Organocatalytic asymmetric sulfa-michael addition to α,β- unsaturated ketones

Article abstract of DOI:10.1002/adsc.200700382

The highly enantioselective organocatalytic sulfa-Michael addition to α,β-unsaturated ketones has been accomplished using benzyl and tert-butyl mercaptans as the sulfur-centered nucleophiles. Optically active products are obtained in high yields and good

Full text of DOI:10.1002/adsc.200700382

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DOI: 10.1002/adsc.200700382
Organocatalytic Asymmetric Sulfa-Michael Addition to
a,b-Unsaturated Ketones
Paolo Ricci,a Armando Carlone,a Giuseppe Bartoli,a Marcella Bosco,a
Letizia Sambri,a and Paolo Melchiorrea,*
a
Department of Organic Chemistry “A. Mangini”, Alma Mater Studiorum – Università di Bologna, Viale Risorgimento 4,
40136 Bologna, Italy
Fax : (+39)-051-209-3654; e-mail: p.melchiorre@unibo.it
Received: August 2, 2007; Revised: October 16, 2007; Published online: November 23, 2007
Supportinginformation for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The highly enantioselective organocata-
lytic sulfa-Michael addition to a,b-unsaturated ke-
tones has been accomplished usingbenzyl and tert-
butyl mercaptans as the sulfur-centered nucleo-
philes. Optically active products are obtained in
high yields and good to excellent stereocontrol (up
to 96% ee) from a large variety of enones. Central
to these studies has been the use of the catalytic
primary amine salt A, derived from 9-amino-(9-
deoxy)-epi-hydroquinine and d-N-Boc-phenylgly-
cine, in which both the cation and the anion are
chiral, that exhibits high reactivity and selectivity
for iminium ion catalysis with enones.
optical purity and with important restrictions in sub-
strate scope.[8] Thus, the use of simple a,b-unsaturated
ketones still remains an important challenge for the
asymmetric SMA strategy. Additionally, the range of
sulfur-centered nucleophiles well suited for both cata-
lytic and stoichiometric methodologies is generally re-
stricted to aromatic thiols.[9]
Recently, we have developed a new primary amine
salt catalyst, in which both the cation and the anion
are chiral, that exhibits high reactivity and selectivity
for iminium ion catalysis with a,b-unsaturated ke-
tones.[10] In particular we have shown that salt A,
Keywords: asymmetric catalysis; conjugate addi-
tion; ketones; organocatalysis; sulfur
The enantioselective construction of carbon-sulfur
stereogenicity represents an important objective in or-
ganic and pharmaceutical synthesis.[1] Amongthe ex-
istingmethods for the preparation of chiral sulfur-
containingmolecules, the asymmetric sulfa-Michael
made by combiningthe easily available 9-amino-(9-
addition (SMA), the reaction of sulfur-centered nucle- deoxy)-epi-hydroquinine[11] with d-N-Boc-phenylgly-
ophiles with electron-deficient olefins, is of prime im- cine as the chiral counteranion, can function as highly
portance.[2] While the use of stoichiometric chiral aux- efficient catalyst for the asymmetric conjugated addi-
iliaries and reagents has been established as an effec- tion of indoles[10a] and oximes[10b] to simple enones;
[3]
À
tive strategy for C S bond construction, the corre- the efficient activation relies on the proven ability of
spondingcatalytic variants have been far less devel-
primary amines to form iminium ion intermediates
oped.[4]
from ketones, owingto reduced steric constraints,
[12]
Highly enantioselective sulfa-Michael additions combined synergistically with the benefits of asym-
promoted by both metal and organic catalysts have metric counteranion-directed catalysis (ACDC), an
been limited to unsaturated imides,[5] cyclic enones[6] efficient strategy for enantioselective transformations
and, more recently, unsaturated aldehydes.[7] On the that proceed via cationic species.[13]
contrary, just two organocatalytic asymmetric SMA to
Herein, we further advance this organocatalytic ac-
simple enones have been reported recently, affording tivation strategy to document an operationally trivial
the b-functionalized carbonyl derivatives in moderate procedure for the highly chemo- and enantioselective
Adv. Synth. Catal. 2008, 350, 49 – 53
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49

Paolo Ricci et al.
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Table 1. Screeningresults for the organocatalytic addition of different thiols ( 1) to enone (2a).[a]
Entry
R
A [mol%]
Solvent
T [8C]
Time [h]
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
Ph, 1a
Ph, 1a
20
20
20
20
10
10
20
20
10
10
10
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
Et2O
r.t.
