C-3 branched δ-3,5-cis- and trans-THF sugar amino acids: Synthesis of the first generation of branched homooligomers

Article abstract of DOI:10.1007/s00726-011-0849-7

This article describes the efficient synthesis of the first generation of branched sugar amino acid (SAA) oligomers in solution phase via two main routes: by the use of a standard coupling reagent and via the use of active ester intermediates. Benzyl-protected dimeric carbopeptoid and methyl-protected dimeric and tetrameric, hexameric and octameric carbopeptoids were obtained from a branched δ-3,5-trans-tetrahydrofuran (THF) SAA and methyl-protected dimeric and tetrameric carbopeptoids were synthesised from a branched δ-3,5-cis-THF SAA. These systems are of interest because of their potential to display foldameric properties reminiscent of those observed in α-peptides and proteins. Amongst their many uses, foldamers provide simpler models in the study of the factors which induce the folding and unfolding of proteins and, ultimately, potential insights into their functioning.

Full text of DOI:10.1007/s00726-011-0849-7

Amino Acids (2011) 41:643–661
DOI 10.1007/s00726-011-0849-7
ORIGINAL ARTICLE
C-3 branched d-3,5-cis- and trans-THF sugar amino acids:
synthesis of the first generation of branched homooligomers
•
Michela I. Simone Alison A. Edwards
•
•
George E. Tranter George W. J. Fleet
Received: 4 January 2011 / Accepted: 12 February 2011 / Published online: 25 February 2011
Ó Springer-Verlag 2011
Abstract This article describes the efficient synthesis of
the first generation of branched sugar amino acid (SAA)
oligomers in solution phase via two main routes: by the use
of a standard coupling reagent and via the use of active
ester intermediates. Benzyl-protected dimeric carbopeptoid
and methyl-protected dimeric and tetrameric, hexameric
and octameric carbopeptoids were obtained from a bran-
ched d-3,5-trans-tetrahydrofuran (THF) SAA and methyl-
protected dimeric and tetrameric carbopeptoids were
synthesised from a branched d-3,5-cis-THF SAA. These
systems are of interest because of their potential to display
foldameric properties reminiscent of those observed in
a-peptides and proteins. Amongst their many uses, folda-
mers provide simpler models in the study of the factors
which induce the folding and unfolding of proteins and,
ultimately, potential insights into their functioning.
Keywords Sugar amino acids ꢀ Branched carbohydrates ꢀ
Secondary structure ꢀ Foldamers ꢀ Carbopeptoids
Introduction
In the mid-1990s, Gellman (Appella et al. 1996; Gellman
1998) and Seebach et al. (1996) and Seebach and Matthews
(1997) independently demonstrated that designed short-
chain homooligomers made of unnatural amino acids could
self-organise in a controlled fashion to form defined sec-
ondary structures (helices, sheets, b-hairpins, etc.) remi-
niscent of those observed in a-peptides and proteins. These
structures have been defined foldamers because of their
propensity to fold into well-defined secondary structures
(Gellman 1998).
Numerous classes of foldamers have since been syn-
thesised from a plethora of chemical scaffolds and their
properties investigated (Kirshenbaum et al. 1999; Lohof
et al. 1999; Dondoni and Marra 2000; Hill et al. 2001;
Chakraborty et al. 2002a, b, 2004, 2005; Gruner et al. 2002;
Schweizer 2002; Jensen and Brask 2005; Hecht and Huc
2007; Risseeuw et al. 2007). For example, homooligomers
based on aromatic systems (Ohkita et al. 1999; Dolain et al.
2005; Hu et al. 2006) have been shown to display helical
folding. This predisposition to fold is partly driven by p–p
stacking and promoted by protic solvents (Ohkita et al.
1999; Dolain et al. 2005; Hu et al. 2006). Other foldamers
based on aromatic systems fold into well-defined secondary
structures thanks to intramolecular hydrogen bonds
(Hamuro et al. 1997; Dolain et al. 2003; Ernst et al. 2003;
Kolomiets et al. 2003; Estroff et al. 2004; Wu et al. 2004).
The Gellman, Seebach and Hanessian groups synthesised
foldameric structures from oligomerisation of linear-
(Appella et al. 1996; Seebach et al. 1996) and cyclically
M. I. Simone (&)
School of Chemistry, Building F11, The University of Sydney,
Sydney, NSW 2006, Australia
e-mail: michela.simone@sydney.edu.au
M. I. Simone ꢀ A. A. Edwards ꢀ G. W. J. Fleet (&)
Chemistry Research Laboratory, Department of Chemistry,
University of Oxford, Mansfield Road,
Oxford OX1 3TA, UK
e-mail: george.fleet@chem.ox.ac.uk
A. A. Edwards
Medway School of Pharmacy, Universities of Kent
and Greenwich at Medway, Central Avenue,
Chatham Maritime, Kent ME4 4TB, UK
G. E. Tranter
Chiralabs Limited, Begbroke Centre for Innovation
and Enterprise, Oxford University Begbroke
Science Park, Oxfordshire OX5 1PF, UK
123

644
M. I. Simone et al.
constrained-b-peptides (Appella et al. 1996; Appella et al.
1999a, b; Barchi et al. 2000; Schinnerl et al. 2003), and c-
peptides (Hanessian et al. 1998; Hintermann et al. 1998;
Seebach et al. 2001, 2002). Other research groups syn-
thesised supramolecular polymers (Brunsveld et al. 2001;
Schenning et al. 2001; Hoeben et al. 2005; Lohr et al.
2005) which self-assemble into specific three-dimensional
structures (super-structures) in solution via non-covalent
interactions [e.g. intermolecular hydrogen bonds (Bruns-
veld et al. 2001; Schenning et al. 2001) and p–p interac-
tions (Schenning et al. 2001; Hoeben et al. 2005)].
2002), and also provide insight into the processes of protein
folding and unfolding (Baron et al. 2004).
Previously, all SAAs have been synthesised from linear-
carbon chain carbohydrates, which limited the number of
accessible structures. In the past, the main obstacle in the
synthesis of novel-branched building blocks was the lack of
simple derivatives of monosaccharides with a carbon
branch available cheaply and easily (Bols 1996). No
branched carbohydrates had ever been commercially
available before efficient synthetic strategies were devised
for their production (Hotchkiss et al. 2004; Simone et al.
2005, 2008; Soengas et al. 2005; Booth et al. 2008; Best
et al. 2010).
Carbohydrates have been employed as both starting
materials and scaffolds for the synthesis of foldameric
structures. Monosaccharides provide linear or cyclic sys-
tems which can be used as molecular templates to display
pharmacophoric groups in well-defined spatial orientations
by utilisation of their stereodiversity (Gruner et al. 2002).
Sugar amino acids (SAAs) are carbohydrate-derived amino
acids usually based on tetrahydropyran (THP), tetrahy-
drofuran (THF) or oxetane scaffolds and thus are cyclically
constrained (Fig. 1). They possess amine and carboxylic
acid moieties along with a number of other substituents. A
Branched carbohydrate systems are important for two
reasons. Firstly, their synthesis gives access to novel
classes of SAAs and has provided compounds with potent
biological activities. For example, the branched carbohy-
drate derivative 2,3:4,5-bis-O-(1-methylethylidene)-b-D-
fructopyranose sulfamate (TopiramateÒ) was marketed in
1987 as an anti-epileptic drug (Seeberger and Werz 2005).
Branched pyrrolidine imino sugars have recently been
synthesised from branched carbohydrate chirons and have
been shown to possess potent biological activities: isoDAB
is a potent and specific inhibitor of a-glucosidases and
isoLAB 1L shows a strong rescue of CFTR function in CF-
KM4 cells (Best et al. 2010). Secondly, the investigation of
the biological roles of branched carbohydrates is vital as
are found to have widespread use in nature (e.g. D-ham-
amelose, apiose, amipurimycin, Yoshimura 1984; aceric
acid, de Oliveira et al. 2008; myharamycin B, Knapp
1995).
´
plethora of a- (Bleriot et al. 2006), b- (Watterson et al.
1999; Edwards et al. 2006b; Jagadeesh et al. 2007, 2009),
c- (Claridge et al. 1999; Chakraborty et al. 2000; Watterson
et al. 2003; van Well et al. 2003; Edwards et al. 2006b) and
d- (Long et al. 1999; Hungerford et al. 2000) SAAs have
been synthesised and their propensity to fold into well-
defined secondary structures ascertained by the study of the
corresponding homooligomers (Smith et al. 1999; Hung-
erford et al. 2000; Grotenbreg et al. 2003; Watterson et al.
2003; Suhara et al. 2006; Claridge et al. 2008). In addition
to use as building blocks in the construction of carbopep-
toids, they have also been utilised as dipeptide isosteres
and incorporated into peptidomimetics (Gruner et al. 2002;
Chakraborty et al. 2008; Tuin et al. 2009).
This paper describes the oligomerisation routes employed
for the synthesis of the first generation of carbopeptoids from
branched SAAs (Scheme 1). The synthesis of the branched
SAA monomers has been described previously (Simone
et al. 2005, 2008). The d-3,5-trans branched THF SAA and
the d-3,5-cis branched THF SAA were both ultimately
synthesised from D-ribose. The efficient synthesis of the
corresponding homooligomers was achieved by two differ-
ent synthetic routes. The first route was partially successful
and employed coupling of amino- and carboxylic acid
derivatives of the SAAs with the standard coupling
reagent O-(benzotriazol-yl)-N,N,N0,N0-tetramethyluronium
SAA-based carbopeptoids and SAA-peptide hybrids
(Suhara et al. 1997) have been shown to possess important
biological and structural properties (von Roedern et al.
1996; Suhara et al. 1996a, b, 1997; Szabo et al. 1998).
They have potential applications as drugs that can block
protein–protein interactions and inhibit enzyme catalysis
(Chakraborty et al. 2002a; Gruner et al. 2002; Schweizer
Fig. 1 Families of cyclically
constrained d-SAA building
blocks
δ
α
O
CO2H
OH
δ
δ
H2N
O
O
α
O
CO2H
α
δ
CO2H
H2N
H2N
α
HO
CO2H
H2N
OH
HO OH
HO OH
OH
δ-Oxetane
δ-THP
δ-THF
Branched δ-THF
123

C-3 branched d-3,5-cis- and trans-THF SAAs
645
tetrafluoroborate (TBTU). However, the second route was
more efficient and utilised ‘active ester’ intermediates for
coupling with SAA-amine derivatives. Dimeric-, tetrameric-,
hexameric- and octameric-branched homooligomers were
thus derived from the d-3,5-trans branched THF SAA and
dimeric- and tetrameric-branched homooligomers from the
d-3,5-cis branched THF SAA. The foldameric properties
(Edwards et al. 2006a, 2008) of these oligomers were
analysed and these results will be published shortly.
produced, and coupled to afford the longer oligomers. In
the second strategy, the SAA building block was deriva-
tised into an active ester intermediate (C) which readily
reacted with amine (A) to form the corresponding dimer
(D where n = 0) without need of coupling reagents. The
dimer was then derivatised into its corresponding amine
and active ester, which were then coupled to form longer
oligomers.
It is noteworthy that the carboxylic acid and active ester
moieties on monomeric intermediates (B) and (C) and
subsequent oligomeric intermediates are neopentylic. Such
centres are very sterically hindered and typically highly
unreactive (Smith and March 2007). There are very few
examples in literature of the successful coupling of neo-
pentyl (or a,a-disubstituted) carboxylic acids to amines
(Wanner and Stamenitis 1993; Youssef et al. 2002).
Synthesis
General synthetic strategies
Two strategies were employed to achieve the synthesis of
the carbopeptoids in solution phase (Scheme 2). In the first
approach, a suitably O-protected branched d-THF SAA
building block was derivatised into the corresponding
amine (A) and acid (B) which, in the presence of a suitable
peptide coupling reagent, gave the dimeric product
(D where n = 0). The dimer was then subjected to the
same procedure and its corresponding amine and acid were
Strategy 1: synthesis of homooligomers via TBTU
couplings of d-3,5-trans branched SAA monomer
units protected at C-3 and C-4 hydroxyls
The main pre-requisite for the success of the iterative
coupling reactions of the branched SAA building blocks
O
O
N3
O
O
O
O
O
O
O
HO
N3
D-ribo series
H2N
N
RO OR
O
CO2H
HO OH
H
OH
N
H
O
O
O
O
RO OR
CO2Me
RO OR
n
branched δ-3,5-trans
2,3-O-isopropylidene-
-ribono-1,4-lactone
D
-ribono-2-hydroxymethyl
n = 0, 2, 4, 6
oligomers
THF SAA
D
branched lactone derivative
Oligomerisation;
formation
of 1st generation of
branched foldamers
O
OH
OH
Branching: Ho
crossed aldol
reaction
Formation
of SAA
HO
OH
D
-ribose
O
O
O
O
N3
O
O
O
O
O
HO
N3
H2N
N
RO OR
CO2H
O
H
OH
O
O
O
O
HO OH
N
RO OR
CO2Me
RO OR
H
L-lyxo series
n
2,3-O-isopropylidene-
-lyxono-1,4-lactone
L
-lyxono-2-hydroxymethyl
branched δ-3,5-cis
n = 0, 2
L
branched lactone derivative
THF SAA
oligomers
Scheme 1 First generation of branched carbopeptoids synthesised from two branched d-3,5-THF building blocks
H2N
H2N
CO2Me
PO OP
CO2Me
PO OP
N3
O
O
Coupling
reagent
CO2Me
PO OP
N3
N3
A
A
O
O
N
H
N
H
PO OP
PO OP
Protected
Branched
THF SAA
N
H
N
PO OP
PO OP
CO2Me
H
CO2Me
PO OP
-
PO OP
n
n
N3
N3
D
D
CO2
PO OP
H
CO2Pfp
PO OP
B
C
Active ester
Synthetic strategy 1
Synthetic strategy 2
Scheme 2 Strategies employed for the synthesis of the carbopeptoids (where P denotes a suitable protecting group)
123

