Desymmetrization of C 2‐Symmetric Bis(Boronic Esters) by Zweifel Olefinations

Abstract anti‐Configured 1,3‐dimethyl deoxypropionate motifs are important sub structures in natural products. Herein, we describe a bidirectional approach for the rapid construction of natural products featuring such motifs by using C 2‐symmetrical 1,3‐bis(boronic esters). As for its application in convergent syntheses it was important to establish a selective mono‐Zweifel olefination we describe the scope and limitations by using different 1,3‐bis(boronic esters) and nucleophiles. This protocol takes advantage of the combination of the Hoppe–Matteson–Zweifel chemistry, which was elegantly put into practice by Aggarwal et al. In order to show its applicability the total syntheses of two natural products, serricornin and (+)‐invictolide, were performed.

Abstract: anti-Configured 1,3-dimethyl deoxypropionate motifs are important sub structures in natural products. Herein, we describe ab idirectional approach for the rapid constructiono fn atural products featuring such motifs by using C 2 -symmetrical 1,3-bis(boronic esters). As for its application in convergent syntheses it was importantt oe stablish as electivem ono-Zweifel olefination we describe the scopea nd limitations by using different 1,3-bis(boronic esters) and nucleophiles. This protocol takes advantage of the combination of the Hoppe-Matteson-Zweifel chemistry,which was elegantly put into practice by Aggarwal et al. In order to show its applicability the total syntheses of two naturalproducts, serricornin and (+)-invictolide, were performed.
In the context of our program to establish synthetic access to variousn atural products [1] we focused on those featuringt he 1,3-(poly)deoxypropionate motif. Polyketides and polyketidepeptideh ybrids featuring this motif like sambutoxin (1), borrelidin (2), (+)-kalkitoxin (3), and (+)-invictolide (4)a re challenging to synthesize without functional group interconversions by using established aldol chemistry ( Figure 1). [2] On the other hand, an elegant and rapid conceptf or the synthesis of those polydeoxypropionates is the so called assembly line synthesis developedb yA ggarwal and co-workers by using boronic esters. [3] This methodw as applied to the total synthesis of (+)-hydroxyphthioceranic acid, (+)-kalkitoxin (3), [2c] and many more natural products. [6] One advantage of this strategy,n amely the individual control of each chiral center,i s also ad rawbacka si tr equires al inear work flow and an iterative introduction of every single methylo rethyl group. [2c, 4] Based on this state of development and the fact that al arge varietyo fn atural products feature anti-configured1 ,3-dimethyl deoxypropionate motifs, we envisioned to use C 2 -symmetrical 1,3-bis(boronic esters) for the sequential Zweifelo lefination with different nucleophiles. The synthesis of such ap recursor was already described by the group of Aggarwal [5] and recently,A ggarwal and co-workerss ubjected this 1,3-bis(boronic ester) to ad ouble-sided vinylidene homologation. [6] However, our goal was to use this C 2 -symmetrical 1,3-bis(boronic esters) in desymmetrizing mono-Zweifel olefinations (Scheme1). [7] Scheme1.Desymmetrization of C 2 -symmetric 1,3-bis(boronic esters) by mono-Zweifel olefination (pin = pinacolato,TIB = 2,4,6-triisopropylbenzoyl, TMS = trimethylsilyl).   At the outset of our investigation we started by optimizing the reactionc onditions fort he addition of simple vinyl metal speciest ot he 1,3-bis(boronic ester) 5a [5] (Scheme 2). First transformationsw ith vinyl lithium [8] generatedy ields around 35 %, but duringt he upscaling process the yield dropped drastically to 10 %o rl ess (Scheme 2). Subsequently,v inylmagnesium bromide was used as the nucleophile [9] and the yields were around2 5%.W et hen furthero ptimized the mono-Zweifel olefination by adding iodine as as olid [10] and not as am ethanolic solution.T he subsequentm ethanola ddition was done with a very slow addition rate of 0.15 mL min À1 .T his variation gave satisfactory and reliable yields around 48 and 94 %b ased on recovered startingm ateriala nd works equally well for small and large scale reactions (for details see the Supporting Information). It should be pointed out that separation of the starting materiala nd the olefination product wase asily achievable upon standard column chromatography.
After havings uccessfully accomplishedt he addition of vinylmagnesium bromide we turned our attentiont oo ther olefins that could be useful intermediates in total synthesis (Scheme 2). For this we used but-1-en-2-ylmagnesium bromide [11] and obtained, by using the previously optimized conditions, the corresponding product 7a.A sw ew ill describe below,t his product can be easily converted to its corresponding ethyl ketone. We also investigated the addition of different lithiatede nol ethers, [8b, 9, 12] however,o nly the lithiated vinyl carbamate led to the desired Zweifel olefinationp roduct 7c.I n the beginning, we obtainedt he double-olefination product in favor of the mono-olefination but we overcame this problem by reducing the equivalents of the vinyl speciest oo nly 1.1 equivalents and obtained the desired mono-Zweifel product 7c in 73 %y ield. Beyond that, lithiated vinyl bromide was used as nucleophile giving us the versatile boronic ester 7b in 46 %y ield. Interestingly,a ll of these nucleophilesw ere more reactivet han vinylmagnesium bromide because unreacted startingm aterial could not be re-isolated. To show the utility of these products,m ono-Zweifel product 7c was subjected to an elimination under basic conditions affording alkyne 8.I n our case highery ields were observed when LDA (73 %) was used instead of tBuLi (41 %, Scheme 2). In both cases no epimerization was observed. [12] Alkyne 8 could be ap owerful intermediate in total synthesis after hydrometalation, cross-coupling or even additional hydroboration.
