Synthesis of Cyclic Phosphonate Analogs of Ribose and Arabinose

Article abstract of DOI:10.1021/jo9706382

The cyclic phosphonates of ribose and arabinose (phostones) 10-13 were synthesized by a Lewis acid-catalyzed addition of trimethyl phosphite to the partially protected D-threose 7 to give the acyclic phosphonates 8 and 9. This Abramov reaction was moderately stereoselective (3:1). A base-catalyzed cyclization of the mixture of 8 and 9 gave the four isomeric phosphonates 10-13. Two of the isomers, 10 and 11, could be crystallized from the reaction mixture. The stereochemistries of 11 and 16, the tribenzyl ether from 10, were proven by X-ray crystallography, and the stereochemistries of the other isomers and derivatives were determined by ³¹P NMR chemical shift data. The X-ray data and solution NMR data indicate that these phostones and their derivatives exist exclusively in a chair conformation.

Full text of DOI:10.1021/jo9706382

6722
J . Org. Chem. 1997, 62, 6722-6725
Syn th esis of Cyclic P h osp h on a te An a logs of Ribose a n d Ar a bin ose
Thomas C. Harvey, Ce´cile Simiand, Larry Weiler,* and Stephen G. Withers
Department of Chemistry, University of British Columbia, Vancouver, BC, Canada V6T 1Z1
Received April 9, 1997X
The cyclic phosphonates of ribose and arabinose (phostones) 10-13 were synthesized by a Lewis
acid-catalyzed addition of trimethyl phosphite to the partially protected D-threose 7 to give the
acyclic phosphonates 8 and 9. This Abramov reaction was moderately stereoselective (3:1). A base-
catalyzed cyclization of the mixture of 8 and 9 gave the four isomeric phosphonates 10-13. Two
of the isomers, 10 and 11, could be crystallized from the reaction mixture. The stereochemistries
of 11 and 16, the tribenzyl ether from 10, were proven by X-ray crystallography, and the
stereochemistries of the other isomers and derivatives were determined by 31P NMR chemical shift
data. The X-ray data and solution NMR data indicate that these phostones and their derivatives
exist exclusively in a chair conformation.
Recently, there has been renewed interest in the
in situ cyclization gave a mixture of the four isomers, 10-
13. While flash chromatography provided isomerically
enriched product, none of the four isomers could be
obtained chromatographically pure. We can estimate the
relative amounts of the four isomers as 10:5:2:3 from the
NMR spectra of the crude material.
synthesis of phosphonate derivatives of carbohydrates.1,2
In these cases the cyclic phosphonate analogs (phostones)
of hexopyranoses were synthesized and characterized.
Such compounds are potential inhibitors of glycosidases
since they can be viewed as potential analogs of the
transition state of these reactions.3 They are also,
therefore, starting points for the generation of catalytic
antibodies to effect glycoside hydrolysis. At this time we
report the synthesis of the cyclic phosphonate analogs of
pentoses, namely, the xylo analogs 1 and 2 and lyxo
analogs 3 and 4.
One of the isomers crystallized from the syrup and was
isolated in 19% yield. The single phosphorus peak at δ
21.96 and the clean doublet at δ 3.82 due to the methyl
1
group in the H NMR spectra were strong evidence that
the crystals were of a single compound. The stereochem-
istry of this material was determined by converting it
into the corresponding tri-O-acetate by hydrogenolysis
of the benzyl protecting groups followed by acetylation
(Scheme 2). The stereochemistry of this product was
determined to be that shown in 14. The signal for the
proton on C-1 was a triplet at δ 5.25 (J ) 9 Hz) due to
coupling with phosphorus and H-2. The large J 1,2 is
consistent with a xylose, or trans stereochemistry for C-1
and C-2. The stereochemistry of the phosphorus was
suggested from NOE experiments. Irradiation of the
signal due to the phosphorus methyl group resulted in
an enhancement of H-1 only, which suggests that the
methyl group is equatorial (vide infra). Thus, the
compound leading to 14 should have the stereochemistry
shown in 10 (Scheme 1). This was confirmed by forming
the tri-O-benzyl ether 16 from 10 which gave crystals
suitable for X-ray crystallography.
