Branched tetrahydrofuran α,α-disubstituted-δ-sugar amino acid scaffolds from branched sugar lactones: A new family of foldamers?

Article abstract of DOI:10.1016/j.tetlet.2005.06.029

Efficient S_N2 ring closure of open chain trihydroxytriflates-in which the leaving group is on a primary carbon adjacent to a quaternary centre-provides access to tetrahydrofurans with branched carbon chains from branched carbohydrate lactones;

Full text of DOI:10.1016/j.tetlet.2005.06.029

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5761–5765
Branched tetrahydrofuran a,a-disubstituted-d-sugar
amino acid scaffolds from branched sugar lactones:
a new family of foldamers?
Michela Iezzi Simone, Raquel Soengas, Christopher R. Newton,
David J. Watkin and George W. J. Fleet*
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Received 4 April 2005; revised 23 May 2005; accepted 6 June 2005
Abstract—Efficient SN2 ring closure of open chain trihydroxytriflates—in which the leaving group is on a primary carbon adjacent
to a quaternary centre—provides access to tetrahydrofurans with branched carbon chains from branched carbohydrate lactones; the
first examples of a new class of branched chain tetrahydrofuran a,a-disubstituted-d-sugar amino acid scaffolds are described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
gave the open chain ester 2, which closed to form the
d-SAA scaffold 3.14 The combination of the excellent tri-
flate leaving group and of an a-carbonyl functionality
makes this an efficient SN2 reaction. This letter reports
the synthesis of branched THF d-SAA scaffolds by
an unexpectedly efficient [presumably] SN2 closure of
trihydroxytriflates in which the leaving group is on a
primary carbon adjacent to a quaternary centre. Thus,
the azidolactones 4 and 7 were converted in good iso-
lated yields to the carbon branched THF esters 6
(77%) and 9 (79%), respectively, by reaction with hydro-
gen chloride in methanol; the sequence involves removal
of the acetonide protecting group and ester exchange to
give the open chain trihydroxy triflates 5 and 8, which
undergo spontaneous closure to the branched carbon
chain d-SAA scaffolds (Scheme 1).
Sugar amino acids (SAAs) are an important class of pep-
tidomimetics1 as building blocks in combinatorial che-
mistry2 and as an extensive class of foldamers.3 Their
predisposition to induce novel secondary structures is
well established.4 Although pyranose5 and oxetanose6
d-SAAs have been widely studied, furanose tetrahydro-
furan (THF)d-SAAs7 are the mostthoroughlyinvestigated
dipeptide isosteres with significant biological activity.8
Almost all SAAs have linear carbon chains, since the
only carbohydrates from which they may be derived also
have unbranched chains;9 the rare examples of SAA,
which have a branched carbon chain10 require substan-
tial synthetic effort. Recently, the Kiliani reaction on
ketohexoses, followed by acetonation, has provided a
number of easily accessible diacetonides11,12 containing
branched chains, which may allow ready access to a
new class of a,a-disubstituted-d-SAAs.
2. Synthesis of trans-THF d-SAA scaffold 6 from
D-ribonolactone
In the synthesis of a series of THF d-SAAs, the THF
ring was generated by a nucleophilic displacement of a
triflate at C-2 of a lactone by conversion into an open
chain hydroxymethyl ester [not isolated], which closed
in situ to the THF carboxylate;13 for example, the lac-
tone triflate 1 in methanol in the presence of pyridine
For the synthesis of the d-SAA scaffold 6, in which the
azide component on the THF is trans to the ester func-
tion, the primary alcohol in the protected D-ribonolac-
tone15 10 was esterified with triflic anhydride in
dichloromethane in the presence of pyridine, and the
resulting triflate treated with sodium azide in ethyl ace-
tate to afford the azide 11 {[mp 36 ꢁC, ½aŠ23 +18.9 (c, 1.66
D
16
in CHCl3) [Lit.,
CHCl3)]]} (Scheme 2).
mp 39 ꢁC, [a]D +15.0 (c, 1.00 in
*
Corresponding author. E-mail: george.fleet@chem.ox.ac.uk
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.029

