Proline-catalyzed asymmetric aldol reactions of tetrahydro-4H-thiopyran-4- one with aldehydes

Article abstract of DOI:10.1016/j.tetlet.2004.09.061

Proline-catalyzed enantioselective direct intermolecular aldol reactions of tetrahydro-4H-thiopyran-4-one with various aldehydes give anti adducts with high diastereo- and enantioselectivities in moderate to excellent yields. With the aromatic aldehydes b

Full text of DOI:10.1016/j.tetlet.2004.09.061

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8347–8350
Proline-catalyzed asymmetric aldol reactions of
tetrahydro-4H-thiopyran-4-one with aldehydes
Dale E. Ward* and Vishal Jheengut
Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, SK S7N 5C9, Canada
Received 26 August 2004; accepted 8 September 2004
Available online 23 September 2004
Abstract—Proline-catalyzed enantioselective direct intermolecular aldol reactions of tetrahydro-4H-thiopyran-4-one with various
aldehydes give anti adducts with high diastereo- and enantioselectivities in moderate to excellent yields. With the aromatic aldehydes
best results were obtained in wet DMF whereas dry DMSO generally was superior with the aliphatic aldehydes. Desulfurization of
the adducts with Raney Ni provides products equivalent to aldols from 3-pentanone with potential applications in polypropionate
synthesis.
Ó 2004 Elsevier Ltd. All rights reserved.
The ÔdirectedÕ aldol reaction1 of preformed enol(ate)
derivatives with aldehydes is among the most powerful
methods for stereocontrolled carbon–carbon bond for-
mation2 as evidenced by numerous applications3 in nat-
ural product syntheses. The development of methods to
achieve stereoselective ÔdirectÕ aldol reactions of unmodi-
fied ketones and(or) aldehydes is an important objective
in the evolution of modern aldol chemistry.4 A number
of strategies have been investigated and methods based
on enzyme-, antibody-, organometallic-, and organo-
catalysis have been reported recently.4 In this regard,
the use of proline and its derivatives to catalyze enantio-
selective direct intermolecular aldol reactions has
attracted considerable attention since the initial report5
by List, Lerner, and Barbas.6,7 Although the results
achieved to date are impressive, one of the major limita-
tions of the proline-catalyzed direct aldol reaction is the
rather narrow substrate scope.6 For example, good to
excellent stereoselectivity has been realized in certain
cross-aldol reactions and generally in reactions of ace-
tone and hydroxyacetone with various aryl and alkyl
aldehydes.6,7 However, reactions of cyclic ketones often
proceed with modest diastereoselectivity and other sim-
ple ketones such as acetophenone and pentanone are
unreactive.6 In this letter we report that aldol reactions
of tetrahydro-4H-thiopyranone (1) with various alde-
hydes are effectively catalyzed by proline in wet DMF
or DMSO to give the anti adducts in good yield with
good to excellent enantioselectivity. Desulfurization of
these adducts gives products with applications in poly-
propionate synthesis and equivalent to those that would
be derived from the unreactive 3-pentanone.
We have been investigating sequential two-directional
aldol reactions of 18 in the context of a thiopyran-based
synthetic route to polypropionates.9 In the course of
these studies we noted higher reactivity9d and diastereo-
selectivity9a,c,f in aldol reactions 1 compared to those of
cyclohexanone. Thus, despite the relatively mediocre re-
sults reported for cyclohexanone in proline-catalyzed
enantioselective direct aldol reactions,6 we were
prompted to study the reaction of 1 with benzaldehyde
(2a) in the presence of proline (Scheme 1, Table 1).10
Adapting the conditions reported for the reaction of 2a
with cyclohexanone,11 reaction of 2a (0.15M in DMSO)
with 1 (3equiv) in the presence of proline (0.5equiv) at
room temperature for an arbitrary reaction time of
3days furnished a 2:1 mixture of aldols 3a (anti) and
4a (syn),9a,d respectively, in low yield (entry 1). Several
solvents were screened but only DMF was promising
(entry 4).12 Optimization of these conditions clearly
showed increased yields at higher concentrations and
superior stereoselectivity in DMF. Conversions were
not improved with additional proline (cf. entries 5 and
6)13 or with prolonged reaction times (cf. entries 8 and
9). Both the ratio of 3a:4a and the ee of 3a decreased
with increased reaction times presumably due to the
Keywords: Direct aldol; Proline; Thiopyranone; 3-Pentanone
surrogate.
*
Corresponding author. Tel.: +1 306 966 4656; fax: +1 306 966
4730; e-mail: dale.ward@usask.ca
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.061

