Convergent Asymmetric Synthesis Research Articles

Chiral Pool Meets Chiral Catalysis: Eight-Step Convergent Total Synthesis of Anticancer Natural Lipid Mycalol.

An exemplary blend of chiral pool with chiral catalysis is exhibited in an eight-step (longest) convergent asymmetric total synthesis of mycalol, which is a promising anticancer natural lipid from a marine source. The polyhydroxy lipid is constructed by using four blocks, and two of which are derived from the chiral pool (d-mannitol and d-gluconolactone) and the other two by chiral catalysis (Sharpless epoxidation and Keck allylation). Alkylation and metathesis were used to knit the blocks in an excellent display of a modular convergent eight-step synthesis. The modular excess will enable rapid analogue generation as revealed by the convenient synthesis of 4-epi-mycalol similarly in an eight-step sequence.

Synthetic Efforts and Ultimate Limitation to an Asymmetric Achmatowicz Approach Toward EBC-23.

An effort toward the total synthesis of the polyketide natural product EBC-23 is reported. The asymmetric approach is convergent and uses a late-stage Claisen-like enolate/acid chloride coupling to establish a key 1,3-diketone intermediate. The 1,3-diketone target is an oxidized form of the hydrated natural product, which fails to spiroketalize. The convergent asymmetric synthesis uses an asymmetric Noyori transfer hydrogenation of a β-furyl ketoester to enantioselectively form a chiral furyl alcohol. An Achmatowicz/Jones/Luche three-step reaction sequence was used to stereoselectively convert the furyl alcohol into the 5-hydroxy-pyran-2-one. The absolute stereochemistry of the 1,3-polyol fragment was established by a Leighton allylation. A subsequent Grubbs cross-metathesis, and Evans acetalation were used to install the 1,3-syn-diol stereochemistry.

De Novo Asymmetric Approach to Aspergillide‐C: Synthesis of 4‐epi‐seco‐Aspergillide‐C

AbstractAn asymmetric approach toward the synthesis of the marine natural product aspergillide‐C has been developed. The convergent asymmetric synthesis uses two asymmetric Noyori transfer hydrogenations to enantioselectively prepare the two key fragments, aC‐1 toC‐7 pyranone fragment and aC‐8 toC‐14β‐keto‐sulfone fragment. The absolute stereochemistry of the pyranone fragment was established by a Noyori reduction ofβ‐furylketoester to form a furyl alcohol. An Achmatowicz rearrangement was used to stereoselectively convert the furyl alcohol in to the key pyranone fragment. The absolute stereochemistry of theβ‐keto‐sulfone fragment was established by a Noyori reduction of an ynone to form a propargyl alcohol. An alkyne zipper isomerization was used to stereospecifically convert the propargyl alcohol in to theβ‐keto‐sulfone fragment. Finally, a Pd‐catalyzedC‐glycosylation was used to diastereoselectively couple the two fragments, which when combined with a reduction and Julia‐Kocienski type elimination formed a protected variant of the 4‐epi‐seco‐acid of aspergillide‐C.

General Asymmetric Synthetic Strategy for the α‐Alkylated 2,5,6‐Trisubstituted Pyran of Indanomycin and Related Natural Products

A general synthetic strategy for convergent asymmetric synthesis of C1–C10 fragment of tetraene‐containing natural product indanomycin was achieved starting from 2‐(benzyloxy)acetaldehyde which in turn was obtained from very inexpensive material cis‐1,4‐butene‐diol. Key steps include Evans' aldol reaction, HWE olefination, iodine‐catalyzed tandem isomerization followed by C–O and C–C bond formation similar to our earlier report in constructing the trans‐2,6‐disubstituted dihydropyran ring and Evans' asymmetric alkylation.

Total Synthesis of (-)-Phorbaketal A.

A convergent asymmetric total synthesis of phorbaketal A was achieved in 10 steps through a Au(I)-catalyzed intramolecular spiroketalization reaction of an alkyne diol intermediate prepared from (R)-carvone and geranial. The spiroketalization reaction was regio- and stereoselective and was accompanied by isomerization of an exo-olefin into the trisubstituted olefin to form a unique spiroketal structure of phorbaketals.

