Intramolecular Diels-Alder reactions of ester-linked 1,3,8-nonatrienes

[structures: see text] Penta-1,3-dienyl acrylates undergo kinetically controlled intramolecular Diels-Alder (IMDA) reactions and DFT calculations (B3LYP/6-31+G(d)) predict stereoselectivities that are in very good agreement with the experimental values. The nature of the diene C1 substituent has virtually no influence upon reactivity or trans/cis-stereoselectivity whereas terminal C9 dienophile substituents have a substantial effect on both the reactivity and stereoselectivity of these IMDA reactions. The TSs highlight contributions from strain in the developing tether-containing ring, and steric and electronic effects between tether and dienophile substituents, thus providing insight into the origins of IMDA reactivity and stereoselectivity.     

On the origin of cis/trans stereoselectivity in intramolecular Diels-Alder reactions of substituted pentadienyl acrylates: a comprehensive density functional study

[structures: see text] A gas-phase B3LYP/6-31+G(d) study of substituent effects on the stereochemistry of both intramolecular Diels-Alder (IMDA) reactions of 9-E- and 9-Z-substituted pentadienyl acrylates and intermolecular Diels-Alder (DA) reactions between butadiene and monosubstituted alkenes and 3-substituted acrylates is reported and involves the calculation of 230 transition structures. It was found that, although exo ("anti-Alder") addition of monosubstituted ethenes to butadiene is the norm, Alder endo selectivity is more widely predicted for 3-substituted methyl acrylate dienophiles, and this was explained in terms of secondary orbital interactions (SOIs). Whereas cis/trans selectivity for IMDA reactions involving 9-E-substituted pentadienyl acrylates generally follows the normal pattern found for the corresponding intermolecular DA reactions, the 9-Z-substituted stereoisomers generally displayed trans selectivity that was much stronger than can be attributed to effects of the isolated substituent. This is strikingly so with unsaturated electron-withdrawing substituents whose endo selectivities, displayed in intermolecular DA reactions, are reversed in the IMDA reactions of pentadienyl acrylates. The origin of this anomalous Z-effect is explained in terms of the twist-mode asynchronicity concept of Brown and Houk. These ideas are used to explain the stereochemical outcomes of IMDA reactions of other triene systems.     

Synthesis of new tricyclic phosphines and phosphinites by intramolecular Diels-Alder reactions of trivalent phospholes

Phospholes bearing an allyl-X substituent at phosphorus tend to undergo an intramolecular Diels-Alder cycloaddition (IMDA) leading to the corresponding tricyclic derivative. When X = O or NR, the IMDA easily takes place at room temperature. When X = CH2, the IMDA slowly takes place around 110-140 degrees C, as a function to the substitution pattern of the dienic system. Two tricyclic derivatives (X = O and CH2) have been characterized by X-ray crystal structure analysis of the P-sulfides.     

Stereocontrol of intramolecular Diels-Alder reactions by an allylic diphenylcyclopropyl group

Intramolecular Diels-Alder reactions of ester-linked 1,3,8-nonatrienes carrying a diphenylcyclopropyl substituent attached to C1 proceed with high levels of stereoselectivity. The stereochemical outcomes of these reactions are explained by reference to B3LYP/6-31G(d) transition structures. Experimentally, the diphenylcyclopropane rings remain intact through these IMDA reactions, notwithstanding their predicted extremely high degree of asynchronicity (the B3LYP-computed lengths in the IMDA transition structures differ by as much as 1.1 angstroms), providing support to the notion that these reactions are concerted processes.     

Total synthesis of (-)-spinosyn A: examination of structural features that govern the stereoselectivity of the key transannular Diels-Alder reaction

A study of elements of stereochemical control in transannular Diels-Alder reactions leading to the decahydro-as-indacene core of (-)-spinosyn A is described. Initial studies focused on macrocyclic pentaene 9, which includes C(6)-Br and C(8)-OTBS substituents. Excellent selectivity (>95:5) was observed in the cycloaddition of 9 as a consequence of 1,3-allylic strain interactions involving the C(6) and C(8) substituents in the disfavored TS-2. The major cycloadduct 22 was used in a formal synthesis of (-)-spinosyn A. The TDA cyclizations of 12 (which lacks the C(8)-OTBS unit of 9), 13 (which lacks the C(6)-Br substituent of 12), and 14 (which lacks the C(6)-Br and C(21)-Et substituents of 12) were also studied. Macrocycles 12 and 13 served as precursors to (-)-spinosyn A and the (-)-spinosyn A aglycon (34), respectively. It is striking that substrates 12-14 give very similar distributions of transannular Diels-Alder cycloadducts, indicating that the C(6)-Br and C(21)-stereocenter do not play a significant role in the diastereoselectivity of the TDA cycloaddition of spinosyn A precursor 12. It is likely that some as yet unidentified conformational or structural features of macrocycles 12-14 contribute to the levels of diastereoselectivity achieved, since these TDA reactions are more selective for the C(7)-C(9) stereochemical relationship found in the natural product than are the IMDA reactions of trienes 4 and 7.     

