Enantioselective Conversion of Primary Alcohols to α-Exo-Methylene γ-Butyrolactones via Iridium Catalyzed C-C Bond Forming Transfer Hydrogenation: 2-(Alkoxycarbonyl)allylation

Abstract

Upon exposure of acrylic ester 1 to alcohols 2a–2i in the presence of a cyclometallated iridium catalyst modified by (−)-TMBTP, catalytic C-C coupling occurs to provide enantiomerically enriched 5-substituted α-exo-methylene γ-butyrolactones 3a–3i. Bromination of the methylene butyrolactone products followed by zinc mediated reductive aldehyde addition provides the disubstituted α-exo-methylene γ-butyrolactones 6a and 6b with good to excellent levels of diastereoselectivity.

α-Exo-methylene γ-butyrolactones display an enormous array of biological activities and constitute approximately 10% of the >30,000 known natural products.¹ Among methods for their preparation, carbonyl addition triggered lactonization reactions involving 2-(alkoxycarbonyl)allylmetal reagents are especially convergent protocols. To date, discrete 2-(alkoxycarbonyl)allylmetal reagents based on boron,² silicon,³ tin⁴ and zinc⁵ have been utilized in this capacity. Additionally, umpoled reactions of 2-(alkoxycarbonyl)allylhalides promote formation of α-exo-methylene γ-butyrolactones, including Reformatsky and Nozaki-Hiyama type reactions.⁶ Methods for asymmetric carbonyl addition-lactonization to form α-exo-methylene γ-butyrolactones largely rely upon stoichiometric chirality transfer from auxiliaries.^{2a,b,d,e,l,7j} Furthermore, high enantioselectivities are obtained only when two chiral auxiliaries are used in concert.^2b,d Remarkably, related catalytic enantioselective processes for the formation of α-exo-methylene γ-butyrolactones remain an unmet challenge.⁸ Here, we report the first highly enantioselective catalytic 2-(alkoxycarbonyl)allylations to form α-exo-methylene γ-butyrolactones, which are achieved directly from the alcohol oxidation level under the conditions of iridium catalyzed C-C bond forming transfer hydrogenation (Figure 1).⁹

Figure 1.

α-Exo-methylene γ-butyrolactones via enantioselective carbonyl 2-(alkoxycarbonyl)allylation.

Our earlier work on iridium catalyzed enantioselective carbonyl allylation¹⁰ reveals that allylic carboxylates incorporating monosubstituted olefins are required. This constraint arises as olefin coordination precedes ionization of the allylic leaving group to form the π-allyl, and the stability of late transition metal-olefin π-complex decreases with increasing degree of olefin substitution.¹¹ However, recently we found that enhanced π-backbonding^12,13 associated with carboxy substitution compensates for such destabilization, enabling vinylogous aldol addition from the alcohol or aldehyde oxidation level.¹⁴ This result supported the feasibility of using acrylic ester 1 as a 2-(alkoxycarbonyl)allylmetal equivalent.

In preliminary experiments, the catalytic C-C coupling of acrylic ester 1 and alcohol 2b was explored using the achiral π-allyliridium C,O-benzoate complex derived from [Ir(cod)Cl]₂, 4-chloro-3-nitrobenzoic acid, allyl acetate and BIPHEP [(2,2'-bis(diphenylphosphino)biphenyl)], designated Ir(BIPHEP). The complex Ir(BIPHEP) was isolated by conventional silica gel chromatography. However, upon exposure of acrylic ester 1 to alcohol 2b under conditions effective in related vinylogous aldol additions, only trace quantities of the desired butyrolactone 3b were generated (Table 1, entry 1). The catalyst used in the vinylogous aldol addition was isolated by precipitation and, hence, may contain residual cesium carbonate. This hypothesis prompted us to conduct the reaction under the aforementioned conditions in the presence of added cesium carbonate (20 mol%), which promoted generation of butyrolactone 3b in 31% isolated yield (Table 1, entry 2). Decreased loadings of cesium carbonate (10 mol% and 5 mol%) increased the isolated yield of butyrolactone 3b (Table 1, entries 3 and 4). Finally, by adjusting reaction temperature, acrylic ester 1 and alcohol 2b could be converted to butyrolactone 3b in 77% isolated yield (Table 1, entries 5 and 6). The concentration of trace metals in the cesium carbonate had a significant impact on isolated yield. For the best results, high grade cesium carbonate (>99.7% purity) with trace metal concentrations of <10 ppm should be employed.

Table 1.

Selected optimization experiments in the C-C coupling of ester 1 to alcohol 2b (R = (CH₂)₂Ph).^a

Entry	Cs2CO3 (mol %)	T°C	Yield %
1	0	90	trace
2	20	90	31
3	10	90	54
4	5	90	65
⇨5	5	80	77
6	5	70	48

^aYields are of material isolated by silica gel chromatography. See Supporting Information for further details.

