Modern Organocopper Chemistry

198 6 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

versely, the bulky lithium di-t-butylcuprate displayed 4:1 selectivity in favor of the anti diastereomer of 85. Interestingly, the stereogenic center in the 5-position had a significant influence, as the syn derivative 86 provided the conjugate adduct 87 with significantly higher diastereoselectivity under otherwise identical reaction conditions (dr > 93:7). Furthermore, investigations with analogous pseudotripeptide derivatives (L,L,L and D,L,L, respectively) found that an unusual remote 1,8-induction may even be operative in some cases [35].

For a cuprate addition reaction to a diester derivative such as 88, it might be expected that the anti addition product would be favored, since a pronounced allylic A1; 3 strain in these substrates along ‘‘modified’’ Felkin–Anh lines should favor transition state 52 (see Fig. 6.1). However, experiments produced the opposite result, with the syn product 89 being obtained as the major diastereomer (Scheme 6.18) [36, 37].

Scheme 6.18. Diastereoselective cuprate addition to diester 88.

This result clearly marks the di culties and limitations inherent in the ‘‘modified’’ Felkin–Anh model, which so far is nothing more than a rule of thumb. To account for these results, a switch in mechanism towards a ‘‘p-complex’’ model has been proposed [36b, 37].

6.1.2.2 g-Alkyl-substituted a, b-Unsaturated Carbonyl Derivatives

Diastereofacial selection on addition of organocoppper reagents to chiral g-alkyl- substituted Michael acceptors has been investigated less extensively, due to the usually low selectivities generally observed for these systems [38, 39]. This is exemplified by the reaction of E and Z enoates 90 (Scheme 6.19). Thus, either syn-91 or anti-93 is formed upon conjugate addition with BF3-modified reagents, as a function of enoate geometry. The stereochemistry of the reaction is in accordance with the ‘‘modified’’ Felkin–Anh model [40].

Better stereoselectivities have been noted for conjugate addition reactions to the steroidal enone 95 (Scheme 6.20, Tab. 6.2). Irrespective of the enone geometry, addition of lithium dimethylcuprate provided the anti addition product 96 in high yield and with good diastereoselectivity (Tab. 6.2, entries 1 and 2). Interestingly, addition of chlorotrimethylsilane to the reaction mixture had a dramatic e ect. The E isomer of enone 95 still gave the anti addition product 96 with perfect stereoselectivity (entry 3). With the Z isomer of the enone, however, the syn addition product 97 was formed in good yield and with high diastereoselectivity (entry 4)

6.1 Conjugate Addition 199

Scheme 6.19. Diastereoselective cuprate addition to g-methyl-substituted enoates 90.

Scheme 6.20. Diastereoselective cuprate addition to steroidal enone 95 (MOM ¼ methoxymethyl).

[41]. This result fits with the notion that addition of chlorotrimethylsilane changes the rate and selectivity-determining step of the conjugate addition reaction [22, 42].

Tab. 6.2. Results of diastereoselective cuprate additions to enone 95 (TMS ¼ trimethylsilyl, HMPT ¼ hexamethylphosphoric triamide).

Entry	Substrate	Reagents	96:97	Yield [%]
1	(E )-95	Me2CuLi	98:2	91
		0 C, THF
2	(Z )-95	Me2CuLi	98:2	78
		0 C, THF
3	(E )-95	Me2CuLi, TMSCl, HMPT	100:0	95
		78 C, THF
4	(Z )-95	Me2CuLi, TMSCl, HMPT	3:97	75
		78 C, THF

2006 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

6.1.2.3 a,b-Unsaturated Carbonyl Derivatives with Stereogenic Centers in Positions other than the g-Position

When the chiral a; b-enone enoate 98 was treated with magnesiocuprates in the presence of 1.5–2 equivalents of diethylaluminium chloride, the anti addition product 99 was obtained in moderate yield and with good diastereoselectivity (Scheme 6.21) [43, 44]. A reasonable explanation might assume a chelating coordination of the aluminium reagent [45]. Thus, if the enone 98 were to adopt an s-trans conformation, as indicated for complex 100, subsequent front side attack of the nucleophile would furnish the major diastereomer anti-99.

