Asymmetric de novo synthesis of fluorinated d-glucitol and d-mannitol analogues

Article abstract of DOI:10.1016/j.tetasy.2009.03.001

A highly efficient anti-S_E2′ electrophilic fluorination of enantioenriched allylsilanes a subsequent dihydroxylation of the resulting allylic fluorides were used as key steps for the synthesis of three fluorinated carbohydrate analogues, 1,5-di-O-benzyl-2-deoxy-2-fluoro-d-glucitol, 2,6-di-O-benzyl-5-deoxy-5-fluoro-l-glucitol and 1,5-di-O-benzyl-2-deoxy-2-fluoro-d-mannitol. A new catalytic asymmetric route to 1-benzyloxy-4-trimethylsilyl-but-3-yn-2-ol, a common precursor to two advanced allylsilanes, is also described featuring a Noyori asymmetric transfer hydrogenation reaction.

Full text of DOI:10.1016/j.tetasy.2009.03.001

Tetrahedron: Asymmetry 20 (2009) 910–920
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric de novo synthesis of fluorinated D-glucitol
and D-mannitol analogues
*
Guy T. Giuffredi, Sophie Purser, Marcin Sawicki, Amber L. Thompson, Véronique Gouverneur
Chemistry Research Laboratory, University of Oxford, Mansfield Road, OX1 3TA Oxford, UK
a r t i c l e i n f o
a b s t r a c t
A highly efficient anti-SE20 electrophilic fluorination of enantioenriched allylsilanes a subsequent dihydr-
oxylation of the resulting allylic fluorides were used as key steps for the synthesis of three fluorinated
Article history:
Received 16 February 2009
Accepted 6 March 2009
Available online 1 April 2009
carbohydrate analogues, 1,5-di-O-benzyl-2-deoxy-2-fluoro-
D-glucitol, 2,6-di-O-benzyl-5-deoxy-5-flu-
oro- -glucitol and 1,5-di-O-benzyl-2-deoxy-2-fluoro- -mannitol. A new catalytic asymmetric route to
L
D
1-benzyloxy-4-trimethylsilyl-but-3-yn-2-ol, a common precursor to two advanced allylsilanes, is also
described featuring a Noyori asymmetric transfer hydrogenation reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to Professor George W. F. Fleet at
the occasion of his 65th birthday
1. Introduction
position.5 The fluorodesilylation of various homochiral allylsilanes
combined with key dihydroxylation events has offered synthetic
The chemical modification of carbohydrates is a well-estab-
lished strategy to probe the origin of the specificity in recognition
processes with proteins or nucleic acids. Fluorinated carbohydrates
are important analogues since the fluorine substituents affect
hydrogen-bonding interactions while maintaining key structural
features of the parent compounds. Carbohydrate modifications in-
volve the chemoselective replacement of hydroxyl groups or the
endocyclic oxygen atom by fluorine substituents or CF2 groups.1
For example, fluorinated sialic acid derivatives have served as
important mechanistic probes for kinetic and crystal structural
studies of sialidases and sialyl transferases for elucidation of their
catalytic mechanistic profile.2 In more extreme sugar mimesis,
more heavily fluorinated sugars with advantageous properties
were studied.3 The hexafluorinated glucose derivative 1-hydroxy-
5-hydroxymethyl-2,2,3,3,4,4-hexafluorooxane was found to cross
routes to novel enantioenriched mono- and difluorinated cycli-
tols.6 In these syntheses, the silyl group served the purpose of
enhancing the reactivity of the alkene and of controlling the regio-
and stereoselective installation of the fluorine substituents. With
the long-term aim of preparing multi-site modified enantioen-
riched fluorinated sugar mimics, our primary objective was to val-
idate the first asymmetric synthesis of fluorinated carbohydrates
starting from allylsilanes. We selected fluorinated
D-glucitol and
D-mannitol analogues as our first targets and envisaged that these
may be accessible from the appropriately functionalised acyclic
allylsilanes (Fig. 1).
2. Results and discussion
Our retrosynthetic analysis to access 1 and 2 is based on the use
of the enantioenriched isomeric syn- and anti-allylsilanes
(2R,3R,4E)-3 and (2R,3S,4E)-3 for the stereocontrolled introduction
of the allylic fluorine substituent (Scheme 1). Recently, we have re-
ported that an efficient transfer of chirality from the silylated to
the fluorinated stereocentre is observed upon electrophilic fluori-
nation of structurally related racemic allylsilanes.7 We therefore
anticipated that synthetically useful stereocontrol will be observed
upon fluorodesilylation of (2R,3R,4E)-3 and (2R,3S,4E)-3, with the
configuration of the newly formed fluorinated carbon programmed
in line with an anti-SE20 mechanism.8 Dihydroxylation of the
resulting allylic fluorides should lead to our targets. This retrosyn-
thesis was also driven by the availability of robust synthetic routes
to these advanced intermediates. Panek et al. have reported that
the Ireland–Claisen [3,3]-sigmatropic rearrangement of optically
active Z- and E-vinylsilanes led to structurally related syn-and
anti-crotylsilanes, respectively, in high yields with an excellent
the erythrocyte membrane with a faster rate compared to D-glu-
cose, due to enhanced specific binding to the transport protein.3c,3d
For further experimentation in this field, complex fluorinated car-
bohydrate analogues resulting from multi-site chemical modifica-
tions may be required, rendering synthetic protocols based on the
manipulation of natural sugars increasingly difficult to apply. De-
spite the fact that asymmetric de novo syntheses complement
enzymatic approaches and offer the flexibility one might need for
the preparation of more disguised fluorinated sugars, this strategy
is not frequently used especially when the target structures feature
the fluorine substituents on stereogenic centres.3a,4 Previous inves-
tigations from this laboratory have shown that allylsilanes are suit-
able substrates for the introduction of fluorine on an allylic
* Corresponding author.
E-mail address: veronique.gouverneur@chem.ox.ac.uk (V. Gouverneur).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.001

G. T. Giuffredi et al. / Tetrahedron: Asymmetry 20 (2009) 910–920
911
of enantioenriched allylsilanes (2R,3R,4E)-3 and (2R,3S,4E)-3 were
not considered in our previous work.7
Mono- and difluorinated cyclitols from allylsilanes
OH
SiMe3
Our study began with the validation of an alternative route to
access the silylated propargylic alcohol (S)-5, a common precur-
sor to both allylic alcohols (2S,3E)-4 and (2S,3Z)-4 (Scheme
2).9d,10 Based on the literature precedents,11 we selected an
asymmetric catalytic reduction of ynone 6 to install the stereo-
genic centre within (S)-5. Ynone 6 was obtained in 95% yield
by oxidation of ( )-5 using freshly prepared IBX. Deprotonation
of trimethylsilylacetylene with n-BuLi in THF followed by addi-
tion of 2-(benzyloxy)acetaldehyde12 afforded ( )-5 in 82% yield.
The reduction of ynone 6 was performed using a Noyori asym-
metric transfer hydrogenation reaction in the presence of the
chiral ruthenium catalyst A. This catalyst was prepared following
the literature procedure.13 It was used successfully in thoroughly
degassed isopropyl alcohol to reduce 6. This catalytic asymmet-
ric transfer hydrogenation delivered the propargylic alcohol (S)-5
in 83% yield and 93% ee. The enantiomeric excess was measured
by chiral stationary phase HPLC against the racemic reference
( )-5. At this stage, the absolute configuration of compound
(S)-5 was assigned by analogy with the stereochemical outcome
observed for the reduction of structurally related ynones using
the same catalyst A.11 This assignment was confirmed in the
HO
F
O
O
O
O
F
HO
HO
O
O
O
O
Me3Si
Me3Si
F
Fluorinated D-glucitol and D-mannitol from allylsilanes
F
OH
BnO
BnO
OH
OH
Me3Si
1
2
OH OBn
OH
BnO
OH
OBn
F
next stage of the synthesis by comparing the ½a D20
ꢀ
value of the
OH OBn
reduced allylic alcohol (2S,3E)-4 {½a D25
¼ ꢁ4:3 (c 1.1, CHCl3)} with
ꢀ
the literature data since this is a known compound {½a D25
¼ ꢁ1:9
ꢀ
Figure 1. Fluorinated cyclitol and carbohydrate analogues from allylsilanes.
(c 1.1, CHCl3)}.14
With (S)-5 in hand, we studied its conversion into one or the
other diastereomeric allylsilanes 3 (Scheme 3). To programme
the desired stereochemistry of the fluorinated centre within tar-
gets 1 and 2, it was necessary to access both the allylsilanes
(2R,3R,4E)-3 and (2R,3S,4E)-3, since the fluorodesilylation is ex-
pected to operate via an anti-SE20 mechanism. These novel allylsi-
lanes were prepared based on the literature protocols.9a The
conversion of (S)-5 into (2R,3R,4E)-3 commenced with a sodium
bis-(2-methoxyethoxy)aluminium hydride-mediated reduction
leading to the allylic alcohol (2S,3E)-4, which was isolated in
85% yield. The enantiomeric excess of this compound was deter-
mined by the 19F NMR of the corresponding Mosher ester and
found to be 93%, a result indicating that no racemisation occurred
upon reduction. Subsequent esterification with 2-benzyloxy ace-
tic acid using DCC and DMAP delivered (2S,3E)-7 in 97%. Treat-
ment of this ester with LiHMDS and TMSCl provided the Z-O-
silylketene acetal intermediate, the Z geometry being dictated
by the strong chelating ability of the glycolate oxygen upon enoli-
sation. Subsequent [3,3]-sigmatropic rearrangement of this
in situ-formed Z-O-silylketene acetal afforded the hexenoic acid
(2R,3R,4E)-8 in 80% isolated yield. The diastereomeric ratio of
the purified product is excellent (dr > 20:1). Analysis of the 1H
NMR of the crude mixture indicated the presence of a minor dia-
stereomer (dr = 5:1). To access (2R,3S,4E)-8, we performed a sim-
ilar esterification and Ireland–Claisen rearrangement with the Z-
vinylsilane (2S,3Z)-4, a compound prepared in 73% yield by reduc-
tion with BH3ꢂTHF and freshly distilled cyclohexene in THF
(ee = 93%). Esterification and rearrangement using conditions sim-
ilar to the ones applied to (2S,3E)-4 were successful and high
yielding steps. The acid (2R,3S,4E)-8 was isolated in 94% yield
as a single diastereomer (dr of crude and purified material was
>20:1). The relative stereochemistry of both (2R,3R,4E)-8 and
(2R,3S,4E)-8 was assigned by analogy with the literature based
level of stereocontrol.9 This work led us to consider the use of the
vinylsilanes (2S,3E)-4 and (2S,3Z)-4 as precursors to syn-
(2R,3R,4E)-3 and anti-(2R,3S,4E)-3, respectively. Both vinylsilanes
can be prepared from the propargylic alcohol (S)-5. Key aspects
of the suggested de novo asymmetric synthesis are the develop-
ment of an alternative catalytic asymmetric route for the prepara-
tion of (S)-5 and the level and sense of stereocontrol for the
fluorination and the dihydroxylation. The synthesis and reactivity
F
OH
F
OH
BnO
BnO
OH
OH
OH OBn
OH OBn
2
1
fluorodesilylation
dihydroxylation
Me3Si
Me3Si
BnO
BnO
OH
OH
OBn
OBn
(2R,3R,4E)-3
3
(2R,3S,4E)-
esterification
[3,3]-sigmatropic
rearrangement
reduction
OH
OH SiMe3
BnO
BnO
SiMe3
(2S,3Z)-4
4
(2S,3E)-
reduction
3
on the distinctive vicinal coupling constants J2,3 (3J2,3 = 7.1 Hz
OH
3
for syn-(2R,3R,4E)-8 and J2,3 = 3.2 Hz for anti-(2R,3S,4E)-8).
