Modern Organocopper Chemistry

208 6 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

Most of the useful auxiliaries are chiral amine or alcohol derivatives readily available from the chiral pool, and most of them possess rigid cyclic or bicyclic structures to allow e cient di erentiation of the two competing diastereomorphic transition states. In some cases, additional rigidity was achieved with the aid of an external chelating Lewis acid (entries 6, 10, 12). In certain cases, however, acyclic auxiliaries may also be useful (see entry 15).

Selective labelling of the two diastereotopic methyl groups of l-leucine (144) has enabled their fates during secondary metabolic reactions to be elucidated [66]. Moreover, in the context of protein interactions, di erentiation of the leucine pro-R and pro-S methyl groups in protein NMR spectra allows molecular recognition phenomena to be studied [67]. Recently, e cient routes to both forms of 13C- labeled leucine, based on application of an auxiliary-controlled stereoselective conjugate addition reaction (Scheme 6.27) have been described [68]. Thus, starting

Scheme 6.27. Auxiliary-controlled stereoselective cuprate addition as the key step for the construction of both diastereomeric forms of [5-13C]-leucine 144.

6.1 Conjugate Addition 209

from either enamide 139 or 140, it was possible to obtain both enantiomers of the [5-13C]-3-methylbutanoic acid 143. An additional three steps transformed the acids 143 into the desired leucines 144.

As well as organic chiral auxiliaries, organometallic fragments have found some application as chiral auxiliaries in conjugate addition reactions. Particularly noteworthy are chiral molybdenum allyl complexes [69], chiral iron complexes [70], and planar chiral arene chromium species [71].

An interesting chromium system example is represented by complex 145. Addition of cyano-Gilman cuprates occurred with complete diastereoselectivity to give conjugate adducts 146 (Scheme 6.28). Interestingly, the opposite diastereomer was accessible by treatment of enone 145 with a titanium tetrachloride/Grignard reagent combination [71c].

Scheme 6.28. Diastereoselective cuprate addition to a planar chiral arylchromium enone complex 145.

When the chiral molybdenum p-allyl-substituted enone 147 was treated with lithium dimethylcuprate, formation of adduct 148 with fair selectivity was observed (Scheme 6.29) [69]. Interestingly, higher selectivities were obtained in the presence of boron trifluoride etherate. It is assumed that Lewis acid coordination induces the s-trans reactive conformation 149 [64]. Consequently, nucleophile attack anti to the molybdenum fragment should a ord the major diastereomer 148.

Scheme 6.29. Diastereoselective cuprate addition to chiral molybdenum p-allyl enone complex 147.

2106 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

6.2

Allylic Substitution

Treatment of allylic substrates 150, possessing suitable leaving groups X in their

allylic positions, with organocopper reagents may result either in an SN2-type process (a-attack) or alternatively in an SN20 one (g-attack), giving the substitution products 151 and 152, respectively (Scheme 6.30) [1j].

Scheme 6.30. Potential reaction products from allylic substitution with organocopper reagents (¼ Nu).

The ratio of a-attack to g-attack is a subtle function of substrate structure (steric and electronic properties), the leaving group, and also the nature of the organocopper reagent employed. Like the SN2 process, the SN20 reaction with organocopper reagents generally occurs with inversion of configuration, resulting from the attack of the organocopper reagent anti to the leaving group in the allylic position. An instructive example is o ered in the reaction of substrate 153 in Scheme 6.31. Treatment of the enantiomerically enriched cyclohexenyl acetate 153 with lithium dimethylcuprate yielded the racemate 154. Hence, for the sterically unbiased substrate 153, both SN2 and SN20 attacks took place, in a ratio of approximately 1:1. Interestingly, when the organocopper reagent was changed to the lower order methylcyanocuprate, a clear preference for the SN20 pathway was found [72].

Scheme 6.31. Di erent results of allylic substitution of cyclohexenyl acetate ( )-153 with dimethylcuprate and with a lower order cyano cuprate.

To explain the stereochemistry of the allylic substitution reaction, a simple stereoelectronic model based on frontier molecular orbital considerations has been proposed (155, Fig. 6.2). Organocopper reagents, unlike C-nucleophiles, possess filled d-orbitals (d10 configuration), which can interact both with the p -(CbC) orbital at the g-carbon and to a minor extent with the s -(CaX) orbital, as depicted

6.2 Allylic Substitution 211

Fig. 6.2. Frontier orbital-based model to explain the stereochemistry of allylic substitution.

in Fig. 6.2 [73]. To achieve optimal orbital overlap, the s -orbital of the CaX bond should be aligned coplanar to the alkene p-system.

Interestingly, this intrinsic stereoelectronic control over allylic substitution can be overridden when a reagent-coordinating leaving group is employed. Suitable leaving groups have been found in carbamates [74, 75], (O/S)-benzothiazoles [76, 77] (Scheme 6.32) and, very recently, the ortho-diphenylphosphinobenzoyl (o- DPPB)-group was identified as an e cient reagent-directing leaving group (Scheme 6.44) [91].

