Reversal of facial selectivity in a thia-Claisen rearrangement by incorporation of a vinylic bromine substituent

Article abstract of DOI:10.1039/c3ob41580e

Thia-Claisen rearrangements have been carried out using N-benzylpyrrolidine-2-thione and chiral allylic bromides derived from d-mannitol. Introduction of a bromine atom onto the double bond of the allylic bromide reverses the sense of diastereoselectivity in the [3,3]-sigmatropic rearrangement. Density functional theory calculations lead us to rationalise the observed selectivity in terms of a Cieplak effect.

Full text of DOI:10.1039/c3ob41580e

Organic &
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Reversal of facial selectivity in a thia-Claisen
rearrangement by incorporation of a vinylic bromine
Cite this: Org. Biomol. Chem., 2013, 11,
7530
substituent†
Adam R. Ellwood,a Anne J. Price Mortimer,a Jonathan M. Goodmanb and
Michael J. Porter*a
Received 1st August 2013,
Thia-Claisen rearrangements have been carried out using N-benzylpyrrolidine-2-thione and chiral allylic
bromides derived from D-mannitol. Introduction of a bromine atom onto the double bond of the allylic
bromide reverses the sense of diastereoselectivity in the [3,3]-sigmatropic rearrangement. Density func-
tional theory calculations lead us to rationalise the observed selectivity in terms of a Cíeplak effect.
Accepted 25th September 2013
DOI: 10.1039/c3ob41580e
www.rsc.org/obc
while rearrangement of the related ketene dithioacetal 3
occurs at room temperature to give 4 as the major component
Introduction
The Claisen rearrangement of allyl vinyl ethers and related of a 1.9 : 1 mixture.7 Johnson–Claisen rearrangement of allylic
[3,3]-sigmatropic rearrangements have been extensively alcohol 5, bearing a sulfur substituent at the allylic stereogenic
studied and widely utilised in synthesis.1 In these reactions, a centre, gives ester
6
as the major component of
new carbon–carbon bond is formed, and one or two new 1.5 : 1 mixture of stereoisomers.8 Reformatskii–Claisen
stereogenic centres may be created. rearrangement of allylic ester 7 gives 8 as the major compound
As a consequence of the ordered transition state of such in an 8.7 : 3.4 : 1.8 : 1 mixture of diastereomers.9
a
rearrangements, it is possible to use existing stereogenic
A higher level of asymmetric induction is observed in the
centres to direct the formation of new ones.2 Most of the Ireland–Claisen rearrangement of amino acid-derived esters
examples of stereoselective rearrangement reported in the lit- such as 9, with 10 being the only product stereoisomer
erature involve 1,3-chirality transfer from a stereogenic centre obtained.3 Similarly,
a stereoselective zwitterionic [3,3]-
within the six atoms of the allyl vinyl ether system. Examples rearrangement takes place on treatment of 11 with dichloro-
of asymmetric induction from an external stereogenic centre ketene, leading to 12 as a single stereoisomer.4a
are less common; in particular, there are very few cases in
As part of a programme directed towards the synthesis of
which such a stereogenic centre on the “allyl” portion of the the sarain alkaloids, we have utilised a thia-Claisen rearrange-
molecule has proven effective in inducing high levels of asym- ment10 to establish the two stereogenic centres in thiolactam
metry in the rearrangement step.3,4
intermediate 14 (Scheme 2). Following S-alkylation of N-benzyl-
Several [3,3]-sigmatropic rearrangements of E-alkenes pyrrolidine-2-thione (13) with the appropriate allylic bromide,
bearing an electronegative substituent in the allylic position deprotonation with triethylamine afforded directly the
are depicted in Scheme 1; the sense of asymmetric induction rearranged product 14 with >40 : 1 diastereoselectivity.11
is the same in all cases, although its magnitude varies. For
Herein we report our efforts to modify this diastereoselec-
example, Ireland–Claisen rearrangement of ester 1 gives 2 as tive reaction to give products such as 14 in enantiomerically
the major product with a diastereomeric ratio of 1.4 : 1,5,6 enriched form. Our hope at the outset was that replacement of
the achiral allylic bromide in Scheme 2 with chiral analogues
such as 15 would lead to a preponderance of one of the dia-
aDepartment of Chemistry, University College London, Christopher Ingold Building,
stereomeric products 16 and 17 (Scheme 3). Following separ-
20 Gordon Street, London, WC1H 0AJ, UK. E-mail: m.j.porter@ucl.ac.uk;
ation of these compounds, cleavage of the protected diol
unit could potentially lead to compound 14 as a single
enantiomer.12
Six allylic bromides were investigated (Fig. 1): E-disubsti-
tuted alkenes 18a and 19a and Z-alkene 20a, together with the
analogous compounds 18b–20b in which the double bond
carries an additional bromine substituent.
Fax: +44 (0)20 7679 7463; Tel: +44 (0)20 7679 4710
bUnilever Centre for Molecular Science Informatics, Department of Chemistry,
Lensfield Road, Cambridge, CB2 1EW, UK
†Electronic supplementary information (ESI) available: Details of the synthesis
of allylic bromides 18a–20b and of stereochemical assignments of thia-Claisen
products; NMR spectra for all new compounds synthesised. Details of compu-
tational studies, with Cartesian coordinates and energies of transition states
Ia–IIc and Ia*–IIc* for substrates 27a and 27b. See DOI: 10.1039/c3ob41580e
7530 | Org. Biomol. Chem., 2013, 11, 7530–7539
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Scheme 3 Proposed diastereoselective thia-Claisen rearrangement.