Our synthesis is outlined in Scheme 1 and starts with
D-xylal (5).4 The two hydroxyl groups in 5 were protected
as benzyl ethers. The double bond in the protected xylal
6 was oxidatively cleaved, and the resulting aldehyde 7
was not purified but was immediately treated with
trimethyl phosphite in an acid-catalyzed Abramov
reaction.1a,5 This reaction gave two chromatographically
inseparable isomers, 8 and 9, in a ratio of 3:1 as
determined by NMR. The major isomer is assigned as 8
on the basis of subsequent transformations. Darrow and
Drueckhammer found that the analogous reaction with
the arabinose derivative was not stereoselective.1a How-
ever, the Lewis acid-catalyzed addition of phosphite to
R-benzyloxy aldehydes is stereoselective and has the
same stereochemical preference that we find in the
reaction of 7.6 Cleavage of the formate ester followed by
Further crystallization of the mother liquors from the
reaction of 8 and 9 gave a second crystalline product. The
31P NMR had a single peak at δ 19.98 indicating that
the product was isomeric with 10. The stereochemistry
of this compound was determined by X-ray crystal-
lography to be 11. Compound 11 was also subjected to
the hydrogenolysis-acetylation sequence (Scheme 2) to
yield 15. Again the H-1 signal was a triplet at δ 5.46 (J
) 9.5 Hz) consistent with the xylo configuration for C-1
and C-2. When the phosphorus methyl in 15 was
irradiated, there was an enhancement of H-2 consistent
with these two substituents having a 1,3-diaxial relation-
ship. Both 11 and 16 have a well-defined chair confor-
mation in the solid state,7 despite the fact that it has been
X Abstract published in Advance ACS Abstracts, September 1, 1997.
(1) (a) Darrow, J . W.; Drueckhammer, D. G. J . Org. Chem. 1994,
59, 2976. (b) Darrow, J . W.; Drueckhammer, D. G. Bioorg. Med. Chem.
1996, 4, 1341.
(2) Hanessian, S.; Gale´otti, N.; Rosen, P.; Oliva, G.; Babu, S. Bioorg.
Med. Chem. Lett. 1994, 4, 2763.
(3) McCarter, J . D.; Withers, S. G. Current Opin. Struct. Biol. 1994,
4, 885.
(4) Weygand, F. Methods Carbohydr. Chem. 1962, 1, 184.
(5) Abramov, V. S. Dokl. Akad. Nauk SSSR 1954, 95, 991; Chem.
Abstr. 1955, 49, 6084d.
(6) Yokomatsu, T.; Yoshida, Y.; Shibuya, S. J . Org. Chem. 1994, 59,
7930.
(7) Also see: Masood, P.; Napper, A. D.; Benkovic, S. J . Acta
Crystallogr. 1988, C44, 1414.
S0022-3263(97)00638-5 CCC: $14.00 © 1997 American Chemical Society

Cyclic Phosphonate Analogs of Ribose and Arabinose
J . Org. Chem., Vol. 62, No. 20, 1997 6723
Sch em e 1
a
(a) BnCl, NaH, DMF (90%); (b) NaIO4, cat. OsO4, H2O-Et2O; (c) (MeO)3P, AcOH (69% for two steps); (d) NaOMe, MeOH (95%).
Ta ble 1. 31P NMR Sh ifts for Cyclic P h osp h on a tes
Sch em e 2
P-OMe
stereochemistry
compd
31P shift
∆(eq - ax)
10
11
2
eq
ax
eq
ax
eq
ax
eq
ax
eq
ax
21.90
20.04
26.44
24.07
16.37
14.06
18.34
15.90
17.13
16.23
1.9
2.3
2.3
2.4
0.9
1
14
15
17
19
18
20
phosphonates.8,9 The one exception is the 18 and 20 pair
in which the difference in chemical shift for the two
isomers is 0.89 ppm. In related cases, it has been
suggested that some of the isomers which would have
an equatorial P-OR group may in fact have a significant
amount of the twist-boat conformation present, thus
leading to a reduction in the difference in 31P NMR shifts
between the two isomers.9 We believe that is the reason
for the small difference in 31P NMR shifts between 18
and 20.
a
(a) H2, Pd-C, EtOH (93% for 2, 77% for 1); (b) Ac2O, pyridine
(15% for 14, 22% for 15).
suggested that such six-membered-ring phosphonates
with an axial P-OMe group may also exist in a twist-
boat conformation.8
The mixture of phosphonates 10-13 was benzoylated,
and we were able to isolate two pure compounds from
this mixture. The first was shown to be identical to the
ester obtained by benzoylation of 11 and thus has
structure 19. The second benzoate was shown to have
structure 20. A dd at δ 5.92 (J 1,2 ) 3.3 Hz, J 1,P ) 11.7
Hz) was assigned to H-1, and a ddd at δ 4.15 (J 1,2 ) 3.3
Hz, J 2,P ) 7 Hz, J 2,3 ) 13.7 Hz) was assigned to H-2.
