Catalytic, asymmetric inverse electron demand hetero diels-alder reactions of o-benzoquinone derivatives and ketene enolates

Article abstract of DOI:10.2533/chimia.2007.240

We present an array of [4+2] cycloaddition reactions between ketene enolates, catalytically derived from acid chlorides and cinchona alkaloid nucleophilic catalysts in the presence of stoichiometric base, and o-benzoquinone derivatives. These cycloadditio

Full text of DOI:10.2533/chimia.2007.240

ORGANOCATALYSIS
240
doi:10.2533/chimia.2007.240
CHIMIA 2007, 61, No. 5
Chimia 61 (2007) 240–246
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Catalytic, Asymmetric Inverse Electron
Demand Hetero Diels-Alder Reactions of
o-Benzoquinone Derivatives and Ketene
Enolates
Daniel H. Paull, Jamison Wolfer, James W. Grebinski, Anthony Weatherwax, and Thomas Lectka*
Abstract: We present an array of [4+2] cycloaddition reactions between ketene enolates, catalytically derived from
acid chlorides and cinchona alkaloid nucleophilic catalysts in the presence of stoichiometric base, and o-benzo-
quinone derivatives. These cycloaddition reactions proceed with excellent stereochemical control (up to >99%
ee). In fact, for both the o-benzoquinone imide and the o-benzoquinone diimide manifolds, these Diels-Alder reac-
tions occurred with uniformly >99% ee. The wide scope of this methodology provides access to a diverse range
of biologically and synthetically useful chiral products, including α-hydroxyesters, non-natural α-amino acids,
quinoxalinones, and many others, all with remarkable, catalytic control of regio- and stereochemistry.
Keywords: Asymmetric catalysis · Bifunctional catalysis · [4+2] Cycloaddition · Hetero Diels-Alder ·
Ketene enolates
1. Introduction
reaction with a chiral ketene derived enolate:
R
R
Catalytic, enantioselective cycloaddition
reactions of p-quinones are well docu-
R
Y
O
Nu
R
Y
O
mented.[1] The products of these reactions
R
X
R
X
R'
are potentially very useful in the realm of
natural product synthesis. However, little
work has been done on the catalytic, asym-
metric reactions of o-quinones and deriva-
tives. o-Quinones have a potentially much
richer reactivity spectrum – cycloaddition
reactions may involve the ring carbons (as
in the well-studied p-quinone isomers), but
more interestingly, reactions may proceed
through the o-heteroatoms to provide useful
bicyclic products (Scheme 1).
R'
R
R
X, Y = O, NR
R
R
R
R'
R
R
O
R
R
O
R
N
R
O
N
N
R
R
R'
R
R'
o-quinones
o-quinone imides
o-diimides
Scheme 1. o-Benzoquinones as substrates for asymmetric ketene enolate
cycloadditions
While the products of these cycload- treatment of Alzheimer’s disease.[2] Chiral
ditions are interesting and useful as chiral α-oxygenatedcarboxylicacidproductscan
building blocks for organic synthesis, both also be derivatized in a variety of useful
they and their readily obtained derivatives ways. o-Quinone imides can provide easy
show even greater utility and promise in a access to invaluable, non-natural α-amino
variety of physiological applications. For acids (both protected and unprotected),
example, the α-hydroxy esters obtained which find uses in all areas of biochemical
from o-quinones have found application study. Quinone imides also provide access
as inhibitors of amyloid-β (Αβ) protein to oxazinones and oxazines, bicyclic prod-
production, and thus show promise in the ucts that are useful as antitumor agents,
*Correspondence: Prof. T. Lectka
Department of Chemistry
Johns Hopkins University
3400 N. Charles St.
Baltimore, MD 21218, USA
Tel.: +1 410 516 6448
Fax: +1 410 516 7044
E-Mail: lectka@jhu.edu

ORGANOCATALYSIS
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CHIMIA 2007, 61, No. 5
Cl
Cl
Cl
Cl
Cl
O
Me
OMe
Cl
Cl
O
O
Cl
Cl
O
O
Cl
Cl
O
O
N
N
O
O
O
O
Ph
Bn
N
N
R
a
CH3
b
Cl
c
Cl
O
O
O
O
H
O
90% ee,90% yield
99% ee,72% yield
99% ee,91% yield
Hünig's base
o
R
T
HF, -78 C
Fig. 1. o-Chloranil-derived cycloadducts
benzoylquinidine ( BQd )
chiral ketene enolate
R
R
R
Scheme 2. Catalytic generation of ketene enolate
R
R
O
O
O
R
R
OH
O
R'
CAN
NuH
R'
Nu
HO
Nu
R'
O
R
O
Cl
Cl
Br
Br
Cl
Cl
O
O
O
O
Me
O
O
O
Br
Br
O
O
Scheme 4. Derivatization of benzodioxinone cycloadducts
MeO
a
b
c
d
ployed these conditions with all substrates.
