Asymmetric tandem Michael-Aldol reactions between 3-cinnamoyloxazolidine-2- thiones and aldehydes

Article abstract of DOI:10.1002/chem.200501435

Reactions between chiral 3-cinnamoyl-4-methyl-5-phenyl-1,3-oxazolidine-2- thiones and aromatic aldehydes in the presence of BF₃·Et ₂O diastereoselectively produced tricyclic compounds incorporating a bridgehead carbon bound to four heteroatoms in high yields. Four stereocenters were induced during the reaction. The tricyclic products were transformed into propane-1,3-diols bearing three consecutive stereocenters by acid hydrolysis, S-methylation, and reductive removal of the chiral auxiliary.

Full text of DOI:10.1002/chem.200501435

DOI: 10.1002/chem.200501435
Asymmetric Tandem Michael-Aldol Reactions between
3-Cinnamoyloxazolidine-2-thiones and Aldehydes
Hironori Kinoshita,[a] Takashi Osamura,[a] Kazumi Mizuno,[a] Sayaka Kinoshita,[a]
Tatsunori Iwamura,[a] Shin-ichi Watanabe,[a] Tadashi Kataoka,*[a] Osamu Muraoka,[b] and
Genzoh Tanabe[b]
Abstract: Reactions between chiral 3-cinnamoyl-4-methyl-5-phenyl-1,3-oxazoli-
dine-2-thiones and aromatic aldehydes in the presence of BF3·Et2O diastereoselec-
tively produced tricyclic compounds incorporating a bridgehead carbon bound to
four heteroatoms in high yields.Four stereocenters were induced during the reac-
tion.The tricyclic products were transformed into propane-1,3-diols bearing three
consecutive stereocenters by acid hydrolysis, S-methylation, and reductive removal
of the chiral auxiliary.
Keywords: aldehydes · asymmetric
synthesis
·
oxazolidinethiones
·
sulfanylpropanediols
·
tandem
Michael-aldol reactions
Introduction
Results and Discussion
We have previously developed a chalcogenide/Lewis acid
mediated tandem Michael-aldol reaction, which produced
Morita–Baylis–Hillman adducts after treatment of the reac-
tion mixture with a base.[1] This reaction proceeded quickly,
so the main defect of the Morita–Baylis–Hillman reac-
tion[2]—its very slow reaction rate—was alleviated, so our
reaction can be utilized as an alternative to the Morita–
Baylis–Hillman reaction.During the course of our study we
found that a chalcogenide caused the intramolecular Mi-
chael addition in the presence of a Lewis acid[3] and that a
thioketone[4] or a thioamide[5] group worked as a catalyst.
On the other hand, it is well known that N-unsubstituted
thioamides undergo Michael additions with a,b-unsaturated
carbonyl compounds.[6] Michael additions of N-substituted
thiocarbamates, however, are scarcely known, though
Palomo and co-workers reported the sulfur-transfer reaction
of N-enoyl thiocarbamates with a Lewis acid followed by
hydrolysis of the products.[7]
We combined the above findings, the intramolecular Mi-
chael cyclization of the chalcogenide group and the catalytic
action of thioamides, and studied a new tandem Michael-
aldol reaction between N-cinnamoyl cyclic thiocarbamates
and aldehydes.[8] Herein we report the details of the reaction
and the transformation of the products into propane-1,3-
diols.Reactions between 3-cinnamoyl-1,3-thiazolidine-2-
thione (1) and p-chlorobenzaldehyde (2a) in the presence of
BF3·Et2O were examined first (Table 1).When two equiva-
lents of 1, one equivalent of 2a, and three equivalents of
BF3·Et2O were used, tricyclic compounds 3 and 4 were ob-
tained in yields of 58% and 31%, respectively.The struc-
1
tures of 3 and 4 were determined by comparison of their H
and 13C NMR spectral data with those for 6c and 7c shown
below.
We next applied this approach to asymmetric reactions
between (4S,5R)-4-methyl-5-phenyloxazolidine-2-thione
5
and aldehydes (Table 2).Treatment of 5 with 2a at À408C
for 24 h produced a mixture of diastereoisomers 6a, 7a, and
8a in the ratio of 86:7:7 (Table 2,entry 1).The p- and m-ni-
trobenzaldehydes 2b–c similarly produced the tricyclic com-
pounds 6b–c, 7b–c, and 8b–c in good yields and with high
diastereoselectivity (Table 2, entries 2 and 3).The reactions
with benzaldehyde (2d) and p-tolualdehyde (2e) were slow,
so the reaction temperature was raised to 08C.The yields,
however, were moderate and in the case of 2d the diastereo-
selectivity had decreased (Table 2, entries 4 and 5).
[a] Dr.H.Kinoshita, T.Osamura, K.Mizuno, S.Kinoshita,
Dr.T.Iwamura, Dr.S-.i.Watanabe, Prof.Dr.T.Kataoka
Gifu Pharmaceutical University
6–1 Mitahora-higashi 5-chome, Gifu 502–8585 (Japan)
Fax : (+81)58-237-5979
E-mail: kataoka@gifu-pu.ac.jp
[b] Prof.Dr.O.Muraoka, Dr.G.Tanabe
Faculty of Pharmaceutical Sciences, Kinki University
3–4–1 Kowakae, Higashi-Osaka 577–8502 (Japan)
3896
ꢀ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3896 – 3904

FULL PAPER
Table 1.Reactions between the N-enoylthiocarbamate 1 and the alde-
hyde 2a.
Entry
Enone
([equiv])
Aldehyde
([equiv])
Products
(yield [%])
G
G
ACHTREUNG
1
1 (2)
1 (2)
1 (1)
2a (1)
2a (1)
2a (1)
3 (58), 4 (31)
3 (50), 4 (33)
3 (48), 4 (30)
Figure 1.Structure of 6c (ORTEP drawing).
2[a]
3
[a] Two equivalents of BF3·Et2O were used.
The structurally rare compounds 6–8 were presumably
formed along the reaction pathways shown in Scheme 1.
BF3·Et2O coordinates with the carbonyl oxygen of the N-
Table 2.Reactions between N-cinnamoylthiocarbamate 5 and aldehydes
2a–e.
Entry
R
Conditions
Yield [%][a]
6:7:8
1
2
3
4
5
p-ClC6H4 (2a)
p-NO2C6H4 (2b)
m-NO2C6H4 (2c)
C6H5 (2d)
À408C, 24 h
À408C, 24 h
À408C, 24 h
08C, 1 h
71
93
85
69
59
86:7:7
95:5:0
95:5:0
71:0:29
92:0:8
Scheme 1.Reaction mechanism.
p-MeC6H4 (2e)
08C, 1 h
cinnamoylthiocarbamate 5, and the enone moiety is activat-
ed.The intramolecular Michael addition of the thione group
to the enone moiety proceeds via 9, and forms the boron
enolate-iminium salt 10.An aldol reaction between the
boron enolate moiety and an aldehyde yields the aldol prod-
uct 11, which intramolecularly cyclizes (i.e., its alkoxide ion
nucleophilically attacks the iminium carbon) to afford the
tricyclic products 6–8.
[a] Mixture of diastereomers.
The diastereomer ratios were determined from the signal
1
intensities in the H NMR spectra, and the structure of the
m-nitro derivative 6c was determined by X-ray analysis
(Figure 1), which showed that 6c was not a Morita–Baylis–
Hillman adduct, but an unexpected tricyclic compound in-
corporating a bridgehead carbon bound to four heteroa-
toms.
The newly induced stereocenters were assigned as 1R, 7R,
8R, and 11R on the basis of the 3R and 4S absolute configu-
rations.The m-nitrophenyl group of 6c is located on the
À
À
According to high-resolution mass-spectral data, product
8 had the same molecular formula as products 6 and 7.Its
1H and 13C NMR spectra indicated that compound 8 had a
tricyclic structure and was a diastereomer of 6 and 7, but its
stereostructure could not be determined because of its small
amount.
same side of the SCHPh moiety.The phenyl groups at
the 3- and 11-positions (3-Ph and 11-Ph) and 4-Me adopt
the endo configuration.The stereostructure of the diaster-
eomer 7c was determined by its 1H NMR spectrum and
NOE enhancement data through comparison with those of
6c and the isopropyl derivative 12,[8] the structure of which
Chem. Eur. J. 2006, 12, 3896 – 3904
ꢀ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
3897

T.Kataoka et al.
had been assigned by X-ray
crystallography.The signals of
7c due to 3-H, 4-H, and 4-Me
appeared at d = 5.98, 4.70, and
1.09 ppm, respectively, close to
those of 6c at d = 5.83 (3-H),
4.72 (4-H), and 1.14 ppm (4-
À
Me), indicating that the O
À
CH(Ph) CH(Me) moiety in the
oxazolidine ring has a configu-
ration similar to that of 6c.The
11-H signal of 7c at
d =
5.21 ppm was similar to that of
12 at d = 5.15 ppm, but differ-
ent from that of 6c at d = 4.34.
This large downfield shift im-
plies that 11-H of 7c was not
affected by the anisotropic
effect of the m-nitrophenyl
group and that the aryl ring was
situated on the same side of the
À À
À
N CO
moiety.NOE en-
hancement in 7c was observed
between 7-H and 8-H (7%), 7-
H and 11-H (9%), and 8-H and
11-H (15%) and was very simi-
lar to that of 12, shown in
Figure 2.
Scheme 2.Cyclic model.
Figure 2.NOE data for tricyclic compounds 7c and 12.
It became apparent that the tandem Michael-aldol reac-
tions between the (4S,5R)-4-methyl-5-phenyloxazolidine-2-
thione 5 and aldehydes simultaneously induced four chiral
stereocenters and diastereoselectively afforded novel tricy-
clic compounds 6, incorporating a bridgehead carbon bound
to four heteroatoms, in high yields.
Scheme 3.Acyclic model.
The reaction mechanism for the formation of tricyclic
compounds 6 and 7 is discussed from the viewpoints of the
cyclic transition state and the acyclic one, shown in
Scheme 2 and Scheme 3, respectively.The boron enolate-
iminium salt 10 formed through the cyclization of 5 with
BF3·Et2O (Scheme 1) consists of two diastereomers, 10A
and 10B; the former has the anti configuration between the
phenyl group a to the sulfur atom and the methyl and the
phenyl groups of the oxazolidine ring, whilst the latter has
the syn configuration between them.The approach of an al-
dehyde from the Si- and the Re-faces to the boron enolate
moiety is hindered by the methyl and phenyl groups of the
oxazolidine ring and the phenyl group a to the sulfur in
isomer 10A.If the reaction were to proceed via 10A, the
chiral carbon a to the sulfur of the product should have an
(S) configuration, but it actually had the (R) configuration.
