On the influence of chiral auxiliaries in the stereoselective cross-coupling reactions of titanium enolates and acetals

Article abstract of DOI:10.1016/j.tet.2008.04.044

Titanium enolates from chiral N-propanoyl-1,3-thiazolidine-2-thiones containing bulky substituents at C4 turned out to be excellent platforms to get highly stereocontrolled cross-coupling reactions with acetals. Related oxazolidinethiones also afforded go

Full text of DOI:10.1016/j.tet.2008.04.044

Tetrahedron 64 (2008) 5637–5644
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On the influence of chiral auxiliaries in the stereoselective cross-coupling
reactions of titanium enolates and acetals
*
*
´
´
`
´
Jessica Baiget, Annabel Cosp, Erik Galvez, Loreto Gomez-Pinal, Pedro Romea , Felix Urpı
`
´
´
Departament de Qu´ımica Organica, Universitat de Barcelona, Martı i Franques 1–11, 08028 Barcelona, Catalonia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 March 2008
Received in revised form 2 April 2008
Accepted 10 April 2008
Available online 15 April 2008
Titanium enolates from chiral N-propanoyl-1,3-thiazolidine-2-thiones containing bulky substituents at
C4 turned out to be excellent platforms to get highly stereocontrolled cross-coupling reactions with
acetals. Related oxazolidinethiones also afforded good results, but the corresponding oxazolidinones
resulted completely unselective for such reactions, which proves that an exocyclic C]S bond is essential
to attain a synthetically useful stereocontrol.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Chiral auxiliaries
Titanium enolates
Acetals
1. Introduction
contributions have shown that other thiazolidinethiones also impart
excellent levels of stereocontrol provided that a bulky substituent is
It is beyond all doubt that chiral auxiliaries have been greatly
responsible for the amazing development of highly stereoselective
methodologies occurred throughout the last decades, which have
made possible the construction of structurally complex molecular
architectures that were considered unattainable few years ago.1
Even in our days, when the state of the art in the asymmetric
synthesis arena is currently associated to the accomplishments on
catalysis, chiral auxiliary-based processes still maintain a prom-
inent position among the most reliable strategies for accessing
a single stereoisomer in high yields.2 Moreover, a thorough and
endless analysis of the influence of the structural features of many
chiral auxiliaries on the stereochemical outcome of the processes in
which they are involved has provided a better understanding of
their reactivity and improved their synthetic efficiency.2
incorporated tothe heterocycle.8 Onthewhole, ithasbeenestablished
that a sulfur atom at the exocyclic position offers different modes of
metal binding for enolates and gives access to alternative stereoiso-
mers. Thus, chiral 1,3-thiazolidine- and 1,3-oxazolidine-2-thiones
represented in Figure 1 have emerged as suitable platforms to attain
highly stereoselective carbon–carbon bond formation reactions.7–10
In this context, we have disclosed a straightforward entry to
enantiopure anti b-alkoxy-a-methyl oxygenated derivatives based
on the Lewis acid-mediated addition of titanium enolates from
(S)-4-isopropyl-N-propanoyl-1,3-thiazolidine-2-thione to aliphatic,
aromatic, and a,b-unsaturated acetals and the easy removal of the
chiral auxiliary (Scheme 1).11
Once established the synthetic potential of this new methodol-
ogy, two structural issues remained still unclear: the influence of (i)
That is the case for oxazolidinones, probably the most represen-
tative family of chiral auxiliaries.3 Indeed, chiral 1,3-oxazolidinones,
first introduced by Evans,4 have turned out to be a superb tool for the
stereoselective construction of carbon–carbon bonds and have
enjoyed tremendous success.5 Nevertheless, the diastereoselectivity
impartedbytheseauxiliariesisoccasionallylow, asfortheacetate-like
aldol reaction.4,6 Interestingly, Nagao and Fujita recognized that tin(II)
enolate from analogous N-acetyl-1,3-thiazolidine-2-thiones could
participate in highly stereoselective aldol processes.7 Further
O
O
NH
R
1,3-Oxazolidin-2-ones
S
S
O
NH
S
NH
R
R
* Corresponding authors. Tel.: þ34 93 4021247/4039106; fax: þ34 93 3397878
1,3-Oxazolidine-2-thiones
1,3-Thiazolidine-2-thiones
(F.U.).
´
E-mail addresses: pedro.romea@ub.edu (P. Romea), felix.urpi@ub.edu (F. Urpı).
Figure 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.044

5638
J. Baiget et al. / Tetrahedron 64 (2008) 5637–5644
S
S
different 1,3-thiazolidine-2-thiones and (ii) related chiral auxilia-
O
ries on the stereochemical outcome of the process. Herein, we
document the impact of different substituents R positioned at C4 in
N-propanoyl-1,3-thiazolidine-2-thiones on the addition of their ti-
tanium enolates to a representative acetal, namely the dimethyl
acetal of benzaldehyde (see Scheme 2). Additionally, these studies
have been expanded to related 1,3-oxazolidine-2-thione and 1,3-
oxazolidin-2-one chiral auxiliaries (see Scheme 2).
S
S
N
N
1) TiCl4, i-Pr2NEt
2) Lewis acid, RCH(OR')2
OR'
O
OR'
O
OR'
HO
R
R
R
X
2. Results and discussion
At first, we were concerned with the stereochemical control
imparted by the 1,3-thiazolidine-2-thiones 1 shown in Scheme 3.
With the exception of 1f (R: t-Bu), these sulfur-containing hetero-
cycles were easily prepared by refluxing an alkaline solution
R: alkyl, aryl, α,β-unsaturated
R': Me, Bn
Scheme 1.
(2.25 M KOH in 1:1 EtOH/H2O) of the corresponding b-amino al-
cohol and carbon disulfide for three days.12 In turn, the thiazolidi-
nethione 1f derived from the (S)-tert-leucinol required harsher
conditions (5 M KOH in H2O) due to the steric hindrance imposed
by the bulky tert-butyl group (Scheme 3).8b As a rule, such stringent
conditions are needed to overcome the formation of the related 1,3-
oxazolidine-2-thiones and to obtain the 1,3-thiazolidine-2-thiones
1 as a sole product, usually pure enough to be used in the next step
without any chromatographic purification. Thus, such experimen-
tal procedure turns out to be particularly useful to prepare the
chiral auxiliaries 1 in multigram scale. Eventually, their acylation
with propanoyl chloride proceeded smoothly to afford the desired
N-propanoyl-1,3-thiazolidine-2-thiones 2 in high yields.
S
S
X
O
O
OMe
Ph
1) TiCl4, i-Pr2NEt
S
N
S
N
2) BF3·OEt2, PhCH(OMe)2
R
R
R: H, Ph, i-Bu, Bn, i-Pr, t-Bu
X
O
O
OMe
Ph
1) TiCl4, i-Pr2NEt
O
N
O
N
2) BF3·OEt2, PhCH(OMe)2
With a reliable supply of a wide set of N-propanoyl-1,3-thiazo-
lidine-2-thiones 2, we began to study the addition of their titanium
enolates to the dimethyl acetal of benzaldehyde in the presence of
BF3$OEt2 under the conditions previously optimized.13 The results
are summarized in Table 1.
R
R
X: S, O
R: i-Pr, t-Bu
Scheme 2.
S
S
O
a
b
NH2
S
NH
R
S
N
HO
50–95%
58–98%
R
R
β-Amino alcohol
a (R:H), b (R:Ph), c (R:i-Bu), d (R:Bn), e (R:i-Pr)
1
2
S
S
S
O
c
b
a
NH2
t-Bu
(S)-tert-Leucinol
O
NH
t-Bu
S
NH
t-Bu
S
N
HO
55%
93%
72%
t-Bu
2f
1f
3f
Scheme 3. Reagents and conditions: (a) CS2, KOH, EtOH/H2O 1:1, reflux, 72 h. (b) EtCOCl, BuLi, THF, ꢀ78 ꢁC. (c) CS2, KOH, H2O, reflux, 72 h.
