Intramolecular 1,3-Dipolar Cycloadditions of Sugar Ketonitrones: A Convenient Method for Stereoselective Formation of Nitrogenated Quaternary Centers

Full text of DOI:10.1021/jo9710893

6710
J . Org. Chem. 1997, 62, 6710-6711
In tr a m olecu la r 1,3-Dip ola r Cycloa d d ition s
of Su ga r Keton itr on es: A Con ven ien t
Meth od for Ster eoselective F or m a tion of
Nitr ogen a ted Qu a ter n a r y Cen ter s
S. Torrente, B. Noya, M. D. Paredes, and R. Alonso*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al
CSIC, Universidad de Santiago de Compostela,
15706 Santiago, La Corun˜a, Spain
F igu r e 1.
we found only a single application of this transformation
of the more hindered sugar-ketonitrones: the cycloaddi-
tion of N-methylketonitrone 3 to phenylacetylene, which
gives the isoxazolidine 4 and the aziridine 5 (eq 2).7
Received J une 17, 1997
Cycloaddition reactions are among the most important
transformations in organic chemistry.1 Currently, they
are the focus of much interest in the carbohydrate field,2
where the use of some of them has hitherto been rare or,
at most, limited. A case in point is the 1,3-dipolar
cycloaddition of ketonitrones, which is schematically
illustrated for a protected cyclic sugar in eq 1.
Herein we report the first results of our investigation
of the 1,3-dipolar cycloaddition of ketonitrones, which
show that this reaction is a synthetically useful procedure
for the stereocontrolled generation of nitrogenated qua-
ternary centers in sugar substrates.
Initial experiments were carried out with ketonitrone
7, which was prepared from the known 4-oxo-mannopy-
ranose derivative 68 (eq 3). Gratifyingly, reaction of 7
Our interest in this reaction stems from our studies
toward the synthesis of (-)-tetrodotoxin (TTX, 1)3,4 and
(+)-lactacystin (2).5 Specifically, we envisaged that it
might be of utility in the formation of the nitrogenated
quaternary centers at positions C8a and C5 of 1 and 2,
respectively (Figure 1).
Although use of the 1,3-dipolar cycloaddition of aldoni-
trones has been widespread,2,6 at the outset of this study
(1) (a) For a general treatise see Cycloaddition Reactions in Organic
Synthesis; Carruthers, W., Ed.; Tetrahedron Organic Chemistry Series,
Vol. 8, Pergamon Press: New York, 1990. (b) See also Advances in
Cycloaddition; Vol. 1 (1988), Vol. 2 (1990), and Vol. 3 (1993); Curran,
D. P., Ed.; J ai Press Inc.: London. (c) An extensive review of the
synthetic utility of cycloaddition reactions can be found in Compre-
hensive Organic Synthesis; Trost, B., Ed.; Pergamon Press: New York,
1992; Vol. 5. In Vol. 4 of the same collection, A. Padwa reviews
intermolecular 1,3-dipolar cycloadditions (Chapter 4.9, pp 1069-1109),
and P. A. Wade reviews intramolecular 1,3-dipolar cycloadditions
(Chapter 4.10, pp 1111-1168). See also Confalone, P. N.; Huie, E. M.
Org. React. 1988, 36, 1-173. (d) The mechanisms of two of the most
important cycloaddition reactions (the Diels-Alder reaction and the
1,3-dipolar cycloaddition) are discussed from a historical perspective
(1935-1995) in Houk, K. N.; Gonza´lez, J .; Li, Y. Acc. Chem. Res. 1995,
28, 81-90.
(2) (a) For a monograph, see Cycloaddition Reactions in Carbohy-
drate Chemistry; Giuliano, R. M., Ed.; ACS Symposium Series No. 494,
1992. (b) For a discussion of the applications of cycloaddition reactions
in the transformation of carbohydrate derivatives into functionalized
cyclohexanes and cyclopentanes, see Ferrier, R. J .; Middleton, S. Chem.
Rev. 1993, 93, 2779-2831.
