Sigmatropic Rearrangement of Vinyl Aziridines: Expedient Synthesis of Cyclic Sulfoximines from Chiral Sulfinimines

Article abstract of DOI:10.1002/anie.201604188

A novel rearrangement of 2-vinyl aziridine 2-carboxylates to unusual chiral cyclic sulfoximines is described herein. The method allows the synthesis of substituted cyclic sulfoximines in high yields with complete stereocontrol, and tolerates a wide substrate scope. A one-pot process starting directly from sulfinimines provides access to complex chiral sulfoximines in only two steps from commercially available aldehydes. A mechanistic hypothesis and synthetic application in the formal synthesis of trachelanthamidine, by transformation of a cyclic sulfoximine into a pyrroline, is also disclosed.

Full text of DOI:10.1002/anie.201604188

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604188
German Edition: DOI: 10.1002/ange.201604188
Rearrangements
Sigmatropic Rearrangement of Vinyl Aziridines: Expedient Synthesis
of Cyclic Sulfoximines from Chiral Sulfinimines
Toni Moragas, Ryan M. Liffey, Dominika Regentovꢀ, Jon-Paul S. Ward, Justine Dutton,
William Lewis, Ian Churcher, Lesley Walton, Josꢁ A. Souto, and Robert A. Stockman*
Abstract: A novel rearrangement of 2-vinyl aziridine 2-
carboxylates to unusual chiral cyclic sulfoximines is described
herein. The method allows the synthesis of substituted cyclic
sulfoximines in high yields with complete stereocontrol, and
tolerates a wide substrate scope. A one-pot process starting
directly from sulfinimines provides access to complex chiral
sulfoximines in only two steps from commercially available
aldehydes. A mechanistic hypothesis and synthetic application
in the formal synthesis of trachelanthamidine, by transforma-
tion of a cyclic sulfoximine into a pyrroline, is also disclosed.
a simple and versatile method for the synthesis of nonfused
six-membered cyclic sulfoximines with complete diastereo-
control and a wide substrate range.
Building on our prior work in the area of aza-Darzens-
type aziridinations of chiral tert-butanesulfinimines[14] and S-
mesitylsulfinimines,[15] we were drawn to the potential use of
2-bromobut-2-enoic acid methyl ester as a potential partner
for an aza-Darzens-type aziridination of chiral sulfinimines.
The products, trisubstituted vinyl aziridine 2-carboxylates,
would be potentially versatile intermediates for asymmetric
synthesis.[16] Thus, we investigated the aza-Darzens reaction of
the acetaldehyde-derived S-mesitylsulfinimine 1a using
LiHMDS as base in THF at À788C (Scheme 1). Pleasingly,
Since the first isolation of sulfoximines by Bentley and co-
workers in 1950[1] these sulfur-containing compounds have
found applications in functional-group transformations and
asymmetric synthesis,[2] drug development,[3] crop treat-
ment,[4] and insect control.[5] Largely ignored in medicinal
chemistry for around 50 years, the sulfoximine group has
recently been the object of significant new interest.[3] Sulfox-
imines are three-dimensional motifs with three points of
attachment in orthogonal vectors,[6] and functionalisation at
the nitrogen and carbon centers a to the sulfur atom is
versatile and facile.[7–9]
Scheme 1. Unprecedented rearrangement of aziridines leading to sulf-
oximines. HMDS=hexamethyldisilazide, Mes=2,4,6-trimethylphenyl,
THF=tetrahydrofuran.
Despite the promising biological activity showed by the
few previously synthesised cyclic sulfoximines,[3] methods
describing the synthesis of these compounds are scarce and
mainly involve the multistep synthesis of linear sulfox-
imines[10,11] and subsequent cyclizations.[12] Furthermore,
they generally describe benzofused cyclic sulfoximines. This
limitation is found in the recent work reported by Hu et al.
where a very elegant one-step synthesis of cyclic sulfoximines
was achieved, starting from enantiomerically pure sulfini-
mines, by cycloaddition with benzynes.[13] Herein we describe
we found excellent conversion into the vinyl aziridine 2a.
However, upon standing in deuterochloroform, we observed
that this vinyl aziridine underwent a rearrangement to afford
a new compound. After purification and extensive character-
ization we found that the isolated product corresponds to the
cyclic sulfoximine 3a wherein chiral information is retained.
Herein, we present our findings on the substrate scope of
this novel rearrangement and offer a mechanistic hypothesis
for this interesting transformation.
Intrigued by the observed rearrangement, we wanted to
explore the influence of solvent and temperature on the
sulfoximine formation (Table 1). No clear correlation was
found between the nature of solvent and the reaction
performance, and best results obtained when CDCl3,
[D6]DMSO, MeOD, and C6D6 were used as a solvent. C6D6
was the selected solvent to study the influence of temperature
on the described rearrangement. In a very straightforward
manner we determined that an increase in temperature
clearly improves the yield of the reaction, thus leading to the
desired compound in 80 and 92% yield when the solution was
heated at 40 and 708C, respectively.
