Asymmetric addition of α-hetero-disubstituted aldehydes to vinyl sulfones; Formation of highly functionalized tetrasubstituted carbon centres

Article abstract of DOI:10.1039/c000326c

Aminal-pyrrolidine catalysed addition of α-hetero-disubstituted aldehydes to vinyl sulfones is described in high enantioselectivity (ee up to 97%). The obtained adducts can easily be converted to enantioenriched synthons as for example 2,2-dialkylepoxide. Evidence for a kinetic resolution is also observed.

Full text of DOI:10.1039/c000326c

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Asymmetric addition of a-hetero-disubstituted aldehydes to vinyl
sulfones; formation of highly functionalized tetrasubstituted carbon
centresw
Adrien Quintard and Alexandre Alexakis*
Received 6th January 2010, Accepted 26th March 2010
First published as an Advance Article on the web 16th April 2010
DOI: 10.1039/c000326c
Aminal–pyrrolidine catalysed addition of a-hetero-disubstituted
aldehydes to vinyl sulfones is described in high enantioselectivity
(ee up to 97%). The obtained adducts can easily be converted to
enantioenriched synthons as for example 2,2-dialkylepoxide.
Evidence for a kinetic resolution is also observed.
Preliminary experiments using classical nitroolefins showed
that they were too poor Michael acceptors to react with
aldehyde 1a (entries 1 and 2).10
A beginning of reactivity was first observed with the
1,2-di-activated vinyl sulfone 2c (entry 3), which led to the
rearranged gem-disulfone (R2 = SO2Ph).5b As expected,
the 1,1-di-activated sulfone did react with aldehyde 1a,
furnishing cleanly the corresponding Michael adduct in 2 h
using diphenyl prolinol silyl ether 4a as catalyst (entry 4).
Unfortunately, a disappointing 75% ee was obtained using
this commercially available catalyst. Fluorinated 4b, led to a
slight improvement of the ee, but with a lower conversion
(entry 5). Gratifyingly, turning our attention to aminal–
pyrrolidine catalysts 4c and 4d5 led to an increase in terms
of enantioselectivities while keeping a good reactivity (entries 6
and 7). Under these conditions, an excellent 93% ee was
obtained using catalyst 4d, while catalyst 4c gave a slightly
lower 88% ee. Finally, replacing the chloride by a bromide in
the aldehyde starting material only led to partial conversion
after prolonged reaction time. This probably arises from the
consumption of a part of the catalyst by SN2 reaction of the
amine on the bromide. This control in the difference of
reactivity between the nucleophilic attack on the halogen,
and the reactivity of the enamine on the Michael acceptor is
the key to obtaining the Michael adducts.
Catalytic generation of enantiopure tetrasubstituted carbon
centres is a great challenge for modern chemists. Indeed, due
to high steric hindrance, these stereocenters are often associated
with poor reactivity and difficulties in the differentiation of
the different substituents, leading to poor enantiocontrol.1
Recently, enamine catalysis appeared as a method of choice
for the formation of stereogenic carbon centres.2 Unfortunately,
the use of a,a-disubstituted aldehydes has long been limited
due to the lack of reactivity of such substrates towards various
electrophiles.3 Furthermore, the reactions are often highly
substrate dependent with high levels of steric differentiation
needed on the aldehyde. Thus, the discovery of new nucleophiles/
electrophiles for such reactions would be of high interest. Our
group was the first to disclose bis-activated vinyl sulfone in
enamine catalysis.4 Due to its high reactivity, all-carbon
quaternary carbon centres could be obtained in high enantio-
selectivities notably by using our recently developed aminal–
pyrrolidine organocatalysts.5 In 2008, Shibatami and Yamamoto
reported the use of more reactive a-chloro aldehydes in
combination with an electrophilic fluoride to form optically
active tetrasubstituted a,a-chlorofluoro aldehydes.6 We thus
wondered whether the combination of a,a-disubstituted
aldehydes with enhanced acidity due to the presence of an
heteroatom,7 and the exceptionally reactive 1,1-vinyl sulfone,
could afford a valuable protocol for the formation of tetra-
substituted carbon molecules. In addition, due to the high
versatility of the sulfone group8 and to the presence of a
carbonyl and an extra heteroatom as chloride, nitrogen or
oxygen, highly useful chiral synthons could be obtained.
