SN2′ addition/1,2-elimination of dimethylsulfonium methylide with epoxy vinyl sulfones: Synthesis of exocyclic cross-conjugated dienyl sulfones

Article abstract of DOI:10.1039/c0cc05405d

Dimethylsulfonium methylide undergoes S_N2′ addition/1,2-elimination with epoxy vinyl sulfones to generate enantiopure six and seven membered cross-conjugated hydroxy vinyl sulfones. Moderate to excellent yields were obtained for both six and se

Full text of DOI:10.1039/c0cc05405d

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COMMUNICATION
SN20 addition/1,2-elimination of dimethylsulfonium methylide with epoxy
vinyl sulfones: synthesis of exocyclic cross-conjugated dienyl sulfonesw
Vikas Sikervar and Philip L. Fuchs*
Received 6th December 2010, Accepted 17th January 2011
DOI: 10.1039/c0cc05405d
Dimethylsulfonium methylide undergoes SN20 addition/
1,2-elimination with epoxy vinyl sulfones to generate enantio-
pure six and seven membered cross-conjugated hydroxy vinyl
sulfones. Moderate to excellent yields were obtained for both six
and seven membered substrates.
Dimethylsulfonium methylide is easily prepared by the
reaction of trimethylsulfonium iodide with base.1 It has been
Scheme 1 Reaction of epoxide 1 with dimethylsulfonium methylide.
widely used for the conversion of aldehydes and ketones to
epoxides and excess reagent leads to the in situ consumption of
the epoxide with formation of an allylic alcohol.2 It also
performs the analogous cleavage of aziridines3 generating
larger excess of sulfurane to deliver high yields. Particularly
interesting is the case of substrate 20, which proceedes in the
presence of a free alcohol, giving product 21 in 63% yield.
The mechanism is presumably similar to the one reported
for related homologations3 and is outlined in Scheme 2: SN20
addition of the ylide to epoxy vinyl sulfone 4 with concomitant
epoxide opening yields the betaine intermediate 4b which is
metalated to sulfurane 4c followed by b-elimination of
dimethyl sulfide, a process isostructural to the mechanism of
Swern oxidation.
allylic amines and converts halides and mesylates to
one-carbon-homologated terminal alkenes.4 The methylide is
likewise employed for the cyclopropanation of vinyl sulfones
and other electron-deficient olefins.5
In conjunction with our program involving synthesis of
natural and unnatural products using segments derived from
six and seven membered vinyl sulfones,6 we now report the
reaction of epoxy vinyl sulfones with dimethylsulfonium
methylide. Reaction of 1 with 3.7 equiv. dimethylsulfonium
methylide at ꢀ10 1C followed by warming to room temperature
over 4 h in the absence of additional external base initially
formed cross-conjugated hydroxy dienyl sulfone 5, but
proceeded further to cyclopropylsulfone 2 (Scheme 1). Reducing
the methylide stoichiometry to 2.5 equiv. afforded the desired
product 3 in 52% isolated yield (Scheme 1).
The method is applied for the synthesis of enantiomerically
pure A-ring precursors for 1,25-dihydroxyvitamin D3,
[1a,25(OH)2D3]. 1a,25(OH)2D3 is the most biologically active
metabolite of Vitamin D3, and is involved in the regulation of
calcium homeostasis and bone metabolism. In addition, it
suppresses the growth of numerous human cancer cell lines by
inhibiting cell cycle progression and inducing cell death.9 The
chemical synthesis of 1a,25(OH)2D3 and its many analogs has
been a specific focus of several prominent research groups who
have been responsible for developing an extensively defined
SAR.10 A plethora of approaches have also focused on
modification of the C/D-ring moiety and many analogs have
been found to increase potency relative to 1a,25(OH)2D3.11
Access to highly-functionalized A-ring precursors should thus
facilitate preparation of new vitamin D3 analogs.
Dimethylsulfoxonium methylide reacted with 1 in a similar
fashion giving 3 in 57% yield. Dimethylsulfonium methylide
was more reactive than dimethylsulfoxonium methylide. A
reaction using the former reagent is complete within two
minutes, while the latter required 35 minutes with substrate
1 at ꢀ78 1C. Excellent chemo- and regioselectivity was
