New access to 7-membered heterocyclic C-glycosides by the Cyclo-Addition-Ring-Expansion (CARE)-reaction

Article abstract of DOI:10.1055/s-1998-3141

CARE-reaction of methyl 3-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)propiolate 1 and methyl 4(R)-4,5-O-isopropylidene-2-pentynecarboxylate 10 leading to 7-membered heterocyclic C-glycosides is reported.

Full text of DOI:10.1055/s-1998-3141

November 1998
SYNLETT
1193
New Access to 7-Membered Heterocyclic C-Glycosides by the Cyclo-Addition-Ring-
Expansion (CARE)-Reaction
Heinrich Wamhoff*a, Heiko Warneckea, Pál Sohárb, Antal Csámpaib
Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, Gerhard-Domagk-Str.1, D-53121 Bonn, Germanya
Fax: +49-228-732651, e-mail: wamhoff@uni-bonn.de
Department of Inorganic and General Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1, H-1117 Budapest, Hungaryb
Fax: +36(1)2090602, e-mail: Sohár@para.chem.elte.hu
Dedicated to Professor Alan R. Katritzky, on the occasion of his 70th birthday.
Received 20 July 1998
Abstract: CARE-reaction of methyl 3-(2,3-O-isopropylidene-5-O-
trityl-β-D-ribofuranosyl)propiolate
1 and methyl 4(R)-4,5-O-iso-
propylidene-2-pentynecarboxylate 10 leading to 7-membered
heterocyclic C-glycosides is reported.
Several naturally occurring and synthetic heterocyclic C-glycosides
exhibit strong biological activities (anti-cancer, anti-virus, antibiotic).
The synthesis of a first example, pseudocytidine,1 has been reported by
Fox et al.2 in 1975.
Now, we want to describe a novel class of C-glycosides containing a 7-
membered heterocyclic base. In this course, we have modified the
CARE (Cyclo-Addition-Ring-Expansion)-reaction3 which has served
as a useful access to 7- and 8-membered heterocyclic ring systems. For
this purpose, heterocyclic β-enaminonitriles and -esters have been
protected at their 2-amino function by phosphorylation with
dihalotriphenylphosphoranes.4 Subsequent reaction with acetylenic
esters gave stepwise thermal [2+2]-cycloaddition, followed by ring
enlargement (5→7; 6→8) leading to the correspondent enlarged ring
systems. Due to their enaminoester moiety these are capable of several
subsequent cyclization reactions.5
In the present case, the acetylenic esters that had been used in former
investigations (e.g. diethyl acetylenedicarboxylate or ethyl propiolate),
were firstly replaced by methyl 3-(2,3-O-isopropylidene-5-O-trityl-β-D-
ribofuranosyl)propiolate (1).6 Upon reaction with the β-enaminonitriles
and -esters (2 a-c) in dry acetonitrile we obtained the ring enlarged C-
glycosides
5
a-c (Scheme 1).7 Due to the instability of these
iminophosphoranes towards hydrolysis under acidic conditions,
purification had to be carried out on neutral aluminum oxide. Thereby,
the heteroatoms and substituents of 2 a-c play a decisive role on the
reaction rate to a more or less polarized enamine double bond.3f
Another important chiral building block for the synthesis of many
biologically active compounds is D-glyceraldehyde8 and its derivatives
such as (+)-3,4-O-isopropylidenebutyne 9,9 which are easily accessible
Scheme 1
from 1,2:5,6-di-O-isopropylidene-D-mannitol 6. We developed
a
smooth carboxylation of 9 using methyl chloroformate in dry THF10 for
obtaining a suitable new precursor 10 for the CARE-reaction.
The resulting D-glyceraldehyde derivative 10 is of high optical purity
and undergoes CARE-reaction with 2c as expected under similar
conditions as the ribose derivative 1.7
The yield of 11 (41%) is higher compared with 5 a-c (< 20%). This
leads to the conclusion that the sterical demand of the protected ribose 1
influences the formation rate of 5 a-c. Nevertheless, due to the
instability of the iminophosphorane group in 11 towards hydrolysis,
considerable loss during the chromatographic purification, even on
neutral aluminum oxide, is observed.
In order to get a higher amount of a CARE-product comparable to 11,
any attempt of the hydrolysis of the iminophosphorane group using
acetic acid, diluted HCl or H2SO4 failed. Another approach is the
cyclization reaction of the phosphorylated β-enaminonitrile
chromophore in 11 using an isocyanate3c,d,11 as e.g. phenylisocyanate
Scheme 2: a) NaIO4 (2 eq), CH2Cl2, H2O, RT (82%). b) CBr4 (1.3 eq),
PPh3 (2.6 eq), NEt3 (1 eq), CH2Cl2, 0 - 15°C (75%). c) EtMgBr (2 eq),
THF, 25 -30°C (71%). d) cf. ref. 9.

