Enantioselective α-vinylation of aldehydes via the synergistic combination of copper and amine catalysis

Article abstract of DOI:10.1021/ja303116v

The enantioselective α-vinylation of aldehydes using vinyl iodonium triflate salts has been accomplished via the synergistic combination of copper and chiral amine catalysis. These mild catalytic conditions provide a direct route for the enantioselective construction of enolizable α-formyl vinylic stereocenters without racemization or olefin transposition. These high-value coupling adducts are readily converted into a variety of useful olefin synthons.

Full text of DOI:10.1021/ja303116v

Subscriber access provided by EDINBURGH UNIVERSITY LIBRARY | @ http://www.lib.ed.ac.uk
Communication
Enantioselective #-Vinylation of Aldehydes Via the
Synergistic Combination of Copper and Amine Catalysis
Eduardas Skucas, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja303116v • Publication Date (Web): 22 May 2012
Downloaded from http://pubs.acs.org on May 23, 2012
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 4
Journal of the American Chemical Society
1
2
3
4
5
Enantioselective α-Vinylation of Aldehydes Via the Synergistic
Combination of Copper and Amine Catalysis
Eduardas Skucas and David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544
dmacmill@princeton.edu
6
7
8
RECEIVED DATE
9
Scheme 1. Proposed Synergistic Cycles for Aldehyde α-Vinylation
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Abstract: The enantioselective α-vinylation of aldehydes
OTf
Ph
oxidative
addition
using vinyl iodonium triflate salts has been accomplished
via the synergistic combination of copper and chiral amine
catalysis. These mild catalytic conditions provide a direct
route for the enantioselective construction of enolizable α-
formyl vinylic stereocenters without racemization or olef-
in transposition. These high-value coupling adducts are
readily converted into a variety of useful olefin synthons.
I
Y
vinyl iodonium
Copper
Catalytic Cycle
Y
CuIBr
BrCuIII
1
2
While mono-catalysis strategies have successfully delivered
vast numbers of new reactions over many decades, multi-
catalysis concepts that allow access to many elusive or
unattainable transformations have only recently begun to evolve.
In particular, synergistic catalysis, wherein two catalysts and two
catalytic cycles work in concert to create a single new bond, has
emerged as a powerful mechanistic approach to asymmetric
reaction engineering.1-3 In this context, our laboratory has
recently described the enantioselective α-trifluoromethylation
and α-arylation of aldehydes via the synergistic combination of
copper catalysis, organocatalysis and iodonium salts (eq 1), two
protocols that enable the production of structural motifs of high
value to the pharmaceutical sciences.4-6 Continuing this theme,
we questioned whether this multi-catalysis strategy might be
extended to the enantioselective α-vinylation of carbonyls, an
important yet complex synthetic task given the capacity of such
adducts to readily undergo olefin-carbonyl conjugation or
product racemization.7 Herein we describe the successful
execution of these ideals via the combination of two discrete
catalytic cycles (chiral amine–enamine, Cu(I)–Cu(III)) that
enables the enantioselective construction of a wide variety of α-
substituted-β,γ-unsaturated aldehydes without olefin iso-
merization or stereochemical ablation (eq 2).8-11
Merging Copper
Catalysis with
Enantiofacial
Coordination
5
Organocatalysis
Br Cu
Y
Me
N
O
Me
O
N
t-Bu
Ph
t-Bu
Ph
Organocatalytic
Cycle
N
N
Y
6
4
R
R
Me
O
N
O
Y
t-Bu
Ph
•TFA
N
H
H
H
R
R
catalyst 3
enantioenriched
aldehyde
α-vinyl aldehyde
Design Plan. As shown in Scheme 1, we postulated that a
Cu(I) catalyst 1 (e.g. CuBr), in the presence of a vinyl iodonium
triflate, will undergo chemoselective oxidative addition into the
weak alkenyl-iodine bond to generate a highly electrophilic
Cu(III)-vinyl complex 2.12,13 In a simultaneous organocatalytic
cycle, condensation of chiral amine catalyst 3 with an aldehyde
should furnish the transient yet nucleophilic enamine 4.
