Julia-Kocienski Olefination Research Articles

Stereoselective Synthesis of the Proposed C79-C104 Fragment of Symbiodinolide.

Stereoselective and streamlined synthesis of the proposed C79-C104 fragment 2 of symbiodinolide (1), a polyol marine natural product with a molecular weight of 2860, was achieved. In the synthetic route, the proposed C79-C104 fragment 2 was synthesized by utilizing a Julia-Kocienski olefination and subsequent Sharpless asymmetric dihydroxylation as key transformations in a convergent manner. Detailed comparison of the 13 C NMR chemical shifts between the natural product and the synthetic C79-C104 fragment 2 revealed that the stereostructure at the C91-C99 carbon chain moiety of symbiodinolide (1) should be reinvestigated.

Total Synthesis and Structural Confirmation of the Antimalarial Naphthopyrone Lasionectrin.

The total synthesis of lasionectrin, a naphthopyrone metabolite of an Acremonium-like fungus collected in Equatorial Guinea, is reported. Divergent access to four stereoisomers confirmed the natural product to be the enantiomer of the originally proposed structure. Highlights of the synthesis include ring opening of a chiral oxetane using a thiol, a highly E-selective Julia-Kocienski olefination, and a modified Sharpless/Upjohn dihydroxylation. Palladium-catalyzed carbonylative lactonization was used to assemble the fused naphthopyrone ring system.

Total Synthesis of Mycalolides A and B through Olefin Metathesis

AbstractAn asymmetric total synthesis of the trisoxazole marine macrolides mycalolides A and B is described. This synthesis involves the convergent assembly of highly functionalized C1–C19 trisoxazole and C20–C35 side‐chain segments through the use of olefin metathesis and esterification as well as Julia–Kocienski olefination and enamide formation as key steps.

Total Synthesis of Mycalolides A and B through Olefin Metathesis.

An asymmetric total synthesis of the trisoxazole marine macrolides mycalolides A and B is described. This synthesis involves the convergent assembly of highly functionalized C1-C19 trisoxazole and C20-C35 side-chain segments through the use of olefin metathesis and esterification as well as Julia-Kocienski olefination and enamide formation as key steps.

Studies directed towards the total synthesis of polyether antibiotic ionomycin: asymmetric synthesis of fragments C(24)–C(32) and C(1)–C(23)

A convergent and stereoselective approach for the synthesis of C1–C23 and C24–C32 segments of polyether antibiotic, ionomycin has been achieved. The key steps involved in this approach are the elaboration of two advanced fragments from a common precursor using enzymatic desymmetrization to create two methyl chiral centers, desymmetrization of the bicyclic olefin to introduce two methyl and two hydroxyl chiral centers, the use of Evans auxiliary to introduce another methyl group and the creation of four chiral centers in bis-tetrahydrofuran ring by Sharpless asymmetric epoxidation and the regioselective opening of epoxide with methyl sulphone. The coupling of C11–C16 with C17–C23 was achieved through a Julia-Kocienski olefination and directed Aldol reaction. Oxidation of C9 alcohol facilitates the coupling of C10–C23 with C1–C9.

Convergent and stereoselective synthesis of (−)-zeaenol

Stereoselective synthesis of (−)-zeaenol has been accomplished from d-xylose as a chiral pool starting material. The key steps of this convergent synthetic strategy involves a Stille coupling, a Noyori reduction, a Julia–Kocienski olefination and a macrolactonization to obtain (−)-zeaenol. We have also explored a Sonogashira coupling along with a Trost protocol for the intramolecular hydrosilylation on the homopropargylic alcohol system as an alternative synthetic approach to this molecule.

Asymmetric Total Synthesis of Bioactive Natural Lipid Mycalol.

A concise and convergent route for stereoselective total synthesis of promising anticancer natural lipid mycalol has been achieved using cheap and readily available l-arabinose as a chiral pool. The notable features of our synthesis comprised regioselective Wacker oxidation, Sharpless asymmetric dihydroxylation, Julia-Kocienski olefination, Wittig olefination, Zipper reaction, and Sonogashira reaction. Comparison of the spectroscopic data on a series of isomers supports the revised structure (Org. Lett. 2015, 17, 1652) instead of the one originally proposed.

