Birch reduction-alkylation

A more traveled route to the absolute configuration represented by cyclohexa-1,4-diene 8 involves Birch reduction-alkylation of benzoxazepinone 9.2.5 heterocycle is best prepared by the base-induced cyclization of the amide obtained from 2-fiuorobenzoyl chloride and (5)-pyrrolidine-2-metha-nol. o The molecular shape of enolate 10 is such that the hydrogen at the stereogenic center provides some shielding of the a-face of the enolate double bond. Thus, alkylation occurs primarily at the 3-face of 10 to give 11 as the major diastereomer. The diastereoselectivity for alkylation with methyl iodide is only 85 15, but with more sterically demanding alkyl halides such as ethyl iodide, allyl bromide, 4-bromobut-1-ene etc., diastereoselectivities are greater than 98 2. 

Companion reactions that serve to expand the scope of the asymmetric Birch reduction-alkylation strategy... 

The development of facial selective addition reactions of cyclohexa-1,4-dienes 7 and 14 has greatly extended the value of the asymmetric Birch reduction-alkylation. For example, amide directed hydrogenation of 15 with the Crabtree catalyst system occurs with outstanding facial selectivity iyw to the amide carbonyl group to give 16 (Scheme 5)."... 

The reluctance of tertiary amides to undergo hydrolysis, especially those produced in the Birch reduction-alkylation with a quaternary center next to the carbonyl group, has inspired the development of a variety of intramolecular transacylation reactions as illustrated by the cleavage of the SEM ether in 16... 

We were interested in applications of the high level of stereocontrol associated with the asymmetric Birch reduction-alkylation to problems in acyclic and heterocyclic synthesis. The pivotal disconnection of the six-membered ring is accomplished by utilization of the Baeyer-Villiger oxidation (Scheme 7). Treatment of cyclohexanones 25a and 25b with MCPBA gave caprolactone amides 26a and 26b with complete regiocon-trol. Acid-catalyzed transacylation gave the butyrolactone carboxylic acid 27 from 26a and the bis-lactone 28 from 26b cyclohexanones 31a and 31b afforded the diastereomeric lactones 29 and 30. ... 

A structural requirement for the asymmetric Birch reduction-alkylation is that a substituent must be present at C(2) of the benzoyl moiety to desymmetrize the developing cyclohexa-1,4-diene ring (Scheme 4). However, for certain synthetic applications, it would be desirable to utilize benzoic acid itself. The chemistry of chiral benzamide 12 (X = SiMes) was investigated to provide access to non-racemic 4,4-disubstituted cyclohex-2-en-l-ones 33 (Scheme 8). 9 Alkylation of the enolate obtained from the Birch reduction of 12 (X = SiMes) gave cyclohexa-1,4-dienes 32a-d with diastereoselectivities greater than 100 1 These dienes were efficiently converted in three steps to the chiral cyclohexenones 33a-d. 

What truly distinguishes the asymmetric Birch reduction-alkylation protocol from other methods for preparation of non-... 

The tricyclic sesquiterpene longifolene has served as a vehicle for the illustration of new strategies for organic synthesis.25 Both enantiomers have been obtained from natural sources (-i-)-longifolene occurs in several Firms species and is commercially available while the rare (—)-longifolene has been found in certain liver mosses.2 We elected to prepare (—)-longifolene 49 from the cyclohexa-1,4-diene 45, obtained from the Birch reduction-alkylation of benzoxazepinone 9 in 96% yield with a diastereomeric excess of greater than 98% (Scheme 13).22... 

The diastereomerically related keto esters 53 and 55, activated for removal of the chiral auxiliary, were obtained from 5 and 9. The requisite nitrogen atom was introduced by an azide displacement of chloride and at an opportune stage of the synthesis an intramolecular aminolysis of the carboxylic ester provided the enantiomerically related keto lactams 54 and 56. Although shorter routes to these popular synthetic targets have been reported in recent years, the conversion of 9 to (—)-iso-nitramine (ten steps, 50% overall yield) clearly illustrates the efficiency of the asymmetric Birch reduction-alkylation strategy for construction of the azaspiroundecane ring system. 

The first asymmetric total synthesis of (+)-lycorine is outlined in Scheme 15. While our earlier applications of the Birch reduction-alkylation of chiral benzamide 5 were focused on target structures with a quaternary stereocenter derived from C(l) of the starting benzoic acid derivative, the synthesis of 64 demonstrates that the method also is applicable to the construction of chiral six-membered rings containing only tertiary and trigonal carbon atoms. s... 

