Pentenylboronates, either > 90% 2 (4) or > 95% E (3), can be obtained by reaction of the pentenyl Grignard reagent with different borates. The 2-pentenylboronates 4 add to aldehydes under high simple diastereoselection to give the diastereomerically pure syn-homoallyl alcohols 10. The corresponding addition of the E-.pentenylboronates leads to the anti-homoallyl alcohols as E-(lJ)/ 2417) mixtures.Stereogenic carbon -carbon bond forming reactions are of prime interest in stereoselective synthesis*). A wellestablished3) reaction is the addition of E-and Z-crotylb o r o n a t e~~~~) such as 1, or of E-and Z-crotylboranes') to aldehydes, a reaction which proceeds with high simple diastereoselection.These reagents are in general prepared by deprotonation of E-or Z-butene to E-or Z-butenylpotassium') followed Stereoselektive Syntbese von Alkoholen, XXX '? -E-und 2-Pentenylboronsiiuter, Reagenzien, die sich onter einfacher Diastereoselektivit&t an Aldehyde addieren Durch Reaktion des Pentenyl-Grignard-Reagenzes 2 mit verschiedenen Borslureestern erhalt man Pentenylboronslureester entweder zu >90% als Z-Isomer 4 oder zu >95% als E-Isomer 3. A#-dition der 2-Pentenylboronsaureester 4 an Aldehyde ergibt die 'diastereomerenreinen syn-Homoallylalkohole 10. Entsprechende Addition des E-Pentenylboronsauresters 3 fiirt zu anti-Homoallylalkoholen als E-( 15)/2-(17)-Gernische.by borylation. The generation of butenylpotassium does not lend itself to scale up readily. Of the other routes to such crotylboron compound^^.'^) some require separation of geometric isomers of a precursor [E/Z-1 -bromopropene"' or E/Z-crotylbis(dimethylamino)boranes4~] in a spinning band column. As long as only simple diastereoselection on addition to aldehydes is concerned, the E-and Z-pentenylboronates 3 and 4 might do as well. The E reagent 3 can easily be prepared in a diastereomeric purity of >95% by reaction of the simple pentadienyl Grignard reagent 2 with triisopropylborate") and this has been achieved on a scale of up to 0.36 mole. However, for adhtion to aldehydes the crude product had to be used, since 3 has a tendency to decompose to a solid material on distillation (polymerisation?).Further experiments showed that the 3/4 ratio depends on the borylating agent. Representative results are given in Scheme 1.
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...
We report a systematic analysis of the P1' and P2' substrate specificity of TNF-alpha converting enzyme (TACE) using a peptide library and a novel analytical method, and we use the substrate specificity information to design novel reverse hydroxamate inhibitors. Initial truncation studies, using the amino acid sequence around the cleavage site in precursor-TNF-alpha, showed that good turnover was obtained with the peptide DNP-LAQAVRSS-NH2. Based on this result, 1000 different peptide substrates of the form Biotin-LAQA-P1'-P2'-SSK(DNP)-NH2 were prepared, with 50 different natural and unnatural amino acids at P1' in combination with 20 different amino acids at P2'. The peptides were pooled, treated with purified microsomal TACE, and the reaction mixtures were passed over a streptavidin affinity column to remove unreacted substrate and the N-terminal biotinylated product. C-terminal cleavage products not binding to streptavidin were subjected to liquid chromatography/mass spectrometry analysis where individual products were identified and semiquantitated. 25 of the substrates were resynthesized as discrete peptides and assayed with recombinant TACE. The experiments show that recombinant TACE prefers lipophilic amino acids at the P1' position, such as phenylglycine, homophenylalanine, leucine and valine. At the P2' position, TACE can accommodate basic amino acids, such as arginine and lysine, as well as certain non-basic amino acids such as citrulline, methionine sulfoxide and threonine. These substrate preferences were used in the design of novel reverse hydroxamate TACE inhibitors with phenethyl and 5-methyl-thiophene-methyl side-chains at P1', and threonine and nitro-arginine at P2'.
The scope of the Lewis acid-promoted ene cyclization has been expanded to include 12-, 14-, and 16-membered rings. Thus, the ynals 1.8,2.5, and 3.5 undergo efficient type-I cyclization upon addition to 1.0 equiv of EtAICk in CH2CI2 at -78 °C. The epoxy ynal 4.3 undergoes pinacol rearrangement under these conditions. However, treatment with a 1:1 mixture of Et^AlCl and EtAlCL effects conversion to the cyclic products 4.4/4.S (92:8) in satisfactory yield. Facile type-II cyclizations were readily achieved with ynals 5.7,6.4,7.6, and 8.3 with EtAlCl2 as the Lewis acid. In the latter case, a 16-membered propargylic alcohol was produced in 84% yield.We recently showed that certain terminal isopropylidene-and isopropenyl-substituted acetylenic aldehydes undergo efficient type-I and type-II ene cyclizations in the presence of alkylaluminum chlorides to afford cyclic propargylic alcohols of 12 and 14 members (eq l).1•2
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