Charles Fehr

Synthesis of (−)‐Cubebol by Face‐Selective Platinum‐, Gold‐, or Copper‐Catalyzed Cycloisomerization: Evidence of Chirality Transfer and Mechanistic Insights

We describe in detail a direct, stereoselective synthesis of (-)-cubebol based on a Pt-, Au-, or Cu-catalyzed cycloisomerization in which control of the configuration of the propargylic center is essential for the facial selectivity. In addition, we show that cycloisomerization reactions of enantioenriched propargyl pivalates occur with substantial chirality transfer. We confirm a mechanism by means of cyclization followed by an [1,2]-acyl migration for the Pt- and the Au-catalyzed cycloisomerization. So far, no evidence supports that the Cu-catalyzed cycloisomerization follows the same reaction course.

Enantioselective Synthesis of (−)‐β‐Santalol by a Copper‐Catalyzed Enynol Cyclization–Fragmentation Reaction

We report herein the first enantioselective, direct synthesis of the highly prized natural sandalwood odorant ( )-b-santalol (( )-1). The key step in the synthesis is an efficient copper-catalyzed rearrangement of an enynol. The increasing scarcity of East Indian sandalwood oil has motivated research chemists over the last 40 years to develop a synthesis of the most valuable component, ( )-b-santalol ( )-1, which makes up 20–25% of the composition of the oil, or its racemate. Despite extensive efforts, this excellent fragrance ingredient is still not commercially available. Recently, we reported the cost-efficient copper-catalyzed cycloisomerization of 5-en-1-yn-3-ols (cyclopropanation/1,2alkyl shift; Scheme 1, A!E) and related enynol esters.

A New Variant of the Claisen Rearrangement from Malonate-Derived Allylic Trimethylsilyl Ketene Acetals: Efficient, Highly Enantio- and Diastereoselective Syntheses of (+)-Methyl Dihydroepijasmonate and (+)-Methyl Epijasmonate.

Complete chirality transfer occurs in the smooth Claisen rearrangement of the trimethylsilyl (TMS) ketene acetals, which were prepared from allylic malonates (R)-1 (R=pentyl, 2-(Z)-pentenyl). These are in turn accessible by enantioselective reduction/esterification or by enzymatic kinetic resolution. The cis configuration in (+)-3 was achieved by highly syn-selective epoxidation of (+)-2, followed by suprafacial 1,2-H migration.

Diastereoface‐Selective Epoxidations: Dependency on the Reagent Electrophilicity

Substrate-imposed steric constraints can be overriden by the pronounced preference of strong peracids for epoxidation on the π face, which has the highest electron density. For example, the syn:anti ratio for reaction (1) with CF3 CO3 H in CH2 Cl2 is 82:18, that with CH3 CO3 H in toluene is 3:97.

Synthesis of (-)-Vulcanolide by enantioselective protonation

Two efficient enantioselective syntheses of the more active (S,S)-enantiomer of the powerful musk odorant Vulcanolide are described. In both syntheses, the key step is an enantioselective protonation of a ketone enolate. A third enantioselective protonation, of a thiol ester enolate, was applied for the determination of the absolute configuration of Vulcanolide by comparison with a known compound.

Gold‐ and Copper‐Catalyzed Cycloisomerizations towards the Synthesis of Thujopsanone‐Like Compounds

In the search for a new access to thujopsanone related compounds by cycloisomerization reactions of unsaturated propargylic alcohols and acetates, we found several interesting reaction types and demonstrated the complementarity of Au, Pt, and Cu catalysts. Thus, 6-en-1-yn-3-ol 10a underwent clean cyclization/ether formation to 16, in particular using Au catalysts (76-98%) or a newly prepared Cu(I)-triflimidate-catalyst (94%). The corresponding acetate 11 a underwent either the cycloisomerization with concomitant [1,2]-acyl shift (to 12: 78% using AuCl(3)) or an unprecedented rearrangement-cycloaddition leading to 20 (43% using [(tBuXPhos)AuNTf(2)]), a strained fused tricyclic ring system containing a [2.2.0] bicyclic subunit.

Chemical Classification and Structure­ Odour Relationships

The physical and chemical properties required of a suitable sensory active molecule are determined by the location, molecular architecture and physiological medium of the chemoreceptor. Clearly sensory activity in human olfaction is exclusively associated with volatile molecules. The higher limit of molecular weight found for odorants is around 300 (for some examples, see Refs 1–3). Chemical reactivity of a ligand has little if any direct connection with olfactory activity since odorant molecules are uncharged and hardly require metabolic activation. Nevertheless, several molecular requirements must be met. Thus most odorous molecules contain both a strong hydrophobic and a relatively weak polar region. The latter, usually termed the ‘osmophore’,4 is associated with a functional group such as carbonyl, hydroxyl, occasionally an ether or a limited variety of heteroatomic homologues. However, the presence of a functional group is not a conditio sine qua non for receptor interaction. Even alkanes can have distinctive odours.

The Synthesis of (Z)‐Trisubstituted Allylic Alcohols by the Selective 1,4‐Hydrogenation of Dienol Esters: Improved Synthesis of (−)‐β‐Santalol

(E)-Trisubstituted allylic alcohols are commonly prepared from the corresponding (E)-enals, themselves readily accessible by a simple aldol condensation reaction. We demonstrate that these very same (E)-enals can be converted into (Z)-trisubstituted allylic acetates (and thus alcohols) by a ruthenium-catalyzed 1,4-hydrogenation of the corresponding dienol acetates. This simple solution to a long-lasting problem was applied to an industrially feasible synthesis of (-)-β-santalol.

Diastereocontrolled synthesis of functionalized transdecalins via electrocyclic reaction of trienol ethers

(E)-Trienol silyl ethers 10 and 11, selectively, prepared by mono-Grignard reaction on methyl β-cyclogeranate (7) or by deprotonation of enone 8 were transformed to trans-decalins 5 and 6 by a thermal electrocyclic reaction. The hitherto unknown enones 5 and 6 exhibit interesting organoleptic properties and show promise as versatile synthetic intermediates. The herein described transformation opens a new route for the direct construction of C(6)-functionalized drimanes such as cinnamodial (3) and forskolin (4).

(+)-(R,Z)-5-Muscenone and (−)-(R)-Muscone by Enantioselective Aldol Reaction and Grob Fragmentation

(+)-(R,Z)-5-Muscenone ((R)-1) was synthesized by an enantioselective aldol reaction, catalyzed by new ephedrine-type Ti reagents (up to 70 % enantiomeric excess). Substrate-directed diastereoselective reduction of the aldol product and Grob fragmentation of the tosylate of the resultant 1,3-diol afforded (+)-1. This approach also gave access to (-)-(R,E)-5-muscenone and (-)-(R)-muscone.