Table 1
S
S
S
O
O
OMe
O
OMe
1) TiCl4, i-Pr2NEt
2
2
+
3
3
S
N
S
N
S
N
2) BF3·OEt2, PhCH(OMe)2
R
R
R
2,3-anti
4
2,3-syn
5
2
Entry
2
R
dr (4/5)a
Yieldb (%)
1
2
3
4
5
6
a
b
c
d
e
f
H
Ph
i-Bu
Bn
i-Pr
t-Bu
65:35
76:24
76:24
85:15
88:12
90:10
40 (61)
64 (86)
(88)
(73)
75 (87)
(57)
a
Determined by HPLC.
Isolated yield of the 2,3-anti diastereomer 4; values in brackets denote overall yield.
b

J. Baiget et al. / Tetrahedron 64 (2008) 5637–5644
5639
O
S
O
O
O
N
O
N
i-Pr
8e
R
7e R: i-Pr
7f R: t-Bu
Figure 3.
Importantly, only two of four possible diastereomers, namely
2,3-anti 4 and 2,3-syn 5 adducts, are observed across all the reaction
mixtures. Therefore, it occurs as the substituent positioned at C4
in 2 prevents the addition of the electrophile to the Re face of
the enolate and is responsible for the R configuration of the
a-
stereocenter in 4 and 5. This and other evidences suggest that the
addition proceeds through a SN1-like mechanism that involves the
formation of an oxonium cation.19–21 Then, such oxonium cation
reacts with the less sterically hindered face of a chelated enolate
following an antiperiplanar approach in an open transition state
(Scheme 5). This mechanistic picture would be common for all the
N-propanoyl-1,3-thiazolidine-2-thiones 2. Regarding the influence
of R on the configuration of the b-stereocenter, we are aware that
this model does not account easily for the differences on diaste-
reoselectivity. We just speculate that the improvement of dia-
stereomeric ratios achieved from achiral 2a to the more bulky 2f
might be due to subtle changes on the structure of the enolate
produced by the substituent positioned at C4.22
Figure 2.
The absolute configuration of the 2,3-anti adduct 4e was firmly
established through X-ray analysis (Fig. 2).14 Other 2,3-anti re-
lationships on major diastereomers 4 were secured by removal
of the chiral auxiliaries with methanol and comparison of the re-
sultant methyl esters 6 (Scheme 4). Furthermore, the 3J2,3 coupling
constants of 4 (3J2,3 9.8–9.9 Hz, see Section 3) and 5 (3J2,3 6.6–
7.0 Hz) resulted to be independent of the C4 substituent and were
used as a diagnostic tool to assign the relative configuration of the
adducts 4 and 5.15
Having disclosed the influence of 2 on the stereochemical
outcome of the Lewis acid-mediated addition of their titanium
enolates to PhCH(OMe)2, we next evaluated the behavior of
N-propanoyl 1,3-oxazolidine-2-thiones 7 and 1,3-oxazolidin-2-one
8e containing isopropyl and tert-butyl groups at C4 (Fig. 3).
The N-propanoyl 1,3-oxazolidin-2-thiones 7 were prepared in
good yields by acylation with propanoyl chloride of the chiral
1,3-oxazolidin-2-thiones 3, which, in turn, were obtained from
the corresponding amino alcohols (Scheme 6). As represented in
Scheme 3, (S)-4-tert-butyl-1,3-oxazolidine-2-thione (3f) was un-
expectedly obtained when (S)-tert-leucinol was treated with car-
bon disulfide in a strong basic solution for a long time. Conversely,
the less bulky (S)-4-isopropyl-1,3-oxazolidine-2-thione (3e) re-
quired milder experimental conditions and was isolated in good
yield by simple stirring at room temperature in the presence of
a weak base as triethylamine. Otherwise, standard acylation of the
commercially available (S)-4-isopropyl-1,3-oxazolidin-2-one with
propanoyl chloride delivered the desired (S)-4-isopropyl-N-prop-
anoyl-1,3-oxazolidin-2-one (8e) in 81% yield.
S
O
OMe
O
OMe
a
MeO
S
N
95–100%
R
4
6
Scheme 4. Reagents and conditions: (a) MeOH, K2CO3, rt.
As shown in Table 1, the diastereoselectivity achieved in such
cross-coupling reactions depends on the heterocycles 1. The most
simple N-propanoyl-1,3-thiazolidine-2-thione (R: H) 2a affords the
2,3-anti adduct 4a in a moderate selectivity (dr 65:35), which is
improved byall the other C4 substituted chiral auxiliaries. In fact, the
diastereoselectivity increases with steric bulk of R (compare entries
1 and 2–6 in Table 1)16 to reach the best figures with 2e (R: i-Pr) and
2f (R: t-Bu), respectively (see entries 5 and 6 in Table 1). From
practical purposes, the valine-derived auxiliary 1e might be the
most reasonable choice because the stereochemical control ach-
ieved by 2e and 2f is veryclose (dr 88:12 vs 90:10) being much better
than the yield for 2e (87 vs 57%, see entries 5 and 6 in Table 1).17,18
S
S
O
a
b
NH2
O
NH
R
O
N
HO
75%
85–95%
R
R
7
β-Amino alcohol
e (R: i-Pr), f (R: t-Bu)
3
Scheme 6. Reagents and conditions: (a) CS2, Et3N, THF, reflux, 12 h [for R: t-Bu, see
Scheme 3]. (b) EtCOCl, BuLi, THF, ꢀ78 ꢁC.
Cl4
Ti
Cl4
Me
H
O
Ti
S
S
S
O
O
O
OMe
Ph
Ph
S
N
S
N
S
N
H
O
Me
R
R
R
4
Scheme 5.

5640
J. Baiget et al. / Tetrahedron 64 (2008) 5637–5644
Unfortunately, the N-acyl oxazolidinone 8e proved to be ste-
Spherisorb S3W (250ꢂ4 mm) column with a 0.9 mL minꢀ1 flux.
reochemically unselective in the cross-coupling reaction with the
dimethyl acetal of benzaldehyde. Indeed, the addition of the tita-
nium enolate from 8e to PhCH(OMe)2 in the presence of a wide
array of Lewis acids (BF3$OEt2, BCl3, SnCl4, TiCl4, etc.) proceeded
smoothly and delivered the corresponding adducts in good yields
but in unacceptable low diastereomeric ratios (dr<60:40). In-
terestingly, only two diastereomers were observed, which proves
the absolute control exerted by the isopropyl group positioned at
Flash chromatography was performed on SDS silica gel (35–70 mm).
Analytical thin layer chromatography was carried out on Merck
Kieselgel 60 F254 plates. The following solvents and reagents were
purified and dried according to the standard procedures: CH2Cl2,
THF, and i-Pr2NEt. All other reagents were used as received.
3.2. General procedure for the preparation of 1,3-
thiazolidine-2-thiones (1)
C4 on the configuration of the new a-stereocenter.
Better results were achieved with the N-acyl oxazolidinethiones
7 (Fig. 3). As shown in Scheme 7, both (S)-4-isopropyl-N-propanoyl-
1,3-oxazolidine-2-thione (7e) and (S)-4-tert-butyl-N-propanoyl-
1,3-oxazolidine-2-thione (7f) afforded the corresponding adducts
in close diastereoselectivity than the related thiazolidinethiones 2e
and 2f, which proves that the stereochemical control on these
cross-coupling reactions is associated to the presence of an exo-
cyclic sulfur atom (C]S).23 Once again, the most sterically hindered
tert-leucine derived oxazolidinethione 7f afforded the 2,3-anti
adduct 9f in higher diastereomeric ratio but in modest yield.
A 2.25 M KOH in 1:1 EtOH/H2O solution (120 mL) was added
dropwise to a solution of enantiomerically pure b-amino alcohol
(0.1 mol) and carbon disulfide (18 mL, 0.265 mol) in ethanol
(30 mL) at room temperature and under N2. The reaction mixture
was stirred and heated at reflux for 72 h under N2. After cooling, the
volatiles were removed with a rotary evaporator. Then, a 0.5 M
aqueous HCl (350 mL) was carefully added at room temperature
and the resulting mixture was extracted with CH2Cl2 (3ꢂ100 mL).
