Palladium‐Catalyzed Asymmetric Intramolecular Reductive Heck Desymmetrization of Cyclopentenes: Access to Chiral Bicyclo[3.2.1]octanes

A palladium‐catalyzed asymmetric reductive Heck reaction of unactivated aliphatic alkenes, with eliminable β‐hydrogen atoms, has been realized for the first time. A series of optically active bicyclo[3.2.1]octanes bearing chiral quaternary and tertiary carbon stereocenters were obtained in good yields with excellent enantioselectivities, exhibiting good functional‐group tolerance and scalability. Moreover, deuterated optically active bicyclo[3.2.1]octanes were also obtained in high efficiency.     

Catalytic Asymmetric Synthesis of Benzobicyclo[3.2.1]octanes

Lawsone aldehydes were directly transformed into the biologically important, unique carbon skeleton of chiral methanobenzo[f]azulenes/methanodibenzo[a,d][7]annulenes in high dr and ee and in very good yields by using quinine-thiourea-catalyzed tandem Wittig/intramolecular Michael/intramolecular aldol reactions. This asymmetric catalytic tandem protocol will be highly useful because these final molecules are basic skeletons of important antibiotics.     

A general and efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes

A convenient and efficient synthesis of N⁶-substituted 3,6-diazabicyclo[3.2.1]octanes (6a-c) has been achieved starting from suitably substituted lactams, which were converted to nitroenamines followed by reductive cyclization to afford 3,6-diazabicyclo[3.2.1]octane-2-ones in good yields. These bicyclic lactams were then reduced to the corresponding 3,6-diazabicyclo[3.2.1]octanes and converted to the required N³,N⁶-disubstituted 3,6-diazabicyclo[3.2.1]octanes (7a-h), which were screened for α₁-adrenoceptors antagonistic activities.     

Functionalized Cycloheptanes from Bicyclo[4.2.1]nonanes

Several oxidative, reductive and C,C-cleavage reactions were performed starting from the three bicyclo[4.2.1]nona-3,7-diene-2-one derivatives 1, 5 and 18 . The oxidations were selective and led to the diols 2,8 and 9 , and the epoxides 6,9 , and 20 . The reductions were selective only in the case of 20 21 ; otherwise they led to mixtures of the alcohols 10 and 11 , and of the dienes 14 and 15 . The periodate ring cleavages afforded the functionalized cycloheptane derivatives 3, 12, 13 and 16 . Configurational assignments were made on the basis of detailed ¹H-NMR and X-ray analysis of 20 .     

Aspects of the chemistry of 8-azabicyclo[3.2.1]octanes

Mesylation and elimination from dimethyl 3-hydroxy-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate gave a conjugated alkenyl ester. Reduction of the mesyloxy ester by di-isobutylaluminium hydride was also accompanied by elimination giving an unsaturated aldehyde. Treatment of the mesylate of the corresponding monoprotected diol with potassium tert-butoxide gave a 2-unsubstituted alkene via a Grob fragmentation but a different alkene was obtained using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile. Epoxidation of both the protected hydroxy-alkene and the free hydroxy-alkene was stereoselective in favour of epoxidation from the exo-face, and ring-opening of the hydroxy-epoxide using hydrogen bromide gave the diaxial bromohydrin. Treatment of a 2-iodomethyl-3-oxo-8-azabicyclo[3.2.1]octane with tert-butyllithium gave a cyclopropane, whereas the corresponding iodo-alcohol gave the 1-azatricyclo[5.3.0.0^4,10]decan-2-one as the major product.     

2,2,3,3-Tetracyano-7,8-dithiabicyclo[3.2.1]octanes: Structural studies

2,2,3,3-Tetracyano-7,8-dithiabicyclo[3.2.1]octanes were formed in the reaction of dithiocarboxyclic acid allyl and cinnamyl esters with tetracyanoethylene, and their structure was determined by a number of physico-chemical methods, including x-ray structural study.K. A. Timiryazev Agricultural Academy, Moscow 127550. A. N. Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences, Moscow 117813. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 770–780. June, 1994. Original article submitted May 18, 1994. eskikh Soedinenii, No. 6, pp. 770–780.     