646
M. I. Simone et al.
was the protection of the two hydroxyls at C-3 and C-4.
The coupling of unprotected SAA monomeric units was
unsuccessful; therefore, various protecting groups were
explored: tert-butyldimethylsilyl (TBDMS), benzyl (Bn)
and methyl (Me). The main advantage in using TBDMS
and Bn groups over Me groups is that they can be readily
cleaved once the oligomers have been synthesised. This
would allow access to a series of deprotected oligomers
facilitating aqueous solubility and allowing the hydroxyls
to participate in, and perhaps shape, the foldameric pref-
erences of this new class of carbopeptoid.
Initially, the protection of the two hydroxyls of 1 was
carried out with TBDMS-trifluoromethanesulfonate in
dichloromethane and 2,6-lutidine (Scheme 3). The reaction
afforded the di-silylated product 2 in 86% yield. Aqueous
hydrolysis of the protected methyl ester 2 gave, after
treatment with Amberlite IR-120 [H?], the crude acid 3 in
quantitative yield. Catalytic reduction of azide 2 with
O
N3
ii)
CO2H
[Si]O O[Si]
O
O
O
N3
iv)
N3
O
CO2Me
[Si]O O[Si]
X
N
[Si]O O[Si]
3
H
CO2Me
[Si]O O[Si]
iii)
O
H2N
2
CO2Me
5
[Si]O O[Si]
4
O
A
B
i)
N3
vi)
CO2H
O
BnO OBn
O
O
R
N3
viii)
O
CO2Me
N
BnO OBn
8
BnO OBn
H
CO2R'
BnO OBn
vii)
O
1
6
H2N
O
6
2
CO2Me
BnO OBn
N3
3
v)
10
CO2Me
HO OH
10: R=N3, R'= Me
9
O
ix)
x)
11: R=N3, R'=H
xi)
N3
1
X
CO2Bn
12: R=NH2, R'=Me
BnO OBn
7
O
O
N3
O
O
xii)
N
OBn
BnO
O
H
O
N
H
BnO OBn
O
N
BnO OBn
O
H
CO2Me
BnO OBn
xiii)
N3
CO2H
O
13
MeO OMe
O
O
R
O
xv)
N3
CO2Me
OMe
N
MeO OMe
15
H
CO2R'
MeO OMe
MeO
xiv)
O
H2N
14
CO2Me
MeO OMe
O
17
O
N3
O
17: R=N3, R'= Me
O
N
H
OMe
xvi)
MeO
O
xvii)
18: R=N3, R'=H
xviii)
16
O
N
MeO OMe
19: R=NH2, R'=Me
O
H
N
MeO OMe
H
CO2Me
MeO OMe
Reagents and conditions. i) TBDMSOTf, lutidine, DCM, 86%; ii) Aq. NaOH soln (1M), 1,4-dioxane, then
Amberlite IR-120 [H+], quant.; iii) Pd-black, 1,4-dioxane, H2, 82%; iv) TBTU, Et3N, DMF; v) TBAI, DMF, BnBr,
NaH, 54% (6), 5% (7); vi) Aq. NaOH soln (1M), 1,4-dioxane, then Amberlite IR-120 [H+], quant.; vii) Pd/C (10%),
THF, H2, quant.; viii) TBTU, DIPEA, DMF, 77%; ix) Aq. NaOH soln (1M), 1,4-dioxane, then IR-120 [H+], quant.; x)
Pd/C (10%), THF, H2, quant.; xi) TBTU, Et3N, DMF; xii) MeI, NaH, DMF, 83%; xiii) Aq. NaOH soln (1M), 1,4-
dioxane, then Amberlite; xiv) Pd/C, 1,4-dioxane, H2; xv) TBTU, Et3N, DMF, 65% (over three steps); xvi) Aq. NaOH
soln (1M), 1,4-dioxane, then Amberlite IR-120 [H+]; xvii) Pd/C (10%), 1,4-dioxane H2; xviii) TBTU, Et3N, DMF,
67% (over three steps).
Scheme 3 Synthesis of homooligomers via TBTU coupling of SAAs derived from 2,3-O-isopropylidene-D-ribono-1,4-lactone
123

C-3 branched d-3,5-cis- and trans-THF SAAs
647
palladium black and hydrogen gas afforded crude amine 4
in 82% yield. Coupling of the protected intermediates 3
and 4 with the standard coupling reagent TBTU, however,
did not provide dimer 5. This was most probably due to the
neopentyl carboxylic acid moiety being further sterically
hindered by the large TBDMS groups.
was attempted according to the same procedures described
for 10. The dimeric azido acid 11 and amino-ester 12 were
both obtained quantitatively from dimer 10 by, respec-
tively, hydrolysis of the ester functionality and reduction of
the azide. Coupling with TBTU and triethylamine, how-
ever, did not afford any of the desired tetramer 13. This
may be attributed to increased steric hindrance produced by
the protecting groups at the neopentyl carboxylic acid
moiety of the dimeric acid relative to the monomeric acid.
Methyl protection of the two hydroxyls on C-3 and C-4
of 1 was also investigated for three reasons: (a) they are
much smaller, non-bulky groups, (b) they lack chromoph-
ores, so will not complicate CD study and (c) the signals
from the methyl groups will not clutter the carbohydrate
Protection of the free hydroxyls of 1 with the smaller
benzyl protecting groups was subsequently explored. The
reaction was carried out in N,N-dimethylformamide (DMF),
with benzyl bromide, sodium hydride as base and TBAI as
catalyst (Scheme 4). Moderate yields (54%) of 6 were
obtained and accompanied by the formation of the triply
benzylated product 7 (5%). The use of THF as the reaction
solvent provided poorer yields of the benzylated product 6.
Hydrolysis of the protected methyl ester 6 with an
aqueous solution of sodium hydroxide afforded the corre-
sponding carboxylic acid 8, and reduction of the azido
group of protected precursor 6 with palladium on carbon
(10%) in the presence of hydrogen gave amine 9, both in
quantitative yield. When acid 8 and amine 9 were coupled
in DMF in the presence of N,N-diisopropylethylamine
(DIPEA) and the coupling reagent TBTU, the corre-
sponding dimer 10 was isolated in 74% yield.
1
region in the H NMR of the corresponding homooligo-
mers. However, the main short-coming is that they could
not be readily cleaved after oligomerisation. Therefore, the
secondary structural preferences of these carbopeptoids can
only be established as their protected derivatives. Methyl-
ation of the SAA precursor 1 was carried out in DMF with
sodium hydride as base and methyl iodide to give the
protected azidoester 14 in 83% yield. The synthesis of the
corresponding acid 15 and amine 16 from 14 was achieved
according to the same strategy discussed previously for the
derivatisation of precursor 6 into acid 8 and amine 9.
Following the successful synthesis of the perbenzylated
dimer 10, the synthesis of the corresponding tetramer 13
O
O
O
O
F
F
F
F
O
i)
ii)
N3
N3
O
CO2H
R
O
MeO OMe
F
MeO OMe
O
O
O
N
O
MeO OMe
iv)
R
O
N3
H
O
O
CO2Me
N
MeO OMe
15
21
N
MeO OMe
O
H
MeO OMe
H
CO2R'
MeO OMe
N
MeO OMe
O
CO2R'
H
iii) H2N
14
MeO OMe
CO2Me
MeO OMe
17
viii)
20: R=N3, R'= Me
23: R=NH2, R'= Me
17: R=N3, R'= Me
18: R=N3, R'=H
ix)
16
v)
vii)
vi)
22: R=N3, R'=Pfp
19: R=NH2, R'=Me
x)
O
O
R
O
O
N
MeO OMe
O
H
O
O
O
N
MeO OMe
N3
O
O
H
O
O
N
MeO OMe
N
MeO OMe
O
H
O
H
O
O
N
MeO OMe
N
H
MeO OMe
O
H
O
O
N
H
OMe
MeO
N
MeO OMe
CO2R'
MeO OMe
O
H
O
N
MeO OMe
O
H
24: R=N3, R'= Me
22: R=N3, R'=Pfp
25: R=NH2, R'= Me
O
N
MeO OMe
O
H
xi)
xii)
O
N
MeO OMe
O
H
N
H
MeO OMe
CO2Me
MeO OMe
Reagents and conditions. i) Aq. NaOH soln (1M), then Amberlite IR-120 [H+], 92%; ii) Pfp-OH, EDCI.HCl, 1,4-
dioxane, 93%; iii) Pd/C (10%), 1,4-dioxane, H2; iv) 1,4-dioxane, 86% (over two steps); v) Aq. NaOH soln (1M), then
Amberlite IR-120 [H+]; vi) Pfp-OH, EDCI.HCl, 1,4-dioxane, 67% (over two steps); vii) Pd-black, 1,4-dioxane, H2;
viii) 1,4-dioxane, 94% (over two steps); ix) Pd-black, 1,4-dioxane, H2; x) Pfp-ester 22, 1,4-dioxane, 99% (over two
steps); xi) Pd-black, 1,4-dioxane, H2; xii) 1,4-dioxane, 51% (over two steps).
Scheme 4 Synthesis of homooligomers via ‘active ester’ SAA intermediates derived from 2,3-O-isopropylidene-D-ribono-1,4-lactone
123

648
M. I. Simone et al.
TBTU coupling of these monomer units afforded the
methylated dimer 17 in 65% yield over three steps.
Hydrolysis of the ester and azide reduction of dimer 17
gave the corresponding acid 18 and amine 19, which upon
coupling with TBTU afforded tetramer 20 in 67% yield
(over three steps). Purification of dimer 17 and of tetramer
20 proved difficult as removal of the by-product HOBt
from the homooligomers was problematic.
reasons. Firstly, the reactions are very clean as the only by-
product was pentafluorophenol, which was easily separated
from the oligomeric products by flash column chromatog-
raphy—unlike HOBt. The reactions proceeded via the
synthesis of very stable intermediates (pentafluorophenyl
esters) which could be synthesised in high yields. Most
importantly, the overall coupling yields were much higher
when active esters were employed.
Thus, the first generation of branched THF-based ho-
mooligomers were synthesised from a novel-branched
SAA derived from 2,3-O-isopropylidene-D-ribono-1,4-lac-
tone: a benzyl-protected dimer and methyl-protected
dimer, tetramer, hexamer and octamer. Controlled iterative
couplings of SAAs were carried out with the standard
peptide coupling reagent TBTU and also via active ester
intermediates. In particular, the synthesis of higher ho-
mooligomers (hexamer and octamer) was only possible via
the use of active ester intermediates.
Strategy 2: synthesis of d-3,5-trans-homooligomers
via ‘‘active esters’’ from 14
There are many synthetic pathways and conditions which
can be utilised to form peptidic bonds (Jones 1997). Apart
from the use of coupling reagents, various methods operate
via the synthesis of ‘‘active ester’’ intermediates which
overcome the prohibitively slow reaction rates of simple
esters (e.g. methyl) towards aminolysis at room tempera-
ture. Increased activation has been achieved by the
attachment of electron-withdrawing groups, such as phenyl
and substituted phenyls, to the ester carbonyl (Schmidt
et al. 1981, 1987; Bodanszky and Bednarek 1989;
Bodanszky 1993; Mayes et al. 2004). It was possible to
obtain the pentafluorophenyl ester 21 (Scheme 4) in 85%
yield over two steps from methyl ester 14 by hydrolysis
and subsequent reaction of acid 15 in 1,4-dioxane with
pentafluorophenol and EDCIꢀHCl. Although highly reac-
tive, the active ester 21 is a stable crystalline solid.
Dimer 17 was obtained in 86% yield over two steps by
stirring pentafluorophenyl ester 21 and amine 16 in 1,4-
dioxane. The only by-product formed in the coupling
reaction was pentafluorophenol, which was easily sepa-
rated from the dimeric product by flash column chroma-
tography. The same procedure was followed for the
synthesis of tetramer 20 by an iterative approach. Dimer 17
was derivatised into the corresponding dimeric amine 19
quantitatively and the dimeric pentafluorophenyl ester 22
obtained in 67% yield over two steps. The active ester
intermediate 22 was a colourless crystalline solid whose
structural integrity was confirmed by X-ray crystallography
(Punzo et al. 2006). The coupling of the dimeric amine 19
and dimeric pentafluorophenyl ester 22 in 1,4-dioxane
occurred in excellent yield (94%) to give the pure tetramer
20 after flash column chromatography.
Synthesis of homooligomers from the d-3,5-cis-THF
SAA 27
The synthesis of unprotected oligomers was similarly not
possible from 27. However, interestingly the amine 28,
produced from the catalytic hydrogenation of SAA pre-
cursor azide 27, was an unstable intermediate (Scheme 5).
The amine moiety of intermediate 28 spontaneously
cyclised intramolecularly onto the ester group (i.e. ne-
opentylic carbon) to form the corresponding bicyclic
lactam (1R, 5S, 8R)-1,8-dihydroxybicyclo[3.2.1]-6-oxa-3-
aza-octan-2-one 29 when left at room temperature over-
night. Spontaneous cyclisations of d-cis-THF SAAs have
been observed previously (Smith et al. 1998; Long et al.
1999). This cyclisation was followed by the change of the
retention factors by t.l.c. analysis (ethyl acetate/methanol,
9:1, Rf(amine 28) baseline, Rf(bicyclic lactam 29) 0.21). Once
again, the neopentylic position was found to be highly
accessible and reactive, even though aminolyses of simple
esters (e.g. methyl esters as in this case) at room tem-
perature proceed at prohibitively slow rates in most cases
and the tetrahedral mechanism for substitution at a car-
bonyl carbon are also severely slowed or blocked at
neopentyl centres (Smith and March 2007). X-ray crys-
tallographic analysis confirmed formation of compound
29 (Punzo et al. 2004).
The synthesis of the hexamer 24 was achieved in 99%
yield over two steps by reaction of an excess of tetrameric
amine 23 and dimeric pentafluorophenyl ester 22 in 1,4-
dioxane. Finally, the synthesis of the octamer 26 was
achieved in 51% yield (over two steps) via the coupling of
hexameric amine 25 and dimeric pentafluorophenyl ester
22 in 1,4-dioxane.
Coupling of methyl protected d-3,5-cis-monomer units
via ‘‘active esters’’
To be prudent versus time, it was decided to directly pro-
tect the two free hydroxyls of the SAA precursor 27 as
methyl ethers since this was the optimal synthetic route for
the D-ribo series.
The active ester-mediated coupling reactions were more
successful than the TBTU-mediated route for various
123

