ARTICLE

https://doi.org/10.1038/s41467-020-20727-7 OPEN Passerini-type reaction of boronic acids enables α-hydroxyketones synthesis ✉ Kai Yang1, Feng Zhang1, Tongchang Fang1, Chaokun Li1, Wangyang Li1 & Qiuling Song 1

Multicomponent reactions (MCRs) facilitate the rapid and diverse construction of molecular scaffolds with modularity and step economy. In this work, engagement of boronic acids as carbon nucleophiles culminates in a Passerini-type three-component coupling reaction α 1234567890():,; towards the synthesis of an expanded inventory of -hydroxyketones with skeletal diversity. In addition to the appealing features of MCRs, this protocol portrays good tolerance, broad substrate scope under mild conditions and operational simplicity. The utility of this is further demonstrated by amenable modifications of bioactive products and pharmaceuticals as well as in the functionalization of products to useful compounds.

1 Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian 350108, ✉ China. email: [email protected]

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-Hydroxyketones (also known as acyloins) are structural intriguing access to α-hydroxyketone products; yet such synthetic units ubiquitously found in natural products1–5 and maneuver remains underexplored59,60. Central to the successful α 6,7 pharmaceuticals . They are also oft-employed synthetic establishment of this chemistry would lie in choosing suitable precursors in a panel of high-value transformations (Fig. 1a)8–13. carbon nucleophiles that would not interfere with the formation The construction of these important molecules is therefore the of the nitrilium intermediate while possess sufficient nucleophi- subject of substantial synthetic efforts14. Traditional benzoin licity to capture this electrophile. condensation method assembles α-hydroxyketones via con- On the other hand, boronic acids are easily available, benign and densation of different , thus limits its applicability common building blocks for C-C bond cross-coupling reactions, in within this substrate class15–17. The alternate oxidative pathways both transition-metal catalysis61,62 and metal-free that encompass α-hydroxylation of ketones18–22 and ketohy- regimes63–75. In boronic acid-Mannich reaction (or Petasis reac- droxylation of olefins23–27 are certainly enabling, but continues to tion), for instance, the nucleophilic feature of boronic acids effects be challenged in terms of substrate diversity and poor selectivity. the formation of “ate” complex, leading to functionalized Hence, devising complementary routes towards these useful amines following 1,3-metallate migration (Fig. 1c)76–80.Tothisend, entities from readily available starting materials is highly relevant a recent endeavor of our group has unraveled a 1,4-metallate shift of and desirable. boron “ate” nitrilium species generated from nitrile oxide and Multicomponent reactions (MCRs) are often prized for their arylboronic acid, thus mediating stereospecific formation of C-C concise and modular features in forging complex molecules with bond between oxime chlorides and arylboronic acids under metal- synthetic and biological interest28–36. The representative Passerini free conditions81. Grounded in these knowledges, we envisioned reaction37–46 or Ugi reaction47–54 efficiently assembles α-acy- that a boron “ate” nitrilium intermediate could be released from co- loxyamides or α-acylaminoamides from several reactant compo- treatment of , , and boronic acid; 1,4-metallate nents via the intermediacy of nitrilium species in single-pot shift of which will invoke C-C bond coupling and α-hydro- operation (Fig. 1b)55–58. Interception of this electrophilic inter- xyketones could be revealed on hydrolysis (Fig. 1d). Here, we dis- mediate in Passerini reaction pathway by carbon nucleophiles (in close the development of a Passerini-type coupling reaction, which place of conventionally used carboxylic acids) would offer an afforded α-hydroxyketones from the combination of readily

a OH OH OH O CO2H OH O O O OH HO O O O MeO O O OH O OH OH OH O OH OH O Phenatic acid B Hypothemycin Taxifolin NR2 N O O N H N OH N OH N H O O R Versatile Precursors Inhibitors of amyloid-β protein production

b c

O O O O H R2 R3 O 4 2 3 1 3 N N R R R R H R OH O R3 1 2 3 XH R3 X C R H R R OH N NHR B 2 4 R1 O OH 1 R 1 4 RNH2 R2 NC R O R1 R R N R2 B H X = O, α-Acyloxyamides HO OH Functionalized nitrilium boron "ate" amines X = NR, α-Acylaminoamides

d O ◊ multicomponent reaction OH R2 NC 1 Transition-metal-free R H R3 ◊ mild conditions R1 1 3 R = alkyl, aryl; R = aryl, alkenyl, alkynyl O R3 [B] ◊ good functional group tolerance α-Hydroxyketone ◊ broad substrate scope O[B] 3 [B] [B] R 3 H2O O 3 R ◊ gram-scale O R R1 R1 N ◊ synthetic applications 1 R 2 N R2 CNR R2 boron "ate" nitrilium

Fig. 1 Precedent works and proposed Passerini-type coupling reaction with boronic acids as nucleophilic agents. a α-Hydroxyketones in bioactive moleculars or as synthetic precursors. b Classic Passerini or . c Petasis boronic acid-Mannich reaction. d Passerini-type coupling reaction of boronic acids (this work).

