A ring-closing metathesis strategy to phosphonosugars

Article abstract of DOI:10.1021/ol016491p

Equation presented Syntheses of cyclic phosphonate (phostone) analogues of carbohydrates containing a phosphorus atom at the anomeric position are described. The ring-closing metathesis reaction of mixed allylic phenyl esters of allylphosphonic acid 2 and

Full text of DOI:10.1021/ol016491p

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3285-3288
A Ring-Closing Metathesis Strategy to
Phosphonosugars
Diana S. Stoianova and Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582
phanson@ku.edu
Received July 24, 2001
ABSTRACT
Syntheses of cyclic phosphonate (phostone) analogues of carbohydrates containing a phosphorus atom at the anomeric position are described.
The ring-closing metathesis reaction of mixed allylic phenyl esters of allylphosphonic acid 2 and 22 generates the six-membered allylic
phosphonates 3 and 23 in excellent yields. Introduction of the polyhydroxy functionality in these cyclic phosphonates provides facile entry
into an array of phostone sugar analogues.
The ring-closing metathesis (RCM) reaction continues to
emerge as a powerful approach for the construction of
complex organic molecules.1 Recently, we and others have
shown that the RCM reaction catalyzed by the Grubbs
ruthenium catalyst2 is an effective method for the construc-
tion of cyclic phosphonates (phostones).3 As a part of our
program aimed at developing transition metal catalyzed
approaches to diverse phosphorus-containing compounds, we
herein report our efforts toward the synthesis of phostone
analogues of carbohydrates using RCM as a key step. Sugar
analogues containing a phosphorus atom in place of the
anomeric carbon have received continued attention in the
literature due to their potential to serve as carbohydrate
mimics.4 Previous routes to phostone sugar analogues have
employed the Abramov reaction of sugar aldehydes and di-
or trialkyl phosphites, followed by intramolecular transes-
terification of the resulting hydroxyphosphonates.4,5 Our
strategy utilizes the RCM reaction for the formation of six-
membered cyclic allylic phosphonates. Epoxidation or di-
hydroxylation of these highly versatile compounds followed
by opening of the epoxide or cyclic carbonate results in the
formation of vinylphosphonates containing a hydroxyl group
at C(5) (Scheme 1). Subsequent dihydroxylation of these
vinylphosphonates can be used to introduce hydroxyl groups
at the C(3) and C(4) positions. Our route, which starts from
simple precursors, is amenable to variations at several
positions and should prove valuable in the diastereoselective
(4) (a) Hanessian, S.; Rogel, O. J. Org. Chem. 2000, 65, 2667-2674.
(b) Hanessian, S.; Rogel, O. Bioorg. Med. Chem. Lett. 1999, 9, 2441-
2446. (c) Harvey, T. C.; Simiand, C.; Weiler, L.; Withers, S. G. J. Org.
Chem. 1997, 62, 6722-6725. (d) Darrow, J. W.; Drueckhammer, D. G.
Bioorg. Med. Chem. 1996, 4, 1341-1348. (e) Hanessian, S.; Galeotti, N.;
Rosen, P.; Oliva, G.; Babu, S. Bioorg. Med. Chem. Lett. 1994, 4, 2763-
2768. (f) Darrow, J. W.; Drueckhammer, D. G. J. Org. Chem. 1994, 59,
2976-2985. (g) Molin, H.; Noren, J. O.; Claesson, A. Carbohydr. Res.
1989, 194, 209-221. (h) Wroblewski, A. E. Tetrahedron 1986, 42, 3595-
3606. (i) Thiem, J.; Gu¨nther, M.; Paulsen, H.; Kopf, J. Chem. Ber. 1977,
110, 3190-3200. (j) Engel, R. Handbook of Organo-phosphorus Chemistry;
Marcel Dekker: New York, 1992.
(5) For some recent examples of the synthesis of non-functionalized cyclic
phosphonates, see: (a) Tasz, M. K.; Rodriguez, O. P.; Cremer, S. E.;
Hussain, M. S.; Haque, M. J. Chem. Soc., Perkin Trans. 2 1996, 2221-
2226. (b) Yokomatsu, T.; Shioya, Y.; Iwasawa, H.; Shibuya, S. Heterocycles
1997, 46, 463-472. (c) Brel, V. K. Synthesis 1998, 710-712. See also ref
3b.
