Stereoselective synthesis of the 5′-aminofuranoside part of polyoxins via (3,3)-sigmatropic rearrangement of allylic thiocyanates

Article abstract of DOI:10.1016/S0040-4039(01)00735-3

A new and stereoselective route for the synthesis of the benzyl 5-(R)-N-Cbz-5,6-dideoxy-2,3-O-isopropylidene-β-D-ribo-hept-6- enfuranoside 5e and 5-(R)-N-acetyl-5,6-dideoxy-1,3-O-isopropylidene-β-D-ribo-hept-6- enfuranoside 12 as useful protected precursors of the 5′-aminofuranoside part of polyoxins is presented. The key-step involves diastereoselective introduction of the amino group at C-5 of the ribose and xylose by (3,3)-sigmatropic rearrangements of the corresponding allylic thiocyanates.

Full text of DOI:10.1016/S0040-4039(01)00735-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4401–4404
Stereoselective synthesis of the 5%-aminofuranoside part of
polyoxins via (3,3)-sigmatropic rearrangement of
allylic thiocyanates
Jozef Gonda,a,* Miroslava Martinkova´,a Martin Walko,a Eva Zavacka´,a Milosˇ Budeˇsˇ´ınsky´b and
Ivana C´ısarˇova´c
a
&
Department of Organic Chemistry, P. J. Safa´rik University, Moyzesova 11, 04167 Kosˇice, Slovak Republic
bInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610 Prague 6, Czech Republic
cDepartment of Inorganic Chemistry, Charles University, Albertov 2030, 12840 Prague 2, Czech Republic
Received 5 February 2001; accepted 2 May 2001
Abstract—A new and stereoselective route for the synthesis of the benzyl 5-(R)-N-Cbz-5,6-dideoxy-2,3-O-isopropylidene-b-
D-ribo-
hept-6-enfuranoside 5e and 5-(R)-N-acetyl-5,6-dideoxy-1,3-O-isopropylidene-b-
D
-ribo-hept-6-enfuranoside 12 as useful protected
precursors of the 5%-aminofuranoside part of polyoxins is presented. The key-step involves diastereoselective introduction of the
amino group at C-5 of the ribose and xylose by (3,3)-sigmatropic rearrangements of the corresponding allylic thiocyanates.
© 2001 Elsevier Science Ltd. All rights reserved.
The polyoxins are a class of pyrimidine nucleoside
peptide antibiotics that were first isolated from Strepto-
myces cacaoi var asoensis over 30 years ago.1 Polyoxins
and closely related compounds such as nikkomycins
(Fig. 1), display significant activity against phytopatho-
genic fungi2 and are ineffective against other microor-
ganisms, plants or animals.3 Since 1970, with the first
published synthesis4 of the sugar component of the
nucleoside portion of the polyoxins, the synthesis of
polyoxin C,5 polyoxin L,6 polyoxin J,7 and/or frag-
ments of the polyoxins8 have been undertaken by vari-
ous groups.
oxamic acid,10 lincosamine precursors11 and branched-
chain amino Overman’s thermal
sugars.12
rearrangement of trichloro- and trifluoroacetimidates
derived from uridine led only to an inseparable mixture
of isomers.13
The starting thiocyanates 2a–e were prepared by SN2
displacement of the O-mesyl group of the correspond-
ing mesylates derived from trans-allylic alcohols13,14
1a–e by thiocyanate (KSCN/CH3CN) (Scheme 1). The
thermal rearrangements of the thiocyanates 2a–e were
carried out at 70–80°C in benzene under N2 for 1.5–5 h
to give good yields of the isothiocyanates 3a–e and 4a–e
(61–80%). Excellent stereoselectivity was observed for
the rearrangement of 2e (4e:3e=98:2) (Scheme 1, Table
1). The absolute configuration at C-5 in 4e was unam-
biguously determined by chemical tranformations.
Thus, reaction of the isothiocyanate 4e with toluene-
3,4-dithiol15 in MeOH/H2O led to the corresponding
This paper concerns a simple approach to the stereo-
selective introduction of a nitrogen atom at C-5 of ribose
and xylose via aza-Claisen rearrangements of thio-
cyanates leading to benzyl 5-(R)-N-Cbz-5,6-dideoxy-
2,3-O-isopropylidene-b-
and 5-(R)-N-acetyl-5,6-dideoxy-1,3-O-isopropylidene-
-ribo-hept-6-enfuranoside 12, useful protected pre-
D
-ribo-hept-6-enfuranoside 5e
b-D
cursors of the 5%-aminofuranoside part of polyoxins.
Analogous methodology was previously used for the
stereoselective synthesis of thymine polyoxin C,9 poly-
Keywords: rearrangements; polyoxins; diastereoselection; thio-
cyanates.
* Corresponding author. Fax: +421-95-62 22124; e-mail: jgonda
@kosice.upjs.sk
Figure 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00735-3

