Catalytic Asymmetric Acyl Halide-Aldehyde Cyclocondensation Reactions of Substituted Ketenes

Article abstract of DOI:10.1021/ja0391208

Catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions of alkyl-substituted ketenes with structurally diverse aldehydes provide cis-disubstituted β-lactones with high enantioselectivity. The AAC reactions utilize a novel Al(III)-triamine catalyst in which the metal′s dynamic coordination geometry leads to a highly selective catalyst complex. These AAC reactions represent a functional solution to highly enantioselective substituted ester enolate aldol additions. Copyright

Full text of DOI:10.1021/ja0391208

Published on Web 12/18/2003
Catalytic Asymmetric Acyl Halide-Aldehyde Cyclocondensation Reactions of
Substituted Ketenes
Scott G. Nelson,* Cheng Zhu, and Xiaoqiang Shen
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received October 18, 2003; E-mail: sgnelson@pitt.edu
Recent success in developing de novo asymmetric syntheses of
enantioenriched â-lactones has created renewed interest in these
heterocycles as versatile platforms for asymmetric organic synthe-
sis.1,2 â-Lactones are direct progenitors of numerous useful building
blocks, including enantioenriched â-amino acids,3 allenes,4 and â,â-
disubstituted carboxylic acids.5 â-Lactones are also functional
equivalents of ester enolate aldol addition products.6 In this latter
context, we developed acyl halide-aldehyde cyclcondensation
(AAC) reactions that deliver enantioenriched â-lactone acetate aldol
surrogates from commercially available starting materials (eq 1).2c,7
However, these first-generation AAC reactions proved to be
generally useful only for reactions involving unsubstituted ketene.8
Herein, we report generally applicable catalytic asymmetric AAC
reactions of alkyl-substituted ketenes with structurally diverse
aldehydes as a functional solution to highly enantio- and diaste-
reoselective substituted ester enolate aldol additions.
of the desired â-lactone 3 (eq 3). Kinetic evidence indicated that
while ketene trimerization was Lewis acid (catalyst)-independent,
this reaction manifold was accelerated substantially by the am-
monium bromide byproduct of amine-mediated ketene generation.10
This analysis suggested that elucidating reaction conditions that
would effectively remove the ammonium halide salts would slow
unproductive methylketene homocoupling. We discovered that
pseudo-salt-free conditions could be achieved by substituting
benzotrifluoride (BTF) for CH2Cl2 as the AAC reaction solvent.11
In BTF, the ammonium bromide salts are insoluble and AAC
reaction conversions improved considerably in the standard pro-
pionyl bromide-hydrocinnamaldehyde test reaction (<10% f
47%) due to extended ketene lifetimes.
Mechanistic investigations of the catalyzed AAC reactions
revealed these reactions to be kinetically complex processes.9 First-
generation AAC reactions successfully mediate up to four compet-
ing reaction pathways to deliver the desired [2 + 2] ketene-
aldehyde cycloadduct (â-lactone) 1 in high yield (eq 2). This
reaction fidelity is notable considering that ketene dimerization,
ketene trimerization, and aldehyde homoaldol addition are all
accessible processes under the AAC reaction conditions. While
AAC reactions employing acetyl bromide-derived ketene faithfully
generate the â-lactone cycloadducts, substituted ketenes exhibited
substantially suppressed reactivity toward aldehydes, allowing
competing reaction manifolds to interfere with the desired [2 + 2]
pathway. For example, reacting propionyl bromide (methylketene
precursor) with various aliphatic aldehydes affords methylketene
trimer 2 as the major reaction product, while analogous acetyl
bromide AAC reactions deliver exclusively â-lactone 1. These
observations highlight the significant differences existing between
AAC reactions involving ketene and those employing substituted
ketenes despite the superficial similarity of these transformations.
