P-heterocyclic building blocks: Application to the stereoselective synthesis of P-sugars

Article abstract of DOI:10.1021/jo0505122

A strategy relying on the utilization of stereoselective additions to allyldiphenylphosphonate esters and subsequent ring-closing metathesis (RCM) to access P-chiral P-heterocyclic building blocks for the synthesis of phosphono sugars is described. These

Full text of DOI:10.1021/jo0505122

P-Heterocyclic Building Blocks: Application to the Stereoselective
Synthesis of P-Sugars
Diana S. Stoianova, Alan Whitehead, and Paul R. Hanson*
Department of Chemistry, 1251 Wescoe Hall Drive, Malott Hall, University of Kansas,
Lawrence, Kansas 66045-7582
phanson@ku.edu
Received March 14, 2005
A strategy relying on the utilization of stereoselective additions to allyldiphenylphosphonate esters
and subsequent ring-closing metathesis (RCM) to access P-chiral P-heterocyclic building blocks
for the synthesis of phosphono sugars is described. These building blocks possess several attractive
components, including the following: (i) P(2) and C(6) stereogenic centers for directing stereoselective
transformations; (ii) an activated C(3) methylene group that promotes base-mediated olefin
transposition to generate vinyl phosphonates available for further stereoselective reactions; and
(iii) a P(2)-stereogenic center containing an exchangeable phosphonate ester armed to attenuate
the “stereochemical environment” at phosphorus. Taken collectively, these attributes contribute to
a concise method for the stereoselective synthesis of an array of P-sugars.
Carbohydrates offer excellent opportunities to exploit
stereochemical diversity, since subtle changes in confor-
mation, stereochemistry, and substituents at various
positions are all known to illicit biological responses.1
Recent interest in the development of new carbohydrate-
based mimetics has focused on the development of scaf-
folds that can serve as effective biological probes and/or
potential therapeutic agents.1 A number of innovative
synthetic approaches toward this goal have been under-
taken,2 including the development of new phosphorus-
based sugars (P-sugars).3 The emergence of P-sugars has
resulted largely from previous successes with organo-
phosphorus compounds,4 in both drug5 and agricultural6
discovery programs. Most notably, recent successes with
anomerically modified P-sugars3f,3h have validated their
utility and warranted the continued screening of new
derivatives. Overall, a multitude of P-sugar analogues
have been constructed starting from naturally occurring
(3) (a) Thiem, J.; Gu¨nther, M.; Paulsen, H.; Kopf, J. Chem. Ber. 1977,
110, 3190-3200. (b) Wro´blewski, A. E. Tetrahedron 1986, 42, 3595-
3606. (c) Molin, H.; Noren, J. O.; Claesson, A. Carbohydr. Res. 1989,
194, 209-221. (d) Darrow, J. W.; Drueckhammer, D. G. J. Org. Chem.
1994, 59, 2976-2985. (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. Bioorg. Med. Chem. 1996, 4, 1341-1348.
(g) Harvey, T. C.; Simiand, C.; Weiler, L.; Withers, S. G. J. Org. Chem.
1997, 62, 6722-6725. (h) Hanessian, S.; Rogel, O. Bioorg. Med. Chem.
Lett. 1999, 9, 2441-2446. (i) Hanessian, S.; Rogel, O. J. Org. Chem.
2000, 65, 2667-2674.
(4) (a) Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley-
Interscience: New York, 2000. (b) Engel, R. Handbook of Organo-
phosphorus Chemistry; Marcel Dekker: New York, 1992. (c) In
Phosphorous-Carbon Heterocyclic Chemistry: The Rise of a New
Domain; Mathey, F., Ed.; Pergamon: New York, 2001. (d) Quin, L. D.
The Heterocyclic Chemistry of Phosphorous: Systems Based on the
Phosphorous-Carbon Bond; Wiley & Sons: New York, 1981.
(5) For examples of phosphorus compounds as pharmaceuticals,
see: (a) Kafarski, P.; Lejczak, B. Curr. Med. Chem. 2001, 1, 301-312.
(b) Colvin, O. M. Curr. Pharm. Des. 1999, 5, 555-560. (c) Zon, G. Prog.
Med. Chem. 1982, 19, 205-246. (d) Stec, W. J. Organophosphorus
Chem. 1982, 13, 145-174. (e) Mader, M. M.; Bartlett, P. A. Chem. Rev.
1997, 97, 1281-1301. (f) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur,
Silicon Relat. Elem. 1991, 63, 193-215.
* Corresponding author.
(1) (a) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem.
Rev. 2002, 102, 491-514. (b) Lillelund, V. H.; Jensen, H. H.; Liang,
X.; Bols, M. Chem. Rev. 2002, 102, 515-553.
(2) (a) Kunz, H. Angew. Chem., Int. Ed. Engl. 1987, 26, 294-308.
(b) Musser, J. H., Ed. Carbohydrates as Drug Discovery Leads. In
Annual Reports in Medical Chemistry; Academic Press: New York,
1992; Vol. 27, pp 301-310. (b) Danishefsky, S. J.; Roberge, J. Y. Pure
Appl. Chem. 1995, 67, 1647-1662.
(6) For an example of a phosphorus-containing herbicide, see Franz,
J. E.; Mao, M. K.; Sikorski, J. A. Glyphosate: A Unique Global
Herbicide; American Chemical Society: Washington, DC, 1997.
10.1021/jo0505122 CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/29/2005
5880
J. Org. Chem. 2005, 70, 5880-5889

P-Heterocyclic Building Blocks
SCHEME 1
SCHEME 2
sugars.3 These routes have mainly employed the Abra-
mov reaction between preformed or commercially avail-
able sugar aldehydes and di- or trialkyl phosphites,
followed by intramolecular transesterification of the
resulting hydroxyphosphonates.7,4b As part of our pro-
gram aimed at the development of synthetic routes to
new P-heterocycles with biological and synthetic utility,8
we herein report our continued efforts9 for the synthesis
of novel P-sugars.
Our approach hinges on routes emphasizing stereo-
chemical diversity10 and focuses on the production of a
key P-chiral allylphostone building block 8, using ring-
closing metathesis (RCM),9 to generate versatile epimeric
vinylphostones 4 and 5, respectively (Scheme 1). These
vinylphostone substrates serve as diverse building blocks
for the stereo-controlled synthesis of C(3)-C(5) O- and
N-substituted P-sugars (1-3, Scheme 1). Several attrac-
tive features of scaffold 8 are worth mentioning: (i) P(2)
and C(6) stereogenic centers (phostone numbering) for
directing stereoselective transformations upon the olefin
moiety subunit of 8; (ii) an activated C(3) methylene
group that promotes base-mediated olefin transposition
to generate vinyl phosphonates 4 and 5 possessing P(2)
and C(5) stereocenters for further stereoselective reac-
tions; and (iii) a P(2)-stereogenic center containing an
exchangeable phenyl phosphonate ester which allows for
attenuation of the “stereochemical environment” at phos-
phorus. Overall, the method reported herein allows for
the generation of an array of stereochemically rich
phosphono sugars.
diastereoselective process, first introduced by Moriarty,11
effectively differentiates the two enantiotopic phenyl
esters of 11 (ds ) 3.5-8:1, selectivities determined by
31P NMR). This procedure has been shown to be success-
ful with the commercially available racemic 3-butene-2-
ol (12) to yield products possessing a 1,3-trans-relation-
ship between the PhO- and Me-groups,9 or more elaborate
allylic alcohols 13 and 14 (vide infra). Subsequent RCM
of acyclic precursors 9 using the 1st generation Grubbs
metathesis catalyst (cat-A)12 provides allyl phostones 8
in excellent yields.
Elaboration of allylphostone 15, via the aforementioned
stereo-divergent oxidation pathways, is outlined in Scheme
3. As previously reported,9 both C(5) epimers are avail-
able from 15 by employing either OsO4 or trifluoromethyl
dioxirane. Dihydroxylation of substrate 15 provided diol
16a in high stereoselectivity (ds ) 15:1) in a process that
adheres to the Donohoe/Kishi model,13 whereby dihy-
droxylation occurs anti to the C(5) hydroxyl group.9
Subsequent eliminative opening of the corresponding
carbonate or mesylate of the C(4)/C(5) diol subunit in 16a
afforded vinyl phostones 17a (R1 ) H) and 17b (R1 ) Ms).
Alternatively, epoxidation of 15 led to the C(5) epimer
16b in modest selectivity (ds ) 4:1), but in excellent
isolated yields. As previously reported, we believe the
latter is governed by electrostatic repulsion of the P-OR
ester and the incoming dipolar dioxirane reagent.14
Results and Discussion
Our strategy begins with a stereoselective alkoxide
addition of the readily available allylic alcohols 12, 13,
or 14 to allyl diphenyl phosphonate (11) to derive dienes
9 (R1 ) CH3, CH2OBn, CH2OTr) (Scheme 2). This
(7) For some recent examples of the synthesis of nonfunctionalized
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.
(8) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem. Rev.
2004, 104, 2239-2258.
(9) Stoianova, D. S.; Hanson, P. R. Org. Lett. 2001, 3, 3285-3288.
(10) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. Engl.
2004, 43, 46-58.
(11) Moriarty, R. M.; Tao, A.; Condeiu, C.; Gilardi, R. Tetrahedron
Lett. 1997, 38, 2597-2600.
(12) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 8, 100-110.
(13) (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) Donohue, T. J.; Moore, P. R.; Beddoes,
R. L. J. Chem. Soc., Perkin Trans. 1 1997, 43-51.
J. Org. Chem, Vol. 70, No. 15, 2005 5881

Stoianova et al.
SCHEME 3
FIGURE 1. Dihedral coupling constant analysis for com-
pounds 18a and 20.
