227

RECENT ADVANCES IN THE ASYMMETRIC SYNTHESIS OF CHROMANE DERIVATIVES DOI: http://dx.medra.org/ 10.17374/targets.2021.24.227 Renato Dalpozzo * a , Raffaella Mancuso a , Yan - Kai Liu b a Department of Chemistry and Chemical Technologies , Università della Calabria, 87030 Arcavacata di Rende (Cosenza ), Italy b Key Laboratory of Marine Drugs, Chinese Ministry of Education, S chool of Medicine and Pharmacy, Ocean University of China, 266003 Qingdao, P.R. China (e - mail: [email protected] ; raffaella. [email protected] [email protected] )

Abstract. Chromane derivatives are the core structure of many natural products, most of them having nutraceutical properties. As many natural products, this scaffold often carries out asymmetric carbon atoms. Therefore, asymmetric syntheses are of great importance in order to prepare th ese important building blocks. Our aim is to collect the asymmetric methods and some examples of total syntheses of natural product appeared in the literature in the last three years.

Contents 1. Introduction 2. DFT studies on the reaction m echanisms 3. C yclization of hydroxystyrene d erivatives 3.1. From 2 - n itrovinylphenols 3.2. From c halcones 3.3. From 2 ′ - hydroxycinnamaldehyde 3.4. From other derivatives 4. C ycloaddition of ortho - quinone m ethides 5. Asymmetric a lkylation 6. Desymmetrization 7. Reaction of phenols with activated a lkenes 8. Reduction of chromones 9. Spiro, fused and bridged chromane - i ndoles 10. Miscellaneous 11 . Examples of total syntheses 12 . Conclusion References and notes

Abbreviations Binap , (1,1 ′ - binaphthalene - 2,2 ′ - diyl)bis (diphenylphosphine); BINOL , 1,1 ′ - bi - 2 - naphthol; Boc , t - BuOCO; Cbz , BnOCO; Cod , 1,5 - cyclooctadiene; Cp* , pentamethylcyclopentadienyl; m - CPBA , m - chloroperbenzoic acid; DBU , 1,5 - diazabicyclo(5.4.0)undec - 7 - ene; DFT , Density Functional Theory; (DHQD) 2 PYR , hydroquinidine - 2,5 - diphenyl - 4,6 - pyrimidinediyl diether; DIBAL , ( i - Bu 2 AlH) 2 ; DIPEA , N,N - diisopropylethylamine; DMAP , 4 - (dimethylamino)pyridine; DMF , N,N - dimethylformamide; β‐ICD , β‐isocupreidine; Mes , MeSO 3 ; MNP , magnetic nanoparticles; MOM , MeOCH 2 ; MS , molecular sieves; NBS , N - bromosuccinimide; NHC , N - heterocyclic carbene; NIS , N - iodosuccinimide; PCC , pyridinium chlorochromate; PPTS , pyridinium p - toleuensulfonate; (QD) 2 PHAL , quinidine - 1,4 - phthalazinediyl diether ; Segphos , 5,5 ′ - bis(diphenylphosphino) - 4,4 ′ - bi - 1,3 - benzodioxole; TBS , t - BuMe 2 Si; Tf , CF 3 SO 2 ; TMS , Me 3 Si; Ts , MeC 6 H 4 SO 2 .

1. Introduction The c hiral chromane skeleton is a motif present in a plethora of natural products and, in particular, in flavonoids . 1 These substances contribute to organoleptic and nutritional quality of many vegetables and fruits and often act as nutraceutical substances . In fact, they can show anti - HIV, antitumor, anticancer, antioxidant, anti - aging, anti - inflammatory, antibacterial p roperties . 2 Natural flavonoids are generally complex molecules; however, simpler chromanes can mai ntain the biological properties. 3 Commonly, 228 chromanes are prepared starting from benzene derivatives, annulating the pyran moiety in several steps. Clearly , such a procedure sets the challenge to perform enantioselective reactions in case enantiomerically pure chroman e s are needed. T he refore, the asymmetric synthesis approach has been extensively studied over the years and a plethora of methodologies are now available , applying chiral catalysis to the classical reaction. Many chemists have already ventured in summarizing asymmetric synthesis of these compounds . 1 , 4 However, in the last three years, new synthetic methods for the preparation the chromane nucleus have appeared in the literature, and we aim to give an overview of these recent synthetic methods and also we wish to report some application to the total synthesis of complex molecules. Asymmetric syntheses can be performed by chiral metal catalysts or by organocatalysis . Metal ions have variable oxidation states, thus they can form  or π complexes with substrates and accommodate chiral ligands, which can hide one of the faces of the substrate, inducing enantioselectivity. However, the best catalysts are elements situated in the middle of the periodic table, the ions of which with higher oxidation state are toxic. Therefore, if their trace remains in the product, they can make unusable as drugs. In Italy e very year , many drugs are removed from the commerce due to the presence of trace toxic substances. 5 On the other hand , organocatalysis uses small organic molecules , often from non - toxic natural sources, the organocatalysts have many simultaneous activation mod es for substrates and reagents allowing easy ca scade reactions, the y are easy availab le and cheap , and the y operate at very mild conditions. However, these advantages do not impede the possible formation of toxic by - products.

2. DFT s tudies on the r eaction m echanisms Many authors explained their results envisaging plausible mechanisms for their reactions and they will be pictured in the reaction scheme, sometimes supported by theoretical calculations. However, there are also some general theoretical studies about asymm etric syntheses of chromane derivatives, and in last few years some examples have been reported. Among them, a DFT study was carried out for the mechanism of the asymmetric intramolecular nucleophilic substitution of ortho - allyloxy benzaldehydes catalyzed by NHCs. 6 The reaction proceeds through three stages: (i) the combination of NHC with the substrate from the Si face; (ii) the SN2 ′ reaction, which is the rate - and enantioselectivity - determining step giving the stereocenter in the favored R configuration; and (iii) the release of the product. Another DFT study was performed for the addition of arylboronic acid to coumarin substrates, catalyzed by a chiral rhodium catalyst. 7 The calculations showed that the best ligands for the acceleration of the insertion of ArB(OH) 2 should carry electron - withdrawing substituents and should give CH – π interactions with coumarin substrates . From the computational information, a rhodium ligand which worked at only 0.025 mol% catalysts loading was designed and successfully tested (see section 5). Also t he mechanism of the reaction of ortho - hydroxystyrene and azlactone catalyzed by chiral ( BINOL ) - phosphoric acid with and without chiral guanidine as the co - catalyst was studied in d etail with the DFT method . 8 Both reactions were found to proceed stepwise and not by a classical [4+ 2] Diels - Alder reaction. The steps are: C – C then C – O bond formation and, finally, azlactone ring - opening.

3 . Cyclization of h ydroxystyrene d erivatives o - Hydroxystyrene derivatives are certainly one of the most useful starting materials for building the chromane nucleus . Since 1999 , 9 many nonracemic metal complexes and organocatalysts later have been introduced to catalyze th e asymmetric version of this reaction , and the reader can find a detailed overview in the review cited in the introduction . However, the interest of chemists goes on and also in the last years other interesting papers h ave appeared in the literature.

3.1. From 2 - n itrovinylphenols In the last three years this reaction was essentially developed under organocatalysis and bifunctional catalysts have been revealed the best choice. Thus, An and co - workers prepared a heterogeneous catalyst , in which the silanol groups of mesoporous silica are the achiral acid site and an immobilized chiral amine is the basic site . 10 I n Scheme 1 11 is reported the mechanism envisaged by the authors . It is very similar to the proposed mechanism for homogenous catalysis. By this hypothesis, the surface silanols bind and activate the 229 n itro group , while the proline forms an iminium ion intermediate with the aldehyde , which is attacked from the less hindered face by t he hydroxy framework . Then, C - 1 of the nitro - olefin closes the six - membered ring . Also the pore wal l concurs to enhance the enantioselectivity, as demonstrated by the higher enantioselectivity obtained with larger groups adjacent to the nitrogen atom in the catalyst. Th e reaction was also extended to the Michael - hemiacetalization reaction followed by ox idation, with good results (Scheme 1 , eq . 3). The heterogeneous catalyst was reused up to five times without significantly affecting the yield and enantioselectivity.

N O 2 H O H O O H

O H C O S H N O 2 N ( 2 0 m o l % ) C H O 2 5 ° C , 7 2 h t o l u e n e O = H , 6 7 % , 7 1 % e e H 2 O N H O = P h 2 , 5 5 % , 9 7 % e e O H O O O N H O S

N H O O O O O N H O e q 1 S

O N C H O 2 N O 2 s a m e c o n d i t i o n s C H O + O H e q 2 P h O P h

= H , 8 8 % , 4 5 % e e

= P h 2 , 8 0 % , 9 6 % e e c a t ( 2 0 m o l % ) 4 0 ° C , 7 2 h O 2 N N O 2 C H 2 C l 2 t h e n P C C E t e q 3 + P r C H O O H O O = H , 8 6 % , 8 3 % e e

= P h 2 , 7 3 % , 9 5 % e e Scheme 1 . Heterogeneous enantioselective synthesis of chromanes.

In principle, two molecules of nitrostyrene could react together, but this oxa - Michael - Henry reaction was never observed. In fact, also Xia, Xu and co - workers, who performed an enantioselective, organocatalytic oxa - Michael - nitro - Michael reaction, observed only the reaction with β - nitroole fi ns different from nitrovinylphenols. 12 The reaction afforded chiral chromane derivatives bearing three contiguous stereogenic centers (Scheme 2). The stereochemistry was assigned by X - ray analysis. Then, Andrés, Pedrosa and co - workers tested the reaction onto polymer - supported squaramides. 13 They prepared some monomers and found Squa2 (Scheme 2) as the best. In fact a 5 mol% catalyst loading in dichloromethane at room temp erature provided products in 65 - 88% yields with 63:27 to >99:1 dr , 70 - > 99% ee (13 examples) after 12 - 72 h. The absolute configuration of the major isomer was once more (2 S ,3 S ,4 S ) and was established by X - ray analysis. The configuration of the minor isomer was instead established as (2 S ,3 R ,4 S ) by comparison of the 1 H - NM R coupling constants of the two diastereomers. Then Squa2 was co - polymerized with styrene and divinylbenzene and th e experiments were repeated (65 - 86% yields, 58:42 to > 99:1 dr, 56 - 74% ee). The polymer - supported catalyst was also recovered and recycled fiv e times without affecting yields and 230 selectivity. Authors were able to obtain the enantiomers by using Squa3 (Scheme 2). The opposite stereochemistry was very likely due to a different assembly of the ternary complex formed by catalyst, nitroalkene and 2 - h ydroxynitrostyrene.

5 X 4 * o n l y w h e n R = 4 F - C H d r = 1 3 : 1 6 4 F C 6 3 R X = H , 6 - M e O , 6 - E t O , 5 - M e O , 4 - M e O , 3 O O O M e + 4 - M e , 4 - F , 4 - C l , 4 - B r , 4 , 6 - C l 2 N H O 1 2 R = B u , i - P r , c - C 6 H 1 1 , P h , 2 - M e O C 6 H 4 , N O N N 2 2 - C l C 6 H 4 , 2 - B r C 6 H 4 , 3 - M e O C 6 H 4 , F 3 C H H 3 - C l C 6 H 4 , 3 - N O 2 C 6 H 4 , 4 - M e O C 6 H 4 , N O 2 S q u a 1 ( 5 m o l % ) 4 - M e C 6 H 4 , 4 - C l C 6 H 4 , 4 - F C 6 H 4 , 2 - N a p h t h y l S q u a 1 N r t , 2 4 h , C H 2 C l 2 N N O O 2 M e O O C F N O 2 O O 3 C l C l N N N C l C l H 5 7 - 8 2 % X O R H > 2 0 : 1 d r * O 2 N H C F 7 1 - > 9 9 % e e O O O 3 H N O H N O N A l l - S

H N O H N O X R t - B u N

N M e 2 S q u a 2 S q u a 3 Scheme 2 . Organocatalytic oxa - Michael nitro - Michael domino reaction.

A more general domino Michael/hemiacetalization with respect to that reported in Sc h eme 1 was reported by Zhao and co - workers (Scheme 3 ). 14 The hemiacetal intermediate was either oxidized to c is - 3,4 - disubstituted chroman - 2 - ones or dehydroxylated to chromanes. The reaction was scaled up to 0.5 mmol scale, without significant modification of yield and selectivity. The absolute stereochemistry was determined by the optic al rotation of known compounds.

O 2 N X R R C F + 3 C O C H O X O O N 2 H O O 2 N S H X = H , 6 - C l , 6 - B r , 6 - N O 2 , 6 - M e , 6 - M e O , R N O 2 F 3 C N N H 7 - M e , 8 - M e , H M D O ( 1 0 m o l % ) R = B n , M e , E t , P r , N O H t o l u e n e , r t , 1 6 h i - P r , n - C H 5 1 1 R = E t , P r , i - P r N a n d i s o b u t y r a l d e h y d e C F 7 2 - 9 4 % 3 6 5 - 9 7 % 8 5 : 1 5 t o 9 5 : 5 d r N O M e 8 0 : 2 0 t o 9 9 : 1 d r 9 2 - 9 8 % e e ( 3 R , 4 S ) S 8 7 - 9 9 % e e ( 3 R , 4 S ) X = H M D O F 3 C P C C ( 3 e q ) E t S i H ( 3 e q ) N O M e 3 N C H C l r t , 2 4 h B F E t O ( 3 e q ) H 2 2 , 3 2 H N C H 2 C l 2 , 0 ° C , 2 h O H O R O O N N O 2 C H O O 2 N N R R O H H O

X O O H X X Scheme 3 . Domino reaction catalyzed by MDO organocatalysts.

( E ) - 2 - (2 - Nitrovinyl)phenols were also allowed to react with az a lactones (Scheme 4). 15 The required high excess (twelve - fold) of azlactone is certainly a drawback of this reaction. However, t he reaction was also performed at a gram scale and 1.06 g were recovered in 84% yield with 92% ee and >19:1 dr . The absolute configuration was determined by X - ray analysis. It is noteworthy that these compounds have the opposite configuration at the 4 - position with respect to all those reported in the above reactions .

231

X 1 O F 5 X 4 G u a n i d i n e O 2 N ( 1 0 m o l % ) H N P h H 6 3 N T H F , - 6 0 ° C , 7 2 h O S F R 1 O 2 + X N H O 1 2 6 3 - 9 9 % P h N > 1 9 : 1 d r X O O H O N 9 1 - 9 9 % e e ( 3 R , 4 R ) N N O 2 R O N H X = H , 4 - F , 4 - C l , 4 - B r , 5 - M e , 5 - C l , 6 - F , 6 - C l , 6 - B r , 6 - M e , 6 - M e O , 6 - E t O 6 - t - B u X 1 = H , 4 - C l , 4 - B r , 4 - C N , 4 - M e O , 4 - E t G u a n i d i n e R = B n , 4 - C l C 6 H 4 C H 2 , M e , i - B u , ( C H 2 ) 2 P h , 3 - i n d o l y l m e t h y l Scheme 4. Chiral guanidine catalyzed cascade reaction of az a lactones.

The Jørgensen - Hayashi catalyst allowed the enantioselective Michael - acetalization - Henry reaction of ( E ) - 2 - (2 - nitrovinyl)phenols and 5 - oxohexanal followed by oxidation with PCC, affording hexahydro - 6 H - benzo[c]chromenones with four stereogenic centers ( Scheme 5). 16 Longer reaction times were required with electron - donating groups on the phenyl ring. During the reaction course three stereogenic centers were produced almost in single configuration, while the fourth stereogenic center was obtained in both configurations. However, the cis diastereomer was predominant. The aflatoxin skeleton was then obtained after reduction of these products, followed by Nef - cyclization with ZnBr 2 .

1 ) J - H ( 2 0 m o l % ) ( R ) N O 2 A c O H ( 2 0 m o l % ) H O C H 3 H O C H 3 O N O N O H 2 O , r t , 1 8 - 3 0 h 2 2 H O 2 ) P C C , C H C l ( S ) H 1 2 2 , 2 r t , 1 2 - 1 9 h P h + ( S ) ( R ) + H 6 3 N P h X 5 1 - 6 4 % H C H O c i s : t r a n s 7 9 : 2 1 t o 9 6 : 4 X O O X O O O T M S 5 4 J - H 9 9 % e e ( c i s ) c i s t r a n s 9 2 - 9 9 % e e ( t r a n s )

X = H , 4 - B r , 4 - C l , 4 - M e O , 4 - N O 2 , 4 - M e , 4 - B n O , 5 - M e , 6 - B r , 6 - C l , 6 - M e O 1 ) J - H ( 2 0 m o l % ) O M O M A c O H ( 2 0 m o l % ) O H O O N 1 ) Z n B r ( 1 . 5 e q ) H O , r t , 2 4 h 2 2 2 M O M O C H C l 3 0 h O 2 ) N a B H M e O H , 2 2 , 4 , H 2 ) P C C , C H C l ( R ) + 0 ° C , 0 . 5 h 2 2 M O M O r t , 2 h H H O O M O M H 5 5 % 4 8 % ( S ) O M O M O O H O H 9 9 % e e C H O M O M O O H N O 2 ( R ) a f l a t o x i n a n a l o g u e Scheme 5 . Cascade reaction of 2 - hydroxynitrostyrene and 5 - oxohexanal.

Recently, a reaction involving alko xy nitrostyrenes instead of hydoxynitrostyrenes has been reported: th at is th e vinylogous Michael - Michael cascade reaction of 3 - alkylidene oxindole s, with nitroolefin enolates (Scheme 6) . 17 The reaction was also successfully extended to isopropylidene benzofuran - 2 - one and the desired was recovered in 59% yield with 10:1 dr and 93% ee. A gram - scale reaction afforded 1.23 g of the ( 67% yield, with 14:1 dr and 94% ee). The absolute configuration was determined by X - ray analysis. Finally, the reduction by SnCl 2 proceeded without affecting selectivity and affording an interesting chiral γ - amino acid ester structure.

3.2. From c halcones An interesting reaction was reported by Ranganath and co - workers in 2017 staring from 2 ′ - hydroxychalcones [1 - (2 - hydroxyaryl) α,β - unsaturated aliphatic ketones. 18 They were able to obtain both enantiomers of the product with high enantioselectivity by employing two heterogeneous catalysts prepared from magnetite and cobal t ferrite nanoparticles with a binaphthol phosphate as the chiral ligand and confined into nanotubes (Scheme 7). The authors attributed the different stereochemistry to the confinement effect of the two different nanoparticles and to the π - interactions of aromatic groups with cobalt ferrite. No reaction was observed with 1 - (2 - hydroxyaryl) α,β - unsaturated aliphatic ketones. The catalyst can be easily recovered by external magnet and reused five times without a decrease in yield and selectivity. A quite long asymmetric synthesis of 4 - amino - 3 - hydroxybenzopyrans was performed starting from chalcones. 19 The asymmetric step was the synthes is of epoxy alcohols by a Corey - B akshi - Shibata reduction 232 followed by Sharpless asymmetric epoxidation. Then alcohol protection, regioselective ring - opening with various amines, orthogonal protection of the new free alcohol group, deprotection of the other alcohol moiety, intramolecular nucleophilic aromatic substitution provided the products (Scheme 8). The reaction is quite compl ex, overall yields are low, authors do not explain if they deduced the configuration and ee from optical rotation and from what previous data and, finally, they did not give any information if the last steps affect either the diastereomeric or the enantiom eric excesses.

B o c 4 5 N X O M e R X O 3 6 S q u a ( 2 0 m o l % ) H N C H C l 3 5 ° c , 2 2 , R X 4 A M S , 9 6 h N H O + O O N N E t O N X H H N O N O O B o c 2 N C O 2 E t H O N O X = H , 5 - F , 5 - C l , 5 - B r , 6 - C l N O O C F R = P h , 2 - M e O C H 3 - C l C H 3 - B r C H 3 6 4 , 6 4 , 6 4 , O 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 4 - M e O C 6 H 4 , 4 - M e C 6 H 4 , F 3 C M e 5 5 - 8 5 % 5 : 1 t o > 1 9 : 1 d r S q u a X 1 = H , 5 - F , 5 - C l , 5 - B r , 5 - M e O , 5 - M e , 4 - M e O 8 9 - > 9 9 % e e ( 2 S , 3 S , 4 R ) C O E t O 2

X 1

R N O 2

O X N B o c Scheme 6. Michael - Michael cascade reactions of 3 - alkylidene oxindoles and nitroolefin enoates.

O

P A - M N P f e r r i t e P A - M N P c o b a l t f e r r i t e O O ( 4 0 m g / m m o l ) ( 4 0 m g / m m o l ) P c h l o r o b e n z e n e O H c h l o r o b e n z e n e 1 0 0 ° C 1 0 0 ° C O O X O O 5 8 - 8 2 % 7 2 - 8 6 % 2 7 - 7 0 % e e 5 0 - 9 4 % e e P A - M N P

O O

X X X = H , 4 - B r , 4 - M e O , 4 - M e , 4 - C l , 3 - C l , 3 - N O 2 Scheme 7. Oxa - Michael addition of 2 ′ - hydroxychalcones in carbon confined spaces.

3.3. From 2 ' - h ydroxycinnamaldehydes Many asymmetric synthesis of chromane derivatives have been performed starting from o - hydroxycinnamaldehydes. The Jørgensen - Hayashi class of catalysts is the best choice. In fact, it easily forms a relatively stable cyclic aminal, which, under basic conditions, is converted into a zwitterionic intermediate, or, under acidic conditions, into the iminium ion. Then both open - chain intermediates can be attacked by nucleophiles from the less hindered face. Alternatively, the acidic condi tions can form an enamine that can attack electrophiles (Scheme 9). An example of a reaction carried out under acidic conditions is the formal cycloaddition of trans - β - nitrostyrenes. 20 Recently, a diversity - oriented version of this reaction allow ed preparing some different compounds (Scheme 10). 21 The Hantzsch ester can reduce either the 2 - hydroxycinnamaldehyde or the trans - β - nitrostyrene. When the double bond of the aldehyde was reduced (Scheme 10, eq . 1), the reaction proceeded via enamine inter mediate. The chroman - 2 - ol intermediate could be oxidized with PCC or treated with a base leading to chroman - 2 - ones or to polycyclic O,O - acetals with five adjacent stereocenters, respectively. It should be noted that significant amounts from iminium ion pat hway (Scheme 10, eq . 2) lowered the yields with aliphatic trans - β - nitrostyrenes. If the nitrostyrene was reduced before adding the o - hydroxycinnamaldehydes (Scheme 10, eq . 2), the reaction exclusively occurred via iminium ion 233 intermediate, leading to o pen - chain compounds as a mixture of two diastereomers in different ratios, in which only the stereochemistry of the benzyl position is defined. The absolute configuration was determined by X - ray analysis of one of the tricyclic O,O - acetals and t he other attributed by analogy.

P h ( R ) - C B S ( 5 0 m o l % ) P h O F O H F H B H 3 . T H F ( 1 e q ) O 4 A M S , T H F , - 2 0 ° C , 5 h N B 9 8 % 8 0 % e e ( S ) B r B r ( R ) - C B S ( - ) - D I P T ( 2 e q ) 6 9 % O H O T i ( O i - P r ) 4 ( 2 e q ) t h e n t - B u O O H ( 4 e q ) d r > 2 0 : 1 i - P r O a l l - ( R ) O i - P r 4 A M S , C H 2 C l 2 , - 2 0 ° C , 4 8 h O O H O T B S F T B S C l ( 2 . 5 e q ) O H F i m i d a z o l e ( 5 e q ) D M F , r t , o v e r n i g h t ( - ) - D I P T O O 9 4 % B r B r A m i n e 1 8 - 9 3 % E u ( O T f ) 3 ( 2 0 m o l % ) n o d r o r e e P h M e , 1 3 0 ° C . 2 4 h r e p o r t e d C s F ( 2 e q ) 1 1 1 R R R R K C O ( 4 e q ) R R T B S O N F T B S O N F 2 3 N D M F , B n B r B r O B n N a H , D M F 1 3 0 ° C , 2 4 h O H O B n 5 8 - 9 3 % 3 2 - 4 7 % O n o d r o r e e B r n o d r o r e e r e p o r t e d B r r e p o r t e d R = H , R 1 = i - P r , B u , 2 , 4 - ( M e O ) C H 1 2 6 3 R - R = ( C H 2 ) 5 , ( C H 2 ) 2 O ( C H 2 ) 2 , ( C H 2 ) 2 N B o c ( C H 2 ) 2 , R = R 1 = E t 1 R - R = ( C H 2 ) 5 , ( C H 2 ) 4 , ( C H 2 ) 2 O ( C H 2 ) 2 , ( C H 2 ) 2 N H ( C H 2 ) 2 , ( C H 2 ) 2 N B o c ( C H 2 ) 2 , Scheme 8. Enantioselective Synthesis of 4 - Amino - 3 - hydroxybenzopyran.

O

N

N u

H + O H O H + J - H O N H N C H O E O H - O H

N N u H Scheme 9. The accepted mechanism for asymmetric reactions of o - hydroxycinnamaldehydes.