O
Hünig's base
HF
We also screened o-bromanil, which was
found to form product f (Scheme 3) in high
ee (95%), and 90% yield. 9,10-Phenan-
threnequinone was screened using similar
conditions; its reactivity proved to be much
lower than o-chloranil. However, when the
reaction temperature was raised to 0 °C, re-
action occurred sluggishly to afford product
in reasonable yield. On the other hand, 4,5-
dimethoxy-o-quinone failed to provide ap-
preciable product under any conditions.
Given the superiority of o-chloranil in
our initial tests, we decided to investigate
its reaction with a variety of acid chlorides.
For example, dihydrocinnamoyl chloride
performed similarly, affording product
1
0 mol% BQd
T
H C
3
Cl
Cl
Br
n
o detecte
cyclo uct
O
d
add
O
O
Cl
Cl
O
O
Br
Br
O
O
O
O
g
e
CH3
Cl
CH3
Br
CH3
f
9
9% ee,91% yield
95% ee,90% yield
89% ee,60% yield
Scheme 3. Preliminary o-quinone reactions
topoisomerase inhibitors, and antibiotics.[3]
o-Benzoquinone diimides produce quinox-
alinones and their quinoxaline derivatives,
all of which exhibit a wide range of bio-
logical activity including antiviral effects,
particularly against retroviruses such as
HIV.[4]
2. o-Quinones
c (Fig. 1) in high ee (99%). Additionally,
The chemistry of o-quinones has been
extensively outlined.[7] Many isolable o-
quinones are known in the literature, and
α-arylacetyl chlorides proved to be excel-
lent substrates. For example, phenylacetyl
many more can be made through straight- chloride generated product b (Fig. 1) in
forward catechol oxidations.[8] Recently, high yield (90%) and good ee (90%). Us-
The use of chiral, catalytically-derived
Pettus et al. have reported a very useful
synthesis of o-quinones from phenols using
hypervalent iodane oxidants.[9] In many in-
stances o-quinones can be isolated, but they
are also commonly used in situ. o-Quinone
cycloadditions give rise to several different
product classes, depending on the reaction
partners.[10] For example, reactions with
acetylenes may afford bridged bicyclic ad-
ducts,[11] whereas cycloadditions with nu-
cleophilic alkenes, such as enol ethers and
enamines, are anecdotally noted to proceed
through the quinone oxygens.[12] Since ke-
tene enolates are close in structure and re-
activity to these substrates, we anticipated
reaction at the oxygen atoms as well.
ing BQd as catalyst, the (R)-enantiomer
zwitterionic ‘ketene’ enolates have pro-
vided the means for the synthesis of di-
verse, optically enriched products. Chiral
ketene enolates are well known for their
highly enantioselective reactions to form
β-lactones and β-lactams via [2+2] cy-
cloaddition with aldehydes and imines.[5]
However, previously, [4+2] cycloaddition
reactions of ketene enolates were virtually
formed preferentially. The (S)-enantiomers
can be obtained in similarly high enanti-
oselectivity when benzoylquinine (BQ) is
used. This sense of induction held for all
quinone derivative substrates, as well as all
acid chlorides, and is consistent with other
asymmetric reactions that have employed
these cinchona alkaloid derivatives to cata-
lytically generate ketene enolates.[14]
unknown. The ketene enolates are formed
The o-chloranil-derived cycloadducts
from acid chlorides and a catalytic nu-
cleophile, benzoylquinidine (BQd), or its
pseudoenantiomer benzoylquinine (BQ),
in the presence of a stoichiometric base
(Scheme 2).[6] We recently discovered
that these catalytically generated chiral
nucleophiles can be used to initiate a cy-
cloaddition reaction with a wide variety of
o-benzoquinone derivatives to give [4+2]
bicycloadducts in good to excellent yield
and very good to excellent enantiomeric
excess (up to >99% ee).
can be further modified to produce chiral,
α-oxygenated carboxylic acid derivatives
(Scheme 4). For example, methanolysis
of benzodioxinone b (Fig. 1) followed by
ceric ammonium nitrate (CAN) oxidation
affords (+)-methylmandelate (b, Fig. 2) in
excellent yield (95%) and ee (90%). For
maximum utility, reaction with the nucleo-
phile (H2O, ROH, or RNH2) may occur in
Our initial screen employed o-chloran-
il, butyryl chloride, and benzoylquinidine
(BQd) as the chiral nucleophile (10 mol%)
in the presence of Hünig’s base (1 equiv.)