These versatile intermediates could lead to numerous
possible transformations by a Diversity Oriented Synthesis
(Scheme 1). Moreover, heteroatom a,a-disubstituted aldehydes
can easily be prepared via organocatalytic one-step reactions.9
From the outset, we investigated a-chloro aldehydes in the
Michael addition to various Michael acceptors (Table 1).
To probe the scope of the reaction we then tested the
conjugate addition of various chlorinated aldehydes to vinyl
sulfone 2d catalysed either by catalyst 4c or 4d (Table 2).z
When branched aldehydes were used, high enantiomeric
excesses (93, 91% ee) were obtained with catalyst 4d (entries
1–3). This is due to a strong differentiation between the
chloride and the bulky branched chain. Enantiomerically pure
citronellal derivative also gave a good 94/6 dr (entry 4). The
use of highly hindered tBu substituent did not lead to any
product formation with the various catalysts (entry 5). When
linear chains were used, lower enantioselectivities were
obtained using catalyst 4d (entry 6). Fortunately, thanks to
the high complementarity of Aminal–pyrrolidine,5 catalysts 4c
Department of Organic Chemistry, University of Geneva,
Quai Ernest Ansermet, 30, 1211, Geneva 4, Switzerland.
E-mail: alexandre.alexakis@unige.ch; Tel: 0041 (0)22 379 65 22
w Electronic supplementary information (ESI) available: Experimental
details and data analysis. See DOI: 10.1039/c000326c
Scheme 1 Hypothesis for the synthesis of highly functionalized
molecules.
ꢀc
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Table 1 Catalyst screening for the addition of a-chloroaldehydes to
Michael acceptors
Entry Catalyst Michael acceptor t/h Conv. (yield)a (%) eeb (%)
Scheme 2 Synthetic transformations of the Michael adducts and
1
4a
4a
4c
4a
4b
4c
4d
2a
2b
2c
2d
2d
2d
2d
24 nrc
24 nrc
24 20
2 100 (85)
48 72
ndc
ndc
ndc
75
78
88
postulated transition state.
2
3d
4
We postulate that the high enantioselectivity of the Michael
addition comes from the steric control achieved by both the
aminal and the phenol group.12 The Z-anti enamine is thus
favoured and only the Si face attack remains possible. In view
of the lower enantioselectivities obtained with small linear
chain (due to the difficulty in controlling the enamine geometry),
we wondered about incorporating a methyl group a to the
carbonyl in conjunction with other heteroatoms containing
bulkier substituents (Table 3).
5
6
7
2
2
100
100 (79)
93
a
Conversion determined by 1H NMR. Isolated yield shown in
b
parentheses. Determined by chiral super fluid chromatography.
c
d
nr: no reaction. nd: not determined. Reaction performed in DMF.
Table 2 Asymmetric addition of a-chloro aldehydes to vinyl sulfone
2d
Enantiopure aldehyde 9 reacted with vinyl sulfone 2d in an
excellent 97% ee in the presence of our aminal catalyst 4d
(entry 1). However, surprisingly, when the enantiomer of 9 was
used, only traces of the Michael adduct were observed. This
result suggested that the reaction was ongoing through a
kinetic resolution, only one enantiomer of the starting material
being able to react. We thus decided to investigate the same
reaction using the easily available racemic catalyst rac-4a
(entry 2). Gratifyingly, 65% ee of the Michael adduct was
obtained using this racemic catalyst in poor yield due to the
Entry
Catalyst
R (product)
t/h
Yielda
eeb (%)
1
2
3
4d
4d
4c
i-Pr (3a)
Bn (3b)
Bn (3b)
2
2.5
2
79
75
88
93
91
87
4
4d
4
72
99 (94/6 dr)
5
6
7
8
9
4d
4d
4c
4c
4c
t-Bu (3c)
n-Pent (3d)
n-Pent (3d)
n-Pr (3e)
Ph (3f)
24
3
3.5
4
nrc
90
86
69
24
ndc
79
82
75
58
Table 3 Asymmetric addition of a-functionalized aldehyde to vinyl
sulfone 2d
4.5
a
b
Isolated yield. Determined by chiral super fluid chromatography.
