Developing asymmetric iron and ruthenium-based cyclone complexes; complex factors influence the asymmetric induction in the transfer hydrogenation of ketones

Abstract

The preparation of a range of asymmetric iron and ruthenium-cyclone complexes, and their application to the asymmetric reduction of a ketone, are described. The enantioselectivity of ketone reduction is influenced by a single chiral centre in the catalyst, as well as by the planar chirality in the catalyst. This represents the first example of asymmetric ketone reduction using an iron cyclone catalyst.

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Introduction

The ruthenium complex 1 (the Shvo catalyst)^1–4 reversibly splits to give hydride 2 and the unsaturated species 3.

By ‘shuttling’ between 2 and 3, the Shvo catalyst transfers pairs of hydrogen atoms between secondary alcohols and ketones and has been used to good effect in dynamic kinetic resolution (DKR) reactions of alcohols and amines.^2,3 There is evidence,⁴ largely based on kinetic isotope effects, that the hydrogen transfer to ketones and aldehydes, by the Shvo catalyst, takes place via a concerted ‘outer sphere’ mechanism (Fig. 1a). This is analogous to that of ketone reduction by the Noyori catalyst 4 (Fig. 1b).⁵

Fig. 1 Comparison of mechanisms of hydrogen transfer by a) ruthenium hydride 2, b) Noyori catalyst 4 and c) iron hydride 5. In c, the potential for substituents R^L (large) and R^S (small) to influence the enantioselectivity is illustrated.

The Shvo catalyst is also an efficient ketone reducing agent when using an excess of an alcohol (usually iPrOH) or formic acid as hydrogen source,^1d and can also catalyse hydrogenation reactions.^1b,c,4d,6 The closely related iron complex 5 has recently been prepared from the tricarbonyl precursor 6⁷ and employed in catalytic reduction reactions of ketones by Casey and Guan.⁸ The mechanism appears to be analogous to that of the Shvo catalyst 2 (Fig. 1c). In recent studies, complex 5 has been applied to the oxidation of alcohols using acetone as an acceptor, and a number of its derivatives have been reported and evaluated in this role.⁹ In our own studies,¹⁰ we reported the synthesis and applications of racemic complexes 7a–7g in alcohol oxidations. The complexes were formed by an intramolecular cyclisation from a linear dialkyne precursor 8, followed by diastereoisomer separation.^7,11

However, given their proposed mechanism for reduction of ketones, we reasoned that asymmetric derivatives of 7b–7g complexes should be capable of enantioselective ketone reduction reactions. Asymmetric induction would be predicted to be achieved by the steric and/or electronic effects of the groups flanking the central ‘C–O’ bond of the cyclone ligand (Fig. 1c).

Since the start of our studies in this area, Yamamoto has reported the synthesis of the asymmetric Shvo-type catalyst precursors 9a/9b, which are capable of asymmetric hydrogenation (35 atm H₂) of acetophenone in 14–21% ee and up to 100% conversion.^12a As far as we are aware this is the first example of an asymmetric Shvo-type catalyst, although Berkessel has very recently published a closely related system based on chiral-at-Fe complexes which catalysed pressure hydrogenation (i.e. with H₂ gas) of acetophenone in up to 31% ee.^12b Despite the difference in planar chirality, it was found that the same enantiomer of alcohol product (R) was formed by both 9a and 9b. Herein we disclose our own results in the area of asymmetric Shvo-type reduction catalysts using both iron- and ruthenium-based cyclone catalysts in asymmetric transfer hydrogenation (ATH) reactions (Table 1).

Table 1 Asymmetric reduction of acetophenone using iron and ruthenium cyclone complexes^a

Complex	Conditions	Time/h	Conv/%^b (alcohol)	Ee (R/S)
a 10 mol% iron catalyst was used, with 10 mol% Me3NO. b form. = formate byproduct. c ee was 20% (R) at 10 h and decreased with time. d Reactions at 28 °C, 1 M with 7c; 48h, 5% conv, 10% ee (R), 7f; 96h, 2% conv, 29% ee, 7g; 96 h, trace conversion.
7a	FA/TEA 28 °C 1 M	18	60 (<1 form)	n/a
7a	FA/TEA 40 °C 1 M	18	90 (+2 form)	n/a
7a	FA/TEA 60 °C 1 M	18	89 (+10 form.)	n/a
7a	iPrOH 28 °C 0.2 M	18	6.8	n/a
7a	iPrOH 60 °C 0.2 M	18	52	n/a
7b	FA/TEA 28 °C 1 M	48	25	15 (R)
7b	FA/TEA 40 °C 1 M	48	36	10 (R)
7c	FA/TEA 40 °C 1 M	96	10	10 (R)
7d	FA/TEA 28 °C 1 M	48	40	25 (R)
7d	FA/TEA 28 °C 1 M	96	69	23 (R)
7e	FA/TEA 28 °C 1 M	48	46	11 (R)
7d	FA/TEA 40 °C 1 M	96	80 (+5 form)	23 (R)
7e	FA/TEA 40 °C 1 M	48	91 (+5 form.)	11 (R)
7f	FA/TEA 40 °C 1 M^d	96	66 (+10 form.)	25 (R)
7g	FA/TEA 40 °C 1 M^d	96	17	5 (R)
12a	FA/TEA 60 °C 1.6 M	160	50	12 (R)^c
12a	iPrOH 60 °C 0.18 M	160	28	11 (R)
12b	FA/TEA 60 °C 1.6 M	160	61	3 (R)
12b	iPrOH 60 °C 0.18 M	160	35	4 (R)
12c	FA/TEA 60 °C 1.6 M	150	48	5 (R)
12c	iPrOH 60 °C 0.18 M	150	58	3 (R)
12e	FA/TEA 60 °C 1.6 M	18	31	17 (R)
12e	iPrOH 60 °C 0.18 M	18	13	11 (R)
13a/b	FA/TEA 60 °C 1.6 M	150	19	15 (S)
13a/b	iPrOH 60 °C 0.18 M	150	20	5 (S)
16	FA/TEA 60 °C 1.6 M	168	35 (+5 form.)	n/a
16	iPrOH 60 °C 0.18 M	184	17	n/a
17	FA/TEA 60 °C 1.6 M	168	80 (+7 form.)	n/a
17	iPrOH 60 °C 0.18 M	168	90	n/a
18	FA/TEA 60 °C 1.6 M	168	12.5	n/a
18	iPrOH 60 °C 0.18 M	168	21	n/a

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Racemic complex 7a¹⁰ was first tested and was found to work efficiently in a formic acid/triethylamine (FA/TEA) system, as commonly used in ATH reactions (Table 1).⁵ At low temperature only a trace of formate byproduct was observed. Raising the temperature to 60 °C resulted in essentially complete reduction although some formate co-product was formed. The use of 10 mol% catalyst was required, along with 10 mol% of trimethylamine N-oxide to initiate hydride formation.^9b,10,13 An inferior result was observed in iPrOH.⁵ Enantiopure complexes 7b–7g were prepared (Scheme 1) from alcohol (R)-11a (made in 96% ee by reduction of the precursor ketone 10a by ATH using an established catalyst¹⁴). Elaboration of (R)-11a following the reported route¹⁰ gave in each case (i.e. from 8b–d where R¹ = TBDMS, TMS and Ph respectively) two enantiomerically-enriched complexes which were separated by chromatography on silica gel. In our previous studies on the racemic series, we had established the relative configuration of the chiral centres via an X-ray crystallographic solution of 7c; the other iron complexes are assigned by analogy with 7b/c.¹⁰ The enantiomeric purity of catalyst 7d was established using a shift reagent and was established to be ca. 92% ee, indicating a small loss of ee relative to the alcohol but a high enough level to be meaningful in these investigations (see supporting information†). Conversions were in all cases measured by integrating the product peaks in the GC against the starting material peaks.

Scheme 1 Synthesis of iron catalysts 7b–7g.

The new catalysts were tested in the ATH of acetophenone (Table 1). In the case of 7b/c, the catalyst proved to be of low activity and a reduction product of low ee was formed in the same major enantiomeric form. Each purified, enantiomerically-pure diastereoisomer of 7d/e was found to be a more effective catalyst for ketone reduction in 5 : 2 FA/TEA, giving almost complete transformation within 48–96 h at 40 °C. Again, both gave reduction products of the same absolute configuration, mirroring the activity of the ruthenium complexes reported by Yamamoto.¹² More interestingly, catalysts 7f/g, which bear identical (phenyl) groups flanking the central C=O function in the cyclone, also gave the same alcohol enantiomers. The chiral centre on the backbone of the cyclone clearly has a significant effect on the catalyst enantioselectivity, possibly due to an influence on the conformation of the phenyl rings. Although the ees are low, the isomer with the methyl group positioned proximal to the Fe(CO)₃ group gave a higher ee in each case (7b,d,fvs.7c,e,g respectively). The effect may arise via an influence on the positions of the CO ligands which subsequently communicates to the reduction transition state.

Monitoring the reductions over time indicated that the ees did not change significantly over time, even after several days (e.g.7d after 48 and 96 h), indicating that product racemisation is not taking place. Although the conversions appear to level out over time, it is at present unclear as to whether this may be due to catalyst deactivation or a solvent effect. Formic acid/triethylamine was used in the traditional azeotrope ratio of 5 : 2 throughout. A ratio of 1 : 1 FA : TEA gave a conversion of 25% in 96 h and 21% ee when 7d was used as catalyst. A 1 : 2 FA : TEA mixture was not homogeneous, whilst a 5 : 1 FA : TEA mixture gave only 11% conversion after 96h, in 26% ee. These results indicate that the FA : TEA ratio effects the rate but not the ee of the reaction, with 5 : 2 being the best ratio of those tested.

As far as we are aware, this represents the first application of any iron cyclone complex to the asymmetric reduction of ketones by transfer hydrogenation,¹² and also reveals an unusual effect of a backbone chiral centre on the observed enantiocontrol.

We also wished to establish whether the analogous ruthenium-based catalysts would exhibit a similar pattern of enantioselectivity. To this end, complexes 12a–12f were prepared and evaluated, using the corresponding diyne precursors.¹⁵

Alcohol (R)-11a (96% ee) was converted to the three derivatives 12a–12f following the precedent for the iron complexes¹⁰ but with the use of Ru₃(CO)₁₂ in the complexation step.¹⁵ Complexes 12a/b, were formed as a mixture of two separable diastereoisomers of product in 27 and 12% isolated yields respectively. Although the relative position of the Me group has not been established, we have assumed that, in analogy with the iron series, that the major enantiomer is that in which the Me on the backbone is proximal to the Ru(CO)₃ group. Both 12a and 12b were effective in catalysing the reduction of acetophenone, again in the same absolute sense (Table 1). Unlike the Fe series, there was evidence of racemisation during extended reaction times; for example in the case of 12a, the ee was 20% after 10 h. For the Ru complexes, in situ formation of the hydride using NaOH in THF followed by phosphoric acid was completed prior to the reduction,^7a and Me₃NO was not required. The ruthenium catalysts were also used at lower loadings (1 mol%) than the iron complexes (10 mol%). In the case of 12c/d, only one isomer was isolated, and in low yield, from the cyclisation, and was assumed to be of the configuration shown in 12c. This complex promoted reduction but in poor enantioselectivity.

