Cinchona Alkaloid-Lewis Acid Catalyst Systems for Enantioselective Ketene-Aldehyde Cycloadditions

Article abstract of DOI:10.1021/ja0492900

Asymmetric cinchona alkaloid-catalyzed acid chloride-aldehyde cyclocondensation (AAC) reactions afford enantioenriched 4-substituted and 3,4-disubstituted β-lactones with near perfect absolute and relative stereocontrol. These reactions are characterized

Full text of DOI:10.1021/ja0492900

Published on Web 04/13/2004
Cinchona Alkaloid-Lewis Acid Catalyst Systems for Enantioselective
Ketene-Aldehyde Cycloadditions
Cheng Zhu, Xiaoqiang Shen, and Scott G. Nelson*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received February 9, 2004; E-mail: sgnelson@pitt.edu
In 1982, Wynberg reported an extraordinary example of asym-
metric Lewis base catalysis in the context of cinchona alkaloid-
catalyzed ketene-chloral cycloadditions (Figure 1).1 Wynberg’s
pioneering investigations undoubtedly provided inspiration to recent
reports of asymmetric alkaloid-catalyzed ketene-imine cycload-
ditions,2 ketene dimerizations,3 and intramolecular ketene-aldehyde
cycloadditions.4 The success of these latter investigations, however,
serves to emphasize the absence of a ketene-aldehyde cycloaddition
based on the Wynberg model addressing the original transforma-
tion’s severe substrate limitations. Successfully extending the
Figure 1. Alkaloid-Catalyzed Ketene-Aldehyde Cycloadditions.
Wynberg ketene-aldehyde cycloadditions to structurally diverse
aldehydes would afford access to versatile enantioenriched â-lac-
tones using a commercially available catalyst.5 Herein, we report
asymmetric cinchona alkaloid (1 or 2)-catalyzed acid chloride-
aldehyde cyclocondensation (AAC) reactions applicable to a range
of structurally diverse aldehydes. These reactions are characterized
by exceptionally high enantio- and diastereoselection and the
operational simplicity derived from using commercially available
reaction catalysts and in situ ketene generation.
Alkaloid additives catalyze ketene-aldehyde additions through
nucleophilic addition to ketene, generating the acylammonium
enolate 3 responsible for mediating C-C bond construction (Figure
2).6 The specificity of Wynberg’s original cycloaddition for highly
electrophilic aldehydes (e.g., chloral) suggested that these enolates
possess relatively limited nucleophilicity. In considering strategies
for generalizing the alkaloid-catalyzed ketene-aldehyde additions,
Lewis acid activation of the aldehyde electrophile emerged as an
alternative for eliciting the requisite nucleophilicity from the
ammonium enolates.7 Furthermore, alkaloid-mediated enolate for-
mation in the presence of metallic Lewis acid cocatalysts (M) was
considered a plausible conduit to metal-stabilized ammonium
enolates 4. Such enolates could be expected to mediate aldehyde
addition through a metal-templated, closed transition state 5,
providing both enthalpic and entropic activation to the ensuing
enolate-aldehyde addition.
Figure 2. Postulated Mechanism for Alkaloid-Catalyzed AAC Reactions.
dehyde test reaction afforded the first indication of this reaction
design’s validity, delivering the desired â-lactone 6 in 62% ee.
