Synthesis of highly functionalized chiral nitriles by radical fragmentation of β-hydroxy azides. Convenient transformation of aldononitriles into 1,4- and 1,5-iminoalditols

Article abstract of DOI:10.1021/jo049026p

The synthesis of highly functionalized nitriles by an alkoxyl radical fragmentation of cyclic β-hydroxy azides is described. The alkoxyl radicals were generated by reaction of the alcohols with (diacetoxyiodo)benzene and iodine under mild conditions compa

Full text of DOI:10.1021/jo049026p

Synthesis of Highly Functionalized Chiral Nitriles by Radical
Fragmentation of â-Hydroxy Azides. Convenient Transformation
of Aldononitriles into 1,4- and 1,5-Iminoalditols
Rosendo Herna´ndez, Elisa I. Leo´n, Pilar Moreno, Concepcio´n Riesco-Fagundo, and
Ernesto Sua´rez*
Instituto de Productos Naturales y Agrobiologı´a del CSIC, Carretera de La Esperanza 3,
38206 La Laguna, Tenerife, Spain
esuarez@ipna.csic.es
Received June 9, 2004
The synthesis of highly functionalized nitriles by an alkoxyl radical fragmentation of cyclic â-hydroxy
azides is described. The alkoxyl radicals were generated by reaction of the alcohols with
(diacetoxyiodo)benzene and iodine under mild conditions compatible with the presence of sensitive
substituents and the protective groups most frequently used in carbohydrate chemistry. To explore
the scope and limitations of this methodology, experiments were carried out using a variety of
â-hydroxy azides of the carbohydrate (1-6, 33, and 41), monoterpenoid (21 and 22), and steroid
(23-25) families of natural products. Of special interest are the aldopentonitriles (15-18, 34, and
42) and aldotetrononitriles (19 and 20) synthesized from the corresponding 2-azido-2-deoxycarbo-
hydrates. To demonstrate the versatility of these aldononitriles as chiral synthons, 1,4-imino-1-
deoxysugar (37) and 1,5-imino-1-deoxysugar (43) analogues of the polyhydroxypyrrolidine and
-piperidine types were prepared.
Introduction
aldose oximes,5b,6 and the reaction of N-bromoglyco-
sylimines with Zn/Ag-graphite.7 The first method pro-
vides aldononitriles with one more carbon atoms than
the starting carbohydrate, while the aldononitriles syn-
thesized by the other two methods retain the same
number of carbon atoms. Also, special types of sugar
nitriles, the 2,6-anhydro- and 2,5-anhydroaldononitriles
(pyranosyl and furanosyl cyanides), have attracted con-
siderable attention since they are valuable intermediates
in the synthesis of C-glycosides.8
We have recently published the latest results of several
of our ongoing studies of the alkoxyl radical fragmenta-
tion (ARF) of reducing sugars.9 In this paper, we report
on an extension of the ARF methodology to cyclic â-hy-
droxy azides that may be suitable for the synthesis of δ-
or ꢀ-ketonitriles. The reaction is triggered by the alkoxyl
The synthesis of ꢀ-ketonitriles from cyclic R-hydroxy
oximes through a Beckmann fragmentation has fre-
quently been utilized in synthetic organic chemistry.1
Related methodologies for the synthesis of ꢀ-ketonitriles
by cleavage of trisubstituted cyclic olefins with DIB/
(TMS)N3 or LTA/(TMS)N3,2 CAN/NaN3,3 or photooxygen-
ation in the presence of NaN3/Cu(OTf)2 have also been
described.
On the other hand, several methods for preparing
aldononitriles from carbohydrates are described in the
literature, involving direct addition of HCN to aldoses
(Fischer-Kiliani cyanohydrin synthesis),5 dehydration of
4
* To whom correspondence should be addressed. Fax: 34-922260135.
(1) For recent examples, see: (a) Magyar, A.; Schonecker, B.;
Wolfling, J.; Schneider, G.; Gunther, W.; Gorls, H. Tetrahedron:
Asymmetry 2003, 14, 2705-2715. (b) Ho, T.-L.; Gorobets, E. Tetrahe-
dron 2002, 58, 4969-4973. (c) Mart´ınez, A. G.; Vilar, E. T.; Fraile, A.
G.; Cerero, S. D. M.; Maroto, B. L. Eur. J. Org. Chem. 2002, 781-783.
(d) Tokic-Vujosevic, Z.; Cekovic, Z. Synthesis 2001, 2028-2034. (e) Biju,
P. J.; Laxmisha, M. S.; Rao, G. S. R. S. J. Chem. Soc., Perkin Trans.
1 2000, 4512-4519. (f) Pejanovic, V. M.; Petrovic, J. A.; Csanadi, J.
J.; Stankovic, S. M.; Miljkovic, D. A. Tetrahedron 1995, 51, 13379-
13384.
(2) (a) Zbiral, E.; Nestler, G.; Kischa, K. Tetrahedron 1970, 26,
1427-1434. (b) Zbiral, E.; Nestler, G. Tetrahedron 1970, 26, 2945-
2951. (c) Ehrenfreund, J.; Zbiral, E. Tetrahedron 1972, 28, 1697-1704.
(d) Hugl, H.; Zbiral, E. Tetrahedron 1973, 29, 759-767.
(3) Nair, V.; Rajan, R.; Balagopal, L.; Thomas, S.; Narasimlu, K.
Tetrahedron Lett. 2002, 43, 8971-8974.
(6) For the dehydration of aldose oximes, see: (a) Chen, C. C.;
McGinnis, G. D. Carbohydr. Res. 1981, 90, 127-130. (b) Ermert, P.;
Vasella, A. Helv. Chim. Acta 1991, 74, 2043-2053. (c) Dorsey, A. D.;
Barbarow, J. E.; Trauner, D. Org. Lett. 2003, 5, 3237-3239. For many
aldoxime dehydration reagents, see: (d) Molina, P.; Alajarin, M.;
Vilaplana, M. J. Synthesis 1982, 1016-1017. (e) Attanasi, O.; Palma,
P.; Serra-Zanetti, F. Synthesis 1983, 741-742 and references cited
therein.
(7) Fu¨rstner, A.; Praly, J.-P. Angew. Chem., Int. Ed. Engl. 1994, 33,
751-753.
(8) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Pergamon
Press: Oxford, U.K., 1995; pp 29-40.
(9) (a) Francisco, C. G.; Gonza´lez, C. C.; Kennedy, A. R.; Paz, N. R.;
Sua´rez, E. Tetrahedron: Asymmetry 2004, 15, 11-14. (b) Gonza´lez, C.
C.; Leo´n, E. I.; Riesco-Fagundo, C.; Sua´rez, E. Tetrahedron Lett. 2003,
44, 6347-6350. (c) Gonza´lez, C. C.; Kennedy, A. R.; Leo´n, E. I.; Riesco-
Fagundo, C.; Sua´rez, E. Chem.sEur. J. 2003, 9, 5800-5809. (d)
Francisco, C. G.; Gonza´lez, C. C.; Paz, N. R.; Sua´rez, E. Org. Lett. 2003,
5, 4171-4173. (e) Gonza´lez, C. C.; Kennedy, A. R.; Leo´n, E. I.; Riesco-
Fagundo, C.; Sua´rez, E. Angew. Chem., Int. Ed. 2001, 40, 2326-2328.
(4) Shimizu, I.; Fujita, M.; Nakajima, T.; Sato, T. Synlett 1997, 887-
888.
(5) (a) Hough, L.; Richardson, A. C. In The Carbohydrates. Chemistry
and Biochemistry; Pigman, W., Horton, D., Eds.; Academic Press: San
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10.1021/jo049026p CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/05/2004
J. Org. Chem. 2004, 69, 8437-8444
8437

Herna´ndez et al.
TABLE 1. Aldononitriles by â-Fragmentation of
â-Hydroxy Azides in Carbohydrate Systemsa
TABLE 2. Ketonitriles by â-Fragmentation of
â-Hydroxy Azides in Terpene and Steroid Systemsa
a All reactions were performed under nitrogen containing (di-
acetoxyiodo)benzene (1.2 mmol) and iodine (1 mmol) per millimole
of substrate, in dry CH2Cl2 and under irradiation with two 80 W
tungsten-filament lamps. b DIB (2.5 mmol) was used.
terpenic and steroid families of natural products (Table
2). The structures of the new compounds were routinely
confirmed by H and 13C NMR spectroscopy including
1
a All reactions were performed at 20 °C under nitrogen contain-
ing (diacetoxyiodo)benzene (1.2 mmol) and iodine (1 mmol), per
millimole of substrate, in dry CH2Cl2 under normal laboratory
lighting conditions.