2 NATURE COMMUNICATIONS | (2021) 12:441 | https://doi.org/10.1038/s41467-020-20727-7 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-20727-7 ARTICLE available aldehydes, , and boronic acids (aryl, alke- Scope of aldehydes. Having optimized the model coupling of this nylboronic acids, and alkynyl trifluoroborate salts) under transition- Passerini-type reaction, we examined the generality of these metal-free conditions. Mild reaction conditions, ease of execution, conditions with respect to a range of aldehyde components high functional group tolerance, broad substrate scope, and utility (Fig. 2). Delightfully, diverse aliphatic aldehydes were aptly are practical features of this methodology. transformed in moderate to high yields. Phenylpropyl aldehydes with strong electron-withdrawing groups and 3-(furan-2-yl)pro- panal furnished the α-hydroxyketone products 4b–4d in 66% to Results 90% yields. The chain length of aldehydes posed no effect on the Investigation of reaction conditions. Exploratory investigations effectiveness of this reaction, providing respective α-hydro- towards our envisioned Passerini-type reaction involving xyketones (4e–4g) in moderate yields. Primary aldehydes bearing boronic acids were conducted with phenylpropyl aldehyde (1a), ester, adamantyl, and benzyloxy moieties were tolerated well to tertbutyl isocyanide (2a) and 4-methoxyphenyl boronic acid yield 4h–4j in moderate efficiencies. Secondary aldehydes com- (3a) as test substrates (Table 1). To our delights, simple mixing prised of acyclic and cyclic analogs (cyclopropyl, cyclohexyl, of the three reactants (1a, 2a,and3a) without any other piperidinyl) were incorporated in 4k–4q with moderate to good additive in DCM furnished the desired α-hydroxyketone pro- yields as well. The diastereomeric ratios (dr) of compounds 4l and duct 4a in 60% isolated yield (entry 1). A screen of 4n are 1.13:1 and 1.38:1. Comparable outcome was observed for a DCE, MeCN, toluene, MeOH, and THF revealed that the best tertiary 1-phenylcyclobutane-1-carbaldehyde substrate, which fi reaction ef ciency was endowed by CHCl3,whereasusing afforded 4r in 54% yield. It merits mention that transformation of MeOH caused a complete reaction inhibition (entries 1−7). As paraformaldehyde has given rise to 4s, which serves as versatile reaction temperature was decreased to 10 °C, the yield of 4a synthetic intermediate for a variety of bioactive molecules. More improved to 68% (entry 8). Binary mixture of CHCl3 and water importantly, this reaction was well suited to diverse aromatic in a ratio of 7:3 (entries 9−11) minimally but meaningfully aldehydes when treated in concert with cyclohexyl isocyanide enhanced the delivery of 4a to 72% yield (entry 11). This has (2b). The electronic property and the position of substituents on guided our subsequent study of mixed solvent system with the benzene ring had minimal bearing on the efficiency of this – CHCl3 against various buffer solutions (entries 12−15) where transformation. Neutral (4t), electron-rich (4u 4y), or electron- the combination with pH = 8.0 buffer delightfully provided deficient (4z–4aa) functionalities found good compatibility and 81% yield of target product (entry 14). We reasoned that a basic were left unscathed in respective molecular outputs. The – fi reaction medium could sequester the byproduct B(OH)3 gen- accommodation of halogen substituents (4ab 4ae) signi ed erated during reaction, thus promoting this boronic acid- potential structural elaborations from these handles. Fused ring involved Passerini-type reaction. It was further established that reactants including 2-naphthaldehyde (4af) and 1- on replacement of tertbutyl isocyanide (2a) with cyclohexyl naphthaldehyde (4ag) were also suitable candidates for this MCR. isocyanide (2b), benzyl isocyanide (2c), or ethyl 2- isocyanoacetate (2d), formation efficiency of α-hydroxyketone product 4a was diminished (entry 16). None of the other ratios Scope of boronic acids. This protocol featured an admirable scope of the three reagents resulted in higher yields (entries 17−18). with respect to arylboronic acid substrates (Fig. 3). For electron-rich

Table 1 Optimization of the reaction conditionsa.

OMe 2a, R = tert-butyl O OH ++RNC MeO B(OH)2 2b, R = cyclohexyl Ph Ph H 2c, R = benzyl O 2d, R = ethoxycarbonylmethyl 1a 2 3a 4a

Entries Isocyanide 1a:2:3a Solvent Temp. (°C) Yield (%)b 1 2a 1:1.5:1.8 DCM rt 60 2 2a 1:1.5:1.8 DCE rt 55 3 2a 1:1.5:1.8 CHCl3 rt 64 4 2a 1:1.5:1.8 MeCN rt 50 5 2a 1:1.5:1.8 toluene rt 48 6 2a 1:1.5:1.8 MeOH rt N.R 7 2a 1:1.5:1.8 THF rt 30 8 2a 1:1.5:1.8 CHCl3 10 68 9 2a 1:1.5:1.8 CHCl3/H2O (3:7) 10 62 10 2a 1:1.5:1.8 CHCl3/H2O (1:1) 10 67 11 2a 1:1.5:1.8 CHCl3/H2O (7:3) 10 72 12 2a 1:1.5:1.8 CHCl3/pH = 6.5 buffer (7:3) 10 66 13 2a 1:1.5:1.8 CHCl3/pH = 7.8 buffer (7:3) 10 74 14 2a 1:1.5:1.8 CHCl3/pH = 8.0 buffer (7:3) 10 81 15 2a 1:1.5:1.8 CHCl3/pH = 9.0 buffer (7:3) 10 79 16 2b/2c/2d 1:1.5:1.8 CHCl3/pH = 8.0 buffer (7:3) 10 55/21/trace 17 2a 1:1:1 CHCl3/pH = 8.0 buffer (7:3) 10 52 18 2a 1:1.2:1.8 CHCl3/pH = 8.0 buffer (7:3) 10 62 aReaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 3a (0.36 mmol), and solvent (1 mL) under an argon atmosphere for 24 hours unless otherwise specified. bIsolated yield.

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CHCl3/ pH = 8 buffer OMe OH O or DCM/ pH = 8 buffer + RNC + MeO B(OH)2 R H 10 °C or rt R 2a, R = tert-butyl O 12b, R = cyclohexyl 3a 4

OMe OMe OH OH OMe OMe OH OH O Me O O O O O2N F3C 4b, 66% with 2a, rt 4c, 85% with 2a, 10 °C 4d, 90% with 2a, 10 °C 4e, 57% with 2a, 10 °C OMe OMe OMe OMe OH OH O OH HO EtO O O O O 4f. 68% with 2a, rt 4g, 59% with 2a, 10 °C 4h, 68% with 2a, 10 °C 4i, 42% with 2a, rt OMe OMe OMe OMe OH OH OH OH Ph O

O O O O 4j, 66% with 2a, 10 °C 4k, 61% with 2a, 10 °C 4l, 44% with 2a, 10 °C, dr: 1.13:1b 4m, 45% with 2a, 10 °C

