Reductive fragmentation of carbohydrate anomeric alkoxy radicals. Synthesis of alditols with potential utility as chiral synthons

Article abstract of DOI:10.1021/jo0156565

A series of anomeric nitrate esters and N-phthalimido glycosides of carbohydrates in furanose and pyranose forms have been synthesized in order to generate the corresponding alkoxy radicals and study the C1-C2 fragmentation reaction under reductive conditions. This reaction constitutes a two-step method for the transformation of carbohydrates into the corresponding alditols with one less carbon. Using this methodology, interesting four- and five-carbon building blocks for natural products synthesis possessing D-erythritol, D-threitol, D-xylitol, and D-arabinitol stereochemistry have been prepared. The synthesis of 1,2-?-isopropylidene-β-L-threose (40) and 1-acetamido-2,4,5-tri-?-acetyl-D-arabinitol (50) have also been achieved from 1,2:5,6-di-?-isopropylidene-β-D-glucofuranose and 2-acetamido-3,4,6-tri-?-acetyl-2-deoxy-D-glucopyranose, respectively.

Full text of DOI:10.1021/jo0156565

J . Org. Chem. 2001, 66, 6967-6976
6967
Red u ctive F r a gm en ta tion of Ca r boh yd r a te An om er ic Alk oxy
Ra d ica ls. Syn th esis of Ald itols w ith P oten tia l Utility a s Ch ir a l
Syn th on s
Cosme G. Francisco,† Elisa I. Leo´n,† Angeles Mart´ın,† Pilar Moreno,† Mar´ıa S. Rodr´ıguez,‡ and
Ernesto Sua´rez*,†
Instituto de Productos Naturales y Agrobiologı´a del CSIC, Carretera de La Esperanza 3,
38206-La Laguna, Tenerife, Spain, and Departamento de Qu´ımica Orga´nica, Universidad de La Laguna,
Tenerife, Spain
esuarez@ipna.csic.es
Received March 30, 2001
A series of anomeric nitrate esters and N-phthalimido glycosides of carbohydrates in furanose and
pyranose forms have been synthesized in order to generate the corresponding alkoxy radicals and
study the C1-C2 fragmentation reaction under reductive conditions. This reaction constitutes a
two-step method for the transformation of carbohydrates into the corresponding alditols with one
less carbon. Using this methodology, interesting four- and five-carbon building blocks for natural
products synthesis possessing D-erythritol, D-threitol, D-xylitol, and D-arabinitol stereochemistry
have been prepared. The synthesis of 1,2-O-isopropylidene-â-L-threose (40) and 1-acetamido-2,4,5-
tri-O-acetyl-D-arabinitol (50) have also been achieved from 1,2:5,6-di-O-isopropylidene-â-D-gluco-
furanose and 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucopyranose, respectively.
The preparation of chiral synthons from carbohydrates
has received considerable attention from organic chem-
ists.1 Among them, homochiral erythritol2 and threitol3
derivatives are important four-carbon building blocks for
natural product synthesis. Two characteristics of these
compounds are of special interest from the synthetic point
of view: the related alcohols in the chiral threitols are
homotopic groups due to the C2 axis of symmetry,3a,d,h and
meso-erythritol can be transformed into chiral derivatives
by appropriate desymmetrization.4,2c,e,h This last feature
is of interest when an enantiodivergent synthesis is
planned since, in this case, the related alcohols are
enantiotopic groups.
anomeric alcohols with hypervalent iodine reagents in
the presence of iodine.5 Presumably, the reaction proceeds
through an alkyl hypoiodite intermediate.6 The alkoxy
radical subsequently undergoes a â-fragmentation to give
a C2 radical, which in the great majority of cases is
oxidized with an excess of the reagent to an oxycarbe-
nium ion (Scheme 1, path a).5f This ion may participate
in a number of inter- and intramolecular reactions to give
modified carbohydrates with one less carbon.5
An alternative approach to this alkoxy radical frag-
mentation (ARF) was then considered, and it was envi-
sioned that if the generation of the alkoxy radical is
achieved under reductive conditions, the reaction may
have different synthetic possibilities (Scheme 1, path b).
In previous papers from this laboratory, we have
described the facile formation of glycopyran-1-O-yl and
glycofuran-1-O-yl radicals by reaction of carbohydrate
(3) (a) Mukaiyama, T.; Suzuki, K.; Yamada, T. Chem. Lett. 1982,
929-932. (b) Abushanab, E.; Bessodes, M.; Antonakis, K. Tetrahedron
Lett. 1984, 25, 3841-3844. (c) Metz, P.; Schoop, A. Tetrahedron 1993,
49, 10597-10608. (d) Adam, G.; Seebach, D. Synthesis 1988, 373-
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L.; Theophanides, T. Can. J . Chem. 1993, 71, 880-885. (f) Somfai, P.
Tetrahedron 1994, 50, 11315-11320. (g) Somfai, P. J . Chem. Soc.,
Perkin Trans. 1 1995, 817-819. (h) Taunton, J .; Collins, J . L.;
Schreiber, S. L. J . Am. Chem. Soc. 1996, 118, 10412-10422. (i) Pierce,
M. E.; Harris, G. D.; Islam, Q.; Radesca, L. A.; Storace, L.; Waltermire,
R. E.; Wat, E.; J adhav, P. K.; Emmett, G. C. J . Org. Chem. 1996, 61,
444-450. (j) Kang, S. H.; Choi, H. J . Chem. Soc., Chem. Commun.
1996, 1521-1522. (k) Kanger, T.; Niidas, P.; Mu¨u¨risepp, A.-M.; Pehk,
T.; Lopp, M. Tetrahedron: Asymmetry 1998, 9, 2499-2508. (l) Robbins,
M. A.; Devine, P. N.; Oh, T. Org. Synth. 1999, 76, 101-109. (m) Ghosh,
A. K.; Wang, Y. Tetrahedron 1999, 55, 13369-13376. (n) Tuyet, T. M.
T.; Harada, T.; Hashimoto, K.; Hatsuda, M.; Oku, A. J . Org. Chem.
2000, 65, 1335-1343.
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A. Synlett 1994, 95-104. See also: Kinugasa, M.; Harada, T.; Oku, A.
J . Am. Chem. Soc. 1997, 19, 9067-9068. Kinugasa, M.; Harada, T.;
Oku, A. Tetrahedron Lett. 1998, 39, 4529-4532.
(5) (a) Armas, P.; Francisco, C. G.; Sua´rez, E. Angew. Chem., Int.
Ed. Engl. 1992, 31, 772-774. (b) Armas, P.; Francisco, C. G.; Sua´rez,
E. J . Am. Chem. Soc. 1993, 115, 8865-8866. (c) Herna´ndez, R.; Leo´n,
E. I.; Moreno, P.; Sua´rez, E. J . Org. Chem. 1997, 62, 8974-8975. (d)
Francisco, C. G.; Freire, R.; Gonza´lez, C. C.; Sua´rez, E. Tetrahedron:
Asymmetry 1997, 8, 1971-1974. (e) Francisco, C. G.; Mart´ın, C. G.;
Sua´rez, E. J . Org. Chem. 1998, 63, 2099-2109. (f) Francisco, C. G.;
Mart´ın, C. G.; Sua´rez, E. J . Org. Chem. 1998, 63, 8092-8093.
(6) Courtneidge, J . L.; Lusztyk, J .; Page´, D. Tetrahedron Lett. 1994,
35, 1003-1006.
† Instituto de Productos Naturales y Agrobiolog´ıa.
‡ Universidad de La Laguna.
(1) (a) Bols, M. Carbohydrate Building Blocks; J ohn Wiley and
Sons: New York, 1996. (b) Collins, P.; Ferrier, R. J . Monosaccharides.
Their Chemistry and Their Roles in Natural Products; J ohn Wiley and
Sons: New York, 1995. (c) Monneret, C.; Florent, J .-C. Synlett 1994,
305-318. (d) Ferrier, R. J .; Middleton, S. Chem. Rev. 1993, 93, 2779-
2831. (e) Lichtenthaler, F. W. In Modern Synthetic Methods 1992;
Scheffold, R., Ed.; Verlag Helvetica Chimica Acta-VCH: Basel-
Weinheim, 1992; pp 273-376. (f) Inch, T. D. Tetrahedron 1984, 40,
3161-3213. (g) Hanessian, S. Total Synthesis of Natural Products. The
Chiron Approach; Pergamon Press: Oxford, 1983. (h) Vasella, A. In
Modern Synthetic Methods 1980; Scheffold, R., Ed.; Salle & Sauer-
la¨nder Verlag: Frankfurt, 1980 (i) Fraser-Reid, B.; Anderson, R. C.
Prog. Chem. Org. Nat. Prod. 1980, 39, 1-61. For a general review on
carbon synthons, see: Scott, J . W. In Asymmetric Synthesis; Morrison,
J . D., Ed.; Academic Press: New York, 1984; Vol. 4, pp 1-226.
(2) (a) Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.;
Mikkilineni, A. B.; Wu, D. C.-J .; Saibaba, R.; Panzica, R. P. J . Org.
Chem. 1988, 53, 2598-2602. (b) Le Merre, Y.; Gravier-Pelletier, C.;
Dumas, J .; Depezay, J . C. Tetrahedron Lett. 1990, 31, 1003-1006. (c)
Bestmann, H. J .; Philipp, U. C. Angew. Chem., Int. Ed. Engl. 1991,
30, 86-88. (d) Pottie, M.; Van der Eycken, J .; Ro¨per, H.; Vandewalle,
M. Tetrahedron: Asymmetry 1991, 2, 329-330. (e) Pottie, M.; De
Lathauwer, G.; Vandewalle, M. Bull. Soc. Chim. Belg. 1994, 103, 285-
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10.1021/jo0156565 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/18/2001

6968 J . Org. Chem., Vol. 66, No. 21, 2001
Francisco et al.
Sch em e 1
Sch em e 2a
At the time this work was initiated, several methods to
prepare alcohol derivatives, precursors of alkoxy radicals,
under these conditions were available. However, it soon
became apparent that most of them, although very
efficient to generate the O-radical, were unsuitable from
a preparative point of view. Thus, hypohalogenites,7
nitrite esters,8 O-arylsulfenates,9 and N-alkoxypyridine-
2(1H)-thiones10 were in general too unstable to be of any
practical use. We decided that anomeric nitrate esters
were at least in these primary steps of the study the only
possible solution to this problem.11 Since the work of
Binkley and Koholic, nitrate esters11f have been used as
alkoxy radical promoters under tri-n-butyltin hydride/
AIBN conditions. Moreover, we were encouraged because
at least two examples of anomeric nitrate esters (2,3,4,5-
tetra-O-acetyl-1-O-nitro-D-glucopyranose12 and 1,2:5,6-
di-O-isopropylidene-1-O-nitro-D-mannofuranose13) were
known at that time, and they seem to have substantial
stability and can be easily handled at room temperature.
Subsequently, we have also used N-phthalimido glyco-
sides to generate anomeric alkoxy radicals. The reduction
of N-alkoxyphthalimides with tri-n-butyltin hydride/
AIBN to give alcohols has been described previously.14
It is also known that N-acyloxyphthalimides can be
transformed into alkyl chlorides by photosensitized chlo-
rodecarboxylation15 or into alkanes by reduction with tri-
n-butyltin hydride/AIBN.16 Both reactions occur through
an O-radical intermediate.
a
Key: (a) Ac2O, fuming HNO3, 0 °C; (b) Ac2O, py, rt; (c) H2,
Pd/C, EtOAc, rt; (d) tBuMe2SiCl, imidazole, DMF, rt; (e) tBuPh2SiCl,
imidazole, DMF, rt, 1 h, 88%; (f) Ac2O, py, N,N-(dimethylami-
no)pyridine, rt, 2 h, 92%.
