Efficient trans-selectivity in the cyclocondensation of (S)-2-[2-(p-tolylsulfinyl)phenyl]acetaldehyde with activated dienes catalyzed by Yb(OTf)3

Article abstract of DOI:10.1021/jo061128n

(Chemical Equation Presented) Reactions of (S)-2-[2-(p-tolylsulfinyl) phenyl]acetaldehyde 1 with Danishefsky's and related dienes took place in the presence of Yb(OTf)₃ in a completely stereoselective manner, mediated by a remote sulfinyl group

Full text of DOI:10.1021/jo061128n

Efficient trans-Selectivity in the Cyclocondensation of
(S)-2-[2-(p-Tolylsulfinyl)phenyl]acetaldehyde with Activated Dienes
Catalyzed by Yb(OTf)3
Jose´ L. Garc´ıa Ruano,* M. AÄ ngeles Ferna´ndez-Iba´n˜ez, and M. Carmen Maestro*
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid, Cantoblanco,
28049-Madrid, Spain
joseluis.garcia.ruano@uam.es; carmen.maestro@uam.es
ReceiVed June 1, 2006
Reactions of (S)-2-[2-(p-tolylsulfinyl)phenyl]acetaldehyde 1 with Danishefsky’s and related dienes took
place in the presence of Yb(OTf)3 in a completely stereoselective manner, mediated by a remote sulfinyl
group (1,5-asymmetric induction), to afford the corresponding 2,3-dihydro-4H-pyran-4-ones. These
reactions followed a stepwise mechanism, as was corroborated by isolation of the corresponding
intermediates, with a high level of trans-selectivity for 4-methyl-substituted dienes. Treatment of the
adducts with Raney Ni provided concomitant cleavage of the C-S bond and reduction of the conjugated
carbonyl grouping.
SCHEME 1
Introduction
The hetero Diels-Alder (HDA) reactions of aldehydes with
1-alkoxy-3-(trialkylsilyloxy)-1,3-butadiene (Danishefsky’s di-
ene) and related dienes, mediated by Lewis acids, provide one
of the most powerful synthetic tools to construct chiral 2,3-
dihydro-4-pyranone moieties widely used in the preparation of
specific carbohydrates, as well as in the total synthesis of natural
products.1 The stereochemical results obtained in these reactions
depend on the nature of the catalyst, which determines their
evolution via a concerted or stepwise mechanism (Scheme 1).
Thus, Danishefsky et al.2 reported that the reaction of benzal-
dehyde with 1-methoxy-2-methyl-3-(trimethylsilyloxy)-1,3-buta-
diene in the presence of BF3 proceeded in a stepwise pathway,
mainly yielding trans-2,3-disubstituted dihydropyranones, whereas
it followed a concerted mechanism, affording the cis-2,3-
disubstituted isomers almost exclusively, when catalyzed by
ZnCl2. The use of bulkier lanthanides(III) complexes also
catalyzes these reactions and significantly increases the cis-
stereoselectivity.3 However, the factors determining the mech-
anism followed by these reactions are not completely clear. In
most cases, the isolation of the intermediates is the only possible
way to distinguish between the two mechanisms.
The high stereoselectivity of the concerted reactions yielding
major cis-2,3-disubstituted dihydropyranones (cis-selectivity) has
been explained by assuming that the endo approach was the
preferred one. It is additionally favored by the steric interactions
between diene and catalyst in a cis-arrangement with respect
to the aldehydic hydrogen, which destabilizes the exo approach
mode. The stereoselectivity of the stepwise mechanism is
(1) Reviews: (a) Bednarski, M. D.; Lyssikatos, J. P. In ComprehensiVe
Organic Synthesis; Trost, B., Fleming, I. Eds.; Pergamon Press: Oxford,
1991; Vol. 2, Heathcock, C. H., Ed., pp 661-706. (b) Waldmann, H.
Synthesis 1994, 535. (c) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000,
39, 3558.
(2) Danishefsky, S. J.; Larson, E.; Askin, D.; Kato, N. J. Am. Chem.
Soc. 1985, 107, 1246 and references therein.
(3) Bednarski, M. D.; Danishefsky, S. J. J. Am. Chem. Soc. 1983, 105,
3716.
10.1021/jo061128n CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/25/2006
J. Org. Chem. 2006, 71, 7683-7689
7683

Garc´ıa Ruano et al.
TABLE 1. Reaction of 1 and Danishefsky’s Diene under Different
Conditions
explained on the basis of an extended TS to give anti-aldol
products (trans-selectivity) that evolve into the trans-2,3-
disubstituted dihydropyranones (Scheme 1). However, the trans-
selectivity has also been found in concerted processes that occur
with aldehydes in the presence of Lewis acids. The resulting
chelates exhibit favored exo approaches of the dienes in order
to avoid the strong steric interactions of the endo approaches.4
The most widely used asymmetric version of these reactions
is that involving chiral catalysts, which provides high levels of
cis-selectivity.1c The low diastereofacial or endo-selectivity
observed in reactions of enantiomerically pure dienes5 and the
easy racemization of the aldehydes with chiral centers at C-R
under the experimental conditions have seriously limited the
use of chiral auxiliaries. Although a limited number of examples
affording optically pure trans-2,3-disubstituted dihydropyra-
nones has been reported,2,6 the search for efficient methods for
preparing these compounds in processes evolving with trans-
selectivity remains nowadays as an interesting challenge in
asymmetric synthesis.
