Enantioselective synthesis of β-iodo Morita-Baylis-Hillman esters by a catalytic asymmetric three-component coupling reaction

Full text of DOI:10.1002/anie.200900351

Communications
DOI: 10.1002/anie.200900351
Multicomponent Reactions
Enantioselective Synthesis of b-Iodo Morita–Baylis–Hillman Esters by
a Catalytic Asymmetric Three-Component Coupling Reaction**
Bidyut Kumar Senapati, Geum-Sook Hwang, Sungil Lee, and Do Hyun Ryu*
Dedicated to Professor Sung Ho Kang on the occasion of his 60th birthday
Optically active a-methylene-b-hydroxy carbonyl derivatives
can be prepared by the asymmetric Morita–Baylis–Hillman
(MBH) reaction.[1] These derivatives are useful chiral building
blocks for biologically active molecules and natural products
because of their multifunctional composition.[2] Even with
recent advances in this area, asymmetric synthesis of b-
substituted MBH products such as b-branched MBH ketones
or esters have not been successful by this method.[2] One
efficient route to give various b-branched MBH products[3]
can be achieved through the cross-coupling reaction of chiral
b-halo MBH products (Scheme 1). The presence of a halogen
E/Z-stereocontrolled synthesis of b-halo MBH products can
provide efficient entry to give various optically active b-
substituted MBH products. Although racemic E-[5] or Z-
stereocontrolled[6] synthetic approaches to give b-halo MBH
esters or ketones have been reported by our research group
and others, methods for asymmetric conversion[7] are cur-
rently limited. Li et al. have reported the asymmetric syn-
thesis of b-iodo MBH ketones by using an aldol reaction
between preformed silyl allenolates and aldehydes that was
catalyzed by N-heptafluorobutyryl oxazaborolidine.[7a] They
also reported a catalytic, asymmetric synthetic method to give
b-iodo MBH esters, which are more useful than their ketone
counterparts.[7b] However, there have been no reports of
highly enantioselective and E/Z-stereocontrolled synthetic
methods to give optically active b-halo MBH esters.
We report herein the highly enantioselective and Z-
stereocontrolled three-component coupling reaction of a,b-
acetylenic esters, aldehydes, and trimethylsilyl iodide (TMSI)
using chiral cationic oxazaborolidinium catalysts (Scheme 1).
The reaction provides the optically active b-iodo MBH esters
with good to excellent yield and enantioselectivity in a
straightforward way. In addition, the subsequent metal-
catalyzed cross-coupling of these esters are performed
directly to access the synthetically more useful b-branched
MBH esters through a single step (Scheme 1). The stereo-
chemical course of the reaction and its high Z selectivity are
rationalized by the preassembly of the transition state, shown
in Scheme 3.
Scheme 1. Enantioselective synthesis of Z-selective b-branched MBH
esters through b-halo MBH esters.
atom in the b position is beneficial for numerous further
transformations on the products and is useful for the rapid
construction of complex organic molecules.[4] Consequently,
the development of efficient methods for enantioselective and
The chiral oxazaborolidinium salts (1 and 2; Scheme 2)
behave as powerful Lewis acids and have been proven to be
effective catalysts for enantioselective Diels–Alder reaction-
s,[8a,e,f] cyanosilylations,[8b,c] and Michael reactions.[8d] There is
much evidence for the formation of the complex between
catalyst 1 and aldehydes.[8a,b] We applied these oxazaboroli-
dinium catalysts in a three-component coupling reaction
involving an aldehyde, an alkyl propiolate, and TMSI.
[*] Dr. B. K. Senapati, S. Lee, Prof. Dr. D. H. Ryu
Department of Chemistry, Sungkyunkwan University
300 Cheoncheon-dong, Jangan-gu, Suwon City
Gyeonggi-do, 440-746 (Korea)
Fax: (+82)31-290-5976
E-mail: dhryu@skku.edu
Prof. Dr. G.-S. Hwang
KoreaBasic Science Institute and
Graduate School of Analytical Science and Technology
Chungnam National University
5St, Anam-Dong, Seongbuk-Gu, Seoul, 136-713 (Korea)
[**] This work was supported by a Korea Research Foundation Grant
funded by the Korean Government (MEST) (grant nos. KRF-2008-
005-J00701, KRF-2008-331-C00160), by the Korea Science and
Engineering Foundation (KOSEF) grant funded by the Korea
government (MEST) (grant no. R01-2008-000-11094-0), and by the
Postdoctoral Research Program of Sungkyunkwan University
(2008).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900351.
