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Synthesis 2024; 56(20): 3215-3219
DOI: 10.1055/a-2361-0069
paper

Efficient Oxidation with Singlet Oxygen from 5,10,15,20-Tetraphenylporphyrin under Blue LED Irradiation and Air Atmosphere: Simplified Preparation of Key Building Blocks for Natural Product Synthesis

Masato Hasumi‡
,
Tomohiro Tsutsumi‡
,
Daiki Shikama
,
Ichiro Hayakawa∗

This work was supported by Grant-in-Aid for Scientific Research (Grant Number 20H02867) from the Japanese Society for the Promotion of Science (JSPS), the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan; by a grant from the Naito Foundation; by a grant from the Yamada Science Foundation; and by a grant from the Research Grant of Institute of Natural Science at Nihon­ University for 2023.
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Abstract

A method for preparing important building blocks for natural product synthesis has been developed using singlet oxygen generated from 5,10,15,20-tetraphenylporphyrin under blue LED irradiation. Using this method, the allylic oxidation of dicyclopentadiene proceeded smoothly in air atmosphere with an 87% yield. The conditions, using TPP under blue LED irradiation, were expanded to include the oxidation of cyclopentadiene. The approach offers a simple and cost-effective method of synthesizing important building blocks for natural product synthesis.


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Key words

5,10,15,20-tetraphenylporphyrin - blue LED - air atmosphere - singlet oxygen - dicyclopentadiene - cyclopentadiene

The allylic oxidation of dicyclopentadiene (1) using singlet oxygen generated with O2 bubbling and 5,10,15,20-tetraphenylporphyrin (TPP) under light irradiation conditions is a well-known reaction (Scheme [1]A).[1] [2] The resultant enone 2 has been used for the syntheses of numerous natural products. For example, Stoltz, Grubbs, and co-workers reported the enantioselective synthesis of 15-deoxy-Δ12,14-prostaglandin J2 (5) from enone 2 (Scheme [1]B).[3] Thus, racemic enone 2, synthesized by the allylic oxidation of dicyclopentadiene (1) using singlet oxygen generated from TPP under high-pressure sodium-vapor lamp irradiation, was converted into chiral acetate 3 and chiral alcohol 4 by a stereoselective reduction and an enzymatic kinetic resolution sequence, and acetate 3 was transformed into 15-deoxy-Δ12,14-prostaglandin J2 (5) in eight steps. Also, Ogasawara and co-workers reported the asymmetric total synthesis of (–)-goniomitine (6) using this chiral alcohol 4.[4] Our group used this enone 2 for the synthetic study of yuzurimine-type alkaloids and SB-203207.[5] On the other hand, oxidation of cyclopentadiene (7) using singlet oxygen to yield cis-2-cyclopentene-1,4-diol (8) is also a well-known reaction (Scheme [1]C). Generally, this oxidation utilizes rose bengal as a photosensitizer under various light irradiation conditions, typically using a mercury lamp.[6] Also, conditions using 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TPFPP)[7] or a polymer-supported platinum catalyst[8] as a photosensitizer under irradiation using various lamps have been reported. This meso-diol 8 was converted into chiral acetate 9 through diacetylation and enzymatic desymmetrization.[9] Chiral acetate 9 is a widely used chiral building block in natural product synthesis. For example, Overman and co-workers reported the total synthesis of strychnine (10) from acetate 9.[10] Also, Stork and co-workers achieved the asymmetric total synthesis of prostaglandin F2α (11) using acetate 9 (Scheme [1]D).[11] Furthermore, diol 8 was used for the synthesis of untenone A and its derivatives by Kobayashi and co-workers[12] and for the synthetic study of bilobalide by Yokoshima and co-workers.[13] Thus, enone 2 and diol 8 are important building blocks for natural product synthesis.

However, reactions employing singlet oxygen encounter two primary issues: (1) significant O2 consumption due to the reaction conditions requiring O2 bubbling and (2) safety concerns arising from the prolonged need for O2 bubbling during the reaction. In 2018, Iwabuchi and co-workers reported the synthesis of peroxide 12, an intermediate in the allylic oxidation of dicyclopentadiene (1), employing an O2 atmosphere condition (using an O2 balloon), TPP, and irradiation using a fluorescence lamp, in 65% yield (Scheme [2]A).[14] Additionally, Trauner and co-workers reported the allylic oxidation of dicyclopentadiene (1) using the conditions reported by Mihelich and co-workers[1] employing an O2 balloon instead of O2 bubbling in moderate yield (Scheme [2]B).[15] The development of these reaction conditions represents pioneering efforts to minimize the consumption of O2. In 2023, DiLabio, Wulff, and co-workers reported the allylic oxidation of dicyclopentadiene (1) under an air atmosphere (Scheme [2]C).[16] However, these reaction conditions involved a very long time (27 days). Inspired by these reports, we aimed to develop reaction conditions suitable for the oxidation of dicyclopentadiene (1) and cyclopentadiene (7). In this paper, we present efficient oxidation conditions for dicyclopentadiene (1) and cyclopentadiene (7) using TPP under blue LED irradiation and an air atmosphere.