entry Lewis acid solvent
temp
CH2Cl2 rt
THF rt
additive
time
2:3 ratio
1
16 h
16 h
7 h
2
3
4
5
6
7
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Ti(Oi-Pr)4
BF3OEt2
In(OTf)3
a
a
toluene rt
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 rt
16 h
13 h
13 h
13 h
20 h
24 h
36 h
3 h
74:26b
46:54c
8
Yb(Oi-Pr)3 CH2Cl2 rt
d
9
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
CH2Cl2 -40 °C
CH2Cl2 -78 °C
CH2Cl2 rt
CH2Cl2 0 °C
CH2Cl2 -78 °C MS 4Å
CH3CN rt
CH3CN -40 °C
EtCN
DMF
86:14b
90:10c
74:26a
77:33b
88:12c
In the course of our research program related to the use of
the sulfinyl group to achieve a remote control of the stereose-
lectivity,7 we have recently described the significant role of Yb-
(OTf)3 in the stereochemical control of different nucleophilic
addition of hydrides and cyanides to δ-ketosulfoxides.8 The
efficiency of this catalyst seems to be due to the formation of
stable chelated species with the sulfinyl and carbonyl oxygens,
which are highly reactive and show a strong facial discrimination
toward the attack of nucleophiles. With the aim of widening
the scope of the remote stereoselective functionalization medi-
ated by sulfoxides, we decided to study the hetero Diels-Alder
reactions of (S)-2-[2-(p-tolylsulfinyl)phenyl]acetaldehyde 1 with
oxygenated dienes. According to the above-mentioned prece-
dents, 1 could be a substrate liable to evolve with trans-
selectivity in the reactions catalyzed by Yb(OTf)3 (the exo
approach would be the preferred one in concerted processes as
a result of the formation of the chelated species with the
catalyst), which would increase the interest of this study. Their
possible evolution through a stepwise mechanism could also
take place with trans-selectivity. Additionally, this aldehyde
should be configurationally stable under the conditions used in
these reactions. In this paper, we report the results obtained in
the reactions of aldehyde 1 with different Danishefsky-type
dienes catalyzed by Yb(OTf)3. They provide a new example
evidencing the efficiency of a remote sulfinyl group to control
the stereoselectivity of these reactions that evolve with a high
trans-selectivity through a stepwise mechanism. The results
10
11
12
13
14
15
16
17
MS 4Å
MS 4Å
20 h
30 h
5 min 78:22b
5 min 88:12c
-78 °C
-40 °C
2 h
2 h
90:10b
a Traces of the adducts were detected. b Determined by NMR. c Deter-
mined by HPLC. d Complex reaction mixture.
obtained in the reactions of the resulting 2,3-dihydropyranones
with Raney nickel are also reported.
Results and Discussion
We have used the recently reported (S)-2-[2-(p-tolylsulfinyl)-
phenyl]acetaldehyde 19 as the starting material. We first
investigated its reaction with the Danishefsky’s diene under
different conditions (Table 1). The reaction did not evolve in
the absence of Lewis acids (entry 1), but when it was performed
in the presence of Yb(OTf)3, the formation of the HDA adducts
2 and 3 could be observed. The composition of the reaction
mixture was dependent on the solvent. In toluene or THF only
traces of adducts were detected (entries 2 and 3), but complete
disappearance of the starting material was observed in CH2Cl2
with formation of a 3:1 mixture of adducts 2:3 (entry 4). The
use of other Lewis acids as catalysts did not improve the
reactivity, either by decreasing the stereoselectivity or by
precluding the reaction (entries 5-8). The stereoselectivity was
substantially improved by lowering the temperature in CH2Cl2
(entries 9 and 10), with the best result being obtained at -78
°C. Under these conditions a 90:10 mixture of 2 and 3 was
obtained (entry 10). The addition of molecular sieves (4 Å)
enhanced the reactivity (shorter reaction times were necessary
for the reaction to reach completion) without affecting the
stereoselectivity (entries 11-13).10 The best results were
(4) Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Maring, C. J.;
Springer, J. P. J. Am. Chem. Soc. 1985, 107, 1256.
(5) See ref 1a, p 681.
(6) For reactions with achiral catalysis, see: (a) Mu´jica, M. T.; Afonso,
M. M.; Galindo, A.; Palenzuela, J. A. Tetrahedron 1996, 52, 2167. For
reactions with chiral catalysis, see: (b) Yamashita, Y.; Saito, S.; Ishitani,
H.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793.
(7) (a) Garc´ıa Ruano, J. L.; Carren˜o, M. C.; Toledo, M. A.; Aguirre, J.
M.; Aranda, M. T.; Fischer, J. Angew. Chem., Int. Ed. 2000, 39, 2736. (b)
Garc´ıa Ruano, J. L.; Alema´n, J.; Soriano, J. F. Org. Lett. 2003, 5, 677. (c)
Garc´ıa Ruano, J. L.; Alema´n, J. Org. Lett. 2003, 5, 4513. (d) Garc´ıa Ruano,
J. L.; Aranda, M. T.; Aguirre, J. M. Tetrahedron 2004, 60, 5383. (e) Garc´ıa
Ruano, J. L.; Mart´ın-Castro, A. M.; Tato, F.; Ca´rdenas, D. J. Tetrahedron:
Asymmetry 2005, 16, 1963. (f) Garc´ıa Ruano, J. L.; Mart´ın-Castro, A. M.;
Tato, F.; Pastor, C. J. J. Org. Chem. 2005, 70, 7346.
