A stereoselective synthesis of 2,6-dideoxy-6,6,6-trifluoro-arabino-hexoses via an asymmetric diels-alder strategy

Article abstract of DOI:10.1071/CH99067

The enantioselective syntheses of each enantiomer of ethyl 2,6-dideoxy-6,6,6-trifluoro-β-arabino-hexopyranoside (3) and of 2,6-dideoxy-6,6,6-trifluoro-araino-hexose (4) are described. The key step in the approach is the inverse electron demand Lewis acid

Full text of DOI:10.1071/CH99067

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 52, 1999
© CSIRO Australia 1999
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Aust. J. Chem., 1999, 52, 921–927
A Stereoselective Synthesis of
2,6-Dideoxy-6,6,6-trifluoro-arabino-hexoses
via an Asymmetric Diels–Alder Strategy
Colin M. Hayman,A Lyall R. Hanton,A David S. Larsen A,B
and Jenness M. GuthrieA
A Department of Chemistry, University of Otago,
P.O. Box 56, Dunedin, New Zealand.
B Author to whom correspondence should be addressed.
The enantioselective syntheses of each enantiomer of ethyl 2,6-dideoxy-6,6,6-trifluoro- -arabino-hexopyranoside (3)
and of 2,6-dideoxy-6,6,6-trifluoro-arabino-hexose (4) are described. The key step in the approach is the inverse elec-
tron demand Lewis acid catalysed Diels–Alder reaction of the heterodiene (E)-1,1,1-trifluoro-4-[(1R)-1-
phenylethoxy]but-3-en-2-one (5) and either ethyl vinyl ether (7a) or benzyl vinyl ether (7b). The titanium(IV) chloride
catalysed cycloadditions at low temperature displayed high endo-selectivity and modest diastereofacial selectivity.
Hydroboration of the mixture of the cis-cycloadducts (8a) afforded the separable diastereoisomers (9a) and (10a).
Hydrogenolysis of (9a) gave ethyl 2,6-dideoxy-6,6,6-trifluoro- -L-arabino-hexopyranoside (+)-(3), and of (10a) gave
the corresponding D-glycoside (–)-(3). Similarly, hydroboration of the cis-cycloadducts (8b) gave the protected benzyl
glycosides (9b) and (10b). Hydrogenolysis of each gave 2,6-dideoxy-6,6,6-trifluoro-L-arabino-hexopyranose (–)-(4)
and the corresponding D-sugar (+)-(4) respectively. The absolute configurations of fluorinated carbohydrates (+)- and
(–)-(3) were determined by comparison of their molar rotations with those of the parent glycosides. These assignments
were confirmed by an X-ray crystallographic structure determination of the glycoside (9a).
Introduction
A common feature in a large number of glycosylated
antibiotics, including the anthracycline, angucycline,
macrolide and enediyne families, is the 2,6-dideoxyhexopy-
ranose unit.1–4 For some of these groups of antibiotics the
saccharides have been implicated in the delivery and binding
of the biologically active agent to a target site.5,6 It appears
that the balance between the hydrophobic and hydrophilic
regions of deoxygenated carbohydrates is important for
molecular recognition. Modification of these carbohydrate
units, by interfering with that balance, could be of interest as
a means of changing the biological activity of the parent
antibiotic. Although the preparation of fluorine-containing
carbohydrate analogues has been well studied,7,8 systems in
which the methyl group of a 2,6-dideoxyhexopyranose has
been replaced by a trifluoromethyl group have received rela-
tively little attention.9–14 The high electronegativity and
hydrophobicity of the trifluoromethyl group15 is likely to sig-
nificantly alter the chemical reactivity and binding ability of
the carbohydrate. This in turn has the potential to affect the
biological activity of the modified antibiotic.
lated methyl L-lyxoside derivative. Relative to adriamycin
(2), compound (1) displayed greater antitumour activity
against adriamycin-resistant P388 murine leukaemia in vitro
and was also shown to have markedly higher potency against
L1210 murine leukaemia in vivo. This early result estab-
lishes the merit of further study of 2,6-dideoxy 6,6,6-triflu-
oro carbohydrate systems.
The abundance of 2,6-dideoxy carbohydrates of arabino
stereochemistry, especially as residues in the angucycline
and aureolic antibiotics, make compounds such as (3) and (4)
interesting synthetic targets. We have recently reported a
synthesis of the racemic forms of (3) and the corresponding
Tsuchiya et al. have reported the synthesis of (1), the tri-
fluoromethylated analogue of 3´-deamino-3´-hydroxyadri-
amycin.13 Their synthesis of the intermediate
1,3,4-tri-O-acetyl-2,6-dideoxy-6,6,6-trifluoro-L-lyxo-hex-
opyranose involved an 11-step sequence starting from a tosy-
Manuscript received 1 June 1999
© CSIRO 1999
0004-9425/99/100921
10.1071/CH99067

C. M. Hayman et al.
922
Scheme 1. Reagents and conditions: (i) TiCl4, –78°C, CH2Cl2, 10 min; (ii) BH3·Me2S, CH2Cl2, then H2O2, OH–, then
silica gel chromatography; (iii) H2, Pd–C.
free sugar (4) using an inverse electron demand Diels–Alder
strategy.14 In this report we describe the use of (E)-1,1,1-tri-
fluoro-4-[(1R)-1-phenylethoxy]but-3-en-2-one (5) in a simi-
lar Diels–Alder process for a brief and efficient preparation
of each enantiomer of both (3) and (4).
range of monochiral vinyl ethers were prepared.
Unfortunately, in our preliminary work we found that, using
the reaction conditions established for the synthesis of rac-
(4),14 polymerization and decomposition of the chiral vinyl
ethers occurred.
The remaining option involving the use of chiral hetero-
dienes was explored. The source of chirality for this
approach was (R)-1-phenylethanol obtained from the enan-
tioselective lipase Amano PS-mediated acylation of
(±)-1-phenylethanol with succinic anhydride.16 Our choice
of the 1-phenylethyl group as the chiral auxiliary was made
because of the ease with which it could be removed from the
target carbohydrates. The e.e. of the (R)-1-phenylethanol
obtained was >98% as determined by optical rotation and
was confirmed by gas chromatography. From this alcohol,
heterodiene (5) was easily prepared by initial formation of
the respective vinyl ether and subsequent trifluoroacetyl-
ation in an overall yield of 59%.
The titanium(IV) chloride catalysed cycloaddition
between (5) and either ethyl vinyl ether (7a) or benzyl vinyl
ether (7b) proceeded smoothly at low temperature. High
endo-selectivities were observed for the cycloadditions
which afforded the cis-cycloadducts (8a) or (8b) in yields of
96 and 84% respectively (Scheme 1). The diastereofacial
selectivity of the cycloadditions with ethyl vinyl ether and
benzyl vinyl ether was estimated from the 1H n.m.r. spectra
Discussion
In our preceding paper14 we described the synthesis of
2,6-dideoxy-6,6,6-trifluoro-DL-arabino-hexose (4). The syn-
thesis relied on the Lewis acid catalysed inverse electron
demand Diels–Alder reaction of the vinylogous ester (6) and
either ethyl vinyl ether or benzyl vinyl ether. The latter
highly diastereoselective reaction formed an endo
cycloadduct, which after hydroboration and hydrogenolytic
deprotection gave (±)-(4).
