Dilactones, macrocyclic

Syntheses of macrocyclic musks, among them lactones, dilactones, and oxalac-tones 99S1707. 

Perhydropyrido[l,2-A][l,2]oxazines have been utilized as key intermediates in a stereospecific total syntheses of (—)-pumiliotoxin C and 5-< />z-pumiliotoxin C <1996J(P1)1113>, and the marine alkaloids (—)-lepadins A, B, and C and macrocyclic dilactones, (+)-azimine and (+)carpaine <20000L2955, 2001JOC3338, 2003OL3839>. In the total synthesis of the marine alkaloids ( )-fasicularin and ( )-lepadiformine, perhydro[l,2]oxazino[3,2 /]quinolines were used to control the stereochemistry <2000JA4583, 2000TL1205>. 

Macrocyclic tetralactones. A method for preparation of these lactones (2) uses a stannoxane (1) as a covalent template (equation I). Formation of dilactones is not observed. 

Knust H, Hoffmann RW (2003) Synthesis and Conformational Analysis of Macrocyclic Dilactones Mimicking the Pharmacophore of Aplysiatoxin. Helv Chim Acta 86 1871... 

Glucolipsin A (21) is a macrocyclic dilactone natural product that exhibits glucokinase-activating properties. Fiirstner et al. employed an Evans aldol strategy to synthesize the syn -aldol intermediate 2310 (Scheme 2.1j). The aldol reaction of the boron enolate of 14 with 14-methylpentadecanal (22) delivered the yyn-aldol product 23 in essentially diastereomerically pure form (99% de) after purification. Subsequent glycosidation of the alcohol 23 with trichloroacetimidate (24) was facilitated by catalytic amounts of TMSOTf (20 mol %) to afford the key intermediate (25) in moderate yield. 

Several macrocyclic dilactones such as 80 were prepared by reaction of dicarboxylic acid difluorides (e.g. 78) with triphenyltin derivatives of diols (e.g. 79) in excellent yields [63]. The required acid fluorides can be synthesized by reaction of the acids with 2-fluoro-iV-methylpyridmiumtosylate (81) and addition of triethylamine. The triphenyltin derivatives of the diols were prepared in situ from PhsSn—O—SnPh3 and the diols. 

Another useful reagent for macrolactonization via mixed phosphoric anhydride is N,N- bis(2-oxo-3-oxazolidinyl)phosphordiamidic chloride (BOP-Cl, 64), which was used by Corey and coworkers [41] in the first synthesis of aplasmomycin (67), a novel boron-containing macrocyclic antibiotic. As shown in Scheme 21, the linear precursor 65 was treated with 3 equiv of BOP-Cl (64) and 7 equiv of triethylamine in dichloromethane at 23 °C for 6 h to give the dilactone 66 in 71% yield. 

Phosphonoacetate cycHzation. Intramolecular cyclization of keto phosphonates can be used for construction of macrocyclic a, -unsaturated lactones. Stork s laboratory found that use of lithium isopropoxide or lithium hexamethyidisilazide in THF containing 1% HMPT minimized formation of cyclic dilactones. Use of sodium or potassium counterions was much less satisfactory. An example is shown in equation (I). 

Prochiral y-hydroxy diesters underwent enantioselective lactonization with PPL to afford the (S)-lactone in a highly enantioselective fashion (eq 17). Formation of macrocyclic lactones by the condensation of diacids or diesters with diols, leading to mono- and dilactones, linear oligomeric esters, or high molecular weight optically active polymers, depending upon type of substrates as well as reaction conditions, has also been described. 

The marine strain of Streptomyces griseus produces the boron-containing macrocyclic dilactone aplasmomycin (106), 2 Belonging to a family of borate-bridged macrocycles (which includes boromycin), 106 exhibits activity against gram-positive bacteria and the microorganisms of Plasmodia. Structurally, 106... 

A synthesis of pyrenophorin using dithian shows how it works. The target 23 is a macrocyclic (16-membered ring) dilactone and disconnection of the ester linkages reveals two identical halves 24 pyrenophorin has C2 symmetry.7... 

Cathedulins -K17, -K19, and -K20 have been isolated from C. edulis, and their structures determined using FABMS, and one- and two-dimensional and NMR [169]. Cathedulins -K17 and -K19 each contain edulinic acid (B) as the acid component of the macrocyclic dilactone. The absolute configuration of B derived from cathedulin -K19 was established by synthesis of the (5)-dialcohol C from methyl (R)-3-hydroxy-2-methylpropionate. The product (C) was identical to the compound produced by UAIH4 reduction of cathedulin -K19, in sign of optical rotation, IR, H and NMR spectra [170]. 

Some alkaloids have macropolylide skeletons in their structures in particular, many pyrrolizidine alkaloids have structures with each pyrrolizidine skeleton fused to a macrocyclic dilactone or trilactone [169]. Crotalarine (Fig. 25,141) is a 10-membered ring macrodiolide isolated from Crotalaria burhia [170]. Seneci-phylline (142) is a 12-membered ring macrodiolide isolated from Senecio spp. 

Macrocyclic lactones. Seebach it al. have synthesized the diketo dilactone (- )-pyrenophorin (3) by cyclodimerization of the dithiane derivative 1 with triphenylphosphine and diethyl azodicarboxylate. The product 2 on hydrolysis of the dithiane groups (HgO-BFa etherate) yields the corresponding diketone (3). 

Total stereospecific syntheses of (+)-azimic (35) and (+)-carpamic acids (36), which are the hydroxy-acids in the macrocyclic dilactone structures of azimine and carpaine respectively, have been described, starting from (+)-glucose. ... 

Macrocyclic dilactones via dicarboxylic acid stannyl esters O... 

Macrocyclic dilactones from dicarboxylic acid chlorides s. 42, 92s44 Potassium salt s.a. under Microwaves... 

Macrocyclic dilactones from dicarboxylic acid anhydrides and chlorhydrins... 

It was mentioned above that the industry has carrying out synthetic research to find alternatives to the nitro and polycyclic musks. Another approach to this problem is the investigation of known macrocyclic ketones and lactones (24) in search of more efficient processes that could be practiced on larger scales than had previously been contemplated. Some of the materials that have received this sort of attention are muskalactone (79) (25), cyclopentadecanone (44), hexadecanolide (80) (26) as well as the dilactone ethylene bras-sylate (81) and its lower homolog prepared from dodecanedioic acid. Reaction scheme shows some of the chemistry that has been developed in connection with the new chemical, oxacyclohexadecen-2-one (77) and muskalactone (79). 

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