Therefore, this pathway via intermediate 10A does not
appear to be productive.
3898
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3896 – 3904

Asymmetric Tandem Michael-Aldol Reactions
FULL PAPER
On the other hand, isomer 10B has three substituents on
the Si-face, and an aldehyde can easily attack the enolate
carbon from the sterically relaxed Re-face.If the reaction
between 10B and an aldehyde were to proceed via the
cyclic chelation mechanism, the two transition states shown
in Scheme 2 should be considered for the aldol reaction
step.The transition state 13B, bearing an equatorial R
group, should be more stable than the transition state 13A,
bearing an axial R group.The reaction via 13B should form
the aldol product 11B, which should afford the tricyclic
product 7.This is inconsistent with the finding that com-
pound 7 is not the major product but the minor one.
To solve this contradiction, we discuss other pathways
going through the acyclic transition states shown in
Scheme 3.
The two transition states 14A and 14B are important for
controlling the stereoselection in the aldol reaction.The
transition state 14A should be more stable than 14B, which
should have steric repulsion between the iminium moiety
and the R group.The pathway via 14A should produce the
aldol adduct 11A, which should cyclize to product 6.This
mechanism is consistent with the finding that product 6 is
the major product.From the above discussion, it is conclud-
ed that these tandem Michael-aldol reactions between 5 and
aldehydes proceed via the boron–enolate–iminium salts 10B
and acyclic transition states 14A.
Scheme 5.Attempted transformations of the tricyclic compounds.
noyl)oxazolidines 20a (78%) and 20b (72%) through the
À
The reaction between the N-enoylthiocarbamate 15, the
enantiomer of 5, and p-nitrobenzaldehyde (2b) produced
the tricyclic products 16 (86%) and 17 (5%), enantiomers
of 6b and 7b, respectively (Scheme 4).
selective C S bond cleavage of the six-membered ring.The
methylation of a sulfanyl group with methyl iodide and trie-
thylamine converted 20a,b into 21a,b in high yields.The
transformation of the amide 21a into a thioester was at-
tempted by treatment with lithium ethanethiolate, producing
the S-ethyl 3-methylsulfanyl-3-phenylpropanethioate 22
(55%), the oxazolidinone 23 (59%), and p-chlorobenzalde-
hyde (2a; 40%).
The thioester 22 was formed through the retro-tandem
Michael-aldol reaction of 21a, followed by transformation
of the amide moiety into a thioester and the Michael addi-
tion of the ethanethiolate ion to the enone moiety.
The reductive removal of a chiral auxiliary 23 from 21a
was conducted with LiBH4, affording the propanol 24
(44%), the oxazolidinone 23 (100%), and the benzyl alco-
hol 25 (36%), which were formed by the reduction of the
retro-aldol products.
These results indicated that the presence of the free hy-
droxy group in 21a was causing the retro-aldol reaction
upon treatment with a basic reagent.We therefore protected
the hydroxy group with a silyl group to prevent it from un-
dergoing the retro-aldol reaction and to achieve smooth re-
moval of the auxiliary 23.Silylation of 21a with trimethylsil-
yl chloride produced the silyl ether 26 in 91% yield, and the
reduction of 26 with LiBH4 brought about the oxazolidine
ring opening to give the amide 27 in a quantitative yield
(Table 3, entry 1).Treatment with sodium ethanethiolate
(Table 3, entry 2) or sodium methoxide (Table 3, entry 3)
gave the same product 27 in 35% or 83% yields, respective-
ly.Protection of the hydroxy group prevented 21a from un-
dergoing the retro-aldol reaction, but the bulky trimethylsil-
Scheme 4.Reaction between 15 (the enantiomer of 5) and aldehyde 2b.
We next examined the removal of the chiral auxiliary
from the tricyclic compounds, as shown in Scheme 5.Alka-
line hydrolysis of the thiazolidine compound 4 did not take
place, and 4 was recovered.Acidic hydrolysis of 4 was then
conducted with HCl (2m) at 1008C for 3 h and produced
À
products 18 (21%) and 19 (52%).Since two C S bonds
were cleaved and the desired product 18 was a minor one,
the oxazolidine derivatives 6a,b were employed instead at
room temperature for 5 h, affording the N-(3-sulfanylpropa-
Chem. Eur. J. 2006, 12, 3896 – 3904
ꢀ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
3899

T.Kataoka et al.
Table 3.Transformation of O-TMS aldol 26.
EX-400 (400 MHz) spectrometers with
tetramethylsilane as an internal stand-
ard. 13C NMR spectra were obtained
on
a JEOL EX-400 spectrometer.
Mass spectra were recorded on
a
JEOL JMS-SX102 A spectrometer
with a direct-insertion probe at 70 eV.
Elemental analyses of new compounds
were performed with a Yanaco CHN
Corder MT-5.All chromatographic
isolations were carried out with BW-
350 (Fuji Silysia) for column chroma-
tography or with Kieselgel 60 PF254
containing gypsum (Merck) for prepa-
rative TLC.CH 2Cl2 was washed with
Entry
Reagents (equiv)
Solvent
Conditions
Yield [%]
1
2
3
LiBH4 (1.1)
EtSH (1.1), NaH (0.25)
MeONa (1.1)
dry THF
dry THF
dry CH2Cl2
RT, 4 h
100
35
83
08C add, RT, 50 min
À258C, 8 min
yl group interfered with the attack of a nucleophile on the
exo-carbonyl group, the nucleophile exclusively attacking
the endo-carbonyl group.
water, dried over CaCl2, and freshly distilled.The recycling preparative
HPLC was performed by LC-918 liquid chromatography (Japan Analyti-
cal Industry Co., Ltd.) on JAIGEL-1H and -2H columns (polystyrene
gels).
We therefore sought means to remove the chiral auxilia-
ries from 21a,b without protecting the hydroxy group, and
succeeded in the reductive removal of the oxazolidinone
moiety by use of sodium borohydride in aqueous THF[9] to
give propanediols 28a,b and the oxazolidinone 23
(Scheme 6).The recovered oxazolidinone 23 can be convert-
ed into the oxazolidinethione by treatment with Lawessonꢁs
reagent and is reusable for the synthesis of the N-enoyloxa-
zolidinethiones.[7]
Reaction between N-enoylthiocarbamate 1 and p-chlorobenzaldehyde
(2a): BF3·Et2O (190 mL, 1.5 mmol) was added dropwise at 08C to a stir-
red solution of 3-((E)-cinnamoyl)-1,3-thiazolidine-2-thione[10] (1, 249 mg,
1.0 mmol) and 2a (70 mg, 0.5 mmol) in dry CH2Cl2 (1.5 mL). The mixture
was stirred at the same temperature for 15 min, poured into an aqueous
NaHCO3 solution, and extracted with CH2Cl2.The organic layers were
dried (MgSO4) and concentrated in vacuo.Purification of the residue by
preparative TLC with elution with CH2Cl2/AcOEt 50:1 furnished
3
(113 mg, 58%) and 4 (60 mg, 31%).
(1R*,7R*,8R*,11R*)-8-(4-Chlorophenyl)-11-phenyl-9-oxa-2,10-dithia-5-
azatricyclo[5.2.2.01.5]undecan-6-one (3): Colorless prisms (from CH2Cl2/
hexane); m.p. 220.5–221.08C (dec); 1H NMR (400 MHz, CDCl3): d
3.23–3.29 (m, 1H; 3-H), 3.25 (t, J = 2.5 Hz, 1H; 7-H), 3.38–3.45 (m, 1H;
3-H), 4.00–4.06 (m, 1H; 4-H), 4.40–4.45 (m. 1H; 4-H), 4.43 (d, J
=
=
3.4 Hz, 1H; 11-H), 5.39 (d, J = 2.5 Hz, 1H; 8-H), 7.15 (d, J = 8.3 Hz,
2H; ArH), 7.21–7.30 (m, 3H; ArH), 7.44 (d, J = 8.8 Hz, 2H; ArH),
7.52 ppm (d, J = 8.8 Hz, 2H; ArH); 13C NMR (100 MHz, CDCl3): d =
30.3 (t), 45.2 (d), 47.5 (t), 52.9 (d), 77.8 (d), 104.4 (s), 127.1 (d), 127.9 (d),
128.2 (d), 128.7 (d), 129.0 (d), 134.4 (s), 134.9 (s), 138.6 (s), 166.6 ppm (s),
four aromatic carbons were overlapped; IR (KBr): n˜ = 1682 cmÀ1 (C=
O); MS (EI): m/z (%): 389 (15) [M]+, 165 (100); elemental analysis calcd
(%) for C19H16ClNO2S2: C 58.53, H 4.14, N 3.59; found: C 58.35, H 4.07,
N 3.61.
Scheme 6.Synthesis of propanediols 28a and 28b and recovery of the
chiral auxiliary 23.
Conclusions
(1R*,7R*,8S*,11R*)-8-(4-Chlorophenyl)-11-phenyl-9-oxa-2,10-dithia-5-
azatricyclo[5.2.2.01.5]undecan-6-one (4): Colorless prisms (from CH2Cl2/
hexane); m.p. 188.0–192.08C (decomp); 1H NMR (400 MHz, CDCl3): d
= 3.28–3.36 (m, 1H; 3-H), 3.33 (d, J = 3.5 Hz, 1H; 7-H), 3.39–3.46 (m,
1H; 3-H), 4.03–4.07 (m, 1H; 4-H), 4.32–4.38 (m. 1H; 4-H), 5.09 (d, J =
3.5 Hz, 1H; 11-H), 5.45 (s, 1H; 8-H), 7.20 (d, J = 7.0 Hz, 2H; ArH),
7.22–7.38 ppm (m, 7H; ArH); 13C NMR (100 MHz, CDCl3): d = 30.3 (t),
47.6 (t), 52.5 (d), 54.2 (d), 80.2 (d), 103.9 (s), 127.1 (d), 127.8 (d), 128.3
(d), 128.9 (d), 129.0 (d), 134.5 (s), 137.3 (s), 138.6 (s), 164.0 ppm (s), four
aromatic carbons were overlapped; IR (KBr): n˜ = 1682 cmÀ1 (C=O); MS
(EI): m/z (%): 389 (20) [M]+, 165 (100); elemental analysis calcd (%) for
C19H16ClNO2S2: C 58.53, H 4.14, N 3.59; found: C 58.36, H 4.22, N 3.59.