SCHEME 4
Dihydroxylation of 17a under catalytic OsO4 conditions
was previously shown, by X-ray crystallographic analysis
of the product, to occur anti to the C(5) allylic hydroxy
group to afford triol 18b in modest selectivity (ds ) 5:1).9
We were able to improve this selectivity by protecting
the hydroxy-group as a benzyl ether using in situ formed
benzyl triflate to derive 19. Subsequent dihydroxylation
generated triol 20 in excellent yield (92%) and selectivity
(15:1).18
We assumed that the dihydroxylation of 19 occurred
anti to the C(5) benzyloxy group to derive 20, in an
analogous manner to the dihydroxylation of 17a affording
18b.19 This assumption was confirmed by three-bond
coupling analysis of coupling constants (JHP) between the
C(4) proton and P(1) atoms in the fully dihydroxylated
compounds 20 and 18a as shown in Figure 1. A signifi-
cantly higher coupling constant (35 Hz) is observed for
18a when the H-C-C-P dihedral angle is 180°. Alter-
natively, an H-C-C-P dihedral angle of <90° in 20
affords a much smaller coupling constant (5.8 Hz). This
coupling constant data was substantiated by a 5.8 Hz
coupling in the previously reported X-ray supported
structure 18b.19
Alternatively, introduction of nitrogen at the C(4)
position could also be achieved from vinylphosphonate
17a via treatment with Cl3CCN to form the correspond-
ing trichloroacetimidate, which underwent facile 1,4-
conjugate addition to afford 21 in excellent yield. At-
tempts at the aminohydroxylation of 17a have thus far
failed.
Opening of epoxide 16b with (nucleophilic) Li-alkoxide
bases cleanly afforded the desired vinylphostone 17c and
also promoted phenoxy displacement with retention of
configuration at phosphorus in addition to the eliminative
opening. The relative stereochemistry of compounds 16b
and 17d (R2 ) Me) was determined by X-ray crystal-
lographic analysis.9 It is noteworthy that attempts to
open the epoxide with nonnucleophilic bases such as
KHMDS or LDA resulted in decomposition.
Functionalization of vinyl phostone intermediate 17a
is highlighted in Scheme 4. Directed dihydroxylation
using the Donohoe protocol15 with stoichiometric amounts
of OsO4/TMEDA provided the C(3)-C(5) all syn-triol 18a
with excellent selectivity (ds ) 13:1). Hydrolysis of the
osmate ester was accomplished with citric acid, which
has been previously shown to facilitate catalytic osmium-
promoted dihydroxylation reactions due to its ability to
readily hydrolyze osmate esters.16 The excellent selectiv-
ity of this directed-dihydroxylation reaction is in agree-
ment with the results of Donahoe, showing that sub-
strates possessing equatorial hydroxy-groups are very
selective under hydrogen-bonding conditions.17
Introduction of nitrogen nucleophiles at the C(5) posi-
tion was achieved from the mesylated vinylphosphonate
17b. Thus, treatment with sodium azide afforded C(5)-
inverted azide product 22. Subsequent dihydroxylation
proceeded with complete selectivity to afford 23 as a
single diastereomer (Scheme 5). The relative stereochem-
(17) Donohoe, T. J.; Blades, K.; Helliwell, M.; Moore, P. R.; Winter,
J. J. J. Org. Chem. 1999, 64, 2980-2981.
(14) (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.
(15) Donohoe, T. J. Synlett 2002, 1223-2332.
(16) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. A.; Sharpless,
B. K. Adv. Synth. Catal. 2002, 344, 421-433.
(18) Benzylation with BnBr under basic conditions gave very low
yields of the desired product accompanied by some epimerization. For
use of BnBr/AgOTf for benzylation of alcohols, see: Burk, R. M.; Gac,
T. S.; Roof, M. B. Tetrahedron Lett. 1994, 44, 8111-8112.
(19) We have previously reported the X-ray structure of 18b; see
ref 9.
5882 J. Org. Chem., Vol. 70, No. 15, 2005

P-Heterocyclic Building Blocks
SCHEME 5
SCHEME 7
SCHEME 8
SCHEME 6
ed alcohol 26 was achieved using similar sequences as
previously described for 17b (Scheme 7). Formation of
the mesylated diol intermediate followed by elimination
provided vinyl phostone 28. Addition of a single equiva-
lent of azide produced 29 in excellent yield.25 Dihydroxy-
lation of the vinyl phostone 29 produced azido P-sugar
(+)-30 as a single diastereoisomer in modest yield.
Alternatively, installation of nitrogen at the C(4)
position can be accomplished by facile formation of the
trichloroacetimidate and subsequent Michael addition in
the presence of DBU to yield the bicyclic trichlorooxazo-
line (Scheme 8). Hydrolysis of this product yielded the
trichloroacetamide of the C(4)/C(5) amino alcohol. Dihy-
droxylation of 27 gave triol 31 with excellent selectivity
(ds ) 15:1), but only moderate yield (53%).
Problems associated with the base lability of phenoxy
phosphonate esters led us to develop an alternate route
employing BnO-substituted phosphonate esters. Thus,
mixed phosphonate ester 34 could be produced by dis-
placement of the PhO-group in the acyclic mixed phos-
phonate with BnOLi in DME (Scheme 9). This reaction
occurs with inversion of the configuration at phosphorus26
to afford 34.27 Subsequent RCM afforded phostone 35
possessing a cis relationship between the C(6) trity-
loxymethyl group and the P(2)-benzyl phosphonate ester.
Dihydroxylation of 35 with OsO4/NMO in the presence
of citric acid yielded diol 36 with excellent selectivity (ds
istry of this compound was confirmed by X-ray crystal-
lographic analysis.20
Having established this method with a racemic allylic
alcohol, we turned to the use of nonracemic allyl alcohols,
which we conveniently derived from commercially inex-
pensive enantio-enriched (97-99% ee) benzyl- and trityl-
protected21 glycidyl ethers.22,23 Transformation of these
readily available epoxides into corresponding allyl alco-
hols 13 and 14 was achieved in a single step via addition
of trimethylsulfonium ylide (Scheme 6).24 Diastereo-
selective addition of benzyl protected (2S)-1,2-butenediol
13 proceeded in good yield and selectivity (ds ) 6:1) to
produce phosphonate 24 as a mixture of P(2)-epimers.
RCM of 24 provided nonracemic allyl phostone interme-
diate 25. Dihydroxylation of substrate 25 provided diol
26 as a single diastereomer using 1% OsO4, m-CPBA and
NMM (N-methyl morpholine). Noteworthy, reactions with
4% OsO4, m-CPBA/NMM or OsO4/NMO gave a dramatic
decrease in selectivity (ds ) 2-5:1). Subsequent carbon-
ate formation using the aforementioned triphosgene
conditions, and elimination led to vinylphosphonate
(-)-27 in good yield.
Installation of nitrogen nucleophiles at the C(5) posi-
tion within the framework of nonracemic benzyl-protect-
(20) See Supporting Information (S-68).
(21) The mixed phosphonate, derived from optically pure Tr-
protected (2S)-1,2-butenediol, was also prepared as described in our
previous paper. Stability issues with the Tr-protected compounds led
us to focus on the more robust Bn-protected vinylphosphonate (+)-27.
(22) We kindly acknowledge Daiso Co., Ltd., Fine Chemical Depart-
ment for donating 100 g of each antipode of both the benzyl and trityl
protected glycidols (e-mail: akkimura@daiso.co.jp).
(25) Displacement of the C(5) mesylate in compound 28 using a
slight excess of sodium azide was complicated by the formation of an
inseparable side product (5-10 mol %). This side product most likely
arose from conjugative addition of a second azide into the vinylphos-
phonate.
(26) Thatcher, G. R. J.; Kluger, R. Adv. Phys. Org. Chem. 1989, 25.
(27) Product 34 was contaminated with ∼4% of the vinylphospho-
nate arising from double bond isomerization. Reactions run in THF
gave extensive isomerization of the double bond (40%).
(23) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307-1315.
(24) Davoille, R. J.; Rutherford, D. T.; Christie, S. D. R. Tetrahedron
Lett. 2000, 41, 1255-1259.
J. Org. Chem, Vol. 70, No. 15, 2005 5883

Stoianova et al.
SCHEME 9
SCHEME 10
of 18-Crown-6 in DMF. Use of other reagents (Bu4NOAc,
NaOAc, KO2, CH3CH2CO2Cs/CH3CH2CO2H) led to cleav-
age of the Bn-group on the P-atom and formation of a
substantial amount of the free acid.30 Dihydroxylation of
40 gave diol 42 in good yields and selectivity, but
attempts to deprotect this compound were unsuccessful.
Deprotection of the benzoate in 40 using Mg(OMe)2,
followed by dihydroxylation, and cleavage of the Tr-group
gave desired tetraol 43 (Scheme 10) as a single diaste-
reoisomer.
In conclusion, a facile strategy has been developed that
allows for the diastereoselective generation of a number
of novel P-sugar analogues. Additional stereoselective
routes to nonracemic phosphono sugars are currently
being pursued as well as the generation of libraries of
pertinent analogues. Further synthetic studies, the pro-
duction of chemical libraries, and biological screening of
these P-sugars are underway and will be reported in due
course.
) 10-14:1) and in good isolated yields. On the basis of
the aforementioned selectivity seen in the dihydroxyla-
tion of the C(6)-Me-substituted allylphostone 15, we
tentatively assigned the major product 36 occurring via
dihydroxylation anti to the C(6)-trityloxymethyl group.28
Conversion of diol 36 into the corresponding carbonate
and treatment with KHMDS gave vinyl phosphonate 37
(Scheme 9). Dihydroxylation of this compound under
standard conditions (cat. OsO4, NMO, citric acid) pro-
ceeded with very low selectivity (ds ) 2:1), presumably
due to the anti relationship between the P(2)-benzyloxy
phosphonate ester and the equatorial C(5)-OH which
provide opposing factors. Alternatively, directed-dihy-
droxylation using the Donohoe conditions15 provided C(3)/
C(4)/C(5) all syn-triol 38 as a single diastereoisomer (ds
> 20:1). Attempts to hydrolyze the osmate ester using
literature conditions (HCl in MeOH)8 gave only decom-
position of the product. Treatment with citric acid16 gave
clean hydrolysis of the osmate without cleaving the Tr-
group. This product was filtered through silica gel29 and
treated with catalytic amount of TsOH to give fully
deprotected tetraol 38.
