Enantioselective total synthesis of the antitumor macrolide rhizoxin D

The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9) fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate ultimately derived from gamma-butyrolactone. The central core of rhizoxin D was prepared via a chiral resolution/asymmetric aldol protocol. Several methods for the generation of the polyene fragment were explored, and the side-chain was ultimately prepared from serine in six steps. The unification of the left and right wings of the molecule was achieved using a one-step olefination protocol, and the macrocyclization was carried out using a Horner-Emmons olefination at the C(2)-C(3) olefin.     

Stereoselective total synthesis of antitumor macrolide (+)-rhizoxin D

[structure: see text] A convergent, stereoselective total synthesis of the macrolide antitumor agent rhizoxin D is described. (+)-DIPCl-promoted asymmetric aldol reaction, Evans-Tishchenko 1,3-diol synthesis, modified Julia coupling, and Horner-Wadsworth-Emmons reactions are featured.     

A concise total synthesis of the lichen macrolide (+)-aspicilin

The total synthesis of the polyhydroxylated macrolide (+)-aspicilin 5 is described using as a key step a highly diastereoselective allylation of aldehyde 6 with the uniquely functionalized allylstannane 1. (+)-Aspicilin is obtained in 18 steps and 10% overall yield. [structure: see text]     

Toward the synthesis of macrolide aspergillide D

Stereoselective synthesis of 16-membered macrocyclic core of marine natural product, Aspergillide D is described using linear strategy. The salient features of this synthetic study include the Sharpless asymmetric kinetic resolution followed by regioselective ring-opening reaction of corresponding epoxide to establish the stereo centers and ring-closing metathesis (RCM) by Grubbs'-II catalyst for the construction of macrocyclic ring.     

Stereoselective synthesis of the C1-C10 fragment of rhizoxin D

A novel approach towards the synthesis of the C1-C10 fragment of the biologically active antimitotic agent rhizoxin D is described. The synthesis involves a stereoselective Michael addition reaction of lithium diallyl cuprate with an α,β-unsaturated six membered lactone.     

Asymmetric total synthesis and absolute stereochemistry of the neuroactive marine macrolide palmyrolide A

The first asymmetric total synthesis and determination of the absolute configuration for the neuroactive marine macrolide palmyrolide A is described. The highlight of the synthesis is macrocyclization via trans-enamide formation catalyzed by copper(I) iodide and cesium carbonate. Comparison with the authentic spectral data confirms the synthesis of (+)-ent-palmyrolide A.     

Enantioselective formal total synthesis of the antitumor macrolide bryostatin 7

A new enantioselective synthesis of Masamune's AB fragment (1) for bryostatin 7 is described. Key steps in the new route include a Meerwein-Ponndorf-Verley reduction to set the O(7) stereocenter and an alkylative union between the dithiane 6 and iodide 5 to construct the C(9)-C(10) bond. Because we have previously published a synthesis of Masamune's C-ring phenyl sulfone 2, our new route to 1 constitutes a formal total synthesis of bryostatin 7; it also corrects the previously reported spectral data for 1 in CDCl3.     

Enantioselective total synthesis of macrolide antitumor agent (-)-lasonolide A

[structure: see text] An enantioselective total synthesis of (-)-lasonolide A is described. The upper tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The bicyclic isooxazoline led to the tetrahydropyran ring as well as the quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a catalytic asymmetric hetero-Diels-Alder reaction as the key step. Three stereocenters were enantioselectively installed in this single step reaction.     

First stereoselective total synthesis of antibiotic macrolide Berkeleylactone F

The first stereoselective total synthesis of antibiotic macrolide Berkeleylactone F is described. The synthetic sequence notably features Sharpless kinetic resolution to access chiral epoxide followed by its regioselective ring-opening reaction, Sharpless asymmetric reaction and ring-closing metathesis.     

A concise stereoselective formal total synthesis of the cytotoxic macrolide (+)-Neopeltolide via Prins cyclization

A convergent and highly stereoselective formal total synthesis of the naturally occurring, cytotoxic 14-membered macrolide neopeltolide has been achieved via two Prins cyclizations.     

