Organocatalytic peroxy-asymmetric allylic alkylation

Article abstract of DOI:10.1039/b912110b

The peroxy-asymmetric allylic alkylation of hydroperoxyalkanes with Morita-Baylis-Hillman carbonates was catalysed by modified cinchona alkaloids (up to 93% ee), from which chiral α-methylene-β-hydroxy esters could be efficiently derived.

Full text of DOI:10.1039/b912110b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Organocatalytic peroxy-asymmetric allylic alkylation†
Xin Feng,a Yu-Qing Yuan,b Hai-Lei Cui,a Kun Jianga and Ying-Chun Chen*a
Received 19th June 2009, Accepted 17th July 2009
First published as an Advance Article on the web 31st July 2009
DOI: 10.1039/b912110b
Table 1 Screening studies of organocatalytic peroxy-AAA reaction of
hydroperoxyalkanes 1 and MBH carbonate 2aa
The peroxy-asymmetric allylic alkylation of hydroperox-
yalkanes with Morita–Baylis–Hillman carbonates was catal-
ysed by modified cinchona alkaloids (up to 93% ee), from
which chiral a-methylene-b-hydroxy esters could be efficiently
derived.
The a-methylene-b-hydroxy esters, which contain both an a,b-
unsaturated ester system and an allylic alcohol fragment, are
useful compounds and are often employed for the synthesis of
biologically important materials and natural products.1 They are
usually prepared via a Lewis base-catalysed aldol-type reaction
of acrylates and aldehydes, the so-called Morita–Baylis–Hillman
(MBH) reaction.2 Much efforts have been devoted to the asym-
metric MBH reaction over the past decades.3 Nevertheless, the
advancements for MBH reaction of acrylates are still far from
satisfying.4 A notable example was reported by Hatakeyama
et al. who developed a highly enantioselective asymmetric MBH
reaction of the activated 1,1,1,3,3,3-hexafluoroisopropyl acrylate
and aldehydes catalysed by b-isocupreidine (b-ICD).5 Chiral Lewis
acid catalysts have also been employed for the asymmetric MBH
reaction of acrylates, however, there were limitations for the enan-
tioselectivity, chemical yields and generality of the substrates.6 On
the other hand, some indirect ways for the preparation of chiral a-
methylene-b-hydroxy esters have been disclosed. Shimazaki et al.
presented a tandem asymmetric aldol reaction and oxidative
deselenisation to afford chiral a-methylene-b-hydroxy esters.7
Connon et al. described the first nonenzymatic acylative kinetic
resolution of MBH adducts.8 Trost and co-workers have developed
elegant deracemisation of MBH adducts catalysed by chiral Pd-
complexes.9 Therefore, the development of effective protocols to
access enantiomerically pure a-methylene-b-hydroxy esters is still
in demand.
Entry
Catalyst
Solvent
Yieldb (%)
eec (%)
1d
2
3
4
5
6
7
8
9
10
11
12e
13e
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2PHAL
(DHQD)2PYR
(DHQ)2PHAL
(DHQD)2PHAL
(DHQD)2PHAL
(DHQD)2PHAL
(DHQD)2PHAL
(DHQD)2PHAL
(DHQD)2PHAL
(DHQD)2PHAL
(DHQ)2PHAL
toluene
toluene
toluene
toluene
toluene
m-xylene
mesitylene
PhCF3
DCM
DCE
CCl4
CCl4
CCl4
52
64
60
63
66
67
67
74
72
65
76
79
71
30
32
82
79
-80
80
82
82
77
77
91
93
-90
a Unless noted otherwise, reactions were performed with 0.12 mmol of 1a,
0.1 mmol of 2a, 10 mol% of catalyst in 0.4 mL solvent for 48 h. b Isolated
yield. c Determined by chiral HPLC analysis. d At 50 ◦C. e 1b was used.
through the same strategy. Moreover, as outlined in Scheme 1,
chiral a-methylene-b-hydroxy esters would be smoothly prepared
from the corresponding chiral peroxides.
Compounds that contain peroxide fragments are widely used
in medical and chemical fields. Reliable approaches to peroxides,
however, are extremely limited, especially for chiral peroxides.10
Deng et al. have developed a highly enantioselective peroxidation
of a,b-unsaturated ketones via iminium activation.11 Very recently,
we reported that commercially available cinchona alkaloids can
act as excellent organocatalysts for asymmetric allylic alkylation
(AAA) reactions with MBH carbonates.12,13 It could be envisioned
that an enantioselective peroxy-asymmetric allylic alkylation of
hydroperoxyalkanes with MBH carbonates might be developed
Scheme 1 A tandem peroxy-AAA–reduction reaction to access chiral
a-methylene-b-hydroxy esters.
The initial study was conducted with commercially available
cumene hydroperoxide 1a and MBH carbonate 2a in toluene under
the catalysis of (DHQD)2AQN at 50 ◦C. To our gratification,
the desired peroxide 3a was isolated in a moderate yield after
48 h, albeit in a poor ee value (Table 1, entry 1). A similar
enantioselectivity was obtained at 35 ◦C but with a slightly
better yield (entry 2). Subsequently, other modified cinchona
alkaloids were screened at 35 ◦C. Good enantioselectivity (82%
ee) was observed when (DHQD)2PHAL was used (entry 3),
and (DHQD)2PYR showed similar enantiocontrol (entry 4). It
