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Synthesis 2009(11): 1761-1785  
DOI: 10.1055/s-0029-1216818
REVIEW
© Georg Thieme Verlag Stuttgart ˙ New York

Transition-Metal-Catalyzed Enantioselective Synthesis of Compounds with Non-Centrochirality

Masamichi Ogasawara*, Susumu Watanabe
Catalysis Research Center and Graduate School of Life Science, Hokkaido University, Kita-ku, Sapporo 001-0021, Japan
Fax: +81(11)7069150; e-Mail: ogasawar@cat.hokudai.ac.jp;

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Publication History

Received 10 March 2009
Publication Date:
14 May 2009 (online)

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Transition-Metal-Catalyzed Enantioselective Synthesis of Compounds with Non-CentrochiralitySynthesis 2009; 2009(18): 3177-3178
DOI: 10.1055/s-0029-1216988

Biographical Sketches

Masamichi Ogasawara was born in Funabashi City, Japan, in 1966. He obtained a bachelor’s degree from the University of Tokyo in 1989, and his Ph.D. from the same institute in 1994 under the supervision of Professor Masahiko Saburi. He then spent three years as a postdoctoral researcher in two research groups, firstly with Professor Kenneth G. Caulton at Indiana University (Bloomington, IN, USA) from 1994 to 1996, then with Professor Tobin J. Marks at Northwestern University (Evanston, IL, USA) from 1996 to 1997. In 1997, he was appointed as an Assistant Professor at Department of Chemistry, Kyoto University. Since 2002, he has been an Associate Professor at the Catalysis Research Center at Hokkaido University. He was a recipient of the Daicel Award in Synthetic Organic Chemistry in 2003 and the Incentive Award in Synthetic Organic Chemistry, Japan in 2006. His research interests lie in the development of transition-metal-catalyzed reactions for enantioselective organic synthesis and organometallic chemistry of phosphole derivatives.
Susumu Watanabe was born in Osaka­, Japan, in 1981. He graduated from Kyoto Pharmaceutical University in 2005 before joining the Catalysis Research Center, Hokkaido University in the same year as a graduate student. He obtained a master’s degree in Pharmacy from Hokkaido University in 2007, and is now in a Ph.D. course at the same institute. He has been a Research Fellow of the Japan­ Society for the Promotion of Science since 2009. His Ph.D. studies with Professor Masamichi Ogasawara and Professor Tamotsu Takahashi are focused on the development of catalytic enantioselective synthetic methods towards planar-chiral metallocenes and their applications as chiral ligands and catalysts.

Abstract

Although central chirality based on stereogenic carbon atoms is arguably the most common chiral element in organic chemistry, chiral molecules devoid of stereogenic centers play important roles in stereoselective organic transformations. In spite of the usefulness of these chiral compounds with ‘non-centrochirality’ in asymmetric synthesis, enantiomerically enriched forms (scalemic forms) of these compounds are primarily obtained by rather classical methods. Examples of catalytic enantioselective induction of such non-centrochirality have been extremely rare and this is thus still a developing area in synthetic organic chemistry. In this review article, transition-metal-catalyzed enantioselective preparations of various non-centrochiral compounds, which include compounds with planar, axial, or helical chirality, are surveyed.

1 Introduction

2 Planar Chirality in Organometallic and Organic Compounds

3 Axial Chirality in Allenes

4 Atropisomeric Axial Chirality in Biaryls

5 Atropisomeric Axial Chirality about Carbon-Nitrogen or Carbon-Carbon Single Bonds in Nonbiaryl Systems

6 Axial Chirality in Spiro Compounds

7 Helical Chirality in ortho-Fused Polycyclic Aromatic Compounds

8 Conclusions

Key words

catalytic asymmetric synthesis - enantioselective reaction - transition-metal catalyst - homogeneous catalysis - non-centrochirality

1 Introduction

In modern organic chemistry, it has been a great challenge for synthetic chemists to control various stereochemical issues in complex organic molecules. Particularly, the development of novel enantioselective transformations has been one of the most active research fields in synthetic organic chemistry, and transition-metal-catalyzed asymmetric reactions have played pivotal roles in terms of atom economy and synthetic efficiency. Most of the metal-catalyzed asymmetric reactions reported so far are those that induce ‘centrochirality’ on stereogenic tertiary or quaternary carbon atoms. This is attributed to the fact that carbon centrochirality is the most common chiral phenomenon in organic molecules, occurring in various natural products as well as in pharmaceutically or biologically active compounds.