In our previous work outlined in Scheme 3, we used
epoxidation to derive 16b as an alternative route of
functionalizing the RCM product 15, and ultimately to
derive diastereomer 17c. Unlike the dihydroxylation of
15 (Scheme 3), the major product of the epoxidation
resulted from attack syn to the C(6)-methyl group.
Unfortunately, all epoxidations of nonracemic phostones
25 and 35 were low yielding and not very selective.
Attempts to access a vinyl phosphonate with a syn
stereochemical relationship between the C(5) and C(6)
substituents using Mitsunobu inversion of the C(5)
hydroxy group in 37 gave only starting material. Alter-
natively, the desired intermediate was accessed by
conversion of diol 36 into mesylate 39 and carrying out
SN2-substitution with an alkoxide-containing nucleophile.
The best results were seen using KOBz in the presence
Experimental Section
Experimental Procedures and Spectral Data for Compounds
17b, 18-42.
(2SP*,3S*,4R*,5R*,6R*)-6-Methyl-2-phenoxy-1,2-oxaphos-
phorinane-3,4,5-triol-2-oxide [(()-18a]. To a solution of 17a
(20 mg, 0.083 mmol) in CH2Cl2 (1.5 mL) were added OsO4 (28
mg, 0.11 mmol) and TMEDA (13 mg, 0.11 mmol) at -60 °C.
The reaction mixture was stirred for 2 h at -60 °C and warmed
to room temperature. Removal of the solvent under reduced
pressure under reduced pressure afforded the crude osmate
as a mixture of diastereoisomers (12.5:1 by 31P NMR analysis).
The product was dissolved in 1.5 mL MeOH and treated with
citric acid overnight. Removal of the solvent under reduced
pressure and flash chromatography (EtOAc/4% MeOH) af-
forded 16 mg (70%) of 18a as an oil; 1H NMR δ 7.29-7.09 (m,
5H), 4.63-4.55 (m, 1H), 4.26 (dd, J ) 35.2, 3.9, 2.5 Hz, 1H),
4.05 (dd, J ) 7.6, 4.0 Hz, 1H), 3.38 (dd, J ) 9.4, 2.2 Hz, 1H),
1.38 (dd, J ) 6.3, 1.9 Hz, 3H); 13C NMR δ 150.0 (d, JCP ) 10.0
Hz), 129.5 (d, JCP ) 125.0 Hz), 120.3 (d, JCP ) 4.3 Hz), 74.4 (d,
JCP ) 6.2 Hz), 72.5, 72.3, 66.3 (d, JCP ) 146.9 Hz), 18.4 (d, JCP
) 8.3 Hz); 31P NMR δ 16.4.
(2SP*,5S*,6R*)-5,6-Dihydro-6-methyl-2-phenoxy-2H-1,2-
oxaphosphorinan e-5-methanesulfonate-2-oxide [(()-
17b]. To a solution of the diol 16a (20 mg, 0.077 mmol) in
CH2Cl2 (2.0 mL) was added a catalytic amount of DMAP (1.9
mg, 0.015 mmol), MsCl (0.02 mL, 0.26 mmol), and Et3N (0.04
(28) Exhaustive deprotection of compounds 26 and 36 gave rise to
a common free acid, thus confirming that diols 26 and 36 differ only
in their substitution at phosphorus.
(29) Attempts to isolate this product led to lower yields due to its
instability.
(30) Treatment of the phenoxy substituted P-sugar 28 (Scheme 7)
with KOBz, 18-Crown-6 in DMF gave almost exclusively the free acid.
5884 J. Org. Chem., Vol. 70, No. 15, 2005

P-Heterocyclic Building Blocks
mL, 0.29 mmol) at 0 °C. The reaction mixture was warmed to
room temperature over 1 h and stirred overnight. Brine was
added, and the mixture was extracted with EtOAc (3x) and
dried (Na2SO4). Removal of the solvent under reduced pressure
and flash chromatography (7:3 EtOAc/hexanes) afforded 19 mg
(78%) of 17b; IR (neat) 3028, 2936, 1591, 1490, 1455, 1361,
tion of mesylate 17b (13 mg, 0.041 mmol) in DMF (0.5 mL)
were added NaN3 (13 mg, 0.20 mmol) and 15-crown-5 (9 mg,
0.041 mmol). The reaction mixture was stirred overnight at
room temperature, and the solvent was removed under re-
duced pressure. Flash chromatography of the residue (1:1
hexanes/EtOAc) afforded 10 mg (92%) of 22; IR (neat) 3049,
2993, 2938, 2109, 1612, 1596, 1490, 1455, 1358, 1269, 1162,
1028, 968, 921 cm-1; 1H NMR δ 7.36-7.17 (m, 5H), 6.85 (ddd,
J ) 46.6, 12.5, 5.5 Hz, 1H), 6.44 (dd, J ) 17.3, 12.5 Hz, 1H),
4.92-4.89 (m, 1H), 3.56-3.55 (m, 1H), 1.54 (dd, J ) 6.4, 2.0
1
1270, 1177, 1070, 1023, 931 cm-1; H NMR δ 7.38-7.18 (m,
5H), 6.82 (ddd, J ) 46.8, 12.9, 2.0 Hz, 1H), 6.26 (ddd, J ) 17.4,
12.9, 2.0 Hz, 1H), 5.17-5.13 (m, 1H), 4.75-4.70 (m, 1H), 3.12
(s, 3H), 1.57 (dd, J ) 6.3, 2.0 Hz, 3H); 13C NMR δ 149.6, 146.1,
Hz, 3H); 13C NMR δ 149.8, 142.4, 129.9, 125.2, 121.7 (d, JCP
)
129.9, 125.4, 120.3, 119.7 (d, JCP ) 169.7 Hz), 76.3 (d, JCP
)
8.1 Hz), 75.1 (d, JCP ) 10.8 Hz), 38.8, 18.9 (d, JCP ) 6.9 Hz);
31P NMR δ 5.5. Exact mass: calcd for C12H16O6PS (M+1)
319.0405; found 319.0405 (FAB).
169.5 Hz), 120.2 (d, JCP ) 4.6 Hz), 76.8 (d, JCP ) 7.5 Hz), 57.1
(d, JCP ) 10.1 Hz), 18.5 (d, JCP ) 7.8 Hz); 31P NMR δ 5.8. Exact
mass: calcd for C11H13N3O3P (M+1) 266.0695; found 266.0692
(FAB).
(2SP*,5S*,6R*)-5,6-Dihydro-6-methyl-2-phenoxy-2H-1,2-
oxaphosphorinan e-5-phenylmethoxy-2-oxide [(()-19].
To a solution of the alcohol 17a (10 mg, 0.042 mmol) in
CH2Cl2 (0.6 mL) were added 2,6-di-t-butyl-4-methyl pyridine
(55 mg, 0.26 mmol), AgOTf (54 mg, 0.21 mmol), and BnBr (0.03
mL, 0.25 mmol) at 0 °C. The reaction mixture was stirred at
the same temperature for 3 h and diluted with CH2Cl2, and
the filtrate was washed with brine. Removal of the solvent
under reduced pressure and flash chromatography (4:1 hex-
anes/EtOAc) afforded 10 mg (72%) of 19 as an oil; IR (neat)
3061, 3031, 2982, 2934, 2871, 1723, 1593, 1490, 1454, 1364,
(2SP*,3S*,4R*,5R*,6R*)-6-Methyl-2-phenoxy-1,2-oxaphos-
phorinane-3,4-diol-5-azido-2-oxide [(()-23]. To a solution
of 22 (5 mg, 0.019 mmol) in acetone (0.6 mL) and t-BuOH (0.2
mL) were added citric acid (4 mg, 0.021 mmol), NMO‚H2O (3
mg, 0.022 mmol), and OsO4 (1 drop 4% solution in water). The
reaction mixture was stirred for 24 h, and water was added
and extracted with EtOAc (3x). Removal of the solvent under
reduced pressure and flash chromatography (4:1 EtOAc/
hexanes) afforded 5 mg (88%) of 23; IR (neat) 3350, 2923, 2110,
1590, 1491, 1255, 1199, 1026, 987 cm-1; 1H NMR δ 7.33-7.16
(m, 5H), 5.84 (br. s, 1H), 5.10-5.04 (m, 1H), 4.40 (dt, J ) 35.2,
4.2 Hz, 1H), 4.25 (t, J ) 4.5 Hz, 1H), 3.42 (br. s, 1H), 3.73 (d,
J ) 4.2 Hz, 1H), 1.47 (dd, J ) 6.6, 1.6 Hz, 3H); 13C NMR δ
150.2 (d, JCP ) 9.8 Hz), 129.7, 125.1, 120.4 (d, JCP ) 4.3 Hz),
73.4 (d, JCP ) 7.1 Hz), 71.8 (d, JCP ) 2.9 Hz), 65.2 (d, JCP ) 2.6
Hz), 63.7 (d, JCP ) 145.7 Hz), 18.0 (d, JCP ) 9.0 Hz); 31P NMR
δ 15.9. Exact mass: calculated for C11H15N3O5P (M+1) 300.0749;
found 300.0754 (FAB).
1
1270, 1202, 1095, 1067, 982, 928 cm-1; H NMR δ 7.41-7.31
(m, 7H), 7.21-7.15 (m, 3H), 6.83 (ddd, J ) 48.2, 12.9, 1.6 Hz,
1H), 6.10 (ddd, J ) 18.8, 12.9, 2.1 Hz, 1H), 4.72-4.57 (m, 3H),
4.03-3.99 (m, 1H), 1.49 (dd, J ) 6.2, 2.0 Hz, 3H); 13C NMR δ
149.6, 136.6, 129.8, 128.7, 128.5, 125.1, 120.5 (d, JCP ) 4.6 Hz),
116.8 (d, JCP ) 170.8 Hz), 77.9 (d, JCP ) 8.2 Hz), 76.5 (d, JCP
)
10.1 Hz), 72.8, 19.1 (d, JCP ) 7.5 Hz); 31P NMR δ 7.7. Exact
mass: calcd for C18H20O4P (M+1) 331.1099; found 331.1098
(FAB).
