Oxetane cis- and trans-β-amino-acid scaffolds from l-rhamnose by efficient SN2 reactions in oxetane rings; Pseudoenantiomeric analogues of the antibiotic oxetin

Article abstract of DOI:10.1016/j.tetasy.2004.07.032

An efficient multigram ring contraction of a 1,4-lactone 2-O-triflate derived from l-rhamnose - with retention of configuration in the ring closure - is the key step in the preparation of a series of oxetanes, which are pseudoenantiomeric analogues of the

Full text of DOI:10.1016/j.tetasy.2004.07.032

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2681–2686
Oxetane cis- and trans-b-amino-acid scaffolds from L-rhamnose
by efficient SN2 reactions in oxetane rings;
pseudoenantiomeric analogues of the antibiotic oxetin
a
a
a
a
´
Stephen W. Johnson, Sarah F. Jenkinson (nee Barker), Donald Angus, John H. Jones,
George W. J. Fleeta,* and Claude Taillefumiera,b
aChemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
b
´ ´
Groupe Sucres, UMR 7565 CNRS-Universite Henri Poincare-Nancy I, BP 239, F-54506 Vandoeuvre, France
Received 23 June 2004; accepted 14 July 2004
Available online 24 August 2004
Abstract—An efficient multigram ring contraction of a 1,4-lactone 2-O-triflate derived from L-rhamnose––with retention of config-
uration in the ring closure––is the key step in the preparation of a series of oxetanes, which are pseudoenantiomeric analogues of the
naturally occurring antibiotic oxetin, an oxetane cis-b-amino acid. Subsequent nucleophilic displacements of the corresponding tri-
flates by azide proceed in consistently excellent yields, without any elimination, to provide syntheses of scaffolds for analogues of the
antibiotic.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
enantiomeric with oxetin and the analogues reported
in the preceding paper. Some of this work has been re-
ported in a preliminary form.4,5
Oxetin 1, a naturally occurring antibiotic,1 is a cis-b-
amino acid containing an oxetane ring; the preceding
paper2 reports the synthesis of a series of cis-2 and 3
and trans-4 analogues in which the absolute configura-
tion at C-2 of the oxetane ring is the same as that in oxe-
tin. Oligomers of the cis-amino acids 2 and 3 form a
unique right-handed 10-helix. This is in marked con-
trast to other helical structures derived from oligomers
of trans-cyclohexane, cyclopentane and pyrrolidine
b-amino acid scaffolds.3 Pseudoenantiomers of such
b-amino acid oxetane oligomers afford left-handed 10-
helical structures.
2. Results and discussion
The key steps in the synthesis of the required silyl- and
benzyl-protected azidoester scaffolds 5–7 are (i) the ring
contraction of a suitably protected rhamnose derivative
10 to the oxetane 11 and (ii) the subsequent nucleophilic
displacements of the C-3 oxygen function to introduce
the azido function with inversion or retention of config-
uration (Scheme 1).
Herein we report the synthesis of protected derivatives
of the cis- and trans-b-azido-oxetane-2-carboxylates 5–
7 from L-rhamnose 8 as scaffolds, which are pseudo-
The conversion of L-rhamnose 8 to benzylidene oxetane
11 was performed with minor modifications to the previ-
ously reported procedure6––but on a larger scale and in
OR
OBn
Me
HO
O
OH
OH
R
HOH2C
O
O
O
Me
O
Me
O
N3
N3
H2N
CO2H
N3
CO2Me
N3
CO2Me
CO2Me
CO2Me
OH
1
oxetin
2 R = CH2OH
3 R = Me
4
5
6 R = TBDMS
7 R = Bn
8 L-rhamnose
*
Corresponding author. E-mail: george.fleet@chem.ox.ac.uk
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.032

2682
S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 2681–2686
Me
O
Me
O
Me
O
OH
Me
HO
O
OH
OH
i
ii
iii
O
O
iv
O
O
O
O
Me
HO
O
O
O
Ph
Ph
Ph
CO2Me
CO2Me
v
OH
OH
OTf
10
8
9
11
12
vii
OBn
OBn
OTBDMDS
Me O
OBn
Bn
=
PhCH2
iii
vi
TBDMS = Me2tBuSi
Me
O
Me
TfO
O
Me
O
Tf
= CF3SO2
HO
HO
CO2Me
N3
CO2Me
CO2Me
CO2Me
7
16
15
13
iii
viii
ii
OBn
OBn
OBn
OTBDMDS
O
OTBDMDS
O
vi
vi
Me
O
Me
TfO
O
Me
O
Me
Me
N3
HO
N3
TfO
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
5
18
17
6
14
Scheme 1. Reagents and conditions: (i) Br2, BaCO3, H2O, 0ꢁC to rt; then PhCHO, concd HCl, rt (72% over two steps); (ii) Tf2O, pyridine, THF, ꢀ78
to 0ꢁC; (iii) K2CO3, MeOH, MeCN, ꢀ78 to ꢀ10ꢁC (89%); (iv) HCl, MeOH, rt (70%); (v) TBDMSCl, imidazole, DMF, 0ꢁC (31%); (vi) NaN3, DMF,
rt; (vii) Et3SiH, CF3CO2H, CH2Cl2, rt (82%); (viii) CsOCOCF3, MeCOEt, 70ꢁC (90%).
