A rearrangement-based approach to secondary difluorophosphonates

Article abstract of DOI:10.1039/b005110l

[3,3]-Claisen rearrangements allowed the conversion of a readily available allylic difluorophosphonate to nucleic acid and inositol phosphate-related products via epoxide cyclisation or ring closing metathesis respectively.

Full text of DOI:10.1039/b005110l

A rearrangement-based approach to secondary difluorophosphonates
Afshan H. Butt, Jonathan M. Percy* and Neil S. Spencer
School of Chemistry, University of Birmingham, Edgbaston, Birmingham, UK B15 2TT
Received (in Liverpool, UK) 26th June 2000, Accepted 27th July 2000
[3,3]-Claisen rearrangements allowed the conversion of a
readily available allylic difluorophosphonate to nucleic acid
and inositol phosphate-related products via epoxide cyclisa-
tion or ring closing metathesis respectively.
Secondary hydroxy groups undergo phosphorylation in many of
the key molecules of Nature. Inositols undergo phosphorylation
and dephosphorylation events that are critical in intracellular
signalling pathways while a phosphodiester linkage between
primary 5A-hydroxy and secondary 3A-hydroxy groups provides
the critical structural backbone of the nucleic acids. Oxygen
atom replacement by a CF2 centre has been used extensively as
a mimetic strategy, replacing a scissile O–P bond with a non-
scissile C–P bond, in the quest for enzyme inhibitors and
Fig. 1 Possible attack trajectory to explain the formation of lactone 1.
molecular probes. A relatively limited range of target types has
been synthesised; one of our major interests lies in expanding
the range of species accessible using convenient methodology
and starting materials. In this communication, we wish to show
how a rearrangement-based route affords butyrolactone deriva-
which showed a strong transfer of magnetisation from H-3 to
H-4. Attack from the face occupied by the bulky (diethoxy-
phosphoryl)difluoromethyl group (Fig. 1) appears to have led to
the observed product, suggesting a possible role for the
phosphoryl PNO oxygen atom in delivering the reagent.10
We then tried to reverse the stereochemical relationship and
obtain the trans-lactone by forming epoxide 9b which would
undergo nucleophilic ring-opening under acid catalysis, either
intramolecularly with the ester carbonyl, or intermolecularly by
traces of water in the medium (followed by cyclisation) to form
the trans-lactone (Scheme 2).
Both reactions would involve a single inversion of configura-
tion at the epoxide stereogenic centre. Epoxidation was very
slow indeed under MCPBA or methyl trioxorhenium11 condi-
tions but the in situ dioxirane method of Yang12 proved most
effective and both epoxides 9a and 9b were obtained as an
inseparable mixture in good (91%, 9a+9b 1+2) yield.
However, treatment with Amberlyst-15 in dry dichloro-
methane13 (Scheme 3) resulted in the isolation of only cis-
lactone 1 in good (78%) yield.
A lower facial selectivity for oxidation with the smaller
dioxirane reagent (which cannot coordinate to the phosphoryl
oxygen either) was no surprise, but the convergence of the
epoxides was unexpected. One epoxide (we believe 9a) reacted
considerably more quickly than the other and we were able to
recover the less reactive species as a pure compound by careful
19F NMR monitoring of the consumption of 9a. The stereo-
chemical convergence may involve neighbouring group partici-
pation by the phosphoryl oxygen in a double inversion
mechanism via 10; effectively, the all cis-epoxide 9b must be
opened with overall retention at the secondary carbon for the
cis-lactone to form. Interestingly, an NMR sample of the less
reactive epoxide in untreated CDCl3 was converted to 1 and a
trace of 11 upon standing. Neighbouring group participation by
thiophosphoryl oxygen has been exploited to control glycosyla-
tion stereochemistry14 but we are not aware of examples of a
phosphoryl group exerting such an influence. Further under-
tives 1 (related to building blocks for nucleic acid analogues1,2
)
and cyclohexenone derivatives 2 (related to deoxyinositol
phosphate analogues3). The approach complements our earlier
conjugate addition4,5 and cycloaddition6 chemistry which was
based upon chlorodifluoromethane as a feedstock.
Known alcohol 3 was prepared according to a modification of
the published method7 and protected as the THP ether 4.
Coupling under the Shibuya–Yokomatsu8 conditions afforded a
good yield of 5 which was deprotected smoothly to afford 6
(Scheme 1). Rearrangement under Johnson–Claisen conditions9
was uneventful and alkenoate 7 could be isolated and purified
rigorously. Overall, this sequence is synthetically equivalent to
the selective addition at Cb of a difluoromethylphosphonate
anion equivalent to an alkyl a,b,g,d-unsaturated dienoate.
To learn about the behaviour of the educt, dihydroxylation of
7 was attempted under a range of conditions, none of which
were found to be satisfactory. Though starting material could be
converted completely, apparently in a highly stereoselective
manner, we were never able to isolate more than 11% of lactone
1† formed via diol 8 (the configuration was inferred from that of
1). The 19F NMR spectrum of the crude product appeared to be
that of a single diastereoisomer (as a racemic modification); the
single product was identified as the 5-ring lactone 1 (by gradient
HMBC) of cis-stereochemistry (by GOESY spectroscopy),
Scheme 1 Reagents and conditions: i, dihydropyran, Amberlyst-15, dry
hexane, 86%; ii, BrZnCF2PO(OEt)2, CuBr, DMF, 96%; iii, MeOH,
Amberlyst-15, hexane, 82%; iv, triethyl orthoacetate, propionic acid,
hydroquinone, 140 °C, 86%; v, 10% OsO4, 2.0 NMO, acetone–water (2+1),
rt, 11%.
Scheme 2 Reagents and conditions: i, CF3COCH3, Oxone, NaHCO3,
Na2EDTA, MeCN, H2O, 91%.
DOI: 10.1039/b005110l
Chem. Commun., 2000, 1691–1692
This journal is © The Royal Society of Chemistry 2000
1691