1194
LETTERS
SYNLETT
(4) a) R. Appel, Angew. Chem. 1975, 87, 863-874. b) H. Wamhoff, G.
Richardt, S. Stölben, Adv. Heterocycl. Chem. 1995, 64, 159-249.
(5) H. Wamhoff, Adv. Heterocycl. Chem. 1985, 38, 299-368.
(6) F.G. de las Heras, S. Tam, R. Klein, J.J. Fox, J. Org. Chem. 1976,
41, 84-90.
(7) Typical procedure: the acetylenic compound 10 (240 mg, 1.3
mmol) and the iminophosphorane 2 c (520 mg, 1.3 mmol) in dry
acetonitrile (15 ml) were heated under reflux for 20 h (controlled
by TLC ). The solvent was removed in vacuo. Purification of the
residue by column chromatography on neutral aluminum oxide (n-
hexane/ethyl acetate 2:1 as eluent) gave 11 (310 mg, 41%).
Analytical data of compound 11: Anal. Calcd. For:
C34H35O5N2P1 C: 70.14; H: 6.06; N: 4.81. Found: C: 69.74; H:
5.99; N: 4.39. HRMS (EI): (m/z) calcd. for C34H35O5N2P1 (M)+
582.2283; Found: 582.2284. 1H-NMR (500 MHz, DMSO-d6) δ
0.68 (s, 3H, Oxepine CH3), 0.71 (s, 3H, Oxepine CH3), 1.28 (s,
3H, isopr.CH3), 1.42 (s, 3H, isopr.CH3), 2.30 (d, 2H, Oxepine
CH2), 3.62 (s, 3H, OCH3), 3.65 (t, 1H, J=7.8 Hz, OCH2-), 4.13 (t,
1H, J=7.2 Hz, OCH2-), 4.76 (t, 1H, J=7.5-7.8 Hz, OCH-), 7.7-7.8
(m, 15H, Ph).
Scheme 3
12. A first example 13 of this versatile reaction type4b was characterized
by HRMS and further investigations are in progress.
(8) a) D. Horton, G. Jaques, J. Org. Chem. 1983, 48, 1381-1382. b)
D.Y. Jackson, Synth. Commun. 1988, 18, 337-341.
(9) a) P. Ma, B. Jiang, Synth. Commun. 1995, 25(22), 3641-3645. b)
E.C. Taylor, P.S. Ray, I.S. Darwish, J. Am. Chem. Soc. 1989, 111,
7664-7665.
Scheme 4
Acknowledgements: This work was supported by the Fonds der
Chemischen Industrie, the Bayer AG and the Hungarian-German
Cooperation Project BMBF/OMBF Project UNGX 234.41.
(10) Methyl 4(R)-4,5-O-isopropylidene-2-pentyne carboxylate 10: (+)-
3,4-O-isopropylidenebutyne
9 (500 mg, 3.96 mmol), was
dissolved in 10 ml THF and the solution was cooled to -50°C.
BuLi (2.5 ml of a 1.6 M solution in n-hexane, 3.96 mmol) was
added and the solution was warmed up to 0°C. Then, the mixture
was again cooled to -35°C and a solution of ClCO2Me (750 mg,
7.92 mmol) in 10 ml dry THF was added within 30 min. After 1h
at -35°C, the solvent was removed in vacuo and the residue
diluted in 20 ml CHCl3, washed with H2O and dried (MgSO4).
Purification by column chromatography on silica gel (n-hexane/
ethyl acetate 5:1 as eluent) gave 10, 550 mg (75 %). Analytical
data of 10: Anal. Calcd. For: C9H12O4 C: 58.69; H: 6.57. Found:
C: 58.61; H: 6.54. MS (EI): (m/z) 183.1 (M-H)+. 1H-NMR (400
MHz, CDCl3) δ 1.30 (s, 3H, CH3), 1.41 (s, 3H, CH3), 3.69 (s, 3H,
OCH3), 3.98 (dd, 1H, J=5.4, 8.4 Hz, OCH2-), 4.14 (dd, 1H, J=6.5,
8.4 Hz, OCH2-), 4.75 (dd, 1H, J=5.4, 6.5 Hz, OCH-).
References and Notes:
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