Synthesis of (-)-amphidinolide K fragment C9-C22

[reaction: see text] The key fragment (2a or 2b) in a total synthesis of the cytotoxic macrolide (-)-amphidinolide K (1) has been achieved from synthons C9-C14 (3) and C15-C22 (4), which have both been prepared from glutamic acid in good overall yields.     

Total synthesis of phorboxazole A. 2. Assembly of subunits and completion of the synthesis

[Structure: see text] Subunits of phorboxazole A containing C1-C2, C3-C8, C9-C19, C20-C32, C33-C41, and C42-C46 were connected in a sequence that first linked C32 with C33 and then C41 with C42. A C3-C8 fragment was joined to C9-C19, and the assembled unit was then joined with the left half of 1. Closure of the macrolide was accomplished by esterification of the C24 alcohol followed by intramolecular Horner-Wadsworth-Emmons condensation to set the (E)-C2-C3 alkene.     

Stereoselective synthesis of the C1-C13 fragment of 2,3-dihydrodorrigocin A

[Chemical reaction: see text] The first synthesis of the C1-C13 fragment of 2,3-dihydrodorrigocin A has been achieved from 6-bromohexanoic acid in 14 linear steps and an overall yield of 2%. The configurations of the stereogenic centers C8, C9, and C10 have been determined to be the same as for migrastatin.     

Synthesis and characterization of mono- and binuclear platinum complexes containing terminal and bridging diynyldiphenylphosphine ligands

A series of mononuclear platinum complexes containing diynyldiphenylphosphine ligands [cis-Pt(C(6)F(5))(2)(PPh(2)C[triple bond]CC(6)H(4)C[triple bond]CR)L](n)(n= 0, L = tht, R = Ph 2a, Bu(t)2b; L = PPh(2)C[triple bond]CC(6)H(4)C[triple bond]CR, 4a, 4b; n=-1, L = CN(-), 3a, 3b) has been synthesized and the X-ray crystal structures of 4a and 4b have been determined. In order to compare the eta2-bonding capability of the inner and outer alkyne units, the reactivity of towards [cis-Pt(C(6)F(5))(2)(thf)(2)] or [Pt(eta2)-C(2)H(4))(PPh(3))(2)] has been examined. Complexes coordinate the fragment "cis-Pt(C(6)F(5))(2)" using the inner alkynyl fragment and the sulfur of the tht ligand giving rise the binuclear derivatives [(C(6)F(5))(2)Pt(mu-tht)(mu-1kappaP:2eta2-C(alpha),C(beta)-PPh(2)C[triple bond]CC(6)H(4)C[triple bond]CR)Pt(C(6)F(5))(2)](R = Ph 5a, Bu(t)5b). The phenyldiynylphosphine complexes 2a, 3a and 4a react with [Pt(eta2)-C(2)H(4))(PPh(3))(2)] to give the mixed-valence Pt(II)-Pt(0) complexes [((C(6)F(5))(2)LPt(mu-1kappaP:2eta2)-C(5),C(6)-PPh(2)C[triple bond]CC(6)H(4)C[triple bond]CPh))Pt(PPh(3))(2)](n)(L = tht 6a, CN 8a and PPh(2)C[triple bond]CC(6)H(4)C[triple bond]CPh 9a) in which the Pt(0) fragment is eta2-complexed by the outer fragment. Complex 6a isomerizes in solution to a final complex [((C(6)F(5))(2)(tht)Pt(mu-1kappaP:2eta2)-C(alpha),C(beta)-PPh(2)C[triple bond]CC(6)H(4)C[triple bond]CPh))Pt(PPh(3))(2)]7a having the Pt(0) fragment coordinated to the inner alkyne function. In contrast, the tert-butyldiynylphosphine complexes 2b and 3b coordinate the Pt(0) unit through the phosphorus substituted inner acetylenic entity yielding 7b and 8b. By using 4a and 2 equiv. of [Pt(eta2)-C(2)H(4))(PPh(3))(2)] as precursors, the synthesis of the trinuclear complex [cis-((C(6)F(5))(2)Pt(mu-1kappaP:2eta2)-C(5),C(6)-PPh(2)C[triple bond]CC(6)H(4)C[triple bond]CPh)(2))(Pt(PPh(3))(2))(2)]10a, bearing two Pt(0)(PPh(3))(2)eta2)-coordinated to the outer alkyne functions is achieved. The structure of 7a has been confirmed by single-crystal X-ray diffraction.     

