter-
mined by X-ray crystal structure analysis.36 N-Allyl-
substituted â-lactams are easy to deprotect37 and, addi-
tionally, are interesting precursors for subsequent
transformations. Elaboration of the diazo ketones 2 and
7 derived from Boc-alanine and Cbz-isoleucine with
N-allylbenzaldimine 49 led to the corresponding â-lac-
tams 50a ,b (62%, 68:32) and 51a ,b (56%, 85:15, Scheme
4 and Table 3).
Ta ble 3. Decom p osition of Dia zok eton es in th e
P r esen ce of P MB- a n d N-Allyl-su bstitu ted Im in es (See
Sch em e 4)
parent
amino
acid
diazo
entry ketone PG
yield
R
R1 imine product (%) ratio
1
2
3
4
5
8
2
7
Cbz iPr
Cbz tBu
Boc Me
Cbz sBu
Val PMB
44
44
49
49
45
46
50
51
50 84:16
72 92:8
62 68:32
56 85:15
Tle
Ala
Ile
PMB
Allyl
Allyl
Sch em e 4a
a
For specification of the substituents, see Table 3.
Sch em e 5
When we synthesized â-lactams in accordance with the
above mentioned reaction protocol, we observed the
exclusive formation of the two diastereoisomers in which
the substituents in positions C-3 and C-4 were trans-
oriented. This seemed surprising to us, since electroni-
cally similar ketenes (i.e. the ketene derived from â-si-
lyloxybutyryl chloride)38 are known to yield the cor-
responding cis-substituted ring systems. Georg et al.
presented a useful classification of ketenes which enables
the prediction of whether a cis- or trans-substitution
should be expected. Nevertheless, this classification is
based upon steric rules, which seem to be somewhat
inconsistent, since, according to these rules, the methyl-
substituent is categorized to belong to the bulky substit-
uents, which lead to trans-substitution. Electronic prop-
erties of the ketenes can also be considered. We tested
whether the special amino substitution is responsible for
the observed selectivity in our case using a hydroxyalkyl
ketene and an alkyl-substituted ketene in our reaction
Cbz-valine-derived diazo ketone 5, the corresponding
â-lactams 45a ,b were isolated with a 84:16 ratio and 50%
yield (Table 3 and Scheme 4). Reaction of the tert-
leucine-derived diazo ketone 8 led to the â-lactams 46a ,b
in 72% yield (92:8 ratio). Oxidative deprotection of the
PMB group in 45a with cerium ammonium nitrate (CAN)
led predominantly (50%) to an overoxidation of the
p-methoxybenzyl group to the corresponding N-substi-
tuted p-methoxybenzamide. The deprotected â-lactam 47
was formed in only 17% yield. Selective deprotection of
45a could be successfully performed with potassium
peroxodisulfate in 63% yield (Scheme 5).33 The mild
oxidant 2,3-dichloro-5,6-dicyano-1,4-quinone (DDQ) led
(35) Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis,
2nd ed.; Springer: Berlin, 1994.
(36) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
(37) (a) Rhodium-catalyzed deprotection: Laguzza, B. C.; Ganem,
B. Tetrahedron Lett. 1981, 22, 1483-1486. (b) Multistep deprotec-
tion: Fukuyama, T.; Laird, A. A.; Schmidt, C. A. Tetrahedron Lett.
1984, 25, 4709-4712.
(38) (a) Lynch, J . E.; Riseman, S. M.; Laswell, W. L.; Tschaen, D.
M.; Volante, R. P.; Smith, G. B.; Shinkai, I. J . Org. Chem. 1989, 54,
3792-3796. (b) Tschaen, D. M.; Fuentes, L. M.; Lynch, J . E.; Laswell,
W. L.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1988, 29, 2779-
2782.
(33) Shiozaki, M.; Ishida, N.; Hiraoka, T.; Marayuma, H. Tetrahe-
dron 1984, 40, 1795-1802.
(34) Kocien´ski, P. J . Protecting Groups; Thieme: Stuttgart, 1994; p
224.

Cycloadditions of Ketenes
Sch em e 6
J . Org. Chem., Vol. 62, No. 17, 1997 5877
the observed diastereoselectivity, either due to a photo-
chemical excitation of the intermediate A and therefore
a weakening of the double bond42 or due to a photochemi-
cal-induced equilibration of the imine trans-17 to the cis-
substituted imine cis-17 (Scheme 6). These cis-substi-
tuted imines, which are less hindered with respect to
their nucleophilic attack to the ketene, are known to be
persistent with a half time of 0.1-1 s.42
Fortunately, a previously observed intramolecular
stabilization of peptide-derived ketene C seems to play
no important role in our case.14 Obviously, the dihy-
drooxazinone D, which is much more stable than the
initial ketenes C, is not able to undergo a cycloaddition,
since the double bond is lost. Either, this stabilization
does not occur under our reaction conditions or, as is more
likely, the ketene is trapped in situ by the imine present
in the reaction mixture before the intramolecular attack.
protocol. The diazo ketones derived from racemic O-
methyl mandelic acid (52) and valeric acid (53) again led
to the corresponding trans-substituted â-lactams (54a /
b, ratio 1:1 and 55, respectively). Obviously, the special
aminoalkyl substitution is not responsible for the trans-
selectivity.
The relative configuration of the â-lactams was deter-
mined by three X-ray crystal structures36 and by com-
parision of the NMR spectroscopic data. The crystal
structure of the phthaloyl-protected isomer 20b indicates
a (3S,4R,1′S)-configuration. On the other hand, the
crystal structure of the Cbz-protected isomers 21a and
48, and therefore their derivatives 45a and 47, turned
out to be of the (3R,4S,1′S)-configuration. (This is in
contrast to a previously made assignment, in which the
configuration of the isomers has erroneously been indi-
cated to be (3R,4R) and (3S,4S), respectively.20) Obvi-
ously the product ratio seems to be determined by which
of the two substituents (the protected amino function or
the amino acid side chain) is sterically more demanding.
Fortunately, the relative configuration seems to be
related to the proton NMR coupling constant between the
protons at C-3 and at C-1′ (former R-position of the amino
acid). A larger coupling constant indicates a (3S,4R,1′S)-
configuration, and a small coupling constant indicates a
(3R,4S,1′S)-configuration (for details, see the Experimen-
tal Section).
In the present paper, we have demonstrated the
versatility of amino acid derived ketenes for the prepara-
tion of aminoalkyl-substituted â-lactams. The reaction
conditions used (i.e. photochemical-induced rearrange-
ment of diazo ketones) lead exclusively to trans-substi-
tuted â-lactams, a substitution pattern that is otherwise
difficult to obtain. Diazo ketones derived from other
chiral starting materials (e.g. hydroxy acids) should give
rise to similar compounds; work in this direction is
already ongoing in our laboratories.
This means that it is either the fact that our ketenes
were prepared from diazo ketones or the reaction protocol
that is responsible for the trans-substitution. To the best
of our knowledge, the only preparation of â-lactams from
diazo ketones resulted in the formation of derivatives
bearing two phenyl substituents in the 3-position.18 It
is therefore impossible to determine whether a cis- or
trans-substitution occurred in these cases. Hegedus et
al. have performed photochemically induced Staudinger
reactions starting with chromium carbene complexes.39
In their opinion, the phenyl-substitution is responsible
for the observed trans-substitution. The weakening of
the double bond in the intermediate A should allow for
a rotation to the less hindered intermediate B, which
after ring closure should lead to the trans-substituted
â-lactam (Scheme 6).40 Other examples with the same
imine 17, however, gave rise to cis-substituted â-lac-
tamssobviously no isomerization A f B occurred.7,41
Possibly, the photochemical activation is responsible for
Exp er im en ta l Section
(39) (a) McGuire, M. A.; Hegedus, L. S. J . Am. Chem. Soc. 1982,
104, 5538-5540. (b) Hegedus, L. S.; McGuire, M. A.; Schultze, L. M.;
Yijun, C.; Anderson, O. P. J . Am. Chem. Soc. 1984, 106, 2680-2687.
(c) Borel, C.; Hegedus, L. S.; Krebs, J .; Satoh, Y. J . Am. Chem. Soc.
1987, 109, 1101-1105. (d) Hegedus, L. S.; de Weck, G.; D’Andrea, S.
J . Am. Chem. Soc. 1988, 110, 2122-2126. (e) Hegedus, L. S.; Im-
winkelried, R.; Alarid-Sargent, M.; Dvorak, D.; Satoh, Y. J . Am. Chem.
Soc. 1990, 112, 1109-1117.
Gen er a l. Solvents for chromatography and for workup, e.g.
ethyl acetate (EA) and light petroleum (PE), were distilled
prior to use, diethyl ether (ether) was distilled over KOH/
FeSO4. Ether and THF used for reactions were distilled over
Na/benzophenone. Et3N was distilled over CaH2, and ClCO2Et
(40) Hegedus, L. S.; Montgomery, J .; Narukawa, Y.; Snustad, D. C.
J . Am. Chem. Soc. 1991, 113, 5784-5791.
(42) (a) Wettermark, G.; Wallstrom, E. Acta. Chem. Scand. 1968,
22, 675-680. (b) Wettermark, G. in The Chemistry of the Carbon-
Nitrogen Double Bond; Patai, S.,Ed.; Interscience: London, 1970; pp
565-596.
(41) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1985, 26, 3783-
3786.

5878 J . Org. Chem., Vol. 62, No. 17, 1997
Podlech and Linder
and aldehydes were distilled and stored over molecular sieves
(4 Å). The diazo ketones 1-16,13 5243 and 5344 and the imines
40,28 41,29 42,30 and 1745 were prepared according to literature
procedures; the other imines were used directly after prepara-
tion.46 Amino acid derivatives were prepared by standard
methods.35,47 Common amino acid abbreviations are used.48
Moisture-sensitive reactions were performed in dried vessels
(150 °C, 24 h) under a nitrogen atmosphere using syringe
techniques. Photochemically induced rearrangements were
performed in a UV reactor system (Heraeus) with a quartz or
durane filter. An immersion UV lamp (TQ 150, Philips) was
used. Ca u tion : The generation and the handling of diaz-
omethane requires special precautions.49 Merck silica gel 60
(230-400 mesh) was used for flash column chromatography.
For TLC, Precoated sheets (Alugram SIL G/UV254 Macherey-
Nagel) with detection by UV extinction or by cerium molybdate
solution [phosphomolybdic acid (25 g), Ce(SO4)2‚H2O (10 g),
concn H2SO4 (60 mL), H2O (940 mL)] was used. For MPLC,
detection was done with a UV detector. HPLC analyses of
diastereoisomer distribution were carried out with a Pharma-
cia RSD 2140 apparatus with a Pharmacia RSD 2249 mixer,
and diode-array detection (Pharmacia RSD 2140) on a Li-
Chrosorb Si 60 (Merck) (hexane/EA; flow, 2.0 mL/min) and a
LiChrospher Si 60 (5 µm, Merck) (hexane/iPrOH; flow, 1.5 mL/
min) chromatographic column, respectively. 1H and 13C NMR
spectra were recorded at rt in CDCl3 unless otherwise indi-
cated with δ in ppm relative to internal TMS (0 ppm) or to
resonances of the solvent (1H, CHCl3, 7.24 ppm; 13C, CDCl3,
77.0 ppm), and J are recorded in Hz; in spectra of higher order,
δs and J s are not corrected. Mass spectra were recorded using
FAB or CI (CH4 or NH3) techniques. IR spectra were recorded
with a FTIR instrument. Elemental analyses were performed
by the service of the Institut fu¨r Organische Chemie, Stuttgart.
Melting points are not corrected.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Dia zo
Keton es.13 The amino acid derivative was dissolved in THF
(0.2 M) under an atmosphere of nitrogen. At -15 °C Et3N (1
equiv) and ClCO2Et (1 equiv) were added to the solution. After
15 min the suspension was allowed to warm to 0 °C. A solution
of CH2N2 in Et2O was added until the intense yellow color
persisted over a longer period. The mixture was allowed to
warm to rt and then stirred for 3 h. Excess CH2N2 was
destroyed by addition of a small amount of 0.5 N HOAc. After
aqueous workup by extraction with saturated NaHCO3 and
NaCl solutions, the organic layer was separated and dried
(MgSO4), and the solvents were evaporated. Chromatography
of the residue on silica gel or recrystallization afforded the pure
diazo ketone.