18
30
3
>95
75
>95
>95
>95
40
30
26
37
70
45
55
0
À10
Naphthyl, 1b
Bn, 1c
Bn, 1c
Bn, 1c
Bn, 1c
Bn, 1c
Bn, 1c
Bn, 1c
Bn, 1c
Bn, 1c
Bn, 1c
t-Bu, 1d
r.t.
r.t.
r.t.
18
18
24
18
24
24
24
24
24
66
116
56
40
86
- 8
76
70
79
83
85
85
95
À30
7[d]
8[e]
9
r.t.
À30
À30
À30
À30
À30
À20
r.t.
10
11[f]
12
13
14
toluene
toluene
toluene
toluene
60
20
90 (81)
72 (59)
15
20
[a]
Reactions were carried out in undistilled solvents without any precaution to exclude air, using1.2 equivs. of thiols 1 on a
0.2-mmol scale.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR of the crude mixture; isolated yield is indicated between brackets.
The ee of 3 was determined by HPLC analysis on chiral support.
9-AminoACHTREUNG(9-deoxy)-epi-hydroquinine without any acidic counterion was used as the catalysts.
l-N-Boc-phenylglycine was used as the counterion.
[2a]0 =0.5M.
sulfa-Michael addition of benzyl and tert-butyl mer- ence of 10 mol% of A, the stereoselectivity reached
captans to a,b-unsaturated ketones catalyzed by the satisfactory levels, albeit at the expenses of reactivity
chiral salt A. The high efficiency obtained in terms of (40% conversion and 86% ee, entry 6).
both yield and enantioselectivity (up to 96% ee) for a
Noteworthy, in the absence of an acidic counteran-
large variety of Michael acceptors highlights the ap- ion (entry 7), the diamine 9-amino-(9-deoxy)-epi-hy-
plicability and utility of this catalytic system as an imi- droquinine is still able to promote the sulfa-Michael
nium ion activator of simple enones.
addition, albeit with lower reactivity, by activatingthe
To assess the feasibility of such an asymmetric orga- nucleophilic component 1c through Brønsted base
nocatalytic sulfa-Michael addition to a,b-unsaturated catalysis.[16] However, the observed low optical purity
ketones, we screened various S-centered nucleophiles (8% ee) together with reversal in the stereochemistry
in the addition to trans-4-phenyl-3-buten-2-one 2a in supports an iminium ion activation mode of catalysis
the presence of catalytic salt A;[14] the results of this when the chiral salt A is employed. Remarkably, con-
survey are reported in Table 1. Aromatic thiols did sistently with previous observations,[10] usingthe op-
not furnish the desired product in good enantioselec- posite enantiomeric counteranion (l-N-Boc-phenyl-
tivity. Thiophenol 1a provided the Michael adduct in glycine) afforded the same enantiomeric product 3
45% ee after 18 h at room temperature (entry 1) and with lower reactivity and selectivity (entry 8), illus-
loweringthe reaction temperature to À108C did not tratinga marked case of a matched/mismatched cata-
improve the enantioselectivity to a satisfactory level lyst-ion pair combination.[17]
(55% ee, entry 2).[15] The employment of a more en-
cumbered aromatic thiol brought about a dramatic tification of toluene as the best solvent (entries 6 and
loss in stereocontrol (entry 3). 9–10). Further optimization of standard parameters
Evaluation of usual reaction media led to the iden-
Interestingly, the use of benzyl mercaptan 1c pro- revealed that carryingout the reaction at À208C in
vided the desired product with improved steroselec- the presence of 15 mol% of the catalytic salt A repre-
tivity (56% ee, entry 4) and this prompted us to fur- sents the best compromise between reactivity and
ther screen such a nucleophile. Loweringthe catalyst
loadingshowed the occurrence of a decrease in enan-
enantioselectivity (81% isolated yield and 85% ee
after 66 h, entry 13). Finally tert-butyl mercaptan 1d,
tioselectivity (40% ee, entry 5); nevertheless on carry- albeit less reactive, proved to be a promisingalterna-
ingout the reaction at lower temperature in the pres- tive S-nucleophile for the present SMA strategy, as
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Organocatalytic Asymmetric Sulfa-Michael Addition to a,b-Unsaturated Ketones
Table 2. Organocatalytic asymmetric sulfa-Michael addition of benzyl mercaptan (1c) to enones (2).[a]
COMMUNICATIONS
Entry
R1
R2
A [mol%]
Time [h]
Product and Yield [%][b]
ee [%][c]
1
2
3
4
Ph
Me, 2a
Me, 2b
Me, 2c
Me, 2d
Et, 2e
Et, 2f
15
15
15
20
20
20
20
66
46
66
96
96
96
40
3a 81
3b 78
3c 84
3d 81
3e 75
3f 55
3g 75
85
84
84
89
p-ClC6H4
2-thienyl
Pent
Pent
Me
5
96
6
94
7[d]
Ph
Ph, 2g
54[e]
[a]
Reactions carried out using1.2 equivs. of 1c on a 0.2 mmol scale.