Complexes 12e/f have two identical groups flanking the central C=O group, analogous to 7c/d. The cyclisation to form 12e/f was achieved in low yield, however only one diastereoisomer, assumed to be 12e, could be isolated. This was capable of reduction of acetophenone in up to 17% ee (R), which, although low, confirms that for the Ru catalysts as well as the iron ones, planar asymmetry is not required for the asymmetric reduction. In order to eliminate the effect of one backbone chiral centre, complexes 13a/b were selected for study – in this case containing two methyl groups in a cis arrangement. This was prepared by reacting alcohol (R)-11b (see below) with mesylated (R)-11a, resulting in inversion of configuration. Cyclisation of the resulting diyne with Ru₃(CO)₁₂ gave a mixture from which one isomer of 13 was isolated in pure form. Although the relative positions of the methyl groups to the Ru(CO)₃ centre are not known, this catalyst will rely on planar chirality alone in the reduction reaction. The result was that acetophenone was reduced in up to 15% ee, and in this case unexpected (S) configuration (Table 1). Taken together, these results indicate that asymmetric induction by cyclone catalysts arises from a combination of control by backbone chiral centres and planar chirality.

The synthesis of catalysts 14a–c was investigated. The TBS-substituted alcohol (R)-11b was prepared from 10b in quantitative conversion, 88% isolated yield and over 99% ee using the same ATH catalyst as was used for 11a.¹⁴ Unfortunately, separation of the diastereomers of these complexes could not be achieved and these were not evaluated in reductions.

In studies directed at improving the d.e.s of the cyclisation through the use of a larger group on the chiral centre, we examined derivatives of 8 where R³ = Ph. Ru/TsDPEN catalysts are less effective at reduction of aryl/propargylic ketones 10c–10e,¹⁶ therefore these were reduced using (R)-Alpine borane.¹⁷ For variation of group R¹, we prepared alcohols (R)-11c–11e however the TMS derivative (R)-11c was prone to loss of the silyl group in the subsequent alcohol alkylation step. Reaction of the dialkyne derivatives of (R)-11d (96% ee) and (R)-11e (97% ee) with Ru₃(CO)₁₂ led to the formation of Ru cyclone complexes 15a–f, all of which were formed as inseparable mixtures of diastereoisomers and proved to be poor catalysts (see SI†). For comparison of relative reactivity, symmetrical complexes 16–18 were also prepared and tested in ATH reactions; the TBDMS-substituted catalyst 17 proved to be the most active (Table 1).

In conclusion, a series of enantiomerically enriched iron and ruthenium cyclone complexes have been prepared and applied to the ATH of ketones to alcohols. The iron complexes, in their first reported role as ATH catalysts, are as effective in terms of asymmetric induction as the ruthenium complexes, although higher loadings are required. Other iron-based catalysts have recently been reported to give higher activities and enantioselectivities.¹⁸ The results also indicate that the control of enantioselectivity in the reductions, whilst modest, appears to rely on a novel means of asymmetric induction by a remote chiral centre in addition to the planar symmetry of the catalysts.

Experimental section

Procedures for starting material ketones, racemic reductions, synthesis of 16–18, Tables for reductions using 15a–f and NMR spectra may be found in the Electronic Supporting Information†.

(R)-4-Phenyl-3-butyne-2-ol 11a¹⁴

(R,R)-Tethered Ru(II) catalyst (43 mg, 0.07 mmol)^14b was dissolved in iPrOH (135 cm³) at 28 °C. KOH (0.1 M in iPrOH, 3.46 cm³, 0.0346 mmol) was added and the solution was observed to initially turn dark purple and the gradually become lighter in colour. After stirring for 30 min at 28 °C, 4-phenyl-3-butyne-2-one 10a (2.00 g, 13.88 mmol) was added and again the mixture turned dark purple. After 15 h the solvent was removed in vacuo to afford a dark oil which was purified by short path distillation (125 °C, 5.8 mbar) to afford the alcohol as a colourless oil (1.80 g, 12.32 mmol, 89%); [α]²⁸_D +32.4 (c 0.966 in CHCl₃) (lit.^14a [α]²³_D −35.0 (c 1.0 in CHCl₃) 97% ee (S); m/z (ESI) 169 [M + 23]⁺; (Found (ESI): M + Na 169.0630, C₁₀H₁₀NaO requires 169.0624); ν_max 3298, 2978, 2927, 2870, 2225, 1595 and 1490 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.46–7.41 (2H, m, Ar), 7.34–7.28 (3H, m, Ar), 4.77 (1H, m, CH(OH)CH₃), 2.00 (1H, d, J 5.13, OH), 1.57 (3H, d, J 7.03, CH₃); δ_C (100 MHz, CDCl₃) 131.68 (CH, Ar), 128.42 (CH, Ar), 128.42 (CH, Ar), 122.61 (ipso, Ar), 90.96 (C≡C), 84.05 (C≡C), 58.91 (CH(OH)CH₃), 24.42 (CH(OH)CH₃); The ee was determined using chiral GC of the acetyl derivative of the alcohol synthesised from reacting a sample of the alcohol (<10 mg) with acetic anhydride (<50 μL) and DMAP (<1 mg) in DCM (ca. 1 cm³) overnight; cyclodextrin CB column; 96% ee, 115 °C, H₂, 15 psi, 62.72 (S), 64.18 min (R).^14b

(R)-Dipropargylic ether 8a (8; R¹ = H, R² = Ph, R³ = Me)¹⁹

Sodium hydride (0.190 g, 60% on mineral oil, 4.746 mmol, 1.1 eq.) was added to (R)-4-phenyl-3-butyne-2-ol (0.630 g, 4.315 mmol, 1 eq.) in THF (8 cm³) at 0 °C. After 30 min, propargylic bromide (0.55 cm³, 0.7695 g, 80% in toluene, 5.178 mmol, 1.2 eq.) was added at 0 °C and the reaction was left to warm to room temperature over 2.5 h. The mixture was quenched using saturated NH₄Cl_(aq) (30 cm³) and extracted with ether (3 × 30 cm³). The combined organic fractions were dried over MgSO₄ and the solvent removed in vacuo to afford a yellow oil. Purification by column chromatography (EtOAc/pet. ether (40–60) 1 : 20) afforded propargylic ether 8a (8; R¹ = H, R² = Ph, R³ = Me) as a yellow oil (0.70 g, 3.804 mmol, 88%); [α]²⁸_D +289.04 (c 0.762 in CHCl₃); m/z (ESI) 207 (M⁺ + 23); (Found (ESI): M + Na 207.0788, C₁₃H₁₂NaO requires 207.0780); ν_max 3289, 2985, 2932, 2853, 2361, 2223, 2198, 2115, 1958, 1888, 1724, 1671, 1596, 1489, 1439, 1368 and 1325 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.51–7.45 (2H, m, Ar), 7.38–7.32 (3H, m, Ar), 4.68 (1H, q, J 6.5, OCHCH₃), 4.44 (1H, dd, J 15.6, 2.0, OCHH), 4.36 (1H, dd, J 15.6, 2.0 OCHH), 2.49 (1H, t, J 2.0, C≡CH), 1.59 (3H, d, J 6.5, CH₃); δ_C (100 MHz, CDCl₃) 131.73 (CH, Ar), 128.43 (CH, Ar), 128.25 (CH, Ar), 122.45 (ipso, Ar), 87.88 (C≡C), 85.62 (C≡C), 79.56 ((C≡CH), 74.42 (C≡C), 64.62 (OCH), 55.74 (OCH₂), 22.00 (CH₃).

(R)-Dipropargylic ether 8c (8; R¹ = Me₃Si, R² = Ph, R³ = Me)¹⁰

To 8a (8; R¹ = H, R² = Ph, R³ = Me) (0.350 g, 1.9022 mmol, 1 eq.) in THF (12.5 cm³) was added nBuLi (1.6 M in hexanes, 1.3 cm³, 2.092 mmol, 1.1 eq.) at −78 °C. After 1 h at −78 °C, trimethylsilylchloride (0.29 cm³, 0.248 g, 2.283 mmol, 1.2 eq.) was added and the mixture stirred at −78 °C for 1 h before being allowed to warm to room temperature overnight. The reaction was quenched using saturated NH₄Cl_(aq) (15 cm³) and extracted using Et₂O (3 × 15 cm³). The combined organics were dried over MgSO₄ and the solvent removed in vacuo to afford the product as a dark yellow oil (0.4800 g, 1.86 mmol, 98%) and used without further purification; [α]²⁸_D +160.04 (c 0.57 in CHCl₃); m/z (ESI) 279 [M + 23]⁺; (Found (ESI): M + Na 279.1176 C₁₆H₂₀NaOSi requires 279.1176); ν_max 2985, 2954, 2927, 2890, 2843, 2168, 1763, 1595 and 1487 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.48–7.45 (2H, m, Ar), 7.34–7.30 (3H, m, Ar), 4.62 (1H, q, J 6.5, OCHCH₃), 4.42 (1H, d, J 15.6, OCHH), 4.32 (1H, d, J 15.6, OCHH), 1.57 (3H, d, J 6.5, CH₃), 0.20 (9H, s, Si(CH₃)₃); δ_C (100 MHz, CDCl₃) 131.73 (CH, Ar), 128.39 (CH, Ar), 128.24 (CH, Ar), 122.55 (ipso, Ar), 101.29 (C≡C), 91.35 (C≡C), 88.12 (C≡C), 85.53 (C≡C), 64.66 (OCH), 55.61 (OCH₂), 22.02 (CHCH₃), −0.10 (Si(CH₃)₃).

(R)-Dipropargylic ether 8 (R¹ = (iPr)₃Si, R² = Ph, R³ = Me)

To 8a (8: R¹ = H, R² = Ph, R³ = Me) (0.350 g, 1.9022 mmol, 1 eq.) in THF (12.5 cm³) was added nBuLi (1.6 M in hexanes, 1.3 cm³, 2.092 mmol, 1.1 eq.) at −78 °C. After 1 h at −78 °C triisopropylsilylchloride (0.49 cm³, 0.440 g, 2.283 mmol, 1.2 eq.) was added and the mixture stirred at −78 °C for 1 h before being allowed to warm to room temperature overnight. The reaction was quenched using saturated NH₄Cl_(aq) (15 cm³) and extracted using Et₂O (3 × 15 cm³). The combined organics were dried over MgSO₄ and the solvent removed in vacuo to afford the product as a dark orange oil in quantitative yield and used without further purification; [α]²⁸_D +150.35 (c 0.20 in CHCl₃); m/z (ESI) 363 [M + 23]⁺; (Found (ESI): M + Na 363.2115 C₂₂H₃₂NaOSi requires 363.2115); ν_max 2937, 2890 and 2863 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.47–7.44 (2H, m, Ar), 7.34–7.30 (3H, m, Ar), 4.74 (1H, q, J 6.5, (OCHCH₃)), 4.41 (2H, s, OCH₂), 1.57 (3H, d, J 6.5, CHCH₃), 1.12–1.08 (21H, m, Si(CH(CH₃)₂)₃); δ_C (100 MHz, CDCl₃) 131.82 (CH, Ar), 128.39 (CH, Ar), 128.27 (CH, Ar), 122.67 (ipso, Ar), 103.14 (C≡C), 88.30 (C≡C), 87.73 (C≡C), 85.34 (C≡C), 64.01 (OCH), 56.58 (CH₂), 22.03, 18.61, 17.72, 12.31, 11.19.

