Model studies of terpene biosynthesis. A stepwise mechanism for cyclization of nerol to .alpha.-terpineol

Poulter, C. Dale; King, Chi Hsin R.

doi:10.1021/ja00369a046

Cited by 48 publications

(26 citation statements)

References 2 publications

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“…25 This shows that the aqueous solvent provides nearly equal stabilizing solvation of the reactants (water and Ph 2 CH + ) and the transition state for nucleophile addition so that there is only a small solvent effect on the barrier for formation of this transition state. 37 The conversion of 3 to 5 and 8 with net cis-trans isomerization of the C-2 alkene provides strong evidence for formation of an allylic carbocation intermediate that is sufficiently long-lived to undergo rotation about the C2-C3 bond. 36 Intramolecular Reactions of Alkenes.…”

Section: Discussionmentioning

confidence: 99%

Solvent Effects on Carbocation−Nucleophile Combination Reactions: A Comparison of π-Nucleophilicity in Aqueous and Organic Solvents

1998

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The following selectivities are reported for partitioning of the R-(N,N-dimethylthiocarbamoyl)-4methoxybenzyl carbocation 1 + between nucleophilic addition of π-nucleophiles and a solvent of 50:50 (v:v) acetonitrile/water at 25°C (nucleophile, k Nu /k s ): pyrrole, 23 M -1 ; 2-methoxythiophene, ≈2 M -1 . No nucleophile adducts (<2% of total products) were detected from the reaction of this carbocation in the same solvent containing the following carbon nucleophiles: thiophene (0.10 M), furan (0.10 M), ethyl 1-propenyl ether (0.10 M), amd 1-cyclohexenyl trimethylsilyl ether (0.01 M). These results show that only π-nucleophiles with Mayr nucleophilicity parameters greater than N ≈ 6 are sufficiently reactive to compete with nucleophilic aqueous solvents for addition to 1 + , and they provide support for a simple relationship between the Ritchie N + scale of nucleophilicity in water and the Mayr N scale of nucleophilicity in weakly polar nonnucleophilic solvents. 2,3 Our data require a large effective molarity for the intramolecular addition of a trisubstituted alkene to an allylic carbocation.In recent years there have been many determinations of rate constants for the addition of nucleophiles to carbocations in a variety of solvents, including weakly polar, aprotic, nonnucleophilic solvents such as dichloromethane; 2,3 polar, aprotic, and weakly nucleophilic solvents such as acetonitrile; 4 polar, protic, and weakly nucleophilic solvents such as 1,1,1,3,3,3-hexafluoro-2-propanol; 5,6 and polar, protic, and strongly nucleophilic solvents such as water. 7,8 An important conclusion from this work is that there are large decreases in the reactivity of anionic nucleophiles 4,9 and neutral amines 10 with increasing stabilization of the nucleophilic reagent by hydrogen bonding to solvent. This results from the requirement for the loss of these stabilizing hydrogen-bonding interactions on proceeding to the transition state for the nucleophile addition reaction.The effect of polar protic solvents on the nucleophilic reactivity of alkenes and other π-nucleophiles has not been investigated in detail, but the lack of data in aqueous solvents might suggest that π-nucleophiles are simply too weakly nucleophilic to compete with nucleophilic solvents for addition to unstable carbocations. However, recent studies of photolytically generated ring-substituted diarylmethyl carbocations in acetonitrile have shown that the second-order rate constants for the addition of activated alkenes, such as vinyl ethers and silyl enol ethers, are significantly larger than that for addition of water. 11 These results suggest that it should be possible to study the addition of strongly activated nucleophilic alkenes to carbocations in an aqueous solvent, but we are not aware of any reports of such studies in the chemical literature.We recently reported that the π-nucleophile 2 is 70 000-fold more reactive than a solvent of 50:50 (v:v) methanol/water toward the R-(N,N-dimethylthiocarbamoyl)-4-methoxybenzyl carbocation 1 + (k alk , Scheme 1), 12 g...

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Section: Discussionmentioning

confidence: 99%

Solvent Effects on Carbocation−Nucleophile Combination Reactions: A Comparison of π-Nucleophilicity in Aqueous and Organic Solvents

1998

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“…While the relatively small size of the fluoro group might not perturb active-site binding extensively, its large inductive effect dramatically alters the apparent stability of allylic carbocations that bear a fluorine atom on the central carbon, [8] and seems likely to inactivate fluoro-vinyl double bonds towards protonation or electrophilic alkylation. In fact, 2-fluorogeranyl PP exhibits apparent activesite binding constants with farnesyl PP synthase and several monoterpene synthases similar to those of the natural geranyl substrates.…”

Section: Introductionmentioning

confidence: 99%

Interception of the Enzymatic Conversion of Farnesyl Diphosphate to 5‐Epi‐Aristolochene by Using a Fluoro Substrate Analogue: 1‐Fluorogermacrene A from (2E,6Z)‐6‐Fluorofarnesyl Diphosphate

et al. 2007

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Tobacco 5-epi-aristolochene synthase (TEAS) catalyzes the Mg II -dependent cyclizations and rearrangements of (E,E)-farnesyl diphosphate (PP) to the bicyclic sesquiterpene hydrocarbon via a tightly bound (+)-germacrene A as a deprotonated intermediate. With the native enzyme, only a few percent of the putative germacrene A intermediate is released from the active site during the catalytic cycle. 6-Fluorofarnesyl PP was designed and synthesized with the aim of arresting the cyclization-rearrangement mechanism en route to 5-epi-aristolochene. Indeed, incubation of (2E, 6Z)-6-fluorofarnesyl PP with recombinant TEAS afforded (-)-1-fluororogermacrene A as the sole product in 58% yield. Steady-state kinetic experiments with farnesyl PP and the 6-fluoro analogue showed that the overall catalytic efficiencies (k cat /K m ) are essentially the same for both substrates. 1-Fluorogermacrene A was characterized by chromatographic properties (TLC, GC), MS, optical rotation, UV, IR and 1 H NMR data, and by heat-induced Cope rearrangement to (+)-1-fluoro-β-elemene. 1 H NMR spectra at room temperature revealed that this (E,E)-configured fluorocyclodecadiene exists in solution as a 7:3 mixture of UU and UD conformers. 1-Fluorogermacrene A underwent trifluoroacetic acid-catalyzed cyclization to give three 1α-fluoroselinene isomers at a rate estimated to be about 1000 times slower than that of the similar cyclization of (+)-germacrene A to the parent selinenes.

