Glycosyl transfer to nitrogen via cycloaddition

Article abstract of DOI:10.1021/ol990583l

(Equation Presented) This letter describes the reduction to practice of a novel concept for functionalization of the anomeric carbon of carbohydrates with a nitrogen substituent. Thus, bisheterodienes with a thiono sulfur terminus and a sulfonylimine term

Full text of DOI:10.1021/ol990583l

ORGANIC
LETTERS
1999
Vol. 1, No. 1
111-113
Glycosyl Transfer to Nitrogen via
Cycloaddition
,†
Baoqing Li,† Richard W. Franck,* Giuseppe Capozzi,‡ Stefano Menichetti,‡ and
Cristina Nativi‡
Department of Chemistry, Hunter College/CUNY, 695 Park AVenue,
New York, New York 10021, and Dipartimento di Chimica Organica,
UniVersita di Firenze, Via G. Capponi 9, I-50121 Firenze, Italy
rfranck@shiVa.hunter.cuny.edu
Received April 12, 1999
ABSTRACT
This letter describes the reduction to practice of a novel concept for functionalization of the anomeric carbon of carbohydrates with a nitrogen
substituent. Thus, bisheterodienes with a thiono sulfur terminus and a sulfonylimine terminus are shown to undergo cycloaddition smoothly
and stereoselectively to three different glycals.
Glycoproteins are a class of molecules under intense study
by glycobiologists.1,2 As a consequence of this interest, the
organic chemistry required for the synthesis of glycosylated
amino acids and peptides has been a rapidly developing area
of research. The synthesis of N-linked glycoside derivatives
is almost universally accomplished by derivatizing a glyco-
syl-NH2 species.3 Two recent examples of “the state-of-the-
art” from the Danishefsky lab and the Meldal/Bock/Paulsen
team describe polymer-bound methods. The former uses a
resin-attached trisaccharide-NH2 coupling to tri- and pen-
tapeptides in solution.4 The latter uses solution-phase glycosyl
donors reacting with peptides attached to a PEG-based resin.5
The one exception to this generalization is the modfied Ritter
reaction described by Fraser-Reid.6 We wish to describe a
second exception: our cycloaddition approach depicted in
eq 1 where X ) S and Y) N which delivers functionalized
N to C-1 of glycals.
Our earlier work, where X ) S and Y ) O, used the
computed gap between the LUMO of the heterodiene and
the HOMO of the glycal as a predictor of successful
cycloaddition.7 After completing a computational survey of
potential substitutents for imine nitrogens, we settled on the
sulfonylimine function as being suitable for production of a
low-lying LUMO for our heterodiene. As the model case,
we chose methyl acetoacetate N-phenylsulfonylimine 1
(shown as the predominant enamine tautomer), easily
† Hunter College.
‡ Universita di Firenze.
(1) Varki, A. Glycobiology 1993, 3, 97-130.
(2) (a) Bill, R. M.; Flitsch, S. L. Chem. Biol. 1996, 145. (b) Paulsen, H.;
Peters, S.; Bielfeldt, T. Glycoproteins; Montreuil, J., Schacter, H., Vliegent-
hart, J. F. G., Eds.; Elsevier: New York, 1995; Chapter 4, p 87.
(3) Glycoconjugates resembling glycopeptides, but with “unnatural”
linkers, are also an important area of research, for example: Rodriguez, E.
Z.; Marcaurelle, L. A.; Bertozzi, C. R. J. Org. Chem. 1998, 63, 7134-
7135.
(6) Ratcliffe, A. J.; Konradsson, P.; Fraser-Reid, B. J. Am. Chem. Soc.
1990 112, 5665.
(4) Roberge, J. Y.; Beebe, X.; Danishefsky, S. J. J. Am. Chem. Soc. 1998,
120, 3915-3927.
(5) Schleyer, A.; Meldal, M.; Manat, R.; Paulsen, H.; Bock, K. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1976.
(7) Capozzi, G.; Dios, A.; Franck, R. W.; Geer, A.; Marzabadi, C.;
Menichetti, S.; Nativi, C.; Tamarez, M. Angew. Chem. 1996, 108, 805-
807; Angew. Chem., Int. Ed. Engl. 1996, 35, 777-779. (b) Dios, A.; Geer,
A.; Marzabadi, C.; Franck, R. W. J. Org. Chem. 1998, 63, 6673.
10.1021/ol990583l CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/17/1999

