Direct Catalytic Asymmetric Aldol Reaction of α-Vinyl Acetamide - The

Apr 23, 2018 - A direct catalytic asymmetric aldol addition of an α-vinyl 7-azaindoline amide to both aromatic and aliphatic aldehydes was promoted b...
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Cite This: J. Org. Chem. 2018, 83, 5851−5858

Direct Catalytic Asymmetric Aldol Reaction of α‑Vinyl Acetamide Toshifumi Takeuchi, Naoya Kumagai,* and Masakatsu Shibasaki* Institute of Microbial Chemistry (BIKAKEN), Tokyo 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan S Supporting Information *

ABSTRACT: A direct catalytic asymmetric aldol addition of an α-vinyl 7-azaindoline amide to both aromatic and aliphatic aldehydes was promoted by a cooperative acid/base catalyst in a stereodivergent manner. The key structural element, a 7azaindoline moiety, facilitated catalytic enolization, allowing for subsequent stereoselective aldol addition. Enantioselective synthesis of the key intermediate of blumiolide C and kainic acid supported the synthetic utility of this protocol.

T

he recent focus on sustainability in organic synthesis1 has increased attention toward stereoselective carbon−carbon bond-forming reactions triggered by catalytic enolization.2,3 We have centered intensive efforts on direct enolization chemistry and devised several protocols to achieve catalytic enolization integrated with subsequent stereoselective nucleophilic addition (Scheme 1).4 7-Azaindoline amides are particularly competent

chiral building blocks.6d We reasoned that installing an anionstabilizing vinyl group at the α-position would facilitate chemoselective enolization and expand the scope and synthetic utility of the enantioenriched aldol products.7a,8 Herein we document the successful exploitation of α-vinyl 7-azaindoline acetamide 1 as a competent aldol donor amenable to chemoselective enolization and addition to enolizable aliphatic aldehydes, affording syn-configured aldol adducts. Aromatic aldehydes exhibited anti diastereoselectivity, which is complementary to the syn-selective reaction previously observed with α-Me azaindoline acetamide. The facile transformation capability of the 7-azaindoline amide moiety allowed for stereoselective delivery of the key synthetic intermediate of blumiolide C and kainic acid. At the outset, octanal 2a was used as a model enolizable αnonbranched aliphatic aldehyde in a direct aldol reaction with α-vinyl 7-azaindoline acetamide 1. The previous study of α-Me acetamides demonstrating the particular effectiveness of biphep-type chiral bisphosphine ligand L1 with 3,4,5trimethoxyphenyl groups on the phosphorus atom led us to screen Brønsted bases to identify the reaction conditions enabling the desired aldol reaction without self-condensation of 2a. Exposure of 1 and 2a to the [Cu(CH3CN)4]PF6/L1/base catalytic system generally afforded the desired aldol adduct 3a in high yield, while self-condensed products of 2a were not detected (Table 1). Alkali metal aryloxides prepared from chromanol derivative Ar1OH exhibited sufficient basicity to render enolization of Cu(I)-activated amide 1 at −60 °C in THF, affording 3a in an almost 1:1 diastereomeric ratio, although promising enantiomeric excess was observed with Na and K aryloxides (entries 1−3). A marginal amount of α,βunsaturated amide 4 was associated via olefin isomerization upon enolization, which was more prominent when guanidinetype Barton’s base was employed (entry 4). Less basic Hünig’s base failed to promote the reaction (entry 5), whereas a mesitylcopper/L1 catalytic system performed better to give

Scheme 1. (a) General Scheme of Direct Aldol Reaction; (b) Direct Catalytic Asymmetric Aldol Reaction of α-Vinyl 7Azaindoline Acetamide 1

in facilitated enolization with soft Lewis acid/Brønsted base cooperative catalysts,4a,5 accommodating a range of αsubstituents in direct aldol and Mannich reaction manifolds.6 In direct aldol reactions, enolizable aliphatic aldehydes remain elusive as electrophiles, however, because of their high propensity for self-condensation triggered by enolization over less acidic amide aldol donors.7 Although anion-stabilizing αsubstituents (α-SMe and -N3) enable chemoselective enolization of 7-azaindoline amides in the presence of aliphatic aldehydes,6a,c this is not the case for α-alkyl 7-azaindoline amides, which limits the synthetic utility of the direct aldol protocol as a practical and atom-economical tool to furnish © 2018 American Chemical Society

Received: March 23, 2018 Published: April 23, 2018 5851

DOI: 10.1021/acs.joc.8b00743 J. Org. Chem. 2018, 83, 5851−5858

Note

The Journal of Organic Chemistry Table 1. Screening Conditions for Direct Catalytic Asymmetric Aldol Reaction of α-Vinyl 7-Azaindoline Acetamide 1a

yield (%)b entry

Cu(I) source

ligand

base

additive

3a

4

syn/antic

ee (%)d (syn)

1 2 3 4 5 6 7e 8e 9e 10 11e 12e 13e 14e 15e 16e

[Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6 mesitylcopper mesitylcopper mesitylcopper mesitylcopper mesitylcopper mesitylcopper mesitylcopper mesitylcopper mesitylcopper mesitylcopper mesitylcopper

L1 L1 L1 L1 L1 L1 L2 L3 L4 L5 L6 L1 L1 L1 L1 L1

LiOAr1 NaOAr1 KOAr1 Barton’s base Hünig’s base − − − − − − − − − − −

− − − − − − − − − − − HOAr1 HOAr2 HOAr3 HOAr4 HOAr5

89 93 89 69 0 98 91 98 89 98 94 99 88 14 98 91

9 5 8 28 − − 7 − − − − − − − − −

50/50 51/49 41/59 26/74 − 77/23 88/12 74/26 84/16 47/53 82/18 84/16 90/10 41/59 90/10 95/5

41 96 95 75 − 99 88 78 89 52 80 >99 >99 58 >99 >99

a c

1, 0.1 mmol; 2a, 0.2 mmol. bDetermined by 1H NMR analysis of the crude mixture with 3,4,5-trichloropyridine as an internal standard. Determined by 1H NMR analysis of the crude mixture. dDetermined with normal phase HPLC on a chiral support. eRun at −70 °C.

