Tetrahydrofuran amino acids: β- And γ-azidotetrahydrofuran-carboxylic acid monomers derived from D-glucoheptonolactone as building blocks for β- and γ-oligopeptides

Article abstract of DOI:10.1039/b002997l

The synthesis of both a β(L-allono) and a γ (o-allono) tetrahydrofuran azido acid from a single heptono sugar lactone as monomers for peptidomimetic oligomers is described. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b002997l

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Tetrahydrofuran amino acids: ꢀ- and ꢁ-azidotetrahydrofuran-
carboxylic acid monomers derived from D-glucoheptonolactone
as building blocks for ꢀ- and ꢁ-oligopeptides
1
Natasha L. Hungerford and George W. J. Fleet*
Dyson Perrins Laboratory, University of Oxford, Oxford Centre for Molecular Sciences,
South Parks Road, Oxford OX1 3QY, UK. Tel: ϩ44 1865 275 645; Fax: ϩ44 1865 275 674;
E-mail: george.fleet@chemistry.oxford.ac.uk
Received (in Cambridge, UK) 13th April 2000, Accepted 18th August 2000
First published as an Advance Article on the web 16th October 2000
The synthesis of both a β (-allono) and a γ (-allono) tetrahydrofuran azido acid from a single heptono sugar
lactone as monomers for peptidomimetic oligomers is described.
Introduction
Results and discussion
Relatively short oligomers of β- and γ-amino acids, especially
those of conformationally restricted systems,1,2 have been
shown to adopt ordered secondary structures. Such systems
continue to provide an increased understanding of the factors
which induce secondary structures, and may provide probes of
the complex nature of protein folding. The biological functions
of proteins and RNA, including catalysis and recognition, are
critically reliant on their precise folding into well-ordered struc-
tures. Pyranose sugar amino acids, including β- and γ-amino
acids, have been shown3 to exert predictable conformational
effects in peptidic systems due to the rigid conformations
imposed by the all-equatorial substituents; when such systems
were incorporated into cyclic hexapeptide analogues of
somatostatin, the γ-amino acid served as a β-turn mimetic while
the β-amino acid induced a γ-turn. The synthetic approaches3,4
to these β- and γ-sugar amino acids, including modifications of
a previously reported procedure,5 were described. In contrast to
pyranose sugar systems, the present work describes the syn-
thesis of furanose-based sugar amino acid precursors. In these
systems, the tetrahydrofuran (THF) sugar ring should again
provide the β- and γ-amino acid substituents in distinct
orientations necessary for the conformational properties of
peptidomimetic oligomers. 5-(Azidomethyl)tetrahydrofuran-2-
carboxylic acid 1 scaffolds (building blocks for δ-oligopeptides)
are a family of dipeptide isosteres which show promise of pro-
viding building blocks that are predisposed towards different
secondary structures, depending on the stereochemistry of the
substituents around the THF ring.6 Substitution of azide at
different sites on the tetrahydrofuran ring (such as the β-azido
ester 2 and the γ-azido ester 3) should provide a set of templates
which are predisposed towards induction of varied secondary
structures.
This paper describes the synthesis, from the readily available
seven-carbon sugar lactone 8, of β- and γ-azido THF
monomers 5 and 4 which should allow the generation of
oligopeptides with secondary structure. The 3-azidotetra-
hydrofuran-2-carboxylate 5, a C-glycoside possessing -allonate
stereochemistry (2,5-cis-stereochemistry), is a building block
for the synthesis of C-glycoside β-amino acid oligomers.
Oligomers derived from 5 (with similar stereochemistry to
β--ribofuranose) may have potential as RNA-chain mimics
in which the amide bonds mimic the phosphodiester backbone
of the nucleic acid. Additionally, the -allonate γ-azido THF
ester 4 may be considered as a C-glycoside with 2,5-cis-stereo-
chemistry similar to the β--ribofuranose scaffold and has
potential to generate γ-peptides likely to adopt relatively well
defined secondary structures.
Both the γ-azidoTHF-2-carboxylate 4 and the β-azidoTHF-
2-carboxylate 5 may be derived from azido ester 6 as a common
intermediate (Scheme 1). The azido ester 6 can be formed effi-
ciently by introduction of azide at C-4 of the THF 7 with inver-
sion of configuration to give the -glycero--allo-heptonate
stereochemistry of this building block. A protected form of
-glycero--gulo-heptonate 7 is available in 4 steps7 from the
readily available diacetonide8,9 of -glycero--gulo-heptono-
1,4-lactone 8. The key step in the synthesis of the THF C-glyco-
side 7 involves treatment of a 2-O-triflate of a carbohydrate
lactone with acidic methanol, conditions which result in
hydrolysis of the side-chain acetonide and methanolysis of the
lactone with intramolecular SN2 displacement of the triflate at
C-2 of 8 by 5-OH.7,10 Elaboration by reductive cleavage of the
side-chain C-6 and C-7 in 6 generates the γ-amino acid precur-
sor 4, while reduction of the ester function at C-1 of 6 followed
by oxidative cleavage between C-6 and C-7 would provide
access to β-amino acid building blocks from 5. Oligomers
derived from the β-azido ester 5 could be compared with those
from the four diastereomeric (2,3-cis- and 2,3-trans-) 3-azido-
tetrahydrofuran-2-carboxylates 9–12 which have been prepared
previously from diacetone-glucose.11
The objective of this work is to provide an increasingly
diverse picture of the THF amino acid structures which form
oligomers with a propensity to exhibit secondary structure.
Different diastereomers of 5-(azidomethyl)THF-2-carboxylates
1 produce oligomers which exhibit β-turn12 and α-helical13
structures in solution. Likewise, α-,14 β-15 and γ-16 amino-acid-
3680
J. Chem. Soc., Perkin Trans. 1, 2000, 3680–3685
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b002997l

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Scheme 1
Scheme 2 Reagents and conditions (and yields): (i) 2,2-DMP, CSA, acetone, RT, 16 h (61%) (ii) TBDMSCl, imidazole, DMF, Ϫ25 ЊC to RT, 16 h
(72%) (iii) Tf2O, py, DCM, Ϫ15 to 0 ЊC, 1.5 h (92%) (iv) NaN3, DMF, RT, 1 h (71%).
