Caught in the middle: The ionomycin calcium complex (see structure; O red, Ca green) was the target of an approach featuring the efficient asymmetric synthesis of an allene by a copper(I)-mediated anti-selective S(N)2' reaction, a highly stereoselective gold(III)-catalyzed cycloisomerization of an alpha-hydroxyallene, and a Rh-catalyzed rearrangement of an alpha-diazo-beta-hydroxyketone.

Split-and-mix libraries of resin-bound "tweezer" receptors have been prepared and screened to identify receptors for dye-labelled tripeptides. The receptors incorporate a diamidopyridine unit to serve as a specific recognition site for the CO2H group, leading to strong and selective receptors for peptide guests with a CO2H terminus. The role of the dye-label, attached to the peptide guest to allow visualisation of selective recognition events in the screening experiments, has also been examined and was found to have a significant influence on the binding selectivities.

Ionomycin is a narrow-spectrum ionophore antibiotic isolated from Streptomyces conglobatus. [1] X-ray crystallographic analysis of its calcium complex (1; see Scheme 1) [2] revealed a carboxylic acid group and an unusual b-diketone moiety which, in combination, are responsible for its avidity for divalent cations. Ionomycin has little value as an antibiotic but it is widely used as a tool in cell biology for the investigation of processes requiring calcium mobilization. [3] The three total syntheses reported to date exemplify the utility of chiral enolate chemistry (Evans et al.), [4] the chiron approach (Hanessian et al.), [5] and asymmetric ring-opening of symmetrical 8-oxabicyclo[3.2.1]oct-6-enes (Lautens et al.) [6] for the construction of polypropionate chains. In addition, numerous fragment syntheses have also been reported. [7] Herein, we describe a synthesis of ionomycin and its calcium complex (1) from four key fragments 2-5 (Scheme 1). Our synthesis features: 1) the use of a stereoselective gold(III)catalyzed cycloisomerization of an a-hydroxyallene to create a dihydrofuran ring, and 2) the use of a rhodium-catalyzed rearrangement of an a-diazo-b-hydroxyketone to generate the b-diketone moiety.Our synthesis began with the construction of the C22-C32 bis(tetrahydrofuran) fragment 2. Thus, addition of lithium TMS-acetylide to the known aldehyde 6 [8] gave a racemic propargylic alcohol which was oxidized to the corresponding ketone 7 using pyridinium dichromate (Scheme 2). The asymmetric hydrogen-transfer reaction of ketone 7 by the method of Noyori and Ohkuma [9] led to (R)-9 in 95 % yield and e.r. = 97:3, as determined by 1 H NMR spectroscopic analysis of the mandelate ester. Simultaneous cleavage of the TMS and acetate groups using potassium carbonate in methanol resulted in a water soluble diol (R)-10. This species underwent Sharpless asymmetric epoxidation to form the epoxide intermediate 11, which spontaneously cyclized to the tetrahydrofuran 12. The primary hydroxy group was then removed by tosylation and subsequent reduction using lithium triethylborohydride gave the secondary alcohol 14, which was protected as its TBS silyl ether 15.Addition of the freshly prepared aldehyde 16 to the titanium derivative of alkyne 15 gave the desired propargylic alcohol 17 (anti/syn = 6:1) in accord with the Felkin-Anh model of asymmetric induction (Scheme 3). [10] The corresponding mesylate 18 was treated with MeCu·MgBr 2 ·LiCl by an anti-selective S N 2' mechanism [11] to give allene 19 (d.r. = 6:1) in 93 % yield. Selective removal of the isopropylidene group was accomplished using 0.10 m PPTS in isopropanol at 50 8C to give a mixture of diastereomeric diols (6:1), which were separated by column chromatography. Pure diol 20 was isolated in 53 % overall yield (63 % brsm) for the four steps starting from alkyne 15. In the key step of the sequence, the diol 20 was treated with 1 mol % AuCl 3 in THF at room temperature to afford the dihydrofuran 21 as a single diastereoisomer in 92 % yield. By using the donor solven...

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Key steps in a synthesis of the C17-C32 fragment of ionomycin are (a) an auxiliary-directed oxidative cyclisation of a diene with potassium permanganate to construct a tetrahydrofuran ring and four stereogenic centres in a single operation, and (b) a chainappendage reaction featuring the alkylation of an enolsilane by an oxocarbenium ion generated from a 2-phenylsulfonyl-substituted tetrahydrofuran.Ionomycin (1) is an ionophore isolated from Streptomyces conglobatus with a high affinity for divalent cations. 1-3 A detailed competitive binding study revealed the following selectivity: Pb 2+ > Cd 2+ > Zn 2+ > Mn 2+ > Ca 2+ > Cu 2+ > Co 2+ > Ni 2+ > Sr 2+ . 4 It is widely used as a tool in cell biology for the investigation of processes requiring calcium mobilisation and its use in lead detoxification has been mooted. In 2009 we reported a total synthesis of ionomycin and its calcium complex based on (a) a highly stereoselective Au 3+ -catalysed cycloisomerisation of an ahydroxyallene to create the tetrahydrofuran B, and (b) a rhodium-catalysed rearrangement of an a-diazo-b-hydroxyketone to generate the b-diketone moiety. 5 A key intermediate in our synthesis was the C17-C32 alcohol 2 (Scheme 1), which had also featured in the preceding syntheses developed by Evans 6 and Hanessian 7 reported in 1990. 8 We now report an alternative synthesis of the C17-C32 alcohol 2, and hence a formal synthesis of ionomycin, which features (a) a permanganate-mediated oxidative cyclisation reaction 9 to create the tetrahydrofuran ring A in fragment 4 and four of its stereogenic centres in a single operation, and (b) a Ley a-heteroalkylation reaction to append fragment 3 to C23 of fragment 4.The anti,anti-stereotriad in fragment 3 was installed by a crotylmetallation reaction on the known aldehyde 8 (Scheme 2). 10 Initial attempts to use Roush's easily accessible tartrate-derived (E)-crotylboronic ester reagent 9 were thwarted by poor diastereoselectivity (dr = 2:1). [11][12][13] Better results were obtained with (E)-crotyldiisopinocampheylborane (10) derived from (+)-a-pinene; in this case the desired adduct 11 was obtained in a modest 52% yield but excellent diastereoselectivity (dr >95:5). 14 The yield and diastereoselectivity of the crotylmetallation reaction were very sensitive to the quality of the reagent 10, with the best results being obtained with freshly prepared reagent. 15 After protection of the secondary alcohol as its pmethoxybenzyl ether, the alkene function of 12 was converted into the ketone 13 through a Wacker oxidation. 16 Finally, the ketone was converted into its enolsilane derivative in the usual way, to afford fragment 3 in 30% overall yield from commercial ester 5.