-15 °C to yield a mixture of 18a and 18b (67:33, 294 mg, 71%).
The pure isomers 18a (187 mg, 45%) and 18b (87 mg, 21%)
were obtained by MPLC (PE/iPrOH 98.5:1.5). 18a (first
eluted): colorless solid; mp 132-133 °C; tR (HPLC, hexane/
iPrOH 19:1) 4.23 min; [R]20 -0.2 (c 1.24, CHCl3); IR (KBr)
D
3272, 3012, 1722, 1705 cm-1; 1H NMR (250 MHz) δ 1.33 (d, J
) 6.9, 3 H), 3.13 (s, 1 H), 3.71 (d, J ) 15.0, 1 H), 4.20 (mc, 1
H), 4.24 (s, 1 H), 4.85 (d, J ) 15, 1 H), ca. 4.83 (m, 1 H), 4.91,
5.12 (2 d, J ) 12.3, 12.3, 2 H), 7.09-7.35 (m, 15 H); 13C NMR
(75 MHz) δ 15.0 (q), 44.1 (t), 44.9 (d), 56.5 (d), 65.0 (d), 66.4
(t), 126.3, 127.3, 127.7, 127.8, 128.0, 128.2, 128.2, 128.4, 128.7
(9d), 135.1, 136.2, 137.1 (3 s), 155.9 (s), 167.5 (s); MS (CI, CH4)
m/ z (%) 415 (68, [M + 1]+), 238 (42, [M - C10H10NO2]+), 91
(85, C7H7+), 75 (100). Anal. Calcd for C26H26N2O3 (414.5): C,
75.34; H, 6.32; N, 6.76. Found: C, 75.16; H, 6.41; N, 6.87.
18b (second eluted): colorless solid; mp 118-119 °C; tR (HPLC,
hexane/iPrOH 19:1) 7.00 min; [R]20 -6.5 (c 1.1, CHCl3); IR
D
(KBr) 3340, 3012, 1750, 1705 cm-1; 1H NMR (250 MHz) δ 1.28
(d, J ) 6.7, 3 H), 3.04 (dd, J ) 7.1, 1.6, 1 H), 3.76 (d, J ) 14.9,
1 H), 4.16 (sextet, J ) 7.7, 1 H), 4.32 (s, 1 H), 4.80 (d, J )
14.9, 1 H), 4.85 (d, J ) 7.7, 1 H), 5.03, 5.11 (2 d, J ) 12.3,
12.2, 2 H), 7.10-7.32 (m, 15 H); 13C NMR (63 MHz) δ 18.6 (q),
44.5 (t), 46.4 (d), 58.2 (d), 65.6 (d), 66.7 (t), 126.4, 127.8, 128.2,
128.4, 128.5, 128.8, 129.0 (7 d), 135.4, 136.4, 137.3 (3 s), 155.5
(s), 167.4 (s); MS (CI/CH4) m/ z (%) 415 (10, [M + 1]+), 238
(10, [M - C10H10NO2]+), 91 (100, C7H7+).
(3R,4S,1′S)- a n d (3S,4R,1′S)-1-Ben zyl-3-[1-[(ter t-bu toxy-
ca r bon yl)a m in o]eth yl]-4-p h en yla zetid in -2-on e (19a ,b).
Following the general procedure, diazo ketone 2 (213 mg, 1.00
mmol) and imine 17 (1.56 g, 8.00 mmol) were irradiated at
-15 °C to yield a mixture of 19a and 19b (71:29, 266 mg, 70%).
The pure isomers 19a (179 mg, 47%) and 19b (68 mg, 18%)
were obtained by MPLC (PE/iPrOH 99:1). 19a : colorless oil;
tR (HPLC, hexane/iPrOH 49:1) 6.30 min; [R]20 +17.9 (c 1,
D
CHCl3); IR (film) 3328, 2977, 2932, 1751, 1707 cm-1; 1H NMR
(300 MHz) δ 1.30 (d, J ) 7.0, 1 H), 1.37 (s, 9 H), 3.13 (br s, 1
H), 3.73 (d, J ) 15.0, 1 H), 4.12 (mc, 1 H), 4.24 (d, J ) 2.2, 1
H), 4.71 (br d, J ) 8.5, 1 H), 4.87 (d, J ) 15.0, 1 H), 7.25-7.39
(m, 10 H); 13C NMR (75 MHz) δ 19.7 (q), 28.3 (q) 44.3 (d) 44.3
(t), 56.9 (d), 65.4 (d), 79.4 (s), 126.5, 127.6, 128.3, 128.4, 128.8,
129.0 (6 d), 135.5, 137.3 (2 s), 155.5 (s), 167.9 (s); MS (CI, CH4)
m/ z (%) 381 (8, [M + 1]+), 325 (100, [M - C4H7]+), 281 (21,
[M - C5H7O2]+), 238 (23, [M - C7H12NO2]+), 91 (3, C7H7+), 57
(4, C4H9+). Anal. Calcd for C23H28N2O3 (380.5): C, 72.60; H,
7.42; N, 7.36. Found: C, 72.20; H, 7.61; N, 7.30. 19b (second
eluted): colorless oil; tR (HPLC, hexane/iPrOH 49:1) 10.8 min;
[R]20 -3.4 (c 1.9, CHCl3); IR (film) 3332, 2976, 2932, 1751,
D
1707 cm-1; H NMR (300 MHz) δ 1.27 (d, J ) 6.7, 1 H), 1.41
1
Gen er a l P r oced u r e for th e P r ep a r a tion of â-La cta m s.
In a quartz photo reactor the diazo ketone and the imine were
dissolved in diethyl ether (300 mL), and the mixture was cooled
to -15 °C and irradiated for 90 min. The mixture was stirred
for another 30 min at that temperature and warmed to rt. The
solution was concentrated and the imine, and other nonpolar
compounds (polymerized ether) were removed by filtrative
column chromatography (20 g SiO2, PE/EA 7:1 f 1:1). After
determination of the isomer ratio (HPLC and 1H NMR), the
diastereoisomers were separated by chromatography.
(s, 9 H), 3.02 (br d, J ) 7.3, 1 H), 3.78 (d, J ) 14.8, 1 H), 4.09
(mc, 1 H), 4.38 (br s, 1 H), 4.63 (br d, J ) 8.0, 1 H), 4.80 (d, J
) 14.9, 1 H), 7.11-7.37 (m, 10 H); 13C NMR (75 MHz) δ 18.6
(q), 28.4 (q), 44.5 (d), 45.8 (t), 58.5 (d), 66.0 (d), 79.4 (s), 126.5,
127.7, 128.4, 128.4, 128.8, 128.9 (6 d), 135.5, 137.5 (2 s), 154.9
(s), 167.6 (s); MS (CI, CH4) m/ z (%) 381 (40, [M + 1]+), 325
(100, [M - C4H7]+), 281 (8, [M - C5H7O2]+), 238 (23, [M -
C7H12NO2]+), 91 (3, C7H7+), 57 (3, C4H9+). Anal. Calcd for
C23H28N2O3 (380.5): C, 72.60; H, 7.42; N, 7.36. Found: C,
72.44; H, 7.55; N, 7.18.
(3R,4S,1′S)- a n d (3S,4R,1′S)-1-Ben zyl-3-[1-[(ben zyloxy-
ca r bon yl)a m in o]eth yl]-4-p h en yla zetid in -2-on e (18a ,b).
Following the general procedure, diazo ketone 1 (247 mg, 1.00
mmol) and imine 17 (1.56 g, 8.00 mmol) were irradiated at
(3R,4S,1′S)- a n d (3S,4R,1′S)-1-Ben zyl-4-p h en yl-3-(1-
p h th a lim id oeth yl)a zetid in -2-on e (20a ,b). Following the
general procedure, diazo ketone 3 (486 mg, 2.00 mmol) and
imine 17 (1.56 g, 8.00 mmol) were irradiated at -15 °C to yield
a mixture of 20a and 20b (17:83, 443 mg, 54%). The pure
isomers 20a (58 mg, 7%) and 20b (354 mg, 43%) were obtained
by MPLC (PE/EA 7:3). 20b (first eluted): colorless solid; mp
(43) (a) Balenovic´, K.; Urbas, B.; Deljac, A. Croat. Chem. Acta 1959,
31, 153-155. (b) Yu, Y.; Chen, G.-Q.; Zhu, J .; Zhang, X.-S.; Chen, S.-
X.; Tang, H.-T.; Zhang, P. J . Chem. Soc., Perkin Trans 1 1990, 8, 2239-
2243.
(44) (a) Ernest, I.; J el´ınkova´, H. Collect. Czech. Chem. Commun.
1959, 24, 3341-3347. (b) Nikolaev, V. A.; Utkin, P. Y.; Korobitsyna, I.
K. J . Org. Chem. (USSR), Engl. Transl. 1989, 1059-1061.
(45) J uday, R.; Adkins, H. J . Am. Chem. Soc. 1955, 77, 4559-4564.
(46) Preparation of the imines 34, 35, 43, and 44, is in accordance
with the work of Texier-Boullet, F: Synthesis 1985, 679-681.
(47) Houben Weyl; Wu¨nsch, E., Ed.; Thieme: Stuttgart, 1974; Vol.
15/1.
176-177 °C; tR (HPLC, hexane/EA 7:3) 3.9 min; [R]20 +19.7
D
(c 1.07, CHCl3); IR (KBr) 1755, 1705 cm-1; 1H NMR (300 MHz)
δ 1.61 (d, J ) 7.0, 3 H), 3.72 (d, J ) 15.0, 1 H), 3.78 (dd, J )
11.0, 2.0, 1 H), 4.14 (d, J ) 2.1, 1 H), 4.66 (dq, J ) 11.0, 7.0,
1 H), 4.72 (d, J ) 15.0, 1 H), 6.88-7.69 (m, 14 H); 13C NMR
(75 MHz) δ 17.0 (q), 44.4 (t), 46.8 (d), 59.0 (d), 62.7 (d), 123.3,
126.0, 127.7, 128.3, 128.4, 128.7, 128.9, 134.1 (8 d), 131.4,
135.2, 136.8 (3 s), 167.2, 167.9 (2 s); MS (CI, CH4) m/ z (%)
411 (100, [M + 1]+), 238 (63, [M - C10H6NO2]+), 174 (45,
C10H8NO2+), 91 (20, C7H7+). Anal. Calcd for C26H22N2O3
(410.5): C, 76.08; H, 5.40; N, 6.82. Found: C, 76.15; H, 5.35;
(48) Eur. J . Biochem. 1984, 138, 9-37.
(49) (a) Lombardi, P. Chem. Ind. (London) 1990, Nov 5, 708. (b)
Moss, S. Chem. Ind. (London) 1994, Feb 21, 122.

Cycloadditions of Ketenes
J . Org. Chem., Vol. 62, No. 17, 1997 5879
N, 6.76. 20a (second eluted): colorless solid; mp 124-126 °C;
tR (HPLC, hexane/EA 7:3) 4.9 min; [R]20D +15.5 (c 1.42, CHCl3);
C8H5O2]+). Anal. Calcd for C28H30N2O3 (442.6): C, 75.99; H,
6.83; N 6.33%. Found: C, 76.05; H, 6.87; N, 6.27.