T he synthesis of 4 - (nitromethyl) chroman - 2 - ols can arise from o - hydroxynitrostyrene and aldehydes (Scheme 3) or from o - hydroxycinnamaldehydes and α - nitroalkanes via iminium ion pathway. In particular, with α - nitroketones (Scheme 11), 22 an acyl transfer can occur, thus avoiding the protection or the transformation of t he unstable chroman - 2 - ol. However, the reaction suffered from steric reason: in fact, a t - butyl group in the 6 position of cinnamaldehyde impeded the reaction. Products were also successfully employed in further transformations. The absolute configurat ion was established by X - ray analysis. The addition of diphenylphosphine oxide to o - hydroxycinnamaldehydes via zwitter ion pathway afforded 4 - diphenylphosphinyl chroman - 2 - ols (Scheme 12 ). 23 Although yields are only moderate or good, the stereoselectivities are much higher diasteroselectivity with respect to the same reaction with nitromethane 24 or malonates. 25 The unstable chroman - 2 - ols were protected as acetates. The stereochemistry was determined by X - ray analysis. The asymmetric ( o - anisyl) phenylphosphine oxide was also tested, and a 1:1 mixture of separable diastereomers was obtained in 84% yield with 85% and 94% ee, but the absolute 234 configuration of the chiral phosphorus was not identified. Some transformations of the products were also su ccessfully carried out.

J - H ( 2 0 m o l % ) 4 - M e C 6 H 4 C O 2 H P h C O 2 t - B u ( 2 0 m o l % ) N O 2 C H O N P h O N H O T M S H N H E ( 1 . 2 e q ) O H C 2 R H O H O J - H C H 2 C l 2 , O H C C O t - B u R 2 2 5 ° C , 4 6 h H O H E e q 1 H a n t z s c h e s t e r X X v i a e n a m i n e X

P C C ( 3 e q ) C H 2 C l 2 , O O H K O H , M e O H O O H O O 0 ° C , 1 h 4 0 ° C , 2 h ( S ) X N O 2 2 6 - 8 7 % X N O 2 X N O 2 > 2 0 : 1 d r ( R ) R A R 9 7 - 9 9 % e e R R 1 C H O

B F 3 . E t 2 O ( 3 e q ) , 0 ° C O H 1 ( S ) 1 O H O R 0 . 5 h O O R ( R ) 6 8 - 8 1 % ( S ) N O X N O 2 f r o m A X ( R ) ( S ) 2 R > 2 0 : 1 d r R 9 6 - 9 7 % e e X = H , 4 - M e , 4 - F , 5 - C l R = P h , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 4 - M e C 6 H 4 , 4 - C N C 6 H 4 , 4 - M e O C 6 H 4 , 3 - M e O C 6 H 4 , 2 , 4 - ( M e O ) 2 C 6 H 3 , 2 - f u r y l , 2 - t h i e n y l , 2 - n a p h t h y l , P h ( C H 2 ) 2 , c - C 6 H 1 1 1 R = 4 - C l C 6 H 4 , 4 - N O 2 C 6 H 4 , 4 - C N C 6 H 4 , 2 - t h i e n y l , C O 2 E t H O C H O J - H ( 2 0 m o l % ) C H O R R 4 - M e C 6 H 4 C O 2 H H O ( 2 0 m o l % ) H O H O i - P r O H , 2 5 ° C , 1 8 h N O N a B H 4 ( 2 e q ) N O 2 M e O H , 0 ° C , 1 h 2 v i a i m i n i u m 5 2 - 8 0 % e q 2 m i x t u r e o f O N 2 H E ( 1 . 2 e q ) O 2 N ( S , S ) a n d ( S , R ) i s o m e r 9 2 - 9 9 % e e R R R = P h , 4 - F C 6 H 4 , 4 - M e C 6 H 4 , 3 - M e O C 6 H 4 , 2 - n a p h t h y l , 3 - ( N - t o s y l ) i n d o l y l Scheme 10 . Diversity - oriented one - pot syntheses starting from o - hydroxycinnamaldehydes.

O

J - H ( 2 0 m o l % ) O 2 N P h C O O H ( 2 0 m o l % ) R P h 6 O H D i c h l o r o e t h a n e C H O N 5 P h - 2 0 ° C , 7 d H O T M S 4 J - H X C H O X O H 3 O O H O N O N 2 R 2 R O O O N O N N O 2 2 R 2 O H R

R O X O O H X O O H X O 4 7 - 9 3 % > 2 0 : 1 d r 6 8 - 9 6 % e e ( 2 R , 4 S ) O N 2 X = H , 4 - C l , 4 - B r , 4 - M e , 4 - N O 2 , 5 - M e O , 4 , 6 - C l 2 , 4 , 6 - B r 2 , 4 - C l - 6 - B r R = P h , 4 - M e C 6 H 4 , 4 - i - P r C 6 H 4 , 4 - t - B u C 6 H 4 , 4 - M e O C 6 H 4 , 4 - E t O C 6 H 4 , O 4 - P r O C 6 H 4 , 4 - i - B u O C 6 H 4 . 4 - A l l y l O C 6 H 4 , 4 - B n O C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 3 - M e C 6 H 4 , 3 - C l C 6 H 4 , 2 - M e C 6 H 4 , 2 - M e O C 6 H 4 , X O O R 2 - F C 6 H 4 , 2 , 4 - M e 2 C 6 H 3 , c y c l o h e x y l Scheme 1 1 . Asymmetric Michael/hemiacetalization/acyl transfer reaction.

1 - Aza - 1,3 - butadienes can work both as the four - atom and the two - carbon unit in the cycloaddition with o - hydroxycinnamaldehydes (Scheme 13). 26 As already depicted in Scheme 10, eq. 1, the Hantzsch ester reduced the 2 - hydroxycinnamaldehydes to chroma - 2 - ols, which are the two - atoms partner in the cycloaddition reaction, then, the aminal intermediate was cyclized by medium acidification. On the other 235 hand, 2 - hydroxycinnamaldehydes could work as a four - atom partner. This second reaction was also carried out in 0 .5 - mmol scale, and the product was successfully used for further transformations. The structure was determined by X - ray analysis on a product of each reaction.

J - H ( 1 0 m o l % ) P O P h 2 C H O N a O A c ( 2 0 m o l % ) C H C l r t , 2 4 h P h + H P O P h 2 2 , 2 N P h O H 5 1 - 8 6 % H X O O H O T B S 7 : 1 t o > 2 0 : 1 d r X 8 4 - > 9 9 % e e ( 2 R , 4 S ) J - H X = H , 3 - M e , 3 - C l , 4 - M e O , 5 - M e , 5 - C l , 5 - B r , 5 - N O 2 , 4 , 5 - M e 2 , 3 , 5 - C l 2 , 3 , 5 - B r 2 , Scheme 1 2 . Asymmetric cyclization of o - hydroxycinnamaldehydes with diphenylphosphine oxide.

R 1 C H O R J - H a ( 2 0 m o l % ) N P h O 2 S 4 - N O 2 C 6 H 4 C O 2 H N P h H O S O 2 ( 2 0 m o l % ) N H O T M S H E ( 1 e q ) J - H a a c e t o n e , 4 0 ° C , 8 h O H R 1 O H 4 - a t o m s p a r t n e r C O 2 E t R N R H N H O

p - T s O H C O 2 E t ( 3 . 5 e q ) H E 2 5 ° C , 6 h H a n t z s c h e s t e r

P h S O 2 N N P h S O 2 N H O T B S R 1 4 4 - 7 9 % O J - H b e q 1 > 2 0 : 1 d r R 1 R = H , F , M e 9 4 - 9 9 % e e O H 1 ( 6 S , 6 a R , 1 2 a R ) R = P h , 4 - M e C 6 H 4 , 4 - C l C 6 H 4 , 3 - M e C 6 H 4 , 2 - n a p h t h y l , 2 - t h i e n y l R R

C H O J - H b ( 2 0 m o l % ) N d i c h l o r o e t h a n e , 1 C H O H O O 2 S R 2 5 ° C , 2 4 h e q 2 + O S 5 1 - 7 5 % 2 R N R = H , F 1 7 : 1 t o > 2 0 : 1 d r 1 9 7 - 9 9 % e e R = P h , 4 - M e C 6 H 4 , 4 - C l C 6 H 4 , R 1 O 3 - M e C H 2 - n a p h t h y l R t w o a t o m s p a r t n e r ( 2 R , 3 S , 4 R ) 6 4 ,

O S O 2 N O 6 0 % C H O e q 1 > 2 0 . 1 d r 9 2 % e e O 2 S N P h H O O + P h e q 2 C H O O 8 4 % > 2 0 . 1 d r O 2 S N 9 7 % e e P h O Scheme 13. Synthesis of chiral chromane - containing polyheterocyclic compounds.

2 - Hydroxycinnamaldehydes and γ/δ - hydroxy enones reacted under iminium ion catalysis followed by oxidation with PCC and afforded tetrahydrofuran/tetrahydropyran - fused 3,4 - dihy drocoumarin (Scheme 14). 27 The absolute configuration of products was determined by X - ray analysis. The hemiacetal intermediates arising from aliphatic γ - hydroxy enones could not be oxidized. However, they could be converted in acetals, or submitted to Wittig - Michael reaction without affecting the ArCO moiety, or converted into an allyl derivative with allyl trimethylsilane and BF 3 .Et 2 O. Finally, they could be also reduced with triethylsilane and BF 3 .OEt 2 with the exclusive reduct ion of the hemiacetal gr oup at - 78 °C, and also of the ArCO moiety at 0 °C. All these reaction maintained high enantiopurity. Some papers on the reaction of 2 - hydroxycinnamaldehydes and bis - indolyl derivatives have been recently reported. In the most ancient paper, the target spi ro - bridged compounds were obtained as a mixture of the diastereomers (3 R ,6 ′ S ,13 ′ S ) and (3 S ,6 ′ S ,13 ′ S ) with high enantiomeric excess (Scheme 15, eq . 1), 28 236 because the organocatalyst only controlled the stereochemistry of the 4 - position of the chroman - 2 - ol in termediate (see also Scheme 10, eq . 2). The preparation of chroman - 2 - ols before submitting them to the reaction with 3 - indolyl - 3 - methoxyoxindoles and the use of a different catalyst (Scheme 15, eq . 2) did not overcome this drawback. In fact, a mixture of t he diastereomers (5a R ,11 R ,11a R ) and (5a R ,11 S ,11a R ) with high enantiomeric excess was once more obtained. The absolute configurations of both spiro - bridged and spiro - fused products were determined by X - ray analysis. The synthetic utility of these compounds was also tested, and some transformations were successfully carried out.

R 1 O R 1 P C C ( 1 . 5 e q ) O O C H C l r . t . , 2 2 , P h O C H O R 2 4 - 4 8 h C H O O O N P h H O 5 7 - 8 0 % H O T M S 1 J - H ( 1 0 m o l % ) O H C O R > 2 0 : 1 d r J - H H O 9 2 - > 9 9 % e e A c O H ( 1 0 m o l % ) ( a l l - S ) C H C l r . t . , 7 2 h 2 2 , R = H , M e , C l , B r R 1 R = P h , 4 - M e C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 R R 1 R 1 O O O P C C ( 1 . 5 e q ) 1 O O R C H 2 C l 2 , r . t . , R 2 4 - 4 8 h O H O O 5 8 - 8 2 % H O O 8 : 1 t o > 2 0 : 1 d r 4 6 - > 9 9 % e e ( 3 R , 3 a R , 9 b S ) O R O R = H , M e , C l , B r P h R 1 = P h , 4 - M e O C H 4 - M e C H 4 - i - P r C H 4 - t - B u C H 4 - F C H 6 4 , 6 4 , 6 4 , 6 4 , 6 4 , 7 3 % 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 3 - M e O C 6 H 4 , 3 - M e C 6 H 4 , 3 - C l C 6 H 4 , > 2 0 : 1 d r 2 - M e O C 6 H 4 , 2 - M e C 6 H 4 , 2 - n a p h t h y l , 2 - t h i e n y l , a n d 9 8 % e e O O O M e Scheme 14. Synthesis of tetrahydrofuran/tetrahydropyran - fused 3,4 - dihydrocoumarins.

Then the research group studied the reaction with N - sulfonyl ketimines (Scheme 16). 29 Comparing this reaction with that depicted in Scheme 13, it is clear the role of the exocyclic double bond in the governance of the reaction pathway. The conjugate addition of N - sulfonyl ketimines to 2 - hydroxycinnamaldehydes gave an inseparable equilibrat ing mixture of isomers, but the oxidation with PCC or the dehydration of this mixture led to bridged benzo - fused aminals. The reaction can be scaled up to 1 mmol with similar results and extended to N - protected 2 - amino cinnamaldehydes. It should be noted t hat the reaction of the six - membered cyclic N - sulfonyl ketimine did not give any bridged compound after oxidation. To increase the significance of the reaction some chemical transformations of these compounds were successfully carried out. Then the authors set up the reaction with acyclic N - tosyl ketimines (Scheme 17). 30 Interestingly, the scarcely reactive acyclic N - tosyl ketimine reacted without the addition of a base for their deprotonation. The reaction was solvent dependent: in CH 2 Cl 2 provi ded bridged hemiaminals with excellent enantioselectivity as a single diastereomer; in acetone/H 2 O, 4:1 open - chain product were recovered, which can be treated with BF 3 ·Et 2 O at - 20 °C to furnish bridged aminals. In the former conditions, NAc or NCbz ketimi nes gave low yields and selectivity, while NSO 2 Ph gave similar results. Bulky ketimines did not provided bridged cycloadducts, but chromane aminals, which were characterized after Wittig reaction with Ph 3 P=CHCO 2 Et. The bridged hemiaminals can be efficientl y opened with BF 3 ·Et 2 O at - 20 °C. The absolute configuration depicted in Scheme 16 was assigned by means of TD - DFT calculations of the electronic circular dichroism spectra. In acetone/H 2 O, 4: 1, 2 - amino cinnamaldehyde also reacted leading to the product in 60% yield and 96% ee. Many transformation s w e re carried out on these products without affecting enantioselectivity. The absolute configuration depicted in Scheme 16 was assigned by X - ray analysis. A fourth synthesis allowed the preparation of a 6,6,5 - brid ged or a 6,6,6 - bridged ring system from β - oxoesters (Scheme 18). 31 The 6,6,5 - bridged compound was obtained after oxidation of the oxoester with m - CPBA . Conversely from many reactions involving the Jørgensen - Hayashi catalyst , in which an acidic additive must activate the catalyst, in the present reaction the reduced m - chlorobenzoic acid must be neutralized in order to obtain the products. 2 - Furyl substituted oxoester afforded an inseparable 3:1 mixture 237 of epimers. The 2:1 mixture of epimers from aliphatic oxoester is instead separable. The reaction with N - protected 2 - amino cinnamaldehydes gave worse yields. The structure depicted in Scheme 18 was determined by X - ray analysis. Moreover, several transformations were successful ly attempted on these products.

R 2 C H O 8 O N 7 " 7 6 " X H O 5 1 J - H ( 2 0 m o l % ) O 6 R O H B F 3 . E t 2 O X O 5 " 2 - F C 6 H 4 C O 2 H C H C l 5 ' 4 ' 4 " 2 2 , P h ( 2 0 m o l % ) 0 ° C N X 6 ' 2 T H F , - 2 0 ° C , 1 5 h O R 7 ' R I N P h R 2 1 0 m i n H + + e q 1 O T B S 2 2 N R R N R 2 J - H N O N R 1 R R 1 R 1 X O O N N R 2 R 2 R R I I X H 8 - F 7 - C l 6 - M e 6 - C l H H H H H H H H R H H H H H 5 ' - M e 6 ' - M e O 7 ' - C F 3 5 ' , 6 ' - F 2 H H H H R 1 H H H H H H H H H 5 " - M e 6 " - B r H H R 2 M e M e M e M e M e M e M e M e M e M e M e B n H Y i e l d % ( I ) 2 2 2 3 2 4 2 3 2 7 3 0 1 9 1 0 1 1 2 6 3 0 2 3 1 5 Y i e l d % ( I I ) 6 1 5 4 5 8 5 4 5 9 6 2 3 6 6 5 6 3 5 2 5 6 4 7 3 2 e e % ( I ) > 9 9 > 9 9 9 9 9 8 9 9 > 9 9 > 9 9 8 3 9 3 > 9 9 9 8 9 8 9 6 e e % ( I I ) > 9 9 > 9 9 > 9 9 > 9 9 > 9 9 > 9 9 > 9 9 9 4 9 8 > 9 9 > 9 9 > 9 9 9 8 O O a n d O N O N N N O O O O N N N N

2 5 % , 9 9 % e e 4 9 % , > 9 9 % e e 3 4 % , 9 9 % e e 2 2 % , 9 7 % e e R 2 O H O O N X 1 ) M M ( 2 0 m o l % ) M e C N / H 2 O ( 5 / 1 ) R 1 O X N 2 5 o r 4 0 ° C O + 2 ) T s O H ( 2 0 m o l % N 2 R P h N R C H 2 C l 2 , 4 0 ° C 2 I I I R H 2 N + e q 2 1 C F 3 C O 2 R R 2 O M M O M e N X O N R 1 R R 2 O N I V R R 2 X H 6 - F 8 - M e b e n z o [ h ] H H H H H H H R H H H H 5 ' - M e 6 ' - M e O 7 ' - C l H H 5 ' - C l H R 1 H H H H H H H 5 " - M e 6 " - B r 6 " - M e H R 2 M e M e M e M e M e M e M e M e M e M e H Y i e l d % ( I I I ) 3 0 3 4 2 3 2 4 2 4 2 6 2 3 3 1 1 7 3 1 t r a c e Y i e l d % ( I V ) 4 2 4 8 4 5 3 6 4 0 4 0 3 4 4 8 3 3 4 4 2 0 e e % ( I I I ) 9 8 9 9 9 8 9 4 9 8 9 4 9 8 9 9 9 8 9 8 - e e % ( I V ) 9 9 9 7 9 9 9 4 9 9 9 9 9 8 9 9 9 8 9 9 9 8 Scheme 1 5 . Synthesis of spiro - bridged and spiro - fused chromane derivatives.

A bifunctional tertiary amine - thiourea catalyst activated cyclic β - oxoaldehydes in the reaction with the iminium ion from 2 - hydroxycinnamaldehyde (Scheme 19). 32 Benzofused oxoaldehydes led to spiro - bridged hemiacetal products, and the reaction was scaled up to a 1 mmol scale without affecting yields and selectivity. The less reactive aliphatic cyclic oxoaldehydes gave cage - like polycyclic hemiacetal products in l onger reaction times. Further chemical transformations on the products did not affect stereoselectivity. The absolute configuration of both spiro - bridged and cage - like products was determined by X - ray analysis. Attempts to recover the catalyst were unsucce ssful. Thus, the authors set up a rather curious procedure: they charged 100 mol% catalysts and added the reactants, waited the complete consumption of reactants, added 238 fresh reactants and repeated the procedure five times. Product was recovered with a sli ghtly lower average yield and comparable stereochemistry, and the reaction was faster. However, in our opinion, this procedure did not demonstrate the recyclability of the catalyst, but that, at the last stage, a 20 mol% was still active. They should have loaded only 20 mol% of catalyst and then add fresh portions of reactants and see if the reaction went on. The higher reaction rate was obvious because in the first steps the catalyst is much more abundant.

3 R = H 4 O J - H S O 2 C H O P C C , c e l i t e R ( 2 0 m o l % ) N N 4 0 ° C , 2 h 5 C H 2 C l 2 , X O 2 S O H O + 2 5 ° C , 2 h u n s e p a r a b l e 6 e q u i l i b r a t i n g 4 4 - 7 1 % , 9 4 - 9 7 % e e m i x t u r e o f X = H , 3 - F , 4 - C l , 4 - M e O , 5 - F , 5 - M e , 6 - C l X i s o m e r s 3 T s O H 4 O O 2 C H C l 2 2 N S 4 0 ° C , 8 h 5 X 6 R 5 8 - 8 6 % , 9 3 - 9 9 % e e X = H , 3 - F , 4 - C l , 5 - F , 5 - M e , 6 - C l R = H , M e O O 2 S N O X = O C H O J - H T s O H O 2 S N ( 2 0 m o l % ) C H 2 C l 2 P h X C H C l 4 0 ° C , 8 h H O + 2 2 , R N P h 2 5 ° C , 2 h 5 2 - 7 0 % , 8 8 - 9 8 % e e H O T M S R = H , 4 - M e O , 5 - F , 5 - M e , 6 - M e O O O 2 J - H R R = H S P C C , c e l i t e O N X 4 0 ° C , 2 h

R 4 7 - 6 7 % , 8 5 - 9 6 % e e R = H , 3 - C l , 4 - M e O , 5 - F , 5 - M e , 6 - M e O , b e n z o [ e ] X = O , N M e Scheme 1 6 . Divergent synthesis of chiral bridged and spiro - bridged benzofused aminals.

Finally , the same research group reported an other asymmetric multi - catalytic tandem Michael/cyclization reaction , that is the reaction between 2 - hydroxycinnamaldehydes and 4 - hydroxyc oumarins leading to enantioenriched chiral benzofused 2,8 - dioxabicyclo[3.3.1]nonanes (Scheme 20) . 33 It should be noted that 6 - substituted 2 - hydroxycinnamaldehydes gave the corresponding products with low enantioselectivities (6 - 23% ee ). The absolute config uration of both spiro - bridged and cage - like products was determined by X - ray analysis. Some useful transformations of the products were performed without affecting stereoselectivity. A 1 - mmol scale reaction provided 220 mg of product with 75% yield and 96% ee. In this paper authors provided experiments to elucidate the mechanism and then proposed that the Jørgensen - Hayashi catalysts formed the iminium intermediate according to Scheme 9, while the thiourea catalyst served the dual function of activating the phenoxide anion and the enolic 1,3 - dicarbonyl substrate through three hydrogen bonds.

3.1. From other d erivatives The imine from salicylaldehyde can be deprotonated by a base leading to an azomethine ylide, which in turn can undergo 1,3 - dipolar cycloaddi tion, for instance with 2 - hydoxybenzylidene indandiones. 34 Among the racemic examples, authors also tried a organocatalyzed reaction by a squaramide chiral base ( Scheme 21 ). The absolute configuration of products was established via X - ray analysis. Ortho - s ubstituted salicylaldehyde derivatives were unreactive, perhaps for steric hindrance. Authors did not report mechanisms. A malonate bearing an ortho - hydroxybenzoyl group, having one electrophilic and three nucleophilic sites, is a great candidate for casca de reactions. Thus an N - heterocyclic carbene is able to catalyze the synthesis of enantioenriched cyclopenta[c] - fused chromenones by reaction of these substrates with 239

α,β - unsaturated aldehydes (Scheme 2 2 ). 35 It is worth noting the control of the reactivity of the substrate, which led to a very high chemoselectivity. The reaction did not work with pent - 2 - enal or phenyl rings with three consecutive substituents. The absolute configuration of compounds was determined by X - ray analysis. DFT calculatio ns demonstrated that the δ - lactonization mechanism is more thermodynamically favored with respect to the β - lactonization analysis, thus authors envisaged the mechanism depicted in Scheme 2 2 .

J - H 6 ( 2 0 m o l % ) O H C T s C H C l 2 5 ° C R 5 N 2 2 , O ( S ) P h + 3 - 6 h R 1 R 1 N T s N P h 4 R H H O 5 0 - 8 5 % ( R ) O T M S 3 X X 9 6 - 9 9 % e e ( S ) ( S ) O H J - H X = 3 - F , 4 - C l , 4 - M e O , 5 - F , 5 - C l , 5 - M e , 6 - C l R = P h , 4 - F C 6 H 4 , 4 - M e C 6 H 4 , 4 - P h C 6 H 4 , 3 - F C 6 H 4 , 3 - M e C 6 H 4 , 2 - n a p h t h y l R 1 = H , M e

N T s t - B u A d a m a n t y l O T s N O a f t e r W i t t i g a f t e r W i t t i g f r o m N H T s f r o m N H T s 6 0 % 6 5 % 9 7 % e e 9 6 % e e C O 2 E t C O 2 E t

O H C O H P h P h f r o m O O T s N N T s H O O H 4 5 % 9 9 % e e H O O H

B F 3 . E t 2 O R C H C l - 2 0 ° C O 2 2 , O N H T s 0 . 5 h N T s 4 1 - 6 0 % X X O H 9 9 % e e R X = H , F , M e R = P h , 4 - F C 6 H 4 , 4 - M e C 6 H 4 , 3 - M e C 6 H 4 , 2 - n a p h t h y l O

6 T s 1 ) J - H ( 2 0 m o l % ) , M e 2 C O / H 2 O ( 4 : 1 ) , 2 5 ° C , 2 4 h O H C 5 N O ( R ) 2 ) B F 3 . E t 2 O , C H 2 C l 2 , - 2 0 ° C , 0 . 5 h + R 1 N T s 4 R H O X 5 0 - 8 5 % 3 7 - 8 0 % X 3 9 6 - 9 9 % e e 9 2 - 9 9 % e e ( S ) R 1 X = 3 - F , 4 - C l , 4 - M e O , 5 - F , 5 - C l , 5 - M e R R = P h , 4 - F C 6 H 4 , 4 - M e C 6 H 4 , 4 - P h C 6 H 4 , 3 - M e C 6 H 4 , 2 - F C 6 H 4 , 2 , 4 - F 2 C 6 H 3 , 2 - n a p h t h y l , 2 - f u r y l R 1 = H , M e R - R 1 =

Scheme 1 7 . Reaction of 2 - hydroxycinnamaldehydes and acyclic N - tos yl ketimines .

