Highly Torquoselective Electrocyclizations and Competing 1,7-Hydrogen Shifts of 1-Azatrienes with Silyl Substitution at the Allylic Carbon

Ma, Zewei; Patel, Ashay; Houk, K. N.; Hsung, Richard P.

doi:10.1021/acs.orglett.5b00727

Cited by 14 publications

(14 citation statements)

References 25 publications

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“…The synthesis of silyl-substituted 1-azatrienes and the scope of the ring closures of these compounds are reported separately. 38 The predicted stereochemical outcome is observed experimentally; however, the ring closure of 1-azatriene 10 is reversible at 130°C, and over time the diastereoselectivity of the reaction comes under thermodynamic control. Here we report the origins of the selectivity of the electrocyclization of 10 , using azatriene 12 as a computational model substrate.…”

Section: Resultsmentioning

confidence: 92%

“…The computed t ½ at 130 °C for the ring opening (retroelectrocyclization) of either electrocyclization product is approximately 420 hr, too large a value considering experimental equilibration of the diastereomeric products of electrocyclization occurs within 24 hrs. 38 The bulky TBDPS group employed experimentally likely accelerates equilibration by destabilizing the products of the electrocyclic ring closure. In any case, the relative energy differences between two the dihydropyridine products indicate that the thermodynamic product is also the kinetic product 13a .…”

Section: Resultsmentioning

confidence: 99%

“…Studies of the generality of the stereochemical influence of α-silyl groups and the synthetic utility of the ring closures of α-silyl azatrienes have been reported seperately. 38 …”

Section: Discussionmentioning

confidence: 99%

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Transition State Gauche Effects Control the Torquoselectivities of the Electrocyclizations of Chiral 1-Azatrienes

Patel¹,

Vella²,

et al. 2015

J. Org. Chem.

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Hsung et al. have reported a series of torquoselective electrocyclizations of chiral 1-azahexa-1,3,5-trienes that yield functionalized dihydropyridines. To understand the origins of the torquoselectivities of these azaelectrocyclizations, we modeled these electrocyclic ring closures using the M06-2X density functional. A new stereochemical model that rationalizes the observed 1,2 stereoinduction emerges from these computations. This model is an improvement and generalization of the “inside-alkoxy” model used to rationalize stereoselectivities of 1,3-dipolar cycloaddition of chiral allyl ethers and emphasizes a stabilizing hyperconjugative effect, which we have termed a transition state gauche effect. This stereoelectronic effect controls the conformational preferences at the electrocyclization transition states, and only in one of the allowed, disrotatory electrocyclization transition states is the ideal stereoelectronic arrangement of substituent achieved without the introduction of a steric clash. Computational experiments confirm the role of this effect as a stereodeterminant, since substrates with electropositive groups like a silyl substituent and electronegative groups have different conformational preferences at the transition state and undergo ring closure with divergent stereochemical outcomes. This predicted reversal of stereoselectivity for the ring closure of a silyl-substituted azatriene has been demonstrated experimentally.

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

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Transition State Gauche Effects Control the Torquoselectivities of the Electrocyclizations of Chiral 1-Azatrienes

Patel¹,

Vella²,

et al. 2015

J. Org. Chem.

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“…We anticipated that the TBS-protected chromene 18 could generate the desired diene 19 in situ through retro 6π-electrocyclization followed by deprotonation/protonation (formal [1,7] hydrogen shift). 23 Accordingly, (±)- 18 was employed in cycloadditions with acetylated 2′-hydroxychalcone 20 in the presence of AgNPs to yield a mixture of two endo cycloadducts and minimal production of exo diastereomers. The mixture of endo cycloadducts was sequentially treated with aqueous NaHCO 3 and NEt 3 ·3HF 24 to yield a mixture of (±)-sanggenons C ( 3 ) and O ( 4 ) in 36% yield (3 steps, 4:1 d.r.…”

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confidence: 99%

Asymmetric Syntheses of the Flavonoid Diels–Alder Natural Products Sanggenons C and O

Xiong

Eschenbrenner‐Lux

et al. 2016

J. Am. Chem. Soc.

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Metal-catalyzed, double Claisen rearrangement of a bis-allyloxyflavone has been utilized to enable a concise synthesis of the hydrobenzofuro[3,2-b]chromenone core structure of the natural products sanggenon A and sanggenol F. In addition, catalytic, enantioselective [4+2] cycloadditions of 2′-hydroxychalcones have been accomplished using B(OPh)3/BINOL complexes. Asymmetric syntheses of the flavonoid Diels–Alder natural products sanggenons C and O have been achieved employing a stereodivergent reaction of a racemic mixture (stereodivergent RRM) involving [4+2] cycloaddition.

