Rhodium/chiral urea relay catalysis enables an enantioselective semipinacol rearrangement/Michael addition cascade

Article abstract of DOI:10.1021/ol4017386

The combined use of rhodium and cinchona-based squaramide has first been introduced for asymmetric relay catalysis, enabling a highly enantioselective semipinacol rearrangement/Michael addition cascade.

Full text of DOI:10.1021/ol4017386

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium/Chiral Urea Relay Catalysis
Enables an Enantioselective Semipinacol
Rearrangement/Michael Addition Cascade
Dian-Feng Chen, Pei-Yu Wu, and Liu-Zhu Gong*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of
Chemistry, University of Science and Technology of China, Hefei, 230026, China
gonglz@ustc.edu.cn
Received June 19, 2013
ABSTRACT
The combined use of rhodium and cinchona-based squaramide has first been introduced for asymmetric relay catalysis, enabling a highly
enantioselective semipinacol rearrangement/Michael addition cascade.
The rearrangement reaction represents one of the most
attractive fashions for the formation of new chemical
bonds, especially in the creation of sterically congested
Scheme 1. Profiles of Semipinacol Rearrangement
quaternary carbon centers.1 The semipinacol rearrange-
ment, as a variant of the pinacol rearrangement, has been
intensively studied since 1923, thanks to its diverse active
species with electrophilic carbocenters, which would en-
able subsequent various cascade transformations, together
with its wide applications in elegant total synthesis of
natural products (Scheme 1).2 Remarkably, Tu and co-
workers have successfully developed a series of practical
tandem semipinacol rearrangement transformations, in-
semipinacol-type ring expansions exploring diazo com-
cluding alkylation, bromination, and hydroamination.2b,3
pounds.4 Despite these elegant achievements, some other
Maruoka and others have also established intermolecular
promising active species for this rearrangement are unex-
pectedly fading before flourishing, such as the classical
(1) (a) Coveney, D. J. Comprehensive Organic Synthesis; Trost, B. M.,
rhodium carbenoid,5 which would lead to unprecedented
Fleming, I., Eds.; Pergamon, Oxford, 1991; Chapter 3.4, p 777. (b) Overman,
L. E. Tetrahedron 2009, 65, 6432.
chemical processes.
The asymmetric metal/organo combined catalysis6
has been a unique strategy to circumvent the challenges
that the conventional single type of chiral catalysts
encountered. In particular, asymmetric relay catalysis
(2) (a) Snape, T. J. Chem. Soc. Rev. 2007, 36, 1823. (b) Wang, B.-M.;
Tu, Y.-Q. Acc. Chem. Res. 2011, 44, 1207. (c) Song, Z.-L.; Fan, C.-A.;
Tu, Y.-Q. Chem. Rev. 2011, 111, 7523.
(3) For selected examples, see: (a) Zhang, Q.-W.; Xiang, K.; Tu,
Y.-Q. Chem.;Asian. J. 2012, 7, 894. (b) Chen, Z.-M.; Zhang, Q.-W.;
Chen, Z.-H.; Li, H.; Tu, Y.-Q.; Zhang, F.-M.; Tian, J.-M. J. Am. Chem.
Soc. 2011, 133, 8818. (c) Li, H.; Zhang, F.-M.; Tu, Y.-Q.; Zhang, Q.-W.;
Chen, Z.-M.; Chen, Z.-H.; Li, J. Chem. Sci. 2011, 2, 1839. (d) Zhang, E.;
Fan, C.-A.; Tu, Y.-Q.; Zhang, F.-M.; Song, Y.-L. J. Am. Chem. Soc.
2009, 131, 14626. (e) Zhang, Q.-W.; Fan, C.-A.; Zhang, H.-J.; Tu, Y.-Q.;
Zhao, Y.-M.; Gu, P.-M.; Chen, Z.-M. Angew. Chem., Int. Ed. 2009, 48,
8572. (f) Zhang, E.; Tu, Y.-Q.; Fan, C.-A.; Zhao, X.; Jiang, Y.-J.; Zhang,
S.-Y. Org. Lett. 2008, 10, 4943. (g) Hu, X.-D.; Fan, C.-A.; Zhang, F.-M.;
Tu, Y.-Q. Angew. Chem., Int. Ed. 2004, 43, 1702.
