Asymmetric claisen rearrangements on chiral vinyl sulfoxides

Article abstract of DOI:10.1002/chem.200801680

Highly diastereoselective Claisen rearrangements of acyclic allyl vinyl ethers bearing a chiral sulfoxide at C-5 provide γ-δ-unsaturated aldehydes or ketones with up to two consecutive asymmetric centers in the molecule whilst preserving a useful vinyl su

Full text of DOI:10.1002/chem.200801680

FULL PAPER
DOI: 10.1002/chem.200801680
Asymmetric Claisen Rearrangements on Chiral Vinyl Sulfoxides
Roberto Fernꢀndez de la Pradilla,* Carlos Montero, Mariola Tortosa, and Alma Viso[a]
Abstract: Highly diastereoselective Claisen rearrangements of acyclic allyl vinyl
ethers bearing a chiral sulfoxide at C-5 provide g-d-unsaturated aldehydes or ke-
tones with up to two consecutive asymmetric centers in the molecule whilst pre-
serving a useful vinyl sulfoxide. The reactivity of related vinyl sulfides and sulfones
has also been examined in this work.
Keywords:
rearrangement · sulfides · sulfones ·
sulfoxides
diastereoselectivity
·
Introduction
markably chiral induction of vinyl sulfoxides in many differ-
ent scenarios.[13,14] Within this context, we envisioned that
vinyl sulfoxides B (Scheme 1) could be attractive scaffolds
From its early discovery, the Claisen rearrangement has
become one of the most efficient methods for the stereocon-
trolled synthesis of carbon–carbon bonds.[1] The search for
new asymmetric Claisen protocols is a current problem in
organic synthesis.[2] In fact, there is an important number of
asymmetric Claisen rearrangements based on the transfer-
ence of inner chirality from a substituent at C-4;[3] however,
the number of examples that use an external chiral auxiliary
or a Lewis acid as a source of stereocontrol is significantly
lower.[4,1f] Most of the reported examples of diastereoselec-
tive Claisen rearrangements refer to allyl vinyl ethers with a
chiral auxiliary on the vinylic fragment. In this context, high
diastereoselectivities were observed in the Ireland–Claisen
rearrangement of chiral acyclic a-alkoxy esters[5] and
a-amino esters,[6] the asymmetric Carroll rearrangement of
phosphorimidates[7] and b-hidrazono esters,[8] the Eschen-
moser variant of chiral imidates[9] and b-amino amides,[10]
and the Ficini–Claisen rearrangement with chiral yn-
Scheme 1. Proposed sulfinyl-mediated Claisen rearrangements.
for the asymmetric Claisen rearrangement. Considering the
sigmatropic process as a formal intramolecular addition of
an enol ether onto the a,b-unsaturated sulfoxide, an impor-
tant facial diastereocontrol could be predicted. In addition,
the moderate electron-withdrawing character of the sulfinyl
group would increase the usual reactivity of allyl vinyl
ethers, allowing for lower reaction temperatures. Aside from
the above considerations, the use of chiral sulfur atoms in
the Claisen rearrangement is scarcely documented[15] and
the influence of a chiral auxiliary at C-5 has not been previ-
ously examined.
ACHTUNGTRENNUNG
amides.[11] However, compared to the vinylic part, the
number of diastereoselective Claisen rearrangements bear-
ing a chiral auxiliary on the allylic fragment has hardly been
investigated.[12]
In the past years, we have been involved in devising new
and efficient sulfur-based chirality transfer methodologies
taking advantage of both the versatile reactivity and the re-
In this report, we describe in full our results[16] on the dia-
stereoselective Claisen rearrangements of substrates B, read-
ily available from a-hydroxy vinyl sulfoxides A, bearing a
sulfinyl auxiliary at C-5 and a second chiral center at C-4. In
addition, both (Z)- and (E)-vinyl sulfoxides (R2) are accessi-
ble for A. The reinforcing/nonreinforcing combination of
these three elements of stereocontrol could provide a diaste-
reoselective Claisen rearrangement preserving the useful
vinyl sulfoxide moiety in the final compound C.[17] To dissect
the independent effect on the diastereoselectivity of each of
the stereocenters (C-4 and sulfoxide), vinyl sulfides and
[a] Prof. Dr. R. Fernꢀndez de la Pradilla, Dr. C. Montero,
Dr. M. Tortosa, Dr. A. Viso
Instituto de Quꢁmica Orgꢀnica General, C.S.I.C.
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)915-644-853
E-mail: iqofp19@iqog.csic.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801680.
Chem. Eur. J. 2009, 15, 697 – 709
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697

vinyl sulfones as well as 4,4-dimethyl vinyl sulfoxides related
to B will be considered in this study. On the other hand,
since stereoselectivity in the introduction of the vinyl ether
of B is crucial for a high stereocontrol in the sigmatropic re-
action, several methods have been used that allow for the
examination of both Johnson–Claisen (B, X=OEt, R3 =H,
alkyl) and Claisen (B, X=H, R3 =CO2Me) variants. Finally,
and within the Claisen alternative, the diastereoselective
creation of two consecutive chiral centers has been ad-
dressed by using cyclohexanone-derived enol ethers.
has been successfully inverted in many cases by using Mitsu-
nobu conditions.[21] A simple chromatography on silica gel
allowed for the separation of 2a–c and 3a–c; however, a
careful crystallization from EtOAc was required to isolate
3d as a pure diastereomer. Similarly, capture of lithiated
vinyl sulfoxides (Ar=pTol, 1-Naphth) with acetone pro-
duced 6a and 6c in good yields as enantiopure materials.
For the synthesis of vinyl sulfide 4a, sulfoxide 2a was deoxy-
[22]
genated with Zn(Cu)/TiCl4 and sulfone 5a was prepared
by oxidation of 3a with MMPP in good yield.
The synthesis of (Z)-a-hydroxy vinyl sulfides 10a,c–e and
sulfoxides 15a,c is outlined in Scheme 3. Treatment of
Results and Discussion
Synthesis of starting substrates: Racemic vinyl sulfoxides
1a–d were prepared from isopropyl sulfinates as mixtures of
Z/E isomers by following the method reported by Craig[18]
(Scheme 2). For the synthesis of nonracemic vinyl sulfoxides,
Scheme 3. Synthesis of (Z)-a-hydroxy vinyl sulfoxides, sulfides, and sul-
fones. All compounds are racemic unless otherwise noted. a: Ar=pTol,
R1 =Ph, R2 =nBu; c: Ar=1-Naphth, R1=Ph, R2 =nBu; d: Ar=1-(2-
MeO)Naphth, R1 =Ph, R2 =nBu; e: Ar=pTol, R1 =Et, R2 =Ph.
mCPBA=meta-chloroperbenzoic acid.
1-hexyne with nBuLi followed by capture with diaryl disul-
fides afforded alkynyl sulfides 7a,c,d.[23] At this point, we de-
cided to prepare racemic compounds because their synthesis
is slightly shorter than that of the optically pure materials
and they were adequate substrates to study the diastereose-
lectivity of the process.[24] Then, syn Pd-catalyzed hydrostan-
nylation provided vinyl stannanes 8a,c,d in good yields.[25]
Further transmetallation with nBuLi and addition to benzal-
dehyde or acetone provided a-hydroxy vinyl sulfides 10a,c,d
or 14a,c as racemic materials. In addition, the synthesis of
10e (R2 =Ph) was accomplished by direct deprotonation of
vinyl sulfide 9a followed by addition of the lithium carban-
ion onto propionaldehyde.[14d] Finally, low-temperature oxi-
dation of the (Z)-a-hydroxy vinyl sulfides 14a,c with
mCPBA provided (Z)-a-hydroxy vinyl sulfoxides 15a,c in
good yields without significant amounts of sulfur overoxida-
Scheme 2. Synthesis of (E)-a-hydroxy vinyl sulfoxides, sufides, and sul-
fones. All compounds are racemic unless otherwise noted. a: Ar=pTol,
R1 =Ph, R2 =nBu; b: Ar=pTol, R1 =Et, R2 =Me; c: Ar=1-Naphth, R1 =
Ph, R2 =nBu; d: Ar=1-(2-MeO)Naphth, R1 =Ph, R2 =nBu. LDA=lithi-
um diisopropylamide; MMPP=magnesium bis(monoperoxyphthalate).
the same protocol was applied to enantiopure menthyl ACTHUNTGRNEUNGp-tol-
uene-, 1-naphthalene-,[19] or 1-(2-methoxy)naphthalene[20]
sulfinates. Low-temperature lithiation of the Z/E mixtures
of 1a–d produced a complete isomerization to the E double
bond, which was followed by capture with benzaldehyde or
propionaldehyde to provide mixtures of (E)-a-hydroxy vinyl
sulfoxides 2a–d and 3a–d in good yields but with low selec-
tivity. It should be pointed out that the absolute configura-
tion of the allylic center in (E)-a-hydroxy vinyl sulfoxides
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Asymmetric Claisen Rearrangements
FULL PAPER
tion. Furthermore, the diastereoselectivity in the oxidation
of a-hydroxy vinyl sulfides 10a,c,d with mCPBA has been
examined by using an array of solvents (Table 1). Polar sol-
vents, such as acetone, chloroform, and methanol, dimin-
ished the diastereoselectivity (entries 1, 3, 5–8). In contrast,
by using less polar solvents, such as Et2O and CH2Cl2, a sig-
nificant increase of diastereoselectivity to nearly 10:90 (11/
12) was observed (entries 2 and 4). The above trend in ste-
reoselectivity is compatible with coordination of the hydrox-
yl group and the peracidic reagent prior to the oxidation of
sulfur. The relative configuration of (Z)- and (E)-a-hydroxy
vinyl sulfoxides 2, 3, 11, and 12 was established by the simi-
larity of their data with related compounds previously as-
signed by X-ray analysis.[22]
Sulfinyl-mediated Johnson–Claisen rearrangement: The ini-
tial attempts for the sigmatropic rearrangement were fo-
cused on the Ireland–Claisen rearrangement of acetates
Scheme 4. Claisen–Johnson rearrangements from (E)- and (Z)-hydroxy
vinyl sulfoxides. All compounds are racemic unless otherwise noted.
vinyl ether moiety of sub-
Table 1. Diastereoselective oxidation of (Z)-a-hydroxy vinyl sulfides 10 with mCPBA.
strates B (Scheme 1). The use
of sulfinyl acrylates (X=H,
R3 =CO2Me) seemed an at-
tractive alternative and, there-
fore, we treated allylic alcohols
2, 3, 11, and 12 with Et3N and
methyl propiolate (Table 2).[28]
In most cases, these acrylates
were prepared from diastereo-
merically pure alcohols except
for 2d and 12e (see the Sup-
porting Information for de-
tails). This procedure allowed
for the exclusive isolation of
Entry
Compound
R1
R2
Ar
11
12
13
Solvent
Yield [%][a]
1
2
10a
10a
10a
10a
10a
10c
10d
10e
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
nBu
nBu
nBu
nBu
nBu
nBu
nBu
Ph
pTol
pTol
pTol
pTol
pTol
1-Naphth
1-(2-MeO)
pTol
38
8
23
8
11
34
26
42
62
91
68
92
66
64
60
50
–
1
9
–
23
2
acetone
CH2Cl2
CHCl3
Et2O
MeOH
acetone
acetone
acetone
91
92
3[b,c]
4[d]
5[d]
6[c]
7[c]
8
nd[e]
[e]
nd
nd
[e]
92
93
89
Naphth
14
8
[a] Combined yield of isolated products. Ratios measured in the 1H NMR spectra of the crude mixtures.
