Towards stable analogues of inositol phosphates: Stereoselective syntheses of (α,α-difluoromethyl)phosphonic acid (DFMPA)-containing cyclohexanes

Article abstract of DOI:10.1039/b200560n

Diels-Alder and conjugate addition reactions were used to prepare precursors to a range of fully functionalised and deoxy inositol phosphate analogues.

Full text of DOI:10.1039/b200560n

Towards stable analogues of inositol phosphates: stereoselective
syntheses of (a,a-Difluoromethyl)phosphonic acid (DFMPA)-containing
cyclohexanes
Afshan H. Butt,† B. M. Kariuki, Jonathan M. Percy‡* and Neil S. Spencer
School of Chemistry, University of Birmingham, Edgbaston, Birmingham, UK B15 2TT
Received (in Cambridge, UK) 16th January 2002, Accepted 15th January 2002
First published as an Advance Article on the web 4th March 2002
Diels–Alder and conjugate addition reactions were used to
prepare precursors to a range of fully functionalised and
deoxy inositol phosphate analogues.
protons) was obtained in good yield. Stereoselective dihydrox-
ylation5 and protection was followed by reductive elimination6
to afford a mixture of alcohol 10 and alkene 11. Acetylation of
9 to 12 followed by reductive elimination allowed the formation
of 11 as the sole product in 69% yield. The alkene looks ideal for
further manipulation—the topology and the presence of the
DFMPA group would seem propitious for stereoselective
dihydroxylation to deoxy analogue 13.
Stereoselective syntheses of (a,a-difluoromethyl)phosphonic
acid (DFMPA)-derivatised molecules that may act as hydrolyt-
ically stable analogues of naturally-occurring phosphate esters
remain an important goal.1 Recently, Yokomatsu and co-
workers2 described a strategy in which a DFMPA-butadiene
was used to build a cyclohexane precursor to inositol phosphate
analogues (Scheme 1), complementing our own earlier ap-
proach in which we incorporated the phosphate mimic within a
dienophile.3 Both approaches have their limitations; the former,
based upon 1, suffers from the relatively low reactivity of the
diene, the rather limited range of dienophiles with which the key
building block reacts, and that elaboration of 2 or related species
to inositol phosphate analogues requires the stereoselective
oxidative cleavage of two C–C bonds.
The Diels–Alder reaction can also be used to construct key
precursors into which the DFMPA-group is introduced late in
According to Yokomatsu, our Diels–Alder strategy ‘met with
only limited success due to the low endo–exo selectivity’.
Undeniably, the reaction between furan and 3 afforded a
disappointing outcome in the form of an almost equimolar
mixture of endo and exo cycloadducts 4a and 4b in moderate
yield (Scheme 2).3a Worse was to follow; dihydroxylation of the
mixture of stereoisomers and protection as the acetonides 5a
and 5b set the stage for ring opening. Treatment of the mixture
with n-BuLi in THF at 278 °C returned the endo-isomer 5a
unchanged along with alcohol 6 in poor (12%) yield represent-
ing a further reduction in the potential of the route.§ The
conjugate base of 5a must undergo carbanion inversion to adopt
the correct stereoelectronic relationship for ring opening to
occur. Bulky groups must become eclipsed along this pathway
and there appears to be a prohibitive steric barrier to carbanion
inversion. We should point out though that the successful
removal of the phenylsulfonyl group and dihydroxylation of the
alkene delivers a fully functionalised inositol phosphate
analogue 7 in which a key relationship is set between the (C-
1)–CF2 bond and the C-2, C-4 and C-6 hydroxy groups.4
In the quest for more stereoselective and efficient processes,
we considered an alternative route via commercially-available
1-(trimethylsilyloxy)buta-1,3-diene, which reacted smoothly
(Scheme 3) and completely stereoselectively with 3. After
hydrolysis, racemic trans,trans-alcohol 8 (in which the DFMPA
and phenylsulfonyl groups occupy almost pseudo-axial posi-
tions in the crystal structure (and presumably in solution too,
given the coupling constant of 0 Hz between the relevant
Scheme 2 Reagents and conditions: i, Furan, Ace tube, 80 °C, 18 h, 60%,
(endo+exo 3+2); ii, OsO4, t-BuOH, H2O2, rt, 48 h, 57%; iii, acetone, CuSO4,
TsOH, rt, 24 h, 62%; iv, n-BuLi, THF, 278 °C, 25 min then conc. HCl, 6
12%, 5a 48%.
Scheme 1
Scheme 3 Reagents and conditions: i, 3, Ace tube, 80 °C, 48 h; ii, HCl–
EtOH, rt, 1 h, 77%; iii, OsO4, NMO, t-BuOH–acetone–water, rt, 48 h, 69%;
iv, acetone, CuSO4, TsOH, rt, 24 h, 93%; v, 6% Na(Hg), Na2HPO4, MeOH,
rt, 20 min, 9 33%, 10 33%; vi, Ac2O, pyridine, DMAP, DCM, rt, 48 h,
87%.
† Current address: Evotech OAI, 151 Milton Park, Abingdon, Oxon, UK
OX14 4SD.
‡ Current address: Department of Chemistry, University of Leicester,
University Road, Leicester, UK LE1 7RH. E-mail jmp29@le.ac.uk
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CHEM. COMMUN., 2002, 682–683
This journal is © The Royal Society of Chemistry 2002

