Towards organocatalytic polyketide synthases with diverse electrophile scope: Trifluoroethyl thioesters as nucleophiles in organocatalytic Michael reactions and beyond

Article abstract of DOI:10.1002/anie.200801088

(Chemical Equation Presented) Hot ester nucleophiles! Trifluoroethyl thioesters are effective nucleophiles in direct organocatalytic asymmetric Michael reactions with α,β-unsaturated aldehydes (above). Electronic tuning of thioesters allows for the genera

Full text of DOI:10.1002/anie.200801088

Communications
DOI: 10.1002/anie.200801088
Synthetic Methods
Towards Organocatalytic Polyketide Synthases with Diverse
Electrophile Scope: Trifluoroethyl Thioesters as Nucleophiles in
Organocatalytic Michael Reactions and Beyond**
Diego A. Alonso, Shinji Kitagaki, Naoto Utsumi, and Carlos F. Barbas III*
Dedicated to Professor Chi-Huey Wong on the occasion of his 60th birthday
Catalytic asymmetric synthesis based on simple ester nucle-
ophiles remains an unmet challenge in organic synthesis. The
difficulty with this class of potential nucleophiles lies in the
relatively inert nature of the proton at the a-position of a
simple carboxylic ester; the pKa value is approximately 19.[1]
Direct asymmetric transition-metal-based approaches[2] are
well developed for carbonyl compounds bearing activating
electron-withdrawing groups at the a-position, and organo-
catalytic approaches[3] allow for effective nucleophile gener-
ation from simple ketones and aldehydes (via in situ enamine
formation). In contrast, effective ester-based approaches are
rare. Nature, however, has developed a diverse and elegant
solution to this problem in its use of acyl-CoA thioesters and
diverse families of polyketide synthase enzymes, which
catalyze the reactions of a variety of thioesters like acetyl-
CoA, propionyl-CoA, malonyl-CoA, and others en route to
the synthesis of medicinally important polyketides and
metabolically important fatty acids.[4] This fact has not
escaped the attention of organic chemists, and recently the
groups of Shair, Cozzi, Wennemers, and Ricci have reported
catalytic enantioselective reactions based on either metal
catalysis or organocatalysis.[5] Significantly, each of these
reports utilizes malonic acid half thioesters as enolate
precursors, and the decarboxylation of the malonic acid half
thioester is used to drive enolate formation. We sought a more
atom economical approach that would not require decarbox-
ylation as a driving force for enolization, and would thus not
be constrained by the requirement of an activating carbox-
ylate group at the a-position of the thioester.
Michael reactions involving a,b-unsaturated aldehydes, but
also the versatility of the trifluoroethyl thioester system in
nitroolefin-based Michael, aldol, and amination reactions. We
believe that trifluoroethyl thioesters will prove to be impor-
tant nucleophiles in a wide range of both organocatalytic and
metal-based direct catalytic asymmetric reactions.
As noted above, the use of esters in direct catalytic
asymmetric synthesis is challenging since the proton at the a-
position, which must be removed to generate the nucleophilic
enolate, has a relatively high pKa value. We desired an
approach that would not be limited by malonic acid half
thioester decarboxylation for enolate generation (Scheme 1).
Scheme 1. a) Decarboxylative approach vs. b) equilibrium approach.
E=electrophile.
Rather, we sought to activate a-proton removal by electronic
tuning at the thioester such that a wide variety of carboxylic
ester derivatives might serve as nucleophiles. Indeed,
Natureꢀs access and use of thioester enolates is neither
limited to the use of malonic acid half thioesters nor their
decarboxylative generation of an active enolate.[4]
Direct organocatalytic methods based on amine catalysis
have a functional pKa barrier for nucleophile activation that
lies between the pKa values of 16 and 17 (Figure 1). It is
known that a malonate diester with a pKa value of 16.4 can be
activated by amine bases to act as a nucleophile in asymmetric
Herein we detail the first enantioselective thioester
addition reactions of simple trifluoroethyl thioesters. We not
only demonstrate the enantioselective organocatalytic
[*] Dr. D. A. Alonso, Dr. S. Kitagaki, Dr. N. Utsumi, Prof. Dr. C. F. Barbas,
III
The Skaggs Institute for Chemical Biology and the Departments of
Chemistry and Molecular Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037 (USA)
Fax: (+1)858–784–2583
E-mail: carlos@scripps.edu
[**] We thank The Skaggs Institute for Chemical Biology for funding and
S. Mitsumori for early contributions to this work. D.A.A. thanks the
Secretaría de Estado de Universidades e Investigación del Minis-
terio de Educación y Ciencia for support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Figure 1. pKa values ofthe a-protons ofpotential nucleophiles in
DMSO.[1]
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synthesis,[6h,i] but ketones with a-proton pKa values of ca. 18
require amine activation by enamine formation. The relative
reactivities of these compounds allowed us to define this
functional pKa barrier.[1] As illustrated in Figure 1, the change
from an oxyphenol ester to a thiophenol ester results in a
reduction in the pKa value of the a-proton of an ester by
approximately 2 units, just at the borderline for nucleophile
activation using the currently available amine organocata-
lysts. Thus, we sought appropriate thioesters that might be
used to reduce the pKa value of the a-proton to a suitable
range for organocatalysis. In elegant experiments, Um and
Drueckhammer studied the kinetic acidities of the a-proton
of a series of thioesters.[7] These studies revealed that
trifluoroethyl thioesters have a-proton exchange rates in
toluene/triethylamine solutions that are approximately ten
times faster than phenyl thioesters, suggesting that the
pKa value of the a-proton of trifluoroethyl thioesters might
be close to those of malonate diesters, making them candidate
ester nucleophiles in catalytic direct asymmetric synthesis.
