Column asymmetric catalysis for beta-lactam synthesis.

Article abstract of DOI:10.1021/ol006659r

[structure] A catalytic asymmetric reaction process was designed involving the use of solid-phase reagents and catalysts that constitute the packing of a series of "reaction columns". This process was applied to the catalytic asymmetric synthesis of beta-

Full text of DOI:10.1021/ol006659r

ORGANIC
LETTERS
2000
Vol. 2, No. 25
3963-3965
Column Asymmetric Catalysis for
â-Lactam Synthesis
Ahmed M. Hafez, Andrew E. Taggi, Harald Wack, William J. Drury III, and
Thomas Lectka*
Department of Chemistry, Johns Hopkins UniVersity, 3400 North Charles Street,
Baltimore, Maryland 21218
lectka@jhunix.hcf.jhu.edu
Received September 26, 2000
ABSTRACT
A catalytic asymmetric reaction process was designed involving the use of solid-phase reagents and catalysts that constitute the packing of
a series of “reaction columns”. This process was applied to the catalytic asymmetric synthesis of â-lactams, yielding pure product after
crystallization with exceptional enantio- and diastereoselectivity.
In the realm of chiral synthesis and drug discovery, asym-
metric catalysis1 and solid-phase chemistry2 are playing
increasingly pivotal roles. Since chiral catalysts are often
expensive, it is important that they be easily recovered from
the reaction mixture.3 In addition, to be industrially ap-
plicable, the product must be free of contaminants so as to
avoid the need for extensive purification. Furthermore,
additional reagents and solvents must be reusable whenever
possible. Along these lines, we have designed a catalytic
asymmetric reaction process involving the use of solid-phase
reagents and catalysts that constitute the packing of reaction
columns. Reagents are added to a series of columns, and
gravity or pressure percolate these materials through the
packing, where they react to produce an enantiopure product
that is eluted at the bottom (Figure 1). After products have
been collected, solvent-based regeneration of the solid-phase
packing serves to ready the system for another cycle of
reagents. Similarly, Jacobsen and others have developed
continuous-flow reaction systems incorporating immobilized
catalysts, demonstrating their advantages over homogeneous
systems.4 In this Letter, we demonstrate what we term
column asymmetric catalysis and apply it to the catalytic,
asymmetric synthesis of â-lactams, affording products in high
yields and enantioselectivity (ee). We also discuss general
features of our process and propose how this proof-of-
principle can be applied to other practical problems in
synthetic chemistry.
Figure 1 shows the assembly we designed for this purpose.
It consists of two jacketed columns linked together by a
ground glass joint; the top column is packed with a polymer-
supported dehydrohalogenating agent that produces analyti-
cally pure, extremely reactive ketenes from inexpensive and
widely available acid chlorides. The middle column is packed
(1) (a) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I. Ed.; John Wiley
& Sons: New York, 2000. (b) ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: New
York, 1999.
(2) (a) Solid-Phase Organic Synthesis; Burgess, K., Ed; John Wiley &
Sons: New York, 2000. (b) Seneci, P. Solid-Phase Synthesis and Combi-
natorial Technologies; John Wiley & Sons: New York, 2000. (c) Blackburn,
C. Biopolymers 1998, 47, 311-351. (d) Brown, A. R.; Hermkens, P. H.
H.; Ottenheijm, H. C. J.; Rees, D. C. Synlett 1998, 817-827.
(3) The development of solid-phase chiral catalysts is of recent interest,
see: (a) Kobayashi, S.; Kusakebe, K.; Ishitani, H. Org. Lett. 2000, 2, 1225-
1227. (b) Yu, H.-B.; Hu, Q.-S.; Pu, L. J. Am. Chem. Soc. 2000, 122, 6500-
6501.
(4) (a) Annis, D. A.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 4147-
4154. (b) Kamahori, K.; Ito, K.; Itsuno, S. J. Org Chem. 1996, 61, 8321-
8324.
10.1021/ol006659r CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/16/2000

