Diastereoselective Gold(I)-Catalyzed [2+2+2] Cycloaddition of Oxo-1,5-enynes

^‡ These authors contributed equally.

In memory of Professor Jean Normant.

Abstract

The intramolecular gold(I)-catalyzed [2+2+2] cycloaddition of oxo-1,5-enynes bearing protected homopropargylic alcohols provides access to oxatricyclic adducts with good to excellent diastereoselectivity.

Key words

gold - enynes - cycloisomerization - cycloaddition - Prins reaction

The cycloisomerization of 1,n-enynes catalyzed by gold(I) and other electrophilic metals is a powerful tool for the construction of complex carbocycles and heterocycles, including core scaffolds of biologically active natural products.[1] [2] [3] We have reported that oxo-1,6-enynes react in the presence of gold(I) complexes to give oxatricyclic compounds through a formal [2+2+2] alkyne/alkene/carbonyl cycloaddition process.[4] The transformation presumably proceeds by attack of the carbonyl on the cyclopropyl gold carbene intermediate followed by Prins cyclization and deauration to afford the final oxatricyclic derivative.[4] In a similar vein, terminal alkynes and 5-oxoalkenes undergo a [2+2+2] cycloaddition reaction by intermolecular cyclization of the alkyne and the alkene followed by intramolecular attack of the carbonyl group to form [3.2.1]oxabicycles.[5] [6] Very recently, our group reported a similar transformation involving simple oxo-1,7-allenenes to afford bicyclo[6.3.0]undecane ring systems.[7] The related gold(I)-catalyzed intermolecular reaction between allenamides and oxoalkenes forms seven- to nine-membered rings.[8]

The synthetic potential of this [2+2+2] alkyne/alkene/carbonyl cycloaddition has been exploited for the synthesis of several oxygen-bridged sesquiterpenoids, such as (+)-orientalol F (1)[3a] and (–)-englerin A (2)[3b] [9] (Figure [1]). We envisaged that other naturally occurring compounds, such as isovelerenol (3)[10] and bakkenolide III (4)[11] with an octahydro-1H-indene core (Figure [2]) could be accessed starting from adequately functionalized oxo-1,5-enynes; however, examples involving those enynes are scarce.[1] [12]

Figure 1 Naturally occurring sesquiterpenes with a decahydro-4,8-epoxyazulene structure

Figure 2 Naturally occurring sesquiterpenes with an octahydro-1H-indene structure

In a preliminary study, we found that (E)- and (Z)-enynals 5 bearing a phenylsulfonyl group at the tether undergo an analogous cycloaddition reaction cascade to form related oxatricyclic adducts (Scheme [1]).[12] Surprisingly, the cyclization of substrate (E)-5 was found to be poorly stereoselective yielding syn-6 and anti-6 in ratios that ranged from 1:1.5 to 3–4:1, whereas good stereoselectivities were achieved in the transformation of (Z)-5 into anti-6 (20–30:1 dr). We argued that these results could be explained if a stepwise process was occurring through diastereomeric intermediates that could undergo intramolecular nucleophilic attack of the carbonyl group by inversion or retention of the configuration.[12]

Scheme 1 Gold(I)-catalyzed reaction of (E)- and (Z)-enynals 5

Therefore, we decided to study the stereoselectivity in the reaction of other differently substituted substrates. Herein, we wish to report our findings on the scope of the cycloaddition cascade of O-protected homopropargylic and allylic oxo-1,5-enynes. A theoretical study has also been performed to support the mechanism of this transformation and to explain the overall stereoselectivity of this process.

We first investigated the reaction of (Z)-6-methyl-9-oxo­non-5-en-1-yn-4-yl benzoate [(Z)-7a] as the model substrate, using 5 mol% of commercially available cationic JohnPhos–gold(I) catalyst A (Figure [3]) at 25 °C in CH₂Cl₂. Under these conditions, we observed complete conversion of (Z)-7a to afford the cyclization product anti-8a in moderate yield (Table [1], entry 1) together with decomposition products. Various solvents were also evaluated in order to find the optimum conditions (Table [1], entries 2–7). Whereas no cycloisomerization was observed in THF, DME, DMSO, DMF, MeCN or MeOH,[13] the reaction proceeded in chlorinated or aromatic solvents. The best results were observed in toluene (Table [1], entry 5) giving rise to anti-8a in higher yield. Thus, toluene was selected for further optimization. Efforts to improve this cyclization cascade using other gold catalysts were unsuccessful (Table [1], entries 8–14). Although the reaction proceeded well with gold catalyst E (Table [1], entry 11), the use of sterically hindered phosphines resulted in a decrease in selectivity. To our delight, decreasing the concentration from 0.1 to 0.01 M substantially improved the reaction yield while maintaining the selectivity (Table [1], entries 5, 15 and 16). Further studies revealed that longer reaction times did not have any detrimental influence on the outcome of the transformation (Table [1], entry 18; 88% yield, 91:9 dr), and that performing the reaction at lower temperature did not improve the stereoselectivity (Table [1], entry 17). Under the optimized conditions, the cyclization of (Z)-7a led to the formation of anti-8a in 90% isolated yield (92:8 dr). Additionally, the configuration of the major isomer could be confirmed by X-ray diffraction (Figure [4], anti-8a).

Table 1 Optimization of the Gold-Catalyzed Cyclization of (Z)-7a

Entry	Cat.	Solvent	[M]	Time (h)	Temp (°C)	Yield of anti-8a (%)a	Ratio anti/syn
1	A	CH2Cl2	0.1	3	25	55	93:7
2	A	DCE	0.1	3	25	46	91:9
3	A	CDCl3	0.1	3	25	62	91:9
4	A	benzene	0.1	3	25	64	89:11
5	A	toluene	0.1	3	25	66	92:8
6	A	PhCF3	0.1	3	25	41 (95)b	89:11
7	A	PhCl	0.1	3	25	36	88:12
8	B	toluene	0.1	2	25	29 (80)b	65:35
9	C	toluene	0.1	2	25	<1 (<5)b	n.d.c
10	D	toluene	0.1	2	25	32 (95)b	73:27
11	E	toluene	0.1	2	25	66	81:19
12	F	toluene	0.1	3	25	25 (90)b	68:32
13	G	toluene	0.1	3	25	12	n.d.c
14	H	toluene	0.1	3	25	6 (50)b	n.d.c
15	A	toluene	0.05	2	25	66	90:10
16d	A	toluene	0.01	6	25	83	92:8
17	A	toluene	0.01	24	0	83	92:8
18	A	toluene	0.01	15	25	88	91:9

^a Determined by ¹H NMR (mesitylene as internal standard).

^b % of conversion, 100% if not stated otherwise.

^c Not determined.

^d Average yield of 3 runs.

Figure 3 Gold catalysts

With optimized conditions in hand, we sought to evaluate the generality of the reaction. Different (Z)- and (E)-oxo-1,5-enynes bearing protected homopropargylic alcohols were prepared in four to six steps starting from commercially available nerol and geraniol, respectively (see experimental section). In general, moderate to good yields (38−90%) of the corresponding oxatricyclic adducts anti-8a–j, syn-8a–e, syn-8g–i and syn-8k–l were obtained (Tables 2 and 3). Notably, the [2+2+2]-cycloaddition process never occurred with complete stereoselectivity.

All the studied (Z)-1,5-enynes 7a–j cyclized with good to high diastereoselectivities (Table [2]). The sterics of the substituent attached to the carbonyl group (R² in Table [2]) did not seem to have a clear influence on the stereoselectivity, however, the bulkier TBS protecting group of the alcohol improved the overall diastereoselectivity of the formal cycloaddition compared to the benzoate. The high stereoselectivities observed with (Z)-enynes are in agreement with the previous observations for the related transformation developed in our group.[12] These oxatricycles were formed in generally good yields and the major isomer can, in most cases, be isolated in virtually diastereomerically pure form by standard chromatographic methods or by crystallization. This allowed us to obtain the crystal structures of three derivatives, confirming that the major isomer formed in all cases has the same relative configuration, regardless of the nature of R¹ and R² (see Supporting Information, anti-8a, anti-8b and anti-8g).[14]

Figure 4 ORTEP representations of the X-ray crystal structures of anti-8a and syn-8c with 50% probability of the thermal ellipsoids

Table 2 Gold-Catalyzed Cyclization of (Z)-Oxo-enynes^a

Entry	Enyne	R1	R2	Yield of anti-8 (%)b	Ratio anti/syn
1	(Z)-7a	Bz	H	82	97:3 (91:9)c
2	(Z)-7b	TBS	H	58	≥�98:2 (83:17)c
3	(Z)-7c	Bz	Me	79 (55)d	83:17 (83:17)c
4	(Z)-7d	TBS	Me	70	>98:2 (>98:2)c
5	(Z)-7e	Bz	c-Pr	74	89:11 (83:17)c
6	(Z)-7f	Bz	c-Pent	68	85:15 (84:16)c
7	(Z)-7g	Bz	Ph	88 (69)e	93:7 (91:9)c
8	(Z)-7h	TBS	Ph	61e	>98:2 (93:7)c
9	(Z)-7i	Bz	C6H4CF3	65	>98:2 (87:13)c
10	(Z)-7j	Bz	2-Npf	56e	>98:2 (93:7)c

^a [7] = 0.01 M.

^b Product yields are reported after purification.

^c Crude dr determined by NMR.

^d Result of crystallization (dr ≥98:2).

^e Result of crystallization (dr >98:2).

^f 2-Np = 2-naphthyl.

Interestingly, the cyclization of (E)-enynals 7a,b and 7k,l also proceeded with excellent stereoselectivity to give the expected oxatricyclic products syn-8a,b and syn-8k,l in satisfactory yields (Table [3], entries 1, 2, 9 and 10). Additionally, other (E)-keto-1,5-enynes 7c–i were also examined. As shown in Table [3], different trends were observed depending on the nature of the protecting group. Thus, alkyl- [(E)-7d] and aryl-substituted [(E)-7h] TBS-protected keto-1,5-enynes led to the formation of cyclized derivatives (Table [3], entries 4 and 7) in good yields and with high selectivity. In contrast, benzoate-protected 1,5-enynes bearing bulky substituents on the ketone (Table [3], entries 5, 6 and 8) afforded the expected products, albeit with moderate yields and a dramatic loss of selectivity. The relative configurations of these compounds were assigned by analogy to that of syn-8c, which was established by X-ray crystallography (Figure [4], syn-8c).

Table 3 Gold-Catalyzed Cyclization of (E)-Oxo-enynes^a

Entry	Enyne	R1	R2	Yield of syn-8 (%)b	Ratio syn/anti
1	(E)-7a	Bz	H	83	93:7 (93:7)e
2	(E)-7b	TBS	H	82	>99:1 (99:1)e
3c	(E)-7c	Bz	Me	78	88:12 (89:11)e
4	(E)-7d	TBS	Me	65	>99:1 (99:1)e
5c	(E)-7e	Bz	c-Pr	52	82:18 (87:13)e
6c	(E)-7g	Bz	Ph	38 (20)f	57:43 (58:42)e
7	(E)-7h	TBS	Ph	90	>99:1 (96:4)e
8	(E)-7i	Bz	C6H4CF3	48	91:9 (83:17)e
9d	(E)-7k	MOM	H	81	>99:1 (99:1)e
10	(E)-7l	TES	H	71	>99:1 (95:5)e

^a [7] = 0.01 M.

^b Product yields and dr are reported after purification.

^c Reaction at 30 °C.

^d Reaction at 40 °C.

^e Crude dr determined by NMR.

^f Result of crystallization (dr 56:44).

Scheme 2 Gold(I)-catalyzed reaction of oxo-enyne (E)-7k to give crown ether 9

Figure 5 ORTEP representation of the X-ray crystal structure of 9 with 50% probability of the thermal ellipsoids

Scheme 3 Proposed mechanism for the formation of oxatricyclic derivatives syn-8 and anti-8 starting from enynals (E)-7

Intriguingly, the treatment of 1,5-enyne (E)-7k with cationic JohnPhos–gold(I) catalyst A (3 mol%) in CH₂Cl₂ instead of toluene at 23 °C led to the isolation of unexpected crown ether 9, in low to moderate yield (Scheme [2]). The structure of this compound was confirmed by X-ray diffraction (Figure [5]). The formation of 9 can be rationalized by the bimolecular reaction of two oxocarbenium intermediates 11′ (Scheme [3,] R¹ = R² = H), in which the protecting group has been cleaved under the conditions of the reaction.

We propose a mechanism for the formation of the oxa­tricyclic derivative syn-8 starting from (E)-7 initiated by activation of the alkyne to form a cyclopropyl gold(I)–carbene 10, followed by the intramolecular attack of the carbonyl group to generate the oxocarbenium intermediate 11′ (Scheme [3]). Intermediate 11′ could form a second C–C bond through a Prins-type reaction with the alkenyl metal leading to carbene-like intermediate 12′, which is reminiscent of the mechanism for the gold(I)-catalyzed reaction of oxo-1,6-enynes.[4] A final 1,2-H migration would lead to alkene–gold(I) complex 13′ after deauration and, ultimately, to product syn-8. The formation of the minor stereoisomer anti-8 from (E)-7 is consistent with the existence of another competitive stepwise process. Thus, the nucleophilic attack of the carbonyl group on the opposite face of intermediate 10 would lead to isomer anti-8 through intermediates 11 and 12.

Figure 6 Energy profiles for the competitive reaction pathways of gold(I) complex I. DFT calculations: M06, 6-31G(d) (C, H, P, O) and SDD (Au), IEFPCM (toluene). Values for free energies in kcal·mol^–1.