Since our 2000 report,[3c] a variety of pyrrolidine-based
iminium catalysts of Michael additions have broadened the
scope and efficiency of the iminium-based Michael reac-
tion.[3,6] As illustrated in Scheme 2, we screened a number of
these organocatalysts together with benzoic acid co-catalyst,
for catalysis of the Michael addition of thioester 1a to
cinnamaldehyde 2a. A number of the pyrrolidine-based
catalysts were effective. In particular, the trialkylsilyl-pro-
tected diarylprolinols (4–6) pioneered by Hayashi and co-
workers and Jørgensen and co-workers provided the product
in excellent chemical yield and with high enantioselectivity.[6]
With respect to our hypothesis concerning the pKa window
accessible for catalysis with these catalysts, the analogous
phenylthioester of 1a was unreactive, whereas the trifluoro-
ethyl thioester was reactive.
Catalyst 4 was the most promising of those evaluated with
respect to chemical yield and ee values; we therefore set out
to optimize this reaction. A variety of solvents and co-
catalysts were evaluated (see Table 1S in the Supporting
Information). Nonpolar solvents were ineffective in the
absence of a co-catalyst (Table 1S, entries 2–4); however,
the polar protic solvents, such as methanol and ethanol, were
highly effective and provided the desired product in 95% and
83% yield, respectively, on the basis of conversion after
48 hours at room temperature (Table 1S, entries 9 and 10).
Surprisingly, isopropanol provided less than 5% conversion.
We next studied a variety of acid co-catalysts in methanol. We
found that the co-catalysts benzoic acid, 5-methyl-1H-tetra-
zole, or water were equally effective, whereas trifluoroacetic
acid poisoned the reaction (Table 1S, entries 12–15).
To determine the scope of this reaction we synthesized a
variety trifluoroethyl thioesters derived from arylacetic acids,
and analyzed the products and the yields of the addition
reactions to a,b-unsaturated aldehydes (Table 1). We noted
significant electronic effects: faster reactions were observed
with thioesters derived from arylacetic acids having electron-
withdrawing groups, whereas reaction of thioesters derived
from arylacetic acids with electron-donating groups were
significantly slower (compare Table 1, entries 4 and 8). With
cinnamaldehyde as the Michael acceptor substrate, the yields
of the isolated products ranged from 46 to 88% and the
enantioselectivities were up to 98%. Although most of these
reactions were performed at room temperature, we were able
to demonstrate in the p-nitrophenylacetic acid ester case that
the ee value of the product could be improved from 66 to 91%
by simply performing the reaction at 08C (compare Table 1,
entries 4 and 6). With the highly reactive p-nitrophenylacetic
acid ester substrate, we observed that the reaction was
reversible during extended reaction times, ultimately eroding
the ee value of the product (compare Table 1, entries 4 and 5).
Other less active thioesters such as p-methoxyphenylacetic
acid and napthylacetic acid esters (Table 1, entries 8 and 9)
were studied by monitoring the reaction under extended
reaction times or with excess catalyst, and no erosion of the
ee values was noted. The trifluoroethyl thioester of propionic
acid was not reactive under these conditions, suggesting that
an aromatic functionality was required to bring the pKa value
of the a-proton down to a functional range.
Modification of the Michael acceptor substrate was also
possible and the o-methoxycinnamaldehyde acceptor pro-
vided product with 96% ee (Table 1, entry 12). Crotonalde-
hyde was significantly less effective, and Michael product 3k
was obtained with only 54% ee. It is known that catalyst 4
may be a poor catalyst for crotonaldehyde-based Michael
reactions.[6h] The overall diastereoselectivity of these reac-
tions was modest and the relative configurations of the
products were assigned after conversion of the phenylacetic
acid product (Table 1, entry 7) into a known product (see the
Scheme 2. Evaluation oforganocatalysts together with a benzoic acid
co-catalyst, of r catalysis ofthe Michael addition ofthioester 1a to
cinnamaldehyde 2a. The yields of 3a are shown below the respective
catalysts. [a] Reaction was performed in a 1.0m solution in the
presence of15 mol% of 7 and benzoic acid.