COSY, HSQC, HMBC, and DEPT experiments. To our
knowledge the radical fragmentation of â-hydroxy azides
has not previously been attempted. The methodology
developed here has been used by Wipf and Mareska in a
study of the reversal of regioselectivity in the fragmenta-
tion of hydroindoles.11
The present study also shows the utility of these
aldononitriles as chiral synthons for the preparation of
polyhydroxypiperidines (1,5-iminoalditols) and polyhy-
droxypyrrolidines (1,4-iminoalditols) related to glycosi-
dase inhibitors.
radical generated in situ by reaction of the alcohol with
the hypervalent iodine reagent (diacetoxyiodo)benzene
(DIB) in the presence of iodine under mild conditions.
Of special interest is the ARF of glycopyranosyloxy and
glycofuranosyloxy radicals in 2-azido-2-deoxycarbohy-
drates, which leads to aldononitriles with one carbon less
than the starting saccharide. In a previous paper we
described the preliminary results obtained,10 and we now
disclose herein the full details of these experiments. To
examine the scope of this reaction, we attempted the
fragmentation of a variety of substrates of the pentose
and hexose series of carbohydrates in both pyranose and
furanose forms as depicted in Table 1. The reaction can
also be extended to â-hydroxy azides belonging to the
Results and Discussion
Synthesis of Substrates. Several excellent methods
exist in the literature for the synthesis of â-hydroxy
azides in general by electrophilic or radical additions to
olefins.12 The known 2-azido-2-deoxysaccharides 113 and
2
14 (Table 1) were prepared by a sequence of azidonitra-
(10) Herna´ndez, R.; Leo´n, E. I.; Moreno, P.; Sua´rez, E. J. Org. Chem.
1997, 62, 8974-8975.
(11) Wipf, P.; Mareska, D. A. Tetrahedron Lett. 2000, 41, 4723-
4727.
8438 J. Org. Chem., Vol. 69, No. 24, 2004

Radical Fragmentation of â-Hydroxy Azides
SCHEME 1. Synthesis of 3a
SCHEME 2. Synthesis of 5 and 6a
a Reagents and conditions: (a) TBAF, (TMS)N3, N-(phenylse-
leno)phthalimide, CH2Cl2, 83%; (b) N-iodosuccinimide, THF-H2O,
81%.
tion of the respective glycals with the CAN/NaN3 reagent
according to the procedure of Lemieux and Ratcliffe,15
followed by anomeric denitration with hydrazine ac-
etate.16 The mixtures of D-gluco and D-manno (1) and â-D-
Galp-(1f4)-D-Glcp and â-D-Galp-(1f4)-D-Manp (2) dias-
tereoisomers were subjected to the radical fragmentation
without previous separation.
a Reagents and conditions: (a) triflyl anhydride, Py, 94%; (b)
LiN3, DMF, 77%; (c) L-Selectride, THF, 61%; (d) TFA, 72%; (e)
tBuMe2SiCl, imidazole, DMF, 68%; (f) dimethoxymethane, P2O5,
CHCl3, 69%.
The 2-azido-2-deoxy-D-glucofuranose derivative 3 and
2-azido-2-deoxy-D-galactopyranose derivative 4 were ob-
tained starting from 1,4-anhydro-2-deoxy-3-O-methyl-5,6-
O-isopropylidene-D-arabino-hex-1-enitol (7)17 and 2,6-
anhydro-5-deoxy-D-arabino-hex-5-enitol, respectively, by
azidophenylselenation with N-(phenylseleno)phthalimide
and (TMS)N3 followed by anomeric dephenylselenation
with N-iodosuccinimide, as illustrated for 3 (Scheme 1).18
Compounds 5 and 6 were prepared as described in
Scheme 2 starting from 3,4-O-benzylidene-D-ribono-1,5-
lactone (9). Nucleophilic displacement of the triflate
group in 10 with lithium azide afforded deoxy derivative
11, which was subsequently reduced with L-Selectride
to give the desired â-hydroxy azide 5. The hydrolysis of
the 3,4-O-benzylidene protective group in compound 11
afforded the rearranged19 1,4-lactone 12, which was
consecutively protected with (TBDMS)Cl and (MOM)Cl,
leading to compound 14. Under the benzylidene hydroly-
sis reaction conditions, concomitant partial isomerization
of the 2-azide group also occurred. In this case, as a
precursor of a nonstereogenic center, the C2 stereochem-
istry is irrelevant, and no diastereoisomeric separation
of compound 14 was attempted at this stage. Finally, the
reduction of the carboxyl group with L-Selectride afforded
the required â-hydroxy azide 6.
Monoterpenoid azides 21 and 22 were prepared by
photooxygenation in the presence of sodium azide of the
corresponding olefins (+)-limonene and (-)-R-pinene and
subsequent reduction, with sodium sulfite, of the hydro-
peroxy azide intermediates (Table 2).20
The reaction of cholesterol R-epoxide with sodium azide
gave â-hydroxy azide 23 following a previously reported
procedure.21 The diol was later transformed into the
monoacetate 24 with acetic anhydride and pyridine. The
pregnene derivative 25 was also synthesized by acid-
catalyzed opening of the corresponding R-epoxide. It is
worthy of note that, under exactly the same reaction
conditions, Ponsold described the formation of a deriva-
tive with ring D rearranged to a six-membered hydroxy
azide (3â-acetoxy-16â-azido-17R-hydroxy-17â-methyl-D-
homoandrost-5-en-17a-one) as the sole product22 but, in
our hands, the hitherto unknown five-membered hydroxy
azide 25 (77%) is the principal product, the six-membered
azide being formed in only 9% yield.
Our fragmentation procedure was applied to differently
protected 2-azido-2-deoxyglucopyranose and -glucofura-
nose derivatives 1-3 to give arabinononitriles 15-17 in
good yields. The reactions proceeded smoothly under the
conditions shown in Table 1 (entries 1-3), using ap-
proximately equimolecular amounts of DIB and iodine
(12) Boche, G. In Stereoselective Synthesis, Methods of Organic
Chemistry (Houben-Weyl); Helmchen, G., Hoffmann, R. W., Mulzer,
J., Schaumann, E., Eds.; Thieme: Stuttgart, 1995; Vol. E 21-9, pp
5190-5221.
(13) BeMiller, J. N.; Blazis, V. J.; Myers, R. W. J. Carbohydr. Chem.
1990, 9, 39-57.
(14) (a) Arnarp, J.; Lo¨nngren, J. J. Chem. Soc., Perkin Trans. 1 1981,
2070-2074. (b) Kinzy, W.; Schmidt, R. R. Carbohydr. Res. 1987, 164,
265-276. (c) Li, Q.; Li, H.; Cai, M.-S.; Li, Z.-J.; Zhou, R.-L. Tetrahedron:
Asymmetry 1999, 10, 2675-2683. (d) Tietze, L. F.; Janssen, C. O.;
Gewert, J.-A. Eur. J. Org. Chem. 1998, 1887-1894.
(15) (a) Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1979, 57,
1244-1251. (b) Grundler, G.; Schmidt, R. R. Liebigs Ann. Chem. 1984,
1826-1847.
(16) Toyokuni, T.; Cai, S.; Dean, B. Synthesis 1992, 1236-1238.
(17) (a) Lee, J. B.; Nolan, T. J. Tetrahedron 1967, 23, 2789-2794.
(b) Eitelman, S. J.; Hall, R. H.; Jordaan, A. J. Chem. Soc., Perkin Trans.
1 1978, 595-600.
(18) (a) Czernecki, S.; Randriamandimby, D. Tetrahedron Lett. 1993,
34, 7915-7916. (b) Santoyo-Gonza´lez, F.; Calvo-Flores, F. G.; Garc´ıa-
Mendoza, P.; Herna´ndez-Mateo, F.; Isac-Garc´ıa, J.; Robles-D´ıaz, R. J.