Success in this preliminary reaction provided a platform for
evaluating the impact of Lewis base (alkaloid) structure, solvent
composition, and catalyst stoichiometry on the alkaloid/LiClO4-
catalyzed AAC reactions. Lewis base catalyst candidates were
drawn from easily accessed cinchona alkaloid derivatives differing
in C9 oxygen substitution. Systematically investigating AAC
efficiency as a function of the quinidine O-protecting group revealed
that the O-trimethylsilyl derivative (2, TMSQ) afforded optimum
reaction yields while enantioselection was relatively insensitive to
oxygen substitution.11,12 Catalytic competency of the pseudoenan-
tiomeric Lewis base catalyst O-trimethylsilyl quinine (TMSq)
paralleled closely that of TMSQ and, thus, provided convenient
access to the enantiomeric â-lactone series. Solvent systems for
the TMSQ/LiClO4-catalyzed AAC reactions composed predomi-
nately of methylene chloride but containing sufficient diethyl ether
to ensure solubility of the LiClO4 at low temperatures delivered
optimum reaction yields and stereoselection. Lewis acid stoichi-
ometry emerged as a crucial variable that could be conveniently
modulated to maximize reaction efficiency depending on aldehyde
structure. Thus, slow addition of acid chloride (2 equiv over ∼1-4
h) to a CH2Cl2/Et2O (2:1) solution containing TMSQ (10 mol %)/
Preliminary reaction development emphasized the identification
of cinchona alkaloid-Lewis acid combinations that would allow in
situ ketene generation to be integrated with the catalyzed ketene-
aldehyde cycloadditions. Our prior success in merging tertiary
amine-mediated dehydrohalogenation of acyl halides with asym-
i
metric ketene-aldehyde cycloadditions led us to explore the Pr2-
NEt-acid chloride combination as the ketene source.8,9 Quinine was
employed initially as the requisite Lewis base catalyst (5 mol %)
for evaluating various Lewis acid cocatalysts (15 mol %) in the
reaction of acetyl chloride/iPr2NEt (ketene) with hydrocinnamal-
dehyde as a representative unactivated aldehyde (eq 1). Among
the various Lewis acids examined, lithium perchlorate emerged as
a uniquely effective cocatalyst for mediating the desired AAC
reaction.10 The catalyst system composed of 5 mol % quinine and
15 mol % LiClO4 in the standard acetyl chloride-hydrocinnamal-
9
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J. AM. CHEM. SOC. 2004, 126, 5352-5353
10.1021/ja0492900 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Cinchona Alkaloid/LiClO4-Catalyzed AAC Reactions
afforded similarly high absolute and relative stereocontrol under
analogous conditions and, when necessary, using increased amounts
of LiClO4 for aldehydes affording sluggish reaction rates (e.g., the
sterically hindered aldehyde pivaldehyde requires 3 equiv LiClO4;
entry b). As observed in the ketene cyclocondensations, the
R-branched aldehyde cyclohexanecarboxaldehyde delivers the cis-
disubstituted â-lactone 7i in good yield and with very high enantio-
and diastereoselection (entry i; 97% ee, >96% de). Modulating
Lewis acid loading also succeeded in rendering aryl aldehydes
(entries j-m), including ortho-substituted derivatives, as useful
AAC substrates, delivering the cis-4-aryl-3-methyl-2-oxetanones
in >99% ee (g96% de, 76-85% yield).
Cinchona alkaloid-Lewis acid-catalyzed AAC reactions dramati-
cally expand the scope of Wynberg’s original ketene-aldehyde
cycloadditions. These reactions are mechanistically distinct and,
in several important aspects, directly complement the asymmetric
Lewis acid-catalyzed reaction variants. In particular, the TMSQ/
LiClO4 catalyst system relieves the limitation R-branched aldehydes
previously imposed on AAC reactions and engages methylketene
in exceptionally stereoselective cyclocondensations. These reaction
attributes combined with the ready availability of the necessary
reaction components promise to further expand the scope and utility
of the AAC reaction technology.
1
2
c
entry
product
7a
7b
7c
ent-7d
ent-7e
ent-7f
ent-7g
ent-7h
7i
ent-7j
ent-7k
7l
R
R
%eea,b
%de
% yield
a
b
c
d
e
f
g
h
i
H
cC6H11
CMe3
94d
96e
92
84
>99
99
-
-
85
71
80
70
84
74
68
72
74
78
85
80
76
H
H
H
CH2CH2Ph
CH2OBn
CH2CH2Ph
(CH2)8CHCH2
CH2OBn
CH2CH(CH3)2
cC6H11
-
-
Me
Me
Me
Me
Me
Me
Me
Me
Me
96
90
76
90
>96
96
>96
96
>96
99
99
97f
j
k
l
C6H5
>99
>99
>99
>99
pC6H4F
oC6H4Cl
m
ent-7m
oC6H4CH3
a
b
Enantiomer ratios determined by chiral GLC or HPLC. Minor
c
enantiomer not observed for values >99%. Diastereomer ratios determined
by 1H NMR of crude product mixtures. 90% ee using TMSq as catalyst.
d
e
f
95% ee using TMSq as catalyst. 96% ee using TMSq as catalyst.
i
LiClO4 (30-300 mol %) and Pr2NEt (2.5 equiv) provided the
optimized conditions for AAC reactions employing a range of
structurally diverse aldehydes (eq 2).13
Acknowledgment. Support from the National Institutes of
Health (R01 GM63151-01), Eli Lilly & Co., the Bristol-Myers
Squibb Foundation, and the Merck Research Laboratories is
gratefully acknowledged.
