Site-switchable mono-O-allylation of polyols

Site-selective modification of complex molecules allows for rapid accesses to their analogues and derivatives, and, therefore, offers highly valuable opportunities to probe their functions. However, to selectively manipulate one out of many repeatedly occurring functional groups within a substrate represents a grand challenge in chemistry. Yet more demanding is to develop methods in which alterations to the reaction conditions lead to switching of the specific site of reaction. We report herein the development of a Pd/Lewis acid co-catalytic system that achieves not only site-selective, but site-switchable mono-O-allylation of polyols with readily available reagents and catalysts. Through exchanging the Lewis acid additives that recognize specific hydroxyls in a polyol substrate, our system managed to install a versatile allyl group to the target in a site-switchable manner. Our design demonstrates remarkable scope, and is amenable to the direct derivatization of various complex, bioactive natural products.

are average of at least two runs.

Procedures and Characterization Data for Compounds in Figure 2c
The full NMR spectra of the reaction mixtures were shown below.
To another vial, compound 2 (51.0 mg, 0.32 mmol, 1.6 equiv), Pd 2 (dba) 3 •CHCl 3 (5.2 mg, 5 µmol, 0.025 equiv), PPh 3 (5.4 mg, 0.02 mmol, 0.1 equiv), and THF (200 µL) were added in sequence. The mixture was stirred for 10 min, and then transferred to Vial A. An additional portion of THF (1.6 mL) was added to Vial A so that [10] was adjusted to 0.1 M. Vial A was tightly capped, taken out of the glove box, and stirred at 25 ˚C (plate temperature) for 12 h (500 rpm). The reaction mixture was then concentrated in vacuo. An aliquot of the residue was taken for 1 H NMR analysis, which indicated that products 10a and 10b were formed in a ratio of 4:1.
To another vial, compound 2 (71.2 mg, 0.45 mmol, 1.5 equiv), Pd 2 (dba) 3 •CHCl 3 (7.8 mg, 7.5 µmol, 0.025 equiv), PPh 3 (7.9 mg, 0.03 mmol, 0.1 equiv), and THF (200 µL) were added in sequence. The mixture was stirred for 10 min, and then transferred to Vial A. An additional portion of THF (2.3 mL) was added to Vial A so that [10] was adjusted to 0.1 M. Vial A was tightly capped, taken out of the glove box, and stirred at 25 ˚C for 12 h (400 rpm). The reaction mixture was then concentrated in vacuo. An aliquot of the residue was taken for 1 H NMR analysis, which indicated that products 10a and 10b were formed in a ratio of 1:6. Flash chromatography (SiO 2 ) using petroleum ether/EtOAc (6:1 to 3:1) as eluent afforded 10b as a pale yellow oil (69.0 mg, 0.198 mmol, 66%). The full NMR spectra of the reaction mixtures were shown below.
To another vial, compound 2 (47.5 mg, 0.30 mmol, 1.5 equiv), Pd 2 (dba) 3 •CHCl 3 (10.4 mg, 0.01 mmol, 0.05 equiv), PPh 3 (10.4 mg, 0.04 mmol, 0.20 equiv), and THF (200 µL) were added in sequence. The mixture was stirred for 10 min, and then transferred to Vial A. An additional portion of THF (1.6 mL) was added to Vial A so that [11] was adjusted to 0.1 M. Vial A was tightly capped, taken out of the glove box, and stirred at 25 ˚C for 12 h (400 rpm). The reaction mixture was then concentrated in vacuo. An aliquot of the residue was taken for 1 H NMR analysis, which indicated that products 11a and 11b were formed in a ratio of 7:1. Flash chromatography (SiO 2 ) using petroleum ether/EtOAc (3:1 to 2:1) as eluent afforded 11a as a pale yellow oil (59.9 mg, 0.172 mmol, 86%).

Methyl 3-O-(allyl)-α-L-fucopyranoside (13b)
In a N 2 -filled glovebox, compound 13 (35.6 mg, 0.20 mmol, 1.0 equiv) and quinoline-8-  The full NMR spectra of the reaction mixtures were shown below. For the top and bottom spectra , NMR was taken after purification by the reaction mixture was passed through a pad of silica gel to remove additives and unreacted starting materials.