The combined organic layers were dried (MgSO4), filtered, and the
solvent was removed to give the corresponding 1,3-thiazolidine-
2-thiones 1 as a solid, which was usually used in the next step
without further purification. Otherwise, this material was purified
through a short column chromatography to afford purer samples.
S
S
O
O
OMe
a
O
N
O
N
3.2.1. 1,3-Thiazolidine-2-thione (1a)
R
7
R
Yield: 58%; white solid; Rf 0.20 (CH2Cl2); mp 105–106 ꢁC; IR
(KBr): 3141, 2849, 1516, 1296, 1051; 1H NMR (CDCl3, 300 MHz):
9
e
R: i-Pr dr 80:20 57% overall yield
R: t-Bu dr 89:11 62% overall yield
d
8.00 (1H, br s, NH), 4.04–3.96 (2H, AA0BB0X system, NCH2), 3.61–
f
3.54 (2H, AA0BB0X system, SCH2); 13C NMR (CDCl3, 75.4 MHz):
201.8, 51.3, 33.6; MS–CI (NH3): m/z (%) 120 [MþH]þ (100).
Scheme 7. Reagents and conditions: (a) (i) TiCl4, i-Pr2NEt, CH2Cl2. (ii) BF3$OEt2,
d
PhCH(OMe)2.
3.2.2. (S)-4-Phenyl-1,3-thiazolidine-2-thione (1b)
Yield: 77%; white solid; Rf 0.40 (CH2Cl2); mp 124–126 ꢁC [lit.12a
In conclusion, the stereochemical outcome of the cross-coupling
reactions of titanium enolates from C4 substituted N-propanoyl-1,3-
thiazolidine-2-thiones with PhCH(OMe)2 in the presence of
BF3$OEt2 relies on the steric bulk of the C4 substituent, being the
valine-derived chiral auxiliary the best choice to obtain the corre-
sponding 2,3-anti adduct in high yield and diastereomeric ratio.
Related 1,3-oxazolidine-2-thiones afford similar results but in
poorer yield and diastereoselectivity. Furthermore, the valine-de-
rived 1,3-oxazolidin-2-one resulted useless for such reactions. Thus,
the presence of a sulfur atom in the exocyclic double bond is es-
sential to attain a synthetically useful stereocontrol.
mp 124–125 ꢁC]; [
a]
ꢀ213.5 (c 1.1, CHCl3) [lit.12a
[
a
]
D
ꢀ209.3 (c
D
0.35, CHCl3)]; IR (KBr): 3124, 2950, 1492, 1453, 1258, 1050; 1H NMR
(CDCl3, 300 MHz):
d 7.60 (1H, br s, NH), 7.50–7.40 (5H, m, ArH),
5.35–5.25 (1H, m, NCH), 3.85 (1H, dd, J¼11.2, 8.0, SCHxHy), 3.51 (1H,
dd, J¼11.2, 8.3, SCHxHy); 13C NMR (CDCl3, 75.4 MHz):
d 201.7, 138.0,
129.3, 129.2, 126.2, 67.3, 41.6; MS–CI (NH3): m/z (%) 196 [MþH]þ
(100).
3.2.3. (S)-4-Isobutyl-1,3-thiazolidine-2-thione (1c)
Yield: 50%; white solid; Rf 0.40 (CH2Cl2); mp 48–50 ꢁC; [
a]
D
ꢀ28.8 (c 1.0, CHCl3); IR (KBr): 3143, 2957, 2869, 1507, 1467, 1305,
1033; 1H NMR (CDCl3, 300 MHz):
8.06 (1H, br s, NH), 4.38–4.26
3. Experimental
3.1. General
d
(1H, m, NCH), 3.59 (1H, dd, J¼11.0, 7.7, SCHxHy), 3.22 (1H, dd, J¼11.0,
7.9, SCHxHy), 1.80–1.60 (2H, m, CHxHyCH(CH3)2), 1.55–1.45 (1H, m,
CHxHyCH(CH3)2), 0.97 (3H, d, J¼6.6, CH3), 0.96 (3H, d, J¼6.4, CH3);
Melting points were taken on an Electrothermal apparatus and
are uncorrected. Specific rotations were determined at 20 ꢁC on
a Perkin–Elmer 241 MC polarimeter. IR spectra were recorded on
a Nicolet 510FT spectrometer and only the more representative
frequencies (cmꢀ1) are reported. 1H NMR (300 MHz) and 13C NMR
(75.4 MHz) spectra were recorded on a Varian Unity Plus spec-
trometer; 1H NMR (400 MHz) spectra were recorded on a Varian
13C NMR (CDCl3, 75.4 MHz):
d 200.7, 62.5, 42.9, 38.9, 25.3, 22.6,
22.2. Anal. Calcd for C7H13NS2: C, 47.96; H, 7.47; N, 7.99. Found: C,
47.91; H, 7.50; N, 7.71.
3.2.4. (S)-4-Benzyl-1,3-thiazolidine-2-thione (1d)
Yield: 95%; white solid; Rf 0.35 (CH2Cl2); mp 74–75 ꢁC [lit.12a mp
84–85 ꢁC]; [
a
]
D
ꢀ119.2 (c 1.0, CHCl3) [lit.12a
[
a
]
D
ꢀ129.2 (c 0.96,
Mercury; chemical shifts (
d
) are quoted in parts per million and
CHCl3)]; IR (KBr): 3134, 2969, 1509, 1494, 1004; 1H NMR (CDCl3,
referenced to internal TMS for 1H NMR and CDCl3
(d
77.0) for 13C
300 MHz): d 7.45 (1H, br s, NH), 7.40–7.26 (3H, m, ArH), 7.23–7.17
NMR; data are reported as follows: s, singlet; d, doublet; t, triplet; q,
quartet; hept, heptuplet; oct, octet; m, multiplet; br, broad; cou-
pling constants (J) are quoted in hertz; where appropriate, 2D
techniques were also used to assist in structural elucidation. Mass
spectra were obtained from the Centro de Apoio Cientifico Tecno-
loxico a Investigacion (C.A.C.T.I.), Universidad de Vigo and from the
Servei d’Espectrometria de Masses, Universitat de Barcelona. Ele-
(2H, m, ArH), 4.52–4.40 (1H, m, NCH), 3.60 (1H, dd, J¼11.2, 7.7,
SCHxHy), 3.33 (1H, dd, J¼11.2, 6.8, SCHxHy), 3.03 (1H, dd, J¼13.6, 7.6,
PhCHaHb), 2.98 (1H, dd, J¼13.6, 6.7, PhCHaHb); 13C NMR (CDCl3,
75.4 MHz):
d
200.8, 135.7, 129.0 (ꢂ2), 127.4, 65.0, 39.9, 38.0; MS–CI
(NH3): m/z (%) 210 [MþH]þ (100).
3.2.5. (S)-4-Isopropyl-1,3-thiazolidine-2-thione (1e)
mental analyses were obtained from the Servei de Microanalisi
Yield: 92%; white solid; Rf 0.25 (CH2Cl2); mp 68–69 ꢁC [lit.7 mp
`
(CID–CSIC, Barcelona). HPLC was carried out with a silica gel
67–68 ꢁC, lit.12a mp 66–67 ꢁC]; [
a]
ꢀ34.9 (c 1.1, CHCl3) [lit.7
[a]
D
D

J. Baiget et al. / Tetrahedron 64 (2008) 5637–5644
5641
ꢀ36.8 (c 1.16, CHCl3), lit.12a
[a
]
ꢀ34.6 (c 0.94, CHCl3)]; IR (KBr):
1099; 1H NMR (CDCl3, 300 MHz):
d
5.35–5.20 (1H, m, NCH), 3.56
D
3190, 2965, 1500, 1410, 1385, 1030; 1H NMR (CDCl3, 300 MHz):
(1H, ddd, J¼11.2, 7.2, 1.2, SCHxHy), 3.36 (1H, dq, J¼18.1, 7.2,
COCHxHy), 3.10 (1H, dq, J¼18.1, 7.2, COCHxHy), 2.91 (1H, dd, J¼11.2,
0.7, SCHxHy), 1.98–1.86 (1H, m, CHxHyCH(CH3)2), 1.74–1.48 (2H,
m, CHxHyCH(CH3)2), 1.17 (3H, t, J¼7.2, COCH2CH3), 1.01 (3H, d,
J¼6.4, CHCH3), 1.00 (3H, d, J¼6.4, CHCH3); 13C NMR (CDCl3,
d
7.42 (1H, br s, NH), 4.03 (1H, td, J¼8.2, 7.8, NCH), 3.52 (1H, dd,
J¼11.0, 8.2, SCHxHy), 3.34 (1H, dd, J¼11.0, 8.2, SCHxHy), 2.10–1.95
(1H, m, CH(CH3)2), 1.04 (3H, d, J¼7.0, CH3), 1.01 (3H, d, J¼7.2, CH3);
13C NMR (CDCl3, 75.4 MHz):
d 201.5, 70.6, 36.5, 32.5, 19.3, 18.7. Anal.