BnO
Reduction of (2R,3R,4E)-8 and (2R,3S,4E)-8 with LiAlH4 in Et2O
afforded the alcohols (2R,3R,4E)-3 and (2R,3S,4E)-3 in good yields.
The enantiomeric excesses of these allylsilanes 3 were found to
be 93%.
SiMe3
5
(S)-
Scheme 1. Retrosynthetic analysis of 1 and 2.

912
G. T. Giuffredi et al. / Tetrahedron: Asymmetry 20 (2009) 910–920
OH
O
O
BnO
BnO
(ii)
(i)
BnO
SiMe3
SiMe3
6 95%
( )-5 82%
(iii)
Ts
N
Ph
Ph
OH
Ru
BnO
N
H
SiMe3
5
(S)- 88% 93% ee
A
Noyori Catalyst
Scheme 2. Reagents and conditions: (i) trimethylsilylacetylene, n-BuLi, THF, ꢁ78 °C then 0 °C; (ii) IBX, DMSO–THF (1:5), rt, 16 h; (iii) 8 mol % Catalyst A, i-PrOH, 30 °C, 16 h.
O
OBn
Me3Si
Me3Si
O
OH
OH
(iv)
O
(ii)
(iii)
BnO
BnO
BnO
BnO
BnO
OH
OH
SiMe3
SiMe3
OBn
OBn
(2R,3R,4E)-3
(2S,3E)-7
97%
(2R,3R,4E)-8
(i)
(2S,3E)-4
85%
ee 93%
70%
80%
ee 93%
d.r. = 5.1 (d.r.> 20:1)
5
SiMe3
(S)-
OBn
(v)
SiMe3
Me3Si
BnO
O
(iv)
OH SiMe3
(iii)
O
O
SiMe3
(ii)
BnO
BnO
OH
BnO
OH
OBn
OBn
4
(2R,3S,4E)-3
72%
ee 93%
(2S,3Z)-
(2S,3Z)-7
97%
(2R,3S,4E)-8
94%
d.r. > 20:1
73%
ee 93%
Scheme 3. Reagents and conditions: (i) sodium bis(2-methoxyethoxy)-aluminium hydride, Et2O, 0 °C–rt, 16 h; (ii) benzyloxyacetic acid, DMAP, DCC, CH2Cl2, 0 °C–rt, 16 h;
(iii) LiHMDS, THF, ꢁ78 °C, 1 h, then TMSCl, ꢁ78 °C–rt, 16 h; (iv) LiAlH4, Et2O, 0 °C, 3 h; (v) BH3ꢂTHF complex, freshly distilled cyclohexene, THF, 0 °C, 3 h, then AcOH, 0 °C, 16 h.
The next task was to perform the fluorodesilylation and subse-
quent dihydroxylation. First we focused our attention on the reac-
tivity of (2R,3R,4E)-3 (Scheme 4). The fluorination was performed
at room temperature in acetonitrile with 1.5 equiv of 1-chloro-
F
Me3Si
(i)
BnO
BnO
OH
OH
(2S,3E,5R)-9 (major)
16% (E/Z > 20:1)
74% (E/Z = 4:1)
overall yield 90%
ee 93%
OBn
(ii)
OBn
methyl-4-fluorodiazoniabicyclo[2.2.2]octane
bis(tetrafluorobo-
(2R,3R,4E)-3
rate) (Selectfluor) and with 1 equiv of NaHCO3. The resulting
anti-allylic fluoride 9 was isolated in 90% overall yield as a 4:1 mix-
ture of E:Z isomers. Purification by short plug silica gel filtration
delivered an analytically pure sample of the sole diastereoisomer
(2S,3E,5R)-9 (16% yield), which was used for the subsequent step.
Dihydroxylation of (2S,3E,5R)-9 was performed using 5 mol %
OsO4 with three equiv of the co-oxidant NMO in a 3:1 mixture of
CH2Cl2 and H2O. This oxidation delivered two diastereomers in a
ꢃ3:2 ratio indicating that the fluorine and the benzyloxy substitu-
ent are inducing an opposite sense of stereocontrol. Silica gel chro-
matography allowed for the separation of these two products that
were isolated in 51% and 29% yields. We were able to unambigu-
ously assign by X-ray crystallography followed by single crystal
1H and 19F NMR the relative stereochemistry of the major stereo-
overall 80%
d.r. ~ 3:2
F
OH
BnO
OH
10
(2R,3S,4R,5S)-
2,6-di-O-benzyl-5-deoxy-5-fluoro-L-glucitol
OH OBn
51%
F
OH
BnO
OH
isomer 10, namely 2,6-di-O-benzyl-5-deoxy-5-fluoro-L-glucitol
1
(2S,3S,4R,5R)-
1,5-di-O-benzyl-2-deoxy-2-fluoro-D-glucitol
OH OBn
29%
10. Esterification of the minor isomer ( )-1 with p-nitrobenzoyl
chloride gave compound ( )-11, which was found suitable for X-
ray crystallography. This analysis confirmed that the minor diaste-
Scheme 4. Reagents and conditions: (i) Selectfluor, NaHCO3, MeCN, rt, 16 h; partial
separation of the two stereoisomers by silica gel filtration (ii) OsO4, NMO, CH2Cl2–
H2O 3:1, rt, 3 d; separation by silica gel chromatography.
reomer formed upon dihydroxylation is 2-deoxy-2-fluoro-
D-gluci-
tol doubly protected by benzyl groups at positions 1 and 5. It is

G. T. Giuffredi et al. / Tetrahedron: Asymmetry 20 (2009) 910–920
913
2-fluoro-D-mannitol (2R,3S,4R,5R)-2 in 96% yield (dr = 11:1). The
F
OH
excellent level of stereocontrol observed for the dihydroxylation
of (2S,3E,5S)-9 indicates that the two stereogenic centres of the
syn-allylic fluoride (2S,3E,5S)-9 both direct an anti-delivery of
OsO4. Although X-ray analysis was not possible for (2R,3S,4R,5R)-
2, esterification of ( )-2 with p-nitrobenzoyl chloride led to com-
pound ( )-12, a crystal of which was found suitable for X-ray crys-
tallography. This analysis confirmed unambiguously the structure
and relative stereochemistry of ( )-12 and, by default, of
(2R,3S,4R,5R)-2 (Fig. 3).
BnO
OH
OH OBn
( ) 10
-
F
OH
O
BnO
O
OH OBn
F
OH
O
NO2
( )-12
BnO
O
OH OBn
NO2
11
( )-
Figure 3. X-ray crystallography of ester ( )-12.
Figure 2. X-ray crystallography of ( )-10 and ( )-11.
3. Conclusions
interesting to note that the compounds ( )-10 and ( )-11 adopt
significantly different conformations in the solid state. Impor-
tantly, these data unambiguously demonstrate that the fluorodesi-
lylation proceeded, as anticipated, with the approach of the
electrophilic fluorinating reagent Selectfluor anti with respect to
the silyl group (anti-SE20 mechanism) (Fig. 2).
In conclusion, we have validated the first asymmetric de novo
synthesis of three fluorinated carbohydrate analogues, 1,5-di-O-ben-
zyl-2-deoxy-2-fluoro-
D
-glucitol 1, 2,6-di-O-benzyl-5-deoxy-5-flu-
oro- -glucitol 10, and 1,5-di-O-benzyl-2-deoxy-2-fluoro-
L
D-mannitol
2. This work advances our understanding of the fluorodesilylation
reaction since we have confirmed that the electrophilic fluorination
of allylsilanes featuring a stereogenic silylated carbon operates with
a stereochemical outcome in line with a stereoselective anti-SE20
mechanism. This result is consistent with the sense of stereocontrol
observed upon fluorination of allenylsilanes.8 In addition, the work
reported herein sets solid foundations for the synthesis of more com-
plex fluorinated carbohydrates. The main advantage of our approach
is its intrinsic flexibility since functional alterations are possible at
several levels. Carboxylic acids other than 2-benzyloxy acetic acid
may be used and processes other than dihydroxylations may allow
for alternative functionalisations of the allylic fluorides.
With the successful preparation of (2S,3S,4R,5R)-1, the fluorina-
tion and subsequent dihydroxylation of the allylsilane (2R,3S,4E)-3
were next examined (Scheme 5). Upon fluorodesilylation using our
standard conditions, the syn-allylic fluoride (2S,3E,5S)-9 was
formed in 83% yield. Two diastereomers were detected in the crude
reaction mixture, the E-isomer being formed predominantly (E:Z
ratio = 12:1). The dihydroxylation gave 1,5-di-O-benzyl-2-deoxy-
F
Me3Si
(i)
BnO
BnO
OH
OH
4. Experimental
OBn
(ii)
9
(2S,3E,5S)- (major)
OBn
3
(2R,3S,4E)-
E/Z 12:1
overall yield 83%
4.1. General procedures
ee 93%
All 1H NMR spectra were recorded in deuterated solvents using
Bruker DPX200, DPX400, AV400 and AV500 spectrometers, cali-
brated using residual protonated solvents as an internal reference.
13C NMR spectra were recorded in deuterated solvents using Bru-
ker DPX400, AV400 and AV500 spectrometers with a carbon-13
cryoprobe. 19F spectra (both with and without proton decoupling
were recorded on a Bruker AVANCE AV400 spectrometer. Proton
and carbon-13 NMR spectra are reported as chemical shifts (d) in
parts per million (ppm) relative to the solvent peak using the Bru-
ker internal referencing procedure (edlock). Fluorine-19 NMR
spectra are referenced relative to CFCl3 in CDCl3. Coupling
F
OH
BnO
OH
OH OBn
96%
d.r. = 10:1
2
(2R,3S,4R,5R)-
1,5-di-O-benzyl-2-deoxy-2-fluoro-D-mannitol
Scheme 5. Reagents and conditions: (i) Selectfluor, NaHCO3, MeCN, rt, 16 h; (ii)
OsO4, NMO, CH2Cl2–H2O 3:1, rt, 2 d.