[b] The reaction was carried out at À608C. [c] A small amount (ꢀ8%) of starting material was also found in
the crude. [d] Results for 85% conversion. [e] nd=not determined.
compounds with
chemistry in the new acrylate
moiety (J(H2,H3)=12.3–
12.5 Hz) and E (21 and 22) or
E
stereo-
AHCTUNGTRENNUNG
A
Z (26 and 27) stereochemistry in the vinyl sulfoxide moiety
(H7 shifted d=0.30–0.70 ppm downfield for E isomers 21
and 22) (Table 2).
less experimentation,[26] we turned our attention to the John-
son–Claisen alternative for substrates (E)-3a and (Z)-12a
(Scheme 4).[27] Thus, upon heating (E)-3a with triethyl
The first substrates examined were (E,E)-vinyl sulfinyl
acrylates (+)-21a and (+)-22a (Table 2, entries 1 and 10).
The sigmatropic rearrangement took place upon heating a
solution of (+)-21a in DMF giving an excellent yield of al-
dehyde 31a containing a (Z)-alkene as a single diastereo-
mer. Surprisingly, a concurrent decarboxylation was ob-
served under these conditions even in the absence of any
additives. Upon prolonged heating (>3 h) small amounts of
diastereomerization at sulfur was observed (32a). In con-
trast, (+)-22a gave a 73:27 mixture of (Z)- and (E)-vinyl
sulfoxides ent-32a and 34a along with small amounts (<5%
ratio) of ent-31a derived from diastereomerization at sulfur
and 35 obtained by sulfinyl elimination from 34a. In spite of
the diastereomeric nature of the final products, their optical
purity was secured by 1H NMR spectroscopic experiments
ACHTUNGTRENNUNGorthoACHTUNGTRENNUNGacetate and propionic acid, the ketene acetal formed
in situ underwent a highly diastereoselective [3,3]-sigma-
tropic rearrangement producing (Z)-16 in 63% yield. In
contrast, when (Z)-12a was submitted to the above reaction
conditions, a 40:60 mixture of (Z)-19 and (E)-20 was found.
Pursuing the formation of an additional stereocenter in the
final product, 3a was treated with triethyl orthopropionate
and propionic acid to furnish an equimolecular mixture of
C-2 epimers 17 and 18. The lack of Z/E selectivity in the for-
mation of the ketene acetal and the epimerization of the
final compounds under acidic conditions could explain the
low selectivity found.
Sulfinyl-mediated Claisen rearrangement: At this point, we
shifted our attention to the stereoselective formation of the
by using (+)-EuACHTNGUTERNNU(G tfc)3 (tfc=tris[3-(trifluoromethylhydroxy-
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699

R. Fernꢀndez de la Pradilla et al.
Table 2. Sulfinyl-mediated Claisen rearrangements of (E,E)- and (Z,E)-vinyl sulfinyl acrylates.[a]
Entry
Compound
Conditions
R1
R2
Ar
31 (Z)
33 (E)
Yield [%][b]
1
(+)-21a (87%)
21b (67%)
21c (87%)
(+)-21d (85%)
21e
27a (93%)
27c (78%)
27d (88%)
27e (77%)
1308C, 1 h
1348C, 3 h
1308C, 75 min
1208C, 5 h
1348C, 4 h
1208C, 3 h
1208C, 5 h
1108C, 7 h
1348C, 11 h
Ph
Et
Ph
Ph
Et
Ph
Ph
Ph
Et
nBu
Me
nBu
nBu
Ph
nBu
nBu
nBu
Ph
pTol
pTol
100
100
100
97
100
8
4
0
28
0
0
0
3
0
92
96
100
72
79
78
79
79
75
74
57
77
69
2[c]
3
1-Naphth
1-(2-MeO)Naphth
pTol
4[d]
5[e]
6[f]
7[f]
8
pTol
1-Naphth
1-(2-MeO)Naphth
pTol
9
Entry
Compound
Conditions
R1
R2
Ar
ent-32 (Z)
34 (E)
Yield [%][b]
10[g]
11[g]
12[g]
13[h]
14[i]
15[j]
16[j]
17[e]
(+)-22a (86%)
22b (72%)
22c (71%)
22d (81%)
26a (95%)
26c (91%)
26d (89%)
26e
1348C, 3 h
1348C, 3 h
1388C, 7 h
1308C, 7 h
1268C, 150 min
1268C, 4 h,
1108C, 4 h
1348C, 11 h
Ph
Et
Ph
Ph
Ph
Ph
Ph
Et
nBu
Me
pTol
pTol
1-Naphth
1-(2-MeO)Naphth
pTol
1-Naphth
73
74
69
52
25
22
0
27
26
31
48
75
78
100
76
79
76
71
nd
74
78
77
84
nBu
nBu
nBu
nBu
nBu
Ph
1-(2-MeO)Naphth
pTol
24
ꢁ
[a] Reaction conditions: a) HC CCO2Me, NEt3, Et2O/CH2Cl2, 08C–RT; b) DMF, BHT. [b] Combined yield of isolated Claisen products. Ratios measured
in the 1H NMR spectra of the crude mixtures. All compounds are racemic unless otherwise noted. [c] A 5% ratio of 32b was detected in the crude.
[d] A 15% ratio of 32d was detected in the crude. [e] 26e and 21e were obtained from an 85:15 of 12e and 3e. [f] Small amounts (<5% ratio) of ent-34
and 35 were detected in the crude. All compounds are racemic unless otherwise noted. [f] Small amounts (nearly 5% ratio) of ent-31 and 35 were detect-
ed in the crude. [g] A 19% ratio of ent-31d was detected in the crude. nd=not determined [h] Small amounts (ꢂ5% ratio) of ent-33 and 35 were detect-
ed in the crude. [i] A 13% ratio of 35 was detected in the crude. [j] A 3% ratio of ent-33d was also found in the crude.
methylene)-(+)-camphorate]) as a chiral shift reagent. The
relative stereochemistry for the new stereocenter was estab-
lished by comparison with related compounds previously as-
signed by X-ray analysis.[22] In addition, although a number
of the compounds examined were racemic, we have main-
tained the ent nomenclature for a better understanding of
the stereochemical relationship between the products. The
same pattern of reactivity and selectivity was observed for
other compounds within these series (21b,e and 22b,d, en-
tries 2,5 and 11,13). The influence of the Ar substituent on
sulfur was explored with substrates 21c,d and 22c,d with the
21d, along with a 97% ratio of 31d as the major product.
Additionally, the longer heating periods required for these
substrates provided a higher degree of diastereomerization
at sulfur on the final compounds (15% ratio of 32d from
(+)-21d and 19% ratio of ent-31d from 22d). The influence
of a tert-butyl group on sulfur was also studied (not shown)
but the rearrangement was not successful, probably due to
elimination of the sulACHTUNRGTNEfNUG inyl moiety on the acrylates, prior to
the Claisen rearrangement.
The influence of the geometry of the vinyl sulfoxide was
then addressed with compounds 27a,c–e and 26a,c–e. Simi-
larly to the E,E series, a remarkable difference in selectivity
was observed for each diastereomer. While 27a provided a
good yield of 31a and 33a (Z/E 8:92), 26a (epimer of 27a
at C-4) led to a less selective mixture (Z/E 25:75) of ent-32a
and 34a (Table 2, entries 6 and 14). In both cases, it was
noteworthy that 33a and 34a containing an (E)-vinyl sulfox-
ide were formed of as major isomers.[29] Compound 27e
(R2 =Ph) showed lower reactivity and selectivity (entry 9)
than 27a, but similar to that found for its diastereomer 26e
readily available 1-naphthyl and ACHTUNTRGNEUNG1-(2-methoxy)naphthyl
moieties. The introduction of a bulky 1-naphthyl group at
sulfur did not modify the selectivity for 21c (entry 3); how-
ever, a decrease in reactivity and selectivity was observed
for 22c (1388C, 7 h, 69:31, entry 12). In contrast, a substitut-
ed naphthyl group (Ar=1-(2-MeO)Naphth) produced a de-
crease in selectivity for both diastereomers 21d and 22d
(entries 4 and 13) allowing for the first time the detection of
a small amount (3% ratio) of (E)-vinyl sulfoxide 33d from
700
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Asymmetric Claisen Rearrangements
FULL PAPER
(entry 17). This was in contrast with the difference in selec-
tivity observed for diastereomers 27a and 26a. Replacement
of the p-tolyl for the 1-naphthyl group at the sulfoxide
moiety in the Z,E series, produced a small but significant in-
crease of selectivity for both diastereomers (26c and 27c,
entries 7 and 15). However, the most remarkable effect was
induced by the introduction of the 1-(2-methoxy)naphthyl
group as Ar. Gratifyingly, acrylates 27d and 26d gave alde-
hydes 33d and 34d, respectively, as single isomers contain-
ing an (E)-vinyl sulfoxide (entries 8 and 16). In contrast, the
rearrangement of (Z)-tert-butylsulfinyl acrylates (not shown)
led only to decomposition products.
with those previously obtained for the related sulfide and
sulfoxides, pointed out that steric hindrance at C-5 could
cause a dramatic change in the E/Z selectivity of the Claisen
rearrangement.
Finally, we examined the behavior of vinyl sulfinyl acryl-
ates lacking the allylic chiral center (Scheme 6). Instead, a
gem-dimethyl motif at C-4 in substrates 25a,c and 29a,c
would allow to assess the independent stereocontrol exerted
Seeking to independently assess the level of stereocontrol
of the allylic stereocenter (C-4), we prepared (E,E)- and
(Z,E)-vinyl sulfenyl acrylates 23 and 28 from 4a and 10a,
respectively, and methyl propiolate (Scheme 5). With the
same purpose, (E,E)-vinyl sulfonyl acrylate 24a was
ACHTUNGTRENNUNGprepared by treating vinyl sulfonyl alcohol 5a methyl pro-
piolate and Et3N. Additionally, sulfonyl acrylates 24b and 30
were obtained by oxidation of (E,E)-vinyl sulfinyl acrylates
22b and 26a, respectively, with MMPP.
