Highly enantioselective conjugate additions of aldehydes to vinyl sulfones

Article abstract of DOI:10.1002/chem.200802441

The use of less basic chiral amine catalysts for highly enantioselective conjugate additions of aldehydes to vinyl sulfones was reported. The results show that the addition of aldehydes to α-cyano vinyl sulfones takes place at -40°C to give alcohols. The

Full text of DOI:10.1002/chem.200802441

DOI: 10.1002/chem.200802441
Highly Enantioselective Conjugate Additions of Aldehydes to Vinyl Sulfones
Aitor Landa,[a] Miguel Maestro,[b] Carme Masdeu,[a] ꢀngel Puente,[a] Silvia Vera,[a]
Mikel Oiarbide,[a] and Claudio Palomo*[a]
Given the vast chemistry of the aldehyde and the sulfone
groups,[1] a combination of both functionalities through ste-
À
reoselective C C bond-forming reactions is highly appeal-
ing. Towards this goal, the 1,4-addition of aldehydes to un-
ACHTUNGTRENNUNGsatACHTUNGTRENNUNGurated sulfones is a highly valuable tool. Unfortunately,
Figure 1. Amine catalysts explored for the conjugate addition of alde-
hydes to vinyl sulfones: a) Previous studies; b) this work.
catalytic and enantioselective variations of the reaction are
seemingly elusive.[2] First reports of catalytic enantioselec-
tive conjugate additions of aldehydes to vinyl sulfones in-
volve secondary/tertiary 1,2-diamine organocatalysts 1 and
2,[3] which activate the aldehyde component through en-
laboratory,[10] were tested for the reaction between alde-
hydes 6 and vinyl bisACTHUGNTERN(UNG sulfone) 7. At the outset, it was not
A
nificant, but the method holds important limitations with re-
gards to substrate scope and enantioselectivity: a large
excess (10 equivalents) of the aldehyde is usually required
and modest selectivities (typically 70% ee) are obtained. On
the other hand, while the direct catalytic and asymmetric
1,4-addition of aldehydes to certain electron-deficient ole-
fins,[6,7] most particularly nitroolefins,[7,8] have met success
recently, one accompanying problem to the reaction with
vinyl sulfone acceptors is the retroaddition, which causes
formation of undesired dimeric side products.[3] Herein we
report the use of less basic chiral amine catalysts (see
Figure 1) to provide a solution to these problems thus con-
siderably expanding the utility of vinyl sulfones in organic
synthesis.
clear whether each catalyst would be equally effective. Be-
sides the above problems, there is the fact that diaryl proli-
nol ethers may exhibit certain substrate specificity.[11]
To our delight, by using catalyst 3, products 10 were ob-
tained (Table 1), after reduction of the 1,4-addition adduct,
in yields typically over 90% and enantioselectivities greater
than 95% for both linear as well as b-branched aldehydes.
For example, propionaldehyde, which provides racemic ad-
ducts with catalyst 1, affords 10a with 95% ee. Similarly,
Table 1. Addition of aldehydes
6 to vinyl sulfones promoted by 3.
In an initial screen, commercially available prolinol silyl
ethers 3 and 4,[9] and analogue 5, recently disclosed from our
Aldehyde 6, R Sulfone Product Yield [%][a] syn/anti[b] ee [%][c]
a, CH3
7
8
7
9
7
8
9
7
7
7
10a
11a
10b
12b
10c
11d
12d
10e
10 f
10g
95
60
93
49
94
52
51
95
92
91
–
95
99(99)[d]
98
ACHTUNGTRENNUNG(n.d.)
