A stereoselective synthesis of 6,6,6-trifluoro-l-daunosamine and 6,6,6-trifluoro-l-acosamine

Article abstract of DOI:10.1039/b606055b

A short synthesis of 6,6,6-trifluoro-l-acosamine 15 and 6,6,6-trifluoro-l-daunosamine 19 has been accomplished. The pyranose ring system of these carbohydrate analogues was formed by a hetero-Diels-Alder reaction of vinylogous imide 11 and ethyl vinyl eth

Full text of DOI:10.1039/b606055b

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A stereoselective synthesis of 6,6,6-trifluoro-L-daunosamine and
6,6,6-trifluoro-L-acosamine†
Colin M. Hayman, David S. Larsen,* Jim Simpson, Karl B. Bailey and Gurmit Singh Gill
Received 28th April 2006, Accepted 30th May 2006
First published as an Advance Article on the web 21st June 2006
DOI: 10.1039/b606055b
A short synthesis of 6,6,6-trifluoro-L-acosamine 15 and 6,6,6-trifluoro-L-daunosamine 19 has been
accomplished. The pyranose ring system of these carbohydrate analogues was formed by a
hetero-Diels–Alder reaction of vinylogous imide 11 and ethyl vinyl ether which gave adduct 12a in 40%
yield. Hydroboration gave 13 and subsequent hydrogenolytic removal of the (R)-2-phenylethyl chiral
auxiliary gave ethyl 6,6,6-trifluoro-L-acosaminide 14. Acid hydrolysis furnished target 15. Glycoside 13
was N-trifluoroacetylated to give 16, the structure was confirmed by single crystal X-ray diffraction.
The C-4 stereochemistry of 16 was inverted by Swern oxidation of the 4-OH group, and subsequent
borohydride reduction to give 17. Hydrogenolytic removal of the auxiliary gave
ethyl-6,6,6-trifluoro-L-daunosaminide 18. Acid hydrolysis provided 19.
The synthesis of the carbohydrate moiety of 3 involved mod-
Introduction
ification of a tosylated methyl L-lyxo-hexopyranoside derivative
using an eleven-step reaction sequence where trifluoromethylation
was effected by a fluoride catalysed addition of TMSCF3 to the
intermediary aldehyde 6.1 In a similar fashion, Takagi et al.2
developed a synthesis of a glycosyl donor for the preparation of
4 and 5 from carbohydrate-derived intermediate 7 in a multi-step
sequence.
In earlier work, Taguchi et al.4 have reported the synthesis
of the p-nitrobenzoyl glycoside of a protected 6,6,6-trifluoro-L-
daunosamine derivative starting from 2,3-O-cyclohexylidene-L-
glyceraldehyde, also in eleven steps. The critical trifluoromethy-
lation of the glyceraldehyde was achieved upon treatment with
trifluoromethyl iodide and zinc dust.
Tietze et al.5 have reported a hetero-Diels–Alder approach to
racemic 3-amino-carbohydrate derivatives and we have previously
described the syntheses of 2,6-dideoxy-6,6,6-trifluoro-D- and L-
arabino-hexose using the Diels–Alder reaction of hetero-diene 8
and ethyl vinyl ether.6,7 We now report on a short and efficient
synthesis of 6,6,6-trifluoro-L-acosamine and 6,6,6-trifluoro-L-
daunosamine derivatives using an adaptation of this method.
Takagi et al.1–3 have reported the syntheses of several trifluo-
rinated analogues of daunomycin 1 and adriamycin 2 which
have shown good antitumour activities. The analogues, 3–
5, incorporated 2,6-dideoxy-6,6,6-trifluoro-L-lyxo-hexopyranosyl
and 2,3,6-trideoxy-3-amino-6,6,6-trifluoro-L-lyxo-hexopyranosyl
(6,6,6-trifluoro-L-daunosamine) residues as the carbohydrate moi-
ety. They reasoned that the strongly electron-withdrawing C-5
trifluoromethyl group of the sugar would stabilise the glycosidic
bond against acid hydrolysis and, due to its high lipophilicity,
would facilitate cellular uptake of the compound. Anthracycline
3 showed stronger activity than adriamycin 1 against murine
leukaemia L1210 in vivo in the low dose range1 and both 4 and 5
showed 60 to 70 fold stronger activity against human epitheliod
carcinoma (HeLa) and human leukaemia (HL60) in vitro.2
Department of Chemistry, University of Otago, P.O. Box 56, Dunedin, New
Zealand
† Electronic supplementary information (ESI) available: HPLC data,
NMR spectra, molecular structures, and tables of bond lengths and angles.
See DOI: 10.1039/b606055b
2794 | Org. Biomol. Chem., 2006, 4, 2794–2800
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
Scheme 1 Reagents and conditions: (i) (R)-a-methylbenzylamine; CH2Cl2, 0 ◦C; (ii) TFAA, py, CH2Cl2, 0 ◦C (96% from 9); (iii) 60–65 ◦C, 42 h (40% of
12a).
The spectral and analytical data were consistent with 12a and its
absolute structure was determined by a crystallographic study of
Discussion
a derivative (vide supra).‡ The signals in the 1H NMR spectrum of
12a were also broadened and the 19F NMR spectrum showed that
12a existed as an approximately 9 : 1 mixture of isomers about the
amide bond. Attempts were unsuccessfully made to remove the
trifluoroacetamido moiety to simplify the structural analysis by
NMR. Unfortunately, this group was remarkably resilient to both
acid and base promoted hydrolysis.