OMe OMe OMe OMe OH OH OH OH H Ph

O O O N O MeO2C Boc 4n, 57% with 2a, 10 °C, dr: 1.38:1b 4o with 2a, 69%, rt 4p, 76% with 2a, rt 4q, 80% with 2a, rt OMe OMe OMe OMe OH OH OH Ph HO O O O O MeS 4r, 54% with 2a, 10 °C 4s, 38% with 2a, 10 °C 4t, 70% with 2b, 38% with 2a, rt 4u, 45% with 2b, rt 5 mmol trace with 2c, 2d, rt OMe OMe OMe OMe OH OH OH OH Me Me Me O O O O Me Me Me 4v, 47% with 2b, rt 4w, 48% with 2b, rt 4x, 53% with 2b, rt 4y, 51% with 2b, rt OMe OMe OMe OMe OH OH OH OH

MeO2C Me Cl

O O O O MeO2C F 4z, 60% with 2b, rt 4aa, 42% with 2b, rt 4ab, 49% with 2b, 10 °C 4ac, 49% with 2b, 10 °C OMe OMe OMe OMe OH OH OH OH I

O Br O O O 4ad, 50% with 2b, rt 4ae, 69% with 2b, rt 4af, 62% with 2b, rt 4ag, 55% with 2b, rt

a a Fig. 2 Scope of aldehydes . Reaction conditions: aldehyde 1 (0.2 mmol, 1 equiv), 2a (0.3 mmol), 3a (0.36 mmol), and CHCl3/pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours unless otherwise specified; bThe dr was determined by 1H NMR analysis. caldehyde 1 (0.2 mmol, 1 equiv), 2b (0.3 mmol), 3a (0.36 mmol), and DCM/pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours. congeners, good reactivities were exhibited. Arylboronic acids with dibenzothiophene (5w)andcarbazole(5x) cores. Remarkably, both electronically neutral meta-para-dimethyl, para-methyl, and para- aryl and alkyl substituted alkenylboronic acids could rendered the tertbutyl substituents produced α-hydroxyketones 5a–5c in mod- corresponding α-hydroxy enones 5y and 5z in 82% and 63% yields, erate yields. Analogs with electron-rich substituents such as acetal, which broadly expand the scope of the products. For electron- alkoxy, and diphenylamino groups reacted smoothly towards pro- deficient substituted boronic acids, such as the halobenzene boronic ducts 5d–5l in 51–85% yields. Inclusion of alkenyl or alkynyl group acids, only trace amounts of products could be obtained, which was noteworthy; from which products 5j and 5k were acquired in probably is due to their low nucleophilicity that cannot capture the 80% and 77% yield. This study was auspiciously and effortlessly nitrilium intermediates. Aliphatic boronic acids, such as phe- extendable to a series of heteroarylboronic acids containing furan nethylboronic acid and cyclopentylboronic acid, do not react under (5m), thiophene (5n–5p), benzofuran (5q), benzothiophen (5r), our standard conditions, perhaps owing to the lack of π electrons protected or unprotected indoles (5s, 5u), 7-azaindole (5t), which makes 1,4-alkyl shift difficult68.

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OH O CHCl3/ pH = 8 buffer R' B(OH) R' + tBu NC + 2 R R H or DCM/ pH = 8 buffer O 12a30 °C-rt 5

O O O O Ph Me Ph Ph Ph Me

OH OH OH OH Me R O O OMe R = Me, 5b, 50%, 10 °C 5a, 71%, 10 °C 5d, 54%, rt 5e, 80%, 10 °C R = tBu, 5c, 42%, rt

O O O O Ph OMe Ph O Ph Ph O

OH OH OH OH O OMe O O 5f, 75%, rt 5g, 67%, 10 °C 5h, 85%, 10 °C 5i, 51%, rt

O O O O Ph Ph Ph Ph X OH OH OH OH O O NPh2 5j, 80%, 10 °C 5k, 77%, 10 °C 5l, 82%, 10 °C X = O, 5m, 85%, 10 °C X = S, 5n, 90%, rt O O O O Ph Ph Ph S Ph Br S OH O OH OH OH S 5o, 49%, 10 °C 5p, 54%, 10 °C 5q, 41%, 10 °C 5r, 82%, 10 °C

O O O O Ph Ph Ph N Ph OH OH N N OH OH N O Boc Ts H 5s, 85%, 10 °C 5t, 41%, 10 °C 5u, 42%, rt 5v, 52%, 10 °C Ph O Boc O S O N O Ph Ph OH OH N OH OH Cl Ph 5w, 43%, rt 5x, 85%, rt 5y, 82%, 0 °Cb 5z, 63%, 0 °Cb

a a Fig. 3 Scope of boronic acids . Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (0.3 mmol), 3 (0.36 mmol), and CHCl3/pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours unless otherwise specified. b1 (0.2 mmol, 1 equiv), 2a (0.3 mmol), 3 (0.36 mmol), and DCM/pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours.

OH Ph O Sc(OTf)3 (30 mol%) + tBu NC + Ph BF3K R H THF, rt R O 162a 7

OH Ph OH Ph OH Ph OH Ph O Ph O O O O

7a, 47% 7b, 45% 7c, 52% 7d, 53%

Fig. 4 Passerini-type reaction of alkynyl trifluoroborate . Reaction conditions: 1 (0.2 mmol, 1 equiv), 2a (0.5 mmol), 6 (0.6 mmol), and THF (1.5 mL) under an argon atmosphere for 12 hours unless otherwise specified.

