An efficient and stereocontrolled synthesis of the nephritogenoside core structure

Tetrahedron Letters. Vo1.32. N0.47, pp 6873.6876, 1991 Rinred in Great Britain

00-20-4039/91s3.00 + .oo Pcrgamon Press plc

An Efficient and Stereocontrolled Synthesis the Nephritogenoside Core Structure Makoto

Sasaki* and Kazuo

of

Tachibana

Department of Chemistry, Faculty of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan

Hiroshi

Nakanishi

National Chemical Laboratory for Indushy, Tsukuba, Ibaraki 305, Japan

Key Words: nephritogenoside:

glycopeptidc;

glomemlonephritis;

p-selective glycosylation;

a-n Valium ion

An efJicient and stereocontrolled synthesis of the core trisaccharide 2 ofnephritogenic glyropeptide, nephritogenoside 1 is described. Key to our synthetic strategy wtls @selective glycosylation without neighboring group participation.

Abstract:

1 was isolated as a minor component

Nephritogenosidel normal rats after exhaustive progressive

Structurally,

trisaccharide

exhibits

membrane

of

an activity for the induction

basement

of

animals by a single footpad injection

with incomplete

is uniquely distinct from common glycoproteins;

namely, the

linked to the peptide chain through a-D-gIucose.2 The full sequence of the

in the peptide

chain was proposed

and biological investigations,

In this communication

from the glomerular

This compound

in homologous

the glycopeptide

core is N-glycosidically

21 amino acid residues confirmation

digestions.

chronic glomerulonephritis

Freund’s adjuvant. trisaccharide

proteolytic

recently. 3 In view of the unambiguous

we wish to report an efficient and stereocontroIled

2 ?f this novel nephritogenic

structural

we initiated a synthetic program directed toward nephritogenosidc

glycopeptide,

synthesis of the asparagine-linked

based on p-selective

glycosylation

group participation.

1:

R = peptide (nephritogenoside)

2:

R=OH

o

NH 2

6873

I4 core

without neighboring

6874

Our convergent

synthetic

planned stereoselective and asparagine-linked

plan is outlined in Scheme

construction

of the p-glycosidic

monosaccharide

1. For the overall simplicity

bond in 2 from benzyl-protected

and efficiency,

we

phenyl thioglycoside

3

alcohol 4. In connection with the crucial coupling reaction, we applied the

putative cx-nitrilium ion as an intermediate

in order to control the P-stereoselectivity

in the glycosylation

of 4

without anchimeric assistance. OBn

t

2

OH

0

En0

0

BnO

>

+

BnO BnO +%

+

BnOO 0 BnO BnO *

BnO

SPh HNl-Yo2Bn

BnO

4

3

NHC02Bn

O

Scheme 1 For the synthesis Acetylation

of the left half 3, we chose

of 5 afforded octaacetate

method of Hanessian7 gave phenyl thioglycoside cleavage

derivative

3, [cx]$

56 as the starting

material

with (trimethylsilyl)thiophenol

(Scheme

according

2).

to the

7, [rx]D27 + 76.5 (c 1.40, CHC13). Under these conditions,

no

bond was obsmv~d. This ctxnpuund was emvem~d into the desired

of the internal a-glycosidic

isomaltosyl

isomaltose

6, which upon treatment

+2.5.1 (c 1.03, CHC13), in the usual manner.

b

SPh

(a) Ac20, 4-dimethylaminopyridine (DMAP), r.t. (98%); (b) PhSSiMe3, &I,, n-BuqNI, ClCHzCH2C1, 60 T (98%); (c) (i) NaOMe, MeOH, r.t.; (ii) NaH, BnBr, n-Bu4N1, DMF, r.t. (90% overall).

Scheme 2 The right half 4, also used as an intermediate according

to essentially

thioglycoside

(Scheme

butyldiphenylsilyl Conversion

the same procedure 3). Selective

of 9 into a-imide

influence of N-iodosuccinimide for the corresponding halonium

protection

ether and subsequent

of 2 by Ratcliffe

that we employed

et LzZ.,~~was prepared

the readily available phenyl

of the primary alcohol of the known thio,glycoside

benzylation

afforded

compound

11, [al $6 -7.7 (c 1.29, CHC13), proceeded

9, [a]D22 -13.2’

via the a-acetoniklium

(C

88 as its I-

1.83, CHC13). ion under the

(NIS) in acetonitrile at room temperature in higher yield (854;) than that described

pent-4-enyl

ion in place of NIS, none

mixture of the corresponding

in the synthesis

with the exception

glycoside. 4d When N-bromosuccinimide of

the imide formation

proceeded

glycosyl esters was formed instead.