Resu lts a n d Discu ssion
Here, we report on an application of the ARF meth-
odology under reductive conditions to carbohydrates that
is particularly effective for the synthesis of alditols having
one less carbon. The necessary glycopyran-1-O-yl and
glycofuran-1-O-yl radicals are generated by reaction of
1-O-nitro and 1-O-phthalimido derivatives of carbohy-
drates with tri-n-butyltin hydride in the presence of
AIBN. In previous communications, we described the
preliminary results obtained,17 and we now disclose
herein the full details of these experiments. The scope of
the reaction was tested in substrates of the pentose and
hexose series of carbohydrates, both in pyranose and
furanose forms as depicted in Schemes 2 and 3.
(7) (a) Walling, C. Bull. Soc. Chim. Fr. 1968, 1609-1615. (b)
Walling, C.; Clark, R. T. J . Am. Chem. Soc. 1974, 96, 5430-4534.
(8) Barton, D. H. R.; Beaton, J . M.; Geller, L. E.; Pechet, M. M. J .
Am. Chem. Soc. 1961, 83, 4076-4083.
(9) (a) Beckwith, A. L. J .; Hay, B. P.; Williams, G. M. J . Chem. Soc.,
Chem. Commun. 1989, 1202-1203. (b) Pasto, D. J .; Cottard, F.
Tetrahedron Lett. 1994, 35, 4303-4306.
(10) (a) Beckwith, A. L. J .; Hay, B. P. J . Am. Chem. Soc. 1988, 110,
4415-4416. (b) Hay, B. P.; Beckwith, A. L. J . J . Org. Chem. 1989, 54,
4330-4334.
(11) (a) Batsanov, A. S.; Begley, M. J .; Fletcher, R. J .; Murphy, J .
A.; Sherburn, M. S. J . Chem. Soc., Perkin Trans. 1 1995, 1281-1294.
(b) Begley, M. J .; Fletcher, R. J .; Murphy, J . A.; Sherburn, M. S. J .
Chem. Soc., Chem. Commun. 1993, 1723-1725. (c) Hussain, N.;
Morgan, D. O.; White, C. R.; Murphy, J . A. Tetrahedron Lett. 1994,
35, 5069-5072. (d) Vite, G. D.; Fraser-Reid, B. Synth. Commun. 1988,
18, 1339-1342. (e) Lo´pez, J . C.; Alonso, R.; Fraser-Reid, B. J . Am.
Chem. Soc. 1989, 111, 6471-6473. (f) Binkley, R. W.; Koholic, D. J . J .
Org. Chem. 1979, 44, 2047-2048. (g) Binkley, R. W.; Koholic, D. J . J .
Carbohydr. Chem. 1984, 3, 85-106. (h) Easton, C. J .; Ivory, A. J .;
Smith, C. A. J . Chem. Soc., Perkin Trans. 2 1997, 503-507. (i) Robins,
M. J .; Guo, Z.; Samano, M. C.; Wnuk, S. F. J . Am. Chem. Soc. 1999,
121, 1425-1433.
Syn t h esis of Nit r a t e E st er s. Although tetra-O-
acetyl-1-O-nitro-D-glucopyranose has been known since
1901,12b the preparation of other 1-O-nitrocarbohydrate
derivatives is limited to a few examples.13,18 Reports on
their exploitation as synthetic intermediates are also
(15) (a) Okada, K.; Okamoto, K.; Oda, M. J . Am. Chem. Soc. 1988,
110, 8736-8738. (b) Okada, K.; Okamoto, K.; Oda, M. J . Chem. Soc.,
Chem. Commun. 1989, 1636-1637.
(12) For a dated review on sugar nitrates, see: (a) Honeyman, J .;
Morgan, J . W. W. Adv. Carbohydr. Chem. 1957, 12, 117-135. (b)
Koening, W.; Knorr, E. Chem. Ber. 1901, 34, 957, 4343.
(13) (a) Honeyman, J .; Stening, T. C. J . Chem. Soc. 1958, 537-541.
(b) Boigegrain R.-A.; Castro, B.; Gross, B. Bull. Soc. Chim. Fr. 1974,
2623-2627.
(16) Barton, D. H. R.; Blundell, P.; J aszberenyi, J . Cs. Tetrahedron
Lett. 1989, 30, 2341-2344.
(17) (a) Francisco, C. G.; Leo´n, E. I.; Moreno, P.; Sua´rez, E.
Tetrahedron: Asymmetry 1998, 9, 2975-2978. (b) Mart´ın, A.; Rod-
r´ıguez, M. S.; Sua´rez, E. Tetrahedron Lett. 1999, 40, 7525-7528.
(14) Kim, S.; Lee, T. A.; Song, Y. Synlett 1998, 471-472.

Fragmentation of Carbohydrate Anomeric Alkoxy Radicals
J . Org. Chem., Vol. 66, No. 21, 2001 6969
Sch em e 3a
Ta ble 1. Syn th esis of Ald itols by Alk oxy Ra d ica l
F r a gm en ta tion of An om er ic Nitr a te Ester sa
a
t
Key: (a) BuPh2SiCl, imidazole, DMF, rt; (b) Ac2O, fuming
HNO3, 0 °C; (c) PPh3, I2, imidazole, PhH, reflux, 10 min, 95%; (d)
NaCN, DMSO, rt, overnight, 58%; (e) NaOMe, MeOH, -15 °C, 4
h, 86%.
rather scarce in the literature.19 The conditions used for
the synthesis of nitrate esters from alcohols are rather
harsh, mixtures of nitric and sulfuric acids and nitric acid
or dinitrogen pentoxide in chloroform often being em-
ployed. In this paper, we have demonstrated that ano-
meric alcohols of carbohydrates can easily be converted
into the corresponding nitrate esters by a simple modi-
fication of the method of Honeyman, fuming nitric acid
in acetic anhydride. Under these reaction conditions,
acid-sensitive protecting groups such as isopropylidene,
tert-butyldimethylsilyl or tert-butyldiphenylsilyl ethers
survive and yields of 60-80% are normally obtained, the
1-O-acetyl derivative is the only side product observed.
On the other hand, this reagent is not compatible with
easily oxidized or highly acid-sensitive substrates such
as benzyl, p-methoxybenzyl, and sensitive silyl ethers.
The starting alcohols 1, 5, 7, 15, and 19 were prepared
from readily available carbohydrates using well-estab-
lished methods as shown in Scheme 2. The nitrate esters
2, 16, and 20 were synthesized using the above-
mentioned methodology in the yields stated in Table 1
(entries 1, 4, and 5). These compounds are stable enough
to be purified by quick chromatography and stored in the
refrigerator. Nitrate esters 8 and 10 were unstable,
although they can be purified by chromatography with
substantial loss of material by hydrolysis (Table 1, entries
2 and 3). Nitrate 21 is a known stable compound
prepared by nitration of 2,3:5,6-di-O-isopropylidene-D-
mannofuranose13 (Table 1, entry 6).
a
The reactions were performed in dry PhH at reflux temper-
b
ature under nitrogen. mmol of n-Bu3SnH per mmol of substrate.
c Method A. Method B. e Pure compound 8 was used. f Crude
d
compound 10 was used.
nitration gave the nitrate ester 24 in 93% yield as a
mixture of anomers with a ratio of 1:3. The 5-cyanoribo-
furanoside 29 was prepared from alcohol 25,5e after
iodination of the primary alcohol, treatment with NaCN
in DMSO, deprotection of the anomeric alcohol and
nitration. Compound 30, obtained in a single step from
oxidative degradation of 1,2:5,6-di-O-isopropylidene-D-
glucofuranose,21 was nitrated analogously at the hemi-
acetal alcohol to give nitrate ester 31 in good yield.
Alk oxy Ra d ica l F r a gm en ta tion Rea ction fr om
Nitr a te Ester s. The ARF methodology was applied to
carbohydrate derivatives of the pentose and hexose series
in pyranose or furanose form as can be observed in Table
1. The optimization of the reaction conditions was
established with readily accessible D-ribofuranosyl nitrate
2. A good yield of D-erythritol derivative 32 (89%) was
To further test the scope and stereoselectivity of the
ARF reaction, we prepared a number of nitrate esters of
compounds possessing modified carbohydrate skeletons
(Scheme 3). Disilylation with tert-butyldiphenylsilyl chlo-
ride and imidazole of the known triol 2220 followed by
(18) (a) Kno¨chel, A.; Rudolph, G. Tetrahedron Lett. 1974, 3739-
3740. (b) Roland, A.; Quivoron, C. Bull. Soc. Chim. Fr. 1985, 1107-
1114.
(19) Illarionov, P. A.; Torgov, V. I.; Hancock, I. C.; Shibaev, V. N.
Tetrahedron Lett. 1999, 40, 4247-4250.
(20) (a) Armas, P.; Francisco, C. G.; Sua´rez, E. Tetrahedron Lett.
1993, 34, 7331-7334. (b) Ho, P.-T. Tetrahedron Lett. 1978, 19, 1623-
1626. (c) Ho, P.-T. Can. J . Chem. 1979, 57, 381-383, 384-386.
(21) Berges, D. A.; Ridges, M. D.; Dalley, N. K. J . Org. Chem. 1998,
63, 391-392.

6970 J . Org. Chem., Vol. 66, No. 21, 2001
Francisco et al.
Ta ble 2. Alk oxy Ra d ica l F r a gm en ta tion of
obtained when the reaction was carried out with tri-n-
butyltin hydride (9 mmol) and AIBN (0.4 mmol) per mmol
of 2 at reflux temperature in dry benzene under nitrogen
(method A). The ratio between formate and hydrolyzed
alcohol 32a /32b was 1:4. The addition of pyridine (1
mmol) increased the overall ARF reaction yield to 95%
and avoided formate hydrolysis, the 32a /32b ratio now
being approximately 4:1 (method B) (Table 1, entry 1).
A number of reaction conditions were explored including
decreasing the tri-n-butyltin hydride rate or increasing
the amount of pyridine but all gave distinctly inferior
results.
Ca r boh yd r a te w ith Mod ified Sk eleton sa
The use of meso-erythritol derivatives that have be-
come asymmetric by substitution has attracted consider-
able attention from synthetic organic chemists as four
carbon chiral synthons in enantiodivergent synthesis.4
Taking this observation into account, we have prepared
L-arabinopyranosyl nitrates 8 and 10 in order to prepare
homochiral erythritol derivatives 33 and 34 with a very
different substitution pattern from that of 32.
The reaction proceeded in good yield when pure chro-
matographed nitrate 8 was used as starting material
(Table 1, entry 2), although, due to instability of the
nitrate upon exposure to silica gel, the best overall yield
(42%, two steps) of the fragmented compounds 33 was
obtained by using crude 8 prepared immediately prior
to use. A similar situation was observed during the ARF
reaction of tert-butyldimethylsilyl ether 10, the overall
yield using crude nitrate being 51% (Table 1, entry 3). It
is worth mentioning that, in some experiments, partial
racemization of alcohol 33b was detected. This process
was probably due to a base- or acid-catalyzed transes-
terification reaction during the isolation or purification
steps. To clarify the reaction mechanism, we performed
hydrolysis of formate ester 33a under various conditions
and then analyzed the enantiomeric purity of the 33b
obtained in each case by converting it into its Mosher’s
ester.22 The hydrolysis of formate 33a with NaHCO3 in
MeOH at 0 °C led to 33b (42%) with total racemization.
When a solution of 33a in wet MeOH was refluxed
overnight, the optical purity of the alcohol 33b obtained
was determined to be 54% ee. Notwithstanding, the
alcohol 33b was obtained with 100% ee when the later
experiment was modified by the use of recently dried
MeOH.
a
The reactions were performed in dry PhH at reflux temper-
b
ature under nitrogen using method A. mmol of n-Bu3SnH per
mmol of substrate. c Arabinitol derivative 38c (13%) is also
obtained.
This feature may be of practical interest when the
required alditols need further chemical transformations.
The fragmentation reaction of compound 20 was realized
under the conditions of method B, adding to the solution
of n-Bu3SnH/AIBN an equimolecular amount of pyridine.