Following the same pattern of selectivity observed for
sulfoxides, (E)-vinyl sulfide results in greater selectivity than
its Z isomer (Scheme 5). Thus, upon heating (E,E)-vinyl sul-
fenyl acrylate 23 (1348C, 75 min) a 93:7 mixture of (Z)-36
and (E)-37 was obtained in good yield. (Z,E)-Vinyl sulfenyl
acrylate 28 furnished a moderately selective mixture in
favor of the (Z)-sulfide 36. This result was in contrast with
the E selectivity observed for the corresponding sulfoxides
(Table 2, entries 6 and 14).
Subsequently, (E,E)- and (Z,E)-vinyl sulfonyl acrylates
were examined (Scheme 5). (E,E)-Sulfones 24a and 24b
were slightly less selective than sulfide 23 giving 85:15 and
88:12 mixtures of aldehydes 38a,b and 39a,b, respectively.
In contrast, submitting (Z)-vinyl sulfone 30 to the reaction
conditions allowed for the isolation of aldehyde 39a con-
taining an E alkene as the single product. This result, along
Scheme 6. Influence of the sulfinyl moiety. All compounds are racemic
ꢁ
unless otherwise noted. a) HC CCO2Me, NEt3, Et2O/CH2Cl2, 08C–RT;
b) DMF, BHT. BHT=2,6-di-tert-butyl-4-methylphenol.
by the sulfinyl group in the Claisen rearrangement. Thus,
heating in DMF (E,E)-vinyl sulfinyl acrylate (+)-25a (Ar=
pTol), afforded an 86:14 mixture of 40a and 41a; however,
an increase in the size of the sulfinyl moiety ((+)-25c, Ar=
1-Naphth) resulted in the isolation of (+)-40c practically as
a single isomer. On the contrary, this effect was not ob-
served for the Z,E compounds 29a and 29c since upon the
reaction conditions each of them furnished 17:83 and 14:86
mixtures of 40a,c and 41a,c,
respectively. These results indi-
cate that the sulfinyl moiety
alone is capable of efficiently
controlling the diastereoselec-
tivity of the process.
Seeking to explore the reac-
tivity of the compounds pro-
duced with the above method-
ology, we examined the reduc-
tion of vinyl sulfinyl and vinyl
sulfenyl carbaldehydes. To our
delight, reduction with NaBH4
in EtOH proved to be a gener-
al method for the synthesis of
these carbinols (Scheme 7).
Thus, (Z)-and (E)-vinyl sulfinyl
carbaldehydes ent-32a and 33a
gave good yields of g-hydroxy
vinyl sulfoxides 42 and 43.
ꢁ
Scheme 5. Influence of the allylic center in (E)- and (Z)-vinyl sulfides and sulfones. a) HC CCO2Me, NEt3,
Et2O/CH2Cl2, 08C–RT; b) MMPP, MeOH, 08C–RT.
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701

R. Fernꢀndez de la Pradilla et al.
Scheme 7. Reduction of (Z)- and (E)-sulfinyl and sulfenyl carbaldehydes.
a) NaBH4, EtOH, 08C.
Likewise, diastereomeric 31a and 34a were easily reduced
with NaBH4 furnishing primary alcohols 44 and 45, respec-
tively, in good yields. Finally, the reactivity of vinyl sulfides
was examined by using a 33:67 mixture of (Z)- and (E)-
vinyl sulfenyl carbaldehydes 36 and 37 and an 80% yield of
alcohols 46 and 47 was obtained keeping the same ratio.
Scheme 8. Attempts for the Claisen rearrangement on carbinols.
a) LiAlH4, À788C, THF; b) NaBH4, LiI, THF, 08C–RT; c) DIBAL-H,
CH2Cl2, À788C–RT; d) DMF, BHT, 120–1228C, 1h. DIBAL-H=diisobu-
tylaluminum hydride.
1-ethoxy-1-cyclohexene in the presence of
a catalytic
amount of 2,3-DMP furnished a remarkably diastereoselec-
tive mixture of (E)-vinyl sulfinyl cyclohexanone 53 (97%
ratio) along with small amounts of diastereomers 54 (1%
ratio), 55 (2% ratio), and the sulfur epimer of 53 (<2%
ratio, not shown). Similarly, (Z)-12d was submitted to the
above conditions giving (E)-vinyl sulfinyl cyclohexanone 56
as the major product (85% ratio) with traces of diastereo-
merization at sulfur and small amounts of diastereomers 57
(5% ratio) and 58 (10% ratio). In both reactions, com-
pounds 55 and 58 were probably formed from 53 and 56 by
epimerization under acidic reaction conditions. This fact was
secured by heating in toluene/HOAc pure samples of 53 and
56 to yield mixtures of 53/55 and 56/58, respectively
(Scheme 10).
Construction of two consecutive stereocenters: While the
use of acrylates allowed for the straightforward stereocon-
trolled construction of the (E)-vinyl ether fragment, the con-
current decarboxylation represented a shortcoming of the
method, since one of the chiral centers is lost in the final
molecule. Consequently, we considered that reduction of
acrylates D could afford allylic alcohols E that upon heating
would give g-d unsaturated aldehydes F with an additional
chiral center (Scheme 8).
Unfortunately, attempts to reduce vinyl sulfinyl acrylates
21b and 22b by using LiAlH4 or NaBH4 only gave vinyl
sulfoxide 48 through hydride SN2’ displacement. Alternative-
ly, treatment of 21a with DIBAL-H gave allylic alcohol 49
in 31% yield along with 3a (44%) and vinyl sulfoxide 50
(25%). In spite of the discouraging results, we examined the
reactivity of 49 under Claisen conditions. Thus, heating 49 at
120–1228C in DMF provided an 80% yield of 51 as a single
diastereomer along with a 20% yield of dehydration by-
product 52.
In contrast, 2,3-DMP was too mild to effect the trans-
AHCTUNGTREGeNNUN therification of 3c. Alternatively, pTsOH (0.1 equiv) along
with an excess of 1-ethoxy-1-cyclohexene was employed
(Scheme 9). Under these conditions, a mixture of 59 and the
intermediate ketal 59’ was produced. Recovered 59’ was
again submitted to the reaction conditions yielding a 60:40
mixture of both compounds. Finally, pure 59 underwent a
highly diastereoselective Claisen rearrangement furnishing
(Z)-vinyl sulfinyl cyclohexanone 60 as a single isomer in
75% yield. To avoid epimerization at C-2, compound 59 had
to be isolated prior to the Claisen rearrangement. When 59
was formed in situ by treatment of 3c with acetic acid in re-
fluxing toluene, a 33:67 mixture of C-2 epimers, 60 and 61,
was obtained (Scheme 10). This result, along with those ob-
tained for the epimerization of 53 and 56 (Scheme 10),
pointed out that epimerization at C-2 was influenced by the
vinyl sulfoxide geometry. As shown in Scheme 10, treatment
In view of the difficulties found to prepare these allylic al-
cohols, we envisioned other substrates suitable for setting
two consecutive stereocenters in the molecules. Therefore,
to avoid the lack of stereocontrol in the generation of the
vinyl ether, we focused our attention in the formal trans-
ACHTUNGTRENNUNGetherification of 1-ethoxy-1-cyclohexene generated in two
steps from cyclohexanone.[30] Initial Claisen attempts were
carried out by using 2,3-dimethylphenol (2,3-DMP) for the
preparation of the vinyl ether since its mildly acidic charac-
ter could prevent further epimerizations in the final prod-
ucts.[31] Thus, refluxing in toluene a mixture of (Z)-11d and
702
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Chem. Eur. J. 2009, 15, 697 – 709

Asymmetric Claisen Rearrangements
FULL PAPER
0.7 ppm higher for E isomers,
which follows a similar trend
to related compounds. The rel-
ative syn/anti stereochemistry
of the new stereocenters was
tentatively determined by anal-
ysis of the NOESY-1D spectro-
scopic data for each isomer.[32]
To further secure the structural
assignment of (E)-56 and (E)-
53, oxidation with MMPP was
carried out. Thus, oxidation of
56 along with its epimer at
sulfur (ent-53, not shown) gave
a
single
sulfone
62
(Scheme 11). Subsequently, 53
underwent oxidation to ent-62
verifying the RR or SS relative
configuration of the adjacent
stereocenters in (E)-53 and
(E)-56. On the other hand, oxi-
dation of (E)-58 allowed for
the isolation of sulfone 63
pointing out an RS relative
configuration of the stereocen-
ters in (E)-58.
Scheme 9. Preparation of two consecutive chiral centers by Claisen rearrangement of cyclohexene derivatives.
2,3-DMP=2,3-dimethylphenol; Ts=tosyl.
Scheme 11. Oxidation of sufinyl cyclohexenones.
Stereochemical pathway of the Claisen rearrangement:
These results for the Claisen rearrangement of vinyl sulfinyl
acrylates may be rationalized in terms of diastereomeric
chairlike transition states derived of conformers D–G
Scheme 10. Acid-promoted epimerization of sulfinyl cyclohexenones.
of (E)-53 and (E)-56 with AcOH in refluxing toluene gave
anti products 55 and 58 as major isomers, while syn product
61 was preferentially obtained from (Z)-60. Importantly,
these C-2 epimers (55/53, 58/56, 60/61) were easily separated
by chromatography on silica gel. Consequently, the overall
yield of 55, 58, and 61 could be potentially increased after
several epimerization cycles.
(Figure 1) with an (s)-cis C=C/S=O conformation around
[33]
the C S bond. In the case of 5-E substrates (R4 =H), 21
À
displays a reinforcing relationship of stereocontrolling ele-
ments with D accounting for the observed selectivity and
providing 31 with complete selectivity, since E would have a
severe 1,3-diaxial interaction between R1 and R2 and the
bulky aryl group pointing toward the incoming vinyl ether
residue. For nonreinforcing diastereomer 22, the energy dif-
ference between F (1,3 diaxial interactions) and G (aryl
The geometry of these trisubstituted alkenes was estab-
lished by the chemical shift of the vinyl proton, nearly d=
Chem. Eur. J. 2009, 15, 697 – 709
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www.chemeurj.org
703

R. Fernꢀndez de la Pradilla et al.
Experimental Section
General: Reagents and solvents were handled by using standard syringe
techniques. All reactions were carried out under an argon atmosphere.