Scheme 6.21. Lewis acid-promoted diastereoselective conjugate addition to enone 98 (Bn ¼ benzyl).

Michael acceptors possessing stereogenic centers in their d-position or in any position further remote do not exhibit significant levels of stereochemical control if passive substrate control is relied on exclusively. The d-methyl-substituted epoxyenoate 101, for example, reacted with lithum dibutylcyanocuprate in a chemoselective but stereorandom fashion (Scheme 6.22) [46, 47].

Scheme 6.22. Non-stereoselective conjugate addition to the d-chiral enoate 102.

6.1.2.4Directed Conjugate Addition Reactions

As discussed, conjugate addition reactions involving chiral g-alkyl-substituted a; b- unsaturated carbonyl derivatives usually occur with low levels of diastereoselectivity. In accord with this general trend, the benzyloxy and silyloxy derivatives 103 and 104 (Scheme 6.23) both reacted with a silyl cuprate in non-selective fashion, to give the conjugate adducts 108 and 109, respectively (entries 1 and 2, Tab. 6.3) [39]. Conversely, high levels of diastereoselectivity were found for the corresponding carbamates, and even better results were obtained for carbonates, giving the anti esters 110–112 as the major diastereomers (entries 3–5) [39].

6.1 Conjugate Addition 201

Scheme 6.23. Diastereoselective cuprate addition to d-functionalized enoates 103–107.

Tab. 6.3. Results of diastereoselective cuprate addition to d-functionalized enoates 103–107 (TBS ¼ t-butyldimethylsilyl, Bn ¼ benzyl).

Entry	Substrate	R	Product	anti:syn	Yield [%]
1	103	Bn	108	50:50	95
2	104	TBS	109	50:50	45
3	105	CONHPh	110	89:11	77
4	106	COOMe	111	>95:5	80
5	107	COOBn	112	>95:5	85

Interestingly, even derivative 113, with the carbamate-functionalized stereogenic center in the d-position, exhibited significant levels of diastereoselectivity to give ester 114 (Scheme 6.24). In this case, however, the syn addition product 114 was formed as the major isomer.

Scheme 6.24. Diastereoselective cuprate addition to d-carbamate-functionalized enoate 113.

It has been proposed that a directed cuprate addition with a carbamate or a carbonate serving as a reagent-directing functional group may account for the stereochemical outcome of these reactions (see models 115 and 116 in Scheme 6.25) [39, 48].

Scheme 6.25. Proposed explanation for directed cuprate addition to carbonates 106 and 107 and carbamate 105.

A new concept, employing a specifically introduced reagent-directing group [49], allowed more e cient use to be made of substrate direction in conjugate addition of cuprates to acyclic enoates [50]. The ortho-diphenylphosphinobenzoyl (o-DPPB) functionality was identified as an ideal directing group. This group is easily attached to the substrate through esterification of an appropriate alcohol function. The multifunctional character of this group is notable; it can act as an e cient directing

202 6 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

group for a number of late transition metal-mediated or -catalyzed reactions. To date, directed hydroformylations [51], rhodium-catalyzed domino-type processes [52, 53], and a palladium-catalyzed atropselective biaryl coupling [54] have been described.

Thus, enoates 127–131 were prepared e ciently by means of a combination of an o-DPPB-directed stereoselective hydroformylation and a Horner–Wadsworth– Emmons (HWE) olefination (Scheme 6.26). In general, chiral d-methyl-substituted enoates are known to react non-selectively in lithium dimethylcuprate additions [46]. Conjugate addition reactions between enoates 127–131 and lithium dialkylcuprates, however, gave the corresponding anti 1,4-addition products 132–138 in good yields and with high diastereoselectivities [50]. Thus, the combination of o-DPPB-directed hydroformylation and o-DPPB-directed cuprate addition a orded useful building blocks, with up to four stereogenic centers, for polyketide synthesis (132–138, see Scheme 6.26, Tab. 6.4). Control experiments with a corresponding phosphane oxide suggested that the o-DPPB group controls both reactivity and stereoselectivity in the course of this conjugate addition reaction. However, it has been found that the stereoselectivity of the o-DPPB-directed cuprate addition is a sensitive function of the enoate structure and so is so far limited to the E enoates of the general structure shown in Scheme 6.26 [50b].

