Stereochemistry intramolecular cyclizations

The iminium salt 165, derived from acid treatment of 1,4-dihydropyridine 164, on intramolecular cyclization on the indole nucleus gave pentacyclic compound 166 (83T3673). The tmns stereochemistry of H3 and H9 in 166 (biogenetic... 

Studies of the intramolecular cyclization of P-amino acids have included the use of camphor-derived oxazoline A-oxide 66 and a [3+2] cycloaddition reaction as a step in the formation of the amino acid with the required stereochemistry <00OL1053, OOEJOC1595>. A diastereoselective synthesis of a ip-methylcarbapenem intermediate utilises a cyclization of a P-amino acid <99CC2365>. 

A Mitsunobu reaction then inverts the C-4 configuration to provide compound 151, and subsequent isomerization provides compound 152, which is ready for Lewis acid-mediated cyclization to construct the eight-membered firing. Using MeiAlOTf as a catalyst, intramolecular cyclization occurs, giving product 153 in which A, B, and C rings have been introduced with the desired stereochemistry (Scheme 7-45). 

The effects of stereochemistry, substitution, and (for 2-phenylimino derivatives) an intramolecular cyclization of the ions [M-H] have been observed in the electron ionization mass spectra of as- and /ra r-fused 4-phenyloctahy-dro-2//-3,l-benzoxazin-2-ones 21 and -2-thiones 22, 2,4-diphenylhexahydro-3,l-benzoxazines 23, and 2-phenyl-imino-4-phenylhexahydro-3,l-benzoxazines 24. The mass spectral behavior was similar for the isomeric compounds, although they could usually be differentiated from each other on the basis of the relative abundances of their characteristic fragment ions <2005ARK(iv)39>. 

Cyclization of nitrile oxides with a four-atom intervening chain to the alkene always leads to 5,6-fused bicylic isoxazolines possessing a bridgehead C—N double bond. This is in contrast to nitrone cycliza-tions where competition to form bridged bicyclic isoxazolidines is observed. The alkenyl oximes (73) and (74) cyclize in typical fashion via nitrile oxide intermediates (Scheme 21).33a>36 The stereochemistry of cyclization here was studied both experimentally and by calculation. The higher stereoselectivity observed with the (Z)-alkene is typical. (Z)-Alkenes cycloadd much slower than ( >alkenes in intermole-cular reactions this is attributed to greater crowding in the transition state. Thus, intramolecular cycloaddition of (Z)-alkenes depends on a transition state that is heavily controlled by steric factors. 

A Lewis-acid-mediated intramolecular cyclization of allenyl stannane 344 furnishes 2,6- //-tetrahydropyran as the major product, the stereochemistry of which can be switched to syn with moderate effect if a propargylstannane 345 is used as a substrate (Equation 147, Table 16) <1996TL3059>. The stereoselectivity observed in an analogous system, the intramolecular cyclization of y-alkoxyallyl stannanes 346 with a tethered aldehyde, can be controlled by changing the geometry of the alkene (Scheme 83) <1997JOC7439>. y-Alkoxyallyl stannanes are also known to cyclize both diastereoselectively and enantioselectivity, by incorporation of both a chiral auxiliary and a chiral catalyst respectively into the reaction <1999JOC4901>. 

Several indium-mediated intramolecular carbonyl allylation reactions have been investigated, and it has been found that these reactions provide an easy access to a variety of cyclic compounds. The intramolecular cyclization of 49a-c mediated by indium in aqueous media proceeds smoothly to afford carbocyclic systems containing y-hydroxy-Q -methylene esters 50a-c, which either spontaneously or readily cyclize to give fused o -methylene-y-butyrolactones 51a-c (Scheme 52). The same cyclization of 49d is too slow to compete with the side-reaction, in which the bromide is substituted by a hydroxy group. The ring junction stereochemistry of fused lactones 51 has been found to be cis in all cases. Of the two possible transition states, the one leading to the m-fused compounds is preferred, because the chair-chair conformation is favored over the chair-boat conformation.209... 

A remarkable example of [2-1-2] photocycloaddition of furans with alkenes, as shown in Equation (58), is the pivotal intramolecular cyclization employed in the total synthesis of ginkgolide B <2000JA8453>. The stereochemical outcome of this triplet transformation was predominately influenced by the relative 1,3-stereochemistry of the substrate 76. 

Diastereoselective macrocyclizjation.1 A key step in a synthesis of the 14-membered cembranoid asperdiol (4) involves intramolecular cyclization of the aldehydo allylic bromide (1) with chromium(II) chloride. The intermolecular version of this reaction is known to be awft-selective (8,112). Treatment of racemic 1 with CrCl2 (5 equiv., THF) results in a 4 1 mixture of the two anri-diastereomers 2 and 3 in 64% combined yield. The stereochemistry of this cyclization is evidently controlled by the remote epoxide group. The natural product was obtained by deprotection of 2 (Na/NH3, 51% yield). 

