Development of a common fully stereocontrolled access to the medicinally important and promising prostacyclin analogues iloprost, 3-oxa-iloprost and cicaprost

We describe new fully stereocontrolled syntheses of the prostacyclin analogues iloprost (2), the most active component of the drugs Ilomedin and Ventavis, and 3-oxa-iloprost (3), a derivative that is expected to have a significantly higher metabolic stability than 2 perhaps allowing an oral application. The syntheses are based on the same strategy and chiral bicyclic building block as used in the synthesis of cicaprost (4), the third most potent analogue that exhibits, besides prostacyclin-like activities, antimetastatic activities. Reaction of the enantiopure C6-C13 bicyclic aldehyde 17 with Cl(3)CCOOH/Cl(3)CCOONa afforded trichlorocarbinol 24 which was converted via mesylate 25 to the C6-C14 bicyclic alkyne 9. The palladium-catalysed hydrostannylation of alkyne 9 gave with high regio- and stereoselectivity the alkenylstannane 26, Sn/Li exchange of which afforded the E-configured alkenyllithium derivative 8. Coupling of the C6-C14 building block 8 with the enantiopure C15-C20 building block, the N-methoxyamide 7, gave the C6-C20 bicyclic ketone 6 in high yield without epimerisation at C16. The configuration at C15 of iloprost (2) and 3-oxa-iloprost (3) was established through a highly diastereoselective reduction of ketone 6 with catecholborane and the chiral oxazaborolidine 28 which furnished alcohol (15S)-29. The highly stereoselective conversions of alcohol (15S)-29 to iloprost (2) and 3-oxa-iloprost (3), which include as key stereoselective steps an olefination with a chiral phosphonoacetate and a copper-mediated allylic alkylation, have already been described.     

Fully stereocontrolled syntheses of 3-oxacarbacyclin and carbacyclin by the conjugate addition-azoalkene-asymmetric olefination strategy

A fully stereocontrolled synthesis of 3-oxacarbacyclin (3) and a formal synthesis of carbacyclin (2) are described. The syntheses are based on the conjugate addition-azoalkene-asymmetric olefination strategy. Its key features are (1) the stereoselective establishment of the complete omega-side chain of 2 and 3 through conjugate addition of the enantiopure C13-C20 alkenylcopper derivative 10 to the enantiopure C6-C12 bicyclic azoalkene 9 and (2) the 5E-stereoselective construction of the alpha-side chain through a Horner-Wadsworth-Emmons olefination of the bicyclic ketone 7 with the chiral lithium phosphonoacetate 26 with formation of ester E-27. The allylic alcohol 6 serves at late stage as the joint intermediate in the synthesis of 2 and 3.     

Fully stereocontrolled total syntheses of the prostacyclin analogues 16S-iloprost and 16S-3-oxa-iloprost by a common route, using alkenylcopper-azoalkene conjugate addition, asymmetric olefination, and allylic alkylation

In this article we describe fully stereocontrolled total syntheses of 16S-iloprost (16S-2), the most active component of the drugs Ilomedin and Ventavis, and of 16S-3-oxa-iloprost (16S-3), a close analogue of 16S-2 having the potential for a high oral activity, by a new and common route. The key steps of this route are (1) the establishment of the complete C13-C20 omega side chain of the target molecules through a stereoselective conjugate addition of the alkenylcopper derivative 9 to the bicyclic C6-C12 azoalkene 10 with formation of hydrazone 8, (2) the diastereoselective olefination of ketone 7 with the chiral phosphoryl acetate 39, and (3) the regio- and stereoselective alkylation of the allylic acetate 43 with cuprate 42. These measures allowed the 5E,15S,16S-stereoselective synthesis of 16S-2 and 16S-3, a goal which had previously not been achieved. Azoalkene 10 was obtained from the achiral bicyclic C6-C12 ketone 11 as previously described by using as key step an enantioselective deprotonation. The configuration at C16 of omega-side chain building block 9 has been installed with high stereoselectivity by the oxazolidinone method and that at C15 by a diastereoselective oxazaborolidine-catalyzed reduction of the C13-C20 ketone 23 with catecholborane. Surprisingly, a high diastereoselectivity in the reduction of 23 was only obtained by using 2 equiv of oxazaborolidine 24. Application of substoichiometric amounts of 24 resulted in irreproducible diastereoselectivities ranging from very high to nil.     