Calcd for C6H11NS2: C, 44.68; H, 6.87; N, 8.68. Found: C, 44.74; H,
6.81; N, 8.55.
75.4 MHz): d 201.4, 174.7, 66.1, 39.6, 33.0, 32.2, 25.4, 23.5, 21.2,
8.8; HRMS (þESI): calcd for [MþH]þ C10H18NOS2 232.0824, found
232.0828.
3.3. Preparation of (S)-4-tert-butyl-1,3-thiazolidine-2-
thione (1f)
3.4.4. (S)-4-Benzyl-N-propanoyl-1,3-thiazolidine-2-thione (2d)
Yield: 89%; yellow solid; Rf 0.40 (50:50 CH2Cl2/hexanes); mp
A mixture of (S)-tert-leucinol (2.09 g, 17.8 mmol), carbon disul-
fide (9.2 mL, 150 mmol) in 5 M KOH aqueous solution (100 mL) was
heated for 72 h under N2. The reaction mixture was extracted with
CH2Cl2 (3ꢂ100 mL), the organic layers were dried (MgSO4), and
concentrated. The resulting oil was purified by flash chromatog-
raphy (CH2Cl2) to afford 1.74 g (9.9 mmol, 55%) of (S)-4-tert-butyl-
1,3-thiazolidine-2-thione (1f). White solid; Rf 0.65 (CH2Cl2); mp
95–97 ꢁC; [
a
]
D þ196.4 (c 1.1, CHCl3); IR (KBr): 2977,1706,1264,1165,
1032; 1H NMR (CDCl3, 400 MHz):
d
7.38–7.26 (5H, m, ArH), 5.42–
5.35 (1H, m, NCH), 3.42 (1H, dq, J¼18.2, 7.2, COCHxHy), 3.38 (1H,
ddd, J¼11.5, 7.2, 1.2, SCHxHy), 3.22 (1H, dd, J¼13.1, 3.8, PhCHxHy),
3.13 (1H, dq, J¼18.2, 7.2, COCHxHy), 3.05 (1H, dd, J¼13.1, 10.5,
PhCHxHy), 2.88 (1H, dd, J¼11.5, 0.7, SCHxHy), 1.19 (3H, t, J¼7.2, CH3);
13C NMR (CDCl3, 75.4 MHz):
d 201.1, 174.9, 136.6, 129.4, 128.9, 127.2,
134–135 ꢁC [lit.24 mp 143–144 ꢁC]; [
a]
ꢀ35.8 (c 1.1, CHCl3) [lit.24
68.6, 36.7, 32.3, 31.9, 8.8. Anal. Calcd for C13H15NOS2: C, 58.83; H,
5.70; N, 5.28. Found: C, 58.67; H, 5.62; N, 5.22.
D
[
a]
ꢀ33.2 (c 1.03, CHCl3)]; IR (KBr): 3157, 2958, 1507, 1475, 1368,
D
1293, 1042; 1H NMR (CDCl3, 300 MHz):
d 7.60 (1H, br s, NH), 4.07–
3.98 (1H, m, NCH), 3.45 (1H, dd, J¼11.3, 8.4, SCHxHy), 3.39 (1H, dd,
3.4.5. (S)-4-Isopropyl-N-propanoyl-1,3-thiazolidine-2-thione (2e)
Yield: 98%; bright yellow oil; Rf 0.45 (50:50 CH2Cl2/hexanes);
J¼11.3, 9.0, SCHxHy), 1.02 (9H, s, C(CH3)3); 13C NMR (CDCl3,
75.4 MHz):
d
201.6, 73.4, 34.4 (ꢂ2), 25.9; HRMS (þESI): calcd for
[a
]
D þ428.5 (c 1.0, CHCl3); IR (film): 2961, 1699, 1349,1259, 1167; 1H
[MþH]þ C7H14NS2 176.0562, found 176.0567.
NMR (CDCl3, 300 MHz):
d
5.17 (1H, ddd, J¼8.1, 6.1, 1.2, NCH), 3.51
(1H, dd, J¼11.4, 8.1, SCHxHy), 3.36 (1H, dq, J¼18.0, 7.2, COCHxHy),
3.15 (1H, dq, J¼18.0, 7.2, COCHxHy), 3.02 (1H, dd, J¼11.4, 1.2,
SCHxHy), 2.41–2.32 (1H, m, CH(CH3)2), 1.15 (3H, t, J¼7.2, COCH2CH3),
1.06 (3H, d, J¼6.6, CH3CCH3), 0.98 (3H, d, J¼6.6, CH3CCH3); 13C NMR
3.4. General procedure for the acylation of the 1,3-
thiazolidine-2-thiones
A 1.5 M solution of n-BuLi in hexanes (7.4 mL, 11 mmol) was
(CDCl3, 75.4 MHz): d 203.3, 174.8, 71.6, 32.0, 30.8, 30.4, 19.0, 17.6,
added dropwise to
a
solution of 1,3-thiazolidine-2-thione
1
8.9. Anal. Calcd for C9H15NOS2: C, 49.73; H, 6.96; N, 6.44. Found: C,
49.67; H, 6.94; N, 6.36.
(10 mmol) in THF (6.6 mL) at ꢀ78 ꢁC under N2. The reaction mix-
ture was stirred for 15 min and propanoyl chloride (1.1 mL,
12.5 mmol) was carefully added. The resulting clear solution was
stirred for 5 min and the solution was allowed to warm to room
temperature and stirred for 1.5 h. The reaction mixture was cooled
with an ice-water bath and was quenched with a saturated solution
of NH4Cl (4 mL) and water (10 mL). This mixture was extracted with
CH2Cl2 (3ꢂ20 mL), the combined organic layers were dried
(MgSO4), filtered, and concentrated. The resultant oil was purified
through column chromatography to afford the corresponding N-
propanoyl-1,3-thiazolidine-2-thione 2.
3.4.6. (S)-4-tert-Butyl-N-propanoyl-1,3-thiazolidine-2-thione (2f)
Yield: 93%; yellow solid; Rf 0.50 (50:50 CH2Cl2/hexanes); mp
29–30 ꢁC; [
a]
þ602.4 (c 0.85, CHCl3); IR (KBr): 2964, 1703, 1353,
D
1325, 1250, 1156, 1045; 1H NMR (CDCl3, 300 MHz):
d 5.35 (1H, dd,
J¼8.4, 0.7, NCH), 3.54 (1H, dd, J¼11.4, 8.4, SCHxHy), 3.36 (1H, dq,
J¼17.9, 7.2, COCHxHy), 3.21 (1H, dq, J¼17.9, 7.2, COCHxHy), 3.10 (1H,
dd, J¼11.4, 0.7, SCHxHy), 1.18 (3H, t, J¼7.2, COCH2CH3), 1.03 (9H, s,
C(CH3)3); 13C NMR (CDCl3, 75.4 MHz):
d 204.7, 174.5, 72.4, 37.9, 31.8,
30.5, 26.8, 9.2.
