Synthesis of Glycophostones: Cyclic Phosphonate Analogues of Biologically Relevant Sugars

Article abstract of DOI:10.1021/jo991696l

Analogues of L-fucose, N-acetyl-D-glucosamine, N-acetyl-D-mannosamine, and N-acetyl neuraminic acid in which the anomeric carbon atom was replaced by a phosphonyl group (phostones or cyclic phosphonates) were synthesized by stereocontrolled methods relying on the Abramov reaction.

Full text of DOI:10.1021/jo991696l

J . Org. Chem. 2000, 65, 2667-2674
2667
Syn th esis of Glycop h oston es: Cyclic P h osp h on a te An a logu es of
Biologica lly Releva n t Su ga r s
Stephen Hanessian* and Olivier Rogel
Department of Chemistry, Universite´ de Montre´al, C.P. 6128, Succursale Centre-ville, Montre´al,
Que´bec H3C 3J 7 Canada
Received October 28, 1999
Analogues of L-fucose, N-acetyl-D-glucosamine, N-acetyl-D-mannosamine, and N-acetyl neuraminic
acid in which the anomeric carbon atom was replaced by a phosphonyl group (phostones or cyclic
phosphonates) were synthesized by stereocontrolled methods relying on the Abramov reaction.
In tr od u ction
Aminodeoxy and deoxy sugars are important compo-
nents of biologically relevant natural products such as
antibiotics and other anti-infective agents.1 They also
play a critical role in conferring specificity in the interac-
tion of oligosaccharide components of glycoproteins with
proteins, for example.2 The relevance of such interactions
is manifested by vital physiological effects related to
health issues for mankind.
F igu r e 1.
As a result, the field of glycobiology has emerged as
an important area of research on many fronts.3 Concur-
rently, much attention has been focused on synthetic
methods for the stereocontrolled synthesis of glycosides
and oligosaccharides4 to be used as tools and probes to
elucidate interactions at the molecular level. As in
peptide and oligonucleotide chemistry, carbohydrate-
based substrates are subject to degradation under physi-
ological conditions through the action of specific glycosi-
dases.5 The modification of amide bonds in certain
peptide sequences6 and the internucleotidic linkages in
oligonucleotides7 has been successfully accomplished,
with dramatic results, often culminating with the dis-
covery of new therapeutic agents. Because of the fidelity
of the interactions of carbohydrates with proteins, their
chemical modification to glycomimetics has been inves-
tigated to a lesser degree.8 Invariably, conformation,
configuration, the nature of the functional groups, as well
as stereochemistry play critical roles in such recognition
phenomena. Therefore, it is not surprising that even
subtle modifications such as configurational inversion,
deoxygenation, etc. may result in a loss of the original
effect with a biological target.
It occurred to us some years ago that the replacement
of the anomeric carbon atom of a sugar by a pentacova-
lent phosphorus atom would be of interest in the search
for anomerically modified glycomimetics.9 Such molecules
would correspond to functionalized versions of cyclic
phosphonates also known as phostones (Figure 1). Fol-
lowing earlier reports of simple phostones,10 we disclosed
our syntheses of D-gluco, D-manno, and disaccharide
phostones, including X-ray crystal structures that re-
vealed interesting functional features at phosphorus.9
Cyclic phosphonates in the D-gluco- and D-manno series
were also reported by Drueckammer,11 Withers,12 and
their respectives co-workers.
* To whom correspondence should be addressed. Phone: (514) 343-
6738. Fax: (514) 343-5728. E-mail: hanessia@ere.umontreal.ca.
(1) See, for example: Carbohydrates in Drug Design; Witczak, Z.
J ., Nieforth, K. A., Eds.; Dekker: New York, 1997. Witczak, Z. J . Curr.
Med. Chem. 1995, 1, 392. Petitou, M. In Synthetic Oligosaccharides;
Kovac, P., Ed.; ACS Symposium Series 560; American Chemical
Society: Washington, DC, 1994; Chapter 2, p 19. Musser, J . H. Ann.
Rep. Med. Chem. 1992, 27, 301.
(2) Lis, H.; Sharon, N. Chem. Rev. 1998, 98, 637. Schnaar, R. L.
Adv. Pharmacol. 1992, 23, 35.
(3) See, for example: Dwek, R. A. Chem. Rev. 1996, 96, 683. See
also: Glycopeptides and Related Compounds, Synthesis, Analysis and
Applications; Large, D. G., Warren, C. D., Eds.: Marcel Dekker: New
York, 1997. Glycoscience: Synthesis of Oligosaccharides and Glycoju-
gates (Topics in Current Chemistry 186); Driguez, H., Thiem, J ., Eds.;
Springer-Verlag: Berlin, 1997. Glycoproteins. In New Comprehensive
Biochemistry; Vol. 29a, Neuberger, A., Van Deenen, L. L. M., Eds.;
Montreuil, J ., Vliegenthart, J . F. G., Schachter, H., Eds.; Elsevier:
Oxford, 1995. Molecular Glycobiology; Fukuda, M., Hindsgaul, O., Eds.;
IRL Press at Oxford University Press: Oxford, 1994.
(4) For several chapters on glycoside and oligosaccharide synthesis,
see: Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Dek-
ker: New York, 1996; Chapters 11-22.
(5) For a recent review, see: Heightman, T. D.; Vasella, A. T. Angew.
Chem., Int. Ed. Engl. 1999, 38, 750.
(6) See, for example: Bohacek, R. S.; McMartin, C.; Guida, W. C.
Med. Chem. Rev. 1996, 16, 3. Gante, J . Angew. Chem., Int. Ed. Engl.
1994, 33, 1699. Adang, A. E. P.; Hermkens, P. H. H.; Linders, J . T.
M.; Ottenheijm, H. C. J .; van Staveren, C. J . Rec. Trav. Chim. Pays
Bas 1994, 113, 63. Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl.
1993, 32, 1244.
(8) For some examples of carbohydrate mimetics, see: Carbohy-
drates Mimics; Chapleur, Y., Ed.; Wiley-VCH: New York, 1998.
(9) Hanessian, S.; Gale´otti, N.; Rosen, P.; Oliva, G.; Babu, S. Bioorg.
Med. Chem. 1994, 4, 2763.
(10) Cremer, S. E.; Sommese, A. G.; Rodriguez, O. Phosphorus,
Sulfur Silicon 1993, 75, 107. Kobayashi, S.; Suzuki, M.; Saegusa, T.
Bull. Chem. Soc. J pn. 1985, 58, 2153. Calvo, K. C.; Westheimer, F. H.
J . Am. Chem. Soc. 1984, 106, 4205. Stachel, H.-D.; Hampl, B. Chem.
Berr. 1981, 114, 405. Thiem, J .; Gu¨nther, M. Phosphorus Sulfur 1984,
20, 67. Thiem, J .; Gu¨nther, M.; Paulsen, H.; Kopf, J . Chem. Ber. 1977,
110, 3190. Wroblewski, A. E. Z. Naturforsch. 1986, B41, 791. Wrob-
lewski, A. E. Carbohydr. Res. 1986, C1, 125. Wroblewski, A. E.
Tetrahedron 1986, 42, 3595. Benezra, C.; Collard, J .-N. Tetrahedron
Lett. 1982, 23, 3725.
(7) See for example: Cook, P. D. Ann. Rep. Med. Chem. 1998, 33,
313. Antisense Research and Applications; Crooke, S. T., Lebleu, B.,
Eds.; CRC Press: Boca Raton, 1993.
(11) Darrow, J . W.; Dueckhammer, D. G. Bioorg. Med. Chem. 1996,
4, 1341. Darrow, J . W.; Drueckhammer, D. G. J . Org. Chem. 1994, 59,
2976.
10.1021/jo991696l CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/09/2000

2668 J . Org. Chem., Vol. 65, No. 9, 2000
Hanessian and Rogel
Sch em e 1
Sch em e 2
We now extend our studies to the synthesis of phos-
tones corresponding to L-fucose, N-acetyl-D-glucosamine,
N-acetyl-D-mannosamine, and N-acetyl neuraminic acid.
In each case, we obtained the anomeric methyl phospho-
nate esters as well as the free acids. The synthesis
protocol for each analogue consisted of the oxidative
cleavage of the corresponding O-benzylated glycal to the
aldehydo sugar bearing a formate ester at C-5 (originally
the anomeric carbon atom), followed by condensation
with trimethyl phosphite in glacial acetic acid11 to
introduce the dimethylphosphonyl moiety (Abramov re-
action).13
The stereochemistry at the phosphorus atom in com-
pounds 6 and 7 was deduced from NMR proton signals.
Protons on the same face of the ring as the PdO bond
are deshielded.14 For instance, ring protons H4, H5 and
H6 are deshielded if the PdO bond is axial, and H3 is
deshielded if the PdO is equatorial. The H4, H5, and H6
signals of 6 have extra upfield shifts of 0.08, 0.04, and
0.11 ppm, respectively, compared to the shifts in 7. The
stereochemistry at the phosphorus atom in compound 9
was assumed to be as shown based on the X-ray structure
obtained from the polyacetylated derivative 10.
