Functionalized Cyclopentanes via Sc(III)-Catalyzed Intramolecular Enolate Alkylation

Abstract

We report herein the intramolecular α-tert-alkylation of unsaturated β-ketoesters which gives rise to highly functionalized cyclopentanes. This strategy is characterized by its operational simplicity, mild reaction conditions and the use of scandium(III) triflate as a Lewis acid catalyst. Of interest, cyclopentanes bearing heterocycles, sites for post reaction functionalization and spirocyclic architectures are accessible with this strategy.

Graphical Abstract

1. Introduction

The α-alkylation of carbonyl functionalities and related Schiff bases has proven valuable for the formation of carbon–carbon bonds in organic synthesis.¹ Traditionally, this is accomplished by employing basic conditions to deprotonate in the α-position to generate a reactive enolate which can engage a suitable electrophile in an addition reaction to afford the desired C-alkylated product.² These reactions have been developed into powerful synthetic strategies to access complex molecular structures;² however, limitations arising from competing over-alkylation³ and difficulties in controlling the regioselectivity^1,2 still exist. Additionally, highly activated electrophiles such as primary halides bearing methyl, benzyl, or allyl substitution are superior substrates,¹ while their corresponding secondary analogs often undergo base-induced eliminations as competing reaction paths.⁴ In comparison, only few literature examples exist for the direct enolate anion coupling with tertiary alkyl halides to give rise to the corresponding α-tert-alkylation products due to the preferred formation of E1elimination products.⁵ To circumvent this challenge, Reetz and coworkers developed a unique strategy whereby silyl enol ether (2), derived from commercial ketone 1, can engage tertiary carbocations generated in situ in the presence of tertiary halide and stoichiometric TiCl₄ (Fig. 1A).^5,6 Alternative strategies for α-tert-alkylation of carbonyl-containing compounds rely on intramolecular cyclization of enolatesand π-systems.^5,7,8 For example, homo-prenylated β-ketoester 4 was shown to undergo intramolecular cyclization to methyl ketone 5 upon reaction with stoichiometric amount of SnCl₄ (Figure 1B.).⁹ This cyclization strategy is proposed to rely on initial enolate O-stannylation with concomitant formation of equimolar amounts of Brønsted acid. An intermediate carbocation is generated upon protonation of the alkene under acidic conditions which subsequently undergoes the final enolate alkylation to result in 5 as the α-tert-alkylation product.⁹

Figure 1.

Strategies reported for α-tert-alkylation and work reported herein.

We have recently developed an iron-catalyzed carbonyl-olefin ring-closing metathesis reaction¹⁰ of β-ketoesters such as 6a to form the corresponding cyclopentene 7 as the exclusive products (Fig. 1C). In the course of these studies, we evaluated a series of additional Lewis acids in substoichiometric quantities and observed that aliphatic β-ketoesters such as 6b formed the corresponding intramolecular α-tert-alkylation products 8 in low yields (Fig. 1C). Based on a paucity of general synthetic methodologies for catalytic intramolecular α-tert-alkylations of carbonyls and the 1,1,2,2-functionalized cyclopentane substructure present in some natural product families, including herbertane-type sesquiterpenoids,¹¹ we sought to further investigate this reactivity. Herein, we report a mild and operationally simple approach toward α-tert-alkylation of aliphatic β-ketoesters relying on catalytic amount (5 mol%) of Sc(OTf)₃ as Lewis acid catalyst.

2. Results and Discussion

In order to identify an optimal set of reaction conditions for the synthesis of 1,1,2,2-tetrasubstituted cyclopentanes via α-tert-alkylation of acyclic β-ketoesters, we initially focused on the evaluation of Lewis acids able to promote the desired transformation. Iso-propyl ketone 9, which is accessible in a single step from commercially available materials, was chosen as an initial scaffold to identify optimal reaction conditions. Surprisingly, catalytic amounts of strong Lewis acids such as AlCl₃ and FeCl₃ in 1,2-dichloroethane (DCE) at elevated temperatures led to no or poor formation of methyl ester 10, and incomplete conversion of the starting material (entries 1 and 2, Table 1). However, relying on SnCl₄ or GaCl₃ as Lewis acid catalysts under otherwise identical reaction conditions led to the formation of 10 in 35% and 49% yield, respectively, with complete conversion of β-ketoester 9 (entries 3 and 4, Table 1). Similar results were obtained when substrate 9 was converted in the presence of 5 mol% In(OTf)₃ or Fe(OTf)₃ (entries 5 and 6, Table 1). Subsequent efforts identified Sc(OTf)₃ as the optimal Lewis acid catalyst, resulting in the formation of 10 in 90% yield with complete conversion of β-ketoester 9 (entry 7, Table 1). Overall, yields and conversions were found to be lower when the reaction was conducted in nonpolar aromatic solvents including benzene (PhH) and toluene (PhMe) (entries 8 and 9, Table 1). Notably, increasing catalyst loading of Sc(OTf)₃ to 100 mol% led to the formation of the desired α-tert-alkylation product 10 in only 19% yield with complete conversion of substrate 9 (entry 10, Table 1). Furthermore, decreasing the reaction temperature to 40 °C with 5 mol% Sc(OTf)₃ in DCE or employing 5 mol % triflic acid (TfOH) in DCE at 80 °C proved to be ineffective toward promoting the desired reaction (entries 11 and 12, Table 1). Ultimately, conducting the transformation with 5 mol% Sc(OTf)₃ in DCE (0.05 M) at 80 °C was identified as optimal for the conversion of β-ketoester 9 to α-tert-alkylation product 10.

Table 1.

Optimization studies for the formation of α-tert-alkylated product 10.

entry	Lewis acid	temp	solvent	yield 10(%)a	conversion(%)a
1	AlCl3	80	DCE	0	3
2	FeCl3	80	DCE	20	70
3	SnCl4	80	DCE	35	100
4	GaCl3	80	DCE	49	100
5	ln(OTf)3	80	DCE	58	100
6	Fe(OTf)3	80	DCE	59	100
7	Sc(OTf)3	80	DCE	90	100
8	Sc(OTf)3	80	PhH	25	40
9	Sc(OTf)3	80	PhMe	25	38
10b	Sc(OTf)3	80	DCE	19	100
11	Sc(OTf)3	40	DCE	0	11
12	TfOH	80	DCE	14	100

Conditions: reactions were performed using 0.20 mmol β-ketoester,5 mol% Lewis acid in solvent (0.05 M) at 80°C for 12 hours.

^b100 mol% Sc (OTf)₃.

^adetermined by crude NMR analysis with 1,3,5-trimethoxybenzene as internal standard.

