A General Synthetic Approach to Functionalized Dihydrooxepines

Abstract

A three-step sequence to access functionalized 4,5-dihydrooxepines from cyclohexenones has been developed. This approach features a regioselective Baeyer–Villiger oxidation and subsequent functionalization via the corresponding enol phosphate intermediate.

4,5-Dihydrooxepines are featured as structural motifs within various natural products, ranging from sesquiterpenes, such as miscandenin¹ and endiadric acid derivative beilshmiedin, ² to polyketides, such as conioxepinol A³ (Figure 1). This framework is also found in some of the most interesting members of the epidithiodiketopiperazine family as represented by aranotin ⁴ (Figure 1). Consequently, a number of approaches have been developed to access this structural motif. These include acid-catalyzed cyclization, ⁵ Rh-catalyzed cycloisomerization, ⁶ ring-closing metathesis, ⁷ [4+2] cycloaddition/epoxidation/retro [4+2] cycloaddition, ⁸ Cope rearrangement, ⁹ fragmentation, ¹⁰ and Criegee rearrangement.¹¹

Figure 1.

Selected natural products containing the 4,5-dihydrooxepine structural motif.

Despite this progress, the synthesis of related natural products in which the dihydrooxepine unit is highly functionalized remains challenging, in part because the scope and generality of existing methods are rather limited. Post-functionalization of pre-formed dihydrooxepines is also difficult due to the sensitive nature of these structural moieties. Therefore, a general approach through which substrates with a diverse array of substitution patterns can be reliably transformed into functionalized dihydrooxepines is highly desirable.

As part of our continuing efforts toward the total synthesis of members of the dihydrooxepine epidithiodiketopiperazine family,^8a,12 we opted to develop a method to synthesize 4,5-dihydrooxepines from cyclohexenones. Such a strategy would benefit from the ready availability of functionalized cyclohexenones, thus allowing access to a broad range of dihydrooxepine structures. We reasoned that ring expansion of the cyclohexenone could be achieved through a regioselective Baeyer–Villiger oxidation. Further functionalization of the resulting enol lactone through either reduction or C–C bond formation would give rise directly to the bis-enol ether moiety found in 4,5-dihydrooxepines (Figure 2).¹³

Figure 2.

Proposed synthesis of functionalized 4,5-dihydrooxepines from the corresponding cyclohexenones.

Our experimentation began with the Baeyer–Villiger oxidation of enone 1a (Table 1). Thus, reaction of 1a with mCPBA gave the desired enol lactone as a single regioisomer, albeit in low conversion (Table 1, entry 1). Attempts to use stronger oxidants such as CF₃CO₃H led to partial decomposition of the product (entry 2). We then reasoned that substrate activation by a suitable Lewis acid would improve conversion under milder reaction conditions that would avoid product decomposition. Indeed, the combination of SnCl₄ and bis(trimethylsilyl)peroxide (BTSP), in the presense of trans-1,2-diaminocyclohexane (ligand A), generated the desired product 2a in 83% yield (entry 3).¹⁴ The use of this ligand proved to be critical as it successfully tempered the Lewis acidity of SnCl₄. Neither SnCl₄ itself nor its combination with other ligands tested, such as trans-1,2-di(tosylamino)cyclohexane (ligand B), led to comparable yields (entries 4–6). The presence of dry molecular sieves was essential for the success of this reaction, as in its absence, only trace amounts of the product was observed (entry 7).

Table 1.

Study of the Baeyer–Villiger Oxidation of Enones^a

entry	conditions	yield (%)b
1c	mCPBA, CH2Cl2	15
2c	UHP, TFAA, CH2Cl2	decomp.
3c	BTSP, SnCl4, ligand A, 4 Å MS, CH2Cl2	83
4d	BTSP, SnCl4, 4 Å MS, CH2Cl2	trace
5d	BTSP, SnCl4, ligand B, 4 Å MS, CH2Cl2	22
6d	BTSP, SnCl4, pyridine, 4 Å MS, CH2Cl2	32
7d	BTSP, SnCl4, ligand A, CH2Cl2	trace

^aReactions were carried out on 0.25 mmol scale.

^b1H NMR yield.

^cReactions were carried out at 0.1 M concentration with 0.5 equiv of SnCl₄, 0.5 equiv of ligand A, 3.0 equiv of BTSP and 50 mg 4 Å MS at 25 °C.

^dReactions were carried out under the identical conditions in entry 3 with changes indicated in the table.

mCPBA = meta-chloroperoxybenzoic acid, UHP = urea hydrogen peroxide, TFAA = trifluoroacetic anhydride, BTSP = bis(trimethylsilyl)peroxide.

Conversion of the Baeyer–Villiger product 2a to the corresponding enol phosphate 3a went smoothly under our previously developed conditions (Scheme 1).¹⁵ The phosphate group was chosen over the more common triflate group because the former is well-known to be more stable than the latter.¹⁵

Scheme 1.

Enol Phosphate Formation and Pd-Catalyzed Reduction to 4,5-Dihydrooxepine

Pd-catalyzed reduction of the diphenyl phosphate 3a proved to be unsuccessful when using either Ph₂SiH₂ or nBu₃SnH as the reducing agent. After extensive screening, Et₃Al turned out to be the optimal reducing agent, giving the desired 4,5-dihydrooxepine 4a in 81% yield (Scheme 1). However, when applying the same reduction conditions to phosphate 3b (Table 2), we obtained an inseparable mixture of the desired product 4b and the ethylated product 5b in ca. 3:2 ratio (Table 2, entry 1). This result reflects the competition between β-hydride elimination and reductive elimination of the ethylated intermediate (see Table 2). ¹⁶ Attempts to optimize the reduction of 3b by changing the solvent (entry 2) or using the diethyl phosphate 3b′ (entry 3) gave a mixture of 4b and 5b, albeit in different ratios (see Table 2). We then turned to some other reducing agents and found that LiBH₄ proved to be the best, giving exclusively the benzodihydrooxepine 4b in good yield [entries 4 (66% yield) and 5 (67% yield)].