3.4.1. N-Propanoyl-1,3-thiazolidine-2-thione (2a)
3.5. General procedure for the titanium-mediated addition of
2 to PhCH(OMe)2
Yield: 58%; bright yellow oil; Rf 0.65 (CH2Cl2); IR (film): 2979,
2938, 1702, 1365, 1281, 1222, 1157; 1H NMR (CDCl3, 300 MHz):
d
4.59 (2H, t, J¼7.6, NCH2), 3.28 (2H, t, J¼7.6, SCH2), 3.26 (2H, q,
Neat TiCl4 (0.12 mL, 1.1 mmol) was added dropwise to a solution
of 2 (1.0 mmol) in anhydrous CH2Cl2 (8 mL), at 0 ꢁC under N2. The
yellow suspension was stirred for 5 min at 0 ꢁC, cooled at ꢀ78 ꢁC,
J¼7.3, COCH2), 1.18 (3H, t, J¼7.3, CH3); 13C NMR (CDCl3, 75.4 MHz):
d
201.5, 175.5, 56.0, 32.2, 28.2, 8.7; MS–CI (NH3): m/z (%) 176
[MþH]þ (100).
and a solution of anhydrous diisopropylethylamine (0.19 mL,
1.1 mmol) in anhydrous CH2Cl2 (1 mL) was added. The dark red
3.4.2. (S)-4-Phenyl-N-propanoyl-1,3-thiazolidine-2-thione (2b)
enolate solution was stirred for 2 h at ꢀ40 ꢁC and cooled at ꢀ78 ꢁC.
Yield: 84%; viscous yellow oil; Rf 0.65 (CH2Cl2); [
1.0, CHCl3); IR (KBr): 2977, 1692, 1320, 1254, 1233, 1164, 1052; 1H
NMR (CDCl3, 300 MHz): 7.40–7.30 (5H, m, ArH), 6.24 (1H, dd,
a
]
ꢀ301.3 (c
Then, BF3$OEt2 (140 mL, 1.1 mmol) and PhCH(OMe)2 (166 mL,
D
1.1 mmol) were successively added dropwise. The resulting mix-
ture was stirred at ꢀ78 ꢁC for 2.5 h. The reaction was quenched by
the addition of a saturated solution of NH4Cl (6 mL) with vigorous
stirring and the layers were separated. The aqueous layer was re-
extracted with CH2Cl2 (10 mL), and the combined organic extracts
were washed with brine (10 mL), dried (Na2SO4), filtered, and
concentrated. The residue was analyzed by HPLC and purified
through flash column chromatography with deactivated silica gel
(2.5% Et3N) to afford the 2,3-anti adduct 4 as a pure diastereomer or
as a mixture with the 2,3-syn adduct 5. Eventually, the product was
kept in the fridge under nitrogen atmosphere to avoid undesired
decompositions.
d
J¼8.2, 1.6, NCH), 3.93 (1H, dd, J¼11.3, 8.2, SCHxHy), 3.38 (1H, dq,
J¼18.1, 7.3, COCHxHy), 3.20 (1H, dq, J¼18.1, 7.3, COCHxHy), 3.07 (1H,
dd, J¼11.3, 1.6, SCHxHy), 1.13 (3H, t, J¼7.3, COCH2CH3); 13C NMR
(CDCl3, 75.4 MHz):
d 202.1, 174.8, 139.3, 129.0, 128.4, 125.4, 69.8,
36.6, 32.5, 8.7; HRMS (þESI): calcd for [MþH]þ C12H14NOS2
252.0511, found 252.0509.
3.4.3. (S)-4-Isobutyl-N-propanoyl-1,3-thiazolidine-2-thione (2c)
Yield: 81%; bright yellow oil; Rf 0.45 (50:50 CH2Cl2/hexanes);
[
a
]
þ269.8 (c 1.05, CHCl3); IR (film): 2959, 1701, 1341, 1269, 1161,
D

5642
J. Baiget et al. / Tetrahedron 64 (2008) 5637–5644
3.5.1. (ꢃ) N-[2,3-anti-3-Methoxy-2-methyl-3-phenylpropanoyl]-
1,3-thiazolidine-2-thione (4a)
3.5.6. (S)-4-tert-Butyl-N-[(2R,3S)-3-methoxy-2-methyl-3-
phenylpropanoyl]-1,3-thiazolidine-2-thione (4f)
Yield: 40%; yellow solid; Rf 0.70 (CH2Cl2); mp 132–133 ꢁC; IR
Yield of the mixture: 57%; bright yellow oil; Rf 0.40 (95:5 hex-
anes/EtOAc); HPLC (99:1 hexanes/EtOAc) tR 41.4 min [2,3-syn dia-
stereomer, tR 37.1 min]; IR (film): 2965, 1698, 1454, 1370, 1242,
(KBr): 2981, 2934,1700,1364,1278,1153; 1H NMR (CDCl3, 300 MHz):
d
7.42–7.28 (5H, m, ArH), 4.72–4.60 (2H, m, COCHCH3, NCHxHy), 4.46
(1H, ddd, J¼11.9,11.1, 7.6, NCHxHy), 4.33 (1H, d, J¼9.8, CHOCH3), 3.43
(1H, td, J¼11.1, 7.8, SCHxHy), 3.21 (1H, ddd, J¼11.1, 7.6, 3.2, SCHxHy),
3.11 (3H, s, OCH3), 0.95 (3H, d, J¼6.7, COCHCH3); 13C NMR (CDCl3,
1134; 1H NMR (CDCl3, 400 MHz):
d 7.38–7.29 (5H, m, ArH), 5.53 (1H,
dd, J¼8.5, 0.9, NCH), 5.42 (1H, dq, J¼10.0, 6.9, COCHCH3), 4.37 (1H,
d, J¼10.0, CHOCH3), 3.49 (1H, dd, J¼11.7, 8.5, SCHxHy), 3.09 (3H, s,
OCH3), 3.07 (1H, dd, J¼11.7, 0.9, SCHxHy), 1.10 (9H, s, C(CH3)3), 0.80
75.4 MHz):
d 201.6, 178.6, 138.8, 128.5, 128.3, 127.9, 87.6, 56.8, 56.5,
46.2, 28.9, 14.1; MS–CI (NH3): m/z (%) 264 [MꢀOMe]þ (60), 296
(3H, d, J¼6.9, COCHCH3); 13C NMR (CDCl3, 75.4 MHz):
d 205.0, 176.3,
[MþH]þ (100).
139.3, 128.4, 128.2, 128.1, 87.2, 72.5, 56.5, 44.1, 37.9, 29.5, 26.7, 14.3;
HRMS (þESI): calcd for [M–OMe]þ C17H22NOS2 320.1137, found
320.1149; calcd for [MþH]þ C18H26NO2S2 352.1399, found 352.1408.
3.5.2. (S)-N-[(2R,3S)-3-Methoxy-2-methyl-3-phenylpropanoyl]-4-
phenyl-1,3-thiazolidine-2-thione (4b)
Yield: 64%; bright yellow oil; Rf 0.55 (CH2Cl2); [
a
]
D ꢀ175.0 (c 1.0,
3.6. General procedure for the removal of chiral auxiliaries:
obtention of methyl ester 6
CHCl3); HPLC (98:2 hexanes/EtOAc) tR 54.6 min [2,3-syn di-
astereomer, tR 38.0 min]; IR (film): 2931, 1702, 1457, 1302, 1254,
1150, 1025; 1H NMR (CDCl3, 300 MHz):
d
7.50–7.20 (10H, m, ArH),
A solution of 4 (0.15 mmol) in anhydrous MeOH (3 mL) was
treated with anhydrous K2CO3 (104 mg, 0.75 mmol) at 0 ꢁC under
N2. The resultant mixture was stirred at room temperature. The
bright yellow color faded slowly and, finally, a control TLC proved
that the starting material had been consumed (3–4 h). The reaction
was quenched by addition of a saturated solution of NH4Cl (5 mL)
and the resulting suspension was diluted with CH2Cl2 (15 mL). The
organic layer was washed with a 0.5 M NaOH aqueous solution
(5 mL), and water (5 mL), and dried (Na2SO4). Removal of the vol-
atiles afforded a colorless oil, which was purified through a short
pad of silica when required. Yield: 95–100%; colorless oil; Rf 0.30
6.34 (1H, dd, J¼8.2, 3.3, NCH), 5.08 (1H, dq, J¼9.8, 6.9, COCHCH3),
4.19 (1H, d, J¼9.8, CHOCH3), 3.84 (1H, dd, J¼11.2, 8.2, SCHxHy), 3.14
(1H, dd, J¼11.2, 3.3, SCHxHy), 2.87 (3H, s, OCH3), 0.85 (3H, d, J¼6.9,
COCHCH3); 13C NMR (CDCl3, 75.4 MHz):
d 202.3, 177.3, 139.0, 138.9,
128.7, 128.4,128.2 (ꢂ2), 128.0,126.0, 87.7, 70.3, 56.5, 45.5, 36.2, 14.4.
