Synthesis of enantioenriched α,α-disubstituted cyclopentenes catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1055/s-0028-1083284

The desymmetrization of 1,3-diketones using N-heterocyclic carbenes results in the formation of highly enantioenriched cyclopentenes in good yield. The reaction proceeds through a catalytic intramolecular aldol reaction and subsequent β-lactone formation.

Full text of DOI:10.1055/s-0028-1083284

PRACTICAL SYNTHETIC PROCEDURES
687
Synthesis of Enantioenriched a,a-Disubstituted Cyclopentenes Catalyzed by
N-Heterocyclic Carbenes
C
arbene-Cataly
r
S
ynt
i
hesis
o
c
f
a
,
a
-Disubstituted
M
Cyclopentene
s
. Phillips, Manabu Wadamoto, Karl A. Scheidt*
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA
Fax +1(847)4672184; E-mail: scheidt@northwestern.edu
PSP
Received 5 August 2008; revised 23 September 2008
No148
Abstract: The desymmetrization of 1,3-diketones using N-heterocyclic carbenes results in the formation of highly enantioenriched cyclo-
pentenes in good yield. The reaction proceeds through a catalytic intramolecular aldol reaction and subsequent b-lactone formation. The
expulsion of carbon dioxide at mild reaction temperatures affords the cyclopentene products.
Key words: carbenes, asymmetric catalysis, Umpolung, b-lactones, aldol reactions
O
O
O
O
Ph
Ph
Ph
Ph
O
NHC catalyst
– CO2
Me
Ph
Me
Ph
Me
O
H
CHO
80% yield
93% ee
Scheme 1
R2
Ar
N
Introduction
OH
H
OH
R2
N
Ar
Ar
O
H+
N
N
N
R1
R1
Generating enantioenriched compounds from simple pre-
cursors is a persistent goal in organic chemistry.1,2 De-
symmetrization reactions of achiral starting materials
have become an efficient and topologically interesting ap-
proach to produce optically active products.3–6 The utili-
zation of this strategy can be advantageous particularly for
the stereoselective formation of quaternary carbon cen-
ters.7–9 Herein, we report an efficient and practical method
for the construction of a,a-disubstituted cyclopentene
rings through an aldol reaction catalyzed by a chiral N-
heterocyclic carbene (NHC) (Scheme 1).10
R1
H
N
N
N
N
R2
+
enolate
equivalent
homoenolate
equivalent
Scheme 2
the catalyst followed by a decarboxylation to form enan-
tioenrinched cyclopentenes (Scheme 3).21 The achiral
symmetric substrates are readily available from simple
palladium(0)-catalyzed alkylations of 1,3-diketones with
The opportunity to catalyze aldol reactions emerged with butadiene monoepoxide followed by oxidation. In this
our previous studies into NHC-catalyzed processes.11–15 manner, substitution in the 2-position can be varied and
The application of carbene catalysis in these studies in- the a,b-unsaturated aldehyde is easily appended.
volves the protonation of an in situ generated homoenolate
To determine the optimal reaction conditions for this pro-
to produce a reactive enol intermediate (Scheme 2).16–18
cess, several combinations of azolium salts and bases
With the appropriate Lewis base precursor (azolium salt)
were surveyed. While 1,8-diazabicyclo[5.4.0]undec-7-
ene in conjunction with any pre-catalyst (Table 1, entry 1)
does not result in product formation, employment of a
stoichiometric amount of N,N-diisopropylethylamine with
and conditions, the a,b-unsaturated aldehyde can serve
as the progenitor for either homoenolate or enolate reac-
tivity.19
Our goal was to leverage our knowledge of carbene-cata- a triazolium salt is quite successful. A variety of L-phenyl-
lyzed Michael reactions20 to produce an aldol-mediated alanine-derived azolium salts deliver the cyclopentene
desymmetrization of 1,3-diketones. In the proposed reac- product in moderate yield but the selectivity obtained with
tion pathway, b-lactone formation would then regenerate these salts is not optimal (entries 2–4). Interestingly, em-
ployment of pre-catalyst C allows for the synthesis of the
opposite enantiomer even though the catalyst structure is
still derived from L-phenylalanine. We are investigating
this unusual observation and details on this study are
SYNTHESIS 2009, No. 4, pp 0687–0690
Advanced online publication: 19.12.2008
DOI: 10.1055/s-0028-1083284; Art ID: M04108SS
x
x
.