(Scheme 3). Acetonide deprotection of 6 using 80% aq. acetic
acid gave 17 in 98% yield. Periodate cleavage of the diol 17 was
followed by immediate hydride reduction of the aldehyde 18.
However, reduction with sodium borohydride in aq. ethanol
gave diol 19 (in 59% over 3 steps from 6) obtained from con-
comitant reduction of the ester; only a trace of the required
ester 20 was isolated. Although esters are not usually reduced
by sodium borohydride, the ester carbonyl group in 18 is acti-
vated by the presence of the α oxygen of the THF ring. Reduc-
tion of 18 with sodium cyanoborohydride in acetic acid caused
regioselective reduction of the aldehyde in 18 to afford the ester
20 in an overall yield of 76% from 6 in 3 steps.
containing oligomers, in addition to other scaffolds,17 have
For access to the β-azidoTHF-2-carboxylate from the azido
adopted defined secondary conformations.
For the synthesis of the divergent intermediate 6, it was
necessary to protect all the hydroxy groups in 7 other than the
C-4 OH. Treatment of the tetraol 7 with 2,2-dimethoxypropane
ester 6, the ester functionality was reduced by sodium boro-
hydride in aq. ethanol to yield the primary alcohol 21 in 64%
yield (Scheme 4). Protection of the primary hydroxy group as
the tert-butyldiphenylsilyl (TBDPS) ether to give 22 (73% yield)
(2,2-DMP) and ( )-camphor-10-sulfonic acid (CSA) in acetone
was followed by selective deprotection of the 6,7-acetonide by
gave the 6,7-monoacetonide 1318 in 61% yield (Scheme 2),
aq. acetic acid to afford the diol 23 in 65% yield. Oxidation of
together with the 4,6-acetonide 14 in 26% yield. Selective pro-
the diol moiety in 23 with sodium periodate in the presence
tection with tert-butyldimethylsilyl chloride (TBDMSCl) and
of catalytic ruthenium() chloride19 resulted in the formation
imidazole in dimethylformamide (DMF) afforded 15 in 72%
of the target 3-azidotetrahydrofuran-2-carboxylate 24 in 62%
yield; 2D NMR experiments (COSY, HMQC, HMBC) estab-
yield.
lished that the silyl ether was at C-3. Esterification of the
remaining free C-4 hydroxy group with Tf2O and pyridine (py)
in dichloromethane (DCM) gave 16 in 92% yield; subsequent
Conclusions
azide displacement of the triflate with inversion of configur-
ation formed the key intermediate azido ester 6 in 71% yield.
Divergence of the synthetic scheme at this point provided
access to the β- and γ-amino acid building blocks.
Synthesis of the γ-azidoTHF-2-carboxylate involved reduc-
tive cleavage between C 6 and C 7 of the side-chain diol in 6
This paper describes a viable synthetic route to the 3-azido-
and 4-azido-tetrahydrofuran-2-carboxylates 20 and 24 from a
readily available seven-carbon sugar lactone as building blocks
for the generation of β- and γ-oligopeptides. These materials
provide further examples of an increasingly diverse library
of THF amino acid building blocks for the generation of
J. Chem. Soc., Perkin Trans. 1, 2000, 3680–3685
3681

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Scheme 3 Reagents and conditions (and yields): (i) 80% AcOH (aq.), RT, 16 h; (ii) H5IO6, THF, RT, 5 min; (iii) NaBH4, aq. EtOH, RT, 15 min [59%
(3 steps)]; (iv) NaBH3CN, AcOH, 10 min, RT [76% (3 steps)].
Scheme 4 Reagents and conditions (and yields): (i) NaBH4, aq. EtOH, RT, 3 h (64%) (ii) TBDPSCl, imidazole, DMF, Ϫ30 ЊC to RT, 16 h (73%) (iii)
80% AcOH (aq.), RT, 36 h (65%) (iv) NaIO4, RuCl3ؒH2O, CCl4–CH3CN–water, RT, 5 h (62%).
THF-based peptidomimetic oligomers and for the incorpor-
ation of such units into libraries. Comparison of the structures
of the oligomers derived from these monomers with those
derived from other THF systems should eventually provide a
set of monomers for the design of foldamers17b with predictable
conformations, or for the incorporation of peptide mimetics
with a predisposition for the generation of designed secondary
structures.
0.2% w/v cerium() sulfate and 5% ammonium molybdate in
2 M sulfuric acid. Flash chromatography was carried out using
Sorbsil C60 40/60 silica. Solvents and commercially available
reagents were dried and purified before use according to stand-
ard procedures. A solution of KH2PO4 (85 g) and NaOH (14.5
g) in distilled water (950 ml) was used as a pH 7 buffer solution.
The tetrahydrofuran ester 7 was prepared from the heptono-
lactone 8 as previously described.7
Methyl 2,5-anhydro-6,7-O-isopropylidene-D-glycero-D-gulo-
heptonate18 13 and methyl 2,5-anhydro-4,6-O-isopropylidene-D-
glycero-D-gulo-heptonate 14
Experimental
1H NMR (δH) spectra were recorded on a Bruker DPX 400
spectrometer (at 400 MHz), Bruker DPX 200 or Varian Gemini
200 (200 MHz), Bruker AMX 500 or AM 500 (500 MHz) spec-
trometer at ambient probe temperatures (≈298 K). Coupling
constants (J) were measured in Hz and are averaged. 13C NMR
(δC) spectra were recorded on a Bruker DPX 200 (at 50 MHz),
Bruker DPX 400 spectrometer (at 100 MHz) or Bruker AMX
500 or AM500 (125 MHz) spectrometer; multiplicities were
assigned using a DEPT sequence. All chemical shifts are quoted
on the δ-scale using residual solvent as internal standard. IR
spectra were recorded on a Perkin-Elmer 1750 IR FT spectro-
photometer. Mass spectra were recorded on VG Micromass 20–
250, ZAB 1F, Micromass Platform 1 or Trio-1 GCMS (DB-5
column) spectrometers using chemical ionisation (CI, NH3),
atmospheric pressure chemical ionisation (APCI) or electro-
spray techniques (ES) as stated. Optical rotations were meas-
ured on a Perkin-Elmer 241 polarimeter with a path length
The tetrahydrofuran ester 77 (4.36 g, 19.6 mmol) was stirred in
acetone (90 mL) containing 2,2-dimethoxypropane (2.45 g, 23.6
mmol). -Camphor-10-sulfonic acid (0.23 g, 0.98 mmol) was
added and the mixture was stirred for 16 h at room temperature.