(9) Garc´ıa Ruano, J. L.; Alema´n, J.; Aranda, M. T.; Ferna´ndez-Iba´n˜ez,
M. A.; Rodr´ıguez-Ferna´ndez, M. M.; Maestro, M. C.; Tetrahedron 2004,
60, 10067.
(8) (a) Garc´ıa Ruano, J. L.; Ferna´ndez-Iba´n˜ez, M. A.; Maestro, M. C.;
Rodr´ıguez-Ferna´ndez, M. M. J. Org. Chem. 2005, 70, 1796. (b) Garc´ıa
Ruano, J. L.; Ferna´ndez-Iba´n˜ez, M. A.; Maestro, M. C.; Rodr´ıguez-
Ferna´ndez, M. M. Tetrahedron 2006, 62, 1245.
(10) The importance of molecular sieves in Lewis acid promoted Diels-
Alder cycloadditions has been reported: Posner, G. H.; Dai, H.; Bull, D.
S.; Lee, J.-K.; Eydoux, F.; Ishihara, Y.; Welsh, W.; Pryor, N.; Pert, S., Jr.
J. Org. Chem. 1996, 61, 671.
7684 J. Org. Chem., Vol. 71, No. 20, 2006

Reactions of (S)-2-[2-(p-Tolylsulfinyl)phenyl]acetaldehyde
TABLE 2. Reaction of 1 with Dienes 4 and 5
entry
diene
solvent
CH3CN
CH3CN
CH3CN/CH2Cl2
CH3CN
temp (°C)
time (h)
additive
isolated yield (%)
products ratioa
1
2
3
4
5
4
4
4
5
5
-40
-40
-78
-40
-78
2
3
13
2
b
54
32
57
49
MS 4Å
MS 4Å
MS 4Å
MS 4Å
2(92):3(8)
2(94):3(6)
6(88):7(12)
6(88):7(12)
CH3CN/CH2Cl2
8
a Measured by HPLC. b Traces of the product were detected.
TABLE 3. Reaction of 1 with
obtained by using CH3CN as the solvent, which strongly
increased the reactivity but scarcely affected the stereoselectivity
(entries 14 and 15). When the reaction was conducted at -40
°C in this solvent (entry 15), a 88:12 mixture of 2 and 3 was
obtained in only 5 min. By lowering the temperature to -78
°C (which required the use of EtCN as the solvent) the
diastereoselectivity was only slightly improved (entry 16). The
reaction did not work in DMF (entry 17). The major diastere-
oisomer 2, which was easily separated from 3 by crystallization,
was obtained in 69% isolated yield from the mixture obtained
under conditions of entry 15.
trans-1-Methoxy-2-methyl-3-(trialkylsilyloxy)-1,3-pentadienes 8 and
11
Once we had determined the best conditions for these
cyclocondensation reactions, we studied the influence of the
size of the silyloxy group at C-32,11 as well as that of one methyl
group at C-2. The results are summarized in Table 2.
diene
(equiv)
temp
(°C)
time
(h)
conversiona
(yield %)
9:10
The reaction of aldehyde 1 with 1-methoxy-3-(tert-butyldim-
ethylsilyloxy)-1,3-butadiene (4) did not work in the conditions
indicated in entry 1. In the presence of molecular sieves (4 Å)
the reaction required 3 h in acetonitrile at -40 °C to reach
completion, affording a 92:8 mixture of compounds 2 and 3
(entry 2, Table 2). This result is indicative of a stereoselectivity
slightly higher than that observed with Danishefsky’s diene
(entry 15, Table 1). However, the increase in the size of the
silyloxy group also produced a substantial decrease in both
reactivity and yield (compare entry 2, Table 2 and entry 15,
Table 1). By lowering the temperature to -78 °C (CH3CN/
CH2Cl2 1:1 as the solvent) the stereoselectivity became only
slightly higher (88% de), but the yield is much poorer (32%,
entry 3). The reactions of 1 with dienes bearing even bulkier
sililoxy groups, such as trans-1-methoxy-3-(triisopropylsily-
loxy)-1,3-butadiene, were unfruitful.
entry
additive
ratioa
1
2
3
8 (1.5)
8 (1.5)
8 (1.5)
8 (3)
20
0
3
3.5
7
3
14
6
6
6
21
14
85b
73:27
78:22
90:10
90:10
90:10
61:39
62:38
63:37
62:38
60:40
80b
-40
-40
-78
-10
-40
-40
-40
-78
80
4
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
100 (65)
(63)d
97
89
90
5c
6
8 (3)
11 (1.5)
11 (1.5)
11 (3)
11 (1.5)
11 (3)
7
8
9
100 (56)
36
10c
a Measured by 1H NMR. b Unreacted starting material could be recovered.
c A 1:1 mixture of CH3CN/CH2Cl2 was used as the solvent. d Incomplete
conversion (% conversion not determined).
provide information about the stereoselectivity control at the
diene moiety. The results are summarized in Table 3.
The reaction of 1 with 1-methoxy-2-methyl-3-(trimethylsi-
lyloxy)-1,3-butadiene (5) afforded a mixture of 6 and 7, readily
separated by crystallization or chromatography. The stereose-
lectivity of this reaction at -40 °C (entry 4) in the presence of
MS (4 Å) was similar to that observed for Danishefsky’s diene
(76% de), but the yield was lower (57%). The major component
could be isolated in 39% yield after crystallization. In this case,
both the stereoselectivity and the yield were only scarcely
modified by lowering the temperature to -78 °C (entry 5,
Table 2).
