Stereoselective synthesis of trans β-lactams through iridium-catalyzed reductive coupling of imines and acrylates

Article abstract of DOI:10.1021/ol020106u

(Matrix presented) Iridium-catalyzed reductive coupling of acrylates and imines provides trans β-lactams with high diastereoselection. The optimal catalyst allows for the synthesis of trans β-lactams bearing aromatic, alkenyl, and alkynyl side chains. Thi

Full text of DOI:10.1021/ol020106u

ORGANIC
LETTERS
2
002
Vol. 4, No. 15
537-2540
Stereoselective Synthesis of trans
â-Lactams through Iridium-Catalyzed
Reductive Coupling of Imines and
Acrylates
2
Jennifer A. Townes, Michael A. Evans, Jerome Queffelec, Steven J. Taylor, and
James P. Morken*
Department of Chemistry, Venable and Kenan Laboratories, The UniVersity of
North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
morken@unc.edu
Received May 24, 2002
ABSTRACT
Iridium-catalyzed reductive coupling of acrylates and imines provides trans â-lactams with high diastereoselection. The optimal catalyst allows
for the synthesis of trans â-lactams bearing aromatic, alkenyl, and alkynyl side chains. This reaction appears to proceed through a reductive
Mannich addition−cyclization mechanism. Examination of substituent effects reveals a linear Hammett correlation for both the N-aryl group on
the imine and the aryloxy group on the acrylate, thereby pointing to rate-determining cyclization in the reaction mechanism.
6
a
Interest in the stereocontrolled synthesis of â-lacams has been
asymmetric ketene-glyoxal imine cycloaddition, Doyle and
Hashimoto have reported intramolecular C-H insertion
spurred by their use as effective antibiotic agents, protease
1
6b
inhibitors, and cholesterol absorption inhibitors. While a
reactions, Fu and Miyaura have reported asymmetric
versions of the Kinugasa reaction, and Tomioka has
reported a route to trisubstituted â-lactams by catalytic
enantioselective ester enolate-imine condensation. In regards
6
c
variety of single isomer â-lactams may be accessed by routes
2
such as the Staudinger ketene-imine [2 + 2] cycloaddition
3
7
and the ester enolate-imine condensation, only three asym-
metric catalytic routes to these materials have been de-
scribed. Alper has reported a rhodium-catalyzed carbon-
to expanding the scope of catalytic â-lactam synthesis and
with pertinence to asymmetric transition-metal catalysis, we
disclose a novel and highly diastereoselective iridium-
catalyzed synthesis of trans â-lactams, which appears to
proceed through a reductive Mannich addition-cyclization
4
ylative ring-opening kinetic resolution of racemic aziridines
5
to provide monosubstituted â-lactams, Lectka has reported
a route to cis disubstituted â-lactams by amine-catalyzed
8
,9
mechanism.
Our studies were initiated by the observation that imine
1, phenyl acrylate, and Et MeSiH could be converted to trans
(1) Reviews: (a) Synthesis of Lactones and Lactams; Ogliaruso, M. A.,
Wolfe, J. F., Eds.; John Wiley and Sons: New York, 1993. (b) The Oranic
Chemistry of â-Lactams; Georg, G. I., Ed.; Verlag Chemie: New York,
2
1
993.
(
2) Review: Palomo, C.; Aizpura, J. M.; Ganboa, I.; Oiarbide, M. Eur.
J. Org. Chem. 1999, 3223-3235.
3) Reviews: (a) Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J. Org.
(6) (a) Taggi, A. E.; Hafez, A. M.; Wack, H.; Youngs, B.; Drury, W. J.,
III; Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831-7832. (b) For lead
references, see: Doyle, M. P.; Protopopova, M. N.; Winchester, W. R.;
Daniel, K. L. Tetrahedron Lett. 1992, 33, 7819. Anada, M.; Hashimoto,
S.-I. Tetrahedron Lett. 1998, 39, 9063. (c) Miura, M.; Enna, M.; Okura,
K.; Nomura, M. J. Org. Chem. 1995, 60, 4999. Lo, M. M.-C.; Fu, G. C. J.
Am. Chem. Soc. 2002, 124, 4572.
(
Chem. 2000, 563-572. (b) Hart, D. J.; Ha, D.-C. Chem. ReV. 1989, 89,
1
447-1465.
4) Review: Magriotis, P. A. Angew. Chem., Int. Ed. 2001, 40, 4377-
379.
(
4
(5) (a) Davoli, P.; Moretti, I.; Prati, F.; Alper, H. J. Org. Chem. 1999,
6
4, 518. (b) Calet, S.; Urso, F.; Alper, H. J. Am. Chem. Soc. 1989, 111,
(7) Tomioka, K.; Fujieda, H.; Hayashi, S.; Hussein, M. A.; Kambara,
T.; Nomura, Y.; Kanai, M.; Koga, K. Chem. Commun. 1999, 715-716.
9
31.
1
0.1021/ol020106u CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/29/2002

