Asymmetric synthesis of functionalized dihydronaphthoquinones containing quaternary carbon centers via a metal-free catalytic intramolecular acylcyanation of activated alkenes

Article abstract of DOI:10.1021/ol501427h

A novel metal-free catalytic annulation was developed through a Lewis base-catalyzed asymmetric allylic alkylation and the ensuing unprecedented asymmetric intramolecular acylcyanation of alkenes. This protocol provides a unique and facile access to prepare enantioenriched densely functionalized dihydronaphthoquinones accompanied by enantiomerically pure 3,3-disubstituted phthalides bearing quaternary carbon centers.

Full text of DOI:10.1021/ol501427h

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of Functionalized Dihydronaphthoquinones
Containing Quaternary Carbon Centers via a Metal-Free Catalytic
Intramolecular Acylcyanation of Activated Alkenes
Zhe Zhuang, Zhi-Peng Hu, and Wei-Wei Liao*
Department of Organic Chemistry, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China
S
* Supporting Information
ABSTRACT: A novel metal-free catalytic annulation was
developed through a Lewis base-catalyzed asymmetric allylic
alkylation and the ensuing unprecedented asymmetric intra-
molecular acylcyanation of alkenes. This protocol provides a
unique and facile access to prepare enantioenriched densely
functionalized dihydronaphthoquinones accompanied by
enantiomerically pure 3,3-disubstituted phthalides bearing quaternary carbon centers.
o develop new enantioselective transformations to meet an
increasing demand for the economical syntheses of
Recently, we reported the first metal-free intramolecular
carbocyanations of alkenes which provided an efficient approach
to construct nitriles with diverse carbon frameworks incorporat-
ing quaternary carbon centers.4,5 Inspired by the high efficiency
of Hauser−Kraus annulation on C−C bond formation and
recent reports from our laboratory, we hypothesize that a novel
atom-economic asymmetric annulation which would take full
advantages of the elements of Hauser−Kraus annulation and the
principle of metal-free intramolecular acylcyanations of alkenes
(IAA) can be established and would construct enantioenriched
and carboannulated functionalized dihydronaphthoquinone
structural motif incorporating a cyano group in catalytic fashion
as follows: a metal-free catalytically generated enantiomerically
enriched 3-allylic-3-cyano-substituted phthalide 2, formed via a
Lewis base-catalyzed asymmetric allylic alkylation (AAA),6
would undergo a Lewis base mediated acylcyanation of activated
alkenes to furnish annulated enantioenriched dihydronaphtho-
quinone 3 enantiospecifically via a putative highly functionalized
intermediate (II) (Scheme 1B). This novel protocol would be
highly attractive not because it offers a unique strategy to design
and develop new asymmetric annulation methods to access a
diverse pool of enantioenriched densely functionalized dihy-
dronaphthoquinones accompanied by enantiomerically pure 3,3-
disubstituted phthalides bearing quaternary carbon centers7,8 but
also greatly extends the applicability of metal-free intramolecular
carbocyanations of alkenes on assembling enantiopure substrates
containing higher levels of molecular complexity in possession of
cyclic frameworks in contrast to our previous works. Herein, we
report our results of this unprecedented annulation via a metal-
free AAA and the ensuing IAA reactions.
T
enantiomerically pure chiral compounds is a great continuous
challenge for synthetic chemists.1 Among them, asymmetric
annulations have proven to be efficient synthetic routes to access
chiral compounds.2 The Hauser−Kraus annulation reported in
1978 has found wide applications in assembling many important
naphthol/naphthoquinone based frameworks in synthetic
chemistry (Scheme 1A).3 In a typical Hauser−Kraus annulation,
Scheme 1. Synthetic Strategies
3-cyanophthalide is utilized as an annulating agent to react with
various activated alkenes to construct highly substituted 1, 4-
dioxygenated naphthalenes, and the entire process involves
fusion of a new ring to a molecule via two new bonds and the
expulsion of stoichiometric cyanide ion as waste. However, the
distinct feature of this classic transformation wherein all
generated sp3 carbon centers undergo further aromatization to
offer a substituted aromatic ring impedes the potential
generation of chiral sp3 carbon centers and makes the application
of this annulation strategy to an asymmetric C−C bond
formation reaction inconceivable.