Finally, we have checked the influence of a methyl group at
C-4 by studying the behavior of the trans-1-methoxy-2-methyl-
3-(trialkylsilyloxy)-1,3-pentadienes 8 and 11 in their reaction
with the aldehyde 1. These reactions are much more interesting
because the resulting adducts had two chiral stereocenters and
The reaction between aldehyde 1 and diene 8 at room
temperature in the absence of MS 4 Å afforded a 73:27 mixture
of only two compounds 9 and 10, epimers at C-3, the trans-
isomer 9 being the major one (entry 1). After 3 h the conversion
was not complete, and the signals attributed to the enolic form
1
of aldehyde 1 could be detected in H NMR spectrum of the
crude reaction.12 At lower temperatures, the stereoselectivity
increased, but the conversion remained incomplete even at larger
reaction times (compare entries 2 and 3). Complete conversion
was achieved in the presence of molecular sieves (4 Å) by
using 3 equiv of the diene (entry 4) with formation of a 90:10
(11) Danishefsky, S. J.; Chao, K.-H.; Schulte, G. J. Org. Chem. 1985,
50, 4650.
(12) Unreacted aldehyde 1 can be recovered by column chromatography.
J. Org. Chem, Vol. 71, No. 20, 2006 7685

Garc´ıa Ruano et al.
SCHEME 2
SCHEME 4
SCHEME 3
The absolute configuration of compound 2 was unequivocally
determined as [(S)S,2R] by X-ray diffraction studies.13 As
compound 3 is epimer of 2 at the only chiral center created in
the reaction of 1 with Danishefsky’s diene, we have assigned
[(S)S,2S] configuration to compound 3. Therefore, the absolute
configuration of compounds 12 [(S)S,2R] and 13 [(S)S,2S],
intermediates in the formation of 2 and 3, can also be
unequivocally established.
The configurations of adducts 6 and 7, obtained in the
reactions of 1 with the diene 5, were assigned by assuming the
same facial preference in the attack of 5 and Danishefsky’s diene
to the carbonyl group at 1. This assumption is supported by the
NMR spectra of the major isomers 2 and 6, which show a similar
pattern of signals for the benzylic ABX system and are
completely different to that of the minor isomers 3 and 7.
The absolute configuration of compound 9 was unequivocally
assigned as [(S)S,2R,3R] by X-ray analysis.13 It allowed the
assignment of the configuration of 14 (Scheme 3), which is
presumably its precursor. Bearing in mind that two chiral centers
are created in these reactions, the configuration of the minor
epimer 10 could be [(S)S,2R,3S], [(S)S,2S,3R], or [(S)S,2S,3S],
the former ones differing from 9 in only one of the two new
chiral centers and the third one differing in both of them. To
exclude the last possibility we performed the reaction in a 60:
40 mixture of 9 and 10 with m-CPBA, which gave a 60:40
mixture of two nonenantiomeric sulfones, 16 and 17, with
mixture of 9 and 10, with the trans-9 isomer being obtained as
the major product. The stereoselectivity did not improve at -78
°C (entry 5). Surprisingly, an increase of the size of the
trialkylsilyloxy group, as it was the case of diene 11, caused a
decrease in the stereoselectivity, thus yielding a ca. 60:40
mixture of compounds trans-9 and cis-10 in all the studied
conditions (entries 6-10). These mixtures could be separated
by flash column chromatography. Under conditions of entry 4,
optically pure major trans-isomer 9 was obtained in a 51% yield.
In summary, these results indicate that any increase in the
size of the silyloxy group has a scarce influence on the
stereoselectivity control in reactions from 1,3-disubstituted
dienes (4 and Danishefsky’s diene), but it is large and negative
for 1,2,3,4-tetrasubstituted ones (8 and 11). By comparison of
the results obtained from Danishefsky’s diene and 5, it can be
stated that the presence of the methyl group at C-2 does not
affect significantly the stereoselectivity. Finally, the reactivity
is strongly dependent on the solvent (larger in CH3CN than in
CH2Cl2). All of these facts are not easily compatible with a
concerted mechanism. Therefore, the formation of the trans
isomers as the major ones in these reactions suggested that they
are stepwise processes involving Mukaiyama’s aldol condensa-
tion followed by intramolecular cyclization of the resulting
intermediate. To confirm this hypothesis, we investigated the
reaction between aldehyde 1 and Danishefsky’s diene (1.5 equiv)
in the presence of Yb(OTf)3 treating the resulting mixture with
water instead of TFA (Scheme 2). Under these conditions a
mixture of â-hydroxyketones 12 and 13 was isolated in the same
proportion that 2 and 3 were obtained when the mixture was
treated with TFA (Table 1, entry 15). These compounds were
those resulting from Mukaiyama’s reaction of the silylenolether
moiety of Danishefsky’s diene to the carbonyl group of 1
activated by the Lewis acid. When the mixture 12 + 13 was
treated with TFA, the formation of the mixture 2 + 3 (in
identical proportion to that of the starting products) was
observed. This fact strongly supports that 12 and 13 are the
intermediates in the reactions shown in Table 1.
1
different H NMR spectra (Scheme 4).
To confirm the absolute configuration of 10, we performed
the oxidation with PCC of the 90:10 mixture of 14 and 15,
obtained under the conditions shown at the Scheme 3. The
reaction afforded a mixture of two 1,3-diketosulfoxides 18 and
19 (Scheme 3), which indicates that they (as well as their
precursors 14 and 15) differ in the configuration at the methinic
carbon. The proportion of 18 and 19 (82:12) is very similar but
not identical to that of the starting 14 and 15 (90:10), which is
not unexpected on the basis of the high acidity of the methinic
proton flanked by two carbonyl groups in 18 and 19.
