Intramolecular Michael-type additions to vinyl bissulfoxides: Enantioselective synthesis of chiral aldehydes

Article abstract of DOI:10.1055/s-2008-1067176

The diastereoselective auxiliary-based intramolecular Michael-type additions to alkylidene bissulfoxides derived from dithiane and dithiolane were investigated. Utilization of substrates bearing N- and O-nucleophilic functions led to the formation of the

Full text of DOI:10.1055/s-2008-1067176

2476
FEATURE ARTICLE
Intramolecular Michael-Type Additions to Vinyl Bissulfoxides:
Enantioselective Synthesis of Chiral Aldehydes
Intramolecular
M
i
ichae
m
l-Type Additions to
o
V
inyl Bissulfoxide
G
s
ehring,a Joachim Podlech,*a Alexander Rothenbergerb
a
Institut für Organische Chemie, Universität Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6087652; E-mail: joachim.podlech@ioc.uka.de
b
Institut für Anorganische Chemie, Universität Karlsruhe (TH), Engesserstraße 15, 76131 Karlsruhe, Germany
Received 5 May 2008
Dedicated to Volker Jäger on the occasion of his 65th birthday
In our previous work, we found that the addition to vinyl
bissulfoxides is strongly, albeit not exclusively ruled by
stereoelectronic effects.6d The primarily formed carban-
ionic center is preferentially configured in a way allowing
Abstract: The diastereoselective auxiliary-based intramolecular
Michael-type additions to alkylidene bissulfoxides derived from
dithiane and dithiolane were investigated. Utilization of substrates
bearing N- and O-nucleophilic functions led to the formation of the
respective cyclic substrates with selectivities ranging from 51:49 to an antiperiplanar orientation of the lone pair and an axial
85:15. Cleavage of the bissulfoxide moiety by a two-step sequence
S=O double bond. This has a strong influence on the tra-
yielded chiral carbaldehydes. The enantiomerically pure com-
jectory of a nucleophilic attack (Scheme 1). Other stereo-
pounds obtained by this procedure, for example, tetrahydropyran-2-
electronic effects including S–C bonds contribute
carbaldehyde and homopipecolic aldehyde, are hardly accessible by
significantly less.6d Dithiolane-derived alkylidene bissulf-
other routes. Both enantiomers of the target molecules are available
oxides proved to be significantly better acceptors than the
respective dithiane-derived substrates.6b,d This might be
due to the presence of two stabilizing S=O double bonds
in the intermediate carbanion, interacting with the p-lone
pair (Scheme 1, bottom). We assumed that similar effects
are working – if not exceeded by, for example, steric ef-
fects – during intramolecular nucleophilic additions to an
alkylidene bissulfoxide moiety.
since the stereochemical information is introduced with the readily
available diethyl D- and L-tartrates.
Key words: nucleophilic additions, sulfoxides, thioacetals, umpol-
ung, stereoelectronic effects
Introduction
Inter- and intramolecular Michael additions to a,b-unsat-
urated carbonyl compounds are well known to every
chemist.1 The installation of one or two stereogenic cen-
ters during these additions leads to widely used chiral sub-
strates, and the configuration of a newly defined
stereogenic center can be controlled during the reaction.1
O
O
S
Nu
H
S
Re attack
S
Nu
S
Ph
O
O
Ph
stabilized
O
H
O
S
S
S
Si attack
S
Although vinyl sulfoxides show a similar reactivity as
a,b-unsaturated carbonyl compounds, much less is known
about additions of C-, N- or O-nucleophiles to vinyl sul-
foxides.2 Unsymmetrically substituted sulfoxides are
chiral and are easily prepared as enantiopure compounds
by asymmetric oxidation of the parent sulfides.3 During
our studies on intermolecular Michael-type additions to
chiral dioxygenated ketene S,S-acetals (alkylidene
bissulfoxides4,5) we found good selectivities in the addi-
tions of C- and N-nucleophiles.6 Formal hydrolysis of the
bissulfoxide moiety yielded 1,4-dicarbonyl compounds
O
Ph
O
Nu
Ph
H
Nu
hardly stabilized
H
O
S
Nu
S
R
O
Scheme 1 Carbanion formation through nucleophilic attack to alky-
lidene bissulfoxides
with a defined stereogenic center in the a-position.6a To the best of our knowledge, intramolecular additions to
While we investigated the utilization of 1,3-dithiane- alkylidene bissulfoxides have not been investigated yet.
and 1,3-dithiolane-derived alkylidene bissulfoxides, Aggarwal et al. reported on intramolecular [3+2] cycload-
Malacria, Fensterbank et al. used bis(tolylsulfinyl)alkenes ditions of nitrone moieties in bissulfoxide systems yield-
in their studies.7
ing five- and six-membered rings.5d,e Intramolecular
additions of O- and N-nucleophiles to p-tolyl-derived vi-
nyl sulfoxides have occasionally been reported and used
for the synthesis of optical active natural compounds.2d,e,i
The selectivities in these asymmetric intramolecular
Michael-type additions were strongly dependent on the
utilized solvents and bases, and ranged from 58:42 to
SYNTHESIS 2008, No. 15, pp 2476–2487
x
x.
x
x
.
2
0
0
8
Advanced online publication: 08.07.2008
DOI: 10.1055/s-2008-1067176; Art ID: E22108SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Intramolecular Michael-Type Additions to Vinyl Bissulfoxides
2477
93:7.2i Intramolecular Michael-type additions of C-, N-,
or O-nucleophiles to vinyl bissulfoxides should give rise
to useful chiral scaffolds hardly accessible by other routes
(Scheme 2).
n
S
Sn
S
H
O
Y
S
O
O
O
O
formal
hydrolysis
*
*
Y
Structures 1, 2, and 3 are a-functionalized carbonyl com-
pounds or 1,4-dicarbonyl compounds usually accessible
only by umpoled reactions. To study the scope of intramo-
lecular Michael-type additions of different nucleophiles
in the synthesis of these and similar compounds, the un-
derlying bissulfoxides were synthesized and conditions
for the addition were optimized.
X
m
m
m
X = OH, OTBS, NHBoc
Y = O, NBoc
n = 1, 2
m = 0, 1, 2
possible target structures:
R
O
R
O
R
*
O
O
*
*
PG
N
*
O
R'
m
Synthesis of Oxidized Ketene S,S-Acetals
m
m
2
3
1
Stereochemically uniform oxidized cyclic ketene S,S-ace-
tals are easily obtained by diastereoselective and enantio-
selective oxidation of ketene S,S-acetals (vide infra). The
Scheme 2 General scheme for the intramolecular nucleophilic addi-
tions to vinyl bissulfoxides and possible target molecules
Biographical Sketches
Timo Gehring was born in Podlech’s group in Karls- tung
der
deutschen
Heilbronn in 1979. He stud- ruhe. In 2008, he started a Wirtschaft. His research fo-
ied chemistry and mathe- Feasibility Study for Young cuses on the application of
matics at the University of Scientists (FYS) about the chiral bissulfoxide auxilia-
Karlsruhe (TH) and ob- Soai reaction. His scholar- ries for asymmetric intra-
tained his Diplomas in 2005 ships include those from molecular
Michael-type
(Chemistry) and 2006 Fonds der chemischen In- additions, Morita–Baylis–
(Mathematics). Since 2006, dustrie, Studienstiftung des Hillman reactions, and
he is a Ph.D. student in Prof. deutschen Volkes, and Stif- asymmetric autocatalysis.
Joachim Podlech is Profes- for
a
postdoctoral stay gemeinschaft (1998–1999).
sor of Organic Chemistry at (1993–1995) and completed His research interests focus
the Universität Karlsruhe his Habilitation at the Uni- on the development of or-
(TH). He studied chemistry versity of Stuttgart (1999) in ganic synthetic methods
in his native city at the Lud- the group of V. Jäger. He starting from amino acids,
wig-Maximilians-Universi-
became Professor at the on the synthesis of peptido-
tät in Munich, Germany, University of Karlsruhe in mimetics, natural product
where he received his Dr. 2003. He was, inter alia, a synthesis (especially on the
rer. nat. (1993) in organic Liebig Fellow (1995–1997) synthesis of mycotoxins),
chemistry under the super- of the Fonds der Chemis- syntheses involving sulfox-
vision of G. Szeimies. He chen Industrie and held a ides, and on the elucidation
joined the group of D. See- Habilitandenstipendium of of stereoelectronic effects of
bach at the ETH in Zürich the Deutsche Forschungs- sulfur-containing functional
groups.
Alexander Rothenberger sity of Cambridge in 2002 Cambridge European Trust
was born in Stuttgart in under the guidance of Dr. Bursary, and a DFG-Fors-
1972 and is Privatdozent in Ron Snaith and Dominic S. chungsstipendium. In 2008,
the Institute of Inorganic Wright. In 2002 he joined he will join the group of
Chemistry at the University the group of Prof. Dieter Prof.
of Karlsruhe (TH). He stud- Fenske at the University of Nortwestern
Kanatzidis
at
University,
ied chemistry in Würzburg Karlsruhe (TH) and com- Evanston. His research in-
and completed his diploma pleted his habilitation in terests include the develop-
thesis in the group of Prof. 2007. His scholarships in- ment of novel synthetic
Stalke in 1998. He received clude a Gottlieb-Daimler- routes, cluster chemistry,
his Ph.D. from Gonville & and Karl-Benz-Stipendium, and materials chemistry of
Caius College at the Univer- an EPSRC quota award, a Group 15/16 systems.