We next turned our attention to evaluating the substrate scope amenable to the Sc(OTf)₃ catalyzed intramolecular α-tert-alkylation of acyclic β-ketoesters. The reaction conditions developed herein proved viable for a broad range of sterically and electronically distinct β-ketoesters as shown in Table 2. Substrates incorporating methyl-(9), ethyl-(11) and benzyl esters (13) were smoothly converted to the corresponding functionalized cyclopentanes (10, 12 and 14) in up to 85% isolated yield (entries 1, 2 and 3, Table 2). Alkylation product 16 bearing an allyl ester as a functional group capable of undergoing secondary functionalization¹² was formed in 67% yield (entry 4, Table 2). Additionally, halo benzyl ester alkylation products 18 and 20 containing sites for functional manipulation were obtained in 78% and 74% yield, respectively (entries 5 and 6, Table 2). Substrates incorporating thiophenyl (21), thiophene (23) and phthalimide(25) gave rise to the anticipated polycyclic (22) and heterocyclic α-tert-alkylation products24 and 26 in up to 79% yield (entries 7, 8 and 9, Table 2). Furthermore, homo-prenylated β-ketoester 27 containing a sterically demanding adamantyl side chain was converted under the optimal reaction conditions to give rise to the desired product 28 in 75% yield (entry 10, Table 2).

Table 2.

Substrate scope of aliphatic β-ketoester derivatives.

entity	substrate	product	yield%
1			85
2			82
3			70
4			67
5			76
6			74
7			21
8			67
9			79
10			75

Conditions: Substrate (1.0 equiv), Sc(OTf)₃ (5 mol%) in dichlorethane (0.05M) at 80 °C for 12 h.

We next evaluated functional tolerance at the ketone subunit as well as the olefin moiety (Table 3). Importantly, iso-propyl ketones were tolerated well under the optimized reaction conditions while sterically less congested methyl (30) and cyclopropyl (32 and 34) ketones underwent the desired alkylation in diminished yields of up to 40% (entries 1, 2 and 3, Table 3). Interestingly, sterically dense cyclohexyl ketone 35 restored favorable reactivity as polycycle 36 was isolated in 63% yield (entry 4, Table 3). Exocyclic olefin 37 underwent α-tert-alkylation affording a unique spirocyclic scaffold in good yield of 43% (entry 5, Table 3).

Table 3.

Substrate scope incorporating ketone and alkene functionalization.

entity	substrate	product	yield%
1			38
2			40
3			35
4			63
5			43

Conditions: Substrate (1.0 equiv), Sc(OTf)₃ (5 mol%) in dichlorethane (0.05M) at 80 °C for 12 h.

Our current mechanistic hypothesis for the Sc(OTf)₃-catalyzed carbocyclization of 9 to 10 is outlined in Figure 2. Scandium enolate 39 is generated upon coordination of the oxophilic Sc(OTf)₃¹³ to ketone 9. The concomitant formation of equimolar amounts of Brønsted acid affords tertiary carbocation 40, followed by incipient intramolecular enolate cyclization to liberate α-tert-alkylated product 10.

Figure 2.

Mechanistic proposal for the α-tert-alkylation of β-ketoester 9.

In conclusion, we have developed a mild and operationally robust protocol for the intramolecular α-tert-alkylation of readily available α-alkenyl β-ketoesters. This methodology enhances the current synthetic repertoire of carbonyl α-tert-alkylation through the development of a distinct Sc(OTf)₃-catalytic manifold relying on an intramolecular enolate cyclization. Additionally, diversification at the ketone, ester and olefin were tolerated well under the carbocyclization reaction conditions reported herein, which allowed for access to 15 electronically and sterically distinct 1,1,2,2-tetrasubstituted cyclopentanes in good to excellent yields.

3. Experimental section

Materials and Instrumentation.

All chemicals were purchased from commercial suppliers and were used as received unless otherwise stated. Proton Nuclear Magnetic Resonance NMR (¹H NMR) spectra and carbon nuclear magnetic resonance (¹³C NMR) spectra were recorded on a Varian Unity Plus 400, Varian MR400, Varian vnmrs 500, Varian Inova 500, Varian Mercury 500, and Varian vnmrs 700 spectrometers. Chemical shifts for protons are reported in parts per million and are references to the NMR solvent peak (CDCl₃: δ 7.26). Chemical shifts for carbons are reported in parts per million and are referenced to the carbon resonances of the NMR solvent (CDCl₃: δ 77.23). Data are represented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, dq = doublet of quartet, ddq = doublet of doublet of quartet, p = pentet, dd = doublet of doublet, ddd = doublet of doublet of doublet, hept = heptet, m = multiplet), coupling constants in Hertz (Hz) and integration. Mass spectroscopic (MS) data was recorded at the Mass Spectrometry Facility at the Department of Chemistry of the University of Michigan in Ann Arbor, MI on an Agilent Q-TOF HPLC-MS with ESI high resolution mass spectrometer. Infrared (IR) spectra were obtained using either an Avatar 360 FT-IR or Perkin Elmer Spectrum BX FT-IR spectrometer. IR data are represented as frequency of absorption (cm⁻¹).

General procedure for the synthesis of β-ketoester substrate precursors via transesterification of methyl 4-methyl-3-oxopentanoate

The starting β-ketoester substrate precursors (benzyl 4-methyl-3-oxopentanoate, allyl 4-methyl-3-oxopentanoate, 4-chlorobenzyl 4-methyl-3-oxopentanoate, 2-iodobenzyl 4-methyl-3-oxopentanoate, 2-(phenylthio)ethyl 4-methyl-3-oxopentanoate, 2-(thiophen-2-yl)ethyl 4-methyl-3-oxopentanoate, 2-(1,3-dioxoisoindolin-2-yl)ethyl 4-methyl-3-oxopentanoate and (adamantan-2-yl)methyl 4-methyl-3-oxopentanoate) were synthesized according to the following protocol: To a stirred solution of methyl 4-methyl-3-oxopentanoate (7.0 mmol, 1 equiv) and toluene (25 mL, 0.3 M) was added DMAP (20 mol%) and the respective alcohol (21.0 mmol, 3.0 equiv). The resultant suspension was then heated to reflux. After 24 h, the mixture was cooled to rt and concentrated under reduced pressure to afford a crude oil. The residue was purified via flash column chromotagraphy over silica with ethyl acetate in hexanes (5% to 30%) to afford the desired transesterified β-ketoester.

The following β-ketoester substrate precursors are commercially available: methyl 4-methyl-3-oxopentanoate, ethyl 4-methyl-3-oxopentanoate, methyl 3-oxobutanoate, methyl 3-cyclopropyl-3-oxopropanoate, ethyl 3-cyclopropyl-3-oxopropanoate and ethyl 3-cyclohexyl-3-oxopropanoate.