Passerini-type reaction of alkynylboron compounds. α-Hydroxy a straightforward and efficient method could be disclosed for the alkynylketones are important intermediates for the synthesis of synthesis of α-hydroxy alkynylketones, which further demon- natural products and drug molecules82,83. However, the synthesis strates the strengths and capability of our protocol (Fig. 4). of such α-hydroxyketones has faced significant challenges and Alkynyl trifluoroborate salt was employed as the source of alkyne usually multiple steps are required82,83. We sought to explore the in our transformation owing to the instability of alkynylboronic Passerini-type reaction on alkynylboron compounds, if successful, acid. To our delight, the Passerini-type reaction of alkynyl

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OH O CHCl3/ pH = 8 buffer R' B(OH) R' + tBu NC + 2 R R H or DCM/ pH = 8 buffer O 12a310 °C-rt 8

O O O O

OH OH OH OMe MeO OMe OMe

8a, 68%, 10 °C, dr: 1.7:1a,b 8b, 54%, 10 °C, dr: 2.5:1a,b 8c, 75%, 10 °C, dr: 2.1:1a,b from Ibuprofen from Naproxen from Ketoprofen

MeO

O O O O O OMe

N HO OH O OH OMe Cl OMe O

8d, 38%, 10 °C 8e, 53%, 10 °C 8f, 82%, rt, dr: 1:1c,d from Gemfibrozil from Indometacin from L-Menthol

OH OMe O O O H OMe O O H O H OH H 8g, 56%, rt, dr: 1:1c,d from L-Borneol 8h, 40%, rt,, dr: 1:1c,d from Cholesterol

O O O Ph H Ph OH O H H O OH O O H 8i, 54%, 10 °C, dr: 1:1c,d from Epiandrosterone 8j, 54%, rt, from Clofibrate

a Fig. 5 Late-stage modifications of bioactive or drug molecules. Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (0.3 mmol), 3 (0.36 mmol), and CHCl3/ pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours unless otherwise specified. bThe dr was determined by 1H NMR analysis. c1 (0.2 mmol, 1 equiv), 2a (0.3 mmol), 3 (0.36 mmol) and DCM/pH = 8 buffer (7:3, 1 mL) under an argon atmosphere for 24 hours. dThe dr was determined by HPLC analysis. trifluoroborate salt could proceed smoothly under the action of stereoselectivity. This Passerini-type reaction of boronic acids – Lewis acid (Sc(OTf)3), and the target products (7a 7d) could be showed similar results in terms of stereochemical control. In most obtained in a moderate yield. This reaction could not occur cases (4l, 4n, 8a–8c, and 8f–8i), the dr values remained between without Lewis acid (Sc(OTf)3), probably because a four- 1:1 and 2.5:1 (see the Supplementary Information for details). coordinated boron “ate” nitrilium intermediate could not be generated from potassium phenyltrifluoroborate, aldehyde, and Gram-scale synthesis and synthetic applications. The practical isocyanide. Lewis acid may promote the conversion of potassium constraint of this Passerini-type MCR with boronic acids was phenyltrifluoroborate (6) into phenyldifluoroborane, which could next evaluated through translation to gram-scale synthesis. As form a four-coordinated boron intermediate84. shown in Fig. 6a, reaction efficiencies were preserved on 2 gram- scale (10 mmol, 50 times), thus implying the application potential Late-stage modifications of complex molecules. The excellent for industrial production of the α-hydroxyketones. functional group compatibility prompted our endeavors to The readiness of α-hydroxyketone products for chemical extrapolate this synthesis scheme to late-stage modification of manipulations was pronounced in production of 1,2-diol (9), bioactive or therapeutic agents (Fig. 5). A series of bioactive or 1,2-dione (10), quinoxaline (11), cyclic sulfamate imine (12), and drug molecules (Ibuprofen, Naproxen, Ketoprofen, Gemfibrozil, poly-substituted oxazole (13) (Fig. 6b). The innate step economy Indometacin, L-Menthol and L-Borneol, and Cholesterol) were of MCRs has also presented an abbreviated route towards (±) derivatized into corresponding aldehydes which, upon treatment Harmandianone, a phenylpropanoid derivative isolated from with 4-methoxyphenyl boronic acid under established Passerini- Clausena Harmandiana fruits85, from simple building blocks type coupling conditions, were smoothly incorporated in eventual (Fig. 6c). Of further significance, products could be precursors for α-hydroxyketone derivatives 8a–8h. Futhermore, conversions of entities that constitute the structural core of bioactive compounds arylboronic acids that were derived from drug molecules such as such as α-acyloxy lactone and α,β-unsaturated lactone. The Epiandrosterone and Clofibrate had brought forth drug analogs former (19) was fabricated upon lactonization of α-hydroxyke- 8i and 8j in moderate yields. It was thus envisioned that this tone 18 formed from methyl 4-oxobutanoate (17) (Fig. 6d). A method would simplify access to discover other bioactive mole- two-step olefination and ring-closing olefin metathesis of 4a cules. The previous MCRs involving isocyanide exhibit poor afforded α,β-unsaturated lactone product (±) 22 (Fig. 6e). The

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a OMe standard OH S Me B(OH)2 B(OH)2 OH conditions 1a+ 2a + or or Ph Me Ph MeO S O O 3e3r 5e 5r 10 mmol 15 mmol 18 mmol 18 mmol89% yield, 2.53 g 63% yield, 1.86 g

b Me OH S O S MeO

Ph Ph N OH O B F Ph N B 3 •E 10,90% equiv) 9, 83% (dr > 20:1) u t ) 11, 64% 3 S 2 O (1.5 to n (1 mol% lu H .2 en (1 (50 e I 2 e .2 q ), h , -7 e uiv) IBX (1.5 equiv) inobenzene 8 qu ° iv DMSO mol% °C, 14 C ) 1,2-diam (5 , 2 80 oC, 4 h h PTSA toluene, 120

O Cl O 1) chloroacetyl chloride (1.1 equiv) S O N OH O 1) sulfamoyl chloride (2 equiv) Et3N (1.5 equiv), DMAP (1.5 equiv) N DMA, 0 oC-rt, 2 h Ar DCM, 0 oC-rt, 16 h Ph Ph

2) PTSA (20 mol%) O 2) NH4OAc (15 equiv) Ph S toluene, 110 °C, 1h 5e or 5r HOAc, 110 °C, 3 h S