8348
D. E. Ward, V. Jheengut / Tetrahedron Letters 45 (2004) 8347–8350
10–13) and with longer reaction times (cf. entries 10
and 14); however, excellent results were obtained under
optimized conditions (entry 15). Several authors have
reported on the effects of water in proline-catalyzed di-
rect aldol reactions. Although reactions typically pro-
ceed with low enantioselectivity in aqueous media,16
small amounts of water are often tolerated11b,17 and
are sometimes beneficial.18 In the present case, the ori-
gins of the positive effects from added water are uncer-
tain but presumably relate to improved catalyst
turnover and suppression of parasitic equilibria.19
O
O
O
S
OH
O
OH
L-proline
DMF or DMSO
H
R
R
+
R
rt, 0.5-4 days
+
2
S
3
4
S
1
Et2BOMe
NaBH4
70-85%
Ra-Ni
70-94%
OH OH
O
OH
OH OH
Ra-Ni
70-94%
R
R
R
S
7
5
6
To ascertain the scope of the process we investigated
reactions of 1 with aldehydes 2b–g (Table 2). Using
the conditions optimized for 2a, reaction of 2b gave 3b
in good yield and with excellent stereoselectivity. Similar
reaction with the more reactive 2c gave 3c with poor dia-
stereoselectivity; however, selectivity commensurate
with that observed for 3b was obtained simply by reduc-
ing the reaction time to 12h. In contrast to the aromatic
aldehydes 2a–c, reactions of the aliphatic aldehydes 2d–
g did not benefit from the presence of water and most
gave superior results in DMSO compared to DMF.
Nonetheless, with minor adjustments in conditions, the
anti aldols 3d–g were generally obtained with high ste-
reoselectivity. In keeping with previous reports,20 reac-
tions with the a-unsubstituted aldehydes 2f and 2g gave
lower stereoselectivities and yields than reactions with
the a-branched aldehydes 2d and 2e. The stereoselectiv-
ities (particularly the diastereoselectivities) and yields
obtained in proline-catalyzed aldol reactions of 1 are
generally higher than those reported for similar reac-
tions of cyclohexanone.11,16a–c,20,21
TsOH
Me2C(OMe)2
95%
a R = phenyl
b R = 2-naphthyl
c R = 4-NO2-C6H4
d R = isopropyl
e R = cyclohexyl
f R = ethyl
O
S
O
R
8
g R = pentyl
Scheme 1.
Table 1. Proline-catalyzed aldol reactions of 1 with 2aa
Entry [2a] Solvent H2O
Time %Yieldb drc
(equiv) (d)
d
%ee
(M)
1
0.15 DMSO
0
0
0
0
0
0
0
0
0
1
2
4
8
1
1
3
3
3
3
3
3
3
4
8
2
2
2
2
4
4
15
34
33
10
44
43
46
55
52
51
53
52
60
70
92
2
2
1
2
DMSO
DMSO
3
3.5
78
83
3
4
0.15 DMF
10
5
1
1e
2
1
1
1
1
1
1
1
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
10
10
14
10
5
>98
97
87
93
87
95
92
93
98
92
96
6
7
8
The anti relative configurations for aldols 3a–g was
9
3
suggested by the characteristic22 large JHH observed
10
11
12
13
14
15
14
11
8
for O@CCHCHOH (7–10Hz) previously shown to be
diagnostic for anti aldols of 1.9c,d This assignment was
confirmed for 3a,d, and 3e by diastereoselective reduc-
tions to the corresponding diols 7a,d, and 7e,
3
7
14
1
respectively (Scheme 1); H and 13C NMR analysis (as
detailed earlier)9a,b of the derived acetonides 8a,d, and
8e fully corroborated the illustrated relative configura-
tions. The absolute configuration for 3b was established
by X-ray crystallographic analysis and is consistent
with that expected from previous studies6 and from
the proposed mechanistic model for proline-catalyzed
aldol reactions.23 The absolute configurations for 3a
and 3c–g are assigned by analogy.
a Reactions at room temperature with 2a (ca. 0.6mmol), 1 (3equiv),
L-proline (0.5equiv).
b Isolated yield of 3a after chromatography; see Supplementary data
for spectroscopic data.
c Ratio of 3a:4a by 1H NMR of the crude reaction mixture.
d ee of 3a Determined by 1H NMR in the presence of (R)-(À)-2,2,2-
trifluoro-1-(9-anthryl)ethanol (TFAE) as a chiral solvating agent.
The absolute configuration of the major enantiomer is as shown.
e With 1equiv of L-proline.
Desulfurizations of the enantioenriched aldols 3a,b,d,
and 3e were achieved using Raney Ni (W-2) in EtOH/
THF in the presence of acetate buffer (pH = 5.2) and so-
dium hypophosphite (10equiv)24 to give 5a,25 5b,26 5d,27
and 5e,28 respectively, in good yields (Scheme 1, Table
3). Despite the mildness of the conditions, the products
reversibility of the reaction (retroaldol) and/or isomeri-
zation of 3a and 4a via enolization. Although in many
examples of proline-catalyzed direct aldol reactions the
adducts were shown or assumed to be stable to the con-
ditions,6 both retroaldol14 and isomerization15 by enoli-
zation have been observed. We have previously shown
the aldols derived from 1 are particularly susceptible
to syn–anti isomerization via enolization.9d The reaction
was substantially improved in the presence of water
(entries 10–15) giving much higher yields while main-
taining excellent stereoselectivity. Lower stereoselectiv-
ity was observed with greater water content (entries
Crystallographic data (excluding structure factors) for (+)-3b have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 247160. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].