The synthesis of the N-acetyl-D-glucosamine and N-
acetyl-D-mannosamine phostones 18 and 19 presented a
new challenge in the application of the Abramov reaction
(Schemes 2). Addition of O-benzyl hydroxylamine to 2,3,5-
tri-O-benzyl D-arabinose15 led to the corresponding oxime
11 in quantitative yield. We were pleased to find that
the addition of trimethyl phosphite in acetic acid pro-
ceeded smoothly giving a mixture D-gluco and D-manno
isomers each consisting of a pair of two isomeric phos-
phonate esters. In this case, cyclization to the phostones
was spontaneous under the reaction conditions. Flash
The synthesis of the acyclic L-talo and L-fuco dimeth-
ylphosphonates 2 and 3, which were obtained in a 2:3
ratio, respectively, is shown in Scheme 1. In view of the
greater potential relevance of the L-fuco isomer, we
focused on the synthesis of the corresponding phostone.
Nevertheless, it was of interest that there was a modest
level of selectivity in the Abramov reaction favoring the
desired L-fuco isomer. Treatment of 2 with sodium
methoxide led to the two methyl phosphonates 4 and 5
in a ratio of 3:2. The L-fuco isomers 4 and 5 showed H-2
coupling constants of J H3,H4 ) 8.1 Hz and J H3,P ) 10.5
Hz for a doublet of doublets, reflecting on a trans diaxial
orientation. For comparison, the corresponding L-talo
analogues had J H3,H4 ) 4.0 Hz and J H3,P ) 10.5 Hz,
respectively.
(14) Abraham, R. J .; Fisher, J .; Loftus, P. In Introduction to NMR
Spectroscopy; J ohn Wiley
& Sons: New York, 1988. Sturtz, G.;
Pondaven-Raphalen, A. Phosphorus Sulfur 1988, 36, 39. Cooper, D.
B.; Harrison, J . M.; Inch, T. D. Tetrahedron Lett. 1974, 2697.
(15) Finch, P.; Iskander, G. M.; Siriwardena, A. H. Carbohydr. Res.
1991, 210, 319.
(12) Harvey, T. C.; Simiand, C.; Weiler, L.; Withers, S. G. J . Org.
Chem. 1997, 62, 6722.
(13) Abramov, V. S. Zh. Obshch. Khim. 1957, 22, 647.

Synthesis of Glycophostones
J . Org. Chem., Vol. 65, No. 9, 2000 2669
chromatography allowed the isolation of the D-gluco
isomer with the R-methoxy configuration 12a , and a
mixture of the D-gluco S-methoxy isomer 12b, along with
the corresponding D-manno R- and S-methoxy isomers
13a ,b in 75% overall yield.
It was found practical to continue the synthesis with
the D-gluco isomer 12a and the mixture of D-manno
isomers 13a ,b (containing residual amounts of 12b).
Acetylation of 12a gave the corresponding N-acetyl
D-gluco derivative 14a , while acetylation of the remaining
mixture of isomers led to the other D-gluco phosphonate
ester 14b and D-manno analogues 15a ,b.
Hydrolysis16 of the methyl esters 14a ,b and 15a ,b gave
the corresponding free acids 16 and 17 which were
separated chromatographically. Finally, hydrogenolysis
of each isomer gave N-acetyl-D-glucosamine phostone 18
and N-acetyl-D-mannosamine phostone 19 as the free
acids.
Although the N-acetyl neuraminic acids have been
known as components of glycoproteins, their role as
chemotherapeutic agents was not appreciated until re-
cently.17 Two major areas of interest are concerned with
influenza virus A and B and cell adhesion molecules in
relation to inflammation. Haemagglutinin18 and neur-
aminidase19 are two major glycoproteins expressed by
influenza A and B viruses. Since neuraminidase has been
implicated in enhancing viral infectivity as well as in
other processes dealing with the movement of viruses, it
has been considered as a suitable target to inhibit.20
Several analogues of N-acetyl neuraminic acid have been
synthesized in the search for effective anti-influenza
agents.21 Zanamivir,22 a 2,3-unsaturated 4-guanidino-4-
N-acetyl neuraminic acid, is a potent inhibitor of
neuraminidase (Figure 2). Inhibition has also been
reported with the phosphonic acid analogue23 of N-acetyl
neuraminic acid and its 2-deoxy phosphonic acid.24
Surprisingly potent compounds have resulted from the
replacement of the trihydroxypropyl side chain with an
isopentyl group and the substitution of the 4-hydroxy
group with an amine as in GS 4074.25
F igu r e 2.
The cyclic phosphonate analogue of N-acetyl neuramin-
ic acid (sialophostone) (Figure 2) presented interesting
features that included among others the presence of a
phosphonic acid at the anomeric carbon. Sialophostone
can be regarded as an anomerically truncated hybrid of
the natural compound and its 1-phosphonic acid ana-
logue. A related phostone analogue of phosphoramidon,26
an inhibitor of endothelin converting enzyme, was re-
cently synthesized in our laboratory.27
As in the synthesis of the glycophostones described
above, it was more practical to excise the anomeric carbon
from a suitably O-protected 5-N-acetyl neuraminic acid
and to apply the conditions of the Abramov reaction. For
practical reasons, it was decided to start with the known
tetra-O-benzyl derivative 20.28 In our hands, the benz-
ylation of the precursor tetrol proceeded best with sodium
hydride as base, rather than with barium hydroxide29
although the yield was still modest. Ozonolysis of 20 and
treatment of the corresponding aldehydo ester with
trimethyl phosphite in acetic acid gave a 3:2 ratio of the
epimeric phosphonates 21 and 22. Several attempts to
deoxygenate the hydroxy group in these molecules re-
sulted in inseparable mixtures possibly due to concomi-
nant deoxygenation of the oxalate ester.30 We therefore
converted each isomer to the corresponding cyclic phos-
phonate. Treatment of 21 with aqueous sodium hydroxide
led to a 1:2 mixture of methyl esters 23 and 24. Similar
treatment of 22 led to the corresponding cyclic phospho-
nate as an inseparable mixture of methyl esters 25.
The successful application of the Barton-McCombie
deoxygenation reaction31 to highly functionalized 2-hy-
(16) McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna, M. C.
Tetrahedron Lett. 1977, 2, 155.
(17) Sialic Acids. Chemistry, Metabolism and Function; Schauer, R.,
Ed.; Springler-Verlag: New York, 1982. Wade, R. C. Structure 1997,
5, 1139.
(18) Whitesides, G. M.; Lees, W. J .; Spaltenstein, A.; Kingery-Wood,
J . E. J . Med. Chem. 1994, 37, 3419. Hirst, G. K. Science 1941, 94, 22.
Gottschalk, A. Biophys. Acta 1957, 23, 645.
(19) Gottschalk, A. In The Viruses; Burnet, F. M., Stanley, W. M.,
Eds.; Academic Press: New York, 1959; Vol. 3, pp 51-61.
(20) Edmond, J . D.; J ohnstone, R. G.; Kidd, D.; Rylance, H. J .;
Sommerville, R. G. Br. J . Pharmacol. Chemother. 1966, 27, 415.
(21) For selected recent papers, see: Brouillette, W. J .; Atigadda,
V. R.; Luo, M.; Air, G. M.; Babu, Y. S.; Bantia, S. Bioorg. Med. Chem.
Lett. 1999, 9, 1901. Smith, P. W.; Sollis, S. L.; Howes, P. D.; Cherry,
P. C.; Starkey, I. D.; Cobley, K. N.; Weston, H.; Scicinski, J .; Merritt,
A.; Whittington, A.; Wyatt, P.; Taylor, N.; Green, D.; Bethell, R.; Madar,
S.; Fenton, R. J .; Morley, P. J .; Pateman, T.; Beresford, A. J . Med.
Chem. 1998, 41, 787. Taylor, N. R.; Cleasby, A.; Singh, O.; Skarzynski,
T.; Wonacott, A. J .; Smith, P. W.; Sollis, S. L.; Howes, P. D.; Cherry,
P. C.; Bethell, R.; Colman, P.; Varghese, J . J . Med. Chem. 1998, 41,
798. Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.;
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai,
C. Y.; Laver, W. G.; Stevens, R. C. J . Am. Chem. Soc. 1997, 119, 681.
Chand, P.; Babu, Y. S.; Bantia, S.; Chu, N.; Cole, L. B.; Kotian, P. L.;
Laver, W. G.; Montgomery J . A.; Pathak, V. P.; Petty, S. L.; Shrout,
D. P.; Walsh, D. A.; Walsh, G. M. J . Med. Chem. 1997, 40, 4030.
Bamford, M. J .; Pichel, J . C.; Husman, W.; Patel, B.; Storer, R.; Weir,
N. G. J . Chem. Soc., Perkin Trans. 1 1995, 1181. Kong, D. C. M.; von
Itzstein, M. Tetrahedron Lett. 1995, 36, 957.
(25) Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H.; Zhang, L.; Chen,
X.; Escarpe, P. A.; Mendel, D. B.; Laver, W. G.; Stevens, R. C. J . Med.
Chem. 1998, 41, 2451.
(26) Umezawa, S.; Tatsuta, K.; Izawa, O.; Tsuchiya, T. Tetrahedron
Lett. 1972, 97.
(27) Hanessian, S.; Rogel, O.Bioorg. Med. Chem. Lett. 1999, 9, 2441.
(28) Czollner, L.; Kuszmann, J .; Vasella, A. Helv. Chim. Acta 1990,
73, 1338.
(29) Ito, Y.; Ogawa, T. Tetrahedron 1990, 46, 89. Sharma, M.; Petrie,
C. R.; Korytnyk, E. Carbohydr. Res. 1988, 175, 25.
(30) Dolan, S. C.; MacMillan, J . J . Chem. Soc., Chem. Commun.