Fig. 1 Allylic bromides used in the study.
these syntheses, including full spectroscopic data, can be
found in the ESI.†
Thia-Claisen rearrangements
Initial attempts at the key thia-Claisen rearrangement were
carried out using bromide 18a under the conditions which we
had previously developed.11 Thus N-benzylpyrrolidine-2-thione
(13) was alkylated with allylic bromide 18a in acetonitrile.
Addition of 4 Å molecular sieves was found to be helpful in
suppressing undesired side reactions. Following dilution with
further acetonitrile, the mixture was warmed to 40 °C and tri-
ethylamine was added. The thia-Claisen rearrangement took
place to give a mixture of three stereoisomeric thiolactam pro-
ducts, 21a, 22a and 23a in a ratio of 69 : 28 : 3 (Scheme 4 and
Table 1, entry 1). The two predominant products were those
expected if the rearrangement proceeds through a chair
transition state (see ESI† for details of the assignment of
stereochemistry).
Scheme 1 Previously reported diastereoselective Claisen rearrangements.
We anticipated that the use of trisubstituted alkene sub-
strate 18b would give 21b with an enhanced level of asym-
metric induction. Surprisingly, use of 18b instead led to a
reversal in the stereochemical preference of the reaction, and
products 21b, 22b and 23b were formed in a 7 : 88 : 5 ratio
(Table 1, entry 2).
The two geometrically isomeric allylic bromides 20a and
20b were also subjected to the thia-Claisen sequence; with
these substrates, diastereoselectivities were modest and, as
expected, the major stereoisomer 23 from these rearrange-
ments was one which had been a minor component in the pre-
vious reactions (Table 1, entries 3 and 4), consistent with a
chair-like transition state. The same stereoisomer was the
major product for both substrates.
Scheme 2 Thia-Claisen reaction. Reagents and conditions: (E)-HOCH2CHv
CHCH2Br, MeCN then Et3N, 40 °C, 67%.
Results and discussion
Preparation of allylic bromides
Allylic bromides 18a–20b were all synthesised by standard
methods from 1,2 : 5,6-diisopropylidene-D-mannitol. Details of
Use of the bis-silyl ether 19a in place of the acetonide
18a gave a markedly higher ratio of thia-Claisen products
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Scheme 4 Thia-Claisen rearrangement of acetonide-containing substrates. Reagents and conditions: (i) MeCN, rt, 4 Å molecular sieves; (ii) Et3N, 40 °C.
Table 1 Products of thia-Claisen rearrangements
Entry
Bromide
Ratio 21 : 22 : 23 : 24a
Yield 21b/%
Yield 22b/%
Yield 23b/%
Yield 24b/%
1
2
3
4
18a
18b
20a
20b
69 : 28 : 3 : 0
7 : 88 : 5 : 0
25 : 25 : 50 : 0
5 : 17 : 61 : 17
38
2
10
1
10
52
11
6
1
2
18
39
—
—
—
9
a Ratios determined from the 1H NMR spectra of the crude reaction mixtures. b Isolated yields following column chromatography.
Fig. 2 Facial selectivity in the N,S-ketene acetal intermediates derived from 18
and 19.
and 19a). The choice of protecting groups was seen to have a
significant effect: bis-silyl ether 19a (entry 1, Table 2) gave a
much more diastereomerically enriched mixture of products
than acetonide 18a.
Scheme 5 Thia-Claisen rearrangement of silyl ether-containing substrates.
Reagents and conditions: (i) 13, MeCN, rt, 4 Å molecular sieves; (ii) Et3N, 40 °C.
Table 2 Products of thia-Claisen rearrangements
Installation of a bromine atom on the double bond had a
profound effect on stereoselectivity, with the sense of asym-
metric induction reversed between acetonides 18a and 18b
(entries 1 and 2, Table 1).
Entry
Bromide
Ratio 25 : 26a
Yield 25b/%
Yield 26b/%
1
2
19a
19b
>97 : 3
—
41
—
1
—
c
In each of the rearrangement reactions, the relative con-
figuration of the two newly-formed stereogenic centres in the
major product is consistent with a chair-like transition state,
while their absolute configuration is determined by any facial
selectivity imparted by the pre-existing stereogenic centre. Ana-
lysis of the stereochemical course of the reaction indicates that
the non-brominated substrates 18a and 19a show a tendency
for reaction through the conformation I (Re-face selectivity at
the N,S-ketene acetal, Fig. 2) while vinyl bromide 18b reacts
primarily through conformation II (Si-face selectivity).
In trying to elucidate the reasons for this divergent stereo-
selectivity, it is necessary to consider six reactive confor-
mations of the diene, corresponding to three rotamers about
the bond linking the alkene to the stereogenic centre for each
of the conformations I and II. These conformations are
depicted in Fig. 3: in conformations Ia and IIa, the new C–C
a Ratio determined from the 1H NMR spectrum of the crude reaction
mixture; the reaction of 19a also generated some unidentified
by-products. b Isolated yields following column chromatography.
c No thia-Claisen rearrangement product was obtained from this reaction.
(Scheme 5, Table 2, entry 1); in this case only two stereo-
isomers, 25a and 26a, were observed. Attempts to use bis-silyl
ether 19b in thia-Claisen reactions were completely unsuccess-
ful, yielding none of the expected products 25b and 26b.
Discussion
The diastereoselectivity of the thia-Claisen rearrangements
ranged from poor (in the case of 18a and 20a) to excellent (18b
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product 22b. As there was no obvious explanation for the change
in stereochemical preference on bromination of the double
bond, we carried out a computational study to gain further
insight into the stereochemical course of these reactions.16
Computational studies
Initial attempts to locate transition states for compounds con-
taining a dioxolane ring indicated a complicated potential
energy surface on which multiple transition states, differing
only in the conformation of the dioxolane, could be identified.