The reaction in the absence of base (method A) deserves
some comment. Under these conditions a new alcohol 36c
is formed by intramolecular transesterification. The
structures of alcohols 36b,c were determined by NMR
spectra, including DEPT, COSY, HMBC and HMQC
experiments which permit unambiguous assignment of
carbons and hydrogens. The transesterification mecha-
nism was confirmed since both compounds 36a and 36b
were transformed into 36c when heated under reflux in
wet MeOH.
A 2-C-branched-chain sugar nitrate 24 was used to
investigate the stereoselectivity of the ARF reaction
(Table 2, entry 1). The fragmentation-reduction of the
C1-C2 bond proceeded preferentially with retention of
configuration through the more stable transition state
to give the D-xylitol derivative 38a ,b (83%). The less
stable diastereoisomeric 1,5-di-O-(tert-butyldiphenyl)silyl-
2-O-formyl-3,4-O-isopropylidene-D-arabinitol (38c)23 was
also obtained in 13% yield (dr, 6.7:1). The disposition
trans (xylitol derivative) or cis (arabinitol derivative) of
the two protons of the dioxolane ring was determined by
intramolecular NOE experiments. Irradiation of H3 in
the 1H NMR spectrum of the D-arabinitol derivative 38c23
D-Threitol derivatives 35, which are also important
four-carbon chiral synthons,3 can be obtained by reduc-
tive fragmentation of the 1-O-nitro-D-xylofuranose de-
rivative 16 as shown in entry 4 of Table 1.
To investigate further the scope of this reaction, we
extended our studies to encompass carbohydrates of the
hexose series (Table 1, entries 5 and 6). Thus, D-
glucopyranosyl nitrate 20 and D-mannofuranosyl nitrate
21 were transformed into the D-arabinitol derivatives 36
and 37, respectively, in excellent yields. This is an
example of the potential interest of this reaction in the
preparation of chiral synthons or chiral auxiliaries; two
D-arabinitol derivatives possessing very different protec-
tion patterns were synthesized from easily accessible
carbohydrates. As can be observed, the position of the
readily hydrolyzable formate group depends only on the
furanose or pyranose form of the starting carbohydrate.
(23) Arabinitol derivative 38c obtained from the ARF reaction of
nitrate 24.
(22) (a) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512-
519. (b) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.

Fragmentation of Carbohydrate Anomeric Alkoxy Radicals
J . Org. Chem., Vol. 66, No. 21, 2001 6971
Ta ble 3. Syn th esis of Ald itols by Alk oxy Ra d ica l
enhanced the H4 proton by 7%. Moreover, no NOE
interaction was observed between the H2 and H3 protons
in the spectrum of the D-xylitol derivative 38a .
F r a gm en ta tion of N-P h th a lim id o Glycosid esa
The 5-cyano-D-ribofuranoside 29 was synthesized with
the goal of obtaining polyhydroxylated cyclopentanones
by eventual intramolecular radical cyclization (Table 2,
entry 2).24 Unfortunately, 29 completely failed to undergo
the desired ring closure upon treatment with n-Bu3SnH/
AIBN under various conditions. The sole product that
could be isolated from these attempts was the 4-cyano-
4-deoxy-D-erythritol derivative 39. The best yield (83%)
was achieved under the conditions summarized in Table
2. The high concentration of the reducing reagent neces-
sary for the ARF reaction to take place apparently reduce
the C2 radical before the cyclization reaction occurs. The
reaction was also applied to the nitrate ester of a non
anomeric hemiacetal, the dialdose 31, as a method for
the synthesis of 1,2-O-isopropylidene-â-L-threose (40), an
interesting chiral building block in synthetic organic
chemistry (Table 2, entry 3).25 The reaction proceeded
smoothly in 96% yield and may be one of the best
protocols for the preparation of L-threose, requiring only
three steps from the readily accessible and inexpensive
1,2:5,6-di-O-isopropylidene-D-glucofuranose in 55% over-
all yield.
Alk oxy Ra d ica l F r a gm en ta tion Rea ction fr om
N-P h th a lim id o Glycosid es. Although the ARF reac-
tions described in Tables 1 and 2 proceeded satisfactorily
in high yields, the formation of nitrate esters presents
two major drawbacks: the incompatibility of the nitrating
system with easily oxidized or highly acid-sensitive
substrates and the instability observed in some cases.
Thus, for example, nitrates 8 and 10 are easily hydro-
lyzed and substantial loss of material occurs during the
isolation and purification steps (Table 1, entries 2 and
3). Some useful protective groups in carbohydrate chem-
istry are oxidized or hydrolyzed under these conditions
(e.g. benzyl, p-methoxybenzyl, and sensitive silyl ethers).
For example, we were unable to synthesize the nitrate
ester of 2,3,4,6-tetra-O-benzyl-D-glucopyranose using this
methodology. All this experimental evidence suggests
that at least in some cases a more stable alkoxy radical
precursor would be desirable. Therefore, an alternative
and complementary approach to this methodology was
explored using N-phthalimido glycosides. These com-
pounds can be easily prepared by two general methods,
from the corresponding alcohol and N-hydroxyphthalim-
ide under Mitsunobu conditions26 and from alkyl halides
by displacement with the sodium salt of N-hydroxyph-
thalimide.14 To prepare phthalimido glycosides we have
used the Mitsunobu protocol as previously described.
a
The reactions were performed in dry PhH at reflux temper-
ature under nitrogen containing n-Bu3SnH (9 mmol) and AIBN
(0.1 mmol) per mmol of substrate. After the reaction was
b
completed, imidazole was added and the mixture stirred at 80 °C
for 1.5 h. After this, the reaction mixture was cooled to room
temperature and more imidazole (4 mmol) and tBuPh2SiCl (2
mmol) were added. The mixture was stirred for 1 h at this
temperature. NPht- ) phthalimido.
derivative 32 (Table 3, entry 1) was obtained in a
somewhat lower yield compared to the fragmentation of
nitrate ester 2 (Table 1, entry 1). The carbonate 42 was
prepared in order to study the effect of a stronger
electron-withdrawing group at C2 that should decrease
the electron density at this position (Table 3, entry 2).5f
A significantly better yield of the ARF reaction is
obtained as compared to the fragmentation of the 2,3-
isopropylidene derivative 41 (Table 3, entry 1). The
preparation of the D-erythritol derivative 34 is better
accomplished using this methodology (Table 3, entry 3)
than that of the nitrate ester (Table 1, entry 3). The
stable N-phthalimido L-arabinofuranoside 44 is more
conveniently purified and handled than its homologous
unstable nitrate 10, and consequently, the yield can be
substantially improved. The ARF of the 2-deoxy-D-
The results of the ARF reaction using the system
n-Bu3SnH/AIBN are outlined in Table 3. The D-erythritol
(24) (a) Tanner, D. D.; Rahimi, P. M.; J . Org. Chem. 1979, 44, 1674-
1677. (b) Clive, D. L. J .; Beaulieu, P. L.; Set, L. J . Org. Chem. 1984,
49, 1313-1314.
(25) (a) Dhavale, D. D.; Tagliavini, E.; Trombini, C.; Umani-Ronchi,
A. Tetrahedron Lett. 1988, 29, 6163-6166. (b) Smith, A. B.; Sulikowski,
G. A.; Sulikowski, M. M.; Fujimoto, K. J . Am. Chem. Soc. 1992, 114,
2567-2576. (c) Blackburn, G. M.; Rashid, A. J . Chem. Soc., Chem.
Commun. 1988, 317-319. (d) Wei, C. C.; De Bernardo, S.; Tengi, J .
P.; Borgese, J .; Weigele, M. J . Org. Chem. 1985, 50, 3462-3467.
(26) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Grochowski, E.;
J urczak, J . Synthesis 1976, 682-684. (c) J urczak, J .; Grochowski, E.
In International Symposium on Phosphorus Chemistry Directed To-
wards Biology; Burzenin, Poland, 1979; Stec, W. J ., Ed.; Franklin Book
Company: Philadelphia, 1980; p 54. (d) Grochowski, E.; Nashed, E.
M.; J urczak, J . Bull. Pol. Acad. Sci. Chem. 1987, 35, 255-260.

6972 J . Org. Chem., Vol. 66, No. 21, 2001
Francisco et al.
in H2SO4-EtOH (4:1) and further heating until development
of color. Fuming nitric acid 100% (d ) 1.52) was purchased
from Fluka.
ribopyranose derivative 45 gave a volatile mixture of the
expected alcohol and formate which was hydrolyzed in
situ with imidazole and subsequently treated with tert-
butyldiphenylsilyl chloride to give the 1-deoxy-D-eryth-
ritol derivative 46 in order not to lose material during
the workup and purification steps.
Gen er a l P r oced u r e for th e Syn th esis of th e Nitr a te
Ester s. A vigorously stirred solution of the alcohol (1 mmol)
in Ac2O (0.6 mL, 6.5 mmol) was treated with a solution of
fuming nitric acid 100% (0.3 mL, 7.5 mmol) in Ac2O (0.3 mL,
3.2 mmol) at 0 °C for 35-60 min (CAUTION: keep solutions
of nitric acid and Ac2O below room temperature; otherwise,
vigorous exothermic decomposition may occur. Although when
this precaution was observed the reactions occurred without
incident, the use of a protective shield and a good hood is
recommended). The reaction was quenched with a cooled
saturated solution of NaHCO3 and extracted with CH2Cl2. The
organic phase was washed with water, dried over Na2SO4, and
concentrated under reduced pressure. The obtained residue
was purified by chromatography under the conditions specified
in each case. Full details of physical properties and spectro-
scopic data for compounds 2, 8, 16, 20, 21, 24, 29, and 31 are
given in the Supporting Information.
Gen er a l P r oced u r e for th e Syn th esis of N-P h th a l-
im id o Glycosid es. DEAD (4 mmol) was added dropwise to a
stirred solution of the alcohol (1 mmol), N-hydroxyphthalimide
(4 mmol), and PPh3 (4 mmol) in dry THF (11 mL), and the
resulting solution was stirred at 0 °C for 1-2.5 h. The reaction
was quenched with water and extracted with CHCl3. The
combined extracts were dried over Na2SO4 and concentrated
under reduced pressure. The residue obtained was purified by
chromatography under the conditions specified in each case.
Full details of physical properties, and spectroscopic data for
compounds 41, 42, 44, 45, 47, 49, and 51 are given in the
Supporting Information.
N-Phthalimido D-glucosides 47 and 49 were prepared
since all attempts to generate the homologous nitrate
esters failed completely (Table 3, entries 5 and 6). Tetra-
O-benzyl-D-arabinitol (48) was obtained in good yield but
1-acetamido-2,4,5-tri-O-acetyl-1-deoxy-D-arabinitol (50)
was formed only in 47% yield. The only feasible mecha-
nism for the formation of compound 50 involves the
complete hydrolysis of the formate group and a subse-
quent intramolecular transesterification from the acetate
at C3 to the alcohol at C4. The process is similar to that
observed in the case of compound 36 (Table 1, entry 5).
The complete hydrolysis of the formate, produced during
the relatively long reaction time required for its comple-
tion, permits the acetyl transesterification. These side
reactions are most likely responsible for the low yield
observed. The 5-O-phthalimido-R-D-xylo-pentodialdo-1,4-
furanose 51 was prepared in order to check the Mit-
sunobu reaction with a nonanomeric alcohol. The two
isomeric N-phthalimido derivatives 51-R and 51-S were
separately submitted to the ARF reaction, and the
L-threose 40 was obtained in similar yields (Table 3, entry
7).
Gen er a l P r oced u r e for th e Alk oxy Ra d ica l F r a gm en -
ta tion Rea ction . Meth od A. A solution of nitrate or N-
phthalimide glycoside (1 mmol) in dry benzene (10-17 mL)
was heated to reflux with n-Bu3SnH (7-9 mmol) and AIBN
(0.2-0.4 mmol) for 1-5 h. After being cooled to room temper-
ature, the solution was concentrated under reduced pressure.
Two procedures were used to remove tin salts: (a) The reaction
residue was treated with a saturated solution of potassium
fluoride in CH3CN, stirred for 20 min, and filtered over Celite
and the filtrate concentrated under reduced pressure. (b) The
residue was dissolved in CH3CN and washed with n-hexane,
and the combined more polar extracts were concentrated under
reduced pressure. The residue obtained was purified by
chromatography under the conditions specified in each case.