Figure 1 Representative examples of useful chiral compounds with non-centrochirality: planar-chiral ferrocenyl phosphines 1 and 2, and axially chiral biaryl-based phosphines 3 and 4

On the other hand, compounds with ‘non-centrochirality’ [¹] , which include compounds with planar, axial, or helical chirality, have made significant contributions to asymmetric synthesis. Notable examples can be seen in the development of chiral phosphines, which are a class of compounds frequently used as chiral ligands in asymmetric transition-metal catalysts and are arguably the chiral auxiliaries most extensively studied. Two series of the most successful chiral phosphine ligands to date are ferrocenyl phosphines [²] such as bppfa [³] (1) and Josiphos [4] (2), and biaryl-based phosphines such as binap [5] (3) and MeO-mop6 (4). In the former compounds, metallocene-based planar chirality is the dominant chiral element (though these compounds possess stereogenic chiral carbons in their side arms), and the latter compounds are axially chiral atropisomers. In spite of the usefulness of chiral compounds with non-centrochirality in asymmetric synthesis, enantiomerically enriched forms of these compounds (or their precursors) are primarily obtained either by resolution of the racemates or stoichiometric derivatization from the appropriate enantiomerically enriched precursors. Examples of catalytic enantioselective induction of such non-centrochirality have been extremely rare and this is thus still a developing area in synthetic organic chemistry.

In this review article, transition-metal-catalyzed enantio­selective preparation of various non-centrochiral compounds (Figure  [²] ) are surveyed. This article covers enantioselective reactions with substoichiometric chiral transition-metal catalysts, and thus diastereomeric induction of non-centrochirality or chirality transfer from other stoichiometric chiral sources is excluded. In addition, asymmetric reactions with nonmetal catalysts (such as organocatalysts) are beyond the scope of this article.

Figure 2 Representative examples of non-centrochiral compounds

2 Planar Chirality in Organometallic and Organic­ Compounds

Even a chemical species with planar (flat) shape by nature, such as an arene or a cyclopentadienyl anion, can be chiral by concomitant differentiation of its top face from its bottom face and of its left-hand side from its right-hand side (Figure  [³] ). Chirality based on these circumstances is generally referred to as ‘planar chirality’. Differentiation of the left-hand and right-hand sides of the species can be realized by unsymmetrical introduction of appropriate substituents. Discrimination of the two faces, on the other hand, needs a rather non-classical modification. One way is π-complexation of a transition-metal fragment onto one face of the planar species. This situation can be seen, for example, in (η6-arene)CrL3 complexes or (η5-cyclopentadienyl)metal species (metallocenes, half-metallocenes). Another approach to discriminating the two faces of an arene molecule can be seen in a sterically congested cyclophane, in which dynamic motion of the bridging moiety is restricted. Indeed, transition-metal-catalyzed asymmetric synthesis of these planar-chiral molecules has been developed.

Figure 3 Examples of planar-chiral molecules

2.1 Synthesis of Planar-Chiral Chromium(0)-(η 6 -arene) Complexes by Palladium-Catalyzed Cross-Coupling

The palladium-catalyzed asymmetric synthesis of planar-chiral chromium(0)-arene complexes was reported by Uemura and Hayashi in 1993 (Scheme  [¹] ). [7] The enantioposition-selective cross-coupling of planar-prochiral tricarbonyl(η6-o-dichlorobenzene)chromium(0) (5) with various alkenyl- or arylmetal nucleophiles proceeded with moderate enantioselectivity in the presence of 10 mol% of a palladium catalyst, Pd/(S)-(R)-ppfa, generated in situ from [PdCl(η³-C3H5)]2 and the ferrocenylmonophosphine. An enantioposition-selective substitution took place at one of the two chloro substituents to give planar-chiral monosubstitution products 6 together with a minor amount of the achiral disubstitution products 7. The highest enantiomeric excess of monosubstitution product was 69% ee, and was achieved for the phenylation of 5 with phenylboronic acid, giving (1S,2R)-6a. Alkenylation with ethenylboronic acid or propen-2-ylboronic acid also proceeded enantioselectively to give the corresponding monoalkenylation product 6b in 38% ee and 6c in 44% ee, respectively. Interestingly, the use of ethenyltributyltin as a vinylation reagent in place of the vinylboronic acid resulted in the formation of nearly racemic product 6b while vinylzinc chloride gave 6b of 42% ee.