Once it has been established that these reactions take place
following a two-step process, their stereochemical results must
be explained as a consequence of an intermolecular approach
of the silylenolether moiety of the dienes to the less hindered
face of the carbonyl. Concerning the π-facial selectivity at the
electrophile, it is very high with Danishefsky’s diene as well
as with 5 (up to 80% de), it increases with the size of the
trialkylsilyloxy group for 4 (up to 88% de) and is complete
with 8 and 11 (>98% de). Concerning the facial selectivity at
the nucleophile (only possible for 8 and 11), it is also very high
for 8 (80% de) but significantly decreases for 11 (ca. 20% de).
This behavior can be explained by assuming that chelated
Under similar conditions, reaction of 1 with 8 also provided
a mixture of hydroxyketones 14 and 15 (Scheme 3) in
proportions identical to that observed for adducts 9 and 10, thus
suggesting that reactions shown in Table 3 also evolve in a two-
step sequence, 14 and 15 acting as the intermediates.
(13) Crystallographic data of structures 2 and 9 have been deposited with
the Cambridge Crystallographic Data Center, deposition no. CCDC 601082
(2) and deposition no. 601083 (9). The coordinates can be obtained on
request from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax +44
1223 336033; e-mail: deposit@ccdc.cam.ac.uk].
7686 J. Org. Chem., Vol. 71, No. 20, 2006

Reactions of (S)-2-[2-(p-Tolylsulfinyl)phenyl]acetaldehyde
SCHEME 5
SCHEME 7
SCHEME 8
SCHEME 9
antiperiplanar arrangement with respect to the arylsulfinyl group
(Scheme 6). TS-1A and TS-1B are the transition states fulfilling
these requirements. They differ in the face of the nucleophile
which is being attacked by the electrophile and afford com-
pounds anti-14 and syn-15 respectively, that finally will be
transformed with TFA into 9 and 10. The fact that the anti-14
isomer is obtained as the major one suggests the greater stability
of TS-1A with respect to TS-1B. Although it is not obvious
from Scheme 6, it could be explained by assuming that the steric
interactions between the CH2 at the chelated species and the
methyl group (tetrahedral) are higher than those with the alkenyl
group (trigonal).
SCHEME 6
The increase in the size of the silyloxy group (as it is the
case for diene 11 with respect to 8) leads to a substantial
decrease in the stereoselectivity, which means that the stability
differences between TS-1A and TS-1B are smaller. From
Scheme 6, it could be inferred that interactions H/OSiR3 in TS-
1A could distort the planarity of the dienic system thus
increasing its steric interactions with the benzylic protons of
the aldehyde. This effect must be more important for 11
(OSiMe2But), and therefore the relative stabilities of its corre-
sponding TS-1A and TS-1B should be more alike, which
accounts for the observed decrease in stereoselectivity.
The reaction of 2 with Raney Ni (EtOH) for 20 min at 0 °C
afforded a 89:11 mixture of alcohols 20 and 21 in 56% yield
(Scheme 7), which evidenced that hydrogenolysis of the C-S
bond and reduction of the olefinic and carbonylic double bonds
took place simultaneously under these conditions. The separation
of the mixture by flash column chromatography gave the major
stereoisomer 20 in 40% isolated yield. The configurational
assignment of compounds 20 and 21 was unequivocally
established by NMR (see Supporting Information).
To the best of our knowledge, this is the first reported
complete reduction of the conjugated carbonyl system of these
dihydropyranones with Raney Ni. As the mechanism of these
reductions presumably involves free radicals, the use of Raney
Ni could be complementary to other reducing agents, such as
Pd/H2 or NaBH3CN/BF3, usually employed for this type of
reductions.14
The reaction of 6 with Raney Ni (EtOH) also provokes the
C-S cleavage and the total reduction of the conjugated system.
However, its reactivity is much lower, requiring 26 h at room
species formed from 1 and Yb(OTf)3 act as the electrophile in
Mukaiyama’s reaction. Two chelated species, A and B, could
be formed, the latter one being the most stable due to steric
reasons. The favored approach of the nucleophile will take place
to the less hindered pro-R face of the aldehyde in its B chelated
conformation (TS-1), yielding intermediate 12 or 12′ that
evolves into 2 or 6 by reaction with TFA (Scheme 5). The
approach of the nucleophile to the pro-S face (TS-2), which
gives 13 and 13′, would be highly hindered, and it is only
possible for dienes, such as 4, 5, and Danishefsky’s diene, with
no substituents at C-4. The selectivity must be slightly higher
as the size of the silyloxy group becomes larger (compound 4)
and is scarcely modified by the presence of a methyl group at
C-2 (compound 5), as can be deduced from Scheme 5.
Reactions of aldehyde 1 with dienes 8 and 11, which bear a
methyl group at C-4, take place with a complete control of the
configuration at the hydroxylic carbon (TS-2 at Scheme 5 would
be strongly hindered). The formation of a mixture of epimers
is the result of the approach to the less hindered face of the
electrophile from both faces of the nucleophile. The strong
preference for the trans-isomer can be explained assuming that
only those approaches exhibiting antiperiplanar arrangement
between the hydrogen at nucleophile and the CdO bond at
electrophile are possible. The other two conformations would
be strongly destabilized by steric interactions of the carbons in
(14) (a) Hauser, F. M.; Hu, X. Org. Lett. 2002, 4, 977. (b) Zhang, S.;
Zhen, J.; Reith, M. E. A.; Dutta, A. K. Bioorg. Med. Chem. 2004, 12, 6301.
