William H. Pearson

Synthesis and mannosidase inhibitory activity of 3-benzyloxymethyl analogs of swainsonine

Abstract Swainsonine ( 3 ), an inhibitor of Golgi α-mannosidase II, is a clinical candidate for cancer treatment. In order to avoid potential problems arising from its co-inhibition of lysosomal mannosidases, we have synthesized 3-benzyloxymethyl analogs of swainsonine ( 17 and 18 ). Initial screening of these new compounds is reported.

The intramolecular cycloaddition of azides with ω-chloroalkenes. A facile route to (±)-swainsonine and other indolizidine alkaloids

Abstract A potentially general route to the 1-azabicyclo[n.m.O]alkane skeleton of various alkaloids is embodied in the intramolecular 1,3-dipolar cycloaddition of aliphatic azides with ω-chloroalkenes. Cycloaddition is followed by rearrangement and intramolecular N-alkylation, affording bicyclic iminium ions 1 in one operation. The application of this method to the synthesis of (±)-δ-coniceine 6 , (1S,2R,8aR)-indolizidine-1,2-diol 13 and (−)-swainsonine 15 is described.

Alkaloid synthesis via [3+2] cycloadditions

Tin-lithium exchange on (2-azaallyl)stannanes affords nonstabilized 2-azaallyllithiums (2-azaallyl anions) that undergo [π4s+π2s] cycloadditions with alkenes to afford pyrrolidines. The scope of this method has been expanded to include 2-azapentadienyllithiums and heteroatom-substituted 2-azaallyllithiums. Alternatively, the (2-azaallyl)stannanes may also be used to generate nonstabilized azomethine ylides via N-alkylation/destannylation or N-protonation/destannylation, and these ylides were also found to be useful for the synthesis of pyrrolidines by [π4s+π2s] cycloadditions with alkenes. Applications of both methods to the total synthesis of alkaloids such as (+)-coccinine, lepadiformine stereoisomers, lapidilectine B, and indolizidine 239CD have been accomplished.

Synthesis of fused pyrrolines by the intramolecular cycloadition of azides application to the pyrrolizidine alkaloids.

Intramolecular 1,3-dipolar cycloaddition of azide 4 proceeds through triazoline 5 and vinyl aziridine 6, resulting in the formation of the 1,5-homodienyl shift product 7 and the tetrahydropyrrolizines 8 and 9. Compound 8 represents a formal total synthesis of supinidine.

Synthetic studies on the perhydropyrrolo[2,1-j]quinoline marine alkaloids lepadiformine and cylindricine C using a 2-azapentadienyl anion cycloaddition. Synthesis of 2,13-diepilepadiformine (or 2-epi-11-deoxycylindricine C)

Abstract Tin-lithium exchange of 13 with n-BuLi produced the 2-azapentadienyl anion 6 (R = CH3), which participated in a [π4s+π2s] cycloaddition reaction with phenyl vinyl sulfide to afford the spirocyclic pyrrolidine 14, which as coverted to 2,13-diepilepadiformine (or 2-epi-11-deoxycylindricine C) 17 by a sequence of steps involving oxidative cleavage of the propenyl side-chain, intramolecular reductive amination, and desulfurization.

An efficient synthesis of (±)-crinane using an intramolecular azide-olefin cycloaddition

Abstract Refluxing 3-(2-azidoethyl)-3-[3,4-(methylenedioxy)phenyl]cyclohex-1-ene ( 2 ) in toluene for 24 hours afforded 3a-[3,4-methylenedioxy)phenyl]-3,3a,4,5,6,7-hexahydro-2 H -indole ( 12 ) in quantitative yield. This reaction proceeds by intramolecular 1,3-dipolar cycloaddition of the azide onto the alkene followed by loss of nitrogen from the triazoline intermediate to give an imine. Reduction of the imine 12 with sodium cyanoborohydride in acetic acid/THF gave (3aR ∗ , 7aR ∗ )-3a-[3,4-methylenedioxy)phenyl]-2,3,3a,4,5,6,7,7a-octahydroindole ( 13 ). Warming 13 with Eschenmosers salt provided (±)-crinane ( 1 ). The synthesis of (±)-crinane ( 1 ) from cyclohexenone was accomplished in 8 steps in 23% overall yield.