Several options were available to extend this method to
allow the asymmetric synthesis of each enantiomer of (4)
and related glycosides. These included the reaction of chiral
vinyl ethers as dienophiles with the heterodiene (6), the reac-
tion of chiral vinylogous esters with achiral vinyl ethers, and
double stereodifferentiation reactions involving chiral
dienes and dienophiles.
The first option was preferred as a wide range of
monochiral vinyl ethers are available and, regardless of the
source of chirality, the chiral auxiliary would be easily
removed by hydrolysis of the corresponding glycosides. A

Synthesis of 2,6-Dideoxy-6,6,6-trifluoro-arabino-hexoses
923
of the crude product mixtures to be approximately 1 : 1.4 and
1 : 1.5 respectively. The diastereomeric cis-cycloadducts
were not readily separable by flash silica-gel chromatogra-
phy; thus, the mixtures were subjected to standard hydro-
boration and oxidation conditions. Flash silica-gel
chromatography enabled isolation of the individual glyco-
sides (9a) (29%) and (10a) (39%), and similarly (9b) (31%)
and (10b) (45%), from the respective crude hydrobora-
tion–oxidation reaction mixtures.
Catalytic hydrogenolysis of (9a) and (10a) was non-prob-
lematical, quantitatively affording the debenzylated ethyl
glycosides (+)-(3) and (–)-(3) respectively. The enantiomeric
purities of (+)- and (–)-(3) were confirmed by gas chro-
matography, in which each enantiomer was shown to have an
e.e. of >98%. The hydrogenolyses of (9b) and (10b) also
proceeded smoothly to give the free sugar analogues (–)-(4)
and (+)-(4) in yields of 99 and 89% respectively.
configuration. Conversely, both (9b) and (–)-(4) were
assigned the L-configuration (Scheme 2).
Further evidence to support the configurational assign-
ments was obtained by the acetylation of (–)-(4). Treatment
with pyridine and acetic anhydride gave, after separation by
column chromatography, tri-O-acetyl-2,6-dideoxy-6,6,6-
trifluoro- -L-arabino-hexopyranose (14a) and the corre-
sponding -anomer (14b). Of note was the fact that, in
accord with Hudson’s isorotation rule, the rotations of these
compounds were consistent with the parent sugar having the
L-configuration.19 The rotation of the -anomer (14a) {[ ]2D0
–76} was more negative than that of the -anomer (14b)
{[ ]2D0 –9}.
The absolute stereochemistry depicted for the intermedi-
ates and final compounds in Scheme 1 has been assigned on
the basis of the signs of their molar rotations. That of (+)-
(3){[ ]2D1 +164 (c, 0.34 in CH2Cl2)} has the same sign and a
similar magnitude to that of the non-fluorinated analogue,
Unequivocal support for the configurational assignments
was finally obtained from a single-crystal X-ray crystallo-
graphic study of glycoside (9a). Final atomic coordinates,
bond lengths and bond angles are given in Tables 1–3. A per-
spective view of (9a) is given in Fig. 1 which clearly depicts
ethyl
2,6-dideoxy- -L-arabino-hexopyranoside*
(11)
{[ ]2D2 +116 (c, 1.3 in CH2Cl2)}. As the absolute stereo-
chemistry of (11) was known to be L, the 6,6,6-trifluoro ana-
logue of like sign [i.e. (+)-(3)] was assigned as the
L-configuration. A similar trend in molar rotation data can be
seen in the comparison of 1,3,4-tri-O-acetyl-2,6-dideoxy- -
L-lyxo-hexopyranose (12)18 and its trifluorinated analogue
(13).13 Their reported molar rotations, measured in chloro-
form ([ ]D –375 and –328 respectively), showed the same
sign and were of similar magnitudes.
1
the pyranose ring in a regular C4 chair conformation. The
substituents at C 3, 4 and 5 are all trans-related, thus con-
firming the arabino stereochemistry of the system. More
importantly, Fig. 1 clearly shows the R- and the L-configura-
tion of the 1-phenylethyl protecting group and pyranose ring
system respectively, confirming the absolute configurational
assignment of (9a), and hence those of (+)-(3), (–)-(3), (–)-
(4) and (+)-(4).
Conclusion
The synthesis described here provides a rapid and cheap
route to enantiomerically pure 2,6-dideoxy-6,6,6-trifluoro-
arabino-hexoses. Both enantiomers of (3) are available in a
five-step sequence from ethyl vinyl ether. Further investiga-
tions assessing other asymmetric heterodienes and
dienophiles with the aim of enhancing the diastereofacial
selectivity of the Diels–Alder cycloaddition and developing
a route to the trifluorinated analogue of L-daunosamine are
underway.
Experimental
Assignments of the absolute configuration of the benzyl
glycosides (9b) and (10b) were made on the basis of the rota-
tions measured in water of their respective hydrogenolysis
products, namely (–)-(4) ([ ]2D3 –11) and (+)-(4) ([ ]2D3 +11).
Acid-promoted hydrolysis of the ethyl glycoside (–)-(3) also
afforded (+)-(4). As (–)-(3) had been shown to have the D-
configuration, both (10b) and (+)-(4) were assigned the D-
Melting points were measured on a Mettler Toledo FP52 melting
point apparatus and are uncorrected. Unless otherwise noted, all 1H, 13
C
and 19F n.m.r. spectra were obtained at 300, 75 and 282 MHz respec-
tively on a Varian VXRS300 spectrometer. Chemical shifts are reported
as parts per million using the scale. All 1H n.m.r. spectra were mea-
sured on solutions of the compound in (D)chloroform by using the
residual chloroform ( 7.26) as internal reference unless otherwise
stated. 1H and 13C n.m.r. spectra in D2O are referenced to 1,4-dioxan as
* Compound (11) was prepared by using the procedure of Honda et al. from di-O-acetyl-L-rhamnal.17 Full experimental details are given in the exper-
imental section.

C. M. Hayman et al.
924
Table 1. Atomic coordinates and equivalent isotropic displace-
ment parameters (Å2) for compound (9a)
U
eq is defined as one-third of the trace of the orthogonalized Uij tensor
Atom
104x
104y
104z
103Ueq
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
O(1)
O(3)
O(4)
O(5)
F(1)
8533(3)
8246(3)
8961(3)
8324(3)
8637(3)
7998(3)
8233(3)
8000(4)
9654(3)
11359(3)
12550(3)
14111(3)
14510(3)
13328(3)
11774(3)
8951(3)
7788(2)
8632(2)
9075(2)
7865(2)
6430(2)
8223(2)
8693(2)
6948(2)
6948(2)
7886(2)
8806(2)
8712(2)
9552(2)
5947(2)
4860(2)
7450(2)
7793(2)
7143(2)
7464(2)
8434(2)
9087(2)
8777(2)
7585(2)
6140(1)
8014(1)
9665(1)
7840(1)
9690(1)
9400(1)
10415(1)
10417(2)
11451(2)
11862(2)
11386(2)
10344(2)
9767(2)
28(1)
31(1)
28(1)
30(1)
30(1)
36(1)
33(1)
46(1)
30(1)
26(1)
34(1)
39(1)
38(1)
36(1)
32(1)
40(1)
31(1)
30(1)
44(1)
29(1)
53(1)
54(1)
46(1)
9064(2)
8889(2)
13440(2)
13373(1)
13111(2)
13045(2)
13238(2)
13503(2)
13574(2)
14401(2)
10019(1)
12822(1)
11756(1)
10013(1)
9887(1)
Fig. 1. View of compound (9a) showing the crystallographic num-
bering scheme. Thermal ellipsoids are drawn with boundary surfaces at
the 50% probability level.
