A chemoenzymatic total synthesis of the undecenolide (-)-cladospolide B via a mid-stage ring-closing metathesis and a late-stage photo-rearrangement of the E-isomer

A sixteen-step synthesis of the twelve-membered macrolide (-)-cladospolide B(2) from the microbially-derived cis-1,2-dihydrocatechol 5 is described. Pivotal steps include the ring-closing metathesis (RCM) of diene 12 to give the ten-membered lactone 13 together with small amounts of the head-to-tail and head-to-head dimers 14 and 15, respectively. The saturated lactol 19 derived from compounds 13 and 14 readily participates in a Wadsworth-Horner-Emmons reaction to give the E-configured alpha,beta-unsaturated ester 20. This last compound is then converted, through application of a Yamaguchi lactonisation reaction on the derived acid 22, into the macrolide 23 which, upon removal of the bis-acetal protecting group, affords compound 24, the E-isomer of target 2. Irradiation of a benzene solution of compound 24 results in its partial photoisomerisation to (-)-cladospolide B(2).     

Total synthesis of (-)-callipeltoside A

A total synthesis of (-)-callipeltoside A (1) has been achieved. The core macrocycle was made via a dual macrolactonization/pyran hemiketal formation reaction, developed to circumvent issues related to the reversible nature of acylketene formation from β-keto lactone substrates. Initial approaches to the core of the natural product that revolved around ring-closing metathesis (RCM) and relay ring-closing metathesis (RRCM) reactions are also described.     

Studies towards the total synthesis of Phostriecin

A synthetic approach toward the phostriecin, an antitumor natural product is described. The key features of the present synthesis are Wittig reaction, synthesis of homoallylic alcohol using Brown’s protocol (alkoxyallylboration) and RCM for the creation of unsaturated lactone moiety of phostriecin.     

Total synthesis of aspercyclide C

The first total synthesis of (+)-aspercyclide C (1) is reported using a kinetically controlled RCM reaction to form the 11-membered, unsaturated lactone ring of this bioactive diaryl ether macrolide.     

Synthesis of novel, simplified, C-7 substituted eleutheside analogues with potent microtubule-stabilizing activity

The synthesis of a number of novel, simplified, C-7 substituted eleutheside analogues with potent tubulin-assembling and microtubule-stabilizing properties is described, using ring closing metathesis as the key-step for obtaining the 6-10 fused bicyclic ring system. The RCM precursors were synthesized starting from aldehyde 3 [prepared in six steps on a multigram scale from R-(−)-carvone in 30% overall yield] via multiple stereoselective Hafner-Duthaler allyltitanations and/or Brown allylborations. ‘Second generation’ RCM-catalyst 15 gave the desired ring closed ten-membered carbocycles as single Z stereoisomers in good yields. The RCM stereochemical course (100% Z) is likely to reflect thermodynamic control. Molecular mechanics and semi-empirical calculations also show that the Z stereoisomers of these ten-membered carbocycles are consistently more stable than the E. The crucial role of the homoallylic and allylic substituents and of their protecting groups for the efficiency of the RCM reactions is discussed. In particular, we have found that p-methoxyphenyl (PMP) protected allylic alcohols, the products of a stereoselective oxyallylation, are compatible with the RCM reaction and give better yields than the corresponding free allylic alcohols. One of the simplified analogues of the natural product (44, lacking inter alia the C-4/C-7 ether bridge) retains potent microtubule-stabilizing activity. However, the cytotoxicity tests did not parallel the potent tubulin-assembling and microtubule-stabilizing properties: limited cytotoxicity was observed against three common tumor cell lines (human ovarian carcinoma, human colon carcinoma and human leukemia cell lines, IC₅₀ in the μM range), approximately two orders of magnitude less than paclitaxel (IC₅₀ in the nM range). The mechanism of cell cycle arrest induced by compound 44 is similar to that obtained with paclitaxel.     

Synthesis of the floresolide B hydroquinone lactone core using ring-closing metathesis

The hydroquinone lactone core of the floresolides was synthesized through a ring-closing metathesis (RCM) approach. Optimal RCM efficiency was obtained at higher reaction concentration. An unexpected Lewis acid-promoted rearrangement of the hydroquinone and other observations relevant to on-going total synthesis efforts are discussed.     

Catalytic enantioselective synthesis of naturally occurring butenolides via hetero-allylic alkylation and ring closing metathesis

An efficient catalytic asymmetric synthesis of chiral γ-butenolides was developed based on the hetero-allylic asymmetric alkylation (h-AAA) in combination with ring closing metathesis (RCM). The synthetic potential of the h-AAA-RCM protocol was illustrated with the facile synthesis of (-)-whiskey lactone, (-)-cognac lactone, (-)-nephrosteranic acid, and (-)-roccellaric acid.     

Stereoselective synthesis and structural correction of the naturally occurring lactone stagonolide G

A convergent synthesis of the structure proposed for the naturally occurring lactone stagonolide G is described. All three stereocenters were created with the aid of asymmetric Brown allylations. The lactone ring was built by means of a ring-closing metathesis (RCM). The synthetic and the natural compound differed in their spectral properties. A new structure is now proposed for stagonolide G and demonstrated by means of a chemical transformation.     

A rapid formal synthesis of the macrolide (−)-A26771B

(−)-A26771B, a novel 16-membered macrolide with antibiotic activity, has been formally synthesized. In the synthesis ruthenium catalyzed ring-closing olefin metathesis (RCM) was used as a key reaction to construct the lactone ring.     