General procedure for the synthesis of carbocyclization substrates 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, and 35

To a flame-dried 100 mL round-bottom flask equipped with a magnetic stir bar was successively added β-ketoester (3.5 mmol, 1.0 equiv), DMF (0.3 M) and K₂CO₃ (2.0 equiv). The flask was topped with a rubber septum and a nitrogen inlet. 5-iodo-2-methylpent-2-ene¹⁴ (1.3 equiv) was then added dropwise to the reaction suspension via syringe and the resultant solution was allowed to stir at rt. When there was complete consumption of starting material (determined by TLC), EtOAc (30 mL) was added to the reaction mixture and then poured into an extraction funnel along with water (40 mL) and then separated. The organic phase was further extracted with water (3 × 30 mL), washed with brine (30 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude oil was purified via flash column chromatography over silica with EtOAc in hexanes (5% to 20%) to afford the carbocyclization substrate.

Methyl 2-isobutyryl-6-methylhept-5-enoate (9)

Isolated as a clear oil (40%). ¹H NMR (401 MHz, CDCl₃) δ 5.04 (tt, J = 7.1, 1.4 Hz, 1H), 3.69 (s, 3H), 3.61 (t, J = 7.0 Hz, 1H), 2.75 (hept, J = 6.9 Hz, 1H), 2.02 – 1.91 (m, 2H), 1.91 – 1.77 (m, 2H), 1.67 (s, 3H), 1.55 (s, 3H), 1.08 (t, J = 7.8, 6.9 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 209.4, 17, 0.7, 133.6, 123.2, 56.6, 52.6, 40.8, 28.7, 26.2, 26.1, 18.7, 18.5, 18.0. IR (cm⁻¹): 2964.6, 1720.4, 1445.5, 1202.5, 1157., 8, 1103.0, 1007.6, 834.8. HRMS (ESI+) m/z calcd for C₁₃H₂₂O₃Na⁺ [M+Na⁺]: 246.1461, found 249.1465.

Ethyl 2-isobutyryl-6-methylhept-5-enoate (11)

Isolated as a clear oil (57%). ¹H NMR (401 MHz, CDCl₃) δ 5.05 (ddd, J = 7.2, 5.6, 1.4 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.59 (t, J = 7.0 Hz, 1H), 2.76 (hept, J = 6.9 Hz, 1H), 1.96 (q, J = 7.4 Hz, 2H), 1.85 (m, 8.6, 6.4 Hz, 2H), 1.67 (s, J = 1.4 Hz, 3H), 1.56 (s, J = 1.3 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 8.0, 6.8 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 209.4, 170.1, 133.3, 123.2, 61.4, 56.7, 40.7, 28.6, 26.1, 25.9, 18.6, 18.4, 17.9, 14.4. IR (cm⁻¹): 2970.7, 1720.2, 1453.3, 1369.8, 1159.4, 1100.5, 1019.6, 846.7. HRMS (ESI+) m/z calcd for C₁₄H₂₅O₃⁺ [M+H]⁺: 241.1798, found 241.1798.

Benzyl 2-isobutyryl-6-methylhept-5-enoate (13)

Isolated as a clear oil (24%). ¹H NMR (700 MHz, CDCl₃) δ 7.42 – 7.29 (m, 5H), 5.15 (s, 2H), 5.05 (t, J = 7.0 Hz, 1H), 3.66 (t, J = 7.0 Hz, 1H), 2.78 – 2.69 (m, 1H), 2.01 – 1.82 (m, 4H), 1.67 (s, 3H), 1.54 (s, 3H). ¹³C NMR (176 MHz, CDCl₃) δ 209.24, 170.03, 135.80, 133.55, 128.91, 128.72, 128.63, 123.21, 67.30, 56.75, 40.87, 28.72, 26.20, 26.04, 18.68, 18.39, 18.04. IR (cm⁻¹): 2965.8, 1717.5, 1452.3, 1370.0, 1149.8, 1001.8, 832.5, 741.2, 696.4. HRMS (ESI+) m/z calcd for C₁₉H₂₇O₃⁺ [M+H]⁺: 303.1955, found 303.1958.

Allyl 2-isobutyryl-6-methylhept-5-enoate (15)

Isolated as a clear oil (32%). ¹H NMR (700 MHz, CDCl₃) δ 5.89 (m, 1H), 5.31 (dd, J = 17.2, 1.1 Hz, 1H), 5.24 (d, J = 10.4 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H), 3.65 (t, J = 7.1 Hz, 1H), 2.78 (dt, J = 13.7, 6.9 Hz, 1H), 1.98 (m, 2H), 1.94 – 1.83 (m, 2H), 1.68 (s, 3H), 1.57 (s, 3H), 1.12 – 1.09 (m, 6H). ¹³C NMR (176 MHz, CDCl₃) δ 209.4, 169.9, 133.6, 132.0, 123.2, 119.1, 66.1, 56.7, 40.9, 28.7, 26.2, 26.1, 18.7, 18.5, 18.1. IR (cm⁻¹): 2968.5, 1718.4, 1451.1, 1368.9, 1155.1, 986.9, 934.0. HRMS (ESI+) m/z calcd for C₁₅H₂₅O₃⁺ [M+H]⁺: 253.1798, found 253.1797.

4-Chlorobenzyl 2-isobutyryl-6-methylhept-5-enoate (17)

Isolated as clear oil (42%). ¹H NMR (500 MHz, CDCl₃) δ 7.33 (s, 1H), 7.32 (s, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 5.10 (s, 2H), 5.04 (tt, J = 7.2, 1.5 Hz, 1H), 3.65 (t, J = 7.0 Hz, 1H), 2.73 (hept, J = 6.9 Hz, 1H), 2.01 – 1.91 (m, 2H), 1.91 – 1.81 (m, 2H), 1.67 (s, 3H), 1.53 (s, 3H), 1.06 (d, 6H). ¹³C NMR (126 MHz CDCl₃) δ 209.2, 169.9, 134.6, 134.3, 133.6, 130.0, 129.1, 129.1, 123.1, 66.4, 56.6, 40.9, 28.7, 26.1, 26.0, 18.5, 18.3, 17.9. IR (cm⁻¹): 2966.9, 1717.6, 1452.8, 1369.3, 1150.0, 1092.2, 1006.9, 810.1. HRMS (ESI+) m/z calcd for C₁₉H₂₆ClO₃⁺ [M+H]⁺: 337.1565, found 337.1565.