F(2)
8866(1)
9973(1)
F(3)
an internal reference at 3.74 (1H) and 67.4 (13C). 19F n.m.r. spectra are
referenced to an external standard of 5% trifluoroacetic acid in CDCl3
at –78.5. I.r. spectra were recorded on a Perkin–Elmer 1600 Fourier-
transform i.r. spectrophotometer. Optical rotation measurements were
made with a Jasco DIP-1000 digital polarimeter. Mass spectra (e.i.)
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 ionization energy of 70 eV. Elemental analyses
were carried out by Dr R. G. Cunninghame and associates at the
Campbell Microanalytical Laboratory, University of Otago, Dunedin,
New Zealand. Flash column chromatography was carried out with
silica gel (Merck 60 Å, 230–400 mesh). Thin-layer chromatography
was performed on silica-gel precoated aluminium plates (Merck 60 Å,
F254, 0.2 mm); these were visualized under a u.v. lamp and/or with an
alkaline KMnO4 dip or with a spray consisting of 5% w/v dode-
camolybdophosphoric acid in ethanol with subsequent heating. Gas
chromatography was performed on a Perkin Elmer 8420 capillary gas
chromatograph with a 30 m Cyclodex-B chiral column fitted with a 1 m
guard column. Helium was used as the carrier gas with an operating
pressure of 170 kPa and a flow rate of 1.08 ml min–1. Dichloromethane
was distilled from P2O5 and tetrahydrofuran (thf) was distilled from
sodium/potassium–benzophenone ketyl under nitrogen. All other sol-
vents and reagents were purified by using standard methods.20
Table 2. Bond lengths (Å) for compound (9a)
Atoms
Distance
Atoms
Distance
C(1)–O(1)
C(1)–O(5)
C(1)–C(2)
C(2)–C(3)
C(3)–O(3)
C(3)–C(4)
C(4)–O(4)
C(4)–C(5)
C(5)–O(5)
C(5)–C(6)
C(6)–F(2)
C(6)–F(3)
1.380(3)
1.448(3)
1.514(3)
1.519(3)
1.424(3)
1.514(3)
1.422(3)
1.533(3)
1.424(3)
1.504(3)
1.331(3)
1.334(3)
C(6)–F(1)
1.345(3)
1.453(3)
1.498(3)
1.453(3)
1.512(3)
1.520(3)
1.383(3)
1.400(4)
1.387(4)
1.376(4)
1.382(4)
1.378(3)
C(7)–O(1)
C(7)–C(8)
C(9)–O(3)
C(9)–C(10)
C(9)–C(16)
C(10)–C(11)
C(10)–C(15)
C(11)–C(12)
C(12)–C(13)
C(13)–C(14)
C(14)–C(15)
(E)-1,1,1-Trifluoro-4-[(1R)-1-phenylethoxy]but-3-en-2-one
A mixture of ethyl vinyl ether (25 ml, 0.26 mol), mercuric acetate
(0.34 g, 1 mmol) and (R)-(+)-1-phenylethanol (2.8 g, 23 mmol) was
heated at reflux for 48 h. The cooled mixture was concentrated under
reduced pressure to remove the excess ethyl vinyl ether. Purification
was effected by flash silica-gel chromatography in pentane. The appro-
priate fractions were concentrated at room temperature to return a
sample of (R)-1-phenylethyl vinyl ether containing a small amount of
pentane (2.3 g). Trifluoroacetic anhydride (4.0 ml, 28 mmol) was added
to a stirred solution of this mixture and pyridine (0.4 ml, 5 mmol) in
CH2Cl2 (8 ml). The reaction mixture was stirred under an atmosphere
of N2 for 17 h and worked up by diluting with CH2Cl2 and washing con-
secutively with dilute HCl and saturated NaHCO3 solution. The organic
layer was dried over MgSO4 and concentration under reduced pressure
gave (5) (3.3 g, 59%) as a yellow oil.
Table 3. Bond angles (degrees) for compound (9a)
Atoms
Angle
Atoms
Angle
O(1)–C(1)–O(5)
O(1)–C(1)–C(2)
O(5)–C(1)–C(2)
C(1)–C(2)–C(3)
O(3)–C(3)–C(4)
O(3)–C(3)–C(2)
C(4)–C(3)–C(2)
O(4)–C(4)–C(3)
O(4)–C(4)–C(5)
C(3)–C(4)–C(5)
O(5)–C(5)–C(6)
O(5)–C(5)–C(4)
C(6)–C(5)–C(4)
F(2)–C(6)–F(3)
F(2)–C(6)–F(1)
F(3)–C(6)–F(1)
F(2)–C(6)–C(5)
108.00(18)
109.72(19)
109.61(18)
108.77(19)
105.91(19)
113.79(19)
111.15(18)
109.7(2)
F(3)–C(6)–C(5)
111.9(2)
112.6(2)
107.5(2)
111.39(19)
105.5(2)
113.1(2)
118.2(2)
121.0(2)
120.8(2)
120.6(3)
120.9(3)
118.9(3)
120.8(3)
120.6(2)
114.72(18)
114.80(18)
111.74(16)
F(1)–C(6)–C(5)
O(1)–C(7)–C(8)
O(3)–C(9)–C(10)
O(3)–C(9)–C(16)
C(10)–C(9)–C(16)
C(11)–C(10)–C(15)
C(11)–C(10)–C(9)
C(15)–C(10)–C(9)
C(10)–C(11)–C(12)
C(13)–C(12)–C(11)
C(12)–C(13)–C(14)
C(15)–C(14)–C(13)
C(14)–C(15)–C(10)
C(1)–O(1)–C(7)
111.0(2)
108.53(19)
105.62(19)
108.57(19)
114.9(2)
An analytical sample was obtained as a colourless oil by flash chro-
106.8(2)
106.7(2)
matography (5% ether–hexanes), [ ]2D3 +11 (neat) (Found: C, 59.1; H,
106.4(2)
C(3)–O(3)–C(9)
C(5)–O(5)–C(1)
4.7; F, 23.6. C12H11F3O2 requires C, 59.0; H, 4.5; F, 23.3%).
max
112.1(2)
(neat)/cm–1 3069, 3035, 2986, 2935, 1707 (C=O), 1606, 1200, 1145, 1053,

Synthesis of 2,6-Dideoxy-6,6,6-trifluoro-arabino-hexoses
925
1
Representative Hydroboration Procedure: Ethyl 2,6-Dideoxy-6,6,6-
760, 723, 700. H n.m.r. 1.67, d, J 6.6 Hz, CH3; 5.19, q, J 6.6 Hz,
trifluoro-3-O-[(1 R)-1-phenylethyl]- -L-arabino-hexopyranoside (9a)
and Ethyl 2,6-Dideoxy-6,6,6-trifluoro-3-O-[(1 R)-1-phenylethyl]- -D-
arabino-hexopyranoside (10a)
OCH(CH3)Ph; 5.93, dd, J 0.9, 12.2 Hz, H3; 7.27–7.42, 5H, m, Ph; 7.85,
d, J 12.2 Hz, H 4. 13C n.m.r. 23.1, CH3; 83.3, OCH(CH3)Ph; 99.8, C 3;
116.4, q, J 291 Hz, C 1; 125, 128.9, 129.1, 140.1, Ph; 167.1, C 4; 180.1, q,
J 35 Hz, C 2. 19F n.m.r. –80.8, s, CF3. m/z [no M+] 149 (58%), 105 (100).
