our synthetic strategy ( figure 2 ) , inspired by stork s elegant synthesis of reserpine , targets a variety of yohimbinoid alkaloid natural products from the elaboration of pentacycles related to 15 , which vary only in the indole moiety .
pentacycle 15 could in turn arise from aminonitrile 16 , where careful tuning of the reaction conditions would enable cyclization to either series of c(3 ) epimeric natural products .
the aminonitriles related to 16 would arise from a condensation / strecker sequence with a common intermediate aldehyde ( 17 ) and the requisite amine derivative .
aldehyde 17 was expected to arise from oxidative cleavage of hydrindanone 18 , which could be constructed from a diels - alder reaction between diene 19 and enone ester 20 .
this cycloaddition would set four contiguous stereocenters , leaving only the c(3 ) stereocenter to be set at a later stage .
our synthetic studies commenced with readily available diene 19 ( figure 2 ) and enone ester 20 .
heating the mixture of these two compounds in toluene at 100 c afforded hydrindanone 18 in 89% yield as a > 10:1 ratio of the endo : exo diastereomers ( endo assignment is in reference to the more electron withdrawing ketone moiety ) , which were readily separated by column chromatography .
of note , the enantiomers of the endo adducts can be readily separated on a preparatory scale using supercritical fluid chromatography and a chiral odh column ( for further details , see the supporting information ) . while access to 18 sets the stage for preparing the natural products in enantioenriched form , the syntheses reported herein were carried out in racemic form .
hydrogenation of 18 , silyl ether cleavage and sulfonation of the resulting primary alcohol group yielded benzenesulfonate 21 in 82% yield over three steps . at this juncture ,
treatment of aldehyde 17 with potassium cyanide in the presence of various tryptamine derivatives then furnished the desired aminonitriles ( 16a - c ) as single diastereomers and in excellent overall yields .
the relative stereochemistry of the 4-ome tryptamine aminonitrile was unambiguously established by x - ray crystallographic analysis ( see ortep 16b , figure 2 ; some hydrogen atoms removed for clarity ) .
substrates 16a - c were subjected to pictet - spengler cyclization conditions ( table 1 ) , with special attention paid to the role arene nucleophilicity plays in both the rate and stereoselectivity of the pentacycle formation .
consistent with the elegant studies of the stork group , treatment of aminonitriles 16a - c with hydrochloric acid ( 0.1 m in thf ) at 23 c resulted in exclusive formation of the -diastereomer ( i.e. , 23a - c ; see entries 1 - 3 ) for all substrates .
the relative stereochemistry was unambiguously assigned for substrate 23b by x - ray crystallographic analysis ( see ortep , table 1 ; some hydrogen atoms removed for clarity ) .
more surprising , however , was that the inherent diastereoselectivity of the thermal pictet - spengler cyclization ( heating to 160 c in acetonitrile ; method b in table 1 ) of the substrates was greatly influenced by the nature of the indole fragment ( see entries 4 - 6 ) .
tryptamine - derived aminonitrile 16a cyclized upon heating in acetonitrile to afford a 1:3 ( : ) mixture of diastereomers , whereas 4-methoxytryptamine substrate 16b and 6-methoxytryptamine substrate 16c cyclized to give a 1:1.8 ( : ) and 1:8 ( : ) mixture of diastereomers , respectively . of note ,
the latter observation is in line with the observed diastereoselectivity for the thermal cyclization of aminonitrile 3 in refluxing acetonitrile reported by stork . because several yohimbinoid natural products possess the indole substitution pattern present in 16a and 16b , the stereoselectivities for these cyclizations needed to be improved if a versatile approach to the yohimbinoid natural products was to be realized .
as such , we embarked upon a campaign to optimize the diastereoselectivity of the pictet - spengler cyclization under thermal conditions ( i.e. , method b ) and chose to focus on substrate 16b as it represented the most challenging selectivity scenario
. stork has previously proposed the formation of a tight ion pair between the departing cyanide and forming iminium ion under thermal pictet - spengler conditions for aminonitriles , which leads to attack of the arene nucleophile from the -face ( see 2624b , figure 3 ) . on the basis of this analysis , we reasoned that a solvent with a lower static permittivity ( dielectric constant ) would lead to tighter ion pairing and further enhance the diastereoselectivity of the cyclization . in an initial investigation of solvent effects ( entries 3 - 7 , table 2 ) , only acetonitrile and isopropanol , among solvents of similar polarity , provided the desired diastereomer ( 24b ) as the major product , suggesting a more participatory role of the solvent .
several mechanistic possibilities that may exist are shown in figure 3 . in one scenario ,
an acetonitrile solvent molecule could engage iminium ion 26  to form a different electrophilic species ( see 27 or 28 , figure 3 ) that could then be displaced by the indole moiety in a direct intramolecular sn2-like process . as a probe for this mechanistic possibility , nucleophilic additives such as dmap and imidazole were investigated .
gratifyingly , heating aminonitrile 16b to 160 c in the presence of dmap in toluene led to reversal of the stereoselectivity ( from a 1.8:1.0 d.r .
( : ) for the thermal cyclization without additives in toluene ; entry 7 , table 2 ) to favor the  diastereomer ( 1:2 d.r .