In conclusion, we have developed asymmetric tandem Mi-
chael-aldol reactions between N-enoylthiocarbamates and
aldehydes, which simultaneously induced four stereocenters,
giving tricyclic compounds incorporating
a bridgehead
carbon bound to four heteroatoms.The tricyclic compounds
were converted into propanediols bearing three consecutive
chiral centers 28, accompanied in each case by the oxazolidi-
none chiral auxiliary, by a sequence of reactions involving
hydrolysis, S-methylation, and reduction.Investigations into
the transformation of 23 into other derivatives and the uti-
lization of the chiral thiols 20 and propanediols 28 are now
in progress.
AHCTREUNG
a
(3.9 g, 20 mmol) and cinnamoyl chloride (3.67 g, 22 mmol) in benzene
(25 mL).The reaction mixture was stirred at room temperature for 23 h
and then poured into water.The organic layer was separated and the
aqueous layer was extracted with AcOEt.The organic layer and the ex-
tracts were combined, washed successively with 2% hydrochloric acid,
water, and saturated aqueous NaHCO3, dried (MgSO4), and concentrated
in vacuo.The residue was purified by column chromatography on silica
gel (hexane/AcOEt 3:1) to give 5 (6.3 g, 97%). Yellow crystals (from
AcOEt/hexane); m.p. 82.0–82.58C; [a]2D4 = À247.7 (c = 1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d = 1.03 (d, J = 6.8 Hz, 3H; Me), 5.04
(quintet, J = 6.8 Hz, 1H; 4’-H), 5.83 (d, J = 6.8 Hz, 1H; 5’-H), 7.26–7.46
Experimental Section
Melting points were obtained with a Yanagimoto micro-melting-point ap-
paratus and are uncorrected.IR spectra of solids (KBr) and liquids
(NaCl) were recorded on
a JASCO IRA-100 spectrophotometer.
1H NMR spectra were recorded on JEOL GX-270 (270 MHz) or JEOL
3900
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3896 – 3904

Asymmetric Tandem Michael-Aldol Reactions
FULL PAPER
(m, 8H; ArH), 7.57–7.63 (m, 2H; ArH), 7.78 (d, J = 15.6 Hz, 1H; 3-H),
8.41 ppm (d, J = 15.6 Hz, 1H; 2-H); 13C NMR (100 MHz, CDCl3): d =
14.2 (q), 59.2 (d), 83.6 (d), 118.8 (d), 125.8 (d), 128.5 (d), 128.6 (d), 128.8
(d), 128.9 (d), 130.5 (d), 132.4 (s), 134.6 (s), 145.1 (d), 166.2 (s),
(s), 138.2 (s), 144.2 (s), 148.1 (s), 164.5 ppm (s), six aromatic carbons
were overlapped; IR (KBr): n˜ = 1701 (C=O), 1522 (NO2), 1347 cmÀ1
(NO2); MS (EI): m/z (%): 474 (45) [M]+, 122 (100); elemental analysis
calcd (%) for C26H22N2O5S: C 65.81, H 4.67, N 5.90; found: C 65.58, H
4.58, N 5.86.
185.4 ppm (s), four aromatic carbons were overlapped; IR (KBr): n˜
=
1676 cmÀ1 (C=O); MS (EI): m/z (%): 323 (8) [M]+, 157 (100); elemental
analysis calcd (%) for C19H17NO2S: C 70.56, H 5.30, N 4.33; found: C
70.66, H 5.28, N 4.28.
(1R,3R,4S,7R,8S,11R)-4-Methyl-8-(4-nitrophenyl)-3,11-diphenyl-2,9-
dioxa-10-thia-5-azatricyclo[5.2.2.01.5]undecan-6-one (7b): Colorless plates
(from CH2Cl2/hexane); m.p. 203.5–205.08C; [a]2D4 = +11.1 (c = 0.25 in
1
A typical reaction between N-enoylthiocarbamate 5 and an aldehyde 2:
BF3·Et2O (190 mL, 1.5 mmol) was added dropwise at À408C to a stirred
solution of 5 (323 mg, 1.0 mmol) and p-nitrobenzaldehyde (2b, 76 mg,
0.5 mmol) in dry CH2Cl2 (1.6 mL). The mixture was stirred at the same
temperature for 24 h, poured into a saturated aqueous NaHCO3 solution,
and extracted with CH2Cl2.The organic layers were dried (MgSO 4) and
concentrated in vacuo.Purification of the residue by the recycling prepa-
rative HPLC with elution with chloroform furnished 6b (209 mg, 88%)
and 7b (13 mg, 5%).
CHCl3); H NMR (400 MHz, CDCl3): d = 1.09 (d, J = 6.3 Hz, 3H; Me),
3.41 (d, J = 3.7 Hz, 1H; 7-H), 4.68 (quintet, J = 6.3 Hz, 1H; 4-H), 5.20
(d, J = 3.7 Hz, 1H; 11-H), 5.59 (s, 1H; 8-H), 5.92 (d, J = 6.3 Hz, 1H; 3-
H), 7.26–7.48 (m, 10H; ArH), 7.52 (d, J = 8.8 Hz, 2H; ArH), 8.25 ppm
(d, J = 8.8 Hz, 2H; ArH); 13C NMR (100 MHz, CDCl3): d = 14.8 (q),
50.3 (d), 54.3 (d), 54.6 (d), 77.0 (d), 85.1 (d), 113.8 (s), 124.1 (d), 126.2
(d), 126.6 (d), 127.8 (d), 128.6 (d), 128.7 (d), 128.8 (d), 128.9 (d), 133.6
(s), 138.2 (s), 145.7 (s), 148.0 (s), 162.2 ppm (s), six aromatic carbons
overlapped; IR (KBr): n˜ = 1692 (C=O), 1524 (NO2), 1344 cmÀ1 (NO2);
MS (EI): m/z (%): 474 (43) [M]+, 122 (100); elemental analysis calcd
(%) for C26H22N2O5S: C 65.81, H 4.67, N 5.90; found: C 65.65, H 4.60, N
5.79.
(1R,3R,4S,7R,8R,11R)-8-(4-Chlorophenyl)-4-methyl-3,11-diphenyl-2,9-
dioxa-10-thia-5-azatricyclo[5.2.2.01.5]undecan-6-one (6a): Colorless prisms
(from AcOEt/hexane); m.p. 85.0–87.08C; [a]D24
=
À24.8 (c
= 1.0 in
1
CHCl3); H NMR (400 MHz, CDCl3): d = 1.13 (d, J = 6.5 Hz, 3H; Me),
3.24 (t, J = 2.5 Hz, 1H; 7-H), 4.45 (d, J = 2.5 Hz, 1H; 11-H), 4.70 (quin-
tet, J = 6.5 Hz, 1H; 4-H), 5.40 (d, J = 2.5 Hz, 1H; 8-H), 5.80 (d, J =
6.5 Hz, 1H; 3-H), 7.20–7.29 (m, 4H; ArH), 7.36–7.47 (m, 8H; ArH),
7.58 ppm (d, J = 8.3 Hz, 2H; ArH); 13C NMR (100 MHz, CDCl3): d =
14.4 (q), 43.3 (d), 53.7 (d), 54.3 (d), 76.4 (d), 84.6 (d), 113.8 (s), 126.0 (d),
126.9 (d), 127.8 (d), 128.1 (d), 128.46 (d), 128.54 (d), 128.6 (d), 129.0 (d),
133.7 (s), 134.2 (s), 135.2 (s), 138.5 (s), 164.9 ppm (s), six aromatic car-
bons were overlapped; IR (KBr): n˜ = 1702 cmÀ1 (C=O); MS (EI): m/z
(%): 463 (32) [M]+, 191 (100); elemental analysis calcd (%) for
C26H22ClNO3S: C 67.30, H 4.78, N 3.02; found: C 67.04, H 4.62, N 3.00.
(1R,3R,4S,7R,8R,11R)-4-Methyl-8-(3-nitrophenyl)-3,11-diphenyl-2,9-
dioxa-10-thia-5-azatricyclo[5.2.2.01.5]undecan-6-one (6c): Colorless prisms
(from CH2Cl2/hexane); m.p. 195.0–195.58C; [a]2D0 = À35.7 (c = 1.0 in
1
CHCl3); H NMR (400 MHz, CDCl3): d = 1.14 (d, J = 6.3 Hz, 3H; Me),
3.36 (t, J = 2.8 Hz, 1H; 7-H), 4.34 (d, J = 2.8 Hz, 1H; 11-H), 4.72 (quin-
tet, J = 6.3 Hz, 1H; 4-H), 5.51 (d, J = 2.8 Hz, 1H; 8-H), 5.83 (d, J =
6.3 Hz, 1H; 3-H), 7.21–7.30 (m, 5H; ArH), 7.40–7.47 (m, 5H; ArH), 7.70
(t, J = 8.1 Hz, 1H; ArH), 8.00 (d, J = 8.1 Hz, 1H; ArH), 8.30 (d, J =
8.1 Hz, 1H; ArH), 8.56 ppm (s, 1H, ArH); 13C NMR (100 MHz, CDCl3):
d = 14.5 (q), 43.6 (d), 53.4 (d), 54.5 (d), 76.1 (d), 84.9 (d), 114.0 (s), 120.9
(d), 123.6 (d), 126.1 (d), 127.8 (d), 128.4 (d), 128.6 (d), 128.7 (d), 128.8
(d), 130.0 (d), 131.6 (s), 133.6 (s), 138.2 (s), 139.3 (s), 148.7 (s), 164.5 ppm
(s), four aromatic carbons were overlapped; IR (KBr) n˜ = 1705 (C=O),
1532 (NO2), 1349 cmÀ1 (NO2); MS (EI): m/z (%): 474 (12) [M]+, 122
(100); elemental analysis calcd (%) for C26H22N2O5S: C 65.81, H 4.67, N
5.90; found: C 65.66, H 4.60, N 5.90.