These coupling constants indicated a lyxose-like config-
uration for C-1 to C-3. The two remaining compounds
were isolated as an inseparable mixture, and their
structures were determined to be 17 and 18 by 1H NMR.
Compound 17 was identical to the benzoate from 10.
A mixture of 1 and 2 was demethylated with NaI (eq
1).10 The reaction was readily monitored by 31P NMR.
Thus, the disappearance of the peaks at δ 26.44 and
24.07, and the appearance of a single new peak at δ 19.98
showed that 1 and 2 differed only in the stereochemistry
at the phosphorus center. In addition, the tribenzyl
ethers 16 and 22 were each hydrolyzed with trimethyl-
silyl bromide11 to give the same phosphonic acid 23 (eq
2).
Table 1 contains a summary of the 31P NMR shifts for
the compounds which have firmly established structures.
In general, the signal for the axial P-OMe isomer is 2
ppm upfield from the corresponding equatorial isomer.
This trend has been observed in the cyclic phosphonates
of hexopyranoses1,2 and in other six-membered ring
(9) Chang, J . W.; Gorenstein, D. G. Tetrahedron 1987, 43, 5187.
(10) See, for example, ref 1a.
(8) Gorenstein, D. G. Chem. Rev. 1987, 87, 1047.
(11) Salomon, C. J .; Breuer, E. Tetrahedron Lett. 1995, 36, 6759.

6724 J . Org. Chem., Vol. 62, No. 20, 1997
Harvey et al.
starting materials. After being stirred for 4 h, the solution
was concentrated and purified by flash chromatography
(EtOAc) to give a colorless syrup (3.3 g, 95%) containing the
four isomers 10, 11, 12, and 13. Analysis of the 31P NMR
spectrum of the crude material revealed that the ratio of
isomers 10-13 was 10:5:2:3. Crystallization of the mixture
of four isomers from EtOAc:hexanes gave 10 as white crystals
(0.467 g, 19%), mp 138-140 °C. 1H NMR (400 MHz, CDCl3)
δ: 7.35 (m, 10 H), 4.77 (s, 2H), 4.65 (s, 2H), 4.05-4.25 (m,
2H), 4.02-3.87 (m, 2H), 3.82 (d, J ) 10.9 Hz, 3H), 3.60 (ddd,
J ) 4.0, 6.0, 7.2 Hz, 1H). 31P NMR (81 MHz, CDCl3) δ: 21.90
ppm. FABMS(+) m/ z: 379 (M+ + H). Anal. Calcd for
C19H23O6P: C, 60.32; H, 6.13. Found: C, 60.34; H, 6.01.
Crystallization of the mother liquor using the same solvent
system gave 11 as white crystals (0.374 g, 15%), mp 97-100
°C. 1H NMR (400 MHz, CDCl3) δ: 7.35 (m, 10H), 4.85 (d, J )
11.2 Hz, 1H), 4.81 (d, J ) 11.2 Hz, 1H), 4.71 (d, J ) 11.5 Hz,
1H), 4.62 (d, J ) 11.5 Hz, 1H), 4.15 (ddd, J 4e,3 ) 4.5 Hz, J 4e,4a
) 11.5 Hz, J 4e,P ) 22.5 Hz, 1H), 4.02 (ddd, J 1,2 ) J 1,P ) 8.6 Hz,
J 1,OH ) 5.7 Hz, 1H), 3.77-3.90 (m, 2H), 3.87 (d, J CH3,P ) 10.4
Hz, 3H), 3.63 (ddd, J 3,2 ) J 3,4a ) 8.5 Hz, J 3,4e ) 4.5 Hz, 1H),
3.3 (dd, J OH,1 ) 5.7 Hz, 1H). 31P NMR (81 MHz, CDCl3) δ:
20.04 ppm. FABMS (+) m/z 379: (M+ + H). Anal. Calcd for
C19H23O6P: C, 60.32; H, 6.13. Found: C, 60.10; H, 6.00.
Data for the mixture of 12 and 13. 31P NMR for 12 (81 MHz,
CDCl3) δ: 21.58 ppm. 31P NMR for 13 (81 MHz, CDCl3) δ:
19.97 ppm.
We shall report the glycosidase inhibition studies with
these phostones12 and their use as haptens in the
generation of catalytic antibodies elsewhere.
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra were recorded at 200
or 400 MHz relative to TMS using the solvent as standard.
