Solid-phase synthesis of monocyclic β-lactam derivatives

Article abstract of DOI:10.1021/jo0261552

Liquid-phase studies concerning the solid-phase synthesis of monocyclic β-lactams via the esterenolate imine condensation route have been conducted utilizing triazene esters 1 and 2 as model compounds. Esters were attached to benzylamine resin 6 by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates 8 and 10 were reacted with various imines and imine precursors to give polymer-bound β-lactams 14 and 17 in different substitution patterns. Traceless cleavage from the triazene linker yields the desired β-lactams 16 and 19.

Full text of DOI:10.1021/jo0261552

Solid -P h a se Syn th esis of Mon ocyclic â-La cta m Der iva tives
S. Schunk and D. Enders*
Institut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule, Professor-Pirlet-Strasse 1,
52074 Aachen, Germany
enders@rwth-aachen.de
Received J uly 9, 2002
Liquid-phase studies concerning the solid-phase synthesis of monocyclic â-lactams via the ester-
enolate imine condensation route have been conducted utilizing triazene esters 1 and 2 as model
compounds. Esters were attached to benzylamine resin 6 by a triazene linker employing the
respective diazonium salts. Immobilized ester-enolates 8 and 10 were reacted with various imines
and imine precursors to give polymer-bound â-lactams 14 and 17 in different substitution patterns.
Traceless cleavage from the triazene linker yields the desired â-lactams 16 and 19.
In tr od u ction
synthesis of â-lactams.8,9 Solid-phase organic synthesis
enables the preparation of large numbers of structurally
related molecules in short periods of time, which is
especially important for the optimization of lead struc-
tures in the pharmaceutical industry.10
The ester-enolate imine condensation route is a readily
developed synthetic methodology for the preparation of
â-lactams.11 The main advantage of this approach, from
One of the most fortunate discoveries in modern times
was that of penicillin by Sir Alexander Fleming in 1929.1
As a result several â-lactam based antibiotics (e.g.
penicillins, cephalosphorins, and monobactams) were
developed, defeating formerly lethal diseases such as
plague, wound sepsis, and tuberculosis.2 â-Lactam anti-
biotics inhibit transpeptidase enzymes (penicillin-binding
proteins, PBP’s) by acylation of the serinyl residue at
their active site, which leads to cell wall lysis, since
blocking PBP’s circumvents proper murein membrane
formation.2c Recent results suggest that the azetidin-2-
one ring can be considered a general lead structure for
the design of new inhibitors of enzymes containing a
nucleophilic serine in their active site.3 Human elastase,
acetyl-CoA-cholesterin-acetyltransferase (ACAT), and
â-lactamases are currently the most important medicinal
targets.4-6 The constant need for new antibiotics and the
search for novel enzyme inhibitors has kept interest in
the synthesis of azetidin-2-one based lead structures at
a high level.7 Recent developments have mainly focused
on the catalytic asymmetric and the polymer supported
(6) â-Lactamases: (a) Page, M. I.; Laws, A. P. J . Chem. Soc., Chem.
Commun. 1998, 1609-1617. (b) Hubschwerlen, C.; Angehrn, P.;
Gubernator, K.; Page, M. G. P.; Specklin, J . L. J . Med. Chem. 1998,
41, 3972-3975. (c) Bulychev, A.; O’Brien, M. E.; Massova, I.; Teng,
M.; Gibson, T. A.; Miller, M. J .; Mobashery, S. J . Am. Chem. Soc. 1995,
117, 5938-5943.
(7) (a) Niccolai, D.; Tarsi, L.; Thomas, R. J . J . Chem. Soc., Chem.
Commun. 1997, 2333-2342. (b) Chu, D. T. W.; Plattner, J . J .; Katz,
L. J . Med. Chem. 1996, 39, 3853-3874.
(8) Catalytic asymmetric synthesis: (a) Hodous, B. L.; Fu, G. C. J .
Am. Chem. Soc. 2002, 124, 1578-1578. (b) Taggi, A. E.; Wack, H.;
Hafez, A. M.; France, S.; Lectka, T. Org. Lett. 2002, 4, 627-629. (c)
Magriotis, P. A. Angew. Chem. 2001, 113, 4507-4509; Angew. Chem.,
Int. Ed. 2001, 40, 4377-4379. (d) Taggi, A. E.; Hafez, A. M.; Wack,
H.; Young, B.; Drury, W. J .; Lectka, T. J . Am. Chem. Soc. 2000, 122,
7831-7832.
(9) Polymer-supported synthesis: (a) Delpiccolo, C. M. L.; Mata, E.
G. Tetrahedron: Asymmetry 2002, 13, 905-910. (b) Meloni, M. M.;
Taddei, M. Org. Lett. 2001, 3, 337-340. (c) Gordon, K. H.; Balasubra-
manian, S. Org. Lett. 2001, 3, 53-56. (d) Annunziata, R.; Benaglia,
M.; Cinquini, M.; Cozzi, F. Chem. Eur. J . 2000, 6, 133-138. (e) Schunk,
S.; Enders, D. Org. Lett. 2000, 2, 907-910. (f) Gordon, K.; Bolger, M.;
Khan, N.; Balasubramanian, S. Tetrahedron Lett. 2000, 41, 8621-
8625. (g) Furman, B.; Thurmer, R.; Kaluza, Z.; Lysek, R.; Voelter, W.;
Chmielewski, M. Angew. Chem. 1999, 111, 1193-1195; Angew. Chem.,
Int. Ed. 1999, 38, 1121-1123. (h) Ruhland, B.; Bhandari, A.; Gordon,
E. M.; Gallop, M. A. J . Am. Chem. Soc. 1996, 118, 253-254.
(10) Trias, J . Curr. Opin. Microbiol. 2001, 4, 520-525.
(11) Reviews: (a) Hart, D. J .; Ha, D. C. Chem. Rev. 1989, 89, 1447-
1465. (b) Van der Steen, F. H.; Van Koten, G. Tetrahedron 1991, 47,
7503-7524. (c) Fujisawa, T.; Shimizu, M. Rev. Heteroatom Chem. 1996,
15, 203-225. (d) Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J . Org.
Chem. 2000, 563-572.
(12) 1,4-Bisaryl â-lactams: see ref 11. 4-Oxo- and 4-thioxo-substi-
tuted â-lactams: (a) Cainelli, G.; Gaicomini, D.; Panunzio, M.; Martelli,
G.; Spunta, G. Tetrahedron Lett. 1987, 28, 3593-3596. (b) Battaglia,
A.; Cainelli, G.; Giacomini, D.; Martelli, G.; Panunzio, M. Tetrahedron
Lett. 1987, 28, 4347-4350. N-Unsubstituted â-lactams: (c) Hart, D.