nr: no reaction. nd: not determined.
c
gave good 82 and 75% ee for these more challenging
substrates (entries 7 and 8).11 Finally, the use of a phenyl
subsituent led to disappointing 24% yield and 58% ee
probably due to the irreversible nucleophilic attack of the
catalyst on the activated benzylic position leading to its
deactivation (entry 9).
To demonstrate the utility of the obtained Michael adducts,
further transformations in other useful synthons were under-
taken (Scheme 2). After reduction to the corresponding
alcohol, formation of the 2,2-disubstituted epoxide 7 could
be carried out without any decrease in enantiomeric purity
using Cs2CO3 as base. Addition of KCN or NaN3 led to the
intermediate epoxide formation followed by in situ epoxide
opening with only a little loss of enantiopurity to 88% ee in the
case of the sodium salt.
Entry
Catalyst
Product
t/h
Yielda
eeb (%)
1
2
3
4
4d
11
11
11
12
19
16
16
24
58
13 (100)c,d
55
52
97
rac-4a
4a
4a
65 (87)c
97
97
a
b
Isolated yield. Determined by chiral super fluid chromatography.
Results in parentheses refer to the use of 30 mol% of catalyst.
1
Conversion observed by H NMR.
c
d
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lower amount of catalyst available in the reaction mixture. The
ee could be further increased to 87% by using 30 mol% of
racemic catalyst. Furthermore, a control experiment showed
that the chiral catalyst 4a also led to 97% ee in this reaction.
These results clearly indicate a kinetic resolution mechanism,
the catalyst being the compound resolved here.13 In this
case, the formation of the iminium or the corresponding
enamine is the crucial resolution step, also dependent on the
stability of the starting material. This kinetic resolution
mechanism was further confirmed in the case of chlorinated
aldehydes by studying the evolution of the diastereomeric ratio
of citronellal derivative. The two diastereoisomers reacted in a
75/25 ratio confirming the major kinetic resolution pathway.14
Finally, a-aminated aldehyde 12 was also obtained in 97% ee
using commercially available catalyst 4a (entry 4).15 These
results enlarge the scope of the reaction to a-methylated
compounds. Other functionalized aldehydes as Garner’s
aldehyde or glyceraldehyde acetonide led to disappointing
low reactivity and enantiocontrol.
M. Marigo, A. Carlone and G. Bartoli, Angew. Chem., Int. Ed.,
2008, 47, 6138–6171; (d) S. Mukherjee, J. W. Yang, S. Hoffmann
and B. List, Chem. Rev., 2007, 107, 5471–569; (e) P. I. Dalko,
Enantioselective Organocatalysis, Wiley-VCH, Weinheim, 2007.
3 For examples of the use of a,a-disubstituted aldehydes in Michael
addition: (a) N. Mase, R. Thayumanavan, F. Tanaka and
C. F. Barbas III, Org. Lett., 2004, 6, 2527–2530;
(b) M. P. Lalonde, Y. Chen and E. N. Jacobsen, Angew. Chem.,
Int. Ed., 2006, 45, 6366–6370; (c) S. H. McCooey and S. J. Connon,
Org. Lett., 2007, 9, 599–602; (d) S. Zhu, S. Yu and D. Ma, Angew.
