Diastereoselective Thia-Claisen rearrangement of pyrrolidinone-derived ketene N,S-acetals

Article abstract of DOI:10.1055/s-2008-1078030

Thia-Claisen rearrangements of S-allylic ketene N,S-acetals were carried out using substrates with an external allylic stereogenic centre. High levels of diastereoselectivity were observed only when a bromine substituent was introduced onto the double bon

Full text of DOI:10.1055/s-2008-1078030

LETTER
2199
Diastereoselective Thia-Claisen Rearrangement of Pyrrolidinone-Derived
Ketene N,S-Acetals
D
iastereoselective
d
T
hia-Claisen
a
R
earrange
m
ment of
K
etene
N
,
S
-Aceta
R
ls . Ellwood, Anne J. Price Mortimer, Derek A. Tocher, Michael J. Porter*
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London WC1H 0AJ, UK
Fax +44(20)76797463; E-mail: m.j.porter@ucl.ac.uk
Received 19 May 2008
Dedicated to Professor Sir Jack Baldwin FRS, an inspirational scientist, on his 70th birthday
Abstract: Thia-Claisen rearrangements of S-allylic ketene N,S-
acetals were carried out using substrates with an external allylic ste-
reogenic centre. High levels of diastereoselectivity were observed
only when a bromine substituent was introduced onto the double
bond.
R1
R1
R1
O
O
O
MeC(OR2)3
H+
O
O
O
OH
OR2
OR2
1 (R1 = H)
O
O
Key words: sulfur, bromine, diastereoselectivity, pericyclic reac-
tions, rearrangements
up to 3.1:1
2 (R1 = Me)
OBn R1
OBn R1
OBn R1
The Claisen rearrangement of allyl enol ethers and its
variants have been extensively studied and widely used in
synthesis.1 Among the desirable features of these reac-
tions is the reliable and predictable stereochemistry of the
products, arising through a chair-like transition state.
S
SMe
SMe
SMe
S
S
3 (R1 = H)
up to 1.5:1
4 (R1 = Me)
As a consequence of this ordered transition state, 1,3-
chirality transfer from a stereogenic centre within the six-
atom chain of the [3,3]-sigmatropic process is generally
excellent. Asymmetric induction from external stereogen-
ic centres has been much less frequently reported.2 In par-
ticular there are very few cases in which a stereogenic
centre attached to the ‘allyl fragment’ has been shown to
be effective in inducing asymmetry. For example,
Johnson–Claisen rearrangement of either the E- or Z-iso-
mers of alcohols 1 and 2 gives the corresponding products
in a ratio of no greater than 3.1:1 (Scheme 1).3 Similar re-
sults are obtained with a tetrahydropyranyl ether4 or a sug-
ar-derived 1,3-dioxane5 in place of the acetonide moiety,
although in the latter case, use of the Z-alkene geometry
raises the diastereoselectivity to >10:1. Slightly better re-
sults are obtained in the Ireland–Claisen rearrangement of
esters derived from 1; diastereomeric ratios up to 4.4:1 are
obtained from the E-isomer, and up to 9:1 from the Z-iso-
mer.6 The thia-Claisen rearrangements of compounds 3
(E-isomer) and 4 (E- and Z-isomers) also proceed with
low levels of stereoselectivity (Scheme 1).7
NBoc
NBoc
LDA, TMSCl
–110 to 0 °C
O
OTMS
BnO
BnO
O
O
5
6
Scheme 1
R2
R2
R2
H
R2
S
N
R1
S
S
S
N
R1
N
R1
N
R1
+
Br
7
8
9
10
11
Scheme 2 Thia-Claisen rearrangement of N,S-ketene acetals
amides or thiolactams such as 7 with allylic halides 8 and
deprotonation of the resulting salts 9 gives N,S-ketene ac-
etals 10 (Scheme 2). Rearrangement occurs spontaneous-
ly to give 11, and proceeds with high levels of
diastereoselectivity.10
A rare example of efficient asymmetric induction in such
reactions comes in the Ireland–Claisen rearrangement of
pyrrolidine substrate 5; in this case, product 6 is obtained
as a single stereoisomer (Scheme 1).8,9
As part of an ongoing project to synthesise the core of the
sarain alkaloids,10c we were interested in using such a re-
arrangement to prepare compound 11 (R1 = Bn, R2 =
CH2OH) in enantiomerically pure form. In this letter, we
describe our achievement of this goal through the use of
allylic bromides bearing a sacrificial stereogenic centre
which can subsequently be excised.