A formal [3+2] cycloaddition for the synthesis of bicyclo[3.2.1]octanes

A new and a direct synthetic method for the construction of the bicyclo[3.2.1]octane system is envisioned by assembling cyclic allylsilanes with electron-deficient double bonds in a single step via a formal diastereoselective Lewis acid-promoted [3+2] cycloaddition.     

A synthesis of 6-azabicyclo[3.2.1]octanes. The role of N-substitution

The intramolecular cyclization reactions of aziridines with pi-nucleophiles can be a useful route to a number of heterocyclic and carbocyclic ring systems. We were particularly interested in the use of this cyclization reaction for the synthesis of 6-azabicyclo[3.2.1]octanes. We report here the development of a new synthesis of the aziridine necessary for the aziridine--pi-nucleophile cyclization. We also report on the cyclization of aziridines with three different substitutions on the aziridine nitrogen. We have found that N-diphenylphospinyl and N-H aziridines, while participating in the initial ring-opening reaction, do not lead to the desired bicyclic ring systems. In contrast, a nosyl group on the aziridine nitrogen leads efficiently to the bicyclic ring system and can be readily deprotected.     

8-phosphabicyclo[3.2.1]octanes—II: The synthesis and stereochemistry of 8-phosphabicyclo[3.2.1]oct-6-enes

Several new 8-phosphabicyclo[3.2.1]oct-6-enes and -6-en-3-yl acetates were prepared by the alkyl (or aryl)dihalophosphane addition to cyclohepta -1,3-diene and 1-acetoxy cyclohepta-3,5-diene. The P-configuration in two P-epimer pairs (3, 4 and 5, 6) and three other compounds which were each obtained as a single isomer (1, 2 and 7) was determined by investigation of the NMR spectra, i.e. by complexation of the compounds with Eu(dpm)₃ as well as from the various phosphorus-hydrogen coupling constants. Compounds possessing the same P-substituent were correlated among themselves and in the case of the PPh bearing compounds (1 and 7) further correlation to a known compound (8a) was established. The chemical behaviour of the C₆C₇ double bond is discussed and compared with the corresponding behaviour in trop-6-enes. Great steric hindrance was found for this bond, for which the following sequence is suggested:

The synthesis of a phosphaatropine analog is described.     

The Reaction of Bicyclo [3.2.1] octenyl Halides with Metal Hydrides

Reduction of 2-phenyl- and 2-methyl-exo-3,4-dichlorobicyclo[3.2.1]oct-2-enes with lithium aluminium hydride (LAH) or tributyltin hydride (TBTH) gave endo-2-phenyl-3-chlorobicyclo[3.2.1]oct-3-ene, 2-phenyl-3-chlorobicyclo[3.2.1]oct-2-ene and their methyl analogues. The action of both reagents on 2-phenyl-exo-3, 4-dibromobicyclo[3.2.1]oct-2-ene similarly resulted in reductive monodebromination to give normal and allylically rearranged products. Additionally, further reduction occurred to give endo-2-phenylbicyclo[3.2.1]oct-3-ene and 2-phenylbicyclo[3.2.1]-oct-2-ene. In all cases, LAH gave mainly the allylic rearrangement product whereas TBTH gave mostly unrearranged product. The reason for these differences could have been due either to the intervention of allylic radicals in the TBTH reduction or to differences in nucleophilicity. The results also show that LAH is equally efficaceous as TBTH in the reduction of these allylic halides and equally selective in the reduction of the vinyl bromides. The stereochemistry of the allylic rearrangement was shown to be synfacial in that hydride replaced halide on the same face of the molecule.     