decreased stereoselectivity observed with p-nitrophenol (Ar3OH) was presumably ascribed to disruptive effects of the coordinative nitro functional group on the desired stereochemical course of the aldol addition. By further screening phenols bearing electron-donating groups, we identified that pmethoxyphenol (Ar4OH) and phloroglucinol (Ar5OH) outperformed Ar1OH (entries 15 and 16), and phloroglucinol (Ar5OH) was optimal for the reaction of 2a to deliver syn-3a with high diastereo- and enantioselectivity. The scope of applicable aliphatic aldehydes is summarized in Table 2.10 In general, the optimized conditions for 2a fit a range of aliphatic aldehydes to afford corresponding aldol adducts 3 with high diastereo- and enantioselectivity. As little as 3 mol % of catalyst loading was sufficient to complete the reaction (3a), and both an oxygen-functionalized aldehyde (3g) and an αbranched aldehyde (3h) were compatible. Of note, the reaction with aromatic aldehydes proceeded in an anti-selective manner

almost full conversion in a syn-selective manner without forming undesired isomerized compound 4 (entry 6).9 The mesitylcopper system is advantageous due to its operational simplicity, and the Cu-alkoxide intermediate derived from the in situ generated Cu-enolate of 1 drove the following catalytic cycle. To obtain higher diastereoselectivity, we screened additional ligands with the mesitylcopper catalytic system. None of the other chiral ligands examined surpassed L1 (entries 7−11), however, leading us to examine phenolic additives to perturb the stereochemical course at the aldol addition step. The use of 2,2,5,7,8-pentamethylchromanol Ar1OH improved the syn-selectivity without affecting the conversion or enantioselectivity (entry 12). On the other hand, lower conversion was observed when phenol derivatives (Ar2OH, Ar3OH) bearing electron-withdrawing groups were used, likely due to the lower basicity of the in situ formed Cu(I)/aryloxide complex (entries 13 and 14). The significantly 5852

DOI: 10.1021/acs.joc.8b00743 J. Org. Chem. 2018, 83, 5851−5858

Note

The Journal of Organic Chemistry Table 2. Direct Catalytic Asymmetric Aldol Reaction of αVinyl 7-Azaindoline Acetamide 1 and Aliphatic Aldehydesa

activity (Scheme 2).12 A direct aldol reaction of oxygenfunctionalized aliphatic aldehyde 2o and 1 proceeded smoothly with the mesitylcopper/L1/phloroglucinol catalytic system to give syn-3o with high enantioselectivity. Protection of the secondary hydroxyl group with TBS followed by reduction of the 7-azaindoline moiety via Myers’ protocol gave primary alcohol 5,13 which was subjected to esterification with acryloyl chloride to afford 6. Following the literature precedents,14 unsaturated valerolactone 7 was constructed via ring-closing metathesis with Grubbs’ second-generation catalyst,15 and subsequent delivery of a branched C5 unit by conjugate addition furnished 8, the reported intermediate for blumiolide C in full accordance with the spectroscopic data. The versatility of the α-vinyl group also allowed for the catalytic enantioselective access to intermediate 9 for kainic acid, a marine natural product exhibiting neuroexcitatory, insecticidal, and anthelmintic activities.16,17 The antipodal aldol product ent3b was obtained using ent-L1 with high stereoselectivity, and a subsequent similar silylation/reduction sequence afforded 9 en route to kainic acid.16,18 In summary, we developed an efficient direct aldol protocol furnishing β-hydroxy amides bearing a pendant α-vinyl group. Strategic use of the vinyl group enabled the incorporation of enolizable aliphatic aldehydes as tractable aldol acceptors and application to the stereoselective synthesis of key intermediates for blumiolide C and kainic acid. The full compatibility of aldol donors including α-C(sp), C(sp2), and C(sp3) aldehydes is noteworthy and allows for prospective use of the protocol to deliver a range of aldol-type chiral building blocks bearing a pendant vinyl group for further transformations.

a , 0.1 mmol; 2, 0.15 mmol. Combined yield of syn and anti-isomers is reported. Isolated yield of syn-isomer is reported in the Experimental Section. Ar5OH denotes phloroglucinol. b0.5 mmol of aldehyde (5 equiv) was used. cThe reaction was run without Ar5OH.

(Table 3).10,11 p-Methoxyphenol (Ar4OH) generally exhibited better performance over phloroglucinol (Ar 5OH). The Table 3. Direct Catalytic Asymmetric Aldol Reaction of αVinyl 7-Azaindoline Acetamide 1 and Aromatic Aldehydes and Ynala

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EXPERIMENTAL SECTION

General Experimental Methods. Unless otherwise indicated, all the reactions were performed in oven-dried glassware fitted with a three-way glass stopcock under an argon atmosphere and stirred with Teflon-coated magnetic stir bars. All workup and purification procedures were performed with reagent-grade solvents under an ambient atmosphere. Thin-layer chromatography (TLC) was performed on Merck TLC plates (0.25 mm) precoated with silica gel 60 F254 and visualized by UV quenching and staining with KMnO4, anisaldehyde, or ceric ammonium molybdate solution. Flashcolumn chromatography was performed using a Biotage Isolera Spektra One. Infrared (IR) spectra were recorded on a HORIBA FT210 Fourier transform infrared spectrophotometer. NMR spectra were recorded on a JEOL ECZ-600 or Bruker AVANCE III HD400 Prodigy. Chemical shifts (δ) are expressed in parts per million relative to the residual solvent peaks.1 The 1H NMR data are reported as chemical shift; multiplicity [s (singlet), d (doublet), t (triplet), dd (doublet of doublet), dt (doublet of triplet), ddd (doublet of doublet of doublet), q (quartet), m (multiplet), and br (broad)]; coupling constants (where applicable); and number of hydrogens. The single-crystal X-ray data were obtained on a Rigaku R-AXIS RAPID II imaging plate area detector with graphite-monochromated Cu Kα radiation. Optical rotation was measured using a 1 mL cell with a 1.0-dm path length on a JASCO polarimeter P-1030. High-resolution mass spectra (ESI TOF (+)) were measured on a Thermo Fisher Scientific LTQ Orbitrap XL. Purification of THF, Et2O, and CH2Cl2 was achieved by passing them through a solvent purification system (Glass Contour). The aldehydes were either purchased or synthesized, and all other starting materials and chiral ligands were used as supplied by commercial vendors or prepared according to the method described in the corresponding reference. 1-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)but-3-en-1-one (1). To a stirred solution of EDCI (2.26 g, 11.8 mmol) in CH2Cl2 (70 mL) at 0 °C was added 3-butenoic acid (1 mL, 11.8 mmol), and the

a 1, 0.1 mmol; 2, 0.15 mmol. Combined yield of syn and anti isomers is reported. Isolated yield of anti-isomer is reported in the Experimental Section. Ar4OH denotes p-methoxyphenol. Ee of major enantiomers is reported. bMesitylcopper/L1/phloroglucinol (Ar5OH) (5 mol % each) was used as catalyst.

observed anti-diastereoselectivity was complementary to the syn-diastereoselectivity observed in the reaction of α-Me 7azaindoline acetamide when using (S,S)-Ph-BPE as a chiral ligand. Ynal also served as a suitable substrate (3n), accommodating all α-C(sp), C(sp2), and C(sp3) aldehydes in the present direct aldol protocol. The pendant α-vinyl group was useful for enantioselective synthesis of the key intermediate for blumiolide C, a diterpenoid natural product that is isolated from a soft coral Xenia blumi and characterized by its potent antiproliferative 5853

DOI: 10.1021/acs.joc.8b00743 J. Org. Chem. 2018, 83, 5851−5858

Note

The Journal of Organic Chemistry Scheme 2. Stereoselective Synthesis of Key Intermediate for Blumiolide C and Kainic Acid

