Synthesis of seven-membered ring glycals via endo-selective alkynol cycloisomerization

Article abstract of DOI:10.1021/ol0483495

Alkynyldiols 1 undergo cycloisomerization to the corresponding seven-membered cyclic enol ethers 2 under tungsten carbonyl catalysis. This novel transformation proceeds with good yields and virtually complete regioselectivity for all diastereomers of 1, f

Full text of DOI:10.1021/ol0483495

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3877-3880
Synthesis of Seven-Membered Ring
Glycals via endo-Selective Alkynol
Cycloisomerization
Eva Alca´zar,† Joseph M. Pletcher, and Frank E. McDonald*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
fmcdona@emory.edu
Received August 19, 2004
ABSTRACT
Alkynyldiols 1 undergo cycloisomerization to the corresponding seven-membered cyclic enol ethers 2 under tungsten carbonyl catalysis. This
novel transformation proceeds with good yields and virtually complete regioselectivity for all diastereomers of 1, favoring the product 2
resulting from endo-mode cyclization. The unexpected regioselectivity may be dependent on the presence of the dioxolane structure tethering
the terminal alkyne and diol functional groups.
Our laboratory has reported the synthesis of five- and six-
membered ring glycals using group VI metal-catalyzed endo-
regioselective cycloisomerizations of alkynyl alcohols.1 This
reaction type is similar to the formation of cyclic metal
oxacarbenes via the intermediacy of transition metal vi-
nylidenes,2 arising from 1,2-migration of the terminal alkyne
hydrogen. While the cyclic oxacarbene structures can be
converted into metal-free cyclic enol ether structures (Figure
1), a more efficient transformation to cyclic enol ethers is
accomplished in one step from the corresponding alkynyl
alcohol. This novel reaction type is tolerant of many different
functional groups and has been used in syntheses of several
biologically active cyclic ether and polysaccharide structures.3
The current study began with the recognition that D-ribose
could be easily converted into an alkynyl alcohol precursor,
which would provide the hexopyranose glycal with the
stereochemistry of D-allose. From the known ribofuranose
acetonide 3 (Scheme 1),4 the alkynyl alcohol substrate 4 was
produced by Wittig chloromethylenation and dehydrohalo-
genation.5 Alternately, the alkynyldiol 5 could be produced
in one step using a diazophosphonate reagent for one-carbon
homologation, with concomitant loss of the tert-butyldiphen-
ylsilyl ether.6
† Current address: GlaxoSmith-Kline, Process Development, Verona,
Italy.
(1) (a) McDonald, F. E. Chem.sEur. J. 1999, 5, 3103. (b) McDonald,
F. E.; Reddy, K. R.; D´ıaz, Y. J. Am. Chem. Soc. 2000, 122, 4304. (c)
McDonald, F. E.; Reddy, K. R. J. Organomet. Chem. 2001, 617-618, 444.
(2) (a) Chisholm, M. H.; Clark, H. C. Acc. Chem. Res. 1973, 6, 202. (b)
Bruce, M. I.; Swincer, A. G. AdV. Organomet. Chem. 1983, 22, 59.
(3) (a) McDonald, F. E.; Reddy, K. S. Angew. Chem., Int. Ed. 2001, 40,
3653. (b) Cutchins, W. W.; McDonald, F. E. Org. Lett. 2002, 4, 749. (c)
McDonald, F. E.; Wu, M. Org. Lett. 2002, 4, 3979. (d) Davidson, M. H.;
McDonald, F. E. Org. Lett. 2004, 6, 1601.
Figure 1. Metal-promoted alkynyl alcohol cyclizations.
10.1021/ol0483495 CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/15/2004