1
IR (KBr) 1745, 1707 cm-1; H NMR (300 MHz) δ 1.42 (d, J )
(3R,4S,1′S)- a n d (3S,4R,1′S)-1-Ben zyl-3-[1-[[(flu or en -9-
ylm e t h oxy)ca r b on yl]a m in o]-2-m e t h ylp r op yl]-4-p h e n -
yla zetid in -2-on e (23a ,b). Following the general procedure,
diazo ketone 6 (727 mg, 2.00 mmol) and imine 17 (781 mg,
4.00 mmol) were irradiated at -15 °C to yield a mixture of
23a and 23b (77:23, 838 mg, 79%). The pure isomers 23a (615
mg, 58%) and 23b (170 mg, 16%) were obtained by column
chromatography (PE/EA 8:1 f 2:1). 23a (first eluted): color-
less foam, softening range 40-70 °C; tR (HPLC, hexane/EA
4:1) 6.61 min; [R]20D +12.2 (c 1.05, CHCl3); IR (KBr) 3300, 2940,
7.0, 3 H), 3.63 (dd, J ) 9.5, 1.9, 1 H), 3.64 (d, J ) 14.6, 1 H),
4.26 (d, J ) 2.0, 1 H), 4.66 (dq, J ) 9.5, 7.1, 1 H), 4.74 (d, J )
15.0, 1 H), 7.05-7.76 (m, 14 H); 13C NMR (75 MHz) δ 16.3 (q),
44.2 (t), 45.5 (d), 58.7 (d), 61.9 (d), 123.2, 126.6, 127.6, 128.3,
128.5, 128.7, 128.9, 133.8 (8 d), 131.8, 135.3, 136.8 (3 s), 166.9,
167.9 (2 s); MS (CI, CH4) m/ z (%) 821 (8, [2 M + 1]+), 411 (95,
[M + 1]+), 238 (100, [M - C10H6NO2]+), 174 (85, C10H8NO2+),
91 (70, C7H7+). Anal. Calcd for C26H22N2O3 (410.5): C, 76.08;
H, 5.40; N, 6.82. Found: C, 75.84; H, 5.55; N, 6.79.
1
1740, 1712 cm-1; H NMR (300 MHz) δ 0.93, 0.95 (2 d, J )
(3R,4S,1′S)- a n d (3S,4R,1′S)-1-Ben zyl-3-[1-[(ben zyloxy-
ca r b on yl)a m in o]-3-m e t h ylb u t yl]-4-p h e n yla ze t id in -2-
on e (21a ,b). Following the general procedure, diazo ketone
4 (579 mg, 2.00 mmol) and imine 17 (1.56 g, 8.00 mmol) were
irradiated at -15 °C to yield a mixture of 21a and 21b (70:30,
816 mg, 89%). The pure isomers 21a (525 mg, 57%) and 21b
(215 mg, 24%) were obtained by column chromatography (PE/
EA 5:1). 21a (first eluted): colorless solid; mp 134.5-135.0
6.4, 6.3, 6 H), 1.96 (octet, J ) 7.0, 1 H), 3.29 (t, J ) 2.7, 1 H),
3.74 (d, J ) 14.9, 1 H), 3.84 (ddd, J ) 10.2, 7.8, 2.9, 1 H), 4.10-
4.23 (m, 3 H), 4.54 (dd, J ) 10.0, 6.5, 1 H), 4.81 (d, J ) 14.9,
1 H), 4.88 (d, 1 H), 7.07-7.80 (m, 18 H); 13C NMR (63 MHz) δ
19.0, 19.9 (2 q), 31.6 (d), 44.6 (t), 47.3 (d), 55.1 (d), 57.5 (d),
62.6 (d), 66.9 (t), 120.0, 125.1, 126.7, 127.1, 127.6, 127.8, 128.4,
128.5, 128.7, 129.0 (10 d), 135.3, 137.2, 141.3, 143.9 (4 s), 156.7
(s), 167.5 (s); MS (CI, CH4) m/ z (%) 309 (100, [M - C15H9O2]+),
179 (95, C14H11+), 132 (48, C8H6NO+), 91 (16, C7H7+). Anal.
Calcd for C35H34N2O3‚1/2H2O (539.7): C, 77.90; H, 6.54; N, 5.19.
Found: C, 78.24; H, 6.57; N, 5.11. 23b (second eluted):
colorless foam, softening range 60-75 °C; tR (HPLC, hexane/
EA 4:1) ) 11.4 min; [R]20D +11.9 (c 1.07, CHCl3); IR (KBr) 3310,
°C; tR (HPLC, hexane/EA 4:1) 5.47 min; [R]20 +3.99 (c 1,
D
CHCl3); IR (KBr) 3310, 1745, 1680 cm1; 1H-NMR (300 MHz) δ
0.86, 0.88 (2 d, J ) 6.7, 6.6, 6 H), 1.28-1.37 (m, 1 H), 1.59-
1.83 (2 m, 2 H), 3.12 (s, 1 H), 3.72 (d, J ) 15.0, 1 H), 4.16 (mc,
1 H), 4.27 (s, 1 H), 4.75 (d, J ) 9.5, 1 H), 4.84 (d, J ) 15.0, 1
H), 4.90, 5.14 (2 d, J ) 12.4, 12.3, 2 H), 7.11-7.37 (m, 15 H);
13C NMR (75 MHz) δ 21.4, 23.0 (2 q), 24.6 (d), 42.5, 44.3 (2 t),
47.3 (d), 56.6 (d), 64.9 (d), 66.6 (t), 126.5, 127.4, 127.6, 127.9,
128.1, 128.3, 128.4, 128.5, 128.8 (9 d), 135.3, 136.3, 137.2 (3
s), 156.4 (s), 167.7 (s); MS (CI, CH4) m/ z (%) 457 (100, [M +
1]+), 91 (16, C7H7+). Anal. Calcd for C29H32N2O3 (456.6): C,
76.29; H, 7.06; N, 6.14. Found: C, 76.41; H, 7.12; N, 6.09.
21b (second eluted): colorless solid; mp 124.0-124.5 °C; tR
(HPLC, hexane/EA 4:1) 7.00 min; [R]20D -33.2 (c 0.94, CHCl3);
IR (KBr) 3308, 1745 cm-1; 1H NMR (300 MHz) δ 0.89, 0.90 (2
d, J ) 6.2, 6.5, 6 H), 1.27-1.37, 1.49-1.75 (2 m, 3 H), 3.04
(dd, J ) 7.8, 1.1, 1 H), 3.78 (d, J ) 14.9, 1 H), 4.16 (mc, 1 H),
4.31 (d, J ) 1.6, 1 H), 4.67 (d, J ) 9.5, 1 H), 4.78 (d, J ) 15.0,
1 H), 5.01, 5.16 (2 d, J ) 12.3, 12.3, 2 H), 7.09-7.37 (m, 15 H);
13C NMR (75 MHz) δ 19.5, 21.5 (2 q), 22.6 (d), 39.7 (t), 42.6
(t), 46.8 (d), 56.1 (d), 63.6 (d), 64.7 (t), 124.9, 125.8, 126.2, 126.4,
126.5, 126.5, 126.8, 127.0 (8 d), 133.4, 134.5, 135.5 (3 s), 153.9
(s), 165.6 (s); MS (CI, CH4) m/ z (%) 457 (100, [M + 1]+), 91
(16, C7H7+). Anal. Calcd for C29H32N2O3 (456.6): C, 76.29;
H, 7.06; N, 6.14. Found: C, 76.13; H, 7.15; N, 5.90.
1
2940, 1745, 1717 cm-1; H NMR (300 MHz) δ 0.84, 0.90 (2 d,
J ) 6.9, 6.8, 6 H), 2.21 (mc, 1 H), 3.10 (dd, J ) 9.1, 1.7, 1 H),
3.81 (d, J ) 14.9, 1 H), 4.11 (mc, 1 H), 4.20 (t, J ) 6.5, 1 H),
4.32 (d, J ) 1.8, 1 H), 4.42-4.50 (m, 2 H), 4.54 (d, J ) 10.4, 1
H), 4.77 (d, J ) 15.0, 1 H), 7.09-7.78 (m, 18 H); 13C NMR (63
MHz) δ 16.1, 19.8 (2 q), 30.1 (d), 44.4 (t), 47.3 (d), 55.6 (d),
58.6 (d), 63.3 (d), 66.4 (t), 119.9, 124.8, 126.2, 127.0, 127.6,
128.3, 128.7, 129.0 (8 d), 135.2, 137.4, 141.2, 143.7 (4 s), 156.2
(s), 167.2 (s); MS (CI, CH4) m/ z (%) 309 (100, [M - C15H9O2]+),
178 (82, C14H10+), 132 (80, C8H6NO+), 91 (10, C7H7+). Anal.
Calcd for C35H34N2O3‚1/2H2O (539.7): C, 77.90; H, 6.54; N, 5.19.
Found: C, 77.81; H, 6.54; N, 5.13.
(3R,4S,1′S,2′S)- a n d (3S,4R,1′S,2′S)-1-Ben zyl-3-[1-[(ben -
zyloxycar bon yl)am in o]-2-m eth ylbu tyl]-4-ph en ylazetidin -
2-on e (24a ,b). Following the general procedure, diazo ketone
7 (579 mg, 2.00 mmol) and imine 17 (1.56 g, 8.00 mmol) were
irradiated at -15 °C to yield a mixture of 24a and 24b (83:17,
820 mg, 90%). The pure isomers 24a (507 mg, 56%) and 24b
(59 mg, 6%) were obtained by column chromatography (PE/
EA 7:1). 24a (first eluted): colorless oil; tR (HPLC, hexane/
EA 4:1) 5.1 min; [R]20D +19.4 (c 1.75, CHCl3); IR (CDCl3) 1730
cm-1; 1H NMR (300 MHz) δ 0.84 (t, J ) 7.3, 3 H), 0.93 (d, J )
6.7, 3 H), 1.08 (mc, 1 H), 1.55 (mc, 1 H), 1.71 (mc, 1 H), 3.28 (br
s, 1 H), 3.72 (d, J ) 15.0, 1 H), 3.93 (ddd, J ) 10.3, 7.7, 2.8, 1
H), 4.22 (d, J ) 2.1, 1 H), 4.83 (d, J ) 15.0, 1 H), 4.89 (d, J )
7.9, 1 H), 4.93, 5.15 (2 d, J ) 12.3, 12.4, 2 H), 7.08-7.42 (m,
15 H); 13C NMR (75 MHz) δ 11.0 (q), 15.8 (q), 25.4 (t), 38.1 (d),
44.4 (t), 53.7 (d), 57.3 (d), 62.3 (d), 66.8 (t), 126.5, 127.5, 127.7,
128.0, 128.2, 128.4, 128.4, 128.6, 128.9 (9 d), 135.3, 136.4, 137.2
(3 s), 156.6 (s), 167.4 (s); MS (CI, NH3) m/ z (%) 457 (100, [M
+ 1]+), 323 (11, [M - C8H5O2]+), 91 (28, C7H7+). Anal. Calcd
for C29H32N2O3 (456.6): C, 76.29; H, 7.06; N, 6.14. Found: C,
76.19; H, 7.13; N, 6.17. 24b (second eluted): colorless oil; tR
(3R,4S,1′S)- a n d (3S,4R,1′S)-1-Ben zyl-3-[1-[(ben zyloxy-
ca r b on yl)a m in o]-2-m et h ylp r op yl]-4-p h en yla zet id in -2-
on e (22a ,b). Following the general procedure, diazo ketone
5 (551 mg, 2.00 mmol) and imine 17 (429 mg, 2.20 mmol) were
irradiated at -15 °C to yield a mixture of 22a and 22b (82:18,
786 mg, 89%). The pure isomers 22a (543 mg, 61%) and 22b
(75 mg, 9%) were obtained by column chromatography (PE/
EA 5:1). 22a (first eluted): colorless solid; mp 75-76 °C; tR
(HPLC, hexane/EA 4:1) 6.2 min; [R]20 +23.6 (c 1.33, CHCl3);
D
1
IR (film) 3300, 2940, 1720 cm-1; H NMR (300 MHz) δ 0.94,
0.94 (2 d, J ) 6.8, 6.7, 6 H), 1.94 (octet, J ) 6.9, 1 H), 3.28 (br
s, 1 H), 3.72 (d, J ) 14.9, 1 H), 3.86 (ddd, J ) 10.3, 7.5, 3.0, 1
H), 4.20 (d, J ) 2.1, 1 H), 4.83 (d, J ) 14.9, 1 H), 4.87 (d, J )
7.7, 1 H), 4.93, 5.16 (2 d, J ) 12.3, 12.3, 2 H), 7.08-7.42 (m,
15 H); 13C NMR (75 MHz) δ 19.1, 19.9 (2 q), 31.8 (d), 44.4 (t),
55.1 (d), 57.5 (d), 62.7 (d), 66.8 (t), 126.7, 127.5, 127.8, 128.0,
128.3, 128.5, 128.51, 128.7, 129.0 (9 d), 135.4, 136.6, 137.3 (3
s), 156.9 (s), 167.5 (s); MS (CI, NH3) m/ z (%) 460 (62, [M +
NH4]+), 443 (100, [M + H]+), 309 (41, [M - C8H5O2]+). Anal.