Hexane, toluene, and CH2Cl2 were distilled from CaH2, and THF and
Et2O from sodium. Crude products were purified by flash chromatogra-
phy on 230–400 mesh silica gel with distilled solvents. Analytical TLC
was carried out on silica-gel plates with detection either by using UV
light, iodine, acidic vanillin solution, or a 10% solution of phosphomolyb-
dic acid in ethanol. All reagents were commercial products. Throughout
this section, the volume of solvents is reported in mLmmolÀ1 of starting
1
material. The H and 13C NMR spectra were recorded at 200, 300, 400, or
500 MHz (1H) using CDCl3 as the solvent, and with the residual solvent
signal as the internal reference (CDCl3: 7.24 and 77.0 ppm) unless other-
wise stated. The following abbreviations are used to describe peak pat-
terns when appropriate: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and br (broad). Melting points are uncorrected. Optical rota-
tions were measured at 208C in CHCl3 solution by using a sodium lamp.
Low-resolution mass spectra were recorded by using the electronic
impact (EI) technique with an ionization energy of 70eV or by using the
atmospheric pressure chemical ionization (ACPI) or electrospray (ES)
chemical ionization techniques in their positive or negative modes.
Figure 1. Proposed reactive conformers for sulfinyl-mediated Claisen re-
arrangements.
group facing the incoming vinyl ether) should be smaller
than for 21 (D vs. E), with F being more stable.
General procedure for Johnson–Claisen rearrangements: A kimble vial
equipped with a stirring bar was charged with the corresponding hydroxy
vinyl sulfoxide (1.0 equiv), the appropriate orthoester (25 equiv), and
propionic acid (0.4 equiv). Argon was bubbled through the solution for
15 min by using a needle, and the vial was quickly stoppered. The vial
was then immersed in a preheated oil bath (130–1348C) and the reaction
was monitored by TLC until the starting material disappeared (5–8 h).
The mixture was concentrated under reduced pressure and the crude
product was purified by column chromatography using the appropriate
mixture of solvents.
The case of 5-Z isomers 26–28 (R2 =H) was predicted to
follow an increased stereodirecting contribution by A1,2
strain relative to 1,3-diaxial interactions (E vs. D and G vs.
F). Nonetheless, sulfide 28 displayed moderate Z selectivity
(72:28, Scheme 5). For diastereomer 26 (R2 =H), a nonrein-
forcing scenario was found, with conformer E being favored
relative to D. Likewise, for 27 (R2 =H), F and G are opera-
tive with the latter being substantially more stable providing
selectively 33. The phenyl group in 27e is probably responsi-
Synthesis of (Æ)-(3R,SS)-(Z)-ethyl 3-n-butyl-5-phenyl-4-(p-tolylsulfinyl)-
pent-4-enoate (16): From alcohol 3a (33 mg, 0.10 mmol) and CH3C-
AHCTUNRTGEG(NUNN OEt)3 (0.50 mL, 2.50 mmol), by following the general procedure (1308C,
À
ble for a change in conformation around the C S bond al-
8 h), ester 16 was obtained. Purification by chromatography (10–30%
EtOAc/hexane) afforded 16 (25 mg, 0.063 mmol, 63%) as a colorless oil.
Rf =0.33 (30% EtOAc/hexane); 1H NMR (CDCl3, 300 MHz): d=0.53
(m, 1H; nBu), 0.61 (t, 3H, J=7.1 Hz; Me-nBu), 0.73–0.96 (m, 3H), 1.22
(t, 3H, J=7.1 Hz; Me-EtO), 1.23–1.43 (m, 2H), 2.34 (s, 3H; Me-pTol),
2.46 (dd, 1H, J=15.2, 8.5 Hz; H-2), 2.76 (dd, 1H, J=15.3, 5.0 Hz; H-2),
3.03 (m, 1H; H-3), 4.10 (qd, 2H, J=7.1, 1.0 Hz; CH2O), 6.97 (s, 1H; H-
5), 7.23 (d, 2H, J=8.5 Hz), 7.33–7.43 (m, 5H), 7.49–7.53 ppm (m, 2H);
13C NMR (50 MHz): d=13.8 (Me-nBu), 14.2 (Me-EtO), 21.3 (Me-pTol),
22.2, 28.6, 32.8, 33.3, 42.5, 60.3, 124.4 (2C), 128.4, 128.6 (2C), 129.6 (4C),
134.5, 135.1, 139.5, 140.8, 149.0, 171.8 ppm; IR (film): n˜ =2929, 2860,
1732, 1597, 1492, 1445, 1375, 1248, 1174, 1080, 1044, 920, 877, 809,
751 cmÀ1; MS (APCI): m/z (%): 391 (100) [M+1]+; elemental analysis
calcd (%) for C24H30O3S: C 72.32, H 7.59, S 8.05; found: C 72.06, H 7.80,
S 8.29.
tering the energy differences for the transition states F/G.
The more hindered 1-(2-OMe)Naphthyl moiety (26–27d) re-
sults in very high stereoselectivity producing exclusively the
E rearrangement products 33 and 34.
Conclusion
The first examples of Claisen rearrangements of substrates
bearing a chiral sulfinyl functionality at C-5 have been de-
scribed. The rearrangement takes place under mild condi-
tions, preserving the configurational stability of the sulfinyl
group, which could racemize at higher temperatures. A
second chiral center at C-4 along with the Z or E stereo-
chemistry in the starting vinyl sulfoxides provide a rein-
General procedure for the synthesis of sulfenyl, sulfinyl, and sulfonyl
acrylates: To a solution of methyl propiolate in dry Et2O (3.0 equiv,
15 mLmmolÀ1 of alcohol) at 08C, Et3N (2.5 equiv) was added. The mix-
ture was stirred for 20 min at this temperature and then a solution of the
corresponding alcohol in CH2Cl2 (6 mLmmolÀ1 of alcohol) was added.
The mixture was allowed to warm to RT and was monitored by TLC
until the starting material disappeared (1–4 h). Then water
(10 mLmmolÀ1 of alcohol) and EtOAc (5 mLmmolÀ1 of alcohol) were
added and the layers were separated. The aqueous phase was extracted
twice with EtOAc (5 mLmmolÀ1 of alcohol) and the combined organic
extracts were washed with a saturated solution of NaCl, dried over
MgSO4, and filtered to give, after evaporation of the solvents, a crude
product that was purified by chromatography on silica gel (7–10 gmmolÀ1
of alcohol) by using the appropriate mixture of solvents.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
nyl acrylates showed an unusual stereodirecting contribution
by A1,2 strain relative to 1,3-diaxial interactions. This meth-
odology entails three to four steps for 5-E isomers or six to
seven steps for 5-Z isomers from commercially available
starting materials and allows for the creation of up to two
asymmetric centers with regeneration of the valuable vinyl
sulfoxide moiety in an expedient manner. Further applica-
tions to the synthesis of more complex molecules are cur-
rently being pursued in our laboratory.
Synthesis of (+)-(E)-methyl 3-[(1S,SS)-2-(E)-1-phenyl-2-(p-tolylsulfinyl)-
hept-2-en-1-oxy]acrylate (21a): From alcohol 3a (180 mg, 0.55 mmol),
methyl propiolate (0.15 mL, 1.65 mmol), and Et3N (0.19 mL, 1.37 mmol),
by following the general procedure (3 h), acrylate 21a was obtained. Pu-
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Chem. Eur. J. 2009, 15, 697 – 709

Asymmetric Claisen Rearrangements
FULL PAPER
rification by chromatography (0–10% EtOAc/CH2Cl2) afforded 21a
(200 mg, 0.48 mmol, 87%) as a pale-yellow oil. From racemic 3a, by fol-
lowing the general procedure, (Æ)-21a was obtained as a white solid that
was recrystallized from Et2O/hexane. M.p. (Æ)74–758C; Rf =0.15 (10%
EtOAc/CH2Cl2); [a]D20 =+55.0 (c=0.86 in CHCl3); 1H NMR (CDCl3,
300 MHz): d=0.83 (t, 3H, J=7.2 Hz; Me-nBu), 1.19–1.40 (m, 4H; nBu),
2.19 (m, 1H; H-4’), 2.29 (m, 1H; H-4’), 2.30 (s, 3H; Me-pTol), 3.66 (s,
3H; CO2Me), 5.36 (d, 1H, J=12.3 Hz; H-2), 5.63 (s, 1H; H-1’), 6.71 (t,
1H, J=7.7 Hz; H-3’), 6.81 (d, 2H, J=8.3 Hz), 7.08–7.14 (m; 5H), 7.34
(d, 2H, J=8.2 Hz), 7.46 ppm (d, 1H, J=12.4 Hz; H-3); 13C NMR
(50 MHz): d=13.7 (Me-nBu), 21.2 (Me-pTol), 22.3 (C-6’), 28.9 (C-4’),
30.6 (C-5’), 51.1 (CO2Me), 76.4 (C-1’), 99.1 (C-2), 125.1 (2C), 126.3 (2C),
128.0, 128.2 (2C), 129.7 (2C), 136.7, 138.9, 141.4, 141.7, 142.5, 160.8 (C-
3), 167.7 ppm (CO2Me); IR (CCl4): n˜ =3000, 2920, 2890, 2820, 1700,
Me-nBu), 1.21–1.41 (m, 4H; 2CH2-nBu), 2.36 (s, 3H; Me-pTol), 2.45 (m,
1H; H-4’), 2.67 (ddt, 1H, J=14.7, 8.7, 7.4 Hz; H-4’), 3.56 (s, 3H;
CO2Me), 4.83 (d, 1H, J=12.3 Hz; H-2), 5.81 (s, 1H; H-1’), 5.93 (dd, 1H,
J=8.5, 6.8 Hz; H-3’), 6.87 (d, 1H, J=12.3 Hz; H-3), 7.19–7.34 (m, 7H),
7.45 ppm (d, 2H, J=8.3 Hz); 13C NMR (50 MHz): d=13.7 (Me-nBu),
21.3 (Me-pTol), 22.2, 28.6, 30.9, 50.9 (CO2Me), 75.9 (C-1’), 98.2 (C-2),
124.1 (2C), 126.3 (2C), 128.0, 128.6 (2C), 129.8 (2C), 137.8, 138.9, 141.1,
144.2, 144.8, 160.8 (C-3), 167.6 ppm (CO2Me); IR (KBr): n˜ =2900, 1680,
1610, 1420, 1195, 1155, 1105, 1050, 810, 760, 700 cmÀ1; MS (APCI): m/z
(%): 411 (100) [MÀ1]À, 271, 257, 171; elemental analysis calcd (%) for
C24H28O4S: C 69.87, H 6.84, S 7.77; found: C 70.10, H 7.10, S 8.00.
