Alkaloid synthons, synthesis

Alkaloid synthons, synthesis, 191 Alkylation, zeolitic solid acid catalyzed, kinetics, 105-114 Alternative feedstocks and starting materials... 

A photochemical preparation of a Cephalotaxus alkaloid synthon (20) has been reported (Scheme 2).10 The readily accessible maleimide (17) was iodinated with iodine and silver trifluoroacetate, in 71% yield, and the resulting compound was transformed in two steps (70% overall yield) into the methylene-pyrrolone (18) by the action of methylmagnesium iodide followed by dehydration. Irradiation of (18) afforded (19) (46% yield), which, by successive hydrogenation and reduction with lithium aluminium hydride, gave the dihydro-pyrrolo[2,l-b][3]benzazepine (20). This derivative has served as a key intermediate in the total synthesis of cephalo-taxine described previously (see Vol. 7 of these Reports). 

The first asymmetric synthesis of (-)-monomorine I, an enantiomer of the natural alkaloid, by Husson and co-workers starts with the chiral 2-cyano-6-oxazolopiperidine synthon (385) prepared from (-)-phenylglycinol (384), glu-taraldehyde (383), and KCN (443). Alkylation of 385 with an iodo ketal led to the formation of a single product (386). The cyano acetal (386) was treated with silver tetrafluoroborate and then zinc borohydride to afford a 3 2 mixture of C-6 epimeric oxazolidine (387) having the (2S) configuration. Reaction of 387 with... 

The a-methoxylated derivatives are shown to be versatile synthons because of the reactivity of the methoxy group near the nitrogen atom, a-Methoxycarbamates, prepared by anodic oxidation, were used as key intermediates in the synthesis of a-amino acids,200 a new carbon-phosphorus bond-forming reaction,200 and in a new method of acylation of aliphatic amines at the -position.201 The application of this reaction to the synthesis of pyrrolidine, piperidine, and tropane alkaloids is also described.202... 

An impressive number of alkaloids has been generated from the synthon (202), which is accessible by an acid catalyzed rearrangement of the appropriately substituted cyclopropyl-imine. The endocyclic enamine (202) should react with electrophiles on the /8-carbon in a process which simultaneously renders the a-carbon electrophilic and therefore susceptible to capture by nucleophilic reagents. The application of this methodology to the synthesis of ipalbidine (191a) and septicine (204) is shown in Scheme 30. Here, the unusual 3-phenylthio-2-pyrroline intermediate (203) serves as a relatively stable equivalent synthon of the unsubstituted 2-pyrroline analogue which is notoriously unstable (77ACR193). 

Fig. 10 Enzyme-catalysed formation of chiral monoacetate synthons from meso-diacetate or meso-diol for chemo-enzymatic synthesis of monoterpenoid indole alkaloids...

The iminium salts of 2,3-dihydropyridines are far more stable than the free bases and have been used extensively in the synthesis of alkaloids. N-Benzyl iminium salt 26, formed from the Polonovski-Potier reaction of V-oxide 25, was transformed into enol ether 27, which is a synthon for the unstable AT-benzvl-l, 2-dihvdropyridine 28 (Scheme 5) <2004LOC168>. The same transformation on a similar iminium salt has been used in the formation of macrocyclic marine alkaloids <1995TL2059>. Carbon nucleophiles, such as the silylenol ethers of esters, have been shown to undergo 1,2-addition rather than 1,4-addition to 2,3-dihydropyridinium salts <1999T14995>. 

Two new approaches to the synthesis of deoxynupharidine (14) and its C-l and C-7 epimers were reported. Arata et al. (67) made use of the Mannich reaction of a suitable derivative of isopelletierine and 3-furylaldehyde ( )-7-epideoxy-nupharidine (15) and ( )-l-epideoxynupharidine (8) were proved to be the main products of the reaction. The synthetic route is shown in Scheme 11. Intramolecular Diels-Alder condensation of 1-Azadienes was shown (68) to be a stereoselective route to the total synthesis of (-)-deoxynupharidine (14). The key steps are shown in Scheme 12 from synthon A in four steps alkaloid 14 was obtained. 

Some selected alkaloids are readily accessible via the corresponding chromium carbenes. A versatile synthesis of indolocarbazoles 133 and 134, bioactive natural products with interesting protein kinase C inhibiting properties, is based on photobenzannulation. Depending on the nature of the Cj-synthon, dioxy and oxyamino derivatives have been synthesized in good to very good yields (Scheme 46) [96]. 

Sceletium Alkaloids.—A new synthesis of (+)-mesembrine has been reported it uses a chiral y-lactone as a synthon." An alternative synthesis of ( )-sceletium alkaloid A4 has also been described.12... 

One of the first apphcations of this reaction in the stereoselective synthesis of natural products exploiting the mechanism-controlled 1,3-chirality transfer appeared in 1991 by Dolle et al. (Scheme 72) [160]. Their retrosyn-thetic analysis of alkaloid 292 ((+)-pinidine) led to a a -synthon 293 which... 

The cyclopropylimine ynoline rearrangement (equation 68) has been exploited by Stevens in alkaloid syntheses. - Wenkert s cyclopropylcarbinyl rearrangement (equation 69) served extremely well in the design of 1,4-dicarbonyl synthons or 3,-y-unsaturated carbonyl compounds which then were expressed in numerous syntheses of terpenoid and alkaloid natural products. Donor-acceptor concepts continue to be express in the applicability of these rearrangements to organic synthesis. 