From meiogynin A to the synthesis of dual inhibitors of Bcl-xL and Mcl-1 anti-apoptotic proteins.

The synthesis of one of the most potent dual inhibitors of the anti-apoptotic proteins Bcl-xL and Mcl-1 is reported. This analogue of a natural sesquiterpenoid dimer meiogynin A was elaborated by a convergent asymmetric synthesis with 36% yield in ten steps.

Convergent Asymmetric Synthesis of a Renin Inhibitor: A Highly Efficient Construction Method of Three Stereogenic Centers

An improved asymmetric synthesis of renin inhibitor DS-8108b (1) is described. This compound consists of three intermediates: 4-aminoadamantan-1-ol, ketopiperazine, and chiral lactone which contain...

Convergent Asymmetric Synthesis of (+)-Aureothin Employing an Oxygenase-Mediated Resolution Step

Convergent Asymmetric Synthesis of (+)-Aureothin Employing an Oxygenase-Mediated Resolution Step

Convergent Asymmetric Synthesis of (+)-Aureothin Employing an Oxygenase-Mediated Resolution Step

Enzymatischer Stups: Die Desymmetrisierung von α,α′-Dimethoxy-γ-pyron ermöglicht den konvergenten und schnellen Aufbau des kompletten Kohlenstoffgerüsts von (+)-Aureothin (siehe Schema). Der letzte Schritt in der Synthese der Zielverbindung ist die regiodivergente parallele kinetische Racematspaltung mithilfe der Cytochrom-P450-Monooxygenase AurH, die den enantionmerenreinen Naturstoff liefert.

Convergent Asymmetric Synthesis of Two Complex TRPV1 Antagonists

The convergent scale-up synthesis of two complex TRPV1 antagonists to support exploratory toxicology studies is described. Both compounds contain three chiral centers introduced by asymmetric synthesis with chiral control being critical for the success of the project. Preparation of the key cyclopropyl intermediate utilised an asymmetric cyclopropanation using thermally unstable ethyl diazoacetate. Ellman’s auxiliary was used to synthesize the chiral α-methyl benzylamine fragments. This paper highlights some of the key synthetic challenges, processing issues, and safety aspects from the scale-up of this chemistry.

Asymmetric Total Synthesis of (+)-Danicalipin A

A convergent asymmetric total synthesis of (+)-danicalipin A is accomplished, in which two chlorinated fragments are stereoselectively joined by 1,3-dipolar coupling, leading to the confirmation of the absolute configuration of the natural product.

ChemInform Abstract: Synthetic Studies in the Lysocellin Family of Polyether Antibiotics. The Total Synthesis of Ferensimycin B.

A convergent asymmetric synthesis of the polyether antibiotic ferensimycin B has been completed. Chiral enolate bond constructions were employed to establish seven of the 16 stereocenters of the subunits 35 and 52, which comprise the C& and CI&3 portions of ferensimycin B. The stereogenic centers at C3, C4, Cg, Clo, CI6, C,,, and CIS were incorporated through internal asymmetric induction, while those at Cm and C1l were established by using asymmetric epoxidation methodology. In this transformation, a vanadium-catalyzed internal epoxidation of a bis-homoallylic alcohol was employed to relay chirality from the C13 to the CI6 oxygen-bearing stereocenter. A final aldol addition reaction on intermediates devoid of protecting groups united the fragments 52 and 35 to provide synthetic ferensimycin B, whose absolute configuration was found to be

ChemInform Abstract: Synthesis and Enzymatic Cyclization of (3S)-14-Fluoro-2,3-oxidosqualene.

Abstract A convergent asymmetric synthesis led to ( 3S )-14-fluoro-2,3-oxidosqualene (14-FOS, 16 ), which was cyclized by bacterial squalene:hopane cyclase to a monocarbocyclic product with a bridged ether and a 2:3 mixture of bicyclic alcohols. 14-FOS was neither a substrate nor an inhibitor for vertebrate oxidosqualene:lanosterol cyclase.