The mechanistic proposal outlined in Scheme [3] is supported by DFT calculations at the M06, 6-31G(d) (C, H, P, O) and SDD (Au) levels, taking into account the solvent effect (IEFPCM = toluene) and employing PMe₃ as the phosphine ligand (Figure [6]). This study shows that the first cyclization giving rise to intermediate II (corresponding to 10 in Scheme [3]) has the highest activation energy. It would thus be the rate-determining step if the ligand exchange equilibrium that regenerates the entering reactive species I from the final substrate–gold(I) complex is not considered. The calculated energy differences for the two competitive transition states, TS_II–III (ΔG^# = 3.3 kcal·mol^–1) and TS_II–V (ΔG^# = 9.5 kcal·mol^–1), show that the formation of oxocarbenium intermediate III is kinetically more favored than the formation of V, which is in general agreement with our experimental findings. Furthermore, our calculations support the existence of a discrete intermediate II in the cyclization of the 1,5-enyne,[15] which undergoes intramolecular nucleo­philic opening to form preferentially intermediate III by an overall anti-type attack.

In summary, we have extended the scope of the intramolecular gold(I)-catalyzed formal [2+2+2] cycloaddition reaction to O-protected homopropargylic and allylic oxo-1,5-enynes. Under the optimized reaction conditions, the cyclization of (Z)- and (E)-isomers takes place with moderate to excellent yield (38–90%) and increased selectivity in most of the cases, providing access to substituted octahydro-1H-indenes. DFT calculations suggest that after the formation of the cyclopropyl gold(I)–carbene, two competitive pathways arising from the preferred face for the nucleophilic attack of the carbonyl group are involved in this transformation and can explain the observed lack of complete stereoselectivity. Investigations toward the synthesis of larger ring systems to access other natural sesquiterpene motifs are currently underway.

Reactions were performed under argon atmosphere in solvents dried by passing through an activated alumina column on a PureSolv™ solvent purification system (Innovative Technologies, Inc., MA). Thin-layer chromatography was carried out using TLC aluminum sheets coated with 0.2 mm of silica gel (Merck Gf234). Chromatographic purifications were carried out using flash grade silica gel (SDS Chromatogel 60 ACC, 40–60 μm). Melting points were determined using a Büchi melting point apparatus. NMR spectra were recorded at 25 °C on a Bruker Avance 300, 400 Ultrashield and Bruker Avance 500 Ultrashield apparatus. The data are reported as such: chemical shift (δ, ppm) [multiplicity, coupling constant (Hz), integration]. The chemical shifts are given in ppm downfield from tetramethylsilane using the residual protiosolvent as internal reference. The abbreviations for multiplicities are: s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sext (sextet), sept (septet). Mass spectra were recorded on a Waters Micromass LCT Premier (ESI) instrument. Crystal structure determinations were carried out using a Bruker-Nonius diffractometer equipped with an APEX II 4K CCD area detector, an FR591 rotating anode with MoKα radiation, Montel mirrors as the monochromator and a Kryoflex low temperature device (T = –173 °C). Full-sphere data collection was used with w and j scans. Programs used: data collection APEX-2, data reduction Bruker Saint V/.60A and absorption correction SADABS. Structure solution and refinement: crystal structure solution was achieved using direct methods as implemented in SHELXTL and visualized using the program XP. Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F2 using all measured intensities was carried out using the program SHELXTL. All non-hydrogen atoms were refined including anisotropic displacement parameters.

Allylic Homopropargylic Protected Alcohols S1; General Procedure

(E)-6,10-Dimethylundeca-5,9-dien-1-yn-4-ol [(E)-S1] and (Z)-6,10-dimethylundeca-5,9-dien-1-yn-4-ol [(Z)-S1] were prepared according to known literature procedures.[16] Spectroscopic data were in agreement with those reported (see Supporting Information).

Preparation of Benzoic Esters of S1 (S2a)

In a dry round-bottom flask under argon, S1 (1 equiv) was dissolved in pyridine (1 M solution) and the solution was cooled to 0 °C. Benzoyl chloride (1.1 equiv) was added slowly dropwise. The mixture was stirred at 0 °C for 1 h after which time TLC indicated full conversion of S1. The suspension was poured over 3–5% aq HCl (10 volumes of pyridine) and extracted with Et₂O (2 × volume HCl_aq). The combined ethereal extracts were washed with 3–5% aq HCl (5 × 1/2 initial volume HCl_aq), the washed organic phase dried over Na₂SO₄ and the filtrate concentrated. The crude material was purified by column chromatography on silica gel eluting with pentane/Et₂O (98:2 to 9:1) or cyclohexane/EtOAc (95:5 to 9:1).

(E)-6,10-Dimethylundeca-5,9-dien-1-yn-4-yl Benzoate [(E)-S2a]

Prepared on 3 g scale from (E)-S1; the product was isolated as a pale yellow oil (3.70 g, 80%).

¹H NMR (400 MHz, CDCl₃): δ = 8.08–8.03 (m, 2 H), 7.58–7.52 (m, 1 H), 7.46–7.40 (m, 2 H), 5.87 (dt, J = 9.1, 6.1 Hz, 1 H), 5.35 (dq, J = 9.1, 1.3 Hz, 1 H), 5.08 (tq, J = 5.4, 1.6 Hz, 1 H), 2.71–2.55 (m, 2 H), 2.16–2.02 (m, 4 H), 1.98 (t, J = 2.6 Hz, 1 H), 1.82 (d, J = 1.4 Hz, 3 H), 1.65 (d, J = 1.4 Hz, 3 H), 1.59 (app s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 165.9, 142.3, 133.0, 131.9, 130.6, 129.8 (2 C), 128.4 (2 C), 123.8, 122.0, 79.9, 70.3, 69.7, 39.7, 26.4, 25.8, 25.3, 17.9, 17.2.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₀H₂₄O₂Na: 319.1669; found: 319.1666.

(Z)-6,10-Dimethylundeca-5,9-dien-1-yn-4-yl Benzoate [(Z)-S2a]

Prepared on 2.5 g scale from (Z)-S1; the product was isolated as a pale yellow oil (2.90 g, 84%).

¹H NMR (500 MHz, CDCl₃): δ = 8.09–8.04 (m, 2 H), 7.55 (ddt, J = 8.8, 7.0, 1.4 Hz, 1 H), 7.46–7.41 (m, 2 H), 5.88 (dt, J = 9.4, 5.9 Hz, 1 H), 5.40 (dd, J = 9.4, 1.6 Hz, 1 H), 5.14 (ddt, J = 7.1, 4.2, 1.6 Hz, 1 H), 2.63 (dd, J = 6.0, 2.7 Hz, 2 H), 2.42–2.33 (m, 1 H), 2.21–2.08 (m, 3 H), 2.00 (t, J = 2.6 Hz, 1 H), 1.79 (d, J = 1.4 Hz, 3 H), 1.67 (s, 3 H), 1.61 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 165.8, 142.7, 133.0, 132.3, 130.7, 129.8 (2 C), 128.4 (2 C), 123.9, 122.6, 80.0, 70.4, 69.3, 32.9, 26.7, 25.8, 25.5, 23.6, 17.8.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₀H₂₄O₂Na: 319.1669; found: 319.1673.

Preparation of the TBS Ether of S1 (S2b)

In a dry round-bottom flask under argon, S1 (1 equiv) was dissolved in CH₂Cl₂ (0.3–0.6 M solution) and the solution was cooled to 0 °C. Imidazole (1.8–2 equiv) and DMAP (ca. 1–5 mol%) were added followed by the addition of TBSCl (1.5 equiv) [solid or as a solution in CH₂Cl₂ (3.78 M)]. The mixture was then allowed to warm to 25 °C and stirred for 2–6 h after which time TLC indicated full conversion of S1. The suspension was poured on brine (3 volumes of CH₂Cl₂) and the organic layer collected. The aq layer was re-extracted with CH₂Cl₂ (2 × 1/2 volume brine). The combined organic extracts were washed with brine (1/2 initial volume brine), the washed organic phase dried over Na₂SO₄ or MgSO₄ and the filtrate concentrated. The crude material was purified by column chromatography on silica gel eluting with pentane/Et₂O (100:0 to 95:5) or cyclohexane/EtOAc (95:5) to afford the pure TBS ether.

(E)-tert-Butyl[(6,10-dimethylundeca-5,9-dien-1-yn-4-yl)oxy]dimethylsilane [(E)-S2b]

Prepared on 1.5 g scale from (E)-S1; the product was isolated as a pale yellow oil (2.24 g, 93%).

¹H NMR (500 MHz, CDCl₃): δ = 5.16 (dq, J = 8.7, 1.4 Hz, 1 H), 5.10 (ddq, J = 8.4, 5.6, 1.4 Hz, 1 H), 4.53 (dt, J = 8.7, 6.4 Hz, 1 H), 2.38 (ddd, J = 16.5, 6.6, 2.7 Hz, 1 H), 2.27 (ddd, J = 16.5, 6.3, 2.7 Hz, 1 H), 2.09 (app q, J = 7.3 Hz, 2 H), 2.03–1.98 (m, 2 H), 1.92 (t, J = 2.7 Hz, 1 H), 1.67 (s, 3 H), 1.66 (d, J = 1.3 Hz, 3 H), 1.60 (s, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.04 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 136.4, 131.7, 128.0, 124.2, 82.0, 69.3, 68.6, 39.6, 28.7, 26.4, 26.0 (3 C), 25.8, 18.4, 17.8, 16.9, –4.2, –4.6.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₉H₃₄OSiNa: 329.2271; found: 329.2270.

(Z)-tert-Butyl[(6,10-dimethylundeca-5,9-dien-1-yn-4-yl)oxy]dimethylsilane [(Z)-S2b]

Prepared on 2.5 g scale from (Z)-S1; the product was isolated as a pale yellow oil (3.20 g, 83%).

¹H NMR (400 MHz, CDCl₃): δ = 5.16 (app d, J = 8.7 Hz, 1 H), 5.11 (app tdd, J = 5.1, 2.8, 1.4 Hz, 1 H), 4.53 (ddd, J = 8.8, 6.7, 5.9 Hz, 1 H), 2.37 (ddd, J = 16.5, 6.7, 2.6 Hz, 1 H), 2.26 (ddd, J = 16.5, 5.9, 2.7 Hz, 1 H), 2.19–1.96 (m, 4 H), 1.93 (t, J = 2.6 Hz, 1 H), 1.71 (d, J = 1.4 Hz, 3 H), 1.69 (s, 3 H), 1.62 (s, 3 H), 0.88 (s, 9 H), 0.07 (s, 3 H), 0.03 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 136.6, 132.1, 128.7, 124.2, 82.1, 69.4, 68.2, 32.7, 29.0, 26.7, 26.0 (3 C), 25.8, 23.2, 18.3, 17.8, –4.1, –4.5.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₉H₃₄OSiNa: 329.2271; found: 329.2268.

Preparation of the TES Ether of S1 (S2c)

In a dry round-bottom flask under argon, S1 (1 equiv) was dissolved in CH₂Cl₂ (0.3 M solution) and the solution was cooled to 0 °C. Imidazole (2 equiv) and DMAP (1.11 equiv) were added followed by the addition of TESCl (1.5 equiv). The mixture was then allowed to warm to 25 °C and stirred for 1 h after which time TLC indicated full conversion of S1. The suspension was poured on brine (3 volumes of CH₂Cl₂) and the organic layer collected. The aq layer was re-extracted with CH₂Cl₂ (2 × 1/2 volume brine). The combined organic extracts were washed with brine (1/2 initial volume brine), the washed organic layer dried over MgSO₄ and the filtrate concentrated. The crude material was purified by column chromatography on silica gel eluting with pentane/Et₂O (90:10).

(E)-[(6,10-Dimethylundeca-5,9-dien-1-yn-4-yl)oxy]triethylsilane [(E)-S2c]

Prepared on 579 mg scale from (E)-S1; the product was isolated as a pale yellow oil (795 mg, 87%).

¹H NMR (500 MHz, CDCl₃): δ = 5.19 (dq, J = 8.7, 1.3 Hz, 1 H), 5.10 (ddq, J = 8.4, 5.7, 1.4 Hz, 1 H), 4.53 (dt, J = 8.7, 6.4 Hz, 1 H), 2.41 (ddd, J = 16.5, 6.2, 2.7 Hz, 1 H), 2.29 (ddd, J = 16.5, 6.6, 2.7 Hz, 1 H), 2.13–2.06 (m, 2 H), 2.03–1.98 (m, 2 H), 1.92 (t, J = 2.6 Hz, 1 H), 1.68–1.66 (m, 6 H), 1.60 (s, 3 H), 0.95 (t, J = 7.9 Hz, 9 H), 0.59 (q, J = 7.9 Hz, 6 H).

¹³C NMR (126 MHz, CDCl₃): δ = 136.7, 131.7, 127.8, 124.2, 81.8, 69.4, 68.2, 39.7, 28.8, 26.4, 25.8, 17.8, 16.9, 6.9 (3 C), 5.0 (3 C).

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₉H₃₄OSiNa: 329.2271; found: 329.2272.

Preparation of the MOM Ether of S1 (S2d)

In a dry round-bottom flask under argon, S1 (1 equiv) was dissolved in CH₂Cl₂ (0.3 M solution) and the solution was cooled to 0 °C. N,N-Diisopropylethylamine (3 equiv) was added followed by the addition of MOMCl (3 equiv). The mixture was then allowed to warm to 25 °C and stirred for 2 h after which time TLC indicated full conversion of S1. The suspension was poured on brine (3 volumes of CH₂Cl₂) and the organic layer collected. The aq layer was re-extracted with CH₂Cl₂ (2 × 1/2 volume brine). The combined organic extracts were washed with brine (1/2 initial volume brine), the washed organic phase dried over MgSO₄ and the filtrate concentrated. The crude material was purified by column chromatography on silica gel eluting with pentane/Et₂O (9:1 to 8:2).

(E)-4-(Methoxymethoxy)-6,10-dimethylundeca-5,9-dien-1-yne [(E)-S2d]

Prepared on 579 mg scale from (E)-S1; the product was isolated as a pale yellow oil (657 mg, 93%).