Carbonyl olefination of diaryl ketones with heteroaryl sulfoxides

Heteroaryl sulfones are capable of converting the carbonyl functionalities to alkenyl motifs, which is well-known as Julia–Kocienski olefination reaction. However, their sulfoxide analogues have failed in such an olefination reaction for over twenty years. In this Letter, we demonstrate that the heteroaryl sulfoxide-participated carbonyl olefination reaction can be realized under certain conditions. Furthermore, a novel defluorinative olefination of diaryl ketones has been achieved with 2-pyridyl sulfoxides.

Synthetic Studies toward the C32-C46 Segment of Hemicalide. Assignment of the Relative Configuration of the C36-C42 Subunit.

The synthesis of five diastereomeric model compounds incorporating the C32-C46 segment of the antitumor marine natural product hemicalide has been achieved through a convergent approach relying on the 1,4-addition of an alkenyl boronate to an α,β-unsaturated δ-lactone followed by α-hydroxylation of an enolate and a Julia-Kocienski olefination. Comparison of the (1)H and (13)C NMR data of the model compounds with those of hemicalide enabled the assignment of the relative configuration of the C36-C42 subunit.

Asymmetric synthesis of cytospolides C and D through successful exploration of stereoselective Julia–Kocienski olefination and Suzuki reaction followed by macrolactonization

Asymmetric total synthesis of two naturally occurring nonenolides cytospolides C (3) and D (4) was accomplished through successful exploration of stereoselective Julia–Kocienski (JK) olefination reaction for the construction of the required E-olefinic geometry (C4–C5) present in the target molecule. In an alternative approach Suzuki cross coupling reaction of an E-vinylic bromide and an alkylborane species was also efficiently applied to access the macrolactonization precursor. Late stage lactonization through Mitsunobu cyclization afforded the target molecules in good yield.

ChemInform Abstract: Stereoselective Total Syntheses of Paecilomycins E and F Through a Protecting Group Directed Diastereoselective Intermolecular Nozaki—Hiyama—Kishi (NHK) Reaction.

An efficient and concise approach to the total syntheses of paecilomycins E (1) and F (2) is described. A protecting group directed intermolecular diastereoselective Nozaki–Hiyama–Kishi (NHK) reaction, a Julia–Kocienski olefination, a Sharpless asymmetric dihydroxylation, and De Brabander's lactonization protocol are used as the key steps.

ChemInform Abstract: Synthesis of Tetrahedral Diarylheptanoid ent‐Diospongin A (I) and epimer‐Diospongin B (II) by Employing Julia—Kocienski Olefination.

ChemInform Abstract: Synthesis of Tetrahedral Diarylheptanoid ent‐Diospongin A (I) and epimer‐Diospongin B (II) by Employing Julia—Kocienski Olefination.

A chain extension method for apocarotenoids; lycopene and lycophyll syntheses

The novel C5 benzothiazolyl (BT) sulfone containing an acetal group was prepared as a building block for the chain-extension of apocarotenoids. The double Julia–Kocienski olefination of the BT-sulfone with C10 2,7-dimethyl-2,4,6-octatrienedial and deprotection of the resulting acetal groups efficiently produced C20 crocetin dial. The higher homologues of C30 and C40 apocarotenoids were prepared from C20 crocetin dial by the repeated application of the Julia–Kocienski olefination of the C5 BT-sulfone and hydrolysis. The scopes of the Julia–Kocienski olefination in the total synthesis of carotenoid natural products were evaluated using the C10+C20+C10 coupling protocol. The olefination was sensitive to the steric factor and bulky C10 β-cyclogeranyl BT-sulfone was not able to react with C20 crocetin dial, however, lycopene and lycophyll were efficiently produced by the Julia–Kocienski olefination of C10 geranyl BT-sulfone and hydroxygeranyl BT-sulfone, in which protection of the hydroxyl group was not necessary.

Stereoselective synthesis of the C1-C29 part of amphidinol 3.

Stereoselective synthesis of the C1-C29 part of amphidinol 3 (AM3) was achieved. The C1-C20 part was assembled from three building blocks via regioselective cross metathesis to form the C4-C5 double bond and addition of an alkenyllithium and a lithium acetylide to two Weinreb amides followed by asymmetric reduction to form the C9-C10 and C14-C15 bonds, respectively. The C21-C29 part was synthesized via successive cross metathesis and oxa-Michael addition sequence to construct the 1,3-diol system at C25 and C27 and Brown asymmetric crotylation to introduce the stereogenic centers at C23 and C24. Coupling of the C1-C20 and C21-C29 parts was achieved by Julia-Kocienski olefination and regio- and stereoselective dihydroxylation of the C20-C21 double bond in the presence of the C4-C5 and C8-C9 double bonds to afford the C1-C29 part of AM3.