In order to simplify the computational problem, while retain-
ing the salient features of substrates 18 and 19, we chose to
carry out the computational study on the rearrangement of
allylic methyl ethers 27a and 27b (Fig. 4).
Fig. 3 Possible reactive conformations of the N,S-ketene acetal intermediates
derived from 18 and 19.
A detailed search for chair-like transition state geometries
was undertaken using density functional theory: for each of
the two substrates 27a and 27b, we considered (i) Re and Si-
face reaction of the N,S-ketene acetal (i.e. I and II, Fig. 2); (ii)
three rotamers about the bond linking the alkene to the stereo-
genic centre (i.e. a, b and c, Fig. 3); and (iii) three staggered
rotamers about the MeO–C bond, giving a total of 18 possible
transition state structures for each compound. For each of the
two compounds 27a and 27b, transition states were located for
17 of the 18 possible conformations – the missing confor-
mation in each case being one of type IIb in which the
O-methyl group would be directed into the pyrroline ring.
For all six conformer types Ia–IIc for both substrates, the
rotamer in which the O–CH3 bond lay antiperiplanar to the
alkene portion of the molecule was markedly lower in energy
than the other two rotamers around the C–OCH3 bond, and so
only these rotamers were considered for the remainder of the
study.
Having identified transition states corresponding to the
conformers Ia–IIc, it was noted that two different confor-
mations of the pyrroline ring, differing in the direction of pyra-
midalisation of the nitrogen atom, were present among the
transition states identified. Further searching was therefore
carried out to locate transition states for both pyrroline confor-
mers in every case.
This exhaustive search resulted in twelve transition state
structures for each of the two substrates, corresponding to the
six conformations Ia–IIc each with two different pyrroline con-
formations. Fig. 5 shows twelve of these 24 transition state
structures17 – in each case, the structure depicted is the lower-
bond is formed antiperiplanar to the allylic C–O bond; in con-
formations Ib and IIb, it is formed antiperiplanar to the allylic
C–C bond; while in conformations Ic and IIc, it is formed anti-
periplanar to the allylic C–H.‡
The selectivity observed for the non-brominated substrates
18a and 19a is consistent with that shown by all the related lit-
erature examples (Scheme 1); such selectivity has previously
been rationalised in terms of a reactive conformation corres-
ponding to Ia. The electron-rich character of the N,S-ketene
acetal component means that the rearrangement is expected to
occur through a polarised transition state, with a “nucleo-
philic” ketene acetal fragment and an “electrophilic” allyl
component.13 Attack on the electrophilic component is
assumed to take place antiperiplanar to the allylic C–O bond,
as this allows stabilization of the newly forming σ-bond by
interaction with the low-lying σ*-orbital of the C–O bond;13,14
hence reaction should take place through either conformation
Ia or IIa. The preference for the former conformation can be
understood as Ia will suffer less allylic (A1,3) strain15 than IIa.
The stereochemical preferences of vinyl bromide substrate
18b are contrary to all previously reported [3,3]-sigmatropic
rearrangement substrates with an electronegative allylic substi-
tuent, and this behaviour is harder to explain. Our a priori
expectation had been that the increased allylic (A1,3) strain in
conformation IIa when R ≠ H would lead to a stronger prefer-
ence for reactive conformation Ia and hence an enhanced level
of stereoselectivity in favour of product 21b. The experimental
observation, conversely, was that 22b is the major product in
the reaction of bromide 18b.
It seems unlikely that the reaction of bromide 18b proceeds
through conformation IIa, in which allylic strain will be more
severe than in conformer Ia, and so the other possible confor-
mations must be considered. Conformations Ib or Ic would lead
to product 21b, while IIb or IIc would lead to the observed major
‡The structures in Fig. 3 are depicted for clarity with a substituent at the allylic
stereocentre eclipsing the vinylic substituent R; the conformations in which the
new σ-bond is formed antiperiplanar to an existing substituent are obtained by a
rotation of 30° about the C(sp2)–C(sp3) bond.
Fig. 4 Simplified structures for computational studies.
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Fig. 5 Transition state structures for thia-Claisen rearrangement of 27a (left) and 27b (right). Hydrogen atoms, other than the one at the stereogenic centre, are
omitted for clarity.
Table 3 Properties of the thia-Claisen transition states
Transition
structure
Facial
Antiperiplanar
atomb
27a ΔΔG‡/kJ mol−1
27b ΔΔG‡/kJ mol−1
orientationa
[M06-2X/B3LYP]c,d
[M06-2X/B3LYP]c,d
Ia
IIa
Ib
IIb
Ic
IIc
Re
Si
Re
Si
Re
Si
O
O
C
C
H
H
21.1 (17.5)
9.9 (7.2)
0.0 (0.0)
3.7 (5.6*)
8.3 (10.3*)
22.1 (21.0)
10.4 (8.2)
27.4 (21.7)
11.3 (9.9*)
0.0 (0.0)
6.0 (8.1)
7.3 (8.6*)
a Face selectivity as defined by reaction of the N,S-ketene acetal moiety. b Atom bonded to the stereogenic centre which is most nearly
antiperiplanar to the forming C–C bond. c Gibbs energy of transition states relative to the lowest in energy for that set. Figures in parentheses
indicate solution (THF) phase energies calculated for the gas-phase optimised structures. An asterisk denotes the Gibbs energy of a structure
differing in the pyrroline conformation from that depicted. d Gibbs energy calculated by a single-point energy calculation with the M06-2X
functional on the B3LYP gas-phase optimised structure, followed by a free energy correction from the B3LYP values.17
energy of the two pyrroline conformations. The relative Gibbs C–C bond. Rather the most favourable transition states are
energies of these transition states are collected in Table 3.18 In those in which the allylic C–C bond occupies the antiperipla-
four cases, the energetic ordering of the two pyrroline confor- nar position (i.e. Ib and IIb), with structure Ib (corresponding
mations was reversed between gas-phase and solution-phase to the observed major product) having the lowest energy of all
calculations; these cases are marked with an asterisk.