[a] Dr. A. Landa, Dr. C. Masdeu, ꢀ. Puente, S. Vera,
Prof. Dr. M. Oiarbide, Prof. Dr. C. Palomo
Departamento de Quꢁmica Orgꢂnica I, Facultad de Quꢁmica
Universidad del Paꢁs Vasco, Apdo. 1072
20080 San Sebastiꢂn (Spain)
85:15
–
70:30
–
70:30
70:30
–
–
–
b, CH3CH2
99
97
c, CH
3A
d, CH
3A
99(99)[d]
Fax : (+34)943-015-270
E-mail: claudio.palomo@ehu.es
99
96
95
99
ACHTUNGTRENNUNG(n.d.)
e, CH
N
f, PhCH2
g, (CH3)2CH
[b] Dr. M. Maestro
(X-ray analyses)
Departamento de Quꢁmica Fundamental, Facultad de Ciencias, Uni-
versidade da CoruÇa, Campus Zapateira s/n, 15071A CoruÇa (Spain)
[a] Isolated yield of product alcohol after column chromatography (hex-
anes/EtOAc 60:40). [b] Determined by 1H/13C NMR and chiral HPLC.
[c] Determined by chiral HPLC. [d] ee of the minor diastereomer. n.d.:
not determined.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802441.
1562
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1562 – 1565

COMMUNICATION
val
G
E
ularly noteworthy the fact that the sulfone group is key for
the 1,4-addition reaction to proceed satisfactorily. For in-
stance, whilst vinyl sulfones 13a and 13c, upon reaction with
propanal and pentanal, respectively, afforded products 16a
is obtained with catalyst 1 (74% ee with 2). Among the sol-
vents methylene chloride and toluene gave the best results.
No reaction was observed in protic solvents such as ethanol,
methanol or isopropyl alcohol, whilst in DMF—a typical sol-
vent for other enamine-based reactions—low ee values are
obtained. Catalyst 4 behaved similarly, but 5, which per-
forms very well in other 1,4-addition reactions,[10] gave rise
to 60–75% ee at best.[12] Formation of dimeric side product
was determined to be below the limit of detection of
1H NMR spectroscopy. On the other hand, b-substituted sul-
fones 8 and 9 were also good electrophiles, giving rise ad-
ducts 11 and 12 with good yields, diastereomeric ratios in
the range from 70:30 to 80:20, and essentially complete
enantioselectivity.[13]
and 16c in 85 and 60% yield, the respective arylACHTNUTRGNEiUNG dene ethyl
malonates, which would generate analogous d-lactones, were
unreactive regardless of the reaction conditions employed.[14]
In this respect, d-lactones are common structural units of
natural products as well as versatile building blocks of sever-
al classes of biologically active compounds.[15]
A third variation concerns a,b-unsaturated nitriles, a re-
calcitrant class of Michael acceptors[16] that remain com-
pletely unreactive under the present catalytic conditions.
However, addition of aldehydes to a-cyano vinyl sulfones
17–20 took place smoothly at À408C (Table 3) to give, after
reduction of the resulting adduct, alcohols 21. The latter
compounds are versatile intermediates which allow, for ex-
ample, access to lactones 22 or cyano alcohols 23 in good
yields, diastereomeric ratio, and again essentially perfect
enantioselectivity. This approach constitutes a new enantio-
selective entry to building blocks otherwise difficult to
access from unsaturated nitriles.[16] In the above reactions a
threefold excess of aldehyde substrate is employed regularly,
but nearly equimolar amounts suffice for achieving equal ef-
ficiency. Configuration of the products was established by
X-ray analyses of syn-12b, 16a, and trans-22b,[17] and by as-
suming a uniform reaction mechanism.[18]
Table 2. Aldehyde addition to E-a-ethoxycarbonyl vinyl sulfones pro-
moted by 3/4.[a]
R
a Me
b Me
c Pr
The potential of this catalytic methodology can further be
shown by the reductive double desulfonation of 10 f and
syn-11d to afford alcohols 24 and 25 (Scheme 1). This
d Pn
ACHUTNGRENaNUG chieveACHTUNGTNERmNUGN ent represents a formal catalytic enantioselective
a-alkylation of aldehydes with secondary alkyl halides, a
process that still bears a considerable challenge.[19] When the
desulfonation step is preceded with a prior alkylation reac-
tion under standard conditions, as in the transformation of
10 f into alcohols 26, the above approach serves to access to
[a] Reactions conducted at 0.5 mmol scale in CH2Cl2 at RT overnight. Al-
dehyde/vinyl sulfone 3:1 ratio. [b] Isolated yield of lactone product after
column chromatography (Hex/EtOAc 90:10). [c] Determined by
13C NMR; relative and absolute configuration of the minor diastereomer
not determined. [d] Determined by chiral HPLC. n.d.: not determined.
