Toward the synthesis of reidispongiolide a: stereocontrolled synthesis of the C17-C22 and C23-C35 degradation fragments

[structure: see text] By relying on the asymmetric aldol reactions of chiral ketones, a highly stereocontrolled synthesis of each of the C(17)-C(22) and C(23)-C(35) degradation fragments of reidispongiolide A has been achieved. This permits a configurational assignment of the complete C(17)-C(36) region of this antimitotic macrolide, along with providing advanced intermediates for a projected total synthesis.     

Synthetic studies of tedanolide, a marine macrolide displaying potent antitumor activity. Stereoselective synthesis of the C13-C23 segment

[structure: see text] A highly stereoselective synthesis of the C13-C23 segment of tedanolide (1), an 18-membered macrolide isolated from the Caribbean sponge Tedania ignis, displaying significant cytotoxicity against KB and PS tumor cell lines, is described which involves two stereoselective epoxidations of regioisomeric trisubstituted double bonds and a stereospecific S(N)2' methylation reaction of a trans-gamma,delta-epoxy-cis-alpha,beta-unsaturated ester as the key steps.     

Synthetic studies of mycalolide B, an actin-depolymerizing marine macrolide: construction of the tris-oxazole macrolactone using ring-closing metathesis

Tris-oxazole macrolactone 2, a key intermediate of mycalolide B (1), which has 13 stereogenic centres, was synthesized through the use of ring-closing metathesis (RCM). The E/Z ratio of the RCM product 2 was reversed by the use of CH₂Cl₂ and toluene, whereas a cross-metathesis reaction yielded the C1-C35 long-chain compound 19 in a highly E-selective manner. Thus, the loss of flexibility in aliphatic carbon chains and the steric hinderance of β- and γ-substituents of the C20 olefin in the precursor 11 may affect the stereoselectivity in RCM reactions.     

Studies towards the total synthesis of cruentaren A and B: Stereoselective synthesis of fragments C1-C11, C12-C22 and C23-C28

A convergent and stereoselective approach for the synthesis of C1-C11, C12-C22, and C23-C28 fragments of cytotoxic natural products cruentaren A and B are accomplished. Highlights of the strategy include a Sharpless epoxidation followed by a regioselective opening of epoxide to generate anti and syn-stereochemistry at C9-C10 and C15-C16, an Alder-Rickert reaction between a 1,5-dimethoxy-1,4-cyclohexadiene and dienophile to construct the aromatic ring, and a lithium-mediated aldol reaction to install the C17-C18 anti-stereochemistry. The synthesis of C1-C11 and C12-C22 fragments proceed with a longest linear sequence of 10 and 17 steps from commercially available 2-butyne-1,4-diol and cis-2-butene-1,4-diol respectively.     

Synthetic studies toward potent cytostatic macrolide rhizopodin: stereoselective synthesis of the C16-C28 fragment

A stereoselective synthesis of the C16-C28 fragment of cytostatic C₂-symmetric macrolide rhizopodin is described. Enantioselective addition of a chiral thiazolidinethione derived titanium enolate to acetal, Evans’ aldol reaction, Horner-Wadsworth-Emmons reaction, and Mukaiyama aldol reaction were applied as key steps.     

Synthetic studies toward the total synthesis of tedanolide: assembly of the C1-C23 carbon backbone

A stereoselective assembly of the C1-C23 fragment representing the carbon backbone of tedanolide was accomplished utilizing a chiral boron reagent to effect the aldol coupling of the C1-C12 diketoester fragment with the C13-C23 aldehyde fragment.     

Synthetic studies of an 18-membered antitumor macrolide, tedanolide. 5. Stereoselective synthesis of the C13-C23 part via condensation of two fragments, C13-C17 and C18-C21, by taking advantage of the 3,4-dimethoxybenzyl protecting group.

An efficient and stereoselective synthesis of the C13-C23 part (8) was achieved starting from methyl (R)- and (S)-3-hydroxy-2-methylpropionates (9) via coupling of the C13-C17 aldehyde (6), prepared by Evans asymmetric aldol reaction, with the C18-C21 iodoalkene (5b) by taking advantage of the 3,4-dimethoxybenzyl protecting group.     

Synthetic studies on borrelidin: enantioselective synthesis of the C1-C12 fragment

[structure: see text] An efficient, enantioselective synthesis of the C1-C12 fragment 2 of borrelidin is presented. Construction of the "skipped" polymethylene chain of 2 was accomplished by iteration of Myers' alkylation, while formation of the C3 stereocenter was achieved by Roush's asymmetric allylboration methodology.     