Reaction of trifluorinated vinylogous ester
9 with (R)-a-
methylbenzylamine gave vinylogous amide 10 (Scheme 1). Treat-
ment with trifluoroacetic anhydride and pyridine gave the het-
erodiene 11 in 96% yield for the two steps. The thermal Diels–
Alder reaction of 11 and ethyl vinyl ether proceeded slowly and,
1
after 2 d, the reaction was close to completion. The H NMR
spectrum of the crude reaction product gave little information
on its composition due to peak overlap and signal broadening
presumably due to amide isomerism. The crude product was
found to contain a mixture of four cycloadducts 12a–d in an
approximately 8 : 3 : 1 : 1.5 ratio based upon integration of the
resonances for the trifluoromethyl and C-5 trifluoromethyl groups
in the 19F NMR spectrum and analysis by reverse phase (C-18)
HPLC. Partial separation of two of the minor isomers, 12c and
12d by preparative HPLC aided these analyses. Purification of the
crude product by column chromatography and crystallisation gave
the major cycloadduct 12a in 40% yield in multigram quantities.
Hydroboration of 12a gave, after workup with alkaline hy-
drogen peroxide, ethyl glycoside 13 in 37% yield (69% corrected
yield) along with 48% recovered starting material (Scheme 2).
Concomitant hydrolysis of the amide occurred under the reaction
conditions, presumably due to participation of the C-4 hydroxyl
group. Attempts to optimise the conversion of 12a to 13 by
increasing the reaction time for the hydroboration resulted in a
‡ CCDC reference number 605958. For crystallographic data in CIF
format see DOI: 10.1039/b606055b
Scheme 2 Reagents and conditions: (i) BH3·SMe2, CH2Cl2, 4 ◦C, 42 h then H2O2, 3 M NaOH, THF, MeOH (69% corrected); (ii) H2, 10% Pd on C,
EtOAc, 17 h (100%); (iii) aqueous 0.5 M HCl, 100 ◦C (100%); (iv) TFAA, py then IRA 400 (OH) resin, MeOH (84%).
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2794–2800 | 2795
©

View Article Online
Scheme 3 Reagents and conditions: (i) a. DMSO, (COCl)2, −60 ◦C, 16, 2 h, b. NEt3, rt, c. NaBH4, IPA, rt (78%); (ii) H2, 10% Pd on C, EtOAc (85%);
(iii) aqueous 0.5 M HCl, 100 ◦C (100%).
complex mixture of products due to a combination of reduction
of the trifluoroacetamido and loss of the 2-phenethyl groups.
The NMR spectral data were consistent with the proposed
structure of 13. The doublet at d −77.7 ppm (3JF–H 6.1 Hz) in the
19F NMR spectrum confirmed the success of the hydroboration.
The coupling constants for the signals assigned to H-1 (3J1,2ax
9.7 Hz) and H-4 (3J3,4 and 3J4,5 9.3 Hz) indicated that 13 existed in
a chair-like conformation. Hydrogenolysis of the a-methylbenzyl
group was effected under standard conditions to give ethyl 6,6,6-
trifluoro-b-L-acosamidine 14 in quantitative yield. Acosaminide
14 was hydrolysed under acidic conditions to give acosamine
15 which was isolated as the hydrochloride salt. The H NMR
spectrum, recorded in D2O showed that 15 existed as a 1.9 : 1
mixture of the a- and b-pyranose forms.
The structures of 12a, 13 and 14 and 15 were unambiguously
confirmed from the following synthetic sequence (Scheme 2).
Trifluoroacetylation of 13 and subsequent hydrolysis of the
trifluoroacetate group gave 16 in 84% yield. Single crystals of
16 were obtained from dichloromethane and hexanes and an X-
ray diffraction study confirmed its structure and revealed that
each of the two unique molecules in the unit cell possessed an
L-arabino-configuration based upon the (R)-phenylethyl chiral
auxiliary (Fig. 1).‡ Small differences in the bond distances and
angles may be ascribed to crystal packing effects with a significant
variation of the ethoxy substituent with C-1–O1–C-1ꢀ–C-2ꢀ torsion
angles 164.6(2) and 173.48(19)◦, respectively.
The next objective of the study was to invert the stereochemistry
at C-4 of the acosamine derivative to produce a daunosamine ana-
logue. This was achieved by Swern oxidation of 16 and subsequent
reduction of the ketone intermediate with sodium borohydride to
give the L-lyxo glycoside 17 in 78% yield. As before, removal of
the a-methylbenzyl group was effected by catalytic hydrogenolysis
which gave ethyl 6,6,6-trifluoro-b-L-daunosaminide 18 in 85%
yield (Scheme 3).
1
Fig. 1 Perspective view of one of the unique molecules of 16 with displacement ellipsoids drawn at the 50% probability level.
2796 | Org. Biomol. Chem., 2006, 4, 2794–2800 This journal is The Royal Society of Chemistry 2006
©

View Article Online
Hydrolysis of 18 in 0.5 M hydrochloric acid gave 6,6,6-trifluoro-
L-daunosamine hydrochloride 19 in near quantitative yield. In
D2O 19 existed as an approximately 8 : 4 : 3 : 1 mixture of 19ap:
19bp: 19af: 19bf forms at room temperature based upon its 1H and
19F NMR spectra. The assignment of anomeric configurations
of the pyranose forms of 19 was made by comparison with the
chemical shifts and coupling constants of the anomeric protons to
those of 15. The assignment of the anomeric configurations of the
furanose forms of 19 are tentative.
