Abstract
Herein, we report a novel photocatalytic tandem Ueno–Stork cyclization/intermolecular Giese addition sequence for the stereoselective difunctionalization of allylic alcohols. This reaction avoids the use of toxic reagents and complicated protocols typically required under classical Ueno–Stork conditions. Furthermore, the reaction system demonstrated good stereoselectivity with both cyclic and linear allylic alcohols.
The Ueno–Stork cyclization is a well-known method for the efficient difunctionalization of allylic alcohols, abundant and versatile structural units in synthetic organic chemistry (Scheme 1A).1 This reaction involves three steps: (1) haloacetalization of the alcohol group, followed by (2) radical formation and intramolecular addition of the resulting radical to the alkene group and (3) trapping the generated alkyl radical with an appropriate radical acceptor, enabling the formation of a C–C bond at a sterically congested carbon center and generating a cyclic acetal with multiple stereocenters, including a quaternary carbon center, in a stereoselective manner. Given the enriched availability of chiral allylic alcohols, this methodology can be easily applied to enantiocontrolled synthesis.2 Because of these benefits, Ueno–Stork cyclization has been widely used in the total synthesis of natural products.1c,3 Nevertheless, there is room for improvement, as this reaction typically requires an excess of toxic tin hydride to terminate the radical reaction reductively, which often inhibits trapping with a radical acceptor (i.e., tandem reaction) in step 3 except the hydrogen atom.4
Scheme 1. Ueno–Stork Cyclization and Its Tandem Reaction.
Recently, Dai and co-workers reported a tin hydride-free, Ni-catalyzed tandem Ueno–Stork cyclization that enables efficient vicinal difunctionalization of cyclic allylic alcohols to build continuous carbon stereocenters in a single step from iodoacetals (Scheme 1B).3c,5 This reaction protocol avoids the use of tin reagents and can build all-carbon quaternary centers. Unfortunately, their protocol is highly sensitive to the Zn source (requiring a reliable supplier and varying by lot number). Therefore, a highly reproducible and user-friendly protocol is required.
We became interested in updating the tandem-type Ueno–Stork reaction for reliability and operability. Inspired by several successful examples of homolytic C(sp3)–halogen bond cleavage under photoredox conditions, we aimed to develop a green and practical tandem Ueno–Stork cyclization/intermolecular carbofunctionalization reaction.6,7 Herein, we report a novel photocatalytic tandem Ueno–Stork cyclization/intermolecular Giese addition sequence as a new catalytic method for vicinal difunctionalization of allylic alcohols, offering high stereoselectivity and a broad substrate scope (Scheme 1C).
We commenced our study by evaluating various photoredox catalysts, bases, additives, and solvents using α-iodoacetal 1a as the model substrate (Table 1). Blue light-emitting diode (LED) light (456 nm) in the presence of a catalytic amount (2.0 mol %) of Ir[dF(CF3)ppy2](dtbbpy)PF6, i-Pr2NEt, and H2O in MeCN enabled the tandem reaction, affording the desired cyclic acetal product 2a in 59% yield and the undesired diester 3a in 8.2% yield (entry 1). Notably, under these conditions, cyclized product 2a was obtained with high diastereoselectivity (17:1) at the two newly formed vicinal stereocenters. Next, detailed optimization of the reaction conditions was performed, with results evaluated using the combined 1H nuclear magnetic resonance (NMR) yield of 2a and 3a. The addition of water proved to be important, as the conversion was low without it (entry 2). Substituting Ir[dF(CF3)ppy2](dtbbpy)PF6 with Ru(bpy)3Cl2 decreased the yield and conversion (entry 3), and other photoredox catalysts were ineffective in conversion. Next, amine bases instead of i-Pr2NEt were screened. The reaction hardly proceeded with quinuclidine (entry 4), while Et3N slightly decreased the combined yield (entry 5). A DMF or DMSO solvent instead of acetonitrile also reduced the yield (entry 6 or 7, respectively). To suppress the generation of diester 3a, we varied the amount of methyl acrylate; decomposition of 1a was observed with 1.1 equiv of methyl acrylate (entry 8), but 1.5 equiv improved the yield of 2a and suppressed the formation of 3a (entry 9). Finally, extending the reaction time to 12 h led to the full conversion of starting materials, affording ester 2a in 84% isolated yield (entry 10).8 We confirmed the scalability of the developed reaction system by using 1.00 mmol of 1a, and cyclic acetal 2a was obtained with a similar yield on a 0.100 mmol scale (entry 11).
