Preparation of Substituted Enol Derivatives From Terminal Alkynes and Their Synthetic Utility

Abstract

Stereodefined enol derivatives of aldehydes are prepared from terminal alkynes. Specifically, terminal alkynes are known to undergo Cp₂ZrCl₂-catalyzed methylalumination. Here, we show that the resultant vinylalanes can be oxygenated with peroxyzinc species to generate trisubstituted enolates. Electrophilic trapping with carboxylic anydrides or silyl triflates yields trisubstituted enol esters or silanes, respectively. The tandem carbometalation/oxygenation tolerates free and protected alcohols, heterocycles, olefins and nitriles. Likewise, amination can be accomplished using azodicarboxylates. Stereodefined enol esters can undergo asymmetric dihydroxylation to yield optically-active α-hydroxy aldehydes. Reduction with NaBH₄ provides the diols of 1,1-disubstituted olefins in excellent ee. An application of this methodology to the enantioselective synthesis of the insect pheromone frontalin is presented. Finally, α-hydroxy aldehydes are shown to undergo homologation to a terminal alkyne, reductive amination, oxidation and olefination. Preliminary results indicate that tandem carbometalation/amination can be accomplished with azodicarboxylates. In this way, ene-hydrazines are formed in excellent yield.

Stereodefined enol derivatives of α-branched aldehydes (4) represent valuable building blocks for organic synthesis, but limited access to them has compromised their utility. They are most often prepared from the corresponding aldehyde, although these approaches generally afford mixtures of olefin stereoisomers.¹ Furthermore, current strategies for obtaining the α-substituted aldehydes themselves are limited in reaction scope and require multiple synthetic operations.² An alternative synthesis of trisubstituted enol derivatives might involve tandem carbometalation-oxygenation of terminal alkynes (Scheme 1). In this regard, we previously documented the carbocupration-oxygenation of terminal alkynes, in which a vinyl copper intermediate (2, M = Cu) was oxidized with ^tBuOOLi.³ Electrophilic trapping of the resultant E-enolate (3) generated E-enol esters and silanes. However, methyl-substituted products were not accessible by this method because methyl-cupration of alkynes is not efficient.⁴ Accordingly, we sought a general method for obtaining methyl-substituted enol esters and ethers (4, R′=Me). As described below, we have accomplished this objective and have begun to explore the asymmetric transformations of stereodefined enol derivatives.

Scheme 1.

Negishi’s catalytic methylalumination reaction provides a complimentary method for carbometalation.⁵ Methylalumination-oxygenation of monosubstituted olefins has been reported,⁶ but analogous chemistry of alkynes is unknown (5, Table 1). Trialkyl alanes are oxidized cleanly with molecular oxygen. Therefore, our initial investigations aimed to oxidize alkenyl aluminum intermediates with O₂, but these experiments proved unsuccessful. Under these conditions, incomplete conversion and over-oxidation limited yields. Results with the oxenoid ^tBuOOLi were more promising.⁷ With this reagent, we observed 65% conversion of vinylalane 5a (R = n-C₁₀H₂₁) to the corresponding aldehyde (E⁺ = H) with 2-methyl-1-dodecene accounting for the remainder of the starting material. Further evaluation of peroxymetal oxidants revealed that peroxyzinc reagents EtZnOO^tBu and MeZnOO^tBu effected the oxidation of 5a to the corresponding aldehyde with 85% and 98% conversions, respectively. Thus when 5a was oxidized with freshly prepared MeZnOO^tBu (1.3 equiv to AlMe₃) at 0°C and subsequently trapped with Bz₂O, enol benzoate 4a was obtained in 78% isolated yield (Table 1, entry 1). Zinc peroxides have been used in epoxidation reactions,⁸ but, to the best of our knowledge, they have not been used previously to oxidize carbanions.

Table 1.

Preparation of Enol Derivatives from Terminal Alkynes^a

Entry	Alkyne	EX	Product	Yield (%)b
1	1a	Bz2Oc	R = C10H21; E = Bz	78
2	1b	Bz2Oc	R = CH2Ph; E = Bz	89
3	1c	Bz2Oc		82
4	1d	Bz2Oc	R = Ph; E = Bz	80
5	1e, 1f	Bz2Oc,d		4e: n = 1, 59 4f: n = 2, 79
6	1g	Bz2Oc		71
7	1h	Bz2Oc		83
8	1i, 1j	Bz2Oc		4i: n = 3, 75 4j: n = 4, 76
9	1k	Ac2O		91
10	1l	Ac2O		97
11	1m	Ac2O		92
12	1n	Ac2O		90
13	1o	TESOTf		79
14	1p	TESOTf		83

^a1.0 equiv alkyne, 1.2–4 equiv Me₃Al, 5–30 mol% Cp₂ZrCl₂, 2.5–30 mol%, H₂O or MAO, 0.3 M in CH₂Cl₂; MeZnOO^tBu (0.3M in Toluene, 1.3–1.4 equiv to Me₃Al).

^bIsolated yields (chromatography not necessary for entries 10–14).

^cCatalytic ⁿBu₃P added.

^dBzCl was added after benzoylation of the enolate. See supporting information for complete experimental details.