Although solvent modification assisted in improving AAC
reaction conversions, the need for improved catalysts that would
further accelerate the desired ketene-aldehyde cross-coupling
remained evident. Designs for more reactive reaction catalysts were
predicated on structural investigations of the first-generation Al-
triamine catalyst 4.12 Crystallographic studies revealed complex 4
to adopt a four-coordinate, trigonal monopyramidal (tmp) geometry;
this Al(III) coordination geometry and the central Al-N Lewis
acid-base contact that defines the tmp geometry were demonstrated
to be crucial to catalyst activity. Thus, new catalyst designs evolved
from Al(triamine)-based structures that retain the essential metal
coordination geometry while delivering enhanced metal electro-
philicity. For example, the N-2,2,2-trifluoroethyl-substituted catalyst
5 expressed significantly enhanced reactivity relative to the
analogous N-benzyl catalyst 4 (eq 3). We speculate that inductive
electron withdrawal from nitrogen decreases electron density at
aluminum, thereby enhancing Lewis acidity, while retaining suf-
ficient central nitrogen Lewis basicity to maintain the integrity of
the catalytically active tmp coordination geometry.13 Propionyl
bromide AAC reactions employing catalyst 5 in conjunction with
BTF solvent combined to define ketene-aldehyde cross-coupling
as the dominant reaction pathway, affording the desired â-lactone
“propionate” aldol adduct 3 as the sole reaction product.
The next phase of our investigation focused on identifying
modified Al-triamine catalysts that would provide the requisite
levels of enantioselectivity at reaction temperatures above the
freezing point of BTF (-29 °C). Various Al(III) catalysts derived
from C2-symmetric triamine ligands differing in sulfonamide
Attempted AAC reactions of substituted ketenes with aliphatic
aldehydes employing first-generation reaction conditions (10-20
mol % 4, CH2Cl2) afforded primarily ketene trimer 2 and <10%
9
14
J. AM. CHEM. SOC. 2004, 126, 14-15
10.1021/ja0391208 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
i
RCOBr, 2 equiv of Pr2NEt) afforded the syn-propionate aldol
surrogate 9a in 90% ee (syn:anti ) 95:5) (entry a). Methylketene
seems to be uniquely disposed toward trimerization; as a result,
slow-reacting aliphatic aldehydes require 20 mol % catalyst to
ensure that ketene-aldehyde cycloaddition competes effectively
with ketene homocoupling (entries a-c). However, unsaturated
aldehydes provide sufficiently accelerated [2 + 2] reaction rates
such that efficient AAC cross-coupling is achieved with 10 mol %
7 (entries d and e). Similarly, ethylketene trimerization is sufficiently
retarded relative to the AAC process that 10 mol % 7 affords
efficient cross-coupling for both enolizable aliphatic and unsaturated
aldehydes (entries f-i). Propylketene and i-propylketene, derived
from valeryl bromide and isovaleryl bromide, respectively, also
participate in highly stereoselective AAC reactions under the
second-generation reaction conditions, although i-propylketene
reactions are currently limited to relatively reactive, nonenolizable
aldehydes (entries j-m).15
The structural homology existing between traditional aldol
adducts and â-lactones reveals the second-generation AAC reactions
to be effective surrogates for syn-selective asymmetric aldol
additions. In this context, the AAC reactions deliver enantioenriched
ester enolate “aldols” free of the requirement for pre-enolization
or special substrate derivatization beyond preparation of the requisite
acyl bromide. These reaction attributes coupled with the array of
transformations available to the AAC-derived â-lactones portend
considerable utility for this reaction technology in a variety of
synthesis enterprises.
Figure 1. Second-Generation AAC Catalyst Structure (from X-ray 8).14
Table 1. Asymmetric AAC Reactions of Substituted Ketenes
1
2
entry
R
R
%ee 9a
syn:antib,c
% yield 9d
a
b
c
d
e
f
g
h
i
Me
Me
Me
Me
Me
Et
CH2CH2Ph
(CH2)8CHCH2
CH2CH2OBn
C6H5
CtCSiMe3
CH2CH2Ph
CH2CH2OBn
CH2OBn
C6H5
CH2CH2OBn
C6H5
CtCSiMe3
C6H5
90
88
91
96
95
91
91
93
94
91
96
94
96
95:5
94:6
86:14
>98:2
98:2
71
77
75
80
76e
81
83
78
83
88
85
71e
84
Acknowledgment. Support from the National Institutes of
Health (R01 GM63151-01), the Bristol-Myers Squibb Foundation,
and Eli Lilly & Co. is gratefully acknowledged.
95:5
Et
Et
Et
88:12
89:11
>98:2
91:9
>98:2
>98:2
>98:2
Supporting Information Available: Experimental procedures and
1
representative H and 13C spectra. This material is available free of
j
k
l
nPr
nPr
iPr
iPr
charge via the Internet at http://pubs.acs.org.