4402
J. Gonda et al. / Tetrahedron Letters 42 (2001) 4401–4404
Scheme 1.
Table 1. Isothiocyanates 3a–e and 4a–e produced via Scheme 1
Entry
Educt
Products
R
Conditions (°C, h)
Ratioa
Yield (%)
1
2
3
4
5
2a
2b
2cb
2d
2e
4a/3a
4b/3b
4c/3c
4d/3d
4e/3e
OCH3
Benzene (80, 1.5)
Benzene (70, 2)
Benzene (70, 4)
Xylene (70, 5)
Xylene (70, 4)
72:28
75:25
81:19
60:40
98:2
68
71
78
61
80
OCH2ꢀCH2
O-2-THP
1-Uridyl
OBn
a Determined by 1H NMR.
b Mixture of the diastereoisomers.
Scheme 2.
A second approach was examined simultaneously and
was based on the stereoselective introduction of an
amino group at C-5 of xylose with a bulky substituent
at C-3 as chiral selector. The allylic alcohols13,16 6a,b
were converted to thiocyanates 7a,b in an analogous
manner to 1a–e (Scheme 2). The thermal rearrangement
of thiocyanates 7a,b was carried out at 70°C in benzene
under N2 for 3 h to give a mixture of isothiocyanates
8a/9a and 8b/9b with very good stereoselectivities
(Scheme 2). Reaction of 9a and 9b with thioacetic acid
(1.3 mol) and t-BuOK (0.2 mol) in the presence of
18-crown-6 in THF at 60°C (4 h) gave 11a (76%) and
11b (82%). The configuration of the newly introduced
stereocenter at C-5 in 11a was established by X-ray
analysis17 (Fig. 2), thus confirming the configuration at
C-5 as (R). Inversion of the xylo-configuration at C-3
amine which, after reaction with BnOCOCl in CH2Cl2,
afforded the amide 5e (77%). Heating 5e with 2,2-
dimethoxypropane/HCl in acetone/MeOH at 60°C for
24 h gave 5a (64% from 4e). Spectroscopic data for 5a†
(having the 5-(R) configuration) are identical with
recently published results.14
† All compounds showed 1H, 13C, IR and HRMS spectra consistent
with the reported structures. Spectroscopic data of 5e: 1H NMR
(400 MHz, CDCl3): 1.45 (s, 3H), 3.33 (s, 3H), 3.99 (dd, 1H, J=1.1,
9.4 Hz), 4.29 (dd, 1H, J=5.6, 9.8 Hz), 4.59 (d, 1H, J=4.9 Hz), 4.74
(d, 1H, J=4.9 Hz), 4.97 (br s, 1H), 4.99 (s, 1H), 5.11 (dd, 1H,
J=4.7, 17 Hz), 5.24 (dd, 1H, J=1, 4.7 Hz), 5.27 (d, 1H, J=11.4
Hz), 5.95 (m, 1H), 7.25–7.37 (m, 5H); 13C NMR (100 MHz,
CDCl3): 25.0, 26.4, 55.0, 55.4, 66.9, 88.8, 109.7, 112.6, 116.8, 126.9,
12765, 128.0, 128.1, 128.4, 135.3, 136.2, 155.9. [h]2D2=−12 (c 0.19,
CHCl3). Mp 80–82°C.

J. Gonda et al. / Tetrahedron Letters 42 (2001) 4401–4404
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Figure 2. ORTEP diagram of 11a showing crystallographic
numbering.
in 11a,b to the ribo-configuration in 12‡ was accom-
plished by a series of functional group manipulations:
(1) selective removal TBDMS group with Bu4NF in
MeCN (93 and 94%); (2) oxidation of the 3-OH group
with PDC (Ac2O, CH2Cl2, 76%); (3) NaBH4 reduction
in CH3OH (90%).
In conclusion, a stereoselective synthesis of the 5%-
aminofuranoside part of polyoxins has been accom-
plished via (3,3)-sigmatropic rearrangement of ribose-
and xylose-derived allylic thiocyanates.
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Acknowledgements
The present work was supported by a Grant Agency
(1/6080/99) from the Ministry of Education, Slovak
Republic.
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4404
J. Gonda et al. / Tetrahedron Letters 42 (2001) 4401–4404
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17. Single-crystal X-ray diffraction: 11a: Empirical formula
C18H33NO5Si, Mw 371.55, orthorhombic, space group
intensities variation of 3%. Of 3363 measured reflections,
3354 were unique (Rint=0.026) and 2932 were regarded
as ‘observed’ according to the I]2l (I) criterion. Data
treatment: the structure was solved by direct methods
(SHELX-86) and refined by SHELXL-93 using a full-
matrix least-squares procedure based on F2. Hydrogen
atoms were refined isotropically, all other atoms
anisotropically. Convergence for observed reflections and
332 parameters was achieved at R=0.0312, Rw=0.0831,
GOF=1.040, (D/l)max= 0.001. The final difference elec-
P212121 (no. 19), a=9.069(7), b=9.376(11), c=28.140(9)
3
A, V=2392.7(2) A , Z=4, Dc=1.026 cm−3, F(000)=800.
A colorless plate-like crystal of the dimensions 0.5×0.3×
0.15 mm (from acetone/hexane) was measured at 293(2)
K on CAD4 diffractometer with graphite-monochro-
,
,
,
mated Mo Ka radiation (u=0.71073 A). Absorption was
neglected (v=0.124 mm−1). The cell parameters were
determined from 23 reflections in the 12–13° q range. The
tron density map was featureless with extreme values of
−3
,
0.30; −0.16 e A
.
.