Org. Chem. 1993, 58, 6122-6125. (c) Santoyo-Gonza´lez, F.; Calvo-
Flores, F. G.; Garc´ıa-Mendoza, P.; Herna´ndez-Mateo, F.; Isac-Garc´ıa,
J.; Robles-D´ıaz, R. Carbohydr. Res. 1994, 260, 319-321. (d) Czernecki,
S.; Ayadi, E.; Randriamandimby, D. J. Org. Chem. 1994, 59, 8256-
8260. (e) Czernecki, S.; Ayadi, E.; Randriamandimby, D. J. Chem. Soc.,
Chem. Commun. 1994, 35-36. (f) Czernecki, S.; Ayadi, E. Can. J.
Chem. 1995, 73, 343-350. (g) Paulsen, H.; Sumfleth, B. Chem Ber.
1979, 112, 3203-3213.
(20) Griesbeck, A. G.; Hundertmark, T.; Steinwascher, J. Tetrahe-
dron Lett. 1996, 37, 8367-8370.
(21) (a) Houminer, Y. J. Chem. Soc., Perkin Trans. 1 1975, 1663-
1669. (b) Ponsold, K. Chem. Ber. 1962, 95, 1727-1732. (c) Ponsold, K.
Chem. Ber. 1963, 96, 1411-1417. (d) Kirk, D. N.; Wilson, M. A. J.
Chem. Soc. C 1971, 414-424.
(22) (a) Ponsold, K.; Scho¨necker, B.; Rosenberger, H.; Prousa, R.;
Mu¨ller, B. J. Prakt. Chem. 1969, 311, 912-918. For other related
examples see: (b) Protiva, J.; Nguyen, T. T. H.; Urban, J.; Klinotova´,
E. Collect. Czech. Chem. Commun. 1997, 62, 1095-1104. (c) Nathansohn,
G.; Winters, G.; Vigevani, A. Gazz. Chim. Ital. 1965, 95, 1338-1370.
(19) For a previous example of this rearrangement, see: (a) Baggett,
N.; Buchanan, J. G.; Fatah, M. Y.; Lachut, C. H.; McCullough, K. J.;
Webber, J. M. J. Chem. Soc., Chem. Commun. 1985, 1826-1827. (b)
Chen, S.-Y.; Joullie´, M. M. J. Org. Chem. 1984, 49, 2168-2174.
J. Org. Chem, Vol. 69, No. 24, 2004 8439

Herna´ndez et al.
SCHEME 3. Mechanism of the ARF Reaction
at room temperature. The diastereoisomeric mixture of
D-galacto and D-talo azides 4 gave the lyxononitrile
derivative 18 (entry 4). For the sake of completeness this
methodology was also extended to several additional
examples of the pentose series of carbohydrates, the
results of which are also included in Table 1. We have
involved in this study two different D-ribo-protected
compounds, 5 and 6, which gave the erythrononitriles 19
and 20 (entries 5 and 6).
The ARF reaction also occurred in â-hydroxy azides
on carbocyclic systems as depicted in Table 2. The
reaction of â-hydroxy azides 21 and 22 belonging, re-
spectively, to the (+)-limonene and (-)-R-pinene monot-
erpene families, afforded ꢀ-ketonitriles 2623b and 2723
(entries 1 and 2). The reaction is compatible with other
hydroxyl groups present in the molecule, but in this case
it might be necessary to tune the reaction conditions to
increase the chemoselectivity. For example, the temper-
ature of the fragmentation of the steroidal diol 23 had
to be lowered with an ice-water bath for optimum yield
(entry 3), while a higher temperature led to clearly
inferior results (a 51% yield of nitrile 2824 was obtained
at 20 °C, and a complex mixture of unidentified products
was produced at higher temperatures). In any case, a
significantly higher yield of ketonitrile 2925 (88%) was
obtained when the 3â-alcohol was protected with an
acetyl group such as compound 24 (entry 4).
An interesting R-diketone, 30, was obtained when the
â-hydroxy azide of the pregnane type 25 was submitted
to the DIB/I2 system; the reaction proceeded in moderate
yield at 0 °C (entry 5). Control of the reaction tempera-
ture was found to be critical since the yield was signifi-
cantly reduced at room temperature. Taking into account
the possibility of further oxidation of the sensitive R-di-
ketone by the excess of reagent, we examined whether
the yield could be improved by decreasing the oxidant
ratio. However, this did not result in a significant
increase in yield. The R-diketone 30 obtained as light
yellow crystals was characterized by spectroscopic means,
and by analogy with the related progestomimetic steroid
oxopromegestone.26
absence of iodine the starting material was recovered
quantitatively. As shown in Scheme 3, the C2 radical
consequently formed must be oxidized by the reagent to
a carbocation which generates the nitrile group after loss
of a molecule of nitrogen.
From the products obtained in Table 1, it can be
inferred that the aldononitriles possess an easily hydro-
lyzable formate group at C3 or C4 and that this position
only depends on the furanose or pyranose form of the
starting carbohydrate. We believe that this is a charac-
teristic of these compounds that could be most valuable
in synthetic organic chemistry. 1-Deoxyiminosugar ana-
logues of the polyhydroxypyrrolidine and -piperidine
types were prepared to demonstrate the versatility of
these aldononitriles as chiral synthons. The methodology
developed by Buchanan et al.27 for the synthesis of 1,4-
imino sugar was used.
1,4-Anhydro-5-O-benzyl-(4-tert-butoxycarbonyl)amino-
1,4-dideoxy-2,3-isopropylidene-L-ribitol (37) was synthe-
sized in six steps from the D-galactal derivative 3128 as
described in Scheme 4. Azidophenylselenation of the
double bond followed by anomeric deselenation afforded
alcohol 33,18f which was submitted to the ARF reaction
to give the D-lyxononitrile 34.
Hydrolysis of the formate group under mild conditions
afforded the alcohol 35, which afterward was mesylated,
leading to compound 36. After some experimentation
with several well-known nitrile reductants (Raney Ni,29
BH3‚THF,30 and activated NaBH431) we were pleased to
find that the simple addition of LiAlH4 in Et2O is quite
effective at reducing the nitrile group and promoting the
desired cyclization.32 The crude pyrrolidine was protected
as its Boc-carbamate to give the L-iminoribitol derivative
37 since the aminocyclization occurred with inversion of
configuration at C4.33
Although in all cases shown in Table 2 the reaction
proceeded under natural lighting conditions, assisted
irradiation with 2 × 80 W tungsten filament lamps
reduced the reaction times, this shortening being espe-
cially significant in low-temperature reactions (entries
3 and 5).
The reaction mechanism deserves special comment.
According to the above results, it seems reasonable that
the first step is an alkoxyl radical generation through a
hypoiodite intermediate, supported by the fact that in the
Alternatively, this protocol can be used for the syn-
thesis of 1,5-iminoalditols. As described in Scheme 5, the
(27) (a) Buchanan, J. G.; Lumbard, K. W.; Sturgeon, R. J.; Thomp-
son, D. K.; Wightman, R. H. J. Chem. Soc., Perkin Trans. 1 1990, 699-
706. (b) Buchanan, J. G.; Jigajinni, V. B.; Singh, G.; Wightman, R. H.
J. Chem. Soc., Perkin Trans. 1 1987, 2377-2384. (c) Buchanan, J. G.;
MacLean, K. A.; Wightman, R. H.; Paulsen, H. J. Chem. Soc., Perkin
Trans. 1 1985, 1463-1470.
(23) For the synthesis of compound 27 using different methodologies,
see: (a) Stutz, A.; Zbiral, E. Justus Liebigs Ann. Chem. 1972, 765, 34-
46. (b) Tkachev, A. V.; Rukavishnikov, A. V.; Chibirjaev, A. M.;
Volodarsky, L. B. Synth. Commun. 1990, 20, 2123-2132. (c) Morzherin,
Y. Y.; Glukhareva, T. V.; Mokrushin, V. S.; Tkachev, A. V.; Bakulev,
V. A. Heterocycl. Commun. 2001, 7, 173-176.
(24) (a) Rosini, G.; Medici, A.; Cacchi, S. Synthesis 1975, 665-666.
(b) Shah, J. N.; Mehta, Y. P.; Shah, G. M. J. Org. Chem. 1978, 43,
2078-2079.
(25) Knof, L. Justus Liebigs Ann. Chem. 1961, 642, 194-199.
(26) (a) Gertosio, V.; Santini, C. C.; Basset, J.-M.; Bayard, F.; Vivat,
M.; Buendia, J. Eur. J. Org. Chem. 2000, 65, 1521-1525. For related
steroidal R-diketones synthesized by oxidation of the pregn-16-en-20-
one moiety, see: (b) Marker, R. E.; Lawson, E. J. J. Am. Chem. Soc.