Calcd for C28H30N2O3 (442.6): C, 75.99; H, 6.83; N, 6.33.
Found: C, 76.04; H, 6.83; N, 6.26. 22b (second eluted):
yellowish oil; tR (HPLC, hexane/EA 4:1) ) 9.6 min; [R]20D -6.5
(c 0.95, CHCl3); IR (film) 3310, 2945, 1740 cm-1; 1H NMR (300
MHz) δ 0.75, 0.83 (2 d, J ) 6.9, 6.8, 6 H), 2.13 (mc, 1 H), 3.01
(dd, J ) 9.6, 1.8, 1 H), 3.71 (d, J ) 15.0, 1 H), 4.02 (mc, 1 H),
4.27 (d, J ) 1.7, 1 H), 4.56 (d, J ) 10.1, 1 H), 4.67 (d, J ) 15.0,
1 H), 4.93, 5.13 (2 d, J ) 12.2, 12.2, 2 H), 6.97-7.25 (m, 15 H);
13C NMR (75 MHz) δ 14.2, 17.9 (2 q), 28.1 (d), 42.5 (t), 53.7
(d), 56.7 (d), 61.6 (d), 64.9 (t), 124.4, 125.7, 126.3, 126.4, 126.6,
126.8, 127.0 (7 d), 133.4, 134.5, 135.5 (3 s), 154.3 (s), 165.3 (s);
MS (CI, NH3) m/ z (%) 443 (100, [M + 1]+), 309 (80, [M -
(HPLC, hexane/EA 4:1) 9.2 min; [R]20 -18.2 (c 1.3, CHCl3);
D
IR (CDCl3) 1740, 1715 cm-1; 1H NMR (300 MHz) δ 0.86-1.90
(m, 9 H), 3.17 (dd, J ) 9.0, 1.9, 1 H), 3.78 (d, J ) 15.0, 1 H),
4.10-4.17 (m, 1 H), 4.32 (d, J ) 1.8, 1 H), 4.57 (d, J ) 10.0, 1
H), 4.77 (d, J ) 15.0, 1 H), 5.02, 5.21 (2 d, J ) 12.2, 12.2, 2 H),
7.06-7.36 (m, 15 H); 13C NMR (75 MHz) δ 11.6 (q), 16.1 (q),
23.6 (t), 37.1 (d), 44.5 (t), 55.4 (d), 58.3 (d), 63.3 (d), 66.8 (t),
126.4, 127.7, 128.3, 128.4, 128.6 128.8, 129.0 (7 d), 135.4, 136.4,
137.5 (3 s), 156.3 (s), 167.4 (s); MS (CI, NH3) m/ z (%) 457 (100,
[M + 1]+), 323 (24, [M - C8H5O2]+), 91 (10, C7H7+).
(3R,4S,1′S)-1-Ben zyl-3-[1-[(ben zyloxyca r bon yl)a m in o]-
2,2-d im eth ylp r op yl]-4-p h en yla zetid in -2-on e (25). Follow-
ing the general procedure, diazo ketone 8 (579 mg, 2.00 mmol)
and imine 17 (586 mg, 3.00 mmol) were irradiated at -15 °C
to yield a mixture of 25a and 25b (93:7, 804 mg, 88%). The
major isomer 25a (731 mg, 80%) could be isolated by column
chromatography (PE/EA 7:1): colorless oil; tR (HPLC, hexane/

5880 J . Org. Chem., Vol. 62, No. 17, 1997
Podlech and Linder
EA 4:1) 4.10 min; [R]20 +40.7 (c 1, CHCl3); IR (film): 3319,
tyl]-4-p h en yl-a zetid in -2-on e (28a ,b). Following the general
procedure, diazo ketone 11 (195 mg, 499 µmol) and imine 17
(390 mg, 2.00 mmol) were irradiated at -15 °C to yield a
mixture of 28a and 28b (70:30, 203 mg, 73%). MPLC (PE/
iPrOH 97:3) gave rise to the pure isomers 28a (95 mg, 34%)
and 28b (39 mg, 14%). 28a (first eluted): colorless oil; tR
D
3031, 2962, 1756 cm-1
;
1H NMR (300 MHz) δ 0.94 (s, 9 H),
3.34 (br s, 1 H), 3.70 (d, J ) 15.1, 1 H), 3.90 (dd, J ) 10.7, 2.1,
1 H), 4.18 (d, J ) 2.2, 1 H), 4.82 (d, J ) 15.0, 1 H), 4.93 (d, J
) 12.3, 1 H), 5.04 (d, J ) 10.7, 1 H), 5.19 (d, J ) 12.4, 1 H),
7.08-7.40 (m, 15 H); 13C NMR (75 MHz): δ 26.5 (q), 34.3 (s),
44.1 (t), 57.8 (d), 57.9 (d), 61.2 (d), 66.5 (t), 126.4, 127.2, 127.5,
127.8, 127.9, 128.2, 128.3, 128.7 (8 d), 135.0, 136.2, 136.8 (3
s), 156.6 (s), 166.8 (s); MS (CI,CH4) m/ z (%) 457 (100, [M +
1]+), 238 (43, [M - C13H16NO2]+), 196 (35, PhCH2NHdCHPh+),
91 (23, C7H7+). Anal. Calcd for C29H32N2O3 (456.6): C, 76.29;
H, 7.06; N, 6.14. Found: C, 75.98; H, 7.07; N, 5.91.
(HPLC, hexane/iPrOH 19:1) 8.95 min; [R]20 +2 (c 1, CHCl3);
D
1
IR (film) 3329, 3032, 2975, 1706 cm-1; H NMR (250 MHz) δ
1.36 (s, 9 H), 1.45-1.74 (m, 4 H), 3.12 (s, 2 H), 3.18 (d, J )
5.3, 1 H), 3.73 (d, J ) 15.0, 1 H), 4.00 (m, 1 H), 4.21 (s, 1 H),
4.64 (d, J ) 9.4, 1 H), 4.87 (m, 2 H), 5.07 (s, 2 H), 7.16-7.37
(m, 15 H); 13C NMR (63 MHz) δ 26.6, 31.1, 40.6 (3 t), 28.2 (q),
44.4 (t), 48.3 (d), 56.9 (d), 64.5 (d), 66.6 (t), 79.6 (s), 126.6, 127.7,
128.1, 128.4, 128.5, 128.8, 129.0 (7 d), 135.5, 136.6, 137.2, (3
s), 156.0, 156.4 (2 s), 167.7 (s); MS (FAB) m/ z (%) 558 (100,
[M + 1]+). Anal. Calcd for C33H39N3O5‚1/2H2O (566.7): C, 69.94;
H, 7.11; N, 7.41. Found: C, 70.02; H, 7.03; N, 7.35. 28b
(second eluted): colorless oil; tR (HPLC, hexane/iPrOH 19:1)
(3R,4S,1′S)- a n d (3S,4R,1′S)-1-Ben zyl-3-[1-[(ben zyloxy-
ca r b on yl)a m in o]-2-p h e n yle t h yl]-4-p h e n yla ze t id in -2-
on e (26a ,b). Following the general procedure, diazo ketone
9 (582 mg, 1.80 mmol) and imine 17 (1.41 g, 7.22 mmol) were
irradiated at -15 °C to yield a mixture of 26a and 26b (59:41,
512 mg, 58%). The pure isomers 26a (265 mg, 32%) and 26b
(185 mg, 23%) were obtained by column chromatography (PE/
EA 5:1). 26a (first eluted): colorless solid; mp 147-148 °C;
tR (HPLC, hexane/EA 4:1) 7.4 min; [R]20D +18.8 (c 1.07, CHCl3);
11.0 min; [R]20 -2 (c 1, CHCl3); IR (film) 3329, 3032, 2975,
D
1701 cm-1; 1H NMR (250 MHz) δ 1.41 (s, 9 H), 1.47-1.82 (m,
4 H), 3.02 (d, J ) 8.2, 1 H), 3.19 (q, J ) 6.3, 2 H), 3.79 (d, J )
15.0, 1 H), 4.00 (d, J ) 7.1, 1 H), 4.38 (s, 1 H), 4.54 (d, J ) 9.3,
1 H), 4.77 (d, J ) 15.0, 1 H), 4.92 (br s, 1 H), 5.08 (s, 2 H),
7.11-7.36 (m, 15 H); 13C NMR (63 MHz) δ 26.2, 30.0, 40.7 (3
t), 28.4 (q), 44.6 (t), 49.9 (d), 58.6 (d), 65.3 (d), 66.7 (t), 79.7
(s), 126.6, 127.0, 128.1, 128.6, 128.9, 129.0 (6 d), 135.4, 136.7,
137.5 (3 s), 155.4, 156.5 (2 s), 167.6 (s); MS (FAB) m/ z (%)
558 (100, [M + 1]+).
1
IR (KBr) 3260, 1720, 1708 cm-1; H NMR (300 MHz) δ 3.02
(d, J ) 7.7, 2 H), 3.18 (br s, 1 H), 3.72 (d, J ) 15.0, 1 H), 4.26
(d, J ) 1.7, 1 H), 4.35 (mc, 1 H), 4.84 (mc, 2 H), 4.92 (d, J )
9.4, 1 H), 5.08 (d, J ) 12.5, 1 H), 7.06-7.35 (m, 20 H); 13C
NMR (75 MHz) δ 39.8 (t), 44.5 (t), 50.5 (d), 56.9 (d), 62.9 (d),
66.7 (t), 126.6, 127.6, 128.0, 128.3, 128.5, 128.5, 128.7, 128.9,
129.2 (9 d), 135.3, 136.3, 136.9, 137.1 (4 s), 156.3 (s), 167.7 (s);
MS (CI, NH3) m/ z (%) 491 (100, [M + 1]+), 357 (17, [M -
C8H5O2]+), 266 (8, [357 - C7H7]+), 91 (6, C7H7+). Anal. Calcd
for C32H30N2O3‚1/2H2O (499.6): C, 76.93; H, 6.25; N, 5.61.