Stereoselective synthesis of the C(1)-C(11) fragment of peloruside A

A highly stereoselective synthesis of the C(1)-C(11) fragment 4 of peloruside A has been accomplished via a stereoselective double allylboration and an intramolecular epoxide opening to provide the functionally dense C(3)-C(11) segment 14. A glycolate aldol reaction was then employed to introduce the remaining stereocenters at C(2)-C(3). [reaction: see text]     

Efficient synthesis of the C(1)-C(11) fragment of the tedanolides. The nonaldol aldol process in synthesis

[reaction: see text] The nonaldol aldol process developed in our laboratories has been applied to the synthesis of a C(1)-C(11) fragment 22 of the novel macrocyclic cytotoxic agents tedanolide and 13-deoxytedanolide 1 and 2. The commercially available hydroxy ester 7 was converted in 24 steps into compound 22 using two nonaldol aldol reactions.     

Stereoselective synthesis of the C1-C13 fragment of (+)-discodermolide using asymmetric allyltitanations

[reaction: see text] The synthesis of the C1-C13 fragment of (+)-discodermolide has been achieved. The configurations of the stereogenic centers have been controlled by enantioselective allyl- and crotyltitanations of aldehydes, and the Z configuration of the olefin at C8-C9 was controlled by a ring-closing metathesis.     

Enantioselective synthesis of the [6,6] spiroketal core of reveromycin A

[structure: see text] Reveromycin A (1) belongs to a family of microbial polyketides with unusual structural features and biological activities. The structure of 1 is composed of a [6,6] spiroketal core decorated with highly unsaturated side chains. As a prelude to the synthesis of 1, we present herein a short, efficient, and enantioselective synthesis of the C9-C21 fragment 5 (spiroketal core) of reveromycin A.     

Synthesis of the ABC fragment of the pectenotoxins

[reaction: see text] A highly stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing fragment 5 of PTX7 (4) has been achieved. Appendage of the C ring to the AB fragment involved Wittig reaction of spiroacetal aldehyde 8 with a stabilized ylide 9 followed by displacement of allylic iodide 27 with a lithium acetylide to afford enyne 7. Fructose-derived chiral dioxirane and dihydroxylation were then used to introduce the correct functionality in the tetrahydrofuran C ring.     

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 C11-C29 fragment of amphidinolide F

[reaction: see text] An efficient synthesis of the C(11)-C(29) fragment 31 of amphidinolide F has been accomplished via a diastereoselective [3 + 2]-annulation reaction of allylsilane 5 and ethyl glyoxylate to prepare the key tetrahydrofuran 15 and a highly stereoselective methyl ketone aldol reaction to generate the C(11)-C(16) segment.     

Unexpected coupling between an eta5-indenyl ligand and alkenyl-vinylidene fragments: synthesis of unprecedented (eta6-indene)ruthenium(II) metallacycles

Vinylidene complexes [Ru[=C=C(H)CR1R2CH2C(Me)=CH2](eta5-C9H7)(PPh3)2][BF4] undergo an intramolecular coupling between the alkenyl-vinylidene fragment and the eta5-indenyl ligand to afford indene-metallacyclic compounds (6a,b) in which the resulting functionalised indene group is eta6-coordinated to the metal.     

Synthesis, structure, and magnetic properties of (6-9)-nuclear Ni(II) trimethylacetates and their heterospin complexes with nitroxides