[*] Dr. T. Moragas, R. M. Liffey, Dr. D. Regentovꢀ, J.-P. S. Ward, J. Dutton,
Dr. W. Lewis, Dr. J. A. Souto, Prof. R. A. Stockman
School of Chemistry, University of Nottingham
University Park, Nottingham, NG7 2RD (UK)
E-mail: robert.stockman@nottingham.ac.uk
Prof. I. Churcher
GlaxoSmithKline Medicines Research Centre
Gunnels Wood Road, Stevenage, SG1 2NY (UK)
Dr. L. Walton
Lilly (UK)
Erl Wood Manor, Windlesham, GU20 6PH (UK)
Dr. J. A. Souto
Departamento de Quꢁmica Orgꢀnica, Universidade de Vigo
36310 Vigo (Spain)
Initially, reaction conditions performed at 408C were
chosen for the purpose of scope determination (Table 2).
Several aziridines were synthesised following our previously
reported method,[15] and they were subsequently submitted to
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201604188.
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Table 1: Optimisation of reaction conditions.
Table 2: Sulfoximine synthesis from vinyl aziridines 2.
Entry
Solvent
Yield [%][a]
Entry
Solvent
Yield [%][a]
1
2
3
4
5
CDCl3
50
57
22
50
15
6
7
8
9
[D7]DMF
C6D6
C6D6
C6D6
cyclohexene
12
50
[D6]DMSO
[D6]Et2O
CD3OD
CD3CN
80[b]
92[c]
60[b,d]
10
[a] Yield determined by NMR spectroscopy. [b] 408C. [c] 708C. [d] Yield of
isolated product. DMF=N,N-dimethylformamide. DMSO=dimethyl-
sulfoxide.
the rearrangement reaction conditions. The rearrangement
reaction showed broad scope for substitution at the 3-position
of the vinylaziridine. The rearrangement seemed tolerant of
sterically hindered alkylaziridines, which transformed into the
corresponding sulfoximines in good yields (entries 2 and 3).
The reaction also performed well in the presence of saturated
carbocycles (entries 4 and 5). Unsaturation and silylethers
were also tolerated under the reaction conditions, thus
affording sulfoximines in good yields (entries 6–8)
We were pleased to find that suitable crystals for X-ray
analysis were isolated for sulfoximine 3b (Figure 1), 3i and 3k
from which unambiguous confirmation of the structure and
configuration of the formed heterocycle was obtained (see the
Supporting Information for further details).
In the case of aziridine 2j (Table 2, entry 10), we noted
that the two diastereomeric aziridines formed from the
corresponding sulfinimine rearranged to the same cyclic
sulfoximine 3j. We therefore decided to investigate whether
the rate of rearrangement of these diastereomers was differ-
ent. The rearrangement reactions of (E)-2j and (Z)-2j were
1
monitored by H NMR spectroscopy.[17] The rearrangement
of (E)-2j was found to be around three times faster than the
corresponding Z isomer. Presuming a concerted rearrange-
ment,[18] we attribute this difference in rate to the increased
steric bulk around the mesityl group for the Z-isomer
(Scheme 2). As the reaction works in a wide range of solvents,
including polar and nonpolar, as well as in nucleophilic
solvents like methanol, this gives further evidence of a con-
certed rearrangement. De Kimpe and co-workers previously
disclosed a related rearrangement wherein a 2-aryl, 2-vinyl
aziridine heterolyses, thus yielding a transient allyl cation, and
in that case the products formed are pyrrolines.[19] Similarly
Njardarson and co-workers have reported on the copper-
catalyzed transformation of vinyl azidirines to pyrrolines.[20]
In our case it can be postulated that the ester functionality
activates the alkene such that a sigmatropic rearrangement is
possible. We believe that homolysis is not involved, as we saw
no signs of radical trapping when carrying out reactions in the
presence of radical traps or in cyclohexene as solvent (see the
Supporting Information).
[a] Yield of product isolated after purification. Scale: 0.5 mmol. [b] 708C.
[c] 1.2:1 trans/cis. TBS=tert-butyldimethylsilyl.
we envisaged a one-pot protocol. Thus, after the formation of
aziridine was deemed complete, as determined by TLC,
excess base in the reaction was quenched by addition of water,
and benzene was added to the reaction mixture before
heating. Pleasingly, the telescoped procedure resulted in good
Although efficient for the preparation of mesityl sulfox-
imines, our procedure revealed low reactivity for tert-butyl-
sulfoximines. In an effort to develop a more efficient process
2
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Table 3: One-pot preparation of the sulfoximines 3.
Figure 1. X-Ray structure of sulfoximine 3b (CCDC 1484617 ). Thermal
elipsoids shown at 50% probability.
