Mitsunobu Inversion Research Articles

First total synthesis of macrosphelides C and F

Macrosphelides C and F were synthesized by lactonization of 14-oxo seco acids at the O(10)C(11) bond followed by reduction and Mitsunobu inversion of the resulting hydroxyl group. The seco acids were prepared from the corresponding furans by furan ring-opening with NBS followed by further oxidation of the 4-oxo-2-alkenals with NaClO2.

Parallel modification of tropane alkaloids

Various tropane alkaloids have been prepared by structural modification of the readily available natural product, scopolamine 1 . Reaction of isocyanates with 6,7-dehydrotropine 5 provided a number of urethanes 6a– e . Reductive amination of tropinone 7 and subsequent reaction with isocyanates provided ureas 9a– f . Mitsunobu inversion of the C-3 alcohol of tropine 10 afforded the epimeric ester 11 .

Furan ring oxidation strategy for the synthesis of macrosphelides A and B.

By using the convenient protocol for conversion of 2-substituted furans into 4-oxo-2-alkenoic acids ((i) NBS, (ii) NaClO(2)), macrosphelide B (2) was synthesized from furyl alcohol 5 (>98% ee) and acid 6 (99% ee). The protocol was first applied to the PMB ether of 5 to afford acid 13b. On the other hand, DCC condensation of acid 6 with 5 gave 16 after deprotection of the TBS group. Condensation was again carried out between 13b and 16 to furnish the key ketone 17, which upon reduction with Zn(BH(4))(2) afforded anti alcohol 18 stereoselectively (15:1). After protection/deprotection steps, the furan 18 was converted to seco acid 3 by using the furan oxidation protocol mentioned above, and lactonization of 3 with Cl(3)C(6)H(2)COCl, Et(3)N, and DMAP afforded 22 (MOM ether of 2), which upon deprotection with TFA produced 2. Transformation of 22 to macrosphelide A (1) was then investigated. Although the chelation-controlled reduction of 22 should afford the desired anti alcohol 24, Zn(BH(4))(2) at <-90 degrees C gave a 2 approximately 1:1 mixture of anti/syn alcohols. On the contrary, reduction with NaBH(4) in MeOH at -15 degrees C produced the syn isomer 23 with >10:1 diastereoselectivity. Mitsunobu inversion of the resulting C(14)-hydroxyl group and deprotection of the MOM group with TFA afforded 1. Similarly, reduction of 2 with NaBH(4) afforded the C(14)-epimer of 1 stereoselectively. The observed stereoselectivity in the reductions of 22 and 2 could be explained on the basis of computer-assisted calculation, which showed presence of the low-energy conformers responsible for the stereoselective reduction. In addition, conversion of 2 to 1 was established, for the first time.

ChemInform Abstract: Total Synthesis and Preliminary Biological Evaluations of 15(R) and 15(S) Aza-dEpoB: A Mitsunobu Inversion at C-15 in Pre-Epothilone Fragments.

ChemInform Abstract: Total Synthesis and Preliminary Biological Evaluations of 15(R) and 15(S) Aza-dEpoB: A Mitsunobu Inversion at C-15 in Pre-Epothilone Fragments.

Stereoselective Reduction of Cyclopropylalkaones Possessing a Difluoromethylenephosphonate Group at the Ring: Application to Stereoselective Synthesis of Novel Cyclopropane Nucleotide Analogues

Difluoro{(1 S ∗,2 S ∗)-2-[(1 S ∗)-1-(6-oxo-1,6-dihydro-9 H-purin-9-yl)ethyl]cyclopropyl}methylphosphonic acid 12a and the related analogues were prepared as ‘multi-substrate analogue’ inhibitors for purine nucleoside phosphorylase. Reduction of diethyl [(1 S ∗,2 S ∗)-2-acethylcyclopropyl](difluoro)methylphosphonate 8a with K-Selectride at a low temperature proceeded from the less-hindered face of the carbonyl in the bisected s- cis conformation to give the corresponding cyclopropylalkanol 9a in high diastereoselectivity (94% de). In an analogous manner, several cyclopropylalkanols 8b– g possessing a difluoromethylene phosphonate functional group at the ring were stereoselectively synthesized. The cyclopropylalkanol 9a was manipulated to the nucleotide analogue 12a through a conventional method. The diastereomeric nucleotide analogue 15 was prepared from 9a via the Mitsunobu inversion. Preliminary results on an assay of PNP inhibitory activity of 9a and 15 are presented.

