Rhodium(I)-catalyzed allenic carbocyclization reaction affording δ- and ε-lactams

Article abstract of DOI:10.1021/ol062842u

(Chemical Equation Presented) This letter extends the scope of the rhodium(I)-catalyzed allenic Alder-ene carbocyclization reaction to the preparation of δ- and ε-lactams from amides. A variety of allenic propiolamides were cycloisomerized to give a numbe

Full text of DOI:10.1021/ol062842u

ORGANIC
LETTERS
2007
Vol. 9, No. 2
347-349
Rhodium(I)-Catalyzed Allenic
Carbocyclization Reaction Affording
δ
- and E-Lactams
Kay M. Brummond,* Thomas O. Painter, Donald A. Probst, and Branko Mitasev
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
kbrummon@pitt.edu
Received November 22, 2006
ABSTRACT
This letter extends the scope of the rhodium(I)-catalyzed allenic Alder-ene carbocyclization reaction to the preparation of
from amides. A variety of allenic propiolamides were cycloisomerized to give a number of unsaturated -lactams. In addition, allenic
propargylamides give good yields of the corresponding -lactams. Formation of lactams possessing these ring sizes has rarely been accomplished
carbon bond forming strategies. Thus, this approach provides an alternative strategy for synthesizing
δ- and E-lactams
δ
E
via transition-metal-catalyzed carbon
−
these substructures.
Discovery of new and biologically significant compounds
from nature provides a remarkable collection of structurally
complex targets. Thus, there is a continual need for the
development of new, more robust strategies for stitching
atoms together. Expanding the synthetic toolbox to include
under-utilized functional groups can serve as a springboard
for these investigations. Our group is involved in examining
transition metal-catalyzed reactions of allenes, and these
investigations have led to useful arrays of functionality via
novel cyclocarbonylation and carbocyclization reactions. For
example, we have previously demonstrated that the Rh(I)-
catalyzed Alder-ene carbocyclization process affords cross-
conjugated trienes in high yields and is tolerant of a wide
array of functionality.1 Moreover, the resulting trienes can
be used in a variety of ways, including tandem transition
metal-catalyzed carbon-carbon bond forming reactions2 and
DOS strategies.3 It was consideration of these triene products
that inspired us to explore the formal Alder-ene reaction of
alkynyl allenes possessing amide tethers as a method for
preparing highly unsaturated lactams.4 Lactams are most
commonly obtained via cyclodehydration reactions of amino
acids, from ketones using either the Schmidt or Beckmann
rearrangement reactions or cyclization of the amide nitrogen
onto an alkene, alkyne, or allene.5 It is much less common
to access amides via carbon-carbon bond forming reactions.6
There are a handful of reports demonstrating the feasibility
of an amide tether in carbocyclization reactions but these
protocols have been limited to the preparation of γ-lactams.7
Moreover, the reaction conditions are not generally tolerant
of an unprotected amide, which is typically attributed to a
disfavored rotamer population of the amide bond.8 We would
(4) For examples of the wide biological profile of δ-lactams, see: (a)
Boll, P. M.; Jansen, J.; Simonsen, O. Tetrahedron 1984, 40, 171. (b)
Anderson, D. J. Eur. J. Pharmacol. 1994, 253, 261. (c) Honda, T.;
Takahashi, R.; Namiki, H. J. Org. Chem. 2005, 70, 499. (d) Minami, N.
K.; Reiner, J. E.; Semple, E. J. Bioorg. Med. Chem. Lett. 1999, 9, 2625.
(5) See: ComprehensiVe Organic Transformations. A Guide to Func-
tional Group Preparations, 2nd ed.; Larock, R. C., Ed,: VCH Publishers:
New York, 1995; p 1870.
(6) For an excellent review see: Nakamura, I.; Yamamoto, Y. Chem.
ReV. 2004, 104, 2127.
(7) (a) Cook, G. R.; Sun, L. Org. Lett. 2004, 6, 2481. (b) Lei, A.;
Waldkirch, J. P.; Minsheng, H.; Zhang, X. Angew. Chem., Int. Ed. 2002,
41, 4526. (c) Xie, X.; Lu, X.; Liu, Y.; Xu, W. J. Org. Chem. 2001, 66,
6545. (d) Trost, B. M.; Pedregal, C. J. Am. Chem. Soc. 1992, 114, 7292.
(e) δ and ꢀ-lactams have been obtained by using an olefin methathesis
reaction, see: Hanessian, S.; Sailes, H.; Munro, A.; Therrien, E. J. Org.
Chem. 2003, 68, 7219.
(1) Brummond, K. M.; Chen, H.; Sill, P. C.; You, L. J. Am. Chem. Soc.
2002, 124, 15186.
(2) Brummond, K. M.; You, L. Tetrahedron 2005, 61, 6180.
(3) Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245.
10.1021/ol062842u CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/14/2006