(3) Tetrodotoxin, Saxitoxin and the Molecular Biology of the Sodium
Channel; Annals of The New York Academy of Sciences; Kao, C. Y.,
Levinson, S. R., Eds.; New York Academy of Sciences: New York, 1986;
Vol. 479. To date only one total synthesis of tetrodotoxin in racemic
form has been accomplished: Kishi, Y.; Aratani, M.; Fukuyama, T.;
Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiure, S.; Kakoi, H.
J . Am. Chem. Soc. 1972, 94, 9217. Ibid. 1972, 94, 9219.
with ethyl vinyl ether took place regioselectively to give
cycloadducts 8 and 9 in an acceptable 73% combined
yield. Formation of the nitrogenated quaternary center
proceeded, however, with modest stereoselectivity (8:9 )
6:1).
Next, we explored an intramolecular version of this
reaction. Cycloaddition of compound 10, which has a
4-O-allyl group as the internal dipolarophile (entry 1,
Table 1), proceeded with yield similar to that of the
intermolecular reaction, but in this case a single stere-
oisomer was isolated. Spectroscopic analysis of this
product strongly suggested it to be the adduct 11.
Nonetheless, to rule out isomeric products such as 13 and
15, which could have been formed by R-epimerization of
ketone 10 prior to the intramolecular cycloaddition, the
corresponding epimeric ketones 12 and 14 were subjected
(4) We recently reported a free radical approach to the formation of
the quaternary C8a center of this molecule: Noya, B.; Alonso, R.
Tetrahedron Lett. 1997, 38, 2745. This paper lists references relating
to the main attempts at development of a total synthesis of the
enantiomerically pure toxin and to the recent isolation of new
congeners.
(5) (+)-Lactacystin was recently reported as the first non-protein
neurotrophic factor: Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki,
K.; Moriguchi, R.; Tanaka, H.; Sasaki, Y. J . Antibiot. 1991, 44, 113.
(6) For the 1,3-dipolar cycloaddition of glycosyl aldonitrones, see
Fisera, L.; Al-Timari, V. A. R.; Ertl, P. in ref 2a, Chapter 11. For a
recent review of asymmetric cycloadditions of nitrones, including sugar-
derived aldonitrones, see Frederickson, M. Tetrahedron 1997, 53, 403.
(7) Tronchet, J . M. J .; Mihaly, M. E. Helv. Chim. Acta 1972, 55,
1266. See also ref 11.
For
a discussion of the main attempts at total synthesis of (+)-
lactacystin, see Casiraghi, G.; Rassu, G.; Zanardi, F. Chemtracts-Org.
Chem. 1994, 266-272. See also: Fenteany, G.; Standaert, R. F.; Lane,
W. S.; Choi, S.; Corey, E. J .; Schreiber, S. L. Science 1995, 268, 726
and references cited therein.
(8) Cerny, M.; Stanek, J ., J r. Adv. Carbohydr. Chem. 1977, 34, 23-
177.
S0022-3263(97)01089-X CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 20, 1997 6711
Ta ble 1. In tr a m olecu la r Cycloa d d ition of Ketosu ga r
Nitr on esa
F igu r e 2. Alternative view of 17 and 18 to facilitate com-
parison with (-)-tetrodotoxin.
Next, we investigated the utility of the 1,3-dipolar
cycloaddition for the construction of a nitrogen-bearing
quaternary center at position C5 of the R-D-glucofuranose
derivative 19.10,11 The tetracyclic adduct 20 was obtained
as the main product in 69% yield, the formation of the
bridged isoxazolidine being in keeping with the results
obtained for cycloaddition of structurally related
aldonitrones.12,13
Finally, two additional cycloaddition experiments were
performed (entries 6 and 7, Table 1). Although the yields
for these reactions are moderate, they serve to illustrate
the potential of this methodology for the preparation of
a variety of heterocyclic and carbocyclic systems.
In summary, we have shown that nitrones derived
from ketosugars can undergo both inter- and intramo-
lecular 1,3-dipolar cycloadditions to afford carbohydrate
derivatives containing nitrogenated quaternary centers
at various positions (e.g. C4 in 8, C3 in 11, and C5 in
20). It was also shown that the stereochemistry of the
reaction could be efficiently controlled by tethering the
dipolarophile to a sugar hydroxyl group. Thus this
methodology was successfully used to prepare synthetic
precursors of (-)-tetrodotoxin, and to form a quaternary
center at C5 of a glucofuranose derivative, which may
have implications for the synthesis of (+)-lactacystin.
