Ozora Kubo

Reversing the Reactivity of Carbonyl Functions with Phosphonium Salts: Enantioselective Total Synthesis of (+)‐Centrolobine

The control of chemoselective transformations irrespective of the individual reactivity of functional groups still remains a largely unanswered challenge. Carbonyl groups, such as aldehydes and ketones, are without doubt the most important functional groups in organic chemistry and their reactions are well known. The order of the reactivity of carbonyl groups toward nucleophiles is generally aldehyde> ketone> ester. Therefore, it is easy to react an aldehyde in the presence of ketones and esters. In contrast, it is difficult to react a ketone prior to an aldehyde. Therefore, protective groups have to be employed for such transformations, which thus become intrusive three-step operations that involve the protection of the aldehyde, transformation of the ketone, and deprotection of the aldehyde. The reversal of the reactivity of functional groups is a challenging theme in chemistry and there are few reports on such transformations. Luche and Gemal reported pioneering and representative work, in which a ketone was selectively reduced in the presence of an aliphatic aldehyde. The conversion of the aldehyde into an acetal, the subsequent reduction of the ketone with NaBH4, and the deacetalization were carried out in one pot by using the CeCl3–MeOH–NaBH4 system. However, this reaction was limited to reductions and is difficult to apply to other reactions. Other methods, such as the use of metal amides, a bulky Lewis acid, and a copper catalyst with a bulky phosphine ligand, were reported. However, these methods have drawbacks, such as lower generality, the need to prepare special reagents, and strict control of stoichiometry because of the use of highly reactive reagents. Therefore, more practical and facile methods for the selective transformation of carbonyl groups are required. Herein we report the convenient and versatile selective one-pot transformation of less-reactive carbonyl groups in the presence of aldehydes (or ketones) by using the combination of PPh3 (or PEt3) and TMSOTf to selectively mask the aldehyde prior to the addition of the nucleophile (Scheme 1). The asymmetric transformation of a less-reactive carbonyl group in the presence of a more-reactive carbonyl group was also accomplished, and was applied to the short asymmetric total synthesis of (+)-centrolobine.

Synthesis of the C1-C26 Hexacyclic Subunit of Pectenotoxin 2

Synthesis of the C1-C26 hexacyclic subunit of pectenotoxin-2 (PTX-2) is described that features a stereoselective annulation to generate the C-ring by triple asymmetric Nozaki-Hiyama-Kishi coupling followed by oxidative cyclization. Preparation of the C1-C14 AB spriroketal-containing subunit employs a recently developed metallacycle-mediated reductive cross-coupling between a TMS-alkyne and a terminal alkene.

Mild and efficient deprotection of acetal-type protecting groups of hydroxyl functions by triethylsilyl triflate: 2,4,6-collidine combination

Deprotection of acetal-type protecting groups of hydroxyl functions has been studied in detail. The treatment of alcohol derivatives protected by acetal-type protecting groups with TESOTf-2,4,6-collidine followed by H 2 O-treatment produces the corresponding hydroxyl compounds in good yields. The characteristic features of the method are very mild and chemoselective, and acid-labile functional groups can tolerate these conditions.

Novel Regiocontrolled Protection of 1,2- and 1,3-Diols via Mild Cleavage of Methylene Acetals

The regiocontrolled protection of unsymmetrical 1,2- and 1,3-diols has been developed. Different types of protected diols are available from the methylene acetal in a one-pot procedure. Highly regioselective protection of diols with a silyl group at the less hindered hydroxy group as well as with a MOM group at the more hindered one were achieved. The reaction conditions are mild without affecting other functional groups including acid-labile function.

An unusual reaction of α-alkoxyphosphonium salts with Grignard reagents under an O2 atmosphere

An unusual and novel reaction of α-alkoxyphosphonium salts, generated from O,O-acetals and Ph(3)P, with Grignard reagents under an O(2) atmosphere afforded alcohols in moderate to high yields. It was clarified by isotopic labelling experiments that the reaction proceeded via a novel radical pathway.

ORGANIC CHEMISTRY USING WEAKLY ELECTROPHILIC SALTS : THE REACTION WITH NITROGEN NUCLEOPHILES

The reaction of electrophilic salts, which were obtained by the treatment of acetals with TESOTf•2,4,6-collidine, with nitrogen nucleophiles was studied in detail. Treatment of the salts with potassium phthalimide afforded the corresponding N,O-acetals in good yields. The use of hydrazine in place of potassium phthalimide gave the corresponding hydrazones. The reaction is very mild and chemoselective, and acid-labile functional groups can tolerate these conditions.

Alkyl-and arylation of oxacyclic ethers with triethylsilyl triflate -2,4,6 -collidine -gilman reagent combination : Remarkable discrimination of two ether oxygens

The alkylation reaction of oxacyclic ethers such as THP-ethers, THF-ethers, etc., has been developed. The treatment of oxacyclic ether with TESOTf and 2,4,6-collidine gives the collidinium salt intermediate obtained by the reaction of the cyclic oxygen atom. The addition of Gilman reagent to the mixture gives the alkylated product. The reaction proceeds with high chemoselectivity though there are two different oxygen atoms in the oxacyclic ethers.

Effects of Phosphorus Substituents on Reactions of α‐Alkoxyphosphonium Salts with Nucleophiles

The effects of phosphorus substituents on the reactivity of α-alkoxyphosphonium salts with nucleophiles has been explored. Reactions of α-alkoxyphosphonium salts, prepared from various acetals and tris(o-tolyl)phosphine, with a variety of nucleophiles proceeded efficiently. These processes represent the first examples of high-yielding nucleophilic substitution reactions of α-alkoxyphosphonium salts. The reactivity of these salts was determined by a balance between steric and electronic factors, respectively, represented by cone angles θ and CO stretching frequencies ν (steric and electronic parameters, respectively). In addition, a novel reaction of α-alkoxyphosphonium salts derived from Ph(3)P with Grignard reagents was observed to take place in the presence of O(2) to afford alcohols in good yields. A radical mechanism is proposed for this process that has gained support from isotope-labeling and radical-inhibition experiments.

Preparation of THP‐Ester‐Derived Pyridinium‐Type Salts and their Reactions with Various Nucleophiles

Nucleophilic substitution at the anomeric positions of tetrahydropyranyl (THP) and related carbohydrate-derived esters that proceeded through pyridinium-type salt intermediates have been developed. Treatment of the 6-substituted α-acetoxy-tetrahydropyrans with TMSOTf (TMS=trimethylsilyl) and 2-substitutited pyridines, such as 2-p-tolylpyridine and 2-methoxypyridine, led to the efficient generation of cis-pyridinium-type salts. These salts reacted with various nucleophiles, such as alcohols, azides, and organozinc reagents, to form nucleophilic-substitution products. A characteristic feature of these processes was that they took place under mild conditions, which did not affect acid-labile protecting groups. Furthermore, the reactions that employed azides and C-nucleophiles generated 2,6-trans products with high degrees of stereoselectivity.