Stereocontrolled Total Synthesis of (−)‐Stemaphylline

Abstract Homologation of readily available α‐boryl pyrrolidines with metal carbenoids is especially challenging even when good leaving groups (Cl−) are employed. By performing a solvent switch from Et2O to CHCl3, efficient 1,2‐metalate rearrangement of the intermediate boronate occurs with both halide and ester leaving groups. The methodology was used in the total synthesis of the Stemona alkaloid (−)‐stemaphylline in just 11 steps (longest linear sequence), with high stereocontrol (>20:1 d.r.) and 11 % overall yield. The synthesis also features a late‐stage lithiation–borylation reaction with a tertiary amine containing carbenoid.

Homologation through lithiation-borylation has emerged as ap owerful tool for the assembly of multiple stereogenic centers with high stereocontrol (Scheme 1A), [1] and the method has been applied in total synthesis,p articularly for acyclicp olyketide-type natural products. [2] Part of the power of the method stems from the ready availability of the coupling partners,n amely alcohols and boronic esters.T o significantly extend the reach of this chemistry to other classes of natural products,w ec onsidered its application to the synthesis of alkaloids,for example the Stemona family of alkaloids,alarge class of natural products featuring apyrrolo-[1,2-a]azepine moiety. [3] This would require the use of lithiation-borylation on nitrogen-containing boronic esters, ap rocess which ultimately required considerable development.
The Stemonaceae family of plants,f rom which the Stemona alkaloids have been isolated, have al ong history of use in China and East Asia as traditional remedies for arange of ailments including respiratory diseases and infection with parasitic worms.F or example,( À)-stemaphylline ((À)-1; Scheme 1B), exhibits significant insecticidal and antiparasitic properties, [4] and features the characteristic pyrrolo- [1,2a]azepine core as well as a g-lactone and five stereogenic centers,t hree of which are contiguous.( À)-Stemaphylline (À)-1 was recently synthesized (19 steps) but several steps showed poor stereocontrol and furthermore it was obtained as an inseparable mixture of diastereoisomers,a lthough the corresponding N-oxide was obtained in pure form. [5] Herein, we report the development of lithiation-borylation on nitrogen-containing boronic esters and its application to aconcise, stereocontrolled, and scalable total synthesis of (À)-1 from readily available building blocks.
Our retrosynthetic analysis (Scheme 1C)i nvolved disconnection of the C4 À C5 bond leading to the advanced intermediates,t riisopropyl benzoate (TIB) ester 3 and boronic ester 4.T he coupling of 3 and 4 was anticipated to test the utility of lithiation-borylation in late-stage assembly. Ester 3 could be constructed by ring-closing metathesis (RCM) from the allyl pyrrolidine 5.P yrrolidine 5 could then be traced back to the simple building blocks 6 and 7, [6] where at andem lithiation-borylation-Zweifel olefination [7] sequence would be used to assemble the three contiguous stereogenic centers C7 À C8 À C9 in asingle operation.
Ak ey step is the lithiation-borylation reaction between building blocks 6 and 7.Whilst potentially feasible,the use of a-amino boronic esters in homologation reactions is notoriously troublesome,a sd ocumented by Matteson [8] and Whiting [9] (Scheme 2A). [10] The N-Boc/N-Ac pyrrolidine ring is ar eluctant migrating group,e ven with exceptionally good leaving groups (Cl À ), leading to unwanted side-reactions and low conversions.E vidently,t he adjacent electron-withdrawing N-Boc group makes the migrating carbon much less nucleophilic. [11] Over the course of our investigations we have identified many reaction parameters that can be used to facilitate recalcitrant 1,2-metalate rearrangements and we were keen to evaluate if they could be applied to the N-Boc pyrrolidine system. As shown in Scheme 2B,lithiation of TIB ester 8 and electrophilic trapping with rac-7 gave the boronate complex 9,a sd etermined by 11 BNMR spectroscopy.U nsurprisingly,this intermediate proved to be stable under avariety of conditions including refluxing in Et 2 Oo ra ddition of the Lewis acid, MgBr 2 ·Et 2 O( entries 1a nd 2);n om igration occurred in either case.H owever,u nder more forcing conditions,w ef ound that treatment of 9 with MgBr 2 ·Et 2 O under reflux gave boronic ester 10,albeit in low yield (entry 3, 19 %). We have found that the solvent can sometimes affect the outcome of 1,2-metalate rearrangements and decided to perform as olvent screen. [12] This revealed that, in refluxing toluene,t he efficiencyo ft he 1,2-shift 9!10 improved dramatically and 10 was obtained in 67 %y ield (entry 4). Theyield was further improved by using CHCl 3 as the solvent (entry 5) which gave 10 in 85 %yield. By analyzing the rate of migration in TBME and CHCl 3 at various temperatures,w e constructed an Eyring plot which showed that the 1,2migration had ac onsiderably lower enthalpy of activation in CHCl 3 compared to TBME (28.7 vs.3 4.2 kcal mol À1 respectively;s ee the Supporting Information for details) indicating aspecific solvent effect. This is most likely to result from the enhanced Lewis acidity of Li + in the less coordinating solvent, [13] thereby promoting 1,2-migration.