the transition states. Only a small Gibbs energy difference was
Contrary to our expectation, the lowest-energy transition found between structures Ib and IIb (3.7 kJ mol−1 in the gas
states for the reaction of 27a did not place the C–O bond phase, 5.6 kJ mol−1 in solution). This corresponds qualitatively
of the stereogenic centre antiperiplanar to the newly-forming to the low stereoselectivity observed in the reaction.
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In the case of brominated substrate 27b, the lowest energy
transition state is again one in which the newly forming C–C
bond is situated antiperiplanar to the C–C bond at the stereo-
genic centre; for this compound however, structure IIb is
markedly lower in energy than structure Ib, as would be
expected from the greater degree of A1,3-strain in Ib. Indeed,
while IIb is the lowest-energy transition state structure for this
substrate, the next-lowest is Ic, in which a hydrogen atom
occupies the antiperiplanar position. The Gibbs energy differ-
ence between transition states IIb and Ic was found to be
6.0 kJ mol−1, rising to 8.1 kJ mol−1 when solvation effects were
included. These increased energy differences, compared to
those found for substrate 27a, again agree qualitatively with
the experimental observation that substrate 18b reacts with
reversed and higher levels of stereoselectivity compared to sub-
strate 18a.
Fig. 6 Possible chair (top) and boat (bottom) conformations of the N,S-ketene
acetal intermediates derived from 20.
The indication from these computational studies is thus
that there is an intrinsic preference for reaction to take place
anti- to the carbon substituent at the stereogenic centre and
not anti- to the oxygen substituent as has been suggested for
related systems.3b,4a,b,5,6e,7,8,13 Intriguingly, an AM1 study of
the zwitterionic Claisen reaction of 11 to give 12 (Scheme 1)
also appears to show a preference for reaction anti- to the
carbon substituent but no comment is made by the authors
on the conformation of the transition states located.4c
A possible explanation for the preferred reactive confor-
mation is that stabilisation of the transition state occurs most
effectively not through interaction of the newly forming σ-bond
with a low-lying σ* orbital but rather through a Cíeplak effect19
in which a σ-bonding orbital at the stereogenic centre interacts
with the low-lying antibonding orbital of the incipient σ-bond.
favoured over VI due to the minimisation of allylic strain and
hence product 22 should be favoured over 21.
Experimentally, significant amounts of products arising
from boat transition states are seen for both substrates. For
compound 20b, as expected, product 22b predominates over
21b while for compound 20a, the products 21a and 22a are
formed in equal amounts. The reasons for this lack of select-
ivity between the competing boat transition states when R = H
are unclear.
Conclusions
While the C–H bond is likely to be the best σ-donor, the confor- Moderate to high levels of diastereoselectivity can be obtained
mations in which this bond is antiperiplanar to the newly in the thia-Claisen rearrangement of allyl vinyl sulfides derived
forming σ-bond (Ic and IIc) are also likely to be the most steri- from chiral allylic bromides and N-benzylpyrrolidine-2-thione.
cally hindered; reaction anti- to the C–C bond is thus a compro- By installing an additional bromine atom on the alkene of the
mise between σ-donor ability and steric hindrance.
allylic bromide, the stereochemical preference of the reaction
For non-brominated substrate 27a, the energy of transition may be reversed. These results are summarised in the upper
state Ib is slightly lower than that of IIb – possibly due to the part of Scheme 7: the major isomers obtained from the reac-
steric interactions between the pyrroline ring and the allylic tion of bromides 18a and 18b have different relative stereo-
methoxy substituent in conformer IIb.
chemistry, while those from the reactions of 20a and 20b have
In the case of brominated substrate 27b, however, transition the same stereochemistry.
state Ib is greatly destabilised by the increased A1,3-strain
Density functional theory calculations suggest that the pre-
resulting from introduction of the bromine atom; this leaves ferred reactive conformation positions a C–C bond at the exist-
IIb as the lowest energy transition state structure.
ing stereogenic centre antiperiplanar to the newly forming
If Z-allylic bromide 20a and its vinyl bromide congener 20b C–C bond, consistent with the operation of a Cíeplak effect.
also react with Cíeplak diastereoselection, the corresponding Cíeplak-type diastereoselection in [3,3]-sigmatropic rearrange-
chair conformations should be III and IV, depicted in Fig. 6. In ments has been reported previously. Betson and Fleming20
conformation III, A1,3-strain is minimised and this should thus found that Ireland–Claisen rearrangement of silyl ketene
represent the dominant reaction pathway regardless of the iden- acetal 28 proceeded through the conformation shown (reaction
tity of R. Indeed, the major product observed for both substrates antiperiplanar to the electropositive silyl substituent) to give
is 23, corresponding to reaction through conformation III.