â-lactam 2 and PhOSiEt
amount of [(cod)RhCl]
2
Me under the influence of a catalytic
complexed with dppe (Scheme 1).
before and after addition of Fast Red TR, allowed for
detection of diazocoupled 1-naphthol (3) produced during
the assay sequence (see Scheme 2). The screen was
performed twice, each time with a different spatial arrange-
ment of catalysts. Both screens revealed reactivity with a
number of iridium salts at 50 °C, whereas the original Rh-
dppe complex is ineffective at this temperature as determined
2
Scheme 1
1
from the arrayed assay and also by H NMR analysis of
isolated experiments. The most effective metal-ligand-
silane combination appeared to be [(cod)IrCl]
2
-P(OPh) -
3
Et MeSiH, which is able to effect transformation at room
2
2
temperature, converting phenyl acrylate, Et MeSiH, and 1
to â-lactam 2 in 13% yield.
To improve product yields and understand the impact of
the various reaction components, the series of experiments
described in Table 1 was performed. Notably, use of electron-
While this reaction proceeds with good diastereoselectivity
>20:1 trans:cis), it requires elevated temperatures (80 °C)
and provides only modest chemical yield.
(
In an effort to improve reaction efficiency we examined
an array of 96 metal-ligand-silane combinations using a
1
0
naphthol-based detection assay as described in Scheme 2.
Table 1. Catalytic Reductive Coupling of 1 To Give 2a
Scheme 2
temp yield
entry
R
metal salt
ligand
(°C)
(%)
1
2
3
4
5
6
7
1-Np
Ph
2.5% [(cod)IrCl]2 10% P(OPh)3
2.5% [(cod)IrCl]2 10% P(OPh)3
50
25
25
25
25
25
25
14
13
56
68
28
0
pNO2-Ph 2.5% [(cod)IrCl]2 10% P(OPh)3
C6F5
C6F5
C6F5
C6F5
2.5% [(cod)IrCl]2 10% P(OPh)3
2.5% [(cod)IrCl]2 none
none
10% P(OPh)3
2.5% [(cod)IrCl]2 5% P(OPh)3
58
a
Conditions: 1:1:1 ratio of imine/acrylate/silane in dichloroethane
solvent. >20:1 trans:cis stereoisomer ratio obtained in all cases.
deficient aryl acrylates results in improved product yields
with p-nitrophenyl acrylate (entry 3) furnishing 56% reaction
product and pentafluorophenyl acrylate (entry 4) resulting
in a 68% yield of â-lactam at room temperature. The
transition metal is required for efficient reaction (entry 6),
as is the ligand; reaction without ligand proceeds in only
28% yield (entry 5). Further, a 2:1 ligand:metal complex
appears to be optimal for high product yields (cf. entries 4
and 7).
In each of these experiments, naphthyl acrylate and imine 1
were reacted at 50 °C for 12 h. The reactions were then
treated with TFA to hydrolyze the phenolic silyl ether and
treated with the diazonium salt Fast Red TR.11 Parallel
measurement of the UV absorbance (540 nm) in each well,
Reaction scope was assessed with the series of substrates
described in Table 2. In order that reactions reach completion
rapidly, all experiments were carried out at 60 °C for 6 h.
As noted in entry 1, C-aryl imines furnish acceptable yields
of the desired â-lactam in high diastereoselection (determined
(
8) For related asymmetric reductive aldol reactions, see: (a) Taylor, S.
J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc. 2000, 122, 4528-
529. (b) Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org.
4
Lett. 2001, 3, 1829-1831. For early reports on nonstereoselective reductive
aldol reactions, see: (c) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28,
1
by H NMR analysis). It is also noteworthy that allylic and
propargylic imines react without competitive hydrosilation
4
809-4812. (d) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989 2005-2008.
(
e) Matsuda, I.; Takahashi, K.; Sato, S. Tetrahedron Lett. 1990, 31, 5331-
of the C-C π bond. Entries 3-6 demonstrate that a
5
5
334. (f) Kiyooka, S.; Shimizu, A.; Torii, S. Tetrahedron Lett. 1998, 39,
237-5238.
12
removable p-methoxyphenyl group can be used effectively
(9) For a review of catalytic enantioselective addition to imines, see:
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094.
10) Lavastre, O.; Morken, J. P. Angew. Chem., Int. Ed. 1999, 38, 3163-
165.
11) Fast Red TR salt (4-chloro-2-methylbenzenediazonium chloride) is
commercially available from Aldrich Chemical Co.
(12) The PMP group is readily removed from the â-lactam nitrogen under
CAN oxidation conditions, see: (a) Georg, G. I.; Kant, J.; Gill, H. S. J.
Am. Chem. Soc. 1987, 109, 1129-1135. (b) Ojima, I.; Habus, I.; Zhao,
M.; Zucco, M.; Park, Y. H.; Sun, C. M.; Brigaud, T. Tetrahedron 1992,
48, 6985-7012.
(
3
(
2538
Org. Lett., Vol. 4, No. 15, 2002