aKey Laboratory of Drug-Targeting and Drug Delivery System of Educa-
tion Ministry, Department of Medicinal Chemistry, West China School
of Pharmacy, Sichuan University, Chengdu, 610041, China. E-mail:
ycchenhuaxi@yahoo.com.cn; Fax: 86 28 85502609
bThe Third Hospital of Chengdu, Chengdu, China
† Electronic supplementary information (ESI) available: Experimental
procedures, structural proofs, NMR spectra and HPLC chromatograms
of the products. See DOI: 10.1039/b912110b
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was pleasing that a good ee value was also obtained in the
presence of (DHQ)2PHAL, while the peroxide 3a possesses the
opposite configuration (entry 5). Encouraged by these results,
we further investigated the effects of solvent by the catalysis
of (DHQD)2PHAL. Almost the same results were afforded in
various arene solvents (entries 6–8). Although slightly decreased
enantioselectivity was observed in DCM and DCE (entries 9
and 10), fortunately, a significantly improved enantioselectivity
was gained when CCl4 was utilised as the solvent (entry 11).
Moreover, an excellent ee value (93% ee) was attained when a
slightly more bulky hydroperoxyalkane 1b was applied without
affecting the reaction efficacy (entry 12). In addition, a satisfactory
enantioselectivity could be obtained with (DHQ)2PHAL under
the optimised conditions. Thus both enantiomers of the target
peroxide could be available in a highly enantioenriched form.
Consequently, an array of MBH carbonates 2 were explored in
the reactions with hydroperoxyalkane 1b to establish the generality
of this asymmetric transformation. The reactions were generally
conducted in CCl4 with 10 mol% of (DHQD)2PHAL at 35 ◦C. As
summarised in Table 2, the electronic characteristics of MBH
carbonates seemed to have limited effects on the enantioselectivity.
Good to excellent ee values were obtained for a diversity of
MBH carbonates bearing electron-withdrawing or -donating aryl
groups, and moderate to good isolated yields were delivered
(entries 1–9). In addition, heteroaryl-substituted MBH carbonates
could be successfully applied, and excellent enantioselectivities
were attained (entries 10 and 11).14 On the other hand, we
have tested more asymmetric reactions with (DHQ)2PHAL, the
peroxides 3d and 3i with the opposite configuration were also
provided in high enantioselectivity (entries 12 and 13).
As illustrated in Scheme 2, the peroxo-allylic alkylation prod-
uct 3b could be efficiently converted to the corresponding
a-methylene-b-hydroxy ester (S)-(+)-4a in high yield (93%)
without any racemisation,15 employing zinc powder as thereducing
reagent in a mixture of acetic acid and water (1:1).
Scheme 2 Synthesis of a-methylene-b-hydroxy ester.
In conclusion, we have developed the first peroxo-asymmetric
allylic alkylation of bulky hydroperoxyalkanes with Morita–
Baylis–Hillman (MBH) carbonates by the catalysis of commer-
cially available modified cinchona alkaloids. The peroxides were
generally obtained in high enantioselectivities (84–93% ee) in
fair to good yields, from which the corresponding a-methylene-
b-hydroxy esters could be smoothly derived without affecting
the optical purity. Currently, the further application of modified
cinchona alkaloids in other asymmetric allylic alkylations is under
investigation in this laboratory.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (20772084).
Notes and references
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Table 2 Organocatalytic peroxy-AAA reaction of hydroperoxyalkane 1b
and MBH carbonates 2a
2 For reviews on the Morita–Baylis–Hillman reaction, see: (a) D.
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Entry
R
3
t (h) Yieldb (%) eec(%)
1
2
3
4
5
6
7
8
9
10
11
12f
13f
Ph
p-F-C6H4
p-Cl-C6H4
m-Cl-C6H4
3,4-Cl2-C6H3
p-Me-C6H4
m-Me-C6H4
p-MeO-C6H4
3,4-methylene-dioxo-C6H3
2-thienyl
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3d
3i
48
58
58
48
46
50
47
47
52
48
56
58
56
79
69
71
71
73
65
67
73
50
53
62
72
65
93d
90e
89e
83e
88e
86e
92
93
89
92e
91
2-furyl
p-Cl-C6H4
p-MeO-C6H4
-89
-91e
a Unless noted otherwise, reactions were performed with 0.12 mmol of
1b, 0.1 mmol of 2, 10 mol % of (DHQD)2PHAL in 0.4 mL CCl4 at
35 ◦C. b Isolated yield. c Determined by chiral HPLC analysis. d The
absolute configuration of 3b was determined by comparison with literature
optical rotation data after reduction with zinc powder (see Scheme 2).
e Determined after conversion to the corresponding a-methylene-b-
hydroxy ester. f (DHQ)2PHAL was used.
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3662 | Org. Biomol. Chem., 2009, 7, 3660–3662
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The Royal Society of Chemistry 2009
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