-chiral ethers are present in many natural products , biologically active molecules and synthetic intermediates.1 therefore , much effort has been directed towards efficient routes to enantiomerically enriched chiral ethers through allylic etherification reactions.2 within this context , there is currently ongoing interest in utilising unactivated allylic alcohol electrophiles in transition - metal - catalysed allylations of various nucleophiles,3 as the use of unactivated allylic alcohol electrophiles reduces the number of synthetic steps required ( by virtue of not requiring prior derivatisation ) and minimises byproduct formation . in terms of asymmetric intermolecular etherifications , a recent notable advance by carreira et  al
. uses ir catalysis to effect allylic etherifications on secondary allylic alcohols through formal sn2 selectivity.4 one of the key research efforts within our group has been to develop gold - catalysed5 regioselective methods towards allylic ethers6 and allylic thioethers.7 within this context , we recently developed a mild and air - stable gold(i)-catalysed direct allylic etherification of allylic alcohols.8 this dehydrative formal sn2 procedure9 requires neither the allylic alcohol electrophile nor the alcohol nucleophile to be activated ( either to install a leaving group in the former or form an alkoxide in the latter ) , leading to mild reaction conditions that are tolerant of various functional groups as well as air and moisture ( scheme  1  a).3a ,  10 we were keen to extend this methodology to asymmetric methods by investigating various chiral , non - racemic -substituted substrates , which should be amenable to chirality transfer . in theory , an enantioenriched chiral allylic alcohol with -substitution
( e.g. , 4 , scheme  1 ) , which is easily accessible in good enantioselectivities by sharpless kinetic resolution11 or enzyme resolution,12 should be able to transfer its chirality13 to the allylic ether product 5 , especially if a 6-membered ring hydrogen - bonded intermediate i is involved ( scheme  1  b ) .
access to chiral , non - racemic ,-disubstituted allylic ethers such as 5 from unactivated alcohols also nicely complements recent ir - catalysed allylation methods by carreira et  al.,4a which are confined to formation of unsubstituted secondary allylic ethers ( r = h ) .
it should be noted that shortly after our initial communication,8a mukherjee and widenhoefer disclosed an independent report on the same reaction.14 using a different set of catalysts and conditions , they carried out a substrate - scope study on the racemic reaction .
in addition , they also elegantly show one example of a chirality - transfer reaction ( see below ) .
however , as the substrate scope of their chirality - transfer reaction was not reported and there was room for improvement with regards to the regioselectivity ( 5:1 of formal sn2/sn2 5/6 ) , we decided that it was still important to continue with our independent studies .
these are reported here , and include optimisation to give greatly improved regioselectivities , full substrate - scope studies and experimental and computational mechanistic investigations .
our investigation began with the optimisation of reaction conditions to improve the regioselectivity for allylic etherifications , using secondary allylic alcohol 4  a as a model substrate ( table  1 ) .
our previously reported conditions provided a poor 2:1 ratio of formal sn2/sn2 ( 5  aa/6  aa , entry  1 ) , which needed to be improved drastically before chirality transfers could be investigated . during our optimisation
, we discovered that addition of molecular sieves ( ms ) to the reaction mixture greatly improved the selectivity , exclusively yielding the formal sn2 product 5  aa ( entries  28 ) . 3 
 ms provided slightly higher yields compared to 4   ms ( entry  2 vs. entry  5 ) , however , the yields were modest when only 5  mol  % of gold catalyst was employed ( 42  % and 56  % , respectively ) .
portion - wise addition of gold catalyst ( 25  mol  % ) greatly improved the yields ( entries  3 and 6 ) , but addition of another portion of molecular sieves makes little difference ( entry  3 vs. entry  4 ) .
finally , as a compromise between shorter reaction times and acceptable yield , we settled for the protocol shown in entry  8 as our optimised conditions for investigating the chirality - transfer reaction . note that under these newly optimised conditions , the formal sn2 product 5 is formed exclusively for all subsequent substrate - scope screens ( tables  2 and2 , 3 ) .