Computational studies predict that the Si-face of this enamine
will be shielded by the phenyl ring of the imidazolidinone
framework, leaving the Re-face accessible to electrophilic attack
(see DFT-5).14 On this basis, complexation of the enamine π-
system with Cu(III)-vinyl complex 2 is expected to lead to η1-
iminium organocopper species (not shown), which, upon
reductive elimination, will forge a carbon–carbon bond and
reconstitute the active Cu(I) catalyst (thereby completing the
metal cycle). Hydrolysis of the resulting iminium 6 will also
release amine 3 to complete the organocatalysis cycle while
furnishing the desired enantioenriched α-vinyl aldehyde.
Challenging Transformation: Aldehyde !-Vinylation w/o Conjugation
O
O
O
metal or
H
H
Me
H
X
organocatalyst
R
R
R
desired
undesired
Enantioselective Trifluoromethylation: Mild and w/o Racemization (Eq 1)
O
O
CF3
I
O
CF3
amine catalyst
Me
Me
H
H
R
R
Lewis acid catalyst
!-CF3 aldehyde
aldehyde
Togni's reagent
Synergistic Catalysis: Enantioselective Aldehyde !-Vinylation (Eq 2)
O
O
OTf
amine catalyst
Cu(I) salt
Y
I
H
H
Y
Ph
R
R
Results. Our investigation began with an examination of the
coupling of octanal with styrenyl iodonium triflate 7 in the
presence of chiral amine catalyst 3 and various Cu(I) catalysts.
As expected, no product formation was observed in the absence
!-vinyl aldehyde
aldehyde
vinyl iodonium
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 4
Table 1. Impact of Amine and Copper Catalysts on Vinylation
Table 3. Scope of the Vinyl Iodonium Coupling Component a,b,c
1
2
3
4
O
O
O
O
A
B
copper catalyst
10 mol% amine 3
OTf
OTf
Ph
Ph
C
amine catalyst 3
5 mol% CuBr
I
I
H
H
H
H
Ph
Ph
C
C6H13
C6H13
Et2O, Na2CO3
23 °C
Et2O, Na2CO3
23 °C
C6H13
C6H13
B
A
aldehyde
vinyl iodonium 7
!-vinyl aldehyde
5
vinyl iodonium
!-vinyl aldehyde
aldehyde
6
7
entry
catalyst 3 mol%
copper catalyst (mol %)
yield (%)a ee (%)b
Cl
O
O
1
2
8
9
--
97
97
97
97
97
1
2
3
4
5
6
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
10 mol%
None
0
67
82
23
98
97
H
H
CuOAc (10 mol%)
CuCl (10 mol%)
CuI (10 mol%)
CuBr (10 mol%)
CuBr (5 mol%)
C6H13
C6H13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
84% yield, 97% ee
87% yield, 96% ee
O
O
3
4
a1H NMR yield. bDetermined by chiral SFC analysis of the
corresponding alcohol, absolute configuration determined by chemical
correlation.
H
H
Ph
C6H13
C6H13
76% yield, 97% ee
89% yield, 97% ee
of copper salts (Table 1, entry 1). However, upon exposure to a
catalytic amount of CuOAc, the desired α-vinyl aldehyde was
produced with moderate yield and with excellent levels of
asymmetric induction (entry 2, 67% yield, 97% ee). While the
use of CuI resulted in diminished yields (entry 4, 23% yield),
CuCl was found to be a competent coupling catalyst (entry 3,
82% yield, 97% ee). Optimal efficiency and enantiocontrol was
achieved, however, using CuBr to afford the desired α-vinyl
aldehyde adduct in 98% yield and 97% ee (entry 5).
Importantly, lowering the copper and chiral amine catalyst
loadings to 5 mol% and 10 mol%, respectively, had little impact
on the overall performance of this multi-catalysis protocol (entry
6, 97% yield, 97% ee).