Neat BH3·S(CH3)2 (1.6 ml, 17 mmol) was added dropwise to a
stirred mixture of the cis-cycloadducts (8a) (1.65 g, 5.2 mmol) in dry
CH2Cl2 (80 ml) at 0ºC under an atmosphere of N2. After 10 min the
reaction flask was allowed to warm to room temperature. After 17 h
methanol (21 ml), thf (50 ml), aqueous NaOH solution (40 ml, 3 M) and
30% H2O2 (40 ml) were added and the reaction mixture was stirred at
room temperature for 5 h. Potassium carbonate (25 g) was added and
the mixture stirred for a further 10 min. The mixture was extracted with
CH2Cl2 (3×200 ml) and the combined organic layers were dried
(MgSO4) and concentrated under reduced pressure to give a colourless
solid. Purification by flash chromatography (5% ether–hexanes) gave
two fractions. The high RF diastereoisomer (9a) (0.50 g, 29%) was
Representative Diels–Alder Cycloaddition: (2S,4S)- and (2R,4R)-2-
Ethoxy-4-[(1R)-1-phenylethoxy]-6-trifluoromethyl-3,4-dihydro-2H-
pyran (8a)
A nitrogen-flushed flame-dried Schlenk tube was charged with a
stirred solution of CH2Cl2 (40 ml), ketone (5) (1.3 g, 5.2 mmol) and
ethyl vinyl ether (7a) (0.98 g, 14 mmol) and the resulting mixture
cooled in a dry ice–acetone bath. Asolution of TiCl4 in CH2Cl2 (0.86ml,
0.78 mmol) was added and the mixture was stirred for 10 min, then
poured into saturated NaHCO3 solution (150 ml) and extracted with
CH2Cl2 (2×150 ml). The combined organic layers were dried over
Na2SO4, concentrated under reduced pressure and purified by flash
chromatography (5% ether–hexanes) to give the title compounds (8a)
(1.6 g, 96%) as a 1: 1.4 [(2S,4S)/(2R,4R)] mixture of isomers as a
colourless oil (Found: C, 60.5; H, 6.3; F, 17.4. C16H19F3O3 requires C,
60.8; H, 6.1; F, 18.0%). max (neat)/cm–1 3064, 3030, 2980, 2934, 2880,
1685 (C=C), 1185, 1141, 1091, 1051, 763, 702. m/z [no M+] 315
obtained as
a colourless oil, which solidified on standing.
Crystallization from hexane gave colourless crystals, m.p. 92ºC, [ ]2D0
+154 (c, 0.53 in CH2Cl2) (Found: C, 57.2; H, 6.2; F, 16.9. C16H21F3O4
requires C, 57.5; H, 6.3; F, 17.1%). max (neat)/cm–1 3560 (OH), 3443,
1
2987, 2936, 2899, 1445, 1385, 1279, 1187, 1080, 926, 767, 706. H
n.m.r. 1.22, t, J 7.1 Hz, OCH2CH3; 1.47, d, J 6.5 Hz, OCH(CH3)Ph;
1.62, ddd, J 9.8, 11.6, 12.7 Hz, H 2ax; 2.33 and 2.34, 1H each, overlap-
ping d and ddd, for d J 2.2 Hz, for ddd J 2.0, 4.9, 12.7 Hz, OH and
H2eq; 3.29, ddd, J 4.9, 8.7, 11.6 Hz, H 3; 3.46–3.57, m, 1×OCH2CH3
and H 5; 3.69, ddd, J 2.2, 8.7, 9.5 Hz, H4; 3.93, qd, J 7.1, 9.5 Hz,
1×OCH2CH3; 4.43, dd, J 2.0, 9.8 Hz, H1; 4.59, q, J 6.5 Hz,
OCH(CH3)Ph; 7.28–7.41, 5H, m, Ph. 13C n.m.r. 15.1, OCH2CH3;
24.5, OCH(CH3)Ph; 35.3, C 2; 65.3, OCH2CH3; 69.4, C 4; 73.3, q, J
31 Hz, C 5; 75.3; 75.4; 100.1, C 1; 123.5, q, J 281 Hz, C 6; 126.3, 128.2,
129.0, 142.7, Ph. 19F n.m.r. –77.3, br s, CF3. m/z 334 (M+, 2%), 333
(2), 319 (19), 288 (7), 273 (11), 213 (19), 167 (40), 121 (78), 105 (100).
(M+ – 1, <1%), 211 (97), 196 (64), 165 (42), 121 (74), 106 (100).
1
For the minor isomer: H n.m.r.
(CDCl3) (inter alia) 1.26, t, J
7.1 Hz, OCH2CH3; 1.45, d, J 6.3 Hz, OCH(CH3)Ph; 2.11–2.16, 2H, m,
H3; 3.51–3.64, 1H, m, OCH2CH3; 3.86–4.09, 2H, m, 1×OCH2CH3,
H4; 4.60, q, J 6.3 Hz, OCH(CH3)Ph; 5.12, dd, J 3.7, 5.1 Hz, H2; 5.45,
d, J 3.7 Hz, H 5; 7.25–7.40, 5H, m, Ph. 13C n.m.r. (inter alia) 15.0,
OCH2CH3; 24.6, OCH(CH3)Ph; 32.6, C 3; 64.3, C 4; 65.2, OCH2CH3;
75.4, OCH(CH3)Ph; 98.9, C 2; 104.9, C 5; 119.6, q, J 272 Hz, CF3;
126.3, 127.8, 128.6, Ph; 141.6, q, J 35 Hz, C 6; 143.4. 19F n.m.r.
(CDCl3) –75.7, s, CF3.