Chem., Int. Ed., 2008, 47, 545–548. Mannich reaction:
(e) N. S. Chowdari, J. T. Suri and C. F. Barbas III, Org. Lett.,
2004, 6, 2507–2510. Aldol reaction: (f) N. Mase, F. Tanaka and
C. F. Barabas III, Angew. Chem., Int. Ed., 2004, 43, 2420–2423.
Intramolecular alkylation: (g) D. Enders, C. Wang and J. W. Bats,
Angew. Chem., Int. Ed., 2008, 47, 7539–7542Fluorination:
(h) S. Brandes, B. Niess, M. Bella, A. Prieto, J. Overgaard and
K. A. Jørgensen, Chem.–Eur. J., 2006, 12, 6039–6052. Amination:
(i) H. Vogt, S. Vanderheiden and S. Brase, Chem. Commun., 2003,
2448–2449; (j) N. S. Chowdari and C. F. Barbas III, Org. Lett.,
2005, 7, 867–870.
4 (a) S. Mosse and A. Alexakis, Org. Lett., 2005, 7, 4361–4364;
(b) S. Sulzer-Mosse, A. Alexakis, J. Mareda, G. Bollot,
G. Bernardinelli and Y. Filinchuk, Chem.–Eur. J., 2009, 15,
3204–3220.
5 (a) A. Quintard, C. Bournaud and A. Alexakis, Chem.–Eur. J.,
2008, 14, 7504–7507; (b) A. Quintard and A. Alexakis, Chem.–Eur.
J., 2009, 15, 11109–11113; (c) A. Quintard, S. Belot, E. Marchal
and A. Alexakis, Eur. J. Org. Chem., 2010, 927–936.
6 K. Shibatomi and H. Yamamoto, Angew. Chem., Int. Ed., 2008, 47,
5796–5798.
7 For an example of enhanced reactivity by the addition of an extra
hetereoatom, see: S. Belot, S. Sulzer-Mosse, S. Kehrli and
A. Alexakis, Chem. Commun., 2008, 4694.
In conclusion, we have disclosed the first addition of
functionalized a-disubsituted aldehydes to vinyl sulfone. The
reaction proceeds in high enantioselectivity and rapidly due to
the increased acidity of the hydrogen a- to the carbonyl. The
obtained adducts are of high interest and can readily
be converted in few steps to useful synthons via Diversity
Oriented Synthesis.
8 For selected reviews on sulfones, see: (a) N. S. Simpkins, Sulfones
in Organic Synthesis, Pergamon Press, Oxford, 1993; (b) C. Najera
and M. Yus, Tetrahedron, 1999, 55, 10547–10658;
(c) E. N. Prilezhaeva, Russ. Chem. Rev., 2000, 69, 367–408.
9 For the organocatalysed preparation of a-chloro aldehydes, see:
(a) N. Halland, A. Braunton, S. Brachmann, M. Marigo and
K. A. Jørgensen, J. Am. Chem. Soc., 2004, 126, 4790–4791;
(b) M. P. Brochu, S. P. Brown and D. W. C. MacMillan, J. Am.
Chem. Soc., 2004, 126, 4108–4109; (c) M. Amatore, T. D. Beeson,
S. P. Brown and D. W. C. MacMillan, Angew. Chem., Int. Ed.,
2009, 48, 5121–5124. For the organocatalysed preparation of
a-bromo aldehydes, see: (d) S. Bertelsen, N. Halland,
S. Bachmann, M. Marigo, A. Braunton and K. A. Jørgensen,
Chem. Commun., 2005, 4821–4823. For the organocatalysed
preparation of a-nitrogen aldehydes, see: (e) A. Bogevig, K. Juhl,
N. Kumaragurubaran, W. Zhuang and K. A. Jørgensen, Angew.
Chem., Int. Ed., 2002, 41, 1790–1793; (f) B. List, J. Am. Chem. Soc.,
2002, 124, 5656–5657.
