“…Morken and co-workers 9 have recently reported the first total synthesis of borrelidin utilizing enantioselective asymmetric methods of subunit construction and assembly. The synthesis of individual deoxypropionate subunits has been the subject of two reports, , relying on a Sharpless asymmetric epoxidation and a Myers enolate alkylation as key reactions, respectively. 1 Borrelidin and its chiral progenitors.…”
The total synthesis of (-)-borrelidin (treponemycin), a structurally distinct 18-membered macrolide antibiotic, has been achieved. It was isolated as the crystalline benzene solvate, and its structure was confirmed by a single-crystal X-ray analysis. The deoxypropionate subunit consisting of four alternating C-methyl groups with a C(4)-C(10) syn/syn/anti orientation was elaborated by a new method of iterative cuprate additions to acyclic alpha,beta-unsaturated esters relying on two consecutive 1,3-inductions and starting with d-glyceraldehyde as the chiral progenitor. The unique Z/E cyanodiene unit was obtained as a single isomer by application of the Still-Gennari olefination protocol. The gamma-hydroxycyclopentane carboxylic acid subunit was prepared from L-malic acid utilizing a sequential introduction of C-vinyl and C-allyl groups, capitalizing on 1,2-induction in an acyclic alpha,beta-unsaturated ester and carbocyclization by a Grubbs ring closure metathesis reaction. The prevalence of 1,3-syn-disposed deoxypropionate triads in the cuprate additions is rationalized on the basis of minimized syn-pentane interactions in the transition states. A virtual diamond lattice was used as a visual tool to portray the low-energy conformations of the acyclic substrates, and corroborated by (1)H NMR homodecoupling studies.
“…Morken and co-workers 9 have recently reported the first total synthesis of borrelidin utilizing enantioselective asymmetric methods of subunit construction and assembly. The synthesis of individual deoxypropionate subunits has been the subject of two reports, , relying on a Sharpless asymmetric epoxidation and a Myers enolate alkylation as key reactions, respectively. 1 Borrelidin and its chiral progenitors.…”
The total synthesis of (-)-borrelidin (treponemycin), a structurally distinct 18-membered macrolide antibiotic, has been achieved. It was isolated as the crystalline benzene solvate, and its structure was confirmed by a single-crystal X-ray analysis. The deoxypropionate subunit consisting of four alternating C-methyl groups with a C(4)-C(10) syn/syn/anti orientation was elaborated by a new method of iterative cuprate additions to acyclic alpha,beta-unsaturated esters relying on two consecutive 1,3-inductions and starting with d-glyceraldehyde as the chiral progenitor. The unique Z/E cyanodiene unit was obtained as a single isomer by application of the Still-Gennari olefination protocol. The gamma-hydroxycyclopentane carboxylic acid subunit was prepared from L-malic acid utilizing a sequential introduction of C-vinyl and C-allyl groups, capitalizing on 1,2-induction in an acyclic alpha,beta-unsaturated ester and carbocyclization by a Grubbs ring closure metathesis reaction. The prevalence of 1,3-syn-disposed deoxypropionate triads in the cuprate additions is rationalized on the basis of minimized syn-pentane interactions in the transition states. A virtual diamond lattice was used as a visual tool to portray the low-energy conformations of the acyclic substrates, and corroborated by (1)H NMR homodecoupling studies.
“…The structural novelty and relevant biological activity of borrelidin present an exciting challenge for chemical synthesis and are the focus of this report. 8 Our strategy for the synthesis of 1 focused on the use of an iridium-indanepybox (2)-catalyzed enantioselective reductive aldol reaction to establish the stereogenic centers at C3, C4, C10, and C11. 9 This represents the first example of the use of this transformation in the context of complex natural product synthesis.…”
mentioning
confidence: 99%
“…The structure of borrelidin is characterized by an 18-membered macrolactone carrying a cyclopentane carboxylic acid and a unique conjugated cyanodiene (Figure ). The structural novelty and relevant biological activity of borrelidin present an exciting challenge for chemical synthesis and are the focus of this report 1 Structure of borrelidin and retrosynthetic disconnections. …”
The first total synthesis of the natural product borrelidin is described. The propionate fragment of the molecule was concisely synthesized through catalytic enantioselective reductive aldol reactions, a catalytic Negishi coupling, and a catalytic directed hydrogenation. The propionate segment was then fused to the vinyl iodide fragment through a catalytic Sonogashira coupling. Subsequent catalytic hydrostannylation and catalytic cyanation allowed access to the target structure.
“…The dense arrangement of chiral centres in this 18-membered macrocycle, together with the peculiar and sensitive Z,E-cyanodiene moiety, has attracted considerable attention from organic chemists. [11] After an early study by Haddad et al, [12] the groups of Morken [13] and Hanessian [14] first reported total syntheses of the compound, closely followed by the groups of Theodorakis [15] and Omura. [16] The strategies reported essentially rely on starting materials from the chiral pool, chiral auxiliaries or kinetic resolution of advanced intermediates.…”
Borrelidin (1) is a polyketide that possesses extremely potent anti-angiogenesis activity. This paper describes its formal total synthesis by the most efficient route to date. This modular approach takes optimal benefit of asymmetric catalysis and permits the synthesis of analogues; in addition, the high yields and selectivities obtained eliminate the need for separation of stereoisomers. The upper half of borrelidin has been accessed by iterative copper-catalysed asymmetric conjugate addition of methylmagnesium bromide, whereas synthesis of the lower half of the molecule was achieved by relying on asymmetric hydrogenation and cross-methathesis as key steps.
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