Cyclization stereoselectivity

Open-chain 1,5-polyenes (e.g. squalene) and some oxygenated derivatives are the biochemical precursors of cyclic terpenoids (e.g. steroids, carotenoids). The enzymic cyclization of squalene 2,3-oxide, which has one chiral carbon atom, to produce lanosterol introduces seven chiral centres in one totally stereoselective reaction. As a result, organic chemists have tried to ascertain, whether squalene or related olefinic systems could be induced to undergo similar stereoselective cyclizations in the absence of enzymes (W.S. Johnson, 1968, 1976). 

The early Escherunoser-Stork results indicated, that stereoselective cyclizations may be achieved, if monocyclic olefins with 1,5-polyene side chains are used as substrates in acid treatment. This assumption has now been justified by many syntheses of polycyclic systems. A typical example synthesis is given with the last reaction. The cyclization of a trideca-3,7-dien-11-ynyl cyclopentenol leads in 70% yield to a 17-acetyl A-norsteroid with correct stereochemistry at all ring junctions. Ozonolysis of ring A and aldol condensation gave dl-progesterone (M.B. Gravestock, 1978 see p. 279f.). 

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereoselectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanostetol with no less than seven asymmetric centres (W.S. Johnson, 1%8, 1976 E.E. van Tamden, 1968). 

Aqueous hydrofluoric acid dissolved in acetonitrile is a good catalyst for intramolecular Diels-Alder reactions [9] This reagent promotes highly stereoselective cyclizations of different triene esters (equation 8) The use of other acids, such as hydrochloric, acetic, and trifluoroacetic acid, results in complete polymerization of the starting trienes [9] (equation 8)... 

An example of a completely stereoselective cyclization of an allylsilane, leading to a seven-mem-bered ring in excellent yield, is known158. Treatment of the hydroxy compound with methanesulfonyl chloride and triethylamine in acetonitrile gives a single isomer of the bicyclic compound via cyclization of the (T )-iminium ion. 

This catalytic system has been applied to the synthesis of the core of complex antibiotic tetrapetalones. Hong and coworkers have successfully established the W-acyliminium ion cyclization in the preparation of 1-benzazepine derivatives. A combination of FeCls (0.5 equiv) and TMSCl (2 equiv) was selected as an optimized condition for such stereoselective cyclization (Scheme 35) [45]. 

In Entry 13, the dioxinone ring undergoes thermal decomposition to an acyl ketene that is trapped by the solvent methanol. The resulting (3-keto-y,8-enoate ester then undergoes stereoselective cyclization. The stereoselectivity is controlled by the preference for pseudoequatorial conformations of the C(6) and C(9) substituents. 

Enantiospecific syntheses of amino derivatives of benzo[ ]quinolizidine and indolo[2,3- ]quinolizidine compounds have also been achieved via A-acyliminium ion cyclization reactions, as an alternative to the more traditional Bischler-Napieralski chemistry (see Section 12.01.9.2.2). One interesting example involves the use of L-pyroglutamic acid as a chiral starting material to construct intermediates 240 via reaction with arylethylamine derivatives. Diisobutylaluminium hydride (DIBAL-H) reduction of the amide function in 240 and subsequent cyclization and further reduction afforded piperidine derivatives 241, which stereoselectively cyclized to benzo[ ]quinolizidine 242 upon treatment with boron trifluoride (Scheme 47) <1999JOC9729>. 

Other radical cyclization approaches to the synthesis of piperidines include a CAN-mediated stereoselective cyclization of epoxypropyl cinnamyl amines <06TL705> and a cyclization of (-trimethylsilylmethylamine radical cation, generated via a photoinduced electron transfer reaction to a tethered -functionality <06JOC8481>. 

Recently, Yu and co-workers developed an operationally simple catalytic system based on [RuCl2(/>-cymene)]2 for stereoselective cyclization of a-diazoacetamides by intramolecular carbenoid C-H insertion.192 /3-Lactams were produced in excellent yields and >99% m-stereoselectivity (Equation (53)). The Ru-catalyzed reactions can be performed without the need for slow addition of diazo compounds and inert atmosphere. With a-diazoanilide as a substrate, the carbenoid insertion was directed selectively to an aromatic C-H bond leading to y-lactam formation (Equation (54)). 

Stereoselective cyclization controlled by a substituent remote from the reaction center is often difficult to achieve. However, 1-mediated cyclization of the substrates illustrated in Eq. 9.54 proceeds in a highly stereoselective manner when the hydroxy group is converted to a magnesium alkoxide prior to cyclization [99,100]. The effect of the alkoxide group is much more favorable than that of the corresponding TBS ether. 