1985, 1588. See also: Hanessian, S.; Abad-Grillo, T.; McNaughton-
Smith, G. Tetrahedron 1997, 53, 6281. Nishi, T.; Kataoka, M.;
Morisawa, Y. Chem. Lett. 1989, 1993. Corey, E. J .; Su, W.-G. J . Am.
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(22) Woods, J . M.; Bethell, R. C.; Hotham, V. J .; Cameron, J . M.;
Penn, C. R. Nature 1993, 363, 418.
(23) Chan, T.-H.; Xin, Y.-C. J . Org. Chem. 1997, 62, 3500.
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1 1975, 1574.

2670 J . Org. Chem., Vol. 65, No. 9, 2000
Hanessian and Rogel
Sch em e 3
mined in CDCl3 unless otherwise noted. Wherever necessary,
1H NMR assignments were supported by appropriate homo-
nuclear correlation experiments (COSY). Optical rotations
were measured at 25 °C at the sodium line.
droxyphosphonates exemplified by compounds 23-25
was a rewarding result, in view of the lack of precedents.
Thus, formation of the phenylthionocarbonate from 23
and 24 individually, followed by treatment with tribu-
tyltin hydride under standard conditions, led to the
expected deoxygenated phosphonates 26 and 27 in 65%
yield in each case. Similarly, deoxygenation of the
mixture of esters 25 gave the corresponding deoxy
phosphonates 26 and 27 (Scheme 3).
Hydrogenolysis of each of the esters 26 and 27 gave
the corresponding methyl phosphonates 29 and 30. The
stereochemistry of the phosphorus atom in compounds
29 and 30 was assigned on the basis of the observation
of an anisotropic effect of the PdO on the protons located
on the same face of the ring (vide supra).
3,4-Di-O-ben zyl-L-fu ca l (1). Sodium hydride (60% disper-
sion in mineral oil, 120 mg, 3 equiv) was added to a stirred
solution of L-fucal (130 mg, 1 mmol) in dry DMF (5 mL), and
the slurry was stirred at room temperature for 1 h. The
mixture was cooled in an ice bath, and benzyl bromide (595
µL, 5 equiv) was added gradually. When the intensive evolu-
tion of hydrogen ceased the clear solution was kept for 1 h at
room temperature and then poured into ice-water (20 mL),
sulfuric acid 1 M (1 mL), and chloroform (20 mL). The organic
layer was dried (sodium sulfate), filtered, and evaporated
under diminished pressure. Flash chromatography on silica
gel, eluting with ethyl acetate/hexanes 1:9, gave 1 as a syrup
1
(295 mg, 95%): [R]D +76.6 (c 0.5, CHCl3); H NMR (CDCl3) δ
Cleavage of the ester with trimethylsilyl bromide16
gave the phosphonic acid 28, which could be obtained
from 26 or 27. Hydrogenolysis of the benzyl ethers in 28
led to the sialophostone acid 31. Unfortunately, com-
pounds 29, 30, and 31 were found to be inactive when
tested for neuraminidase B (Memphis 3/89) inhibiting
activity (<10% at 1 µM).
7.45-7.22 (m, 10H), 6.40 (dd, 1H, J ) 4.5, 6.2 Hz), 5.01 (d,
1H, J ) 11.9 Hz), 4.90-4.87 (m, 1H), 4.78-4.65 (m, 3H), 4.30-
4.28 (m, 1H), 4.09 (q, 1H, J ) 6.6 Hz), 3.75-3.73 (m, 1H), 1.33
(d, 3H, J ) 6.5 Hz); 13C NMR (CDCl3) δ 144.3, 138.1, 138.0,
128.2-127.3, 99.4, 73.6, 73.1, 72.8, 72.1, 70.7, 16.5; HMRS
calcd for C20H23O3 (M+) 311.30670, found 311.30790.
2,3-Di-O-b en zyl-5-d eoxy-1-d im et h ylp h osp h on yl-4-O-
for m yl-L-fu cose (2) a n d 2,3-Di-O-b en zyl-5-d eoxy-1-d i-
m eth ylp h osp h on yl-4-O-for m yl-L-ta lose (3). A stream of O3/
O2 was passed into a cooled solution of 1 (200 mg, 0.64 mmol)
in dichloromethane (10 mL) at -78 °C until the color turned
blue (15 min). Methyl sulfide (10 µL) was added, and the
solution was purged at 0 °C with nitrogen (10 min). The clear
solution was evaporated under diminished pressure, the
residue was dissolved in glacial acetic acid (10 mL) at room
temperature, and trimethyl phosphite (152 µL, 2 equiv) was
added gradually. After the reaction mixture was stirred
overnight, evaporation and flash chromatography on silica gel
(eluting with ethyl acetate/hexanes 1:1) gave 2 (93 mg) and 3
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, all starting
materials and solvents were obtained from commercial sup-
pliers and used without further purification. Flash chroma-
tography was performed on 230-240 mesh silica gel. Thin-
layer chromatography (TLC) was performed on glass plates
coated with 0.02 mm layer of silica gel 60 F254. All solvents
were freshly distilled before use.
NMR a n d An a lytica l Da ta . 1H NMR (400 MHz), 13C NMR
(100.6 MHz), and 31P NMR spectra (162.0 MHz) were deter-
1
(140 mg). For 2: [R]D -2.35 (c 0.85, CHCl3); H NMR (CDCl3)

Synthesis of Glycophostones
J . Org. Chem., Vol. 65, No. 9, 2000 2671
δ 8.35 (s, 1H), 7.68-7.53 (m, 10H), 5.64-5.62 (m, 1H), 5.14
(d, 1H, J ) 9.9 Hz), 5.05 (d, 1H, J ) 11.2 Hz), 4.96 (d, 1H,
J ) 11.2 Hz), 4.68 (d, 1H, J ) 9.9 Hz), 4.53 (t, 1H, J ) 10.7
Hz), 4.25 (dd, 1H, J ) 5.3, 8.5 Hz), 4.09 and 4.07 (2d, 6H, J )
10.7, 10.1 Hz), 3.94 (dd, 1H, J ) 1.2, 8.3 Hz), 3.56 (dd, 1H,
J ) 3.2, 10.3 Hz), 1.62 (d, 3H, J ) 6.5 Hz); 13C NMR (CDCl3)
δ 160.5, 137.3, 137.0, 128.5-127.98, 79.3 (d, J ) 11.9 Hz), 77.3,
75.4, 74.0, 69.4, 66.2 (d, J ) 162.9 Hz), 53.5 (d, J ) 7.2 Hz),
52.89 (d, J ) 7.2 Hz), 16.9; 31P NMR (CDCl3) (H3PO4 in CDCl3
external reference δ 0.0 ppm) δ 25.5; HMRS calcd for C22H30O8P
(M+) 426.30670, found 426.30790. For 3: [R]D -6.1 (c 1.1,
78.1 (d, J ) 10.4 Hz), 77.1, 70.3 (d, J ) 144.8 Hz), 56.3 (d,
J ) 7.8 Hz), 20.4 (d, J ) 10.8 Hz); 31P NMR (CD3OD) (H3PO4
in CD3OD external reference δ 0.0 ppm) δ 22.5; HMRS calcd
for C6H14O6P (M+) 213.28480, found 213.28320.
4,5-Di-O-ben zyl-6-m eth yl-L-ga la cto-(2R)-h yd r oxy-1,2λ5-
oxa p h osp h or in a n -2-on e (8). Compound 4 and/or 5 (112 mg,
0.28 mmol) was dissolved in dichloromethane (10 mL), and
trimethylsilyl bromide (190 µL, 5 equiv) was added. The
solution was stirred overnight at room temperature with
protection from atmospheric moisture. Water (50 µL) was
added, and the solution was stirred for 30 min. After concen-
tration, the residue was purified by precipitation (ethyl acetate/
pentane) to give 8 as an amorphous powder (87 mg, 80%): [R]D
1
CHCl3); H NMR (CDCl3) δ 7.97 (s, 1H), 7.37-7.25 (m, 10H),
5.40 (t, 1H, J ) 6.4 Hz), 4.82-4.65 (m, 5H), 4.39 (dd, 1H, J )
5.0, 10.4 Hz), 4.00 (ddd, 1H, J ) 5.0, 6.2, 17.0 Hz), 3.71 (d,
3H, J ) 10.4 Hz), 3.68 (d, 3H, J ) 10.4 Hz), 1.33 (d, 3H, J )
6.5 Hz); 13C NMR (CDCl3) δ 160.7, 137.7, 137.5, 128.3-127.7,
81.1 (d, J ) 6.9 Hz), 79.6, 74.6, 74.0, 70.2, 68.1 (d, J ) 160.8
Hz), 53.3 (d, J ) 6.6 Hz), 52.9 (d, J ) 6.9 Hz), 17.1; 31P NMR
(CDCl3) (H3PO4 in CDCl3 external reference δ 0.0 ppm) δ 26.8;
HMRS calcd for C22H30O8P (M+) 426.30670, found 426.30790.
1
-54.4 (c 1.0, CHCl3); mp 248-250 °C; H NMR (DMSO-d6) δ
7.40-7.25 (m, 10H, arom.), 4.83 (d, 1H, J ) 10.5 Hz), 4.75 (s,
2H), 4.56 (d, 1H, J ) 10.5 Hz), 4.17 (br, 1H), 3.78-3.50 (m,
2H), 3.38 (br, 1H), 1.16 (s, 3H); 13C NMR (DMSO-d6) δ 140.3,
140.0, 129.1-128.2, 85.1 (d, J ) 9.0 Hz), 80.4, 75.6, 73.3, 71.4
68.6 (d, J ) 136.2 Hz), 19.1; 31P NMR (DMSO-d6) (H3PO4 in
DMSO-d6 external reference δ 0.0 ppm) δ 20.1; HMRS calcd
for C19H24O6P (M+) 379.08484, found 379.08410.
