Highly efficient synthesis of medium-sized lactones via oxidative lactonization: concise total synthesis of isolaurepan

Abstract

A catalytic amount of TEMPO in the presence of PhI(OAc)₂ effected oxidative lactonization of 1,6- and 1,7-diols, directly affording seven- and eight-membered lactones, respectively, in good yields.

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Lactone is a common structural motif widely found in biologically active natural products and pharmaceuticals. In addition, a number of synthetic methods for functionalization of lactones are currently available, making them especially useful synthetic intermediates for the preparation of cyclic ethers.¹ Thus, the development of practical synthetic methods for lactones continues to be an important and fundamental research in organic synthesis.²

A variety of methods for the synthesis of medium-sized lactones via the formation of the ester linkage have been reported, which generally involve activation of an ω-hydroxy acid precursor (Scheme 1, strategy A). However, ω-hydroxy acids are often prepared from differentially protected α,ω-diols via multi-step synthesis including oxidations and protective group manipulations. In contrast, the synthesis of lactones via oxidative lactonization of α,ω-diols represents a more direct and step-economical strategy due to the fact that oxidation and lactonization occur in a single flask and that protecting group chemistry is not necessary (Scheme 1, strategy B).^3,4 In fact, there has been growing interest in oxidative lactonization of α,ω-diols in recent years. There are a number of precedents that describe oxidative lactonization of 1,4- and 1,5-diols, although most of the reported examples utilized meso-diols. In contrast, there are only a few specific examples for oxidative lactonization of seven- and eight-membered lactones⁵ presumably because of the increased enthalpic and entropic penalties associated with their formation.⁶ Thus, the development of a practical and efficient method for oxidative lactonization of α,ω-diols remains a significant challenge for organic chemists.

Scheme 1 Schematic presentation of lactonization strategies for the synthesis of medium-sized lactones

Herein we report that oxidative lactonization of 1,6- and 1,7-diols using a catalytic amount of TEMPO and PhI(OAc)₂ as stoichiometric oxidant⁷ proceeds efficiently to provide synthetically useful seven- and eight-membered lactones, respectively, in good yields.⁸ The remarkable efficiency of the TEMPO/PhI(OAc)₂-mediated oxidative lactonization strategy was highlighted by its successful implementation to a concise total synthesis of (±)-isolaurepan.^9,10

Piancatelli, Margarita, and co-workers have reported that TEMPO/PhI(OAc)₂ oxidizes alcohols to carbonyl compounds in CH₂Cl₂ at room temperature.⁷ Moreover, primary alcohols can be selectively oxidized in the presence of secondary alcohols under these conditions. Forsyth et al. have reported the synthesis of δ-lactones by TEMPO/PhI(OAc)₂ oxidation of 1,5-diols.^3j Based on these precedents, we investigated the scope of the TEMPO/PhI(OAc)₂-mediated oxidative lactonization⁸ by using various substrates with or without conformational constraint (Table 1). In contrast to the previous synthesis of 2¹¹ that relied on Yamaguchi lactonization¹² of the corresponding hydroxy acid using a high-dilution technique, the TEMPO/PhI(OAc)₂-mediated oxidative lactonization directly afforded 2 from 1,6-diol 1 in 93% yield under non-high-dilution conditions (0.1 M) (entry 1). Even under a higher concentration (0.3 M) and on a large scale, 2 was isolated in 83% yield after single recrystallization, and the formation of dimer or higher oligomers was not observed (entry 2). Hence we were able to synthesize >15 grams of 2 in a single experiment. Importantly, 2 is a versatile intermediate in the synthesis of marine polycyclic ethers.¹³ A variety of 1,6-diols 3, 5, 7, 9, 11, 13, and 15 could be cleanly oxidized under the TEMPO/PhI(OAc)₂ conditions to afford the respective seven-membered lactones 4, 6, 8, 10, 12, 14a,b, and 16⁴ⁿ in good to excellent yields (entries 3–10).‡ Oxidative lactonization of 1,6-diol 17 required some optimization. Treatment of 17 with 10 mol% of TEMPO and 2.5 equiv of PhI(OAc)₂ in CH₂Cl₂ (0.1 M, room temperature) gave the desired lactone 18 in 40% yield (entry 11). Increasing both the amount of the reagents and the concentration of the reaction mixture was beneficial, giving 18 in 69% yield (entry 12). Thus, it seems that TEMPO/PhI(OAc)₂-mediated oxidative lactonization is generally applicable to the synthesis of seven-membered lactones from 1,6-diols. We were pleased to find that oxidative lactonization of 1,7-diol 19 proceeded to afford eight-membered lactone 20 in good yield (entry 13), which should be useful as an intermediate for the synthesis of eight-membered unsaturated cyclic ether Laurencia metabolites, as exemplified by (+)-laurencin.¹⁴ However, 1,7-diol 21 did not give the corresponding eight-membered lactone; instead the hydroxy aldehyde 22 was isolated in 80% yield (entry 14).