914
G. T. Giuffredi et al. / Tetrahedron: Asymmetry 20 (2009) 910–920
constants (J) are reported in units of hertz (Hz). The following
abbreviations are used to describe multiplicities, s = singlet,
d = doublet, t = triplet, q = quartet, br = broad m = multiplet. Low
resolution mass spectra were recorded on Micromass GCT (CI)
AutospecoaTof instruments. High resolution mass spectra (HRMS,
m/z) were recorded on a Bruker MicroTof spectrometer using posi-
tive electrospray ionisation (EI+). Optical rotations were deter-
was not recorded due to the explosive nature of the compound
(lit.17 233 °C); mmax (film) 1640 (C@O); dH (400 MHz, DMSO-d6)
7.84 (1H, t, J 7.8 Hz, CH(CH)2), 7.98 (1H, t, J 7.8 Hz, CH(CH)2), 8.01
(1H, d, J 7.8 Hz, CHCHC), 8.15 (1H, d, J 7.8 Hz, CHCHC); dC
(101 MHz, DMSO-d6) 125.9, 131.0, 131.3, 132.3, 133.8, 147.4,
168.4; m/z (ESI+) 263.2 [MꢁOH]ꢁ.
mined on a Perkin Elmer 241 polarimeter in a 1 dm cell. [
a
]
D
4.4. 1-(Benzyloxy)-4-(trimethylsilyl)but-3-yn-2-one 6
values are given in 10ꢁ1 deg cm2 gꢁ1. IR spectra were recorded as
thin films on NaCl plates neat or in solution in CHCl3 or CH2Cl2
on a Bruker Tensor 27 FTIR spectrometer. Absorptions are mea-
sured in wavenumbers (cmꢁ1) and only peaks of interest are re-
ported. Melting points of solids were measured on a Griffin
apparatus and are uncorrected. All reactions requiring anhydrous
conditions were conducted in dried apparatus under an inert
atmosphere of argon or nitrogen. Solvents were dried and purified
before use according to standard procedures. All reactions were
monitored by TLC using Merck Kiesegel 60 F254 plates. Visualisa-
tions of the reaction components were achieved using UV fluores-
cence (254 nm) and KMnO4 stain. Column chromatography was
O
BnO
SiMe3
To a stirred solution of IBX (38 g, 136 mmol) in DMSO (180 mL),
( )-5 (22.5 g, 90 mmol) in THF (900 mL) was added and the reac-
tion mixture was stirred at room temperature for 16 h. H2O
(20 mL) was added and the resulting precipitate was filtered. The
filtrate was extracted with EtOAc (3 ꢄ 300 mL) and the combined
organics were washed with brine (600 mL), dried over MgSO4
and the solvent was removed in vacuo at room temperature. Filtra-
tion through a short plug of silica gel (EtOAc) furnished 6 as a yel-
low oil (21.1 g, 86 mmol, 95% yield). mmax (film) 3032 (C–H), 2152
(C„C), 1737 (C@O); dH (400 MHz, CDCl3): 0.25 (9H, s, Si(CH3)3),
4.24 (2H, s, CH2OBn), 4.68 (2H, s, CH2Ph), 7.30–7.48 (5H, m, Harom);
dC (101 MHz, CDCl3): ꢁ0.9 (Si(CH3)3), 73.4 (CH2Ph), 74.7 (CH2OBn),
101.3 (CSi(CH3)3), 102.6 (CCO), 128.0, 128.1, 128.5 (CHarom), 137.0
(Carom), 184.7 (CO); HRMS (ESI+) C14H18O2Siþ ([M+Na]+) requires
269.0968; found 269.0968.
carried out over Merck Silica Gel C60 (40–60 lm).
4.2. 1-(Benzyloxy)-4-(trimethylsilyl)but-3-yn-2-ol ( )-515
OH
BnO
SiMe3
n-BuLi (130 mL of a 2.5 M solution in hexanes, 325 mmol) was
added to a solution of trimethylsilylacetylene (39.5 mL, 280 mmol)
in THF (450 mL) at ꢁ78 °C, and the reaction mixture was stirred at
ꢁ78 °C for 30 min. A solution of freshly prepared 2-(benzyl-
oxy)acetaldehyde (42.5 g, 280 mmol) in THF (110 mL) was added
dropwise and the reaction mixture was stirred at ꢁ78 °C for
5 min, then at 0 °C for 2 h. H2O was added at 0 °C and the mixture
was extracted with Et2O (3 ꢄ 500 mL). The combined organic lay-
ers were washed with brine (1 L), dried over MgSO4 and the solvent
was removed in vacuo. Purification by column chromatography
(60–40 petrol ether–Et2O, 60:40, Rf = 0.5) furnished the racemic
propargylic alcohol ( )-5 as a colourless oil (57.1 g, 230 mmol,
82% yield). mmax (film) 3416 (br, O–H), 3064, 2959, 2864 (C–H),
2175 (C„C); dH (400 MHz, CDCl3) 0.20 (9H, s, Si(CH3)3), 3.57 (1H,
dd, J 9.9, 7.6 Hz, CHAOBn), 3.67 (1H, dd, J 9.9, 3.5 Hz, CHBOBn),
4.58 (1H, dd, J 7.6, 3.4 Hz, CHOH), 4.59 (1H, d, J 12.3 Hz, CHAPh),
4.66 (1H, d, J 12.3 Hz, CHBPh), 7.26–7.41 (5H, m, Harom); dC
(101 MHz, CDCl3) -0.2 (Si(CH3)3), 62.3 (CHOH), 73.4 (CH2OBn),
73.5 (CH2Ph), 90.6 (CSi(CH3)3), 102.9 (CCHOH), 127.6, 128.30,
128.7 (CHarom), 137.6 (Carom); m/z (ESI+) 271.3 [M+Na]+.
4.5. Di-
benzene)ruthenium(II)11
l-chloro-bis[chloro(g
6–1-isopropyl-4-methyl-
Cl
Cl
Cl
Ru
Ru
Cl
A solution of ruthenium(III) chloride hydrate (5.0 g, 21.5 mmol)
in EtOH (250 mL) was treated with -phellandrene (25 mL) and
heated at 120 °C for 4 h. The solution was cooled to room temper-
ature and the solid filtered to furnish di- -chloro-bis[chloro(
6-1-
isopropyl-4-methyl-benzene)ruthenium(II) as a red-brown crys-
talline solid (4.5 g, 13.7 mmol, 64% yield). mmax (film) 3050 (C–H);
dH (400 MHz, CDCl3): 1.28 (12H, d, J 7.0 Hz, CH(CH3)2), 2.16 (6H,
s, CCH3), 2.92 (2H, septet, J 7 Hz, CH(CH3)2), 5.34 (4H, d, J 6.3 Hz,
CHCCH3), 5.48 (4H, d, J 6.3 Hz, CHCCH(CH3)2); dC (101 MHz, CDCl3):
18.9 (CCH3), 22.1 (CH(CH3)2), 30.6 (CH(CH3)2), 80.3 (CHCCH3), 81.4
(CHCCH(CH3)2), 96.7, 101.2 (Carom); m/z (ESIꢁ) 576.93 [MꢁCl]ꢁ.
a
l
g
4.3. 2-Iodoxybenzoic acid16
4.6. N-[(1R,2R)-2-Amino-1,2-diphenylethyl]methanesulfonamide11
O
O
I
Ph
Ph
NHTs
NH2
OH
O
2-Iodobenzoic acid (50 g, 200 mmol) was added to a solution of
oxoneÒ (181 g, 290 mmol) in H2O (650 mL) and the reaction mix-
ture was mechanically stirred at 70 °C for 3 h. The suspension
was cooled to 0 °C and stirred slowly for a further 1.5 h. The mix-
ture was filtered, and the filtered was washed with cooled H2O
(500 mL) and acetone (200 mL) to furnish iodobenzoic acid (IBX)
as a white solid (49.5 g, 177.4 mmol, 89% yield). Melting point
Anhydrous NEt3 (2.5 mL) was added to a solution of (1R,2R)-1,2-
diphenylethane-1,2-diamine (5.0 g, 24 mmol) in THF (190 mL) at
0 °C prior to the addition of a solution of p-TsCl (4.9 g, 26 mmol) in
THF (50 mL) over 30 min at the same temperature. The mixture
was stirred at 0 °C for 16 h. The solvent was removed in vacuo and
satd NaHCO3 (sat.) (200 mL) was added. The mixture was extracted

G. T. Giuffredi et al. / Tetrahedron: Asymmetry 20 (2009) 910–920
915
with CH2Cl2 (3 ꢄ 200 mL) and the combined organic layers were
washed with brine (400 mL), dried over MgSO4 and the solvent
was removed in vacuo. Purification by column chromatography
(EtOAc, Rf = 0.4) furnished N-[(1R,2R)-2-amino-1,2-diphenyl-
ethyl]methanesulfonamide as a white solid (7.4 g, 20 mmol, 86%
was allowed to warm to room temperature and the reaction mix-
ture was stirred for 16 h. Then 1 M H2SO4 (32 mL) was added at
0 °C and the mixture was extracted with Et2O (3 ꢄ 30 mL) and
the combined organics were washed with brine, dried over MgSO4
and the solvent was removed in vacuo to obtain pure product
yield): MP 127–128 °C, (lit.18 125–126 °C); ½a 2D5
ꢀ
¼ ꢁ17:4 (c 1.3,
(2S,3E)-4 as a pale yellow oil (3.4 g, 13.6 mmol, 85% yield,
CHCl3), {lit.18
considerably};
½
a 2D5
m
ꢀ
¼ ꢁ36:7 (c 1.0, CHCl3), other literaturevalues vary
E:Z > 20:1): 93% ee (determined by Mosher esterification);
max (film) 3365 (br, N–H), 2254 (C–H), 1601 (S@O);
½
a 2D5
ꢀ
¼ ꢁ4:3 (c 1.1, CHCl3, {lit.14
½
a 2D5
ꢀ
¼ ꢁ1:9 (c 1.1, CHCl3)}; mmax
dH (400 MHz, CDCl3): 2.33 (3H, s, CH3), 4.14 (1H, d, J 5.2 Hz, CHNH2),
4.39 (1H, d, J 5.2 Hz, CHNHTs), 6.98 (2H, d, J 8.2 Hz, CHCH3), 7.09–
7.25 (10H, m, Harom), 7.32 (2H, d, J 8.2 Hz, CHCSO2); dC (101 MHz,
CDCl3): 21.4 (CH3), 60.5 (CHNH2), 63.1 (CHNHTs), 126.5, 126.8,
127.0, 127.4, 127.5, 128.2, 128.4, 129.1 (CHarom), 137.5, 139.2,
141.4, 142.5 (Carom); MS m/z (ESI+) 367.2 [M+H]+.
(film) 3440 (br, O–H), 3031, 2954, 2897 (C–H), 1621 (C@C); dH
(400 MHz, CDCl3) 0.08 (9H, s, Si(CH3)3), 2.49 (1H, s, OH), 3.36
(1H, dd, J 9.6, 8.5 Hz, CHAOBn), 3.57 (1H, dd, J 9.6, 3.3 Hz, CHBOBn),
4.33–4.39 (1H, m, CHOH), 4.59 (2H, s, CH2Ph), 6.00–6.04 (2H, m,
CHCHSi), 7.29–7.41 (5H, m, Harom); dC (101 MHz, CDCl3) ꢁ1.4
(Si(CH3)3), 73.0 (CH2OBn), 73.3 (CH2Ph), 73.9 (CHOH), 127.8,
127.8, 128.5 (CHarom), 131.7 (CHSi), 137.9 (Carom), 143.5 (CHCOH),
m/z (ESI+) 268.2 [M+NH4]+, 309.2 [M+CH3CN+NH4]+.
4.7. (1R,2R)-(ꢁ)-N-Tosyl-1,2-diphenylethane-1,2-diamine[
g
6-1-
isopropyl-4-methylbenzene)-ruthenium(II)] A11
4.10. (2S,3E)-1-(Benzyloxy)-4-(trimethylsilyl)but-3-en-2-yl
(benzyloxy)acetate (2S,3E)-7
Ts
Ph
N
Ru
O
N
Ph
H
OBn
O
BnO
A mixture of di-l-chloro-bis[chloro(g
6-1-isopropyl-4-methyl-
SiMe3
benzene)ruthenium(II) (1.8 g, 2.8 mmol), N-[(1R,2R)-2-amino-1,2-
diphenylethyl]methanesulfonamide (2.0 g, 5.5 mmol) and KOH
(2.3 g, 41 mmol) in CH2Cl2 (40 mL) was stirred at room tempera-
ture for 5 min. Then H2O (30 mL) was added and the mixture
was stirred until the colour changed from orange to deep purple.
