Asymmetric hydroformylation-initiated tandem sequences for syntheses of (+)-patulolide C, (-)-pyrenophorol, (+)-decarestrictine L, and (+)-prelog djerassi lactone.

Four different Rh-catalyzed asymmetric hydroformylation (AHF) tandem reactions have been developed in the context of the total syntheses of (+)-patulolide C, (-)-pyrenophorol, (+)-decarestrictine L, and (+)-Prelog-Djerassi lactone. A total synthesis of (+)-patulolide C has been accomplished in three steps utilizing a Rh(I)-catalyzed Z-selective anti-Markovnikov hydroacetoxylation of a known alkyne to give a Z-enol acetate with excellent selectivity. An AHF/intramolecular Wittig olefination cascade was utilized to set the C4-hydroxyl stereochemistry, E-olefin geometry, and form the macrolactone. In addition, both (-)-pyrenophorol and (+)-decarestrictine L have been synthesized from the enantiomeric (4R)- and (4S)-4-(tert-butyldimethylsiloxy)-1-pentyne in five and four steps, respectively. These syntheses feature Ru(II)-catalyzed Z-selective anti-Markovnikov hydroacetoxylation of terminal alkynes followed by AHF/Wittig olefination sequences to rapidly establish functionality and stereogenicity. A synthesis of (+)-Prelog-Djerassi lactone was accomplished in three isolations from the known 1-vinyl-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane ortho ester. An AHF/crotylation tandem sequence has been developed to set the C2-C4 stereochemistry. An asymmetric hydrogenation was employed to set the C6 stereochemistry, resulting in an especially efficient enantioselective synthesis from achiral starting material. In summary, these syntheses have greatly improved efficiency in terms of atom-economy, catalytic stereoselective transformations, inexpensive reagents, step-counts, and overall yield when compared with previous synthetic attempts.

Synthesis of the Prelog-Djerassi lactone via an asymmetric hydroformylation/crotylation tandem sequence.

A synthesis of the Prelog-Djerassi lactone [(+)-1] has been accomplished in three isolations and 57% overall yield from the known vinyl ortho ester 2. A Rh(I)-catalyzed asymmetric hydroformylation/crotylation tandem sequence has been developed and used to set the C2-C4 stereochemistry. A Rh(I)-catalyzed asymmetric hydrogenation was employed to set the C6 sterechemistry, resulting in an unusually short and efficient enantioselective synthesis of this touchstone molecule from achiral starting material.

Enantioselective synthesis of Garner's aldehyde by asymmetric hydroformylation.

Both enantiomers of Garner's aldehyde (3) are prepared from the same alkene 4 by catalytic asymmetric hydroformylation.

Synthesis of (+)-patulolide C via an asymmetric hydroformylation/macrocyclization cascade.

A highly atom-economical total synthesis of (+)-patulolide C has been accomplished in three steps from the known (2R)-8-nonyn-2-ol in 49% overall yield and 93% de. A Rh(I)-catalyzed asymmetric hydroformylation (AHF)/ intramolecular Wittig olefination cascade was utilized to set the C4-hydroxyl stereochemistry and E-olefin geometry as well as form the macrolactone.

A citric acid-derived ligand for modular functionalization of metal oxide surfaces via "click" chemistry.

Citric acid is a widely used surface-modifying ligand for growth and processing of a variety of nanoparticles; however, the inability to easily prepare derivatives of this molecule has restricted the development of versatile chemistries for nanoparticle surface functionalization. Here, we report the design and synthesis of a citric acid derivative bearing an alkyne group and demonstrate that this molecule provides the ability to achieve stable, multidentate carboxylate binding to metal oxide nanoparticles, while also enabling subsequent multistep chemistry via the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The broad utility of this strategy for the modular functionalization of metal oxide surfaces was demonstrated by its application in the CuAAC modification of ZnO, Fe(2)O(3), TiO(2), and WO(3) nanoparticles.

Synthesis of (+)-didemniserinolipid B: application of a 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis.

The synthesis of didemniserinolipid B utilizing a ketalization/ring-closing metathesis (K/RCM) strategy is described. In the course of this work, a novel 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis (RRCM) was developed, which increased the yield of the RCM. The resulting 6,8-dioxabicyclo[3.2.1]octene core was selectively functionalized by complimentary dihydroxylation and epoxidation routes to install the C10 axial alcohol. This bicyclic ketal core was further functionalized by etherification and an alkene cross metathesis with an unsaturated alpha-phenylselenyl ester en route to completing the total synthesis.

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.

Synthesis of thromboxane B2 via ketalization/ring-closing metathesis.

Total synthesis of thromboxane B2 using intermolecular ketalization followed by ring-closing metathesis is reported. Other key steps include a Sharpless asymmetric epoxidation to form an oxirane on the endo face of the bicyclic acetal, epoxide opening using lithioacetonitrile, an allylic alcohol 1,3-transposition, and Mitsunobu lactonization.

Synthesis of (+)-didemniserinolipid B via ketalization/ring-closing metathesis.

