Abstract:An inexpensive proline derivative and chiral control feature in the total synthesis of securinega alkaloids (-)-norsecurinine (1) and phyllanthine (2). Key steps in the synthesis of 1 include an intramolecular ketonitrile coupling and application of a radical-based generation of N-acylimines. The total synthesis of 2 utilizes a stereoselective imino Diels - Alder construction of the methoxypiperidine ring.
“…74 Allylation of cyclic iminium ions generated from fiveor sixmembered hemiaminal precursors and allyltrimethylsilane or allylmagnesium bromide, usually in the presence of boron trifluoride etherate and mostly in the early stage of the synthetic sequence, was also adopted in the total syntheses of quinolizidine alkaloid (+)-epiquinamide, 75 marine alkaloids (±)-halichlorine, (±)-pinnaic acid, and (±)-tauropinnaic acid (from Halichondria okadai), 76 simple piperidine alkaloid (+)-deoxyprosopinine, 77 indolizine alkaloid (−)-2-epi-lentiginosine, 78 and securinega plant alkaloid (−)-norsecurinine. 79 An intramolecular variant using propargylic silane was used in the synthesis of (−)-stemoamide. 80 An interesting variant of the N-acyliminium allylation reaction was investigated during the synthesis of (+)-negamycin, a microbial antibiotic from Streptomyces purpeofuscus (Scheme 8d).…”
The main objective of this review is to provide a comprehensive survey of methods used for stereoselective construction of carbon-nitrogen bonds during the total synthesis of nitrogen-containing natural products that have appeared in the literature since 2000. The material is organized by specific reaction in order of decreasing number of applications in natural product synthesis. About 800 total syntheses of natural products with stereogenic carbon-nitrogen bonds described since 2000 have been reviewed.
“…74 Allylation of cyclic iminium ions generated from fiveor sixmembered hemiaminal precursors and allyltrimethylsilane or allylmagnesium bromide, usually in the presence of boron trifluoride etherate and mostly in the early stage of the synthetic sequence, was also adopted in the total syntheses of quinolizidine alkaloid (+)-epiquinamide, 75 marine alkaloids (±)-halichlorine, (±)-pinnaic acid, and (±)-tauropinnaic acid (from Halichondria okadai), 76 simple piperidine alkaloid (+)-deoxyprosopinine, 77 indolizine alkaloid (−)-2-epi-lentiginosine, 78 and securinega plant alkaloid (−)-norsecurinine. 79 An intramolecular variant using propargylic silane was used in the synthesis of (−)-stemoamide. 80 An interesting variant of the N-acyliminium allylation reaction was investigated during the synthesis of (+)-negamycin, a microbial antibiotic from Streptomyces purpeofuscus (Scheme 8d).…”
The main objective of this review is to provide a comprehensive survey of methods used for stereoselective construction of carbon-nitrogen bonds during the total synthesis of nitrogen-containing natural products that have appeared in the literature since 2000. The material is organized by specific reaction in order of decreasing number of applications in natural product synthesis. About 800 total syntheses of natural products with stereogenic carbon-nitrogen bonds described since 2000 have been reviewed.