J .; Kanai, K.-I.; Thomas, D. G.; Yang, T.-K. J . Org. Chem. 1983, 48,
289-294. (d) Ha, D.-C.; Hart, D. J .; Yang, T.-K. J . Am. Chem. Soc.
1984, 106, 4819-4825. 4-Unsubstituted â-lactams: (e) Overman, L.
E.; Osawa, T. J . Am. Chem. Soc. 1985, 107, 1698-1701.
(1) Fleming, A. Br. J . Exp. Pathol. 1929, 10, 226-236.
(2) (a) Manhas, M. S.; Bose, A. K. â-lactams: Natural and Synthetic;
Wiley: New York, 1971; Part 1. (b) The Chemistry of â-lactams; Page,
M. I., Ed.; Blackie Academic & Professional/Chapman and Hall:
London, UK, 1992. (c) Page, M. I. In Advances in Physical Organic
Chemistry; Bethell, D., Ed.; Academic Press: London, UK, 1987.
(3) (a) Wilmouth, R. C.; Kasamally, S.; Westwood, N. J .; Sheppard,
R. J .; Claridge, T. D.; Alpin, R. T.; Wright, P. A.; Pritchard, G. J .;
Schofield, C. J . Biochemistry 1999, 38, 7989-7998. (b) Beauve, C.;
Bouchet. M.; Touillaux, R.; Fastrez, J .; Marchand-Brynaert, J . Tetra-
hedron 1999, 55, 13301-13320. (c) Mascaretti, O. A.; Boschetti, C. E.;
Danelon, G. O.; Mata, E. G.; Roveri, O. A. Curr. Med. Chem. 1995, 1,
441-470.
(4) Human elastases: (a) Doucet, C.; Vergely, I.; Rebound-Ravaux,
M.; Guilhem, J .; Kobaiter, R.; J oyeau, R.; Wakselman, M. Tetrahe-
dron: Asymmetry 1997, 8, 739-751. (b) Cvetovich, R. J .; Chartrain,
M.; Hartner, F. W.; Roberge, C.; Amato, J . S.; Grabowski, E. J . J . Org.
Chem. 1996, 61, 6575-6580. (c) Firestone, R. A.; Barker, P. L.; Pisano,
J . M.; Ashe, B. M.; Dhaigren, M. E. Tetrahedron 1990, 46, 2255-2262.
(5) Acetyl-CoA-cholesterin-acetyltransferases: (a) Rosenblum, S. B.;
Huynh, T.; Afonso, A.; Davis, H. R.; Yumbile, N.; Clader, J . W.; Burnett,
D. A. J . Med. Chem. 1998, 41, 937-980. (b) Wu, B.; Tormos, W. J .
Org. Chem. 1997, 62, 6412-6414.
10.1021/jo0261552 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/23/2002
8034
J . Org. Chem. 2002, 67, 8034-8042

Solid-Phase Synthesis of Monocyclic â-Lactam Derivatives
SCHEME 1a
SCHEME 2a
a
Reagents and conditions: (a) (1) p-Aminobenzoic acid (5 equiv),
BF3‚Et2O (10 equiv), t-BuONO (10 equiv), THF, -10 °C, 1 h. (2)
6, pyridine/DMF (1:1), rt, 1 h. (b) 7, amino acid methyl ester‚HCl
(3 equiv), 2-chloro-1-methylpyridinium iodide (2 equiv), NEt3 (20
equiv), CH2Cl2, rt, 12 h. (c) 5% TFA in CH2Cl2.
propionic acid methyl ester and conversion with diben-
zylamine in 64% overall yield.
a
Reagents and conditions: (a) (1) LiHMDS (2.2 equiv), THF,
-78 °C, 1 h; (2) R2CHdNHR3 (1-3 equiv), THF, -78 °C to room
temperature, 23 h. (b) (1) LiHMDS (1.2 equiv), THF, -78 °C, 1 h;
(2) R2CHdNHR3 (1-3 equiv), THF, -78 °C to room temperature,
23 h.
The well-established reaction of R-substituted ester-
enolates with bisarylimines was used for initial investi-
gations. Treatment of methyl ester 1b with LiHMDS and
benzylidene phenylamine gave â-lactam 3b in 71% yield
with a diastereomeric excess greater than 96%. NOE
experiments established the relative configuration of 3b
as trans. Condensation of triazene 2 and benzylidene
phenylamine gave â-lactam 4a in 69% yield with a
diastereomeric excess of 46% (Table 1). The trans con-
figuration of the major diastereomer was confirmed by
NOE experiments. The different de values of the reaction
toward â-lactams 3b and 4a are probably due to the
difference in reactivity of the respective ester-enolates.
Preparation of 3b proceeds via the dianion of 1b, which
is more reactive than the anion of 2 and therefore reacts
at lower temperatures to give a higher diastereomeric
excess.
a solid-phase chemists’ point of view, is the wide variety
of easily available imines and imine precursors. This
allows for the variation of every position of the azetidin-
2-one ring.12 The ester-enolate, which has to be attached
to the polymer support for this strategy, was immobilized
by a triazene linker system, stable under the required
basic conditions.13 This linker allows for the introduction
of a variety of functionalities by applying different
cleavage procedures.14 We herein report the solid-phase
synthesis of diverse monocyclic â-lactams via the ester-
enolate imine condensation route, employing an im-
mobilized ester-enolate moiety.
The cyclization reaction of benzylidene phenylamine
with R-unsubstituted ester 1a afforded a complex product
mixture, from which compound 3a could not be isolated.16
Having successfully prepared 1,4-bisaryl azetidin-2-
ones, other â-lactam substitution patterns were investi-
gated utilizing N-silyl imines, amino nitriles, and het-
erocumulenes.17
The preparation of N-unsubstituted â-lactam 3c can
be achieved by utilizing N-silyl imines.12c The ester-
enolate reacts with the imine to form an N-silyl azetidi-
none, which is hydrolyzed to the corresponding N-un-
substituted lactam. Disappointingly we were only able
Resu lts a n d Discu ssion
Liqu id -P h a se Mod el Com p ou n d s.15 The feasibility
of the triazene linking system for the ester-enolate imine
condensation was initially investigated on model com-
pounds 1 and 2 (Scheme 1). Dibenzyltriazene 1 was used
as a model compound for monobactam derivatives and
prepared by diazotation of hippuric acid methyl ester and
conversion to 1a (81%) with dibenzylamine. R-Alkylation
of ester 1a with iodomethane/LiHMDS yields R-substi-
tuted methyl ester 1b (90%). Dibenzyltriazene 2 was used
as a model compound for 3-phenyl-substituted azetidin-
2-ones and prepared by diazotation of 2-(4-aminophenyl)-
(16) Low yields of R-unsubstituted esters in ester-enolate imine
condensation reactions have been described in the literature, see e.g.,
ref 11a.