Controlling cis/trans-selectivity in intramolecular Diels-Alder reactions of benzo-tethered, ester linked 1,3,9-decatrienes

Predictions from DFT (B3LYP/6-31 G(d))-computed stereoisomer product distributions for intramolecular Diels-Alder (IMDA) reactions have been successfully replicated in the laboratory. Benzo-tethered hexadienyl acrylates generally undergo moderately trans-selective IMDA reactions which, as suggested by DFT calculation, arise from two opposing transition structure (TS) features: stabilising secondary orbital interactions, which are stronger in the cis-TSs, and stabilising pi-conjugative interactions between the benzo moiety and the 1,3-diene component - which are stronger in trans-TSs. Substrates carrying a removable substituent (i.e. Br or TMS) at C3 of the diene or C12 of the aromatic ring are predicted to undergo highly cis-selective thermal IMDA reactions by steric destabilisation of the trans-TS. A substrate carrying a two atom tether between C3 and C12 is predicted to undergo a highly trans-selective intramolecular cycloaddition by destabilisation of the cis-TS. These calculations are borne out experimentally.     

Stereocontrolled IMDA reaction of styrene derivatives. A way to enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines

IMDA reactions on chiral perhydro-1,3-benzoxazines, derived from (-)-8-amino menthol, bearing a styrene substituent at C-2 acting as diene and an acryl amide acting as dienophile occur with high stereoselection and excellent chemical yields. After elimination of the chiral appendage, enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines are prepared in this way. The effect of the substituents at both diene and dienophile are studied, showing that a methyl group at C-1 in the diene inhibited the reaction, while the ene adduct, instead of the IMDA product, was obtained when a methyl group was at C-2.     

An atom-economical approach to conformationally constrained tricyclic nitrogen heterocycles via sequential and tandem Ugi/intramolecular Diels-Alder reaction of pyrrole

An efficient approach to rigid tricyclic nitrogen heterocycles via sequential and tandem Ugi/intramolecular Diels-Alder (IMDA) cycloaddition of pyrrole is described. The one-pot Ugi four-component condensation (4CC) reaction was used as the key transformation to prepare trienes with a carboxamide substituent on the tether. The use of acrylic acid (21) and N-propyl- and N-benzylmaleamic acids (24b and 24C) as the acid components provided trienes 22, 25b, and 25c, respectively, which upon heating at 120 degrees C for 12 h yielded the corresponding [4 + 2] cycloaddition products. In the case of maleic acid derivative 24a, heating the reaction mixture at 60 degrees C for 6 h promoted the cycloaddition reaction and provided the desired product 26a in 78% yield. In contrast, fumaric acid monoethyl ester (27a) and 3-acetyl- and 3-(4-methylbenzoyl) acrylic acids (27b-c) directly yielded the corresponding Ugi/IMDA cycloaddition products 29a-c in high yields at room temperature without any trace of initially formed trienes 28a-c. The IMDA cycloaddition reactions proceed with excellent stereoselectivity with the formation of five stereogenic centers and three rings.     

A Synthesis of (+)-Oblongolide

The absolute configuration of natural oblongolide is reassigned as (3aS,5aR,7S,9aS,9bS)-3a,5a,6,7,8,9,9a,9b-octahydro-7,9b-dimethylnaphtho[1,2-c]furan-1(3H)-one 2 by a 7-stage synthesis of its enantiomer 1 from (+)-citronellol involving a regioselective reduction and an intramolecular Diels-Alder reaction (IMDA) as the key steps. (+)-Citronellol was converted into methyl (2E,4E,10E)-(S)-(+)-11-tert-butoxycarbonyl-7-methyl-undeca-2,4,10-trienoate 7 by sequential Lemieux-Johnson oxidation, Wittig reaction, pyridinium chlorochromate oxidation, and Wadsworth-Emmons-Homer alkenation. A regioselective reduction of the methoxycarbonyl group in 7 afforded tert-butyl (2.E,8E,10E)-(S)-(+)-2,6-dimethyl-12-hydroxy-dodeca-2,8,10-trienoate 8 from which (+)-oblongolide was readily obtained via an IMDA reaction.     