C-3 branched d-3,5-cis- and trans-THF SAAs
649
6
O
7
3
NH
O
O
O
5
4
ii)
iii)
i)
N3
N3
H2N
8
CO2Me
CO2Me
CO2Me
2
1
HO
HO OH
MeO OMe
HO OH
O
HO
27
28
29
30
i)
iv)
O
O
N3
O
O
O
O
O
O
vi)
O
F
F
F
F
O
N
MeO OMe
v)
H2N
N3
N3
R
O
H
O
CO2Me
CO2H
O
N
MeO OMe
O
F
N
MeO OMe
MeO OMe
MeO OMe
MeO OMe
O
H
H
CO2R'
N
MeO OMe
MeO OMe
H
CO2Me
31
32
33
MeO OMe
34
vi)
34: R=N3, R'= Me
35: R=N3, R'=H
iv)
i) v)
36: R=N3, R'=Pfp
37: R=NH2, R'=Me
Reagents and conditions. i) Pd-black, 1,4-dioxane, H2, rt; ii) Overnight standing of amine 28, rt, 72% (over two
steps); iii) MeI, NaH, DMF, rt, 98%; iv) Aq NaOH soln (1M), acetone, then Amberlite IR-120 [H+], rt; v)
Pentafluorophenol, EDCI.HCl, 1,4-dioxane, rt, 96% (over two steps); vi) Pd-black, 1,4-dioxane, H2, rt; vii) 1,4-
dioxane, rt, 95% (over two steps); viii) Aq. NaOH soln (1M), 1,4-dioxane, then Amberlite IR-120 [H+], rt, 99%; ix)
Pentafluorophenol, EDCI.HCl, 1,4-dioxane, rt, 79%; x) Pd-black, 1,4-dioxane, H2; xi) 1,4-dioxane, 60°C, 88% (over
two steps).
Scheme 5 Synthesis of homooligomers via ‘active ester’ SAA intermediates derived from 2,3-O-isopropylidene-L-lyxono-1,4-lactone
Methylation gave 30 in 98% yield, although the yield
was poorer (69%) on a larger 700 mg scale. The protected
SAA precursor 30 was activated at the 20-position by
synthesis of the corresponding pentafluorophenyl ester 33
in excellent yield (96% over two steps from 30). The
protected SAA precursor 30 was also reduced to the cor-
responding amine 31. An excess of the stable pentafluor-
ophenyl ester intermediate 33 was then coupled to amine
31 in 1,4-dioxane to afford the corresponding dimer 34 in
an excellent 95% yield (over two steps from 30) as a white
crystalline solid. As for 21, the neopentylic position of the
active ester intermediate 33 was highly accessible and the
coupling reaction proceeded readily to afford the corre-
sponding dimer.
ester 36 in DMF at 60°C and (b) coupling of the tetrameric
pentafluorophenyl ester with the dimeric amine 37 in 1,4-
dioxane at 60°C. The desired hexamer was not isolated by
these conditions, despite the pentafluorophenyl ester starting
materials being consumed in the reaction.
Summary
It was possible to efficiently synthesise the first generation
of branched SAA oligomers in solution phase via two main
routes: by the use of a standard coupling reagent and via
the use of active ester intermediates. From the branched d-
3,5-trans-THF SAA 1, it was possible to obtain a benzyl-
protected dimeric carbopeptoid and methyl-protected
dimeric and tetrameric, hexameric and octameric carbo-
peptoids. From the branched d-3,5-cis-THF SAA 27, it was
possible to achieve the synthesis of methyl-protected
dimeric and tetrameric carbopeptoids.
The synthesis of the tetramer 38 was achieved according
to the same procedure: the dimeric acid 35 was produced in
99% yield as a white crystalline solid. This was followed
by the formation of the corresponding pentafluorophenyl
ester intermediate 36 in 79% yield. This active ester
intermediate 36 was also a stable compound for which it
was possible to obtain an X-ray crystallographic structure
(Simone et al. 2010). Subsequently, the dimeric amine 37
was produced and coupled to the pentafluorophenyl ester
36 in 1,4-dioxane at 60°C to yield the tetrameric species 38
in 88% yield over two steps. An excess of 1.05 equivalents
of the dimeric amine was used for this coupling, which
required heating to ensure reaction completion.
Experimental
General experimental
All commercial reagents were used as supplied. THF and
DMF were purchased dry from the Aldrich chemical
company in Sure-SealTM bottles. All other solvents were
used as supplied (analytical or HPLC grade) without prior
The synthesis of the hexamer was attempted by (a) cou-
pling of the tetrameric amine with the pentafluorophenyl
123

650
M. I. Simone et al.
purification. Water was distilled. Unless stated otherwise,
all moisture-sensitive reagents were handled and all reac-
tions were performed under an atmosphere of argon gas.
The gas atmospheres were maintained by an inflated bal-
loon. Thin layer chromatography (t.l.c.) was performed on
aluminium sheets coated with 60 F254 silica, visualised
using a spray of 0.2% (w/v) cerium (IV) sulphate and 5%
ammonium molybdate in 2 M sulfuric acid or 0.5% nin-
hydrin in methanol. Purification via flash column chro-
matography was performed on Sorbsil C60 40/60 silica or
neutral alumina. Melting points were recorded on a Kofler
hot block. Nuclear magnetic resonance spectroscopy
(NMR) spectra were recorded on Bruker AMX 500, DRX
500, DPX 400 or DQX 400 spectrometers in the deuterated
solvent stated. Chemical shifts (d) are quoted in ppm and
coupling constants (J) in Hz. Coupling constants are quoted
twice, each being recorded as observed in the spectrum
without averaging. Residual signals from the deuterated
solvents were used as an internal reference. The assign-
carboxylic acid methyl ester 1 (75 mg, 0.34 mmol) and 2,6-
lutidine in anhydrous dichloromethane (0.3 mL). After 15 h,
t.l.c. analysis (ethyl acetate:cyclohexane, 1:1) showed the
presence of one product (Rf 0.84) and complete consumption
of the starting material (Rf 0.18). The reaction mixture was
concentrated in vacuo and co-evaporated (ethyl acetate/tol-
uene) to afford a residue which was pre-absorbed on silica
(ethyl acetate/methanol) and purified by flash chromatog-
raphy (ethyl acetate:cyclohexane, 1:6) to yield the di-sily-
lated product 2 (132 mg, 86%) as a colourless oil. m/z (TOF
MS ES?): 446.2 ([M?H]?, 100%); HRMS (ES?): found
446.2509 [M?H]? C19H40N3O5Si2 requires 446.2507; [a]D21
?17.3 (c, 0.52 in chloroform); mmax (thin film): 2,931 (s, C–
H), 2,102 (s, N3), 1,750 (C=OOCH3) cm-1; dH (CDCl3,
400 MHz): 0.04 (3H, s, C3OSiC(CH3)), 0.08 (6H, s,
C3OSiC(CH3), C4OSiC(CH3)), 0.12 (3H, s, C4OSiC(CH3)),
0.85 (9H, s, C3OSiC(CH3)3), 0.92 (9H, s, C4OSiC(CH3)3),
0
3.39 (1H, dd, JH-6,H-6 12.9, JH-6,H-5 6.2, H-6), 3.45 (1H, dd,
0
J
(1H, d, JH-2,H-2 9.9, H-2), 3.97 (1H, m, J 4.4, H-5), 4.06 (1H,
H-6 ,H-6 12.9, JH-6 ,H-5 4.8, H-60), 3.74 (3H, s, CO2CH3), 3.95
0
1
ments of the H and 13C NMR spectra were obtained from
0
d, JH-4,H-5 4.4, H-4), 4.35 (1H, d, JH-2 ,H-2 10.0, H-20); dC
0
2D methods: COSY, HMQC, HMBC, HSQC and DEPT
correlations. Infra-red (IR) spectra were recorded on a
Perkin-Elmer 1750 IR Fourier Transform spectrophotom-
eter and on a Bruker Tensor 27 FT-IR spectrophotometer
using thin films on NaCl or Ge plates as stated. Only the
(CDCl3, 100 MHz): -4.9, -4.8 (C3OSiC(CH3)2), -4.1,
-3.8 (C4OSiC(CH3)2), 17.7 (C4OSiC(CH3)3), 18.1
(C3OSiC(CH3)3), 25.5 (C4OSiC(CH3)3), 25.6 (C4OSiC
(CH3)3), 51.8 (CO2CH3), 52.3 (C-6), 74.6 (C-2), 82.2 (C-4),
84.1 (C-5), 86.3 (C-3), 170.7 (CO2CH3).
characteristic peaks are quoted and in units of cm-1
.
Optical rotations were measured on a Perkin-Elmer 241
polarimeter with a path length of 1.0 dm. Concentrations
are quoted in g/100 mL. Low-resolution mass spectra were
recorded using the following techniques: electrospray
ionisation (ES) or field ionisation (FI). Low-resolution
mass spectra were measured on Micromass BioQ II-ZS,
Micromass 500 OAT, Micromass TofSpec 2E, Micromass
GCT, or Micromass Platform 1 mass spectrometers. High-
resolution mass spectra (HRMS) were measured on a Mi-
cromass 500 OAT spectrometer by CI or on a Waters
2790-Micromass LCT by ES. Elemental analyses were
performed by the microanalysis service of the Inorganic
Chemistry Laboratory, University of Oxford, Oxford.
Reactions were run at room temperature unless stated
otherwise. The numbering of all compounds and the
assignment of the spin systems for NMR data are in
accordance with the IUPAC nomenclature (as indicated in
Scheme 3 for compounds 1 and 10 and in Scheme 5 for
compound 29).
(3R, 4R, 5R)-5-Azidomethyl-3,4-di-O-benzyl-
tetrahydrofuran-3-carboxylic acid methyl ester 6 and (3R,
4R, 5R)-5-azidomethyl-3,4-di-O-benzyl-tetrahydrofuran-3-
carboxylic acid benzyl ester 7
A solution of benzyl bromide (1.25 mL, 10.51 mmol) and
tetrabutylammonium iodide (185 mg, 0.50 mmol) in DMF
(1.4 mL) were added dropwise to a stirred mixture of diol 1
˚
(1.087 g, 5.01 mmol) and 3 A molecular sieves in DMF
(21 mL). After 5 min, sodium hydride (60% dispersion in
natural oil, 601 mg, 15.03 mmol), freshly washed three
times with dry diethyl ether and successively dissolved in
DMF (14 mL), was added dropwise to the reaction mix-
ture. After 2.5 h, t.l.c. analysis (ethyl acetate:cyclohexane,
1:1) showed the presence of a minor UV-active product (Rf
0.82), a major UV-active product (Rf 0.77) and complete
consumption of the starting material (Rf 0.18). The reaction
mixture was diluted with diethyl ether (85 mL), washed
with brine (85 mL) and the brine extract was washed with
diethyl ether (39 250 mL). The organic extracts were
combined, dried (magnesium sulfate), concentrated in
vacuo and purified by flash column chromatography (ethyl
acetate:cyclohexane, 1:8) to afford the desired product 6
(Rf 0.77, 1.065 g, 54%) as a colourless oil and tri-benzy-
lated compound 7 (Rf 0.82, 125 mg, 5%) as a colourless
oil.
(3R, 4R, 5R)-5-Azidomethyl-3,4-di-O-tert-butyldimethyl
silanyloxy-tetrahydrofuran-3-carboxylic acid methyl
ester 2
tert-Butyldimethylsilyl trifluoromethanesulfonate (200 lL,
0.86 mmol) was added dropwise to a stirred solution of (3R,
4R, 5R)-5-azidomethyl-3,4-dihydroxy-tetrahydrofuran-3-
123