employed resin-bound dehydrohalogenation reagents to allow
for the simple isolation of the ketene solution under inert
atmosphere at reduced temperature. Standard solid-phase
bases such as Amberlite IRA-67, a tertiary amine-based
polymer, failed to promote ketene formation to any ap-
preciable extent when phenylacetyl chloride 2 in THF was
passed through it in a jacketed column at -78 °C. However,
the extremely basic resin BEMP 5,9 containing a triamino-
phosphoamide imine bound to a polymeric support,10 was
found to produce ketenes rapidly and quantitatively (eq 1).
Simply by passing a solution of acid chloride 2 in THF over
polymer 5 (1.1 basic equivalents), a yellow solution of
phenylketene 3 was eluted instantaneously in high yield. We
found that we could also form highly reactive ketenes such
as ethylketene, phenoxyketene, benzyloxyketene, acetoxy-
ketene, and phthalamidoketene and believe that this approach
should be amenable to the formation of pure solutions of
most reactive ketenes. The prime advantage to placing BEMP
resin 5 separately on a column is that in a reaction flask the
resin was generally found to destroy the imino ester and
epimerize the â-lactam product.
In preliminary work, we discovered that when a cold
solution of phenylketene (-78 °C) is treated with 1 equiv
of imino ester 4 and 10 mol % of benzoylquinine (BQ),
â-lactam 1 is formed in 65% yield, 98% de, and 96% ee
after purification by column chromatography.7 Under these
conditions the catalyst is difficult to recover in a pure form
from the reaction mixture, so a solid phase-based system
was immediately deemed desirable. Moreover, the column
asymmetric catalysis system eliminated the shortcomings of
performing this reaction with the solid-phase components
in a conventional reaction flask. In the next step, we attached
quinine units to a solid support (Scheme 1) in order to
synthesize the chiral packing of the middle reaction column.11
We chose to derivatize the inexpensive Wang resin with an
excess of terephthaloyl chloride. Quinine units were then
attached to the derivatized resin by a simple esterification
reaction to form solid-phase catalyst 6. It is significant to
note that the length of the catalyst-solid-phase linker is
Figure 1. Column asymmetric catalysis assembly.
with a nucleophile-based solid-phase asymmetric catalyst.
Between the two columns, an imine is added to the system.
An optional third column is packed with a scavenger resin
to remove any unreacted ketene or imine from the eluent.5
The advantages of conducting this type of reaction on a
column include (1) obviating the need to isolate and/or
manipulate highly reactive ketenes, (2) separating the dif-
ferent solid-phase components easily, (3) recycling the
polymer supported reagents and catalysts for additional
catalytic reactions, and, finally, (4) avoiding vigorous agita-
tion that can degrade resin beads.
The well precedented6 in situ generation of ketenes using
triethylamine (or other tertiary amines such as Hu¨nig’s base)
is problematic because the amine itself catalyzes the cy-
cloaddition of ketene 3 and imino ester 4.7 Additionally, the
byproduct hydrochloride salts also interfere with the catalytic,
asymmetric reaction.8 To overcome these difficulties, we
(7) We have used R-imino ester 4 in the catalytic, asymmetric synthesis
of R-amino acid derivatives: (a) Drury, W. J., III; Ferraris, D.; Cox, C.;
Young, B.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 11006-11007. (b)
Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998,
120, 4548-4549. Imine 4 was first featured in work by: (c) Tschaen, D.
H.; Turos, E.; Weinreb, S. M. J. Org. Chem. 1984, 49, 5058-5064.
(8) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III;
Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831-7832.
(9) The pKa of the conjugate acid of BEMP in DMSO is 16.2. See:
O’Donnell, M. J.; Delgado, F.; Hostettler, C.; Schwesinger, R. Tetrahedron
Lett. 1998, 39, 8775-8778.
(5) Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.; Parlow,
J. J.; South, M. S.; Woodard, S. J. Am. Chem. Soc. 1997, 119, 4874-4881.
(6) (a) Palomo, C.; Aizpurua, J. M.; Inaki, G.; Oiarbide, M. Eur. J. Org.
Chem. 1999, 3223-3235. (b) Tidwell, T. T. Ketenes; John Wiley & Sons:
New York, 1995.
(10) Schwesinger, R.; Willaredt, J.; Schlemper, H.; Keller, M.; Schmitt,
D.; Fritz, H. Chem. Ber. 1994, 127, 2435-2454.
(11) For other examples of polymer-supported asymmetric catalysts
utilizing cinchona alkaloids, see: Bolm, C.; Gerlach, A. Eur. J. Org. Chem.
1998, 21-27.
3964
Org. Lett., Vol. 2, No. 25, 2000

