Pseudoenantiomeric oxetane δ-amino acid scaffolds derived from L-rhamnose and D-xylose: D/L-alanine-D-serine and glycine-L-serine dipeptide isosteres

Article abstract of DOI:10.1016/j.tetasy.2004.08.023

A series of oxetane δ-amino acid scaffolds derived from L-rhamnose and D-xylose provide a new class of templated sugar amino acids (SAA), which can be considered as D/L-alanine-D-serine and glycine-L-serine dipeptide isosteres.

Full text of DOI:10.1016/j.tetasy.2004.08.023

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3263–3273
Pseudoenantiomeric oxetane d-amino acid scaffolds derived
from L-rhamnose and D-xylose: D/L-alanine-D-serine
and glycine-L-serine dipeptide isosteres
´
Stephen W. Johnson, Sarah. F. Jenkinson (nee Barker), Donald Angus,
John H. Jones, David J. Watkin and George W. J. Fleet*
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Received 26 July 2004; accepted 20 August 2004
Available online 1 October 2004
Abstract—A series of oxetane d-amino acid scaffolds derived from L-rhamnose and D-xylose provide a new class of templated sugar
amino acids (SAA), which can be considered as D/L-alanine-D-serine and glycine-L-serine dipeptide isosteres.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1.Introduction
pyl esters 3 allowing access to amines 6 as stable syn-
thetic intermediates.
The preparations of the diastereomers of 1 from L-rham-
nose and of the pseudoenantiomeric esters 2 and 3 from
D-xylose provide oxetane d-amino acid scaffolds suitable
for incorporation as peptidomimetics. On hydrogena-
tion, methyl esters 1 form amines 4 (in which the pri-
mary amine is attached to a secondary carbon), which
are stable enough to use as building blocks. However,
the corresponding methyl esters 2 give amines 5, which
tend to oligomerise. For the use of these building blocks,
it is therefore necessary to use the more hindered isopro-
Sugar amino acids (SAAs) constitute an important class
of peptidomimetics in both their potential as library
building blocks1 and their innate predisposition to in-
duce novel secondary structures.2 In particular, it is well
established that d-SAAs can act as conformationally
restricted dipeptide isosteres. Saturated 73 and unsatu-
rated 84 pyranose and furanose 95 SAA scaffolds have
been extensively studied but there are no previous re-
ports of the corresponding oxetanose derivatives 10.
Me
O
O
O
OH
OH
Me
HO
O
OH
OH
O
O
N3
OR
N3
OMe
HO
HO
HO
OH
OH
2 R = Me
1
L-rhamnose
D-xylose
3 R = CHMe2
(i)
(i)
(i)
(i) Pd, H2
Me
O
O
O
O
O
O
H2N
OMe
H2N
OMe
H2N
OCHMe2
HO
HO
5 in situ oligomerisation
HO
6 stable
4 stable
*
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.2004.08.023

3264
S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 3263–3273
O
O
O
O
O
R
O
O
O
O
H
N
N
H
N
H
N
H
N
H
N
H
RO
OR
RO
RO
OR
OR
O
R
OR
OR
dipeptide
9
7
10
8
L-Rhamnose may be efficiently converted into the benz-
ylidene acetal 12,6,7 a key intermediate for the prepara-
tion of a series of oxetane b-amino acids (Scheme 1).8
Introduction of an azide functionality with retention
of configuration at C-5 of 12 provided scaffolds 11 and
14, both of which may be viewed as conformationally
restricted mimetics of L-alanine-D-serine; in contrast,
when the nitrogen function was introduced with an
inversion of configuration in 12, the D-alanine-D-serine
scaffolds 13 and 15 were accessible.
oxetane as an acetal. All efficient ring contractions of
sugar triflates a- to the lactone carbonyl result in the
C-2 carboxylate being trans to the C-3 oxygen.6 In the
case of d-amino acids containing a THF ring, secondary
structural features are usually established in short
homooligomers from 2,5-cis substituted THF SAAs;11
in contrast there is only one case where a 2,5-trans sub-
stituted THF SAA gives rise to a helical structure.12
A
different [and more lengthy] protecting group strategy
to that used in the present work is required for the syn-
thesis of cis-2,4-disubstituted oxetanes.
The approach to the pseudoenantiomeric scaffolds for
Gly-L-Ser 17 and 18 relied on a short and efficient syn-
thesis of the benzylidene oxetane 16 from D-xylose,9,10
which may be further elaborated to the target building
blocks (Scheme 2).
2.Results and discussion
2.1. Synthesis of D/L-Ala-D-Ser oxetane dipeptide iso-
steres from L-rhamnose
The synthetic strategy described herein of using acetal
protection, limits the targets to oxetane scaffolds, which
have the C-2 and C-4 carbon substituents trans to each
other. This is the consequence of the shortest sequences
for the synthesis of oxetane carboxylates from sugar lac-
tones requiring a cis relationship between the efficient
protection of C-3 and C-5 OH groups of the incipient
For the preparation of D-Ala-D-Ser scaffolds, it is neces-
sary to introduce a nitrogen function at C-5 of L-rham-
nose with a single inversion of configuration. While
aqueous hydrolysis of 12 gave diol 19 in good yield,
attempts to discriminate between the C-3 and C-5 hydr-
oxyl groups were unsuccessful (Scheme 3). The reaction
Me
O
Me
O
Me
O
O
O
O
O
N3
OMe
OMe
N3
OMe
OMe
Ph
CO2Me
HO
11
HO
13
Me
Me
O
O
H
N
H
N
12
N
H
N
H
O
O
HO
HO
Me
Me
O
OH
OH
Me
O
O
O
O
N3
N3
HO
D-Ala-D-Ser
L-Ala-D-Ser
dipeptide isosteres
OH
OH
14
OH
15
dipeptide isosteres
L-rhamnose
Scheme 1. D/L-Alanine-D-serine dipeptide isosteres derived from L-rhamnose.
O
H
O
OH
OH
N3H2C
HO
N3H2C
HO
N
O
O
O
O
N
H
HO
O
Ph
O
CO2Me
CO2CHMe2
CO2CHMe2
HO
OH
16
17
18
Gly-L-Ser
D-xylose
Scheme 2. Glycine-L-serine dipeptide isosteres derived from D-xylose.

S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 3263–3273
3265
OH
OTBDMDS
O
Me
O
OH
(i)
(i)
Me
O
Me
O
O
Me
O
+
HO
HO
Ph
TBDMSO
CO2Me
CO2Me
CO2Me
CO2Me
12
19
20
21
(i)
(iv)
(iii)
OBn
OBn
N3
Me
Bn = PhCH2
TBDMS = Me2 BuSi
Tf = CF3SO2
(ii)
t
Me
O
Me
TBDMSO
O
O
RO
TBDMSO
CO2Me
CO2Me
CO2Me
22 R = H
(v)
24
25
23 R = Tf
(vi)
OBn
OBn
OH
Me
N3
(ii)
(iv)
(vii)
Me
O
Me
O
O
Me
TBDMSO
O
TBDMSO
HO
RO
CO2Me
(viii)
CO2Me
CO2Me
CO2Me
26
27
28 R = TBDMS
29 R = H
30
Scheme 3. Reagents and conditions: (i) see text and Ref. 7; (ii) tert-BuMe2SiOSO2CF3, pyridine, CH2Cl2; (iii) H2, Pd black, MeOH; (iv) Ph3P,
EtO2CN@NCO2Et, DPPA, THF; (v) Tf2O, pyridine, CH2Cl2; (vi) CF3CO2Cs, MeCOEt; (vii) H2, Pd black, MeOH; (viii) H2, Pd black, dioxane.
of 19 with TBDMS chloride and TBDMS triflate under
a variety of conditions gave approximately a 1:1 mixture
of the two monosilyl derivatives 20 and 21, which were
difficult to separate (Scheme 3). It is clear that such a
procedure was not a feasible way to make large quanti-
ties of 20 meaning that a different strategy had to be
employed.
ence of pyridine to the corresponding triflate 23 (98%
yield), and subsequent treatment with caesium trifluoro-
acetate in butanone, gave L-altronate 26 in 95% yield.
Reaction of 26 with TBDMS triflate afforded silyl ether
27 (95% yield), which on hydrogenolysis of the benzyl
ether in dioxane gave access to alcohol 28 (99% yield);
hydrogenolysis in methanol was accompanied by sub-
stantial loss of the silyl protecting group to give 29.
Introduction of an azide function in 28 by the Mitsun-
obu reaction formed the 2,3-cis-D-Ala-D-Ser dipeptide
scaffold 30 (91% yield) in an overall yield of 80% from
22 (Scheme 3).