(1R,3R,4S,7R,8S,11R)-8-(4-Chlorophenyl)-4-methyl-3,11-diphenyl-2,9-
dioxa-10-thia-5-azatricyclo[5.2.2.01.5]undecan-6-one (7a): White powder;
1
m.p. 55.0–55.58C; [a]2D3 = À20.0 (c = 1.0 in CHCl3); H NMR (400 MHz,
CDCl3): d = 1.07 (d, J = 6.5 Hz, 3H; Me), 3.35 (d, J = 3.4 Hz, 1H; 7-
H), 4.66 (quintet, J = 6.5 Hz, 1H; 4-H), 5.15 (d, J = 3.4 Hz, 1H; 11-H),
5.44 (s, 1H; 8-H), 5.88 (d, J = 6.5 Hz, 1H; 3-H), 7.23–7.45 ppm (m, 14H;
ArH); 13C NMR (100 MHz, CDCl3): d = 14.8 (q), 50.3 (d), 54.1 (d), 54.7
(d), 77.4 (d), 84.9 (d), 113.6 (s), 126.2 (d), 127.0 (d), 127.7 (d), 128.3 (d),
128.57 (d), 128.65 (d), 128.8 (d), 129.0 (d), 133.8 (s), 134.4 (s), 137.3 (s),
138.5 (s), 162.7 ppm (s), six aromatic carbons were overlapped; IR
(KBr): n˜ = 1695 cmÀ1 (C=O); MS (EI): m/z (%): 463 (53) [M]+, 191
(100); elemental analysis calcd (%) for C26H22ClNO3S: C 67.30, H 4.78,
N 3.02; found: C 67.07, H 4.66, N 3.13.
(1R,3R,4S,7R,8S,11R)-4-Methyl-8-(3-nitrophenyl)-3,11-diphenyl-2,9-
dioxa-10-thia-5-azatricyclo[5.2.2.01.5]undecan-6-one (7c): Colorless prisms
(from CH2Cl2/hexane); m.p. 201.5–202.08C; [a]2D0 = À11.1 (c = 1.0 in
1
CHCl3); H NMR (400 MHz, CDCl3): d = 1.09 (d, J = 6.5 Hz, 3H; Me),
3.41 (d, J = 3.4 Hz, 1H; 7-H), 4.70 (quintet, J = 6.5 Hz, 1H; 4-H), 5.21
(d, J = 3.4 Hz, 1H; 11-H), 5.61 (s, 1H; 8-H), 5.98 (d, J = 6.5 Hz, 1H; 3-
H), 7.26–7.47 (m, 10H; ArH), 7.58 (t, J = 8.1 Hz, 1H; ArH), 7.66 (d, J
= 8.1 Hz, 1H; ArH), 8.20 (d, J = 8.1 Hz, 1H; ArH), 8.24 ppm (s, 1 Hz,
1H; ArH); 13C NMR (100 MHz, CDCl3): d = 14.8 (q), 50.0 (d), 54.3 (d),
54.9 (d), 76.8 (d), 85.2 (d), 113.8 (s), 120.8 (d), 123.5 (d), 126.2 (d), 127.8
(d), 128.5 (d), 128.6 (d), 128.8 (d), 128.9 (d), 130.0 (d), 131.4 (d), 133.6
(s), 138.3 (s), 141.1 (s), 148.5 (s), 162.2 ppm (s), four aromatic carbons
were overlapped; IR (KBr): n˜ = 1646 (C=O), 1530 (NO2), 1344 cmÀ1
(NO2); MS (EI): m/z (%): 474 (10) [M]+, 456 (100); elemental analysis
calcd (%) for C26H22N2O5S: C 65.81, H 4.67, N 5.90; found: C 65.63, H
4.68, N 5.94.
Product of undetermined structure (8a): White powder; m.p. 158.0–
159.08C; [a]2D0
=
À252.1 (c
=
1.0 in CHCl3); 1H NMR (400 MHz,
CDCl3): d = 0.70 (d, J = 6.6 Hz, 3H; Me), 3.89 (quintet, J = 6.6 Hz,
1H; 4-H), 4.54 (d, J = 6.6 Hz, 1H; 3-H), 5.09 (d, J = 10.3 Hz, 1H; 11-
H), 5.20 (dd, J = 8.3 and 10.3 Hz, 1H; 7-H), 5.75 (d, J = 8.3 Hz, 1H; 8-
H), 7.09 (d, J = 7.3 Hz, 2H; ArH), 7.31–7.42 (m, 8H; ArH), 7.61 (d, J =
7.8 Hz, 2H; ArH), 7.66 ppm (d, J
=
7.8 Hz, 2H; ArH); 13C NMR
(100 MHz, CDCl3): d = 14.4 (q), 40.0 (d), 41.0 (d), 55.1 (d), 57.6 (d),
79.5 (d), 125.4 (d), 128.3 (d), 128.6 (d), 128.8 (d), 128.9 (d), 129.2 (d),
132.6 (s), 133.5 (s), 140.3 (s), 140.7 (s), 152.1 (s), 168.9 ppm (s), eight aro-
matic carbons are overlapped; IR (KBr): n˜ = 1698 cmÀ1 (C=O); MS
(EI): m/z (%): 463 (73) [M]+, 191 (100); elemental analysis calcd (%) for
C26H22ClNO3S: C 67.30, H 4.78, N 3.02; found: C 67.30, H 4.85, N 3.14.
(1R,3R,4S,7R,8R,11R)-4-Methyl-3,8,11-triphenyl-2,9-dioxa-10-thia-5-aza-
tricyclo[5.2.2.01.5]undecan-6-one (6d): White powder; m.p. 92.0–93.08C;
1
[a]2D4 = À21.0 (c = 1.0 in CHCl3); H NMR (400 MHz, CDCl3): d = 1.14
(d, J = 6.3 Hz, 3H; Me), 3.28 (t, J = 2.4 Hz, 1H; 7-H), 4.50 (d, J =
2.4 Hz, 1H; 11-H), 4.71 (quintet, J = 6.3 Hz, 1H; 4-H), 5.45 (d, J =
2.4 Hz, 1H; 8-H), 5.81 (d, J = 6.3 Hz, 1H; 3-H), 7.20–7.29 (m, 6H;
ArH), 7.36–7.50 (m, 7H; ArH), 7.64 ppm (d, J = 7.8 Hz, 2H; ArH);
13C NMR (100 MHz, CDCl3): d = 14.5 (q), 43.4 (d), 54.0 (d), 54.4 (d),
77.1 (d), 84.6 (d), 114.0 (s), 125.6 (d), 126.2 (d), 127.9 (d), 128.1 (d), 128.4
(d), 128.55 (d), 128.59 (d), 128.7 (d), 128.8 (d), 133.9 (s), 136.7 (s), 138.9
(s), 165.4 ppm (s), six aromatic carbons were overlapped; IR (KBr): n˜ =
1702 cmÀ1 (C=O); MS (EI): m/z (%): 429 (55) [M]+, 157 (100); elemental
analysis calcd (%) for C26H23NO3S: C 72.70, H 5.40, N 3.26; found: C
72.85, H 5.48, N 3.14.
(1R,3R,4S,7R,8R,11R)-4-Methyl-8-(4-nitrophenyl)-3,11-diphenyl-2,9-
dioxa-10-thia-5-azatricyclo[5.2.2.01.5]undecan-6-one
(6b):
Colorless
prisms (from acetone/hexane); m.p. 208.0–208.58C; [a]2D0 = À46.5 (c =
1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.15 (d, J = 6.3 Hz,
3H; Me), 3.34 (t, J = 2.7 Hz, 1H; 7-H), 4.35 (d, J = 2.7 Hz, 1H; 11-H),
4.72 (quintet, J = 6.3 Hz, 1H; 4-H), 5.51 (d, J = 2.7 Hz, 1H; 8-H), 5.83
(d, J = 6.3 Hz, 1H; 3-H), 7.20–7.25 (m, 2H; ArH), 7.27–7.31 (m, 2H;
ArH), 7.38–7.47 (m, 6H; ArH), 7.86 (d, J = 8.8 Hz, 2H; ArH), 8.36 ppm
(d, J = 8.8 Hz, 2H; ArH); 13C NMR (100 MHz, CDCl3): d = 14.5 (q),
43.6 (d), 53.4 (d), 54.5 (d), 76.3 (d), 84.9 (d), 113.9 (s), 124.1 (d), 126.1
(d), 126.7 (d), 127.8 (d), 128.4 (d), 128.6 (d), 128.7 (d), 128.8 (d), 133.6
Product of undetermined structure (8d): White solid (from AcOEt/
hexane); m.p. 147.0–150.08C; [a]D24
=
À209.2 (c
=
1.0 in CHCl3);
Chem. Eur. J. 2006, 12, 3896 – 3904
ꢀ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
3901

T.Kataoka et al.
1H NMR (400 MHz, CDCl3): d = 0.69 (d, J = 6.8 Hz, 3H; Me), 3.90
(quintet, J = 6.8 Hz, 1H; 4-H), 4.53 (d, J = 6.8 Hz, 1H; 3-H), 5.11 (d,
J = 10.3 Hz, 1H; 11-H), 5.28 (dd, J = 8.0 and 10.3 Hz, 1H; 7-H), 5.79
(d, J = 8.0 Hz, 1H; 8-H), 7.10 (d, J = 7.3 Hz, 2H; ArH), 7.28–7.42 (m,
9H; ArH), 7.67 (d, J = 7.3 Hz, 2H; ArH), 7.68 ppm (d, J = 7.8 Hz, 2H;
ArH); 13C NMR (100 MHz, CDCl3): d = 14.4 (q), 40.6 (d), 41.0 (d), 55.1
(d), 57.5 (d), 79.4 (d), 125.4 (d), 127.7 (d), 127.8 (d), 128.2 (d), 128.4 (d),
128.54 (d), 128.59 (d), 128.63 (d), 128.7 (d), 132.7 (s), 140.5 (s), 142.2 (s),
152.1 (s), 169.0 ppm (s), six aromatic carbons are overlapped; IR (KBr):
n˜ = 1695 cmÀ1 (C=O); MS (EI): m/z (%): 429 (13) [M]+, 131 (100); ele-
mental analysis calcd (%) for C26H23NO3S: C 72.70, H 5.40, N 3.26;
found: C 72.50, H 5.35, N 3.11.