With conditions established using racemic 7,e nantioenriched 7 (98:2 e.r.) [6,14] was homologated with lithiated TIB esters (+ +)/(À)-8a giving the syn and anti diastereoisomers of 11 in high yield and with very high levels of enantio-and diastereocontrol (Scheme 3). Matteson homologation of 7 (ClCH 2 Li)also benefited from solvent exchange,enabling 12 to be obtained in amuch improved 79 %yield without the use of further additives (compare Scheme 2A). TheC À Bbond of 7 could also be functionalized through Zweifel olefination [7] (13)ingood yield and complete stereospecificity.F inally,this strategy was extended to the 2-B(pin)-N-Boc-piperidine building block 15 which was again homologated with lithiated TIB-ester rac-8a to give 16 in excellent yield. Without solvent exchange to CHCl 3 ,this substrate also performed poorly (no 1,2-migration was observed after 24 hu nder reflux in Et 2 O) showing the general applicability of the new conditions.
With suitable conditions established for the key step,t he total synthesis of (À)-1 was pursued (Scheme 4). TIB ester 6 was prepared in two steps from commercially available diol 17,byselective TBDPS protection [15] and Mitsunobu esterification (70 %yield over 2steps). Building blocks 6 and 7 were then coupled in the first key lithiation-borylation reaction which gave 18 in 58 %y ield and 96:4 d.r.F ollowing Zweifel olefination, pyrrolidine 5 was obtained in 71 %y ield. Pleasingly,t hese two transformations could be carried out on agram scale and in aone-pot fashion, by adding the reagents sequentially,g iving 5 in an improved 70 %y ield (Scheme 3). With as hort and scalable method for the assembly of the three contiguous stereocenters of (À)-1,w em oved to the formation of the pyrrolo [1,2a]azepine core.Upon removal of the TBDPS group of 5,T IB ester 19 was formed under Mitsunobu conditions. N-Boc deprotection and alkylation with 4-bromo-1-butene gave diene 20 in 87 %y ield over two steps.T reatment of 20 with the Hoveyda-Grubbs secondgeneration catalyst in the presence of camphor sulfonic acid (CSA) [5] promoted the desired RCM. Then, by simply adding PtO 2 and ab alloon of H 2 to the crude RCM mixture,t he desired saturated bicycle 3 was obtained as as ingle diastereoisomer in as ingle operation and 80 %overall yield. [16] We were now in ap osition to examine the key and final late-stage lithiation-borylation reaction. However,t he lithiation of TIB ester 3 proved difficult;standard conditions [s-BuLi·(+ +)-sp (1.0 equiv), Et 2 O, 5h]w ith aM eOD quench returned starting material with no incorporation of deuterium. Unfortunately,i ncreasing the amount of base up to 3equivalents as well as changing the reaction solvent and temperature did not improve this step.Speculating that steric hindrance could be responsible for the poor result, we tested the less hindered chiral diamine ligand, (+ +)-sparteine surrogate [(+ +)-sps]. [17] With the aid of in situ IR spectroscopic monitoring (see the Supporting Information for details), we examined the lithiation of 3 with the s-BuLi·(+ +)-sps complex in various solvents,f ollowed by trapping with Me 3 SnCl (Scheme 5). Pleasingly,u sing CPME as the solvent and 3.0 equiv of s-BuLi·(+ +)-sps at À78 8 8Cg ave full lithiation in less than 1h,f urnishing stannane 27 in 92 %i solated yield (entry 5). Under the same conditions,but using (+ +)-sparteine instead of (+ +)-sparteine surrogate gave about 35 %lithiation (entry 6).
Having identified conditions for the asymmetric lithiation of 3,w et hen turned to the building block 4,w hich was prepared in two steps from alcohol 23 (2 steps from t-butyl acrylate) [18] through iodination (Appel, 89 %) and borylation (t-BuLi, i-PrOB(pin);69%). Forthe latter reaction, the use of in situ conditions (iodine-lithium exchange in the presence of i-PrOB(pin)) gave superior yields of 4 than the ex situ conditions.
With the final substrates 3 and 4 in hand, we turned our attention to the pivotal coupling.T hus,l ithiation of 3 and addition of boronic ester 4 led to immediate formation of aboronate complex as detected by 11 BNMR. Unfortunately, despite all our efforts (addition of Lewis acids and solvent exchange), we were not able to promote the 1,2-metalate rearrangement and the desired homologated product 2 could not be obtained. To determine whether there was an inherent problem with the use of boronic ester 4,itwas tested with the simple TIB ester 8 and smooth 1,2-metalate rearrangement occurred leading to the product in good yield. This demonstrated that in aless challenging situation boronic ester 4 can be employed in lithiation-borylation reactions (see the Supporting Information for details).
As boronic esters bearing electron-withdrawing functionalities (for example, 4 and 7)a re known to be poorer migrating groups, [19] we reasoned that the less oxygenated coupling partner 26 might perform better in our late-stage lithiation-borylation reaction. We then prepared building block 26 in one step from known iodide 25 [20] (3 steps from (S)-Roche ester) using the same procedure (96 %yield) as for preparing 4. [21] Gratifyingly,the lithiation-borylation coupling of 4 and 26 was successful and, after oxidation, the desired secondary alcohol 21 was obtained in 52 %y ield as as ingle diastereoisomer (Scheme 4). Subsequent silyl deprotection and selective oxidation of the primary alcohol [22] furnished the g-lactone functionality and completed the total synthesis of (À)-stemaphylline in 11 steps (longest linear sequence from commercially available diol 17)with full stereocontrol.
In conclusion, we have found conditions under which N-Boc a-boryl pyrrolidine 7 can be used in lithiation-borylation reactions and have employed this reaction in as hort stereocontrolled synthesis of (À)-stemaphylline.B ye xtending lithiation-borylation to including this readily available building block we have now opened up the method to not just polyketide-like natural products,b ut also to ar ange of alkaloid natural products as well.