Reduction of the benzylidene acetal 12 with triethylsi-
lane in the presence of triflic acid13 gave a highly regio-
selective reductive cleavage to form the 5-O-benzyl ether
22 in 82% yield;7 this efficient procedure allowed 22 to be
the key intermediate for the D-Ala-D-Ser building
blocks. Treatment of alcohol 22 with TBDMS triflate
gave silyl ether 24 (97% yield), which on hydrogenation
in the presence of palladium black in methanol afforded
L-rhamnonate 20 (99% yield) in which only the C-5
hydroxyl group is unprotected. A Mitsunobu reaction
of the L-rhamnonate 20 with diphenylphosphorylazide
(DPPA), triphenylphosphine and diethyl azodicarboxyl-
ate (DEAD) introduced an azide at C-5 with a single
inversion to give the required D-gulonate 25 in 70%
yield. The overall yield of TBDMS protected 2,3-trans-
D-Ala-D-Ser dipeptide scaffold 25 from the benzyl ether
22 was 67%.
The introduction of a nitrogen function at C-5 of L-
rhamnose with two inversions of configuration was re-
quired for the generation of the L-Ala-D-Ser scaffolds
(Scheme 4). Bromination of benzylidene oxetane 12 by
N-bromosuccinimide (NBS) in the presence of barium
carbonate (Hanessian–Hullar conditions14) gave
a
highly regioselective ring opening with an initial inver-
sion at C-5 to form bromobenzoate 31 in 86% yield.
Reaction of bromide 31 with sodium azide in DMSO
proceeded with a second inversion at C-5 to give the azi-
dorhamnonate 32 in 65% yield. Attempts to remove the
benzoate protecting group in 32 by transesterification
with methoxide resulted in a retro-aldol reaction of the
product (this reaction is discussed in more detail in
regard to the xylose-derived azidoesters below); accord-
ingly both the ester functionalities in 32 were hydrolysed
with aqueous sodium hydroxide in tetrahydrofuran
with the resulting sodium salt treated with methanolic
Inversion of the configuration of the hydroxyl group in
the oxetane ring by an efficient SN2 reaction allows ac-
cess to the 2,3-cis-D-Ala-D-Ser dipeptide scaffold 30.
Esterification of alcohol 22 with trifluoromethanesulf-
onic (triflic) anhydride in dichloromethane in the pres-

3266
S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 3263–3273
Br
Me
O
N3
N3
(iii)
(i)
(ii)
O
O
Me
PhCOO
O
Me
O
Me
O
Ph
PhCOO
HO
CO2Me
CO2Me
CO2Me
CO2Me
(iv)
12
31
11
32
(v)
N3
N3
N3
N3
(iv)
(vi)
Me
TBDMSO
O
Me
O
Me
O
Me
O
HO
TBDMSO
CO2Me
TfO
CO2Me
CO2Me
CO2Me
15
33
35
34
Scheme 4. Reagents and conditions: (i) NBS, BaCO3, CCl4; (ii) NaN3, DMSO; (iii) NaOH, H2O, THF; then HCl, MeOH; (iv) tert-
BuMe2SiOSO2CF3, pyridine, CH2Cl2; (v) Tf2O, pyridine, CH2Cl2; (vi) CF3CO2Cs, MeCOEt.
hydrogen chloride to form the deprotected azidoester
11, in which the OH at C-3 is trans to the C-2 carboxy-
late, 11 (89% yield). Reaction of alcohol 11 with
TBDMS triflate gave the target azidorhamnonate 35
(87% yield; 43% overall yield from 12).
afforded the target 2,3-cis- L-Ala-D-Ser dipeptide
scaffold 33 (99% yield).
2.2. Synthesis of oxetane dipeptide isosteres from
D-xylose
The azido-L-altronate 15, with the OH at C-3 cis to the
C-2 carboxylate, was prepared by an efficient SN2 dis-
placement of the triflate at C-3 of the oxetane ring in
11. Esterification of the rhamnonate alcohol 11 with tri-
flic anhydride gave the corresponding triflate 34 (100%
yield), which on treatment with caesium trifluoroacetate
in butanone gave the altronate alcohol 15 (99% yield).
The structure of azidoalcohol 15, which from L-rham-
nose involved five highly efficient inversions of configu-
ration—two SN2 displacements at C-5, a double
inversion at C-2 and a single inversion at C-3—was
firmly established by X-ray crystallographic analysis.15
Further treatment of alcohol 15 with TBDMS triflate
The benzylidene oxetane 16 (derived from D-xylose)
with NBS in carbon tetrachloride in the presence of bar-
ium carbonate gave the bromobenzoate 36 in 81% yield
as previously described (Scheme 5).9 Reaction of bro-
mide 36 with sodium azide in DMF produced azide 37
(89% yield). Attempts to remove the benzoate ester
function in 37 by transesterification were unsuccessful;
treatment of 37 with sodium methoxide in methanol
gave a number of products, at least some of which arose
from a reverse aldol reaction following ester exchange of
the benzoate. The major product isolated in 37% yield
had IRand NMRspectra consistent with the structure
shown for 38. The base-catalysed reverse aldol could
N3H2C
BrH2C
(ii)
O
O
(iii)
O
CO2Me
O
(i)
O
N3
Ph
O
PhCOO
PhCOO
CO2Me
CHO
38
CO2Me
CO2Me
37
36
16
(iv)
N3H2C
HO
N3H2C
HO
N3H2C
HO
N3H2C
TfO
O
(vi)
O
O
O
(v)
CO2Me
CO2Na
CO2CHMe2
CO2CHMe2
41
42
39
40
(viii)
(vii)
O
N3H2C
N3H2C
N3H2C
HO
O
Bn = PhCH2
Tf = CH3SO2
O
(viii)
TBDMSO
TBDMSO
CO2CHMe2
CO2CHMe2
CO2CHMe2
44
43
45
Scheme 5. Reagents and conditions: (i) NBS, BaCO3, CCl4; (ii) NaN3, DMF; (iii) NaOMe, MeOH; (iv) NaOH, H2O, THF; then MeOH, HCl; (v)
Me2CHOH, p-TSA; (vi) Tf2O, CH2Cl2, pyridine; (vii) CF3COOCs, MeCOEt; (viii) tert-BuMe2SiOSO2CF3, pyridine, CH2Cl2.

S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 3263–3273
3267
be avoided by aqueous hydrolysis of both esters with
aqueous sodium hydroxide; the resultant sodium salt
42 with hydrogen chloride in methanol afforded methyl
ester 41 (90% yield). Reaction of methyl ester 41 with p-
TSA in isopropanol resulted in transesterification to the
isopropyl ester 40 (88% yield), which on treatment with
TBDMS triflate gave the 2,3-trans-Gly-L-Ser dipeptide
scaffold 45 (98% yield) (Scheme 5).
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 deuter-
ated solvent. Chemical shifts (d) are quoted in ppm
and coupling constants (J) in Hz. Residual signals from
the solvents were used as an internal reference. Infrared
spectra were recorded on a Perkin–Elmer 1750 IRFou-
rier Transform, or Perkin–Elmer Paragon 1000 spectro-
photometer using thin films on NaCl plates (thin film).
Only the characteristic peaks are quoted. Low resolution
mass spectra (m/z) were recorded using the following
techniques: electrospray ionisation (ES), chemical ion-
isation (CI, NH3), or atmospheric pressure chemical ion-
isation (APCI). ES mass spectra were measured on a
Micromass BioQ II-ZS mass spectrometer. CI mass
spectra were recorded on a Micromass 500 OAT spec-
trometer. APCI mass spectra were recorded on a Micro-
mass Platform 1 mass spectrometer via an ÔOpenlynxÕ
system. High resolution mass spectra (HRMS) were
recorded on a Micromass 500 OAT spectrometer by
chemical ionisation (CI, NH3) or a Waters 2790-Micro-
mass LCT mass spectrometer by electrospray ionisation
(ES) as stated. For ES mass spectra the spectrometer
was operated at a resolution of 5000 full width half
height. Positive ion spectra were calibrated relative to
PEG with tetraoctylammonium bromide as the internal
lock mass. Negative ion spectra were calibrated relative
to poly-DL-alanine with Leu-enkephalin as the internal
lock mass. Optical rotations were recorded on a Per-
kin–Elmer 241 polarimeter with a path length of 1dm.
Concentrations are quoted in g/100mL.
Scaffold 44 in which the C-3 oxygen is cis to the carb-
oxylate was prepared from 40 by conversion to triflate
39 (96% yield), after which an efficient SN2 displacement
by caesium trifluoroacetate in butanone afforded the in-
verted alcohol 43 (98% yield). Finally protection of alco-
hol 43 by treatment with TBDMS triflate gave the target
scaffold 44 in 48% yield.
3.Conclusion
A series of dipeptide isosteres based on oxetane d-amino
acid scaffolds were prepared in short efficient sequences
from L-rhamnose and D-xylose by a series of highly reg-
ioselective reactions and SN2 displacements. The scaf-
folds from L-rhamnose may be viewed as L-Ala-D-Ser
and D-Ala-D-Ser and dipeptide isosteres; they may also
be viewed as isosteres for D/L-Ala-D-lactate. The use of
acetals for protection in the construction of the oxetane
ring provided high yield short sequences but has the
consequence that all the amino acids described have
the carbon chain at C-4 of the oxetane ring trans to
the carboxylate at C-2. A lengthier sequence with a dif-
ferent protecting group strategy, which allows the syn-
thesis of oxetanes in which the C-2 and C-4 chains of
the oxetane are cis to each other, together with the syn-
thesis of homooligomers of oxetane d-amino acids and
studies on their secondary structures,16 will be reported
in due course.
