Stereoselective synthesis of the C14-C24 degraded fragment of symbiodinolide

Symbiodinolide is a polyol macrolide isolated from the marine dinoflagellate Symbiodinium sp. in 2007. The C14-C24 fragment of symbiodinolide possessing the 17R/18R/21R absolute configuration, which was obtained as one of the degraded products of symbiodinolide, was synthesized stereoselectively from cis-2-butene-1,4-diol. The detailed comparison of the synthetic product with the degraded product in the spectroscopic data confirmed that the stereostructure of the C14-C24 fragment was 17R, 18R, and 21R.     

Stereocontrolled synthesis and structural confirmation of the C14-C24 degraded fragment of symbiodinolide

The C14-C24 fragment of symbiodinolide possessing the 17R/18R/21R absolute configuration, which was obtained as one of the degraded products of symbiodinolide, and its diastereomer possessing the 17R/18S/21R absolute stereochemistry were synthesized stereoselectively from cis-2-butene-1,4-diol, respectively. The detailed comparison of the synthetic products with the degraded product in the spectroscopic data confirmed unambiguously that the stereostructure of the C14-C24 fragment was 17R, 18R, and 21R.     

Towards a simplified peloruside A: synthesis of C1-C11 of a dihydropyran analogue

A simplified analogue of the C1-C11 fragment of peloruside A has been synthesised starting from a monoprotected 2,2-dimethylpropane-1,3-diol. Oxidation, asymmetric allylation and acryloylation provided a substrate for ring-closing metathesis to a δ-lactone. Reduction, acylation and homologation with trimethyl(vinyloxy)silane provided a protected C3-C11 analogue in a stereoisomer manner. Introduction of the C1-C2 fragment and incorporation of the 2,3-syn stereochemistry was achieved by a boron-mediated Evans aldol reaction.     

Synthesis of amphidinolide E C10-C26 fragment

The key C10-C26 fragment in a total synthesis of (-)-amphidinolide E has been prepared from an oxolane-containing C10-C17 segment (9, derived from L-glutamic acid) via a Julia-Kocienski reaction with aldehyde 3, followed by a Sharpless AD to obtain the desired diol. The C22-C26 fragment was installed by means of an efficient Suzuki-Molander coupling, with an organotrifluoroborate reagent (4, arising from a cross-metathesis reaction between a vinylboronate and 2-methyl-1,4-pentadiene).     

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.     

Synthetic studies on reidispongiolide A, an actin-depolymerizing marine macrolide: synthesis of C11-C22 and C23-C35 segments

The C11-C22 and C23-C35 segments 2 and 3 of reidispongiolide A (1), an actin-depolymerizing marine macrolide, were synthesized enantioselectively in 12 steps from (R)-glycidyl trityl ether and in 12 steps from chiral ketone 15, respectively.     

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 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.     

Stereoselective synthesis and absolute configuration of the C33-C42 fragment of symbiodinolide

Cross-metathesis of methyl ester which was prepared from symbiodinolide with ethylene was performed to give the C33-C42 degraded fragment. This fragment was estimated to be (36S,40S)-diol by the modified Mosher method. Stereoselective synthesis of the (36S,40S)-diol and its diastereomer (36R,40S)-diol was achieved from l-aspartic acid. Synthetic bis-(S)- and (R)-MTPA esters which were derivatized from the (36S,40S)-diol exhibited spectroscopic data identical with those of bis-(S)- and (R)-MTPA esters derived from the degraded product. Thus, the absolute stereochemistry of the C33-C42 fragment was elucidated to be (36S,40S).     

Stereoselective synthesis of C1-C9 and C9-C17 fragments of (+)-13-deoxytedanolide

An efficient and highly stereoselective asymmetric synthesis of C1-C9 and C9-C17 fragments of (+)-13-deoxytedanolide have been achieved. Utilization of desymmetrization technique to prepare the triol with five stereogenic centers, regioselective Sharpless asymmetric dihydroxylation, Evans' aldol reaction, chiral methylation, and Wittig olefination are highlights of the synthesis.     

Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones

A highly stereocontrolled total synthesis of the 18-membered macrolide (+)-concanamycin F, a potent inhibitor of vacuolar ATPases, is described that proceeds in 5.8% yield over 26 steps. The three key fragments, C1-C13 vinyl iodide, C14-C22 vinyl stannane and C23-C28 aldehyde, were efficiently constructed using asymmetric boron-mediated aldol reactions of appropriate chiral ketone building blocks. The nature of the silyl protection of the C7/C9 hydroxyls proved to be critical for achieving macrocyclisation, with TES ethers being superior to a cyclic silylene derivative. Following a Liebeskind-Stille cross-coupling reaction between the C1-C13 vinyl iodide and C14-C22 vinyl stannane fragments to assemble the (12E,14E)-diene, a modified Yamaguchi macrolactonisation delivered the requisite 18-membered macrocyclic core. This advanced intermediate was also obtained by an alternative sequence using an esterification step to connect the C1-C13 and C14-C22 fragments followed by a Pd-catalysed intramolecular Stille reaction to install the (12E,14E)-diene. Conversion of the resulting macrocyclic intermediate into a methyl ketone then enabled a highly diastereoselective Mukaiyama aldol coupling of the derived silyl enol ether with the C13-C28 aldehyde fragment to install the fully elaborated side chain, whereby subsequent global deprotection of the resulting β-hydroxyketone under suitable conditions (TASF followed by p-TsOH) afforded (+)-concanamycin F.     