Bicyclo[3.2.1]amide-DNA: a chiral,nonchiroselective base-pairing system

The design, synthesis, and base-pairing properties of bicyclo[3.2.1]amide-DNA (bca-DNA), a novel phosphodiester-based DNA analogue, are reported. This analogue consists of a conformationally constrained backbone entity, which emulates a B-DNA geometry, to which the nucleo-bases were attached through an extended, acyclic amide linker. Homobasic adenine-containing bca decamers form duplexes with complementary oligonucleotides containing bca, DNA, RNA, and, surprisingly, also L-RNA backbones. UV and CD spectroscopic investigations revealed the duplexes with D- or L-complements to be of similar stability and enantiomorphic in structure. Bca oligonucleotides that contain all four bases form strictly antiparallel, left-handed complementary duplexes with themselves and with complementary DNA, but not with RNA. Base-mismatch discrimination is comparable to that of DNA, while the overall thermal stabilities of bca-oligonucleotide duplexes are inferior to those of DNA or RNA. A detailed molecular modeling study of left- and right-handed bca-DNA-containing duplexes showed only minor changes in the backbone structure and revealed a structural switch around the base-linker unit to be responsible for the generation of enantiomorphic duplex structures. The obtained data are discussed with respect to the structural and energetic role of the ribofuranose entities in DNA and RNA association.     

Synthesis of bicyclo[3.2.1]octanes by a tandem Diels-Alder-carbocation cyclization strategy

The bicyclo[3.2.1]octane ring system is assembled by a three-step process featuring a thermally induced [4+2] cycloaddition followed by a 1,3-benzodithiolium ion mediated cyclization onto an enol or silyl enol ether double bond.     

Asymmetric Organocatalytic Domino Michael/Aldol Reactions: Enantioselective Synthesis of Chiral Cycloheptanones,Tetrahydrochromenones, and Polyfunctionalized Bicyclo[3.2.1]octanes

C′mon 1,2‐dione : A new diastereo‐ and enantioselective Lewis base catalyzed domino Michael/aldol reaction converts α,β‐unsaturated aldehydes and 1,2‐diones into chiral bicyclo[3.2.1]octane‐6‐carbaldehydes. The products are produced in good to excellent enantioselectivities (90–98 % ee) and can be transformed into bicyclic diols and triols. Additionally, a retro‐aldol cyclization provides access to valuable tetrahydrochromenones (see scheme).

     

Exploiting the regioselectivity of pyroglutamate alkylations for the synthesis of 6-azabicyclo[3.2.1]octanes and 4-azabicyclo[3.3.0]octanes

Depending on the N-protecting group of pyroglutamates, the reactivity can be directed to the formation of 6-azabicyclo[3.2.1]octanes or 4-azabicyclo[3.3.0]octanes, which are conformationally restricted glutamate analogues.     

Bicyclo[3.2.1]octane and 6-oxabicyclo[3.2.2]nonane type neolignans from Magnolia denudata

From the ethyl acetate soluble fraction of twigs of Magnolia denudata (Magnoliaceae), seven new neolignan derivatives, 1-7, were isolated along with eighteen known lignan and neolignan derivatives, 8-25. The structures of the new neolignans were elucidated by means of spectral methods, especially by 1H-NMR and 13C-NMR spectra, and two dimensional NMR methods such as 1H-detected heteronuculear multiple bond connectivity1 (HMBC), 1H-detected multiple quantum coherence (HMQC) and 1H-1H-correlation spectroscopy (COSY). Compounds 1-4 have novel structures possessing a 6-oxabicyclo[3.2.2]nonane skeleton and compounds 5-8 also have novel structures possessing a bicyclo[3.2.1]octane skeleton. The anti-platelet-activating factor (PAF) activity of these compounds was tested by measurement of inhibition activity against acetyl transferase to lyso-PAF.     

Reaction of Bicyclo[3.2.1]octenols with Thionyl Chloride. Preliminary paper

The allylic 1-methyl-3-bromobicyclo[3.2.1]octenyl exo-2 and exo-4 alcohols were treated with thionyl chloride in ether or pentane solution at 0°. In each case, a 50/50 mixture of exo allylic chlorides was obtained. No evidence for a predominant S_N l′ reaction was detected; reported cases of such S_N l′ processes using these conditions should therefore be treated with reserve.