Scheme 1

2.2 Synthesis of Planar-Chiral Ferrocenes by Copper-Catalyzed Intramolecular C-H Insertion­ of Carbenoids

In 1997, Schmalz and Siegel described the enantioselective synthesis of planar-chiral ferrocenes 9 by copper-catalyzed intramolecular C-H insertion of diazoketone-tethered ferrocenes 8 (Scheme  [²] ). [8] The reaction took place smoothly in the presence of a copper(I) catalyst (5 mol%) coordinated with the bisoxazoline ligand (S,S)-Ph-box. The C-H insertion proceeded onto the same cyclopentadienyl moiety exclusively and no interannular bridging species were detected. The highest enantioselectivity of 78% ee was achieved in the cyclohexanone-fused ferrocene 9a (72% yield), while 9b was obtained in 62% ee (89%).

Scheme 2

2.3 Kinetic Resolution of Racemic Planar-Chiral Ferrocenes by Molybdenum- or Ruthenium-Catalyzed Asymmetric Metathesis

Kinetic resolution of racemic planar-chiral ferrocenes was developed by Ogasawara and Takahashi in 2006. [9] Interannular ring-closing metathesis of 1,1′-diallylferrocene derivatives took place enantioselectively in the presence of the (R)-Mo* or (S,S)-Ru* catalyst. The C 1-symmetric substrates, rac-10, possess an unsymmetrically substituted η5-(C5H2-1-allyl-2,4-R¹ 2) and a monosubstituted η5-cyclopentadienyl ring with an allylic side chain (Scheme  [³] ). [9] The selectivity in the asymmetric ring-closing metathesis (ARCM) kinetic resolution was strongly dependent on the allylic group in the monosubstituted cyclopentadienyl moiety. When 10a was treated with the (R)-Mo*-catalyst (5 mol%) for 15 minutes in benzene at 23 ˚C, the corresponding ferrocenophane 11a was obtained in 73% yield and the unreacted 10a was recovered in 26%. However, the selectivity of the reaction was very low (k rel = 1.03). The enantioselectivity was dramatically improved by introducing a η5-(C5H4-methallyl) moiety in 10. The ARCM reaction of 10b at 23 ˚C (initial concentration of 10b = 0.1 mol/L) proceeded with excellent enantioselectivity. The bridged ferrocene 11b was obtained in >99.5% ee in 23% yield and 10b was recovered in 30% yield with 78% ee. The k rel value for this reaction was >500. Unfortunately, however, 47% of the substrate was converted into the dimer 12b. The dimerization was minimized under dilute conditions. The reaction of 10b at 50 ˚C with initial concentration of 0.005 mol/L afforded 11b of 96% ee in 46% yield and the unreacted 10b of 95% ee was recovered in 47% yield (k rel = 183). Similarly high levels of enantioselectivity and reaction efficiency were observed for the kinetic resolution of 10c (k rel = 26) and 10d (k rel = 165) with the (R)-Mo* catalyst.

The chiral ruthenium catalyst (S,S)-Ru* was also effective for the kinetic resolution of 10b, but was much less enantioselective than (R)-Mo* (k rel = 5.9 at 23 ˚C).

Scheme 3

Scheme 4

The chemical separation of the three stereoisomers in 13, namely (R,R)-13, (S,S)-13, and (R,S)-13 (meso-13), was also possible (Scheme  [4] ).9b The (R)-Mo* catalyst (5 mol%) preferentially cyclized (R,R)-13 in benzene at 60 ˚C and the bridged ferrocene (R,R)-14 of 64% ee was obtained in 24% yield. From the reaction mixture, (R,R)-14 and the unreacted 13 were easily separated by preparative GPC. The separated isomeric mixture of 13, which contained mainly (S,S)-13 and meso-13, was treated with the first-generation Grubbs catalyst (3 mol%), and (S,S)-13 was selectively cyclized to give (S,S)-14 of 60% ee in 25% yield and the unreacted meso-13 was recovered in 41% as a single isomer. The k rel value for the first step in Scheme  [4] was 8.2.