A new effective metal-ffee radical approach by Murphy et al generates the free radical by treatment with tetrathiafulvalene (TTF).1491 As depicted in scheme 16 the aromatic amine 79 is transformed into the diazonium salt 81 which on treatment with TTF leads to the radical 82. The following stereoselective cyclization gives the hexahydrocarba-zole scaffold 80, a substructure of alkaloids like aspi-dospermidin, strychnin and vinblastin. Also the non-toxic tris(trimethylsilyl)silane was employed for domino reactions, eg. for the preparation of the alkaloid aspidospermidin. 

Neutral aminyl radicals generated by anodic oxidation of lithium alkenyl amides undergo a stereoselective cyclization to cis-l-methyl-2,5-disubstituted pyrrolidines [249]. 

Fig. 58 Cathodic stereoselective cyclization of nonconjugated aromatic ketones [317, 318].

Mattay et al. examined the regioselective and stereoselective cyclization of unsaturated silyl enol ethers by photoinduced electron transfer using DCA and DCN as sensitizers. Thereby the regiochemistry (6-endo versus 5-exo) of the cyclization could be controlled because in the absence of a nucleophile, like an alcohol, the cyclization of the siloxy radical cation is dominant, whereas the presence of a nucleophile favors the reaction pathway via the corresponding a-keto radical. The resulting stereoselective cis ring juncture is due to a favored reactive chair like conformer with the substituents pseudoaxial arranged (Scheme 27) [36,37]. 

Scheme 27 Regioselective and stereoselective cyclization of unsaturated silyl enol ethers.

A stereoselective cyclization of (Z)-(2R,3R,4R)-6-cyclohexyloxy-1,3,4-tribenzyloxy-5-hexen-2-ol promoted by mercuric trifluoroacetate or PhSeCl is successfully achieved (38). 2-Deoxy-0(-hexopyranoside derivative is obtained almost exclusively by the treatment of 22 with mercuric trifluoroacetate followed by reductive work up, while a predominant formation of the 3 3no 6r is achieved by the reaction of 22 with PhSeCl, and the successive deselenylation. 

Aldehydes constitute useful electrophilic partners in such nickel-catalyzed reactions because the condensation between alkynes, aldehydes and diorganozinc compounds can afford stereodefined cyclic or acyclic ally lie alcohols67-69, as illustrated by the stereoselective cyclization of 111 to the corresponding 3-hydroxypyrrolidine (equation 46). Allenes or 1,3-dienes instead of alkynes also lead to similar reactivity70. 

Nitrile oxides are linear as opposed to nitrones which are planar with an approximately 120 C—N—O bond angle. Consequently, the cycloaddition transition states are rather different for these two dipoles. The nitrone usually, although not always, offers more promise of stereoselective cyclization the nitrile oxide can offer more promise of regiospecific cyclization, especially in forming 5,6-, 5,7- and larger fused bicyclic systems. 

A new metabolite from Streptomyces olivaceus has been shown to be (2S)-1-oxo-2,3-dihydropyrrolizine-3-carboxylic acid (15b) by total synthesis. The pyrrolizine ring was formed from the pyrrole (14) by stereoselective cyclization with phosphorus pentoxide in toluene in 37% yield. Partial racemization occurred during the hydrolysis of ester 15a.21... 

In 2005, the group of Choi has reported a catalytic system based on [RuC12 (p-cymene)2] that produced the stereoselective cyclization of a-diazoacetamides by intramolecular carbenoid C-H insertion and afforded [I-lactams in excellent yield (>97%) with m-stereoselectivity (>99%), (Scheme 110), [239]. 

The copper complexed aminyl radical cyclization has been used as a key step in a short total synthesis of ( )-gephyrotoxin 223AB (60). The alkenyl substituted ALchloropiperidine 59 was stereoselectively cyclized to construct the indolizidine ring system (Scheme 17) (86JOC5043). Tribu-... 

Hirano et al. reported on the stereoselective cyclization to give tetralin derivatives using the phenanthrene-p-dicyanobenzene sensitizer system. Pandey independently reported the intramolecular photocyclization of methoxybenzene derivatives bearing silyl enol ether chromophore via their heterodimer radical cations in the presence of 1,4-dicyanonaphthalene gave benzo-annulated cyclic ketones in 70% yields [490] (Scheme 133). 

Ruthenium porphyrins are effective catalysts for the cyclization of A-tosylhydrazones via intramolecular carbenoid C-H insertion to afford azetidin-2-ones <2003OL2535, 2003TL1445>. A non-porphyrin-based ruthenium catalyst, [RuCl2(/>-cymene)]2, has been developed recently for catalytic carbenoid transformation <20050L1081>. A [RuCl2(/>-cymene)]2-catalyzed stereoselective cyclization of a-diazoacetamides 418 by intramolecular C-H insertion produced azetidin-2-ones 419 in excellent yields and excellent (>99%) air-stereoselectivity (Equation 168). 

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