A novel reagent for the synthesis of geminal di-sulfones

Article abstract of DOI:10.1016/S0040-4039(01)01004-8

A novel reagent (diisopropoxyphosphorylmethanesulfonylmethanesulfonylmethyl)-phosphonic acid diisopropyl ester (8) capable of forming symmetrical and non-symmetrical α,β unsaturated gem-disulfones is reported. Both aromatic and aliphatic aldehydes react i

Full text of DOI:10.1016/S0040-4039(01)01004-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5137–5140
A novel reagent for the synthesis of geminal di-sulfones
Michael J. Hadd, Mark A. Smith and Jacquelyn Gervay-Hague*
The University of Arizona, Department of Chemistry, Tucson, AZ 85721, USA
Received 6 April 2001; accepted 8 June 2001
Abstract—A novel reagent (diisopropoxyphosphorylmethanesulfonylmethanesulfonylmethyl)-phosphonic acid diisopropyl ester (8)
capable of forming symmetrical and non-symmetrical a,b unsaturated gem-disulfones is reported. Both aromatic and aliphatic
aldehydes react in good yields to give exclusively the trans isomer. Selectivity for the mono-olefin can be achieved by varying the
stoichiometry of reagents. © 2001 Published by Elsevier Science Ltd.
The diphosphate functionality is ubiquitous in nature
where it serves several important roles. For example,
diphosphates are known to chelate metalloenzymes,
which can result in nucleophilic displacement of the
pyrophosphate group.1 In this capacity, diphosphates
serve as nature’s leaving group. A number of studies
have focused on the synthesis of diphosphate mimics as
potential inhibitors of important enzymatic transforma-
tions. The diphosphate has been successfully replaced
with several other functionalities including methylene
diphosphonates,2 sulfonamides,3 and monophosphates4
to provide potent inhibitors of targeted enzymes.
Diphosphate isosteric design and synthesis has also
included the use of gem-disulfones as potential trans-
ferase inhibitors.5
In their syntheses of differentially functionalized gem-
disulfones, Spencer and co-workers showed that double
deprotonation of bis(methylsulfonyl)methane (1)
occurred at the a-position forming the a,a dianion.6
Upon reaction with a third equiv. of base, the a,a,a%
tri-anion (2) was generated (Scheme 1). Subsequent
alkylation of the trianion with alkyl halides resulted in
only moderate yields of the a% substituted product.
Similar difficulties were encountered in our attempted
alkylation of C-glycosyl sulfones (Scheme 2).7 Alkyla-
tion of both the mono (3), and gem-disulfones (4) gave
complex reaction mixtures under a variety of conditions
(Scheme 2). We attributed the failure of these reactions
to competing formation of the methyl and methylene
anions, either of which could be alkylated. Complica-
Scheme 1.
Scheme 2.
* Corresponding author. Tel.: 520-621-8843; fax: 520-621-8407; e-mail: gervay@email.arizona.edu
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01004-8

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M. J. Hadd et al. / Tetrahedron Letters 42 (2001) 5137–5140
Scheme 3.
tions arising from retro-Michael of the methylene anion
also seemed plausible.
only the isopropyl protons (multiplet at 4.80, doublet at
1.32) were visible in the NMR. The rapid exchange of
the methylene protons suggests that they are relatively
acidic.
To circumvent difficulties resulting from multiple anion
generation, other methods of selectively functionalizing
the a% positions of gem-disulfones were investigated. We
reasoned that incorporation of a phosphonate function-
ality at both a% positions would allow generation of
stabilized anions under relatively mild conditions. The
phosphonate functionality would also serve to direct
the carbonꢀcarbon bond forming reaction to the a%
position, due to the irreversibility of the Horner–
Emmons–Wadsworth (HEW) reaction. Reported herein
is the synthesis of a novel reagent (8) that provides
selective and differential functionalization of geminal
disulfones under mildly basic conditions.8
Investigations of 8 as a HEW reagent were first con-
ducted on several aromatic aldehydes. Good yields, and
high stereoselectivities (no Z isomers were identified)
were observed. Three equiv. of benzaldehyde were
reacted with 1 equiv. of 8 to give a 70% yield of the bis
adduct 9 after 20 h. Three equiv. of the aldehyde were
used in order to assure bis addition. Both activated and
deactivated aldehydes underwent reaction with 8, how-
ever, p-nitrobenzaldehyde (10) reacted much more
rapidly and in higher yield than p-methoxybenzalde-
hyde (11). Reactions with phenols failed, but this limi-
tation was easily overcome by simple acetate protection
of the hydroxyl functionality (entry 4).
The synthesis of 89 began with commercially available
diisopropyl bromomethylphosphonate 5, which was
treated with potassium thioacetate to afford 6. Depro-
tection of the thioester with sodium methoxide pro-
vided the thiolate, which was subsequently reacted with
diiodomethane to yield the thioacetal 7. Oxidation of 7
with oxone provided the symmetrical reagent 8 (Scheme
3). The yield of (diisopropoxyphosphorylmethanesul-
fonylmethanesulfonylmethyl)-phosphonic acid diiso-
propyl ester for the 3-step process was 64% and this
reagent has been prepared on multiple gram scale. The
250 MHz NMR of compound 8 in chloroform showed
as singlet at l 5.57, a multiplet at l 4.80, a doublet at
l 3.91 (J=16.0 Hz) and a doublet at l 1.32 (J=6.2
Hz). Interestingly, when 8 was dissolved in deuterated
methanol all of the methylene protons exchanged and
A typical reaction involved deprotonation of 8 with 3
molar equiv. of base (3 equiv. of base was found to be
the most efficient due to the presence of three acidic
methylenes) followed by addition of excess aldehyde
(typically 3 equiv.). We have used a number of different
bases and solvents and the yields do not vary signifi-
cantly. However, the Masamune/Roush conditions for
generating anions in the presence of lithium salts and
an amine base are most convenient, due to the
availability of pure reagents and the ease of measuring
them.10 Entry 5 in Table 1 nicely illustrates that
aliphatic aldehydes undergo efficient coupling using
these conditions, and there was no evidence of compli-
cations from possible aldol condensation.
Table 1. Reaction conditions for bis-adduct formation

