Studies directed towards the synthesis of antascomicin A: stereoselective synthesis of the C1-C21 fragment of the molecule

A stereoselective synthesis of the C1-C21 fragment of the non-immunosuppressive immunophilin-binding natural product, antascomicin A was achieved using, as key steps, highly stereoselective Aldol reactions to build the C1-C17 fragment and a Nozaki-Hiyama-Kishi reaction to couple it with the remaining C18-C21 moiety.     

Synthesis of the C21-C34 fragment of antascomicin B

The C21-C34 fragment of the potent FKBP12-binding macrolide antascomicin B was prepared using Ireland-Claisen and allylic diazene rearrangements to establish the C26/C27 and the C23 stereocenters, respectively. Directed hydrogenation installed the C29 β-configuration. The fragment possesses 7 of the 11 fixed stereocenters contained in the natural product.     

Asymmetric Synthesis of Calyculin C. 1. Synthesis of the C(1)-C(25) Fragment

We report our synthesis of the C(1)-C(25) fragment of serine/threonine phosphatase PP1 and PP2A inhibitor, calyculin C. Synthetic efforts were directed initially toward the synthesis of a spiroketal core fragment (7), which culminated in completion of the bottom half of the natural product. The synthesis of fragment 7 and subsequent elaboration relied on an allylboration strategy for introduction of chirality. The C(1)-C(8) fragment representing the potentially unstable tetraene moiety was introduced as a separate entity.     

Stereoselective synthesis of the C1–C12 fragment of the thuggacins

A concise asymmetric synthesis of the C1–C12 fragment of the antibacterial natural product thuggacins has been achieved. The stereochemistry of this fragment was established efficiently via stereoselective reduction and Evans-aldol condensation. Hanztsch’s method and a Horner–Wadsworth–Emmnons reaction were employed for thiazole formation and the construction of the E-α,β-unsaturated double bond.     

Towards the synthesis of Palmerolide A: asymmetric synthesis of C1–C14 fragment

The synthesis of a C1–C14 fragment of a marine cytotoxic natural product Palmerolide A is described. The key steps involved in this synthesis are deoxygenative rearrangement of an alkynol followed by an asymmetric dihydroxylation of a diene ester and CBS-reduction.     

Stereoselective Synthesis of the Proposed C79–C104 Fragment of Symbiodinolide

Stereoselective and streamlined synthesis of the proposed C79–C104 fragment 2 of symbiodinolide ( 1 ), a polyol marine natural product with a molecular weight of 2860, was achieved. In the synthetic route, the proposed C79–C104 fragment 2 was synthesized by utilizing a Julia–Kocienski olefination and subsequent Sharpless asymmetric dihydroxylation as key transformations in a convergent manner. Detailed comparison of the ¹³C NMR chemical shifts between the natural product and the synthetic C79–C104 fragment 2 revealed that the stereostructure at the C91–C99 carbon chain moiety of symbiodinolide ( 1 ) should be reinvestigated.     

Stereoselective synthesis of the C21C27 fragment of the phorboxazoles

A stereoselective synthesis of the C21C27 fragment of phorboxazoles A and B was achieved in 12 linear steps via an intramolecular cyclization induced by mercury acetate, to afford a functionalized tetrahydropyran.     

Stereodivergent Synthesis and Stereochemical Reassignment of the C79–C104 Fragment of Symbiodinolide

We have synthesized eight possible diastereoisomers 3 a – h of the C79–C97 fragment of symbiodinolide ( 1 ) in a stereodivergent manner by utilizing a dithiane addition to the aldehyde as a key step. Comparison of the ¹³C NMR chemical shifts of the natural product 1 and the synthetic products 3 a – h indicated that the relative stereostructure of this fragment in symbiodinolide ( 1 ) is that represented in 3 a or f . We have stereodivergently synthesized eight possible diastereoisomers of the C94–C104 fragment 4 a – h , and we have compared their ¹³C NMR chemical shifts with those of the natural product, which established the relative stereochemistry of this fragment to be that described in diastereoisomers 4 a or e . By combining the stereostructural outcomes of the C79–C97 and C94–C104 fragments, we have proposed four candidate compounds of the C79–C104 fragment 2 a – d . We also synthesized diastereoisomers 2 a and b ( 2 a in the preceding article; Chem. Eur. J. 2015 , DOI: 10.1002/chem.201503880) by a Julia–Kocienski olefination and diastereoisomers 2 c and d by a Wittig reaction. By comparing the ¹³C NMR chemical shifts of natural symbiodinolide ( 1 ) with those of the synthetic products 2 a – d , we have reassigned the stereostructure of the C79–C104 fragment of natural product 1 to be that depicted in diastereoisomer 2 b .     

Studies directed toward the total synthesis of discodermolide: asymmetric synthesis of the C1-C14 fragment

[structure: see text] A convergent and stereoselective assembly of the C1-C14 subunit of marine natural product (+)-discodermolide has been completed. The approach employs chiral allylsilane bond construction methodology to establish four of the eight stereogenic centers. Key fragment coupling is achieved via an efficient stereoselective acetate aldol reaction between C1-C6 and C7-C14 subunits.     

Studies of the Total Synthesis of Epothilone B and D:A Facile Synthesis of C7-C14 and C15-C21 Fragments

A mild and highly efficient synthesis of C7-C14 and C15-C21 fragments of epothilone B and D is described in which racemic C7-C14 fragment is prepared from nerol through four steps and C15-C21 fragment is obtained from 1,3-dichloroacctone.thioacetamide and propionaldehyde.     

