Modern Organocopper Chemistry

Modern Organocopper Chemistry. Edited by Norbert Krause

Copyright > 2002 Wiley-VCH Verlag GmbH

ISBNs: 3-527-29773-1 (Hardcover); 3-527-60008-6 (Electronic)

188

6

Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

Bernhard Breit and Peter Demel

Abstract

Conjugate additions and allylic substitution reactions of organocopper reagents are synthetically valuable CaC bond-forming reactions. New stereogenic centers may be introduced in the course of either reaction. Their selective formation may be controlled either by the reagent or by the substrate, the latter being the focus of this review. The subject has recently been summarized comprehensively [1], and so this chapter focuses on important basic principles and the most recent progress, with emphasis on reactions of potential value in organic synthesis.

6.1

Conjugate Addition

6.1.1

Stereocontrol in Cyclic Derivatives

Cyclic systems usually adopt distinct preferred conformations, which frequently allow them to pass through a single reactive conformation in the course of a chemical reaction; this may result in the formation of a single product. In this context, addition of organocuprates to a number of chiral, cyclic enone systems frequently occurs with high levels of stereoselectivity. Historically, this chemistry has had a major impact on the field of total synthesis of steroids and prostaglandins [1a, k]. In this chapter we would thus like to present an overview of the most general stereochemical trends underlying the addition of organocuprates to chiral cyclic enones.

When organocuprates are added either to 4-substituted cyclopentenones 1, or to 4-substituted or 5-substituted cyclohexenones (4 and 7), the trans addition product is generally obtained with good to excellent levels of diastereoselectivity (Scheme 6.1) [2–4]. The 6-substituted cyclohexenone 10, however, predominantly gave the syn addition product [5, 6].

A beautiful illustration of the power of diastereoselective cuprate addition to cyclopentenone systems is given in the course of the synthesis of the prostaglandin E2 (PGE2) (Scheme 6.2) [7]. Thus, addition of the functionalized organocuprate

6.1 Conjugate Addition 189

Scheme 6.1. Diastereoselectivity in conjugate addition of organocuprates to chiral cyclic enones.

reagent obtained from iodide 13 to the chiral cyclopentenone 14 occurred in trans selective fashion to give enolate 15. Transmetalation to the tin enolate, followed by stereoselective propargylation, furnished a 76% overall yield of cyclopentanone 16, which was transformed into prostaglandin E2 [7c].

Scheme 6.2. Diastereoselective addition of a functionalized cuprate to cyclopentenone 14 in the synthesis of prostaglandin E2 (PGE2) (TBS ¼ t-butyldimethylsilyl, HMPT ¼ hexamethylphosphoric triamide).

190 6 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

Addition of Lewis acids may not only accelerate the reaction rate of a conjugate addition but may also alter the stereochemical outcome of a cuprate addition. Interestingly, when the 6-t-butyl-substituted cyclohexenone derivative 17 was exposed to dibutylcuprate, followed by silylation of the resulting enolate, the cis enol ether 18 was obtained (Scheme 6.3) [8]. If, however, the cuprate addition was performed in the presence of chlorotrimethylsilane, the stereochemical outcome of the conjugate addition reaction was reversed to give trans enol ether 19.

Scheme 6.3. Influence of added TMSCl on the diastereoselectivity of the conjugate addition of dibutylcuprate to enone 17 (TMS ¼ trimethylsilyl, HMPT ¼ hexamethylphosphoric triamide).

It has recently been shown that the intrinsic substrate-directing capability of 5- substituted chiral cyclohexenenones can be overruled by making use of active substrate direction. Proper choice of the cuprate reagent made it possible to switch between standard passive substrate control and an alternative active substrate control, and hence to reverse the stereochemical outcome of the conjugate addition reaction [9]. Thus, treatment of 5-oxygen-substituted cyclohexenones 20 and 21 with a cyanoGilman reagent gave the expected trans addition products 24 and 25, respectively (entries 1, 4, 6, Tab. 6.1, Scheme 6.4). Conversely, when the corresponding lower order cyanocuprate was employed, diastereoselectivity was reversed and the cis addition products 22 and 23, respectively, were formed with high selectivities (entries 2, 3, 5). A very reasonable explanation for this result is a benzyloxyor silyloxy-directed cuprate addition through transition state 26 (Scheme 6.5) [9b–e, 10].

Tab. 6.1. Results of conjugate addition of organocopper reagents to enones 20 and 21.

Entry	Substrate	R1	Method a)	cis:trans	Yield [%]	Ref.
1	20	n-Bu	B	10:90	87	9b
2	20	n-Bu	A	>98:2	80	9b
3	21	n-Bu	Ab)	>99:1	92	9b
4	21	n-Bu	B	2:98	92	9a, b
5	21	Me	A	>99:1	83	9b
6	21	Me	B	3:97	83	9a, b

a)Et2O, 78 C, 2.4 eq. of cuprate reagent (A: R1Cu(CN)Li; B: R12CuLi LiCN).

b)1.2 eq. of cuprate reagent.