in THF at –78 °C.[13]
The yield of the reac-
the same pot as the cycloaddition. Depend-
ing on how activated the product aromatic
ring is, the nucleophilic ring opening may
tion was an excellent 91% and the ee was
99% (e, Scheme 3). Henceforth, we em-

ORGANOCATALYSIS
242
CHIMIA 2007, 61, No. 5
inexpensive, it can be readily acylated with
a virtually limitless variety of substituents,
HO
O
HO
O
HO
O
and is easily oxidized to the corresponding
quinone imide. The chlorines in the 4- and
5-positions are present to block undesired
reactivity at the quinone ring, as well as to
enhance the overall electrophilicity of the
H C
O
Me
Ph
O
Me
Bn
OMe
3
a
b
c
99% ee,88% yield
99% ee,86% yield 90% ee,95% yield
system.
Fig. 2. α-Hydroxyester derivatives
We found that reaction of various com-
binations of acid chlorides and quinone
imides, in the presence of 10 mol% BQd
O
R
R
R
R
R
R
R
and Hünig’s base in THF at –78 °C, formed
the desired cycloadducts in good yield and
R''
R
R
OH
R
R
O
N
R
R
O
N
R
R
O
N
O
R''
Pb(OAc)
[red]
Cl
4
B
Qd/ B
Q
uniformly excellent ee (>99% ee in all
NH
R''
b
ase
cases, Fig. 3).[18] The benzoxazinone cy-
COR'
COR'
C
OR'
R
C
O
R'
cloadducts are also readily converted into
1,4-b
e
nzoxazines
1,4-b
e
nzoxazinones
benzoxazines. A simple reduction with di-
methyl sulfide-borane complex[19] leads to
the corresponding benzoxazine (Scheme 7)
Scheme 5. Synthesis of optically active benzoxazinones and benzoxazines
in good yield and with full retention of ee.
Oxazines are found in the core structure of
many medicinally important compounds,
including Levaquin.
The efficient synthesis of non-natural
α-amino acid derivatives has been a para-
mount goal of asymmetric catalysis for
Cl
Cl
O
O
H
N
Cl
Cl
O
O
R
1. R''OH
2. CAN
O
Nu cat.
base
Nu
O
N
R
OR''
O
COR'
R'
R
Cl
R
N
more than a generation. Many approaches
to the synthesis of these compounds rely on
COR'
metal-based catalysts, for example, asym-
Scheme 6. Quinone imides as amino acid templates
metric hydrogenation[20] and Lewis acid
catalyzed alkylations.[21] The O’Donnell
phase-transfer system is a good example of
an ‘organocatalyzed’ process.[22] One other
study published in 2001, Nicolaou et al. ex-
plored the use of o-benzoquinone imides as
be fast, allowing CAN oxidation to occur in
advance is represented by the asymmetric
the same pot as well. Thus, the quinone can
Diels-Alder dienes, finding that they react
through the N and O atoms, as desired.[16]
Importantly, their reactivity can be tuned by
modifying the substituent on N. For exam-
ple, an electron-withdrawing group (such
as an acyl group) on the nitrogen should en-
hance the electrophilicity towards the eno-
late. Initially we chose to screen quinone
imides derived from 2-amino-4,5-dichloro-
phenol[17] as α-amino acid templates for a
variety of reasons – the starting material is
Strecker reaction, which can be catalyzed
be thought of as a ‘template’for α-hydroxy-
carboxylic acid and ester synthesis. Several
other cycloadducts were likewise converted
to optically active α-hydroxyesters (Fig. 2).
In each case, the reaction proceeds in high
yield and with full retention of optical ac-
tivity.
by either metal-based or organic systems.[23]
We have developed a complementary ap-
proach to the synthesis of α-amino acid
derivatives that relies on an asymmetric cy-
cloaddition of o-benzoquinone imides with
chiral ketene enolates. The cycloadducts are
derivatized in situ to provide the α-amino
acid derivatives in high chemical yield, and
very high enantioselectivity. As a testament
to the flexibility of this methodology, a wide
3. o-Benzoquinone Imides
o-Benzoquinone imides are intriguing
for several reasons. The products of their
cycloaddition with ketene enolates are
Cl
chiral benzoxazinones and benzoxazines
Cl
O
O
O
O
Me
O
O
O
O
(Scheme 5), interesting compounds with
biological potential for which few asym-
metric syntheses exist. For example, they
have been investigated as antitumor agents,
as selective inhibitors of drug metabolism
and topoisomerase,[3] and have been shown
to possess promising neuroprotective an-
tioxidant activity.[15] Prescription drugs,
such as the new generation antibiotic Leva-
quin (levofloxacin) for example, are also
oxazines.[3d] Perhaps most importantly,
o-benzoquinone imides can function as a
scaffold for the synthesis of optically ac-
tive non-natural α-amino acid derivatives
(Scheme 6).
