Unusual sugars of the GPL-type antigen of Mycobacterium avium serovar 19. Stereoselective synthesis of methyl 6-deoxy-3-C-methyl-2,4-di-O-methyl-α-L-mannopyranoside and its C-4 epimer

Article abstract of DOI:10.1055/s-1998-1608

Completely reversed stereoselectivity of reduction of methyl 6-deoxy-2,3-O-isopropylidene-3-C-methyl-α-L-mannopyranoside (2) and its deisopropylidenated derivative (7) was observed. Compound 2 gave exclusively the L-talo-isomer (3) with NaBH₄ in MeOH, but the reduction of 7 with NaBH₄ in acetic acid resulted in the L-manno-derivative 8. It is assumed that in the first case the stereoselectivity is determined by the steric accessibility of the carbonyl group, while in the second case free OH-groups direct the selectivity of the reduction by complexation or ligand exchange.

Full text of DOI:10.1055/s-1998-1608

February 1998
SYNLETT
127
Unusual sugars of the GPL-type antigen of Mycobacterium avium serovar 19. Stereoselective
synthesis of methyl 6-deoxy-3-C-methyl-2,4-di-O-methyl-α-L-mannopyranoside and its
C-4 epimer
a,*
a,b,*
K. Gyergyói, A. Tóth, I. Bajza and A. Lipták
a
Research Group for Carbohydrates of the Hungarian Academy of Sciences, H-4010 Debrecen, P.o.b. 55, Hungary
b
Institute of Biochemistry, L. Kossuth University, Debrecen, P.o.b. 55, H-4010 Hungary
Received 11 November 1997
Dedicated to Prof. Cs. Szántay on the occasion of his 70th birthday.
Abstract:
Completely reversed stereoselectivity of reduction of methyl
2
6-deoxy-2,3-O-isopropylidene-3-C-methyl-α-L-mannopyranoside ( )
7
2
and its deisopropylidenated derivative ( ) was observed. Compound
3
gave exclusively the L-talo-isomer ( ) with NaBH in MeOH, but the
4
7
reduction of with NaBH in acetic acid resulted in the L-manno-
4
8
derivative . It is assumed that in the first case the stereoselectivity is
determined by the steric accessibility of the carbonyl group, while in the
second case free OH-groups direct the selectivity of the reduction by
complexation or ligand exchange.
1,2
Members of the Mycobacterium avium serocomplex are opportunistic
pathogens and can cause serious infections. Structural analysis of the
cell-surface glycopeptidolipid-type (GPL) antigen of serovar 19 showed
3
1
that it contains the O-linked pentasaccharide . While most of the
structural features of the penultimate residue (Fig.) have been
determined, ambiguity persists regarding the stereochemistry at C-4 of
this unit.
6, 12
Here we report stereoselective syntheses of both epimers (
) of the
Figure
unidentified unit as their methyl glycosides in the proposed, α anomeric
3
forms . Precursor to both targets was methyl 6-deoxy-2,3-O-
2
isopropylidene-3-C-methyl-α-L-lyxo-hexopyranosid-4-ulose ( ) that
3
C-4 carbon atom only from the α-(L) face. Methylation of compound
4
was prepared as described by Klemer from L-rhamnose in four steps .
Reduction of compound either with NaBH or with LiAlH (Scheme)
resulted in the 6-deoxy-L-talo isomer exclusively, as confirmed by the
coupling constant. The complete
stereoselectivity of this reduction can be explained by the extremely
crowded β-(L) side of compound : the hydride anion can approach the
4
resulted in from which the isopropylidene group was removed by
2
4
4
5
5
acidic hydrolysis to obtain . Methylation of the axial OH-2 of
3
6
required rather drastic conditions to give , and formation of the fully
methylated product ( ) was also observed (15 %). Compound exists
3
low value (1 Hz) of the
J
4,5
13
13
4
exclusively in C (L) conformation.