13C NMR spectra were recorded at 50 MHz relative to TMS
using the solvent as standard. 31P NMR spectra were recorded
at 81 MHz using 85% H3PO4 as an external standard.
Reactions were monitored by thin layer chromatography (TLC)
using Merck Kieselgel 60 (F254) analytical plates. Spots were
detected under UV light or by charring with 10% H2SO4 in
MeOH. Flash chromatography13 was performed using Merck
silica gel 60 (230-400 mesh).
3,4-Di-O-ben zyl-D-xyla l (6). To a solution of D-xylal (5)
(2.14 g, 18.4 mmol) in DMF at 0 °C was added NaH (2.56 g,
60% in mineral oil, 64.0 mmol). After the mixture was stirred
for 15 min, the reaction was treated with 8.0 mL (69 mmol) of
benzyl chloride, and the mixture was then stirred at room
temperature for an additional 6 h. The reaction mixture was
then cooled to 0 °C and treated with MeOH to destroy the
excess NaH. The solution was concentrated, diluted with
CHCl3, and washed with water. Evaporation of the organic
solvents gave an oil which was purified by flash chromatog-
raphy (eluant gradient: hexanes-EtOAc, 97:3; hexanes-
EtOAc, 93:7) to give 5.0 g (91%) of 6 as a colorless syrup. 1H
NMR (200 MHz, CDCl3) δ: 7.25 (m, 10H), 6.55 (d, J ) 6.0 Hz,
1H), 5.00 (ddd, J ) 1.4, 4.6, 6.0 Hz, 1H), 4.66 (s, 2H), 4.62 (d,
J ) 12.0 Hz, 1H), 4.53 (d, J ) 12.0 Hz, 1H), 4.14 (ddd, J )
1.4, 4.0, 12.0 Hz, 1H), 3.97 (dd, J ) 2.0, 12.0 Hz, 1H), 3.86
(ddd, J ) 1.4, 2.7, 4.6 Hz, 1H), 3.69 (dddd, J ) 1.4, 2.0, 2.7,
4.0 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ: 146.7, 138.4, 138.0,
128.5, 128.5, 127.9, 127.8, 127.7, 99.0, 72.8, 71.3, 70.0, 69.2,
64.0. CIMS (NH3) m/z: 314 (M + NH4)+.
2,3-Di-O-ben zyl-4-O-for m yl-D-th r eose (7). 3,4-Di-O-ben-
zyl-D-xylal (6) (2.81 g, 9.48 mmol) was dissolved in Et2O (8
mL). To this solution was added water (60 mL), followed by
NaIO4 (22.0 g, 103 mmol) and a catalytic quantity of OsO4
solution (400 µL, 4% in H2O). The reaction flask was covered
with foil and stirred vigorously at room temperature for 24 h.
The solution was filtered, and the filtrate was extracted with
EtOAc (2 × 30 mL). The organic layers were dried (MgSO4),
filtered, and evaporated at low temperature (less than 40 °C)
to yield the aldehyde 7 as a colorless syrup which was used
immediately in the next step.
(1S,R)-3,4-Di-O-ben zyl-4-O-for m yl-D-th r eose 1-(Dim eth -
yl p h osp h on a te) (8) a n d (9). Trimethyl phosphite (1.17 mL,
9.95 mmol) was added to a solution of the crude 7 from above
in glacial acetic acid (30 mL). The reaction was stirred at room
temperature for 2 h until TLC showed one predominant
compound (EtOAc:Rf ) 0.6). The solution was diluted with
EtOAc (50 mL) and washed with saturated aqueous NaHCO3
(5 × 40 mL). The aqueous washes were combined and
extracted with EtOAc (2 × 30 mL). The organic layers were
combined and washed with saturated aqueous NaHCO3 (3 ×
30 mL). The organic extracts were dried (MgSO4) and
concentrated to give a colorless oil. Flash chromatography
(eluant gradient: hexanes-EtOAc, 1:1; EtOAc) gave a mixture
of 8 and 9, 3:1 by NMR, as a colorless syrup (2.88 g, 69% from
6). 1H NMR (400 MHz, CDCl3) δ: 8.01 (s, 0.75H), 7.97 (s,
0.25H), 7.28 (m, 10H), 4.70 (m, 2H), 4.52 (m, 2H), 4.20-4.39
(m, 3H), 4.02 (m, 0.25H), 3.85 (m, 0.75H), 3.81 (d, J ) 10.4
Hz, 0.75H), 3.77 (d, J ) 10.4 Hz, 2.25H), 3.76 (d, J ) 10.6 Hz,
2.25H), 3.72 (d, J ) 10.6 Hz, 0.75H); 31P NMR (81 MHz, CDCl3)
δ: 22.21 and 22.17 ppm; FABMS (+) m/ z: 439 (M+ + H).