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“…[2] However,a ccess to different structural variants is constrained by reported synthetic routes to the approved semisynthetic opioid ligands,w hich rely on morphine,t hebaine,a nd other morphinoid natural products as heavily functionalized starting materials. [8][9][10] Thep recursor for this cascade reaction, imine 6,s hould be readily accessible from ester 7 through straightforward functional-group transformations.E ster 7 should be obtainable by regioselective Sharpless asymmetric dihydroxylation, [11] isopropylidene protection, and alkyne benzylation of the achiral dienoate 8. ent-Ketorfanol should be accessible through acid-catalyzed intramolecular Friedel-Crafts cycliza-tion of intermediate 2.…”

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confidence: 99%

ChemInform Abstract: Synthesis of ent‐Ketorfanol via a C—H Alkenylation/Torquoselective 6π Electrocyclization Cascade.

et al. 2016

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The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A Rh I -catalyzed intramolecular CÀHa lkenylation/torquoselective 6p electrocyclization cascade provides afused bicyclic 1,2-dihydropyridine as ak ey intermediate.C omputational studies were performed to understand the high torquoselectivity of the key 6p electrocyclization. The computational results demonstrate that ac onformational effect is responsible for the observed selectivity.T he ketone functionality and final ring are introduced in as ingle step by ar edox-neutral acidcatalyzedr earrangement of av icinal diol to give the requisite carbonyl, followed by intramolecular Friedel-Crafts alkylation. Oxycodone[1] and related semisynthetic opioid ligands are effective and pervasively used medications for the management of pain. However,t hese compounds have significant liabilities that include dependency, tolerance,which results in increasing doses being required to maintain efficacy, and the serious side effects of higher doses,such as respiratory failure. Therecently reported high-resolution structures of anumber of opioid receptor ligands in complex with several receptor subtypes provide an exceptional opportunity for the structure-based design of new opioid ligands with reduced drawbacks.[2] However,a ccess to different structural variants is constrained by reported synthetic routes to the approved semisynthetic opioid ligands,w hich rely on morphine,t hebaine,a nd other morphinoid natural products as heavily functionalized starting materials. [3,4] Our recently developed Rh-catalyzed CÀHfunctionaliza-tion/6p electrocyclization cascade [5] should enable direct and rapid entry to this important class of alkaloids from readily available achiral precursors.H erein, we demonstrate this approach with the asymmetric synthesis of ent-ketorfanol (1), the nonregulated enantiomer of the semisynthetic opioid drug ketorfanol (Scheme 1). ent-Ketorfanol should be accessible through acid-catalyzed intramolecular Friedel-Crafts cyclization of intermediate 2.[6] This intermediate could potentially be obtained in situ from 3 under the acidic reaction conditions via aspeculative redox-neutral process [7] proceeding through ionization of the allylic oxygen functionality followed by ah ydrogen shift (see below). Fused bicyclict etrahydropyridine 3 would then be obtained through reduction of dihydropyridine 4 under mildly acidic reductive amination conditions.Int he key step,bicyclici ntermediate 4 should be accessible via an intramolecular Rh-catalyzed syn CÀHbond addition to the alkyne,f ollowed by electrocyclization, which should hopefully proceed with high torquoselectivity owing to remote asymmetric induction provided by the isopropylidine protected diol. [8][9][10] Thep recursor for this cascade reaction, imine 6,s hould be readily accessible from ester 7 through straightforward functional-group transformations.E ster 7 should be obtainable by regioselective Sharpless asymmetric dihydroxylation, [11] isopropy...

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Highly Torquoselective Electrocyclizations and Competing 1,7-Hydrogen Shifts of 1-Azatrienes with Silyl Substitution at the Allylic Carbon

Cited by 14 publications

References 25 publications

Transition State Gauche Effects Control the Torquoselectivities of the Electrocyclizations of Chiral 1-Azatrienes

Transition State Gauche Effects Control the Torquoselectivities of the Electrocyclizations of Chiral 1-Azatrienes

Asymmetric Syntheses of the Flavonoid Diels–Alder Natural Products Sanggenons C and O

ChemInform Abstract: Synthesis of ent‐Ketorfanol via a C—H Alkenylation/Torquoselective 6π Electrocyclization Cascade.

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