TLC (ethyl acetate–MeOH 9:1) showed no starting material
(Rf 0.2) and a major product (Rf 0.6) and a minor product (Rf
0.5). Sodium bicarbonate (0.4 g) was added and stirring was
continued until the solution was pH 6. The mixture was filtered
through Celite, the filter was washed with acetone, and the sol-
vent was removed in vacuo. Repeated flash chromatography
(ethyl acetate–hexane 2:1 followed by DCM–MeOH 19:1, then
9:1) yielded the side-chain acetonide 13 (3.13 g, 61%), mp 98–
100 ЊC (lit.,18 87–89 ЊC) [α]D22 Ϫ45.0 (c 1.00 in CHCl3) [lit.,18
Ϫ41.6 (c 1.00 in CHCl3)] [HRMS m/z (CIϩ) Found: 263.1135
(M ϩ Hϩ). C11H19O7 requires m/z, 263.1131] (Found: C, 50.29;
H, 6.91. Calc. for C11H18O7: C, 50.38; H, 6.92%); νmax (thin film)
of 1 dm. [α]D-Values are given in units of 10Ϫ1 deg cm2 gϪ1
.
Concentrations are given in g/100 ml. Mps were recorded on a
Kofler block and are uncorrected. Microanalyses were per-
formed by the microanalysis service of the Inorganic Chemistry
Laboratory, Oxford. TLC was carried out on plastic or
aluminium sheets coated with 60F254 silica or glass plates coated
with silica blend 41. Plates were developed using a spray of
3700–3100 (OH), 1734 (C᎐O) cmϪ1; δH (CD3CN; 400 MHz)
᎐
1.35 (3H, s, CH3C), 1.41 (3H, s, CH3C), 3.24 (1H, d, J 4.6,
4-OH), 3.68 (1H, d, J 4.1, 3-OH), 3.72 (3H, s, CH3O), 4.01 (1H,
ddd, J 4.6, 3.4, 1.2, H-4), 4.06–4.11 (3H, m, H-5, H2-7), 4.30
(1H, d, J 1.2, H-2), 4.33 (1H, a-dt, J ≈ 4.0, 1.2, H-3), 4.37 (1H,
a-q, J 6.3, H-6); δC (CD3CN; 125 MHz) 25.0 (q, CH3C), 26.4
3682
J. Chem. Soc., Perkin Trans. 1, 2000, 3680–3685

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(q, CH3C), 51.9 (d, CH3O), 67.0 (t, C-7), 73.6 (d, C-6), 76.2 (d,
C-4), 81.2 (d, C-3), 83.5 (d, C-5), 84.0 (d, C-2), 108.8 (s, O–C–
O), 171.6 (s, C-1); m/z (APCIϩ) 285 (M ϩ Naϩ, 100%), 263
(M ϩ Hϩ, 80), 205 (90).
92%) as an unstable material which was used directly in the next
reaction.
Methyl 2,5-anhydro-4-azido-3-O-(tert-butyldimethylsilyl)-4-
deoxy-6,7-O-isopropylidene-D-glycero-D-allo-heptonate 6
Further elution afforded the 4,6-O-isopropylidene ester 14
(1.34 g, 26%), mp 117–119 ЊC; [α]D22 Ϫ9.4 (c 1.09 in acetone)
[HRMS m/z (CIϩ) Found: 263.1133 (M ϩ Hϩ). C11H19O7
requires m/z, 263.1131] (Found: C, 50.38; H, 6.94. C11H18O7
requires C, 50.38; H, 6.92%); νmax (thin film) 3700–3100 (OH),
The triflate 16 (0.138 g, 0.27 mmol) was dissolved in dry DMF
(3 mL) and sodium azide (0.019 g, 0.29 mmol) was added. The
mixture was stirred at room temperature for 1 h, when TLC
(ethyl acetate–hexane 1:4) showed very little starting material
(Rf 0.6) and the presence of product (Rf 0.5). Water (80 mL) was
added and the mixture was extracted with ethyl acetate (5 × 50
mL). The combined extracts were dried over MgSO4 and
concentrated. Residual DMF was removed by in vacuo co-
evaporation with toluene. Flash chromatography (ethyl acetate–
hexane 1:8) afforded the protected azide 6 (0.77 g, 71%) as a
colourless oil, [α]D25 Ϫ27.6 (c 0.32 in CHCl3) [HRMS m/z (CIϩ)
Found: 402.2075 (M ϩ Hϩ). C17H32N3O6Si requires m/z,
402.2060] (Found: C, 50.70; H, 7.69; N, 9.94. C17H31N3O6Si
requires C, 50.85; H, 7.78; N, 10.47%); νmax (thin film) 2108
(N ), 1752 (C᎐O) cmϪ1; δH (CD3CN; 400 MHz) 0.28 (3H, s,
1734 (C᎐O) cmϪ1; δH (CD3CN; 500 MHz) 1.25 (3H, s, CH3C),
᎐
1.31 (3H, s, CH3C), 3.05 (1H, a-t, J 6.0, 7-OH), 3.57 (1H, ddd,
J 11.9, 6.6, 6.0, H-7), 3.70 (3H, s, OCH3), 3.72 (1H, ddd, J 11.9,
6.0, 2.9, HЈ-7), 3.86 (1H, d, J 4.7, 3-OH), 3.88 (1H, ddd, J 7.9,
6.6, 2.9, H-6), 4.10 (1H, dd, J 4.3, 0.5, H-4), 4.20 (1H, dd, J 7.9,
4.3, H-5), 4.42–4.44 (2H, m, H-2, -3); δC (CD3CN; 50 MHz)
23.6 (q, CH3C), 23.9 (q, CH3C), 52.0 (q, CH3O), 63.3 (t, C-7),
72.6 (d, C-6), 76.7 (d, C-4), 79.0 (d, C-3), 80.3 (d, C-5), 84.6 (d,
C-2), 100.6 (s, O–C–O), 171.4 (s, C-1); m/z (APCIϩ) 285
(M ϩ Naϩ, 100%), 263 (M ϩ Hϩ, 35), 205 (60).