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgP has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including A-phenylmaleimide (13) can be used for the cycloaddition. When iV-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgP in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [8]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgP, with methyl propiolate (18) provides 3-carbomethoxy-A-benzylpyrrole (19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 2] cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [10]. 

The pyrrolidine synthon (48) is useful for the chiral synthesis of pyrrolizidine, pyrrolidine, indolizidine and azabicyclic alkaloids (see Scheme 23). 

In a similar manner, the 2-cyano-6-oxazolopiperidine synthon is useful for the chiral synthesis of in-dolizidine (monomerine piperidine [(+)- and (-)-coniine and dihydropinidine] and quinolizidine alkaloids.2-Hydroxymethyl-1-amino-1-cyclopropanecarboxylic acid (-)-(2I )-hydroxy-(3S)-nonylamine and a-substituted phenylethylamines are obtained in optically active form from (-)-N-cyanomethyl-4-phenyloxazolidine. 

Tyrosine spirolactones are not only promising synthetic intermediates for bioactive natural products such as alkaloids and antibiotics but also synthons useful in peptide chemistry. For example, N-protected tyrosine derivatives 104 and 105, prepared from 2,6-di(ferf-butyl)-4-chloromethylphenol, were electrolyzed at a controlled potential (+1.3-1.4 V Vi. Ag/Ag+) in MeCN to give spirolactones 106 and 107 (64 and 85%, respectively). These spirolactones are used for peptide synthesis, as shown in Scheme 19. 

From the viewpoint of organic synthesis, nature provides us with a number of target molecules, which have novel structures and a variety of biological activities. As already shown in Section II.A, electrochemical oxidation of phenols has been applied successfully to natural products synthesis. Hypervalent (diacyloxyiodo)benzenes have also been proved to be effective for natural products synthesis. Generally, oxidation of o- and p-methoxyphenols in MeOH provides the corresponding o- and p-quinone monoketals, respectively. They are utilized as promising synthons for natural products and related bioactive compounds, as demonstrated by Swenton . Recently, these quinone monoketals have been utilized for syntheses of terpenoids, neolignans, anthraquinones, alkaloids and related compounds. 

Homophthalic anhydrides are valuable synthons for the synthesis of isocoumarins, isoquinolones and particularly for several berbine alkaloids. 

In 1988 and 1990, Fuchs reported a new approach to the synthesis of the Cephalotaxus alkaloids ( )-cephalotaxine (1) (30,31), ( )-ll-hydroxyceph-alotaxine (26) (31), and ( )-drupacine (28) (31), which was based on the exploitation of vinyl sulfones as convenient multifunctional synthons (Schemes 7 and 8). The synthesis of cephalotaxine (Scheme 7) began with the ortho ester 77, obtained from piperonyl alcohol in five steps, which was... 

Sulfoxide, sulfinate and sulfonate are used as activators of acetylenic or vinyl units. Several a, P unsaturated synthons, namely acetylenic sulfoxide (1), vinyl sulfoxide (2), acetylenic sulfinate (3), acetylenic sulfonate (4), and l-propene-l,3-sultone (5) are developed. Their applications in Diels-Alder reactions, heterocycle and alkaloid syntheses are also investigated. For the chiral acetylenic sulfoxide, the sulfoxide moiety not only enables chemical activation of the acetylene unit, it can also induce stereochemical control at the adjacent carbon centers to achieve enantioselective synthesis. 

We view acetylenic sulfoxide 1 as a two-carbon synthon in alkaloid synthesis. Our general approach, as depicted in Scheme 4, called for a Michael addition of Nu1 to the terminal acetylenic position followed by a cyclization by Nu2 (an intramolecular second Michael addition). This Michael addition cyclization step will build up the basic skeleton of the alkaloid system and at the same time control the absolute stereochemistry of the newly created chiral center through asymmetric induction of the chiral sulfoxide moiety. Finally, the sulfoxide can be transformed to another functional group (X) or used to promote the formation of another bond with Nu3 via trapping of the sulfenium ion intermediate under Pummerer rearrangement conditions (Scheme 4). 

Yohimbine alkaloids possess a characteristic pentacyclic indole skeleton. Representative members of the family include the rauwolfia (reserpine and deserpidine) and the yohimbines. A wide range of medicinal properties has been associated with these compounds and extensive studies have been carried out on the synthesis of the yohimbine alkaloids, including enantioselective syntheses [13,14]. In our approach, we view the acetylenic sulfoxide as a two-carbon synthon for the C3-C14 segment of the pentacyclic system (see 27). The chirali-... 

The diastereoselective hetero-Diels Alder reaction of imines leads to enantiomerically pure 2-substituted piperidines, important synthons for the synthesis of nitrogen-containing natural products. 2,3,4,6-Tetra-0-pivaloyl-/ -D-galactopyranosylimines 1, easily synthesized from the respective 1-galactosamine. react with isoprene (2a), 2,3-dimethyl-l,3-butadiene (2b) and ( )-l-methoxy-3-trimethylsiloxy-l,3-butadiene (4) under zinc chloride etherate catalysis71. Adducts 3 are obtained with moderate to good diastereoselectivities, while adduct 5 is produced with a diastereomeric ratio of greater than 95 5. Adduct 5 can then be converted into the alkaloid (S)-anabasin. 

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