1939, 61, 852-855. (c) Piatak, D. M.; Bhat, H. B.; Caspi, E. J. Org.
Chem. 1969, 34, 112-116.
(28) Fernandez-Mayoralas, A.; Marra, A.; Trumtel, M.; Veyrieres,
A.; Sinay, P. Carbohydr. Res. 1989, 188, 81-96.
(29) Shih, T. L.; Ruiz-Sa´nchez, J.; Mroizk, H. Tetrahedron Lett. 1987,
28, 6015-6018.
(30) Nagarajan, S.; Ganem, B. J. Org. Chem. 1986, 51, 4856-4861.
(31) Caddick, S.; Haynes, A. K. K.; Judd, D. B.; Williams, M. R. V.
Tetrahedron Lett. 2000, 41, 3513-3516.
(32) (a) Rahman, S. M. A.; Ohno, H.; Yoshino, H.; Satoh, N.;
Tsukaguchi, M.; Murakami, K.; Iwata, C.; Maekazi, N.; Tanaka, T.
Tetrahedron 2001, 57, 127-134. (b) Cimino, G.; Gavagnin, M.; Sodano,
G.; Spinella, A.; Strazzullo, G.; Schmitz, F. J.; Yalamanchili, G. J. Org.
Chem. 1987, 52, 2301-2303.
8440 J. Org. Chem., Vol. 69, No. 24, 2004

Radical Fragmentation of â-Hydroxy Azides
to give the required 1,5-iminoarabinitol 43.34 From the
above examples, it is clear that this methodology may
be useful for the preparation of 1,4- and 1,5-iminopen-
titols from a common precursor, in this case 3,4-isopro-
pylidene-D-galactal.
SCHEME 4. Synthesis of 37a
In summary, the application of the ARF reaction to
five- and six-membered carbocyclic â-hydroxy azides led
to acyclic δ- and ꢀ-ketonitriles, respectively. One espe-
cially important use of this methodology was the frag-
mentation of 2-azido-2-deoxyaldoses, which afforded al-
dononitriles in good yield. The pyranose and furanose
models, prepared to study the scope of this method, were
constructed to incorporate a variety of commonly em-
ployed carbohydrate protecting groups, each of which
proved tolerant to the mild reaction conditions. The
utility of these aldononitriles as chiral building blocks
has been demonstrated by a short synthesis of 1,4- and
1,5-imino-1-deoxypentitols, which are considered to be
potential glycosidase inhibitors.33,34
a Reagents and conditions: (a) TBAF, (TMS)N3, N-(phenylse-
leno)phthalimide, CH2Cl2, 67%; (b) N-iodosuccinimide, THF-H2O,
79%; (c) DIB, I2, CH2Cl2, 86%; (d) CSA, MeOH, 70%; (e) MsCl,
Et3N, CH2Cl2, 71%; (f) LiAlH4, Et2O, then di-tert-butyl dicarbonate,
69%.
Experimental Section
General Procedure for the Preparation of Compounds
15-20. A solution of the â-hydroxy azide (1 mmol) in CH2Cl2
(20 mL) containing DIB (1.2 mmol) and iodine (1 mmol) was
stirred at 20 °C for the time specified in Table 1, under
exposure to ambient light but without irradiation from an
external source. The reaction mixture was then poured into a
10% aqueous Na2S2O3 solution, extracted with CH2Cl2, dried
(Na2SO4), and concentrated in vacuo. Chromatotron chroma-
tography of the residue (hexanes-EtOAc) as specified gave
the nitriles.
SCHEME 5. Synthesis of 43a
2,3,5-Tri-O-acetyl-4-O-formyl-D-arabinononitrile (15).
The product was isolated by chromatography (hexanes-
EtOAc, 70:30) as a crystalline solid (88%): mp 82-83 °C (from
n-hexane-EtOAc); [R]D -10 (c 0.4); IR 2100, 1764, 1740 cm-1
;
1H NMR δH 2.07 (3H, s), 2.17 (3H, s), 2.20 (3H, s), 4.21 (1H,
dd, J ) 5.0, 12.6 Hz), 4.32 (1H, dd, J ) 3.0, 12.6 Hz), 5.39
(1H, m), 5.59 (1H, d, J ) 3.4 Hz), 5.61 (1H, dd, J ) 3.4, 5.4
Hz), 8.01 (1H, s); 13C NMR δC 20.1 (CH3), 20.4 (CH3), 20.5
(CH3), 59.5 (CH), 61.0 (CH2), 67.2 (CH), 67.7 (CH), 113.8 (C),
159.0 (CH), 168.5 (C), 168.8 (C), 170.3 (C); FABMS m/z
(glycerol, NaCl) (rel intens) 302 (M+ + H, 21). Anal. Calcd for
C12H15NO8: C, 47.84; H, 5.02; N, 4.65. Found: C, 47.92; H,
5.11; N, 4.56.
2,5-Di-O-acetyl-4-O-formyl-3-O-(2,3,4,6-tetra-O-acetyl-
â-D-galactopyranosyl)-D-arabinononitrile (16). The prod-
uct was isolated by chromatography (hexanes-EtOAc, 1:1) as
a crystalline solid (97%): mp 36-38 °C (from n-hexane-
EtOAc); [R]D +4 (c 0.74); IR 2125, 1756 cm-1; 1H NMR δH 1.97
(3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.07 (3H, s), 2.15 (3H, s),
2.16 (3H, s), 3.96 (1H, dd, J ) 6.5, 6.4 Hz), 4.20-4.11 (4H, m),
4.51 (1H, dd, J ) 3.1, 12.4 Hz), 4.67 (1H, d, J ) 7.9 Hz), 5.00
(1H, dd, J ) 3.4, 10.5 Hz), 5.21 (1H, dd, J ) 7.9, 10.5 Hz),
5.37 (1H, d, J ) 3.3 Hz), 5.39 (1H, ddd, J ) 3.1, 5.8, 6.0 Hz),
5.75 (1H, d, J ) 4.3 Hz), 8.02 (1H, s); 13C NMR (100.4 MHz)
δC 20.1 (CH3), 20.4 (CH3), 20.5 (2 × CH3), 20.56 (CH3), 20.60
(CH3), 60.6 (CH), 61.2 (2 × CH2), 66.7 (CH), 68.5 (CH), 69.0
(CH), 70.6 (CH), 71.2 (CH), 76.4 (CH), 101.8 (CH), 114.3 (C),
159.1 (CH), 168.3 (C), 169.2 (C), 170.0 (C), 170.1 (C), 170.13
(C), 170.4 (C); MS m/z (rel intens) 529 (M+ - AcOH, 1), 516
(<1), 331 (56), 169 (100); HRMS m/z calcd for C22H27NO14
529.1432, found 530.1437. Anal. Calcd for C24H31NO16: C,
48.88; H, 5.30; N, 2.38. Found: C, 48.69; H, 5.23; N, 2.31.
a Reagents and conditions: (a) TBAF, (TMS)N3, N-(phenylse-
leno)phthalimide, CH2Cl2, 51%; (b) MsCl, Et3N, CH2Cl2, 85%; (c)
NIS, THF-H2O, 87%; (d) DIB, I2, CH2Cl2, 71%; (e) LiAlH4, Et2O,
then di-tert-butyl dicarbonate, 62%.
galactal derivative 38 was transformed into the 1,5-
imino-D-arabinitol 43. In a very similar sequence of
reactions, the synthesis commenced with azidoselenation
of the double bond,18f followed by mesylation of the
primary alcohol, and anomeric deselenation. The ARF
reaction of â-hydroxy azide 41 afforded the D-arabinono-
nitrile 42, which was subsequently reduced with LiAlH4
(33) For other syntheses of 1,4-iminoalditols using different meth-
odologies, see: (a) Huang, Y.; Dalton, D. R.; Carroll, P. J. Org. Chem.
1997, 62, 372-376. (b) Takano, S.; Moriya, M.; Ogasawara, K.
Tetrahedron: Asymmetry 1992, 3, 681-684. (c) Fleet, G. W. J.; Son, J.
C.; Green, D. St. C.; Bello, I. C.; Winchester, B. Tetrahedron 1988, 44,
2649-2655. (d) Setoi, H.; Kayakiri, H.; Takeno, H.; Hashimoto, M.