(17) N-Silyl imines: Kru¨ger, C.; Rochow, E. G.; Wannagat, U. Chem.
Ber. 1963, 96, 2132. Amino nitriles: Baker, W.; Ollis, W. D.; Poole, V.
D. J . Chem. Soc. 1949, 307-313. Heterocumulenes: Pak, C. S.; Youn,
I. K.; Lee, Y. S. Synthesis 1982, 969-970.
(13) (a) Young, J . K.; Nelson, J . C.; Moore, J . S. J . Am. Chem. Soc.
1994, 116, 10841-10842. (b) Bra¨se, S.; Enders, D.; Ko¨bberling, J .;
Avemaria, F. Angew. Chem. 1998, 110, 3614-3616; Angew. Chem., Int.
Ed. Engl. 1998, 37, 3413-3415.
(14) Bra¨se, S.; Dahmen, S. Chem. Eur. J . 2000, 6, 1899-1905.
(15) Reaction conditions were not optimized.
J . Org. Chem, Vol. 67, No. 23, 2002 8035

Schunk and Enders
TABLE 1. Yield s a n d Dia ster eom er ic Ra tios of Solu tion -P h a se Mod el Com p ou n d s 3, 4, a n d 5
ester
imine/precursor
lactama
R1
R2
R3
yield, %
de,b %
1
1
1
2
2
2
PhCHdNPh
PhCHdNPh
PhCHdNTMS
PhCHdNPh
BzNHCH2CN
PhNdCdS
3a
3b
3c
4a
4b
5
H
Ph
Ph
Ph
Ph
H
Ph
Ph
H
Ph
Bz
complex mixture
CH3
CH3
CH3
CH3
CH3
71
32
69
58
86
g96
g96c
46
uncyclized material
a
b
Reaction conditions not optimized. Determined by 13C NMR of crude product. c Determined by 13C NMR of product after column
chromatography.
SCHEME 3a
amino acetonitrile hydrochloride was added. The desired
lactam 4b was obtained in 58% yield after overnight
condensation (Table 1).
The synthesis of 4-thioxo substituted lactams has been
achieved using 1-isothiocyanato-4-methoxybenzene.12a
Due to the reduced nucleophilicity of the thioamidic
nitrogen, the preparation of azetidin-2-ones from enolates
and heterocumulenes has to be accomplished by a two-
step procedure. In the first step the uncyclized ester is
formed, which undergoes a Lewis acid-promoted cycliza-
tion in a second step. Disappointingly the cyclization of
5 could not be achieved (Table 1). The use of different
Lewis acids and increased temperatures only led to the
formation of complex product mixtures, due to the acid
liability of the triazene linker moiety.
These preliminary investigations, which gave lactams
3b, 3c, 4a , and 4b in reasonable to good yields (Table 1),
showed that the ester-enolate imine condensation is
compatible with the benzyl triazene moiety, therefore a
solid-phase synthesis via a triazene linker should be
possible. The low yields of N-unsubstituted lactams,
during the model studies, hint at a problematic transfer
to solid support. The synthesis of 4-thioxo-substituted
lactams will not be investigated on solid support after
the failed model studies.
Ester Resin s. The triazene linker can be used for the
immobilization of aromatic diazonium salts, and therefore
for aromatic amines, but not for aliphatic amines due to
the instability of their diazonium salts. Cleavage of the
linker can be achieved under mild acidic conditions to
yield the benzylamine resin and the corresponding dia-
zonium salt.13,14
a
Reagents and conditions: (a) (1) 2-(4-Aminophenyl)propionic
acid methyl ester (6 equiv), BF3‚Et2O (12 equiv), isoamylnitrite
(12 equiv), THF, -10 °C, 1 h. (2) 6 (1 equiv), pyridine (6 equiv),
THF, -10 °C, add diazonium salt (3 equiv), -5 °C, 25 min. (3)
filtration of resin under argon, wash with dry THF (×1), suspend
in dry THF, repeat step 2. (b) 5% TFA in CH2Cl2.
SCHEME 4a
The main difference between the preparation of tria-
zenes 1 and 2 in solution and triazenes 8 and 10 on solid
support is the respective amine, namely bisbenzylamine
and polymer-supported benzylamine 6. In solution it was
used in excess to quench unstable diazonium salts and
force the reaction to completion. In the solid-phase
approach it was immobilized and cannot be used in excess
with respect to low loadings. Therefore, the reaction had
to proceed under basic conditions, which was accompa-
nied by two different problems: decomposition and side
reactions of the diazonium salts under basic conditions.
We attempted to prepare esther resins 8 and 10 from
benzylamine resin 6 and the diazonium salts of the
corresponding R-unsubstituted ester (8a , R1 ) H, from
4-diazobenzoyl amino acetic acid methyl ester trifluoro-
acetate; 10a , R1 ) H, from 4-diazophenyl acetic acid
methyl ester trifluoroacetate), followed by an alkylation
reaction to introduce various substituents R1. Methyl
ester 8a could be prepared in 78% loading and g96%
purity via this route. The main obstacle in this approach
was the instability of the diazonium salt under basic
a
Reagents and conditions: (a) (1) 5% TFA in CH2Cl2. (2) remove
solvent. (b) See Table 2.
to obtain the desired lactam 3c in 32% yield after
prolonged reaction times (Table 1).
Formaldehyde imines, which are needed for the syn-
thesis of 4-unsubstituted lactams, are unstable in solu-
tion and readily trimerize to give hexahydro triazenes.18
Consequently they have to be generated in situ from
N-cyanomethyl derivatives. The synthesis of 4-unsubsti-
tuted lactam 4b was accomplished using benzyl meth-
ylene amine.12e Ester 2 was deprotonated with 3.3 equiv
of LiHMDS at -78 °C, before a suspension of benzyl
(18) Harff, G. A.; Sinnema, A.; Wepster, B. M. Recl. Trav. Chim.