C-3 branched d-3,5-cis- and trans-THF SAAs
651
Data for 6 HRMS (ES?): found 420.1530 [M?Na]?
C21H23N3O5Na requires 420.1535; [a]2D0 ?35.4 (c, 0.75 in
methanol); mmax (thin film): 3,065, 3,033 (m, ArC–H),
2,951 (s, C–H), 2,101 (s, N3), 1,747 (CO2CH3) cm-1; dH
ethyl acetate) to afford (3R, 4R, 5R)-5-azidomethyl-3,4-di-
O-benzyl-tetrahydrofuran-3-carboxylic acid 8 (480 mg,
quant.) as a viscous colourless oil. m/z (ES?): 382.4 ([M-
H]-, 100%); HRMS (ES-): found 382.1406 [M-H]-
C20H20N3O5 requires 382.1403.
0
(CDCl3, 400 MHz): 3.30 (1H, dd, JH-6,H-6 13.0, JH-6,H-5
0
5.7, H-6), 3.36 (1H, dd, JH-6 ,H-6 12.9, JH-6 ,H-5 4.4, H-60),
3.83 (3H, s, CO2CH3), 4.04–4.11 (1H, m, J 4.4, H-5), 4.06
0
A
solution of di-benzylated ester
6
(500 mg,
1.26 mmol) in tetrahydrofuran (88 mL) was vigorously
stirred under an atmosphere of hydrogen in the presence of
palladised carbon (10%, 97 mg). After 3 h, t.l.c. analysis
(ethyl acetate:cyclohexane, 1:1) showed the presence of
one product (Rf baseline) and complete consumption of the
starting material (Rf 0.80). The reaction was degassed,
filtered through Celite (eluent: tetrahydrofuran) and con-
centrated in vacuo to afford (3R, 4R, 5R)-5-aminomethyl-
3,4-di-O-benzyl-tetrahydrofuran-3-carboxylic acid methyl
ester 9 (465 mg, quant.) as a colourless oil.
0
(1H, a-s, H-4), 4.34 (1H, d, JH-2,H-2 10.5, H-2), 4.40 (1H, d,
H-2 ,H-2 10.4, H-20), 4.49 (1H, d, JH-A,H-B 10.8, OHAHBPh),
0
J
4.51 (1H, d, JH-B,H-A 10.8, OHAHBPh), 4.57 (1H, d, JH-C,H-D
11.9, OHCHDPh), 4.72 (1H, d, JH-D,H-C 11.6, OHCHDPh),
7.24–7.42 (10H, m, Ar–Hs); dC (CDCl3, 100 MHz): 52.1
(C-6), 52.4 (CO2CH3), 68.6 (OCHAHBPh), 70.5 (C-2), 72.6
(OCHCHDPh), 81.9 (C-5), 86.5 (C-4), 90.2 (C-3), 127.7,
127.9, 128.0, 128.1, 128.5 (10C, 109 Ar–CH), 137.1, 137.3
(29 ArCCH2), 169.6 (CO2CH3).
The acid 8 (480 mg, 1.25 mmol) was then dissolved in
dichloromethane and combined with amine 9 (465 mg,
1.25 mmol). The dichloromethane was evaporated in vacuo
and DMF (6.6 mL), DIPEA (238 lL, 1.37 mmol) and
TBTU (642 mg, 2.00 mmol) were successively added to
the residues. After 19 h, t.l.c. analysis (ethyl ace-
tate:cyclohexane, 1:1) showed the presence of a major
product (Rf 0.68). The reaction mixture was concentrated
in vacuo, pre-absorbed on silica (ethyl acetate) and the
residue purified by flash column chromatography (ethyl
acetate:cyclohexane, 1:6 to 1:3) to yield the dimer 10
(712 mg, 77%) as a colourless oil. m/z (ES?): 795.5
([M?MeCN?NH4]?, 100%); HRMS (ES?): 737.3193
[M?H]? C41H45N4O9 requires 737.3187; [a]2D3 -4.7 (c,
1.00 in ethyl acetate); mmax (thin film): 3,417 (s, NH), 3,033
(ArC–H), 2,881 (C–H), 2,100 (s, N3), 1,743 (s,
C=OOCH3), 1,682 (s, C=ONH, I), 1,518 (s, C=ONH, II)
Data for 7 m/z (ES?): 496.3 ([M?Na]?, 15%), 532.4
([M?NH4?MeCN]?, 100%); HRMS (ES?): found
496.1839 [M?Na]? C27H27N3O5Na requires 496.1848;
[a]2D0 ?37.1 (c, 0.34 in methanol); mmax (thin film): 3,065,
3,033 (s, ArC–H), 2,882 (s, C–H), 2,101 (s, N3), 1,739
(CO2Bn) cm-1; dH (CDCl3, 400 MHz): 3.27 (1H, dd,
0
JH-6,H-6 12.8, JH-6,H-5 6.0, H-6), 3.33 (1H, dd, JH-6 ,H-6 12.8,
0
J
a-s, H-4), 4.35 (1H, d, JH-2,H-2 10.4, H-2), 4.42 (1H, d,
H-6 ,H-5 4.4, H-60), 4.04–4.11 (1H, m, J 4.4, H-5), 4.06 (1H,
0
0
JH-2 ,H-2 10.4, H-20), 4.46, 4.47 (2H, 29 s, OCHAHBPh),
0
4.52 (1H, d, JH-C,H-D 12.0, OCHCHDPh), 4.63 (1H, d,
JH-D,H-C 11.8, OCHCHDPh), 5.22 (1H, d, JH-E,H-F 12.2,
CO2CHEHFPh), 5.30 (1H, d, JH-F,H-E 12.2, CO2CHEHFPh),
7.19–7.41 (15H, m, 159 Ar–H); dC (CDCl3, 100 MHz):
52.1(C-6), 67.4(CO2CH2Ph), 68.5(OCHAHBPh), 70.4(C-2),
72.8 (OCHCHDPh), 82.0 (C-5), 86.5 (C-4), 90.2 (C-3), 127.8,
127.9, 128.0, 128.4, 128.5, 128.6, 128.7 (159 Ar–CH),
135.1 (CO2CH2C-Ar), 137.1, 137.2 (29 ArCCH2), 169.0
(CO2Bn).
cm-1; dH (C6D6, 500 MHz): 2.84 (1H, dd, JH-6,H-6 13.0,
0
0
0
JH-6,H-5 5.7, H-6, A), 2.92 (1H, dd, JH-6 ,H-6 12.9, JH-6 ,H-5
4.0, H-60, A), 3.34 (3H, s, CO2CH3, B), 3.57–3.62 (2H, m,
H-6 & H-60, B), 3.70 (1H, d, JH-4,H-5 5.2, H-4, A), 3.99 (1H,
d, JH-4,H-5 5.0, H-4, B), 4.02 (1H, d, JH-C,H-D 10.7,
OCHCHDPh), 4.05–4.10 (1H, m, J 5.1, H-5, B), 4.05 (1H,
a-q, J 5.3, H-5, A), 4.07 (1H, d, JH-A,H-B 10.1,
(3R, 4R, 5R)-5-{[((3R, 4R, 5R)-5-Azidomethyl-3,4-di-O-
benzyl-tetrahydrofuran-3-carbonyl)-amino]-methyl}-3,4-
di-O-benzyl-tetrahydrofuran-3-carboxylic acid methyl
ester 10
0
OCHAHBPh), 4.12 (1H, d, JH-2,H-2 10.3, H-2, B), 4.20
(3Hs, d, JH-B,H-A 10.6, OCHAHBPh & JH-D,H-C 10.6,
0
OCHCHDPh & JH-2 ,H-2 10.6, H-20, A), 4.21 (1H, d, JH-E,H-F
12.3, OCHEHFPh), 4.31 (1H, d, JH-G,H-I 11.3, OCHGHIPh),
An aqueous solution of sodium hydroxide (1 M, 4 mL) was
added to a stirred solution of dibenzylated ester 6 (500 mg,
1.26 mmol) in acetone (20 mL) and dioxane (33 mL).
After 15.5 h, t.l.c. analysis (ethyl acetate:cyclohexane, 1:1)
showed the presence of one product (Rf 0.19) and complete
consumption of the starting material (Rf 0.80). The reaction
mixture was stirred with ion exchange resin (Amberlite IR-
120 [H?]) at room temperature for 30 min. The solution
was filtered (eluents: acetone and water) and concentrated
in vacuo to yield a residue which was purified by flash
column chromatography (ethyl acetate:cyclohexane, 1:1 to
4.36 (1H, d, JH-2 ,H-2 10.2, H-20, B), 4.40 (1H, d, JH-I,H-G
11.5, OCHGHIPh), 4.50 (1H, d, JH-F,H-E 12.4, OCHEHFPh),
0
0
4.69 (1H, d, JH-2,H-2 10.7, H-2, A), 6.93 (1H, t, JNH,H-6&H-6
0
5.3, NH), 6.99–7.30 (20H, m, 209 ArH); dC (C6D6,
100 MHz): 41.2 (C-6, B), 51.9 (CO2CH3), 52.4 (C-6, A),
68.1 (OCHAHBPh), 69.0 (OCHCHDPh), 69.8 (C-2, A), 70.5
(C-2, B), 72.9 (OCHEHFPh), 73.4 (OCHGHIPh), 82.4 (C-5,
A), 82.9 (C-5, B), 86.8 (C-4, A), 88.0 (C-4, B), 90.64 (C-3,
B), 91.5 (C-3, A), 128.0, 128.1, 128.2, 128.3, 128.4, 128.6,
123

652
M. I. Simone et al.
128.7, 128.8, 128.9, 129.0 (209 Ar–CH), 137.8, 138.0,
138.2, 138.6 (49 ArCq), 168.7 (CONH), 169.6 (CO2CH3);
elemental analysis: C41H44N4O9 required C 66.83%, H
6.02%, N 7.60%; found C 66.63%, H 6.00%, N 7.58%.
material (Rf baseline) to a major UV-active product (Rf
0.90). The solvent was concentrated in vacuo and the resi-
due dissolved in dichloromethane (10 mL). The solution
was washed with sodium hydrogen carbonate solution (5%,
w/v, 5 mL), with citric acid solution (5%, w/v, 5 mL), then
again with sodium hydrogen carbonate solution (5%, w/v,
5 mL), and finally with water (5 mL). The organic layer
was dried (magnesium sulfate), filtered (eluent: dichloro-
methane) and concentrated in vacuo. The residue was
purified by flash column chromatography (ethyl ace-
tate:cyclohexane, 1:3) to yield the pentafluorophenyl ester
21 (110 mg, 93%; 85% over 2 steps) as a colourless oil.
HRMS (ES?): found 420.0589 [M?Na]? C14H12F5N3NaO5
requires 420.0589; [a]D23 ?43.7 (c, 2.56 in chloroform); mmax
(thin film): 2,940, 2,839 (C–H), 2,102 (s, N3), 1,784 (s,
C=OOPfp), 1,520 (Ar C=C), 1,274, 1,200, 1,093, 1,014 (s,
(3R, 4R, 5R)-5-Azidomethyl-3,4-dimethoxy-
tetrahydrofuran-3-carboxylic acid methyl ester 14
Sodium hydride (60% dispersion in natural oil, 96 mg,
2.40 mmol) was washed three times with dry diethyl ether.
It was then dissolved in DMF (2.4 mL) and added drop-
wise to a stirred solution of the diol 1 (87 mg, 0.40 mmol)
dissolved in DMF (2 mL). After 5 min, methyl iodide
(150 lL, 2.40 mmol) was added dropwise to the reaction
mixture. After 35 min, t.l.c. analysis (ethyl acetate:cyclo-
hexane, 1:1) revealed the presence of one product (Rf 0.74)
and complete consumption of the starting material (Rf
0.18). The reaction mixture was filtered (eluent: ethyl
acetate), concentrated in vacuo and purified by flash col-
umn chromatography (ethyl acetate:cyclohexane, 1:1) to
afford the dimethyl ether 14 (82 mg, 83%) as a pale yellow
oil. HRMS (FI?): found 245.1006 [M]? C9H15N3O5
requires 245.1012; mmax (thin film): 3,057, 2,954, 2,836 (C–
H), 2,104 (s, N3), 1,744 (s, C=OOCH3), 1,268, 1,138, 1,110
(s, C–O) cm-1; dH (CD3OD, 400 MHz): 3.30 (3H, s,
C3OCH3), 3.38 (3H, s, C4OCH3), 3.38 (1H, m, J 6.5, H-6),
C–F) cm-1; dH (CDCl3, 400 MHz): 3.45 (1H, dd, JH-6,H-6
0
12.8, JH-6,H-5 6.0, H-6), 3.45 (3H, s, C3OCH3), 3.47 (3H, s,
C4OCH3), 3.51 (1H, dd, JH-6 ,H-6 12.8, JH-6 ,H-5 5.1, H-60),
3.90 (1H, d, JH-4,H-5 4.2, H-4), 4.06–4.10 (1H, m, J 5.2,
0
0
0
0
H-5), 4.28 (1H, d, JH-2,H-2 10.6, H-2), 4.35 (1H, d, JH-2 ,H-2
10.6, H-20); dC (CDCl3, 100 MHz): 52.1 (C-6), 53.9
(C3OCH3), 58.6 (C4OCH3), 69.1 (C-2), 81.9 (C-5), 88.7 (C-
4), 90.7 (C-3), 124.5 (m, ArCq), 136.7, 138.5 (2C, m, 29
meta Ar–CH), 139.2, 139.7 (1C, m, para Ar–CH), 141.0,
142.2 (2C, m, 29 ortho Ar–CH), 165.2 (CO2Pfp). 19F NMR
3
3.46 (1H, dd, JH-6 ,H-6 12.9, JH-6 ,H-5 4.4, H-60), 3.72 (1H, d,
dF (benzene d6, 376 MHz): -161.9 (2F, dd, JFmeta,Fpara
0
0
3
21.6, JFmeta,Fortho 18.4, 29 Fmeta), -157.1 (1F, t,
J
J 4.9, H-5), 4.18 (1H, d, JH-2,H-2 10.4, H-2), 4.23 (1H, d,
H-4,H-5 4.8, H-4), 3.81 (3H, s, CO2CH3), 3.92–3.99 (1H, m,
0
3JFpara,Fmeta 21.6, Fpara), -151.9 (2F, d, JFortho,Fmeta 18.0,
29 Fortho).
3
JH-2 ,H-2 10.4, H-20); dC (CD3OD, 100 MHz): 51.7
0
(CO2CH3), 52.3 (C-6), 53.0 (C3OCH3), 58.2 (C4OCH3),
69.8 (C-2), 82.4 (C-5), 89.4 (C-4), 90.5 (C-3), 169.9
(CO2CH3).
(3R, 4R, 5R)-5-{[((3R, 4R, 5R)-5-Azidomethyl-3,4-
dimethoxy-tetrahydrofuran-3-carbonyl)-amino]-methyl}-
3,4-dimethoxy-tetrahydrofuran-3-carboxylic acid methyl
ester 17
(3R, 4R, 5R)-5-Azidomethyl-3,4-dimethoxy-
tetrahydrofuran-3-carboxylic acid pentafluorophenyl
ester 21
TBTU method An aqueous solution of sodium hydroxide
(1 M, 4 mL) was added to a solution of dimethyl ether 14
(108 mg, 0.44 mmol) and stirred at room temperature.
After 20 min, t.l.c. analysis (ethyl acetate:cyclohexane, 1:1)
showed the presence of one product (Rf baseline) and
complete consumption of the starting material (Rf 0.74). Ion
exchange resin (Amberlite IR-120 [H?]) was added to the
reaction mixture and stirred at room temperature for
15 min. The solution was filtered and concentrated in vacuo
to yield acid 15. A solution of dimethyl ether 14 (112 mg,
0.46 mmol) in 1,4-dioxane (7.5 mL) was vigorously stirred
under an atmosphere of hydrogen in the presence of palla-
dised carbon (10%, 40 mg). After 4 h, t.l.c. analysis (ethyl
acetate:cyclohexane, 1:1) showed the presence of one
product (Rf baseline) and complete consumption of the
starting material (Rf 0.74). The reaction was degassed, fil-
tered through Celite (eluent: 1,4-dioxane) and concentrated
An aqueous solution of sodium hydroxide (1 M, 2 mL) was
added to a stirred solution of dimethyl ether 14 (80 mg,
0.33 mmol) in 1,4-dioxane (2 mL). After 2 h, t.l.c. analysis
(ethyl acetate:cyclohexane, 1:1) indicated complete con-
version of the starting material (Rf 0.70) to one product (Rf
baseline). Amberlite IR-120 [H?] resin was added to the
solution which was then stirred for 15 min. The resin was
removed by filtration and the filtrate was concentrated in
vacuo to give (3R, 4R, 5R)-5-azidomethyl-3,4-dimethyl-
tetrahydrofuran-3-carboxylic acid 15 as white crystals
(69 mg). Pentafluorophenol (115 mg, 0.63 mmol) and
EDCIꢀHCl (95 mg, 0.50 mmol) were added to a stirred
solution of the acid 15 (69 mg, 0.30 mmol) in 1,4-dioxane
(3.5 mL). After 18 h, t.l.c. analysis (ethyl acetate:cyclo-
hexane, 1:1) indicated complete conversion of the starting
123

