Templated scaffolds of cis- and trans-tetrahydrofuran γ-amino acids: γ-azido-β-hydroxy-tetrahydrofuran-2-carboxylates from pentono-δ-lactones

Article abstract of DOI:10.1016/S0040-4039(03)01415-1

Short syntheses of enantiomeric templated scaffolds of cis- and trans-tetrahydrofuran γ-amino acids from pentono-δ-lactones derived from arabinose and ribose are reported; an unexpectedly efficient synthesis of a templated tetrahydrofuran β-amino acid by

Full text of DOI:10.1016/S0040-4039(03)01415-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5847–5851
Templated scaffolds of cis- and trans-tetrahydrofuran g-amino
acids: g-azido-b-hydroxy-tetrahydrofuran-2-carboxylates from
pentono-d-lactones
Gangadharar J. Sanjayan, Alistair Stewart, Shuji Hachisu, Raquel Gonzalez, Mark P. Watterson
and George W. J. Fleet*
Dyson Perrins Laboratory, South Parks Road, University of Oxford, Oxford OX1 3QY, UK
Received 18 September 2002; revised 29 May 2003; accepted 5 June 2003
Abstract—Short syntheses of enantiomeric templated scaffolds of cis- and trans-tetrahydrofuran g-amino acids from pentono-d-
lactones derived from arabinose and ribose are reported; an unexpectedly efficient synthesis of a templated tetrahydrofuran
b-amino acid by azide displacement of a triflate b to an ester function proceeds with remarkably little elimination. These materials
should allow evaluation of such peptidomimetics to induce predisposition towards secondary structures.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
[which constitute the most extensively characterised
class of foldamer], the controlled assembly of compact
tertiary structures (helical bundles) is likely be achieved
soon.5 Structural studies via solution NMR have iden-
tified a multitude of helical, turn and sheet structures in
organic and aqueous solvents.6 Resistance of these
molecules to degradation by proteolytic enzymes7 has
led to a variety of studies of their biological properties,
including: antimicrobial action;8,9 inhibition of small-
intestinal fat and cholesterol absorption;10 as b-peptide
based somatostatin mimics;11 as anti-proliferatives
against human cancer cell growth;12 their cellular
uptake;13 and their biodegradability.14
The design of molecules that mimic the secondary and
tertiary structures of proteins and RNA, yet that are
composed of non-natural building blocks is a com-
pelling challenge, offering the possibility of reproducing
and extending the functional capabilities of Nature’s
macromolecules. Although to date this ‘foldamer’1
approach has not achieved the successes of de novo
protein design2 and protein redesign,3 protein-like sec-
ondary folding has been demonstrated for homo- and
heterooligomers derived from a diverse array of pep-
tidic and non-peptidic templates.4 For b-peptides
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01415-1

5848
G. J. Sanjayan et al. / Tetrahedron Letters 44 (2003) 5847–5851
allow studies on the conformational properties of g-
peptides bearing cyclically constrained residues. In this
first paper, the synthesis of the 2,4-cis- and 2,4-trans-
substituted b-hydroxy THF g-azido esters 7 and 8 is
described from pentono-d-lactones. The following
paper highlights routes to all diastereomeric 3-deoxy
analogues 9 bearing C-5 hydroxymethyl side chains
from hexono-g-lactones.
Like b-peptides, g-peptides built from acyclic residues
form stable helical,15 turn16 and sheet15a structures in
organic solvents (together with some, as yet, uncharac-
terised structures17), and display resistance to prote-
olytic enzymes.7 However, in contrast to the extensive
studies on b-peptides built from residues containing 5-
or 6-membered rings, there are only limited reports of
g-peptides based on cyclic templates. This is somewhat
surprising given that for b-peptides, the use of cyclically
constrained residues resulted in increased population of
folded states in aqueous media.18 Gellman has reported
parallel sheet formation between extended strands built
2-O-Trifluoromethanesulfonate derivatives (triflates) of
carbohydrate d-lactones 10 undergo efficient ring con-
traction to highly substituted tetrahydrofuran-2-car-
boxylates 11 when treated with methanol in the
presence of either an acid30 or base31 catalyst. Initial
nucleophilic opening of the lactone ring by methanol,
followed by subsequent SN2-type ring closure of an
intermediate hydroxy triflate (or the corresponding
alkoxide anion) forms the THF ring with inversion of
configuration at the C-2 position. In applying this
methodology to the synthesis of THF g-azido esters 12
there is scope for introduction of the C-4 azido group
either after [Strategy 1] or before [Strategy 2] formation
of the THF ring in Scheme 1. Such flexibility is not
available when g-lactone starting materials are
employed (see the following paper29).