(R)-Dipropargylic ether 8b (8: R¹ = (tBu)₃SiMe₂, R² = Ph, R³ = Me)¹⁰

Compound 8a (8: R¹ = H, R² = Ph, R³ = Me) (0.195 g, 1.06 mmol) was dissolved in dry THF (15 cm³) and cooled to −78 °C. n-Butyllithium in hexanes (1.6 M, 0.79 cm³, 1.26 mmol) was added dropwise and the mixture was allowed to stir for 1 h after which time tert-butyldimethylsilylchloride (0.207 g, 1.37 mmol) in dry THF (5 cm³) was added. After 17 h the reaction was quenched with H₂O (20 cm³), the THF was removed under reduced pressure and the product was extracted into Et₂O (3 × 20 cm³). The combined organic phase was dried over Na₂SO₄, filtered and the solvent was removed under reduced pressure to give the product as a brown oil which was purified by column chromatography on silica with a gradient elution from 100% petroleum ether to 80 : 20 petroleum ether : ethyl acetate to give the product 8 as a yellow oil (0.206 g, 0.69 mmol, 65%). The measured data is in agreement with that previously reported for the racemic compound.¹⁰ [α]²⁴_D +150.7 (c 1.0 in CHCl₃); δ_H (300 MHz, CDCl₃) 7.42–7.46 (2H, m, Ar), 7.28–7.34 (3H, m, Ar), 4.64 (1H, q, J 6.8, CCH(CH₃)O), 4.41 (1H, d, J 15.8, CCH₂O), 4.33 (1H, d, J 15.8, CCH₂O), 1.55 (3H, d, J 6.8 Hz, (CCH(CH₃)O), 0.95 (9H, s, Si(CH₃)₂C(CH₃)₃) 0.12 (6H, s, Si(CH₃)₂C(CH₃)₃.

(R)-Dipropargylic ether 8d (8: R¹ = Ph, R² = Ph, R³ = Me)

To 8a (8: R¹ = H, R² = Ph, R³ = Me) (0.400 g, 2.1739 mmol, 1 eq.), phenyliodide (0.29 cm³, 0.5322 g, 2.6087 mmol, 1.2 eq.) in triethylamine (7 cm³) at 50 °C was added Pd(Cl₂)(PPh₃) (0.031 g, 0.043 mmol, 0.02 eq.) After stirring for 5 min, CuI (0.04 g, 0.0217 mmol, 0.01 eq.) was added and the mixture kept at 50 °C for 18 h. The mixture was then hot filtered to remove the amide salts. Removal of the remaining aminein vacuo afforded a yellow oil which was purified by column chromatography to afford the product as a light yellow oil (0.358 g, 1.3769 mmol, 63%); [α]²⁸_D +180.00 (c 0.16 in CHCl₃); m/z (ESI) 261 [M + 1]⁺, 283 [M + 23]⁺; (Found (ESI): M + Na 283.1093 C₁₉H₁₆NaO requires 283.1093); ν_max 3052, 2981, 2934, 2843, 2219 and 1716 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.50–7.46 (4H, m, Ar), 7.35–7.30 (6H, m, Ar), 4.73 (1H, q, J 6.5, OCHCH₃), 4.65 (1H, d, J 15.6, OCHH), (R¹ = Ph, R² = Ph, R³ = Me).^10,19 4.73 (1H, q, J 6.5, OCHCH₃), 4.65 (1H, d, J 15.6, OCHH), 4.57 (1H, d, J 15.6, OCHH), 1.61 (3H, d, J 6.5, OCHCH₃); δ_C (100 MHz, CDCl₃) 131.81 (CH, Ar), 131.76 (CH, Ar), 128.42 (CH, Ar), 128.40 (CH, Ar), 128.25 (CH, Ar), 128.23 (CH, Ar), 122.61 (ipso, Ar), 122.54 (ipso, Ar), 88.18 (C≡C), 86.22 (C≡C), 85.61 (C≡C), 84.92 (C≡C), 64.66 (OCH), 56.60 (OCH₂), 22.08 (OCHCH₃).

(R)-Alcohol 11b²⁰

Tethered-TsDPEN (R,R) Ru(II) catalyst^14b (31 mg, 0.005 mmol, 0.5 mol%) was dissolved in anhydrous iPrOH (97 cm³) and warmed to 28 °C. On addition of KOH (in iPrOH, 0.1 M, 2.5 cm³, 0.25 mmol) the colourless solution turned dark purple and was stirred at 28 °C for 30 min before TBDMS-3-butyn-2-one 10b (1.840 g, 10 mmol) was added. After 18 h at 28 °C the solvent was removed in vacuo and the resulting alcohol was purified by column chromatography (EtOAc/hexane 5%) to afford a yellow oil (1.630 g, 8.76 mmol, 88%); m/z (ESI) 207 [M + 23]⁺; [α]²⁸_D +26.29 (c 0.978 in CHCl₃); ν_max 3315, 2954, 2924, 2887, 2853, 2168, 1470 1358, 1251, 1112, 1072, 1041 and 940 cm⁻¹; δ_H (300 MHz, CDCl₃) 4.52 (1H, dq, J 6.6, 5.3, CH(OH)CH₃), 1.77 (1H, d, J 5.3, OH), 1.45 (3H, d, J 6.6, CH(OH)CH₃), 0.93 (9H, s, SiC(CH₃)₃), 0.10 (6H, s, Si(CH₃)₂); δ_C (100 MHz, CDCl₃) 108.35 (quat., C≡C), 86.64 (quat., C≡C), 58.75 (CH(OH)CH₃), 26.00 (CH₃), 24.35 (CH₃), 16.42 (quat., SiC(CH₃)₃), −4.71 (CH₃, Si(CH₃)₂). The ee was determined using the acetyl derivative of the alcohol synthesised from reacting a trace amount of the alcohol (<10 mg) with acetic anhydride (<50 μL) and DMAP (<1 mg) in DCM (ca. 1 cm³) overnight. cyclodextrin CB column; 99% ee, 115 °C, H₂, 15 psi, 14.19 (S), 14.51 min (R).

(R)-Mesyl derivative of (R)-4-phenyl-3-butyne-2-ol 11a²¹

To (R)-4-phenyl-3-butyne-2-ol 11a (1.00 g, 1.00 cm³, 6.833 mmol, 1 eq.) and triethylamine (1.90 cm³, 13.46 mmol, 2 eq.) in DCM (10 cm³) at −78 °C was slowly added methanesulfonyl chloride (0.80 cm³, 10.13 mmol, 1.5 eq.) after 1 h the mixture was allowed to warm to room temperature and quenched with NaHCO_3(aq) (15 cm³), extracted with DCM (3 × 10 cm³) and dried over Na₂SO₄. Removal of the solventin vacuo afforded the mesylate as a colourless oil in quantitative yield and was used immediately without further purification; δ_H (400 MHz, d₆-DMSO) 7.50–7.46 (2H, m, Ar), 7.43–7.34 (3H, m, Ar), 5.55 (1H, q, J 6.5, CHCH₃), 3.18 (3H, s, SO₂CH₃), 1.77 (3H, d, J 6.5, CHCH₃).

(R,S)-Dipropargyl ether precursor of ligand 13a/b

To (R)-4-(t-butyldimethylsilyl)-3-butyne-2-ol 11b (0.3852 g, 2.0710 mmol, 1 eq.) in THF (5 cm³) was added sodium hydride (0.083 g, 2.0710 mmol, 60% in mineral oil, 1 eq.) at 0 °C. After 30 min the mesyl derivative of (R)-4-phenyl-3-butyne-2-ol 11a (0.46 g, 2.0710 mmol, 1 eq.) was added and the reaction was allowed to warm to room temperature over 18 h. After quenching the mixture using saturated aqueous sodium bicarbonate (5 cm³) the mixture was extracted with Et₂O (3 × 7 cm³) and dried over NaSO₄, removal of the solventin vacuo afforded a yellow oil which was purified by column chromatography (EtOAc/hexane gradient 1 : 100 to 1 : 10) yielding the product as a colourless oil (0.1911 g, 0.6125 mmol, 30%); [α]²⁸_D +0.19 (c 0.78 in CHCl₃); m/z (ESI) 335.2 [M + 23]⁺; (Found (ESI): M + Na 335.1801 C₂₀H₂₈NaOSi requires 335.1802); ν_max 2983, 2952, 2929, 2880 and 2853 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.48–7.42 (2H, m, Ar), 7.33–7.28 (3H, m, Ar), 4.72 (1H, q, J 6.5, CH), 4.51 (1H, q, J 6.5, CH), 1.55 (3H, d, J 6.5, CH₃), 1.50 (3H, d, J 6.5, CH₃), 0.95 (9H, s, SiC(CH₃)₃), 0.10 (6H, s, SiCH₃); δ_C (100 MHz, CDCl₃) 131.76 (Ar), 131.70 (Ar), 128.29 (Ar), 128.19 (Ar), 128.14 (Ar), 106.30 (C≡C), 89.35 (C≡C), 84.73 (C≡C), 63.47 (C≡C), 63.45 (C≡C), 26.04, 22.10, 21.79. −4.70 (Si(CH₃)₂).

Iron cyclone complexes 7b/c

(R)-Dipropargylic ether 8b (8: R¹ = (tBu)₃SiMe₂, R² = Ph, R³ = Me, 96% ee) (0.206 g, 0.69 mmol) and Fe(CO)₅ (0.27 cm³, 2.05 mmol) were dissolved in dry toluene (3 cm³) and heated at 130 °C for 24 h after which time the solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The brown residue was filtered through celite using a 9 : 1 mixture of hexane : ethyl acetate and subsequent purification by column chromatography on silica with a gradient elution from 100% petroleum ether to 40 : 60 petroleum ether : ethyl acetate gave two diastereomers of product, which were separated. The measured data is in agreement with that previously reported for the racemic compound.¹⁰ Minor diastereomer, yellow solid (0.026 g, 0.056 mmol, 8%); [α]²⁶_D −47.0 (c 0.05 in CHCl₃); δ_H (300 MHz, CDCl₃) 7.99–8.05 (2H, m, Ar), 7.29–7.39 (3H, m, 3H, Ar), 5.56 (1H, q, J 6.8 Hz, CCH(CH₃)O), 4.81 (1H, d, J 13.2 Hz, CH₂), 4.71 (1H, d, J 13.2 Hz, CH₂), 1.53 (3H, d, J 6.8 Hz, CH₃), 1.01 (9H, s, SiC(CH₃)₃) 0.47 (3H, s, Si(CH₃)₂C(CH₃)₃), 0.08 (3H, s, Si(CH₃)₂C(CH₃)₃). Major diastereomer, brown oil (0.140 g, 0.300 mmol, 44%); [α]²⁸_D +20.0 (c 0.05 in CHCl₃); δ_H (300 MHz, CDCl₃) 7.47–7.53 (2H, m, Ar), 7.29–7.41 (3H, m, Ar), 5.38 (1H, q, J 6.0 Hz, CCH(CH₃)O), 4.79 (1H, d, J 13.2 Hz, CH₂), 4.73 (1H, d, J 13.2 Hz, CH₂), 1.65 (3H, d, J 6.0 Hz, CH₃), 0.97 (9H, s, SiC(CH₃)₃) 0.51 (3H, s, Si(CH₃)₂C(CH₃)₃), 0.06 (3H, s, Si(CH₃)₂C(CH₃)₃).

