Stereoselective synthesis of the C(1)-C(19) fragment of tetrafibricin

[reaction: see text] A stereoselective synthesis of the C(1)-C(19) fragment of tetrafibricin has been accomplished via a highly diastereoselective double allylboration reaction of 6-8 and an iodonium ion promoted urethane cyclization for the installation of the C(15) alkoxy function in 3.     

Enantio- and diastereoselective additions to aldehydes using the bifunctional reagent 2-(chloromethyl)-3-(tributylstannyl)propene: application to a synthesis of the C16-C27 segment of bryostatin 1

[reaction: see text] Reactions of the bifunctional allylstannane 2-(chloromethyl)-3-(tributylstannyl)propene with aldehydes have been examined. These generally occur in high yields using Lewis acid promoters and the products can be isolated and purified without incident. Good yields and high enantioselectivities are also realized in catalytic asymmetric allylations (CAA reactions) using the previously described BITIP catalyst system. Protection of the free hydroxyl can be accomplished without cyclization to the derived tetrahydrofuran, although this transformation is also facile. The utility of the incorporated allyl chloride functionality allows for the obvious use of such products in reactions with nucleophiles. Use of these products in a less obvious connective strategy is demonstrated in the synthesis of the C12-C27 segment of bryostatin 1 where a connective, or "lynchpin", double-allylation process was employed. The beta-hydroxy allyl chloride obtained from an initial chelation-controlled allylation of aldehyde 16 was converted to allylstannane 19 and applied in a second allylation reaction, thus allowing for a highly convergent synthesis of the bryostatin C ring backbone in a stereoselective fashion.     

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.     

Synthesis of C1-C20 and C21-C40 fragments of tetrafibricin

Efficient syntheses of suitably functionalized top and bottom fragments of tetrafibricin are described. The bottom fragment is prepared by two consecutive Kocienski-Julia couplings, while the top fragment synthesis features a dithiane alkylation and a Horner-Wadsworth-Emmons reaction.     

Enantioselective synthesis of 1,5-anti- and 1,5-syn-diols using a highly diastereoselective one-pot double allylboration reaction sequence

Highly diastereo- and enantioselective syntheses of 1,5-disubstituted (E)-1,5-anti-pent-2-endiols 1 and (Z)-1,5-syn-pent-2-endiols 2 have been achieved via the one-pot coupling of two different aldehydes with either (E)-gamma-(1,3,2-dioxaborinanyl)-allyl]diisopinocampheylborane (4) or (E)-gamma-(4,4,5,5-tetraphenyl-1,3,2-dioxaborolanyl)allyl]diisopinocampheylborane (11), respectively. The indicated diols 1 and 2 are obtained in 63-95% yield with 89-96% ee and >/=20:1 diastereoselectivity in all cases. The bifunctional gamma-boryl-substituted allylborane reagents 4 and 11 were generated in situ by the hydroboration of allenes 3 and 10 with diisopinocampheylborane. The keys to the success of this method are the excellent stereocontrol in the allylboration step leading to 5 and the corresponding substituted methallylboronate derived from 11, the stereospecificity of the subsequent allylboration reaction of the substituted methallylboronate intermediates, and the ability of the diol auxiliary to induce equatorial or axial placement of the substituent alpha to boron in transition states 7 and 8.     

Model studies on a diastereoselective synthesis of the C(33)-C(37) fragment of Amphotericin B

A new, short and highly diastereoselective synthetic route aiming at the C(33)-C(37) fragment of Amphotericin B has been developed. Studies with a model aldehyde (benzaldehyde) have given very promising results: the desired stereochemistry of all four stereocenters of the target molecule has been achieved with high diastereoselection. The stereochemistry of three key intermediates and the target segment has been confirmed by X-ray crystallography.     

Concerning the synthesis of the tedanolide C(13)-C(23) fragment via anti-aldol reaction

Synthesis of C(13)-C(23) aldehyde 4, an important intermediate in a planned total synthesis of tedanolide, is described. The stereoselectivity of the key anti-aldol reaction of aldehyde 5 and ketone 6 (en route to 4) perfectly tracks the enantiomeric purity of 5. It is demonstrated that aldehyde 24, a precursor of 5, undergoes facile epimerization during a Swern oxidation and stabilized ylide olefination sequence.     