29 in a 93 : 7 diastereomeric ratio (Scheme 6). Similarly, Yama-
It is clear from inspection of structures III and IV that sig- zaki et al.21 showed that Ireland–Claisen rearrangement of 30
nificant destabilising interactions could exist between the proceeded with bond formation antiperiplanar to the isopropyl
allylic substituents and the pyrroline ring; these interactions rather than the trifluoromethyl substituent, while Yadav
would be removed in the boat conformations V and VI. Of the et al.22 found that Johnson–Claisen rearrangement of allylic
two possible boat conformations, we would expect V to be alcohol 32 occurred solely on the alkene face which is anti- to
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reacts preferentially through the conformation shown, with
the allylic C–O bond approximately eclipsing the alkene and
the allylic C–H bond projecting towards the pyrroline portion
of the molecule. When a vinylic substituent is present that is
syn- to the allylic stereocentre, allylic strain becomes the domi-
nant factor. Hence the diene intermediate derived from vinylic
bromide substrate 18b adopts the reactive conformation
shown, in which the allylic C–H bond eclipses the alkene such
that A1,3-strain is minimised. A similar effect is seen in the
reactions of allylic bromides 20a and 20b; here, the steric inter-
action is with the allylic methylene group rather than the
bromine atom and so both bromides react with the same
sense of stereoinduction.
Scheme 6 Cíeplak diastereoselection in [3,3]-sigmatropic rearrangements.20–22
Experimental section
For general experimental procedures, see the ESI.†
the sulfur of the oxathiolane ring, yielding 33. The preference
for this orientation of reaction, together with considerations of
allylic strain and other steric interactions, allow us to rational-
ise the observed stereoselectivities, as shown schematically in
the lower part of Scheme 7. In the absence of a vinylic bromide
substituent, the intermediate arising from compound 18a
Thia-Claisen rearrangement: general procedure
A mixture of thioamide 13 (116 mg, 0.61 mmol), allylic
bromide (0.67 mmol), MeCN (1 mL) and 4 Å molecular sieves
(250 mg) was stirred under an argon atmosphere for
Scheme 7 Summary of major products and reactive conformations.
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4 d. Further MeCN (2 mL) was added and the mixture warmed (3H, m, CvSCH and NCH2CH2), 3.75 (1H, dd, J 7.9, 5.7 Hz)
to 40 °C. Et3N (94 μL, 0.67 mmol) was added and the resulting and 4.06 (1H, dd, J 7.9, 6.0 Hz, OCH2), 4.07 (1H, dt, J 9.6,
solution stirred at 35 °C for 7 h. The mixture was cooled to 6.0 Hz, OCH), 4.90 (1H, d, J 14.3 Hz) and 5.11 (1H, d,
room temperature, diluted with CH2Cl2 (30 mL) and washed J 14.3 Hz, NCH2Ph), 5.13 (1H, dd, J 10.5, 1.4 Hz) and 5.24 (1H,
with 2% citric acid (2 × 50 mL). The combined aqueous wash- ddd, J 17.3, 1.7, 1.0 Hz, CH2vCH), 5.57 (1H, ddd, J 17.3, 10.5,
ings were extracted with CH2Cl2 (50 mL), and the combined 8.4 Hz, CH2vCH), 7.28–7.34 (5H, m, ArH); 13C NMR (CDCl3,
organic layers dried (MgSO4) and concentrated in vacuo to give 125 MHz) δ 20.4 (NCH2CH2), 25.7 and 27.0 (C(CH3)2), 49.5
the crude product. Individual components were isolated by (CH2vCHCH), 51.7 (NCH2Ph), 52.7 (NCH2CH2), 54.6
flash chromatography (SiO2; petrol–EtOAc 19 : 1).
(CvSCH), 68.6 (OCH2), 75.7 (OCH), 109.4 (C(Me)2), 120.1
(3S,1′R,4″S)-1-Benzyl-3-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)- (CH2vCH), 127.9, 128.3 and 128.7 (aromatic CH), 132.9
allyl]pyrrolidine-2-thione (21a). Pale yellow oil: Rf = 0.82 (CH2vCH), 135.1 (aromatic C), 203.9 (CvS); m/z (EI) 331 (M+,
(petrol–EtOAc 7 : 3); [α]1D7 −5.6 (c 0.68, CHCl3); νmax/cm−1 (film) 16%), 316 (14), 91 (12), 65 (19), 55 (21), 51 (100); HRMS found
3067, 2931 (CH), 1638 (CvC), 1605, 1585; 1H NMR (CDCl3, 331.1605, C19H25NO2S (M+) requires 331.1601.