Synthesis of (Æ)-(E)-methyl 3-[(E)-1-phenyl-2-(p-tolylsulfenyl)hept-2-en-
1-oxy]acrylate (23): From alcohol 4a (30 mg, 0.10 mmol), methyl propio-
late (27 mL, 0.30 mmol), and Et3N (35 mL, 0.25 mmol), by following the
general procedure (1 h 30 min), acrylate 23 was obtained. Purification by
chromatography (80% CH2Cl2/hexane) afforded 23 (32 mg, 0.081 mmol,
1620, 1480, 1430, 1420, 1310, 1270, 1160, 1110, 1060, 1030, 750, 670 cmÀ1
;
MS (EI, 70 eV): m/z (%): 311, 171, 139 (100), 129, 115, 103, 91, 77, 65; el-
emental analysis calcd (%) for C24H28O4S: C 69.87, H 6.84, S 7.77; found:
C 71.12, H 7.06, S 7.45.
81%) as
a
colorless oil. Rf =0.44 (80% CH2Cl2/hexane); 1H NMR
(CDCl3, 300 MHz): d=0.88 (t, 3H, J=7.1 Hz; Me-nBu), 1.25–1.41 (m,
4H; nBu), 2.28 (m, 2H; H-4’), 2.30 (s, 3H; Me-pTol), 3.67 (s, 3H;
CO2Me), 5.26 (d, 1H, J=12.4 Hz; H-2), 5.79 (s, 1H; H-1’), 5.82 (t, 1H,
J=7.7 Hz; H-3’), 7.05 (d, 2H, J=8.2 Hz), 7.19 (d, 2H, J=8.2 Hz), 7.29–
7.40 (m, 5H), 7.47 ppm (d, 1H, J=12.4 Hz; H-3); 13C NMR (50 MHz):
d=13.9 (Me-nBu), 21.0 (Me-pTol), 22.4, 29.2, 31.4, 51.1 (CO2Me), 82.1
(C-1’), 98.5 (C-2), 126.5 (2C), 128.2, 128.4 (2C), 129.8 (2C), 130.5, 132.4
(2C), 133.7, 137.5, 137.6, 138.6, 160.9 (C-3), 168.0 ppm (CO2Me); IR
(film): n˜ =3021, 2955, 2859, 1716, 1644, 1492, 1435, 1328, 1283, 1190,
1132, 1049, 809, 736 cmÀ1; MS (APCI): m/z (%): 397 [M+1]+, 379, 295
(100), 171; elemental analysis calcd (%) for C24H28O3S: C 72.69, H 7.12,
S 8.09; found: C 72.85, H 6.91, S 8.33.
Synthesis of (+)-(E)-methyl 3-[(1R,SS)-2-(E)-1-phenyl-2-(p-tolylsulfinyl)-
hept-2-en-1-oxy]acrylate (22a): From alcohol 2a (163 mg, 0.49 mmol),
methyl propiolate (0.13 mL, 124 mg, 1.47 mmol), and Et3N (0.17 mL,
123 mg, 1.22 mmol), by following the general procedure (3 h), acrylate
22a was obtained. Purification by chromatography (1% EtOAc/CH2Cl2)
afforded 173 mg (0.42 mmol, 86%) of 22a as a pale-yellow oil. From rac-
emic 2a, following the general procedure, (Æ)-22a was obtained as a
white solid that was recrystallized from Et2O/hexane. M.p. (Æ) 80–818C;
Rf =0.25 (2ꢃ1% EtOAc/CH2Cl2); [a]2D0 =+68.4 (c=1.30 in CHCl3);
1H NMR (CDCl3, 300 MHz): d=0.76 (t, 3H, J=7.0 Hz; Me-nBu), 1.13–
1.35 (m, 4H; nBu), 2.13 (m, 2H; 2H-4’), 2.36 (s, 3H; Me-pTol), 3.59 (s,
3H; CO2Me), 4.95 (d, 1H, J=12.3 Hz; H-2), 5.59 (s, 1H; H-1’), 6.68 (t,
1H, J=7.7 Hz; H-3’), 6.73 (d, 1H, J=12.3 Hz; H-3), 7.22–7.33 (m, 7H),
7.46 ppm (d, 2H, J=8.3 Hz); 13C NMR (75 MHz): d=13.7 (Me-nBu),
21.3 (Me-pTol), 22.2 (C-6’), 28.5 (C-4’), 30.3 (C-5’), 51.0 (CO2Me), 77.4
(C-1’), 98.3 (C-2), 125.1 (2C), 125.8 (2C), 127.9, 128.4 (2C), 129.9 (2C),
137.6, 139.2, 141.8, 142.8, 143.6, 160.6 (C-3), 167.4 ppm (CO2Me); IR
(CCl4): n˜ =3000, 2910, 2880, 2820, 1690, 1620, 1470, 1430, 1410, 1300,
1260, 1110, 1060, 1030, 920, 760, 670, 620 cmÀ1; MS (APCI): m/z (%): 411
(100) [MÀ1]À, 271, 171, 139; MS (EI, 70 eV): m/z (%): 311, 171, 139
(100), 129, 115, 105, 91, 77, 65; elemental analysis calcd (%) for
C24H28O4S: C 69.87, H 6.84, S 7.77; found: C 69.70, H 6.99, S 7.92.
Synthesis of (Æ)-(E)-methyl 3-[(Z)-1-phenyl-2-(p-tolylsulfonyl)hept-2-en-
1-oxy]acrylate (30): From acrylate 26a (124 mg, 0.30 mmol) and MMPP
(371 mg (80%), 0.60 mmol), by following the general procedure (12 h),
sulfone 30 was obtained. Purification by chromatography (10–30%
EtOAc/hexane) afforded 30 (105 mg, 0.24 mmol, 80%) as a white solid
that was recrystallized from Et2O/hexane. M.p. 68–698C; Rf =0.35 (30%
EtOAc/hexane); 1H NMR (CDCl3, 200 MHz): d=0.80 (t, 3H, J=7.0 Hz;
Me-nBu), 1.18–1.25 (m, 4H, nBu), 2.40 (s, 3H; Me-pTol), 2.55 (m, 2H;
H-4’), 3.64 (s, 3H; CO2Me), 5.25 (d, 1H, J=12.5 Hz; H-2), 6.05 (s, 1H;
H-1’), 6.06 (t, 1H, J=7.8 Hz; H-3’), 7.19–7.36 (m, 7H), 7.43 (d, 1H, J=
12.4 Hz; H-3), 7.60 ppm (d, 2H, J=8.5 Hz); 13C NMR (50 MHz): d=13.7
(Me-nBu), 21.6 (Me-pTol), 22.3, 28.5, 30.5, 51.1 (CO2Me), 81.6 (C-1’),
99.4 (C-2), 127.2 (2C), 127.6 (2C), 128.8 (3C), 129.6 (2C), 136.5, 138.5,
140.8, 144.4, 148.6, 160.7, 167.6 ppm (CO2Me); IR (KBr): n˜ =2956, 2927,
1710, 1641, 1303, 1188, 1131, 729 cmÀ1; MS (APCI): m/z (%): 429 (100)
[M+1]+; elemental analysis calcd (%) for C24H28O5S: C 67.26, H 6.59, S
7.48; found: C 67.35, H 6.71, S 7.62.
Synthesis of (Æ)-(E)-methyl 3-[(1S,SS)-2-(Z)-1-phenyl-2-(p-tolylsulfinyl)-
hept-2-en-1-oxy]acrylate (26a): From alcohol 12a[14d] (300 mg, 1.0 mmol),
methyl propiolate (0.26 mL, 3.0 mmol), and Et3N (0.35 mL, 2.5 mmol),
by following the general procedure (2 h), acrylate 26a was obtained. Pu-
rification by chromatography (0–15% EtOAc/CH2Cl2) afforded 26a
(395 mg, 0.95 mmol, 95%) as a colorless oil that was crystallized as a
white solid from Et2O/hexane. M.p. 55–578C; Rf =0.50 (10% EtOAc/
CH2Cl2); 1H NMR (CDCl3, 300 MHz): d=0.92 (t, 3H, J=7.1 Hz; Me-
nBu), 1.32–1.54 (m, 4H; nBu), 2.28 (s, 3H; Me-pTol), 2.49 (m, 1H; H-4’),
2.77 (ddt, 1H, J=14.5, 8.7, 7.2 Hz; H-4’), 3.64 (s, 3H; CO2Me), 5.40 (d,
1H, J=12.4 Hz; H-2), 5.67 (s, 1H; H-1’), 6.33 (ddd, 1H, J=8.9, 6.8,
0.6 Hz; H-3’), 6.74 (m, 2H), 6.99–7.12 (m, 5H), 7.19 (d, 2H, J=8.2 Hz),
7.53 ppm (d, 1H, J=12.4 Hz; H-3); 13C NMR (50 MHz): d=13.8 (Me-
nBu), 21.2 (Me-pTol), 22.3, 28.7, 31.2, 51.0 (CO2Me), 76.1 (C-1’), 98.9 (C-
2), 124.0 (2C), 126.6 (2C), 127.9, 128.2 (2C), 129.6 (2C), 137.6, 138.2,
140.7, 142.3, 142.8, 160.8 (C-3), 167.9 ppm (CO2Me); IR (KBr): n˜ =2900,
1690, 1590, 1465, 1430, 1410, 1300, 1200, 1100, 1010, 980, 905, 800, 780,
730, 670, 630 cmÀ1; MS (APCI): m/z (%): 411 (100) [MÀ1]À, 271, 171; el-
emental analysis calcd (%) for C24H28O4S: C 69.87, H 6.84, S 7.77; found:
C 70.08, H 7.00, S 7.56.
General procedure for Claisen rearrangements: A kimble vial equipped
with a stirring bar was charged with a solution of the corresponding acry-
late and BHT (0.2 equiv) in DMF (10 mLmmolÀ1 of acrylate). Argon
was bubbled through the solution for 15 min by using a needle, and the
vial was quickly stoppered. The vial was then immersed in a preheated
oil bath (110–1388C) and the reaction was monitored by TLC until the
starting material disappeared (1–7 h). The solution was then allowed to
cool and was diluted with water (10 mLmmolÀ1 of acrylate) and EtOAc
(10 mLmmolÀ1 of acrylate). The layers were separated and the organic
phase was washed with water (ꢃ3 10 mLmmolÀ1 of acrylate) and a satu-
rated solution of NaCl, dried over MgSO4, and filtered to give, after
evaporation of the solvent, a crude product that was purified by chroma-
tography on silica gel (6–12 gmmolÀ1 of acrylate) by using the appropri-
ate mixture of solvents.