1
The low RF diastereoisomer (10a) (0.68 g, 39%) was isolated as a
For the major isomer: H n.m.r. (inter alia) 1.23, t, J 7.1 Hz,
20
colourless oil, [ ]2D0 –1.6 and [ ] +9.4 (c, 0.79 in CH2Cl2) (Found: C,
OCH2CH3; 1.45, d, J 6.3 Hz, OCH(CH3)Ph; 1.98–2.03, 2H, m, H3;
3.51–3.64, 1H, m, OCH2CH3; 3.86–4.09, m, 1×OCH2CH3 and H4;
4.58, q, J 6.3 Hz, OCH(CH3)Ph; 5.04, dd, J 3.7, 5.4 Hz, H 2; 5.64, d, J
405
57.2; H, 6.5; F, 17.1. C16H21F3O4 requires C, 57.5; H, 6.3; F, 17.1%).
max (KBr)/cm–1 3468 (OH), 3086, 3064, 3031, 2979, 2934, 2887, 1436,
1380, 1274, 1180, 1096, 762, 701. 1H n.m.r. 1.17, t, J 7.1 Hz,
OCH2CH3; 1.47, d, J 6.6 Hz, OCH(CH3)Ph; 1.55, ddd, J 9.8, 11.9,
12.9 Hz, H2ax; 1.90, ddd, J 2.0, 4.9, 12.9 Hz, H2eq; 2.47, d, J 2.9 Hz,
OH; 3.40–3.51, 2H, m, H3 and 1×OCH2CH3; 3.61, qd, J 6.1, 9.5 Hz,
H5; 3.76, ddd, J 2.9, 8.6, 9.5 Hz, H4; 3.88, qd, J 7.1, 9.5 Hz,
1×OCH2CH3; 4.39, dd, J 2.0, 9.8 Hz, H1; 4.72, q, J 6.6 Hz,
OCH(CH3)Ph; 7.25–7.38, 5H, m, Ph. 13C n.m.r. 15.0, OCH2CH3;
24.1, OCH(CH3)Ph; 37.1, C 2; 65.2, OCH2CH3; 70.4, C 4; 73.5, q, J
30 Hz, C 5; 77.5, C 3; 78.9, OCH(CH3)Ph; 100.1, C 1; 123.6, q, J
281 Hz, C 6; 126.2, 127.8, 128.6, 143.9, Ph. 19F n.m.r. –77.0, s, CF3.
m/z 334 (M+, 4%), 333 (4), 319 (26), 288 (18), 273 (21), 213 (37), 167
(61), 121 (77), 105 (100).
3.1 Hz, H 5; 7.25–7.40, 5H, m, Ph. 13C n.m.r.
inter alia) 15.0,
OCH2CH3; 24.5, OCH(CH3)Ph; 34.3, C 3; 65.0, OCH2CH3; 65.5, C 4;
76.1, OCH(CH3)Ph; 99.4, C 2; 103.7, C 5; 119.6, q, J 272 Hz, CF3;
126.3, 127.7, 128.6, Ph; 141.6, q, J 35 Hz, C 6; 143.6. 19F n.m.r. –75.6,
s, CF3.
(2S,4 S)- and (2R,4 R)-2-Benzyloxy-4-[(1R)-1-phenylethoxy]-6-
trifluoromethyl-3,4-dihydro-2H-pyran (8b)
A mixture of the cis-cycloadducts (8b) was prepared from heterodi-
ene (5) (1.0 g, 4.1 mmol) and benzyl vinyl ether (7b) (1.3 g, 9.7 mmol)
by the cycloaddition procedure described above. The title compounds
(8b) (1.3 g, 84%) were isolated as a 1: 1.5 [(2S,4S)/(2R,4R)] mixture of
isomers as a colourless oil (Found: C, 66.6; H, 5.6; F, 15.0. C21H21F3O3
requires C, 66.7; H, 5.6; F, 15.1%). max (neat)/cm–1 3064, 3032, 2978,
2933, 2877, 1955, 1884, 1815, 1686, 1189, 1138, 761, 736, 700. m/z
378 (M+, <1%), 363 (<1), 287 (7), 273 (62), 149 (35), 105 (89), 91
(100).
Benzyl 2,6-Dideoxy-6,6,6-trifluoro-3-O-[(1 R)-phenylethyl]- -L-
arabino-hexopyranoside (9b) and Benzyl 2,6-Dideoxy-6,6,6-trifluoro-
3-O-[(1 R)-phenylethyl]- -D-arabino-hexopyranoside (10b)
Compounds (9b) and (10b) were prepared from (8b) (1.3 g, 3.4
mmol) by using the hydroboration and oxidation procedure described
above. The high RF diastereoisomer (9b) (0.42 g, 31%) was isolated as
a colourless solid, m.p. 62ºC, [ ]2D0 +161 (c, 0.32 in CH2Cl2) (Found: C,
63.6; H, 5.6; F, 14.4. C21H23F3O4 requires C, 63.6; H, 5.9; F, 14.4%).
max (KBr)/cm–1 3487 (OH), 3066, 3036, 2977, 2931, 2881, 1669, 1454,
1276, 1087, 935, 764, 748, 703. 1H n.m.r. 1.46, d, J 6.6 Hz, CH3; 1.69,
ddd, J 9.8, 11.7, 12.7 Hz, H 2ax; 2.34, 2H, coincident d and ddd, for d J
2.0 Hz, for ddd J 2.0, 4.9, 12.7 Hz, 4-OH and H2eq; 3.28, ddd, J 4.9,
8.8, 11.7 Hz, H 3; 3.51, qd, J 6.0, 9.5 Hz, H 5; 3.72, ddd, J 2.0, 8.8,
9.5 Hz, H4; 4.48, dd, J 2.0, 9.8 Hz, H1; 4.54–4.61, 2H, m, 1×OCH2Ph
and OCH(CH3)Ph; 4.88, d, J 12.0 Hz, 1×OCH2Ph; 7.26–7.40, 10H, m,
Ph. 13C n.m.r. 24.4, CH3; 35.2, C 2; 69.3, C 4; 70.6, OCH2Ph; 73.2, q,
J 31 Hz, C 5; 75.3, OCH(CH3)Ph and C 3; 98.6, C 1; 123.5, q, J 281 Hz,
C 6; 126.2, 128.0, 128.1, 128.2, 128.5, 128.9, 136.7, 142.7, Ph. 19F
n.m.r. –77.4, s, CF3. m/z 396 (M+, 12%), 381 (11), 305 (14), 273 (68),
167 (77), 105 (100).
For the minor isomer:1H n.m.r. (inter alia) 1.454, d, J 6.3 Hz, CH3;
1.95–2.27, 2H, m, H 3; 3.93–4.06, m, H 4; 4.55–4.64, m, OCH(CH3)Ph
and 1×OCH2Ph; 4.92 d, J 12.0 Hz, 1×OCH2Ph; 5.18, dd, J 2.9, 5.6 Hz,
H2; 5.50, d, J 3.9 Hz, H 5; 7.25–7.39, 10H, m, Ph. 13C n.m.r. (inter
alia) 24.6, CH3; 32.3, C 3; 63.8, C 4; 70.4, OCH2Ph; 75.4,
OCH(CH3)Ph; 97.3, C 2; 105.1, C 5; 119.6, q, J 273 Hz, CF3; 126.3,
127.7, 127.8, 127.9, 128.0, 128.5, 128.6, 137.0, Ph; 141.4, q, J 36 Hz,
C 6; 143.4. 19F n.m.r. –75.6, s, CF3.