Zoom Image
Scheme 1 Syntheses of enone 2 and diol 8, and their application to natural product synthesis
Zoom Image
Scheme 2 Recent progress in the oxidation of dicyclopentadiene (1) using singlet oxygen generated from TPP under light irradiation

First, we optimized the reaction conditions for the allylic oxidation of dicyclopentadiene (1) (Table [1]). We screened a series of lamps for this reaction (entries 1–4) and found that under halogen lamp[16] irradiation, the desired enone 2 was obtained in 13% yield (entry 1). We examined the use of a fluorescence lamp[14] in this oxidation and the resulting enone 2 was obtained in 25% yield (entry 2). The use of a white LED[14] yielded the same result as with the fluorescence lamp (entry 3). Several instances of the generation of singlet oxygen using TPP and blue or green LED irradiation were reported recently.[17] Therefore we employed a blue LED (entry 4), which resulted in a slight increase in yield (cf. entries 1–3). Following these results, we found that the use of a blue LED was suitable for this allylic oxidation. We then conducted this reaction using an O2 balloon instead of O2 bubbling (entry 5) and found that the yield decreased slightly to 23%. When the reaction time was extended to 92 hours under an O2 atmosphere, enone 2 was obtained in 81% yield on a 6.0 g scale (entry 6). Surprisingly, this reaction under an air atmosphere yielded equivalent results (87%) to those obtained under an O2 atmosphere (entry 7). Because TPP is expensive, we next investigated the reaction conditions using rose bengal[6] [18] (0.01 mol%) as a photosensitizer (entries 8–11). However, almost no reaction took place under various sources of light irradiation; we assumed that the rose bengal decomposed under the conditions given in Table [1], entry 11. Thus, we investigated this reaction using an increased amount of rose bengal (0.1 mol%), but the yield remained low (3%) (entry 12). These results indicated that the stability of the photosensitizer was an important factor in this reaction.[19] From these results, we decided that the optimal reaction condition involved the use of TPP under blue LED irradiation and an air atmosphere (entry 7).

Table 1 Optimization of Allylic Oxidation of Dicyclopentadiene (1)a

Entry

Photosensitizer (mol%)

Bubbling or atmosphere

Lamp (power, W)

Time (h)

Yield (%)

 1

TPP (0.01)

O2 bubbling

halogen (150)

 7.5

13

 2

TPP (0.01)

O2 bubbling

fluorescence (22)

10

25

 3

TPP (0.01)

O2 bubbling

white LED (12)

10

27

 4

TPP (0.01)

O2 bubbling

blue LED (24)

10

35

 5

TPP (0.01)

O2 atmosphere

blue LED (24)

22

23

 6

TPP (0.01)

O2 atmosphere

blue LED (24)

92

81

 7

TPP (0.01)

air atmosphere

blue LED (24)

93

87

 8

rose bengal (0.01)

O2 atmosphere

halogen (150)

24

 3

 9

rose bengal (0.01)

O2 atmosphere

fluorescence (22)

24

 2

10

rose bengal (0.01)

O2 atmosphere

white LED (12)

24

 2

11

rose bengal (0.01)

O2 atmosphere

blue LED (24)

24

 0.1

12

rose bengal (0.1)

O2 atmosphere

blue LED (24)

24

 3

a Reaction conditions: 1 (45.4 mmol), pyridine (22.7 mmol), Ac2O (49.9 mmol), DMAP (0.908 mmol), CH2Cl2 (0.4 M).