The organic layer was washed with H2O, dried over CaH2 and the
solvent was removed in vacuo to furnish catalyst A as a deep pur-
ple solid (3.13 g, 5.2 mmol, 94% yield): dH (400 MHz, toluene-d8)
1.09 (6H, d, J 7.0 Hz, CH(CH3)2), 1.89 (3H, s, TsCCH3), 2.05 (3H, s,
CCH3), 2.37 (1H, m, CH(CH3)2), 3.91 (1H, d, J 4.0 Hz, CHNH), 4.71
(1H, d, J 4.0 Hz, CHNTs), 4.94 (2H, d, J 5.0 Hz, RuCH), 5.22 (2H, d,
J 5.0 Hz, RuCH), 6.42 (1H, br s, NH), 6.70 (2H, d, J 8.0 Hz, TsCH),
7.00–7.23 (10H, m, Harom), 7.49 (2H, d, J 8.0 Hz, TsCH), m/z (ESI+)
601.1 [M+H]+.
To a solution of (2S,3E)-4 (2.95 g, 11.8 mmol), 2-benzyloxy ace-
tic acid (1.78 mL, 12.4 mmol) and DMAP (0.14 mg, 1.2 mmol) in
CH2Cl2 (28 mL), was added a solution of DCC (2.5 g, 12.2 mmol,)
in CH2Cl2 (10 mL) at 0 °C and the reaction left to warm to room
temperature over 16 h with out removal of the cooling bath. The
reaction mixture was filtered through a short pad of silica (hex-
ane–EtOAc, 90:10) and furnished (2S,3E)-7 as a pale yellow oil
(4.56 g, 11.4 mmol, 97% yield): Rf = 0.4 (hexane–Et2O 75:25);
½
a 2D1
ꢀ
¼ þ21:3 (c 1.1, CH2Cl2); mmax (film) 3031, 2954, 2862 (C–H),
1757 (C@O), 1621 (C@C); dH (400 MHz, CDCl3) 0.09 (9H, s,
Si(CH3)3), 3.59 (1H, dd, J 10.9, 6.3 Hz, CHAOBn), 3.62 (1H, dd, J
10.9, 4.6 Hz, CHBOBn), 4.20 (2H, s, CH2CO2), 4.53 (1H, d, J 12.1 Hz,
CHAPh), 4.61 (1H, d, J 12.1 Hz, CHBPh), 4.67 (2H, s, CH2Ph), 5.64
(1H, dddd, J 8.1, 6.3, 4.6, 1.8 Hz, CHOR), 5.61–5.98 (2H, m, CHCHSi),
7.21–7.41 (10H, m, Harom); dC (101 MHz, CDCl3) ꢁ1.4 (Si(CH3)3),
67.2 (CH2CO2), 71.1 (CH2OBn), 73.1 (CH2Ph), 73.3 (CH2Ph), 74.9
(CHOR), 127.6, 127.7, 128.0, 128.1, 128.4, 128.5 (CHarom), 133.9
(CHSi), 137.2, 137.9 (Carom), 139.6 (CHCOR), 169.7 (CO2); HRMS
(ESI+) C23H30O4Siþ ([M+Na]+) requires 421.1806; found 421.1807.
4.8. (2S)-1-(Benzyloxy)-4-(trimethylsilyl)but-3-yn-2-ol (S)-515
OH
BnO
SiMe3
4.11. (2R,3R,4E)-2,6-Bis(benzyloxy)-3-(trimethylsilyl)hex-4-
enoic acid (2R,3R,4E)-8
Catalyst A (3.00 g, 5.0 mmol) was added to a solution of 6 (14.8 g,
60 mmol) in degassed IPA (700 mL) and the reaction mixture was stir-
red at 30 °C for 16 h. The solvent was removed in vacuo. Purification by
column chromatography (40–60 petrol ether–Et2O, 80:20, Rf = 0.3)fur-
nished (S)-5 as a pale yellow oil (13.1 g, 53 mmol, 88% yield): 93% ee
(Major 8.8 min, Minor 10.1 min, Chirapak AD, hexane–IPA 97:3,
207 nm, flow rate 1 mL/min. The ee has been confirmed by Mosher
Me3Si
O
BnO
OH
OBn
At first, LiHMDS 1 M in THF (20 mL, 20 mmol) was added drop-
wise to a solution of (2S,3E)-7 (4.4 g, 11 mmol) in THF (110 mL) at
ꢁ78 °C and the reaction mixture was stirred for 1 h. Chlorotrimeth-
ylsilane (2.1 mL, 17 mmol) was added dropwise and the reaction
left to warm to room temperature over 16 h without removing
the cooling bath. 10% HCl (50 mL) was added at 0 °C and the mix-
ture extracted with EtOAc (3 ꢄ 50 mL). The combined organic lay-
ers were washed with brine (150 mL), dried over MgSO4 and the
solvent was removed in vacuo to afford a crude mixture of 5:1 E/
Z. Purification by column chromatography (CH2Cl2–MeOH, 90:10,
esterification); ½a D25
ꢀ
¼ þ3:9 (c 1.0, CH2Cl2), {lit.15
½
a 3D0
ꢀ
¼ þ7:3 (c 1.0,
CHCl3), 93% ee}; all other data were identical to ( )-5.
4.9. (2S,3E)-1-(Benzyloxy)-4-(trimethylsilyl)but-3-en-2-ol-(ꢁ)
(2S,3E)-414
OH
BnO
SiMe3
A solution of (S)-5 (4.0 g, 16 mmol) in Et2O (10 mL) was added
to sodium bis-(2-methoxyethoxy)aluminium hydride (65% w/t in
toluene, 9.0 mL, 28 mmol) in Et2O (10 mL) at 0 °C, the reaction
Rf = 0.6) furnished (2R,3R,4E)-8 as
a
pale yellow oil (3.5 g,
8.9 mmol, 80% yield; E/Z > 20:1): ½a D21
ꢀ
¼ þ15:0 (c 1.0, CH2Cl2); mmax
(film) 3031, 2952 (C–H), 1720 (C@O); dH (400 MHz, CD2Cl2) 0.08

916
G. T. Giuffredi et al. / Tetrahedron: Asymmetry 20 (2009) 910–920
(9H, s, Si(CH3)3), 2.28 (1H, dd, J 9.9, 7.1 Hz, CHSi), 3.99 (1H, dd, J
12.6, 6.1 Hz, CHAOBn), 4.03 (1H, dd, J 12.6, 5.6 Hz, CHBOBn), 4.14
(1H, d, J 7.1 Hz, CHOBn), 4.49 (1H, d, J 11.1 Hz, CHOCHAPh), 4.50
(2H, s, CH2OCH2Ph), 4.68 (1H, d, J 11.1 Hz, CHOCHBPh), 5.56 (1H,
dt, J 15.4, 5.9 Hz, CHCH2OBn), 5.67 (1H, dd, J 15.4, 9.9 Hz, CHCHSi),
7.29–7.41 (10H, m, Harom), 8.57 (1H, br s, OH); dC (101 MHz,
CD2Cl2) ꢁ1.7 (Si(CH3)3), 38.2 (CHSi), 71.0 (CH2OBn), 71.7
(CH2OCH2Ph), 72.9 (CHOCH2Ph), 80.5 (CHOBn), 127.4, 127.9,
128.2, 127.4, 128.7 (CHarom), 128.7 (CHCHSi), 128.8 (CHarom), 131.3
(CHCH2OBn), 137.6 139.0 (Carom), 176.9 (CO2); HRMS (ESI+)
C23H30O4Siþ ([M+Na]+) requires 421.1806; found 421.1807.
(10H, m, Harom); dC (101 MHz, CDCl3) 65.1 (CH2OH), 70.8
(CH2OCH2Ph), 71.9 (d, J 23 Hz, CH2OBn), 73.5 (CHOCH2Ph), 79.7
(CHOBn), 91.4 (d, J 172 Hz, CHF), 127.8, 127.9, 127.9, 128.5, 128.5
(CHarom), 129.4 (d, J 19 Hz, CHCHF), 131.0 (d, J 11 Hz, CHCHOBn),
139.28, 139.40 (Carom); dF (376 MHz, CDCl3) ꢁ183.4 (dtd, J 48, 25,
+
14 Hz); HRMS (ESI+) C20H23FO3 ([M+Na]+) requires 353.1523;
found 353.1525.
4.14. 1,5-Di-O-benzyl-2-deoxy-2-fluoro-D-glucitol (2S,3S,4R,5R)-1
and 2,6-di-O-benzyl-5-deoxy-5-fluoro- -glucitol (2R,3S,4R,5S)-10
L
F
OH
F
OH
4.12. (2R,3R,4E)-2,6-Bis(benzyloxy)-3-(trimethylsilyl)hex-4-en-
1-ol (2R,3R,4E)-3
BnO
BnO
OH
OH
OH OBn
OH OBn
SiMe3
At first, (2S,3E,5R)-9 (260 mg, 0.8 mmol) and NMO (280 mg,
2.4 mmol) in CH2Cl2 (6 mL) and H2O (2 mL) were treated with
OsO4 (9 mg, 0.04 mmol) and the reaction mixture was stirred at
room temperature for 3 days. Then Na2SO3 (0.2 g) was added and
the reaction mixture was stirred at room temperature for 30 min-
utes. The mixture was extracted with EtOAc (3 ꢄ 30 mL) and the
combined organics were washed with brine (50 mL), dried over
MgSO4 and the solvent was removed in vacuo to furnish
(2R,3S,4R,5S)-10 and (2S,3S,4R,5R)-1 in a 60:40 ratio. Purification
by column chromatography (40–60 petrol ether–EtOAc 50:50)
gave an (2R,3S,4R,5S)-10 as a pale yellow solid (145 mg, 0.4 mmol,
51%) and (2S,3S,4R,5R)-1 as a white solid (82 mg, 0.2 mmol, 29%).
BnO
OH
OBn
At first, LiAlH4 (1.9 g, 40 mmol) in Et2O (100 mL) was cooled to
0 °C and a solution of (2R,3R,4E)-8 (3.2 g, 8 mmol) in Et2O (100 mL)
was added dropwise and the reaction mixture was stirred at 0 °C
for 3 h. Then NH4Cl sat. (16 mL) was added. The resulting suspen-
sion was then dried over MgSO4, filtered and the solvent removed
in vacuo. Purification by column chromatography (40–60 petrol
ether–Et2O, 80:20, Rf = 0.1) furnished (2R,3R,4E)-3 as a colourless
oil (2.2 g, 5.6 mmol, 70% yield, E/Z > 20:1): ½a D25
¼ ꢁ12:6 (c 1.0,
ꢀ
CH2Cl2); mmax (film) 3425 (O-H), 3088, 3063, 3030, 2949 (C–H),
1656 (C@C); dH (400 MHz, CDCl3) 0.07 (9H, s, Si(CH3)3), 2.26 (1H,
dd, J 10.0, 6.9 Hz, CHSi), 2.38 (1H, br s, OH), 3.66–3.73 (2H, m,
CHOBn, CHAOH), 3.74–3.81 (1H, m, CHBOH), 4.03 (2H, d, J 5.4,
CH2OBn), 4.51 (2H, s, CH2OCH2Ph), 4.55 (1H, d, J 11.2 Hz, CHO-
CHAPh), 4.61 (1H, d, J 11.2 Hz, CHOCHBPh), 5.55 (1H, dt, J 15.2,
6.3 Hz, CHCH2OBn), 5.65 (1H, dd, J 15.2, 10.0 Hz, CHCHSi), 7.28–
7.39 (10H, m, Harom); dC (101 MHz, CDCl3) -1.6 (Si(CH3)3), 35.8
(CHSi), 62.7 (CH2OH), 70.9 (CH2OBn), 71.1 (CH2OCH2Ph), 71.5
(CHOCH2Ph), 80.8 (CHOBn), 126.9 (CHCHSi), 127.6, 127.7, 127.8,
128.0, 128.4, 128.5 (CHarom), 132.0 (CHCH2OBn), 138.1, 138.4
(Carom); HRMS (ESI+) C23H32O3Si+ ([M+Na]+) requires 407.2013;
found 407.2010.
