An Efficient Strategy for the Synthesis of α,α′-cis and trans-Disubstituted Medium Ring Ethers

An asymmetric alkylation-ring-closing metathesis strat-egy was developed for the construction of a,a'-disubstituted medi-um ring ethers. The approach features an asymmetric alkylation of highly functionalized a-alkoxy acyl oxazolidinones followed by ring closure effected by Grubbs' ruthenium catalyst. The relation-ship between diene conformation and the rate of ring-closure was examined. Medium ring ethers are a common structural feature of many ladder ether marine toxins, as well as simpler me-tabolites from Laurencia species. This diverse collection of natural products often contains seven, eight, and nine membered ring ethers. 1 The challenge of efficient con-struction of medium ring ethers has led to the develop-ment of numerous strategies for their synthesis. 2-5 The vast majority of these approaches have focused on the a,a'-cis-disubstitution pattern rather than a,a'-trans-di-substituted medium ring ethers, despite their similar fre-quency of occurrence. trans-Isoprelaurefucin (1), 6 isolau-refucin methyl ether (2), 7 chlorofucin (3), 8 bromofucin (4), 9 isolaureatin (5), 10 and obtusenyne (6), 8 for example, all contain a,a'-trans-disubstituted medium ring ethers (Figure 1). Murai's synthesis of obtusenyne (6) 11 and our own recent syntheses of prelaureatin and laurallene 12 con-stitute the only known syntheses of medium ring ether natural products with the a,a'-trans-disubstitution ar-rangement. The investigation of a versatile, general strat-egy for the synthesis of both a,a'-cis and a,a'-trans-disubstituted medium ring ethers is described here. We recently published a total synthesis of the marine nat-ural product (+)-laurencin (9), in which the key steps were an asymmetric alkylation of the sodium enolate of substi-tuted acyl oxazolidinone 7, followed by ring-closing met-athesis of the resultant diene to give cyclic ether 8 (Scheme 1). 2 Previous work in our laboratory has demon-strated that an asymmetric aldol-ring-closing metathesis strategy for the assembly of medium ring ethers was equally adaptable to both the a,a'-cis and a,a'-trans-di-substituted medium ring ethers. 3,12 The asymmetric alky-lation-ring-closing metathesis approach to cyclic ethers also offered the potential for a similar adaptable strategy

Establishing the Absolute Configuration of the Asbestinins: Enantioselective Total Synthesis of 11-Acetoxy-4-deoxyasbestinin D

A highly stereoselective synthesis of 11-acetoxy-4-deoxyasbestinin D (1) has been completed in 26 linear steps. The synthesis hinges on a selective glycolate aldol addition to establish the C-2 stereocenter, a ring-closing metathesis reaction to complete the oxonene, and an intramolecular Diels-Alder cycloaddition to establish the relative configuration at C-1, C-10, and C14. This initial total synthesis of an asbestinin also serves to confirm the absolute configuration of this sub-class of the C2-C11-cyclized cembranoid natural products

Enantioselective Total Synthesis of FD-891

The enantioselective synthesis of FD-891 has been achieved with a longest linear sequence of 21 steps. The synthetic strategy involves the use of aldol additions of a chlorotitanium enolate of N-acylthiazolidinethiones as the key reaction to establish 6 of the 10 stereogenic centers. A key cross-metathesis and a late-stage Julia olefination serve to assemble three key subunits

Asymmetric Total Synthesis of Pyranicin

The asymmetric total synthesis of pyranicin (1) is reported. The butenolide ring was constructed via an asymmetric alkylation/ring-closing metathesis strategy. The three stereocenters in the left-hand tetrahydropyran ring were installed by sequential chiral auxiliary-mediated aldol reactions. Closure of the tetrahydropyran and fusion of the alkyl backbone were affected via a sequential ring-closing metathesis cross-metathesis strategy

A Hetero-Diels−Alder Approach to Complex Pyrones: An Improved Synthesis of the Spongistatin AB Spiroketal

The conversion of a substituted dioxinone to a pyrone was used in an improved synthesis of the AB spiroketal subunit of the spongistatins. This transformation occurred via a hetero-Diels-Alder reaction of an acyl ketene with butyl vinyl ether. A double diastereoselective Mukaiyama aldol reaction is used to provide the hetero-Diels-Alder precursor

Enantioselective Total Synthesis of Spirofungins A and B

The enantioselective total synthesis of spirofungins A (1) and B (2) is reported in 14 steps over the longest linear sequence. Key steps include the use of thiazolidinethione mediated aldol reactions to assemble the major fragments and installation of the C1–C6 side chain using a cross metathesis reaction

Formal Synthesis of 6-Deoxyerythronolide B

The enantioselective synthesis of the carbon skeleton of 6-deoxyerythronolide B has been achieved in 23 linear steps from propionaldehyde. The synthesis relies on an iterative approach employing an asymmetric acyl-thiazolidinethione propionate aldol reaction to establish eight of nine stereogenic centers. The remaining stereogenic center at C6 was set through a Myers alkylation employing a complex alkyl iodide

Enantioselective Total Synthesis of Bistramide A

The enantioselective synthesis of bistramide A has been achieved with a longest linear sequence of 18 steps. The synthetic strategy involves the use of a distereoselective glycolate alkylation, an aldol addition of a chlorotitanium enolate of N-acylthiazolidinthione, and a Sharpless asymmetric epoxidation to synthesize the three key fragments

Enantioselective Synthesis of the C1–C6 and C7–C23 Fragments of the Proposed Structure of Iriomoteolide 1a

Synthesis of the C1-C6 and C7-C23 fragments of the proposed structure of iriomoteolide 1a has been accomplished. Key steps include a cross metathesis to form the C15-C16 E olefin and a chelation controlled Grignard addition to form the tertiary alcohol at C14. Notably, 7 of the 9 stereocenters of the proposed structure have been set using various aldol reactions employing metallo enolates of thiazolidinethiones

Enantioselective Total Synthesis of (−)-Pironetin: Iterative Aldol Reactions of Thiazolidinethiones

The enantioselective total synthesis of pironetin has been achieved in 11 steps from known aldehyde 2. The synthesis relies on the formation of 5 out of 6 stereocenters through titanium mediated iterative aldol reactions. Key steps in this synthesis include an acetal aldol reaction to establish the stereochemistry at C8 and C9, an acetate aldol reaction, and “Evans” syn aldol reaction