prepared from methyl acetoacetate by heating with benzene-
sulfonamide. Phthalimidosulfenylation of 1 smoothly af-
forded derivative 2, the key precursor to the transient thiono
sulfonylimine 3. When 2 was treated with pyridine in the
presence of tribenzyl glucal 4, tribenzyl galactal 5, and
tribenzyl allal 6, the cycloadducts 7, 8, and 9 were produced
in very good yield (Scheme 1).
Scheme 2. Cleavage of Cycloadducts
Scheme 1. Iminothione for N-Linkage to Carbohydrate C-1
to the sulfonylimine 16.10 Then, mild thermolysis of this
modified anthracene adduct in the presence of glycals 4 and
5 liberates the transient thiono species 3c (R2 ) Et) which
is smoothly trapped in cycloaddition to afford 7a and 8a
(R2 ) Et) (Scheme 3).
Scheme 3. Retrocycloaddition Route to N-Transfer Reagent
a PhSO2NH2, TsOH, benzene, 95%. b TMSCH2CH2SO2NH2,
TsOH, benzene, 93%. c PhthNSCl, 2a >95%, 2b 95%. d Pyridine,
CH2Cl2.
The experiments were also repeated with the TMS-
ethylsulfonyl N-protecting group developed by Weinreb,8
with similar results. The TMS-ethyl group can be cleanly
removed with CsF to afford the NH species 8c. Preliminary
ozonolysis experiments with adducts 7a and 8c showed that
the bicyclic species could be cleaved to produce the
glycosylamide function illustrated in compounds 10 and 11
(Scheme 2).
a Pyridine (1 equiv), anthracene, 90%. b NH2OH, 85%. c PhSOCl,
Et3N, Et2O/CH2Cl2 (1:1), -10 oC to rt. 20 h, 40%. d Lutidine (0.2
o
equiv), CHCl3 60 C.
As an alternate route to the key sulfonylimino thione 3,
we took advantage of the reversibility of the anthracene
adduct 14 of thiono keto ester 13.9 Adduct 14 was converted
to its oxime 15. The oxime, when treated with toluenesulfinyl
chloride, undergoes sulfinylation followed by rearrangement
To develop our cycloaddition for a direct transfer to a
model peptide, we modified aspartic acid as shown in
(9) Capozzi, G.; Menichetti, S.; Nativi, C.; Vergamini, C. Synthesis 1998,
915-918. Cycloadditions to simple dienophiles of an NOAc heterodiene
related to 3c, and also prepared via retrocycloaddition.
(10) Brown, C.; Hudson, R. F.; Record, K. A. F. J. Chem. Soc., Perkin
Trans. 2 1978, 822-826.
(8) Weinreb, S. M.; Ralbovsky, J. L. Trimethylsilyl ethanesulfonyl
chloride. In Encylopedia of Reagents for Organic Synthesis; Paquette, L.
A., Ed.; Wiley: Chichester, U.K., 1995; Vol. 7, pp 5255-5256.
112
Org. Lett., Vol. 1, No. 1, 1999