One variant of the Claisen rearrangement which has
received relatively little attention is the thia-Claisen rear-
rangement of N,S-ketene acetals. Alkylation of thio-
SYNLETT 2008, No. 14, pp 2199–2203
2
2
.0
8
.2
0
0
8
Advanced online publication: 05.08.2008
DOI: 10.1055/s-2008-1078030; Art ID: D16708ST
© Georg Thieme Verlag Stuttgart · New York
The initial substrate selected was allylic bromide 14a.
Conversion of 1,2:5,6-di-O-isopropylidene-D-mannitol

2200
A. R. Ellwood et al.
LETTER
OH
Br
Table 1 Product Ratios in Thia-Claisen Rearrangements
O
O
R
R
OH
i–iii
Entry Bromide Ratio
Yield of 17 Yield of 18 Yield of 19
iv
17:18:19a (%)b
(%)b
(%)b
O
O
O
O
O
O
HO
1
2
14a
14b
2.5:1:0.1 38
1:12.2:0.6c
10
1
2
2
52
12
13a (R = H)
13b (R = Br)
14a (R = H)
14b (R = Br)
a Ratios measured from the 1H NMR spectrum of the crude reaction
mixture.
Scheme 3 Reagents and conditions: (i) NaIO4, NaHCO3, H2O, 0 °C
to r.t.; (ii) EtO2CCHRPO(OEt)2, K2CO3, H2O, 0 °C to r.t.; (iii)
DIBAL-H, CH2Cl2, –78 °C, 13a (75%) from 12; 13b (43%) from 12;
(iv) NBS, PPh3, CH2Cl2, 0 °C to r.t., 14a (93%); 14b (67%).
b Isolated yields of single diastereomers.
c A trace amount of another compound, thought to be the fourth dia-
stereomer, was also observed.
O
O
In an attempt to bias the conformation of 16 towards a sin-
gle rotamer, an analogue of 14a was chosen in which the
alkene bears a further substituent; this should induce sig-
nificant A1,3-strain, restricting rotation about the relevant
C–C bond, and improving the diastereoselectivity of the
sigmatropic rearrangement.13
R
i. 14a or 14b, MeCN
ii. Et3N, MeCN, 35 °C
S
S
N
N
Bn
15
Bn
16a (R = H)
16b (R = Br)
The chemistry used previously was thus modified by the
use
of
a
brominated
phosphonate
reagent,
EtO2CCH(Br)PO(OEt)2,14 in the Wadsworth–Emmons
step to give the corresponding ester as a 1.6:1 Z:E mixture
(Scheme 3). After reduction to the alcohol 13b, the geo-
metric isomers were separated and the Z-isomer converted
into allylic bromide 14b.
O
O
O
O
O
H
O
H
H
R
R
R
This allylic bromide was next employed in the thia-
Claisen rearrangement (Scheme 4) and, pleasingly, af-
forded the products 17b–19b with good diastereoselectiv-
ity (Table 1, entry 2).15 The major product in this
rearrangement was the (2R,3¢S,4¢S)-isomer 18b, in con-
trast to the nonbrominated substrate which afforded pri-
marily the (2S,3¢R,4¢S)-isomer 17a.