¹H NMR (400 MHz, CDCl₃): δ = 5.13–5.04 (m, 2 H), 4.67 (d, J = 6.7 Hz, 1 H), 4.55–4.47 (m, 2 H), 3.39 (s, 3 H), 2.48 (ddd, J = 16.7, 6.5, 2.6 Hz, 1 H), 2.41 (ddd, J = 16.7, 5.9, 2.7 Hz, 1 H), 2.15–2.02 (m, 4 H), 1.98 (t, J = 2.6 Hz, 1 H), 1.70 (d, J = 1.4 Hz, 3 H), 1.67 (app d, J = 1.4 Hz, 3 H), 1.60 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 141.7, 131.9, 124.0, 123.6, 93.4, 81.3, 69.9, 69.6, 55.5, 39.8, 26.4, 25.9, 25.8, 17.8, 16.8.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₅H₂₄O₂Na: 259.1669; found: 259.1668.

Preparation of Aldehydes 7 from S2; General Procedure

In a dry round-bottom flask under argon, AD-mix-α (1.4 g per mmol of S2) and methylsulfonamide (1 equiv) were dissolved in t-BuOH/H₂O (1:1) (15 mL per mmol of S2) and the solution was cooled to 0 °C. S2 (1 equiv) was added slowly as a solution in t-BuOH (0.5 mL per mmol). The mixture was stirred at 0 °C for 5 min then allowed to warm to 25 °C and stirred for 16 h. TLC indicated full conversion of S2 into the diol. The suspension was quenched by addition of a sat. solution of Na₂SO₃ (15 mL per mmol) and then solid Na₂SO₃ (2 g per mmol). The resulting mixture was stirred at 25 °C for 1 h, then poured on brine (5 volumes of t-BuOH) and extracted with EtOAc (4 × volume t-BuOH). The combined organic extracts were washed with a sat. solution of Na₂SO₃ (15 mL per mmol) (2 × volume t-BuOH) and a sat. solution of NaHCO₃ (volume t-BuOH). The washed organic extracts were dried over Na₂SO₄ and the filtrate concentrated. The crude diol was redissolved in HPLC grade CH₂Cl₂ (20 mL per mmol) and the solution cooled to 0 °C and NaIO₄@SiO₂ [17] (2 g per mmol) was added. The suspension was stirred at 25 °C for 1.5–3 h after which time TLC indicated full conversion of the diol. The solids were filtered off on a pad of Celite and washed with Et₂O (3 × 10 mL per mmol) and the filtrate concentrated. The resulting crude aldehyde was purified by column chromatography on silica gel eluting with pentane/Et₂O (98:2 to 9:1) or cyclohexane/EtOAc (90:10 to 80:20) to afford the pure aldehyde.

(E)-6-Methyl-9-oxonon-5-en-1-yn-4-yl Benzoate [(E)-7a]

Prepared on 2.63 g scale from (E)-S2a; the product was isolated as a pale yellow oil (1.59 g, 66%).

¹H NMR (400 MHz, CDCl₃): δ = 9.77 (t, J = 1.7 Hz, 1 H), 8.07–8.02 (m, 2 H), 7.56 (ddt, J = 8.7, 6.9, 1.3 Hz, 1 H), 7.47–7.40 (m, 2 H), 5.84 (dt, J = 9.0, 6.1 Hz, 1 H), 5.38 (ddq, J = 9.1, 2.7, 1.4 Hz, 1 H), 2.70–2.55 (m, 4 H), 2.42–2.36 (m, 2 H), 1.99 (t, J = 2.7 Hz, 1 H), 1.85 (d, J = 1.3 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 201.8, 165.8, 140.4, 133.1, 130.4, 129.8 (2 C), 128.5 (2 C), 122.8, 79.5, 70.5, 69.4, 41.9, 31.7, 25.2, 17.4.

HRMS (ESI+): m/z [M + MeOH + Na]⁺ calcd for C₁₈H₂₂O₄Na: 325.1410; found: 325.1403.

(Z)-6-Methyl-9-oxonon-5-en-1-yn-4-yl Benzoate [(Z)-7a]

Prepared on 2.5 g scale from (Z)-S2a; the product was isolated as a pale yellow solid (2.90 g, 84%).

Mp 33–35 °C (CH₂Cl₂/pentane).

¹H NMR (500 MHz, CDCl₃): δ = 9.81 (t, J = 1.2 Hz, 1 H), 8.06–8.02 (m, 2 H), 7.58–7.53 (m, 1 H), 7.46–7.41 (m, 2 H), 5.86 (dt, J = 9.4, 6.1 Hz, 1 H), 5.38 (app dd, J = 9.4, 1.5 Hz, 1 H), 2.70–2.53 (m, 6 H), 2.01 (t, J = 2.6 Hz, 1 H), 1.77 (d, J = 1.4 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 201.7, 165.8, 140.6, 133.1, 130.4, 129.8 (2 C), 128.5 (2 C), 123.9, 79.7, 70.7, 69.2, 42.3, 25.3, 25.1, 23.3.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₇H₁₈O₃Na: 293.1148; found: 293.1154 (also observed: m/z [M + MeOH + Na] calcd for C₁₈H₂₂O₄Na: 325.1410; found: 325.1423).

(E)-6-[(tert-Butyldimethylsilyl)oxy]-4-methylnon-4-en-8-ynal [(E)-7b]

Prepared on 2.24 g scale from (E)-S2b; the product was isolated as a pale yellow oil (1.314 g, 64%).

¹H NMR (400 MHz, CDCl₃): δ = 9.78 (t, J = 1.8 Hz, 1 H), 5.19 (dq, J = 8.7, 1.3 Hz, 1 H), 4.52 (dt, J = 8.6, 6.5 Hz, 1 H), 2.58–2.51 (m, 2 H), 2.43–2.31 (m, 3 H), 2.27 (ddd, J = 16.5, 6.7, 2.7 Hz, 1 H), 1.92 (t, J = 2.7 Hz, 1 H), 1.69 (d, J = 1.4 Hz, 3 H), 0.87 (s, 9 H), 0.06 (s, 3 H), 0.02 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 202.1, 134.7, 128.8, 81.6, 69.6, 68.4, 42.0, 31.7, 28.6, 25.9 (3 C), 18.3, 17.1, –4.3, –4.6.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₆H₂₈O₂SiNa: 303.1751; found: 303.1744.

(Z)-6-[(tert-Butyldimethylsilyl)oxy]-4-methylnon-4-en-8-ynal [(Z)-7b]

Prepared on 3.0 g scale from (Z)-S2b; the product was isolated as a pale yellow oil (2.40 g, 87%).

¹H NMR (500 MHz, CDCl₃): δ = 9.80 (t, J = 1.5 Hz, 1 H), 5.20 (app dd, J = 8.8, 1.4 Hz, 1 H), 4.52 (ddd, J = 8.9, 6.9, 6.0 Hz, 1 H), 2.58–2.53 (m, 2 H), 2.51–2.44 (m, 1 H), 2.40 (ddd, J = 16.5, 6.0, 2.7 Hz, 1 H), 2.35–2.24 (m, 2 H), 1.93 (t, J = 2.6 Hz, 1 H), 1.70 (d, J = 1.4 Hz, 3 H), 0.86 (s, 9 H), 0.06 (s, 3 H), 0.02 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 201.7, 134.6, 129.9, 81.8, 69.8, 68.0, 42.5, 28.9, 25.9 (3 C), 24.7, 23.0, 18.3, –4.2, –4.5.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₆H₂₈O₂SiNa: 303.1751; found: 303.1752 (also observed: m/z [M + MeOH + Na] calcd for C₁₇H₃₂O₃SiNa: 335.2013; found: 335.2025).

(E)-4-Methyl-6-[(triethylsilyl)oxy]non-4-en-8-ynal [(E)-7l]

Prepared on 790 mg scale from (E)-S2c; the product was isolated as a pale yellow oil (506 mg, 70%).

¹H NMR (500 MHz, CDCl₃): δ = 9.78 (t, J = 1.7 Hz, 1 H), 5.24–5.19 (m, 1 H), 4.53 (ddd, J = 8.7, 7.0, 5.9 Hz, 1 H), 2.55 (ddd, J = 8.0, 6.9, 1.6 Hz, 2 H), 2.41 (ddd, J = 16.4, 5.9, 2.6 Hz, 1 H), 2.36–2.32 (m, 2 H), 2.29 (ddd, J = 16.5, 7.1, 2.7 Hz, 1 H), 1.92 (t, J = 2.7 Hz, 1 H), 1.70 (d, J = 1.3 Hz, 3 H), 0.94 (t, J = 7.9 Hz, 9 H), 0.58 (q, J = 7.7 Hz, 6 H).

¹³C NMR (126 MHz, CDCl₃): δ = 202.1, 134.9, 128.7, 81.4, 69.6, 68.0, 42.0, 31.7, 28.7, 17.2, 6.9 (3 C), 5.0 (3 C).

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₆H₂₈O₂SiNa: 303.1751; found: 303.1756.

(E)-6-(Methoxymethoxy)-4-methylnon-4-en-8-ynal [(E)-7k]

Prepared on 650 mg scale from (E)-S2d; the product was isolated as a pale yellow oil (385 mg, 57%).

¹H NMR (400 MHz, CDCl₃): δ = 9.77 (t, J = 1.7 Hz, 1 H), 5.17–5.12 (m, 1 H), 4.62 (d, J = 6.8 Hz, 1 H), 4.55–4.46 (m, 2 H), 3.38 (s, 3 H), 2.60–2.53 (m, 2 H), 2.47 (ddd, J = 16.7, 6.2, 2.7 Hz, 1 H), 2.44–2.35 (m, 3 H), 1.98 (t, J = 2.6 Hz, 1 H), 1.73 (d, J = 1.4 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 201.9, 139.6, 124.5, 93.6, 80.9, 69.8, 69.8, 55.5, 42.0, 31.8, 25.7, 17.1.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₂H₁₈O₃Na: 233.1148; found: 233.1158.

Ketones 7c–j; General Procedure

Depending on the polarity of the alcohol intermediate S3 (and the ease of purification), one of the two following methods was used for the preparation of ketones 7c–j.

Method A

In a dry flask under argon, the corresponding aldehyde 7a,b (1 equiv) was dissolved in anhydrous THF (ca. 4 mL per mmol) and the solution was cooled to –78 °C. A solution of Grignard reagent R–MgX (1.5 equiv) was added slowly at –78 °C. The mixture was stirred at –78 °C for 1.5–3 h during which time a milky suspension was observed. The suspension was quenched by addition of a sat. aq solution of NH₄Cl (ca. 5 mL per mmol) at –78 °C, then allowed to warm to 25 °C whilst stirring vigorously. It was then poured on brine (70 mL per mmol) and extracted with Et₂O (3 × 40 mL per mmol). The combined ethereal extracts were dried over Na₂SO₄ and the filtrate concentrated. The crude material was purified by column chromatography on silica gel eluting with cyclohexane/EtOAc to afford the alcohol as a mixture of diastereomers (the unreacted aldehyde can be recovered and recycled at this stage).

The pure alcohol was redissolved in CH₂Cl₂ (ca. 10 mL per mmol) and the solution cooled to 0 °C and NaHCO₃ (5 equiv) and Dess–Martin periodinane (1.2 equiv) were added sequentially. The mixture was stirred at 0 °C for 1–2 h and then at 25 °C for 1–2 h after which time TLC showed full conversion of the alcohol into the less polar ketone. The mixture was either quenched by addition of a sat. solution of Na₂S₂O₃ and extracted with CH₂Cl₂ or diluted with pentane (2–3 × volume CH₂Cl₂) and filtered. The resulting crude product was purified by chromatography on silica gel eluting with cyclohexane/EtOAc to afford the title ketone.

Method B

In a dry flask under argon, the corresponding aldehyde 7a,b (1 equiv) was dissolved in anhydrous THF (ca. 4 mL per mmol) and the solution was cooled to –78 °C. A solution of Grignard reagent R–MgX (1.5 equiv) was added slowly at –78 °C. The mixture was stirred at –78 °C for 1.5–3 h during which time a milky suspension was observed. The suspension was quenched by addition of a sat. aq solution of NH₄Cl (ca. 5 mL per mmol) at –78 °C, then allowed to warm to 25 °C whilst stirring vigorously. It was then poured on brine (70 mL per mmol) and extracted with Et₂O (3 × 40 mL per mmol). The combined ethereal extracts were dried over Na₂SO₄ and the filtrate concentrated. The crude alcohol (containing the unreacted starting aldehyde) was redissolved in CH₂Cl₂ (ca. 10 mL per mmol) and the solution cooled to 0 °C and NaHCO₃ (5 equiv) and Dess–Martin periodinane (1.2 equiv) were added sequentially. The mixture was stirred at 0 °C for 1–2 h and then at 25 °C for 1–2 h after which time TLC showed full conversion of the alcohol into the less polar ketone. The mixture was either quenched by addition of a sat. solution of Na₂S₂O₃ and extracted with CH₂Cl₂ or diluted with pentane (2–3 × volume CH₂Cl₂) and filtered. The resulting crude product was purified by chromatography on silica gel eluting with cyclohexane/EtOAc to afford the title ketone (the unreacted aldehyde can be recovered and recycled).

(E)-9-Hydroxy-6-methyldec-5-en-1-yn-4-yl Benzoate [(E)-S3c]

Prepared on 300 mg scale from (E)-7a according to method A and using a commercial solution of MeMgBr in Et₂O (3 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (4:1 to 3:1) and obtained as a colorless oil (221 mg, 70%, ca. 1:1 dr). Note: in the proton assignments below ‘1 H + 1 H’ refers to a signal accounting for one proton of each diastereomer; likewise, ‘1 C + 1 C’ refers to a signal accounting for one carbon of each diastereomer.