Scheme 1. Synthesis of Alkynyl Alcohol Substrates from
Scheme 3. Cycloisomerizations of Alkynyl Diols 5 and 10
D-Ribosea
a Conditions: (a) ClCH2PPh3Cl/n-BuLi, TMEDA, THF (62%
yield). (b) n-BuLi, THF, -78 °C (50% yield). (c) K2CO3,
MeOH,MeC(O)C(N2)P(O)(OMe)2, 65 °C (50% yield).
Initial studies on the cycloisomerization of alkynyl alcohol
substrate 4 resulted in a mixture of products 6 and 7, arising
from endo- and exo-mode cyclizations, respectively (Scheme
2). The ratio of isomers was not significantly affected by
complete regioselectivity for endo-mode cyclization and
virtually complete selectivity for reaction of the primary
alcohol, with less than 2% of a probable six-membered ring
1
glycal byproduct observed in the crude H NMR spectrum.
1H NMR resonances at 6.6 and 5.1 ppm were consistent with
endocyclic glycal hydrogens 1 and 2, respectively (exo-
methylenic hydrogens appear around 4.2-4.4 ppm, as in 7).
Furthermore, derivatization of product 8 as its acetate 9
resulted in deshielding of only one hydrogen, consistent with
a secondary alcohol in 8.7 Compound 8 slowly decomposed
upon standing (perhaps via oligomerization), but acylation
of 8 prior to purification gave the septanose glycal acetate
ester 9 in an isolated yield of 82% from 5. The corresponding
substrate 10 with benzylidene acetal protection also provided
the seven-membered glycal 11. As this work progressed, we
found that isolated yields were improved in some cases by
using DABCO as the base and toluene as the solvent.
Furthermore, formation of seven-membered ring glycals
is general for all diastereomers of acetonide-protected
alkynyldiol 5, including 12 (from D-lyxose), 14 (from
D-xylose), and 16 (from L-arabinose, Scheme 4).7 Although
seven-membered ring formation for 15 and 17 might be
favored over six-membered ring formation due to the ring
strain required for formation of the unobserved trans-fused
bicyclic[4.3.0] structure, the cis-fused seven-membered ring
products 9 and 13 are also favored even though the
six-membered ring regioisomers are anticipated to be un-
strained.
What factors are responsible for the unexpected but
interesting regioselectivity for seven-membered ring forma-
tion? A primary alcohol is apparently not required for
regioselective formation of the seven-membered ring product,
as demonstrated for alkynyl diol substrate 18 with two
secondary alcohols, obtained from L-rhamnose (Scheme 5).6
At this stage, it appears likely that the cyclic 1,3-dioxolane
protective group is responsible for endo-selective reaction
of the distal hydroxyl group to give seven-membered ring
products.
Scheme 2. Cycloisomerizations of Alkynyl Alcohol 4
solvent effects, although changing the tertiary amine from
triethylamine to DABCO resulted in nearly complete recov-
ery of the desired endo-mode selectivity producing 6 in both
THF and toluene, providing a successful synthesis of the
protected D-allose glycal 6.
Although alkynyl diol 5 could also be converted into 4
by selective silylation of the primary alcohol, we anticipated
that the primary alcohol would be compatible and unreactive
upon cyclization to the six-membered ring glycal, given the
closer proximity of the secondary alcohol oxygen to the
terminal alkyne carbon. To our surprise, tungsten-catalyzed
cycloisomerization of 5 provided not the expected pyranose
glycal analogue of 6 with an unprotected primary alcohol
but rather gave the seven-membered ring glycal 8 in 68%
isolated yield (Scheme 3). This compound was produced with
(4) (a) Jiang, S.; Singh, G.; Batsanov, A. S. Tetrahedron: Asymmetry
A control experiment changing the protective pattern from
acetonide-protected substrate 5 was attempted by preparing
2000, 11, 3873. (b) Hughes, N. A.; Speakman, P. R. H. Carbohydr. Res.
1965, 1, 171.
(5) Mella, M.; Panza, L.; Ronchetti, F.; Toma, L. Tetrahedron 1988,
44, 1673.
(6) Thie´ry, J.-C.; Fre´chou, C.; Demailly, G. Tetrahedron Lett. 2000, 41,
6337.
(7) See Supporting Information for substrate syntheses, cycloisomeriza-
tion conditions, and detailed product characterization.
3878
Org. Lett., Vol. 6, No. 21, 2004