4.1. Methyl 2,4-anhydro-5-O-benzyl-3-O-tert-butyl-
dimethylsilyl-L-rhamnonate 24
TBDMS triflate (0.87mL, 3.8mmol) was added drop-
wise to a stirred solution of the benzyl protected L-
rhamnonate 227 (0.506g, 1.90mmol) and pyridine
(0.61mL, 7.6mmol) in dichloromethane (12mL) at
ꢀ20ꢁC under nitrogen. The reaction mixture was al-
lowed to stir for 20min at ꢀ20ꢁC, then warmed to
0ꢁC. After 2h, TLC (1:1, EtOAc/hexane) indicated the
formation of a single major product (Rf 0.64) and the
absence of starting material (Rf 0.40). The solution
was diluted with dichloromethane (100mL), washed
with water (23mL), dried over magnesium sulfate, fil-
tered and the solvent removed. The residue was purified
by flash chromatography (1:1, EtOAc/hexane) to give
silyl ether 24 (0.70g, 97%) as a clear oil. Found: C,
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/SealTM 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 was purchased dry from the
Aldrich Chemical Company in Sure/Seale bottles. All
other solvents were used as supplied (analytical or
HPLC grade) without prior purification. Reactions per-
formed under an atmosphere of nitrogen or hydrogen
gas were maintained by an inflated balloon. pH7 Buffer
was prepared by dissolving KH2PO4 (85g) and NaOH
(14.5g) in distilled water (950mL). All other reagents
were used as supplied, without prior purification. Thin
layer chromatography (TLC) was performed on alumin-
ium sheets coated with 60 F254 silica. Sheets were visual-
ised 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
63.10; H, 8.47; C20H32O5Si requires: C, 63.12; H, 8.48;
22
D
½aŠ ¼ þ33:5 (c, 1.25 in Me2CO); mmax (NaCl) 2858–
2954 (C–H), 1737, 1758 (C@O); dH (CDCl3, 400MHz):
0.05, 0.09 (2 · s, 2 · 3H, SiMe2), 0.92 (s, 9H, SitBu),
1.33 (d, 3H, H-6, J 6.4), 3.82 (s, 3H, –CO2Me),
4.18 (dq, 1H, H-5, J4,5 ꢁ J5,6 ꢁ 6.5), 4.51 (d, 1H,
PhCH2O–, JGEM 11.6), 4.62 (d, 1H, PhCH2O–, JGEM
11.6), 4.70 (dd, 1H, H-4, J 7.0, 5.8), 4.82–4.86 (m, 2H,
H-2, H-3), 7.29–7.35 (m, 5H, Ph); dC (CDCl3,
100.6MHz): ꢀ4.66 (–Si(CH3)2), 15.13 (C-6), 18.44
(–SiCMe3), 26.14 (SiC(CH3)3), 52.62 (–CO2CH3), 70.55
(C-2 or C-3), 70.84 (PhCH2O–), 72.84 (C-5), 86.20

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S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 3263–3273
(C-2 or C-3), 87.84 (C-4), 127.84–128.70 (Ph), 139.15
(CIPSO), 171.54 (C-1).
and alcohol 22 (0.359g, 1.348mmol) in dichloromethane
(5.4mL) under nitrogen at ꢀ78ꢁC; the mixture was stir-
red at ꢀ78ꢁC for a further 20min, before warming to
0ꢁC. After 3h, TLC (1:1, EtOAc/hexane) revealed that
the starting material (Rf 0.46) had been completely re-
placed by one product (Rf 0.65). At this point, the reac-
tion mixture was diluted with dichloromethane (40mL),
washed with 0.1M aqueous hydrochloric acid (20mL)
and then water (20mL). The organic fraction was dried
over magnesium sulfate, filtered and the solvent re-
moved. The crude material was purified by flash chro-
matography (2:3, EtOAc/hexane) to give triflate 23
(0.519g, 97% yield) as a clear oil. Found: C, 45.48; H,
4.2. Methyl 2,4-anhydro-3-O-tert-butyldimethylsilyl-L-
rhamnonate 20
A solution of benzyl ether 24 (0.345g, 0.907mmol) in
methanol (2.35mL) was stirred under hydrogen in the
presence of palladium black (0.035g). After 17h, TLC
(1:1, EtOAc/hexane) indicated the presence of one prod-
uct (Rf 0.55) and no starting material. The reaction mix-
ture was degassed, flushed with nitrogen and then
filtered through Celiteꢂ. The solvent was removed to
give silyl ether 20 (0.262g, 99% yield) as a clear oil.
4.28; C15H17F3O7S requires: C, 45.23; H, 4.30;
26
D
Found: C, 53.82; H, 9.06; C13H26O5Si requires: C,
½aŠ ¼ þ13:1 (c, 1.64 in CHCl3); mmax (NaCl) 2873–
23
D
53.76; H, 9.02; ½aŠ ¼ þ26:6 (c, 0.70 in Me2CO); mmax
3040 (C–H), 1760 (C@O); dH (CDCl3, 400MHz): 1.31
(d, 3H, H-6, J 6.2), 3.87 (s, 3H, CO2Me), 4.16 (dq,
1H, H-5, J 8.4, 6.2), 4.56 (d, 1H, PhCH, JGEM 10.8),
4.64 (d, 1H, PhCH0, JGEM 10.8), 4.75 (ddd, 1H, H-4, J
8.4, 6.1, 1.2), 5.16 (dd, 1H, H-2, J 4.6, 1.2), 5.72 (dd,
1H, H-3, J 6.1, 4.6), 7.28–7.36 (m, 5H, Ph); dC (CDCl3,
100.6MHz): 14.60 (C-6), 53.01 (CO2CH3), 70.77
(PhCH2), 72.08 (C-5), 79.29 (C-3), 81.14 (C-2), 84.36
(C-4), 127.77, 127.91, 128.37 (Ph), 137.64 (CIPSO),
168.17 (C-1); MS (APCI+) m/z: 416.00 (MNHþ4 , 100%).
(NaCl) 3532 (O–H), 2931 (C–H), 1757 (C@O); dH
(CDCl3, 400MHz): 0.12, 0.14 (2 · s, 2 · 3H, SiMe2),
0.92 (s, 9H, SitBu), 1.24 (d, 3H, H-6, J 6.4), 2.64 (d,
1H, –OH, J 0.4), 3.82 (s, 3H, –CO2Me), 4.29–4.35 (m,
1H, H-5), 4.39 (dd, 1H, H-4, J3,4 ꢁ J4,5 ꢁ 7.0), 4.89
(dd, 1H, H-3, J 6.4, 5.2), 4.96 (d, 1H, H-2, J 5.2); dC
(CDCl3, 100.6MHz): ꢀ5.55, ꢀ4.85 (–Si(CH3)2),
17.70, 18.06 (C-6, –SiCMe3), 25.56 (SiC(CH3)3), 52.25
(–CO2CH3), 67.02 (C-5), 70.22 (C-3), 85.30 (C-2),
86.63 (C-4), 170.67 (C-1).
4.5. Methyl 2,4-anhydro-5-O-benzyl-6-deoxy-L-altronate
26
4.3. Methyl 2,4-anhydro-5-azido-3-O-tert-butyldimethyl-
silyl-5,6-deoxy-D-gulonate 25
Caesium trifluoroacetate (0.970g, 3.909mmol) was
added to a solution of triflate 23 (0.519g, 1.303mmol)
in butanone (7mL), and heated for 17h at 60ꢁC. At this
point TLC (1:1, EtOAc/hexane) indicated the formation
of a major product (Rf 0.43). The solvent was removed,
and the crude material purified by flash chromatography
(1:1, EtOAc/hexane) to give the inverted alcohol 26
(0.329g, 95% yield) as a white crystalline solid. Found:
A solution of silyl ether 20 (0.117g, 0.403mmol) and tri-
phenylphosphine (0.212g, 0.806mmol) in tetrahydrofu-
ran (5.2mL) was prepared and stirred under nitrogen
at 0ꢁC in the dark. Diethyl azodicarboxylate
(0.127mL, 0.806mmol) was added dropwise, then
DPPA (0.087mL, 0.403mmol) added dropwise. After
15min, the solution was allowed to warm to room tem-
perature. After 18h, TLC (1:2, EtOAc/hexane) revealed
the formation of a major product (Rf 0.50). The solvent
was removed and the residue purified by repeated flash
chromatography (1:3, EtOAc/hexane), to give the 2,3-
trans-D-Ala-D-Ser dipeptide scaffold 25 (0.090g, 70%)
as a white crystalline solid. Found: C, 49.91; H, 8.25;
N, 13.15; C13H25N3O4Si requires: C, 49.50; H, 7.99; N,
C, 63.24; H, 6.75; C14H18O5 requires: C, 63.15; H,
26
D
6.81; mp 97–98ꢁC; ½aŠ ¼ þ34:4 (c, 1.42 in CHCl3); mmax
(NaCl) 3417 (OH) 2874–3032 (C–H), 1734 (C@O); dH
(CDCl3, 400MHz): 1.15 (d, 3H, H-6, J 6.8), 3.25 (br s,
1H, –OH), 3.75–3.84 (m, 4H, H-5 and CO2Me), 4.65–
4.69 (m, 3H, H-4 and PhCH2), 4.96 (dd, 1H, H-3,
J2,3 ꢁ J3,4 ꢁ 5.6), 5.08 (d, 1H, H-2, J 7.2), 7.27–7.36
(m, 5H, Ph); dC (CDCl3, 100.6MHz): 14.87 (C-6),
52.22 (CO2CH3), 67.10 (C-3), 72.13 (PhCH2), 74.01
(C-5), 81.88 (C-2), 93.45 (C-4), 127.53, 127.57, 128.36
(Ph), 138.57 (CIPSO), 170.69 (C-1). MS (APCI+) m/z:
284.1 (MNHþ4 , 100%).