Table 1 Oxidative lactonization of various α,ω-diols

Entry	Diol	Lactone	Yield%
a TEMPO (10 mol%), PhI(OAc)2 (2.5 equiv), CH2Cl2 (0.1 M), room temperature.b TEMPO (20 mol%), PhI(OAc)2 (2.2 equiv), CH2Cl2 (0.3 M), room temperature.c TEMPO (10 mol%), PhI(OAc)2 (2.5 equiv), CH2Cl2 (0.5 M), room temperature.d TEMPO (30 mol%), PhI(OAc)2 (5 equiv), CH2Cl2 (0.5 M), room temperature.
1^a			93
2^b			83
	1	2
3^a			95
	3	4
4^a			98
	5	6
5^a			85
	7	8
6^a			62
7^c			76
	9	10
8^a			54
	11	12
9^a			100 (14a:14b = 51 : 49)
	13	14a
		14b
10^a			63
	15	16
11^a			40
12^d			69
	17	18
13^a			67
	19	20
14^a			80
	21	22

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The effectiveness of our developed TEMPO/PhI(OAc)₂-mediated oxidative lactonization strategy was demonstrated in a concise total synthesis of (±)-isolaurepan (23) (Scheme 2). The synthesis commenced with allylation of 1-heptanal to give homoallylic alcohol 24. Olefin cross-metathesis^15,16 of 24 with 3-buten-1-ol afforded olefin 25 as a 1.6 : 1 mixture of E/Z isomers, which was hydrogenated to deliver diol 26 in 53% overall yield.¹⁷ Treatment of diol 26 with 10 mol% of TEMPO and 2.5 equiv of PhI(OAc)₂ in CH₂Cl₂ (0.1 M) at room temperature directly afforded seven-membered lactone 27 in 73% yield. Introduction of a propyl side chain was achieved via the intermediacy of a lactone-derived enol phosphate. Thus, enolization of lactone 27 with KHMDS in the presence of (PhO)₂P(O)Cl generated the corresponding enol phosphate, which without isolation was alkylated using an organocopper reagent.¹⁸ The resulting enol ether 28 was sensitive to hydrolysis during chromatographic purification. Thus, upon isolation, 28 was immediately treated with TMSOTf/Et₃SiH to furnish (±)-isolaurepan (23) in 74% overall yield from 27 as a single diastereomer. The ¹H, ¹³C NMR, and HRMS spectra of synthetic 23 matched those reported in the literature.^9,10 The present total synthesis proceeded in only six steps from 1-heptanal with an overall yield of 29%, which constitutes the most concise and high-yielding synthesis hitherto reported.

Scheme 2 Total synthesis of (±)-isolaurepan. Reagents and conditions: (a) allylMgCl, THF, 0 °C; (b) 3-buten-1-ol, Grubbs’ 2nd-generation catalyst, CH₂Cl₂, 40 °C; (c) H₂, Pd/C, EtOAc, room temperature, 53% (three steps); (d) TEMPO (10 mol%), PhI(OAc)₂ (2.5 equiv), CH₂Cl₂ (0.1 M), room temperature, 73%; (e) KHMDS, (PhO)₂P(O)Cl, HMPA, THF, −78 °C; then n-PrMgBr, CuI, Me₂S, −30 °C; (f) TMSOTf, Et₃SiH, CH₂Cl₂, 0 °C, 74% (two steps).

In summary, we have developed an efficient method for the synthesis of medium-sized lactones based on the TEMPO/PhI(OAc)₂-mediated oxidative lactonization of α,ω-diols, which is operationally simple and cost effective and proceeds cleanly even under high concentration conditions without the formation of dimer or higher oligomers. In addition, the TEMPO/PhI(OAc)₂-oxidative lactonization strategy alleviates protective group chemistry as well as separate oxidation steps. These features highlight the efficiency and practicality of the oxidative lactonization strategy, being suitable even for multi-gram scale preparation of synthetically useful medium-sized lactones. The remarkable efficiency of the synthesis of (±)-isolaurepan demonstrates the power and usefulness of the oxidative lactonization strategy in the synthesis of medium-sized cyclic ethers.

Acknowledgements

We thank Mr. Kazuya Ishigai for his contributions to the early stage of this work. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Representative experimental procedure and spectroscopic data for all newly synthesized products. See DOI: 10.1039/b919673k

‡ For oxidative lactonization of 9, we have also evaluated other oxidation reagents such as Ag₂CO₃ on Celite, PCC, TPAP/NMO, Dess–Martin periodinane, and IBX and found that TEMPO/PhI(OAc)₂ is far superior to these oxidants.

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