Organocatalytic asymmetric desymmetrization-fragmentation of cyclic ketones

Full text of DOI:10.1002/anie.200903253

Communications
DOI: 10.1002/anie.200903253
Asymmetric Synthesis
Organocatalytic Asymmetric Desymmetrization–Fragmentation of
Cyclic Ketones**
Gustav Dickmeiss, Vincenzo De Sio, Jonas Udmark, Thomas B. Poulsen, Vanesa Marcos, and
Karl Anker Jørgensen*
Within the last decade, the field of asymmetric organo-
catalysis has been the focus of immense interest and
research.[1] A myriad of catalysts and reaction protocols
have been developed to provide access to enantiomerically
enriched compounds. However, despite the numerous suc-
cesses in organocatalysis, the fundamental class of fragmen-
tation reactions remains virtually unexplored. These reactions
are useful synthetic tools, as exemplified by the synthesis of
(ꢀ )-brefeldin A by Corey and Wollenberg:[2] In an initial
step, the meso compound 1 fragments under base catalysis
Scheme 2. Organocatalytic desymmetrization–fragmentation of meso
cyclopentanones.
great importance. For example, the tert-butyldimethylsilyl
(TBS) ether derivative of 4a has been used extensively as a
starting material in the synthesis of prostaglandins and their
analogues (Scheme 3).[3]
Although compound 4a and derivatives in which the
hydroxy group is protected have been approached previously
by desymmetrization of the corresponding meso com-
pounds,[4–6] the method described herein is the first example
of an organocatalytic,[7] asymmetric synthesis of 4-hydroxy-
cyclopent-2-enones 4 by the desymmetrization–fragmenta-
tion of epoxycyclopentanones 3. Furthermore, various one-
Scheme 1. Synthesis of (ꢀ)-brefeldin A by Corey and Wollenberg.
into chiral, racemic 2, which is subsequently con-
verted into the target compound (Scheme 1).
Considering the importance of optically active
cyclopentenone derivatives as starting materials for
the synthesis of biologically active compounds, we
envisioned that a general asymmetric protocol for
the desymmetrization of not only the meso com-
pound 1, but also of the related epoxides 3, might be
a highly attractive new fundamental chemical trans-
formation. Herein we present the development of
the organocatalytic asymmetric desymmetrization–
fragmentation of meso compounds with a cyclo-
pentanone skeleton (Scheme 2). In particular, the
conversion of epoxycyclopentanones 3 into 4 is of
Scheme 3. Examples of prostaglandins and analogues that have been synthesized
from TBS-protected 4a.
[*] G. Dickmeiss, V. De Sio, J. Udmark, Dr. T. B. Poulsen, V. Marcos,
Prof. Dr. K. A. Jørgensen
pot transformations of the optically active products are
demonstrated, and the concept is extended to the kinetic
resolution of a chiral, racemic epoxycyclohexanone. Finally, a
simplified mechanistic model for the reaction is proposed.
We selected the transformation of diethyl 3-oxobicyclo-
[3.1.0]hexane-6,6-dicarboxylate (1) into diethyl 2-(4-oxocy-
clopent-2-enyl)malonate (2) as a model reaction for the
organocatalytic asymmetric desymmetrization–fragmenta-
tion (Scheme 4). No enantioselective procedure had been
described previously for the synthesis of this optically active
The Danish National Research Foundation: Center for Catalysis
Department of Chemistry, Aarhus University
8000 Aarhus C (Denmark)
Fax: (+45)8919-6199
E-mail: kaj@chem.au.dk
[**] This research was funded by a grant from The Danish National
Research Foundation and the OChemSchool.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903253.
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Table 1: Organocatalytic asymmetric desymmetrization–fragmentation
of epoxide 3a.[a]
Entry
Catalyst
t [h]
ee [%][b]
1
2
6b
7a
7b
7b
24
15
48
15
racemic
53 (R)
90 (R)
90 (R)
3
4[c]
[a] Reactions were carried out with 0.05 mmol of 3a. All reactions
proceeded to complete conversion, as determined by 1H NMR spec-
troscopy of the crude reaction mixture. [b] The ee value was determined
by HPLC on a chiral stationary phase by using a Chiralpak OJ column
after derivatization of the product as the corresponding dimethylphe-
nylsilyl ether. The absolute configuration was determined by comparison
of the optical rotation of 4a with a literature value.[10] [c] The reaction was
carried out with 0.4 mmol of 3a. The product was obtained in 93% yield
after flash chromatography. Bn=benzyl, TIPS=triisopropylsilyl.
