Cooperative catalysis with chiral Bronsted acid-Rh 2(OAc)4: Highly enantioselective three-component reactions of diazo compounds with alcohols and imines

Article abstract of DOI:10.1021/ja801755z

An asymmetric three-component reaction of diazo compounds and alcohols with imines catalyzed cooperatively by a rhodium complex and a chiral Bronsted acid provides a general and efficient entry to β-amino-α-hydroxyl acid derivatives in high yields with excellent stereoselectivities. Copyright

Full text of DOI:10.1021/ja801755z

Published on Web 05/31/2008
Cooperative Catalysis with Chiral Brønsted Acid-Rh2(OAc)4: Highly
Enantioselective Three-Component Reactions of Diazo Compounds with
Alcohols and Imines
Wenhao Hu,*,† Xinfang Xu,† Jing Zhou,† Wei-Jun Liu,‡ Haoxi Huang,† Juan Hu,† Liping Yang,† and
Liu-Zhu Gong*,‡
Department of Chemistry, East China Normal UniVersity, Shanghai 200062, China, Hefei National Laboratory for
Physical Sciences at the Microscale and Department of Chemistry, UniVersity of Science and Technology of China,
Hefei 230026, China
Received March 10, 2008; E-mail: whu@chem.ecnu.edu.cn; gonglz@ustc.edu.cn
Scheme 1. Proposed Reaction Mechanism of the Title Reaction
Multicomponent reactions (MCRs) offer numerous benefits over
traditional chemical synthesis,1 and catalytic enantioselective MCRs
provide expedient access to chiral polyfunctional molecules.
However, the development of this reaction class presents numerous
challenges,1b,2 as transition state orientations of three or more
reactants must be well controlled by a single chiral catalyst in order
to achieve high enantioselectivity.
Asymmetric synthesis of ꢀ-amino-R-hydroxyl acid derivatives
has attracted much attention due to both varied biological activities
and their occurrences in many medicinal compounds.3 As such,
efficient access to this important class of molecules with high optical
purity is highly desirable. Recently, our group discovered novel
three-component reactions of diazo compounds 1, alcohols 2, and
imines 3 to afford racemic polyfunctional hydroxyl/amino acid
frameworks (4) bearing a quaternary stereogenic center (eq 1).4
The reaction proceeds through oxonium ylide intermediates IIa or
IIb, which are generated in situ from 1 and Rh2(OAc)4 (Scheme
1). These intermediates can be trapped by electrophiles such as
imines. To obtain satisfactory chemoselectivity, electron-deficient
imines were required to suppress an O-H insertion side product.
Herein, we report the development of a catalytic asymmetric version
of the three-component reaction of aryldiazoacetates, alcohols, and
imines. The reaction employs a novel cooperative catalysis strategy
by Rh2(OAc)4-initiated generation of oxonium ylide intermediates
and chiral Brønsted acid activation of the imine electrophile, leading
to efficient synthesis of chiral ꢀ-amino-R-hydroxyl acid derivatives
with excellent enantioselectivities.
and oxonium ylide II, formed in situ from a diazoacetate and an
alcohol initiated by a rhodium complex, would undergo an
enantioselective Mannich-type reaction via proposed transition state
IV to generate optically active 4 (Scheme 1).
To validate our hypothesis, we carried out a catalytic asymmetric
three-component reaction using chiral phosphoric acid 5a. Methyl
phenyldiazoacetate 1a was added to a mixture of benzylic alcohol
2a and imine 3a in the presence of rhodium acetate. We were
gratified to find that the desired product, 4a, was obtained in 84%
isolated yield, 81:19 dr, and 53% ee, favoring the syn-isomer (Table
1, entry 1). In contrast, a control experiment of the same reaction
in the absence of rhodium acetate resulted in total recovery of
starting materials, indicating that phosphoric acid 5a alone was
unable to catalyze the reaction.8 To improve stereoselectivity,
various reaction conditions were optimized. The identity of the
alcohol component (2) was found to have significant effects on
both diastereo- and enantioselectivity (entries 2–6). The use of bulky
alcohols increased the dr value to 99:1 and the ee value to greater
than 80% (entries 5-6). The evaluation of various chiral phosphoric
acids derived from BINOL and H8-BINOL (5a-e) revealed that
9-phenanthryl-derived catalyst 5b was optimal, affording the syn-
product with greater than 90% ee (entries 7-10). Notably, catalyst
loadings could be decreased to 2 mol % without a deleterious effect
on the reaction yield or selectivity (entry 11 vs 7). The best results
were obtained at -20 °C, providing 4e in 86% yield, >99:1 dr,
and 93% ee (entry 12).
The ability of a metal complex and an organic molecule to
cooperatively catalyze a chemical reaction may broaden the reaction
scope within organic synthesis. Recently, this strategy has been
shown to be effective in asymmetric catalysis.5 In the course of
research in our laboratories, we observed that the aforementioned
Rh2(OAc)4-catalyzed three-component reaction (eq 1) was acceler-
ated by proton donors. This observation, coupled with the recent
success of chiral phosphoric acids in promoting asymmetric addition
reactions to imines,6 in particular, the multicomponent reactions,7