126.1 (d), 126.7 (d), 127.8 (d), 128.4 (d), 128.6 (d), 128.7 (d), 128.8 (d),
133.6 (s), 138.2 (s), 144.2 (s), 148.1 (s), 164.5 ppm (d), six aromatic car-
bons overlapped; IR (KBr): n˜ = 1704 (C=O), 1522 (NO2), 1347 cmÀ1
(NO2); MS (EI): m/z (%): 474 (30) [M]+, 122 (100); elemental analysis
calcd (%) for C26H22N2O5S: C 65.80, H 4.67, N 5.90; found: C 65.56, H
4.71, N 5.79.
(1S,3S,4R,7S,8R,11S)-4-Methyl-8-(4-nitrophenyl)-3,11-diphenyl-2,9-
dioxa-10-thia-5-azatricyclo[5.2.2.01.5]undecan-6-one (17): Colorless plates
(from acetone/hexane); m.p. 208.5–2098C (decomp); [a]2D4 = À9.88 (c =
1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.09 (d, J = 6.8 Hz,
3H; CH3), 3.41 (d, J = 3.4 Hz, 1H; 7-H), 4.68 (quintet, J = 6.4 Hz, 1H;
4-H), 5.20 (d, J = 3.9 Hz, 1H; 11-H), 5.59 (s, 1H; 8-H), 5.92 (d, J =
6.4 Hz, 1H; 3-H), 7.26–7.55 (m, 12H; ArH), 8.25 ppm (d, J = 8.8 Hz,
2H; ArH); 13C NMR (100 MHz, CDCl3): d = 14.8 (q), 50.2 (d), 54.2 (d),
54.5 (d), 85.1 (d), 113.7 (s), 124.1 (d), 126.1 (d), 126.2 (d), 126.8 (d), 127.8
(d), 128.5 (d), 128.6 (d), 128.8 (d), 128.9 (d), 133.6 (s), 138.2 (s), 145.7 (s),
147.9 (s), 162.2 ppm (s), six aromatic carbons overlapped; IR (KBr): n˜ =
1692 (C=O), 1524 (NO2), 1344 cmÀ1 (NO2); MS (EI): m/z (%): 474 (87)
[M]+, 122 (100); elemental analysis calcd (%) for C26H22N2O5S: C 65.80,
H 4.67, N 5.90; found: C 65.40, H 4.87, N 5.75.
(1R,3R,4S,7R,8R,11R)-4-Methyl-3,11-diphenyl-8-p-tolyl-2,9-dioxa-10-
thia-5-azatricyclo[5.2.2.01.5]undecan-6-one (6e): Yellow powder; m.p.
105.0–105.58C; [a]2D0 = À18.9 (c = 1.0 in CHCl3); 1H NMR (400 MHz,
CDCl3): d = 1.13 (d, J = 6.3 Hz, 3H; Me), 2.41 (s, 3H; Me), 3.25 (t, J =
2.5 Hz, 1H; 7-H), 4.52 (d, J = 2.5 Hz, 1H; 11-H), 4.70 (quintet, J =
6.3 Hz, 1H; 4-H), 5.42 (d, J = 2.5 Hz, 1H; 8-H), 5.81 (d, J = 6.3 Hz,
1H; 3-H), 7.20–7.46 (m, 12H; ArH), 7.52 ppm (d, J
= 7.8 Hz, 2H;
ArH); 13C NMR (100 MHz, CDCl3): d = 14.4 (q), 21.2 (q), 43.3 (d), 53.4
(d), 54.3 (d), 77.1 (d), 84.6 (d), 114.0 (s), 125.4 (d), 125.7 (d), 126.2 (d),
126.38 (d), 126.43 (d), 127.9 (d), 128.0 (d), 128.2 (d), 128.5 (d), 128.54 (d),
128.65 (d), 128.5 (d), 128.8 (d), 129.8 (d), 133.6 (s), 133.9 (s), 138.2 (s),
139.0 (s), 165.5 ppm (s); IR (KBr): n˜ = 1701 cmÀ1 (C=O); MS (EI): m/z
(%): 443 (23) [M]+, 171 (100); HRMS (EI): calcd for C27H25NO3S [M]+:
443.1555; found 443.1550.
Hydrolysis of tricyclic compound 4: HCl (2m, 7.5 mL) was added to a
mixture of 4 (97 mg, 0.25 mmol) in CH3CN (7.5 mL). The mixture was
stirred at 1008C for 3 h, the reaction mixture was then extracted with
CH2Cl2, and the organic phase was dried (MgSO4) and concentrated in
vacuo.Purification of the residue by column chromatography over silica
gel (hexane/AcOEt 2:1) furnished 18 (21 mg, 21%) and 19 (53 mg,
52%).
Product of undetermined structure (8e): White needles (from CH2Cl2/
hexane); m.p. 107.0–107.58C; [a]D20
=
À224.3 (c
= 1.0 in CHCl3);
(2’R*,3’R*,1’’S*)-3-[3’-(4-Chlorophenyl)-3’-hydroxy-2’-(1’’-sulfanyl-1’’-
phenylmethyl)propionyl]thiazolidin-2-one (18): Yellow oil; 1H NMR
(400 MHz, CDCl3): d = 2.27 (d, J = 10.3 Hz, 1H; SH), 2.87 (ddd, J =
2.4, 7.8, 11.2 Hz, 1H; 5-H), 3.08 (ddd, J = 4.9, 7.8, 11.2 Hz, 1H; 5-H),
3.79 (d, J = 10.3 Hz, 1H; OH), 3.87–3.98 (m, 1H; 4-H), 4.00–4.05 (m,
1H; 4-H), 4.41–4.47 (m, 2H; 2’-H and 1’’-H), 5.08 (dd, J = 3.9, 11.2 Hz,
1H; 3’-H), 7.12 (d, J = 8.5 Hz, 2H; ArH), 7.25–7.31 (m, 3H; ArH),
7.37–7.41 (m, 2H, ArH), 7.49 ppm (d, J = 8.5 Hz, 2H; ArH); 13C NMR
(100 MHz, CDCl3): d = 24.8 (t), 43.0 (d), 46.8 (t), 57.1 (d), 72.1 (d),
126.3 (d), 127.3 (d), 127.9 (d), 128.4 (d), 129.1 (d), 133.1 (s), 140.4 (s),
141.7 (s), 173.3 (s), 173.9 ppm (s), four aromatic carbons overlapped; IR
1H NMR (400 MHz, CDCl3): d = 0.68 (d, J = 6.7 Hz, 3H; Me), 2.36 (s,
3H; Me), 3.89 (quintet, J = 6.7 Hz, 1H; 4-H), 4.54 (d, J = 6.7 Hz, 1H;
3-H), 5.10 (d, J = 10.5 Hz, 1H; 11-H), 5.26 (dd, J = 8.1 and 10.5 Hz,
1H; 7-H), 5.75 (d, J = 8.1 Hz, 1H; 8-H), 7.10 (d, J = 6.7 Hz, 2H; ArH),
7.20 (d, J = 8.3 Hz, 2H; ArH), 7.31–7.42 (m, 6H; ArH), 7.57 (d, J =
8.3 Hz, 2H; ArH), 7.67 ppm (d, J
=
7.3 Hz, 2H; ArH); 13C NMR
(100 MHz, CDCl3): d = 14.3 (q), 21.0 (q), 40.5 (d), 40.8 (d), 54.9 (d),
57.6 (d), 79.3 (d), 125.3 (d), 125.5 (d), 127.7 (d), 128.0 (d), 128.3 (d), 128.4
(d), 128.5 (d), 128.6 (d), 128.8 (d), 129.2 (d), 132.6 (s), 137.4 (s), 139.1 (s),
140.5 (s), 151.9 (s), 168.9 ppm (s), four aromatic carbons are overlapped;
IR (KBr) n˜ = 1694 cmÀ1 (C=O); MS (EI): m/z (%): 443 (11) [M]+, 171
(100); elemental analysis calcd (%) for C27H25NO3S: C 73.11, H 5.68, N
3.16; found: C 72.87, H 5.59, N 3.37.
(NaCl): n˜
=
1690 cmÀ1 (C=O); MS (FAB, NBA) m/z (%): 408 (1)
[M+H]+, 154 (100); HRMS (FAB, NBA): calcd for C19H18ClNO3S2
[M+H]+: 408.0495; found 408.0501.
X-ray determination of compound 6c: CCDC-289047 contains the sup-
plementary crystallographic data for this paper.These data can be ob-
tained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
(5R*,6R*,1’S*)-5-(4-Chlorobenzoyl)-3-(2-sulfanylethyl)-6-phenyl-
[1,3]thiazinane-2,4-dione (19): Yellow oil; 1H NMR (400 MHz, CDCl3): d
= 1.33 (t, J = 8.5 Hz, 1H; SH), 2.40 (d, J = 7.5 Hz, 1H; OH), 2.64–2.71
(m, 2H; CH2SH), 3.50 (dd, J = 5.0, 7.5 Hz, 1H; 5-H), 3.86–4.00 (m, 2H;
NCH2), 4.25 (t, J = 7.5 Hz, 1H; 1’-H), 5.36 (d, J = 5.0 Hz, 1H; 6-H)
7.23–7.33 (m, 3H, ArH), 7.36–7.42 ppm (m, 6H, ArH); 13C NMR
(100 MHz, CDCl3): d = 22.1 (t), 41.8 (d), 44.5 (t), 53.8 (d), 76.5 (d),
127.3 (d), 127.5 (d), 128.4 (d), 129.1 (d), 129.5 (d), 133.9 (s), 135.6 (s),
139.7 (s), 150.1 (s), 167.4 ppm (s), four aromatic carbons overlapped; IR
(NaCl): n˜ = 1759, 1705 cmÀ1 (C=O); MS (EI): m/z (%): 407 (5) [M]+,
131 (100); HRMS (EI): calcd for C19H18ClNO3S2 [M+]: 407.0417; found
407.0405.