500 MHz) δ 1.21 (3H, s) and 1.34 (3H, s, C(CH3)2), 2.13 (1H,
(3S,1′R,4″S)-1-Benzyl-3-[2-bromo-1-(2,2-dimethyl-1,3-dioxolan-
dtd, J 13.0, 9.2, 5.5 Hz) and 2.30 (1H, ddt, J 13.0, 9.0, 6.5 Hz, 4-yl)allyl]pyrrolidine-2-thione (21b). Colourless oil: Rf = 0.29
NCH2CH2), 3.05 (1H, dt, J 9.2, 3.3 Hz, CH2vCHCH), 3.15 (1H, (petrol–EtOAc 85 : 15); [α]2D0 −33.5 (c 0.65, CHCl3); νmax/cm−1
ddd, J 9.7, 6.5, 3.8 Hz, CvSCH), 3.47 (1H, ddd, J 11.0, 8.9, (CHCl3 cast) 2985, 2883 (CH), 1625 (CvC), 1507, 1452, 1311
1
6.3 Hz) and 3.62 (1H, m, NCH2CH2), 3.64 (1H, t, J 7.9 Hz) and (CvS); H NMR (CDCl3, 500 MHz) δ 1.25 (3H, s) and 1.42 (3H,
4.05 (1H, dd, J 8.0, 6.4 Hz, OCH2), 4.29 (1H, ddd, J 7.8, 6.4, s, C(CH3)2), 2.20 (1H, dddd, J 13.4, 8.8, 7.6, 6.9 Hz) and 2.31
2.8 Hz, OCH), 4.83 (1H, d, J 14.2 Hz, NCHHPh), 5.21–5.28 (3H, (1H, dtd, J 13.4, 8.9, 4.6 Hz, NCH2CH2), 3.37 (1H, m, CSCH),
m, CH2vCH and NCHHPh), 5.96 (1H, ddd, J 17.3, 10.2, 9.2 Hz, 3.49 (1H, ddd, J 11.1, 8.5, 6.9 Hz, NCHHCH2), 3.59–3.64 (2H,
CH2vCH), 7.30–7.36 (5H, m, ArH); 13C NMR (CDCl3, 125 MHz) m, CH2vC(Br)CH and NCHHCH2), 3.89 (1H, t, J 7.9 Hz) and
δ
22.4 (NCH2CH2), 25.4 and 26.3 (C(CH3)2), 47.7 4.02 (1H, dd, J 8.0, 6.5 Hz, OCH2), 4.43 (1H, dt, J 7.6, 6.1 Hz,
(CH2vCHCH), 51.8 (NCH2Ph), 52.9 (NCH2CH2), 58.0 OCH), 4.88 (1H, d, J 14.3 Hz) and 5.16 (1H, d, J 14.3 Hz,
(CvSCH), 68.0 (OCH2), 74.5 (OCH), 109.1 (CMe2), 118.7 NCH2Ph), 5.69 (1H, d, J 1.8 Hz) and 6.08 (1H, dd, J 1.8, 0.5 Hz,
(CH2vCH), 128.0, 128.3 and 128.8 (aromatic CH), 135.0 (aro- CH2vCBr), 7.30–7.37 (5H, m, ArH); 13C NMR (CDCl3,
matic C), 135.1 (CH2vCH), 205.4 (CvS); m/z (CI+) 332 (MH+, 125 MHz) δ 22.7 (NCH2CH2), 25.1 and 26.5 (C(CH3)2), 52.1
31%), 316 (24), 275 (37), 230 (80), 191 (100), 91 (40); HRMS (NCH2Ph), 52.5 (NCH2CH2), 52.8 (CH2vC(Br)CH), 56.2
found 332.1677, C19H26NO2S (MH+) requires 332.1684.
(CvSCH), 67.2 (OCH2), 74.6 (OCH), 109.1 (C(Me)2), 120.9
(3R,1′S,4″S)-1-Benzyl-3-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)- (CH2vCBr), 128.1, 128.4, 128.9 (aromatic CH), 131.7 (CBr),
allyl]pyrrolidine-2-thione (22a). Pale yellow oil: Rf = 0.76 135.0 (aromatic C), 201.6(CvS); m/z (CI+) 410/412 (MH+,
(petrol–EtOAc 7 : 3); [α]2D2 +82.2 (c 0.60, CHCl3); νmax/cm−1 24/26%), 338 (79), 141 (100); HRMS found 410.0774,
(CHCl3 cast) 2983, 2931, 2873 (CH), 1637 (CvC), 1503, 1452 C19H2579BrNO2S (MH+) requires 410.0789.
1
(CvS); H NMR (CDCl3, 500 MHz) δ 1.38 (3H, s) and 1.42 (3H,
(3R,1′S,4″S)-1-Benzyl-3-[2-bromo-1-(2,2-dimethyl-1,3-dioxolan-
s, C(CH3)2), 1.89 (1H, ddt, J 12.8, 8.8, 6.3 Hz) and 2.21 (1H, 4-yl)allyl]pyrrolidine-2-thione (22b). Pale yellow oil: Rf 0.43
dtd, J 12.8, 9.1, 5.9 Hz, NCH2CH2), 2.62 (1H, m, CH2vCHCH), (petrol–EtOAc 85 : 15); [α]2D0 +31.5 (c 1.08, CHCl3); νmax/cm−1
3.43 (1H, ddd, J 10.7, 9.0, 6.1 Hz, CvSCH), 3.50–3.55 (2H, m, (CHCl3 cast) 2983, 2934, 2874 (CH), 1625 (CvC), 1499, 1452,
NCH2CH2), 3.60 (1H, dd, J 8.2, 6.6 Hz) and 3.98 (1H, dd, J 8.2, 1316 (CvS); 1H NMR (CDCl3, 600 MHz) δ 1.31 (3H, s) and 1.37
6.1 Hz, OCH2), 4.94 (1H, d, J 14.4 Hz, NCHHPh), 5.00 (1H, m, (3H, s, C(CH3)2), 2.31–2.41 (2H, m, NCH2CH2), 3.22 (1H, t,
OCH), 5.05 (1H, d, J 14.4 Hz, NCHHPh), 5.09 (1H, dd, J 10.2, J 8.6 Hz, CHCvS), 3.52 (1H, ddd, J 10.8, 8.4, 7.1 Hz) and 3.66
1.6 Hz) and 5.19 (1H, dd, J 17.2, 1.0 Hz, CH2vCH), 5.79 (1H, (1H, ddd, J 10.8, 8.9, 5.2 Hz, NCH2CH2), 3.76 (1H, dd, J 8.5,
dt, J 17.2, 9.9 Hz, CH2vCH), 7.29–7.35 (5H, m, ArH); 13C NMR 6.9 Hz, CHHO), 3.89 (1H, dd, J 10.1, 1.6 Hz, H2CvC(Br)CH),
(CDCl3, 125 MHz) δ 24.4 (NCH2CH2), 25.7 and 27.0 (C(CH3)2), 4.11 (1H, dd, J 8.5, 6.0 Hz, CHHO), 4.45 (1H, dt, J 10.1, 6.5 Hz,
51.5 (NCH2Ph), 52.5 (CvSCH), 53.0 (CH2vCHCH), 54.1 CHO), 4.82 (1H, d, J 14.6 Hz) and 5.19 (1H, d, J 14.6 Hz,
(NCH2CH2), 68.6 (OCH2), 75.0 (OCH), 109.2 (C(Me)2), 119.1 PhCH2), 5.54 (1H, dd, J 1.9, 0.5 Hz) and 5.93 (1H, d, J 1.9 Hz,
(CH2vCH), 127.9, 128.3 and 128.7 (aromatic CH), 134.9 CvCH2), 7.29–7.36 (5H, m, ArH); 13C NMR (CDCl3, 150 MHz)
(CH2vCH), 135.2 (aromatic C), 202.6 (CvS); m/z (CI+) 332 δ 22.1 (NCH2CH2), 25.9 and 26.4 (C(CH3)2), 51.8 (PhCH2), 52.7
(MH+, 22%), 274 (100); HRMS found 332.1676, C19H26NO2S (NCH2CH2), 55.1 (H2CvC(Br)CH), 56.8 (CHCvS), 68.6 (CH2O),
(MH+) requires 332.1684.