5d
6
O
O
H
Cl
H
OMe
C6H13
C6H13
91% yield, 94% ee
73% yield, 95% ee
7
8e,f,g
O
O
( )
Me
H
3 Cl
H
C6H13
C6H13 Me
81% yield, 93% ee
73% yield, 97% ee
9e
10e
O
O
H
H
Table 2. Scope of Aldehyde in Enantioselective Vinylation a,b,c
C6H13
C6H13
O
O
10 mol% amine 3
OTf
71% yield, 96% ee
77% yield, 94% ee
5 mol% CuBr
Ph
I
H
H
Ph
Ph
Et2O, Na2CO3
23 °C
aAbsolute configuration assigned by chemical correlation or analogy.
bIsolated yield of the corresponding alcohol. cEnantiomeric excess
determined by chiral HPLC or SFC analysis of the corresponding
R
R
aldehyde styrenyl iodonium 7
!-vinyl aldehyde
alcohol. d1H NMR yield. eUsing 20 mol% 3. Using 30 mol% CuBr.
f
gUsing the corresponding mesitylvinyliodonium triflate.
O
O
Ph
Ph
82% yield
83% yield
H
2d,e
H
1
With optimal conditions in hand, we next examined the
structural diversity of the aldehydic coupling partner (Table 2).
Notably, sterically demanding β-branched aldehydes were found
to be competent substrates, providing α-vinylated products with
excellent levels of optical purity (entries 3, 4 and 6, 73–79%
Me
94% ee
96% ee
( )
2
OTBS
O
Me
O
O
Ph
Ph
H
H
yield, 96–99% ee).
Moreover, the presence of pendent
75% yield
99% ee
79% yield
99% ee
3
5
4
heteroatom functionalities does not have a deleterious impact on
the reaction performance (entries 2, 5 and 6). It should be noted
that the two cycles involved are sufficiently mild to maintain
configurational integrity of the pendent Z-alkene (entry 1, 69%
yield, 96% ee). More importantly, aldehydes bearing β-
stereogenicity can be routinely employed to enable the highly
diastereoselective construction of both syn- and anti-α,β-
disubstituted adducts (entries 7 and 8, 81–84% yield, ≥20:1 dr).
As a salient indicator of the dominance of catalyst versus
substrate control in these processes, both β-stereocenter
containing antipodes undergo α-olefination with the same sense
of induction (as dictated by the amine catalyst).
Next we turned our attention to the scope of the vinyl
coupling partner. As demonstrated in Table 3, these merged
catalysis conditions are amenable to a broad range of iodonium
triflates. Both electron-neutral and electron-poor styrenes
(entries 1 and 2) as well as alkylvinyl groups (entries 3, 4 and 7)
are transferred with high levels of enantiocontrol (≥93% ee).15
Me
O
81% yield
91% ee
Ph
Ph
H
H
6
73% yield
96% ee
N
Boc
N
Boc
O
O
Ph
Ph
8f
81% yield
7
H
H
84% yield
"20:1 dr
"20:1 dr
Ph
Me
Ph
Me
aAbsolute configuration assigned by chemical correlation or analogy.
bIsolated yield of the corresponding alcohol. cEnantiomeric excesss
determined by chiral HPLC analysis of the corresponding alcohol.
dUsing 20 mol% 3. eUsing 20 mol% CuBr. fUsing (S,S)-3 catalyst.
2
ACS Paragon Plus Environment

Page 3 of 4
Journal of the American Chemical Society
Scheme 2. Access to Diverse Enantioenriched Vinyl Synthons
1
2
3
4
Acknowledgement. Financial support was provided by the
O
HNBn
NIHGMS (R01 GM103558-01) and kind gifts from Merck,
Amgen and Abbott. E.S. thanks NIHGMS for a postdoctoral
fellowship (5F32 GM096738-01).
BnNH2
NaClO2
Ph
Ph
Na(OAc)3BH
NaH2PO4
HO
C6H13
C6H13
O
5
6
Supporting Information Available. Experimental procedures
and spectral data are provided.
91% yield, 97% ee
69% yield, 95% ee
homoallylic amine
Ph
!-vinyl acid
H
7
8
C6H13
References
97% ee
OH
O
(1) For reviews on synergistic catalysis, see: (a) Shao, Z.; Zhang, H. Chem. Soc.
Rev. 2009, 38, 2745. (b) Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2999. (c)
Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2011, 633. (d) Patil, N. T.;
Shinde, V. S.; Gajula, B. Org. Biomol. Chem. 2012, 10, 211.