higher yield (60% overall yield on a 5g scale). In the case
of the L-rhamnose triflate 10, however, the triflate of the
c-lactone is cis to the C-3 substituent. Oxidation of L-
rhamnose 8 with bromine water buffered by barium car-
bonate gave a mixture of open chain acid and lactones;
removal of the solvent followed by treatment of the
crude residue with benzaldehyde in the presence of con-
centrated hydrochloride acid gave the benzylidene lac-
tone 9, easily purified by crystallisation, in 72% overall
yield. Esterification of 9 with trifluoromethanesulfonic
(triflic) anhydride afforded triflate 10 as a stable white
solid, readily prepared on a 15g scale. As illustrated in
the preceding paper,2 oxetanes can be readily formed
by the ring contraction of suitably protected a-triflates
of c-lactones with basic methanol in good yield, provid-
ing that the triflate is trans to the oxygen substituent at
C-3. The ring contraction of triflate 10 to oxetane 11
therefore required closure of the ring with overall reten-
tion of configuration during the nucleophilic displace-
ment; this probably involved epimerisation of an open
chain triflate ester. After careful optimisation of the
reaction conditions, treatment of 6.8g of 10 with potas-
sium carbonate in methanol/acetonitrile gave the 2,3-
trans-substituted oxetane 11 in 89% yield.
silyl and disilyl compounds, both in approximately
10% yield.7 No significant improvement in selectivity
was achieved on attempted optimisation of the reaction.
Activation towards nucleophilic substitution of the
3-OH in 13 with triflic anhydride and pyridine in dichlo-
romethane gave triflate 14 (76% yield), which on subse-
quent reaction with sodium azide in DMF afforded the
TBDMS protected azide 6 in 96% yield.
For the 5-O-benzyl protected scaffolds 5 and 7, reduc-
tion of acetal 11 with triethylsilane and trifluoroacetic
acid8 in dichloromethane gave highly regioselective ring
opening of the acetal with no reduction of the oxetane
ring, producing the 5-O-benzyl protected oxetane 15 in
82% yield. A series of efficient SN2 displacements of
the activated 3-hydroxyl group in 15 gave access to the
cis and trans benzyl-protected b-azido oxetane carboxyl-
ates. Reaction of 15 with triflic anhydride gave the cor-
responding triflate 16 in 96% yield. Treatment of triflate
16 with sodium azide in DMF gave the 2,3-cis azido
ester 7 (97% yield), whereas reaction of 16 with caesium
trifluoroacetate gave the altrono-alcohol 17 in 90% yield.
Subsequent esterification of 17 with triflic anhydride
gave triflate 18 in 99% yield, which upon treatment with
sodium azide gave the 2,3-trans azido ester 5 in 87%
yield (74% over four steps from 15). This is a notewor-
thy set of efficient SN2 displacements in oxetane rings
with no sign of any competing elimination reactions.
Structural studies on oligomers of the scaffolds required
the use of a protecting group with no chromophores so
that the tert-butyldimethyl silyl (TBDMS) scaffold 6 was
chosen as the initial target. Treatment of benzylidene
acetal 11 with hydrogen chloride in methanol afforded
diol 12 (70% yield). Attempts to discriminate between
the two secondary hydroxyl group in the diol 12 with
TBDMS chloride and imidazole in DMF at 0ꢁC were
unsuccessful. The desired 5-O-silyl ether 13 was formed
in only 30% yield, along with the corresponding 3-O-
3. Conclusions
Herein we have reported the synthesis of oxetane cis-
and trans-b-azidoesters with silyl and benzyl protection,
which are peptidomimetics likely to provide access to

S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 2681–2686
2683
homooligomers with novel secondary structure; these
materials are pseudoenantiomeric with the amino acids
formed from D-xylose in the preceding paper.2 The syn-
thesis of oligomers from both series, together with de-
tailed structural studies by NMR, infrared and circular
dichroism will be reported in due course.
Leu-enkephalin as the internal lock mass. Optical rota-
tions were recorded on a Perkin–Elmer 241 polarimeter
with a path length of 1dm. Concentrations are quoted in
g/100mL.
4.1. 3,5-(R)-O-Benzylidene-L-rhamnono-1,4-lactone 9
Barium carbonate (104.4g, 1.5equiv) was added to a
stirred solution of L-rhamnose monohydrate 8 (48.45g,
266mmol) in water (360mL) at 0ꢁC. Bromine
(20.4mL, 1.5equiv) was added to the reaction mixture
in four portions (4 · 5.1mL) at 15min intervals. The
reaction mixture was stirred at 0ꢁC for 2h, and then al-
lowed to warm to room temperature and stirred over-
night. TLC (EtOAc/MeOH 9:1) revealed that the
starting material (Rf 0.23) had been completely con-
sumed, and been replaced by major (Rf 0.36) and minor
(Rf 0.46) products. The reaction mixture was then fil-
tered through celiteꢃ. Nitrogen was passed through
the filtrate until the solution was decolourised; the sol-
vent was removed to yield the crude product (170.2g).