25.8, 24.1, 22.6, 14.1; [α]D26 −6.9 (c 1.05, CHCl3, 99% ee sample); HRMS (ESI-Orbitrap): m/z calcd for C19H29N2O2 [M + H]+ 317.2224, found 317.2228. HPLC conditions: CHIRALPAK AY-H (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 8.0 min (syn-major), 10.1 min (syn-minor). (R)-1-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-((S)-1hydroxyethyl)but-3-en-1-one (3b). Prepared by the general procedure 1 from acetaldehyde 2b (28 μL, 0.5 mmol, 5 equiv) and isolated as an amorphous solid (17.0 mg, 74%). IR (film) 3452, 3078, 2976, 2931, 1650, 1443 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06−8.12 (m, 1H), 7.44−7.51 (m, 1H), 6.90 (dd, J = 7.3, 5.1 Hz, 1H), 6.07 (ddd, J = 17.4, 10.3, 9.1 Hz, 1H), 5.27 (dd, J = 17.4, 1.7, 1.0 Hz, 1H), 5.22 (dd, J = 10.3, 1.7 Hz, 1H), 5.12 (br d, J = 5.4 Hz, 1H), 4.30 (br, 1H), 4.22 (qd, J = 6.4, 3.7 Hz, 1H), 4.03−4.18 (m, 2H), 2.96−3.12 (m, 2H), 1.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.3, 155.4, 145.7, 133.7, 133.0, 126.4, 119.5, 118.5, 68.8, 53.1, 45.9, 24.0, 19.4; [α]D26 −35.5 (c 1.00, CHCl3, 99% ee sample); HRMS (ESI-Orbitrap): m/z calcd for C13H17N2O2 [M + H]+ 233.1285, found 233.1284. HPLC conditions: CHIRALPAK ID (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 11.0 min (synmajor), 13.9 min (syn-minor). (2R,3S)-1-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-hydroxy2-vinylpentan-1-one (3c). Prepared by the general procedure 1 from n-propanal 2c (11 μL, 0.15 mmol, 1.5 equiv) and isolated as a colorless oil (21 mg, 95%). IR (NaCl) 3446, 3077, 2964, 1649, 1402 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06−8.26 (m, 1H), 7.45−7.56 (m, 1H), 6.92 (dd, J = 7.3, 5.1 Hz, 1H), 6.08 (ddd, J = 17.1, 10.2, 9.3 Hz, 1H), 5.30 (dd, J = 17.1, 2.0, 1.0 Hz, 1H), 5.24 (dd, J = 10.2, 2.0 Hz, 1H), 5.19−5.39 (br, 1H), 4.10−4.25 (br m, 1H), 4.13 (dd, J = 9.8, 7.7 Hz, 1H), 4.09 (dd, J = 9.8, 7.7 Hz, 1H), 3.94 (ddd, J = 9.3, 6.1, 3.2 Hz, 1H), 2.99−3.16 (m, 2H), 1.50−1.65 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 173.9, 155.3, 145.6, 133.9, 132.9, 126.6, 119.5, 118.5, 73.9, 51.7, 46.0, 26.6, 24.1, 10.3; [α]D26 −13.4 (c 0.54, CHCl3, 99% ee sample); HRMS (ESI-Orbitrap): m/z calcd for C14H19N2O2 [M + H]+ 247.1441, found 247.1431. HPLC conditions: CHIRALPAK ID (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 10.7 min (syn-major), 13.7 min (syn-minor). (2R,3S)-1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-hydroxy5-methyl-2-vinylhexan-1-one (3d). Prepared by the general procedure 1 from isovaleraldehyde 2d (16 μL, 0.15 mmol, 1.5 equiv) and isolated as a colorless oil (26.3 mg, 96%). IR (NaCl) 3457, 2954, 4646,

resulting mixture was stirred for 10 min at the same temperature. After addition of 7-azaindoline (945 mg, 7.87 mmol) in CH2Cl2 (20 mL), the resulting solution was stirred for 24 h at room temperature. After the addition of water at 0 °C, the mixture was diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude mixture was purified by silica gel column chromatography (n-hexane/EtOAc = 4/1 to 1/1) to give amide 1 as an amorphous solid (1.35 g, 91%). IR (NaCl) 3080, 1653, 1588, 1427, 1241 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08−8.14 (m, 1H), 7.43−7.49 (m, 1H), 6.87 (dd, J = 7.3, 5.1 Hz, 1H), 6.05−6.18 (m, 1H), 5.23 (dq, J = 17.1, 1.7 Hz, 1H), 5.16 (dq, J = 10.3, 1.7 Hz, 1H), 4.07−4.15 (m, 2H), 3.97 (d, J = 6.6 Hz, 2H), 3.06 (t, J = 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 170.8, 155.9, 146.1, 133.3, 131.8, 126.0, 117.9, 117.7, 45.6, 41.3, 24.1; HRMS (ESI-Orbitrap): m/z calcd for C11H13ON2 [M + H]+ 189.1022, found 189.1023. General Procedure 1 for Aliphatic Aldehydes in Table 2 and Ynal in Table 3. To a stirred THF solution (700 μL) of amide 1 (18.8 mg, 0.1 mmol), aldehyde (0.15 mmol, 1.5 equiv), and phlorolglucinol (0.6 mg, 0.005 mmol, 5 mol %) in a flame-dried test tube equipped with a magnetically stirred chip and a three-way stopcock at −70 °C was added a solution of mesitylcopper (0.9 mg, 0.005 mmol, 5 mol %) and L1 (4.7 mg, 0.005 mmol, 5 mol %) in THF (50 μL) via a syringe, and the resulting solution was stirred for 24 h at the same temperature. After the addition of sat aq NH4Cl at −70 °C, the mixture was diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was submitted to 1H NMR analysis to determine the diastereoselectivity. The crude material was purified by preparative TLC (n-hexane/EtOAc = 1/1). (2R,3S)-1-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-hydroxy2-vinyldecan-1-one (3a). Prepared by the general procedure 1 from noctanal 2a (19 μL, 0.15 mmol) and isolated as a colorless oil (30.3 mg, 96%). IR (NaCl) 3462, 2927, 1641, 1420 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08−8.15 (m, 1H), 7.47−7.53 (m, 1H), 6.92 (dd, J = 7.3, 5.1 Hz, 1H), 6.10 (ddd, J = 17.2, 10.3, 9.1 Hz, 1H), 5.30 (dd, J = 17.2, 1.8, 0.7 Hz, 1H), 5.24 (dd, J = 10.3, 1.8 Hz, 1H), 5.15−5.30 (br, 1H), 4.00−4.22 (m, 4H), 2.99−3.14 (m, 2H), 1.20−1.62 (m, 12H), 0.88 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.9, 155.4, 145.7, 133.8, 133.0, 126.5, 119.5, 118.5, 72.5, 52.0, 45.9, 33.7, 31.8, 29.5, 29.3, 5854

