Stereocontrolled introduction of an amino group at C-6 of D-galactose via (3,3)-sigmatropic rearrangements - Novel synthesis of lincosamine and 7- epi-lincosamine precursors

Article abstract of DOI:10.1016/S0040-4039(99)02110-3

A new and stereoselective route to the aminoglycoside components of the antibiotics lincomycin and clindamycin is presented. The key step involves diastereoselective introduction of the amino group at C-6 of D-galactose by (3,3)-sigmatropic rearrangements of the corresponding allylic (Z)- trifluoroacetimidate and (Z)- and (E)-allylic thiocyanates. Epoxidation of the resulting trifluoroacetamide with m-CPBA led to the epoxide with high threo-selectivity.

Full text of DOI:10.1016/S0040-4039(99)02110-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 525–529
Stereocontrolled introduction of an amino group at C-6 of
D-galactose via (3,3)-sigmatropic rearrangements — novel
synthesis of lincosamine and 7-epi-lincosamine precursors
Jozef Gonda,a,∗ Eva Zavacká,a Miloslav Budešínský,b Ivana Císarová c and Jaroslav Podlaha c
aDepartment of Organic Chemistry, P.J. Šafarik University, Moyzesova 11, 04167 Košice, 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 20 September 1999; accepted 10 November 1999
Abstract
A new and stereoselective route to the aminoglycoside components of the antibiotics lincomycin and clindamy-
cin is presented. The key step involves diastereoselective introduction of the amino group at C-6 of D-galactose
by (3,3)-sigmatropic rearrangements of the corresponding allylic (Z)-trifluoroacetimidate and (Z)- and (E)-allylic
thiocyanates. Epoxidation of the resulting trifluoroacetamide with m-CPBA led to the epoxide with high threo-
selectivity. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: rearrangements; diastereoselection; imidic acid; imidic acid derivatives; thiocyanates.
Lincomycin 1 and the semi-synthetic 7-chloro analogue clindamycin 2 are commercial antibiotics used
against bacterial infections in humans and animals.1 Synthetic work on the preparation of 1 and 2 has
mainly been focused on lincosamine (3), i.e. the carbohydrate moiety of lincomycin (Fig. 1). Synthesis
of 32 entailed the stereocontrolled construction of the pyranose ring using furan-based chemistry3 or
hetero Diels–Alder cycloaddition.4 Syntheses starting from myo-inositol5 or D-threonine6 have also
Fig. 1.
∗
Corresponding author. Fax: +421-95-62 22124; e-mail: jgonda@kosice.upjs.sk (J. Gonda)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02110-3
tetl 16038