4,5-Di-O-b en zyl-6-m et h yl-L-ga la cto-(2R)-m et h oxy-1,-
2λ5-oxa p h osp h or in a n -2-on e (4) a n d 4,5-Di-O-ben zyl-6-
m eth yl-L-ga la cto-(2S)-m eth oxy-1,2λ5-oxa p h osp h or in a n -
2-on e (5). A quantity of 2 (100 mg, 0.23 mmol) was dissolved
in dry methanol (10 mL), and a few drops of freshly prepared
sodium methoxide in methanol were added with stirring. After
2 h, the pH was made neutral by addition of Amberlite IR-
120 (H+). The filtered solution was evaporated to give a white
foam. Preparative TLC in ethyl acetate was used to isolate
and purify 4 (52 mg) and 5 (35 mg) in 95% yield as syrups.
For 4: [R]D -36.0 (c 0.7, CHCl3); 1H NMR (CDCl3) δ 7.40-
7.26 (m, 10H), 4.97 (d, 1H, J ) 11.5 Hz), 4.85 (d, 1H, J ) 11.7
Hz), 4.74 (d, 1H, J ) 11.7 Hz), 4.66 (d, 1H, J ) 11.5 Hz), 4.60
(dd, 1H, J ) 8.1, 11.5 Hz), 4.21-4.19 (m, 1H), 3.89 (d, 3H,
J ) 10.2 Hz), 3.82 (td, 1H, J ) 2.3, 10.5 Hz), 3.66-3.39 (m,
1H), 1.30 (dd, 3H, J ) 1.5, 6.5 Hz); 13C NMR (CDCl3) δ 138.2,
137.8, 128.4-127.6, 82.9 (d, J ) 10.1 Hz), 78.0, 74.9, 74.6 (d,
J ) 5.7 Hz), 74.2, 67.4 (d, J ) 143.0 Hz), 53.6 (d, J ) 7.0 Hz),
17.8 (d, J ) 10.8 Hz); 31P NMR (CDCl3) (H3PO4 in CDCl3
external reference δ 0.0 ppm) δ 19.8; HMRS calcd for C20H26O6P
(M+) 393.30981, found 393.31130. For 5: [R]D -35.3 (c 0.85,
6-Meth yl-L-ga la cto-(2R)-h yd r oxy-1,2λ5-oxa p h osp h or i-
n a n -2-on e (L-F u cop h oston e) (9). A solution of 8 (30 mg, 0.08
mmol) in methanol (2 mL) was hydrogenated in the presence
of 10 mg of palladium hydroxide on carbon (Degussa) at 60
psi overnight. The solution was filtered over Celite and
evaporated to give 9 as a syrup (15 mg, quant): [R]D -64.4 (c
0.7, MeOH); 1H NMR (CD3OD) δ 4.38 (l, 1H), 4.04 (l, 1H), 3.86
(l, 1H), 3.76 (l, 1H), 1.36 (d, 3H, J ) 5.0 Hz); 13C NMR (CD3-
OD) δ 74.7 (d, J ) 8.9 Hz), 74.4, 74.0, 66.9 (d, J ) 146.9 Hz),
17.1 (d, J ) 10.6 Hz); 31P NMR (CD3OD) (H3PO4 in CD3OD
external reference δ 0.0 ppm) δ 20.1; HMRS calcd for C5H12O6P
(M+) 199.01154, found 199.01230.
3,4,5-Tr i-O-acetyl-6-m eth yl-L-galacto-(2R)-h ydr oxy-1,2λ5-
oxa p h osp h or in a n -2-on e (10). A solution of 4 and/or 5 (40
mg, 0.1 mmol) in methanol (2 mL) was hydrogenated in the
presence of 10 mg of palladium hydroxide on carbon (Degussa)
at 60 psi overnight. The solution was filtered over Celite and
evaporated. The residue was dissolved in acetic anhydride (5
mL) and cooled at 0 °C, BF3‚Et2O (20 µL) was added, and the
mixture was stirred at room temperature overnight. The
solution was poured into aqueous saturated sodium bicarbon-
ate, and the solution was extracted with chloroform (2 × 5
mL) and concentrated. The residue was dissolved in dichlo-
romethane (5 mL), and trimethylsilyl bromide (90 µL, 5 equiv)
was added. The solution was stirred overnight at room
temperature with protection from atmospheric moisture.
Water (50 µL) was added, and the solution was stirred for 30
min. After concentration, the residue was purified by crystal-
lization (ethyl acetate/pentane) to give 10 as fine needles (20
1
CHCl3); H NMR (CDCl3) δ 7.39-7.26 (m, 10H), 4.97 (d, 1H,
J ) 11.4 Hz), 4.78 (q, 2H, J ) 11.7 Hz), 4.67 (d, 1H, J ) 11.4
Hz), 4.44-4.39 (m, 2H), 3.94 (td, 1H, J ) 3.1, 10.6 Hz), 3.84
(d, 3H, J ) 11.0 Hz), 3.69 (s, 1H), 1.31 (d, 3H, J ) 6.4 Hz); 13
C
NMR (CDCl3) δ 137.7, 137.6, 128.5-127.7, 83.1 (d, J ) 8.0
Hz), 75.0, 73.8 (d, J ) 3.3 Hz), 73.7, 66.1 (d, J ) 138.6 Hz),
53.9 (d, J ) 6.5 Hz), 17.8 (d, J ) 10.9 Hz); 31P NMR (CDCl3)
(H3PO4 in CDCl3 external reference δ 0.0 ppm) δ 24.1; HMRS
calcd for C20H26O6P (M+) 393.30981, found 393.31130.
6-Meth yl-L-ga la cto-(2R)-m eth oxy-1,2λ5-oxa p h osp h or i-
n a n -2-on e (6). A solution of 4 (17 mg, 0.04 mmol) in methanol
(2 mL) was hydrogenated in the presence of 10 mg of palladium
hydroxide on carbon (Degussa) at 60 psi overnight. The
solution was filtered over Celite and evaporated to give 7 as a
syrup (9 mg, quant); [R]D -45.8 (c 0.9, MeOH); 1H NMR (CD3-
OD) δ 4.48 (qdd, 1H, J ) 0.9 Hz, 2.8, 6.4, 9.3 Hz), 4.13 (dd,
1H, J ) 8.0, 10.2 Hz), 3.92 (td, 1H, J ) 2.7, 10.7 Hz), 3.83 (d,
3H, J ) 10.9 Hz), 3.79-3.78 (m, 1H), 1.37 (dd, 3H, J ) 1.5,
6.5 Hz); 13C NMR (CD3OD) δ 75.7 (d, J ) 3.0 Hz), 75.0 (d, J )
13.0 Hz), 74.8, 65.9 (d, J ) 142.6 Hz), 54.4 (d, J ) 6.7 Hz),
17.9 (d, J ) 10.9 Hz); 31P NMR (CD3OD) (H3PO4 in CD3OD
external reference δ 0.0 ppm) δ 26.3; HMRS calcd for C6H14O6P
(M+) 213.28480, found 213.28320.
6-Meth yl-L-ga la cto-(2S)-m eth oxy-1,2λ5-oxa p h osp h or i-
n a n -2-on e (7). A solution of 5 (14 mg, 0.037 mmol) in
methanol (2 mL) was hydrogenated in the presence of 10 mg
of palladium hydroxide on carbon (Degussa) at 60 psi over-
night. The solution was filtered over Celite and evaporated to
give 6 as a syrup (8 mg, quant): [R]D -77.4 (c 0.7, MeOH); 1H
NMR (CD3OD) δ 4.35 (qdd, 1H, J ) 1.1, 2.3, 6.5 Hz), 4.11 (dd,
1H, J ) 9.3, 9.8 Hz), 3.86 (d, 3H, J ) 10.2 Hz), 3.83 (td, 1H,
J ) 2.6, 9.8 Hz), 3.74 (dd, 1H, J ) 2.3, 2.6 Hz), 1.37 (dd, 3H,
J ) 1.6, 6.5 Hz); 13C NMR (CD3OD) δ 79.1 (d, J ) 5.5 Hz),
1
mg, 75%): mp 80-82 °C; [R]D -43.5 (c 0.8, MeOH); H NMR
(CD3OD) δ 5.41 (t, 1H, J ) 10.9 Hz), 5.27 (s, 1H), 5.23 (td, 1H,
J ) 3.3 et 6.5 Hz), 4.56-4.54 (m, 1H), 3.19-3.18 (m, 1H), 2.08
1.99 1.84 (3s, 9H), 1.17 (d, 3H, J ) 6.3 Hz); 13C NMR (CD3-
OD) δ 171.9, 171.5, 171.1 (d, J ) 4.5 Hz), 73.9 (d, J ) 5.4 Hz),
73.5 (d, J ) 11.5 Hz), 73.2, 66.4 (d, J ) 147.8 Hz), 20.6, 20.5,
20.4, 17.6 (d, J ) 10.5 Hz); 31P NMR (CD3OD) (H3PO4 in CD3-
OD external reference δ 0.0 ppm) δ 12.9.