¹H NMR (400 MHz, CDCl₃): δ = 8.07–8.02 (m, 2 H + 2 H), 7.58–7.52 (m, 1 H + 1 H), 7.47–7.40 (m, 2 H + 2 H), 5.89–5.81 (m, 1 H + 1 H), 5.39 (app d quin, J = 9.0, 1.4 Hz, 1 H + 1 H), 3.80 (app sept, J = 5.7 Hz, 1 H + 1 H), 2.71–2.56 (m, 2 H + 2 H), 2.24–2.06 (m, 2 H + 2 H), 1.99 and 1.99 (two t, J = 2.5 Hz, 1 H + 1 H), 1.84 (s, 3 H + 3 H), 1.63–1.55 (m, 2 H + 2 H), 1.20 (d, J = 6.2 Hz, 3 H + 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 165.9, 165.9, 142.4 (1 C + 1 C), 133.0 (1 C + 1 C), 130.7 (1 C + 1 C), 129.8 (2 C + 2 C), 128.5 (2 C + 2 C), 122.3, 122.3, 79.8, 79.8, 70.4, 70.4, 69.7, 69.7, 68.0, 67.9, 37.2, 37.2, 36.1, 36.0, 25.3 (1 C + 1 C), 23.7, 23.7, 17.2 (1 C + 1 C).

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₈H₂₂O₃Na: 309.1461; found: 309.1457.

(E)-6-Methyl-9-oxodec-5-en-1-yn-4-yl Benzoate [(E)-7c)]

Prepared on 221 mg scale from S3c according to method A. The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (9:1 to 4:1) to afford a colorless oil (186 mg, 85%); 60% yield over 2 steps.

¹H NMR (400 MHz, CDCl₃): δ = 8.06–8.02 (m, 2 H), 7.55 (ddt, J = 8.0, 6.9, 1.4 Hz, 1 H), 7.48–7.40 (m, 2 H), 5.84 (dt, J = 9.0, 6.1 Hz, 1 H), 5.38–5.32 (m, 1 H), 2.69–2.53 (m, 4 H), 2.36–2.29 (m, 2 H), 2.15 (s, 3 H), 1.99 (t, J = 2.6 Hz, 1 H), 1.83 (d, J = 1.4 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 208.1, 165.8, 141.0, 133.1, 130.5, 129.8 (2 C), 128.5 (2 C), 122.4, 79.7, 70.4, 69.5, 41.9, 33.4, 30.1, 25.2, 17.4.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₈H₂₀O₃Na: 307.1305; found: 307.1306.

(Z)-9-Hydroxy-6-methyldec-5-en-1-yn-4-yl Benzoate [(Z)-S3c]

Prepared on 300 mg scale from (Z)-7a according to method A and using a commercial solution of MeMgBr in Et₂O (3 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (85:15 to 7:3) and obtained as a colorless oil (208 mg, 65%, ca. 1.15:1 dr; 80% based on recovered starting material) (plus 55 mg recovered aldehyde, 18%).

¹H NMR (500 MHz, CDCl₃): δ = 8.07–8.03 (m, 2 H major + 2 H minor), 7.58–7.52 (m, 1 H major + 1 H minor), 7.46–7.40 (m, 2 H major + 2 H minor), 5.92 (app dt, J = 9.3, 6.1 Hz, 1 H major + 1 H minor), 5.38–5.32 (m, 1 H major + 1 H minor), 3.84–3.73 (m, 1 H major + 1 H minor), 2.70–2.56 (m, 2 H major + 2 H minor), 2.50 (dt, J = 13.6, 8.2 Hz, 1 H major), 2.38 (ddd, J = 13.5, 10.0, 5.6 Hz, 1 H minor), 2.30 (ddd, J = 13.4, 9.8, 6.7 Hz, 1 H minor), 2.19 (ddd, J = 13.7, 8.0, 5.7 Hz, 1 H major), 2.00 and 2.00 (two t, J = 2.6 Hz, 1 H major + 1 H minor), 1.78 (d, J = 1.4 Hz, 3 H minor), 1.76 (d, J = 1.4 Hz, 3 H major), 1.66–1.50 (m, 2 H major + 2 H minor), 1.20 (d, J = 6.2 Hz, 3 H minor), 1.19 (d, J = 6.2 Hz, 3 H major).

¹³C NMR (126 MHz, CDCl₃): δ = 166.1, 165.9, 143.0, 142.1, 133.2, 133.1, 130.5, 130.4, 129.9 (2 C one diastereomer), 129.8 (2 C one diastereomer), 128.5 (2 C one diastereomer), 128.4 (2 C one diastereomer), 123.2, 122.6, 79.9, 79.8, 70.5, 70.5, 69.7, 69.3, 68.0, 66.6, 37.7, 36.9, 29.2, 28.5, 25.6, 25.4, 23.9, 23.7, 23.5, 23.2.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₈H₂₂O₃Na: 309.1461; found: 309.1451.

(Z)-6-Methyl-9-oxodec-5-en-1-yn-4-yl Benzoate [(Z)-7c)]

Prepared on 190 mg scale from S3c according to method A. The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (4:1) to afford a colorless oil (179 mg, 95%); 62% yield over 2 steps (76% based on recovered starting material).

¹H NMR (400 MHz, CDCl₃): δ = 8.07–8.01 (m, 2 H), 7.58–7.51 (m, 1 H), 7.47–7.39 (m, 2 H), 5.85 (dt, J = 9.3, 6.1 Hz, 1 H), 5.39–5.33 (m, 1 H), 2.70–2.41 (m, 6 H), 2.14 (s, 3 H), 2.00 (t, J = 2.7 Hz, 1 H), 1.74 (d, J = 1.5 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 208.0, 165.7, 141.1, 133.0, 130.5, 129.8 (2 C), 128.4 (2 C), 123.5, 79.8, 70.5, 69.3, 42.0, 30.0, 26.8, 25.3, 23.3.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₈H₂₀O₃Na: 307.1305; found: 307.1304.

(E)-7-[(tert-Butyldimethylsilyl)oxy]-5-methyldec-5-en-9-yn-2-ol [(E)-S3d]

Prepared on 500 mg scale from (E)-7b according to method A and using a commercial solution of MeMgBr in Et₂O (3 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (95:5 to 9:1) and obtained as a colorless oil (470 mg, 89%, ca. 1:1 dr). Note: in the proton assignments below ‘1 H + 1 H’ refers to a signal accounting for one proton of each diastereomer; likewise, ‘1 C + 1 C’ refers to a signal accounting for one carbon of each diastereomer.

¹H NMR (500 MHz, CDCl₃): δ = 5.20 (app d quin, J = 8.6, 1.3 Hz, 1 H + 1 H), 4.53 (app dt, J = 8.6, 6.5 Hz, 1 H + 1 H), 3.80 (app sext J = 6.4 Hz, 1 H + 1 H), 2.40 (app ddd, J = 16.5, 6.2, 2.6 Hz, 1 H + 1 H), 2.28 (app ddd, J = 16.5, 6.7, 2.6 Hz, 1 H + 1 H), 2.15–2.02 (m, 2 H + 2 H), 1.92 and 1.91 (two t, J = 2.6 Hz, 1 H + 1 H), 1.69 (d, J = 1.4 Hz, 3 H one diastereomer) and 1.68 (d, J = 1.4 Hz, 3 H other diastereomer), 1.64–1.50 (m, 2 H + 2 H), 1.20 (d, J = 0.6 Hz, 3 H one diastereomer) and 1.19 (d, J = 0.6 Hz, 3 H other diastereomer), 0.87 (s, 9 H + 9 H), 0.06 (s, 3 H + 3 H), 0.03 (s, 3 H + 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 136.6, 136.4, 128.2 (1 C + 1 C), 81.8, 81.8, 69.5, 69.4, 68.4 (1 C + 1 C), 68.2, 67.8, 37.2, 37.2, 36.2, 35.9, 28.7, 28.7, 26.0 (3 C + 3 C), 23.6 (1 C + 1 C), 18.3 (1 C + 1 C), 17.0 (1 C + 1 C), –4.2, –4.2, –4.6 (1 C + 1 C).

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₇H₃₂O₂SiNa: 319.2064; found: 319.2072.

(E)-7-[(tert-Butyldimethylsilyl)oxy]-5-methyldec-5-en-9-yn-2-one [(E)-7d)]

Prepared on 470 mg scale from (E)-S3d according to method A. The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (9:1) to afford a colorless oil (338.7 mg, 73%); 65% yield over 2 steps.

¹H NMR (500 MHz, CDCl₃): δ = 5.15 (app d sept, J = 8.6, 1.4 Hz, 1 H), 4.51 (dt, J = 8.6, 6.5 Hz, 1 H), 2.57–2.51 (m, 2 H), 2.38 (ddd, J = 16.5, 6.3, 2.6 Hz, 1 H), 2.30–2.22 (m, 3 H), 2.15 (s, 3 H), 1.91 (t, J = 2.6 Hz, 1 H), 1.67 (d, J = 1.3 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 3 H), 0.02 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 208.3, 135.3, 128.3, 81.7, 69.5, 68.4, 42.1, 33.3, 30.0, 28.7, 26.0 (3 C), 18.3, 17.2, –4.2, –4.6.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₇H₃₀O₂SiNa: 317.1907; found: 317.1909.

(Z)-7-[(tert-Butyldimethylsilyl)oxy]-5-methyldec-5-en-9-yn-2-ol [(Z)-S3d]

Prepared on 300 mg scale from (Z)-7b according to method A and using a commercial solution of MeMgBr in Et₂O (3 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (95:5 to 9:1) and obtained as a colorless oil (220 mg, 69%, ca. 1.35:1 dr; 81% based on recovered starting material) (plus 45 mg recovered aldehyde, 15%).

¹H NMR (500 MHz, CDCl₃): δ = 5.20–5.14 (m, 1 H major + 1 H minor), 4.59–4.52 (m, 1 H major + 1 H minor), 3.83–3.75 (m, 1 H major + 1 H minor), 2.43–2.36 (m, 1 H major + 1 H minor), 2.32–2.19 (m, 2 H major + 2 H minor), 2.13–2.02 (m, 1 H major + 1 H minor), 1.94 and 1.93 (two t, J = 2.7 Hz, 1 H major + 1 H minor), 1.72 (d, J = 1.4 Hz, 3 H minor), 1.71 (d, J = 1.4 Hz, 3 H major), 1.59–1.51 (m, 2 H major + 2 H minor), 1.21 and 1.21 (two d, J = 6.2 Hz, 3 H major + 3 H minor), 0.87 (s, 9 H minor), 0.87 (s, 9 H major), 0.06 (s, 3 H major + 3 H minor), 0.04 (s, 3 H minor), 0.03 (s, 3 H major).

¹³C NMR (126 MHz, CDCl₃): δ = 136.7, 136.6, 128.8, 128.7, 82.1, 82.0, 69.7, 69.6, 68.3, 68.1, 68.0, 67.8, 37.7, 37.4, 29.0, 29.0, 28.9, 28.7, 26.0 (3 C major + 3 C minor), 23.9, 23.8, 23.3, 23.3, 18.3 (1 C major + 1 C minor), –4.1 (1 C major + 1 C minor), –4.5, –4.5.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₇H₃₂O₂SiNa: 319.2064; found: 319.2074.

(Z)-7-[(tert-Butyldimethylsilyl)oxy]-5-methyldec-5-en-9-yn-2-one [(Z)-7d]

Prepared on 205 mg scale from (Z)-S3d according to method A. The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (95:5 to 9:1) to afford a colorless oil (193 mg, 93%); 65% yield over 2 steps (75% based on recovered starting material).

¹H NMR (500 MHz, CDCl₃): δ = 5.20–5.15 (m, 1 H), 4.52 (dt, J = 8.8, 6.4 Hz, 1 H), 2.53 (app t, J = 7.9 Hz, 2 H), 2.44–2.34 (m, 2 H), 2.30–2.23 (m, 2 H), 2.15 (s, 3 H), 1.92 (t, J = 2.6 Hz, 1 H), 1.68 (d, J = 1.4 Hz, 3 H), 0.86 (s, 9 H), 0.06 (s, 3 H), 0.02 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 208.0, 135.2, 129.5, 81.9, 69.6, 68.0, 42.2, 30.1, 28.9, 26.4, 25.9 (3 C), 23.1, 18.3, –4.2, –4.5.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₇H₃₀O₂SiNa: 317.1907; found: 317.1906.

(E)-9-Cyclopropyl-9-hydroxy-6-methylnon-5-en-1-yn-4-yl Benzoate [(E)-S3e]

Prepared on 268 mg scale from (E)-7a according to method A and using a freshly prepared solution of c-C₃H₅MgBr in Et₂O (~0.4 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (8:2) and obtained as a colorless oil (116 mg, 37%, ca. 1:1 dr). Note: in the proton assignments below ‘1 H + 1 H’ refers to a signal accounting for one proton of each diastereomer; likewise, ‘1 C + 1 C’ refers to a signal accounting for one carbon of each diastereomer.

¹H NMR (400 MHz, CDCl₃): δ = 8.07–8.02 (m, 2 H + 2 H), 7.55 (app t, J = 7.2 Hz, 1 H + 1 H), 7.43 (app t, J = 7.8 Hz, 2 H + 2 H), 5.86 (app dtd, J = 8.9, 6.1, 1.5 Hz, 1 H + 1 H), 5.39 (app d, J = 9.2 Hz, 1 H + 1 H), 2.85 (app quin, J = 6.4 Hz, 1 H + 1 H), 2.70–2.56 (m, 2 H + 2 H), 2.29–2.10 (m, 2 H + 2 H), 2.00–1.96 (m, 1 H + 1 H), 1.84 (s, 3 H + 3 H), 1.79–1.70 (m, 2 H + 2 H), 0.96–0.85 (m, 1 H + 1 H), 0.57–0.45 (m, 2 H + 2 H), 0.30–0.16 (m, 2 H + 2 H).

¹³C NMR (101 MHz, CDCl₃): δ = 165.9, 165.9, 142.5, 142.4, 133.0 (1 C + 1 C), 130.6, 130.6, 129.8 (2 C + 2 C), 128.5 (2 C + 2 C), 122.1, 122.0, 79.8, 79.8, 76.5, 76.4, 70.4, 70.3, 69.7 (1 C + 1 C), 35.8, 35.8, 35.2, 35.1, 25.3, 25.3, 18.1, 18.1, 17.3, 17.3, 2.9, 2.9, 2.7, 2.7.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₀H₂₄O₃Na: 335.1618; found: 335.1614.