Studies on the synthesis of bafilomycin A(1): stereochemical aspects of the fragment assembly aldol reaction for construction of the C(13)-C25) segment

Highly stereoselective syntheses of aldols 8a-c corresponding to the C(13)-C(25) segment of bafilomycin A(1) were developed by routes involving fragment assembly aldol reactions of chiral aldehyde 6a and the chiral methyl ketones 7. A remote chelation effect plays a critical role in determining the stereoselectivity of the key aldol coupling of 6a and the lithium enolate of 7b. The protecting group for C(23)-OH of the chiral aldehyde fragment also influences the selectivity of the lithium enolate aldol reaction. In contrast, the aldol reaction of 6a and the chlorotitanium enolates of 7a,c were much less sensitive to the nature of the C(15)-hydroxyl protecting group. Studies of the reactions of chiral aldehydes with Takai's (gamma-methoxyallyl)chromium reagent 40 are also described. The stereoselectivity of these reactions is also highly dependent on the protecting groups and stereochemistry of the chiral aldehyde substrates.     

Application of the Lewis acid-Lewis base bifunctional asymmetric catalysts to pharmaceutical syntheses: stereoselective chiral building block syntheses of human immunodeficiency virus (HIV) protease inhibitor and beta3-adenergic receptor agonist

Chiral building block syntheses of promising drugs were achieved using two types of catalytic stereoselective cyanosilylations of aldehydes promoted by Lewis acid-Lewis base bifunctional catalysts 1 and 2 as the key steps (diastereoselective cyanosilylation of amino aldehyde and enantioselective cyanosilylation). In the first part of this article, syntheses of chiral building blocks (6) of Atazanavir (3: human immunodeficiency virus (HIV) protease inhibitor) using the bifunctional catalyst 2 are discussed. The reaction of Boc-protected phenylalaninal 21 in the presence of 1 mol% catalyst 2 selectively afforded the anti isomer 22 as the major product (diastereomeric ratio=97 : 3), which was successively converted to the corresponding epoxide 6 in six steps. In the second part, we describe a chiral building block synthesis of beta(3)-adrenergic receptor agonists. The enantioselective cyanosilylation of 3-chlorobenzaldehyde (38) with 9 mol% catalyst 1 gave the chiral cyanohydrin 39, which was converted to beta-hydroxyethylamine 40 by reduction. Moreover, the chiral ligand of catalyst 1 could be recovered without column chromatography and reused without decreasing its activity.     

Asymmetric synthesis of 3-oxa-15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin and its neuroprotective analogue 15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin based on the conjugate addition-azoalkene-asymmetric olefination strategy

A fully stereocontrolled synthesis of 3-oxa-15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (3-oxa-15-deoxy-TIC, 7 b) and a formal one of 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC, 7 a) are described. 15-Deoxy-TIC is specific for the neuronal prostacyclin receptor (IP2) and exhibits neuroprotective activities, and the new 3-oxa-15-deoxy-TIC is expected to be metabolically more stable than 15-deoxy-TIC. The syntheses of 7 a and 7 b are based on the convergent conjugate addition-azoalkene-asymmetric olefination strategy. Key building blocks are the readily available bicyclic azoalkene 14 and the alkenylcopper derivative 15. The stereoselective conjugate addition of 15 to 14 gave hydrazone 13, which was stereoselectively converted to the bicyclic ketone 11. The key steps for the construction of the alpha side chain of 7 a and 7 b and the regioselective introduction of the endocyclic Delta6,6a double bond are: 1) a highly selective asymmetric olefination of ketone 11 with the chiral Horner-Wadsworth-Emmons reagent 28 and 2) a regioselective deconjugation of the alpha,beta-unsaturated ester (E)-10 with the chiral lithium amide 29, which gave the beta,gamma-unsaturated ester anti-9 with high selectivity. The homoallylic alcohol 8 served at a late stage as the joint intermediate in the syntheses of 7 a and 7 b. While an etherification of 8 furnished, after hydrolysis and deprotection, 3-oxa-15-deoxy-TIC, its alkylation afforded alcohol 37, the known precursor for the synthesis of 15-deoxy-TIC.     