3.5.3. (S)-4-Isobutyl-N-[(2R,3S)-3-methoxy-2-methyl-3-
phenylpropanoyl]-1,3-thiazolidine-2-thione (4c)
Yield of the mixture: 88%; yellow viscous oil; Rf 0.60 (CH2Cl2);
HPLC (97:3 hexanes/EtOAc) tR 13.4 min [2,3-syn diastereomer, tR
14.5 min]; 1H NMR (CDCl3, 300 MHz):
d
7.40–7.20 (5H, m, ArH), 5.45–
(CH2Cl2); [
a
]
D ꢀ73.0 (c 1.5, CHCl3); IR (film): 2958, 1740, 1459, 1268,
5.35 (1H, m, NCH), 5.08 (1H, dq, J¼9.9, 7.0, COCHCH3), 4.36 (1H, d,
J¼9.9, CHOCH3), 3.53 (1H, ddd, J¼11.1, 7.6, 0.7, SCHxHy), 3.10 (3H, s,
OCH3), 2.93 (1H, dd, J¼11.1, 2.6, SCHxHy), 2.00–1.60 (3H, m,
CH2CH(CH3)2), 1.02 (3H, d, J¼6.2, CH3), 1.01 (3H, d, J¼6.4, CH3), 0.88
1167, 1098; 1H NMR (CDCl3, 300 MHz):
d
7.35–7.30 (5H, m, ArH),
4.25 (1H, d, J¼9.8, CHOCH3), 3.76 (3H, s, COOCH3), 3.15 (3H, s,
CHOCH3), 2.77 (1H, dq, J¼9.8, 7.0, COCHCH3), 0.87 (1H, d, J¼7.0,
COCHCH3); 13C NMR (CDCl3, 75.4 MHz):
d 175.8, 138.8, 128.4, 128.2,
(3H, d, J¼7.0, CH3); 13C NMR (CDCl3, 75.4 MHz):
d
201.5, 177.9, 139.0,
127.6, 85.8, 56.7, 51.7, 46.9, 14.0; MS–CI (NH3): m/z (%) 209 (35)
[MþH]þ, 226 (100) [MþNH4]þ; HRMS (þESI): calcd for [MꢀOMe]þ
C11H13O2 177.0910, found 177.0904; calcd for [MþH]þ C12H17O3
209.1172, found 209.1167.
128.4,128.2,128.0, 87.7, 66.5,56.5, 45.5, 40.7, 33.0,25.3, 23.6, 21.3,14.4.
3.5.4. (S)-4-Benzyl-N-[(2R,3S)-3-methoxy-2-methyl-3-
phenylpropanoyl]-1,3-thiazolidine-2-thione (4d)
Yield of the mixture: 73%. A small amount of pure 4d was isolated
and characterized. Bright yellow oil; Rf 0.17 (70:30 hexanes/CH2Cl2);
HPLC (99:1 hexanes/EtOAc) tR 36.6 min [2,3-syn diastereomer, tR
3.7. Preparation of (S)-4-isopropyl-1,3-oxazolidine-2-
thione (3e)
46.2 min]; [
a
]
D ꢀ41.2 (c 1.05 in CHCl3); IR (film): 2932, 1697, 1454,
Anhydrous triethylamine (5.4 mL, 38.7 mmol) was added
dropwise to a solution of (S)-valinol (1.01 g, 9.8 mmol) and carbon
disulfide (3.0 mL, 50.0 mmol) in anhydrous THF (40 mL) at 0 ꢁC
under N2 and the resultant mixture was heated at reflux for 12 h
under N2. After cooling, the volatiles were removed with a rotary
evaporator and the mixture was partitioned with CH2Cl2 (150 mL)
and water (50 mL). The aqueous layer was further extracted with
CH2Cl2 (3ꢂ100 mL), the combined organic layers were dried
(Na2SO4), filtered, and concentrated. The resultant brown residue
was purified through a column chromatography (CH2Cl2) to afford
1.07 g (7.4 mmol, 75% yield) of (S)-4-isopropyl-1,3-oxazolidine-2-
thione (3e). White solid; mp 49–50 ꢁC [lit.12a mp 45–46 ꢁC]; Rf 0.20
1344,1252,1160,1097; 1H NMR (CDCl3, 300 MHz):
d
7.40–7.25 (10H,
m, ArH), 5.60–5.45 (1H, m, NCH), 5.22 (1H, dq, J¼9.8, 6.9, COCHCH3),
4.42 (1H, d, J¼9.8, CHOCH3), 3.40–3.25 (2H, m, PhCHxHy and
SCHxHy), 3.12 (3H, s, OCH3), 3.08 (1H, dd, J¼13.4,10.5, PhCHxHy), 2.90
(1H, dd, J¼11.4, 2.0, SCHxHy), 0.91 (3H, d, J¼6.9, COCHCH3); 13C NMR
(CDCl3, 75.4 MHz):
d 201.4, 177.8, 139.0, 136.8, 129.4, 128.9, 128.5,
128.3, 128.1, 127.2, 87.6, 68.9, 56.7, 45.4, 37.4, 31.5, 14.5; HRMS
(þESI): calcd for [MꢀOMe]þ C20H20NOS2 354.0980, found
354.0964; calcd for [MþH]þ C21H24NO2S2 386.1242, found 386.1233.
3.5.5. (S)-4-Isopropyl-N-[(2R,3S)-3-methoxy-2-methyl-3-
phenylpropanoyl]-1,3-thiazolidine-2-thione (4e)
Yield: 75%; yellow solid; mp 82–83 ꢁC; Rf 0.60 (CH2Cl2); HPLC
(97:3 hexanes/EtOAc) tR 17.1 min [2,3-syn diastereomer, tR
(CH2Cl2); [
a
]
D ꢀ27.4 (c 0.65, CHCl3) [lit.12a
[
a]
D ꢀ21.4 (c 0.4, CHCl3)];
IR (KBr): 3191, 2964, 1526, 1274, 1171; 1H NMR (CDCl3, 300 MHz):
d
8.46 (1H, br s, NH), 4.69 (1H, t, J¼9.1, OCHxHy), 4.39 (1H, dd, J¼9.1,
38.0 min]; [
a
]
D þ120.2 (c 1.96 in CHCl3); IR (KBr): 2927, 1704, 1368,
6.7, OCHxHy), 3.86 (1H, dt, J¼9.1, 6.7, NCH), 1.84 (1H, oct, J¼6.7,
1245, 1156; 1H NMR (CDCl3, 300 MHz):
d
7.36–7.22 (5H, m, ArH),
CH(CH3)2), 0.99 (3H, d, J¼6.7, CH3), 0.94 (3H, d, J¼6.7, CH3); 13C NMR
5.36 (1H, ddd, J¼8.9, 5.5, 2.1, NCH), 5.26 (1H, dq, J¼9.8, 7.0,
COCHCH3), 4.35 (1H, d, J¼9.8, CHOCH3), 3.46 (1H, dd, J¼11.5, 8.9,
SCHxHy), 3.08 (3H, s, OCH3), 3.01 (1H, dd, J¼11.5, 2.1, SCHxHy), 2.40
(1H, heptd, J¼8.0, 5.5, CH(CH3)2), 1.11 (3H, d, J¼8.0, CH3CHCH3), 1.03
(3H, d, J¼8.0, CH3CHCH3), 0.86 (3H, d, J¼7.0, COCHCH3); 13C NMR
(CDCl3, 75.4 MHz): d 189.5, 73.4, 62.4, 32.1, 17.9, 17.8; MS–CI (NH3):
m/z (%) 146 (100) [MþH]þ.