(E)-9-Cyclopropyl-6-methyl-9-oxonon-5-en-1-yn-4-yl Benzoate [(E)-7e]

Prepared on 115 mg scale from (E)-S3e according to method A. The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (8:2) to afford a colorless oil (84.3 mg, 73%); 27% yield over 2 steps.

¹H NMR (500 MHz, CDCl₃): δ = 8.07–8.02 (m, 2 H), 7.58–7.53 (m, 1 H), 7.46–7.41 (m, 2 H), 5.85 (dt, J = 9.1, 6.1 Hz, 1 H), 5.39–5.35 (m, 1 H), 2.72–2.67 (m, 2 H), 2.67–2.57 (m, 2 H), 2.36 (td, J = 7.7, 1.3 Hz, 2 H), 1.98 (t, J = 2.6 Hz, 1 H), 1.92 (tt, J = 7.8, 4.5 Hz, 1 H), 1.84 (d, J = 1.4 Hz, 3 H), 1.04–0.96 (m, 2 H), 0.90–0.80 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 210.2, 165.9, 141.2, 133.1, 130.5, 129.8 (2 C), 128.5 (2 C), 122.3, 79.7, 70.4, 69.5, 41.8, 33.6, 25.2, 20.6, 17.4, 10.9, 10.9.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₀H₂₂O₃Na: 333.1461; found: 333.1450.

(Z)-9-Cyclopropyl-9-hydroxy-6-methylnon-5-en-1-yn-4-yl Benzoate [(Z)-S3e]

Prepared on 300 mg scale from (Z)-7a according to method A and using a freshly prepared solution of c-C₃H₅MgBr in Et₂O (~0.4 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (9:1 to 3:1) and obtained as a colorless oil (230 mg, 66%, ca. 4:3 dr; 80% based on recovered starting material) (plus 51 mg recovered starting material, 17%).

¹H NMR (500 MHz, CDCl₃): δ = 8.07–8.02 (m, 2 H major + 2 H minor), 7.58–7.52 (m, 1 H major + 1 H minor), 7.46–7.40 (m, 2 H major + 2 H minor), 5.96–5.89 (m, 1 H major + 1 H minor), 5.39–5.33 (m, 1 H major + 1 H minor), 2.92–2.82 (m, 1 H major + 1 H minor), 2.69–2.57 (m, 2 H major + 2 H minor), 2.53 (dt, J = 13.5, 8.3 Hz, 1 H major), 2.50–2.33 (m, 2 H minor), 2.22 (ddd, J = 13.5, 8.5, 5.3 Hz, 1 H major), 2.00 and 1.99 (two t, J = 2.7 Hz, 1 H major + 1 H minor), 1.87–1.62 (m, 3 + 2 H major + 3 + 2 H minor), 0.95–0.86 (m, 1 H major + 1 H minor), 0.55–0.43 (m, 3 H major + 1 H minor), 0.31–0.23 (m, 1 H major + 1 H minor), 0.23–0.17 (m, 1 H minor), 0.17–0.12 (m, 1 H minor).

¹³C NMR (126 MHz, CDCl₃): δ = 166.1, 165.9, 143.2, 142.3, 133.1, 133.0, 130.6, 130.5, 129.9 (2 C one diastereomer), 129.8 (2 C one diastereomer), 128.5 (2 C one diastereomer), 128.4 (2 C one diastereomer), 123.1, 122.6, 80.0, 79.8, 76.3, 75.5, 70.5, 70.4, 69.7, 69.3, 35.6, 35.0, 29.0, 28.7, 25.6, 25.4, 23.5, 23.3, 18.1, 17.9, 2.8, 2.7, 2.7, 2.6.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₀H₂₄O₃Na: 335.1618; found: 335.1620.

(Z)-9-Cyclopropyl-6-methyl-9-oxonon-5-en-1-yn-4-yl Benzoate [(Z)-7e]

Prepared on 215 mg scale from (Z)-S3e according to method A. The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (9:1) to afford a colorless oil (184 mg, 86%); 57% yield over 2 steps (69% based on recovered starting material).

¹H NMR (500 MHz, CDCl₃): δ = 8.07–8.02 (m, 2 H), 7.57–7.52 (m, 1 H), 7.46–7.40 (m, 2 H), 5.86 (dt, J = 9.3, 6.0 Hz, 1 H), 5.40–5.35 (m, 1 H), 2.75 (ddd, J = 16.7, 9.7, 5.9 Hz, 1 H), 2.71–2.59 (m, 3 H), 2.56 (dddd, J = 13.7, 9.7, 5.9, 0.7 Hz, 1 H), 2.49 (dddd, J = 13.8, 9.7, 6.0, 0.8 Hz, 1 H), 2.00 (t, J = 2.7 Hz, 1 H), 1.93 (tt, J = 7.8, 4.6 Hz, 1 H), 1.76 (d, J = 1.4 Hz, 3 H), 1.04–1.00 (m, 2 H), 0.88–0.83 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 210.1, 165.8, 141.3, 133.0, 130.5, 129.8 (2 C), 128.4 (2 C), 123.4, 79.9, 70.5, 69.3, 41.8, 27.0, 25.4, 23.4, 20.5, 10.9 (2 C).

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₀H₂₂O₃Na: 333.1461; found: 333.1458.

(Z)-9-Cyclopentyl-6-methyl-9-oxonon-5-en-1-yn-4-yl Benzoate [(Z)-7f]

Prepared on 300 mg scale from (Z)-7a according to method B and using a freshly prepared solution of c-C₅H₉MgBr in Et₂O (~1.2 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (95:5 to 4:1) and isolated as a colorless oil (109 mg, 29% over 2 steps; 75% based on recovered starting material) (plus 184 mg of recovered aldehyde, 61%).

¹H NMR (500 MHz, CDCl₃): δ = 8.06–8.02 (m, 2 H), 7.54 (ddt, J = 8.8, 7.0, 1.4 Hz, 1 H), 7.45–7.40 (m, 2 H), 5.85 (dt, J = 9.3, 6.0 Hz, 1 H), 5.37 (dd, J = 9.2, 1.5 Hz, 1 H), 2.89–2.81 (m, 1 H), 2.68–2.41 (m, 6 H), 2.00 (t, J = 2.7 Hz, 1 H), 1.84–1.49 (m, 11 H).

¹³C NMR (126 MHz, CDCl₃): δ = 212.4, 165.7, 141.5, 133.0, 130.6, 129.8 (2 C), 128.4 (2 C), 123.3, 79.9, 70.5, 69.3, 51.5, 40.1, 29.0, 29.0, 26.9, 26.1, 26.1, 25.3, 23.4.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₂H₂₆O₃Na: 361.1774; found: 361.1767.

(E)-6-Methyl-9-oxo-9-phenylnon-5-en-1-yn-4-yl Benzoate [(E)-7g]

Prepared on 300 mg scale from (E)-7a according to method B and using a commercial solution of PhMgBr in Et₂O (3 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (4:1 to 3:1) and isolated as a colorless oil (233 mg, 61% over 2 steps).

¹H NMR (300 MHz, CDCl₃): δ = 8.10–8.03 (m, 2 H), 8.00–7.93 (m, 2 H), 7.61–7.53 (m, 2 H), 7.51–7.41 (m, 4 H), 5.89 (dt, J = 9.0, 6.1 Hz, 1 H), 5.43 (app dq, J = 9.1, 1.3 Hz, 1 H), 3.17–3.08 (m, 2 H), 2.64 (dt, J = 5.8, 2.5 Hz, 2 H), 2.56–2.47 (m, 2 H), 1.98 (t, J = 2.4 Hz, 1 H), 1.91 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 199.6, 165.9, 141.3, 137.1, 133.2, 133.1, 130.5, 129.8 (2 C), 128.7 (2 C), 128.5 (2 C), 128.2 (2 C), 122.5, 79.7, 70.4, 69.5, 37.0, 33.9, 25.2, 17.5.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₃H₂₂O₃Na: 369.1461; found: 369.1449.

(Z)-6-Methyl-9-oxo-9-phenylnon-5-en-1-yn-4-yl Benzoate [(Z)-7g]

Prepared on 300 mg scale from (Z)-7a according to method B and using a commercial solution of PhMgBr in Et₂O (3 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (95:5 to 9:1) and isolated as a colorless solid (279 mg, 73% over 2 steps).

Mp 40–43 °C.

¹H NMR (500 MHz, CDCl₃): δ = 8.07–8.02 (m, 2 H), 7.99–7.93 (m, 2 H), 7.58–7.51 (m, 2 H), 7.48–7.39 (m, 4 H), 5.88 (dt, J = 9.3, 6.0 Hz, 1 H), 5.41 (app d, J = 9.9 Hz, 1 H), 3.21 (ddd, J = 17.0, 9.6, 5.7 Hz, 1 H), 3.09 (ddd, J = 17.0, 9.7, 6.1 Hz, 1 H), 2.75–2.60 (m, 4 H), 2.00 (t, J = 2.6 Hz, 1 H), 1.82 (d, J = 1.4 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 199.6, 165.7, 141.3, 137.0, 133.1, 133.0, 130.5, 129.8 (2 C), 128.7 (2 C), 128.4 (2 C), 128.2 (2 C), 123.6, 79.9, 70.5, 69.4, 37.1, 27.3, 25.4, 23.5.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₃H₂₂O₃Na: 369.1461; found: 369.1469.

(E)-6-[(tert-Butyldimethylsilyl)oxy]-4-methyl-1-phenylnon-4-en-8-yn-1-one [(E)-7h]

Prepared on 309 mg scale from (E)-7b according to method B and using a commercial solution of PhMgBr in Et₂O (3 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (4:1 to 3:1) and isolated as a colorless oil (201 mg, 51% over 2 steps).

¹H NMR (500 MHz, CDCl₃): δ = 7.98–7.93 (m, 2 H), 7.59–7.54 (m, 1 H), 7.49–7.44 (m, 2 H), 5.21 (app dq, J = 8.6, 1.3 Hz, 1 H), 4.54 (dt, J = 8.6, 6.5 Hz, 1 H), 3.11–3.06 (m, 2 H), 2.46–2.41 (m, 2 H), 2.39 (ddd, J = 16.5, 6.5, 2.7 Hz, 1 H), 2.27 (ddd, J = 16.5, 6.4, 2.7 Hz, 1 H), 1.91 (t, J = 2.6 Hz, 1 H), 1.74 (d, J = 1.3 Hz, 3 H), 0.87 (s, 9 H), 0.07 (s, 3 H), 0.03 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 199.7, 137.1, 135.5, 133.1, 128.7 (2 C), 128.4, 128.2 (2 C), 81.8, 69.5, 68.5, 37.1, 33.8, 28.7, 26.0 (3 C), 18.4, 17.3, –4.2, –4.6.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₂H₃₂O₂SiNa: 379.2064; found: 369.2057.

(Z)-7-[(tert-Butyldimethylsilyl)oxy]-4-methyl-1-phenylnon-4-en-8-yn-1-one [(Z)-7h]

Prepared on 300 mg scale from (Z)-7b according to method B and using a commercial solution of PhMgBr in Et₂O (3 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (95:5 to 9:1) and isolated as a pale yellow oil (232 mg, 61% over 2 steps) (plus 75 mg of recovered aldehyde, 25%; 81% based on recovered starting material).

¹H NMR (500 MHz, CDCl₃): δ = 7.99–7.93 (m, 2 H), 7.60–7.54 (m, 1 H), 7.50–7.44 (m, 2 H), 5.25–5.20 (m, 1 H), 4.57 (dt, J = 8.8, 6.4 Hz, 1 H), 3.15–3.02 (m, 2 H), 2.65–2.57 (m, 1 H), 2.46–2.37 (m, 2 H), 2.30 (ddd, J = 16.5, 6.7, 2.7 Hz, 1 H), 1.91 (t, J = 2.6 Hz, 1 H), 1.77 (d, J = 1.4 Hz, 3 H), 0.87 (s, 9 H), 0.07 (s, 3 H), 0.04 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 199.6, 137.0, 135.5, 133.2, 129.6, 128.8 (2 C), 128.1 (2 C), 82.0, 69.7, 68.1, 37.3, 28.9, 26.9, 26.0 (3 C), 23.3, 18.3, –4.1, –4.5.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₂H₃₂O₂SiNa: 379.2064; found: 379.2069.

(E)-6-Methyl-9-oxo-9-[4-(trifluoromethyl)phenyl]non-5-en-1-yn-4-yl Benzoate [(E)-7i]

Prepared on 300 mg scale from (E)-7a according to method B and using a freshly prepared solution of 4-F₃C-C₆H₄MgBr in Et₂O (~0.8 M). The product was purified by silica gel column chromatography eluting with pentane/Et₂O (95:5 to 9:1) and isolated as a pale yellow oil (324 mg, 71% over 2 steps).

¹H NMR (400 MHz, CDCl₃): δ = 8.06–8.02 (m, 4 H), 7.73–7.69 (m, 2 H), 7.59–7.53 (m, 1 H), 7.47–7.41 (m, 2 H), 5.86 (dt, J = 9.0, 6.1 Hz, 1 H), 5.40 (app dq, J = 9.1, 1.3 Hz, 1 H), 3.16–3.10 (m, 2 H), 2.69–2.57 (m, 2 H), 2.54–2.48 (m, 2 H), 1.97 (t, J = 2.6 Hz, 1 H), 1.89 (d, J = 1.3 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 198.6, 165.8, 140.8, 139.7 (app d, J _C–F = 1.0 Hz), 134.5 (q, J _C–F = 32.5 Hz), 133.1, 130.4, 129.8 (2 C), 128.5 (4 C), 125.8 (q, J _C–F = 3.7 Hz, 2 C), 123.7 (q, J _C–F = 273.4 Hz), 122.8, 79.6, 70.5, 69.5, 37.3, 33.6, 25.2, 17.5.