Iron cyclone complexes 7d/e

These complexes (two diastereomers) were synthesised by the same procedure as for 7d/e using (R)-dipropargylic ether 8c (8: R¹ = TMS, R² = Ph, R³ = Me, 96% ee) (0.390 g, 1.53 mmol) and Fe(CO)₅ (0.60 cm³, 4.56 mmol) and were purified by column chromatography on silica gel with a gradient elution from 100% petroleum ether to 80 : 20 petroleum ether : ethyl acetate to give two diastereomers of product which were separated, as brown oils. The measured data is in agreement with that previously reported for the racemic material.¹⁰ Minor diastereomer (0.111 g, 0.262 mmol, 17%); [α]²⁸_D −166.0 (c 0.05 in CHCl₃); δ_H (300 MHz, CDCl₃) 7.99–8.03 (2H, m, Ar), 7.29–7.40 (3H, m, Ar), 5.57 (1H, q, J 6.4 Hz, CCH(CH₃)O), 4.81 (1H, d, J 12.8 Hz, CH₂), 4.71 (1H, d, J 12.8 Hz, CH₂), 1.52 (3H, d, J 6.4 Hz, CH₃), 0.33 (9H, s, Si(CH₃)₃). Major diastereomer (0.240 g, 0.566 mmol, 37%); [α]²⁸_D +101.0 (c 0.05 in CHCl₃); δ_H (300 MHz, CDCl₃) 7.48–7.52 (2H, m, Ar), 7.30–7.40 (3H, m, Ar), 5.36 (1H, q, J 6.4 Hz, CCH(CH₃)O), 4.79 (1H, d, J 13.2 Hz, CH₂), 4.71 (1H, d, J 13.2 Hz, CH₂), 1.65 (3H, d, J 6.4 Hz, CH₃), 0.31 (9H, s, Si(CH₃)₃).

Iron cyclone complexes 7f/g

These complexes (two diastereomers) were synthesised by the same procedure as for 7b/c using (R)-dipropargylic ether 8d (8: R¹ = Ph, R² = Ph, R³ = Me, 96% ee) (0.165 g, 0.63 mmol) and Fe(CO)₅ (0.25 cm³, 1.90 mmol) and were purified by column chromatography on silica with a gradient elution from 100% petroleum ether to 80 : 20 petroleum ether : ethyl acetate to give two diastereomers of product, which were separated. The measured data is in agreement with that previously reported for the racemic material.¹⁰ Minor diastereomer; brown powder (0.026 g, 0.061 mmol, 10%); [α]²⁸_D −75.0 (c 0.01 in CHCl₃); δ_H (300 MHz, CDCl₃) 8.06–8.11 (2H, m, Ar), 7.86–7.93 (2H, m, Ar), 7.32–7.45 (6H, m, Ar), 5.64 (1H, q, J 6.4 Hz, (CCH(CH₃)O), 5.17 (2H, s, CH₂), 1.54 (3H, d, J 6.4 Hz, (CCH(CH₃)O). A broad resonance exists from 6.5–7.6 ppm in the ¹H NMR spectrum that has not been assigned; this may be due to paramagnetic impurities. Major diastereomer; brown powder (0.039 g, 0.091 mmol, 14%); [α]²⁸_D +23.0 (c 0.05 in CHCl₃); δ_H (300 MHz, CDCl₃) 7.90–7.96 (2H, m, Ar), 7.53–7.59 (2H, m, Ar), 7.32–7.45 (6H, m, Ar), 5.40 (1H, q, J 6.0 Hz, (CCH(CH₃)O), 5.25 (1H, d, J 13.2 Hz, CH₂), 5.03 (1H, d, J 13.2 Hz, CH₂) 1.67 (3H, d, J 6.0 Hz, (CCH(CH₃)O). A broad resonance exists from 6.6–7.8 ppm in the ¹H NMR spectrum that has not been assigned; this may be due to paramagnetic impurities.

Ruthenium cyclone complex 12a/b

A sealed tube was charged with 8c (8: R¹ = Me₃Si, R² = Ph, R³ = Me) (0.3813 g, 1.4894 mmol, 3eq.) and Ru₃(CO)₁₂ (0.3173 g, 0.4965 mmol, 1 eq.) in acetonitrile (5 cm³) and the reaction heated to 100 °C over 2 days. The solvent was removed in vacuo and redissolved in DCM then filtered to remove any unreacted Ru₃(CO)₁₂ and purified by column chromatography (EtOAc/pet. ether (40–60) 1 : 10) to afford the major 12a (0.1787, 0.404 mmol, 27%) and minor 12b (0.0768 g, 0.1738 mmol, 12%) diastereoisomers. Configurations assigned by analogy with Fe complexes; Major; m/z (ESI) 471 [M + 1]⁺, 493 [M + 23]⁺; [α]²⁸_D +79.20 (c 0.11, CHCl₃); (Found (ESI): M + H 471.0218 C₂₀H₂₁O₅RuSi requires 471.0201); (Found (ESI): M + Na 493.0039 C₂₀H₂₀NaO₅RuSi requires 493.0021); ν_max 2075, 2006 and 1626 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.43 (2H, d, J 7.0, Ar), 7.35 (2H, t, J 7.5, Ar), 7.30–7.25 (1H, m, Ar), 5.29 (1H, q, J 6.0, OCHCH₃), 4.83–4.73 (2H, m, OCH₂), 1.59 (3H, d, J 6.0, OCHCH₃), 0.32 (9H, s, Si(CH₃)₃); δ_C (100 MHz, CDCl₃) 193.82 (C=O), 179.00 (C=O), 130.44 (ipso, Ar), 129.80 (CH, Ar), 128.35 (CH, Ar), 127.64 (CH, Ar), 114.40, 112.85, 80.04, 74.81 (OCHCH₃), 67.27, 62.54, 23.73 (OCHCH₃), −0.51 (Si(CH₃)₃); Minor [α]²⁸_D −8.30 (c 0.112, CHCl₃); m/z (ESI) 471 [M + 1]⁺, 493 [M + 23]⁺; (Found (ESI): M + H 471.0200 C₂₀H₂₁O₅RuSi requires 471.0201); (Found (ESI): M + Na 493.0019 C₂₀H₂₀NaO₅RuSi requires 493.0021); ν_max 2080, 2020 and 1989 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.97 (2H, d, J 7.5, Ar), 7.35 (2H, t, J 7.5, Ar),7.29–7.25 (1H, m, Ar), 5.60 (1H, q, J 6.5, OCHCH₃), 4.89 (1H, dd, J 12.6, 1.0, OCHH), 4.78 (1H, d, J 12.6, OCHH), 1.43 (3H, d, J 6.5, OCHCH₃), 0.33 (9H, s, Si(CH₃)₃); δ_C (100 MHz, CDCl₃) 193.94 (C=O), 180.55 (C=O), 132.74 (ipso, Ar), 128.72 (CH, Ar), 127.36 (CH, Ar), 126.54 (CH, Ar), 110.96, 109.65, 76.48 (OCHCH₃), 75.74, 70.64, 66.33, 63.86, 27.90, 19.06, −0.40 (Si(CH₃)₃).

Ruthenium cyclone complex 12c/d

A sealed tube was charged with 8 (R¹ = (iPr)₃Si, R² = Ph, R³ = Me) (0.5898 g, 1.798 mmol, 3eq.) and Ru₃(CO)₁₂ (0.3830 g, 0.5994 mmol, 1 eq.) in acetonitrile (6 cm³) and the reaction heated to 100 °C over 2 days. The solvent was removed in vacuo and redissolved in DCM and filtered to remove any unreacted Ru₃(CO)₁₂ and purified by column chromatography (EtOAc/pet. ether (40–60) 1 : 10) to afford only one diastereoisomer cleanly (0.1197 g, 0.2213 mmol, 12%); [α]²⁸_D +39.11 (c 0.140, CHCl₃); m/z (ESI) 555 [M + 1]⁺, 577 [M + 23]⁺; (Found (ESI): M + H 555.1148 C₂₂H₃₃O₅RuSi requires 555.1142); ν_max 2944, 2860, 2077, 2023, 1999 and 1622 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.37–7.32 (2H, m, Ar), 7.29–7.24 (2H, m, Ar), 7.21–7.15 (1H, m, Ar), 5.22 (1H, q, J 6.0, OCHCH₃), 4.74 (2H, s, OCH₂), 1.53 (3H, d, J 6.0, OCHCH₃), 1.32 (3H, sept., J 7.5, Si(CH(CH₃)₂)₃), 1.15–1.08 (18H, m Si(CH(CH₃)₂)₃); δ_C (100 MHz, CDCl₃) 193.83 (C=O), 178.95 (C=O), 130.38 (ipso, Ar), 129.89 (CH, Ar), 128.37 (CH, Ar), 127.62 (CH, Ar), 116.19, 111.69, 79.37, 74.72 (OCHCH₃), 68.36, 62.42, 23.66, 19.12, 12.32.

Ruthenium cyclone complex 12e/f

A sealed tube was charged with 8d (8: R¹ = Ph, R² = Ph, R³ = Me) (0.3580 g, 1.3769 mmol, 3eq.) and Ru₃(CO)₁₂ (0.2933 g, 0.4586 mmol, 1 eq.) in acetonitrile (5 cm³) and the reaction was heated to 100 °C over 2 days. The solvent was removed in vacuo and redissolved in DCM and filtered to remove any unreacted Ru₃(CO)₁₂ and purified by column chromatography (EtOAc/pet. ether (40–60) 1 : 20) to afford only one diastereoisomer cleanly (0.1371 g, 0.2898 mmol, 21%); [α]²⁸_D −61.96 (c 0.092, CHCl₃); m/z (ESI) 475 [M + 1]⁺, 497 [M + 23]⁺; (Found (ESI): M + H 475.0123 C₂₃H₁₇O₅Ru requires 475.0120); ν_max 2074, 1999 and 1622 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.87 (2H, d, J 7.5, Ar), 7.50 (2H, d, J 7.0, Ar), 7.43–7.36 (4H, m, Ar), 7.35–7.28 (2H, m, Ar), 5.34 (1H, dq, J 1.5, 6.0, CHCH₃), 5.25 (1H, d, J 12.6, CHH), 5.07 (1H, dd, J 2.0, 12.6, CHH), 1.61 (3H, d, J 6.0, CHCH₃); δ_C (100 MHz, CDCl₃) 193.80 (C=O), 132.39 (ipso, Ar), 130.08 (ipso, Ar), 128.88 (CH, Ar), 128.47 (CH, Ar), 127.85 (CH, Ar), 127.76 (CH, Ar), 127.00 (CH, Ar), 109.03 (quat.), 107.13 (quat.), 77.98 (quat.), 74.92 (CH), 74.06 (quat.), 67.75 (quat.), 23.74 (CH₃).

Ruthenium cyclone complex 13a/b

A sealed tube was charged with the dipropargyl ether precursor of ligand 13a/b (0.083 g, 0.26 mmol, 3eq.) and Ru₃(CO)₁₂ (0.056 g, 0.0.887 mmol, 1 eq.) in acetonitrile (1 cm³) and the reaction heated to 100 °C over 2 days. The solvent was removed in vacuo and redissolved in DCM and filtered to remove any unreacted Ru₃(CO)₁₂ and purified by column chromatography (EtOAc/hexane 1 : 20) to afford only one diastereoisomer cleanly (0.040 g, 0.0805 mmol, 31%); [α]²⁸_D +38.60 (c 0.020, CHCl₃); m/z (ESI) 527 [M]⁺; (Found (ESI): M + H 527.0822 C₂₄H₂₉O₅RuSi requires 527.0828); ν_max 2075, 1999 and 1638 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.44–7.40 (2H, m, Ar), 7.37–7.32 (2H, m, Ar), 7.29–7.26 (1H, m, Ar), 5.22 (1H, qd, J 6.0, 1.5, CHCH₃) 5.00 (1H, qd, J 6.0, 1.5, CHCH₃), 1.58 (3H, d, J 6.0, CHCH₃), 1.55 (3H, d, J 6.0, CHCH₃), 0.99 (9H, s, SiC(CH₃)₃), 0.51 (3H, s, SiCH₃), 0.18 (3H, s, SiCH₃); δ_C (100 MHz, CDCl₃) 193.91 (C=O), 180.04 (C=O), 130.34 (ipso, Ar), 130.07 (CH, Ar) 128.38 (CH, Ar), 127.70 (CH, Ar), 119.99, 116.40, 78.22, 74.82, 73.51, 60. 83, 31.56, 28.06, 27.23, 23.76, 22.63, 18.81, −2.04, −3.67.