Enantioselective synthesis of the larger fragment of pamamycin-607

The enantiomerically pure methyl ester of the complete larger hydroxy acid (C(1)C(18)) of the macrodiolide antibiotic pamamycin-607 has been synthesized using a general sultone route to actic acids and analogs. The requisite N, N-dimethylamino moiety was introduced by Mitsunobu inversion with hydrazoic acid followed by a reaction cascade involving hydrogenation and double reductive methylation.

A brief synthesis of the Aplasmomycin tetrahydrofuran

A highly stereoselective iodocyclisation of the 3-alkene-1,2-diol 9, derived from asymmetric dihydroxylation of the dienyl benzoate 8, gives the β-iodotetrahydrofuran 10 and thence the Aplasmomycin precursor 13, following deiodination and Mitsunobu inversion.

Total synthesis of macrosphelides B and A

An efficient total synthesis of macrosphelide B has been developed in which the C(5)–O(10) and the C(11)–O(16) fragments were prepared from ( S)-1-(2-furyl)ethanol of >98% ee via oxidation of the furan part. In addition, macrosphelide B was transformed stereoselectively into macrosphelide A by reduction followed by Mitsunobu inversion.

Practical syntheses of [13C]- and [14C]-labelled glucosphingolipids

Synthetic routes to [glucose-U-14C]-1-O-(β-D-glucopyranosyl)-N-stearoyl-D-erythro-sphingosine 1b and to [glucose-13C6]-1-O-(β-D-glucopyranosyl)sphingosine ([glucose-13C6]glucopsychosine, 2b) are described. Whereas the protected ceramide precursor for 1b was prepared using conventional methodology, two new strategies were developed in the course of the synthesis of 2b. Of these, one relies on keeping a protecting group in place at all times to avoid the handling difficulties associated with sphingosine 4, while the other generates a protected derivative (24) of sphingosine indirectly by means of a Mitsunobu inversion.

Novel Synthesis of (-)-Bestatin from L-Aspartic Acid.

Oxazoline-4-acetate derivative 3 that could be readily obtained from L-aspartic acid was subjected to highly stereoselective hydroxylation, and subsequent Mitsunobu inversion of the hydroxyl group led to (2S,3R)-3-amino-3-benzyl-2-hydroxybutanoic acid derivative 8 in a good yield. Coupling of 8 with L-leucine benzyl ester and subsequent cleavage of the protective groups provided (-)-bestatin 1 in a high yield.

A novel stereoselective route to some uncommon amino acids

An efficient synthesis of a d- erythro-β-methylaspartic acid analog was achieved in six steps from commercially available material. Evans' aldol reactions were utilized followed by Weinreb amide formation and Mitsunobu inversion to achieve the necessary stereochemistry of the amino acid target. The technique was applied to the synthesis of an aspartic acid analog as well as a diaminobutyric acid analog.

Synthetic Studies of Antitumor Macrolide Rhizoxin: Stereoselective Syntheses of the C(1)-C(9) and C(12)-C(26) Subunits.