Table 1. Optimization of the Reaction Conditions.
| entry | deviation from the initial conditions | combined yield of 2a and 3aa (%) | residual 1aa (%) | isolated yield of 2ab (3a) (%) |
|---|---|---|---|---|
| 1 | none | 68 | 11 | 59 (8.2) |
| 2 | H2O (0 equiv) | 19 | 64 | – |
| 3 | Ru(bpy)3Cl2 instead of Ir[dF(CF3)ppy2](dtbbpy)PF6 | 36 | 37 | – |
| 4 | quinuclidine instead of i-Pr2NEt | 4 | 88 | – |
| 5 | Et3N instead of i-Pr2NEt | 65 | 13 | – |
| 6 | DMF instead of MeCN | 30 | 38 | – |
| 7 | DMSO instead of MeCN | 44 | 45 | – |
| 8 | methyl acrylate (1.1 equiv) | 67 | 8 | – |
| 9 | methyl acrylate (1.5 equiv) | 74 | 16 | 64 (5.8) |
| 10 | methyl acrylate (1.5 equiv)c | 89 | 0 | 84 (5.9) |
| 11 | methyl acrylate (1.5 equiv)c,d | – | – | 78 (5.8) |
The yield was determined via 1H NMR of the crude mixture using 1,3,5-trimethoxybenzene as an internal standard.
Isolated yield of 2a. The diastereomeric ratio at the newly formed stereocenters was 17:1.
The reaction time was extended to 12 h.
With 1.00 mmol of 1a.
A variety of substrates were examined under the optimized conditions (Figure 1). First, the substituent effect of the cyclohexene ring on the reactivity was investigated. Disubstituted alkenes also afford good diastereoselectivity and yield (2b). Dimethyl substitution provided a good yield and diastereoselectivity (2c and 2d). However, trisubstituted alkene 1e exhibited low diastereoselectivity. Trisubstituted alkene having TBS oxy group was investigated as bulky substrates, and a good yield and good diastereoselectivity were obtained (2f). We also investigated the iodoacetal synthesized from carvone, but the yield and diastereoselectivity were relatively low (2g). Next, cyclic alkenes with different ring sizes were tested under the optimized conditions. Here, 5,5- or 5,7-fused ring systems afforded products in good yields (2h–2l). Di- and trisubstituted cyclopentenes were compatible for the reaction conditions. In particular, cyclopentene having a methyl group at position C1, which was not applicable in Dai’s procedure, gave the desired cyclic acetal (2k). Polycyclic iodoacetal 1m was investigated, and the desired cyclic acetal was obtained in good yield and diastereoselectivity (2m).
Figure 1.
Substrate scope. adr value at the newly formed stereocenters. bThe dr ratio of the newly formed stereocenters was determined by reducing the acetal to a tetrahydrofuran ring. cWith 3.0 equiv of the radical acceptor. dThe dr ratio of the newly formed stereocenters was determined by oxidizing the acetal to a lactone. eThe E:Z ratio of alkene on starting material 1u is 2.3:1.
Various electron-deficient alkenes were also compatible. Methyl vinyl ketone (2n), vinyl sulfone (2o), and vinyl phosphonate (2p) produced good results with a high diastereoselectivity. Acrylonitrile, however, showed an inferior yield compared to those of the others (2q). We also tested other radical acceptors, but the reaction did not proceed (Supporting Information).