(R)-Alcohol 11d

A flask was charged with (R)-Alpine borane solution (45.08 cm³, 22.54 mmol, 0.5 M in THF) and the solvent was removed in vacuo. The flask was cooled to 0 °C and 3-(t-butyldimethylsilyl)-1-phenyl-prop-2-ynone 10d (5.00 g, 20.49 mmol) was added dropwise. After 4 days acetylaldehyde (5 cm³) was added. After 1 h, NaOH_(aq) (10 cm³, 5 N), THF (10 cm³) and hydrogen peroxide (11.5 cm³, 30%wt) added. CAUTION: addition of peroxide is very exothermic. After heating to 40 °C for 4 h, in air, the reaction was extracted using Et₂O (3 × 30 cm³) and the combined organic phases washed using brine (30 cm³), dried over MgSO₄ and the solvent removed in vacuo. Purification by column chromatography (EtOAc/hexane 0.5%–5%) afforded a colourless oil (R_f 0.13 (10% EtOAc/hexane), 3.67 g, 14.918 mmol, 73%, 96% ee); [α]²⁸_D +4.2 (c 1.054 in CHCl₃); m/z 269.2 [M + 23]⁺; (Found (ESI): M + Na 269.1333. C₁₅H₂₂NaOSi requires 269.1332); ν_max 3362 (OH), 2926, 2857, 1671, 1446 and 1003 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.56 (2H, d, J 7.1, Ar), 7.36 (3H, m, Ar), 5.47 (1H, s, Ar), 0.99 (9H, s, SiC(CH₃)₃), 0.17 (6H, s, Si(CH₃)₂); δ_C (100 MHz, CDCl₃) 140.36 (ipso, Ar), 128.49 (CH, Ar), 128.26 (CH, Ar), 126.70 (CH, Ar), 105.69 (quat., C≡C), 89.81 (quat., C≡C), 64.90 (CH(OH)), 26.03 (SiC(CH₃)₃), 16.50 (quat., SiC(CH₃)₃), −4.71 (Si(CH₃)₂); δ_Si (99 MHz, CDCl₃) −7.64 (s, Si(CH₃)₂C(CH₃)₃). The ee was determined by chiral GC; cyclodextrin CB column; 96% ee, 100 °C, H₂, 15 psi, 83.70 min (S), 85.99 min (R).¹⁷

(R)-Dipropargylic ether 8 (R¹ = H, R² = Si(tBu)Me₂, R³ = Ph)

To a solution of (R)-alcohol 11d (1.1606 g, 6.0976 mmol 1 eq.) in THF (20 cm³) at 0 °C was added NaH (0.2881 g, 60% in mineral oil, 7.2019 mmol, 1.1 eq.). The reaction mixture was stirred for 30 min at 0 °C after which propargylic bromide was added (0.85 cm³, 80%wt in toluene, 1.17 g, 7.86 mmol, 1.2 eq.) and the ice bath removed. After 4 h the reaction was quenched using saturated NaHCO_3(aq) solution (20 cm³) and extracted using Et₂O (3 × 10 cm³). The combined organic fractions were dried over MgSO₄ and the solvent removed in vacuo. Purification column chromatography (EtOAc/hexane 0% to 1%) afforded a colourless oil (1.121 g, 3.948 mmol, 60%); [α]²⁸_D +27.3 (c 0.68 in CHCl₃); m/z 307.2 [M + 23]⁺; (Found (ESI): M + Na 307.1483, C₁₈H₂₄NaOSi requires 307.1489); ν_max 2952, 2927, 2884, 2855, 1250 and 1059 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.56 (2H, d, J 7.2, Ar), 7.41-7.34 (3H, m, Ar), 5.45 (1H, s, ArCH), 4.41 (1H, dd, ⁴J 2.3, J 15.7, OCHH), 4.29 (1H, dd, ⁴J 2.3, J 15.7, OCHH), 2.48 (1H, t, ⁴J 2.3, C≡CH), 0.98 (9H, s, SiC(CH₃)₃), 0.17 (6H, s, Si(CH₃)₂); δ_C (100 MHz, CDCl₃) 137.65 (ipso, Ar), 128.69 (CH, Ar), 128.44 (CH, Ar), 126.75 (CH, Ar), 102.50 (quat., C≡C), 91.77 (quat., C≡C), 74.82 (quat. C≡C), 70.44 (ArCH), 55.26 (OCH₂), 26.05 (SiC(CH₃)₃), 16.55 (SiC(CH₃)₃), −4.70 (Si(CH₃)₂); δ_Si (99 MHz, CDCl₃) −7.51 (s, Si(CH₃)₂C(CH₃)₃).

(R)-Dipropargylic ether 8 (R¹ = TMS, R² = Si(tBu)Me₂, R³ = Ph)

A flask was charged with (R)-dipropargylic ether 8 (R¹ = H, R² = Si(tBu)Me₂, R³ = Ph) (0.500 g, 1.7606 mmol) in THF (12 cm³) and cooled to −78 °C. Addition of nBuLi (1.21 cm³, 1.94 mmol, 1.6 M in hexane, 1.1 eq.) afforded a dark green solution. After 1 h TMSCl (0.27 cm³, 2.11 mmol, 1.2 eq.) was added and the ice bath removed after 5 min. After 30 min the reaction mixture colour had changed from green to yellow. After 3 h the reaction was quenched using water (10 cm³) and extracted with Et₂O (3 × 10 cm³), the organic fractions combined and dried over MgSO₄ and the solvent removed under reduced pressure to afford a yellow oil which was purified using column chromatography (EtOAc/hexane 0 to 20%) to afford a pale yellow oil (0.4300 g, 1.208 mmol, 69%); [α]²⁸_D +27.3 (c 0.68 in CHCl₃); m/z (ESI) 379.2 [M + 23]⁺; (Found (ESI): M + Na 379.1881. C₂₁H₃₂NaOSi₂ requires 379.1884); ν_max 2954, 2928, 2898, 2856, 2173, 1249 and 1059 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.56 (2H, d, J 7.5, Ar), 7.40–7.31 (3H, m, Ar), 5.45 (1H, s, ArCH), 4.40 (1H, d, J 15.8, OCHH), 4.28 (1H, d, J 15.8, OCHH), 0.98 (9H, s, SiC(CH₃)₃), 0.21 (9H, s, Si(CH₃)₃), 0.17 (6H, s, Si(CH₃)₂); δ_C (100 MHz, CDCl₃) 137.77 (ipso, Ar), 128.50 (CH, Ar), 128.41 (CH, Ar), 127.83 (CH, Ar), 102.70 (quat., C≡C), 101.11 (quat., C≡C), 91.81 (quat. C≡C), 91.60 (quat. C≡C), 70.39 (ArCH), 56.07 (OCH₂), 26.08 (SiC(CH₃)₃), 16.56 (SiC(CH₃)₃), −0.16 (Si(CH₃)₃, −4.70 (Si(CH₃)₂); δ_Si (99 MHz, CDCl₃) −7.57 (s, Si(CH₃)₂C(CH₃)₃), −17.73 (s, Si(CH₃)₃).

(R)-Dipropargylic ether 8 (R¹ = TIPS, R² = Si(tBu)Me₂, R³ = Ph

A flask was charged with (R)-dipropargylic ether 8 (R¹ = H, R² = Si(tBu)Me₂, R³ = Ph) (0.500 g, 1.7606 mmol) in THF (10 cm³) and cooled to −78 °C. Addition of nBuLi (1.35 cm³, 2.17 mmol, 1.6 M in hexane, 1.2 eq.) afforded a dark green solution. After 30 min TIPSCl (0.50 cm³, 2.36 mmol, 1.3 eq.) was added and the ice bath removed after 30 min. After 5 h the reaction was quenched using water (10 cm³) and extracted with Et₂O (3 × 10 cm³), the organic fractions combined and dried over MgSO₄ and the solvent removed under reduced pressure to afford a yellow oil which was purified using column chromatography (EtOAc/hexane 0 to 5%) to afford a bright yellow oil (0.219 g, 0.53 mmol, 30%); [α]²⁸_D +50.1 (c 0.825 in CHCl₃); m/z (ESI) 463.3 [M + 23]⁺; (Found (ESI): M + Na 463.2821. C₂₇H₄₄NaOSi₂ requires 463.2823); ν_max 2928, 2889, 2863, 1462, 1249, 1060, 1038,1027 and 1007 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.56–7.53 (2H, m, Ar), 7.40–7.32 (3H, m, Ar), 5.55 (1H, s, ArCH), 4.51 (1H, d, J 16.1, OCHH), 4.31 (1H, d, J 16.1, OCHH), 1.08 (21H, m, Si(CH(CH₃)₂)₃) (0.97 (9H, s, SiC(CH₃)₃), 0.17 (6H, s, Si(CH₃)₂); δ_C (100 MHz, CDCl₃) 137.97 (ipso, Ar), 128.49 (CH, Ar), 128.44 (CH, Ar), 127.87 (CH, Ar), 102.74 (quat., C≡C), 102.70 (quat., C≡C), 91.49 (quat. C≡C), 88.42 (quat., C≡C), 69.75 (ArCH), 56.22 (OCH₂), 26.09 CH₃, SiC(CH₃)₃), 18.61 (Si(CH(CH₃)₂)₃), 16.58 (SiC(CH₃)₃), 11.18 (CH₃, Si(CH(CH₃)₃)₃), −4.68 (Si(CH₃)₂); δ_Si (99 MHz, CDCl₃) −1.86 (s, Si(CH(CH₃)₂)₃), −7.57 (s, Si(CH₃)₂C(CH₃)₃).

(R)-Dipropargylic ether 8 (R¹ = Ph, R² = Si(tBu)Me₂, R³ = Ph)

A flask was charged with (R)-dipropargylic ether 8 (R¹ = H, R² = Si(tBu)Me₂, R³ = Ph) (0.500 g, 1.7606 mmol), PhI (0.26 cm³, 2.34 mmol, 1.3 eq.) and Et₃N (6.3 cm³). To this mixture was added PdCl₂(PPh₃)₂ (27.4 mg, 0.0391 mmol, 0.02 eq.) and after 5 min CuI (3.7 mg, 0.0195 mmol, 0.01 eq.) was added and the reaction heated to 50 °C for 20 h. The reaction mixture was then filtered and the remaining amine removed in vacuo. Purification by column chromatography (EtOAc/hexane 0 to 2%) afforded a light yellow oil (0.3693 g, 1.03 mmol, 58%); [α]²⁸_D +58.0 (c 1.02 in CHCl₃); m/z (ESI) 361.2 [M + 1]⁺; 383.1 [M + 23]⁺; (Found (ESI): M + Na, 383.1802. C₂₄H₂₈NaOSi requires 383.1802); ν_max 2952, 2927, 2884, 2855 and 1057 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.56 (2H, d, J 7.6, Ar), 7.50–7.48 (2H, m, Ar), 7.41–7.31 (6H, m, Ar), 5.53 (1H, s, ArCH), 4.63 (1H, d, J 15.7, OCHH), 4.51 (1H, d, J 15.7, OCHH), 1.05 (9H, s, SiC(CH₃)₃), 0.18 (6H, s, Si(CH₃)₂); δ_C (100 MHz, CDCl₃) 137.82 (ipso, Ar), 131.81 (CH, Ar), 128.57 (CH, Ar), 128.53 (CH, Ar), 128.45 (CH, Ar), 128.25(CH, Ar), 127.81 (CH, Ar), 122.60 (ipso, Ar), 102.83 (quat., C≡C), 91.70 (quat., C≡C), 86.62 (quat., C≡C), 84.71 (quat., C≡C), 70.50 (ArCH), 56.10 (OCH₂), 26.08 (SiC(CH₃)₃), 16.56 (SiC(CH₃)₃), −4.67 (Si(CH₃)₂); δ_Si (99 MHz, CDCl₃) −7.52 (s, Si(CH₃)₂C(CH₃)₃).