O H C

H O X J - H ( 2 0 m o l % ) m - C P B A ( 2 . 4 e q ) D I P E A ( 2 . 4 e q ) d i c h l o r o e t h a n e d i c h l o r o e t h a n e 6 O O 6 0 ° C , 2 0 h O O 2 5 ° C 5 O O O R O R 1 R O R 1 t h e n B F 3 . E t 2 O ( 1 e q ) 4 C H 2 C l 2 , 0 ° C X O H 3 R 1 O R

R = P h , 4 - M e O C 6 H 4 , 4 - M e C 6 H 4 , 4 - F C 6 H 4 , 3 - M e C 6 H 4 , 2 - M e C 6 H 4 , 2 - f u r y l , 4 8 - 7 3 % 2 - n a p h t h y l , P r , d r > 2 0 : 1 R 1 = E t , t - B u e x c e p t f o r R = 2 - f u r y l ( 3 . 1 ) a n d R = P r ( 2 : 1 ) X = 4 - F , 4 - B r , 4 - M e O , 5 - M e O , 5 - C l , 6 - F 9 0 - 9 7 % e e

J - H ( 2 0 m o l % ) O d i c h l o r o e t h a n e O H C O O O 2 5 ° C P h + X N P h R R O E t H O t h e n B F 3 . E t 2 O ( 1 e q ) H O T M S X C H C l 0 ° C C O E t 2 2 , 2 J - H R = P h , 4 - M e O C H 4 - F C H 3 - M e C H 2 - M e C H P r , 5 3 - 7 3 % 6 4 , 6 4 , 6 4 , 6 4 , d r > 2 0 : 1 X = 3 - C l , 4 - M e , 5 - C l , 6 - F 9 2 - 9 6 % e e Scheme 1 8 . Synthesis of chiral acetal - containing bridged cyclic compounds.

240

The intramolecular Alder - ene reaction of 1,7 - dienes is a useful method for the synthesis of nonracemic functionalized heterocyclic compounds. Recently, it was applied to the synthesis of chromane derivatives (Scheme 2 3 ). 36 It was found that: (i) increasing steric hindrance of the ester group the diasteroselectivity increased; (ii) long chain olefin needed 10 mol% catalyst loading; (iii) lower yields and dr values were obtained with 5 - or 6 - substituted phenyl rings; (iv) naphthyl ring gave only 49% yield, with 6:1 dr and 20% ee. The absolute configuration of compounds was determined by X - ray analysis. When d iastereomeric ratios are low, the enantiomeric excess of the minor isomer is reported in the paper, but they are not copied here for sake of simplicity. The reaction was also extended to the synthesis of benzothiopyran and tetrahydroquinolines, and in this last case the reaction was also scaled up to gram scale. Interestingly one of the compounds was efficiently transformed into a tetrahydropyranochromene skeleton typical of potentially antiproliferative, polyphenolic compounds isolated from Alpinia blephar ocalyx .

J - H ( 2 0 m o l % ) T H 2 0 m o l % ) P h C O O H ( 2 0 m o l % ) 3 O d i c h l o r o e t h a n e 4 O 3 , 5 - ( C F 3 ) 2 C 6 H 3 O H C C H O 0 ° C , 2 4 - 1 4 4 h O N 3 , 5 - ( C F 3 ) 2 C 6 H 3 + 5 H O T M S 5 4 - 8 8 % X H O 1 6 O O H J - H X X n s i n g l e d i a s t e r e o m e r 9 8 - 9 9 % e e 6 ' n S X = H , 3 - F , 3 - M e , 4 - C l , 5 - F , 5 - B r , 5 - M e 5 ' 3 ' 1 X = 3 ' - M e O , 4 ' - C l , 4 ' - M e O , 5 ' - B r , 5 ' - M e O X 1 4 ' N N n = 1 , 2 H H J - H ( 2 0 m o l % ) N M e 2 T H 2 0 m o l % ) O 3 T H P h C O O H ( 2 0 m o l % ) O O H C C H O d i c h l o r o e t h a n e 4 0 ° C , 8 - 2 6 d O + 5 Y H O Y 4 0 - 6 8 % X X 6 O s i n g l e d i a s t e r e o m e r H O 8 7 - 9 9 % e e X = H , 3 - F , 3 - f u r y l , 4 - C l , 5 - F , 5 - C l , 5 - B r , 5 - M e , 5 - P h , 5 - T M S C C 5 ( E ) - P h C H = C H , 6 - C l O Y = C H 2 , O Scheme 1 9 . Construction of spiro - bridged or cage - like polyheterocyclic compounds.

C F C H O 3 J - H ( 2 0 m o l % ) S H O O H T H 2 0 m o l % ) C H 2 C l 2 , 0 ° C N N C F + 3 N M e 2 H H X X 1 O O H O O N X = H , 3 - F , 4 - C l , 5 - M e O , 5 - B r , 5 - C l , 5 - C O 2 E t , 5 - N O 2 , 6 - C l , 6 - M e O X 1 = H , 5 - C l , 6 - F , 6 - M e O , 6 - C N , 7 - F , 7 - B r , X 1 O O X S i - f a c e 7 - M e , 8 - C l ( n u m b e r s r e f e r t o s t a r t i n g m a t e r i a l s ) P h N P h O O H H O T M S O O H O B F 3 . E t 2 O , O O H J - H X C H 2 C l 2 , C F 3 0 ° t o 2 5 ° C 1 S 1 X O O X 3 6 - 7 3 % X O O X 1 O O > 2 0 : 1 d r X N N C F 3 6 - 9 9 % e e H H ( 8 R , 1 4 S ) N M e 2 T H Scheme 20. Asymmetric multicatalytic reaction sequence to construct bridged bicyclic acetals .

4. C ycloaddition of ortho - quinone m ethides The cycloaddition of both stable and in situ prepared o - quinone methides is a classical method for preparing the benzopyran nucleus. 37 In the last years, two papers described this reaction referring to chiral reactions but, actually they are only diasteros elective reactions. Those are: (i) the or ganocatalytic dearomative [4+2] cycloadditions of biomass - derived 2,5 - dimethylfuran with ( - ) - camphor sulfonic acid as the catalyst, in which authors reported 241 excellent diasteroselectivities but not enantiomeric excesses; 38 (ii) the Diels - Alder reaction between the o - quinone methides of resorcin[4]arene and styrenes, which provided only two of the possible diastereoisomers but in a racemic form. 39

C O 2 E t C O 2 E t O M e S q u a ( 2 0 m o l % ) E t O 2 C E t O 2 C N 4 A m o l e c u l a r s i e v e s N N C H C l - 5 ° C , 1 - 8 d O H 3 , O H H N N H O X X N 1 X 3 0 - 8 4 % O > 2 0 : 1 d r O 5 8 - 9 6 % e e C F 3 O H ( 2 S , 3 a R , 9 b R ) F 3 C 5 ' 4 ' O X 1 S q u a 6 ' 3 ' O

2 O H 9 O 9 b N H X = H , 6 - M e O , 6 - M e , 7 - M e O , 8 8 - C l , 8 - B r , 8 - M e O 3 a C O 2 E t X 1 = H , 4 ' - M e O , 5 ' - B r , 5 ' - C l , 5 ' - M e O X O O 7 6 Scheme 2 1 . Chromenopyrrolidines from azomethine ylides and 2 - hydroxyb enzylideneindandiones via [3+2] cycloaddition.

R O C O N 2 B F 4 C O 2 R X = H , 7 - C l , 7 - M e , 8 - M e , 8 - B r , 8 - F , 8 - C l N N M e s 1 R = M e , E t , B n R 1 8 R = P h , 4 - M e C 6 H 4 , 4 - M e O C 6 H 4 , 4 - 7 ( N M e ) 2 C 6 H 4 , 4 - B r C 6 H 4 , 4 - C l C 6 H 4 , 4 - A c O - 3 - X O O R 1 C H O M e O C 6 H 3 , 2 - n a p h t h y l , 2 - f u r y l , M e C H = C H , 6 5 - 9 2 % N O 2 9 9 - 7 9 % e e ( S ) ( 2 0 m o l % ) d i m e t h o x y e t h a n e , r t O H

H 2 O 1 N R N N O H R O 2 C M e s C O 2 R O C O 2 R H O X R 1 t - B u t - B u O C O 2 R

X O O ( 1 . 5 e q ) D B U ( 1 . 5 e q ) L i C l ( 5 0 m o l % )

O H t - B u t - B u O R O O X O 1 N R O L i R O O N N R O 2 C M e s C O 2 R H O X R 1 O O R 1 O X O O H N M e s N N N R O 2 C C O 2 R N N M e s

X N O N O H N M e s R 1 O C O 2 R R O 2 C Scheme 2 2 . Quadruple domino reactions for the asymmetric synthesis of cyclopenta[c]chromenones.

Some reactions were set up with stable o - quinone methides, but the useful substrates are very scarce, thus the reactions are not widely applicable even if highly efficient. For instance, allene ketones were allowed to react with stable o - quinone methides (Scheme 2 4 ). 40 Interestingly, changing the catalyst b oth enantiomers can be obtained. However, a particular c atalysts had to 242 be used when Ar= 4 - MeOC 6 H 4 in the quinone methides in order to obtain the ( S ) - isomer. The ( S ) - configuration was determined by X - ray analysis and the ( R ) deduced as a consequence. The reaction worked also with in situ prepared o - quinone methides, thus enlarging the scope of the reaction . Moreover, the reaction was successfully scaled up to 1 mmol. The mechanism suggested by the authors was not supported b y experimental evidence or ab initio calculations.

R O 2 C C O 2 R C O R N N O / N i ( N T f 2 ) 2 R O C 2 R 2 6 2 2 ( 5 m o l % e a c h ) 5 R ( C H C l ) 6 0 ° C 2 2 , R 1 N N 4 1 6 - 1 2 0 h 1 O O X O R 3 5 8 - 9 0 % O O O 1 . 5 : 1 t o > 1 9 : 1 N H H N 7 6 - 9 9 % e e ( R , R ) i - P r i - P r R = M e , E t , i - P r i - P r i - P r X = 3 - F , 3 - M e O , 4 - C l , 4 - M e , 5 - C l , 5 - B r , 5 - M e , 5 - M e O , 6 - F 1 1 2 R = M e , P h , R - R = ( C H 2 ) 3 , ( C H 2 ) 4 , ( C H 2 ) 5 N N O R 2 = H , C H C H = C M e 2 2 Scheme 23 . Chromanes from Alder - ene reaction of 1,7 - dienes

O R R t - B u P P h 2 O O H N O O R 1 P h o s R 1 O ( 1 0 m o l % ) P h M e , r t , 2 4 h A r F C C F 6 3 - 9 9 % 3 3 9 5 - 9 9 % e e P h o s O R P h o s 1 O O P h o s O R P P h O 1 2 R R 1 O N H O A r O O T B S O C F N 3 O H A r P h o s 2 C F 3 P h o s 1 g a v e ( R ) - i s o m e r s O T B S P h o s 2 g a v e ( S ) - i s o m e r s w h e n A r = 4 - M e O C 6 H 4 P h o s 3 g a v e ( S ) - i s o m e r s w h e n A r = 4 - M e O C 6 H 4 P P h 2 R = M e , E t , c - C 6 H 1 1 , P h , 2 - F C 6 H 4 , 2 - M e O C 6 H 4 , O N H O 3 - C l C 6 H 4 , 3 - B r C 6 H 4 , 4 - M e C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 2 - t h i e n y l , 1 - n a p h t h y l T B S O C F 3 1 N R = B n , M e , E t , 4 - C l C 6 H 4 C H 2 , 4 - M e O 2 C C 6 H 4 C H 2 , H 4 - C F 3 C 6 H 3 , 4 - M e O C 6 H 4 C H 2 , 1 - n a p h t h y l C H 2 A r = 4 - M e O C H ( E ) - P h C H = C H , ( E ) - ( 4 - M e C H ) C H = C H , 6 4 , 6 4 C F 3 ( E ) - ( 4 - M e O C 6 H 4 ) C H = C H , ( E ) - ( 2 - t h i e n y l ) C H = C H , P h o s 3 Scheme 2 4 . Asymmetric [4+2] annulation of allenic ketones with ortho - quinone methides.

Some examples are applied to enolizable ketones as the two - atom partner. Among them a chiral amidine - derivative catalyzed tandem Michael addition - lactonization of enolizable carboxylic acids (Scheme 2 5 ). 41 Unfortunately, all diastereomeric mixtures were inseparable except that arising from the reaction of indole - 3 - acetic acid. N - protected indole gave better results than N - H indole. The absolute configuration of products was determined by X - ray analysis. The authors envisaged the mechanism depicted in Scheme 2 5 , without providing evidence for it. C hiral squaramides with a tertiary amine framework are other useful catalysts, because they can deprotonate the carbonyl compound generating an enolate and an ionic interaction catalyst - substrate and, at the same time, link the o - quinone methides by hydroge n bonds. These catalysts were used in the reaction both of enolizable homophthalic anhydrides or a succinic anhydride (Scheme 2 6 ). 42 and of aryl β - keto acylpyrazoles (Scheme 2 7 ) . 43 The absolute configuration of products in both reactions was determined by X - ray analysis. Although these reactions are formal asymmetric [4+2] cyclization, they are actually stepwise reactions (see the mechanism envisaged by authors depicted in Schemes 2 6 ). The first reaction was scaled up to 1 mmol with a slight decrease in yi eld while maintaining excellent stereoselectivity. The second one could bot applied to aliphatic β - keto acylpyrazoles, which were unreactive. The reaction was also attempted on an o - quinone methide generated in situ , but, albeit it proceeded smoothly, both yield and enantioselectivity were low. 243

O O O

t - B u C O C l ( 2 e q ) O R O O N E t 3 ( 2 e q ) 3 8 - 9 9 % R R C O 2 H 5 9 : 4 1 t o 9 5 : 5 d r O t - B u 1 N N 9 7 - > 9 9 % e e R R = P h , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , ( 7 S , 8 S ) 4 - C F C H 4 - M e O C H 4 - M e C H B n 3 6 4 , 6 4 , 6 4 , 3 - M e O C 6 H 4 , 2 - C l C 6 H 4 , 2 - M e C 6 H 4 , O 3 , 4 - M e C H 2 - t h i e n y l , 1 - n a p h t h y l , N 2 6 3 , N R 2 - n a p h t h y l , 3 - i n d o l y l , N - M e - 3 - i n d o l y l B n O O O N O R N

R 1 B n

N E t 3 ( 4 0 m o l % ) 4 A m o l e c u l a r s i e v e s O O O r t N N O R B n

R 1 1 R = P h , 4 - C l C 6 H 4 , 4 - M e O C 6 H 4 , 4 - B r C 6 H 4 , 2 - M e O C 6 H 4 , 1 - n a p h t h y l , 2 - t h i e n y l , i - P r Scheme 2 5 . [4+2] Cycloadditions of o - quinone methides catalyzed by amidine.

O O O S q u a ( 1 0 m o l % ) O t - B u O M e , 3 0 ° C , 1 h + 7 O N O H O 6 O R X O O N H O X P h O O O O O P h O C O 2 R O M e 2 N O O O O R R H O O X M e 3 S i C H N 2 , X M e O H , 0 . 5 h

O O O F 3 C O O C O 2 M e P h O N N R N M e 2 F C H H X 3 P h S q u a 5 0 - 7 1 % > 1 9 : 1 d r 8 1 - 9 8 % e e ( 7 R , 8 S ) R = 4 - M e O C 6 H 4 , P h C H = C H , 2 - C l C 6 H 4 C H = C H , 2 - M e C 6 H 4 C H = C H , 3 - C l C 6 H 4 C H = C H , 3 - M e C 6 H 4 C H = C H , 4 - F C 6 H 4 C H = C H , 4 - C l C 6 H 4 C H = C H , 4 - M e C 6 H 4 C H = C H , 4 - M e O C 6 H 4 C H = C H , M e 2 C H = C H , 2 - t h i e n y l C H = C H ( a l l s t y r y l d e r i v a t i v e s a r e ( E ) - c o n f i g u r e d ) X = H , 6 - F , 6 - M e O , 7 - F , 7 - M e , 6 , 7 - ( M e O ) a n d O 2 P h O

O Scheme 26 . Asymmetric [4+2] addition of enolizable homophthalic anhydrides to ortho - quinone methides.

A r O O O O O S q u a ( 5 o r 1 0 m o l % ) C H C l 0 ° C , 4 h O N + 2 2 , R R N O 4 1 - 9 6 % O O A r > 1 9 : 1 d r 9 0 - 9 6 % e e ( 7 S , 8 R )

R = P h , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , F 3 C O O 4 - M e C 6 H 4 , 3 - M e C 6 H 4 , 3 - B r C 6 H 4 , N O M e 3 - C l C 6 H 4 , 3 - M e O C 6 H 4 , 3 - F C 6 H 4 , 2 - F C 6 H 4 , 2 - M e C 6 H 4 , 2 , 4 - M e 2 C 6 H 3 , N N H 3 , 5 - M e 2 C 6 H 3 , 2 - n a p h t h y l , 2 - t h i e n y l F 3 C H A r = 4 - M e O C H ( E ) - P h C H = C H , ( E ) - 4 - B r C H C H = C H , 6 4 , 6 4 S q u a N ( E ) - 4 - M e C 6 H 4 C H = C H , ( E ) - 4 - M e O C 6 H 4 C H = C H Scheme 2 7 . Asymmetric [4+2] addition of aryl β - keto acylpyrazoles to ortho - quinone methides.

Instead chiral metal complexes catal yzed true enantioenriched [4+2] cycloadditions. In fact, a chiral N,N’ - dioxide/Sc(III) complex allowed the asymmetric reaction of o - quinone methides with fulvenes 244

(Scheme 28 ). 44 Unsymmetrical fulvenes gave poor E/Z ratios (1:1 to 4:1 instead of >19:1 for symmetrical fulvenes) , but the substrates containing aliphatic cyclohexyl groups have better ratios than those containing aromatic rings. Thus authors envi saged a π – π stacking between o - quinone methides and fulvenes in the transition state to account for these low ratios. The absolute configuration of products was determined by X - ray analysis. In a gram - scale reaction 1.153 g (99% yields with 92% ee) were obtained from a symmetrical fulvene.

N N O / S c ( O T f ) 3 O R 1 2 ( 1 0 m o l % ) O R O O N N E t O A c , 0 ° C , 4 8 h * + O O O O O 5 5 - 9 9 % O N H H N 1 : 1 t o > 1 9 : 1 E / Z r a t i o A r A r R 2 1 - A d a m a n t y l 1 - A d a m a n t y l 7 9 - 9 6 % e e R 1 ( 5 a S , 8 a R , 9 R ) N N O

* f o r u n s y m m e t r i c a l f u l v e n e s 0 ° C f o r 2 4 h a n d t h e n 2 5 ° C O M e    s t a c k i n g A r = 4 - M e O C 6 H 4 , P h C H = C H , 4 - F C 6 H 4 C H = C H , 4 - M e O C 6 H 4 , C H = C H 4 - M e C 6 H 4 C H = C H , 3 - M e C 6 H 4 C H = C H , 2 - M e C 6 H 4 C H = C H , 3 - t h i e n y l C H = C H 1 2 R - R = ( C H 2 ) 3 , ( C H 2 ) 4 , ( C H 2 ) 5 , ( C H 2 ) 6 , ( C H 2 ) 2 O ( C H 2 ) 2 R 1 = R 2 = M e , E t 1 2 O R = H , R = P h , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 4 - M e C 6 H 4 , 2 - M e C 6 H 4 , 1 - n a p h t h y l , 2 - n a p h t h y l , 3 - t h i e n y l , 3 - b e n z o t h i e n y l , c y c l o h e x y l O O R H N O O N S c T f O O N O N H R Scheme 2 8 . Reaction of o - quinone methides with fulvenes .

The same research group found that another scandium chiral N, N' - dioxide complex (0.1 - 0.01 mol %) allowed the reaction of o - quinone methides with o - hydroxyphenyl α,β - unsaturated compounds (Scheme 2 9 ) . 45 2 - Hydroxychalcones, 2 - hydroxynitrostyrenes, 2 - hydroxyphenyl - acrylate and 2 - hydroxyphenylacroleins worked as two atom partner in this reaction. In the last substra te a double cyclization occurred and hexahydropyrano[4,3 - b]chromanes with four adjacent stereocenters were obtained. The absolute configuration of products was determined by X - ray analysis. A gram - scale reaction produced 1.41 g (98% yield) of the product in 99% ee. Some control experiments were carried out to elucidate the reaction mechanism, and on these basis authors proposed the mechanism depicted in Scheme 2 9 . Finally, in situ generated o - quinone methides from ortho - hydroxybenzyl alcohols were tested and products were obtained in 70 - 99% yields, with >19:1 dr and 98 - 99% ee (6 examples). If stable o - quinone methides are rare, ortho - alkylphenols, bearing a leaving group in the benzylic posit ion, can in situ form o - quinone methides by acid or basic catalysis. If the catalyst is a chiral acid or base, we can obtain enantioenriched product. In the reactions described above, authors sometimes attempted the reaction with in situ generated o - quinone methides, 40,43,45 but there are also successful reactions completely devoted to in situ generated o - quinone methides. The reaction with allenoates, reported by Fan and co - workers, is an example. 46 o - Quinone methides were generated by fluorine deprotection of 2 - silyloxybenzyl chlorides and allowed to react with ortho - substituted aryl butadienoates (Scheme 30 ). Phenyl - and 4 - methoxyphenyl - butadienoates gave the expected products, but in lower yields, while 2,6 - dimethylphenylbutadienoate was unreactive, perhaps for steric hindrance. The absolute configuration was determined by X - ray analysis. It should be noted that 6 - arylmethylidenebenzo[ d ][1,3]dioxol - 5(6 H ) - ones are stable, while their precursors are not. However, o - hydroxy benzhydryl alc ohols are the more classical starting material for the in situ preparation of o - quinone methides. For instance, they are widely employed in the reaction with enolizable carbonyl compounds. All these reactions required significant amounts of enol in the ket o - enol tautomerism for their occurrence; used chiral phosphoric acids as the catalysts, which had to form at least two hydrogen bonds to give the three - membered o - quinone methide - catalyst - enol intermediate responsible of the enantioselectivity. The reactio n of o - hydroxybenzhydryl alcohols with β - keto acids follows this pattern to give 2,4 - diaryl - 1 - benzopyrans after decarboxylation and dehydration (Scheme 3 1 ). 47 The absolute configuration of products was determined by comparison of their optical values with the literature. The reaction was scaled up to gram scale with a 78% yield and 91% ee. In the mechanism proposed by authors, the chiral phosphoric acid promoted the dehydration of the o - hydroxy benzhydryl alcohols, the 245 decarboxylation of the β - keto acids and determined the stereochemistry, while scandium triflate promoted cyclization and dehydration of the lactol intermediate.

H O X O O R t - B u O O N N O / S c ( O T f ) 3 + O O H ( 0 . 1 - 0 . 0 1 m o l % ) X t - B u C H 2 C l 2 , 3 5 ° C , 2 4 h O R A r O A r N 7 3 - 9 9 % H > 1 9 : 1 d r M e O O N 9 4 - 9 9 % e e R ( 6 S , 7 S , 8 R ) N N O

O O X O N H O N O N S c O O R H N O O t - B u O N H R N t - B u

R = C H O S c N N O A r = 4 - M e O C 6 H 4 O X

H O X O O

O O O R A r O O O H A r = 4 - M e O C 6 H 4 , P h C H = C H , 4 - M e C 6 H 4 C H = C H , 4 - M e O C 6 H 4 C H = C H , 4 - F C 6 H 4 C H = C H , 3 - t h i e n y l C H = C H R = C O P h , C O ( 2 - M e C 6 H 4 ) , C O ( 3 - M e C 6 H 4 ) , C O ( 3 - F C 6 H 4 ) , C O ( 4 - M e C 6 H 4 ) , 8 1 - 9 9 % O M e C O ( 4 - t - B u C 6 H 4 ) , C O ( 4 - M e O C 6 H 4 ) , C O ( 4 - F C 6 H 4 ) , C O ( 4 - C l C 6 H 4 ) , C O ( 4 - B r C 6 H 4 ) , > 1 9 : 1 d r C O ( 4 - C F 3 C 6 H 4 ) , C O ( 2 - b e n z o f u r a n y l ) , C O [ 3 , 4 - ( M e t h y l e n e d i o x y ) p h e n y l ] , 9 6 - 9 8 % e e C O ( 2 - n a p h t h y l ) , N O 2 , C O 2 M e , C H O ( 6 S , 6 a S , 7 R , 1 3 a S ) X = 3 - F , 4 - F , 4 - C l , 4 - B r , 5 - F , 5 - C l Scheme 2 9 . Reaction of o - quinone methides with o - hydroxyphenyl α,β - unsaturated compounds .

t - B u O O A r 1 O O O O A r N A r O N S i M e 2 - t - B u X ( 1 0 m o l % ) 3 0 - 8 1 % O 8 7 - 9 7 % e e ( R , E ) C s F , N a 2 S O 4 T H F , 0 ° C , 2 4 h - 7 d C l X N O N A r 1 O A r 1 O H F O A r t - B u M e S i F O 2 N O O O X O O C l X X A r 1 A r 1 C l A r 1

X A r = P h , 4 - M e O C 6 H 4 , 2 - M e O C 6 H 4 , 2 - E t O C 6 H 4 , 2 - M e C 6 H 4 , 2 - i - P r C 6 H 4 , 2 - t - B u C 6 H 4 , 2 - B r C 6 H 4 1 A r = P h , 2 - M e O C 6 H 4 , 3 - M e O C 6 H 4 , 3 - C F 3 C 6 H 4 , 4 - C l C 6 H 4 , 1 - n a p h t h y l , ( E ) - s t y r y l X = H , 8 - M e O , 6 - M e O , 6 - M e , 6 - P h , 6 , 7 - O C H 2 O Scheme 30 . Asymmetric [4+2] annulation of allenic esters with ortho - quinone methides.