Under the optimal conditions identified for the conversion of acrylic ester 1 and alcohol 2b to racemic butyrolactone 3b, catalysts modified by diverse axially chiral chelating phosphine ligands were assayed. The chiral ligands assayed included BINAP, Xylyl-BINAP, SEGPHOS, DM-SEGPHOS, C3-TUNEPHOS, MeO-BIPHEP, Cl,MeO-BIPHEP, and CTH-PPHOS among others. However, the degree of asymmetric induction was disappointing, with 80% enantiomeric excess or lower in each case. In contrast, the chiral complex modified by (−)-TMBTP,¹⁵ Ir(TMBTP), provided butyrolactone 3b in 79% yield and 88% enantiomeric excess (Table 2, entry 1). Isolated yields and the degree of asymmetric induction are both highly solvent dependent. Whereas reactions performed in 2-Me-THF and dioxane provide butyrolactone 3b in 68% yield and 77% enantiomeric excess and 33% yield and 72% enantiomeric excess, respectively, a 31% yield and 92% enantiomeric excess are obtained in acetonitrile (MeCN) (Table 2, entries 2–4). In order to balance yield and enantioselectivity, reactions were conducted in THF-MeCN mixtures over 3 days (Table 2, entries 5 and 6).

Table 2.

Selected optimization experiments in the enantioselective C-C coupling of ester 1 to alcohol 2b (R = (CH₂)₂Ph).^a

Entry	Solvent (0.5 M)	Hours	Yield% (ee%)
1	THF	48	79 (88)
2	2-Me-THF	48	68 (77)
3	dioxane	48	33 (72)
4	MeCN	48	31 (92)
5	THF:MeCN (1:1)	48	52 (90)
5	THF:MeCN (1:1)	72	57 (90)

^aYields are of material isolated by silica gel chromatography. Enantiomeric excess was determined by chiral stationary phase HPLC analysis. See Supporting Information for further details.

Optimal conditions identified for the enantioselective process were applied to primary aliphatic alcohols 2a–2i. The corresponding α-exo-methylene γ-butyrolactones 3a–3i were produced in good to excellent isolated yields with enantioselectivities ranging from 82–95% ee (Table 3). Benzylic alcohols also participate in 2-(alkoxycarbonyl)allylation, but enantioselectivities were modest.¹⁶ As illustrated by the conversion of aldehyde 4g to butyrolactone 3g, 2-(alkoxycarbonyl)allylation can be conducted from the aldehyde oxidation level using isopropanol as terminal reductant (Scheme 1). Butyrolactones 3a and 3b previously were prepared in optically enriched form and serve to corroborate the assignment of absolute stereochemistry for butyrolactones 3a–3i.

Table 3.

Enantioselective 2-(alkoxycarbonyl)allylation via iridium catalyzed C-C bond forming transfer hydrogenation.^a

^aAs described for Table 2.

^bTHF (0.5 M).

^cThe cyclometallated catalyst derived from 4-CN-3-NO₂-BzOH was used.

^d(R)-DM-SEGPHOS was used as ligand. See Supporting Information for further details.

Scheme 1.

Enantioselective 2-(alkoxycarbonyl)allylation via iridium catalyzed aldehyde reductive coupling via transfer hydrogenation.a

^aAs described in Table 3. See Supporting Information for further details.

To illustrate the potential utility of adducts 3a–3i, butyrolactone 3f was converted to the allylic bromide 5, which was subjected to zinc-mediated reductive coupling to p-bromobenzaldehyde and 3-phenyl propanal.¹⁷ The adducts 6a and 6b are generated diastereoselectively, thereby establishing entry to disubstituted α-exo-methylene γ-butyrolactones with control of relative and absolute stereochemistry.

In summary, although α-exo-methylene γ-butyrolactones represent a vast family of naturally occurring compounds, catalytic enantioselective formation of such butyrolactones via carbonyl 2-(alkoxycarbonyl)allylation was hitherto unknown. Here, we report the first example of catalytic enantioselective carbonyl 2-(alkoxycarbonyl)allylation through iridium catalyzed transfer hydrogenative C-C coupling of acrylic ester 1 to alcohols 2a–2i. As illustrated by the formation of adducts 6a and 6b, this methodology provides entry to fully substituted α-exo-methylene γ-butyrolactones with control of relative and absolute stereochemistry. Future studies will focus on the application of this methodology to the synthesis of α-exo-methylene γ-butyrolactone natural products.

Scheme 2.

Conversion of rac-3f to disubstituted α-exo-methylene γ-butyrolactones 6a and 6b.a

^aReagents: (a) Br₂ (110 mol%), NaOAc (150 mol%), DCM (0.08 M), 25 °C. (b) Li₂CO₃ (500 mol%), LiBr (500 mol%), DMF (0.3 M), 60 °C. 55% Yield (2 steps). (c) RCHO (100 mol%), Zn (118 mol%), NH₄Cl (10 uL, saturated aqueous solution), DMF (0.5 M), 25 °C.