Andreas Goeke

Mechanistic insights in gold-stabilized nonclassical carbocations: gold-catalyzed rearrangement of 3-cyclopropyl propargylic acetates.

The reaction of 3-cyclopropyl propargylic carboxylates with Au(I) and Au(III) catalysts affords selectively 5-(E)-alkylidenecyclopentenyl acetates via [3,3]-sigmatropic rearrangement of the carboxylic moiety followed by cyclopropyl ring opening and cyclization. DFT calculations have been performed, supporting a two-step no-intermediate mechanism along the cyclization coordinate. The stereoselective formation of the exocyclic alkenes is kinetically controlled in the first of these events. Although stereospecific in nature through a gold-stabilized nonclassical carbocation, the chirality transfer in these cyclopentannulations is not complete. Computational and experimental evidence is provided for a Au-promoted cyclopropyl ring opening/epimerization/ring closure in both cis- and trans-cyclopropyl settings, which competes with the cyclization event, thus eroding the stereochemical information transfer. When tertiary acetates were used, products of both 1,2- and 1,3-acyloxy migration processes could be isolated, supporting the competitive coexistence of these two pathways along the reaction profile, as suggested also by DFT calculations.

Gold‐Catalyzed Cycloisomerization of Cyclopropyl Alkynyl Acetates: A Versatile Approach to 5‐, 6‐, and 7‐Membered Carbocycles

During the last decade, late-transition-metal-catalyzed cycloisomerizations have emerged as a powerful tool to access unprecedented structural and mechanistic diversity. In this context, a rapidly developing area involves the use of propargylic esters, preferably acetates, in which the carbonyl unit acts as a nucleophile onto the metal-activated alkyne complex I (Scheme 1). Two distinct mechanistic scenarios

Efficient Macrocyclization by a Novel Oxy‐Oxonia‐Cope Reaction: Synthesis and Olfactory Properties of New Macrocyclic Musks

Musk odorants are indispensable in perfumery to lend sensuality to fine fragrances, a nourishing effect to cosmetics, and a comforting feeling to laundry. Due to a certain phototoxicity of nitro musks, and the lack of biodegradation of polycyclic musks, the two most important musk families at present are macrocycles 1–5 (Figure 1), derived from the natural lead muscone (1), and linear alicyclic musks such as 6–7, the odor of which has been attributed to horseshoeshaped conformers that mimic macrocyclic rings on the odorant receptors. Both musk families, linear as well as macrocyclic, comprise highly flexible structures, which make double bonds and methyl groups ideal design elements to rigidify and conformationally constrain them. The two most powerful macrocyclic musks, (+)-(3R,5Z)-5-muscenone (2) and (13R,10Z)-Nirvanolide (3) both feature a double bond and a methyl substituent, and Cosmone (4) can be regarded as a “nor-muscenone”. By introduction of two double bonds such as in 5, the conformational freedom can be further restricted, enabling a targeted design of potent musk odorants. Methyl substituents determine the conformational space of linear musks to a great extend; yet, as apparent from the two dehydro-derivatives 6 and 7 of Serenolide (Figure 1), a shift of a double bond can change the odor threshold by a factor of over 150. The synthesis of further unsaturated macrocyclic musks can shed light upon similarities in the structure–odor correlation of these two musk families, and to this purpose we herein report on the intramolecular application of a new reaction of b,g-unsaturated aldehydes with different aldehydes in the presence of Lewis acids. The projected macrocyclization can be regarded as an oxy-version of the established 2-oxonia Cope rearrangement, but as illustrated in Scheme 1, could as well proceed through compound 11 in a Prins-type manner by coordination of the Lewis acid to the opposite formyl function. Both pathways would however lead to the same macrocyclic alk-3-en-1-yl formates 10. Hydride reduction and subsequent oxidation of 10 should provide b,g-unsaturated macrocyclic ketones, which could then be hydrogenated to the saturated macrocycles; thus, could then also open up a new route to ( )-muscone (1). As delineated in Scheme 2, the dicarbonyl substrates 8 a–g were prepared from commercial bromo alcohols 12 a–g by protection as tert-butyldiphenylsilyl (TBDPS) ethers 13 a–g, and subsequent Finkelstein reaction with KI in acetone to afford iodides 14 a–g in excellent yields. Deconjugated a-alkylation of the Weinreb amide 15 with 14 a–g afforded alkylated amides 16 a–g in 39–60 % yield, with unreacted 14 a–g being recovered. Deprotection of the Weinreb amides 16 a–g with tetrabutylammonium fluoride (TBAF) in THF [a] Dr. Y. Zou, Prof. Dr. Q. Wang Department of Chemistry, Fudan University 220 Handan Road, Shanghai, 200433 (P.R. China) Fax: (+86) 216-564-1740 E-mail : qrwang@fudan.edu.cn [b] Dr. Y. Zou, Dr. A. Goeke Givaudan Fragrances (Shanghai) Ltd 298 Li Shi Zhen Road, Shanghai, 201203 (P.R. China) [c] Dr. H. Mouhib, Prof. Dr. W. Stahl RWTH Aachen University, 52056 Aachen (Germany) Institute of Physical Chemistry [d] Dr. P. Kraft Givaudan Schweiz AG, Fragrance Research berlandstrasse 138, 8600 D bendorf (Switzerland) Fax: (+41) 44-8242926 E-mail : philip.kraft@givaudan.com Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201200882. Figure 1. Macrocyclic musks 1–5, and linear musk structures 6 and 7.