x
x
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

688
E. M. Phillips et al.
PRACTICAL SYNTHETIC PROCEDURES
O
O
O
R1
Table 1 Reaction Optimization
R2
H
R1
R1
Ph
O
Ph
Me
R2
A–D (10 mol%)
O
O
R1
addition
O
Ph
CH2Cl2, 12 h
R3
Me
H
Ar
N
N
Ph
O
2
– CO2
1
N
R3
Basea
Azolium Yieldb
eec
(%)
NHC
O
O
N
Entry
Temp
(°C)
R1
O
R2
O
N
O
salt
A
A
B
(%)
R1
N
R1
IV
H
R2
Ar
1
23
23
23
23
23
23
40
40
DBU
0
–
OH
R1
I
2
i-Pr2EtN
i-Pr2EtN
i-Pr2EtN
i-Pr2EtN
i-Pr2EtN
i-Pr2EtN
i-Pr2EtN
47
38
45
40
66
80
70
–83
–76
51
94
94
93
93
+
acylation
OH
(R4)3NH
(R4)3N
β-protonation
3
R3
R3
O
aldol
reaction
R1
O
N
R2
O
4
C
D
D
D
D
N
N
R1
N
+
R1
N
5
R2
N
Ar
+
H
OH
Ar
O
R1
6d
7d
8d,e
III
II
Scheme 3
forthcoming. Utilization of azolium salt D results in simi-
lar yields, but the selectivity of this reaction greatly im-
proves (entry 5). Further investigation revealed that the
incorporation of oxygen into the reaction may be affecting
the yield of desired compounds due to the isolation of the
unsaturated carboxylic acid derived from 1. In order to
circumvent this potential problem, dichloromethane and
N,N-diisopropylethylamine were degassed prior to use.
The interaction of a strongly nucleophilic Lewis base,
such as an NHC, and oxygen is indeed plausible.19 To the
best of our knowledge, there are no literature examples to
date that specifically examine this parameter and report
that the exclusion of oxygen directly increases yields us-
ing N-heterocyclic carbenes.22 Future carbene catalysis
efforts may well be impacted by this curious, yet critical,
observation.
Me
Me
N
N
O
O
N
Me
N
Me
+
N
+
N
R
R
Ph
R = H (A)
R = Me (B)
R = Ph (C)
Me
Me
–
Ph
–
BF4
Ph
D
BF4
a 1 equiv of base used.
b Isolated yields.
c Determined by HPLC (Chiralcel OD-H).
d Careful exclusion of oxygen.
e 5 mol% of D.
dated under the reaction conditions with similar enantio-
selectivity (entry 7). Increasing the size of this group to
allyl, methallyl, or cinnamyl groups results in good yields
with a small decrease in the levels of selectivity (entries
8–10).
To our delight, this simple procedure to minimize the ox-
ygen content increased the yield to 66% (entry 6). Finally,
slightly heating the reaction ensures that the b-lactone in-
termediate fully decarboxylates23,24 to form the cyclopen-
tene product in 80% yield (entry 7). Importantly, the
increased temperature does not diminish the enantioselec-
tivity of the reaction (93% ee). Decreasing the catalyst
loading leads to similar levels of selectivity but lower
yields (entry 8).
Surprisingly, alkyl ketones allow for the isolation of the b-
lactones with excellent diastereoselectivity and enantio-
selectivity (entries 11 and 12). It is interesting to note the
favored diastereomer when employing a cyclic or acyclic
diketone. The acyclic diketone substrate provides a b-lac-
tone product with the methyl group anti to the tertiary
alkoxide (entry 11). However, the relationship is syn with
the cyclic diketones (entries 12 and 13). We believe that
in these cases, the relative stereochemistry of the methyl
group and lactone is determined by the ability of the 1,3-
diketone to form a hydrogen-bonded network during the
aldol reaction. Unfortunately, indanedione-derived com-
pound 13 was low yielding and had low levels of enan-
tioselectivity (entry 13).
Scope and Limitations
Various 1,3-diketones with different substitution patterns
were subjected to the optimal reaction conditions
(Table 2). Aryl ketones are good substrates for this pro-
cess, save for electron-rich aryl ketones (entry 6). We
have found that these reactions can be scaled up to pro-
duce large amounts of product without diminishing the
yield or selectivity (entry 2). Substitution in the 2-position
can be varied as well, but the selectivity decreases when
the groups become too large. Ethyl groups are accommo-
In conclusion, a direct route to highly functionalized cy-
clopentene rings has been developed. By using a chiral
azolium salt as a pre-catalyst, a desymmetrization of 1,3-
diketones through a tandem aldol/acylation reaction oc-
curs to form b-lactones. When a decarboxylation is cou-
pled to the desymmetrization event, cyclopentene rings
Synthesis 2009, No. 4, 687–690 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES Carbene-Catalyzed Synthesis of a,a-Disubstituted Cyclopentenes
689
Table 2 Substrate Scope
generate homoenolate and enolate intermediates with
unique properties are continuing in our laboratory and will
be reported in due course.
