Enantioselective synthesis of the bottom half of chlorothricolide. 3. Studies of the steric directing group strategy for stereocontrol in intramolecular Diels-Alder reactions

An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol has been devised. This new route increases the throughput and yield of the diene product by circumventing a low yielding preparation of boronic acid intermediate as well as removing the need to use multi-gram quantities of highly toxic thallium salts. In the process of developing this new route, a higher yielding preparation of ( E)-3-hydroxyprop-1-enylboronic acid was also achieved. (c) 2007 Elsevier Ltd. All rights reserved

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“…15,16 Wittig olefination installed the second double bond as a single (E)-geometric isomer in a yield of 64%.…”

Section: Resultsmentioning

confidence: 99%

An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol

et al. 2007

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“…(E)-Alkenyl boronates 20 a,b were obtained in high yield and excellent stereoselectivity from commercially available benzaldehydes 19 a,b using the Takai-Utimoto condensation reaction, [44] after activation of 2-(dichloromethyl)pinacolboronate with chromium(II) in the presence of lithium iodide. [45] Two previously described alkenylboron reagents 21 [46] and 22 [47] were obtained by the hydroboration of the precursor alkynes and hydrolysis for 22.…”

Section: Synthesismentioning

confidence: 99%

New Anacardic Acid‐Inspired Benzamides: Histone Lysine Acetyltransferase Activators

et al. 2010

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A series of N-(4-cyano-3-trifluoromethyl-phenyl)-2-ethoxy-6-alkyl (and alkenyl) benzamides related to the anacardic acid derivative CTPB have been prepared from 2,6-dihydroxybenzoic acid with a Suzuki coupling and addition of the anion of 4-cyano-3-trifluoromethylphenylamine to a benzodioxinone as the key steps. In U937 cells, these analogues, in particular 7 c, 7 d, 7 f and 7 j, induced cell-cycle arrest in the G1 phase, caused apoptosis in about 20 % of the cells, and increased the acetylation levels of H3. These activities correlate with the enzymatic activation of histone lysine acetyltransferases (KATs): CBP and PCAF.

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“…We initially hoped to use the steric directing-group strategy to control the diastereoselectivity of the Diels-Alder reaction (15)(16)(17), which could involve appending a bromine steric directing group at C(6) of the IMDA or TDA substrate to control the stereochemical outcome of the cycloaddition, leading to the desired C(7)OC(11) trans-fused diastereomer. It was anticipated that TS2, which leads to the undesired C(7)OC(11) trans-fused isomer 10 and is favored in the absence of the C(6)OBr steric directing group, may be destabilized relative to TS1 by a steric interaction between C(6)OBr and the C(9)Oalkoxy substituent (Scheme 3).…”

Section: Synthetic Strategymentioning

confidence: 99%

Total synthesis of (–)-spinosyn A

Mergott

Frank

Roush

2004

Proc. Natl. Acad. Sci. U.S.A.

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127

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A convergent, highly stereoselective total synthesis of (؊)-spinosyn A (1) is described. Key features of the synthesis include the transannular Diels-Alder reaction of macrocyclic pentaene 11 and the transannular Morita-Baylis-Hillman cyclization of 12 that generates tetracycle 26. The total synthesis of (؊)-spinosyn A was completed by a sequence involving the highly ␤-selective glycosidation reaction of 13 and glycosyl imidate 30.T he spinosyns are a family of polyketide natural products that possess extraordinary insecticidal activity. The biosynthetic mixture, generated by Saccharopolyspora spinosa, comprises mostly spinosyn A (1) (Scheme 1) (Ϸ85%) and spinosyn D (Ϸ10-15%) (1-8). This mixture is currently marketed for use as an insecticide against a variety of insects (6). Total syntheses of spinosyn A have been reported by Evans and Black (9) and Paquette et al. (10,11). Synthetic StrategyDiels-Alder reactions have been proposed as key steps in the biogenesis of several natural products, including lovastatin, solanapyrone, nargenicin, and ikarugamycin (12). Kirst et al. (3) suggested that the biosynthesis of spinosyn A may involve a transannular Diels-Alder (TDA) (13) reaction of a macrocyclic pentaene to form the C(4)OC(12) and C(7)OC (11) bonds (see 4 3 3; Scheme 1). Kirst also suggested that a transannular cyclization of a 1,3-dicarbonyl nucleophile may generate the C(3)OC (14) bond (3). Alternatively, we speculated that the C(3)OC(14) bond may be formed by a vinylogous Morita-Baylis-Hillman (MBH) reaction mediated by an enzymatic nucleophile (compare 3 3 1; Scheme 1). Based on these biosynthetic considerations, we sought to assemble spinosyn A (1) via a TDA and MBH cyclization sequence of an appropriately functionalized macrocyclic pentaene 4.Diastereoselectivity of the Diels-Alder Reaction. Paramount to the success of this synthetic strategy is the control of the diastereoselectivity of the TDA reaction (4 3 3). It is known from the work of Evans and Black (9) that the intrinsic diastereofacial selectivity of the intramolecular Diels-Alder (IMDA) reaction of 5a favors the incorrect C(7)OC(11) trans-fused diastereomer 6a with 6:1 selectivity (Scheme 2). Although Evans and Black (9) addressed this issue by incorporating a chiral auxiliary (13) in the dienophile (see 5b 3 7b), we would not have recourse to this strategy for the TDA cyclization of 4. Thus, some means for controlling the stereochemistry at the C(7)OC(11) ring fusion relative to the C(9)Oalkoxy substituent in the Diels-Alder reaction was required.We initially hoped to use the steric directing-group strategy to control the diastereoselectivity of the Diels-Alder reaction (15-17), which could involve appending a bromine steric directing group at C(6) of the IMDA or TDA substrate to control the stereochemical outcome of the cycloaddition, leading to the desired C(7)OC(11) trans-fused diastereomer. It was anticipated that TS2, which leads to the undesired C(7)OC(11) trans-fused isomer 10 and is favored in the absence of the C(6)OBr steric direct...

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Enantioselective synthesis of the bottom half of chlorothricolide. 3. Studies of the steric directing group strategy for stereocontrol in intramolecular Diels-Alder reactions

Cited by 72 publications

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An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol

An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol

New Anacardic Acid‐Inspired Benzamides: Histone Lysine Acetyltransferase Activators

Total synthesis of (–)-spinosyn A

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