APPLICATION OF THE 2-AZAALLYL ANION CYCLOADDITION METHOD TO AN ENANTIOSELECTIVE TOTAL SYNTHESIS OF (+)-COCCININE

A highly functionalized perhydroindole is formed by the intramolecular [π4s+π2s] cycloaddition of a 2-azaallyl anion with a vinyl sulfide [Eq. (a)]. This is the key step in the total synthesis of (+)-coccinine, the enantiomer of the Amaryllidaceae alkaloid (-)-coccinine.

Solid-phase synthesis of pyrrolidines via 2-azaallyl anion cycloadditions with alkenes

Abstract The preparation of a variety of highly substituted pyrrolidines was achieved by solid-phase synthesis through the [2 π s + 4 π s] cycloaddition of 2-azaallyl anions with alkenes. Resin-bound aldehydes 2 were condensed with α-amino stannanes 3 to afford (2-azaallyl)stannanes 4 . Transmetalation of 4 with n -BuLi in the presence of electron-rich alkenes followed by the addition of an electrophle provided the polymer-bound pyrrolidines 7 . The free pyrrolidines 9–23 were obtained upon cleavage from the solid support.

A synthesis of (+)-7-Epiaustraline and (−)-7-Epialexine

Reducttve cycliration of the aztdo epoxides 19a and 19/3followed by &protection afforded the HN rnkbttor (+)-7-eptatutraline 7 ar(d (-)-l-epialextne 9. The formatwn of 7 proceeded with an unusual tnverston of configuratton at C-7. Polyhydroxylated indolizidine alkaloids such as castanospermine 1 and swainsonine 2 have attracted considerable interest in recent years due to their ability to inhibit glycosidases.1 In addition to their use in the study of glycoprotein-processing enzymes, such alkaloids are promising anticancer and antrretrovnal agents. More recently, polyhydroxylated pyrrolizidine alkaloids with similar biological activities have emerged from the independent investigations of research teams in the U.K. and the U.S.A. The isolation of alexine 3 from Alexa leiopetala was reported in 1988.2 The isolation of similar alkaloids from Castanospetmwn australe quickly followed, including 3,7a-diepialexine (or 3-epiaustraline) 4,3,4 australine 5,5 I-epiaustraline (or 1,7a- dieptalexine) 6,6*7 and 7,7a-diepialexme (or 7-epiaustraline) 7 .7 While alexine 3 and 3-eptaustraline 4 are generally poor inhibitors of glucosidases and galactosidases,*,4 they display a m lo y g lucostdase inhibition which is on par with that of castanospermine,7 and alexine is an effective thioglucosidase inhibitor.8 Compounds 5-7 are also good amyloglucosidase inhibitors. 5,779 Australine 5 inhibits glucosidase I, but not glucosidase II,9 and has recently been shown to exhibit antiviral activity. 10 Modest glucosidase I, g-glucosidase, and rx-mannosidase inhibition was observed for I-epiaustraline 6.6 but it displayed good acttvity in a mouse gut digestive a- glucosidase assay, as did 7-epiaustmliie 7. 7.11 An exciting recent report shows that australme 5, l- epiaustraline 6, and 7-epiaustraline 7 inhibit HIV-induced syncytia formation in N cells1 1 The potential of the polyhydroxylated pyrrolizidine alkaloids as selective glycosidase inhibitors and as antiviral and antiretrovtral agents makes them attractive targets for synthesis. In particular, the ability to prepare alternative stereoisomers of these alkaloids would be desirable, since the biological activity of these compounds varies substantially with their stereochemistry. We wish to report our initial efforts in this area, which have led to the synthesis of the naturally occurring alkaloid (+)-7-epiaustraline 7 (also known as 7,7a_diepialexme) which shows anti-HIV

An intramolecular, Schmidt reaction of an alkyl azide with a carbocation. The generation and rearrangement of a conformationally restricted secondary aminodiazonium ion.

Treatment of azidoalkene2 with triflic acid produced the bridged bicyclic enamine3 by an intramolecular Schmidt reaction. Rearrangement of the intermediate aminodiazonium ion5 is completely regioselective.