Synthesis 2008, No. 15, 2476–2487 © Thieme Stuttgart · New York

2478
T. Gehring et al.
FEATURE ARTICLE
Table 1 Ketene S,S-Acetals 4–12 Prepared
latter compounds have frequently been used in organic
synthesis8 and can be obtained by various methods
(Scheme 3).
n
S
R
S
R'
BuLi
O
S
S
S
S
A–C)
Entry R
n + 4
(ring size)
Methoda Product Yield
(%)
R
R'
R: A) SiMe3 (Peterson)
B) PO(OEt)2 (HWE)
c
1
2
(CH2)2OH
5
5
5
6
6
6
6
5
6
6
Db
Db
Db
Db
Db
Db
A
4
–
–
–
–
C) PPh3+ BF4– (Wittig)
c
c
c
(CH2)3OH
515
6
3
(CH2)4OH
HS
Me3Al
n
S
SH
O
S
R
4
(CH2)2OH
716
813a
913a
10
11
12
12
D)
E)
R
OR'
Me2AlS
5
(CH2)3OH
64
SAlMe2
SH
n=1,2
n
6
(CH2)4OH
quantc,d
75
O
1) HS
S
R
S
7
(CH2)4OTBS
(CH2)4NHBoc
(CH2)4NHBoc
(CH2)4NHBoc
R
8
D
61e
2) HClO4
3) Et3N
Cl
9
D
80d,f
73
Scheme 3 Methods for the preparation of ketene S,S-acetals
10
B
These include Peterson olefination (A, Scheme 3),9
Horner–Wadsworth–Emmons (HWE) reaction (B),5c,10
Wittig reaction (C),11 reaction of esters or lactones with
trimethylaluminum and dithiols (D),12,13 or elimination in
pre-formed dithiolanium salts (E).14
a Method as specified in Scheme 3.
b Starting from the respective lactone.
c Immediately oxidized without purification.
d Crude product.
e Starting from methyl N-tert-butyloxycarbonyl-6-aminohexanoate,
r.t., 14 h.
Ketene S,S-acetals synthesized in the present work are
summarized in Table 1. We obtained tert-butyldimethyl-
silyl (TBS)-protected ketene S,S-acetal 10 (entry 7) in
good yields by Peterson olefination starting from TBS-
protected 5-hydroxypentanal.
f Starting from N-tert-butyloxycarbonyl-e-caprolactam.
ketene S,S-acetals of type 12. Compound 12 is also acces-
sible via HWE reaction in 73% yield starting from tert-bu-
tyl 5-oxopentylcarbamate (Table 1, entry 10). It is known
that N-acyl derivatives of lactams can be ring-opened by
nucleophiles like alcoholates or Grignard reagents.18 So
we tried a direct synthesis of ketene S,S-acetal 12 starting
from tert-butyl 2-oxoazepane-1-carboxylate (N-Boc-e-
caprolactam) by reacting with trimethylaluminum and
propane-1,3-dithiol (Scheme 4). Under the same condi-
tions, a synthesis of 11 with ethane-1,2-dithiol failed. To
the best of our knowledge, this synthesis of ketene S,S-
acetals starting from protected lactams has not been pub-
lished previously. The scope of this reaction is currently
under investigation in our laboratories.
For the preparation of dithiolane-derived ketene S,S-ace-
tals, Peterson olefination or HWE reaction are not suitable
since deprotonation of dithiolane would induce a cyclore-
version leading to the formation of ethene and dithiofor-
mate.1,7 In our previous work,6b we utilized method E
starting from ethane-1,2-dithiol and an acyl chloride.14
Due to the higher functionalized substrates needed in the
present work, we decided to use a method developed by
Corey et al. who synthesized ketene S,S-acetals contain-
ing unprotected hydroxy groups by reaction of carboxylic
esters or lactones with trimethylaluminum and dithiols
(route D in Scheme 3).12 This route was successfully fol-
lowed in the synthesis of the previously unknown sub-
strates 4 and 6.
propanedithiol (1.05 equiv)
AlMe3 (2.1 equiv)
toluene–CH2Cl2, reflux, 14 h
O
Boc
S
S
N
Most hydroxy-substituted S,S-acetals are not stable under
acidic conditions due to a fast nucleophilic addition of a
free hydroxy group. This side reaction, which is observed
within minutes even during the acquisition of NMR spec-
tra, is usually prevented by the addition of a small amount
of triethylamine. The S,S-acetals thus prepared are either
directly used for the subsequent oxidation or are purified
by chromatography.
80%
NHBoc
12
Scheme 4 Synthesis of N-Boc-protected amino-substituted ketene
S,S-acetals
A well-established oxidation protocol developed by
Kagan19 and co-workers and optimized by Modena et
We were able to advance method D for the synthesis of N-
tert-butyloxycarbonyl (Boc)-protected amino-substituted
Synthesis 2008, No. 15, 2476–2487 © Thieme Stuttgart · New York

FEATURE ARTICLE
Intramolecular Michael-Type Additions to Vinyl Bissulfoxides
2479
al.3,20 was first used by Aggarwal et al.9b for the enantio- minutes to intramolecular addition with formation of the
and diastereoselective oxidation of ketene S,S-acetals, and tetrahydropyran derivatives 21a and 21b with a 45:55 se-
has been slightly modified by us to improve the workup lectivity (Scheme 6, Table 3). Bissulfoxide 15 was not
process.6 With these conditions, generally good yields up stable over a longer period since deprotection and addition
to 87% were obtained (Scheme 5, Table 2), though in occurred upon allowing to stand on the bench for several
some cases already addition occurred. Purification by days to weeks. To avoid a TBS-protection during the
chromatography gave enantiomerically and diastereomer- preparation of the bissulfoxide, a domino sequence con-
ically uniform product.
sisting of asymmetric oxidation und Michael-type addi-
tion of an unprotected substrate was tested. It turned out
that oxidation of dithiane-derived ketene S,S-acetal 9 de-
livered a substrate 14 reactive enough for a partial imme-
diate intermolecular addition of the hydroxy group.
Complete addition was observed upon standing on the
bench or after treatment with triethylamine or lithium hy-
droxide even at room temperature. Tetrahydropyrans
21a,b were obtained with this variation in 80% yield and
with 45:55 (21a:21b) selectivity.
cumene hydroperoxide
(+)-DET
n
n
Ti(O-i-Pr)4, CH2Cl2
S
R
S
S
R
S
O
O
Scheme 5 Asymmetric oxidation of ketene S,S-acetals
Table 2 Oxidation of Ketene S,S-Acetals (Scheme 5)
Entry R
n + 4
Starting Product
Yield
(%)
(ring size) material
O
propanedithiol
Me3Al
S
S
S
S
oxidation
a
O
O
O
1
2
(CH2)2OH
5
5
5
6
6
6
6
5
6
6
4
5
–
–
9
14
OH
OH
(CH2)3OH
18a,bb
19a,bb
13 a,e
56c
74d
3
(CH2)4OH
6
a
4
(CH2)2OH
7
–
1) separation of isomers
2) ReOCl3(PPh3)2, Ph3P
3) Bi(NO3)3, BiCl3
O
b
S
S
5
(CH2)3OH
8
–
50
O
O
*
*
87f
50g
57
O
45:55
6
(CH2)4OH
9
14/21a,b
O
26a,b
ee = 96%
21a,b
7
(CH2)4OTBS
(CH2)4NHBoc
(CH2)4NHBoc
(CH2)4OH
10
11
12
9
15
16
17
8
Scheme 6 Intramolecular additions of O-nucleophiles
Table 3 Intramolecular Additions of O-Nucleophiles (cf. Scheme 6)
9
80d
10
ent-14/21a,b ~80f,h
n
n
a Presumably polymerization had occurred.
S
S
S
S
b Addition occurred during oxidation, see Table 3.
c Over 2 steps starting from d-valerolactone.
d Over 2 steps starting from tert-butyl 2-oxoazepane-1-carboxylate.
e Impure product.
O
O
O
O
O
O
a
b
m
m
f Partial addition occurred; yield given over 2 steps starting from e-ca-
prolactone.
Entry m + 4
n + 4
Starting Product
dr
(R/S)
Yield
(%)
g Slightly impure material due to partial deprotection and subsequent
addition.
(ring size) (ring size) material
h Oxidation with (–)-D-DET.
1
2
3
4
5
6
5
6
5
6
6
6
5
5
6
6
6
6
5
6
18a,b
19a,b
20a,b
21a,b
21a,b
49:51a–c 56d
85:15a–c 74d
Intramolecular Additions of O-Nucleophiles
8
46:54b
45:55
45:55
45
64
15
14e
Intramolecular addition of a hydroxy function to the alky-
lidene bissulfoxide moiety should lead to tetrahydrofuran
or tetrahydropyran derivatives and their homologues. The
thus obtained enantiomerically pure carbaldehydes were
hardly accessible before. Whenever used (in different ox-
idation states) they were obtained by resolution of racemic
materials.21
80f
ent-14g ent-21a,b 55:45
~80f
a Not separable by conventional chromatography.
b Cyclization occurred during asymmetric oxidation.
c Assignment of isomers was not possible.
d Over 2 steps.
Alkylidene bissulfoxide 15 bearing a TBS-protected alco-
hol was obtained by Peterson olefination and subsequent
oxidation. Liberation of the hydroxy function by treat-
ment with tetrabutylammonium fluoride led within 45
e Contained already traces of 21a,b.
f Cyclization with LiOH.
g ent-14 contained already traces of ent-21a,b.
Synthesis 2008, No. 15, 2476–2487 © Thieme Stuttgart · New York

2480
T. Gehring et al.
FEATURE ARTICLE
As observed previously,6b,d dithiolane-derived bissulfox- the presence of triethylamine even at –78 °C (16a in
ides proved to be even more reactive: During the oxida- Scheme 7).
tion of 6 to the corresponding unprotected bissulfoxide a
complete concomitant cyclization occurs in good yield
(74% over 2 steps) leading to 19a and 19b with 85:15 se-
lectivity (Table 3, entry 2). Though significantly better se-
lectivities were obtained in this case, these isomers could
not be separated by conventional chromatography at this
stage.