Although cyclization can take place in many ways, according to Kallen [11] the most preferred pathway involves imine formation followed by intramolecular cyclization. During the course of cyclization a new chiral center at C-2 is created thereby giving rise to a diastereomeric mixture namely 2R, 4R and 2S, 4R. An interesting situation arises when the reactant aldehyde is also chiral. The stereochemistry at the newly formed center is controlled by the stereochemistry of the aldehyde [12]. In view of the biological importance of thiazolidine, Patek et al. reported a solid-phase synthesis protocol (Scheme 4) [13]. This enables the synthesis of compound libraries for quick lead optimization. 

As a sequel to the elegant and highly efficient synthesis of camphor by an intramolecular cyclization. Money et have successfully applied this method to the synthesis of the naturally-occurring sesquiterpenoids campherenone (110) and campherenol (111) whose structures and absolute stereochemistries have recently been deduced.In this sequence, dihydrocarvone (112) was readily converted into the keto-ketal (113) from which the homologated chloro-ketone (114) was obtained. Treatment of the corresponding enol acetate (115) with boron trifluoride in wet methylene chloride afforded the two bicyclic chloro-ketones (116) and (117) in 55-60% yield. Conversion of the corresponding iodo-ketals... 

An intramolecular cyclization of -hydroxysulfoxides effected by At-chloro-succinimide, A bromosuccinimide, or sulfuryl chloride gives 1,2-oxathietane 2-oxides, for example, 496, via a sulfoxonium salt. These cyclic sulfoxonium intermediates have been suggested in the conversion of /3-hydroxy-sulfoxides to /3-chlorosulfones, and to a,j3-unsaturated sulfones, in the conversion of /3-ethoxycarbonylsulfoxides to alkenes and of /3-hydroxysulfides to /3-hydroxysulfoxides, and in the conversion of 3-hydroxy- 3-vinylsulfoxides (e.g., 497) to useful terpene building blocks. The yields of the products from 497 vary somewhat depending on the stereochemistry about the two chiral centers. The more highly substituted 1,2-oxathietane 2-oxides are the most stable, because of... 

Cross-Coupling with Carbonyl Compounds. The electroreductive cross-coupling of olefins with carbonyl compounds, which are initially reduced to radical or anion intermediates to attack the olefins, is synthetically useful. The stereochemistry of this type of intermolecular reaction has lately been examined less [70-72] than that of intramolecular cyclization [73-77]. 

Intramolecular cyclizations offer a versatile method for the preparation of bicyclic and polycyclic ketones. Indeed, in favorable cases, reaction can ensue on simply heating the acyl halide " as well as on treatment with a Lewis acid, offering control of the product isolated (Scheme 3). However, the structural constraints imposed in detailed examination of specific ring systems in which the stereochemistry of cyclization can be determined may well preclude the deduction of more general conclusions about stereochemical control. 

The intramolecular cyclization route to a specific P-lactam often depends on the availability of a P-aminoester having the required stereochemistry. A review which considers the asymmetric synthesis of p-aminoesters is available (94MI475). Ytterbium promoted addition of benzylamine to 2-alkenoic esters having a stereogenic centre at the y-position (94CL827) and triphenyl borate mediated reaction of chiral imines with silylketene acetals have been utilised to give P-aminoesters stereoselectively (93BMC2337). 

Since oximes of erythromycin are less prone to intramolecular cyclization than the parent compound, a structure-activity study was conducted on a series of 9-(0-alkyl)oxime derivatives of erythromycin [84]. From this work, roxithromycin, the 9-[D-(2-methoxyethoxy)methyl]oxime (12), was selected for further development. The isomer with E stereochemistry (oxime substituent syn to C-8 of lactone) is more active than the Z isomer [84]. The X-ray crystal structure of roxithromycin reveals a conformation of the lactone similar to that of erythromycin [85]. The similarity was also established by solution NMR studies, which suggested that the orientation of the oxime substituent helped to explain the increased hydrophobicity of roxithromycin and its greater penetration into certain tissues [86, 87]. 

Imides prepared from a-aminoacid esters with an extractable y-proton (with respect to the phthalimide nitrogen as a) have been reported to furnish benz[c]diazepine-2,5-diones in a Norrish Type II process with retention of stereochemistry of the aminoacid asymmetric centre <92CB2467, 94T3627). Similar results are reported in the intramolecular cyclization of iV-alkyl succinimides, in contrast to the reaction of such compounds with alkenes in an intermolecular reaction, when the usual product is an oxetane <84CPB950,85MI901-02). 

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