DOI: 10.1021/acs.joc.8b00743 J. Org. Chem. 2018, 83, 5851−5858

Note

The Journal of Organic Chemistry 1589, 1420 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.05−8.20 (m, 1H), 7.45−7.55 (m, 1H), 6.92 (dd, J = 7.3, 5.1 Hz, 1H), 6.10 (ddd, J = 17.4, 10.3, 9.1 Hz, 1H), 5.29 (dd, J = 17.4, 2.0, 0.7 Hz, 1H), 5.24 (dd, J = 10.3, 2.0 Hz, 1H), 5.17 (br s, 1H), 4.07−4.40 (m, 4H), 2.99−3.15 (m, 2H), 1.81−1.95 (m, 1H), 1.55 (ddd, J = 13.9, 9.3, 5.4 Hz, 1H), 1.29 (ddd, J = 13.9, 8.8, 4.2 Hz, 1H), 0.94 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.9, 155.4, 145.6, 133.9, 133.0, 126.6, 119.5, 118.5, 70.4, 52.4, 46.0, 42.7, 24.3, 24.1, 23.5, 21.9; [α]D26 −10.2 (c 0.29, CHCl3, 99% ee sample); HRMS (ESIOrbitrap): m/z calcd for C16H23N2O2 [M + H]+ 275.1754, found 275.1760. HPLC conditions: CHIRALPAK AD-3 (ϕ 0.46 cm × 25 cm) and AD-H (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 21.2 min (syn-major), 25.0 min (syn-minor). (R)-2-((S)-2-Cyclohexyl-1-hydroxyethyl)-1-(2,3-dihydro-1Hpyrrolo[2,3-b]pyridin-1-yl)but-3-en-1-one (3e). Prepared by the general procedure 1 from cyclohexylacetaldehyde 2e (20 μL, 0.15 mmol, 1.5 equiv) and isolated as a colorless oil (27.4 mg, 87%). IR (film) 3462, 2961, 1645, 1396, 1240 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08−8.14 (m, 1H), 7.46−7.52 (m, 1H), 6.92 (dd, J = 7.3, 5.1 Hz, 1H), 6.11 (ddd, J = 17.4, 10.3, 9.1 Hz, 1H), 6.29 (ddd, J = 17.4, 2.0, 1.0 Hz, 1H), 5.24 (dd, J = 10.3, 2.0 Hz, 1H), 5.19 (br d, J = 6.4 Hz, 1H), 4.06−4.23 (m, 4H), 2.99−3.14 (m, 2H), 1.80−1.88 (m, 1H), 1.46−1.76 (m, 6H), 1.09−1.39 (m, 4H), 0.81−1.02 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 173.9, 155.5, 145.8, 133.8, 133.1, 126.5, 119.5, 118.5, 69.9, 52.3, 45.9, 41.3, 34.2, 33.8, 32.7, 26.7, 26.5, 26.3, 24.1; [α]D27 −3.3 (c 0.55, CHCl3, 99% ee sample); HRMS (ESIOrbitrap): m/z calcd for C19H27N2O2 [M + H]+ 315.2067, found 315.2057. HPLC conditions: CHIRALPAK AY-H (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 15.1 min (syn-major), 18.7 min (syn-minor). (2R,3S)-1-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-hydroxy5-phenyl-2-vinylpentan-1-one (3f). Prepared by the general procedure 1 from hydrocinnamaldehyde 2f (20 μL, 0.15 mmol, 1.5 equiv) and isolated as a colorless oil (28.8 mg, 89%). IR (NaCl) 3457, 3024, 2923, 2858, 1659, 1417 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.07−8.22 (m, 1H), 7.47−7.54 (m, 1H), 7.21−7.30 (m, 4H), 7.14− 7.20 (m, 1H), 6.92 (dd, J = 7.3, 5.1 Hz, 1H), 6.10 (ddd, J = 17.1, 10.0, 9.3 Hz, 1H), 5.16−5.35 (m, 3H), 3.95−4.65 (m, 4H), 2.99−3.16 (m, 2H), 2.89 (ddd, J = 13.9, 9.8, 5.4 Hz, 1H), 2.71 (ddd, J = 13.9, 9.8, 6.9 Hz, 1H), 1.87−1.99 (m, 1H), 1.76−1.87 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 173.7, 155.3, 145.7, 142.3, 133.9, 132.8, 128.6 (2C), 128.3 (2C), 126.6, 125.6, 119.8, 118.6, 71.7, 52.1, 46.0, 35.5, 32.1, 24.1; [α]D26 +14 (c 0.13, CHCl3, 99% ee sample); HRMS (ESIOrbitrap): m/z calcd for C20H23N2O2 [M + H]+ 323.1754, found 323.1738. HPLC conditions: CHIRALPAK OJ-H (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 11.3 min (syn-major), 19.3 min (syn-minor). (2R,3S)-6-(tert-Butyldimethylsilyloxy)-1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-hydroxy-2-vinylhexan-1-one (3g). Prepared by the general procedure 1 from 4-(tert-butyldimethylsilyloxy)butanal 2g (30.3 mg, 0.15 mmol, 1.5 equiv) and isolated as a colorless oil (36.7 mg, 92%). IR (NaCl) 3462, 2953, 2856, 1652, 1589, 1421 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06−8.15 (m, 1H), 7.44−7.52 (m, 1H), 6.91 (dd, J = 7.3, 5.1 Hz, 1H), 6.09 (ddd, J = 17.4, 10.3, 8.8 Hz, 1H), 5.29 (ddd, J = 17.4, 2.0, 0.7 Hz, 1H), 5.23 (dd, J = 10.3, 2.0 Hz, 1H), 5.19−5.33 (br, 1H), 4.00−4.35 (m, 4H), 3.58−3.72 (m, 2H), 2.98− 3.13 (m, 2H), 1.51−1.79 (m, 4H), 0.88 (s, 9H), 0.04 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.7, 155.4, 145.8, 133.7, 133.1, 126.4, 119.5, 118.5, 72.3, 63.2, 52.1, 45.9, 30.3, 29.1, 25.9 (3C), 24.0, 18.3, −5.3, −5.3; [α]D26 −7.3 (c 1.82, CHCl3, 99% ee sample); HRMS (ESI-Orbitrap): m/z calcd for C21H35N2O3Si [M + H]+ 391.2411, found 391.2418. HPLC conditions: CHIRALPAK AS-H (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 6/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 4.2 min (syn-major), 6.4 min (syn-minor). (2R,3S)-1-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-hydroxy4-methyl-2-vinylpentan-1-one (3h). Prepared by the general procedure 1 from isobutanal 2h (13.7 μL, 0.15 mmol, 1.5 equiv) with a slight modification, where the use of phloroglucinol was omitted and 200 μL of THF were used, and isolated as a colorless oil (21.1 mg,