synthesis. Phenyl vinyl sulfone and furan undergo smooth
cycloaddition to afford a mixture of adducts which afford 14
upon dihydroxylation (Scheme 4); protection and treatment
with n-BuLi converges the diastereoisomers in 15. Protection to
16 then cerium-mediated conjugate addition7 from the least
hindered face of the bicycle and quenching at low temperature
delivers 17 in moderate (62%) yield stereoselectively (trans
addition was observed in all previous cases and would be
anticipated strongly here); however, when the reaction mixture
was allowed to warm to rt before quenching, we also isolated a
product which was revealed to be alkene 19 by 2D NMR
(gradient HMBC). Presumably, this product arises from a 1,2-H
shift in carbene 18.
and versatile approaches to analogues of inositol phosphates
that bear the DFMPA-group.
The authors wish to thank the Engineering and Physical
Sciences Research Council of Great Britain for a Quota
Studentship (to AHB) and Dr K. Blades for preliminary
experiments on the chemistry of Schemes 2 and 3.
Notes and references
§
Selected data for 6. Rf (60% ethyl acetate in light petroleum) 0.21; dH
(300 MHz, CD2Cl2) 7.86–7.64 (3H, m), 7.54 (2H, t, 3J 7.7), 7.27 (1H, br s),
4.74 (1H, d, 3J 7.7), 4.66 (1H, br s), 4.55–4.47 (1H, m), 4.34–4.19 (4H, m),
3.91–3.73 (2H, m), 1.45 (3H, s), 1.40 (3H, s), 1.39 (3H, t, 3J 6.8), 1.35 (3H,
t, J 6.9); dF (282 MHz, CDCl3) 2101.8 (ddd, 2J 311.4, JF-P 99.2, JF-H
3
2
3
5.1), 2111.1 (ddd, 2J 311.4, JF-P 108.1, JF-H 33.1, JF-H 5.1); dP (121
MHz, CDCl3) 5.1 (dd, 2JF-P 108.7, 2JF-P 99.2); [HRMS (ES, M + Na) Found:
519.1022. Calc. for C20H27O8F2PSNa 519.1030]; m/z (ES) 519 (100%, M +
Na).
2
3
4
Selected data for 8. Rf (ethyl acetate) 0.46; mp 82–83 °C; (Found: C, 48.0;
H, 5.5%. C17H23 F2O6PS requires C, 48.1; H, 5.4%); dH (300 MHz, CDCl3)
7.95 (2H, d, 3J 8.5), 7.71–7.51 (3H, m), 5.90–5.80 (2H, m), 4.47 (1H, d, 3J
7.0), 4.35–4.15 (4H, m, OCH2CH3), 3.92 (1H, s), 3.75 (1H, d, 3J 7.0, O-H,
exchanged with D2O), 3.45–3.24 (1H, m), 2.59–2.42 (2H, m), 1.35 (6H, t,
3J 7.0, OCH2CH3); dC (75 MHz, CDCl3) 137.6, 134.2, 129.5, 128.8, 127.3,
126.5, 120.6 (td, 1JC-F 264.5, 1JC-P 211.4), 65.5 (d, 2JC-P 6.2), 65.0 (d, 2JC-P
2
7.4), 64.7–64.5 (m)*, 60.6, 34.0 (td, JC-F 22.0, 2JC-P 17.0), 20.5–20.22
(m)*, 16.4 (d, 3JC-P 5.1), 16.3 (d, 3JC-P 5.7); dF (282 MHz, CDCl3) 2104.8
(ddd, 2J 302.0, 3JF-P 102.1, 3JF-H 17.2), 2111.2 (ddd, 2J 302.0, 2JF-P 109.8,
3JF-H 19.9); dp (300 MHz, CDCl3) 6.95 (ddd, 2JP-F 109.8, 2JP-F 102.1, 3JP-H
7.7); m/z (EI) 425 (15%, M + 1), 407 (70), 283 (75), 265 (100), 188 (85).
*Multiplet signals arise from superimposed longer range C–F and C–P
couplings. C17H23 F2O6PS crystal size 0.50 3 0.30 3 0.30 mm, M =
424.38, crystal system monoclinic, unit cell dimensions a = 9.9968(6), b =