Synthetic study of 1,3-butadiene-based IMDA approach to construct a [5-7-6] tricyclic core and its application to the total synthesis of C8-epi-guanacastepene O

An efficient intramolecular Diels-Alder (IMDA) strategy for the construction of the [5-7-6] tricyclic core (18) of guanacastepenes has been developed from cis- and trans-1,3-butadiene-tethered 4-oxopent-2-ynoic acid ethyl esters 10 and 11. This method facilitates the synthesis of C8-epi-guanacastepene O (36) in a very efficient manner.     

Dual behavior of masked o-benzoquinones in intramolecular Diels-Alder reactions. Expedient synthesis of highly functionalized cis-decalins from 2-methoxyphenols

[Reaction: see text]. The potential dual behavior as dienes and dienophiles of the diene moieties of masked o-benzoquinones (MOBs) 10a-e-12a-e, generated upon oxidation of 2-methoxyphenols 1-3 with BTIB in the presence of appropriate dienols, in their intramolecular Diels-Alder (IMDA) reactions has been examined. The IMDA reactions of MOBs 10a-d, 11a,b,d, and 12a,b,d resulted in highly functionalized oxatricyclic compounds 18a-d, 19a,b,d, and 20a,b,d, respectively, with concomitant formation of cis-decalin derivatives 21a-d, 22a,b,d, and 23a,b,d in a highly regio- and stereoselective manner. However, the MOBs 10e-12e provided exclusively oxatricyclic compounds 18e-20e. The formation of cis-decalins in these IMDA reactions illustrates the dienophilic character of MOBs, in addition to their behavior as dienes. The ratio of the two cycloadducts obtained in each reaction as a result of the dual character of MOBs depends on the nature and/or position of the substituents on both the cyclohexadienone moiety and the added 2,4-dienol. The majority of the cycloadducts resulted from the diene property of MOBs in intramolecular Diels-Alder reactions smoothly underwent Cope rearrangement to furnish cis-decalins as sole products in excellent to quantitative yields that provides a short and efficient entry to polyfunctionized cis-decalins from 2-methoxyphenols. Furthermore, the variation of dienophilic and diene characters of MOBs in the IMDA reactions with the electron-donating or electron-withdrawing substituent of both cyclohexadienone moiety and the added conjugated acyclic diene or 2,4-dienol has been studied in detail.     

NR transfer reactivity of azo-compound I of P450. How does the nitrogen substituent tune the reactivity of the species toward C-H and C=C activation?

We studied electronic structures and reactivity patterns of azo-compound I species (RN-Cpd I) by comparison to O-Cpd I of, e.g., cytochrome P450. The study shows that the RN-Cpd I species are capable of C=C aziridination and C-H amidation, in a two-state mechanism similar to that of O-Cpd I. However, unlike O-Cpd I, here the nitrogen substituent (R) exerts a major impact on structure and reactivity. Thus, it is demonstrated that Fe=NR bonds of RN-Cpd I will generally be substantially longer than Fe=O bonds; electron-withdrawing R groups will generate a very long Fe=N bond, whereas electron-releasing R groups should have the opposite effect and hence a shorter Fe=N bond. The R substituent controls also the reactivity of RN-Cpd I toward C=C and C-H bonds by exerting steric and electronic effects. Our analysis shows that an electron-releasing substituent will lower the barriers for both bond activation reactions, since the electronic factor makes the reactions highly exothermic, while an electron-withdrawing one should raise both barriers. The steric bulk of the substituent is predicted to inhibit more strongly the aziridination reactions. It is predicted that electron-releasing substituents with small bulk will create powerful aziridination reagents, whereas electron-withdrawing substituents like MeSO(2) will prefer C-H bond activation with preference that increases with steric bulk. Finally, the study predicts (i) that the reactions of RN-Cpd I will be less stereospecific than those of O-Cpd I and (ii) that aziridination will be more stereoselective than amidation.     

