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 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.     

Studies on the synthesis of phorboxazole B: stereoselective synthesis of the C28-C46 segment

A stereoselective synthesis of C28-C46 segment of phorboxazole B is described. Key features of the synthetic route involved the use of 1,3-asymmetric induction of Mukaiyama aldol reaction to construct the stereogenic center at C35, and the employment of metalated oxazole chemistry to prepare the ketal 6.     

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.     

A stereoselective synthesis of the C(1)-C(16) fragment of the bryostatins

A synthesis of the C(1)-C(16) fragment of the brysostatins has been developed. Key steps are the stereoselective copper(I) catalysed addition of allylmagnesium bromide to an alkynyl ester, a condensation of a βγ-unsaturated aldehyde with a ketophosphonate, and the formation of the B-ring under mild conditions by stereoselective intramolecular conjugate addition.     

Studies directed toward the synthesis of rhizopodin: stereoselective synthesis of the C1-C15 fragment

A stereoselective synthesis of the C1-C15 fragment of a G-actin binding natural macrodiolide, rhizopodin was achieved using, as key steps, highly stereoselective acetate aldol reactions to build the C1-C7 fragment, one pot oxazole synthesis and an asymmetric Keck allylation reaction to build the C8-C15 fragment and finally, a Stille reaction to couple both the fragments.     

A highly stereoselective synthesis of the C10-C23 fragment of (-)-dictyostatin

A highly stereoselective synthesis of the C10-C23 fragment of (-)-dictyostatin has been achieved using a Carreira alkynylation and a Marshall-Tamaru allenylzinc addition as key steps.     

Synthetic studies on neomarinone: practical and efficient stereoselective synthesis of the side chain

A practical and efficient stereoselective synthesis of the side chain of neomarinone is reported. The synthesis was achieved in six steps (41% overall yield) from 2-methyl-2-cyclohexenone. The key step is a novel stereoselective 1,4-conjugate addition/enolate alkylation by an epoxide-opening reaction.     

Studies on the total synthesis of sanglifehrin A: stereoselective synthesis of the C(29)-C(39) fragment

A highly stereoselective synthesis of the C(29)-C(39) fragment of the potent immunosuppressant sanglifehrin A has been accomplished by a sequence involving 16 steps (18% overall yield) from N-propionyloxazolidinone 9. Key steps are a diastereoselective hydroboration, and a diastereoselective epoxidation of an allylic alcohol followed by a 1,5-anti boron-mediated aldol reaction of methyl ketone 4 with chiral aldehyde 5.     

A stereoselective synthesis of the C11-C19 fragment of (+)-peloruside A

A new route to the synthesis of the C11-C19 fragment of peloruside A is described, which includes an aldol reaction with ethyl acetoacetate, β-hydroxyl-directed reduction of β-hydroxy ketone, as well as methylation of C13 hydroxyl moiety in the system of MeI-Ag₂O-MgSO₄-CH₂Cl₂.     

Studies toward the total synthesis of irumamycin: stereoselective preparation of the C(15)-C(27) segment via two-directional chain synthesis

The basic structure of the C(15)-C(27) part of irumamycin (1) was synthesized. Stereoselective assembly of C16, 17, 22, and an extra C21 stereocenter was achieved by two-directional Brown’s asymmetric allyl boration. Group selective PMP acetal formation and oxidative cleavage of vinyl group facilitated the differentiation of the ends of a two-directionally synthesized chain.     

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 toward pectenotoxin 2. Part I. Stereocontrolled access to the C10-C22 fragment

A highly stereocontrolled and efficient synthesis for a fully functionalized C 10-C 22 fragment of pectenotoxin 2 is described using a convergent sequence involving a stereoselective methylation of beta-hydroxyketone as a key step.     

Toward the total synthesis of phorboxazole B: an efficient synthesis of the C20-C46 segment

An efficient synthesis of the C20-C46 segment of phorboxazole B is described. The key steps involved Hg(OAc)(2)/I(2)-induced cyclization to construct the cis-tetrahydropyran moiety, the coupling of the metalated 2-methyloxazole 7 with lactone 6, and Julia olefination to furnish the conjugated diene moiety.     

Studies toward the total synthesis of tedanolide: stereoselective synthesis of the C(8)-C(17) segment

The stereoselective synthesis of the C(8)-C(17) sub-unit (−)-5 of tedanolide (1), which involves iterative Evans aldol reactions as the key steps, is described.     

A stereoselective synthesis of the C(3)-C(13) and C(14)-C(24) fragments of macrolactin A

Synthetic studies towards(he C(3)-C(13)and C(14)-C(24)segments(3,4)of the potent antiviral and antitumor compound macrolactin A(1)are presented.Compound 3 was constructed via a convergent and facile approach,exploiting Wittig olefination to generate the sensitive E,Z-diene moiety.Compound 4 was synthesized from the chiral-pod derived sul-fone 39a via an o-alkylation-desulfonation reaction sequence.Cu(Ⅱ)-catalyzed coupling of a Grignard reagent with an al-lylic bromide and Julia olefination were also investigated for the preparation of compound 4.     

Short synthesis of the C16-C28 polyketide fragment of apoptolidin A aglycone

Starting from (E,E)-1-[(1R)-(phenylethyl)oxy]-2-methylpenta-1,3-diene and triethylsilyl enol ether of butanone rapid access to Koert's advanced C10-C28 polyketide fragment of apoptolidin A is now possible.     

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 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.     

Approach toward the total synthesis of orevactaene. 2. Convergent and stereoselective synthesis of the C18-C31 domain of orevactaene. Evidence for the relative configuration of the side chain

The synthesis of the C18-C31 subunit of orevactaene (1) in an enantioselective and convergent manner is reported. Four chiral centers in the structure (i.e., carbons 23, 25, 32, and 33) have unknown configuration; thus, a modular approach has been devised to link the two stereocenter-containing ends of the structure together via a trisubstituted olefin template to ultimately produce all possible diastereomers of the target. Keys to the success of this approach include (i) an efficient synthesis of four diastereomeric hydrophobic tails (C22-C29) of the molecule with two stereogenic centers at C23 and C25; (ii) the synthesis of three stereodefined trisubstituted olefins 37, 38, and 43 using palladium(0)-catalyzed hydrometalation and metallometalation; and (iii) the convergent assembly of the aforementioned sections by a 'one-pot' lithium/halogen exchange, boron/lithium exchange, borate ester saponification, and Suzuki cross-coupling followed by oxidative deprotection. The sequence provided the desired aldehydes 49 and 50 as single isomers in good yields. Compiled spectroscopic data from the literature and present work provides evidence that the relative configuration of the methyl groups in the side chain of orevactaene may be 1,3-syn, which will be confirmed when the total synthesis has been completed. These results have paved the way for a parallel synthesis approach to prepare all 16 possible stereoisomers of orevactaene so that the relative and absolute stereochemistry of this compound can be determined.