New polynuclear nickel trimethylacetates [Ni6(OH)4(C5H9O2)8(C5H10O2)4] (6), [Ni7(OH)7(C5H9O2)7(C5H10O2)6(H2O)] x 0.5 C6H14 x 0.5 H2O (7), [Ni8(OH)4(H2O)2(C5H9O2)12] (8), and [Ni9(OH)6(C5H9O2)12(C5H10O2)4] x C5H10O2 x 3 H2O (9), where C5H9O2 is trimethylacetate and C5H10O2 is trimethylacetic acid, have been found. Their structures were determined by X-ray crystallography. Because of their high solubility in low-polarity organic solvents, compounds 6-9 reacted with stable organic radicals to form the first heterospin compounds based on polynuclear Ni(II) trimethylacetate and nitronyl nitroxides containing pyrazole (L(1)-L(3)), methyl (L(4)), or imidazole (L(5)) substituent groups, respectively, in side chain [Ni7(OH)5(C5H9O2)9(C5H10O2)2(L(1))2(H2O)] x 0.5 C6H14 x H2O (6+1a), [Ni7(OH)5(C5H9O2)9(C5H10O2)2(L2)2(H2O)] x H2O (6+1b), [Ni7(OH)5(C5H9O2)9(C5H10O2)2(L(3))2(H2O)] x H2O (6+1c), [Ni6(OH)3(C5H9O2)9(C5H10O2)4(L(4))] x 1.5 C6H14 (6'), and [Ni4OH)3(C5H9O2)5(C5H10O2)4(L(5))] x 1.5 C7H8 (4). Their structures were also determined by X-ray crystallography. Although Ni(II) trimethylacetates may have varying nuclearity and can change their nuclearity during recrystallization or interactions with nitroxides, this family of compounds is easy to study because of its topological relationship. For any of these complexes, the polynuclear framework may be derived from the [Ni6] polynuclear fragment {Ni6(mu4-OH)2(mu3-OH)2(mu2-C5H9O2-O,O')6(mu2-C5H9O2-O,O)(mu4-C5H9O2-O,O,O',O')(C5H10O2)4}, which is shaped like an open book. On the basis of this fragment, the structure of 7-nuclear compounds (7 and 6+1a-c) is conveniently represented as the result of symmetric addition of other mononuclear fragments to the four Ni(II) ions lying at the vertexes of the [Ni6] open book. The 9-nuclear complex is formed by the addition of trinuclear fragments to two Ni(II) ions lying on one of the lateral edges of the [Ni6] open book. This wing of the 9-nuclear complex preserves its structure in another type of 6-nuclear complex (6') with the boat configuration. If, however, two edge-sharing Ni(II) ions are removed from [Ni6] (one of these lies at a vertex of the open book and the other, on the book-cover line), we obtain a 4-nuclear fragment recorded in the molecular structure of 4. Twinning of this 4-nuclear fragment forms highly symmetric molecule 8, which is a new chemical version of cubane.     

A ketal-tethered RCM strategy toward the synthesis of spiroketal related natural products

An unconventional approach to construct spiroketals and spiroaminals via ring-closing metathesis [RCM] of cyclic ketals and aminals, respectively, is described here. This method possesses a good generality with no loss of stereochemical integrity at the spirocenter under the standard RCM conditions. This approach has been applied to the synthesis of an insect pheromone to demonstrate its synthetic potential, and also to the synthesis of the C11-epi-C22-C23 fragment in spirastrellolide A. Both are proof-of-concept applications to feature a ketal-tethered RCM as an alternative strategy for construction of spiroketals.     

Synthesis of the C3-C18 fragment of amphidinolides G and H

A synthesis of an amphidinolides G and H C3-C18 subunits is reported. The C10-C18 segment 4 was prepared by a Negishi cross-coupling, whereas the synthesis of the C3-C9 fragment 5 employed an asymmetric cyanosilylation as the key step. The two segments were coupled by lithiation of iodide 4 and trapping of the anion with amide 5. The allylic epoxide moiety could be synthesized from the protected anti- mesylate 22.     

Silver as an exopolyhedral auxiliary to the rhenacarborane anion [Re(CO)3(eta5-7,8-C2B9H11)]-