O
R1
R2
O
R1
O
D (10 mol%)
i-Pr2EtN (1 equiv)
O
R1
H
R2
CH2Cl2, 40 °C
R1
Herein we describe the procedure for the desymmetrization of 1,3-
diketones catalyzed by N-heterocyclic carbenes.
Entry R1
R2
Cyclopentene
Yielda eeb
(%) (%)
[(R)-1-Methyl-2-phenylcyclopent-2-enyl](phenyl)methanone
(2); Typical Procedure
1
Ph
Me
Me
Me
Me
Me
Me
Et
2
2
3
4
5
6
7
8
80
78
76
60
65
<5
73
70
93
91
94
94
93
nd
90
83
In a glove-box, under inert atmosphere, to a flame-dried round bot-
tom flask equipped with magnetic stirring bar was added azolium
salt D (12.6 mg, 0.03 mmol) and enal 1 (92 mg, 0.3 mmol). The
flask was sealed with a rubber septum. The flask was charged with
degassed CH2Cl2 (6 mL, 0.05 M). Once the material dissolved, de-
gassed i-Pr2NEt (54 mL, 0.3 mmol) was added via syringe. The flask
was removed from the glove box and heated to 40 °C under N2 at-
mosphere for 12 h. The soln was diluted with hexanes (2 mL) and
was directly subjected to flash column chromatography (silica gel,
5% to 12% EtOAc–hexanes) to afford 2 (63 mg, 80%) as a colorless
oil. For large-scale reactions the material was first washed with sat.
aq NH4Cl (20 mL). The layers were separated and the aqueous layer
was extracted with CH2Cl2 (2 × 20 mL). The combined organics
were dried (Na2SO4), filtered, and concentrated. The residue was
then purified by flash column chromatography (silica gel, 5% to
12% EtOAc–hexanes).
2c Ph
3
4
5
6
7
8
4-ClC6H4
4-MeC6H4
3-MeC6H4
4-MeOC6H4
Ph
Ph
allyl
O
Ph
O
Ph
Ph
O
H
Ph
Me
O
O
9
69
64
83
82
HPLC (Chiralcel OD-H, 3% i-PrOH–hexanes, 1 mL/min): tR = 5.87
(major), 9.22 min (minor).
Me
Ph
O
IR (film): 3057, 2962, 2929, 2847, 1670, 1596, 1496, 1446, 1372,
1261, 1240, 1172, 976, 758, 692 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.98 (d, J = 7.7 Hz, 2 H), 7.40 (t,
J = 7.3 Hz, 1 H), 7.38–7.34 (m, 4 H), 7.21 (t, J = 7.3 Hz, 2 H), 7.15
(m, 1 H), 6.36 (s, 1 H), 2.73–2.60 (m, 3 H), 1.99–1.97 (m, 1 H), 1.55
(s, 3 H).
13C NMR (125 MHz, CDCl3): d = 205.0, 148.6, 137.5, 135.2, 132.0,
129.3, 128.9, 128.7, 128.3, 127.5, 126.5, 62.1, 39.0, 31.1, 24.1.
GC-MS (CI): m/z [M + H]+ calcd for C19H19O: 263.1; found: 263.0.
9
O
Ph
O
H
Ph
10d
Ph
Ph
O
Ph
10
Bn
Bn
O
O
O
O
11d
12d
65e 93
O
Bn
H
Me
H
Me
Bn
Acknowledgment
11
O
O
O
Funding for this research was provided by NIH/NIGMS (RO1
GM73072). We thank Abbott Laboratories, Amgen, GlaxoSmith-
Kline, AstraZeneca, and Boehringer Ingelheim for generous unre-
stricted support. We thank FMCLithium, Wacker Chemical
Company, Sigma-Aldrich, and BASF for providing reagent sup-
port.
O
O
Me
51e 96
O
H
H
Me
12
O
O
O
O
O
Me
13d
36e 15
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H
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O
13
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Synthesis 2009, No. 4, 687–690 © Thieme Stuttgart · New York