1) 20% TFA–CH2Cl2, r.t., 1 h
2) Na2CO3, 0 °C, 1 h
3) Z-Cl, 14 h
S
S
N
S
S
O
O
Z
O
O
*
NHBoc
91%
23a,b 69:31
17
formal
hydrolysis
Not astonishingly, immediate cyclization was observed
during the oxidation of dithiolane species 5 leading to the
tetrahydrofuran derivatives 18a and 18b with 51:49 selec-
tivity. Similarly, poor selectivities have been observed for
the intermolecular additions of O-nucleophiles.22 The
structures of isomers 19b, 20b and 21b were unambigu-
ously determined by X-ray crystallographic analysis
(Figure 1).27
n
O
S
S
O
O
*
Z
N
27a,b
NHBoc
n = 1 16a
n = 2 17a
formal
hydrolysis
S
S
S
S
O
O
Z
O
O
20% TFA–CH2Cl2, r.t., 1 h
62%
*
N
NHBoc
16
22a,b ~1:1
Scheme 7 Intramolecular additions of N-nucleophiles to dithiane-
and dithiolane-derived bissulfoxides
In the deprotected amine 17 cyclization was achieved by
treatment with excess base (Na2CO3 or BaCO3) for one
hour at 0 °C in water, and the adducts were trapped as the
Z-protected derivatives 23a,b. The initially formed addi-
tion products (secondary amines) were quite polar. While
they could be purified, the different diastereomers could
not be separated. After Z-protection, the obtained diaste-
reomers could be separated by column chromatography.
This three-step deprotection–cyclization–protection se-
quence proceeded in the case of substrate 17 in excellent
yield (91%) (Scheme 7). Diastereoselectivity was 69:31
(23a:23b) when the cyclization was performed at 0 °C.
Assignment of the absolute configuration in 17 was not
possible. Aldehyde 27a obtained at the end of the se-
quence was known and comparison with the published
specific optical rotation25 gave evidence for a preferential
Si attack at this stage of the synthesis. The newly formed
stereogenic center in the major isomers a is S-configured,
the minor isomer b has an R-configuration. No improve-
ment of selectivities could be achieved by variation of re-
action conditions like solvent, base, or temperature
(Table 4).
Figure 1 Structure of tetrahydropyran 20b in the crystal.23
The intramolecular reaction of the bissulfoxides derived
from substrates 4 and 7 should lead to four-membered
rings, where the ring closure should be favored according
to Baldwin’s rules.24 Nevertheless this type of reaction
was not observed; presumably the intermolecular reac-
tions resulted in the formation of unspecified oligomers.
Intramolecular Additions of N-Nucleophiles
Deprotection of the N-Boc-protected derivatives 16 and
17 was achieved with 20% trifluoroacetic acid in dichlo-
romethane at room temperature for one hour. In the highly
reactive dithiolane dioxide 16 addition occurred even un-
der acidic conditions with ~1:1 selectivity and 62% yield.
The resulting secondary amine was precipitated as tri-
fluoroacetate salt from tetrahydrofuran–diethyl ether as a
mixture of diastereomers. Separation of the diastereomers
via column chromatography was achieved after protection
of the amine moiety with the benzyloxycarbonyl (Z)
group. It should be noted that to some extent a shift of the
double bond of Boc-protected amine 16 was observed in
These intramolecular additions of N-nucleophiles turned
out to be significantly faster than the respective intermo-
lecular reactions. While the intermolecular reaction of a
similar alkylidene sulfoxide with piperidine as solvent led
to a 20% conversion within 48 hours at room temperature,
the here presented intramolecular additions were complet-
ed in less than one hour at 0 °C.6d Cleavage of the bissulf-
oxide auxiliaries with liberation of a carbonyl group (e.g.,
an aldehyde function) led to compounds which are diffi-
cult to access by other methods in enantiomerically pure
form. While the 5-membered rings are proline derivatives,
Synthesis 2008, No. 15, 2476–2487 © Thieme Stuttgart · New York

FEATURE ARTICLE
Intramolecular Michael-Type Additions to Vinyl Bissulfoxides
2481
Table 4 Intramolecular Additions of N-Nucleophiles (Scheme 7)
Entry
Starting material Conditions
Deprotection
Product (dr) (S,R)
Yield (%)
91b
Cyclization
1
2
3
4
5
6
17
17
17
17
16
16
20% TFA in CH2Cl2,
r.t., 1 h
Na2CO3 or BaCO3 (20 equiv) H2O, 23a,b (69:31)a
0 °C, 1 h
c
20% TFA in CH2Cl2,
r.t. 1 h
LiOH, MeOH,
–40 °C, 40 h
23a,b (47:53)a
mixture of 23a,b and 17a
23a,b (47:53)a
22a,b (~1:1)
–
c
20% TFA in CH2Cl2,
r.t., 1 h
BnNMe3OH, MeOH,
–40 °C, 40 h
–
c
20% TFA in CH2Cl2,
r.t., 1 h
BnNMe3OH, CH2Cl2,
–40 °C, 40 h
–
d
10% TFA in CH2Cl2,
r.t., 1 h
–
62
c
none
Et3N, r.t., 1 h
16a
–
a Concomitant protection with Z-Cl in the presence of Na2CO3 and H2O; dr was determined as Z-protected derivative (1H NMR).
b Yield over 3 steps from 17 (deprotection-cyclization-protection sequence).
c Not determined.
d Cyclization occurred during deprotection.
which are simply obtained in any enantiomeric form and Similarly plenty of methods have been published for the
oxidation state, the higher homologue pipecolic acid is hydrolysis of dithioacetals.31 We found that this transfor-
very expensive in enantiomerically pure form. Though its mation is highly substrate-specific not allowing the utili-
derivatives were frequently used especially in medicinal zation of a generally applicable method. It turned out that
chemistry,26 it was mandatory either to resolve the racem- in very sensitive substrates partial racemization is difficult
ic material27 or to apply enantioselective multistep reac- to avoid. We obtained satisfactory results in the cleavage
tions like Seebach’s Boc-BMI method.28
of 2-(1,3-dithian-2-yl)tetrahydropyrans 24a and 24b for
this transformation using bismuth nitrate in the presence
of oxygen according to
a
published protocol
(Scheme 9).32
Cleavage of the Auxiliary
Chiral aldehyde 26b was obtained with 96% ee. This kind
of hydrolysis failed for compound 25a; best results were
obtained with an slightly modified two-step protocol us-
ing PhI(O2CCF3)2 in MeOH–THF followed by treatment
with p-toluenesulfonic acid in dioxane–water as described
by Danishefsky et al.33 The high volatility of the alde-
hydes (e.g., 26), their instability25 and their tendency to ra-
cemize suggests an immediate transformation of these
compounds, possibly even without extensive purification
(26 showed an ee of 86% after standing for several days at
room temperature, 27 showed an ee of 70% after purifica-
tion by column chromatography).
Cleavage of the auxiliary liberating a carbonyl compound
has been performed by Aggarwal et al. using a Pummerer
reaction yielding the respective carbothioate. Substrates
used by them were – due to the substitution pattern – not
prone to racemization or epimerization.5b,29 We tested a
Pummerer reaction with substrate 19 (dr = 85:15) leading
to S-ethyl tetrahydro-2H-pyran-2-carbothioate in 59%
yield but poor enantioselectivity (31% ee). In our previous
work, we used a two-step protocol with reduction of the
sulfoxide groups and subsequent hydrolysis of the
dithiane liberating an aldehyde function. From the pletho-
ra of methods available for the reduction of sulfoxides we
chose for the formation of the corresponding dithioacetals
a rhenium-catalyzed reduction with triphenylphosphine in
dichloromethane (not anhydrous) at 45 °C, which was
achieved in high yields exceeding 77% (Scheme 8).30
Table 5 Cleavage of the Auxiliary (Schemes 8 and 9)
Entry Starting Dithianea Yield Hydrolysis
Aldehyde Yield
(config.) (%)
material
(%)
91
88
87
77
1
2
4
5
21a
24a
24b
25a
25b
Bi(NO3)3
26a (S)
26b (R) 63
17
PhI(O2CCF3) 27b (R) 19
75
ReOCl3(PPh3)2 (5 mol%)
Ph3P (1.9 equiv)
S
S
X
S
S
X
O
O
21b
Bi(NO3)3
CH2Cl2, 45 °C, 12 h
23a
PhI(O2CCF3) 27a (S)
X = O, N-Z
23b
Scheme 8 Reduction of bissulfoxides (Table 5)
a Reduction was achieved with ReOCl3(PPh3)2/Ph3P in CH2Cl2 at
45 °C.
Synthesis 2008, No. 15, 2476–2487 © Thieme Stuttgart · New York

2482
T. Gehring et al.
FEATURE ARTICLE
sponding ester, lactone, or lactam (1.00 equiv) in CH2Cl2 (1 mL per
2 mmol) was added within 15 min via a syringe pump. The resulting
mixture was stirred at r.t. or refluxed for 12 h at 85 °C yielding a
clear solution, which was concentrated in vacuo. Et2O and Et3N (3
drops) were added and moist Na2SO4 was carefully (!) added until
evolution of gas ceased. After filtration over Celite and Na2SO4, the
solvent was removed in vacuo. The crude product was obtained as
a colorless liquid and either used without purification in the next
step or purified by column chromatography.
Bi(NO3)3⋅5H2O (20 mol%)
BiCl3 (10 mol%)
benzene, r.t., air, 14 h
O
S
S
O
63% to 75%
O
26b
24b
ee = 96%
1. PhI(O2CCF3)2 (2 equiv)
MeOH–THF, 15 min, r.t.