The group of Schneider group prepared cis - 3,4 - diarylchromanols from acetaldehydes (Scheme 32 ). 48 Also in this reaction, ortho substitution in the aryl group of o - hydroxybenzhydryl alcohol enhanced the enantioselectivity (see also above ref . 46 ). Diasteroselectivity was generally low (only 3 - 4:1), because the acidic conditions could open the lactol intermediate, so that the cis/trans ratio was dynamic. However, authors found that a 4 - methoxy group in the o - hydroxybenzhydryl alcohol locked the equilibrium leading to a >20:1 cis/trans ratio, but they did not give an explanation. The very low enol content in the keto - enol 246 tautomerism of aliphatic aldehydes did not allow the reaction occurrence. Then the lactol intermediate was transformed into a variety of other useful compounds.

A r ( R ) - P A 9 - A n t h r y l A r 1 ( 1 0 m o l % ) O H O C H C l r t , 1 2 h H O A r + 3 , O O A r 1 O O H P C O 2 H P O H O O H H 2 O , C O 2 O

9 - A n t h r y l ( R ) - P A A r S c ( O T f ) 3 A r O ( 5 0 m o l % ) 6 0 ° C , 1 2 h A r 1 O A r 1 O H 5 7 - 8 1 % H 2 O 7 6 - 9 4 % e e ( R ) A r = P h , 4 - M e O C 6 H 4 , 4 - M e C 6 H 4 , 3 - M e O C 6 H 4 , 3 - M e C 6 H 4 , 2 - M e O C 6 H 4 , 2 - M e C 6 H 4 1 A r = P h , 4 - M e O C 6 H 4 , 4 - M e C 6 H 4 , 4 - F C 6 H 4 , 4 - B r C 6 H 4 , 3 - M e C 6 H 4 , 3 - F C 6 H 4 , 2 - t h i e n y l , 2 - n a p h t h y l Scheme 31 . Decarboxylative alkylation of β - keto acids to o - quinone methides.

( R ) - P A ( 1 0 m o l % ) A r 1 t - B u C H C l 3 , r t , 9 - 3 6 h A r t h e n P C C ( 3 e q ) A r X X O C H 2 C l 2 , r t 1 6 h O H C H O H + O H A r 1 O O O O H P P O O O H

5 7 - 9 1 % A r 2 . 5 : 1 t o > 2 0 : 1 d r 1 t - B u X A r ( R ) - P A 6 6 - 8 4 % e e ( 3 S , 4 R ) X = H , B r , C l , t - B u O O

A r = P h , 4 - M e O C 6 H 4 , 4 - M e C 6 H 4 , 4 - B r C 6 H 4 , 4 - P h C 6 H 4 , 4 - t - B u C 6 H 4 , 2 - M e C 6 H 4 , 1 - n a p h t h y l 1 A r = P h , 4 - M e C 6 H 4 , 4 - F C 6 H 4 , 4 - B r C 6 H 4 , 4 - C l C 6 H 4 , 3 - M e C 6 H 4 , 3 - C l C 6 H 4 , 2 - M e C 6 H 4 , , 2 - n a p h t h y l Scheme 3 2 . Aldehyde addition to in situ generated o - quinone methides.

Also stable alkenes have been e mployed as partner in the [4+2] cycloaddition with o - quinone methides. An example was the reaction of vinyl sulfides setup by Wang and Sun (Scheme 3 3 ) . 49 The absolute configuration was determined by X - ray analysis. The absence of sites for hydrogen bond interaction between vinyl sulfides and the catalysts made the authors speculate a transition, in which only the o - quinone methide has effective interaction with the catalyst. A gram - scale synthesis allowed the recover y of 1.41 g of product (88% yield, >30:1 dr, 91% ee).

A r ( R ) - P A ( 1 0 m o l % ) A r 9 - p h e n a n t h r y l 4 A - M S , C H 2 C l 2 - 2 0 ° C , 4 d O H O O + O H P P O H A r 1 S X O O X A r 1 S O O H

9 - p h e n a n t h r y l 4 8 - 9 1 % > 3 0 : 1 d r * ( R ) - P A * o n l y w h e n A r 1 = 1 - n a p h t h y l d r = 1 4 : 1 7 3 - 9 6 % e e ( 2 S , 4 S ) A r = P h , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - M e O C 6 H 4 , 4 - M e S C H 4 - P h C H 4 - ( C H = C H ) C H A r 6 4 , 6 4 , 2 6 4 5 2 - M e O C 6 H 4 , 2 - t h i e n y l , 3 - t h i e n y l , P h C C 6 1 A r = P h , 2 - M e C 6 H 4 , 1 - n a p h t h y l , 2 - n a p h t h y l 7 X = 6 - M e , 6 - M e O , 6 - C l , 6 - B r , 8 - M e O S A r 1 X 8 Scheme 33 . Vinyl sulfides addition to in situ generated o - quinone methides.

247

The products were efficiently oxidized to sulfone and then some transformations were performed essentially maintaining the enantiopurity of the products. In particular, the syntheses of 2,3 - unsubstituted chromane and chromenes are interesting, because the direct cycloaddition with ethylene and acetylene cannot be performed. Acyclic enecarbamates are another simple alk ene, whi ch can undergo to [4+2] cycloaddition with 50 o - quinone methides (Scheme 34 ). The reaction was sluggish when Ar= 4 - MeOC 6 H 4 , X= 6,8 - Cl 2 , 6,8 - Br 2 , R= Cbz (only 30 - 33% yields after 3 - 6 days at 50 °C). The absolute configuration was determined by the Mosher a mide method .

A r t - B u A r ( S ) - P A R A r 1 i - P r N A r 1 ( 1 0 m o l % ) O H P h M e , r t , 3 d H + O O i - P r X O H N H R X O H P O O P O O H i - P r 3 0 - 8 9 % A r = 4 - M e O C 6 H 4 , P h , 3 - M e O C 6 H 4 , P h C C H 1 1 . 5 : 1 t o > 2 0 : 1 d r A r = P h , 4 - M e C 6 H 4 , 4 - i - P r C 6 H 4 , 4 - t - B u C 6 H 4 , 5 2 - 9 5 % e e 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 3 - M e C 6 H 4 , ( 2 S , 3 R , 4 R ) i - P r i - P r 3 - C l C 6 H 4 , 3 - B r C 6 H 4 , 2 - M e C 6 H 4 , 2 - F C 6 H 4 , A r ( S ) - P A 2 - C l C H 2 - B r C H 2 , 4 - M e C H 5 A r 1 6 4 , 6 4 , 2 6 3 6 R = C O 2 B n ( C b z ) , C O S B n , C O 2 - t - B u , C O 2 A l l y l , C O 2 P r o p a r g y l 7 O N H R X 8 X = H , 6 - B r , 6 , 8 - C l 2 , 6 , 8 - B r 2 , Scheme 3 4 . E necarbamates addition to in situ generated o - quinone methides.

Very recently, a reaction, in which the staring material provided t he chirality, has been reported 51 that is the FeCl 3 catalyzed synthesis of enantioenriched benzopyran from a ( S,E ) - crotyl silane. However, the catalyst promoted both a [4+2] cycloaddition and a 1,4 - addition reaction; therefore a mixture of products was obtained, albeit the benzopyrans are always recovered as a single diastereomer, while conjugate addition products were recovered as a mixture of diastereomers. Benzhydryl alcohols with a double bond at a suitable distance to give stable five - or six - membered can give an intramolecular version of this reaction (Scheme 35 ) . 52 The phenyl ring denoted with the index “prime” in Scheme 3 5 is peculiar for the reaction occurrence; in fact , s imple benzyl alcohols with suitable double bonds were unreactive. On the other hand, al so cinnamyl ether is peculiar to the reaction, because prenyl and phenylpropargylic ethers gave very low enantioselectivity, while other allyl - or vinyl ethers did not react at all. ( E ) - Cinnamyl ethers led to exo - trans compounds, while the ( Z ) - cinnamyl eth ers led to the endo - cis product, but with very low ee ’ s.

5 ' 4 ' 6 ' 1 3 ' X X = H , 4 - M e , 4 - M e O , 4 - F , 5 - C l , 5 - B r , 6 - M e O , 6 - B r ( R ) - P A ( 1 0 m o l % ) X 1 O O X 1 = H , 4 ' - M e , 4 ' - t - B u , 4 ' - M e O , 4 ' - B r , 5 ' - M e , 5 ' - t - B u , 3 E t 2 O , 5 5 ° C , 4 h H R S 5 ' - M e O , 5 ' - E t O , 5 ' - B r , 6 ' - M e O O H 4 3 5 - 9 9 % X = H , X 1 = 3 ' - C l , 3 ' - 5 ' - M e ( e n d o - t r a n s i s o m e r ) R H 2 7 4 : 2 6 t o 9 4 : 6 d r X = 3 - M e , X 1 = H ( e x o : e n d o = 4 8 : 5 2 ) 5 X O H P h X O P h 6 1 0 - 9 2 % e e 4 a S , 5 R , 1 0 b R P h O O R O

O P h O P h O O O O O O P h H H P P P H O O P O O O H

e x o - t r a n s e n d o - t r a n s e n d o - c i s t r a n s i t i o n s t a t e t r a n s i t i o n s t a t e t r a n s i t i o n s t a t e ( R ) - P A P h Scheme 35 . Intramolecular oxa - Diels - Alder reaction of ortho - quinone methides.

When the 3 ′ - position (see Scheme 34) was occupied, the endo - trans - isomers were recovered from ( E ) - cinnamyl ethers. On the other hand, when the 3 - position (see Scheme 34) was occupied, a fast 248 equilibrium between E - and Z - configured o - quinone methide occurs, thus the endo - exo - selectivity was completely lost. The absolute configuration of products was determined by X - ray analysis. In a large - scale experiment (3.30 mmol) 913 mg (80% yield, 92:8 dr, 92% ee), and 530 mg, (51% yield, single diastereomer, 50% ee) were recovered from ( E ) - and ( Z ) - products respectivel y. A particular o - quinone methides arose from salicylaldehydes and they were allowed to react with unsaturated alcohols (Scheme 3 6 ). 53 The absolute configuration of products was determined by X - ray analysis. Chiral unsaturated alcohols retained the configu ration, thus authors setup a k inetic resolution from racemic chiral unsaturated alcohols. Moreover, some experiments allowed envisaging a [4+2] addition mechanism, but the authors did not rule out a stepwise mechanism.

R 2 - n a p h t h y l H O P A ( 5 m o l % ) O 2 - n a p h t h y l n C H O R C y c l o h e x a n e 5 A M S , r t , 1 6 h - 1 0 d + 1 O O n R O H O X O H X O P P O N O R 1 P A 7 5 - 9 1 % 2 - n a p h t h y l > 2 0 : 1 d r 2 - n a p h t h y l X = H , 8 - M e O , 8 - C O E t , 8 - M e , 8 - t - B u , 2 8 4 - 9 8 % e e 8 - F , 8 - C l , 8 - B r , 7 - M e , 6 - M e , 6 , 8 - C l 2 ( 3 a S , 4 S , 9 b S ) P A R = H , 2 - ( S ) - M e , 3 - ( S ) - M e 2 R 1 = ( E ) - b u t - 2 - e n - 2 - y l , p r o p - 1 - e n - 1 - y l , O R ( E ) - p e n t - 2 - e n - 2 - y l , ( E ) - p e n t - 2 - e n - 3 - y l , 8 n 3 ( E ) - 1 - p h e n y l p r o p - 1 - e n - 1 - y l , 7 c y c l o h e x - 1 - e n - 1 - y l , P h X O R 1 n = 1 , 2 6 Scheme 36 . Furano - and pyrano - chro manes from asymmetric intramolecular [4+2] cycloaddition.

2,6 - Di - t - butyl - 4 - (2 - hydroxybenzylidene)cyclohexa - 2,5 - dienone is a stable p - quinone methide, which under acidic conditions, is in equilibrium with an o - quinone methide structure, and, consequently it can undergo [4+2] addition as above. The isomerization energy was calculated by DFT and was found to be very low (7.0 kcal/mol). 54 However, also a 1,6 - conjugated addition can explain the reactivity of this compound, so that all papers generally justifie d the observed stereochemistry with both mechanisms (Scheme 37 ). For instance, this substrate allowed the preparation of dihydrocoumarins from azlactones (Scheme 3 7 ). 55 A gram - scale reaction worked with a lower loading of the catalyst (3 mol% vs. 5 mol%) a nd gave the product in higher yield (87% vs. 65%), but with little low enantiomeric excess (95% vs. 98%). The products were also submitted to some transformation in order to discover the potentiality of the reaction. The absolute configuration of products was determined by X - ray analysis. Another example from the same research allowed the synthesis of spiro - dihydrocoumarins (Scheme 3 8 ). 56 If all p - quinone methides gave high diasteroselectivity (>19:1) in the reaction with 1 - oxot etralin - 2 - carbaldehyde, varying the aldehydes diasteroselectivity ranged from 1.5:1 to >19:1. The absolute configuration of products was determined by X - ray analysis. The reaction was scaled up to gram - scale, without significant modification of yield and selectivity. The products were also submitted to some transformation in order to discover the potentiality of the reaction and only the de - tert - butylation (Tf 2 O/TfOH at 60 °C) gave racemization, very likely for t he higher required temperature. The reac tion with enamides afforded products in high yields and selectivity (Scheme 39 ). 54 The only exception was when X= H, X 1 = 4 - MeO, in which the diastereomeric ratio was only 64:36. T he absolute configuration of products was determined by X - ray analysis. A gram - scale reaction gave product in a 96% yield with 95:5 dr and 96% ee. 3 - Alkyl - 2 - vinylindoles were also used as reactants and the NH group of indole was found to be very important, in fact, N - methyl - protected indole was unreactive (Scheme 40 ). 57 Clear ly in the transition state, a hydrogen bond between the chiral phosphoric acid and the NH group of indole and another with the OH group of the substrate (in a fashion of a 1,6 - conjugate addition), or with the OH group of the o - quinone methide form (in a fa shion of a [4+2] cycloaddition) must be involved. The absolute configuration of products was determined by X - ray analysis. The reaction was scaled up to gram scale, and product was recovered in 96% yield with >95:5 dr and 96% ee. Finally, two papers report ed the reaction of 2,6 - di - t - butyl - 4 - (2 - hydroxybenzylidene)cyclohexa - 2,5 - dienone with isocyanates 58 and isoxazolones, 59 affording benzoxazin - 2 - one and spiro - isoxazolonechromans, 249 respectively. Both papers mainly described the reaction, under asymmetric condi tions and envisaged a 1,6 - conjugate addition mechanism. Only at the end of the papers, an example of the asymmetric version was reported. In the reaction with isocyanates, a series of chiral phosphoric acids gave the product in moderate to high yields, but without any enantioselectivity. On the other hand, a squaramide {namely 3 - [(1 R ,2 R ) - 2 - (piperidin - 1 - yl)cyclohexylamino] - 4 - (4 - (trifluoromethyl)phenylamino)cyclobut - 3 - ene - 1,2 - dione} gave 4 - (3,5 - di - t - butyl - 4 - hydroxyphenyl) - 3 - tosyl - 3,4 - dihydro - 2H - benzo[1,3 - e]oxazin - 2 - one in 98% yield with 56% ee, while the ( S,S ) squaramide led to the enantiomer in 95% yield with 30% ee (absolute configurations not reported). In the reaction with isoxazolones, the chira l catalyst was quinine and 4 - (3,5 - di - t - butyl - 4 - hydroxyphenyl) - 3 ′ - methyl - 2 - ( p - tolyl) - 5 ′H - spiro[chromane - 3,4 ′ - isoxazol]5 ′ - one was recovered in 82% yield with 21:79 dr and 11/48% ee (absolute configuration not reported) .

5 4 X 6 3 t - B u O R H O O + O O N O P 1 t - B u R O O H X = H , 4 - F , 4 - C l , 4 - B r , 4 - M e , 4 - M e O , R = P h , B n , 4 - C l C 6 H 4 C H 2 , M e S ( C H 2 ) 2 , i - P r 1 5 - M e O , 6 - M e O , b e n z o [ f ] R = P h , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , P A 4 - M e O C 6 H 4 , 3 - M e C 6 H 4 , 2 - M e C 6 H 4 , 2 - f u r y l , 2 - t h i e n y l

P A ( 5 m o l % ) C 6 F 6 , r t , 1 2 - 7 2 h

O H R 1 1 R t - B u t - B u O N O N H H O c y c l o a d d i t i o n O O O O H O R O R 1 P X P t - B u R O t - B u O O O O H N R H O O H t - B u X O O t - B u X O H c o n j u g a t e a d d i d i o n O H O H t - B u t - B u t - B u t - B u

R 1 R 1 N N H C O R R O O O X O H O X 3 0 - 9 4 % > 1 9 : 1 d r 8 9 - 9 9 % e e ( 3 R , 4 S ) Scheme 3 7 . Cycloannulation of p - quinone methides with azlactones.

O O H t - B u t - B u S q u a t - B u t - B u F 3 C O O O ( 1 0 m o l % ) C H C l N O M e C H O 3 , 3 r t , 1 2 h n 4 + N N 1 H H 1 X F 3 C 5 X n X O H X O O N 6 O H S q u a D e s s - M a r t i n 7 1 - 9 9 % p e r i o d i n a n e 1 . 5 : 1 t o > 1 9 : 1 d r ( 1 . 5 e q ) 9 8 - 9 9 % e e , C H 2 C l 2 , r t , 1 h ( 3 R , 4 S ) O H t - B u t - B u

X = H , 4 - F , 4 - C l , 4 - B r , 4 - M e ,

4 - M e O , 5 - M e O , 6 - M e O n X 1 = H , 7 - M e O , 7 - B r , 7 - M e , 1 7 - P h , 6 - M e O , 5 - M e O , 4 - M e X n = 0 , 1 , 2 a n d 2 - o x o c y c l o h e x a n e c a r b a l d e h y d e O O X O Scheme 3 8 . Synthesis of spiro - dihydrocoumarins by reaction of p - quinone methides and 1 - oxotetralin - 2 - carbaldehydes. 250

O O H t - B u t - B u t - B u t - B u t - B u i - P r N H C O M e ( S ) - P A ( 2 m o l % ) C H 2 C l 2 , r t , 1 h + 8 6 i - P r 7 3 - 9 9 % 9 5 O O X 1 8 2 : 1 8 - 9 6 : 4 d r 4 P 8 1 - 9 8 % e e 1 0 O H O H X O O X ( 6 a R , 7 S , 1 2 a S ) 1 1 X 1 i - P r M e C O N H 1 3 2 X = H , 9 - M e , 9 - M e O , 9 - C l , 9 - F , 1 0 - M e , 1 0 - M e O , 1 0 - C l , 1 0 - B r X 1 = H , 2 - M e O , 3 - M e , 3 - M e O , 3 - B r , 3 - F , 4 - M e , 4 - M e O , 4 - B r i - P r i - P r a n d P h ( S ) - P A

N H C O M e N H C O M e Scheme 3 9 . Acetamido - substituted tetrahydroxanthenes by reaction of p - quinone methides and enamides.

O 9 - A n t h r y l O H t - B u t - B u ( S ) - P A o r t - B u t - B u ( S ) - T P A O O R ( 5 m o l % ) P 5 A M S , o - x y l e n e , O H 3 R 1 O 4 + - 2 0 ° C , 1 2 h R 1 6 2 – 9 8 % 5 1 N H 9 - A n t h r y l O H X 7 8 : 2 2 t o > 9 5 : 5 d r N X H O 6 9 0 – 9 6 % e e X ( S ) - P A X 1 ( 2 S , 3 R , 4 R ) X = H , 5 - M e O , 5 - B r , 4 - M e R 9 - A n t h r y l R = M e , E t , B n 1 R = P h , 2 - M e C 6 H 4 , 2 - F C 6 H 4 , 2 - C l C 6 H 4 , 2 - B r C 6 H 4 , 3 - M e C 6 H 4 , 3 - F C 6 H 4 , O O 3 - C l C 6 H 4 , 3 - B r C 6 H 4 , 4 - M e C 6 H 4 , 4 - t - B u C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 P X 1 = H , 6 - C l O S H

9 - A n t h r y l ( S ) - T P A Scheme 40 . Reaction of p - quinone methides with 3 - alkyl - 2 - vinylindoles.

5. Asymmetric a lkylation The asymmetric synthesis of the benzopyran derivatives mainly contemplates the de novo construction of the pyran ring. However, some interesting asymmetric alkylations of the benzopyran ring have been reported in recent years and they are described in this section. The Pd - catalyzed oxidative Heck reaction of 4 H - chromenes and ar yl boronic aci ds in the presence of a chiral pyridine - oxazole ligand is an example of this reaction (Scheme 41 ) . 60 It was found that 6 - and 7 - Me 4H - chromenes gave the lowest enantioselectivity, and that electron - withdrawing substituted arylboronic acids gave unknown sid e products. No envisaged mechanism or transition state was reported to explain the observed stereochemistry. The absolute configuration of products was determined by comparison of their optical values with the literature. One of the synthesized compounds was easily converted in the potent antiviral compound BW683C (4 ′,6 - dichloroflavan) .

P d ( M e C N ) 2 C l 2 ( 6 m o l % ) O L i g a n d ( 1 3 m o l % ) F 3 C C u ( O T f ) 2 ( 1 2 m o l % ) N N t - B u 3 a M S , O 2 ( b a l o o n ) , L i g a n d M e C O N M e 2 , 4 0 ° C , 1 8 - 2 4 h + A r B ( O H ) 2 C l O 2 1 - 8 8 % O A r X X * 6 6 - 9 5 % e e ( R ) O X = H , 6 - F , 6 - B r , 6 - C l , 6 - M e , 7 - M e B W 6 8 3 C C l A r = P h , 4 - M e C 6 H 4 , 4 - F C 6 H 4 , 4 - B r C 6 H 4 , 4 - C N C 6 H 4 , 4 - A c C 6 H 4 , 4 - M e O C 6 H 4 , 4 - ( M e O 2 C ) C 6 H 4 , 4 - C l C 6 H 4 , 3 - M e C 6 H 4 , 2 - M e C 6 H 4 , 1 - n a p h t h y l , 2 - n a p h t h y l Scheme 41 . Palladium - catalyzed asymmetric redox - relay Heck reaction.

Arylboronic acids were also added to 2 H - chromenes in the presence of a chiral rhodium catalyst to g ive 3 - arylchromanes (Scheme 4 2 ). 61 The reaction was also unsuccessfully attempted with 2 H - thiochromene or 1,1 - dimethyl - 1,2 - dihydronaphthalene, while 1,2 - dihydroquinoline afforded the expected product in 76% yields with 97% ee. The absolute configuration was attributed by comparison of optical rotation with the known values. The observed stereo chemistry was explained by authors with a transition state, which 251 minimizes the steric repulsions between the substituent on the diene ligand and the benzo moiety. Moreover, deuterium - labeling experiments accounted for 1,4 - Rh shift before the final protono lysis.

A r F F F X O 4 5 - 7 7 % F 9 2 - 9 7 % ( S ) P h A r B ( O H ) 2 [ R h ( O H ) ] 2 H 2 O R h ( 5 m o l % ) P h A r d i o x a n e , 6 0 ° C , 2 0 h H 3 B O 3

X O A r - R h

R h X A r O X O O X P h P h R h A r

A r = P h , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - M e O C 6 H 4 , 4 - B n C 6 H 4 , 3 - M e O C 6 H 4 , 2 - M e O C 6 H 4 3 , 4 - ( O C H 2 O ) C 6 H 3 , 2 - n a p h t h y l X = H , 6 - F , 6 - C l , 6 - M e O , 8 - F , 8 - C l , 8 - M e , 6 - C l - 8 - B r Scheme 4 2 . Asymmetric addition of arylboronic acids to 2 H - chromenes .