The crude solid (164.3g) was suspended in benzaldehyde
(475mL), and concentrated hydrochloric acid (142mL)
added; the mixture was stirred at room temperature to
afford after 2days a major product (EtOAc/hexane,
2:1, Rf 0.27). The reaction mixture was filtered and
approximately half the solvent removed; diethyl ether
was added until the product crystallised out. The solid
was then filtered and washed with Et2O. The washings
were re-concentrated, and more material was crystal-
lised out to give, after three re-crystallisations, the benz-
ylidene lactone 9 (45.8g, 72%), with physical properties
4. Experimental
Tetrahydrofuran was distilled under an atmosphere of
dry nitrogen from sodium benzophenone ketyl or pur-
chased dry from the Aldrich Chemical Company in
Sure/Sealꢂ bottles; dichloromethane was distilled from
calcium hydride; pyridine was distilled from calcium hy-
˚
dride and stored over dried 3A molecular sieves; hexane
refers to 60–80ꢁC petroleum ether; water was distilled.
N,N-Dimethylformamide (DMF) was purchased dry
from the Aldrich Chemical Company in Sure/Sealꢂ bot-
tles. All other solvents were used as supplied (analytical
or HPLC grade) without prior purification. Reactions
performed under an atmosphere of nitrogen or hydro-
gen gas were maintained by an inflated balloon. Imidaz-
ole was recrystallised from dichloromethane. All other
reagents were used as supplied, without prior purifica-
tion. Thin layer chromatography (TLC) was performed
on aluminium sheets coated with 60 F254 silica. Sheets
were visualised using a spray of 0.2% w/v cerium(IV)
sulfate and 5% ammonium molybdate in 2M sulfuric
acid. Flash column chromatography was performed on
Sorbsil C60 40/60 silica. Melting points were recorded
on a Ko¨fler hot block and are uncorrected. Nuclear
magnetic resonance (NMR) spectra were recorded on
a Bruker AM 500 or AMX 500 (1H: 500MHz and
13C: 125.3MHz) or where stated on a Bruker AC 200
(1H: 200MHz and 13C: 50.3MHz) or Bruker DPX 400
(1H: 400MHz and 13C: 100.6MHz) spectrometer in deu-
terated solvent. Chemical shifts (d) are quoted in parts
per million and coupling constants (J) in hertz. Residual
signals from the solvents were used as internal refer-
ences. 13C multiplicities were assigned using a DEPT
sequence. Infrared spectra were recorded on a Perkin–
Elmer 1750 IR Fourier Transform, or Perkin–Elmer
Paragon 1000 spectrophotometer using thin films on
NaCl plates (thin film). Only the characteristic peaks
are quoted. Low resolution mass spectra (m/z) were re-
corded using the following techniques: electrospray ion-
isation (ES), chemical ionisation (CI, NH3) or
atmospheric pressure chemical ionisation (APCI). ES
mass spectra were measured on a Micromass BioQ II-
ZS mass spectrometer. CI mass spectra were recorded
on a Micromass 500 OATspectrometer. APCI mass
spectra were recorded on a Micromass Platform 1 mass
spectrometer via an ÔOpenlynxÕ system. High resolution
mass spectra (HRMS) were recorded on a Micromass
500 OATspectrometer by chemical ionisation (CI,
NH3) or a Waters 2790-Micromass LCTmass spectro-
meter by electrospray ionisation (ES) as stated. For ES
mass spectra the spectrometer was operated at a resolu-
tion of 5000 full width half height. Positive ion spectra
were calibrated relative to PEG with tetraoctylammo-
nium bromide as the internal lock mass. Negative ion
spectra were calibrated relative to poly-DL-alanine with
identical to those previously described,6 mp 175–177ꢁC;
22
½aŠ ¼ ꢀ48:7 (c 0.99 in MeCN).
D
4.2. 3,5-(R)-O-Benzylidene-2-O-trifluoromethanesulfonyl-
L-rhamnono-1,4-lactone 10
Pyridine (17.46mL, 5equiv) was added to a solution of
benzylidene lactone 9 (10.52g, 42mmol) in THF
(220mL) under nitrogen at ꢀ78ꢁC. Trifluoromethane-
sulfonic (triflic) anhydride (14.63mL, 2equiv) was added
dropwise. The reaction mixture was stirred at ꢀ78ꢁC for
a further 20min, and then allowed to warm to 0ꢁC. After
1.5h, TLC (EtOAc/hexane, 2:1) revealed that the starting
material (Rf 0.21) had been completely replaced by one
product (Rf 0.55). The reaction mixture was then diluted
with dichloromethane (400mL), washed with aqueous
hydrochloric acid (0.1M, 200mL) and water (200mL).