Isolated yield.
Determined by HPLC analysis on chiral support.
Reaction carried out at room temperature.
[b]
[c]
[d]
[e]
The absolute configuration of the product 3g was assigned to be (S) by comparison of the measured optical rotation with
the value reported in the literature.[8a]
the correspondingproduct was isolated in satisfactory
yield and very high enantiomeric excess (59% yield stereochemical induction is in agreement with the ob-
value reported in the literature.[8a] The sense of the
and 95% ee, entry 14). Besides these interestingre-
servation made in the previously reported Michael
sults, the use of benzyl and tert-butyl mercaptan rep- additions catalyzed by the catalytic salt A.[10] Theoret-
resents an important feature from a synthetic stand- ical studies based on DFT calculations on the iminium
point, providingorthogonal sets of removable S-pro- ion intermediate to understand the origin of the enan-
[18]
tectinggroups.
tioselectivity are ongoing and will be reported in due
Havingidentified 1c and 1d as two suitable nucleo- course.
philes, we set out to investigate the scope of the orga-
We next examined whether the presented organo-
nocatalyzed SMA reaction with respect to various catalytic SMA protocol could be extended to an alter-
a,b-unsaturated ketones. The addition of benzyl mer- native thiol havinga different removable protecting
captan 1c proved to be efficiently activated by the group. Indeed, the catalytic salt A efficiently cata-
catalytic salt A, providingthe desired adduct in good
lyzed the sulfa-Michael addition of tert-butyl mercap-
yields and high ee (Table 2). There appears to be sig- tan 1d to a large variety of simple enones. Albeit the
nificant tolerance towards steric and electronic de- low reactivity of 1d required the use of 20 mol% of
mands of the b-olefin substituent as highly enantioen- the catalyst and prolonged reaction time, impressive
riched adducts could be obtained usingaromatic, het-
eroaromatic and alkyl groups.
levels of stereocontrol was achieved even at room
temperature (Table 3).
Variation in the steric contribution of R2 ketone
In the presence of aromatic substituents at the b-
substituents (compare entries 4 and 5) revealed that position of the Michael acceptor, enantioselectivities
the more encumbered ethyl group engenders higher ranging from 91% to 95% were obtained with great
selectivity, albeit at the expenses of the reactivity; the tolerance for heteroaromatic and variously substituted
sulfa-Michael adducts could be isolated in good yields functional groups (entries 1–5). The protocol was also
and very high optical purity (ee values ranging from efficient for aliphatic enones providingthe expected
94% to 96%) by adjustingthe catalyst loadingand
products in high optical purity and good yields (en-
tries 6–9).
the reaction time (entries 5–6).[19]
In our previous studies[10a] we observed that the
Interestingly, the presented organocatalytic SMA
chiral salt A was an effective catalyst also for aromat- proceeds efficiently also with cyclic enones, the prod-
ic ketones (R2 =Ph), a class of substrates which is not uct derived from 2-cycloexen-1-one beingisolated in
generally suitable for iminium ion activation. Notably, high yield and enantioselectivity (96% yield, 87% ee,
our organocatalytic protocol confirms its efficiency in entry 10). This result, in conjunction with the observa-
activatingaromatic ketones such as trans-chalcone 2g tion that reaction with trans-chalcone provided prod-
providingthe desired product 3g, albeit with moder- uct 4k with excellent enantiomeric excess (95% ee,
ate stereocontrol (entry 7). The absolute configura- entry 11), adds significant importance to the present
tion of the product 3g was assigned to be (S) by com- organocatalytic SMA protocol demonstrating that A
parison of the measured optical rotation with the is able to activate efficiently and in a high stereoselec-
Adv. Synth. Catal. 2008, 350, 49 – 53
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51

Paolo Ricci et al.