The development of a complementary pathway for the synthesis of aliskiren.

The synthesis of aliskiren (1), a recently marketed drug for the treatment of hypertension, is presented. The focus of our synthetic effort is to develop an efficient pathway for the synthesis of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-N,N,8-trimethylnon-4-enamide (2a), which has been used as the advanced intermediate toward aliskiren. After an extensive investigation of three different strategies designed to construct the E-olefin functionality in 2a by employing the olefin cross-metathesis, Horner-Wadsworth-Emmons (HWE), and Julia-type olefinations, we have established a new protocol for the synthesis of 2a with a substantially improved overall efficiency in terms of the yield (ca. 33%), and diastereo- and E/Z-selectivity. The key transformations were the Evans chiral auxiliary-aided asymmetric allylation for the synthesis of the appropriate chiral intermediates in excellent enantiomeric purity of higher than 97% ee and a modified Julia-Kocienski olefination for the highly selective construction of E-2a with up to 13.6:1 E/Z ratio from the chiral intermediates. Consequently, the results provide an appealing option for the synthesis of aliskiren.

ChemInform Abstract: Asymmetric Synthesis of C11‐C23 Fragment of Pladienolide B (I).

Synthesis of C11-C23 fragment of an antitumor natural product, Pladienolide B, in gram-scale, is described. The key steps involved in this synthesis are Julia-Kocienski olefination, opening of epoxide with TBSOTf to form the corresponding –OTBS protected aldehyde and Evans aldol reaction.

Synthesis of the C6–C21 fragment of epothilone analogues

(2S,4E,6Z,9S,10E)-9-[tert-Butyl(diphenyl)silyloxymethyl]-2,6,10-trimethyl-11-(2-methylthiazol-4-yl)undeca-4,6,10-trien-1-ol, a key precursor for epothilone analogues, was prepared by multi-step synthesis using the Julia–Kocienski olefination at the key step.

Phormidolides B and C, cytotoxic agents from the sea: enantioselective synthesis of the macrocyclic core.

New cytotoxic polyketide macrolides named phormidolides B and C were isolated from a marine sponge of the Petrosiidae family collected off the coast of Pemba (Tanzania). The isolation, structure elucidation, and enantioselective synthesis of three diastereomers of the macrocyclic core is described herein. The described synthetic methodology started from 2-deoxy-D-ribose or 2-deoxy-L-ribose and afforded the desired macrocycles with high enantiomeric purity. The key step of the synthesis is the formation of the Z-trisubstituted double bond using a Julia-Kocienski olefination. The versatility of the synthetic methodology may provide access to other enantiopure macrocycles by making changes in the starting materials or chiral inductors.

ChemInform Abstract: Stereoselective Approach to Potential Scaffold of A‐nor B‐Aromatic OSW‐1 Analogues via [4 + 2] Cycloaddition of O‐Quinodimethane.

Abstract A-nor B-aromatic steroidal skeleton was efficiently constructed by means of o -quinodimethane chemistry with exclusive stereoselectivity. The benzocyclobutene substrate for generation of the o -quinodimethane intermediate and subsequent [4+2] cycloaddition could be synthesized via ( E )-selective Julia–Kocienski olefination and diastereoselective Grignard addition reactions. The synthesized tricyclic steroid-like compound with a trans -diol substructure would be utilized for divergent syntheses of potentially antitumor OSW-1 analogues with the truncated steroidal aglycone.

Selective formation of a Z-trisubstituted double bond using a 1-(tert-butyl)tetrazolyl sulfone.

In our effort to gain further insight into the enantioselective synthesis of the structural core of phormidolides B and C, we have discovered the formation of a Z-trisubstituted double bond. Here, we describe a highly selective process that can be applied to our target following a strategy that is based on Julia-Kocienski olefination. The use of 1-(tert-butyl)tetrazolyl sulfone affords the construction of the Z-trisubstituted alkene with high efficiency and stereoselectivity.