the discovery and asymmetric 
 synthesis of novel polyketides and 
 their unnatural analogs fuel the development of new therapeutic agents . 

the structural complexity of this class of molecules has inspired 
 and tested synthetic organic chemistry .
woodward pioneered the use of cyclic stereocontrol followed by ring - opening 
 to reveal a single diastereomer of an acyclic target . for example , in the first synthesis of erythromycin a , 
 a dithiadecalin template was employed to control relative stereochemistry 
 of ensuing reactions ; subsequent ring - opening provided a highly substituted 
 acyclic polyketide .
this general strategy has been applied successfully 
 to the synthesis of many natural products .
ring - opening reactions of tetrahydrofurans and tetrahydropyrans 
 have been developed ; however , there are 
 few examples that occur with formation of a new csp  csp bond .
panek 
 and co - workers have achieved diastereoselective ring - opening reactions 
 of tetrahydropyrans with cyanide in the presence of a lewis acid ( scheme 1a ) . the stereochemical 
 course is consistent with a stereoablative reaction ; minimization 
 of a strain in a carbocation intermediate and 
 attack of cyanide on the least hindered face provides the major diastereomer .
a complementary approach to 
 control of relative stereochemistry 
 is via a stereospecific reaction , where stereochemical information 
 is conserved throughout the transformation .
hoveyda and co - workers 
 demonstrated that unsaturated cyclic ethers activated by pendant alcohols 
 undergo stereospecific sn2 reactions with grignard 
 reagents to yield enantioenriched acyclic products ( scheme 1b ) .
we sought to expand 
 stereospecific ring - opening reactions to include saturated cyclic ethers that are not activated by ring strain .
we envisioned stereospecific nickel - catalyzed ring - opening reactions 
 of cyclic ethers , based on our enantiospecific kumada - type cross - coupling 
 of ethers ( scheme 1c ) .
we anticipated that cross - coupling would proceed with inversion 
 at the electrophilic carbon .
therefore , by appropriate choice of diastereomer 
 of starting material 5 , either the syn or anti diastereomer 
 of 6 could be obtained selectively .
this work would harness 
 diastereoselective synthesis of tetrahydrofurans and tetrahydropyrans 
 to provide complex acyclic fragments .
the products would contain a 
 free alcohol that could be further utilized in synthetic sequences . 

this method would provide stereospecific incorporation of a benzylic 
 methyl substituent , a common motif in medicinal agents .
in addition , strategic use of extended alkyl 
 or aryl grignard reagents would allow for the generation of a wide 
 range of unnatural polyketide analogs for biological testing . in this 
 manuscript ,
we report the stereospecific kumada - type cross - coupling 
 of tetrahydrofurans and tetrahydropyrans with a range of grignard 
 reagents . we also report stereospecific negishi - type cross - coupling 
 reactions of benzylic lactones with dimethyl zinc to provide enantioenriched 
 carboxylic acids .
to establish 
 nickel - catalyzed ring - opening of cyclic ethers and determine the stereospecificity 
 of the reaction , we designed model substrate ( r)-7 based on our prior experience developing kumada - type cross - coupling 
 reactions of benzylic ethers .
we chose to first examine coupling with 
 methyl grignard reagent , as incorporation of  magic  

naphthyl - substituted 
 tetrahydropyran ( r)-7 is straightforward 
 to prepare in high enantiomeric excess ( ee ) utilizing the corey  bakshi 
we were pleased to see 
 that in the presence of a nickel catalyst and grignard reagent , ( r)-7 provided acyclic alcohol ( s)-8 with cross - coupling at the benzylic center ( scheme 2 ) .
the reaction was highly enantiospecific , providing 
 the product in 96% ee and > 99% enantiospecificity ( es ) .
no reaction occurs in the presence of grignard reagent in the absence 
 of nickel catalyst .