1
2
Scheme

128
LETTERS
SYNLETT
To prepare the rhamno-isomer (12) from compound 2, its
isopropylidene group was hydrolyzed, then the free ulose-derivative (7)
3.36 (bs, 2H, 2 x OH), 3.28 (s, 1H, H-2), 2.89 (s, 1H, H-4), 1.32
13
(s, 3H, CH (3)), 1.3 (d, 3H, J 6.5 Hz, CH (6)); C NMR : δ
3
5,6
3
5,6
was treated with NaBH(OAc) (Scheme 1)
.
Methyl α-L-
102.49 (C-1), 87.27 (C-2), 73.80 and 65.13 (C-4 and C-5), 69.48
(C-3), 62.84 (OCH (4)), 55.27 (OCH (1)), 22.42 and 17.00
3
1
evalopyranoside was isolated in nearly quantitative yield. In its H-
NMR spectrum H-4 gave a doublet at 3.39 ppm having J 10 Hz, that
3
3
3
(CH (3) and CH (6));
3 3
6 [α] -56.33 (c 1.04); H NMR: δ 4.78 (s, 1H, H-1), 3.91 (d, 1H,
D
4,5
1
confirms the trans-diaxial relationship of the H-4 and H-5 protons. The
completely reversed stereoselectivity compared to the reduction of 2
could only be achieved in the presence of the free OH groups suggesting
that these play a role in the complexation of the hydride donor thus
governing the direction of the attack of the hydride anion.
Isopropylidenation of 8 gave compound 9 and after methylation (→10)
and deprotection (→11) the resulting diol was selectively methylated at
OH-2 at 0 °C under phase-transfer conditions. The isolated yield of
J
6 Hz, H-5), 3.56 (s, 3H, OCH (4)), 3.47 (s, 1H, OCH (2)),
3 3
5,6
3.37 (s, 1H, OCH (1)), 2.84 and 2.76 (2s, 1-1H, H-2 and H-4),
3
13
1.33 (s, 3H, CH (3)), 1.32 (d, 1H, J 6 Hz, CH (6)); C NMR : δ
3
5,6
3
98.75 (C-1), 85.9 (C-2), 82.87 and 64.76 (C-4 and C-5), 69.1 (C-
3), 55.73 (OCH ), 23.86 and 16.77 (CH (3) and CH (6));
3
3
3
1
7 [α] -101.5 (c 1.26); H NMR : δ 4.85 (s, 1H, H-1), 4.52 (d, 1H,
D
J
6.5 Hz, H-5), 4.22 and 3.97 (2s, 1-1H, 2 x OH), 3.52 (s, 3H,
5,6
compound 12 was 67 % after chromatographic purification.
OCH ), 3.43 (s, 1H, H-2), 1.54 (s, 3H, CH (3)), 1.34 (d, 3H, J
3 3 5,6
13
1
6.5 Hz, CH (6)); C NMR : δ 204.04 (C-4), 100.47 (C-1), 86.58
The [α] value and the H-NMR data of 12 were in good agreement
3
D
(C-3), 78.23 and 66.78 (C-2 and C-5), 55.98 (OCH ), 23.88
with the data of one of the intermediates of L-nogalose synthesis that
was obtained from methyl 3,6-dideoxy-2,4-di-O-methyl-3-C-
methylene-α-L-arabino-hexopyranoside by epoxidation to provide a 1 :
3
(CH (3)), 13.81 (CH (6));
3
3
1
8 [α] -83.3 (c 0.85, MeOH); H NMR: δ 4.58 (s, 1H, H-1), 3.56
D
(dd, 1H, J 10 Hz, J 6 Hz, H-5), 3.47 (s, 1H , H-2), 3.39
5,Me(6)
1 ratio of two diastereoisomers followed by LiAlH reduction of one of
the epoxides .
4,5
4
7
(d, 1H, J 10 Hz, H-4) 3.34 (s, 3H, OCH ), 1.26 (d, 3H, J
5,Me (6)
4,5
3
13
6 Hz, CH (6)), 1.24 (s, 3H, CH (3)); C NMR : δ 103.28 (C-1),
3
3
76.39 (C-2), 76.12 and 68.56 (C-4 and C-5), 73.58 (C-3) 55.3
(OCH ), 19.18 and 18.4 (CH (3) and CH (6));
In summary, we developed synthetic routes to C-4 epimers of a
branched monosaccharide residue of the glycopeptidolipid antigen of
Mycobacterium avium serovar 19 based on common precursor 2.
