New applications of organometallic reagents in the synthesis of natural products

Maruoka, Keiji
Journal Title
Journal ISSN
Volume Title
Starting Page
Ending Page
Alternative Title
Five new synthetic reactions are described. These methods are characterized by exquisite selectivity and stereochemical control, using organometallic reagents to realize the key step in the total synthesis of various natural products. The organometallics used in this study include zinc, aluminum, iron, copper, lithium, magnesium, and boron compounds. A new approach has been demonstrated for the regio-specific aldol synthesis by simultaneous addition of a-halo carbonyl derivatives and aldehydes or ketones to a suspension of diethylaluminum chloride and zinc in tetra-hydrofuran at low temperature. This technique is also employable under mild conditions for the Reformatsky reaction to give β-hydroxy esters in excellent yield. One of the unique synthetic applications of this process is illustrated by the intramolecular cyclization of α-bromo esters of ω-hydroxyaldehyde, which produces macrolides, an important class of compounds in the antibiotic field. A biogenetically patterned synthesis of camphor-type terpenoid compounds is described. 1,3-Dibromo-3,7-dimethyl--9-octen-2-one can be obtained from geraniol through five steps in 68% overall yield. Reaction of the dibromoketone and Fe2(CO)9 in benzene at 100-110°C leads directly to (±)-camphor in 38% yield. In addition, several six-membered monocyclic terpenoids, (±)-dihydrocarvone and (±)-carvenone have also been isolated. In a similar manner, reaction of 1,3-dibromo-3,7,11-trimethyl-6,10-dodecadien-2-one and Fe(CO)5 produces a 2:1 mixture of (±)-campherenone and (±)-epicampherenone in 58% yield. A new, selective, and mild approach to N-alkylation of polyamines has been demonstrated, which involves the novel reductive cleavage of the carbon-nitrogen bond in cyclic amidines by diisobutylaluminum hydride. This method provides a new entry to a wide variety of N-alkylated polyamines and many interesting macrocyclic polyamines hitherto accessible only by length or complicated synthesis. Moreover, the synthesis of the plant alkaloid, spermine, was successfully accomplished by the reductive cleavage of carbon-nitrogen bonds in 1,2-bis(2'-tetrahydropyrimidyl)-ethane, which was readily available from succinonitrile and 1,3-diaminopropane mono-p-toluenesulfonate. An efficient method for the N-alkylation of amines is described based on the oxidative coupling of lithium alkyl-copper amide, which is derived from lithium dialkylcuprates and primary or secondary amines. The high chemospecificity of the method was demonstrated by the selective tert-butylation of m-aminoacetophenone without any protection of the carbonyl group. The present N-alkylation process should be extremely useful for complex or polyfunctional molecules, the reaction conditions being so mild as to minimize the possibility of involvement of most functional or protecting groups. A total synthesis of spermidine alkaloids, celacinnine, celabenzine, and celafurine, is described in which a key step is the boron-templated cyclization of ethyl 3-phenyl-4,9,13-triazatridecanoate to 12-phenyl-2,6,11-triazacyclo-tridecanone. Further transformation of the amide involving selective acylation with the corresponding acid chlorides led to the natural products, celacinnine, celabenzine, and celafurine. A noteworthy feature of the present cyclization apart from its simplicity and high overall yield is that carbon-nitrogen bond formation takes place only intramolecularly. Thus, high dilution or slow addition techniques are no longer necessary for the new process.
Photocopy of typescript.
Thesis (Ph. D.)--University of Hawaii at Manoa, 1980.
Bibliography: leaves 125-126.
x, 126 leaves, bound 28 cm
Organic compounds -- Synthesis, Chemical tests and reagents
Geographic Location
Time Period
Related To
Theses for the degree of Doctor of Philosophy (University of Hawaii at Manoa). Chemistry; no. 1370
Table of Contents
All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Rights Holder
Local Contexts
Email if you need this content in ADA-compliant format.