Pays-Bas. 1979, 98, 71-74.
8036 J . Org. Chem., Vol. 67, No. 23, 2002

Solid-Phase Synthesis of Monocyclic â-Lactam Derivatives
SCHEME 5 a
TABLE 2. Clea va ge Con d ition s for Resin 8a a n d
P u r ities of Ester s 13a
entry
reaction conditions (b)
R4
purity (13),b %
a
b
c
d
e
f
d4-MeOH, rt, 48 h
MeOH, rt, 48h
MeOH, 2% TFA, rt, 48 h
MeOH, 2% TFA, 60 °C, 1.5 h
THF/DMF 5:2, rt, 12 h
THF/CH3CN 4:1, rt, 12 h
OCD3
H
H
OCH3
H
H
g99
85
91
67
g99
88
a
b
R1 ) H. Purity of esters 13 determined by GC-MS analysis.
TABLE 3. Loa d in g of Ester Resin s 8, 10 a n d P u r ity of
Dia zon iu m Sa lts 9 a n d 11, a n d P u r ity of Ester s 13
producta
R1 loading,b % purity (9, 11),c % purity (13),d
%
8a , 9a , 13a
H
94
97
94
98
g96
95
92
94
95
91
94
93
8b, 9b, 13b Me
8c, 9c, 13c iPr
8d , 9d , 13d Ph
10a , 11a
10b, 11b
H
Me
could not be immobilized
91
79
decomp
a
b
Resins characterized by IR spectroscopy. Loading of resins
8 and 10 determined by nitrogen elemental analysis, based on
loading of Merrifield resin. c Purity of diazonium salts 9 and 11
1
d
determined by H NMR spectroscopy (solvent: d4-MeOH). Reac-
tion conditions: 9 or 11 in THF/DMF (5:2), 60 °C, 15 min. Purity
of esters 13 determined by GC-MS analysis.
a
Reagents and conditions: (a) (1) LiHMDS (2.2 equiv), THF,
-78 °C, 1.5 h. (2) R2CHdNR3 (3 equiv), THF, -78 °C to room
temperature, 23 h. (3) H2O. (b) (1) 5% TFA in CH2Cl2. (c) THF/
DMF (5:2), 60 °C, 15 min.
conditions with only pyridine and lutidine found to be
reasonable bases to enhance triazene formation. Other
bases, e.g. triethylamine, Hu¨nig’s base, DMAP, and
t-BuOK, resulted in decomposition of 4-diazobenzoyl
amino acetic acid methyl ester trifluoroacetate and
therefore in very low loadings of the desired resin.
A simple three-step procedure (Scheme 2) starting from
benzylamine resin 6 via carboxylate 7 led to the success-
ful preparation of ester resins 8 in essentially higher
loadings. Treatment of resin 6 with 4-carboxybenzene
diazonium tetrafluoroborate yielded benzoic acid resin 7.
Due to the excellent stability of this diazonium salt under
basic conditions, a large excess of pyridine could be used
to obtain high loadings. Nonaqueous conditions were
applied for the diazotation of p-aminobenzoic acid with
tert-butylnitrite/BF3‚Et2O. Several peptide-coupling re-
agents (e.g., 2-chloro-1-methylpyridinium iodide, N-ethyl-
N′-[3-(dimethylamino)propyl]carbodiimide hydrochloride/
1-hydroxybenzotriazole (EDC/HOBt) and pentafluoro-
phenyl diphenyl phosphinate (FDPP)) were investigated
in the synthesis of resin 8. Since all coupling reagents
gave similar results concerning loading and purity,
2-chloro-1-methylpyridinium iodide was used for conven-
ience. Resin 8 affords diazonium salt 9 after treatment
with 5% TFA in CH2Cl2.
Table 3 shows the results for the reaction sequence (a),
(b), and (c) (Scheme 2) with different R-substituted amino
acid methyl esters. Loading of resins 8a -d (94-98%) and
purity of the corresponding diazonium salts 9a -d (91-
95%) were very good.
Since 4-diazo phenyl acetic acid methyl ester trifuoro-
acetate was only stable under acidic conditions, resin 10a
could not be prepared. The acidic benzylic protons in the
R-position of the ester functionality probably allow for
J app-Klingemann19 type side reactions under basic
SCHEME 6a
a
Reagents and conditions: (a) (1) LiHMDS (1.5 equiv), THF,
-78 °C, 1.5 h. (2) R2CHdNR3 (3 equiv), THF, -78 °C to room
temperature, 23 h. (3) H2O. (b) (1) 5% TFA in CH2Cl2. (c) THF/
DMF (5:2), 60 °C, 15 min.
conditions leading to the polymerization of the reaction
mixture rather than coupling with the polymer-supported
amine.
R-Alkylation lowers the acidity and therefore allows
for the preparation of ester resin 10b (Scheme 3).
Coupling of diazotized 2-(4-aminophenyl)propionic acid
methyl ester with resin 6 had to be conducted twice to
obtain satisfying loadings (79%) and purity (91%). Larger
amounts of pyridine drastically enhance the coupling
reaction and loading of 10b, but also led to an increased
(19) (a) J app, F. R.; Klingemann, F. J ustus Liebigs Ann. Chem. 1888,
247, 190-225. (b) Phillips, R. R. Org. React. 1959, 10, 143-178.
J . Org. Chem, Vol. 67, No. 23, 2002 8037

Schunk and Enders
TABLE 4. P r ep a r a tion of 1,4-Bisa r yl-â-la cta m s 16
a
b
R3 ) Ph. Compounds 16 characterized by 1H and 13C NMR spectroscopy and MS analysis. Resins 14 characterized by IR spectroscopy.
Loading of resins 14 determined by nitrogen elemental analysis, based on loading of Merrifield resin. c Yields of 16 after 6 steps based on
loading of Merrifield resin. Purity of 16 determined by HPLC-analysis. e de determined by 13C NMR spectroscopy. f Based on the loading
d
of benzylamine resin. Not in accordance with 1H NMR, which suggests a much lower purity.
g
formation of J app-Klingemann type byproducts 12. This
loading and purity was regarded as a good basis for
â-lactam formation (Table 3).
pure reaction products. The diazonium salts obtained by
triazene cleavage with 5% TFA in CH2Cl2 were reason-
ably stable at room temperature and could be analyzed
1
by H NMR spectroscopy in d4-MeOH.