observed in all cases, with only SN20 products being observed.
As seen in Table 1, the parent six-membered epoxide7 gave
the desired one carbon homologated allylic alcohol in modest
to excellent yields using 2.5–3.7 equivalents of dimethylsulfo-
nium methylide. The seven-membered substrates8 required a
Efforts to exploit vinyl sulfone chemistry has led to
preparation of A-ring precursors of 1a,25(OH)2D3 and other
analogs from intermediate dienyl sulfone 22. Substrate 22 is
synthesized in our laboratory from cyclohexanone on the
kilogram scale.12 The asymmetric center is then enantio-
specifically introduced using Jacobsen epoxidation.
Department of Chemistry, Purdue University, West Lafayette
Indiana 47907, USA. E-mail: pfuchs@purdue.edu;
Fax: +1765-494-0239; Tel: +1765-494-5242
w Electronic supplementary information (ESI) available: See DOI: 10.
1039/c0cc05405d
Epoxy vinyl sulfone 6 is easily synthesized in three steps
from dienyl sulfone 2213,14 and further reaction with dimethyl-
sulfonium methylide gives cross conjugated allylic alcohol 7
c
3472 Chem. Commun., 2011, 47, 3472–3474
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Table 1 Reaction of dimethyl sulfonium methylide with 6- and
7-membered epoxy vinyl sulfones
Ylide
(equiv.) Product
Yield
(%)
Entry Reactant
1
2.5
3.7
85
84
2
Scheme 2 Mechanism.
3
4
5
6
3.7
72
90
61
92
6
Fig. 1 Conformers of Targets A and B
The b-chair conformation of the A-ring is currently
accepted as being responsible for the aforementioned bio-
15
6
logical activities. Diastereomers of 2-methyl Vitamin D3
and DeLuca’s analog16 also supports the axial 1a-OH
orientation hypothesis. In 2000, Moras reported the crystal
structure of a hVDR ligand binding domain complexed with
1a,25(OH)2D3, showing a 1a,25(OH)2D3 compound with its A
ring in a b-chair conformation.17 However, all the analogs
departed strongly from the ideal situation where both free
hydroxyl groups and the C10,19 exocyclic olefin are present
where the A-ring is biased but conformationally mobile. It
therefore seemed desirable to synthesize and test a pair of
2,4-cis-dimethyl 1a,25(OH)2D3 analogs (targets A and B;
Fig. 1, CD rings not shown). Methyl groups in the 2-position
are readily accommodated, and although previously untested,
the 4-position appears unencumbered.
6
7
8
6
6
91
63
The A-ring precursor to target A is synthesized from
starting material 22 and in 4 steps gives dienyl sulfone 23,18
which on reaction with in situ generated TFDO affords epoxide
8 as a single diastereomer. Further reaction with dimethyl-
sulfonium methylide provides the allylic alcohol 9 (Scheme 3).
The A-ring precursor to the target B uses the epoxide 24 as
starting material. The epoxide cleavage using Me3Al gave the
anti stereoselective methylated product 25 with 100 : 1
diastereoselectivity using the procedure developed with the
seven-membered epoxy vinyl sulfone.19 O,C-dimetalation
followed by quenching with PhSSPh gave the required vinyl
sulfide 26.8c Lewis acid (TMSOTf) promoted elimination of
benzenesulfinic acid in the presence of base (Et3N) gives the
dienyl sulfide, which cleanly affords dienyl sulfone 27 after
which can serve as an A-ring precursor for 1a,25(OH)2D3 and
its analogs.
c
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Chem. Commun., 2011, 47, 3472–3474 3473

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as a key A-ring precursor to target B after reaction with
dimethyl sulfonium methylide (Table 1, entry 3).
In summary, we have developed a one step protocol leading
to the synthesis of enantiopure cross conjugated allylic alcohol
from readily available epoxy vinyl sulfones. The method gives
an easy access to the A-ring precursors to the 1a,25(OH)2D3
and its analogs, synthesis of which will be reported in due
course.
Notes and references
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The epoxidation of diene 27 proceeds with 11 : 1 selectivity
using in situ generated TFDO.7 Allylic alcohol 11 is obtained
c
3474 Chem. Commun., 2011, 47, 3472–3474
This journal is The Royal Society of Chemistry 2011