[ a ] isolated yields . 5/6 and e / z ratios determined by h  nmr analysis . with these optimised conditions in hand , we turned our attention to effecting chirality transfer in etherifications of a range of enantioenriched allylic alcohols ( table  2 ) . for this assay , alcohol 2  b was chosen as the nucleophile for ease of chiral stationary phase ( csp)-hplc enantiomer separation in the product .
gratifyingly , our first attempt with enantioenriched n - butyl allylic alcohol ( r)-4  a gave the desired product ( e)-5  ab in 88:12  e.r . from > 99:1  e.r .
alternatively , starting with ( z)-allylic alcohol 4  b , the opposite enantiomer of the product could be obtained with good transfer of chirality ( entry  2 ) .
it should be noted , however , that the z - allylic alcohol starting materials ( e.g. , 4  b , entry  2 ) are more difficult to access in high e.r . , resulting in poorer e.r . of product 5  bb , despite displaying a good degree of chirality transfer ( 81:1976:24  e.r . ) . reversing the substituents at the - and
-positions of the allylic alcohol similarly gave high yield of product 5  cb with a high degree of chirality transfer ( entry  3 ) .
replacing the n - butyl substituent with the sterically more demanding cyclohexyl also works well with the cy at the -position , but only moderately at the -position ( entries  45 ) . to verify that a more sterically hindered substituent at the -position causes a drop in chirality transfer , allylic alcohol 4  f , with an ipr at the -position was investigated .
indeed , moderate chirality transfer of > 99:177:23  e.r . is observed ( entry  6 ) .
[ c ]  determined by csp - hplc . [ d ]  e.r .
benzyl - substituted allylic alcohol 4  g provided the best result in this assay , with excellent chirality transfer ( > 99:199:1  e.r . ) and > 20:1 e / z observed ( entry  7 ) . replacing the benzyl in 4  g ( entry  7 ) with a ph substituent ( 4  h ,
entry  8) causes a drastic change ( racemic product 5  hb ) . unlike with alkyl substituents ( entries  1 vs. 3 and entries  4 vs. 5 )
, swapping the ph substituent around now forms the same product ( 4  i5  hb , entry  8) , so aryl substituents appear to be detrimental to both chirality transfer and formal sn2 selectivity .
next , we decided to compare our procedure with substrate 4  j , which was the substrate chosen by widenhoefer et  al . in their studies
( entry  9).14 the chirality transfer is once again excellent ( 99:198:2  e.r . ) .
it should be noted that using our newly optimised conditions , etherification proceeds with significantly higher formal sn2 selectivity ( > 20:1 vs. 5:1 formal sn2/sn2 ) .
certain substituents on the allylic alcohol substrate were found to cause the chirality transfer to proceed moderately to poorly ( entries  1013 ) .
for example , dimethyl allylic alcohol 4  k gave a high degree of racemisation ( 71:29  e.r .
; likewise , increasing the steric bulk of the substituent at the alcohol centre to tert - butyl alcohol 4  l also led to some racemisation during reaction ( entry  11 ) .
substrates with -substituents performed the worst : 4  m and 4  n both give excellent > 20:1 e / z ratios , but almost complete racemisation under these conditions ( entries  1213 ) and are therefore not suitable substrates for chirality transfer . we next turned our attention to investigating the tolerance of a range of different nucleophile alcohols by using model allylic alcohol substrate ( r)-4  a ( table  3).15 although para - bromobenzyl alcohol 2  d ( entry  3 ) gave a comparable result to the original nucleophile alcohol 2  b , benzyl alcohol 2  c and para - methoxybenzyl alcohol 2  e yielded products 5  ac and 5  ae , respectively , with a greater degree of chirality transfer ( 97:3  e.r .
, entry  4).16 furfuryl alcohol 2  f was also tolerated , though with a reduction of enantioenrichment in product 5  af ( entry  5 ) .
we then turned our attention to alkyl alcohols . extending the alkyl chain of benzyl alcohol by two methylene units preserved yield , formal sn2/sn2 and e / z alkene selectivity as well as chirality - transfer efficiency ( entry  2 vs. entry  6 ) .
pleasingly , trifluoromethyl substitution of the nucleophile was tolerated ( entry  7 ) as were haloalkanes ( entry  8) and unprotected terminal alkenes ( entry  9 ) . when utilising diol 2  k , reaction occurred exclusively through the primary alcohol to give 5  ak in high yield and selectivity ( entry  10 ) .
acid - labile groups such as acetals 2  l and 2  m were also found to be compatible with the reaction ( entries  11 and 12 ) .
finally , we demonstrated that the reaction also proceeds very well ( > 99:1  e.r . ) using a more hindered secondary nucleophile alcohol such as cyclohexanol 2  n ( entry  13 ) .
values determined by h  nmr analysis . [ b ]  determined by csp - hplc of a derivative .