Tr ia zen e Lin k er Clea va ges. Depending on their
substitution pattern and the reaction conditions, e.g.,
temperature, solvent, and pH value, aromatic diazonium
salts are rather unstable. They can be converted into
stable compounds by a series of classical methods, e.g.
Gomberg-Bachmann reaction, Sandmeyer reaction, Meer-
wein arylation, or Schiemann reaction.
It was our primary objective to develop a mild, effec-
tive, and traceless cleavage21 procedure for the triazene
linker that can be applied in the solid-phase synthesis
of sensitive â-lactams.22 Several procedures to transform
the diazonium salts into traceless products had to be
(20) (a) Galli, C. Chem. Rev. 1988, 88, 765-792. (b) Zollinger, H.
Angew. Chem. 1978, 90, 151-232; Angew. Chem., Int. Ed. Engl. 1978,
17, 141-220. (c) Zollinger, H. Acc. Chem. Res. 1973, 6, 335-341. (d)
Gasper, S. M.; Devadoss, C.; Schuster, G. B. J . Am. Chem. Soc. 1995,
117, 5206-5211. (e) Colas, C.; Goeldner, M. Eur. J . Org. Chem. 1999,
1357-1366.
Decomposition of the diazonium salt is, in all cases,
initiated by the elimination of nitrogen and may proceed
via a cationic or a radical intermediate.20 Differentiation
between these two intermediates is essential to obtain
(21) Blaney, P.; Grigg, R.; Visuvanathar, S. Chem. Rev. 2002, 102,
2607-2624.
8038 J . Org. Chem., Vol. 67, No. 23, 2002

Solid-Phase Synthesis of Monocyclic â-Lactam Derivatives
TABLE 5. P r ep a r a tion of 1,4-Bisa r yl-â-la cta m s 19
a
R3 ) Ph. Compounds 19 characterized by 1H and 13C NMR-spectroscopy, MS- and HRMS-analysis. bResins 17 characterized by IR-
c
spectroscopy. Loading of 17 determined by nitrogen elemental analysis, based on loading of Merrifield resin. Yields of 19 after 5 steps
based on loading of Merrifield resin. dPurity of 19 determined by HPLC-analysis. de determined by GC-measurements.
e
TABLE 6. P r ep a r a tion of 4-Un su bstitu ted â-La cta m s
19j-l
(Scheme 4) and then further optimized on resin 14b for
the preparation of â-lactams.
During the investigations on cleavage conditions of
triazene resins, we observed that the diazonium salts
were easily transformed into deuteriomethoxy-substitut-
ed products (Table 2, entry a). Surprisingly replacing d4-
MeOH with MeOH did not yield the desired methoxy-
substituted product. A traceless, hydrogen-substituted
product was found instead (Table 2, entries b and c). The
reaction conditions had to be altered to 5% TFA in MeOH,
60 °C, 30 min (Table 2, entry d) to yield methoxy-
substituted products. Traceless cleavage with methanol
could not be applied to a wide range of resins, because
in most cases the reaction yielded mixtures of methoxy-
substituted and traceless compounds.23 Since these mix-
tures could only be purified by column chromatography
we decided to investigate other methods.The best condi-
a
b
R2 ) H. Resins characterized by IR spectroscopy. Imine
R3NHCH2CN utilized. c Loading of resins 8 and 10 determined by
nitrogen elemental analysis, based on loading of Merrifield resin.
Yields of 19 after 5 steps based on loading of Merrifield resin.
(22) For other traceless cleavages from a T1-triazene linker see: (a)
ref 13b. (b) Lormann, M.; Dahmen, S.; Bra¨se, S. Tetrahedron Lett. 2000,
41, 3813-3816. Application of (a) resulted in decomposition of the
esters/â-lactams.
(23) Broxton, T. J .; Bunnett, J . F.; Paik, C. H. J . Org. Chem. 1977,
42, 643-649.
d
investigated before formation of pure â-lactams was
achieved. All methods were first investigated on resin 8a
J . Org. Chem, Vol. 67, No. 23, 2002 8039

Schunk and Enders
tions for traceless cleavage turned out to be simplified
Keumi conditions (2-fluorene diazonium tetrafluorobo-
rate, chlorotrimethylsilane (1.2 equiv), THF/DMF (5:3),
60 °C, 60 min).24 Optimized conditions for diazonium salt
9a were THF/DMF (5:2), rt, 12 h (Table 2, entry b). These
conditions, applied to diazonium salt 15b, led to the
formation of intensely colored side products. The use of
elevated temperatures (60 °C) for 15 min in THF/DMF
(5:2) appeared to be the best reaction conditions for
lactam resins and for resins 8 (Table 3). Disappointingly
these reaction conditions did not yield the expected
traceless compound from resin 10b, with only decomposi-
tion products found. To ensure easier handling, we
substituted DMF with other solvents, which had a lower
boiling point. Good results were achieved with acetoni-
trile (Table 2, entry e).
1,4-Bisa r yl â-La cta m s (19). The preparation of 4-phe-
nyl-substituted â-lactams 19 on the solid phase was
conducted in an analogous manner to the previous
investigations in liquid phase, beginning with the bisaryl
imines (Scheme 6).
Very good results have been obtained concerning
loading of the lactam resins 17 and purity of the cleaved
diazonium salts 18 (Table 5). 1,4-Bisaryl â-lactams 19,
obtained by traceless cleavage, were easily separated
from byproducts by dissolving them in Et2O/n-pentane
(1:3) and eluting through silica gel. In this way nine
different â-lactams 19 were prepared in reasonable to
high purities (68-98%), medium to high diastereomeric
excesses (48 to g96%), and reasonable to good yields (35-
92%).
The main reason for the lower diastereomeric excess
of the phenyl-substituted azetidin-2-ones compared to the
monobactam derivatives is probably due to the lower
reactivity of the monodeprotonated ester-enolate com-
pared to the previously used enolate dianions.