(1S,SP)-2-Propenyl-1-phenylmethoxymethyl-2-prope-
nyl Phenyl Ester Phosphonic Acid [(+)-24]. To a solution
of the 2-benzyl-(2R)-1,2-butenediol 13 (69 mg, 0.388 mmol) in
dry THF (2 mL) was added BuLi (0.27 mL 1.4 M in hexanes,
0.38 mmol) at -40 °C, and the solution was warmed to room
temperature over 2 h and stirred at room temperature for an
additional 4 h. This solution was added to the diphenyl
allylphosphonate (127 mg, 0.42 mmol) in THF (0.6 mL) and
HMPA (0.1 mL) at -78 °C over 30 min. The reaction mixture
was stirred overnight at -78 °C, quenched with NH4Cl (sat′d
aq.), extracted with EtOAc (3x), and dried (Na2SO4). Removal
of the solvent under reduced pressure and flash chromatog-
raphy (4:1 hexanes/EtOAc) afforded 75 mg (54%) of 24 as a
mixture of diastereoisomers (6:1 by 31P analysis); [R]D +5.3 (c
0.3, CH2Cl2); IR (neat) 3065, 3029, 2982, 2861, 1639, 1593,
1490, 1454, 1364, 1265, 1208, 1091, 1013, 926 cm-1; 1H NMR
(only signals for major isomer) δ 7.36-7.11 (m, 10H), 5.92-
5.14 (m, 2H), 5.46-5.14 (m, 5H), 4.64-4.53 (m, 2H), 3.62-
3.53 (m, 2H), 2.85-2.75 (m, 2H); 13C NMR (only signals for
major isomer) δ 150.3 (d, JCP ) 8.9 Hz), 137.5, 129.4, 128.3,
127.7, 127.6, 124.7, 124.63, 120.59, 120.2 (d, JCP ) 15.1 Hz),
118.3, 76.5 (d, JCP ) 6.6 Hz), 73.0, 72.3 (d, JCP ) 4.8 Hz), 32.1
(d, JCP ) 140.7 Hz); 31P NMR δ 25.6. Exact mass: calculated
for C20H24O4P (M+1) 359.1412; found 359.1406 (FAB).
(2SP,6S)-2-Phenoxy-6-[(phenylmethoxymethyl]-2H-1,2-
oxaphosphorin-3,6-dihydro-2-oxide [(-)-25]. To a solution
of 24 (75 mg, 0.23 mmol, 9:1 mixture) in dry CH2Cl2 (20 mL)
was added (PCy3)2Cl2RudCHPh (6 mg, 3 mol %), and the
mixture was refluxed overnight. An additional amount of
catalyst (3 mg, 0.0036 mmol) was added, and reflux was
continued for 14 h. The mixture was diluted with CH2Cl2 and
flushed with air, 3 drops DMSO were added, and the solution
was stirred overnight at room temperature. Removal of the
solvent under reduced pressure and flash chromatography (1:1
hexanes/EtOAc) afforded 60 mg (83%) of 25 as an oil; [R]D
-42.1 (c 1.2, CH2Cl2); IR (neat) 3062, 3033, 2905, 2866, 1592,
1491, 1454, 1297, 1254, 1207, 1083, 1026, 927 cm-1; 1H NMR
δ 7.36-7.13 (m, 10H), 5.88-5.77 (m, 2H), 5.14-5.13 (m, 1H),
4.58 (s, 2H), 3.73-3.62 (m, 2H), 2.68-2.48 (m, 2H); 13C NMR
(2SP*,3R*,4S*,5S*,6R*)-6-Methyl-2-phenoxy-1,2-oxaphos-
phorinane-3,4-diol-5-phenylmethoxy-2-oxid e [(()-20]. To
a solution of 19 (15 mg, 0.045 mmol) in acetone (0.9 mL) and
t-BuOH (0.3 mL) were added citric acid (19 mg, 0.10 mmol),
NMO‚H2O (12 mg, 0.09 mmol), and OsO4 (2 drops of a 4%
solution in water). The reaction mixture was stirred for 24 h,
followed by the addition of Na2SO3. Water was added, and the
mixture was extracted with EtOAc (3x) and dried (Na2SO4).
Removal of the solvent under reduced pressure and flash
chromatography (EtOAc/1% MeOH) afforded 15 mg (92%) of
1
20 as an oil; H NMR δ 7.36-7.16 (m, 10H), 5.45 (br. s, 1H),
4.94 (d, J ) 10.7 Hz, 1H), 4.65 (t, J ) 10.8 Hz, 1H), 4.38 (q, J
) 3.8 Hz, 1H), 4.22-4.11 (m, 2H), 3.62 (t, J ) 9.2, 1H), 3.24
(d, J ) 8.6, 1.6 Hz, 1H), 1.47 (dd, J ) 6.2, 1.3 Hz, 3H); 13C
NMR δ 149.6, 137.6, 130.0, 128.5, 128.2, 128.1, 125.4, 119.7
(d, JCP ) 4.7 Hz), 80.0, 75.7, 75.5 (d, JCP ) 5.8 Hz), 73.5 (d, JCP
) 6.2 Hz), 65.6 (d, JCP ) 144.3 Hz), 19.2 (d, JCP ) 9.0 Hz); 31
NMR δ 16.2.
P
[(()-21]. To a solution of 17a (16 mg, 0.067 mmol) in
CH2Cl2 (0.6 mL) were added Cl3CCN (0.01 mL) and a catalytic
amount of DBU (2.0 mg, 0.013 mmol) at -50 °C, and the
solution was warmed to -20 °C over 4 h. The cooling bath
was removed, and the stirring was continued at room tem-
perature overnight. The reaction mixture was quenched with
NH4Cl (sat’d aq), extracted with CH2Cl2 (3x) and dried (Na2-
SO4). Removal of the solvent under reduced pressure and flash
chromatography (EtOAc/1% MeOH) afforded 24 mg (93%) of
product 21; IR (neat) 2918, 1725, 1521, 1486, 1256, 1182, 1039,
1008, 918, 899 cm-1; 1H NMR δ 7.37-7.18 (m, 5H), 4.97-4.88
(m, 1H), 4.83 (d, J ) 9.0 Hz, 1H), 4.49-4.44 (m, 1H), 2.80 (ddd,
J ) 18.3, 15.6, 6.5 Hz, 1H), 2.29 (ddd, J ) 17.8, 15.8, 9.5 Hz,
1H), 1.59 (dd, J ) 6.2, 1.0 Hz, 3H); 13C NMR δ 162.4 (d, JCP
6.6 Hz), 149.4 (d, JCP ) 8.9 Hz), 129.9, 125.4, 119.9 (d, JCP
)
)
4.8 Hz), 77.1 (d, JCP ) 6.6 Hz), 70.4 (d JCP ) 5.5 Hz), 48.8 (d,
JCP ) 4.0 Hz), 24.6 (d, JCP ) 126.9 Hz), 19.0 (d, JCP ) 6.2 Hz);
31P NMR δ 20.0.
(2SP*,5R*,6R*)-5,6-Dihydro-6-methyl-2-phenoxy-2H-
1,2-oxaphosphorinan e-5-azido-2-oxide [(()-22]. To a solu-
J. Org. Chem, Vol. 70, No. 15, 2005 5885

Stoianova et al.
δ 149.9 (d, JCP ) 7.8 Hz), 137.4, 129.7, 128.2, 127.6, 127.5,
126.2 (d, JCP ) 16.0 Hz), 124.8, 121.2 (d, JCP ) 9.8 Hz), 129.9
1 h and stirred overnight at room temperature. Et3N (0.10
mL, 0.72 mmol) was added, and the stirring was continued
for 6 h. After addition of brine the mixture was extracted
with EtOAc (3x) and dried (Na2SO4). Removal of the solvent
under reduced pressure and flash chromatography (1:1 hex-
anes/EtOAc) afforded 95 mg (83%) of 28; [R]D +30.7 (c 0.91,
CH2Cl2); IR (neat) 3060, 3044, 3023, 2931, 2896, 2865, 1590,
(d, JCP ) 4.5 Hz), 79.7 (d, JCP ) 8.5 Hz), 63.4, 71.6 (d, JCP
)
7.4 Hz), 21.4 (d, JCP ) 132.4 Hz); 31P NMR δ 17.5. Exact
mass: calculated for C18H20O4P (M+1) 331.1099; found 331.1110
(FAB).
(2SP,4R,5S,6S)-2-Phenoxy-6-[(phenylmethoxy)methyl]-
1,2-oxaphosphorinane-4,5-diol-2-oxide [(+)-26]. To a solu-
tion of 25 (12 mg, 0.036 mmol in 1.2 mL acetone and t-BuOH
(0.4 mL) were added citric acid (10 mg, 0.052 mmol), m-CPBA
(26 mg 70-75%), NMM (11 mg, 0.11 mmol) and OsO4 (1 drop
of a 1% solution in water). After stirring for 24 h one more
drop of OsO4 was added and the stirring continued for 24 h.