In summary, we have reported a short and facile synthesis of
6,6,6-trifluoro-L-acosamine 15 and 6,6,6-trifluoro-L-daunosamine
19 from cheap and readily available starting materials. Other
6,6,6-trifluoro-3-amino-hexoses would be available by minor
modifications of this methodology. We are currently utilising
these fluorinated carbohydrates for the preparation of a range
of anthracycline and angucycline analogues.
7.12 (1H, dd, J 7, 13.5 Hz, H-4), 7.25–7.45 (5H, m, Ph), 10.40–
10.70 (1H, br s, NH).
(E)-4-[(1R)-phenethyltrifluoroacetamido]-1,1,1-trifluorobutenone
(11)
Trifluoroacetic anhydride (16.2 g, 77 mmol) was added to a cooled
(ice bath) stirred solution of 10 (15.5 g, 64 mmol) and pyridine
(6.1 g, 77 mmol) in CH2Cl2 (40 mL) under a N2 atmosphere
over a period of 10 min. The cooling bath was removed and the
reaction mixture was left to stand for 4 h. The reaction mixture
was concentrated under reduced pressure and the residue was
suspended in hexane (50 mL) and filtered through a sintered glass
funnel. Concentration of the filtrate and Kugelrohr distillation
(115–120 ◦C, 0.1 mm Hg) gave the title compound 11 (21.0 g, 96%)
as a pale-yellow oil; [a]2D2 +56.5 (c 1.1, CH2Cl2); tmax (neat)/cm−1
1
=
=
3068, 3035, 2990, 2950, 1784 (C O), 1731 (C O), 1599; H NMR
(300 MHz, CDCl3) d 1.84 (3H, d, J 7.1 Hz, CH3), 5.89 (1H, q, J
7.1 Hz, CH(Ph)CH3), 6.17 (1H, d, J 13.8 Hz, H-3), 7.22–7.44 (5H,
m, Ph), 7.95 (1H, d, J 13.8 Hz, H-4); 13C NMR (75 MHz, CDCl3)
d 15.9 (CH3), 55.6 (CH(Ph)CH3), 105.7, 115.8 (q, J 289 Hz, CF3),
116.0 (q, J 290 Hz, CF3), 126.2, 128.6, 129.3, 136.7, 142.1, 157.4
(q, J 38 Hz, CO), 179.3 (q, J = 36 Hz, CO); 19F NMR (282 MHz,
CDCl3) d −81.0 (s, CF3), −70.3 (s, CF3); m/z (EI) 339 (M+, 58%),
243 (M+- 96, 54%), 105 (M+-234, 100%); found: C, 49.86; H, 3.51;
N, 4.27; F, 33.81%. C14H11F6NO2 requires C, 49.57; H, 3.27; N,
4.13; F, 33.6.
General experimental
Melting points were measured on a Mettler Toledo FP52 melting
point apparatus or a Reichardt hot stage and are uncorrected.
1H, 13C and 19F NMR spectra were recorded on a Varian
VXRS300 spectrometer. Chemical shifts are reported as parts per
million. Deuteriochloroformsamples are referencedto the residual
chloroform (dH 7.26, dC 77.08), and D2O samples are referenced to
dioxane as an internal standard (dH 3.74, dC 67.4). All 19F spectra
are referenced to an external standard of 5% trifluoroacetic acid
in CDCl3 (dF −78.5). All IR spectra were recorded on a Perkin
Elmer Spectrum BX FT-IR spectrophotometer. Optical rotations
were recorded on a Jasco DIP-1000 digital polarimeter. Mass
spectra (EI) were recorded at the University of Canterbury, New
Zealand on a Kratos MS80RFA mass spectrometer operating
with an accelerating voltage of 4 kV and an ionisation energy
of 70 eV. Electrospray ionisation mass spectra were recorded on
a micromass LCT mass spectrometer. Elemental analyses were
carried out the Campbell Microanalytical Laboratory, University
of Otago, Dunedin, New Zealand. Flash column chromatog-
(2S,4S)-cis-2-Ethoxy-4-[(1R)-phenethyltrifluoroacetamido]-6-
trifluoromethyl-3,4-dihydro-2H-pyran (12a)
A solution of 11 (14.9 g, 44 mmol) and ethyl vinyl ether (15 g,
208 mmol) was split into three equal portions and heated in
three screw cap test tubes for 42 h in an oil bath maintained
between 60–65 ◦C. The portions were recombined and excess
ethyl vinyl ether was removed under reduced pressure. The residue
was passed through a silica column (gradient elution, 1 to
2.5% ether–hexanes). Fractions containing the target cycloadducts
(Rf = 0.36, 10% ether–hexanes) were collected and concentrated.