No change in diastereomeric purity could be observed
1,4-Bisa r yl â-La cta m s 16. We investigated the prepa-
ration of monobactam like 1,4-bisaryl â-lactams 16. The
liquid-phase reaction conditions were employed for the
solid-phase system (Scheme 5) without any problems. It
is most likely that the reaction proceeds, as in the liquid
phase, via the respective dianion.12e
1
by comparing the H NMR spectra of diazonium salts 18
The condensation reaction of 8 was carried out with a
range of bisarylimines, which all gave very good results
concerning loading of the lactam resins 14 and purity of
the cleaved diazonium salts 15. These diazonium salts
were reasonably stable at room temperature and were
analyzed by 1H NMR spectroscopy in d4-MeOH. The
traceless cleaved â-lactams 16, obtained from diazonium
salts 15 by the previously developed procedure, were
easily separated from yellow byproducts by dissolving
them in EtOAc/pentane (2:3) and eluting through silica
gel. In this way, 10 differently substituted â-lactams 16
were prepared in high purity (84-98%), good to excellent
diastereomeric excess (50 to g96%), and reasonable to
good yields (26-71%) (Table 4).
and lactams 19. The trans configuration of â-lactams 19a ,
19d , 19h , and 19i was confirmed by NOE experiments.
Assuming a uniform reaction pathway, we assign com-
pounds 19a -i as having trans configuration.
Oth er â-La cta m Su bstitu tion P a tter n s. To increase
the diversity of the synthesized â-lactams, other substi-
tution patterns were investigated. By applying the ap-
proach used for the synthesis of 4b to resin 10b,
4-unsubstituted â-lactams 19j-l were obtained (Table 6).
Traceless cleavage of resins 17j-l yielded complex
product mixtures, which could not be purified by elution
through silica gel, and had to be purified by column
chromatography. 4-Unsubstituted lactams were obtained
in notably lower yields (24-43%). It was not possible to
obtain 4-unsubstituted monobactam derivatives 16 via
this approach. The double addition at C and N of the
reactive formaldehyde imine to the dianion is a notable
side reaction.
Disappointingly, N-silylimines could not be applied
successfully in the solid-phase synthesis of N-unsubsti-
tuted lactams. Neither the cleaved diazonium salts nor
the traceless cleaved mixtures gave any indication of a
successful reaction of the N-silylimine with the ester-
enolate.
Con clu sion . The ester-enolate imine condensation
route to â-lactams via an immobilized ester-enolate has
been achieved. Key steps in the synthesis were the
immobilization of the ester-enolates in high loadings and
purities and the mild traceless cleavage of the triazene
linker. Monocyclic â-lactams were obtained in good
purities after simple workup. Although the method does
not provide all desired substitution patterns it is a
valuable tool for the preparation of diverse â-lactam
libraries.
To investigate the steric effects of R1 in the ester-
enolate imine condensation, different R-substituted ester
resins 8 were used. For R1 ) alkyl, good results regarding
yield, purity, and diastereomeric excess were obtained.
Problematic cases were R1 ) H and phenyl, where either
no product was formed (16a ) or a product was formed in
low yield and purity (16d ). This suggests that the
nucleophilicity of the R-position is of more importance
than steric hindrance factors. The best results were
obtained with tertiary esters 8b and 8c. In the case of
phenylic substitution (8d ), which reduces the nucleophi-
licity of the R-position, the corresponding â-lactam could
still be obtained, but in low yield and lower purity. The
â-lactam 16a could not be obtained from the least
nucleophilic secondary ester 8a .
All â-lactams were obtained in very good diastereo-
meric excesses. No change in diastereomeric purity could
1
be observed by comparing the H NMR spectra of diazo-
nium salts 15 and lactams 16. The trans configuration
of â-lactams 16f, 16h , 16j, and 16k was confirmed by
NOE experiments. Assuming a uniform reaction path-
way, we assign compounds 16b-k as having trans
configuration, which corresponds with the configuration
found in the liquid-phase synthesis of 16b.25
Exp er im en ta l Section
All moisture-sensitive reactions were carried out using
standard Schlenk techniques. Solvents were dried and purified
by conventional methods prior to use. Tetrahydrofuran (THF)
was freshly distilled under Ar from Na/Pb alloy and benzophe-
none. Reagents of commercial quality were used from freshly
opened containers.
(24) Keumi, T.; Umeda, T.; Inoue, Y.; Kitajima, H. Bull. Chem. Soc.
J pn. 1989, 62, 89-95.
(25) Gluchowski, C.; Cooper, L.; Breigbreiter, D. E.; Newcomb, M.
J . Org. Chem. 1980, 45, 3413-3416.
8040 J . Org. Chem., Vol. 67, No. 23, 2002

Solid-Phase Synthesis of Monocyclic â-Lactam Derivatives
Typ ica l P r oced u r e for th e P r ep a r a tion of Diben zyl-
tr ia zen es (1, 2). tert-Butylnitrite (2 equiv) was added to a
solution of the aromatic amine (1 equiv) and BF3‚Et2O (1.5-2
equiv) in anhyd THF at -10 °C. After the mixture was stirred
for 1 h at -10 °C dibenzylamine (2-5 equiv) was added. The
mixture was diluted with Et2O after 15 min and washed with
saturated aqueous NaHCO3 solution (×3) and brine (×2). The
organic layer was dried (MgSO4), concentrated in vacuo, and
purified by recrystallization from EtOH or flash chromatog-
raphy.
114.0, 121.7, 125.0, 127.7, 128.0, 128.3, 128.7, 128.8, 132.6,
139.2, 150.7, 158.2, 173.8, 201.2 ppm. MS (EI, 70 eV) m/z (rel
intensity, %) 552 (0.4, M+), 387 (5). IR (KBr) υ 1735, 1605,
1511, 1446 cm-1. Anal. Calcd for C32H32N4O3S: C 69.54, H
5.84, N 10.14. Found: C 69.34, H 5.67, N 10.39.
Typ ica l P r oced u r e for th e P r ep a r a tion of Mon oba c-
ta m -lik e 1,4-Bisa r yl â-La cta m s (16) LiHMDS (2.2 equiv)
was added to a suspension of triazene resin 8 (1 equiv) in
anhyd THF at -78 °C. Imine (3 equiv) in anhyd THF was
added after the suspension had been stirred for 1.5 h at -78
°C. The reaction mixture was warmed to 0 °C within 14 h and
then stirred at room temperature for 5 h. The resin was filtered
off after quenching with water and washed with THF (×3),
Et2O (×3), and MeOH (×3). Resin 14 was dried in vacuo after
being washed with n-pentane (×2).