C-3 branched d-3,5-cis- and trans-THF SAAs
653
in vacuo to afford (3R, 4R, 5R)-5-aminomethyl-3,4-dime-
thoxy-tetrahydrofuran-3-carboxylic acid methyl ester 16.
The acid 15 was dissolved in dichloromethane and com-
bined with the amine 16, evaporated in vacuo and the res-
idues dissolved in DMF (2.1 mL). DIPEA (77 lL,
0.45 mmol) was then added to the stirred solution followed
by TBTU (205 mg, 0.64 mmol). After 14.5 h, more DIPEA
(200 lL, 1.16 mmol) was added dropwise to the stirred
solution bringing its pH from 6 to 9–10. After 6.5 h, t.l.c.
analysis (ethyl acetate:cyclohexane, 1:1) showed the pres-
ence of one major product (Rf 0.26) and complete con-
sumption of the starting materials (Rf baseline). The
reaction mixture was concentrated in vacuo and purified by
flash column chromatography (ethyl acetate:cyclohexane,
1:1) to afford the dimer 17 as a yellow oil. The product 17
was contaminated with 1-hydroxybenzotriazole which was
crystallised out of solution (ethyl acetate/cyclohexane). The
dimer 17 was obtained from the mother liquor as a col-
ourless oil (124 mg, 65%).
10.4, H-20, A), 6.90–7.00 (1H, br s, NH); dC (C6D6,
125 MHz): 40.9 (C-6, B), 51.8 (CO2CH3), 52.4 (C-6, A),
52.6 (C3OCH3, A), 53.3 (C3OCH3, B), 58.4 (C4OCH3, A),
58.8 (C4OCH3, B), 69.1 (C-2, A), 70.0 (C-2, B), 82.0 (C-5,
A), 82.1 (C-5, B), 88.4 (C-4, A), 89.3 (C-4, B), 90.4 (C-3,
A), 91.1 (C-3, B), 168.7 (CONH), 169.3 (CO2CH3).
(3R, 4R, 5R)-5-{[((3R, 4R, 5R)-5-Azidomethyl-3,4-
dimethoxy-tetrahydrofuran-3-carbonyl)-amino]-methyl}-
3,4-dimethoxy-tetrahydrofuran-3-carboxylic acid
pentafluorophenyl ester 22
An aqueous solution of sodium hydroxide (1 M, 2 mL), was
added to a stirred solution of dimer 17 (112 mg, 0.26 mmol)
in 1,4-dioxane (2 mL). After 1 h, t.l.c. analysis (ethyl ace-
tate:cyclohexane, 1:1) indicated complete conversion of the
starting material (Rf 0.26) to one product (Rf baseline).
Amberlite IR-120 [H?] resin was added to the solution
which was then stirred for 15 min. The resin was removed
by filtration and the filtrate was concentrated in vacuo to
give (3R, 4R, 5R)-5-{[((3R, 4R, 5R)-5-azidomethyl-3,
4-dimethoxy-tetrahydrofuran-3-carbonyl)-amino]-methyl}-
3,4-dimethoxy-tetrahydrofuran-3-carboxylic acid 18 as
white crystals. Pentafluorophenol (91 mg, 0.49 mmol) and
EDCIꢀHCl (57 mg, 0.30 mmol) were added to a stirred
solution of the acid 18 in 1,4-dioxane (4 mL) at 10°C. The
mixture was allowed to warm to room temperature. After
18 h, t.l.c. analysis (ethyl acetate:cyclohexane, 1:1) indi-
cated complete conversion of the starting material (Rf
baseline) to a major UV-active product (Rf 0.52). The sol-
vent was concentrated in vacuo and the residue was sus-
pended in dichloromethane (10 mL). The suspension was
washed with sodium hydrogen carbonate solution (5%, w/v,
5 mL), with citric acid solution (5%, w/v, 5 mL), then again
with sodium hydrogen carbonate solution (5%, w/v, 5 mL),
and finally with water (5 mL). The organic layer was dried
(magnesium sulfate), filtered (eluent: dichloromethane) and
concentrated in vacuo. The residue was purified by flash
column chromatography (ethyl acetate:cyclohexane, 1:1) to
yield the dimeric pentafluorophenyl ester 22 (102 mg, 67%)
as a colourless oil which crystallised on standing. M.p.
68–69°C (ethyl acetate/cyclohexane); m/z (ES-): 583.3
([M-H]-, 65%); HRMS (ES-): found 583.1463 [M-H]-
C22H24N4O9F5 requires 583.1263; [a]2D3 ?35.3 (c, 1.07 in
ethyl acetate); mmax (thin film): 3,350 (s, br, NH), 2,940
(C–H), 2,103 (s, N3), 1,785 (m, C=OOPfp), 1,678 (m,
C=ONH, I), 1,522 (s, C=ONH, II), 1,262, 1,202, 1,015 (m,
C–F) cm-1; dH (CDCl3, 400 MHz): 3.35 (3H, s, C3OCH3,
‘Active ester’ method A solution of the dimethyl ether 14
(80 mg, 0.33 mmol) in 1,4-dioxane (4 mL) was vigorously
stirred under an atmosphere of hydrogen in the presence of
palladised carbon (10%, 30 mg). After 2 h and 15 min,
t.l.c. analysis (ethyl acetate:cyclohexane, 1:1) showed the
presence of one product (Rf baseline) and complete con-
sumption of the starting material (Rf 0.74). The reaction
was degassed and filtered through Celite (eluent: 1,4-
dioxane) and concentrated in vacuo to afford amine 16.
The amine 16 was dissolved into 1,4-dioxane (5 mL) and
transferred into the flask containing the pentafluorophenyl
ester 21 and stirred. After 25 h, t.l.c. analysis (ethyl ace-
tate:cyclohexane, 1:1) showed the presence of one product
(Rf 0.23) and complete consumption of the pentafluor-
ophenyl ester (Rf 0.90). The reaction mixture was con-
centrated in vacuo and purified by flash column
chromatography (ethyl acetate:cyclohexane, 1:1 to ethyl
acetate) to afford dimer 17 (103 mg, 86%) as a colourless
oil. m/z (ES-): 431.4 ([M-H]-, 100%); HRMS (ES-):
found 431.1790 [M-H]- C17H27N4O9 requires 431.1778;
[a]2D5 ?28.3 (c, 0.62 in chloroform); mmax (thin film): 3,349
(s, NH), 2,939, 2,835 (C–H), 2,102 (s, N3), 1,743 (s,
C=OOCH3), 1,676 (s, C=ONH, I), 1,525 (s, C=ONH, II)
cm-1; dH (C6D6, 500 MHz): 2.95 (3H, s, C3OCH3, A), 3.05
0
(1H, dd, JH-6,H-6 13.1, JH-6,H-5 4.8, H-6, A), 3.11 (3H, s,
0
C3OCH3, B), 3.22 (1H, dd, JH-6 ,H-6 13.2, JH-6 ,H-5 4.5, H-60,
A), 3.28 (3H, s, C4OCH3, B), 3.31 (3H, s, C4OCH3, A),
0
0
3.47 (3H, s, CO2CH3, B), 3.60 (1H, dd, JH-6,H-6 14.2,
J
H-6,H-5 3.5, H-6, B), 3.79 (1H, d, JH-4,H-5 5.2, H-4, A), 3.84
0
0
A), 3.38 (1H, dd, JH-6,H-6 12.8, JH-6,H-5 5.3, H-6, A), 3.42
(1H, dd, JH-6 ,H-6 14.1, JH-6 ,H-5 4.4, H-60, B), 3.88 (1H, d,
JH-4,H-5 5.6, H-4, B), 4.10 (1H, m, H-5, B), 4.12 (1H, d,
(3H, s, C4OCH3, B), 3.45 (3H, s, C4OCH3, B), 3.47 (3H, s,
0
C3OCH3, B), 3.54 (1H, dd, JH-6 ,H-6 12.8, JH-6 ,H-5 4.9, H-60,
A), 3.57–3.62 (1H, a-dt, J 14.4, J 3.8, H-6, B), 3.74 (1H, d,
0
0
0
JH-2,H-2 10.1, H-2, B), 4.14–4.20 (2H, m, H-2 & H-5, A),
4.36 (1H, d, JH-2 ,H-2 10.0, H-20, B), 4.67 (1H, d, JH-2 ,H-2
0
0
0
JH-4,H-5 4.9, H-4, A), 3.76 (1H, ddd, JH-6 ,H-6 14.5, JH-6 ,H-5
0
123