12, 90% 13,32%

c O O standard O MeO OMe conditions Cl CH3CHO 2a 3a + + O 51% OH DMAP(1.5 equiv), DCM, 0 °C-rt MeO MeO 14 65% O 15 16, (±) Harmandianone

d

O standard O O O conditions TFA/H2O (9:1), DCM, 0 °C-rt + 2a+ 3a MeO MeO CHO 50% 54% O OH MeO OMe O 17 18 19

e Cl Ph OH O Ph OO MgCl Ph DMAP(10 mol%) O O 4a Grubbs II (4 mol%) THF, -78 °C OH TEA(3 equiv), DCM, 0 °C toluene, 70 °C MeO MeO OH 50% HO 80% 66% MeO 20 (dr > 20:1) 21 (±) 22

Fig. 6 Gram-scale synthesis and synthetic applications. a Gram-scale synthesis. b Transformations of α-hydroxyketones. c Synthesis of Harmandianone. d Syntheis of α-acyloxy lactone. e Synthesis of α, β-unsaturated lactone.

high diastereoselectivity of compound 20 may originate from the performed on procured α-hydroxyketones has additionally chelation of hydroxyl, carbonyl oxygen, and magnesium86. illustrated the utility of this method. In conclusion, we have realized the application of boronic acid as carbon nucleophiles in the manifold of Passerini reaction. Methods Accordingly, this protocol provided simplified modular access of General procedure A for the synthesis of α-hydroxyketones from alkylalde- α-hydroxyketones from aldehydes, isocyanide, and boronic acids. hydes. In air, a 10 mL schlenk tube was charged with arylboronic acids (0.36 The functional group tolerance of this chemistry has supported mmol, 1.8 equiv). The tube was evacuated and filled with argon for three cycles. = late-stage diversifications of bioactive products and pharmaceu- Then, chloroform (0.7 mL), pH 8 buffer (0.3 mL), alkylaldehydes (0.20 mmol, 1 equiv), tertbutyl isocyanide (34 μl, 0.30 mmol, 1.5 equiv) were added under argon. ticals through this three-component coupling reaction. The The reaction was allowed to stir at corresponding temperature for 24 hours. Upon wealth of follow-up chemical conversions that could be completion, proper amount of silica gel was added to the reaction mixture. After