2.4 Kinetic Resolution of Racemic Planar-Chiral Ferrocenes by Sharpless Asymmetric Dihydroxylation

Kinetic resolution of various racemic planar-chiral 2-substituted vinylferrocene 15 was achieved by the osmium-catalyzed Sharpless asymmetric dihydroxylation (Scheme  [5] ). [¹0] The enantioselectivity factors, k rel values, were as high as 62.3. The (DHQD)2PYR ligand was more selective for 15 than (DHQ)2PYR. The general trend showed that the vinylferrocenes 15 with the bulkier 2-substituents were better as substrates for the kinetic resolution than those having less bulky substrates. The (DHQD)2PYR/Os catalyst reacted preferentially with the (R)-15, leading to (R p,S c)-16 and to unreacted (S)-15, while the (DHQ)2PYR/Os species showed the opposite stereoselectivity. The dihydroxylation products 16 were always isolated in high diastereoselectivity (>90% de).

Scheme 5

2.5 Rhodium-Catalyzed 1,4-Addition of Phenylboronic Acid to Ferrocobenzoquinone

A rhodium complex coordinated with the chiral diene (R,R)-Bn-bod* showed effective facial discrimination in the 1,4-addition reaction of ferrocobenzoquinone (17) with phenylboronic acid (Scheme  [6] ). [¹¹] Thus, phenylation took place at the opposite side of iron of the ferrocene core, effectively creating a carbon central chirality in R-configuration and a ferrocene planar chirality in R p-configuration at the same time to give 18 in 96% ee.

Scheme 6

2.6 Synthesis of Planar-Chiral Metacyclophanes by Rhodium-Catalyzed Alkyne Cyclotrimerization

The intramolecular [2+2+2] cyclotrimerization of triynes 19 proceeded with a cationic rhodium catalyst (5 mol%) coordinated with (R)-H8-binap to give a mixture of metacyclophanes 20 and achiral 21. Although the yields remained modest, the enantioselectivity of the reaction in 20 was very high and the various planar-chiral metacyclophanes were obtained in better than 93% ee (Scheme  [7] ). [¹²]

Scheme 7

The rhodium-catalyzed reaction was extended to an intermolecular process between diyne 22 and an alkyne 23 to give an analogous planar-chiral metacyclophane 24 of 92% ee in 15% yield together with 5% of an achiral paracyclophane 25 (Scheme  [8] ). [¹²]

2.7 Rhodium-Catalyzed Synthesis of Planar-Chiral Dithiaparacyclophanes

Scheme 8

A catalytic enantioselective synthesis of planar-chiral dithiaparacyclophanes 28 from dithiols 26 and 1,4-bis(bromomethyl)benzenes 27 was developed by Tanaka and co-workers in 2007. [¹³] The dehydrobrominative sulfur-carbon bond-formation reactions were catalyzed by a cationic rhodium(I) species coordinated with (S)-binaphane, and moderate enantioselectivity of up to 60% ee was achieved in 28 (Scheme  [9] ).

Scheme 9

3 Axial Chirality in Allenes

The two cumulated carbon-carbon double bonds in an allenic unit are perpendicular to each other, and the four atoms/substituents in the allenic framework are arranged in an elongated tetrahedral fashion. Thus, a substituted allene becomes chiral if R¹ ¹ R² and R³ ¹ R4 (Figure  [4] ). Whereas the rotation barrier of the allenic C=C=C axis is generally high (about 46 kcal/mol for 1,3-dialkylallenes), [¹4] enantiomeric pairs of axially chiral allenes can be separable as persistent isomers under usual conditions. The possible existence of two enantiomeric forms in a properly substituted allene was predicted by van’t Hoff as early as 1875. [¹5] Experimental confirmation of van’t Hoff’s prediction was realized sixty years later by two independent research groups. [¹6]

Figure 4 Enantiomeric pair of axially chiral allenes

3.1 Palladium-Catalyzed Cross-Coupling of Metalated Terminal Allenes

The first example of transition-metal-catalyzed enantioselective synthesis of axially chiral allenes was reported by Elsevier and co-workers in 1989 (Scheme  [¹0] ). [¹7] Lithiation of 4,4-dimethylpenta-1,2-diene (29) took place highly regioselectively at the terminal position, and various metalated allenes 30 were generated in situ from the lithiated species by metal-exchange with the appropriate metal salt. The metalated allenes 30 underwent the cross-coupling reaction with iodobenzene in the presence of a palladium species coordinated with a chiral ligand to give an axially chiral allene 31 with modest enantioselectivity. Among the chiral ligands examined, the bidentate bisphos­phine (R,R)-diop showed the highest enantioselectivity for the reaction with the chlorozinc nucleophile ([M] = ZnCl in 30) giving (S)-31 of 26% ee. For the reactions with the chloromagnesium ([M] = MgCl) or the copper ([M] = Cu) nucleophile, a reversal of the configuration in the allenic product was observed, and (R)-(-)-31 of low enantiopurity (3-10% ee) was obtained, despite the use of the same Pd/(R,R)-diop catalyst. Although the metalated allenes 30 are axially chiral in principle, the two enantiomers are in rapid equilibrium. Thus, enantioselective substitution was realized (dynamic kinetic resolution).