81%). IR (film) 3462, 2961, 1645, 1418, 1240 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.10−8.18 (m, 1H), 7.46−7.52 (m, 1H), 6.92 (dd, J = 7.3, 5.1 Hz, 1H), 6.10 (ddd, J = 17.4, 10.3, 9.1 Hz, 1H), 5.55 (br s, 1H), 5.34 (ddd, J = 17.4, 1.9, 0.7 Hz, 1H), 5.24 (dd, J = 10.3, 1.9 Hz, 1H), 4.13 (t, J = 8.7 Hz, 2H), 3.71−4.28 (m, 1H), 3.64 (dd, J = 8.3, 2.7 Hz, 1H), 3.08 (t, J = 8.7 Hz, 2H), 1.72−1.86 (m, 1H), 1.03 (d, J = 6.6 Hz, 1H), 0.99 (d, J = 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 175.0, 155.9, 145.9, 133.7, 132.8, 126.3, 119.5, 118.5, 77.1, 49.4, 45.8, 30.9, 24.1, 19.0, 18.9; [α]D26 −20.8 (c 0.41, CHCl3, 92% ee sample); HRMS (ESI-Orbitrap): m/z calcd for C15H21N2O2 [M + H]+ 261.1598, found 261.1600. HPLC conditions: CHIRALPAK IE (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 12.0 min (syn-major), 15.5 min (syn-minor). General Procedure 2 for Aromatic Aldehydes in Table 3. To a stirred THF solution (200 μL) of amide 1 (18.8 mg, 0.1 mmol), aldehyde (0.15 mmol, 1.5 equiv), and p-methoxyphenol (2.4 mg, 0.02 mmol, 20 mol %) in a flame-dried test tube equipped with a magnetically stirred chip and a three-way stopcock at −70 °C was added a solution of mesitylcopper (1.8 mg, 0.01 mmol, 10 mol %) and L1 (9.4 mg, 0.01 mmol, 10 mol %) in THF (50 μL) via a syringe, and the resulting solution was stirred for 24 h at the same temperature. After the addition of sat aq NH4Cl at −70 °C, the mixture was diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was submitted to 1H NMR analysis to determine the convergent yield and the diastereoselectivity. The crude material was purified by preparative TLC (n-hexane/EtOAc = 1/1). (R)-1-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-((R)-hydroxy(phenyl)methyl)but-3-en-1-one (3i). Prepared by the general procedure 2 from benzaldehyde 2i (15.3 μL, 0.15 mmol, 1.5 equiv) and isolated as a colorless oil (21.9 mg, 74%). IR (film) 3417, 2922, 1653, 1590, 1520, 1423, 1347 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.11−8.22 (m, 1H), 7.46−7.53 (m, 1H), 7.40−7.49 (m, 2H), 7.29− 7.53 (m, 2H), 7.20−7.26 (m, 1H), 6.90−6.97 (m, 1H), 5.94−6.09 (m, 1H), 5.42−5.54 (m, 1H), 4.95−5.10 (m, 1H), 4.95−5.10 (m, 3H), 4.70 (br, 1H), 4.04−4.22 (m, 2H), 2.92−3.13 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 172.9, 145.6, 134.5, 133.9, 128.1 (2C), 128.1, 127.4 (2C), 126.7, 118.6, 118.4, 77.2, 54.8, 46.1, 24.2; [α]D27 +22.4 (c 0.07, CHCl3, 97% ee sample); HRMS (ESI-Orbitrap): m/z calcd for C18H19O2N2 [M + H]+ 295.1438, found 295.1441. HPLC conditions: CHIRALPAK IE (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 15.7 min (anti-major), 19.6 min (anti-minor). (R)-1-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-((R)-hydroxy(naphthalen-2-yl)methyl)but-3-en-1-one (3j). Prepared by the general procedure 2 from 2-naphthoaldehyde 2j (23.4 mg, 0.15 mmol, 1.5 equiv) and isolated as a colorless oil (21.0 mg, 61%). IR (film) 3428, 2921, 1632, 1422, 1241 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.13−8.22 (m, 1H), 7.76−7.88 (m, 4H), 7.57−6.63 (m, 1H), 7.51−7.43 (m, 3H), 6.98−6.88 (m, 1H), 5.99−6.14 (m, 1H), 5.70−5.54 (br, 1H), 5.27−4.61 (m, 4H), 4.21−3.99 (m, 2H), 3.11− 2.96 (m, 1H), 2.96−2.83 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 173.9, 155.6, 145.7, 140.1, 134.5, 133.9, 133.1, 132.9, 128.1, 127.8, 127.6, 126.7, 126.3, 125.9, 125.7, 124.6, 118.6, 118.5, 77.2, 54.6, 46.1, 24.1; [α]D27 +3.0 (c 0.065, CHCl3, 98% ee sample); HRMS (ESIOrbitrap): m/z calcd for C22H21N2O2 [M + H]+ 345.1598, found 345.1596. HPLC conditions: CHIRALPAK IE (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 28.2 min (anti-major), 26.0 min (anti-minor). (R)-2-((R)-(4-Chlorophenyl)(hydroxy)methyl)-1-(2,3-dihydro-1Hpyrrolo[2,3-b]pyridin-1-yl)but-3-en-1-one (3k). Prepared by the general procedure 2 from p-chlorobenzaldehyde 2k (21.1 mg, 0.15 mmol, 1.5 equiv) and isolated as a colorless oil (19.7 mg, 69%). IR (film) 3422, 3009, 1658, 1589, 1422 cm−1; 1H NMR (600 MHz, 253 K, CDCl3) δ 8.13−8.18 (m, 1H), 7.33−7.58 (m, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 6.99 (dd, J = 7.2, 5.2 Hz, 1H), 6.01 (ddd, J = 17.2, 10.3, 8.5 Hz, 1H), 5.48 (d, J = 8.6 Hz, 1H), 5.26 (t, J = 8.6 Hz, 1H), 5.03 (dd, J = 10.3, 0.7 Hz, 1H), 4.92−4.99 (m, 2H), 4.19 (ddd, J = 11.7, 10.3, 4.5 Hz, 1H), 4.06 (ddd, J = 11.7, 10.3, 8.5 Hz, 5855