2. TsOH (3 equiv), 50 °C, 2 h
O
S
S
N
Z
Asymmetric Oxidation of Dithiolanes and Dithianes; General
Procedure 2 (GP 2)
N
Z
17% to 19%
(+)-DET (2 equiv, traces of H2O were removed by azeotropic distil-
lation with toluene) and freshly distilled Ti(O-i-Pr)4 (0.5 equiv)
were dissolved in CH2Cl2 (2 mL per mmol DET) at r.t. under argon
and stirred for 30 min. The solution became yellow. The (crude)
ketene dithioacetal (1 equiv) was dissolved in CH2Cl2 (1 mL per
mmol) and added to the mixture, which was then cooled to –45 °C
and stirred for 2 h. Cumene hydroperoxide (80%; 4 equiv) in
CH2Cl2 (1 mL per 10 mmol) was added over a period of 1 h. The
mixture was stored for 12–24 h in a freezer (about –25 °C). Distilled
H2O (20 equiv) was added and the mixture was stirred vigorously
for 1 h. The resulting gel was placed in an ultrasonic bath for 1 h to
afford a filterable suspension, which was filtered by suction through
a large sintered-glass funnel filled with Celite (1.5 cm height). The
Celite pad was excessively washed with small portions of CH2Cl2
(at least 7 times) until TLC showed complete elution of the product.
The filtrate was dried (Na2SO4) and evaporated to leave an oily
material containing (+)-DET, cumene hydroxide, and the desired
bissulfoxide. Pure bissulfoxide was obtained by column chromato-
graphy.
27a,b
25a,b
Scheme 9 Hydrolysis of S,S-acetals (Table 5)
In conclusion, we have presented an auxiliary-based
method for the preparation of a-functionalized cyclic al-
dehydes, which are hardly accessible in enantiomerically
pure form by other routes. The stereochemical informa-
tion of the auxiliary is introduced by means of diethyl tar-
trate, which is available and inexpensive in both
enantiomeric forms. This gives access to each enantiomer
of the target molecules, depending on the chosen configu-
ration of the auxiliary. Application of this method to the
preparation of 1,4-dicarbonyl compounds is currently un-
der investigation in our group.
THF was distilled over sodium benzophenone ketyl and CH2Cl2
was distilled from CaH2. Abbreviations: tert-butyloxycarbonyl
(Boc), diethyl tartrate (DET), 3-(heptafluoropropylhydroxymethyl-
ene)-d-camphorate (hfc), thin-layer chromatography (TLC), tri-
fluoroacetic acid (TFA), tert-butyldimethylsilyl (TBS), p-
toluenesulfonyl (Ts), benzyloxycarbonyl (Z). All moisture-sensi-
tive reactions were carried out under oxygen-free argon using oven-
dried glassware and a vacuum line. Flash column chromatography34
was carried out using Merck silica gel 60 (230–400 mesh) and TLC
using commercially available Merck F254 pre-coated sheets. 1H and
13C NMR spectra were recorded on a Bruker Cryospek WM-250,
AM-400, DRX 500, and Avance 600 spectrometers. The spectra
were measured at r.t., unless otherwise stated. Chemical shifts are
given in ppm downfield of TMS. 13C NMR spectra were recorded
with broad band proton decoupling and were assigned using DEPT
experiments. Melting points were measured on a Büchi apparatus
and are not corrected. IR spectra were recorded on a Bruker IFS-88
spectrometer. Elemental analyses were performed on a Heraeus,
CHN-O-rapid or on an elementar vario MICRO apparatus. Electri-
cal ionization and high-resolution mass spectra were recorded on a
Finnigan MAT-90 spectrometer. Gas chromatography/mass spec-
trometry (GC-MS) measurements were performed on a GC (Agi-
lent), model 6890 N on capillary column HP-5MS (length 30 m,
inner diameter 0.25 mm, thickness of the film 0.25 mm); carrier gas:
He. Mass spectrometer (Agilent) used was model 5975B VL MSD.
Optical rotations were recorded on a Perkin–Elmer 241 polarimeter
Rhenium-Catalyzed Reduction; General Procedure 3 (GP 3)
ReOCl3(PPh3)2 (0.05 equiv), Ph3P (1.90 equiv), and the correspond-
ing bissulfoxide (1.00 equiv) were stirred for 14 h at 45 °C in
CH2Cl2. After removal of the solvent in vacuo, the residue was pu-
rified by column chromatography to yield the desired pure dithio-
acetal.
tert-Butyl-(5-[1,3]dithian-2-ylidenepentyloxy)dimethylsilane
(10)
1,3-Dithiane (1.11 g, 9.24 mmol) was suspended in THF (30 mL)
under argon. After cooling to –78 °C, a solution of n-BuLi in hex-
ane (1.69 M, 5.74 mL, 9.70 mmol) was added dropwise. The solu-
tion was allowed to warm to 0 °C in 1 h followed by recooling to
–78 °C. A solution of TMSCl (1.23 mL, 9.70 mmol) in THF (5 mL)
was added and the mixture was allowed to warm to 0 °C within 1 h.
After recooling to –78 °C, a solution of n-BuLi in hexane (1.69 M,
5.74 mL, 9.70 mmol) was added dropwise and the solution was
warmed to 0 °C within 1 h. After recooling to –78 °C, 5-(tert-bu-
tyldimethylsilyloxy)pentanal (2.10 g, 9.70 mmol) in THF (10 mL)
was added. After warming to r.t., aq sat. NH4Cl solution (30 mL)
was added. The aqueous layer was extracted with EtOAc (3 × 50
mL). The combined organic layers were dried (Na2SO4) and con-
centrated. The remaining crude ketene dithioacetal (3.1 g) was pu-
rified by column chromatography (hexanes–EtOAc, 10:1) to yield
10 (2.21 g, 75%) as a colorless oil; Rf = 0.64 (hexanes–EtOAc, 2:1).
and specific optical rotations [a]D are given in units of 10–1 deg
20
IR (KBr): 2928, 2856, 1471, 1254, 1099, 836, 776 cm–1.
cm2 g–1.
1H NMR (250 MHz, CDCl3): d = 0.03 [s, 6 H, Si(CH3)2], 0.88 [s, 9
H, SiC(CH3)3], 1.47 (m, 4 H), 2.17 (m, 4 H), 2.84 (m, 4 H), 3.60 (t,
J = 6.2 Hz, 2 H, OCH2), 5.94 (t, J = 7.3 Hz, 1 H, H-5).
13C NMR (101 MHz, CDCl3): d = –5.3 (q), 18.3 (q), 25.2 (t), 25.3
(t), 26.0 (t), 29.0 (t), 29.6 (t), 30.4 (t), 32.3 (t), 62.9 (t), 125.5 (s),
134.6 (d).
Ketene S,S-Acetals; General Procedure 1 (GP 1)
Propane-1,3-dithiol or ethane-1,2-dithiol (1.05 equiv) was added
dropwise at 0 °C (in the case of ethane-1,2-dithiol: –78 °C) to a so-
lution of CH2Cl2 (1 mL per mmol dithiol) and Me3Al (2 M solution
in toluene, 2.10 equiv). The formation of methane gas was ob-
served. After removing the cooling bath, the solution was allowed
to stir for 30 min at r.t. resulting in a milky solution. The corre-
MS (EI, 70 eV): m/z (%) = 319 (10, [M]+), 261 (87, [M – t-Bu]+),
187 (100, [M – OTBS]+), 75 (43).
Synthesis 2008, No. 15, 2476–2487 © Thieme Stuttgart · New York

FEATURE ARTICLE
Intramolecular Michael-Type Additions to Vinyl Bissulfoxides
2483
HRMS-EI: m/z calcd for C15H30OS2Si [M]+: 318.1507; found:
mL) were added and the mixture was extracted with portions of
318.1504.
CH2Cl2 until monitoring by TLC (CH2Cl2–MeOH, 10:1) confirmed
complete extraction. The organic layers were concentrated and the
residue (4.0 g, 80%) containing a 45:55 mixture of 21a:21b was pu-
rified by MPLC (CH2Cl2–MeOH, 100:1 → 20:1) to yield 21a (1.80
g) and 21b (2.20 g).
(2¢R,6¢R)-tert-Butyl-[5-(1,3-dioxo[1,3]dithian-2-ylidene)pentyl-
oxy]dimethylsilane (15)
Oxidation of 10 according to GP 2 followed by column chromato-
graphy (CH2Cl2–acetone, 10:1 → 4:1) yielded 15 as an unstable col-
orless oil (1.22 g, 50%), which reacted upon standing at r.t. over
some days yielding the solid addition product 21a,b; [a]D20 –12.2 (c
1.01, CHCl3); Rf = 0.53 (CH2Cl2–acetone, 2:1).
Using D-DET instead of L-DET in this sequence yielded a mixture
of ent-21a/ent-21b = 55:45 in comparable yields.
21a
IR (KBr): 3437, 2952, 2929, 2857, 1047 (S=O), 835, 775 cm–1.
Mp 174–175 °C; [a]D +165 (c 1.01, CHCl3); Rf = 0.24 (CH2Cl2–
20
acetone, 1:1), 0.40 (CH2Cl2–MeOH, 10:1).
IR (KBr): 2920, 2865, 1048 cm–1 (S=O).
1H NMR (400 MHz, CDCl3): 2 Rotamers, d = 0.01 (0.04) [2 s, 6 H,
Si(CH3)2], 0.87 (0.85) [2 s, 9 H, SiC(CH3)3], 1.56 (m, 4 H, H-3, H-
2), 2.30–2.50 (m, 2 H, H-4), 2.62 (m, 2 H), 2.76 (m, 1 H), 3.03 (m,
1 H), 3.18 (m, 1 H), 3.59 (m, 3 H, H-1, dithiane-H), 6.65 (t, J = 8.0
Hz, 1 H, H-5).