74.6 (CHO), 110.0 (C(CH3)2), 119.8 (CvCH2), 127.8, 128.1 and
(3S,1′S,4″S)-1-Benzyl-3-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)allyl]- 128.7 (aromatic CH), 133.3 (CvCH2), 135.1 (aromatic C), 203.5
pyrrolidine-2-thione (23a). Pale yellow oil: Rf = 0.62 (petrol– (CvS); m/z (CI+, CH4) 410/412 (MH+, 16/14%), 352/354 ([MH −
EtOAc 7 : 3); [α]2D2 −27.7 (c 1.35, CHCl3); νmax/cm−1 (CDCl3 cast) Me2CO]+, 46/50), 338 (63), 330 ([MH − HBr]+, 100); HRMS
2981, 2920 (CH), 1644 (CvC); 1H NMR (CDCl3, 500 MHz) found 410.0799, C19H2579BrNO2S (MH+) requires 410.0789.
δ 1.36 (3H, s) and 1.48 (3H, s, C(CH3)2), 1.97 (1H, ddt, J 13.2,
(3S,1′S,4″S)-1-Benzyl-3-[2-bromo-1-(2,2-dimethyl-1,3-dioxolan-
8.5, 7.5 Hz) and 2.17 (1H, dddd, J 13.2, 9.3, 7.8, 5.6 Hz, 4-yl)allyl]pyrrolidine-2-thione (23b). Colourless oil: Rf = 0.19
NCH2CH2), 3.35 (1H, td, J 8.9, 3.0 Hz, CH2vCHCH), 3.45–3.54 (petrol–EtOAc 8 : 2); νmax/cm−1 (CHCl3 cast) 2984, 2932, 2877
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(CH), 1615 (CvC), 1507, 1453 (CvS); 1H NMR (CDCl3, 3.37 (1H, ddd, J 10.9, 8.8, 6.6 Hz) and 3.45 (1H, m, NCH2CH2),
500 MHz) δ 1.38 (3H, s) and 1.50 (3H, s, C(CH3)2), 2.19 (1H, 3.48 (1H, dd, J 10.7, 4.1 Hz, OCHH), 3.64 (1H, m, CvSCH),
dtd, J 13.2, 9.5, 6.0 Hz) and 2.42 (1H, ddt, J 13.2, 8.8, 6.1 Hz, 3.67 (1H, dd, J 10.7, 2.6 Hz, OCHH), 4.88 (1H, m, OCH), 4.90
NCH2CH2), 3.48–3.70 (4H, m, CvSCH, CH2vC(Br)CH and (1H, d, J 14.4 Hz, NCHHPh), 5.03 (1H, dd, J 10.2, 2.3 Hz,
NCH2CH2), 3.82 (1H, dd, J 8.6, 5.1 Hz) and 4.16 (1H, dd, J 8.6, CHHvCH), 5.07 (1H, d, J 14.4 Hz, NCHHPh), 5.08 (1H, dd,
6.0 Hz, OCH2), 4.38 (1H, dt, J 9.2, 5.6 Hz, OCH), 4.92 (1H, d, J 17.2, 2.3 Hz, CHHvCH), 5.91 (1H, dt, J 17.2, 10.2 Hz,
J 14.4 Hz) and 5.09 (1H, d, J 14.4 Hz, NCH2Ph), 5.56 (1H, d, CH2vCH), 7.28–7.33 (5H, m, ArH); 13C NMR (CDCl3, 125 MHz)
J 1.6 Hz) and 6.06 (1H, d, J 1.6 Hz, CH2vCBr), 7.30–7.36 (5H, δ −5.5, −5.4, −4.1 and −4.0 (2 × Si(CH3)2), 18.3 and 18.4
m, ArH); 13C NMR (CDCl3, 125 MHz) δ 20.5 (NCH2CH2), 25.5 (2 × C(CH3)3), 25.9 and 26.0 (2 × C(CH3)3), 26.2 (NCH2CH2),
and 27.0 (C(CH3)2), 51.9 (NCH2Ph), 52.7 (CH2vC(Br)CH), 53.0 51.2 (NCH2Ph), 52.1 (NCH2CH2), 52.3 (CvSCH), 53.1
(NCH2CH2), 54.9 (CvSCH), 68.0 (OCH2), 76.0 (OCH), 109.9 (CH2vCHCH), 66.2 (OCH2), 72.8 (OCH), 118.4 (CH2vCH),
(C(Me)2), 123.5(CH2vCBr), 128.0, 128.4 (aromatic CH), 128.5 127.8, 128.2 and 128.6 (aromatic CH), 135.4 (aromatic C),
(CBr), 128.7 (aromatic CH), 135.0 (aromatic C), 202.8 (CvS); 135.9 (CH2vCH), 202.8 (CvS); m/z (CI+) 520 (MH+, 100%),
m/z (CI+) 410/412 (MH+, 2/2%), 183 (100) 141 (17), 119 (18); 504 (44), 388 (42); HRMS found 520.3110, C28H50NO2SSi2
HRMS found 410.0786, C19H2579BrNO2S (MH+) requires (MH+) requires 520.3101.
