Synthesis of (sulfonyl)methylphosphonate analogs of prenyl diphosphates

Article abstract of DOI:10.1016/j.tetlet.2009.10.119

Syntheses of several (sulfonyl)methylphosphonate analogs of geranyl, neryl, and farnesyl diphosphates are described. Key steps include utilization of an (E)-selective Horner-Wadsworth-Emmons olefination which couples an aldehyde to the sulfone phosphonate moiety, and a selective reduction of the resulting dienyl sulfone phosphonate substrates.

Full text of DOI:10.1016/j.tetlet.2009.10.119

Tetrahedron Letters 51 (2010) 170–173
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of (sulfonyl)methylphosphonate analogs of prenyl diphosphates
*
Michael W. Lodewyk, Victor G. Lui, Dean J. Tantillo
University of California, Davis, Department of Chemistry, One Shields Avenue, Davis, CA 95616, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Syntheses of several (sulfonyl)methylphosphonate analogs of geranyl, neryl, and farnesyl diphosphates
are described. Key steps include utilization of an (E)-selective Horner–Wadsworth–Emmons olefination
which couples an aldehyde to the sulfone phosphonate moiety, and a selective reduction of the resulting
dienyl sulfone phosphonate substrates.
Received 6 October 2009
Revised 22 October 2009
Accepted 23 October 2009
Available online 6 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Prenyl diphosphate analog
Terpene
Sulfone
Reduction
Analogs of prenyl diphosphates (e.g., Chart 1) have received
much attention over the years for their ability to bind to and com-
petitively inhibit prenyl transferase enzymes.1–3 Disruption of the
prenylation process has been shown to inhibit the growth of malig-
nant tumor cells, for which prenylation is key for various cell sig-
naling and regulatory processes, thus leading to significant anti-
cancer activities.1
Prenyl diphosphate analogs can also bind to terpene synthase
enzymes, which utilize prenyl diphosphates as substrates for com-
plex reactions that produce the varied and complicated molecular
architectures of terpene natural products.4–6 Beyond inhibition
activity, prenyl diphosphate analogs could be exploited for crystal-
lographic studies of terpene synthase enzymes.4–6 To date, rela-
tively few terpene synthase crystal structures have been
reported, and although there is occasionally a prenyl diphosphate
or analog in these structures, most have ammonium ion analogs
of putative carbocation intermediates or no discernable organic
molecule bound.4–6 It is our hope that binding with one or more
of our analogs may not only facilitate crystallization of the enzyme
but may also produce complexes that reveal important details of
the folding adopted by the substrate upon binding, since the ana-
logs should not be processed by the enzyme (prenyl diphosphates
are rapidly ionized in the enzyme active site).
Furthermore, farnesyl diphosphate is a substrate for squalene syn-
thase, which has been targeted for cholesterol-lowering activity.10–
14
Finally, farnesyl diphosphate is also a reported substrate for
dehydrosqualene synthase (CrtM), which is involved in the biosyn-
thesis of the carotenoid staphyloxanthin, a known virulence factor
in Staphylococcus aureus.15 Inhibitors with structures based on that
of farnesyl diphosphate have shown potent activities and may
serve as the basis for new therapies for bacterial infections.15
In this Letter, we report the synthesis and characterization of
several compounds (Chart 2) lacking an ionizable group, which
we believe are excellent mimics of geranyl, neryl, and farnesyl
diphosphates, and which therefore have a strong potential for the
applications discussed above. Chart 2 shows both free phosphonic
acids and their isopropyl-protected precursors. While the phos-
phonic acids are expected to be closer mimics to the diphosphates
in Chart 1, their isopropyl ester counterparts may have useful
applications as well.10–12,16 As one measure of the similarity be-
tween these mimics and the diphosphates, electrostatic potential
maps (Fig. 1) of geranyl diphosphate and deprotonated forms of
1b and 2b were generated (see Supplementary data for details).
O
P
O
O
P
O
Additionally, prenyl diphosphates have been reported to serve
as substrates for soluble epoxide hydrolase (sEH), which displays
lipid phosphate phosphatase activity that is linked to sterol syn-
thesis and inflammation.7–9 Not surprisingly, compounds that mi-
mic the substrates of this enzyme are often potent inhibitors.7–9
O
O
O
O
O
P
O
O
P
O
geranyl diphosphate
O
O
O
neryl diphosphate
O
O
P
O
P
O
O
O
farnesyl diphosphate
* Corresponding author.
E-mail address: tantillo@chem.ucdavis.edu (D.J. Tantillo).
Chart 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.119