NATURE COMMUNICATIONS | (2021) 12:441 | https://doi.org/10.1038/s41467-020-20727-7 | www.nature.com/naturecommunications 7 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-20727-7 removal of the solvent, the crude reaction mixture was purified on silica gel 17. Staudinger, H. The autooxidation of organic compounds: connection between (petroleum ether and ethyl ) to afford the desired products. autooxidation and benzoin formation. Ber. Dtsch. Chem. Ges. 46, 3535–3538 (1913). General procedure B for the synthesis of α-hydroxyketones from arylalde- 18. Adam, W., Lazarus, M., Saha-Möller, C. R. & Schreier, P. Biocatalytic α hydes. In air, a 10 mL schlenk tube was charged with arylboronic acids (0.36 synthesis of optically active -oxyfunctionalized carbonyl compounds. Acc. – mmol, 1.8 equiv). The tube was evacuated and filled with argon for three cycles. Chem. Res. 32, 837 845 (1999). Then, dichloromethane (0.7 mL), pH = 8 buffer (0.3 mL), arylaldehydes (0.20 19. Bouma, M. J. & Olofsson, B. In Comprehensive Organic Synthesis II (second – mmol, 1 equiv), cyclohexyl isocyanide (37 μl, 0.30 mmol, 1.5 equiv) were added edition) (ed Paul Knochel) 213 241 (Elsevier, 2014). under argon. The reaction was allowed to stir at room temperature for 24 hours. 20. Davis, F. A. & Chen, B. C. Asymmetric hydroxylation of enolates with N- Upon completion, proper amount of silica gel was added to the reaction mixture. sulfonyloxaziridines. Chem. Rev. 92, 919–934 (1992). After removal of the solvent, the crude reaction mixture was purified on silica gel 21. Chuang, G. J., Wang, W., Lee, E. & Ritter, T. A dinuclear palladium catalyst for α – (petroleum ether and ethyl acetate) to afford the desired products. -hydroxylation of carbonyls with O2. J. Am. Chem. Soc. 133, 1760 1762 (2011). fi α 22. Liang, Y.-F. et al. I2- or NBS-catalyzed highly ef cient -hydroxylation of with dimethyl sulfoxide. Org. Lett. 17, 876–879 (2015). General procedure C for the synthesis of α-hydroxyketones from alkynyl 23. Plietker, B. New oxidative pathways for the synthesis of α-hydroxy ketones—the trifluoroborate salt. In air, a 10 mL schlenk tube was charged with alkynyl tri- α-hydroxylation and ketohydroxylation. Tetrahedron 16, 3453–3459 (2005). fluoroborate salt (0.60 mmol, 3 equiv) and Sc(OTf) (30.0 mg, 0.06 mmol, 0.3 3 24. Plietker, B. The RuO -catalyzed ketohydroxylation. part 1. development, equiv). The tube was evacuated and filled with argon for three cycles. Then, THF 4 scope, and limitation. J. Org. Chem. 69, 8287–8296 (2004). (1.5 mL), aldehydes (0.20 mmol, 1 equiv), and tertbutyl isocyanide (57 μl, 0.50 mmol, 2.5 equiv) were added under argon. The reaction was allowed to stir at room 25. Huang, J. et al. Dual role of H2O2 in palladium-catalyzed dioxygenation of terminal alkenes. Org. Lett. 19, 3354–3357 (2017). temperature for 12 hours. Upon completion, proper amount of silica gel was added fi to the reaction mixture. After removal of the solvent, the crude reaction mixture 26. Plietker, B. RuO4-catalyzed ketohydroxylation of ole ns. J. Org. Chem. 68, – was purified on silica gel (petroleum ether and ethyl acetate) to afford the desired 7123 7125 (2003). α products. 27. Wu, X., Gao, Q., Lian, M., Liu, S. & Wu, A. Direct synthesis of - hydroxyacetophenones through molecular iodine activation of carbon–carbon double bonds. RSC Adv. 4, 51180–51183 (2014). Data availability 28. de Graaff, C., Ruijter, E. & Orru, R. V. A. Recent developments in asymmetric The data supporting the finding of this study are available within the paper and its multicomponent reactions. Chem. Soc. Rev. 41, 3969–4009 (2012). Supplementary Information. 29. Dömling, A. Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem. Rev. 106,17–89 (2006). Received: 6 September 2020; Accepted: 10 December 2020; 30. Dömling, A. & Ugi, I. Multicomponent reactions with isocyanides. Angew. Chem. Int. Ed. 39, 3168–3210 (2000). 31. Dömling, A., Wang, W. & Wang, K. Chemistry and biology of multicomponent reactions. Chem. Rev. 112, 3083–3135 (2012). 32. Nair, V. et al. Strategies for heterocyclic construction via novel multicomponent reactions based on isocyanides and nucleophilic carbenes. Acc. Chem. Res. 36, 899–907 (2003). References 33. Touré, B. B. & Hall, D. G. Natural product synthesis using multicomponent α 1. Escandón-Rivera, S. et al. -Glucosidase inhibitors from Brickellia cavanillesii. reaction strategies. Chem. Rev. 109, 4439–4486 (2009). – J. Nat. Prod. 75, 968 974 (2012). 34. Wessjohann, L. A., Rivera, D. G. & Vercillo, O. E. Multiple multicomponent Ō 2. Fukuda, T., Matsumoto, A., Takahashi, Y., Tomoda, H. & mura, S. Phenatic macrocyclizations (MiBs): a strategic development toward macrocycle acids A and B, new potentiators of antifungal miconazole activity produced by diversity. Chem. Rev. 109, 796–814 (2009). – Streptomyces sp. K03-0132. J. Antibiot. 58, 252 259 (2005). 