[ c ]  determined by csp - hplc . [ d ]  determined by chiral shift h  nmr spectroscopy . [ e ]  determined by csp - gc . [ f ]  using allylic alcohol ( s)-4  j , > 99:1  e.r .
the mechanism that we originally proposed for the allylic etherification reaction8a can also account for the chirality transfer and stereospecificity of the reaction ( scheme  1 ) . as gold(i ) is an excellent -lewis acid,5e it is likely to activate the alkene functionality in the allylic alcohol towards attack by an external alcohol nucleophile ( i , scheme  2).10f demetallation and elimination of water ( enabled by intramolecular hydrogen - bonding , ii ) will then regenerate the catalyst and produce the desired allylic ether product 5 .
a tightly bound chair - like 6-membered ring transition state17 is required for efficient chirality transfer , and also accounts for the stereospecificity of the e and z isomers . as shown in scheme  1  a , the e isomer has its substituent r in the equatorial position , whereas the z isomer has r axial ( scheme  2  b ) , thus leading to the different stereochemical outcomes . having the substituent r equatorial also accounts for the e - selectivity of the reaction . proposed mechanism for successful chirality transfer and stereospecificity .
it is clear from the proposed mechanism in scheme  1 that the hydrogen - bonded 6-membered transition state i is crucial for the chirality transfer , and also the e - selectivity .
any erosion of ee could therefore be attributed to the disruption of this hydrogen - bonding pattern that would allow the reaction to occur without this 6-membered transition state i. one such mechanism is explored in the computational section below ( see scheme  9 ) .
however , a second possibility for erosion of ee is the racemisation of the product 5 through isomerisation between the formal sn2 ( 5 ) and formal sn2 ( 6 ) products , catalysed by gold(i).6b ,  c ,  17 indeed , during our related studies using thiols for thioetherification reactions , chirality transfer does not occur in the thioetherification reactions.7a ,  18 experimental and computational studies showed that the racemisation is due to isomerisation between the formal sn2 and sn2 thioether products . clearly , using alcohol instead of thiol as a nucleophile allows for successful chirality transfer , except in certain substrates , such as -substituted 4  m and 4  n ( entries  1213 , table  2 ) .
therefore , we carried out several control experiments to ascertain the role of isomerisation of the products 5 and 6 in the erosion of ee . firstly , product 5  db ( entry  4 , table  2 ) was resubjected to the reaction conditions and no change was observed after 24  h ( scheme  3  a ) .
next , 5  eb was investigated , as this product was formed with only moderate chirality transfer ( 77:23  e.r . ,
once again , no change was observed upon resubjection to the reaction conditions ( scheme  3  b ) .
finally , product 5  mb , which is formed as a racemic mixture by our method ( entry  12 , table  2 ) was investigated .
this species , obtained in 98:2  e.r . by an alternative route,19 was found to racemise upon resubjection to the reaction conditions ( scheme  3  c).20 from these results , it appears that slight erosion of ee is not caused by isomerisation / racemisation of the product ( see later and scheme  9 for plausible racemisation mechanism ) .
however , instances of complete racemisation , such as the formation of 5  mb and 5  nb from -substituted 4  m and 4  n , respectively , could be due to isomerisation and racemisation of the products under the reaction conditions .
resubjection of products 5  db , 5  eb and 5  mb to the reaction conditions .
it is clear from the results in table  1 that addition of molecular sieves is the key factor to improving the formal sn2/sn2 ( 5/:6 ) regioselectivity .
our next control reaction ( scheme  4 ) shows that molecular sieves are also crucial for chirality transfer and e / z selectivities . removing molecular sieves from the reaction results in a completely racemic product 5  db and a poor 3:1 e / z ratio ( vs. 89:11  e.r . and
9:1 e / z with molecular sieves added).21 allylic etherification of 4  d without molecular sieves results in racemic product . previously , widenhoefer et  al .
had shown that chirality transfer is possible on substrate 4  j , without the need for molecular sieves ( scheme  5).14 having just ascertained that molecular sieves are crucial to avoid racemisation , we therefore thought it important to investigate whether the conditions in scheme  5 allow for the omission of molecular sieves in chirality - transfer reactions , or whether successful chirality transfer without molecular sieves is in fact specific to substrate 4  j. our results in scheme  6 show that the latter is true .