Scheme 2. Catalysts screened for enantioselective synthesis of b-iodo
MBH esters.
4398
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 4398 –4401

Angewandte
Chemie
Benzaldehyde was selected as a model substrate for the
initial optimization (Table 1). The three-component coupling
reaction between benzaldehyde, ethyl propiolate, and
nBu4NI, using 0.2 equivalents of catalyst 1a in CH2Cl2 at
After optimization of the reaction parameters for Z ster-
eoselective, asymmetric three-component coupling reactions,
the scope of this methodology was studied (Table 2). Reac-
tions with various aldehydes provided the corresponding Z-
selective b-iodo MBH esters 4 in high to excellent enantio-
Table 1: Enantioselective Z stereocontrolled three-component coupling
between benzaldehyde, alkyl propiolate, and TMSI[a]
Table 2: Results of the catalytic enantioselective synthesis of Z-selective
b-iodo MBH esters.[a]
Entry Cat. R1 Reaction conditions
Yield
[%][b]
Z/E[c] ee
[%][d]
Entry Catalyst
R
t [h] Yield [%][b]
Z/E[c] ee [%][d]
1
2
3
4
5
6
7
8
9
10
1a Et nBu4NI, CH2Cl2, À408C, 10 h
1a Et TMSI, CH2Cl2, À408C, 3 h
26
68
85:15 20
90:10 77
88:12 69
92:8 84
94:6 67
99:1 84
1
2
3
4
5
6
7
8
1c
1c
1a
1a
1a
1a
1a
1a
1c
1c
1a
1b
1b
1b
Ph
1
3
4
2
5
5
6
95
92
75
99
95
90
91
66
92
95
65
72
61
50
>99:1
94
92
92
96
90
93
95
90
62
90
91
93
90
90
4-FC6H4
4-CF3C6H4
4-ClC6H4
2-BrC6H4
4-BrC6H4
4-CNC6H4
>99:1
99:1
99:1
>99:1
96:4
97:3
92:8
99:1
92:8
98:2
96:4
97:3
95:5
1a Et TMSI, CH3CH2CN, À408C, 10 h 38
1a Et TMSI, toluene, À788C, 5 h
1b Et TMSI, CH2Cl2, À788C, 3 h
1a Me TMSI, CH2Cl2, À788C, 1.5 h
1a tBu TMSI, CH2Cl2, À788C, 10 h
1a Et TMSI, CH2Cl2, À788C, 2 h
85
92
92
0
93
90
95
–
–
>99:1 87[e]
>99:1 87[f]
>99:1 94[e]
4-NO2C6H4 30
2
Et TMSI, CH2Cl2, À788C, 2 h
9
4-MeC6H4
4-PhC6H4
2-naphthyl
nPr
n-hexyl
iPr
1.5
1.5
12
8
12
12
1c Et TMSI, CH2Cl2, À788C, 1 h
10
11
12[e]
13[e]
14[e]
[a] Reactions run with 1.0 mmol of benzaldehyde, 2.0 mmol of ethyl-
propiolate, 1.5 mmol of the iodide source, and 0.2 mmol of catalyst.
[b] Yield of isolated product. [c] Determined after separation by column
chromatography. [d] Determined by HPLC on a chiral stationary phase.
[e] The absolute configuration of 3 was determined to be R enriched. For
details see the Supporting Information. [f] The absolute configuration of
3 was determined to be S enriched.
[a] Reactions run with 1.0 mmol of aldehyde, 2.0 mmol of ethylpropio-
late, 1.5 mmol of TMSI, and 0.2 mmol of catalyst. [b] Yield of isolated
product. [c] Determined after separation by column chromatography.
[d] Determined by HPLC on a chiral stationary phase. [e] Reaction run
using 2.5 equivalents of ethyl propiolate and 2.0 equivalents of TMSI at
À608C.