ACHTREUNG(4R,5S)-3-[(E)-Cinnamoyl]-4-methyl-5-phenyl-1,3-oxazolidine-2-thione
(15): This compound was prepared from (4R,5S)-4-methyl-5-phenyl-1,3-
oxazolidine-2-thione[11] in a similar way as for isomer 5 above.Yellow
prism (from AcOEt/hexane); m.p. 87.0–87.58C (decomp); [a]D20
=
+224.4 (c = 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.04 (d,
J = 6.8 Hz, 3H; CH3), 5.05 (quintet, J = 6.8 Hz, 1H; 4’-H), 5.83 (d, J =
6.8 Hz, 1H; 5’-H), 7.35–7.46 (m, 8H; ArH), 7.62 (q, J = 3.4 Hz, 2H;
ArH), 7.78 (d, J = 15.6 Hz, 1H; 2-H), 8.41 ppm (d, J = 15.6 Hz, 1H; 3-
H); 13C NMR (100 MHz, CDCl3): d = 14.3 (q), 59.3 (d), 83.7 (d), 118.8
(d), 125.9 (d), 128.6 (d), 128.7 (d), 128.9 (d), 130.6 (d), 132.5 (s), 134.7 (s),
145.3 (d), 166.3 (s), 185.5 ppm (s), five aromatic carbons overlapped; IR
(KBr): n˜ = 1677 cmÀ1 (C=O); MS (EI): m/z (%): 323 (15) [M]+, 157
(100); elemental analysis calcd (%) for C19H17NO2S: C 70.56, H 5.30, N
4.33; found: C 70.63, H 5.29, N 4.19.
Hydrolysis of tricyclic compound 6a: HCl (2n, 7.5 mL) was added to a
mixture of 6a (116 mg, 0.25 mmol) in CH3CN (7.5 mL). The mixture was
stirred at room temperature for 5 h and was then extracted with CH2Cl2.
The organic phase was washed with a saturated aqueous NH4Cl solution,
dried (MgSO4), and concentrated in vacuo.Purification of the residue by
column chromatography over silica gel (hexane/AcOEt 3:1) furnished 20
(94 mg, 78%).
(1S,3S,4R,7S,8S,11S)-4-Methyl-8-(4-nitrophenyl)-3,11-diphenyl-2,9-dioxa-
10-thia-5-azatricyclo[5.2.2.01.5]undecan-6-one (16): White powder; m.p.
(4S,5R,2’R,3’R,1’’R)-3-[3’-(4-Chlorophenyl)-3’-hydroxy-2’-(1’’-sulfanyl-1’’-
203.5–2058C (decomp); [a]D24
=
+51.4 (c = 1.0 in CHCl3); 1H NMR
phenylmethyl)propionyl]-4-methyl-5-phenyloxazolidin-2-one
(20a):
White powder; m.p. 70.5–71.08C; [a]D20
= +82.2 (c = 1.0 in CHCl3);
(400 MHz, CDCl3): d = 1.14 (d, J = 6.8 Hz, 3H; CH3), 3.34 (t, J =
2.9 Hz, 1H; 7-H), 4.35 (d, J = 3.4 Hz, 1H; 11-H), 4.71 (quintet, J =
6.8 Hz, 1H; 11-H), 5.51 (d, J = 2.9 Hz, 1H; 8-H), 5.82 (d, J = 5.9 Hz,
1H; 3-H), 7.19–7.47 (m, 10H; ArH), 7.86 (d, J = 8.3 Hz, 2H; ArH),
8.36 ppm (d, J = 8.8 Hz, 2H; ArH); 13C NMR (100 MHz, CDCl3): d =
14.5 (q), 43.6 (d), 53.4 (d), 54.5 (d), 76.3 (d), 84.9 (d), 113.9 (s), 124.1 (d),
1H NMR (400 MHz, CDCl3): d = 0.57 (d, J = 6.8 Hz, 3H; Me), 2.36 (d,
J = 8.6 Hz, 1H; SH), 2.71 (d, J = 3.4 Hz, 1H; OH), 4.48 (t, J = 8.6 Hz,
1H; 1’’-H), 4.59 (quintet, J
= 6.8 Hz, 1H; 4-H), 5.13 (dd, J = 3.4,
7.3 Hz, 1H; 3’-H), 5.25 (dd, J = 7.3, 8.6 Hz, 1H; 2’-H), 5.31 (d. J =
6.8 Hz, 1H; 5-H), 7.18–7.48 ppm (m, 14H; ArH); 13C NMR (100 MHz,
3902
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3896 – 3904

Asymmetric Tandem Michael-Aldol Reactions
FULL PAPER
CDCl3): d = 13.9 (q), 43.6 (d), 54.7 (d), 55.7 (d), 74.0 (d), 78.8 (d), 125.5
(d), 127.5 (d), 127.7 (d), 128.1 (d), 128.5 (d), 128.6 (d), 128.7 (d), 128.8
(d), 132.7 (s), 133.6 (s), 138.6 (s), 141.3 (s), 152.6 (s), 171.6 ppm (s), six ar-
omatic carbons overlapped; IR (KBr): n˜ = 3498 (OH), 2569 (SH), 1766
(C=O), 1685 cmÀ1 (C=O); MS (FAB, Gly) m/z (%): 482 (10) [M+H]+,
308 (100); HRMS (FAB, Gly): calcd for C26H24ClNO4S [M+H]+:
482.1115; found 482.1187.
organic phase was separated, washed with brine, dried (MgSO4), and con-
centrated in vacuo.Purification of the residue by column chromatogra-
phy over silica gel (hexane/EtOAc 5:1) furnished 22 (33 mg, 55%), oxa-
zolidinone 23 (21 mg, 59%), and p-chlorobenzaldehyde (2a) (11 mg,
40%).
S-Ethyl 3-ethylsulfanyl-3-phenylpropanethioate (22):[12] Colorless oil;
1H NMR (400 MHz, CDCl3): d = 1.14–1.19 (m, 6H; CH3), 2.29–2.38 (m,
2H; CH2), 2.83 (q, J = 7.5 Hz, 2H; COSCH2), 3.05–3.08 (m, 2H; 2-H),
4.36 (t, J = 7.6 Hz, 1H; 3-H), 7.21–7.34 ppm (m, 5H; ArH); 13C NMR
(100 MHz, CDCl3): d = 14.3 (q), 14.5 (d), 23.4 (t), 25.3 (t), 45.1 (d), 50.3
(t), 127.4 (d), 127.7 (d), 128.5 (t), 141.0 (s), 196.5 ppm (s), two aromatic
carbons overlapped; IR (NaCl): n˜ = 1686 cmÀ1 (C=O); MS (FAB, NBA)
m/z (%): 255 (35) [M+H]+, 154 (100); HRMS (FAB, NBA): calcd for
C13H18OS2 [M+H]+: 255.0799; found 255.0884.
(4S,5R,2’R,3’R,1’’R)-3-[3’-Hydroxy-3’-(4-nitrophenyl)-2’-(1’’-phenylmeth-
yl)-1’’-sulfanylpropionyl]-4-methyl-5-phenyloxazolidin-2-one (20b): Col-
orless plates (from AcOEt/hexane); m.p. 146.5–149.08C; [a]D20
=
+51.5
(c = 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 0.72 (d, J
=
6.4 Hz, 3H; Me), 2.30 (d, J = 8.8 Hz, 1H; SH), 3.17 (brs, 1H; OH), 4.48
(t, J = 8.8 Hz, 1H; 1’’-H), 4.68 (quintet, J = 6.9 Hz, 1H; 4-H), 5.24 (d,
J = 5.6 Hz, 1H; 3’-H), 5.29 (dd, J = 5.6, 8.8 Hz, 1H; 2’-H), 5.44 (d, J =
6.9 Hz, 1H; 5-H), 7.16–7.43 (m, 12H; ArH), 8.00 ppm (d, J = 8.3 Hz,
2H; ArH); 13C NMR (100 MHz, CDCl3): d = 11.8 (q), 42.9 (d), 55.1 (d),
55.7 (d), 73.2 (d), 79.2 (d), 123.0 (d), 125.5 (d), 127.5 (d), 127.6 (d), 127.9
(d), 128.8 (d), 128.9 (d), 129.0 (d), 132.5 (s), 140.9 (s), 147.15 (s), 147.23
(s), 153.0 (s), 172.3 ppm (s); IR (KBr) n˜ = 3483 (OH), 2570 (SH), 1778
(C=O), 1689 (C=O), 1520 (NO2), 1345 cmÀ1 (NO2); MS (FAB, NBA) m/z
(%): 493 (7) [M+H]+, 154 (100); elemental analysis calcd (%) for
C26H24N2O6S: C 63.40, H 4.91, N 5.69; found: C 63.65, H 5.03, N 5.53.
Reaction of 21 with lithium borohydride: Lithium borohydride (6 mg,
0.28 mmol) was added to a mixture of 21 (49.6 mg, 0.1 mmol) in dry THF
(1 mL).The mixture was stirred at room temperature for 2 h, and a satu-
rated aqueous NH4Cl solution (5 mL) was then added dropwise at room
temperature.The reaction mixture was then extracted with CH 2Cl2.The
organic phase was washed with a saturated aqueous NaCl solution, dried
(MgSO4), and concentrated in vacuo.Purification of the residue by
column chromatography over silica gel (hexane/AcOEt 5:1) furnished 24
(8 mg, 44%), 23 (100%), and p-chlorobenzyl alcohol (25) (56%).
3-Methylsulfanyl-3-phenylpropan-1-ol (24):[13] Colorless oil; 1H NMR
(400 MHz, CDCl3): d = 1.15 (brs, 1H; OH), 1.88 (s, 3H; Me), 2.04–2.17
(m, 2H; CH2), 3.60–3.65 (m, 1H; CH2), 3.72–3.78 (m, 1H; CH2), 3.88 (t,
J = 7.8 Hz, 1H; 3-H), 7.23–7.26 (m, 1H; ArH), 7.32–7.33 ppm (m, 4H;
ArH); 13C NMR (100 MHz, CDCl3): d = 14.1 (q), 38.4 (t), 47.9 (d), 60.5
(t), 127.1 (d), 127.7 (d), 128.4 (d), 141.9 ppm (s), two aromatic carbons
overlapped; IR (NaCl): n˜ = 3357 cmÀ1 (OH); MS (FAB, NBA): m/z
(%): 183 (28) [M+H]+, 154 (100); HRMS (FAB, NBA): calcd for
C10H14OS [M+H]+: 183.0765; found 183.0852.