(1) For recent reviews see: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3013-3043. (c) Wright, D. L. Curr. Org. Chem. 1999, 3, 211-240. (d)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (e) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388. (f) Blechert, S.;
Schuster, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-2056.
(2) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110. (b) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2039-2041.
(3) (a) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1998, 39, 3939-
3942. (b) Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel, G.
A.; van Boom, J. H. Tetrahedron Lett. 2000, 41, 8635-8638. (c)
Hetherington, L.; Greedy, B.; Gouverneur, V. Tetrahedron 2000, 56, 2053-
2060.
10.1021/ol016491p CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/25/2001

isolated yield (80%, Scheme 1). The major product of this
epoxidation (DMD and TFD) resulted from attack syn to the
allylic C(6) methyl group. The reason for this selectivity is
not obvious and may result from a number of steric and
electronic factors. Murray has shown that epoxidation of
3-methyl-1-cyclohexene with DMD shows virtually no
selectivity.10 Thus, it appears that the distal homoallylic
phosphorus center may be dictating the selectivity. It is
conceivable that the polar PdO group is directing the
epoxidation (syn to itself) via a favorable dipole-dipole
interaction.11 Alternatively, a repulsive dipole-dipole inter-
action between the P-OPh and the incoming dioxirane could
be invoked.12
Scheme 1a
Attempts to convert epoxide 4 into allylic alcohol 5/6 (R1
) Ph) by treatment with various nonnucleophilic bases were
unsuccessful. We were able to overcome this problem using
lithium alkoxide as a base (Scheme 1). However, under these
conditions, displacement of the phenoxy group with retention
of configuration at phosphorus and epoxide opening took
place.13 The best yields were achieved using a large excess
of benzyl alcohol in THF or MeOH as the solvent for the
formation of the benzyl and methyl esters 5 and 6,9
respectively. Dihydroxylation of the methyl ester 6 with
OsO4/NMO was very sluggish and gave, in addition to the
desired diol, an epoxide as side product. Addition of citric
acid14 to the reaction mixture dramatically accelerated the
reaction and gave the corresponding diol as a single
diastereoisomer. However, extensive decomposition during
chromatography of this diol, derived from methyl ester 6,
led us to work with the more stable benzyl ester 5.
Dihydroxylation of 5 afforded 7 in 78% isolated yield as a
single diastereoisomer9 (Figure 1), which was converted into
a Reagents and conditions: (a) DME/HMPA, -78 °C, 82%, 5:1
mixture. (b) (PCy3)2Cl2RudCHPh, CH2Cl2, reflux, 68%. (c)
CH2Cl2, -78 °C, 80%. (d) BnOLi, THF, 10 °C, 67%. (e) LiOMe,
MeOH, 0 °C, 84%. (f) OsO4, NMO, citric acid, acetone/MeCN/
tBuOH, 78%. (g) 10% Pd/C, H2, EtOH, 100%.
synthesis of an array of highly functionalized cyclic phos-
phonates.
The sequences that we have developed start from mixed
allyl phenyl esters of allylphosphonic acids derived from
racemic 2-butenol (Scheme 1) or optically pure protected
(2S)-1,2-butenediol (vide infra). These compounds were
prepared using a modification of a procedure described by
Moriarity and co-workers for the diastereoselective displace-
ment of either of the two phenoxy groups in diphenyl
methylphosphonate.6 Thus, deprotonation of (()-2-butenol
with BuLi followed by treatment with diphenyl allylphos-
phonate afforded a pair of inseparable racemic diastereo-
isomers, the major isomer corresponding to (()-2 (Scheme
1). The best selectivities7 (5:1) were achieved by slow
addition of the alkoxide solution to phosphonate 1 in THF/
HMPA at -78 °C.8 Under these conditions partial isomer-
ization of the double bond occurred (20-30%), which we
were able to diminish significantly by using DME/HMPA
(6-8% isomerization). Treatment of the mixture of phos-
phonates with the Grubbs catalyst, followed by chromatog-
raphy, gave the diastereomerically pure allylphosphonate 3.
