Direct asymmetric michael addition to nitroalkenes: Vinylogous nucleophilicity under dinuclear zinc catalysis

Full text of DOI:10.1021/ja809723u

Published on Web 03/12/2009
Direct Asymmetric Michael Addition to Nitroalkenes: Vinylogous
Nucleophilicity under Dinuclear Zinc Catalysis
Barry M. Trost* and Julien Hitce
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received December 12, 2008; E-mail: bmtrost@stanford.edu
Table 1. Selected Optimization Resultsa
The Michael addition is certainly one of the most powerful bond-
forming transformations, and the diversity in donors and acceptors
that can be combined is remarkable. Recent efforts have focused
on the development of efficient methods to perform direct,
asymmetric Michael addition reactions, and notable success has
been achieved by using both organocatalysis1 and transition metal
catalysis.2 The self-assembled dinuclear complexes generated from
our Bis-ProPhenol ligand and adequate metal sources3 are poten-
tially suitable catalysts.4 The complementary reactivity of the two
metal centers allows for dual activation whereas conformational
rigidity enables chiral recognition, as illustrated in a variety of direct
asymmetric addition reactions and desymmetrization processes.5
Selecting the Michael addition to nitroalkenes as a probe reaction,
we decided to incorporate a new concept into our general strategy,
namely vinylogous nucleophilicity.6,7 As the donor, 2(5H)-furanone
2 was envisioned to be a challenging yet ideal candidate to
demonstrate the synthetic efficiency of our system. Indeed, this
commonly utilized nucleophile usually requires preactivation as a
siloxydiene a` la Mukaiyama,8 and direct approaches are conse-
quently highly valuable from the standpoint of atom economy.
While such a strategy was reported in a stereoselective vinylogous
1,2-addition,9 the direct use of 2 in asymmetric conjugate addition
has not been precedented.
entry
solvent
[nitroalkene]
time (h)
yield (%)b
drc
ee (%)d
1
2
3
4
5
6
THF
toluene
Et2O
dioxane
THF
THF
0.5 M
0.5 M
0.5 M
0.5 M
0.25 M
0.125 M
19
8
26
22
19
35
75
71
40
69
76
71
8:1
5:1
1:1
6:1
10:1
17:1
91
92
65
93
91
92
a All reactions were carried out using 1 equiv of 3a (0.50 mmol), 2
equiv of 2, 0.10 equiv of (S,S)-complex 1, and 100 mg of 4 Å MS.
b Refers to the isolated mixture of diastereoisomers. c Determined by 1H
NMR of the crude reaction mixture. d Enantiomeric excess of the major
diastereoisomer, determined by chiral HPLC.
Table 2. Variation of the Nitroalkenea
As previously reported,3 the dinuclear zinc complex 1 was
prepared by treating the commercially available (S,S)-Bis-ProPhenol
ligand with 2 equiv of Et2Zn. Early optimization with Michael
acceptor 3a proved that 1 was competent at promoting the alkylation
of butenolide 2 at the γ-position at room temperature. Among the
solvents that were screened, THF gave the highest diastereoselec-
tivity (Table 1, entries 1-4). Interestingly, the reaction proceeded
faster in toluene with similar yield and enantioselectivity. Dilution
had a beneficial effect on the diastereoselectivity: Michael adduct
4a was obtained with 10:1 dr by lowering the concentration of
nitroalkene to 0.25 M (entry 5). Upon dilution to 0.125 M,
diastereoselectivity could be further improved to 17:1 dr, albeit at
the expense of an extended reaction time (entry 6).
entry
R
product
yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
9
2-Me-Ph (3b)
4-Me-Ph (3c)
4-MeO-Ph (3d)
4-Cl-Ph (3e)
3-Br-Ph (3f)
1-naphthyl (3g)
2-furanyl (3h)
3-furanyl (3i)
2-thiophenyl (3j)
3-thiophenyl (3k)
N-Boc-3-indolyl (3l)
PhCH2CH2 (3m)
PhCHCH (3n)
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
74
70
78
70
72
75
77
65
69
71
73
47
52
8:1
17:1
20:1
9:1
92
95
96
90
87
94
95
95
94
95
85
83
91
7:1
>20:1
18:1
14:1
>20:1
17:1
6:1
10
11e f
,
12e
13e
4:1g
3:1
Adopting the conditions described in Table 1, entry 5 as the
optimal compromise between reactivity and stereoselectivity, the
generality of the method was demonstrated by evaluating a variety
of nitroalkenes (Table 2). ꢀ-Nitrostyrenes (entries 1-5) tolerated
substitution at any position of the aromatic ring, and both electron-
donating and electron-withdrawing functionalities were compatible.