The reaction mixture was diluted with CHCl3, solid Na2SO3
and water was added, stirred for 30 min and extracted with
CHCl3. Removal of the solvent under reduced pressure and
flash chromatography (EtOAc/1% MeOH) afforded 11 mg (84%)
of 26 as a white solid; mp ) 145-148; [R]D +51.1 (c 0.980,
CH2Cl2); IR (neat) 3341, 3062, 2969, 1591, 1490, 1454, 1251,
1197, 933 cm-1; 1H NMR δ 7.32-7.11 (m, 10H), 4.71-4.68 (m,
1H), 4.55-4.48 (m, 2H), 4.12 (dd, J ) 35.8, 1.8 Hz, 1H), 3.85
(br. s, 1H), 3.75-3.71 (m, 4H), 2.32 (ddd, J ) 19.4, 15.8, 3.6
Hz, 1H), 2.04-1.94 (m, 1H); 13C NMR δ 149.6 (d, JCP ) 8.4
Hz), 137.6, 129.9, 129.6, 128.3, 127.7, 127.5, 125.1, 120.6 (d,
JCP ) 4.3 Hz), 76.4 (d, JCP ) 6.7 Hz), 73,4, 69.9 (d, JCP ) 7.8
Hz), 68.0 (d, JCP ) 6.5 Hz), 67.1 (d, JCP ) 9.1 Hz), 27.2 (d, JCP
) 125.9 Hz); 31P NMR δ 20.2. Exact mass: calculated for
C18H22O6P (M+1) 365.1154; found 365.1160 (FAB).
1491, 1454, 1348, 1268, 1204, 1171, 1101, 1018, 985, 939 cm-1
;
1H NMR δ 7.37-7.16 (m, 10H), 6.87 (ddd, J ) 47.2, 12.9, 1.9
Hz, 1H), 6.24 (ddd, J ) 17.9, 12.9, 2.0 Hz, 1H), 5.53-5.49 (m,
1H), 4.76-4.71 (m, 1H), 4.66 (d, J ) 11.5 Hz, 1H), 4.60 (d, J
) 11.7 Hz, 1H), 3.88-3.80 (m, 2H), 3.00 (s, 3H); 13C NMR δ
149.5 (d, JCP ) 8.2 Hz), 146.6, 137.0, 129.9, 128.4, 127.9, 127.8,
125.4, 120.4 (d, JCP ) 4.4 Hz), 119.3 (d, JCP ) 170.5 Hz), 78.7
(d, JCP ) 8.0 Hz), 73.8, 70.7 (d, JCP ) 10.7 Hz), 68.0 (d, JCP
)
7.1 Hz), 38.1; 31P NMR δ 6.1. Exact mass: calculated for
C19H22O7PS (M+1) 425.0824; found 425.0809 (FAB).
(2SP,5R,6R)-5,6-Dihydro-2-phenoxy-2H-1,2-oxaphos-
phorinane-5-azido-6-[( phenylmethoxy)methyl]-2-oxide
[(-)-29]. Mesylated alcohol 28 (63 mg, 0.148 mmol) was taken
up in DMF (0.3 mL) at room temperature, followed by the
subsequent addition of 15-crown-5 ether (33 mg, 0.148 mmol)
and sodium azide (9 mg, 0.140 mmol). Upon completion (2.5-3
h), removal of solvent under reduced pressure followed by flash
chromatography (1:1 EtOAc/hexanes) afforded 45 mg (82%) of
compound 29; [R]D -316.3 (c 0.4, CH2Cl2); IR (neat) 3062, 2106,
1
1590, 1488, 1271, 1198 cm-1; H NMR δ 7.12-7.39 (m, 10H),
6.85 (ddd, JHP ) 46.4, J ) 12.5, 5.6 Hz, 1H), 6.44 (dd, J )
17.4, J ) 12.9 Hz, 1H), 4.93 (ddd, J ) 11.4, 6.9, 3.3 Hz, 1H),
4.59 (s, 2H), 3.89 (m, 1H), 3.84 (d, J ) 6.39 Hz, 2H); 13C NMR
δ 149.5 (JCP ) 8.3 Hz), 142.2, 137.3, 129.8 (JCP ) 11.0 Hz),
128.6 (JCP ) 10.1 Hz), 128.1 (JCP ) 5.7 Hz), 127.8, 125.4, 121.8
(JCP ) 171.2 Hz), 120.4 (JCP ) 4.5 Hz), 78.3 (JCP ) 7.1 Hz),
73.9, 69.1 (JCP ) 9.3 Hz), 54.2 (JCP ) 11.1 Hz); 31P NMR δ 5.72.
Exact mass: calcd for C18H19N3O4P (M+1) 372.1113; found
372.2313 (FAB).
(2SP,4R,5S,6S)-2-Phenoxy-6-[(phenylmethoxy)methyl]-
1,2-oxaphosphorinane-4,5-carbonate-2-oxide. To a solu-
tion of 26 (450 mg, 1.24 mmol) in CH2Cl2 (20 mL) were added
triphosgene (770 mg, 2.59 mmol) and Et3N (0.80 mL, 5.75
mmol) at -40 °C, and the solution was warmed to 10 °C over
3 h. The reaction mixture was diluted with CH2Cl2, quenched
with NH4Cl (sat′d aq.), extracted with CH2Cl2 (3x), and dried
(Na2SO4). Removal of the solvent under reduced pressure and
flash chromatography (7:3 EtOAc/hexanes) afforded 460 mg
(2SP,3S,4R,5R,6R)-2-Phenoxy-6-[(phenylmethoxy)-
methyl]-1,2-oxaphosphorinane-3,4-diol-5-azido-2-oxide
[(+)-30]. To a solution of 29 (12 mg, 0.032 mmol) in acetone
(0.9 mL) and t-BuOH (0.3 mL) were added citric acid (6 mg,
0.031 mmol), NMO‚H2O (5 mg, 0.037 mmol), and OsO4 (1 drop
of a 4% solution in water). After stirring for 24 h at room
temperature, one more drop OsO4 was added, and the stirring
was continued for 8 h. Water was added to the reaction
mixture and extracted with EtOAc (3x). Removal of the solvent
under reduced pressure and flash chromatography (3:2 EtOAc/
hexanes) afforded 30 (7 mg, 54%) as an oil; [R]D +41.1 (c
0.0072, CH2Cl2); IR (neat) 3343, 3065, 2922, 2113, 1590, 1491,
1
(95%) of the carbonate; H NMR δ 7.42-7.18 (m, 10H), 5.25
(ddd, J ) 25.0, 7.8, 6.2, 4.1 Hz, 1H), 4.94 (dd, J ) 8.1, 4.5 Hz,
1H), 4.86-4.85 (m, 1H), 4.65 (d, J ) 11.1 Hz, 1H), 4.53 (d, J
) 11.5 Hz, 1H), 3.94 (dd, J ) 11.1, 2.0 Hz, 1H), 3.80 (dt, J )
11.1, 3.0 Hz, 1H), 2.70 (ddd, J ) 18.7, 16.3, 6.2 Hz, 1H), 2.48
(ddd, J ) 17.6, 16.3, 4.0 Hz, 1H); 13C NMR δ 152.6, 149.3 (d,
JCP ) 8.6 Hz), 136.4, 129.6, 128.4, 128.0, 127.7, 125.2, 120.1
(d, JCP ) 4.7 Hz), 77.9 (d, JCP ) 7.7 Hz), 73,6, 73.0 (d, JCP
)
6.1 Hz), 72.7 (d, JCP ) 11.9 Hz), 69.6 (d, JCP ) 3.8 Hz), 24.3 (d,
JCP ) 128.2 Hz); 31P NMR δ 15.2.
(2SP,5S,6R)-5,6-Dihydro-2-phenoxy-6-[(phenylmethoxy)-
methyl]-2H-1,2-oxaphosphorinane-5-ol-2-oxide [(-)-27].
To a solution of the carbonate (430 mg, 1.10 mmol) in THF
(20 mL) was added KHMDS (2.5 mL, 0.5 M in toluene, 1.25
mmol) at -50 °C, and the solution was warmed to 0 °C over
2.5 h. The reaction mixture was quenched with NH4Cl (sat′d
aq.), extracted with EtOAc (3x), and dried (Na2SO4). Removal
of the solvent under reduced pressure and flash chromatog-
raphy (9:1 EtOAc/hexanes) afforded 280 mg (74%) of 27; [R]D
-4.6 (c 0.5, CH2Cl2); IR (neat) 3341, 3062, 2869, 1591, 1490,
1454, 1356, 1251, 1198, 1077, 1007, 985, 932 cm-1; 1H NMR δ
7.34-7.12 (m, 10H), 6.68 (ddd, J ) 49.4, 12.9, 1.3 Hz, 1H),
5.93-5.85 (m, 1H), 4.70-4.49 (m, 4H), 4.36 (d, J ) 1.5 Hz,
1H), 3.83-3.71 (m, 1H); 13C NMR δ 154.0, 149.5 (d, JCP ) 8.5
1
1454, 1256, 1201, 1024, 981, 938 cm-1; H NMR δ 7.38-7.11
(m, 10H), 5.07-5.05 (m, 1H), 4.56 (s, 2H), 4.50-4.39 (m, 2H),
4.06 (d, J ) 3.7 Hz, 1H), 3.78-3.70 (m, 2H); 13C NMR δ 150.0
(d, JCP ) 10.3 Hz), 137.2, 129.7, 128.5, 127.9, 125.2, 120.4 (d,
JCP ) 4.2 Hz), 74.8 (d, JCP ) 6.8 Hz), 73.6, 71.7 (d, JCP ) 3.2
Hz), 68.1 (d, JCP ) 11.0 Hz), 64.3 (d, JCP ) 146.7 Hz), 61.6; 31
P
NMR δ 16.2. Exact mass: calcd for C18H21N3O6P (M+1)
406.1168; found 406.1159 (FAB).
(2SP,3R,4S,5S,6R)-2-Phenoxy-6-[(phenylmethoxy)-
methyl]-1,2-oxaphosphorinane-3,4,5-triol-5-2-oxide [(+)-
31]. To a solution of 27 (65 mg, 0.187 mmol) in acetone (5.2
mL) and tert-butyl alcohol (2.1 mL) were added citric acid (72
mg, 0.374 mmol), NMM (100 µl, 0.560 mmol), and a 1%
solution of OsO4 in water (24 µL). A solution of m-CPBA (137
mg, 0.560 mmol) in acetone (1 mL) was added over 30 min.