Enantioselective total synthesis of the proposed structure of macrolide iriomoteolide-1b

An enantioselective total synthesis of the proposed structure of macrolide iriomoteolide-1b has been achieved by a convergent protocol, which was featured by an enantioselective organocatalytic transfer hydrogenation of enal, a Julia-Kocienski olefination to establish the C15-C16 E-olefin moiety, a Kulinkovich reaction associated with cyclopropyl-allyl rearrangement to produce allyl stannane and ytterbium triflate and carboxylic acid promoted allylation between allyl stannane and aldehyde with tertiary alcohol at the α-position. The construction of macrolide 2 was realized by the successful implementation of RCM utilizing 5 mol % Grubbs’s second generation catalyst at room temperature with E-isomer as a single product.     

Total synthesis of rhizoxin D,a potent antimitotic agent from the fungus Rhizopus chinensis

Rhizoxin D (2) was synthesized from four subunits, A, B, C, and D representing C3-C9, C10-C13, C14-C19, and C20-C27, respectively. Subunit A was prepared by cyclization of iodo acetal 21, which set the configuration at C5 of 2 through a stereoselective addition of the radical derived from dehalogenation of 21 at the beta carbon of the (Z)-alpha,beta-unsaturated ester. Aldehyde 29 was obtained from phenylthioacetal 24 and condensed with phosphorane 30, representing subunit B, in a Wittig reaction that gave the (E,E)-dienoate 31. This ester was converted to aldehyde 33 in preparation for coupling with subunit C. The latter in the form of methyl ketone 55 was obtained in six steps from propargyl alcohol. An aldol reaction of 33 with the enolate of 55 prepared with (+)-DIPCl gave the desired beta-hydroxy ketone 56 bearing a (13S)-configuration in a 17-20:1 ratio with its (13R)-diastereomer. After reduction to anti diol 57 and selective protection as TIPS ether 58, the C15 hydroxyl was esterified to give phosphonate 59. An intramolecular Wadsworth-Emmons reaction of aldehyde 62, derived from delta-lactone 60, furnished macrolactone 63, which was coupled in a Stille reaction with stannane 68 to give 2 after cleavage of the TIPS ether.     

Studies in macrolide synthesis: A concise asymmetric synthesis of a macrolide intermediate for the erythronolides.

The enantiomerically-pure 14-membered ring macrolide 1 is prepared in 14 steps from the racemic aldehyde 4, Z=SPh. The C₂-C₄ and C₈-C₁₀ stereorelationships in 1 are controlled in a single step by an Evans aldol condensation with (±)-4. Macrolactonisation, 23 → 1, takes place in high yield (91%).     

A convergent synthesis of the macrolide core of migrastatin

We describe an efficient synthesis of the 14-membered macrolide core 2 of migrastatin via key intermediate 3 employing a diastereoselective aldol condensation, Lewis acid mediated diastereoselective addition and an exclusive (Z)-olefination sequence. Yamaguchi esterification of the key intermediate 3 followed by ring-closing metathesis (RCM) produced macrolide 2 with high selectivity and good yield.     

Improved biomimetic total synthesis of D,L-stephacidin A

The direct conversion of beta-hydroxyproline derivatives into 5-hydroxypyrazin-2(1H)-ones under Mitsunobu conditions has been discovered to be a general biomimetic protocol generating IMDA intermediates and has been applied to the concise, biomimetic total syntheses of D,L-stephacidin A and D,L-brevianamide B.     

A chiron approach to the total synthesis of (+)-aculeatin D

A synthesis of natural aculeatin D has been achieved, with the key stereogenic centers taken from inexpensive and readily available D-xylose. In elaboration of D-xylose into a desired form readily applicable in synthesis a previously misinterpreted and overlooked abnormal selectivity in hydroxyl protection was noticed and exploited. Protocols were developed for monotosylation of a triol insoluble in CH2Cl2 and "freezing" the less stable isomer (aculeatin D) at the PIFA-mediated oxidative spirocyclization, respectively. An unexplained deprotonation at a benzyl protecting group by a thermodynamically more stable dithiane carbanion in the literature was also addressed.     

A carbohydrate-based approach for the total synthesis of aculeatin D and 6-epi-aculeatin D

A concise approach for the total synthesis of aculeatin D and 6-epi-aculeatin D employing differentially protected anti, anti-1,3,5-triol alkyne prepared from alpha-D-glucoheptonic-gamma-lactone derivative is documented. Phenol protecting group manipulation for selective O-debenzylation during the hydrogenation of the diyne intermediate and one-pot phenolic oxidation with concomitant spiroketalization highlight the accomplished total synthesis.