“…We next aimed for a unified synthesis of C4-oxidized securinine-type alkaloids . Even though groups I and II (C4-oxygenated members) constitute 44% of all known high-oxidation-state Securinega alkaloids, phyllanthine ( 42 ) had remained the only member to succumb to synthesis among the C4-oxidized Securinega alkaloids. , We identified three key challenges en route to a unified synthetic solution to these type of natural products. Firstly, the stereoselective introduction of oxygens at C2, C3, and C4 positions should be accomplished (Scheme A, Challenge 1).…”
Section: Synthesis
Of High-oxidation State Securinega Alkaloidsmentioning
confidence: 99%
“…Stereochemical variations at C2 and C4 sites of this subgroup’s members are notable. For example, securitinine ( 41 ), phyllanthine ( 42 ), − and 4- epi -phyllanthine ( 43 ) are diastereomers stemming from different configurations at the C2 and C4 positions.…”
Section: Introductionmentioning
confidence: 99%
“…Even though groups I and II (C4-oxygenated members) constitute 44% of all known highoxidation-state Securinega alkaloids, phyllanthine(42) had remained the only member to succumb to synthesis among the C4-oxidized Securinega alkaloids 18,19. We identified three key challenges en route to a unified synthetic solution to these type of natural products.…”
Conspectus
Securinega alkaloids,
composed of more than 100
members characterized by the compact tetracyclic scaffold, have fascinated
the synthetic community with their structural diversity and notable
bioactivities. On the basis of the structural phenotype, oligomerizations
and oxidations are major biosynthetic diversification modes of the
basic Securinega framework. Despite the rich history
of synthesis of basic monomeric Securinega alkaloids,
the synthesis of oligomeric Securinega alkaloids,
as well as oxidized derivatives, has remained relatively unexplored
because of their extra structural complexity. In the first half of
this Account, our synthetic studies toward high-order Securinega alkaloids are described. We aimed to establish a reliable synthetic
method to form C14–C15′ and C12–C15′ bonds,
which are prevalent connection modes between monomers. During our
total synthesis of flueggenine C (9), we have invented
an accelerated Rauhut–Currier reaction capable of forming the
C14–C15′ bond stereoselectively. Installation of the
nucleophilic functionality to the Michael acceptor, which ushers the
C–C bond forming conjugate addition to follow the intramolecular
pathway, was the key to success. The C12–C15′ linkage,
which was inaccessible via an accelerated Rauhut–Currier reaction,
was established by devising a complementary cross-coupling/conjugate
reduction-based dimerization strategy that enabled the total synthesis
of flueggenines D (11) and I (14). In this
approach, the C12–C15′ linkage was established via a
Stille cross-coupling, and the stereochemistry of the C15′
position was controlled during the following conjugate reduction step.
In the later half of this Account, our achievements in the field of
high-oxidation state Securinega alkaloids synthesis
are depicted. We have developed oxidative transformations at the N1
and C2–C4 positions, where the biosynthetic oxidation event
occurs most frequently. The discovery of a VO(acac)2-mediated
regioselective Polonovski reaction allowed us to access the key 2,3-dehydroallosecurinine
(112). Divergent synthesis of secu′amamine A (62) and fluvirosaones A (60) and B (61) was accomplished by exploiting the versatile reactivities of the
C2/C3 enamine moiety in 112. We have also employed a
fragment-coupling strategy between menisdaurilide and piperidine units,
which allowed the installation of various oxygen-containing functionality
on the piperidine ring. Combined with the late-stage, light-mediated
epimerization and well-orchestrated oxidative modifications, collective
total synthesis of seven C4-oxygenated securinine-type natural products
was achieved. Lastly, the synthesis of flueggeacosine B (70) via two synthetic routes from allosecurinine (103)
was illustrated. The first-generation synthesis (seven overall steps)
employing Pd-catalyzed cross-coupling between stannane and thioester
to form the key C3–C15′ bond enabled the structural
revision of the natural product. In the second-generation synthesis,
we have invented visible-light-mediated, Cu-catalyzed cross-d...
“…Importantly, the tetrahydro-1,2-oxazine core could also be established by the Kerr group via a Lewis acid-catalyzed three-component homo [3 + 2] dipolar cycloaddition 24 and by the Wood group via an acyloxy nitroso ring expansion strategy 25 en route to their total synthesis of phyllantidine ( 14 ), respectively. With respect to the C4-oxygenated high-oxidation state securinega alkaloid, the Weinreb group’s total synthesis of phyllanthine ( 5 ) via SmI 2 -mediated intramolecular ketonitrile coupling and stereoselective imino Diels–Alder reaction has remained as the only synthesis of securinega alkaloid with a C4-oxygenation 26 , 27 . Fig.…”
Securinega alkaloids have fascinated the synthetic chemical community for over six decades. Historically, major research foci in securinega alkaloid synthesis have been on the efficient construction of the fused tetracyclic framework that bears a butenolide moiety and tertiary amine-based heterocycles. These “basic” securinega alkaloids have evolved to undergo biosynthetic oxidative diversifications, especially on the piperidine core. However, a general synthetic solution to access these high-oxidation state securinega alkaloids is lacking. In this study, we have completed the total synthesis of various C4-oxygenated securinine-type alkaloids including securingines A, C, D, securitinine, secu’amamine D, phyllanthine, and 4-epi-phyllanthine. Our synthetic strategy features stereocontrolled oxidation, rearrangement, and epimerization at N1 and C2–C4 positions of the piperidine core within (neo)securinane scaffolds. Our discoveries provide a fundamental synthetic solution to all known securinine-type natural products with various oxidative and stereochemical variations around the central piperidine ring.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