Table 2.

Optimization of Enol Phosphate Reduction^a

entry	R	reducing agent	solvent	yield (%)b (4b+5b)	4b:5bc
1	Ph	Et3Al	ClCH2CH2Cl	58	60:40
2	Ph	Et3Al	CH2Cl2	62	37:63
3	Et	Et3Al	ClCH2CH2Cl	70	90:10
4	Et	LiBH4	THF	66	4b only
5	Ph	LiBH4	THF	67	4b only

^aReactions were run on 0.1 mmol scale at 0.05 M concentration with 0.2 equiv of Pd(PPh₃)₄ and 2.5 equiv of Et₃Al at 25 °C or 10 equiv of LiBH₄ at 0 °C.

^b1H NMR yield.

^cRatios determined by ¹H NMR spectroscopic analysis.

With the developed optimized conditions in hand, we then proceeded to assess the generality and scope of this three-step procedure to functionalized dihydrooxepines. As shown in Table 3, a variety of substrates with diverse substitution patterns and functional groups could be reliably transformed into the corresponding 4,5-dihydrooxepines. Cyclohexenones with either a methyl group on the olefinic bond (entries 3 and 5) or gem-dimethyl groups on the 4-position (entry 4) are good substrates for these transformation, although the latter exhibits lower reactivity in the first and third steps as compared to the others. Functional groups such as an isolated olefinic bond, an electron-rich arene, a TBS-protected secondary alcohol, or a ketal group are all tolerated in these procedures (entries 5–8). Most notably, the current method is also applicable to relatively complex structures, including the protected Wieland-Miescher ketone 1h and the cholesterol derivative 1i (entries 8 and 9, respectively). Thus, application of the present method to these substrates allows rapid access to the relatively complex dihydrooxepines 4h and 4i, respectively.

Table 3.

Scope and Generality of the 4,5-Dihydrooxepine-Forming Sequence^a

entry	substrate	lactone (% yield)b	enol phosphate (% yield)b	4,5-dihydrooxepine (% yield)b
1	1a	2a (83)	3a (92)	4a (81)c
2	1b	2b (70)	3b (93)	4b (67)d,e
3	1c	2c (72)	3c (89)	4c (90)c
4	1d	2d (70)	3d (55)	4d (81)c
5	1e	2e (74)e	3e (84)	4e (61)d,e
6	1f	2f [34 (46 brsm)]f	3f (75)	4f (64)d,e
7	1g	2g (79)	3g (83)	4g (86)d
8	1h	2h (54)	3h (90)	4h (71)d
9	1i	2i (99)	3i (57)	4i (82)d

^aLactone formation: reactions were carried out on 1.0 mmol scale at 0.1 M concentration in CH₂Cl₂ with 0.5 equiv of SnCl₄, 0.5 equiv of ligand A, 3.0 equiv of BTSP and 200 mg 4 Å MS at 25 °C; enol phosphate formation: reactions were carried out on 0.5 mmol scale at 0.1 M concentration in THF with 2.0 equiv of KHMDS, 2.0 equiv of (PhO)₂P(O)Cl, 3.0 equiv of HMPA at −78 °C; dihydrooxepine formation (method A): reactions were carried out on 0.2 mmol scale at 0.05 M concentration in ClCH₂CH₂Cl with 0.2 equiv of Pd(PPh₃)₄ and 2.5 equiv of Et₃Al; dihydrooxepine formation (method B): reactions were carried out on 0.2 mmol scale at 0.05 M concentration in THF with 0.2 equiv of Pd(PPh₃)₄ and 10 equiv of LiBH₄ at 0 °C.

^bIsolated yield unless otherwise noted.

^cUsing method A.

^dUsing method B.

^eDue to the volatility of the product, the yield refers to ¹H NMR yield.

^fAnhydrous K₂CO₃ (200 mg) was added.

brsm = based on recovered starting material.

In addition to the above Pd-catalyzed reduction, the enol phosphate intermediate also provides a platform for a series of C–C bond forming reactions, thereby allowing further functionalization of the dihydrooxepine system. Thus, as demonstrated in Scheme 2, 3b could be successfully engaged in Ni-catalyzed Negishi (conditions a) and Kumada couplings (conditions b), leading to the corresponding alkyl-substituted products 5b and 6b, respectively, without competition from the β-hydride elimination pathway. Introduction of phenyl (conditions c), 3-thienyl (conditions d) and alkylnyl (conditions f) substituents can also be achieved in high yields using PdCl₂(dppf) as the catalyst (products 7b, 8b and 10b, respectively). The same catalyst is also effective in converting the phosphate into an ester group (conditions e), albeit in moderate yield (product 9b).

Scheme 2.

Functionalization of the 4,5-Dihydrooxepine Structural Motif via the Corresponding Enol Phosphate

In summary, we have developed a three-step approach for the synthesis of functionalized dihydrooxepines from readily available cyclohexenones. This sequence features a regioselective Baeyer–Villiger oxidation, subsequent enol phosphate formation and Pd-catalyzed functionalization. The large variety of available cyclohexenones provides the basis for the generality of this approach, while the mildness of reaction conditions ensures their reliable transformation to functionalized dihydrooxepines with minimal loss due to facile decomposition. The current method holds considerable promise for application to the synthesis of bioactive natural products and their analogs.