Lewis acid-catalyzed intramolecular condensation of ynol ether-acetals. Synthesis of alkoxycycloalkene carboxylates

Abstract

Treatment of ynol ether-tethered dialkyl acetals with catalytic quantities of scandium triflate in CH₃CN gives rise to five-, six-, and seven-membered alkoxycycloalkene carboxylates in good to excellent yields. Trisubstituted and tetrasubsituted carbocyclic and heterocyclic alkenes may be formed by this method, and the products obtained may serve as useful intermediates for natural product synthesis.

Alkoxycycloalkene carboxylates are highly useful starting materials for organic synthesis (Figure 1). Stereoselective introduction of carbon substituents β to the ester functional group may be accomplished by allylic substitution or Michael addition reactions, as shown by Villieras et al.¹ Ogasawara has prepared the nitraria alkaloids (+)-nitramine, (+)-isonitramine, and (−) sibirine from 2-carboethoxy-2-cyclohexen-1-ol.² Similarly, Iwabuchi’s recent synthesis of idesolide commences from 2-carbomethoxy-2-cyclohexen-1-ol.³ Lupton has also accomplished an elegant total synthesis of 7-deoxyloganin from 2-carboethoxy-2-cyclopenten-1-ol.⁴ In all cases, the hydroxycycloalkene carboxylate starting material is prepared in moderate yields by the Horner-Wadsworth-Emmons reaction of an appropriate dialdehyde with trialkyl phosphonacetate.⁵ Since the efficiency of this protocol is often low, the development of an alternative method for the preparation of cycloalkenol carboxylates of varying ring sizes would clearly be of value for natural product synthesis. In this Letter we report our efforts toward the realization of this goal and detail a novel Lewis acid-catalyzed condensation of ynol ether-acetals that yields alkoxycycloalkene carboxylates in high yields.

Figure 1.

The utility of alkoxycycloalkene carboxylates in natural product synthesis.

Electron-rich alkynes, such as ynamines and ynol ethers, are functional groups that possess significant potential in organic chemistry for the formation of carbon-carbon bonds.⁶ Due to their linear geometry, alkynyl ethers are relatively unhindered to approach by functional groups present in the same or different molecules; furthermore, alkynyl ethers can prospectively form up to three new bonds in a single reaction (Figure 2).

Figure 2.

The reactivity of 1-alkynyl ethers and their transformation to cyclobutanones

We have recently shown that tert-butyl ynol ethers bearing tethered alkenes form substituted cyclobutanones in high yields under mild thermal conditions.^7a In attempting to extend this method to the preparation of β-lactones and lactams through thermolysis of ketone and aldehyde-tethered ynol ethers, we discovered that attempted deprotection of the acetal precursors led to the formation not of the desired carbonyl-containing ynol ethers, but rather of alkoxycycloalkene carboxylates (Scheme 1). Thus, treatment of acetal 2aa( prepared from aldehyde 1a by addition of tert-butoxyethynyllithium^7b and silyl protection of the resulting propargylic alcohol) with 5 mol % I₂ in acetone⁸ at room temperature for five minutes gave rise to silyloxycycloalkene carboxyate 3aa in 45% yield, as well as a 1:1 mixture of the more polar methyl esters 3ab and 3ac in 40% yield. Interestingly, treatment of ethyl alkynyl ether 2ab with Sc(OTf)₃ in CH₃CN led to the formation of ethyl ester 3ad cleanly in 80% yield; however, addition of up to 15 mol % of catalyst was necessary in order to achieve optimal conversion of 2ab to 3ad. On large scale (>500 mg), the increased amounts of Lewis acid catalyst required led to side products arising from cleavage of the silyl ether protecting group and lower (60–70%) yields of 3ad.

Scheme 1.

Attempted deprotection of dimethyl acetals 2aa, 2ab

These initial results prompted us to evaluate the use of other Lewis acids to catalyze the apparent cyclocondensation process (Table 1). Addition of Sc(OTf)₃ (5 mol %) to substrate 2aa in CH₃CN gave a 78% yield of 3aa within 5 minutes at room temperature with only trace amounts of 3ab and 3ac formed. In(OTf)₃^9a and Zn(OTf)2 also provided 3aa, although in significantly lower yields (50% and 25%, respectively); moreover, complete consumption of 2a was never achieved, even with the addition of excess catalyst (up to 15 mol %) to the reaction mixture.

Table 1.

Screen of Lewis acid catalysts for the transformation of 2aa to 3aa.^a

entry	catalyst	solvent	time (min)	% yield 3aab
1	I2	acetone	5	45
2	Sc(OTf)3	CH3CN	5	78
3	In(OTf)3	CH3CN	10	50
4	Zn(OTf)2	CH3CN	10	25
5	AgOTf	CH3CN	10	<5c
6	BiCl3	CH3CN	10	<5c
7	InCl3	CH3CN	60	nr
8	TMSOTfd	CH2Cl2	10	70

^aAll reactions were performed with 5 mol % catalyst in solvent (0.15 M) at room temperature before quenching with saturated NaHCO₃ solution.

^bIsolated yield after silica gel chromatography.

^cSubstrate decomposition occurred.

^dReaction performed at −78 °C for 10 min.