the cyclohexene template. The products of this study are under
evaluation as components for novel nucleoside and inositol
phosphate analogues as we learn more about the steric and
electronic effects of the mimetic group.
The authors wish to thank the Engineering and Physical
Sciences Research Council of Great Britain for support (Quota
Award to A. H. B).
Notes and references
† Selected data for 1: nmax (film)/cm21 3434br s, 1786s; dH(CDCl3, 300
2
MHz) 4.88–4.79 (m, 1H), 4.32–4.20 (m, 4H), 3.95 (dd, 1H, JH-H 12.5,
2
3
3JH-H 2.2), 3.65 (dd, 1H, JH-H 12.5, JH-H 2.6), 3.5 (br s, 1H, OH),
3.44–3.20 (m, 2H), 2.85 (dd, 1H, 2JH-H 18.8, 3JH-H 9.2), 2.77 (dd, 1H, 2JH-H
18.4, 3JH-H 7.0), 1.38 (t, 6H, 3JH-H 7.0); 13C dC(CDCl3, 75 MHz) 175.2 (s),
1
1
3
2
119.4 (td, JC-F 263.4, JC-P 214.8), 78.8 (q, JC-FNC-P 4.5), 65.4 (d, JC-P
6.8), 65.2 (d, 2JC-P 6.8), 63.4 (s), 40.3 (td, 2JC-F 20.9, 2JC-P 15.3), 29.1 (td,
3JC-F 5.1, 3JC-P 2.3), 16.4 (d, 3JC-P 5.7); dF(CDCl3, 282 MHz) 2116.8 (ddd,
2JF-F 342.1, 2JF-P 105.5, 3JF-H 16.5). 2117.99 (ddd, 2JF-F 343.3, 2JF-P 104.3,
3JF-H 17.8); dP(CDCl3, 121 MHz) 5.6 (t, 2JP-F 103.9 Hz); m/z (ES) 325 (M
+ Na, 100) HRMS calc. for C10H17O6F2NaP 325.0629, found 325.0632.
Anal. Calcd for C10H17O6F2P: C, 39.74, H, 5.70; found: C, 39.55, H,
5.45%.
Scheme 3 Reagents and conditions: i, Amberlyst-15, dry DCM, rt; ii,
CDCl3, rt, 18 h.
‡ Selected data for 2: nmax (film)/cm21 2987m, 1725s, 1684m; dH(CDCl3,
300 MHz) 6.10–5.89 (m, 2H), 4.25–4.10 (m, 4H), 3.39–3.19 (m, 1H), 2.89
(d, 1H, 2JH-H 22.4), 2.77 (d, 1H, 2JH-H 22.6), 2.71 (dd, 1H, 2JH-H 14.7, 3JH-H
6.6), 2.55 (dd, 1H, 2JH-H 15.1, 3JH-H 6.3), 1.28 (t, 6H, 3JH-H 6.3); dC(CDCl3,
75 MHz) 206.5 (s), 128.7 (s), 122.2–122.0 (m), 120.4 (td, 1JC-F 264.5, 1JC-P
211.9), 64.7 (t, 3JC-F 7.4), 41.9 (td, 2JC-F 21.5, 2JC-P 15.8), 39.1 (s), 37.5 (q,
3JCFNCP 5.1), 16.3 (d, JC-P 5.7); dF(CDCl3, 282 MHz) 2114.1 (ddd, JF-F
300.1, 2JF-P 105.5, 3JF-H 15.3), 2115.8 (ddd, 2JF-F 300.1, 2JF-P 109.8, 3JF-H
17.8); dP(CDCl3, 121 MHz) 6.0 (t, 2JF-P 106.8); m/z (ES) 305 (M + Na, 100);
HRMS calc. for C11H17O4F2P 305.0730, found 305.0722.
standing of this process is sought currently, but clearly the direct
cyclisation of 9b via nucleophilic attack involving the ester