13.32; HRMS m/z (CI+): found 316.1690 (MH+),
25
D
C13H26N3O4Si requires 316.1693; mp 29–30ꢁC; ½aŠ
¼
þ10:4 (c, 0.96 in CHCl3); mmax (NaCl) 2859–2955 (C–
H), 2093 (N3), 1739, 1759 (C@O); dH (CDCl3,
400MHz): 0.08, 0.11 (2 · s, 2 · 3H, SiMe2), 0.92 (s,
9H, SitBu), 1.16 (d, 3H, H-6, J 6.7), 3.82 (s, 3H,
–CO2Me), 4.06 (dq, 1H, H-5, J 8.2, 6.7), 4.55 (ddd,
1H, H-4, J 8.2, 6.3, 0.7), 4.79 (dd, 1H, H-3, J 4.9, 6.3),
4.96 (dd, 1H, H-2, J 4.9, 0.7); dC (CDCl3, 100.6MHz):
ꢀ5.44, ꢀ4.85 (–Si(CH3)2), 15.47 (C-6), 17.83 (–SiCMe3),
25.56 (SiC(CH3)3), 52.22 (–CO2CH3), 57.08 (C-5), 69.44
(C-3), 85.59 (C-2), 87.82 (C-4), 170.58 (C-1); MS (ESI+)
m/z: 338.06 (MNa+, 100%).
4.6. Methyl 2,4-anhydro-5-O-benzyl-3-O-tert-butyldi-
methylsilyl-6-deoxy-L-altronate 27
TBDMS triflate (0.061mL, 0.27mmol) was added drop-
wise to a stirred solution of alcohol 26 (0.036g,
0.135mmol) and pyridine (0.043mL, 0.54mmol) in
dichloromethane (0.8mL) at ꢀ20ꢁC under nitrogen.
The solution was stirred for a further 20min at
ꢀ20ꢁC, then warmed to 0ꢁC. After 1h, TLC (1:2,
EtOAc/hexane) indicated the formation of a major
product (Rf 0.56) and the absence of any starting mate-
rial (Rf 0.19). The solution was diluted with dichloro-
methane (10mL), washed with water (2.5mL), dried
4.4. Methyl 2,4-anhydro-5-O-benzyl-3-O-trifluoro-
methanesulfonyl-L-rhamnonate 23
Triflic anhydride (0.442mL, 2.696mmol) was added
dropwise to a solution of pyridine (0.544mL, 6.74mmol)

S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 3263–3273
3269
over magnesium sulfate, filtered and the solvent re-
moved. The crude product was purified by flash chroma-
tography (1:2, EtOAc/hexane) to give fully protected
altronate ester 27 (0.049g, 95% yield) as a clear oil.
Found: C, 62.65; H, 8.01; C20H32O5Si requires: C,
4.8. Methyl 2,4-anhydro-5-azido-3-O-tert-butyldimethyl-
silyl-5-deoxy-D-fuconate 30
Triphenylphosphine (0.120g, 0.454mmol) in tetra-
hydrofuran (1.3mL) was added dropwise to a stirred
solution of silyl ether 28 (0.066g, 0.227mmol) in tetra-
hydrofuran (1.3mL) under nitrogen at room tempera-
ture in the dark. DEAD (0.072mL, 0.454mmol) and
DPPA (0.049mL, 0.227mmol) were added sequentially.
After 15h, TLC (1:2, EtOAc/hexane) revealed the
formation of a major product (Rf 0.61). The solvent
was removed, and the residue purified by flash chroma-
tography (1:3, EtOAc/hexane), to give the 2,3-cis-D-Ala-
D-Ser dipeptide scaffold 30 (0.065g, 91% yield) as a clear
63.12; H, 8.48; HRMS m/z (CI+): found 398.2360
22
D
(MNHþ4 ), C20H36NO5Si requires 398.2363; ½aŠ ¼ þ1:5
(c, 0.58 in CHCl3); mmax (NaCl) 2858–2953 (C–H),
1738, 1762 (C@O); dH (CDCl3, 400MHz): 0.05, 0.06
(2 · s, 2 · 3H, SiMe2), 0.86 (s, 9H, SitBu), 1.15 (d, 3H,
H-6, J 6.4), 3.75–3.81 (m, 4H, H-5 and –CO2Me), 4.66
(dd, 1H, H-4, J3,4 ꢁ J4,5 ꢁ 4.2), 4.69 (s, 2H, PhCH2O–),
4.95 (dd, 1H, H-3, J 7.0, 4.8), 5.08 (d, 1H, H-2, J
7.0), 7.28–7.38 (m, 5H, Ph); dC (CDCl3, 100.6MHz):
ꢀ5.16, ꢀ5.05 (–Si(CH3)2), 15.15 (C-6), 17.72 (–SiCMe3),
25.43 (SiC(CH3)3), 51.80 (–CO2CH3), 67.48 (C-3), 72.04
(PhCH2O–), 74.15 (C-5), 82.46 (C-2), 94.30 (C-4),
127.47, 127.56, 128.29 (Ph), 138.65 (CIPSO), 170.08 (C-
1). MS (ESI+) m/z: 381.21 (MH+, 24%), 398.24
(MNHþ4 , 100%), 403.19 (MNa+, 67%).
oil. HRMS m/z (CI+): found 316.1697 (MH+),
23
D
C13H26N3O4Si requires 316.1693; ½aŠ ¼ ꢀ50:9 (c, 0.74
in CHCl3); mmax (NaCl) 2859–2954 (C–H), 2113 (N3),
1740, 1761 (C@O); dH (CDCl3, 400MHz): 0.05 (s, 6H,
SiMe2), 0.86 (s, 9H, SitBu), 1.35 (d, 3H, H-6, J 6.8),
3.51 (dq, 1H, H-5, J 6.8, 3.7), 3.80 (s, 3H, –CO2Me),
4.68 (dd, 1H, H-4, J 4.7, 3.7), 4.83 (dd, 1H, H-3, J 7.0,
4.7), 5.07 (d, 1H, H-2, J 7.0); dC (CDCl3, 100.6MHz):
ꢀ5.19, ꢀ5.08 (–Si(CH3)2), 14.02 (C-6), 17.79 (–SiCMe3),
25.43 (SiC(CH3)3), 51.91 (–CO2CH3), 57.55 (C-5), 68.05
(C-3), 82.19 (C-2), 93.19 (C-4), 169.60 (C-1); MS (ESI+)
m/z: 316.2 (MH+, 94%), 333.2 (MNHþ4 , 100%).
4.7. Methyl 2,4-anhydro-3-O-tert-butyldimethylsilyl-6-
deoxy-L-altronate 28
A solution of benzyl ether 27 (0.343g, 0.901mmol) in
1,4-dioxane (5.5mL) was stirred under hydrogen in the
presence of palladium black (0.086g). After 18h, TLC
(1:1, EtOAc/hexane) indicated the formation of one
product (Rf 0.43) and the absence of any starting mate-
rial (Rf 0.68). The reaction mixture was degassed,
flushed with nitrogen and then filtered through Celiteꢂ.