5762
M. I. Simone et al. / Tetrahedron Letters 46 (2005) 5761–5765
δ
N3H2C
HO
O
β
OH
pyridine
MeOH
CO2Me
OTf
N3H2C
CO2Me
α
N3H2C
O
O
γ
HO
OH
HO
OH
HO
OTf
1
2
3
O
δ
O
γ
N3H2C
O
OH
N3H2C
N3H2C
OTf
HCl
CH2OTf
α
β
HO
CO2Me
OH
CO2Me
O
O
MeOH
HO
OH
6
4
5
O
O
N3H2C
O
OH
N3H2C
N3H2C
OTf
HCl
CH2OTf
CO2Me
OH
CO2Me
O
O
MeOH
HO
HO
OH
9
7
8
Scheme 1. Synthesis of branched THF d-SAAs.
O
O
O
O
O
O
O
N3CH2
OH
OH
CH2OH
O
HOH2C
N3CH2
N3CH2
N3CH2
(iv)
(ii)
(i)
(iii)
CH2OH
O
O
O
O
O
O
O
O
O
O
11
10
12
14
13
(v)
Bn = PhCH2; Tf = CF3SO2
O
MeC
HNCH2
O
O
O
O
O
(vii)
H2NCH2
N3CH2
N3CH2
N3CH2
(vi)
O
(ix)
(viii)
CONHBn
OH
CONHBn
OH
CO2Me
OH
CH2OTf
CONHBn
OH
HO
HO
HO
O
O
HO
16
15
6
4
17
Scheme 2. Reagents and conditions: (i) Tf2O, pyridine, CH2Cl2; then NaN3, EtOAc (77%); (ii) DIBAL, CH2Cl2 À78 ꢁC (93%); (iii) CH2O, K2CO3,
H2O (92%); (iv) Br2, BaCO3, H2O (92%); (v) Tf2O, pyridine, CH2Cl2 (100%); (vi) HCl, MeOH (77%); (vii) BnNH2, 120 ꢁC (83%); (viii) H2, 10% Pd/C,
dioxane (91%); (ix) (MeCO)2O, pyridine; then K2CO3, MeOH (82%).
Reduction of the azidolactone 11 with diisobutylalu-
minium hydride (DIBAL) in dichloromethane gave 12,
which underwent an efficient Ho crossed aldol conden-
sation17 with aqueous formaldehyde in the presence of
tecting group, ring opening to the trihydroxy triflate
ester and subsequent ring closure to give the key azido
ester 6.20
potassium carbonate to afford the carbon branched lac-
The sterically hindered carbonyl group in 6 underwent
relatively easy nucleophilic attack; treatment of 6 with
25
D
tol 13 [mp 115–117 ꢁC, ½aŠ +23.1 (c, 0.95 in MeCN)].
Oxidation of the lactol 13 by aqueous bromine in the
presence of barium carbonate gave the azido lactone
14,18 the structure of which was confirmed by X-ray
analysis.19 Esterification of the primary alcohol in 14
benzylamine at 120 ꢁC gave the corresponding benzyl-
21
amide 15 [mp 109–110 ꢁC, ½aŠ +61.1 (c, 0.44 in metha-
D
nol)], which on hydrogenation in 1,4-dioxane in the
presence of 10% palladium on carbon afforded the
23
D
with triflic anhydride in dichloromethane in the pres-
amine 16 [mp 85–85.5 ꢁC, ½aŠ +8.5 (c, 2.49 in MeOH)].
21
ence of pyridine gave the triflate 4 [an oil, ½aŠ +58.9
Peracetylation of 16 with acetic anhydride in pyridine,
followed by removal of the esters by ester exchange with
potassium carbonate in methanol, gave the bis-amide 17
D
(c, 0.52 in CH2Cl2)]. Reaction of 4 with hydrogen chlo-
ride in methanol caused removal of the acetonide pro-

