An expeditious route towards pyranopyran sugar amino acids

Article abstract of DOI:10.1055/s-2004-820021

The synthesis of two diastereoisomeric pyranopyran sugar amino acids, starting from (+)-D-3,4,6-tri-O-benzylglucal, is described. The key reaction sequence towards the bicyclic structure entails Petasis olefination followed by ring closing metathesis.

Full text of DOI:10.1055/s-2004-820021

904
LETTER
An Expeditious Route Towards Pyranopyran Sugar Amino Acids
A
n
E
xpeditious Ro
i
ute
T
o
j
w
ards
P
yranopyr
b
a
n
Sugar Am
e
ino Acids rt M. Grotenbreg, Adriaan W. Tuin, Martin D. Witte, Michiel A. Leeuwenburgh, Jacques H. van Boom,
Gijsbert A. van der Marel, Herman S. Overkleeft,* Mark Overhand*
Leiden Institute of Chemistry, Gorlaeus Laboratories, P. O. Box 9502, 2300 RA Leiden, The Netherlands
Fax +31(71)5274307; E-mail: overhand@chem.leidenuniv.nl
Received 4 February 2004
merous variations in the number, nature and position of
the functional groups attached to the parent carbohy-
drates.2
Abstract: The synthesis of two diastereoisomeric pyranopyran
sugar amino acids, starting from (+)-D-3,4,6-tri-O-benzylglucal, is
described. The key reaction sequence towards the bicyclic structure
entails Petasis olefination followed by ring closing metathesis.
Several research groups, including ours, have reported on
Key words: amino acids, bicyclic compounds, carbohydrates, py- the use of SAAs for the introduction of conformational
constraints in both linear and cyclic oligopeptides.3 From
ranopyran, ring-closing metathesis
these studies it became apparent that, although the confor-
mational freedom of the target peptides is partially re-
duced, an equilibrium of a number of conformers is
normally present.4 This may be attributed to the inherent
flexibility of the parent sugar ring from which the SAAs
are derived. With the aim to increase conformational con-
straints, we, and others, have reported on the development
of ‘locked’ SAAs, carbohydrate derived peptide building
blocks with an additional ring fused to a furanoid SAA
core.5 In line with these studies, we here present the syn-
thesis of two new conformationally constrained SAA
building blocks having a glucose-based pyranopyran tem-
plate.
Sugar amino acids (SAAs), carbohydrate structures func-
tionalized with an amine and a carboxylic acid, have
found wide application as building blocks for the con-
struction of both glyco- and peptidomimetic compounds.1
Oligomeric structures of these molecular frameworks can
be obtained through facile peptide bond formation. Apart
from this, SAAs were found to be useful for the develop-
ment of enantiopure, diversely functionalized scaffolds
for application in dedicated library synthesis. The struc-
tural and functional diversity inherent to the parent sugars
provides entry to a myriad of different structures with nu-
Ph
O
O
O
BnO
Ph
BnO
BnO
BnO
BnO
i, ii
iii
BnO
OH
OH
BnO
3
BnO
BnO
1
2
iv
H
H
O
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
Ph
Ph
O
v
vi
O
O
O
O
BnO
BnO
BnO
O
6
4
5
vii
H
H
O
O
Mes-N N-Mes
BnO
BnO
Ph
Cl
Cl
Ru
PCy3
8
O
BnO
7
Scheme 1 i) DMDO (1.2 equiv), CH2Cl2, 0 °C, 10 min, quant.; ii) lithium phenylacetylide (2 equiv), ZnCl2 (2 equiv), THF, –70 °C to r.t.,
1 h, 78%; iii) H2, Lindlar (cat.), quinoline, EtOAc, quant.; iv) methylbromoacetate (3 equiv), TBAI (0.1 equiv), NaH (7 equiv), DMF, 16 h,
4; 72% and recovered 3; 23%; v) Cp2TiMe2 (2.5 equiv), THF, 60 °C, 48 h, 82%; vi) 8 (0.05 equiv), CH2Cl2, reflux, 48 h, 88%; vii) TFA/H2O
(3:7 v/v), CH2Cl2, 1 h, 92%.
SYNLETT 2004, No. 5, pp 0904–0906
0
2.
0
4.
2
0
0
4
Advanced online publication: 04.03.2004
DOI: 10.1055/s-2004-820021; Art ID: D02804ST.pdf
© Georg Thieme Verlag Stuttgart · New York