D. E. Ward, V. Jheengut / Tetrahedron Letters 45 (2004) 8347–8350
Table 2. Proline-catalyzed aldol reactions of 1 with 2b–ga
8349
Entry
RCHO
Solventb
Time (d)
Product
%Yieldc
drd
%eee
>98f
1
2b
2c
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMFg
4
3b
80
72
97
39
62
53
96
93
68
20
47
<5
38
28
>20
2
2
4
3c + 4c
3c
3d
96(82)f
3
0.5
4
>20
95f
4
2d
5
3
9
11
6
DMSO/H2O
DMSOg
4
7
3
>20
10
>98h
76i
92i
8
2e
2f
DMSO/H2O
DMSO
4
3e + 4e
9
4
>20
5
10
11
12
13
14
DMF/H2O
DMFg
DMSOg
4
3f
3
16
80i
3
2g
DMSO/H2O
DMSO
4
3g
>20
14
90j
93j
4
a Reactions at room temperature: [RCHO] = 2M (ca. 0.6mmol), 1 (3equiv), L-proline (0.5equiv).
b Containing 1equiv of H2O where indicated.
c Isolated yield of indicated product after chromatography; see Supplementary data for spectroscopic data.
d Ratio of 3:4 by 1H NMR of the crude reaction mixture.
e ee of 3 (ee of 4 in parentheses).
f Determined by 1H NMR in the presence of (R)-(À)-2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE).
g [RCHO] = 1M.
h Determined by 1H NMR of the bis MosherÕs ester of the derived diol 7e.
i Determined by 1H NMR of the derived MosherÕs ester.
j Determined by 1H NMR in the presence of (+)-Eu(hfc)3.
Table 3. Desulfurizations of 3 and 7a
structure of 3b. Financial support from the Natural Sci-
ences and Engineering Research Council (Canada) and
the University of Saskatchewan is gratefully
acknowledged.
Entry Substrate Temperature Time Product %Yieldb
(°C)
(h)
1
2
3
4
5
6
7
3a
3b
3d
3e
7a
7d
7e
25
25
25
75
25
75
75
1
5ac
5bc
5dc
5ec
6a
94
76
70
94
93
70
80
9
9
Supplementary data
1.5
1.5
3
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2004.09.061.
6d
6e
1.5
a Raney Ni (W-2) in EtOH/THF with acetate buffer (pH = 5.2) and
NaH2PO2 (10equiv).
b Isolated yield of indicated product after chromatography; see Sup-
plementary data for spectroscopic data.
References and notes
c A 10–15:1 mixture of 5 and the corresponding syn diastereomer.
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In summary, enantioselective direct aldol reactions of
tetrahydro-4H-thiopyran-4-one with aldehydes is effec-
tively catalyzed by proline. Desulfurization of the aldol
adducts or the derived diols gives products equivalent to
those that would be obtained from 3-pentanone, a
ketone that does is unreactive in these reactions. The
aldols and their derivatives are useful in polypropionate
synthesis and the details of our applications in this con-
text will be communicated in due course.31
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31. Note added in proof: During the review of this paper a
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added water in proline-catalyzed direct aldol reactions
including some examples with 1: Nyberg, A. I.; Usano, A.;
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qualitatively in agreement with those reported by Pihko
et al.