13C NMR (101 MHz, CDCl3): 2 Rotamers (3:1), d (major
rotamer) = –3.7 (q), 14.8 (t), 17.9 [q, C(CH3)3], 25.1 (t), 25.8 (q),
28.6 (t), 31.7 (t), 48.7 (t), 55.2 (t), 61.9 (t), 140.7 (d, 1¢-C), 144.2 (s,
1-C); d (minor rotamer) = –5.4 (q), 14.8 (t), 18.2 [q, C(CH3)3], 25.3
(t), 25.6 (q), 28.8 (t), 32.0 (t), 48.8 (t), 55.3 (t), 62.3 (t), 140.8 (d),
144.1 (s).
1H NMR (400 MHz, CDCl3): d = 1.58 (m, 3 H, H-4, H-5), 1.83
(ddd, J = 2.9, 5.5, 6.4 Hz, 1 H, H-3), 1.97 (m, 2 H, H-3, H-4), 2.59
(m, 2 H, dithiane-H), 3.00 (m, 2 H, dithiane-H), 3.37 (ddd, J = 3.0,
9.2, 12.9 Hz, 1 H, dithiane-H), 3.51 (m, 2 H, H-6), 3.95 (d, J = 2.8
Hz, 1 H, H-2), 4.03 (tdd, J = 1.8, 3.7, 11.2 Hz, 1 H, dithiane-H),
4.32 (td, J = 2.6, 11.6 Hz, 1 H, H-2).
13C NMR (101 MHz, CDCl3): d = 14.7 (dithiane-C), 23.2 (t, C-4),
25.2 (t, C-5), 29.7 (t, C-3), 46.1 (dithiane-C), 48.1 (dithiane-C), 68.9
(t, C-6), 69.9 (d, C-2¢), 74.9 (d, C-2).
MS (FAB): m/z = 351 [M + H]+, 293 [M – t-Bu]+.
MS (FAB): m/z = 237 [M + H]+.
ent-21a
5-([1,3]Dithian-2-ylidene)pentan-1-ol (9)
[a]D20 –156 (c 1.01, CHCl3).
Following GP 1, e-caprolactone (2.85 g, 24.8 mmol) reacted to
yield crude 9 (5.0 g, quant) as a colorless liquid, which was used
without further purification; Rf = 0.22 (hexane–EtOAc, 2:1).
IR (KBr): 3353, 2932, 2858, 1421, 1276, 1063, 912 cm–1.
Further spectroscopic data were in full agreement with those of
enantiomer 21a.
1H NMR (250 MHz, CDCl3): d = 1.36–1.64 (m, 5 H), 2.09–2.29 (m,
4 H), 2.80–2.87 (m, 4 H), 3.63 (t, J = 6.4 Hz, 2 H, CH2OH), 5.93 (t,
J = 7.3 Hz, 1 H, H-5).
21b
Mp 188–190 °C; [a]D20 –37.5 (c 0.12, CHCl3); Rf = 0.18 (CH2Cl2–
acetone, 1:1), 0.30 (CH2Cl2–MeOH, 10:1).
IR (KBr): 2933, 2854, 1431, 1349, 1045 cm–1 (S=O).
MS (EI, 70 eV): m/z (%) = 204 (74, [M]+), 145 (100), 71 (73).
1H NMR (400 MHz, CDCl3): d = 1.57 (m, 3 H, H-4, H-5), 1.76 (m,
2 H, H-3), 1.90 (m, 1 H, H-4), 2.31 (m, 1 H, dithiane-H), 2.67 (m, 1
H, dithiane-H), 2.86 (m, 2 H, dithiane-H), 3.15 (m, 1 H, dithiane-
H), 3.21 (d, J = 4.9 Hz, 1 H, H-2¢), 3.50 (dt, J = 2.3, 11.7 Hz, 1 H,
H-6), 3.61 (m, 1 H, dithiane-H), 4.10 (dtd, J = 1.6, 3.8, 5.8 Hz, 1 H,
H-6), 4.23 (m, 1 H, H-2).
13C NMR (101 MHz, CDCl3): d = 14.6 (t, C-5¢), 23.0 (t, C-4), 25.2
(t, C-5), 30.0 (t, C-3), 46.1 (dithiane-C), 52.1 (dithiane-C), 69.3 (t,
C-6), 72.7 (d, C-2), 78.9 (d, C-2¢).
HRMS-EI: m/z calcd for C9H16OS2 [M]+: 204.0642; found:
204.0639.
(2¢R,6¢R)-5-(1,3-Dioxo[1,3]dithian-2-ylidene)pentan-1-ol (14)
Crude 9 (5.00 g, 24.5 mmol) reacted following GP 2 (14 h at
–25 °C). Purification by column chromatography (CH2Cl2–acetone,
2:1 → 1:1) afforded 14 together with the product of intramolecular
addition 21a,b (total yield: 5.06 g, 87%); Rf = 0.29 (CH2Cl2–
MeOH, 10:1).
MS (FAB): m/z = 237 [M + H]+.
14
1H NMR (250 MHz, CDCl3): d = 1.50–1.62 (m, 4 H), 2.28–2.84 (m,
5 H), 3.05 (tdd, J = 2.5, 13.0, 18.1 Hz, 1 H), 3.14–3.24 (m, 1 H),
3.57–3.64 (m, 3 H), 6.67 (t, J = 8.0 Hz, 1 H).
Anal. Calcd for C9H16O3S2: C, 45.74; H, 6.82; S, 27.13. Found: C,
45.65; H, 6.55; S, 27.26.
ent-21b
[a]D20 +40.5 (c 0.97, CHCl3).
(2S,2¢R,6¢R) and (2R,2¢R,6¢R)-2-(1,3-Dioxo[1,3]dithian-2-yl)tet-
rahydropyran (21a,b)
Further spectroscopic data were in full agreement with those of
From Silyl Ether 15: Compound 15 (1.46 g, 4.16 mmol) and
Bu4NF·3H2O (1.19 g, 3.76 mmol) were dissolved in CH2Cl2 (20
mL) and the resulting solution was stirred for 45 min at r.t. [the re-
action was monitored by TLC (CH2Cl2–MeOH, 10:1)]. After re-
moval of the solvent in vacuo, the residue was purified by
conventional chromatography (CH2Cl2–acetone, 2:1 → 1:1) yield-
ing a mixture of 21a and 21b (45:55, 0.63 g, 64%). The diastere-
omers were separated by MPLC (CH2Cl2–MeOH, 100:1 → 20:1)
affording 21a and 21b as pure isomers.
enantiomer 21b.
(2SR,2¢R,5¢R)-2-(1,3-Dioxo[1,3]dithiolan-2-yl)tetrahydropyran
(19a,b)
Compound 6 [synthesized according to GP 1 starting from e-capro-
lactone (4.54 g, 39.4 mmol)] was oxidized according to GP 2 and
purified by column chromatography (CH2Cl2–acetone, 2:1) yield-
ing 19 (6.47 g, 74%, over 2 steps) as a white solid mixture of iso-
mers (85:15) not separable by column chromatography; Rf = 0.26
(CH2Cl2–acetone, 1:1).
IR (KBr): 2926, 2854, 1087, 1024 cm–1 (S=O).
1H NMR (400 MHz, CDCl3): d = 1.45–1.76 (m, 4 H), 1.82–2.14 (m,
2 H), 3.40–3.75 (m, 7 H), 3.96–4.01 (m, 1 H).
From Alcohol 14: Compound 14 (5.00 g, 21.1 mmol, containing
small amounts of 21a,b) as prepared above was dissolved in CH2Cl2
(100 mL). To this solution was added LiOH (5.0 g) and the mixture
was stirred at 45 °C for 12 h [until TLC (CH2Cl2–MeOH, 10:1)
showed complete addition]. H2O (100 mL) and aq 1 M HCl (200
Synthesis 2008, No. 15, 2476–2487 © Thieme Stuttgart · New York

2484
T. Gehring et al.
FEATURE ARTICLE
13C NMR (101 MHz, CDCl3): Mixture of isomers, d (major
isomer) = 22.6, 25.1, 31.1, 51.1, 51.9, 68.8, 71.7 (d), 94.7 (d); d (mi-
nor isomer) = 22.7, 25.1, 30.6, 50.5, 51.3, 68.8, 70.4 (d), 96.5 (d).
and 18b as a white, solid, and inseparable mixture of isomers
(51:49) (4.64 g, 56%, 2 steps). The diastereomers could not be as-
signed; Rf = 0.21 (CH2Cl2–acetone, 2:1).
MS (FAB): m/z = 223 [M + H]+.
IR (KBr): 2985, 2934, 2880, 1396, 1033 cm–1 (S=O).
HRMS-FAB: m/z calcd for C8H14O3S2 [M + H]+: 223.0462; found:
223.0465.
1H NMR (400 MHz, CDCl3): d = 1.90–2.06 (m, 3 H), 2.28–2.40 (m,
1 H), 3.52–3.95 (m, 7 H), 4.22–4.33 (m, 1 H).
Anal. Calcd for C8H14O3S2: C, 43.22; H, 6.35; S, 28.85. Found: C,
43.15; H, 6.12; S, 28.36.
13C NMR (101 MHz, CDCl3): Mixture of isomers, d = 25.6 (t), 25.9
(t), 30.5 (t), 31.7 (t), 51.4 (t), 51.5 (t), 51.6 (t), 52.2 (t), 68.5 (t), 69.0
(t), 72.0 (d), 72.8 (d), 94.3 (d), 95.9 (d).