Given that practical access to enantioenriched 3-allylic-3-
cyano substituted phthalides would be crucial to investigate this
unique annulation, we first assessed the feasibility of
enantioselective construction of these chiral scaffolds via a
Received: May 18, 2014
Published: June 9, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
Lewis base-catalyzed AAA reaction. Although AAA reactions of
3-carboxylate phthalides with the substituted Morita−Baylis−
Hillman (MBH) carbonates have been reported,6h the employ-
ment of 3-cyano phthalides in this allylic alkylation has not been
developed. Besides, the enantioselective examples of pronucleo-
philes with the unsubstituted MBH carbonates in this alkylation
are rare. Keeping these surveys in mind, our initial efforts focused
on the identification of effective catalysts and conditions for the
enantioselective allylic alkylation reaction between 3-cyanoph-
thalide 1a and unsubstituted MBH carbonate 2b to afford 3,3-
disubstituted phthalide 3ba (Scheme 2). Cinchona alkaloid
Table 1. Screening of AAA Reactions
b
c
entry
R
R2
2
time (h)
yield (%)
ee (%)
1
2
H
H
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2a
2c
2d
2e
24
36
1
99 (3ba)
92 (3bb)
99 (3bc)
92 (3bd)
91 (3be)
97 (3bf)
99 (3bg)
99 (3bh)
99 (3bi)
99 (3bj)
73 (3bk)
98 (3aa)
97 (3ca)
94 (3da)
73 (3ea)
92
88
89
93
90
95
92
96
96
96
82
90
81
4-Me
4-OMe
3-Me
2-OMe
3,4-Me
4,5-OMe
4-F
H
d
3
H
d
4
H
1
d
Scheme 2. Selection of Chiral Catalysts Examined
5
H
1
d
6
H
1
d
7
H
1
8
H
24
24
24
24
48
48
48
24
9
4-Cl
4-Br
3-F
H
10
11
12
13
14
H
H
H
H
H
H
e
,
,
f
H
Me
nPr
99
96
d
e
g
15
H
a
Performed with 1 (0.1 mmol), 2a (0.12 mmol), and catalyst C-9 (10
b
c
mol %) in toluene (1.0 mL) at −30 °C. Isolated yields. Determined
d
e
by chiral HPLC analysis. Performed with 4 Å MS at 25 °C. Ee value
of major diastereomer; dr value was determined by 1H NMR analysis.
f
g
dr = 2.5/1. dr = 2.3/1.
reaction (Table 2). The intramolecular acylcyanation of
compound 3ba was investigated first in DMSO with a catalytic
a
Table 2. Optimization of Annulation Reactions
derivatives were selected as catalysts first and provided the
moderate enantioselectivity. To our delight, bifunctional
phosphines incorporating thioureas moieties and hindered
silyloxy groups were found to be superior in stereochemical
control, which furnished the desired product 3ba in high yields
with 87% and 88% ee, respectively, by using catalyst C-9 and C-
10. Decreasing the reaction temperature resulted in the best
stereochemical control and excellent chemical yield in the
presence of catalyst C-9 (99% yield, 92% ee).
We next examined the substrate scope of phosphine (C-9)-
catalyzed enantioselective allylic alkylation reactions of MBH
carbonates 2 with 3-cyanophthalides 1 (Table 1). In general, high
yields and enantioselectivities were observed for a broad range of
phthalides. 3-Allylic-3-cyano-substituted phthalides, having
electron-deficient groups at the 4-position gave excellent results
(Table 1, entries 8−10), while 3-fluoro-substituted phthalide
provided the decreased enantioselectivity (Table 1, entry 11).
The more electron-rich group substituted phthalides generally
required higher reaction temperatures and gave high enantiose-
lection (Table 1, entries 3−7). The reaction between 1a and
MBH carbonates 2c with bulky ester groups afforded the product
3ca in high yield with the decreased ee value, while treatment of
1a and MBH carbonate 2a provided chemical and optical yields
similar to those of its ethyl ester analogue 2b (Table 1, entries 12
and 13). MBH carbonates with the alkyl moieties were well-
tolerated and delivered the congested products 3 in good to high
yields and excellent enantioselectivities (up to 99% ee, Table 1,
entries 14 and 15), albeit with low diastereoselectivity.9
b
c
entry
cat.