6.1 Conjugate Addition 191

Scheme 6.4. Diastereoselectivity in conjugate addition of organocopper reagents to alkoxy-substituted cyclohexenones 20 and 21 (Bn ¼ benzyl, TBS ¼ t-butyldimethylsilyl).

Scheme 6.5. Rationale for the stereochemical outcome of diastereoselective conjugate addition to cyclohexenones 20 and 21.

The addition of organocuprates to chiral decalin enone systems has been explored in the context of steroid synthesis. For the addition of lithium dimethylcuprate to enones 28, 31, and 34, the major diastereomer obtained can easily be predicted by employment of a qualitative conformational analysis (Scheme 6.6) [11–13]. Thus,

Scheme 6.6. Diastereoselectivity in conjugate additions of organocuprates to chiral bicyclic cyclohexenones (TMS ¼ trimethylsilyl).

192 6 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

attack of the copper nucleophile occurs in all cases through the most stable halfchair conformation to give the corresponding addition products. A similar analysis also accounts for the 1,6-addition to dienone 37 [14].

Rather less information on addition of cuprates to larger cyclic enone systems is available. 4-Substituted cycloheptenones (such as 40) have been shown to give the trans addition products preferentially (Scheme 6.7) [15]. Furthermore, interesting selectivities have been noted upon addition of lithium dimethylcuprate to cyclodecanone systems 43 and 46. These systems should adopt the preferred conformations 45 and 48, which on addition of the nucleophile provide either the trans adduct 44 or the cis product 47, respectively [16]. Similar results have been obtained from conjugate additions of organocopper reagents to mediumand large-ringed a; b-unsaturated lactone systems. This field has been reviewed recently [1i].

Scheme 6.7. Diastereoselectivity in conjugate addition of organocuprates to chiral cyclic enones of medium ring size.

6.1.2

Stereocontrol in Acyclic Derivatives

6.1.2.1 g-Heteroatom-substituted Michael Acceptors

Conjugate addition reactions of acyclic Michael acceptors possessing heteroatomsubstituted stereogenic centers in their g-positions may provide useful levels of diastereoselectivity. A typical example is given with the g-alkoxy-substituted enoate 49 in Scheme 6.8 [17]. High levels of diastereoselectivity in favor of the anti addition product 50 were found in the course of dimethylcuprate addition.

To account for the observed diastereoselectivity, a ‘‘modified’’ Felkin–Anh model has been proposed [18]. In analogy to the classical Felkin–Anh model, originally developed for the addition of organometallic reagents to aldehydes possessing a

6.1 Conjugate Addition 193

Scheme 6.8. Diastereoselective addition of lithium dimethylcuprate to acyclic enoate 49 (TBDPS ¼ t-butyldiphenylsilyl, BOM ¼ benzyloxymethyl,

TMS ¼ trimethylsilyl).

stereogenic center in the a-position, the largest substituent or, more precisely, the substituent with the lowest lying s -orbital (L in Fig. 6.1), should be orientated so as to allow e cient overlap with the p-system of the Michael acceptor. As a consequence, the LUMO (p -CbC) should be lowered in energy, which provides a more reactive conformation. This holds for both rotamers 51 and 52. Rotamer 51, however, su ers to a greater extent from repulsive allylic A1; 3 strain [19]. Accordingly, for Z-configured p-systems, A1; 3 strain should become the decisive factor. Conversely, nucleophile attack is more hindered for rotamer 52. Hence, for E-configured Michael acceptors in particular, a subtle balance of these two repulsive interactions should govern the overall stereochemical outcome of the conjugate addition reaction. Finally, it should be kept in mind that this model relies on the basic assumption that nucleophile attack is the step that determines stereoselectivity. This notion has been challenged, however, both in recent high level calculations and in experimental studies [20–22]. Nevertheless, this simple model provides at least a rough first order analysis for the stereochemical outcome that should be expected in the course of a conjugate addition reaction to g-chiral Michael acceptors.

Stereoselective addition of cuprates to g-alkoxy enoates of type 49 [17] (see Schemes 6.8 and 6.9) has been used in the construction of polypropionate-type structures. Thus, a sequence of diastereoselective cuprate addition, enolate formation, and diastereoselective oxygenation with Davis’s reagent has been applied iteratively to provide a C19 aC28 segment of Rifamycin S (60) [17c, d].

Chlorotrimethylsilane-accelerated divinylcuprate addition to enal 61, followed by a Wittig olefination, provided enoate 62 as a single stereoisomer in excellent yield (Scheme 6.10) [23]. The enoate 62 could be transformed in further steps into olivin (63), the aglygon of olivomycin.

Fig. 6.1. ‘‘Modified’’ Felkin–Anh model to account for the observed diastereoselectivity in conjugate addition reactions to g-chiral Michael acceptors.