(4-(3-Diben zyl-1-tr ia zen yl)ben zoyla m in o)a cetic a cid
m eth yl ester (1a ): Yield 81% (colorless solid). Mp 125 °C
1
3
(EtOH). H NMR (CDCl3) δ 3.80 (s, 3H), 4.26 (d, 2H, J ) 5.2
Hz), 4.91 (s, 4H), 6.70 (m, 1H), 7.05-7.37 (m, 10H), 7.56 (d,
2H, 3J ) 8.8 Hz), 7.81 (d, 2H, 3J ) 8.8 Hz) ppm. 13C NMR
(CDCl3) δ 41.8, 52.5, 120.8, 128.0, 128.3, 128.7, 130.3, 153.3,
170.7, 167.2 ppm. MS (CI, isobutane) m/z (rel intensity, %)
4-(3-Ben zyl-3-m eth ylp olystyr yl-1-tr ia zen yl)-N-(3-m eth -
yl-2-oxo-1-diph en ylazetidin -3-yl)ben zam ide (14b): IR (KBr)
417 (100, M+ + 1). IR (KBr) υ 1736, 1651, 1605, 1535 cm-1
Anal. Calcd for C24H24N4O3: C 69.21, H 5.81, N 13.45. Found:
C 69.60, H 5.76, N 13.16.
.
υ 1752 (vs), 1662 (vs), 1599 (vs), 1491 (vs), 1439 (vs, br) cm-1
.
Anal. Calcd for
C147H143N5O2: C 87.77, H 7.16, N 3.48.
Found: C 85.59, H 7.78, N 3.32. Loading: 96% (by combustion
analysis, based on the loading of Merrifield resin).
2-(4-(3-Dib en zyl-1-t r ia zen yl)p h en yl)p r op ion ic a cid
m eth yl ester (2): Yield 64% (colorless solid). Mp 56 °C. 1H
NMR (CDCl3) δ 1.42 (d, 3H, 3J ) 7.2 Hz), 3.29 (s, 3H), 3.58 (q,
4-Dia zo-N-(3-m et h yl-2-oxo-1-d ip h en yla zet id in -3-yl)-
ben za m id e tr iflu or oa ceta te (15b): 1H NMR (CD3OD) δ 1.21
(s, 3H), 5.66 (s, 1H), 7.25-7.45 (m, 10H), 8.36 (d, 2H, 3J ) 9.1
3
1H, J ) 7.2 Hz), 4.72 (s, 4H), 7.0-7.2 (m, 10H), 7.31 (d, 2H,
3
3J ) 8.5 Hz), 7.71 (d, 2H, J ) 8.5 Hz) ppm. 13C NMR (C6D6)
3
Hz), 8.73 (d, 2H, J ) 9.1 Hz) ppm.
δ 18.1, 45.3, 48.5, 56.8, 51.5, 121.6, 127.7, 128.0, 128.3, 128.4,
128.4, 128.8, 136.9, 138.8, 150.2, 174.6 ppm. MS (EI, 70 eV)
m/z (rel intensity, %) 387.2 (6, M+). IR (KBr) υ 1740, 1603,
1494 cm-1. Anal. Calcd for C24H25N3O2: C 74.39, H 6.50, N
10.85. Found: C 74.20, H 6.47, N 10.76.
N -(3-Me t h y l-2-oxo -1-d ip h e n yla ze t id in -3-y l)b e n za -
m id e (16b): Purity 89% (by HPLC). De g96% (by 13C NMR).
Yield 54% (based on the loading of Merrifield resin). HPLC Rt
) 6.5 min (pressure 41.6 bar; flow 1 mL/min, n-heptane/
isopropane 99:1, Spherical 5 µm Silica 3.9 × 150 mm). 1H NMR
(CDCl3) δ 1.24 (s, 3H), 5.57 (s, 1H), 6.89 (s, 1H), 7.15-7.55
Typ ica l P r oced u r e for th e Syn th esis of Tr ia zen e
â-La cta m s (3, 4). LiHMDS (1.2 equiv, respectively, 2.3 equiv)
was added to a solution of the triazene ester (1 equiv) in anhyd
THF at -78 °C. After the mixture was stirred at -78 °C for 1
h the corresponding imine (1-3 equiv) in anhyd THF was
added. The reaction mixture was allowed to warm to 0 °C
within 14 h and stirring was continued for 5 h at room
temperature. The reaction was quenched with saturated
aqueous NaHCO3 solution and diluted with Et2O. The organic
layer was washed with saturated aqueous NaHCO3 solution
(×3) and brine (×2), dried (MgSO4), and concentrated in vacuo.
The crude product was purified by flash chromatography (SiO2;
EtOAc/n-pentane).
3
(m, 13H), 7.85 (d, 2H, J ) 7.1 Hz) ppm. 13C NMR (CDCl3) δ
16.8, 65.7, 68.9, 117.8, 124.3, 127.2, 127.5, 128.3, 128.7, 129.1,
132.1, 133.0, 134.2, 137.5, 166.6, 167.2 ppm. MS (CI, isobutane)
m/z (rel intensity, %) 357 (M+ + 1, 100), 182 (31).
Typ ica l P r oced u r e for th e P r ep a r a tion of 3-P h en yl-
Su bstitu ted 1,4-Bisa r yl â-La cta m s (19). LiHMDS (1.5
equiv) was added to a suspension of triazene resin 10 (1 equiv)
in anhyd THF at -78 °C. Imine (3 equiv) in anhyd THF was
added after the suspension had been stirred for 1.5 h at -78
°C. The reaction mixture was warmed to 0 °C within 14 h and
stirred at room temperature for 5 h. The resin was filtered off
after quenching with water and washed with THF (×3), Et2O
(×3), and MeOH (×3). Resin 17 was dried in vacuo after being
washed with n-pentane (×2).
4-(3-Diben zyl-1-tr ia zen yl)-N-(3-m eth yl-2-oxo-1,4-d ip h e-
n yla zetid in -3-yl)ben za m id e (3b): Yield 71% (colorless solid).
1
De g96%. Mp decomposition. H NMR (CDCl3) δ 1.25 (s, 3H),
3-(4-(3-Ben zyl-3-m eth ylp olystyr yl-1-tr ia zen yl)p h en yl)-
3-m eth yl-1-d ip h en ya zetid in -2-on e (17a ): IR (KBr) υ 1749
(vs, br), 1600 (vs), 1492 (vs), 1449 (vs, br), cm-1. Anal. Calcd
for C146H143N4O1: C 89.03, H 7.32, N 2.85. Found: C 72.39, H
6.59, N 2.03. Loading: 71% (by combustion analysis, based
on the loading of Merrifield resin).