On the Effect of Tether Composition on cis/trans Selectivity in Intramolecular Diels–Alder Reactions

Intramolecular Diels–Alder (IMDA) transition structures (TSs) and energies have been computed at the B3LYP/6‐31+G(d) and CBS‐QB3 levels of theory for a series of 1,3,8‐nonatrienes, H₂C?CH? CH?CH? CH₂? X? Z? CH?CH₂ [? X? Z? =? CH₂? CH₂? ( 1 ); ? O? C(?O)? ( 2 ); ? CH₂? C(?O)? ( 3 ); ? O? CH₂? ( 4 ); ? NH? C(?O)? ( 5 ); ? S? C(?O)? ( 6 ); ? O? C(?S)? ( 7 ); ? NH? C(?S)? ( 8 ); ? S? C(?S)? ( 9 )]. For each system studied ( 1 – 9 ), cis‐ and trans‐TS isomers, corresponding, respectively, to endo‐ and exo‐positioning of the ? C? X? Z? tether with respect to the diene, have been located and their relative energies (E_rel^TS) employed to predict the cis/trans IMDA product ratio. Although the E_rel^TS values are modest (typically <3 kJ mol^?1), they follow a clear and systematic trend. Specifically, as the electronegativity of the tether group X is reduced (X?O→NH or S), the IMDA cis stereoselectivity diminishes. The predicted stereochemical reaction preferences are explained in terms of two opposing effects operating in the cis‐TS, namely (1) unfavorable torsional (eclipsing) strain about the C4? C5 bond, that is caused by the ? C? X? C(?Y)? group’s strong tendency to maintain local planarity; and (2) attractive electrostatic and secondary orbital interactions between the endo‐(thio)carbonyl group, C?Y, and the diene. The former interaction predominates when X is weakly electronegative (X?N, S), while the latter is dominant when X is more strongly electronegative (X?O), or a methylene group (X?CH₂) which increases tether flexibility. These predictions hold up to experimental scrutiny, with synthetic IMDA reactions of 1 , 2 , 3 , and 4 (published work) and 5 , 6 , and 8 (this work) delivering ratios close to those calculated. The reactions of thiolacrylate 5 and thioamide 8 represent the first examples of IMDA reactions with tethers of these types. Our results point to strategies for designing tethers, which lead to improved cis/trans‐selectivities in IMDAs that are normally only weakly selective. Experimental verification of the validity of this claim comes in the form of fumaramide 14 , which undergoes a more trans‐selective IMDA reaction than the corresponding ester tethered precursor 13 .     

3-Aza-cope rearrangement of quaternary N-allyl enammonium salts. Stereospecific 1,3 allyl migration from nitrogen to carbon on a tricyclic template

N-Allyl enamines can undergo a [3,3] sigmatropic rearrangement known as a 3-aza-Cope (or amino-Claisen) reaction. We explored a 3-aza-Cope reaction involving 1,3 allylic migration from nitrogen to carbon in N-allyl enammonium quaternary salts, exemplified by benzo[a]quinolizine 8 and pyrrolo[2,1-a]isoquinoline 13, with an interest in stereochemistry and mechanism. Salts 8 and 13 were accessed, respectively, through stereospecific allylation of hydroxy amines 4 and 11a/11b to give 7 and 12a/12b, which were dehydrated with trifluoroacetic acid. Allylic migration in these tricyclic tetrahydroisoquinolines occurred with high stereospecificity, with the major products 9 (from 8) and 15a (from 13) apparently deriving from a concerted suprafacial [3,3] rearrangement. The rearrangement of 8 to 9 was facile at 23 degrees C (t(1/2) = ca. 5 h) and was >98% stereospecific, whereas the rearrangement of 13 to 15a/15b required heating between 50 and 100 degrees C, with ca. 90-95% stereospecificity (t(1/2) = ca. 0.3 h at 100 degrees C). A deuterium-labeling experiment with 21 ((2)H-13) confirmed that allylic inversion accompanies the 1,3 migration en route to major isomer 22a ((2)H-15a), supporting the predominance of a concerted [3, 3] sigmatropic mechanism. However, the 5-10% loss of stereospecificity in the rearrangements of the pyrroloisoquinolines 13 and 21, reflected by formation of minor isomers 15b and 22b, respectively, indicates a minor nonconcerted reaction pathway.     

A concise total synthesis of (±)- and (-)-okilactomycin D

The spirotetronate okilactomycin D (7) has been efficiently synthesized by a route featuring a substrate-controlled, diastereoselective (8:1) intramolecular Diels-Alder (IMDA) reaction of 11. The assigned absolute configuration of (-)-7 was confirmed.     

1H and 13C NMR spectral assignment of androstane derivatives

(1)H and (13)C NMR spectroscopic data for 5alpha-androstanes and halo-5alpha-androstanes with different substituents at positions C-3, C-9, C-11 and C-17 were examined and assigned by a combination of 1D and 2D NMR experiments. The substituent effects on the (13)C chemical shifts were compared with those of epi-androsterone, used as a reference compound. The coupling constants (n)J((19)F,(13)C) were measured for compounds 6, 8, 11 and 14.     