Table 3. Addition to E-a-cyano vinyl sulfones promoted by 3.[a]
The present catalytic reac-
tion can also be applied to
other vinyl sulfones with main-
tained levels of stereoselectiv-
ity. For example, as shown in
Table 2,
a-ethoxycarbonyl
vinyl sulfones 13, 14, and 15
reacted with aldehydes in the
presence of catalysts 3/4
(10 mol%) to give, after re-
duction and cyclisation, the
corresponding lactone adducts
16 with three contiguous ste-
reocenters. Nearly perfect
enantiocontrol is observed in
most cases for both catalysts,
but catalyst 3 provided better
yields (up to 85% yield over
three steps) than 4. It is partic-
Compound
R
Product 22
Product 23
R1
Yield[b] [%]
dr[c] trans/cis
ee[d] [%]
Yield[b] [%]
dr[c] syn/anti
ee[d] [%]
a
b
c
d
e
f
Me
Ph
57
59
65
65
65
72
70
75:25
80:20
80:20
70:30
70:30
70:30
75:25
99(99)
99(99)
70
–
75:25
–
99(98)
–
99(97)
99(90)
99(99)
4-ClC6H4
4-MeC6H4
2-naphthyl
Ph
Ph
Ph
99
N
70
52[e]
65
70
–
75:25
80:20
60:40
85:15
–
99(99)
99(99)
99(99)
99(99)
Et
Pr
99
–
ACHTUNGTRENNUNG(n.d.)
g
Bu
[a] Ratio of aldehyde/vinyl sulfone 3:1. [b] Combined yield of diastereomers over the three steps. [c] Deter-
1
mined by H NMR and/or HPLC. [d] Determined by HPLC. ee values in brackets refer to the minor diastereo-
mer cis-22 and anti-23, respectively. n.d.: not determined.
Chem. Eur. J. 2009, 15, 1562 – 1565
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1563

C. Palomo et al.
[1] N. S. Simpkins, Sulphones in Organic Synthesis, Pergamon Press,
Oxford, 1993.
[2] Enantioselective additions of active methylenes to vinyl sulfones:
a) H. Li, J. Song, Z. Liu, L. Deng, J. Am. Chem. Soc. 2005, 127,
8948–8949; b) T.-Y. Liu, J. Long, B.-J. Li, L. Jiang, R. Li, Y. Wu, L.-
S. Ding, Y.-C. Chen, Org. Biomol. Chem. 2006, 4, 2097–2099.
[3] a) S. Mossꢆ, A. Alexakis, Org. Lett. 2005, 7, 4361–4364; b) S. Mossꢆ,
M. Laars, K. Kriis, T. Kanger, A. Alexakis, Org. Lett. 2006, 8, 2559–
2562; c) A. Quintard, C. Bournaud, A. Alexakis, Chem. Eur. J. 2008,
14, 7504–7507.
[4] Reviews on enamine catalysis: a) P. Melchiorre, M. Marigo, A. Car-
lone, G. Bartoli, Angew. Chem. 2008, 120, 6232–6265; Angew.
Chem. Int. Ed. 2008, 47, 6138–6171; b) S. Mukherjee, J. W. Yang, S.