(2R,3S,4R,5S)-10: mp = 88–89 °C; ½a D25
¼ ꢁ2:0 (c 1.3, MeOH);
ꢀ
mmax (CHCl3) 3283 (O-H); dH (400 MHz, MeOD) 3.64 (1H, dt, J 5.4,
4.6 Hz, CHOBn), 3.71–3.98 (6H, m, CH2OBn, CH2OH, 2 ꢄ CHOH),
4.59 (2H, s, CH2OCH2Ph), 4.66 (1H, d, J 11.5 Hz, CHOCHAPh), 4.67
(1H, dm, J 48 Hz, CHF), 4.74 (1H, d, J 11.5 Hz, CHOCHBPh), 7.24–
7.44 (10H, m, Harom); dC (101 MHz, MeOD) 60.5 (CH2OH), 68.5 (d, J
24 Hz, CHCF), 69.0 (d, J 3.3 Hz, CHCHOBn), 69.9 (d, J 20 Hz, CH2OBn),
72.7 (CHOBn), 73,4 (CH2OBn), 71.6 (CHOBn), 91.7 (d, J 175 Hz, CHF),
127.7, 127.7, 127.8, 128.1, 128.3, 128.4 (CHarom), 138.5, 139.0 (Carom);
dF (376 MHz, MeOD) -194.4 (dtdd, J 48, 28, 5.7, 2.5 Hz); HRMS (ESI+)
+
C20H25F1O5 ([M+Na]+) requires 387.1578; found 387.1577.
(2S,3S,4S,5R)-1: Rf (40–60 petrol ether:EtOAc 50:50) = 0.25;
mp = 58–60 °C; ½a 2D5
¼ þ2:6 (c 0.4, MeOH); mmax (CHCl3) 3440 (O–
ꢀ
H), 2935 (C–H); dH (400 MHz, MeOD) 3.63–3.68 (1H, m, CHOBn),
3.71–3.97 (5H, m, CH2OBn, CH2OH, CHCHOBn), 4.16 (1H, ddd, J
16.1, 6.8, 2.0 Hz, CHCHF), 4.53 (1H, d, J 11.8 Hz, CH2OCHAPh), 4.59
(1H, d, J 11.8 Hz, CH2OCHBPh), 4.61 (1H, d, J 11.1 Hz, CHOCHAPh),
4.74 (1H, dddd, J 48, 6.6, 4.8, 2.8 Hz, CHF), 4.76 (1H, d, J 11.1 Hz,
CHOCHBPh), 7.23–7.42 (10H, m, Harom); dC (101 MHz, MeOD) 61.0
(CH2OH), 69.5 (d, J 22 Hz, CH2OBn), 69.6 (d, J 29 Hz, CHCF), 69.6
(d, J 3.5 Hz, CHCHOBn), 72.6 (CHOBn), 73,5 (CH2OBn), 71.6 (CHOBn),
94.7 (d, J 172 Hz, CHF), 127.6, 127.7, 127.9, 128.0, 128.3, 128.4
(CHarom), 138.3, 139.0 (Carom); dF (376 MHz, MeOD) ꢁ199.3 (dddd, J
4.13. (2S,3E,5R)-2,6-Bis(benzyloxy)-5-fluorohex-3-en-1-ol
(2S,3E,5R)-9
F
BnO
OH
OBn
At first, (2R,3R,4E)-3 (1.7 g, 4.4 mmol) and NaHCO3 (0.36 g,
4.4 mmol) in acetonitrile (45 mL) were treated with Selectfluor
(2.3 g, 6.6 mmol) and the reaction mixture was stirred at room
temperature for 16 h. Et2O (30 mL) was added and the mixture
was filtered. The organic phases were washed with H2O (30 mL),
dried over MgSO4 and the solvent was removed in vacuo to give
crude products A and B in a 85:15 ratio. Short plug silica filtration
(50:50 hexane–Et2O, then 100% Et2O, Rf = 0.1 (hexane–Et2O 50:50))
furnished pure (2S,3E,5R)-9 as a colourless oil (0.3 g, 0.8 mmol, 16%
yield) and a 80:20 mixture of A and B (1.1 g, 3.3 mmol, 74%).
+
48, 28, 24, 16 Hz); HRMS (ESI+) C20H25FO5 ([M+Na]+) requires
387.1578; found 387.1582.
4.15. (2S,3Z)-1-(Benzyloxy)-4-(trimethylsilyl)but-3-en-2-ol
(2S,3Z)-4
OH SiMe3
BnO
½
a 2D1
ꢀ
¼ ꢁ31:2 (c 1.0, CH2Cl2); For the major E isomer mmax (film)
3425 (O-H), 3088, 3063, 3031, 2866 (C–H), 1604 (C@C); dH
(400 MHz, CDCl3) 2.18 (1H, br s, OH), 3.56–3.68 (4H, m, CH2OBn,
CH2OH), 3.97–4.05 (1H, m, CHOBn), 4.42 (1H, d, J 11.7 Hz, CHO-
CHAPh), 4.62 (2H, s, CH2CH2Ph), 4.62 (1H, d, J 11.9 Hz, CHOCHBPh),
5.15 (1H, ddd, J 49, 5.3, 4.0 Hz, CHF), 5.80 (1H, ddm, J 15.8, 6.9 Hz,
CHCHOBn), 5.90 (1H, dddm, J 15.8, 14.9, 5.4 Hz, CHCHF), 7.27–7.40
Freshly distilled cyclohexene (4.2 mL, 72 mmol) was added
dropwise over 10 min to a solution of BH3 (1 M in THF, 72 mL,
72 mmol) under argon at 0 °C. The reaction mixture was stirred
for 1 h at 0 °C before the dropwise (15 min) addition of a solution
of (S)-5 (8.8 g, 36 mmol) in THF (36 mL). The reaction mixture was
stirred at 0 °C until everything is dissolved and warmed to room

G. T. Giuffredi et al. / Tetrahedron: Asymmetry 20 (2009) 910–920
917
temperature. After 1 h at this temperature acetic acid (14.7 mL,
145 mmol) was added and the mixture stirred for 16 h. Et2O
(100 mL) and water (100 mL) were added and the aqueous phase
was extracted with ether (3 ꢄ 100 mL). Combined organic layers
were washed with brine, dried over MgSO4, filtered and the solvent
removed in vacuo. Purification by column chromatography (hex-
ane–EtOAc 80:20, Rf = 0.41) furnished (2S,3Z)-4 as a colourless oil
(6.6 g, 26 mmol, 73% yield, E/Z > 1:20, 93% ee (determined by
by column chromatography (CH2Cl2–MeOH, 90:10, Rf = 0.6) fur-
nished (2R,3S,4E)-8 as a pale yellow oil (8.4 g, 21 mmol, 94% yield):
½
a 2D1
ꢀ
¼ ꢁ11:3 (c 1.0, CH2Cl2); mmax (film) 3031, 2954, 2866 (C–H),
1746 (C@O), 1605 (C@C); dH (400 MHz, CDCl3): 0.01 (9H, s,
Si(CH3)3), 2.10 (1H, dd, J 10.7, 3.2 Hz, CHSi(CH3)3), 3.98 (1H, ddd,
J 12.2, 6.7, 1.1 Hz, CHAOBn), 4.01 (1H, ddd, J 12.2, 6.3, 1.1 Hz,
CHBOBn), 4.16 (1H, d, J 3.2 Hz, CHCOOH), 4.30 (1H, d, J 11.1 Hz,
CHOCHAPh), 4.46 (2H, s, CH2OCH2Ph), 4.69 (1H, d, J 11.1 Hz,
CHOCHBPh), 5.51 (1H, dt, J 15.5, 6.5 Hz, CHCH2OBn), 5.85 (1H, dd,
J 15.5, 10.7 Hz, CHCHCH2OBn), 7.34 (10H, m, Harom), 7.90 (1H, br
s, COOH); dC (101 MHz, CDCl3): ꢁ2.4 (Si(CH3)3), 38.2 (CHSi(CH3)3),
70.7 (CH2OBn), 70.9 (CH2OCH2Ph), 72.7 (CHOCH2Ph), 78.4 (CHOBn),
127.2 (CHCH2OBn), 127.5, 127.9, 128.4, 128.5 (CHarom), 130.6
(CHCHCH2OBn), 137.1, 138.3 (Carom), 176.9 (CO2H); HRMS (ESI+)
C23H30O4Siþ ([M+Na]+) requires 421.1806; found 421.1810.
Mosher esterification). ½a D21
¼ þ55:7 (c 1.3, CH2Cl2), mmax (film)
ꢀ
3433 (br, O–H), 3032, 2955, 2860 (C–H), 1613 (C@C); dH
(400 MHz, CDCl3): 0.14 (9H, s, Si(CH3)3), 3.40 (1H, dd, J 9.6,
8.4 Hz, CHAOBn), 3.49 (1H, dd, J 9.6, 8.4 Hz, CHBOBn), 4.49 (1H,
tdd, J 8.3, 3.4, 0.8 Hz, CHOH), 4.57 (1H, d, J 12.0 Hz, CHAPh), 4.61
(1H, d, J 12.0 Hz, CHBPh), 5.78 (1H, dd, J 14.4, 0.8 Hz, CHSi), 6.22
(1H, dd,
J 14.4, 8.4 Hz, CHCHOH), 7.34 (5H, m, Harom); dC
(101 MHz, CDCl3): 0.3 (Si(CH3)3), 71.1 (CHOH), 73.4 (CH2Ph), 73.9
(CH2OBn), 127.8, 127.9, 128.5 (CHarom), 134.2 (CHSi), 137.8 (Carom),
145.1 (CHCHOH); HRMS (ESI+) C14H22O2Siþ ([M+Na]+) requires
273.1281; found 273.1281.
4.18. (2R,3S,4E)-2,6-Bis(benzyloxy)-3-(trimethylsilyl)hex-4-en-
1-ol (2R,3S,4E)-3
SiMe3
BnO
4.16. (2S,3Z)-1-(Benzyloxy)-4-(trimethylsilyl)but-3-en-2-yl
(benzyloxy)acetate (2S,3Z)-7
OH
OBn
OBn
At first, LiAlH4 (3.9, 100 mmol) in Et2O (250 mL) was cooled to
0 °C and a solution of (2R,3S,4E)-8 (8.2 g, 21 mmol) in Et2O
(250 mL) was added drop wise and the reaction mixture was stirred
at 0 °C for 3 h. Then NH4Cl sat. (40 mL) was added. The resulting
suspension was then dried over MgSO4, filtered and concentrated
in vacuo. Purification by column chromatography (40–60 petrol
ether–Et2O, 80:20, Rf = 0.1) furnished (2R,3S,4E)-3 as a colourless
O
O
SiMe3
BnO
To a solution of (2S,3Z)-4 (5.9 g, 23.5 mmol), 2-benzyloxy acetic
acid (3.54 mL, 24.7 mmol) and DMAP (0.29 mg, 2.4 mmol) in
CH2Cl2 (57 mL), was added a solution of DCC (5.0 g, 24.2 mmol)
in CH2Cl2 (19 mL) at 0 °C and the reaction left to warm to room
temperature over 16 h without removal of the cooling bath. The
reaction mixture was filtered through a short pad of silica (hex-
ane–EtOAc, 90:10) and furnished (2S,3Z)-7 as a pale yellow oil
(9.09 g, 22.7 mmol, 97% yield): Rf = 0.4 (hexane–Et2O, 75:25);
oil (5.9 g, 15 mmol, 72% yield): ½a D21
¼ ꢁ22:1 (c 1.0, CH2Cl2); mmax
ꢀ
(film) 3423 (O-H), 3063, 3030, 2951 (C–H), 1654 (C@C); dH
(400 MHz, CDCl3): 0.07 (9H, s, Si(CH3)3), 1.91 (1H, br s, OH), 1.98
(1H, dd, J 10.7, 3.8 Hz, CHSi(CH3)3), 3.73 (3H, m, CH2OH, CHOBn),
4.03 (2H, d, J 6.3 Hz, CH2OBn), 4.48 (1H, d, J 12.0 Hz, CH2OCHAPh),
4.57 (1H, d, J 12.0 Hz, CH2OCHBPh), 4.60 (1H, d, J 11.1 Hz, CHO-
CHAPh), 4.67 (1H, d, J 11.1 Hz, CHOCHBPh), 5.55 (1H, dt, J 15.4,
6.4 Hz, CHCH2OBn), 5.84 (1H, ddt, J 15.4, 10.7, 1.1 Hz, CHCHCH2OBn),
7.35 (10H, m, Harom); dC (101 MHz, CDCl3): ꢁ2.0 (Si(CH3)3), 37.1
(CHSi(CH3)3), 64.3 (CHOBn), 71.1 (CH2OBn), 71.5 (CHOCH2Ph), 72.2
(CH2OCH2Ph), 80.1 (CHOH); 126.5 (CHCH2OBn), 127.5, 127.6,
127.7, 127.8, 128.3, 128.4 (CHarom), 132.3 (CHCHCH2OBn), 138.5,
138.5 (Carom); HRMS (ESI+) C23H32O3Siþ ([M+Na]+) requires
407.2013; found 407.2015.
