Alkaloids, enantiomerically pure

As an application of this method1S, the preparation of enantiomerically pure piperidine alkaloids ( )-(i )-coniine (3 steps, 72% overall yield) and (-)-(2i ,6S)-dihydropinidine (6) from 5 is described. For related works, see refs 16, 19-29 and literature cited therein. 

The molecular modelling approach, taking into account the pyruvate—cinchona alkaloid interaction and the steric constraints imposed by the adsorption on the platinum surface, leads to a reasonable explanation for the enantio-differentiation of this system. Although the prediction of the complex formed between the methyl pyruvate and the cinchona modifiers have been made for an ideal case (solvent effects and a quantum description of the interaction with the platinum surface atoms were not considered), this approach proved to be very helpful in the search of new modifiers. The search strategy, which included a systematic reduction of the cinchona alkaloid structure to the essential functional parts and validation of the steric constraints imposed to the interaction complex between modifier and methyl pyruvate by means of molecular modelling, indicated that simple chiral aminoalcohols should be promising substitutes for cinchona alkaloid modifiers. Using the Sharpless symmetric dihydroxylation as a key step, a series of enantiomerically pure 2-hydroxy-2-aryl-ethylamines... 

A representative series of enantiomerically pure alkaloids and other compounds having known biological activity was synthesized using the above described strategy by the group of Prof. Denmark (Chart 3.19). 

Such lanthanide catalysts were also used in hydroamination/cyclization strategies for the synthesis of the alkaloid (+)-xenovenine. This reaction of enantiomerically pure 147 leading to 148 via two C-N bond formations was used in a late step of the synthesis after a hydrogenation, the natural product was isolated (Scheme 15.46) [100]. 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

The bis-carbazole alkaloids contain previously known monomeric carbazoles as structural subunits. All bis-carbazole alkaloids were isolated only from plants of the genus Murray a, until 1996, when clausenamine-A (203) (see Scheme 2.48) was isolated from the stem bark of C. excavata. The plant M. euchrestifolia is one of the richest sources of carbazole alkaloids. The bis-carbazoles often co-occur with monomeric carbazoles in the root bark, stem bark, and leaves of this plant (3,5-7,158,159). The aspect of atropisomerism for axially chiral, bis-carbazoles was considered only recently. Thus, in many cases it is not clear whether the isolated natural products are racemic or enantiomerically pure. Moreover, little attention has been paid to the relationship between their stereochemistry and biological activity. 

Oppolzer et al. (321) applied his own sultam as the auxiliary for a cychc nitrone in the synthesis of (—)-allosedamine (Scheme 12.60). The enantiomerically pure nitrone 209 was synthesized from 208 by base treatment, attack of the enolate on 1-chloro-l-nitrosocyclohexane at the nitrogen atom, and subsequent elimination of chloride. Subsequent addition of aqueous HCl gave the cyclic nitrone 209. The nitrone participated in a 1,3-dipolar cycloaddition with styrene, proceeding with complete exo-specificity. The product, 210, was obtained with a de of 93%. Two further reaction steps yield the piperidine alkaloid ( )-aUosedamine 211 in an overall yield of 21%. 

The cyclic ammonium ylide/[l,2]-shift approach has been successfully applied by West and Naidu to a key step in the total synthesis of (—)-epilupinine, one of the biologically active lupin alkaloids. Cu(acac)2-catalyzed diazo decomposition of enantiomeric pure diazoketone 160 in refluxing toluene generates a spiro ammonium ylide 161 and 162, which then undergoes [l,2]-shift to give rise to a quinolizidine skeleton as a mixture of diastereomers (95 5) (Scheme Major diastereomer 164 has enantiomeric purity of 75% ee. The partial retention of stereo-... 

The tetracyclic alkaloid quinine 1 and the diastereomeric alkaloid quinidine 2 share a storied history. Eric Jacobsen of Harvard recently completed (J. Am. Chem. Soc. 2004, 126, 706) syntheses of enantiomerically-pure 1 and of 2. For each synthesis, the key reaction for establishing the asymmetry of the target molecule was the enantioselective conjugate addition developed by the Jacobsen group. 

Joseph P.A. Harrity of the University of Sheffield has reported (J. Org. Chem. 2005, 70, 207) a complementary approach to enantiomerically-pure piperidines. Alkylated azridines such as 17 are readily available from aspartic acid. Pd-catalyzed condensation of 17 with the Trost reagent 18 was found to be most effectively mediated by bis-phosphines such as dppp , 1,3-bis-diphenylphosphinopropane. The piperidine 19 was the key intermediate for the preparation of several of the Nuphar alkaloids, including 20. 

A RCM-ROM-RCM strategy was employed as the key step to the synthesis of these alkaloids (Scheme 10). Both alkaloids can be derived from the protected bis-hydropyrrole 31 which is the ring rearranged product from the seven-membered carbocycle 32. Compound 32 can be obtained from the enantiomerically pure triol derivative 33, which in turn can be obtained from commercially available tropone 34.34... 

The intramolecular alkylation of the enolate derived from phenylalanine derivatives 22a,b to form P-lactams 23a,b has also been achieved using Taddol as a chiral phase-transfer catalyst (Scheme 8.11) [23]. In this process, the stereocenter within enantiomerically pure starting material 22 is first destroyed and then regenerated, so that the Taddol acts as a chiral memory relay. Taddol was found to be superior to other phase-transfer catalysts (cinchona alkaloids, binol, etc.) in this reaction, and under optimal conditions (50 mol % Taddol in acetonitrile with BTPP as base), P-lactam 23b could be obtained with 82% et. The use of other amino acids was also studied, and the... 