employing the conditions of widenhoefer et  al . on substrate 4  d ( which undergoes chirality transfer with molecular sieves under our conditions , table  2 , but racemises in the absence of 3   ms , scheme  4 ) , results in racemic product 5  db .
however , employing substrate 4  j under conditions that usually result in racemisation ( i.e. , no 3   ms ) , results in efficient chirality transfer .
therefore , it appears that the substituent on substrate 4  j plays a significant role in allowing the chirality - transfer process to proceed efficiently even without molecular sieves . for a more general substrate scope , however , the addition of molecular sieves to the reaction is crucial for successful chirality transfer .
results by widenhoefer et  al.14 control reactions to ascertain effects of conditions vs. substrate .
( a )  standard substrate by using the conditions of widenhoefer et  al .
( b ) substrate 4  j by using conditions that usually result in racemisation .
there are several possibilities regarding the mode of action of molecular sieves in the reaction that may lead to the observed chirality - transfer outcome .
possible reasons for this could be : i )  removal of excess water from the reaction ; ii )  the slightly basic nature of molecular sieves , which may deactivate the gold catalyst;22 and iii )  the polar surface of molecular sieves may result in the reaction occurring closer to the surface , thereby changing the aggregation levels or transition state .
however , a control reaction to test point ( i ) shows that chirality transfer is observed regardless of whether the molecular sieves are activated or not , thus ruling out this possibility ( scheme  7 ) .
in fact , the reaction occurs with even better yields and e.r . with unactivated vs. activated sieves ( 67  % , 94:6  e.r . vs. 90  % , 98:2  e.r . ,
density functional theory ( dft ) calculations were therefore employed to explore the mechanism of these direct allylic etherification reactions . in particular
scheme  1 and 2 ) was not borne out , except in the presence of molecular sieves . in the calculations
we have studied the symmetrically substituted dimethyl allylic alcohol 4  k ( as the r , e - isomer ) reacting with ethanol ( 2  o ) to give 5  ko .
this choice removes the potential complication of any subsequent sn2 reaction at 5  ko as this would return the same 5  ko product .
experimental studies indicate that the catalysis is not significantly affected by the nature of the alcohol and so ethanol was chosen for simplicity .
the calculations ( run with sdd pseudopotentials and basis sets on au and p , with d - orbital polarization on the latter , and 6 - 31 g * * basis sets on other centres ) report free energies derived from a bp86-d3(toluene ) protocol , that is , gas - phase free energies based on bp86 optimisations , corrected for dispersion and toluene solvation ( using grimme s d3 parameter set and the pcm approach respectively , see supporting information for full details ) .
the au - catalysed direct allylic etherification reaction is thought to proceed23 via coordination of the { au(pph3 ) } fragment at the c = c -bond of the allylic alcohol . as shown by mukherjee and widenhoefer,14
if the alcohol nucleophile attacks at the opposite face to au then only two outcomes are possible with an enantiopure substrate : with ( r , e)-4  k either ( s , e)-5  ko or ( r , z)-5  ko will be formed ( scheme  8) . the formation of both products ( alongside water )
is computed to be thermodynamically downhill , with the e - isomer favoured over the z - form by 1.3  kcal  mol .
this equates to a e / z ratio of approximately 9:1 at 298  k , fairly typical of the e / z selectivities seen with dialkyl - substituted allylic alcohols ( tables  1 and 2 ) .
possible outcomes of the au - mediated reaction of ( r , e)-4  k with ethanol ( 2  o ) to give either ( s , e)- or ( r , z)-5  ko .
computed product free energies are indicated in kcal  mol , relative to the reactant set to 0.0  kcal  mol . for the computed mechanism ,
we consider the direct etherification to start from the -bound adduct [ ( ph3p)au{(r , e)-4  k}]etoh , i , in which the etoh is hydrogen - bonded to the oh group of the allylic alcohol.24 several arrangements of this adduct were located in the course of this study and the most stable of these , i  a , has the etoh lying over the au centre ( i.e. , syn to au ) , with interactions to both the o of the allyl group ( 1.86   ) and also to one ch bond of the pph3 ligand ( 2.26   , see figure  1 , which also provides the associated labelling scheme ) .
the most stable adduct , where the etoh is located on the other side of the c = c -bond ( i.e. , anti to au , i  b ) , is 6.6  kcal  mol higher in energy , with the etoh showing close contacts with one allylic proton , as well as the oh group .