½
a 2D1
ꢀ
¼ þ21:3 (c 1.1, CH2Cl2); mmax (film) 3032, 2954, 2862 (C–H),
1755 (C@O), 1613 (C@C); dH (400 MHz, CDCl3): 0.2 (9H, s, Si(CH3)3),
3.54 (1H, dd, J 10.8, 3.7 Hz, CHAOBn), 3.61 (1H, dd, J 10.8, 7.4 Hz,
CHBOBn), 4.13 (2H, s, CH2CO2R), 4.55 (1H, d, J 12.2 Hz, CHAPh),
4.61 (1H, d, J 12.2 Hz, CHBPh), 4.64 (2H, s, CH2Ph), 5.77 (1H, dddd,
J 9.1, 7.4, 3.7, 0.5 Hz, CHOR), 5.87 (1H, dd, J 14.4, 0.5 Hz, CHSi), 6.21
(1H, dd, J 14.4, 9.1 Hz, CHCHOH), 7.35 (10H, m, Harom); dC
(101 MHz, CDCl3): 0.0 (Si(CH3)3), 67.2 (CH2CO2R), 71.6 (CH2OBn),
73.1 (CH2Ph), 73.2 (CH2Ph), 73.7 (CHOR), 73.4 (CH2Ph), 127.7,
127.7, 128.0, 128.1, 128.4, 128.5 (CHarom), 136.2 (CHSi), 137.2,
137.8 (Carom), 141.0 (CHCHOR), 169.6 (CO2R); HRMS (ESI+)
C23H30O4Siþ ([M+Na]+) requires 421.1806; found 421.1787.
4.19. (2S,3E,5S)-2,6-Bis(benzyloxy)-5-fluorohex-3-en-1-ol
(2S,3E,5S)-9
F
4.17. (2R,3S,4E)-2,6-Bis(benzyloxy)-3-(trimethylsilyl)hex-4-
enoic acid (2R,3S,4E)-8
BnO
OH
OBn
Me3Si
O
At first, (2R,3S,4E)-3 (4.8 g, 12 mmol) and NaHCO3 (1.05 g,
4.4 mmol) in acetonitrile (125 mL) were treated with Selectfluor
(6.7 g, 19 mmol) and the reaction mixture was stirred at room tem-
perature for 16 h. Then Et2O (100 mL) was added and the mixture
was filtered. The organic phases were washed with H2O (100 mL),
dried over MgSO4 and the solvent was removed in vacuo. Short plug
silica filtration (hexane–Et2O, 50:50, Rf = 0.1 then 100% Et2O) fur-
nished pure (2S,3E,5S)-9 as a colourless oil (3.5 g, 11 mmol, 83%
BnO
OH
OBn
At first, (2S,3Z)-7 (8.9 g, 22 mmol) in THF (220 mL) was cooled
to ꢁ78 °C, then LiHMDS 1 M in THF (40 mL, 40 mmol) was added
drop wise and the reaction mixture was stirred for 1 h at ꢁ78 °C.
Chlorotrimethyl silane (4.3 mL, 34 mmol) was added drop wise
and the reaction left to warm to room temperature over 16 h with-
out removing the cooling bath. Then 10% HCl (100 mL) was added
at 0 °C and the mixture was extracted with EtOAc (3 ꢄ 75 mL). The
combined organic layers were washed with brine (250 mL), dried
over MgSO4 and the solvent was removed in vacuo. Purification
yield, E:Z 12:1). ½a D21
¼ ꢁ38:4 (c 1.1, CH2Cl2); mmax (film) 3440 (O-
ꢀ
H), 3088, 3064, 3021, 2866 (C–H), 1605 (C@C); dH (400 MHz, CDCl3)
2.10 (1H, br s, OH), 3.58 (1H, dd, J 11.6, 6.9 Hz, CHAOH), 3.62 (1H, dd, J
11.6, 4.6 Hz, CHAOH), 3.68 (2H, dd, J 23.3, 4.8 Hz, CH2OBn), 4.02 (1H,
dtm, J 7.0, 4.9 Hz, CHOBn), 4.43 (1H, d, J 11.7 Hz, CHOCHAPh), 4.61

918
G. T. Giuffredi et al. / Tetrahedron: Asymmetry 20 (2009) 910–920
(1H, d, J 12.5 Hz, CH2OCHAPh), 4.64 (1H, d, J 12.5 Hz, CH2OCHBPh),
4.66 (1H, d, J 11.7 Hz, CHOCHBPh), 5.15 (1H, ddt, J 48, 5.5, 4.8 Hz,
CHF), 5.81 (1H, ddm, J 15.9, 7.2 Hz, CHCHOBn), 5.90 (1H, ddd, J
15.9, 13.9, 5.5 Hz, CHCF), 7.28–7.40 (10H, m, Harom); dC (101 MHz,
CDCl3) 65.2 (d, J 1.5 Hz, COH), 70.8 (CHOCH2Ph), 71.8 (d, J 22.8 Hz,
CH2OBn), 73.5 (CH2OCH2Ph), 91.4 (d, J 172 Hz, CHF), 127.8, 127.9,
127.9, 128.5, 128.5, 128.5 (CHarom), 129.6 (d, J 19.2 Hz, CHCHF),
131.0 (d, J 10.3 Hz, CHCHOBn), 137.6, 137.9 (Carom); dF (376 MHz,
CDCl3), ꢁ183.1 (dddd, J 48, 23.3, 13.9, 2.1 Hz); HRMS (ESI+)
C20H23FO3+ ([M+Na]+) requires 353.1523; found 353.1525.
1532 (N@O); dH (400 MHz, CDCl3) 2.87 (1H, br s, OH), 2.95 (1H, br
s, OH), 3.78–3.87 (2H, m, CH2OBn), 3.89–3.92 (2H, m, CHOHCHOBn),
4.20 (1H, dd, J 19.4, 4.9 Hz, CHOHCHF), 4.54 (1H, dm, J 11.9 Hz,
CHAOR), 4.56 (1H, d, J 11.8 Hz, CH2OCHAPh), 4.62 (1H, d, J 11.8 Hz,
CH2OCHBPh), 4.65 (1H, d, J 11.4 Hz, CHOCHAPh), 4.77 (1H, d, J
11.4 Hz, CHOCHBPh), 4.80 (1H, ddt, J 47, 8.9, 4.1 Hz, CHF), 4.85 (1H,
dm, J 11.9 Hz, CHBOR), 7.27–7.35 (10H, m, Harom), 8.15 (2H, d, J
9.0 Hz, HaromNO ), 8.25 (2H, d, J 9.0 Hz, HaromNO ); dC (101 MHz, CDCl3):
2
2
64.2 (CH2OR), 68.9 (d, J 20 Hz, CHCHF), 69.0 (d, J 23 Hz, CH2OBn),
69.9 (d, J 3.6 Hz, CHCHOBn), 72.9 (CHOCH2Ph), 73.8 (CH2OCH2Ph),
77.0 (CHOBn), 93.8 (d, J 174 Hz, CHF), 123.6 (HaromNO ), 127.7,
2
128.0, 128.0 128.1, 128.5, 128.5 (CHarom), 130.7 (HaromNO ), 135.3
4.20. 1,5-Di-O-benzyl-2-deoxy-2-fluoro-D-mannitol (2R,3S,4R,5R)-2
2
(HaromNO ), 137.2 137.5 (Carom), 150.5 (CNO2), 164.7 (CO2); dF
2
(376 MHz, CDCl3) ꢁ200.0 (dddd, J 47, 25, 22, 19 Hz); HRMS (ESI+)
F
OH
+
þ
BnO
C27H28FNO8 ([M+Na] ) requires 536.1691; found 536.1694.
OH
OH OBn
4.21.2. 1,5-Di-O-benzyl-2-deoxy-2-fluoro-6-O-(4-nitrobenzoyl)-
mannitol ( )-12
(2S,3E,5S)-9 (2.0 g, 6 mmol) and NMO (2.1 g, 18 mmol) in
CH2Cl2 (60 mL) and H2O (20 mL) was treated with OsO4 (76 mg,
0.3 mmol) and the reaction mixture was stirred at room tempera-
ture for 2 days. Na2SO3 (2 g) was added and the reaction mixture
was stirred at room temperature for 30 min. The mixture was ex-
tracted with EtOAc (3 ꢄ 100 mL) and the combined organics were
washed with brine (150 mL), dried over MgSO4 and the solvent was
removed in vacuo to furnish (2R,3S,4R,5R)-2. Purification by col-
umn chromatography (40–60 petrol ether–EtOAc, 50:50) furnished
(2R,3S,4R,5R)-2 as a pale white solid (2.1 g, 5.8 mmol, 96%, dr 11:1).