Total synthesis, assignment of the relative and absolute stereochemistry, and structural reassignment of phostriecin (aka Sultriecin).

A total synthesis of phostriecin (2), previously known as sultriecin (1), its structural reassignment as a phosphate versus sulfate monoester, and the assignment of its relative and absolute stereochemistry are disclosed herein. Key elements of the work, which provided first the originally assigned sulfate monoester 1 and then the reassigned and renamed phosphate monoester 2, relied on diagnostic (1)H NMR spectroscopic properties of the natural product for the assignment of relative and absolute stereochemistry as well as the subsequent structural reassignment, and a convergent asymmetric total synthesis to provide the unequivocal authentic materials. Key steps of the synthetic approach include a Brown allylation for diastereoselective introduction of the C9 stereochemistry, an asymmetric CBS reduction to establish the lactone C5-stereochemistry, diastereoselective oxidative ring expansion of an alpha-hydroxyfuran to access the pyran lactone precursor, and single-step installation of the sensitive Z,Z,E-triene unit through a chelation-controlled cuprate addition with installation of the C11 stereochemistry. The approach allows ready access to analogues that can now be used to probe important structural features required for protein phosphatase 2A inhibition, the mechanism of action defined herein.

Total Synthesis of Pteridic Acids A and B

The total synthesis of pteridic acids A and B is reported. The convergent asymmetric synthesis involved the use of a diastereoselective ethyl ketone aldol reaction followed by an efficient spiroketalization and provided pteridic acids A and B in 2.9% and 2.8% overall yield, respectively.

Stereoselective total synthesis of polyketide lactone, (3 R,4 S,5 S,9 S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone

The total synthesis of lactone 1 has been described. The convergent asymmetric synthesis relies on the use of an Evans’ syn-aldol, chain extension with lithio tert-butyl acetate, and the stereoselective reduction of a ketone as the key reactions.

Total Synthesis of (−)‐Basiliskamide B

AbstractThe total synthesis of the polyketide antibiotic (−)‐basiliskamide B is described. The convergent asymmetric synthesis relies on the use of a diastereoselective ethyl ketone aldol reaction followed by asynselective reduction of a β‐hydroxy ketone and a Stille cross‐coupling between aZ‐vinylstannane and anE‐vinyl iodide to establish the(Z,E)‐dienamide moiety.

The first total synthesis of emericellamide A

A highly convergent asymmetric total synthesis of emericellamide A, a 19-membered antibacterial depsipeptide isolated from the co-culture of an Emericella sp. (strain CNL-878) and a Salinispora arenicola (strain CNH-665) is described.

Asymmetric Total Synthesis of (−)‐Pironetin Employing the SAMP/RAMP Hydrazone Methodology

A convergent asymmetric total synthesis of pironetin (1), a polyketide with immunosuppressive, antitumor, and plant-growth regulating activities is described. The synthesis was realized by coupling between the C(8)-C(14) 2 and C(7)-C(2) 15 fragments, respectively, by using a Mukaiyama-aldol reaction. The stereogenic centers of each fragment were generated by employing the SAMP/RAMP hydrazone (SAMP=(S)-1-amino-2-methoxymethylpyrrolidine, RAMP=(R)-1-amino-2-methoxymethylpyrrolidine) methodology as a key step. An asymmetric alpha-alkylation of diethyl ketone permitted the introduction of the C(10) stereogenic center of 2, whereas the stereocenters C(4) and C(5) of 15 were installed by an asymmetric aldol reaction. Finally, the formation of the alpha,beta-unsaturated delta-lactone was achieved by ring-closing metathesis in the presence of catalytic amounts of titanium tetraisopropoxide.

Asymmetric Total Synthesis of (−)‐Cribrostatin 4 (Renieramycin H)

Out of the blue: The convergent asymmetric total synthesis of the antitumor antibiotic (−)-cribrostatin 4 from the blue sponge Cribrochalina features asymmetric Staudinger and Pictet–Spengler reactions to form the tetrahydroisoquinoline moiety. These reactions were followed by a reductive opening/elimination of a tricyclic β-lactam and a Pictet–Spengler cyclization to access the unsaturated pentacyclic core.