Meth od B. To a stirred solution of the nitrate (1 mmol) in
dry benzene (10-16 mL) were added under nitrogen n-Bu3-
SnH (6-9 mmol), AIBN (0.2-0.4 mmol), and dry pyridine (1
mmol), and the mixture was heated to reflux for 0.5-4 h.
Workup as in method A.
In conclusion, this ARF reaction permits the prepara-
tion of alditols with one carbon less from carbohydrates
under reductive mild conditions. This is a convenient
procedure for the synthesis of chiral polyhydroxylated
four- and five-carbon building blocks for organic synthe-
sis. The protocol proved to be extremely versatile, adapt-
able to a variety of carbohydrate skeletons, and compat-
ible with numerous protective groups. The relative
position of the readily hydrolyzable formyl group depends
only on the pyranose or furanose form of the starting
carbohydrate and may be very convenient when further
transformations are required. Although precautions have
to be taken with the use of HNO3/Ac2O mixtures,
specially in scaled-up reactions (see general procedure),
the nitrate method seems to us cheaper and more
straightforward and is recommended when the ester is
stable. Notwithstanding, the N-phthalimide glycoside
methodology is more generally applicable.
4-O-(ter t-Bu tyld im eth yl)silyl-3-O-for m yl-1,2-O-isop r o-
p ylid en e-D-er yth r itol (32a ) a n d 4-O-(ter t-Bu tyld im eth yl)-
silyl-1,2-O-isop r op ylid en e-D-er yth r itol (32b). Following
the general procedure (method A), a solution of nitrate 2 (100
mg, 0.286 mmol) in dry benzene (3 mL) was heated to reflux
with n-Bu3SnH (702 µL, 2.61 mmol) and AIBN (20 mg, 0.12
mmol) for 4 h. Chromatotron chromatography (hexanes-
EtOAc, 9:1) gave the formate 32a (16 mg, 0.05 mmol, 17%)
and the alcohol 32b (59.2 mg, 0.21 mmol, 72%). Compound
32a : oil; [R]D -23.2 (c ) 0.108); IR 2931, 1725, 1182 cm-1; 1H
NMR 0.03 (6H, s), 0.86 (9H, s), 1.33 (3H, s), 1.38 (3H, s), 3.75
(1H, dd, J ) 11.5, 5.0 Hz), 3.84 (1H, dd, J ) 11.5, 3.3 Hz),
3.89 (1H, dd, J ) 8.6, 6.3 Hz), 4.03 (1H, dd, J ) 8.6, 6.5 Hz),
4.25 (1H, ddd, J ) 6.1, 6.1, 6.1 Hz), 5.03 (1H, ddd, J ) 5.3,
5.3, 3.4 Hz), 8.11 (1H, s); 13C NMR (50.3 MHz) -5.5 (2 × CH3),
18.2 (C), 25.2 (CH3), 25.7 (3 × CH3), 26.4 (CH3), 62.0 (CH2),
65.9 (CH2), 74.1 (CH), 74.8 (CH), 109.3 (C), 160.4 (CH); MS
m/z (rel intensity) (FAB) 305 (M+ + H, 31), 289 (M+ - CH3,
54), 247 (100); HRMS calcd for C13H25O5Si 289.1471, found
289.1452. Anal. Calcd for C14H28O5Si: C, 55.23; H, 9.27.
Found: C, 55.10; H, 9.22. Compound 32b: oil; [R]D -1.3 (c )
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined with
a hot-stage apparatus and are uncorrected. Optical rotations
were measured at the sodium line at ambient temperature in
CHCl3 solutions. IR spectra were recorded in CHCl3 solutions
unless otherwise stated. NMR spectra were determined at 500
MHz for 1H and 125.7 MHz for 13C in CDCl3 unless otherwise
stated, in the presence of TMS as internal standard. Mass
spectra were determined at 70 eV. Merck silica gel 60 PF
(0.063-0.2 mm) were used for column chromatography. Cir-
cular layers of 1 mm of Merck silica gel 60 PF254 were used on
a Chromatotron for centrifugally assisted chromatography.
Commercially available reagents and solvents were analytical
grade or were purified by standard procedures prior to use.27
All reactions involving air- or moisture-sensitive materials
were carried out under a nitrogen atmosphere. The spray
reagents for TLC analysis were conducted with 0.5% vanillin
0.08); IR 3563, 2931, 1256 cm-1 1H NMR 0.08 (6H, s), 0.90
;
(9H, s), 1.34 (3H, s), 1.40 (3H, s), 2.50 (1H, d, J ) 5.0 Hz),
3.59 (1H, m), 3.66 (1H, dd, J ) 10.1, 5.4 Hz), 3.78 (1H, dd, J
(27) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: New York, 1988.

Fragmentation of Carbohydrate Anomeric Alkoxy Radicals
J . Org. Chem., Vol. 66, No. 21, 2001 6973
) 10.1, 3.6 Hz), 3.96-4.29 (2H), 4.07 (1H, dd, J ) 11.9, 5.9
Hz); 13C NMR -5.5 (2 × CH3), 18.2 (C), 25.2 (CH3), 25.8 (3 ×
CH3), 26.6 (CH3), 63.9 (CH2), 66.7 (CH2), 72.3 (CH), 75.6 (CH),
109.0 (C); MS m/z (rel intensity) 261 (M+ - CH3, 31), 219 (4),
161 (44), 131 (71); HRMS calcd for C12H25O4Si 261.1522, found
261.1521. Anal. Calcd for C13H28O4Si: C, 56.48; H, 10.21
Found: C, 56.28; H, 10.23. Following the general procedure
(method B), to a stirred solution of the nitrate 2 (100 mg, 0.286
mmol) in dry benzene (3 mL) were added under nitrogen n-Bu3-
SnH (702 µL, 2.61 mmol), AIBN (20 mg, 0.12 mmol) and dry
pyridine (23 µL, 0.29 mmol) and the mixture was heated to
reflux for 4 h. Chromatotron chromatography (hexanes-
EtOAc, 9:1) afforded the formate 32a (65 mg, 0.21 mmol, 79%)
and the alcohol 32b (12.8 mg, 0.05 mmol, 16%).
matotron chromatography (hexanes-EtOAc, 7:3) to obtain the
alcohol 33b (5.6 mg, 0.03 mmol, 64%, 100%ee) and starting
material 33a (3.1 mg, 0.01 mmol, 31%). The enantiomeric
excess of 33b obtained by the different procedures, was
determined by the 1H NMR spectroscopic analysis of the
Mosher esters.
P r ep a r a tion a n d An a lysis of Mosh er Ester s of 33b:
4-O-Acetyl-2,3-O-isopr opyliden e-1-O-[(S)-r-m eth oxyph en -
yl)]a cetyl-D-er yth r itol a n d 1-O-Acetyl-2,3-O-isop r op yli-
den e-4-O-[(S)-r-m eth oxyph en yl)]acetyl-D-er yth r itol. A so-
lution of 33b (2.5 mg, 0.012 mmol), DCC (3.1 mg, 0.015 mmol),
and (S)-(+)-R-methoxyphenylacetic acid (2.3 mg, 0.014 mmol)
in dry CH2Cl2 (0.5 mL) was stirred at room temperature
overnight. The reaction mixture was concentrated under
reduced pressure and purified by chromatotron chromatogra-
phy (hexanes-EtOAc, 7:3) to afford the Mosher esters. Com-
pound 4-O-acetyl-2,3-O-isopropylidene-1-O-[(S)-R-methoxyphe-
nyl)]acetyl-D-erythritol: 1H NMR 1.33 (3H, s), 1.42 (3H, s), 2.06
(3H, s), 3.42 (3H, s), 3.93 (1H, m), 4.16-4.31 (4H), 4.82 (1H,
s). Compound 1-O-acetyl-2,3-O-isopropylidene-4-O-[(S)-R-meth-
oxyphenyl)]acetyl-D-erythritol: 1H NMR 1.34 (3H, s), 1.45 (3H,
s), 2.07 (3H, s), 3.42 (3H, s), 3.94 (1H, m), 4.13-4.31 (4H), 4.81
(1H, s). 1H NMR analysis in CDCl3 at 500 MHz focused on
the isopropylidene methyls that are found in the region 1.33-
1.45 ppm.
4-O-Acetyl-1-O-for m yl-2,3-O-isop r op ylid en e-D-er yth r i-
tol (33a ) a n d 4-O-Acetyl-2,3-O-isop r op ylid en e-D-er yth r i-
tol (33b). Following the general procedure (method B), the
nitrate 8 (25 mg, 0.09 mmol) was dissolved in dry benzene (1.5
mL) and heated to reflux with n-Bu3SnH (0.145 mL, 0.54
mmol), AIBN (2.5 mg, 0.0152 mmol), and dry pyridine (7.3 µL,
0.09 mmol) for 30 min. Chromatotron chromatography (hex-
anes-EtOAc, 95:5 f 92:8) of the residue yielded the formate
33a (15.7 mg, 0.07 mmol, 75%) and the alcohol 33b (3 mg,
0.014 mmol, 16%). Compound 33a : oil; [R]D -3.5 (c ) 1.58);
1
IR 2990, 1730, 1094 cm-1; H NMR 1.39 (3H, s), 1.50 (3H, s),
2.11 (3H, s), 4.12 (1H, dd, J ) 11.7, 6.3 Hz), 4.21 (1H, dd, J )
11.6, 6.4 Hz), 4.27 (1H, dd, J ) 11.7, 4.7 Hz), 4.36 (1H, dd, J
) 11.6, 4.1 Hz), 4.41 (1H, ddd, J ) 6.3, 6.3, 4.7 Hz), 4.43 (1H,
ddd, J ) 6.4, 6.3, 4.1 Hz), 8.10 (1H, s); 13C NMR (50.3 MHz)
20.8 (CH3), 25.2 (CH3), 27.7 (CH3), 61.8 (CH2), 62.3 (CH2), 74.1
(CH), 74.4 (CH), 108.7 (C), 160.4 (CH), 170.6 (C); MS m/z (rel
intensity) 217 (M+ - CH3, 100), 172 (2), 129 (8), 115 (44);
HRMS calcd for C9H13O6 217.0712, found 217.0726. Anal.
Calcd for C10H16O6: C, 51.72; H, 6.94. Found: C, 51.43; H,
7.28. Compound 33b: oil; [R]D +15.2 (c ) 0.56) [lit.2e [R]D +16.6
(c ) 1.0)]; IR 3605, 2936, 1740, 1232 cm-1; 1H NMR 1.36 (3H,
s), 1.47 (3H, s), 1.84 (1H, dd, J ) 6.2, 6.2 Hz), 2.07 (3H, s),
3.67 (1H, ddd, J ) 11.7, 6.2, 6.2 Hz), 3.74 (1H, ddd, J ) 11.7,
6.2, 4.3 Hz), 4.12 (1H, dd, J ) 11.7, 7.2 Hz), 4.26 (1H, dd, J )
11.7, 4.8 Hz), 4.28 (1H, ddd, J ) 7.2, 6.2, 4.3 Hz), 4.36 (1H,
ddd, J ) 7.2, 7.2, 4.8 Hz); 13C NMR 20.7 (CH3), 25.0 (CH3),
27.6 (CH3), 60.9 (CH2), 62.9 (CH2), 74.5 (CH), 77.2 (CH), 109.0
(C), 170.6 (C); MS m/z (rel intensity) 189 (M+ - CH3, 32), 131
(32), 129 (32), 115 (95); HRMS calcd for C8H13O5 189.0763,
found 189.0763. Anal. Calcd for C9H16O5: C, 52.93; H, 7.90.