16.8039(14), c = 12.5119(11) Å, b = 104.776(2)°, U = 2032.3(3) Å3, T =
296(2) K, space group P21/a, Absorption coefficient m(Mo-Ka) = 0.285
mm21, 11831 reflections collected, 3531 unique [R(int) = 0.0364], which
were used in all calculations. Final R indices [I > 2s(I)] R1 = 0.0715 wR2
= 0.1572; R indices (all data) R1 = 0.0756, wR2 = 0.1680. CCDC 178066.
See http://www.rsc.org/suppdata/cc/b2/b200560n/ for crystallographic files
in .cif or other electronic format.
Scheme 4 Reagents and conditions: i, Furan, ZnI2, hydroquinone, Ace tube,
90 °C, 5 d, 85% (endo+exo 7+3); ii, OsO4, NMO, t-BuOH–acetone–water,
rt, 48 h, 69%, iii, acetone, CuSO4, TsOH, rt, 48 h, 89% over 2 steps; iv, n-
BuLi, THF, 278 °C, 0.5 h, 73%; v, NaH, BnBr, THF, 0 °C, 1 h, 67%; vi,
LiCF2PO(OEt)2, CeCl3, THF, 278 °C then quench (see text).
Selected data for 11. Rf (60% ethyl acetate in light petroleum) 0.51; dH
(300 MHz, CDCl3) 6.02 (1H, br d, 3J 10.3), 5.83 (1H, br d, 3J 10.3),
4.55–4.42 (2H, m), 4.35–4.20 (4H, m), 3.20–2.98 (1H, m), 2.35 (1H, dt, 2J
14.7, 3J 3.7), 2.00–1.88 (1H, m), 1.39–1.34 (12H, m); dC (75 MHz, CDCl3)
Reductive desulfonation of 17 to 21 was successful though
we also isolated the intriguing product 22 in trace amounts
(Scheme 5). We believe that this arises from intramolecular
attack at phosphorus followed by C–C cleavage with protona-
tion and assign the cis-stereochemistry to the C–CF2 and C–P
bonds accordingly.
Clearly considerable optimisation of a number synthetic steps
is required but we would argue that strategically, these
applications of the Diels–Alder reaction still represent powerful
3
3
1
129.5, 124.7 (td, JC-F 6.2, JC-P 3.4), 120.8 (td, JC-F 262.8, 1JC-P 212.5),
108.8, 71.6, 71.4, 64.8 (d, 2JC-P 6.8), 64.6 (d, 2JC-P 6.8), 36.6 (q, 2JC-F=C-P
20.4), 27.9, 26.7, 25.0–24.9 (m)*, 16.6, 16.5; dF (282 MHz, CDCl3) 2114.4
2
3
2
(dd, JF-P 108.1, JF-H 17.8); dP (121 MHz, CDCl3) 6.73 (t, JF-P 108.3);
[HRMS (ES, M + Na) Found: 363.1147. Calc. for C14H23O5F2NaP
363.1149]; m/z (ES) 363 (100%, M + Na). *Multiplet signals arise from
superimposed longer range C–F and C–P couplings.
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Lequeux and J. M. Percy, J. Chem. Soc., Perkin Trans. 1, 1999, 3609; (c)
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1691.
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5 A crystal structure was obtained for 9 also; these results will be published
elsewhere.
6 R. V. C. Carr, R. V. Williams and L. A. Paquette, J. Org. Chem., 1983,
48, 4976.
7 K. Blades, D. Lapoˆtre and J. M. Percy, Tetrahedron Lett., 1997, 38,
5895.
Scheme 5 Reagents and conditions: i, 6% Na(Hg), Na2HPO4, MeOH, rt, 30
min, 21 49%, (22 trace).
CHEM. COMMUN., 2002, 682–683
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