led us to envision the possibility to incorporate a chiral Brønsted
acid catalyst into the ylide-based three-component reaction to
achieve asymmetric catalysis. As shown in Scheme 1, activated
iminium III, formed from a chiral phosphoric acid and the imine,
† East China Normal University.
‡ University of Science and Technology of China.
9
7782 J. AM. CHEM. SOC. 2008, 130, 7782–7783
10.1021/ja801755z CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Catalyst Screening and Optimization of Reaction
The stereochemistry of the major isomer of brominated analogue
7k was determined to be (2S,3S) by single-crystal X-ray analysis,
and other compounds were tentatively assigned by analogy. The
9-anthryl protecting group of the products 7 can be readily removed
according to literature procedure9 to give free the hydroxyl analogue
of 7 in good yield10 (see Supporting Information).
In summary, we have developed an enantioselective three-
component reaction of diazo compounds and alcohols with imines
in the presence of Rh2(OAc)4 and a chiral Brønsted acid. The
reaction provides an efficient entry to syn-ꢀ-amino-R-hydroxyl acid
derivatives bearing a quaternary carbon stereogenic center in high
yields with excellent enantioselectivities. We anticipate that the
concept of Brønsted acid-metal cooperative catalysis will be
applicable to other reactions involving the addition of oxonium ylide
nucleophiles to various electrophiles that can be activated by
Brønsted acids. Our results to this end will be reported in due
course.
Conditionsa
catalyst
(mol %)
yield
(%)b
ee
(%)d
entry
2 (Ar)
2a (Ph)
4
drc
1
2
4a
4b
4c
4d
4e
4f
5a(10)
5a(10)
5a(10)
5a(10)
5a(10)
5b (5)
5b (5)
5c (5)
5d (5)
5e (5)
5b (2)
5b (2)
84
73
70
89
86
85
95
89
78
86
97
86
81/19
79/21
80/20
90/10
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
56
35
47
70
81
88
92
77
75
75
91
93
2b (p-NO2C6H4)
2c (p-MeOC6H4)
2d (1-naphthyl)
2e (9-anthryl)
2f (9-phenanthryl)
2e (9-anthryl)
2e (9-anthryl)
2e (9-anthryl)
2e (9-anthryl)
2e (9-anthryl)
2e (9-anthryl)
3
4
5
6
7
8
9
10
4e
4e
4e
4e
4e
4e
11
12
e
a Unless otherwise noted, the reaction was carried out by addition of
1a (0.25 mmol) in CH2Cl2 (1 mL) to a mixture of 2 mol % of
Rh2(OAc)4, 2 (1 equiv), 3a (1.1 equiv), 4 Å MS (0.1 g), and 5 in 2 mL
of CH2Cl2 under an argon atmosphere at 0 °C for 1 h. b Isolated yield.
c Determined by 1H NMR spectroscopy of the unpurified reaction
mixture. d Determined by HPLC. e T ) -20 °C.
Acknowledgment. We are grateful for financial support from
the NSFC (Grant Nos. 20772033, 20732006, and 20325211), the
Chinese Academy of Sciences (L.-Z.G.), and Shanghai Pujiang
Program (W.H.).
Supporting Information Available: Experimental details and
characterization of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Table 2. Enantioselective three-Component Reaction of Alcohol 2e
with Various Diazo Compounds and Iminesa
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yield
(%)b
ee
(%)d
entry
1 (Ar1)
3 or 6 (Ar3)
7
drc
1
2
1a (Ph)
1a (Ph)
6a (m-CH3C6H4) 7a
6b (C6H5) 7b
6c (2,3-Cl2C6H3) 7c
95
83
95
95
92
91
87
83
82
88
96
98
97
84
95
84
91
43
34
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
90
94
93
93
98
92
92
93
94
95
84
e
3
4
5
6
7
8
9
1a (Ph)
1a (Ph)
6d (o-CH3C6H4)
6e (p-CH3C6H4)
6f (o-ClC6H4)
3b (p-BrC6H4)
6g (p-ClC6H4)
6h (p-BrC6H4)
6i (1-naphthyl)
3a (C6H5)
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
10
11
12
13
14
15
16
17
1a (Ph)
1b (m-BrC6H4)
1c (p-MeOC6H4) 6b (C6H5)
>99/1 >99
1c (p-MeOC6H4)
1d (p-BrC6H4)
1d (p-BrC6H4)
1d (p-BrC6H4)
1e (o-BrC6H4)
1f (trans-styryl)
1c (p-MeOC6H4)
6h (p-BrC6H4)
6b (C6H5)
6g (p-ClC6H4)
3a (C6H5)
6h (p-BrC6H4)
6h (p-BrC6H4)
6j (cyclohexyl)
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
95/5
95
94
92
92
83
95
49
f
18
19
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a For conditions, see Supporting Information. b Isolated yield.
c Determined by 1H NMR spectroscopy of the unpurified reaction
mixture. d Determined by HPLC. e Reaction performed on a 2.5 mmol
scale with Rh2(OAc)4 (0.5 mol %) and 5b (1 mol %). f 1f (2 equiv) was
used, T ) 0 °C.
Under the optimized conditions, alcohol 2e undergoes highly
selective reaction with structurally diverse imines and diazo
compounds (Table 2). In most cases, only syn-products were
obtained in greater than 90% ee. Notably, one example stereospe-
cifically provided (S,S)-syn 7l in high yield (entry 12). Extension
of aryldiazo compounds 1a-1e to ethyl trans-styryldiazoacetate
(1f) gave the desired product 7r with moderate yield while
maintaining high ee (entry 18). When imine derived from aliphatic
aldehyde such as cyclohexyl formaldehyde was employed, both
yield and ee dropped significantly (entry 19). Unfortunately, the
reaction did not work well with ethyl diazoacetate under the current
reaction conditions.
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A.; Pastori, N.; Porta, O. J. Org. Chem. 2005, 70, 4174. (b) Roers, R.;
Verdine, G. L. Tetrahedron Lett. 2001, 42, 3563.
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J. AM. CHEM. SOC. VOL. 130, NO. 25, 2008 7783