The electron-rich substrate 3d gave the best results: the corre-
sponding adduct 4d was obtained in 78% yield with 20:1 dr and
96% ee (entry 3). In the case of the 1-naphthyl derivative 3g,
excellent diastereo- and enantioselectivity were achieved as well
(entry 6). Nitroalkenes bearing heteroaromatic ꢀ-Substituents were
also suitable substrates as exemplified by the preparation of both
regioisomers 4h and 4i in 95% ee (entries 7 and 8). Similarly good
yields and stereoselectivities were observed with the thiophene
counterparts (entries 9 and 10). The indole-substituted nitroalkene
a All reactions were carried out using 1 equiv of nitroalkene 3 (0.50
mmol, 0.25 M), 2 equiv of 2, 0.10 equiv of (S,S)-complex 1, and 100
mg of 4 Å MS. b Refers to the isolated mixture of diastereoisomers.
c Determined by 1H NMR of the crude reaction mixture. d Enantiomeric
excess of the major diastereoisomer, determined by chiral HPLC.
e Reaction performed in toluene instead of THF. f Results using THF:
60% yield, 7:1 dr, 62% ee. g Determined by chiral HPLC.
3l proved to be a more challenging acceptor under the optimized
conditions. However, switching the solvent to toluene improved
the yield and the enantioselectivity (entry 11). As it could be
expected from the optimization studies, toluene was also more
appropriate for the less reactive aliphatic substrate 3m and the
corresponding Michael adduct was isolated in 47% yield with 4:1
dr and 83% ee (entry 12). Similarly, starting from the 1-nitro-1,3-
9
4572 J. AM. CHEM. SOC. 2009, 131, 4572–4573
10.1021/ja809723u CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
diene 3n the 1,4-addition product 4n was obtained with moderate
yield and diastereoselectivity but with high enantioselectivity (entry
13). In several instances, the stereoisomeric purity of the Michael
adducts could be enhanced by recrystallization. For example,
product 4a could be isolated with 20:1 dr and 98% ee with excellent
mass recovery (65% yield from 3a). Moreover, crystals from
chloride 4e were suitable for an X-ray analysis which established
the syn stereochemical outcome of the reaction as well as the
absolute configuration. The stereochemistry of the other Michael
adducts 4 was assigned by analogy.
A tentative catalytic cycle that accounts for the observed
stereoselectivity is depicted in Scheme 1. Binding of the nucleophile
as a bidentate bridging aromatic enolate3b,10 would ensure diaste-
reoselection in the attack on the electrophile activated by com-
plexation to the Lewis acidic zinc atom in the indicated orientation.
Formation of the new C-C bond within this highly organized
environment would lead to a zinc nitronate intermediate. Finally,
proton transfer with an incoming molecule of nucleophile would
release product 4 and complete the catalytic cycle. The fact that
open coordination sites remain on the zinc that may allow additional
entities present to ligate and thereby modify the nature of the chiral
space may account for the dilution effect.3d
We believe this reactivity feature paves the way for a wide diversity
of potential donors, and further exploration is currently underway.
Scheme 2. Elaboration of a Vinylogous Michael Adducta
a Conditions: (a) RuCl3 ·6H2O (7 mol%), NaIO4 (1.5 equiv), CH3CN/
H2O 5:1, 0 °C, 76% yield; (b) TBSOTf (3 equiv), 2,6-lutidine (3 equiv),
CH2Cl2, 0 °C to rt, 84% yield; (c) 10% Pd/C, 1 atm of H2, MeOH, rt, 69%
yield; (d) neat, rt, 7 d.
Acknowledgment. We thank the NSF and NIH (GM13598) for
their generous support. J.H. acknowledges the Ministe`re Franc¸ais
des Affaires Etrange`res et Europe´ennes for a Lavoisier postdoctoral
fellowship.
Supporting Information Available: Detailed experimental proce-
dures and characterization data for 4-7; CIF file for 4e and 5. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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Scheme 1. Proposed Catalytic Cycle
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The Michael adducts 4 are versatile building blocks as one can
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nitro functionality. Compound 4a served as a model to straight-
forwardly illustrate this synthetic potential (Scheme 2). Thus, Ru-
catalyzed cis-dihydroxylation11 of the conjugated olefin led to diol
5 in 76% yield with complete diastereoselectivity.12 In this way,
excellent control was achieved over four adjacent stereocenters,
newly created in only two steps from 3a. The hydroxyl groups were
masked as silyl ethers to avoid handling of otherwise highly polar
products resulting from the reduction of the nitro substituent. The
latter transformation proceeded smoothly under standard conditions
to afford the densely functionalized primary amine 6. Spontane-
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into lactam 7. Interestingly, similar polyhydroxyazepanones are
being actively investigated in search of potent glycosidase inhibi-
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nucleophile.
In summary, synthetically versatile γ-substituted butenolides were
prepared stereoselectively by direct asymmetric Michael addition
to nitroalkenes.14 This extension of the scope of our dinuclear zinc
catalyst showcases its ability to promote vinylogous nucleophilicity.
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