(1S,R)-2,3-Di-O-ben zyl-D-th r eose 1-(Meth yl p h oston e)
(10, 11, 12 a n d 13). The mixture of 8 and 9 (4.0 g, 9.1 mmol)
was dissolved in MeOH (80 mL) and a catalytic amount of
NaOMe (40 mg) was added. The solution was stirred at room
temperature, and the reaction was monitored by 1H and 31P
NMR because the products had the same Rf values as the
(1S)-D-Th r eose 1-(Meth yl p h oston e) (2). Compound 10
(270 mg, 0.71 mmol) was dissolved in EtOH (60 mL), and 200
mg of 10% Pd on C was added. The reaction was stirred at
room temperature under a H2 atmosphere for 8 h. The
solution was filtered through Celite, and the filtrate was
evaporated to give 2 (131 mg, 93%) as a colorless syrup. 1H
NMR (400 MHz, CD3CN) δ: 4.10 (ddd, J 4e,3 ) 4.7 Hz, J 4e,4a
)
11.3 Hz, J 4e,P ) 23.1 Hz, 1H), 3.84 (ddd, J ) 6.0, 9.6, 11.3 Hz,
1H), 3.75 (d, J CH ) 10.8 Hz, 3H), 3.70 (m, 1H), 3.67 (ddd, J
,P
3
) 4.8, 8.3, 9.2 Hz, 1H), 3.58 (ddd, J ) 4.7, 8.3, 9.6 Hz, 1H). 31
P
+
NMR (81 MHz, D2O) δ: 26.44 ppm; FABMS m/z: 199 (M+
H). Anal. Calcd for C5H11O6P: C, 30.31; H, 5.60. Found: C,
30.29; H, 5.77.
(1S)-1,2,3-Tr i-O-a cetyl-D-th r eose 1-(Meth yl p h oston e)
(14). Compound 1 (43 mg, 0.21 mmol) was acetylated as
described for the preparation of 15. After the solution was
washed with water, evaporation of the organic solvents gave
a syrup which crystallized from EtOAc-hexanes to give pure
14 (11 mg, 15%). 1H NMR (400 MHz, CDCl3) δ: 5.55 (ddd,
J 2,1 ) J 2,3 ) 9 Hz, J 2,P ) 6 Hz, 1H), 5.25 (dd, J 1,P ) J 1,2 ) 9 Hz,
1H), 5.05 (ddd, J 3,4e ) 4.8 Hz, J 3,2 ) J 3,4a ) 9 Hz, 1H), 4.28
(ddd, J 4e,3 ) 4.8 Hz, J 4e,4a ) 12 Hz, J 4e,P ) 21 Hz, 1H), 4.17
(ddd, J 4a,3 ) 9 Hz, J 4a,4e ) 12 Hz, J 4a,P ) 9 Hz, 1H), 3.85 (d,
J CH3,P ) 10.8 Hz, 3H), 2.14 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H);
31P NMR (81 MHz, CDCl3) δ: 16.37 ppm. FABMS (+) m/ z:
325 (M+ + H).
(1S)-D-Th r eose 1-(Meth yl p h oston e) (1). Compound 11
(243 mg, 0.64 mmol) was debenzylated as described for the
preparation of 2 to give 1 (98 mg, 77%) as a colorless syrup.
1H NMR (400 MHz, D2O) δ: 4.17 (ddd, J 4e,3 ) 2.5 Hz, J 4e,4a
10.4 Hz, J 4e,P ) 26.5 Hz, 1H), 3.55-3.95 (m, 4H), 3.84 (d, J CH
)
,P
3
) 10.4 Hz, 3H). 31P NMR (81 MHz, D2O) δ: 24.07 ppm. CIMS
(isobutane) m/ z: (M+ + H) calcd for C5H12O6P 199.0371, found
199.0378. Anal. Calcd for C5H11O6P‚1/3H2O: C, 29.42; H, 5.76.
Found: C, 29.65; H, 5.93.
