Total Synthesis of Sekothrixide Strategically Utilizing Regioselective Coupling of TMS-Protected Epoxy sec-Alcohol with Gilman Reagent.

A new efficient synthesis of sekothrixide was established on the basis of our developed regioselective coupling of epoxy sec-alcohol with Gilman reagent guided by a TMS group. The new synthetic route allowed an overall yield of 6.3% (26 steps) from optically active 3-silyloxy-2-methylaldehyde.

Total synthesis of zoanthamine alkaloids.

Zoanthamine alkaloids, isolated from organisms in the Zoanthus genus, constitute a distinctive family of marine metabolites. These molecules exhibit a broad spectrum of unique biological properties. For example, norzoanthamine inhibits interleukin-6, the key mediator of bone resorption in osteoporosis, providing a promising drug candidate for a disease that affects more than 10 million people over age 50 in the United States. In addition, these natural products are characterized by a densely functionalized heptacyclic framework, as exemplified by the structures of zoanthamine, norzoanthamine, and zoanthenol, which makes them extremely attractive targets for chemical synthesis. Prior to our first total synthesis of norzoanthamine in 2004, the densely functionalized and complex stereostructures of the zoanthamine alkaloids had impeded synthetic studies of these molecules. In this Account, we describe our synthetic approach toward the total synthesis of zoanthamine alkaloids, focusing on how we overcame various synthetic challenges. At the beginning of our synthetic studies, we aimed to develop an efficient route that was flexible enough to provide access to several members of the family while allowing the synthesis of various analogues for biological testing. Our first project was the total synthesis of norzoanthamine, and we established an efficient synthetic route based on a novel strategy involving the following key features. First, we used a sequential three-component coupling reactions and subsequent photosensitized oxidation of a furan moiety to synthesize the precursor for the key intramolecular Diels-Alder reaction. Second, the key intramolecular Diels-Alder reaction constructed the ABC-ring carbon framework bearing two adjacent quaternary asymmetric carbon atoms at the C12 and C22 positions in a single stereoselective step. Third, we installed the third quaternary asymmetric carbon center at the C9 position by an intramolecular acylation of a keto alcohol followed by successive O-methylation and C-methylation reactions with complete stereoselectivity. Through the exploitation of a deuterium kinetic isoptope effect, we then efficiently synthesized the alkyne segment. Next, a coupling reaction between the alkyne segment and the amino alcohol segment and several subsequent synthetic transformations afforded the bis-aminoacetalization precursor. Finally, bis-aminoacetalization reactions carried out in one-pot constructed the DEFG-ring system and culminated in the total synthesis of norzoanthamine. Our synthetic route to norzoanthamine also allowed access to other zoanthamine alkaloids from a common synthetic intermediate, by way of stereoselective introduction of the C19 methyl group for zoanthamine, and isoaromatization for construction of the aromatic A-ring in zoanthenol. The chemistry described here not only allowed us to overcome formidable synthetic challenges but also opened a completely chemical avenue to naturally occurring zoanthamine alkaloids and their synthetic derivatives.

Synthetic studies of the lichen macrolide lepranthin. Stereoselective synthesis of the diolide framework based on regioselective epoxide-opening reactions.

Stereoselective synthesis of the 16-membered diolide 27, a fully functionalized congener of lepranthin (1), is described. The requisite five asymmetric carbon centers in monomer 23 were constructed in a highly stereoselective manner by using different epoxide-opening reactions of α,ß-unsaturated γ,δ-epoxy esters and epoxy alcohol derivatives as the key steps. The monomer 23 was successfully transformed into the MOM protected diolide 27 by Yamaguchi macrolactonization.

Synthetic studies of the zoanthamine alkaloids: the total syntheses of norzoanthamine and zoanthamine.