from
trans-3-amino-cyclopentanecarboxylic
acid
residues 1 and a non-g-peptide linker.19 In addition
Toniolo predicts an extended left-handed helix (with 13
,
A pitch length) for homooligomers of the structurally
related g-lactam building block 2 on the basis of the
X-ray crystal structure of a homotrimer.20 Studies of
the conformational preferences of single cis-configured
g-amino acids based on proline and g-lactam scaffolds
321 and 422 indicate propensities to act as g-turn and
type IVa b-turn mimetics respectively. However, it is
not clear that the nearest neighbour hydrogen bonds
present in these examples will dominate in oligomeric
derivatives. Oligomers of tetrahydrofuran and oxetane
templated b-and d-amino acids derived from carbohy-
drates can form novel peptidic structures that fold
predictably. Examples include repeating b-turn
structures23 (reminiscent of the b-bend ribbon spiral24)
and a 16-helix25 from diastereomers of the d-amino acid
template 5, and 10-helices for hexapeptides of cis-oxe-
tane b-amino acids.26
2.1. Synthesis of 2,4-cis (
L
-lyxo) g-azido ester 7 and
2,3-cis ( -xylo) b-azido ester 23 from arabinose
D
The 2,5-anhydro-
L
-ribonate 19, available from
L-ara-
bino-configured precursors, served as the key intermedi-
ate in the synthesis of the 2,4-cis g-azido ester 7 and its
regioisomer 23 (Scheme 2). Oxidation of the kinetic
acetonide of -arabinose 13 using N-bromosuccinimide
L
and pyridine in dichloromethane (DCM) gave the
Previous syntheses of THF g-amino acids building
blocks are limited. cis- And trans-forms of the simplest
THF g-amino acid framework 6 were synthesised from
diethyl allylmalonate as potential GABA mimics,27
whereas Vogel generated a C-5 substituted g-azido acid
en route to a C-nucleoside analogue of AZT.28
known d-lactone product 14 in 58% yield32 {mp 94–
96°C (ethyl acetate/hexane), lit.33 95–97°C; [h]D −28.0
23
(c, 1.0), lit.33 [h]D −1.0 (c, 3.0)}. Esterification of the
free C-2 hydroxyl group with triflic anhydride in DCM
in the presence of pyridine afforded the corresponding
triflate 15, which after aqueous extraction and concen-
tration was used crude in subsequent steps. Ring con-
traction of the triflate intermediate to tetrahydrofuran
products was investigated under both basic and acidic
conditions. Treatment of 15 with potassium carbonate
in methanol gave a mixture of two isopropylidene-con-
2. Synthesis
This and the following paper29 describe short syntheses
of protected g-amino acids based on THF templates to
taining products: the expected L-ribo THF carboxylate
Scheme 1. Synthetic routes to THF-templated g-amino acids from pentono-1,5-lactones.

G. J. Sanjayan et al. / Tetrahedron Letters 44 (2003) 5847–5851
5849
Scheme 2. Reagents and conditions: (i) N-bromosuccinimide, pyridine, CH2Cl2, 0°C to rt, 14 h; (ii) Tf2O, pyridine, DCM, −20°C;
(iii) 1% v/v AcCl in MeOH, rt, 13 h; (iv) 1.1 equiv. K2CO3, MeOH, 0°C, 1.5 h; (v) 0.3 equiv. K2CO3, MeOH, rt, 14 h; (vi) 5%
v/v AcCl in Me2CHOH, 80°C, 48 h; (vii) TBDPSCl, imidazole, DMF, 0°C to rt, 10 h; (viii) 4 equiv. NaN3, DMF, rt, 10 h.