References
m
(1) For excellent reviews: (a) Yang, H. W.; Romo, D. Tetrahedron 1999,
55, 6403. (b) Orr, R. K.; Calter, M. A. Tetrahedron 2003, 59, 3545.
(2) Leading references to catalytic asymmetric â-lactone preparation: (a)
Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166. (b)
Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.;
Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255.
(c) Nelson, S. G.; Peelen, T. J.; Wan. Z. J. Am. Chem. Soc. 1999, 121,
9742. (d) Nelson, S. G.; Wan, Z. Org. Lett. 2000, 2, 1883. (e) Tennyson,
R.; Romo, D. J. Org. Chem. 2000, 65, 7248. (f) Evans, D. A.; Janey, J.
M. Org. Lett. 2001, 3, 2125. (g) Cortez, G. S.; Tennyson, R. L.; Romo,
D. J. Am. Chem. Soc. 2001, 123, 7945. (h) Calter, M. A.; Liao, W. J. Am.
Chem. Soc. 2002, 124, 13127 and references therein.
(3) Nelson, S. G.; Spencer, K. L. Angew. Chem., Int. Ed. 2000, 39, 1323.
(4) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122, 10470.
(5) Nelson, S. G.; Wan, Z.; Stan, M. A. J. Org. Chem. 2002, 67, 4680.
(6) Nelson, S. G.; Wan. Z.; Peelen, T. J.; Spencer, K. L. Tetrahedron Lett.
1999, 40, 6535.
(7) For examples of direct catalytic asymmetric ester enolate aldols, see: (a)
Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Commun. 2000, 2211.
(b) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc. 2000,
122, 4528. See also: (c) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey,
C. W. J. Am. Chem. Soc. 2002, 124, 392.
(8) AAC reactions involving substituted ketenes had previously been ap-
plicable only to a very limited subset of activated aldehydes; see ref 2d.
(9) Nelson, S. G.; Peelen, T. J.; Wan, Z. Tetrahedron Lett. 1999, 40, 6541.
(10) Ketene trimerization is accelerated considerably for substituted ketenes
relative to unsubstituted ketene under the AAC reaction conditions.
(11) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
(12) Nelson, S. G.; Kim, B.-K.; Peelen, T. J. J. Am. Chem. Soc. 2000, 122,
9318.
a Enantiomeric ratios determined by chiral GLC or HPLC. b Diastereo-
meric ratios determined by 1H NMR of crude product mixtures except for
entries b and e (GLC). c Relative and absolute stereochemical assignments
based on prior literature precedent; see ref 2d. d Yields for diastereomerically
pure materials except entries g and j (diastereomers were inseparable).
e Yield for the amide derived from amine-mediated ring opening of the
crude â-lactone. See Supporting Information for details.
structure and backbone alkyl groups provided little improvement
in enantioselectivity relative to 4. However, the catalyst derived
from unsymmetrical triamine 6 provided an Al(III)-derived complex
7 exhibiting substantially improved competency in the substituted
ketene AAC reactions (eq 4). Although unsymmetrical ligands
offered the potential for generating diastereomeric tmp Al(III)
complexes, NMR analysis of the closely related complex 8 revealed
a significant bias favoring one diastereomer (∼14:1, 23 °C). X-ray
analysis of 8 revealed the major diastereomer to orient the larger
aryl sulfonamide in the sterically less congested “outside” position
relative to the [3.3.0] ring system defined by the Al-coordinated
triamine ligand (Figure 1). A similar conformational bias expressed
in 7 would position the large aryl residue ideally to block the Si
diastereoface of an apically coordinated aldehyde.
The second-generation Al(triamine) catalyst 7 in conjunction with
pseudo-salt-free reaction conditions (BTF, -25 °C) combined to
deliver substituted ketene AAC reactions exhibiting consistently
high levels of enantioselection (Table 1). The standard test reaction
involving propionyl bromide and hydrocinnamaldehyde under the
optimized reaction conditions (10-20 mol % 7, 2-4 equiv of
(13) Ligands having a central nitrogen atom devoid of Lewis basicity
(noncoordinating) afford catalytically inactive Al(III) complexes; see ref
12.
(14) Phenyl and NO2 groups have been omitted from Figure 1 for clarity.
(15) R-Branched aldehydes and conjugated enals are not effective substrates
for the AAC reactions, affording substantially attenuated enantioselection
(60-70% ee) or no reaction, respectively.
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