Organocatalytic enantioselective aminosulfenylation of α,β- unsaturated aldehydes

Article abstract of DOI:10.1002/anie.200802335

(Chemical Equation Presented) Domino theory: A simple, highly enantioselective organocatalytic aminosulfenylation of α,β- unsaturated aldehydes affords orthogonally protected β-amino-α- mercaptoaldehydes in high yields and 93 to >99% ee (see scheme, Bn=benzyl). Notably, the catalytic transformation shows that it is possible to efficiently employ all components of an electrophile, which includes a nucleofuge, in organocatalytic domino reactions of enals.

Full text of DOI:10.1002/anie.200802335

Communications
DOI: 10.1002/anie.200802335
Synthetic Methods
Organocatalytic Enantioselective Aminosulfenylation of a,b-
Unsaturated Aldehydes**
Gui-Ling Zhao, Ramon Rios, Jan Vesely, Lars Eriksson, and Armando Cꢀrdova*
Domino, tandem, or cascade reactions, that involve the
formation of multiple carbon–carbon or carbon–heteroatom
bonds and stereocenters in one-pot reactions, are a rapidly
growing research field within the synthesis of small molecules
with complex molecular scaffolds.[1] The advantages of
domino reactions include “green chemistry” factors, such as
atom economy,[2] reduction in the number of synthetic steps,
and minimization of solvents and waste.[3] Thus, asymmetric
domino reactions using chiral precursors for stereocontrol
have been developed.[1] A more challenging task is to develop
catalytic asymmetric domino reactions. In this context, the
development of organocatalytic, asymmetric, one-pot domino
reactions is a rapidly growing research area.[4–5] In particular,
versions involving a subsequent intramolecular reaction step
that forms cyclic products are economical, since the donor
species includes both nucleophilic and electrophilic reactiv-
ities. However, in intermolecular domino reactions that form
acyclic products, the nucleophilic and the electrophilic sub-
strates are added sequentially in one pot [Eq. (1); Nu =
nucleophile, E = electrophile, LG = leaving group].
Scheme 1. Proposed reaction pathway. Nu=nucleophile; E=electro-
phile.
Based on our research interest in organocatalysis,[6] we
became intrigued as to whether it would be possible to
efficiently incorporate all components of the reacting sub-
strates in a catalytic domino process encompassing entirely
intermolecular reaction steps using a small organic catalyst
[Eq. (2), Scheme 1], thus reducing the generation of side
products and waste.
According to this scenario, all components of electrophile
À
2 (Nu E), which includes a masked nucleophilic component,
are incorporated into the electrophilic enal 1 by the merging
of the two catalytic cycles shown in Scheme 1, affording the
aldehyde product 3. Herein, we demonstrate for the first time
that it is possible to efficiently apply this strategy in
intermolecular organocatalytic domino reactions and to the
novel highly enantioselective aminosulfenylation of a,b-
unsaturated aldehydes (93– > 99% ee).
[*] Dr. G.-L. Zhao, Dr. R. Rios, Dr. J. Vesely, Prof. Dr. A. Cꢀrdova
Department of Organic Chemistry
The Arrhenius Laboratory, Stockholm University
10691 Stockholm (Sweden)
Fax: (+46)8-154-908
The b-amino-a-mercapto carbonyl motif displays potent
biological activity, for example, in potent inhibitors of amino-
peptidase A,[7] tetanus neurotoxin,[8] botolinium neurotoxin
type B,[9] and cholesterol absorption.[10,11] As a result of the
important biological activity associated with this motif, we
decided to investigate the catalytic domino approach depicted
in Scheme 1 for the aminosulfenylation of a,b-unsaturated
E-mail: acordova@organ.su.se
Prof. Dr. L. Eriksson
Department of Structural Chemistry, Stockholm University
[**] We gratefully acknowledge the Swedish National Research Council
and Carl Trygger Foundation for financial support.
Supporting Information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802335.
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Chemie
Table 1: Catalyst screen for the reaction between 1a and 2a.[a]
aldehydes. In addition, a-sulfeny-
lation reagents looked promising
since they usually contain a weakly
basic heterocyclic nitrogen-cen-
tered nucleofuge.[12] However, the
conjugate
transformations
between the nucleofuges of N-
(alkylthio)succinimides or N-
(alkylthio)phthalimides (succini-
mide and phthalimide, respec-
tively) and cinnamic aldehyde
derivatives 1 are not productive
[Eq. (3)].[13]
Moreover, the use of N-
(alkylthio)succinimides
2
in
amine-catalyzed a-sulfenylation
Entry
Catalyst
Solvent
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
reactions of aldehydes proceeds
with only sluggish conversion and,
in the past, 1-benzylsulfanyl-1,2,4-
triazole has been used instead.[12]
Nevertheless, we began the asym-
metric aminosulfenylation reaction
between cinnamic aldehyde 1a and
N-(benzylthio)succinimide 2a, as a
successful merging of the two cata-
lytic cycles in the domino process
has the potential to push the equi-
librium towards product formation
(Table 1).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4
5
6
7
8
9
8
8
8
8
8
8
8
8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Toluene
CH3CN
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
16
16
16
16
16
16
16
16
0
36
traces
33
83
traces
49
traces
51
80
73
78
–
–
47:53
n.d.