3.8. Preparation of (S)-4-tert-butyl-1,3-oxazolidine-2-
thione (3f)
(CDCl3, 75.4 MHz): d 202.6, 177.7, 139.1, 128.3, 128.2, 128.1, 87.7, 71.9,
56.4, 45.1, 30.4, 28.8, 19.0, 17.0, 14.3; HRMS (þFAB): calcd for
A 2.5 M KOH in 1:1 EtOH/H2O solution (15 mL) was added
dropwise to a solution of (S)-tert-leucinol (2.52 g, 21.5 mmol) and
[MþH]þ C17H24NO2S2 338.1249, found 338.1251.

J. Baiget et al. / Tetrahedron 64 (2008) 5637–5644
5643
carbon disulfide (3.9 mL, 65 mmol) in ethanol (5 mL) at room
3.10.2. (S)-4-tert-Butyl-N-[(2R,3S)-3-methoxy-2-methyl-3-
temperature under N2 and the reaction mixture was stirred and
heated at reflux for 72 h under N2. After cooling, the volatiles were
removed with a rotary evaporator. Then, a 2 M aqueous HCl
(350 mL) was carefully added at room temperature until pH 2 and
the resulting mixture was extracted with CH2Cl2 (3ꢂ50 mL). The
combined organic layers were dried (MgSO4), filtered, and the
solvent was removed. The resulting white solid was purified by
flash chromatography (CH2Cl2) to afford 0.32 g (1.8 mmol, 8%) of 1f
and 2.46 g (15.4 mmol, 72%) of (S)-4-tert-butyl-1,3-oxazolidine-2-
thione (3f). White solid; mp 146–149 ꢁC [lit.24 mp 153–156 ꢁC]; Rf
phenylpropanoyl]-1,3-oxazolidine-2-thione (9f)
Yield: 56%; colorless oil; Rf 0.75 (CH2Cl2); HPLC (96:4 hexanes/
EtOAc) tR 26.3 min [2,3-syn diastereomer, tR 30.8 min]; [
þ34.4
(c 0.4 in CHCl3); IR (film): 2965, 1701, 1456, 1358, 1254, 1174; 1H
NMR (CDCl3, 300 MHz): 7.42–7.29 (5H, m, ArH), 5.46 (1H, dq,
a
]
D
d
J¼10.0, 6.9, COCHCH3), 4.91 (1H, dd, J¼7.8, 1.8, NCH), 4.45 (1H,
dd, J¼9.5, 1.8, OCHxHy), 4.36 (3H, d, J¼10.0, CHOCH3), 4.32 (1H, dd,
J¼9.5, 7.8, OCHxHy), 3.08 (3H, s, OCH3), 1.01 (9H, s, C(CH3)3), 0.84
(3H, d, J¼6.9, COCHCH3); 13C NMR (CDCl3, 75.4 MHz):
d 186.9, 177.4,
139.1, 128.5, 128.3, 128.2, 87.4, 68.6, 65.0, 56.4, 43.8, 36.2, 25.6, 14.3;
HRMS (þESI): calcd for [MþH]þ C18H26NO3S 336.1627, found
336.1616; calcd for [MꢀOMe]þ C17H22NO2S 304.1365, found
304.1355.
0.35 (CH2Cl2); [
a
]
ꢀ8.4 (c 1.0, CHCl3) [lit.24
[
a]
ꢀ11.8 (c 0.98,
D
D
CHCl3)]; IR (KBr): 3184, 2960, 1534, 1285, 1183; 1H NMR (CDCl3,
300 MHz):
d
8.40 (1H, br s, NH), 4.62 (1H, t, J¼9.6, OCHxHy), 4.46
(1H, dd, J¼9.6, 6.3, OCHxHy), 3.81 (1H, dd, J¼9.6, 6.3, NCH), 0.94 (9H,
s, C(CH3)3); 13C NMR (CDCl3, 75.4 MHz)
d 189.6, 71.8, 65.8, 33.6,
25.0; MS–CI (NH3): m/z (%) 160 (100) [MþH]þ.
Acknowledgements
Financial support from the Spanish Ministerio de Ciencia y Tec-
3.9. Acylation of the 1,3-oxazolidine-2-thiones
´
nologıa and Fondos FEDER (Grants BQU2002-1514 and CTQ2006-
13249/BQU), and the Generalitat de Catalunya (2005SGR00584), as
well as doctorate studentship to A.C. (Generalitat de Catalunya) and
E.G. (Universitat de Barcelona) are acknowledged.
The acylation of oxazolidinethiones 3 was carried out follow-
ing the experimental procedure reported for the thiazolidine-
thiones 1.
References and notes
3.9.1. (S)-4-Isopropyl-N-propanoyl-1,3-oxazolidine-2-thione (7e)
Yield: 85%; white solid; mp 42–43 ꢁC [lit.25 mp 43–44 ꢁC]; Rf
1. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1996.
2. For recent contributions, see: (a) Gnas, Y.; Glorius, F. Synthesis 2006, 1899; (b)
Evans, D. A.; Helmchen, G.; Ru¨ping, M.; Bru¨ ckner, R.; Davis, F. A.; Enders, D.;
Bettray, W.; Hoffmann, R. W.; Kunz, H.; Meyers, A. I.; Murahashi, S.-I.; Imada, Y.
Asymmetric SynthesisdThe Essentials; Christmann, M., Bra¨se, S., Eds.; Wiley-
VCH: Weinheim, 2008; Part I, pp 3–47.
3. Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; John
Wiley & Sons: New York, NY, 1995.
4. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
5. (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3; (b) Evans,
D. A.; Shaw, J. T. Actual. Chim. 2003, 35.
0.65 (CH2Cl2); [
a
]
D þ126.6 (c 1.05, CHCl3); [lit.25
[a
]
D þ140.2 (c 1.07,
CHCl3)]; IR (KBr): 2968, 1706, 1465, 1405, 1328, 1200; 1H NMR
(CDCl3, 300 MHz):
d 4.79–4.64 (1H, m, NCH), 4.42–4.38 (2H, m,
OCH2), 3.41 (1H, dq, J¼18.1, 7.2, COCHxHy), 3.27 (1H, dq, J¼18.1, 7.2,
COCHxHy), 2.36 (1H, dhept, J¼6.9, 3.9, CH(CH3)2), 1.20 (3H, t, J¼7.2,
COCH2CH3), 0.95 (3H, d, J¼6.9, CH3CHCH3), 0.90 (3H, d, J¼6.9,
CH3CHCH3); 13C NMR (CDCl3, 75.4 MHz):
d 186.0, 174.8, 67.5, 63.2,
31.3, 28.9, 18.2, 14.9, 8.5; HRMS (þESI): calcd for [MþH]þ
C9H16NO2S 202.0896, found 202.0899.
6. Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56, 2489.
7. Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita,
E. J. Org. Chem. 1986, 51, 2391.
3.9.2. (S)-4-tert-Butyl-N-propanoyl-1,3-oxazolidine-2-thione (7f)
´
´
´
8. (a) Gonzalez, A.; Aiguade, J.; Urpı, F.; Vilarrasa, J. Tetrahedron Lett. 1996, 37,
8949; (b) Zhang, Y.; Phillips, A. J.; Sammakia, T. Org. Lett. 2004, 6, 23; (c) Zhang,
Y.; Sammakia, T. Org. Lett. 2004, 6, 3139; (d) Crimmins, M. T.; Shamszad, M. Org.
Lett. 2007, 9, 149; (e) Osorio-Lozada, A.; Olivo, H. F. Org. Lett. 2008, 10, 617.
9. For similar processes based on N-acetyl-1,3-oxazolidine-2-thiones, see: (a) Yan,
T.-H.; Hung, A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H. J. Org. Chem. 1995, 60,
3301; (b) Guz, N. R.; Phillips, A. J. Org. Lett. 2002, 4, 2253.