654
M. I. Simone et al.
6.8, JH-6 ,NH 4.8, H-60, B), 3.83 (1H, d, JH-4,H-5 4.3, H-4, B),
4.06 (1H, m, H-5, A), 4.10–4.16 (1H, m, H-5, B), 4.25 (2H,
0
ethyl acetate to methanol) to yield tetramer 20 as a yellow
oil contaminated with 1-hydroxybenzotriazole. The
1-hydroxybenzotriazole was crystallised out of solution
(ethyl acetate). Tetramer 20 was obtained from the mother
liquor as a colourless oil (60 mg, 67%) which crystallised
on standing.
0
0
d, JH-2,H-2 10.9, H-2, B & H-2, A), 4.34 (1H, d, JH-2 ,H-2
0
10.9, H-20), 4.36 (1H, d, JH-2 ,H-2 11.0, H-20), 7.10–7.20 (1H,
m, NH); dC (CDCl3, 100 MHz): 40.8 (C-6, B), 52.3 (C-6,
A), 52.8 (C3OCH3, A), 53.7 (C3OCH3, B), 58.4, 58.9 (29
C4OCH3), 68.4, 68.7 (29 C-2), 81.5 (C-5, A), 81.9 (C-5, B),
88.0 (C-4, A), 89.4 (C-4, B), 89.8, 90.8 (29 C-3), 124.5 (m,
ArCq), 139.0, 137.0 (2C, m, meta Ar–CH), 137.0, 139.9
(1C, m, para Ar–CH), 140.0, 142.0 (2C, m, ortho Ar–CH),
165.1 (CONH), 169.0 (CO2Pfp); 19F NMR dF (CDCl3,
376 MHz): -161.6 (2F, dd, JFmeta,Fpara 22.0, JFmeta,Fortho
3
16.8, 29 Fmeta), -156.8 (1F, t, JFpara,Fmeta 21.9, Fpara),
3
-151.9 (2F, d, JFortho,Fmeta 16.6, 29 Fortho).
‘‘Active ester’’ method Dimer 17 (75 mg, 0.17 mmol) in
1,4-dioxane (3 mL) was vigorously stirred under an
atmosphere of hydrogen in the presence of palladium black
(30 mg). After 2 h, t.l.c. analysis (ethyl acetate:cyclohex-
ane, 1:1) showed the presence of one product (Rf baseline)
and complete consumption of the starting material (Rf
0.23). The reaction was degassed, filtered through Celite
(eluent: 1,4-dioxane) and concentrated in vacuo to afford
amine 19. The amine 19 was dissolved in 1,4-dioxane
(4 mL) and added to the residue of the pentafluorophenyl
ester 22 (102 mg, 0.18 mmol) and stirred. After 18 h, t.l.c.
analysis (ethyl acetate:cyclohexane, 1:1) showed almost
complete consumption of 22 (Rf 0.52). T.l.c. analysis (ethyl
acetate:methanol, 4:1) showed the presence of one product
(Rf 0.10). The reaction mixture was concentrated in vacuo
and purified by flash column chromatography (ethyl ace-
tate:cyclohexane, 1:1 to ethyl acetate to ethyl ace-
tate:methanol, 19:1 to 9:1) to yield tetramer 20 (100 mg,
72%; 94% based on recovered 22) as a colourless crys-
talline solid.
3
3
(3R, 4R, 5R)-5-{[((3R, 4R, 5R)-5-{[((3R, 4R, 5R)-5-{[((3R,
4R, 5R)-5-Azidomethyl-3,4-dimethoxy-tetrahydrofuran-
3-carbonyl)-amino]-methyl}-3,4-dimethoxy-
tetrahydrofuran-3-carbonyl)-amino]-methyl}-3,4-
dimethoxy-tetrahydrofuran-3-carbonyl)-amino]-methyl}-
3,4-dimethoxy-tetrahydrofuran-3-carboxylic acid methyl
ester 20
TBTU method An aqueous solution of sodium hydrox-
ide (1 M, 2 mL) was stirred with dimer 17 (48 mg,
0.11 mmol). After 30 min, t.l.c. analysis (ethyl ace-
tate:cyclohexane, 1:1) showed the presence of one prod-
uct (Rf baseline) and complete consumption of the starting
material (Rf 0.23). The reaction mixture was stirred with
ion exchange resin (Amberlite IR-120 [H?]) at room
temperature for 15 min. The solution was filtered and
concentrated in vacuo to yield acid 18 as a white crys-
talline solid. M.p. 166°C (water/acetone). A solution of
dimer 17 (50 mg, 0.12 mmol) in 1,4-dioxane (2 mL) was
vigorously stirred under an atmosphere of hydrogen in the
presence of palladised carbon (10%, 20 mg). After
30 min, t.l.c. analysis (ethyl acetate:cyclohexane, 1:1)
showed the presence of one product (Rf baseline) and
complete consumption of the starting material (Rf 0.23).
The reaction was degassed, filtered through Celite (eluent:
1,4-dioxane) and concentrated in vacuo to afford (3R,
4R, 5R)-5-{[((3R, 4R, 5R)-5-aminomethyl-3,4-dimethoxy-
tetrahydrofuran-3-carbonyl)-amino]-methyl}-3,4-dimethoxy-
tetrahydrofuran-3-carboxylic acid methyl ester 19. The
dimer acid 18 was dissolved in dichloromethane and
combined with the amine 19. The dichloromethane was
evaporated in vacuo and the residue stirred in DMF
(2 mL). DIPEA (96 lL, 0.55 mmol) was added to the
stirred solution followed by TBTU (56 mg, 0.17 mmol).
After 16 h, t.l.c. analysis (ethyl acetate) showed the
presence of one major product (Rf 0.10). The reaction
mixture was concentrated in vacuo, purified by flash
column chromatography (ethyl acetate:cyclohexane, 1:1 to
M.p. 38–39°C (ethyl acetate/methanol); HRMS (ES?):
found 807.3622 ([M?H]?, 85%), 824.3908 ([M?NH4]?,
100%), 829.3452 ([M?Na]?, 63%), C33H55N6O17 requires
807.3624; [a]2D3 ?31 (c, 4.2 in methanol); mmax (thin film):
3,349 (br, NH), 2,940 (C–H), 2,102 (m, N3), 1,741 (m,
C=OOCH3), 1,670 (s, C=ONH, I), 1,528 (s, C=ONH, II)
cm-1; dH (C6D6, 500 MHz): 2.93, 2.94, 2.96, 3.10 (49 3H,
49 s, 49 C3OCH3, all rings), 3.05 (1H, dd, JH-6,H-6 13.1,
0
0
0
JH-6,H-5 4.6, H-6, A), 3.23 (1H, dd, JH-6 ,H-6 13.1, JH-6 ,H-5
4.8, H-60, A), 3.30, 3.33, 3.48, 3.51 (49 3H, 49 s, 49
C4OCH3, all rings), 3.49 (3H, s, CO2CH3, D), 3.59–3.71
(3H, m, 39 H-6), 3.77–3.97 (3H, m, 39 H-60), 3.79 (1H, d,
JH-4,H-5 5.7, H-4), 3.84 (1H, d, JH-4,H-5 6.4, H-4, A), 3.87
(1H, d, JH-4,H-5 6.4, H-4), 3.95 (1H, d, JH-4,H-5 5.8, H-4),
4.09–4.19 (5H, m, H-5, 49 H-2, all rings), 4.21 (1H, m,
J
H-5,H-6 4.9, H-5, A), 4.22–4.32 (2H, m, 29 H-5), 4.40 (1H,
0
d, JH-2 ,H-2 10.3, H-20), 4.66 (1H, d, JH-2 ,H-2 10.4, H-20),
0
4.73 (1H, d, JH-2 ,H-2 10.2, H-20), 4.74 (1H, d, JH-2 ,H-2 10.2,
H-20), 6.80–6.89 (2H, m, 29 NH), 6.92–6.97 (1H, m, NH);
dC (C6D6, 125 MHz): 40.6, 40.7, 40.8 (C-6), 51.6
(CO2CH3, D), 52.5 (C-6, A), 52.1, 52.8, 52.9, 53.2 (49
C3OCH3, all rings), 58.4, 58.8, 58.9, 59.0 (49 C4OCH3,
all rings), 69.1, 69.2, 69.3, 70.2 (49 C-2, all rings), 81.0,
81.6, 81.7 (39 C-5), 81.1 (C-5, A), 88.2, 88.3, 89.0 (39
C-4), 88.4 (C-4, A), 90.2, 90.6, 90.6, 90.9 (49 C-3, all
rings), 168.6, 168.7, 168.8 (39 CONH), 169.3 (CO2CH3).
0
0
123

C-3 branched d-3,5-cis- and trans-THF SAAs
Hexamer 24
655
Octamer 26
A solution of tetramer 20 (30 mg, 0.04 mmol) in 1,4-
dioxane (2 mL) and methanol (1 mL) was vigorously
stirred under an atmosphere of hydrogen in the presence
of palladium black (5 mg). After 1 h, t.l.c. analysis (ethyl
acetate:methanol, 4:1) showed the presence of one
product (Rf baseline) and complete consumption of the
starting material (Rf 0.20). The reaction was degassed,
filtered through Celite (eluent: methanol) and concen-
trated in vacuo to afford tetrameric amine 23. Amine 23
was dissolved in 1,4-dioxane (2 mL) and combined with
the dimeric pentafluorophenyl ester 22 (15 mg,
0.03 mmol) and stirred. After 17.5 h, t.l.c. analysis (ethyl
acetate:methanol, 4:1) showed complete consumption of
the starting material 22 (Rf 0.90) and the presence of a
major product (Rf 0.38). The reaction mixture was con-
centrated in vacuo and purified by flash column chro-
matography (ethyl acetate:methanol, 19:1 to 9:1) to yield
hexamer 24 (30 mg, 99%) as a colourless crystalline
A solution of hexamer 24 (76 mg, 0.06 mmol) in 1,4-
dioxane (5 mL) was vigorously stirred under an atmo-
sphere of hydrogen in the presence of palladium black
(30 mg). After 3 h, t.l.c. analysis (ethyl acetate:methanol,
4:1) showed the presence of one product (Rf baseline) and
complete consumption of the starting material (Rf 0.38).
The reaction was degassed, filtered through Celite (eluent:
methanol) and concentrated in vacuo to afford hexameric
amine 25. The dimeric pentafluorophenyl ester 22 (37 mg,
0.06 mmol) was dissolved in 1,4-dioxane (8 mL) com-
bined with the amine 24 and stirred. After 15.5 h, t.l.c.
analysis (ethyl acetate:methanol, 4:1) showed complete
consumption of the starting material 22 (Rf 0.90) and the
presence of a major product (Rf 0.22). The reaction mixture
was concentrated in vacuo and purified by flash column
chromatography (ethyl acetate:methanol, 4:1) to yield
octamer 26 (50 mg, 51%) as white crystalline solid. M.p.
87–88°C (ethyl acetate/methanol); isotopic distribution
(ES?): found 778.35 (100%), 778.86 (71%), 779.36 (33%),
solid. M.p. 72–74°C (ethyl acetate/methanol); m/z (ES?)
?
1,203.3 ([M?Na]?, 100%), 1,239.5 ([M?NH4
?
779.86 (11%), 780.36 (4%) [C65H106N10O33?2H]2?
,
MeCN]?, 87%); isotopic distribution (ES?): found
1,203.52 (100%), 1,204.54 (24%), 1,205.56 (3%),
1,206.60 (0.2%), required 1,203.51 (100%), 1,204.52
(60%), 1,205.52 (22%), 1,206.52 (6%); [a]2D3 ?0.71 (c,
0.21 in methanol); mmax (thin film): 3,348 (br, NH), 2,934
(s, C–H), 2,102 (s, N3), 1,741 (m, C=OOCH3), 1,670 (s,
C=ONH, I), 1,522 (s, C=ONH, II) cm-1; dH (C6D6,
500 MHz): 2.96 (6H, s, 29 C3OCH3), 2.97 (3H, s,
C3OCH3), 2.98, 2.99 (29 3H, 29 s, 29 C3OCH3), 3.08
required 778.35 (100%), 778.86 (76%), 779.36 (35%),
779.86 (12%), 780.36 (4%); [a]2D3 ?19.7 (c, 0.30 in
methanol); mmax (thin film): 3,348 (br, NH), 2,942, 2,836 (s,
C–H), 2,104 (m, N3), 1,739 (m, C=OOCH3), 1,668 (s,
C=ONH, I), 1,531 (s, C=ONH, II) cm-1
;
dH
(C6D6:CD3OD, 7:1, 500 MHz): 3.07 (3H, s, C3OCH3),
3.10 (29 3H, s, 29 C3OCH3), 3.12 (3H, s, C3OCH3), 3.13
(29 3H, s, 29 C3OCH3), 3.14, 3.17 (29 3H, 29 s, 29
C3OCH3), 3.07–3.17 (2H, m, H-6 & H-60, A), 3.33, 3.36,
3.51, 3.51, 3.52 (59 3H, 59 s, 59 C4OCH3), 3.53 (39 3H,
s, 29 C4OCH3 & CO2CH3, H), 3.54 (3H, s, C4OCH3),
3.61–3.88 (22H, m, 89 H-4, 79 H-6, 79 H-60), 4.13–4.33
0
(1H, ddd, JH-6,H-6 13.1, JH-6,H-5 4.8, JH-6,NH 1.5, H-6, A),
0
3.13 (3H, s, C3OCH3), 3.26 (1H, ddd, JH-6 ,H-6 13.0,
JH-6 ,H-5 4.6, JH-6 ,NH 1.2, H-60, A), 3.31, 3.34 (6H, 29 s,
29 C4OCH3), 3.51 (6H, s, C4OCH3 & CO2CH3, F), 3.52,
3.53, 3.54 (39 3H, 39 s, 39 C4OCH3), 3.60–3.74 (5H,
m, 59 H-6), 3.80–3.98 (5H, m, 59 H-60), 3.81 (1H, d,
JH-4,H-5 5.6, H-4, A), 3.87 (1H, d, JH-4,H-5 6.5, H-4), 3.91
(1H, d, JH-4,H-5 6.2, H-4), 3.94 (2H, d, JH-4,H-5 6.3, 29
H-4), 3.97 (1H, d, JH-4,H-5 6.0, H-4), 4.10–4.20 (7H, m,
69 H-2 & H-5), 4.21 (1H, m, H-5, A), 4.25–4.35 (4H, m,
0
0
0
(16H, m, 59 H-2, 59 H-5), 4.37 (1H, d, JH-2 ,H-2 10.4,
0
H-20), 4.56 (1H, d, JH-2 ,H-2 10.4, H-20), 4.59–4.65 (6H, m,
69 H-20, all rings), 7.15–7.51 (m, 79 NH); dC
(C6D6:CD3OD, 7:1, 125 MHz): 40.9, 41.0, 41.1, 41.2, 41.3
(79 C-6), 51.8 (CO2CH3, H), 52.2 (C-6, A), 52.6, 52.8 (39
C3OCH3), 52.9 (4C, s, 49 C3OCH3), 53.2 (C3OCH3), 58.4,
58.6, 58.7 (49 C4OCH3), 58.8 (4C, s, 49 C4OCH3), 69.0
(2C, 29 s, 39 C-2), 69.1 (3C, s, 39 C-2), 69.9 (2C, s, 29
C-2), 81.3 (5C, s, 59 C-5), 81.4, 81.7, 81.9 (39 C-5), 88.4,
88.5 (29 C-4), 88.6 (3C, s, 39 C-4), 88.6, 89.1 (39 C-4),
90.1 (C-3), 90.5 (6C, 29 s, 69 C-3), 90.8 (C-3), 169.4
(CONH), 169.4, 169.5, 169.6 (6C, 39 s, 69 CONH), 169.7
(CONH).
49 H-5), 4.40 (1H, d, JH-2 ,H-2 10.3, H-20), 4.66 (1H, d,
0
JH-2 ,H-2 10.4, H-20), 4.72 (1H, d, JH-2 ,H-2 10.5, H-20),
0
0
4.73 (1H, d, JH-2 ,H-2 10.0, H-20), 4.74 (1H, d, JH-2 ,H-2
10.9, H-20), 4.75 (1H, d, JH-2 ,H-2 10.1, H-20), 6.87–6.92
0
0
0
(2H, m, 29 NH), 6.91–6.97 (2H, m, 29 NH), 6.96–7.01
(1H, m, NH); dC (C6D6, 125 MHz): 40.6, 40.7, 40.8, 40.9
(59 C-6), 51.7 (CO2CH3, F), 52.2 (C-6, A), 52.5, 52.9
53.0, 53.3 (69 C3OCH3), 58.4, 58.8, 58.9, 59.0, 59.1 (69
C4OCH3), 69.1, 69.2, 69.4, 70.2 (6C, 69 C-2), 80.9, 81.0,
81.1, 81.6 (6C, 69 C-5), 88.1, 88.2, 88.3, 88.4, 89.0 (6C,
69 C-4), 90.2, 90.6, 90.9 (6C, 69 C-3), 168.6, 168.8,
168.9, 169.3 (69 CONH).
(1R, 5S, 8R)-1,8-Dihydroxybicyclo-[3.2.1]-6-oxa-3-
aza-octan-2-one 29
Palladium black (20 mg) was added to a stirred solution
of methyl (3R, 4R, 5S)-5-azidomethyl-3,4-dihydroxy-
123

