Studies were carried out to determine the absolute stereochemistry of
botryococcene (1). The natural product was degraded to two sets of 'y- and 8-
valerolactones. All enantiomeric variations of these lactones were synthesized in
optically pure form starting from (S)- and (R)-methyloxiranes. 1H NMR correlation of
natural and synthetic materials...
A synthetic approach toward the two major fragments of cathedulin K-19,
euonyminol (4) and dimethyl cathate (69), was investigated. Synthesis of
dimethyl cathate was accomplished in 3 steps starting from 73. Efforts directed
towards the synthesis of euonyminol, a highly oxygenated dihydroagarofuran
sesquiterpene, was advanced to a stage in which...
Several approaches to the synthesis of methymycin were
investigated. Segment A (39), containing functionality corresponding
to C-9, 10, and 11 of methynolide was made in
six steps from propionaldehyde in an overall yield of 37%.
Oxidation of 34 with silver nitrate gave 35 which, upon hydroxylation
with hydrogen peroxide, gave...
Several approaches to the synthesis of penicillin from 2-iminothioazolidine
50, from 2-thiothiazolidine 66 and by photocyclization of
77 and 78 were investigated. 2-Iminothiazolidine 50 was prepared
from dibromoester 45 by the action of benzylamine followed by treatment
of aziridine 46 with potassium or ammonium thiocyanate. Attempted
introduction of a two-carbon...
An approach to the generation of polyketides was investigated,
which involved ozonolysis of 6, 7 cyclopenteno -1> 4, 5, 8 -tetrahydromethoxy-
3-methylnaphthalene (26), to produce what is believed to be
polyketide 27. Compound 26 was formed by the following sequence:
Die ls -Alder addition of 1, 2 -dim.ethylenecyclopentane and 2...
A formal total synthesis of the macrolactone pyrolizidine alkaloid (-)-integerrimine (2), from R-(+)-citronellal (93) is described. Aldehyde 93 was converted to exo methylene derivative 94 which was reduced to allylic alcohol 95. The epoxides 96 and 98, obtained in a ratio of 3:1 respectively by Sharp less epoxidation of 95...
Verrucarol is the sesquiterpene portion of a number of macrocyclic di- and triesters of potential medicinal importance. In this study, a novel approach to the synthesis of this fungal metabolite is presented. An A-B-C route was investigated in which C-3 and C-4 of the C-ring were emplaced using a [2+2]...
The mycosporins, formerly called P310's are secondary metabolites
of fungi closely associated with fungal reproductive processes that
require light. The structurally related iminomycosporins are found in
marine plants and animals and may also have functions related to
light. In this study, approaches toward the asymmetric synthesis of
the mycosporins are...
The rearrangement of a homoallyl cation to a cyclopropylcarbinyl cation is thought to play a role in the biogenesis of a variety of cyclopropane-containing natural products,¹ a hypothesis which has previously led to the design of successful biomimetic syntheses of several natural products.² The strategy underlying this approach to cyclopropane...
Bromoalkoxylation of dihydropyran with bromine and 1-borneol, followed by dehydrobromination and epoxidation, afforded trans-2-1- bornyloxy-3,4-epoxytetrahydropyran as a major product. This was treated with sodium phenylselenide to give a 1:1 mixture of (2R,3R,4R)- 2-1-bornyloxy-3-hydroxy-4-phenylselenotetrahydropyran and its (2S,3S, 4S) diastereomer. Elimination of the selenoxide, derived from oxidation of the former with hydrogen...
This thesis describes the development of a new enantioselective synthetic method employing chiral cis-2,5-diaminobicyclo[2.2.2]octane-based organometallic catalysts. The significance of this new method to organic synthesis is illustrated with preparation of enantioenriched products that are transformed to important pharmaceutical agents. Chapter 1 provides a brief historical overview of asymmetric catalysis, especially...
PART I. Asymmetric syntheses of both natural (+)- and nonnatural (-)-byssochlamic acid via a [2+2] photoaddition-cycloreversion strategy are described. X-ray crystallographic analysis of the cyclohexylamine salt 99 showed that the structure of the monomethyl ester 100 from esterase hydrolysis of 44 was originally misassigned as 56. The enantiomeric relationship of...
Various hypervalent iodine compounds were evaluated as reagents
for intramolecular phenolic oxidative coupling. It was found that
phenyliodine(III) bis(trifluoroacetate) was effective for the coupling
of the monophenolic substrate 13a to 14a under neutral conditions.
Vanadium oxytrifluoride and hypervalent iodine compounds were compared
as oxidants for the conversion of 32 to...
The stereocontrolled synthesis of the southern lactone 17 of
boromycin and of the northern segments of both boromycin and aplasmomycin
are described. The syntheses begin with enantioselective
epoxidation of 3-buten-2-ol (42) to provide the optically active
2(S),3(R) epoxy alcohol 43. The absolute configuration was confirmed
by preparing 43 from (-)-2,3-dihydroxybutyric...
Studies toward the total synthesis of (+)-providencin (1), a highly oxygenated cembranoid dipterpene with a unique bicyclo[12.2.0]hexadecane skeleton and pronounced biological activity, are described. These studies resulted in the synthesis of advanced intermediates 320 and 332 which contain all of the carbon atoms of 1. In a first generation approach...
Studies toward the total synthesis of a highly potent cytotoxic marine natural product, phorboxazole A, were conducted and resulted in a route to an advanced intermediate, C4-C32, for this purpose. A key feature of our approach is the stereoselective synthesis of two cis-2,6-disubstituted tetrahydropyrans present in the macrolide portion of...