9
Ph
Ph
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Crabtree's cat
H2 (1 atm)
NaBH4
C6H13
C6H13
(2) It should be noted that synergistic catalysis can lead to the formation of
multiple new bonds, as in the case of cycloaddition processes.
85% yield, 97% ee
84% yield, 97% ee
homoallylic alcohol
!-alkyl aldehyde
(3) For selected examples of synergistic catalysis, see: (a) Sawamura, M.; Sudoh,
M.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309. (b) Nakoji, M.; Kanayama, T.;
Okino, T.; Takemoto, Y. Org. Lett. 2001, 3, 3329. (c) Kamijo, S.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2002, 41, 3230. (d) Sammis, G. M.; Danjo, H.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928. (e) Ibrahem, I.; Córdova,
A. Angew. Chem., Int. Ed. 2006, 45, 1952. (f) Komanduri, V.; Krische, M. J.
J. Am. Chem. Soc. 2006, 128, 16448. (g) Mukherjee, S.; List, B. J. Am. Chem.
Soc. 2007, 129, 11336. (h) Hu, W.; Xu, X.; Zhou, J.; Liu, W.; Huang, H.; Hu,
J.; Yang, L.; Gong, L. J. Am. Chem. Soc. 2008, 130, 7782. (i) Nicewicz, D.
MacMillan, D. W. C. Science 2008, 322, 77. (j) Shi, Y.; Roth, K. E.;
Ramgren, S. D.; Blum, S. A. J. Am. Chem. Soc. 2009, 131, 18022. (k) Ikeda,
M.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2010, 49, 7289. (l)
Raup, D. E. A.; Cardinal-David, B.; Holte, D.; Scheidt, K. A. Nature
Chemistry 2010, 2, 766. (m) Trost, B. M.; Luan, X.; Miller, Y. J. Am. Chem.
Soc. 2011, 133, 12824. (n) Ibrahem, I.; Santoro, S.; Himo, F.; Córdova, A
Adv. Synth. Catal. 2011, 353, 245. (o) Simonovich, S. P.; Van Humbeck, J. F.
MacMillan, D. W. C. Chem. Sci. 2012, 3, 58.
(4) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 4986.
(5) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 4260.
(6) The combination of copper catalysts and aryliodonium salts has been elegantly
employed to generate arylated indoles via a Cu(III) species: Phipps R. J.;
Grimster, N. P.; Gaunt, M. J. J. Am Chem. Soc. 2008, 130, 8172.
(7) For transition metal catalyzed enolate vinylations, see: (a) Chieffi, A.;
Kamikawa, K.; Ahman, J.; Fox, J. M.; Buchwald, S. L. Org. Lett. 2001, 3,
1897. (b) Poulsen, T. B.; Bernardi, L.; Bell, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2006, 45, 6551. (b) Taylor, A. M.; Altman, R. A.; Buchwald,
S. L. J. Am. Chem. Soc. 2009, 131, 9900.
(8) For transition metal catalyzed vinylation of α-halo carbonyl compounds, see:
(a) Dai, X.; Strotman. A.; Fu, G. C. J. Am Chem. Soc. 2008, 130, 3302. (b)
Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 5010.
(9) For enantioselective organocatalytic SOMO vinylation of aldehydes, see:
Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 398.
(10) For reviews on iodonium salts, see: (a) Varvoglis, A. The Organic Chemistry
of Polycoordinated Iodine; VCH Publishers: New York, 1992. (b) Zhdakin, V.
V.; Stang, P. J. Chem. Rev. 2002, 102, 2523. (c) Stang, P. J. J. Org. Chem.
2003, 68, 2997. (d) Zhdakin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(11) For carbonyl α-vinylation with iodonium salts, see: (a) Beringer, F. M.;
Galton, S. A. J. Org. Chem. 1965, 30, 1930. (b) Ochiai, M.; Sumi, K.;
Takaoka, Y.; Kunushima, M.; Nagao, Y.; Shiro, M.; Fujita, E. Tetrahedron
1988, 44, 4095. (c) Ochiai, M.; Shu, T.; Nagaoka, T.; Kitagawa, Y. J. Org.