Scheme 4. Organocatalytic asymmetric desymmetrization–fragmenta-
tion of 1 as a model reaction.
compound. When we attempted the reaction with quinine
(5a) as the organocatalyst, cyclopentenone 2 was obtained
with 40% ee, which encouraged us to screen further catalysts
and reaction conditions (see the Supporting Information). We
found that bifunctional thiourea–cinchona alkaloid catalysts,
such as 6a and 6b, afforded superior results.[8] Accordingly,
when 10 mol% of the quinidine-derived thiourea catalyst 6b
was used, the product (S)-2 was isolated in 84% yield and
with 96% ee (Scheme 4), whereas (R)-2 was obtained with
90% ee when 6a, the quasienantiomer of 6b, was used as the
catalyst (see the Supporting Information).
Following the initial encouraging results, which confirmed
the possibility of effectively desymmetrizing meso cyclopen-
tanones, we focused our attention on the conversion of
epoxides 3 into the very important 4-hydroxycyclopent-2-
enone products 4. However, when we carried out
the desymmetrization–fragmentation of 6-oxabicyclo-
[3.1.0]hexan-3-one (3a) under the conditions found suitable
for 1, racemic 4-hydroxycyclopent-2-enone 4a was formed
(Table 1, entry 1). Nevertheless, with catalyst 7a, product 4a
was formed with 53% ee (Table 1, entry 2). Thus, the direct
attachment of the thiourea moiety to the quinoline system in
the catalyst appeared to provide selectivity.[9] The replace-
ment of the benzyl group with the bulkier TIPS protecting
group led to a satisfying improvement in the ee value of 4a to
90% (Table 1, entry 3). Under these conditions, 4a was
isolated in excellent yield (93%) with 90% ee (Table 1,
entry 4).
The protocol was then extended to epoxides 3b and 3c,
which have aliphatic and aromatic substituents, respectively,
in the 3- and 4-positions; the products 4b and 4c contain
quaternary stereogenic centers (Scheme 5). When 1,5-
dimethyl-6-oxabicyclo[3.1.0]hexan-3-one (3b) was treated
with catalyst 7b under the conditions identified for 3a,
optically active (R)-4-hydroxy-3,4-dimethylcyclopent-2-
enone (4b)[11] was formed in 90% yield and with good
enantioselectivity (87% ee). In the case of the phenyl-
substituted analogue, 1,5-diphenyl-6-oxabicyclo[3.1.0]hexan-
3-one (3c), excellent selectivity was observed with catalyst 6b.
Following a short optimization process (results not shown),
Scheme 5. Desymmetrization–fragmentation of substituted epoxides,
and the X-ray crystal structure of product 4c. Reagents and conditions:
a) catalyst 7b (10 mol%), CH2Cl2 (0.10m), 408C, 28 h, 90%, 87% ee;
b) catalyst 6b (10 mol%), CH2Cl2 (1.0m), ꢁ208C, 18 h, 92%, 93% ee
(97% ee after recrystallization).
(S)-4-hydroxy-3,4-diphenylcyclopent-2-enone (4c) was syn-
thesized in 92% yield and with 93% ee. The absolute
configuration of 4c was verified by X-ray crystallography[12]
after recrystallization (Scheme 5).
To account for the selectivity of the asymmetric fragmen-
tation, we propose a mechanism in which the thiourea part of
the catalyst interacts with the carbonyl functionality of the
cyclopentanone and thus increases the acidity of the
a-hydrogen atoms. The quinuclidine moiety then removes
one of the a-hydrogen atoms stereoselectively by deprotona-
tion.
It is notable that the substrates 1 and 3c, giving 96% and
93% ee, respectively, when being exposed to the same catalyst
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6b, show a reversed orientation of the C X bond being
cleaved. Accordingly, the leaving group of the bond-breaking
process is opposite in the two products. A hypothesis for this
observation is outlined in Scheme 6. The cyclopropane ring in
The addition of a carbon nucleophile was also possible in a
one-pot reaction. When diethyl malonate and a base were
added after the consumption of the starting material, the trans
adduct diethyl 2-((1S,2R)-2-hydroxy-4-oxocyclopentyl)malo-
nate (9) was formed in 39% yield with 90% ee and d.r. > 95:5
(Scheme 7). The configuration of the newly constructed
stereocenter was determined after the exposure of 9 to
methanesulfonyl (Ms) chloride/NEt3. Under these conditions,
the hydroxy group was eliminated to yield (R)-2, the
configuration of which had been determined earlier.