Found: C, 76.94; H, 6.08; N, 5.54. 26b (second eluted): mp
(3R,4S,1′S)- a n d (3S,4R,1′S)-1-Ben zyl-3-[1-[(ben zyloxy-
ca r bon yl)a m in o]-4-[[(ter t-bu tyloxy)ca r bon yl]a m in o]bu -
tyl]-4-p h en yla zetid in -2-on e (29a ,b). Following the general
procedure, diazo ketone 12 (780 mg, 2.00 mmol) and imine 17
(390 mg, 2.00 mmol) were irradiated at -15 °C to yield a
mixture of 29a and 29b (70:30, 778 mg, 70%). The pure
isomers 29a (345 mg, 31%) and 29b (148 mg, 13%) were
obtained by MPLC (PE/iPrOH 49:1). 29a (first eluted): color-
126-127 °C; tR (HPLC, hexane/EA 4:1) 8.9 min; [R]20 -9.93
D
(c 1.09, CHCl3); IR (KBr) 3290, 1721, 1710 cm-1; 1H NMR (300
MHz) δ 2.99 (m, 3 H), 3.82 (d, J ) 14.9, 1 H), 4.35-4.45 (m, 2
H), 4.61 (d, J ) 9.3, 1 H), 4.80 (d, J ) 14.7, 1 H), 4.99, 5.10 (2
d, J ) 12.2, 12.0, 2 H), 7.05-7.32 (m, 20 H); 13C NMR (75 MHz)
δ 38.3 (t), 44.5 (t), 51.3 (d), 58.9 (d), 63.5 (d), 66.7 (t), 126.4,
126.7, 127.8, 128.1, 128.2, 128.4, 128.5, 128.8, 129.0, 129.9 (10
d), 135.3, 136.3, 137.2 (3 s), 155.6 (s), 167.3 (s); MS (CI, NH3)
m/ z (%) 491 (100, [M + 1]+), 357 (16, [M - C8H5O2]+), 266 (9,
[357 - C7H7]+), 91 (13, C7H7+). Anal. Calcd for C32H30N2O3
(490.6): C, 78.34; H, 6.16; N, 5.71. Found: C, 78.31; H, 6.23;
N 5.62.
less oil; tR (HPLC, hexane/iPrOH 19:1) 8.23 min; [R]20 +12 (c
D
1, CHCl3); IR (film) 3318, 3032, 2931, 1714 cm-1; 1H NMR (250
MHz) δ 1.41 (s, 9 H), 1.47-1.77 (m, 4 H), 3.08 (d, J ) 5.9, 1
H), 3.15 (s, 2 H), 3.71 (d, J ) 14.9, 1 H), 4.07 (m, 1 H), 4.23 (d,
J ) 1.8, 1 H), 4.52 (br s, 1 H), 4.84 (d, J ) 15.0, 1 H), 4.91 (s,
1 H), 4.94 (d, J ) 12.3, 1 H), 5.13 (d, J ) 12.3, 1 H), 7.08-7.36
(m, 15 H); 13C NMR (75 MHz) δ 26.8, 31.1, 40.1 (3 t), 28.5 (q),
44.6 (t), 49.3 (d), 56.9 (d), 64.5 (d), 67.0 (t), 79.2 (s), 126.7, 127.7,
128.0, 128.2, 128.4, 128.6, 128.8, 129.1 (8 d), 135.4, 136.4, 137.2
(3 s), 156.0, 156.6 (2 s), 167.7 (s); MS (FAB) m/ z (%) 558 (100,
[M + 1]+). Anal. Calcd for C33H39N3O5 (557.7): C, 71.07; H,
7.05; N, 7.53. Found: C, 71.04; H, 7.08; N, 7.44. 29b (second
eluted): colorless oil; tR (HPLC, hexane/iPrOH 19:1) 9.68 min;
(2S,3′R,4′S)- a n d (2S,3′S,4′R)-ter t-Bu tyl 2-(1-Ben zyl-2-
oxo-4-p h e n yla ze t id in -3-yl)p yr r olid in e -1-ca r b oxyla t e
(27a ,b). Following the general procedure, diazo ketone 10 (480
mg, 2.01 mmol) and imine 17 (1.57 g, 8.04 mmol) were
irradiated at -15 °C to yield a mixture of 27a and 27b (63:37,
515 mg, 63%). The pure isomers 27a (275 mg, 34%) and 27b
(179 mg, 22%) were obtained by MPLC (PE/EA 3:1). 27a (first
[R]20D -27 (c 1, CHCl3); IR (film) 3325, 3031, 2930, 1712 cm-1
;
1H NMR (250 MHz) δ 1.43 (s, 9 H), 1.50-1.83 (m, 4 H), 3.02-
3.11 (m, 3 H), 3.77 (d, J ) 14.9, 1 H), 4.02-4.10 (m, 1 H), 4.33
(d, J ) 1.6, 1 H), 4.57 (br s, 1 H), 4.78 (d, J ) 14.9, 1 H), 4.84
(s, 1 H), 5.00-5.17 (m, 2 H), 7.09-7.33 (m, 15 H); 13C NMR
(63 MHz) δ 26.4, 29.9, 40.1 (3 t), 28.4 (q), 44.6 (t), 50.6 (d),
58.2 (d), 65.0 (d), 66.8 (t), 79.2 (s), 126.4, 127.8, 128.2, 128.4,
128.5, 128.8, 129.0 (7 d), 135.3, 136.4, 137.3 (3 s), 156.0 (s),
167.3 (s); MS (FAB) m/ z (%) 558 (100, [M + 1]+). Anal. Calcd
for C33H39N3O5‚1/2H2O (566.7): C, 69.94; H, 7.11; N, 7.41.
Found: C, 69.94; H, 6.97; N, 7.33.
eluted): colorless oil; tR (HPLC, hexane/EA 3:1) 5.17 min; [R]20
D
+131 (c 0.5, CHCl3); IR (film) 2976, 2882, 1749, 1690 cm-1
;
1H NMR (300 MHz) δ 1.24-1.47 (m, 9 H), 1.86-1.96 (m, 4 H),
3.00-3.12 (m, 1 H), 3.21-3.25 (m, 2 H), 3.71-3.84 (m, 1 H),
4.15-4.26 (m, 1 H), 4.84-4.79 (m, 1 H), 4.92 (mc, 1 H), 7.13-
7.29 (m, 10 H); 13C NMR (250 MHz) δ 23.4, 29.1 (2 t), 28.3 (q),
44.2 (t), 46.4 (t), 56.4 (d), 59.7 (d), 64.5 (d), 79.1 (s), 126.6, 127.5,
128.0, 128.4, 128.6 (5 d), 135.6, 137.9 (2 s), 154.7 (s), 167.8 (s);
MS (FAB) m/ z (%) 836 (3, [2 M + Na + 1]+), 429 (18, [M +
Na]+), 407 (62, [M + 1]+), 351 (31, [M - C4H7]+), 307 (100, [M
- C5H7O2]+), 91 (35, C7H7+). 27b (second eluted): colorless
solid; mp 123-124 °C; tR (HPLC, hexane/EA 3:1) 6.02 min;
(3R,4S,1′S)- a n d (3S,4R,1′S)-1-Ben zyl-3-[5-[(ben zyloxy-
ca r bon yl)a m in o]-1-[[(ter t-bu tyloxy)ca r bon yl]a m in o]p en -
tyl]-4-p h en yla zetid in -2-on e (30a ,b). Following the general
procedure, diazo ketone 13 (1.21 g, 2.99 mmol) and imine 17
(1.17 g, 5.99 mmol) were irradiated at -15 °C to yield a
mixture of 30a and 30b (65:35, 1.21 g, 71%). The pure isomers
30a (440 mg, 26%) and 30b (260 mg, 15%) were obtained by
MPLC (PE/iPrOH 9:1). 30a (first eluted): colorless oil; tR
[R]20 -4.59 (c 0.5, CHCl3); IR (film) 2976, 1748, 1694 cm-1
;
D
1H NMR (250 MHz) δ 1.14-1.53 (m, 9 H), 1.52-.20 (m, 4 H),
3.28-3.76 (m, 4 H), 4.10-4.51 (m, 2 H), 4.87 (d, J ) 15.0, 1
H), 7.12-7.37 (m, 10 H); 13C NMR (75 MHz, 325 K) δ 23.7,
28.8 (2 t), 28.2 (s), 44.5 (t), 47.2 (t), 54.8 (d), 56.6 (d), 64.2 (d),
79.5 (s), 126.4, 127.5, 128.1, 128.3, 128.6, 128.9 (6 d), 135.9,
138.0 (2 s), 156.0 (s), 168.2 (s); MS (FAB) m/ z (%) 836 (3, [2
M + Na + 1]+), 429 (23, [M + Na]+), 407 (100, [M + 1]+), 351
(41, [M - C4H7]+), 307 (35, [M - C5H7O2]+), 91 (32, C7H7+).
Anal. Calcd for C25H30N2O3 (406.5): C, 73.86; H, 7.44; N, 6.89.
Found: C, 73.66; H, 7.40; N, 6.85.
(HPLC, hexane/iPrOH 19:1) 8.68 min; [R]20 -1 (c 1, CHCl3);
D
IR (film) 3344, 3032, 2926, 1720, 1708 cm-1
;
1H NMR (250
MHz) δ 1.36 (s, 9 H), 1.42-1.61, 1.70 (m, s, 6 H), 3.13-3.19
(m, 3 H), 3.73 (d, J ) 15.0 Hz, 1 H), 3.97 (m, 1 H), 4.21 (d, J
) 2.1, 1 H), 4.58 (d, J ) 9.5, 1 H), 4.81 (s, 1 H), 4.87 (d, J )
15.1, 1 H), 5.07 (s, 2 H), 7.25-7.41 (m, 15 H); 13C NMR (75
MHz) δ 23.1, 29.3, 33.3, 40.6 (4 t), 28.2 (q), 44.4 (t), 48.2 (d),
56.9 (d), 64.5 (d), 66.5 (t), 79.4 (s), 126.5, 127.6, 127.9, 128.0,
(3R,4S,1′S)- a n d (3S,4R,1′S)-1-Ben zyl-3-[4-[(ben zyloxy-
ca r bon yl)a m in o]-1-[[(ter t-bu tyloxy)ca r bon yl]a m in o]bu -

Cycloadditions of Ketenes
J . Org. Chem., Vol. 62, No. 17, 1997 5881
128.3, 128.4, 128.7, 128.9 (8 d), 135.5, 136.6, 137.2 (3 s), 156.0,
156.4 (2 s), 167.8 (s); MS (FAB) m/ z (%) 572 (100, [M + 1]+).
Anal. Calcd for C34H41N3O5 (571.7): C, 71.43; H, 7.23; N, 7.35.
Found: C, 71.27; H, 7.12; N, 7.33. 30b (second eluted):
colorless solid; mp 100-102 °C; tR (HPLC, hexane/iPrOH 49:
1) 5.24 min; [R]20 -29.1 (c 1, CHCl3); IR (KBr) 2940, 1720,
D
1708 cm-1; H NMR (300 MHz) δ 1.31 (d, J ) 7.0 Hz, 3 H),
1
1.39 (s, 9 H), 1.78 (d, J ) 7.2, 3 H), 3.04 (t, J ) 2.8, 1 H), 4.10
(m, 1 H), 4.21 (d, J ) 2.3, 1 H), 4.30 (q, J ) 7.2, 1 H), 4.63 (br
d, J ) 8.0 Hz, 1 H), 7.17-7.30 (m, 10 H); 13C NMR (75 MHz)
δ 19.7 (q), 20.1 (q), 28.2 (q), 44.3 (d), 54.4 (d), 56.8 (d), 64.5
(d), 79.4 (s), 126.6, 126.8, 127.4, 128.2, 128.6, 128.7 (6 d), 137.8,
141.3 (2 s), 155.5 (s), 168.1 (s); MS (FAB) m/ z (%) 395 (100,
[M + 1]+), 339 (82, [M - C4H7]+), 252 (35, [M - C7H12NO2]+),
105 (56, C8H9+), 57 (27, C4H9+). Anal. Calcd for C24H30N2O3
(394.5): C, 73.07; H, 7.66; N, 7.10. Found: C, 72.91; H, 7.64;
N, 7.06.
colorless oil; tR (HPLC, hexane/iPrOH 19:1) 12.2 min; [R]20
D
-23 (c 1, CHCl3); IR (film) 3333, 3031, 2933, 1701 cm-1; H
1
NMR (250 MHz) δ 1.40 (s, 9 H), 1.40-1.50, 1.68 (m, s, 6 H),
3.02 (d, J ) 8.7, 1 H), 3.17 (s, 2 H), 3.80 (d, J ) 15.0, 1 H),
3.98 (d, J ) 8.6, 1 H), 4.41 (s, 1 H), 4.55 (d, J ) 9.3, 1 H), 4.77
(d, J ) 15.0, 1 H), 4.89 (s, 1 H), 5.09 (s, 2 H), 7.21-7.34 (m, 15
H); 13C NMR (75 MHz) δ 22.3, 29.4, 32.1, 40.4 (4 t), 28.3 (q),
44.4 (t), 49.9 (d), 58.6 (d), 65.3 (d), 66.5 (t), 79.4 (s), 126.4, 127.7,
128.0, 128.4, 128.7, 128.9 (6 d), 135.3, 136.6, 137.4 (3 s), 155.4,
156.4 (2 s), 167.5 (s); MS (FAB) m/ z (%) 572 (100, [M + 1]+).
