Cobalt-Mediated, Enantioselective Synthesis of C₂ and C₁ Dienes

In recent years, enantiopure C₂- and C₁-symmetric dienes have been established as authoritative ligands for asymmetric reactions mediated by late transition metals.¹ Despite their utility, current synthetic routes to these ligands remain unsatisfying and often rely upon preparative chiral HPLC, chiral auxiliaries, chiral pool starting materials, or chemoenzymatic reactions to access enantiopure material.^2–6 Hayashi and co-workers reported an effective enantioselective synthesis of C₂-symmetric dienes based upon the desymmetrization of norbornadiene.2a-b In the first step in the synthesis of the chiral ligand, a double asymmetric hydrosilylation of norbornadiene with HSiCl₃ catalyzed by [PdCl(η³-C₃H₅)]₂ and a chiral phosphine ligand was reported to yield an enantiopure di(silane). However, a multi-step reaction sequence was required to re-establish the diene moiety and build steric bulk into the chiral scaffold.2a-b^,3

If the synthesis of C₂-dienes could be achieved via a direct desymmetrization of the parent diene by an asymmetric C-H functionalization of the sp²-carbons, it would represent a concise approach to this important class of chiral ligands (Scheme 1). In addition, the use of a prochiral electrophile in the reaction would allow for the preparation of enantiopure ligands that bear additional stereocenters, provided these reactions proceed with high stereoselectivities.

Scheme 1.

Synthesis of C₂-dienes by desymmetrization of norbornadiene.

Recently, we reported a stepwise C-H functionalization of the sp² carbon of simple alkenes mediated by the reactive intermediate [CpCo(NO)₂] (Scheme 2).^7–9 Herein we report that N-benzylated ammonium chloride salts (Chart 1, 1–4) combined with sodium hexamethyldisilazide (NaHMDS) can promote this reaction, while serving as a source of chirality to desymmetrize norbornene and norbornadiene. This methodology has been applied to a modular asymmetric synthesis of C₁- and C₂-symmetric diene ligands.

Scheme 2.

C-H functionalization mediated by [CpCo(NO)₂].

Chart 1.

N-benzylated ammonium chlorides.

Initial experiments demonstrated that addition of a mixture of NaHMDS and the quininium salt 1 to a mixture of 2- cyclohexen-1-one and cobalt complex 5 gave adduct 6 in 87% d.e. and high yield. Subsequent cycloreversion of 6 in the presence of norbornene yielded 5 and the diastereomerically impure alkene 7 which was obtained in a low but significant 18% e.e. (Table 1, entry 1). The order of reagent addition proved to be critical to the enantioinduction; in fact, adding NaHMDS to a mixture containing the remaining reagents gave the product with only 2% e.e. (entry 2). As NaHMDS alone can promote a racemic background reaction, we suspect a chiral base formed upon mixing 1 with NaHMDS is responsible for the observed enantioinduction.

Table 1.

Screening of reaction conditions for addition of norbornene to 2- cyclohexen-1-one.

Entry	Temp.(°C)	Solvent	Cp'	(R*)4NCI	time	Yield of 6	d.e. of 6	e.e. of 7a
1	25	THF/HMPAc	Me4Cp	1	3h	87%	87%	18%
2b	25	THF/HMPAc	Me4Cp	1	4h	81%	72%	2%
3	25	THF	Me4Cp	1	17.5h	75%	94%	36%
4	−60 to 0	THF	Me4Cp	1	6 days (14 h at 0 °C)	74%	>99%	58%
5	0	THF	tBuCp	1	22 h	35%	>99%	72%
6	−45	THF	tBuCp	2	17 h	53%	>99%	74%
7	−58	THF	TBDMSCp	3	15 h	73%	>99%	83%

^aNaHMDS and (R*)₄NCl premixed and filtered, e.e. of major diastereomer only,

^bNaHMDS added to mixture of substrates and (R*)₄NCl,

^c5.3:1 THF to HMPA.

Abbreviations: Me₄Cp = η⁵-Me₄C₅H, ^tBuCp = η⁵-^tBuC₅H₄, TBDMSCp = η⁵- ^tBuMe₂SiC₅H₄.

Several alternative solvents gave comparable or inferior results compared to those observed with THF/hexamethylphosphoramide (HMPA). Performing reactions in THF, however, gave significantly higher e.e. at room temperature (entry 3), while lowering the reaction temperature to −60 °C increased the e.e. to 58% (entry 4). It is noteworthy that at lower temperatures, commensurate with the improvement of enantioselectivity, there was an improvement in the diastereoselectivity of the reaction. Employing the bulkier and more directional ligand [η⁵-(^tBu)C₅H₄] on cobalt allowed optimization to 72% e.e. (entry 5). Comparable results were obtained with [η⁵-(^tBuMe₂Si)C₅H₄] in place of the [η⁵- (^tBu)C₅H₄] ligand, and using quininium salts bearing trifluoromethyl groups on their N-benzyl moieties allowed further optimization, with the bis(trifluoromethyl) substituted salt 3 yielding the Michael adduct 6 in 73% yield and >99% d.e and the corresponding alkene in 83% e.e. (entry 7).