After 24 h of stirring, additional amounts of OsO4 (0.024
mL) and m-CPBA (70 mg) were added, and the reaction was
stirred for an additional 24 h. The reaction was quenched with
Na2SO3 (sat’d aq.) and extracted with CH2Cl2 (3x), and the
combined organic layers were dried (Na2SO4). 31P analysis of
the crude reaction mixture showed a diastereomeric ratio of
15:1. Subsequent flash chromatography (9:1 EtOAc/MeOH)
afforded 38 mg (53%) of 31 as the major isomer; [R]D +21.6 (c
0.94, CH2Cl2); IR (CHCl3) 3352, 2922, 1590, 1491, 1267, 1196,
Hz), 137.5, 129.1, 128.3, 127.7, 127.5, 125.3, 120.5 (d, JCP
4.2 Hz), 114.4 (d, JCP ) 171.7 Hz), 81.4, 73.4, 69.7 (d, JCP
)
)
7.5 Hz), 64.3; 31P NMR δ 8.0. Exact mass: calculated for
C18H20O5P (M+1) 347.1048; found 347.1055 (FAB).
(2SP,5S,6R)-5,6-Dihydro-2-phenylmethoxy-2H-1,2-
oxaphosphorinane-5-methanesulfonate-6-[(triphenyl-
methoxy)methyl]-2-oxide [(+)-28]. To a solution of the diol
(100 mg, 0.27 mmol) in CH2Cl2 (8 mL) were added a catalytic
amount of DMAP (6.6 mg, 0.054 mmol) and MsCl (0.07 mL,
0.90 mmol) at 0 °C, followed by Et3N (0.15 mL, 1.08 mmol).
The reaction mixture was warmed to room temperature over
5886 J. Org. Chem., Vol. 70, No. 15, 2005

P-Heterocyclic Building Blocks
1
736, 690 cm-1; H NMR δ 7.31-7.13 (m, 10H), 4.52-4.49 (m,
CH2Cl2 (13 mL) was added catalyst A (3 mg, 3 mol %), and
the mixture was refluxed for 6 h, diluted with CH2Cl2, flushed
with air, and stirred overnight at room temperature. Removal
of the solvent under reduced pressure and flash chromatog-
raphy (7:3 EtOAc/hexanes) afforded 63 mg (98%) of 35 as white
solid; mp 153-155 °C; [R]D -38.4 (c 0.56, CH2Cl2); IR (neat)
3058, 3032, 2929, 1490, 1448, 1279, 1248, 1077, 1001, 899
cm-1; 1H NMR δ 7.45-7.21 (m, 20H), 5.82-5.72 (m, 2H), 5.19-
5.14 (m, 2H), 4.19 (dd, J ) 11.9, 8.3 Hz, 1H), 3.37 (dd, J )
9.5, 6.3 Hz, 1H), 3.26 (dd, J ) 9.6, 5.3 Hz, 1H), 2.50-2.04 (m,
2H); 13C NMR δ 143.5, 136.0 (d, JCP ) 6.3 Hz), 128.6, 128.5,
128.3, 127.8, 127.8, 127.1, 126.7 (d, JCP ) 16.9 Hz), 121.0 (d,
JCP ) 9.5 Hz), 86.7, 78.8 (d, JCP ) 7.4 Hz), 67.1 (d, JCP ) 6.0
Hz), 65.6 (d, JCP ) 5.0 Hz), 22.3 (d, JCP ) 132.3 Hz); 31P NMR
δ 21.4. Exact mass: calcd for C31H30O4P (M+1) 497.1882; found
497.1883 (FAB).
2H), 4.47-4.43 (m, 1H), 4.21-4.18 (m, 1H), 4.03 (dd, JHP
)
9.53, 9.53 Hz, 1H), 3.96 (dd, JHP ) 11.3, 1.81 Hz, 1H), 3.86-
3.84 (m, 1H), 3.76 (dd, JHP ) 10.9, 5.81 Hz); 13C NMR δ 149.5
(d, JCP ) 9.6 Hz), 137.8, 130.0, 128.4, 127.6, 127.6, 125.5, 120.0
(d, JCP ) 4.4 Hz), 78.7 (d, JCP ) 3.6 Hz), 73.4, 73.3 (d, JCP
)
7.2 Hz), 69.8 (d, JCP ) 12.6 Hz), 66.8, 65.7 (d, JCP ) 145.9 Hz);
31P NMR δ 17.1. Exact mass: calcd for C18H22O7P (M+1)
381.1025; found 381.1103 (FAB).
Trichlorooxazoline-Containing Phosphonate [(-)-32].
To a solution of 27 (32 mg, 0.092 mmol) in CH2Cl2 (2 mL) were
added Cl3CCN (0.01 mL) and a catalytic amount of DBU at
-50 °C. The solution was allowed to warm to -20 °C over 5 h.
The reaction mixture was quenched with NH4Cl (sat′d aq.),
extracted with CH2Cl2 (3x) and dried (Na2SO4). Removal of
solvent under reduced pressure and flash chromatography (1:1
hexanes/EtOAc) afforded 36 mg (80%) of 32; [R]D -1.88 (c 2.6,
CH2Cl2); IR (neat) 3063, 3030, 2927, 2868, 1716, 1664, 1591,
(2SP,4R,5S,6S)-2-Phenylmethoxy-6-[(triphenylmethoxy)-
methyl]-1,2-oxapho sphorinane-4,5-diol-2-oxide [(+)-36].
To a solution of 35 (61 mg, 0.12 mmol) in acetone (2 mL) and
t-BuOH (0.8 mL) were added citric acid (30 mg, 0.16 mmol),
NMO (18 mg, 0.13 mmol) and OsO4 (1 drop 4% solution
in water). The reaction mixture was stirred for 48 h, solid
Na2SO3 and 3% aq. NaHSO4 were added, and the mixture was
stirred for 30 min and extracted with EtOAc (3x). Removal of
the solvent under reduced pressure and flash chromatography
(EtOAc/4% MeOH) afforded 51 mg (81%) of 36 as an oil; [R]D
+26.0 (c 0.19, CH2Cl2); IR (neat) 3363, 3059, 3033, 2934, 1490,
1491 1454, 1271, 1203, 985, 930 cm-1; H NMR δ 7.38-7.15
1
(m, 10H), 5.12-5.08 (m, 1H), 4.99-4.89 (m, 1H), 4.70-4.57
(m, 3 H), 3.92 (d, J ) 11.2 Hz, 1H), 3.82 (dd, J ) 11.1, 4.6 Hz,
1H), 2.75 (dd, J ) 18.2, 15.9, 7.0 Hz, 1H), 2.32 (dd, J ) 17.0,
7.5 Hz, 1H); 13C NMR δ 162.3, 149.5 (d, JCP ) 8.5 Hz), 137.1,
129.8, 128.5, 128.0, 127.8, 120.7 (d, JCP ) 4.3 Hz), 85.8, 79.2
(d, JCP ) 7.6 Hz), 77.4, 73,8, 69.8 (d, JCP ) 5.9 Hz), 63.1 (d, JCP
) 3.7 Hz), 24.9 (d, JCP ) 126.3 Hz); 31P NMR δ 19.5. Exact
mass: calcd for C20H20Cl3NO5P (M+1) 490.0145; found 490.0145
(FAB).
1
1449, 1226, 1079, 1022, 983 cm-1; H NMR δ 7.44-7.19 (m,
20H), 5.13-5.01 (m, 2H), 4.70-4.64 (m, 1H), 4.26 (br. d, J )
31.6 Hz, 1H), 3.89 (d, J ) 7.8 Hz, 1H), 3.39 (d, J ) 2.8 Hz,
2H), 2.31 (ddd, J ) 15.6, 15.2, 5.7 Hz, 1H), 1.98 (ddd, J ) 18.1,
14.9, 3.4 Hz, 1H); 13C NMR δ 143.6, 135.6 (d, JCP ) 5.8 Hz),
128.6, 128.5, 127.9, 128.8, 127.1, 86.7, 76.5 (dd, JCP ) 4.9 Hz),
68.8 (d, JCP ) 5.4 Hz), 67.6 (d, JCP ) 6.4 Hz), 67.3 (d, JCP ) 7.1
Hz), 63.2 (d, JCP ) 6.4 Hz), 28.6 (d, JCP ) 124.6 Hz); 31P NMR
δ 26.6.
Trichloroacetimidate-Containing Phosphonate [(+)-
33]. Compound 32 (15 mg, 0.031 mmol) was dissolved in
acetone (0.6 mL), followed by the addition of H2O (0.1 mL).
PPTS (2 mg, 0.0093 mmols) was added, and the reaction was
stirred at room-temperature overnight. Concentration under
reduced pressure and flash chromatography (3:2 EtOAc/
hexanes), provided 12 mg (76% yield) of the 33 as an oil; [R]D
+36.0 (c 1.6, CH2Cl2); 1H NMR δ 7.70 (d, J ) 7.5 Hz, 1H),
7.37-7.19 (m, 10H), 4.17 (dddd, J ) 33.6, 8.0, 8.0, 4.0 Hz, 1H),
4.62 (d, J ) 11.8 Hz, 1H), 4.57 (d, J ) 11.8 Hz, 1H), 4.48 (ddd,
J ) 8.8, 8.8, 4.4 Hz, 1H), 4.17 (dd, J ) 9.0, 3.6 Hz, 1H), 3.85
(m, 2H), 2.61 (dd, J ) 15.9, 15.9, 4.6 Hz, 1H), 2.41 (ddd, J )
19.1, 15.9, 4.6 Hz, 1H); 13C NMR δ 163.2, 149.4 (d, JCP ) 9.3
(2SP,4R,5S,6S)-2-Phenylmethoxy-6-[(triphenylmethoxy)-
methyl]-1,2-oxaphosphorinane-4,5-carbonate-2-oxide. To
a solution of 36 (23 mg, 0.043 mmol) and triphosgene (27 mg,
0.09 mmol) in CH2Cl2 (1.0 mL) was added Et3N (0.03 mL, 0.22
mmol) at -40 °C, and the solution was warmed to room
temperature over 5 h. The reaction mixture was diluted with
CH2Cl2, quenched with NH4Cl (sat’d aq.), extracted with
CH2Cl2, and dried (Na2SO4). Removal of the solvent under
reduced pressure and flash chromatography (3:2 EtOAc/
hexanes) afforded 20 mg (84%) of the carbonate as a white
solid; mp 162-164 °C; [R]D +43.0 (c 3.6, CH2Cl2); IR (neat)
3059, 3032, 2929, 1817, 1599, 1491, 1448, 1354, 1272, 1170,
Hz), 137.2, 130.2, 128.6, 128.1, 127.8, 125.8, 120.0 (d, JCP
4.6 Hz), 95.2, 73.9, 72.2, 70.0 (d, JCP ) 8.0 Hz), 68.5 (d, JCP
)
)
6.1 Hz), 49.4 (d, JCP ) 7.8 Hz), 25.3 (d, JCP ) 126.3 Hz); 31P
NMR δ 18.7.