We then applied our established conditions (using TPP under blue LED irradiation) for the oxidation of cyclopentadiene (7) (Table [2]), using 0.2 mol% TPP and thiourea (0.67 equiv) in MeOH under an O2 atmosphere and blue LED irradiation (entry 1).[6] The desired diol 8 was obtained in a 54% yield. We then extended the reaction time to 20 hours (entry 2); however, the yield of diol 8 decreased slightly (44%). Under the conditions given in entries 1 and 2, it was difficult to dissolve TPP in MeOH, so we attempted to use CH2Cl2 as a reaction solvent, but this gave a yield of only 9% (entry 3). In this case, it was difficult to dissolve thiourea in CH2Cl2­. Therefore, we investigated a mixed solvent of MeOH and CH2Cl2 and found that the yield increased to 68% (entry 4). This yield suggested that there was an insufficient amount of thiourea (0.67 equiv). When we attempted this oxidation with a 1.0 equivalent of thiourea, the yield of diol 8 increased slightly to 75% (entry 5). When we used 0.2 mol% TPP, the light permeability was not good; therefore, we reduced the amount of TPP to 0.01 mol% and observed an improved yield of this oxidation, reaching 84% (entry 6). Considering an increase in the reaction concentration to facilitate the scale-up process, we conducted the reaction at 0.2 M concentration on a 10 g scale and found that the yield was maintained (85%) (entry 7). Finally, we attempted this oxidation under an air atmosphere instead of an O2 atmosphere. The oxidation reaction proceeded under an air atmosphere, resulting in the desired diol 8 with a 61% yield (entry 8). In contrast, extending the reaction time to 6 hours under the same reaction conditions did not improve the yield (63%) (entry 9). Based on the outcomes from entries 8 and 9, our established reaction conditions enabled the oxidation of cyclopentadiene (7) under an air atmosphere in approximately 60% yield. It can be concluded that the optimal conditions for the oxidation of cyclopentadiene (7) involve using a mixed solvent of MeOH and CH2Cl2, TPP (0.01 mol%) under blue LED irradiation, and an O2 atmosphere.

Table 2 Optimization of Oxidation of Cyclopentadiene (7)a

Entry

TPP (mol%)

Thiourea (equiv)

Solvent (M)

O2/air

Time (h)

Yield (%)

1

0.2

0.67

MeOH (0.05)

O2

 3

54

2

0.2

0.67

MeOH (0.05)

O2

20

44

3

0.2

0.67

CH2Cl2 (0.05)

O2

 3

9

4

0.2

0.67

MeOH/CH2Cl2 (0.05)

O2

 3

68

5

0.2

1.0

MeOH/CH2Cl2 (0.05)

O2

 3

75

6

0.01

1.0

MeOH/CH2Cl2 (0.05)

O2

 3

84

7b

0.01

1.0

MeOH/CH2Cl2 (0.2)

O2

 3

85

8

0.01

1.0

MeOH/CH2Cl2 (0.05)

air

 3

61

9

0.01

1.0

MeOH/CH2Cl2 (0.05)

air

 6

63

a Reaction conditions: 7 (7.56 mmol).

b Reaction conditions: 7 (151 mmol).

In conclusion, we have developed an allylic oxidation reaction of dicyclopentadiene (1) under an air atmosphere condition using TPP and blue LED irradiation. These conditions do not require O2 bubbling or even an O2 atmosphere (O2 balloon), and were also applicable to the oxidation of cyclopentadiene (7). This reaction represents a simple and cost-effective method of synthesizing important building blocks utilized in natural product synthesis. Because high-pressure sodium-vapor lamps[20] and mercury lamps[20] are no longer available for purchase, employing blue LED irradiation for this oxidation reaction instead of these lamps is highly beneficial. By simply replacing such lamps with a blue LED lamp, this method efficiently generates singlet oxygen without the need for additional oxygen. Therefore, we believe that this method should be shared widely with synthetic organic chemists. Further investigation to apply these reaction conditions to more complex substrates is in progress.

All reactions were performed either with O2 bubbling or under an O2 or air atmosphere. Anhydrous MeOH and CH2Cl2 were purchased from Kanto Chemical Co., Inc. or Wako Pure Chemical Industries Ltd. and used without further drying. For light irradiation, no-bland blue LED lamp for coral growth (ca. 450 nm, 24 W, 12 blue LEDs), TOSHIBA LDR12N-W/150W white LED (12 W), HATAYA MH-C15 minihalogen light (150 W), and Panasonic EFR25ED/22-SP F fluorescence lamp (22 W) were employed. TLC analysis was conducted on E. Merck precoated silica gel 60 F254 (0.25 mm layer thickness). Reaction components were visualized by UV-light irradiation (254 nm) and staining with p-anisaldehyde in 10% sulfuric acid in CLYNSOLVE P (containing 95.8% EtOH and 4.2% i-PrOH). Fuji Silysia silica gel PSQ 100B was used for column chromatography. Melting points were measured with an AS ONE ATM-02 melting-point apparatus. Infrared (IR) spectra were recorded with a JASCO FT/IR-460 Plus spectrophotometer using NaCl plate, and only selected peaks are reported (wavenumbers, cm–1). 1H and 13C NMR spectra were recorded with a JEOL JNM-ECA 500 spectrometer. The 1H and 13C chemical shifts (δ) are reported in parts per million (ppm) downfield relative to solvent peaks: δH = 7.26 ppm for CDCl3 (residual CHCl3), δC = 77.0 ppm for CDCl3. J values are given in Hz. The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. High-resolution electron ionization/time-of-flight (EI/TOF) and field ionization/time-of-flight (FI/TOF) mass spectra were recorded with a JEOL JMS-T100GCV spectrometer.