Found: C, 52.70; H, 8.23. Alternatively the crude nitrate (300
mg) obtained in the previous reaction from compound 5 (300
mg, 1.29 mmol) was dissolved in dry benzene (10 mL) and
heated to reflux with n-Bu3SnH (1.55 mL, 5.76 mmol) and
AIBN (30 mg, 0.18 mmol) for 30 min. Chromatotron chroma-
tography of the residue (hexanes-EtOAc, 95:5 f 92:8) gave
the formate 33a (103.2 mg, 0.445 mmol, 34%), the alcohol 33b
(20.7 mg, 0.101 mmol, 8%), the acetate 9 (41.6 mg, 0.152 mmol,
12%) and alcohol 5 (62.1 mg, 0.268 mmol, 21%).
Hyd r olysis of 4-O-Acetyl-2,3-O-isop r op ylid en e-D-er yth -
r itol (33a ). Meth od A. To a stirred solution of the formate
33a (25 mg, 0.108 mmol) in MeOH (0.5 mL) at 0 °C was added
a solution of sodium bicarbonate (13.4 mg, 0.16 mmol) in
MeOH (1.5 mL). After 3 h at that temperature, the mixture
was neutralized with acid resin (Dowex 50-X), filtered, and
concentrated. The residue was purified by chromatotron
chromatography (hexanes-EtOAc, 8:2 f 6:4) giving the
compounds 33b (9.2 mg, 0.05 mmol, 42%, 0%ee) and 2,3-O-
isopropylideneerythritol 33c (10.2 mg, 0.06 mmol, 58%).
Compound 33c: 1H NMR (200 MHz) 1.37 (3H, s), 1.46 (3H,
s), 2.78 (2H, br s), 3.75-3.80 (4H), 4.27-4.31 (2H). Meth od
B. A solution of the formate 33a (5 mg, 0.02 mmol) in MeOH
Merck (0.2 mL) was heated to reflux overnight. Then the
mixture was concentrated and the residue purified by chro-
matotron chromatography (hexanes-EtOAc, 7:3) to give the
acetyl derivative 33b (3.8 mg, 0.019 mmol, 86%, 54%ee).
Meth od C. A solution of the formate 33a (10 mg, 0.043 mmol)
in dry MeOH (distilled over Na and collected over molecular
sieves 4 Å) (0.43 mL) was heated to reflux for 4 h. Then the
mixture was concentrated and the residue purified by chro-
2-O-(ter t-Bu t yld im et h yl)silyl-3,4-O-isop r op ylid en e-1-
O-n itr o-L-a r a bin op yr a n ose (10). Following the general
procedure, compound 7 (250 mg, 0.82 mmol) in Ac2O (0.5 mL,
5.3 mmol) was treated with a solution of fuming nitric acid
(0.25 mL, 6.2 mmol) in Ac2O (0.25 mL, 2.7 mmol) at 0 °C for
45 min. The crude residue was used in the next reaction
without further purification.
4-O-(ter t-Bu tyld im eth yl)silyl-1-O-for m yl-2,3-O-isop r o-
p ylid en e-D-er yth r itol (34a ) a n d 4-O-(ter t-Bu tyld im eth yl)-
silyl-2,3-O-isop r op ylid en e-D-er yth r itol (34b). Following
the general procedure (method A), the crude 10 (320 mg)
obtained from the previous reaction was dissolved in dry
benzene (13.7 mL) and heated to reflux with n-Bu3SnH (1.78
mL, 6.60 mmol) and AIBN (13.4 mg, 0.082 mmol) for 2 h.
Column chromatography (hexanes-EtOAc, 98:2 f 9:1) af-
forded the formate 34a (82.5 mg, 0.27 mmol, 33%), the alcohol
34b (41 mg, 0.15 mmol, 18%), and the acetate 11 (98.3 mg,
0.28 mmol, 34%) as an anomeric mixture (R:â, 4:1), a byproduct
in the formation of the nitrate 10. Compound 34a : oil; [R]D
-35.0 (c ) 0.98); IR 2932, 1727, 1178 cm-1; 1H NMR 0.08 (6H,
s), 0.90 (9H, s), 1.38 (3H, s), 1.47 (3H, s), 3.68-3.70 (2H), 4.21-
4.25 (2H), 4.43 (1H, ddd, J ) 6.5, 6.5, 3.0 Hz), 4.55 (1H, dd, J
) 11.7, 3.0 Hz), 8.12 (1H, s); 13C NMR (CDCl3, 50.3 MHz) -5.6
(2 × CH3), 18.1 (C), 24.5 (CH3), 25.5 (3 × CH3), 27.8 (CH3),
61.3 (CH2), 63.0 (CH2), 75.1 (CH), 76.4 (CH), 109.1 (C), 160.7
(CH); MS m/z (rel intensity) 289 (M+ - CH3, 13), 247 (4), 229
(4), 219 (1), 189 (18), 143 (100); HRMS calcd for C13H25O5Si
289.1471, found 289.1446. Anal. Calcd for C14H28O5Si: C,
55.23; H, 9.27. Found: C, 55.25; H, 9.57. Compound 34b: oil;
1
[R]D -2.6 (c ) 0.87); IR 3500, 2990, 1167 cm-1; H NMR 0.11
(3H, s), 0.12 (3H, s), 0.91 (9H, s), 1.36 (3H, s), 1.42 (3H, s),
3.00 (1H, dd, J ) 8.4, 5.6 Hz), 3.69 (1H, dd, J ) 10.6, 4.0 Hz),
3.76 (1H, ddd, J ) 11.7, 8.4, 5.8 Hz), 3.78 (1H, dd, J ) 10.6,
6.0 Hz), 3.82 (1H, ddd, J ) 11.7, 5.8, 5.6 Hz), 4.23 (1H, ddd, J
) 6.0, 6.0, 4.0 Hz), 4.35 (1H, ddd, J ) 6.0, 5.8, 5.8 Hz); 13C
NMR (CDCl3, 125.8 MHz) -5.7 (CH3), -5.6 (CH3), 18.1 (C),
25.1 (CH3), 25.7 (3 × CH3), 27.7 (CH3), 60.6 (CH2), 61.5 (CH2),
76.7 (CH), 76.8 (CH), 108.3 (C); MS m/z (rel intensity) 261 (M+
- CH3, 40), 245 (9), 187 (10), 161 (58); HRMS calcd for
C12H25O4Si 261.1522, found 261.1526. Anal. Calcd for C13H28O4-
Si: C, 56.48; H, 10.21. Found: C, 56.31; H, 10.44. Compound
11: white crystalline solid; IR 2931, 1745, 1142 cm-1; 1H NMR
0.09 (3H, s), 0.10 (3H, s), 0.13 (3H, s), 0.15 (3H, s), 0.88 (18H,
s), 1.38 (6H, s), 1.54 (6H, s), 2.11 (6H, s), 3.75 (1H, dd, J )
7.2, 7.2 Hz), 3.88-3.93 (2H), 3.99 (1H, d, J ) 13.2 Hz), 4.05-
4.12 (3H), 4.18 (1H, dd, J ) 6.3, 6.3 Hz), 4.26-4.28 (2H), 5.46
(1H, d, J ) 7.0 Hz), 6.05 (1H, d, J ) 3.5 Hz); 13C NMR (CDCl3,
50.3 MHz) -5.0 (CH3), -4.8 (CH3), -4.7 (CH3), -4.5 (CH3),
17.9 (C), 18.1 (C), 20.9 (2 × CH3) 25.6 (6 × CH3), 25.9 (2 ×
CH3), 27.7 (CH3), 27.8 (CH3), 61.4 (CH2), 63.6 (CH2), 69.9 (2 ×

6974 J . Org. Chem., Vol. 66, No. 21, 2001
Francisco et al.
CH), 72.7 (CH), 72.8 (CH), 75.9 (CH), 79.0 (CH), 91.5 (CH),
92.7 (CH), 109.2 (C), 109.2 (C), 169.2 (C), 170.4 (C); MS m/z
(rel intensity) 331 (M+ - CH3, 9), 289 (3), 287 (11), 229 (15);
HRMS calcd for C15H27O6Si 331.1577, found 331.1561. Anal.
Calcd for C16H30O6Si: C, 55.46; H, 8.73. Found: C, 55.27; H,
8.98.
69.27 (CH), 69.33 (CH), 70.5 (CH), 169.7 (C), 170.2 (C), 170.4
(C); MS m/z (rel intensity) 335 (M+ - C4H9, 8), 275 (24), 259
(2), 215 (6); HRMS calcd for C13H23O8Si 335.1162, found
335.1165. Anal. Calcd for C17H32O8Si: C, 52.02; H, 8.22.
Found: C, 51.88; H, 8.60. Compound 36c: oil; [R]D +9.0 (c )
1
0.20); IR 3550, 2993, 1748, 1140 cm-1; H NMR 0.05 (6H, s),
0.88 (9H, s), 2.02 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 3.01 (1H,
d, J ) 5.6 Hz), 3.77 (1H, dd, J ) 10.9, 5.1 Hz), 3.89 (1H, dd, J
) 10.9, 4.1 Hz), 4.05 (1H, ddd, J ) 9.0, 5.6, 2.0 Hz), 4.16 (1H,
dd, J ) 11.6, 7.4 Hz), 4.39 (1H, dd, J ) 11.6, 5.1 Hz), 4.79
(1H, ddd, J ) 9.0, 5.1, 4.1 Hz), 5.23 (1H, ddd, J ) 7.4, 5.1, 2.0
Hz); 13C NMR -5.7 (CH3), -5.6 (CH3), 18.1 (C), 20.7 (CH3),
20.7 (CH3), 20.8 (CH3), 25.7 (3 × CH3), 62.6 (CH2), 62.9 (CH2),
69.3 (CH), 69.9 (CH), 70.7 (CH), 169.9 (C), 170.2 (C), 170.8
(C); MS m/z (rel intensity) 335 (M+ - C4H9, 12), 275 (24), 233
(6), 215 (6); HRMS calcd for C13H23O8Si 335.1162, found
335.1167. Anal. Calcd for C17H32O8Si: C, 52.02; H, 8.22.
Found: C, 52.01; H, 8.47. Alternatively, and following the
general procedure (method B), nitrate 20 (80 mg, 0.172 mmol)
was dissolved in dry benzene (3 mL) and heated to reflux with
n-Bu3SnH (0.42 mL, 1.548 mmol), AIBN (8 mg, 0.049 mmol),
and dry pyridine (14 µL, 0.172 mmol) for 2 h. Chromatotron
chromatography (hexanes-EtOAc, 95:5 f 92:8) gave the
formate 36a (60.1 mg, 0.14 mmol, 83%) and the alcohol 36b
(7.8 mg, 0.02 mmol, 12%).
1,2-Di-O-acetyl-4-O-(ter t-bu tyldiph en yl)silyl-3-O-for m yl-
D-th r eitol (35a) an d 1,2-Di-O-acetyl-4-O-(ter t-bu tyldiph en -
yl)silyl-D-th r eitol (35b). Following the general procedure
(method A), the nitrate 16 (15 mg, 0.029 mmol) in dry benzene
(0.5 mL) was heated to reflux with n-Bu3SnH (70 µL, 0.261
mmol) and AIBN (2 mg, 0.012 mmol) for 1.5 h. The residue
was purified by chromatotron chromatography (hexanes-
EtOAc, 95:5) giving the formate 35a (8 mg, 0.017 mmol, 58%),
the alcohol 35b (2.1 mg, 0.005 mmol, 16%) and compound 15
(2.6 mg, 0.005 mmol, 19%). Compound 35a : oil; [R]D +17.2 (c
) 0.25); IR 2959, 1732, 1240 cm-1; 1H NMR 1.07 (9H, s), 1.96
(3H, s), 2.00 (3H, s), 4.07 (1H, dd, J ) 11.4, 5.7 Hz), 4.12 (1H,
ddd, J ) 5.7, 4.4, 3.9 Hz), 4.16 (1H, dd, J ) 11.9, 6.6 Hz), 4.21
(1H, dd, J ) 11.4, 3.9 Hz), 4.42 (1H, dd, J ) 11.9, 3.7 Hz),
5.15 (1H, ddd, J ) 6.6, 4.4, 3.7 Hz), 7.38-7.42 (4H), 7.44-
7.48 (2H), 7.68 (4H, d, J ) 6.6 Hz), 7.77 (1H, s); 13C NMR 19.3
(C), 20.6 (CH3), 20.7 (CH3), 26.8 (3 × CH3), 62.0 (CH2), 63.8
(CH2), 69.6 (CH), 71.5 (CH), 127.6 (2 × CH), 127.7 (2 × CH),
129.9 (CH), 130.0 (CH), 132.6 (C), 132.9 (C), 135.7 (4 × CH),
160.2 (CH), 169.2 (C), 170.4 (C) MS m/z (rel intensity) 415 (M+
- C4H9, 52), 327 (6), 309 (5), 267 (19); HRMS calcd for
C21H23O7Si 415.1213, found 415.1204. Anal. Calcd. for C25H32O7-
Si: C, 63.54; H, 6.82. Found: C, 63.66; H, 7.01. Compound
Hyd r olysis of 1,2,3-Tr i-O-a cetyl-5-O-(ter t-bu tyld im eth -
yl)silyl-4-O-for m yl-D-a r a bin itol (36a ). A solution of the
formate 36a (5 mg, 0.01 mmol) in wet MeOH (0.25 mL) was
heated to reflux for 6 h. Then the mixture was concentrated
and the residue purified by chromatotron chromatography
(hexanes-EtOAc, 92:8) to obtain the alcohol 36c (2.1 mg, 0.005
mmol, 45%).