The organic extract was dried over magnesium sulfate
and the solvent removed. The crude product was purified
by flash chromatography (EtOAc/hexane, 1:1) to give tri-
flate 10 (14.78g, 92%) as a white solid, with physical
properties identical to those previously described.6 Mp
22
D
139–140ꢁC; ½aŠ ¼ ꢀ63:9 (c 0.98 in MeCN).
4.3. Methyl 2,4-anhydro-3,5-(R)-O-benzylidene-L-rhamno-
nate 11
A solution of triflate 10 (6.79g, 17.8mmol) in acetonit-
rile (25mL) was added to potassium carbonate (4.97g,
2equiv) in methanol (140mL) and stirred at ꢀ78ꢁC
under nitrogen. The reaction mixture was then stirred

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S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 2681–2686
for 10min, at which point it was warmed to ꢀ30ꢁC, then
allowed to warm slowly to ꢀ10ꢁC over the following
30min. The reaction mixture was then diluted with
dichloromethane (340mL). The starting material 10
and the product 11 were indistinguishable by TLC
(EtOAc/hexane, 1:1, Rf 0.48). The reaction mixture
was washed with water (2 · 170mL), the aqueous
fractions combined and then extracted with dichloro-
methane (170mL). The organic fractions were com-
bined, dried over magnesium sulfate and the solvent
removed to give benzylidene oxetane 11 (4.20g, 89%
yield), mp 126–127ꢁC [Lit.6 Mp 115–116ꢁC];
and pyridine (153lL, 1.89mmol) in dichloromethane
(5mL) at ꢀ78ꢁC under nitrogen. The reaction mixture
was stirred at ꢀ78ꢁC for 20min, and then at 0ꢁC for
1h after which time TLC showed the formation of one
major product (Rf 0.64, EtOAc/hexane, 1:3). The reac-
tion mixture was then diluted with dichloromethane
(30mL), washed with water (5mL), dried over MgSO4
and the organic layer evaporated to dryness. Column
chromatography (EtOAc/hexane, 1:5) afforded triflate
22
D
14 as a clear oil (122mg, 76%). ½aŠ ¼ þ17:7 (c 1.13 in
CHCl3); mmax (thin film): 1754 (C@O); dH (200MHz,
CDCl3): 0.16 (s, 6H, Si(CH3)2), 0.96 (s, 9H, SiC(CH3)3),
1.28 (d, 3H, J6,5 6.4Hz, H-6), 3.90 (s, 3H, CO2Me),
4.26–4.32 (m, 1H, H-5), 4.66 (ddd, 1H, J4,5 7.8, J4,3
6.9, J4,2 1.0Hz, H-4), 5.16 (dd, 1H, J2,3 4.6, J2,4 1.0Hz,
H-2), 5.72 (dd, 1H, J3,4 6.9, J3,2 4.6Hz, H-3); dC
(50.3MHz, CDCl3): ꢀ5.5, ꢀ4.8 (Si(CH3)2), 17.2
(SiC(CH3)3), 17.7 (C-6), 25.0 (SiC(CH3)3), 52.1
(CO2CH3), 66.3 (C-5), 78.1, 80.7 (C-2/C-3), 85.3 (C-4),
114.5, 120.9 (J 322Hz, SO2CF3), 167.6 (C@O); m/z
(CI+): 445 [M+Na+] (35%), 194 (100).
23
23
½aŠ ¼ þ3:0 (c 1.01 in CHCl3) {Lit.6 ½aŠ ¼ þ3:0 (c
D
1.01 in CHCl3)}.
D
4.4. Methyl 2,4-anhydro-L-rhamnonate 12
Benzylidene acetal 11 (500mg, 1.89mmol) was added in
one portion to a mixture of acetyl chloride (80lL) and
methanol (8mL). After 10min, TLC (EtOAc/hex, 1:1)
showed the consumption of the starting material (Rf
0.47) and the appearance of a single spot (Rf 0.09).
The mixture was then neutralised with sodium bicarbo-
nate, filtered and evaporated to dryness. Column chro-
matography (acetone/hexane, 1:2 ! 1:1) afforded diol
12 as a clear oil, which solidified upon standing and
4.7. Methyl 2,4-anhydro-3-azido-5-O-tert-butyldimethyl-
silyl-3,6-dideoxy-L-altronate 6
Sodium azide (120mg, 1.84mmol) was added in one
portion to a stirred solution of triflate 14 (600mg,
1.42mmol) in DMF (6mL) at room temperature under
an inert atmosphere. After 4h no starting material re-
mained and a single product (Rf 0.40, acetone/hexane,
1:5) had formed. The solvent was removed and the resi-
due dissolved in ethyl acetate (60mL); the reaction mix-
ture was washed with water (15mL) and dried over
magnesium sulfate. Column chromatography (EtOAc/
hexane, 1:5) of the crude product afforded cis-azide 6
as a clear oil (430mg, 96%). Found C, 49.33, H, 7.99,
had identical physical properties to those previously
22
D
described.6 Mp 52–54ꢁC; ½aŠ ¼ þ84:6 (c 0.94 in
CHCl3).