4.93 (s, 4H), 5.59 (s, 1H), 6.73 (s, 1H), 7.00-7.50 (m, 20H),
3
3
7.57 (s, 2H, J ) 8.5 Hz), 7.85 (s, 2H, J ) 8.5 Hz) ppm. 13C
NMR (CDCl3) δ 16.9, 48.3, 57.3, 65.7, 68.8, 117.6, 120.7, 124.1,
127.3, 127.9, 128.0, 128.5, 128.9, 129.7, 134.2, 137.3, 153.3,
166.5, 166.6 ppm. MS (EI, 70 eV) m/z (rel intnesity, %) 459
(1), 398 (8). MS (CI, isobutane) m/z (rel intensity, %) 580 (M+
+ 1, 3). IR (KBr) υ 1762 (vs), 1657 (s), 1627 (s), 1601 (vs), 1571
(m) cm-1. Anal. Calcd for C37H33N5O2: C 76.66, H 5.74, N
12.08. Found: C 76.41, H 5.97, N 11.97.
3-(4-Dia zop h e n yl)-3-m e t h yl-1-d ip h e n yla ze t id in -2-
on e tr iflu or oa ceta te (18a ): 1H NMR (CD3OD) (major dias-
tereomer) δ 1.29 (s, 3Hmj), 5.60 (s, 1Hmj), 7.00-7.50 (m,
3
3
10Hmj,min), 8.19 (d, 2Hmj, J ) 9.1 Hz), 8.70 (d, 2Hmj, J ) 9.1
Hz) ppm. 1H NMR (CD3OD) (minor diastereomer) δ 2.01 (s,
1-Ben zyl-3-(4-(3-d iben zyl-1-tr ia zen yl)p h en yl)-3-m eth y-
la zetid in -2-on e (4b): Yield 58% (colorless oil). 1H NMR (CD3-
3Hmin), 5.50 (s, 1Hmin), 7.00-7.50 (m, 10Hmj,min), 7.81 (d, 2Hmin
,
2
2
3J ) 9.1 Hz), 8.37 (d, 2Hmin, J ) 9.1 Hz) ppm.
3
OD) δ 1.58 (s, 3H), 3.15 (d, 1H, J ) 5.2 Hz), 3.33 (d, 1H, J )
5.2 Hz), 4.30 (d, 1H, 2J ) 14.8 Hz), 4.43 (d, 1H, J ) 14.8 Hz),
2
3-Met h yl-1,3,4-t r ip h en yla zet id in -2-on e (19a ): Purity
g99% (by HPLC). De 57% (by GC). Yield 35% (by combustion
analysis, based on the loading of Merrifield resin). GC Rt(major
diastereomer) ) 12.1 min; Rt(minor diastereomer) ) 10.7 min
4.79 (s, 4H), 7.00-7.50 (m, 19H) ppm. 13C NMR (CD3OD) δ
23.15, 45.7, 54.1, 58.1, 120.5, 120.9, 125.7, 126.4, 127.3, 127.5,
128.0, 128.1, 128.5, 128.7, 135.5, 136.3, 136.3, 138.2, 159.3,
171.6 ppm. MS (EI, 70 eV) m/z (rel intensity, %) 475 (23, M+
+ 1). IR (KBr) υ 1746, 1604, 1496, 1448 cm-1. Anal. Calcd for
1
(OV-17, 160-10-260). H NMR (CD3OD) (major diastereomer)
1
δ 1.16 (s, 3Hmj), 5.17 (s, 1Hmj), 6.9-7.6 (m, 15Hmj,min) ppm. H
C
31H30N4O: C 78.45, H 6.37, N 11.81. Found: C 78.07, H 6.64,
N 11.83.
2-(4-(3-Diben zyl-1-tr ia zen yl)p h en yl)-2-(4-m eth oxyp h e-
NMR (CD3OD) (minor diastereomer) δ 1.85 (s, 3Hmin), 4.98 (s,
1Hmin), 6.9-7.6 (m, 15Hmj,min) ppm. 13C NMR (CDCl3) (major
diastereomer) δ 19.2 (Cmj), 62.0 (Cmj), 66.4 (Cmj), 116.8, 116.9,
123.4, 123.4, 125.4, 126.2, 126.5, 126.7, 126.7, 126.8, 127.4,
127.4, 127.7, 127.8, 128.3, 128.4, 128.5, 128.5 (Cmj,min), 134.4,
137.0, 141.3 (Cmj), 168.7 (Cmj) ppm. 13C NMR (CDCl3) (minor
diastereomer) δ 23.9 (Cmin), 64.2 (Cmin), 68.2 (Cmin), 116.8, 116.9,
123.4, 123.4, 125.4, 126.2, 126.5, 126.7, 126.7, 126.8, 127.4,
n ylth ioca r ba m oyl)p r op ion ic a cid m eth yl ester (5): Yield
86% (yellow oil). 1H NMR (CD3OD) δ 2.29 (s, 3H), 3.22 (s, 3H),
3.35 (s, 3H), 4.60-4.80 (s, 4H), 6.63 (d, 2H, 3J ) 8.8 Hz), 7.10-
3
7.19 (m, 10H), 7.50 (m, 4H), 7.71 (d, 2H, J ) 8.8 Hz), 9.51 (s,
1H) ppm. 13C NMR (CD3OD) δ 28.0, 48.6, 52.7, 54.9, 57.3, 65.8,
J . Org. Chem, Vol. 67, No. 23, 2002 8041

Schunk and Enders
127.4, 127.7, 127.8, 128.3, 128.4, 128.5, 128.5 (Cmj,min), 134.8,
chen Industrie. We thank Calbiochem Novabiochem AG,
Degussa-Hu¨ls AG, BASF AG, the former Hoechst AG,
Bayer AG, and Wacker Chemie for the donation of
chemicals.
137.2, 141.3 (Cmin), 168.7 (Cmin) ppm. MS (CI, isobutane) m/z
12
(rel intensity, %) 314.1 (68, M+ + 1). HRMS Calcd for
C -
22
1H19
N O 313.146 6, found 313.146 5.
16
14
Ack n ow led gm en t. We thank Dr. J . Runsink for
carrying out the NOE investigations and T. Balensiefer
for experimental support. This work was supported by
the Deutsche Forschungsgemeinschaft (Sonderfors-
chungsbereich 380, Graduiertenkolleg 440, Graduierten-
kolleg Scholarship to S.S.) and the Fonds der Chemis-
Su p p or tin g In for m a tion Ava ila ble: General procedures
and spectral and physical data of new compounds which were
not included in the Experimental Section. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0261552
8042 J . Org. Chem., Vol. 67, No. 23, 2002