A triply convergent synthetic approach which culminates in the enantioselective syntheses of the C(1)-C(9) and C(12)-C(26) subunits of the macrolide antitumor agent rhizoxin is described. The central C(12)-C(20) subunit 4 has been prepared efficiently via diastereoselective enzymatic acetate hydrolysis of 15 with porcine pancreatic lipase, a chelation-controlled Ireland-Claisen rearrangement (10 --> 12) combined with kinetic bromolactonization (12 --> 14), and Mitsunobu inversion (23 --> 26) to introduce the three contiguous C(15)-C(17) stereocenters. Formation of the C(18)-C(19) trisubstituted (E)-olefin was achieved by a stereoselective Horner-Wadsworth-Emmons reaction. The central segment 4 and the oxazole chromophore side chain 3 were coupled using another highly stereoselective Horner-Wadsworth-Emmons reaction. Two different lactone subunits [C(1)-C(9) segment 5 and C(3)-C(10) segment 47] were also prepared, employing a thermodynamically controlled diastereotopic group differentiation tactic for establishing the C(5) stereochemistry.

HIV-1 Reverse Transcriptase Can Discriminate between Two Conformationally Locked Carbocyclic AZT Triphosphate Analogues

It has been proposed that the preference of 3‘-azido-3‘-deoxythymidine (AZT) for the extreme 3E (south) conformation, as observed in its X-ray structure, is responsible for its potent anti-HIV activity. However, it has also been suggested that the antipodal north conformation may be required for the strong interaction of AZT 5‘-triphosphate with its target enzyme, HIV reverse transcriptase (RT). To resolve this issue, we have constructed two conformationally rigid carbocyclic analogues of AZT which are locked permanently into opposite 2E (north) and 3E (south) conformations in order to test the ability of the corresponding 5‘-triphosphates to inhibit RT. The two isomeric carbocyclic analogues of AZT, (N)-methano-carba-AZT (1) and (S)-methano-carba-AZT (2), were constructed on a bicyclo[3.1.0]hexane template that exhibits a rigid pseudoboat conformation, capable of mimicking the furanose pucker in the classical north and south conformations that are characteristic of standard nucleosides. The unique conformational properties of 1 and 2 observed by both X-ray and solution NMR studies showed the existence of the same invariant conformations in solution and in the solid state. In addition, differences observed in the outcome of the Mitsunobu inversion of a secondary hydroxyl function attempted with both bicyclo[3.1.0]hexane nucleoside analogues could be explained by the rigid pseudoboat nature of this system. In one case, the bicyclic system facilitated formation of an anhydronucleoside intermediate, whereas in the other it completely prevented its formation. The chemically synthesized 5‘-triphosphates of 1 and 2 were evaluated directly as RT inhibitors using both a recombinant enzyme and enzyme obtained and purified directly from wild-type viruses. The results showed that inhibition of RT occurred only with the conformationally locked 2E (N)-methano-carba-AZT 5‘-triphosphate. This inhibition was equipotent to and kinetically indistinguishable from that produced by AZT 5‘-triphosphate. The antipodal 3E (S)-methano-carba-AZT 5‘-triphosphate, on the other hand, did not inhibit RT.

Exploring functional and molecular diversity with polymer-bound p-alkoxybenzyl ethers — Scope and applications of preparatively useful organic reactions

Abstract Alcohols immobilized as p-alkoxybenzyl ethers on Wang resins have been subjected to a variety of chemical transformations based on existing functionality (enolate chemistry, carbonyl group reactivity, Mitsunobu inversion, ozonolysis, Heck reactions, etc.), in an effort to test the suitability of this novel resin-bound ether linkage. The modified substrate was released from the resin by mild acid treatment.

Asymmetric syntheses of panclicins A–E via [2+2] cycloaddition of alkyl(trimethylsilyl)ketenes to a β-silyloxyaldehyde

Panclicins A–E, pancreatic lipase inhibitors from Streptomyces, were synthesised in a modular fashion starting with three alkyl(trimethylsilyl)ketenes, two amino acids and a single aldehyde component, (3R)-3-(tert-butyldimethylsilyloxy)decanal 11. The lone stereocentre in 11 which governs the stereochemistry in subsequent steps was generated by Noyori asymmetric hydrogenation. The key step, a Lewis acid catalysed [2+2] cycloaddition of alkyl(trimethylsilyl)ketenes 13a–c to 11, gave three 3-trimethylsilyloxetan-2-ones with good 1,3-asymmetric induction. After C- and O-desilylation the amino acid side chains were introduced using a Mitsunobu inversion.