The solvent was removed to give silyl ether 28 (0.258g,
99% yield) as a clear oil. Found: C, 53.28; H, 8.70;
C13H26O5Si requires: C, 53.76; H, 9.02; HRMS m/z
4.9. Methyl 2,4-anhydro-3-O-benzoyl-5-bromo-5,6-di-
deoxy-D-gulonate 31
N-Bromosuccinimide (0.595g, 3.267mmol) and barium
carbonate (0.307g, 1.56mmol) were added to a solution
of benzylidene acetal 12 (0.784g, 2.97mmol) in carbon
tetrachloride (20mL). The reaction mixture was stirred
at 60ꢁC for 22h, at which point TLC (1:2, EtOAc/hex-
ane) revealed that the starting material (Rf 0.26) had
been replaced by a major product (Rf 0.38). Dichloro-
methane (100mL) was added to the reaction mixture,
and the solution washed with brine (85mL). The aque-
ous layer was further extracted with dichloromethane
(3 · 50mL), the organic fractions then combined, dried
over magnesium sulfate, filtered and the solvent was re-
moved. The crude material was purified by flash chro-
matography (1:3, EtOAc/hexane) to give the bromide
31 (0.875g, 86%) as a white crystalline solid. Found:
(CI+): found 291.1624 (MH+), C13H27O5Si requires
22
D
291.1628; ½aŠ ¼ ꢀ0:3 (c, 1.10 in CHCl3); mmax (NaCl)
3460 (O–H), 2859–2954 (C–H), 1746 (C@O); dH
(CDCl3, 400MHz): 0.05, 0.07 (2 · s, 2 · 3H, SiMe2),
0.85 (s, 9H, SitBu), 1.12 (d, 3H, H-6, J 6.8), 2.47 (br s,
1H, –OH), 3.80 (s, 3H, –CO2Me), 3.99 (dq, 1H, H-5, J
6.8, 2.8), 4.67 (dd, 1H, H-4, J 5.3, 2.8), 4.94 (dd, 1H,
H-3, J 7.1, 5.3), 5.01 (d, 1H, H-2, J 7.1); dC (CDCl3,
100.6MHz): ꢀ5.21, ꢀ4.95 (–Si(CH3)2), 16.00 (C-6),
17.72 (SiCMe3), 25.43 (SiC(CH3)3), 51.94 (–CO2CH3),
65.80 (C-3), 66.33 (C-5), 82.65 (C-2), 94.65 (C-4),
169.94 (C-1). MS (TOF FI+) m/z: 291.15 (MH+, 100%).
C, 48.81; H, 4.46; C14H15BrO5 requires: C, 49.00;
22
D
H, 4.41; mp 93–94ꢁC; ½aŠ ¼ ꢀ31:6 (c, 0.97 in CHCl3);
When the hydrogenation was conducted in methanol as
solvents silyl ether 28 was formed in 62% yield together
with methyl 2,4-anhydro-6-deoxy-L-altronate 29
(0.021g, 31% yield) as a white crystalline solid. Found:
C, 47.99; H, 7.12; C7H12O5 requires: C, 47.72; H, 6.87;
mmax (NaCl) 2955 (C–H), 1731 (br, 2 · C@O); dH
(CDCl3, 400MHz): 1.72 (d, 3H, H-6, J 6.8), 3.86 (s,
3H, CO2Me), 4.56 (dq, 1H, H-5, J 8.6, 6.8), 4.99 (ddd,
1H, H-4, J 8.6, 6.7, 0.7), 5.13 (dd, 1H, H-2, J 4.6,
0.7), 5.85 (dd, 1H, H-3, J 6.7, 4.6), 7.47–7.51 (m, 2H,
m-Ph), 7.61–7.65 (m, 1H, p-Ph), 8.04–8.06 (m, 2H, o-
Ph); dC (CDCl3, 100.6MHz): 21.08 (C-6), 46.65 (C-5),
52.87 (CO2CH3), 69.66 (C-3), 81.65 (C-2), 85.89 (C-4),
128.47, 128.87, 129.96, 134.14 (Ph), 165.09, 169.46
(2 · C@O).
HRMS m/z (CI+): found 194.1024 (MNHþ4 ), C7H13O5
22
D
requires 194.1028; mp 100–101ꢁC; ½aŠ ¼ þ48:3 (c,
0.84 in H2O); mmax (KBr) 3433 (O–H), 2935 (C–H),
1737 (C@O); dH (D2O, 400MHz): 1.13 (d, 3H, H-6, J
7.0), 3.84 (s, 3H, –CO2Me), 4.03 (dq, 1H, H-5, J 7.0,
4.0), 4.60 (dd, 1H, H-4, J3,4 ꢁ J4,5 ꢁ 4.6), 4.95 (dd, 1H,
H-3, J 7.2, 5.6), 5.20 (d, 1H, H-2, J 7.2); dC (D2O,
100.6MHz): 16.25 (C-6), 53.20 (–CO2CH3), 66.10 (C-
3), 66.92 (C-5), 82.77 (C-2), 93.56 (C-4), 172.74 (C-1).
MS (APCI+) m/z: 177.17 (MH+, 100%), 194.21
(MNHþ4 , 66%).
4.10. Methyl 2,4-anhydro-5-azido-3-O-benzoyl-5-deoxy-
L-rhamnonate 32
Sodium azide (1.25g, 19.2mmol) was added to a solu-
tion of the D-gulonate bromide 31 (4.40g, 12.8mmol)

3270
S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 3263–3273
in DMSO (30mL) under nitrogen. The reaction mixture
was heated at 85ꢁC for 17h at which point it was diluted
with dichloromethane (150mL). TLC (1:2, EtOAc/hex-
ane) revealed that both the starting material and prod-
uct had Rf 0.46. The solution was washed with water
(30mL), and the aqueous layer further extracted with
dichloromethane (2 · 150mL); the organic fractions
were then combined, dried over magnesium sulfate, fil-
tered and the solvent removed. The crude material was
purified by flash chromatography (1:2, EtOAc/hexane)
to give azide 32 (2.38g, 61%) as a colourless oil. Found:
hexane) indicated the formation of one product (Rf
0.62) and the absence of the starting material (Rf
0.28). The solution was diluted in dichloromethane
(65mL), washed with water (16mL), dried over magne-
sium sulfate, filtered and the solvent removed. The resi-
due was purified by flash chromatography (2:3, EtOAc/
hexane), to give L-ala-D-ser scaffold 35 (0.445g, 87%) as
a clear oil. HRMS m/z (CI+): found 333.1954 (MNHþ4 );
C13H29N4O4Si requires 333.1958; ½aŠ22=+44.8 (c, 1.16 in
D
CHCl3); mmax (NaCl) 2936 (C–H), 2096 (N3), 1755
(C@O); dH (CDCl3, 400MHz): 0.11 (s, 6H, SiMe2),
0.92 (s, 9H, SitBu), 1.35 (d, 3H, H-6, J 6.5), 3.81 (s,
3H, –CO2Me), 4.06 (dq, 1H, H-5, J 8.6, 6.5), 4.45 (dd,
1H, H-4, J 8.6, 6.0), 4.78 (dd, 1H, H-3, J 6.0, 4.7),
4.82 (d, 1H, H-2, J 4.7); dC (CDCl3, 100.6MHz):
ꢀ5.25, ꢀ5.11 (–Si(CH3)2), 14.55 (C-6), 17.94 (–SiCMe3),
25.56 (SiC(CH3)3), 52.21 (–CO2CH3), 54.97 (C-5), 69.68
(C-3), 85.69 (C-2), 86.52 (C-4), 170.64 (C-1); MS
(APCI+) m/z: 200.16 (100%), 316.20 (MH+, 23%),
333.22 (MNHþ4 , 83%).
C, 55.30; H, 4.95; N, 13.37; C14H15N3O5 requires:
22
D
C, 55.08; H, 4.95; N, 13.76; ½aŠ ¼ þ43:5 (c, 0.99 in
CHCl3); mmax (NaCl) 2954 (C–H), 2108 (N3), 1720 (br,
2 · C@O); dH (CDCl3, 400MHz): 1.38 (d, 3H, H-6, J
6.5), 3.87 (s, 3H, CO2Me), 4.10 (dq, 1H, H-5, J 8.4,
6.5), 4.75 (dd, 1H, H-4, J 8.4, 6.5), 5.12 (d, 1H, H-2, J
4.6), 5.90 (dd, 1H, H-3, J 6.5, 4.6), 7.47–7.51 (m, 2H,
m-Ph), 7.60–7.65 (m, 1H, p-Ph), 8.08–8.10 (m, 2H, o-
Ph); dC (CDCl3, 100.6MHz): 14.75 (C-6), 52.92
(CO2CH3), 55.92 (C-5), 69.28 (C-3), 82.32 (C-2), 84.66
(C-4), 128.75–133.99 (Ph), 165.12, 169.64 (2 · C@O).