S
S
S
N
N
N
Bn
Bn
Bn
17a (R = H)
17b (R = Br)
18a (R = H)
18b (R = Br)
19a (R = H)
19b (R = Br)
Scheme 4 Thia-Claisen rearrangements
(12) into allylic alcohol 13a was achieved using the pro-
cedure of Marshall et al.,11 which consists of periodate
cleavage, Wadsworth–Emmons reaction under aqueous
conditions, and DIBAL-H reduction. Treatment of the al-
cohol 13a with N-bromosuccinimide and triphenylphos-
phine led to allylic bromide 14a (Scheme 3).12
Assignment of the configuration of products 17–19 was
accomplished through a combination of crystallography
and chemical correlations.
Removal of the acetonide from 18a with 60% aqueous
acetic acid afforded the crystalline diol 20, whose struc-
ture was unambiguously assigned by X-ray crystallogra-
phy (Scheme 5).16
Alkylation of N-benzylpyrrolidine-2-thione (15) with bro-
mide 14a was followed by deprotonation with triethyl-
amine in acetonitrile to give the transient intermediate
16a; following thia-Claisen rearrangement, this afforded a
mixture of thiolactams 17a, 18a and 19a, three of the four
possible stereoisomeric products (Scheme 4) (see below
for stereochemical assignment). The results are sum-
marised in Table 1 (entry 1).
The major products were the expected isomers 17a and
18a, arising from a chair transition state, with only a small
amount of a third diastereomer 19a. However, the levels
of diastereoselectivity were disappointingly low (2.5:1),
reflecting a low level of facial selectivity imparted upon
the exocyclic double bond by the adjacent stereocentre in
16a. We postulated that this lack of selectivity could be
due to the presence of more than one significantly popu-
lated rotamer about the bond between the alkene and the
stereogenic centre.
Scheme 5 Preparation of diol 20 and thermal ellipsoid plot; ellip-
soids are drawn at 50% probability level and the H atoms have an ar-
bitrary radius
Synlett 2008, No. 14, 2199–2203 © Thieme Stuttgart · New York

LETTER
Diastereoselective Thia-Claisen Rearrangement of Ketene N,S-Acetals
2201
O
O
O
OH
O
O
O
H
O
H
O
H
OH
HO
H
OH
H
H
H
Br
i or ii
i–iii
ii,iii
S
S
S
S
N
S
S
S
N
N
N
N
N
N
Bn
Bn
Bn
Bn
Bn
Bn
Bn
18b
18a
19a
17a
21
20
22
Scheme 6 Reagents and conditions: (i) 60% aq AcOH, 88%; (ii)
NaIO4, SiO2, CH2Cl2, H2O; (iii) NaBH4, EtOH, THF, 21 (51%), 22
(31%) (two steps).
O
O
O
O
H
H
Br
ii
Assignment of the stereochemistry of 17a was achieved
by cleavage of the protected diol unit. Deprotection of 17a
with aqueous acetic acid (as for 18a), followed by cleav-
age with silica-supported periodate17 and reduction with
sodium borohydride gave alcohol 21, whereas oxidative
cleavage and reduction of diol 20 gave alcohol 22
(Scheme 6). These products had identical 1H NMR spec-
tra but opposite specific rotations.18 As the stereochemis-
try of 22 could be deduced from the previously obtained
crystal structure of 18a, 21 could be identified as its enan-
tiomer and hence 17a assigned the structure shown.
S
S
N
N
Bn
Bn
17b
17a
Scheme 7 Reagents and conditions: (i) Et3N, HCOOH, Pd(OAc)2,
PPh3, DMF, 65 °C, 18a (35%) + 19a (21%); (ii) Bu3SnH, Pd(PPh3)4,
THF, reflux, 18a (50%) from 18b; 17a (60%) from 17b.
BnN
R
BnN
R
O
O
H
O
17a,b
18a,b
S
S
H
Correlation between the brominated and nonbrominated
series of compounds was next sought by carrying out pal-
ladium-catalysed debromination of the major bromoalk-
ene product 18b. Initially, triethylammonium formate was
used as the reducing agent;19 however, this gave a mixture
of two nonbrominated products, 18a and 19a, due to
epimerisation either preceding or following the debromi-
nation event (Scheme 7). While this result did not allow
assignment of the stereostructure of 18b, it did indicate
that 18a and 19a were epimeric at the position a to the
thiocarbonyl group.