66:34
52:48
n.d.
56, 56
n.d.
85, 86
96, >99
n.d.
54:46
n.d.
95, >99
n.d.
16[e,h]
16[f,h]
72[g]
48[h,k]
16[i]
40[j,l]
33:67
49:51
50:50
53:47
55:45
48:58
94, 97
94, 97
96, >99
96, 99
96, 99
93, 99
81
55
A small amount of succinimide
(10 mol%) was also added in order
to initiate cycle 1 in Scheme 1.
After screening various chiral
amines as catalysts and different
suitable conditions for the amino-
sulfenylation of 1a, we found that
amines 5–9 catalyzed the asymmet-
ric domino reaction (Table 1). The
protected chiral diarylprolinols 7
[a] Experimental conditions unless otherwise stated: A mixture of 1a (0.25 mmol), 2a (0.30 mmol),
catalyst (20 mol%, TMS=trimethylsilyl), and succinimide (0.025 mmol) in solvent (0.5 mL) was stirred
at room temperature and reaction times given. [b] Yield of 3a and 3a’ isolated by silica-gel column
chromatography. [c] Determined by 1H NMR spectroscopic analysis of the crude reaction mixture.
[d] Syn, anti; determined by chiral-phase HPLC analysis. [e] Reaction performed at 408C. . [f] Benzoic
acid (20 mol%) was added. [g] Reaction run at 48C. [h] Reaction run without succinimide. [i] 4 mol%
succinimide was used. [j] 10 mol% of catalyst 8 was used. [k] 10 mol% of a-sulfenylated cinnamic
aldehyde[15] was also formed. [l] 5 mol% of a-sulfenylated cinnamic aldehyde was also formed.
ieved in toluene (Table 1, entry 7). The reaction was also
productive without the initial addition of a small amount of
succinimide (Table 1, entries 9 and 12). However, the reaction
rate slightly decreased. The rate loss could be avoided if a
small amount of organic acid (20 mol%) was added (Table 1,
entry 10). Running the reaction at a lower temperature also
decreased the reaction rate (Table 1, entry 11). The amount of
initiating succinimide could be decreased to 4 mol% without
affecting the efficiency and enantioselectivity of the trans-
formation (Table 1, entry 13). The domino reaction also
worked at lower catalyst loadings without significantly
affecting the enantioselectivity, however a slight decrease in
efficiency was detected (Table 1, entry 14). Based on these
results, we decide to investigate the amine 8-catalyzed
enantioselective aminosulfenylation of enals 1 in CHCl3
with 10 mol% of succinimide as an additive (Table 2).
The organocatalytic asymmetric domino reactions gave
the corresponding syn- and anti-b-amino-a-mercaptoalde-
hydes 3a–3i and 3a’–3i’, respectively, in high yields (60–83%)
and 8[12,14] exhibited the highest reactivity and catalyzed the
formation of the corresponding b-amino-a-mercaptoalde-
hydes 3a and 3a’ in 33% and 83% combined yields,
respectively (Table 1, entries 4 and 5). The highest enantio-
selectivity was achieved in chloroform solution when chiral
amine 8 was the catalyst. The two diastereoisomers 3a and 3a’
were readily separated and isolated by silica-gel column
chromatography with 96% and > 99% ee, respectively
(Table 1, entry 5). Excellent enantioselectivity was also ach-
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Table 2: Catalytic asymmetric aminosulfenylation of enals 1.[a]
and diastereomeric ratios varying
from 52:48 to 77:23. The enantio-
selectivity of the reaction was high
in all cases (93– > 99% ee). In
general, the syn- and anti-diaste-
reoisomers can be separated from
each other by silica-gel column
chromatography. Notably, no con-
jugate addition product was
Entry
R1
Product
3a/3a’
3b/3b’
3c/3c’
3d/3d’
Yield [%][b]
d.r.[c]
52:48
55:45
63:37
57:43
ee [%][d]
96, >99
94, 99
1
2
3
4
83
73
60
65
formed
if
first
succinimide
(1.2 equiv) was added to the 3-
aryl-substituted enals 1a–h and
catalyst 8 under our reaction con-
ditions. Hence, the equilibrium of
the first conjugate addition is not
towards product formation. How-
ever, when aliphatic enal 1i was
used as the substrate, the conjugate
addition gave the corresponding
Michael product after 16 h, before
the electrophile 2a was added
(Table 2, entry 10). This procedure
gave nearly identical results as to
when electrophile 2a was directly
added to the aliphatic enal
(Table 2, entry 9). However, the
reaction time was increased. The
reaction also worked with other
thiosuccinimides 2. For example,
the reaction between 4-cyanocin-
namic aldehyde and N-(4-chloro-
phenylthio)succinimide 2b gave
the corresponding mercaptoalde-
hydes 3j and 3j’ in 55% yield
with 62:38 diastereomeric ratio
94, 98
98, 99
5
3e/3e’
67
49:51
95, 95
6
7
8
3 f/3 f’
3g/3g’
3h/3h’
79
78
67
55:45
56:44
71:29
93, 99
95, 95
95, 95
9
3i/3i’
3i/3i’
67
74[e]
71:29
77:23
95, n.d.