À408C gave the desired product (26% yield) with a poor
enantioselectivity (20% ee) for the Z isomer (Table 1,
entry 1). Replacement of nBu4NI by TMSI under similar
reaction conditions produced the desired product with an
improved yield and ee value (Table 1, entry 2). The resulting
Z and E isomers of 3 could be easily separated by column
chromatography on silica gel. The Z configuration of the
major product was determined unambiguously by 2D
ROESY analysis, as mentioned in our previous report.[6g]
The reaction conditions were then optimized by varying the
reaction parameters and catalysts. During our investigation, it
emerged that catalyst 1a provided better ee values than 1b in
CH2Cl2 compared to toluene or propionitrile. The Z selectiv-
ity of product 3 was excellent (> 99:1) at À788C compared to
À408C (compare Table 1, entries 2 and 8). This high stereo-
selectivity obtained at low temperature is due to the multi-
coordinating Lewis acidic catalyst 1, which prefers the
chairlike transition state 5a to give the kinetically favored
Z product (Scheme 3).[6g,7a] Both ethyl and methyl propiolates
provided high enantioselectivity under similar conditions
(Table 1, entries 6 and 8). However, in the case of tert-butyl
propiolate a coupling product could not be isolated (Table 1,
entries 7). Both catalysts 1a and 2 were effective at providing
(R)- and (S)-b-iodo MBH esters in high yield and ee,
respectively (Table 1, entries 8 and 9). The use of mexyl-
substituted catalyst 1c improved the ee value of 3 up to 94%
(Table 1, entry 10).
meric excess. For aromatic aldehydes, substitution with
electron-withdrawing groups lowered the reaction rate but
provided excellent enantioselectivites (90–96% ee; Table 2,
entries 2–8). The strong electron-withdrawing 4-nitro group
can be expected to lower the basicity of the aldehyde carbonyl
group and thereby reduce the degree of complexation which
results in the catalyst reacting at a slow rate (Table 2, entry 8).
Conversely, electron-donating substituents such as p-tolual-
dehyde caused
a significant loss in enantioselectivity
(62% ee; Table 2, entry 9).[9] Similar results were observed
for the cyanosilylation of ketones.[8c] 4-Biphenyl and 2-
naphthyl carboxaldehyde were also treated under similar
reaction condition to produce b-iodo MBH esters with
excellent yield and enantioselectivity (Table 2, entry 10 and
11). The reaction rate of aliphatic aldehydes was considerably
slow at À788C. Optimal results were obtained at À608C when
1a was replaced with the triflimide-activated catalyst 1b
owing to the higher stability of triflimide-activated catalysts[8a]
(Table 2, entries 12–14). The reaction of iosobutyraldehyde
(Table 2, entry 14) resulted in high enantioselectivities and
moderate yield.
The absolute configuration of the major enantiomeric
isomer was assigned as R by chemical correlations. Product 3
(Table 1, entries 8 or 10) was transformed into (R)-2-
methoxy-2-phenylacetic acid (see the Supporting Informa-
Angew. Chem. Int. Ed. 2009, 48, 4398 –4401
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4399

Communications
1
tion) and its H NMR spectrum and specific rotation data
the presence of Pd(OAc)2 under known reaction conditions
proceeded smoothly to give (Z)-b-phenyl MBH ester 6 with a
91% yield without an obvious loss of enantiopurity.[12]
Sonogashira coupling with phenyl acetylene and [PdCl2-
(PPh3)2] produced 7 in a 95% yield.[13] Similarly, organo-
cuprate-promoted conjugate addition of Grignard reagent
provided exclusively (Z)-b-branched allylic alcohols 8 with an
excellent yield without loss of enantiopurity.[14]
correlates with those reported earlier.[10] The resulting
Z geometry and stereochemical course of the three-compo-
nent coupling reactions (represented in Table 2) can be
explained by the asymmetric aldol reaction between trime-
thylsilyl b-iodo allenoate and aldehydes via a cyclic transition
state of pentacoordinated[11] catalyst 1 (Scheme 3).[7a] As
In summary, we have developed a highly enantioselective,
catalytic three-component coupling reaction between an
aldehyde, ethyl propiolate, and TMSI to give chiral (Z)-b-
iodo MBH esters. Both the enantiomers of (Z)-b-iodo MBH
esters (R/S) could be obtained enantioselectively by using an
S- or R-oxazaborolidinium catalyst (1 or 2). These esters can
be directly converted into the optically active (Z)-b-branched
derivatives with retention of configuration. The absolute
configuration of the product was that predicted by the
transition state model 5a. We believe that these results
should be useful in the synthesis of various optically active
(Z)-b-branched Morita–Baylis–Hillman esters. Further opti-
mization of this catalytic asymmetric reaction, extension of
the scope, and synthetic applications are in progress.