Hoffmann, B. List, Chem. Rev. 2007, 107, 5471–5569; c) M. Marigo,
K. A. Jørgensen, Chem. Commun. 2006, 2001–2011; d) G. Guillena,
D. J. Ramꢅn, Tetrahedron: Asymmetry 2006, 17, 1465–1492.
[5] Reviews on asymmetric organocatalysis: a) A. Dondoni, A. Massi,
Angew. Chem. 2008, 120, 4716–4739; Angew. Chem. Int. Ed. 2008,
47, 4638–4660; b) A. Berkessel, H. Grçger, Asymmetric Organoca-
talysis: From Biomimetic Concepts to Applications in Asymmetric
Synthesis Wiley-VCH, Weinheim, 2005.
[6] Enones: a) P. Melchiorre, K. A. Jørgensen, J. Org. Chem. 2003, 68,
4151–4157; b) Y. Chi, S. H. Gellman, Org. Lett. 2005, 7, 4253–4256;
c) T. J. Peelen, Y. Chi, S. H. Gellman, J. Am. Chem. Soc. 2005, 127,
11598–11599; d) M. T. Hechevarria Fonseca, B. List, B. Angew.
Chem. 2004, 116, 4048–4050; Angew. Chem. Int. Ed. 2004, 43, 3958–
3960. Benzoquinones: e) J. Aleman, S. Cabrera, E. Maerten, J. Over-
gaard, K. A. Jørgensen, Angew. Chem. 2007, 119, 5616–5619;
Angew. Chem. Int. Ed. 2007, 46, 5520–5523. Maleimides: f) G.-L.
Zhao, Y. Xu, H. Sundꢆn, L. Eriksson, M. Sayah, A. Cꢅrdova, Chem.
Commun. 2007, 734–735. Vinyl phosphonates: g) S. Sulzer-Mossꢆ,
M. Tissot, A. Alexakis, Org. Lett. 2007, 9, 3749–3752. Alkylidene
malonates: h) G.-L. Zhao, J. Vesely, J. Sun, K. E. Christensen, C.
Bonneau, A. Cꢅrdova, Adv. Synth. Catal. 2008, 350, 657–661; i) a-
keto-a,b-unsaturated esters: J. Wang, F. Yu, X. Zhang, D. Ma, Org.
Lett. 2008, 10, 2561–2564; a-cyanoacrylates: j) O. Penon, A. Car-
lone, A. Mazzanti, M. Locatelli, L. Sambri, G. Bartoli, P. Melchiorre,
Chem. Eur. J. 2008, 14, 4788–4791.
Scheme 1. Elaboration of adducts via desulfonation/alkylation standard
protocols.
longer chain alkylated products in a practical way. These ex-
amples demonstrate how the present organocatalytic conju-
gate addition to vinyl bisACTHNUTRGENU(GN sulfone)s, in conjunction with a
subsequent alkylation step, opens up new opportunities for
the asymmetric synthesis of a-branched aldehydes and prod-
ucts thereof.
In summary, although further optimisation is needed to
improve reaction diastereocontrol,[20] the present catalytic
system introduces an operationally simple protocol for ac-
cessing a variety of structural motifs from readily available
vinyl sulfones and unmodified aldehydes as starting mat
ACHTUNGTNEReNUNG ri-
ACHTUNGTRENNUNGals. The trick of success is the use of a diarylprolinol silyl
ether as reaction promoter that leads to the highest enantio-
selectivity reported to date for this class of Michael accept-
ors. Further investigations on the utility of gem-disulfone ad-
ducts as alkyl carbanion surrogates are currently underway
in our laboratory and will be reported in due course.
Experimental Section
[7] Reviews on enantioselective organocatalytic conjugate additions:
a) D. Almasi, D. A. Alonso, C. Nꢂjera, Tetrahedron: Asymmetry
2007, 18, 299–365; b) S. B. Tsogoeva, Eur. J. Org. Chem. 2007,
1701–1716; c) J. L. Vicario, D. Badꢁa, L. Carrillo, Synthesis 2007,
2065–2092.