we envisioned that the most 
 powerful application of this method 
 would be in ring - opening reactions of heterocycles containing multiple 
 stereogenic centers . to test our hypothesis that the nickel - catalyzed 
 ring opening would occur with inversion at the electrophilic carbon , 
 irrespective of the presence of other stereogenic centers , we examined 
 both diastereomers of substituted tetrahydrofuran 9 . 
 in the presence of ni(cod)2 and
dpephos each diastereomer 
 underwent cross - coupling with clean inversion at the site of oxidative 
 addition ( scheme 3 ) .
tetrahydrofuran trans-9 ( dr > 20:1 ) 
 afforded acyclic anti-10 in 93% and 
 a dr of > 20:1 .
the other diastereomer , cis-9 ( dr > 20:1 ) , afforded syn-10 in 93% yield and >
the relative configuration of tetrahydrofuran cis-9 was determined by x - ray crystallographic 
 analysis .
the relative configuration of both diastereomers of acyclic 10 was assigned based on analysis of chemical shifts in the h nmr spectra , based on the pioneering strategy of kishi for 
 assignment of relative configuration of acyclic polyketide fragments 
 using the breit model for 1,3-deoxypropionates . to determine whether or not 
 there is a match / mismatch effect in 
 reactions employing chiral catalysts , we examined ring - opening of 
 both diastereomers of tetrahydrofuran 11 with each enantiomer 
 of binap ( table 1 ) .
if the reaction proceeds 
 strictly with inversion , regardless of the catalyst chirality , then 
 both enantiomers of binap would provide similar results in the ring - opening 
 reactions .
however , if the chiral catalyst influences the stereochemical 
 outcome of the cross - coupling reaction , then one enantiomer of binap 
 should provide diminished or inverted diastereoselectivity . in reactions 
 of tetrahydrofuran cis-11 both enantiomers 
 of binap afforded acyclic syn-12 in 
 similar yield and 20:1 dr ( entries 1 and 2 ) .
similarly , use of 
 either enantiomer of binap in reactions of trans-11 provided anti-12 in good 
 yield and 20:1 dr ( entries 3 and 4 ) .
therefore , we conclude that there 
 is no match / mismatch between the chirality of the catalyst and substrate . 

all reactions proceed strictly with inversion without influence by 
 the chirality of the catalyst .
these results are consistent with our 
 previous observations of robust substrate control in stereospecific 
 kumada and negishi coupling reactions .
we next examined 
 the application of the methodology to a series of substituted tetrahydrofurans 
 with a broad array of substituent patterns and stereochemical relationships 
 found in polyketides .
our starting materials 
 were 2-aryltetrahydrofurans , a motif at the core of natural products 
 such as the lignans sesaminone and pinoresinol .
as such , there are outstanding methods for diastereoselective 
 synthesis of highly substituted 2-aryltetrahydrofurans . furthermore , development of methods for their 
 direct derivatization could have application in natural product editing .
we prepared substrates using the general strategy 
 outlined in scheme 4 , employing lewis - acid 
 catalyzed cyclization of the requisite diols ( see si for full details ) .
this synthesis 
 typically provides access to both diastereomers , important for interrogation 
 of the influence of additional stereogenic centers on the stereochemical 
 course of the cross - coupling reactions .
the relative configuration 
 of starting materials and products could be assigned using well established 
 methods typically employed for polyketides , including noe experiments , 
 analysis of h nmr spectra , and x - ray crystallography .
we continued our studies with 
 2,4-disubstituted tetrahydrofurans , 
 as ring - opening provides the 1,3-dimethyldeoxypropionate fragment 
 ( e.g. , 9 to 10 , scheme 3 ) .
to determine the stereochemical course of the reaction , 
 we examined reactions of both diastereomers of tetrahydrofuran 11 ( table 2 , entries 1 and 2 ) . under kumada - type coupling conditions ,
tetrahydrofuran trans-11 ( dr > 20:1 ) afforded acyclic anti-12 in 82% and > 20:1 dr ( entry 1 ) .
the diastereomer , cis-11 , ( dr 9:1 ) gave syn-12 in 
 86% and 9:1 dr ( entry 2 ) .
