POBLACION VEREDAS DEL MUNICIPIO

The asymmetric synthesis of tertiary allylic alcohols, particularly in acyclic systems, is extremely challenging. In this context, a number of lengthy synthetic routes, generally involving the asymmetric epoxidation of a trisubstituted alkene, can be envisaged for their preparation.35 However, in order for our proposed stereospecific allylic alkylation to find widespread utility, we were keen to develop a highly practical substrate synthesis, which led to a thorough examination of the available methods. The addition of an organometallic reagent to a ketone, which may be rendered asymmetric by a chiral catalyst, represents perhaps the most obvious strategy towards the synthesis of tertiary alcohols; however, these reactions are often limited to the introduction of simple alkyl groups.36 To our knowledge, the highly asymmetric addition of an unsubstituted vinylmetal reagent to a simple ketone, to provide the requisite monosubstituted alkene, has yet to be described. In contrast, a

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great deal of success has been achieved in the asymmetric synthesis of tertiary allylic alcohols via the oxidation of their corresponding allylboronates. For example, Hoveyda recently described the NHC-copper complex-catalysed allylic substitution of a range of alkyl- and aryl-substituted (E)-linear carbonates 43 with

bis(pinacolato)diboron, to provide the requisite allylic alcohols 45 upon treatment

with alkaline hydrogen peroxide (eq. 10). Despite having a relatively broad substrate scope, the enantioselectivity of this reaction was shown to be particularly sensitive to the steric nature of the substituent R, with only particularly bulky groups (e.g. R =

c

Hex & 2-BrC6H4) providing exceptional ee values. In addition, the practicality of

this method is limited by the relatively lengthy syntheses of both 43 (3 steps), which

must be prepared as a single geometrical isomer, and the imadazolinium salt 44 (4

steps including two Buchwald-Hartwig cross coupling reactions).

In 2008, Aggarwal described a remarkably general approach towards the enantiodivergent synthesis of acyclic tertiary alcohols, including monosubstituted allylic alcohols (Scheme 13).37 This process involves the borylation of an

enantiomerically enriched lithiated carbamate, which may proceed with either retention or inversion of configuration, depending on the nature of the boron reagent. Thus, both enantiomers of the alcohol 47 may be obtained in excellent enantiomeric

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excess from the same enantiomer of the carbamate 46. A mechanistic pathway for

this transformation is depicted in Scheme 13.

Scheme 13. Enantiodivergent synthesis of tertiary alcohols via lithiation-borylation

of the benzylic carbamate 46.

Due to the predictably high levels of stereocontrol afforded by the borylation of lithiated carbamates (Scheme 13), we elected to utilise this process in the synthesis

of an enantiomerically enriched tertiary allylic alcohol, namely 45a (Table 8). Thus,

treatment of the benzylic carbamate 48a with sBuLi at -78 °C, followed by the addition of vinylboronic acid pinacol ester 49, warming to ambient temperature and

in situ oxidation of the subsequently formed allylboronate, furnished the tertiary allylic alcohol 45a in excellent yield and 96% ee (entry 1). The transfer of chirality

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complete, and is in agreement with the mechanism of addition outlined in Scheme

13. Consistent with Aggarwal’s subsequent mechanistic studies,38 which were published during the course of our work, we also found that with the addition of 1M magnesium bromide/methanol to the reaction mixture prior to warming, the tertiary allylic alcohol 45a could be obtained in essentially enantiopure form (entry 2). Using

this method, we expected a wide variety of aryl alcohols such as 45a to be readily

available in excellent enantiomeric excess. Additionally, this process has very recently been extended to the corresponding allylic carbamates,39 enabling the synthesis of alkyl-substituted analogues.

Table 8.Asymmetric synthesis of the tertiary alcohol 45a via lithiation-borylation of

the carbamate 48a.

Entry Additive Yield (%)a ee (%)b

1 - 89 96

2 MgBr2/MeOH 83 99

a

Isolated yields. b ee values were determined by chiral HPLC on the isolated product.

2.2.4.3. Reaction Optimisation

The required tertiary allylic carbonate 50 was prepared by treatment of the allylic

alcohol 45a with n-butyllithium, followed by the addition of methyl chloroformate.

However, upon attempted purification by flash column chormatography (FCC), the tertiary carbonate 50 underwent significant allylic rearrangement to the achiral linear

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mixture. Presumably, the carbonate 50 is subject to facile ionisation under mildly

acidic conditions, to provide a stable tertiary, benzylic and allylic carbocation. Nucleophilic attack of the resultant carboxylate anion must then occur largely on the terminal double bond (SN1’ substitution), to provide the conjugated styrene

derivative 51, which is thermodynamically favoured. Alternatively, this reaction

could be envisaged to proceed via Claisen-type [3,3]-sigmatropic rearrangement of the tertiary allylic carbonate 50.

