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Org. Synth. 2019, 96, 300-311

DOI: 10.15227/orgsyn.096.0300

Discussion Addendum for:Allylic Oxidation Catalyzed by Dirhodium(II) Tetrakis[ε-caprolactamate] of tert-Butyldimethylsilyl-protected trans-Dehydroandrosterone

Yong-Liang Su, Luca De Angelis and Michael P. Doyle*1

Original Article: Org. Synth. 2012, 89, 19

Discussion

Allylic oxidation of alkenes, which converts an allylic methylene group to a carbonyl group,² is powerful methodology for the synthesis of unsaturated ketones.³ Compared with more traditional oxidative reagents, such as stoichiometric oxidants selenium dioxide⁴ and chromium(VI),⁵ the mild tert-butyl hydroperoxide (TBHP) oxidant, when combined with select transition metals, has advantages, ⁶ especially in large-scale reactions and natural product syntheses. Doyle and coworkers have developed an efficient and selective oxidative system using dirhodium(II) caprolactamate Rh₂(cap)₄ as the catalyst and tert-butyl hydroperoxide (TBHP) as the terminal oxidant.⁷ Since this protocol was first reported for the allylic oxidation of cyclic alkenes, a variety of oxidative transformations, including benzylic oxidations,⁸ propargylic oxidations,⁹ oxidative reactions with phenols and aniline,¹⁰ imine formation from secondary amines,¹¹ and oxidative Mannich reactions of N,N-dialkylanilines, have also been shown to be efficient.¹²

The success of TBHP as a selective oxidant is due to formation of the tert-butylperoxy radical (Scheme 1).¹³ Although the initial reaction with the transition metal is O-O cleavage, the initially formed and more reactive tert-butoxy radical preferentially abstracts a hydrogen atom from TBHP at a near diffusion-controlled rate. The oxidized transition metal compound then undergoes reductive elimination with the formation of water and the tert-butylperoxy radical. In these reactions dirhodium caprolactamate appears to have an advantage over other transition metal complexes because of its low oxidation potential and high turnover rates.¹⁴ A competing reaction for the tert-butylperoxy radical is dimerization that results in the production of dioxygen and di-tert-butyl peroxide.

Scheme 1. Catalytic production of the tert-butylperoxy radical

At the time of our 2012 Org. Synth. report, allylic oxidations catalyzed by Rh₂(cap)₄ and TBHP focused on cyclic alkenes, including unsaturated steroids, and on electron-deficient acyclic alkenes. The applications of this powerful catalytic oxidative method to other substrates bearing allylic C-H bonds, especially in the total synthesis of natural products, are summarized in this Discussion Addendum.

N-Substituted 2,3-dihydro-4-piperidones and substituted 4-pyranone compounds are important intermediates in natural products and drug candidates.¹⁵ Allylic oxidations of cyclic enamides and enol ethers provide substituted piperidones and pyranones by Rh₂(cap)₄-catalyzed oxidations using TBHP with NaOAc as the additive (Scheme 2).¹⁶ Initial hydrogen atom abstraction produces a heteroatom-stabilized allylic radical, with ketone formation at the 4-position when R= aryl or alkyl and at the 2-position when R = H. Oxidation occurs under mild conditions with very low catalyst loading.

Scheme 2. Catalytic oxidation of cyclic enamides and enol ethers

Although many allylic oxidation methods have been reported, it is challenging to find the optimal methodology that provides the necessary chemo-, regio- and stereoselectivity for the synthesis of multifunctional natural products.^3b The Rh₂(cap)₄-catalyzed TBHP allylic oxidation was employed for the synthesis of dehydroaltenuene B, which had been isolated from cultures of an unidentified freshwater aquatic fungal species from the Tubeufiaceae family.¹⁷ In the first total synthesis of dehydroaltenuene B by the Barrett group,¹⁸ the authors found that α, β -unsaturated ketone 8, which was the key intermediate, could be obtained by TBHP allylic oxidation of fused cyclic alkene 7 in good yield (Scheme 3).

Scheme 3. Preparation of 8 in the total synthesis of dehydroaltenuene B

In the synthesis of antifungal glucan synthase inhibitors from enfumafungin, the allylic oxidation of amide 10 to enone 11 is one of the key steps.¹⁹ The method first reported by Merck Research Laboratories and Scynexis Inc., required 45 equivalents of CrO₃ and 3,5-dimethylpyrazole (3,5-DMP) (Table 1, entry 1).²⁰ The yield of enone 11 decreased to 36% when CrO₃ and 3,5-DMP were reduced to 15 equivalents (Table 1, entry 2). Further optimization of this step with catalytic metal catalyst and TBHP or cumene hydroperoxide (CHP) demonstrated that the oxidation of 10 catalyzed by Rh₂(cap)₄ afforded enone 11 and tert-butylperoxy ether 12 (1.3 : 1), with a 30% isolated yield of enone 11. The oxidation of amide 10 under Corey-Yu conditions²¹ gave a similar result, which could be further optimized with a bulkier oxidant CHP (Table 1, entries 4-5).