526
been reported. An alternative approach7 towards the preparation of 3 comprises a chain-extension of
D-galactopyranose, illustrating the very hindered nature of C-6 and the difficulty of introducing the
amino group at this position stereoselectively. An elegant solution to this problem has been independently
presented by Stick8 and Knapp9 and recently by van Delft.10
This paper concerns a simple approach to introducing a nitrogen atom at C-6 of galactose,
stereoselectively via aza-Claisen rearrangements of trifluoroacetimidates and thiocyanates and
subsequent diastereoselective epoxidation of the resulting double-bonds leading to 7,8-anhydro-
6-deoxy-6-trifluoroacetamide-1,2:3,4-di-O-isopropylidene-D-threo-D-galacto-octopyranose 18 as a
useful lincosamine and 7-epi-lincosamine precursor. This methodology was previously used for
the stereoselective synthesis of the (+)-polyoxamic acid,11 thymine polyoxin C12 and 50-branched
50-aminoribonucleoside derivatives.13
The starting (Z)- and (E)-allylic imidates 7, 8, 9, and 10 were synthesized from the 1,2:3,4-di-
O-isopropylidene-α-D-galacto-hexaldioaldo-1,5-pyranose 4 by the route shown in Scheme 1. The
Wittig olefination of 4 with Ph3P=CHCOOCH3 in MeOH and reduction of the resulting ester with
DIBAL-H led selectively to the (Z)-allylic alcohol 5.14 Side-chain elongation of the dialdose 4 with
(CH3O)2POCH2COOCH3/NaH in THF and reaction of the (E)-ester using DIBAL-H afforded the (E)-
allylic alcohol 6, selectively. Subsequently, 5 was converted to the (Z)-trichloroacetimidate 8 and (Z)-
trifluoroacetimidate 10 by reaction with CCl3CN/NaH and CF3CN/NaH (diethyl ether, 0°C), respectively.
The imidates (E)-7 and (E)-9 were prepared from (E)-allylic alcohol 6 (Scheme 1). The crude imidates
were purified by flash chromatography (SiO2, diethyl ether:hexane=50:50).
Scheme 1.
Thermal rearrangement of the trichloroacetimidates (E)-7 and (Z)-8 (in xylene at 200°C, 30 h) takes
place with decomposition and gave the trichloroacetamides 11 and 12 obtained as a mixture (50:50) in
low yields (22 and 25%) (Scheme 1). In contrast, thermolysis (2 h, 200°C) of the (E)-trifluoroacetimidate
9 afforded a 42:58 mixture of the trifluoroacetamides 13 and 14 in 93% yield. Finally, rearrangement
of the (Z)-trifluoroacetimidate 10 gave the trifluoroacetamides 13 and 14 with good stereoselectivity
(13:14=9:91) and yield (95%) (Scheme 1). The (3,3)-sigmatropic rearrangement of allylic imidates
can often be accelerated by the use of metal catalysis, particularly by the Hg(II) and Pd(II) species.15
However, despite repeated attempts, no rearrangement was observed when 7–10 were exposed to such

527
catalysts. These negative results can be compared with literature data.16 The resulting product 14† was
then transformed into the α-aminoaldehyde 15 (Scheme 2) which is a precursor of lincosamine (3).2 We
found that epoxidation of 14 with m-CPBA in CH2Cl2 (2 days at RT) led to the epoxide 18‡ with high
threo-selectivity17 (18:19=97:3) (Scheme 2).
Scheme 2.
The configurations of the newly introduced stereocenters at C-6 and C-7 in 18 were established by
X-ray analysis (Fig. 2), thus confirming the configurations at C-6 and C-7 as (R).
Fig. 2. ORTEP diagram of epoxide 18 showing crystallographic numbering
†
1
All compounds showed H, 13C, IR, and HRMS spectra consistent with the reported structures. Spectroscopic data of 14:
1H NMR data (500 MHz, CDCl3): 1.33 (3H, s, CH3), 1.35 (3H, s, CH3), 1.50 (3H, s, CH3), 1.52 (3H, s, CH3), 3.86 (1H, dd,
H5, J5,4=1.8 Hz, J5,6=4.7 Hz), 4.32 (1H, dd, H2, J2,1=5.1 Hz, J2,3=2.3 Hz), 4.42 (1H, dd, H4, J4,3=8.1 Hz, J4,5=1.8 Hz), 4.61
(1H, dd, H3, J3,2=2.3 Hz, J3,4=8.1 Hz), 4.79 (1H, m, H6), 5.32 (1H, ddd, H8a, J8a,8b=1.7 Hz, J8a,7=10.4 Hz, J8a,6=0.8 Hz), 5.35
(1H, ddd, H8b, J8b,8a=1.7 Hz, J8b,7=17.4 Hz, J8b,6=0.8 Hz), 5.55 (1H, d, H1, J1,2=5.1 Hz), 5.81 (1H, ddd, H7, J7,8a=10.4 Hz,
J7,8b=17.4 Hz, J7,6=5.9 Hz), 8.06 (1H, bd, N–H, J=0.8); 13C NMR data (125.7 MHz, CDCl3): 23.80 (CH3), 24.77 (CH3), 25.45
(CH3), 26.03 (CH3), 54.71 (C-6), 65.88 (C-2), 70.28 (C-4), 70.94 (C-4), 71.69 (C-5), 96.64 (C-1), 108.80 (C(CH3)2), 109.73
(C(CH3)2), 116.02 (CF3), 118.39 (C-8), 132.15 (C-7), 156.72 (C_O).
‡
Spectroscopic data of 18: 1H NMR data (500 MHz, CDCl3): 1.34 (3H, s, CH3), 1.37 (3H, s, CH3), 1.47 (3H, s, CH3), 1.52
(3H, s, CH3), 2.54 (1H, dd, H8b, J8b,8a=4.5 Hz, J8b,7=2.6 Hz), 2.80 (1H, dd, H8a, J8a,8b=4.5 Hz, J8a,7=4.0 Hz), 3.28 (1H, dt, H7,
J7,8a=4.0 Hz, J7,8b=2.6 Hz, J7,6=2.4 Hz), 4.04 (1H, dd, H5, J5,6=4.7 Hz, J5,4=1.7 Hz), 4.34 (1H, dd, H2, J2,1=4.9 Hz, J2,3=2.3
Hz), 4.52 (1H, dd, H4, J4,3=8.1 Hz, J4,5=1.7 Hz), 4.55 (1H, ddd, H6, J6,5=4.7 Hz, J6,7=2.4 Hz, J6,NH=8.6 Hz), 4.65 (1H, dd, H3,
J3,2=2.3 Hz, J3,4=8.1 Hz), 5.55 (1H, d, H1, J1,2=4.9 Hz), 7.49 (1H, bd, NH, J=8.6 Hz); 13C NMR data (125.7 MHz, CDCl3):
23.98 (CH3), 24.80 (CH3), 25.53 (CH3), 26.05 (CH3), 43.80 (C-8), 49.92 (C-7), 51.11 (C-6), 66.42 (C-2), 70.44 (C-3), 70.90
(C-4), 72.23 (C-5), 96.57 (C-1), 108.90 (C(CH3)2), 109.85 (C(CH3)2), 116.0 (CF3), 157.43 (C_O).