(1S)-1,2,3-Tr i-O-a cetyl-D-th r eose 1-(Meth yl p h oston e)
(15). Compound 2 (15 mg, 0.07 mmol) was acetylated in 2:1
pyridine-Ac2O (2 mL). The reaction was stirred at room
temperature for 12 h, then diluted with CH2Cl2, and washed
with water. Evaporation gave a syrup which crystallized from
EtOAc-hexanes to give pure 15 (5 mg, 22%). 1H NMR (400
MHz, CDCl3) δ: 5.46 (dd, J 1,2 ) J 1,P ) 9.5 Hz, 1H), 5.38 (ddd,
J 2,1 ) J 2,3 ) 9.5 Hz, J 2,P ) 3.7 Hz, 1H), 5.10 (ddd, J 3,4e ) 5.1
Hz, J 3,2 ) J 3,4a ) 9.5 Hz, 1H), 4.28 (ddd, J 4e,3 ) 5.1 Hz, J 4e,4a
) 11 Hz, J 4e,P ) 21 Hz, 1H), 3.92 (d, J CH ) 10.7 Hz, 3H),
,P
3
3.92 (m, 1H), 2.10 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H). 31P NMR
(81 MHz, CDCl3) δ: 14.06 ppm. FABMS (+) m/z: 325 (M+
H).
+
(12) For a discussion of this nomenclature, see: Thiem, J .; Gu¨nther,
M.; Paulsen, H.; Kopf, J . Chem. Ber. 1977, 110, 3190.
(13) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem.1978, 43, 2923.
(1S)-1,2,3-Tr i-O-ben zyl-D-th r eose 1-(Meth yl p h oston e)
(16). The tribenzyl ether 16 was prepared by two methods.

Cyclic Phosphonate Analogs of Ribose and Arabinose
J . Org. Chem., Vol. 62, No. 20, 1997 6725
Meth od A. NaH (5.0 mg, 60% in mineral oil, 0.13 mmol) was
added to a solution of 10 (50 mg, 0.13 mmol) in 5 mL of THF
at 25 °C. After being stirred for 5 min, the solution was treated
with benzyl bromide (23 mg, 0.13 mmol) and a catalytic
amount of n-Bu4NI (1 mg). After 2 h of stirring, the reaction
was treated with an additional 5 mg of NaH (0.13 mmol) to
ensure that the reaction was complete. After stirring for an
additional 0.5 h, the reaction was carefully treated with H2O
(0.5 mL) to quench any remaining NaH and then diluted with
EtOAc and brine (1:1, 20 mL). The layers were separated, and
the organic layer was washed with brine (1 × 10 mL). The
aqueous washes were combined and extracted with EtOAc (1
× 10 mL). The organic layers were combined, dried over
MgSO4, and concentrated under reduced pressure to give a
nearly colorless oil. Flash chromatography (eluant gradient:
50:50 hexanes-EtOAc; EtOAc) provided 44 mg (71%) of 16 as
a colorless, crystalline solid. Recrystallization from EtOAc-
hexanes gave crystals suitable for X-ray crystallography.
Meth od B. Benzyl 2,2,2-trichloroacetimidate (316 mg, 1.25
mmol) and a catalytic amount of triflic acid (12 mg) were added
to a solution of 16 (394 mg, 1.04 mmol) in CH2Cl2 (25 mL) at
25 °C. After 1 h of stirring, the reaction had proceeded about
half-way according to TLC and was not progressing any
further. Thus, another 150 mg of benzyl 2,2,2-trichloro-
acetimidate (0.59 mmol) and a catalytic amount of triflic acid
(10 mg) were added. The reaction was stirred an additional 2
h and then washed with NaHCO3 (2 × 20 mL). The aqueous
washes were combined and extracted with CH2Cl2 (1 × 20 mL).
The organic layers were combined, dried over MgSO4, and
concentrated under reduced pressure to provide a colorless oil/
solid. Flash chromatography (eluant gradient: 70:30 hex-
anes-EtOAc; 50:50 hexanes-EtOAc) provided 387 mg (79%)
of 16 as a colorless, crystalline solid. 1H NMR (200 MHz,
CDCl3) δ: 7.23-7.40 (m, 15H), 4.70-4.90 (m, 4H), 4.75 (d, J
) 11.8 Hz, 1H), 4.60 (d, J ) 11.8 Hz, 1H), 3.85-4.10 (m, 3H),
3.53-3.80 (m, 2H), 3.70 (d, J ) 11.0 Hz, 3H). 31P NMR (81
MHz, CDCl3) δ: 22.98. CIMS (NH3) m/ z: 469 (M + H)+.