M. I. Simone et al. / Tetrahedron Letters 46 (2005) 5761–5765
5763
O
O
O
O
O
O
O
O
O
HOH2C
N3H2C
N3H2C
N3H2C
(iii)
(ii)
(iv) N3H2C
(i)
CH2OTf
CH2OH
CO2Me
OH
O
O
O
O
O
O
O
O
HO
19
9
18
20
7
(vi)
(v)
O
Me
(vii)
O
(viii)
O
O
O
HNCH2
H2NCH2
N3H2C
NH
O
CONHBn
CONHBn
CONHBn
OH
OH
OH
HO
HO
HO
HO
OH
24
23
21
22
Scheme 3. Reagents and conditions: (i) Tf2O, pyridine, CH2Cl2; then NaN3, Me2CO (74%); (ii) DIBAL, CH2Cl2; then CH2O, K2CO3, H2O; then Br2,
BaCO3, H2O (68%); (iii) Tf2O, pyridine, CH2Cl2 (100%); (iv) HCl, MeOH (79%); (v) H2, 10% Pd/C, dioxane (72%); (vi) BnNH2, 120 ꢁC (95%); (vii)
H2, 10% Pd/C, dioxane (89%); (ix) (MeCO)2O, pyridine; then K2CO3, MeOH (74%).
23
[mp 155–155.5 ꢁC; ½aŠ +0.64 (c, 0.70 in methanol)] as a
which on catalytic hydrogenation gave the correspond-
D
novel dipeptide isostere.
21
D
ing amine 23 [mp 112–113 ꢁC; ½aŠ À6.7 (c, 0.39 in
MeOH)]. Treatment of the amine 23 with acetic anhy-
dride in pyridine, followed by removal of the esters by
transesterification with potassium carbonate in metha-
The ease of these reactions suggests that, together with
the overall yield for the formation of 6 from 10 of
47% allowing significant quantities to be prepared, 6
can be studied as a member of a potential new class of
foldamer.
nol afforded the dipeptide mimetic 24 [mp 164–166 ꢁC;
23
½aŠ À6.7 (c, 0.39 in MeOH)], the structure of which
D
was confirmed by X-ray crystallographic analysis.28
3. Synthesis of cis-THF d-SAA scaffold 9 from
L-lyxonolactone
4. Summary
This letter reports the first examples of the efficient
generation of THF rings with branched carbon chains
from branched sugar lactones, producing carboxylates
with quaternary centres adjacent to the acid functional-
ity. More efficient routes to these and other such
THF SAA scaffolds should be available from the
diacetonides generated from the Kiliani reaction on
ketohexoses.11,12 This will allow studies on the struc-
ture of homooligomers from this new class of potential
foldamer.
A similar sequence was followed from the readily avail-
able protected L-lyxonolactone 1821 for the epimeric d-
SAA scaffold 9, in which the azide component in the
THF ring is cis to the ester function. The alcohol 18
was converted by triflation and azide displacement to
22
D
the azide 19 [mp 72–74 ꢁC, ½aŠ À76.8 (c, 0.52 in
CHCl3)] by an identical procedure to that for the prepa-
ration from D-lyxonolactone22 of the corresponding
enantiomer [mp 59.7 ꢁC, [a]D À71.0 (c, 2.0 in CHCl3)].23
DIBAL reduction of the lactone 19, followed by a Ho
crossed aldol condensation to the branched lactol,24
and subsequent oxidation by aqueous bromine afforded
the branched lyxonolactone 20.25 Esterification of the
primary alcohol in 20 with triflic anhydride in dichloro-
Acknowledgements
Financial support provided by the European Commu-
nityÕs Human Potential Programme under contract
HPRN-CT-2002-00173 and by the Xunta de Galicia is
gratefully acknowledged.
methane in the presence of pyridine gave the triflate 7
21
D
[mp 33.5–34 ꢁC; ½aŠ À29.4 (c, 0.70 in EtOAc)], which
on treatment with hydrogen chloride in methanol gave
the branched scaffold 9.26 The overall yield of 9 from
the protected lyxonolactone 18 was 40% (Scheme 3).
References and notes
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23
D
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21
D
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18. Data for the azido hamamelonolactone 14: mp 100.5–
25
102 ꢁC; ½aŠ +11.3 (c, 0.31 in MeCN); m/z (AutoSpec-
D
ETOF CI+): 261.0 (M þ NHþ4 , 100%), found: 261.1197
[M þ NHþ4 ] C9H17N4O5 requires 261.1199; mmax (thin
film): 3430 (OH), 2129 (N3), 1782 (C@O) cmÀ1; dH
(CDCl3, 400 MHz): 1.45, 1.47 (6H, 2 · s, C(CH3)2), 2.30
(1H, b, OH), 3.70 (2H, m, H-50 and H-5), 3.94 (1H, d,
JH-2 ,H-2 11.7 Hz, H-20), 4.08 (1H, d, H-20), 4.66 (1H, a-t,
0
0
JH-4,H-5 , JH-4,H-5 5.58 Hz, H-4), 4.64 (1H, s, H-3); dC
(CDCl3, 100 MHz): 26.7, 26.9 (C(CH3)2), 51.9 (C-5), 61.5
(C-20), 79.7 (C-3), 81.7 (C-4), 85.3 (C-2), 114.0 (C (CH3)2),
174.4 (C@O). C9H17N4O5 requires: C 44.44, H 5.39, N
17.28; found C 44.39, H 5.37, N 17.32.
19. Cambridge Crystallographic Data Centre deposition
CCDC
number
www.ccdc.cam.ac.uk.
for
14:
267517
[http://
21
D
20. Data for the trans-azido ester 6: viscous oil, ½aŠ +24.5 (c,
4.38 in MeOH); m/z (AutoSpecETOF CI+): 235.1
(M þ NHþ4 , 28%), found: 235.1048 [M þ NHþ4 ]
C7H15N4O5 requires 235.1042; mmax (thin film): 3428
(OH), 2106 (N3), 1735 (C@O) cmÀ1
; dH (CDCl3,
400 MHz): 3.44 (1H, dd, JH-6,H-6 13.4 Hz, JH-6,H-5
0
5.0 Hz, H-6), 3.60 (1H, dd, JH-6 ,H-5 3.6 Hz, H-60), 3.71
(1H, d, JOH-4,H-4 5.5 Hz, OH-4), 3.86 (3H, s, OMe), 3.96
0
0
(1H, d, JH-2,H-2 9.7 Hz, H-2), 4.02-4.08 (1H, m, H-5), 4.18
8. Grotenbreg, G. M.; Witte, M. D.; van Hooft, P. A. V.;
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Overhand, M. J. Org. Chem. 2004, 69, 7851–7859; El
Oualid, F.; Baktawar, J.; Leroy, I. M.; van den Elst, H.;
Cohen, L. H.; van der Marel, G. A.; Overkleeft, H. S.;
JH-20,H-2
(1H, a-t, H-4), 4.21 (1H, s, OH-3), 4.26 (1H, d,
9.7 Hz, H-20); dC (CDCl3, 100 MHz): 51.7 (C-5), 53.4
(OMe), 74.5 (C-2), 81.2 (C-4), 82.6 (C-5), 84.0 (C-3), 172.9
(C@O).
21. Varela, O.; Zunszain, P. A. J. Org. Chem. 1993, 58, 7860–
7864; Kold, H.; Lundt, I.; Pedersen, C. Acta Chem. Scand.
1994, 48, 675–678.
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3359–3366.