᎐
3
Methyl 2,5-anhydro-3-O-(tert-butyldimethylsilyl)-6,7-O-
isopropylidene-D-glycero-D-gulo-heptonate 15
SiCH3), 0.31 (3H, s, SiCH3), 1.08 [9H, s, SiC(CH3)3], 1.46 (3H, s,
CCH3), 1.54 (3H, s, CCH3), 3.84 (3H, s, OCH3), 3.87 (1H, m,
H-4), 4.04 (1H, dd, J 8.5, 5.2, H-7), 4.06 (1H, m, H-5), 4.25 (1H,
dd, J 8.6, 6.5, HЈ-7), 4.31 (1H, a-dt, J ≈ 6.6, 5.2, H-6), 4.42 (1H,
d, J 4.1, H-2), 4.70 (1H, dd, J 4.8. 4.1, H-3); δC (CD3CN; 100.6
MHz) Ϫ5.6 (q, SiCH3), Ϫ5.3 (q, SiCH3), 18.1 [s, SiC(CH3)3],
24.8 (q, CH3C), 25.4 [q, SiC(CH3)3], 26.2 (q, CH3C), 52.2 (q,
CH3O), 64.2 (d, C-4), 67.1 (t, C-7), 76.5 (d, C-6), 77.2 (d, C-3),
82.1 (d, C-5), 82.9 (d, C-2), 109.8 (s, O–C–O), 171.0 (s, C-1);
m/z (APCIϩ) 402 (M ϩ Hϩ, 20%), 374 (M ϩ Hϩ Ϫ N2, 100).
The acetonide 13 (2.30 g, 8.8 mmol) was dissolved in dry DMF
(2.3 mL). Imidazole (0.72 g, 10.5 mmol) was added and the
mixture was cooled to Ϫ25 ЊC. tert-Butyldimethylsilyl chloride
(1.46 g, 9.7 mmol) was added and the mixture was stirred at
room temperature overnight. TLC (ethyl acetate–hexane 1:1)
showed a major product at Rf 0.5 and only a small amount of
residual starting material (Rf 0.2). Ethanol (3 drops) was added
and the solvent was removed under reduced pressure. The resi-
due obtained was co-evaporated with toluene and then dis-
solved in ethyl acetate (80 mL); the solution was washed with
pH 7 buffer solution (50 mL), dried (MgSO4), and concen-
trated. Flash chromatography purification (ethyl acetate–
hexane 1:3) afforded the silyl ether 15 (2.39 g, 72%) as a colour-
less oil, [α]D22 Ϫ28.6 (c 1.09 in acetone) (Found: C, 54.13; H, 8.46.
C17H32O7Si requires C, 54.23; H, 8.57%); νmax (thin film) 3200–
Methyl 2,5-anhydro-4-azido-3-O-(tert-butyldimethylsilyl)-4-
deoxy-D-glycero-D-allo-heptonate 17
The azide 6 (0.100 g, 0.25 mmol) was dissolved in a mixture of
acetic acid and water (8 mL:2 mL) and the solution was stirred
at room temperature overnight. TLC (ethyl acetate–hexane 1:1)
showed complete conversion of starting material (Rf 0.8) to a
single product (Rf 0.2). The reaction mixture was concentrated
in vacuo with toluene co-evaporation to give the diol 17 (0.88 g,
98%), which was used without further purification in the follow-
ing reactions. A sample was purified by flash chromatography
(ethyl acetate–hexane 1:1) to give the diol 17 as a colourless oil,
[α]D22 Ϫ27.6 (c 0.71 in MeOH) (Found: C, 46.47; H, 7.65, N,
11.28. C14H27N3O6Si requires C, 46.52; H, 7.53, N, 11.62%); νmax
3600 (O–H), 1738 (C᎐O) cmϪ1; δH (CD3CN; 400 MHz) 0.16
᎐
[6H, s, Si(CH3)2], 0.93 [9H, s, SiC(CH3)3], 1.32 (3H, s, CCH3),
1.38 (3H, s, CCH3), 3.33 (1H, d, J 4.4, 4-OH), 3.69 (3H, s,
OCH3), 3.94 (1H, ddd, J 4.4, 3.2, 1.1, H-4), 4.05–4.08 (3H,
m, H-5, H2-7), 4.28 (1H, d, J 0.6, H-2), 4.34 (1H, a-dt, J 6.7,
6.3, H-6), 4.41 (1H, br s, H-3); δC (CD3CN; 100.6 MHz) Ϫ5.4
(q, CH3Si), Ϫ5.3 (q, CH3Si), 18.0 [s, SiC(CH3)3], 25.0 (q,
CH3C), 25.5 [q, SiC(CH3)3], 26.5 (q, CH3C), 51.9 (q, CH3O),
66.9 (t, C-7), 73.5 (d, C-6), 76.3 (d, C-4), 82.4 (d, C-3), 83.4 (d,
C-5), 84.6 (d, C-2), 108.7 (s, O–C–O), 171.4 (s, C-1); m/z
(APCIϩ) 399 (M ϩ Naϩ, 90%), 377 (M ϩ Hϩ, 15), 319 (100),
169 (80).