F
OH
O
BnO
O
OH OBn
O
N
O
Dr 89: 11; Rf = 0.35 (hexane–EtOAc; 50:50); mp (crystal): 118–
122 °C mmax (CH2Cl2) 3550 (O-H), 3055, 2984, 2953, 2871 (C–H),
1727 (C@O) 1530 (N@O); dH (400 MHz, CDCl3) 2.90 (2H, br s,
OH), 3.72–3.98 (4H, m, CH2OBn, CHCHOBn), 4.20 (1H, dd, J 8.0,
7.9 Hz, CHOHCHF), 4.57 (1H, dd, J 12.1 Hz, CHAOR), 4.58 (1H, d, J
12.0 Hz, CH2OCHAPh), 4.62 (1H, d, J 12.0 Hz, CH2OCHBPh), 4.63
(1H, d, J 11.6 Hz, CHOCHAPh), 4.68 (1H, ddt, J 47, 8.1, 4.1 Hz,
CHF), 4.77 (1H, d, J 11.6 Hz, CHOCHBPh), 4.82 (1H, dd, J 12.1,
2.9 Hz, CHBOR), 7.27–7.35 (10H, m, Harom), 8.16 (2H, d, J 9.0 Hz,
HaromNO ), 8.26 (2H, d, J 9.0 Hz, HaromNO ); dC (101 MHz, CDCl3):
Mp: 92–96 °C; ½a 2D5
ꢀ
¼ þ20:4 (c 0.5, CH2Cl2);
mmax (CH2Cl2) 3383 (O–
H), 3089, 3064, 3032, 2934, 2872 (C–H); dH (400 MHz, MeOD)
3.59–3.65 (1H, m, CHOBn), 3.75–4.00 (5H, m, CH2OBn, CH2OH,
CHOH), 4.10 (1H, dd, J 9.0, 0.9 Hz, CHCHF), 4.60 (2H, s, CH2OCH2Ph),
4.61 (1H, d, J 11.3 Hz, CHOCHAPh), 4.68 (1H, ddmd, J 48, 5.4, 2.1 Hz,
CHF), 4.77 (1H, d, J 11.3 Hz, CHOCHBPh), 7.22–7.41 (10H, m, Harom);
dC (101 MHz, MeOD) 61.1 (CH2OH), 67.7 (d, J 25 Hz, CHCF), 68.3 (d,
J 2.7 Hz, CHCHOBn), 70.1 (d, J 20 Hz, CH2OBn, 72.60 (CHOBn), 73,5
(CH2OBn), 79.6 (CHOBn), 91.6 (d, J 175 Hz, CHF), 127.6, 127.7,
127.8, 128.0, 128.3, 128.4 (CHarom), 138.5, 139.0 (Carom); dF
(376 MHz, MeOD) ꢁ193.4 (dtdd, J 48, 28, 4.6, 2.5 Hz, Fmajor),
2
2
64,2 (CH2OR), 68.4 (d, J 3.6 Hz, CHCHOBn), 68.5 (d, J 25 Hz, CHCHF),
69.2 (d, J 22 Hz, CH2OBn), 72.8 (CHOCH2Ph), 73.8 (CH2OCH2Ph),
77.4 (CHOBn), 90.7 (d, J 175 Hz, CHF), 123.6 (CHaromNO ), 127.2,
2
128.0, 128.1 128.1, 128.5, 128.6 (CHarom), 130.8 (CHaromNO ), 135.2
2
+
ꢁ195.1 (dtt, J 48, 24, 21 Hz, Fminor); HRMS (ESI+) C20H25FO5
(CaromNO ), 137.4 137.4 (Carom), 150.6 (CNO2), 164.8 (CO2); dF
2
([M+Na]+) requires 387.1578; found 387.1578.
(376 MHz, CDCl3) -194.3 (dddd, J 47, 28, 21, 7.9 Hz), -200.7 (dddd,
J 47, 28, 20, 18 Hz); HRMS (ESI+) C27H28FNO8 ([M+Na]+) requires
þ
536.1691; found 536.1695.
4.21. General procedure: esterification of primary alcohols
4.22. General procedure: Mosher esterification
A solution of 4-nitrobenzoyl chloride (49 mg, 0.32 mmol) in
CH2Cl2 (2 mL) was added dropwise to a solution of primary alcohol
(70 mg, 0.27 mmol), triethylamine (0.16 ml, 1.3 mmol, 5 equiv)
and DMAP (7 mg, 0.1 mmol) in CH2Cl2 (5 mL) at 0 °C. The reaction
mixture was stirred overnight at room temperature. CH2Cl2 (2 mL)
and NH4Cl sat. (2 mL) was added and the organic layer was washed
subsequently with sodium bicarbonate (2 mL of a saturated aque-
ous solution) and water (2 mL), dried over MgSO4, filtered and the
solvent removed in vacuo. Purification by column chromatography
(hexane–EtOAc, 50:50) furnished the corresponding nitrobenzoic
esters as white solids.
A solution of (R)-(ꢁ)-a-methoxy-a-(trifluoromethyl)phenylace-
tyl chloride (2.8 equiv) in DCM (0.5 mL) was added to a solution of
alcohol (10 mg, 1 equiv), Et3N (5 equiv) and catalytic DMAP
(>1 mg) in DCM (0.8 mL) at 0 °C. The reaction mixture was stirred
overnight at room temperature. Dichloromethane (2 mL) and
NH4Cl sat. (2 mL) were added and the organic layer was washed
subsequently with NaHCO3 sat. (2 mL) and water (2 mL), dried over
MgSO4, filtered and the solvent removed in vacuo to afford analyt-
ically pure Mosher esters.
4.22.1. (2S)-1-(Benzyloxy)-4-(trimethylsilyl)but-3-yn-2-yl (2S)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
4.21.1. 1,5-Di-O-benzyl-2-deoxy-2-fluoro-6-O-(4-nitrobenzoyl)-
glucitol ( )-11
O
F
OH
O
Ph
O
BnO
O
OMe
F3C
BnO
OH OBn
O
N
O
SiMe3
Dr 96.5: 3.5; Rf = 0.64 (hexane–EtOAc; 80:20); ½a D25
¼ þ40:2 (c
ꢀ
Rf = 0.34 (hexane–EtOAc; 50:50); mp (crystal): 77–80 °C; mmax
(CH2Cl2) 3540 (O–H), 3055, 2984, 2953, 2864 (C–H), 1724 (C@O)
1.0, CH2Cl2); mmax (CH2Cl2) 3065, 3032, 2953, 2857 (C–H), 1742

G. T. Giuffredi et al. / Tetrahedron: Asymmetry 20 (2009) 910–920
919
(C@O), 2171 (C„C); dH (400 MHz, CDCl3) 0.18 (9H, s, Si(CH3)3),
3.61 (3H, s, OCH3), 3.67–3.74 (2H, m, CH2OBn), 4.45 (1H, d, J
11.9 Hz, CHAPh), 4.49 (1H, d, J 11.9 Hz, CHBPh), 5.88 (1H, dd, J
7.7, 4.4 Hz, CHOR), 7.21–7.45 (8H, m, Harom), 7.58 (2H, d, J 7.6 Hz,
Harom); dC (101 MHz, CDCl3): 0.4 (Si(CH3)3), 55.5 (d, J 1.4 Hz,
OCH3), 65.3 (CHOR), 70.9 (CH2OBn), 73.1 (CH2Ph), 93.3 (CSi), 98.0
(CCHOR), 124.5 (q, J 289 Hz, CF3), 127.8, 127.9, 128.1, 128.7,
128.8, 130.0 (CHarom), 132.7, 137.9 (Carom), 166.0 (CO2); dF
(376 MHz, CDCl3) ꢁ71.2 (3.5%), ꢁ71.7 (96.5%); HRMS (ESI+)
C24H27F3O4Siþ ([M+Na]+) requires 487.1523; found 487.1520.
(C@O), 1656 (C@C); dH (400 MHz, CDCl3) 0.09 (9H, s, Si(CH3)3),
2.03 (1H, dd, J 9.8, 8.5 Hz, CHSi), 3.52 (3H, d, J 1.0 Hz, OCH3), 3.76
(1H, ddd, J 8.5, 5.4, 2.4 Hz, CHOBn), 4.25 (1H, dd, J 11.7, 5.3 Hz,
CHAOR), 4.37 (1H, d,
J 10.9 Hz, CHOCHBPh), 4.49 (2H, s,
CH2OCH2Ph), 4.61 (1H, d, J 10.9 Hz, CHOCHBPh), 4.80 (1H, dd, J
11.7, 2.6 Hz, CHBOR), 5.30 (2H, s, CH2OBn), 5.47 (1H, dt, J 15.4,
5.7 Hz, CHCH2OBn), 5.56 (1H, dd, J 15.4, 9.8 Hz, CHCHSi), 7.21–
7.41 (13H, m, Harom), 7.55 (2H, d, J 7.4 Hz, Harom); dC (101 MHz,
CDCl3); ꢁ1.5 (Si(CH3)3), 53.4 (CH2OR) 55.5 (OCH3), 66.6
(CHOCH2Ph), 71.6, 71.9 (CH2OCHPh), 78.6 (CHOBn), 122.7 (q, J
329 Hz, CF3), 127.1 (CHSi), 127.4, 127.6, 127.6, 127.7, 128.0,
128.2, 128.4, 128.4, 129.6 (CHarom), 131.6 (CHCH2OBn), 132.2,
137.8, 138.4 (Carom), 166.6 (CO2); dF (376 MHz, CDCl3) ꢁ71.4
(3.0%), ꢁ71.4 (97.0%); HRMS (ESI+) C33H39F3O5Siþ ([M+Na]+)
requires 623.2411; found 623.2399.
4.22.2. (2S,3E)-1-(Benzyloxy)-4-(trimethylsilyl)but-3-en-2-yl
(2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
MeO
Ph
F3C
4.22.5. (2R,3S,4E)-2,6-Bis(benzyloxy)-3-(trimethylsilyl)hex-4-
en-1-yl (2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
O
O
BnO
SiMe3
SiMe3
O
Dr 96.5: 3.5; Rf = 0.66 (hexane–EtOAc; 80:20); ½a D25
¼ þ46:3 (c
ꢀ
BnO
Ph
F3C OMe
1.0, CH2Cl2); mmax (CH2Cl2) 3065, 3032, 2956, 2860 (C–H), 1750
(C@O), 1600 (C@C); dH (400 MHz, CDCl3) 0.07 (9H, s, Si(CH3)3),
3.55 (3H, d, J 1.1 Hz, OCH3), 3.57 (1H, d, J 3.4 Hz, CHAOBn), 3.59
(1H, s, CHBOBn), 4.45 (1H, d, J 11.9 Hz, CHAPh), 4.49 (1H, d, J
11.9 Hz, CHBPh), 5.77–5.82 (1H, mdd, J 5.7, 0.7 Hz, CHOR), 5.99
(1H, dd, J 18.9, 5.7 Hz, CHCHOR), 6.10 (1H, dd, J 18.9, 0.7 Hz, CHSi)
7.22–7.41 (8H, m, Harom), 7.56 (2H, d, J 7.5 Hz, Harom); dC (101 MHz,
CDCl3) 1.6 (Si(CH3)3), 55.4 (OCH3), 71.0 (CH2OBn), 73.0 (CH2Ph),
76.8 (CHOR), 123.2 (q, J 317 Hz, CF3), 127.5, 127.6, 127.7, 128.3,
128.4, 129.5 (CHarom), 132.3 (Carom), 136.1 (CHSi), 137.8 (Carom),
138.4 (CHCHOR), 165.8 (CO2); dF (376 MHz, CDCl3) ꢁ71.4 (3.5%),
ꢁ71.5 (96.5%); HRMS (ESI+) C24H29F3O4Siþ ([M+Na]+) requires
489.1679; found 489.1678.