Cross metathesis as a general strategy for the synthesis of prostacyclin and prostaglandin analogues

[reaction: see text] A cross metathesis (CM) approach has been successfully applied to introduce fully functionalized omega-side chain appendages of various prostacyclin and prostaglandin analogues, resulting in high (E)-selectivities for the C13-C14 double bond and leading to the total syntheses of isocarbacyclin, 15R-TIC, carbacyclin, and PGF(2)(alpha) and the formal syntheses of 15-deoxy-TIC and PGJ(2).     

Synthesis of the C8-C20 and C21-C30 segments of pectenotoxin 2

In this study, we synthesized the C8-C20 and C21-C30 segments of the diarrhetic shellfish toxin pectenotoxin 2. The C8-C20 segment was assembled from a phosphonate corresponding to the C8-C15 segment (prepared from l-malic acid in 19 steps) and an aldehyde corresponding to the C16-C20 segment (synthesized from 3-methyl-3-butenol in nine steps) by a twelve-step process including the Horner-Wadsworth-Emmons reaction, regio- and stereoselective reduction of the resulting enone, diastereoselective epoxidation, and 5-exo epoxide cleavage forming the C-ring. The C21-C30 segment was constructed in 13 steps from (S)-glycidol via a route involving E-ring formation by 5-exo epoxide cleavage and stereoselective methylation at C27 by the Evans method.     

Synthetic studies of an 18-membered antitumor macrolide, tedanolide. 5. Stereoselective synthesis of the C13-C23 part via condensation of two fragments, C13-C17 and C18-C21, by taking advantage of the 3,4-dimethoxybenzyl protecting group.

An efficient and stereoselective synthesis of the C13-C23 part (8) was achieved starting from methyl (R)- and (S)-3-hydroxy-2-methylpropionates (9) via coupling of the C13-C17 aldehyde (6), prepared by Evans asymmetric aldol reaction, with the C18-C21 iodoalkene (5b) by taking advantage of the 3,4-dimethoxybenzyl protecting group.     

Synthesis and Biological Activity of 7,8,9‐Trideoxy‐ and 7R DesTHP‐Peloruside A

The stereoselective syntheses of 7,8,9‐trideoxypeloruside A ( 4 ) and a monocyclic peloruside A analogue lacking the entire tetrahydropyran moiety ( 3 ) are described. The syntheses proceeded through the PMB‐ether of an ω‐hydroxy β‐keto aldehyde as a common intermediate which was elaborated into a pair of diastereomeric 1,3‐syn and ‐anti diols by stereoselective Duthaler–Hafner allylations and subsequent 1,3‐syn or anti reduction. One of these isomers was further converted into a tetrahydropyran derivative in a high‐yielding Prins reaction, to provide the precursor for bicyclic analogue 4 . Downstream steps for both syntheses included the substrate‐controlled addition of a vinyl lithium intermediate to an aldehyde, thus connecting the peloruside side chain to C15 (C13) of the macrocyclic core structure in a fully stereoselective fashion. In the case of monocyclic 3 macrocyclization was based on ring‐closing olefin metathesis (RCM), while bicyclic 4 was cyclized through Yamaguchi‐type macrolactonization. The macrolactonization step was surprisingly difficult and was accompanied by extensive cyclic dimer formation. Peloruside A analogues 3 and 4 inhibited the proliferation of human cancer cell lines in vitro with micromolar and sub‐micromolar IC₅₀ values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for nM biological activity.     