410.0789.
(3R,1′R,4″S)-1-Benzyl-3-[2-bromo-1-(2,2-dimethyl-1,3-dioxolan-
4-yl)allyl]pyrrolidine-2-thione (24b). Colourless oil: Rf = 0.50
(petrol–EtOAc 7 : 3); H NMR (CDCl3, 600 MHz) δ 1.41 (3H, s)
Acknowledgements
1
We thank Dr Abil Aliev for assistance with NMR spectroscopy,
and Mr John Hill and Dr Lisa Haigh for mass spectrometry.
We also thank UCL Graduate School and EPSRC (grant no
EP/C509153/1) for funding.
and 1.46 (3H, s, C(CH3)2), 2.00–2.48 (2H, m, NCH2CH2), 2.97
(1H, m), 3.52 (1H, m) and 3.65–3.71 (2H, m, CvSCH,
CH2vC(Br)CH and NCH2CH2), 3.87 (1H, dd, J 8.0, 7.6 Hz) and
4.14 (1H, dd, J 8.0, 5.8 Hz, OCH2), 4.49 (1H, m, OCH), 4.92
(1H, d, J 14.3 Hz) and 5.08 (1H, d, J 14.3 Hz, NCH2Ph), 5.61
(1H, d, J 1.4 Hz) and 5.98 (1H, d, J 1.4 Hz, CH2vCH(Br)),
7.30–7.36 (5H, m, aromatic CH).
Notes and references
(3S,3′R,4′S)-1-Benzyl-3-[4,5-di-(tert-butyldimethylsilanyloxy)-
pent-1-en-3-yl]pyrrolidine-2-thione (25a). White solid, m.p.
51–52 °C; Rf = 0.57 (petrol–EtOAc 9 : 1); [α]1D7 −14.0 (c 0.88,
CHCl3); νmax/cm−1 (film) 2932 (CH), 1630 (CvC); 1H NMR
(CDCl3, 500 MHz) δ −0.02 (3H, s), 0.06 (3H, s), 0.07 (3H, s) and
0.07 (3H, s, 2 × Si(CH3)2), 0.86 (9H, s) and 0.91 (9H, s, 2 ×
C(CH3)3), 2.05–2.19 (2H, m, NCH2CH2), 2.79 (1H, dt, J 9.5,
4.8 Hz, CH2vCHCH), 3.30 (1H, m, CvSCH), 3.39 (1H, ddd,
J 11.0, 8.6, 6.4 Hz) and 3.51 (1H, ddd, J 11.0, 8.7, 5.7 Hz,
NCH2CH2), 3.63 (1H, dd, J 10.5, 4.8 Hz) and 3.82 (1H, dd,
J 10.5, 4.3 Hz, OCH2), 4.30 (1H, q, J 4.7 Hz, OCH), 4.86 (1H, d,
J 14.3 Hz, NCHHPh), 5.06–5.11 (2H, m, CH2vCH), 5.14 (1H,
J 14.3 Hz, NCHHPh), 5.95 (1H, m, CH2vCH), 7.30–7.36 (5H,
m, ArH); 13C NMR (CDCl3, 125 MHz) δ −5.4, −5.3, −4.6 and
−3.7 (2 × Si(CH3)2), 18.2 and 18.3 (2 × C(CH3)3), 24.5
(NCH2CH2), 26.0 (2 × C(CH3)3), 49.6 (CH2vCHCH), 51.5
(NCH2Ph), 52.2 (NCH2CH2), 56.0 (CvSCH), 66.0 (OCH2), 72.8
(OCH), 117.8 (CH2vCH), 127.9, 128.3 and 128.7 (aromatic
CH), 135.3 (aromatic C), 136.8 (CH2vCH), 203.3 (CvS); m/z
(CI+) 520 (MH+, 18%), 504 (25), 462 (44), 388 (100), 330 (11),
230 (54), 191 (33), 91 (34); HRMS found 520.3115,
C28H50NO2SSi2 (MH+) requires 520.3101.
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(3R,3′S,4′S)-1-Benzyl-3-[4,5-di-(tert-butyldimethylsilanyloxy)-
pent-1-en-3-yl]pyrrolidine-2-thione (26a). Yellow oil: Rf = 0.36
(petrol–EtOAc 19 : 1); [α]2D0 +14.0 (c 0.3, CHCl3); νmax/cm−1
(CHCl3 cast) 2928 (CH), 1624 (CvC); 1H NMR (CDCl3,
500 MHz) δ 0.01 (3H, s), 0.03 (3H, s), 0.18 (3H, s) and 0.23 (3H,
s, 2 × Si(CH3)2), 0.90 (9H, s) and 0.92 (9H, s, C(CH3)3), 1.85
(1H, ddt, J 12.9, 8.9, 6.6 Hz) and 2.19 (1H, dtd, J 12.9, 9.1,
5.4 Hz, NCH2CH2), 2.43 (1H, td, J 9.9, 2.0 Hz, CH2vCHCH),
7538 | Org. Biomol. Chem., 2013, 11, 7530–7539
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Paper
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This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 7530–7539 | 7539