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Table 1: Thioester addition reactions to a,b-unsaturated aldehydes.[a]
Entry
Thioester (R1)
Aldehyde (R2)
Product
t [h]
Yield [%][b]
anti:syn[c]
ee [%][d]
1
2
3
4
1a (4-ClC6H4)
1b (2-ClC6H4)
1c (4-CF3C6H4)
1d (4-NO2C6H4)
1d (4-NO2C6H4)
1d (4-NO2C6H4)
1e (Ph)
1 f (4-MeOC6H4)
1g (1-naphthyl)
1h (2-thienyl)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2b (2-MeOC6H4)
2c (Me)
3a
3b
3c
3d
3d
3d
3e
3 f
3g
3h
3i
17
19
18
1
16
2
16
48
48
24
24
72
36
70
75
74
88
45
84
71
46 (44)
66 (28)
57
70
63
65:35
65:35
74:26
57:43
60:40
61:39
67:33
64:36
63:37
81:19
78:22
71:29
63:37
90[e]
89
93
66[e,f]
33[e,f]
91[e,f]
82[e]
84
5
6[g]
7[h]
8[h,i]
9[h,i]
10
11[h]
12[h]
13[h,j]
67[e]
84
1i (PhCH CH)
98[e]
96
=
1a (4-ClC6H4)
1a (4-ClC6H4)
3j
3k
51
54[e]
[a] See the Experimental Section for reaction conditions. [b] Yield of products that were isolated as a mixture of anti:syn isomers. Yields ofrecovered 1
is shown in parentheses. [c] Determined by 1H NMR analysis ofthe crude reaction mixture. [d] Enantiomeric excess ofr the anti product was
determined by chiral phase HPLC analysis. [e] Determined by chiral phase HPLC analysis after NaBH4 reduction. [f] NaBH4 was added directly to the
Michael reaction mixture. [g] Reaction performed at 48C. [h] Reaction performed in 1.0m solution. [i] Used 20 mol% of 4. [j] DMF was used as the
solvent.
Supporting Information). The relative configurations of the
other products were assigned by analogy.
Having established the direct organocatalytic asymmetric
Michael reaction of trifluoroethyl thioesters with a,b-unsatu-
rated aldehydes, we examined the reactivity of trifluoroethyl
To study the role of the a-proton acidity of our esters and
its influence on reactivity and enantioselectivity in the
Michael reaction, we performed deuterium exchange experi-
ments under conditions similar to those established by Um
and Drueckhammer[7] (Figure 2). There was a good correla-
tion between the exchange rate and the Michael reaction
times noted in Table 1. No significant correlation of the
electronic effect with the ee value was noted. The trifluoro-
ethyl thioester of propionic acid did not undergo a-proton
exchange under these conditions and was not active in the
Michael reaction, indicating that the pKa value of the a-
proton was outside of the range of these organocatalytic
conditions.
À
À
thioesters in other key C C and C N bond-forming reactions.
Trifluoroethyl thioesters were very reactive in direct cross-
aldol reactions catalyzed by DBU, in amination reactions
catalyzed under mild proline catalysis conditions, and in
nitroolefin Michael reactions catalyzed by quinuclidine
(Scheme 3). These reactions hold considerable promise in
Figure 2. Time course for a-proton exchange for thioesters 1 as
Scheme 3. Other reactions using thioester 1a. Conditions: a) 4-
NO2PhCHO, DBU (10 mol%), toluene, 48C, 3 h; b) (NCO2Bn)2, dl-
proline (20 mol%), DMF, 48C, 72 h; c) (E)-PhCHCHNO2, quinuclidine
(20 mol%), DMF, 48C, 1 h. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
monitored by 1H NMR analysis. The t1/2 was <5 min for 1d ( ),
&
~
~
45 min for 1a (&), 120 min for 1e ( ), 230 min for 1 f ( ), >5000 min
*
for S-trifluoroethyl thiopropionate ( ).
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reactions.
In summary, we have developed the first direct catalytic
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establishing a new class of nucleophiles for direct catalytic
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thioester-based reactions promise access not only to the
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Experimental Section
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Typical procedure for Michael addition of thioesters to a,b-unsatu-
rated aldehydes (Table 1, entry 1): 2a (1.3 equiv, 0.26 mmol, 32.5 mL)
was added to a solution of catalyst 4 (10 mol%, 12.0 mg, 0.02 mmol)
and benzoic acid (10 mol%, 2.4 mg, 0.02 mmol) in MeOH (0.2 mL).
After stirring the resulting mixture at room temperature for 15 min, a
previously prepared (2–3 minutes before addition) MeOH (0.2 mL)
solution of 1a (53.3 mg, 0.2 mmol) was added dropwise, after which
the reaction mixture was stirred for 17 h. MeOH was then evaporated
and the diastereomeric ratio was determined by 1H NMR analysis of
the crude product mixture. The crude product mixture was purified by
flash chromatography (hexane/EtOAc = 20:1) to afford 3a as a
mixture of diastereomers in a total yield of 70%. The major
diastereomer (anti product) could be obtained in pure form by flash
chromatography. The ee value was determined by chiral-phase HPLC
analysis of the corresponding alcohol, which was obtained after
reaction with NaBH4 in MeOH at 08C.
Received: March 6, 2008
Published online: May 7, 2008
Keywords: amination · asymmetric synthesis · Michael reaction ·
.
organocatalysis · polyketide synthases
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