rigorous assignment of the relative configuration 
 of the starting materials and products demonstrates that the kumada - type 
 couplings proceeded with inversion .
we next examined introduction 
 of a substituent at the 5-position , 
 to determine whether the method would be amenable to synthesis of 
 secondary alcohols .
both diastereomers of 2,5-disubstituted tetrahydrofuran 13 were synthesized by the stetter reaction , reduction of the ketones and diol cyclization .
tetrahydrofuran cis-13 ( dr 9:1 ) underwent cross - coupling in 
 82% yield with inversion to yield syn-14 ( dr 9:1 , entry 3 ) .
the diastereomer trans-13 ( dr 8:1 ) , afforded anti-14 with high stereospecificity and in a slightly lower yield of 61% 
 ( entry 4 ) .
this lower yield is presumably due to steric interactions 
 with the pseudo axial c5 methyl that would be present in the trans 
 diastereomer but not in the cis diastereomer .
vicinal methyl - bearing 
 stereogenic centers are motifs in natural 
 products such as kalkitoxin and nordihydroguaiaretic acid .
starting materials trans-15 and trans-17 were prepared 
 in 9:1 dr using the nozaki  hiyama 
kishi reaction as 
 a key step . using dpephos as the ligand , trans-15 afforded syn-16 in 65% yield and 9:1 dr ( entry 5 ) .
in addition to benzofuran - substituted 
 tetrahydrofuran 9 , benzothiophene - substituted trans-17 ( dr 9:1 ) afforded syn-18 in good yield and 9:1 dr ( entry 6 ) .
while coupling 
 reactions of both 15 and 17 proceed with 
 inversion , more modest yields are likely an impact of steric crowding 
 near the site of oxidative addition .
we examined 4-methoxytetrahydrofurans 
 for synthesis of a 1,3-disubstituted 
 ether unit as found in fk-506 and geldanamycin .
we found that methoxy - substituted tetrahydrofurans trans-19 and cis-19 underwent the reaction to afford good yields and excellent transfer 
 of stereochemical information ( entries 7 and 8) .
we attribute slightly 
 diminished yields with both diastereomers of 19 to formation 
 of an allylic ether via -hydride elimination , which further 
 reacted to a mixture of products under the reaction conditions .
reaction performed using dpephos 
 ( 10 mol % ) instead of rac - binap .
nap = 2-naphthyl . to further expand 
 the scope and utility of this method to include synthesis of 5-substituted 
 alcohols , we next turned our attention to tetrahydropyrans .
we chose 
 to examine cis-()-2,4-disubstituted tetrahydropyrans , 
 subunits of the calyxin family of natural products .
there are several 
 elegant methods for the diastereoselective synthesis of highly substituted 
 tetrahydropyrans .
for example , these 
 tetrahydropyrans are easily accessed by diastereoselective prins cyclization 
 reactions , as outlined in scheme 5a .
clay - mediated prins cyclization of 2-napthaldehyde 
 with 4-buten-1-ol in benzene provided cis-()-21 in a single step with high diastereoselectivity and reasonable 
 yield . ( a ) montmorillonite k10 ( 1.1 
 equiv ) , meoh , c6h6 , reflux , 18 h ; ( b ) p - tsa ( 1.0 equiv ) , mgbr2 ( 1.1 equiv ) , ch2cl2 , rt , 18 h ; ( c ) ni(cod)2 ( 10 mol 
 % ) , bathophenanthroline ( bphen ) ( 20 mol % ) , arb(oh)2 ( 1.2 
 equiv ) , kotbu ( 1.6 equiv ) , s - buoh , 
 60 c , 24 h. we developed an alternative 
 two - step diastereoselective strategy 
 to prepare tetrahydropyrans containing a broad range of aryl substituents 
 at the c4 position ( scheme 5b ) .