Cl
F C
Cl
t -Bu
N
i -Bu
N
Et
N
Bn
N
Bn
3
Fmoc
O
Ph-p-NO2
O
Ph-p-NO2
O
Ph-p-NO2
>99% ee,65% yield
>99% ee,62% yield
>99% ee,63% yield
>99% ee,61% yield
Fig. 3. Benzoxazinone products
Cl
O
N
Cl
Cl
O
N
O
Et
BH3•SMe
2
>99% ee,77% yield
Cl
Et
Ph- p -N 2
O
O
O
Ph-p -NO2
The isolable o-benzoquinone imides are
easily synthesized via lead(iv) oxidation of
the corresponding 2-aminophenols. In a
Scheme 7. Reduction to benzoxazines

ORGANOCATALYSIS
243
CHIMIA 2007, 61, No. 5
variety of R-substituents, N-acyl groups,
and carboalkoxy groups can be incorporat-
Cl
ed into the optically enriched products. The
bicyclic products can be seen as active es-
ters and do, indeed, react smoothly with al-
cohols and amines to afford α-aminoesters
and amides (Scheme 8, Fig. 4). Notably,
this reaction is carried out simply by adding
8.
Cl
Cl
O
N
O
R
H
O
Cl
O
H
CAN
NuH
O
N
Nu
O
N
R
Nu
O
p-N 2
O -Ph
H O
Me2CN
p-N 2
O -Ph
R
O
Ph-p-NO2
the desired nucleophile to the reaction pot
once the cycloaddition is complete.
N-protected
Nu =-OH, -OR,-NH2,-NHR
Among the amino acid derivative prod-
ucts, the most interesting are three biologi-
cally significant[24] derivatives: β,γ-alkynyl
Scheme 8. Synthesis of α-amino acid derivatives
amino acid, β,γ-alkenyl amino acid, and
α-fluoro amino acid (Fig. 5). These were
produced in good yield and, once again,
excellent ee. These three examples are of
significance due not only to their high ee,
but also to the difficulty of accessing them
Cl
Cl
Cl
through other catalytic, asymmetric meth-
H
O
CF3
Cl
H
O
Cl
H
O
H
O
Cl
odologies.[25] Subsequent oxidation by
O
O
O
O
CAN[26] affords α-amino acid derivatives,
again without loss of ee (Fig. 6). A great
variety of R groups (derived from the acid
chloride) are possible, so that the number of
N
O
Me
N
NH2
N
O
Me
N
N
HBn
p-N 2
O -Ph
p-N 2
O -Ph
p-N 2
O -Ph
p-N 2
O -Ph
O
O
O
O
O
CH3
C 3
H
H C
3
non-natural amino acid derivatives acces-
sible by this method is considerable. In the
case of N-Fmoc products, removal of the
>99% ee,77% yield
>99% ee,71% yield
>99% ee,83% yield
>99% ee,90% yield
protecting group with piperidine followed
by CAN oxidation leads to N-unprotected
α-amino esters in good overall yield and
with full retention of enantiomeric excess
Fig. 4. N-Aryl α-amino acid derivatives
(Scheme 9).
The yields for these cycloaddition re-
actions were good, but not as high as we
would have liked. We reasoned that the
sluggishness of the reaction may allow
time for unwanted byproduct formation;
O
R
Ar
O
R
Ar
O
R
Ar
Ar =
Cl
Cl
N
O
Me
N
O
Me
N
OMe
OH
O
F
O
O
therefore, by further activating the quinone
imides, perhaps by making them more elec-
trophilic through coordination with a Lewis
acid, the reaction rate and subsequently the
Et
>99% ee,59% yield >99% ee,60% yield
Ph
R=p -NO2 -Ph
>99% ee,60% yield
yield could be increased. o-Benzoquinone
imides should be excellent candidates for
Fig. 5. Highly biologically significant amino acid derivatives
Lewis acid activation.[27] They bear a strik-
ing resemblance to the imino esters that
we have successfully activated towards at-
tack by similar catalytically derived ketene
enolates.[28] We decided to screen several
O
H
O
H
H
metal triflates for their ability to increase
N
OMe
N
OMe
Fmoc
N
OMe
the reaction rate and yield of the cycload-
p -N 2
O -Ph
p -NO2 -Ph
dtion reaction.[29] We found that, while both
Ph
O
C 2
H
O
Bn
O
Bn
O
zinc(ii) and indium(iii) increased the yield,
scandium(iii) had the most pronounced
>99% ee,71% yield
>99% ee,72% yield
>99% ee,71% yield
effect. Addition of a catalytic amount of
scandium triflate to the reaction mixture
provided up to a 42% increase in yield (Fig.