Scheme 14. One pot conversion of the tertiary allylic alcohol 45a to the acyclic α-

aryl ketone 52a.

In order to circumvent this issue, we chose to develop an efficient one pot procedure in which the reactive allylic carbonate 50 could be formed in situ, followed directly

by the addition of 24a and a rhodium catalyst, to provide the enantiomerically

enriched ketone 52 upon deprotection of the resultant cyanohydrin adduct (Scheme

14).40 Arguably the most significant difference between this reaction and those of the

isolated alkyl carbonates 26 is that one equivalent of lithium chloride is generated

upon acylation of the alcohol 45a, which should remain in solution over the course of

the subsequent alkylation. However, due to the relatively weak trans effect of the chloride ligand, we were hopeful that this would have a minimal influence on the rate

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of π-σ-π isomerisation, and hence the stereospecificity of the alkylation.41

Gratifyingly, this salt was also shown to have little impact on the reactivity of the intermediate allylic carbonate 50, as shown in Table 9.

Under our previously optimal reaction conditions, the stereospecific rhodium- catalysed allylic alkylation with the cyanohydrin 24 failed to proceed to completion,

affording the ketone 52a in 66% yield, albeit with excellent regioselectivity and good

enantiospecificity (entry 1). While the regioselectivity of this reaction is seemingly independent of the phosphite ligand, presumably due to the electronically biased aryl substituent, the stereospecificity was shown to vary greatly with the steric and electronic properties of this reaction component, as outlined in Table 9. For example,

the bulky tris(tert-butyldimethylsilyl) phosphite provided almost complete stereoerosion (entry 2), which suggests that a dynamic kinetic asymmetric transformation (DYKAT) of racemic tertiary alcohols with the cyanohydrin 24 may

be feasible.42 In contrast, the considerably smaller and more electron poor tris(2,2,2- trifluoroethyl)phosphite proved optimal in terms of both enantiospecificity and yield (entry 5), furnishing the acyclic α-aryl ketone 52a in excellent yield and 90% enantiomeric excess (91% cee43) (entry 5). With the exception of P(O-2,4-di-

t

BuC6H3)3 (entry 1), there would appear to be a correlation between the size of the

phosphite ligand and the stereospecificity of the alkylation, though a more exhaustive ligand screen is clearly required in order to fully elucidate this trend.

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Table 9. Effect of the phosphite ligand in the stereospecific rhodium-catalysed

allylic substitution with the acyl anion equivalent 24 (R = Ph, Ar = Ph).

Entrya L rsb ee (%)c cee (%) Yield (%)d

1 P(O-2,4-di-tBuC6H3)3 ≥ 19:1 82 85 66 2 P(OTBS)3 “ 18 19 72 3 P(OPh)3 “ 59 61 78 4 P(OMe)3 “ 83 86 80 5 P(OCH2CF3)3 ≥ 19:1 90 91 87 a

All reactions were performed on a 0.5 mmol reaction scale using 1 equiv. nBuLi, 1 equiv. MeOCOCl, 2.5 mol% [Rh(COD)Cl]2, 10 mol% L, 1.3 equiv. 24 and 1.8 equiv. LiHMDS in THF (5

ml) at -10 °C for ca. 5 h, followed by the addition of 4.0 equiv. TBAF at room temperature. b Regioselectivity was determined by 500 MHz 1H NMR on the crude reaction mixtures before deprotection of the cyanohydrin adduct. c ee values were determined by chiral HPLC on the isolated products. d Isolated yields.

While a competing mechanistic pathway cannot be altogether ruled out, it seems reasonable that the marginally incomplete transfer of chirality from the (R)-alcohol

45 to the (R)-ketone 52 is predominantly caused by π-σ-π isomerisation of the

transient rhodium-enyl complex (Scheme 12), which occurs in competition with the

nucleophilic displacement of this intermediate. This is consistent with the almost complete retention of configuration observed in the presence of small, electron poor ligands such as tris(2,2,2-trifluoroethyl) phosphite, which would be expected to provide a more rapid rate of alkylation. Subsequent attempts to further increase the rate of nucleophilic attack relative to π-σ-π isomerisation, for example by increasing the reaction temperature and concentration, in addition to the stoichiometry of the

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nucleophile, were largely unsuccessful. As a result, the reaction conditions outlined in Table 9 (entry 5) were shown to be optimal. Although the stereospecificity is

slightly lower than that typically obtained with secondary allylic carbonates, this reaction provides proof of concept for this novel transformation, and was deemed satisfactory given the challenges usually associated with the asymmetric construction of acyclic α-quaternary substituted carbonyl compounds.