After examination of different nucleophiles we investigated structuralv ariations of the 1,3-bis(boronic esters, Scheme 3). The sterically demanding isobutyl and cyclohexylr esidues were well tolerated by the mono-Zweifel olefination, which is quite remarkable due to the steric hindrance next to the reaction center. [7, 8b] Boronic esters containing terminal double bonds( 6g-6h)c ould also be prepared in good yields. Due to their additional functionalities they could be valuable building blocks in total synthesis. Compounds 6i and 6j could also be synthesized by using the mono-Zweifel olefination, but partial epimerization was observed. In the case of boronic ester 6k we observed traces of the double-olefination product.
With ar eliable methodi nh and, we applied buildingb lock 6a to the total synthesis of (+)-invictolide (4)a nd serricornin (20). [2d-f, 13] (À)-Invictolide is one of the lactons usedf or the queen recognitiono ft he red fire ant Solenopsis invicta (Buren). [13] With its three methyl groups and the 1,3-anti-deoxypropionate motif (+)-invictolide (4)m atches perfectlyo ur synthetic strategy.I no ur retrosynthetic analysis (Scheme 4) we envisionedl actol formation ando xidation as the last steps, whereby the double bond of the Zweifel olefination functions as precursor for the carbonyl moiety.T he required secondary alcoholi nt he linear precursor 9 should be installed by lithiation-borylation chemistry from the mono-Zweifel product 6a and the TIB ester 10.T he corresponding alcohol could either be derived from 1-propylboronic acid pinacol ester (17)b ya ssembly line synthesis or by Myers alkylation by using auxiliary 14.Weonpurpose performed both routes in order to compare steps and yields and by doing so obtaining an assessment of both strategies.
Our synthesis started with the gram-scale preparation of the C 2 -symmetric 1,3-bis(boronic ester) 5a [5] by using as lightly modified protocol of the Aggarwal group (see the Supporting Information). The described mono-Zweifel olefination gave us boronic ester 6a in an overall yield of 45 % [14] (Scheme 5).
Comparison of the two different routes showed that the stereoselectivity was excellent (e.r.9 9:1) in both approaches. One step less is needed in the Myers route (three vs.f our) whereby the yields are within the same range. However,1 -propylboronic acid pinacol ester (17)i sa lso commercially available but Scheme4.Retrosynthetic analysis of (+)-invictolide (4).
Scheme3.Substrate scope of the mono-Zweifel olefination. All reactionsw ere run by using the optimized conditionso fS cheme 2. Yields refer to isolated products after flash column chromatography.The diastereomeric ratio (d.r.) was determined by 1 HNMR spectroscopy(brsm = based on recoveredstartingm aterial). quite expensive. However,i nt he case 17 is purchased three steps would be needed in both approaches. One drawback of the Myers route is the use of an auxiliary and the relatedl ow atom economy.A nother difference is the number of purification steps, with the Myers route requiring three and the assembly line approachr equiring two. Ap ractical disadvantage of the assembly line approach is the required very slow addition rate (20 mLmin À1 )o fnBuLi during the Matteson homologation.
However,w ith both fragments in hand, the fragment coupling by using lithiation-borylation chemistry was the next step. The obtained boronic ester was directlys ubjected to an oxidation giving us secondary alcohol 9 in good yield and high diastereoselectivity. [18] The subsequent two-steps equence consisting of ozonolysis [19] and  of the intermediately formed lactol finished the-to the best of our knowledge-shortestt otal synthesis of (+)-invictolide (4,Scheme7).
By using the same strategy we also accomplished the synthesis of serricornin (20), the female sex pheromone of the cigarette beetle Lasioderma serricorne. [21] TIB ester 18 was prepared by using established phase-transfer conditions. [5,22] Lithiation-borylation chemistry of boronic ester 7a with TIB ester 18 [5,22] and subsequento xidation gave us secondary alcohol 19 in 70 %y ield over two steps in a1 0:1d iastereomeric ratio. Finally,o zonolysis [19] provided serricornin (20)a samixture of its open-chain and hemiketal form (Scheme 8). [11] In summary,w ed eveloped ab idirectionala pproacht op olyketides or polyketide fragments featuring the 1,3-deoxypropionate motif. The key step in this approachi sadesymmetrization by using the mono-Zweifel olefination. We could show the value of key intermediates 6a and 7a in the syntheses of (+)-invictolide (4)a nd serricornin (20). Furthermore, ad etailed substrate scope showed the general applicability of the developed methodology.F inally,t he use of different nucleophiles enabless ynthetic access to av ariety of valuable building blocks.