Crystallisation from hexanes afforded t◦he title compound 12a
(7.3 g, 40%) as a white solid; mp 101 C; [a]2D1 −24.5 (c 0.64,
˚
raphy was carried out using silica-gel (Merck 60 A, 230–400
mesh). Thin layer chromatography was performed on silica-gel
˚
precoated aluminium plates, (Merck 60 A, F254, 0.2 mm) and
were visualised under a UV lamp and with alkaline KMnO4 or
phosphomolybdic acid dips with subsequent heating. Analytical
HPLC was performed using a Jasco PU-980 pump and a Jasco
UV-975 detector set at 254 nm equipment on a Phenomonex Luna
RP-C18 (200 mm × 5 mm) column using 80% aqueous methanol
with 0.1% TFA as the mobile phase with a flow rate of 1 ml min−1.
Dichloromethane was distilled from P2O5. All other solvents and
reagents were purified using standard methods.8
CH2Cl2); tmax (KBr)/cm−1 3447 (br, OH), 3100, 3072, 3042,◦2989
1
=
2942, 2904, 1687 (C O); H NMR (300 MHz, CDCl3, −50 C) d
inter alia 1.04 (0.9H, br dd, J 6.6, 11.8 Hz, 0.9 of H-3) 1.14 (3H,
t, J 7.1 Hz, CH2CH3), 1.68 (2.7H, d, J 6.7 Hz, CH(Ph)CH3), 1.80
(0.3H, d, J 7.0 Hz, CH(Ph)CH3), 2.10–2.20 (0.1H, m, 0.1 of H-3),
2.34–2.43 (0.1H, m, 0.1 of 3-H), 2.50 (0.9H, q, J 11.3 Hz, 0.9 of H-
3), 3.41 (0.9H, qd, J 7.1, 9.1 Hz, 0.9 of CH2CH3), 3.53–3.63 (0.1H,
m, 0.1 of CH2CH3), 3.78–4.05 (2H, m, H-4, 1 of CH2CH3), 4.54
(0.1H, q, J 7.0 Hz, 0.1 of CH(Ph)CH3), 4.70 (0.9H, d, J 9.0 Hz,
H-2), 4.92–5.02 (0.1H, br s, H-2), 5.18–5.32 (1.8H, m, 0.9 of H-5,
0.9 of CH(Ph)CH3), 7.18–7.42 (5H, m, Ph); 19F NMR (282 MHz,
CDCl3) for the major amide isomer/rotamer d −69.3 (CF3CO),
−73.6 (3F, d, J 1 Hz, 6-F3); for the minor amide isomer/rotamer
d −69.7 (3F, br s, CF3CO), −73.7 (3F, br s, J 1 Hz, 6-F3); m/z (EI)
411 (M+, 9%), 365 (M+-46, 8%), 339 (M+-72, 14%), 306 (M+-105,
68%), 105 (M+-306, 100%); found: C, 52.42; H, 4.61; N, 3.47; F,
27.94%. C18H19F6NO3 requires C, 52.56; H, 4.66; N, 3.41; F, 27.71.
(Z)-4-[(1R)-phenethylamino]-1,1,1-trifluorobutenone (10)
(R)-a-Methylbenzylamine (7.8 g, 64 mmol) was added to a cold
(ice bath) stirred solution of 9 (10.9 g, 65 mmol) in CH2Cl2 (50 mL)
over a period of 5 min. Concentration under reduced pressure gave
the title compound 10 (16.0 g, 100%) as a slightly impure brown oil
1
that was used without further purification; H NMR (200 MHz,
CDCl3) inter alia 1.64 (3H, d, J 7 Hz, CH3), 4.59 (1H, apparent
quin, separation 7 Hz, CH(Ph)CH3), 5.38 (1H, d, J 7 Hz, H-3),
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2794–2800 | 2797
©

View Article Online
Small quantities of 12c and 12d were obtained by HPLC
separation on a Merck Lichrospher RP18 (10 l) 250 mm × 20 mm
column using 80% aqueous methanol as the mobile phase with a
flow rate of 4 ml min−1.
NH2, OH), 2.13 (1H, ddd, J 2.0, 4.4, 12.8 Hz, H-2eq), 2.80 (1H,
ddd, J 4.4, 9.3, 12.3 Hz, H-3), 3.39 (1H, t, J 9.3 Hz, H-4), 3.56
(1H, dq, J 9.6, 7.1 Hz, 1 of CH2CH3), 3.65 (1H, qd, J 6.2, 9.3 Hz,
H-5), 3.95 (1H, dq, J 9.6, 7.1 Hz, 1 of CH2CH3), 4.60 (1H, dd, J
2.0, 9.6 Hz, H-1). 13C NMR (75 MHz, CDCl3) d 15.1 (CH3), 39.0
(C-2), 52.6, 65.2 (CH2CH3), 70.9, 74.6 (q, J 29 Hz, C-5), 100.6
(C-1), 123.8 (q, J 281 Hz, C-6); 19F NMR (282 MHz, CDCl3) d
−77.2 (3F, d, J 6.2 Hz, F-6); m/z (ESI) 230 (MH+, 100%); found:
m/z 2320.0997 (MH+). C8H15NO3F3 requires m/z 230.1004.
For 12c, 9 : 1 mixture of amide isomers/rotamers; for the major
amide isomer/rotamer 19F NMR (282 MHz, CDCl3) d −69.1
(3F, s, CF3CO), −73.7 (3F, d, J 2.5 Hz, 6-F3); for the minor amide
isomer/rotamer 19F NMR (282 MHz, CDCl3) d −70.1 (3F, br s,
CF3CO), −73.9 (3F, br s, J 1 Hz, 6-F3).