LETTER
An Expeditious Route Towards Pyranopyran Sugar Amino Acids
905
H
H
H
H
O
OMs
O
OMs
O
OH
RO
RO
RO
RO
BnO
ii
+
O
O
BnO
O
H
H
RO
10
RO
BnO
9
R = Bn
R = H
11
R = Bn
R = H
iii
iii
12
13
i
iv
iv
H
H
H
H
R
R
O
N3
O
N3
O
O
5
5
7
6
7
8
9
4
3
8
9
BnO
BnO
6
4
3
1
1
2
O
10
2
O
10
HO
HO
O
H
H
HO
14
16
HO
15
BnO
R = CH2OH
R = COOH
R = CH2OH
R = COOH
7
v
v
17
Scheme 2 i) L-selectride (1.5 equiv), THF, –78 °C to r.t., 16 h, 71% (endo:exo = 2:1); ii) MsCl (1.2 equiv), Et3N (1.5 equiv), CH2Cl2, 0 °C to
r.t., 10; 56% and 11; 36%; iii) H2, 10% Pd/C (cat.), EtOH, 3 h, 12; quant. and 13; quant.; iv) NaN3 (5 equiv), DMF, 70 °C, 16 h, 14; 90% and
15; 94%; v) TEMPO (cat.), NaOCl, NaHCO3 (aq), MeCN, 0 °C, 16; 53% and 17; 52%.
We have previously reported the facile construction of C- in 94%. Finally, the carboxylic acid was installed by se-
glycosidic alkene 3 and its use in the assembly of a variety lective oxidation of the primary alcohol of 14 and 15 using
of fused oxacycles.6 Starting from commercially available a catalytic amount of TEMPO (2,2,6,6-tetramethyl-pi-
(+)-D-3,4,6-tri-O-benzylglucal 1 (Scheme 1), epoxidation peridinyl-1-oxy) and NaOCl as co-oxidant, delivering
of the enol ether by reaction with dimethyldioxirane SAAs 1611 and 1712 in 53% and 52% yield, respectively.
(DMDO), followed by ZnCl2-mediated propargylation The structures of cis-fused oxacycles 16 and 17 were
furnished the a-substituted 2 as the major product. Selec- analyzed by 1H NMR and 13C NMR spectroscopy using a
tive hydrogenolysis of the acetylene moiety employing combination of COSY, NOESY and HMQC data sets.
Lindlar’s catalyst gave alkene 3 in good yield.6 Adapta- Characteristic NOEs and long range couplings (Figure 1)
tion of these synthetic studies enables the construction of confirmed the rigid structure adopted by the pyranopyran
pyranopyran-based SAAs, as follows.
sugar amino acids.
Alkylation of the free hydroxyl functionality in compound In conclusion, we have developed an efficient route to cis-
3, using an excess of sodium hydride and methylbromo- fused pyranopyranoid e-SAAs. Starting from differently
acetate in the presence of a catalytic amount of tetrabutyl- functionalized monosaccharides, our strategy may give
ammonium iodide, afforded methyl ester 4 in 72% with access to a range of carbohydrate-derived bicyclic amino
recovery of 23% of alcohol 3 (a repeated alkylation step acids. Research effort is currently focussed on further im-
resulted in an overall yield of 95% of 4).7 Olefination of plementing the presented strategy towards trans-fused
the methyl ester in 4, employing freshly prepared pyranopyran SAAs. The required b-substituted C-glyco-
Cp2TiMe2 (Petasis reagent)8 yielded enol ether 5 in 82%. side precursors are accessible through Co2(CO)8 complex-
Ring-closing metathesis of 5 in refluxing dichloro- ation to acetylene 2, followed by acid-catalyzed
methane under the agency of ruthenium-alkylidene 89 af- epimerisation and oxidative release of the cobalt com-
forded the fused oxacycle 6 in 88% yield. Hydrolysis of plex.6 Finally, the application of the cis- and trans-fused
the enol ether by treatment with aqueous TFA in CH2Cl2 pyranopyran SAA building blocks in oligomeric struc-
gave bicyclic ketone 7 in 92%. Reduction of ketone 7 tures as well as their in depth conformational analysis is
(Scheme 2) by the sterically congested lithium tri-sec-bu- currently pursued and will be reported in due course.
tyl borohydride (L-selectride®) in THF afforded an insep-
arable mixture of alcohols 9 in 71% yield (endo:exo 2:1,
as judged by 1H NMR analysis).10 Installation of the me-
H
O
H
O
H
sylate functionality using methylsulfonylchloride and tri-
ethylamine in CH2Cl2 gave, after silicagel column
chromatography, endo-substituted 10 and exo-substituted
11 in a 56% and 36% yield, respectively. Hydrogenation
of the benzyl protective groups in mesylates 10 and 11
furnished triols 12 and 13, respectively, in near quantita-
tive yield. Nucleophilic substitution on the endo-mesylate
12 by prolonged heating in DMF in the presence of an ex-
cess of NaN3 afforded exo-azide 14 in 90%. Similarly,
exo-mesylate 13 was readily converted into endo-azide 15
H
HO
HO
HO
HO
O
O
O
O
H
H
HO
H
HO
H
H
H
H
H
H
H
H
N3
H
H
N3
16
17
= NOE
= long range coupling
Figure 1 1H NMR evaluation of the SAAs 16 and 17.
Synlett 2004, No. 5, 904–906 © Thieme Stuttgart · New York