Catalytic conjugate addition of aldehydes to vinyl sulfones: To a mixture
of the catalyst 3 or 4 (10–20 mol%) and vinyl sulfone (1 mmol) in tolu-
ene (1 mL) (for sulfones 7–9) or CH2Cl2 (1 mL) (for 13–15 and 17–20) at
À408C was added aldehyde 6 (1.5–3.0 equiv), and the mixture stirred
overnight (16 h) at the same temperature. The resulting solution was di-
luted with EtOH (1 mL) and a suspension of NaBH4 (2 equiv) in EtOH
(2 mL) was then added drop-wise. The mixture was stirred at À408C for
30 min and quenched with H2O (10 mL). The aqueous phase was extract-
ed with CH2Cl2 (3ꢄ10 mL). The combined organic layers were dried
over MgSO4, filtered, concentrated under reduced pressure and the crude
product purified by flash column chromatography (hexane/EtOAc
60:40).
[8] Review: a) S. Sulzer-Mossꢆ, A. Alexakis, Chem. Commun. 2007,
3123–3135. Selected, more recent examples: b) L.-q. Gu, G. Zhao,
Adv. Synth. Catal. 2007, 349, 1629–1632; c) Y. Chi, L. Guo, N. A.
Kopf, S. H. Gellman, J. Am. Chem. Soc. 2008, 130, 5608–5610; d) S.
Zhu, S. Yu, D. Ma, Angew. Chem. 2008, 120, 555–558; Angew.
Chem. Int. Ed. 2008, 47, 545–548; e) M. Wiesner, J. D. Revell, H.
Wennemers, Angew. Chem. Int. Ed. 2008, 47, 1871–1874; f) P.
Garcꢁa-Garcꢁa, A. Ladꢆpeche, R. Halder, B. List, Angew. Chem.
2008, 120, 4797–4799; Angew. Chem. Int. Ed. 2008, 47, 4719–4721;
g) Y. Hayashi, T. Itoh, M. Ohkubo, H. Ishikawa, Angew. Chem.
2008, 120, 4800–4802; Angew. Chem. Int. Ed. 2008, 47, 4722–4724.
[9] First reports documenting catalysts 3 and 4: a) M. Marigo, T. C.
Wabnitz, D. Fielenbach, K. A. Jørgensen, Angew. Chem. 2005, 117,
804–807; Angew. Chem. Int. Ed. 2005, 44, 794–797; b) J. Franzꢆn,
M. Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjaersgaard, K. A. Jør-
gensen, J. Am. Chem. Soc. 2005, 127, 18296–18304; c) Y. Hayashi,
H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem. 2005, 117, 4284–
4287; Angew. Chem. Int. Ed. 2005, 44, 4212–4215. For a review:
d) A. Mielgo, C. Palomo, Chem. Asian J. 2008, 3, 922–948.
Acknowledgements
We thank Dr. E. Barragꢂn for control experiments with vinyl sulfone 7.
This work was financially supported by The University of the Basque
Country (UPV/EHU), Basque Government (GV), and Ministerio de Ed-
ucaciꢅn y Ciencia (MEC, Spain). A.L. thanks MEC and European Social
Foundation (ESF) for a Ramꢅn y Cajal contract. C.M. thanks GV for a
fellowship.
[10] C. Palomo, A. Landa, A. Mielgo, M. Oiarbide, A. Puente, S. Vera,
Angew. Chem. 2007, 119, 8583–8587; Angew. Chem. Int. Ed. 2007,
46, 8431–8435.
[11] Diarylprolinol ethers such as 3 and 4 display considerable reaction-
and substrate specificity (see ref. [9d]). For recent examples illustrat-
ing this behaviour, see: Conjugate addition to enals and enones:
Keywords: alkylation
addition · organocatalysis · vinyl sulfones
· asymmetric catalysis · Michael
1564
www.chemeurj.org
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1562 – 1565

Enantioselective Conjugate Additions
COMMUNICATION
a) see ref. [6d,k]; b) D. A. Alonso, S. Kitagaki, N. Utsumi, C. F.
Barbas III, Angew. Chem. 2008, 120, 4664–4667; Angew. Chem. Int.