(2S,2¢R,6¢R) and (2R,2¢R,6¢R)-2-(1,3-Dioxo[1,3]dithian-2-yl)tet-
rahydrofuran (20a,b)
MS (EI, 70 eV): m/z (%) = 208 (83, [M]+), 132 (100, [M –
C2H4SO]+), 108 (22), 84 (47), 71 (73) [C4H7O]+.
Compound 8 was synthesized according to GP 1 starting from
freshly distilled d-valerolactone (2.16 g, 21.6 mmol). After purifi-
cation by column chromatography [cyclohexane–EtOAc, 2:1,
Rf = 0.28 (hexane–EtOAc, 2:1)], 8 was obtained as a colorless oil
(2.94 g, 64%), which was oxidized according to GP 2 and purified
by column chromatography (CH2Cl2–acetone, 4:1 → 1:1) yielding
20a,b (1.40 g, 45%) as a white solid mixture of diastereomers (20a/
20b, 46:54), which could be separated by MPLC (CH2Cl2–MeOH,
50:1 → 20:1).
HRMS-EI: m/z calcd for C7H12O3S2 [M]+: 208.0228; found:
208.0230.
Anal. Calcd for C7H12O3S2: C, 40.36; H, 5.81; S, 30.79. Found: C,
40.37; H, 5.60; S, 30.92.
tert-Butyl (2¢R,5¢R)-[5-(1,3-Dioxo[1,3]dithian-2-ylidene)pen-
tyl]carbamate (17)
Compound 12 was synthesized according to GP 1 starting from tert-
butyl 2-oxoazepane-1-carboxylate (N-Boc-e-caprolactam) and stir-
ring overnight at reflux. The resulting crude colorless liquid was ox-
idized without further purification according to GP 2 and purified
by column chromatography (CH2Cl2–acetone, 10:1 → 1:1) yielding
17 as a yellowish highly viscous oil (4.00 g, 63%, 2 steps).
20a
20
Mp 92–94 °C; [a]D +123.8 (c 1.01, CHCl3); Rf = 0.28 (CH2Cl2–
MeOH, 10:1).
IR (KBr): 3810, 3438, 2876, 2075, 1741, 1400, 1178, 1035 cm–1
(S=O).
1H NMR (600 MHz, CDCl3): d = 1.99 (m, 1 H, H-4), 2.07 (m, 1 H,
H-4), 2.31 (td, J = 5.2, 13.8 Hz, 2 H, H-3), 2.61 (m, 2 H, dithiane-
H), 3.02 (m, 2 H, dithiane-H), 3.33 (m, 1 H, dithiane-H), 3.47 (m, 1
H, dithiane-H), 3.86 (m, 1 H, H-5), 4.00 (m, 1 H, H-5), 4.11 (d, 1 H,
J = 3.3 Hz, H-2¢), 4.72 (dt, J = 3.6, 7.7 Hz, 1 H, H-2).
Ketene S,S-Acetal 12
Rf = 0.52 (hexane–EtOAc, 2:1).
IR (KBr): 3348, 2931, 1698 (s, C=O), 1515, 1171 cm–1.
MS (EI): m/z (%) = 303 (1, [M]+), 205 (11), 164 (15), 113 (100), 85
(41), 84 (43), 57 (41), 55 (33), 41 (41).
13C NMR (151 MHz, CDCl3): d = 14.6 (t), 25.3 (t, C-4), 29.9 (t, C-
HRMS: m/z calcd for C14H25NO2S2 [M]+: 303.1327; found:
303.1326.
3), 45.8 (t), 48.1 (t), 69.1 (t, C-5), 72.0 (d, C-2), 74.0 (d, C-2¢).
MS (EI, 70 eV): m/z (%) = 222 (58, [M]+), 90 (51), 84 (100), 71
(92), 43 (80), 41 (81).
HRMS-EI: m/z calcd for C8H14O3S2 [M]+: 222.0384; found:
222.0382.
Bissulfoxide 17
[a]D20 –18.9 (c 0.99, CHCl3); Rf = 0.31 (CH2Cl2–acetone, 1:1).
IR (KBr): 3330, 2929, 1703 (s, C=O), 1526, 1170, 1050 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.41 (s, 9 H, t-C4H9), 1.52 (m, 4
H), 2.34 (m, 1 H), 2.46 (dt, J = 6.9, 14.1 Hz, 1 H, H-4), 2.63 (m, 2
H), 2.78 (ddd, J = 2.5, 11.9, 13.4 Hz, 1 H), 3.05 (m, 3 H), 3.18 (td,
J = 3.3, 14.3 Hz, 1 H), 3.60 (dddd, J = 1.0, 2.1, 3.6, 7.7 Hz, 1 H),
4.60 (s br, 1 H, NH), 6.63 (t, J = 8.0 Hz, 1 H, H-5).
13C NMR (126 MHz, CDCl3): d = 14.8 (t), 25.8 (t), 28.4 [q,
C(CH3)3], 28.5 (t), 29.5 (t), 39.9 (t), 48.9 (t), 55.4 (t), 79.2 (s), 140.2
(d, C-5), 144.8 (s), 155.9 (s).
Anal. Calcd for C8H14O3S2: C, 43.22; H, 6.35; S, 28.85. Found: C,
43.17; H, 6.05; S, 28.72.
20b
20
Mp 138–140 °C; [a]D –2.0 (c 1.02, CHCl3); Rf = 0.21 (CH2Cl2–
MeOH, 10:1).
IR (KBr): 2950, 2950, 2900, 2880, 1728, 1424, 1041, 1021 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.96–2.10 (m, 3 H, H-3, H-4),
2.25–2.40 (m, 2 H, H-3, dithiane-H), 2.68–2.97 (m, 3 H, dithiane-
H), 3.23 (dddd, J = 1.0, 2.7, 3.8, 14.2 Hz, 1 H, dithiane-H), 3.31 (d,
J = 7.8 Hz, 1 H, H-2¢), 3.61 (dddd, J = 1.0, 2.1, 5.6, 12.2 Hz, 1 H,
dithiane-H), 3.85 (m, 1 H, H-5), 3.95 (td, J = 7.0, 13.8 Hz, 1 H, H-
5), 4.66 (dd, J = 7.0, 14.5 Hz, 1 H, H-2).
13C NMR (101 MHz, CDCl3): d = 14.5 (t), 25.9 (t, C-4), 30.8 (t, C-
3), 45.4 (t), 51.3 (t), 68.2 (t, C-5), 74.8 (d, C-2), 78.1 (d, C-2¢).
MS (EI, 70 eV): m/z (%) = 222 (9, [M]+), 90 (23), 84 (45), 71 (64),
63 (19), 55 (44), 43 (100), 41 (77).
MS (FAB): m/z = 336 [M + H]+.
HRMS-FAB: m/z calcd for C14H25NO4S2 [M + H]+: 336.1303;
found: 336.1305.
Benzyl (2S,2¢R,6¢R)- and (2R,2¢R,6¢R)-2-(1,3-Dioxo[1,3]dithian-
2-yl)piperidine-1-carboxylate (23a,b)
Boc-protected bissulfoxide 17 (4.10 g, 12.2 mmol) was dissolved in
CH2Cl2 (100 mL). Deprotection was performed at r.t. by adding
TFA (10 mL) followed by stirring at r.t. for 30–60 min (monitoring
with TLC). The solution was concentrated and traces of TFA were
removed by co-evaporation with CHCl3 (3 × 15 mL). H2O (100 mL)
and Na2CO3 (10 g) were then added. The mixture was stirred for 1
h at 0 °C and warmed to r.t., Z-Cl (2.20 mL, 14.7 mmol) was added,
and the stirring was continued overnight at r.t. The mixture was ex-
tracted with CH2Cl2 (5 × 25 mL), dried (Na2SO4), and concentrated.
The resulting oil (1H NMR: 23a/23b 69:31) was purified by MPLC
(CH2Cl2–MeOH, 50:1 → 20:1) yielding 23a (2.83 g, 63%) and 23b
(1.27 g, 28%) as colorless, slowly solidifying oils.
HRMS-EI: m/z calcd for C8H14O3S2 [M]+: 222.0384; found:
222.0388.
(2SR,2¢R,5¢R)-2-(1,3-Dioxo[1,3]dithiolan-2-yl)tetrahydrofuran
(18a,b)
Compound 5 was synthesized starting from d-valerolactone accord-
ing to GP 1 and directly oxidized according to GP 2 and purified by
column chromatography (CH2Cl2–acetone, 4:1 → 1:1) to give 18a
Synthesis 2008, No. 15, 2476–2487 © Thieme Stuttgart · New York

FEATURE ARTICLE
23a
Mp 39–43 °C (softening range); [a]D +92.8 (c 1.04, CHCl3);
Rf = 0.39 (CH2Cl2–MeOH, 10:1).
Intramolecular Michael-Type Additions to Vinyl Bissulfoxides
2485
IR (KBr): 3356 (N–H), 2929, 1697 (C=O), 1598, 1516, 1365, 1276,
1170 cm–1.
MS (FAB): m/z = 290 [M + H]+, 234, 171, 131.
20
IR (KBr): 2938, 1692 (C=O), 1424, 1259, 1044 (S=O), 699 cm–1.
HRMS-FAB: m/z calcd for C13H23NO2S2 [M + H]+: 290.1248;
1H NMR (500 MHz, acetone-d6): d = 1.44–1.54 (m, 1 H), 1.62–1.70
(m, 2 H), 1.72–1.83 (m, 2 H), 2.27 (br d, J = 13.0 Hz, 1 H), 2.33–
2.42 (m, 1 H), 2.51–2.61 (m, 1 H), 3.00 (ddd, J = 3.7, 9.4, 13.1 Hz,
1 H), 3.06–3.15 (m, 1 H), 3.17–3.26 (m, 2 H), 3.37 (ddd, J = 3.4,
7.9, 13.2 Hz, 1 H), 4.08 (br d, J = 13.4 Hz, 1 H), 4.29 (br d, J = 9.2
Hz, 1 H), 5.16 (m, 3 H), 7.28–7.44 (m, 5 H, Ph).