a white precipitate formed and was filtered off to give the
sodium salt of 21 (109 mg, 77%). 1H NMR (400 MHz, D2O) δ:
3.95 (m, 1H), 3.4-3.75 (m, 4H). 31P NMR (81 MHz, D2O) δ:
16.99. FABMS (-) m/ z: 183 (M- - H).
(1R)-1,2,3-Tr i-O-ben zyl-D-th r eose 1-(Meth yl p h oston e)
(22). Benzyl 2,2,2-trichloroacetimidate (363 mg, 1.44 mmol)
and a catalytic amount of triflic acid (10 mg) were added to a
solution of 10-13 that was enriched with isomer 11 (455 mg,
1.20 mmol) in CH2Cl2 (20 mL) at 25 °C. After 2 h of stirring,
the reaction had proceeded about half-way according to TLC
and was not progressing any further. Thus, another 363 mg
of benzyl 2,2,2-trichloroacetimidate (1.44 mmol) was added.
After an additional 2 h of stirring, the reaction was washed
with NaHCO3 (2 × 30 mL). The aqueous layers were combined
and extracted with CH2Cl2 (1 × 20 mL). The organic layers
were combined, dried over MgSO4, and concentrated under
reduced pressure to afford a colorless oil. Flash chromatog-
raphy (eluant gradient: 50:50 hexanes-EtOAc; EtOAc) pro-
vided 490 mg (87%) of the four possible isomers of the tribenzyl
ethers. One set of pooled fractions gave 206 mg (37%) of a
colorless oil that was highly enriched with 22 and with only a
minor amount of 16 present (10:1). 1H NMR (200 MHz, CDCl3)
δ: 7.00-7.25 (m, 15H), 5.07 (d, J ) 11.0 Hz, 1H), 4.92 (s, 2H),
4.86 (d, J ) 11.0 Hz, 1H), 4.82 (d, J ) 11.4 Hz, 1 H), 4.64 (d,
J ) 11.4 Hz, 1H), 3.60-4.20 (m, 5H), 3.94 (d, J ) 10.0 Hz,
3H). 31P NMR (81 MHz, CDCl3) δ: 18.52.
(1S)-1,2,3-Tr i-O-ben zyl-D-th r eose 1-P h oston e (23). Tri-
methylsilyl bromide (0.33 mL, 2.48 mmol) was added to a
solution of 16 (387 mg, 0.826 mmol) in 10 mL of CH2Cl2. The
solution was warmed to reflux. After 1 h of stirring, the
reaction was treated with 3 N HCl (2 mL) and stirred for
another 15 min at 25 °C. The aqueous layer of the reaction
was separated and extracted with CH2Cl2 (1 × 3 mL). The
organic layers were combined, dried (MgSO4), and concen-
trated under reduced pressure to afford a brown oil. Flash
chromatography (eluant gradient: 50:50 hexanes-EtOAc;
EtOAc) gave 257 mg (69%) of 23 as a colorless oil. Structure
proof of 23 was realized after coupling of a side chain in the
equatorial position at the phosphorus stereocenter that was
suitable for our work in catalytic antibody production (details
to be presented elsewhere).
Beginning with (1S)-1,2,3-tri-O-benzyl-D-threose 1-(methyl
phostone) (22), which is the stereoisomer of 16 at the phos-
phorus center, the same product 23 was prepared. Hence,
trimethylsilyl bromide (202 mg, 1.32 mmol) was added to a
solution of 22 (206 mg, 0.440 mmol) in 7 mL of CH2Cl2. The
solution was warmed to reflux. After 1 h of stirring, the
reaction was treated with 3 N HCl (2 mL) and stirred for
another 15 min at 25 °C. The aqueous layer of the reaction
was separated and extracted with CH2Cl2 (1 × 2 mL). The
organic layers were combined, dried (MgSO4), and concen-
trated under reduced pressure to afford a whitish oil. Flash
chromatography (eluant gradient: 50:50 hexanes-EtOAc; 80:
20 EtOAc-MeOH; MeOH) gave 189 mg (95%) of 23 as a
colorless oil. As with the product from 16, structure proof of
23 was realized after coupling of a side chain in the equatorial
position at the phosphorus stereocenter that was suitable for
our work in catalytic antibody production (details to be
presented elsewhere). Thus, both 16 and 22 led to the same
product, indicating that they differ only at the phosphorus
stereocenter.
Ben zoyla tion of th e Mixtu r e of 10, 11, 12 a n d 13. To
an ice-cold solution of 10, 11, 12, and 13 (0.95 g, 2.5 mmol)
and pyridine (1 mL) in CH2Cl2 (25 mL) was added benzoyl
chloride (650 µL, 5.6 mmol). The reaction was stirred over-
night. TLC (EtOAc:hexanes 1:1) showed three new spots.