35. Wille, U. Radical cascades initiated by intermolecular radical addition to 3. Miles, Z. D. et al. A unifying paradigm for naphthoquinone-based alkynes and related triple bond systems. Chem. Rev. 113, 813–853 (2013). – meroterpenoid (bio)synthesis. Nat. Chem. 9, 1235 1242 (2017). 36. Wang, Q., Wang, D.-X., Wang, M.-X. & Zhu, J. Still unconquered: 4. Roush, W. R., Briner, K., Kesler, B. S., Murphy, M. & Gustin, D. J. Studies on enantioselective Passerini and Ugi multicomponent reactions. Acc. Chem. Res. the synthesis of aureolic acid antibiotics: acyloin glycosidation studies. J. Org. 51, 1290–1300 (2018). – Chem. 61, 6098 6099 (1996). 37. Passerini, M. Isonitriles. II. Compounds with aldehydes or with ketones and 5. Wee, J. L., Sundermann, K., Licari, P. & Galazzo, J. Cytotoxic hypothemycin monobasic organic acids. Gazz. Chim. Ital. 51, 181–189 (1921). – analogues from Hypomyces subiculosus. J. Nat. Prod. 69, 1456 1459 (2006). 38. Chandgude, A. L. & Dömling, A. Unconventional Passerini reaction toward α- α 6. Tanaka, T., Kawase, M. & Tani, S. -Hydroxyketones as inhibitors of urease. aminoxy-. Org. Lett. 18, 6396–6399 (2016). – Bioorg. Med. Chem. 12, 501 505 (2004). 39. Denmark, S. E. & Fan, Y. The first catalytic, asymmetric α-additions of 7. Wallace, O. B., Smith, D. W., Deshpande, M. S., Polson, C. & Felsenstein, K. isocyanides. Lewis-base-catalyzed, enantioselective Passerini-type reactions. J. β α M. Inhibitors of A production: solid-phase synthesis and SAR of - Am. Chem. Soc. 125, 7825–7827 (2003). – hydroxycarbonyl derivatives. Bioorg. Med. Chem. Lett. 13, 1203 1206 (2003). 40. Mihara, H., Xu, Y., Shepherd, N. E., Matsunaga, S. & Shibasaki, M. A α 8. Palomo, C., Oiarbide, M. & García, J. M. -Hydroxy ketones as useful heterobimetallic ga/yb-schiff base complex for catalytic asymmetric α-addition – templates in asymmetric reactions. Chem. Soc. Rev. 41, 4150 4164 (2012). of isocyanides to aldehydes. J. Am. Chem. Soc. 131, 8384–8385 (2009). 9. Ghiringhelli, F., Nattmann, L., Bognar, S. & van Gemmeren, M. The direct 41. Soeta, T., Matsuzaki, S. & Ukaji, Y. A one-pot o-phosphinative Passerini/ α – conversion of -hydroxyketones to alkynes. J. Org. Chem. 84, 983 993 (2019). Pudovik reaction: efficient synthesis of highly functionalized α- 10. Kang, S., Han, J., Lee, E. S., Choi, E. B. & Lee, H.-K. Enantioselective synthesis (phosphinyloxy) derivatives. Chem. Eur. J. 20, 5007–5012 (2014). of cyclic sulfamidates by using chiral rhodium-catalyzed asymmetric transfer 42. Wang, S., Wang, M.-X., Wang, D.-X. & Zhu, J. Asymmetric Lewis acid – hydrogenation. Org. Lett. 12, 4184 4187 (2010). catalyzed addition of isocyanides to aldehydes – synthesis of 5-amino-2-(1- α 11. Li, G. et al. Investigation and application of amphoteric -amino aldehyde: an hydroxyalkyl)oxazoles. Eur. J. Org. Chem. 2007, 4076–4080 (2007). in situ generated species based on Heyns rearrangement. Org. Lett. 18, 43. Yue, T., Wang, M.-X., Wang, D.-X., Masson, G. & Zhu, J. Catalytic – 4526 4529 (2016). asymmetric Passerini-type reaction: chiral aluminum−organophosphate- 12. Liu, W., Chen, C. & Zhou, P. N,N-dimethylformamide (DMF) as a source of catalyzed enantioselective α-addition of isocyanides to aldehydes. J. Org. α α oxygen to access -hydroxy arones via the -hydroxylation of arones. J. Org. Chem. 74, 8396–8399 (2009). – Chem. 82, 2219 2222 (2017). 44. Yue, T., Wang, M.-X., Wang, D.-X. & Zhu, J. Asymmetric synthesis of 5-(1- 13. Ooi, T., Uraguchi, D., Morikawa, J. & Maruoka, K. Unique synthetic utility of hydroxyalkyl)tetrazoles by catalytic enantioselective Passerini-type reactions. BF3·OEt2 in the highly diastereoselective reduction of hydroxy carbonyl and Angew. Chem. Int. Ed. 47, 9454–9457 (2008). – dicarbonyl substrates. Org. Lett. 2, 2015 2017 (2000). 45. Zeng, X. et al. Chiral Brønsted acid catalyzed enantioselective addition of α- 14. Hoyos, P., Sinisterra, J.-V., Molinari, F., Alcántara, A. R. & Domínguez de isocyanoacetamides to aldehydes. Org. Lett. 12, 2414–2417 (2010). α María, P. Biocatalytic Strategies for the asymmetric synthesis of -hydroxy 46. Zhang, J., Lin, S.-X., Cheng, D.-J., Liu, X.-Y. & Tan, B. Phosphoric acid- – ketones. Acc. Chem. Res. 43, 288 299 (2010). catalyzed asymmetric classic Passerini reaction. J. Am. Chem. Soc. 137, 15. Lapworth, A. J. Reactions involving the addition of hydrogen cyanide to 14039–14042 (2015). carbon compounds. J. Chem. Soc. 83, 995 (1903). 47. Aknin, K. et al. Squaric acid is a suitable building-block in 4C-Ugi reaction: 16. Lapworth, A. J. Reactions involving the addition of hydrogen cyanide to access to original bivalent compounds. Tetrahedron Lett. 53, 458–461 (2012). carbon compounds. Part II. cyanohydrins regarded as complex acids. J. Chem. 48. Barthelon, A., El Kaïm, L., Gizolme, M. & Grimaud, L. in Ugi- and – Soc. 85, 1206 1215 (1903). Passerini–Smiles-type couplings. Eur. J. Org. Chem. 2008, 5974–5987 (2008).