2,3,5-Tr i-O-ben zyl-D-a r a bin ose-O-ben zyloxim e (11). To
a suspension of 2,3,5-tri-O-benzyl-D-arabinose (3 g, 7.14 mmol)
in dry methanol (50 mL) were added O-benzylhydroxylamine
hydrochloride (2.5 g, 2 equiv) and pyridine (2.5 mL). After
being stirred overnight, the clear solution was concentrated,
and dichloromethane (20 mL) was added. After filtration and
concentration, the residue was purified by flash chromatog-
raphy on silica gel, eluting with ethyl acetate/hexanes 1:4, to
give 11 as a colorless oil (3.81 g, quant): [R]D -34.36 (c 1.1,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.73-7.14 (m, 20H),
5.27-5.19 (m, 2H), 4.76-4.44 (m, 5H), 4.21-4.04 (m, 1H),
3.85-3.72 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 152.1, 149.1,
138.0-127.6, 80.2, 79.1, 76.5, 76.4, 76.0, 74.2, 74.1, 74.5, 73.4,
72.4, 72.3, 71.2, 71.0, 70.8, 70.0, 69.9; HRMS calcd for C33H36
-
NO5 (M+) 526.25934, found 526.26040.

2672 J . Org. Chem., Vol. 65, No. 9, 2000
Hanessian and Rogel
4,5-Di-O-b en zyl-3-b en zyloxya m in o-3-d eoxy-6-b en zyl-
oxym eth yl-D-glu co-(2R/S)-m eth oxy-1,2λ5-oxa p h osp h or i-
n an -2-on e (12a,b) an d 4,5-Di-O-ben zyl-3-ben zyloxyam in o-
3-d eoxy-6-b en zyloxym et h yl-D-m a n n o-(2R/S)-m et h oxy-
1,2λ5-oxa p h osp h or in a n -2-on e (13a ,b). To a solution of 11
(2 g, 3.8 mmol) in glacial acetic acid (20 mL) was added
trimethyl phosphite (1.34 mL, 3 equiv). After being stirred at
room temperature for 36 h, the solution was evaporated, and
the residue was purified by flash chromatography on silica gel,
eluting with ethyl acetate/hexanes 3:1 to give the D-glucopho-
stone isomer 12a as a pale yellow solid (300 mg) and the other
isomers (12b, 13a ,b) as a yellow oil (1.45 g) for an overall yield
CDCl3 external reference δ 0.0 ppm) δ 22.1, 20.6 and 19.7 (ratio
1:2:3.3); HRMS calcd for C36H41NO8P (M+) 646.25696, found
646.25850.
3-N-Acetyl-4,5-d i-O-ben zyl-3-N-ben zyloxya m in o-3-d e-
oxy-6-b en zyloxym et h yl-D-glu co-(2R)-h yd r oxy-1,2λ5-ox-
a p h osp h or in a n -2-on e (16) a n d 3-N-Acetyl-4,5-d i-O-ben z-
yl-3-N-b en zyloxya m in o-3-d eoxy-6-b en zyloxym et h yl-D-
m a n n o-(2R)-h yd r oxy-1,2λ5-oxa p h osp h or in a n -2-on e (17).
A mixture containing 14a ,b and 15a ,b (100 mg, 0.16 mmol)
was dissolved in dichloromethane (10 mL), and trimethylsilyl
bromide (5 equiv, 100 µL) was added. The solution was stirred
overnight at room temperature with protection from atmo-
spheric moisture. Water (20 µL) was added, and the solution
was stirred for 30 min. After concentration, the residue was
purified by flash chromatography on silica gel, eluting with
chloroform/methanol 95:5, to give 16 (55 mg) and 17 (35 mg)
as white powders after precipitation (chloroform/pentane) for
an overall yield of 90%. For 16: [R]D +33.5 (c 1.0, CHCl3); mp
1
of 75%. For 12a : [R]D +55.2 (c 0.5, CHCl3); H NMR (C6D6) δ
7.31-7.00 (m, 20H), 4.79 (d, 1H, J ) 11.4 Hz), 4.73 (d, 1H,
J ) 11.1 Hz), 4.70 (d, 1H, J ) 15.7 Hz), 4.68 (d, 1H, J ) 6.9
Hz), 4.59 (d, 1H, J ) 11.0 Hz), 4.47 (d, 1H, J ) 11.1 Hz), 4.34
(d, 1H, J ) 9.5 Hz), 4.20 (dd, 2H, J ) 12.0, 50.3 Hz), 3.97 (t,
1H, J ) 10.3 Hz), 3.81 (t, 1H, J ) 19.2 Hz), 3.57 (td, 1H, J )
2.6, 11.5 Hz), 3.49 (d, 3H, J ) 11.2 Hz), 3.43 (dd, 1H, J ) 1.4,
10.9 Hz), 2.05 (s, 3H); 13C NMR (C6D6) δ 135.5, 139.2, 138.8,
138.6, 129.3-128.1, 81.3 (d, J ) 10.0 Hz), 79.0, 75.5, 77.0, 76.3,
75.6, 73.9, 69.3 (d, J ) 9.7 Hz), 62.2 (d, J ) 130.0 Hz), 53.3 (d,
J ) 5.3 Hz); 31P NMR (C6D6) (H3PO4 in C6D6 external reference
δ 0.0 ppm) δ 25.4; HRMS calcd C34H39NO7P (M+) 604.24640,
found 604.24810. For 12b, 13a ,b: 1H NMR (CDCl3) δ 7.43-
7.22 (m, 20H), 6.45-6.10 (m, total 1H), 4.90-4.55 (m, 9H),
4.35-4.0 (m, 3H), 3.92 3.90 3.78 (3d, total 3H, J ) 11.0, 10.7
and 10.8 Hz); 13C NMR (CDCl3) δ 138.0-137.2, 128.8-127.6,
79.5, 79.4, 78.9, 78.7, 78.4, 76.6, 76.5, 76.4, 76.3, 75.7, 75.2,
74.4, 74.0, 73.9, 73.7, 73.6, 73.5, 73.4, 73.3, 72.7, 69.4 (d, J )
6.9 Hz), 68.9 (d, J ) 8.2 Hz), 68.7 (d, J ) 9.7 Hz), 61.2 (d, J )
142.3 Hz), 57.1 (d, J ) 140.5 Hz), 56.5 (d, J ) 139.1 Hz), 53.4
(d, J ) 5.4 Hz), 52.7 (d, J ) 7.0 Hz), 52.3 (d, J ) 6.4 Hz); 31P
NMR (CDCl3) (H3PO4 in CDCl3 external reference δ 0.0 ppm)
δ 22.0, 20.5 and 19.6 (ratio 1:2:3.3); HRMS calcd C34H38NO7P
(M+) 604.24640, found 604.24810.
1
116-118 °C; H NMR (DMSO-d6) δ 7.73-7.06 (m, 20H), 5.84
(d, 1H, J ) 9.7 Hz), 4.87 (d, 1H, J ) 9.7 Hz), 4.77-4.62 (m,
2H), 4.56-4.36 (m, 5H), 4.11-4.02 (m, 2H), 3.73-3.54 (m, 3H),
1.98 (s, 3H);13C NMR (100 MHz, DMSO-d6) δ 174.6, 139.6-
127.9, 82.0, 81.5, 77.9, 75.0, 74.7, 74.3, 73.8, 73.2, 70.6, 56.9
(d, J ) 121.5 Hz), 21.1; 31P NMR (162 MHz, DMSO-d6) (H3-
PO4 in DMSO external reference δ 0.0 ppm) δ 7.8; HRMS calcd
for C35H39NO8P (M+) 632.24133, found 632.23930. For 17: [R]D
1
+27.0 (c 1.0, CHCl3); mp 120-122 °C; H NMR (DMSO-d6) δ
7.5-7.0 (m, 20H), 5.69 (d, 1H, J ) 9.4 Hz), 4.76 (d, 1H, J )
9.5 Hz), 4.66 (d, 1H, J ) 10.4 Hz), 4.57 (d, 1H, J ) 10.4 Hz),
4.50 (s, 2H), 4.30 (dd, 2H, J ) 11.0 and 16.9 Hz), 4.16 (s, 1H),
3.89 (t, 1H, J ) 9.4 Hz), 3.59-3.39 (m, 2H), 2.07 (s, 3H); 13C
NMR (DMSO-d6) δ 174.8, 139.3-128.1, 82.6, 78.1, 77.5, 75.0,
73.4, 72.4, 71.5 (d, J ) 8.9 Hz), 53.1 (d, J ) 136.5 Hz), 21.2;31P
NMR (162 MHz, DMSO-d6) (H3PO4 in DMSO external refer-
ence δ 0.0 ppm) δ 5.9; HRMS calcd for C35H39NO8P (M+)
632.24133, found 632.23930.