13C NMR (101 MHz, CDCl3): d = 11.5 (t), 18.7 (t), 24.4 (t), 26.8 (t),
40.7 (t), 42.2 (t), 42.6 (t), 48.2 (d), 67.4 (d), 70.4 (s), 127.9 (d), 128.0
(d), 128.3 (d), 136.1 (t), 155.0 (s).
found: 290.1247.
tert-Butyl (2¢R,6¢R)-[5-(1,3-Dioxo[1,3]dithiolan-2-ylidene)pen-
tyl]carbamate (16)
Compound 11 (3.46 g, 12.0 mmol) reacted according to GP 2 fol-
lowed by column chromatography (CH2Cl2–acetone, 2:1 → 1:1)
yielding 16 (1.92 g, 50%) as a colorless oil, which solidified slowly.
Product 16 was of limited stability; it partly decomposed during col-
20
umn chromatography; [a]D –96.6 (c 1.00, CHCl3); Rf = 0.18
(CH2Cl2–acetone, 1:1).
MS (FAB): m/z (%) = 370 (40, [M + H]+), 91 (100, [C7H7]+).
HRMS-FAB: m/z calcd for C17H23NO4S2 [M + H]+: 370.1147;
IR (KBr): 3356, 2972, 2052, 1683 (C=O), 1533, 1174, 1020 cm–1
(S=O).
1H NMR (400 MHz, CDCl3): d = 1.44 (s, 9 H, t-C4H9), 1.54–1.68
(m, 4 H, 3-H, 2-H), 2.69–2.86 (m, 2 H, 4-H), 3.14 (m, 2 H, 1-H),
3.60–3.84 (m, 4 H, 3¢-H, 4¢-H), 4.78 (br, 1 H, NH), 7.33 (t, J = 7.8
Hz, 1 H, 5-H).
13C NMR (101 MHz, CDCl3): d = 25.2 (t, C-2 or C-3), 28.3 [q,
C(CH3)3], 29.4 (t, C-3 or C-2), 32.6 (t, C-4), 39.7 (t, C-1), 50.3 (t,
C-3¢ or C-4¢), 50.6 (t, C-4¢ or C-3¢), 79.0 [s, C(CH3)3], 155.0 (d, C-
5), 155.8 (s, C-2¢ or C = O), 156.8 (C=O or C-2¢).
found: 370.1152.
23b
[a]D20 +29 (c 1.1, CHCl3); Rf = 0.34 (CH2Cl2–MeOH, 10:1).
IR (KBr): 2928, 1694, 1662, 1423, 1262, 1042 cm–1 (S=O).
1H NMR (400 MHz, CDCl3): Rotamers, only selected signals are
given, d = 1.76–2.02 (m, 1 H), 3.58–3.65 (m, 1 H), 3.75–3.89 (m, 1
H), 3.90–4.24 (m, 1 H), 5.04–5.32 (m, 3 H), 7.24–7.44 (m, 5 Harom).
MS (FAB): m/z (%) = 370 (100, [M + H]+), 114 (91), 91 (64,
MS (FAB): m/z = 322 [M + H]+, 266.
HRMS-FAB: m/z calcd for C13H23NO4S2 [M + H]+: 322.1147;
[C7H7]+).
HRMS-FAB: m/z calcd for C17H23NO4S2: [M + H]+: 370.1147;
found: 370.1143.
found: 322.1144.
Benzyl (2S,2¢R,6¢R)- and (2R,2¢R,6¢R)-2-(1,3-Dioxo[1,3]dithi-
olan-2-yl)piperidine-1-carboxylate (22a,b)
Benzyl (S)-2-([1,3]Dithian-2-yl)piperidine-1-carboxylate (25a)
Compound 23a (1.13 g, 3.09 mmol) reacted according to GP 3
yielding 25a (900 mg, 87%) as a colorless oil; [a]D20 –26.5 (c 1.03,
CHCl3); Rf = 0.41 (hexane–EtOAc, 2:1).
Compound 16 (200 mg, 0.622 mmol) was dissolved in CH2Cl2 (10
mL). Deprotection (and concomitant addition) was performed at r.t.
by adding TFA (1 mL) followed by stirring at r.t. for 30–60 min
(monitoring with TLC). The solution was concentrated and traces of
TFA were removed by co-evaporation with CHCl3 (3 × 4 mL). H2O
(10 mL), Na2CO3 (1.3 g, 12.4 mmol), and Z-Cl (0.140 mL, 0.933
mmol) were added and the stirring was continued overnight at r.t.
The mixture (1H NMR: 22a/22b ~1:1) was extracted with CH2Cl2
(5 × 5 mL), dried (Na2SO4), and concentrated. The resulting oil was
purified by MPLC (CH2Cl2–MeOH, 50:1 → 20:1) to give 22 (137
mg, 62%). A pure fraction of one isomer was obtained, though its
configuration could not be assigned unambiguously.
IR (KBr): 2935, 1696 (C=O), 1423, 1255, 1169 cm–1.
1H NMR (500 MHz, 353 K, DMSO-d6): d = 1.30–1.40 (m, 1 H),
1.48–1.67 (m, 4 H), 1.71–1.80 (m, 1 H), 1.95–2.02 (m, 1 H), 2.05–
2.11 (m, 1 H), 2.72 (ddd, J = 2.8, 9.9, 14.0 Hz, 1 H), 2.79–2.89 (m,
4 H), 3.94 (dd, J = 4.3, 14.0 Hz, 1 H), 4.39 (br s, 1 H), 4.55 (d,
J = 10.9 Hz, 1 H), 5.10 (q, J = 12.7 Hz, 2 H, OCH2), 7.27–7.32 (m,
1 H, C6H5), 7.34–7.40 (m, 4 H, C6H5).
13C NMR (126 MHz, 353 K, DMSO-d6): d = 17.8, 24.1, 24.9, 25.0,
27.3, 27.4, 44.8, 52.5, 65.8, 126.9, 127.1, 127.8, 136.6, 154.2,
205.6.
22; First Isomer
Rf = 0.29 (CH2Cl2–acetone, 1:1).
MS (EI, 70 eV): m/z (%) = 337 (13, [M]+), 262, 218 (100, [M –
C4H7S2]+), 174, 119 [C4H7S2]+, 91 [C7H7]+.
1H NMR (400 MHz, acetone-d6): d = 1.44–1.56 (m, 1 H), 1.68–1.92
(m, 5 H), 3.06 (m, 1 H), 3.45 (m, 1 H), 3.52–3.92 (m, 3 H), 4.23 (br
t, 1 H), 4.58 (dd, J = 4.3, 12.5 Hz, 1 H), 4.80 (m, 1 H), 5.04–5.26
(m, 2 H), 7.30–7.44 (m, 5 H).
HRMS-EI: m/z calcd for C17H23NO2S2 [M]+: 337.1170; found:
337.1173.
13C NMR (101 MHz, acetone-d6): 2 Rotamers, d = 20.2 (20.3) (t),
26.8 (27.1) (t), 29.5 (29.7) (t), 41.8 (42.4) (t), 48.7 (48.9) (d), 52.7
(52.9) (t), 54.5 (54.5) (t), 68.6 (68.7) (t), 93.2 (93.4) (d), 129.5 (d),
129.7 (129.8) (d), 130.3 (d), 138.8 (139.0) (s), 156.0 (156.7) (s)
Benzyl (R)-2-([1,3]Dithian-2-yl)piperidine-1-carboxylate (25b)
Compound 23b (800 mg) reacted according to GP 3 yielding 25b
(564 mg, 77%) as a colorless oil; [a]D20 +25.6 (c 1.03, CHCl3).
Further spectroscopic data were in full agreement with those of
enantiomer 23a.
22; Second Isomer
Spectroscopic data from the mixture of isomers.
tert-Butyl 5-([1,3]Dithiolan-2-ylidene)pentylcarbamate (11)
Methyl N-tert-butyloxycarbonyl-6-aminohexanoate (4.56 g, 19.6
mmol) reacted according to GP 2 for 14 h at r.t. yielding after col-
umn chromatography (cyclohexane–EtOAc, 10:1) 11 as a colorless
oil (3.46 g, 61%), which was immediately oxidized in the next step;
Rf = 0.56 (cyclohexane–EtOAc, 2:1).
Rf = 0.19 (CH2Cl2–acetone, 1:1).
IR (KBr): 3485, 2937, 2242, 1691 (C=O), 1340, 1259, 1032 cm–1
(S=O).
MS (FAB): m/z (%) = 356 (100, [M + H]+), 91 (51, [C7H7]+).
HRMS-FAB: m/z calcd for C16H21NO4S2 [M + H]+: 356.0990;
found: 356.0994.
Synthesis 2008, No. 15, 2476–2487 © Thieme Stuttgart · New York

2486
T. Gehring et al.
FEATURE ARTICLE
(S)-2-([1,3]Dithian-2-yl)tetrahydropyran (24a)
combined organic layers were dried (Na2SO4), concentrated, dis-
solved in dioxane–H2O (10:1, 20 mL), treated with TsOH·H2O (812
mg, 4.27 mmol), and stirred for 3 h at 50 °C. After cooling to r.t.,
the solution was diluted with Et2O (30 mL) and washed successive-
ly with aq NaHCO3 (20 mL) and brine (20 mL). The organic layer
was dried (Na2SO4), filtered over Celite and concentrated. Purifica-
tion of the residue by chromatography over silica gel (cyclohexane–
EtOAc, 4:1) afforded aldehyde 27b (67 mg, 19%) as a colorless liq-
uid.