656
M. I. Simone et al.
(3R, 4R, 5S)-5-Azidomethyl-3,4-dimethoxy-
tetrahydrofuran-3-carboxylic acid pentafluorophenyl
ester 33
tetrahydrofuran-3-carboxylate 27 (34 mg, 0.16 mmol) in
1,4-dioxane (5 ml) under an atmosphere of hydrogen at
room temperature. After 1.5 h, t.l.c. analysis (ethyl ace-
tate:cyclohexane, 1:1) showed complete conversion of the
starting material (Rf 0.23) to one product (Rf baseline). The
reaction mixture was filtered through Celite (eluent: 1,4-
dioxane) and concentrated in vacuo. The residue was left at
room temperature overnight, after which t.l.c. analysis
(ethyl acetate:methanol, 9:1) showed the presence of one
spot (Rf 0.21). Purification by flash column chromatogra-
phy (ethyl acetate:methanol, 93:7) yielded the bicyclic
lactam 29 (25 mg, 72%) as a white crystalline solid. M.p.
194–197°C (decomposition; ethyl acetate/methanol);
m/z (ES-): 158.05 ([M-H]-, 100%); HRMS (ES-): found
158.0459 [M-H]- C6H8NO4 requires 158.0453; [a]2D3
-5.2 (c, 0.22 in methanol); mmax (thin film): 3,463 (OH),
3,285 (br s, NH), 2,887 (s, C–H), 1,691 (s, C=ONH, I),
1,651 (s, C=ONH, II) cm-1; dH (D2O, 500 MHz): 3.35
An aqueous sodium hydroxide solution (1 M, 1.5 mL), was
added to a stirred solution of the dimethyl ether 30 (117 mg,
0.48 mmol) in acetone (3 mL). After 45 min, t.l.c. analysis
(ethyl acetate:cyclohexane, 1:1) indicated complete con-
version of the starting material (Rf 0.79) to one product (Rf
baseline). Amberlite IR-120 [H?] resin was added to the
solution which was then stirred for 15 min. The resin was
removed by filtration and the filtrate was concentrated in
vacuo to give (3R, 4R, 5S)-5-azidomethyl-3,4-dimethyl-tet-
rahydrofuran-3-carboxylic acid 32 as white crystals. Penta-
fluorophenol (167 mg, 0.91 mmol) and EDCIꢀHCl (137 mg,
0.72 mmol) were then added to a stirred solution of the acid
32. After 24 h, t.l.c. analysis (ethyl acetate:cyclohexane, 1:1)
indicated complete conversion of the starting material (Rf
baseline) to a major UV-active product (Rf 0.83). The solvent
was concentrated in vacuo and the residue was suspended in
dichloromethane (25 mL). The organic layer was washed
with sodium hydrogen carbonate solution (5%, w/v, 10 mL),
with citric acid solution (5%, w/v, 10 mL), then with sodium
hydrogen carbonate solution (5%, w/v, 5 mL), and finally
with water (5 mL). The organic layer was dried (magnesium
sulfate), filtered (eluent: dichloromethane) and concentrated
in vacuo. The residue was purified by flash column chro-
matography (ethyl acetate:cyclohexane, 1:5) to yield the
pentafluorophenyl ester 33 (182 mg, 96% over two steps) as
a pale yellow oil. m/z (FI?): 397.06 [M]? C14H12F5N3O5
requires 397.0697; mmax (thin film): 2,946 (C–H), 2,105 (s,
N3), 1,785 (s, CO2Pfp) cm-1; [a]2D3 ?20.9 (c, 0.67 in chlo-
roform); dH (CDCl3, 400 MHz): 3.43 (3H, s, C3OCH3), 3.47
0
(1H, dd, JH-4,H-4 13.5, JH-4,H-5 1.8, H-4), 3.50 (1H, dd,
0
JH-4 ,H-4 13.4, JH-4 ,H-5 1.6, H-40), 3.84 (1H, d, JH-7,H-7 8.3,
0
0
H-7), 4.09 (1H, d, JH-7 ,H-7 8.3, H-70), 4.41 (1H, ddd, JH-5,H-4
0
0
1.8, JH-5,H-4 1.6, JH-5,H-8 6.0, H-5), 4.52 (1H, d, JH-8,H-5 6.1,
H-8); dC (D2O, 125 MHz): 45.8 (C-4), 72.2 (C-8), 74.4
(C-5), 74.5 (C-7), 77.0 (C-1), 175.0 (CONH).
(3R, 4R, 5S)-5-Azidomethyl-3,4-dimethoxy-
tetrahydrofuran-3-carboxylic acid methyl ester 30
Sodium hydride (60% dispersion in natural oil, 156 mg,
3.90 mmol) was washed three times with dry diethyl ether
and then dissolved in DMF (2.0 mL). This solution was
added dropwise to a stirred solution of diol 27 (141 mg,
0.65 mmol) in DMF (7.0 mL). 5 min later, methyl iodide
(247 lL, 3.97 mmol) was added dropwise to the stirred
reaction mixture. After 24 h, t.l.c. analysis (ethyl ace-
tate:cyclohexane, 1:1) revealed the presence of one product
(Rf 0.79) and complete consumption of the starting material
(Rf 0.23). The reaction mixture was filtered (eluent: ethyl
acetate), concentrated in vacuo and purified by flash col-
umn chromatography (ethyl acetate:cyclohexane, 1:3) to
afford the dimethyl ether 30 (156 mg, 98%) as a pale
yellow oil. m/z (ES?): 268.1 ([M?Na]?, 100%); HRMS
(ES?): found 268.0899 [M?Na]? C9H15N3O5Na requires
268.0909; [a]2D3 -18.7 (c, 1.11 in methanol); mmax (thin
0
(1H, dd, JH-6,H-6 12.4, JH-6,H-5 6.2, H-6), 3.52 (3H, s,
0
C4OCH3), 3.62 (1H, dd, JH-6 ,H-6 12.5, JH-6 ,H-5 7.2, H-60),
0
0
4.00 (1H, d, JH-4,H-5 3.6, H-4), 4.19 (1H, d, JH-2,H-2 10.7,
0
H-2), 4.32–4.36 (1H, m, H-5), 4.37 (1H, d, JH-2 ,H-2 10.7,
H-20); dC (CDCl3, 100 MHz): 49.4 (C-6), 53.3 (C3OCH3),
60.9 (C4OCH3), 68.3 (C-2), 80.0 (C-5), 87.1 (C-4), 91.0 (C-
3), 124.5 (m, ArCq), 137.0, 138.9 (2C, m, 29 meta Ar–CH),
138.8, 140.8 (1C, m, para Ar–CH), 139.9, 142.0 (2C, m, 29
ortho Ar–CH), 164.9 (CO2Pfp). 19F NMR dF (CDCl3,
3
3
376 MHz): -161.5 (2F, dd, JFmeta,Fpara 21.1, JFmeta,Fortho
3
17.3, 29 Fmeta), -156.7 (1F, t, JFpara,Fmeta 21.4, Fpara),
-151.9 (2F, d, 3JFortho,Fmeta 16.9, 29 Fortho).
film): 2,952 (C–H), 2,100 (s, N3), 1,740 (C=OOCH3) cm-1
;
dH (CDCl3, 400 MHz): 3.27 (3H, s, C3OCH3), 3.40 (3H, s,
C4OCH3), 3.40 (1H, dd, JH-6,H-6 12.5, JH-6,H-5 7.1, H-6), 3.56
0
(3R, 4R, 5S)-5-{[((3R, 4R, 5S)-5-Azidomethyl-3,4-
dimethoxy-tetrahydrofuran-3-carbonyl)-amino]-methyl}-
3,4-dimethoxy-tetrahydrofuran-3-carboxylic acid methyl
ester 34
(1H, dd, JH-6 ,H-6 12.4, JH-6 ,H-5 7.0, H-60), 3.81(1H, d, JH-4,H-5
0
0
0
4.1, H-4), 3.82 (3H, s, CO2CH3), 4.05 (1H, d, JH-2,H-2 10.4,
0
H-2), 4.22–4.26 (1H, m, J 4.1, H-5), 4.26 (1H, d, JH-2 ,H-2
10.3, H-20); dC (CDCl3, 100 MHz): 49.6 (C-6), 52.3
(CO2CH3), 52.9 (C3OCH3), 60.5 (C4OCH3), 68.4 (C-2), 79.7
(C-5), 87.1 (C-4), 90.4 (C-3), 168.9 (CO2CH3).
‘‘Active ester’’ method A solution of the dimethyl ether
30 (36 mg, 0.15 mmol) in 1,4-dioxane (10 mL) was
123