J. Org. Chem, Vol. 71, No. 20, 2006 7687

Garc´ıa Ruano et al.
SCHEME 10
acetate-hexane) affords pure 2 (69%) as a white solid. The de
was determined by HPLC (Chiralcel OD, i-PrOH-hexane, 10:90,
temperature to complete the reduction, providing a mixture of
the four possible stereoisomers (Scheme 8) in 66% combined
yield. This mixture could not be separated. Only the structure
of the major alcohol 22 could be established from the NMR
spectrum of the reaction mixture (see Supporting Information).
Finally, the reaction of 9 with Raney Ni only produced the
hydrogenolysis of the C-S bond in good yield without affecting
the dihydropyranone moiety (Scheme 9).
The results obtained in the reduction of 2 with Raney Ni could
be explained by assuming the formation of 4-tetrahydropyranone
C as the intermediate that resulted from the reduction of the
CdC bond and the hydrogenolysis of the C-S bond. Compound
C reacted with the Raney Ni according to a set mechanism
(Scheme 10) affording a mixture of the two possible alcohols.
The higher stability of the intermediate II with the OH group
in equatorial arrangement would account for the formation of
the isomer 20 as the major one. Starting from 6 a mixture of
two diastereoisomeric 2-benzyl-5-methyl 4-pyranones would be
formed in the first step, whose further reduction would provide
the four possible alcohols.
1.0 mL/min, [2R,(S)S]-2 tR ) 58.3, [2S,(S)S]-3 tR ) 81.2). [R]20
D
-84.5 (c 0.5, CHCl3). Mp: 150-152 °C. IR (film): 3054, 2923,
2360, 1677 and 1593. 1H NMR: 7.93 (m, 1H), 7.50-7.41 (m, 4H),
7.29-7.23 (m, 4H), 5.36 (dd, J 6.0 and 0.9 Hz, 1H), 4.39 (m, 1H),
3.27 (dd, J 14.5 and 8.1 Hz, 1H), 3.07 (dd, J 14.5 and 5.0 Hz, 1H),
2.48 (dd, J 16.6 and 12.2 Hz, 1H), 2.40 (ddd, J 16.6, 4.5 and 0.9
Hz, 1H), 2.35 (s, 3H). 13C NMR: 191.5, 162.6, 143.7, 141.9, 141.3,
134.6, 131.4, 131.2, 130.1, 128.3, 126.0, 125.9, 107.2, 78.8, 41.4,
36.1, 21.3. MS (FAB+) m/z: 327 (100) [M + 1], 154 (18), 91 (7).
HRMS [M + 1]: calcd for C19H19O3S 327.1054, found 327.1044.
Anal. Calcd for C19H18O3S: C, 69.91; H, 5.56; S, 9.82. Found: C,
69.53; H, 5.67; S, 9.48.
Minor diastereoisomer 3 was not isolated. It was characterized
from a 52:48 mixture of 2 and 3. 1H NMR (representative
parameters): 5.39 (dd, J 6.0 and 1.1 Hz, 1H), 3.26-3.18 (m, 2H),
2.60-2.44 (m, 2H). 13C NMR: 191.1, 162.5, 143.8, 142.0, 141.4,
134.8, 131.5, 131.3, 130.2, 128.4, 126.5, 126.0, 107.3, 78.8, 41.5,
36.3, 21.3. HRMS (ES+) [M + 1]: calcd for C19H19O3S 327.1049,
found 327.1057.
[2R,(S)S]-5-Methyl-2-[2-(p-tolylsulfinyl)benzyl]-2,3-dihydro-
4H-pyran-4-one (6) was obtained as a 88:12 mixture of 6 and 7,
following the general procedure in the presence of MS 4 Å from
diene 5 at -40 °C for 2 h. The crude mixture was purified by flash
chromatography (ethyl acetate-hexane, 1:1). Combined yield 57%.
Recrystallization (ethyl acetate-hexane) afforded diastereomerically
pure 6 (39%) as a white solid. The de was determined by HPLC
(Chiralcel OD, i-PrOH-hexane, 10:90, 1.0 mL/min, [2R,(S)S]-6
Conclusions
In summary, we have demonstrated that the asymmetric HDA
reactions of aldehyde 1 with 1,3-dioxygenated dienes catalized
by Yb(OTf)3 proceeds in a highly stereoselective way controlled
by a remote sulfinyl group (1,5-asymmetric induction). The
reactions occur following a stepwise mechanism (the intermedi-
ates could be isolated) with a high level of trans-selectivity for
4-methyl-substituted dienes. The reduction of the resulting
sulfinyl dihydropyranones with Raney Ni provided 4-hydroxy-
oxanes with concomitant cleavage of the C-S bond and
reduction of the conjugated carbonyl grouping.
tR ) 47.9, [2S,(S)S]-7 tR ) 66.9). [R]20 -92.1 (c 0.9, CHCl3).
D
1
Mp: 148-150 °C. IR (film): 3008, 1657, 1616 and 1154. H
NMR: 7.93 (m, 1H, Ar), 7.50-7.43 (m, 4H, Ar), 7.29-7.16 (m,
4H), 4.35 (m, 1H), 3.26 (dd, J 14.4 and 7.8 Hz, 1H), 3.01 (dd, J
14.5 and 5.0 Hz, 1H), 2.53-2.36 (m, 2H), 2.36 (s, 3H), 1.64 (s,
3H). 13C NMR: 192.1, 159.0, 143.8, 141.9, 141.4, 134.8, 131.3,
131.2, 130.1, 128.3, 125.9 (2C), 113.9, 78.6, 41.2, 36.3, 21.3, 10.3.