One example is the optically active amino acid derivative (S)-20n which contains a bipyridyl substituent (Scheme 3.14). The alkylation reaction in the presence of the cinchona alkaloid catalyst 33 proceeds with 53% ee (83% yield of (S)-20n) and gave the desired enantiomerically pure a-amino acid ester (S)-20n in >99% ee after re-crystallization [43]. Subsequent hydrolysis of the optically pure (S)-20n furnished the desired unprotected a-amino acid 35. A different purification method, subsequent enzymatic resolution, reported by Bowler et al., furnished the a-amino acid product 35 with enantioselectivity of 95% ee [44],... 

The field of organocatalytic enantioselective anhydride transformations has seen tremendous progress during recent years. For example, the alcoholytic desymmetrization of meso anhydrides, effected by stoichiometric quantities of inexpensive and readily available cinchona alkaloids, has been developed to a very practical level, and several applications, e.g. for the synthesis of enantiomerically pure... 

Quite remarkable progress has also been achieved in enantioselective transformation of cyclic anhydrides derived from a-hydroxy and a-amino carboxylic acids. By careful choice of the reaction conditions, dynamic kinetic resolution by alcoholysis has become reality for a broad range of substrates. Again, the above mentioned dimeric cinchona alkaloids were the catalysts of choice. In other words, organoca-talytic methods are now available for high-yielding conversion of racemic a-hydroxy and a-amino acids to their enantiomerically pure esters. If desired, the latter esters can be converted back to the parent - but enantiomerically pure - acids by subsequent ester cleavage. 

A short chemo-enzymatic approach to the enantiomerically pure alkaloid, published in 2008 is notable, because it avoids long sequences with low overall yields, mixtures of isomers and at the end racemic alkaloid which is outlined in Fig. 21 ([134], also includes citations for earlier syntheses). 

This is nicely demonstrated by two contributions to this volume. On one hand, electrochemical strategies for the synthesis of complex bioactive alkaloid structures are developed, and on the other, the electrochemical transformation of readily available bio-molecules (terpenoids and p-lactarns) into enantiomerically pure complex synthetic building blocks is demonstrated. 

Fig. 17.21 Parti. Asym metric os-idc-dihydroxylation ("AD")ofalkeneswith catalytic amounts of Os(VIII), stoichiometric amounts of K3Fe(CN)6 and an enantiomerically pure hexaamine. The latter is derived from the hydrogenation products of enantiomerically pure alkaloids, i.e., from di hydroquinine ("DHQ") or from dihydroquinidine (DHQD), as specified in between the dashed horizontal lines as phthalazine (DHQ)2-PHAL and (DHQD)2-PHAL, respectively. The structural formulas presented here become true structural formulas if the text is replaced by the fragments "dihydroquinuclidine l," "dihydroquinuclidine II" and "methoxyquinoline," which are explained at the bottom of Figure 17.21.

The photochemical electrocyclic reaction of acrylamides represents a versatile strategy for alkaloid synthesis. Thus, (S)-pipecoline has been synthesized using the photochemical cyclization of enantiomerically pure acrylamide derivatives in the presence of NaBH4, which causes reduction of the imonium intermediate. The lactam may then easily be transformed into the desired heterocyclic compound (Scheme 9.26) [38]. 

The stereochemical course of these reactions was also explained by assuming an exo approach of dipole to the vinyl sulfoxide in s-trans conformation, which in this case would be the less destabilized by electrostatic repulsions (Scheme 95). A similar stereochemical course would explain the results obtained in the reactions of nitrone 194 with (Z)-vinyl sulfoxides 13 (Scheme 96) [159a]. With these dipolarophiles, the exo selectivity is complete, and the 7r-facial selectivity is very high (de 82-98 %) and depends on the size of the R group, which must be responsible for the shifting the conformational equilibrium around the C-S bond toward the s-trans rotamer. The major adduct exo(t)-202 (R = Me) was transformed into the enantiomerically pure piperidine alkaloid (-l-)-sedridine. 

Much more successful in a pyrrolidine synthesis was the use of a stereochemically defined organolithium 362 formed by tin-lithium exchange from an almost enantiomerically pure stannane 361, itself a product of Beak s sparteine lithiation chemistry. Despite the high temperature (20 °C) required for tin-lithium exchange in hexane-ether, it is nonetheless possible to carry out a stereospecific cyclisation via an organolithium which is configurationally stable, even at 20 °C, on the timescale of the cyclisation.169 The cyclisation proceeds with retention and gives the alkaloid pseudoheliotridane 363 in 87% yield and with no loss of enantiomeric excess. 

Alder reaction [524, 525]. Danishefsky et al. have used nitroso dienophiles for the synthesis of mitomycin K and antibiotics of the FR 900482 family, the latter ones are structurally unique aziridino-l,2-oxazine derivatives [526-529]. An approach directed to the cephalotaxus alkaloids has been worked out by Fuchs et al. [530], and several indolizidine alkaloids have been prepared by Keck s [531] and Kibayashi s groups [532,533]. Kibayashi et al. also synthesised Nuphar piperidine alkaloids in enantiomerically pure form by means of an asymmetric nitroso Diels-Alder reaction [534]. 

---