Stereoselective synthesis of bicyclo[3.n.1]alkenone frameworks by Lewis acid-catalysis

Abstract

An intermolecular cyclization of alkynyl enones with cyclic ketones for the synthesis of bicyclo[3.n.1]alkenones is reported. This protocol exhibits a high functional group tolerance and provides access to a variety of bicyclic systems found as skeletons in many natural products.

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Bicyclo[3.n.1]- and [4.n.1]-alkenones as privileged structural subunits¹ are widely present in numerous bioactive natural products, such as (+)-ingenol,² clusianone,³ and enaimeone A⁴ (Fig. 1). Additionally, such bridged skeletons can also be used as versatile cyclic precursors for the synthesis of complex molecules.⁵ Consequently, considerable research efforts have been devoted to develop methodologies for the synthesis of bicyclo[3.2.1] and [3.3.1] molecular skeletons and related structural motifs via intra- or intermolecular approaches.^1a–d,6 In particular, α,α′-annulations of cyclic ketones (via enamine formation) with the appropriate C3-synthons ((E)-2-nitroallylic acetates,⁷ α-nitrocycloalkanones,⁸ Fischer carbene complexes,⁹ allenyl esters,^5c,10 or/and activated enones^6b,8,11) into these frameworks, have recently attracted significant attention.

Fig. 1 Bioactive natural products containing the bicycloalkenone scaffold.

Electron-deficient 1,3-conjugated alkynyl enones are useful building-blocks for a variety of rather complex structural motifs (Scheme 1). Generally, alkynyl enones are good Michael acceptors, which can undergo tandem reactions with different nucleophiles, leading to various acyclic and cyclic targets.¹²

Scheme 1 Synthetic utility of 2-(1-alkynyl)-2-alken-1-ones 1.

For example, the base-catalysed intermolecular cyclization of 2-(1-alkynyl)-2-alken-1-one 1 with 2-aminomalonates¹³ to access structurally diverse heterocyclic compounds was reported by Zhang and co-workers. The reaction was postulated to proceed via a 1,2-allene intermediate (Scheme 1a). Recently, our group reported a highly diastereoselective intermolecular annulation of alkynyl enones 1 with enamines formed in situ, demonstrating the versatility of alkynyl enones (Scheme 1b).¹⁴ One of the key features of this transformation was the excellent catalytic activity of indium salts which allowed for a wide variety of alkynyl enones, aldehydes, and amines as substrates. Herein, we report on the extension of this methodology for the synthesis of bicyclo[3.2.1] and [3.3.1] molecular skeletons from alkynyl enones, possibly via allene intermediates¹²ⁱ (Scheme 1c).

The initial study of alkynyl enone 1a with cyclopentanone and morpholine was performed; the desired bicyclo[3.2.1]alkenone product 3a was obtained in 61% yield as a single diastereomer along with the alkyne hydroamination product 4a in 17% yield using InBr₃ (Table 1, entry 1). We observed an improved yield of 3a (84%) and a reduced amount of the alkyne hydroamination side-product when molecular sieves (4 Å) were used, and by decreasing the solvent volume from 2 mL to 1 mL (entries 2 and 3). Other solvents were slightly less efficient (entries 4–6). It should be noted that product 3a was also formed in the absence of a catalyst, albeit in lower yield and with more side-products (entry 7). Employing different triflate-based metal salts like AgOTf and InOTf₃ yielded 3a in 76 and 35% yield respectively (entries 8 and 9). The use of ZnCl₂ led to a moderate yield of the desired product 3a (62%, entry 10). Gratifyingly, the yield of product 3a increased when InCl₃ was used as a catalyst (entry 11). A similar result was also obtained with only 10 mol% of InCl₃; product 3a was obtained in 90% yield (entry 12). Further decreasing the catalyst loading to 5 mol% resulted in a lower yield of 3a (entry 13). A Brønsted acid as catalyst resulted in a lower yield and a complex reaction mixture (entry 14). Screening of various amines and loadings did not improve the yield of 3a. We speculate that amine is not fully deliberated under the reaction, preventing the use of a catalytic amount of the amine. Additional screening data can be found in the ESI.†

Table 1 Screening of reaction conditions^a

Entry	Catalyst (mol%)	Solvent (mL)	Yield 3a^b [%]	Yield 4a^b [%]
a Reaction conditions: 1 (0.10 mmol), 2 (0.15 mmol), morpholine (0.20 mmol), catalyst (0–20 mol%), solvent (1.0–2.0 mL), activated molecular sieves 4 Å (45 mg), 80 °C for 18 h. b The yields were determined by ^1H NMR analysis with 1,3,5-trimethoxy benzene as an internal standard. c Without molecular sieves. d Isolated yield.
1^c	InBr3 (20)	DCE (2.0)	61	17
2	InBr3 (20)	DCE (2.0)	84	2
3	InBr3 (20)	DCE (1.0)	89	6
4	InBr3 (20)	EtOAc (1.0)	74	4
5	InBr3 (20)	CH3CN (1.0)	79	9
6	InBr3 (20)	CH2Cl2 (1.0)	85	2
7	None	DCE (1.0)	39	16
8	AgOTf (20)	DCE (1.0)	76	9
9	InOTf3 (20)	DCE (1.0)	35	9
10	ZnCl2 (20)	DCE (1.0)	62	6
11	InCl3 (20)	DCE (1.0)	91	3
12	InCl 3 (10)	DCE (1.0)	90 (86)	4
13	InCl3 (5)	DCE (1.0)	74	4
14	TsOH·H2O (20)	DCE (1.0)	57	12

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With the optimal conditions for the synthesis of bicyclo[3.2.1]alkenone 3a established, we further explored the substrate scope of this transformation with a variety of alkynyl enones 1 and cyclic ketones 2 (Scheme 2).