For 12d, 17 : 1 mixture of amide isomers/rotamers; for the
major amide isomer/rotamer 19F NMR (282 MHz, CDCl3) d
−69.1 (3F, s, CF3CO), −73.6 (3F, d, J 2.5 Hz, 6-F3); for the minor
amide isomer/rotamer 19F NMR (282 MHz, CDCl3) d −70.0 (3F,
br s, CF3CO), −73.8 (3F, br s, J 1 Hz, 6-F3).
3-Amino-2,3,6-trideoxy-6,6,6-trifluoro-L-arabino-hexopyranose
hydrochloride (15)
A solution of 14 (220 mg, 1.0 mmol) in 0.5 M HCl (10 mL) was
heated over a steam bath for 1 h. Concentration under reduced
pressure afforded the title compound 15 (230 mg, 100%) (a : b
1.9 : 1) as a white powder; [a]2D4 −17.2 (c 0.4, H2O, 12 h); tmax
Ethyl 4-amino-4-N-[(1R)-phenethyl]-6,6,6-trifluoro-2,3,6-
trideoxy-b-L-arabino-hexopyranoside (13)
1
(KBr)/cm−1 3384, 2961, 1617, 1598; H NMR (300 MHz, D2O)
BH3·S(CH3)2 (3.0 mL, 30 mmol) was added to a cooled (ice-bath)
solution of 12a (5.0 g, 12 mmol) in dry CH2Cl2 (200 mL) under an
atmosphere of N2. The reaction was left at 4 ◦C for 42 h. Methanol
(30 mL), THF (80 mL) and 1 : 1 mixture of 3 M NaOH and 30%
H2O2 (100 mL) were cautiously added and the reaction mixture
was stirred vigorously at ambient temperature for 2 h. Potassium
carbonate (50 g) was added and the reaction mixture was stirred for
a further 5 min, transferred to a separating funnel and diluted with
hexane (100 mL). The phase was separated and back extracted
with CH2Cl2 (2 × 100 mL). The combined organic phases were
dried (Na2SO4) and concentrated. Purification by silica-gel column
chromatography (2.5–30% ethyl acetate–hexanes as eluent) gave
recovered 12a (2.3 g, 48%) and the title compound 13 (1.5 g,
37%) as a hygroscopic white solid; [a]2D2 +147 (c 0.30, CH2Cl2);
d 1.76 (0.34H, ddd, J 9.6, 12.6, 12.7 Hz, b-H-2ax), 1.97 (0.66H,
ddd, J 3.5, 12.5, 13.4 Hz, a-H-2ax), 2.25 (0.66H, ddd, J 1.4, 4.4,
13.4 Hz, a-H-2eq), 2.40 (0.34H, ddd, J 2.1, 4.6, 12.7 Hz, b-H-2eq),
3.50 (0.34H, ddd, J 4.6, 10.1, 12.6 Hz, b-H-3), 3.65 (0.66H, ddd,
J 4.4, 10.3, 12.5 Hz, a-H-3), 3.79–3.90 (1H, m, H-4), 4.02 (0.34H,
dq, J 6.3, 9.4 Hz, b-H-5), 4.39 (0.66H, dq, J 6.5, 9.6 Hz, a-H-
5), 5.12 (0.34H, dd, J 2.1, 9.6 Hz, b-H-1), 5.48–5.18 (0.66H, m,
a-H-1); 13C NMR (75 MHz, D2O) d 33.9 (a-C-2), 35.7 (b-C-2),
49.8 (a-C-3), 52.1 (b-C-3), 66.8 (b-C-4), 67.0 (a-C-4), 70.0 (q, J
29 Hz, a-C-5), 74.1 (q, J 30 Hz, b-C-5), 91.2 (a-C-1), 94.5 (b-C-1),
123.9 (q, J 280 Hz, b-C-6), 124.6 (q, J 280 Hz, a-C-6); 19F NMR
(282 MHz, D2O) d −77.2 (1F, d, J 6.3 Hz, b-F-6), −76.9 (2F, d, J
6.5 Hz, a-F-6); m/z (ESI) 202 (MH+, 100%), 184 (M+-OH, 55%);
found: m/z 202.0682 (MH+). C6H11NO3F3 requires m/z 202.0691.
1
tmax (KBr)/cm−1 3846 (OH), 3029, 2979, 2932, 2891; H NMR
(300 MHz, CDCl3) d 1.21 (3H, t, J 7.1 Hz, CH2CH3), 1.37 (3H, d,
J 6.5 Hz, CH(Ph)CH3), 1.28–1.42 (1H, m, H-2ax), 2.29–2.42 (2H,
m, H-2eq and 3-H), 3.40 (1H, t, J = 9.3 Hz, H-4), 3.50 and 3.52 (1H
each, 2 × overlapping qd, J 7.1, 9.5 Hz and J 6.1, 9.3 Hz, CH2CH3,
H-5), 3.92 (1H, qd, J 7.1, 9.5 Hz, 1 of CH2CH3) overlapping with
3.96 (1H, q, J 6.5 Hz, CH(Ph)CH3), 4.40 (1H, dd, J 2.0, 9.7 Hz,
H-1), 7.20–7.40 (5H, m, Ph); 13C NMR (75 MHz, CDCl3) d 15.1,
25.5, 35.6, 54.2, 55.7, 65.1, 69.1, 74.5 (q, J 31 Hz, C-5), 100.8 (C-
1), 123.6 (q, J 281 Hz, C-6), 126.6, 127.5, 128.8, 140.3; 19F NMR
(282 MHz, CDCl3) d −77.7 (d, J 6.1 Hz, F-6); m/z (EI) 333 (M+,
19%), 318 (M+-15, 68%), 288 (M+-45, 44%), 204 (M+-129, 70%),
105 (M+-228, 100%); found: C, 57.35; H, 6.50; N, 4.23; F, 16.98%.