DOI: 10.1021/acs.joc.8b00743 J. Org. Chem. 2018, 83, 5851−5858

Note

The Journal of Organic Chemistry 1H), 3.07−3.15 (m, 1H), 3.03 (ddd, J = 16.5, 10.3, 4.5 Hz, 1H); 13C NMR (150 MHz, 253 K, CDCl3) δ 172.5, 155.3, 145.3, 141.1, 134.3, 134.0, 132.8, 128.2, 128.0 (2C), 127.0 (2C), 119.0, 118.9, 76.2, 55.0, 46.3, 24.2; [α]D27 +2.9 (c 0.55, CHCl3, 96% ee sample); HRMS (ESIOrbitrap): m/z calcd for C18H18ClN2O2 [M + H]+ 329.1051, found 329.1061. HPLC conditions: CHIRALPAK AD-H (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 14.1 min (anti-major), 19.1 min (anti-minor). (R)-2-((R)-(4-Bromophenyl)(hydroxy)methyl)-1-(2,3-dihydro-1Hpyrrolo[2,3-b]pyridin-1-yl)but-3-en-1-one (3l). Prepared by the general procedure 2 from p-bromobenzaldehyde 2l (27.8 mg, 0.15 mmol, 1.5 equiv) and isolated as a colorless oil (23.0 mg, 62%). IR (film) 3428, 3010, 1649, 1590, 1423 cm−1; 1H NMR (600 MHz, 253 K, CDCl3) δ 8.15−8.19 (m, 1H), 7.55−7.60 (m, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.01 (dd, J = 7.2, 5.0 Hz, 1H), 6.03 (ddd, J = 17.3, 10.1, 8.1 Hz, 1H), 5.50 (d, J = 8.1 Hz, 1H), 5.28 (t, J = 8.1 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H), 4.94−4.99 (m, 2H), 4.21 (td, J = 10.3, 5.0 Hz, 1H), 4.04−4.11 (m, 1H), 3.09−3.17 (m, 1H), 3.05 (ddd, J = 16.6, 10.3, 5.0 Hz, 1H); 13C NMR (150 MHz, 254 K, CDCl3) δ 172.5, 155.3, 145.3, 141.6, 134.3, 134.0, 131.1 (2C), 128.3 (2C), 127.0, 121.1, 119.0, 118.9, 76.2, 54.9, 46.3, 24.2; [α]D26 +3.1 (c 0.27, CHCl3, 97% ee sample); HRMS (ESI): m/z calcd for C18H18BrN2O2 [M + H]+ 373.0546, found 373.0543. HPLC conditions: CHIRALPAK AD-3 (ϕ 0.46 cm × 25 cm), n-hexane/ IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 21.2 min (anti-major), 25.0 min (anti-minor). (R)-1-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-((R)-hydroxy(4-nitrophenyl)methyl)but-3-en-1-one (3m). Prepared by the general procedure 2 from p-nitrobenzaldehyde 2m (22.7 mg, 0.15 mmol, 1.5 equiv) and isolated as a colorless oil (20.0 mg, 59%). IR (film) 3413, 2920, 1640, 2349, 1423 cm−1; 1H NMR (600 MHz, 253 K, CDCl3) δ 8.20 (d, J = 8.6 Hz, 2H), 8.16 (br d, J = 5.1 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.56 (br d, J = 7.2 Hz, 1H), 7.01 (dd, J = 5.1 Hz, 1H), 6.05 (ddd, J = 17.4, 10.1, 8.6 Hz, 1H), 5.80 (br d, J = 9.1 Hz, 1H), 5.34 (br t, J = 8.0 Hz, 1H), 5.06−5.11 (m, 2H), 4.98 (br d, J = 17.4 Hz, 1H), 4.19 (td, J = 10.4, 4.2 Hz, 1H), 4.03 (ddd, J = 11.7, 9.6, 8.6 Hz, 1H), 3.08−3.16 (m, 1H), 3.03 (ddd, J = 16.4, 10.7, 4.6 Hz, 1H); 13C NMR (150 MHz, 253 K, CDCl3) δ 172.1, 155.1, 150.3, 146.8, 145.3, 134.4, 133.6, 127.4 (2C), 127.0, 123.4 (2C), 119.5, 119.1, 76.0, 54.6, 46.2, 24.2; [α]D26 +26.3 (c 0.1, CHCl3, 95% ee sample); HRMS (ESIOrbitrap): m/z calcd for C18H18N3O4 [M + H]+ 340.1292, found 340.1285. HPLC conditions: CHIRALPAK ID-H (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 24.0 min (anti-major), 19.9 min (anti-minor). (2R,3R)-1-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-hydroxy5-(triisopropylsilyl)-2-vinylpent-4-yn-1-one (3n). Prepared by the general procedure 1 from 3-(triisopropylsilyl)propiolaldehyde (2n) (16 μL, 0.15 mmol, 1.5 equiv) and isolated as an amorphous solid (3n) (32 mg, 96%). IR (film) 3428, 2944, 2865, 1643, 1590, 1423 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08−8.15 (m, 1H), 7.47−7.56 (m, 1H), 6.93 (dd, J = 7.3, 5.1 Hz, 1H), 6.11 (dd, J = 17.4, 10.3, 8.3 Hz, 1H), 5.47 (br s, 1H), 5.36 (ddd, J = 17.4, 1.4, 1.1 Hz, 1H), 5.24 (d, J = 10.3 Hz, 1H), 4.58−4.66 (m, 2H), 4.15 (t, J = 8.8 Hz, 1H), 2.98− 3.15 (m, 2H), 0.87−1.73 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 172.3, 155.5, 145.9, 133.8, 133.6, 126.4, 119.2, 118.6, 107.7, 85.5, 65.3, 53.8, 45.9, 24.1, 18.5 (3C), 18.5 (3C), 11.1 (3C); [α]D27 +5.6 (c 0.31, CHCl3, 96% ee sample); HRMS (ESI-Orbitrap): m/z calcd for C23H35N2O2Si [M + H]+ 399.2462, found 399.2463. HPLC conditions: CHIRALPAK IC (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 3/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 7.0 min (antimajor), 8.4 min (anti-minor). (2R,3S)-5-(tert-Butyldimethylsilyloxy)-1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-hydroxy-2-vinylpentan-1-one (3o). Prepared by the general procedure 1 from 3-(tert-butyldimethylsilyloxy)propanal (2o) (28.2 mg, 0.15 mmol, 1.5 equiv) and isolated as a colorless oil (30.0 mg, 80%). IR (film) 3474, 2954, 2856, 1653, 1589, 1421 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.07−8.19 (m, 1H), 7.45− 7.53 (m, 1H), 6.91 (dd, J = 7.3, 4.9 Hz, 1H), 6.11 (ddd, J = 17.4, 10.3, 8.7 Hz, 1H), 5.31 (ddd, J = 17.4, 2.0, 0.7 Hz, 1H), 5.24 (dd, J = 10.3, 2.0 Hz, 1H), 5.18−5.27 (br, 1H), 4.26 (dt, J = 8.7, 4.2 Hz, 1H), 4.00−