Epoxidation of the major isomer with m-CPBA led mostly
to decomposition. Reaction with dimethyldioxirane (DMD)
gave the desired products with modest selectivity (3.5:1) but
required prolonged reaction times (2 weeks) and a large
excess of the dioxirane. Epoxidation with the more reactive
methyl(trifluoromethyl)dioxirane (TFD) at -78 °C proceeded
with similar selectivity (4:1); however, quantitative reaction
was achieved, producing the major epoxide9 4 in good
Figure 1. Crystal structure for compound 7.
the free phosphonic acid 8 by hydrogenation. The major
product of the dihydroxylation of 5 resulted from attack anti
(6) Moriarty, R. M.; Tao, A.; Condeiu, C.; Gilardi, R. Tetrahedron Lett.
1997, 38, 2597-2600.
(9) The relative stereochemistry of this compound was determined by
single-crystal X-ray crystallography.
(10) (a) Murray, R. W.; Singh, M.; Williams, B. L.; Moncrieff, H. M. J.
Org. Chem. 1996, 61, 1830-1841. (b) For a comparative study of oxidations
using DMD and TFD, see: Adam, W.; Paredes, R.; Smerz, A. K.; Veloza,
L. A. Eur. J. Org. Chem. 1998, 349-354.
(7) The selectivities of all reactions were determined from the 31P NMR
spectra of the crude reaction mixtures.
(8) Reaction in pure THF gave lower selectivity (3.5:1). Reaction in
DME, without HMPA, was sluggish and did not go to completion.
3286
Org. Lett., Vol. 3, No. 21, 2001

to the C(5) hydroxyl group. This result is in agreement with
the seminal work published by Kishi and later substantiated
by Donohoe, where osmium-mediated dihydroxylations occur
anti to the hydroxyl group in the oxidation of 2-cyclohex-
enols.15
With 8 in hand, we attempted to prepare additional
diastereomeric phosphonosugars utilizing this strategy. At-
tempts to selectively invert one of the hydroxyl groups in
compound 7 under Mitsunobu conditions gave only starting
material. We were able to invert the allylic hydroxyl group
in 5 by treatment with p-nitrobenzoic acid to yield vinyl
phophonate 9 bearing a protected C(5) hydroxyl group
(Scheme 2). Attempts to dihydroxylate 9 gave multiple
Efforts to switch the protecting group led us to employ a
Mitsunobu inversion of phostone 6 with p-methoxyphenol
(PMP), producing 11 in good yield (78%) (Scheme 2).
Subsequent dihydroxylation of 11 afforded the corresponding
diol with good selectivity (5:1). After chromatography, a
mixture enriched in the major isomer 12 (11:1) was isolated
in 69% yield. Conversion of the diol 12 into the correspond-
ing acetonide16 and deprotection of the PMP group with
AgO/pyridinedicarboxylic acid17 gave 14 as a single dias-
tereoisomer.9 Cleavage of both the acetonide and the methyl
ester with TMSBr18 gave the fully deprotected phosphonic
acid 15.
Introduction of nitrogen at C(5) was also attainable by
employing N-benzyl-o-nitrobenzenesulfonamide19 in the Mit-
sunobu reaction of the vinyl phosphonate 6 to yield phostone
16 (Scheme 2). Dihydroxylation of 16 afforded 75% of
compound 17 as a single diastereoisomer9 as indicated by
the 31P NMR spectrum. All signals in the 1H NMR and some
of the signals in the 13C NMR spectra of this compound are
very broad, probably as a result of the hindered rotation in
the secondary sulfonamide. Attempts to cleave the o-
nitrobenzenesulfonamide have thus far been unsuccessful.