all energies in this section will be quoted relative to i  a set to 0.0  kcal  mol .
computed structures of two forms of [ ( ph3p)au{(r , e)-4  k}]etoh , i , with computed free energies ( kcal  mol , relative to i  a set to zero ) and selected distances in  .
phosphine h atoms are omitted for clarity , with the exception of that interacting with the etoh molecule in i  a. the key steps and associated energetics for direct etherification through anti - attack of etoh are outlined in figure  2 . starting from i  b , co bond formation proceeds through a transition state at + 10.9  kcal  mol to give intermediate ii  b at + 9.1  kcal  mol .
the computed structure of this species is shown in figure  3 and displays the anticipated hydrogen - bonded chair - like structure with the au and both me substituents all occupying equatorial positions .
similar structures have been reported at a { au(nhc ) } fragment.17a from here h transfer induces loss of water and concomitant formation of the auc bond to give intermediate iii  b in which the allylic ether product is bound through the c = c bond and water is hydrogen - bonded to the ether oxygen .
iii)b at + 11.1  kcal  mol . an analogous series of events accounts for the formation of ( r , z)-5  ko . starting from i  c ( g=+6.8  kcal  mol ) , the chair - like intermediate ii  c is formed via ts(i 
ii  c is similar to ii  b but now has one methyl substituent in an axial position .
iii)c at + 13.2  kcal  mol leads to iii  c from which the allylic ether product is lost as the ( r , z)-form .
overall , these two allylic etherification processes proceed with modest barriers ( < 14  kcal  mol ) .
in addition , as these reactions are only marginally downhill thermodynamically ( scheme  8) , they are likely to be reversible under the reaction conditions .
hence , a thermodynamic distribution of products is seen that favours the ( s , e)-5  ko product .
key intermediates and energetics for the au - catalysed reaction of ( r , e)-4  k with ethanol ( 2  o ) through anti attack to give either ( s , e)-5  ko or ( r , z)-5  ko ( l = pph3 ) . computed free energies are indicated in kcal  mol and quoted relative to i  a set to 0.0  kcal  mol .
different forms of intermediate ii : ii  b and ii  c are alternative species formed by anti attack of ethanol , whereas ii  a is formed by syn attack .
computed free energies ( kcal  mol ) are quoted relative to i  a set to zero and selected distances are in  .
the observation of the enhanced stability of precursor i  a in which etoh is positioned syn to au suggests the possibility of alternative syn attack mechanisms and two such processes have been characterised ( see figure  4 ) .
hydrogen - bonded chair - like intermediates ii  a and ii  d are located , but now with the au in an axial position ( see figure  3 for the structure of ii  a ) .
loss of water from ii  a and ii  d then leads to the formation of ( r , z)-5  ko and ( s , e)-5  ko , respectively , that is , the same products as seen in the anti attack processes .
syn attack , however , entails barriers of 17.7 and 18.4  kcal  mol , and so these processes will not be competitive with the anti attack mechanisms described above .
key intermediates and energetics for the au - catalysed reaction of ( r , e)-4  k with ethanol ( 2o ) by syn attack to give either ( s , e)-5  ko or ( r , z)-5  ko ( l = pph3 ) . computed free energies are indicated in kcal  mol and quoted relative to i  a set to 0.0  kcal  mol .
the mechanisms outlined so far are consistent with the transfer of chirality shown in widenhoefer s example ( scheme  5 ) and anticipated prior to our work .
however , our experimental studies have shown that in most cases such chirality transfer only occurs in the presence of molecular sieves and that in fact under sieve - free conditions loss of chirality dominates . to account for this a mechanism , involving nucleophilic attack at one face of the allylic alcohol and loss of water from the opposite face
one way to achieve this is to invoke a proton chain transfer mechanism25 involving several etoh molecules .
pathway ( i )  is equivalent to the anti attack in scheme  8 , where a three etoh molecule chain now promotes loss of water anti to au with formation of ( s , e)-5  ko .
in contrast , pathway ( ii )  is able to accommodate a syn attack by etoh while still delivering a proton onto the allylic hydroxyl group that is in an anti position .
this leads to the formation of ( r , e)-5  ko . if the barriers to pathways ( i ) and ( ii ) are comparable , the result will be the loss of chirality transfer that is seen experimentally .