4-bromotetrahydropyran 22 is easily synthesized as a 2:1 mixture of diastereomers 
 under mild conditions via a mgbr2 and p - tsoh - promoted prins cyclization . to 
 further derivatize 22 , we employed a nickel - catalyzed 
 suzuki - type cross - coupling reaction .
based 
 on the seminal work of fu , we hypothesized that the coupling would 
 be stereoconvergent and afford the more stable diastereomer , cis-23 .
indeed , 
 cross - coupling of 22 with a range of commercially available 
 aryl boronic acids afforded a wide variety of 4-aryltetrahydropyrans 
 in high diastereoselectivity .
these results are consistent with a 
 stereoablative cross - coupling reaction that proceeds through a radical 
 intermediate , with a strong preference 
 for formation of the thermodynamic product .
the relative configuration 
 of these cis-2,4-diaryl tetrahydropyrans was assigned 
 by x - ray crystallographic analysis and noe nmr experiments ( see si for details ) .
as with the tetrahydrofuran 
 substrates , we examined the transfer 
 of stereochemical information in the cross - coupling reaction by comparing 
 the diastereomeric ratios of the starting materials to those of the 
 acyclic products .
we observed that employing a catalyst loading of 
 15 mol % resulted in good to excellent yields with high diastereomeric 
 ratios ( table 3 ) .
tetrahydropyran 21 ( dr > 20:1 ) afforded syn-24 in 84% 
 yield and > 20:1 dr ( entry 1 ) indicating the complete transfer of 
 stereochemical 
 information in the cross - coupling .
we found that both electron - rich 
 and electron - poor aryl substituents at the c4 position of the tetrahydropyran 
 are well tolerated in the reaction ( entries 2 and 3 ) . to further challenge 
 the tetrahydropyran ring - opening
for example , the cross - coupling 
 of tetrahydropyran cis-29 proceeded 
 in 81% yield and >
1,4-benzodioxanes are present 
 in a range of pharmaceutical agents such as piperoxan and idazoxan .
we were also pleased to see that 3-furan - substituted 
 tetrahydropyran cis-31 was well tolerated 
 in the reaction .
product syn-32 was 
 formed in high yield and dr and contains a furan substituent that 
 can be readily derivatized by oxidation or cycloaddition reactions 
 ( entry 5 ) .
reaction performed 
 using ni(acac)2 ( 10 mol % ) and dpephos ( 10 mol % ) instead 
 of rac - binap .
, we examined 
 kumada coupling of 2,4,6-trisubstituted tetrahydropyran cis-33 . subjecting cis-33 to the reaction conditions afforded the secondary alcohol syn-34 , containing three stereogenic centers , 
 as a single diastereomer and with good yield ( entry 6 ) .
this strategy 
 provides a modular three - step synthesis of polyketide analogs where 
 substituents in the c2 , c4 , and c6 positions can be easily altered 
 by the use of commercially available aldehydes , arylboronic acids , 
 and homoallylic alcohols , respectively .
we set out to determine 
 the compatibility of the reaction conditions 
 with silylethers , common protecting groups .
4-hydroxytetrahydropyrans 
 are straightforward to prepare in high diastereoselectivity by prins 
 cyclization employing trifluoroacetic acid .
using dpephos , we found that benzofuran- and benzothiophene - substituted 
 tetrahydropyrans 35 and 37 afforded the 
 acyclic products in good yields and > 20:1 dr ( entries 7 and 8) . 
 to 
 further challenge the ring - opening reaction , we employed a substrate 
 activated by a simple aromatic substituent .
3-furan - substituted tetrahydropyran cis-39 formed syn-40 in high yield and > 20:1 dr ( entry 9 ) .
the ability of a synthetic method 
 to easily provide access to analogs with a range of substituent patterns 
 is critical for the discovery of new therapeutics as well as for conducting 
 structure  activity relationship ( sar ) studies .
we next wanted 
 to examine the scope with respect to the transmetallating agent , which 
 would provide access to a variety of benzylic substituents in the 
 acyclic products .
our laboratory has recently demonstrated that ni(dppe)cl2 is a broadly applicable catalyst for cross - coupling of alkyl 
 and aryl grignard reagents with benzylic ethers . to examine the generality of conditions for a range of 
 grignard reagents , we applied this catalyst system to the cross - coupling 
 reactions of a representative series of tetrahydropyrans and tetrahydrofurans 
 ( table 4 ) .
cross - coupling with tetrahydrofuran 19 afforded the desired 
 product in 75% yield and high dr ( entry 1 ) .