4.5. Methyl 2,4-anhydro-5-O-tert-butyldimethylsilyl-L-
rhamnonate 13
tert-Butyldimethylsilyl chloride (171mg, 1.35mmol) was
added to a solution of the diol 12 (200mg, 1.13mmol)
and imidazole (81mg, 1.19mmol) in DMF (10mL) at
0ꢁC under an inert atmosphere. After 2h TLC indicated
the presence of a major compound (Rf 0.38, EtOAc/hex-
ane, 1:3). The reaction mixture was diluted with EtOAc
(30mL), washed with H2O (10mL), dried over MgSO4
and the solvent removed under reduced pressure. Col-
umn chromatography (EtOAc/hexane, 1:3) afforded silyl
ether 13 as a clear oil, which solidified upon standing
(102mg, 31%). Found: C, 53.73, H, 9.05; C13H26-
N, 13.29; C13H25N3O4Si requires: C, 49.50, H, 7.99, N,
22
D
13.32; ½aŠ ¼ ꢀ69:5 (c 0.8 in CHCl3); mmax (thin film):
2111 (N3), 1761 (C@O); dH (200MHz, CDCl3): 0.12 (s,
6H, Si(CH3)2), 0.97 (s, 9H, SiC(CH3)3), 1.13 (d, 3H,
J6,5 6.5Hz, H-6), 3.85 (s, 3H, CO2Me), 3.97 (qd, 1H,
J5,6 6.5, J5,4 2.7Hz, H-5), 4.46 (ddd, 1H, J4,3 5.1, J4,5
2.7, J4,2 0.4Hz, H-4), 4.82 (dd, 1H, J3,2 7.8, J3,4 5.1Hz,
H-3), 5.03 (d, 1H, J2,3 7.8Hz, H-2); dC (50.3MHz,
CDCl3): ꢀ3.9 (Si(CH3)2), 18.0 (C-6, SiC(CH3)3), 25.7
(SiC(CH3)3), 52.2 (CO2CH3), 55.3 (C-3), 67.3 (C-5),
79.1 (C-4), 90.3 (C-2), 169.6 (C@O).
O5Si requires: C, 53.76, H, 9.02; mp 49–51ꢁC;
22
½aŠ ¼ þ0:65 (c 0.8 in CHCl3); mmax (thin film) 3461
D
(OH), 1756 (C@O); dH (200MHz, CDCl3): 0.22 (2 · s,
6H, Si(CH3)2), 1.02 (s, 9H, SiC(CH3)3), 1.32 (d, 3H,
J6,5 6.8Hz, H-6), 3.86 (s, 3H, CO2Me), 4.26 (ddd, 1H,
J5,6 = J5,4 6.8, J5,3 1.8Hz, H-5), 4.62 (ddd, 1H, J4,5 6.8,
J4,3 1.8 J4,2 0.6Hz, H-4), 4.79 (sept, 1H, J3,OH 11.8,
J3,2 5.0, J3,4 1.8Hz, H-3), 4.98 (dd, 1H, J2,3 5.0, J2,4
0.6Hz, H-2), 5.10 (d, 1H, JOH,3 11.8Hz, 3-OH); dC
(50.3MHz, CDCl3): ꢀ4.5 (Si(CH3)2), 18.3 (C-6), 19.1
(SiC(CH3)3), 26.3 (SiC(CH3)3), 52.7 (CO2CH3), 72.5,
72.8 (C-3/5), 87.2 (C-2), 87.6 (C-4), 171.5 (C@O); m/z
(CI+): 313 [M+Na] (35%), 291 [M+H] (30), 158 (100).
4.8. Methyl 2,4-anhydro-5-O-benzyl-L-rhamnonate 15
A solution of benzylidene oxetane 11 (0.946g, 3.58
mmol) and triethylsilane (2.80mL, 17.9mmol) in dry
dichloromethane (16mL) was stirred under nitrogen at
room temperature. Trifluoroacetic acid (1.37mL,
17.9mmol) was added dropwise over 5min. After
105min, TLC (EtOAc/hexane, 1:1) indicated the forma-
tion of a major product (Rf 0.35). Ethyl acetate (80mL)
was added to the reaction mixture, which was then
washed with saturated sodium bicarbonate (30mL)
and then brine (30mL). The organic fraction was dried
over magnesium sulfate, filtered and the solvent
removed. The crude material was purified by flash
chromatography (EtOAc/hexane, 2:3) to give benzyl
4.6. Methyl 2,4-anhydro-5-O-tert-butyldimethylsilyl-3-O-
trifluoromethanesulfonyl-L-rhamnonate 14
Triflic anhydride (127lL, 0.757mmol) was added drop-
wise to a solution of silyl ether 13 (110mg, 0.378mmol)

S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 2681–2686
2685
22
D
ether 15 (0.784g, 82% yield) as a white crystalline solid.