Development of a Double Allylboration Reagent Targeting 1,5-syn-(E)-Diols: Application to the Synthesis of the C(23)-C(40) Fragment of Tetrafibricin

Interest in the synthesis of the C(23)-C(40) fragment 2 of tetrafibricin prompted us to develop a new method for the synthesis of 1,5-syn-(E)-diols. Toward this end, the kinetically controlled hydroboration of allenes 6, 33, ent-39, 42, and 45 with the Soderquist borane 25R were studied. Tetrabutylammonium allenyltrifluoroborate 45 gave superior results and was utilized in a double allylboration sequence with two different aldehydes to provide the targeted 1,5-syn-(E)-diols in generally high yields (72-98%), and with high enantioselectivity (>95% ee), diastereoselectivity (dr >20:1), and (E)/(Z) selectivity (>20:1). This new method was applied to the synthesis of the C(23)-C(40) fragment 2 of tetrafibricin.     

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.     

Enantio- and diastereoselective synthesis of (R,R)-beta-methoxytyrosine

The nonproteinogenic amino acid (2R,3R)-beta-methoxytyrosine, a constituent of several cyclic depsipeptide natural products, was synthesized in protected form (8) from a readily available cinnamate ester in four steps and 62% overall yield with a greater than 28:1 er and 19:1 dr. This method provides a highly efficient, enantio- and diastereoselective synthesis of an important amino acid.     

Synthesis of the C(1)-C(25) fragment of amphidinol 3: application of the double-allylboration reaction for synthesis of 1,5-diols

[structure: see text] A synthesis of the C(1)-C(25) fragment of amphidinol 3 is described. The synthesis features two applications of double allylboration reaction methodology for the highly stereoselective synthesis of 1,5-diol units in the C(1)-C(15) segment.     

Enantio- and diastereoselective synthesis of erysulfone and erysulfoxide

The natural products erysulfone (1) and erysulfoxide (2) have been prepared from (+)-muconolactone (3). This synthetic work has substantiated the earlier, probable assignment of absolute configuration of these targets.     

Enantio- and diastereoselective synthesis of syn-beta-hydroxyallylsilanes via a chiral (Z)-gamma-silylallylboronate

syn-beta-Hydroxyallylsilanes of general structure 11 and 28 are prepared in 50-86% yield and 91-95% ee (for aliphatic aldehydes; 50% ee for benzaldehyde) via the BF(3).Et(2)O-promoted gamma-silylallylboration reactions, using reagents 14 and 15.     

Stereoselective synthesis of the C15-C26 fragment of the antitumor agent (-)-dictyostatin

The synthesis of the C15-C26 fragment of (-)-dictyostatin is reported in 10 steps and 28% overall yield. The key steps are the two stereoselective sulfoxide-directed processes: a Reformatsky-type reaction and a β-keto sulfoxide reduction.     

C(21)-C(40) of tetrafibricin via metal catalysis: beyond stoichiometric chiral reagents, auxiliaries, and premetalated nucleophiles

The C(21)-C(40) fragment of fibrinogen receptor inhibitor tetrafibricin was prepared in 12 steps from propane diol (longest linear sequence). In this approach, 6 C-C bonds are formed via asymmetric iridium catalyzed transfer hydrogenative carbonyl allylation and 2 C═C bonds are formed via Grubbs olefin cross-metathesis.     

Gram scale synthesis of the C(18)-C(34) fragment of amphidinolide C

The synthesis of the C(18)-C(34) fragment of amphidinolide C has been achieved via two routes, culminating in both the shortest (11 steps) and highest yielding (26% overall yield) approaches to this segment. The highly convergent approach will facilitate the synthesis of analogues, including the C(18)-C(29) fragment of amphidinolide F. Synthetic highlights include the selective methylation of a diyne, and the highly efficient use of a second generation cobalt catalyst in the Mukaiyama oxidative cyclization to form the trans-THF ring.     

Towards the total synthesis of amphidinolide E: an enantioselective synthesis of C12-C29 fragment

An enantioselective synthesis of the C12-C29 fragment of amphidinolide E is described. Key transformations include an intramolecular mercuriocyclization reaction, stereoselective introduction of methyl group at the C2 position, and Stille coupling for the introduction of the diene side chain.     

A two-directional approach to a (-)-dictyostatin C11-C23 segment: development of a highly diastereoselective, kinetically-controlled Meerwein-Ponndorf-Verley reduction

A three-step synthesis of a precursor to the C11-C23 segment of (-)-dictyostatin is described. The sequence features a sonication-assisted, enantioselective double hetero Diels-Alder (HDA) reaction catalyzed by Jacobsen's Cr(III) Schiff base catalyst, followed by a novel, highly diastereoselective Meerwein-Ponndorf-Verley (MPV) reduction of the hydropyranone subunits under kinetic control to yield the bis(axial alcohol) 4. Generalized studies of both the HDA and MPV methodologies are also described.