Yield: 95%; colorless oil; Rf 0.40 (50:50 hexanes/CH2Cl2); [
þ152.2 (c 1.1, CHCl3); IR (film): 2968, 1708, 1402, 1326, 1179, 1015;
1H NMR (CDCl3, 300 MHz):
a]
D
d
4.78 (1H, dd, J¼7.5, 1.7, NCH), 4.45
(1H, dd, J¼9.5, 1.7, OCHxHy), 4.34 (1H, dd, J¼9.5, 7.5, OCHxHy), 3.32
(1H, dq, J¼18.1, 7.2, COCHxHy), 3.25 (1H, dq, J¼18.1, 7.2, COCHxHy),
1.21 (3H, t, J¼7.2, COCH2CH3), 0.94 (9H, s, C(CH3)3); 13C NMR
10. For recent reviews on the synthesis and reactivity of chiral oxazolidinethiones
and thiazolidinethiones, see: (a) Vela´zquez, F.; Olivo, H. F. Curr. Org. Chem. 2002,
6, 1; (b) Ortiz, A.; Sansinenea, E. J. Sulfur Chem. 2007, 29, 109.
11. (a) Cosp, A.; Romea, P.; Talavera, P.; Urpı´, F.; Vilarrasa, J.; Font-Bardia, M.; Solans,
X. Org. Lett. 2001, 3, 615; (b) Cosp, A.; Romea, P.; Urpı´, F.; Vilarrasa, J. Tetrahedron
Lett. 2001, 42, 4629.
(CDCl3, 75.4 MHz):
d 187.0, 174.9, 69.2, 65.1, 36.1, 31.1, 25.8, 8.9;
HRMS (þESI): calcd for [MþH]þ C10H18NO2S 216.1052, found
216.1053.
12. For the preparation of thiazolidinethione-like chiral auxiliaries, see: (a)
Delaunay, D.; Toupet, L.; Le Corre, M. J. Org. Chem. 1995, 60, 6604; (b) See Ref. 10.
13. Other Lewis acids (BCl3, TiCl4, Et2AlCl, TMSOTf, Ti(i-PrO)4, MgCl2$OEt2, ZnCl2,
and LaCl3) were also surveyed, but all of them turned out to be less suitable.
Otherwise, the same overall yield (87%) and diastereomeric ratio (dr 88:12)
were achieved with SnCl4, but BF3$OEt2 was chosen because its milder char-
acter as Lewis acid.
3.10. General procedure for the titanium-mediated addition
of 7 to PhCH(OMe)2
The cross-coupling reaction of N-propanoyl-1,3-oxazolidine-
2-thiones 7 and PhCH(OMe)2 was carried out according to the
experimental procedure described for 2.
14. Crystallographic data (excluding structure factors) for this structure has been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC-150269. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
þ44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
3.10.1. (S)-4-Isopropyl-N-[(2R,3S)-3-methoxy-2-methyl-3-
phenylpropanoyl]-1,3-oxazolidine-2-thione (9e)
15. For a structural study on these adducts, see: Cosp, A.; Larrosa, I.; Anglada, J. M.;
´
Bofill, J. M.; Romea, P.; Urpı, F. Org. Lett. 2003, 5, 2809.
Yield of mixture: 57%; colorless viscous oil; Rf 0.45 (CH2Cl2);
HPLC (98:2 hexanes/EtOAc) tR 40.2 min [2,3-syn diastereomer, tR
16. The steric hindrance of the phenyl group has not been clearly established.
According to the A values (for a comprehensive list, see: Eliel, E. L.; Wilen, S. H.
Stereochemistry of Organic Compounds; John Wiley & Sons: New York, NY, 1994),
it is more bulky (A¼2.8 kcal molꢀ1) than other groups such as isopropyl (A¼
2.21 kcal molꢀ1). However, it is accepted that it becomes smaller than a methyl
group (A¼1.74 kcal molꢀ1) on the basis of the different conformational ar-
rangements available for the alternative transition states (for a nice discussion,
see: Roush, W. R. J. Org. Chem. 1991, 56, 4151). Since the diastereoselectivity of
the cross-coupling addition of the titanium enolates from 3 to PhCH(OMe)2
relies on kinetic grounds, it may be helpful to consider the phenyl group as the
smallest substituent positioned at C4 in the N-propanoyl thiazolidinethiones 3.
48.7 min]; 1H NMR (CDCl3, 300 MHz):
d 7.40–7.25 (5H, m, ArH),
5.35 (1H, dq, J¼9.9, 6.9, COCHCH3), 4.86 (1H, ddd, J¼7.7, 4.9, 3.8,
NCH), 4.45–4.35 (2H, m, OCH2), 4.33 (3H, d, J¼9.9, CHOCH3), 3.08
(3H, s, OCH3), 2.37 (1H, heptd, J¼7.0, 3.8, CH(CH3)2), 0.97 (3H, d,
J¼7.0, CH3), 0.96 (3H, d, J¼7.0, CH3), 0.90 (3H, d, J¼6.9, CH3); 13C
NMR (CDCl3, 75.4 MHz)
d 185.5, 175.2, 139.2, 128.2, 127.9, 127.8,
84.3, 66.9, 62.5, 56.8, 44.6, 28.6, 18.1, 14.4, 13.2.

5644
J. Baiget et al. / Tetrahedron 64 (2008) 5637–5644
17. For the effect of the C4 substituent of such chiral auxiliaries in the context of the
acetate aldol reaction, see Ref. 8b.
20. Unpublished results from Erik Galvez, Ph.D. Thesis in course.
21. However, it has been also reported that Lewis acid-mediated additions to
chiral dioxane acetals can proceed by an SN2 mechanism. For a nice account
on this issue, see: Denmark, S. E.; Almstead, N. G. J. Am. Chem. Soc. 1991, 113,
8089.
22. For related examples on the influence of C4 substituents on the structure of
several enolates, see: (a) Hintermann, T.; Seebach, D. Helv. Chim. Acta 1998, 81,
2093; (b) Bull, S. D.; Davies, S. G.; Key, M.-S.; Nicholson, R. L.; Savory, E. D. Chem.
Commun. 2000, 1721.
23. For the crucial role played by the exocyclic sulfur atom in the addition of
titanium enolates from N-acetyl-1,3-oxazolidine-2-thiones to 2,5-disubstituted
tetrahydrofurans, see: Jalce, G.; Seck, M.; Franck, X.; Hocquemiller, R.; Figade`re,
B. J. Org. Chem. 2004, 69, 3240.
24. Yamada, S.; Katsumata, H. J. Org. Chem. 1999, 64, 9365.
25. Cuzzupe, A. N.; Hutton, C. A.; Lilly, M. J.; Mann, R. K.; McRae, K. J.; Zammit, S. C.;
Rizzacasa, M. A. J. Org. Chem. 2001, 66, 2382.
18. An excellent analysis on the steric bulk of the C4 substituent in the addition of the
titanium enolates from N-acetyl-1,3-thiazolidine-2-thiones to dimethyl acetals
in the course of the total synthesis of (ꢀ)-hennoxazole has been recently re-
ported, see: Smith, T. E.; Kuo, W.-H.; Balskus, E. P.; Bock, V. D.; Roizen, J. L.; The-
berge, A. B.; Carroll, K. A.; Kurihara, T.; Wessler, J. D. J. Org. Chem. 2008, 73, 142.
19. Lewis acid-mediated additions of carbon nucleophiles to acetals usually
proceed through carbocation intermediates. For example, see: (a) Sammakia, T.;
Smith, R. S. J. Am. Chem. Soc. 1992, 114, 10998; (b) Sammakia, T.; Smith, R. S.
J. Am. Chem. Soc. 1994, 116, 7915; (c) Matsutani, H.; Ichikawa, S.; Yaruva, J.;
Kusumoto, T.; Hiyama, T. J. Am. Chem. Soc. 1997, 119, 4541; (d) Romero, J. A. C.;
Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 122, 168. For earlier
mechanistic discussions, see: (e) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki, K.;
Yamamoto, H.; Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 6107 and
references therein.