35b: oil; [R]D -18.3 (c ) 0.40); IR 3686, 2962, 1739, 1113 cm-1
;
1H NMR 1.07 (9H, s), 1.71 (3H, s), 2.00 (3H, s), 2.49 (1H, d, J
) 7.3 Hz), 3.81 (1H, dddd, J ) 7.3, 7, 5.6, 3.2 Hz), 3.95 (1H,
ddd, J ) 6.6, 4.6, 3.2 Hz), 4.07 (1H, dd, J ) 11.7, 4.6 Hz), 4.11
(1H, dd, J ) 11.4, 5.6 Hz), 4.12 (1H, dd, J ) 11.7, 6.6 Hz),
4.17 (1H, dd, J ) 11.4, 7.0 Hz), 7.38-7.48 (6H), 7.64 (2H, d, J
) 6.7 Hz), 7.71 (2H, d, J ) 6.7 Hz); 13C NMR (50.3 MHz) 19.4
(C), 20.4 (CH3), 20.8 (CH3), 27.0 (3 × CH3), 65.0 (2 × CH2),
70.2 (CH), 71.0 (CH), 127.5 (2 × CH), 127.89 (2 × CH), 129.8
(CH), 130.2 (CH), 132.2 (C), 133.4 (C), 135.5 (2 × CH), 135.9
(2 × CH), 170.5 (C), 170.9 (C); MS m/z (rel intensity) 429 (M+
- CH3, <1), 387 (10), 327 (14), 267 (56); HRMS calcd for
C23H29O6Si 429.1733, found 429.0798. Anal. Calcd for C24H32O6-
Si: C, 64.84; H, 7.25. Found: C, 64.90; H, 7.39.
Tr a n sester ifica tion of 1,2,3-Tr i-O-a cetyl-5-O-(ter t-bu -
tyld im eth yl)silyl-D-a r a bin itol (36b). A solution of 36b (4.8
mg, 0.012 mmol) in wet MeOH (0.3 mL) was heated to reflux
for 30 min. Then the mixture was concentrated and the residue
purified by chromatotron chromatography (hexanes-EtOAc,
92:8) to give the alcohol 36c (2.6 mg, 0.007 mmol, 54%).
3-O-F or m yl-1,2:4,5-d i-O-isop r op ylid en e-D-a r a b in it ol
(37a ) a n d 1,2:4,5-Di-O-isop r op ylid en e-D-a r a bin itol (37b).
Following the general procedure (method A), to compound 21
(80 mg, 0.26 mmol) in dry benzene (4.3 mL) were added n-Bu3-
SnH (489 µL, 1.82 mmol) and AIBN (10 mg, 0.06 mmol), and
the mixture was heated to reflux for 2 h. Chromatotron
chromatography (hexanes-EtOAc, 95:5 f 92:8) of the residue
gave the formate 37a (39 mg, 0.15 mmol, 58%) and the alcohol
37b (24.5 mg, 0.10 mmol, 38%). Compound 37a : oil; [R]D +19.7
1,2,3-Tr i-O-a cet yl-5-O-(ter t-b u t yld im et h yl)silyl-4-O-
for m yl-D-a r a bin itol (36a ), 1,2,3-Tr i-O-a cetyl-5-O-(ter t-bu -
tyld im eth yl)silyl-D-a r a bin itol (36b), a n d 1,2,4-Tr i-O-a ce-
tyl-5-O-(ter t-bu tyld im eth yl)silyl-D-a r a bin itol (36c). Fol-
lowing the general procedure (method A), nitrate derivative
20 (80 mg, 0.172 mmol) in dry benzene (3 mL) was heated to
reflux with n-Bu3SnH (0.42 mL, 1.548 mmol) and AIBN (8 mg,
0.049 mmol) for 2 h. Chromatotron chromatography (hexanes-
EtOAc, 95:5 f 92:8) of the residue afforded the formate 36a
(23.8 mg, 0.06 mmol, 33%) and the alcohols 36b (16.3 mg, 0.04
mmol, 24%) and 36c (26.3 mg, 0.07 mmol, 39%). Compound
1
(c ) 0.178); IR 3018, 1728, 1175 cm-1; H NMR 1.36 (6H, s),
1.41 (3H, s), 1.43 (3H, s), 3.82 (1H, dd, J ) 8.8, 6.2 Hz), 3.88
(1H, dd, J ) 8.8, 6.2 Hz), 4.07 (1H, dd, J ) 8.8, 6.2 Hz), 4.09
(1H, dd, J ) 8.8, 6.2 Hz), 4.26 (1H, ddd, J ) 6.2, 6.2, 6.2 Hz),
4.34 (1H, ddd, J ) 6.2, 6.2, 4.3 Hz), 5.12 (1H, dd, J ) 6.2, 4.3
Hz), 8.19 (1H, s) 13C NMR 25.2 (CH3), 25.3 (CH3), 26.0 (CH3),
26.5 (CH3), 65.8 (CH2), 66.3 (CH2), 72.6 (CH), 74.6 (CH), 74.7
(CH), 109.6 (2 × C), 160.3 (CH); MS m/z (rel intensity) 245
(M+ - CH3, 71), 187 (100), 141 (10), 127 (11); HRMS calcd for
1
36a : oil; [R]D +30.0 (c ) 0.20); IR 3031, 1744, 1047 cm-1; H
NMR 0.03 (3H, s), 0.02 (3H, s), 0.86 (9H, s), 2.02 (3H, s), 2.05
(3H, s), 2.09 (3H, s), 3.66 (1H, dd, J ) 11.2, 5.2 Hz), 3.76 (1H,
dd, J ) 11.2, 4.1 Hz), 4.00 (1H, dd, J ) 11.8, 6.6 Hz), 4.26
(1H, dd, J ) 11.8, 4.9 Hz), 5.16 (1H, ddd, J ) 7.2, 5.2, 4.1 Hz),
5.38 (1H, ddd, J ) 6.6, 4.9, 3.5 Hz), 5.43 (1H, dd, J ) 7.2, 3.5
Hz), 7.98 (1H, s); 13C NMR -5.7 (2 × CH3), 18.1 (C), 20.5 (2 ×
CH3), 20.6 (CH3), 25.6 (3 × CH3), 61.1 (CH2), 62.0 (CH2), 68.4
(CH), 68.6 (CH), 70.5 (CH), 159.6 (CH), 169.4 (C), 170.0 (C),
170.4 (C); MS m/z (rel intensity) 405 (M+ - CH3, 2), 363 (72),
275 (15), 117 (100); HRMS calcd for C17H29O9Si 405.1581,
found 405.1539. Anal. Calcd for C18H32O9Si: C, 51.41; H, 7.67.
Found: C, 51.10; H, 7.67. Compound 36b: oil; [R]D +26.0 (c )
C
11H17O6 245.1025, found 245.1010. Anal. Calcd for C12H20O6:
C, 55.37; H, 7.74. Found: C, 55.23; H, 7.87. Compound 37b:
1
oil; [R]D -14.3 (c ) 0.21); IR 3560, 2990, 1240, 1154 cm-1; H
NMR 1.36 (3H, s), 1.39 (3H, s), 1.44 (3H, s), 1.45 (3H, s), 2.30
(1H, d, J ) 6.4 Hz), 3.43 (1H, ddd, J ) 7.7, 6.4, 4.3 Hz), 3.92
(1H, dd, J ) 8.2, 6.7 Hz), 3.99 (1H, ddd, J ) 7.7, 5.7, 5.7 Hz),
4.02 (1H, dd, J ) 8.3, 5.7 Hz), 4.09 (1H, dd, J ) 8.2, 6.7 Hz),
4.13 (1H, dd, J ) 8.3, 5.7 Hz), 4.26 (1H, ddd, J ) 6.7, 6.7, 4.3
Hz); 13C NMR 25.1 (CH3), 25.1 (CH3), 26.3 (CH3), 26.6 (CH3),
66.1 (CH2), 67.2 (CH2), 72.5 (CH), 76.0 (CH), 76.1 (CH), 109.2
(C), 109.3 (C); MS m/z (rel intensity) 217 (M+ - CH3, 50), 159
(32), 101 (100); HRMS calcd for C10H17O5 217.1076, found
217.1075. Anal. Calcd for C11H20O5: C, 56.88; H, 8.68. Found:
C, 56.74; H, 8.96.
1
0.20); IR 3548, 2930, 1744, 1372 cm-1; H NMR 0.03 (3H, s),
0.04 (3H, s), 0.87 (9H, s), 2.01 (3H, s), 2.07 (3H, s), 2.09 (3H,
s), 2.70 (1H, d, J ) 2.3 Hz), 3.51 (1H, dd, J ) 10.0, 5.1 Hz),
3.63 (1H, dd, J ) 10.0, 3.4 Hz), 3.68 (1H, dddd, J ) 8.3, 5.1,
3.4, 2.3 Hz), 4.00 (1H, dd, J ) 11.6, 7.0 Hz), 4.25 (1H, dd, J )
11.6, 5.1 Hz), 5.10 (1H, dd, J ) 8.3, 2.9 Hz), 5.50 (1H, ddd, J
) 7.0, 5.1, 2.9 Hz); 13C NMR -5.6 (2 × CH3), 18.2 (C), 20.6 (2
× CH3), 20.7 (CH3), 25.7 (3 × CH3), 62.3 (CH2), 63.0 (CH2),
Hyd r olysis of 3-O-F or m yl-1,2:4,5-d i-O-isop r op ylid en e-
D-a r a bin itol (37a ). A solution of the formate 37a (9.3 mg,
0.036 mmol) in DBU (1 mL, 6.7 mmol) was stirred at room-
temperature overnight. After concentration under reduced
pressure, the residue was purified by chromatotron chroma-

Fragmentation of Carbohydrate Anomeric Alkoxy Radicals
J . Org. Chem., Vol. 66, No. 21, 2001 6975
tography (hexanes-EtOAc, 9:1), giving the alcohol 37b (6.2
mg, 0.03 mmol, 75%).
68.7 (CH), 77.1 (CH), 109.8 (C), 117.4 (C); MS m/z (rel
intensity) 172 (M+ + H, 1), 156 (100), 101 (75); HRMS calcd
for C8H14NO3 172.0974, found 172.0989. Anal. Calcd for C8H13-
1,5-Di-O-(ter t-bu tyld ip h en yl)silyl-4-O-for m yl-2,3-O-iso-
p r op ylid en e-D-xylitol (38a ), 1,5-Di-O-(ter t-bu tyld ip h en -
yl)silyl-2,3-O-isop r op ylid en e-D-xylitol (38b), a n d 1,5-Di-
O-(t er t -b u t yld ip h e n yl)silyl-2-O-for m yl-3,4-O-isop r o-
p ylid en e-D-a r a b in it ol. Following the general procedure
(method A), the nitrate 24 (100 mg, 0.135 mmol) was dissolved
in dry benzene (3 mL) and heated to reflux with n-Bu3SnH
(290 µL, 1.08 mmol) and AIBN (10 mg, 0.06 mmol) for 50 min.