6-(tert-Butyldimethylsilyloxyl)-4-O-(allyl) -α-D-mannopyranoside (14c)
Compound 14 (77. To another vial, compound 2 (63.3 mg, 0.40 mmol,1.6 equiv), Pd 2 (dba) 3 •CHCl 3 (13.1 mg, 12.5 µmol, 0.05 equiv), PPh 3 (13.1 mg, 0.05 mmol, 0.2 equiv), and THF (200 µL) were added in sequence under N 2 atmosphere. The mixture was stirred for 10 min, and then transferred to Vial A. An additional portion of THF (2.3 mL) was added to Vial A so that [14] was adjusted to 0.1 M. Vial A was tightly capped, taken out of the glove box, and stirred at 25 ˚C (plate temperature) for 12 h (400 rpm). After that, a solution of glycerol (1 M, aq., 0.5 mL) and Na 2 CO 3 (1 M, aq., 0.5 mL) was added and vigorously stirred for additional 30 min, the organic layer was extracted with EtOAc and concentrated. The residue was passed through a pad of silica gel and then concentrated. An aliquot of the residue was taken for 1 H NMR analysis, which indicated that products 14a and 14c were formed in a ratio of 1:7. Flash chromatography (SiO 2 , ca. 3 g) using petroleum ether/EtOAc (3:1 to 1:1) as eluent afforded diallylated product (6.0 mg, 6%), 14c as a pale yellow oil (44.4 mg, 0.127 mmol, 51%), and starting material 14 [When no Lewis acid or base was used, 14a, 14b and 14c were obtained at a ratio of 2  Figure 4 The full NMR spectra of the reaction mixtures were shown below. For the top spectra , NMR was taken after the reaction mixture was passed through a pad of silica gel to remove additives and unreacted starting materials.
To another vial, compound 2 (23.7 mg, 0.15 mmol, 1.5 equiv), Pd 2 (dba) 3 •CHCl 3 (5.2 mg, 5 µmol, 0.05 equiv), PPh 3 (5.2 mg, 0.02 mmol, 0.2 equiv), and THF (200 µL) were added in sequence. The mixture was stirred for 10 min, and then transferred to Vial A. An additional portion of THF (300 µL) was added to Vial A so that [16] was adjusted to 0.1 M. Vial A was tightly capped, taken out of the glove box, and stirred at 25 ˚C for 12 h (400 rpm). The reaction mixture was then concentrated in vacuo. The residue was passed through a pad of silica gel and then concentrated. An aliquot of the residue was taken for 1 H NMR analysis, which indicated that products 16a and 16b were formed in a ratio of 4:1. Flash chromatography (SiO 2 ) using petroleum ether/AcOEt (2:1 to 1:1) as eluent afforded 16a as a light yellow foam (37 mg, 0.056 mmol, 56%) and starting material 16 (9.7 mg, 16%). Product 16a was further treated with DMAP and Ac 2 O to afford the per-acylated product for characterization.
To another vial, compound 2 (24.0 mg, 0.15 mmol, 1.5 equiv), Pd 2 (dba) 3 •CHCl 3 (5.2 mg, 5 µmol, 0.05 equiv), PPh 3 (5.2 mg, 0.02 mmol, 0.2 equiv), and THF (200 µL) were added in sequence. The mixture was stirred for 10 min, and then transferred to Vial A. An additional portion of THF (300 µL) was added to Vial A so that [17] was adjusted to 0.1 M. Vial A was tightly capped, taken out of the glove box, and stirred at 25 ˚C (plate temperature) for 12 h (400 rpm). The reaction mixture was then concentrated in vacuo. The residue was passed through a short pad of silica gel and concentrated. An aliquot of the residue was taken for 1 H NMR analysis, which indicated that products 17a and 17b were formed in a ratio of >10:1. Flash chromatography (SiO 2 ) using petroleum ether/EtOAc (3:1 to 1:1) as eluent afforded 17a as a yellow oil (52.9 mg, 0.073 mmol, 73%).
To another vial, compound 2 (24.0 mg, 0.15 mmol, 1.5 equiv), Pd 2 (dba) 3  [When no additive was used, 17a and 17b were obtained with a ratio of 4.0:1.0.] Figure 5 The full NMR spectra of the reaction mixtures were shown below. For the top and bottom spectra, NMR was taken after the reaction mixture was passed through a pad of silica gel to remove additives and unreacted starting materials.

21-O-(allyl)-20-hydroxyecdysone (18b)
In   [When no additive is used, 18a and 18b were obtained at a ratio of ca. 1.0:1.0.] The full NMR spectra of the reaction mixtures were shown below. For the top and bottom spectra , NMR was taken after the reaction mixture was passed through a pad of silica gel to remove additives and unreacted starting materials.

10-O-(allyl)-geniposide (19b)
In a N 2 -filled glovebox, geniposide 19 (77.6 mg, 0.20 mmol, 1.0 equiv), Phenylboronic acid (24.2 mg, 0.20 mmol, 1.0 equiv), and THF (500 µL) were weighed into a screw capped The full NMR spectra of the reaction mixtures were shown below. For all of the spectra , NMR was taken after the reaction mixture was passed through a pad of silica gel to remove additives and unreacted starting materials.

1-O-(allyl)-salicin (20c)
In   The full NMR spectra of the reaction mixtures were shown below.