16 {30%; oil; [h]2D3 +64.6 (c, 1.2)} and a second product,
assumed to be the C-2 epimer 17 {17%; oil; mp 61–
62°C; [h]2D3 +88.5 (c, 1.1)}. Smooth conversion of 16 to
the thermodynamically more stable all-cis product 17
(in 89% yield) under basic conditions confirmed that
the two products differ only in C-2 stereochemistry; the
proportion of 16 to 17 under basic conditions depends
on the length of time of the reaction. In contrast, while
treatment of the triflate 15 with hydrogen chloride in
methanol at room temperature gave a mixture of the
acetonide 16 together with the diol 18, no epimerisation
at C-2 of the THF was observed. When the methanol
reaction mixture was heated to 70°C, only 18 was
formed. Transesterification of 18 by reaction with
Triflation of the remaining free hydroxyl group in 20,
followed by reaction of the crude triflate with sodium
azide gave the
yield of 95%. More surprisingly, the
D
-lyxo g-azido ester 734 in an overall
L
-xylo b-azido
ester 2335 {oil; [h]2D3 −12.6 (c, 1.0)},was formed in 81%
yield by similar treatment of 21; only a very small
amount of the b-elimination product 24 {4%; oil; [h]D23
−22.3 (c, 1.8)} was isolated. The effective substitution
[with little elimination] in this case is contrasted with
the complete absence of substitution products for a
related example reported in the following paper; in
general, sodium azide is an excellent base for inducing
elimination rather than substitution of b-triflates of
carboxylic esters in THF rings.29
acidic iso-propanol at 80°C gave the
L-ribo isopropyl
ester 19 {oil; [h]2D3 +44.3 (c, 1.0)} in 63% yield from 14.
2.2. Synthesis of 2,4-trans (
L
-xylo) g-azido ester 8
from -ribose
D
Reaction of the diol 19 with tert-butyldiphenylsilyl
chloride in dimethylformamide (DMF) afforded an eas-
ily separable mixture of the 3-O-silyl and 4-O-silyl
derivatives 20 {oil; [h]2D3 −28.9 (c, 1.9)} and 21 {oil [h]D24
−16.5 (c, 1.6)}, in 34% and 56% yields, respectively. The
crystalline disilyl compound 22 {mp 135–136°C (ethyl
acetate/hexane); [h]2D4 +15.1 (c, 0.5)} was isolated from
the reaction mixture in 8% yield; the structure of 22 was
firmly established by X-ray crystallographic analysis
which confirmed that the acid-mediated ring contrac-
tion of 15 proceeded with complete inversion of
configuration at C-2.
The synthesis of the enantiomeric 2,4-trans g-azido
ester 8 from the -lyxo THF carboxylate 27 generated
from the easily accessible benzylidene -ribonolactone
25 uses essentially the same strategy (Scheme 3). The
L
D
2-O-triflate 26, available in three steps from
D-ribose
25,36 was purified on a multigram scale via crystallisa-
tion from acetonitrile.
Reaction of 26 with a methanolic solution of hydrogen
chloride under reflux afforded the diol-2-carboxylate 27

5850
G. J. Sanjayan et al. / Tetrahedron Letters 44 (2003) 5847–5851
Scheme 3. Reagents and conditions: (i) 5% v/v AcCl in MeOH, rt to 70°C, 3 h then aq. HCl added, 70°C, 15 h; (ii) CSA, acetone,
rt, 24 h; (iii) 1.5 equiv. Tf2O, pyridine, DCM, −25°C, 4 h then rt, 3 h; (iv) 5 equiv. NaN3, DMF, rt, 15 h; (v) p-toluenesulfonic
acid, Me2CHOH, 80°C, 24 h.
{mp 72–73°C; [h]2D3 −22.3 (c, 1.8)} in 84% yield,
together with small quantities of the epimeric benzyli-
dene protected products 28 {7%; mp 79–80°C (ethyl
acetate/hexane); [h]2D4 −160.5 (c, 1.0)} and 29 {6%; mp
125–126°C; [h]2D3 −71.9 (c, 1.0)}.37 Reaction of the diol
27 into a single isopropylidene derivative 30 {mp 60–
61°C; [h]2D4 confirmed the 2,3-cis stereochemistry of the
diol. The optical rotation of 30 [which otherwise had
identical NMR and other physical data to that of its
enantiomer 17] confirms the stereochemistry of the acid
catalysed ring contraction.