Additional cycloaddition reactions examined (entries 6
and 7, Table 1) extend the utility of this method for the
preparation of other heterocyclic and carbocyclic systems
from carbohydrates.2b
a
Cycloadditions were carried out by treatment of the ketone
precursor with excess MeNHOH‚HCl or BnNHOH‚HCl and pyri-
dine in ethanol in the presence of 4 Å molecular sieves, initially
at rt and then at 45-65 °C. See ref 9. c CH2Cl2 was used as
b
Ack n ow led gm en t. We thank the Xunta de Galicia
(XUGA 20902B95) and the DGES (PB95-0824) for
funding this work. S.T. thanks the Ministry of Educa-
tion (Spain) for a fellowship. B.N. and M.D.P. thank
the Xunta de Galicia for predoctoral fellowships. M.D.P.
is grateful to the Segundo Gil Da´vila Foundation
(Galicia) for a fellowship.
solvent; no molecular sieves were employed.
to independent cycloaddition reactions (entries 2 and 3,
Table 1). In each case, a single adduct different from 11
was isolated; identification of these adducts as 13 and
15 confirmed that no epimerization had taken place
under the reaction conditions. Regarding yields, the
efficient cycloadditions of 12 (77%) and 14 (65%), in which
the dipolarophile must approach the nitrone molecule
from its more hindered concave face, are especially
noteworthy.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data are provided for new
compounds (34 pages).
These results also clearly show that the stereochem-
istry of the reaction can be controlled by tethering the
dipolarophile to one of the sugar hydroxyl groups. Use
of the R C4-hydroxyl for this purpose, as in 10, allowed
the exclusive formation of the C3S adduct 11, while
tethering the allyl group to the â C4-hydroxyl, as in 12
and 14, gave the C3R isomers 13 and 15, respectively.
Having established the feasibility of the cycloaddition
procedure, we next evaluated its suitability for the
formation of the N-C8a bond in (-)-tetrodotoxin. Treat-
ment of 16 with MeNHOH‚HCl and pyridine in CH2Cl2
gave the desired cycloadduct 17 in good yield (79%, entry
4, Table 1).9 The more versatile N-benzyl derivative 18
could be prepared similarly. Except for the C11-hy-
droxymethyl group, all the carbon atoms in TTX are
present in intermediates 17 and 18, and those destined
to form the C4a, C7, C8, C8a and C9 centers already
possess the required configuration (Figure 2).
J O9710893
(9) A solution of ketone 16 (564 mg), MeNHOH‚HCl (474 mg, 300
mol %), and dry pyridine (0.52 mL, 350 mol %) in dry CH2Cl2 (16 mL)
was refluxed for 28 h. The organic phase was washed with water,
dried, and concentrated. Flash chromatography of the residue afforded
isoxazolidine 17 (485 mg, 79%).
(10) Formation of a nitrogenated quaternary center at position C5
of a glucofuranose derivative analogous to 19 (by trichloroacetimidate
rearrangement), and final conversion to (+)-lactacystin, has recently
been reported: Chida, N.; Takeoka, J .; Tsutsumi, N.; Ogawa, S. J .
Chem. Soc., Chem. Commun. 1995, 793.
(11) In the course of this work, a related 1,3-dipolar cycloaddition
was reported for the furanose of nucleoside derivatives: Rong, J .;
Roselt, P.; Plavec, J .; Chaltopadhyaya, J . Tetrahedron 1994, 50, 4921.
(12) (a) Datta, S.; Chattopadyay, P.; Mukhopadhyay, T.; Bhatta-
charjya, A. Tetrahedron Lett. 1993, 34, 3585. (b) Shing, T. K. M.; Wong,
C.; Yip, T. Tetrahedron: Asymmetry 1996, 7, 1323.
(13) The high yield obtained in the cycloaddition of 19 strongly
suggests that a synthetic approach to (+)-lactacystin and/or lactacystin
analogues based on this methodology would be viable (see also note
10).