M. W. Lodewyk et al. / Tetrahedron Letters 51 (2010) 170–173
171
O
P
(E)/(Z)
(E)/(Z)
O
O
O
O
S
S
OR
OR
OR
IBD, TEMPO (cat)
MeCN, pH 7, 0 °C to rt
1a, 1b
2a, 2b
OH
O
O
P
n
n
O
P
O
O
3a, 3b
S
OR
OR
7: geraniol (n=1, (E))
10: n=1, (E)
11: n=1, (Z)
12: n=2, (E)
86-91%
OR
8: nerol (n=1, (Z))
9: farnesol (n=2, (E))
Scheme 1.
O
P
O
O
O
O
S
S
OR
OR
OR
O
P
5a, 5b
O
O
S
OR
OR
O
P
O
O
P
(E)/(Z)
(E)/(Z)
O
O
O
P
OR
S
O
O
O
O
P
O
O
O
4a, 4b
13
6a, 6b
S
O
O
LiBr, DIPEA, THF
n
n
a: R=isopropyl
b: R=H
10: n=1, (E)
11: n=1, (Z)
12: n=2, (E)
1a: n=1, (E)
3a: n=1, (Z)
5a: n=2, (E)
47-52%
Chart 2.
+
(E)/(Z)
(E)/(Z)
O
O
S
n
n
14: n=1, (E)
15: n=1, (Z)
16: n=2, (E)
36-48%
Scheme 2.
coupling reactions (Scheme 2) proceeded smoothly to produce the
desired (dienylsulfonyl)methylphosphonate products in approxi-
mately 50% yield and with complete (E) selectivity,23 along with
the formation of the bis-coupled adducts 14–16, approximately
40%). It was observed that the yield of the desired product could
be increased, along with a concomitant decrease in bis-coupled ad-
duct formation, through the use of a larger excess of sulfone-phos-
phonate reagent (as reported for other systems).16,20–22 However,
consideration of the time and cost associated with synthesizing
this reagent, along with the relative ease by which the two prod-
ucts could be isolated, led us to use, in general, only a two-fold ex-
cess. The highly acidic methylene protons situated between the
sulfone and phosphonate ester, along with the susceptibility of
the conjugated diene to (E)/(Z) isomerization necessitated extra
caution during the workup procedure. Here, the THF solvent was
removed and replaced with CHCl3 prior to the addition of 1 N
HCl at 0 °C. The remainder of the workup steps were also rigor-
ously carried out at this temperature.
Figure 1. Computed electrostatic potential maps of fully anionic geranyl diphos-
phate and compounds 1 and 2.
These images suggest that, despite the difference in overall charge,
the charge distributions in the mimic structures are quite similar
to those of the diphosphate compound itself.
Some of our analogs are rigid in the vicinity of the sulfone
group, while others are not. If the preferred conformation of a
bound natural prenyl diphosphate is effectively mimicked by an
(E) double bond,4–6 then the rigidity of compounds 1, 3, or 5 should
enhance binding. However, the flexibility of compounds 2, 4, and 6
will allow for a more thorough sampling of conformational space.
Our synthetic scheme allows for the production of both types of
prenyl diphosphate analogs.
At this point, a portion of each of the three intermediates was
subjected to further transformation via a reduction of the
ble bond of the dienyl sulfone moiety. There are only scattered re-
ports in the literature of
–b unsaturated sulfone reductions24–35
and, to our knowledge, no reports of the reduction of an –b/ –d
a–b dou-
Our syntheses began with commercially-available geraniol, ner-
ol, and farnesol. These alcohols were oxidized to the corresponding
aldehydes in high yields via a catalytic TEMPO oxidation with iodo-
sobenzene diacetate (IBD) as the stoichiometric oxidant
(Scheme 1).17 Initial attempts to oxidize these substrates using
either PDC18 or hydrogen peroxide and platinum19 resulted in
the formation of a significant amount (ꢀ10–25%) of (E)/(Z) isomer-
a
a
c
dienyl sulfone, selective or otherwise. While we expected that this
would be a challenging transformation, we were optimistic that a
larger LUMO coefficient on the b carbon (relative to the d carbon),
along with the greater steric accessibility of this site would favor
ization of the a–b alkene. In contrast, the TEMPO oxidation proved
a,b-reduction with a hydride-donor reagent. Figure 2, which in-
highly reliable for the clean conversion of the alcohols to the alde-
hydes and had the additional benefits of being procedurally simple
and avoiding the use of heavy metals.
The next step involved a Horner–Wadsworth–Emmons cou-
pling of the aldehydes to a diisopropoxyphosphonate sulfone re-
agent (13, Scheme 2) developed by Gervay-Hague and co-
workers, which was synthesized in three steps without intermedi-
ate purification from commercially-available materials.16,20–22 The
cludes the computed LUMO, highlights these two features for a
model dienyl sulfone (see the Supplementary data for details).
Consistent with this prediction, numerous trials with various
conditions involving the use of NaBH4 with InCl3,36 CoCl2,37 and
38
RuCl3
catalysts, along with uncatalyzed NaBH4, super hy-
dride,25,35 and bulky K-Selectride all led to the predominant forma-
tion of the desired product. Unfortunately, none of these reactions
were highly selective, and each was accompanied by significant