8 NATURE COMMUNICATIONS | (2021) 12:441 | https://doi.org/10.1038/s41467-020-20727-7 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-20727-7 ARTICLE

49. Chandgude, A. L. & Dömling, A. N-Hydroxyimide Ugi reaction toward α- 76. Petasis, N. A. & Akritopoulou, I. The boronic acid Mannich reaction: a new hydrazino amides. Org. Lett. 19, 1228–1231 (2017). method for the synthesis of geometrically pure allylamines. Tetrahedron Lett. 50. El Kaïm, L., Grimaud, L. & Oble, J. Phenol Ugi–Smiles systems: strategies for 34, 583–586 (1993). the multicomponent N-arylation of primary amines with isocyanides, 77. Petasis, N. A. & Zavialov, I. A. A new and practical synthesis of α-amino acids aldehydes, and phenols. Angew. Chem. Int. Ed. 44, 7961–7964 (2005). from alkenyl boronic acids. J. Am. Chem. Soc. 119, 445–446 (1997). 51. Keating, T. A. & Armstrong, R. W. Postcondensation modifications of Ugi 78. Petasis, N. A. & Zavialov, I. A. Highly stereocontrolled one-step synthesis of four-component condensation products: 1-isocyanocyclohexene as a anti-β-amino alcohols from organoboronic acids, amines, and α-hydroxy convertible isocyanide. mechanism of conversion, synthesis of diverse aldehydes. J. Am. Chem. Soc. 120, 11798–11799 (1998). structures, and demonstration of resin capture. J. Am. Chem. Soc. 118, 79. Candeias, N. R., Montalbano, F., Cal, P. M. S. D. & Gois, P. M. P. Boronic 2574–2583 (1996). acids and esters in the Petasis-borono Mannich multicomponent reaction. 52. Oh, J., Kim, N. Y., Chen, H., Palm, N. W. & Crawford, J. M. An Ugi-like Chem. Rev. 110, 6169–6193 (2010). biosynthetic pathway encodes bombesin receptor subtype-3 agonists. J. Am. 80. Wu, P., Givskov, M. & Nielsen, T. E. Reactivity and synthetic applications of Chem. Soc. 141, 16271–16278 (2019). multicomponent Petasis reactions. Chem. Rev. 119, 11245–11290 (2019). 53. Waki, M. & Meienhofer, J. Peptide synthesis using the four-component 81. Yang, K., Zhang, F., Fang, T., Zhang, G. & Song, Q. Stereospecific 1,4- condensation (Ugi reaction). J. Am. Chem. Soc. 99, 6075–6082 (1977). metallate shift enables stereoconvergent synthesis of ketoximes. Angew. Chem. 54. Zhang, J. et al. Asymmetric phosphoric acid–catalyzed four-component Ugi Int. Ed. 58, 13421–13426 (2019). reaction. Science 361, eaas8707 (2018). 82. Kuethe, J. T. & Comins, D. L. Addition of metallo enolates to chiral 1- 55. Baker, R. H. & Stanonis, D. The Passerini reaction. III. stereochemistry and acylpyridinium salts: total synthesis of (+)-Cannabisativine. Org. Lett. 2, mechanism. J. Am. Chem. Soc. 73, 699–702 (1951). 855–857 (2000). 56. Chéron, N., Ramozzi, R., Kaïm, L. E., Grimaud, L. & Fleurat-Lessard, P. 83. Ziegler, F. E., Jaynes, B. H. & Saindane, M. T. A synthetic route to forskolin. J. Challenging 50 years of established views on Ugi reaction: a theoretical Am. Chem. Soc. 109, 8115–8116 (1987). approach. J. Org. Chem. 77, 1361–1366 (2012). 84. Mundal, D. A., Lutz, K. E. & Thomson, R. J. A direct synthesis of allenes by a 57. Iacobucci, C., Reale, S., Gal, J.-F. & De Angelis, F. Insight into the mechanisms traceless Petasis reaction. J. Am. Chem. Soc. 134, 5782–5785 (2012). of the multicomponent Ugi and Ugi–Smiles reactions by ESI-MS(/MS). Eur. J. 85. Maneerat, W. et al. Phenylpropanoid derivatives from Clausena harmandiana Org. Chem. 2014, 7087–7090 (2014). fruits. Phytochem. Lett. 6,18–20 (2013). 58. Maeda, S., Komagawa, S., Uchiyama, M. & Morokuma, K. Finding reaction 86. Wildemann, H., Dünkelmann, P., Müller, M. & Schmidt, B. A short olefin pathways for multicomponent reactions: the Passerini reaction is a four- metathesis-based route to enantiomerically pure arylated dihydropyrans and component reaction. Angew. Chem. Int. Ed. 50, 644–649 (2011). α,β-unsaturated δ-valero lactones. J. Org. Chem. 68, 799–804 (2003). 59. El Kaim, L. & Grimaud, L. Beyond the Ugi reaction: less conventional interactions between isocyanides and iminium species. Tetrahedron 65, 2153–2171 (2009). Acknowledgements 60. Banfi, L. & Riva, R. The Passerini reaction. Org. React. 65, 1 (2005). Financial supports from the National Natural Science Foundation of China (21772046, 61. Lundgren, R. J. & Stradiotto, M. Addressing challenges in palladium-catalyzed 2193103) are gratefully acknowledged. cross-coupling reactions through ligand design. Chem. Eur. J. 18, 9758–9769 (2012). Author contributions 62. Miyaura, N. & Suzuki, A. Palladium-catalyzed cross-coupling reactions of Q.S. conceived the project. K.Y., F.Z., T.F., C.L., and W.L. performed experiments and organoboron compounds. Chem. Rev. 95, 2457–2483 (1995). prepared the Supplementary Information. Q.S. and K.Y. prepared the manuscript. All 63. Barluenga, J., Tomás-Gamasa, M., Aznar, F. & Valdés, C. Metal-free authors discussed the results and commented on the manuscript. carbon–carbon bond-forming reductive coupling between boronic acids and tosylhydrazones. Nat. Chem. 1, 494–499 (2009). 64. Roscales, S. & Csákÿ, A. G. Transition-metal-free C–C bond forming reactions Competing interests of aryl, alkenyl and alkynylboronic acids and their derivatives. Chem. Soc. Rev. The authors declare no competing interests. 43, 8215–8225 (2014). 65. Sun, C.-L. & Shi, Z.-J. Transition-metal-free coupling reactions. Chem. Rev. Additional information 114, 9219–9280 (2014). Supplementary information 66. Zhu, C. & Falck, J. R. Transition metal-free ipso-functionalization of is available for this paper at https://doi.org/10.1038/s41467- arylboronic acids and derivatives. Adv. Synth. Catal. 356, 2395–2410 (2014). 020-20727-7. 67. Greb, A. et al. A versatile route to unstable diazo compounds via oxadiazolines Correspondence and their use in aryl–alkyl cross-coupling reactions. Angew. Chem. Int. Ed. 56, and requests for materials should be addressed to Q.S. 16602–16605 (2017). Peer review information 68. He, Z., Song, F., Sun, H. & Huang, Y. Transition-metal-free Suzuki-type cross- Nature Communications thanks Carlos Andrade and the other, coupling reaction of benzyl halides and boronic acids via 1,2-metalate shift. J. anonymous, reviewer(s) for their contribution to the peer review of this work. Peer Am. Chem. Soc. 140, 2693–2699 (2018). reviewer reports are available. 69. Huang, H. et al. Synthesis of aldehydes by organocatalytic formylation Reprints and permission information is available at http://www.nature.com/reprints reactions of boronic acids with glyoxylic acid. Angew. Chem. Int. Ed. 56, 8201–8205 (2017). Publisher’s note 70. Li, C. et al. Transition-metal-free stereospecific cross-coupling with Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. alkenylboronic acids as nucleophiles. J. Am. Chem. Soc. 138, 10774–10777 (2016). 71. Peng, C., Zhang, W., Yan, G. & Wang, J. Arylation and vinylation of α- diazocarbonyl compounds with boroxines. Org. Lett. 11, 1667–1670 (2009). Open Access This article is licensed under a Creative Commons 72. Pérez-Aguilar, M. C. & Valdés, C. Olefination of carbonyl compounds Attribution 4.0 International License, which permits use, sharing, through reductive coupling of alkenylboronic acids and tosylhydrazones. adaptation, distribution and reproduction in any medium or format, as long as you give Angew. Chem. Int. Ed. 51, 5953–5957 (2012). appropriate credit to the original author(s) and the source, provide a link to the Creative 73. Plaza, M. & Valdés, C. Stereoselective domino carbocyclizations of γ- and δ- Commons license, and indicate if changes were made. The images or other third party cyano-n-tosylhydrazones with alkenylboronic acids with formation of two material in this article are included in the article’s Creative Commons license, unless different C(sp3)–C(sp2) bonds on a quaternary stereocenter. J. Am. Chem. indicated otherwise in a credit line to the material. If material is not included in the Soc. 138, 12061–12064 (2016). article’s Creative Commons license and your intended use is not permitted by statutory 74. Tian, D. et al. Stereospecific nucleophilic substitution with arylboronic acids as regulation or exceeds the permitted use, you will need to obtain permission directly from nucleophiles in the presence of a CONH group. Angew. Chem. Int. Ed. 57, the copyright holder. To view a copy of this license, visit http://creativecommons.org/ – 7176 7180 (2018). licenses/by/4.0/. 75. Wu, G., Deng, Y., Wu, C., Zhang, Y. & Wang, J. Synthesis of α-aryl esters and nitriles: deaminative coupling of α-aminoesters and α-aminoacetonitriles with arylboronic acids. Angew. Chem. Int. Ed. 53, 10510–10514 (2014). © The Author(s) 2021

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