O
OBn
Dr 97.0:3.0; Rf = 0.55 (hexane–EtOAc; 80:20); ½a D25
¼ þ11:0 (c
ꢀ
0.7, CH2Cl2); mmax (CH2Cl2) 3065, 3032, 2953, 2851 (C–H), 1750
(C@O), 1655 (C@C); dH (400 MHz, CDCl3) 0.09 (9H, s, Si(CH3)3),
1.79 (1H, dd, J 10.6, 2.8 Hz, CHSi), 3.53 (3H, d, J 0.9 Hz, OCH3),
3.84 (1H, ddd, J 6.1, 5.3, 2.8 Hz, CHOBn), 4.25 (1H, ddd, J 12.3,
6.4, 1.0 Hz, CHAOR), 4.02 (1H, ddd, J 12.3, 6.4, 1.0 Hz, CHBOR),
4.37 (1H, dd, J 11.3, 5.8 Hz, CHAOBn), 4.38 (1H, d, J 11.2 Hz,
CHOCHBPh), 4.46 (1H, dd, J 11.3, 5.3 Hz, CHBOBn), 4.47 (1H, d, J
11.9 Hz, CH2OCHAPh), 4.50 (1H, d, J 11.9 Hz, CH2OCHAPh), 4.60
(1H, d,
J 11.2 Hz, CHOCHBPh), 5.47 (1H, dt, J 15.4, 6.4 Hz,
CHCH2OBn), 5.78 (1H, dd, J 15.4, 10.7 Hz, CHCHSi), 7.21–7.41
(13H, m, Harom), 7.53 (2H, d, J 7.4 Hz, Harom); dC (101 MHz, CDCl3);
-2.3 (Si(CH3)3), 55.5 (OCH3), 68.6 (CH2OR), 70.9 (CHOCH2Ph), 71.4
(CH2OCH2Ph), 72.4 (CH2OBn), 76.7 (CHOBn), 123.5 (q, J 289 Hz,
CF3), 127.3 (CHSi), 127.5, 127.5, 127.6, 127.7, 128.3, 128.4, 128.5,
128.6, 129.7 (CHarom), 130.5 (CHCH2OBn), 132.1, 138.1, 138.5 (Car-
om), 166.4 (CO2); dF (376 MHz, CDCl3) ꢁ71.3 (97.0%), ꢁ71.3
(3.0%); HRMS (ESI+) C33H39F3O5Siþ ([M+Na]+) requires 623.2411;
found 623.2412.
4.22.3. (2S,3Z)-1-(Benzyloxy)-4-(trimethylsilyl)but-3-en-2-yl
(2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
CF3
Ph
OMe
O
O
SiMe3
BnO
Dr 97.3:2.7; Rf = 0.66 (hexane–EtOAc; 80:20); ½a D25
¼ þ45:8 (c
ꢀ
1.1, CH2Cl2); mmax (CH2Cl2) 3065, 3032, 2954, 2852 (C–H), 1748
(C@O), 1604 (C@C); 0.21 (9H, s, Si(CH3)3), 3.50 (1H, dd, J 10.9,
3.4 Hz, CHAOBn), 3.56 (3H, d, J 0.9 Hz, OCH3), 3.56 (1H, dd, J 10.9,
8.0 Hz, CHBOBn), 4.45 (1H, d, J 12.1 Hz, CHAPh), 4.50 (1H, d, J
12.1 Hz, CHBPh), 5.93 (1H, d, J 14.4 Hz, CHSi), 5.96 (1H, ddd, J 9.7,
8.0, 3.4 Hz, CHOR), 6.22 (1H, dd, J 14.4, 9.7 Hz, CHCHOR), 7.21–
7.42 (8H, m, Harom), 7.56 (2H, d, J 7.7 Hz, Harom); dC (101 MHz,
CDCl3) -0.1 (Si(CH3)3), 55.5 (OCH3), 71.5 (CH2OBn), 73.1 (CH2Ph),
75.5 (CHOR), 123.4 (q, J 288 Hz, CF3), 127.5, 127.5, 127.6, 128.2,
128.3, 129.5 (CHarom), 132.4 (Carom), 137.5 (CHSi), 137.7 (Carom),
139.8 (CHCHOR), 165.6 (CO2); dF (376 MHz, CDCl3) ꢁ71.5 (2.7%),
ꢁ71.7 (97.3%); HRMS (ESI+) C24H29F3O4Siþ ([M+Na]+) requires
489.1679; found 489.1679.
4.22.6. (2S,3E,5R)-2,6-Bis(benzyloxy)-5-fluorohex-3-en-1-yl
(2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
F
O
BnO
Ph
F3C OMe
O
OBn
Dr 96.0:4.0; Rf = 0.45 (hexane–EtOAc; 80:20); ½a D25
¼ þ16:0 (c
ꢀ
0.7, CH2Cl2); mmax (CH2Cl2) 3065, 3032, 2918, 2852 (C–H), 1751
(C@O), 1648 (C@C); dH (400 MHz, CDCl3) 3.52 (3H, d, J 1.0 Hz,
OCH3), 3.58 (2H, dd, J 21.5, 5.8 Hz, CH2OBn), 4.16–4.22 (1H, m,
CHOBn), 4.35 (1H, dd, J 11.3, 4.4 Hz, CHOCHAPh), 4.36 (1H, dd, J
11.3, 7.9 Hz, CHOCHBPh), 4.40 (1H, d, J 11.7 Hz, CHAOR), 4.56 (1H,
d, J 11.7 Hz, CHBOR), 4.59 (1H, d, J 12.1 Hz, CH2OCHAPh), 4.61
(1H, d, J 12.1 Hz, CH2OCHBPh), 5.12 (1H, ddt, J 48, 10.1, 5.6 Hz,
CHF), 5.78 (1H, dddd, J 15.9, 6.6, 2.3, 1.2 Hz, CHCHOBn), 5.91 (1H,
dddd, J 15.9, 14.7, 5.6, 1.1 Hz, CHCHF), 7.21–7.42 (13H, m, Harom),
7.54 (2H, d, J 7.4 Hz, Harom); dC (101 MHz, CDCl3) 55.5 (d, J 1.5 Hz,
OCH3), 67.5 (d, J 1.5 Hz, CHOCH2Ph), 71.0 (CH2OR), 71.7 (d, J
23 Hz, CH2OBn), 73.4 (CH2OCH2Ph), 76.3 (CHOBn), 91.2 (d, J
172 Hz, CHF), 123.1 (q, J 289 Hz, CF3), 127.4, 127.6, 127.7, 127.8,
127.9, 128.1, 128.4, 128.5, 129.6 (CHarom), 129.7 (d, J 10.1 Hz,
4.22.4. (2R,3R,4E)-2,6-Bis(benzyloxy)-3-(trimethylsilyl)hex-4-
en-1-yl (2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
SiMe3
O
BnO
Ph
F3C OMe
O
OBn
Dr 97:3; Rf = 0.55 (hexane–EtOAc; 80:20); ½a D25
¼ þ24:3 (c 1.0,
ꢀ
CH2Cl2); mmax (CH2Cl2) 3065, 3032, 2952, 2851 (C–H), 1750

920
G. T. Giuffredi et al. / Tetrahedron: Asymmetry 20 (2009) 910–920
CHCHOBn), 130.0 (d, J 22 Hz, CHCHF) 132.1, 137.6, 137.9 (Carom),
166.4 (CO2); dF (376 MHz, CDCl3) ꢁ71.6 (96%, CF3), ꢁ71.6 (4%,
CF3), ꢁ184.2 (dtdd, J 48, 24.1, 14.7, 2.3 Hz, CHF); HRMS (ESI+)
program SIR92,19 which located all non-hydrogen atoms. Subse-
quent full-matrix least-squares refinement was carried out using
the CRYSTALS20 program suite to refine coordinates and aniso-
tropic thermal parameters of all non-hydrogen atoms (Figs. 2 and
3). Hydrogen atoms were located in the difference map and refined
before being added to the model using a riding constraint. Crystal-
lographic data (excluding structure factors) for all structures have
been deposited with the Cambridge Crystallographic Data Centre
(CCDC 721663–721665) and copies of these data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif.
C30H30F4O5 ([M+Na]+) requires 569.1922; found 569.1901.
þ
4.22.7. (2S,3E,5S)-2,6-Bis(benzyloxy)-5-fluorohex-3-en-1-yl
(2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
F
O
BnO
Ph
O
F3C OMe
OBn
Acknowledgements
Dr 96.5:3.5; Rf = 0.45 (hexane–EtOAc; 80:20); ½a D25
¼ þ12:9 (c
ꢀ
We thank the Berrow Foundation for a Scholarship to GTG, the
EPSRC, AstraZeneca as well as the European Community (MRTN-
CT-2003-505020) for generous financial support.
0.9, CH2Cl2); mmax (CH2Cl2) 3065, 3032, 2953, 2862 (C–H), 1751
(C@O), 1603 (C@C); dH (400 MHz, CDCl3) 3.52 (3H, d, J 1.0 Hz,
OCH3), 3.58 (2H, dd, J 23.8, 4.8 Hz, CH2OBn), 4.14–4.22 (1H, m,
CHOBn), 4.34 (1H, dd, J 11.4, 4.1 Hz, CHOCHAPh), 4.39 (1H, dd, J
11.4, 7.3 Hz, CHOCHBPh), 4.40 (1H, d, J 11.7 Hz, CHAOR), 4.57 (1H,
d, J 11.7 Hz, CHBOR), 4.58 (1H, d, J 12.1 Hz, CH2OCHAPh), 4.62
(1H, d, J 12.1 Hz, CH2OCHBPh), 5.11 (1H, ddt, J 48, 9.7, 4.7 Hz,
CHF), 5.77 (1H, dddd, J 15.8, 6.9, 2.3, 1.4 Hz, CHCHOBn), 5.90 (1H,
dddd, J 15.8, 14.6, 5.5, 0.8 Hz, CHCHF), 7.22–7.42 (13H, m, Harom),
7.54 (2H, d, J 7.4 Hz, Harom); dC (101 MHz, CDCl3) 55.5 (OCH3),
67.5 (CHOCH2Ph), 70.9 (CH2OR), 71.7 (d, J 23 Hz, CH2OBn), 73.5
(CH2OCH2Ph), 76.3 (CHOBn), 91.2 (d, J 174 Hz, CHF), 123.1 (q, J
289 Hz, CF3), 127.4, 127.6, 127.7, 127.8, 127.9, 128.4, 128.4,
128.5, (CHarom), 129.7 (d, J 10.5 Hz, CHCHOBn), 129.6 (CHarom),
130.1 (d, J 20 Hz, CHCHF) 132.1, 137.6, 137.6 (Carom), 166.4 (CO2);
dF (376 MHz, CDCl3) ꢁ71.6 (96%, CF3), ꢁ71.6 (4%, CF3), ꢁ184.3
References
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+
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(dtd,
J
48, 24.0, 14.8 Hz, CHF); HRMS (ESI+) C30H30F4O5
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4.23. Single-crystal X-ray diffraction, compounds 1, 11 and 12
Crystals of 2,6-di-O-benzyl-5-deoxy-5-fluoro- glucitol 10 were
grown by recrystallisation from EtOAc/hexane and a crystal having
dimensions approximately 0.13 ꢄ 0.18 ꢄ 0.45 nm was used.
1,5-Di-O-benzyl-2-deoxy-2-fluoro-6-O-(4-nitrobenzoyl)-glucitol
11 were grown by recrystallisation from EtOAc/hexane and a crys-
tal having dimensions approximately 0.16 ꢄ 0.32 ꢄ 0.35 nm was
used.
1,5-Di-O-benzyl-2-deoxy-2-fluoro-6-O-(4-nitrobenzoyl)-mannitol
12 were grown by recrystallisation from EtOAc/hexane and a crystal
having dimensions approximately 0.10 ꢄ 0.20 ꢄ 0.54 nm was used.
In all three cases, a typical single crystal was chosen and was
mounted on a hair using perfluoropolyether oil and cooled rapidly
to 150 K in a stream of cold N2 using an Oxford Cryosystems Cryo-
stream N2 open flow cooling device.17 Diffraction data were mea-
sured using an Enraf-Nonius KappaCCD diffractometer (graphite-
monochromated Mo Ka radiation, k = 0.71073 Å) to a maximum
resolution of 0.77 Å. Intensity data were processed using the DEN-
ZO-SMN package and were corrected for absorption and other ef-
fects using SCALEPACK.18
The systematic absences in the intensity data were examined to
determine the space group (P21/n for 10 and 12 and P21/c for 11).
In each case, the structure was solved using the direct-methods
19. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.;
Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435.
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