The zoanthamine alkaloids, a type of heptacyclic marine alkaloid isolated from colonial zoanthids of the genus Zoanthus sp., have distinctive biological and pharmacological properties in addition to their unique chemical structures with stereochemical complexity. Namely, norzoanthamine (1) can suppress the loss of bone weight and strength in ovariectomized mice and has been expected as a promising candidate for a new type of antiosteoporotic drug, while zoanthamine (2) has exhibited potent inhibitory activity toward phorbol myristate-induced inflammation in addition to powerful analgesic effects. Recently, norzoanthamine derivatives were demonstrated to inhibit strongly the growth of P-388 murine leukemia cell lines, in addition to their potent antiplatelet activities on human platelet aggregation. Their distinctive biological properties, combined with novel chemical structures, make this family of alkaloids extremely attractive targets for chemical synthesis. However, the chemical synthesis of the zoanthamine alkaloids has been impeded owing to their densely functionalized complex stereostructures. In this paper, we report the first and highly efficient total syntheses of norzoanthamine (1) and zoanthamine (2) in full detail, which involve stereoselective synthesis of the requisite triene (18) for an intramolecular Diels-Alder reaction via the sequential three-component coupling reactions, the key intramolecular Diels-Alder reaction, and subsequent crucial bis-aminoacetalization as the key steps. Ultimately, we achieved the total synthesis of norzoanthamine (1) in 41 steps with an overall yield of 3.5 % (an average of 92 % yield each step) and that of zoanthamine (2) in 43 steps with an overall yield of 2.2 % (an average of 91 % yield each step) starting from (R)-5-methylcyclohexenone (3), respectively.

Stereoselective synthesis of premisakinolide A, the monomeric counterpart of the marine 40-membered dimeric macrolide misakinolide A.

[structure: see text] The first synthesis of premisakinolide A, the monomeric counterpart of misakinolide A, the marine 40-membered macrolide displaying potent activity against a variety of human carcinoma cell lines, has been reported. The strategy was highlighted by a crucial coupling of a tetrahydropyran fragment and an alkynylaluminum reagent having a polypropionate chain, the highly stereoselective cross aldol reaction of segment A and segment B, and the stereospecific construction of the polypropionate structure based on original acyclic stereocontrol.

Synthetic studies of tedanolide, a marine macrolide displaying potent antitumor activity. Stereoselective synthesis of the C13-C23 segment.

[structure: see text] A highly stereoselective synthesis of the C13-C23 segment of tedanolide (1), an 18-membered macrolide isolated from the Caribbean sponge Tedania ignis, displaying significant cytotoxicity against KB and PS tumor cell lines, is described which involves two stereoselective epoxidations of regioisomeric trisubstituted double bonds and a stereospecific S(N)2' methylation reaction of a trans-gamma,delta-epoxy-cis-alpha,beta-unsaturated ester as the key steps.

R3Al-R'3SiOTf: novel and powerful reagent system for stereospecific alkylation-silylation reactions of epoxides.

[reaction: see text] A novel and powerful reagent system R(3)Al-R'(3)SiOTf for the one-pot alkylation-silylation reaction of epoxides was discovered, and the reactions of various epoxides with the new reagent system have been demonstrated to occur stereospecifically giving rise to the corresponding alkylation-silylation products in excellent yields.

Total synthesis of scytophycin C. 2. Coupling reaction of the C(1)-C(18) segment and the C(19)-C(31) segment, a key macrolactonization, and the crucial terminal amidation reaction.

[reaction: see text] Stereoselective syntheses of the C(1)-C(18) segment (segment A) and the C(19)-C(31) segment (segment B) are described in the preceding paper. This paper reports the key coupling reaction of both segments, 22-membered lactonization, and the crucial terminal amidation reaction culminating in the total synthesis of scytophycin C.

Total synthesis of scytophycin C. 1. Stereoselective syntheses of the C(1)-C(18) segment and the C(19)-C(31) segment.

[structure: see text] Stereoselective total synthesis of scytophycin C, a marine 22-membered macrolide displaying potent activity against a variety of human carcinoma cell lines, has been reported in which the polypropionate structure bearing contiguous asymmetric centers was stereospecifically constructed by using new acyclic stereocontrol. This paper describes stereoselective syntheses of the C(1)-C(18) segment (Segment A) including a trans-disubstituted dihydropyran ring and the C(19)-C(31) segment (Segment B) having eight stereogenic centers.