3
solvent
time (h) yield (%) es (%)
1
2
3
4
5
6
7
8
9
TBACN
PBu3
3ba
3ba
3ba
3ba
3ba
3ba
3ba
3aa
3ca
3ba
3ba
3ba
DMSO
DMSO
DMSO
DMSO
DMF
1
24
24
12
12
12
24
24
24
48
72
48
70 (4ba)
29 (4ba)
39 (4ba)
d
85
89
86
PPhEt2
PPh3
TBACN
TBACN
TBACN
TBACN
TBACN
TBACN
TBACN
TBACN
69 (4ba)
d
88
HMPA
NMP
68 (4ba)
59 (4aa)
52 (4ca)
57 (4ba)
71 (4ba)
72 (4ba)
90
86
86
94
95
86
NMP
NMP
e
10
NMP
e
11
NMP
e,f
12
NMP
a
Performed with 3ba (0.1 mmol) and catalyst (5 mol %) in solvent
(1.0 mL) at 25 °C. Isolated yields. es = (product ee/starting material
ee) × 100%. Ee values were determined by chiral HPLC analysis. No
desired product was detected. Run at 0 °C. TBACN (10 mol %) was
b
c
d
e
f
used.
amount of TBACN (tetrabutylammonium cyanide), which was
previously identified as effective catalyst in intramolecular
carbocyanation of cyanohydrins and α-amino nitriles.4,10 To
our delight, the desired annulation occurred and gave rise to the
highly functionalized dihydronaphthoquinone product 4ba in
With these enantioenriched 3,3-disubstituted phthalides in
hand, we set out to study this novel annulation via metal-free IAA
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Organic Letters
Letter
70% yield in the presence of TBACN (5 mol %) with good
chirality transfer (85% es, Table 2, entry 1). Phosphine catalysts
such as PPhEt2 and PBu3 (5 mol %) gave the lower conversion
with the marginally high stereospecificities, whereas the reaction
did not occur in the presence of PPh3 (Table 2, entries 2−4).
Further survey on solvents revealed that the acylcyanation
reaction worked well in polar solvents in the presence of catalytic
amount of TBACN, with regard to the chemical yield and
efficiency of chirality transfer.11 The higher es value was observed
in DMF, while chemical yield was similar to that of DMSO
(Table 2, entry 5). However, nondesired product was detected in
HMPA (Table 2, entry 6). The further enhanced es value was
obtained in NMP which provided 4ba in 68% yield with 90% es
(Table 2, entry 7). Methyl and tert-butyl ester analogues (3aa and
3ca) were employed, and both yield and es value decreased
marginally (Table 2, entries 8 and 9). Decreasing temperature
improved the efficiency of chirality transfer markedly (95% es
and 71% yield), albeit with prolonged reaction time (Table 2,
entries 10 and 11). The attempt to accelerate this process by
increasing the amount of TBACN worked, whereas the
effectiveness of chirality transfer deteriorated dramatically
(Table 1, entry 12).