O
I
II
Scheme 8 Proposed reactive conformations of 16a (R = H) and 16b
(R = Br)
picted as I and II in Scheme 8. Conformation I gives rise
to products 18a and 18b while conformation II leads to
products 17a and 17b.
The preference for reaction on the allylic sulfide compo-
nent to take place anti to the oxygen substituent can be un-
derstood if the reaction is considered as a nucleophilic
attack on this component; the newly forming s-bond is
then stabilised by overlap with the low-lying s* orbital of
the C–O bond.21 Such an effect, in related Ireland–Claisen
rearrangements, has been characterised computationally
by Kahn and Hehre as involving the more electron-poor
face of the electrophilic component.22
In the case of brominated intermediate 16b, A1,3-strain en-
sures that conformation I is strongly favoured over II, and
the major product is 18b. For the nonbrominated analogue
16a, the absence of a double bond substituent means that
the energy difference between the two possible transition
states is much smaller and indeed a slight preference for
product 17a, arising through conformation II, is ob-
served.23
Epimerisation was avoided through the use of tributyltin
hydride as the reductant20 in the palladium-catalysed de-
bromination. Under these conditions, 18a was obtained as
a single isomer, confirming that 18b had the structure
shown and indirectly confirming the structure of 19a.
Debromination of bromoalkene 17b under the same con-
ditions gave solely 17a, establishing the stereochemical
equivalence of these two compounds.
Definitive assignments of five of the six rearrangement
products could thus be made; minor bromoalkene product
19b was not obtained in sufficient quantity to carry out its
debromination, and its stereostructure was assigned only
tentatively, by analogy with 19a.
The stereochemical course of the thia-Claisen reaction
can be rationalised by considering the reactive conforma-
tions of intermediates 16a and 16b. If it is assumed that (i)
the reaction takes place through a chair transition state,
and that (ii) reaction of the ‘nucleophilic’ N,S-ketene ace-
tal fragment on the ‘electrophilic’ allyl sulfide fragment
occurs anti to the allylic oxygen substituent, then two pos-
sible reactive conformations can be drawn, these are de-
It is noteworthy that in previously reported examples of
asymmetric induction in Claisen-type rearrangements, the
presence of a methyl substituent on the double bond had
little effect on diastereoselectivity (e.g. 1 vs. 2, 3 vs. 4,
Scheme 1). By contrast, in the present example the intro-
duction of a bromine substituent greatly increases the
Synlett 2008, No. 14, 2199–2203 © Thieme Stuttgart · New York

2202
A. R. Ellwood et al.
LETTER
with 2% citric acid (2 × 50 mL). The combined aqueous
washings were extracted with CH2Cl2 (50 mL), and the
combined organic layers were dried (MgSO4) and
magnitude of the diastereoselectivity, and reverses its
sense. Furthermore, the bromine substituent can be re-
moved after the rearrangement step.