Using these conditions, we examined the asymmetric C-H functionalization of both norbornene and norbornadiene with 5, 6, and 7-membered cyclic enones. The details of these experiments are provided in the Supporting Information (Table S3). Michael addition reactions proceeded in good yields (66–90%) to give enantioenriched cobalt complexes with high diastereoselectivity (>99% d.e.) with subsequent retrocycloaddition yielding alkene products with moderate enantioselectivity (43–85% e.e.). The enantioselective functionalization of norbornadiene prompted the application of this methodology to asymmetric ligand synthesis (Scheme 3). If two sequential C-H activation/Michael addition steps could be carried out efficiently and benefit from double stereodifferentiation, it could not only result in overall higher enantioselectivities, but would obviate the requirement for enantiopure precursors in the synthesis of chiral diene ligands.

Scheme 3.

Synthesis of C-H functionalized norbornadiene complexes

The first step of this preparation was the isomerization of enantioenriched complexes 8a-c to 10a-c (Scheme 4). Despite the fact that the alkene that accepts the [Cp’Co(NO)₂] fragment is not present in excess, these reactions proceeded cleanly and in high yield (80–93 %) by simply heating samples of 8a-c in toluene or THF solution. A second asymmetric C-H functionalization of 10a-c yielded a mixture of cobalt complexes anti-11a-d and syn-11a-d which could be converted, via alkene exchange with norbornadiene, to a mixture of the corresponding dienes anti-12a-d and syn-12a-d respectively (Table 2).

Scheme 4.

Isomerization of 8a-c to 10a-c

Table 2.

Asymmetric synthesis of C₂- and C₁-dienes

n	m	complex	yield of 11a	diene	anti : syn	e.e. of anti-12
1	1	11a	42%	12a	3.7:1	90% (R,R,R,R)
2	2	11b	67%	12b	20:1	96% (R,R,R,R)
2	2	11b	73%b	12b	10:1	94% (S,S,S,S)c
3	3	11c	87%	12c	11:1	91%(R,R,R,R)
2	3	11d	84%b	12d	11:1	96%(R,R,R,R)

^achiral conditions; 3/NaHMDS pre-mixed, filtered and then added to reaction mixture at −58 °C,

^breaction conducted at −75 °C.

^csalt 4 used in place of 3.

While poor anti:syn selectivity (1.3–2.7:1) was observed using achiral starting materials and a non-chiral base (see supporting information, Figure S6),¹⁰ using enantioenriched starting materials and the asymmetric base mixture (vide supra) anti:syn ratios were 3.7–20:1 across the series of substrates. Under these conditions only one diastereomer of each regioisomeric product was observed, and following retrocycloaddition, dienes anti-12a-d were isolated in good yield and 90–96% e.e.

Recrystallization of a mixture of anti- and syn-12b from n- pentane removed the minor regioisomer and increased the e.e. to 99%. The absolute configuration of anti-12b was determined as (R,R,R,R)-12b by single crystal X-ray diffraction analysis (Figure 1). The enantiomer, (S,S,S,S)-12b, is available in 94 % e.e. via use of chiral ammonium salt 4 in the synthetic sequence.

Figure 1.

ORTEP representation of (R,R,R,R)-12b. H-atoms omitted for clarity. Selected bond lengths (Å): C(5)-C(6) 1.332(2), C(5)-C(4) 1.502(2), C(2)-O(2) 1.216(2). Flack parameter = 0.1451(0.1655).

We propose that the high selectivity in this C-H functionalization reaction sequence occurs because desymmetrization of the nucleophile controls enantioselectivity while approach of the electrophile controls diastereoselectivity (Figure 2). The two stereoselection events are orthogonal and two pairs of non-contiguous stereocenters are set with near perfect control in the enantioselective synthesis of the anti-regioisomer of these diene ligands. The minor regioisomeric products, syn-12a-c, are meso-symmetric and arise from imperfect regiocontrol in the second carboncarbon bond forming step.

Figure 2.

Proposed origin of stereoselectivity.

In a further demonstration of utility, the ease of ligand derivatization by functional group manipulation of the ketone moieties of (R,R,R,R)-12b was demonstrated. Thus, reduction of the carbonyl groups with NaBH₄ followed by xanthate formation and Barton-McCombie reduction yielded (1R,4R)- 2,5-dicyclohexylbicyclo[2.2.1]hepta-2,5-diene, an effective ligand for rhodium-catalyzed asymmetric conjugate addition (see supporting information for experimental details).³

In short, we have demonstrated an asymmetric synthesis of C₂- and C₁-symmetric dienes, based upon a C-H functionalization reaction mediated by cobalt di(nitrosyl) complexes that proceeds with excellent regio-, diastereo- and enantiocontrol. We are continuing to study the nature of the active base derived from quininium salt/metal amide mixtures and the applications of the enantiopure products described herein as ligands in asymmetric catalysis.