C-3 branched d-3,5-cis- and trans-THF SAAs
657
M.p. 166°C (water/acetone); m/z (ES-): 417.4 ([M-H]-,
100%); HRMS (ES-): found 417.1629 [M-H]-
C16H25N4O9 requires 417.1616; [a]2D3 -44.7 (c, 0.30 in
methanol); mmax (thin film): 3,357 (br, NH, OH), 2,940 (C–
H), 2,104 (s, N3), 1,736 (C=OOH), 1,664 (s, C=ONH, I),
1,530 (s, C=ONH, II) cm-1; dH (CD3CN, 400 MHz):
2.20–3.35 (1H, br s, CO2H), 3.23 (3H, s, C3OCH3, A), 3.26
vigorously stirred under an atmosphere of hydrogen in the
presence of palladium black (10 mg). After 2 h and
15 min, t.l.c. analysis (ethyl acetate:cyclohexane, 1:1)
showed the presence of one product (Rf baseline), (3R, 4R,
5S)5-aminomethyl-3,4-dimethoxy-tetrahydrofuran-3-car-
boxylic acid methyl ester 31, and complete consumption of
the starting material (Rf 0.74). The reaction was degassed
and filtered through Celite (eluent: 1,4-dioxane) into the
flask containing the pentafluorophenyl ester 33 (64 mg,
0.16 mmol) and stirred. After 25 h, t.l.c. analysis (ethyl
acetate:cyclohexane, 1:1) showed the presence of one
product (Rf 0.23) and complete consumption of the pen-
tafluorophenyl ester (Rf 0.90). The reaction mixture was
concentrated in vacuo and purified by flash column chro-
matography (ethyl acetate:cyclohexane, 1:1 to ethyl ace-
tate) to yield the dimer 34 (60 mg, 95%) as a colourless oil
which crystallised on standing. M.p. 64–65°C (dichloro-
methane); m/z (ES-): 431.3 ([M-H]-, 100%); HRMS
(ES-): found 431.1796 [M-H]- C17H27N4O9 requires
431.1778; mmax (thin film): 3,369 (s, NH), 2,960, 2,850 (C–
H), 2,103 (s, N3), 1,742 (s, C=OOCH3), 1,668 (s, C=ONH,
I), 1,518 (s, C=ONH, II) cm-1; [a]D23 -40.9 (c, 0.25 in
methanol); dH (C6D6, 400 MHz): 2.96 (3H, s, C3OCH3, A),
3.07 (3H, s, C3OCH3, B), 3.18 (3H, s, C4OCH3, B), 3.24
(3H, s, C3OCH3, B), 3.34 (1H, dd, JH-6,H-6 12.8, JH-6,H-5
0
4.9, H-6, A), 3.35 (3H, s, C4OCH3, B), 3.41 (1H, m, J 7.8,
J 5.6, H-6, B), 3.45 (3H, s, C4OCH3, A), 3.49 (1H, dd,
H-6 ,H-6 12.8, JH-6 ,H-5 8.2, H-60, A), 3.58 (1H, ddd, JH-6 ,H-6
0
0
0
J
13.9, JH-6 ,H-5 6.4, JH-6 ,NH 5.2, H-60, B), 3.73 (1H, d, JH-4,H-5
4.5, H-4, A), 3.85 (1H, d, JH-4,H-5 4.0, H-4, B), 3.95 (1H, d,
0
0
0
0
JH-2,H-2 10.4, H-2, B), 4.04 (1H, d, JH-2,H-2 10.7, H-2, A),
0
4.18 (1H, d, JH-2 ,H-2 10.4, H-20, B), 4.15–4.22 (1H, m, H-5,
0
B), 4.19–4.26 (1H, m, H-5, A), 4.27 (1H, d, JH-2 ,H-2 10.6,
H-20, A), 7.12–7.16 (1H, m, CONH). dC (CD3CN,
100 MHz): 38.4 (C-6, B), 50.3 (C-6, A), 52.3 (C3OCH3, A),
52.8 (C3OCH3, B), 60.1 (C4OCH3, A), 60.4 (C4OCH3, B),
67.2 (C-2, A), 68.9 (C-2, B), 79.4, 80.5 (29 C-5, A & B),
88.1, 88.3 (29 C-4, A & B), 90.7, 90.9 (29 C-3, A & B),
168.0 (CONH).
(3R, 4R, 5S)-5-{[((3R, 4R, 5S)-5-Azidomethyl-3,4-
dimethoxy-tetrahydrofuran-3-carbonyl)-amino]-methyl}-
3,4-dimethoxy-tetrahydrofuran-3-carboxylic acid
pentafluorophenyl ester 36
0
(1H, dd, JH-6,H-6 12.4, JH-6,H-5 6.2, H-6, A), 3.31 (3H, s,
0
C4OCH3, A), 3.46 (3H, s, CO2CH3), 3.46 (1H, ddd, JH-6,H-6
0
13.9, JH-6,H-5 6.1, JH-6,NH 4.0, H-6, B), 3.53 (1H, dd, JH-6 ,H-6
0
12.4, JH-6 ,H-5 7.3, H-60, A), 3.58 (1H, d, JH-4,H-5 4.8, H-4,
0
A), 3.80 (1H, d, JH-4,H-5 4.1, H-4, B), 4.02 (1H, ddd, JH-6 ,H-6
0
Pentafluorophenol (73 mg, 0.40 mmol) and EDCIꢀHCl
(60 mg, 0.31 mmol) were added to a stirred solution of the
dimeric acid 35 (87 mg, 0.21 mmol) in 1,4-dioxane
(3.0 mL). After 18 h, t.l.c. analysis (ethyl acetate:cyclo-
hexane, 1:1) indicated conversion of the starting material
(Rf baseline) to a UV-active product (Rf 0.60). The reaction
mixture was concentrated in vacuo and the residue was
suspended in dichloromethane (25 mL). The organic layer
was washed with sodium hydrogen carbonate solution (5%,
w/v, 5 mL), with citric acid solution (5%, w/v, 5 mL), then
with sodium hydrogen carbonate solution (5%, w/v, 5 mL),
and finally with water (5 mL). The organic layer was dried
(magnesium sulfate), filtered (eluent dichloromethane) and
concentrated in vacuo. The residue was purified by flash
chromatography (ethyl acetate:cyclohexane, 1:3 to ethyl
acetate) to yield the dimeric pentafluorophenyl ester 36
(96 mg, 79%) as a colourless oil which crystallised on
standing. M.p. 91–92°C (ethyl acetate/petroleum ether
60–80°C); m/z (ES?): 585.2 ([M?H]?, 60%), 607.2
([M?H]?, 37%), 1,191.1 ([2M?Na]?, 100%); HRMS
(ES?): found 585.1612 [M?H]? C22H26N4O9F5 requires
585.1620; mmax (thin film): 3,426 (br s, NH), 2,947, 2,839
(C–H), 2,103 (s, N3), 1,784 (m, C=OOPfp), 1,657 (s,
C=ONH, I), 1,524 (s, C=ONH, II) cm-1; [a]D24 -32.5 (c,
0.17 in dichloromethane); dH (C6D6, 500 MHz): 3.00 (3H,
14.0, JH-6 ,H-5 7.9, JH-6 ,NH 4.0, H-60, B), 4.07 (1H, d, JH-2,H-2
0
0
0
10.3, H-2, B), 4.10 (1H, d, JH-2,H-2 10.8, H-2, A), 4.34–4.40
0
(2H, m, H-5, A, H-5, B), 4.51 (1H, d, JH-2 ,H-2 10.2, H-20, B),
4.80 (1H, d, JH-2 ,H-2 10.8, H-20, A), 6.88 (1H, m, CONH); dC
0
(C6D6, 100 MHz): 38.9 (C-6, B), 50.0 (C-6, A), 51.5
(CO2CH3), 51.5 (C3OCH3, A), 52.0 (C3OCH3, B), 59.9
(C4OCH3, A), 60.2 (C4OCH3, B), 67.4 (C-2, A), 68.9 (C-2,
B), 79.6, 80.4 (29 C-5, A & B), 87.9 (C-4, B), 88.2 (C-4, A),
90.5 (C-3, A), 91.1 (C-3, B), 167.9 (CONH), 168.8
(CO2CH3).
(3R, 4R, 5S)-5-{[((3R, 4R, 5S)-5-Azidomethyl-3,4-
dimethoxy-tetrahydrofuran-3-carbonyl)-amino]-methyl}-
3,4-dimethoxy-tetrahydrofuran-3-carboxylic acid 35
Aqueous sodium hydroxide (1 M, 2 mL), was added to a
stirred solution of dimer 34 (90 mg, 0.21 mmol) in acetone
(2 mL). After 1.5 h, t.l.c. analysis (ethyl acetate:cyclo-
hexane, 1:1) indicated complete conversion of the starting
material (Rf 0.10) to one product (Rf baseline). Amberlite
IR-120 [H?] resin was added to the solution which was
then stirred for 15 min. The resin was removed by filtration
and the filtrate was concentrated in vacuo to give the
dimeric acid 35 (87 mg, 99%) as a white crystalline solid.
123

658
M. I. Simone et al.
s, C3OCH3, A), 3.18 (3H, s, C3OCH3, B), 3.26 (3H, s,
NH), 2,938 (C–H), 2,101 (m, N3), 1,740 (m, C=OOCH3),
1,663 (s, C=ONHs, I), 1,535 (s, C=ONHs, II) cm-1; dH
(CD2Cl2, 400 MHz): 3.26, 3.27, 3.28 (49 3H, 39 s, 49
C3OCH3, all rings), 3.31–3.40 (49 1H, m, 49 H-6, all
rings), 3.41, 3.44, 3.45 (49 3H, 39 s, 49 C4OCH3, all
C4OCH3, B), 3.30 (1H, dd, JH-6,H-6 12.6, JH-6,H-5 6.3, H-6,
0
A), 3.33 (3H, s, C4OCH3, A), 3.42 (1H, ddd, JH-6,H-6 13.1,
0
0
JH-6,H-5 8.5, JH-6,NH 4.0, H-6, B), 3.53 (1H, dd, JH-6 ,H-6
0
12.7, JH-6 ,H-5 7.2, H-60, A), 3.58 (1H, d, JH-4,H-5 4.8, H-4,
A), 3.85 (1H, d, JH-4,H-5 4.3, H-4, B), 4.02–4.05 (1H, m,
rings), 3.54 (1H, dd, JH-6 ,H-6 12.8, JH-6 ,H-5 7.6, H-60, A),
3.73 (1H, d, JH-4,H-5 4.8, H-4), 3.74–3.85 (3H, m, 39 H-60,
B, C, D), 3.77 (1H, d, JH-4,H-5 4.8, H-4), 3.80 (1H, d, JH-4,H-5
5.2, H-4), 3.83 (3H, s, CO2CH3, D), 3.85 (1H, d, JH-4,H-5
0
0
H-60, B), 4.06 (1H, d, JH-2,H-2 10.5, H-2, B), 4.09 (1H, d,
0
0
JH-2,H-2 10.7, H-2, A), 4.32–4.38 (1H, m, H-5, A),
0
4.34–4.40 (1H, m, H-5, B), 4.53 (1H, d, JH-2 ,H-2 10.4, H-20,
B), 4.77 (1H, d, JH-2 ,H-2 10.7, H-20, A), 6.85–6.90 (1H, m,
4.0, H-4), 3.99 (1H, d, JH-2,H-2 10.0, H-2), 4.02 (2H, d,
0
0
0
0
J
NH,H-6 4.0, NH); dC (C6D6, 125 MHz): 38.8 (C-6, B), 49.9
JH-2,H-2 10.0, 29 H-2), 4.07 (1H, d, JH-2,H-2 10.4, H-2),
4.18–4.31 (49 1H, m, 49 H-5, all rings), 4.27 (1H, d,
(C-6, A), 52.0 (C3OCH3, A), 53.1 (C3OCH3, B), 59.9
(C4OCH3, A), 60.5 (C4OCH3, B), 67.4 (C-2, A), 68.6 (C-2,
B), 79.9 (C-5, B), 80.3 (C-5, A), 88.1 (C-4, B), 88.3 (C-4,
A), 90.5 (C-3, B), 91.7 (C-3, A), 124.8 (m, ArCq), 137.1,
139.1 (2C, m, 29 meta Ar–CH), 138.7, 140.7 (1C, m, para
Ar–CH), 140.2, 142.1 (2C, m, 29 ortho Ar–CH), 165.2
(CONH), 168.2 (CO2Pfp); 19F NMR dF (C6D6, 376 MHz):
JH-2 ,H-2 10.0, H-20), 4.37 (1H, d, JH-2 ,H-2 10.8, H-20), 4.38
0
0
(1H, d, JH-2 ,H-2 10.4, H-20), 4.39 (1H, d, JH-2 ,H-2 10.4,
H-20), 6.92–6.97 (1H, m, NH), 6.95–7.02 (2H, m, 29 NH);
dH (CD2Cl2, 125 MHz): 39.0 (C-6, B), 50.3 (C-6, A), 52.5
(CO2CH3), 52.7, 52.9, 53.3. (4C, 49 C3OCH3, all rings),
60.5, 60.7, 60.8 (4C, 49 C4OCH3, all rings), 67.5, 67.7,
67.8, 69.1 (49 C-2, all rings), 79.3, 79.4, 79.5, 80.4 (59
C-5, all rings), 88.5, 88.6, 89.5, 89.6 (49 C-4, all rings),
90.6, 90.8, 91.1 (4C, 49 C-3, all rings), 168.2, 168.5 (3C,
39 CONH), 169.5 (CO2CH3).
0
0
3
3
-162.3 (2F, dd, JFmeta,Fpara 23.2, JFmeta,Fortho 18.8, 29
F
3
meta), -157.3 (1F, t, JFpara,Fmeta 23.3, Fpara), -153.0 (2F,
3
d, JFortho,Fmeta 18.5, 29 Fortho).
(3R, 4R, 5S)-5-{[((3R, 4R, 5S)-5-{[((3R, 4R, 5S)-5-{[((3R,
4R, 5S)-5-Azidomethyl-3,4-dimethoxy-tetrahydrofuran-3-
carbonyl)-amino]-methyl}-3,4-dimethoxy-tetrahydrofuran-
3-carbonyl)-amino]-methyl}-3,4-dimethoxy-tetrahydro-
furan-3-carbonyl)-amino]-methyl}-3,4-dimethoxy-
tetrahydrofuran-3-carboxylic acid methyl ester 38
Acknowledgments Financial support (to M. I. S.) provided through
the European Community’s Human Potential Programme under
Contract HPRN-CT-2002-00173 is gratefully acknowledged.
Conflict of interest The authors declare that they have no conflict
of interest.
A solution of dimer 34 (65 mg, 0.15 mmol) in 1,4-dioxane
(3 mL) was vigorously stirred under an atmosphere of
hydrogen in the presence of palladium black (20 mg). After
2.5 h, t.l.c. analysis (ethyl acetate) showed the presence of
(3R, 4R, 5S)-5-{[((3R, 4R, 5S)-5-aminomethyl-3,4-dime-
thoxy-tetrahydrofuran-3-carbonyl)-amino]-methyl}-3,4-
dimethoxy-tetrahydrofuran-3-carboxylic acid methyl ester
37 (Rf baseline) and complete consumption of the starting
material (Rf 0.59). The reaction was degassed and filtered
through Celite (eluent: 1,4-dioxane) into the flask con-
taining dimeric pentafluorophenyl ester 36 (84 mg,
0.21 mmol) and the reaction mixture stirred at 60°C. After
17 h, t.l.c. analysis (ethyl acetate:methanol, 23:2) showed
the presence of one product (Rf 0.15). The reaction mixture
was concentrated in vacuo and purified by flash column
chromatography (ethyl acetate:methanol, 23:2) to yield
tetramer 38 (106 mg, 88%) as a white crystalline solid.
M.p. 208–209°C (ethyl acetate/methanol); m/z (ES?):
865.5 ([M?NH4?MeCN]? 100%); HRMS (ES?): found
829.3450 [M?Na]? C33H54N6O17Na requires 829.3443;
isotopic distribution: found 829.34 (100.0%), 830.35
(38.5%), 831.35 (11.0%), 832.35 (3.5%), required 829.34
(100.0%), 830.35 (35.7%), 831.35 (6.2%), 831.35 (3.5%);
[a]2D3 -60.5 (c, 0.37 in CH2Cl2); mmax (thin film): 3,326 (br,
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