The C2 selective nucleophilic substitution reactions of 2,3-epoxy alcohols mediated by trialkyl borates: the first endo-mode epoxide-opening reaction through an intramolecular metal chelate.

[reaction: see text] Highly efficient C2 selective substitution reactions of 2,3-epoxy alcohols with nucleophiles were developed by using NaN(3)-(CH(3)O)(3)B, NaSPh-(CH(3)O)(3)B, or NaCN-(C(2)H(5)O)(3)B system. The reaction proceeds through novel endo-mode epoxide opening of an intramolecular boron chelate, which was suggested from both experimental and quantum mechanic studies.

Stereoselective synthesis of cycloheptanone derivatives via an intermolecular [5 + 2] cycloaddition reaction.

[reaction: see text] A [5 + 2] cycloaddition reaction of a new five-carbon unit was developed on the basis of a dicobalt hexacarbonyl propargyl cation species. Under the influence of EtAlCl(2), [5-benzoyloxy-2-(triisopropylsiloxy)-1-penten-3-yne)]dicobalt hexacarbonyl reacted with enol triisopropylsilyl ethers to yield seven-membered dicobalt acetylene complexes in good yield. The reactions with cyclic enol silyl ethers as well as acyclic enol silyl ethers exhibited remarkably high diastereoselectivity. The cycloadducts can be easily converted into various kinds of cycloheptanone derivatives.

Palladium-catalyzed stereospecific epoxide-opening reaction of gamma,delta-epoxy-alpha,beta-unsaturated esters with an alkylboronic acid leading to gamma,delta-vicinal diols with double inversion of the configuration.

A palladium-catalyzed stereospecific epoxide-opening reaction of gamma,delta-epoxy-alpha,beta-unsaturated esters with an alkylboronic acid leading to gamma,delta-vicinal diols is described, which proceeds with retention of the configuration, i.e., via two consecutive S(N)2 processes, to afford the corresponding gamma,delta-cyclic boronates in high yields.

A regio- and stereoselective alpha-methylation of gamma,delta-epoxy-alpha,beta-unsaturated esters with a Me2Zn-CuCN reagent.

A highly regio- and stereoselective alpha-methylation reaction of gamma,delta-epoxy-alpha,beta-unsaturated esters was achieved by using a Me2Zn-CuCN reagent.

Total synthesis and structural revision of sekothrixide.

The first total synthesis of 14-membered macrolide sekothrixide and the originally proposed structure are reported. Seven contiguous asymmetric centers in the side chain were constructed using ring-openings of several kinds of epoxide. Assembly of the left segment and right segment was performed on the basis of the RCM reaction to generate 14-membered lactones having an E-trisubstituted olefin. These synthetic results led to a revision of C4, C6, and C8 stereochemistry in the structure of natural sekothrixide.

Synthetic studies of the zoanthamine alkaloids: total synthesis of zoanthenol based on an isoaromatization strategy.

The total synthesis of zoanthenol, a unique aromatic member of the zoanthamine alkaloids, which has exhibited potent anti-platelet activities on human platelet aggregation, is described in full detail. The key step involves a Brønsted acid-promoted isoaromatization in the AB ring system to install the crucial aromatic ring. We have not only succeeded in the first total synthesis of zoanthenol, but also established an alternative efficient synthetic route from the commercially available norzoanthamine hydrochloride to zoanthenol.

Total synthesis of solanoeclepin A.

Cyst nematodes are troublesome parasites that live on, and destroy, a range of important host vegetable plants. Damage caused by the potato cyst nematode has now been reported in over 50 countries. One approach to eliminating the problem is to stimulate early hatching of the nematodes, but key hatching stimuli are not naturally available in sufficient quantities to do so. Here, we report the first chemical synthesis of solanoeclepin A, the key hatch-stimulating substance for potato cyst nematode. The crucial steps in our synthesis are an intramolecular cyclization reaction for construction of the highly strained tricyclo[5.2.1.0¹'6]decane skeleton (DEF ring system) and an intramolecular Diels-Alder reaction of a furan derivative for the synthesis of the ABC carbon framework. The present synthesis has the potential to contribute to addressing one of the critical food issues of the twenty-first century.