Owing to the mild conditions under which vinylic boronic
acids undergo rhodium-catalyzed addition to a,b-unsaturated
ketones, we finally chose to apply a highly diastereoselective
protocol[15] to introduce propenyl (!10a) and styryl (!10b)
substituents. Following opening of the epoxide under the
previously determined conditions, the crude reaction mixture
was filtered through silica gel and treated with the corre-
sponding boronic acid in the presence of catalytic [{Rh-
(cod)Cl}2] and Cs2CO3. This procedure provided 10a in two
steps in 84% yield. An ee value of 90% and diastereomeric
ratio of 98:2 were obtained. The structure of 10a is closely
related to the core of enprostil (Scheme 3) and other
prostaglandin derivatives. Product 10b was formed in 82%
yield with 90% ee and d.r. 98:2 (Scheme 7). The relative
configuration of 10b was determined by elimination of the
hydroxy group with MsCl/NEt3, followed by standard hydro-
genation with H2 and catalytic Pd/C to yield (S)-3-phenethyl-
cyclopentanone, a known compound.[16]
Scheme 6. Mechanistic proposal for the desymmetrization–fragmenta-
tion of 1 and 3c.
1 and the phenyl substituents attached to the epoxide ring in
3c are oriented away from the quinuclidine moiety of the
catalyst to avoid steric repulsion. In this conformation,
selective deprotonation yields the observed products, (S)-2
and (S)-4c, by an E1cb-like mechanism.[13]
Having synthesized a variety of optically active a,b-
unsaturated ketones with a cyclopentanone skeleton, we
hoped to exploit this functionality in a tandem Michael
addition reaction. Accordingly, the desymmetrization of 3a in
the presence of BnSH led to subsequent addition to
give (3S,4R)-3-(benzylthio)-4-hydroxycyclopentanone (8;
Scheme 7).[14] Remarkably, the presence of BnSH had a
beneficial effect on the enantioselectivity: 8 was formed in
90% yield with 94% ee and d.r. 10:1.
To elaborate the new reaction type in a conceptually
different approach, we explored the possibility of using
catalyst 7b for the kinetic resolution of chiral, racemic
7-oxabicyclo[4.1.0]heptan-3-one (11; Scheme 8). We sus-
Scheme 8. Organocatalytic kinetic resolution of 11.
pected that 7b might show different catalytic activity towards
the two enantiomers of 11. Product 12 obtained in this
reaction has been used as a starting material in a number of
syntheses of biologically active compounds.[17] We were
pleased to find that when racemic 11 was exposed to catalyst
7b (2.5 mol%) at ꢁ208C, enantiomerically enriched (R)-12[18]
was formed in 48% yield and with 69% ee.
In summary, we have developed a protocol for the high-
yielding desymmetrization–fragmentation of a number of
meso cyclopropane cyclopentanones and epoxycyclopenta-
nones under the catalysis of thiourea-containing cinchona
alkaloids to give optically active products with good to
excellent enantioselectivities. Furthermore, we developed
organocatalytic asymmetric one-pot and tandem desymmet-
rization–fragmentation–Michael addition reactions of an
Scheme 7. Organocatalytic desymmetrization–Michael addition of 3a.
Reagents and conditions: a) BnSH (2 equiv), 7b (10 mol%), CH2Cl2
(0.10m), 408C, 2 h, 90%, 94% ee; b) 1) 7b (10 mol%), CH2Cl2
(0.10m), 408C, 45 min; 2) Cs2CO3 (1.1 equiv), CH2(CO2Et)2 (1.5 equiv),
room temperature, 30 min, 39%, 90% ee; c) 1) 7b (10 mol%), CH2Cl2
=
(0.10m), 408C, 45 min; 2) filtration; 3) RCH CHB(OH)2 (1.2 equiv),
[{Rh(cod)Cl}2] (3 mol%), Cs2CO3 (10 mol%), dioxane/H2O (4:1;
0.33m), room temperature; R=Me: 30 min, 84%, 90% ee; R=Ph:
2 h, 82%, 90% ee. cod=1,5-cyclooctadiene.
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Finally, this organocatalytic concept was extended to the
kinetic resolution of a racemic epoxycyclohexanone, which
was converted into optically active 4-hydroxycyclohex-2-
enone with promising enantioselectivity.
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Received: June 16, 2009
Published online: August 5, 2009
Keywords: asymmetric catalysis · cinchona alkaloids ·
.
desymmetrization · fragmentation · thiourea functionality
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