Mimicry of polyketide synthases - Enantioselective 1,4-addition reactions of malonic acid half-thioesters to nitroolefins

Article abstract of DOI:10.1002/anie.200702187

Bifunctionality is the key for mimicking the active site of polyketide synthases with synthetic metal-free organocatalysts (see picture). Cinchona alkaloid derivatives bearing both a basic site and a urea moiety catalyze conjugate enantioselective addition reactions of malonic acid half thioesters (MAHTs) to nitroolefins with up to quantitative yields and selectivities up to 90% ee. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200702187

Angewandte
Chemie
DOI: 10.1002/anie.200702187
Organocatalysis
Mimicry of Polyketide Synthases—Enantioselective 1,4-Addition
Reactions of Malonic Acid Half-Thioesters to Nitroolefins**
Jana Lubkoll and Helma Wennemers*
Thioesters are versatile building blocks that allow for a wide
range of subsequent transformations into, for example,
amides, aldehydes, a-ketoalkynes, and ketones.[1] Astraight-
forward method for the introduction of thioesters is the
addition of thioester enolates to electrophiles. In organic
synthesis, thioester enolates are typically generated by
reaction of the thioester with a metal-based Lewis acid.[2] In
contrast, nature does not rely on metal ions for the generation
of thioester enolates. Instead, malonic acid half-thioesters
(MAHTs) serve as thioester enolate equivalents and are used
in the biosynthesis of fatty acids and polyketides in all
kingdoms of life.[3] The activation and reaction of MAHTs is
achieved by polyketide synthases (PKSs), which lack metal
ions and have in common the amino acids cysteine (Cys),
histidine (His), and asparagine (Asn; or another histidine) in
their active sites.[3,4] Within the catalytic triad, the His-Asn
motive is responsible for activating the CoA-bound depro-
tonated MAHT that reacts upon decarboxylation with a
second Cys-bound thioester (Figure 1). This inspired us to
cinchona alkaloids catalyze the conjugate addition of MAHTs
to nitroolefins under mild reaction conditions. Furthermore,
we demonstrate that the resulting g-nitrothioesters can be
readily converted into chiral g-butyrolactams such as the
antidepressant rolipram.
We started our investigations by examining the reactivity
of MAHTs with nitrostyrene in the presence of different
bases. Substoichiometric amounts (20 mol%) of tertiary
amines (for example, NEt3, Hünigꢀs base, quinuclidine) or
imidazole in THF led to the formation of the desired
conjugate addition product, but in yields lower than 15%;
the main product was decarboxylated MAHT. These initial
experiments also showed that the stability of MAHTs
depends largely on the solvent.[9,10] Decarboxylation occurs
in polar protic solvents within hours, while the stability is
significantly higher in, for example, CH2Cl2, THF, and other
ethers. Thus, these initial trials revealed that there is a subtle
balance between product formation and nonproductive
decarboxylation, thus demonstrating that controling the
reactivity of the MAHTs is a challenging task.
Since PKSs accomplish the activation of MAHTs by
coordination through Asn and protonated His residues,[3,4] we
speculated that bifunctionality within the catalyst structure
would be the key to efficient catalysis. Abasic site was
envisioned to allow for deprotonation of the MAHT and,
together with a second coordination site, for orienting the
MAHTand the nitroolefin in a chiral environment (Figure 1).
Since urea and thiourea functionalities are known to be
excellent coordination sites for carbonyl moieties[11] we chose
to use urea-functionalized cinchona alkaloids to evaluate our
catalyst design. Cinchona alkaloid derivatives 1–8
(Scheme 1), which have previously been used as catalysts
for a range of different reactions,[11,12] were prepared and their
catalytic activity tested in the reaction of MAHT 9 with
nitrostyrene as a first test substrate.
We were pleased to observe both catalyst turnover and
enantioselectivity when compounds 1–8 were added to the
reaction of MAHT 9 and nitrostyrene (Table 1). Epiquinine-
urea 2 proved to be the most active and selective catalyst:
Mixing a 2:1 mixture of MAHT 9 and nitrostyrene in THF
with 20 mol% of 2 afforded the 1,4-addition product in 94%
yield and 63% ee within 24 h (Table 1, entry 2).
Figure 1. Left: Activation of MAHT in the active site of polyketide
synthases (adapted from reference [4b]); right: schematic representa-
tion of the catalyst design.
address the question of whether metal-free organocatalysts
can catalyze addition reactions of MAHTs to electrophiles.[5–7]
Herein we report details of our discovery of the first
enantioselective MAHT addition reactions catalyzed in the
absence of metal ions.[8] We show that urea derivatives of
[*] Dipl.-Chem. J. Lubkoll, Prof. Dr. H. Wennemers
Department of Chemistry
University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax: (+41)61-267-0976
Experiments with the other catalysts (Table 1, entries 1–8)
demonstrated the importance of the relative configuration at
C(8) and C(9) (1, Table 1, entry 1), the methoxyquinoline
moiety (4, Table 1, entry 4), and an electron-poor urea
substituent (6 and 7, Table 1, entries 6 and 7) for good