Ed. 2008, 47, 4588–4591; c) P. T. Franke, B. Richter, K. A. Jørgen-
sen, Chem. Eur. J. 2008, 14, 6317–6321. Other conjugate additions:
d) Y. Hayashi, T. Itoh, M. Ohkubo, H. Ishikawa, Angew. Chem.
2008, 120, 4800–4802; Angew. Chem. Int. Ed. 2008, 47, 4722–4724;
e) P. Garcꢁa-Garcꢁa, R. Ladꢆpeche, R. Halder, B. List, Angew.
Chem. 2008, 120, 4797–4799; Angew. Chem. Int. Ed. 2008, 47, 4719–
4721.
[16] For a review on unsaturated nitriles, see: F. F. Fleming, Q. Wang,
Chem. Rev. 2003, 103, 2035–2077.
[17] CCDC-706443 (syn-12b), 706444 (16a), 706445 (trans-22b) contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallograph-
ic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[18] For a theoretical study of enamine catalysis involving diaryl prolinol
ethers, see: P. Dinꢆr, A. Kjaersgaard, M. A. Lie, K. A. Jørgensen,
Chem. Eur. J. 2008, 14, 122–127.
[12] For details, see Supporting Information. While still premature, the
superior performance of diaryl catalysts 3 and 4, with respect to the
dialkyl catalyst 5, might be indicative of p-p interactions between
the catalysts 3/4 and the arylsulfonyl moiety of substrates being op-
erative.
[19] To the best of our knowledge, catalytic a-alkylation of unmodified
aldehydes with concomitant generation of two stereocenters remains
unsolved. For an organocatalytic entry to the asymmetric intramo-
lecular a-alkylation of aldehydes with alkyl iodides, see: a) N. Vi-
gnola, B. List, J. Am. Chem. Soc. 2004, 126, 450–451. For emergent
intermolecular approaches, see: b) D. A. Nicewicz, D. W. C. MacMil-
lan, Science 2008, 322, 77–80; c) R. R. Shaikh, A. Mazzanti, M. Pet-
rini, G. Bartoli, P. Melchiorre, Angew. Chem. 2008, 120, 8831–8834;
Angew. Chem. Int. Ed. 2008, 47, 8707–8710.
[13] During the preparation of this manuscript, a highly enantioselective
conjugate addition of aldehydes to vinyl bisACTHNUTRGENUG(N sulfone)s catalysed by
3/4 has appeared wherein comparatively higher dr and opposite
sense of enantioinduction are reported for the reactions involving b-
substituted vinyl bis
10, 4803–4806.
(sulfone)s; see: Q. Zhu, Y. Lu, Org. Lett. 2008,
[20] Current catalytic asymmetric Michael reaction protocols in which
adducts with either syn or anti relative configuration can be formed
tend to show, with few exceptions, moderate levels of diastereocon-
trol (see ref. [7]). While results in Tables 1 and 2 confirm this inher-
ent problem, we have found that improved dr values are affordable
by changing the nature of the sulfone group. For instance, starting
from the respective tert-butyl sulfone analogue to 17 and 20, respec-
tively, and propanal, lactones 22a and 22d were obtained in 90:10
and 85:15 diastereomeric ratios.
[14] After 24 h of stirring with the corresponding aldehyde in either
CH2Cl2 or CH3CN at room temperature in the presence of 10–
20 mol% of catalyst 3, both benzylidene and 4-methylbenzylidene
ethyl malonates were recovered unchanged. Apparently, only elec-
tron deficient arylidene malonates react satisfactorily with aldehydes
under enamine catalysis; see ref. [6h].
[15] For leading references, see: a) A. Habel, W. Boland, Org. Biomol.
Chem. 2008, 6, 1601–1604; b) R. K. Dieter, F. Guo, Org. Lett. 2006,
8, 4779–4782; c) O. Pꢇmies, J.-E. Bꢈckvall, J. Org. Chem. 2002, 67,
1261–1265.
Received: November 21, 2008
Published online: January 2, 2009
Chem. Eur. J. 2009, 15, 1562 – 1565
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1565