Scheme 6.32. Di erent stereochemical results with mesylate (156) and carbamate (158) leaving groups upon allylic substitution with organocuprates.

When the non-coordinating mesitoate system 156 was treated with lithium dimethylcuprate, formation of the anti-SN20 substitution product 157 was observed. Notably, the exclusive formation of the g-substitution product is the result of severe steric hindrance at the a-position, originating from the adjacent isopropyl group [78]. Conversely, the corresponding carbamate 158 was reported, on treatment with a higher order cuprate, to form the syn-SN20 product 159 exclusively [74]. The lithiated carbamate is assumed to coordinate the cuprate reagent (see 160), which forces the syn attack and gives trans-menthene (159).

Associated with the propensity to intramolecular delivery of the organocopper reagent is the benefit of high regioselectivity, since an intramolecular trajectory prohibits the alternative a-attack. This is best exemplified by the reaction behavior of the cyclic system 161 (Scheme 6.33). For this substrate, g-attack is sterically hindered. Hence, treatment of the acetate of 161 with a higher order methyl cuprate

212 6 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

Scheme 6.33. Di erent stereochemical and regiochemical results with acetate (!157) and carbamate (!162) leaving groups on allylic substitution of 161 with a higher order methylcuprate.

exclusively gave the SN2-type product 157. Conversely, the carbamate of 161 is able not only to direct the stereochemistry to produce a syn-attack but also permits the exclusive formation of the SN20 product 162 [74]. Similar results were obtained upon treatment of 161 with silylcuprates [79]. The generalization can therefore be made that carbamate leaving groups induce high g-selectivity in allylic substitution with organocuprates, irrespective of steric hindrance at the g-position in the allylic framework.

For acyclic allylic substrates the situation is more complex, since a larger number of reactive conformations, and hence corresponding transition states, compete. Thus, methyl cinnamyl derivatives 163 (X ¼ OAc), upon treatment with lithium dimethylcuprate, mainly gave the SN2 substitution product 166 (entry 1, Tab. 6.6 and Scheme 6.34) [80]. The preference for the SN2 product is expected, since deconjugation of the alkene system is electronically unfavorable.

Scheme 6.34. Leaving group and reagent dependence of allylic substitution in acyclic derivative 163.

Tab. 6.6. Results of allylic substitution of styrene system 163 with organocopper reagents.

Entry	X	Reaction conditions	164:165:166	Yield [%]	Ref.
1	OAc	Me2CuLia)	4:0:96	>99	80
2	OAc	MeCu(CN)Lia)	39:12:49	—c)	81
3	OCONHPh	i. MeLi, ii. CuI, iii. MeLib)	89:11:0	—c)	75, 80

a)Et2O.

b)THF.

c)Yields are not given in the original literature.

As already noted, lower order cyanocuprates are more SN20-selective reagents. On treatment with acetate 163, however, a mixture of the two regioisomers was obtained (entry 2) [81]. In addition, g-alkylation had taken place with ca. 25% loss of double bond configuration [82].

6.2 Allylic Substitution 213

Better results were obtained for the carbamate of 163 (entry 3) [75, 80]. Thus, deprotonation of the carbamate 163 with a lithium base, followed by complexation with copper iodide and treatment with one equivalent of an alkyllithium, provided exclusive g-alkylation. Double bond configuration was only partially maintained, however, giving 164 and 165 in a ratio of 89:11. The formation of both alkene isomers is explained in terms of two competing transition states: 167 and 168 (Scheme 6.35). Minimization of allylic A1; 3 strain should to some extent favor transition state 167. Employing the enantiomerically enriched carbamate (R)-163 (82% ee) as the starting material, the proposed syn-attack of the organocopper nucleophile could then be as shown. Thus, after substitution and subsequent hydrogenation, (R)-2- phenylpentane (169) was obtained in 64% ee [75].

Scheme 6.35. Interpretation of the chirality transfer during the course of allylic substitution of acyclic carbamate derivative (R)-163.

As a consequence of this model, it should be foreseeable that increasing allylic A1; 3 strain – arising from employment of a Z alkene system, for example – should favor transition state 167 even more, giving higher levels of E selectivity for the

214 6 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

corresponding allylic substitution product. Accordingly, treatment of the Z allylic carbamate 170 with the mixed silyl cuprate resulted in exclusive formation of the E alkene 171 (Scheme 6.36) [83]. Interestingly, the Z allylic substrates also provide higher E selectivities in the case of non-directed allylic substitutions.

Scheme 6.36. Regioselective allylic substitution of Z carbamate 170 with a silylcuprate reagent.