An alternative route of functionalizing the RCM product
3, which capitalizes on a diastereoselective dihydroxylation,
is shown in Scheme 3. Our initial attempts using OsO4 and
Scheme 2a
Scheme 3a
a Reagents and conditions: (a) p-O2NC6H4COOH, Ph3P, DEAD,
benzene, 97%. (b) p-MeOC6H4OH, Ph3P on polymer, DEAD, THF,
35 °C, 78%. (c) Mg(OMe)2, MeOH, 92%. (d) OsO4, NMO, citric
acid, acetone/tBuOH, 69%, 11:1 mixture. (e) 2-Methoxypropene,
TsOH, CH2Cl2, 95%, 15:1 mixture. (f) AgO, 2,6-pyridinedicar-
boxylic acid, MeCN/H2O, 0 °C, 78%. (g) (i) TMSBr, CH2Cl2; (ii)
H2O, 94%. (h) N-Benzyl-o-nitrobenzene-sulfonamide, Ph3P, DEAD,
THF, 91%. (i) OsO4, NMO, citric acid, acetone/tBuOH/MeCN,
75%.
a Reagents and conditions: (a) OsO4, NMM, m-CPBA, citric
acid, acetone/tBuOH, 78%. (b) (i) Triphosgene, Et3N, CH2Cl2, 96%;
(ii) KHMDS, THF, 87%. (c) OsO4, NMM, m-CPBA, citric acid,
acetone/tBuOH, 78%, 5:1 mixture. (d) PtO2, H2, MeOH, 93%.
products, so we next turned to the dihydroxylation of the
free alcohol 10. To our disappointment, the selectivity of
the reaction was very low (the relative stereochemistry of
the major isomer was not determined).
NMO led only to decomposition of the starting material as
a result of the instability of this compound (lability of the
phenoxy group) in the presence of nucleophiles. The os-
mium-catalyzed reaction in which N-methylmorpholine
(NMM) is reoxidized by m-CPBA20 afforded diol 18 with
excellent selectivity (15:1) and with good isolated yield of
(11) For examples of the syn-directing effect of a carbonyl group in DMD
epoxidations, see: (a) Bovicelli, P.; Lupattelli, P.; Mincione, E.; Prencipe,
T.; Curci, R. J. Org. Chem. 1992, 57, 2182-2184. (b) See also ref 10a,
Table 3.
(12) (a) D’Accolti, L.; Fiorentino, M.; Fusco, C.; Rosa, A. M.; Curci,
R. Tetrahedron Lett. 1999, 40, 8023-8027. (b) Curci, R.; Dinoi, A.; Rubino,
M. F. Pure Appl. Chem. 1995, 67, 811-822. (c) Adam, W.; Paredes, R.;
Smerz, A. K.; Veloza, L. A. Liebigs Ann. 1997, 547-551.
(13) Displacement of the phenoxy group in acyclic mixed phenyl
phosphonates occurs with inversion of the configuration; see ref 6.
(14) Sharpless, K. B. Presented at the 220th National ACS Meeting,
Washington, DC, August 2000; paper ORGN-282.
(16) Attempts to deprotect the free diol led to decomposition.
(17) Deprotection with CAN gave considerably lower yields. For
oxidation of 1,4-dimethoxybenzene in the presence of pyridinecarboxylic
acids, see: Syper, L.; Klock, K. Mlochowski, J.; Szulc, Z. Synthesis 1979,
36, 123-129. Syper, L.; Mlochowski, J. Tetrahedron 1980, 521-522.
(18) For cleavage of methylphosphonates with TMSBr, see: McKenna,
C. E.; Higa, M. T.; Cheung, N. H.; McKenna. M.-C. Tetrahedron Lett.
1977, 155-158.
(15) (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983, 24,
3943-3946. (b) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983,
24, 3947-3950. (c) Donohoe, T. J.; Moore, P. R.; Beddoes, R. L. J. Chem.
Soc., Perkin Trans. 1 1997, 43-51.
(19) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373-6374.
Org. Lett., Vol. 3, No. 21, 2001
3287

the major product (Scheme 3). Again, this reaction was
accelerated dramatically by the addition of citric acid without
any significant changes in the selectivity. Dihydroxylation
of 3 with OsO4/NMO facilitated by citric acid occurred in
good yield; however, the selectivity under these conditions
was considerably lower (5:1). Unlike the epoxidation of 3
(Scheme 1), the major product of the dihydroxylation resulted
from attack anti to the C(6) methyl group. This result is again
in agreement with Kishi’s work,15a,b where dihydroxylation
of 3-methyl-1-cyclohexene yields exclusively the anti-
diastereomer. Initial attempts to convert this compound into
the free phosphonic acid using conditions described for the
cleavage of phenyl phosphates (H2, stoichiometric amount
of PtO2, CF3COOH/CH3COOH)21 led to decomposition, but
reaction in MeOH gave the desired product 19 in excellent
yield.