(4) For selected examples, see: (a) Hishimoto, T.; Naanawa, Y.;
Maruoka, K. J. Am. Chem. Soc. 2011, 133, 8834. (b) Hishimoto, T.;
Naanawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2009, 131, 6614. (c)
Hishimoto, T.; Naanawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2008, 130,
2434. (d) Moebius, D. C.; Kingsbury, J. S. J. Am. Chem. Soc. 2009, 131,
878. (e) Li, W.; Liu, X.-H.; Hao, X.-Y.; Cai, Y.-F.; Lin, L.-L.; Feng,
X.-M. Angew. Chem., Int. Ed. 2012, 51, 8644.
r
10.1021/ol4017386
XXXX American Chemical Society

(ARC)7À11 that emphasized independent but methodical
activations of different substrates has been accepted as a
robust generic concept, capable of creating otherwise
inaccessible enantioselective cascade reactions with high
step efficiency. We and others have disclosed a range of
hybrid metal/organo binary systems including transition
metals, such as gold,8 ruthenium,9 and rhodium,10 basi-
cally combined with Brønsted acids, such as chiral phos-
phoric acids. In contrast, nitrogen or sulfur containing
bifunctional organocatalysts have been exploited to a
lesser extent in ARC presumably due to the deactivation
effect of both catalytic cycles.6b Herein, we will report the
first combined use of a rhodium complex and cinchona-
based bifunctional catalyst12 rendering a highly enan-
tioselective relay catalytic semipinacol rearrangement/
Michael addition cascade that is unrealizable otherwise.
Diazoalcohols of type 1 have been found to undergo
semipinacol rearrangement through 1,2-H or 1,2-C migration
Scheme 2. Combination of Transition Metal and Chiral
Bifunctional Organocatalysts for Relay Catalysis
in the presence of transition metal complexes, including
copper and rhodium complexes, to give β-keto esters III
via intermediates I and II.5cÀ5g We proposed that the
resultant ketoester intermediateIII in situgeneratedwould
undergo an enantioselecitive Michael addition with ni-
troalkenesundertheinfluenceofchiralbifunctionalurea.13
As such, a relay catalytic semipinacol rearrangement/
Michael addition cascade would likely be driven by a
transition metal/chiral urea collaboration (Scheme 2).
The initial experiment to validate our hypothesis ex-
plored the reaction of 1a with 2a under the catalysis of
5 mol % of copper salt and 10 mol % of chiral bifunctional
urea(inCH2Cl2, 25°C, Table1, entries1À3). However, the
(5) For reviews involving a rhodium carbenoid, see: (a) Doyle, M. P.;
Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704. (b)
Davies, H. M. L.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857. For Rh
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Z.-H.; Wang, J.-B. Org. Lett. 2001, 3, 2989. (d) Shi, W.-F.; Xiao, F.-P.;
Wang, J.-B. J. Org. Chem. 2005, 70, 4318. (e) Li, B.-S.; Liu, W.-X.;
Zhang, Q.-W.; Wang, S.-H.; Zhang, F.-M.; Zhang, S.-Y.; Tu, Y.-Q.;
Cao, X.-P. Chem.;Eur. J. 2013, 19, 5246. (f) Selander, N.; Worrell,
B. T.; Fokin, V. K. Angew. Chem., Int. Ed. 2012, 51, 13054. (g) Miura, T.;
Funakoshi, Y.; Morimoto, M.; Biyajima, T.; Murakami, M. J. Am.
Chem. Soc. 2012, 134, 17440.