Synthetic studies of the 18-membered antitumor macrolide, tedanolide. 3. Stereocontrolled synthesis of the C1-C12 part via a synthesis of the C1-C7 fragment by a mismatched but efficient sharpless dihydroxylation and its coupling with the C8-C11 fragment

The C1-C12 part (4) of tedanolide (1) was synthesized starting from methyl (R)-3-hydroxy-2-methylpropionate (11a) via a coupling between the C1-C7 aldehyde (6) and the C8-C11 iodoalkene (7a). For a synthesis of 6, a mismatched but highly efficient Sharpless dihydroxylation of the alpha, beta-unsaturated ester (15) with AD-mix-alpha was successfully applied. Compound 7a was synthesized using hydrozirconation to the alkyne (32).     

Synthetic studies of incednine: synthesis of C1-C13 pentaenoic acid segment

Stereoselective synthesis of the C1-C13 pentaenoic acid segment (4) of the novel antibiotic incednine (1) is described.     

Synthetic studies on macrolactin A: construction of C4-C24 fragment

The preparation of the C4-C24 fragment of the macrolactin A is described. The adopted synthetic strategy involves two isomerizations to selectively construct the (8E,10Z) and (16E,18E) dienes, using a sequential Claisen rearrangement/allene isomerization and a Ph3P-catalyzed isomerization of an yne-one, respectively.     

Synthetic studies on amphidinolides C and F: synthesis of the C18-C29 segment of amphidinolide F

The C18-C29 segment of amphidinolide F is synthesised in 12 steps from 1,4-butanediol. Key steps include a mono-Sharpless dihydroxylation of a dienoate, iodocyclisation to construct the trans-THF ring and an E-selective Wittig reaction to introduce the C25-C26 olefin.     

Synthetic studies toward amphidinolide B1: synthesis of the C9-C26 fragment

[reaction: see text] The synthesis of the C9-C26 portion of amphidinolide B1 is described. A Fleming allylation followed by elimination was employed for the construction of the C13-C15 diene portion. Sharpless asymmetric dihydroxylation was utilized for regioselective functionalization of a styrene-derived alkene, in the presence of the C13-C15 diene functionality. A highly diastereoselective aldol reaction was developed to establish the C18 stereochemistry.     

Synthetic studies on antascomicin A: construction of the C18-C34 fragment

Stereoselective synthesis of the C18-C34 fragment of antascomicin A is described. Construction of the C27-C34 carbocycle moiety was achieved via catalytic Ferrier carbocylization and Johnson-Claisen rearrangement, which was converted to iodide 2 by use of asymmetric alkylation and Sharpless epoxidation as key transformations. Coupling of iodide 2 and sulfone 3 furnished the C18-C34 fragment.     

Synthetic studies on antibiotic A23187 I. Chiral synthons for C9-C13 and C14-C20

Chiral synthons $\text{3}$ and $\text{4}$ for the synthesis of antibiotic A23187 $\text{1}$ were prepared from methyl α-D-glucopyranoside.     

Halichondrin B: synthesis of the C1-C22 subunit

[Reaction: see text]. Two efficient routes to the C1-C22 subunit of halichondrin B are described. The cage ketal 7, which contains 11 asymmetric centers embedded within the ABCDEF-ring framework, was assembled from (+)-conduritol E (27) in 18 steps and 4% overall yield. In a separate route, 7 was also synthesized in 18 steps and 2% overall yield from a derivative of alpha-d-glucoheptonic acid gamma-lactone (62). While the former route installs the fully elaborated C-ring endowed with the correct C12 stereochemistry early in the synthesis, the latter features a late-stage introduction of the C12 stereocenter during the ultimate one-pot Michael addition/ketalization cascade to form the CDE-ring system of the cage. The importance of the C12 stereocenter to the crucial ketalization event is discussed through comparison of these two strategies.     

Synthetic studies on apoptolidin: synthesis of the C12-C28 fragment via a highly stereoselective aldol reaction

The stereoselective and convergent synthesis of the C12-C28 segment 2 of the apoptosis inducing macrolide antibiotic, apoptolidin (1), is described. The synthesis involves a highly stereoselective tin(II)-mediated aldol reaction between the C17-C22 ethyl ketone 3 and the C23-C28 aldehyde 4 as the key step.     

Macrocyclization studies and total synthesis of cyclomarin C, an anti-inflammatory marine cyclopeptide

The studies on macrocyclization at possible sites toward the total synthesis of cyclomarin C are described. The results showed that both Trp and Phe derivatives involved in the target could not be the terminals of the final linear peptide precursors. Additionally, preparation of corresponding dipeptides with an N-methyl amide bond is not favorable in the synthesis of linear precursors. Site d was finally proved a proper site for the cyclopeptide formation, and the corresponding head-to-tail macrocyclization was achieved under mild conditions and gave repeatable and satisfactory yields.     

Synthesis of the C1-C20 and C15-C27 segments of aplyronine A

The synthesis of C1-C20 and C15-C27 segments of Aplyronine A is described. Oxidative cleavage of cyclic vinyl sulfones has been used to prepare key fragments of Aplyronine A. Key precursors are united by Horner-Wadsworth-Emmons and Julia-Kociensky olefination for the respective elaboration of the C1-C20 and C15-C27 segments.