M. I. Simone et al. / Tetrahedron Letters 46 (2005) 5761–5765
5765
23. Fleet, G. W. J.; Petursson, S.; Campbell, A.; Mueller, R.
A.; Behling, J. R.; Babiak, K. A.; Ng, J. S.; Scaros, M. G.
J. Chem. Soc., Perkin Trans. 1 1989, 665–666.
requires: C 44.44, H 5.39, N 17.28; found: C 44.41, H 5.39,
N 17.10.
26. Data for the cis-azido ester 9: yellow oil, m/z (AutoSpec-
24. Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J.
Am. Chem. Soc. 1998, 120, 3007–3018.
E
CI+): 218.0 ([M + H]+, 100%), found: 218.0776
21
D
[M + H]+ C7H12N3O5 requires 218.0777; ½aŠ À39.5 (c,
21
D
25. Data for branched lyxonolactone 20: mp 98–99 ꢁC; ½aŠ
0.61 in MeOH); mmax (thin film): 3418 (OH), 2107 (N3),
À0.11 (c, 0.73 in CHCl3); m/z (AutoSpeC CI+): 261.1
([M+NH4]+, 100%), found: 261.1204 (M+NH4)+
C9H17N4O5 requires 261.1199; mmax (thin film): 3221
1732 (C@O) cmÀ1; dH (CD3CN, 400 MHz): 2.85 (1H, dd,
0
0
JH-6 ,H-6 12.8 Hz, JH-6 ,H-5 5.0 Hz, H-6), 2.92 (1H, dd,
0
JH-6,H-5 7.7 Hz, H-6), 3.18 (1H, d, JH-2,H-2 9.8 Hz, H-2),
(OH), 2101 (N3), 1784 (C@O) cmÀ1
;
dH (CDCl3,
3.19 (3H, s, OMe), 3.38 (1H, d, JOH-4,H-4 5.9 Hz, OH-4),
3.47-3.52 (1H, dd, JH-4,H-5 3.5 Hz, H-4), 3.65 (1H, ddd, H-
5), 3.79 (1H, d, H-20), 3.80 (1H, br, OH-3); dC (CD3CN,
100 MHz): 49.83 (C-6), 51.81 (OMe), 73.42 (C-2), 77.92
(C-4), 80.04 (C-5), 84.39 (C-3), 170.93 (C@O).
400 MHz): 1.43 and 1.49 (6H, 2 · s, C(CH3)2), 2.19–2.25
(1H, m, JOH-2 ,H-2 and H-2 3.9 Hz, OH), 3.65 (1H, dd,
0
0
0
JH-5,H-5 13.1 Hz, JH-5,H-4 6.1 Hz, H-5), 3.73 (1H, dd, JH-
5 ,H-4 7.3 Hz, H-50), 3.94 (1H, a-dd, JH-2,H-2 11.4 Hz, H-2),
4.03 (1H, a-dd, H-20), 4.58 (1H, ddd, JH-4,H-3 3.4 Hz, H-4),
4.79 (1H, d, H-3); dC (CDCl3, 125 MHz): 26.4, 26.9
(C(CH3)2), 49.5 (C-5), 61.4 (C-20), 77.2 (C-4), 78.4 (C-3),
86.0 (C-2), 114.2 (C (CH3)2), 174.7 (C@O); C9H17N4O5
0
0
27. Punzo, F.; Watkin, D. J.; Simone, M. I.; Fleet, G. W. J.
Acta Cryst. 2004, E60, o2315–2317.
28. Punzo, F.; Watkin, D. J.; Simone, M. I.; Fleet, G. W. J.
Acta Cryst. 2005, E61, o513–515.