Fig. 6. N-Protected α-amino acid derivatives
7). This remarkable bifunctional catalytic
system (Scheme 10) improved the yield of
every reaction, and, most importantly, did
not degrade the enantioselectivity.
Ar
Ar
H
CAN
piperidine
Fmoc
N
OMe
H
N
OMe
H
N
OMe
H O, MeCN
2
THF
R
O
R
O
R
O
4. o-Benzoquinone Diimides
Quinoxalinones, products of the Diels-
Alder reaction between ketene enolates
Scheme 9. Synthesis of N-unprotected α-amino acids

ORGANOCATALYSIS
244
CHIMIA 2007, 61, No. 5
and o-benzoquinone diimides, are useful
Cl
Cl
Cl
templates for drug development because of
their structural relationship to benzodiaz-
H
O
Cl
H
O
Cl
H
O
Cl
O
O
O
epines.[30] These attractive targets exhibit a
wide range of biological activity, including
N
O
Me
N
O
Me
N
O
Me
p-N 2
O -Ph
p-N 2
O -Ph
p-NO2 -Ph
antidiabetic[31] and antiviral effects, in par-
O
H C
O
O
3
ticular against retroviruses such as HIV.[4]
C 3
H
CH3
In addition, they are partial agonists of the
γ-aminobutyric acid (GABA)/benzodiaz-
>99% ee,
84% yield (42% increase)
>99% ee,
92% yield (39% increase)
>99% ee,
86% yield (39% increase)
epine receptor complex,[32] inhibitors of al-
dose reductase,[33] and agonists of the AM-
PA and antiotensin II receptors.[34] Related
Fig. 7. Examples of improved yield for bifunctional system
quinoxalines, which are easily made from
the respective quinoxalinones by a simple
reduction(seeScheme13), alsopossessbio-
O
Ph-p-NO2
O
Ph-p-NO2
logical activity, for example, as inhibitors
Cl
Cl
N
O
Cl
Cl
N
O
10 mol%
of cholesteryl ester transferase proteins.[35]
Cl
Sc(OTf)
Sc
3
o-Benzoquinonediimidesareeasilypre-
pared by lead(iv) oxidation of the relevant
H
O
Cl
1. THF
-78 C
3OTf
1,2-dianilides, as outlined by Adams and
o
O
Way.[36] Initially, we screened 4,5-dichloro
N
OMe
2. MeOH
diimide (a, R,R’ = Cl, Scheme 11) in a re-
action with butyryl chloride, Hünig’s base,
p-N 2
O -Ph
O
H
BQd
10 mol% BQd
H C
O
3
and BQd at –78 °C in THF.[37]
reaction formed several byproducts along
The sluggish
Hünig's base
>99% ee,91% yield
H C
Cl
3
H C
3
O
with the desired cycloaddition product. We
reasoned that activation of the diimide by
coordination of a Lewis acid would render
Scheme 10. Bifunctional system to form α-amino acid derivatives
the system more electrophilic, thereby in-
creasing the reaction rate. We screened a
O
Ph
number of metal triflates that were chosen
O
Cl
R
N
N
based on our previous success with activa-
tion of imino esters.[28] Aluminum(iii) and
''
R
'
R
indium(iii) provided 64% and 65% yield
respectively in the standard reaction. How-
ever, scandium(iii) and zinc(ii) were far
superior. For example, the initial rate of
reaction increased by over 2000% and the
product yield increased significantly (82%
for the standard reaction) when 10 mol%
zinc triflate was used as a cocatalyst. An
IR test confirmed our notion that the Lewis
acid operates through coordination with the
diimide. Zinc triflate was used as a cocata-
lyst in subsequent reactions, providing the
a
b
O
O
Ph
Ph
10 mol%
ML
n
10 mol% Nu
Hünig'sbase
( BQd or BQ)
O
O
Ph
Ph
R
N
N
O
R
N
N
H
Nu
T
HF
ML
n
o
''
-78 C
''
'
R
O
R'
R
R
d
e
c
O
Ph
bifunctional catalytic system depicted in
Scheme 11.