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combination of either CuBr or CuSO4 5H2O with 4a gave
3
disappointing results presumably due to the low solubility
(entries 1À2). To our delight, the presence of Cu(OTf)2 led
to generation of the desired product 3aa in a 29% isolated
yield and with 73% and 79% ee respectively for two diaste-
reomers (entry 3). Interestingly, the conventional highly
active Rh2(OAc)4, in combination with 4a, rendered the
tandem reaction to proceed completely within 2 h, almost
quantitatively affording 4a (97% yield) with 82%/88% ee
(entry 4). The great advantage of Rh2(OAc)4 encouraged
us to improve the stereocontrol by evaluating a series of
ureas or thioureas incorporated with different chiral scaf-
folds (entries 5À7). Basically, in comparison with thiourea
organocatalysts 4b and 4d, urea analogues 4a and 4c gave
similar levels of enantioselectivity, but much higher yields
(entry 4 vs 5 and entry 6 vs 7). In particular, 4a showed the
most efficient catalytic activity (entry 4). Subsequently, a
variety of solvents were evaluated and we found that
toluene could further accelerate the whole process, how-
ever, at the cost of a significantly eroded yield (entry 8).
Neither tetrahydrofuran (THF) or ethyl ether (Et2O) was
able to enhance the stereocontrol (entries 9 and 10), and
CH2Cl2 was therefore the solvent of choice. More inter-
estingly, a quinine-based squaramide 4e13d substantially
improved the enantioselectivity to 99%/99% ee (entry 11).
Notably, the combination of 0.5 mol % Rh2(OAc)4 and
2 mol % 4e provided an even better result (entry 12).
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Investigation of Binary Catalystsa
Table 2. Scope for Multifunctionalized Diazoalcoholsa
yield
(%)b
entry
catalyst I
CuBr
4
t (h)
drc
eed
1
4a
4a
4a
4a
4b
4c
4d
4a
4a
4a
4e
4e
À
48
48
24
2
À
À
À
À
2
CuSO4 5H2O
N.R
29
À
3
3
Cu(OTf)2
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
À
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
À
73/79
82/88
88/90
À82/-82
À80/-83
84/88
18/33
73/80
99/99
99/99
À
4
97
5
2
74
6
4
71
7
4
43
8e
9f
0.5
12
12
1
70
59
10g
11
12h,i
13h
14h
78
94
1
97
48
48
N.R.
N.R.
4e
À
À
a Unless indicated otherwise, reactions of 1a (0.15 mmol), 2a
(0.10 mmol), catalyst I (0.005 mmol), and 4 (0.010 mmol) were carried
out in DCM (1 mL). b Isolated yield. c Determined by crude H1 NMR.
d Determined by HPLC analysis. e In toluene. f In THF. g In Et2O.
h 0.5 mol % Rh2(OAc)4 and 2.0 mol % 4e were used. i 0.20 mmol scale
in DCM (1 mL).
As anticipated, neither Rh2(OAc)4 or 4e could catalyze this
tandem reaction alone (entries 13À14).
With the optimal conditions in hand, we investigated the
generality of this protocol for diazoalcohols (Table 2).
Very high levels of enantioselectivity were achieved for
various secondary alcohol substrates (entries 1À7). Both
the ester group and substituents on the R-position of the
hydroxyl influenced the diastereoselectivity slightly be-
cause of the nature of monosubstituted β-keto esters.
Significantly, the protocol was amenable to diazoalcohols
bearing a spectrum of functional groups, including alky-
nyl, alkenyl, and protected hydroxyl, to furnish the corre-
sponding products in high yields and with excellent
enantioselectivities, which would allow further synthetic
applications by virtue of the rich chemistry in these func-
tionalities (entries 4À6).
a Unless indicated otherwise, reactions of 1 (0.30 mmol), 2a
(0.20 mmol), Rh2(OAc)4 (0.001 mmol), and 4e (0.004mmol) were carried
out in 1 mL of DCM for 1 h. b Isolated yield. c Determined by crude H1
NMR. d Determined by HPLC analysis. e The reaction was conducted in
0.5 mL of DCM for 24 h.
creating two vicinal carbon stereocenters involving a qua-
ternary one in one step (Table 2, entries 8À12). Generally,
the desired ring-expanded products were obtained in ex-
cellent yields and with high levels of stereoselectivity for
cyclic substrates within 1 h (entries 8, 10, and 11), except
that 1j and 2a required a higher concentration and pro-
longed time to accomplish a complete process (60% yield,
50:1 dr, 98% ee; entry 9). Moreover, the acyclic tertiary
substrate like 1m was also able to participate in the tandem
reaction to provide 3ma in 89% yield and with 99%/97%
ee (entry 12).