This knowledge was elegantly exploited in a recent synthesis of prostaglandins (Scheme 6.37). The starting point was a mixture of diastereomeric propargylic alcohols 175, obtained from a non-selective 1,2-addition of an alkynylcerium reagent to aldehyde 174. Subsequent cis hydrogenation with a palladium catalyst gave the diastereomeric Z allylic alcohols 176 and 177. The two diastereomers were separated and transformed either into the carbamate 178 or into the benzoate 179. Allylic substitution of both substrates with phosphine-modified silylcuprate reagents converged to the formation of a single allyl silane 180 [84].

Upon allylic substitution with organocopper reagents, both E and Z allylic carbamates generally furnish E alkene systems, either exclusively or preferentially. In contrast, it was recently found that E allylic carbamates bearing silyl groups in their g-positions provide remarkable Z selectivities under reaction conditions involving mixed organomagnesium/copper reagents (Scheme 6.38) [85].

Thus, enantiomerically pure carbamate (E )-181 furnished the Z allylsilane 182 in high yield and with good Z selectivity. After transformation into the saturated alcohol 184, an enantiomeric excess of 88% was determined, consistent with the E:Z ratio of the allylsilane with respect to the ee of the starting compound (entry 1, Tab. 6.7). On switching to an isobutyl organocopper reagent obtained from the corresponding isobutyllithium, however, the carbamate (E )-181 furnished the E allylsilane 183 (entry 2). Conversely, both reagent types reacted with the Z isomer of 181 to give the E allylsilane 183 (entries 3 and 4). To explain the inverse stereochemical outcome of allylic substitution of the E vinylsilane 181 with the magnesium/copper reagents, two arguments have been put forward (Scheme 6.39).

According to these, reaction takes place either through the sterically less favorable transition state 185 or by a pathway involving an exo attack of the Grignard reagent on the copper-complexed carbamate, as shown in 187 [75, 85]. For Z car-

6.2 Allylic Substitution 215

Scheme 6.37. Allylic substitution with silylcuprates in the course of a prostaglandin synthesis.

bamate 181, minimization of allylic A1; 3 strain again seems to dictate the stereochemical outcome of the allylic substitution, irrespective of the reagent employed [85].

As well as coordinating leaving groups, a second general solution to the problem of obtaining high SN20 selectivities makes use of sulfonate leaving groups in combination with Lewis acid-activated organocopper reagents [86–89]. For example, the Z g-mesyloxy enoate 189 reacted with lithium methylcyanocuprate-boron trifluoride

216 6 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

Scheme 6.38. Influence of reagent and alkene geometry on allylic substitution of g-silyl-substituted allylic carbamates 181 (Ts ¼ para-toluenesulfonyl, NMP ¼ N-methylpyrrolidinone).

Tab. 6.7. Results of allylic substitution of g-silyl-substituted allylic carbamates 181 with organocopper reagents.

Entry	Substrate	Basea)	M	182:183	Yield b) [%]	ee 184 [%]
1	(E )-181	n-BuLi	MgCl	94:6	90	88
2	(E )-181c)	n-BuLi	Li	9:91	69	—
3	(Z )-181d)	MeLi	MgCl	3:97	93	92
4	(Z )-181d)	MeLi	Li	<1:99	93	94

a)THF, 0 C.

b)yield of 182 and 183.

c)Racemic starting material was employed.

d)96% ee, E:Z ¼ 3:97.

Scheme 6.39. Interpretation of the results of allylic substitution of g-silyl-substituted allylic carbamates.

to give the 1,4-syn-configured b; g-unsaturated ester 190 in high yield and with good stereoselectivity (Scheme 6.40). Interestingly, the corresponding E enoate 192, under identical conditions, gave the 1,4-anti-configured product 193 [86]. Thus, olefin geometry provides a convenient handle with which to control the configuration of

the newly formed stereogenic center [88].

Transition state models that minimize allylic A1; 3 strain (191 and 194) provide

6.2 Allylic Substitution 217

Scheme 6.40. Influence of alkene geometry on stereoselectivity of allylic substitution of mesylates 189 and 192 with boron trifluoride-modified lower order cyanocuprate reagents.

interpretations of the stereochemical outcome of both reactions [86b]. Interestingly, it has been possible to use the method for stereoselective construction of quaternary carbon centers (Scheme 6.41) [87].

Scheme 6.41. Stereoselective construction of a quaternary stereocenter by allylic substitution of mesylate 195 with a boron trifluoride-modified cyano-Gilman cuprate reagent.

More recent investigations have shown that this reaction operates even under catalytic conditions (3–10 mol% of copper(II) salt), with alkylzinc reagents as the stoichiometric organometallic source (Scheme 6.42) [89].

Scheme 6.42. Copper-catalyzed allylic substitution of mesylate 197 with an organozinc reagent.

To achieve diastereoselectivity in the course of allylic substitution, the controlling chiral information may not only reside in the substrate skeleton but may also be part of the allylic leaving group. Thus, a chiral carbamate has been developed as a