Chromatotron chromatography (hexanes-EtOAc, 98:2 f 95:
5) of the residue gave the formates 1,5-di-O-(tert-butyldiphe-
nyl)silyl-2-O-formyl-3,4-O-isopropylidene-D-arabinitol (12.3 mg,
0.02 mmol, 13%) and 38a (76.5 mg, 0.11 mmol, 81%) and the
alcohol 38b (2.1 mg, 0.003 mmol, 2%). 1,5-Di-O-(tert-butyl-
diphenyl)silyl-2-O-formyl-3,4-O-isopropylidene-D-arabinitol: oil;
[R]D -14.0 (c ) 0.20); IR 2932, 1725, 1113 cm-1; 1H NMR 1.04
(9H, s), 1.07 (9H, s), 1.33 (3H, s), 1.34 (3H, s), 3.68 (1H, dd, J
) 11.3, 5.5 Hz), 3.79 (1H, dd, J ) 11.3, 5.5 Hz), 3.90 (1H, dd,
J ) 11.6, 5.2 Hz), 3.95 (1H, dd, J ) 11.6, 2.5 Hz), 4.26 (1H,
ddd, J ) 5.5, 5.5, 5.5 Hz), 4.44 (1H, dd, J ) 8.4, 5.5 Hz), 5.16
(1H, ddd, J ) 8.4, 5.2, 2.5 Hz), 7.36-7.43 (12H), 7.66-7.70
(8H), 7.80 (1H, s); 13C NMR 19.2 (2 × C), 25.2 (CH3), 26.7 (3 ×
CH3), 26.9 (3 × CH3), 27.3 (CH3), 62.5 (CH2), 63.0 (CH2), 72.6
(CH), 74.0 (CH), 77.6 (CH), 108.6 (C), 127.6-127.7 (8 × CH),
129.7 (4 × CH), 133.1 (2 × C), 133.2 (2 × C), 135.6-135.7 (8
× CH), 160.0 (CH); MS m/z (rel intensity) 681 (M+ - CH3, 4),
NO3: C, 56.13; H, 7.65; N, 8.18. Found: C, 56.46; H, 7.68; N,
7.85. Acetylation of 39 (21 mg, 0.12 mmol) in dry pyridine (1.2
mL, 0.015 mmol) and Ac2O (0.4 mL, 4.2 mmol) at room
temperature for 4 h gave after Chromatotron chromatography
(hexanes-EtOAc, 9:1) 3-O-acetyl-4-cyano-4-deoxy-1,2-O-iso-
propylidene-D-erythritol (24.2 mg, 0.11 mmol, 92%): oil; [R]D
-44.3 (c ) 0.20); IR 2256, 1755, 1061 cm-1; 1H NMR 1.36 (3H,
s), 1.40 (3H, s), 2.11 (3H, s), 2.77 (1H, dd, J ) 17.3, 5.0 Hz),
2.84 (1H, dd, J ) 17.3, 4.4 Hz), 3.78 (1H, dd, J ) 9.0, 4.7 Hz),
4.08 (1H, dd, J ) 9.0, 6.4 Hz), 4.22 (1H, ddd, J ) 7.8, 6.4, 4.7
Hz), 4.84 (1H, ddd, J ) 7.8, 5.0, 4.4 Hz); 13C NMR 19.9 (CH2),
20.7 (CH3), 24.8 (CH3), 26.5 (CH3), 66.5 (CH2), 69.3 (CH), 74.6
(CH), 110.4 (C), 116.0 (C), 169.7 (C); MS m/z (rel intensity)
198 (M+ - CH3, 100), 115 (12), 101 (47); HRMS calcd for C9H12
-
NO4 198.0766, found 198.0772. Anal. Calcd for C10H15NO4: C,
56.33; H, 7.09; N, 6.57. Found: C, 56.37; H, 7.21; N, 6.47.
1,2-O-Isop r op ylid en e-â-L-t h r eose (40). Following the
general procedure (method A), a solution of nitrate 31 (60 mg,
0.23 mmol) in dry benzene (4 mL) was heated to reflux with
n-Bu3SnH (0.56 mL, 2.07 mmol) and AIBN (6 mg, 0.04 mmol)
for 5.5 h. Chromatotron chromatography (hexanes-EtOAc,
7:3) gave the title compound 40 (35 mg, 0.22 mmol, 96%): mp
84-85 °C (from n-hexane); [R]D +13.4 (c ) 0.8); IR 3467, 2993,
1163, cm-1; 1H NMR (200 MHz) 1.32 (3H, s), 1.49 (3H, s), 3.88
(1H, dd, J ) 10.1, 0.8 Hz), 4.10 (1H, dd, J ) 10.1, 2.3 Hz),
4.26 (1H, dd, J ) 2.3, 0.8 Hz), 4.50 (1H, d, J ) 3.6 Hz), 5.96
(1H, d, J ) 3.6 Hz); 13C NMR (CDCl3, 50.3 MHz) 26.2 (CH3),
26.7 (CH3), 72.9 (CH2), 75.2 (CH), 84.9 (CH), 105.2 (CH), 111.8
(C); MS m/z (rel intensity) 159 (M+ - 1, 1), 145 (80), 127 (27),
102 (4), 85 (100); HRMS calcd for C7H11O4 159.065734, found
159.065662. Anal. Calcd for C7H12O4: C, 52.49; H, 7.55.
Found: C, 52.54; H, 7.54.
4-O-(ter t-Bu tyld im eth yl)silyl-3-O-for m yl-1,2-O-isop r o-
p ylid en e-D-er yth r itol (32a ) a n d 4-O-(ter t-Bu tyld im eth yl)-
silyl-1,2-O-isop r op ylid en e-D-er yth r itol (32b). Following
the general procedure (method A), to a solution of 41-R (107
mg, 0.238 mmol) in dry benzene (3.6 mL) were added, under
nitrogen, n-Bu3SnH (0.576 mL, 2.142 mmol) and AIBN (4 mg,
0.024 mmol) and the solution was heated to reflux for 30 min.
Chromatotron chromatography (hexanes-EtOAc, 95:5) af-
forded the formate 32a (30.2 mg, 0.099 mmol, 42%) and the
alcohol 32b (25.6 mg, 0.093 mmol, 39%) identical to those
previously described (vide supra).
4-O-(ter t-Bu t yld im et h yl)silyl-3-O-for m yl-1,2-O-(oxo-
m eth ylen e)-D-er yth r itol (43a ) a n d 4-O-(ter t-Bu tyld im eth -
yl)silyl-3-O-formyl-1,2-O-(oxomethylene)-D-erythritol (43b).
Following the general procedure (method A), to a solution of
the carbonate 42-R (94 mg, 0.216 mmol) in dry benzene (3.24
mL) were added n-Bu3SnH (523 µL, 1.944 mmol) and AIBN
(3.6 mg, 0.022 mmol), and the solution was heated to reflux
for 30 min. Chromatotron chromatography (hexanes-EtOAc,
9:1) afforded the formate 43a (30 mg, 0.103 mmol, 48%) and
the alcohol 43b (28 mg, 0.107 mmol, 49%). Data compound
for 43a and 43b were identical to those given by us previously.5f
4-O-(ter t-Bu tyld im eth yl)silyl-1-O-for m yl-2,3-O-isop r o-
p ylid en e-D-er yth r itol (34a ) a n d 4-O-(ter t-Bu tyld im eth yl)-
silyl-2,3-O-isop r op ylid en e-D-er yth r itol (34b). Following
the general procedure (method A), a solution of the anomeric
mixture 44 (103 mg, 0.229 mmol) in dry benzene (3.4 mL) was
heated to reflux with n-Bu3SnH (554 µL, 2.061 mmol) and
AIBN (3.8 mg, 0.023 mmol) for 30 min. Chromatotron chro-
matography of the residue (hexanes-EtOAc, 95:5) afforded the
formate 34a (45 mg, 0.148 mmol, 64%) and the alcohol 34b
(20 mg, 0.072 mmol, 31%).
639 (6), 581 (8), 535 (33); HRMS calcd for
C40H49O6Si2
681.3068, found 681.3080. Anal. Calcd for C41H52O6Si2: C,
70.65; H, 7.52. Found: C, 70.50; H, 7.64. Compound 38a : oil;
[R]D +13.0 (c ) 0.20); IR 2932, 1732, 1177 cm-1; 1H NMR 1.03
(9H, s), 1.04 (9H, s), 1.33 (3H, s), 1.40 (3H, s), 3.65 (1H, dd, J
) 11.2, 4.0 Hz), 3.80 (1H, dd, J ) 11.2, 4.0 Hz), 3.86 (1H, dd,
J ) 11.5, 7.0 Hz), 3.91 (1H, dd, J ) 11.5, 3.2 Hz), 4.00 (1H,
ddd, J ) 7.0, 4.0, 4.0 Hz), 4.31 (1H, dd, J ) 7.0, 7.0 Hz), 5.16
(1H, ddd, J ) 7.0, 7.0, 3.2 Hz), 7.34-7.43 (12H), 7.64-7.70
(8H), 7.92 (1H, s); 13C NMR 19.17 (C), 19.21 (C), 26.7 (3 × CH3),
26.8 (3 × CH3), 27.1 (2 × CH3), 62.6 (CH2), 63.9 (CH2), 74.7
(CH), 74.8 (CH), 79.5 (CH), 109.7 (C), 127.68-127.73 (8 × CH),
129.7-129.8 (4 × CH), 133.0 (2 × C), 133.1 (2 × C), 135.62-
135.65 (8 × CH), 160.2 (CH); MS m/z (rel intensity) 681 (M+
- CH3, 2), 639 (6), 581 (17), 535 (15); HRMS calcd for C40H49O6-
Si2 681.3068, found 681.3070. Anal. Calcd for C41H52O6Si2: C,
70.65; H, 7.52. Found: C, 70.65; H, 7.49. Compound 38b: oil;
[R]D +10.0 (c ) 0.44); IR 3583, 3071, 1073 cm-1; 1H NMR 1.06
(9H, s), 1.07 (9H, s), 1.33 (3H, s), 1.40 (3H, s), 2.71 (1H, d, J )
5.2 Hz), 3.70 (1H, m), 3.79-3.89 (4H), 4.08-4.13 (2H), 7.36-
7.43 (12H), 7.68-7.72 (8H); 13C NMR (50.3 MHz) 19.2 (C), 19.3
(C), 26.79 (CH3), 26.81 (6 × CH3), 27.2 (CH3), 64.4 (CH2), 65.1
(CH2), 73.5 (CH), 76.4 (CH), 80.6 (CH), 109.2 (C), 127.7 (8 ×
CH), 129.8 (4 × CH), 133.2 (4 × C), 135.6 (8 × CH); MS m/z
(rel intensity) 653 (M+ - CH3, 4), 611 (1), 553 (1), 535 (20);
HRMS calcd for C39H49O5Si2 653.3119, found 653.3113. Anal.
Calcd for C40H52O5Si2: C, 71.81; H, 7.83. Found: C, 72.02; H,
7.90.
Hyd r olysis of 1,5-Di-O-(ter t-bu tyld ip h en yl)silyl-4-O-
for m yl-2,3-O-isop r op ylid en e-D-xylitol (38a ). A solution of
the formate 38a (11.6 mg, 0.017 mmol) in MeOH (0.17 mL)
was heated to reflux overnight. Then the mixture was con-
centrated and the residue purified by chromatotron chroma-
tography (hexanes-EtOAc, 95:5) to give the alcohol 38b (9.8
mg, 0.015 mmol, 88%).
4-Cyan o-4-deoxy-1,2-O-isopr opyliden e-D-er yth r itol (39).
