Asymmetric Synthesis of Hydrobenzofuranones via Desymmetrization of Cyclohexadienones using the Intramolecular Stetter Reaction

Abstract

Dearomatization of phenols followed by oxidation affords cyclohexadienyloxyacetaldehydes, which produce hydrobenzofuranones via asymmetric intramolecular Stetter reaction in good to excellent yield. Quaternary as well as up to three contiguous stereocenters may be formed in good to excellent enantioselectivities and high diastereoselectivities.

Dearomatization of aromatic compounds provides a useful alicyclic synthetic building block due to its high economy and simple elegance.¹ When coupled with a stereoselective process, it has the potential for affording enantioenriched material from commonly available precursors in rapid fashion.² Reactivity umpolung³ affords an opportunity to take advantage of unobvious, complementary bond disconnections in the synthesis of complex molecules. One such reaction is the Stetter reaction, the nucleophile-catalyzed addition of an aldehyde to a Michael acceptor.⁴ If the Michael acceptor involves a prochiral alkene, this reaction generates new stereocenters.⁵ We have recently developed a family of catalysts capable of inducing highly enantioselective intramolecular Stetter reactions.⁶ As part of an effort to extend the power of this transformation, we considered that cyclohexadienones, readily available from dearomatization of phenols,⁷ could be suitable substrates for a desymmetrizing Stetter reaction. Herein we disclose that treatment of such substrates with chiral triazolium salts affords, in high yields and enantioselectivities, hydrobenzofurans, which are core skeletons found in many natural products.⁸

The requisite substrates are readily accessible from the corresponding phenols (Scheme 1). Hypervalent iodine reagents are used in conjunction with glycol to afford the dienone alcohols in good yield, whereupon Dess-Martin oxidation leads to the aldehydes and sets the stage for the asymmetric Stetter reaction. Upon cyclization, the desired product hydrobenzofuranones would contain at least two contiguous stereocenters.

Scheme 1.

Asymmetric Synthesis of Hydrobenzofuranones

The reactivity of a series of catalysts⁶ was studied using substrate 1 (eq 1). The reactions were conducted in the presence of 20 mol% catalyst and 20 mol% KHMDS in toluene at 25 °C, and proceeded to completion in less than 5 min affording desired product 2. Aminoindanol-derived triazolium salt 3 bearing an anisyl substituent was found to be the best catalyst precursor for this reaction, again reflecting the subtle impact of electronics arising from aryl substitution.⁶

A range of substrates was synthesized following the general procedure (Scheme 1). Under optimized conditions,⁹ the asymmetric intramolecular Stetter reaction proceeds very well, Table 1. The enantioselectivities are excellent (92-94 % ee) when groups at the 4-position of the substrates are methyl, ethyl, isopropyl and tert-butyl (entries 1-4). Aromatic substituents result in slightly lower, but still synthetically useful enantioselectivities (Table 1, entries 5-6). Similar effects are observed with more functionalized sidechains at that position, entries 7-9. With all substrates, the reaction proceeds with very high diastereoselectivities (> 95:5 by ¹H NMR).¹⁰

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Table 1.

Asymmetric Intramolecular Stetter Reaction of Mono-Substituted Cyclohexadienones

entrya	R	substrate	product	Yield (%)	ee (%)b
1	Me	1	2	90	92
2	Et	6	7	86	94
3	iPr	8	9	87	94
4	tBu	10	11	86	94
5	Ph	12	13	87	88
6	4-BrPh	14	15	78	85
7	CH2OAc	16	17	86	83
8	CH2CH2OMe	18	19	86	82
9	CH2CH2CO2Me	20	21	94	87

^aAll reactions conducted in the presence of 10 mol% catalyst and 10 mol% KHMDS in toluene at 23 °C.

^bDetermined by HPLC or GC using a chiral stationary phase.

We have previously documented the ability of the Stetter reaction to form contiguous stereocenters with trisubstituted alkene acceptors.^6d The use of 2,4,6-trisubstituted phenols as precursors in this chemistry allow a rapid entry into suitably functionalized substrates to test whether the desymmetrization would proceed. In the event, the dienone derived from 2,4,6-trimethylphenol proved remarkably efficient. This reaction provides hexahydrobenzofuranone 23 possessing three contiguous stereocenters in excellent yield and ee, entry 1 in Table 2. The reaction is tolerant of alkoxymethyl groups at the 2-position, providing 25 in excellent ee and good yield, entry 2. No elimination of the methoxy group is observed under these conditions. Remarkably, this reaction is also tolerant of as many as three tert-butyl groups in the vicinity of the reaction center and the substrates provide one (entry 3), or two (entry 4) neopentyl stereocenters in excellent selectivity. In each of the cases examined to date, a single diastereomer is formed.¹⁰

Table 2.

Reaction of Tri-Substituted Substrates

Entrya	Substrate	Product	Yield (%)	ee (%)b
1			86c	>99
2			71c	99
3			80d	>99
4			62d	>99

^aSee Table 1.

^bSee Table 1.

^cReaction time: 5 min.

^dReaction time: 2h.

Commercially available 3,4,5-trimethylphenol provides an opportunity to test whether this approach is capable of forming quaternary stereocenters as per our previous report.^6c In the event cyclization of substrate 30 affords one quaternary stereocenter adjacent to a tertiary ether in excellent enantioselectivity and good yield (eq 2).

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Although the bulk of our work focused on oxygen-tethered substrates due to their accessibility, the reaction is also capable of forming carbocycles. To that end, when 32 is subjected to the reaction conditions, hydrindane 33 is isolated in good yield and 90% ee, eq 3.

In conclusion, a family of phenol-derived substrates have been

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successfully synthesized and found to undergo asymmetric intramolecular Stetter reactions in very good yields. Quaternary stereocenters and up to three contiguous stereocenters may be formed in excellent enantioselectivities and diastereoselectivities.