carbonyl group is highly unfavourable.15
A change of tactics allowed access to an attractively
functionalised cyclohexenone (Scheme 4); vinylation of 3
protected the hydroxy group as 12 for the Shibuya–Yokomatsu
coupling allowing Dauben–Dietsche rearrangement16 to pro-
ceed affording enal 14.
3
2
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Tetrahedron Asymm., 1998, 9, 1979; I2, MeCN, rt, 18 h) of 7 afforded
exclusively the cis-iodolactone 19 (68%, stereochemistry assigned by
Scheme 4 Reagents and conditions: i, ethyl vinyl ether, Hg(OAc)2, reflux,
70%; ii, BrZnCF2PO(OEt)2, CuBr, DMF, 84%; iii, 140 °C, xylene, 75%; iv,
allylmagnesium bromide, ethyl ether, 60% (1+1 ratio); v, Grubbs’ catalyst,
DCM, reflux, 48 h; vi, allyltrimethylsilane, BF3·OEt2, DCM, rt, 83% (7+2
ratio); vii, PDC, DCM, rt.
Allylation under Grignard conditions afforded a pair (in a 1+1
ratio) of diastereoisomeric phosphodiesters 15a and 15b; slow
(48 h) RCM under standard Grubbs’ conditions17 then closed
the cis congener to yield 16 (64% by NMR) leaving the trans
isomer 15b unchanged. We inferred that cyclisation with loss of
ethanol had occurred after Grignard addition. Boron trifluoride-
catalysed (Sakurai) allylation with allyltrimethylsilane18 af-
forded homoallyl alcohols 17a and 17b in a 7+2 ratio
(unassigned) then RCM afforded a 7+2 mixture of cyclohex-
enols 18a and 18b which were converged by oxidation to 2‡
with PDC. Enone 2 contains a pattern of functional groups from
which four contiguous hydroxylated positions could be devel-
oped and we will explore its chemistry further.
GOESY); this process must follow a trajectory similar to that of the
closure of 9a to 1.
16 W. G. Dauben and T. J. Dietsche, J. Org. Chem., 1972, 37, 1212.
17 For a review, see R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54,
4413.
The appeal of this strategy lies in the possibility of
asymmetric catalysis of the [3,3] rearrangement controlling the
absolute configuration of the mimetic-bearing carbon atom and
the potential for a high degree of subsequent stereocontrol on
18 A. Bottoni, A. L. Costa, D. DiTommaso, I. Rossi and E. Tagliavini,
J. Am. Chem. Soc., 1997, 119, 12131.
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Chem. Commun., 2000, 1691–1692