Synthesis of 21: A solution of 20 (78 mg, 0.17 mmol), MeI (60.3 mg,
0.43 mmol), and triethylamine (43 mg, 0.43 mmol) in dry CH2Cl2 (2 mL)
was stirred at 08C.After the addition was complete, the reaction was al-
lowed to continue at room temperature for 1.5 h. The reaction mixture
was extracted with AcOEt.The extract was washed successively with
HCl (10%), water, and brine and then dried (MgSO4).After removal of
the solvent, purification of the residue by the recycling preparative
HPLC with elution with chloroform furnished 21 (72 mg, 85%).
(4S,5R,2’R,3’R,1’’R)-3-[3’-(4-Chlorophenyl)-3’-hydroxy-2’-(1’’-methylsul-
fanyl-1’’-phenylmethyl)propionyl]-4-methyl-5-phenyloxazolidin-2-one
(21a): Colorless prisms (from CHCl3/hexane); m.p. 170.0–170.58C;
Synthesis of trimethylsilyl ether 26: Pyridine (18.2 mL, 0.2 mmol) was
added to a solution of 21 (49.6 mg, 0.1 mmol) in dry CH2Cl2 (3 mL), fol-
lowed by a catalytic amount of 4-(N,N-dimethylamino)pyridine.To this, a
solution of trimethylsilyl chloride (25 mL, 0.2 mmol) was added dropwise
with stirring at 08C.After the addition was complete, the reaction was
continued at room temperature for 1 h.The excess solvent and pyridine
were removed under reduced pressure to afford a residue, which was
taken up in AcOEt and water.The organic phase was separated, washed
with brine, dried (MgSO4), and concentrated in vacuo.Purification of the
residue by column chromatography over silica gel (hexane/EtOAc 5:1)
furnished 26 (50 mg, 91%).
[a]2D0
=
+96.1 (c = 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d =
0.57 (d, J = 6.8 Hz, 3H; Me), 1.90 (s, 3H; SMe), 2.81 (d, J = 2.4 Hz,
1H; OH) 4.20 (d, J = 8.3 Hz, 1H; 1’’-H), 4.63 (quintet, J = 6.8H, 1H;
4-H), 5.12–5.57 (m, 2H; 2’-H and 3’-H), 5.39 (d, J = 6.8 Hz, 1H; 5-H),
7.16–7.41 ppm (m, 14H; ArH); 13C NMR (100 MHz, CDCl3): d = 13.9
(q), 15.0 (q), 51.7 (d), 54.1 (d), 54.7 (d), 73.8 (d), 78.8 (d), 125.5 (d), 127.7
(d), 128.0 (d), 128.3 (d), 128.4 (d), 128.5 (d), 128.6 (d), 128.7 (d), 132.8
(s), 133.4 (s), 138.8 (s), 138.9 (s), 152.6 (s), 171.3 ppm (s), six aromatic
carbons overlapped; IR (KBr): n˜ = 3579 (OH), 1779 (C=O), 1696 cmÀ1
(C=O); MS (FAB, NBA) m/z (%): 496 (5) [M+H]+, 154 (100); elemental
analysis calcd (%) for C27H26ClNO4S: C 65.38, H 5.28, N 2.82; found: C
65.25, H 5.22, N 2.84.
(4S,5R,2’R,3’R,1’’R)-3-[3’-(4-Chlorophenyl)-2’-(1’’-methylsulfanyl-1’’-phe-
nylmethyl)-3’-trimethylsilanyloxypropionyl]-4-methyl-5-phenyloxazolidin-
2-one (26): White powder; m.p. 159.5–160.08C; [a]2D0 = +104.3 (c = 1.0
(4S,5R,2’R,3’R,1’’R)-3-[3’-Hydroxy-2’-(1’’-methylsulfanyl-1’’-phenylmeth-
yl)-3’-(4-nitrophenyl)propionyl]-4-methyl-5-phenyloxazolidin-2-one
(21b): Pale yellow plates (from AcOEt/hexane); m.p. 216.5–217.08C;
1
in CHCl3); H NMR (400 MHz, CDCl3): d = 0.01 (s, 9H; Me3Si), 0.44 (d,
J = 6.8 Hz, 3H; Me), 1.93 (s, 3H; SMe), 4.28 (d, J = 5.9 Hz, 1H; 1’’-H),
4.57 (q, J = 3.4 Hz, 1-H; 4-H), 5.16–5.23 (m, 3H; 5-H, 2’-H, and 3’-H),
7.16–7.50 ppm (m, 14H; ArH); 13C NMR (100 MHz, CDCl3): d = 0.0
(q), 13.7 (q), 14.9 (q), 52.1 (d), 54.4 (d), 54.9 (d), 74.4 (d), 78.3 (d), 125.4
(d), 127.4 (d), 127.5 (d), 127.8 (d), 127.9 (d), 128.2 (d), 128.3 (d), 128.4
(d), 128.5 (d), 129.1 (d), 133.1 (s), 133.3 (s), 139.8 (s), 140.1 (s), 151.7 (s),
170.8 ppm (s), two TMS carbons and four aromatic carbons overlapped;
IR (KBr): n˜ = 1782 (C=O), 1693 cmÀ1 (C=O); MS (FAB, NBA) m/z
(%): 568 (7) [M+H]+, 137 (100); elemental analysis calcd (%) for
C30H34ClNO4SSi: C 63.41, H 6.03, N 2.47; found: C 63.40, H 6.09, N 2.46.
[a]2D0
=
+66.0 (c = 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d =
0.74 (d, J = 6.7 Hz, 3H; Me), 1.89 (s, 3H; SMe), 3.27 (s, 1H; OH), 4.20
(d, J = 9.8 Hz, 1H; 1’’-H), 4.71 (quintet, J = 6.7H, 1H; 4-H), 5.17–5.20
(m, 1H; 3’-H), 5.23–5.25 (m, 1H; 2’-H), 5.52 (d, J = 6.7 Hz, 1H; 5-H),
7.16–7.44 (m, 12H; ArH), 8.00 ppm (d, J = 8.8 Hz, 2H; ArH); 13C NMR
(100 MHz, CDCl3): d = 14.3 (q), 14.9 (q), 50.8 (d), 53.6 (d), 55.2 (d),
73.1 (d), 79.2 (d), 122.9 (d), 125.5 (d), 127.5 (d), 127.8 (d), 128.5 (d), 128.7
(d), 128.8 (d), 128.9 (d), 132.6 (s), 138.4 (s), 147.0 (s), 147.4 (s), 153.0 (s),
172.2 ppm (s); IR (KBr): n˜ = 3588 (OH), 1772 (C=O), 1697 (C=O), 1515
(NO2), 1345 cmÀ1 (NO2); MS (FAB, NBA) m/z (%): 507 (9) [M+H]+,
154 (100); elemental analysis calcd (%) for C27H26N2O6S: C 64.02, H
5.17, N 5.53; found: C 63.78, H 5.09, N 5.49.
Treatment of 26 with lithium borohydride (Table 3, entry 1): Lithium bor-
ohydride (6 mg, 0.28 mmol) was added to a mixture of 26 (56.8 mg,
0.1 mmol) in dry THF (1 mL). The mixture was stirred at room tempera-
ture for 4 h, and a saturated aqueous NH4Cl solution (5 mL) was then
added dropwise at room temperature.The reaction mixture was then ex-
tracted with CH2Cl2, and the organic phase was washed with a saturated
aqueous NaCl solution, dried (MgSO4), and concentrated in vacuo.Puri-
fication of the residue by column chromatography over silica gel
(hexane/AcOEt 5:1) furnished 27 (54 mg, 100%).
Reaction of 21 with lithium ethanethiolate: n-Butyllithium (150 mL,
0.3 mmol) was added at À788C to a solution of ethanethiol (30 mL,
0.4 mmol) in dry THF (2 mL). The solution was transferred to an ice/
water bath and stirred for 10 min until it became milky.A solution of 21
(96.2 mg, 0.2 mmol) in dry THF (2 mL) was transferred into the thiolate
solution by cannula, and the reaction mixture was stirred at 08C for
20 min.The reaction mixture was poured into a separating funnel con-
taining a saturated aqueous NH4Cl solution and extracted with Et2O.The
Treatment of 26 with sodium ethanethiolate (Table 3, entry 2): Sodium
hydride (3 mg, 0.025 mmol) was added to a solution of ethanethiol
Chem. Eur. J. 2006, 12, 3896 – 3904
ꢀ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
3903

T.Kataoka et al.
(7.5 mL, 0.1 mmol) in dry THF (1 mL). After 30 min, the mixture was
cooled to 08C, and a solution of 26 (56.8 mg, 0.1 mmol) in dry THF
(1 mL) was added by cannula over 5 min.An additional quantity of dry
THF (1 mL) was added to rinse the flask.After 50 min at room tempera-
ture, the reaction mixture was poured into a separating funnel containing
a saturated aqueous NH4Cl solution and extracted with Et2O.The organ-
ic phase was separated, washed with a saturated aqueous NaCl solution,
dried (MgSO4), and concentrated in vacuo.Purification of the residue by
column chromatography over silica gel (hexane/EtOAc 5:1) furnished 27
(19 mg, 35%).
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Re-
search (B) (No.16390009) from the Japanese Society for the Promotion
of Science.
Treatment of 26 with sodium methoxide (Table 3, entry 3): Sodium meth-
oxide in methanol (20 mL, 0.11 mmol, 28%) was added at À258C to a
mixture of 26 (56.8 mg, 0.1 mmol) in dry CH2Cl2 (0.83 mL). After 8 min
at À258C, the reaction mixture was poured into a separating funnel con-
taining a saturated aqueous NH4Cl solution and extracted with CH2Cl2.
The organic phase was separated, washed with a saturated aqueous NaCl
solution, dried (MgSO4), and concentrated in vacuo.Purification of the
residue by column chromatography over silica gel (hexane/EtOAc 5:1)
furnished 27 (45 mg, 83%).
[1] For a review of the chalcogenide/Lewis acid mediated tandem Mi-
chael-aldol reaction: T.Kataoka, H.Kinoshita, Eur. J. Org. Chem.
2005, 45–58.
[2] For reviews of the Morita–Baylis–Hillman reaction: a) S.E.Drewes,
G.H.P. Roos, Tetrahedron 1988, 44, 4653–4670; b) D.Basavaiah,
P.D.Rao, R.S.Hyma,
Tetrahedron 1996, 52, 8001–8062; c) E.Ciga-
nek, Org. React. 1997, 51, 201–350; d) P.Langer, Angew. Chem.