Organocatalytic Multicomponent α-Methylenation/Diels-Alder Reactions : A Versatile Route to Substituted Cyclohexenecarbaldehyde Derivatives

This article describes the design and optimization of an effective organocatalytic three-component domino alpha-methylenation/Diels-Alder reaction to produce vinyl-substituted cyclohexenecarboxaldehydes in a highly regioselective fashion. In these one-pot transformations, 2-formyl-1,3-butadienes (4) were prepared in situ from alpha,beta-unsaturated aldehydes and formalin and were subsequently trapped with a variety of buta-1,3-dienes. The outcomes of the reactions were dependent on the electronic properties of the dienes. 1-Vinylcyclohexenecarbaldehydes 6 were formed by use of acyclic electron-rich dienes, while the initially formed cycloadducts of 4 with cyclopentadiene underwent Cope rearrangements, leading to the formation of tetrahydro-3H-indene-5-carbaldehyde compounds 7. The mechanisms involved in these reactions were deduced from experimental findings. Furthermore, the method was also extended to one-pot domino methylenation/Diels-Alder reactions of dihydrofurans and dihydropyrans to yield spirocyclic lactols 22. In these reactions, the unstable intermediate hydroxyethyl and hydroxypropyl acroleins behaved as dienophiles, undergoing cycloaddition reactions with dienes with good yields and selectivities. The wide variety of functionalized 1-vinylcyclohex-3-enecarbaldehydes 6, 4-vinylcyclohex-1-enecarbaldehydes 7, and spiro lactols 22 generated through the use of these organocatalytic domino processes as a diversity-oriented synthesis provided useful intermediates for the construction of novel odorants.

Total Synthesis of Junionone, a Natural Monoterpenoid from Juniperus communis L., and Determination of the Absolute Configuration of the Naturally Occurring Enantiomer by ROA Spectroscopy

Recently, we reported a novel access to 2,2‐diethyl‐3‐[(E/Z)‐prop‐1‐en‐1‐yl]cyclobutanone by an intramolecular nucleophilic substitution with allylic rearrangement (SNi′) of (E)‐6‐chloro‐3,3‐diethylhept‐4‐en‐2‐one. The ring closure reaction was found to proceed with selective syn‐displacement of the leaving group. This method was now applied to the total synthesis of junionone, an olfactorily interesting cyclobutane monoterpenoid isolated from Juniperus communis, L. SNi′ Ring closure of the ketone enolate of (E)‐3,3‐dimethyl‐5‐[(2R,3R)‐3‐methyloxiran‐2‐yl]pent‐4‐en‐2‐one (R,R)‐(E)‐4′ proceeded only after the epoxide moiety had been activated by Lewis acid and led to the junionone precursors (3R)‐ and (3S)‐3‐[(1E,3R)‐3‐hydroxybut‐1‐en‐1‐yl]‐2,2‐dimethylcyclobutanone (S/R,R)‐(E)‐3. The ratio of syn‐ and anti‐conformers in the transitory molecular arrangement was found to depend on the nature of the Lewis acid. The absolute configuration of both the synthetic as well as the natural junionone, isolated from juniper berry oil, was determined by Raman Optical Activity (ROA) spectroscopy. Our experiments led to a novel synthetic route to both (+)‐ and (−)‐junionone, the first determination of the absolute configuration of natural junionone, and to the development of a practical ROA procedure for measuring milligram quantities of volatile liquids.

Catalytic Asymmetric Prins Bicyclization for the endo-Selective Formation of 2,6-dioxabicyclo[2.2.2]octanes.

A new Lewis acid-catalyzed endo-selective Prins bicyclization of γ,δ-unsaturated aldehydes or ketones with a broad range of aldehydes to dioxabicyclo[2.2.2]octanes is disclosed. When using a chiral BINOL-derived N-triflylphosphoramide (NTPA) as catalyst and glyoxylate esters as substrates, the cross-dimerization afford functionalized bicyclic acetals with excellent diastereo- and enantioselectivities.

A novel oxy-oxonia(azonia)-cope reaction: serendipitous discovery and its application to the synthesis of macrocyclic musks.

This brief review, including new experimental results, is the summary of a talk at the GDCh conference ‘flavors & fragrances 2013’ in Leipzig, Germany, 11th–13th September, 2013. Musk odorants are indispensable in perfumery to lend sensuality to fine fragrances, a nourishing effect to cosmetics, and a comforting feeling to laundry. We have recently found serendipitously a new oxy‐oxonia‐Cope rearrangement. In this account, we review the background of oxonia‐sigmatropic rearrangements and the discovery of this novel reaction. Special attention is focused on the versatile lactone and lactam formation reactions via [n+4] ring enlargement and the macrocyclization in the synthesis of new macrocyclic musks. The synthesized structures provide new insights into the structureodor relationships of musks.

Titanacyclopentene complexes and their application as 1,4-dicarbanion equivalentsElectronic supplementary information (ESI) available: experimental details. See http://www.rsc.org/suppdata/cc/b3/b311572k/

The treatment of Ti(OiPr)(4) with 3-butenylmagnesium chloride generates titanacyclopentene complexes which effectively add to carbonyl compounds and nitriles to afford the 1,4-coupling products with high Z:E selectivities.

Sequential Diels–Alder Reaction/Rearrangement Sequence: Synthesis of Functionalized Bicyclo[2.2.1]heptane Derivatives and Revision of Their Relative Configuration

A sequential Diels-Alder reaction/rearrangement sequence was developed for the synthesis of diverse functionalized bicyclo[2.2.1]heptanes as novel floral and woody odorants. The outcome of the rearrangement depended on the substitution pattern of the dienes. 2D NMR analysis has established the correct relative configuration of the bicyclo[2.2.1]heptanone, which was originally misassigned. Furthermore, when the initiating DA reaction was catalyzed by a chiral Lewis acid, the bicyclo[2.2.1]heptane derivatives including (+)-herbanone can be obtained in an enantiomeric ratio (er) up to 96.5:3.5.