concentrated in vacuo to give the crude product (190 mg,
76%). Flash chromatography (SiO2; EtOAc–PE, 1:19)
afforded 18b (130 mg, 52%) as a pale yellow oil; Rf 0.43
(EtOAc–PE, 15:85); [a]D20 +31.5 (c = 1.08, CHCl3). IR
(CHCl3 cast): 2983, 2934, 2874 (CH), 1625 (C=C), 1499,
1452, 1316 (C=S) cm–1. 1H NMR (500 MHz, CDCl3): d =
1.28 (3 H, s) and 1.34 [3 H, s, C(CH3)2], 2.30–2.40 (2 H, m,
NCH2CH2), 3.21 (1 H, br t, J = 8.5 Hz, CHC=S), 3.51 (1 H,
ddd, J = 11.0, 8.5, 7.0 Hz) and 3.62 (1 H, ddd, J = 11.0, 8.8,
5.2 Hz, NCH2CH2), 3.76 (1 H, dd, J = 8.5, 6.8 Hz, CHHO),
3.88 [1 H, dd, J = 10.1, 1.8 Hz, H2C=C(Br)CH], 4.10 (1 H,
dd, J = 8.5, 6.1 Hz, CHHO), 4.44 (1 H, ddd, J = 10.1, 6.8, 6.1
Hz, CHO), 4.79 (1 H, d, J = 14.6 Hz) and 5.16 (1 H, d, J =
14.6 Hz, PhCH2), 5.51 (1 H, dd, J = 1.8, 0.5 Hz) and 5.90 (1
In conclusion, we have ensured high levels of diastereose-
lectivity in the thia-Claisen rearrangement of chiral sub-
strates through the judicious exploitation of allylic strain.
Further studies into these reactions, and their application
in synthesis, are ongoing.
Acknowledgment
We thank Dr. Abil Aliev for assistance with NMR experiments, and
UCL Graduate School and EPSRC for funding.
H, dd, J = 1.8, 0.4 Hz, C=CH2), 7.26–7.32 (5 H, m, ArH). 13
NMR (125 MHz, CDCl3): d = 22.2 (NCH2CH2), 26.0 and
26.5 [C(CH3)2], 51.9 (PhCH2), 52.8 (NCH2CH2), 55.2
C
References and Notes
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(2) For reviews of asymmetric [3,3]-sigmatropic
rearrangements, see: (a) Enders, D.; Knopp, M.; Schiffers,
R. Tetrahedron: Asymmetry 1996, 7, 1847. (b) Ito, H.;
Taguchi, T. Chem. Soc. Rev. 1999, 29, 43. (c)Nubbemeyer,
U. Synthesis 2003, 961.
(3) (a) Suzuki, T.; Sato, E.; Kamada, S.; Tada, H.; Unno, K.;
Kametani, T. J. Chem. Soc., Perkin Trans. 1 1986, 387.
(b) Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K.
J. Chem. Soc., Perkin Trans. 1 1987, 91. (c) Nemoto, H.;
Satoh, A.; Ando, M.; Fukumoto, K. J. Chem. Soc., Perkin
Trans. 1 1991, 1309.
[H2C=C(Br)CH], 56.9 (CHC=S), 68.7 (CH2O), 74.7 (CHO),
110.1 [C(CH3)2], 119.8 (C=CH2), 127.9, 128.2 and 128.7
(aromatic CH), 133.5 (C=CH2), 135.3 (aromatic C), 203
(C=S). MS (CI+, CH4): m/z = 410 (16), 412 (14) [MH+], 352
(46), 354 (50) [MH+ – Me2CO], 338 (63), 330 (100) [MH+ –
HBr]. HRMS: m/z [MH+] calcd for C19H2579BrNO2S:
410.0789; found: 410.0799.
(16) X-ray data: C16H21NO2S, M = 291.40; T = 150(2) K;
orthorhombic, P212121, a = 8.6108(10), b = 13.2760(16),
c = 13.3204(16) Å; Z = 4; Dc = 1.271 g/cm3; F(000) = 624;
m(Mo–Ka) = 0.214 mm–1; 12892 reflection, 3586
(4) Hatakeyama, S.; Saijo, K.; Takano, S. Tetrahedron Lett.
independent (Rint = 0.0336) measured on a Bruker SMART
APEX CCD diffractometer using Mo–Ka radiation; R1 =
0.0350, wR2 = 0.0834 (3346 reflections F2 >2s F2), R1 =
0.0382, wR2 = 0.0855 (all data). Atomic coordinates and
further crystallographic details have been deposited at the
Cambridge Crystallographic Data Centre, deposition
number CCDC 687669. Copies of these data can be obtained
by applying to CCDC, University Chemical Laboratory,
Lensfield Road, Cambridge CB2 1EW, U.K.; fax: +44
(1223)336033; email: deposit@ccdc.cam.ac.uk.