MS (FAB+) m/z: 341 (100) [M + 1], 139 (23), 14 (91). HRMS
[M + 1]: calcd for C20H21O3S 341.1211, found 341.1217. Anal.
Calcd for C20H20O3S: C, 70.56; H, 5.92; S, 9.42. Found: C, 70.44;
H, 5.95; S, 9.38.
Experimental Section
Hetero Diels-Alder Reaction. General Procedure. A solution
of aldehyde 1 (0.39 mmol) and Yb(OTf)3 (0.46 mmol) in CH3CN
(3.4 mL) was stirred for 30 min at room temperature under argon
atmosphere (in the presence of MS 4 Å if so indicated). Then, the
solution was cooled to the temperature shown in each case, and
the corresponding diene (0.59 mmol) was added via syringe. The
resulting solution was stirred at the same temperature for the
indicated time, TFA (0.2 mL) was added, and the mixture stirred
at room temperature for 2 h. Saturated aqueous Na2CO3 solution
(1 mL) was added, and the aqueous layer was extracted with CH2-
Cl2 (3 × 3 mL). The organic layers were collected and dried (Na2-
SO4), and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography using the eluent
indicated in each case.
Minor diastereoisomer 7 was not isolated. It was characterized
from a 82:12 mixture of 6 and 7. 1H NMR (200 MHz) (representa-
tive parameters): 3.22-3.15 (m, 2H), 2.60-2.41 (m, 2H). HRMS
(ES+) [M + 1]: calcd for C20H21O3S 341.1205, found 341.1214.
[2R,3R,(S)S]-3,5-Dimethyl-2-[2-(p-tolylsulfinyl)benzyl]-2,3-di-
hydro-4H-pyran-4-one (9) was obtained as a 90:10 mixture of 9
and 10 (combined yield 65%), following the general procedure in
the presence of MS 4 Å from diene 8 at -40 °C for 3 h. Compound
9 was isolated diastereomerically pure (51%) as a white solid by
flash column chromatography (ethyl acetate-hexane, 1:2). [R]20
D
-81.0 (c 1.5, CHCl3). Mp: 130-132 °C. IR (film): 2997, 2927,
1666, 1595 and 1171. 1H NMR: 7.88 (m, 1H), 7.48-7.37 (m, 4H),
7.31-7.09 (m, 4H), 4.12 (m, 1H), 3.17 (dd, J 14.6 and 8.0 Hz,
1H), 3.08 (dd, J 13.9 and 3.6 Hz, 1H), 2.50-2.38 (m, 1H), 2.34 (s,
3H), 1.63 (s, 3H), 1.17 (d, J 7.3 Hz, 3H). 13C NMR: 194.8, 157.8,
144.0, 141.7, 141.6, 135.7, 131.2, 130.1, 128.2, 126.0, 125.8 (2C),
112.7, 83.5, 44.0, 34.6, 21.4, 11.8, 10.6. MS (FAB+) m/z: 355 (100)
[2R,(S)S]-2-[2-(p-Tolylsulfinyl)benzyl]-2,3-dihydro-4H-pyran-
4-one (2) was obtained as a 88:12 mixture of 2 and 3, following
the general procedure from Danishefsky’s diene, at -40 °C for 5
min. The crude mixture was purified by flash chromatography (ethyl
acetate-hexane, 1:1). Combined yield 87%. Recrystallization (ethyl
7688 J. Org. Chem., Vol. 71, No. 20, 2006

Reactions of (S)-2-[2-(p-Tolylsulfinyl)phenyl]acetaldehyde
[M + 1], 139 (39), 91 (96). HRMS [M + 1]: calcd for C21H23O3S
355.1362, found 355.1350.
Compound 22 was obtained, following the general procedure,
as the major diastereoisomer (proportion 72%) from the mixture
obtained by treatment of the pyranone 6 with Raney nickel for 26
h at room temperature. It was characterized from the above mixture,
previously purified by flash column chromatography (ethyl acetate-
hexane, 1:1). Combined yield: 66%. IR (film): 3395, 2901, 2845
Minor diastereoisomer 10 was not isolated. It was characterized
from a 58:42 mixture of 9 and 10. 1H NMR (representative
parameters): 3.16-3.04 (m, 1H), 2.76 (dd, J 14.7 and 3.8 Hz, 1H),
2.27 (s, 3H), 1.55 (d, J 1.1 Hz, 3H), 1.05 (d, J 7.3 Hz, 3H). 13C
NMR: 196.7, 158.5, 143.7, 142.0, 141.5, 135.5, 131.1, 130.0, 129.7,
126.1, 126.0 (2C), 112.4, 81.4, 43.4, 32.4, 21.3, 11.4, 9.7. HRMS
(ES+) [M + 1]: calcd for C21H23O3S 355.1362, found 355.1357.
Reaction with Raney Nickel. General Procedure. An excess
of activated Raney nickel was added, at the temperature shown for
each case, to a solution of the corresponding pyranone (0.22 mmol)
in absolute EtOH (2 mL). The reaction mixture was stirred for the
indicated time, prior its filtration through Celite. The solvent was
removed under vacuum, and the residue was purified by flash
column chromatography with the specified eluent.