Scheme 1. Synthesis of Solid-Phase Catalyst 6
Scheme 2. Synthesis of Optically Enriched â-Lactams through
Dual Solid-Phase Reagents
resin column, the eluted reaction mixture was concentrated
to afford crude â-lactam 1 in 91% ee. Without further
purification, crystallization of the residue affords optically
and analytically pure material in 65% yield.
To ready the apparatus for another catalytic cycle, the
columns were separated and regenerated. The catalyst-loaded
resin column was washed with methanol and dried under
high vacuum. The BEMP resin was regenerated by rinsing
with phosphazene base P4-t-Bu in THF/MeCN (1:1), until
the eluent was free from Cl-, and then dried under high
vacuum at 120 °C.14 The scavenger resin was washed with
ammonia and dried under high vacuum. In the extreme, the
reaction has been successfully run through the catalyst
column 20 times with no significant loss in selectivity or
yield (90% ee and 62% yield for run 20).
One can envision practical applications for the synthesis
of enantiopure compounds using this methodology. Reactants
can be passed through discrete columns containing recyclable
reagents, which upon degradation can be swapped out of
the production stream and regenerated. The use of reagents
on solid support greatly simplifies the purification of the
crude reaction mixture, allowing for shorter production times
and thus lower costs under certain circumstances. We are
currently applying our concept of column asymmetric
catalysis to other asymmetric reactions involving solid-phase
catalysts.
crucial to the success of the reaction; short linkers give
inferior results, presumably due to the steric encumbrance
of the polymeric support.12
Assembly of the system began by loading two fritted,
jacketed columns (each 2 cm wide) under nitrogen, the top
column with the BEMP resin 5 and the middle column with
catalyst-loaded beads 6 (3 cm). The scavenger resin was
loaded into a column and attached to the bottom of the
apparatus. All columns were flushed with THF (3 mL) under
nitrogen. The BEMP column was cooled to -78 °C with a
dry ice/acetone mixture. The catalyst-loaded column was
cooled to -43 °C by dry ice/acetonitrile.13 An ambient
temperature solution of phenylacetyl chloride 2 (0.14 mM)
in THF (0.5 mL) was added to the top column and allowed
to percolate by gravity through the BEMP resin and onto
the lower catalyst-loaded resin of the bottom column
(Scheme 2). Imino ester 4 (0.13 mM in 0.5 mL of THF)
was then added through a port onto the lower column. The
reaction was initiated by allowing a slow drip of THF from
the catalyst column, enough to allow complete elution of
the column contents dropwise over the course of 2 h. An
additional amount of THF (3 mL) was added to flush the
column free of reagants. After passing through the scavenger
Acknowledgment. T.L. thanks DuPont, Eli Lilly, and the
NSF Career Program for support, the Dreyfus Foundation
for a Teacher-Scholar Award, and the Alfred P. Sloan
Foundation for a Fellowship. H.W. thanks Johns Hopkins
for a Whittaker Chambers Fellowship.
Supporting Information Available: General experimen-
tal procedures. This material is available free of charge via
the Internet at http://pubs.acs.org.
(12) The use of shorter linkers decreased the diastereoselectivity to 7:1
possibly because the catalyst was constrained to a nonoptimal conformation.
(a) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1990, 31, 3003-3006.
(b) Pini, D.; Petri, A.; Nardi, A.; Rosini, C.; Salvadori, P. Tetrahedron Lett.
1992, 32, 5175-5178.
(13) The optimal temperature for column asymmetric catalysis of
phenylketene 3a and imino ester 4 was found to be -43 °C.
OL006659R
(14) Schwesinger, R.; Willaredt, J.; Schlemper, H.; Keller, M.; Schmitt,
D.; Fritz, H. Chem. Ber. 1994, 127, 2435-2454.
Org. Lett., Vol. 2, No. 25, 2000
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