Chem. Pharm. Bull. 1987, 35, 3995-3999. (e) Sawada, D.; Takahashi,
H.; Ikegami, S. Tetrahedron Lett. 2003, 44, 3085-3088. For the
synthesis of ent-37 see: (f) Kumareswaran, R.; Hassner, A. Tetrahe-
dron: Asymmetry 2001, 12, 3409-3415.
(34) Compound 43 has been previously prepared as an intermediate
in the synthesis of 1-iminosugars but was not characterized; see: (a)
Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J. Am. Chem. Soc.
1998, 120, 3007-3018. (b) Igarashi, Y.; Ichikawa, M.; Ichikawa, Y.
Tetrahedron Lett. 1996, 37, 2707-2708.
J. Org. Chem, Vol. 69, No. 24, 2004 8441

Herna´ndez et al.
3-O-Formyl-4,5-O-isopropylidene-2-O-methyl-D-ara-
binononitrile (17). The product was isolated by chromatog-
raphy (hexanes-EtOAc, 80:20) as a syrup (71%): [R]D -11.0
(c 0.3); IR 2112, 1737 cm-1; 1H NMR δH 1.35 (3H, s), 1.43 (3H,
s), 3.57 (3H, s), 3.90 (1H, dd, J ) 5.0, 9.0 Hz), 4.06 (1H, dd, J
) 6.3, 9.0 Hz), 4.34 (1H, m), 4.42 (1H, d, J ) 3.0 Hz), 5.31
(1H, ddd, J ) 0.7, 3.0, 7.4 Hz), 8.17 (1H, s); 13C NMR δC 25.1
(CH3), 28.6 (CH3), 58.8 (CH3), 65.9 (CH2), 69.5 (CH), 71.3 (CH),
72.5 (CH), 110.1 (C), 115.3 (C), 159.1 (CH); MS m/z (rel intens)
214 (M+ - Me, 100), 101 (27); HRMS m/z calcd for C9H12NO5
214.0715, found 214.0721. Anal. Calcd for C10H15NO5: C,
52.39; H, 6.59; N, 6.11. Found: C, 52.48; H, 6.62; N, 6.01.
25.9 (CH2), 29.4 (CH3), 40.3 (CH2), 43.0 (CH), 114.0 (CH2),
118.1 (C), 144.0 (C), 205.3 (C); MS m/z (rel intens) 165 (M+,
6), 150 (7), 147 (12), 132 (6), 125 (15), 122 (57), 108 (59), 58
(100); HRMS m/z calcd for C10H15NO 165.1154, found 165.1124.
Anal. Calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found:
C, 72.47; H, 9.31; N, 8.36.
(1S,3S)-(3-Acetyl-2,2-dimethylcyclobutyl)acetonitrile
(27). The product isolated by chromatography (hexanes-
EtOAc, 85:15) has already been partially described.2b In our
hands, it was obtained as an oil (82%): [R]D -97 (c 0.196) (lit.2b
[R]D -215.0); IR 2250, 1703, 1185 cm-1; 1H NMR δH 0.94 (3H,
s), 1.39 (3H, s), 1.99 (2H, m), 2.06 (3H, s), 2.29 (3H, m), 2.91
(1H, dd, J ) 7.7, 9.8 Hz); 13C NMR δC 16.9 (CH3), 17.5 (CH2),
22.8 (CH2), 30.0 (CH3), 30.2 (CH3), 38.1 (CH), 42.9 (C), 53.7
(CH), 118.5 (C), 206.6 (C); MS m/z (rel intens) 165 (M+, 15),
150 (16), 125 (40), 122 (26), 108 (12), 98 (42), 95 (37), 83 (100),
71 (77), 68 (36); HRMS m/z calcd for C10H15NO 165.1154, found
165.1150. Anal. Calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48.
Found: C, 72.57; H, 9.35; N, 8.30.
3â-Hydroxy-5,6-seco-5-oxocholestane-6-nitrile (28). The
product isolated by chromatography (hexanes-EtOAc, 70:30)
has already been partially described.24a It was obtained as a
crystalline solid (64%): mp 68-69 °C (from n-hexane); [R]D
+90.4 (c 0.77, CHCl3) [lit.24a mp 67-69; [R]D +84.6 (MeOH)];
IR 3621, 3489, 2250, 1703 cm-1; 1H NMR δH 0.66 (3H, s), 0.84
(3H, d, J ) 6.7 Hz), 0.85 (3H, d, J ) 6.4 Hz), 0.89 (3H, d, J )
6.4 Hz), 0.96 (3H, s), 2.10 (1H, dd, J ) 3.9, 17.6 Hz), 2.46 (1H,
dd, J ) 3.5, 17.5 Hz), 2.49 (1H, ddd, J ) 2.8, 2.8, 13.6 Hz),
3.42 (1H, dd, J ) 3.9, 14.3 Hz), 4.49 (1H, br s); 13C NMR (125.7
MHz) δC 11.8 (CH3), 17.5 (CH3), 18.5 (CH3), 19.1 (CH2), 22.5
(CH3), 22.69 (CH2), 22.74 (CH3), 23.6 (CH2), 24.3 (CH2), 27.6
(CH2), 27.7 (CH2), 27.9 (CH), 33.6 (CH2), 35.6 (2 × CH), 35.9
(CH2), 39.3 (CH2), 39.4 (CH2), 41.5 (CH), 42.4 (C), 47.2 (CH2),
52.4 (C), 53.2 (CH), 56.0 (CH), 70.8 (CH), 118.7 (C), 217.9 (C);
MS m/z (rel intens) 415 (M+, 4), 397 (10), 371 (18), 343 (68),
317 (94), 128 (100); HRMS m/z calcd for C27H45NO2 415.3450,
found 415.3485. Anal. Calcd for C27H45NO2: C, 78.02; H, 10.91;
N, 3.37. Found: C, 78.09; H, 10.80; N, 3.25.
2,3,5-Tri-O-acetyl-4-O-formyl-D-lyxononitrile (18). The
product was isolated by chromatography (hexanes-EtOAc, 70:
30) as a syrup (65%): [R]D -11 (c 0.12); IR 2115, 1757 cm-1
;
1H NMR δH 2.08 (3H, s), 2.17 (3H, s), 2.22 (3H, s), 4.09 (1H,
dd, J ) 6.5, 12.0 Hz), 4.33 (1H, dd, J ) 5.1, 12.0 Hz), 5.51
(1H, m), 5.53 (1H, d, J ) 6.7 Hz), 5.58 (1H, dd, J ) 3.3, 6.9
Hz), 8.09 (1H, s); 13C NMR δC 20.1 (CH3), 20.3 (CH3), 20.5
(CH3), 59.3 (CH), 61.1 (CH2), 67.1 (CH), 68.2 (CH), 114.0 (C),
159.4 (CH), 168.3 (C), 169.1 (C), 170.1 (C); MS m/z (rel intens)
302 (M+ + 1, <1), 203 (66), 141 (95), 115 (100); HRMS m/z
calcd for C12H16NO8 302.0876, found 302.0878. Anal. Calcd for
C12H15NO8: C, 47.84; H, 5.02; N, 4.65. Found: C, 48.13; H,
5.29; N, 4.50.
2,3-O-Benzylidene-4-O-formyl-D-erythrononitrile (19).
The product was isolated by chromatography (hexanes-
EtOAc, 70:30) as a crystalline solid (64%): mp 78-80 °C (from
1
n-hexane-EtOAc); [R]D -5.1 (c 0.82); IR 2109, 1734 cm-1; H
NMR (C6D6) δH 3.67 (1H, ddd, J ) 5.3, 6.3, 6.3 Hz), 3.96 (1H,
d, J ) 6.3, Hz), 4.24 (1H, dd, J ) 5.3, 11.9 Hz), 4.33 (1H, dd,
J ) 6.3, 11.9 Hz), 5.40 (1H, s), 7.16-7.13 (3H, m), 7.42 (1H,
s), 7.49-7.47 (2H, m); 13C NMR δC 61.3 (CH2), 66.1 (CH), 76.2
(CH), 106.5 (CH), 115.1 (C), 127.0 (2 × CH), 128.6 (2 × CH),
130.4 (CH), 134.5 (C), 159.9 (CH); MS m/z (rel intens) 233 (M+,
25), 232 (30), 105 (100); HRMS m/z calcd for C12H11NO4
233.0688, found 233.0683. Anal. Calcd for C12H11NO4: C,
61.80; H, 4.75; N, 6.01. Found: C, 61.95; H, 4.88; N, 6.08.