3-phenylpropylmagnesium 
 bromide reacted smoothly with tetrahydropyran 37 to form 
 alcohol 42 in good yield and high dr ( entry 2 ) .
phenylmagnesium bromide underwent successful cross - coupling 
 with tetrahydrofuran 9 and tetrahydropyran 21 ( entries 3 and 4 ) . in order to confirm that the reaction proceeded 
 with inversion at the benzylic position , both trans-19 and cis-19 were prepared 
 and subjected to the kumada couplings with phenylmagnesium bromide . 

as with methylmagnesium bromide , the products were afforded in good 
 yield and in high dr ( entries 5 and 6 ) .
the relative configurations 
 of anti-45 and syn-45 were assigned by the preparation of crystalline derivatives 
 that were subjected to x - ray crystallographic analysis ( see si for details ) .
products 46 and 47 were formed in high yield and dr ( entries 7 and 8 , respectively ) .
we have previously demonstrated 
 that diarylalkanes containing a 
 thiophene moiety provide lead compounds with selective anti - breast 
 cancer activity .
we therefore also examined 
 our methodology with 2-thiophenylmagnesium bromide as the nucleophile . 
 with both 2,4-disubstituted
tetrahydropyran 21 and tetrahydrofuran 11 the desired product was afforded in excellent yield and 
 dr ( entries 9 and 10 ) .
we hypothesized 
 that a similar cross - coupling could be applied to benzylic lactones , 
 based on our recently reported negishi - type nickel - catalyzed cross - coupling 
 of benzylic esters .
sawama and co - workers 
 have recently demonstrated that aryl substituted lactones undergo 
 lewis acid - catalyzed ring - opening with allylsilane
. however , to the best of our knowledge , stereoselective 
 ring - opening of lactones with carbon - based nucleophiles has not been 
 reported . as a further benefit ,
the resulting 
 enantioenriched product would contain a benzylic stereocenter with 
 a distal carboxylic acid .
as with the alcohols obtained from the kumada - type 
 opening of cyclic ethers , this carboxylic acid affords a convenient 
 synthetic handle that can be used for further derivatization .
we prepared 
 enantioenriched lactones for cross - coupling by cbs reduction of the 
 benzylic ketones and cyclization of the corresponding 1,5-diols .
the absolute configuration of the lactones were 
 assigned as r by the accepted cbs model of selectivity 
 of the intermediate alcohols ( see si for 
 details ) . after examining a series of 
 bidentate ligands and nickel precatalysts
, we determined that ni(acac)2 and xantphos afforded the highest yield of cross - coupled 
 carboxylic acid .
commercially available 
 lactone 50 afforded the cross - coupled product with excellent 
 es ( table 5 , entry 1 ) , as did benzofuran - substituted 
 lactone 52 and indole - substituted lactone 54 ( entries 2 and 3 , respectively ) .
furan - substituted -valerolactones 
 such as 56 are found in natural products such as ricciocarpin 
 a and salvinorin 
 b ; methods for their ring - opening would 
 provide a strategy for synthesis of analogs for biological testing .
we anticipated that lactone 56 would 
 undergo straightforward nickel - catalyzed negishi - type cross - coupling . 