(NBS) was used as a source of

and an approxim:rtely

The imide 11 was converted

4, mp 143-143.5 “C; [alD2’j +33.1 (c 0.68, CHC13), by sequential deprotection

in two steps.

1 : 1 anomeric into the right half

6875

SPh CO,Bn HO

BnO

8

R*'

9

NHCO@n

C0,Bn

HO,C 10

NHCO,Bn

(a) (i) r-BuPh$iCl, EtxN, DMAP, CHzC12, r.t. (98%); (ii) NaH, BnBr, n-Bu4NI, UMF, r.t. (71%}; (b) 10, NIS, CH$N, r.t. (85%); (c) HFepyridine, pyridine, THF, r.t. (87%); (d) piperidine, DMF, r.t. (92%). Scheme

3

With the desired left and right halves 3 and 4 available, attention was directed toward the crucial coupling of these two fragments model compound

to assemble the glycosidic linkage in 2. Among the reagents and conditions

phenyl 2,3,4,6tetra-Gbenzyl-

observed when a combination

of alcohol 4 with 1.5 equivalent -78 ‘C proceeded

smoothly

1-thio-P-D-glucopyranoside,

of NBS and trifluoromethanesulfonic of phenyl thioglycoside

ion 13 to give trisaccharide

1.50, CHCl3), and its Cc-anomer with a ratio of 96:4 in 74% combined generated glycosidic

bond in 14 was confirmed

Finally, hydrogenolysis protons

resonated

whereas

three anomeric

resonated

in propionitrile

of the newly

hydroxide

on carbon deprotected yield.

all the protecting Three anomeric

4.95 (d, J=4.1 Hz, I”-II), and 4.50 (d, 9=X.0 Hz, 1+-H),

at 6 79.22 (C-l),

105.32 (C-l’), and ltXl.48 (C-l”). Other 1H and

l3C NMR signals were traced in the H-H, and C-H COSY spectra to confirm the above assignments

and thus the

structure of 2 was unambiguous.14

a 3

+4

HN

0

(a) NBS, TfOH, CH3CH$N, EtOH, H20, r.t. (quant.).

at

14, [a],,2s +28.7 (c

yield.12 St,ereochemistry

2, [a] D25 +73.2 (c 0.097 H20), in quantitative

at 6 5.6U (d, J=5.5 Hz, l-H), carbons

result was

Thus, coupling

to be p by C-I I COSY experiment.13

of 14 over 20% palladium

groups to furnish the target compound

the most satisfactory

acid (TfOH) was employed.9

3 under the influence of NBS-TfOH

via the putative a-propionitrilium

tested using it

NH!?

-78 ‘C, 1 h (74%, a:p = 96:4); (b) Hz, 20% Pd(OH)z-C, Scheme

4

THF,

6876

The described stereocontrolled

synthetic

construcrion

route

to the core trisaccharide

or P-glycosidic

bond is considerably

2 of nephritogenoside shorter

1 based

and more eXcient

on the

than those

previously reported and rendered a large quantity of this compound available in a pure form for further biological investigations15

Further extensions

of this strategy for the synthesis of nephritogenoside

1 and its analogues are

currently in progress in these laboratories.

References

and

Notes

1.

(a) Shibata, S.; Miyagawa,

Y.; Naruse, T.; Takuma, T. J. Immunol. 1969, 102, 593. (b) Shibata,

2.

S.; Nagasawa, T. .I. Immunol. 1971,106, 1284. Shibata, S.; Nakanishi, H. Carhohydr. Res. 1980, 81, 345; 1980, 86, 316.

3.

(a) Shibata, S.; Takeda, T.; Natori, Y. J. 1siol. Chem. 1988,263, Ogihara, Y.; Shibata, S. Chem. Pharm. Bull. 1989,37, 54.

12483. (b) Takeda, T.; Sawaki, M.;

4.