yields with decreased es value (4bi−bj), except for 4-fluoro-
substituted phthalide which delivered the high stereospecificity
(4bh). These results indicated that the chirality transfer rather
relied upon the electronic properties of the aromatic system of
3,3-disubstituted phthalides 3 in developed process. The
reactions of phthalides containing substituents at the 3-postion
worked well and provided the desired products in moderate
yields and with the lower stereospecificities than that of the
corresponding 4-substituted phthalides (4bd and 4bk). 3,4-
Dimethyl-substituted phthalide can also serve as suitable
substrate to give the desired product with the similar chemical
yield and stereospecificity to that of the 4-position substituted
analogue (4bf). In contrast, the asymmetric annulations of
phthalides with substituents at the 2 or 5 position demonstrated
the different stereospecificities. The intramolecular acylcyanation
of 2-methoxy-substituted phthalide gave the desired product
with moderate es value (4be), while the 5-substituted analogue
provided the worst stereospecificity and 4,5-dimethoxy-sub-
stituted phthalide gave the similar results to that of the 2-
substituted analogue (4bg),12 which is in accord with the
proposed mechanism, in which a 2- or 5-substitution pattern
would result in an unstable intermediate II (Scheme 1) due to
the unfavorable steric interaction between the 2- (or 5-)
substituted group and oxyanion (or cyano group).13 Further-
more, enantioenriched phthalides bearing adjacent quaternary
and tertiary stereogenic centers have been examined. Treatment
of phthalide 3da furnished the corresponding product 4da
incorporating adjacent quaternary and tertiary stereogenic
centers in 65% yield with 80% es, while n-propyl-substituted
3ea gave the desired product 4ea in relatively low yield with
moderate es value.
With the optimal reaction condition established, the substrate
scope of metal-free catalyzed asymmetric annulation was
examined (Scheme 3). Phthalides including electron-donating
groups at the 4-substituted provided the desired products in
good yields with excellent es value (4bb−bc), while substrates
possessing electron-withdrawing groups at the 4-position
furnished functionalized dihydronaphthoquinones in similar
a
Scheme 3. Substrate Scope of Annulation Reactions
The absolute configurations of the newly formed quaternary
centers of both enantioenriched 3,3-disubstituted phthalide 3bj
and the corresponding dihydronaphthoquinone drivative were
determined on the basis of X-ray crystal structural analyses (see
the Supporting Information for details). Based on the observed
stereochemistry, a possible reaction mechanism is depicted in
Scheme 4. In accord with the previous proposed mechanism, an
Scheme 4. Proposed Mechanism
enolate was first generated from the Michael addition of cyanide
ion to activated CC bond of enantioenriched 3,3-disubstituted
phthalide 3 in this annulation. Due to the facial selectivity of
enolate (I-A), subsequently a tandem intramolecular condensa-
tion between the enolate (Si face) with the ester group pro
ceeded stereospecifically and gave intermediate II-A, which
followed an elimination to afford the desired product 4-(R) with
cyanide ion.
It is noteworthy that this novel annulation protocol can be
further extended beyond the metal-free intramolecular acylcya-
nation. For example, nucleophiles such as alkyl anion also can be
employed in this annulation and react with 3ba to provide
functionalized dihydronaphthoquinone 4bl in 67% yield with
a
Performed with 3 (0.1 mmol) and TBACN (5 mol %) in NMP.
Yields shown are of isolated products. For details, see the Supporting
Information. TBACN (10 mol %). Run in DMSO. Run in DCM
with TBACN (10 mol %).
b
c
d
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Organic Letters
Letter
reviews on the Hauser−Kraus annulation, see: (c) Rathwell, K.; Brimble,
M. A. Synthesis 2007, 643. (d) Mal, D.; Pahari, P. Chem. Rev. 2007, 107,
1892.
good es value, which further expanded the applicability of this
synthetic strategy remarkably (Scheme 5).
(4) (a) Zhuang, Z.; Chen, J.-M.; Pan, F.; Liao, W.-W. Org. Lett. 2012,
14, 2354. (b) Chen, J.-M.; Zou, G.-F.; Liao, W.-W. Angew. Chem., Int. Ed.
2013, 52, 9296.
Scheme 5. Extention of Annulation
(5) For selected recent reviews on the construction of quaternary
carbon centers, see: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363. (b) Trost, B. M.; Jiang, C. Synthesis 2006,
369. (c) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem.
2007, 5969. (d) Hawner, C.; Alexakis, A. Chem. Commun. 2010, 46,
7295. (e) Das, J. P.; Marek, I. Chem. Commun. 2011, 47, 4593.
(6) For recent reviews, see: (a) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem.
Soc. Rev. 2012, 41, 4101. (b) Rios, R. Catal. Sci. Technol. 2012, 2, 267.