Highly convergent three component benzyne coupling: the total synthesis of ent-clavilactone B

The first total synthesis of (+)-clavilactone B, a potent antifungal agent and novel tyrosine kinase inhibitor, is described. The absolute configuration of clavilactones has been unambiguously established by using Sharpless asymmetric epoxidation to generate the enantiomerically pure substrate. The strategy highlights the use of a powerful and convergent three-component benzyne coupling with a methylallyl Grignard and a chiral epoxy-aldehyde to generate two C-C bonds and install the carbon skeleton of clavilactone. Oxidative lactonization, ten-membered ring construction by ring closing metathesis, and oxidation gave clavilactone B.     

Organocatalytic stereoselective synthesis of passifloricin A

The enantioselective synthesis of passifloricin A has been achieved in high diastereomeric excess. The 1,3-polyol moiety was constructed by iterative proline-catalyzed sequential α-aminoxylation and Horner-Wadsworth-Emmons (HWE) olefination of aldehydes while the synthesis of lactone moiety was achieved by ring-closing metathesis (RCM).     

New strategy for the total synthesis of macrosphelides a and B based on ring-closing metathesis

[reaction: see text] A new total synthesis of macrosphelides A and B using ring-closing metathesis (RCM) as a macrocyclization step is described. The substrate of the RCM could be synthesized from readily available chiral materials, methyl (S)-(+)-3-hydroxybutyrate and methyl (S)-(-)-lactate, with a high efficiency. The RCM proceeded in the presence of Grubbs' Ru-complex, providing a new effective synthetic route to these natural products.     

Asymmetric total synthesis of halicholactone.

The asymmetric total synthesis of the marine metabolite, halicholactone 1, is described. The bisallylic triol 6 with three chiral centers at C8, C12, and C15 was constructed by [2,3]-sigmatropic rearrangement of the sulfoxide 18, which was prepared stereoselectively using the chirality of (diene)Fe(CO)3 complexes. Introduction of the trans-substituted cyclopropane subunit into 21 was successfully achieved using the modified regio- and stereoselective Simmons-Smith reaction. The use of RCM (ring-closing metathesis) methodology (4-->35) was pivotal for the formation of a nine-membered unsaturated lactone fragment of halicholactone 1. As this approach is flexible and stereoselective, other oxylipins could be synthesized by the protocol described herein.     

Asymmetric total synthesis of bacillariolide III, a marine oxylipin

[reaction: see text] The asymmetric total synthesis of bacillariolide III has been achieved via 15 linear steps in 14.6% overall yield. The key feature of this synthetic route involves the highly stereoselective construction of the vinyl-substituted bicyclic lactone by an intramolecular Pd(0)-catalyzed allylic alkylation and its facile conversion to the hydroxy bicyclic lactone skeleton of bacillariolide III, induced by stereoselective vinylcerium addition to the aldehyde. In addition, the (Z)-pentenoic acid was efficiently introduced by the internal hydroxy group tethered ring-closing metathesis (RCM).     

RCM/PCC oxidation strategy for synthesis of functionalized cyclic α,β-unsaturated lactones: synthesis of (+)-triacetoxygoniotriol and its diastereomers

A novel methodology leading to the synthesis of (+)-triacetoxygoniotriol 2 from d-glucose is described. Construction of the core six-membered α,β-unsaturated lactone moiety involved ring closing metathesis (RCM) followed by a PCC oxidation. Later exploiting the pseudo-symmetry of d-glucose three other diastereomers of triacetoxygoniotriol were synthesized using the developed methodology.     

Total synthesis of the phytotoxic stagonolides A and B

The chemo-enzymatic and covergent synthesis of stagonolide B and the synthesis of stagonolide A, a phytotoxic 10-membered lactone have been achieved starting from d-ribose with overall yields of 25% and 8.7%, respectively. The synthesis contained simple steps in developing three centers’ key intermediates, namely the enzymatic (Novozyme-435) resolution of a propargylic alcohol followed by macrolactonization and RCM.     

Total synthesis of (-)-okilactomycin

A highly convergent synthesis of (-)-okilactomycin is described. Key reactions of this synthesis include a strategy-level diastereoselective oxy-Cope rearrangement/oxidation sequence, a Petasis-Ferrier union/rearrangement tactic, and an efficient RCM reaction to construct the 13-membered macrocyclic ring.     

Enantioselective total synthesis of (−)-microcarpalide

The enantioselective total synthesis of the actin-targeting metabolite (−)-microcarpalide is described. Key steps include ring-closing metathesis (RCM) for the final construction of the 10-membered lactone framework and stereoselective homologation of boronic esters for the insertion of all stereocentres with the desired absolute configuration. In particular, the acidic fragment was prepared in seven steps from a suitable chiral bromomethane boronate by means of two sequential stereoselective homologations to install the two stereocentres with the correct final R stereochemistry, employing (−)-pinanediol as the chiral director. Subsequent elaboration to the required C₇ backbone entailed nucleophilic displacement with a vinyl Grignard reagent, oxidative cleavage of the boronic scaffold and protection-deprotection manipulations. Interestingly, when the tribenzyloxy diene ester resulting from DCC-mediated coupling of the two key synthons was subjected to RCM in the presence of Grubbs' catalyst, the reaction proceeded stereoselectively to yield the desired trans oxecin-2-one, albeit with poor conversion.     

Stereoselective synthesis of cryptomoscatone D2

Cryptomoscatone D2 was synthesized stereoselectively from trans-cinnamaldehyde. The synthesis of the triol frame work relied on the creations of the stereocenters independently by utilizing double Maruoka allylations and Sharpless epoxidation. The lactone moiety was constructed by RCM reaction.