possible mechanisms accounting for loss of chirality transfer in the au - mediated reactions of ( r , e)-4  k with three ethanol molecules to form both ( s , e)-5  ko ( pathway  ( i ) ) and ( r , e)-5  ko ( pathway  ( ii ) ) . a model incorporating three ethanol molecules was set up to test these ideas ( see figure  5 ) , three being the minimum number of etoh molecules required to access pathway ( ii ) , which requires both faces of the allylic alcohol substrate to be engaged . as in the single etoh system , the most stable form of the hydrogen - bonded precursor has one etoh positioned over the au centre .
this species , i  a , leads ultimately to the ( r , e)-5  ko product along pathway ( ii ) , as described below .
the alternative arrangement relevant for pathway ( i ) is seen in i  a and lies 8.7  kcal  mol higher in energy .
ii)a at + 12.8  kcal  mol ) and the subsequent loss of water ( via ts(ii 
iii)a at + 14.0  kcal  mol ) occur anti to the au and hence yield the ( s , e)-5  ko product . the overall barrier for pathway ( i ) is 14.0  kcal  mol .
key intermediates and energetics for the au - catalysed reaction of ( r , e)-4  k in the presence of three ethanol molecules to give ( i )  ( s , e)-5  ko and ( ii )  ( r , e)-5  ko ( l = pph3 ) .
computed free energies are indicated in kcal  mol and quoted relative to i  a set to 0.0  kcal  mol . in pathway ( ii )
, the etoh molecule lying over the au centre in i  a is linked through two hydrogen - bonded etoh molecules to the allylic hydroxyl group , which maintains a position anti to the au .
syn attack of etoh proceeds to give ii  a ( g=+6.0  kcal  mol ) via ts(i 
figure  6 shows the computed structure of ii  a and highlights the anti arrangement of the etoh nucleophile and the putative h2o leaving group . in this case
, the water dissociation is the easier step and so ( r , e)-5  ko is formed with an overall barrier of 15.6  kcal  mol .
e)-5  ko ( gcalc=14.0  kcal  mol ) and ( r , e)-5  ko ( gcalc=15.6  kcal  mol ) and this , coupled with reversibility of these transformations , means that both enantiomers will be formed over the timescale of the reaction , leading to the unexpected loss of chirality transfer.26 computed structure of intermediate ii  a located along pathway  ( ii ) on route to the formation of ( r , e)-5  ko .
the computed free energy is in kcal  mol and is relative to i  a set to zero .
selected distances are in  and phosphine phenyl substituents are truncated at the ipso carbon for clarity . a plausible explanation for the requirement of molecular sieves for efficient chirality transfer is their role in disrupting the type of proton chain transfer mechanism ( i.e. , aggregation levels of alcohol ) shown in scheme  9 , which are a potential cause of racemisation . to test our hypothesis , the reaction was carried out with a large excess of alcohol nucleophile27 ( scheme  10 ) , which should outcompete the role of the molecular sieves .
indeed , very poor enantiomeric ratios are observed in the presence of 20  equivalents of alcohol 2  i ( scheme  10 ) , thereby lending support to our theory . following this train of thought
, we postulated that the reason substrate 4  j does not require molecular sieves for chirality transfer ( schemes  5 and 6 ) is because the ether moiety ( -ch2obn ) within the substrate may be playing a similar role to molecular sieves : disrupting the proton chain transfer mechanism , presumably by hydrogen - bonding .
indeed , when the reaction with 4  j is repeated with a large excess ( 20  equiv ) of alcohol nucleophile , this overrides any effect of the ether moiety as well as molecular sieves and produces racemic product 5  jb in a poor 1:1 5  jb/6  jb regioselectivity ( scheme  11 ) . comparing results of reactions with no molecular sieves , unactivated sieves and large excess of alcohol nucleophile .
large excess of alcohol nucleophile results in racemisation with 4  j , overriding the effect of the ether moiety ( ch2obn ) and molecular sieves .
an additional explanation for erosion of chirality transfer is possible for allylic ether products such as 5  kb . in this case ,
a second formal sn2 reaction on 5  kb will lead to the same product , but with chirality transfer to the opposite enantiomer .
calculations indicate that the barrier for the second formal sn2 is readily accessible ( via a transition state at 9.8  kcal  mol for 5  ko ) . as , by definition ,
the energies of these two enantiomers of 5  kb are the same , these reversible processes will produce a racemic mixture .
this is exemplified by control experiments shown in scheme  12 , where the product 5  kb from table  2 , entry  10 is resubjected to the reaction conditions without sieves to produce a racemic mixture .
