Consecutive Alkene Cross-Metathesis/Oxonium Ylide Formation−Rearrangement: Synthesis of the Anti-HIV Agent Hyperolactone C

Abstract

Alpha-diazo-beta-ketoesters bearing allylic ether functionality undergo highly stereoselective Ru-carbene-catalyzed alkene cross-metathesis followed by Rh(2)(OAc)(4)-catalyzed oxonium ylide formation/[2,3] sigmatropic rearrangement in a one-flask operation and in a highly diastereoselective manner. The methodology has been demonstrated in a concise synthesis of the anti-HIV agent hyperolactone C.

Synthesis of the Anti‐HIV Agent (−)‐Hyperolactone C by Using Oxonium Ylide Formation–Rearrangement

“…The (E)-enal 12 substrate for oxonium ylide formation-rearrangement had previously been prepared in 21 % yield from racemic diazo ether 10 by cross-metathesis using a large excess of methacrolein. [7] In the present study, ozonolysis followed by a Wittig olefination were found to give improved access to (E)-enal (R)-12 (66 % from diazo ether (R)-10, Scheme 7). The intermediate diazoaldehyde 25 was best obtained (88 %) after ozonolysis by using 1 equiv of PPh 3 (use of Me 2 S, or (MeO) 3 P were less satisfactory); the tolerance of the diazo group to this chemistry is noteworthy.…”

“…Racemic diazo ether 10 was originally prepared from a Lewis acid-catalysed Mukaiyama-type aldol reaction between [bisA C H T U N G T R E N N U N G (allyloxy)methyl]benzene and the silyl enol ether of ethyl diazoacetoacetate, [7] and for which there was no direct asymmetric version. [7] However, a potentially straightforward asymmetric synthesis of diazo ether 10 was considered that involved allylation of the precursor diazoalcohol 17 (Scheme 4), as this alcohol has previously been shown by Kundu and Doyle to be available for R = Me in 80 % yield and 95.5:4.5 e.r. by a catalytic asymmetric aldol reaction using benzaldehyde and the silyl enol ether of methyl a-diazoaceotacetate.…”

“…Reported in 2008, our seven-step approach to rac-hyperolactone C (1) from ethyl acetoacetate involved one-pot Eselective cross-metathesis then oxonium ylide formation- [2,3] sigmatropic rearrangement from diazo ether 10 and methacrolein (11), followed by chemoselective aldehyde reduction, lactonisation and dehydrogenation (Scheme 3). [7] In critically reviewing this first-generation synthesis, we identified several important areas for further investigation: First, was to render the strategy an asymmetric one; secondly, to develop an alternative to the difficult cross-metathesis using methacrolein (100 equiv), which likely contributes to the modest overall yield for the three-step sequence from diazo ether 10 to lactol 15 by way of oxonium ylide 13. Thirdly, to analyse and understand in more detail the origins of selectivity in the key sigmatropic rearrangement (13!14), with the aim of increasing the efficiency/d.r.…”

Neues zur Synthese von Diazoverbindungen

“…[72] Ungesättigte 3-Oxo-2-diazocarbonsäureester wie 38 gehen in mäßigen bis guten Ausbeuten eine Ruthenium-katalysierte Olefin-Kreuzmetathese ein. [70,73] Dies ist insofern bemerkenswert, als derselbe Katalysator (Ruthenium-Carben-Komplex Grubbs II) Diazoessigester unter N 2 -Abspaltung in die entsprechenden Maleinsäureester (formale Carbendimere) umwandelt.…”

“…[62] Acetessigester ( [64] In analoger Weise ließ sich Benzaldehyddiallylacetal als elektrophiler Reaktionspartner einsetzen. [70] Auch die Stereoselektivität der Aldol-Reaktionen war bereits ein Thema: Mit AgF/(R)-Binap als chiralem Katalysator konnte eine mäßige Enantioselektivität der Mukaiyama-Aldol-Reaktion von Diazoacetoacetaten erreicht werden. [67c] Hoch diastereoselektiv verlief hingegen die Addition des Lithiumenolats von 36 (R 1 = H, R 2 = Allyl) an chirale N-Sulfinylimine.…”