For the major isomer:1H n.m.r. inter alia) 1.447, d, J 6.3 Hz, CH3;
1.95–2.27, 2H, m, H 3; 3.93–4.06, m, H 4; 4.55–4.64, m, OCH(CH3)Ph
and 1×OCH2Ph; 4.90, d, J 12.0 Hz, 1×OCH2Ph; 5.12, dd, J 2.9, 6.1 Hz,
H2; 5.70, d, J 3.4 Hz, H 5; 7.25–7.39, 10H, m, Ph. 13C n.m.r. (inter
alia) 24.4, CH3; 34.0, C 3; 64.9, C 4; 70.3, OCH2Ph; 76.1,
OCH(CH3)Ph; 97.7, C 2; 103.9, C 5; 119.6, q, J 273 Hz, CF3; 126.3,
127.7, 127.9, 128.0, 128.4, 128.6, 136.9, Ph; 141.4, q, J 36 Hz, C 6;
143.6. 19F n.m.r. –75.5, s, CF3.

C. M. Hayman et al.
926
The low RF diastereomer (10b) (0.61 g, 45%) was isolated as a
pressure and purification by flash chromatography (ether) gave 2,6-
dideoxy-6,6,6-trifluoro-D-arabino-hexose (+)-(4) (30 mg, 71%) as a
colourless oil, [ ]1D9 +8.9 (c, 0.6 in H2O).
colourless oil, [ ]2D0 –24 (c, 0.71 in CH2Cl2) (Found: C, 63.4; H, 5.7; F,
14.6. C21H23F3O4 requires C, 63.6; H, 5.9; F, 14.4%). max (neat)/cm–1
3464 (OH), 3087, 3063, 3031, 2974, 2933, 2880, 1454, 1360, 1274,
1181, 1086, 721, 701. 1H n.m.r. 1.46, d, J 6.6 Hz, CH3; 1.61, ddd, J
9.8, 11.7, 12.9 Hz, H2ax; 1.92, ddd, J 2.1, 5.1, 12.9 Hz, H 2eq; 2.53, d,
J 2.9 Hz, OH; 3.43, ddd, J 5.1, 8.8, 11.7 Hz, H 3; 3.60, qd, J 6.1, 9.5 Hz,
H5; 3.79, ddd, J 2.9, 9.0, 9.3 Hz, H 4; 4.44, dd, J 2.1, 9.8 Hz, H1; 4.53,
d, J 11.8 Hz, 1×OCH2Ph; 4.70, q, J 6.6 Hz, OCH(CH3)Ph; 4.84, d, J
11.8 Hz, 1×OCH2Ph; 7.25–7.39, 10H, m, Ph. 13C n.m.r. 24.0, CH3;
36.9, C 2; 70.4, C 4; 70.6, OCH2Ph; 73.5, q, J 30 Hz, C 5; 77.4; 78.7;
98.7, C 1; 123.6, q, J 281 Hz, C 6; 126.1, 127.8, 128.0, 128.2, 128.5,
128.6, 136.7, 143.9, Ph. 19F n.m.r. –77.1, s, CF3. m/z 396 (M+, 2%),
381 (5), 305 (290), 273 (65), 167 (77), 105 (100).
Ethyl 3,4-Di-O-acetyl-2,6-dideoxy-L-arabino-hexopyranoside
A solution of di-O-acetyl-L-rhamnal (4.9 g, 19 mmol) in absolute
ethanol (16 ml) was added dropwise to a stirred suspension of
Hg(OAc)2 (6.0 g, 19 mmol) in absolute ethanol. After 10 min NaBH4
(1.0 g, 26 mmol) was added in portions over 10 min. The solution was
stirred for a further 30 min, filtered through a CeliteR pad, concentrated
under reduced pressure and purified by flash chromatography (10%
ether–hexanes) to afford the title compound (3.1 g, 63%) as a colour-
less oil ( / 3: 1) (Found: C, 55.4; H, 7.8. C12H20O4 requires C, 55.4;
H, 7.7%).
(neat)/cm–1 2979m, 2938m, 2903m (all CH), 1746s
(C=O), 1246ms,ax1226s, 1050s. 1H n.m.r. 1.14–1.24, 6H, m, OCH2CH3
and H6; 1.65–1.82, m, H2ax; 1.99, 2.03, 2.15, 6H, 3s, each
OC(O)CH3; 2.19, 0.7H, ddd, J 1.0, 5.4, 12.7 Hz, -H2eq; 2.28, 0.3H,
ddd, J 2.0, 5.3, 12.2 Hz, -H2eq; 3.36–3.58, 1.3H, m, 1× -OCH2CH3,
-H5, 1× -OCH2CH3; 3.66, 0.7H, qd, J 7.1, 9.7 Hz, 1× -OCH2CH3;
Representative Hydrogenolysis Procedure: Ethyl 2,6-Dideoxy-
6,6,6-trifluoro- -L-arabino-hexopyranoside (+)-(3)
A mixture of (9a) (0.11 g, 0.33 mmol) and 5% Pd–C (20 mg) in dis-
tilled ethanol (10 ml) was stirred under an atmosphere of H2 for 15 h at
ambient temperature. The reaction mixture was filtered through CeliteR
and the solvent removed under reduced pressure to yield (+)-(3) (0.076
g, 100%) as a colourless solid. An analytical sample was obtained by
flash column chromatography (ether), m.p. 73°C, [ ]2D1 +71 (c, 0.34 in
CH2Cl2) (Found: C, 41.7; H, 5.7; F, 24.8. C8H13F3O4 requires C, 41.7;
3.79–3.96, m, -H5, 1× -OCH2CH3; 4.53, 0.3H, dd, J 2.0, 9.7 Hz,
-
H1; 4.71, t, J 9.7 Hz, H 4; 4.85, 0.7H, br d, J 2.7 Hz, -H1; 4.96, 0.3H,
ddd, J 5.3 Hz, 5.3, 9.7, 11.8 Hz, -H3; 5.27, 0.7H, ddd, J 5.4, 9.7,
11.9 Hz, -H3. 13C n.m.r. 15.1, 15.2, 17.6, 17.7, 20.9, 21.1, each CH3;
35.5, -C 2; 36.7, -C 2; 62.9, -OCH2CH3; 65.0, -OCH2CH3; 65.5,
69.2, each -CH; 70.0, 70.8, 74.4, each -CH; 75.0, -CH; 96.5, -C 1;
99.0, -C 1. m/z [no M+] 259 (M+ –1, 1%), 215 (4), 186 (5), 156 (67),
114 (100).
H, 5.7; F, 24.8%). max (KBr)/cm–1 3346 (OH), 2984, 2934, 2899, 1466,
1
1383, 1270, 1183, 1048, 926, 898. H n.m.r.
.24, t, J 7.1 Hz, CH3;
1.71, ddd, J 9.5, 11.2, 12.7 Hz, H2ax; 2.26, ddd, J 2.0, 4.9, 12.7 Hz,
H2eq; 2.52, br s, OH; 2.60, br s, OH; 3.57, qd, J 7.1, 9.5 Hz,
1×OCH2CH3; 3.60–3.77, 3H, m, H3, H 4, H 5; 3.95, qd, J 7.1, 9.5 Hz,
1×OCH2CH3; 4.61, dd, J 2.0, 9.5 Hz, H1. m/z [no M+] 229 (M+ –1,
2%), 201 (5), 185 (26), 167 (46), 101 (72), 73 (100).