In section 2, we already reported that Korenaga and co - workers designed the best rhodium ligand for the alkylation of coumarins with boronic acids. 7 The catalyst was then teste d and the good obtained r esults are reported in Scheme 43 . It should be noted that a hydroxy group on the coumarin substrate inhibited the catalyst, while arylboronic acid bearing an electron - withdrawing group such as a chlorine atom competitively decompos ed under the reaction conditions, drastically lowering yields (25%) . The reaction was also successfully scaled up to 15 - gram scale.

C F F 3 R h - ( R ) - L ( 0 . 0 5 m o l % ) A r F P h M e , 2 5 ° C , 3 6 h s a t N a H C O + A r B ( O H ) 3 2 M e O P C F 3 ( 3 e q ) M e O 6 0 - 9 5 % O O R h P h X O O > 9 9 e e ( R ) X P

X = H , 6 - M e , 6 - E t O , 7 - M e O C F 3 A r = P h , 4 - M e C H 3 - M e C H 3 , 5 - M e C H 6 4 , 6 4 , 2 6 3 F F C F 3 R h - ( R ) - L Scheme 43 . Rhodium catalyzed alkylation of coumarins .

Indoles and pyrroles we re added to coumarin - 3 - carbonylates under different chiral BOX complexes (Scheme 44 ). 62 Many combination s of triflate salts with different BOX compounds were tested. Among them a heterogeneous catalyst showed better yield than the homogeneous catalyst (80% vs. 59% ) but it did not improve th e enantioselectivity, so the reaction scope was carried out under the best homogeneous complex.

C u ( O T f ) 2 . t - B u B O X R ( 1 0 m o l % ) N C H C l - 3 0 ° C 2 d X 1 C O E t 2 2 , X 2 t h a n 0 ° C , 5 d + 1 N 4 0 - 8 1 % X C O 2 E t X O O * C u R o n l y t r a n s * t - B u T f O O T f t - B u 6 3 - 8 2 % e e O O C u ( O T f ) 2 . t - B u B O X C u ( O T f ) 2 . t - B u B O X ( 1 0 m o l % ) 1 X C O E t C H 2 C l 2 , - 3 0 ° C 2 d 2 R N X = H , 5 - M e , 5 - M e O , 4 - M e O + t h a n 0 ° C , 2 d R = H , M e N X 1 C O E t O O 4 6 - 7 7 % * 2 X 1 = H , C l , N O R 5 8 - 4 2 t o 8 9 : 1 1 d r * 2 6 0 - 8 2 % e e O O Scheme 44 . Asymmetric addition of indoles and pyrroles to coumarin - 3 - carbox ylates . 252

Authors did not report the absolute configuration of their products and only affirmed that a trans relationship is present. Enders’ group reported t wo asymmetric cascade reactions of nitro - chromenes : (i) with aliphatic aldehydes, and α,β - unsaturated aldehy des (Scheme 4 5 ), 63 or (ii) with two equivalents of α,β - unsaturated aldehydes and an alcohol (Scheme 46 ), 64 providing tricyclic compounds . In both reactions, the surmised reaction mechanism is a classical sequence of enamine, iminium ion, intermediates, s om e transformations of the products were successfully carried out without affecting stereoselectivity and t he absolute configuration of products was determined by X - ray analysis. A gram - scale reaction provided 0.87 g of product (42% yields, with 20:1 dr and > 99% ee) and 0.619 g of product (41% yields, with 20:1 dr and >99% ee), in reaction (i) and (ii), respectively. The drawbacks of the first reaction were: 2 - nitro - 3 H - benzo[ f ]chromane gave product in only 20% yield; 7 - (diethylamino) - 3 - nitro - 2 H - chromene, 1 - nitrocyclohex - 1 - ene, 2 H - chromene - 3 - carbonitrile, isovaleraldehyde and t - butyl acetaldehyde were unreactive. The drawbacks of the second reaction were: methyl ( E ) - 2 - (2 - oxoindolin - 3 - ylidene)acetate and 2 H - chromene - 3 - carbonitrile as the substrate, as well as benzylthiol and dimethyl phosphite as the nucleophil es failed to give the products.

J - H ( 2 0 m o l % ) R C H O P h M e , 0 ° C t o r t H N O P h 2 2 4 - 4 8 h 1 R C H O 1 R + + R N O N P h C H O 2 H O T M S X O 2 0 - 6 6 % O > 2 0 : 1 d r X J - H 9 9 % e e ( 6 a S , 7 S , 1 0 R , 1 0 a R )

X = H , 6 - F , 6 - C l , 6 - B r , 6 - N O 2 , 6 - M e O , 6 - M e , 7 - M e O , 6 , 8 - C l 2 , 6 , 8 - I 2 , 6 , 8 - ( t - B u ) 2 R = M e , E t , P r , B n 1 R = P h , 4 - M e O C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 2 - M e O C 6 H 4 , H , M e Scheme 45 . Triple domino reaction of nitro - chro menes with aliphatic aldehydes, and α,β - unsaturated aldehydes.

J - H ( 1 0 m o l % ) O R P h C O 2 H ( 2 5 m o l % ) C H O 5 A m o l e c u l a r s i e v e s N O H P h 2 C H C l 3 , 0 ° C , 2 4 - 3 6 h + C H O + R O H N P h 3 0 - 7 0 % N O 2 H O T M S X O ( 3 e q u i v ) > 2 0 : 1 d r O J - H > 9 9 % e e ( a l l - S ) X

X = H , 6 - F , 6 - C l , 6 - B r , 6 - N O 2 , 6 - M e O , 6 - M e , 7 - M e O , 7 - M e , 8 - M e O , 8 - A l l y l , 6 , 8 - C l 2 , 6 , 8 - B r 2 , 6 , 8 - I 2 , 6 , 8 - ( t - B u ) 2 R = M e , E t , P r , i - P r , B n , P h 2 C H , A l l y l , P r o p a r g y l Scheme 4 6 . Quadruple domino r eaction of nitro - chromenes with α,β - unsaturated aldehydes and alcohols.

The asymmetric reaction of chroman - 2 - ols and ( E ) - 4 - nitrobut - 3 - en - 1 - ynes led to an enantioenriched 3 - alkyl lactol, which can then undergo ring - closure to tricyclic compounds (Scheme 4 7 ). 65 The absolute configuration of products was determined by X - ray analysis. These compound s were then s ubmitted to the addition of some nucleophiles : N - alkylindoles were the most efficient ; benzyl mercaptan opened the cycle ; triethylsilane reduced the do uble bond ; and N - bromosuccinimide in methanol gave the addition of BrOMe ; ethanol did not react . 4 - H ydroxycoumarin s were asymmetrically alkylated by oxidative β - functionalization of ketones in the presence of 2 - iodoxybenzoic acid (Scheme 48, eq. 1). 66 Many cyclic and aliphatic ketones reacted, but not cyclopentanone . The reaction was scaled up and 1.23 g product ( 95% yield with 94% ee ) was recovered. The desymmetrization of 4 - methyl cyclohexanone was also performed in a one - pot two - stage reaction, lead ing to desired product in 86% yield and with 82% ee as a single diastereoisomer . The absolute configuration was determined by comparing optical rotation with literature and is described in the paper as ( S ) - (+) for cyclic ketones and ( R ) - ( −) for acyclic one s . On the other hand, starting from α , β - unsaturated ketones the oxidation step is not required. Actually, C2 - symmetric squaramide - based primary diamines allowed the Michael asymmetric addition of 4 - hydroxycoumarin to α , β - unsaturated ketones (Scheme 48, eq. 2) . 67 Both enantiomers of the anticoagulant warfarin and some its derivatives were prepared by this method. The absolute configuration was attributed by comparison of the product with known ( S ) - warfarin . Being the c atalyst poorly soluble , catalyst recycles was attempted, but yield and enantioselectivity significantly decreased at every cycle. The catalyst deactivation was attributed by authors to by - side reactions of key 253 iminium ions . T he reaction was also scaled up to 1.62 g of 4 - hydroxycoumarin wi thout affecting yields and enantioselectivity.

N O N O 2 2 J - H ( 2 0 m o l % ) C H 2 C l 2 , 2 5 ° C , 2 8 h P h + A r N P h X O O H H X O O H O T M S A r J - H H g ( O T f ) A r = P h , 3 - M e C 6 H 4 , 4 - M e C 6 H 4 , 4 - F C 6 H 4 , 3 - t h i e n y l 2 X = H , 6 - M e , 7 - F ( 5 m o l % ) C H 2 C l 2 , 0 ° C , 1 0 m i n

N O 1 N 2 X N O N B S N O 2 1 R 2 X M e O H p - T s O H , C H 2 C l 2 2 5 ° C B r 0 ° C , < 3 0 m i n 3 h X O O O O P h A r N X O O A r O M e 8 7 - 4 3 % , R 7 8 % , > 2 0 : 1 d r 1 ) p - T s O H > 9 9 % e e B n S H , p - T s O H , 9 6 - 9 9 % e e ( 2 R , 4 R , 4 a R , 1 0 a S ) M e C N / H 2 O ( 2 S , 3 R , 4 R , 4 a R , 1 0 a S ) C H 2 C l 2 , 2 5 ° C , 4 0 ° C , 1 . 5 h R = M e , B n , A l l y l , B u , P h 4 8 h 1 2 ) B F 3 . E t 2 O X = H , 5 - B r , 6 - M e , 7 - M e , 7 - B r C H C l 1 2 2 R - 7 X = ( C H 2 ) 3 - 1 0 ° C , 1 0 m i n 3 ) E t 3 S i H O 2 N N O 2 O

P h

O S B n O O P h 6 2 % , 5 8 % , 9 9 % e e 9 9 % e e ( 2 R , 4 R , 4 a R , 1 0 a R ) ( a l l - R ) Scheme 47 . Reaction of chroman - 2 - ols and ( E ) - 4 - nitrobut - 3 - en - 1 - ynes .

Bez and co - workers reported the multi - component reaction of 6 - amino - 1,3 - dimethyluracil, 68 4 - hydroxycoumarin and aldehydes with a L - proline derived bifunctional amidothiourea. Although this catalyst is asymmetric, authors did not found any stereoselectivity in the final coumarin - based unsymmetrical trisubstituted methanes . In fact, at 10 °C, the reaction did not occur, while, at room temperature or higher, there was no enantioselectivity. The research group of Nishimura performed the asymmetric hydroarylation of 2 H - chromenes with aromatic ketones by an iridium/chiral phosphine complex (Scheme 49 ). 69 Authors provided evidences by deuterium labeling experiments and DFT calculations that the reaction proceeded via olefin isomerization, followed by enantioselective hydroarylation. When Ar=4 - [Ph 2 C=C(Ph)]C 6 H 4 ; R=Me and Ar=4 - MeOC 6 H 4 ; R=3,5Me 2 C 6 H 3 CH 2 ( R ) - B in ap was used instead of ( R ) - 3,5 - dimethylsegphos and the products were recovered in 95% yield with 81% ee and 97% yield with 53% ee, respectively. The reaction was also successfully applied to benzodioxane (89% yields with 70% ee). The absolute configuration of the products was assigned by transforming into the known chiral flavan one of the products. The asymmetric hydroboration of 2 H - chromenes was performed with a chiral copper complex (Scheme 50 ). 70 Conversely, from the above reported hydroarylation, no do uble bond isomerization was observed, and therefore the 3 - substituted chromane was recovered. The electronic property of the substituents on the phenyl ring influenced the enantioselectivity: electron - withdrawing groups, benzo[h] - and benzo[g]chromenes gav e lower enantioselectivities than electron - donating substituents. Authors did not give product stereochemistry but only a positive optical rotation. 71 Some transformations of the products were successfully carried out without affecting stereoselectivity. Finally, i n a paper aimed at enhancing the properties of chiral silanediols as chiral catalysts, the addition of ketene acetals to chromanones was realized. 72 The reaction conditions allowed the in situ generation of benzopyrylium ions, which are hydrogen bonded to the silanediol before addition of the ketene acetal. Authors reported a 50 - 90% yield range and up to 56% ee, but they reported neither what nor how many substrates submitted to neither the reaction nor the stereochemistry of the main enantiomer ( only a positive optical rotation was given for the sole product reporte d in the experimental section).

254

O

O H R

R 1 * t - B u N E t 2 O O O X N H 8 7 - 9 8 % 2 T f O H 1 8 1 - 9 9 % e e ( 2 0 m o l % ) R R M e C N , 0 ° C . 2 4 h ( 2 e q u i v ) H 2 O X C F C O H 6 5 2 H 2 O ( 3 0 m o l % )

O O H N E t R t - B u 2 O 1 R N t - B u N H e q 1 E t N s t e r i c a l l y 2 1 e n c u m b e r e d R R f a c e

O H N E t 2 C O 2 H t - B u N I O 2 X O O R R 1 ( 1 . 2 e q u i v ) X = H , 6 - F , 7 - M e , 7 - M e O , 7 - F , 7 - C l , 7 - B r , 6 - B r - 8 - C l , b e n z o [ g ] 1 R - R = ( C H 2 ) 3 , ( C H 2 ) 4 , ( C H 2 ) 5 , ( C H 2 ) 2 C M e 2 , ( C H 2 ) 2 C [ O ( C H 2 ) 2 O ] , ( C H 2 ) 2 C H M e 1 R = M e , R = M e , E t , i - P r , B u , ( C H 2 ) 2 C l

O S q u a r ( 1 0 m o l % ) O H C H C l A c O H O H R O 2 2 , r t , 2 4 h 1 + 1 R R R 8 9 - 9 6 % O O 5 0 - 9 6 % ( S ) O O

1 1 e q 2 R = M e , R = P h ( W a r f a r i n ) , 4 - M e C 6 H 4 , 4 - C l C 6 H 4 ; R - R = ( C H 2 ) 3 ( R ) - e n e n t i o m e r s w e r e o b t a i n e d f r o m t h e a l l - ( R ) c a t a l y s t O O P h O N N O P h N N H H O N H H N O N O N R H O P h N H H N P h O R 1 P h N H 2 S q u a r H 2 N P h Scheme 48 . Reaction of 4 - hydroxycoumarins and ketones .

O R O

[ I r ( c o d ) 2 C l ] 2 ( 5 m o l % ) R X O ( R ) - 3 , 5 - M e 2 - s e g p h o s ( 6 m o l % ) 1 N a B [ 3 , 5 - ( C F 3 ) 2 C 6 H 3 ] 4 ( 1 0 m o l % ) X X 1 P h M e , 8 0 ° C , 4 8 h 1 6 3 - 9 9 % X = H , 4 - M e O , 4 - M e , 4 - N M e 2 , 5 3 - 9 8 % e e ( S ) 4 - C l , 4 - F , 4 - P h 2 C = C P h 3 - M e , 2 - M e O R = M e , E t , i - P r , 3 , 5 - M e 2 - C 6 H 3 H I r R a n d O O O R O

X O 1 I r X M e O O O H X 1 H I r O R O

I r H X O I r

X X 1 X O O X = H , 6 - F , 6 - C l , 6 - M e O , 8 - F , 8 - M e , 5 , 7 - M e 2 - 6 - B r Scheme 4 9 . Iridium - catalyzed asymmetric hydroarylation of chromanes .

6. Desymmetrization Another method to obtain chiral benzopyran derivatives was the desymmetrization of racemic compounds . 255

O O O B B B O O O * H X O 5 1 - 9 2 % P H P O M e O B 6 2 - 9 4 % e e ( + ) t - B u t - B u O ( 5 m o l % ) M e O H C u C l ( 5 m o l % ) C u * O M e O K / M e O H B T H F , - 2 0 ° C t o r t , 6 h O O * C u B * O X O

O B O X O * C u

O X

X = H , 8 - C l , 8 - M e , 8 - M e O , 8 - i - P r , 8 - t - B u , 8 - P h , 7 - M e , 7 - M e O , 7 - t - B u , 6 - B r , 7 , 8 - M e 2 , 6 , 8 - M e 2 , 5 , 8 - M e 2 , 5 , 7 , 8 - M e 3 , b e n z o [ g ] , b e n z o [ h ] Scheme 50 . Copper - catalyzed asymmetric hydroboration of 2 H - chromenes .

Ashley and co - workers surmised that a chiral ruthenium complex could be able to reduce ( S ) - chromanones to cis ( S,S ) - chromanols, leaving the ( R ) - enantiomer untouched for torsional strains (Scheme 5 1 ) . 73 However, they also thought that a base - catalyzed β - epimerization via open - chain intermediate allowed a dynamic kinetic resolution driving both substrate enantiomers to a single product stereoisomer . Only 6 - chloro - 2 - isopropyl - 2 - methylchroman - 4 - one gave a 2.3:1 diastereomeric ration albeit both isomers have a >99% ee. Authors supported their experimental data with computational analysis. However, to obtain the best results the reaction conditions (catalyst type and loading, solvent, and temperature) should be adapted to every substrate.

O R u - c a t ( 0 . 5 - 2 . 5 m o l % ) H O H M e C N o r D M F R 2 4 0 ° o r 7 0 ° C , 2 4 h H O H O N 1 R R X O R H R u N X O R H A r R D B U / H C O 2 H ( 5 : 2 ) 7 1 - 9 6 % O O 1 0 : 1 t o > 5 0 : 1 d r 9 3 - > 9 9 % e e ( S , S ) O P h O R O H R X X H N P h R u D B U / H C O H ( 5 : 2 ) N 2 C l S O O H 2 R 2 R O H N O R 1 X O R H H R u N A r o r H R P h H N 2 P h X = H , 6 - C l , 6 - M e O , 6 - C N , 7 - B r , 7 - C l , 7 - M e O , 7 - C N R u N R = M e , i - P r , i - B u , t - B u , N - B o c - p i p e r i d i n - 4 - y l , N - B o c - 4 - m e t h y l p i p e r i d i n - 4 - y l C l S O 2 M e O 2 C ( C H 2 ) 2 , , P h a n d O O H

R u - c a t O O r a c e m i c o n l y o n e e n a n t i o m e r O O H

O O r a c e m i c 1 0 : 1 d r , 9 6 % e e Scheme 5 1 . R uthenium - catalyzed dynamic kinetic resolution as ymmetric transfer hydrogenation of β - chromanones.

256

Authors also found that one - pot condensation - dynamic kinetic resolution - asymmetric transfer hydrogenation from acetophenones and aldehydes occurred in high yield and stereoselectivity, and that products can be further manipulated without affecting selectivity. Another example of dynamic kinetic resolution - asymmetric transfer hydrogenation allowed the e nantioenriched synthesis of cis - 3 - (hydroxymethyl) - chroman - 4 - ol s under chiral rhodium cataly sis ( Scheme 5 2 ) . 74 The absolute configuration of products was determined by X - ray analysis. A 1.0 gram - scale reaction afforded the product in 81% yield with 96:4 dr and >99% ee. Some reactions wer e carried out to the products without affecting stereoselectivity.

O R h - C a t ( 0 . 5 m o l % ) O H O H H C O H / N E t ( 5 : 2 ) ( 7 e q u i v ) C H O 2 3 C H C l 3 0 ° C , 2 4 - 6 5 h 2 2 , R h 7 2 - 9 2 % C l X O 9 6 : 4 t o 9 8 : 2 d r X O M e O T s N 9 7 - > 9 9 % e e ( R , R ) N H X = H , 6 - M e , 6 - E t , 6 - i - P r , 6 - B r , 6 - C l , 6 - F , 7 - M e , 7 - C l , 7 - F P h P h R h - C a t 6 , 8 - B r 2 , 6 , 8 - C l 2 , 6 - C l - 7 - M e Scheme 5 2 . Rh - mediated asymmetric - transfer hydrogenation of 3 - substituted c hromones .

Maguire and co - workers attempted the enzymatic acetylation of some chroman - 2 - ols, testing over than 50 different enzymes. 75 The best results for chroman - 2 - ol, 6 - methylchroman - 2 - ol and 6 - methyl - 4 - phenylchroman - 2 - ol were respectively: lipase B from Alcaligenes sp (77% ee ( R ) with 76% conversion in the presence of 4.2 equiv alents of vinyl acetate in toluene); lipase from Thermomyces lanuginosus (92% ee (+) with 88% conversion in the presence of 100 equivalents of vinyl acetate in hexane); acylase from Aspergillus sp [>98% ee, (2 S ,4 S ) with only 6% conversion in the presence o f 100 equivalents of vinyl acetate without solvent ]. A chiral complex between octahydro - 1,1' - biisoquinoline and CuI allowed the enantioselective desymmetric aryl C − O coupling of different 2 - (2 - iodoaryl) - 1,3 - diols. 76 Among other oxygen - containing heterocycles, chromanes bearing quaternary chiral centers at the 4 - or 3 - position were prepared. However, the two synthesized 4 - substituted chromanes were recovered in 85 and 89% yields, but the enantiomeric excesses were onl y less than 5% and 10%. More successfully was the synthesis of 3 - substituted chromanes (Scheme 5 3 ). Aryl bromides gave only trace amounts of desired coupling products. The absolute configuration was assigned by comparison with literature data. Authors calc ulated the most stable transition states by DFT calculations.

C u I ( 1 0 m o l % ) X Q u i ( 1 5 m o l % ) R R O H N H C s 2 C O 3 ( 2 0 0 m o l % ) O H M e C O , r t , 2 0 h H N O 2 C u I R H N N H X I O H 4 4 - 9 3 % H H X O 5 8 - 7 3 % e e ( R ) H O Q u i

R = H , M e , ( C H 2 ) 5 M e , B n , i - B u , A l l y l , ( C H 2 ) 2 C H ( O C H 2 ) 2 , ( C H 2 ) 2 O H X = H , 7 - M e O ( n u m b e r r e f e r s t o c h r o m a n e ) Scheme 5 3 . Asymmetric d esymmetrization of different 2 - (2 - iodoaryl) - 1,3 - diols.

Another similar enantioselective desymmetric aryl C − O coupling involved 2,2 - b is(2 - bromobenzyl) - 3 - hydroxypropanenitrile s (Scheme 5 4 ). 77 It should be noted that, conversely from the previous reaction, aryl iodides gave very low enantioselectivity. The absolute configuration was determined by X - ray analysis . A gram - scale reaction provided 1.28 g of the product (93% yield, 9 2% ee ) . Some transformations of the products were successfully carried out without affecting stereoselectivity . The reaction can be extended to some alkenyl bromide , thus affording h exahydro - 2 H - chromene s and octahydrocyclohepta[b]pyran . However, tetrahydrocyclopenta[b]pyran, decahydrocycloocta[b]pyran, dihydro pyran and products arising from 2 - or 5 - substituted aryl bromides were recovered with very low enantiomeric excesses. D ihydrodibenzo[b, f ]oxepine was reco vered in only 17% yield . In a feature article devoted to the hydrosilylation of differently γ,γ - disubstituted cyclohexadienones catalyzed by chiral rhodium complexes, 78 four examples were reported for the synthesis of spiro - chromane 257 derivatives (Scheme 5 5 ) . The absolute configuration of products was determined by X - ray analysis. DFT calculations of different reaction pathways allowed explaining the observed asymmetric induction and the substituent effect on enantioselectivity.

C u I ( 2 0 m o l % ) B r B r B r C N L i g ( 2 2 m o l % ) C N 2 C s 2 C O 3 ( 2 e q u i v ) d i o x a n e , 1 0 ° C , 2 4 h 5 3 M e H N N H M e X H O X 6 4 - 9 6 % X O X 4 8 5 - > 9 9 % e e ( S ) L i g

X = H , 4 - M e , 4 - M e O , 4 - F , 4 - C l , 4 - C F 3 , 4 - N O 2 , 3 - M e , 3 - F , 3 - C l , 3 - B r , 3 - C F 3 , 3 , 4 - F 2 , 3 , 4 - ( O C H 2 O ) , Scheme 5 4 . Synthesis of β - quaternary carbon - containing chromanes .

s - B u O N O A c X R h O H 2 O A c s - B u s - B u O O N N N O O O O O s - B u ( 2 m o l % ) R h H R h H ( M e O ) 3 S i H S i ( O M e ) 3 S i ( O M e ) 3 P h M e , 4 0 ° C , 1 h N N + t h e n H 3 O O O s - B u s - B u X O X O 8 8 - 9 7 % 8 4 - 8 8 % e e ( S ) X = H , 6 - M e , 6 - F , 6 - C l Sch eme 5 5 . Asymmetric desymmetrization of spiro - chromanes by rhodium catalyst.

[5]H elicenyl propiolates were converted onto coumarin - fused helicenes by gold catalysis. 79 Besides the racemic reactions, authors rep orted a dynamic kinetic resolution using an Au/chiral bis(phosphine) complex (Scheme 5 6 ) . U nder the reaction conditions the two enantiomeric staring materials rapidly interconverted and the ( M ) - isomer is formed from the most stable transition state, as demonstrated by authors.