Following the general procedure (method A), to compound 29
(100 mg, 0.41 mmol) in dry benzene (5 mL) was added n-Bu3-
SnH (1 mL, 3.69 mmol) and AIBN (10 mg, 0.061 mmol) and
the mixture was heated to reflux overnight. Chromatotron
chromatography (hexanes-EtOAc, 9:1) afforded the alcohol 39
(58.6 mg, 0.34 mmol, 83%) and the lactol 28 (6 mg, 0.03 mmol,
7%). Compound 39: oil; [R]D +12.1 (c ) 1.0); IR 3612, 2254,
1602, 1068 cm-1; 1H NMR 1.32 (3H, s), 1.39 (3H, s), 2.55 (1H,
dd, J ) 16.9, 7.4 Hz), 2.70 (1H, dd, J ) 16.9, 4.0 Hz), 3.84
(1H, ddd, J ) 7.4, 7.1, 4.0 Hz), 3.94 (1H, dd, J ) 8.4, 4.8 Hz),
3.99 (1H, ddd, J ) 7.1, 6.1, 4.8 Hz), 4.09 (1H, dd, J ) 8.4, 6.1
Hz); 13C NMR 22.9 (CH2), 24.8 (CH3), 26.6 (CH3), 66.2 (CH2),
4-O-(ter t-Bu tyld ip h en yl)silyl-1-d eoxy-2,3-O-isop r op yl-
id en e-D-er yth r itol (46). Following the general procedure
(method A), to a solution of the anomeric mixture 45 (200 mg,
0.627 mmol) in dry benzene (10 mL) were added, under
nitrogen, n-Bu3SnH (1.52 mL, 5.64 mmol) and AIBN (10.3 mg,
0.063 mmol), and the solution was stirred at reflux tempera-
ture for 30 min. Then the mixture was cooled, and imidazole
(85 mg, 1.25 mmol) was added. After the mixture was stirred

6976 J . Org. Chem., Vol. 66, No. 21, 2001
Francisco et al.
for 1.5 h at 80 °C, it was cooled to room temperature, and tert-
butyldiphenylsilyl chloride (326 µL, 1.25 mmol) and more
imidazole (171 mg, 2.51 mmol) were added. The reaction
mixture was stirred for another 1 h, concentrated, dissolved
in CH3CN and washed with n-hexane. The combined more
polar extracts were concentrated under reduced pressure to
give a residue, which was purified by flash column chroma-
tography (hexanes-EtOAc, 96:4) to yield compound 46 (188
mg, 0.489 mmol, 78%): oil; [R]D +7.1 (c ) 0.990); IR (film) 2932,
1-Acetam ido-2,4,5-tr i-O-acetyl-1-deoxy-D-ar abin itol (50).
Following the general procedure (method A), a solution of the
anomeric mixture 49 (50 mg, 0.102 mmol) in dry benzene (1.53
mL) was heated to reflux with n-Bu3SnH (247 µL, 0.918 mmol)
and AIBN (1.7 mg, 0.01 mmol) for 4 h. Chromatotron chro-
matography of the residue (hexanes-EtOAc, 1:9) yielded the
alcohol 50 (15.4 mg, 0.048 mmol, 47%): mp 117-118.5 °C
(from ethyl acetate-n-hexane); [R]D +21.7 (c ) 0.410); IR (film)
3322, 1747, 1743, 1716, 1660 cm-1; 1H NMR 1.98 (3H, s), 2.01
(3H, s), 2.03 (3H, s), 2.04 (3H, s), 3.12 (1H, ddd, J ) 14.0, 5.5,
5.4 Hz), 3.73 (1H, br d, J ) 9.3 Hz), 3.79 (1H, ddd, J ) 14.1,
8.7, 8.7 Hz), 4.26 (1H, dd, J ) 12.3, 5.2 Hz), 4.47 (1H, dd, J )
12.3, 2.5 Hz), 4.60 (1H, d, J ) 3.8 Hz), 4.80 (1H, ddd, J ) 8.8,
5.4, 1.6 Hz), 5.08 (1H, ddd, J ) 9.5, 5.3, 2.4 Hz), 6.15 (1H, dd,
J ) 6.5, 6.5 Hz); 13C NMR (50.3 MHz) 20.6 (CH3), 20.7 (CH3),
20.8 (CH3), 23.0 (CH3), 38.8 (CH2), 63.3 (CH2), 67.3 (CH), 69.5
(CH), 70.2 (CH), 169.8 (C), 171.0 (2 × C), 172.3 (C); MS m/z
(rel intensity) (FAB) 342 (M+ + Na, 100), 320 (M+ + H, 40).
Anal. Calcd for C13H21NO8: C, 48.90; H, 6.63; N, 4.39. Found:
C, 48.62; H, 6.68; N, 4.21.
1
1379, 1113 cm-1; H NMR 1.06 (9H, s), 1.33 (3H, d, J ) 6.5
Hz), 1.34 (3H, s), 1.38 (3H, s), 3.66 (1H, dd, J ) 10.4, 4.8 Hz),
3.73 (1H, dd, J ) 10.4, 7.9 Hz), 4.17 (1H, ddd, J ) 7.8, 5.8, 4.9
Hz), 4.39 (1H, dddd, J ) 6.4, 6.4, 6.4, 6.4 Hz), 7.39-7.44 (6H),
7.66-7.69 (4H); 13C NMR (50.3 MHz) 14.9 (CH3), 19.2 (C), 25.5
(CH3), 26.6 (3 × CH3), 28.1 (CH3), 62.5 (CH2), 73.2 (CH), 77.8
(CH), 107.6 (C), 127.7 (4 × CH), 129.7 (2 × CH), 133.2 (C),
133.4 (C), 135.5 (4 × CH); MS m/z (rel intensity) (FAB) 383
(M+ + H, 2), 369 (M+ - CH3, 13), 327 (27), 269 (100); HRMS
calcd for C22H29O3Si 369.1886, found 369.1880. Anal. Calcd for
C23H32O3Si: C, 71.83; H, 8.39. Found: C, 72.01; H, 8.54.
1,2,3,5-Tetr a-O-Ben zyl-4-O-for m yl-D-ar abin itol (48a) an d
1,2,3,5-Tetr a -O-Ben zyl-D-a r a bin itol (48b). Following the
general procedure (method A), to a stirred solution of the
anomeric mixture 47 (103 mg, 0.150 mmol) in dry benzene
(2.25 mL) were added, under nitrogen, n-Bu3SnH (363 µL, 1.35
mmol) and AIBN (2.5 mg, 0.015 mmol), and the solution was
heated to reflux for 35 min. Chromatotron chromatography
(hexanes-EtOAc, 95:5 f 9:1) afforded the formate 48a (51
mg, 0.094 mmol, 63%) and the alcohol 48b (18 mg, 0.035 mmol,
23%). Compound 48a : foam; [R]D -12.9 (c ) 0.975); IR (film)
Red u ction of (5R)-1,2-O-Isop r op ylid en e-3,5-O-m eth yl-
en e-5-O-p h th a lim id o-R-D-xylo-p en tod ia ld o-1,4-fu r a n ose
(51-R) a n d (5S)-1,2-O-Isop r op ylid en e-3,5-O-m eth ylen e-5-
O-p h th a lim id o-r-D-xylo-p en tod ia ld o-1,4-fu r a n ose (51-S).
Following the general procedure (method A), to a stirred
solution of the isomer 51-R (42 mg, 0.116 mmol) in dry benzene
(1.74 mL) were added n-Bu3SnH (280 µL, 1.044 mmol) and
AIBN (1.9 mg, 0.012 mmol), and the solution was heated to
reflux for 1 h and 45 min. Chromatotron chromatography
(hexanes-EtOAc, 7:3) afforded the compound 40 (15 mg, 0.094
mmol, 81%). Data identical to those described above. Alter-
natively, to a stirred solution of the isomer 51-S (76 mg, 0.209
mmol) in dry benzene (3.13 mL) were added n-Bu3SnH (506
µL, 1.88 mmol) and AIBN (3.4 mg, 0.021 mmol) and the
solution was heated to reflux for 1 h and 45 min. Chromatotron
chromatography (hexanes-EtOAc, 7:3) afforded the compound
40 (29.4 mg, 0.184 mmol, 88%). Data were identical to those
described above.
1
1727 cm-1; H NMR 3.60 (1H, dd, J ) 9.8, 6.1 Hz), 3.65 (1H,
dd, J ) 9.8, 5.4 Hz), 3.75 (1H, dd, J ) 11.0, 5.8 Hz), 3.78 (1H,
ddd, J ) 5.8, 5.8, 3.9 Hz), 3.82 (1H, dd, J ) 11.0, 2.9 Hz), 3.94
(1H, dd, J ) 5.9, 3.8 Hz), 4.43 (1H, d, J ) 12.0 Hz), 4.46 (2H,
s), 4.49 (1H, d, J ) 12.0 Hz), 4.53 (1H, d, J ) 11.6 Hz), 4.57
(1H, d, J ) 11.4 Hz), 4.63 (1H, d, J ) 10.4 Hz), 4.65 (1H, d, J
) 11.4 Hz), 5.31 (1H, ddd, J ) 5.8, 5.8, 2.8 Hz), 7.22-7.35
(20H), 7.94 (1H, s); 13C NMR (50.3 MHz) 68.3 (CH2), 69.4 (CH2),
72.7 (CH), 73.1 (2 × CH2), 73.4 (CH2), 74.6 (CH2), 77.4 (CH),
77.6 (CH), 127.6-128.4 (20 × CH), 137.1 (C), 137.9 (2 × C),
138.0 (C), 160.4 (C); MS m/z (rel intensity) (EI, 70 eV) 449
(M+ - Bn, 1), 357 (1), 341 (1), 91 (100); HRMS calcd for C27H29O6
449.1964, found 449.1998. Anal. Calcd for C34H36O6: C, 75.53;
H, 6.71. Found: C, 75.73; H, 6.97. Compound 48b: oil; [R]D
-1.3 (c ) 0.395); IR (film) 3468, 3031, cm-1; 1H NMR 2.89 (1H,
d, J ) 5.4 Hz), 3.59 (1H, dd, J ) 10.0, 5.5 Hz), 3.62 (1H, dd, J
) 10.0, 3.5 Hz), 3.65-3.70 (2H), 3.71 (1H, dd, J ) 7.5, 3.0 Hz),
3.95 (1H, ddd, J ) 5.5, 5.5, 3.5 Hz), 3.99 (1H, dddd, J ) 9.0,
9.0, 5.0, 5.0 Hz), 4.46 (1H, d, J ) 12.0 Hz), 4.48 (1H, s), 4.50
(1H, s), 4.52 (1H, d, J ) 12.0 Hz), 4.53 (2H, s), 4.62 (1H, d, J
) 11.7 Hz), 4.71 (1H, d, J ) 11.6 Hz), 7.21-7.34 (20H); 13C
NMR (50.3 MHz) 69.0 (CH2), 69.6 (CH2), 70.4 (CH2), 72.4 (CH2),
72.6 (2 × CH2), 72.9 (CH2), 77.0 (CH), 77.1 (CH), 127.7-128.3
(20 × CH), 138.1 (2 × C), 138.2 (2 × C); MS m/z (rel intensity)
(EI, 70 eV) 421 (M+ - Bn, 1), 315 (1), 253 (2), 91 (100); HRMS
calcd for C26H29O5 421.2015, found 421.2053. Anal. Calcd for
Ack n ow led gm en t. This work was supported by the
Investigation Program No. PB96-1461 of the Direccio´n
General de Investigacio´n Cient´ıfica y Te´cnica, Spain.
P.M. and A.M. thank the Ministerio de Educacio´n y
Ciencia, Spain, for a fellowship and a contract under
the program Acciones para la Incorporacio´n a Espan˜a
de Doctores y Tecno´logos, respectively.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, physical properties, and spectroscopic data for com-
pounds 2, 4-9, 12-16, 18-21, 23, 24, 26-29, 31, 41, 42, 44,
45, 47, 49, and 51. This material is available free of charge
via the Internet at http://pubs.acs.org.
C
33H36O5: C, 77.32; H, 7.08. Found: C, 77.57; H, 7.23.
J O0156565