194 6 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

Scheme 6.9. Construction of the polypropionate segment of Rifamycin S through iterative diastereoselective cuprate addition to acyclic enoates. a) Me2CuLi, TMSCl, THF, 78 C; b) KHMDS, THF, 78 C; Davis oxaziridine; c) MOMCl, i-Pr2NEt, CH2Cl2; d) DIBAL-H; e) Swern oxidation,

f ) Ph3PbCHCO2Me, CH2Cl2; g) NaBH4, THF/ H2O; h) TrCl, DMAP, CH2Cl2; i) NaH, MeI, DMF; j) TBAF, THF; k) CuBr SMe2, MeLi LiBr,

TMSCl, THF; l) BOMCl, i-Pr2NEt, CH2Cl2;

R1 ¼ BOM, R2 ¼ MOM. (TMS ¼ trimethylsilyl, KHMDS ¼ potassium hexamethyldisilazide, MOM ¼ methoxymethyl, DIBAL-H ¼ diisobutylaluminium hydride, Tr ¼ triphenylmethyl, DMAP ¼ 4-N,N- dimethylaminopyridine, TBAF ¼ tetrabutylammonium fluoride, BOM ¼ benzyloxymethyl)

With glyceraldehyde-derived enones and enoates, it has been found that addition of aryl or alkenyl copper reagents is almost independent of the enone geometry [24, 25]. In agreement with the ‘‘modified’’ Felkin–Anh model, Z enoates usually provide high levels of anti selectivity (Scheme 6.11). Hence, the Z derivative 64 reacted with complete stereochemical control, whereas the E-enoate 64 gave a lower selectivity of 4:1 in favor of the anti-conjugate adduct [25].

A drawback of the Z enoates is usually lower reactivity, reflected in prolonged reaction times and higher reaction temperatures. This may be overcome by switching to more reactive enone systems. Thus, addition of the functionalized cyanoGilman cuprate system 67 to Z enone 66 proceeded smoothly at low temperatures, with excellent acyclic stereocontrol at the b-stereocenter [26, 27]. Stereocontrol upon

6.1 Conjugate Addition 195

Scheme 6.10. Stereoselective cuprate addition to enal 61 – the key step towards the synthesis of olivin. (TBS ¼

t-butyldimethylsilyl, TMS ¼ trimethylsilyl)

Scheme 6.11. Influence of double bond geometry upon addition of diphenylcuprate to enoate 64.

enolate protonation, however, was only moderate. Conjugate adduct 68 was further transformed to give iso[7]-levuglandin D2 (Scheme 6.12) [26].

Scheme 6.12. Diastereoselective cuprate addition to Z enone 61 – key step towards the synthesis of iso[7]-levuglandin D2. (TBS ¼ t-butyldimethylsilyl)

196 6 Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions

The stereochemical trends discussed above are not limited to a; b-unsaturated carbonyl compounds; other Michael acceptors such as nitroalkenes and unsaturated phosphane oxides display similar behavior. A representative example for the nitroalkene class of Michael acceptors is shown with substrate 70 in Scheme 6.13 [28]. The best results were thus obtained for arylcuprates. Other organocuprates were much less selective, which severely restricts their application in organic synthesis.

Scheme 6.13. Diastereoselective cuprate addition to nitroalkene 70.

Similar observations were made in a related series of unsaturated phosphane oxides (such as 73, Scheme 6.14) [29]. Whereas dialkylcuprates mostly reacted nonselectively, the best diastereoselectivities were observed for disilylcuprates (74).

Scheme 6.14. Diastereoselective cuprate addition to a; b- unsaturated phosphane oxide 73 (TBS ¼ t-butyldimethylsilyl).

Obviously, the nature of the organocopper reagent is an important factor with respect to the stereochemical outcome of the cuprate addition. This is nicely illustrated for the cuprate addition reaction of enoate 75 (Scheme 6.15). Here, lithium di-n-butylcuprate reacted as expected by way of the ‘‘modified’’ Felkin–Anh transition state 77 (compare also 52), which minimizes allylic A1; 3 strain, to give the anti adduct 76 with excellent diastereoselectivity [30]. Conversely, the bulkier lithium bis-(methylallyl)cuprate preferentially yielded the syn diastereomer 78 [30, 31]. It can be argued that the bulkier cuprate reagent experiences pronounced repulsive interactions when approaching the enoate system past the alkyl side chain, as shown in transition state 77. Instead, preference is given to transition state 79, in which repulsive interactions to the nucleophile trajectory are minimized.

A similar explanation may also hold for the result of conjugate addition to g- phthalimido enoate 80 (Scheme 6.16). Thus, addition of the bulky cyano-Gilman silyl cuprate gave the syn diastereomer 81 (dr ¼ 96:4) [32, 33]. Preference for the sterically least hindered nucleophile trajectory seems to dictate the overall stereochemical outcome (transition state 82).

The results for conjugate additions to pseudodipeptides 83 and 86 may be interpreted along similar lines. Thus, addition of the fairly ‘‘slim’’ lithium dimethylcuprate nucleophile proceeded non-selectively (84, Scheme 6.17) [34, 35]. Con-

6.1 Conjugate Addition 197

Scheme 6.15. Conjugate addition to enoate 75; influence of the nature of the cuprate reagent on diastereoselectivity.

Scheme 6.16. Diastereoselective cuprate addition to g-phthalimido enoate 80.

Scheme 6.17. Diastereoselective cuprate addition to pseudopeptides 83 and 86.