Aldrichimica Acta - Sigma-Aldrich

62
Discovering New Reactions with N-Heterocyclic Carbene Catalysis
VOL. 42, NO. 3 • 2009
goal was to intercept this nucleophile (II) with a competent
electrophile and thus expand the number of NHC-catalyzed
reactions.
Toward this end, we synthesized substrates that would not
only maximize the potential success of the reaction but also
provide interesting structural motifs (eq 9). 77 This threeatom
functionalization proceeded as envisaged in Scheme 10.
While the b-protonation step is not well-understood, it has
R1 1st H O
α
b Nu
E
2nd
HNu
R 1
H
E
III
3rd
acylation
of nucleophile
O
N N
Ar
N
R
enolate addition
N N
N
Ar
R
NHC
R 1
H
II
addition
& proton
migration
b
protonation
OH
N N
Ar
N
R
O
R 1 H
R1 OH
N N
Ar
I
N
R
extended Breslow
intermediate
Scheme 10. proposed pathway for enolate Formation and threeatom
Functionalization. (Ref. 77)
R 2
R 3
R 1
O
H
+
Me
Ph
Mes
N N
BF4
N
Me
–
11
R1 O 1. 7 (10 mol %)
(i-Pr)2EtN, CH2Cl2
H 2. MeOH
O
N
N
R 2
O
11 (20 mol %)
DBU, CH2Cl2
4 Å MS, 0 °C
R 1
R 1
Ph
4-BrC6H4
Ph
Ph
4-MeC6H4
H
Me
Me
O
R
CO2Me
1
R
dr = 20:1
99% ee (major isomer)
2
R3 R 2
H
H
MeO
F
H
H
H
a
R 1
R 2
R 3
H
H
MeO
H
H
H
H
a
N
N
Ph
Yield
69%
62%
73%
68%
80%
68%
59%
66%
a Using (E,E)-
MeC(O)CH=CH(CH 2)2CH=CHC(O)H.
O
Ph Ph
3-MeOC6H4 Ph
4-ClC6H4 Ph
Me 2-MeC6H4
Ph 4-FC6H4
Ph Pha
R 2
Yield
O
63%
60%
61%
82%
61%
71%
a 3-MeC6H4N=NC(O)Ph used.
eq 8 (Ref. 75)
eq 9 (Ref. 77)
been observed that weaker bases, such as (i-Pr) 2EtN, and their
conjugate acids, are more accommodating in this process. An
intramolecular Michael addition follows the b-protonation
step and results in the construction of a five-membered ring.
Under these conditions, catalyst regeneration is afforded by
the O-acylation of the newly formed (second) enol. However,
the addition of methanol is required to avoid hydrolysis of the
initial labile lactone products and to facilitate purification.
Importantly, when aminoindanol-derived precatalyst 7 is
used in combination with (i-Pr) 2EtN, excellent diastereo-
and enantioselectivities are achieved for a wide range of
substrates.
The success achieved with this highly diastereo- and
enantioselective intramolecular NHC-catalyzed Michael
addition led our group to investigate an intramolecular aldol
reaction. 78,79 Readily prepared symmetrical 1,3-diketones
undergo intramolecular aldol reactions to afford optically active
cyclopentene rings. In this reaction, the enol generated from
the addition of chiral, optically active NHC 10 to the aldehyde
performs a desymmetrization of the 1,3-diketone. Acylation of
the resulting alkoxide is coupled with a decarboxylation step to
afford the cyclopentene adducts with excellent enantiocontrol
(eq 10). 78,79 Importantly, degassing of the solvent leads to a
dramatic increase in yield. In some cases, unsaturated acids are
observed, and they are thought to originate from the oxidation
of the homoenolate intermediate.
The high selectivity achieved with this system is believed
to arise from a 6-membered hydrogen-bonded feature in the
Breslow-type intermediate. The enol proton behaves as a
bridge between the enol oxygen and the ketone oxygen, which
predisposes the complex to undergo the aldol reaction and
minimizes the nonbonding interactions between the catalyst
and the keto group not undergoing attack. The regeneration
of the catalyst is also a result of the hydrogen bonding in the
adduct since an anti disposition of the alkoxide and acyl azolium
groups in the adduct would inhibit subsequent intramolecular
acylation.
In order to demonstrate the intrinsic value of this
desymmetrization process, we adapted this methodology to the
synthesis of the bakkenolide family of natural products. 80,81 The
bakkanes are comprised of a cis-fused 6,5-cyclic system with
two quaternary stereogenic centers, one of which contains an
angular methyl group. This key structural element provided an
excellent opportunity to apply our methodology and provide
a modern demonstration of the power of carbene catalysis in
total synthesis. 82–84 The crucial NHC-catalyzed bond-forming
O
O
R 1
R1 R2 O
H
R 1
Ph
Ph
Ph
Ph
4-ClC 6H 4
a
10 (10 mol %)
(i-Pr)2EtN (1 equiv)
CH 2Cl 2, 40 °C, 12 h
R 2
Me
H 2C=CHCH 2
H 2C=C(Me)CH 2
(E)-PhCH=CHCH 2
Me
a
O
R1 R2 Yield
80%
70%
69%
64%
76%
51%
a O
dr = 20:1;
O
major product = O
Me H
ee
R 1
93%
83%
83%
82%
94%
96%
eq 10 (Ref. 78,79)