97, n.d.
10
[a] Experimental conditions: A mixture of enal 1 (0.25 mmol), 2a (0.30 mmol), catalyst (20 mol%), and
succinimide (0.025 mmol) in solvent (0.5 mL) was stirred at room temperature for 16 h. [b] Yield of 3
and 3’ isolated by silica-gel column chromatography. [c] Determined by H1 NMR spectroscopic analysis
of the crude reaction mixture. [d] Syn, anti; determined by chiral-phase HPLC analysis. [e] Succinimide
(1.2 equiv) was first added to the enal in the presence of catalyst 8 at 48C. After 16 h 2a was added and
the reaction was stirred for an additional 4 h. The formation of the Michael intermediate was monitored
by NMR spectroscopic analysis.
and 90% ee (see Supporting Information).
The b-amino-a-mercaptoaldehydes 3 can
be readily converted into other useful
compounds, such as both diastereoisomers
of b-mercapto-g-amino alcohols 10, esters
11, and a,b-unsaturated esters 12, which
can be further rearranged to unsaturated a-
amino acid derivatives (Scheme 2).[15] The
reduction and Wittig transformations can
also be performed as one-pot operations.
The absolute configuration of b-amino-a-
mercaptoaldehydes 3 at C3 was R as
established by X-ray analysis of 3a
(Figure 1).[16] The absolute configuration
of the anti-diastereomers 3a’–3i’ was deter-
mined by epimerization of pure anti-3a’ to
syn-3a with imidazole (Scheme 2). Chiral-
phase HPLC analysis of the isolated syn-
isomer revealed that the epimerization
gave 3a (R configuration at C3), indicating
that the absolute configuration at C3 of
aminoaldehydes 3a’–3i’ was also R.
Thus, efficient shielding of the Re-face
(R = Ar) of the chiral iminium intermedi-
=
Scheme 2. a) NaBH4, MeOH, 08C; b) 2,4-Cl2C6H3COCl, triethylamine, CH2Cl2; c) Ph3P
CHCO2Et, CHCl3; d) Imidazole, CH2Cl2.
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Figure 1. ORTEP representation of b-amino-a-sulfenyl aldehyde 2a.
Thermal ellipsoids set at 50% probability level
ate I by the bulky aryl groups of 8 leads to stereoselective Si-
facial nucleophilic conjugate attack on the b-carbon by the
succinimide (Scheme 1). Next, the resultant chiral enamine
intermediate II attacks the electrophilic 2a in a SN2-type
mechanism, releasing succinimide (NuÀ in cycle 1). Hydrol-
ysis of iminium intermediate III gives the aldehyde product 3
and regenerates the catalyst (cycle 2). The formation of both
diastereoisomers, as a result of epimerization of the a-carbon
of aminoaldehydes 3 by the chiral amine catalyst, was
established by mixing pure 3a with amine 8, which led to
the formation of anti-3a’ and a-sulfenylated cinnamic alde-
hyde[15] by epimerization and elimination of 3a, respectively.
In summary, we have demonstrated that it is possible to
efficiently employ all components of an electrophile, which
includes a nucleofuge, in organocatalytic domino reactions of
enals. This concept[17] was employed in the highly enantiose-
lective aminosulfenylation of a,b-unsaturated aldehydes that
gives access to valuable b-amino-a-mercaptoaldehydes and
derivatives thereof in high yields with 93– > 99% ee.
Received: May 19, 2008
Revised: June 19, 2008
Published online: September 26, 2008
Keywords: aldehydes · asymmetric catalysis · domino reactions ·
.
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