Supporting Information Available: Experimental procedures,
1
stereochemical proofs, and representative H and 13C spectra (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166-
168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-
1979.
(2) (a) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III;
Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831-7832. (b) Taggi, A. E.;
Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem.
Soc. 2002, 124, 6626-6635.
(3) (a) Calter, M. A. J. Org. Chem. 1996, 61, 8006-8007. (b) Calter, M. A.;
Liao, W. J. Am. Chem. Soc. 2002, 124, 13127-13129. (c) Calter, M. A.;
Orr, R. K.; Song, W. Org. Lett. 2003, 5, 4745-4748.
(4) (a) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001,
123, 7945-7946. (b) Cortez, G. S.; Oh, S. H.; Romo, D. Synthesis 2001,
1731-1736.
(5) For synthesis applications of enantioenriched â-lactones, see: (a) Yang,
H. W.; Romo, D. J. Org. Chem. 1999, 64, 7657-7660 and references
therein. (b) Nelson, S. G.; Cheung, W. S.; Kassick, A. J.; Hilfiker, M. A.
J. Am. Chem. Soc. 2002, 124, 13654-13655 and references therein.
(6) (a) Wynberg, H. Top. Stereochem. 1986, 16, 87-130. (b) France, S.;
Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. ReV. 2003, 103, 2985-
3012.
(7) Lewis acid cocatalysts accelerate alkaloid-catalyzed ketene-imine addi-
tions. See: France, S.; Wack, H.; Hafez, A. M.; Taggi, A. E.; Witsil, D.
R.; Lectka, T. Org. Lett. 2002, 4, 1603-1605.
(8) (a) Nelson, S. G.; Peelen, T. J.; Wan, Z. J. Am. Chem. Soc. 1999, 121,
9742-9743. (b) Nelson, S. G.; Wan, Z. Org. Lett. 2000, 2, 1883-1886.
(c) Nelson, S. G.; Zhu, C.; Shen, X. J. Am. Chem. Soc. 2004, 126, 14-
15.
While these alkaloid-catalyzed AAC reactions are superficially
related to the Al(III)-catalyzed variants developed previously, the
quinidine-LiClO4 catalyst system offers several notable advantages.8
In reactions involving acetyl chloride-derived ketene, the TMSQ/
LiClO4 system renders R-branched and sterically hindered aldehydes
as effective AAC substrates, providing the cyclohexanecarboxal-
dehyde- and pivaldehyde-derived â-lactones 7a and 7b in 94 and
96% ee, respectively (Table 1, entries a and b). Similar R-branched
aldehydes are unreactive under the Al(III) catalyst conditions.
Unbranched aldehydes also afford useful levels of enantioselection
in the ketene AAC reactions (92% and 84% ee for entries c and d,
respectively). From an operational perspective, it is noteworthy that,
except for the simple one-step preparation of TMSQ,3a these results
are obtained using commercially available, inexpensive reagents
and catalysts.
(9) For alkaloid-catalyzed ketene additions to activated aldehydes employing
in situ ketene generation, see: Tennyson, R.; Romo, D. J. Org. Chem.
2000, 65, 7248-7252. See also refs 2 and 3.
Methylketene is also an effective AAC reaction partner using
the TMSQ (or TMSq)/LiClO4 catalyst system. In fact, enantiose-
lection in AAC reactions employing propionyl chloride-derived
methylketene improves dramatically relative to their simple ketene
counterparts (Table 1). Thus, adding propionyl chloride (over 1-4
(10) Lecea, B.; Arrieta, A.; Arrastia, I.; Cossio, F. P. J. Org. Chem. 1998, 63,
5216-5227.
(11) AAC reaction enantioselection is invariant when employing 1 or 2 as the
Lewis basic catalyst; reaction yields are enhanced when using 2.
(12) For asymmetric ketene dimerizations catalyzed by O-silylated cinchona
alkaloids, see ref 3c.
i
h) to a mixture of hydrocinnamaldehyde, Pr2NEt, and TMSq (10
(13) Slow addition of the acid chloride was employed to maintain relatively
low ketene concentrations, thereby minimizing competing ketene
dimerization.
mol %)-LiClO4 (50 mol %) at -78 °C afforded the 3,4-cis-
disubstituted â-lactone ent-7e with near perfect absolute and relative
stereocontrol (>99% ee, 96% de). Other enolizable aldehydes
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