Scheme 2 Substrate scope with respect to various alkynyl enones and cyclic ketones. Compounds 3j–3n were synthesized using pyrrolidine in place of morpholine, see the ESI† for full experimental details.

Gratifyingly, a broad range of alkynyl enones 1 reacted to give the corresponding bicyclo[3.2.1] and [3.3.1] molecular skeletons 3 as single diastereomers in moderate to good yields. As expected, electron-donating and electron-withdrawing substituents at the R¹ position had no significant effect on the outcome of the reaction; 3b and 3c were obtained in 81 and 75% respectively. The use of cyclohexyl- and linear alkane-substituted alkynyl enones with cyclopentanone furnished 3d and 3e, both in 66% yield. It was interesting to find that when a TMS-substituted enynone was used as substrate, an intramolecular rearrangement of the TMS-group from carbon to oxygen (Brook rearrangement) was observed, resulting in product 3f in 42% yield. Moreover, methyl-substitution at the R² position furnished product 3g in a lower yield, whereas phenyl-substitution at the R³ position had a small negative effect on the outcome (3h, 63%). Furthermore, a methoxy-substituent in the R³ position furnished the bicyclo[3.2.1] and [3.3.1] molecular skeletons 3i and 3j in high yields, thus showing the versatile nature of this transformation.

Next, we examined the scope of this transformation with a variety of cyclic ketones to provide bicyclo[3.3.1]alkenones. It was found that the transformation with cyclohexanone derivatives provided products 3j–3n in higher yields when pyrrolidine was used in place of morpholine. Cyclohexanone gave the corresponding product 3k in moderate yield (58%, 33% with morpholine), whereas 1,4-cyclohexanedione resulted in product 3l in a lower yield, 32%. We were pleased to see that the substituted cyclic ketones (4-tert-butyl and 4-phenylcyclohexanone) furnished desymmetrization products 3m and 3n as single diastereomers in good yields. The structure and stereochemistry of product 3n was established by single-crystal X-ray analysis,¹⁵ and other derivatives were assigned by analogy. Unfortunately, cycloheptanone and cyclooctanone furnished only hydroamination products, and no desired products were observed.

The generality of this transformation was further investigated by using cyclic 2-(1-alkynyl)-2-alken-1-ones with cyclic ketones (Scheme 3). The five- and six-membered alkynyl enones with cyclopentanone and cyclohexanone furnished the corresponding polycyclo[3.2.1] and [3.3.1]alkenones (3p–3s) in high yields (52–73%, Scheme 3).

Scheme 3 Synthesis of polycyclo[3.2.1]alkenones with cyclic alkynyl enones and cyclic ketones. See the ESI† for full experimental details.

Next, we evaluated the feasibility of this reaction with α-substituted chiral amines (Scheme 4 & ESI†). In the presence of the secondary chiral amine A, product 3a was formed in 24% yield and 33% ee (Scheme 4). Compared to amine A, the use of TMS-protected diphenyl prolinol B displayed a better enantioselectivity but a poor reactivity (Scheme 4).

Scheme 4 Performing the reaction with chiral amines A and B.

Furthermore, the bicyclo[3.2.1]alkenone product 3a was isolated in 1.08 g upon performing the transformation on a larger scale (4.0 mmol, Scheme 5). The ring-strained bicyclo[3.n.1]keto compounds are highly reactive and can undergo a selective Baeyer–Villiger oxidation in the presence of m-CPBA in DCM at room temperature. As a result, lactone product 5a was obtained in 92% yield from the bicyclo[3.2.1]alkenone 3a (Scheme 5). The lactone functionality of compound 5a is useful as a synthetic intermediate for natural product synthesis and found in a number of bioactive natural products.¹⁶

Scheme 5 Synthesis of 3a on a 4.0 mmol scale and subsequent oxidation of 3a. See the ESI† for full experimental details.

A plausible mechanism for this transformation is shown in Scheme 6. The regioselective nucleophilic addition of the in situ-generated enamine produces intermediate B from the activated intermediate A. The alkyne hydroamination product 4, as well as the 1,2-allenyl ketone intermediate C, were observed during the reaction. Based on these results, one can envisage that the 1,2-allenyl ketone intermediate C was formed by a rearrangement of intermediate B through Lewis acid alkyne activation. From intermediate C, the desired product 3 can be formed via an intramolecular enamine addition at the allene carbon followed by hydrolysis. Our efforts to lower the amount of the cyclic amine remain fruitless.

Scheme 6 Plausible mechanism.

In summary, we have developed a Lewis acid-catalysed intermolecular α,α′-annulation of enamines (generated in situ) with alkynyl enones, providing an easy access to bicyclo[3.n.1]alkenones. The corresponding products can be obtained in high yields under benign reaction conditions.

Desymmetrization products can be achieved with meso-cyclic ketones as substrates. Furthermore, the reaction is scalable and the bicyclo[3.n.1]alkenone product can undergo a selective Baeyer–Villiger oxidation. The use of an indium Lewis acid catalyst reduced the formation of side-products (alkyne hydroamination and aza-Michael addition).

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and spectral data. CCDC 1569101. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7cc06400d

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