Purification by flash chromatography (EtOAc:hexanes 1:2)
gave three fractions A, B, and C. Fraction A (443 mg) was a
mixture of compounds 17 and 18 in a ratio of 3:2 (by NMR)
and a total yield of 40%. The major component was identical
to the product from benzoylation of 10 and thus must have
structure 17. 1H NMR (200 MHz, CDCl3) δ: 7.10-8.10 (m,
15H), 6.00 (dd, J ) 3, 12 Hz, 0.4H, H-1 of 18), 5.50 (dd, J )
9.5, 9.5 Hz, 0.6H, H-1 of 17), 4.50-4.85 (m, 4H), 4.05-4.45
(m, 3H), 3.70-3.94 (m, 1H), 3.87 (d, J ) 10.9 Hz, 1.2H, P-OMe
of 18), 3.80 (d, J ) 10.9 Hz, 1.8H, P-OMe of 17). 31P NMR (81
MHz, CDCl3) δ: 18.34 (17), 17.13 (18). FABMS (+) m/ z: 483
(M+ + H).
Fraction B (400 mg, 36%) was compound 19. The 1H and
31P NMR spectra of this compound were identical to the spectra
of the compound obtained by benzoylation of 11. 1H NMR (400
MHz, CDCl3) δ: 7.05-8.00 (m, 15H), 5.71 (dd, J 1,P ) J 1,2
)
9.9 Hz, 1H), 4.77 (d, J ) 11.2 Hz, 1H), 4.75 (d, J ) 11.4 Hz,
1H), 4.66 (d, J ) 11.2 Hz, 1H), 4.61 (d, J ) 11.4 Hz, 1H), 4.17
(ddd, J 4e,3 ) 4.7 Hz, J 4e,4a ) 11.2 Hz, J 4e,P ) 24.2 Hz, 1H), 3.97
(ddd, J 2,P ) 4.9 Hz, J 2,3 ) 8.5 Hz, J 2,1 ) 9.9 Hz, 1H), 3.91 (ddd,
J 4a,P ) 5.3 Hz, J 4a,3 ) 9.8 Hz, J 4a,4e ) 11.2 Hz, 1H), 3.87 (d,
J CH ) 10.6 Hz, 3H), 3.79 (ddd, J 3,4e ) 4.7 Hz, J 3,2 ) 8.5 Hz,
Ack n ow led gm en t. We are grateful to Dr. S. Rettig
and Professor J . Trotter for the X-ray crystallographic
data and analysis, to the Natural Sciences and Engi-
neering Research Council of Canada for financial sup-
port, and to Hermann Ziltener and Lloyd McKenzie for
fruitful discussions.
J 3,4a ,P) 9.8 Hz, 1H). 31P NMR (81 MHz, CDCl3) δ: 15.90.
3
FABMS (+) m/ z: 483 (M+ + H).
Fraction C (260 mg, 23%) was compound 20. 1H NMR (400
MHz, CDCl3) δ: 7.2-8.1 (m, 15 H), 5.92 (dd, J 1,2 ) 3.3 Hz,
J 1,P ) 11.7 Hz, 1H), 4.85 (d, J ) 11.7 Hz, 1H), 4.71 (d, J )
11.7 Hz, 1H), 4.60 (d, J ) 11.7 Hz, 1H), 4.57 (d, J ) 11.7 Hz,
1H), 4.48 (ddd, J 4e,3 ) 3.4 Hz, J 4e,4a ) 11.9 Hz, J 4e,P ) 14.8 Hz,
1H), 4.15 (ddd, J 2,1 ) 3.3 Hz, J 2,P ) 7.0 Hz, J 2,3 ) 13.7 Hz,
1H), 4.02 (ddd, J ) 6.4, 11.9, 13.0 Hz, 1H), 3.78-3.90 (m, 1H),
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
compounds 1, 2, 6, 10-11, 14-16, and 19-21 and the
mixtures of 8 and 9 and 17 and 18. X-ray structural diagrams
for compounds 11 and 16 (37 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
3.82 (d, J CH ) 10.9 Hz, 3H). 31P NMR (81 MHz, CDCl3) δ:
,P
16.23 ppm. 3 FABMS (+) m/ z: 483 (M+ + H).
D-Th r eose (1S)-1-P h oston e (21). A mixture of 1 and 2
(137 mg, 0.69 mmol) was dissolved in CH3CN (20 mL) and
heated to reflux in the presence of NaI (155 mg). After 12 h
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