our laboratory has observed a strong dependence of the rate of cross - coupling 
 on the identity of the aryl substituent .
we hypothesize that arenes 
 possessing lower aromatic stabilization energy are better ligands for the nickel catalyst and stabilize 
 the transition state for oxidative addition .
benzylic ethers and esters 
 activated by extended aromatic rings such as naphthalene and benzofuran 
 are sufficiently reactive , as are those activated by furan .
furthermore , the incorporation of the furan 
 moiety affords a product with two functional group handles : the carboxylic 
 acid and the furan itself .
therefore , 
 we evaluated a 3-furan - substituted lactone and found that ( r)-56 underwent the cross - coupling with 84% 
 yield and > 99% es ( table 5 , entry 4 ) . to take advantage of the furan s utility for further manipulations
, 
 we derivatized product ( s)-57 by a diels  alder 
 reaction ( scheme 6 ) .
the cycloaddition furnished the enantioenriched bicyclic acid 58 in 64% yield as a 1:1 mixture of diastereomers .
based on 
 woodward s analysis of the thermodynamic product of the reaction , 
 the diels  alder reaction is anticipated to be highly exo selective . yield determined by h nmr based on comparison to phtms 
 as internal standard .
dyslipidemia , a serum 
 lipoprotein level disorder , is implicated in 
 cardiovascular diseases and is often treated with niacin .
anti - dyslipidemia agent 61 was 
 disclosed as part of a campaign for discovery of niacin receptor agonists 
 with reduced side effects .
amide 61 was previously synthesized in seven steps and used chiral 
 chromatography to separate the enantiomers .
( a ) ni(acac)2 ( 10 
 mol % ) , xantphos ( 20 mol % ) , znme2 ( 3.0 equiv ) , phme , rt , 
 24 h ; ( b ) ( i ) ( cocl)2 ( 1.3 equiv ) , c6h6 , rt , 2 h ; ( ii ) anthranilic acid ( 1.1 equiv ) , c6h6 , rt , 3 h. we applied our methodology 
 to the asymmetric synthesis of niacin 
 receptor agonist 61 from commercially available lactone 
 ( r)-59 ( scheme 7 ) . utilizing our optimized cross - coupling 
 conditions , carboxylic acid ( s)-60 was 
 afforded in 76% yield with > 99% es . a subsequent amide coupling 

therefore , using our method either enantiomer 
 of anti - dyslipidemia agent 61 can be prepared in two 
 steps and 57% overall yield from commercially available starting material .
in summary , we have developed the nickel - catalyzed , 
 stereospecific 
 ring - opening cross - coupling reactions of aryl - substituted tetrahydrofurans , 
 tetrahydropyrans , and lactones . through judicious choice of starting 
 materials , cyclic ether intermediates have been utilized to set the 
 desired relative stereochemical relationships and allow for the selective 
 synthesis of syn- and anti- deoxypropionate 
 subunits .
we have demonstrated the high stereospecificity of the reaction , 
 where the dr of the product matches the dr of the starting o - heterocycles . 

the negishi - type cross - coupling of benzylic lactones has allowed for 
 the enantiospecific synthesis of enantioenriched carboxylic acids , 
 which can be further derivatized . using this methodology ,
we report 
 the two - step , enantiospecific synthesis of an anti - dyslipidemia agent 
 with easy access to either enantiomer .
we are currently investigating 
 the application of these methods toward the implementation of natural 
 product editing to generate a library of unnatural polyketides for 
 sar studies .
 the 
 stereospecific ring - opening of o - heterocycles to provide acyclic 
 alcohols and carboxylic acids with controlled formation of a new c  c 
 bond is reported . 
 these reactions provide new methods for synthesis 
 of acyclic polyketide analogs with complex stereochemical arrays . 
 
 stereoselective synthesis of the cyclic template is utilized to control 
 relative configuration ; subsequent stereospecific nickel - catalyzed 
 ring - opening affords the acyclic product . 
 aryl - substituted tetrahydrofurans 
 and tetrahydropyrans undergo nickel - catalyzed kumada - type coupling 
 with a range of grignard reagents to furnish acyclic alcohols with 
 high diastereoselectivity . 
 enantioenriched lactones undergo negishi - type 
 cross - coupling with dimethylzinc to afford enantioenriched carboxylic 
 acids . 
 application in a two - step enantioselective synthesis of an 
 anti - dyslipidemia agent is demonstrated . 