(R)-Alcohol 11e

(R)-Alpine borane solution (0.5 M, in THF, 22 mmol, 44 cm³) was introduced to a flask and the solvent removed in vacuo. The flask was cooled to 0 °C and 3-(tri(isopropyl)silyl)-1-phenyl-prop-2-yn-1-one 10e (5.72 g, 20.0 mmol) was added dropwise. The ice bath was removed and after 4 days the reaction was quenched using acetaldehyde (4.5 cm³). After 1 h THF (10 cm³) and NaOH_(aq) (5 N, 10 cm³) were added and the reaction mixture put in a water bath and H₂O₂ (30 wt%, 11.5 cm³) was added carefully. CAUTION: very exothermic. After complete addition of the peroxide the reaction was heated for 4 h in air followed by extraction with Et₂O (3 × 30 cm³). The combined organic fractions were then washed with brine (30 cm³) and dried over MgSO₄. Removal of the solventin vacuo afforded a colourless oil which on purification by column chromatography (hexane/EtOAc) afforded a colourless oil (2.6031 g, 9.0385 mmol, 45% yield, 97% ee); [α]²⁸_D +5.81 (c 1.32, CHCl₃); m/z 287.2 [M − 1], 309.2 [M + 23]; (Found (ESI): M − H 287.1816 C₁₈H₂₇OSi requires 287.1826, M + Na 309.1631 C₁₈H₂₆NaOSi requires 309.1645); ν_max 3354 (OH), 2941, 2891, 2864 and 2169 cm⁻¹; δ_H (300 MHz, CDCl₃) 7.6–7.56 (2H, m, Ar) 7.42–7.29 (3H, m, Ar), 5.49 (1H, d, J 6.3, ArCH), 2.17 (1H, d, J 6.3, OH), 1.09 (21H, m, Si(CH(CH₃)₃); δ_C (75 MHz, CDCl₃) 128.54 (ipso, Ar), 128.51 (CH, Ar), 128.30 (CH, Ar), 126.77 (CH, Ar), 106.87 (quat., C≡C), 98.02 (quat., C≡C), 65.11 (CH(OH)), 18.59 (Si(CH(CH₃)₂)₃), 11.15 (Si(CH(CH₃)₂)₃); The ee was determined by GC using cyclodextrin CB column; 97% ee, 170 °C, H₂, 15 psi, 61.96 min (S), 63.68 min (R).¹⁷

(R)-Dipropargylic ether 8 (R¹ = H, R² = Si(iPr)₃, R³ = Ph)

To a solution of (R)-alcohol 11e (1.000 g, 3.472 mmol 1 eq.) in THF (11 cm³) at 0 °C was added NaH (0.1527 g, 60% in mineral oil, 3.8194 mmol, 1.1 eq.). The reaction mixture was stirred for 30 min at 0 °C after which propargylic bromide was added (0.45 cm³, 80%wt in toluene, 0.619 g, 4.166 mmol, 1.2 eq.) and the ice bath removed. After 4 h the reaction was quenched using saturated NHCO_3(aq) solution (20 cm³) and extracted using Et₂O (3 × 10 cm³). The combined organic fractions were dried over MgSO₄ and the solvent removed in vacuo. Purification by column chromatography (EtOAc/hexane 0 to 1%) afforded a colourless oil (0.9155 g, 2.8083 mmol, 81%); [α]²⁸_D +24.25 (c 1.048, CHCl₃); m/z 349.2 [M + 23]⁺; (Found (ESI): 349.1953 M + Na C₂₁H₃₀NaOSi requires 349.1958); ν_max 2941, 2924, 2864, 2169, 2031 and 1461 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.59–7.56 (2H, m, Ar) 7.40–7.31 (3H, m, Ar), 5.48 (1H, s, ArCH), 4.44 (1H, dd, ⁴J 2.4, J 15.6, OCHH), 4.31 (1H, dd, ⁴J 2.4, J 15.6, OCHH), 2.47 (1H, t, ⁴J 2.4, C≡CH), 1.10 (21H, m, Si(CH(CH₃)₃); δ_C (100 MHz, CDCl₃) 137.79 (ipso, Ar), 128.47 (CH, Ar), 128.38 (CH, Ar), 127.75 (CH, Ar), 103.62 (quat., C≡C), 89.95 (quat., C≡C), 79.35 (C≡CH), 74.72 (quat., C≡C), 70.50 (ArCH), 55.19 (OCH₂), 18.58 (Si(CH(CH₃)₂)₃), 11.16 (Si(CH(CH₃)₂)₃); δ_Si (99 MHz, CDCl₃) −1.53 (s, Si(CH(CH₃)₂)).

(R)-Dipropargylic ether 8 (R¹ = Me₃Si, R² = Si(iPr)₃, R³ = Ph)

To a solution of (R)-dipropargylic ether 8 (R¹ = H, R² = Si(iPr)₃, R³ = Ph) (0.190 g, 0.582 mmol) in THF (3 cm³) cooled to −78 °C was added nBuLi (0.4 cm³, 0.6404 mmol, 1.6 M in hexane, 1.1 eq.) affording a dark green solution. After 1 h TMSCl (0.089 cm³, 0.699 mmol, 1.2 eq.) was added and the ice bath removed after 5 min. After 6 h the reaction was quenched using water (3 cm³) and extracted with Et₂O (3 × 4 cm³), the organic fractions were combined and dried over MgSO₄ and the solvent removed under reduced pressure to afford a yellow oil which was purified using column chromatography (EtOAc/hexane 0 to 1%) to afford a yellow oil (0.1362 g, 0.3424 mmol, 59%); [α]²⁸_D +42.2 (c 1.106, CHCl₃); m/z 421.2 [M + 23]⁺; (Found (ESI): 421.2354 M + Na C₂₄H₃₈NaOSi₂ requires 421.2353); ν_max 2944, 2893, 2865, 1719 and 1250 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.58 (2H, d, J 7.04, Ar), 7.41–7.31 (3H, m, Ar), 5.49 (1H, s, ArCH), 4.44 (1H, d, J 15.8, OCHH), 4.31 (1H, d, J 15.8, OCHH), 1.10 (21H, m, Si(CH(CH₃)₃), 0.20 (6H, s, Si(CH₃)₃); δ_C (100 MHz, CDCl₃) 137.92 (ipso, Ar), 128.44 (CH, Ar), 128.38 (CH, Ar), 127.85 (CH, Ar), 103.78 (quat., C≡C), 101.17 (quat., C≡C), 91.77 (C≡CH), 89.85 (quat., C≡C) 70.43 (ArCH) 56.02 (OCH₂) 18.62 (Si(CH(CH₃)₂)₃), 11.19 (CH, Si(CH(CH₃)₂)₃), −0.16 (Si(CH₃)₃).

(R)-Dipropargylic ether 8 (R¹ = Si(tBu)Me₂, R² = Si(iPr)₃, R³ = Ph)

To a solution of (R)-dipropargylic ether 8 (R¹ = H, R² = Si(iPr)₃, R³ = Ph) (0.400 g, 1.227 mmol) in THF (7 cm³) cooled to −78 °C was added nBuLi (0.84 cm³, 1.3497 mmol, 1.6 M in hexane, 1.1 eq.) affording a dark green solution. After 1 h TBDMSCl (0.222 g, 1.472 mmol, 1.2 eq.) was added and the ice bath removed after 5 min. After 16 h the reaction was quenched using water (10 cm³) and extracted with Et₂O (3 × 10 cm³), the organic fractions were combined and dried over MgSO₄ and the solvent removed under reduced pressure to afford a crude yellow oil (0.4263 g, 0.9689 mmol, 79%); [α]²⁸_D +65.9 (c 0.50, CHCl₃); m/z 463.2 [M + 23]⁺; (Found (ESI): M + Na 463.2819 C₂₇H₄₄NaOSi₂ requires 463.2823); ν_max 2942, 2927, 2891, 2863, 2173, 1461 and 1063 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.58 (2H, d, J 7.04, Ar) 7.41–7.31 (3H, m, Ar), 5.49 (1H, s, ArCH), 4.44 (1H, d, J 15.8, OCHH) 4.31 (1H, d, J 15.8, OCHH) 1.10 (21H, m, Si(CH(CH₃)₃) 0.20 (6H, s, Si(CH₃)₃); δ_C (100 MHz, CDCl₃) 137.92 (ipso, Ar), 128.44 (CH, Ar), 128.38 (CH, Ar), 127.85 (CH, Ar), 103.78 (quat., C≡C), 101.17 (quat., C≡C), 91.77 (CH, C≡CH), 89.85 (quat., C≡C) 70.43 (CH(OH)) 56.02 (OCH₂) 18.62 (Si(CH(CH₃)₂)₃), 11.19 (Si(CH(CH₃)₂)₃), −0.16 (Si(CH₃)₃).

(R)-Dipropargylic ether 8 (R¹ = Ph, R² = Si(iPr)₃, R³ = Ph)

A flask was charged with (R)-dipropargylic ether 8 (R¹ = H, R² = Si(iPr)₃, R³ = Ph) (0.500 g, 1.534 mmol), PhI (0.21 cm³, 1.84 mmol, 1.2 eq.) and Et₃N (6 cm³). To this mixture was added PdCl₂(PPh₃)₂ (21.5 mg, 0.0306 mmol, 0.02 eq.) and after 5 min CuI (2.9 mg, 0.0153 mmol, 0.01 eq.) was added and the reaction heated to 50 °C for 20 h. The reaction mixture was then filtered and the remaining amine removed in vacuo. Purification by column chromatography (EtOAc/hexane 0 to 0.5%) afforded a light yellow oil (0.5874 g, 1.461 mmol, 95%); [α]²⁸_D +45.0 (c 1.088, CHCl₃); m/z 403.2 [M + 1]⁺, 425.2 [M + 23]⁺; ν_max 2942, 2890, 2864, 1762, 1644, 1450 and 1240 cm⁻¹; (Found (ESI): 425.2265 M + Na C₂₇H₃₄NaOSi requires 425.2271); δ_H (400 MHz, CDCl₃) 7.50 (2H, d, J 7.50, Ar), 7.49–7.45 (2H, m, Ar), 7.40–7.31 (6H, m, Ar), 5.56 (1H, s, ArCH), 4.67 (1H, d, J 15.7, OCHH), 4.54 (1H, d, J 15.7, OCHH), 1.12 (21H, m, Si(CH(CH₃)₃); δ_C (100 MHz, CDCl₃) 138.00 (ipso, Ar), 131.83 (CH, Ar), 128.47 (CH, Ar), 128.45 (CH, Ar), 128.42(CH, Ar), 128.25 (CH, Ar), 127.84 (CH, Ar), 122.65 (ipso, Ar), 103.87 (quat., C≡C), 90.05 (quat., C≡C), 86.54 (quat., C≡C), 84.07 (quat., C≡C) 70.57 (CH(OH)) 56.04 (OCH₂) 18.63 (Si(CH(CH₃)₂)₃), 11.20 (Si(CH(CH₃)₂)₃); δ_Si (99 MHz, CDCl₃) −1.53 (s).