2-Iodobenzyl 2-isobutyryl-6-methylhept-5-enoate (19)

Isolated as a clear oil (31%). ¹H NMR (700 MHz, CDCl₃) δ 7.85 (d, J = 7.8 Hz, 1H), 7.36 – 7.34 (m, 2H), 7.04 – 7.00 (m, 1H), 5.17 (s, 2H), 5.06 (t, J = 7.0 Hz, 1H), 3.71 (t, J = 7.0 Hz, 1H), 2.83 – 2.76 (m, 1H), 2.01 – 1.83 (m, 4H), 1.68 (s, J = 15.7 Hz, 3H), 1.55 (s, 3H), 1.08 (dd, J = 6.8, 1.0 Hz, 6H). ¹³C NMR (176 MHz, CDCl₃) δ 209.13, 169.77, 139.89, 138.24, 133.61, 130.38, 130.08, 128.75, 123.20, 98.85, 71.07, 56.59, 41.01, 28.80, 26.27, 26.06, 18.69, 18.46, 18.10. IR (cm⁻¹): 2965.8, 1716.8, 1449.1, 1370.4, 1147.5, 1007.0, 833.4, 748.5, 642.9. HRMS (ESI+) m/z calcd for C₁₉H₂₆O₃I⁺ [M+H]⁺: 429.0921, found 429.0923.

2-(Phenylthio)ethyl 2-isobutyryl-6-methylhept-5-enoate (21)

Isolated as a clear oil (33%). ¹H NMR (500 MHz, CDCl₃) δ 7.42 – 7.36 (d, J = 7.1 Hz, 2H), 7.32 (t, J = 7.7 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 5.15 – 4.95 (m, 1H), 4.27 (t, J = 7.0 Hz, 2H), 3.62 (t, J = 7.1 Hz, 1H), 3.14 (td, J = 6.9, 3.2 Hz, 2H), 2.79 (hept, J = 6.9 Hz, 1H), 1.99 (q, J = 7.4 Hz, 2H), 1.94 – 1.79 (m, 2H), 1.70 (d, J = 1.4 Hz, 3H), 1.59 (d, J = 1.3 Hz, 3H), 1.11 (dd, J = 12.0, 6.9 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 209.0, 169.8, 135.0, 133.3, 130.1, 129.2, 126.8, 123.0, 63.5, 56.3, 40.7, 32.4, 28.5, 26.0, 25.8, 18.4, 18.3, 17.9. IR (cm⁻¹): 2965.7, 1718.4, 1583.3, 1449.2, 1151.6, 1002.9, 832.3, 736.9, 689.4. HRMS (ESI+) m/z calcd for C₂₀H₂₉O₃S⁺ [M+H]⁺: 349.1832, found 349.1836.

2-(Thiophen-2-yl)ethyl 2-isobutyryl-6-methylhept-5-enoate (23)

Isolated as a clear oil (31%). ¹H NMR (401 MHz, CDCl₃) δ 7.16 (d, J = 4.0 Hz, 1H), 6.93 (dd, J = 5.1, 3.4 Hz, 1H), 6.84 (d, J = 3.4 Hz, 1H), 5.05 (t, J = 7.0 Hz, 1H), 4.34 (td, J = 6.7, 2.5 Hz, 2H), 3.63 (t, J = 6.9 Hz, 1H), 3.15 (t, J = 6.7 Hz, 2H), 2.72 (hept, J = 6.9 Hz, 1H), 1.96 (q, J = 7.4 Hz, 2H), 1.92 – 1.76 (m, 2H), 1.68 (s, 3H), 1.56 (s, 3H), 1.06 (d, J = 6.9 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 209.2, 170.0, 139.8, 133.5, 127.2, 125.9, 124.4, 123.2, 65.6, 56.5, 40.9, 29.5, 28.7, 26.2, 26.0, 18.6, 18.4, 18.0. IR (cm⁻¹): 2965.8, 1718.8, 1583.7, 1448.7, 1152.0, 1003.7, 832.5, 739.4, 689.2. HRMS (ESI+) m/z calcd for C₁₈H₂₇O₃S⁺ [M+H]⁺: 323.1675, found 323.1680.

2-(1,3-Dioxoisoindolin-2-yl)ethyl 2-isobutyryl-6-methylhept-5-enoate (25)

Isolated as a clear oil (32%). ¹H NMR (401 MHz, CDCl₃) δ 7.86 (dd, J = 5.5, 3.0 Hz, 2H), 7.73 (dd, J = 5.5, 3.1 Hz, 2H), 5.01 (tt, J = 7.1, 1.4 Hz, 1H), 4.45 – 4.27 (m, 2H), 4.06 – 3.83 (m, 2H), 3.61 (t, J = 7.0 Hz, 1H), 2.72 (hept, J = 6.9 Hz, 1H), 1.92 (q, J = 7.5 Hz, 2H), 1.87 – 1.73 (m, 2H), 1.65 (s, 3H), 1.52 (s, 3H), 1.02 (dd, J = 6.9, 2.7 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 209.06, 170.0, 168.3, 134.4, 133.4, 132.3, 123.7, 123.2, 62.4, 56.1, 41.0, 37.2, 28.7, 26.2, 26.0, 18.5, 18.3, 18.0. IR (cm⁻¹): 2960.1, 1709.3, 1386.2, 1153.7, 999.5, 880.4, 790.5, 714.7. HRMS (ESI+) m/z calcd for C₂₂H₂₈NO₅⁺ [M+H]⁺: 386.1962, found 386.1961.

Adamantan-2-yl)methyl 2-isobutyryl-6-methylhept-5-enoate (27)

Isolated as a clear oil (28%). ¹H NMR (500 MHz, CDCl₃) δ 5.07 (td, J = 6.9, 6.2, 3.4 Hz, 1H), 3.82 – 3.51 (m, 3H), 2.80 (hept, J = 6.9 Hz, 1H), 2.01 – 1.94 (m, 6H), 1.94 – 1.79 (m, 2H), 1.72 (d, J = 12.0 Hz, 3H), 1.68 (s, 2H), 1.66 – 1.60 (m, 4H), 1.57 (s, 2H), 1.50 (d, J = 2.9 Hz, 6H), 1.11 (dd, J = 9.8, 6.9 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 209.4, 170.3, 133.4, 123.3, 75.1, 56.6, 41.0, 39.5, 37.2, 33.5, 28.7, 28.3, 26.2, 26.0, 18.7, 18.4, 18.1. IR (cm⁻¹): 2904.6, 1718.0, 1450.9, 1343.9, 1156.8, 991.8, 828.5. HRMS (ESI+) m/z calcd for C₂₃H₃₇O₃⁺ [M+H]⁺: 361.2737, found 361.2741.