C16H22F3NO3 requires C, 57.65; H, 6.65; N, 4.20; F, 17.10.
Ethyl 4-trifluoroacetamido-4-N-[(1R)-phenethyl]-6,6,6-trifluoro-
2,3,6-trideoxy-b-L-arabino-hexopyranoside (16)
A stirred solution of 13 (520 mg, 1.6 mmol) and pyridine (190 mg,
2.4 mmol) in CH2Cl2 (10 mL) under an N2 atmosphere was cooled
in an ice-water bath. Trifluoroacetic anhydride (980 mg, 4.4 mmol)
was added dropwise and the reaction flask was left in the cooling
bath for 2 h and then for a further 2 h at ambient temperature. The
reaction mixture was diluted with CH2Cl2 (20 mL) and poured
into a stirring saturated NaHCO3 solution. The organic layer was
washed with 1 M HCl, dried (Na2SO4) and concentrated under
reduced pressure. The resultant oil (800 mg) was dissolved in
reagent grade methanol (10 mL) and stirred in the presence of
R
Amberliteꢀ 400 (OH−) ion exchange resin for 1.75 h. A further
100 mg of fresh resin was added and stirring continued for another
15 min. Filtration and concentration under reduced pressure gave
a colourless oil. Purification by column chromatography (10%
ethyl acetate–hexanes) gave the title compound 16 (565 mg, 84%)
as a white solid; mp 144 ◦C (CH2Cl2/hexanes); [a]2D1 +137 (c 0.49,
Ethyl 3-amino-2,3,6-trideoxy-6,6,6-trifluoro-b−L-arabino-
hexopyranoside (14)
A mixture of 13 (276 mg, 0.84 mmol) and 10% Pd/C (30 mg) in
ethyl acetate (10 mL) was stirred under an atmosphere of H2 for
17 h. Filtration through a Celite pad and removal of the solvent
gave the title compound 14 (190 mg, 100%) as a white solid.
A small sample was purified by column chromatography (10%
methanol–ethyl acetate) for analysis; [a]2D3 +65.4 (c 0.65, MeOH);
tmax (KBr)/cm−1 3551, 3475, 3412 3340, 3282, 2953, 2895, 2862,
1618; 1H NMR (300 MHz, CDCl3) d 1.23 (3H, t, J 7.1 Hz, CH3),
1.53 (1H, ddd, J 9.6, 12.3, 12.8 Hz, H-2ax), 1.62–1.98 (3H, br s,
CH2Cl2); tmax (KBr)/cm−1 3470 (OH), 2989, 1669 (C O), 1114,
=
1
708; H NMR (300 MHz, CDCl3) d 0.78 (1H, ddd, J 2.2, 4.3,
12.7 Hz, H-2eq), 1.09 (3H, t, J 7.1 Hz, CH2CH3), 1.68 (3H, d, J
6.8 Hz, CH(Ph)CH3), 2.24 br (1H, d, J 4.8 Hz, OH), 2.36 (1H,
ddd, J 9.7, 12.7, 12.7 Hz, H-2ax), 3.06 (1H, ddd, J 4.3, 9.7, 12.8 Hz,
H-3), 3.34 (1H, qd, J 7.1, 9.5 Hz, 1 of CH2CH3), 3.52 (1H, qd,
J 6.1, 9.4 Hz, H-5), 3.77 (1H, qd, J 7.1, 9.5 Hz, 1 of CH2CH3),
2798 | Org. Biomol. Chem., 2006, 4, 2794–2800
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
4.02 (1H, dd, J 2.2, 9.5 Hz, H-1), 4.81 (1H, ddd, J 4.8, 9.4, 9.7 Hz,
H-4), 5.32 (1H, q, J 6.8 Hz, CH(Ph)CH3), 7.37–7.43 (5H, m, Ph);
13C NMR (75 MHz, CDCl3) d 14.9, 17.5, 32.7 (C-2), 55.9, 58.1,
62.6, 64.7, 75.2 (q, J 29 Hz, C-5), 100.1 (C-1), 116.6 (q, J 288 Hz,
CF3), 123.7 (q, J 281 Hz, CF3), 128.1, 129.0, 129.1, 137.2, 156.4
(q, J 35 Hz, COCF3); 19F NMR (282 MHz, CDCl3) d −76.6 (3F,
d, J 6.1 Hz, F-6), −70.7 (3F, s, COCF3); m/z (EI) 429 (M+, 13%),
414 (M+-15, 14%), 383 (69%), 286 (19%), 216 (75%), 105 (100%);
found: C, 50.31; H, 4.95; N, 3.36; F, 26.58%. C18H21F6NO4 requires
C, 50.35; H, 4.93; N, 3.26; F, 26.55.