Scheme 3. Transition-state model for the asymmetric Michael-aldol
reaction.
serious steric interactions between the I and R groups are
obvious in transition state 5b, therefore transition state 5a is
favored and predominantly affords the Z isomer. In terms of
R chirality, the mode of complexation of the aldehydes is the
same as that shown in the enantioselective formation of (R)- Experimental Section
cyanohydrins from aldehydes and trimethylsilyl cyanide.[8b]
The formyl carbon atom is situated above the nearby bulky
aryl groups, which effectively shields the re face (back) from
attack by the b-iodo allenoate intermediate. Thus, nucleo-
philic attack of the allenoate carbon atom from the si face
(front) of the formyl carbon atom is facilitated and leads to
R enantioselectivity. Owing to the greater shielding ability of
the mexyl groups, catalyst 1c provided a 1–7% higher
ee value than catalyst 1a.
To extend the application of the resulting b-iodo MBH
adducts, we performed various cross-coupling reactions to
generate chiral (Z)-b-branched MBH adducts without the
need to protect the chiral alcohol (Scheme 4). Suzuki
coupling of 4 (Table 2, entry 1) with phenyl boronic acid in
Synthesis of 4: A freshly prepared solution of triflic acid in CH2Cl2
(0.200m solution, 0.690 mL, 0.138 mmol) was added dropwise to an
aliquot of oxazaborolidine precursor 1c (0.166 mmol, ca. 20 mol%,
theoretical) in of CH2Cl2 (1.5 mL) at À408C under nitrogen. During
the addition, the catalyst solution turned orange in color but then
became clear instantaneously. Towards the end of the reaction, a
small amount of orange precipitate was observed. After stirring for
15–20 min at À408C, the orange precipitate disappeared and a
colourless homogeneous solution of catalyst was obtained. Benzalde-
hyde (0.691 mmol, 70.5 mL) was then added dropwise to the cooled
(À788C) solution of catalyst. After 20 min of stirring at À788C, ethyl
propiolate (1.383 mmol, 140 mL) and TMSI (1.04 mmol, 148 mL) were
quickly added to the mixture sequentially. After stirring for 1 h at
À788C, the reaction mixture was quenched with H2O (2 mL) and the
aqueous layer was extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried (Na2SO4), filtered, and the
solvent removed under vacuum to produce the crude product.
Purification by flash column chromatography on silica gel (eluent:
1:10 EtOAc/hexanes) afforded the corresponding b-iodo MBH ester
4 as a colourless oil in 95% yield (218 mg, 94% ee ; Table 2, entry 1).
Received: January 20, 2009
Published online: May 4, 2009
Keywords: asymmetric synthesis · Morita–Baylis–
.
Hillman esters · multicomponent reactions ·
oxazaborolidinium catalyst · synthetic methods
[1] For recent reviews on the Morita-Baylis–Hillman reaction, see
a) G. Masson, C. Housseman, J. Zhu, Angew. Chem. 2007, 119,
4698; Angew. Chem. Int. Ed. 2007, 46, 4614; b) Y.-L. Shi, M. Shi,
Eur. J. Org. Chem. 2007, 2905; c) D. Basavaiah, K. V. Rao, R. J.
Reddy, Chem. Soc. Rev. 2007, 36, 1581.
Scheme 4. Synthesis of Z-selective b-branched chiral MBH esters by a
direct cross-coupling reaction. DME=1,2-dimethoxyethane, DMSO=
dimethyl sulfoxide.
[2] a) D. Basavaiah, A. J. Rao, T. J. Satyanarayana, Chem. Rev. 2003,
103, 811; b) K. Y. Lee, K. Y. Gowrisankar, J. N. Kim, Bull.
Korean Chem. Soc. 2005, 26, 1481.
4400 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 4398 –4401

Angewandte
Chemie
[3] For other routes to b-branched MBH products, see: a) T.
Kataoka, H. Kinoshita, S. Kinoshita, T. Iwamura, S. Watanabe,
Angew. Chem. 2000, 112, 2448; Angew. Chem. Int. Ed. 2000, 39,
2358; b) P. Ramachandran, M. T. Rudd, T. E. Burghardt,
M. V. R. Reddy, J. Org. Chem. 2003, 68, 9310; c) T. E. Reynolds,
A. R. Bharadwaj, K. A. Scheidt, J. Am. Chem. Soc. 2006, 128,
15382; d) T. E. Reynolds, K. A. Scheidt, Angew. Chem. 2007,
119, 7952; Angew. Chem. Int. Ed. 2007, 46, 7806; e) E. Tarsis, A.