Scheme 2. Proposed mechanistic pathway, and comparison to De
Kimpe’s rearrangement.
yields. In general they surpassed the yields of the two-step
procedure[21] (Table 3). The sulfoximine 3e was isolated in
49% yield following the one-pot procedure compared to the
33% overall yield observed for the two-step method.[22]
Furthermore, the less reactive tert-butylsulfinimines
(entries 3–7) were efficiently converted into the correspond-
ing sulfoximines using this new protocol, although it was
noted that these products were prone to thermal elimination
of the tert-buyl group (this process was also noted by Hu and
co-workers[13] in their cyclic sulfoximines). We also found that
the method is compatible with less common sulfinimines such
as biphenyl- or 3,5-bistrifluoromethylphenyl sulfinimine,
which can be conveniently synthesised in one step from the
parent aldehyde[14c] (entries 9 and 10). In all cases, the cyclic
sulfoximines were isolated as single diastereomers.
Whilst exploring the reactivity of the new cyclic sulfox-
imines, we discovered that these compounds, themselves the
product of a ring-expansion, upon treatment with camphor-
sulfonic acid (CSA) and LiCl in 1,4-dioxane/MeOH at reflux,
undergo ring contraction to yield pyrrolines. Reacting the
sulfoximine 3 f under these reaction conditions yielded
pyrroline 5 in 80% yield (Scheme 3).[23] We believe this
reaction proceeds by N-protonation, followed by an SN2 ring
opening of the sulfoximine[24a] and ring closure onto the alkyl
chloride and chloride-induced deprotection of the amine.[24b]
To exemplify the utility of these two novel ring trans-
formations, we proceeded to carry out a formal synthesis of
the pyrrolizidine alkaloid trachelanthamidine[25] (Scheme 4).
The synthesis started with a monoprotection of 1,4-butanediol
[a] Yield of product isolated after purification. [b] Reaction in toluene for
7 days.
(6) with TBSCl in an 85% yield, followed by Swern oxidation
and condensation of the corresponding aldehyde with mesi-
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yield.[28a] Several groups have previously converted 9 into
trachelanthamidine, and thus this represents a formal syn-
thesis.[31]
In summary, we have developed a methodology for the
synthesis of chiral cyclic sulfoximines starting from simple
sulfinimines. The reaction can be either performed by
isolation of the aziridine intermediate and subsequent
thermal rearrangement (two step protocol) or in a one-pot
fashion, the latter allowing for the isolation of the desired
heterocycle without the need of manipulating otherwise
relatively unstable aziridine intermediates. We have also
demonstrated the formal synthesis of the biologically active
natural product trachelanthamidine in an overall yield of 5%.
Scheme 3. Ring-contraction of sulfoximine to pyrroline.
Acknowledgements
The authors wish to thank Dr. Thomas E. Storr for preparing
the X-ray figures and GlaxoSmithKline (TM, JD), Xunta de
Galicia (JAS), Lilly (JPSW) and EPSRC (DR, JAS, RAS, EP/
015078) for funding.
Keywords: heterocycles · rearrangements ·
small ring compounds · sulfur · synthetic methods
Scheme 4. Formal synthesis of trachelanthamidine. Reagents and con-
ditions: a) TBSCl, NaH, THF, RT, 19 h (93%); b) DMSO, NEt3,
(COCl)2, CH2Cl2, 19 h; c) (S)-mesitylsulfinamide, Ti(OEt)4, THF, RT,
20 h (69% over 2 steps); d) methyl 2-bromo-2-butenoate, LiHMDS,
THF, À788C, 3 h; e) H2O, benzene, 408C to 708C, 19 h (60% over two
steps); f) CSA, LiCl, MeOH/1,4-dioxane 1:1, 908C, 18 h; g) NEt3, TsCl,
CH2Cl2, 08C to RT, 30 min. (44% over two steps); h) Pd/C, H2, MeOH,
RT, 96 h (59%); i) PDC, DMF, RT, 18 h; j) SOCl2, MeOH, 08C to reflux,
18 h (78% over two steps); k) Mg, MeOH, RT. to reflux, 7 h (65%).
PDC=pyridiniumdichromate, Ts=4-toluenesulfonyl.
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4
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À
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Received: April 29, 2016
Revised: June 13, 2016
Published online: && &&, &&&&
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Communications
Rearrangements
T. Moragas, R. M. Liffey, D. Regentovꢁ,
J.-P. S. Ward, J. Dutton, W. Lewis,
I. Churcher, L. Walton, J. A. Souto,
R. A. Stockman*
&&&& — &&&&
Sigmatropic Rearrangement of Vinyl
Aziridines: Expedient Synthesis of Cyclic
Sulfoximines from Chiral Sulfinimines
Making and breaking rings: A novel
rearrangement of 2-vinyl aziridine 2-car-
boxylates to unusual chiral cyclic sulfox-
imines is described. The method allows
the synthesis of substituted cyclic sulfox-
imines in high yields with complete
stereocontrol, and tolerates a wide sub-
strate scope. A one-pot process starting
directly from sulfinimines provides
access to complex chiral sulfoximines in
only two steps from commercially avail-
able aldehydes.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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