O O O O L ( A u C l ) 2 ( 2 . 5 m o l % ) A g S b F 6 ( 5 m o l % ) ( C H 2 C l ) 2 , 5 0 ° C , 1 1 d P h [ L A u * - ( M ) ] f a s t

( M ) - i s o m e r ( M ) - i s o m e r 2 4 % 6 5 % r a c e m i c 8 6 % e e u n r e a c t e d O O O O

[ L A u * - ( P ) ] M e O P A r 2 P h s l o w L = M e O P A r 2

( P ) - i s o m e r ( P ) - i s o m e r A r = 3 , 5 - ( t - B u ) 2 C 6 H 3

Scheme 5 6 . Dynamic kinetic resolution of helicene.

2 - Aryl - 3 - nitro - chromenes were allowed to react with α,  - unsaturated aldehydes under N - heterocyclic carbene catalysis. 80 With a 2:1 chromene :aldehyde ratio, addition products were obtained in good to excellent yield and stereoselectivity (Scheme 5 7 ). An aliphatic unsaturated aldehyde such as crotonaldehyde gave product in a very poor diasteroselectivity (3:1 dr). With a stoichiometric ratio, the kinetic resolution of the starti ng chromene was achieved; in fact, ( R ) - 2 - aryl - 3 - nitro - 2 H - chromenes were recovered unreacted. The absolute configuration of products was determined by X - ray analysis. Some useful transformations of the products were performed without affecting stereoselecti vity. 258

O N ( 2 0 m o l % ) N N K 3 P O 4 ( 1 0 0 m o l % ) ( S ) P h M e - C C l 4 - M e O H R C l r t , 1 2 h M e O 2 C ( R ) H N O 2 ( S ) C H O ( S ) O R X O A r N N N R = P h , 4 - M e C 6 H 4 , 4 - M e O C 6 H 4 , 4 - P h C 6 H 4 , 4 - C l C 6 H 4 , 4 - F C 6 H 4 , M e O H 3 , 4 - ( O C H 2 O ) C 6 H 3 2 - n a p h t h y l , M e O N N N N O N N H O

H O R R N O N O N 2 2 O N N X O A r X O A r H O N O R 2 N O 2 X O A r X O A r A r = 4 - M e C 6 H 4 , 4 - M e O C 6 H 4 , 4 - B r C 6 H 4 , 4 - F C 6 H 4 , 3 - B r C 6 H 4 , 2 - f u r y l , i - P r , X = H , 6 - C l , 8 - M e O c h r o m e n e : a l d e h y d e = 2 : 1 5 3 - 8 9 % , 3 : 1 t o 2 0 : 1 d r , 7 8 - 9 8 % e e c h r o m e n e : a l d e h y d e = 1 : 1 . 2 p r o d u c t : 3 7 - 4 5 % , 7 0 - 8 8 % e e ; ( R ) - s t a r t i n g : 3 1 - 4 3 % , 9 0 - 9 6 % e e Scheme 5 7 . Kinetic resolution of 2 - aryl - 3 - nitro - 2 H - chromenes.

7 . Reaction of p henols with a ctivated a lkenes Some additions of phenols to activated alkenes can afford the construction of the benzopyran nucleus. For example 4 - aryl - 3,4 - dihydrocoumarins can be obtained by reaction of phenols with α,β - unsaturated arylaldehydes, catalyzed by NHC. Then the hemiacetal i ntermediates were oxidized with 3,3 ′,5,5′ - tetra - t - butyldiphenoquinone (Scheme 5 8 ). 81 As in the rea ction described above (Scheme 57 ), 80 aliphatic aldehydes such as crotonaldehyde gave a sluggish reaction. Unfortunately, all reactions give a mixture of the desired products and open - chain byproducts. The absolute configuration of products was determined by X - ray analysis. Some useful transformations of the products for the synthesis of key intermediates of natural products were performed with out affecting stereoselectivity .

P h N H C ( 1 0 m o l % ) P h O H L i N ( S i M e ) ( 2 0 m o l % ) 1 3 2 O T M S X Q ( 1 2 0 m o l % ) X 1 X 1 N + t - B u O H / P h M e , r t , 2 4 - 4 8 h + X N N C H O B F 4 X O O X O M e s N H C 3 2 - 8 1 % 1 7 - 5 1 % 8 5 - 9 7 % e e ( R ) O t - B u t - B u X = 3 , 5 - ( M e O ) 2 , 3 - N M e 2 , 3 , 4 - ( O C H 2 O ) , 2 - E t - 3 , 5 - ( M e O ) 2 , 2 - B r - 3 , 5 ( M e O ) 2 , 2 - ( P h C H = C H ) - 3 , 5 - ( M e O 9 2 , 2 - [ P h ( C H 2 ) 3 ] - 3 , 5 - ( M e O ) 2 1 X = H , 4 - M e O , 4 - M e , 4 - N M e 2 , 4 - F , 4 - C l , 4 - B r , 4 - C O 2 M e , 4 - N O 2 , 3 - B r , 2 - M e O , 3 , 4 - ( O C H 2 O ) a n d 2 - f u r y l C H = C H C H O

t - B u t - B u O Q Scheme 5 8 . Synthesis of 4 - aryl - 3,4 - dihydrocoumarins by N - heterocyclic carbene catalyst.

Electron - rich phenols underwent a formal Diels - Alder reaction with and β,γ - unsaturated α - ketoesters under a chiral N,N ′ - dioxide - scandium(III) complex catalysis (Scheme 5 9 ). 82 The absolute configuration of products was determined by X - ray analysis. Ortho - substituted phenyl groups in the β,γ - unsaturated α - ketoesters did not react for steric reasons, except the little fluorine. 3 - (Dimethylamino)phenol afforded the expected product in 93% yield, with 10:1 dr, but as a racemic mixture. Phenol, resorcinol and 2 - naphthol did not react. A gram - scale reaction afforded 2.02 g of product (92% yield, 14:1 dr, 90% ee). 259

O M e O M e N N

O H S c ( O T f ) 3 ( 1 0 m o l % ) O O C O 2 M e N N O ( 1 2 m o l % ) A r O N H H N O A c O E t , 3 0 ° C , 1 2 h O H O + R H N O O N S c M e O A r O O N H R N N O O O M e M e O 2 C N

A r = P h , 2 - F C 6 H 4 , 3 - C l C 6 H 4 , 3 - M e C 6 H 4 , 3 - M e O C 6 H 4 , 3 - P h O C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 4 - P h C 6 H 4 , 3 , 4 - C l 2 C 6 H 3 , 3 , 4 - ( O C H 2 O ) C 6 H 3 , A r 2 - n a p h t h y l , 2 - t h i e n y l , 3 - t h i e n y l , P h C H = C H M e O 7 5 - 9 7 % C O 2 M e 6 : 1 t o 1 4 : 1 d r M e O O 8 0 - 9 5 % e e ( 2 R , 4 S ) O H Scheme 59. Oxa - [3+3] annulation of phenols with benzylidene pyruvates .

Then the synthesis of enantioenriched 7 - aminated chromanes ha s been successfully performed under a chiral nic kel complex catalysis (Scheme 60 ). 83 The absolute configuration was determined by comparing optical rotation values with literature. A gram scale reaction provided 2.16 g of chromane (93% yield with 91:9 dr and 90% ee). Two potential antitumor drugs were then prepared in a four - step - on e - pot synthesis, which provided the desired products in 50 or 52% overall yields without loss of enantiopurity at the 4 - position of the chromane ring and with 50:50 diastereomeric ratio at the 2 - position.

O H L i g a n d ( 1 2 m o l % ) C O 2 M e A r N i ( C l O 4 ) 2 . 6 H 2 O ( 1 0 m o l % ) P h C l , 4 A M S , r t O + O C O 2 M e N 8 7 - 9 8 % O R 2 N A r R N O 8 5 : 1 5 t o 9 2 : 8 d r 2 O H N 8 9 - 9 3 % e e ( 2 R , 4 S ) N O O H R = M e , B n A r = P h , 4 - M e C 6 H 4 , 4 - M e O C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , a n d 3 , 4 - ( M e O ) 2 - 5 - B r C 6 H 2 L i g a n d 2 - t h i e n y l , P h C H = C H N M e O H L i g a n d ( 1 2 m o l % ) C O 2 M e A r N i ( C l O 4 ) 2 . 6 H 2 O ( 1 0 m o l % ) P h C l , 4 A M S , r t + O C O 2 M e 9 5 - 9 8 % X A r O 7 6 - 2 4 t o 9 2 : 8 d r X O H 9 3 - 9 9 % e e ( 2 R , 4 S )

X = 3 , 4 - ( M e O ) 2 , 3 , 4 - ( O C H 2 O ) , 3 , 4 , 5 - ( M e O ) 3 ( n u m b e r r e f e r s t o p h e n o l ) A r = P h , 4 - M e C 6 H 4 , 4 - M e O C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 3 - B r C 6 H 4 , 2 - t h i e n y l , 1 - n a p h t h y l O M e O M e M e O B r 1 ) L i A l H 4 , E t 2 O , r t 1 8 h M e O B r 2 ) N a I O 4 @ S i O 2 r t , 1 h 3 ) D I B A L , P h M e , - 7 8 ° C p o t e n t i a l a n t i c a n c e r a g e n t s 4 ) ( A c O ) 2 O , N E t 3 , D M A P , r t , 1 h R = A c ( 5 2 % , 1 : 1 d r , 9 0 % e e ) o r T s O H , M e O H , r t , 5 h R = M e ( 5 0 % , 1 : 1 d r , 9 0 % e e ) C O 2 M e M e N O 2 O H M e 2 N O O R ( 9 0 % e e ) Scheme 60 . Another o xa - [3+3] annulation of phenols with benzylidene pyruvates .

The reaction of 2 - hydroxyacetophenones with cyclobutenones was carried out under a chiral N,N ′ - dioxide - scandium(III) complex catalysis (Scheme 61 ). 84 The enantioselectivity suffered from steric hindrance, in fact 2 - hydroxybenzophenone gave the product in 90% yield with only 20% ee and a substituent in the ortho - position with respect to the hydroxy l group lowered enantiomeric excess to 55%. The reaction with salicylaldehyde needed a slightly great catalyst loading (15 mol%) and afforded product in 40% yield with >19:1 dr and 88% ee. The absolute configuration of products was determined by X - ray analysis. Several control experiments were carried out by au thors to elucidate the mechanism depicted in Scheme 60, and they ruled out the formation of o - quinone methides , conversely from what found in Scheme 36 for 2 - hydroxy salicylaldehyde . 53 The transition state leading to the products should minimize the steric shield between the diene moiety of the substrate and the amide subunit of the ligand . 260

N N O O O N H H N O O 1 R i - P r i - P r i - P r R 2 O H i - P r R R 1 R ( 1 0 m o l % ) X O O S c ( O T f ) 3 ( 1 0 m o l % ) d i c h l o r o e t h a n e , 4 A M S O 5 1 - 9 2 % 6 0 ° C , 7 2 h C S c > 1 9 : 1 d r 5 3 - 9 3 % e e ( 3 S , 4 R ) R R = P h , 2 - F C H 3 - M e C H H 6 4 , 6 4 , R 1 3 - F C 6 H 4 , 4 - F C 6 H 4 , 1 4 - M e C 6 H 4 , 4 - M e O C 6 H 4 R 1 S c R = H , C l O O 2 R 2 R = M e , E t , C H 2 B r , P r R 2 e t h y n y l , C O 2 E t , ( C H 2 ) 2 P h R X = H , 4 - M e O , 6 - M e , 6 - F , 6 - C l , O O 6 - B r , 6 - M e O , 7 - F , 7 - M e , O X O H 7 - C l , 6 , 7 - M e 2 , 6 , 8 - M e 2 a n d O H

Scheme 6 1 . Catalytic ring opening/cycloaddition of cyclobutenones to 2 - h ydroxyacetophenones .

2 - H ydroxy - N - Boc - α - amidosulfones can undergo a cascade oxa - Michael - aza - Henry reaction and a cascade Mannich cyclization - tautomerization with trans - β - nitrostyrenes or amidosulfones , respectively (Scheme 62 ) . 85

S R 1 N N N H B o c T H ( 5 m o l % ) N H B o c N O 2 R N H H X K 2 C O 3 a q C H 2 C l 2 2 X N O 2 S O T o l + r t , 6 - 2 4 h H 2 O O N B o c N O H A r 7 9 - 9 7 % O A r H T o l S O 2 H 8 1 : 1 9 t o 1 0 0 : 0 d r O 6 4 - > 9 9 % e e A r X = H , M e , B r , C l , N O 2 ( 2 R , 3 S , 4 S ) A r = P h , 4 - C l C 6 H 4 , 4 - F C 6 H 4 , 4 - M e O C 6 H 4 , 2 - n a p h t h y l X

S C l N H N H N O

C l T H O O A r S q u a ( 5 m o l % ) N N H B o c N H B o c K C O C H C l N S O P h 2 3 a q 2 2 H S O P h X 2 r t , 8 - 2 2 h O H H 2 S O 2 T o l + R 2 H N C N C N N O H O O H X T o l S O 2 H O - t - B u N X = H , M e , B r , C l

S O 2 P h N H B o c X S O 2 P h

R = O O C l N H 2 8 3 - 8 9 % , 8 2 - 9 0 % e e ( R ) O N R N N H H C l i - P r S q u a R = 8 8 - 9 6 % , 8 6 - 9 4 % e e ( S ) N Scheme 6 2 . Stereoselective synthesis of 2 - substituted 4 - amino - 3 - nitrob enzopyrans and 3 - functionalized 3,4 - diamino - 4H - chromenes.

A thiourea was the mo st efficient catalysts for the reaction of trans - β - nitrostyrenes , while two squaramides allowed the preparation of b oth enantiomers in the reaction of amidosulfones. Both catalysts 261 were also co - polymerized with styrene divinylbenzene and tested in the reactions; products were recovered in 91 - 96% yiel d with 82:18 to 99:1 dr and 86 - >99% ee for polymeric thiourea and 78 - 84 % yield, with 78 - 88% ee for polymeric squaramide , and the p olymeric catalysts were recovered and reused five times without loss of efficiency. A mechanism , in which 2 - hydroxy - N - Boc imine was initially formed by the aqueous solution of K 2 CO 3 , was also hypothesized. Then hydrogen bo n ds , in which the nitro group and the acyl imine functionality found the optimum distance in the thiourea and squaramide moieties, respectively , were formed and the tertiary amines deprotonated the phenol framework . A n intramolecular cyclization/decarboxylation can occur in ortho - hydroxyphenyl substituted Meldrum’s acids (Scheme 63 ) . 86 Owing to the difficult purification of these phenols, authors used the corresponding pure silyl ethers , which were efficiently in situ de sylilated. When the R group is a 4 - methoxy substituted benzyl moiety, the reaction time was prolonged to 60 h in order to increase yield from 61 to 99%. The absolute configuration of products was determined by X - ray analysis. The reduction of the carbonyl group to ( S ) - 3 - benzylchromane did not affect the enantiomeric excess. The chlorination instead of protonation of the intermediate was also performed, but some amounts of protonated by - product were always recovered by an independent pathway (from 83:17 to 8 0:20), as proved by control experiments . The absolute configuration of the chlorinated product was not determined.

X O O R = B n , 4 - C l C 6 H 4 C H 2 , 4 - M e C 6 H 4 C H 2 , 4 - M e O C 6 H 4 C H 2 , 4 - F C H C H 3 - C l C H C H 2 - M e O C H C H R 6 4 2 , 6 4 2 , 6 4 2 , O O H 1 - n a p h t h y l , 2 - t h i e n y l , 2 - f u r y l , N - B o c - i n d o l - 3 - y l , P h C H = C H C H P h ( C H ) B n O ( C H ) E t O C C H P h N 2 , 2 3 , 2 2 , 2 2 , O S i E t 3 O X = H , M e , B r H C l , E t O H , 1 h O C i n X R N X O O P h P h C i n R O O ( 2 0 m o l % ) O 5 1 - 9 9 % T H F , 5 ° C , 2 0 h O M e 1 8 - 8 6 % e e ( S ) O H O N p r o t o n a t i o n f r o m t o p C i n 2 X O O N H R N C F X R O O 3 H C i n H C i n O O O O O H C i n C F R C l 3 X N C l C H L C O 2 O H C l / E t O H 1 h C l t h e n C i n 2 ( 2 0 m o l % ) C H L X O O R C H L ( 1 . 5 e q ) , N a H C O 3 X R X R T H F , 1 5 ° C , 4 0 h * O C l O O O O O S i E t O 3 H C i n 2 5 1 - 7 4 % R = B n , 4 - C l C 6 H 4 C H 2 , 4 - M e C 6 H 4 C H 2 , 4 - M e O C 6 H 4 C H 2 , 4 - F C 6 H 4 C H 2 , 1 - n a p h t h y l 5 2 - 5 8 % e e X = H , M e Scheme 6 3 . Synthesis of C3 - alkylated dihydrocoumarins from C5 - disubstituted Meldrum’s acids.

8. Reduction of chromones The asymmetric reduction of 4 - chromones is another travelled way to obtain enantioenriched benzopyran derivatives. For instance a Cu - c hiral complex allowed their as ymmetric reduction in the presence of diethoxymethylsilane as the reductant (Scheme 64). 87 O ne of the reported examples was t he natural product flindersiachromanone [ R=Ph(CH 2 ) 2 ], which was recovered in 97% yield with 98% ee . The absolute configuration of chromanones was assigned as ( S ) by comparison with literature data for the known ( R ) - compound s and confirmed by X - ray analysis . Moreover, the silyl enol ether intermediate s can react with electrophiles such as bromine of NBS or aldehydes to give 2,3 - disubstituted products in 40% yield, 97% ee and in 75% yield , 17 :1 dr, respectively. The reaction w as also successfully applied to thiochromones, despite the affinity of sulfur to transition metals , which generally deactivates the catalysts. An asymmetric Ru - complex allowed instead the complete reduction of chromones to enantioenriched chromanols (Schem e 65). 88 The absolute configuration of products was determined by X - ray analysis. A gram - scale hydrogenation starting from 1.87 g of reactant afforded product in 99% yield and with 96% ee , with 0.1 mol% of catalyst and 5 MPa H 2 at room temperature over 12 h. Some modifications of reaction 262 product were carried out without affecting selectivity; in particular flindersiachromanone was obtained in 92% after two steps with 98% ee . Some control experiments allowed authors envisaging a mechanism in which the C = C double bond w as firstly reduced.

( R ) - 3 , 5 - d i m e t h y l s e g p h o s ( 2 . 7 5 m o l % ) O S i M e ( O E t ) O 2 O C u ( O A c ) 2 ( 2 . 5 m o l % ) ( E t O ) 2 M e S i H ( 2 e q u i v ) T H F , r t , 1 h X Y R X Y R 7 4 - 9 9 % X Y R 9 4 - > 9 9 % e e ( S ) Y = O , S X = H , 6 - M e , 6 - M e O , 6 - B r , 6 - F , 7 - F , 6 , 7 - M e 2 , 6 , 8 - C l 2 R = M e , E t , P r , i - P r , t - B u , n - C 5 H 1 1 , c - C 6 H 1 1 , B n , P h ( C H 2 ) 2 , C O 2 M e , C O 2 E t Scheme 6 4 . Copper - catalyzed asymmetric reduction of chromones and thiochromones .

R u P H O X - R u ( 0 . 5 m o l % ) O H ( 2 M P a ) O O H t - B u O 2 O N a 2 C O 3 ( 0 . 5 e q u i v ) N M e O H , r t , 1 2 h C l R u N t - B u 9 5 - 9 9 % R u X O R X O R X O R P h 3 P P C l 9 4 - > 9 9 % e e ( 2 S , 4 R ) C l P h 2 P h 2 P R u C l P P h 3 X = H , 6 - M e , 6 - M e O , 6 - E t , 6 - F , 6 - C l , 7 - M e R u P H O X - R u R = M e , E t , P r , i - P r , B u , P h ( C H 2 ) 2 , H Scheme 6 5 . Ru - catalyzed asymmetric hydrogenation of chromones .

9. Spiro , f used a nd bridged chromane - i ndoles Oxindoles, chromane s and polycyclic compounds featuring the ir combination have many interesting biological and pharmacological properties , thus their synthesis fascinated many research groups . For example, the group of Li and Liu prepared a series of spiro - , dispiro - , fused, and bridged heterocycles by the reaction of quinones and 3 - keto - oxindoles catalyzed by β - i socupreidine (Scheme 6 6 ) . 89 The absolute configuration of products was determined by X - ray analysis. Authors carrie d out s ome control experiments to elucidate the mechanism and found that the free hydroxy group of the catalyst played a key role in the catalytic process (the methoxy derivative is much more efficient) and that the two spiroxindoles arose both from the he miacetal intermediate by dehydration or ketalization, respectively. An other organocatalytic synthesis of spiro oxindole - chromane derivatives was described by Wang and co - workers (Scheme 67), 90 that is and asymmetric [3+ 2] cycloaddition of oxindole azomethi ne ylides with 3 - nitro - 2 H - chromenes . It should be noted that the reaction of 3 - aminooxindole and aldehyde is more efficient than that of isatin and benzylamine. N - Un substituted oxindoles exhibited inferior reactivity and N - benzyl - protected ones gave the b est results. The absolute configuration of products was determined by X - ray analysis. Also 3 - nitro - 2 H - thiochromene and 3 - nitro - 1,2 - dihydronaphthalene afforded products in 96% (>20:1 dr, 90% ee) and 95% (>20:1 dr, 94% ee). A gram - scale synthesis produced 0.79g of spiro [pyrrolidine - 2,3 ′ - oxindole] (78% yield , >20:1 dr, 76% ee) . S p irooxindole - based hexahydroxant hones with five adjacent stereocentres have been prepared with a thiourea catalyst. The reaction was performed with nitroolefins (Scheme 68, eq. 1), 91 or 3 - methyl - 4 - nitroisoxazole substituted alkylidenoxindoles (Scheme 68, eq. 2). 92 Boc protection of the oxindole - chromene starting material was found to be crucial for obtaining good results in terms of electrophilicity an d efficiency . The absolute configuration of products was determined by X - ray analysis. In the reaction with nitroolefins, a gram - scale experiment provided 1.07 g of the desired product ( 77% yield with >20:1 dr and 98% ee ). A tentative transition state, proposed by authors to explain the observed stereochemistry, is shown in eq. 1. In the reaction with 3 - methyl - 4 - nitroisoxazole substituted alkylidenoxindoles, the most interesting feature was the trans - relationship between the C1 ′ and C2 ′ as in the natural products of the diversonol class, while all the other reported synthesis of this building block have a cis - relationship. 93 Some useful transformations of the products were performed without affecting stereoselectivity.

10. Miscellaneous Other asymmetric reactions afforded benzopyran nucleus that cannot be listed in the above sections.

263

2 O R M e O O + X O N O R 1  - I C D ( 1 m o l % ) C H 2 C l 2 , - 4 0 ° C , 3 h

t h e n T s O H ( 1 0 m o l % ) , t h e n T s O H ( 1 0 m o l % ) , C H 2 C l 2 , 2 5 ° C , 1 h M e O H , 2 5 ° C , 1 h

M e O M e O M e O N a B H M e O H , O 4 , O 2 O O M e 2 0 ° C , 1 h R H O R H O H O t h e n 3 - C l C 6 H 4 C O 3 H 2 X X O H X R C H 2 C l 2 , 2 5 ° C , 1 h O O O N N N K 2 C O 3 , M e I 1 1 1 R M e 2 C O , r e f l u x R R 4 5 - 8 7 % 3 h , 4 9 - 6 1 % 5 0 - 7 3 % 6 9 - 9 9 % e e ( S ) t h e n H C l , 8 0 ° C > 2 0 : 1 d r > 2 0 : 1 d r R 1 = B o c , P h C O , 5 h 9 4 - 9 9 % e e 9 1 - 9 8 % e e ( R , R ) 1 1 P h C H = C H C O , C O 2 M e , R = B n C O , B o c R = B o c 2 2 C l 3 C C H 2 C O , B n C O , R = P h , 4 - C l C 6 H 4 , 4 - M e C 6 H 4 R = P h , 4 - M e O C 6 H 4 , 4 - C l C 6 H 4 , 9 - f l u o r e n y l C H 2 C O 3 - M e O C 6 H 4 , 2 - M e O C 6 H 4 , 3 - C l C 6 H 4 , 3 - M e O C 6 H 4 , 2 2 - t h i e n y l R = P h , 4 - M e O C 6 H 4 , 4 - C l C 6 H 4 , 2 - M e O C 6 H 4 , M e , 2 - t h i e n y l , 3 - C l C 6 H 4 , 3 - M e O C 6 H 4 , O M e X = H , C l 2 - n a p h t h y l 2 - M e O C 6 H 4 , 2 - t h i e n y l O M e X = H , C l , M e X = H , C l , M e M e O 2 C X O N R 2 H 5 6 - 8 2 % > 2 0 : 1 d r 9 2 - 9 9 % e e 2 R = P h , 4 - M e O C 6 H 4 , 3 - C l C 6 H 4 , 2 - M e O C 6 H 4 , 2 - t h i e n y l X = H , C l Scheme 6 6 . Synthesis of spiro - , dispiro - , fused, and bridged heterocyc les by the reaction of quinones and 3 - keto - oxindoles.