Scheme 4. Generality of Seven-Membered Ring Glycal
Scheme 6. Attempted Cycloisomerization of Bis-silyl Ether
Diol 22
Formation from Various Diastereomersa
hydroxymethyl oxygen five atoms away from the C4-
hydrogen, which in turn is anti to the allylic silyloxy
substituent at C3. This previously unobserved limitation of
the cycloisomerization methodology can be avoided by use
of different protective group patterns, as described earlier
with substrate 4.
Classical methods for carbohydrate synthesis are well-
known to favor furanose and/or pyranose structures over
septanose (seven-membered ring sugar) isomers,8,9 and seven-
membered ring sugars can also be produced by multistep
routes involving selective protection of hexose sugar second-
ary alcohols10 or by rearrangement of partially protected
furanoside derivatives.11 Although other methods for the
formation of oxepins (seven-membered cyclic enol ethers)12,13
a Conditions: (a) 15% W(CO)6, Et3N, THF, h (350 nm) 55 °C,
6 h. (b) Ac2O, cat. DMAP.
(8) (a) Stevens, J. D. J. Chem. Soc., Chem. Commun. 1969, 1140. (b)
Ng, C. J.; Stevens, J. D. Carbohydr. Res. 1996, 284, 241.
(9) (a) Anet, E. F. L. J. Carbohydr. Res. 1968, 8, 164. (b) Grindley, T.
B.; Gulasekharan, V. J. Chem. Soc., Chem. Commun. 1978, 1073.
(10) (a) Micheel, F.; Suckfu¨ll, F. Ann. 1933, 502, 85. (b) Ward, D. E.;
Liu, Y.; Rhee, C. K. Can. J. Chem. 1994, 72, 1429. (c) McAuliffe, J. C.;
Hindsgaul, O. Synlett 1998, 307.
(11) Contour, M.-O.; Fayet, C.; Gelas, J. Carbohydr. Res. 1990, 201,
150.
(12) For formation of septanose glycals via ring-closing metathesis of
alkenes tethered to O-vinyl ethers, see: (a) Peczuh, M. W.; Snyder, N. L.
Tetrahedron Lett. 2003, 44, 4057. (b) Peczuh, M. W.; Snyder, N. L.; Fyvie,
W. S. Carbohydr. Res. 2004, 339, 1163.
the bis-silyl ether substrate 227 (Scheme 6), which is nearly
identical to the 6-deoxy substrate 20 that we have previously
established affords cycloisomerization product 21 in excellent
yield.1b,3a Surprisingly, neither cycloisomerization product 23
nor the seven-membered ring isomer was observed as a
product, and the only isolable compound was the unstable
dienyl ether 24.
(13) For representative other methods for formation of oxepins via: ring-
closing metathesis-isomerization: (a) Chatterjee, A. K.; Morgan, J. P.;
Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783. (b) Rainier,
J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66, 1380. (c) Sutton,
A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc.
2002, 124, 13390. (d) Schmidt, B. Eur. J. Org. Chem. 2003, 816.
Oxidation-dehydration of 1,6-hexanediol: (e) Larkin, D. R. J. Org. Chem.
1965, 30, 335. (f) Oakes, F. T.; Yang, F.-A.; Sebastian, J. F. J. Org. Chem.
1982, 47, 3094. Via lactone enol phosphate or triflates: (g) Kane, V. V.;
Doyle, D. L.; Ostrowski, P. G. Tetrahedron Lett. 1980, 21, 2643. (h)
Tsushima, K.; Araki, K.; Murai, A. Chem. Lett. 1989, 1313. (i) Nicolaou,
K. C. J. Am. Chem. Soc. 1997, 119, 5469. Via anionic cyclization of allyl
glycidyl ether: (j) Ichikawa, Y.; Niitsuma, S.; Kato, K.; Takita, T. J. Chem.
Soc., Chem. Commun. 1988, 625. (k) Bird, C. W.; Hormozi, N. Tetrahedron
Lett. 1990, 31, 3501. Oxidative expansion with peroxides: (l) Krafft, G.
A.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1981, 103, 5459. (m)
Goodman, R. M.; Kishi, Y. J. Org. Chem. 1994, 59, 5125. [3.3]-
Rearrangements: (n) Wenkert, E.; Greenberg, R. S.; Kim, H. S. HelV. Chim.
Acta 1987, 70, 2159. (o) Clark, D. L.; Chou, W.-N.; White, J. B. J. Org.
Chem. 1990, 55, 3975. (p) Sugiyama, J.; Tanikawa, K.; Okada, T.; Noguchi,
K.; Ueda, M.; Endo, T. Tetrahedron Lett. 1994, 35, 3111. (q) Hofmann,
B.; Reissig, H.-U. Chem. Ber. 1994, 127, 2337. Conjugate oxacyclization
This compound can be envisioned to arise from hydroxyl-
assisted â-elimination via the intermediacy of expected
product 23, especially given the syn relationship of the
Scheme 5. Cycloisomerization of Substrate 18 with Two
Secondary Alcohols Also Gives Seven-Membered Ring
Product 19
Org. Lett., Vol. 6, No. 21, 2004
3879

are known, our route is notable for its generality to produce
a variety of septanose stereoisomers, ease of preparation for
the alkynyl diol substrates from common pentose and hexose
sugars, and the inexpensive nature of the tungsten carbonyl
catalyst system. The availability of this family of septanose
glycals may offer significant advances in the synthesis of
structurally unusual hexoseptanose glycosides14 as isomers
of the more common hexopyranose glycosides ubiquitous
in glycobiology.
Acknowledgment. We thank the National Institutes of
Health (CA 59703) for support of this research. J.M.P. was
a U.S. Department of Education Graduate Assistance in
Areas of National Needs Fellow (2000-2001). We also
acknowledge the use of shared instrumentation provided by
grants from the National Institutes of Health, National
Science Foundation, and the Georgia Research Alliance
(NMR spectroscopy, mass spectroscopy) and the University
Research Committee of Emory University (polarimeter).
of sulfonylallenes: (r) Mukai, C.; Yamashita, H.; Hanaoka, M. Org. Lett.
2001, 3, 3385. Cyclization of hydroxyl-terminated O-vinyl ethers: (s)
Moody, C. J.; Sie, E.-R. H. B.; Kulagowski, J. J. Tetrahedron 1992, 48,
3991. Intramolecular nucleophilic condensation with ester: (t) Moody, C.
J.; Sie, E.-R. H. B.; Kulagowski, J. J. Tetrahedron Lett. 1991, 32, 6947.
(u) Rahim, M. A.; Fujiwara, T.; Takeda, T. Tetrahedron 2000, 56, 763.
Ruthenium-catalyzed cycloisomerization of R-ω-alkynoic acids: (v) Jime´-
nez-Tenorio, M.; Puerta, M. C.; Valerga, P.; Moreno-Dorado, F. J.; Guerra,
F. M.; Massanet, G. M. Chem. Commun. 2001, 2324.
(14) In addition, the glycal form of the seven-membered ring sugar
products provides considerable potential for stereo- and regioselective
introduction of functional groups across the glycal alkene. (a) Micheel, F.;
Suckfu¨ll, F. Ann. 1933, 507, 138. (b) Refs 10c and 12b.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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