Chem. 1997, 62, 2130.
OLi
(Ph3PCH3)I
O
OH
n-BuLi
tBu
Ph
Ph
tBu
C6H13
C6H13
81% yield, 94% ee
enolate aldol adduct
78% yield, 95% ee
1,4-diene
Traditionally metal-sensitive structural motifs such as allyl
chlorides and allyl ethers (entries 5 and 6, 94–95% ee) are also
readily incorporated to deliver useful synthons for subsequent
elaboration. Moreover, this novel transformation is not limited
to 1,2-disubstituted alkenyl group couplings but can also be
applied to trisubtituted carbocycles (entries 9 and 10, 71–77%
yield, 94–96% ee).16 The selective transfer of sterically
demanding trisubstituted olefins can also be accomplished;
however, this system requires the use of the corresponding
mesityliodonium salt to avoid a competing aryl group transfer
(entry 8).17
To demonstrate the utility of this new enantioselective
vinylation reaction, we performed a series of subsequent
synthetic manipulations to demonstrate that this protocol can
lead to a diverse series of synthons (Scheme 2). For example,
Pinnick oxidation of the formyl group provides an α-olefin
carboxylic acid in high yield with complete preservation of
enantiomeric purity. Moreover, hydrogenation of the alkene
group using Crabtree’s catalyst leads to α-alkyl aldehyde
products, again without loss in optical purity. Importantly, the
formyl group can be utilized in a reductive amination sequence
to afford a homoallylic amine scaffold in 95% ee, a remarkable
outcome given that an iminium intermediate is formed in this
process. As a related system, homoallylic alcohols can also be
readily accessed via NaBH4 reduction, to generate adducts that
should be of value for subsequent diastereoselective reactions
such as epoxidation, cyclopropanation etc.18 The addition of
metal enolates to these vinylation adducts can also be
accomplished to generate aldol products with high efficiency.
Lastly, the use of traditional Wittig conditions leads to 1,4-diene
formation without loss of enantipurity at the sterogenic 3-
position, again demonstrating the versatility of these 1,3-formyl-
olefin adducts.
(12) For studies on the mechanism of copper-catalyzed arylation, see: (a) Beringer,
F. M.; Geering, E. J.; Kuntz, I.; Mausner, M. J. Phys. Chem. 1956, 60, 141. (b)
Lockhart, T. P. J. Am. Chem. Soc. 1983, 105, 1940.
(13) The phenyliodonio group is a great nucleofuge, some 106 times more reactive
than triflate, see: (a) Okuyama, T. Takino, T.; Sueada, T. J. Am. Chem. Soc.
1995, 117, 3360. (b) Okuyama, T. Acc. Chem. Res. 2002, 35, 12
(14) DFT calculations for the enamine were performed with the use of B3LYP/6-
311+G(2d,2p)//B3LYP/6-31G(d).
(15) Electron rich styrenyliodonium salts exhibit poor stability, see; Thielges, S.;
Bisseret, P.; Eustache, J. Org. Lett. 2005, 7, 681.
(16) This result is complementary to enantioselective α-vinylation studies using
organo-SOMO catalysis, wherein carbocyclic olefinic substrates are not
readily employed, see ref 7.
(17) (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc.
2005, 127, 7330. (b) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009,
131, 11234.
In conclusion, we have developed a highly enantioselective
protocol for the α-vinylation of aldehydes with vinyl iodonium
triflates using copper(I) and chiral amine catalysis in
synergistic coupling mechanism. This operationally simple,
room temperature and mild protocol should also be cost effective
given the substrates, catalysts and catalyst loadings employed.
We fully expect that the α-formyl olefin products generated in
this study will be of high value for practitioners of chemical
synthesis and medicinal chemistry.
(18) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
a
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 4
Graphical Abstract
1
2
3
4
5
6
7
O
O
amine
catalyst
X
Ph
X
En
Cu
new reaction
I
H
H
copper
catalyst
synergistic
Y
OTf
R
Y
R
catalysis
enantioselective
aldehyde vinyl iodonium
!-vinyl aldehyde
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
ACS Paragon Plus Environment