Scheme 4. Blocked aspartic acid derivative 17 was converted
to keto ester 18 using Meldrum’s acid as a nucleophilic
analogue 23, thus validating our concept. In conclusion, we
have described a unique method for introducing function-
alized nitrogen to the anomeric carbon of carbohydrates.13,14
Acknowledgment. (a) In Memoriam, Gertrude Elion,
1918-1999. (b) This research was presented at the ACS
Meeting, Boston August 23-27, 1998, ORG 744. (c) The
research in Firenze was carried out within the framework of
the National Project “Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni” supported by the Ministero
dell′Universita` e ella Ricerca Scientifica e Tecnologica,
Rome, and by the University of Firenze.. At Hunter funding
came from NIH grants GM 51216 and RR 03037 and PSC/
CUNY awards. The NMR laboratory has received support
from the NY State GRI and HEAT initiatives. The mass
spectrometry facility has also received funding from GRI
and NSF grant CHE-9708881.
Scheme 4. Transfer of Aspartate
OL990583L
(13) All cycloadducts had molecular ions (either ESMS or CI/MS) and
proton and carbon NMR data consistent with their structures. Adducts 7a,
8b, 10, and 11 have confirming combustion analyses and the structure of
7a has been confirmed by X-ray crystallography.
(14) Representative Procedures. Phthalimidosulfenylation of methyl
3-benzenesulfonylamino-2-butenoate. To a solution of sulfonyl imine 1a
(prepared via refluxing a solution of methyl acetoacetate (1.2 equiv) and
benzenesulfonylamide (1 equiv) in a convenient amount of benzene with a
catalytic amount of p-toluenesulfonic acid followed by conventional workup)
was added PhthN-S-Cl (1.2 equiv) in portions at 0 °C during a period of
15 min. The reaction mixture was stirred at such temperature for an
additional 20 min and allowed to warm to room temperature in 30 min.
Cold n-pentane was added. A lot of white precipitate formed which was
filtered and then washed with cold n-pentane to afford the desired 2a. Yield
of crude suitable for the following step: >99%; 1HNMR (CDCl3) δ 12.53
(s, 1H), 7.95-7.57 (m, 9H), 3.80 (s, 3H), 2.89 (s, 3H). Cycloaddition of
methyl 2-phthalimidosulfenyl-3-benzenesulfonylamino-2-butenoate 2a
with tri-O-benzyl-D-glucal (4). To a solution of the phthalimidosulfenyl
imine 2a (1.2 equiv) and tri-O-benzyl-D-glucal (4) in CHCl3 was added a
catalytic amount of 2,6-lutidine (2 mol %). The resulting solution was stirred
at room temperature until the reaction was complete as monitored by TLC.
The solution was dissolved in dichloromethane and washed with saturated
ammonium chloride and brine and dried over Na2SO4. The organic solvent
was removed under reduced pressure. The crude materials were purified
by a silica gel column (ethyl acetate/petroleum ether) to give the desired
product 7a. When phthalimide residues are not cleanly separated, a 20%
NaOH wash was used to extract the phthalimide after flash chromatography.
Yield of 7a: 82% (140 mg, 0.35 mmol); FTIR (neat) 1715.3, 1585.4, 1448.2,
1357.6, 1251.5, 1169.1; 1HNMR (CDCl3) δ 7.96 (d, 2H), 7.52 (t, 2H), 7.40-
7.16 (m,), 6.33 (d, J ) 7.2, 1H), 4.82-4.57 (m,), 3.71 (s, 3H), 3.52-3.3
(m, 4H), 2.52 (s, 3H); 13CNMR (CDCl3) δ 165.2, 148.1, 139.2, 137.9, 137.6,
133.1, 128.6, 128.2, 128.0, 127.7, 127.6, 127.5, 117.4, 87.9, 79.0, 77.9,
76.1, 74.9, 73.3, 72.0, 67.5, 52.1, 47.9, 21.4. Anal. Calcd for C38H39O8-
NS2: C, 65.03; H, 5.56; N, 2.00. Found: C, 64.67; H, 5.93; N, 2.12.
a (i) Isopropenyl chloroformate, DMAP, Et3N; (ii) EtOH, heat,
c
92% for two steps. b NH2OH. TsCN, Et3N, CCl4, 65% for two
d
steps. PhthNSCl.
C-donor in a peptide coupling protocol following the work
of Shiori.11 The ketone was then converted to its sulfonyl
oxime 19 according to a sulfinylation-rearrangement pro-
cedure reported by Boger.12 Phthalimidosulfenylation of 20
followed by cycloaddition led smoothly to glycopeptide
(11) Hamada, Y.; Kondo, Y.; Shibata, M.; Shioiri, T. J. Am. Chem. Soc.
1989, 101, 669-673
(12) Boger, D. L.; Corbett, W. L. J. Org. Chem. 1992, 57, 4777.
Org. Lett., Vol. 1, No. 1, 1999
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