now like to report on our progress toward extending the scope
of the allenic Alder-ene carbocyclization reaction to amides
for the formation of δ- and ꢀ-lactams.9
Allenic amino ester 1a was prepared as a single dia-
steromer by using a Claisen rearrangment protocol developed
in the Kazmaier laboratories.10 Allenic amino esters 1b and
1c were obtained by using a Claisen rearrangement procedure
developed by Krantz,11 which proceeds through an oxazo-
lidinone intermediate and affords a mixture of diastereomers
(typically 1:1, Scheme 1). Allenic amino esters 1a-c were
Table 1. δ-Lactams Using an Allenic Alder-ene Reaction
entrya
R1
R2
R3
yield, %
5a
5b
5c
5d
5e
5f
5g
5h
5i
Bn
Bn
Bn
Bn
Me
Me
Me
Me
i-Bu
i-Bu
i-Bu
Bn
H
H
H
H
H
H
H
H
H
H
H
H
Bz
45b
92
77
66
70
84
74
72
84
83
74
75c
Me
TMS
Ph
H
Me
TMS
Ph
Me
TMS
Ph
5j
5k
5l
Scheme 1. Allenic Alder-ene Approach to δ-Lactams
Me
a Entries 5a-d run at 0.03 M; entries 5e-m run at 0.01 M; for entries
5b-k, reactions were complete in less than 15 min. b Reaction time 2 h
and the product 5a decomposes upon concentration. c Reaction takes place
at room temperature in 1 h.
proved crucial to the success of the reaction; higher
concentrations give an insoluble precipitate and resulted in
lower yielding reactions. Efforts expended in trying to
characterize this precipitate have not been successful. Most
of these reactions were run on a small scale for convenience
(∼0.1 mmol), but conversion of 4b to 5b was done on nearly
a gram of material and the product was obtained in 92%
yield. Finally, attempts were made to decrease the catalyst
loading from 10 to 5 mol %; however, the reactions did not
go to completion.
Next, we investigated the formation of ꢀ-lactams. Allenyl
ester 6a12 was alkylated using LDA and iodomethane in 70%
yield and the resulting dimethyl allenyl ester 6b was
saponified using 2 M KOH in methanol to afford known
allenyl acid 6c in 90% yield (Scheme 2).13 Allenic acid 6c
was then converted to functionalized amides 8a-f by
reaction of the acid chloride with amines 7a-f.14 The dialkyl
substituent between the allene and carbonyl is essential to
prepared in yields ranging from 60% to 95% and both
protocols afford racemic products. The amine protecting
groups are removed from 1a-c affording 2a-c and the
resulting amine is coupled to the corresponding alkynoic
acids 3a-d to give amides 4a-l (55-95% yield). Next,
subjecting amides 4a-l to 10 mol % of rhodium biscar-
bonylchloride dimer [Rh(CO)2Cl]2 gives the δ-lactams 5a-l
in high yields (Table 1). In most cases the Alder-ene reactions
proceed at 90 °C in less than 15 min. The high temperature
required to effect this carbocyclization process is attributed
to the secondary amide, because protection of the amide
nitrogen as a benzamide affords the carbocyclization product
in less than an hour at room temperature (entry 5l, Table 1).
In all cases (except when R2 ) H), the Z-alkylidene geometry
is obtained exclusively. This is a direct result of the
mechanism of this reaction and has no bearing on the
diastereomeric purity of the allenyl precursors.1
Scheme 2. ꢀ-Lactams Using an Allenic Alder-ene Reaction
Furthermore, it is important to note that the reaction
concentrations are somewhat low (0.01-0.05 M), but this
(8) For a review on NMR studies of amide rotamers, see: Stewart, W.
E.; Sidall, T. H., III Chem. ReV. 1970, 70, 517. For examples of unsuccessful
attempts at cycloisomerization reactions using unprotected amides, see ref
7b and the following: Strubing, D.; Neumann, H.; Hubner, S.; Klaus, S.;
Beller, M. Tetrahedron 2005, 61, 11345. For an exception, see ref 7c.
(9) Nubbemeyer, U. Stereoselective Heterocyclic Synthesis III. In Topics
in Current Chemistry; Metz, P., Ed.; Springer-Verlag: New York, 2001;
Vol. 216, p 126.
(10) Kazmaier, U.; Gorbitz, C. H. Synthesis 1996, 1489.
(11) Castelhano, A. L.; Pliura, D. H.; Taylor, G. J.; Hsieh, K. C.; Krantz,
A. J. Am. Chem. Soc. 1984, 106, 2734. Castelhano, A. L.; Horne, S.; Taylor,
G. J. Tetrahedron 1988, 44, 5451.
348
Org. Lett., Vol. 9, No. 2, 2007