Studies toward synthesis of subunits of sanglifehrin A, an immunosuppressant featuring a highly substituted [5,5]-spirolactam moiety as well as a 22-membered macrocycle are described. The macrolactone contains a peptidic backbone characterized by an unusual [beta]-substituted (S)-piperazic acid and (S)-m-hydroxyphenylalanine units. These studies resulted in the synthesis of advanced intermediate 358...
Studies towards the total synthesis of (-)-gymnodimine (1), a marine neurotoxin with a unique molecular architecture and pronounced biological activity, are described. These studies resulted in a convergent approach to the advanced intermediate 315, containing the C3-C32 section of 1. Two synthetic routes were developed to construct the tetrahydrofuran subunit...
Studies towards the total synthesis of (−)-kendomycin (1), a bacterial metabolite with
a unique molecular architecture and pronounced biological activity, are described. These
studies resulted in the synthesis of advanced intermediate 208, containing all of the
carbon atoms of 1.
A Dötz annulation between alkyne 122 and novel chromium carbenoid...
A convergent synthesis of epothilone B that generates all seven of its
asymmetric centers in a completely stereoselective fashion has been
completed. Key reactions include an anti-Felkin aldol condensation to
set the C6 and C7 stereochemistry, a directed α-hydroxylation to install
the C15 (S)-hydroxyl substituent, and a Wittig condensation to...
Two approaches to the tricyclic core of the furanoeremophilane sesquiterpenoids are described. The first approach entails a projected Diels-Alder/retro Diels-Alder reaction of an acetylenic oxazole 64. Construction of the pivotal aldehyde 67 commenced from ketone 68. The acetyenic moiety was then introduced via a Felkin-Ahn addition of lithiopropyne to aldehyde...
Part I. The total synthesis of (+)-leptosphaerin (2), a metabolite of the marine
Ascomycete Leptosphaeria Oraemaris (Linder) was achieved, unambiguously
establishing both the relative and absolute stereochemistry of this natural product. This
synthesis also resolved the long-standing question of which of the isomeric structures 1
or 2 correctly represents the...
Avermectins are a group of potent anthelmintic agents produced by Streptomyces avermitilis. They are active at extremely low dosages and are now in commercial use. In this study, the synthesis of two segments of avermectin B[subscript 1a] are described. The synthesis of the hexahydrobenzofuran subunit (segment A) began with the...
An asymmetric approach to the synthesis of byssochlamic acid (1) is
described. Regioisomeric enzymatic differentiation is described in the selective
hydrolysis of dimethyl ester 30 by porcine liver esterase. Chiral dimethyl ester 42
was prepared by desymmetrization of cyclopentene 34 using porcine liver
esterase. A key intramolecular [2+2]cycloaddition-cycloreversion
photometathesis of...
Irradiation of a tryptamine linked through its side-chain nitrogen to an alkylidene malonate residue results in an intramolecular [2 + 2] cycloaddition to the indole 2,3-double bond. The resultant cyclobutane undergoes spontaneous retro-Mannich fission to produce a spiro[indoline-3,3-pyrrolenine] with relative configuration defined by the orientation of substituents in the transient...
The ethyl acetate extract of the culture filtrate of the marine Ascomycete,
Leptosphaeria oraemaris (Linder) yielded a novel metabolite
designated by the common name leptosphaerin. An x-ray crystallographic
structure analysis was disproved by the synthesis of 3-acetoxy-S-(1,2-dihydroxyethyl)-
3-pyrrolin-2-one 1, starting with N,N-dibenzylhydroxylamine
47 and D-mannitol 44. Oxidation of 47 followed...
Alkylation of propylene oxide with 2-lithiofuran gave alcohol I,
which was smoothly converted to acetylfuran II. hydrogenation of II
over rhodium on charcoal followed by Jones' oxidation afforded ketone
III. Further transformation into IV was accomplished via a Wittig
reaction followed by saponification with methanolic sodium hydroxide.
Hydroboration of the...
A total synthesis of the fungal hormones, trisporic acids A and B, is described, starting from a -methyltetronic acid 34. A Robinson annelation of 34 with ethyl vinyl ketone affords the lactone 33. Treatment of 33 with N-bromosuccinimide gave 97, which was hydrolyzed to the lactol 103. The reaction of...
The first asymmetric synthesis of (-)-7-epicylindrospermopsin via intramolecular nitrone cycloaddition is described. The synthesis utilized a convergent approach to prepare the cycloaddition precursor 176, which was assembled by condensation of hydroxylamine 175 with aldehyde 145. Hydroxylamine 175 was synthesized from ethylene glycol (166) in seven steps. Aldehyde 145 was completed...
PART I. The preparation of (-)-ibogamine (1) in fourteen steps from benzoquinone and in 10% overall yield is a powerful illustration of the value of the asymmetric Diels-Alder reaction as a starting point in a multistep synthesis. All four cycloadducts, 70, 77, 84 and 96, obtained with the (S)-BINOL-TiCl₂ complex...
The total synthesis of a highly potent cytotoxic marine natural product, phorboxazole A, is described. Both a palladium(II)-mediated and a palladium(II)-catalyzed intramolecular alkoxycarbonylation were used as key steps for the preparation of the two cis-2,6-disubstituted tetrahydropyran rings (C22-C26 and C11-C15) of phorboxazole A.
The synthesis used a convergent approach involving...