Table 2. Iridium-Catalyzed Synthesis of â-Lactamsa
Scheme 3
Subsequent cyclization furnishes the â-lactam and an iridium
phenoxide. An alternate mechanism (cycle B, Scheme 3)
1
5
involving formation of methyl ketene followed by trans-
16
17
selective [2 + 2] cycloaddition is also tenable. We believe
cycle A is more likely since it has been reported that methyl
ketene (generated by pyrolysis of 2-butanone) reacts with
N-phenylcinnamaldimine in a 3:1 trans:cis selectivity at room
temperature whereas the corresponding iridium-catalyzed
reaction proceeds in >20:1 trans:cis selectivity at room
i
18
2
temperature (59% yield after 48 h using PrMe SiH).
a
Conditions: 2.5 mol % [(cod)IrCl]2, 10 mol % P(OPh)3, 1.0:2.5:2.5
Substituent effects at the acrylate aryloxy group and the imine
N-aryl group reveal F values of 1.28 for the former and
-0.48 for the latter (using σ ) thereby implicating rate-
determining cyclization in cycle A (see Supporting Informa-
ratio of imine/pentafluorophenyl acrylate/Et2MeSiH, 60 °C for 6 h. PMP
p-methoxyphenyl. Configuration of product diastereomer determined
b
)
by analysis of coupling constants and X-ray structure determination (entry
p
c
1
d
6
). Stereochemical ratio determined by H NMR analysis. Could not be
freed from ∼10% of an impurity.
tion for these data).
Having established that the stereochemistry-determining
step in the iridium-catalyzed reductive coupling of imines
at the imine nitrogen, and entry 4 indicates that heteroatom
functionality does not interfere. While R-substitution on the
acrylate is tolerated (entry 7), we have yet to achieve efficient
reaction with â substituted acrylates (20% yield, data not
shown). We have also been unable to achieve transformation
with aliphatic Schiff bases. However, these products should
be readily accessible by hydrogenation of the appropriate
unsaturated derivative.
(14) For addition of Pd enolates to imines, see: Fujii, A.; Hagiwara, E.;
Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450-5458. Hagiwara, E.; Fujii,
A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474-2475.
(15) Lithium enolates of aryl esters eliminate to ketene upon warming
to room temperature. See: Seebach, D.; Amstutz, R.; Laube, T.; Schweizer,
W. B.; Dunitz, J. D. J. Am. Chem. Soc. 1985, 107, 5403-5409. The reverse
reaction with addition of a Pd-alkoxide to ketene is postulated in a review
article. See: Geoffroy, G. L.; Bassner, S. L. In AdVances in Organometallic
Chemistry; Stone, F. G. A., West, R., Eds.; Academic Press: San Diego,
In regards to the reaction mechanism, we speculate that
an in situ generated iridium hydride reacts with the acrylate
to provide an iridium enolate,13 which then reacts with the
1
993; Vol. 28, p 6.
(16) [2 + 2] cycloaddition of imine 1 and methyl ketene is reported to
give only the trans stereoisomer when the ketene is generated from pyrolysis
of 2-butanone. See: Tschamber, T.; Streith, J. Tetrahedron Lett. 1980, 21,
1
4
imine (1) to provide a â-amido ester (cycle A, Scheme 3).
4
503-4506.
(
17) [2 + 2] ketene-imine cycloaddition is proposed to proceed through
(13) Addition of an Ir(I) hydride to methyl acrylate in the presence of
a zwiterionic iminium ion generated by nucleophilic addition of the imine
to ketene. For a review, see: ref 1b, pp 295-368.
dioxygen is proposed to provide a C-bound iridium enolate. See: Droiun,
M.; Harrod, J. F. Can. J. Chem. 1985, 63, 353-360.
(18) Streith, J.; Tschamber, T. Liebigs Ann. Chem. 1983, 1393-1408.
Org. Lett., Vol. 4, No. 15, 2002
2539

and acrylates likely occurs at the transition-metal center, we
are now focused on developing asymmetric variants of this
catalytic â-lactam synthesis.
SmithKline, and the David and Lucile Packard Foundation
for support.
Supporting Information Available: Characterization
data for all new compounds, experimental procedures, tables
of crystal data for entry 6, Table 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the NIH
GM 59417-03). J.Q. thanks Elf Aquitaine for a research
fellowship. S.J.T. is grateful for an ACS Organic Division
fellowship sponsored by Abbott Research Labs. J.P.M. is
grateful to Bristol-Myers Squibb, Dow, DuPont, Glaxo-
(
OL020106U
2540
Org. Lett., Vol. 4, No. 15, 2002