Ring Contraction Strategy for the Practical, Scalable, Catalytic Asymmetric Synthesis of Versatile γ-Quaternary Acylcyclopentenes

Abstract

A simple protocol for the practical, scalable, catalytic asymmetric synthesis of γ-quaternary acylcyclopentenes in up to 91% overall yield and 92% ee has been developed. The reaction sequence employs a palladium-catalyzed enantioselective alkylation reaction and exploits the unusual stability of β-hydroxy cycloheptanones to achieve a general and robust method for performing two-carbon ring contractions. The resulting enantioenriched, highly-functionalized acylcyclopentenes provide a variable substituent and four additional functional group handles for chemoselective manipulation and potential application to the total synthesis of a wide array of natural products.

Highly substituted cyclopentanes are a common structural motif integrated into thousands of natural products.^[1] Selected examples of bioactive compounds containing this basic structural unit include the hamigerans (2),^[2a] steroids (3),^[2b] pleuromutilin antibiotics (4),^[2c] cyathane diterpenoids (5),^[2d] cyclic botryococcenes (6),^[2e] and anti-HBV schisanwilsonenes (7a–c)^[2f] (Figure 1). Synthetic methods for the asymmetric preparation of cyclopentanoid cores with multiple functional group handles are highly desirable because they allow for the strategic synthesis of these and other natural products.^[3] Toward this goal, we envisioned that functionalized chiral units such as acylcyclopentene 1 could serve as valuable synthetic intermediates (Figure 1). In this report, we describe a general and enantioselective preparation of versatile chiral acylcyclopentenes^{[4, 5]} that combines a catalytic asymmetric alkylation reaction^[6] and a facile two-carbon ring contraction.

Figure 1.

Representative natural products possessing cyclopentanoid core structures with quaternary stereocenters.

Our work in this area began with observation of the unusual reactivity of seven-membered ring vinylogous esters compared to their six-membered ring counterparts. Although LiAlH₄ reduction of vinylogous ester 8 gave expected enone 9^[7] as the major product after acidic workup (Scheme 1A), subjecting the analogous seven-membered ring vinylogous ester (10a) to identical reaction conditions led to cycloheptenone 11a as only a minor product (Scheme 1B). Interestingly, the major product was identified as stable β-hydroxyketone 12a.^{[ 8 ]} The lack of appreciable β-elimination even under acidic conditions suggests that subtle, but fundamental differences in ring conformational preferences between six- and seven-membered rings may lead to the strikingly different product distributions.^[9]

Scheme 1.

Anomalous reactivity of seven-membered ring vinylogous esters and discovery of a ring contraction reaction.

To further examine the inherent reactivity of β-hydroxyketone 12a, we exposed the compound to a variety of basic reaction conditions. Treatment of β-hydroxyketone 12a with LiOt-Bu in t-BuOH afforded acylcyclopentene 1a in 53% yield without any evidence of direct β-hydroxy elimination to enone 11a. Overall, the reaction constitutes a two-carbon ring contraction that likely proceeds via a retro-aldol fragmentation/aldol cyclization pathway. Although isolated examples of the preparation of acylcyclopentenes from seven-membered rings^[10] are known, general ring contraction methods have not been demonstrated with γ-quaternary stereocenters and catalytic asymmetric routes are unprecedented.

Enticed by this initial finding, we investigated the effect of different bases on product formation (Table 1). Alcohol additives in combination with LiOH in THF improved the yield for the reaction (entries 2–4), with CF₃CH₂OH[11] enabling the production of 1a in 96% yield.^[12] It is interesting to note that enone 11a was not observed under any of the surveyed conditions. Among the conditions that promote the desired ring contraction, the combination of LiOH and CF₃CH₂OH in THF offered a mild, efficient, and selective method for further studies (entry 4).

Table 1.

Ring contraction optimization.^[a]

Entry	Base	Additive	Solvent	T [°C]	Yield [%][b]
1	LiOt-Bu	none	t-BuOH	40	71 (53)[c]
2	LiOH	t-BuOH	THF	60	78
3	LiOH	HFIP[d]	THF	60	87
4	LiOH	CF3CH2OH	THF	60	96 (84)[c]

^[a]Conditions: β-hydroxyketone (1.0 equiv), base (1.5 equiv), additive (1.5 equiv) in solvent (0.1 M) at indicated temperature for 9–24 h.