Anal. Calcd for C34H41N3O5‚1/2H2O (580.7): C, 70.32; H, 7.29;
N, 7.24. Found: C, 70.24; H, 7.22; N, 7.11.
(3R,4S,1′S,1′′S)- a n d (3S,4R,1′S,1′′S)-3-[1-[[(ter t-Bu -
tyloxy)ca r bon yl]a m in o]eth yl]-4-p h en yl-1-(1-p h en yleth -
yl)a zetid in -2-on e (37a ,b). Following the general procedure,
diazo ketone 2 (420 mg, 1.97 mmol) and imine 35 (1.62 g, 7.74
mmol) were irradiated at -15 °C to yield a mixture of 37a
and 37b (88:12, 686 mg, 88%). The pure isomers 37a (560
mg, 72%) and 37b (58 mg, 7%) were obtained by MPLC (PE/
iPrOH 99:1). 37a (first eluted): colorless solid: mp 102-104
°C; tR (HPLC, hexane/iPrOH 49:1) 6.38 min; [R]20D -5.7 (c 1.07,
(3R,4S,1′R,2′R)- an d (3S,4R,1′R,2′R)-1-Ben zyl-3-[1-[(ben -
zyloxyca r b on yl)a m in o]-2-[(t er t -b u t yld im e t h ylsilyl)-
oxy]p r op yl]-4-p h en yla zetid in -2-on e (32a ,b). Following the
general procedure, diazo ketone 15 (740 mg, 1.89 mmol) and
imine 17 (780 mg, 3.99 mmol) were irradiated at -15 °C to
yield a mixture of 32a and 32b (80:20, 480 mg, 45%). The
pure isomers 32a (380 mg, 36%) and 32b (95 mg, 9%) were
obtained by column chromatography (PE/EA 20:1 f 6:1). 32a
(first eluted): colorless oil; tR (HPLC, hexane/EA 4:1) 1.22 min;
[R]20D +20 (c 1, CHCl3); IR (film) 3303, 3032, 2928, 2955, 1756
cm-1; 1H NMR (250 MHz) δ -0.25, -0.05 (2 s, 6 H), 0.70 (s, 9
H), 1.14 (d, J ) 6.2, 3 H), 3.32 (d, J ) 5.9, 1 H), 3.74 (d, J )
15.0, 1 H), 3.85 (m, 1 H), 4.03 (m, 1 H), 4.20 (s, 1 H), 4.85 (d,
J ) 15.0, 1 H), 5.04-5.18 (m, 3 H), 7.12-7.40 (m, 15 H); 13C
NMR (75 MHz) δ -5.4, -4.4 (2 q), 17.7 (s), 20.2 (q), 25.6 (q),
44.3 (t), 55.8, 58.1, 60.7, 68.6 (4 d), 67.0 (t), 126.6, 127.6, 128.1,
128.3, 128.5, 128.7, 129.0 (7 d), 135.3, 136.4, 137.1 (3 s), 156.5
(s), 167.6 (s); MS (FAB) m/ z (%) 559 (100, [M + 1]+). Anal.
Calcd for C33H42N2O4Si (558.8): C, 70.93; H, 7.58; N, 5.01.
Found: C, 70.58; H, 7.64; N, 5.00. 32b (second eluted):
1
CHCl3); IR (KBr) 3260, 2963, 1720, 1693 cm-1; H NMR (250
MHz) δ 1.25 (d, J ) 6.9, 3 H), 1.31 (d, J ) 7.2, 3 H), 1.39 (s, 9
H), 3.07 (br s, 1 H), 4.04 (br s, 1 H), 4.15 (br s, 1 H), 4.49 (br
d, 1 H), 4.99 (q, J ) 7.1, 1 H), 7.21-7.35 (m, 10 H); 13C NMR
(75 MHz) δ 18.9, 19.7 (2 q), 28.3 (q), 44.3 (d), 52.2 (d), 57.2 (d),
64.3 (d), 79.3 (s), 126.8, 127.2, 127.7, 128.3, 128.6, 128.7 (6 d),
139.1, 140.0 (2 s), 155.5 (s), 168.2 (s); MS (CI, CH4) m/ z (%)
395 (100, [M + 1]+), 339 (100, [M - C4H7]+), 295 (15, [M -
C5H7O2]+), 252 (9, [M - C7H12NO2]+). Anal. Calcd for
C24H30N2O3 (394.5): C, 73.07; H, 7.66; N, 7.10. Found: C,
72.83; H, 7.61; N, 6.90. 37b (second eluted): mp 94.5-95.0
°C; tR (HPLC hexane/iPrOH 49:1) 9.32 min; [R]20 -10 (c 0.8,
D
1
CHCl3); IR (KBr) 3280, 2960, 1720, 1690 cm-1; H NMR (250
MHz) δ 1.28 (d, J ) 6.7, 3 H), 1.41 (s, 9 H), 1.76 (d, J ) 7.1, 3
H), 2.94 (dd, J ) 8.4, 2.1, 1 H), 4.07 (sextet, J ) 7.1, 1 H),
4.28-4.35 (m, 2 H), 4.61 (d, J ) 8.6, 1 H), 7.12-7.29 (m, 10
H); 13C NMR (63 MHz) δ 18.6 (q), 20.0 (q), 28.4 (q), 45.8 (d),
54.3 (d), 58.3 (d), 65.1 (d), 79.4 (s), 126.6, 126.9, 127.6, 128.3,
128.6, 128.8 (6 d), 139.0, 141.2 (2 s), 155.0 (s), 167.8 (s); MS
(FAB) m/ z (%) 395 (94, [M + 1]+), 339 (100, [M - C4H7]+),
252 (34, [M - C7H12NO2]+), 105 (53, C8H9+), 57 (12, C4H9+).
(3R,4S,1′S,2′S,1′′R)-3-[1-[(Ben zyloxyca r b on yl)a m in o]-
2-m e t h ylb u t yl]-4-p h e n yl-1-(1-p h e n yle t h yl)a ze t id in -2-
on e (38a ). Following the general procedure, diazo ketone 7
(579 mg, 2.00 mmol) and imine 34 (1.05 g, 5.02 mmol) were
irradiated at -15 °C to yield a mixture of 38a and 38b (73:27,
678 mg, 72%). Isomer 38a (424 mg, 45%) could be isolated by
MPLC (PE/iPrOH 99.5:0.5). 38a (first eluted): colorless oil;
colorless oil; tR (HPLC, hexane/EA 4:1) 1.36 min; [R]20 +4 (c
D
1, CHCl3); IR (film) 3318, 3031, 2954, 2928, 1755 cm-1
;
1H
NMR (250 MHz) δ 0.11, 0.12 (2 s, 6 H), 0.82 (s, 9 H), 1.14 (d,
J ) 6.2, 3 H), 3.16 (dd, J ) 11.4, 2.0, 1 H), 3.82 (d, J ) 15.0,
1 H), 3.94 (m, 1 H), 4.47 (q, J ) 6.1, 1 H), 4.56 (d, J ) 2.0, 1
H), 4.71 (d, J ) 15.0, 1 H), 5.01 (d, J ) 12.1, 2 H), 5.21 (d, J
) 12.2, 1 H), 7.03-7.37 (m, 15 H); 13C NMR (75 MHz) δ -4.7,
-4.5 (2 q), 18.0 (s), 20.8 (q), 25.9 (q), 44.5 (t), 56.6, 59.1, 62.9,
67.4 (4 d), 66.8 (t), 126.4, 127.7, 128.3, 128.4, 128.6, 128.8,
128.9 (7 d), 135.4, 136.5, 137.8, (3 s), 156.5 (s), 167.3 (s); MS
(FAB) m/ z (%) 559 (100, [M + 1]+). Anal. Calcd for
C33H42N2O4Si (558.8): C, 70.93; H, 7.58; N, 5.01. Found: C,
70.66; H, 7.60; N, 4.92.
(3R,4S,1′R,2′R)- a n d (3S,4R,1′R,2′R)-1-Ben zyl-3-[2-[(ter t-
bu tyld im eth ylsilyl)oxy]-1-[[(ter t-bu tyloxy)ca r bon yl]a m i-
n o]p r op yl]-4-p h en yla zetid in -2-on e (33a ). Diazo ketone 16
(360 mg, 1.01 mmol) and imine 17 (390 mg, 2.00 mmol) in Et2O
(300 mL) were irradiated at -15 °C for 90 min. The volatile
components were evaporated and the diastereoisomeric ratio
was determined by 1H NMR spectroscopy (33a /b 80:20).
Purification by column chromatography (PE/EA 20:1) yielded
pure 33a (195 mg, 37%). 33a : colorless oil; tR (HPLC, hexane/
EA 17:3) 5.45 min; [R]20D +8 (c 1, CHCl3); IR (film) 3320, 3031,
2928, 1760, 1715 cm-1; 1H NMR (250 MHz) δ -0.35, -0.17 (2
s, 6 H), 0.60 (s, 9 H), 1.02 (d, J ) 6.2, 3 H), 1.32 (s, 9 H), 3.18
(dd, J ) 5.8, 1.7, 1 H), 3.63 (d, J ) 15.1, 1 H), 3.70 (m, 1 H),
3.83 (m, 1 H), 4.06 (s, 1 H), 4.64-4.74 (m, 2 H), 6.99-7.21 (m,
10 H); 13C NMR (75 MHz) δ -4.9, -4.0 (2 q), 18.2 (s), 20.7 (q),
26.0 (q), 28.8 (q), 44.7 (t), 55.5, 58.6, 61.4, 69.1 (4 d), 79.8 (s),
127.0, 128.0, 128.7, 128.9, 129.1, 129.3 (6 d), 135.8, 137.7 (2
s), 156.3 (s), 168.1 (s); MS (FAB) m/ z (%) 525 (100, [M + 1]+).
Anal. Calcd for C30H44N2O4Si (524.8): C, 68.66; H, 8.45; N,
5.34. Found: C, 68.40; H, 8.67; N, 5.19.
tR (HPLC, hexane/iPrOH 49:1) 3.94 min; [R]20 +32.7 (c 0.94,
D
1
CHCl3); IR (film) 3302, 2945, 2917, 1725 cm-1; H NMR (250
MHz) δ 0.81 (t, J ) 7.3, 3 H), 0.90 (d, J ) 6.7, 3 H), 0.94-1.68
(m, 3 H), 1.27 (d, 3 H), 3.22 (d, J ) 2.5, 1 H), 3.85 (ddd, J )
10.2, 7.7, 2.6, 1 H), 4.12 (d, J ) 2.3, 1 H), 4.78 (d, J ) 10.1, 1
H), 4.90-4.98 (m, 2 H), 5.14 (d, J ) 12.4, 1 H), 7.16-7.43 (m,
15 H); 13C NMR (63 MHz) δ 11.0 (q), 15.8 (q), 18.7 (q), 25.4 (t),
38.1 (d), 52.3 (d), 53.7 (d), 57.6 (d), 61.4 (d), 66.8 (t), 126.9,
127.2, 127.6, 127.9, 128.1, 128.4, 128.5, 128.7 (8 d), 136.4,
139.1, 139.9 (3 s), 156.5 (s), 167.8 (s); MS (CI, CH4) m/ z (%)
471 (97, [M + 1]+), 363 (100, [M - C8H11]+), 91 (72, C7H7+).
Anal. Calcd for C30H34N2O3‚1/2H2O (479.6): C, 75.13; H, 7.36;
N, 5.84. Found: C, 75.39; H, 7.39; N, 5.79.