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“…The topologically related linalyl system is known to cyclize preferentially from an anti-endo conformation, 10 and a similar preference is expected for its allylic isomer. 11 The high sense of asymmetric induction observed here may be envisioned as occurring through transition-state assembly 5, where the cyclization of the neryl cation would arise from a preferential anti-endo conformation. On the other hand, transition-state assembly 6 (anti-exo conformation) would be disfavored not The absolute configuration of the major enantiomer is indicated in brackets.…”

Section: Equationmentioning

confidence: 89%

Asymmetric Synthesis of (R)-Limonene and (S)-Cembrene-A by an Intramolecular Cyclization Reaction Using a Chiral Leaving Group

Ishihara¹,

Nakamura²,

Yamamoto³

2001

Synlett

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A six-membered monocyclic terpene, (R)-limonene, and a 14-membered monocyclic diterpene, (S)-cembrene-A, have been synthesized, respectively, by new enantioselective intramolecular cyclization reactions of neryl ether and (all-E)-geranylgeranyl ether using an (R)-1,1'-binaphthyl-2-benzoxy-2'-oxy auxiliary as a chiral leaving group in the presence of tin(IV) chloride.The structural diversity found in terpene metabolism is mostly due to olefinic cyclization of five basic acyclic precursors, isoprene units. 1 The biological strategy for the construction of new C-C bonds involves intramolecular electrophilic alkylation of remote double bonds to a cationic center generated by the ionization of allylic pyrophosphates, 2 in which the enzyme may require a divalent cation, Mg(II) or Mn(II), for catalytic activity. 3 Assuming that the cyclization of neryl pyrophosphate to limonene (2) is initiated by bidentate coordination of the pyrophosphate moiety to a metal, we have been intrigued for several years in simulating such a cyclization with asymmetric induction in organic chemistry. This assumption regarding the biosynthesis of 2 is also expected to be a suitable model for the biosynthesis of related cyclic terpenes. In 1983, Yamamoto and co-workers reported the first biomimetic asymmetric synthesis of (R)-(+)-2 (up to 77% ee, 54% yield) from (R)-binaphthol(BINOL) mononeryl ether (1a) using a bulky aluminum reagent, (2,4,6-tri-tertbutylphenoxy)isobutylaluminum trifluoromethanesulfonate (3 equiv) in fluorotrichloromethane (CCl 3 F) at -130°C. 4 This is a successful example of diastereodifferentiating asymmetric induction with an addition-elimination reaction using a chiral auxiliary as a leaving group, and provides a direct and efficient route to an enantiomer (Scheme 1). 5,6 Unfortunately, however, the cyclization of (R)-1a using commercially available DIBAH (1.2 equiv) in dichloromethane at -78 ~ 0°C has given (R)-2 with only 12% ee. 4 We describe here a more effective and new diastereodifferentiating intramolecular cyclization using a chiral leaving group for the asymmetric synthesis of 6-and 14-membered monocyclic terpenes, 2 and cembrene-A (8).Recently, we developed (R)-BINOL derivatives-tin(IV) chloride as chiral protonation reagents 7 and trimethylsilylethoxymethyl (SEM) ether of (R)-BINOL-tin(IV) chloride as a chiral SEM-addition reagent (Figure 1). 6 As a new entry to Lewis acid-assisted chiral electrophiles, we envisaged that a high level of asymmetric induction from an allylic ether of (R)-BINOL to a prochiral nucleophile could be achieved by bidentate coordination of tin(IV) chloride with its (R)-BINOL moiety. Figure 1 Examples of Lewis acid-assisted chiral electrophiles.Initially, we examined various protecting groups, R, of (R)-BINOL mononeryl ether derivatives 1 to effect the intramolecular cyclization of 1 in the presence of one equivalent of tin(IV) chloride in toluene (entries 1-5, Table). (R)-BINOL mononeryl ether 1a (R = H) 3 was easily prepared in good yield from (R)-BINOL and nerol by Mitsunobu reacti...

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Model studies of terpene biosynthesis. A stepwise mechanism for cyclization of nerol to .alpha.-terpineol

Cited by 48 publications

References 2 publications

Solvent Effects on Carbocation−Nucleophile Combination Reactions: A Comparison of π-Nucleophilicity in Aqueous and Organic Solvents

Solvent Effects on Carbocation−Nucleophile Combination Reactions: A Comparison of π-Nucleophilicity in Aqueous and Organic Solvents

Interception of the Enzymatic Conversion of Farnesyl Diphosphate to 5‐Epi‐Aristolochene by Using a Fluoro Substrate Analogue: 1‐Fluorogermacrene A from (2E,6Z)‐6‐Fluorofarnesyl Diphosphate

Asymmetric Synthesis of (R)-Limonene and (S)-Cembrene-A by an Intramolecular Cyclization Reaction Using a Chiral Leaving Group

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