Synthesis of (Æ)-(E)-methyl 3-[(1S,SS)-2-(Z)-1-phenyl-2-(p-tolylsulfinyl)-
hept-2-en-1-oxy]acrylate (27a): From alcohol 11a[14d] (188 mg,
0.57 mmol), methyl propiolate (0.15 mL, 1.71 mmol) and Et3N (0.20 mL,
1.43 mmol), by following the general procedure (3 h, 30 min), acrylate
27a was obtained. Purification by chromatography (0–15% EtOAc/
CH2Cl2) afforded 27a (218 mg, 0.53 mmol, 93%) as a white solid that
was recrystallized from EtOAc/hexane. M.p. 68–698C; Rf =0.50 (10%
Sigmatropic rearrangement of 21a: Synthesis of (À)-(3R,SS)-4-(Z)-3-n-
butyl-5-phenyl-4-(p-tolylsulfinyl)pent-4-enal (31a): From acrylate 21a
(37 mg, 0.089 mmol), by following the general procedure (1308C,
60 min), aldehyde 31a was obtained. Purification by chromatography
(10–50% EtOAc/hexane) afforded (25 mg, 0.070 mmol, 79%) 31a as a
colorless oil. M.p. (Æ) 55–568C; Rf =0.20 (30% EtOAc/hexane); [a]D20
=
À360.5 (c=0.80 in CHCl3); 1H NMR (CDCl3, 300 MHz): d=0.61 (t, 3H,
1
EtOAc/CH2Cl2); H NMR (CDCl3, 300 MHz): d=0.86 (t, 3H, J=7.1 Hz;
J=7.2 Hz; Me-nBu), 0.68–1.02 (m, 4H; 2CH2-nBu), 1.14–1.38 (m, 2H),
Chem. Eur. J. 2009, 15, 697 – 709
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
705

R. Fernꢀndez de la Pradilla et al.
2.37 (s, 3H; Me-pTol), 2.57 (ddd, 1H, J=16.3, 7.6, 2.4 Hz; H-2), 2.73
(ddd, 1H, J=16.3, 6.1, 2.2 Hz; H-2), 3.13 (m, 1H; H-3), 6.96 (s, 1H; H-
5), 7.25 (d, 2H, J=8.3 Hz), 7.27–7.44 (m, 5H), 7.50 (d, 2H, J=8.1 Hz),
9.70 ppm (t, 1H, J=2.3 Hz; H-1); DNOE between H-5/H-2 (2.73 ppm):
2.6%, H-5/H-2 (2.57 ppm): 1.3%, H-3/H-1: 1.3%; 1H NMR (C6D6,
300 MHz): d=0.59 (t, 3H, J=7.1 Hz; Me-nBu), 0.45–0.95 (m, 4H; nBu),
1.00–1.25 (m, 2H; nBu), 1.92 (s, 3H; Me-pTol), 2.28 (ddd, 1H, J=16.5,
7.4, 2.1 Hz; H-2), 2.60 (ddd, 1H, J=16.4, 6.2, 2.1 Hz; H-2), 3.27 (m, 1H;
H-3), 6.68 (s, 1H; H-5), 6.80 (d, 2H, J=8.0 Hz), 7.06–7.10 (m, 3H), 7.36
(d, 2H, J=7.3 Hz), 7.45 (d, 2H, J=8.3 Hz), 9.62 ppm (t, 1H, J=2.1 Hz;
H-1); 13C NMR (50 MHz): d=13.7 (Me-nBu), 21.2 (Me-pTol), 22.2, 28.8,
30.5, 34.5, 51.0 (C-2), 124.4 (2 C), 128.6 (2 C), 129.6 (2C), 129.7 (2C),
134.3, 135.7, 139.4, 141.0, 149.2, 201.9 ppm (CHO); IR (CCl4): n˜ =3000,
2980, 2920, 2880, 2820, 2680, 1700, 1580, 1470, 1420, 1370, 1150, 1060,
1020, 990, 890, 770, 730, 620, 600 cmÀ1; MS (EI, 70 eV): m/z (%): 215,
171, 140, 129, 117, 105, 91 (100), 77, 65, 55; elemental analysis calcd (%)
for C22H26O2S: C 75.54, H 7.39, S 9.04; found: C 75.72, H 7.18, S 8.83.
(%): 355 (100) [M+1]+, 256, 215, 178; elemental analysis calcd (%) for
C22H26O2S: C 74.54, H 7.39, S 9.04; found: C 74.23, H 7.52, S 9.27.
Data for 35: Rf =0.50 (30% EtOAc/hexane); 1H NMR (CDCl3,
300 MHz): d=0.91 (t, 3H, J=7.2 Hz; Me-nBu), 1.31–1.60 (m, 6H; nBu),
2.58 (ddd, 1H, J=16.5, 6.3, 2.0 Hz; H-2), 2.66 (ddd, 1H, J=16.6, 7.6,
2.1 Hz; H-2), 3.07 (quint, 1H, J=7.4 Hz; H-3), 7.25–7.28 (m, 3H), 7.35–
7.38 (m, 2H), 9.85 ppm (t, 1H, J=2.3 Hz; H-1); 13C NMR (50 MHz) d=
14.0 (Me-nBu), 22.4, 26.8, 29.4, 34.7, 48.6 (C-2), 91.1, 91.6, 127.9 (2C),
128.2 (2C), 131.5, 131.6 ppm; IR (CCl4): n˜ =3030, 2920, 2890, 2820, 2680,
1710, 1580, 1470, 1450, 1420, 1330, 1050, 1010, 670 cmÀ1; MS (APCI): m/z
(%): 256 (100) [M+CH3CN]+, 215, 171, 138, 105.
Data for ent-31a: Data for ent-31a is identical to that described above
for 31a except for the opposite optical rotation.
Sigmatropic rearrangement of 26a: Synthesis of (Æ)-(3S,SS)-4-(Z)-3-n-
butyl-5-phenyl-4-(p-tolylsulfinyl)pent-4-enal (ent-32a) and (Æ)-(3R,SS)-4-
(E)-3-n-butyl-5-phenyl-4-(p-tolylsulfinyl)pent-4-enal (34a): From acrylate
26a (186 mg, 0.45 mmol), by following the general procedure (1268C,
2 h), a 73:24:2:1 mixture of 34a, ent-32a, ent-33a, and 35 was obtained.
Purification by chromatography (5–30% EtOAc/hexane) afforded ent-
Sigmatropic rearrangement of 22a: Synthesis of (À)-(3S,SS)-4-(Z)-3-n-
butyl-5-phenyl-4-(p-tolylsulfinyl)pent-4-enal (ent-32a) and (+)-(3R,SS)-4-
(E)-3-n-butyl-5-phenyl-4-(p-tolylsulfinyl)pent-4-enal (34a): From acrylate
22a (100 mg, 0.27 mmol), by following the general procedure (1348C,
3 h), a 70:23:4:3 mixture of aldehydes ent-32a, 34a, 35, and ent-31a was
obtained. Purification by chromatography afforded 35 (2 mg) and ent-32a
(55 mg, 0.155 mmol, 57%), both as colorless oils, and 34a (21 mg,
0.059 mmol, 22%) as a white solid (Æ) that was recrystallized from
Et2O/hexane, or as a colorless oil (+). In a previous experiment, from
22a (54 mg, 0.130 mmol) at a higher temperature and with a longer reac-
tion time (1428C, 6 h) a 68:26:15:8 mixture of aldehydes ent-32a, 34a, 35,
and ent-31a was obtained. Purification by chromatography afforded pure
35 (4 mg, 0.018 mmol, 14%), ent-32a (24 mg, 0.068 mmol, 52%), and a
65:15 mixture of 34a and ent-31a (8 mg, 0.022 mmol, 17%). Separation
of ent-31a and 34a was achieved by preparative TLC (2% EtOAc/
CHCl3).
32a (28 mg, 0.08 mmol, 18%) as
a colorless oil and 34a (90 mg,
0.025 mmol, 56%) as a colorless oil that was crystallized as a white solid
from EtOAc/hexane.
Sigmatropic rearrangement of 27a: Synthesis of (Æ)-(3R,SS)-4-(Z)-3-n-
butyl-5-phenyl-4-(p-tolylsulfinyl)pent-4-enal (31a) and (Æ)-(3S,SS)-4-(E)-
3-n-butyl-5-phenyl-4-(p-tolylsulfinyl)pent-4-enal (33a): From acrylate 27a
(161 mg, 0.39 mmol), by following the general procedure (1208C, 3 h), an
88:8:2:2 mixture of 33a, 31a, ent-34a, and 35 was obtained. Purification
by chromatography (0–10% CH2Cl2) afforded 33a (97 mg, 0.27 mmol,
69%) as a white solid that was recrystallized from Et2O/hexane and 31a
(7 mg, 0.017 mmol, 5%) as a colorless oil.
Data for 33a: M.p. 72–738C; Rf =0.20 (30% EtOAc/hexane); 1H NMR
(CDCl3, 300 MHz): d=0.70 (t, 3H, J=6.8 Hz; Me-nBu), 0.93–1.18 (m,
4H; nBu), 1.28 (m, 1H; nBu), 1.34–1.47 (m, 1H; nBu), 2.12 (ddd, 1H,
J=17.7, 8.1, 1.6 Hz; H-2), 2.21 (ddd, 1H, J=17.7, 6.0, 0.8 Hz; H-2), 2.40
(s, 3H; Me-pTol), 3.43 (ddt, 1H, J=8.3, 6.0, 5.9 Hz; H-3), 7.28–7.40 (m,
7H), 7.61 (d, 2H, J=8.1 Hz), 7.61 (s, 1H; H-5), 9.30 ppm (s, 1H; H-1);
13C NMR (50 MHz): d=13.7 (Me-nBu), 21.5 (Me-pTol), 22.3, 29.4, 32.4,
33.2, 48.4 (C-2), 126.4 (2C), 128.2, 128.59 (2C), 128.60 (2C), 130.1 (2C),
132.0, 134.9, 140.3, 142.5, 148.1, 200.1 ppm (CHO); IR (KBr): n˜ =2927,
1718, 1493, 1455, 1079, 1040, 815, 767, 702, 623, 517 cmÀ1; MS (ES): m/z
(%): 409 (100), 377 [M+Na]+, 355 [M+1]+; elemental analysis calcd (%)
for C22H26O2S: C 74.54, H 7.39, S 9.05; found: C 74.27, H 7.12, S 9.07.