Unexpected rearrangement during biomimetic entry toward a taxane skeleton

Bicyclo[9.3.1]pentadecatriene derivative 4 which corresponds to a precursor of taxol in a biomimetic entry was constructed by means of TiCl 4Zn promoted McMurry cyclization and Mitsunobu inversion. Treatment of 4 with mercuric triflate afforded an unexpected rearrangement-transannular cyclization product 5.

Studies on the total synthesis of the macrolide antitumor agent rhizoxin. 1. Synthesis of the C3C13 segment

Abstract An asymmetric synthesis of the C3C13 segment of rhizoxin is described in which the relative stereochemistry of C7 and C8 is established through a chelation-controlled allylation followed by Mitsunobu inversion, and the pyran ring is constructed by a photochemically initiated 6-exo radical cyclization.

Stereocontrolled Synthesis of Cyclic Ethers by Intramolecular Hetero-Michael Addition. 5. Synthesis of All Diastereoisomers of 2,3,5,6-Tetrasubstituted Tetrahydropyrans

A systematic approach to the enantiomeric synthesis of all possible diastereoisomers of 2,6-dialkyl-3,5-dioxytetrahydropyrans is described. The key step in the described methodology is the intramolecular cyclization of enantiomerically enriched (≥95% ee) 7-hydroxy-4-(benzoyloxy)-2,3-unsaturated esters. In fused systems, six of the eight diastereoisomers for one enantiomeric series were synthesized using this procedure as a key step. Using those with the suitable stereochemistry, the two left were synthesized by simple chemical transformations: in one case by the basic isomerization of the carbon with the (methoxycarbonyl)methyl substituent or by a Mitsunobu inversion of a secondary alcohol available from the benzoyloxy group, in the remaining one by a consecutive sequence of oxidation and reduction reactions again over the free secondary alcohol. The stereochemistry of the intramolecular hetero-Michael addition leading to 2,3-disubstituted tetrahydropyrans is highly predictable when kinetic conditions (low temperature and sodium or potassium bases) are used and can be rationalized by invoking a model of a chair-like transition state in which the benzoyloxy group is located in the equatorial mode and the stereochemical course of the approach of the α,β-unsaturated ester is controlled by the geometry of the double bond. As a rule of thumb, the cyclization using E double bonds yielded cis-2,3-disubstituted tetrahydropyrans, while (Z)-unsaturated esters yielded the trans compounds. This empirical rule is followed in highly substituted systems, leading to fused 2,3,5,6-tetrasubstituted tetrahydropyrans, with the same absolute configuration in the carbon where the nucleophilic oxygen is located and the one where the benzoyloxy group is located. Those systems having opposite configurations yield the same trans-2,3-disubstituted compound. The isomerization under thermodynamic conditions (room or higher temperature with excess of base) of the diastereoisomers with the (methoxycarbonyl)methyl substituent in the axial mode led quantitatively to those in which such a group was located equatorially. The scope and limitations of the method are described in both the synthesis of the unsaturated precursor and the stereochemistry reached in the cyclization step.

New indane derived aminoalcohols as chiral ligands for the catalytic enantioselective addition of diethylzinc to aldehydes

Secondary amines react with (1 R,2 S)-indene oxide 1 in a completely regioselective manner leading to trans-2-dialkylamino-1-indanols 4a— d in high yield. A Mitsunobu inversion via the corresponding p-nitrobenzoates, followed by reduction with DIBALH leads to the cis-2-dialkylamino-1-indanols 5a— d also in high yield. These two new classes of aminoindanols have been tested as chiral ligands for the enantioselective addition of diethylzinc to both aliphatic and aromatic aldehydes, leading to 1-substituted 1-propanols with up to 80% e.e. A very simple procedure for the enantiomeric enrichment of 1 from 88% to ≥99% e.e. is also reported.

Towards chemical libraries of annonaceous acetogenins

Abstract