The enantioselective creation of quaternary stereogenic
centers has long received much attention for their ubiquity
in natural products and molecules with significant
bioactivity.14 In this regard, various tertiary diazoalcohols
were subjected to this relay catalytic cascade reaction,
(14) For selected reviews, see: (a) Steven, A.; Overman, L. E. Angew.
Chem., Int. Ed. 2007, 46, 5488. (b) Trost, B. M.; Jiang, C. Synthesis 2006,
369. (c) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 2001, 40,
4591.
The generality for nitroalkenes was also explored. A
variety of nitroalkenes were treated with 1i under the
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Generality for (E)-Nitroalkenesa
Scheme 3. Synthetic Application of Tethered Functional Group
yield
(%)b
entry
2/R1
3
drc
eed
1
2
3
4
5
6
7
8
9e
2b/4-Br-C6H4
2c/4-MeO-C6H4
2d/3-Me-C6H4
2e/2-Cl-C6H4
2f/2-Br-C6H4
2g/2-Me-C6H4
2h/2-naphyl
2i/furanyl
3ib
3ic
3id
3ie
3if
99
99
96
95
84
90
95
99
92
30:1
20:1
50:1
25:1
50:1
25:1
20:1
25:1
99:1
92
90
98
97
99
98
93
94
99
hydrate (p-TSA H2O), the carbonÀcarbon triple bond
3ig
3ih
3ii
3
and keto group in the compound 3ea underwent a cycliza-
tion to form 5 bearing a furan moiety. Followed by a cascade
selective reduction/transesterification of 5 with a combined
2j/isoamyl
3ij
reagent of NiCl2 6H2O and NaBH4,15 3,4-disubstituted
a Unless indicated otherwise, reactions of 1 (0.30 mmol), 2a
(0.20 mmol), Rh2(OAc)4 (0.001mmol), and 4e (0.004 mmol) were carried
out in 1 mL of DCM for 1 h. b Isolated yield. c Determined by crude H1
NMR. d Determined by HPLC analysis. e The reaction time was 12 h.
3
γ-lactam 6 was furnished in an overall 71% yield in two steps
and with maintained enantioselectivity (Scheme 3).
In summary, we have, for the first time, demonstrated
that rhodium and chiral bifunctional urea are highly
compatible and can be combined for asymmetric relay
catalysis. This binary chiral catalyst system rendered
a highly enantioselective semipinacol rearrangement/
Michael addition cascade reaction to proceed cleanly.
Remarkably, the relay catalytic process showed excellent
tolerance to various functionalities and enabled direct
access to highly functionalized chiral nitro compounds
that are basically impracticable otherwise. Moreover, the
presence of the multiple functionalities in the products
allows further transformations intobiologically interesting
optically pure molecules.
optimized conditions to generate a diverse spectrum of
Michael adducts in almost quantitative yields and with
excellent diastereoselectivities, ranging from 20:1 to99:1 dr
(Table 3). Foraryl nitroalkenes, the stereochemicalcontrol
became sensitive to the substitution pattern while it was
somewhat independent of the electron feature. For exam-
ple, either ortho- or meta-substituents of the β-nitrostyrene
provided higher enantioselectivities than para-substituted
nitroolefins (entries 1À2 vs 3À6) while the presence of
the electron-donating or -withdrawing substituents gave
comparable enantioselectivities (entry 1 vs 2 and entries
4À5 vs 6). In addition, for the naphthyl, heteroaryl, and
alkyl nitroalkene, 2h, 2i, and 2j also underwent clean relay
catalytic cascade reactions to give the desired products
in high yields and with excellent stereochemical outcomes
(entries 7À9).
Acknowledgment. We are grateful for financial support
from NSFC (21232007and 21202155), MOST (973 project
2010CB833300).
The highly functionalized products obtained could be
conveniently converted into synthetically important chiral
molecules by using classical reactions. For instance, in the
presence of a catalytic amount of p-toluenesulfonic acid
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Hynes, P. S.; Stupple, P. A.; Dixon, D. J. Org. Lett. 2008, 10, 1389.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX