Diastereo- and Enantioselective Cross-Couplings of Secondary Alkylcopper Reagents with 3-Halogeno-Unsaturated Carbonyl Derivatives.

Chiral secondary alkylcopper reagents were prepared from the corresponding alkyl iodides with retention of configuration by an I/Li-exchange using tBuLi (-100 °C, 1 min) followed by a transmetalation with CuBr⋅P(OEt)3 (-100 °C, 20 s). These stereodefined secondary alkylcoppers underwent stereoretentive cross-couplings with several 3-iodo or 3-bromo unsaturated carbonyl derivatives leading to the corresponding γ-methylated Michael acceptors in good yields and with high diastereoselectivities (dr up to 96:4). The method was extended to enantiomerically enriched alkylcoppers, providing optically enriched advanced natural product intermediates with up to 90 % ee.

α,β‐Unsaturated carbonyl derivatives are valuable synthetic intermediates1 and are present in various natural products such as aranorosin (1)2 or ent‐stelletamide A (2)3 (see Scheme 1 a). For example, Landis et al.4 reported a one‐pot protocol involving an iterative asymmetric hydroformylation and subsequent Wittig olefination for the preparation of such γ‐chiral α,β‐unsaturated carbonyls. Alternatively, chiral molecules of type 3 may be prepared by the retentive cross‐coupling of α‐chiral organometallic reagents (4) with 3‐halogeno‐unsaturated carbonyl derivatives of type 5.

Scheme 1

Natural products bearing a chiral center vicinal to an α,β‐unsaturated carbonyl derivative (a). Cross‐couplings of chiral alkylcopper reagents with 3‐halogeno‐unsaturated carbonyl derivatives (b). i) tBuLi (inv. add., 2.2 equiv), pentane/ether (3:2), −100 °C, 1 min, ii) CuBr⋅P(OEt)3 (in ether, 2.0 equiv) −100 °C, 20 s.

Recently, we have reported the preparation of chiral secondary alkyllithium reagents 6, which were readily prepared from the corresponding alkyl iodides 7 via a stereoretentive I/Li‐exchange reaction performed in a mixture of pentane:ether (3:2) at −100 °C using tBuLi. (see Scheme 1 b).5 Subsequent transmetalation of these secondary alkyllithium intermediates with CuBr⋅P(OEt)3 afforded the corresponding secondary alkylcopper reagents 4, which were configurationally stable in THF at −50 °C for several hours.6 Herein, we wish to report stereoselective cross‐couplings of chiral alkylcopper reagents (4) with a range of 3‐halogeno Michael acceptors of type 5 leading to γ‐methylated α,β‐unsaturated carbonyl derivatives of type 3. (see Scheme 1 b).

In preliminary experiments we have treated the diastereomerically pure alkyl iodide syn‐7 a 5c with tBuLi (2.2 equiv) in a 3:2 mixture of pentane:diethyl ether at −100 °C for 1 min followed by a dropwise addition of CuBr⋅P(OEt)3 solution (2.0 equiv, 3 m in ether) leading to the corresponding alkylcopper reagent syn‐4 a (see Table 1).

Table 1

Determination of appropriate electrophiles for the stereoretentive cross‐coupling of syn‐4 a with electrophiles of type 5 affording the cyclopentenone derivative syn‐3 a.

Entry	Cyclopentenone derivative 5	Yield of syn‐3 a [a]	dr of syn‐3 a [b]
1	5 a: X=OTs	no product[c]	–
2	5 b: X=OTf	traces[c]	–
3	5 c: X=OC(O)C6F5	traces[c]	–
4	5 d: I	35 %	93:7
5	5 e: Br	62 %	92:8

[a] Yield of analytically pure products. [b] The diastereomeric ratio (dr, syn/anti ratio) was determined by 1H and 13C NMR analysis. [c] No product was obtained even after a reaction time of 12 h at −50 °C.

–

–

–

Such chiral secondary alkylcoppers were known to be configurationally stable at −50 °C in THF,6 therefore we have removed the solvents by vacuum and have replaced it with THF. Next, we have investigated this cross‐coupling with various cyclopentenone derivatives bearing a leaving group at position 3. Therefore, cyclopentane‐1,3‐dione was converted into the corresponding tosylate (5 a),7a triflate (5 b)7b and pentafluorobenzoate (5 c).7c Thus, we have noticed that the reaction of syn‐4 a with the electrophiles 5 a–c did not afford any product of type 3 even after stirring for 12 h at −50 °C. However, the reaction of syn‐4 a with 3‐iodocyclopent‐2‐en‐1‐one (5 d)8 afforded the desired product syn‐3 a in 35 % yield with dr=93:7.

Better results were obtained with 3‐bromocyclopent‐2‐en‐1‐one (5 e)9 as substrate and addition thereof to a solution of syn‐4 a provided the cyclopentenone syn‐3 a in 62 % yield with dr=92:8 (entry 5).

