Stereoselective Synthesis of Alcohols, XXXVIII Stereoselective Total Synthesis of the Denticulatins

Abstract

The total synthesis of the denticulatins 1 is described. Key feature is the efficient generation of the C-1-to-C-9 building block 37 by three consecutive stereoselective carbon -carbon bond-forming steps using chiral allylboronates. The C-lO-toMarine organisms have provided chemists with a large number of new natural products, many of which are derived from a polypropionate biogenetic pathway'). Among these products are the denticulatins A and B, which were isolated by Faulkner from Siphonaria denticdata 'I. The structures have been elucidated by a single-crystal X-ray analysis to be 1, differing in configuration at the epimerizable stereocenter at C-10. The absolute configuration was tentatively assigned from the sign of rotation of the degradation product 2 and was confirmed recently by the first total synthesis of the denticulatins by the group of Ziegler4). While the biological significance of the denticulatins is not fully known -these compounds are ichtyotoxic and may be involved as antifeedants -the chemistry of these compounds provides several challenges and questions: First of all, the denticulatins contain a hemiketal ring. They are therefore formally derived from the dihydroxy triketone 3, which could form two further hemiketals by addition of 7-C-17 building block was obtained by kinetic Sharpless resolution of an allylic alcohol followed by an Ireland-Claisen rearrangement.OH to either the C-11 or the C-3 carbonyl group. It was not known, how readily these hemiketals equilibrated and what the factors are that determine their relative stability. From the point of synthesis, the long sequence of contiguous stereocenters is a challenge, since an efficient synthesis would require the controlled generation of the stereogenic centers in the same steps that are used to build the molecular skeleton. For this purpose several strategies for the synthesis of such structures have been developed5) during the last decade, among which the aldol addition and the crotylmetal addition are most prominent. Nevertheless, the stereotriad Dn, occurring in many such polyketide natural products, is one which is still diflicult to attain by these methods. We therefore felt that a synthesis of the denticulatins would provide a severe and realistic test for our ability to efficiently synthesize such molecules by using the crotylboration technique. Our synthesis of denticulatin6) aimed at the construction of a protected equivalent of the aldehyde 4, containing all the relevant stereocenters, which was to be combined with the ketone 2. The same retrosynthetic scheme was the basis of Ziegler's synthesis of the denti~ulatins~). However, as will be shown below, stereoselective crotylboration afforded a much shorter access to the key aldehyde 4. DThe Synthesis of the Aldehyde 7, the C-1-to-C-9 Building BlockThe aldehyde 7 was considered to be a proper C-l-to-C-9 building block for the synthesis of the denticulatins. It was envisioned to be assembled by three consecutive stereoselective crotylboration sequences (Scheme 2).The first se...

Marine polypropionates

“…70 Hoffmann and co-workers intuitively predicted that the protected denticulatin precursor 114, synthesised from two key components 115 and 111, would spontaneously isomerise to give the more thermodynamically favoured denticulatins upon deprotection. 71,72 The former aldehyde component was prepared in three stereoselective consecutive steps using chiral allyl boronates while the latter ketone was obtained via a kinetic Sharpless resolution of the allylic alcohol, (3R)-2-methylpent-1-en-3-ol, followed by an Ireland-Claisen rearrangement. Unfortunately, while deprotection of 114 resulted in the anticipated isomerisation, unwanted epimerization at C-10 also occurred to give a mixture of the denticulatins.…”

(E)-α-Sulfonamidocrotylboronates as Reagents for the Stereoselective Homoaldol Synthesis

“…This preference for transition state 4 over 5 is influenced by the polarity of the C–X bond 19. This prompted us to study the α‐methoxycrotylboronates 1c , which indeed turned out to be superior reagents,20 especially when reagent control of diastereoselectivity on reaction with chiral aldehydes (mismatched cases) were concerned 18. The improvement in going from the α‐chlorocrotylboronate 1b to the α‐methoxycrotylboronate 1c encouraged us to evaluate the potential of α‐sulfonamidocrotylboronates 1d in stereoselective allylmetallation reactions.…”

Total synthesis of nahuoic acid A via a putative biogenetic intramolecular Diels–Alder (IMDA) reaction

“…The p -methoxybenzyl ether, which could eventually be further modified by oxidation with DDQ in order to achieve the double protection of the 1,3-diol, 49 was first selected. However, using a variety of reaction conditions, 50 from the more classical NaH, p -methoxybenzyl chloride and n -Bu 4 NI to modified protocols changing the base to KH and adding DMF, 51 led to complex mixtures of silyl ethers resulting from trans -silylation reactions of reactant 44 . Treatment with the trichloroacetimidate derivative PMBOC(NH)CCl 3 and Cu(OTf) 2 instead led to the recovery of the substrate.…”