¹⁹F NMR (376 MHz, CDCl₃): δ = –62.83.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₄H₂₁F₃O₃Na: 437.1335; found: 437.1333.

(Z)-6-Methyl-9-oxo-9-[4-(trifluoromethyl)phenyl]non-5-en-1-yn-4-yl Benzoate [(Z)-7i]

Prepared on 300 mg scale from (Z)-7a according to method B and using a freshly prepared solution of 4-F₃C-C₆H₄MgBr in Et₂O (~0.8 M). The product was purified by silica gel column chromatography eluting with pentane/Et₂O (95:5 to 9:1) and isolated as a pale yellow solid (204 mg, 44% over 2 steps).

Mp 42–44 °C (pentane).

¹H NMR (400 MHz, CDCl₃): δ = 8.10–8.00 (m, 4 H), 7.71 (app d, J = 8.1 Hz, 2 H), 7.58–7.51 (m, 1 H), 7.46–7.38 (m, 2 H), 5.87 (dt, J = 9.4, 6.1 Hz, 1 H), 5.42 (app dd, J = 9.4, 1.5 Hz, 1 H), 3.26 (ddd, J = 17.2, 9.3, 6.0 Hz, 1 H), 3.09 (ddd, J = 17.2, 9.1, 6.7 Hz, 1 H), 2.75–2.59 (m, 4 H), 2.01 (t, J = 2.6 Hz, 1 H), 1.82 (d, J = 1.4 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 198.6, 165.8, 141.0, 139.6 (app d, J _C–F = 1.1 Hz), 134.4 (q, J _C–F = 32.6 Hz), 133.1, 130.4, 129.8 (2 C), 128.6 (2 C), 128.5 (2 C), 125.8 (q, J _C–F = 3.7 Hz, 2 C), 123.9, 123.8 (q, J _C–F = 272.7 Hz), 79.8, 70.6, 69.4, 37.4, 27.1, 25.3, 23.5.

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.19.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₄H₂₁O₃F₃Na: 437.1335; found: 437.1337.

(Z)-6-Methyl-9-(naphthalene-2-yl)-9-oxonon-5-en-1-yn-4-yl Benzoate [(Z)-7j]

Prepared on 300 mg scale from (Z)-7b according to method B and using a freshly prepared solution of 2-naphthyl-MgBr in Et₂O (~0.4 M). The product was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (9:1 to 3:1) and isolated as a pale yellow solid (269 mg, 61% over 2 steps).

Mp 74–77 °C.

¹H NMR (500 MHz, CDCl₃): δ = 8.52 (d, J = 1.7 Hz, 1 H), 8.08–8.02 (m, 3 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.91–7.85 (m, 2 H), 7.60 (ddd, J = 8.2, 6.9, 1.4 Hz, 1 H), 7.57–7.51 (m, 2 H), 7.44–7.39 (m, 2 H), 5.93 (dt, J = 9.3, 6.1 Hz, 1 H), 5.44 (dd, J = 9.4, 1.6 Hz, 1 H), 3.37 (ddd, J = 16.7, 8.7, 6.7 Hz, 1 H), 3.21 (ddd, J = 16.7, 9.0, 6.9 Hz, 1 H), 2.74 (app ddd, J = 8.6, 6.5, 1.8 Hz, 2 H), 2.71–2.62 (m, 2 H), 2.01 (t, J = 2.6 Hz, 1 H), 1.86 (d, J = 1.4 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 199.6, 165.8, 141.4, 135.7, 134.3, 133.0, 132.7, 130.5, 130.0, 129.8 (2 C), 129.8, 128.6, 128.5, 128.5 (2 C), 127.9, 126.8, 124.0, 123.6, 79.9, 70.6, 69.5, 37.2, 27.6, 25.4, 23.6.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₇H₂₄O₃Na: 419.1618; found: 419.1613.

Cyclization of Aldehydes and Ketones; General Procedure

A round-bottom flask was charged with the oxo-enyne substrate 7 and the flask was placed in a glovebox. In the glovebox, the substrate was dissolved in toluene (0.01 M solution) and a stock solution of [JohnPhosAu(NCMe)]SbF₆ complex [5 mol% in CH₂Cl₂ (1/35 volume of toluene)] was added in one portion to the vigorously stirred solution. The resulting mixture was stirred at 25 °C for the indicated time. It was then removed from the glovebox and quenched by addition of QuadraPure™ resin (ca. 10 mg per 0.1 mmol) and the suspension stirred vigorously for 15–60 min. It was then filtered on a sintered funnel and the volatiles were removed in vacuo. The crude material was redissolved in CDCl₃ and the internal standard added to measure the NMR yields and diastereomeric ratios. All the material was then collected and purified according to the details provided for each compound below.

(1S*,3aS*,4S*,7R*,7aS*)-7-Methyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (syn-8a)

Performed on 0.21 mmol scale from (E)-7a (59 mg) with stirring for 16 h at 25 °C. Crude ¹H NMR yield = 81% (83:8 dr, ca. 10:1). Purified by preparative silica gel TLC eluting with cyclohexane/CH₂Cl₂/EtOAc (80:15:5) and isolated as a pale yellow solid (48.8 mg, 0.181 mmol, 83%, 93:7 dr).

Mp 81–83 °C (pentane).

¹H NMR (400 MHz, CDCl₃): δ = 8.05–8.00 (m, 2 H), 7.58–7.52 (m, 1 H), 7.46–7.40 (m, 2 H), 6.07 (ddd, J = 5.7, 2.2, 1.0 Hz, 1 H), 5.92 (dtd, J = 5.7, 2.1, 0.6 Hz, 1 H), 5.77 (tt, J = 2.5, 1.2 Hz, 1 H), 4.58–4.53 (m, 1 H), 3.64–3.57 (m, 1 H), 2.55 (dddd, J = 9.2, 2.3, 1.4, 0.6 Hz, 1 H), 1.74–1.62 (m, 2 H), 1.61 (s, 3 H), 1.57–1.49 (m, 1 H), 1.45–1.35 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 166.7, 139.9, 133.1, 130.9, 130.5, 129.8 (2 C), 128.5 (2 C), 85.8, 79.9, 78.9, 59.4, 56.2, 30.9, 28.5, 21.4.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₇H₁₈O₃Na: 293.1148; found: 293.1151.

(1S*,3aS*,4R*,7S*,7aS*)-7-Methyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (anti-8a)

Performed on 0.37 mmol scale from (Z)-7a (100 mg) with stirring for 6 h at 25 °C. Crude ¹H NMR yield = 91% (91:9 dr, yield of combined diastereomers). Purified by preparative silica gel TLC eluting with cyclohexane/CH₂Cl₂/EtOAc (80:15:5) and isolated as a pale yellow oil (82 mg, 0.30 mmol, 82%, 97:3 dr). This compound was crystallized from CH₂Cl₂/pentane to obtain single crystals suitable for X-ray diffraction (see Supporting Information).

Mp 75–77 °C (CH₂Cl₂/pentane).

¹H NMR (500 MHz, CDCl₃): δ = 8.05–7.99 (m, 2 H), 7.54 (ddt, J = 7.9, 6.9, 1.3 Hz, 1 H), 7.45–7.39 (m, 2 H), 6.00 (ddd, J = 5.5, 2.2, 0.9 Hz, 1 H), 5.97–5.92 (m, 2 H), 4.19 (d, J = 5.1 Hz, 1 H), 3.15 (dq, J = 6.5, 2.1 Hz, 1 H), 2.32 (dd, J = 6.9, 1.7 Hz, 1 H), 1.87 (ddt, J = 12.9, 11.3, 5.4 Hz, 1 H), 1.68 (s, 3 H), 1.65–1.51 (m, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 166.3, 137.7, 133.0, 131.6, 130.6, 129.7 (2 C), 128.4 (2 C), 84.5, 81.9, 78.1, 57.5, 56.2, 36.5, 31.1, 18.4.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₇H₁₈O₃Na: 293.1148; found: 293.1157.

tert-Butyldimethyl{[(1S*,3aS*,4S*,7R*,7aS*)-7-methyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl]oxy}silane (syn-8b)

Performed on 0.203 mmol scale from (E)-7b (57 mg) with stirring for 16 h at 25 °C. Crude ¹H NMR yield = 82% (99:1 dr). Purified by silica gel column chromatography eluting with cyclohexane/CH₂Cl₂/EtOAc (80:15:5) and isolated as a pale yellow oil (47.7 mg, 0.170 mmol, 82% >99:1 dr).

¹H NMR (500 MHz, CDCl₃): δ = 5.81 (ddd, J = 5.6, 2.2, 0.9 Hz, 1 H), 5.71 (dt, J = 5.7, 2.0 Hz, 1 H), 4.62–4.59 (m, 1 H), 4.47 (t, J = 5.6 Hz, 1 H), 3.56–3.51 (m, 1 H), 2.35 (dt, J = 9.3, 1.7 Hz, 1 H), 1.64–1.53 (m, 1 H), 1.51 (s, 3 H), 1.49–1.41 (m, 2 H), 1.32–1.23 (m, 1 H), 0.88 (s, 9 H), 0.08 (s, 3 H), 0.08 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 136.0, 134.8, 85.6, 79.1, 76.9, 62.6, 56.0, 30.8, 28.4, 26.1 (3 C), 21.7, 18.3, –4.1, –4.3.

HRMS (APCI+): m/z [M + H]⁺ calcd for C₁₆H₂₉O₂Si: 281.1931; found: 281.1929.

tert-Butyldimethyl{[(1S*,3aS*,4R*,7S*,7aS*)-7-methyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl]oxy}silane (anti-8b)

Performed on 0.37 mmol scale from (Z)-7b (104 mg) by addition of solid [JohnPhosAu(NCMe)SbF₆] (5 mol%) to a toluene solution (0.01 M) of (Z)-7b, with stirring for 14 h at 25 °C. Crude ¹H NMR yield = 73% (83:17 dr, yield of combined diastereomers). Purified by silica gel column chromatography eluting with pentane/Et₂O (95:5) and isolated as a pale yellow oil (57 mg, 0.20 mmol, 58%, >98:2 dr) [minor diastereomer syn-8b (12 mg) was also isolated, 12%].

¹H NMR (400 MHz, CDCl₃): δ = 5.76 (app s, 2 H), 4.80–4.76 (m, 1 H), 4.10 (d, J = 5.0 Hz, 1 H), 3.05 (dd, J = 6.9, 2.3 Hz, 1 H), 2.09 (dd, J = 6.9, 2.0 Hz, 1 H), 1.85–1.75 (m, 1 H), 1.63–1.46 (m, 6 H), 0.89 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 135.8, 133.8, 84.3, 79.2, 78.6, 59.8, 57.3, 36.5, 31.2, 26.0 (3 C), 18.6, 18.2, –3.9, –4.3.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₆H₂₈O₂SiNa: 303.1751; found: 303.1748.

(1S*,3aS*,4S*,7R*,7aS*)-1-(Methoxymethoxy)-7-methyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyindene (syn-8k)

Performed on 0.20 mmol scale from (E)-7k (42 mg) with stirring for 24 h at 40 °C. Crude ¹H NMR yield = 82% (>99:1 dr). Purified by silica gel column chromatography eluting with cyclohexane/CH₂Cl₂/EtOAc (80:15:5) and isolated as a pale yellow oil (33.9 mg, 0.161 mmol, 81%, >99:1 dr).

¹H NMR (500 MHz, CDCl₃): δ = 5.91 (ddd, J = 5.7, 2.2, 1.1 Hz, 1 H), 5.82 (dt, J = 5.7, 2.3 Hz, 1 H), 4.68–4.63 (m, 2 H), 4.51–4.47 (m, 2 H), 3.54–3.48 (m, 1 H), 3.35 (s, 3 H), 2.43 (dt, J = 9.4, 1.9 Hz, 1 H), 1.64–1.57 (m, 1 H), 1.51 (s, 3 H), 1.50–1.43 (m, 2 H), 1.32–1.25 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 137.9, 132.4, 95.3, 85.5, 81.4, 79.1, 59.7, 55.9, 55.3, 30.7, 28.4, 21.1.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₂H₁₈O₃Na: 233.1148; found: 233.1143.

Triethyl{[(1S*,3aS*,4S*,7R*,7aS*)-7-methyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl]oxy}silane (syn-8l)

Performed on 0.20 mmol scale from (E)-7l (56 mg) with stirring for 44 h at 25 °C. Crude ¹H NMR yield = 84% (95:5 dr). Purified by silica gel column chromatography eluting with cyclohexane/CH₂Cl₂/EtOAc (80:15:5) and isolated as a pale yellow oil (39.7 mg, 0.142 mmol, 71%, >99:1 dr).

¹H NMR (500 MHz, CDCl₃): δ = 5.83 (ddd, J = 5.6, 2.2, 0.9 Hz, 1 H), 5.72 (dtd, J = 5.7, 2.0, 0.6 Hz, 1 H), 4.58 (app tt, J = 2.3, 1.2 Hz, 1 H), 4.48 (t, J = 5.7 Hz, 1 H), 3.58–3.52 (m, 1 H), 2.37 (d, J = 9.3 Hz, 1 H), 1.65–1.55 (m, 1 H), 1.52 (s, 3 H), 1.50–1.40 (m, 2 H), 1.33–1.26 (m, 1 H), 0.96 (t, J = 7.9 Hz, 9 H), 0.61 (q, J = 7.9 Hz, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 136.2, 134.7, 85.6, 79.1, 76.5, 62.5, 55.9, 30.8, 28.5, 21.6, 6.9 (3 C), 5.0 (3 C).

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₆H₂₈O₂SiNa: 303.1751; found: 303.1751.