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Table 3. Organocatalytic asymmetric sulfa-Michael addition
of tert-butyl mercaptan (1d) to enones (2).[a]
(0.2 mmol), the mixture was stirred at the appropriate tem-
perature for 10 min. Then thiol 1 (0.24 mmol, 1.2 equivs.)
was added in one portion, the tube was closed with a rubber
stopper and stirringwas continued for the indicated time.
Then the crude reaction mixture was diluted with hexane
(2 mL) and flushed through a short plug of silica, using
hexane/Et2O (1/1) as the eluent. Solvent was removed under
vacuum, and the residue was purified by flash chromatogra-
phy to yield the desired product.
Entry
R1
R2
Product and
Yield [%][b]
ee
[%][c]
Supporting Information
1
2
3
4
5
6
7
8
Ph
Me, 2a
Me, 2b
Me, 2i
Me, 2j
Me, 2c
Me, 2d
Me, 2k
Me, 2l
Me, 2m
4a 59
4b 70
4c 98
4d 96
4e 65
4f 76
4g 71
4h 46
4i 49
4j 96
4k 44
95
94
91
94
92
91
82
88
87
87
95
Complete experimental procedures and full characterization
of compounds 3a–g and 4a–k are given in the Supporting In-
formation.
p-ClC6H4
p-NO2C6H4
p-CNC6H4
2-thienyl
Pent
Me
iPr
PhCH2CH2
Acknowledgements
9
10[d]
11
ACHTREUNG(CH2)3, 2n
This research was carried out within the framework of the
National Project “Stereoselezione in Sintesi Organica” sup-
ported by MIUR, Rome, and FIRB National Project “Proget-
tazione, preparazione e valutazione farmacologica di nuove
molecole organiche quali potenziali farmaci innovativi”.
Ph
Ph, 2h
[a]
Reactions carried out using1.2 equivs. of 1d on a 0.2-
mmol scale.
Isolated yield.
Determined by HPLC analysis on chiral support.
Reaction carried out over 5 h.
[b]
[c]
[d]
References
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tones.[20]
In summary, we have disclosed an organocatalytic
asymmetric protocol for the highly enantioselective
sulfa-Michael addition that is effective for a large va-
riety of a,b-unsaturated ketones. The high chemical
yields and enantioselectivities obtained consolidate
the catalytic salt A as a general iminium ion activator
of simple enones. From a synthetic perspective, the
simplicity of the procedure that employs easily avail-
able startingmaterials and catalyst in combination
with the use of S-centered nucleophiles havingdiffer-
ent removable protectinggroups, renders the method
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[2] For a comprehensive review on asymmetric sulfa-Mi-
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Y.-C. Chen, L.-S. Ding, Y. Wu, Synlett 2005, 603; for
General Procedure for the Organocatalytic Sulfa-
Michael Addition to a,b-Unsaturated Ketones
All the reactions were carried out in undistilled toluene
without any precautions to exclude water. In an ordinary
test tube equipped with a magnetic stirring bar, 9-amino-(9-
deoxy)-epi-hydroquinine (10–20 mol%) and d-N-Boc-phe-
nylglycine (20–40 mol%) as the chiral counteranion were
dissolved in 0.8 mL of toluene. The solution was stirred for
20 min at room temperature to allow the formation of the
catalytic salt A. After addition of a,b-unsaturated ketones 2
52
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ꢀ 2008 Wiley-VCH VerlagGmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 49 – 53

Organocatalytic Asymmetric Sulfa-Michael Addition to a,b-Unsaturated Ketones
COMMUNICATIONS
tandem sulfa-Michael/aldol sequences, see: e) L. Zu, J.
Wang, H. Li, H. Xie, W. Jiang, W. Wang, J. Am. Chem.
Soc. 2007, 129, 1036.
[12] For recent use of primary amines in the activation of
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Wei, Chem. Commun. 2006, 1451; b) H. Huang, E. N.
Jacobsen, J. Am. Chem. Soc. 2006, 128, 7170; for the
use of primary amine salts in asymmetric iminium-ion
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[13] a) S. Mayer, B. List, Angew. Chem. 2006, 118, 4299;
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[14] The results obtained by using9-amino-(9-deoxy)- epi-
hydroquinine in combination with different counterions
(TFA, p-TSA, l-N-Boc-phenylalanine) in the organoca-
talyzed SMA did not bringany appreciable improve-
ment in terms of enantioselectivity, confirmingthe su-
perior efficiency of the catalytic salt A.