(3R,4S,1′S,2′S,1′′S)-3-[1-[(Ben zyloxyca r bon yl)a m in o]-2-
m et h ylb u t yl]-4-p h en yl-1-(1-p h en ylet h yl)a zet id in -2-on e
(39a ). Following the general procedure, diazo ketone 7 (579
mg, 2.00 mmol) and imine 35 (1.18 g, 5.64 mmol) were
irradiated at -15 °C to yield a mixture of 39a and 39b (86:14,
527 mg, 56%). Isomer 39a (404 mg, 43%) could be isolated by
MPLC (PE/iPrOH 99.5:0.5). 39a (first eluted): colorless oil;
(3R ,4S ,1′S ,1′′R )-3-[1-[[(t er t -Bu t yloxy)ca r b on yl]a m -
in o]eth yl]-4-ph en yl-1-(1-ph en yleth yl)azetidin -2-on e (36a).
Following the general procedure, diazo ketone 2 (430 mg, 2.02
mmol) and imine 34 (1.61 g, 7.69 mmol) were irradiated at
-15 °C to yield a mixture of 36a and 36b (55:45, 576 mg, 72%).
The pure isomer 36a (292 mg, 37%) was obtained by column
chromatography (PE/EA 20:1 f 6:1). 36a (first eluted):
tR (HPLC, hexane/EA 9:1) 12.1 min; [R]20 +24.8 (c 1, CHCl3);
D
1
IR (film) 3316, 2962, 2931, 1736 cm-1; H NMR (300 MHz) δ
0.83 (t, J ) 7.3, 3 H), 0.92 (d, J ) 6.7, 3 H), 0.99-1.21, 1.43-
1.66 (2 m, 3 H), 1.71 (d, J ) 7.2, 3 H), 3.20 (t, J ) 2.4, 1 H),
3.92 (ddd, J ) 10.1, 7.6, 2.6, 1 H), 4.16 (d, J ) 2.2, 1 H), 4.26
(q, J ) 7.2, 1 H), 4.95 (d, J ) 10.1, 1 H), 5.00, 5.14 (2 d, J )

5882 J . Org. Chem., Vol. 62, No. 17, 1997
Podlech and Linder
12.4, 12.3 , 2 H), 7.14-7.42 (m, 15 H); 13C NMR (63 MHz) δ
10.9 (q), 15.8 (q), 19.8 (q), 25.4 (t), 38.0 (d), 53.7, 54.4 (2 d),
57.3 (d), 61.4 (d), 66.7 (t), 126.6, 127.3, 127.8, 128.0, 128.2,
128.4, 128.7 (7 d), 136.4, 137.6, 141.0 (3 s), 156.6 (s), 167.7 (s);
MS (CI, CH4) m/ z (%) 471 (100, [M + 1]+). Anal. Calcd for
C30H34N2O3 (470.6): C, 76.57; H, 7.28; N, 5.95. Found: C,
76.35; H, 7.34; N, 5.86.
mg, 213 µmol) in CH2Cl2 (4 mL), and the solution was stirred
for 4 h at rt. Brine and Et2O were added, and the organic
layer was subsequently extracted with saturated NH4Cl solu-
tion and brine, dried (MgSO4), and evaporated at reduced
pressure. Purification by column chromatography (PE/EA 9:1)
yielded pure 48 (65 mg, 67%) as a colorless solid: mp 96-98
°C; Rf (TLC, PE/EA 5:1) 0.38; [R]20 -8.6 (c 0.54, CHCl3); IR
D
(KBr) 3350, 2950, 2912, 1796, 1718, 1691 cm-1; 1H NMR (500
MHz) δ 0.92, 0.95 (2 d, J ) 6.7, 6 H), 1.35 (s, 9 H), 1.94 (octet,
J ) 6.8, 1 H), 3.28 (t, J ) 3.5, 1 H), 3.93 (mc, 1 H), 4.72 (d, J
) 3.2, 1 H), 4.85 (d, J ) 10.0, 1 H), 5.18 (s, 2 H), 7.26-7.41
(m, 10 H); 13C NMR (125 MHz) δ 18.8, 19.8 (2 q), 27.8 (q), 31.8
(d), 55.1, 57.9, 62.0 (3 d), 67.1 (s), 83.4 (t), 125.9, 127.9, 128.2,
128.5, 128.6, 128.9 (6 d), 136.3, 137.6 (2 s), 147.2, 156.8 (2 s),
165.6 (s); MS (FAB) m/ z (%) 475 (14, [M + Na]+), 397 (26, [M
- C4H7]+), 353 (14, [M - C5H7O2]+), 91 (100, C7H7+), 57 (25,
C4H9+). Anal. Calcd for C26H32N2O5 (452.6): C, 69.01; H, 7.13;
N, 6.19. Found: C, 69.58; H, 7.13; N, 6.19.
(3R,4S,1′S)- a n d (3S,4R,1′S)-3-[1-[(Ben zyloxyca r b on -
yl)am in o]-2-m eth ylpr opyl]-1-[(4-m eth oxyph en yl)m eth yl]-
4-p h en yla zetid in -2-on e (45a ). Following the general pro-
cedure, diazo ketone 5 (551 mg, 2.00 mmol) and imine 44 (901
mg, 4.00 mmol) were irradiated at -15 °C to yield a mixture
of 45a and 45b (84:16, 473 mg, 50%). The pure isomer 45a
(331 mg, 35%) was obtained by MPLC (PE/EA 4:1). 45a (first
eluted): yellowish oil; tR (HPLC, hexane/EA 4:1) 10.7 min;
[R]20 +13.7 (c 0.9, CHCl3); IR (film) 3315, 2961, 1739 cm-1
;
D
1H NMR (250 MHz) δ 0.93, 0.94 (2 d, J ) 6.8, 6.7, 6 H), 1.93
(mc, 1 H), 3.25 (t, J ) 2.6, 1 H), 3.67 (d, J ) 15.3, 1 H), 3.68 (s,
3 H), 3.85 (ddd, J ) 10.5, 7.6, 3.0, 1 H), 4.19 (d, J ) 2.2, 1 H),
4.77 (d, J ) 14.8, 1 H), 4.88, (d, J ) 10.3, 1 H), 4.93, 5.19 (2 d,
J ) 12.4, 12.5, 2 H), 6.72, 7.02 (2 d, J ) 8.6, 8.6, 4 H), 7.24-
7.37 (m, 10 H); 13C NMR (63 MHz) δ 18.8, 19.7 (2 q), 31.7 (d),
43.7 (t), 54.9, 57.1 (d, q), 62.3 (d), 66.6 (t), 113.9, 126.5, 127.5,
127.9, 128.3, 128.4, 128.8, 129.5 (8 d), 127.2, 136.4, 137.2, 158.9
(4 s), 156.6 (s), 167.3 (s); MS (FAB) m/ z (%) 473 (85, [M +
1]+), 121 (100, C8H9O+), 91 (94, C7H7+). Anal. Calcd for
C29H32N2O4‚1/2H2O (481.6): C, 72.33; H, 6.91; N, 5.82.
Found: C, 72.63; H, 6.88; N, 5.80.
(3R,4S,1′S)- a n d (3S,4R,1′S)-3-[1-[[(ter t-Bu tyloxy)ca r -
b on yl]a m in o]et h yl]-4-p h en yl-1-p r op -2-en yla zet id in -2-
on e (50a ,b). Following the general procedure, diazo ketone
2 (426 mg, 2.00 mmol) and imine 49 (1.16 g, 7.99 mmol) were
irradiated at -15 °C to yield a mixture of 50a and 50b (68:32,
410 mg, 62%). The pure isomers 50a (231 mg, 35%) and 50b
(119 mg, 18%) were obtained by MPLC (PE/EA 4:1). 50a (first
eluted): colorless oil; tR (HPLC, hexane/EA 3:1) 13.2 min; [R]20
D
+24.8 (c 1.02, CHCl3); IR (film) 3320, 2977, 2933, 1746, 1704
1
cm-1; H NMR (300 MHz) δ 1.33 (d, J ) 7.0, 3 H), 1.47 (s, 9
(3R,4S,1′S)- a n d (3S,4R,1′S)-3-[1-[(Ben zyloxyca r b on -
yl)a m in o]-2,2-d im e t h ylp r op yl]-1-[(4-m e t h oxyp h e n yl)-
m eth yl]-4-p h en yla zetid in -2-on e (46a ). Following the gen-
eral procedure, diazo ketone 8 (868 mg, 3.00 mmol) and imine
44 (901 g, 4.00 mmol) were irradiated at -15 °C to yield a
mixture of 46a and 46b (92:8, 1.05 g, 72%). Column chroma-
tography (PE/EA 8:1 f 5:1) yielded the pure isomer 46a (847
mg, 58%). 46a (first eluted): yellowish oil; tR (HPLC, hexane/
H), 3.09 (br s, 1 H), 3.29 (ddd, J ) 15.7, 7.1, 0.9, 1 H), 4.11-
4.27 (m, 2 H), 4.44 (d, J ) 2.2, 1 H), 4.70 (br d, J ) 7.1, 1 H),
5.09-5.12 (m, 2 H), 5.70 (mc, 1 H), 7.29-7.41 (m, 5 H); 13C
NMR (63 MHz) δ 19.7 (q), 28.3 (q), 42.8 (t), 44.2 (d), 57.0 (d),
65.5 (d), 79.4 (s), 118.4 (t), 126.4, 128.3, 128.9, 137.6 (3 d, s),
131.5 (d), 155.6 (s), 167.9 (s); MS (FAB) m/ z (%) 331 (100, [M
+ 1]+), 275 (75, [M - C4H7]+), 188 (38, [M - C7H12NO2]+). Anal.
Calcd for C19H26N2O3 (330.4): C, 69.06; H, 7.93; N, 8.48.
Found: C, 68.90; H, 7.99; N, 8.43. 50b (second eluted):
colorless solid; mp 108.0-108.5 °C; tR (HPLC, hexane/EA 3:1)
EA 4:1) 6.63 min; [R]20 +36.7 (c 1.1, CHCl3); IR (film) 3317,
D
1
2960, 1746 cm-1; H NMR (300 MHz) δ 0.93 (s, 9 H), 3.27 (t,
J ) 1.9, 1 H), 3.65 (d, J ) 15.3, 1 H), 3.69 (s, 3 H), 3.90 (dd, J
) 10.7, 2.3, 1 H), 4.17 (d, J ) 2.3, 1 H), 4.75 (d, J ) 14.9, 1 H),
4.93 (d, J ) 12.5, 1 H), 5.07 (d, J ) 10.7, 1 H), 5.21 (d, J )
12.5, 1 H), 6.72, 7.01 (2 d, J ) 8.6, 8.7, 4 H), 7.24-7.39 (m, 10
H); 13C NMR (250 MHz) δ 26.7 (q), 34.6 (s), 43.8 (t), 55.1 (d),
58.0, 58.1 (q, d), 61.2 (d), 66.8 (t), 114.0, 126.6, 127.5, 128.0,
128.4, 128.5, 128.9, 129.5 (8 d), 127.3, 136.4, 137.1, 158.9 (4
s), 156.8 (s), 167.0 (s); MS (FAB) m/ z (%) 487 (100, [M + 1]+),
121 (43, C8H9O+), 91 (49, C7H7+). Anal. Calcd for C30H34N2O4
(486.6): C, 74.05; H, 7.04; N, 5.76. Found: C, 73.81; H, 7.19;
N, 5.66.
15.0 min; [R]20 -47.6 (c 1.09, CHCl3); IR (KBr) 3291, 2960,
D
2910, 1727, 1690 cm-1; 1H NMR (250 MHz) δ 1.33 (d, J ) 6.7,
3 H), 1.45 (s, 9 H), 2.94 (dd, J ) 9.1, 2.2, 1 H), 3.35 (dd, J )
15.5, 7.1, 1 H), 4.12-4.20 (m, 2 H), 4.57-4.62 (m, 2 H), 5.05-
5.17 (m, 2 H), 5.72 (mc, 1 H), 7.24-7.40 (m, 5 H); 13C NMR (75
MHz) δ 18.9 (q), 28.3 (q), 43.0 (t), 46.1 (d), 58.8 (d), 66.2 (d),
79.4 (s), 118.7 (t), 126.3, 128.3, 128.8 (3 d), 137.8 (s), 131.3
(d), 155.0 (s), 167.5 (s); MS (CI, CH4) m/ z (%) 331 (100, [M +
1]+), 275 (63, [M - C4H7]+), 188 (18, [M - C7H12NO2]+). Anal.