(1S,SP)-2-Propenyl-1-triphenylmethoxymethyl-2-pro-
penyl Phenylmethoxymethyl Ester Phosphonic Acid
[(-)-34]. To a solution of benzyl alcohol (0.51 mL, 4.93 mmol)
in dry DME (25 mL) was added BuLi (3.2 mL 1.3 M in
hexanes) at -30 °C, and the solution was warmed to room
temperature over 1 h and stirred for an additional 4 h. This
solution was added to the mixed phosphonate (1.320 g, 2.59
mmol) in DME (15 mL) at -50 °C over 1 h. The resulting
mixture was transferred back to the alkoxide flask at -50 °C
and allowed to warm to room temperature overnight. This
mixture was stirred for 8 h at room temperature, quenched
with NH4Cl (sat′d aq.), extracted with EtOAc (3x), and dried
(Na2SO4). Removal of the solvent under reduced pressure and
flash chromatography (7:3 hexanes/EtOAc) afforded 1.20 g
(88%) of 34 as an oil; [R]D -4.6 (c 0.16, CH2Cl2); IR (neat) 3059,
3032, 2931, 1638, 1490, 1448, 1257, 1215, 1078, 990 cm-1; 1H
NMR δ 7.49-7.19 (m, 20H), 5.94-5.78 (m, 2H), 5.43-5.01 (m,
7H), 3.30-3.21 (m, 2H), 2.68 (dd, J ) 21.1, 7.3 Hz, 2H); 13C
NMR δ 143.6, 136.3 (d, JCP ) 6.9 Hz), 134.2 (d, JCP ) 3.1 Hz),
128.6, 128.3, 128.0, 127.7, 127.6,127.3 (d, JCP ) 11.5 Hz), 127.0,
120.0 (d, JCP ) 14.8 Hz), 118.4, 86.7, 76.7 (d, JCP ) 15.6 Hz),
1
1069, 1034, 965 cm-1; H NMR δ 7.46-7.26 (m, 20H), 5.25-
5.19 (m, 2H), 5.07 (t, J ) 8.7 Hz, 1H), 5.00-4.91 (m, 1H), 4.47-
4.44 (m, 1H), 3.63 (dd, J ) 11.0, 2.3 Hz, 1H), 3.36 (dt, J )
11.0, 3.0 Hz, 1H), 2.62-2.52 (m, 1H), 2.32 (ddd, J ) 18.3, 15.8,
9.5 Hz, 1H); 13C NMR δ 152.5, 143.0, 135.2 (d, JCP ) 5.6 Hz),
128.9, 128.8, 128.4, 128.0, 127.9, 127.2, 86.9, 75.0 (d, JCP
)
5.7 Hz), 71.7, 71.1 (d, JCP ) 6.5 Hz), 68.3 (d, JCP ) 6.1 Hz),
61.9 (d, JCP ) 7.6 Hz), 24.7 (d, JCP ) 121.7 Hz); 31P NMR δ
21.6. Exact mass: calcd for C32H30O8P (M+1) 557.1729; found
557.1705 (FAB).
(2SP,5S,6R)-5,6-Dihydro-2-phenylmethoxy-6-[(tri-
phenylmethoxy)methyl]2 H-1,2-oxaphosphorinane-5-ol-
2-oxide [(+)-37]. To a solution of the carbonate (150 mg, 0.27
mmol) in THF (10.0 mL) was added KHMDS (0.71 mL 0.5 M
in toluene, 0.35 mmol) at -40 °C, and the solution was warmed
to 0 °C over 3 h. The reaction mixture was quenched with
NH4Cl (sat’d aq.), extracted with EtOAc (3x), and dried
(Na2SO4). Removal of the solvent under reduced pressure and
flash chromatography (4:1 EtOAc/hexanes) afforded 110 mg
(80%) of 37; [R]D +82.9 (c 1.64, CH2Cl2); IR (neat) 3325, 3058,
3032, 2930, 1597, 1490, 1448, 1362, 1228, 1193, 1079, 1019,
982 cm-1; 1H NMR δ 7.40-7.17 (m, 20H), 6.69 (ddd, J ) 47.7,
12.9, 1.5 Hz, 1H), 5.72 (ddd, J ) 18.8, 12.9, 2.2 Hz, 1H), 5.08-
4.97 (m, 2H), 4.55-4.51 (m, 2H), 3.70 (br. s, 1H), 3.44 (d, J )
66.9 (d, JCP ) 6.4 Hz), 66.3 (d, JCP ) 5.2 Hz), 32.6 (d, JCP
)
139.6 Hz); 31P NMR δ 28.3. Exact mass: calcd for C33H34O4P
(M+1) 525.2116; found 525.2195 (FAB).
(2SP,6S)-2-Phenylmethoxy-6-[(triphenylmethoxy)-
methyl]-2H-1,2-oxaphosphorin-3,6-dihydro-2-oxide,
[(-)-35]. To a solution of the 34 (70 mg, 0.13 mmol) in dry
J. Org. Chem, Vol. 70, No. 15, 2005 5887

Stoianova et al.
1.8 Hz, 2H); 13C NMR δ 153.1, 143.4, 135.6,128.5, 127.9, 127.8,
127.1, 115.7 (d, JCP ) 166.2 Hz), 86.8, 79.5 (d, JCP ) 5.6 Hz),
δ 10.3. Exact mass: calcd for C38H34O6P (M+1) 617.2093; found
617.2082 (FAB).
68.5 (d, JCP ) 5.7 Hz), 65.6 (d, JCP ) 10.0 Hz), 63.1 (d, JCP
)
(2SP,5R,6R)-5,6-Dihydro-2-phenylmethoxy-2H-1,2-
oxaphosphorinane-5-ol-6 [(triphenylmethoxy)methyl]-
2-oxide [(+)-41]. To a solution of 40 (40 mg, 0.065 mmol) in
MeOH (1.0 mL) was added Mg(OMe)2 (0.06 mL 7-8% solution
in MeOH) the mixture was stirred overnight at room temper-
ature, quenched with NH4Cl (sat’d aq.). MeOH was removed,
the residue extracted with EtOAc (3x), and dried (Na2SO4).
Removal of the solvent under reduced pressure and flash
chromatography (7:3 EtOAc/hexanes) afforded 25 mg (75%) of
41; [R]D +1.27 (c 0.63, CH2Cl2); 1H NMR δ 7.45-7.24 (m,
20H), 6.82 (ddd, J ) 45.9, 12.5, 5.5 Hz, 1H), 5.09 (dd, J ) 17.7,
12.5 Hz, 1H), 5.16-5.02 (m, 2H), 4.79-4.75 (m, 1H), 4.28 (br.s,
1H), 3.56-3.45 (m, 2H); 13C NMR δ 146.1, 143.1, 135.8 (d, JCP
7.7 Hz); 31P NMR δ 12.7. Exact mass: calcd for C31H30O5P
(M+1) 513.1831; found 513.1812 (FAB).
(2SP,3S,4R,5S,6R)-2-Phenylmethoxy-6-[hydroxymethyl]-
1,2-oxaphosphorinane-3,4,5-triol-2-oxide) (38). To a solu-
tion of OsO4 (43 mg, 0.017 mmol) in CH2Cl2 (0.6 mL) was added
TMEDA (22 mg, 0.19 mmol) followed by the starting alcohol
(68 mg, 0.13 mmol) in CH2Cl2 (1.0 mL) and at -78 °C. The
reaction mixture was stirred for 3 h at -78 °C, warmed to
room temperature, and stirred for 15 min. Removal of the
solvent under reduced pressure afforded the crude osmate
ester, which was dissolved in 1.0 mL MeOH and treated with
citric acid (40 mg, 0.21 mmol) for 24 h. The solvent was
removed, the residue was dissolved in a small amount of
MeOH, and the solvent was filtered through silica gel with
EtOAc/10%MeOH. The crude product was dissolved in 1.0 mL
MeOH and treated with catalytic amount of TsOH‚H2O for 8
h. Removal of the solvent under reduced pressure and flash
chromatography (EtOAc/10% MeOH) afforded 28 mg (71%) of
) 6.0 Hz), 128.5, 128.4, 128.1, 127.9, 127.3, 119.9 (d, JCP
)
165.5 Hz), 87.3, 76.9 (d, JCP ) 4.9 Hz), 68.7 (dt, JCP ) 6.1 Hz),
63.4 (d, JCP ) 10.4 Hz), 62.7 (dt, JCP ) 9.6 Hz); 31P NMR δ
12.1.