Ruthenium cyclone complex 15b

A pressure tube was charged with (R)-dipropargylic ether 8 (R¹ = TMS, R² = Si(tBu)Me₂, R³ = Ph), (1.000 g, 2.808 mmol 3 eq.), acetonitrile (10 cm³) and Ru₃(CO)₁₂ (0.5986 g, 0.9363 mmol, 1 eq.) and purged under a steady stream of N₂. The tube was then sealed and heated to 100 °C. After 2 d the reaction mixture was cooled, carefully depressurised and the solvent removed in vacuo. The resulting black semisolid was dissolved in DCM (4 cm³) and filtered through a cotton wool plug and loaded onto a short silica column (EtOAc/hexane 0 to 10%) to afford a yellow solid (0.4522 g, 0.7947 mmol, 28%). The metal complex was characterised as a mixture of two diastereoisomers in an approximate ratio of 3 : 1; m/z 571.0 [M + 1]⁺; (Found (ESI): 571.0918 M + H C₂₅H₃₃O₅RuSi₂ requires 571.0911); ν_max 2951, 2927, 2894, 2881, 2853, 2077, 2019, 1197 and 1632 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.49–7.44 (1.5H, m, Ar) 7.41–7.36 (3H, m, Ar), 7.20–7.16 (0.5H, m, Ar), 5.85 (1H, s, ArCH), 4.98 (1H, d, J 12.1), 4.85 (0.75H, dd, 2.3, 12.8, OCH₂, major) 4.90 (0.25H, d, J 12.5, OCH₂, minor), 0.99 (6H, s, SitBu), 0.62 (3H, s, Si(CH₃)₂), 0.34 (3H, s, Si(CH₃)₂), 0.30 (6H, s, Si(CH₃)₃), 0.22 (3H, s, Si(CH₃)₂), −0.75 (3H, s, Si(CH₃)₂); δ_C (100 MHz, CDCl₃) 193.80 (quat., C=O), 185.80 (quat., C=O), 138.75 (ipso, Ar), 138.48 (ipso, Ar), 129.59 (CH, Ar), 129.41 (CH, Ar), 129.14 (CH, Ar), 128.42 (CH, Ar), 128.32 (CH, Ar), 127.67 (CH, Ar), 119.91 (quat.), 119.29 (quat.), 117.12 (quat.), 82.56 (CH, ArCH), 81.33 (CH, ArCH), 67.13 (quat./CH₂), 66.92 (quat./CH₂), 64.33 (quat./CH₂), 64.20 (quat./CH₂), 27.67 (CH/CH₃), 27.25 (CH/CH₃), 19.00 (quat./CH₂), 17.74 (quat./CH₂), 14.10 (CH/CH₃), −0.28 (CH/CH₃), −0.45 (CH/CH₃), −3.15 (CH/CH₃), −4.66 (CH₃), −4.78 (CH₃); δ_Si (99 MHz, CDCl₃), 4.03 (s, TBS), 3.20 (s, TBS), −3.72 (s, TMS).

Ruthenium cyclone complex 15a

A pressure tube was charged with (R)-dipropargylic ether 8 (R¹ = TIPS, R² = Si(tBu)Me₂, R³ = Ph) (0.1395 g, 0.3170 mmol 2 eq.), acetonitrile (1 cm³) and Ru₃(CO)₁₂ (0.1013 g, 0.1585 mmol, 1 eq.) and purged under a steady stream of N₂. The tube was then sealed and heated to 100 °C. After 2 d the reaction mixture was cooled, carefully depressurised and the solvent removed in vacuo. The resulting black semisolid was dissolved in DCM (2 cm³) and filtered through a cotton wool plug and loaded onto a short silica column (EtOAc/hexane 0 to 10%) to afford a yellow solid (0.1404 g, 0.2151 mmol, 68%). The metal complex was characterised as a mixture of two diastereoisomers in an approximate ratio of 3 : 1; m/z 655.1 [M + 1]⁺, 677.1 [M + 23]⁺; (Found (ESI): 655.1861 M + H C₃₁H₄₅O₅RuSi₂ requires 655.1851); ν_max 2946, 2926, 2862, 2077, 2019, 1998 and1629 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.50–7.47 (1.5H, m, Ar), 7.42–7.37 (3H, m, Ar), 7.22–7.20 (0.5H, m, Ar), 5.85 (1H, s, ArCH), 5.00 (1H, d, J 12.8, OCHH), 4.88 (0.75H, dd, J 2.1, 12.8, OCHH, major), 4.79 (0.25H, d, J 12.5, OCHH, minor), 1.41 (3H, septet, J 7.2, SiCH(CH₃)₂), 1.18 (18H, pseudo t, J 7.2, SiCH(CH₃)₂), 0.98 (9H, s, SitBu), 0.24 (3H, s, Si(CH₃)₂), −0.71 (3H, s, Si(CH₃)₂); δ_C (100 MHz, CDCl₃) 193.76 (quat., C=O), 185.60 (quat., C=O), 138.53 (ipso, Ar), 129.62 (CH, Ar), 129.41 (CH, Ar), 129.14 (CH, Ar), 128.95 (CH, Ar), 128.54 (CH, Ar), 128.51 (CH, Ar), 128.32 (CH, Ar), 127.70 (CH, Ar), 121.93 (quat.), 118.11 (quat.), 82.02 (CH), 81.25 (CH), 67.88 (quat./CH₂), 64.91 (quat./CH₂), 64.01 (quat./CH₂), 27.81 (CH/CH₃), 27.39 (CH/CH₃), 19.67 (CH₃), 19.33 (CH₃), 19.20 (CH₃), 19.15 (CH₃), 19.07 (quat.), 15.46 (CH/CH₃), 12.37 (CH/CH₃), 12.29 (CH/CH₃), −3.08 (CH₃), −4.40 (CH₃); δ_Si (99 MHz, CDCl₃), 4.22 (s, TBS), 3.31 (s, TBS), 2.51 (s, TIPS).

Ruthenium cyclone complex 15c

A pressure tube was charged with (R)-dipropargylic ether 8 (R¹ = Ph, R² = Si(tBu)Me₂, R³ = Ph), (0.250 g, 0.6944 mmol 2 eq.), acetonitrile (1.5 cm³) and Ru₃(CO)₁₂ (0.2219 g, 0.3472 mmol, 1 eq.) and purged under a steady stream of N₂. The tube was then sealed and heated to 100 °C. After 3 d the reaction mixture was cooled, carefully depressurised and the solvent removed in vacuo. The resulting black semisolid was dissolved in DCM (2 cm³) and filtered through a cotton wool plug and loaded onto a short silica column (EtOAc/hexane; 0 to 10%) to afford a yellow solid (0.1799 g, 0.3139 mmol, 45%). The metal complex was characterised as a mixture of two diastereoisomers in an approximate ratio of 4 : 1; m/z 575.0 [M + 1]⁺; (Found (ESI): M + H 575.0832 C₂₈H₂₉O₅RuSi requires 575.0829); (Found (ESI): M + Na 597.0654 C₂₈H₂₈NaO₅RuSi requires 597.0649); ν_max 2952, 2928, 2883, 2854, 2064, 2020 and 2009 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.87 (0.3H, d, J 7.3, Ar), 7.83 (1.6H, d, J 7.3, Ar), 7.54–7.51 (1.5H, m, Ar), 7.44–7.35(5H, m, Ar), 7.32–7.24 (1.5H, m, Ar) 5.90 (1H, s, ArCH), 5.40 (0.85H, dd, J 0.9, 12.9, OCHH, major), 5.34 (0.15H, dd, J 1.4, 12.5, OCHH, minor) 5.23 (0.15H, d, J 12.5, OCHH, minor), 5.15 (0.85H, dd, J 2.4, 12.9, OCHH, major), 1.03(7.65H, s, SitBu, major), 0.66 (1.35H, s, SitBu, minor), 0.35 (2.35H, s, Si(CH₃)₂, major), 0.33 (0.65H, s, Si(CH₃)₂, minor), −0.03(0.5H, s, Si(CH₃), minor), −0.74 (2.5H, s, Si(CH₃), major); δ_C (100 MHz, CDCl₃) 193.78 (quat, C=O), 193.72 (quat C=O), 180.08 (quat, C=O), 138.32 (ipso, Ar), 138.08 (ipso, Ar), 132.20 (ipso, Ar), 132.15 (ipso, Ar), 129.78 (CH, Ar), 129.56 (CH, Ar), 129.19 (CH, Ar), 128.88 (CH, Ar), 128.86 (CH, Ar), 128.54 (CH, Ar), 128.38 (CH, Ar), 127.79 (CH, Ar), 127.76 (CH, Ar), 127.13 (CH, Ar), 127.11 (CH, Ar), 115.10 (quat.), 113.14 (quat.), 82.62 (CH), 81.46 (CH), 75.53 (quat./CH₂), 67.63 (quat./CH₂), 67.30 (quat./CH₂), 62.34 (quat./CH₂), 34.64 (quat./CH₂), 31.56 (quat./CH₂), 27.72 (CH/CH₃), 27.26 (CH/CH₃), 25.26 (quat./CH₂), 22.63 (quat./CH₂), 19.00 (quat./CH₂), 14.10 (CH₃), −2.96 (CH₃), −4.64 (CH₃), −4.72 (CH₃, SiCH₃); δ_Si (99 MHz, CDCl₃), 4.22 (s, TBS), 3.31 (s, TBS), 2.51 (s, TIPS).