( : ) ; entry 10 , table 2 ) relative to cyclization in the absence of additives ( 1:1.8 d.r .
upon addition of a stronger nucleophile ( in the form of nai ; entry 11 , table 2 ) , a greater than 1:10 d.r .
although the mechanism of the thermal pictet - spengler cyclization and the role of the iodide additive is still unclear , it may be that rapid exchange of the cyanide for the iodide occurs to produce a reactive iodo species ( analogous to 16b , figure 3 ) . at this juncture
, iminium ion 27 could begin to form with the much larger iodide serving as an intimate counteranion and effectively blocking the -face and leading , overwhelmingly , to the -diastereomer ( 24b ) as the major product .
computational studies are currently underway to provide insight on the observed diastereoselectivities of the pictet - spengler reaction as well as the role of additives such as nai . with optimized cyclization conditions leading to either c(3 ) epimer in hand , all that remained to complete the synthesis of venenatine ( 9 ) and alstovenine ( 12 ) was removal of the allyl ester by deallylation / decarboxylation and cleavage of the benzyl ether in 23b and 24b ( figure 4 ) .
toward this end , we have found that treatment of ester 23b with a pd(ii ) precatalyst under neutral conditions and elevated temperature facilitates conversion to the desired monoester ( 29 ) along with some elimination of the benzyloxy group to give an enoate ( 30 ) .
hydrogenolysis of the benzyl ether in 29 to give venenatine ( 9 ) was fraught with its own challenges .
neither increasing the h2 pressure ( up to 200 psi ) nor using acid additives resulted in the desired benzyl ether cleavage . however , treatment of 29 with bbr3 at low temperature selectively cleaved the benzyl ether , leaving both the methyl ester and methyl ether intact , to afford venenatine ( 9 ) in 60% yield .
the stereochemical assignment of the methyl ester group was determined by noesy studies ( for further details , see supporting information ) .
interestingly , in the case of alstovenine the use of the deallylation / decarboxylation conditions employed for venenatine pentacycle 23b led only to recovered starting material and the product of -hydroxy elimination .
this undesirable outcome could be circumvented through the use of a more homogenous catalyst system ( pd2dba3 , pyrrolidine ) to afford 31 .
lastly , bbr3 promoted cleavage of the benzyl ether yielded alstovenine ( 12 ) . while the spectroscopic data for synthetic and natural alstovenine were in reasonable agreement , we were surprised to observe some large inconsistencies ( > 4.8 ppm ) when the c data for synthetic venenatine was compared with that reported for the isolated natural product , especially given the support for our assignment by x - ray and noesy analysis of key intermediates . in an effort to identify the origin of these discrepancies , computational predictions for the c nmr chemical shifts of 9 were undertaken since all attempts to obtain an authentic sample for comparison failed . in general , the computed predictions for the c nmr chemical shifts ( calculated at the smd(chloroform)-mpw1pw91/6 - 311+g(2d , p)//b3lyp/6 - 31+g(d , p ) level with linear scaling ; for complete computational details see the supporting information ) were found to be in better agreement with our synthetic data ( mean absolute deviation ( mad ) of 1.37 ppm ) than with the isolation data ( mad of 1.85 ppm ) . furthermore , the computational predictions identified two c resonances ( at 104.3 ppm and 31.0 ppm ) from the isolation data as outliers ; both deviating by 5.0 ppm or more from the computational data ( a complete line listing comparison can be found in the supporting information ) .
importantly , the outlier at 104.3 ppm reported in the c data for isolated venenatine , which was one of the resonances that differed markedly from our synthetic c data , also varies significantly from the corresponding c resonances reported for closely related congeners including alstovenine , 16-epi - alstovenine , 16-epi - venenatine , and 9-methoxy-3-epi--yohimbine , which are all in line with our synthetic data .
while no conclusive statement can be made regarding the origin of this discrepancy , it is possible that the reported data for isolated venenatine may have been mistabulated . in summary , we have identified , an effective , general path to the syntheses of a subset of yohimbinoid alkaloids that are epimeric at c(3 ) .
this work , which has resulted in the first total syntheses of the alkaloids venenatine and alstovenine in racemic form , builds on important observations by stork pertaining to aminonitrile pictet - spengler cyclizations .
key to the success of our synthetic studies was the identification of conditions to effectively control the diastereoselectivity of a late - stage pictet - spengler cyclization employing a variety of indole nucleophiles .
highlights from this study include : 1 ) the use of a hydrindanone intermediate 18 , which allows rapid , stereoselective synthesis of the yohimbinoid skeleton , 2 ) the discovery that nucleophilicity of the indole moiety plays a significant role in the inherent diastereoselectivity of the pictet - spengler cyclization , and 3 ) the addition of an exogenous nucleophile ( nai ) that leads to the complete reversal of the diastereoselectivity in the installation of the c(3 ) center .
 
 the yohimbinoid alkaloids have received considerable attention from the synthetic community due to their interesting chemical structures and varied biological activity . 
 although there have been several elegant syntheses of certain members of this group of alkaloids , a truly unified approach has yet to be developed . in short , general approaches to this compound class 
 have been hampered by a lack of complete control in setting the c(3 ) stereocenter at a late stage . 
 herein , we report that a functionalized hydrindanone enables a divergent strategy that builds on precedent from stork , which addresses this long standing challenge . utilizing an aminonitrile intermediate , the stereochemistry at c(3 ) of the yohimbinoid skeleton can be effectively controlled in a pictet - spengler reaction . 
 this approach has been applied to the first total syntheses of the c(3 ) epimeric natural products venenatine and alstovenine . 
Results and discussion
Supplementary Material