Data for ent-32a: Rf =0.45 (2ꢃ30% EtOAc/hexane); [a]2D0 =À397.2 (c=
1.50 in CHCl3); 1H NMR (CDCl3, 400 MHz): d=0.87 (t, 3H, J=7.1 Hz;
Me-nBu), 1.27–1.37 (m, 4H; nBu), 1.52–1.65 (m, 2H; nBu), 1.93 (ddd,
1H, J=16.1, 6.4, 2.6 Hz; H-2), 2.16 (ddd, 1H, J=16.1, 7.8, 2.5 Hz; H-2),
2.35 (s, 3H; Me-pTol), 3.25 (quint, 1H, J=7.1 Hz; H-3), 6.95 (s, 1H; H-
5), 7.23 (d, 2H, J=7.9 Hz), 7.33–7.43 (m, 5H), 7.50 (d, 2H, J=7.9 Hz),
1
8.90 ppm (t, 1H, J=2.5 Hz; H-1); H NMR (C6D6, 300 MHz): d=0.90 (t,
3H, J=7.0 Hz; Me-nBu), 1.25–1.49 (m, 7H; nBu), 1.55–1.63 (m, 1H;
nBu), 1.74 (ddd, 1H, J=16.0, 7.1, 2.8 Hz; H-2), 1.89 (s, 3H; Me-pTol),
1.92 (ddd, 1H, J=16.1, 7.4, 2.1 Hz, H-2), 3.38 (quint, 1H, J=6.8 Hz; H-
3), 6.68 (s, 1H; H-5), 6.80 (d, 1H, J=8.4 Hz), 7.03–7.15 (m, 3H), 7.37–
7.40 (m, 2H), 7.45 (d, 2H, J=8.3 Hz), 8.71 ppm (t, 1H, J=2.4 Hz; H-1);
DNOE between H-5/H-2 (1.93 ppm): 3.1%, H-2/H-5: 3.9%, H-5/H-3:
0.8%, H-5/H-1: 0.4%; 13C NMR (50 MHz): d=13.9 (Me-nBu), 21.3 (Me-
pTol), 22.6, 29.1, 29.9, 36.8, 49.4 (C-2), 142.2 (2C), 128.6 (2C), 129.6
(2C), 129.8 (2C), 132.4, 134.2, 135.7, 139.5, 141.1, 149.5, 200.1 ppm
(CHO); IR (CCl4): n˜ =3000, 2980, 2920, 2880, 2820, 2680, 1700, 1580,
Sigmatropic rearrangement of 23: Synthesis of (Æ)-4-(Z)-3-n-butyl-5-
phenyl-4-(p-tolylsulfenyl)pent-4-enal (36) and (Æ)-4-(E)-3-n-butyl-5-
phenyl-4-(p-tolylsulfenyl)pent-4-enal (37): From acrylate 23 (20 mg,
0.05 mmol), by following the general procedure (1348C, 1 h 15 min), a
93:7 mixture of aldehydes 36 and 37 was obtained. Purification by chro-
matography (2% EtOAc/hexane) afforded a mixture of 36 and 37 (5 mg,
0.015 mmol, 30%) and pure 36 (10 mg, 0.029 mmol, 58%) as a colorless
oil.
1470, 1420, 1370, 1280, 1150, 1060, 1020, 990, 900, 790, 730, 670, 600 cmÀ1
;
1
Data for 36: Rf =0.12 (2% EtOAc/hexane); H NMR (CDCl3, 300 MHz):
MS (APCI): m/z (%): 355 (100) [M+1]+, 260; MS (EI, 70 eV): m/z (%):
215, 171, 140, 129, 117, 105, 91 (100), 77, 65, 55, 41; elemental analysis
calcd (%) for C22H26O2S: C 74.54, H 7.39, S 9.04; found: C 74.77, H 7.07,
S 9.40.
d=0.85 (t, 3H, J=6.9 Hz; Me-nBu), 1.17–1.29 (m, 4H; nBu), 1.46 (m,
1H; nBu), 1.66 (m, 1H; nBu), 2.27 (s, 3H; Me-pTol), 2.47 (ddd, 1H, J=
16.5, 6.5, 2.1 Hz; H-2), 2.70 (ddd, 1H, J=16.5, 7.3, 2.3 Hz; H-2), 2.87 (m,
1H; H-3), 6.82 (s, 1H; H-5), 7.03 (d, 2H, J=8.5 Hz), 7.17 (d, 2H, J=
8.2 Hz), 7.20–7.31 (m, 3H), 7.56 (m, 2H), 9.59 ppm (t, 1H, J=2.1 Hz; H-
1); 13C NMR (50 MHz): d=14.0 (Me-nBu), 21.1 (Me-pTol), 22.6, 29.1,
33.8, 41.8, 48.4 (C-2), 127.5, 128.0 (2C), 129.4 (2C), 129.8 (2C), 130.5,
130.7 (2C), 133.4, 136.1, 136.9, 137.3, 201.9 ppm (CHO); IR (film): n˜ =
3021, 2927, 2857, 2717, 1724, 1595, 1491, 1445, 808, 752, 694 cmÀ1; MS
(APCI): m/z (%): 339 (100) [M+1]+, 321, 215, 173; elemental analysis
calcd (%) for C22H26OS: C 78.06, H 7.74, S 9.47; found: C 78.32, H 7.92,
S 9.75.
Data for 34a: M.p. (Æ) 65–668C; Rf =0.28 (2ꢃ30% EtOAc/hexane);
[a]2D0 =+29.3 (c=0.45 in CHCl3); 1H NMR (CDCl3, 300 MHz): d=0.67
(t, 3H, J=6.9 Hz; Me-nBu), 0.80–1.30 (m, 4H; nBu), 1.26 (m, 2H; nBu),
2.39 (s, 3H; Me-pTol), 2.42 (dd, 2H, J=7.6, 1.5 Hz; H-2), 3.19 (quint,
1H, J=7.3 Hz; H-3), 7.27–7.79 (m, 7H), 7.53 (s, 1H; H-5), 7.59 (d, 2H,
J=8.3 Hz), 9.25 ppm (t, 1H, J=1.5 Hz; H-1); DNOE between H-3/H-1:
2.6%, H-3/H-pTol ortho: 1.3%, H-1/H-pTol ortho: 1.9%, H-1/H-3:
3.0%, H-1/H-2: 1.9%; 13C NMR (75 MHz): d=13.7 (Me-nBu), 21.4 (Me-
pTol), 22.3, 29.6, 32.7, 34.1, 47.7 (C-2), 125.9 (2C), 128.1, 128.5 (2C),
128.6 (2C), 129.9 (2C), 132.7, 135.1, 139.9, 142.1, 148.6, 200.3 ppm
(CHO); IR (CCl4): n˜ =3000, 2920, 2890, 2820, 2680, 1700, 1580, 1470,
1430, 1360, 1240, 1060, 1030, 780, 740, 680, 600 cmÀ1; MS (APCI): m/z
Synthesis of (Æ)-4-(E)-3-n-butyl-5-phenyl-4-(p-tolylsulfonyl)pent-4-enal
(39a): From acrylate 30 (30 mg, 0.07 mmol), by following the general
procedure (1368C, 4 h), aldehyde 39a was obtained. Purification by chro-
matography (10–30% EtOAc/hexane) afforded 39a (21 mg, 0.05 mmol,
706
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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 697 – 709

Asymmetric Claisen Rearrangements
FULL PAPER
71%). Rf =0.33 (15% EtOAc/hexane ꢃ3); 1H NMR (300 MHz): d=0.62
(t, 3H, J=7.0 Hz; Me-nBu), 0.78–0.99 (m, 4H; nBu), 1.28 (m, 1H; nBu),
1.45 (m, 1H; nBu), 2.42 (s, 3H; Me-pTol), 2.61 (ddd, 1H, J=17.9, 7.3,
1.5 Hz; H-2), 2.86 (ddd, 1H, J=17.9, 6.8, 1.1 Hz; H-2), 3.50 (m, 1H; H-
3), 7.26–7.40 (m, 7H), 7.80 (d, 2H, J=8.3 Hz), 7.88 (s, 1H; H-5),
9.43 ppm (t, 1H, J=1.2 Hz; H-1); 13C NMR (50 MHz): d=13.7 (Me-
nBu), 21.6 (Me-pTol), 22.2, 29.4, 32.9, 33.2, 48.1 (C-2), 128.3 (2C), 128.4
(2C), 128.6 (2C), 128.8, 129.8 (2C), 134.0, 137.6, 141.2, 144.4, 145.0,
200.2 ppm (CHO); IR (film): n˜ =3021, 2927, 2857, 2717, 1724, 1595, 1491,
1445, 808, 752, 694 cmÀ1; MS (APCI): m/z (%): 339 (100) [M+1]+, 321,
215, 173; elemental analysis calcd (%) for C22H26O3S: C 71.32, H 7.07, S
8.65; found: C 71.52, H 7.32, S 8.75.
Synthesis of (Æ)-(2S,1’R,SS)-2-[(Z)-1-n-butyl-2-(naphthalen-1-ylsulfinyl)-
3-phenyl-2-propen-1-yl]cyclohexanone (60) and (Æ)-(2R,1’R,SS)-2-[(Z)-
1-n-butyl-2-(naphthalen-1-ylsulfinyl)-3-phenyl-2-propen-1-yl]cyclohexa-
none (61): A kimble vial was charged with a solution of sulfoxide 3c
(20 mg, 0.050 mmol), 1-ethoxy-1-cyclohexene (4 equiv, 25 mg, 0.2 mmol)
and acetic acid (0.5 equiv, 2 mL, 0.025 mmol) in of toluene (0.5 mL). The
mixture was heated at 908C for 14 h and then at 1208C for 8 h. The sol-
vent was removed under reduced pressure to give a 33:67 mixture of 60
and 61. Purification by chromatography afforded ketone 60 (4 mg,
0.009 mmol, 18%) and ketone 61 (9 mg, 0.020 mmol, 40%), both as
white solids that were recrystallized from EtOAc/hexane.
Data for 60: M.p. 178–1798C; Rf =0.34 (10% EtOAc/CH2Cl2); 1H NMR
(CDCl3, 300 MHz): d=À0.54 (m, 1H; H-2 nBu), À0.32 (m, 1H; H-2
nBu), 0.13 (t, 3H, J=7.3 Hz; Me-nBu), 0.46 (sext, 2H, J=7.5 Hz), 0.81–
0.88 (m, 1H), 0.93–1.24 (m, 2H), 1.61–2.02 (m, 4H), 2.10–2.16 (m, 1H),
2.22–2.40 (m, 2H), 2.50 (m, 1H), 2.77 (dt, 1H, J=8.8, 4.1 Hz; H-1’), 7.00
(d, 1H, J=8.4 Hz), 7.08 (s, 1H; H-3’), 7.14 (ddd, 1H, J=8.4, 7.0, 1.3 Hz),
7.38–7.45 (m, 2H), 7.49–7.54 (m, 2H), 7.64–7.69 (m, 3H), 7.82 (d, 1H,
J=8.3 Hz), 7.90 (d, 1H, J=8.2 Hz), 8.17 ppm (dd, 1H, J=7.2, 1.1 Hz; H-
8’’); NOESY-1D between H-1’/H-8’’: 7.0%, H-1’/H-1 nBu: 4.1%, H-2/H-
3’: 3.6%, H-3’/H-2: 3.8%, H-3’/H-1 nBu: 5.1%, H-3’/Ph: 5.1%; 13C NMR
(50 MHz): d=13.4 (Me-nBu), 22.3 (C-3 nBu), 24.8, 28.0 (C-2 nBu), 28.5,
33.0 (C-1 nBu), 33.2, 35.9 (C-1’), 42.8 (C-6), 57.8 (C-2), 122.8, 124.3,
125.4, 126.3 (2C), 126.5, 128.6 (4C), 129.3, 129.4, 131.1, 133.4, 135.0,
137.2 (C-3’), 138.1, 146.8, 212.8 ppm (CO); IR (KBr): n˜ =2930, 2855,
1709, 1447, 1038, 806, 774, 751, 699 cmÀ1; MS (APCI): m/z (%): 445 (100)
[M+1]+, 269, 171; elemental analysis calcd (%) for C29H32O2S: C 78.34,
H 7.24, S 7.21; found: C 78.51, H 7.10, S 7.52.
