lar conditions using a suitable dipropargylic-dihydroxyl
9
system. To probe our idea we synthesized a series of
Scheme 6. Simultaneous Stereocontrolled Synthesis of
propargylic tetrols 9 in accordance with Scheme 5. Gratify-
Propargylic Tetracyclic Ethers
Scheme 5. Synthesis of Symmetric and Unsymmetrical
Dipropargylic Cyclic Ethers
Scheme 6.11 In this precursor we have controlled the
stereochemistry of both THP-protected secondary alcohols.
When 13 was submitted to our standard acidic conditions
the tetracyclic system 14 was obtained as the only stereoi-
1
2
somer.
In summary, we have described a new and very efficient
procedure to synthesize linear or cyclic ethers in a highly
efficient and convergent manner. The method permits a high
level of control, affording nonsymmetrical compounds. In
addition, we have shown that the procedure can be used for
the stereocontrolled synthesis of cyclic ethers.
a
The synthesis of 9 (n ) 3, n′ ) 4) was performed in two
Acknowledgment. We thank the DGES (PB98-0443-
C02-01) of Spain and FEDER (1FD97-0747-C04-01) for
supporting this research. D.D. thanks the Spanish M.E.C.
for a F.P.I. fellowship. T.M. thanks the M.E.C. of Spain for
a Postdoctoral Reincorporating Contract.
sequential steps via the monopropargylic alcohol. In all other cases,
2
step.
equiv of the aldehyde was added to dilithium acetylide in one
ingly, when 9 was treated with only 0.5 equiv of BF
3
2
‚OEt ,
a concomitant cyclization occurred in all cases, yielding the
corresponding five- to seven-membered ring bicyclic ethers.
In addition to the significance of the cyclization, two
additional facts should be pointed out: (1) the procedure is
valid for the synthesis of nonsymmetrical cyclic ethers (ca.
Supporting Information Available: 1H and 13C NMR
spectra for all new compounds. In addition, NOE studies of
compound 14. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0164987
1
0) and(2) the reaction works under nonstoichiometric
conditions with only 0.5 equiv of Lewis acid, maintaining
the nucleophilic oxygen protected as a THPO-ether.
To verify whether our methodology was useful for the
stereocontrolled synthesis of cyclic systems, we performed
the synthesis of dipropargyl diol 13 in accordance with
1
0
(10) A plausible mechanism implies catalytic participation of the Lewis
acid, generating the cyclic ether and tetrahydropyran-2-ol:
(5) In all cases reported in this paper, the Co2(CO)6-complexes were
satisfactorily demetalized in the standard manner (CAN, acetone, 0 °C) to
obtain the free acetylenes. See: Seyferth, D.; Nestle, M. O.; Wehman. J.
Am. Chem. Soc. 1975, 97, 7417-7426.
(6) During the formation of 3 it was possible to detect by TLC the
transitory formation of the monoether that evolves to the diether. In
consequence, the species 2 is a sequentially achieved formalism.
(
11) The THP-protected diol 12 was prepared from known 11. See:
Delgado, M.; Mart ´ı n, J. D. J. Org. Chem. 1999, 64, 4798-4816. (a) (i)
Swern oxidation, (ii) (MeO)2P(O)CH2CO2Me, NaH, benzene, (iii) DIBALH,
THF, (iv) H2, PtO2, MeOH, (v) Ac2O, DMAP, CH2Cl2, (vi) HF, CH3CN,
(7) Although 6 is a known compound, the methods for its synthesis
reported in the literature provided very poor yields. See: Gleiter, R.;
Rittinger, S. Tetrahedron Lett. 1988, 29, 4529-4532.
(
vii) DHP, OPCl3, CH2Cl2, then NaH, MeOH, 52% overall.
(8) For the synthesis of sulfur macrocycles containing dialkyne units,
see: Davies, J. E.; Hope-Weeks, L. J.; Mays, M. J.; Raithby, P. R. J. Chem.
Soc., Chem. Commun. 2000, 1411-1412.
(9) For additional methods to synthesize cyclic ethers, see: (a) Alvarez,
E.; Candenas, M. L.; P e´ rez, R.; Ravelo, J. L.; Mart ´ı n, J. D. Chem. ReV.
1
1
995, 95, 1953-1980, and references therein. (b) Hoberg, J. O. Tetrahedron
998, 54, 12631-12670. (c) Yet, L. Chem. ReV. 2000, 100, 2963-3007,
and references therein. (d) Heck, M.-P.; Baylon, C.; Nolan, S. P.;
(12) The stereochemistry of 12 was determined by NOE studies (see
Supporting Information).
Mioskowski, C. Org. Lett. 2001, 3, 1989-1991, and references therein.
Org. Lett., Vol. 3, No. 21, 2001
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