4.13. Methyl 2,4-anhydro-5-azido-5-deoxy-3-O-tri-
fluoromethanesulfonyl-L-rhamnonate 34
4.11. Methyl 2,4-anhydro-5-azido-5-deoxy-L-rhamnonate
11
Triflic anhydride (1.41mL, 8.2mmol) was added drop-
wise to a solution of pyridine (1.68mL, 20.5mmol) and
alcohol 11 (0.82g, 4.1mmol) in dichloromethane
(16mL) under nitrogen at ꢀ78ꢁC. The reaction mixture
was stirred at ꢀ78ꢁC for a further 20min, before warm-
ing to 0ꢁC. After 2.25h, TLC (1:1, EtOAc/hexane) re-
vealed that the starting material (Rf 0.59) had been
completely replaced by one product (Rf 0.69). At this
point, the reaction mixture was diluted with dichloro-
methane (160mL), washed with 0.1M aqueous hydro-
chloric acid (80mL) and then water (80mL). The
organic fraction was dried over magnesium sulfate, fil-
tered and the solvent removed. The crude material was
purified by flash chromatography (2:5, EtOAc/hexane)
to give triflate 34 (1.36g, 100%) as a clear oil. Found:
1M Aqueous sodium hydroxide (31.2mL, 31.2mmol)
was added dropwise to a solution of azide 32 (2.38g,
7.80mmol) in tetrahydrofuran (55mL) and water
(7.7mL) under nitrogen. The solution was stirred at
room temperature overnight, after which TLC (CMAH,
60:30:3:5) indicated the formation of one UV-inactive
product (Rf 0.34). Methanol (1550mL) and concd aque-
ous hydrochloric acid (15.5mL) were then added to the
solution. After a further 24h, TLC (1:2, EtOAc/hexane)
indicated the formation of one product (Rf 0.17). The
solution was neutralised with NaHCO3 to pH6, filtered
and half the solvent removed. Water (250mL) was
added and the solution washed with dichloromethane
(3 · 500mL). The organic fractions were combined,
dried over magnesium sulfate, filtered and the solvent re-
moved to give azide 11 (1.40g, 89%) as a white crystal-
line solid. Found: C, 42.13; H, 5.77; N, 20.90;
C, 29.21; H, 3.10; N, 12.23; C8H10F3N3O6S requires:
25
D
C, 28.83; H, 3.02; N, 12.61; ½aŠ ¼ þ8:6 (c, 0.92 in
CHCl3); mmax (NaCl) 2961 (C–H), 2113 (N3), 1761 (C@O);
dH (CDCl3, 400MHz): 1.41 (d, 3H, H-6, J 6.6), 3.87 (s,
3H, –CO2Me), 4.06 (dq, 1H, H-5, J 9.2, 6.6), 4.62 (ddd,
1H, H-4, J 9.2, 5.9, 1.2), 5.15 (dd, 1H, H-2, J 4.8, 1.2), 5.68
(dd, 1H, H-3, J 5.9, 4.8); dC (CDCl3, 100.6MHz): 14.34
(C-6), 53.09 (–CO2CH3), 55.18 (C-5), 78.65 (C-3), 81.14 (C-
2), 83.76 (C-4), 113.52, 116.70, 119.88, 123.06 (–OTf),
167.76 (C-1); MS (APCI+) m/z: 351.00 (MNHþ4 , 100%).
C7H11N3O4 requires: C, 41.79; H, 5.51; N, 20.89; mp
22
D
55–56ꢁC; ½aŠ ¼ þ75:1 (c, 0.97 in CHCl3); mmax (NaCl)
3433 (O–H), 2939 (C–H), 2099 (N3), 1746 (C@O); dH
(CDCl3, 400MHz): 1.32 (d, 3H, H-6, J 6.8), 3.54 (d,
1H, –OH, J 8.4), 3.81 (s, 3H, CO2Me), 4.10 (dq, 1H,
H-5, J 6.8, 6.6), 4.56 (dd, 1H, H-4, J3,4 ꢁ J4,5 ꢁ 6.6),
4.85 (m, 1H, H-3), 4.99 (d, 1H, H-2, J 5.2); dC (CDCl3,
100.6MHz): 15.06 (C-6), 52.60 (–CO2CH3), 58.02 (C-5),
70.26 (C-3), 85.67 (C-2), 86.21 (C-4), 170.77 (C-1); MS
(CI+) m/z: 219.1 (MNHþ4 , 100%), 202.1 (MH+, 11%).
4.14. Methyl 2,4-anhydro-5-azido-5,6-di-deoxy-L-altronate
15
Caesium trifluoroacetate (0.214g, 0.87mmol) was added
to a solution of triflate 34 (0.097g, 0.29mmol) in buta-
none (1.5mL), and heated for 3.5h at 60ꢁC. At this
point, TLC (1:1, EtOAc/hexane) indicated that the start-
ing material (Rf 0.59) had been replaced by a major
product (Rf 0.29). The solvent was removed, and the
crude material purified by flash chromatography (1:1,
EtOAc/hexane) to give azido ester 15 (0.058g, 99%) as
a white crystalline solid. Found: C, 41.66; H, 5.52; N,
20.82; C7H11N3O4 requires: C, 41.79; H, 5.51; N,
4.12. Methyl 2,4-anhydro-5-azido-3-O-tert-butyldimeth-
ylsilyl-5-deoxy-L-rhamnonate 35
TBDMS triflate (0.747mL, 3.26mmol) was added drop-
wise to a stirred solution of azido alcohol 11 (0.328g,
1.63mmol) and pyridine (0.525mL, 6.52mmol) in
dichloromethane (6.5mL) at ꢀ20ꢁC under nitrogen.
The solution was stirred for a further 20min at ꢀ20ꢁC
and then warmed to 0ꢁC. After 2h, TLC (1:2, EtOAc/

S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 3263–3273
3271
26
D
20.89; mp 78–80ꢁC; ½aŠ ¼ þ15:7 (c, 0.99 in CHCl3);
OMe), 5.15 (1H, ddt, H-4, J 5.9, 5.2, 0.7), 5.27 (1H,
dd, H-2, J 5.1, 0.7), 5.82 (1H, dd, H-3, J 6.6, 5.2), 7.48
(2H, m, m-ArH), 7.64 (1H, m, p-ArH), 8.18 (2H, m, o-
ArH); dC (CDCl3, 100.6MHz): 50.5 (C-5), 69.7 (C-3),
82.1 (C-4, C-2), 128.3 (m-ArCH), 128.7 (o-ArCH),
129.9 (p-ArCH), 134.0 (ArC), 165.2 (PhC@O), 169.4
(C@O); m/z (APCI+ve): 292 (M+H+, 12%), 105 (100%).
mmax (NaCl) 3445 (O–H), 2921–2976 (C–H), 2094, 2136
(N3), 1740 (C@O); dH (CDCl3, 400MHz): 1.20 (d, 3H,
H-6, J 6.8), 3.25 (br s, 1H, –OH), 3.80–3.85 (m, 4H,
–CO2Me and H-5), 4.68 (dd, 1H, H-4, J3,4 ꢁ J4,5 ꢁ 4.8),
4.90 (dd, 1H, H-3, J2,3 ꢁ J3,4 ꢁ 5.8), 5.11 (d, 1H, H-2,
J 7.2); dC (CDCl3, 100.6MHz): 14.10 (C-6), 52.41
(–CO2CH3), 58.37 (C-5), 67.21 (C-3), 81.85 (C-2),
92.34 (C-4), 170.33 (C-1); MS (APCI+) m/z: 202.1
(MH+, 43%), 219.1 (MNHþ4 , 100%).
4.17. Methyl 5-azido-4-formyl-3-oxa-pentanoate 38
Sodium methoxide (1.9mg, 0.035mmol) in methanol
(0.036mL) was added to a solution of azide 37 (21mg,
0.07mmol) in methanol (0.57mL) at 0ꢁC. The reaction
mixture was stirred at room temperature for 4h after
which time a further portion of sodium methoxide
(1mg, 0.018mmol) in methanol (0.018mL) was added.
After another hour, very little starting material (Rf
0.61) was seen to remain by TLC (1:2 EtOAc/hexane)
and the formation of three products observed (Rf 0.89,
0.27 and 0.15). The mixture was neutralised with
4.15. Methyl 2,4-anhydro-5-azido-3-O-tert-butyldimeth-
ylsilyl-5,6-di-deoxy-L-altronate 33
TBDMS triflate (1.32mL, 5.78mmol) was added drop-
wise to a solution of alcohol 15 (0.582g, 2.89mmol)
and pyridine (0.93mL, 11.56mmol) in dichloromethane
(11mL) at ꢀ20ꢁC under nitrogen. The reaction mixture
was stirred for a further 20min at ꢀ20ꢁC, and then
warmed to 0ꢁC. After 1.5h, TLC (1:2, EtOAc/hexane)
indicated the formation of a major product (Rf 0.52)
and the absence of starting material (Rf 0.10). The solu-
tion was diluted in dichloromethane (150mL), washed
with water (40mL), dried over magnesium sulfate, fil-
tered and the solvent removed. The residue was purified
by flash chromatography (1:2, EtOAc/hexane) to give
the silyl protected 2,3-cis-L-Ala-D-Ser dipeptide scaffold
33 (0.906g, 99%) as a clear oil. Found: C, 49.71; H, 8.04;
+
Amberlite resin (IR120, H form), filtered and concen-
trated under reduced pressure. The crude mixture was
partially purified by column chromatography (1:5
EtOAc/hexane). The spectral data of the major product
was consistent with structure 38 (Rf 0.27) (5mg, 37%).
mmax (thin film): 2105 (s, N3), 1760 (s, C@O), 1704 (s,
C@O), 1620 (s); dH (CDCl3, 200MHz): 3.79 (1H, s, H-
4), 3.82 (3H, s, OMe), 4.55 (2H, s, H-5), 5.15–5.25
(2H, dd, H-2, J 3.7, 16.5), 9.35 (1H, s, CHO).
