Synthesis of the C3-C19 segment of phorboxazole B

[reaction: see text]. Three segment-coupling Prins approaches to the C3-C19 segment of phorboxazole B have been developed. One successful strategy utilized a novel TMSBr-mediated cyclization that proceeded with complete axial selectivity. Displacement of bromide with cesium acetate provided the C13 hydroxyl stereocenter of 22. Additionally, treatment of alpha-acetoxy ether 20 with TFA enabled a more concise synthesis of the C3-C19 target 13 by allowing direct access to the equatorial alcohol.     

Synthesis of the C1-C17 segment of phorboxazole B

The C1-C17 bis-oxane subunit 22 of phorboxazole B is efficiently synthesized by exploiting differential reactivities between similar substituents on the hydropyran rings in 4. Selective dihydroxylation of the equatorial vinyl group, hydroboration of the axial vinyl group, and intramolecular Mitsunobu lactonization serve to fully differentiate the similar hydropyrans.     

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.     

Enantioselective synthesis of the C18-C25 segment of lasonolide A by an oxonia-cope prins cascade

[reaction: see text] A 2-oxonia-Cope Prins cascade was developed that led to a facile and stereoselective synthesis of the C18-C25 segment of lasonolide A. The strategy nicely handles the introduction of the quaternary center in the tetrahydropyran ring, and all of the stereogenic centers in the product arise from a single stereocenter introduced in a catalytic enantioselective reaction.     

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.     

Highly stereoselective prins cyclization of silylmethyl-substituted cyclopropyl carbinols to 2,4,6-trisubstituted tetrahydropyrans

The homoallyl cation formed from a cyclopropyl carbinol that was vicinally substituted by a silylmethyl function underwent smooth Prins cyclization with aldehydes and ketones to form 2,4,6-trisubstituted tetrahydropyrans with very high stereoselectivity.     

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.     

CAN mediated cyclization of epoxypropyl cinnamyl ethers: a facile stereoselective synthesis of tetrahydropyran derivatives

Cerium(IV) ammonium nitrate in substoichiometric amounts, promotes the intramolecular cyclization of epoxypropyl cinnamyl ethers to the corresponding 3,4,5-trisubstituted tetrahydropyran derivatives in moderate to good yields.     

Synthetic studies toward phorboxazole A. stereoselective synthesis of the C(28)-C(46) side chain fragment

A stereoselective synthesis of the C(28)-C(46) fragment (3) of phorboxazole A is described. Key advances include an enantioselective allylation to establish the stereochemistry of the tetrahydropyran unit and a useful SmI(2)-mediated modification of the Barbier reaction of iodomethyloxazole 15 with aldehyde 14.     

Synthesis of the C10-C22 bis-spiroacetal domain of spirolides B and D via iterative oxidative radical cyclization

[reaction: see text] A synthetic approach to the novel bis-spiroacetal moiety of spirolides B and D is reported. The strategy hinges upon successive formation of the spirocenters at C15 and C18 by radical oxidative cyclization, followed by base-induced rearrangement of a C19-20 alpha-epoxide to introduce the C19 hydroxyl group.     

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).     

Synthesis of the C21-C28 segment of pectenotoxin-4

The synthesis of the C21-C28 segment of pectenotoxin-4 as the C21 Weinreb amide is described. Feasibility studies for the union of a related Weinreb amide and a functionalized alkyne are also reported.     

Synthesis of the C6-C21 segment of amphidinolide E

[reaction: see text] A convergent approach to a C6-C21 segment of the polyketide amphidinolide E has been developed through combination of three subunits by allenylindium bromide-aldehyde addition and Suzuki sp2-sp3 coupling.     

Synthesis of a C20-C26 segment of superstolide A by addition of a chiral allenylzinc reagent to (R)-N-boc alaninal

[reaction: see text] Additions of chiral allenylzinc and indium reagents to N-Boc alaninal were examined as a possible route to a C20-C26 segment of superstolide A. Allenylzinc reagents, prepared in situ by palladiozincation of (R)- and (S)-5-pivalyloxy-3-butyn-2-ol mesylate, showed excellent reagent control to afford the anti,syn and anti,anti diastereomers as the nearly exclusive adducts.     

Synthesis of the C20-C26 building block of halichondrins via a regiospecific and stereoselective S(N)2' reaction

[reaction: see text] A regiospecific and stereoselective S(N)2' reaction to convert the trisylate into the vinyl iodide is presented. The homoallylic alcohol is used to direct the delivery of LiCu(Me)(2).     

Synthesis of the C15-C23 fragment of dictyostatin using a highly stereoselective Carreira alkynylation

A straightforward synthesis of the C15-C23 fragment of dictyostatin has been achieved by a highly stereoselective Carreira alkynylation between alkyne 1 and aldehyde 2, followed by three chemoselective reductions.     

Concise and highly stereoselective synthesis of the C20-C26 building block of halichondrins and Eribulin

A concise, stereoselective, and scalable synthesis of the C20-C26 building block of halichondrins and Eribulin is reported. The synthesis relies on three key transformations: regiospecific Ru-catalyzed intramolecular hydrosilylation, highly stereoselective S(N)2' substitution, and selective conversion of a C-Si to C-I bond. It is carried out in a 5-pot/4-workup operation without chromatographic purification, except for filtration through a silica-gel plug, to give the C20-C26 building block (dr > 200:1; ee > 99%) in ca. 60% overall yield from epoxide 1.     

Synthesis of C15-C27 segment of venturicidine X by utilizing desymmetrization protocol

We have achieved the synthesis of C15-C27 fragment of venturicidine X using desymmetrization protocol, substrate-controlled Grignard reaction, Barton-McCombie reaction, Sharpless epoxidation, and TBSOTf-mediated rearrangement to produce the aldol product through a non-aldol route as the key step following 23 longest linear sequences with 6.4% overall yield starting from a known intermediate 11.     

Palladium-catalyzed cross-coupling of terminal alkynes with 4-trifloyloxazole: studies toward the construction of the C26-C31 subunit of phorboxazole A

[reaction: see text] A strategy has been developed that successfully takes advantage of transition-metal-catalyzed coupling reactions for the synthesis of highly functionalized oxazoles. Trifloyloxazoles have been used as coupling partners with alkyne-derived vinylmetallic intermediates in Stille- and Negishi-type couplings to assemble the corresponding oxazoles in good isolated yield. The results obtained provide a close analogy and thus good precedent to employ this strategy in the synthesis of the oxazole subunits of phorboxazole A.