Studies towards the synthesis of superstolide A. Synthesis and stereochemical assignment of the C(21)C(26) fragment of superstolide A

An asymmetric synthesis of the C(21)C(26) fragment of superstolide A is described. A fragment, corresponding to a reductive ozonolysis product of superstolide, was also prepared. Comparison of spectroscopic and optical properties of the corresponding fragment obtained by degradation of natural superstolide A allowed the confirmation of the stereochemistry of the natural product.     

Stereocontrolled synthesis of the C21-C38 fragment of the unnatural enantiomer of the antibiotic nystatin A1

The C(21)-C(38) fragment all-trans-41 of the unnatural enantiomer 1 of nystatin A(1) was prepared starting from the N-propionyl oxazolidinone 9. Aldol adduct ent-8 (ee > 96 %) derived in two steps was hydroborated with (thexyl)BH(2). Oxidative work-up and treatment with acid furnished delta-lactone 4. It contains the complete stereotetrade of the target molecule. The alpha,beta-unsaturated ester 28 was reached after another four steps. It should be a precursor for the polyene moieties of a variety of polyol,polyene macrolides. Illustrating that, the alpha,beta-unsaturated aldehyde 29 obtained from 28 and DIBAL was extended by 10 C atoms in four steps yielding the C(21)-C(38) segment 41. The latter set of transformations included the regio- and stereoselective Claisen rearrangement 32-->35.     

Studies on the stereochemistry of aplyronine A: Determination of the stereochemistry of the C21---C34 fragment

The absolute stereochemistry of the C21---C34 fragment 2 of aplyronine A (1), a potent antitumor substance of marine origin, was determined by enantioselective synthesis.     

Studies directed toward the synthesis of rhizopodin: stereoselective synthesis of the C1-C15 fragment

A stereoselective synthesis of the C1-C15 fragment of a G-actin binding natural macrodiolide, rhizopodin was achieved using, as key steps, highly stereoselective acetate aldol reactions to build the C1-C7 fragment, one pot oxazole synthesis and an asymmetric Keck allylation reaction to build the C8-C15 fragment and finally, a Stille reaction to couple both the fragments.     

Synthesis of the C1-C21 Fragment of the Serine/Threonine Phosphatase Inhibitor Tautomycin

Compound 40 containing the C-1-C-21 region of tautomycin has been synthesized. The two halves (4 and 5) of this spirocyclic section were each constructed using Matteson's chloromethylene insertion reaction. Cr/Ni-mediated coupling of compounds 4 and 5 resulted in a structure containing the C-1-C-21 section of tautomycin. Oxidation of the resultant allylic alcohol to the ketone and removal of the alpha,beta unsaturation yielded compound 39. Treatment with DDQ removed both PMB protecting groups and allowed the spirocyclic ketal to form producing compound 40, ready for further extension to the natural product tautomycin.     

Total synthesis of everninomicin 13,384-1--Part 3: synthesis of the DE fragment and completion of the total synthesis

The stereoselective construction of the DE fragment (2) of everninomicin 13,384-1 (1) is reported. From the two possible ways of inserting the DE fragment between the A1B(A)C and FGHA2 domains of the natural product, the sequence involving the DEFGHA2 segment was found to be the most viable. This coupling was followed by attachment of a suitably protected and activated A1B(A)C fragment which led, after orthoester construction and final deprotection to the targeted everninomicin 13,384-1 (1), completing the total synthesis of this complex naturally occurring substance.     

Asymmetric Synthesis of Calyculin C. 2. Synthesis of the C(26)-C(37) Fragment and Model Wittig Couplings

We report our synthesis of the C(26)-C(37) fragment of serine/threonine protein phosphatase PP1 and PP2A inhibitor calyculin C (1). Outlined in this paper are synthetic approaches to the two components based on disconnection at the C(33)-N(3) amide bond. We report the successful synthesis of the C(33)-C(37) aza-sugar derived from D-lyxose which was coupled onto a C(26)-C(32) aminooxazole originating from L-pyroglutamic acid. Elaboration of the resulting amide to a fully deprotected C(26)-C(37) fragment of calyculin C completed our synthesis. This provided an appropriate phosphonium salt for use in a Wittig olefination for joining both halves of the natural product.     

Toward the Total Synthesis of Scleritodermin A: Preparation of the C(1)-N(15) Fragment

The synthesis of the C₁-N₁₅ fragment of the marine natural product Scleritodermin A has been accomplished through a short and stereocontrolled sequence. Highlights of this route include the synthesis of the novel ACT fragment and the formation of the α-keto amide linkage by the use of a highly activated α,β-ketonitrile.     

Studies directed towards the synthesis of antascomicin A: stereoselective synthesis of the C22-C34 fragment of the molecule

A stereoselective synthesis of the C22-C34 fragment of the non-immunosuppressive immunophilin-binding natural product, antascomicin A was achieved using d-quinic acid as the starting material and highly stereoselective aldol reactions were employed, as key steps, to build the remaining stereocentres at C23, C26 and C27.     

Studies Toward the Stereoselective Synthesis of C13 to C21 Fragment of the Brasilinolides Family of Immunosuppressive Macrolides

The work describes our attempts to synthesize the C13 to C21 fragment of brasilinolides, a 32-membered macrolide class of molecule. The C13 to C21 segment encompasses six asymmetric centers and a pyran ketal moiety. The synthesis starts from L-malic acid, and the salient features of our asymmetric synthesis are opening of epoxide, assymmetric dihydroxylation for the creation of vic-diol, and Barbier allylation.