Methyl 2-acetyl-6-methylhept-5-enoate (29)

Isolated as a clear oil (28%).¹H NMR (500 MHz, CDCl₃) δ 5.05 (dd, J = 10.2, 4.0 Hz, 1H), 3.73 (s, 3H), 3.44 (t, J = 7.2 Hz, 1H), 2.21 (s, 3H), 2.02 – 1.94 (m, 2H), 1.89 (m 2H), 1.68 (s, 3H), 1.57 (s, 3H).¹³C NMR (126 MHz, CDCl₃) δ 203.6, 170.7, 133.7, 123.1, 59.3, 52.7, 29.2, 28.6, 26.1, 26.1, 18.0. IR (cm⁻¹): 2952.7, 1742.1, 1714.3, 1435.4, 1357.8, 1199.3, 1144.4, 1108.5, 1052.3, 985.9, 833.6. HRMS (ESI+) m/z calcd for C₁₁H₁₈O₃Na⁺ [M+Na⁺]: 221.1148, found 221.1147.

Methyl 2-(cyclopropanecarbonyl)-6-methylhept-5-enoate (31)

Isolated as a clear oil (59%). ¹H NMR (700 MHz, CDCl₃) δ 5.10 – 5.06 (m, 1H), 3.73 (s, 3H), 3.58 (t, J = 7.2 Hz, 1H), 2.08 – 1.88 (m, 5H), 1.69 (s, 3H), 1.58 (s, 3H), 1.10 – 1.04 (m, 2H), 0.95 – 0.89 (m, 2H). ¹³C NMR (176 MHz, CDCl₃) δ 205.81, 170.84, 133.60, 123.18, 59.47, 52.63, 28.72, 26.16, 26.07, 20.00, 18.02, 12.13, 11.96. IR (cm⁻¹): 2951.1, 1736.6, 1699.2, 1440.4, 1379.6, 1160.1, 1011.6, 900.4, 836.7. HRMS (ESI+) m/z calcd for C₁₃H₂₁O₃⁺ [M+H]⁺: 225.1485, found 225.1478.

Ethyl 2-(cyclopropanecarbonyl)-6-methylhept-5-enoate (33)

Isolated as a clear oil (70%). ¹H NMR (500 MHz, CDCl₃) δ 5.09 (ddd, J = 8.7, 5.1, 1.5 Hz, 1H), 4.21 (dq, J = 7.1, 3.0 Hz, 2H), 3.57 (t, J = 7.1 Hz, 1H), 2.07 (ddd, J = 7.8, 4.5, 3.3 Hz, 1H), 2.02 (q, J = 8.1, 7.0 Hz, 2H), 1.94 (ddq, J = 13.3, 8.8, 6.7, 6.3 Hz, 2H), 1.70 (s, 3H), 1.59 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.11 – 1.04 (m, 2H), 0.93 (tt, J = 5.5, 1.8 Hz, 2H). ¹³C NMR (176 MHz, CDCl₃) δ 205.9, 170.4, 133.5, 123.3, 61.5, 59.7, 28.6, 26.2, 26.1, 19.9, 18.0, 14.5, 12.1, 11.9. IR (cm⁻¹): 2974.0, 1731.7, 1700.5, 1445.7, 1378.7, 1182.2, 1024.1, 857.2. HRMS (ESI+) m/z calcd for C₁₄H₂₂O₃Na⁺ [M+Na]⁺: 261.1461, found 261.1458.

Ethyl 2-(cyclohexanecarbonyl)-6-methylhept-5-enoate (35)

Isolated as a clear oil (51%). ¹H NMR (500 MHz, CDCl₃) δ 5.06 (tt, J = 7.2, 1.4 Hz, 1H), 4.16 (dq, J = 7.1, 2.1 Hz, 2H), 3.58 (t, J = 7.1 Hz, 1H), 2.50 (ddd, J = 11.2, 6.7, 3.3 Hz, 1H), 1.96 (q, J = 7.5 Hz, 2H), 1.91 – 1.75 (m, 6H), 1.68 (s, 3H), 1.57 (s, 3H), 1.39 (m, 1H), 1.25 (t, J = 7.1 Hz, 6H).. ¹³C NMR (126 MHz, CDCl₃) δ 208.7, 170.2, 133.3, 123.3, 61.4, 56.9, 50.8, 28.9, 28.6, 26.2, 26.0, 26.0, 26.0, 25.8, 18.0, 14.4. IR (cm⁻¹): 2927.3, 2858.9, 1714.7, 1447.6, 1370.7, 1151.9, 1027.9, 848.9, 731.7. HRMS (ESI+) m/z calcd for C₁₂H₂₉O₃⁺ [M+H]⁺: 281.2111, found 281.2117.

Methyl 2-(3-cyclohexylidenepropyl)-4-methyl-3-oxopentanoate (37)

To a flame-dried 100 mL round-bottom flask equipped with a magnetic stir bar was successively added β-ketoesters (3.5 mmol, 1.0 equiv), DMF (0.3 M) KI (1.0 equiv) and K₂CO₃ (2.0 equiv). The flask was topped with a rubber septum and a nitrogen inlet. (3-Bromopropylidene)cyclohexane (1.3 equiv) was then added dropwise to the reaction suspension via syringe and the resultant solution was allowed to stir at rt. When there was complete consumption of starting material (determined by TLC), EtOAc (30 mL) was added to the reaction mixture and then poured into an extraction funnel along with water (40 mL) and then separated. The organic phase was further extracted with water (3 × 30 mL), washed with brine (30 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude oil was purified via flash column chromatography over silica with EtOAc in hexanes (5% to 20%) to afford the carbocyclization substrate 37. Isolated as a clear oil (39%). ¹H NMR (700 MHz, CDCl₃) δ 5.01 (t, J = 7.2 Hz, 1H), 3.71 (s, 3H), 3.67 – 3.61 (m, 1H), 2.81 – 2.73 (hept, J = 6.6 Hz, 1H), 2.11 – 2.02 (m, 4H), 1.98 (q, J = 7.3 Hz, 2H), 1.90 (td, J = 14.3, 7.4 Hz, 1H), 1.83 (td, J = 14.0, 7.3 Hz, 1H), 1.58 – 1.41 (m, 6H), 1.10 (dd, J = 13.1, 6.9 Hz, 6H). ¹³C NMR (176 MHz, CDCl₃) δ 209.49, 170.70, 141.82, 119.79, 56.49, 52.59, 40.84, 37.50, 29.07, 29.03, 28.99, 28.14, 27.21, 25.29, 18.69, 18.53. IR (cm⁻¹): 2926.3, 2853.8, 1718.1, 1444.6, 1207.1, 1158.3, 1007.7, 843.3, 652.2. HRMS (ESI+) m/z calcd for C₁₆H₂₇O₃⁺ [M+H]⁺: 267.1955, found 267.1956.