Gromova, D. Lim, G. Zhou, C. Guoqiang, D. M. Coltart, Org.
Lett. 2008, 10, 4819; f) A. J. Mueller, M. P. Jennings, Org. Lett.
2008, 10, 1649.
[4] For the transformation of vinyl halides, see: a) G. S. Zweifel,
M. H. Nantz in Modern Organic Synthesis: An Introduction,
W. H. Freeman and Company, New York, 2007, pp. 290 – 358;
b) J. Tsuji in Palladium Reagents and Catalysts, Wiley, New York,
2004, pp. 109 – 176; c) M. C. Walczak, R. S. Coleman, Org. Lett.
2005, 7, 2289.
Enright, Org. Lett. 2000, 2, 617; f) C. Timmons, A. Kattuboina, S.
Banerjee, G. Li, Tetrahedron Lett. 2006, 62, 7151; g) S. Lee, G.-S.
Hwang, D. H. Ryu, Synlett 2007, 59.
[7] a) G. Li, H.-X. Wei, B. S. Phelps, D. W. Purkiss, S. H. Kim, Org.
Lett. 2001, 3, 823; b) D. Chen, C. Timmons, J. Liu, A. Headley, G.
Li, Eur. J. Org. Chem. 2004, 3330; c) D. Chen, G. Li, Guo,
S. R. S. S. Kotti, G. Li, Tetrahedron: Asymmetry 2005, 16, 1757.
[8] a) D. H. Ryu, E. J. Corey, J. Am. Chem. Soc. 2003, 125, 6388;
b) D. H. Ryu, E. J. Corey, J. Am. Chem. Soc. 2004, 126, 8106;
c) D. H. Ryu, E. J. Corey, J. Am. Chem. Soc. 2005, 127, 5384;
d) D. Liu, S. Hong, E. J. Corey, J. Am. Chem. Soc. 2006, 128,
8160; e) J. Y. Sim, G.-S. Hwang, K. H. Kim, E. M. Ko, D. H. Ryu,
Chem. Commun. 2007, 5064; f) M. Y. Lee, K. H. Kim, S. Jiang,
Y. H. Jung, J. Y. Sim, G.-S. Hwang, D. H. Ryu, Tetrahedron Lett.
2008, 49, 1965.
[9] 4-Methoxybenzaldehyde was found to be incompatible under
our catalytic conditions; it gave a complex mixture. The 4-
methoxy group might be causing problems through some kind of
complexation with the boron atom of the oxazaborolidinium
catalyst.
[5] a) Q. Li, M. Shi, J. M. Lyte, G. Li, Tetrahedron Lett. 2006, 47,
7699; b) S. Lee, G.-S. Hwang, S. C. Shin, T. G. Lee, R. H. Jo,
D. H. Ryu, Org. Lett. 2007, 9, 5087.
[6] For a review on (Z)-b-halo MBH synthesis, see: a) G. Li, J.
Hook, H.-X. Wei in Recent Research Developments in Organic &
Bioorganic Chemistry; Transworld Research Network, Vol. 4,
2001, pp. 49 – 61; b) T. Kataoka, Y. Banno, S. Watanabe, T.
Iwamura, H. Shimizu, Tetrahedron Lett. 1997, 38, 1809; c) S.
Watanabe, K. Yamamoto, Y. Itagaki, T. Kataoka, J. Chem. Soc.
Perkin Trans. 1 1999, 2053; d) G. Li, H.-X. Wei, T. D. Caputo,
Tetrahedron Lett. 2000, 41, 1; e) G. Li, J, Gao, H.-X. Wei, M.
[10] E. Boyd, S. Chavada, J. Eames, Y. Yohannes, Tetrahedron:
Asymmetry 2007, 18, 476.
[11] T. Ooi, D. Uraguchi, N. Kagoshima, K. Maruoka, J. Am. Chem.
Soc. 1998, 120, 5327.
[12] N. A. Bumagin, V. V. Bykov, Tetrahedron 1997, 53, 14437.
[13] Z. Lu, S. Ma, J. Org. Chem. 2006, 71, 2655.
[14] T. B. Ayed, J. Villiꢀras, H. Amri, Tetrahedron 2000, 56, 805.
Angew. Chem. Int. Ed. 2009, 48, 4398 –4401
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4401