4-O-(tert-Butyldimethylsilyl)-3-O-formyl-2-O-(meth-
oxymethyl)-D-erythrononitrile (20). The product was iso-
lated by chromatography (hexanes-EtOAc, 90:10) as a syrup
(90%) which solidified at low temperature: mp 24-26 °C (from
3â-Acetoxy-5,6-seco-5-oxocholestane-6-nitrile (29). The
product isolated by chromatography (hexanes-EtOAc, 93:7)
has already been partially described.25 It was obtained as a
crystalline solid (88%): mp 95-97 °C (from n-hexane); [R]D
+63 (c 0.27) (lit.25 mp 96-97 °C; [R]D +73.7); IR 2250, 1733,
1
n-hexane); [R]D + 42.3 (c 0.26); IR 2109, 1733 cm-1; H NMR
δH 0.08 (6H, s), 0.85 (9H, s), 3.40 (3H, s), 3.79 (1H, dd, J )
5.5, 11.2 Hz), 3.84 (1H, dd, J ) 4.5, 11.2 Hz), 4.68 (1H, d, J )
7.0 Hz), 4.74 (1H, d, J ) 5.5 Hz), 4.81 (1H, d, J ) 7.0 Hz),
5.23 (1H, ddd, J ) 4.5, 5.5, 5.5 Hz), 8.10 (1H, s); 13C NMR δC
-5.5 (2 × CH3), 18.2 (C), 25.8 (3 × CH3), 56.5 (CH3), 60.2 (CH2),
63.7 (CH), 72.1 (CH), 96.0 (CH2), 115.9 (C), 159.5 (CH); MS
m/z (rel intens) 304 (M+ + H, <1), 288 (2), 73 (100); HRMS
m/z calcd for C13H26NO5Si 304.1580, found 304.1490. Anal.
Calcd for C13H25NO5Si: C, 51.46; H, 8.30; N, 4.62. Found: C,
51.24; H, 8.35; N, 4.73.
1
1703 cm-1; H NMR δH 0.67 (3H, s), 0.84 (3H, d, J ) 6.7 Hz),
0.85 (3H, d, J ) 6.4 Hz), 0.90 (3H, d, J ) 6.4 Hz), 0.99 (3H, s),
2.00 (3H, s), 2.11 (1H, dd, J ) 3.8, 17.8 Hz), 2.49 (1H, dd, J )
3.5, 17.8 Hz), 2.57 (1H, ddd, J ) 2.4, 2.4, 15.0 Hz), 3.40 (1H,
dd, J ) 4.3, 15.0 Hz), 5.40 (1H, br s); 13C NMR (125.7 MHz)
δC 11.8 (CH3), 17.5 (CH3), 18.5 (CH3), 19.1 (CH2), 21.2 (CH3),
22.5 (CH3), 22.7 (CH2), 22.8 (CH3), 23.7 (CH2), 24.4 (CH2), 25.0
(CH2), 27.7 (CH2), 28.0 (CH), 34.0 (CH2), 35.6 (CH), 35.7 (CH),
35.9 (CH2), 39.3 (CH2), 39.4 (CH2), 41.5 (CH), 42.4 (C), 43.6
(CH2), 52.0 (C), 53.2 (CH), 56.0 (CH), 73.2 (CH), 118.6 (C),
179.1 (C), 216.5 (C); MS m/z (rel intens) 457 (M+, 18), 397 (47),
369 (71), 110 (100); HRMS m/z calcd for C29H47NO3 457.3470,
found 457.3545. Anal. Calcd for C29H47NO3: C, 76.10; H, 10.35;
N, 3.06. Found: C, 76.15; H, 10.40; N, 3.02.
General Procedure for the Preparation of Compounds
26-30. A solution of â-hydroxy azide (1 mmol) in CH2Cl2 (40
mL) containing DIB (1.2 mmol) and iodine (1 mmol) was
irradiated with two 80 W tungsten-filament lamps at the
temperature and for the time specified in Table 2. The reaction
mixture was then poured into a 10% aqueous Na2S2O3 solution,
extracted with CH2Cl2, dried (Na2SO4), and concentrated in
vacuo. Chromatotron chromatography of the residue (hex-
anes-EtOAc) as specified gave the nitriles.
(3R)-3-(1-Methylethenyl)-6-oxoheptanenitrile (26). The
product was isolated by chromatography (hexanes-EtOAc, 75:
25) as an oil (79%): [R]D -13 (c 0.12); IR 3079, 2243, 1715,
1648, 908 cm-1; 1H NMR (C6D6) δH 1.26 (3H, s), 1.28 (1H, dddd,
J ) 6.0, 8.3, 9.0, 14.1 Hz), 1.39 (1H, dddd, J ) 5.0, 6.7, 8.5,
13.9 Hz), 1.53 (1H, dd, J ) 6.0, 16.8 Hz), 1.54 (1H, dd, J )
7.6, 16.7 Hz), 1.58 (3H, s), 1.70 (1H, ddd, J ) 6.9, 6.9, 8.0 Hz),
1.71 (1H, ddd, J ) 6.0, 6.0, 8.5 Hz), 1.87 (1H, dddd, J ) 5.1,
7.2, 7.2, 10.0 Hz), 4.56 (1H, br s), 4.68 (1H, dd, J ) 1.5, 1.5
Hz); 13C NMR (C6D6, 125.7 MHz) δC 18.1 (CH3), 21.7 (CH2),
3â-Acetoxy-16,17-seco-17,20-dioxopregn-5-ene-16-ni-
trile (30). The product was isolated by chromatography
(benzene-EtOAc, 93:7) as light yellow crystals (51%): mp
121-122 °C (from n-hexane-acetone); [R]D -58.7 (c 1.46); IR
2248, 1722 cm-1; 1H NMR (400 MHz) δ 1.03 (3H, s), 1.33 (3H,
s), 2.02 (3H, s), 2.34 (3H, s), 2.59 (1H, m), 2.37 (1H, m); 13C
NMR (100.4 MHz) δ 14.3 (CH3), 18.0 (CH2), 19.1 (CH3), 19.2
(CH2), 21.3 (CH3), 26.8 (CH3), 27.5 (CH2), 31.3 (CH2), 31.8 (CH),
35.5 (CH2), 36.6 (CH2), 36.7 (C), 37.7 (CH2), 41.9 (CH), 48.4
(CH), 50.1 (C), 73.4 (CH), 118.7 (C), 121.0 (CH), 139.3 (C), 170.4
(C), 200.6 (C), 206.2 (C); MS m/z (rel intens) 342 (M+ - COCH3,
1), 325 (11), 254 (100), 213 (10); HRMS m/z calcd for C21H28-
NO3 342.2069, found 342.2071. Anal. Calcd for C23H31NO4: C,
71.66; H, 8.11; N, 3.63. Found: C, 71.84; H, 8.10; N, 3.63.
8442 J. Org. Chem., Vol. 69, No. 24, 2004

Radical Fragmentation of â-Hydroxy Azides
5-O-Benzyl-4-O-formyl-2,3-O-isopropylidene-D-lyxono-
nitrile (34). A solution of â-hydroxy azide 3318f (100.1 mg, 0.30
mmol) in CH2Cl2 (6 mL) was treated with DIB (115.5 mg, 0.36
mmol) and iodine (75.9 mg, 0.30 mmol). The reaction mixture
was stirred at 20 °C for 1 h, then poured into a 10% aqueous
Na2S2O3 solution, and extracted with CH2Cl2. The organic
layer was dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography (hexanes-EtOAc, 80:20) to give the nitrile
34 (78.3 mg, 0.26 mmol, 86%) as an oil: [R]D +10.1 (c 1.10);
IR 2103, 1732 cm-1; 1H NMR δH 1.39 (3H, s), 1.59 (3H, s), 3.66
(1H, dd, J ) 5.5, 10.8 Hz), 3.77 (1H, dd, J ) 4.3, 10.8 Hz),
4.45 (1H, dd, J ) 5.2, 8.1 Hz), 4.56 (2H, m), 4.75 (1H, d, J )
5.2 Hz), 5.46 (1H, ddd, J ) 4.3, 5.5, 8.1 Hz), 7.32-7.37 (3H,
m), 7.37-7.40 (2H, m), 8.12 (1H, s); 13C NMR (125.7 MHz) δC
25.7 (CH3), 26.8 (CH3), 65.4 (CH), 67.8 (CH2), 70.8 (CH), 73.7
(CH2), 76.5 (CH), 112.4 (C), 116.3 (C), 128.1 (3 × CH), 128.4
(2 × CH), 136.8 (C), 159.6 (CH); MS m/z (rel intens) 305 (M+,
<1), 198 (1), 91 (100); HRMS m/z calcd for C16H19NO5,
305.1263, found 305.1256. Anal. Calcd for C16H19NO5: C,
62.94; H, 6.27; N, 4.59. Found: C, 62.86; H, 6.11; N, 4.73.