1
and 1100. H NMR (500 MHz): 7.22-7.12 (m, 5H), 3.79 (dt, J
11.3 and 5.0 Hz, 1H), 3.72 (dd, J 11.5 and 1.6 Hz, 1H), 3.42 (dd,
J 11.5 and 2.2 Hz, 1H), 3.42 (dtd, J 13.2, 6.6 and 2.2 Hz, 1H),
2.87 (dd, J 13.7 and 6.3 Hz, 1H), 2.64 (dd, J 13.7 and 6.6 Hz, 1H),
1.87-1.78 (m, 1H), 1.56 (dddd, J 12.6, 4.7, 2.2 and 0.9 Hz, 1H,
1.36 (c, J 12.6 Hz, 1H), 0.97 (d, J 6.9 Hz, 3H). 13C NMR: 138.2,
129.4, 128.3, 126.3, 77.5, 71.5, 70.0, 42.5, 35.1, 35.0, 9.7. MS
(FAB+) m/z: 207 (22) [M + 1], 205 (37), 91 (100). HRMS [M -
1]: calcd for C13H17O2 205.1228, found 205.1230.
(2R,3R)-2-Benzyl-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one
(23) was obtained by treatment of the pyranone 9 with Raney nickel
for 14 h at room temperature, following the general procedure. The
residue was purified by flash chromatography (ethyl acetate-
hexane, 1:1) to afford pure 23 (77%) as a colorless oil. [R]20D +87.0
(c 1.2, CHCl3). IR (film): 2928, 1667, 1627, 1171. 1H NMR: 7.27-
7.16 (m, 5H), 7.09 (s, 1H), 4.19 (ddd, J 11.5, 7.8 and 3.8 Hz, 1H),
3.05 (dd, J 14.5 and 3.7 Hz, 1H), 2.87 (dd, J 14.5 and 7.8 Hz, 1H),
2.33 (dc, J 11.4 and 7.0 Hz, 1H), 1.57 (d, J 0.9 Hz, 3H), 1.14 (d,
J 6.9 Hz, 3H). 13C NMR: 195.2, 158.3, 136.7, 129.7, 128.4, 126.7,
112.5, 84.2, 43.0, 38.6, 11.4, 10.7. MS (FAB+) m/z: 217 (92) [M
+ 1], 216 (13), 91 (96). HRMS [M + 1]: calcd for C14H17O2
217.1228; found 217.1226. Anal. Calcd for C14H16O2: C, 77.75;
H, 7.46. Found: C, 77.89; H, 7.83.
(2R,4R)-2-Benzyltetrahydro-2H-pyran-4-ol (20) was obtained
as a 89:11 mixture of diastereoisomers 20 and 21, by treatment of
the pyranone 2 with Raney nickel for 5 min at 0 °C, following the
general procedure. The residue was purified (combined yield 56%),
and the major compound 20 was isolated diastereomerically pure
(40%) as a colorless oil, by flash chromatography (ethyl acetate-
hexane, 1:1). [R]20D +15.0 (c 1.6, CHCl3). IR (film): 3406, 2922,
1
2865 and 1069. H NMR: 7.24-7.12 (m, 5H), 3.94 (ddd, J 11.9,
4.7 and 1.7 Hz, 1H), 3.65 (tt, J 10.9 and 4.5 Hz, 1H), 3.41 (dtd, J
11.1, 6.4 and 1.9 Hz, 1H), 3.29 (dt, J 12.4 and 2.1 Hz, 1H), 2.87
(dd, J 13.6 and 6.6 Hz, 1H), 2.62 (dd, J 13.7 and 7.0 Hz, 1H),
1.89-1.83 (m, 1H), 1.82-1.76 (m, 1H), 1.50-1.36 (m, OH + 1H),
1.21-1.09 (m, 1H). 13C NMR: 138.2, 129.4, 128.3, 126.3, 77.4,
68.2, 66.0, 42.6, 41.0, 35.6. MS (FAB+) m/z: 193 (47) [M + 1],
154 (100), 91 (46). HRMS [M + 1]: calcd for C12H17O2 193.1228,
found 193.1222.
Acknowledgment. This investigation has enjoyed the sup-
port of the CICYT (Grant BQU2003-04012). M.A.F.-I. is
indebted to the Comunidad Auto´noma de Madrid for a predoc-
toral fellowship.
Minor diastereoisomer 21 was characterized from the above
1
mixture. H NMR: 7.23-7.12 (m, 5H), 4.15 (m, 1H), 3.95-3.86
(m, 1H), 3.78 (dt, J 11.8 and 2.3 Hz, 1H), 3.75-3.68 (m, 1H),
2.80 (dd, J 13.8 and 7.0 Hz, 1H), 2.57 (dd, J 13.7 and 6.3 Hz, 1H),
1.78 (m, 1H), 1.62-1.44 (m, 3H). 13C NMR: 138.4, 129.4, 128.2,
126.2, 72.5, 64.2, 62.5, 42.7, 38.4, 33.0. MS (EI+) m/z: 192 (0.8)
[M+], 174 (3), 101 (100), 91 (45). HRMS (GC-MS-EI+) [M+]: calcd
for C12H16O2 192.1150, found 192.1164; [M - 18]: calcd for
C12H14O 174.1045, found 174.1052.
Supporting Information Available: Experimental data of
compounds 12-19. NMR spectra of all compounds. ORTEP
diagram and CIF files for compounds 2 and 9. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO061128N
J. Org. Chem, Vol. 71, No. 20, 2006 7689