(1S*,3aS*,4S*,7R*,7aS*)-4,7-Dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (syn-8c)

Performed on 0.2 mmol scale from (E)-7c (56 mg) with stirring for 17 h at 30 °C. Crude ¹H NMR yield = 87% (89:11 dr, yield of combined dia­stereomers). Purified by preparative silica gel TLC eluting with cyclohexane/CH₂Cl₂/EtOAc (80:15:5) and isolated as a pale yellow oil (44 mg, 0.154 mmol, 78%, 88:12 dr). Further purification by preparative silica gel TLC eluting twice with cyclohexane/CH₂Cl₂/EtOAc (80:15:5) resulted in the isolation of a pale yellow oil (20.2 mg, 0.071 mmol, 36%, >99:1 dr).

¹H NMR (500 MHz, CDCl₃): δ = 8.04–8.01 (m, 2 H), 7.56–7.52 (m, 1 H), 7.45–7.40 (m, 2 H), 6.06 (ddd, J = 5.6, 2.2, 1.0 Hz, 1 H), 5.92 (dtd, J = 5.6, 2.1, 0.6 Hz, 1 H), 5.77 (tt, J = 2.4, 1.2 Hz, 1 H), 3.28 (d quin, J = 9.2, 2.0 Hz, 1 H), 2.65 (dt, J = 9.3, 1.8 Hz, 1 H), 1.72–1.66 (m, 1 H), 1.64–1.57 (m, 1 H), 1.56 (s, 3 H), 1.53 (ddd, J = 12.1, 3.4, 2.2 Hz, 1 H), 1.50 (s, 3 H), 1.48–1.43 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 166.6, 139.7, 133.0, 130.8, 130.6, 129.7 (2 C), 128.4 (2 C), 85.9, 85.5, 80.5, 61.8, 60.5, 34.6, 32.6, 21.8, 21.6.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₈H₂₀O₃Na: 307.1305; found: 307.1297.

(1S*,3aS*,4R*,7S*,7aS*)-4,7-Dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (anti-8c)

Performed on 0.25 mmol scale from (Z)-7c (71 mg) with stirring for 18 h at 25 °C. Crude ¹H NMR yield = 89% (83:17 dr, yield of combined diastereomers). Purified by column chromatography on silica gel eluting with cyclohexane/CH₂Cl₂/EtOAc (80:15:5) and isolated as a pale yellow solid (56 mg, 0.197 mmol, 79%, 83:17 dr). Further crystallization from Et₂O/pentane afforded 39 mg of a colorless solid (55%, ≥98:2 dr) (plus 17 mg of a pale yellow oil, 24%, 56:44 dr).

Mp 79–81 °C (Et₂O/pentane).

¹H NMR (500 MHz, CDCl₃): δ = 8.05–8.00 (m, 2 H), 7.54 (ddt, J = 7.8, 6.9, 1.3 Hz, 1 H), 7.45–7.39 (m, 2 H), 6.02–5.98 (m, 2 H), 5.98–5.95 (m, 1 H), 3.13–3.08 (m, 1 H), 2.43 (dd, J = 6.8, 1.9 Hz, 1 H), 1.74–1.60 (m, 7 H), 1.38 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 166.3, 136.5, 133.0, 132.2, 130.7, 129.7 (2 C), 128.4 (2 C), 84.3, 84.2, 82.1, 60.0, 57.7, 38.6, 38.1, 18.8, 18.5.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₈H₂₀O₃Na: 307.1305; found: 307.1298.

tert-Butyl{[(1S*,3aS*,4S*,7R*,7aS*)-4,7-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl]oxy}dimethylsilane (syn-8d)

Performed on 0.217 mmol scale from (E)-7d (64 mg) with stirring for 17 h at 25 °C. Crude ¹H NMR yield = 97% (>99:1 dr). The product was further purified by silica gel column chromatography eluting with cyclohexane/CH₂Cl₂/EtOAc (80:15:5) and isolated as a pale yellow oil (41.4 mg, 0.141 mmol, 65%, >99:1 dr).

¹H NMR (500 MHz, CDCl₃): δ = 5.81 (ddd, J = 5.6, 2.2, 0.9 Hz, 1 H), 5.71 (dtd, J = 5.6, 2.0, 0.6 Hz, 1 H), 4.61–4.60 (m, 1 H), 3.22 (dd, J = 9.5, 2.0 Hz, 1 H), 2.46 (d, J = 9.4 Hz, 1 H), 1.55–1.50 (m, 2 H), 1.47 (s, 3 H), 1.45 (s, 3 H), 1.41–1.37 (m, 2 H), 0.88 (s, 9 H), 0.08 (s, 3 H), 0.08 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 135.9, 134.7, 86.0, 85.3, 77.6, 63.8, 61.6, 34.6, 32.5, 26.1 (3 C), 21.9, 21.8, 18.3, –4.1, –4.2.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₇H₃₀O₂SiNa: 317.1907; found: 317.1896.

tert-Butyl{[(1S*,3aS*,4R*,7S*,7aS*)-4,7-dimethyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl]oxy}dimethylsilane (anti-8d)

Performed on 0.3 mmol scale from (Z)-7d (88 mg) with stirring for 18 h at 25 °C. Crude ¹H NMR yield = 74% (>98:2 dr). Purified by silica gel column chromatography eluting with pentane/Et₂O (95:5) and isolated as a pale yellow oil (62 mg, 0.211 mmol, 70%, >98:2 dr).

¹H NMR (500 MHz, CDCl₃): δ = 5.79 (dt, J = 5.7, 1.9 Hz, 1 H), 5.74 (ddd, J = 5.7, 2.4, 1.2 Hz, 1 H), 4.80 (dq, J = 2.2, 1.1 Hz, 1 H), 3.00 (dq, J = 6.7, 2.0 Hz, 1 H), 2.18 (dd, J = 7.1, 2.2 Hz, 1 H), 1.71–1.53 (m, 4 H), 1.51 (s, 3 H), 1.31 (s, 3 H), 0.88 (s, 9 H), 0.09 (s 3 H), 0.08 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 136.4, 132.5, 84.5, 84.1, 79.4, 61.4, 59.7, 38.5, 38.2, 26.0 (3 C), 18.9, 18.5, 18.2, –3.9, –4.3.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₇H₃₀O₂SiNa: 317.1907; found: 317.1904.

(1S*,3aS*,4R*,7R*,7aS*)-4-Cyclopropyl-7-methyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (syn-8e)

Performed on 0.2 mmol scale from (E)-7e (62 mg) with stirring for 15 h at 25 °C. Crude ¹H NMR yield = 54% (80:20 dr, yield of combined diastereomers, 77% conversion). Purified by preparative silica gel TLC eluting with cyclohexane/CH₂Cl₂/EtOAc (85:15:5) and isolated as a pale yellow oil (32 mg, 0.103 mmol, 52%, 82:18 dr).

¹H NMR (500 MHz, CDCl₃): δ = 8.05–7.99 (m, 2 H + 2 H minor), 7.57–7.51 (m, 1 H + 1 H minor), 7.45–7.40 (m, 2 H + 2 H minor), 6.05 (ddd, J = 5.7, 2.1, 1.0 Hz, 1 H), 5.93–5.89 (m, 1 H), 5.76 (tt, J = 2.4, 1.2 Hz, 1 H), 3.30 (d quin, J = 9.0, 2.1 Hz, 1 H), 2.62 (dt, J = 9.3, 1.7 Hz, 1 H), 1.70–1.62 (m, 1 H + 1 H minor), 1.54 (s, 3 H), 1.50–1.34 (m, 3 H + 3 H minor), 1.24–1.16 (m, 1 H), 0.60–0.52 (m, 2 H + 1 H minor), 0.53–0.46 (m, 1 H + 2 H minor), 0.45–0.37 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 166.6, 140.3, 133.0, 130.7, 129.7 (2 C), 128.5 (2 C), 88.8, 84.9, 80.3, 60.1, 59.8, 31.8, 31.2, 21.6, 14.9, 1.5, 1.5; 1 C could not be detected due to overlap of signals.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₀H₂₂O₃Na: 333.1461; found: 333.1464.

(1S*,3aS*,4S*,7S*,7aS*)-4-Cyclopropyl-7-methyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (anti-8e)

Performed on 0.2 mmol scale from (Z)-7e (62 mg) with stirring for 18 h at 25 °C. Crude ¹H NMR yield = 83% (87:13 dr, yield of combined diastereomers­). Purified by preparative silica gel TLC eluting with cyclohexane/CH₂Cl₂/EtOAc (85:12:3) and isolated as a pale yellow oil (46 mg, 0.148 mmol, 74%, 89:11 dr).

¹H NMR (500 MHz, CDCl₃): δ = 8.05–8.00 (m, 2 H + 2 H minor), 7.57–7.52 (m, 1 H + 1 H minor), 7.45–7.40 (m, 2 H + 2 H minor), 6.18 (app dq, J = 4.9, 2.2 Hz, 1 H), 5.99–5.95 (m, 2 H), 3.22–3.18 (m, 1 H), 2.43 (dd, J = 6.9, 1.8 Hz, 1 H), 1.67 (ddd, J = 12.0, 9.2, 5.0 Hz, 1 H), 1.63–1.55 (m, 4 H + 3 H minor), 1.46 (td, J = 11.7, 4.9 Hz, 1 H + 2 H minor), 1.39 (ddd, J = 11.6, 9.2, 4.8 Hz, 1 H + 1 H minor), 1.08 (tt, J = 8.5, 5.4 Hz, 1 H), 0.60–0.54 (m, 1 H + 2 H minor), 0.53–0.49 (m, 2 H), 0.33–0.28 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 166.3, 136.8, 133.0, 131.6, 130.7, 129.7 (2 C), 128.4 (2 C), 86.9, 83.7, 82.3, 60.6, 57.6, 37.6, 32.7, 18.7, 12.2, 2.2, 1.4.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₀H₂₂O₃Na: 333.1461; found: 333.1461.

(1S*,3aS*,4S*,7S*,7aS*)-4-Cyclopentyl-7-methyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (anti-8f)

Performed on 0.2 mmol scale from (Z)-7f (68 mg) with stirring for 18 h at 25 °C. Crude ¹H NMR yield = 78% (84:16 dr, yield of combined diastereomers). Purified by preparative silica gel TLC eluting with cyclohexane/CH₂Cl₂/EtOAc (85:12:3) and isolated as a pale yellow oil (46 mg, 0.136 mmol, 68%, 85:15 dr). Note: since the diastereomeric counterpart of this tricycle was not prepared, the distinguishable data for the minor diastereomer are also given below.

¹H NMR (500 MHz, CDCl₃): δ = 8.04–8.00 (m, 2 H + 2 H minor), 7.57–7.51 (m, 1 H + 1 H minor), 7.45–7.39 (m, 2 H + 2 H minor), 6.07 (ddd, J = 5.6, 2.2, 1.0 Hz, 1 H minor), 6.06–6.03 (m, 1 H), 6.00–5.95 (m, 2 H), 5.92–5.89 (m, 1 H minor), 5.76 (tt, J = 2.4, 1.2 Hz, 1 H minor), 3.40–3.35 (m, 1 H minor), 3.19 (td, J = 4.2, 2.1 Hz, 1 H), 2.68 (dt, J = 9.2, 1.7 Hz, 1 H minor), 2.44 (dd, J = 6.9, 1.9 Hz, 1 H), 2.30 (app quin, J = 8.7 Hz, 1 H minor), 2.20 (quin, J = 8.1 Hz, 1 H), 1.86 (app ddq, J = 15.6, 8.0, 3.8 Hz, 1 H), 1.83–1.35 (m, 13 H + 13 H minor), 1.35–1.24 (m, 1 H + 2 H minor).

¹³C NMR (126 MHz, CDCl₃): δ = 166.3, 136.6, 132.9, 132.0, 130.7, 129.7 (2 C), 128.4 (2 C), 89.7, 83.8, 82.3, 60.0, 57.6, 41.0, 37.9, 30.1, 28.9, 27.5, 26.4, 26.2, 18.8. [Signals for syn-8f: 166.6, 141.0, 133.0, 130.6, 129.7, 91.0, 84.6, 80.2, 60.4, 59.3, 45.0, 32.1, 30.6, 28.3, 28.1, 26.0, 21.6.]

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₂H₂₆O₃Na: 361.1774; found: 361.1774.

(1S*,3aS*,4S*,7R*,7aS*)-7-Methyl-4-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (syn-8g)

Performed on 0.2 mmol scale from (E)-7g (64 mg) with stirring for 15 h at 30 °C. Crude ¹H NMR yield = 72% (58:42 dr, yield of combined diastereomers). Purified by preparative silica gel TLC eluting with cyclohexane/CH₂Cl₂/EtOAc (80:15:5) and isolated as an off-white solid (26.1 mg, 0.075 mmol, 38%, 57:43 dr).

Mp 94–98 °C (pentane).

¹H NMR (500 MHz, CDCl₃): δ = 8.05–8.02 (m, 2 H + 2 H minor), 7.58–7.53 (m, 1 H + 1 H minor), 7.45–7.41 (m, 3 H + 2 H minor), 7.39–7.35 (m, 2 H), 7.34–7.32 (m, 1 H + 4 H minor), 7.31–7.27 (m, 1 H), 6.24 (ddd, J = 5.6, 2.2, 1.0 Hz, 1 H), 6.03–6.00 (m, 1 H), 5.85 (d quin, J = 2.5, 1.2 Hz, 1 H), 3.59 (d quin, J = 9.2, 2.1 Hz, 1 H), 2.79 (dt, J = 9.4, 1.8 Hz, 1 H), 2.10–2.02 (m, 1 H), 1.88–1.77 (m, 2 H + 2 H minor), 1.68 (s, 3 H), 1.67–1.61 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 166.7, 143.0, 139.8, 133.1, 131.4, 130.5, 129.8 (2 C), 128.5 (2 C), 128.5 (2 C), 127.4, 125.2 (2 C), 89.4, 85.7, 80.3, 63.2, 60.3, 35.0, 32.3, 21.7.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₃H₂₂O₃Na: 369.1461; found: 369.1450.