A modular synthesis of didemniserinolipid B is reported. Central to this synthesis was the use of a ketalization/ring-closing metathesis (K/RCM) strategy to establish the 6,8-dioxabicyclo[3.2.1]octane core. The C10 axial alcohol was established via a selective epoxidation, followed by reductive trans-diaxial epoxide opening. The serinol and unsaturated ester side chains were introduced by a Williamson etherification and cross metathesis, respectively.

Stereochemically general approach to adjacent bis(tetrahydrofuran) cores of annonaceous acetogenins.

A series of six 2,5-disubstituted adjacent bis(tetrahydrofuran) stereoisomers with trans/erythro/cis, trans/threo/trans, or cis/threo/cis relative stereochemistry have been synthesized from known dihydroxycyclooctenes via ring opening/cross metathesis and Pd(0)-mediated asymmetric double cycloetherification. The stereochemistry of four of these isomers has been found in the biologically active annonaceous acetogenin natural products. [reaction: see text].

Macrocyclic scaffold for the collagen triple helix.

[structure: see text] Three strands of natural collagen are linked by covalent bonds prior to their folding into a triple helix. We report on a synthetic collagen in which the strands are pendent on a rigid macrocyclic scaffold of C(3) symmetry. The scaffold confers substantial conformational stability upon the collagen triple helix and makes its folding independent of concentration, both desirable attributes for exploring and exploiting synthetic collagens.

Halichondrin B: synthesis of the C1-C22 subunit.

[Reaction: see text]. Two efficient routes to the C1-C22 subunit of halichondrin B are described. The cage ketal 7, which contains 11 asymmetric centers embedded within the ABCDEF-ring framework, was assembled from (+)-conduritol E (27) in 18 steps and 4% overall yield. In a separate route, 7 was also synthesized in 18 steps and 2% overall yield from a derivative of alpha-d-glucoheptonic acid gamma-lactone (62). While the former route installs the fully elaborated C-ring endowed with the correct C12 stereochemistry early in the synthesis, the latter features a late-stage introduction of the C12 stereocenter during the ultimate one-pot Michael addition/ketalization cascade to form the CDE-ring system of the cage. The importance of the C12 stereocenter to the crucial ketalization event is discussed through comparison of these two strategies.

A catalytic enantioselective hetero Diels-Alder approach to the C20-C32 segment of the phorboxazoles.

[reaction: see text] An efficient synthesis of the C20-C32 segment of the phorboxazoles has been achieved using an enantioselective hetero Diels-Alder reaction catalyzed by Jacobsen's Cr(III) amino indanol Schiff base catalyst.

Synthetic efforts toward the C22-C36 subunit of halichondrin B utilizing local and imposed symmetry.

The C22-C34 portion (2) of halichondrin B was synthesized from meso-symmetric bis-silyl protected cyclopentenediol (7) in 20 steps and 7% overall yield. This was accomplished through a two-directional synthesis/terminus differentiation strategy that proceeded via achiral, meso-symmetric intermediates for eight steps and employed a Pd(0)-mediated asymmetric double cycloetherification to establish both tetrahydropyran rings. [Structure: see text]

Synthesis of the bryostatin 1 northern hemisphere (C1-C16) via desymmetrization by ketalization/ring-closing metathesis.

[reaction: see text] Synthesis of the northern hemisphere (C1-C16) of bryostatin 1, a potent anticancer agent, has been accomplished in 14 steps and 11% overall yield via desymmetrization by ketalization/ring-closing metathesis. A 2,9-dioxabicyclo[3.3.1]nonane template facilitated stereoselective A-ring functionalization, while an efficient hetero-Diels-Alder reaction was used to elaborate the B-ring.

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.

Concise formal synthesis of the bryostatin southern hemisphere (C17-C27).

An efficient synthesis of Hale and co-workers' C17-C27 bryostatin southern hemisphere intermediate has been accomplished in six steps and 33% overall yield from (R)-2-(benzyloxy)propanal. The synthesis features a one-pot DIBALH/HWE ester homologation as well as a novel acetonide rearrangement/glycal formation cascade.

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 comparison of the ring conformational properties of two derivatives prepared from the same diene diacetate precursor.

Results of single-crystal X-ray experiments performed for the title compounds, (1S,2R,3S,4R,5R)-4-benzyloxy-2-[1-(benzyloxy)allyl]-5-hydroxymethyl-2,3,4,5-tetrahydrofuran-3-ol, C(22)H(26)O(5), (I), and (3R,5S,6S,7S,8S)-3,6-bis(benzyloxy)-5-iodomethyl-2,3,4,5-tetrahydrofuro[3,2-b]furan-2-one, C(21)H(21)IO(5), (II), demonstrate that the tetrahydrofuran ring that is common to both structures adopts a different conformation in each molecule. Structural analyses of (I) and (II), which were prepared from the same precursor, indicate that their different conformations are caused by hydrogen-bonding interactions in the case of (I) and the presence of a fused bicyclic ring system in the case of (II). Density functional theory calculations on simplified analogs of (I) and (II) are also presented.