[15] Consideringthe relative high acidity of phenyl thiol 1a,
its Michael addition to 2a could be easily promoted by
weak bases, see Ref.[16] Since the catalyst amine compo-
nent 9-amino-(9-deoxy)-epi-hydroquinine has three
basic nitrogen atoms, a Brønsted base-catalyzed back-
ground reaction, affecting the stereoselectivity of the
process, could be envisaged. As interestingly suggested
by one reviewer, the use of 3 equivs. of d-N-Boc-phe-
nylalanine as the acidic additive to avoid this parasitic
reaction has been investigated, resulting in only a slight
enhancement of enantioselectivity: T=À108C, 30 h re-
action time, 80% conversion, 62% ee (compare to
entry 2, Table 1).
[6] For leadingreferences, see: a) E. Emori, T. Arai, H.
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348; Angew. Chem. Int. Ed. 2002, 41, 338; see also
Ref.[4b]
[7] a) M. Marigo, T. Schulte, J. FranzØn, K. A. Jørgensen,
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´
[8] a) J. Skarz˙ewski, M. Zielinska-Blajet, I. Turowska-Tyrk,
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[9] For examples of sulfur-centered nucleophiles used in
asymmetric SMA that can be easily removed to afford
versatile SH functionality, see Refs.[7a,8b]
[10] a) G. Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, L.
Sambri, P. Melchiorre, Org. Lett. 2007, 9, 1403; b) A.
Carlone, G. Bartoli, M. Bosco, F. Pesciaioli, P. Ricci, L.
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[11] Recently, 9-amino-(9-deoxy)-epi-Cinchona alkaloids in
combination with achiral acids were reported to be ef-
fective catalysts for the asymmetric conjugate addition
of carbon-centered nucleophiles to simple enones via
iminium ion catalysis: a) J.-W. Xie, W. Chen, R. Li, M.
Zeng, W. Du, L. Yue, Y.-C. Chen, Y. Wu, J. Zhu, J.-G.
Deng, Angew. Chem. 2007, 119, 393; Angew. Chem. Int.
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413; c) W. Chen, W. Du, L. Yue, R. Li, Y. Wu, L.-S.
Ding, Y.-C. Chen, Org. Biomol. Chem. 2007, 5, 816; for
a recent ACDC approach with a multifunctional pri-
mary amine, see: d) W. Chen, W. Du, Y.-Z. Duan, Y.
Wu, S.-Y. Yang, Y.-C. Chen, Angew. Chem. 2007, 119,
7811; Angew. Chem. Int. Ed. 2007, 46, 7667. For the use
in asymmetric enamine catalysis with ketones, see:
e) S. H. McCooey, S. J. Connon, Org. Lett. 2007, 9, 599;
f) T.-Y. Liu, H.-L. Cui, Y. Zhang, K. Jiang, W. Du, Z.-
Q. He, Y.-C. Chen, Org. Lett. 2007, 9, 3671; g) B.-L.
Zheng, Q.-Z. Liu, C.-S. Guo, X.-L. Wang, L. He, Org.
Biomol. Chem. 2007, 5, 2913.
[16] The potentiality of Cinchona alkaloids to act as bases
to deprotonate substrates with relatively acidic protons
such as thiols, thus forminga contact ion-pair between
the resultinganion and the protonated quinuclidine
moiety, is well established, see Refs.[4b,6b]
[17] For a similar behavior in ACDC activation strategy, see
Ref.[13b]
[18] T. W. Greene, P. G. M Wuts, Protective Groups in Or-
ganic Synthesis, 3rd edn., Wiley-VCH, New York, 1999,
chapter 6, p 454.
[19] a,b-Unsaturated ketone with R1 =Ph and R2 =Et gave
a sluggish reaction rate (27% conversion after 42 h), al-
though the product was formed in 90% ee at À308C in
the presence of 20 mol% of catalytic salt A.
[20] Achieving high levels of generality and selectivity in
asymmetric SMA under catalytic conditions is rather
challenging, as methods that provide regularly high
enantioselectivity (ees above 90%) are scarce; see
Refs.[6b,7a–c]
Adv. Synth. Catal. 2008, 350, 49 – 53
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