Found C, 63.07; H, 6.82; C14H18O5 requires C,
63.15; H, 6.81%; HRMS m/z (CI+) Found
97%) as a clear oil. ½aŠ ¼ ꢀ106:3 (c 1.4 in CHCl3);
Found C, 57.82; H, 5.89; N, 14.47; C14H17N3O4 requires
C, 57.72; H, 5.88; N, 14.42; mmax (thin film) 2116 (N3),
1760 (C@O ester) cmꢀ1; dH (CDCl3, 400MHz) 1.14 (d,
3H, J5,6 6.6Hz, H-6), 3.80 (dq, 1H, J5,6 6.6, J4,5
3.7Hz, H-5), 3.87 (s, 3H, CO2CH3), 4.59 (ddd, 1H,
J2,4 0.6, J3,4 5.4, J4.5 3.7Hz, H-4), 4.68 (d, 1H, Jgem
11.5Hz, CHHPh), 4.72 (d, 1H, Jgem 11.5Hz, CHHPh),
4.84 (dd, 1H, J2.3 7.3, J3.4 5.4Hz, H-3), 5.14 (br d, 1H,
J2,3 7.3, H-2), 7.27–7.38 (m, 5H, PhH); dC (CDCl3,
100.6MHz) 14.8 (C-6), 52.3 (CO2CH3), 56.2 (C-3),
72.2 (CH2Ph), 73.6 (C-5), 79.2 (C-2), 92.3 (C-4), 127.6,
127.7, 127.8, 128.4 (5C, Ph), 138.3 (Cipso), 169.5 (C-1);
m/z (APCI+) 264 (M+H+ꢀN2, 95%), 206 (90), 157
(50), 121 (100).
284.1492 (M þ NHþ4 ). C14H22NO5 requires 284.1497;
23
mp 40–42ꢁC; ½aŠ ¼ þ69:7 (c 1.1 in CHCl3); mmax (NaCl)
D
3462cmꢀ1 (OH) 2953cmꢀ1 (C-H), 1752cmꢀ1 (C@O); dH
(CDCl3, 200MHz) 1.30 (d, 3H, H-6, J5,6 = 6.9Hz), 3.81
(s, 3H, –CO2Me), 4.12 (dq, 1H, H-5, J4,5 = 2.3Hz,
J5,6 = 6.9Hz), 4.64 (d, 1H, –OH, J3,OH = 11.7Hz),
4.67–4.90 (m, 4H, H-3, H-4, –CH2Ph), 5.09 (dd, 1H,
H-2, J2,3 = 5.4Hz, J2,4 = 0.7Hz), 7.32–7.42 (m, 5H,
Ph); dC (CDCl3, 50.3MHz) 15.2 (C-6), 52.2 (–CO2CH3),
71.7 (C-3), 72.8 (–CH2Ph), 77.8 (C-5), 87.0 (C-2), 87.3
(C-4), 127.8–128.6 (Ph), 137.5 (Cipso), 170.9 (C-1).
4.9. Methyl 2,4-anhydro-5-O-benzyl-3-O-trifluoro-
methanesulfonyl-L-rhamnonate 16
4.11. Methyl 2,4-anhydro-6-deoxy-5-O-benzyl-L-altro-
nate 17
Triflic anhydride (2.28mL, 13.51mmol) was added
dropwise to a solution of alcohol 15 (2.00g, 7.51mmol)
and pyridine (3.06mL, 37.55mmol) in dichloromethane
(75mL) at ꢀ78ꢁC under an atmosphere of argon. The
reaction mixture was stirred for 30min at ꢀ78ꢁC after
which time the bath at ꢀ78ꢁC was changed for a bath
at ꢀ30ꢁC. The temperature was then allowed to warm
up to ꢀ10ꢁC taking 1.5h. TLC (EtOAc/hexane, 3:7) re-
vealed a single product (Rf 0.60) and no residual starting
material (Rf 0.21). The reaction mixture was diluted with
dichloromethane (300mL) and washed with aqueous
hydrochloric acid (0.1M) and water. The organic layer
was dried over MgSO4 and the solvent removed in
vacuo. The residue was purified by flash chromatography
(EtOAc/hexane, 1:4) to give triflate 16 as an oil (2.88g,
96%). Found C, 45.48; H, 4.28; C15H17F3O7S requires
C, 45.23; H, 4.30%; HRMS m/z (CI+) Found 416.0990
Caesium trifluoroacetate (6.90g, 28.08mmol) was added
to a solution of triflate 16 (2.80g, 7.02mmol) in buta-
none (70mL) under an atmosphere of argon. The reac-
tion mixture was heated at 70ꢁC for 15h after which
TLC (EtOAc/hexane, 3:7) indicated that the starting
material (Rf 0.60) had been replaced by a major product
(Rf 0.11). The solvent was removed and the residue puri-
fied by flash chromatography (EtOAc/hexane,
1:2 ! 1:1) to yield the inverted alcohol 17 as a white
22
D
solid (1.68g, 90%). Mp 93–94ꢁC; ½aŠ ¼ þ30:5 (c 0.5 in
CHCl3); Found C, 62.94; H, 6.78; C14H18O5 requires
C, 63.15; H, 6.81; mmax (KBr plate) 3454 (OH), 1732
(C@O ester) cmꢀ1; dH (CDCl3, 400MHz) 1.15 (d, 3H,
J5,6 6.6Hz, H-6), 3.78 (dq, 1H, J5,6 6.6, J4,5 3.6Hz, H-
5), 3.83 (s, 3H, CO2CH3), 4.66 (m, 1H, H-4), 4.68 (s,
2H, CH2Ph), 4.95 (br dd, 1H, J2.3 7.2, J3.4 5.0Hz, H-
3), 5.07 (br d, 1H, J2,3 7.2, H-2), 7.25–7.38 (m, 5H,
PhH); dC (CDCl3, 100.6MHz) 14.8 (C-6), 52.2
(CO2CH3), 67.0 (C-3), 72.1 (CH2Ph), 73.9 (C-5), 81.9
(C-2), 93.4 (C-4), 127.5, 127.6, 128.3 (5C, Ph), 138.5
(Cipso), 170.7 (C-1); m/z (APCI+) 284 (M þ NHþ4 ,
10%), 267 (M+H+, 65), 121 (100).
