6478
J . Org. Chem. 1996, 61, 6478-6479
Sch em e 1
Nod u la tion F a ctor s: A Str a tegy for
Con ver gen t Assem bly of a La te-Sta ge Key
In ter m ed ia te Illu str a ted by th e Tota l
Syn th esis of Nod Rf-III (C18:1) (MeF u c)†
J ohn S. Debenham, Robert Rodebaugh,‡ and
Bert Fraser-Reid*
Paul M. Gross Chemical Laboratory,
Department of Chemistry, Duke University,
Durham, North Carolina 27708
Received J une 13, 1996
Nodulation factors 1 comprise a family of unique
oligosaccharides composed substantially of glucosamine
(2-amino-2-D-deoxyglucose) units that are N-acylated
with acetic and fatty acid residues, the latter residing at
the nonreducing terminus.1 These lipochitooligosaccha-
rides are secreted by bacteria as signaling devices that
trigger early steps in the formation of root nodules in
leguminous plants.2 As such, nod factors are crucial
effectors in nature’s most prolific factory of organic
metabolizable nitrogen in the global nitrogen cycle and
are therefore important targets for laboratory synthesis.3
In this paper we exemplify a highly convergent approach
to nod factor construction with a synthesis of NodRf-III
(C18:1) (MeFuc)4 (2) produced by Rhizobium fredii.
glycosyl donor 5 (after protection of the 4-OH) or acceptor
6 (by application of dibromination sidetracking).6 The
reducing end retron is identified as a benzyl glycoside 7.
In Scheme 1 is shown the generic form of a nod factor
1, which emphasizes the presence of (a) a nonreducing
end glucosamine bearing a primary or secondary fatty
amide, (b) a repeating â(1f4) linked N-acetylglucos-
The analogous monosaccharide building blocks 4 and
6 were prepared from D-glucosamine hydrochloride 9 by
the same basic strategy. Thus, the procedure of Lemieux7
was followed for preparing the phthalimides 10a and
10b, and a Koenigs-Knorr reaction was used for con-
verting them into the n-pentenyl glycosides 11a and 11b
(Scheme 2). These triols were then benzylidinated so as
to effect the chemoselective Garegg8 reductive cleavage
leading to alcohols 12 and 5.
Acetylation of 12 gave donor 4, while dibromination
of 5 gave 6. However, the latter reaction was not as
straightforward as in previous cases; thus, use of Br2 or
Br2/Et4NBr gave poor yields of 6. Fortunately CuBr2/
LiBr9 afforded quantitative recovery of dibromide 6 and
coupling to 4 proceeded smoothly to give dibromide 13a
in 71% yield. Subsequent debromination with NaI af-
forded donor 13b in 93% yield.10
amide, and (c) a reducing end N-acetylglucosamine in
-
which the C6 OH may be substituted by H, CONH2, SO3
,
or monosaccharide (generally fucose or arabinose). In the
case of NodRf-III (C18:1) (MeFuc) (2), the carbohydrate
backbone is composed of a glucosamine trimer, which is
2-O-methylfucosylated through an R(1f6) linkage on the
reducing terminus, while the nonreducing end glu-
cosamine is acylated with cis-vaccenic acid (11(Z)-octa-
decenoic acid). Ideally, in the preparation of 2, the key
synthetic intermediate 3a should represent a highly
advanced structure that allows various late-stage alter-
ations as may be required for biological evaluations.
Accordingly, in our retrosynthetic plan the unique
glucosamine constituent is carried in tetrachlorophtha-
loyl (TCP)5 protected form 4, while the repeating unit is
an n-pentenyl glycoside (NPG) capable of serving as a
The acceptor disaccharide 15 was prepared by coupling
the n-pentenyl fucoside 14, used as an anomeric mixture,
to diol 7 in a regioselective11 and stereoselective12,13
manner.
Convergent coupling of disaccharides 13b and 15 then
afforded the tetrasaccharide intermediate 3a (Scheme 3).
† This work was supported by NIH grant GM-41071.
‡ Recipient of a Paul M. Gross Fellowship (1994-95) and the Charles
R. Hauser Fellowship (1995-96).
(1) Lerouge, P. Glycobiology 1994, 4, 127-134.
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(9) Additional methodological studies on NPG sidetracking will
appear in the full paper.
(3) For related synthetic efforts see: (a) Nicolaou, K. C.; Bockovich,
N. J .; Carcanague, D. R.; Hummel, C. W.; Even, L. F. J . Am. Chem.
Soc. 1992, 114, 8701-8702. (b) Wang, L. X.; Li, C.; Wang, Q. W.; Hui,
Y. Z. J . Chem. Soc., Perkin Trans. 1 1994, 621-628. (c) Tailler, D.;
J acquinet, J . C.; Beau, J . M. J . Chem. Soc., Chem. Commun. 1994,
1827-1828. (d) Ikeshita, S.; Sakamoto, A.; Nakahara, Y.; Nakahara,
Y.; Ogawa, T. Tetrahedron Lett. 1994, 35, 3123-3126. (e) Ikeshita, S.;
Nakahara, Y.; Ogawa, T. Glycoconjugate J . 1994, 11, 257-261.
(4) Bec-Ferte, M. P.; Savagnac, A.; Pueppke, S. G.; Prome, J . C. In
New Horizons in Nitrogen Fixation. Proceedings of the 9th International
Congress on Nitrogen Fixation; Palacios, R., Mora, J ., Newton, W. E.,
Eds.; Kluwer Academic Publishers: Dordrecht, 1992; pp 157-158.
(5) (a) Debenham, J . S.; Madsen, R.; Roberts, C.; Fraser-Reid, B. J .
Am. Chem. Soc. 1995, 117, 3302-3303. (b) Debenham, J . S.; Fraser-
Reid, B. J . Org. Chem. 1996, 61, 432-433. (c) Castro-Palomino, J . C.;
Schmidt, R. R. Tetrahedron Lett. 1995, 36, 5343-5346.
(10) Merritt, J . R.; Debenham, J . S.; Fraser-Reid, B. J . Carbohydr.
Chem. 1996, 15 (1), 65-72.
(11) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 30, 155-
224.
(12) Rodebaugh, R.; Patel, N. S.; Fraser-Reid, B. Unpublished
results.
(13) Zuurmond, H. M; van der Laan, S.; van der Marel, G. A.; van
Boom, J . H. Carbohydr. Res. 1991, 215, c1-c3.
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