selectivity. Replacement of the vinyl group of 2 with an ethyl
group (5, Table 1, entry 5) had no effect on the enantiose-
lectivity, but reduced the activity of the catalyst. The presence
E-mail: helma.wennemers@unibas.ch
[**] This work was supportedby Bachem andthe Swiss National Science
Foundation. H.W. is grateful to Bachem for an endowed professor-
ship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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selectivity, thereby demonstrating that the degree of coordi-
nation is crucial for efficient catalysis.
In the case of epiquinine-urea 2, lowering the catalyst
loading to 10 mol% or performing the reaction at a lower
reaction temperature (48C) necessitated longer reaction
times but yielded the 1,4-addition product with comparable
or slightly higher enantioselectivity (Table 1, entries 9 and
10). Of the solvents tested (Table 1, entries 11–14 and see the
Supporting Information), THF proved best with respect to
catalytic activity and selectivity. Higher selectivities were
observed in ethyl vinyl ether (EVE).[13] Although the reaction
is slower in EVE, the 1,4-addition product formed with
88% ee (Table 1, entry 14).[14]
With these reaction parameters defined, the reaction of
MAHT 9 with a variety of aromatic and aliphatic nitroolefins
was explored. As shown in Table 2, the reaction catalyzed by 2
in THF generally gave high yields and enantioselectivities of
Table 2: Scope of the decarboxylative 1,4-addition reaction of MAHT 9 to
nitroolefins.
Scheme 1. Cinchona alkaloidderivatives 1–8.
Table 1: Decarboxylative 1,4-addition reactions of MAHT 9 to nitro-
styrene catalyzedby cinchona alkaloidderivatives 1–8.[a]
THF[a]
EVE[b]
Entry
1
R
Yield[c] [%] ee[d] [%]
Yield[c] [%] ee[d] [%]
94
96
63 (90)[e]
61
57
41
88 (99)[e]
79
2
3
4
Entry Cat. Mol% T (8C) Solvent t [h] Yield[%] [b]
ee [%][c]
92
56
63[f]
61[f]
51[f]
84[f]
82[f]
90[f]
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
2
2
2
2
2
2
20
20
20
20
20
20
20
20
20
10
20
20
20
20
25
25
25
25
25
25
25
25
4
25
25
25
25
25
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
72
24
120 69
24
96
24
24
65
94
24
63
54
47
63
58
51
94
55
52
64
47
78
5
99[f]
67[f]
120 no reaction[d]
120 87
120 82
9
66
64
56
55
52
88
6
7
8
89[f]
93[f]
78[f]
65[f]
61[f]
36
13
86
10
11
12
13
14
CH2Cl2 120 13
DME[e] 72
60
40
57
73
EtOAc
EVE
72
72
62[f] (97)[e] nd[g]
nd[g]
[a] Reactions were performedwith 2 equiv of 9 except for the reaction in
ethyl vinyl ether (EVE) where 1.2 equiv of 9 were used. [b] Yields of
isolatedproudcts. [c] Determinedby chiral-phase HPLC analysis.
[d] Starting materials were recovered. [e] DME=1,2-dimethoxyethane.
9
78[f]
66[f]
97[f]
75[f]
10
11
71[f]
16
57[f]
63
43
23
79
78
of a basic site proved crucial since protonation of the
quinuclidine moiety resulted in complete loss of catalytic
activity (8, Table 1, entry 8). In contrast to other reactions
catalyzed by urea-based catalysts,[11,12] the urea moiety (2)
proved superior to a thiourea (3), both in terms of activity and
[a] Reactions were performedat 25 8C for 24 h using 2 equiv of 9.
[b] Reactions were performedat 25 8C for 72 h using 1.2 equiv of 9.
[c] Yields of isolated products. [d] Determined by chiral-phase HPLC
analysis. [e] Values in parentheses are after recrystallisation. [f] Reaction
was performedat 4 8C. [g] Not determined because of reaction of the
phenolic nitroolefin with EVE.
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55–67% ee. Electron-deficient aromatic nitroolefins afforded
products in yields of greater than 89% (Table 2, entries 2–6),
while electron-rich aromatic nitroolefins gave products in
slightly lower yields (Table 2, entries 8 and 9). Poor con-
version was only observed in the case of the cyclohexylni-
troolefin (Table 2, entry 11). It is noteworthy that no protec-
tion of the phenolic hydroxy group was necessary (Table 2,
entry 8). In EVE, the products were obtained in lower yields
but higher enantioselectivities of 73–90% ee. Enantiomeric
enrichment of up to 99% ee was achieved by a single
recrystallization of the solid 1,4-addition products (Table 2,
entries 1 and 8).
Preliminary experiments have been performed to eluci-
date the mechanism of the reaction. The rate of the reaction
decreases with increasing equivalents of MAHT 9, which
suggests that the coordination of MAHT to the urea is crucial
for catalysis. Simple urea compounds did not mediate the
reaction (starting materials could be recovered), further
demonstrating the importance of bifunctionality for catalysis.
More detailed mechanistic insights, for example, determina-
Experimental Section
General procedure for 1,4-addition reactions of MAHT 9 to nitro-
olefins: The nitroolefin (0.67 mmol, 1.0 equiv), (303 mg,
9
1.34 mmol), and the catalyst (0.134 mmol, 20 mol%) were dissolved
in THF (2.5 mL) in a capped vial. After stirring the reactions for 24 h,
the mixture was purified by column chromatography on silica gel
(gradient of pentane/ethyl acetate 5:1 to 3:1; in the case of the
aliphatic compounds the gradient was pentane/ethyl acetate 10:1 to
5:1).
Received: May 17, 2007
Published online: August 6, 2007
Keywords: asymmetric synthesis · biomimetic synthesis ·
.
cinchona alkaloids · enzymes · organocatalysis
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