For the earlier synthetic works, see: (a) Ogawa, T,; Nakabayashi, S.; Shibata, S. Carbohydr. Res. 1980, 86, C7. (bj Ogawa, T.; Nakabayashi, S.; Shibata, S. Agric. Biol. Chem. 1983,47, 1213. (c) Takeda, T.; Sugiura, Y.; Hamada, C.; Fujii, R.; Suzuki, K,; Ogihara, Y.; Shibata, S. Chem. Pharm. Bull. 1981, 29, 3196. (d) Ratcliffe, A. J.; Konradsson, P.; Fraser-Reid, B. J. Am. Chem. Sot. 1990, 112, 5665. (e) Takeda, T.; Utsuno, A.; Okamoto, N.; Ogihara, Y.; Shibata, S. Carbohydr. Res. 1990. 207, 71.

5.

(a) Ratcliffe,

6.

Behrendt, M.; Toepfer, A. Synlett 1990, 694, and references cited therein. Purchased from Sigma Chemical Company, St. l,ouis,MO, 1J.S.A..

7. 8.

Hanessian,

A. .I.; Fraser-Reid,

S.; Guindon,

B. J. Chem. Snc., Perkin Trans. I 1990,747.

Y. Carhohydr.

Res. 1980,86,

(b) Schmidt, R. R.;

C3.

9.

Phenyl thioglycoside 8 was prepared according to the reported method in Nicolaou, K. C.; Randall, J. L.; Furst, G. T. J. Am. Chem. Sot. 1985, 107, 5556. When N-iodosuccinimide (NE)-TfOH, which allowed acyl-protected (“disarmed”) pent-Cenyl glycosidelo

10.

reaction time at -78 ‘C. Sasaki, M, Gama, Y.; Ishigami, Y. unpublished results. (a) Konradsson, P.; Mootoo, D. R.; McDevitt, R. E.; Fraser-reid, B. J. Chem. SW., Cbem. Commun.

11. 12.

Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H. Tetrahedron Lett. 1990,3I, 1331. The ratio was determined by HPLC analysis (Inertsil ODS column, 4.6 x 250 mm; eluent 5%

and l-thioglycosidesll,

was used in place of NBS-TfOH, the coupling reaction was found to take longer

1990, 270. (b) Konradsson,

tetiydrofuran

P,; Udodong,

U. E.; Fraser-Reid,

B. Tetrahedron

Lett. 1990,31,

4313.

in methanol; UV 254 nm; flow rate 1.2 mL/min).

13.

lH NMR (CDCl, SOOMHz) 6 5.74 (dd, J=7.2, 4.7 Hz, l-H), 5.15 (d, J=3.1 Hz, l”-H), and 4.36 (d, J=7.7 Hz, II-H); 13, NMR (CDCl,, 125 MHzj 6 74.33 (C-l), 103.23 (C-l’), and 97.17 (C-1”).

14.

NMR assignments of 2: 1H (D20, 500 MHz) 6 3.02 (dd, lH, 5~17.3, 7.0 Hz, Asn P.-Ha), 3.08 (dd, lH, J=17.3, 4.1 Hz, Asn P-Hb), 3.30 (t, lH, J=8.5 Hz, 2’-H), 3.43 (t, lH, J=3.4 Hz, 4”.I-I), 3.46-3.53 (3H, H-3’, 4-H, and 4’-H), 3.55 (dd, lH, J=9.8, 3.7 Hz, 2”-H), 3.60-3.87 H, S’-H, S-H,

6-Ha, 6’-Ha, and 6”-HZ), 3.95 (dd, lH, J=ll.l,

(lOH, 2-11, 3-H, 3”-H, 5-

4.6 Hz, 6’-Hb), 4.10 (dd, lH, J=11.4,

1.7 Hz, 6-Hb), 4.15 (dd, lH, J=7.0, 4.1 Hz, Asn a-H), 4.50 (d, lH, J=g.OHz, l’-Hj. 4.95 (d, lH, J=4.1 Hz, l”-Hj, and 5.60 (d, lH, J=5.5 Hz, 1-H); 13C (D20, 125 MHz) 6 37.45 (Asn P-C), 53.23 (Asn (r-C), 63.10 (C-6”), 68.13 (C-6’), 71.03 (C-6), 71.81 (C-4’*), 71.96 (C-2), 72.06 (C 4*). 72.11 (C4”), 74.17 (C-2”), 74.51 (C-S’), 74.54 (C-5), 75.62 (C-3), 75.73 (C-2’), 75.77 (C-3”), 76.97 (C-S), 78.49 (C-3’), 79.22 (C-l), 100.48 (C-l”), 105.32 (C-l’), 175.23 (COzH), and 175.76 (CONH). *Assignments may be reversed. 15.

Biological activity of synthetic 2 is currently under evaluation.

(Received in Japan 9 August 1991)