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(9) High levels of asymmetric induction have also been
observed in zwitterionic Claisen-type rearrangements
involving either sulfide-ketene adducts or deprotonated N-
acylammonium salts. See: (a) Nubbemeyer, U.; Öhrlein, R.;
Gonda, J.; Ernst, B.; Belluš, D. Angew. Chem., Int. Ed. Engl.
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(18) Data for 21: Rf 0.23 (EtOAc–PE, 30:70); [a]D20 –73.2 (c =
0.40, CHCl3). IR (CHCl3 cast): 3399 (br, OH), 2923, 2875
(CH), 1635 (C=C), 1508, 1453, 1310 (C=S) cm–1. 1H NMR
(500 MHz, CDCl3): d = 1.87 (1 H, ddt, J = 12.8, 8.8, 6.1 Hz)
and 2.17 (1 H, dtd, J = 12.8, 9.1, 5.9 Hz, NCH2CH2), 2.62 (1
H, br s, OH), 3.02 (1 H, m, H2C=CHCH), 3.33 (1 H, ddd,
J = 9.1, 6.3, 3.6 Hz, CHC=S), 3.44 (1 H, ddd, J = 11.2, 9.1,
6.1 Hz) and 3.49 (1 H, ddd, J = 11.2, 8.8, 5.9 Hz, NCH2CH2),
3.71 (1 H, dd, J = 11.5, 6.5 Hz) and 3.84 (1 H, dd, J = 11.5,
9.1 Hz, CH2OH), 4.90 (1 H, d, J = 14.3 Hz) and 5.05 (1 H, d,
J = 14.3 Hz, PhCH2), 5.10 (1 H, dd, J = 10.5, 1.8 Hz) and
5.20 (1 H, dd, J = 17.3, 1.8 Hz, CH=CH2), 5.64 (1 H, ddd,
J = 17.3, 10.5, 8.8 Hz, CH=CH2), 7.28–7.34 (5 H, m, ArH).
13C NMR (125 MHz, CDCl3): d = 23.1 (NCH2CH2), 49.3
(H2C=CHCH), 51.8 (PhCH2), 52.8 (NCH2CH2), 55.1
(CHC=S), 63.0 (CH2OH), 118.4 (CH=CH2), 128.1, 128.3
and 128.8 (aromatic CH), 134.9 (aromatic C), 135.6
(CH=CH2), 202.7 (C=S). MS (CI+, CH4): m/z = 290 (22)
[M + C2H5]+, 262 (100) [MH+], 244 (32) [MH+ – H2O], 191
(25). HRMS: m/z [M + H+] calcd for C15H20NOS: 262.1266;
found: 262.1260.
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5467.
(15) A mixture of thioamide 15 (116 mg, 0.61 mmol), bromide
14b (200 mg, 0.67 mmol), MeCN (1 mL) and 4 Å molecular
sieves (250 mg) was stirred under an argon atmosphere for 4
d. Further MeCN (2 mL) was added and the mixture warmed
to 35 °C. Et3N (94 mL, 0.67 mmol) was added and the
resulting solution was stirred at 35 °C for 7 h. The mixture
was cooled to r.t., diluted with CH2Cl2 (30 mL) and washed
For 22: [a]D20 +71.4 (c = 0.28, CHCl3).
(19) Rossi, R.; Bellina, F.; Raugei, E. Synlett 2000, 1749.
Synlett 2008, No. 14, 2199–2203 © Thieme Stuttgart · New York

LETTER
Diastereoselective Thia-Claisen Rearrangement of Ketene N,S-Acetals
2203
(20) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033.
(21) (a) Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett.
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(23) An alternative explanation is that both products arise from
transition states in which the methine C–H bond of the
acetonide eclipses the double bond, but the selectivity for
reaction anti to the allylic C–O bond is imperfect. Such an
explanation, however, does not account for the difference
between the brominated and nonbrominated substrates.
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