General procedure for the Sc(OTf)₃ catalyzed intramolecular enolate alkylation to access cyclopentanes 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36 and 38

A flame-dried 4–dram vial was charged with Sc(OTf)₃ (4.9 mg, 0.01 mmol) and DCE (3 mL), and stirred at room temperature. To this solution was added starting β-ketoester (0.2 mmol) in DCE (1 mL), and the resultant mixture was stirred for 12 h at 80 ^oC. Upon completion (as determined by TLC analysis), the reaction mixture was passed through a short silica plug eluting with DCM (25 mL). The filtrate was concentrated under reduced pressure, and the crude material was purified over silica via flash column chromatography with ethyl acetate in hexanes (0% to 15%) to afford the pure cyclized products.

Methyl 1-isobutyryl-2,2-dimethylcyclopentane-1-carboxylate (10)

Isolated as a clear oil (38.7 mg, 86%). ¹H NMR (500 MHz, CDCl₃) δ 3.73 (s, 3H), 2.79 (hept, J = 6.7 Hz, 0H), 2.41 (ddd, J = 14.0, 10.1, 6.4 Hz, 0H), 2.06 (ddd, J = 14.3, 10.0, 4.4 Hz, 0H), 1.86 – 1.73 (m, 1H), 1.73 – 1.63 (m, 0H), 1.62 – 1.54 (m, 1H), 1.14 (s, 1H), 1.04 (t, J = 6.8 Hz, 2H), 0.98 (s, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 212.1, 173.4, 72.5, 52.0, 46.6, 40.4, 39.2, 31.7, 26.6, 24.4, 21.0, 20.3, 19.9. IR (cm⁻¹): 2960.3, 1709.5, 1457.8, 1374.1, 1211.9, 1100.3, 732.7. HRMS (ESI+) m/z calcd for C₁₃H₂₃O₃⁺ [M+H]⁺: 227.1642, found 227.1643.

Ethyl 1-isobutyryl-2,2-dimethylcyclopentane-1-carboxylate (12)

Isolated as a clear oil (39.2 mg, 82%). ¹H NMR (500 MHz, CDCl₃) δ 4.26 – 4.14 (m, 2H), 2.80 (dt, J = 13.3, 6.6 Hz, 1H), 2.42 (ddd, J = 14.2, 10.3, 6.5 Hz, 1H), 2.05 (ddd, J = 14.0, 9.9, 4.4 Hz, 1H), 1.86 – 1.73 (m, 2H), 1.72 – 1.63 (m, 1H), 1.60 – 1.55 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.15 (s, 3H), 1.05 (t, J = 6.5 Hz, 6H), 0.98 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 212.2, 172.9, 72.5, 61.2, 46.5, 40.4, 39.1, 31.6, 26.6, 24.5, 21.2, 20.29, 20.00, 14.43. IR (cm⁻¹): 2963.9, 1708.9, 1460.4, 1373.8, 1207.0, 1097.6, 1041.6, 853.3, 736.9. HRMS (ESI+) m/z calcd for C₁₄H₂₅O₃⁺ [M+H]⁺: 241.1798, found 241.1799.

Benzyl 1-isobutyryl-2,2-dimethylcyclopentane-1-carboxylate (14)

Isolated as a clear oil (42.1 mg, 70%). ¹H NMR (500 MHz, CDCl₃) δ 7.43 – 7.28 (m, 5H), 5.17 (s, 2H), 2.78 (hept, J = 6.7 Hz, 1H), 2.49 – 2.39 (m, 1H), 2.07 (ddd, J = 14.1, 9.9, 4.4 Hz, 1H), 1.87 – 1.72 (m, 2H), 1.72 – 1.63 (m, 1H), 1.60 – 1.53 (m, 1H), 1.14 (s, 3H), 1.00 – 0.92 (m, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 212.02, 172.70, 135.54, 128.96, 128.90, 128.75, 72.51, 67.18, 46.75, 40.41, 39.14, 31.69, 26.60, 24.48, 21.07, 20.31, 19.81. IR (cm⁻¹): 2962.1, 1708.5, 1458.8, 1372.8, 1201.6, 1096.1, 736.1, 698.4. HRMS (ESI+) m/z calcd for C₁₉H₂₇O₃⁺ [M+H]⁺: 303.1955, found 303.1958.

Allyl 1-isobutyryl-2,2-dimethylcyclopentane-1-carboxylate (16)

Isolated as a clear oil (34.0 mg, 67%). ¹H NMR (500 MHz, CDCl₃) δ 5.93 (ddt, J = 16.5, 10.4, 6.0 Hz, 1H), 5.36 (dd, J = 17.2, 1.4 Hz, 1H), 5.27 (dd, J = 10.4, 0.9 Hz, 1H), 4.67 – 4.58 (m, 2H), 2.81 (hept, J = 6.6 Hz, 1H), 2.43 (ddd, J = 14.1, 10.3, 6.5 Hz, 1H), 2.07 (ddd, J = 14.1, 9.9, 4.4 Hz, 1H), 1.86 – 1.54 (m, 4H), 1.16 (s, 3H), 1.04 (dd, J = 6.6, 4.2 Hz, 6H), 0.99 (s, 3H). ¹³C NMR (176 MHz, CDCl₃) δ 212.02, 172.58, 131.86, 119.59, 72.49, 66.05, 46.63, 40.39, 39.16, 31.65, 26.64, 24.47, 21.16, 20.31, 19.96. IR (cm⁻¹): 2962.8, 1708.5, 1460.6, 1371.9, 1256.5, 1202.9, 1098.5, 995.4, 934.7, 733.0. HRMS (ESI+) m/z calcd for C₁₅H₂₅O₃⁺ [M+H]⁺: 253.1798, found 253.1802.

4-Chlorobenzyl 1-isobutyryl-2,2-dimethylcyclopentane-1-carboxylate (18)

Isolated as a clear oil (34.3 mg, 76%). ¹H NMR (500 MHz, CDCl₃) δ 7.32 (q, J = 8.6 Hz, 4H), 5.12 (d, J = 1.9 Hz, 2H), 2.76 (hept, J = 6.6 Hz, 1H), 2.42 (ddd, J = 14.1, 10.2, 6.5 Hz, 1H), 2.08 (ddd, J = 14.2, 9.9, 4.4 Hz, 1H), 1.86 – 1.72 (m, 2H), 1.72 – 1.63 (m, 1H), 1.60 – 1.53 (m, 1H), 1.13 (s, 3H), 0.97 (dd, J = 15.1, 6.7 Hz, 6H), 0.94 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 211.9, 172.6, 134.7, 134.1, 130.4, 129.2, 72.5, 66.3, 46.8, 40.4, 39.2, 31.7, 26.6, 24.5, 21.0, 20.3, 19.9. IR (cm⁻¹): 2964.4, 1708.3, 1464.6, 1373.3, 1257.8, 1200.7, 1092.2, 1012.9, 811.9, 731.8. HRMS (ESI+) m/z calcd for C₁₉H₂₆IO₃⁺ [M+H]⁺: 337.1565, found 337.1567.