Compound 21a (998 mg) reacted according to GP 3 yielding 24a
20
(788 mg, 91%) as a colorless liquid; [a]D –0.6 (c 1.01, CHCl3);
Rf = 0.50 (hexanes–EtOAc, 2:1).
IR (KBr): 2936, 2845, 1090 (C–O), 1049 (C–O) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.54 (m, 4 H, H-3, H-4, H-5), 1.77
(d, J = 12.9 Hz, 1 H, H-3), 1.90 (m, 2 H, H-5¢, H-5), 2.11 (m, 1 H,
H-5¢), 2.88 (m, 4 H, H-4¢, H-6¢), 3.45 (dt, J = 2.1, 11.7 Hz, 1 H, H-
6), 3.51 (ddd, J = 2.0, 5.5, 10.8 Hz, 1 H, H-2), 4.06 (tdd, J = 1.7, 3.9,
6.2 Hz, 1 H, H-6), 4.19 (d, J = 5.5 Hz, 1 H, H-2¢).
13C NMR (500 MHz, CDCl3): d = 23.1 (t), 25.6 (t), 26.1 (t, C-5¢),
29.0 (t, C-3), 30.2 (t,), 30.3 (t), 52.7 (d, C-2¢), 69.0 (t, C-6), 79.5 (d,
C-2).
20
A specific optical rotation of 27a has been published: [a]D –30.5
(c 1.4, CHCl3).25
27b
[a]D20 +24.4 (c 0.86, CHCl3); Rf = 0.26 (hexane–EtOAc, 2:1).
MS (EI, 70 eV): m/z (%) = 204 (49, [M]+), 119 (74, [C4H7S2]+), 85
IR (KBr): 3450, 2943, 2860, 1730 (C=O), 1703 (C=O), 1422, 1253,
1046, 699 cm–1.
(100, [C5H9O]+).
HRMS-EI: m/z calcd for C9H16OS2 [M]+: 204.0643; found:
204.0641.
MS (EI, 70 eV): m/z (%) = 247 (<1, [M]+), 218 (46, [M – HCO]+),
174 (43), 91 (100, [C7H7]+).
HRMS-EI: m/z calcd for C14H17NO3 [M]+: 247.1208; found:
247.1205.
(R)-2-([1,3]Dithian-2-yl)tetrahydropyran (24b)
Compound 21b (540 mg) reacted according to GP 3 yielding 24b
(412 mg, 2.02 mmol, 88%) as a colorless liquid; [a]D20 +0.6 (c 1.01,
CHCl3).
Acknowledgment
Further spectroscopic data were in full agreement with those of the
enantiomer 24a.
We thank Pierre Keller and Oliver Geiseler for their help with the
laboratory work. This work was supported by the Stiftung der
Deutschen Wirtschaft (stipend for T.G.).
(R)-Tetrahydropyran-2-carbaldehyde (26b)
Finely ground Bi(NO3)3·5 H2O (196 mg, 0.403 mmol), BiCl3 (64
mg, 0.20 mmol), and H2O (73 mL) were added to a solution of 24b
(412 mg, 2.02 mmol) in anhyd benzene (20 mL) and the mixture
was stirred for 14 h at r.t (monitoring with TLC). The reaction was
quenched by the addition of H2O (10 mL) and the mixture was ex-
tracted with Et2O (5 × 20 mL). The combined organic layers were
dried (Na2SO4) and carefully concentrated (P ≥ 100 mbar). The re-
sulting colorless liquid was purified by bulb-to-bulb distillation
(60 °C/20 mbar, cooling the receiver with dry ice) to yield the high-
ly volatile, characteristically smelling aldehyde 26b (146 mg, 63%),
which contained traces of benzene. Portionwise addition of Eu(hfc)3
(19 mg) to 26b (15 mg) led to a baseline separation in the 1H NMR
spectra of the signal at d = 9.62 revealing an ee of 96%; [a]D20 +12.8
(c 1.11, CHCl3); Rf = 0.32 (hexane–EtOAc, 2:1).
References
(1) (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
(b) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877. (c) Guo, H.-C.; Ma, J.-A. Angew. Chem.
Int. Ed. 2006, 45, 354; Angew. Chem. 2006, 118, 362.
(d) Vicario, J. L.; Badía, D.; Carrillo, L. Synthesis 2007,
2065. (e) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rössle,
M. Synthesis 2007, 1279. (f) Tsogoeva, S. B. Eur. J. Org.
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Tetrahedron: Asymmetry 2007, 18, 299.
(2) For example: (a) Abbott, D. J.; Colonna, S.; Stirling, C. J. M.
J. Chem. Soc. D 1971, 471. (b) Tsuchihashi, G.-i.;
Mitamura, S.; Inoue, S.; Ogura, K. Tetrahedron Lett. 1973,
323. (c) Posner, G. H. In Asymmetric Synthesis.
IR (KBr): 3449, 2941, 2853, 1738 (C=O), 1208, 1095 (C–O), 1047
(C–O), 898, 733 cm–1.
Stereodifferentiating Addition Reactions, Part A, Vol. 2;
Morrison, J. D., Ed.; Academic Press: New York, 1983,
225. (d) Solladie, G.; Moine, G. J. Am. Chem. Soc. 1984,
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D.; Hehre, W. J. J. Am. Chem. Soc. 1986, 108, 7399.
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E.; He, C.-H.; Clardy, J. Tetrahedron 1986, 42, 2919.
(h) Yamazaki, T.; Ishikawa, N.; Iwatsubo, H.; Kitazume, T.
J. Chem. Soc., Chem. Commun. 1987, 1340. (i) Pyne, S. G.;
Bloem, P.; Chapman, S. L.; Dixon, C. E.; Griffith, R. J. Org.
Chem. 1990, 55, 1086. (j)Mandai, T.; Ueda, M.;Kashiwagi,
K.; Kawada, M.; Tsuji, J. Tetrahedron Lett. 1993, 34, 111.
(k) Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61, 1245.
(3) Bäckvall, J.-E. In Modern Oxidation Methods; Bäckvall,
J.-E., Ed.; Wiley-VCH: Weinheim, 2004, 193.
1H NMR (400 MHz, CDCl3): d = 1.40–1.66 (m, 4 H), 1.82–1.94 (m,
2 H), 3.54 (ddd, J = 2.3, 7.2, 12.4 Hz, 1 H), 3.83 (dd, J = 2.7, 11.0
Hz, 1 H), 4.07 (ddd, J = 2.6, 4.1, 11.6 Hz, 1 H), 9.62 (s, 1 H, CHO).
13C NMR (101 MHz, CDCl3): d = 22.5 (t), 25.5 (t), 26.2 (t), 68.2 (t),
81.5 (d, C-2), 201.9 (d, C-1¢).
GC-MS (EI, 70 eV): m/z (%) = 114 (<1, [M]+), 85 (100, [M –
HCO]+), 67 (28), 57 (27), 41 (44).
(S)-Tetrahydropyran-2-carbaldehyde (26a)
According to the procedure for the synthesis of 26b, compound 24a
(788 mg, 3.86 mmol) yielded 26a (330 mg, 75%) as a colorless liq-
uid; [a]D20 –13.0 (c 2.49, CHCl3).
Further spectroscopic data were in full agreement with those of
enantiomer 26b.
(4) (a) Mikołajczyk, M.; Drabowicz, J.; Kiełbasiński, P. Chiral
Sulfur Reagents; CRC Press: Boca Raton, 1997.
Benzyl (R)-2-Formylpiperidine-1-carboxylate (27b)
A solution of 25b (480 mg, 1.42 mmol) in MeOH–THF, (1:1, 20
mL) was treated with PhI(O2CCF3)2 (1.26 g, 2.84 mmol) at r.t and
stirred for 15 min. The reaction was quenched by the addition of aq
sat. NaHCO3 (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The
(b) Delouvrié, B.; Fensterbank, L.; Nájera, F.; Malacria, M.
Eur. J. Org. Chem. 2002, 3507. (c) See also: Fernández, I.;
Khiar, N. Chem. Rev. 2003, 103, 3651.
Synthesis 2008, No. 15, 2476–2487 © Thieme Stuttgart · New York

FEATURE ARTICLE
Intramolecular Michael-Type Additions to Vinyl Bissulfoxides
2487
(5) Aggarwal and co-workers investigated cycloadditions,
(17) Gröbel, B.-T.; Seebach, D. Synthesis 1977, 357.
epoxidations, and cyclopropanations of dithiane-derived
alkylidenebissulfoxides: (a) Aggarwal, V. K.; Drabowicz,
J.; Grainger, R. S.; Gültekin, Z.; Lightowler, M.; Spargo, P.
L. J. Org. Chem. 1995, 60, 4962. (b) Aggarwal, V. K.;
Gültekin, Z.; Grainger, R. S.; Adams, H.; Spargo, P. L.
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J.; Barrell, J. K.; Alexander, R. Org. Lett. 2002, 4, 1227.
(e) Aggarwal, V. K.; Roseblade, S.; Alexander, R. Org.
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(18) Taubinger, A. A.; Fenske, D.; Podlech, J. Synlett 2008, 539.
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J. Am. Chem. Soc. 1984, 106, 8188.
(20) Di Furia, F.; Modena, G.; Seraglia, R. Synthesis 1984, 325.
(21) For example: (a) Pandey, K. S.; Shriprakash Pandey, M.;
Rao, K. M.; Vaidyanathaswamy, R. Biosci. Biotechnol.
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Synthesis 2008, No. 15, 2476–2487 © Thieme Stuttgart · New York