(2SP,3S,4R,5R,6R)-2-Phenylmethoxy-6-[(triphenyl-
methoxy)methyl]-1,2-oxaphosphorinane-3,4-diol-5-ol-ben-
zoate-2-oxide) [(-)-42]. To a solution of 40 (33 mg, 0.054
mmol) in acetone (1.5 mL) and t-BuOH (0.5 mL) were added
citric acid (13 mg, 0.068 mmol), NMO‚H2O (9 mg, 0.067 mmol)
and OsO4 (1 drop 4% solution in water). After stirring for 24
h at room temperature,one more drop of OsO4 was added, and
the stirring was continued for 24 h. Water was added to the
reaction mixture and extracted with EtOAc (3x). Removal of
the solvent under reduced pressure and flash chromatography
(EtOAc/1% MeOH) afforded 28 mg (80%) of 42 as an oil; [R]D
-36.4 (c 1.3, CH2Cl2); IR (neat) 3325, 3061, 3033, 2926, 1728,
1600, 1491, 1449, 1264, 1241, 1093, 999, 967 cm-1; 1H NMR δ
7.81-7.80 (m, 2H), 7.60-7.56 (m, 1H), 7.40-7.29 (m, 13H),
7.16-7.08 (m, 9H), 5,74 (d, J ) 4.5 Hz, 1H), 5.38 (dd, J ) 6.5,
6.5 Hz, 1H), 5.20-5.17 (m, 2H), 4.68 (ddd, J ) 33.5, 3.8, 3.8
Hz, 1H), 4.19 (dd, J ) 10.7, 2.7 Hz, 1H), 3.46 (dd, J ) 8.5, 6.0
Hz, 1H), 3.22 (dd, J ) 8.6, 8.6 Hz, 1H); 13C NMR δ 164.5, 143.1,
135.5 (d, JCP ) 6.0 Hz), 133.4, 129.8, 129.0, 128.6, 128.5, 128.4,
128.0, 127.8, 127.0, 86.9, 74.6 (d, JCP ) 4.7 Hz), 71.5, 71.4, 68.9
(dt, JCP ) 6.1 Hz), 66.6 (d, JCP ) 140.9 Hz), 60.7 (dt, JCP ) 11.6
Hz); 31P NMR δ 24.3. Exact mass: calcd for C38H36O8P (M+1)
651.2148; found 651.2131 (FAB).
1
38; H NMR δ 7.44-7.31 (m, 5H), 5.21-5.11 (m, 2H), 4.55-
4.50 (m, 1H), 4.24 (dt, J ) 33.7, 2.7 Hz, 1H), 4.01 (dd, J ) 9.8,
3.4 Hz, 1H), 3.90 (ddd, J ) 12.5, 4.4, 2.9 Hz, 1H), 3.75 (dd, J
) 9.8, 2.1 Hz, 1H); 13C NMR δ 137.7 (d, JCP ) 6.4 Hz), 129,7,
129.6, 129.2, 78.4 (d, JCP ) 4.4 Hz), 75.5 (d), 71.4, 69.6 (dt, JCP
) 6.4 Hz), 69.0 (d), 67.7 (d, JCP ) 144.5 Hz), 62.8 (dt, JCP ) 8.0
Hz); 31P NMR δ 24.5. Exact mass: calcd for C38H36O8P (M+1)
651.2148; found 651.2131 (FAB).
(2SP,5S,6R)-5,6-Dihydro-2-phenylmethoxy-2H-1,2-
oxaphosphorinane-5-methanesulfonate-6-[(triphenyl-
methoxy)-methyl]-2-oxide [(+)-39]. To a solution of diol 36
(180 mg, 0.339 mmol) in CH2Cl2 (10 mL) were added a catalytic
amount of DMAP (8.3 mg, 0.068 mmol), MsCl (0.087 mL, 1.13
mmol) at 0 °C followed by Et3N (0.191 mL, 1.36 mmol). The
reaction mixture was warmed to room temperature over 1 h
and stirred overnight at room temperature. Et3N (0.034
mL, 0.339 mmol) was added, and the stirring was continued
for 6 h. After addition of brine the mixture was extracted
with EtOAc (3x) and dried (Na2SO4). Removal of the solvent
under reduced pressure and flash chromatography (1:1 hex-
anes/EtOAc) afforded 120 mg (60%) of 39; [R]D +105.2 (c 1.9,
CH2Cl2); IR (neat) 3032, 2933, 1490, 1449, 1364, 1259, 1180,
985, 961, 853 cm-1; 1H NMR δ 7.44-7.24 (m, 20H), 6.81 (ddd,
J ) 45.9, 12.9, 2.1 Hz, 1H), 6.03 (ddd, J ) 17.2, 12.9, 2.1 Hz,
1H), 5.64-5.60 (m, 1H), 5.20-5.18 (m, 2H), 4.75-4.71 (m, 1H),
3.70 (dd, J ) 11.0, 2.8 Hz, 1H), 3.30 (dt, J ) 11.0, 3.0 Hz, 1H),
2.65 (s, 3H); 13C NMR δ 145.9, 142.8, 135.4 (d, JCP ) 5.9 Hz),
128.7, 128.69, 128.6, 128.0, 127.9, 127.4, 119.9 (d, JCP ) 165.8
Hz), 87.1, 76.9 (d, JCP ) 6.1 Hz), 70.9 (d, JCP ) 10.6 Hz), 68.7
(d, JCP ) 6.2 Hz), 61.4 (dt, JCP ) 6.3 Hz), 38.1; 31P NMR δ 10.9.
Exact mass: calcd for C32H32O7PS (M+1) 591.1606; found
591.1591 (FAB).
(2S,5R,6R)-5,6-Dihydro-2-phenylmethoxy-2H-1,2-
oxaphosphorinane-5-ol-b enzoate-6-[(triphenylmethoxy)-
methyl]-2-oxide, [(-)-40]. To a solution of 39 (24 mg, 0.044
mmol) in DMF (0.5 mL) was added KOBz (10 mg, 0.062 mmol)
and 18-Crown-6 (27 mg, 10 mmol). The resulting reaction
mixture was stirred overnight at room temperature, quenched
with NH4Cl (sat′d aq.), extracted with EtOAc, and dried
(Na2SO4). Removal of the solvent under reduced pressure and
flash chromatography (7:3 hexanes/EtOAc) afforded 20 mg
(74%) of 40; [R]D -100.0 (c 0.51, CH2Cl2); 1H NMR δ 7.82 (dd,
J ) 8.2, 1.2 Hz, 2H), 7.61 (t, J ) 1.2 Hz, 1H), 7.52-7.12 (m,
22H), 7.03 (ddd, J ) 45.5, 12.5, 5.7 Hz, 1H), 6.12 (dd, J ) 17.2,
12.5 Hz, 1H), 5.72-5.69 (m, 1H), 5.15-4.97 (m, 3H), 3.56 (dd,
J ) 8.7, 5.5 Hz, 1H), 3.40 (t, J ) 8.8 Hz, 1H); 13C NMR δ 165.0,
143.0, 142.8, 135.5 (d, JCP ) 6.2 Hz), 133.4, 129.8, 129.0,
128.53, 128.48, 128.45, 128.3, 127.8, 127.6, 127.1, 122.5 (d, JCP
) 164.1 Hz), 87.0, 75.9 (d, JCP ) 5.1 Hz), 68.7 (dt, JCP ) 6.1
Hz), 63.9 (d, JCP ) 10.9 Hz), 61.0 (dt, JCP ) 10.5 Hz); 31P NMR
(2SP,3S,4R,5R,6R)-2-Phenylmethoxy-6-[hydroxymethyl]-
1,2-oxaphosphorinane-3,4-diol-5-ol-2-oxide (43). To a solu-
tion of 42 (24 mg, 0.047 mmol) in acetone (0.9 mL) and t-BuOH
(0.3 mL) were added citric acid (10 mg, 0.052 mmol), NMO‚
H2O (7 mg, 0.052 mmol) and OsO4 (1 drop 4% solution in
water). The reaction was stirred for 24 h. Upon completion
water was added to the reaction mixture and extracted with
EtOAc (3x). The crude mixture was taken up in MeOH (1 mL),
followed by the addition of catalytic TsOH, and stirred for an
additional 24 h. Removal of the solvent under reduced pressure
and flash chromatography (EtOAc/1% MeOH) afforded 10 mg
(70%) of 43 as an oil; IR (neat) 3350, 3025, 2970, 1211, 1045
1
cm-1; H NMR δ 7.31-7.44 (m, 5H), 5.10-5.49 (m, 2H), 4.77
(dt, J ) 5.9, 2.4 Hz, 1H), 4.29 (dd, J ) 9.7, 3.7 Hz, 1H), 4.22
(ddd, J ) 33.4, 4.0, 4.0 Hz, 1H), 3.96 (d, J ) 4.4 Hz, 1H), 3.76-
3.84 (m, 2H); 13C NMR δ 136.7, 128.6, 128.4, 127.9, 77.6 (d,
JCP ) 5.4 Hz), 70.5 (d, JCP ) 2.3 Hz), 68.5 (d, JCP ) 6.6 Hz),
64.5 (d, JCP ) 144.9 Hz), 61.5 (d, JCP ) 10.1 Hz); 31P NMR δ
20.8.
Acknowledgment. This investigation was gener-
ously supported by funds provided by the National
Institutes of Health (National Institute of General
Medical Sciences, RO1-GM58103) and the NIH Dynamic
Aspects in Chemical Biology Training Grant (A.W.). The
authors thank Dr. David Vander Velde and Sarah
Neuenswander for the assistance with the NMR mea-
surements and Dr. Todd Williams for HRMS analysis.
5888 J. Org. Chem., Vol. 70, No. 15, 2005

P-Heterocyclic Building Blocks
The authors thank the National Science Foundation
(Grant CHE-0079282) and the University of Kansas for
funds to purchase the X-ray instrument and computers.
The X-ray structure of compound 23 was determined
by Dr. Douglas R. Powell. The authors kindly acknowl-
edge Daiso Co., Ltd., Fine Chemical Department for
donating 100 g of each antipode of both the benzyl and
trityl protected glycidols (e-mail:akkimura@daiso.co.jp)
and Materia, Inc. for supplying metathesis catalyst and
helpful suggestions.
Supporting Information Available: We have previously
published on compounds 15-17a.9 1H, 13C, and 31P NMR
spectra for compounds 17b and 18-42, and X-ray crystal-
lographic data for compound 23. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO0505122
J. Org. Chem, Vol. 70, No. 15, 2005 5889