906
G. M. Grotenbreg et al.
LETTER
(5) (a) Peri, F.; Cipolla, L.; La Ferla, B.; Nicotra, F. Chem.
Acknowledgment
Commun. 2000, 23, 2303. (b) van Well, R. M.; Meijer, M.
E. A.; Overkleeft, H. S.; van Boom, J. H.; van der Marel, G.
A.; Overhand, M. Tetrahedron 2003, 59, 2423.
(c) Dondoni, A.; Marra, A.; Richichi, B. Synlett 2003, 2345.
(6) (a) Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel,
G. A.; van Boom, J. H. Synlett 1997, 11, 1263.
(b) Leeuwenburgh, M. A.; Kulker, C.; Duynstee, H. I.;
Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron 1999, 55, 8253.
This work was financially supported by the Council for Chemical
Sciences of the Netherlands Organization for Scientific Research
(CW-NWO) and the Netherlands Technology Foundation (STW).
The authors thank Kees Erkelens and Fons Lefeber for their
assistance with NMR measurements. Nico Meeuwenoord and Hans
van der Elst are gratefully acknowledged for providing technical
assistance.
(7) A competing reaction occurred, resulting in the formation of
significant quantities of trans-cyclopropane-1,2,3-
tricarboxylic acid trimethyl ester. This side product was
separated from the target compound 4 by size exclusion
chromatography (Sephadex LH-20).
(8) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392.
(9) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
References
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J. Am. Chem. Soc. 1998, 120, 12962. (d) Smith, M. D.;
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Chem. 2003, 12, 2303.
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(10) Reduction with sodium borohydride gave a diastereo-
isomeric mixture of alcohols 9; endo:exo = 9:1, as judged by
1H NMR analysis.
(11) Physical Data for SAA 16: 1H NMR (400 MHz, D2O): d =
4.49 (m, 1 H, H6), 4.09 (d, 1 H, H8, J8,9 = 5.3 Hz), 4.05 (dd,
1 H, H10, J10,9 = 5.5 Hz, J10,1 = 5.9 Hz), 4.02 (m, 2 H, H3ax
H4), 3.89 (dd, 1 H, H9, J9,8 = 5.3 Hz, J9,10 = 5.5 Hz), 3.65 (dd,
1 H, H1, J1,6 = 3.5 Hz, J1,10 = 5.9 Hz), 3.45 (ddd, 1 H, H3eq
,
,
J3eq,5eq = 1.7 Hz, J3eq,4 = 7.8 Hz, J3eq,3ax = 12.4 Hz), 2.37 (m,
1 H, H5ax), 1.86 (m, 1 H, H5eq). 13C NMR (100 MHz, D2O):
d = 177.3 (C=O), 76.8 (C8) 75.2 (C1), 70.9 (C9), 67.6 (C10),
66.7 (C3), 66.0 (C6), 54.9 (C4), 30.7 (C5). ATR-IR (thin
film): n = 3398.1, 2920.0, 2120.1, 1605.6, 1454.5, 1385.0,
1315.5, 1247.7, 1096.9, 1076.7, 1062.2, 1001.4, 947.7,
923.1, 879.9, 811.4 cm–1. MS (ESI): m/z = 260.0 [M + H]+,
282.1 [M + Na]+, 541.1 [2 M + Na]+.
(12) Physical Data for SAA 17: 1H NMR (400 MHz, D2O): d =
4.31 (m, 1 H, H6), 4.10 (d, 1 H, H8, J8,9 = 5.8 Hz), 4.07 (dd,
1 H, H10, J10,9 = 6.1 Hz, J10,1 = 6.3 Hz), 3.83 (dd, 1 H, H9,
J
9,8 = 5.8 Hz, J9,10 = 6.1 Hz), 3.78 (m, 3 H, H3, H4), 3.70 (dd,
1 H, H1, J1,6 = 3.8 Hz, J1,10 = 6.3 Hz), 2.15 (m, 2 H, H5). 13
NMR (100 MHz, D2O): d = 177.4 (C=O), 76.7 (C8) 75.6
C
(C1), 71.5 (C9), 68.2 (C10), 66.8 (C3, C6), 55.2 (C4), 30.3 (C5).
ATR-IR (thin film): n = 3353.3, 2955.6, 2955.6, 2924.6,
2853.7, 2102.1, 1606.7, 1370.7, 1271.5, 1246.9, 1116.3,
1077.8, 1008.8. 967.4, 941.3 cm–1 MS (ESI): m/z = 260.0
[M + H]+, 282.1 [M + Na]+.
Synlett 2004, No. 5, 904–906 © Thieme Stuttgart · New York