Exocyclic chirality

Two families of complexes having either exocyclic chirality borne by the nitrogen atoms (79,81,82) or endocycUc chirality (f-butyl groups) relayed by benzyUc groups on the nitrogen atoms (83, 84) were tested in the optimized conditions (Fig. 15). 

Stereoselectivity in dearomatising cyclisations may be controlled by a number of factors, including rotational restriction in the organolithium intermediates202 203 and coordination to an exocyclic chiral auxiliary.197 Most usefully, by employing a chiral lithium amide base, it is possible to lithiate 441 enantioselectively (see section 5.4 for similar reactions) and promote a cyclisation to 442 with >80% ee.204... 

A related radical addition/5-exo cyclization cascade involving addition of sulfonyl radicals to alkynes has been used for the diastereoselective synthesis of bicyclic p-lactams 182 from the p-lactamic enyne precursor 181 (Scheme 2.33). In this radical chain sequence, where tosyl bromide is used as source of sulfonyl radicals, the final product is a mixture of epimers (90 10) at the newly formed exocyclic chiral center. 

Figure 5.18 Imidazolium salts with endocyclic and exocyclic chirality.

Generally speaking, exocyclic chirality seems to be better than endocyclic chirality in imidazole based carbenes. Both causes of chirality seem to be additive rather than cancelling each other, but the same is not the case for other combinations of chiral elements. 

Rogers and Manville have isolated the acid (59) from the British Columbia Interior variety of Douglas fir. This compound is closely related to juvabione but one interesting feature is that they differ in absolute stereochemistry at the exocyclic chiral centre. 

Intramolecular carbon-nitrogen bond formation is possible utilizing a catalytic system derived from Pd2(dba)3/P(2-tolyl)3, which gives enantiomerically enriched amine and amide products with either endocyclic or exocyclic chiral centers, e.g., 15 to give 16 (eq 15). Note that no decrease in enantiomeric excess is observed from substrate to product. In contrast, the intermolecular variant, e.g., reaction of 17 and 18 to give 19, conducted under identical reaction conditions, leads to products that are partially or fully racemized. Key to the success of the intermolecular process is the employment of bidentate ligands such as roc-BINAP or DPPF (eq 16). 

However, enantioselectivities remained low untQ in 2004 Page reported the use of modified versions of binaphthyl iminium salt containing exocyclic chirality. 

Figure 10.3-40. The rating for the disconnection strategy carbon-heteroatom bonds is illustrated, Please focus on the nitrogen atom of the tertiary amino group. It is surrounded by three strategic bonds with different values. The low value of 9 for one ofthese bonds arises because this bond leads to a chiral center. Since its formation requires a stereospecific reaction the strategic weight of this bond has been devalued. In contrast to that, the value of the bond connecting the exocyclic rest has been increased to 85, which may be compared with its basic value as an amine bond.

Barluenga et al. have described novel vinylcarbene complexes containing a cyclic BF2 chelated structure which temporarily fixes the s-cis conformation of the exocyclic C=C and Cr=C double bonds. These boroxycarbene complexes behave as dienophiles with 2-amino-l,3-butadienes in a remarkably regio- and exo-selective way. Moreover, high degrees of enantioselectivity are reached by the use of chiral 2-aminodienes derived from (S)-methoxymethylpyrrolidine [101] (Scheme 54). 

Among other types of compounds that contain the system illustrated in Figure 4.2 and that are similarly chiral if both sides are dissymmetric are spiranes (e.g., 21) and compounds with exocyclic double bonds (e.g., 22). 

O-Alkylation of 4-hydroxy-3-morpholino-l,2,5-thiadiazole 132 has been achieved with the chiral cyclic chloro-methyl sulfite 133 which subsequently suffers ring opening on treatment with simple alcohols <2001RCB436> or alkylamines <2002RJ0213> to afford the timolol analogues 134 with very little racemization (Scheme 20). This indicated an almost exclusive attack of the oxy anion on the exocyclic carbon atom and is a significant improvement on the previous oxirane method, which suffers from racemization. An alternative biocatalytic asymmetric synthesis of (A)- and (R)-timolol has also appeared <2004S1625>. 

The 1,3-dipolar cycloaddition reactions of the chiral 3-benzoyl-4-methylene-2-phenyloxazolidin-5-one 118 and nitrile oxides RCNO (R = Ph, Me) had the expected stereochemistry, addition of the 1,3-dipole having occurred from the less hindered n-face of the exocyclic methylene of 118 (282). 

Therefore, chirality is achieved without an exocyclic barrier to rotation as is required in the corresponding carbocyclic aryl substrates. 

Another route to a methyl-branched derivative makes use of reductive cleavage of spiro epoxides ( ). The realization of this process was tested in the monosaccharide series. Hittig olefination of was used to form the exocyclic methylene compound 48. This sugar contains an inherent allyl alcohol fragmenC the chiral C-4 alcohol function of which should be idealy suited to determine the chirality of the epoxide to be formed by the Sharpless method. With tert-butvl hydroperoxide, titanium tetraisopropoxide and (-)-tartrate (for a "like mode" process) no reaction occured. After a number of attempts, the Sharpless method was abandoned and extended back to the well-established m-chloroperoxybenzoic acid epoxida-tion. The (3 )-epoxide was obtained stereospecifically in excellent yield (83%rT and this could be readily reduced to give the D-ribo compound 50. The exclusive formation of 49 is unexpected and may be associated with a strong ster chemical induction by the chiral centers at C-1, C-4, and C-5. 

In addition to the high levels of asymmetric induction, two other attractive features of this sequence of reactions warrant comment. First, both acylation and hydrolysis of the chiral auxiliary are facile, high yield reactions. Second, we have recently found that the lithium hydroperoxide hydrolysis protocol described in Part C is the method of choice for the deaoylation process. This reagent exhibits remarkable regioselectivity for attack at the desired exocyclic acyl carbonyl moiety. ... 

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