N H 3 C l O 1 N O 2 X N O 2 O O + A r C H O + + P h C H 2 N H 2 + N N X O O B n B n P A ( 2 0 m o l % ) P A ( 2 0 m o l % ) 9 5 % N a H C O 3 ( 1 . 5 e q ) 3 A M S , P h M e , 7 : 1 d r 3 A M S , P h M e , 2 5 ° C , 4 d 6 5 % e e i - P r 2 5 ° C , 5 - 6 d i - P r

A r O N O 2 O O H N O i - P r ( S ) ( S ) O P O O O H O X 1 O P ( R ) O O ( S ) O A r O B n X i - P r N X N N B n H 8 2 - 9 9 % i - P r 1 5 : 1 t o > 2 0 : 1 d r i - P r 1 5 0 - 9 6 % e e X P A

A r = P h , 4 - M e C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 4 - N O 2 C 6 H 4 , 4 - C N C 6 H 4 , 3 - M e C 6 H 4 , 3 - N O 2 C 6 H 4 , 3 , 4 - C l 2 C 6 H 3 , 2 - F - 4 - B r C 6 H 3 , 2 - n a p h t h y l , 2 - t h i e n y l X = H , 6 - M e , 6 - B r , 6 , 8 - C l 2 ( n u m b e r s r e f e r t o c h r o m a n e p o s i t i o n s ) X 1 = H , 5 - F , 5 - M e ( n u m b e r s r e f e r t o o x i n d o l e p o s i t i o n s ) Scheme 6 7 . Synthesis of enantioenriched polycyclic spirooxindole - chromane adducts .

In a paper mainly devoted to the a symmetric synthesis of dihydropyranones, some examples of spirochromanes are reported by Michael addition - lactonization reactions of β , γ - unsaturated α - keto esters with chromanone thioesters (Scheme 69). 94 The absolute configuration was determined by X - ray analysis . A gram - scale reaction provided the product in 76% yield and 99% ee. 264

1 X X 1 O X 1 T H ( 1 5 m o l % ) O 2 N O C H C l 3 , r t , 4 d O + X O 6 N O 2 e q 1 O O 1 A r 6 5 - 8 5 % 2 O > 2 0 : 1 d r 4 A r 5 A r N 9 1 - > 9 9 % e e X ( 1 S , 2 R , 4 R , 5 R , 6 S ) H N O B o c O N O X N X = H , 6 - C l , 5 - F , 5 - M e O ( 1 0 : 1 d r ) H O B o c ( n u m b e r r e f e r s t o o x i n d o l e n u c l e u s ) C F 3 1 X = H , M e , F , i - P r N M e 2 H A r = P h , 4 - F C H 4 - C l C H 4 - B r C H 4 - M e C H S 6 4 , 6 4 , 6 4 , 6 4 , N H 3 - N O 2 C 6 H 4 , 2 - B r C 6 H 4 , 2 - t h i e n y l N N N C F 3 S H H N M e 2 T H X 1 O N O 2 O 2 N N O H O O H X 1 N X 2 O H O O O T H ( 1 5 m o l % ) C H C l 4 0 ° C , 3 d 3 , O O + 2 2 1 6 X 7 9 - 9 1 % O 4 5 O O > 2 0 : 1 d r O H N N N 9 2 - > 9 9 % e e d i v e r s o n o l X O R B o c R ( 1 R , 2 R , 4 S , 5 S , 6 S ) X N O B o c e q 2 X = H , 5 - F , 5 - M e O , 6 - C l ( n u m b e r r e f e r s t o o x i n d o l e n u c l e u s ) X 1 = H , M e , F , i - P r X 2 = H , F , C l , B r , M e R = M e , E t , P h , B n Scheme 6 8 . A symmetric synthesis of spirocyclic hexahydroxanthones .

H R C O 2 M e N P h C O 2 M e c a t ( 1 m o l % ) X M e X C O S P h P h C l , r t , 1 - 5 h O O H N S + 5 4 - 8 2 % O O O O H N s i n g l e d i a s t e r e o m e r O C F 3 R 9 7 - 9 9 % e e ( 3 S , 4 ' S )

X = H , M e O , B r c a t F 3 C R = P h , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 4 - M e C 6 H 4 , 3 - B r C 6 H 4 , i - B u , 2 - n a p h t h y l , 2 - f u r y l , 2 - t h i e n y l Scheme 6 9 . Synthesis of spiro - 3,4 - dihydrocoumarin - fused 3 ′ ,4 ′ - dihydropyranones .

S alicylaldehydes have been already used as a starting material for the synthesis of chromane derivatives (see Scheme 2 1 34 and Scheme 3 6 ). 53 However, salicylaldehydes also reacted with 3 - C - vinyl sugar nitro olefins prepared from protected glucofuranose (Scheme 70 ). 95 T his is not an asymmetric catalyzed reaction, but actually a chiral pool reaction. In fact, the exclusive formation of the new chiral center at the C2 position of the chrom ane ring is due to the chiral sugar and not to the catalyst, which is triethylamine. The reaction is fast , affording exclusively (2 S ) - 2 - C - spiro - glycosyl - 3 - nitrochromenes.

R O R R N O O R O O N E t 3 , ( 1 e q ) n e a t 2 O C H O - 4 0 ° C , 5 - 1 5 m i n + O R 6 0 - 9 0 % O O X O H O X O 2 N R O O

R = M e , R - R = ( C H 2 ) 5 R R X = H , 8 - M e O , 8 - E t O , 8 - O H , 7 - M e O , 6 - M e O , 6 - C l , 6 - B r , 6 - A c O , 6 - O H , 6 - N O 2 , 6 , 8 - C l 2 , 6 , 8 - B r 2 , 6 - B r - 8 - M e O , 6 - C l - 8 - B r a n d C H O O H

Scheme 70 . Synthesis of enantiopure 2 - C - spiro - glycosyl - 3 - nitrochromenes .

Some for mal Diels - Alder reaction of β , γ - unsaturated α - ketoesters for the synthesis of chromanes have been already encountered in this review (Schemes 59 82 and 60). 83 Recently this reaction was extended to chroman - 2 - ols by enamine cataly sis (Scheme 71). 96 T he product s from chroman - 2 - ol and different β , γ - unsaturated α - ketoesters precipitate d as a single diastere omer from the reaction mixture when using 265

MeOH as the solvent . As the catalyst remained in the filtrate, it was efficiently recycled eight time s on a 1.5 mmol scale without significantly affecting yield and selectivity , but longer reaction times are required along with the number of recycling increased . The products arising substituted chroman - 2 - ols did not precipitate and were recovered after ch romatography as a mixture of isomers. However, acidic treatment of the reaction mixture allowed dehydration and only the cis - configured product was recovered. Authors surmised that, in the acidic medium, a ring opening of the acetal moiety occurs and then the subsequent closure is obtained from the attack of oxygen anion at the Si - face of the oxocarbenium ion . The absolute configuration of both acetals and dehydrated products was determined by X - ray analysis . Finally, s ome transformations of both products were successfully carried out without affecting stereoselectivity .

J - H ( 2 0 m o l % ) A r C O 2 R P h C O 2 H ( 2 0 m o l % ) M e O H , 4 0 ° C P h O + 5 7 - 7 3 % C O 2 R N P h O O H > 2 0 : 1 d r O O H O T M S A r 9 4 - > 9 9 % e e O H J - H ( 2 S , 4 S , 4 a R , 1 0 a R )

A r = P h , 4 - M e C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 3 - B r C 6 H 4 , 3 - M e C 6 H 4 , 2 - n a p h t h y l , 2 - t h i e n y l R = M e , E t J - H ( 2 0 m o l % ) B F 3 . E t 2 O A r A r C H C l C O 2 R P h C O 2 H ( 2 0 m o l % ) 2 2 , M e O H , 4 0 ° C 2 5 ° C O + C O 2 R X O O H O O X O O C O 2 R A r X O H

A r A r

A r = P h , 4 - M e C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 3 - B r C 6 H 4 , 3 - M e C 6 H 4 , 2 - n a p h t h y l , 2 - t h i e n y l X = H , 7 - C l , 8 - M e O O C O R X O O C O 2 R R = M e , E t X 2 5 3 - 8 5 % > 2 0 : 1 d r 9 3 - > 9 9 % e e ( 4 S , 4 a R , 1 0 a S ) Scheme 71. S ynthesis of both cis - and trans - configured pyrano[2,3 - b ]chromenes .

N aphthopyran is another skeleton widely found in natural products. I ts assembly has been made , 97 but in the last three years, the asymmetric assembly of tetrahydro - 3 H - benzo[f]chromen - 3 - one derivatives has been reported only from the reaction of bromoenal and β - tetralone or β - indanone catalyzed by N - heterocyclic carbene (Scheme 7 2 ) . 98 2 - B romobut - 2 - enal and α - bromoenals containing heterocycles as well as α - tetralone did not give the expected products. The absolute configuration was assigned observing an opposite optical rotation of products with respect to that reported in the litera ture . 97 b At the end of this section, some enantioselective remote formations of bonds will be collected, namely the enantioselective vinylogous γ - allylic alkylation of 4 - methylcoumarins . It should be noted that the control of this remote formation is gener ally difficult. However, in 2017 the group of Antonchick and Waldmann reported an enantioselectiv e copper - catalyzed vinylogous propargylic substitution of coumarins (Scheme 73). 99 Aromatic propargylic acetates react ed smoothly , but aliphatic propargylic acetates did not. On the other hand, perfluorobenzoates efficiently provided the products. The absolute configuration was determined by X - ray analysis . Then some transformations were carried out to prepare a set of derivatives for biological te sts, which revealed a novel class of autophagy inhibitors. Another vinylogous reaction of 3 - cyano - 4 - methylcoumarins involved Morita - Baylis - Hillman 100 101 carbonates . Two different papers described this reaction with (QD) 2 PHAL and (DHQD) 2 PYR catalys t s (Schem e 7 4 ). Both reactions afforded ( R ) - isomers as determined by X - ray analysis. The former reaction was also carried out at a 1.0 mmol scale leading to 250 mg ( 67% yield with 92% ee). Some substrates were unreactive (see Scheme 74). In the latter reaction , a c yano - substituted MBH carbonate showed a lower enantioselectivity . Albeit 6 - chloro - 3 - cyano - 4 - methylcoumarin wa s selected as model reactant , benzo unsubstituted coumarin successfully reacted. A tentative mechanism was also suggested. The vinylogous reaction of 3 - cyano - 4 - methylcoumarins with allyl carbonate s afforded the expected products under iridium complex with chiral ligands (Scheme 75). 102 The gram - scale reaction gave 1.08 g (90% yield with 94% ee) of the product. The absolute configuration was determine d to be S by the comparison of optical rotation value with reported data . 266

O N N N M e s O X 1 B F 4 O N H C ( 2 0 m o l % )

X K 2 C O 3 ( 1 2 0 m o l % ) 6 2 - 9 0 % T H F , 2 5 ° C , N 2 8 1 - 9 6 % e e ( R ) C H O N N B r N X 1 N O N N

X 1 O H O N

B r N N X N X 1 O N N O 1 X N B r O N N X 1 X O O K C O X = H , 5 - M e O , 6 - B r , 7 - M e O 2 3 1 X = H , 4 - M e , 3 - M e , 2 - C l , 2 - N O 2 X X N H C ( 2 0 m o l % ) d i a z a b i c y c l o c t a n e C H O ( 1 2 0 m o l % ) X 1 + O P h M e , 2 5 ° C , N 2 B r 4 1 - 8 3 % O X 1 2 5 - 9 7 % e e ( R ) O X 1 = H , 4 - M e O , 4 - C l , 3 - M e Scheme 7 2 . [3+3] A nnulation of bromoenals with β - tetralones and β - indanone.

C u ( O T f ) 2 ( 5 m o l % ) R L i g a n d ( 7 . 5 m o l % ) P h D I P E A ( 3 e q u i v ) R O P G C N M e O H / C H 2 C l 2 ( 1 : 1 ) C N N - 4 0 ° C , 2 4 - 7 2 h + N P P h 2 X O O 6 2 - 9 8 % O O 4 1 - 9 8 % e e ( R ) X L i g a n d

X = 5 - M e O , 6 - M e , 6 - F , 6 - C l , 6 - B r , 7 - M e , 6 - C l - 7 - M e , 6 , 8 - B r 2 , P G = A c , C 6 F 5 C O R = P h , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 4 - C O 2 M e C 6 H 4 , 4 - C N C 6 H 4 , 4 - M e C 6 H 4 , 4 - M e O C 6 H 4 , 3 - M e C 6 H 4 , 2 - M e C 6 H 4 , 3 , 4 - C l 2 C 6 H 3 , 1 - n a p h t h y l , 2 - t h i e n y l . 2 - f u r y l , P h ( C H 2 ) 2 , P r , i - P r , c - P r , i - B u , t - B u , C H 2 = C H ( C H 2 ) 2 , c - C 6 H 1 1 , B n O C H 2 , M e S ( C H 2 ) , M e 2 C = C H , N - B o c p i p e r i d i n - 4 - y l C H 2 Scheme 7 3 . Vinylogous propargylation of coumarins .

( Q D ) 2 P H A L C O 2 E t ( 1 0 m o l % ) O B o c E t O A c / b r i n e ( 1 : 1 ) C N 2 5 ° C , 5 d R C O E t U n r e a c t i v e : + R 2 C N R = c - C H E t 6 2 - 7 9 % 6 1 1 , O O C N r e p l a c e d b y X 8 4 - 9 4 % e e ( R ) C O N H C O E t , H X O O 2 , 2 X = H , 6 - C l , 7 - M e , 7 - F R = P h , 2 - M e C 6 H 4 , 2 - F C 6 H 4 , 2 - C l C 6 H 4 , 2 - B r C 6 H 4 , 3 - F C 6 H 4 , 3 - B r C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 4 - M e C 6 H 4 , 4 - i - P r C 6 H 4 , 4 - C F 3 C 6 H 4 , 4 - M e O C 6 H 4 , 2 - n a p h t h y l , 2 - t h i e n y l E W G ( D H Q D ) 2 P Y R E W G ( 1 0 m o l % ) R C N O B o c C H 2 C l 2 , 4 0 ° C , 2 4 h R E W G N R * 3 + R 8 9 - 9 8 % C N C N X O O 7 8 % - > 9 9 % e e ( R ) X O O X O O X = 6 - C l , 6 - B r , 6 - F , 6 - M e , H , 6 - C l - 7 - M e , b e n z o [ f ] R = P h , 4 - C F 3 C 6 H 4 , 4 - B r C 6 H 4 , 4 - C l C 6 H 4 , 4 - M e C 6 H 4 , 4 - M e O C 6 H 4 , 3 - C l C 6 H 4 , 2 - C l C 6 H 4 , 3 , 4 - ( O C H 2 O ) C 6 H 3 , 2 - n a p h t h y l , 2 - f u r y l E W G = C O 2 M e , C O 2 E t , C O 2 - t - B u , C N Scheme 7 4 . V inylogous allylic alkylation with Morita - Baylis - Hillman c arbonates .

267

The products were then submitted to some transformations without affecting enantioselectivity. Some interesting feature must be outlined: (i) only this reaction was successfully carried out on isocoumarin (48% yield with 95% ee ); (ii) c oumarins , in which the CN group was replaced with CO 2 Et or CONH 2 frameworks, unreactive in the previous reaction, (see Scheme 73), reacted smoothly leading to 54% yield with 99% ee and 83% yield with 97% ee, by using Feringa ligand instead o f You - ligand.

[ I r ( C O D ) C l ] ( 2 m o l % ) R 2 Y o u l i g a n d ( 4 . 4 m m o l % ) C N H N = C ( N M e 2 ) 2 ( 1 e q u i v ) R T H F , r t + C N P N X O O O C O 2 M e 4 8 - 9 9 % 8 9 - 9 7 % e e ( S ) X O O X = H , 6 - M e , 6 - M e O , 6 - F , 6 - C l , 7 - M e , 7 - M e O , 7 - B r , 8 - M e , b e n z o [ h ] R = P h , 3 - M e C 6 H 4 , 3 - C l C 6 H 4 , 3 - C F 3 C 6 H 4 , 4 - M e C 6 H 4 , 4 - M e O C 6 H 4 , 4 - F C 6 H 4 , 4 - C l C 6 H 4 , 4 - B r C 6 H 4 , 3 , 4 - ( O C H 2 O ) C 6 H 3 , 3 - p y r i d y l , 2 - f u r y l , 2 - t h i e n y l , C H = C H M e , M e , P r , C H B n O ( C H ) C l ( C H ) P h 5 1 1 , 2 2 , 2 4 P N P h Scheme 7 5 . Iridium - catalyzed asymmetric v inylogous allylic alkylation .

Very recently, the enantioselective vinylogous Mannich addition of 3 - cyano - 4 - methylcoumarins to isatin imines was reported by Wu and co - workers (Scheme 7 6 ) . 103 The reaction worked with very low catalyst loading ( 0.1 mol% ) and can be scaled up to 1.44 g ( 92% yield with 99% ee ) . It should be noted that the large scale reaction did not require chromatographic separation, but product was isolated in pure form after filtration through a short silica gel pad. Both N - protections could be efficiently removed with only a slight decrease of the ee. The reaction with N - Boc imine of benzaldehyde was also carried out , but the enantioselectivity was moderate (75% ee) albeit in 97% yield. Unfortunately, authors were unable to establish the configuration of the chiral center, which was tentatively assigned as S by analogy with similar reactions.

O O i - B u P P h N R 1 c a t a l y s t ( 0 . 1 m o l % ) 3 K C O ( 1 . 0 e q u i v ) C N O N H B r C N 2 3 P h M e , - 1 0 ° C , 6 - 1 4 h R 1 H N + O N O O X 9 4 - 9 9 % O R 9 4 - 9 9 % e e N ( p e r h a p s S ) X F 3 C C F 3 R c a t a l y s t X = H , 4 - C l , 5 - M e , 5 - M e O , 5 - F , 5 - C l , 5 - B r , 6 - B r , 7 - C l R = B n , M e , a l l y l , M e O C H 2 , H 1 R = B o c , E t O 2 C Scheme 7 6 . V inylogous allylic alkylation with isatin imines .

11 . Examples of total syntheses Being chromane a “p rivileged structure ”, that is a molecular framework able to provide a series of molecules with potent biological activities ; it is not surprising that many above - described reactions have been used in the total syntheses o f natural products or drugs. The alkylation methods described in section 5 (Schemes 44 and 45) has been applied to the total synthesis of ( R ) - tolterodine by Korenaga and co - workers , applying their computationally designed catalyst 7 (Scheme 77 ). The alkylated chromane derivative was reduced wit h DIBAL and then the reductive amination was carried out with an Ir catalyst and HCO 2 H as hydrogen source. Finally, the crude product, without further purification, was reacted with ( L ) - tartrate affording the salt in >99% ee. With respect to other syntheses of this product, this preparation shows some advantages: no use of hydrogen gas and large amounts of palladium catalyst and no need of intermediate purification. Paecilospirone was isolated from the mari ne fungus Paecilomyces sp. near Yap Island (Micronesia). Being the molecular core a chromane moiety, Pettus and co - workers reported a synthetic strategy for the synthesis of des - hydroxy paecilospirone in ten steps, in which the key step was the reaction of an enol ether and an ortho - quinone methide, eac h derived from the same lactone (Scheme 78). 104 The synthesis is not enantioselective, but authors envisaged that t he approach may become enantioselective by using a chiral ami ne instead of pyrrolidine . 268

C p * I r C l [ 8 - q u i n o l i n o l a t e ] P h P h P h D I B A L H C O 2 H , H N ( i - P r ) 2 P h M e , - 2 5 ° C T H F , 5 0 C , 2 0 ° C N

O O O O H O H ( s e e S c h e m e 4 4 f o r p r e p a r a t i o n ) L - t a r t a r i c a c i d E t O H , 6 0 ° C

( R ) - t o l t e r o d i n e ( L ) - t a r t r a t e 6 0 % o v e r a l l > 9 9 % e e Scheme 77 . Total synthesis of Detrusitol® [( R ) - tolterodine ( L ) - tartrate)] .

C O O H B r B r N O C H 7 1 5 C H C 7 H 1 5 7 1 5

H O T i C l 4 , , T M E D A O Z n , P b C l 2 , T H F O O O B n 3 3 % O B n 8 7 % s i n g l e d i a s t e r e o m e r O 6 4 %

O 4 0 % 7 8 % O O 1 ) p y r r o l i d i n e t - B u M g C l O B n N C 8 H 1 7 O M e 3 A l , C H 2 C l 2 N T H F , - 7 8 ° C 2 ) A c 2 O , E t 3 N , C 7 H 1 5 D M A P , C H 2 C l 2 3 ) P d / C , H 2 O H O A c O E t O A c / E t O H O O O H d e s - h y d r o x y p a e c i l o s p i r o n e Scheme 78 . Total synthesis of des - hydroxy paecilospirone .

From the seeds of Silybum marianum were isolated silymarin a complex mixture of flavonolignans, with bioactive properties. The total synthesis of silybin B and isosilandrin B was performed by Barker and co - workers. 105 The key step converted a chalcone into equimolecular mixtures of ent - silybin A and silybin B or ent - isosilandrin A, and isosilandrin B (Scheme 79), b ecause, unfortunately, the fixed chirality at the C - 2 ′ and C - 3 ′ atoms was not able to address the stereochemistry on the distant dihydroflavonol fragment.

O M O M B r O M O M O T I P S 5 s t e p s M O M O O M O M O + O O M O M O C H O 1 4 % O M e B r M O M O O O M O M O M e 1 . H 2 O 2 , N a O H , M e O H 2 . H C l , M e O H 1 . H C l , M e O H 4 3 % 2 8 % 2 . A c O N a , M e O H O H O H O O

H O O H O O O O

O H O H O H O H O O M e O H O O M e s i l y b i n B i s o s i l a n d r i n B O H O H O O

H O O H O O O O

O H O H O H O H O O M e O H O O M e e n t - s i l y b i n A e n t - i s o s i l a n d r i n A Scheme 7 9 . Total synthesis of some flavonolignans .

(+) - Psiguadial B is a diformyl phloroglucinol with activity against some cancer cell line. The total synthesis reported by Reisman and co - workers accounted for 15 steps, in which the enantioselectivity is governed by the ring contraction of the starting cyclic diazoketone . 106 T hen three routes were at tempted for 2 69 the synthesis of the chromane framework and the most efficient employed an intramolecular O - arylation reaction (Scheme 80).

H C u I , 2 , 2 ' - b i p y r i d i n e H H ( 2 0 m o l % ) O H K O t - B u , O H C H O M F , 1 2 0 * C H N 2 H O O M e O O H 7 5 % M e O B r C H O H H O M e P h O H

( + ) - p s i g u a d i a l B O M e 1 . 3 % o v e r a l l y i e l d Scheme 80 . Total synthesis of (+) - p siguadial B .

(+) - G onytolide A i s a potent innate immune promoter from the fungus Gonytrichum sp . Its synthesis together with its atropisomer was achieved in five steps from a chromone ester monomer. 107 The key steps were the vinylogous addition of chromone to furan and the kinetic resolution by hydrogenation (Scheme 81). It should be n ote that the kinetic resolution of the stable ( ± ) - gonytolide C was less efficient than the kinetic resolution of the less stable butenolide, which decomposed during silica gel chromatography , but can be isolated by crystallizations.

1 ) ( i - P r ) 2 S i ( O T f ) 2 , l u t i d i n e 2 ) O C H 2 C l 2 , 0 ° C O T M S O H O O H O O H O 3 ) E t N . 3 H F H H 3 O + O O O O C O 2 M e O O 6 6 % C O M e 3 : 1 d r r a c e m i c 2 r a c e m i c C O 2 M e 5 0 % c o n v e r s i o n C u ( O A c ) 2 ( 8 m o l % ) 4 9 % , 7 8 % e e J o s i p h o s S L - J 0 0 1 - 2 ( 9 m o l % ) O H O ( a f t e r r e c r y s t a l l i z a t i o n ) ( E t O ) 3 S i H ( 5 e q u i v ) 3 8 % , 9 4 % e e T H F , 0 ° C , 2 h H O O H O O t h r e e s t e p s O H C O 2 M e O O C O 2 M e O O C O 2 M e O O H O ( + ) - g o n y t o l i d e C O + H H O O O H O O ( + ) - g o n y t o l i d e A C O 2 M e 1 2 % C O 2 M e O O O H O O H

( - ) - a t r o p - g o n y t o l i d e A 3 5 % Scheme 81 . Total synthesis of (+) - g onytolide A .