Table 1. Allylic of amide 10 to enone 11

Entry	Catalyst	Additive	Oxidant	T(°C)	11 :12	11 (%)
1	-	3,5-DMP (45 equiv)	CrO₃ (45 equiv)	-25 to 15	-	85
2	-	3,5-DMP (15 equiv)	CrO₃ (15 equiv)	-25 to 15	-	36
3	Rh₂(cap)₄	K₂CO₃	TBHP	rt	1.3:1	30
4	Pd(OH)₂/C	K₂CO₃	TBHP	rt	1.3:1	34
5	Pd(OH)₂/C	K₂CO₃	CHP/TBHP (12/10 equiv)	0-5	6.6:1	64

Δ¹²-Prostaglandin J₃ (Δ¹²-PGJ₃) and analogs have been reported as potent and selective antileukemic prostaglandin compounds.²² In the synthesis of Δ¹²-PGJ₃, Nicolaou and coworkers found that selective allylic oxidation could be achieved by the combination of Rh₂(cap)₄ and TBHP, which produced 14 in 48% yield, while other common conditions like SeO₂, tBuOOH/PDC, tBuOOH-bleach, and Mn(OAc)₃ with or without an O₂ atmosphere were generally inferior (Scheme 4).²³ The effects of ring sizes and side-chain functionalities on the oxidative reactions were also studied (Table 2). Substrates with side-chain electron withdrawing groups undergo direct allylic oxidation without migration of the double bond (Table 2, entries 1 and 2); however, formation of the more stable allylic radical produced transposed enones as the main or exclusive product when other cyclic alkenes were investigated (Table 2, entries 3-11).

Scheme 4. Synthesis of enone 14 as the intermediate of Δ¹²-PGJ₃

Table 2. Regioselective allylic oxidation of substituted cycloalkenes by (A) Rh₂(cap)₄ (0.5 mol%) and tBuOOH (5.0 equiv) or (B) Mn(OAc)₃ (20 mol%)) and tBuOOH (4.0 equiv)

Tu and coworkers developed an efficient synthesis route for the construction of the core structure of calyciphylline A type alkaloids 38 in which the precursor of key rearrangement step was synthesized by Rh₂(cap)₄-catalyzed allylic oxidation of a substituted cyclohexene (Scheme 5).²⁴ This transformation shows good tolerance of functional groups for this oxidative method.

Scheme 5. Synthesis of the rearrangement precursor 37

In the asymmetric total synthesis of longeracinphyllin A 41, Li and coworkers found that the allylic oxidation of enone 39, promoted by DABCO and air, furnished enedione 40 in 91% yield, presumably through enolate peroxidation and hydroxyl elimination (Scheme 6).²⁵ The author also reported that Rh₂(cap)₄-catalyzed TBHP oxidation could also achieve this transformation, but yield of the reaction was moderate.

Scheme 6. Allylic oxidation of enone 39 to enedione 40

The Sarpong group reported the synthesis of a range of phomactin congeners via a common intermediate.²⁶ The allylic oxidation of phomactin P provided phomactin K in 52% yield (Scheme 7). Amazingly, in this process the exocyclic double bond and epoxide functional groups of phomactin P survive.

Scheme 7. Allylic oxidation of phomactin P to phomactin K

7α-Hydroxy-cholest-4-en-3-one has been reported as a biomarker for bile acid loss, irritable bowel syndrome, and other associated disorders and diseases. A key feature of the synthesis of this compound reported by the Yoshimoto group²⁷ involved two allylic oxidative reactions, the C-7 allylic oxidation of 44 to give 45 and the C-3 allylic oxidation of 46 to give 47 (Tables 3 and 4). In the C-3 allylic oxidation, use of Rh₂(cap)₄ as the catalyst with TBHP was competitive with those with CrO₃ or PCC oxidants (entries 1-2) or oxidations by TBHP catalyzed by other transition metal compounds (entries 3 and 6). However, Co(OAc)₂ and CuI were superior to Rh₂(cap)₄ as catalysts for the allylic oxidation of enone 47 (Table 4).