2-Iodobenzyl 1-isobutyryl-2,2-dimethylcyclopentane-1-carboxylate (20)

Isolated as a clear oil (63.0 mg, 86%). ¹H NMR (700 MHz, CDCl₃) δ 7.86 (dd, J = 7.9, 0.7 Hz, 1H), 7.41 (dd, J = 7.6, 1.3 Hz, 1H), 7.35 (td, J = 7.5, 0.8 Hz, 1H), 7.02 (td, J = 7.7, 1.4 Hz, 1H), 5.24 – 5.17 (m, 2H), 2.88 – 2.77 (m, 1H), 2.51 – 2.42 (m, 1H), 2.11 (ddd, J = 14.1, 10.0, 4.4 Hz, 1H), 1.84 – 1.74 (m, 2H), 1.74 – 1.66 (m, 1H), 1.64 – 1.54 (m, 1H), 1.15 (s, 3H), 0.99 (s, 3H), 0.98 (dd, J = 8.8, 6.7 Hz, 6H). ¹³C NMR (176 MHz, CDCl₃) δ 212.06, 172.51, 139.91, 138.11, 130.45, 130.44, 128.78, 99.28, 72.57, 70.97, 46.96, 40.43, 39.18, 31.80, 26.64, 24.63, 21.00, 20.37, 19.79. IR (cm⁻¹): 2961.2, 1706.8, 1458.2, 1372.2, 1198.6, 1097.0, 1011.0, 740.7, 645.3. HRMS (ESI+) m/z calcd for C₁₉H₂₆O₃I⁺ [M+H]⁺: 429.0921, found 429.0920.

2-(Phenylthio)ethyl 1-isobutyryl-2,2-dimethylcyclopentane-1-carboxylate (22)

Isolated as a clear oil (14.5 mg, 21%). ¹H NMR (500 MHz, CDCl₃) δ 7.40 (dd, J = 8.3, 1.3 Hz, 2H), 7.32 (dd, J = 8.6, 6.9 Hz, 2H), 7.26 – 7.21 (m, 1H), 4.30 (qt, J = 11.3, 7.0 Hz, 2H), 3.18 (t, J = 7.0 Hz, 2H), 2.85 (p, J = 6.7 Hz, 1H), 2.42 (ddd, J = 14.2, 10.3, 6.5 Hz, 1H), 2.08 (ddd, J = 14.1, 9.9, 4.5 Hz, 1H), 1.89 – 1.82 (m, 1H), 1.82 – 1.74 (m, 1H), 1.74 – 1.65 (m, 1H), 1.61 – 1.55 (m, 3H), 1.17 (s, 3H), 1.06 (dd, J = 11.1, 6.6 Hz, 6H), 1.01 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 210.96, 171.77, 134.15, 129.32, 128.50, 126.10, 71.52, 62.49, 45.81, 39.42, 38.18, 31.61, 30.70, 29.06, 25.69, 23.53, 20.09, 19.35, 18.94. IR (cm⁻¹): 2933.7, 1706.8, 1582.9, 1462.2, 1374.3, 1201.4, 1093.8, 739.4, 691.6. HRMS (ESI+) m/z calcd for C₂₀H₂₉O₃S⁺ [M+H]⁺: 371.1651, found 371.1650.

2-(Thiophen-2-yl)ethyl 1-isobutyryl-2,2-dimethylcyclopentane-1-carboxylate (24)

Isolated as a clear oil (43.0 mg, 67%). ¹H NMR (500 MHz, CDCl₃) δ 7.16 (dd, J = 5.1, 1.2 Hz, 1H), 6.93 (dd, J = 5.1, 3.4 Hz, 1H), 6.86 (dd, J = 3.4, 1.1 Hz, 1H), 4.36 (qt, J = 10.9, 6.8 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H), 2.77 (p, J = 6.6 Hz, 1H), 2.40 (ddd, J = 14.1, 10.3, 6.5 Hz, 1H), 2.06 (ddd, J = 14.2, 9.9, 4.5 Hz, 1H), 1.85 – 1.77 (m, 1H), 1.72 – 1.63 (m, 1H), 1.59 – 1.50 (m, 2H), 1.11 (s, 3H), 0.98 (dd, J = 6.6, 3.7 Hz, 6H), 0.95 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 212.1, 172.9, 139.9, 127.3, 126.1, 124.4, 72.5, 65.6, 46.8, 40.4, 39.1, 31.7, 29.5, 26.6, 24.5, 21.0, 20.3, 19.7. IR (cm⁻¹): 2964.7, 1709.1, 1459.4, 1261.4, 1207.6, 1099.5, 728.6. HRMS (ESI+) m/z cald for C₁₈H₂₇O₃S⁺ [M+Z]⁺: 323.1680, found 323.1676.

2-(1,3-Dioxoisoindolin-2-yl)ethyl 1-isobutyryl-2,2-dimethylcyclopentane-1-carboxylate (26)

Isolated as a waxy solid (35.6 mg, 79%). ¹H NMR (500 MHz, CDCl₃) δ 7.88 (dd, J = 5.4, 3.0 Hz, 2H), 7.75 (dd, J = 5.5, 3.0 Hz, 2H), 4.48 – 4.35 (m, 2H), 4.05 – 3.99 (m, 2H), 2.79 (hept, J = 6.7 Hz, 1H), 2.35 (ddd, J = 14.1, 9.9, 6.2 Hz, 1H), 2.06 (ddd, J = 15.2, 9.8, 4.4 Hz, 1H), 1.79 – 1.63 (m, 3H), 1.55 – 1.50 (m, 1H), 1.07 (s, 3H), 0.94 (s, 3H), 0.93 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 211.9, 172.7, 168.2, 134.5, 132.2, 123.7, 72.4, 62.0, 46.9, 40.3, 39.0, 37.1, 31.6, 26.4, 24.5, 20.8, 20.3, 19.6. IR (cm⁻¹): 2958.3, 1708.5, 1386.2, 1196.1, 1012.6, 716.0. HRMS (ESI+) m/z calcd for C₂₂H₂₈NO₅⁺ [M+H]⁺: 386.1962, found 386.1962.

