The Vinylogous Intramolecular Morita−Baylis−Hillman Reaction:  Synthesis of Functionalized Cyclopentenes and Cyclohexenes with Trialkylphosphines as Nucleophilic Catalysts

Frank, Scott A.; Mergott, Dustin J.; Roush, William

doi:10.1021/ja017123j

Cited by 227 publications

(59 citation statements)

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“…A variety of Rauhut-Currier conditions, which modified both phosphine and solvent, were explored to determine the optimum method for conversion of 3 to 4 ( Table 1). [33][34][35][36] Consistent with previously reported tendencies in the Rauhut-Currier reaction, 32 the relatively more electrophilic alkenes in 3a and 3c, easily underwent tandem conjugate addition/Michael addition and subsequent phosphine elimination to afford the products, 4a and 4c respectively, in high yield. The regioselectivity of the tandem reaction in 3a and 3c is presumably founded on both electronic and steric principles.…”

Section: Methodssupporting

confidence: 81%

“…[23][24][25][26][27][28][29][30][31] The intramolecular Rauhut-Currier reaction 32 has experienced a resurgence based on groundbreaking studies by Krische, 33 Murphy, 34,35 and Roush. 36 Under the influence of catalytic phosphine, conjugated systems can be merged to form a new ring while retaining one conjugated system for subsequent functionalization. Application of the intramolecular Rauhut-Currier reaction to the cross metathesis product 3 should afford valuable intermediates 4 on the path to a range of complex chemical architectures.…”

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confidence: 99%

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Enantioselective synthesis of bicarbocyclic structures with an all-carbon quaternary stereocenter through sequential cross metathesis and intramolecular Rauhut–Currier reaction

Qiao

Kumar

Malachowski

2010

Tetrahedron Letters

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Section: Methodssupporting

confidence: 81%

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confidence: 99%

Enantioselective synthesis of bicarbocyclic structures with an all-carbon quaternary stereocenter through sequential cross metathesis and intramolecular Rauhut–Currier reaction

Qiao

Kumar

Malachowski

2010

Tetrahedron Letters

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“…Although almost certainly reversible, such a site-selective, intermolecular conjugate addition reaction could trigger an intramolecular conjugate addition (see arrows in 4), resulting in the production of a key carbon-carbon bond and the carbocyclic ring of (ϩ)-harziphilone (for selected tandem conjugate addition͞Michael cyclization reactions see refs. [12][13][14][15][16][17]. A ␤-elimination of the heteroatom nucleophile might then generate 3 and set the stage for a final cycloisomerization to (ϩ)-harziphilone (2; P ϭ H).…”

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confidence: 99%

A nucleophile-catalyzed cycloisomerization permits a concise synthesis of (+)-harziphilone

Stark

Pekari

Sorensen

2004

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

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Substantial structural transformations of much use in complex chemical synthesis can be achieved by channeling the reactivity of highly unsaturated molecules. This report describes the direct conversion of an acyclic polyunsaturated diketone to the HIV-1 Rev͞Rev-responsive element inhibitor harziphilone under mild reaction conditions. nucleophilic catalysis ͉ Baylis-Hillman reaction ͉ conjugate additions ͉ electrocyclizations ͉ domino reactions T he reactivity of activated polyenes is the basis for some of the most impressive structural transformations in nature and chemical synthesis. The biosyntheses of the complex structures of the polycyclic triterpenes from squalene and 2,3-oxidosqualene may be viewed as paragons for processes that build polycyclic molecular complexity directly from reactive polyenes (1-3). In connection with our efforts to channel the reactivity of activated polyunsaturated molecules, we sought mild reaction conditions under which compound 1 could be isomerized to the bicyclic structure of harziphilone (2), a naturally occurring inhibitor of the binding interaction between the HIV-1 Rev protein and the Rev-responsive element (RRE) of viral mRNA (4) (Scheme 1). This report describes an enantioselective synthesis of (ϩ)-harziphilone based on the general idea expressed in Scheme 1.The structure of (ϩ)-harziphilone (2) comprises fifteen carbon atoms, two six-membered ring systems, one carbocyclic and the other heterocyclic, a keto group, two contiguous hydroxylbearing stereocenters, and a pentadienyl side chain. All of the polar groupings of harziphilone are confined to the sixmembered carbocycle, whereas the hydrophobic pentadienyl moiety is displayed as a side chain on the ␣-pyran ring. Our approach to the problem of synthesizing this natural product was guided by the retrosynthetic analysis shown in Scheme 2.The independent early investigations of Büchi (5) and Marvell (6, 7) provided a sound basis for the proposal that the oxacyclic ring of harziphilone, with its particular arrangement of alkenes, could arise by a 6 -electrocyclization of a compound of type 3 (for selected examples of this type of valence isomerization in synthesis see refs. 8-11). With several electrophilic sites and a high degree of unsaturation, 3 was perceived to be a challenging objective for synthesis, and we elected to explore the possibility of producing this potentially transient intermediate in situ from a doubly activated, polyunsaturated acyclic compound of type 1. To implement this concept, we would seek a suitable heteroatom nucleophile that could attack the unsubstituted enone moiety in 1. Although almost certainly reversible, such a site-selective, intermolecular conjugate addition reaction could trigger an intramolecular conjugate addition (see arrows in 4), resulting in the production of a key carbon-carbon bond and the carbocyclic ring of (ϩ)-harziphilone (for selected tandem conjugate addition͞Michael cyclization reactions see refs. 12-17). A ␤-elimination of the heteroatom nucleophile might then genera...

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“…To establish the stereochemistry of the major cycloadduct 12, this intermediate was converted to the spinosyn A pseudoaglycon 28. Thus, treatment of 12 with Me 3 P effected the vinylogous MBH cyclization (18,45,46) and provided an 88:7:5 mixture of the desired product 26, the olefin migration product 27, and the C(3) epimer of 26 (structure not shown) in quantitative yield. After HPLC purification of 26, reductive removal of the C(6)OBr directing group was accomplished by treatment of 26 with (tristrimethylsilyl)silane and azobisisobutyronitrile (AIBN) (47,48).…”

Section: Chemistrymentioning

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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The Vinylogous Intramolecular Morita−Baylis−Hillman Reaction: Synthesis of Functionalized Cyclopentenes and Cyclohexenes with Trialkylphosphines as Nucleophilic Catalysts

Cited by 227 publications

References 19 publications

Enantioselective synthesis of bicarbocyclic structures with an all-carbon quaternary stereocenter through sequential cross metathesis and intramolecular Rauhut–Currier reaction

Enantioselective synthesis of bicarbocyclic structures with an all-carbon quaternary stereocenter through sequential cross metathesis and intramolecular Rauhut–Currier reaction

A nucleophile-catalyzed cycloisomerization permits a concise synthesis of (+)-harziphilone

Total synthesis of (–)-spinosyn A

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