Efficient and Stereoselective Synthesis of Freelingyne via Pd-Catalyzed Cross Coupling and Lactonization¹

Abstract

Freelingyne (1), a sesquiterpene from Eremophila freelingii, 2 features several synthetically interesting structural subunits, such as a methyl-substituted (E)-alkene and a (Z)-γ-alkylidenebutenolide. Although it has been synthesized twice in the past, 3 a mixture of the Z and E isomers of 1 was obtained in either case as a consequence of nonstereoselective olefination, the reported Z/E ratio in one case 3a being 40/60. Herein, we report an efficient synthesis of freelingyne 4 with essentially full control of the alkene geometries, employing the synthetic strategy outlined in Scheme 1.The E and Z methyl-substituted alkene units were prepared by the Zr-catalyzed carboalumination with Me 3 -Al 5 and the Cu-catalyzed methylmagnesation, 6 respectively, of propargyl alcohol, followed by iodinolysis. The stereoselectivity in either case was g99%. The yield of (E)-3-iodo-2-methyl-2-propen-1-ol (2) was 53% and relatively constant. On the other hand, the yield of the Z isomer 3 obtained via methylmagnesation ranged from 30 to 75%. At this point, it is not very clear what factor is responsible for the observed yield fluctuation, but efficient and vigorous mechanical stirring of the reaction mixture appears to be essential to obtaining 3 in high yields. Conversion of 3 into (Z)-3-iodo-2-methylpropenoic acid (4) was achieved by oxidation first with PCC (2 equiv) and Celite in CH 2 Cl 2 7 and then with NaClO 2 -H 2 O 2 in the presence of NaH 2 PO 3 in MeCN 8 in 57% overall yield.After protection of 2 with 3,4-dihydro-2H-pyran in 84% yield, the Pd-catalyzed cross coupling with commercially available ethynylmagnesium chloride 9 in THF in the presence of 5 mol % of Pd(PPh 3 ) 4 afforded enyne 5 in 94% yield. The direct synthesis of terminal alkynes such as 5 using ethynylzinc or ethynylmagnesium derivatives in the Pd-catalyzed cross coupling 9 offers a distinct advantage over the Sonogashira protocol 10 which is known to require protection-deprotection of the ethynyl group. In this case, HCtCMgCl was as satisfactory as HCtCZnBr. However, cross coupling of 5 with 3-iodofuran in the presence of 5 mol % of Pd(PPh 3 ) 4 was best achieved by in situ conversion of 5 into the bromozinc derivatives via sequential treatment with n-BuLi and freshly dried ZnBr 2 . The desired cross-coupling product 6 was obtained in 82% yield along with 5 recovered in 16%. 3-Iodofuran was prepared by treatment of commercially available 3-bromofuran with n-BuLi followed by iodinolysis. After removal of the THP group in 97% yields with p-TsOH in MeOH, oxidation with Dess-Martin periodinane 11 in CH 2 Cl 2 gave the corresponding aldehyde 7 in essentially quantitative yield. Corey-Fuchs olefination 12 of 7 with CBr 4 (3 equiv) and PPh 3 (6 equiv) in the presence of K 2 CO 3 afforded the desired dibromide 8 in 95% yield. Its sequential treatment with NaN(SiMe 3 ) 2 (1.5 equiv) in THF, n-BuLi (3 equiv), and MeOH provided 9 in 86% yield.With 4 and 9 in hand, the stage was set for the crucial Pd-catalyzed cross coupling-lactonization tandem process developed recen...

Palladium-Catalyzed Alkynylation

“…200 As already discussed in sections III.B.1 and III.B.2, this cascade process has been applied to the synthesis of a number of natural products containing (Z)-γ-alkylidenebutenolides. 109,110,200,239,253,254 In sharp contrast with the cascade process mentioned above, the Negishi alkynylation of zinc salts of (Z)-haloacrylic acids with alkynylzinc derivatives produces the expected cross coupling products in excellent yields (Scheme 64). 158,255 Thus, in cases where 2-en-4-ynoic acids are desired, the Negishi protocol may be used, even though the use of esters in place of free carboxylic acids has been shown to permit cross-coupling without lactonization 256 under either the Sonogashira or the Negishi coupling conditions.…”

Marine cytotoxic macrolides haterumalides and biselides, and related natural products

“…The synthetic route reported by Snider begins with the preparation of optically active vinylstannane 33 (Scheme ). The Z ‐methyl‐substituted alkene unit 36 was prepared by the Cu‐catalyzed methylmagnesation of propargyl alcohol 35 22 followed by iodinolysis. Iodoalkene 36 was oxidized with MnO 2 to afford an iodoaldehyde.…”

Gold catalysis-facilitated rapid synthesis of the daphnane/tigliane tricyclic core

“…Sonogashira cross coupling united 13 and 17 successfully and gave the desired coupling products from 52% to 86% yield. In these Sonogashira couplings, the freeze-pump-thaw [20] technique is crucial for high yields; otherwise, a significant amount of alkyne dimerization leads to a dramatic drop of the reaction yield.…”