Notes and references
z Typical procedure for 3a: To a solution of 99 mg of 1a (0.8 mmol,
4 eq.) in 0.8 ml of chloroform at room temperature was added
successively 62.4 mg of the vinyl sulfone (0.2 mmol, 1 eq.) and finally
0.04 mmol (20 mol%) of the aminal–pyrrolidine catalyst. The mixture
was stirred at room temperature for 2 h. When conversion is
completed, the reaction was quenched by addition of 5 ml of 1 M
HCl, the reaction mixture was extracted by 3 ꢁ 5 ml of dichloro-
methane, dried over Na2SO4 and the solvent evaporated. Purification
by flash chromatography using a cyclohexane–ethyl acetate mixture
(85/15) affords the corresponding Michael adduct 3a (68 mg,
0.158 mmol) as a white powder. Yield = 79%. The enantiomeric
excess was determined by SFC (Chiralcel OJ column, 2 ml minꢂ1
,
200 bar, MeOH, 5% during 2 min, then increased 2%/min, 30 1C).
Rt (major): 7.0 Rt: 7.5. [a]2D0 = ꢂ57,9 (CHCl3, c = 1.0, 93% ee).
1H NMR (400 MHz, CDCl3): d 0.93 (d, 3H, J = 6.8 Hz), 1.03 (d, 3H,
J = 6.8 Hz), 2.29–2.41 (m, 1H), 2.82 (dd, 1H, J = 14.4, 2.0 Hz), 3.03
(dd, 1H, J = 10.0. 6.0 Hz), 4.71 (dd, 1H, J = 4.8. 2.0 Hz), 7.50–7.92
(m, 10H), 9.46 (s, 1H). 13C NMR (75 MHz, CDCl3): d 16.6 (CH3), 18.1
(CH3), 31.3 (CH2), 35.4 (CH), 79.4 (CH), 81.4 (Cquat), 129.2 (CH),
129.7 (CH), 134.8 (CH), 137.2 (Cquat), 138.0 (Cquat), 196.7 (CH). MS
10 For the use of nitrodiene in enamine catalysis, see: (a) S. Belot,
A. Massaro, A. Tenti, A. Mordini and A. Alexakis, Org. Lett.,
2008, 10, 4557–4560; (b) S. Belot, K. Vogt, C. Besnard, N. Krause
and A. Alexakis, Angew. Chem., Int. Ed., 2009, 48, 8923–8926.
11 In a control experiment, catalyst 4a was tested in the addition of
aldehyde 3e but led to a poor 58% ee.
12 See ESIw for the determination of the absolute configuration.
13 For a precedent example of kinetic resolution in enamine catalysis,
see: J. Franzen, M. Marigo, D. Fielenbach, T. C. Wabnitz,
A. Kjaersgaard and K. A. Jørgensen, J. Am. Chem. Soc., 2005,
127, 18296–18304.
ESI: m/z = 439.3 [M + NH4]+
.
1 For recent reviews on catalytic construction of quaternary stereo-
centres, see: (a) P. G. Cozzi, R. Hilgraf and N. Zimmermann, Eur.
J. Org. Chem., 2007, 5969–5994; (b) B. M. Trost and C. Jiang,
Synthesis, 2006, 369–396; (c) I. Denissova and L. Barriault, Tetra-
hedron, 2003, 59, 10105–10146; (d) for a review on organocatalytic
formation of quaternary stereocentres, see: M. Bella and
T. Gasperi, Synthesis, 2009, 1583–1614.
14 See ESIw for details.
2 For selected reviews on enamine catalysis, see: (a) S. Bertelsen and
K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178–2189; (b) D. W.
C. MacMillan, Nature, 2008, 455, 304–308; (c) P. Melchiorre,
15 To our disappointment, Aminal–pyrrolidine catalysts only led to
partial conversion and many side products in the addition of
aminated aldehydes.
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This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 4085–4087 | 4087