Table 3: Summary of C7-oxidation conditions^a

Entry	Time	Metal	Solvent	Isolated yield of 45
1	12 h	CrO₃/3,5-DMP	DCM	79%
2	36 h	PCC	Toluene	27%
3	20 h	Co(OAc)₂	CH₃CN	68%
4	24 h	Rh₂(cap)₄	DCE	71%
5	12 h	Rh₂(cap)₄	DCE	45%
6	20 h	CuI	CH₃CN	53%

^a For entries 2-6: the metal was added to the solution of the starting material (44, 300 mg, 0.7 mmol) in indicated solvent (5-6 mL) in a 50 mL screw cap vial fitted with a rubber stopper. The reaction mixture was evacuated and backfilled with nitrogen. For entries 4-6: 1 mg of metal was used. For entry 3: 30 mg of Co(OAc)₂ tetrahydrate (0.12 mmol, 0.17 equiv) was used. For entry 2: 1.8 g of PCC (8.4 mmol, 12 equiv.) and 3.52 g of celite (58 mmol) were used (and stirred at reflux). Entries 3-6:the reaction temperature was 40°C, 1.5 mL (70% in water, v/v) of tert-butyl hydroperoxide (11 mmol, 15 equiv) was used.

Table 4: Summary of C3-oxidation conditions^a

Entry	Time	Metal	Solvent	Isolated yield of 47
1	12 h	CrO₃/3,5-DMP	DCM	56%
2	20 h	Co(OAc)₂	DCM	60%
3	24 h	Rh₂(cap)₄	DCE	33%
4	12 h	Rh₂(cap)₄	DCE	37%
5	20 h	CuI	DCM	58%

For entries 2-5: tert-butyl hydroperoxide was used (0.15 mL, 1.1 mmol), reaction temperature was 40 °C, 5 mL of solvent was used. Entry 2: 105 mg of starting material (0.25 mmol), 10 mg of Co(OAc)₂ (0.04 mmol), gave 66 mg of product (0.15 mmol, 60%). Entry 3: 92 mg of starting material (0.22 mmol), 1 mg of Rh₂(cap)₄ used gave 31 mg of product (0.072 mmol, 33%). Entry 4: 130 mg of starting material (0.31 mmol), 1 mg of Rh₂(cap)₄ used gave 50 mg of product (0.12 mmol, 37%) and 8 mg of 27 (0.019 mmol, 6%). Entry 5: 83 mg of starting material (0.2 mmol), 1 mg of CuI used gave 50 mg of product isolated (0.12 mmol, 58%).

In summary, dirhodium(II) caprolactamate is a selective and efficient catalyst for TBHP oxidations of the allylic C-H bond. The method features high selectivity, low catalyst loading (usually 0.025 mol%-1 mol%), mild conditions, and a broad substrate scope. Substrates that enunciate Rh₂(cap)₄ limitations on allylic oxidations are acyclic olefins, whereas acyclic enones are applicable for this type of oxidation. The reagent's application to allylic oxidations in the total synthesis of natural products demonstrates its utility.

References and Notes

Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas 78249. Email: michael.doyle@utsa.edu. Financial support from the Welch Foundation (AX-1871) is gratefully acknowledged.
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	Yong-Liang Su received his B.S. degree from Shandong University in 2013 under the direction of Prof. De-Qun Sun, and then he obtained his Ph.D. degree from University of Science and Technology of China under the supervision of Prof. Liu-Zhu Gong in 2018. His Ph.D. work focused on transition metal/ organo-cooperatively-catalyzed asymmetric reactions. He is currently a postdoctoral associate with Prof. Doyle at University of Texas at Santo Antonio working on free radical oxidative reactions.
	Luca De Angelis received his Laurea Triennale in Chimica and Laurea Magistrale in Chimica from the Università La Sapienza in Rome. He joined the University of Texas at San Antonio in September 2016 and obtained his Master's degree in inorganic chemistry under the direction of Dr. Ghezai Musie, working on chiral recognition of sugars. In 2018, he joined Dr. Doyle's group, where he has worked on metal carbene projects and free radical oxidative reactions.
	Michael P. (Mike) Doyle is the Rita and John Feik Distinguished University Chair in Medicinal Chemistry at the University of Texas at San Antonio. He is a graduate of the College of St. Thomas and Iowa State University, has had academic appointments at undergraduate institutions (Hope College and Trinity University) and graduate universities (University of Arizona and University of Maryland), as well as being Vice President, then President, of a science foundation (Research Corporation) before taking his current position.

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