Next, α-iodoacetals derived from linear allylic alcohols were investigated as a substrate. Both monosubstituted and 1,1-disubstituted alkenes provided the corresponding cyclic acetal (2r and 2s, respectively). The regioselectivity of the initial radical addition (i.e., 5-exo or 6-endo) and the stereochemistry of 2r–2u were determined using nuclear Overhauser effect correlations of lactones derived from the corresponding acetals. The result for 1,2-disubstituted alkene 1u revealed that the diastereoselectivity of the Giese addition step (∼1:1) does not correlate with the E:Z ratio of the starting alkene (2.3:1 E:Z). The trisubstituted alkene produced the cyclic acetal in good yield (2t). These results indicate that the stability of the generated alkyl radical after the initial addition to the alkene is crucial to achieving high yields of cyclic acetals. This is the first reported example of the vicinal difunctionalization of linear alkenes via tandem-type Ueno–Stork cyclization.
In addition to α-iodoacetals, (iodomethyl)dimethylsilane 4a was found to be compatible, producing oxasilolane 5a (Scheme 2).4e,9 Compound 5 was subjected to Tamao–Fleming oxidation,10 affording 1,3-diol 6a in 56% yield (two steps). This reaction could be applied to various (iodomethyl)dimethylsilane (6b–6d). This enables adjustments of the introduced carbon chain length, thereby increasing the synthetic flexibility for subsequent functionalization.
Scheme 2. Scope of (Iodomethyl)dimethylsilyl Ether Substrate 4 and Following Tamao–Fleming Oxidation.
Finally, a series of experiments were performed to investigate the reaction mechanism. First, we conducted control experiments (Scheme 3A). The results of entries 1–3 indicated that the photocatalyst, blue LED light, and base were all necessary to promote the reaction. When a stoichiometric amount of TEMPO was added as a radical inhibitor, the formation of 2a was mostly inhibited, and TEMPO adduct 2a′ was obtained in 15% yield (Scheme 3B). Next, we conducted an isotope labeling experiment using D2O instead of H2O (Scheme 3C). After oxidation of the resulting acetal into lactone 7, the α-position of the methyl ester was almost fully deuterated (95% based on 1H NMR).
Scheme 3. Mechanistic Studies.
A plausible reaction mechanism based on these mechanistic studies and literature precedent11 is shown in Figure 2. Photoirradiation of Ir(III) with blue LED light produces the excited Ir(III) species [*Ir(III)], which oxidizes the tertiary amine to generate α-amino radical I, accompanied by the formation of Ir(II). Resulting α-amino radical I then abstracts an iodine atom from the α-iodoacetal, forming primary carbon-centered radical II. This radical undergoes cyclization, followed by intermolecular Giese addition to yield an α-carbonyl radical IV. A single-electron transfer from Ir(II) to α-carbonyl radical IV generates enolate V, which is protonated by water to generate the desired product.
Figure 2.
Plausible reaction mechanism.
In summary, we developed a novel photocatalytic tandem Ueno–Stork cyclization/intermolecular Giese addition sequence that enables stereoselective vicinal difunctionalization of allylic alcohols. This reaction requires no special reagents, and is easy to set up. It works well with a variety of cyclic allylic alcohols with five- to seven-membered rings, a polycyclic substrate, and linear alkenes, exhibiting good stereoselectivity. Furthermore, various tethers and radical acceptors are compatible. This approach provides a promising option for the difunctionalization of allylic alcohols and is particularly useful for the synthesis of substrates with contiguous stereocenters. Further applications of this reaction for total synthesis are currently underway in our laboratory.
Acknowledgments
This work was partly supported by a Grant-in-Aid for JSPS fellows (23KJ0098 to Y.T.) and by the Research Support Project for Life Science and Drug Discovery [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] (Grant JP22ama121040j0001 to Y.I.) from AMED.
Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.5c00287.
Experimental details, compound data, and copies of 1H and 13C NMR spectra (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
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Associated Data
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Supplementary Materials
Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.