A second-generation total synthesis of (+)-discodermolide: the development of a practical route using solely substrate-based stereocontrol

A novel total synthesis of the complex polyketide (+)-discodermolide, a promising anticancer agent of sponge origin, has been completed in 7.8% overall yield over 24 linear steps, with 35 steps altogether. This second-generation approach was designed to rely solely on substrate control for introduction of the required stereochemistry, eliminating the use of all chiral reagents or auxiliaries. The common 1,2-anti-2,3-syn stereotriad found in each of three subunits, aldehyde 9 (C(1)-C(5)), ester 40 (C(9)-C(16)), and aldehyde 13 (C(17)-C(24)), was established via a boron-mediated aldol reaction of ethyl ketone 15 and formaldehyde, followed by hydroxyl-directed reduction to give 1,3-diol 14. Alternatively, a surrogate aldehyde 22 was employed for formaldehyde in this aldol reaction, leading to the beta-hydroxy aldehyde 20 as a common building block, corresponding to the discodermolide stereotriad. Key fragment unions were achieved by a lithium-mediated anti aldol reaction of ester 40 and aldehyde 13 under Felkin-Anh control to provide (16S,17S)-adduct 51 and a boron-mediated aldol reaction between enone 10 and aldehyde 9, exploiting unprecedented remote 1,6-stereoinduction, to give the (5S)-adduct 57.     

Exploration of omega-side chain addition strategies for the syntheses of isocarbacyclin and 15R-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin

We describe alternative access to prostacyclin analogues by means of two omega-side chain addition strategies: Grignard reagent addition to an alpha,beta-unsaturated Weinreb amide, followed by diastereoselective reduction of the corresponding enone system, and implementation of Seebach's alkylation chemistry. These strategies have led to the syntheses of biologically active prostacyclin analogues isocarbacyclin and 15R- 16-(m-tolyl)- 17,18,19,20-tetranorisocarbacyclin (15R-TIC), with modest to excellent diastereoselectivity.     

Stereocontrolled synthesis of C10-C22 fragment of the immunosuppressant FK 506. An occurrence of complementary stereoselectivity in the C15 ketone reduction

The stereoselective syntheses of the C10-C22 fragment 2a and its C15-epimer 2b of the immunosuppressant FK 506 1 have been carried out through convergent coupling of the sulfone 3, which could be constructed by highly stereocontrolled ester-enolate Claisen rearrangement of ene-ester 5, and the aldehyde 4 which was prepared from D-mannitol via anti selective methallylsilane addition to aldehyde 6 followed by modest stereoselective hydroboration based on 1,3-asymmetric induction. In the course of this reaction sequence a complementary stereoselection dependent on the used hydride reagents has occurred in reduction of the coupling product 26.     

Access to isocarbacyclin derivatives via substrate-controlled enolate formation: total synthesis of 15-deoxy-16-(m-tolyl)- 17,18,19,20-tetranorisocarbacyclin

[reaction: see text] We describe a convergent and flexible synthesis of 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC), a simple isocarbacyclin derivative. The synthesis takes advantage of two key step reactions: a regioselective deprotonation of the described ketone under substrate control which is then trapped, as the enol triflate, to generate the C6-C9alpha endocyclic double bond, followed by an sp2-sp3 Pd-catalyzed cross-coupling reaction (C5-C6) with a suitable primary alkyl Grignard reagent. Introduction of the C13-C14 (E)-double bond in the omega-side chain is performed by the Julia-Kocie?ski olefination.     

Asymmetric synthesis of the tetrahydropyran ring, C32-C38 fragment, of phorboxazoles

The asymmetric synthesis of a model aldehyde (2R,6R)-2 and the C32-C38 fragment of phorboxazoles, (2R,4R,6R)-1, is described using a sulfoxide as chiral auxiliary. Key advances include the stereoselective reductions of beta-keto- or beta,gamma-diketosulfoxides, the acid-catalyzed cyclization of enantiopure sulfinyl hydroxy ketone precursors to the tetrahydropyran ring, and the Pummerer reaction on the pendant sulfoxide to create the formyl group.     

