Direct Preparation of Z-1,3-Enyne Systems with a TMS-Propargylic Sulfone: Application of a One-Pot Julia Olefination

Abstract

A benzothiazolyl TMS-propargylic sulfone was subjected to one-pot Julia olefinations with a variety of aliphatic and aromatic aldehydes. Predominant Z-selectivity up to 98:2 and good chemical yields were obtained in a facile route to the desired Z-1,3-enyne moieties.Vinylacetylenes are important and direct precursors of conjugated p-systems, including dienic, diacetylenic and aromatic compounds which are common features in natural products. 1 Frameworks like 1 (Scheme 1) are frequently used in multistep syntheses of polyunsaturated compounds, suitable for subsequent coupling reactions after silyl deprotection. For example, the Z-1,3-enyne system is used in the preparation of cyclooctatetraenophanes (2) 2 and of 3-alkoxymethylindolizines (3), 3 the latter are potential new calcium entry blockers, chemotherapeutics and cardiovascular agents. The same moiety 1 is the key intermediate in several total syntheses of natural bioactive compounds like the alkaloid quinolizidine 217A (4) 4 and the (-)-siphonodiol (5), 5 an antifungal and antibacterial polyacetylene.As part of our ongoing projects on natural product syntheses we are interested in the development of an efficient method for the construction of such Z-1,3-enyne system starting from an appropriate acetylenic compound, and in the subsequent stereocontrolled formation of the conjugated double bond. For highly regio-and stereoselective double-bond formation, compatible with multifunctionalized compounds, the most generally applicable methods involve the direct olefination of carbonyl compounds as in the Wittig, 6 Peterson, 7 Johnson, 8 classical Julia 9 and onepot Julia 10 reactions, or the more recently developed olefin metathesis 11 and transition-metal-catalyzed crosscoupling 12 reactions.Together with the seminal work on modified Julia olefination, 10c we have found only a recent report 13 on the preparation of such enyne systems via one-pot reaction of propargylic sulfones with a,b-unsaturated aldehydes, but no applications in total syntheses. Moreover, the reported propargylic sulfones are alkyl-substituted at the end of the acetylenic bond (n-Bu and Me, respectively).We have recently developed a simple and highly efficient procedure for the preparation of different propargylic sulfones starting from the corresponding propargylic alcohols. 14 We have chosen the TMS-propargylic sulfone for a general application of the one-pot Julia reaction. With both benzothiazoyl (BT) sulfones and phenyltetrazoyl (PT) sulfones in hand, we have attempted the olefination with benzaldehyde (Table 1), which was not used with propargylic sulfones in the previously reported olefinations. 10,13 In the first attempts, olefination of sulfone 6a was conducted at -55°C in THF using KHMDS, according to the premetallated 15 or Barbier procedure. 16 Reactions afforded the required enyne 7 in 50% and 80% yields, with Z/E ratios of 87:13 and 96:4, respectively (Table 1, entries 1 and 2).The same Z-selectivity was obtained in the olefination of sulfone 6a with benzaldehyde using DME as solv...

Stereoselective Synthesis of Conjugated Fluoro Enynes

“…19 Yields were typically moderate, but high Z -selectivity was obtained in KHMDS-mediated reactions at −55 °C. 19 In the present case, KHMDS-mediated reaction of 3 with 2-naphthaldehyde at −55 °C gave product 4 in 82/18 E / Z ratio and high 86% yield (entry 1). The use of LHMDS at −78 °C resulted in an increased E / Z ratio (88/12) and 97% yield (entry 2).…”

E- or Z-Selective synthesis of 4-fluorovinyl-1,2,3-triazoles with fluorinated second-generation Julia–Kocienski reagents

“…19 This sulfone on reaction with benzaldehyde gave the enyne product in a low yield, plausibly due to its instability. 20 Because our protocol requires initial fluorination of a TMS-protected propargyl heteroaryl sulfone, followed by CuAAC reactions, we chose the more stable benzothiazolyl derivative (Scheme 1). …”

Divergent Total Synthesis of the Antimitotic Agent Leiodermatolide

“…The cheap malonate derivative 3 served as the point of departure, which was advanced into 3-iodomethacrolein (6) by following a literature procedure. [21] The enyne (Z/E > 24:1) thus obtained was finally deprotected with TBAF to give 11 in readiness for esterification with the acid sector 20. [20] Silylation of the free OH group followed by routine oxidation-state management gave alde-hyde 9, which was immediately subjected to a Julia olefination with the known sulfone derivative 10.…”

“…[20] Silylation of the free OH group followed by routine oxidation-state management gave alde-hyde 9, which was immediately subjected to a Julia olefination with the known sulfone derivative 10. [21] The enyne (Z/E > 24:1) thus obtained was finally deprotected with TBAF to give 11 in readiness for esterification with the acid sector 20.…”