4.55 (br, 1H), 4.06−4.21 (m, 2H), 3.77−3.88 (m, 2H), 2.98−3.14 (m, 2H), 1.71−1.84 (m, 2H), 0.88 (s, 9H), 0.06 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.7, 155.5, 145.8, 133.7, 133.5, 126.4, 119.3, 118.4, 70.6, 61.0, 52.6, 45.9, 36.5, 25.9 (3C), 24.1, 18.3, −5.4, −5.4; [α]D26 −5.8 (c 0.78, CHCl3, 99% ee sample); HRMS (ESIOrbitrap): m/z calcd for C20H33N2O3Si [M + H]+ 377.2255, found 377.2243. HPLC conditions: CHIRALPAK OZ-H (ϕ 0.46 cm × 25 cm), n-hexane/IPA = 6/1, detection at 254 nm, flow rate 1.0 mL/min, tR = 7.2 min (syn-major), 11.2 min (syn-minor). (2R,3S)-3,5-Bis(tert-butyldimethylsilyloxy)-1-(2,3-dihydro-1Hpyrrolo[2,3-b]pyridin-1-yl)-2-vinylpentan-1-one (10). To a stirred solution of amide 3o (1.3 g, 3.45 mmol) and 2,6-lutidine (1.0 mL, 8.6 mmol) in CH2Cl2 at 0 °C was added TBSOTf (1.0 mL, 4.49 mmol), and the resulting reaction mixture was stirred for 1 h at the same temperature. After the addition of sat aq NaHCO3 at 0 °C, the mixture was diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude mixture was purified by silica gel column chromatography (n-hexane/EtOAc = 8/1 to 4/1) to give amide 10 as a colorless oil (1.61 g, 95%). IR (film) 2954, 2856, 1661, 1422, 1254, 1094 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.07−8.13 (m, 1H), 7.42−7.49 (m, 1H), 6.87 (dd, J = 7.3, 5.1 Hz, 1H), 6.06−6.18 (m, 1H), 5.19−5.23 (m, 1H), 5.17 (s, 1H), 5.03−5.14 (m, 1H), 4.28 (q, J = 5.6 Hz, 1H), 4.09 (t, J = 8.6 Hz, 2H), 3.68−3.79 (m, 2H), 2.98−3.07 (m, 2H), 1.76−1.97 (m, 2H), 0.87 (s, 9H), 0.85 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H), −0.01 (s, 3H), −0.02 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 172.1, 155.8, 146.0, 135.4, 133.4, 126.0, 118.1, 117.9, 70.7, 59.9, 54.3, 45.9, 39.0, 26.0 (3C), 25.9 (3C), 24.0, 18.3, 18.1, −4.4, −4.6, −5.3, −5.3; [α]D26 −41.1 (c 1.1, CHCl3); HRMS (ESIOrbitrap): m/z calcd for C26H47N2O3Si2 [M + H]+ 491.3120, found 491.3135. (2S,3S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-vinylpentan-1-ol (5). To a stirred solution of borane−ammonia complex (18.5 mg, 0.60 mmol) in THF (1 mL) at 0 °C was added LDA (600 μL, 0.6 mmol, 1 M in THF), and the resulting mixture was stirred for 1 h at room temperature. After addition of amide 10 (100 mg, 0.20 mmol) in THF (250 μL) at 0 °C, the resulting mixture was allowed to warm up at room temperature and stirred for 1 h. After the addition of sat aq NaHCO3 at 0 °C, the mixture was diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude mixture was purified by silica gel column chromatography (n-hexane/EtOAc = 10/1 to 4/1) to give amide 5 as a colorless oil (72 mg, 97%). IR (film) 3649, 2955, 1472, 1256, 1098 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.72 (ddd, J = 17.4, 10.5, 8.6 Hz, 1H), 5.21 (ddd, J = 10.5, 2.0, 0.7 Hz, 1H), 5.14 (ddd, J = 17.4, 2.0, 1.0 Hz, 1H), 4.02 (ddd, J = 6.6, 6.1, 2.9 Hz, 1H), 3.78 (dd, J = 10.5, 7.3 Hz, 1H), 3.59−3.70 (m, 3H), 2.445−2.53 (m, 1H), 1.645−1.76 (m, 2H), 0.90 (s, 9H), 0.90 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.05 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 135.6, 118.3, 70.8, 63.7, 59.6, 51.0, 36.8, 25.8, 18.2, 18.0, −4.5, −4.6, −5.3, −5.3; [α]D26 −18.5 (c 0.38, CHCl3); HRMS (ESI-Orbitrap): m/ z calcd for C19H43O3Si2 [M + H]+ 375.2745, found 375.2750. (2S,3S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-vinylpentyl Acrylate (6). To a stirred solution of alcohol 5 (27 mg, 0.072 mmol), Et3N (12 μL, 0.86 mmol), and dimethylaminopyridine (0.9 mg, 0.0072 mmol) in CH2Cl2 (200 μL) at 0 °C was added acryloyl chloride (7 μL, 0.079 mmol). After the mixture was stirred for 12 h at room temperature, another portion of Et3N (12 μL, 0.86 mmol) and acryloyl chloride (7 μL, 0.079 mmol) was added, and the resulting mixture was stirred for 8 h. After the addition of sat aq NaHCO3 at 0 °C, the mixture was diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude mixture was purified by silica gel column chromatography (n-hexane/EtOAc = 20/1 to 10/1) to give amide 5 as a colorless oil (28.5 mg, 92%). IR (film) 2954, 2856, 1661, 1422, 1254, 1094 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.40 (dd, J = 17.3, 1.5 Hz, 1H), 6.12 (dd, J = 17.3, 10.5 Hz, 1H), 5.82 (dd, J = 9.1, 1.5 Hz, 1H), 5856