(1S*,3aS*,4R*,7S*,7aS*)-7-Methyl-4-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (anti-8g)

Performed on 0.2 mmol scale from (Z)-7g (69 mg) with stirring for 14 h at 25 °C. Crude ¹H NMR yield = 90% (91:9 dr, yield of combined dia­stereomers). The product was purified by column chromatography on silica gel eluting with cyclohexane/EtOAc (95:5) and isolated as a colorless solid (61 mg, 0.176 mmol, 88%, 93:7 dr). Further crystallization from CH₂Cl₂ (200 μL) + Et₂O (200 μL) + pentane (1 mL), first at 4 °C for 2 h then at –30 °C for 24 h, gave 30 mg of colorless needles (43%, >98:2 dr). The filtrate was recrystallized from CH₂Cl₂ (100 μL) + Et₂O (200 μL) + pentane (1.2 mL) to give a second crop of 18 mg of colorless solid (26%, >98:2 dr). Overall yield after crystallization was 69% (>98:2 dr).

Mp 137–138 °C (CH₂Cl₂/Et₂O/pentane).

¹H NMR (400 MHz, CDCl₃): δ = 8.07–8.01 (m, 2 H), 7.58–7.52 (m, 1 H), 7.47–7.40 (m, 2 H), 7.37–7.30 (m, 4 H), 7.29–7.22 (m, 1 H), 6.06 (dt, J = 3.4, 1.7 Hz, 1 H), 5.89 (dt, J = 5.7, 2.1 Hz, 1 H), 5.45 (ddd, J = 5.7, 2.3, 1.2 Hz, 1 H), 3.52 (dq, J = 6.7, 2.2 Hz, 1 H), 2.55 (dd, J = 6.7, 1.8 Hz, 1 H), 2.24–2.15 (m, 1 H), 1.97–1.79 (m, 3 H), 1.77 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 166.3, 140.9, 137.2, 133.0, 131.5, 130.6, 129.7 (2 C), 128.4 (2 C), 128.2 (2 C), 127.0, 125.4 (2 C), 87.9, 84.4, 82.3, 61.6, 57.4, 38.4, 38.2, 18.8.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₃H₂₂O₃Na: 369.1461; found: 369.1459.

tert-Butyldimethyl{[(1S*,3aS*,4S*,7R*,7aS*)-7-methyl-4-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl]oxy}silane (syn-8h)

Performed on 0.2 mmol scale from (E)-7h (71 mg) with stirring for 15 h at 25 °C. Crude ¹H NMR yield = 98% (>96:4 dr). Purified by silica gel column chromatography eluting with cyclohexane/CH₂Cl₂/EtOAc (80:17:3 to 80:15:5) and isolated as a pale yellow oil (64.4 mg, 0.181 mmol, 90%, 99:1 dr).

¹H NMR (400 MHz, CDCl₃): δ = 7.44–7.39 (m, 2 H), 7.38–7.32 (m, 2 H), 7.29–7.24 (m, 1 H), 6.00 (ddd, J = 5.6, 2.2, 0.9 Hz, 1 H), 5.84–5.80 (m, 1 H), 4.70 (tt, J = 2.3, 1.2 Hz, 1 H), 3.54 (d quin, J = 9.4, 2.0 Hz, 1 H), 2.60 (dt, J = 9.4, 1.7 Hz, 1 H), 1.99 (app ddd, J = 12.4, 9.3, 4.1 Hz, 1 H), 1.76–1.61 (m, 2 H), 1.61 (s, 3 H), 1.58–1.51 (m, 1 H), 0.91 (s, 9 H), 0.12 (s, 3 H), 0.11 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 143.3, 136.0, 135.4, 128.4 (2 C), 127.2, 125.1 (2 C), 89.5, 85.4, 77.5, 63.6, 63.0, 35.1, 32.3, 26.1 (3 C), 22.0, 18.4, –4.1, –4.2.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₂H₃₂O₂SiNa: 379.2064; found: 379.2071.

tert-Butyldimethyl{[(1S*,3aS*,4R*,7S*,7aS*)-7-methyl-4-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl]oxy}silane (anti-8h)

Performed on 0.2 mmol scale from (Z)-7h (71 mg) with stirring for 18 h at 25 °C. Crude ¹H NMR yield = 77% (>98:2 dr). Purified by silica gel column chromatography eluting with pentane/Et₂O (95:5) and isolated as an off-white solid (58 mg). Crystallization from hot pentane gave analytically pure material (43.5 mg, 0.122 mmol, 61%, >98:2 dr).

Mp 72–75 °C (pentane).

¹H NMR (500 MHz, CDCl₃): δ = 7.35–7.27 (m, 4 H), 7.26–7.19 (m, 1 H), 5.68 (dt, J = 5.7, 2.0 Hz, 1 H), 5.21 (ddd, J = 5.7, 2.4, 1.2 Hz, 1 H), 4.91 (dq, J = 3.3, 1.9, 1.2 Hz, 1 H), 3.43 (dq, J = 6.8, 2.2 Hz, 1 H), 2.31 (dd, J = 7.0, 2.0 Hz, 1 H), 2.14 (ddd, J = 10.6, 8.6, 3.9 Hz, 1 H), 1.89–1.72 (m, 3 H), 1.64 (s, 3 H), 0.90 (s, 9 H), 0.12 (s, 3 H), 0.10 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 141.2, 135.7, 133.2, 128.2 (2 C), 126.8, 125.4 (2 C), 88.2, 84.3, 79.6, 61.3, 61.1, 38.5, 38.4, 26.1 (3 C), 19.0, 18.2, –3.9, –4.2.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₂H₃₂O₂SiNa: 379.2064; found: 379.2067.

(1S*,3aS*,4S*,7R*,7aS*)-7-Methyl-4-[4-(trifluoromethyl)phenyl]-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (syn-8i)

Performed on 0.2 mmol scale from (E)-7i (82 mg) with stirring for 17 h at 25 °C. Crude ¹H NMR yield = 78% (83:17 dr, yield of combined diastereomers­). Purified by preparative silica gel TLC eluting with cyclohexane/CH₂Cl₂/EtOAc (85:15:5) and isolated as a pale yellow oil (39.6 mg, 0.096 mmol, 48%, 91:9 dr).

¹H NMR (400 MHz, CDCl₃): δ = 8.06–8.01 (m, 2 H + 2 H minor), 7.66–7.60 (m, 2 H + 2 H minor), 7.59–7.52 (m, 3 H + 1 H minor), 7.47–7.40 (m, 2 H + 4 H minor), 6.23 (ddd, J = 5.7, 2.1, 1.0 Hz, 1 H), 6.05 (dt, J = 5.6, 2.1 Hz, 1 H), 5.85 (sept, J = 1.3 Hz, 1 H), 3.54 (d quin, J = 8.8, 2.2 Hz, 1 H), 2.80 (dt, J = 9.2, 1.7 Hz, 1 H), 2.13–2.04 (m, 1 H), 1.90–1.81 (m, 1 H + 3 H minor), 1.80–1.64 (m, 5 H + 3 H minor).

¹³C NMR (101 MHz, CDCl₃): δ = 166.6, 147.0 (app d, J _C–F = 1.1 Hz), 139.2, 133.2, 132.0, 130.4, 129.8 (2 C), 129.6 (q, J _C–F = 32.4 Hz), 128.5 (2 C), 125.5 (q, J _C–F = 4.0 Hz, 2 C), 125.5 (2 C), 124.3 (q, J _C–F = 271.9 Hz), 89.0, 86.0, 80.1, 63.2, 60.4, 34.9, 32.3, 21.6.

¹⁹F NMR (376 MHz, CDCl₃): δ = 62.55.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₄H₂₁O₃F₃Na: 437.1335; found: 437.1342.

(1S*,3aS*,4R*,7S*,7aS*)-7-Methyl-4-[4-(trifluoromethyl)phenyl]-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (anti-8i)

Performed on 0.2 mmol scale from (Z)-7i (100 mg) with stirring for 17 h at 25 °C. Crude ¹H NMR yield = 99% (86:14 dr, yield of combined diastereomers). Purified by preparative silica gel TLC eluting with cyclohexane/CH₂Cl₂/EtOAc (85:12:3) and isolated as a colorless solid (54 mg, 0.13 mmol, 65% >98:2 dr) (22 mg of a fraction containing a 57:43 dr mixture of diastereomers was also collected, 27%).

Mp 108–110 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.06–8.01 (m, 2 H), 7.60 (app d, J = 8.2 Hz, 2 H), 7.55 (ddt, J = 8.7, 6.9, 1.4 Hz, 1 H), 7.48–7.40 (m, 4 H), 6.05 (app dt, J = 3.2, 1.8 Hz, 1 H), 5.91 (dt, J = 5.7, 2.1 Hz, 1 H), 5.38 (ddd, J = 5.7, 2.3, 1.2 Hz, 1 H), 3.53 (dq, J = 6.7, 2.2 Hz, 1 H), 2.58 (dd, J = 6.8, 1.8 Hz, 1 H), 2.25–2.17 (m, 1 H), 1.94–1.80 (m, 3 H), 1.77 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 166.3, 144.9 (app d, J _C–F = 1.1 Hz), 136.4, 133.1, 132.1, 130.6, 129.7 (2 C), 129.3 (q, J _C–F = 32.3 Hz), 128.5 (2 C), 125.9 (2 C), 125.2 (q, J _C–F = 3.8 Hz, 2 C), 124.4 (q, J _C–F = 271.9 Hz), 87.6, 84.8, 82.1, 61.6, 57.6, 38.3, 38.1, 18.7.

¹⁹F NMR (376 MHz, CDCl₃): δ = –62.53.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₄H₂₁O₃F₃Na: 437.1335; found: 437.1338.

(1S*,3aS*,4R*,7S*,7aS*)-7-Methyl-4-(naphthalen-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-epoxyinden-1-yl Benzoate (anti-8j)

Performed on 0.2 mmol scale from (Z)-7j (79 mg) with stirring for 17 h at 25 °C. Crude ¹H NMR yield = 78% (94:6 dr). Purified by preparative silica gel TLC eluting with cyclohexane/CH₂Cl₂/EtOAc (85:12:3) and isolated as a pale yellow oil that solidified on standing. Further crystallization from CH₂Cl₂ (200 μL) + Et₂O (200 μL) + pentane (1.2 mL), first at 4 °C for 2 h then at –30 °C for 16 h, gave 33 mg of a colorless solid (42%, >98:2 dr). The filtrate was recrystallized from CH₂Cl₂ (100 μL) + Et₂O (100 μL) + pentane (0.8 mL) to give a second crop of 11 mg of colorless solid (14%, >98:2 dr). Overall yield after crystallization was 56% (>98:2 dr).

Mp 125–126 °C (CH₂Cl₂/Et₂O/pentane).

¹H NMR (500 MHz, CDCl₃): δ = 8.09–8.02 (m, 2 H), 7.89–7.80 (m, 4 H), 7.59–7.53 (m, 1 H), 7.52–7.40 (m, 5 H), 6.14–6.09 (m, 1 H), 5.90 (dt, J = 5.7, 2.1 Hz, 1 H), 5.44 (ddd, J = 5.8, 2.1, 1.1 Hz, 1 H), 3.62 (dq, J = 6.7, 2.2 Hz, 1 H), 2.61 (dd, J = 6.7, 1.8 Hz, 1 H), 2.30 (ddd, J = 11.3, 8.5, 4.9 Hz, 1 H), 1.99 (td, J = 11.7, 5.1 Hz, 1 H), 1.95–1.85 (m, 2 H), 1.83 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 166.3, 138.4, 137.2, 133.3, 133.0, 132.6, 131.6, 130.7, 129.7 (2 C), 128.5 (2 C), 128.2, 128.0, 127.8, 126.2, 125.8, 123.9, 123.8, 88.1, 84.6, 82.3, 61.6, 57.6, 38.5, 38.4, 18.9.

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₇H₂₄O₃Na: 419.1618; found: 419.1614.

Crown Ether 9

A solution of (E)-7k (20 mg, 0.1mmol) and [JohnPhosAu(NCMe)]SbF₆ complex (3 mol%) in anhydrous CH₂Cl₂ (1 mL) was stirred at 0 °C for 10 h. It was then quenched by addition of Et₃N (5 μL) and the solvent was removed in vacuo (at 25 °C). The crude material was purified by silica gel column chromatography eluting with cyclohexane/EtOAc (90:10) and isolated as a white solid (8.1 mg, 0.024 mmol, 49%). Note: the reaction was performed under an air atmosphere.

Mp 258–260 °C.

¹H NMR (500 MHz, CDCl₃): δ = 5.83–5.79 (m, 2 H), 5.63 (app ddd, J = 5.6, 4.3, 2.5 Hz, 2 H), 5.33 (dd, J = 6.1, 2.6 Hz, 2 H), 4.72 (d, J = 6.0 Hz, 2 H), 3.27 (app q, J = 2.1 Hz, 2 H), 2.63 (ddt, J = 17.8, 8.2, 2.2 Hz, 2 H), 2.35 (dt, J = 17.9, 2.1 Hz, 2 H), 2.28–2.19 (m, 2 H), 2.13–2.07 (m, 2 H), 2.06–1.98 (m, 2 H), 1.64–1.54 (m, 2 H), 1.02 (s, 6 H).

¹³C NMR (126 MHz, CDCl₃): δ = 131.1 (2 C), 130.6 (2 C), 102.4 (2 C), 85.3 (2 C), 76.1 (2 C), 63.6 (2 C), 40.6 (2 C), 36.6 (2 C), 33.1 (2 C), 22.2 (2 C).

HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₀H₂₈O₄Na: 355.1880; found: 355.1868.

This compound was crystallized from CHCl₃ to obtain single crystals suitable for X-ray diffraction (see Supporting Information).

Acknowledgment

We thank MINECO (Severo Ochoa Excellence Accreditation 2014-2018 (SEV-2013-0319), project CTQ2013-42106-P), the MEC (FPU pre-doctoral fellowship to P.C.), the European Research Council (Advanced Grant No. 321066), the AGAUR (2014 SGR 818), and the ICIQ Foundation. We also acknowledge the COFUND postdoctoral program (Marie Curie actions) for a postdoctoral fellowship to M.E.M.

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