Scheme 11. Bifunctional catalytic system to produce quinoxalinones
This bifunctional catalytic methodol-
ogy was thoroughly screened to determine
its scope. A variety of substituted quinox-
alinones were produced in good to excel-
lent yield and all products were obtained in
>99% ee (Fig. 8). In fact, we did not detect
the minor enantiomer (chiral phase HPLC)
in any chiral reaction. For each reaction,
O
Ph
O
Ph
O
O
Ph
Ph
N
N
O
N
N
O
N
N
O
C 3
H
Ph
C 3
H
F C
3
C 3
H
O
C3
H
O
Ph
O
Ph
only one regioisomer was obtained. This
highly selective methodology was rational-
>99% ee,84% yield
>99% ee,83% yield
>99% ee,83% yield
ized by the stepwise mechanism depicted
O
Ph
O
Ph
in Scheme 12.
N
O
Cl
Cl
N
O
The utility of this methodology was
O
demonstrated through the synthesis of two
drug targets. One compound, a quinoxaline
that is known to inhibit cholesteryl ester
transfer protein,[35] (f, Scheme 13), was
produced by reduction of the cycloaddition
product. Remarkably, LAH[38] cleaves the
benzoyl groups and reduces the lactam car-
Ph
N
N
N
O
O
Cl
Ph
O
Ph
O
>99% ee,87% yield
>99% ee,93% yield
Fig. 8. Quinoxalinone products

ORGANOCATALYSIS
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CHIMIA 2007, 61, No. 5
[3] a) S. K. Sengupta, D. H. Trites, M. S. Mad-
havarao, W. R. Beltz, J. Med. Chem. 1979,
22, 797–802; b) F. Bihel, J.-L. Kraus, Org.
& Biomol. Chem. 2003, 1, 793–799; c) R.
L. Jarvest, S. C. Connor, J. G. Gorniak,
O
O
Ph
Zn
Ph
2OTf
O
Ph
N
N
O
N
N
B
Qd
Ph
L. J. Jennings, H. T. Serafinowska, A.
West, Bioorg. & Med. Chem. Lett. 1997,
7, 1733–1738; d) K. F. Croom, K. L. Goa,
Drugs 2003, 63, 2769–2802.
O
B
Qd
Ph
Ph
H
O
R
O
R
H
O
O
Ph
[4] M. Rösner, U.-M. Billhardt-Troughton,
R. Kirsh, J.-P. Kleim, C. Meichsner, G.
Riess, I. Winkler, U.S. Patent 5723461,
1998.
Ph
O
Ph
O
N
N
N
O
[5] A few precedents for enantioselective β-
BQd
lactone formation: a) H. Wynberg, E. G.
Ph
N
H
J. Staring, J. Am. Chem. Soc. 1982, 104,
166–168; b) M. A. Calter, J. Org. Chem.
1996, 61, 8006–8007; c) S. G. Nelson,
R
R
O
O
O
Ph
O
Ph
T. J. Peelen, Z. Wan, J. Am. Chem. Soc.
1999, 121, 9742–9743; d) G. S. Cortez,
R. L. Tennyson, D. Romo, J. Am. Chem.
Scheme 12. Proposed mechanism of regioselective cycloaddition
Soc. 2001, 123, 7945–7946. For β-lactam
formation: e) A. E. Taggi, A. M. Hafez,
H. Wack, B. Young, W. J. Drury III, T.
Lectka, J. Am. Chem. Soc. 2000, 122,
7831–7832; f) B. L. Hodous, G. C. Fu, J.
O
R
N
R
N
H C
3
H
N
S
Cl
O
O
10 mol%
BQ
TFA
Am. Chem. Soc. 2002, 124, 1578–1579;
S
S
10 mol% Zn(OTf)
2
Cl
N
R
g) S. France, A. Weatherwax, A. E. Tag-
gi, T. Lectka, Acc. Chem. Res. 2004, 37,
592–600; h) S. France, M. H. Shah, A.
Cl
N
R
Cl
N
R
CH3
CH3
Hünig's base
HF, -78 °C
b
a
c
T
Weatherwax, H. Wack, J. P. Roth, T. Lect-
ka, J. Am. Chem. Soc. 2005, 127, 1206–
1215.
O
O
Ph
Ph
O
O
Ph
H C
Cl
3
H
N
[6] A. E. Taggi, A. M. Hafez, H. Wack, B.
N
O
N
LiAlH
10 mol% BQd
4
Young, D. Ferraris, T. Lectka, J. Am.
Chem. Soc. 2002, 124, 6626–6635.
[7] a) ‘The Chemistry of the Quinonoid Com-
CH3
CH3
10 mol% Zn(OTf)
Hünig's base
HF,-78 °C
2
THF
N
N
N
H
e
d
f
T
pounds’, Ed. S. Patai, John Wiley & Sons,
New York, 1974, 4 vols. For a recent re-
view see: b) B. I. Kharisov, M.A. Mendez-
Rojas, A. D. Garnovskii, E. P. Ivakhnenko,
U. Ortiz-Mendez, J. Coord. Chem. 2002,
55, 745–770.