Scheme 4a
a Reagents and conditions: (a) THF/HMPA, -78 °C, 57%. (b)
(PCy3)2Cl2RudCHPh, CH2Cl2, reflux, 98%. (c) OsO4, NMO, citric
acid, acetone/tBuOH, 70%. (d) TsOH, MeOH, 94%. (e) 10% Pd/
C, H2, MeOH, 97%.
Conversion of the diol 18 into the corresponding carbonate
and treatment with the nonnucleophilic base KHMDS gave
the allylic alcohol 20 in excellent yield (Scheme 3). Opening
of the carbonate did not require the use of an alkoxide and
substitution of the phenyl ester as in the case of epoxide 4
(Scheme 1). Dihydroxylation of the resulting vinylphospho-
nate with OsO4/NMO in the presence of citric acid22 afforded
the desired triol as a mixture of inseparable diastereoisomers
in a 3.3:1 ratio. Under the NMM/m-CPBA/citric acid
conditions the selectivity of the reaction was improved to
5:1, affording the triol 21.9 This product again arose from
attack anti to the hydroxyl group, albeit with diminished
selectivity as compared with the dihydroxylation of the C(5)-
epimeric vinylphosphonate 5 (Scheme 1). A similar trend
in selectivity was observed by Donohoe15c in the oxidation
of cis- and trans-5-tert-butyl-2-cyclohexenol.23 Conversion
of 21 into the free phosphonic acid afforded a mixture of
isomers, the major one being identical with 15.
of citric acid yielded diol 24 in good isolated yield. TLC
analysis of the reaction mixtures showed formation of a small
amount of a second product, which disappeared completely
after workup. On the basis of NMR data, we assume that
the diastereofacial preference for dihydroxylation of 23 is
the same as in 3. Deprotection of the primary hydroxyl group
with TsOH followed by hydrogenation afforded the non-
racemic phosphonic acid (+)-26 in excellent yield.
In conclusion, a facile RCM/oxidation strategy has been
developed that allows for the diastereoselective generation
of a number of phosphonosugar analogues. Additional
stereoselective routes to nonracemic phosphonosugars are
currently being pursued and will be reported in due course.
Acknowledgment. This investigation was generously
supported by funds provided the National Institutes of Health
(National Institute of General Medical Sciences, RO1-
GM58103). The authors thank Dr. David Vander Velde for
the assistance with the NMR measurements and Dr. Todd
Williams for HRMS analysis. The authors also thank the
National Science Foundation (grant CHE-0079282) and the
University of Kansas for funds to purchase the X-ray
instrument and computers. The structures of compounds 6,
7, 14, 17, and 21 were determined by Dr. Douglas R. Powell.
We also thank. Dr. Victor Young from the University of
Minnesota for the structure of compound 4.
The strategy we developed was also applied to the
nonracemic mixed allylphosphonate (+)-22 derived from
deprotonation of (2S)-1,2-butenediol with BuLi followed by
treatment with diphenyl allylphosphonate in THF/HMPA
(Scheme 4). RCM of the major diastereoisomer afforded the
phostone 23 in almost quantitative yield. Attempts to
epoxidize 23 proceeded with low selectivity. Dihydroxylation
of cyclic phosphonate 23 with OsO4/NMO in the presence
(20) Bergstad, K.; Piet, J. N.; Ba¨ckvall, J.-E. J. Org. Chem. 1999, 64,
2545-2548.
Supporting Information Available: Experimental details
and spectroscopic data of new compounds, including the
crystallographic data for compounds 4, 6, 7, 14, 17, and 21.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Perich, J. W.; Alewood, P. F.; Johns, R. B. Aust. J. Chem. 1991,
44, 233-252.
(22) It is worth noting that attempts for dihydroxylation without citric
acid gave only unreacted starting material.
(23) Donohoe attributed the difference in selectivity to the orientation
of the hydroxyl group; the trans-isomer bearing a locked axial hydroxy
group gave higher selectivity.
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