Adamantan-2-yl)methyl 1-isobutyryl-2,2-dimethylcyclopentane-1-carboxylate (28)

Isolated as a clear oil (50.2 mg, 70%). ¹H NMR (500 MHz, CDCl₃) δ 3.76 (d, J = 10.9 Hz, 1H), 3.63 (d, J = 10.9 Hz, 1H), 2.87 (p, J = 6.7 Hz, 1H), 2.43 (ddd, J = 14.0, 10.2, 6.4 Hz, 1H), 2.09 (ddd, J = 14.3, 9.9, 4.4 Hz, 1H), 1.99 (s, 3H), 1.85 – 1.62 (m, 8H), 1.55 (d, J = 2.5 Hz, 8H), 1.18 (s, 3H), 1.03 (dd, J = 12.7, 6.7 Hz, 6H), 1.00 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 214.3, 175.2, 77.5, 74.7, 48.7, 42.5, 41.8, 40.9, 39.2, 35.3, 33.8, 30.3, 28.8, 26.7, 22.9, 22.4, 21.6. IR (cm⁻¹): 2905.7, 1708.1, 1457.2, 1371.9, 1206.6, 1098.8, 999.6, 734.6. HRMS (ESI+) m/z calcd for C₂₃H₃₇O₃⁺ [M+H]⁺: 361.2737, found 361.2737.

Methyl 1-acetyl-2,2-dimethylcyclopentane-1-carboxylate (30)

Isolated as a clear oil (11.0 mg, 28%). ¹H NMR (700 MHz, CDCl₃) δ 3.73 (s, 3H), 2.32 – 2.25 (m, 1H), 2.17 – 2.09 (m, 4H), 1.81 – 1.73 (m, 2H), 1.73 – 1.64 (m, 2H), 1.10 (s, 3H), 1.04 (s, 3H). ¹³C NMR (176 MHz, CDCl₃) δ 205.25, 173.48, 72.23, 52.26, 46.07, 40.73, 31.92, 29.38, 26.32, 24.53, 20.28. IR (cm⁻¹): 2960.1, 1705.9, 1433.6, 1249.4, 1115.3, 1088.6, 908.7, 728.4, 648.2. HRMS (ESI+) m/z calcd for C₁₁H₁₉O₃⁺ [M+H]⁺: 199.1329, found 199.1323.

Methyl 1-(cyclopropanecarbonyl)-2,2-dimethylcyclopentane-1-carboxylate (32)

Isolated as a clear oil (18.0 mg, 40%). ¹H NMR (500 MHz, CDCl₃) δ 3.73 (s, 3H), 2.39 – 2.30 (m, 1H), 2.29 – 2.20 (m, 1H), 1.98 – 1.86 (m, 1H), 1.79 – 1.64 (m, 4H), 1.11 (d, J = 6.1 Hz, 6H), 1.02 (t, J = 4.6 Hz, 2H), 0.89 – 0.81 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 207.15, 173.64, 72.43, 52.19, 45.88, 40.84, 31.83, 26.19, 25.01, 20.27, 20.10, 12.26, 11.86. IR (cm⁻¹): 2954.5, 1696.9, 1446.2, 1375.7, 1210.9, 1107.8, 1052.7, 943.9, 823.0. HRMS (ESI+) m/z calcd for C₁₃H₂₁O₃⁺ [M+H]⁺: 225.1485, found 225.1483.

Ethyl 1-(cyclopropanecarbonyl)-2,2-dimethylcyclopentane-1-carboxylate (34)

Isolated as a clear oil (16.1mg, 34%). ¹H NMR (401 MHz, CDCl₃) δ 4.20 (qq, J = 7.2, 3.7 Hz, 2H), 2.40 – 2.19 (m, 2H), 1.94 (tt, J = 8.8, 4.5 Hz, 1H), 1.81 – 1.64 (m, 4H), 1.27 (t, J = 7.1, 1.0 Hz, 3H), 1.12 (d, J = 9.5 Hz, 6H), 1.03 (t, 2H), 0.85 (dd, J = 7.8, 3.5 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 207.17, 173.07, 72.38, 61.07, 45.74, 40.93, 31.84, 26.16, 25.07, 20.24, 20.16, 14.49, 12.21, 11.96. IR (cm⁻¹): 2960.2, 1696.9, 1456.6, 1375.4, 1207.5, 1097.7, 1045.8, 948.5, 863.6. . HRMS (ESI+) m/z calcd for C₁₄H₂₃O₃⁺ [M+H]⁺: 239.1642, found 239.1647.

Ethyl 1-(cyclohexanecarbonyl)-2,2-dimethylcyclopentane-1-carboxylate (36)

Isolated as a clear oil (25.3mg, 45%). ¹H NMR (401 MHz, CDCl₃) δ 3.95 (dd, J = 7.1, 2.8 Hz, 2H), 2.65 – 2.50 (m, 2H), 2.10 (m, 2H), 1.89 (d, J = 12.4 Hz, 1H), 1.63 (m, 9H), 1.36 (s, 3H), 1.09 (s, 6H), 0.95 (t, J = 7.1 Hz, 3H).. ¹³C NMR (126 MHz, CDCl₃) δ 210.0, 172.5, 72.3, 60.8, 49.9, 46.3, 40.4, 31.6, 31.3, 29.8, 26.6, 26.0, 26.0, 25.9, 24.3, 20.3, 14.1. IR (cm⁻¹): 2930.2, 1705.8, 1454.1, 1369.8, 1207.1, 1091.1, 850.5, 737.5. HRMS (ESI+) m/z calcd for C₁₇H₂₉O₃⁺ [M+H]⁺: 281.1111, found 281.2114

Methyl 1-isobutyrylspiro[4.5]decane-1-carboxylate (38)

Isolated as a clear oil (23.1mg, 43%). ¹H NMR (500 MHz, CDCl₃) δ 3.74 (s, 3H), 2.80 (p, J = 6.7 Hz, 1H), 2.36 (ddd, J = 14.0, 10.1, 7.2 Hz, 1H), 2.00 (ddd, J = 13.9, 9.7, 4.1 Hz, 1H), 1.90 – 1.78 (m, 2H), 1.78 – 1.65 (m, 2H), 1.64 – 1.52 (m, 4H), 1.41 – 1.32 (m, 2H), 1.31 – 1.23 (m, 2H), 1.17 – 1.06 (m, 2H), 1.02 (dd, J = 10.8, 6.6 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 211.2, 172.3, 73.1, 51.0, 50.1, 38.4, 31.7, 31.0, 30.7, 30.0, 25.3, 22.8, 22.1, 20.1, 19.2, 18.8. IR (cm⁻¹): 2929.6, 1709.4, 1450.8, 1227.8, 1090.1, 938.9, 833.9. HRMS (ESI+) m/z calcd for C₁₆H₂₇O₃⁺ [M+H]⁺: 267.1955, found 267.1954.

Appendix A. Supplementary data

Supplementary data related to this article contains 1H and 13 358 C spectra for all new compounds.