3-N-Acetyl-3-d eoxy-6-h yd r oxym eth yl-D-glu co-(2R)-h y-
d r oxy-1,2λ5-oxa p h osp h or in a n -2-on e (N-Acetyl-D-glu cos-
a m in op h oston e) (18). A solution of 16 (20 mg, 0.03 mmol)
in methanol (2 mL) was hydrogenated in the presence of 10
mg of palladium hydroxide on carbon (Degussa) and palladium
on carbon 30% (10 mg) at 60 psi for 2 days. The solution was
filtered over Celite and evaporated to give 18 after precipita-
tion (methanol/ethyl acetate) as a white powder (8 mg, 95%):
[R]D +8.5 (c 0.5, MeOH); mp 120-122 °C; 1H NMR (CD3OD) δ
4.34 (dd, 1H, J ) 11.1, 14.4 Hz), 4.03-3.98 (m, 1H), 3.90-
3.87 (m, 1H), 3.86-3.78 (m, 1H), 3.72 (td, 1H, J ) 1.9, 9.1
Hz), 3.54 (t, 1H, J ) 9.1 Hz), 2.01 (d, 3H, J ) 1.3 Hz); 13C
NMR (CD3OD) δ 175.1 (d, J ) 3.5 Hz), 81.5 (d, J ) 3.2 Hz),
76.4 (d, J ) 11.1 Hz), 73.6, 64.2 (d, J ) 9.9 Hz), 50.6 (d, J )
136.9 Hz), 24.1; 31P NMR (CD3OD) (H3PO4in CD3OD external
reference δ 0.0 ppm) δ 15.5; HRMS calcd for C7H15NO7P (M+)
256.05862, found 256.05960.
3-N-Acet yl-3-d eoxy-6-h yd r oxym et h yl-D-m a n n o-(2R)-
h yd r oxy-1,2λ5-oxa p h osp h or in a n -2-on e (N-Acetyl-D-m a n -
n osa m in op h oston e) (19). A solution of 17 (20 mg, 0.03
mmol) in methanol (2 mL) was hydrogenated in the presence
of 10 mg of palladium hydroxide on carbon (Degussa) and 10
mg of palladium on carbon 30% at 60 psi for 2 days. The
solution was filtered over Celite and evaporated to give 19 after
precipitation (methanol/ethyl acetate) as a white powder (8
mg, 95%): [R]D +7.7 (c 0.5, MeOH); mp 130-132 °C; 1H NMR
(CD3OD) δ 4.40 (dd, 1H, J ) 10.7, 16.9 Hz), 3.91-3.73 (m,
3H), 3.59-3.56 (m, 1H), 3.50 (t, 1H, J ) 9.4 Hz), 2.00 (d, 3H,
J ) 1.2 Hz); 13C NMR (CD3OD) δ 175.2 (d, J ) 3.1 Hz), 82.6
(d, J ) 5.4 Hz), 77.1 (d, J ) 9.2 Hz), 73.4, 64.4 (d, J ) 6.6 Hz),
51.9 (d, J ) 140.2 Hz), 24.2; 31P NMR (CD3OD) (H3PO4 in CD3-
OD external reference δ 0.0 ppm) δ 15.3; HRMS calcd for
C7H15NO7P (M+) 256.05862, found 256.05960.
3-N-Acetyl-4,5-d i-O-ben zyl-3-N-ben zyloxya m in o-3-d e-
oxy-6-ben zyloxym eth yl-D-glu co-(2R/S)-m eth oxy-1,2λ5-ox-
a p h osp h or in a n -2-on e (14a ,b) a n d 3-N-Acetyl-4,5-d i-O-
ben zyl-3-N-ben zyloxya m in o-3-d eoxy-6-ben zyloxym eth yl-
D-m a n n o-(2R/S)-m et h oxy-1,2λ5-oxa p h osp h or in a n -2-on e
(15a ,b). Rep r esen ta tive P r oced u r e. To a stirred solution
of 12a (200 mg, 0.33 mmol) at 0 °C in dry dichloromethane
(10 mL) was added a catalytic amount of DMAP and triethyl-
amine (92 µL, 2 equiv) followed by acetyl chloride (50 µL, 3
equiv) under nitrogen. The solution was stirred overnight at
room temperature and poured into a separatory funnel con-
taining cold water (20 mL). After extraction and washing with
a saturated solution of sodium hydrogencarbonate and brine,
the organic layer was concentrated and the residue was
purified by flash chromatography on silica gel, eluting with
ethyl acetate/hexanes 1:1, to give 14a (160 mg, 75%) as an
oil. The same procedure was applied to 12b/13a ,b (1 g, 1.65
mmol) to give 14b/15a ,b (800 mg, 75%). For 14a : [R]D -6.5 (c
1
1.0, CHCl3); H NMR (CDCl3) δ 7.48-7.11 (m, 20H), 5.7 (br,
1H), 5.15 (t, 1H, J ) 10.5 Hz), 4.90 (d, 1H, J ) 9.3 Hz), 4.78
(d, 2H, J ) 10.8 Hz), 4.67-4.60 (m, 4H), 4.55 (d, 1H, J ) 12.0
Hz), 4.41-4.36 (m, 2H), 4.02 (t, 1H, J ) 9.6 Hz), 3.94-3.90
(m, 4H), 3.78 (dd, 1H, J ) 2.0, 11.2 Hz), 2.09 (s, 3H); 13C NMR
(CDCl3) δ 176.2, 138.2, 137.6, 137.5, 134.6, 129.8-126.9, 79.4,
79.0 (d, J ) 13.5 Hz), 78.7, 75.4 (d, J ) 2.0 Hz), 75.3, 74.6,
73.4, 68.2 (d, J ) 9.9 Hz), 54.8 (d, J ) 132.2 Hz), 54.2 (d, J )
6.8 Hz), 20.3; 31P NMR (CDCl3) (H3PO4 in CDCl3 external
reference δ 0.0 ppm) δ 20.5; HRMS calcd for C36H41NO8P (M+)
646.25696, found 646.25850. For 14b, 15a ,b: 1H NMR (CDCl3)
δ 7.43-7.22 (m, 20H), 4.90-4.55 (m, 9H), 4.35-4.0 (m, 3H),
3.92 3.90 3.78 (3d, total 3H, J ) 11.0, 10.7 and 10.8 Hz), 2.09
(3s, total 3H); 13C NMR (CDCl3) δ 176.2, 176.1, 176.0, 138.0-
137.2, 128.8-127.6, 79.5, 79.4, 78.9, 78.7, 78.4, 76.6, 76.5, 76.4,
76.3, 75.7, 75.2, 74.4, 74.0, 73.9, 73.7, 73.6, 73.5, 73.4, 73.3,
72.7, 69.4 (d, J ) 6.9 Hz), 68.9 (d, J ) 8.2 Hz), 68.7 (d, J ) 9.7
Hz), 61.2 (d, J ) 142.3 Hz), 57.1 (d, J ) 140.5 Hz), 56.5 (d,
J ) 139.1 Hz), 53.4 (d, J ) 5.4 Hz), 52.7 (d, J ) 7.0 Hz), 52.3
(d, J ) 6.4 Hz), 20.3, 20.2, 20.1; 31P NMR (CDCl3) (H3PO4 in
3-Aceta m id o-2,5,6,7-tetr a -O-ben zyl-2-d eoxy-4-O-(m eth -
yloxa lyl)-1-d im eth yl ph osp h on yl-D-er yth r o-L-ma n n o-h ep -
titol (21) a n d 3-Aceta m ido-2,5,6,7-tetr a -O-ben zyl-2-deoxy-
4-O-(m et h yloxa lyl)-1-d im et h ylp h osp h on yl-D-er yth r o-L-
glu co-h ep t it ol (22). A stream of O3/O2 was passed into a

Synthesis of Glycophostones
J . Org. Chem., Vol. 65, No. 9, 2000 2673
cooled solution of 20 (450 mg, 0.67 mmol) in dichloromethane
(20 mL) at -78 °C until the color turned blue (15 min). The
solution was purged with nitrogen (10 min) and evaporated
to give a foam, which was suspended in glacial acetic acid (20
mL), and trimethyl phosphite (400 µL, 5 equiv) was added.
The reaction was stirred at room temperature (24 h) and
concentrated, and the residue was purified by flash chroma-
tography on silica gel, eluting with ethyl acetate/hexanes 4:1,
to give 21 (279 mg) and 22 (185 mg) as syrups for an overall
yield of 85%. For 21: [R]D +1.4 (c 1.9, CHCl3); 1H NMR (CDCl3)
δ 7.41-7.06 (m, 20H), 6.44 (d, 1H, J ) 8.7 Hz), 5.47 (dd, 1H,
J ) 2.8, 10.1 Hz), 5.38 (dd, 1H, J ) 6.2, 24.7 Hz), 4.96 (d, 1H,
J ) 9.9 Hz), 4.65 (d, 1H, J ) 11.0 Hz), 4.56 (d, 2H, J ) 10.2
Hz), 4.44-4.37 (m, 4H), 4.28 (d, 1H, J ) 9.9 Hz), 4.12-4.07
(m, 2H), 3.88 (d, 3H, J ) 10.2 Hz), 3.75 (d, 3H, J ) 10.2 Hz),
3.73 (s, 3H), 3.72-3.56 (m, 3H), 1.58 (s, 3H); 13C NMR (CDCl3)
δ 172.9, 157.3, 157.2, 137.9, 137.5, 137.1, 128.4-127.6, 79.4,
76.8 (d, J ) 3.1 Hz), 74.5, 74.4, 73.1, 72.3, 72.0, 67.1, 66.3 (d,
J ) 170.5 Hz), 54.0 (d, J ) 6.9 Hz), 53.4, 52.5 (d, J ) 7.1 Hz),
52.2 (d, J ) 12.7 Hz), 22.3; 31P NMR (CDCl3) (H3PO4 in CDCl3
nates: 1H NMR (CDCl3) δ 7.63-7.17 (m, 20H), 4.90-3.81 (m,
15H), 3.78 and 3.76 (d, total 3H, POMe minor J ) 11.0 Hz
and POMe major J ) 10.2 Hz), 3.75-3.61 (m, 2H), 1.78 and
1.64 (s, total 3H); 13C NMR (CDCl3) δ 170.3 (minor), 170.1
(maj), 138.4-137.7, 128.9-127.7, 80.9 (minor), 80.5 (major),
77.2, 75.1, 74.7, 74.5, 73.9, 73.3, 73.3, 72.3, 71.0 (d, J ) 143
Hz), 67.6 (minor), 67.4 (major), 54.1 (d, J ) 6.9 Hz), 54.0 (d,
J ) 6.5 Hz), 52.2 (major), 50.9 (minor), 23.4 (major), 23.3
(minor); 31P NMR (CDCl3) (H3PO4 in CDCl3 external reference
δ 0.0 ppm) δ 23.9 and 19.8 (ratio 2:5); HMRS calcd for C38H45
-
NO9P (M+) 690.28190, found 690.28320.