N, 13.05; C13H25N3O4Si requires: C, 49.50; H, 7.99; N,
25
D
13.32; ½aŠ ¼ ꢀ7:1 (c, 0.94 in CHCl3); mmax (NaCl)
2859–2954 (C–H), 2128 (N3), 1740, 1762 (C@O); dH
(CDCl3, 400MHz): 0.06, 0.08 (2 · s, 2 · 3H, SiMe2),
0.86 (s, 9H, SitBu), 1.20 (d, 3H, H-6, J 6.8), 3.76 (dq,
1H, H-5, J 5.2, 6.8), 3.80 (s, 3H, –CO2Me), 4.65 (ddd,
1H, H-4, J 0.8, J3,4 ꢁ J4,5 ꢁ 5.0), 4.82 (dd, 1H, H-3, J
7.2, 4.8), 5.07 (dd, 1H, H-2, J 7.2, 0.8); dC (CDCl3,
100.6MHz): ꢀ5.26, ꢀ5.03 (–Si(CH3)2), 14.51 (C-6),
17.76 (–SiCMe3), 25.41 (SiC(CH3)3), 51.94 (–CO2CH3),
58.57 (C-5), 67.83 (C-3), 82.46 (C-2), 93.12 (C-4),
169.62 (C-1); MS (APCI+) m/z: 258.1 (100%), 316.2
(MH+, 93%), 333.2 (MNHþ4 , 95%).
4.18. Methyl 2,4-anhydro-5-azido-5-deoxy-D-lyxonate 41
Aqueous sodium hydroxide (1M, 9mL) was added to a
solution of azide 37 (655mg, 2.2mmol) in a mixture of
THF (14mL) and water (2mL). After 12h, all starting
material had been converted to one spot by TLC
(Rf 0.53, chloroform/methanol/water/acetic acid,
60:30:5:3). A 1% solution of concentrated hydrochloric
acid (3mL) in methanol (300mL) was added to sodium
salt 42 and the reaction stirred at room temperature
overnight to give one major product (Rf 0.32, 1:2
EtOAc/hexane). The reaction mixture was neutralised
with saturated aqueous sodium bicarbonate and concen-
trated under reduced pressure. The residue was purified
by column chromatography to give the deprotected
azide 41 as a white crystalline solid (377mg, 90%).
4.16. Methyl 2,4-anhydro-5-azido-3-O-benzoyl-5-deoxy-
D-lyxonate 37
Sodium azide (449mg, 6.90mmol) was added in one
portion to a solution of bromide 36 (1.033g, 3.14mmol)
in DMF (29mL). The reaction mixture was stirred at
70ꢁC overnight after which complete conversion of the
starting material to one major product was seen (Rf
0.55, 1:2, EtOAc/hexane). A few drops of water were
added and the solvent removed in vacuo. The resulting
solid was dissolved in ethyl acetate (150mL) and washed
with brine (100mL). The aqueous layer was further ex-
tracted with ethyl acetate (3 · 70mL), dried (magnesium
sulfate) and the solvent was removed. The residue was
purified by column chromatography (1:6, EtOAc/hex-
ane) to give the azide 37 (820mg, 89% yield) as a colour-
Found: C, 38.59; H, 4.81; N, 22.59; C6H9N3O4 requires:
22
D
C, 38.51; H, 4.85; N, 22.45; mp 64–67ꢁC; ½aŠ ¼ þ8:8
(c, 0.98 in CHCl3); mmax (thin film): 3440 (br, OH),
2106 (N3), 1739 (C@O); dH (CDCl3, 400MHz): 3.62
(2H, dd, H-5, H-50, J 13.6, 3.9), 3.82 (3H, s, OMe),
3.79–3.85 (1H, br m, OH), 4.87 (1H, dd, H-3, J 6.8,
5.3), 4.91–4.95 (1H, m, H-4), 5.77 (1H, d, H-2, J 5.3);
dC (CDCl3, 100.6MHz): 51.5 (C-5), 52.9 (OCH3), 70.5
(C-3), 84.1 (C-4), 86.8 (C-2), 171.0 (C@O); m/z
(APCI+ve): 205 (M þ NHþ4 , 75%), 188 (M+H+, 22%),
162 (100%), 160 (M+H+ꢀN2, 52%).
less oil. HRMS m/z (CI+): found 292.0936 (M+H+);
4.19. Isopropyl 2,4-anhydro-5-azido-5-deoxy-D-lyxonate
40
22
D
C13H14N3O5 requires 292.0933; ½aŠ ¼ þ103:5 (c, 1.03
in CHCl3); mmax (thin film): 2105 (N3), 1728 (br,
C@O); dH (CDCl3, 400MHz): 3.67 (1H, dd, H-5, J
13.5, 5.0), 3.72 (1H, dd, H-50 J 13.5, 6.0), 3.88 (3H, s,
A solution of methyl ester 41 (225mg, 1.2mmol) in iso-
propanol (2mL) was heated with para-toluenesulfonic

3272
S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 3263–3273
acid (p-TSA) (4.6mg, 0.024mmol) at 70ꢁC overnight,
after which TLC showed that all the starting material
had been converted to one major product (Rf 0.79, 1:1
EtOAc/hexane). Solid sodium bicarbonate was added
to neutralise the solution to pH5. The resulting mixture
was pre-absorbed onto silica gel and purified by column
chromatography (1:5, EtOAc/hexane) to yield isopropyl
azidoester 40 as a white crystalline solid (256mg, 88%).
Found: C, 44.53; H, 5.96; N, 19.10; C8H13N3O4 re-
quires: C, 44.65; H, 6.09; N, 19.53; HRMS: m/z (CI+)
starting material (Rf 0.17) to one product (Rf 0.72).
The solution was diluted with dichloromethane
(40mL) and washed with 2M aqueous hydrochloric acid
(20mL). The aqueous layer was extracted with dichloro-
methane (3 · 10mL) and the combined organic layers
washed with brine (30mL), dried over magnesium sul-
fate and concentrated under reduced pressure. The resi-
due was purified by column chromatography (1:3,
EtOAc/hexane) to yield triflate 39 as a colourless oil
(155mg, 96%). Found: C, 31.58; H, 3.67; N, 12.04;
found 233.1245 (M þ NHþ4 ); C8H17N4O4 requires
C9H12F3N3O6S requires: C, 31.13; H, 3.48; N, 12.10;
23
D
26
D
233.1249; mp 57–59ꢁC; ½aŠ ¼ þ26:4 (c, 0.95 in CHCl3);
½aŠ ¼ þ41:8 (c, 1.04 in CHCl3); mmax (thin film): 2111
mmax (thin film): 3368 (m, br, OH), 2111 (s, N3), 1738 (s,
C@O); dH (CDCl3, 400MHz): 1.29 (3H, d, (CH3)C, J
6.3), 1.31 (3H, d, (CH3)0C, J 6.3), 3.42–3.58 (1H, br,
OH), 3.60 (1H, dd, H-5, J 13.6, 3.6), 3.84 (1H, dd, H-
50, J 13.6, 4.6), 4.83 (1H, dd, H-3, J 6.8, 5.3), 4.91–
4.95 (1H, m, H-4), 5.02 (1H, dd, H-2, J 5.3, 0.8), 5.09–
5.19 (1H, septet, CH(CH3)2, J 6.3); dC (CDCl3,
100.6MHz): 21.7 (2C, C(CH3)2), 51.2 (C-5), 69.4 (C-
3), 70.1 (C-4), 83.4 (C(CH3)2), 86.6 (C-2), 169.6
(C@O); m/z (APCI+ve): 233 (M þ NHþ4 , 62%), 216
(M+H+, 5%), 190 (100%).
(s, N3), 1750 (s, C@O); dH (CDCl3, 400MHz): 1.31
(3H, d, OCH(CH3)2, J 6.3), 1.32 (3H, d, OCH(CH3)2,
J 6.3), 3.72 (1H, dd, H-5, J 13.5, 5.5), 3.77 (1H, dd,
H-5, J 13.5, 5.5), 5.04 (1H, a-dq, H-4, J 5.6, 1.1), 5.16
(1H, septet, CH(CH3)2, J 6.3), 5.23 (1H, dd, H-2, J
5.1, 1.3), 5.68 (1H, a-t, H-3, J 5.8); dC (CDCl3,
100MHz): 21.5, (2 · OCH(CH3)2), 50.0 (C-5), 70.6
(OCH(CH3)2), 78.1 (C-3), 81.0 (C-4), 81.5 (C-2), 116.7,
119.9 (CF3), 166.7 (C@O); m/z (APCI+ve): 365
(M þ NHþ4 , 100%).