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Typical Procedure (Table [1], entry 7)

To a stirred solution of dicyclopentadiene (1) (6.12 g, 46.3 mmol) in CH2Cl2 (120 mL) was added pyridine (1.90 mL, 23.5 mmol), Ac2O (5.60 mL, 59.2 mmol), DMAP (114 mg, 0.933 mmol), and TPP (2.8 mg, 4.6 µmol) at r.t. The reaction mixture was irradiated with blue LED light (ca. 450 nm, 24 W) at r.t. for 93 h. The reaction mixture was poured into a sat. aq. NaHCO3 (100 mL) at 0 °C, and the organic layer was separated. The organic layer was washed with sat. aq. NaHCO3 (100 mL), 1.0 M aq. HCl (100 mL), sat. aq. CuSO4 (2 × 75 mL), and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (41.3 g, n-hexane–CHCl3, 1: 1 to 1: 3) to afford enone 2.

Yield: 5.87 g (40.2 mmol, 87%); white solid; mp 63–64 °C (Lit.[2b] 63.5–64.7 °C).

IR (neat): 2980, 2970, 1697, 1580, 1337, 1195, 850, 780, 644 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.37 (dd, J = 6.0, 2.0 Hz, 1 H), 5.95 (dd, J = 6.0, 1.5 Hz, 1 H), 5.93 (dd, J = 5.5, 2.5 Hz, 1 H), 5.77 (dd, J = 5.5, 2.5 Hz, 1 H), 3.41 (m, 1 H), 3.22 (m, 1 H), 2.96 (m, 1 H), 2.79 (dd, J = 5.5, 5.5 Hz, 1 H), 1.76 (ddd, J = 8.0, 2.0, 2.0 Hz, 1 H), 1.63 (d, J = 9.0 Hz, 1 H).

13C NMR (125 MHz, CDCl3): δ = 210.8, 164.6, 136.9, 132.5, 132.3, 52.7, 50.2, 48.2, 45.0, 44.0.

HRMS (EI-TOF): m/z [M]+ calcd. for C10H10O: 146.0732; found: 146.0732.


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Typical Procedure (Table [2], entry 7)

To a stirred solution of cyclopentadiene (7) (12.5 mL, 152 mmol) in a mixed solvent of MeOH/CH2Cl2 (380 mL/380 mL) were added TPP (9.4 mg, 15 µmol) and thiourea (11.6 g, 152 mmol). An O2 balloon was attached and the flask was placed under O2 gas. The reaction mixture was irradiated with blue LED light (ca. 450 nm, 24 W) at r.t. for 3 h, then concentrated. The crude product was purified by column chromatography on silica gel (159 g, n-hexane–EtOAc, 1: 2 to 0:1) to afford diol 8.

Yield: 13.0 g (129 mmol, 85%); white solid; mp 58–59 °C (Lit.[6a] 59–60 °C).

IR (neat): 3324, 2868, 1409, 1351, 1064, 1016, 1002, 875 cm–1.

1H NMR (500 MHz, CDCl3): δ = 5.97 (s, 2 H), 4.61 (dd, J = 6.0, 3.0 Hz, 2 H), 3.91 (s, 2 H), 2.68 (ddd, J = 14.0, 6.5, 6.5 Hz, 1 H), 1.53 (ddd, J = 14.0, 3.0, 3.0 Hz, 1 H).

13C NMR (125 MHz, CDCl3): δ = 136.3 (2C), 74.8 (2C), 43.3.

HRMS (FI-TOF): m/z [M]+ calcd. for C5H8O2: 100.0524; found: 100.0525.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We would like to thank Drs. Eiyu Imai and Toshihiko Nogawa (RIKEN) for the HREIMS and HRFIMS analyses.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2361-0069.
  • Supporting Information

Corresponding Author

Ichiro Hayakawa
Graduate School of Integrated Basic Sciences, Nihon University
3-25-40 Sakurajosui, Setagaya-ku, Tokyo, 156-8550
Japan   

Publikationsverlauf

Eingereicht: 25. Juni 2024

Angenommen nach Revision: 05. Juli 2024

Accepted Manuscript online:
05. Juli 2024

Artikel online veröffentlicht:
22. Juli 2024

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Zoom Image
Scheme 1 Syntheses of enone 2 and diol 8, and their application to natural product synthesis
Zoom Image
Scheme 2 Recent progress in the oxidation of dicyclopentadiene (1) using singlet oxygen generated from TPP under light irradiation