The rhenacarborane salt Cs[Re(CO)3(eta5-7,8-C2B9H11)] (1) has been used to synthesize the tetranuclear metal complex [[ReAg(mu-10-H-eta5-7,8-C2B9H10)(CO)3]2[mu-Ph2P(CH2)2PPh2]] (3) where two [ReAg(mu-10-H-eta5-7,8-C2B9H10)(CO)3] fragments have been shown by X-ray crystallography to be bridged by a single 1,2-bis(diphenylphosphino)ethane ligand. Reaction of 1 with Ag[BF4] in the presence of the ligands bis- or tris(pyrazol-1-yl)methane yields the complexes [ReAg(mu-10-H-eta5-7,8-C2B9H10)(CO)3[kappa2-CH2(C3H3N2-1)2]] (4) or [[ReAg(mu-10-H-eta5-7,8-C2B9H10)(CO)3]2[mu-kappa1,kappa2-CH(C3H3N2-1)3]] (5), respectively. From X-ray studies, the former comprises a Re-Ag bond bridged by the carborane cage and with the bis(pyrazol-1-yl)methane coordinating the silver(I) center in an asymmetric kappa(2) mode. Complex 5 was unexpectedly found to contain a tris(pyrazol-1-yl)methane bridging two [ReAg(mu-10-H-eta5-7,8-C2B9H10)(CO)3] fragments in a kappa1,kappa2 manner. Treatment of 1 with Ag[BF4] in the presence of 2,2'-dipyridyl and 2,2':6',2' '-terpyridyl yields [ReAg(mu-10-H-eta5-7,8-C2B9H10)(CO)3[kappa2-(C5H4N-2)(2)]] (6) and [ReAg(mu-10-H-eta5-7,8-C2B9H10)(CO)3[kappa3-C5H3N(C5H4N-2)2-2,6]] (7). The X-ray structure determination of 7 revealed an unusual pentacoordinated silver(I) center, asymmetrically ligated by a kappa3-2,2':6',2' '-terpyridyl molecule. The same synthetic procedure using N,N,N',N'-tetramethylethylenediamine gave a tetranuclear metal complex [[ReAg(mu-10-H-eta5-7,8-C2B9H10)(CO)3]2[mu-Me2N(CH2)2NMe2]2] (8) which is believed, in the solid state, to be bridged between the silver atoms by two of the diamine molecules. The salt 1 with Ag[BF4] in the absence of any added ligand gave the tetrameric cluster [ReAg[mu-5,6,10-(H)3-eta5-7,8-C2B9H8](CO)3]4 (9) where, in the solid state, four [ReAg(mu-10-H-eta5-7,8-C2B9H10)(CO)3] units are held together by long interunit B-H right harpoon-up Ag bonds.     

Formal [4+2]-annulation of chiral crotylsilanes: synthesis of the C19-C28 fragment of phorboxazoles

A stereoselective synthesis of the C19-C28 fragment of phoborxazole A and B is described. The key step is an enantioselective [4 + 2]-annulation of a crotylsilane 10 with a propargylic aldehyde 11 affording a functionalized dihydropyran 12. A solvent-dependent stereoselective epoxidation of dihydropyrans is also documented.     

Abbreviated synthesis of the C3-C14 (substituted 1,7-dioxaspiro[5.5]undec-3-ene) system of okadaic acid

[formula: see text] Described is a novel, concise, and flexible synthesis of the C3-C14 portion of okadaic acid. A substituted valerolactone (C3-C8) was prepared in three steps and alpha-hydroxylated using Davis' oxaziridine. Conjugate addition of dimethylcuprate upon ynones derived from the C3-C8 lactones followed by intramolecular ketalization provided the C3-C14 fragment and revealed a significant role of the C7 alpha'-ketone substituent upon the efficiency of spiroketalization.     

Benzimidazoles and related heterocycles

A three-component condensation of 3-benzoylquinoxalin-2(1H)-one with 4-nitrobenzaldehyde and ammonium acetate in AcOH gives 2-[2-(4-nitrophenyl)-5-phenylimidazol-4-yl]benzimidazole via a rearrangement involving the fragment C(2)-C(3)-C(O)Ph of the quinoxaline system and the other two reagents, which supply the fragment -N=C(Ar)-NH- for constructing the imidazole ring. Possible pathways of this reaction are discussed.     

Studies directed toward the total synthesis of discodermolide: asymmetric synthesis of the C1-C14 fragment

[structure: see text] A convergent and stereoselective assembly of the C1-C14 subunit of marine natural product (+)-discodermolide has been completed. The approach employs chiral allylsilane bond construction methodology to establish four of the eight stereogenic centers. Key fragment coupling is achieved via an efficient stereoselective acetate aldol reaction between C1-C6 and C7-C14 subunits.