Birch reduction-alkylation of 5 with 2-bromoethyl acetate was carried out with complete facial selectivity to give 57. This tetrafunctional intermediate was converted to the bicyclic iodolactone 58 ( > 99% ee) from which the radical cyclization substrate 59 was prepared. The key radical cyclization occurred with complete regio- and facial-selectivity and subsequent stereoselective reduction of the resulting tertiary radical gave 60 with the required trans BC ring fusion.The allylic alcohol rmit of (+)-lycorine was obtained by a photochemical radical decarboxylation, 62 63. 

Chiral benzamides I and the pyrrolobenzodiazepine-5,11-dio-nes n have proven to be effective substrates for asymmetric organic synthesis. Although the scale of reaction in our studies has rarely exceeded the 50 to 60 g range, there is no reason to believe that considerably larger-scale synthesis will be impractical. Applications of the method to more complex aromatic substrates and to the potentially important domain of polymer supported synthesis are currently under study. We also are developing complementary processes that do not depend on a removable chiral auxiliary but rather utilize stereogenic centers from the chiral pool as integral stereodirectors within the substrate for Birch reduction-alkylation. 

For the first report of an asymmetric Birch reduction-alkylation, see A. G. Schultz and P. Sundararaman, Tetrahedron Lett., 1984, 25, 4591. 

Birch Reduction—Alkylation of Derivatives of l-Aroyl-2-pyrrolidinemethanol and l-Aroyl-2-pyrrolidinecarboxylic Acids... 

The combined Birch reduction alkylation of chiral, enantiomerically pure aroyl amides of 2-pyrrolidinemethanol (prolinol) or 2-pyrrolidinecarboxylic acid (proline) gives chiral, non-racemic, 1,1-disubstituted 2,5-cyclohexadienes 1 or 2-cyclohexenes 2, respectively, in high diastereomeric ratios. These reactions are useful for the preparation of valuable chiral synthetic intermediates 3 25 29-31-36. 

Table6. 1,1-Dialkylated 2,5-Cyclohexadienes by Birch Reduction-Alkylation of l-Aroyl-2-pyrrolidinemethanol Derivatives32 3, 38,3y 1. k/nh3/thf...

Therefore, using either direct Birch reduction alkylation or Birch reduction-protonation-enolate formation alkylation, both followed by auxiliary removal, it is possible to prepare either enantiomer of a desired 2,5-cyclohexadiene-l -carboxylic acid derivative in excellent enantiomeric purity from the same starting materials. 

The reversed sense of diastereoselectivity is also observed in the direct Birch reduction alkylation of a number of ort/w-alkylated benzamides of 2-(methoxymethyl)pyrrolidine [i.e., l-(2-alkylbenzoyl)-2-(methoxymethyl)pyrrolidines, 8] which also give high diastereoselectivities of a-methylated products (see Table 6)33. Diastereomeric ratios (TR/TS) for the different R groups range from 5 95 for R = ethyl to 2 98 for R = 2-(tm-butyldimethylsilyloxy)ethyl33. 

This type of Birch reduction-alkylation also works in the naphthalene series36. Thus, the naphthalene carboxamides 10. when subjected to the standard Birch reduction-alkylation conditions, furnish a single set of diastereomers 11 (d.r. >95 5 by ]II and 13C NMR no experimental details given)36. 

In the same manner as for l-(2-alkylbenzoyl)-2-(methoxymethyl)pyrrolidines 8 (vide supra), Birch reduction-alkylation of pyrrolobenzoxazepinones, e.g., 1. gives mainly the a-alkylation products (see Table 6)26,2R u. The chemical yields and diastereoselectivities are usually excellent, except for alkylation with iodomethane when the diastereoselectivity is moderate26. The facial selectivity is opposite to that observed upon direct Birch reduction-alkylation of the ortho-methoxy derivatives, i.e., 2-alkoxymethyl-l-(2-methoxybenzoyl)pyrrolidines (vide supra). 

The general Birch reduction-alkylation procedure (ride supra) is employed. In this case A = 1. B = 2.2. C = 0 and D = 2. For specific examples, sec Table 6. 