Photo-oxygenation of Styrenic Estrogens: Product characterization and kinetics of the dye-sensitized photo-oxygenation of 9,11-didehydroestrone derivatives

The dye-sensitized photo-oxygenation of 3-hydroxyestra-1,3,5(10), 9(11)-tetraen-17-one ( 8 ) gives a complex mixture from which only the 1,4-endo-peroxide 10 can be isolated in low yield. In contrast, the 3-methoxy derivative 9 yields the C-seco-aldehyde 11 as a major product, suggesting that 1,2-dioxetane is a primary photo-oxygenation intermediate. As the electron-donating character of the substituent at C(3) decreases in the sequence 12 (R = PhCO), 13 (R = Ac), and 14 (R = Ts), the rate constant in substrate disappearance becomes drastically smaller as compared with 8 and 9 , and no photoproducts are detected. The results are rationalized by means of electronic and conformational factors.     

A general strategy for the synthesis of vincamajine-related indole alkaloids: stereocontrolled total synthesis of (+)-dehydrovoachalotine, (-)-vincamajinine, and (-)-11-methoxy-17-epivincamajine as well as the related quebrachidine diol, vincamajine diol, and vincarinol

[structures: see text] The highly convergent stereocontrolled total synthesis of (-)-vincamajinine (7), (-)-11-methoxy-17-epivincamajine (9), and the oxygen-bridged (+)-dehydrovoachalotine (22) are described. Key steps in the synthesis of 7 and 9 involved the stereospecific enolate-driven palladium-catalyzed cross-coupling reaction, a Tollens reaction, an acid-assisted intramolecular cyclization to form the C(7)-C(17) quaternary center, and two stereospecific reductions. The efficiency of this strategy is illustrated by the completion of the synthesis of 7 and 9 in 16 [from d-(+)-tryptophan methyl ester 17] and 17 (from the Sch?llkopf chiral auxiliary 27) reaction vessels, respectively. This constitutes the first total synthesis of these indole alkaloids and provides the first regiospecific route to 11-methoxy-substituted ajmaline/vincamajine-related alkaloids. The synthesis of 22 required a novel DDQ-mediated cyclization to furnish the C(6)-O(17) bond, executed in stereospecific fashion. Completion of these syntheses illustrates a concise and versatile strategy for the synthesis of vincamajine-related alkaloids, which has also been employed to prepare the related compounds quebrachidine diol (53), vincamajine diol (56), and vincarinol (59).     

Crystal Structure of a Tricyclic Compound C_(20)H)(28)O_6 Obtained through IMDA Reaction

11NTRODUCT1ONlntramolecularDiels-Alder(IMDA)reactionplaysanimportantroleinthetotalsynthesisofnaturalproductscontainingfusedpolycyclicskeleton,sincethedieneanddienophilebothexistinthesamemolecule,theactivatedenergyofthereactionislower,andthefourchiralcentersareretainedatthesametimeduetotheconcertedreaction.Thestructureofthetricycliccompound(2A)obtainedthroughIMDAreac-tionwasstudiedinthisreport.2EXPERIMENTALSECTION2.1Synthesisoftricyclicc0mp0unds"'ThecatalyzedIMDAreacti0nof(1):…     

Supramolecular helical architecture from the self-assemblies of 2-chloro-5-nitro-benzoic acid and organic bases

Assembly of 2-chloro-5-nitro-benzoic acid (CNB) and organic bases containing nitrogen atom, 8-hydroxyquinaldine (purum), 1,2-bis(4-pyridyl)ethane (BPE), and 2-aminobenzimidazole, resulted in novel adducts with helical architecture. We present here an unprecedented single-stranded helix (left-handed and right-handed helices) in adduct 1. The helices are formed via three kinds of hydrogen bonding, O5–H5O1, C11–H11BO3, and C14–H14O1. But the two helices are linked by C9–H9O4 and C11–H11BO3 H-bonds. The interactions result in the cavity with dimensions of 8 × 10.5 Å, respectively. Interestingly, the different single-stranded helical structure in adduct 2 is generated via Cl1O1 interactions, where BPE linking the two helices by C9–H9O1 and O3–H3N2 H-bonds. The ring motifs and novel helical structures observed in the crystal packing suggest for further scopes in exploiting different substituent chloro-nitro-benzoic acid in a predictive manner or capturing useful nanoscale entities for self-assembly.