3
3
3
1
9 [α] -53.7 (c 1.10); H NMR: δ 4.85 (s, 1H, H-1), 3.87 (s, 1H,
D
H-2), 3.61 (dd, 1H, J 9 Hz, J
6 Hz, H-5), 3.54 (dd, 1H,
4,5
5,Me(6)
J
J
9 Hz, J
3.5 Hz, H-4), 3.38 (s, 3H, OCH ), 3.02 (d, 1H,
4,5
4,OH 3
Acknowledgements:
3.5 Hz, OH), 1.53 and 1.38 (2s, 3-3H, 2 x Ip CH ), 1.36 (s,
4,OH
3
13
3H, CH (3)), 1.3 (d, 3H, J
6 Hz, CH (6)); C NMR: δ
3
5,Me(6)
3
108.76 (Ip kvat.), 98.04 (C-1), 81.56 (C-3), 80.74 (C-2), 76.65 and
65.52 (C-4 and C-5), 54.95 (OCH ), 28.2 and 26.4 (2 x Ip CH ),
3
3
17.51 and 17.45 (CH (3) and CH (6));
3
3
1
10 [α] -72.7 (c 1.07); H NMR: δ 4.83 (d, 1H, J 1 Hz, H-1),
D
1,2
3.8 (d, 1H, J 1 Hz, H-2), 3.56 (dd, 1H, J 10 Hz, J 6.5
5,Me(6)
1,2
4,5
References and Notes:
Hz, H-5), 3.54 (s, 3H, OCH (4)), 3.37 (s, 3H, OCH (1)), 3.12 (d,
3
3
1.
2.
Lipták, A.; Borbás, A.; Bajza, I. Med. Res. Rev., 1994, 14, 307.
1H, J 10 Hz, H-4), 1.55 and 1.37 (2s, 3-3H, 2 x Ip CH ), 1.33
4,5
3
Aspinall, G.O.; Chatterjee, D.; Brennan, P.J. Adv. Carbohydr.
Chem. Biochem., 1995, 51, 169.
13
(s, 3H, CH (3)), 1.27 (d, 3H, J
6,5 Hz, CH (6)); C NMR:
3
3
5,Me(6)
δ 108.54 (Ip kvat.), 98.01 (C-1), 85.74 (C-2), 81.90 (C-3), 81.06
and 65.2 (C-4 and C-5), 60.49 (OCH (4)), 54.99 (OCH (1)),
3.
Chatterjee, D.; Bozic, C.; Aspinall, G. O.; Brennan, P. J. J. Biol.
Chem. 1988, 263, 4092.
3
3
28.28 and 27.09 (2 x Ip CH ) 17.87 and 17.73 (CH (3) and
3
3
CH (6));
4.
5.
Klemer, A.; Beermann, H. J. Carbohydr. Chem., 1983, 2, 457.
3
1
11 [α] -99.4 (c 0.81); H NMR: δ 4.67 (d,1H, J 1,5 Hz, H-1),
D
1,2
Gribble, G.W.; Ferguson, D.C. J. Chem. Soc., Chem. Commun.,
1975, 535.
3.59 (dd, 1H, J 10 Hz, J 6 Hz, H-5), 3.57 (s, 3H, OCH (4)),
3.55 (d, 1H, J 1,5 Hz, H-2), 3.36 (s, 3H, OCH (1)), 3.05 (d, 1H,
4,5
5,6
3
1,2
3
6.
Evans, D.A.; Chapman, K.T.; Carreira, E.M. J. Am. Chem. Soc.,
1988, 110, 3560.
J
10 Hz, H-4), 2.68 (bs, 2H, 2 x OH), 1.32 (s, 3H, CH (3)), 1.31
4,5
3
13
(d, 3H, J 6 Hz, CH (6)); C NMR: δ 100.94 (C-1), 85.39 (C-2),
5,6
3
7.
8.
Yoshimura, J.; Hong, N.; Funabashi, M. Chem. Lett., 1979, 687.