(thin film) 3200–3600 (OH), 2107 (N ), 1744 (C᎐O) cmϪ1
;
᎐
3
δH (CD3CN; 400 MHz) 0.18 (3H, s, SiCH3), 0.19 (3H, s, SiCH3),
0.97 [9H, s, SiC(CH3)3], 3.58 (1H, dd, J 11.3, 6.1, H-7), 3.62
(1H, dd, J 11.3, 5.1, HЈ-7), 3.75 (3H, s, CH3), 3.82 (1H, dd,
J 6.9, 5.2, H-4), 3.83 (1H, a-dt, J 6.9, 5.2, H-6), 4.09 (1H, dd,
J 6.8, 5.2, H-5), 4.35 (1H, d, J 3.4, H-2), 4.60 (1H, dd, J 4.9, 3.4,
H-3); δC (CD3CN; 50 MHz) Ϫ4.9 (q, SiCH3), Ϫ4.6 (q, SiCH3),
18.8 [s, SiC(CH3)3], 26.1 [q, SiC(CH3)3], 53.2 (q, OCH3), 62.6 (d,
C-4 or -6), 63.6 (t, C-7), 72.7 (d, C-6 or -4), 78.3 (d, C-3),
82.8 (d, C-5), 83.4 (d, C-2), 173.0 (C-1); m/z (APCIϩ) 334
(M ϩ Hϩ Ϫ N2, 100%), 302 (40), 142 (85).
Continued elution (ethyl acetate–hexane 3:1) afforded
recovered starting material 13 (0.36 g, 16%).
Methyl 2,5-anhydro-3-O-(tert-butyldimethylsilyl)-6,7-O-
isopropylidene-4-O-trifluoromethylsulfonyl-D-glycero-D-gulo-
heptonate 16
Dry pyridine (1.14 mL, 1.11 g, 14.1 mmol) was added to a
solution of the silyl ether 15 (2.30 g, 6.1 mmol) in dry DCM (25
mL). Upon cooling of this solution to Ϫ15 ЊC, trifluoro-
methanesulfonic anhydride (1.34 mL, 2.24 g, 8.0 mmol) was
added dropwise via syringe. Stirring was continued for 1 h
between Ϫ15 and 0 ЊC. TLC (ethyl acetate–hexane 1:1)
revealed a single product (Rf 0.8) together with residual starting
material (Rf 0.5). Additional pyridine (0.8 mL) was added and
the mixture was re-cooled to Ϫ15 ЊC before further trifluoro-
methanesulfonic anhydride (1.0 mL) was added via syringe.
Upon stirring of the mixture for 30 min at 0 ЊC, TLC analysis
revealed the reaction to be complete. Water (10 mL) was added
and the mixture was applied directly to a flash chromatography
column (ethyl acetate–hexane 1:9) to give the triflate 16 (2.87 g,
Methyl 2,5-anhydro-4-azido-3-O-(tert-butyldimethylsilyl)-4-
deoxy-D-allonate 20
The diol 17 (0.088 g, 0.24 mmol) was dissolved in dry THF (1.0
mL) and periodic acid (0.061 g, 0.27 mmol) was added. After
stirring of the mixture for 5 min at room temperature, TLC
(ethyl acetate–hexane 1:1) suggested complete consumption of
starting material (Rf 0.2) and conversion to a new product (Rf
0.5). The reaction mixture was filtered through Celite, with
washing of the filter with THF, and the combined filtrate and
washings were concentrated in vacuo. The residue was dissolved
in acetic acid (0.6 mL) and sodium cyanoborohydride (0.015 g,
0.24 mmol) was added. The mixture was stirred at room
J. Chem. Soc., Perkin Trans. 1, 2000, 3680–3685
3683

View Article Online
temperature for 10 min, when TLC (ethyl acetate–hexane 1:1)
showed complete conversion to product (Rf 0.6). Water
(4 drops) was added and the mixture was concentrated in vacuo.
The resulting residue was re-dissolved in ethyl acetate and pre-
adsorbed onto silica. Flash chromatography (ethyl acetate–
hexane 1:1) gave the ester 20 [0.063 g, 78% (76% overall from
6)]) as a colourless oil, [α]D25 Ϫ20.1 (c 0.77 in CHCl3) [HRMS m/z
(CIϩ) Found: 349.1912 (M ϩ NH4ϩ). C13H29N4O5Si requires
m/z, 349.1907] (Found: C, 47.45; H, 7.92; N, 12.19. C13H25-
N3O5Si requires C, 47.11; H, 7.60; N, 12.68%); νmax (thin film)
3200–3600 (OH), 2107 (N ), 1743 (C᎐O) cmϪ1; δH (CDCl3; 500
MHz) 0.21 (3H, s, SiCH3), 0.23 (3H, s, SiCH3), 0.99 [9H, s,
SiC(CH3)3], 3.69 (1H, br d, J 12.6, H-6), 3.81 (1H, dd, J 8.0, 4.6,
H-4), 3.83 (3H, s, OCH3), 4.06 (1H, dd, J 12.6, 2.4, HЈ-6), 4.30
(1H, a-dt, J 8.0, 2.0, H-5), 4.46 (1H, d, J 2.2, H-2), 4.55 (1H, dd,
J 4.6, 2.1, H-3); δC (CDCl3; 125.6 MHz) Ϫ5.2 (q, SiCH3), Ϫ5.0
(q, SiCH3), 18.0 [s, SiC(CH3)3], 25.6 [q, SiC(CH3)3], 52.7 (q,
OCH3), 60.2 (d, C-4), 61.0 (t, C-6), 77.4 (d, C-3), 81.6 (d, C-5),
83.0 (d, C-2), 172.3 (s, C-1); m/z (APCIϩ) 332 (M ϩ Hϩ, 10%),
304 (M ϩ Hϩ Ϫ N2, 100).
requires C, 51.45; H, 8.37; N, 11.25%); νmax (thin film) 3200–
3600 (OH), 2107 (N3) cmϪ1; δH (CD3OD; 500 MHz) 0.18 (3H, s,
SiCH3), 0.20 (3H, s, SiCH3), 0.98 [9H, s, SiC(CH3)3], 1.36 (3H, s,
CCH3), 1.45 (3H, s, CCH3), 3.54 (1H, dd, J 12.1, 4.4, H-1), 3.67
(1H, dd, J 12.1, 3.4, HЈ-1), 3.71 (1H, a-t, J ≈ 5.5, H-4), 3.82
[1H, a-q (br), J ≈ 4.4, H-2], 3.85 (1H, dd, J 5.7, 5.5, H-5), 3.91
(1H, dd, J 7.7, 4.3, H-7), 4.09–4.16 (2H, m, H-6, HЈ-7), 4.36
(1H, a-t, J ≈ 5.4, H-3); δC (CD3OD; 125 MHz) Ϫ4.9 (q, SiCH3),
Ϫ4.5 (q, SiCH3), 18.9 [s, SiC(CH3)3], 25.3 (q, CCH3), 26.3 [q,
SiC(CH3)3], 26.9 (q, CCH3), 62.4 (t, C-1), 65.5 (d, C-4), 68.0 (t,
C-7), 75.0 (d, C-3), 77.8 (d, C-6), 82.7 (d, C-5), 86.2 (d, C-2),
110.9 (s, O–C–O); m/z (APCIϩ) 346 (M ϩ Hϩ Ϫ N2, 100%).