in contrast , in the presence of sieves , this process is considerably slowed ( scheme  12 ) .
although the reasons for the remarkable impact of the molecular sieves on these transformations are currently unclear , nevertheless , their effect in providing kinetic control for these experiments is remarkable and , moreover , synthetically useful . resubjecting 5 
kb to reaction conditions : racemisation without molecular sieves and much slower erosion of e.r . with molecular sieves .
we have successfully developed conditions for highly regioselective , gold(i)-catalysed direct allylic etherification of alcohols with chirality transfer to access enantioenriched -substituted secondary allylic ethers .
a thorough substrate screen shows that very high levels of chirality transfer can be achieved ( up to > 99:1  e.r . ) .
the reaction is very functional - group tolerant and proceeds in the presence of unprotected groups such as alkyl halides , tertiary alcohols , alkenes and acid - sensitive acetals .
furthermore , we demonstrate that the addition of molecular sieves is crucial not only for excellent formal sn2 selectivity , but also to ensure efficient chirality transfer .
the molecular sieves need not be activated to achieve this effect , which implies that it is not aiding the selectivity by removal of water .
dft calculations suggest that chirality transfer should proceed under conditions that promote the reaction of a single alcohol as nucleophile .
however , at higher alcohol concentrations proton chain transfer mechanisms become accessible , which permit alternative pathways that will erode the chirality transfer
. a plausible role of the molecular sieves is to disrupt the aggregation of alcohol molecules in order to prevent loss of chirality through this pathway .
whatever the underlying reasons , the impact of molecular sieves in controlling the outcome of these allylic etherification reactions is remarkable and synthetically useful .
a solution of [ pph3auntf2 ] ( 2:1 toluene adduct , 5  mol  % ) , allylic alcohol 4 ( 0.101  mmol ) , alcohol 2 ( 0.506  mmol ) and 3   molecular sieves ( 8  mg ) in toluene ( 260  l ) was stirred at 50  c under air for 8  h. then , [ pph3auntf2 ] ( 2:1 toluene adduct , 5  mol  % ) was added and the resulting solution was stirred at 50  c for a further 16  h. the resulting solution was filtered through a short plug of silica , washing with 9:1 hexane / et2o .
the filtrate was evaporated under reduced pressure to give the crude product , which was purified by flash column chromatography .
full experimental procedures , characterisation for all new compounds and copies of h and c  nmr spectra are provided in the supporting information .
a solution of [ pph3auntf2 ] ( 2:1 toluene adduct , 5  mol  % ) , allylic alcohol 4 ( 0.101  mmol ) , alcohol 2 ( 0.506  mmol ) and 3   molecular sieves ( 8  mg ) in toluene ( 260  l ) was stirred at 50  c under air for 8  h. then , [ pph3auntf2 ] ( 2:1 toluene adduct , 5  mol  % ) was added and the resulting solution was stirred at 50  c for a further 16  h. the resulting solution was filtered through a short plug of silica , washing with 9:1 hexane / et2o .
the filtrate was evaporated under reduced pressure to give the crude product , which was purified by flash column chromatography .
full experimental procedures , characterisation for all new compounds and copies of h and c  nmr spectra are provided in the supporting information .
as a service to our authors and readers , this journal provides supporting information supplied by the authors .
such materials are peer reviewed and may be re - organized for online delivery , but are not copy - edited or typeset . technical support issues arising from supporting information ( other than missing files ) should be addressed to the authors
 gold(i)-catalysed direct allylic etherifications have been successfully carried out with chirality transfer to yield enantioenriched , -substituted secondary allylic ethers . 
 our investigations include a full substrate - scope screen to ascertain substituent effects on the regioselectivity , stereoselectivity and efficiency of chirality transfer , as well as control experiments to elucidate the mechanistic subtleties of the chirality - transfer process . 
 crucially , addition of molecular sieves was found to be necessary to ensure efficient and general chirality transfer . 
 computational studies suggest that the efficiency of chirality transfer is linked to the aggregation of the alcohol nucleophile around the reactive -bound au  
 allylic ether complex . with a single alcohol nucleophile , a high degree of chirality transfer 
 is predicted . 
 however , if three alcohols are present , alternative proton transfer chain mechanisms that erode the efficiency of chirality transfer become competitive . 
Introduction
Results and Discussion
Conclusion
Experimental Section
General procedure
Supporting Information