5-Acetam ido-4-O-ben zyl-5-deoxy-6-[(1S,2S)-1,2,3-tr iben -
zyloxyp r op yl]-L-lyxo-(2R)-m eth oxy-1,2λ5-oxa p h osp h or i-
n a n -2-on e (26). Phenyl thiochloroformate (3 equiv, 50 µL) was
added to a solution of compound 23 (50 mg, 0.072 mmol) and
DMAP (5 equiv, 45 mg) in dry acetonitrile (10 mL). After the
mixture was stirred for 16 h at room temperature, water (1
mL) was added and the mixture stirred for a further 30 min.
Ethyl acetate (20 mL) was added, and the organic phase was
washed with 5% sodium hydrogen carbonate (2 × 10 mL) and
hydrochloric acid 1 N (10 mL), dried (sodium sulfate), and
filtered. The solvent was evaporated to give a yellow solid. The
solid was dissolved in dry toluene, and then AIBN (0.1 equiv,
2 mg) and tributyltin hydride (3 equiv, 60 µL) were added.
The mixture was stirred for 2 h at 110 °C. The solvent was
evaporated, acetonitrile (15 mL) added, and the solution
washed with hexanes (15 mL). After concentration of the layer,
the residue was purified by flash chromatography on silica gel,
eluting with ethyl acetate/hexanes 3:2, to give 26 as a syrup
(30 mg, 65%): [R]D -7.5 (c 0.7, CHCl3); 1H NMR (CDCl3) δ
7.57-7.13 (m, 20H, arom.), 5.13 (d, 1H, J ) 9.7 Hz), 4.83-
4.31 (m, 10H), 4.00-3.93 (m, 1H), 3.89-3.85 (m, 1H), 3.80-
3.69 (m, 2H), 3.75 (d, 3H, J ) 9.4 Hz), 3.64 (dd, 1H, J ) 4.0,
11.3 Hz), 2.59-2.49 (m, 1H), 2.04-1.84 (m, 1H), 1.86 (s, 3H);
13C NMR (CDCl3) δ 170.1, 138.0, 137.9, 137.8, 137.5, 128.6-
127.6, 75.8, 75.1, 75.0, 74.5, 74.2, 73.3, 72.7, 70.7, 67.7, 53.0
(d, J ) 6.5 Hz), 51.3, 27.6 (d, J ) 120.7 Hz), 23.6; 31P NMR
(CDCl3) (H3PO4 in CDCl3 external reference δ 0.0 ppm) δ 26.6;
HMRS calcd for C38H45NO8P (M+) 674.28827, found 674.28660.
5-Acetam ido-4-O-ben zyl-5-deoxy-6-[(1S,2S)-1,2,3-tr iben -
zyloxyp r op yl]-L-lyxo-(2S)-m eth oxy-1,2λ5-oxa p h osp h or i-
n a n -2-on e (27). Phenyl thiochloroformate (3 equiv, 50 µL) was
added to a solution of compound 24 (50 mg, 0.072 mmol) and
DMAP (5 equiv, 45 mg) in dry acetonitrile (10 mL). After the
mixture was stirred for 16 h at room temperature, water (1
mL) was added and the mixture stirred for a further 30 min.
Ethyl acetate (20 mL) was then added and the organic phase
washed with 5% sodium hydrogen carbonate (2 × 10 mL) and
hydrochloric acid 1 N (10 mL), dried (sodium sulfate), and
filtered. The solvent was evaporated to give a yellow solid that
was dissolved in dry toluene and heated for 2 h at 110 °C with
AIBN (0.1 equiv, 2 mg) and tributyltin hydride (3 equiv, 60
µL). The solvent was evaporated, acetonitrile (15 mL) was
added, and the solution was washed with hexanes (15 mL).
After concentration of the layer, the residue was purified by
flash chromatography on silica gel, eluting with ethyl acetate/
hexanes 3:2 gave 27 as a syrup (30 mg, 65%): [R]D -34.4 (c
external reference δ 0.0 ppm) δ 26.8; HMRS calcd for C42H51
-
NO13P (M+) 808.30981, found 808.31130. For 22: [R]D +9.0 (c
1
0.8, CHCl3); H NMR (CDCl3) δ 7.39-7.17 (m, 20H), 6.05 (d,
1H, J ) 9.4 Hz), 5.49 (dd, 1H, J ) 3.1, 9.4 Hz), 4.88 (d, 1H,
J ) 10.2 Hz), 4.70-4.62 (m, 3H), 4.53-4.47 (m, 4H), 4.13-
4.07 (m, 2H), 3.79 (d, 3H, J ) 10.5 Hz), 3.77 (d, 3H, J ) 10.5
Hz), 3.73 (s, 3H), 3.63 (dd, 1H, J ) 3.5, 10.4 Hz), 3.28 (t, 1H,
J ) 10.2 Hz), 1.71 (s, 3H); 13C NMR (CDCl3) δ 170.9, 157.5,
157.2, 137.8, 137.7, 137.2, 128.7-127.6, 78.6, 75.1, 74.9 (d,
J ) 4.5 Hz), 74.8, 74.1, 73.5, 73.2, 72.4, 67.9 (d, J ) 161.8
Hz), 67.8, 53.7 (d, J ) 7.7 Hz), 53.3, 53.0 (d, J ) 7.2 Hz), 52.2
(d, J ) 10.4 Hz), 23.0; 31P NMR (CDCl3) (H3PO4 in CDCl3
external reference δ 0.0 ppm) δ 24.8; HMRS calcd for C41H51
-
NO13P (M+) 808.30981, found 808.31130.
5-Acetam ido-4-O-ben zyl-5-deoxy-6-[(1S,2S)-1,2,3-tr iben -
zyloxyp r op yl]-L-glu co-(2R/S)-m eth oxy-1,2λ5-oxa p h osp h o-
r in a n -2-on e (23) a n d (24). A quantity of 21 (200 mg, 0.25
mmol) was dissolved in THF (10 mL), and sodium hydroxide
1 N (800 µL) was added dropwise. After 10 min, the solution
was poured into hydrochloric acid 1 N (10 mL) and chloroform
(20 mL). The organic solution was dried (sodium sulfate),
filtered, and concentrated. The residue was purified by flash
chromatography on silica gel, eluting with ethyl acetate/
hexanes 3:2, to give 23 (80 mg) and 24 (45 mg) as syrups for
1
an overall yield of 75%. For 23: [R]D +6.4 (c 2.1, CHCl3); H
NMR (CDCl3) δ 7.41-7.23 (m, 20H), 5.28 (d, 1H, J ) 9.2 Hz),
4.73 (d, 1H, J ) 11.0 Hz), 4.65-4.39 (m, 1H), 3.79-3.73 (m,
4H), 3.75 (d, 3H, J ) 10.9 Hz), 3.62 (dd, 1H, J ) 3.5, 10.9 Hz),
1.79 (s, 3H); 13C NMR (CDCl3) δ 170.3, 138.2, 137.9, 137.8,
137.0, 128.6-127.5, 79.3, 76.5, 74.9 (d, J ) 8.5 Hz), 74.6, 74.0,
73.3, 72.7, 71.2, 67.8, 64.1 (d, J ) 146.2 Hz), 55.3 (d, J ) 7.3
Hz), 46.7, 23.5; 31P NMR (CDCl3) (H3PO4 in CDCl3 external
reference δ 0.0 ppm) δ 19.9; HMRS calcd for C38H45NO9P (M+)
690.28480, found 690.28320. For 24: [R]D -5.6 (c 2.2, CHCl3);
1H NMR (CDCl3) δ 7.36-7.22 (m, 20H, arom.), 5.32 (d, 1H,
J ) 7.5 Hz), 4.93 (d, 1H, J ) 10.5 Hz), 4.67 (d, 1H, J ) 11.6
Hz), 4.61 (s, 2H), 4.54-4.50 (m, 4H), 4.41-4.37 (m, 2H), 4.16-
4.13 (m, 1H), 3.95-3.85 (m, 3H), 3.77 (dd, 1H, J ) 2.5, 11.0
Hz), 3.64-3.60 (m, 1H), 3.54 (d, 3H, J ) 10.5 Hz), 1.72 (s, 3H);
13C NMR (CDCl3) δ 170.9, 138.2, 138.0, 137.9, 137.4, 128.9-
127.3, 77.3, 76.4, 75.0, 74.2 (d, J ) 8.4 Hz), 73.2, 73.0, 71.9,
71.6, 68.0, 63.2 (d, J ) 145.9 Hz), 52.2 (d, J ) 6.9 Hz), 48.7,
23.4; 31P NMR (162 MHz, CDCl3) (H3PO4 in CDCl3 external
reference δ 0.0 ppm) δ 20.4; HMRS calcd for C38H45NO9P (M+)
690.28480, found 690.28320.