5-O-Benzyl-2,3-O-isopropylidene-D-lyxononitrile (35).
A solution of 34 (188.6 mg, 0.62 mmol) in MeOH was treated
at 0 °C with camphorsulfonic acid (28.3 mg, 15%) and stirred
at this temperature for 5 min. The stirring was continued for
2 h at rt, and then the reaction mixture was poured into a
saturated aqueous solution of NaHCO3 and extracted with
EtOAc. The organic layer was washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography (n-
hexanes-EtOAc, 85:15) to give 35 (120.6 mg, 0.44 mmol, 70%)
as an oil: [R]D +12.0 (c 0.74); IR 3692, 3599 cm-1; 1H NMR δH
1.50 (3H, s), 1.68 (3H, s), 3.61 (1H, dd, J ) 5.5, 9.7 Hz), 3.71
(1H, dd, J ) 4.0, 9.7 Hz), 4.24 (1H, d, J ) 4.6 Hz), 4.26 (1H,
dd, J ) 4.0, 5.5 Hz), 4.60 (2H, m), 4.74 (1H, d, J ) 4.6 Hz),
7.23-7.33 (5H, m); 13C NMR (125.7 MHz) δC 25.8 (CH3), 27.0
(CH3), 65.6 (CH), 69.8 (CH), 70.2 (CH2), 73.7 (CH2), 79.1 (CH),
111.9 (C), 116.6 (C), 127.8 (2 × CH), 128.0 (CH), 128.5 (2 ×
CH), 137.2 (C); MS m/z (rel intens) 277 (M+, <1), 262 (1), 91
(100); HRMS m/z calcd for C15H19NO4, 277.1314, found 277.1287.
Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found:
C, 65.22; H, 6.55; N, 4.95.
5-O-Benzyl-2,3-O-isopropylidene-4-O-(methylsulfonyl)-
D-lyxononitrile (36). A solution of 35 (120.6 mg, 0.44 mmol)
and Et3N (90 µL, 66.0 mg, 0.65 mmol) in dry CH2Cl2 (3 mL)
was treated with MsCl (67 µL, 0.87 mmol) under N2 at 0 °C.
The reaction mixture was then stirred at rt for 1 h and
concentrated under reduced pressure. The residue was purified
by column chromatography (benzene-EtOAc, 93:7) to give 36
(109.9 mg, 0.31 mmol, 71%) as an oil: [R]D +8.0 (c 0.29); IR
1365 cm-1; 1H NMR δH 1.39 (3H, s), 1.59 (3H, s), 3.11 (3H, s),
3.76 (1H, dd, J ) 6.1, 11.2 Hz), 3.86 (1H, dd, J ) 4.6, 11.2
Hz), 4.40 (1H, dd, J ) 5.1, 8.7 Hz), 4.57 (2H, s), 4.74 (1H, d, J
) 5.0 Hz), 4.98 (1H, ddd, J ) 4.8, 5.7, 8.6 Hz), 7.32-7.40 (5H,
m); 13C NMR (125.7 MHz) δC 25.9 (CH3), 26.9 (CH3), 38.3 (CH3),
65.4 (CH), 68.7 (CH2), 73.9 (CH2), 76.9 (CH), 78.9 (CH), 112.4
(C), 116.2 (C), 127.9 (2 × CH), 128.2 (CH), 129.6 (2 × CH),
136.5 (C); MS m/z (rel intens) 355 (M+, 8), 340 (2), 91 (100);
HRMS m/z calcd for C16H21NO6S, 355.1090, found 355.1054.
Anal. Calcd for C16H21NO6S: C, 54.07; H, 5.96; N, 3.94; S, 9.00.
Found: C, 54.19; H, 6.05; N, 3.99; S, 8.91.
1,4-Anhydro-5-O-benzyl-4-[(tert-butoxycarbonyl)amino]-
1,4-dideoxy-2,3-O-isopropylidene-L-ribitol (37). To a stirred
solution of 36 (55.7 mg, 0.16 mmol) in THF (6 mL) at 0 °C
under N2 was added LiAlH4 in Et2O (1 M) (2.8 mL, 2.82 mmol)
dropwise. The mixture was stirred for 1 h, and the excess
reagent was carefully destroyed by dropwise addition of a
saturated aqueous solution of Na2SO4 at 0 °C. After 30 min
Boc2O (0.18 mL, 171.2 mg, 0.78 mmol) was added and stirring
continued at rt for 30 min. The reaction mixture was poured
into water and extracted with EtOAc. The organic layer was
washed with brine, dried over anhydrous Na2SO4, and con-
centrated under reduced pressure. The residue was purified
by column chromatography (hexanes-EtOAc, 85:15) to give
the iminosugar 37 (40.2 mg, 0.11 mmol, 69%) as an oil: [R]D
+63.0 (c 0.35); IR 1687 cm-1; 1H NMR (65 °C) δH 1.34 (3H, s),
1.48 (12H, s), 3.53 (1H, dd, J ) 12.3, 5.3 Hz), 3.61 (1H, m),
3.66-3.83 (2H, m), 4.17 (1H, m), 4.52 (2H, s), 4.71 (1H, d, J )
6.0 Hz), 4.75 (1H, dd, J ) 5.7, 5.5 Hz), 7.26-7.32 (3H, m),
7.36-7.38 (2H, m); 13C NMR (125.7 MHz, 65 °C) δC 25.2 (CH3),
27.1 (CH3), 28.5 (3 × CH3), 53.4 (CH2), 63.5 (CH), 70.4 (CH2),
73.5 (CH2), 79.3 (C), 79.7 (CH), 83.2 (CH), 111.5 (C), 127.4 (2
× CH), 127.7 (CH), 128.5 (2 × CH), 138.1 (C), 154.3 (C); MS
m/z (rel intens) 363 (M+, <1), 348 (2), 262 (6), 142 (100); HRMS
m/z calcd for C20H29NO5, 363.2046, found 363.2088. Anal. Calcd
for C20H29NO5: C, 66.09; H, 8.04, N; 3.85. Found: C, 66.20;
H, 8.10, N; 3.91.
Phenyl 2-Azido-2-deoxy-3,4-O-isopropylidene-6-O-(me-
thylsulfonyl)-1-seleno-r-D-galactopyranoside (40). To a
solution of â-phenylseleno azide 39 (656.8 mg, 1.71 mmol) and
Et3N (0.35 mL, 258.5 mg, 2.6 mmol) in dry CH2Cl2 (17 mL) at
0 °C under N2 was added MsCl (0.26 mL, 391.0 mg, 3.41
mmol). The reaction mixture was stirred at rt for 1 h and
concentrated under reduced pressure. The residue was purified
by column chromatography (hexanes-EtOAc, 60:40) to give
40 (669.7 mg, 1.45 mmol, 85%) as an oil: [R]D +198.5 (c 0.95);
IR 2114 cm-1; 1H NMR δH 1.36 (3H, s), 1.52 (3H, s), 2.80 (3H,
s), 4.01 (1H, dd, J ) 5.2, 7.3 Hz), 4.25 (1H, d, J ) 2.5, 5.8 Hz),
4.31 (1H, dd, J ) 6.1, 7.0 Hz), 4.41 (1H, dd, J ) 4.8, 11.5 Hz),
4.44 (1H, dd, J ) 7.6, 11.5 Hz), 4.72 (1H, ddd, J ) 2.6, 4.7, 7.3
Hz), 5.83 (1H, d, J ) 5.2 Hz), 7.31 (3H, m), 7.61 (2H, m); 13C
NMR (125.7 MHz) δC 26.0 (CH3), 27.8 (CH3), 37.5 (CH3), 62.0
(CH), 68.4 (CH2), 68.6 (CH), 72.2 (CH), 75.0 (CH), 82.8 (CH),
110.7 (C), 127.8 (C), 128.2 (CH), 129.3 (2 × CH), 134.7 (2 ×
CH); MS m/z (rel intens) 463/461 (M+, 12/7), 436/434 (5/3), 306
(40), 251 (100); HRMS m/z calcd for C16H21N3O6S80Se 463.0316,
found 463.0341. Anal. Calcd for C16H21N3O6SSe: C, 41.56; H,
4.58; N, 9.09; S, 6.93. Found: C, 41.73; H, 4.49; N, 9.26; S,
6.73.