The methylalumination-oxygenation reaction tolerates considerable functionality including protected and free alcohols, heterocycles, and olefins.⁹ Electrophilic trapping is not limited to benzoylation: enol acetates and TES enol ethers (entries 9–14) were prepared in high yields as well. Furthermore, in every case studied to date, the enol derivative has been isolated as a single regioisomer with a high E-isomer content (all E/Z ratios > 20/1).¹⁰

Trisubstituted, stereodefined enol derivatives of this type were previously inaccessible, and their ready availability allowed us to explore new chemistry and evaluate their synthetic utility. In particular, we envisioned an entry to chiral α-hydroxy aldehydes (7) and 1,2-diols (8) by employing the enol benzoates in catalytic asymmetric dihydroxylation (AD) reactions.^11,12 As expected, the enol benzoate substrates afforded dihydroxylated products in high enantiomeric purity (Table 2, all entries ≥ 94% ee from 4). In contrast, many 1,1-disubstituted olefins (6) are poor substrates for AD; therefore, AD of the enol benzoates, followed by a reductive workup with NaBH₄, presents a highly enantioselective route to these substances. Of note, controlling stereochemistry of the olefin is critical: a 9:1 E/Z mixture of 4a was converted to 8a in 81% ee under the conditions outlined in Table 2. The utility of the AD reaction was exemplified in the total synthesis of the insect pheromone (+)-frontalin (10, Scheme 2).¹³ Enol benzoate 9 was treated consecutively with AD-mix β and [Me₄N]BH(OAc)₃ to yield (+)-frontalin in 93% ee and in 49% overall yield from the commercially available alkyne 1i. In comparison, the 1,1-disubstituted olefin 11 was dihydroxylated with poor selectivity and in low yield with AD-mix β.

Table 2.

Asymmetric Dihydroxylation (AD) of Enol Benzoates^a

Entry	R	ee (%)b from:		Product	Yield (%)c
		4	6
1	nC10H21	96	78	8a	78
2	PhCH2	94		8b	84
3		96		8c	59
4	Ph	95	94d	8d	75
5		96		8g	87
6		95	32	8qe	75

^aAll AD reactions were performed under standard conditions: AD-mix β, 0.1M in ^tBuOH/H₂O, 0°C.

^bUnless noted otherwise, ee’s determined by HPLC. See supporting information for details.

^cIsolated yields from 4.

^d% ee from reference ^11a.

^e1.0 equiv. MeSO₂NH₂ was added to the reaction.

Scheme 2. Total Synthesis of (+)-Frontalin^a.

^aReagents and conditions: (a) PdCl₂, CuCl, O₂, DMF/H₂O (7:1), quant; (b) AD-mix-β, MeSO₂NH₂, NaHCO₃, ^tBuOH/H₂O (1:1), 0 °C, 18 h, 85%; (c) [Me₄N]BH(OAc)₃, AcOH, CH₃CN, 76%; (d) AD-mix-β, ^tBuOH/H₂O, 0 °C.

The enantioenriched α-hydroxy aldehydes obtained from the dihydroxylations are useful materials for further synthetic manipulation (Scheme 3). For example, following AD, an Ohira-Bestmann homologation of aldehyde 7b provided propargylic alcohol 12 in 77% yield. Reductive amination of 7b proceeded smoothly to yield the corresponding amino alcohol (13, 84% yield).¹⁴ Alternatively, the same starting material (7b) could be oxidized to its methyl ester (14, 92%),¹⁵ or undergo olefination to afford an α,β-unsaturated ester (15, 68%, E:Z = 14.3:1).¹⁶

Scheme 3. Transformations of α-hydroxy aldehydes^a.

^aReagents and conditions: (a) (MeO)₂POCN₂COMe, K₂CO₃, MeOH, 0 °C-r.t.; (b) BnNH₂, Toluene, 4Å MS, 105 °C; NaBH₄, MeOH, 0 °C; (c) I₂, KOH, MeOH, 0 °C; (d) Bu₃PCH₂CO₂EtBr, NaHCO₃, Toluene, 90 °C.

Tandem carbometalation-oxidation is not limited to carbon-oxygen bond formation. Indeed, in preliminary experiments we found that vinyl alane 5 could be aminated in high yields with azodicarboxylates (Table 3).¹⁷ Hydrogenation and deprotection of 16f provided the free amine in >90% yield.¹⁸ With access to stereodefined enol and enamine derivatives, future studies will seek to engage these materials in a variety of asymmetric transformations.

Table 3.

Synthesis of Stereodefined Ene-hydrazines (16) from Terminal Alkynes.^a

Entry	R1	R2	Product	Yield (%)b
1	nC10H21	CO2iPr	16a	79
2	CH2Ph	CO2iPr	16b	90
3	-(CH2)3OH	CO2iPr	16c	86
4	-(CH2)3OSi(iPr)3	CO2iPr	16d	83
5	3-Thienyl	CO2iPr	16e	77
6	CH2Ph	CO2tBu	16f	84

^aMethylalumination as in Table 1; 1.5–3 equiv azodicarboxylate. See supporting information for complete experimental details.

^bIsolated yields.