᎐
3
2,5-Anhydro-4-azido-3-O-(tert-butyldimethylsilyl)-1-O-(tert-
butyldiphenylsilyl)-4-deoxy-6,7-O-isopropylidene-D-glycero-D-
allo-heptitol 22
The heptitol 21 (0.093 g, 0.25 mmol) was dissolved in dry DMF
(100 µL). Imidazole (0.023 g, 0.35 mmol) was added and the
mixture was cooled to Ϫ30 ЊC. tert-Butyldiphenylsilyl chloride
(0.082 g, 0.30 mmol) was added and the mixture was stirred at
room temperature overnight. TLC (ethyl acetate–hexane 1:3)
showed a major product at Rf 0.7. Ethanol (3 drops) was added
and the solvent was removed under reduced pressure. The
residue obtained was co-evaporated with toluene and then
dissolved in ethyl acetate (20 mL); the solution was washed
with pH 7 buffer solution (10 mL), dried (MgSO4), and con-
centrated. Flash chromatography purification (ethyl acetate–
hexane 1:24) gave the silyl ether 22 (0.111 g, 73%) as a colour-
less oil, [α]D22 Ϫ23.7 (c 1.35 in acetone) (Found: C, 62.77; H, 7.98;
N, 6.73. C32H49N3O5Si2 requires C, 62.81; H, 8.07; N, 6.87%);
νmax (thin film) 2103 (N3) cmϪ1; δH (C6D6; 400 MHz) 0.06 (3H, s,
SiCH3), 0.14 (3H, s, SiCH3), 0.95 [9H, s, SiC(CH3)3], 1.12 [9H, s,
SiC(CH3)3], 1.24 (3H, s, CCH3), 1.42 (3H, s, CCH3), 3.62 (1H,
dd, J 11.7, 3.2, H-1), 3.76 (1H, dd, J 11.7, 3.3, HЈ-1), 3.82 (1H,
ddd, J 5.4, 2.5, 2.5, H-4), 3.92–3.98 (3H, m, H-2, H2-7), 4.02–
4.08 (2H, m, H-5, -6), 4.50 (1H, a-t, J 5.4, H-3), 7.20–7.25 (6H,
m, ArH), 7.72–7.79 (4H, m, ArH); δC (CDCl3; 100.6 MHz)
Ϫ4.6 (q, SiCH3), Ϫ4.2 (q, SiCH3), 18.6 [s, SiC(CH3)3], 19.6 [s,
SiC(CH3)3], 25.5 (q, CCH3), 26.2 [q, SiC(CH3)3], 27.0 (q,
CCH3), 27.3 [q, SiC(CH3)3], 63.3 (t, C-1), 65.1 (d, C-4), 67.8 (t,
C-7), 73.9 (d, C-3), 77.3 (d, C-5 or -6), 82.2 (d, C-5 or -6), 84.9
(d, C-2), 110.2 (s, O–C–O), 128.4 (d, Ar CH), 128.4 (d, Ar CH),
130.4 (d, Ar CH), 130.5 (d, Ar CH), 133.6 (s, Ar CC), 133.8
(s, Ar CC), 136.3 (d, Ar CH), 136.3 (d, Ar CH); m/z (APCIϩ)
584 (M ϩ Hϩ Ϫ N2, 100%).
2,5-Anhydro-4-azido-3-O-(tert-butyldimethylsilyl)-4-deoxy-D-
allitol 19
The diol 17 (0.034 g, 0.10 mmol) was dissolved in dry THF (0.4
mL) and periodic acid (0.026 g, 0.11 mmol) was added. After
stirring of the mixture for 10 min at room temperature, TLC
(ethyl acetate–hexane 1:1) suggested complete conversion of
starting material (Rf 0.2) to product (Rf 0.5). The reaction mix-
ture was filtered through Celite, with washing of the filter with
THF, and the combined filtrate and washings were concen-
trated in vacuo. The resulting residue was dissolved in a 9:1
mixture of ethanol and water (0.8 mL), and treated with
sodium borohydride (0.008 g, 0.10 mmol). After 15 min at room
temperature a major product (Rf 0.2) was observed by TLC
(ethyl acetate–hexane 1:1) together with a minor product (Rf
0.6). The reaction mixture was quenched with excess ammo-
nium chloride, concentrated, and partitioned between brine
and DCM. The combined organic phases were dried (MgSO4),
and concentrated in vacuo. Flash chromatography (ethyl
acetate–hexane 1:20, then 1:4, then 1:1) yielded the ester 20
(0.001 g, 3%) and 2,5-anhydro-4-azido-3-O-(tert-butyldimethyl-
silyl)-4-deoxy--allitol 19 (0.017 g, 59% overall from 6) as a
colourless oil, [α]D24 ϩ15.1 (c 0.31 in CHCl3) [HRMS m/z (CIϩ)
Found: 276.1636 (M ϩ Hϩ Ϫ N2). C12H26NO4Si requires m/z,
276.1631]; νmax (thin film) 3200–3600 (OH), 2104 (N3) cmϪ1
;
δH (CDCl3; 400 MHz) 0.14 (3H, s, SiCH3), 0.17 (3H, s, SiCH3),
0.94 [9H, s, SiC(CH3)3], 3.63 (1H, dd, J 12.0, 2.8, H-1), 3.69
(1H, dd, J 12.1, 2.7, H-6), 3.74 (1H, a-t, J 5.9, H-4), 3.87 (1H,
dd, J 12.0, 2.6, HЈ-1), 3.90–3.95 (2H, m, H-2, HЈ-6), 4.07 (1H,
a-dt, J 5.9, 2.6, H-5), 4.41 [1H, a-t (br), J ≈ 5.1, H-3]; δC
(CDCl3; 100.6 MHz) Ϫ5.0 (q, SiCH3), Ϫ4.8 (q, SiCH3), 18.0 [s,
SiC(CH3)3], 25.7 [q, SiC(CH3)3], 61.9, 62.3 (2 × t, C-1, -6), 62.3
(d, C-4), 73.8, 81.1, 85.0 (3 × d, C-2, -3, -5); m/z (APCIϩ) 276
(M ϩ Hϩ Ϫ N2, 50%), 228 (50), 122 (100).