172
M. W. Lodewyk et al. / Tetrahedron Letters 51 (2010) 170–173
The final step in the synthesis of compounds 1b–6b was depro-
tection of the isopropyl phosphonate ester to produce the free
phosphonic acids. This transformation was effected (Scheme 4)
using TMS–Br,39 and inclusion of 2,4,6-collidine as a non-nucleo-
philic base proved essential for the success of these reactions.40
Furthermore, microwave heating promoted rapid and efficient
conversion to product with 21 min reaction times.41 The crude
products were evaporated to dryness and then subjected directly
to HPLC purification to yield the products in approximately 60–
80% yields (likely representing nearly quantitative conversion prior
to purification).
Spectral analysis of the expected nerol-derived products (3b
and 4b), however, showed some peculiarities. Examination of the
NMR and high resolution mass spectra for expected product 3b re-
vealed that a mixture of the expected product and a covalent hy-
drate of 3b was isolated. This is evidenced by the presence of a
C–O–H proton (at d = 4.43 ppm) and a decreased integration value
for one of the vinyl signals in the 1H NMR spectrum, as well as the
presence of a mass + H2O peak in the high resolution mass spec-
trum. However, prior LC–MS analysis completed immediately after
purification but before concentration strongly suggested the pres-
ence of only the desired compound at this stage. Thus it appears
that the observed covalent hydrate was likely formed upon con-
centration (lyophilization of the H2O/MeCN solvent mixture).
Examination of the spectra for expected product 4b also revealed
similar peculiarities. In this case, initial LC–MS analysis following
purification again suggested the presence of only the desired com-
pound, but NMR analysis completed after concentration showed
highly cluttered spectra which were not readily interpretable. Fur-
thermore, LC–MS analysis of a portion of the NMR sample itself
then revealed the presence of an additional unknown compound
of mass 372. Therefore it is clear that although initially formed,
the (Z)-configured free phosphonic acid products were susceptible
to further reaction, an observation which likely reflects the in-
creased reactivity of these alkenes under somewhat acidic condi-
tions. In contrast, all four reactions on the geraniol- and farnesol-
derived intermediates proceeded cleanly to form the expected
products 1b, 2b, 5b, and 6b.
Figure 2. Computed LUMO for a model dienyl sulfone. Shown are two orthogonal
views, with the front half of the orbital removed from the lower image for clarity.
amounts of the
a,d-reduced, and/or over-reduced products. Fur-
thermore, these mixtures proved to be inseparable under standard
chromatographic conditions. It was not until we resorted to the ex-
tremely bulky LS-Selectride reagent that we observed complete
selectivity for the formation of the desired products, albeit in mod-
erate yields (Scheme 3). This selectivity, however, came at the price
of a very sluggish reaction. At temperatures ranging from À78 °C to
40 °C, TLC analysis showed some initial product formation, but the
reaction did not progress even over the course of several days with
the addition of excess equivalents of reagent. In hopes of accelerat-
ing this reaction, we utilized microwave heating at 80 °C, but ob-
tained similar results. On occasion, however, we observed an
apparent modest increase in product formation (via TLC) upon
workup of the reaction. This prompted an approach where, after
initial addition of 2 equiv of reagent at 0 °C and microwave heating
for 25 min, 1–2 equiv of H2O was added to the reaction at 0 °C.
After the reaction was allowed to gradually warm up to room tem-
perature, this cycle was repeated three additional times using
2 equiv of reagent and 1–2 equiv of H2O each time. At this point,
the starting material was virtually undetectable by TLC analysis,
and the reaction was subjected to a standard oxidative workup
procedure (NaOH/H2O2/H2O) to ultimately yield up to 67% of the
desired products after flash chromatography purification.
In summary, we have completed the synthesis of a number of
prenyl diphosphates which we believe are likely to show activity
toward enzymes that utilize these substrates in important biolog-
ical contexts. Efforts to assess the utility of these compounds as
inhibitors and mechanistic probes (through crystallography) are
currently underway.
(E)/(Z)
(E)/(Z)
O
P
O
O
P
O
O
O
O
O
LS-Selectride
S
S
O
O
n
MW, 80 °C, THF
n
1a: n=1, (E)
3a: n=1, (Z)
5a: n=2, (E)
2a: n=1, (E)
4a: n=1, (Z)
6a: n=2, (E)
65-67%
Scheme 3.
(E)/(Z)
(E)/(Z)
O
P
O
O
O
O
O
O
TMS-Br (3 eq)
2,4,6-collidine (3 eq)
MW, 120 °C, MeCN
S
S
P
OH
OH
O
n
n
1a-6a
1b-6b
63-81%
Scheme 4.

M. W. Lodewyk et al. / Tetrahedron Letters 51 (2010) 170–173
6. Christianson, D. W. Chem. Rev. 2006, 106, 3412–3442.
173
Acknowledgments
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the National Science Foundation (CAREER), and the R. B. Miller Fel-
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spectrometers were funded in part by the National Science Foun-
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Jessica Wong, Dr. Urvashi Sahni, and Professor Jacquelyn Gervay-
Hague for sharing their expertise on the synthesis of the dii-
sopropoxyphosphonate sulfone reagent. We are also grateful to
Professor Makluf Haddadin, Professor Mark Mascal, Professor Neil
Schore, and Professor Jared Shaw for helpful discussions. We would
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