Treatment of 2aa with the Lewis acids AgOTf or BiCl₃^9b in CH₃CN led to significant amounts of substrate decomposition, with only minute quantities (<5%) of 3aa recovered from the reaction mixtures. In contrast, no reaction occurred when 2aa was stirred in the presence of InCl₃, even after one hour. Finally, treatment of 2a with 5 mol % TMSOTf in CH₂Cl₂ at −78 °C gave 3aa in 70% yield after silica gel chromatography.

A possible mechanistic pathway for this process (Scheme 2) might involve Lewis-acid coordination of the acetal oxygen atom, followed by ionization and [2+2] cycloaddition. Loss of isobutylene accompanied by ring opening would then furnish either unsaturated methyl ester 3aa or ketene A. Methanol trap of A would provide 3ac; Lewis-acid mediated allylic substitution of 3aa with the liberated methanol molecule could give rise to 3ab. Ester 3ac does not convert into 3aa upon prolonged exposure to Lewis acid; however, extended reaction times and/or the addition of excess Lewis acid results in the conversion of unsaturated ester 3aa into methyl ether 3ab. A similar pathway from 2ab to 3ad could proceed through S_N2-like cleavage of the oxonium methyl group, followed by pericyclic ring opening of the oxetene intermediate (Scheme 3).¹⁰

Scheme 2.

Possible mechanism for formation of 3aa-3ac.

Scheme 3.

Possible mechanism for formation of 3ad

To explore the scope of this process, substrates 2b-2g (Table 2) were prepared in a similar fashion (see Supporting Information)¹² and treated with catalytic amounts of Lewis acid at room temperature or −78 °C. While scandium triflate was an effective Lewis acid for ketone-derived acetals, TMSOTf proved to be similarly efficient for aldehyde derived acetals. Five- (entries 1–4) and six- (entries 5–7) membered rings may be prepared in good to excellent yields in this manner. Furthermore, both trisubstituted (entries 3 and 7) and tetrasubstituted (entries 1, 2 and 4–6) cycloalkenes are formed with similar efficiencies. Silyl protecting groups employed in cyclization substrates 2 include TBS (entry 2) and TBDPS (tert-butyldiphenylsilyl, entries 1 and 3–7) and are necessary to avoid the facile Meyer-Schuster rearrangement¹¹ that is observed for the corresponding propargylic alcohols under Lewis acidic reaction conditions. It was subsequently discovered (Table 3, entry 2) that protection of tertiary propargylic alcohols as their methyl ethers was also suitable for the cyclocondensation process (vide infra).

Table 2.

Scope of Lewis-acid catalyzed intramolecular cyclocondensation, 2→3.^a

entry	2	3	conditionsb	% yieldc3
1			A	78
2			B	68
3			C	57
4			A	82
5			A	92
6			A	55
7			A	50

^aR¹=tert-butyldiphenylsilyl; R²=tert-butyldimethylsilyl.

^bConditions: A, Sc(OTf)₃ (5 mol %), CH₃CN, rt, 10 min; B, I₂ (5 mol %), acetone, rt, 5 min; C, TMSOTf (5 mol %), CH₂Cl₂, −78 °C, 10 min.

^cIsolated yield after column chromatography.

Table 3.

Preparation of seven-membered cycloalkenes^a

entry	2b	3	yieldc
1			72
2			61
3			68d
4			55d
5			49e

^aReaction conditions: 0.33 M 2 in CH₃CN, Sc(OTf)₃ (10 mol %), rt, 10 minutes.

^bFor preparation of 2i-2m, see Supporting Information and references 13–17.

^cIsolated yield after column chromatography

^dCompounds 2k, 2l, 3k, and 3l are composed of a 2:1 mixture of diastereomers. See text and references 15 and 16.

^eCompounds 2m and 3m are composed of a 3:1 mixture of diastereomers. See text and reference 17.

Extension of this chemistry to the synthesis of seven-membered alkoxycycloalkene carboxylates was also possible. While substrate 2h diappointingly gave only a 5:1 mixture of acyclic ketoester 4 and unsaturated ester 5 upon exposure to catalytic quantities of scandium triflate, under the same conditions diethylacetal 2i gave a 72% yield of the expected ethyl ester 3i (Scheme 4). From these data it appears that substrate preorganization to allow proximity of the ynol ether and acetal termini is important for successful application of this method to the synthesis of medium-ring containing products. Table 3 shows several additional examples of the preparation of trisubsituted (entries 1–3, 5) and tetrasubsituted (entry 4) cycloalkenes containing 5–7 and 6–7 ring systems utilizing this methodology. Seven-membered cyclic ethers such as 3j may be prepared containing a tertiary methyl ether (entry 2). Moreover, fused 5–7 ring systems similar to that found in guaiane-type sesquiterpene natural products (m, entry 5) could also be synthesized in moderate yields. Compounds 2k-2m and 3k-3m were obtained as a mixture of diastereomers (2:1 for 2k, 2l, 3k, and 3l, and 3:1 for 2m and 3m) resulting from the low stereoselectivity of the addition of (ethoxyethynyl)lithium to the corresponding aldehyde precursors.

Scheme 4.

Requirements for seven-membered ring formation

In summary, we have shown that acetal-tethered alkynyl ethers undergo facile intramolecular condensation reactions under Lewis acid catalysis to form 5, 6, and 7-membered alkoxycycloalkene carboxylates, compounds which are useful intermediates for natural product synthesis. We are currently exploring methods for the preparation of optically-enriched cycloalkene carboxylates from the asymmetric addition of alkynyl ether anions to aldehyde and ketones, and the results of this study will be reported in due course.