Ethyl 2,6-Dideoxy- -L-arabino-hexopyranoside (11)
A sample of ethyl 3,4-di-O-acetyl-2,6-dideoxy-L-arabino-hexopy-
ranoside was enriched in the -anomer by flash chromatography (10%
ether–hexanes), to give a 1: 1 mixture of / -anomers. A suspension of
this material (1.2 g, 4.6 mmol) and AmberliteR IRA400 (OH–) ion-
exchange resin (1.2 g) in absolute ethanol (10 ml) was stirred for 20 h
at ambient temperature. The ion-exchange resin was removed by filtra-
tion, the filtrate concentrated under reduced pressure and the residue
was partially purified by flash chromatography (50% ether–hexanes):
RF -anomer 0.08; RF (10) 0.05. Removal of the solvent from fractions
containing (11) and crystallization and recrystallization of the residue
from ether and hexanes gave (11) (0.31 g, 38%) as a white solid, m.p.
115ºC, [ ]2D2 + 66 (c, 1.3 in CH2Cl2) (Found: C, 54.7; H, 9.3. C8H16O4
Ethyl 2,6-Dideoxy-6,6,6-trifluoro- -D-arabino-hexopyranoside (–)-(3)
The title compound was prepared from (10a) (0.15 g, 0.45 mmol) by
the hydrogenolysis procedure described above, giving the title com-
pound (–)-(3) (0.10 g, 100%) as a white solid.
An analytical sample of (–)-(3) was obtained by flash chromatogra-
phy (ether), m.p. 73ºC, [ ]2D1 –69 (c, 0.40 in CH2Cl2) (Found: C, 41.9;
H, 5.5; F, 24.6. C8H13F3O4 requires C, 41.7; H, 5.7; F, 24.8%). The 1H
n.m.r. (D2O) data were identical to those obtained for (+)-(3).
max
(KBr)/cm–1 3346 (OH), 2984, 2934, 2899, 1467, 1383, 1270, 1183,
1048, 920, 898. m/z [no M+] 229 (M+ –1, 19%), 201 (29), 185 (62), 167
(67), 101 (75), 73 (100).
requires C, 54.5; H, 9.2%).
(KBr)/cm–1 3294 (OH), 2977, 2959,
max
1
2933, 2904, 1474, 1418, 138, 1176, 1140, 1071. H n.m.r. 1.23, t, J
7.1 Hz, OCH2CH3; 1.33, 3H, d, J 6.1 Hz, H 6; 1.62, dt, J 9.8, 12.2 Hz,
H2ax; 2.20, ddd, J 1.8, 4.9, 12.2 Hz, H 2eq; 2.79, 2H, br s, 2×OH; 3.08,
apparent t, J 8.8, 9.0 Hz, H 4; 3.27, qd, J 6.1, 9.0 Hz, H 5; 3.52, 3.58, 1H
each, overlapping qd and ddd, for qd J 7.1, 9.5 Hz, for ddd J 4.9, 8.5,
11.7 Hz, 1×OCH2CH3, H3; 3.92, qd, J 7.1, 9.5 Hz, 1×OCH2CH3; 4.50,
dd, J 1.8, 9.8 Hz, H1. 13C n.m.r. 15.2, 17.8, 2×CH3; 39.2, C 2; 64.9,
OCH2CH3; 71.6, C 3; 71.7, C 5; 77.4, C 4; 99.4, C 1. m/z [no M+] 175
(M+ –1, 5%), 131 (26), 104 (66), 73 (100).
2,6-Dideoxy-6,6,6-trifluoro-L-arabino-hexose (–)-(4)
The title compound was prepared from (9b) (0.16 g, 0.41 mmol) by
the hydrogenolysis procedure described above except that ethyl acetate
was employed as the solvent. The title compound (74 mg, 89%) was
obtained as a white foam.
An analytical sample of (–)-(4) was obtained by Kugelrohr distillation
(150ºC/0.5 mmHg) to give a colourless glass, [ ]2D3 –11 (c, 1.7 in H2O)
(Found: C, 35.6; H, 4.4; F, 27.9. C6H9F3O4 requires C, 35.7; H, 4.5; F,
28.2%). The 1H n.m.r. (D2O) data were identical to those reported for (±)-
(4).14
1,3,4-Tri-O-acetyl-2,6-dideoxy-6,6,6-trifluoro- -L-arabino-hexo-
pyranose (14a) and 1,3,4-Tri-O-acetyl-2,6-dideoxy-6,6,6-trifluoro-
-L-arabino-hexopyranose (14b)
2,6-Dideoxy-6,6,6-trifluoro-D-arabino-hexose (+)-(4)
A solution of (–)-(4) (125 mg, 0.62 mmol), acetic anhydride (1 ml,
11 mmol) and pyridine (1 ml, 12 mmol) was stirred for 12 h at ambient
temperature and then concentrated under reduced pressure. The result-
ing oil was passed though a silica column (10% ether–hexanes as
eluent) and concentration of the early fractions gave a sample of the
title compounds slightly enriched in the -anomer (60 mg, 35%).
Fractional crystallization from ether–hexanes gave initially the
-anomer (14b) (15 mg, 9%) as a white solid, m.p. 105–109°C, [ ]2D1
–12.3 (c, 0.30 in CH2Cl2) (Found: C 44.1; H, 4.6; F, 17.2. C12H15F3O7
requires C, 43.9; H, 4.6; F, 17.4%). max (KBr)/cm–1 2959 (CH), 1745
(ester C=O) . 1H n.m.r. 1.90, ddd, J 10.0, 11.6, 12.7 Hz, H2ax; 2.05,
s, 6H, 2×OAc; 2.13, s, OAc; 2.37, ddd, J 2.3, 5.3, 12.7 Hz, H 2eq; 3.99,
qd, J 5.6, 5.6, 5.6, 9.6 Hz, H 5; 5.10, ddd, J 5.3, 9.3, 11.6 Hz, H 3; 5.26,
dd, J 9.3, 9.6 Hz, H4; 5.84, dd, J 2.3, 10.0 Hz, H1. 13C n.m.r. 20.6,
20.8, 20.9, 3×CH3; 34.3, C 2; 66.7; 69.6; 72.2, q, J 32 Hz, C 5; 90.7, C 1;
The title compound was prepared from (10b) (0.23 g, 0.57 mmol) by
the hydrogenolysis procedure described above except that ethyl acetate
was employed as the solvent. The title compound (0.11 g, 99%) was
obtained as a white foam.
An analytical sample of (+)-(4) was obtained by Kugelrohr distilla-
tion (150ºC/0.5 mmHg) to give a colourless glass, [ ]2D3 +11 (c, 0.99 in
H2O) (Found: C, 35.4; H, 4.4; F, 28.4. C6H9F3O4 requires C, 35.7; H,
4.5; F, 28.2%).
(neat)/cm–1 3373 (OH), 2940, 1636, 1273, 1183,
max
1
1067, 957. The H n.m.r. (D2O) data were identical to those reported
for (±)-(4).14 m/z [no M+] 201 (M+ –1, <1%), 185 (9), 167 (8), 73 (100).
Hydrolysis of (–)-(3)
A solution of (–)-(3) (48 mg, 0.21 mmol) in 50% acetic acid (2 ml)
was heated over a steam bath for 1.5 h. Concentration under reduced

Synthesis of 2,6-Dideoxy-6,6,6-trifluoro-arabino-hexoses
927
122.5, q, J 281 Hz, C 6; 168.5, 169.2, 170.0, 3×COCH3. 19F n.m.r.