Birch reduction-alkylation of (2S)-2-methoxymethyl-l-(2-phenylbenzoyl)pyrrolidine (1) gives products 2 in high diastereoselectivities29. In contrast to the previous examples, only one double bond remains in the product (if one equivalent of rm-butyl alcohol is used as proton donor). Formally this procedure is a stereoselective cis addition, and is thus particularly useful. Thus, two stereogenic centers are created in the same reaction step with high diastereoselectivities. Subsequent hydrolysis furnishes acids, whereas reaction with methyllithium yields chiral ketones29. 

Similar to 2-methoxymethyl-l-(2-phenylbenzoyl)pyrrolidine, Birch reduction-alkylation of pyrrolobenzodiazepine-5,ll-diones 1 leads to reduction of two double bonds and a-alkylation with the creation of two new stereocenters3. The chemical yields are moderate to good and the diastereomeric ratios are generally >85 15. The products are easily purified by recrystallization. In some cases y-alkylation products, with two double bonds in the reduced ring, are obtained as side products31. 

Enantioselective Birch reduction-alkylation The chiral benzoic acid derivative 1, prepared by condensation of o-hydroxybenzoic acid with L-prolinol followed by cyclization (Mitsunobu reaction), undergoes Birch reduction (K, NH3, THF, t-butyl alcohol) followed by alkylation with C2H5I to give essentially only 2. Acid hydrolysis returns the chiral auxiliary and provides the 2-alkylated cyclo-hexenone 3. 

Birch reductive alkylation of benzamide (24) was optimized to give the corresponding cyclohexa-1,4-diene products in 66-78% isolated yield and with high diastereo- (g) selectivity.386... 

A desymmetrization of cyclohexa-2,5-dienes (22) and (24), obtained by Birch reductive alkylation, through a diastereoselective intramolecular hydroamination led with high selectivity to the corresponding bicyclic allylic amines (23) and (25) (Scheme 6).19... 

Regioselectivity of the Birch reductive alkylation of polysubstituted biaryls is affected by the electronic nature of substituents on both aromatic rings. The electron-rich 3,5-dimethoxyphenyl moiety is selectively reduced and then alkylated, whereas phenols and aniline are not dearomatized under these conditions. Biaryls possessing a phenol moiety are alkylated on the second ring, provided that the acidic proton has been removed prior to the Li-NH3 reduction.300... 

The intramolecular diene-carbene cycloaddition equivalence and an enantioselective Birch reduction-alkylation by the chiral auxiliary approach. Total synthesis of ( )- and (—)-longi-folene. Journal of Organic Chemistry,... 

Reductive alkylation. N-t-Butylnaphthalenesulfonamides can undergo Birch reductive alkylation in acceptable yields. The products undergo pyrolysis to al-kvlnaphthalenes.1... 

Formation of Chiral Quaternary Carbon. Birch reduction-alkylation of benzoic acids and esters establishes quaternary carbon centers. Neighboring stereocenters will influence the stereochemical outcome of the tandem reaction sequence. The following example illustrates how a chiral auxiliary (derived from prolinol) controls the stereoselection in the Birch reduction-alkylation step. ... 

In the laboratory of A.G. Schultz during the asymmetric total synthesis of two vincane type alkaloids, (+)-apovincamine and (+)-vincamine, it was necessary to construct a crucial c/s-fused pentacyclic diene intermediate. The synthesis began by the Birch reduction-alkylation of a chiral benzamide to give 6-ethyl-1-methoxy-4-methyl-1,4-cyclohexadiene in a >100 1 diastereomeric purity. This cyclohexadiene was first converted to an enantiopure butyrolactone which after several steps was converted to (+)-apovincamine. 

In the other synthetic route (119), Birch reduction-alkylation and transformation of functionalized hexahydroindoline derivatives constitute key reactions (Schemes 4 and 5). Birch reduction of A-(2-methoxybenzoyl)-(25)-methoxymethylpyrrolidine, followed by alkylation with 2-acetoxyethyl bromide, produced a key compound 76, azidation of which, followed by hydrolysis with acid, gave the azide 77 in 69% yield (two steps). lodolactoni-... 

Another ether of 9 used as auxiliary is the methoxymethyl (MOM) ether 12 which forms amides with carboxylic acids for sigmatropic rearrangements (Section D. 1.6.3.2.) or enantiose-lective Birch reduction/alkylation (Section D. 1.1.1.3.1.). The ether is obtained by an analogous alkylation procedure with chloromethyl methyl ether15 6. 

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