2-Azido-2-deoxy-3,4-O-isopropylidene-6-O-(methylsul-
fonyl)-D-galactopyranose (41). A solution of 40 (412.2 mg,
0.89 mmol) in THF-H2O (1:1, 9 mL) at 0 °C was treated with
N-iodosuccinimide (1.0 g, 4.45 mmol). The reaction mixture
was stirred for 30 min, poured into an aqueous solution of K2-
CO3, and extracted with EtOAc. The organic layer was washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography
(hexanes-EtOAc, 1:1) to give 41 (251.1 mg, 0.78 mmol, 87%)
as an anomeric mixture (R:â ) 2:1), crystalline solid: [R]D
+83.5 (c 0.71, MeOH); IR 3593, 3473, 2117 cm-1 1H NMR
;
(major isomer) δH 1.35 (3H, s), 1.51 (3H, s), 3.07 (3H, s), 3.46
(1H, dd, J ) 3.3, 7.9 Hz), 4.22 (1H, dd, J ) 2.6, 5.6 Hz), 4.44-
4.47 (3H, m), 4.57 (1H, ddd, J ) 2.6, 4.2, 7.4 Hz), 5.31 (1H, d,
J ) 3.3 Hz); 13C NMR (100.6 MHz) (major isomer) δC 26.1
(CH3), 28.0 (CH3), 37. 5 (CH3), 61.3 (CH), 66.2 (CH), 69.0 (CH2),
72.2 (CH), 73.6 (CH), 91.7 (CH), 110.4 (C); 1H NMR (500 MHz)
(minor isomer) δH 1.34 (3H, s), 1.55 (3H, s), 3.08 (3H, s), 3.40
(1H, dd, J ) 7.9, 7.9 Hz), 4.05 (1H, dd, J ) 7.7, 5.4 Hz), 4.11
(1H, dd, J ) 5.6, 2.3 Hz), 4.14 (1H, ddd, J ) 7.1, 4.8, 2.3 Hz),
4.41 (1H, dd, J ) 11.0, 7.7 Hz), 4.44-4.47 (1H, m), 4.63 (1H,
d, J ) 8.1 Hz); 13C NMR (100.6 MHz) (minor isomer) δC 26.1
(CH3), 28.0 (CH3), 37.5 (CH3), 65.7 (CH), 68.7 (CH2), 71.0 (CH),
72.2 (CH), 77.0 (CH), 95.5 (CH), 111.1 (C); MS m/z (rel intens)
308 (M+ - CH3, 10), 280 (9), 68 (100); HRMS m/z calcd for
C9H14N3O7S, 308.0552, found 308.0562. Anal. Calcd for
C10H17N3O7S: C, 37.15; H, 5.30; N, 13.00; S, 9.90. Found: C,
37.17; H, 5.15; N, 13.02; S, 9.92.
4-O-Formyl-2,3-O-isopropylidene-5-O-(methylsulfonyl)-
D-lyxononitrile (42). A solution of â-hydroxy azide 41 (140.5
mg, 0.43 mmol) in CH2Cl2 (9 mL) was treated with DIB (172.3
mg, 0.53 mmol) and I2 (113.3 mg, 0.45 mmol). The reaction
mixture was stirred at 0-5 °C for 2.5 h under irradiation with
two 80 W tungsten-filament lamps, then poured into a 10%
aqueous Na2S2O3 solution, and extracted with CH2Cl2. The
J. Org. Chem, Vol. 69, No. 24, 2004 8443

Herna´ndez et al.
organic layer was dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The residue was purified by
column chromatography (hexanes-EtOAc, 70:30) to give ni-
trile 42 (90.0 mg, 0.31 mmol, 71%): mp 57-59 °C (from
iminosugar 43 (40.6 mg, 0.15 mmol, 62%) as an oil: [R]D +3.9
1
(c 0.76); IR 3608, 3448, 1682 cm-1; H NMR (65 °C) δH 1.35
(3H, s), 1.46 (9H), 1.47 (3H, s), 1.95 (1H, s), 3.30 (1H, dd, J )
13.6, 5.8 Hz), 3.50 (1H, dd, J ) 14.3, 3.9 Hz), 3.61 (1H, dd, J
) 13.6, 3.4 Hz), 3.78 (1H, dd, J ) 4.2, 14.3 Hz), 3.95 (1H, ddd,
J ) 3.4, 4.6, 5.8 Hz), 4.07 (1H, dd, J ) 4.2, 6.4 Hz), 4.31 (1H,
ddd, J ) 4.0, 4.1, 6.5 Hz); 13C NMR (125.7 MHz, 65 °C) δC
25.3 (CH3), 27.5 (CH3), 28.5 (3 × CH3), 43.3 (CH2), 45.1 (CH2),
68.2 (CH), 72.1 (CH), 76.5 (CH), 80.0 (C), 109.3 (C), 155.8 (C);
MS m/z (rel intens) 273 (M+, 2), 258 (4), 57 (100); HRMS m/z
calcd for C13H23NO5, 273.1576, found 273.1592. Anal. Calcd
C13H23NO5: C, 57.13; H, 8.48; N, 5.12. Found: C, 57.19; H,
8.22, N; 5.04.
1
n-hexane-EtOAc); [R]D +0.7 (c 2.27); IR 2100, 1737 cm-1; H
NMR (C6D6) δH 0.93 (3H, s), 1.32 (3H, s), 2.10 (3H, s), 3.82
(1H, dd, J ) 5.9, 6.0 Hz), 3.91 (1H, dd, J ) 4.9, 11.6 Hz), 3.98
(1H, dd, J ) 5.0, 11.6 Hz), 4.10 (1H, d, J ) 5.8 Hz), 5.41 (1H,
ddd, J ) 4.9, 5.0, 6.0 Hz), 7.47 (1H, s); 13C NMR (100.6 MHz)
δC 25.6 (CH3), 26.6 (CH3), 37.7 (CH3), 64.8 (CH), 66.3 (CH2),
68.8 (CH), 75.1 (CH), 113.1 (C), 116.0 (C), 159.5 (CH); MS m/z
(rel intens) 278 (M+ - CH3, 100), 126 (43); HRMS m/z calcd
for C9H12NO7S, 278.0334, found 278.0329. Anal. Calcd for
C10H15NO7S: C, 40.95; H, 5.15; N, 4.78; S, 10.93. Found: C,
41.12; H, 5.35; N, 4.90; S, 10.92.
1,5-Anhydro-5-[(tert-butoxycarbonyl)amino]-1,5-
dideoxy-2,3-O-isopropylidene-D-lyxitol (43). To a stirred
solution of 42 (70.5 mg, 0.24 mmol) in THF (9 mL) at 0 °C
under N2 was added LiAlH4 in Et2O (1 M) (2.8 mL, 2.82 mmol)
dropwise. The mixture was stirred for 1 h, and the excess
reagent was carefully destroyed by dropwise addition of a
saturated aqueous solution of Na2SO4 at 0 °C. After 30 min at
0-10 °C, Boc2O (0.28 mL, 262.6 mg, 1.2 mmol) was added and
stirring continued for 30 min. The reaction mixture was poured
into water and extracted with EtOAc. The organic layer was
washed with brine, dried over anhydrous Na2SO4, and con-
centrated under reduced pressure. The residue was purified
by column chromatography (hexanes-EtOAc, 1:1) to give the
Acknowledgment. This work was supported by
the Investigation Programme Nos. BQU2000-0650,
BQU2001-1665, and PPQ2000-0728 of the Direccio´n
General de Investigacio´n Cient´ıfica y Te´cnica, Spain.
C.R.-F. thanks the Direccio´n General de Investigacio´n
del Gobierno de Canarias for a fellowship.
Supporting Information Available: Detailed experi-
mental procedures and spectral and analytical data for com-
pounds 3, 5, 6, 8, 10-14, and 25. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO049026P
8444 J. Org. Chem., Vol. 69, No. 24, 2004