2,5-Anhydro-4-azido-3-O-(tert-butyldimethylsilyl)-1-O-(tert-
butyldiphenylsilyl)-4-deoxy-D-glycero-D-allo-heptitol 23
The silyl acetonide 22 (0.087 g, 0.14 mmol) was dissolved in a
mixture of acetic acid and water (8 mL:2 mL) and the solution
was stirred at room temperature for 36 h. TLC (ethyl acetate–
hexane 1:3) showed a small amount of residual starting
material (Rf 0.7) to a single product (Rf 0.2). The reaction mix-
ture was concentrated in vacuo with toluene co-evaporation
and the residue was purified by flash chromatography (ethyl
acetate–hexane 1:3) to give the diol 23 (0.53 g, 65%) as a colour-
less oil, [α]D22 Ϫ18.3 (c 0.80 in MeOH) (Found: C, 61.25; H, 7.51;
N, 6.97. C29H45N3O5Si requires C, 60.91; H, 7.93; N, 7.35%);
νmax (thin film) 3200–3600 (OH), 2105 (N3) cmϪ1; δH (C6D6; 400
MHz) 0.03 (3H, s, SiCH3), 0.13 (3H, s, SiCH3), 0.94 [9H, s,
SiC(CH3)3], 1.14 [9H, s, SiC(CH3)3], 2.57 (1H, br d, J 3.3, 6-OH),
3.42–3.55 (2H, m, H2-7), 3.58 (1H, dd, J 11.7, 3.1, H-1),
3.67–3.73 (1H, m, H-6), 3.79 (1H, dd, J 11.7, 3.2, HЈ-1), 3.85–
3.94 (3H, m, H-2, -4, 7-OH), 4.04 (1H, a-t, J 5.3, H-5), 4.46
(1H, a-t, J 5.5, H-3), 7.20–7.26 (6H, m, ArH), 7.72–7.78 (4H, m,
ArH); δC (C6D6; 63 MHz) Ϫ4.9 (q, SiCH3), Ϫ4.6 (q, SiCH3),
19.3 [s, SiC(CH3)3], 20.5 [s, SiC(CH3)3], 25.9 [q, SiC(CH3)3],
27.1 [q, SiC(CH3)3], 63.3 (2 × t, 1 × d, C-1, -7, -2 or -4), 72.7 (d,
C-6), 73.9 (d, C-3), 82.0 (d, C-5), 84.4 (d, C-4 or -2), 130.2,
2,5-Anhydro-4-azido-3-O-(tert-butyldimethylsilyl)-4-deoxy-6,7-
O-isopropylidene-D-glycero-D-allo-heptitol 21
The protected azide 6 (0.156 g, 0.39 mmol) was dissolved in a
9:1 mixture of ethanol and water (4 mL), and sodium boro-
hydride (0.030 g, 0.78 mmol) was added. After 3 h at room
temperature a major product (Rf 0.4) was observed by TLC
(ethyl acetate–hexane 1:1) with no starting material (Rf 0.8)
remaining. The reaction mixture was quenched with excess
solid ammonium chloride (0.053 g, 1 mmol), concentrated, and
partitioned between brine and DCM. The combined organic
phases were dried (MgSO4), and concentrated in vacuo. Flash
chromatography (ethyl acetate–hexane 1:3) afforded the alcohol
21 (0.093 g, 64%) as a colourless oil, [α]D22 Ϫ10.8 (c 1.04 in
MeOH) (Found: C, 51.26; H, 8.36; N, 10.82. C16H31N3O5Si
3684
J. Chem. Soc., Perkin Trans. 1, 2000, 3680–3685

View Article Online
4 M. Hoffmann and H. Kessler, Tetrahedron Lett., 1994, 35, 6067.
5 Y. Nitta, M. Kuranari and T. Kondo, Yakugaku Zasshi, 1961, 81,
1189.
6 M. D. Smith and G. W. J. Fleet, J. Pept. Sci., 1999, 5, 425.
7 C. J. F. Bichard, T. W. Brandstetter, J. C. Estevez, G. W. J. Fleet,
D. J. Hughes and J. R. Wheatley, J. Chem. Soc., Perkin Trans. 1,
1996, 2151.
130.3, 136.0, 136.0 [4 × d, 4 × Ar CH (some Ar CH obscured
by C6D6)], 133.2, 133.3 (2 × s, 2 × Ar CC); m/z (APCIϩ) 594
(M ϩ Naϩ, 5%), 544 (M ϩ Hϩ Ϫ N2, 80), 466 (100).
2,5-Anhydro-3-azido-4-O-(tert-butyldimethylsilyl)-6-O-(tert-
butyldiphenylsilyl)-3-deoxy-L-allonic acid 24
8 J. S. Brimacombe and L. C. N. Tucker, Carbohydr. Res., 1965, 1,
The diol 23 (0.033 g, 0.58 mmol) was stirred vigorously in a
mixture of CCl4–CH3CN–water (2:2:3) (0.4 mL) to which
sodium periodate (0.052 g, 0.24 mmol) was added. Ruthenium
trichloride hydrate (<1 mg) was then immediately added. Upon
stirring of the mixture for 5 h at room temperature, TLC (ethyl
acetate–hexane 1:1) showed no residual starting material (Rf
0.6) and a major product (Rf 0.7). The reaction mixture was
diluted with ethyl acetate and filtered through Celite, with wash-
ing of the filter with ethyl acetate. Upon concentration in vacuo
the residue obtained was purified by flash chromatography
(ethyl acetate–hexane 1:10, then 1:3) to give the acid 24 an oil
(0.020 g, 62%) [HRMS m/z (CIϩ) Found: 528.2620 (M ϩ Hϩ Ϫ
N2). C28H42NO5Si requires m/z, 528.2602]; [α]D22 ϩ4.16 (c 0.77
in CHCl3); νmax (thin film) 3500–2500 (OH), 2110 (N3), 1733
332.