O
Ph
Scheme 13. Drug target syntheses, R = CO2-i-Pr
[8] Some examples include: a) D. D. Weller,
E. P. Stirchak, J. Org. Chem. 1983, 48,
4873–4879; b) I. W. Sinclair, G. R. Proc-
tor, J. Chem. Soc., Perkin Trans. 1 1975,
23, 2485–2488; c) R. Willstaetter,A. Pfan-
nenstiel, Ber. Dtsch. Chem. Ges. 1904, 37,
4744–4746; d) F. Minisci, A. Citterio, E.
Vismara, F. Fontana, S. De Bernardinis,
bonyl, affording f in quantitative yield with tions of o-quinones and derivatives have not,
full retention of ee. A second drug target, a to the best of our knowledge, been explored),
quinoxalinone that exhibits strong activity but should contribute to the efficient synthe-
against HIV,[4] was produced by the remark- sis of pharmacologically active and biologi-
ably regioselective cycloaddition reaction cally relevant organic molecules.
between a (Scheme 13) and 3-methylthio-
Acknowledgement
propionyl chloride, mediated by cocatalysts
T.L. thanks the NIH (Grant GM064559), the
Sloan and Dreyfus Foundations, and Merck &
Co. for support.
BQ and Zn(OTf)2. This cycloaddition reac-
tion gave the (R)-enantiomer b (Scheme 13)
in >99% ee and moderate yield. Selective
M. Correale, J. Org. Chem. 1989, 54,
728–731.
[9] D. Magdziak, A. A. Rodriguez, R. W. Van
deprotection by TFA produces the target
De Water, T. R. R. Pettus, Org. Lett. 2002,
Received: March 26, 2007
quinoxalinone c in 94% yield with full re-
tention of ee.
4, 285–288.
[10] a) W. Ried, E. Torok, Liebigs Ann. Chem.
[1] a) J. D. White, Y. Choi, Org. Lett. 2000,
2, 2373–2376; b) J. D. White, Y. Choi,
Helv. Chim. Acta 2002, 85, 4306–4327;
c) D. A. Evans, J. Wu, J. Am. Chem. Soc.
2003, 125, 10162–10163; d) D. H. Ryu, G.
Zhou, E. J. Corey, J. Am. Chem. Soc. 2004,
126, 4800–4802; e) Q. -Y. Hu, G. Zhou,
E. J. Corey, J. Am. Chem. Soc. 2004, 126,
13708–13713.
1965, 687, 187–190; b) K. T. Finley, ‘Qui-
nones as Synthones’, in ‘The Chemistry
of Quinonoid Compounds’, Ed. S. Patai,
Wiley & Sons, NewYork, 1988, Vol. 2(Pt.
1), pp. 537–717.
5. Conclusion
We have developed a highly flexible
methodology for the asymmetric [4+2] cy-
cloaddition reaction between heterodienes
based on o-quinones and catalytically de-
rived chiral ketene enolates. Not only are the
proposed routes both novel and chemically
interesting (catalytic, enantioselective reac-
[11] a) D. Bryce-Smith, A. Gilbert, Chem.
Commun. 1968, 21, 1319–1320; b) C.
Liao, H. Lin, J. Lin, J. Chin. Chem. Soc.
1980, 27, 87–95.
[12] a) V. Nair, S. Kumar, J. Chem. Soc., Perkin
Trans. 1 1996, 5, 443–447; b) J. Kaizer,
[2] O. B.Wallace, D.W. Smith, M. S. Deshpan-
de, C. Polson, K. M. Felsenstein, Bioorg. &
Med. Chem. Lett. 2003, 13, 1203–1206.

ORGANOCATALYSIS
246
CHIMIA 2007, 61, No. 5
G. Speier, E. Osz, M. Giorgi, M. Reglier, [25] a) D. P. Huber, K. Stanek, A. Togni, Te-
Tetrahedron Lett. 2004, 45, 8011–8013. trahedron: Asymm. 2006, 17, 658; b) B.
[13] T. Bekele, M. H. Shah, J. Wolfer, C. J. Ab- Mohar, J. Baudoux, J.-C. Plaquevent, D.
raham, A. Weatherwax, T. Lectka, J. Am. Cahard, Angew. Chem., Int. Ed. 2001, 40,
Chem. Soc. 2006, 128, 1810–1811. 4214.
[14] A. E. Taggi, A. M. Hafez, T. Dudding, [26] S. Kobayashi, J. Kobayashi, H. Ishiani, M.