4.22. Isopropyl 2,4-anhydro-5-azido-5-deoxy-D-arabino-
nate 43
4.20. Isopropyl 2,4-anhydro-5-azido-3-O-tert-butyldi-
methylsilyl-5-deoxy-D-lyxonate 45
Caesium trifluoroacetate (366mg, 1.49mmol) was added
to a solution of triflate 39 (129mg, 0.37mmol) in 2-buta-
none (4mL). The reaction mixture was heated to 60ꢁC
for 18h after which TLC (1:3, EtOAc/hexane) showed
conversion of the starting material (Rf 0.72) to one prod-
uct (Rf 0.07). The reaction mixture was concentrated un-
der reduced pressure and the residue purified by column
chromatography (1:1, EtOAc/hexane) to give alcohol 43
as a white solid (78mg, 98%). Found: C, 44.9; H, 6.11;
N, 19.52; C8H13N3O4 requires: C, 44.65; H, 6.09; N,
TBDMS triflate (1.17mL, 5.08mmol) was added drop-
wise to a solution of azide 40 (546mg, 2.54mmol) in
dichloromethane (15mL) and pyridine (0.82mL,
10.16mmol). The reaction mixture was stirred for
20min at ꢀ20ꢁC. The solution was allowed to warm
to 0ꢁC and after 1.25h, TLC (1:2, EtOAc/hexane)
showed the complete conversion to one product (Rf
1.0). The reaction was diluted with dichloromethane
(40mL), washed with water (10mL), dried (magnesium
sulfate) and concentrated under reduced pressure. The
residue was purified by column chromatography (1:2,
EtOAc/hexane) to give title compound 45 as a colourless
oil (822mg, 98%). Found: C, 51.26; H, 8.25; N, 12.43;
19.53;
mp
91–93ꢁC
(from
EtOAc/hexane);
26
D
½aŠ ¼ þ45:9 (c, 1.04 in CHCl3); mmax (thin film): 3412
(br m, OH), 2109 (m, N3), 1726 (s, C@O); dH (CDCl3,
400MHz): 1.31 (3H, d, CH(CH3)2, J 6.2), 1.33 (3H, d,
CH(CH3)2, J 6.2), 2.80–3.00 (1H, br, OH), 3.38–3.43
(1H, dd, H-5, J 14.0, 3.0), 3.63–3.68 (1H, dd, H-50, J
14.0, 2.9), 4.90–5.0 (2H, m, H-3, H-4), 5.07 (1H, d, H-
2, J 6.1), 5.2 (1H, septet, J 6.3); dC (CDCl3, 100MHz):
21.8 (CH(CH3)2), 21.9 (CH(CH3)2), 52.4 (C-5), 67.6
(C-3), 69.6 (CH(CH3)2), 81.7 (C-2), 89.0 (C4), 169.4
(C@O); m/z (APCI+ve): 233 (M þ NHþ4 , 100%), 216
(M+H+, 35%).
C14H27N3O4Si requires: C, 51.04; H, 8.26; N, 12.75;
24
D
½aŠ ¼ ꢀ8:8 (c, 0.98 in CHCl3); mmax (thin film): 2102
(s, N3), 1751 (s, C@O); dH (CDCl3, 400MHz): 0.08
(3H, s, SiCH3), 0.11 (3H, s, SiCH3), 0.91 (9H, s,
SiC(CH3), 1.30 (3H, s, OCH(CH3)), 1.29 (3H, s,
OCH(CH3)), 3.60 (1H, dd, H5, J 13.1, 5.4), 3.71 (1H,
dd, H-50, J 13.1, 6.5), 4.78 (1H, m, H-3), 4.86 (1H, m,
H-4), 4.89 (1H, d, H-2, J 4.9), 5.14 (1H, septet,
CH(CH3)2, J 6.2); dC (CDCl3, 100MHz): ꢀ2.5, ꢀ2.1
(2 · SiCH3), 20.8 (SiC(CH3)3), 24.6 (OCH(CH3)2), 28.5
(SiC(CH3)3), 53.3 (C-5), 72.0 (OCH(CH3)2), 72.2 (C-3),
86.5 (C-4), 88.9 (C-2), 172.4 (C@O); m/z (APCI+ve):
302 (M+H+ꢀN2, 20%), 128 (100%).
4.23. Isopropyl 2,4-anhydro-5-azido-3-O-tert-butyldi-
methylsilyl-5-deoxy-D-arabinonate 44
TBDMS triflate (0.17mL, 0.72mmol) was added to a
solution of alcohol 43 (78mg, 0.36mmol) in dichloro-
methane (2.2mL) and pyridine (0.12mL, 1.45mmol)
added at ꢀ20ꢁC. The reaction mixture was stirred at
ꢀ20ꢁC for 20min and then allowed to warm to 0ꢁC.
After 1h at 0ꢁC, TLC (1:2, EtOAc/hexane) showed
complete conversion of starting material (Rf 0.21) to
one product (Rf 0.86). The reaction was diluted with
dichloromethane (30mL), washed with water (10mL),
dried over magnesium sulfate and concentrated under
reduced pressure. The residue was purified by column
4.21. Isopropyl 2,4-anhydro-5-azido-5-deoxy-3-O-tri-
fluoromethanesulfonyl-D-lyxonate 39
Triflic anhydride (0.125mL, 0.74mmol) was added
a solution of alcohol 40 (100mg,
dropwise to
0.465mmol) in dichloromethane (8mL) and pyridine
(0.113mL, 0.4mmol) at ꢀ30ꢁC. The reaction mixture
was stirred at ꢀ30 to ꢀ10ꢁC for 2.5h when TLC (1:3,
EtOAc/hexane) showed the complete conversion of

S. W. Johnson et al. / Tetrahedron: Asymmetry 15 (2004) 3263–3273
3273
4. Chung, Y.-K.; Claridge, T. D. W.; Fleet, G. W. J.;
Johnson, S. W.; Jones, J. H.; Lumbard, K. W.; Stachulski,
A. V. J. Peptide Sci. 2004, 10, 1–7.
chromatography (1:2, EtOAc/hexane) to give azide 44 as
a colourless oil (57mg, 48%). Found: C, 51.09; H, 8.71;
N, 12.36; C14H27N3O4Si requires: C, 51.04; H, 8.26; N,
26
D
5. Grotenbreg, G. M.; Timmer, M. S. M.; Llamas-Saiz, A.
L.; Verdoes, M.; van der Marel, G. A.; van Raaij, M. J.;
Overkleeft, H. S.; Overhand, M. J. Am. Chem. Soc. 2004,
126, 3444–3446; van Well, R. M.; Marinelli, L.; Altona,
C.; Erkelens, K.; Siegal, G.; van Raaij, M.; Llamas-Saiz,
A. L.; Kessler, H.; Novellino, E.; Lavecchia, A.; van
Boom, J. H.; Overhand, M. J. Am. Chem. Soc. 2003, 125,
10822–10829; van Well, R. M.; Overkleeft, H. S.; van der
Marel, G. A.; Bruss, D.; Thibault, G.; de Groot, P. G.;
van Boom, J. H.; Overhand, M. Bioorg. Med. Chem. Lett.
2003, 13, 331–334; Chakraborty, T. K.; Srinivasu, P.;
Madhavendra, S. S.; Kumar, S. K.; Kunwar, A. C.
Tetrahedron Lett. 2004, 45, 3573–3577; Chakraborty,
T. K.; Jayaprakash, S.; Srinivasu, P.; Madhavendra,
S. S.; Sankar, A. R.; Kunwar, A. C. Tetrahedron 2002,
58, 2853–2859; Chakraborty, T. K.; Jayaprakash, S.;
Diwan, P. V.; Nagaraj, R.; Jampani, S. R. B.; Kunwar,
A. C. J. Am. Chem. Soc. 1998, 120, 12962–12963.
12.75; ½aŠ ¼ þ50:3 (c, 0.815 in CHCl3); mmax (thin film):
2105 (s, N3), 1753, 1732 (s, C@O); dH (CDCl3,
400MHz): 0.051 (3H, s, SiCH3), 0.054 (3H, s, SiCH3),
0.86 (9H, s, SiC(CH3)3), 1.30 (3H, d, CH(CH3)2, J
6.3), 1.31 (3H, d, CH(CH3)2, J 6.3), 3.31–3.35 (1H, dd,
H-5, J 14.0, 3.1), 3.60–3.65 (1H, dd, H-50, J 14.0, 3.1),
4.86–4.93 (2H, m, H-3, H-4), 5.02 (1H, d, H-2, J 6.8),
5.09–5.18 (1H, septet, CH (CH3)2, J 6.3); dC (CDCl3,
100MHz): ꢀ5.2 (SiCH3), ꢀ5.0 (SiCH3), 18.0 (SiC
(CH3)3), 21.9 (CH(CH3)2), 22.0 (CH(CH3)2), 25.6 (·2)
(SiC(CH3)3), 52.3 (C-5), 67.7 (C-3), 69.0 (CH(CH3)2),
82.6 (C-2), 89.8 (C-4), 168.7 (C@O); m/z (APCI+ve):
347 (M þ NHþ4 , 99%), 330 (M+H+, 100%).
Acknowledgements
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.
Support from EPSRC studentships [to S.W.J. and
S.F.J.] are gratefully acknowledged.
´
7. Johnson, S. W.; Jenkinson (nee Barker), S. F.; Angus, D.;
Taillefumier, C.; Jones, J. H.; Fleet, G. W. J. Tetrahedron:
Asymmetry, in press.
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