Ruthenium cyclone complex 15e

A pressure tube was charged with (R)-dipropargylic ether 8 (R¹ = Ph, R² = Si(iPr)₃, R³ = Ph) (0.3906 g, 0.9716 mmol, 2 eq.), acetonitrile (3 cm³) and Ru₃(CO)₁₂ (0.3104 g, 0.4858 mmol, 1 eq.) and purged under a steady stream of N₂. The tube was then sealed and heated to 100 °C. After 2 d the reaction mixture was cooled, carefully depressurised and the solvent removed in vacuo. The resulting black semisolid was dissolved in DCM (2 cm³) and filtered through a cotton wool plug and loaded onto a short silica column (EtOAc/hexane 0 to 5%) to afford a yellow solid (R_f 0.2, 0.1994 g, 0.3242 mmol, 33%). Found to be a 3 : 2 mixture of diastereoisomers; m/z 617.1 [M + 1]⁺; (Found (ESI): M + H 617.1307 C₃₁H₃₅O₅RuSi requires 617.1300); (Found (ESI): M + Na 639.1128 C₃₁H₃₄NaO₅RuSi requires 639.1119); ν_max 2944, 2864, 2076, 2001 and 1636 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.87–7.81 (2H, m, Ar), 7.53–7.48 (1.3H, m, Ar), 7.41–7.35 (4.5H, m, Ar), 7.31–7.23 (2.2H, m, Ar), 5.97 (0.4H, s, ArCH, minor), 5.92 (0.6H, s, ArCH, major), 5.43 (0.6H, d, J 12.8, OCHH, major), 5.27 (0.4H, d, J 12.4, OCHH, minor), 5.21 (0.4H, d, J 12.4, OCHH, minor), 5.15 (0.6H, dd, J 2 Hz, 12.8, OCHH, major), 1.10 (7.5H, s, SiCH(CH₃)₂), 1.05 (3.75H, d, J 7.2, SiCH(CH₃)₂), 1.00 (3.75H, d, J 7.2, SiCH(CH₃)₂), 0.94 (6H, d, J 6.0, SiCH(CH₃)₂); δ_C (100 MHz, CDCl₃) 193.89 (quat., C=O), 193.80 (quat., C=O), 180.18 (quat., C=O), 179.75 (quat., C=O), 138.44 (ipso, Ar), 137.96 (ipso, Ar), 132.22 (ipso, Ar), 132.20 (ipso, Ar), 129.67 (CH, Ar), 129.53 (CH, Ar), 129.06 (CH, Ar), 128.87 (CH, Ar), 128.39 (CH, Ar), 128.22 (CH, Ar)127.73 (CH, Ar), 127.54(CH, Ar), 127.19 (CH, Ar), 127.16 (CH, Ar), 113.27 (quat.), 113.11 (quat.), 107.34 (quat.), 83.00 (ArCH), 81.85 (ArCH), 75.36 (quat.), 67.13 (quat.), 67.08 (quat.), 61.88 (quat.), 19.76 (CH₃/CH), 19.24 (CH₃/CH), 19.18 (CH₃/CH), 19.11 (CH₃/CH), 12.86 (CH₃/CH), 12.78 (CH₃/CH); δ_Si (99 MHz, CDCl₃), 4.22 (s, TBS), 3.31 (s, TBS), 2.51 (s, TIPS).

Ruthenium cyclone complex 15d

A pressure tube was charged with (R)-dipropargylic ether 8 (R¹ = TMS, R² = Si(iPr)₃, R³ = Ph) (0.400 g, 1.005 mmol 3 eq.), acetonitrile (3 cm³) and Ru₃(CO)₁₂ (0.2141 g, 0.3350 mmol, 1 eq.) and purged under a steady stream of N₂. The tube was then sealed and heated to 100 °C. After 3 d the reaction mixture was cooled, carefully depressurised and the solvent removed in vacuo. The resulting black semisolid was dissolved in DCM (2 cm³) and filtered through a cotton wool plug and loaded onto a short silica column (EtOAc/hexane 0 to 5%) to afford a yellow solid (0.1542 g, 0.2524 mmol, 25%). The metal complex was characterised as a mixture of two diastereoisomers in an approximate ratio of 7 : 3; m/z 613.1 [M + 1]⁺; (Found (ESI): MH+ 613.1375 C₂₈H₃₉O₅RuSi₂ requires 613.1381); ν_max 2943, 2891, 2864, 2047 and 1195 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.48–7.43 (1.5H, m, Ar), 7.39–7.33 (3H, m, Ar), 7.19–7.14 (0.5H, m, Ar), 5.92 (0.3H, s, ArCH, minor), 5.86 (0.7H, s, ArCH, major), 5.00 (0.7H, s, J 12.8, OCHH, major), 4.92 (0.3H, d, J 12.5, OCHH, minor), 4.83 (0.7H, dd, J 2.1, J 12.8, OCHH, major), 4.78 (0.3H, d, J 12.5, OCHH, minor), 1.13–1.02 (11H, m, SiiPr), 0.99–0.94 (5H, m, SiiPr), 0.90–0.86 (5H, m, SiiPr), 0.33 (2.7H, s, TMS, minor), 0.29 (6.3H, s, TMS, major); δ_C (100 MHz, CDCl₃) 193.85 (quat., C=O), 185.98 (quat., C=O), 185.91 (quat., C=O), 138.44 (quat., Ar), 138.79(quat., Ar), 138.67 (quat., Ar), 129.49 (CH, Ar), 129.38 (CH, Ar), 128.26 (CH, Ar), 128.13 (CH, Ar), 127.43 (CH, Ar), 119.85 (quat.), 118.49 (quat.), 116.93 (quat.), 114.58 (quat.), 82.90 (ArCH), 81.69 (ArCH), 67.12 (quat.), 66.64 (quat.), 66.58 (quat.), 65.77 (quat.), 64.43 (quat.), 64.05 (quat.), 19.69 (CH₃/CH), 19.18 (CH₃/CH), 19.12 (CH₃/CH), 19.00 (CH₃/CH), 17.68 (CH₃/CH), 12.80 (CH₃/CH), 12.76 (CH₃/CH) 12.27(CH₃/CH), −0.42 (CH₃, TMS), −0.51 (CH₃, TMS); δ_Si (99 MHz, CDCl₃), 4.22 (s, TBS), 3.31 (s, TBS), 2.51 (s, TIPS).

Ruthenium cyclone complex 15f

A pressure tube was charged with (R)-dipropargylic ether 8 (R¹ = TBDMS, R² = Si(iPr)₃, R³ = Ph) (0.3331 g, 0.7571 mmol 3 eq.), acetonitrile (3 cm³) and Ru₃(CO)₁₂ (0.1613 g, 0.2523 mmol, 1 eq.) and purged under a steady stream of N₂. The tube was then sealed and heated to 100 °C. After 3 d the reaction mixture was cooled, carefully depressurised and the solvent removed in vacuo. The resulting black semisolid was dissolved in DCM (2 cm³) and filtered through a cotton wool plug and loaded onto a short silica column (EtOAc/hexane 0 to 5%) to afford a sticky red solid (0.104 g, 0.1596 mmol, 21%). The metal complex was characterised as a mixture of two diastereoisomers in an approximate ratio of 3 : 2; m/z 655.1 [M + 1]⁺; (Found (ESI): M + H 655.1850 C₃₁H₄₅O₅RuSi₂ requires 655.1851); ν_max 2945, 2927, 2890, 2863, 2079, 2022, 2002 and1620 cm⁻¹; δ_H (400 MHz, CDCl₃) 7.47–7.43 (1 H, m, Ar), 7.39–7.34 (3H, m, Ar), 7.20–7.16 (1H, m, Ar), 5.93 (0.45H, s, ArCH, minor), 5.86 (0.55H, s, ArCH, major), 5.01 (0.55H, dd, J 0.8, 12.8, OCHH, major), 4.93 (0.45H, dd, J 1.2, 12.5, OCHH, minor), 4.85 (0.55H, dd, J 2.2, 12.8, OCHH, major), 4.78 (0.45H, d, J 12.5, OCHH, minor), 1.19–0.6 (30H, m, SiⁱPr₃ and Si^tBu), 0.43 (1.35H, s, SiCH₃, minor), 0.41 (1.65H, s, SiCH₃, major), 0.12 (1.35H, s, SiCH₃, minor), 0.10 (1.65H, s, SiCH₃, major); δ_C (100 MHz, CDCl₃) 193.84 (quat., C=O), 185.43 (quat., C=O), 185.34 (quat., C=O), 138.68 (ipso, Ar), 138.31 (ipso, Ar), 129.53 (CH, Ar), 129.37 (CH, Ar), 129.00 (CH, Ar), 128.56 (CH, Ar), 128.51 (CH, Ar), 128.34 (CH, Ar), 128.14 (CH, Ar), 127.54 (CH, Ar), 127.39 (CH, Ar), 121.64 (quat.), 117.79 (quat.), 82.74 (ArCH), 81.70 (ArCH), 66.97 (quat./CH₂), 66.85 (quat./CH₂), 66.82 (quat./CH₂), 65.65 (quat./CH₂), 63.91 (quat./CH₂), 61.87 (quat./CH₂), 27.42 (CH₃), 27.37 (CH₃), 19.67 (CH₃/CH), 19.20 (CH₃/CH), 19.03 (CH₃/CH), 18.84 (quat.), 18.78 (quat.), 18.56 (CH₃/CH), 12.76 (CH₃/CH), 12.63 (CH₃/CH) 11.20 (CH₃/CH), 11.12 (CH₃/CH), 10.95 (CH₃/CH), −4.34 (CH₃, TBS), −4.70 (CH₃, TBS) −4.81; δSi (99 MHz, CDCl₃), 4.22 (s, TBS), 3.31 (s, TBS), 2.51 (s, TIPS).

Reduction of acetophenone using iron catalysts and FA/TEA

Complex 7a (7.8 mg, 19.1 μmol), trimethylamine-N-oxide (2.1 mg, 18.9 μmol) and acetophenone (23.0 mg, 0.191 mmol) were dissolved in 5 : 2 formic acid : triethylamine (0.2 cm³) and heated at 28 °C for 18 h. The reaction was monitored over time by GC (Chrompac cyclodextrin-β-236 M 50 M column, T = 130 °C, inj T = 220 °C, det T = 220 °C, 15 psi He carrier gas). R_T: Acetophenone: 13.4 min. 1-Phenylethyl formate: 15.1 (S), 15.5 (R) min. 1-Phenylethanol: 17.4 (R), 18.0 (S) min.¹ The above procedure was repeated using other complexes, temperatures and reaction times. The product configurations were assigned by comparison to previously quoted data¹ and use of authentic reference samples.

Reduction of acetophenone using iron catalysts and ⁱPrOH

Complex 7a (7.8 mg, 19.1 μmol), trimethylamine-N-oxide (2.1 mg, 18.9 μmol) and acetophenone (23.0 mg, 0.191 mmol) were dissolved in ⁱPrOH (0.96 cm³) and heated at 28 °C for 18 h. The reaction was monitored over time by GC (Chrompac cyclodextrin-β-236 M 50 M column, T = 130 °C, inj T = 220 °C, det T = 220 °C, 15 psi He carrier gas). R_T: Acetophenone: 13.4 min. 1-Phenylethanol: 17.4 (R), 18.0 (S) min.¹ The above procedure was repeated using other temperatures and concentrations.

General ruthenium-hydride synthesis prior to use in reductions¹²

To Ru(TMS-TMS) (22.6 mg, 0.05 mmol) in THF (1 cm³) was added aqueous sodium hydroxide (0.5 cm³, 1 M, 0.50 mmol) and stirred for 2.5 h. An excess of H₃PO₄ (0.3 cm³) was then added and the reaction extracted using Et₂O (3 × 10 cm³), dried over MgSO₄ and the solvent removed all under a nitrogen atmosphere to afford the hydride species as a yellow oil which was used immediately without further purification. Selected data for each hydride this formed is given below.

Reduction of acetophenone using ruthenium hydride complexes

Method A: iPrOH. The ruthenium hydride (0.01 mmol, 0.5 mol%) was dissolved in anhydrous iPrOH (10 cm³) and heated at 60 °C over 30 min. Acetophenone (0.22 cm³, 0.2266 g, 1.89 mmol) was then added and the reaction stirred at 60 °C over 7 days and the reaction was monitored by GC.

Method B: HCOOH/Et₃N. The ruthenium hydride (0.02 mmol, 0.25 mol%) was dissolved in formic acid triethylamine complex (5 : 2, 4 cm³) and heated at 60 °C over 30 min. Acetophenone (0.92 cm³, 0.9476 g, 7.90 mmol) was then added and the reaction stirred at 60 °C over 7 days and the reaction was monitored by GC.

Acknowledgements

We thank EPSRC for financial support of JEDM and JPH (EP/F019424) and TCJ (Supergen XIV H-delivery EP/G01244X/1). JG was an MChem project student supported by Warwick University.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, NMR spectra. See DOI: 10.1039/c1ob06010d

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