73.84 (C-3), 75.29 and 66.77 (C-4 and C-5), 61.72 (OCH (4)),
55.11 (OCH (1)), 19.41 and 18.08 (CH (3) and CH (6));
12 [α] -57.67 (c 0.75); H NMR: δ 4.71 (d, 1H, J 1 Hz, H-1),
D 1,2
3.58 (s, 3H, OCH (4)), 3.53 (dd, 1H, J 10 Hz, J 6 Hz, H-5),
3 4,5 5,6
3
Physical and spectroscopic data of the synthesized compounds: 3
3
3
3
1
1
[α] -42.13 (c 1.08); H NMR: δ 4.93 (s, 1H, H-1), 3.88 (dd, 1H,
D
J
1 Hz, J
6.5 Hz, H-5), 3.75 (s, 1H, H-2), 3.40 (s, 3H,
4,5
5,Me(6)
OCH ), 3.17 (dd, 1H, J 1 Hz, J
5 Hz, H-4), 2.48 (d, 1H,
3
4,5
4,OH
3.49 (s, 3H, OCH (2)), 3.36 (s, 3H, OCH (1)), 3.07 (d, 1H, J
1
3
3
1,2
J
5 Hz, OH), 1.57 and 1.38 (s, 3-3H, Ip CH ), 1.42 (s, 3H,
3
4,OH
Hz, H-2), 3.01 (s, 1H, OH), 2.9 (d,1H, J 10 Hz, H-4), 1.3 (s, 3H,
4,5
13
CH (3)), 1.34 (d, 3H, J
6 Hz, CH (6));
3
3
5,Me(6)
CH (3)), 1.28 (d, 3H, J 6 Hz, CH (6)); C NMR: δ 97.78 (C-
3
5,6
3
1
4 [α] -37.8 (c 0.35); H NMR : δ 4.92 (s,1H, H-1), 3.83 (dd, 1H,
D
1), 86.2 (C-2), 85.08 and 66.69 (C-4 and C-5), 73.25 (C-3), 61.6
and 59.07 (OCH (2) and OCH (4)), 54.94 (OCH (1)), 18.54 and
J
6 Hz, J
1 Hz, H-5), 3.69 (s, 1H, H-2), 3.52 (s, 3H,
5,6
4,5
3
3
3
OCH (4)), 3.37 (s, 3H, OCH (1)), 2.69 (d, 1H, J 1 Hz, H-4),
3
3
4,5
18.01 (CH (3) and CH (6));
3 3
1
1.56 and 1.4 (2s, 3-3H, Ip CH ), 1.37 (s, 3H, CH (3)), 1.31 (d, 3H,
3
3
13 H NMR: δ 4.79 (d, 1H, J 4 Hz, H-1), 4.10 (m, 1H, J 3.5
1,2 4,5
13
J
6 Hz, CH (6)); C NMR : δ 109.03 (Ip), 98.4 (C-1), 89.2 (C-
3
5,6
Hz, J 7 Hz, H-5), 3.51, 3.50, 3.43, 3.35 (s, 3-3H, OMe), 2.98 (d,
5,6
2), 78.69 (C-3) 78.6 and 64.4 (C-4 and C-5), 62.11 (OCH (4)),
3
1H, H-4), 2.89 (d, 1H, H-2), 1.36 (d, 3H, CH (6)), 1.35 (s, 3H,
3
13
55.05 (OCH (1)), 26.78 and 25.69 (2 x Ip CH ), 24.84 and 16.75
3
3
CH (3)) ; C NMR: δ 98.34 (C-1), 83.79 (C-2), 82.92, 67.45 (C-4
3
(CH (3) and CH (6));
3
3
and C-5), 60.76, 60.33, 55.77, 50.82 (OCH ), 18.54 (CH (3)),
3 3
15.01 (CH (6)).
3
1
5 [α] -103.7 (c 1.04); H NMR : δ 4.78 (s,1H, H-1), 3.94 (d, 1H,
D
J
6.5 Hz, H-5), 3.59 (s, 3H, OCH (4)), 3.37 (s, 3H, OCH (1)),
3 3
5,6