DOI: 10.1021/acs.joc.8b00743 J. Org. Chem. 2018, 83, 5851−5858

Note

The Journal of Organic Chemistry 5.78 (ddd, J = 17.3, 10.5, 8.8 Hz, 1H), 5.19 (dd, J = 10.5, 2.0 Hz, 1H), 5.14 (ddd, J = 17.4, 2.0, 0.7 Hz, 1H), 4.16−4.25 (m, 2H), 4.03−4.09 (m, 1H), 3.56−3.66 (m, 2H), 2.52−2.59 (m, 1H), 1.62−1.76 (m, 2H), 0.90 (s, 9H), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 134.6, 130.5, 128.5, 118.6, 86.3, 64.7, 59.5, 48.0, 37.7, 25.9 (3C), 25.9 (3C), 18.2, 18.1, −4.3, −4.8, −5.4, −5.4; [α]D26 −4.4 (c 0.32, CHCl3); HRMS (ESI-Orbitrap): m/z calcd for C22H45O4Si2 [M + H]+ 429.2851, found 429.2860. (S)-5-((S)-2,2,3,3,9,9,10,10-Octamethyl-4,8-dioxa-3,9-disilaundecan-5-yl)-5,6-dihydro-2H-pyran-2-one (7). To a stirred solution of ester 6 (15.5 mg, 0.036 mmol) in CH2Cl2 (200 μL) at room temperature was added Grubbs II catalyst (1.5 mg, 0.0018 mmol), and the resulting reaction mixture was stirred for 12 h under reflux conditions. After the addition of sat aq NaHCO3 at 0 °C, the mixture was diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude mixture was purified by silica gel column chromatography (n-hexane/EtOAc = 20/1 to 10/1) to give lactone 7 as a colorless oil (13.5 mg, 94%). IR (film) 2929, 1733, 1472, 1256, 1096 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.88 (dd, J = 9.9, 3.7 Hz, 1H), 6.05 (dd, J = 9.9, 2.0 Hz, 1H), 4.36−4.47 (m, 2H), 3.97−4.04 (m, 1H), 3.62−3.76 (m, 2H), 2.76−2.84 (m, 1H), 1.64−1.80 (m, 1H), 0.89 (s, 9H), 0.89 (s, 9H), 0.08 (s, 3H), 0.062 (s, 3H), 0.05 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.9, 147.4, 121.4, 68.9, 68.3, 58.8, 39.7, 36.9, 25.8 (3C), 25.7 (3C), 18.1, 18.0, −4.5, −4.8, −5.4, −5.4; [α]D26 −5.9 (c 0.65, CHCl3); HRMS (ESIOrbitrap): m/z calcd for C20H41O4Si2 [M + H]+ 401.2538, found 401.2527. (4R,5S)-4-(3-Methylbut-3-en-1-yl)-5-((S)-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-5-yl)tetrahydro-2H-pyran-2one (8). To a stirred suspension of Mg (14.6 mg, 0.6 mmol) in diethyl ether (400 μL) under reflux conditions were added a drop of dibromoethane and 4-iodo-2-methybut-1-ene (75 μL, 0.6 mmol). After stirring for 30 min, the resulting mixture was added to a stirred suspension of CuI (19 mg, 0.1 mmol) in diethyl ether (500 μL) at −10 °C, and the resulting mixture was stirred for 30 min at the same temperature. To the resulting reaction mixture at −78 °C was added a solution of lactone 7 (40.1 mg, 0.1 mmol) in diethyl ether (200 μL), and the reaction solution was stirred for 2 h at the same temperature. After the addition of sat aq NH4Cl at 0 °C, the mixture was diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude mixture was purified by silica gel column chromatography (n-hexane/ EtOAc = 10/1 to 4/1) to give amide 8 as a colorless oil (45.2 mg, 96%). 1H NMR (400 MHz, CDCl3) δ 4.74 (brs, 1H), 4.68 (br s, 1H), 4.28 (dd, J = 11.7, 5.6 Hz, 1H), 4.27 (dd, J = 11.7, 7.1 Hz, 1H), 3.95 (dt, J = 8.1, 3.4 Hz, 1H), 3.60−3.72 (m, 2H), 2.62 (dd, J = 15.4, 6.4 Hz, 1H), 2.31 (dd, J = 15.4, 7.1 Hz, 1H), 1.95−2.13 (m, 2H), 1.82− 1.94 (m, 2H), 1.72 (s, 3H), 1.52−1.69 (m, 3H), 1.39−1.51 (m, 1H), 0.89 (s, 9H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H), 0.04 (s, 6H); [α]D26 −24.2 (c 0.33, CHCl3); IR, 13C NMR, and MS data were consistent with reported values.14 (S)-1-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-((R)-1(triethylsilyloxy)ethyl)but-3-en-1-one (11). To a stirred solution of alcohol ent-3b (133.3 mg, 0.57 mmol) and imidazole (172 mg, 2.5 mmol) in DMF was added TESCl (90 μL, 0.75 mmol) at 0 °C, and the resulting reaction mixture was stirred for 12 h at room temperature. After the addition of sat aq NaHCO3 at 0 °C, the mixture was diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude mixture was purified by silica gel column chromatography (n-hexane/EtOAc = 40/1 to 8/1) to give amide 11 as a colorless oil (193 mg, 97%). IR (film) 2955, 2876, 1656, 1419, 1241, 1108 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08−8.15 (m, 1H), 7.42− 7.48 (m, 1H), 6.87 (dd, J = 7.3, 5.1 Hz, 1H), 6.12 (ddd, J = 17.4, 10.3, 8.8 Hz, 1H), 5.22 (ddd, J = 17.4, 2.0, 1.0 Hz, 1H), 5.16 (ddd, J = 10.3,

2.0, 0.5 Hz, 1H), 5.10−5.24 (br, 1H), 4.29 (dt, J = 13.0, 6.1 Hz, 1H), 4.06−4.14 (m, 2H), 3.03 (tt, J = 8.6, 1.0 Hz, 2H), 1.23 (d, J = 6.1 Hz, 3H), 0.93 (t, J = 8.0 Hz, 9H), 0.57 (q, J = 8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 172.4, 155.8, 146.0, 135.8, 133.3, 126.0, 118.0, 117.8, 70.1, 56.0, 45.8, 24.1, 22.3, 6.8 (3C), 4.9 (3C); [α]D26 +52.8 (c 0.62, CHCl3); HRMS (ESI-Orbitrap): m/z calcd for C19H31N2O2Si [M + H]+ 347.2149, found 347.2151. (S)-2-((S)-1-(Triethylsilyloxy)ethyl)but-3-en-1-ol (9). To a stirred solution of borane−ammonia complex (13.3 mg, 0.43 mmol) in THF (1 mL) at 0 °C was added LDA (430 μL, 0.43 mmol, 1 M in THF), and the resulting mixture was stirred for 1 h at room temperature. After addition of amide 11 (50 mg, 0.144 mmol) in THF (200 μL) at 0 °C, the resulting mixture was allowed to warm up to room temperature and stirred for 1 h. After the addition of sat aq NaHCO3 at 0 °C, the mixture was diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude mixture was purified by silica gel column chromatography (n-hexane/EtOAc = 40/1 to 10/1) to give amide 9 as a colorless oil (32.5 mg, 98%). [α]D26 +4.5 (c 0.18, CHCl3); IR, 1H and 13C NMR, and MS data were consistent with reported values.18

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00743. Details for the determination of absolute configuration, X-ray crystallographic data, copies of HPLC traces and NMR spectra (PDF) Crystallographic data for 3b (CIF) Crystallographic data for 3n (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Naoya Kumagai: 0000-0003-1843-2592 Masakatsu Shibasaki: 0000-0001-8862-582X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by JST, ACT-C (JPMJCR12YO), and KAKENHI (16K18856) from JSPS. This work was partially supported by JSPS KAKENHI Grant Number JP16H01043 in Precisely Designed Catalysts with Customized Scaffolding. N.K. thanks the Naito Foundation for financial support. Dr. Tomoyuki Kimura at Institute of Microbial Chemistry and Dr. Hiroyasu Sato at Rigaku Corporation are gratefully acknowledged for assistance in the X-ray crystallographic analysis of 3c and 3n.

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REFERENCES

(1) (a) Trost, B. M. The atom economy–a search for synthetic efficiency. Science 1991, 254, 1471. (b) Handbook of Green Chemistry; Anastas, P. T., Ed.; Wiley-VCH: Weinheim, 2009. (2) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Direct catalytic asymmetric aldol reactions of aldehydes with unmodified ketones. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871. (b) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. Direct catalytic asymmetric aldol reaction. J. Am. Chem. Soc. 1999, 121, 4168. (c) List, B.; Lerner, R. A.; Barbas, C. F., III Proline-catalyzed 5857

DOI: 10.1021/acs.joc.8b00743 J. Org. Chem. 2018, 83, 5851−5858

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DOI: 10.1021/acs.joc.8b00743 J. Org. Chem. 2018, 83, 5851−5858