^[b]GC yield using an internal standard.

^[c]Isolated yield in parentheses.

^[d]HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol.

With an optimized procedure for the ring contraction, we turned our attention to the asymmetric synthesis of various quaternary substituted vinylogous esters (e.g., 10, Table 2).^[13,14] A number of racemic β-ketoester substrates (e.g., 14) for catalytic enantioselective alkylation could be obtained by acylation of parent vinylogous ester 13 with allyl cyanoformate^[15] and trapping with a range of electrophiles under basic conditions.^[16] Application of our standard enantioselective decarboxylative alkylation reaction conditions^[6,13] to substrate 14a produced chiral vinylogous ester 10a in 91% yield and 88% ee (entry 1).^[17,18] Substituents such as ethyl, benzyl, propargyl, homoallyl, and 2,4-pentadienyl were well-tolerated in the reaction, giving similarly high yields and enantioselectivity (entries 2–6). A number of heteroatom containing substrates were explored to test if more diverse functionality could be incorporated into our target acylcyclopentenes (entries 7–11). β-Ketoesters bearing a 2-chloroallyl substitutent readily underwent the enantioselective alkylation reaction (entry 7). Gratifyingly, compounds that possess Lewis basic moieties readily furnished the desired products without complications (entries 8–9). Even indoles and free aldehydes could be incorporated into the cycloheptenone products (entries 10–11).

Table 2.

Scope of the Pd-catalyzed enantioselective alkylation of cyclic vinylogous esters.^[a]

Entry	Substrate 14	R	Product 10	Yield [%][b]	ee [%][c]
1	14a	–CH3	10a	91	88
2	14b	–CH2CH3	10b	89	92
3	14c	–CH2Ph	10c	98	86
4	14d	–CH2C≡CH	10d	88	89
5	14e	–CH2CH2CH=CH2	10e	95	87
6	14f		10f	90	90
7	14g		10g	99	86
8	14h	–CH2CH2CN	10h	96	87
9	14i		10i	97	85
10	14j		10j	98	83
11	14k		10k	90	80

^[a]Conditions: β-ketoester (1.0 equiv), Pd₂(pmdba)₃ (2.5 mol %), (S)-t-Bu-PHOX (6.25 mol %) in PhCH₃ (0.1 M) at 30 °C; pmdba = 4,4′-methoxydibenzylideneacetone.

^[b]Isolated yield.

^[c]Determined by chiral HPLC or SFC.

The chiral vinylogous esters (e.g., 10) prepared above allowed us to examine the scope of the ring contraction reaction (Table 3). Substrate reduction with LiAlH₄ and base-promoted rearrangement of vinylogous esters bearing γ-alkyl substituents provided access to the corresponding acylcyclopentenes in excellent yields over the two-step protocol (entries 1–6). The chloroallyl, nitrile, and indole-containing substrates could be transformed with similarly high yields using the same conditions (entries 7–8, 10). Alternatively, DIBAL allowed smooth conversion of vinylogous ester 10i containing an N-basic pyridine (entry 9). Milder reduction under Luche conditions enabled facile conversion of silyl ether substrates (entries 11–12).^[19] Furthermore, trans-propenyl substituted (entry 13) and spirocyclic (entry 14) substrates performed well in the ring contraction chemistry. With the combination of asymmetric alkylation and ring contraction, we achieved a route to substituted acylcyclopentenes with a wide range of functionality at the γ-quaternary stereocenter.

Table 3.

Ring contraction substrate scope.