M. J. Hadd et al. / Tetrahedron Letters 42 (2001) 5137–5140
5139
Scheme 4.
Scheme 5.
References
Varying the ratio of aldehyde to 8 (1:3) was shown to
enhance selectivity for the mono-olefin 14, which could
be reacted in a second step to provide the unsymmetri-
cal geminal disulfones 15 (Scheme 4).
1. (a) Persson, K.; Ly, H. D.; Dieckelmann, M.;
Wakarchuk, W. W.; Withers, S. G.; Strynadka, N. C. J.
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6. Castro, A. Ph.D. Dissertation, Dartmoth College 1992
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Arizona, 1997.
8. Gervay-Hague, J.; Hadd, M. J. US Patent Application
No. 60/138,986.
9. (Diisopropoxyphosphorylmethanesulfonylmethanesulfonyl-
methyl)-phosphonic acid diisopropyl ester (8): To commer-
cially available diisopropyl bromomethylphosphonate
(Lancaster) (5.24 g, 20 mmol) in 15 mL of DMF, potas-
sium thioacetate (3.46 g, 30 mmol) and tetra-
butylamonium iodide (373 mg) were added and heated to
80°C with stirring for 2 h. The solution was cooled and
partitioned between water and ethyl acetate. The ethyl
acetate layer was collected and dried over sodium sulfate
and then evaporated to dryness. To the crude oil was
added acetonitrile (15 mL), 3 M NaOH (7.4 mL) and
methanol (7.4 mL) and the solution was stirred for 30
min. The flask was cooled to 0°C and diiodomethane
(797 mL, 10 mmol) was added and the reaction was
warmed to room temperature and stirred overnight. The
Unsymmetrical geminal disufones have also been gener-
ated in a one-pot procedure (Scheme 5). For example,
p-carbomethoxy benzaldehyde (16) was reacted with
1.5 equiv. 8 for 1.5 h at room temperature before the
addition of 4 equiv. benzaldehyde. After 20 h reaction
time, the unsymmetrical gem-disulfone (17) was iso-
lated and purified in 33% yield. Purification of the
desired product can be problematic (due to similar Rf’s)
depending upon the aldehydes chosen in the condensa-
tion reactions. Nonetheless the feasibility of such a
reaction has been demonstrated.
In summary, the synthesis and characterization of a
novel reagent for the incorporation of geminal disul-
fones has been accomplished. One can achieve mono-
or bis-addition by varying the stoichiometry of
reagents. Aromatic aldehydes containing both electron
withdrawing and electron donating groups undergo
reaction with 8 in an efficient manner, as do aliphatic
aldehydes. The extension of these studies to the synthe-
sis of biologically relevant geminal disulphones is cur-
rently under investigation in our laboratories.
Acknowledgements
The authors thank the Arizona Disease Research Com-
mission for partial support of this research. The finan-
cial contribution of the National Institutes of Health
(GM60917) is also acknowledged. J.G.H. thanks the
Alfred P. Sloan foundation and Eli Lilly for their
generous support of this research.
.

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M. J. Hadd et al. / Tetrahedron Letters 42 (2001) 5137–5140
reaction was then partitioned between water and ethyl
24H, J=6.2 Hz), 3.91 (d, 4H, J=16.0 Hz), 4.80 (m,
4H), 5.58 (s, 2H). 13C NMR (CDCl3, 125 MHz): l
23.7, 24.1, 50.7, 51.8, 68.1, 73.2, 73.3. HRFABMS
calcd for C15H35O10P2S2 (M+H): 501.1147. Found:
501.1151 (M+H).
acetate and the ethyl acetate layer collected and dried
over sodium sulfate. After evaporation, the crude oil
was oxidized using oxone (24.86 g, 40 mmol) in
methanol/water (ꢀ100 mL 1:1) overnight to give a
crude solid after ether/bicarbonate extraction. Recrys-
tallization from ether/hexanes provided 3.15 g of 8
(64% yield). 1H NMR (CDCl3, 500 MHz): l 1.33 (d,
10. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld,
A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetra-
hedron Lett. 1984, 25, 2183–2186.
.