1
0.8, CHCl3); H NMR (CDCl3) δ 7.45-7.13 (m, 20H), 4.84 (d,
1H, J ) 8.5 Hz), 4.71-4.65 (m, 2H), 4.62 (d, 2H, J ) 4.5 Hz),
4.58-4.50 (m, 4H), 4.36 (d, 1H, J ) 11.7 Hz), 4.09 (td, 1H,
J ) 2.6, 9.5 Hz), 3.89 (s, 2H), 3.85-3.67 (m, 3H), 3.55 (d, 3H,
J ) 10.8 Hz), 2.47-2.38 (m, 1H), 1.91-1.78 (m, 1H), 1.77 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 138.0, 137.9, 137.8,
137.5, 128.6-127.6, 77.3, 74.8, 74.2, 73.3, 71.8, 71.0, 67.4, 52.9,
51.5 (d, J ) 6.4 Hz), 27.9 (d, J ) 120.6 Hz), 23.5; 31P NMR
(CDCl3) (H3PO4 in CDCl3 external reference δ 0.0 ppm) δ 24.8;
HMRS calcd for C38H45NO8P (M+) 674.28827, found 674.28660.
5-Acetam ido-4-O-ben zyl-5-deoxy-6-[(1S,2S)-1,2,3-tr iben -
zyloxyp r op yl]-L-lyxo-(2R)-h yd r oxy-1,2λ5-oxa p h osp h or i-
n a n -2-on e (28). The deoxygenation of 25 (50 mg, 0.074 mmol)
gave an inseparable mixture of 26 and 27 that was dissolved
in dichloromethane (10 mL), and trimethylsilyl bromide (5
equiv, 145 µL) was added. The solution was stirred overnight
at room temperature with protection from atmospheric mois-
ture. Water (50 µL) was added, and the solution was stirred
5-Acetam ido-4-O-ben zyl-5-deoxy-6-[(1S,2S)-1,2,3-tr iben -
zyloxyp r op yl]-L-m a n n o-(2R/S)-m et h oxy-1,2λ5-oxa p h os-
p h or in a n -2-on e (25). A quantity of 22 (200 mg, 0.25 mmol)
was dissolved in THF (10 mL), and sodium hydroxide 1 N (800
µL) was added dropwise. After 10 min, the solution was poured
into hydrochloric acid 1 N (10 mL) and chloroform (20 mL).
The organic layer was dried (sodium sulfate), filtered, and
concentrated. The residue was purified by flash chromatog-
raphy on silica gel, eluting with ethyl acetate/hexanes 3:2, to
give 25 (125 mg, 75%) as an inseparable mixture of phospho-

2674 J . Org. Chem., Vol. 65, No. 9, 2000
Hanessian and Rogel
for 30 min. After concentration, the residue was purified by
precipitation (ethyl acetate/pentane) to give 28 (46 mg, 95%)
as an amorphous powder: [R]D -10.0 (c 1.0, CHCl3); mp 120-
122 °C; 1H NMR (CDCl3) δ 7.50-7.14 (m, 20H), 4.70-4.63 (m,
3H), 4.59-4.56 (m, 4H), 4.49-4.46 (m, 2H), 4.33 (t, 1H, J )
4.9 Hz), 3.88-3.84 (m, 3H), 3.70 (dd, 1H, J ) 3.1, 10.7 Hz),
2.63-2.53 (m, 1H), 1.95 (s, 3H), 1.89-1.79 (m, 1H); 13C NMR
(CDCl3) δ 173.5, 78,4, 78.1, 76.7 (d, J ) 8.3 Hz), 76.0, 75.6,
74.3, 73.6, 72.1, 68.9, 52.6, 30.3 (d, J ) 119.7 Hz), 23.1; 31P
NMR (CDCl3) (H3PO4 in CDCl3 external reference δ 0.0 ppm)
δ 18.6; HMRS calcd for C37H43NO8P (M+) 660.27264, found
660.27430.
(s, 3H), 1.89-1.84 (m, 1H); 13C NMR (CD3OD) δ 176.7, 79.2
(d, J ) 5.7 Hz), 72.9, 71.5 (d, J ) 9.2 Hz), 70.5, 66.6, 56.1,
53.9 (d, J ) 6.8 Hz), 33.0 (d, J ) 122.9 Hz), 24.4; 31P NMR
(CD3OD) (H3PO4 in CD3OD external reference δ 0.0 ppm) δ
27.9; HMRS calcd for C10H21NO8P (M+) 314.10049, found
314.09860.
5-Aceta m id o-5-d eoxy-6-[(1S,2S)-1,2,3-tr iben zyloxyp r o-
p yl]-L-lyxo-(2R)-h yd r oxy-1,2λ5-oxa p h osp h or in a n -2-on e
(Sia lop h oston e) (31). A solution of 28 (13 mg, 0.02 mmol) in
methanol (3 mL) was hydrogenated in the presence of 10 mg
of palladium hydroxide on carbon (Degussa) at 60 psi over-
night. The solution was filtered over Celite and evaporated to
give 31 after precipitation as an amorphous powder (6 mg,
5-Aceta m id o-5-d eoxy-6-[(1S,2S)-1,2,3-tr iben zyloxyp r o-
p yl]-L-lyxo-(2R)-m et h oxy-1,2λ5-oxa p h osp h or in a n -2-on e
(29). A solution of 26 (65 mg, 0.01 mmol) in methanol (3 mL)
was hydrogenated in the presence of 20 mg of palladium
hydroxide on carbon (Degussa) at 60 psi overnight. The
solution was filtered over Celite and evaporated to give 29 as
an amorphous powder (30 mg, quantitative): [R]D -7.5 (c 0.7,
1
quantitative): [R]D -7.0 (c 0.3, MeOH); mp 178-180 °C; H
NMR (CD3OD) δ 4.11-4.08 (m, 1H), 3.98-3.91 (m, 1H), 3.88-
3.82 (m, 1H), 3.80-3.75 (m, 2H), 3.62 (q, 1H, J ) 5.5 Hz), 3.45
(d, 1H, J ) 7.5 Hz), 2.23 (t, 1H, J ) 17.5 Hz), 2.02 (s, 3H),
1.76-1.72 (m, 1H); 13C NMR (CD3OD) δ 174.8, 75.0, 70.9, 70.1,
65.0, 55.2, 34.2 (d, J ) 120.4 Hz), 22.7; 31P NMR (CD3OD) (H3-
PO4 in CD3OD external reference δ 0.0 ppm) δ 20.7; HMRS
calcd for C9H18NO8P (M+) 300.08484, found 300.08410.
1
MeOH); mp 118-120 °C; H NMR (CD3OD) δ 4.34 (ddd, 1H,
J ) 1.1, 2.9, 10.6 Hz), 4.10-4.05 (m, 1H), 3.96 (t, 1H, J ) 10.3
Hz), 3.83-3.73 (m, 1H), 3.82 (d, 3H, J ) 11.3 Hz), 3.66-3.58
(m, 2H), 3.54 (ddd, 1H, J ) 1.1, 4.0 and 9.3 Hz), 3.29-3.27
(m, 1H), 2.00 (s, 3H), 1.99-1.86 (m, 1H); 13C NMR (CD3OD) δ
176.6, 78.3, 72.5, 71.9 (d, J ) 9.1 Hz), 70.3, 66.6, 56.4, 55.9,
33.0 (d, J ) 120.9 Hz), 24.4; 31P NMR (CD3OD) (H3PO4 in CD3-
OD external reference δ 0.0 ppm) δ 29.4; HMRS calcd for
Ack n ow led gm en t. We thank NSERCC for general
financial assistance through the Medicinal Chemistry
Chair. We thank Dr. Dale Kempf (Abbott Laboratories)
and his staff for the neuraminidase enzyme inhibitor
studies. We are grateful to Dr. Michel Simard for the
X-ray structural analysis. We thank Nicolas Moitessier,
Se´bastien Martinez, and Linda C. Miller for assistance
in the cover art work.
C
10H21NO8P (M+) 314.10049, found 314.09960.
5-Aceta m id o-5-d eoxy-6-[(1S,2S)-1,2,3-tr iben zyloxyp r o-
p yl]-L-lyxo-(2S)-m et h oxy-1,2λ5-oxa p h osp h or in a n -2-on e
(30). A solution of 27 (65 mg, 0.01 mmol) in methanol (3 mL)
was hydrogenated in the presence of 20 mg palladium hydrox-
ide on carbon (Degussa) at 60 psi overnight. The solution was
filtered over Celite and evaporated to give 30 as an amorphous
powder (30 mg, quantitative): [R]D -34.4 (c 0.8, MeOH); mp
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and 31P
NMR spectra for 6, 7, 10, 12a , 14a , 16-19, 23, 24, and 26-
31 and the X-ray crystal structure data for 10. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
130-132 °C; H NMR (CD3OD) δ 4.22 (ddd, 1H, J ) 1.0, 2.8
and 10.3 Hz), 4.01-3.86 (m, 2H), 3.75 (d, 3H, J ) 10.9 Hz),
3.77-3.72 (m, 1H), 3.69-3.54 (m, 3H), 2.51-2.42 (m, 1H), 1.99
J O991696L