528
With the aim of examining similar methodology for the introduction of nitrogen functionality into
the 6-position of galactose, we investigated the rearrangement of the allylic thiocyanates 20 and 21
(Scheme 3). The starting thiocyanates 20 and 21 were prepared by SN2 displacement of the O-mesyl
group in the corresponding mesylates derived from the (E)-allylic alcohol 6 and the (Z)-allylic alcohol
5 by the thiocyanate group (KSCN, CH3CN, rt, 0.5 h). Thermal rearrangement of the thiocyanates 20
and 21 was carried out at 80°C in xylene under N2 for 2 h to give a high yield of isothiocyanates 22
and 23 (95% for 20, 90% for 21) and good stereoselectivity (16:17=96:4, in both cases) (Scheme 3). The
rearrangement thiocyanate→isothiocyanate is reversible and ratios of isothiocyanates 22 and 23 are time
and temperature dependent. We found that heating the thiocyanates 20 and 21 in xylene at 140°C for 2 h
gave mixtures of the isothiocyanates 22 and 23 in 50:50 ratio; heating for 16 h at the same temperature led
to a mixture of 22 and 23 in a 25:75 ratio. Reaction of 22 with thioacetic acid18 (1.3 mol) and t-BuOK (0.2
mol) in the presence 18-crown-6-ether in THF at 60°C (4 h) gave 6-acetamido-6,7,8-trideoxy-1,2:3,4-
di-O-isopropylidene-D-glycero-D-galacto-oct-6-enopyranose 25. The absolute configuration at C-6 in
22 was unambiguously determined by chemical transformations (Scheme 3). Thus, the reaction of the
isothiocyanate 22 with toluene-3,4-dithiol in MeOH/H2O led to the amine 24 in 69% yield which, after
reaction with (CF3CO)2O/NEt3 in CH2Cl2, afforded trifluoroacetamide 14 in 89% yield. This compound
is in all respects identical with 14 prepared from 10 (Scheme 3).
Scheme 3.
Acknowledgements
The present work was supported by a Grant Agency (No. 1/3229/96) from the Ministry of Education,
Slovak Republic and Tempus Structural Joint European Project S-JEP-09101-95.

529
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