9 J. S. Brimacombe and L. C. N. Tucker, Carbohydr. Res., 1966, 2,
341.
10 J. R. Wheatley, C. J. F. Bichard, S. J. Mantell, J. C. Son, D. J.
Hughes, G. W. J. Fleet and D. Brown, J. Chem. Soc., Chem.
Commun., 1993, 1065.
11 M. P. Watterson, L. Pickering, M. D. Smith, S. J. Hudson, P. R.
Marsh, J. E. Mordaunt, D. J. Watkin, C. J. Newman and G. W. J.
Fleet, Tetrahedron: Asymmetry, 1999, 10, 1855.
12 M. D. Smith, T. D. W. Claridge, G. W. J. Fleet, G. E. Tranter and
M. S. P. Sansom, Chem. Commun., 1998, 2041; D. D. Long,
N. L. Hungerford, M. D. Smith, D. E. A. Brittain, D. G. Marquess,
T. D. W. Claridge and G. W. J. Fleet, Tetrahedron Lett., 1999, 40,
2195; D. D. Long, M. D. Smith, D. G. Marquess, T. D. W. Claridge
and G. W. J. Fleet, Tetrahedron Lett., 1998, 39, 9293.
13 T. D. W. Claridge, D. D. Long, N. L. Hungerford, R. T. Aplin,
M. D. Smith, D. G. Marquess and G. W. J. Fleet, Tetrahedron Lett.,
1999, 40, 2199.
14 P. Armand, K. Kirshenbaum, A. Falicov, R. L. Dunbrack, Jr.,
K. A. Dill, R. N. Zuckermann and F. E. Cohen, Folding Des.,
1997, 2, 369; P. Armand, K. Kirshenbaum, R. A. Goldsmith,
S. Farr-Jones, A. E. Barron, K. T. V. Truong, K. A. Dill, D. F.
Mierke, F. E. Cohen, R. N. Zuckermann and E. K. Bradley,
Proc. Natl. Acad. Sci. USA, 1998, 95, 4309.
15 D. H. Appella, L. A. Christianson, I. L. Karle, D. R. Powell and
S. H. Gellman, J. Am. Chem. Soc., 1996, 118, 13071; D. H. Appella,
J. J. Barchi, Jr., S. R. Durell and S. H. Gellman, J. Am. Chem. Soc.,
1999, 121, 2309; D. Seebach and J. L. Matthews, Chem. Commun.,
1997, 2015; Y. J. Chung, B. R. Huck, L. A. Christianson, H. E.
Stanger, S. Krauthauser, D. R. Powell and S. H. Gellman, J. Am.
Chem. Soc., 2000, 122, 3995; J. D. Fisk, D. R. Powell and S. H.
Gellman, J. Am. Chem. Soc., 2000, 122, 5443; X. Wang, J. F.
Espinosa and S. H. Gellman, J. Am. Chem. Soc., 2000, 122, 4821;
E. A. Porter, X. Wang, H.-S. Lee, B. Weisblum and S. H. Gellman,
Nature (London), 2000, 404, 565.
(C᎐O) cmϪ1; δH (CDCl3; 500 MHz) Ϫ0.01 (3H, s, SiCH3), 0.10
᎐
(3H, s, SiCH3), 0.84 [9H, s, SiC(CH3)3], 1.10 [9H, s, SiC(CH3)3],
3.59 (1H, dd, J 11.6, 1.2, H-6), 4.00 (1H, ddd, J 11.6, 3.1, 0.8,
HЈ-6), 4.03 (1H, ddd, J 7.5, 3.1, 1.2, H-5), 4.11 (1H, dd, J 4.7,
2.4, H-3), 4.44 [1H, dd (br), J 7.5, 4.7, H-4], 4.52 (1H, d, J 2.4,
H-2), 7.40–7.52 (6H, m, ArH), 7.64–7.70 (4H, m, ArH); δC
(CDCl3; 125 MHz) Ϫ4.7 and Ϫ4.3 (q, SiCH3), Ϫ4.1 (q, SiCH3),
18.3 [s, SiC(CH3)3], 19.4 [s, SiC(CH3)3], 26.0 [q, SiC(CH3)3],
27.4 [q, SiC(CH3)3], 61.7 (t, C-6), 66.5 (d, C-3), 71.9 (d, C-4),
79.9 (d, C-2), 83.6 (d, C-5), 128.4 (d, Ar CH), 128.5 (d, Ar CH),
130.6 (d, Ar CH), 130.8 (d, Ar CH), 132.1 (s, Ar CC), 132.2 (s,
Ar CC), 135.9 (d, Ar CH), 136.2 (d, Ar CH); m/z [CI (NH3)]
528 (M ϩ Hϩ Ϫ N2, 100%), 484 (55), 352 (90); m/z (APCIϪ)
554 (M Ϫ HϪ, 100%), 255 (30).
Acknowledgements
16 T. Hintermann, K. Gademann, B. Jaun and D. Seebach, Helv.
Chim. Acta, 1998, 81, 983; S. Hanessian, X. Luo, R. Schaum and
S. Michnick, J. Am. Chem. Soc., 1998, 120, 8569.
17 (a) K. Kirshenbaum, R. N. Zuckermann and K. A. Dill, Curr. Opin.
Struct. Biol., 1999, 9, 530; (b) S. H. Gellman, Acc. Chem. Res., 1998,
31, 173; (c) M. J. Soth and J. S. Nowick, Curr. Opin. Chem. Biol.,
1997, 1, 120.
This work was supported by BBSRC and EPSRC. We are grate-
ful to Dr J. H. Jones (University of Oxford) for helpful
discussions.
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J. Chem. Soc., Perkin Trans. 1, 2000, 3680–3685
3685