Asymmetric total synthesis of spongistatins 1 and 2

The total synthesis of spongistatin 1 (1) and spongistatin 2 (2) has been achieved through an advanced-stage intermediate. The synthesis is highlighted by a highly convergent assembly of the four key fragments (the C1-C15 AB fragment 2, the C16-C28 CD fragment 3, the C29-C43 EF fragment 4, and the C44-C51 side chain 5) at a very advanced stage of the synthesis with minimal functional group interconversion. The CD fragment 3 functions as the central building block to which the other fragments are attached. The synthesis of the AB and CD spiroketal fragments is accomplished through the addition of a metalated gamma-pyrone to a beta-alkoxy aldehyde followed by spiroketalization. The EF subunit was assembled with high diastereoselectivity relying on asymmetric aldol reactions of chlorotitanium enolates of N-propionyl oxazolidinethiones and a double diastereoselective boron aldol to join the E and F fragments. Wittig coupling of the CD and EF fragments followed by a diastereoselective aldol reaction between the CDEF ketone and an AB aldehyde set the stage for attachment of the C44-C51 side chains and final macrolactonization and deprotection.     

Stereoselective synthesis of C5-C20 and C21-C34 subunits of the core structure of the aplyronines. Applications of enantioselective additions of chiral allenylindium reagents to chiral aldehydes

The stereoselective synthesis of a C5-C20 and a C21-C34 subunit of the aplyronine family of polyketide marine macrolides has been achieved. These subunits contain all 15 stereocenters of the core structure. Six of the 15 stereocenters were introduced through enantioselective and diastereoselective additions of chiral allenylindium reagents to alpha-methyl-beta-oxygenated propionaldehydes. The products of these additions were further transformed by reactions involving the terminal alkynyl substituent produced in the addition reactions. Unlike previous applications of this methodology, the present synthesis employs Pd(0)-catalyzed transmetalations of chiral allenylpalladium intermediates to generate the chiral allenylindium reagents in situ.     

Asymmetric synthesis of the core of AMPTD, the key amino acid of microsclerodermins F-I

We report a stereoselective synthesis of the five consecutive stereocenters of AMPTD in seven steps. Highlights include an Evans glycolate aldol reaction, the use of a Weinreb amide as an aldehyde masking group, and a Mannich reaction with an Ellman-type chiral sulfimine.     

Enantioselective Total Syntheses of Pallambins A–D

The first enantioselective total syntheses of (?)‐pallambins A–D have been achieved in 15 or 16 steps from a known chiral cyclohexenone. Salient features of the syntheses include a palladium‐catalyzed oxidative cyclization to assemble the [3.2.1]bicyclic moiety, an Eschenmoser–Claisen rearrangement/lactone formation sequence to construct the C ring, an intramolecular Wittig reaction to form the D ring, and individual transformations of pallambins C and D to generate pallambins A and B. The described synthesis avoids protecting‐group manipulations through the design of highly chemo‐ and stereoselective transformations. During the course of this work, a palladium‐catalyzed method for the dehydrobromination of α‐bromoketones was developed, and the scope of this transformation was also investigated.     

Synthesis of the C1-side chain of zaragozic acid D and progress towards a total synthesis

A synthesis of a 1,3-dithiane corresponding to the C1-side chain of zaragozic acid D is described. An aldol reaction using an Evans oxazolidinone is the key step in controlling stereochemistry. Metallation of the derived dithiane monosulfoxide and coupling to an aldehyde effected construction of the C1-C7 bond. Subsequent steps are also reported, including acid-mediated ketalization resulting in formation of an advanced synthetic intermediate containing the bicyclic ketal core of the natural product.