Calcd for C19H26N2O3 (330.4): C, 69.06; H, 7.93; N, 8.48.
Found: C, 69.11; H, 7.91; N, 8.56.
(3R,4S,1′S)-3-[1-[(Ben zyloxyca r b on yl)a m in o]-2-m et h -
ylpr opyl]-4-ph en ylazetidin -2-on e (47). A solution of K2HPO4
(279 mg, 1.60 mmol) and K2S2O8 (838 mg, 3.10 mmol) in water
(5 mL) was added in 4 portions to a solution of 45a (220 mg,
466 µmol) in water/acetonitrile (15 mL, 1:2). The solution was
kept at 75 °C for 70 min and subsequently concentrated at
reduced pressure and extracted with EA (3 × 5 mL). The
organic layers were extracted with saturated NaHCO3 and
NaCl solutions (20 mL each), and the new aqueous layers were
reextracted with EA (5 mL). The combined organic layers were
evaporated and the residue was purified by MPLC (PE/EA 4:1)
to yield 47 (356 mg, 63%) as a colorless solid: mp 104-105
(3R,4S,1′S,2′S)- a n d (3S,4R,1′S,2′S)-3-[1-[(Ben zyloxy-
c a r b o n y l)a m in o ]-2-m e t h y lb u t y l]-4-p h e n y l-1-p r o p -2-
en yla zetid in -2-on e (51a ,b). Following the general proce-
dure, diazo ketone 7 (579 mg, 2.00 mmol) and imine 49 (1.16
g, 7.99 mmol) were irradiated at -15 °C to yield a mixture of
51a and 51b (85:15, 455 mg, 56%). The pure isomers 51a (317
mg, 39%) and 51b (48 mg, 6%) were obtained by MPLC (PE/
EA 4:1). 51a (first eluted): colorless solid; mp 93.5-94.0 °C;
tR (HPLC, hexane/EA 4:1) 6.00 min; [R]20D +77.8 (c 0.8, CHCl3);
1
IR (KBr) 3290, 2950, 2910, 1750, 1710, 1680 cm-1; H NMR
(300 MHz) δ 0.85 (t, J ) 7.3, 3 H), 0.93 (d, J ) 6.7, 3 H), 1.02-
1.17, 1.50-1.63, 1.65-1.78 (3 m, 3 H), 3.22-3.30 (m, 2 H), 3.99
(ddd, J ) 10.3, 7.7, 2.8, 1 H), 4.15 (ddt, J ) 15.6, 4.9, 1.7, 1
H), 4.37 (d, J ) 2.3, 1 H), 4.92 (br d, J ) 10.2, 1 H), 4.98-5.07
(m, 2 H), 5.12, 5.21 (2 d, J ) 12.3, 12.3, 2 H), 5.59 (mc, 1 H),
7.25-7.41 (m, 10 H); 13C NMR (75 MHz) δ 11.4 (q), 14.6 (q),
25.9 (t), 38.5 (d), 43.3 (t), 54.1 (d), 58.1 (d), 62.9 (d), 67.3 (t),
118.9 (t), 126.9, 128.4, 128.6, 128.8, 128.9, 129.3 (6 d), 136.9,
137.9 (2 s), 131.7 (d), 157.2 (s), 167.9 (s); MS (CI,CH4) m/ z
(%) 407 (100, [M + 1]+), 91 (38, C7H7+). Anal. Calcd for
C25H30N2O3 (406.5): C, 73.86; H, 7.44; N, 6.89. Found: C,
73.84; H, 7.47; N, 6.89. 51b (second eluted): colorless solid;
°C; tR (HPLC, hexane/EA 3:1) 15.7 min; [R]20 +47.4 (c 0.43,
D
CHCl3); IR (KBr) 3295, 2948, 2917, 1755, 1710 cm-1; 1H NMR
(250 MHz) δ 0.95 (d, J ) 6.7, 6 H), 1.97 (octet, J ) 6.9, 1 H),
3.26 (t, J ) 2.9, 1 H), 3.92 (ddd, J ) 10.6, 7.8, 3.5, 1 H), 4.46
(d, J ) 2.3, 1 H), 5.15 (s, 2 H), 5.32 (d, J ) 10.0, 1 H), 6.37 (s,
1 H), 7.25-7.35 (m, 10 H); 13C NMR (63 MHz) δ 19.0, 19.8 (2
q), 31.6 (d), 54.5 (d), 55.1 (d), 63.7 (d), 67.0 (t), 125.7, 128.0,
128.2, 128.6, 128.8 (5 d), 136.4, 139.5 (2 s), 157.0 (s), 168.5 (s);
MS (CI, NH3) m/ z (%) 353 (100, [M + 1]+), 106 (26, C7H6O+),
91 (23, C7H7+). Anal. Calcd for C21H24N2O3 (352.4): C, 71.57;
H, 6.86; N, 7.95. Found: C, 71.20; H, 6.89; N, 7.80.
mp 85-86 °C; tR (HPLC, hexane/EA 4:1) 7.73 min; [R]20 -39
D
ter t-Bu tyl (3R,4S,1′S)-3-[1-[(Ben zyloxycar bon yl)am in o]-
2-m e t h ylp r op yl]-2-oxo-4-p h e n yla ze t id in e -1-ca r b oxy-
la te (48). Boc2O (93 mg, 426 µmol), Et3N (21.6 mg, 213 µmol),
and DMAP (one crystal) were added to a solution of 47 (75
(c 0.3, CHCl3); IR (KBr) 3290, 2942, 1744, 1708, 1686 cm-1
;
1H NMR (300 MHz) δ 0.91-1.00, 1.43-1.52, 1.78-2.00 (3 m,
9 H), 3.08 (dd, J ) 10.2, 2.0, 1 H), 3.34 (dd, 15.5, 7.1, 1 H),
4.09-4.20 (m, 2 H), 4.52 (d, J ) 2.0, 1 H), 4.62 (br d, J ) 10.3,

Cycloadditions of Ketenes
J . Org. Chem., Vol. 62, No. 17, 1997 5883
1 H), 5.04 - 5.13 (m, 2 H), 5.04, 5.26 (2 d, J ) 12.2, 12.2, 2 H),
5.70 (mc, 1 H), 7.10-7.13, 7.26-7.38 (2 m, 10 H); 13C NMR
(75 MHz) δ 11.7 (q), 16.1 (q), 23.1 (t), 36.7 (d), 43.1 (t), 55.9
(d), 58.9 (d), 63.3 (d), 66.8 (t), 118.7 (t), 125.8, 126.2, 127.9,
128.2, 128.5, 128.9 (6 d), 136.4, 137.8 (2 s), 131.3 (d), 156.3
(s), 167.2 (s); MS (FAB) m/ z (%) 836 (5, [2 M + Na + 1]+), 814
(4, [2 M + 2]+), 429 (33, [M + Na]+), 407 (100, [M + 1]+), 91
(78, C7H7+).
-15 °C. The racemic â-lactam 55 (252 mg, 21%) was obtained
by column chromatography (PE/EA 9:1): colorless oil; Rf (TLC,
PE/EA 5:1) 0.4; IR (film) 2956, 2929, 1751 cm-1; 1H NMR (300
MHz) δ 0.85 (t, J ) 7.0, 3 H), 1.23-1.39, 1.60-1.70, 1.78-
1.87 (3 m, 6 H), 3.01 (dd, J ) 8.4, 6.3, 1 H), 3.72 (d, J ) 14.9,
1 H), 4.03 (d, J ) 2.0, 1 H), 4.84 (d, J ) 14.9, 1 H), 7.12-7.40
(m, 10 H); 13C NMR (63 MHz) δ 13.8 (q), 22.6, 28.3, 29.3, 44.2
(4 t), 60.6, 60.8 (2 d), 126.5, 127.6, 128.3, 128.5, 128.7, 129.0
(6 d), 135.8, 138.0 (2 s), 170.5 (s); MS (EI) m/ z (%) 160 (100,
[M - C8H7NO]+), 91 (43, C7H7+). Anal. Calcd for C20H23NO
(293.4): C, 81.87; H, 7.90; N; 4.77. Found: C, 81.32; H, 7.94;
N, 4.73.
(r a c)-(3,4-tr a n s)-1-Ben zyl-3-[(m eth oxyp h en yl)m eth yl]-
4-p h en yla zetid in -2-on e (54a ,b). Following the general pro-
cedure, the racemic diazo ketone 52 (190 mg, 1.00 mmol) and
imine 17 (390 mg, 2.00 mmol) were irradiated at -15 °C, to
yield a mixture of 54a and 54b (50:50). The pure isomers 54a
(110 mg, 31%) and 54b (100 mg, 28%) were obtained by column
chromatography (PE/EA 9:1). 54a (first eluted): colorless oil;
Rf (TLC, PE/EA 5:1) 0.21; IR (KBr) 3030, 2830, 1755 cm-1; 1H
NMR (300 MHz) δ 3.28 (s, 3 H), 3.52 (dd, J ) 4.7, 2.3, 1 H),
3.64 (d, J ) 15.4, 1 H), 4.24 (d, J ) 2.2, 1 H), 4.61 (d, J ) 4.7,
1 H), 4.81 (d, J ) 15.4, 1 H), 6.74-7.45 (m, 15 H); 13C NMR
(75 MHz) δ 43.9 (t), 55.9, 56.9 (d, q), 65.4 (d), 80.5 (d), 126.3,
127.1, 127.5, 127.7, 128.0, 128.1, 128.4, 128.4, 128.7, 135.0,
137.4, 137.9 (9 d, 3 s), 167.2 (s); MS (FAB) m/ z (%) 358 (10,
[M + 1]+), 193 (100, C14H11N+). 54b (second eluted): mp
122.5-123.0 °C; Rf (TLC, PE/EA 5:1) 0.15; IR (KBr) 2910,
2888, 2800, 1750 cm-1; 1H NMR (300 MHz) δ 3.31 (t, J ) 2.6,
1 H), 3.36 (s, 3 H), 3.78 (d, J ) 15.3, 1 H), 4.64 (d, J ) 2.2, 1
H), 4.68 (d, J ) 3.7, 1 H), 4.92 (d, J ) 15.5, 1 H), 6.97-7.31
(m, 15 H); 13C NMR (75 MHz) δ 44.3 (t), 55.5, 57.2 (d, q), 66.4
(d), 79.5 (d), 126.3, 126.4, 127.3, 127.9, 127.9, 128.1, 128.5,
128.5, 128.7 (9 d), 135.4, 137.6, 138.9 (3 s), 168.1 (s); MS (EI)
m/ z (%) 358 (100, [M + 1]+), 224 (47, [M - C8H7NO]+). Anal.
Calcd for C24H23NO2 (357.5): C, 80.64; H, 6.49; N; 3.92.
Found: C, 80.56; H, 6.53; N, 3.95.
Ack n ow led gm en t. The generous support of Prof.
Dr. V. J a¨ger and Prof. Dr. F. Effenberger (Universita¨t
Stuttgart) is gratefully acknowledged. We also thank
Mrs. S. Henkel and Dr. W. U. Frey for the X-ray crystal
structure analyses and R. Heugel, H. Arndt, and M.
Schu¨tz for their work as part of the advanced practical
course. The authors are greatly obliged to Dr. J . L.
Matthews for her help in the final preparation of the
manuscript. This work was supported by the Fonds der
Chemischen Industrie, the Deutsche Forschungsge-
meinschaft and the BASF AG (the gift of phenethyl-
amine).
Su p p or tin g In for m a tion Ava ila ble: NMR data with
peak assignments for all compounds, ORTEP drawings, and
details of X-ray data aquisition for 48, 20b, and 21a (15 pages).
This material is contained in libraries on microfiche, im-
mediately 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.
(3,4-tr a n s)-1-Ben zyl-3-bu tyl-4-ph en ylazetidin -2-on e (55).
Following the general procedure, diazo ketone 53 (505 mg, 4.00
mmol) and imine 17 (1.17 g, 5.99 mmol) were irradiated at
J O9705069