Other atropisomeric flavonoid dimer s are w ikstrol A and wikstrol B isolated from the root of Wikstroemia sikokiana . A 12 step total synthesis was described starting from 2 ′ ,4 ′ ,6 ′ - trihyd roxyacetophenone . 108 Sharpless asymmetric dihydroxylation was the asymmetric step, while the two chromane nuclei were prepared by acid - catalyzed cyclization with triethyl orthoformate and by hetero Diels - Alder cyclization (Scheme 82) . Nishimura and co - workers applied their method to the preparation of ( S ) - equol, a natural isoflavonoid found in soybeans and urine, used for the treatment of menopausal symptoms (Scheme 83 ). 61 After the addition of 4 - methoxyphenylboronic acid to 7 - methoxy - 2H - chromene the product was then deprotected affording equol. P homoarcherins are tetracyclic terpenes isolated from Phomopsis archeri , with moderate to excellent anticancer properties. A nine - steps total synthesis of ( − ) - phomoarcherin C, was described staring from the 270 chiral Wieland - Mischer ketone , in which the key step for the formation of the chromane nucleus was a 6 π - electrocyclization catalyzed by boronic acid - Bronsted acid cocatalyst (Schem e 84). 109

C H ( O E t ) 3 , P P T S ( C H 2 C l ) 2 O M O r t t o 5 0 ° C e M e O O H O M e t h e n K C O M e O O H O O H O H 2 3 M e O H r t

7 4 % O H 6 - s t e p s O M e O H O M e O H 3 0 % o v e r a l l y i e l d O H C H O 3 - s t e p s 7 3 % O - i - P r O - i - P r i - P r - O O - i - P r O M e P h P h

i - P r - O O i - P r - O O P h P h O O R h C l ( c o d ) 2 O M e C u ( O A c ) 2 . H 2 O O M e O M e O M e + O M e o - x y l e n e 1 4 0 ° C M e O O t h e n T B A F , T H F , r t M e O O M e O O O T B S O H O H O M e O M e O M e 1 6 % 1 2 % B B r 3 C H 2 C l 2 - 7 8 ° C t o - 1 0 ° C O H O H

H O O H O O

O O

O H O H O H + O H

H O O H O O

O H O H O H O H 4 8 % 5 0 % w i k s t r o l B w i k s t r o l A Scheme 82 . Total synthesis of w ikstrol A and wikstrol B .

O M e O H N H C l 1 6 0 ° C , 4 8 h

M e O O 7 2 % H O O ( s e e S c h e m e 4 5 9 2 % e e f o r p r e p a r a t i o n i n ( S ) - ( - ) - e q u o l 4 3 % y i e l d s w i t h 9 2 % e e ) Scheme 83 . Total synthesis of ( S ) - equol .

Preussochromones are isolated from the endolichenic fungus, Preussia Africana. Koert and coworkers performed a total 11 - step synthesis of ( −) - preussochromone D from the commercially available 5 - hydroxy - 4H - chromen - 4 - one . T he asymmetric alkylation was carried out in the presence of a phenylglycine derivative and afforded the product in 73% yield and 77% ee (Scheme 85). 110

1 2. Conclusion s Despite the numerous reported examples, the asymmetric synthesis of chromanes remains a challenge for organic chemists. Actually, researchers have obtained multiple stereogenic centers with excellent levels of stereocontrol. These methods ha ve been successfully applied to the synthesis of complex molecules with biological activity and in the total syntheses of natural products. This review, describing the already known 271 methods, aims to encourage scientists to explore new avenues for the synth esis of these biological important heterocycles.

O P h H O B H O O H O O C H O P h B ( O H ) 2 ( 1 e q u i v ) P h C O 2 H ( 5 0 m o l % ) H O O P h M e , 1 1 0 ° C , 1 5 h

O B n O B n O B n O W i e l a n d - M i s c h e r k e t o n e

H O H O

C H O O O H O B n O

( - ) - p h o m o a r c h e r i n C 3 0 % o v e r a l l y i e l d Scheme 8 4 . Total synthesis of ( − ) - phomoarcherin C .

B H 3 . T H F ( 2 . 4 e q u i v ) F F N - T s - a m i n o a c i d ( 1 . 2 e q u i v ) F C l C O 2 M e O H O F O O F O O F Z n ( 1 . 5 e q u i v ) C s 2 C O 3 T H F , - 7 8 ° C t o r t , 1 . 5 h

O O O

O M e

O H O H O C O 2 M e T s H N C O 2 H O H N - T s - a m i n o a c i d O H ( - ) - p r e u s s o c h r o m o n e D 4 % o v e r a l l y i e l d Scheme 85 . Total synthesis of ( −) - preussochromone D .

References and notes 1. (a) Hussain, M. I.; Syed, Q. A.; Khattak, M. N. K.; Hafez, B.; Reigosa, M. J.; El - Keblawy, A. Biologia 2019 , 74 , 863 - 888. (b). Yang, Q.; Guo, R.; Wang, J. Asian J. Org. Chem. 2019 , 8 , 1742 - 1765. (c). Devulapally, S.; Godugu, C.; Dubey, P. K. Mini - Rev. Med. Chem. 2018 , 18 , 113 - 141. 2. Meng, L.; Wang J. J. Recent Progress on Asymmetric Synthesis of Chiral Flavano nes, Chromanones, and Chromenes in Advances in Organic Synthesis Atta - ur - Rahman , Ed.; Benth am Science, Sharjah, UAE, Vol. 11, 2018 , 1 - 42 . 3 . (a) Chen, Z.; Pitchakuntla, M.; Jia, Y. Nat. Prod. Rep. 2019 , 36 , 666 - 690. (b ) Birringer, B.; Siems, K.; Maxones, A.; Frank, J.; Lorkowski, S. RSC Adv. 2018 , 8 , 4803 - 4841. 4 . (a) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2018 , 118 , 2080 - 2248. (b) Yang, B.; Gao, S. Chem. Soc. Rev. 2018 , 47 , 7926 - 7953. (c) Rullo, M.; Pisani, L. Chem. Heterocycl. Com . 2018 , 54 , 394 - 396. (d) Vetica, F.; Chauhan, P.; Dochain, S.; Enders, D. Chem. Soc. Rev. 2017 , 46 , 1661 - 1674. 5. https://ilsalvagente.it/tag/aifa / 6 . Zhang, H.; Xu, H.; Bai, H.; Wei, D.; Zhu, Y.; Zhang, W. Org. Chem. Front. 2018 , 5, 1493 - 1501. 7. Korenaga, T.; Sasaki, R.; Takemoto, T.; Yasuda, T.; Watanabe, M. Adv. Synth. Catal. 2018 , 360 , 322 - 333. 8. Jensupakarn, N.; Gleeson, M. P.; Gleeson, D.; B oonyarattanakalin, K. J. Org. Chem. 2019 , 84 , 4025 - 4032. 272

9. Wipf, P.; Weiner, W. S. J. Org. Chem. 1999 , 64 , 5321 - 5324. 10. Wang, S.; He, J.; An, Z. Chem. Commun. 2017 , 53 , 8882 - 8885. 11. In Scheme 1, eq. 1, we pictured the ( 3 S ,4 S ) - stereochemistry as reported by authors in their schemes, but in the Supplementary Material, the compound headings report ( 3 R ,4 R ) - stereochemistry. However, how the stereochemistry was obtained was not reported in either the text or the Supplementary Mater ial, therefore it is difficult to know what the correct enantiomer is. The stereochemistry of compounds of eqs. 2 and 3 were, conversely, correctly assigned as (4 R ) and ( 3 R ,4 S ) respectively. 12. Tang, C. - K.; Feng, K. - X.; Xia, A. - B.; Li, C.; Zheng, Y. - Y.; X u, Z. - Y.; Xu, D. - Q. RSC Adv. 2018 , 8 , 3095 - 3098. 13. André s, J. M.; Maestro, A.; Valle, M.; Valencia, I.; Pedrosa, R. ACS Omega 2018 , 3 , 16591 - 16600. 14. Jakkampudi, S.; Parella, R.; Zhao, J. C. - G. Org. Biomol. Chem. 2019 , 17 , 151 - 155. 15. Ruan, S.; Lin, X.; Xie, L.; Lin, L.; Feng, X.; Liu, X. Org. Chem. Front. 2018 , 5 , 32 - 35. 16. Hsieh, Y. - Y.; Raja, A.; Hong, B.C.; Kotame, P.; Chang, W. - C.; Lee, G. - H. J. Org. Chem. 2017 , 82 , 12840 - 12848. 17. Feng, J.; Li, X. J. Org. Chem. 2017 , 82 , 7317 - 732 3. 18. Shaikh, M.; Atyam, K. K.; Sahua, M.; Ranganath, K. V. S. Chem. Commun. 2017 , 53 , 6029 - 6032. We report the stereochemistry depicted in the authors’ schemes, but they did not explain how they attributed the exact configuration. 19. Gao, Q.; Xu, L. L. ; Parise, V. P.; Mehta, Y. R.; Aldrich, L. N. Synthesis 2018 , 50 , 4796 - 4808. 20. Zu, L.; Zhang, S.; Xie, X.; Wang, W. Org. Lett. 2009 , 11 , 1627 - 1630. 21. Chen, Y. - H.; Sun, X. - L.; Guan, H. - S.; Liu, Y. - K. J. Org. Chem. 2017 , 82 , 4774 - 4783. 22. Maity, R.; Pan, S. C. Org. Biomol. Chem. 2018 , 16 , 1598 - 1608. 23. Sun, H.; Li, Y.; Liu, W.; Zheng, Y.; He, Z. Chin. Chem. Lett. 2018 , 29 , 1625 - 1628. 24. Lee, Y.; Seo, S. W.; Kim, S. G. Adv. Synth. Catal. 2011 , 353 , 2671 - 2675. 25. Choi, K. S.; Kim, S. G. Eur. J. Org. Chem. 2012 , 2012 , 1119 - 1122. 26. Chen, Y. - H.; Li, D. - H.; Liu, Y. - K. ACS Omega 2018 , 3 , 16615 - 16625. 27. Mondal, B.; Pan, S. C. Adv. Synth. Catal. 2018 , 360 , 4348 - 4353. 28. You, Z. - H.; Chen, Y. - H.; Tang, Y.; Liu, Y. - K. Org. Lett. 2018 , 20 , 6682 - 6686. 29. Lv, X. - J.; Chen, Y. - H.; Liu, Y. - K. Org. Lett. 2019 , 21 , 190 - 195. 30. Chen, Y. - H.; Lv, X. - J.; You, Z. - H - ; Liu, Y. - K. Org. Chem. Front. 2019 , 6 , 3725 - 3730. 31. Chen, Y. - H.; Lv, X. - J.; You, Z. - H.; Liu, Y. - K. Org. Lett. 2019 , 21 , 5556 - 5561. 32. Wang, C.; Chen, Y. - H.; Wu, H. - C.; Wang, C.; Liu, Y. - K. Org. Lett. 2019 , 21 , 6750 - 6755. 33. Zhang, X. - Q.; Lv, X. - J.; Pei, J. - P.; Tan, R.; Liu, Y. - K. Org. Chem. Front. 2020 , 7 , 292 - 297. 34 Yu, J. - K.; Chien, H. - W.; Lin, Y. - J.; Karanam, P.; Chen, Y. - H.; Lin, W. Chem. Commun. 2018 , 54 , 9921 - 9924. 35. Yu, J. - K.; Chien, H. - W.; Lin, Y. - J.; Karanam, P.; Chen, Y. - H.; Lin, W. Chem. Commun. 2018 , 54 , 9921 - 9924. 36. Liu, W.; Zhou, P.; Lang, J.; Dong, S.; Liu, X.; Feng, X. Chem. Commun. 2019 , 55 , 4479 - 4482. 37. Yu, X. - Y.; Xiao, W. - J.; Chen, J. - R. Recent advances in catalytic asymmetric cycloaddition reactions of ortho - quinone methides for synthesis of O - heterocycles. In Targets in Heterocyclic Systems ; Attanasi, O. A.; Merino, P.; Spinelli, D. , Eds.; Italian Chermical Society : Rome, Italy, Vol. 21, 2017 , 181 - 201. 38. Shen , Y. - B.; Li , S. - S.; Wang , L.; An , X. - D.; Liu , Q.; Liu , X.; Xiao , J. Org. Lett. 2018 , 20 , 6069 - 6073. 39. Stefańska, K.; Szafraniec, A.; Szymański, M. P.; Wierzbicki, M.; Szumna, A.; Iwanek, W. New J. Chem. 2019 , 43 , 2687 - 2693. 40. Wang, Z.; Wang, T.; Yao, W.; Lu, Y. Org. Lett. 2017 , 19 , 4126 - 4129. 41. Jin, J. - H.; Li, X. - Y.; Luo, X.; Fossey, J. - S.; Deng, W. - P. J. Org. Chem. 2017 , 82 , 5424 - 5432. 42. Zhang, T.; Ma, C.; Zhou, J. - Y.; Mei, J. - J.; Shi, F. Adv. Synth. Catal. 2018 , 360 , 1128 - 1137 . 43. Cui, L.; Lv, D.; Wang, Y.; Fan, Z.; Li, Z.; Zhou, Z. J. Org. Chem. 2018 , 83 , 4221 - 4228. 44. Zhang, J.; Lin, L.; He, C.; Xiong, Q.; Liu, X.; Feng, X. Chem. Commun. 2018 , 54 , 74 - 77. 45. Zhang, J.; Liu, X.; Guo, S.; He, C.; Xiao, W.; Lin, L.; Feng, X. J. Org. Chem. 2018 , 83 , 10175 - 10185. 46 Deng, Y. - H.; Chu, W. - D.; Zhang, X. - Z.; Yan, X.; Yu, K. - Y.; Yang, L. - L.; Huang, H.; Fan, C. - A. J. Org. Chem. 2017 , 82 , 5433 - 5440. 273

47. Jeong, H. J.; Kim, D. Y. Org. Lett. 2018 , 20 , 2944 - 2947 . 48. Spanka, M.; Schneider, C. Org. Lett. 2018 , 20 , 4769 - 4772. 49. Wang, Z.; Sun, J. Org. Lett. 2017 , 19 , 2334 - 2337. 50 Gharui, C.; Singh, S.; Pan, S. C. Org. Biomol. Chem. 2017 , 15 , 7272 - 7276. 51. Wong, C. R.; Hummel, G.; Cai, Y.; Schaus, S. E.;. Panek, J. S. Org. Lett. 2019 , 21 , 32 - 35. 52. Ukis, R.; Schneider, C. J. Org. Chem. 2019 , 84 , 7175 - 7188. 53. Xie, Y.; List, B. Angew. Chem. Int. Ed. 2017 , 56 , 4936 - 4940 . 54. Yang, G. - H.; Zhao, Q.; Zhang, Z. - P.; Zheng, H. - L.; Chen, L.; Li, X. J. Org. Chem. 2019 , 84 , 7883 - 7893. 55. Zhang, Z. - P.; Xie, K. - X.; Yang, C.; Li, M.; Li, X. J. Org. Chem. 2018 , 83 , 364 - 373 56. Zhang, Z. - P.; Chen, L.; Li, X.; Cheng, J. - P. J. Org. Chem. 2018 , 83 , 2714 - 2724. 57. Jiang, X. - L.; Wu, S. - F.; Wang, J. - R.; Mei, G. - J.; Shi, F. Adv. Synth. Catal. 2018 , 360 , 4225 - 4235 . 58. Cheng, Y. - C.; Wang, C. - S.; Li, T. - Z.; Gao, F.; Jiao, Y.; Shi, F. Org. Biomol . Chem. 2019 , 17 , 6662 - 6670. 59. Ye, Z.; Bai, L.; Bai, Y.; Gan, Z.; Zhou, H.; Pan, T.; Yu, Y.; Zhou, J. Tetrahedron 2019 , 75 , 682 - 687. 60. Jiang, Z. - Z.; Gao, A.; Li, H.; Chen, D.; Ding, C. - H.; Xu, B.; Hou, X. - L. Chem. Asian J. 2017 , 12 , 3119 - 3122. 61. Umeda, M.; Sakamoto, K.; Nagai, T.; N agamoto, M.; Ebe, Y.; Nishimura, T. Chem. Commun. 2019 , 55 , 11876 - 11879. 62. Desyatkin, V. G.; Beletskaya, I. P. Synthesis 2017 , 49 , 4327 - 4334. 63. Kumar, M.; Chauhan, P.; Valkonen, A.; Rissanen, K.; Enders, D. Org. Lett. 2017 , 19 , 3025 - 3028. 64. Kumar, M.; Chauhan, P.; Bailey, S. J.; Jafari, E.; von Essen, C.; Rissanen, K.; Enders, D. Org. Lett. 2018 , 20 , 1232 - 1235. 65. Wu, X. - N.; You, Z. - H.; Liu, Y. - K. Org. Biomol. Chem. 2018 , 16 , 6507 - 6520. 66. Zhu, L.; Zhang, L.; Luo, S. Org. Lett. 2018 , 20 , 1672 - 1675 67. Kochetkov, S. V.; Kucherenko, A. S.; Zlotin, S. G. Org. Biomol. Chem. 2018 , 16 , 6423 - 6429. 68. Basumatary, G.; Mohanta, R.; Bez, G. Catal. Lett. 2019 , 149 , 2776 - 2786. 69. Sakamoto, K.; Nishimura, T. Adv. Synth. Catal. 2019 , 361 , 2124 - 2128. 70. Li, X.; Wang, C.; Song, J.; Yang, Z.; Zi, G.; Hou, G. J. Org. Chem. 2019 , 84 , 8638 - 8645. 71. In the experimental section, authors reported this sentence: “The absolute configuration of [ ( S ) - 2 - (Chroman - 3 - yl) - carboxylate] was assigned by compari son with the optical rotation of the corresponding alcohol product after oxidation reported in literature.” 72. Attarda, J. W.; Osawa, K.; Guan, Y.; Hatt, J.; Kondo, S . - i ; Mattson, A. Synthesis 2019 , 51 , 2107 - 2115. 73. Ashley, E. R.; Sherer, E. C.; Pio, B.; Orr, R. K.; Ruck, R. T. ACS Catalysis 2017 , 7 , 1446 - 1451. 74. He, B.; Phansavath, P.; Ratovelomanana - Vidal, V. Org. Lett. 2019 , 21 , 3276 - 3280. 75. Gavin, D. P.; Foley, A.; Moody, T. S.; Khandavilli, U. B. R.; Lawrence, S. E.; O’Neill, P.; Maguire, A. R. Tetrahedron: Asymmetry 2017 , 28 , 577 - 585. 76. Zhang, Y.; Wang, Q.; Wang, T.: He, H.; Yang, W.; Zhang, X.; Cai, Q. J. Org. Chem. 2017 , 82 , 1458 - 1463. 77. Cai, J.; Wang, Z. - K.; Usman, M.; Lu, Z. - W.; Hu, X. - D.; Liu, W. - B. Org. Lett. 2019 , 21 , 8852 - 8856. 78. Naganawa, Y.; Ito, J. - i.; Kawagishi, M.; Nishiyama, H. Synthesis 2017 , 49 , 4448 - 4460. 79. Usui, K.; Yamamoto, K.; Ueno, Y.; Igawa, K.; Hagihara, R.; M asuda, T.; Ojida, A.; Karasawa, S.; Tomooka, K.; Hirai, G.; Suemune, H. Chem. Eur. J. 2018 , 24 , 14617 - 14621. 80. Bhattacharya, A .; Shukla, P. M .; Kaushika, L. K.; Maji, B. Org. Chem. Front. 2019 , 6 , 3523 - 3529. 81. Li, G. - T.; Li, Z. - K.; Gu, Q.; You, S. - L. Org. Lett. 2017 , 19 , 1318 - 1321. 82. Hao, X.; Lin, L.; Tan, F.; Ge, S.; Liu, X.; Feng, X. Org. Chem. Front. 2017 , 4 , 1647 - 1650. 83. Ren, H.; Song, X. - Y. ;. Wang, S. R.; Wang, L.; Tang, Y. Org. Lett. 2018 , 20 , 3858 - 3861. 84. Zhang, H.; Luo, Y.; Li, D.; Yao, Q.; Dong, S.; Liu, X.; Feng, X. Org. Lett. 2019 , 21 , 2388 - 2392. 85. André s, J. M.; Maestro, A.; Valle, M.; Pedrosa, R. J. Org. Chem. 2018 , 83 , 5546 - 5557. 86. Martzel, T.; Annibaletto, J.; Levacher, V.; Brière, J. - F.; Oudey er, S. Adv. Synth. Catal. 2019 , 361 , 995 - 1000. 87. Xiong, D.; Zhou, W.; Lu, Z.; Zeng, S.; Wang, J. Chem. Commun. 2017 , 53 , 6844 - 6847. 274

88. Ma, Y.; Li, J.; Ye, J.; Liu, D.; Zhang, W. Chem. Commun. 2018 , 54 , 13571 - 13574. 89. Qiao, L.; Duan, Z. - W.; Wu, X. - N.; L i, D. - H.; Gu, Q. - Q.; Liu, Y. - K. Org. Lett. 2018 , 20 , 1630 - 1633. 90. Wu, S.; Zhu, G.; Wei, S.; Chen, H.; Qu, J.; Wang, B. Org. Biomol. Chem. 2018 , 16 , 807 - 815. 91. Zuo, X.; Liu, X. - L.; Wang, J. - X.; Yao, Y. - M.; Zhou, Y. - Y.; Wei, Q. - D.; Gong, Y.; Zhou, Y. J. Org. Chem. 2019 , 84 , 6679 - 6688. 92. Liu, X. - L.; Gong, Y.; Chen, S.; Zuo, X.; Yao, Z.; Zhou, Y. Org. Chem. Front. 2019 , 6 , 1603 - 1607. 93. (a) Albrecht, Ł.; Cruz Acosta, F.; Fraile, A.; Albrecht, A.; Christensen, J.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2012 , 51 , 9088 - 9092 ; (b) Danda, A.; Kesava - Reddy, N.; Golz, C.; Strohmann, C.; Kumar, K. Org. Lett. 2016 , 18 , 2632 - 2635. 94. Jin, H.; Lee, J.; Shi, H.; Lee, J. Y.; Yoo, E. J.; Song, C. E.; Ryu, D. H. Org. Lett. 2018 , 20 , 1584 - 1588. 95. Nayak, S.; Panda, P.; Raiguru, B. P.; Mohapatra, S.; Purohit, C. S. Org. Biomol. Chem. 2019 , 17 , 74 - 82. 96. Lv, X. - J.; Zhao, W. - W.; Chen, Y. - H.; Wan, S. - B.; Kai Liu, Y. - K. Org. Chem. Front. 2019 , 6 , 1972 - 1976. 97. (a) Speranza, G.; Morelli, C. F.; Manitto, P. Synthesis 2000 , 2000 , 123 - 126. (b) Chen, J. H.; Chang, C.; Chang, H. J.; Chen, K. Org. Biomol. Chem. 2011 , 9 , 7510 - 7516. (c) Saha, S.; Schneider, C. Chem. Eur. J. 2015 , 21 , 2348 - 2352. (d) Chen, R.; Cui, S. Org. Lett. 2017 , 19 , 4002 - 4005. (e) Pouramiri, B.; Kermani, E. T.; Khaleghi, M. J. Iran. Chem. Soc. 2017 , 14 , 2331 - 2337. 98. Li, S.; Yao, Y.; Tang, Z.; Sun, B.; Yu, C.; Li, T.; Yao, C. Org. Biomol. Chem. 2019 , 17 , 268 - 274. 99. Xu, H.; Laraia, L.; Schneider, L.; Louven, K.; Strohmann, C.; Antonchick, A. P.; Waldmann, H.; Angew. Chem. Int. Ed. 2017 , 56 , 11232 - 11236. 100. Kayal, S.; Mukherjee, S. Org. Lett. 2017 , 19 , 4944 - 4947 101. Kowalczyk, D.; Albrecht, L. Adv. Synth. Catal. 2018 , 360 , 406 - 410. 102. Shi, C. - Y.; Xiao, J. - Z.; Yin, L. Chem. Commun. 2018 , 54 , 11957 - 11960 103. Wang, J.; Zhang, S.; Ding, W.; Wang, C.; Chen, J.; Cao, W.; Wu, X. ChemCatChem 2020 , 12 , 444 - 448. 104. Feng, Z. - G.; Burnett, G. L.; Pettus, T. R. R. Synlett 2018 , 29 , 1517 - 1519. 105. Pilkington, L. I.; Wagoner, J.; Kline, T.; Polyak, S. J.; Barker, D. J. Nat. Prod. 2018 , 81 , 2630 - 2637. 106. Chapman, L. M.; Beck, J. C.; Lacker, C. R.; Wu, L.; Reisman, S. E. J. Org. Chem. 2018 , 83 , 6066 - 6085. 107. Wu, X ; Iwata, T.; Scharf, A.; Qin, T.; Reichl, K. D.; Porco, Jr., J. A. J. Am. Chem. Soc. 2018 , 140 , 5969 - 5975. 108 . Lu, K.; Li, M.; Huang, Y.; Sun, Y.; Gong, Z.; Wei, Q.; Zhao, X.; Zhang, Y.; Yu, P. Org. Biomol. Chem. 2019 , 17 , 8206 - 8213. 109 . Dethe, D. H.: Vi jayKumar, B. J. Org. Chem. 2019 , 84 , 14053 - 14060. 110 . Kerste, E.; Harms, K.; Koert, U. Org. Lett. 2019 , 21 , 4374 - 4377.