X-Ray data were collected at 153(2)K on a Bruker SMART
CCD diffractometer, processed using SAINT, with empirical ab-
sorption corrections applied using SADABS.‡ Chemical formula
C18H21F6NO4; formula weight = 429.36; crystal system triclinic,
were dried (Na2SO4) and concentrated. Purification by column
chromatography (10–15% ethyl acetate–hexanes) afforded the title
compound 17 (169 mg, 78%) as a colourless syrup; [a]2D4 +60.8
(c 0.49, CH2Cl2); tmax (neat)/cm−1 3441 (br), 2977, 1144, 897,
1
763, 704; H NMR (300 MHz, CDCl3) d 1.22 (3H, t, J 7.1 Hz,
CH2CH3), 1.37 (3H, d, J 6.3 Hz, CH(Ph)CH3), 1.63 (1H, ddd,
J 9.7, 12.4, 12.7 Hz, H-2ax), 1.96 (1H, ddd, J 2.2, 4.8, 12.7 Hz,
H-2eq), 2.67 (1H, ddd, J 2.9, 4.8, 12.4 Hz, H-3), 3.47–3.65 (3H,
m, 1 of CH2CH3, H-4, H-5), 3.87–4.02 (2H, m, CH(Ph)CH3, 1 of
CH2CH3), 4.42 (1H, dd, J 2.2, 9.7 Hz, H-1), 7.20–7.38 (5H, m,
Ph). 13C NMR (75 MHz, CDCl3) d 15.1, 24.6, 32.3, 53.8, 55.0, 64.1,
65.0, 74.0 (q, J 31 Hz, C-5), 101.1 (C-1), 123.1 (q, J 280 Hz, C-6),
126.5, 127.4, 128.7, 144.8; 19F NMR (282 MHz, CDCl3) d −76.4
(d, J 6.6 Hz, 6-F); m/z (EI) 333 (M+, 22%), 318 (M+-15, 66%), 288
(M+-45, 35%), 105 (M+-228, 100%); found: m/z 334.1644 (MH+).
C16H22F3NO3 requires m/z 334.1630.
˚
space group P1. Unit cell dimensions: a = 9.499(2) A, b =
◦
◦
˚
˚
10.601(3) A, c = 11.958(3) A, a = 113.345(3) b = 98.080(3) , c =
◦
3
˚
103.188(3) ; volume 1039.9(4) A , Z = 2, absorption coefficient
0.131 mm−1. Temperature 153(2) K. Reflections collected 13093,
independent reflections 7146 [R(int) = 0.0232]. Final R indices
[I > 2r(I)]: R1 = 0.0311, wR2 = 0.0757; R indices (all data) R1 =
0.0366, wR2 = 0.0779.
Ethyl 3-amino-2,3,6-trideoxy-6,6,6-trifluoro-b-L-lyxo-
hexopyranoside (18)
A mixture of 17 (187 mg, 0.56 mmol) and 10% Pd/C (25 mg)
in ethyl acetate (8 mL) was stirred under an atmosphere of
H2 for 5 d. Filtration through a Celite pad and removal of
the solvent gave a white solid. Column chromatography (10%
methanol–ethyl acetate) gave the title compound 18 (110 mg,
85%) as an amorphous white powder. [a]2D4 +25.0 (c 0.41, MeOH);
The structure was solved using SHELXS9 and refined by
full-matrix least-squares using SHELXL-9710 and TITAN2000.11
Non-hydrogen atoms were assigned anisotropic temperature fac-
tors and the H atoms were included in calculated positions. Tables
of bond lengths, bond angles and torsion angles are provided in
the ESI.
1
tmax (KBr)/cm−1 3420 (br str, OH, NH), 1639, 1188; H NMR
(300 MHz, D2O) d 1.20 (3H, t, J 7.1 Hz, CH3), 1.53 (1H, ddd, J
9.9, 12.6, 12.8 Hz, H-2ax), 1.89 (1H, ddd, J 2.9, 4.5, 12.8 Hz, H-2eq),
3.01 (1H, ddd, J 3.1, 4.6, 12.6 Hz, H-3), 3.71 (1H, qd, J.7.1, 7.8 Hz,
1 of CH2CH3), 3.90–4.03 (2H, H-4, 1 of CH2CH3), 4.12 (1H, dq,
J 1.1, 6.8 Hz, H-5), 4.77 (1H, dd, J 2.9, 9.9 Hz, H-1); 13C NMR
(75 MHz, CDCl3) d 15.0, 34.4, 49.3, 65.6, 66.6, 74.6 (q, J 31 Hz,
C-5), 101.8 (C-1), 124.0 (q, J 280 Hz, C-6); 19F NMR (282 MHz,
CDCl3) d −76.3 (d, J 6.8 Hz, 6-F); m/z (ESI) 230 (MH+, 52%),
170 (100%); found: m/z 230.1013 (MH+). C8H14F3NO3 requires
m/z 230.1004.
Ethyl 4-amino-4-N-[(1R)-phenethyl]-6,6,6-trifluoro-2,3,6-
trideoxy-b-L-lyxo-hexopyranoside (17)
A two necked 50 mL round bottomed flask containing a stirred
solution of CH2Cl2 (5 mL) and DMSO (160 lL, 2.2 mmol) under
an atmosphere of N2 was cooled in a −60 ◦C dry ice–acetone bath.