2000, 112, 3177–3180; Angew. Chem. Int. Ed. 2000, 39, 3049–3052;
e) Y.Iwabuchi, S.Hatakeyama, J. Syn. Org. Chem. Jpn. 2002, 60, 2–
16; f) J.N.Kim, K.Y.Lee, Curr. Org. Chem. 2002, 6, 627–645; g) D.
Basavaiah, A.J.Rao, T.Satyanarayana, Chem. Rev. 2003, 103, 811–
891.
(2R,3R,1’S,2’R,1’’R)-2-[2-[(4-Chlorophenyl)(trimethylsilanyloxy)meth-
yl]]-N-(2’-hydroxy-1’-methyl-2’-phenylethyl)-3-methylsulfanyl-3-phenyl-
propionamide (27): White powder; m.p. 62.5–63.08C; [a]2D3 = +55.7 (c =
1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 0.01 (s, 9H; Me3Si),
0.43 (d, J = 6.8 Hz, 3H; Me), 1.91 (s, 3H; SMe), 2.67 (dd, J = 5.8 and
8.1 Hz, 1H; 2-H), 2.74 (d, J = 4.4 Hz, 1H; OH), 3.88–3.91 (m, 1H;
1’-H), 4.22 (d, J = 5.8 Hz, 1H; 3-H), 4.59 (m, 1H; 2’-H), 4.95 (d, J =
8.1 Hz, 1H; 1’’-H), 5.13 (d, J = 8.1 Hz, 1H; NH), 7.12 (d, J = 7.3 Hz,
[3] a) T.Kataoka, S.Kinoshita, H.Kinoshita, M.Fujita, T.Iwamura, S.
Watanabe, Chem. Commun. 2001, 1958–1959; b) T.Kataoka, H.Ki-
noshita, S.Kinoshita, T.Iwamura,
J. Chem. Soc. Perkin Trans. 1
2002, 2043–2045; c) T.Kataoka, H.Kinoshita, S.Kinoshita, T.Iwa-
mura, Tetrahedron Lett. 2002, 43, 7039–7041; d) H.Kinoshita, T.
Osamura, S.Kinoshita, T.Iwamura, S.Watanabe, T.Kataoka, O.
Muraoka, G.Tanabe, J. Org. Chem. 2003, 68, 7532–7534; e) H.Ki-
noshita, S.Kinoshita, Y.Munechika, T.Iwamura, S.Watanabe, T.
Kataoka, Eur. J. Org. Chem. 2003, 4852–4861.
2H; ArH), 7.20–7.39 (m, 10H; ArH), 7.52 ppm (d, J
= 7.3 Hz, 2H;
ArH); 13C NMR (100 MHz, CDCl3): d = 0.0 (q), 13.4 (q), 15.9 (q), 50.6
(d), 51.7 (d), 63.6 (d), 73.8 (d), 75.3 (d), 126.2 (d), 127.2 (d), 127.3 (d),
128.0 (d), 128.1 (d), 128.2 (d), 128.5 (d), 128.6 (d), 133.4 (s), 140.3 (s),
141.0 (s), 141.2 (s), 169.8 ppm (s), two TMS and six aromatic carbons
overlapped; IR (KBr): n˜ = 3420 (NH), 1647 cmÀ1 (C=O); MS (FAB,
NBA) m/z (%): 542 (5) [M+H]+, 154 (100); HRMS (FAB, NBA): calcd
for C29H36ClNO3SSi [M+H]+: 542.1874; found 542.1943.
[4] T.Iwama, H.Kinoshita, T.Kataoka,
3741–3744.
Tetrahedron Lett. 1999, 40,
[5] S.Kinoshita, H.Kinoshita, T.Iwamura, S.Watanabe, T.Kataoka,
Chem. Eur. J. 2003, 9, 1496–1502.
Synthesis of propanediols 28a,b: A solution of sodium borohydride
(37.5 mg, 1 mmol) in water (0.25 mL) was added to a mixture of 21a
(124 mg, 0.25 mmol) in THF (0.75 mL). The mixture was stirred at room
temperature for 6 h, HCl (2m, 1.5 mL) was added, and the mixture was
then extracted with AcOEt.The organic phase was washed with a satu-
rated aqueous NaCl solution, dried (MgSO4), and concentrated in vacuo.
Purification of the residue by column chromatography over silica gel
(hexane/AcOEt/iPrOH 30:10:1) furnished 28a (51 mg, 63%).Compound
28b was prepared similarly.
[6] a) T.H. Newby, E.C. Howlett, J. Am. Chem. Soc. 1951, 73, 4720–
4721; b) P.Ulrich, A.Cerami,
c) M.Dzurilla, P.Kutschy, P.Kristan, Synthesis 1985, 933–934; d) H.
Takahata, Y.Banba, M.Mozumi, T.Yamazaki, Heterocycles 1986,
24, 947–950; e) K.Toda, K.Tanaka, J.Sato, Tetrahedron: Asymme-
J. Med. Chem. 1982, 25, 654–657;
try 1993, 4, 1771–1774; f) A.Hari, B.L.Miller,
Org. Lett. 2000, 2,
3667–3670.
[7] a) C.Palomo, M.Oiarbide, F.Dias, A.Ortiz, A.Linden,
J. Am.
Chem. Soc. 2001, 123, 5602–5603; b) A.Ortiz, L.Quintero, H.
Hernµndez, S.Maldonado, G.Mendoza, S.Bern›s, Tetrahedron Lett.
2003, 44, 1129–1132; c) C.Palomo, M.Oiarbide, F.Dias, R.López,
A.Linden, Angew. Chem. 2004, 116, 3369–3372; Angew. Chem. Int.
Ed. 2004, 43, 3307–3310.
(1R,2S,1’R)-1-(4-Chlorophenyl)-2-(1’-methylsulfanyl-1’-phenylmethyl)-
propane-1,3-diol (28a): Colorless oil; [a]2D3 = +64.8 (c = 1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d
= 1.84 (s, 3H; Me), 2.21 (brt, 1H;
3-OH), 2.41–2.47 (m, 1H; 2-H), 3.49 (d, J = 5.6 Hz, 1H; 1-OH), 3.72–
3.84 (m, 2H; 3-H), 3.90 (d, J = 6.4 Hz, 1H; 1’-H), 5.02 (t, J = 5.6 Hz,
1H; 1-H), 7.21–7.33 ppm (m, 9H; ArH); 13C NMR (100 MHz, CDCl3):
d = 14.8 (q), 50.0 (d), 51.5 (d), 60.9 (t), 73.6 (d), 127.1 (d), 127.6 (d),
128.2 (d), 128.4 (d), 132.9 (s), 140.0 (s), 140.3 ppm (s), five aromatic car-
bons overlapped; IR (NaCl): n˜ = 3742 cmÀ1 (OH); MS (FAB, Gly) m/z
(%): 323 (3) [M+H]+, 185 (100); HRMS (FAB, Gly): calcd for
C17H19ClO2S [M+H]+: 323.0794; found 323.0879.
[8] For a preliminary communication: T.Kataoka, H.Kinoshita, S.Ki-
noshita, T.Osamura, T.Iwamura, S.Watanabe, O.Muraoka, G.
Tanabe, Angew. Chem. 2003, 115, 2995–2997; Angew. Chem. Int.
Ed. 2003, 42, 2889–2891.
[9] T.D. Penning, S.W. Djuric, R.A. Haack, V.J. Kalish, J.M. Miya-
shiro, B.W.Rowell, S.S.Yu, Synth. Commun. 1990, 20, 307–312.
[10] a) AN. .Cuzzupe, CA. .Hutton, MJ..Lilly, RK. .Mann, KJ..
(1R,2S,1’R)-2-(1’-Methylsulfanyl-1’-phenylmethyl)-1-(4-nitrophenyl)pro-
McRae, S.C. Zammit, M.A. Rizzacasa,
2382–2393; b) T.Izawa, T.Mukaiyama, Bull. Chem. Soc. Jpn. 1979,
52, 555–558.
J. Org. Chem. 2001, 66,
pane-1,3-diol (28b): Colorless oil; [a]D23
=
+57.1 (c = 1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d = 1.81 (s, 3H; Me), 2.43 (brt, 1H; 3-
OH), 2.48–2.53 (m, 1H; 2-H), 3.82–3.87 (m, 1H; 3-H), 3.90 (d, J
=
[11] Y.Nagao, T.Kumagai, S.Yamada, E.Fujita, Y.Inoue, Y.Nagase, S.
Aoyagi, T.Abe, J. Chem. Soc. Perkin Trans. 1 1985, 2361–2367.
[12] H.Eck, H.Prigge, Liebigs Ann. Chem. 1972, 755, 177–190.
5.4 Hz, 1H; 1-OH), 3.93 (d, J = 7.3 Hz, 1H; 1’-H), 3.98–4.04 (m, 1H; 3-
H), 5.02 (t, J = 4.8 Hz, 1H; 1-H), 7.15–7.23 (m, 5H; ArH), 7.41 (d, J =
8.8 Hz, 2H; ArH), 8.08 ppm (d, J
=
8.8 Hz, 2H; ArH); 13C NMR
[13] I.D. Kostas, B.R. Steele, A. Terzis, S.V. Amosova,
Tetrahedron
(100 MHz, CDCl3): d = 14.7 (q), 49.5 (d), 51.6 (d), 61.8 (t), 73.9 (d),
2003, 59, 3467–3473.
123.1 (d), 126.8 (d), 127.2 (d), 128.3 (d), 128.4 (d), 139.7 (s), 146.7 (s),
[14] a) D.Delaunay, L.Toupet, ML. .Corre,
J. Org. Chem. 1995, 60,
149.9 ppm (s); four aromatic carbons overlapped; IR (NaCl): n˜
=
6604–6607; b) G.Li, T.Ohtani, Heterocycles 1997, 45, 2471–2474.
3582 cmÀ1 (OH); MS (FAB, Gly) m/z (%): 334 (4) [M+H]+, 185 (100);
HRMS (FAB, Gly): calcd for C17H19NO4S [M+H]+: 333.1035; found
333.1122.
Received: November 21, 2005
Published online: March 1, 2006
3904
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3896 – 3904