T. Lectka, Tetrahedron 2002, 58, 8351– Ueno, Chem. Eur. J. 2002, 8, 4185–4190.
8356.
[27] See for example: C. B. Castellani, G.
Gatti, R. Millini, Inorg. Chem. 1984, 23,
4004–4008.
[15] a) M. Largeron, B. Lockhart, B. Pfeiffer,
M.-B. Fleury, J. Med. Chem. 1999, 42,
5043–5052; b) M. Largeron, M.-B. Fleury, [28] a) S. France, H. Wack, A. M. Hafez, A. E.
Tetrahedron Lett. 1998, 39, 8999–9002.
[16] K. C. Nicolaou, Y. Zhong, P. S. Baran, K.
Sugita, Angew. Chem., Int. Ed. 2001, 40,
2145–2149.
Taggi, D. R. Witsil, T. Lectka, Org. Lett.
2002, 4, 1603–1605; b) D. Ferraris, B.
Young, C. Cox, T. Dudding, W. J. Drury,
L. Ryzhkov, A.E. Taggi, T. Lectka, J. Am.
Chem. Soc. 2002, 124, 67–77.
[17] H. W. Heine, D. K. Williams, J. L. Ruther-
ford, J. Ramphal, E. A. Williams, Hetero- [29] D. H. Paull, E. Alden-Danforth, J. Wolfer,
cycles 1993, 35, 1126–1140. C. Dogo-Isonagie, C. J. Abraham, T. Lect-
[18] J. Wolfer, T. Bekele, C. J.Abraham, C. Do- ka, J. Org. Chem. 2007, in press.
go-Isonagie, T. Lectka, Angew. Chem., Int. [30] D.A. Horton, G. T. Bourne, M. L. Smythe,
Ed. 2006, 45, 7398–7400.
[19] P. Verma, S. Singh, D. K. Dikshit, R. Su-
prabhat, Synthesis 1987, 68–70.
[20] a) S. Bhaduri, G. K. Lahiri, P. Munshi, J.
Organomet. Chem. 2000, 606, 151–155;
Chem. Rev. 2003, 103, 893–930, and refe-
rences therein.
[31] D. Gupta, N. N. Ghosh, R. Chandra,
Bioorg. Med. Chem. Lett. 2005, 15, 1019–
1022.
b) S. Gladiali, A. Dore, D. Fabbri, S. Me- [32] L. Lee, W. V. Murray, R. A. Rivero, J.
dici, G. Pirri, S. Pulacchini, Eur. J. Org. Org. Chem. 1997, 62, 3874–3879, and re-
Chem. 2000, 16, 2861–2866; c) M. T. ferences therein.
Reetz, G. Mehler, Tetrahedron Lett. 2003, [33] a) R. Sarges, J. W. Lyga, J. Heterocycl.
44, 4593–4596.
[21] a) S. Kobayashi, R. Matsubara, Y. Naka-
mura, H. Kitagawa, M. Sugiura, J. Am.
Chem. 1988, 25, 1475–1479; b) B. A. Bu-
nin, J. A. Ellman, J. Am. Chem. Soc. 1992,
114, 10997–10998.
Chem. Soc. 2003, 125, 2507–2515; b) R. [34] G. A. Morales, J. W. Corbett, W. F. DeGra-
Matsubara, Y. Nakamura, S. Kobayashi, do, J. Org. Chem. 1998, 63, 1172–1177.
Angew. Chem., Int. Ed. 2004, 43, 1679– [35] Z. Jones, R. Groneberg, M. Drew, C. T.
1681. Eary, U.S. Patent 20050282812, 2005.
[22] M. J. O’Donnell, Acc. Chem. Res. 2004, [36] R. Adams, J. W. Way, J. Am. Chem. Soc.
37, 506–517. 1954, 76, 2763–2769.
[23] a) H. Groeger, Chem. Rev. 2003, 103, [37] C. J. Abraham, D. H. Paull, M. T. Scerba,
2795–2827; b) J. Huang, E. J. Corey, Org.
Lett. 2004, 6, 5027–5029; c) C. Becker,
J. W. Grebinski, T. Lectka, J. Am. Chem.
Soc. 2006, 128, 13370–13371.
C. Hoben, D. Schollmeyer, G. Scherr, H. [38] M. Ikeda, K. Ohno, T. Uno,Y. Tamura, Te-
Kunz, Eur. J. Org. Chem. 2005, 8, 1497–
trahedron Lett. 1980, 21, 3403–3406.
1499.
[24] P. Meffre, F. Le Goffic, Amino Acids 1996,
11, 313.