(M þ NHþ4 ),
C15H21NO7F3S
requires
416.0990;
22
D
½aŠ ¼ þ13:4 (c 1.1 in CHCl3); mmax (thin film) 1760
(C@O ester) cmꢀ1; dH (CDCl3, 400MHz) 1.31 (d, 3H,
J5,6 6.1Hz, H-6), 3.86 (s, 3H, CO2CH3), 4.15 (dq, 1H,
J5,6 6.1, J4,5 8.6Hz, H-5), 4.56 (d, 1H, Jgem 11.0Hz,
CHHPh), 4.63 (d, 1H, Jgem 11.0Hz, CHHPh), 4.75
(ddd, 1H, J2,4 1.1, J3,4 6.3, J4.5 8.6Hz, H-4), 5.16 (dd,
1H, J2.3 4.5, J2.4 1.1Hz, H-2), 5.72 (dd, 1H, J2,3 4.5,
J3,4 6.3Hz, H-3), 7.28–7.39 (m, 5H, PhH); dC (CDCl3,
100.6MHz) 14.6 (C-6), 53.0 (CO2CH3), 70.7 (C-5),
72.0 (CH2Ph), 79.3 (C-3), 81.1 (C-2), 84.3 (C-4), 118.3
(q, J13C,19F sHz, CF3), 127.7, 127.9, 128.3 (5C, Ph),
137.6 (Cipso), 168.1 (C-1); m/z (CI+) 416 (M þ NHþ4 ,
100%).
4.12. Methyl 2,4-anhydro-5-O-benzyl-6-deoxy-3-O-tri-
fluoromethanesulfonyl-L-altronate 18
Triflic anhydride (1.36mL, 8.09mmol) was added drop-
wise to a solution of alcohol 17 (1.19g, 4.49mmol) and
pyridine (1.83mL, 22.45 mmol) in dichloromethane
(30mL) at ꢀ45ꢁC under an atmosphere of argon. The
temperature was then allowed to warm up to ꢀ10ꢁC
over 2h. A single product (Rf 0.65, EtOAc/hexane,
3:7) was formed and all the starting material (Rf 0.11)
had been consumed. The reaction mixture was diluted
with dichloromethane (200mL) and washed with aque-
ous hydrochloric acid (0.1M) and water. The organic
layer was dried over MgSO4 and concentrated in vacuo.
The residue was purified by flash chromatography
4.10. Methyl 2,4-anhydro-3-azido-3,6-dideoxy-5-O-benz-
yl-L-altronate 7
Sodium azide (104mg, 1.59mmol) was added in one
portion to a solution of L-rhamnono triflate 16
(394mg, 0.99mmol) in dimethylformamide (5mL) under
an atmosphere of argon when the starting material (Rf
0.60, EtOAc/hexane, 3:7) had been completely replaced
by a new product (Rf 0.58). The solvent was removed
in vacuo, the residue dissolved in ethyl acetate, washed
with water and brine and then dried over MgSO4. After
removal of the solvent, the residue was purified by flash
chromatography (EtOAc/hexane 1:4) to give 7 (280mg,
(EtOAc/hexane, 1:9) to yield triflate 18 as an oil
22
(1.78g, 99%). ½aŠ ¼ ꢀ33:2 (c, 0.9 in CHCl3); HRMS
D
m/z (CI+) Found 416.0989 (M þ NHþ4 ), C15H21NO7F3S
requires 416.0990; mmax (thin film) 1766 (C@O ester)
cmꢀ1; dH (CDCl3, 500MHz) 1.23 (d, 3H, J5,6 6.7Hz,
H-6), 3.91 (dq, 1H, J5,6 6.7, J4,5 2.9Hz, H-5), 3.94 (s,

2686
S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 2681–2686
3H, CO2CH3), 4.75 (d, 1H, Jgem 11.5Hz, CHHPh), 4.80
(d, 1H, Jgem 11.5Hz, CHHPh), 4.96 (ddd, 1H, J2,4 1.2,
J3,4 4.5, J4.5 2.9Hz, H-4), 5.32 (dd, 1H, J2.3 6.7, J2.4
1.2Hz, H-2), 5.92 (dd, 1H, J2,3 6.7, J3,4 4.5Hz, H-3),
7.36–7.47 (m, 5H, PhH); dC (CDCl3, 100.6MHz) 14.4
(C-6), 52.7 (CO2CH3), 72.4 (CH2Ph), 73.1 (C-5), 77.1
(C-3), 78.8 (C-2), 90.0 (C-4), 118.2 (q, J13C,19F 320Hz,
CF3), 127.6, 127.8, 128.4 (5C, Ph), 137.9 (Cipso), 167.4
(C-1); m/z (CI+) 416 (M þ NHþ4 , 100%).