Toward a modular, bidirectional synthesis of (−)-mucocin

A convergent stereoselective synthesis of the C13-C34 fragment of (−)-mucocin is described. The salient features include (a) the bidirectional synthesis of the C-2 symmetric C13-C21 subunit, (b) regio- and stereoselective preparation of a 1,3-diol derivative from a diene activated by NBS via intramolecular nucleophilic sulfinyl group participation, (c) utilizing the self-metathesis reaction to prepare a functionalized C10 alkene, and (d) regio- and stereoselective intermolecular epoxide opening to construct the ether bond between C20 and C24. An organocatalytic α-hydoxylation has been employed to create the C4 stereogenic center of C1-C12 subunit. Attempted union of the two subunits utilizing the B-alkyl Suzuki coupling did not succeed.     

Stereochemically versatile synthesis of the C1-C12 fragment of tedanolide C

A flexible synthesis of the C1-C12 fragment of Tedanolide C has been accomplished in eight steps from 2-methyl-2,4-pentadienal. Asymmetric hydroformylation of a 1,3-diene allows for the late-stage generation of either C10 epimer with complete catalyst control. Diastereoselective addition of an isobutyryl β-ketoester dianion to an α,β-disubstituted chiral aldehyde sets the C5 stereochemistry while installing the geminal dimethyl unit. Differential protection of a syn-1,3-diol is performed as a highly efficient single-pot operation.     

Synthesis of C13-C22 of amphidinolide T2 via nickel-catalyzed reductive coupling of an alkyne and a terminal epoxide

Several stereoselective routes to the synthesis of (1S,3R)-t-butyldimethyl-(1-methyl-3-oxiranyl-propoxy)-silane (13a) were explored, and the use of Jacobsen's hydrolytic kinetic resolution to separate a mixture of diastereomeric epoxides was a key step in the shortest of these. As part of an approach to the total synthesis of amphidinolide T2 (2), this epoxide, corresponding to C17-C22 of the natural product, was successfully joined with an alkyne (C13-C16) by way of a nickel-catalyzed reductive coupling reaction.     

Total synthesis of rutamycin B and oligomycin C

The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C (2) is described. The approach relied on the synthesis and coupling of the individual spiroketal fragments 3a and 3b with the C1-C17 polyproprionate fragment 4. The preparation of the spiroketal fragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowed the introduction of the stereogenic centers prior to spiroketalization. The present work details the synthesis of the C19-C28 and C29-C34 subunits as well as their convergent assembly through an alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individual linear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, these advanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41. The requisite polypropionate fragment was assembled in a convergent manner using asymmetric crotylation methodology for the introduction of six of the nine-stereogenic centers. The use of three consecutive crotylation reactions was used for the construction of the C3-C12 subunit 32. A Mukaiyama-type aldol reaction of 35 with the chiral alpha-methyl aldehyde 39 was used for the introduction of the C12-C13 stereocenters. This anti aldol finished the construction of the C3-C17 advanced intermediate 36. A two-carbon homologation completed the construction of the polypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics was accomplished by the union of two principal fragments that was achieved with an intermolecular palladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of the individual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylic acids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchi reaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin B and oligomycin C.     

Synthesis of the C12-C24 fragment of peloruside A by silyl-tethered diastereomer-discriminating RCM

The C12-C24 fragment of peloruside A has been synthesized using, as a key step, a silyl-tethered ring closing metathesis reaction to form the C16-C17 (Z)-alkene. The metathesis reaction discriminates between diastereoisomers of the starting material. A diphenylsilyl bis-ether provides simultaneous protection for the C15 and C24 hydroxyl groups, and is expected to lead to high 1,5-anti selectivity in subsequent aldol reactions of the methyl ketone, allowing for a convergent stereoselective synthesis of peloruside A.     

Synthesis of the C22-C37 segment of prorocentin

The synthesis of the C22-C37 segment of prorocentin, isolated from the dinoflagellate Prorocentrum lima, was achieved. Because the relative stereochemical relationship between C26 and other stereocenters (C28/C31/C32 established as R*/R*/R*) in the C22-C37 region of natural prorocentin has not yet been determined, both epimers at C26 of the C22-C37 segment were selectively constructed. The synthesis was based on a 5-exo epoxide ring opening reaction to form an oxolane (E-ring), Brown asymmetric methallylation to install the C26-stereocenter, acryloylation of the resulting alcohol, and ring-closing olefin metathesis to establish the Z-olefin at C23/C24.     

A cross metathesis approach to the synthesis of the C11-C23 fragment of (−)-16-normethyldictyostatin

The synthesis of the C11-C23 fragment 2 of (−)-16-normethyldictyostatin has been achieved by cross metathesis between two olefinic fragments 4 and 5 followed by a reduction of the double bond at C16-C17. Both the olefinic fragments are easily synthesized in a diastereoselective manner from the common precursor alcohol 7.     

A formal synthesis of the auriside aglycon

A highly convergent formal synthesis of the auriside aglycon was achieved. An indene-based thiazolidinethione chiral auxiliary was used for the construction of both the C1-C9 and C10-C17 fragments via acetate aldol reactions. A Meinwald reaction was utilized to install the stereocenter at C2, and a conjugated addition to an ynone was used to construct the C9-C11 enone.     

Total synthesis of (−)-dictyostatin, a microtubule-stabilising anticancer macrolide of marine sponge origin

An efficient convergent synthesis of the anticancer marine macrolide (−)-dictyostatin is described that proceeds in 4.6% yield over 27 steps. Most of the stereocentres were configured using substrate control, making use of a common building block to install the C12-C14 and C20-C22 stereotriads, with a lactate boron aldol reaction employed to construct a C4-C10 β-ketophosphonate as utilised in the pivotal Still-Gennari HWE coupling step with a fully elaborated C11-C26 aldehyde. Following introduction of the (2Z,4E)-dienoate, a modified Yamaguchi macrolactonisation and deprotection delivered the requisite 22-membered macrocyclic lactone.