prevent isomerization of the 1,2-diene to a 1,3-diene, a
reaction that is favored by the carbonyl proximity. To our
satisfaction, substrates 8a-e afforded the desired ꢀ-lactams
9a-e under the standard rhodium(I)-catalyzed conditions in
49-65% yield (Table 2). Lactams 9d and 9e are obtained
within arrives at this moiety via a Diels-Alder reaction
opening potentially new avenues for analogue synthesis.
In conclusion, we have shown that δ- and ꢀ-lactams are
obtained via a Rh(I)-catalyzed allenic-Alder-ene reaction,
further demonstrating the scope and utility of this reaction
by its ability to operate on different substrate classes. To
date, the successful formation of lactams possessing these
ring sizes has rarely been accomplished via transition metal-
catalyzed carbon-carbon bond forming strategies. Thus, this
approach provides a potentially useful alternative for syn-
thesizing these substructures.
Table 2. Allenic Alder-ene Approach to ꢀ-Lactams15
entry
R2
R3
yield, %
9a
9b
9c
9d
9e
9f
Bn
H
H
H
Me
65
67
63
50
65
8f: 48
(CH2)2OTBS
furfuryl
Bn
Bn
H
Acknowledgment. We gratefully acknowledge the fi-
nancial support provided by the National Institutes of Health
(P50GM067982 and GM54161). K.M.B. thanks Johnson &
Johnson for a Focused Giving Award and the University of
Pittsburgh for a Chancellor’s Distinguished Research Award.
B.M. thanks the University of Pittsburgh for a Mellon
Fellowship and T.O.P. thanks the Bayer Corporation for a
graduate student fellowship.
C4H4-p-OMe
H
as single isomers possessing the Z-alkylidene geometry
depicted in Scheme 2. Unfortunately, attempts to effect the
carbocyclization reaction on a secondary amide 8f gave 48%
recovery of the starting material.
Next, with analogues of the natural product cephalotaxine
as our target, the Alder-ene carbocyclization of model system
10 was investigated. Indeed, the trienyl bicyclic lactam 11
was synthesized in 62% yield (Scheme 3). Cephalotaxine
Supporting Information Available: Characterization
data and full experimental procedures are provided for all
compounds in Tables 1 and 2 and Schemes 1, 2, and 3. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL062842U
Scheme 3. Allenic Alder-ene Approach to Cephalotaxine
(12) Henderson, M. A.; Heathcock, C. H. J. Org. Chem. 1988, 53, 4736.
(13) This acid was reported once prior to this publication. Grimaldi, J.;
Cormons, A. C. R. Seances Acad. Sci., Ser. C 1980, 290, 461.
(14) Methods to couple the acid to the amine using DCC/DMAP gave
poor yields (28%). Primary amines were coupled in 78% yield by using
the isobutyl chloroformate conditions developed for the propiolamides;
however, when secondary amines were used, carbamate 13 was isolated as
the only product in 92% yield (see the Supporting Information).
(15) Entries 9a-f were run at 0.05 M. For entries 9a-e all reactions
were complete in less than 2 h at 50 °C.
(16) Li, W.-D.; Ma, B.-C. J. Org. Chem. 2005, 70, 3277. Li, W.-D.;
Wang, Y.-Q. Org. Lett. 2003, 5, 2931. Koseki, Y.; Sato, H.; Watanabe, Y.;
Nagasaka, T. Org. Lett. 2002, 4, 885. Tietze, L. F.; Schirok, H. J. Am.
Chem. Soc. 1999, 121, 10264. Isono, N.; Mori, M. J. Org. Chem. 1995,
60, 115. Lin, X.; Kavash, R. W.; Mariano, P. S. J. Am. Chem. Soc. 1994,
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(12) is comprised of a unique benzazepine pentacyclic ring
system that has been a proving ground for a number of new
synthetic methods. To date, all syntheses of this class of
compounds begin with the 2-(benzo[1,3]diox-6-yl)ethan-
amine component intact.16 The unique strategy proposed
Org. Lett., Vol. 9, No. 2, 2007
349