Entry	Substrate 10	R1	R2	Product 1	Overall Yield [%][e]
1[a,d]	10a	–CH3	–CH2CH=CH2	1a	84
2[a,d]	10b	–CH2CH3	–CH2CH=CH2	1b	90
3[a,d]	10c	–CH2Ph	–CH2CH=CH2	1c	86
4[a,d]	10d	–CH2C≡CH	–CH2CH=CH2	1d	95
5[a,d]	10e	–CH2CH2CH=CH2	–CH2CH=CH2	1e	87
6[a,d]	10f		–CH2CH=CH2	1f	91
7[a,d]	10g		–CH2CH=CH2	1g	92
8[a,d]	10h	–CH2CH2CN	–CH2CH=CH2	1h	85
9[b,d]	10i		–CH2CH=CH2	1i	80
10[a,d]	10j		–CH2CH=CH2	1j	87
11[c,d,f]	10l	–CH2OTBDPS	–CH2CH=CH2	1l	91
12[c,d,g]	10m	–(CH2)3OTBDPS	–CH2CH=CH2	1m	85
13[c,d,h]		10n	1n		81
14[a,d,g]		10o	1o		87

^[a]Reduction Conditions A: vinylogous ester (1.0 equiv), LiAlH₄ (0.55 equiv) in Et₂O (0.2 M) at 0 °C, then 10% aqueous HCl quench.

^[b]Reduction Conditions B: 1) vinylogous ester (1.0 equiv), DIBAL (1.2 equiv) in PHCH₃ (0.03 M) at −78 °C; 2) oxalic acid•2H₂O in MeOH (0.02 M).

^[c]Reduction Conditions C: vinylogous ester (1.0 equiv), CeCl₃•7H₂O (1.0 equiv), NaBH₄ (3.0 equiv) in MeOH (0.02 M) at 0 °C, then 10% aqueous HCl in Et₂O at 0 °C.

^[d]Ring Contraction Conditions: β-hydroxyketone (1.0 equiv), CF₃CH₂OH (1.5 equiv), LiOH (1.5 equiv) in THF (0.1 M) at 60 °C.

^[e]Isolated yield over 2–3 steps.

^[f]See Supporting Information for experimental procedures for substrate synthesis.

^[g]Prepared from 14k. See Supporting Information.

^[h]Prepared from 14a. See Supporting Information.

To demonstrate the practicality and scalability of the method, the α-methyl β-ketoester 14a was converted to the corresponding acylcyclopentene 1a in 69% yield over three steps on 15 g scale (Scheme 2A).^[16] Notably, the multi-gram protocol proceeds with reduced catalyst loading and at higher reaction concentrations for the asymmetric alkylation step. Additionally, the enantiopurity of the acylcyclopentene 1a can be increased to 98% ee by recrystallization of semicarbazone 15 (Scheme 2B).^[16] Hydrolysis of hydrazone 15 with aqueous HCl enabled facile recovery of 1a. Further derivatization afforded X-ray quality crystals of 16 for verification of absolute stereochemistry.^[20] To enable access to β-substituted acylcyclopentenes, addition of n-BuMgBr to 10a resulted in formation of tertiary β-hydroxyketone 17 (Scheme 2C).^[16] Application of modified ring contraction conditions allowed access to acylcyclopentene 18.

Scheme 2.

Multi-gram ring contraction, enrichment of ee by recrystallization, and organometallic modified ring contraction sequence.

With a versatile, enantioselective synthesis of γ-quaternary acylcyclopentenes 1 in hand, we sought to demonstrate the further synthetic utility of these compounds. By combining site selective manipulations in short reaction sequences (1–4 steps), any of five reactive handles present in acylcyclopentene 1 can be functionalized (Scheme 3, sites A–E). Through careful implementation of these transformations, diverse monocarbocyclic (1j, 18–23), spirocyclic (24–25), and fused polycyclic structures (26–27) can be obtained.^[16]

Scheme 3.

Versatility and synthetic utility of acylcyclopentenes.

In summary, we have developed a catalytic enantioselective synthesis for the preparation of densely functionalized chiral acylcyclopentenes in excellent yields and enantioselectivities. The protocol exploits a highly efficient Pd-catalyzed asymmetric alkylation reaction and a newly-developed, mild two-carbon ring contraction. The important chiral building blocks formed using this method can undergo a variety of synthetic transformations and will serve as valuable intermediates for the total synthesis of natural products. Efforts directed toward these ends are currently underway and will be reported in due course.