5), 4.56 (d, 1H, Jgem 10.9Hz, CHHPh), 4.61 (dd, 1H,
J3,4 6.8, J4.5 8.3Hz, H-4), 4.67 (d, 1H, Jgem 11.0Hz,
CHHPh), 4.73 (dd, 1H, J2.3 5.6, J3.4 6.8Hz, H-3), 4.85
(d, 1H, J2,3 5.6Hz, H-2), 7.28–7.40 (m, 5H, PhH); dC
(CDCl3, 50.3MHz) 15.3 (C-6), 53.2 (CO2CH3), 59.7
(C-3), 71.5 (CH2Ph), 73.7 (C-5), 81.5 (C-2), 85.2 (C-4),
128.3, 128.6, 128.9 (5C, Ph), 138.4 (Cipso), 170.7 (C-1);
m/z (APCI+) 265 (17%), 264 (M+H+ꢀN2, 100), 220
(17), 158 (80).
4.13. Methyl 2,4-anhydro-3-azido-3-deoxy-5-O-benzyl-L-
rhamnonate 5
References
1. Omura, S.; Murata, M.; Imamura, N.; Iwai, Y.; Tanaka,
H.; Furusaki, A.; Matsumoto, T. J. Antibiot. 1984, 37,
1324–1332.
2. Jenkinson, S. F.; Harris, T.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2004, 15, preceding paper. doi:10.1016/
j.tetasy.2004.07.031.
3. Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev.
2001, 101, 3219–3232.
4. Barker, S. F.; Angus, D.; Taillefumier, C.; Probert, M. R.;
Watkin, D. J.; Watterson, M. P.; Claridge, T. D. W.;
Hungerford, N. L.; Fleet, G. W. J. Tetrahedron Lett. 2001,
42, 4247–4250.
5. Claridge, T. D. W.; Goodman, J. M.; Moreno, A.; Angus,
D.; Barker, S. F.; Taillefumier, C.; Watterson, M. P.; Fleet,
G. W. J. Tetrahedron Lett. 2001, 42, 4251–4254.
6. Johnson, S. W.; Angus, D.; Taillefumier, C.; Jones, J. H.;
Watkin, D. J.; Floyd, E.; Buchanan, J. G.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 4113–4125.
7. Further studies on the silylation of 11 will be reported in
due course in a study of d-azido esters.
Sodium azide (421mg, 6.47mmol) was added in one
portion to a solution of altrono-triflate 18 (1.72g,
4.32mmol) in dimethylformamide (20mL) under an
atmosphere of argon. The reaction mixture was stirred
for 14h at room temperature when a single product
(Rf 0.54, EtOAc/hexane 3:7) and no residual starting
material (Rf 0.65) remained. The solvent was removed
in vacuo. The residue was dissolved in ethyl acetate
and the organic layer washed with water, brine and
dried over MgSO4. After evaporation of the solvent,
the residue was purified by flash chromatography
(EtOAc/hexane 1:9 ! 1:4) to give trans-azide 5 (1.10g,
22
D
87%) as an oil. ½aŠ ¼ ꢀ30:0 (c 1.0 in CHCl3) [Found
C, 57.87; H, 5.90; N, 14.44; C14H17N3O4 requires C,
57.72; H, 5.88; N, 14.42]; HRMS m/z (ESI+) Found
314.1109 (M+Na+), C14H17N3O4Na requires 314.1117;
mmax (thin film) 2117 (N3), 1758 (C@O ester) cmꢀ1; dH
(CDCl3, 500MHz) 1.28 (d, 3H, J5,6 5.8Hz, H-6), 3.85
(s, 3H, CO2CH3), 4.10 (dq, 1H, J5,6 5.8, J4,5 8.3Hz, H-
8. DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C.
Tetrahedron Lett. 1995, 36(5), 669–672.