With these results in hand, we have performed the stereoselective cross‐coupling of syn ‐4 a with a range of 3‐halogeno Michael acceptors of type 5 (see Table 2). Thus, 3‐iodo‐ and 3‐bromocyclohexenone (5 f and 5 g)10 reacted smoothly with syn‐4 a leading to syn ‐3 b in 49–66 % yield with dr >94:6 (entry 1). Similarly, the cross‐coupling of syn‐4 a with 3‐iodo‐2‐methyl cyclohexenone (5 h)12 as electrophile afforded syn‐3 c in 77 % yield with dr=96:4 (entry 2). Furthermore, we have treated several 3‐iodo or 3‐bromo acrylates (5 i–5 m)12, 13, 14 with diastereomerically enriched alkylcoppers of type 4. Therefore, the coupling of syn ‐4 a with either (Z)‐ethyl 3‐iodo‐acrylate (Z‐5 i) or with (Z)‐ethyl 3‐bromo‐acrylate (Z‐5 j) furnished stereoselectively syn‐3 d in 65–81 % yield with dr up to 96:4 (E:Z>1:99, entry 3). Furthermore, the (Z)‐ethyl enoate syn‐3 e was prepared in 49 % yield (dr=94:6, E:Z>1:99, entry 4). The cross‐coupling of syn ‐4 a with either E‐5 l or E‐5 m provided the unsaturated ester syn‐3 f in 45–52 % yield with moderate diastereoselectivity (dr>80:20, entry 5). To our delight, we could expand this cross‐coupling to other secondary alkylcopper reagents (syn‐ and anti ‐4 b‐c)5b, 5d with the iodenoate (Z‐5 i) (entries 6–9). Thus, the reaction of the secondary alkylcopper reagent syn ‐4 b with (Z)‐5 i afforded the corresponding α,β‐unsaturated ester syn‐3 g in 73 % yield and dr=95:5 (entry 6). The corresponding anti‐alkylcopper reagent anti ‐4 b was prepared and subsequent cross‐coupling with (Z)‐5 i afforded anti ‐3 g in 81 % yield and dr=5:95 (entry 7). In addition, the OTBS‐substituted Michael acceptors syn ‐3 h (37 % yield, dr=94:6, entry 8) and anti ‐3 h (44 % yield, dr=9:91, entry 9) were readily prepared.

Table 2

Stereoretentive preparation of secondary alkylcopper reagents 4 and trapping with α,β‐unsaturated carbonyl derivatives of type 5 leading to γ‐methylated Michael acceptors of type 3.

[a] Yield of analytically pure products. [b] The diastereomeric ratio (dr, syn:anti ratio) was determined by 1H NMR, 13C NMR or GC‐analysis. [c] The depicted relative stereochemistry of the major stereoisomer is only presumed on the basis of previous studies.5, 6

We were able to further extend this method to the functionalization of optically enriched secondary alkyl iodides.6b For example, (R)‐3 i and (S)‐3 i were obtained in good yield and enantioselectivity (73 % yield, 88 % ee; 70 % yield, 90 % ee, see Scheme 2).

Scheme 2

Optically enriched α,β‐unsaturated carbonyl derivatives of type 3 prepared by a stereoretentive I/Li sequence and subsequent cross‐coupling with α,β‐unsaturated carbonyl derivatives. [a] In this case the ee% of the starting secondary alkyl iodide was difficult to determine by chiral GC‐analysis. It was estimated to be ca. 85 % ±5 % ee.

Furthermore, intermediates, which are present in the syntheses of several natural products were prepared.2, 3, 15 Thus, (R)‐3 j, occurring in the total synthesis of the above mentioned aranorosin,2 was prepared in 71 % yield and 88 % ee. The corresponding S‐enantiomer (S)‐3 j, which was used for the total synthesis of 6’epi‐aranorosin, was also obtained in 70 % yield, but in lower optical purity (72 % ee). Furthermore, (R)‐3 k (62 % yield and 82 % ee) and (S)‐3 k (67 % yield and 84 % ee), were prepared using this I/Li‐exchange sequence.15 Finally, we prepared the corresponding S‐enantiomer of a precursor, which was used in the total synthesis of ent‐stellettamide A.3 Therefore, (S)‐3 l was obtained in 63 % yield with 81 % ee.

In summary, we have reported that γ‐chiral Michael acceptors were readily prepared from chiral secondary alkyl iodides by an I/Li‐exchange reaction and subsequent transmetalation to copper followed by addition to a broad range of 3‐halogeno‐α,β‐unsaturated carbonyl derivatives. This method afforded γ‐methyl unsaturated enones and enoates from relatively unfunctionalized secondary alkyllithiums. Only a few functional groups are tolerated by this method.6b Nevertheless, advanced precursors for the preparation of natural products were prepared to underline the synthetic value of this approach.

Conflict of interest

The authors declare no conflict of interest.

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.

Supplementary

Click here for additional data file.