Scheme 6.26. Construction of polyketide building blocks by sequential directed stereoselective hydroformylation and directed cuprate addition with the aid of the reagent-directing o-DPPB group. (o-DPPB ¼ ortho-diphenylbenzoylphosphanyl, DME ¼ dimethoxyethane)

6.1.3

Auxiliary-bound Chiral Michael Acceptors and Auxiliary Chiral Metal Complexes

Diastereoselective conjugate additions to chiral Michael acceptors in which the part initially bearing the chiral information is removable (i.e., a chiral auxiliary) provides a means to synthesize enantiomerically pure conjugate adducts. Chiral auxiliaries should ideally be readily available in both enantiomeric forms. They should

6.1 Conjugate Addition 203

Tab. 6.4. Results of o-DPPB-directed cuprate addition to acyclic enoates 127–131 (o-DPPB ¼ ortho-diphenylphosphinobenzoyl, Tr ¼ triphenylmethyl, Piv ¼ pivaloyl).

Entry	Enoate	Product	Yield [%]	anti:syn
1			93	95:5

2
					68		95:5

3	61	80:20

4

68

95:5

5		71			86:14

6				60	85:15

7

75

95:5

furthermore be easily introducible into the substrate and removable from the product. Thus, the most common attachment of an appropriate auxiliary occurs by means of an ester or an amide linkage to the carbonyl group of an a; b-unsaturated carbonyl derivative. A number of auxiliaries have been developed for this purpose and a comprehensive review up to 1992 is available [1g]. A personal selection of useful auxiliaries for achieving high levels of stereoselectivity is given in Tab. 6.5. In each case the assumed reactive conformation is provided, allowing the major stereoisomer to be predicted for each substrate type.

Tab. 6.5. A selection of auxiliary controlled diastereoselective conjugate additions with organocopper reagents. (TMEDA ¼ N,N,N0,N0-tetramethylethylenediamine, Piv ¼ pivaloyl)

Entry	Auxiliary R	Reagents	Assumed Reactive	Product	de [%]	Ref.
			Conformationa)
1		EtCu			>99	55c–e
		BF3 OEt3

2

EtCu

>99

55c–e

BF3 OEt3

3

n-BuCu, TMSI

98

56

4 (vinyl)Cu 98 55a, b P(n-Bu)3

BF3 OEt3

Reactions Substitution Allylic and Addition Conjugate Diastereoselective mediated-Copper 6 204

5

n-PrCu

P(n-Bu)3

BF3 OEt3

6	Ph2CuLi
	P(n-Bu)3
	EtAlCl2
7	MeCu
	P(n-Bu)3
	BF3 OEt3
8	MeCu
	P(n-Bu)3
	BF3 OEt3
9	(allyl)Cu
	TMEDA
	Bu2BOTf
10	(allyl)MgCl
	CuBr SMe2
	BF3 OEt2

97

55a, b

95 57

94 58

98 58

98 59

97 60

205 Addition Conjugate 1.6

Tab. 6.5 (continued)

Entry	Auxiliary R	Reagents	Assumed Reactive	Product	de [%]	Ref.
			Conformationa)
11		PhMgCl			95	61a
		CuBr SMe2
12		MgBr2			78	61b
		(PhMe2Si)2CuLi
13		Ph2CuLi			88	62
14		n-BuCu			>99	63
		BF3 OEt2

Reactions Substitution Allylic and Addition Conjugate Diastereoselective mediated-Copper 6 206

15	Ph2CuLi	92	64
	BF3 OEt3
16	(vinyl)MgBr	>98	65
	CuBr SMe2
17	(vinyl)MgBr	72	65
	CuBr SMe2

a)A bold arrow indicates attack from the upper side or the front side, respectively. A dashed arrow indicates attack from the lower or the back side, respectively.

207 Addition Conjugate 1.6