–78.0, s, CF3.
tion of Amano PS lipase, Professor Ward T. Robinson,
University of Canterbury, N.Z., for X-ray data collection and
the University of Otago for financial support.
A subsequent crop gave the -anomer (14a) (7 mg, 4%) as a white
solid, m.p. 73°C, [ ]2D1 –76° (c, 0.34 in CH2Cl2) (Found: C, 44.1; H, 4.3;
F, 17.6. C12H15F3O7 requires C, 43.9; H, 4.6; F, 17.4%). max (KBr)/cm–1
1
2964 (CH), 1750 (ester C=O). H n.m.r. 1.93–2.04, m, H2ax; 2.05,
2.06, 2.16, 3s, 3×OAc; 2.29, ddd, J 1.8, 4.8, 13.7 Hz, H 2eq; 4.23, qd,
References
5.8, 5.8, 5.8, 9.2 Hz, H 5; 5.24–5.39, m, H 3, H 4; 6.31–6.35, m, H 1. 13
C
1
Lown, J. W., Chem. Soc. Rev., 1993, 165.
n.m.r. 20.6, 20.9, 21.0, 3×CH3; 33.4, C 2; 67.0, 67.6, 69.9, q, J 31 Hz,
C 5; 90.3, C 1; 123.0, q, J 281 Hz, C 6; 168.4, 169.2, 170.1, 3×COCH3.
19F n.m.r. –78.1, s, CF3.
2
Krohn, K., and Rohr, J., Top. Curr. Chem., 1997, 188, 127.
–
3
Omura, S., ‘Macrolide Antibiotics, Chemistry, Biology and
Practice’ (Academic Press: Orlando 1984).
4
Nicolaou, K. C., and Dai, W.-M., Angew. Chem., Int. Ed. Engl.,
Crystal Data and Refinement Details for (9a)
1991, 30, 1387.
C16H21F3O4, M 334.33, orthorhombic, P212121 (D24, No. 19), a
8.422(4), b 13.454(6), c 14.443(6) Å, V 1637(1) Å3, Dc(Z = 4) 1.357 g
cm–3, F(000) 704, (Mo K ) 1.18 cm–1, 0.71073 Å, T 173(2) K.
Compound (9a) was crystallized by slow evaporation from hexanes
and a colourless rhomb of 0.40 by 0.24 by 0.08 mm dimensions was
used for X-ray measurements. A Siemens Smart-CCD system with
graphite-monochromatized Mo K radiation was used to collect a
sphere of intensity data in 1829 frames (width 0.3° per frame). Final cell
constants were calculated from 7246 reflections from the data collec-
tion. A total of 16121 reflections yielded 3360 [Rint 0.0564] unique data
which were corrected for Lorentz and polarization effects.21 A multi-
scan absorption correction22 was applied with Tmin,max 0.768, 1.000. No
decay correction was necessary.
5
Weymouth-Wilson, A. C., Nat. Prod. Rep., 1997, 14, 99.
6
Li, T., Zeng, Z., Estevez, V. A., Baldenius, K. U., Nicolaou, K. C.,
and Joyce, G. F., J. Am. Chem. Soc., 1994, 116, 3709.
7
Penglis, A. A., Adv. Carbohydr. Chem. Biochem., 1981, 38, 195.
8
Tsuchiya, T., Adv. Carbohydr. Chem. Biochem., 1990, 48, 91.
9
Differding, E., Frick, W., Lang, R. W., Martin, P., Schmit, C.,
Veenstra, S., and Greuter, H., Bull. Soc. Chim. Belg., 1990, 99, 647.
10
Hanzawa, Y., Uda, J., Kobayashi, Y., Ishido, Y., Taguchi, T., and
Shiroo, M., Chem. Pharm. Bull., 1991, 39, 2459.
11
Mizutani, K., Yamazaki, T., and Kitazume, T., J. Chem. Soc., Chem.
Commun., 1995, 51.
12
Yamazaki, T., Mizatuni, K., and Kitazume, T., J. Org. Chem., 1995,
60, 6046.
The structure was solved by direct methods with SHELXS-86.23 The
structure, the absolute configuration of which is based on the known
configuration of the precursor, (R)-1-phenylethanol, used in it synthe-
sis, was refined by full matrix least squares on F 2, with all non-hydro-
gen atoms anisotropic, by using SHELXL-97.24 Flack parameters of
–0.8(9) for the structure and 1.8(9) for the inverted structure were
unable to establish reliably the absolute configuration. Hydrogen atoms
were placed in idealized positions and were refined as riding atoms with
individual isotropic thermal parameters. Complex neutral-atom scat-
tering factors24 were employed, with the SHELX-97 weighting scheme w
13
Takagi, Y., Nakai, K., Tsuchiya, T., and Takeuchi, T., J. Med. Chem.,
1996, 39, 1582.
14
Hayman, C. M., and Larsen, D. S., Aust. J. Chem., 1998, 51, 545.
15
McClinton, M. A., and McClinton, D. A., Tetrahedron, 1992, 48,
6555.
16
Gutman, A. L., Brenner, D., and Boltanski, A., Tetrahedron:
Asymmetry, 1993, 4, 839.
17
Honda, S., Izumi, K., and Takiura, K., Carbohydr. Res., 1972, 23,
427.
18
Fuchs, E.-F., Horton, D., and Weckerle, W., Carbohydr. Res., 1977,
= 1/[ 2(Fo )+(0.0506P)2], where P = (max. (Fo ,0)+2Fc2)/3. At conver-
gence for 210 independent parameters, R1 0.0422 and wR2 0.0887 for
2319 reflections with I > 2 (I), and R1 0.0783 and wR2 0.0995 for all
data and the goodness of fit was 1.024. The final difference map
showed no peaks greater than 0.29 or less than –0.20 e Å–3. Final
atomic coordinates are listed in Table 1 and bond lengths and angles are
given in Tables 2 and 3. Lists of structure factors, thermal parameters
and hydrogen atom coordinates are available (until 31 December 2004)
on application to the Australian Journal of Chemistry, P.O. Box 1139,
Collingwood, Vic. 3066.
2
2
57, C36.
19
Ferrier, R. J., and Collins, P. M., ‘Monosaccharide Chemistry’ p.
280 (Penguin: Harmondsworth 1972).
20
Perrin, D. D., Armarego, W. L. F., and Perrin, D. R., ‘Purification of
Laboratory Chemicals’ 2nd Edn (Pergamon Press: Oxford 1980).
21
‘SAINT V4. Area Detector Control and Integration Software’,
Siemens Analytical X-Ray Systems Inc., Madison, Wisconsin,
U.S.A., 1996.
22
Sheldrick, G. M., ‘SADABS. Program for Absorption Correction’,
University of Göttingen, Germany, 1996.
23
Sheldrick, G. M., SHELXS-86, Acta Crystallogr., Sect. A, 1990, 46,
Acknowledgments
We thank the Amano Pharmaceutical Co. Ltd and
Hawkins Watts Ltd, Auckland, N.Z., for the generous dona-
467.
24
Sheldrick, G. M., ‘SHELXL-97. Program for the Refinement of
Crystal Structures’, University of Göttingen, Germany, 1997.