Oxalyl chloride (165 lL,1.9 mmol) was added dropwise and the
solution was left to stir for three min before adding 16 (280 mg,
0.65 mmol) in one portion. The stirred mixture was held in the
cooling bath for 2 h. Triethylamine (335 lL, 2.4 mmol) was added
dropwise and after 5 min the reaction flask was removed from the
cooling bath and left to stir for a further 10 min. The reaction
mixture was diluted with CH2Cl2 (20 mL) and washed with 1 M
HCl (10 mL), dried (Na2SO4) and concentrated under reduced
pressure to give the ketone intermediate as an impure white solid
3-Amino-2,3,6-trideoxy-6,6,6-trifluoro-L-lyxo-hexopyranose (19)
A solution of (49 mg, 1.0 mmol) in 0.5 M HCl (10 mL) was heated
over a steam bath for 1 h. Concentration under reduced pressure
afforded the title compound 19 as a slightly impure white powder
(50 mg, 100%).
1
which was used without purification in the next step; H NMR
◦
In D2O at 25 C, 19 existed as an 8 : 4 : 3 : 1 (ap : bp : af : bf)
(200 MHz, CDCl3) d inter alia 1.14 (3H, t, J 7 Hz, CH2CH3),
1.38–1.51 (1H, m, 1 of H-2), 1.64 (3H, d, J 8 Hz, CH(Ph)CH3),
2.74 (1H, ddd, J 9, 13, 13 Hz, 1 of H-2), 3.40 (1H, dq, J 7, 9.5 Hz,
1 of CH2CH3), 3.59 (1H, dd, J 6, 13 Hz, H-3), 3.85 (1H, dq, J 7,
9.5 Hz, 1 of CH2CH3), 4.37 (1H, q, J 8 Hz, CH(Ph)CH3), 4.65
(1H, dd, J 4.5, 9 Hz, H-1), 5.41 (1H, q, J 7 Hz, H-5), 7.30–7.50
(5H, m, Ph).
Water (2 mL) and NaBH4 (100 mg, 2.6 mmol) were added to
a solution of 16 in isopropyl alcohol (12 mL), and the mixture
was stirred for 10 min. Glacial acetic acid (100 lL) was added
and the mixture was concentrated under reduced pressure until
most of the isopropyl alcohol had been removed. The resultant
syrup was diluted with saturated NaHCO3 solution (10 mL)
and extracted twice with CH2Cl2. The combined organic phases
mixture of pyranose and furanose anomers; 1H NMR (300 MHz,
D2O) d inter alia (0.25H, dd, J 2.2, 9.8 Hz, bp-H-1), 5.54 (0.51H,
br d, J 2.9 Hz, ap-H-1), 5.69–5.76 (0.24H, m, af- and bf- H-1);
19F NMR (282 MHz, CDCl3) d −78.6 (0.54F, d, J 7.6 Hz, af-6-
F), −78.4 (0.18F, d, J 7.3 Hz, bf-F-6), −76.8 (1.53F, d, J 6.8 Hz,
ap-F-6), −76.5 (0.75F, d, J 6.6 Hz, bp-F-6); found: m/z 202.0682
(MH+). C6H11NO3F3 requires m/z 202.0691.
Acknowledgements
We would like to thank Dr Mervyn Thomas and Wayne Redmond,
University of Otago for their assistance in collecting NMR data.
We also thank Bruce Clark for recording mass spectra, and Dr Jan
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2794–2800 | 2799
©

View Article Online
Wikaira and Professor Ward T. Robinson, all from the University
of Canterbury, for the X-ray data collection.
5 L. F. Tietze, U. Hartfiel, T. Huebsch, E. Voss and J. Wichmann, Chem.
Ber., 1991, 124, 881–8.
6 C. M. Hayman, D. S. Larsen and S. Brooker, Aust. J. Chem., 1998, 51,
545–553.
7 C. M. Hayman, L. R. Hanton, D. S. Larsen and J. M. Guthrie,
Aust. J. Chem., 1999, 52, 921–927.
8 D. D. Perrin, W. L. F. Armarego and D. R. Perrin, Purification of
Laboratory Chemicals, 2nd edn, 1980.
9 G. M. Sheldrick, SHELXS, Program for the solution of crystal
structures, University of Go¨ttingen, Germany, 1996.
10 G. M. Sheldrick, SHELXS-97, Program for solution of crystal struc-
tures, University of Go¨ttingen, Germany, 1997.
11 K. A. Hunter and J. Simpson, TITAN2000, Molecular graphics program
to aid structure solution and refinement with the SHELX suite of
programs, University of Otago, New Zealand, 1999.
References
1 Y. Takagi, K. Nakai, T. Tsuchiya and T. Takeuchi, J. Med. Chem., 1996,
39, 1582–8.
2 K. Nakai, Y. Takagi, S. Ogawa and T. Tsuchiya, Carbohydr. Res., 1999,
320, 8–18.
3 K. Nakai, Y. Takagi and T. Tsuchiya, Carbohydr. Res., 1999, 316, 47–
57.
4 Y. Hanzawa, J. Uda, Y. Kobayashi, Y. Ishido, T. Taguchi and M. Shiro,
Chem. Pharm. Bull., 1991, 39, 2459–61.
2800 | Org. Biomol. Chem., 2006, 4, 2794–2800
This journal is
The Royal Society of Chemistry 2006
©