Fellowship (G.J.S.), Ministerio de Ciencia y Tecnolog´ıa
(R.G.) and EPSRC (M.P.W.) is gratefully acknowl-
edged. A generous gift of the lactol 13 from CMS
Chemicals made this project possible.
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34.
D
-lyxo g-Azido ester 7: oil. [h]2D3 +11.3 (c, 1.2). lH (500
MHz): 1.16 (9H, s, SiC(CH3)3), 1.19 (3H, d, J 6.2,
CH(CH3)2), 1.23 (3H, d, J 6.2, CH(CH3)2), 3.80 (1H, d, J
3.5, H-4), 4.11 (1H, d, J5,5% 10.0, H-5), 4.30 (1H, dd, J5%,4
4.5 Hz, J5%,5 10.0, H-5%), 4.50 (1H, b-s, H-2), 4.58 (1H, b-s,
H-3), 5.05 (1H, sept, J 6.2 Hz, CHMe2), 7.43–7.67 (10H,
m, Ar-H). lC (50.3 MHz): 19.1 (C, SiCMe3), 21.6 (2×
CH3, CH(CH3)2), 26.8 (3×CH3, SiC(CH3)3), 66.4 (CH,
CHMe2), 68.9 (CH, C-4), 71.5 (CH2, C-5), 80.7 (CH,
C-3), 84.3 (CH, C-2), 127.9, 128.0, 130.2, 130.3 (Ar-CH),
132.2, 132.7 (Ar-C), 135.6, 135.8 (Ar-CH), 169.1 (C,
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35.
L
-xylo b-Azido ester 23: oil. [h]2D3 −12.6 (c, 1.0). lH (500
MHz): 1.15 (9H, s, SiC(CH3)3), 1.34 (6H, d, J 6.2,
CH(CH3)2), 3.90 (1H, dd, J5,4 0.9, J5,5% 9.8, H-5), 4.03
(1H, app-t, J 4.4 Hz, H-3), 4.08 (1H, dd, J5%,4 3.8 Hz, J5%,5
9.5 Hz, H-5%), 4.40 (1H, m, H-4), 4.81 (1H, d, J2,3 4.9 Hz,
H-2), 5.20 (1H, sept, J 6.4 Hz, CHMe2), 7.42–7.70 (10H,
m, Ar-H). lC (50.3 MHz): 19.0 (C, SiCMe3), 21.7, 21.8
(2×CH3, CH(CH3)2), 26.8 (3×CH3, SiC(CH3)3), 69.3
(CH, CHMe2), 69.7 (CH, C-4), 74.8 (CH2, C-5), 77.0
(CH, C-3), 79.1 (CH, C-2), 128.0, 128.1, 130.2, 130.3
(Ar-CH), 132.6 (Ar-C), 135.6 (Ar-CH), 168.3 (C, C-1).
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37. The stereochemistries at the asymmetric centres of the
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38.
L
-xylo g-azido ester 8: mp 78–80°C; [h]2D4 +28.9 (c, 1.1);
lH (400 MHz) 1.31 (6H, d, J 6.2, CH(CH3)2), 2.71 (1H,
d, JOH,3 5.1, OH), 3.92 (1H, dd, J4,5% 2.1, J5,5% 9.9, H-5%),
4.12 (1H, m, H-4), 4.34 (1H, dd, J4,5 4.6, J5,5% 9.9, H-5),
4.49–4.51 (1H, m, H-3), 4.56 (1H, d, J2,3 4.3 Hz, H-2),
5.16 (1H, sept, J 6.2, CHMe2). lC (50.3 MHz) 22.0
(2×CH3, CH(CH3)2), 66.9 (CH, C-4), 69.8 (CH, CHMe2),
71.3 (CH2, C-5), 76.8 (CH, C-3), 80.3 (CH, C-2), 169.4
(C, C-1).
26. Barker, S. F.; Angus, D.; Taillefumier, C.; Probert, M.
R.; Watkin, D. J.; Watterson, M. P.; Claridge, T. D. W.;