Data for 61: M.p. 103–1058C; Rf =0.20 (5% EtOAc/CH2Cl2); 1H NMR
(CDCl3, 300 MHz): d=À0.37 (m, 1H; H-2 nBu), À0.14 (m, 1H; H-2
nBu), 0.20 (t, 3H, J=7.3 Hz; Me-nBu), 0.42–0.60 (m, 2H; H-3 nBu), 1.06
(m, 2H; H-1 nBu), 1.37 (qd, 1H, J=12.6, 3.5 Hz), 1.50–1.73 (m, 2H),
1.88 (m, 1H), 1.99–2.14 (m, 2H), 2.25–2.43 (m, 2H), 2.90 (ddd, 1H, J=
12.8, 5.3, 2.2 Hz; H-2), 3.20 (td, 1H, J=7.2, 2.2 Hz; H-1’), 6.89 (s, 1H; H-
3’), 6.97 (d, 1H, J=8.3 Hz), 7.14 (ddd, 1H, J=8.2, 6.8, 1.1 Hz), 7.38–7.44
(m, 2H), 7.45–7.55 (m, 2H), 7.65–7.70 (m, 3H), 7.83 (d, 1H, J=8.2 Hz),
7.91 (d, 1H, J=8.2 Hz), 8.14 ppm (dd, 1H, J=7.2, 1.1 Hz; H-8’’);
NOESY-1D: between H-1’/H-2: 5.2%, H-1’/H-8’’: 4.3%, H-1’/H-1 nBu:
3.5%, H-2/H-1’: 5.4%, H-3’/H-1 nBu: 7.9%, H-3’/Ph: 4.8%; 13C NMR
(50 MHz)-HSQC: d=13.6 (Me-nBu), 22.0 (C-3 nBu), 25.0, 26.4, 27.1,
27.5 (C-1 nBu), 28.3 (C-2 nBu), 34.5 (C-1’), 42.2 (C-6), 55.1 (C-2), 122.8,
124.3 (C-8’’), 125.5, 126.2, 126.3, 128.6, 128.7 (3C), 128.9, 129.5 (2C),
131.1, 133.4, 134.9, 136.5 (C-3’), 137.7, 145.1, 210.7 ppm (CO); IR (KBr):
n=3050, 2929, 2855, 1705, 1443, 1042 cmÀ1; MS (APCI): m/z (%): 445
(100) [M+1]+; elemental analysis calcd (%) for C29H32O2S: C 78.34, H
7.24, S 7.21; found: C 78.51, H 7.10, S 7.52.
Synthesis of (Æ)-(2S,1’R,RS)-2-[(E)-1-n-butyl-3-phenyl-2-(2-methoxy-
naphthalen-1-ylsulfinyl)-2-propen-1-yl]cyclohexanone (53): A solution of
sulfoxide 11d (73 mg, 0.2 mmol), 1-ethoxy-1-cyclohexene (10 equiv), and
2,3-dimethylphenol (0.1 equiv, 2.4 mg, 0.02 mmol) in toluene (2 mL) was
heated at 1208C for 3 h. Then the solvent was removed under reduced
pressure and a 97:2:1 mixture of 53 (as a 98:2 mixture of S epimers), 55,
and 54 was obtained. Purification by chromatography (CH2Cl2) afforded
a mixture of 54 and 55 (5 mg) and 53 (75 mg, 0.16 mmol, 80%) with
traces of the epimer at sulfur as a white solid that was recrystallized from
EtOAc/hexane. A second chromatography of the first fraction (50–60%
Et2O-hexane) gave 54 (1 mg) and 55 (1 mg). In a related experiment,
with 1-ethoxy-1-cyclohexene (2.0 equiv) and 2,3-dimethylphenol
(0.5 equiv), the mixture was heated at 1208C for 9 h affording an 85:15
mixture of 53 and its epimer at sulfur. M.p. 127–1288C; Rf =0.14 (40%
EtOAc/hexane); 1H NMR (CDCl3, 400 MHz): d=0.57 (t, 3H, J=7.0 Hz;
Me-nBu), 0.57–0.66 (m, 1H), 0.80–1.10 (m, 6H), 1.21–1.37 (m, 3H), 1.57
(m, 1H), 1.66 (m, 2H), 1.91 (m, 1H), 2.23 (m, 1H), 3.10 (ddd, 1H, J=
9.2, 8.1, 4.4 Hz; H-1’), 3.95 (s, 3H; OMe), 7.24 (m, 1H), 7.33–7.42 (m,
3H), 7.55–7.60 (m, 3H), 7.78 (d, 2H, J=11.0 Hz; H-5’’), 7.80 (s, 1H; H-
3’), 7.95 (dd, 1H, J=9.2, 2.0 Hz; H-4’’), 8.66 ppm (d, 1H, J=8.8 Hz; H-
8’’); 13C NMR (50 MHz): d=13.7 (Me-nBu), 22.5, 25.1, 28.4, 29.5, 30.7,
32.2, 37.8, 41.6 (C-6), 53.6 (C-2), 56.6 (OMe), 113.5, 120.8 (C-1’’), 122.8,
124.4, 127.2, 128.2 (2C), 128.3, 128.7, 128.8 (2C), 129.2, 131.8, 132.7,
134.7, 136.8, 144.3, 158.9 (C-2’’), 211.2 ppm (CO); IR (KBr): n˜ =2933,
2862, 1705, 1621, 1593, 1507, 1467, 1272, 1249, 1151, 1055, 819, 719 cmÀ1
;
MS (APCI): m/z (%): 475 (100) [M+1]+, 346, 310, 269; elemental analy-
sis calcd (%) for C30H34O3S: C 75.90, H 7.21, S 7.26; found: C 75.60, H
7.60, S 7.44.
Synthesis of (Æ)-(2R,1’R,RS)-2-[(E)-1-n-butyl-3-phenyl-2-(2-methoxy-
naphthalen-1-ylsulfinyl)-2-propen-1-yl]cyclohexanone (55): A kimble vial
was charged with a solution of ketone 53 (15 mg, 0.032 mmol) and acetic
acid (1.0 equiv, 2 mL, 0.032 mmol) in toluene (0.3 mL). The mixture was
heated at 1208C for 6 h and then cooled to RT. A saturated solution of
K2CO3 (0.5 mL) and H2O (0.5 mL) was added and the mixture was dilut-
ed with EtOAc. The layers were separated and the aqueous phase was
extracted twice with EtOAc. The combined organic extracts were washed
with a saturated solution of NaCl, dried over anhydrous MgSO4, and con-
centrated under reduced pressure to give a 70:30 mixture of 55 and 53.
Purification by chromatography (20–40% EtOAc/hexane) afforded
ketone 53 (4 mg, 0.008 mmol, 25%) and the title ketone 55 (10 mg,
0.021 mmol, 66%), both as white solids that were recrystallized from
EtOAc/hexane. M.p. 141–1438C; Rf =0.25 (40% EtOAc/hexane);
1H NMR (C6D6, 300 MHz, 608C): d=0.50 (m, 3H; Me-nBu), 0.60–0.98
(m, 4H), 1.13–1.42 (m, 6H), 1.68 (td, 1H, J=12.3, 5.6 Hz), 1.93 (m, 1H),
2.01–2.15 (m, 3H), 3.33 (m, 1H; H-1’), 3.45 (s, 3H; OMe), 6.73 (d, 1H,
J=9.3 Hz), 7.02 (d, 1H, J=7.7 Hz), 7.09–7.15 (m, 4H), 7.26 (d, 1H, J=
7.6 Hz), 7.35 (ddd, 1H, J=8.5, 7.0, 1.5 Hz), 7.52 (d, 2H, J=8.8 Hz), 8.31
(s, 1H; H-3’), 9.41 ppm (d, 1H, J=8.5 Hz; H-8’’); 13C NMR (50 MHz):
d=13.7 (Me-nBu), 22.4, 24.8, 29.2, 29.4, 31.2, 33.7, 38.0, 42.9, 55.5, 56.8,
112.8, 120.4, 123.1, 124.6, 127.5, 128.0 (2C), 128.4, 128.8 (2C), 129.5,
132.8, 133.4, 134.9, 136.3, 144.2, 158.0, 212.2 ppm (CO); IR (KBr): n˜ =
2932, 2857, 1706, 1621, 1593, 1506, 1466, 1430, 1333, 1272, 1248, 1150,
1135, 1051, 1024, 819, 772, 748, 718, 697 cmÀ1; MS (APCI): m/z (%): 971
[2M+Na]+, 475 (100) [M+1]+; elemental analysis calcd (%) for
C30H34O3S: C 75.90, H 7.21, S 7.26; found: C 75.74, H 7.46, S 7.52.
Synthesis of (Æ)-(2S,1’R,SS)-2-[(Z)-1-n-butyl-2-(naphtalen-1-ylsulfinyl)-3-
phenyl-2-propen-1-yl]cyclohexanone (60): From sulfoxide 59 (12 mg,
0.024 mmol), by following the general procedure (908C, 2 h 30 min),
ketone 60 was obtained. Purification by chromatography (CH2Cl2) af-
forded 60 (8 mg, 0.018 mmol, 75%) as a white solid that was recrystal-
lized from EtOAc/hexane.
Acknowledgement
This research was supported by the DGI (CTQ2006–04522/BQU) and
CM (S-SAL-0249–2006). We thank the CM and MEC for doctoral fellow-
ships to C.M. and M.T.
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708
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Chem. Eur. J. 2009, 15, 697 – 709

Asymmetric Claisen Rearrangements
FULL PAPER
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energy difference between the more stable conformers ((s)-cis, C=C/
À
S=O and (s)-cis, C=C/S :) has been evaluated as just
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[32] For a detailed analysis see the Supporting Information.
[33] The possibility of boatlike transition states cannot be ruled out. It
should be noted that, for a simple (Z)-propenyl sulfoxide, the
Received: August 13, 2008
Published online: November 26, 2008
Chem. Eur. J. 2009, 15, 697 – 709
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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