(c) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659. For selected recent
examples of Lewis base-catalyzed AAA reaction of MBH adducts with C-
nuclephiles, see: (d) Jiang, L.; Lei, Q.; Huang, X.; Cui, H. L.; Zhou, X.;
Chen, Y. C. Chem.Eur. J. 2011, 17, 9489. (e) Yang, W.-G.; Wei, X.-L.;
Pan, Y.-H.; Lee, R.; Zhu, B.; Liu, H.-J.; Yan, L.; Huang, K.-W.; Jiang, Z.-
Y.; Tan, C.-H. Chem.Eur. J. 2011, 17, 8066. (f) Furukawa, T.;
Kawazoe, J.; Zhang, W.; Nishimine, T.; Tokunaga, E.; Matsumoto, T.;
Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2011, 50, 9684. (g) Huang,
X.; Peng, J.; Dong, L.; Chen, Y.-C. Chem. Commun. 2012, 48, 2439.
(h) Zhong, F.-R.; Luo, J.; Chen, G.-Y.; Dou, X.-W.; Lu, Y.-X. J. Am.
Chem. Soc. 2012, 134, 10222.
(7) For examples of the natural products containing dihydronaph-
thoquinone structural motif: (a) Opatz, T.; Kolshorn, H.; Thines, E.;
Anke, H. J. Nat. Prod. 2008, 71, 1973−1976. (b) Gu, J.-Q.; Graf, T. N.;
Lee, D.; Chai, H.-B.; Mi, Q.; Kardono, L. B. S.; Setyowati, F. M.; Ismail,
R.; Riswan, S.; Farnsworth, N. R.; Cordell, G. A.; Pezzuto, J. M.;
Swanson, S. M.; Kroll, D. J.; Falkinham, J. O., III; Wall, M. E.; Wani, M.
C.; Kinghorn, A. D.; Oberlies, N. H. J. Nat. Prod. 2004, 67, 1156.
(c) Ernst-Russel, M.; Elix, J.; Chai, C.; Willis, A.; Hamada, N.; Nash, T.,
III. Tetrahedron Lett. 1999, 40, 6321−6324.
In summary, we have developed an unprecedented catalytic
intramolecular annulation via a metal-free AAA and the ensuing
IAA reactions which provided a unique and facile access to
prepare enantioenriched densely functionalized dihydronaph-
thoquinones accompanied by enantiomerically pure 3,3-
disubstituted phthalides bearing quaternary carbon centers
under neutral and mild conditions. The scope and versatility of
the process was demonstrated. Further extension of this
synthetic strategy also has been exhibited. Efforts on the studies
of the synthetic applications are ongoing in our laboratories.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wliao@jlu.edu.cn.
(8) Recent reviews on natural products and biologically important
molecules containing 3,3-disubstituted phthalide structural motifs:
(a) Beck, J. J.; Chou, S.-C. J. Nat. Prod. 2007, 70, 891. (b) Xiong, M. J.;
Li, Z. H. Curr. Org. Chem. 2007, 11, 833.
(9) Reactions between MBH carbonates with the aryl moietie and
phthalides 1 were also well-tolerated. However, the annulation of
corresponding allylic substituted phthalides did not give any desired
products.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSFC (No. 21372096 and
21102054) and the Open Project of State Key Laboratory for
Supramolecular Structure and Materials (sklssm201409).
(10) For recent examples for TBACN-catalyzed reactions, see:
(a) North, M.; Omedes-Pujol, M.; Young, C. Org. Biomol. Chem.
2012, 10, 4289. (b) Ohashi, M.; Maeda, H.; Mizuno, K. Chem. Lett.
2010, 39, 462. (c) Areces, P.; Carrasco, E.; Light, M. E.; Plumet, J. Synlett
2009, 2500. (d) Aljarilla, A.; Cordoba, R.; Csaky, A. G.; Fernandez, I.;
Ortiz, F. L.; Plumet, J.; Ruiz Gomez, G. Eur. J. Org. Chem. 2006, 17, 3969.
(e) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. Org. Lett. 2005,
7, 3981. (f) Holmes, B. T.; Snow, A. W. Tetrahedron 2005, 61, 12339.
(g) Amurrio, I.; Cordoba, R.; Csaky, A. G.; Plumet, J. Tetrahedron 2004,
60, 10521.
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