Scheme 10

3.2 Palladium-Catalyzed Formal S N 2 ′ Substitution of 2-Bromo-1,3-dienes

In 2000, Ogasawara and Hayashi reported that a formal SN2′ substitution of the easily accessible 2-bromobuta-1,3-diene derivatives 32 with an appropriate soft nucleophile 33 took place in the presence of a catalytic Pd/bisphosphine complex. [¹8] While the diene substrates 32 are achiral, the allenic products 34 can be axially chiral with the proper substitution. Consequently, this reaction is an ideal prototype for catalytic asymmetric synthesis of axially chiral allenes (Scheme  [¹¹] ). Indeed, highly enantioselective preparation of various such allenic compounds 34 was achieved in up to 89% ee (for 34an) with the use of a Pd/(R)-binap catalyst. The presence of catalytic dibenzalacetone (dba) played a vital role in achieving the high enantioselectivity of the asymmetric reaction. [¹9a] For the reaction between 32a and 33m, the enantioselectivity was only 11% ee without dba and 68% ee with dba.

Scheme 11

In the palladium-catalyzed asymmetric reaction between 32 and 33 giving the axially chiral allenes 34, atropisomeric biaryl-based chiral bisphosphines showed good enantioselectivity. It was found that tms-binap [¹9b] and segphos [¹9c] [d] performed better than binap. A comparative example between the three chiral ligands is shown in Scheme  [¹²] for the reaction of 32c with 33n.

Scheme 12

A palladium-catalyzed asymmetric SN2′ substitution was utilized for the formal total synthesis of a naturally occurring axially chiral allene, methyl (R,E)-tetradeca-2,4,5-trienoate [(R)-35], a sex attractant of the male dried bean beetle (Scheme  [¹³] ). [¹9d] The unique axial chirality in the pheromone was induced by the palladium-catalyzed asymmetric reaction, and the synthetic pheromone was obtained in 76% ee.

Scheme 13

As in the case of bromodienes 32, the 1,3-dien-2-yl triflates 36, which are easily prepared from the corresponding alkenyl ketones, were reactive substrates for the palladium-catalyzed reactions producing a variety of functionalized allenes in high yields. In the asymmetric reactions catalyzed by Pd/(R)-tms-binap, however, the allenic product from 36 showed lower enantiomeric purity than that from 32 (Scheme  [¹4] ). [¹9b] [²0]

Scheme 14

The axially chiral (allenylmethyl)silanes 38 were prepared from (3-bromopenta-2,4-dienyl)trimethylsilane (37) by the palladium-catalyzed asymmetric reaction with 33 in up to 88% ee. The obtained (allenylmethyl)silanes functioned as chiral synthons, transferring their axial chirality into newly generated stereogenic centers in the 1,3-dienyl products 40 by the desilylative SE2′ reaction with appropriate electrophiles (Scheme  [¹5] ). [¹9c] The 1,3-dienyl products 40 had, exclusively, an E-geometry. The efficiency of the axial-to-central chirality transfer in the SE2′ reaction was highly dependent on the steric characteristics of the proelectrophiles 39. The reaction of (R)-38 (87% ee) with an electrophile generated from pivalaldehyde dimethyl acetal (39a) and titanium(IV) chloride gave 90% yield of 40a, the S-isomer, with 74% ee (85% chirality transfer). In contrast, an analogous reaction between (R)-38 (87% ee) and 39b afforded the 1,3-diene 40b, and with only 30% ee (35% chirality transfer).

Scheme 15

The reaction of (E)-2-bromo-3-exo-methylenecyclononene (41) with 33m proceeded in the presence of the Pd/(R)-segphos catalyst (2 mol%) to give the axially chiral endocyclic allene (R)-42 in moderate enantioselectivity of 65% ee (93% yield). Subsequent [2+2] cycloaddition of the enantiomerically enriched (R)-42 with dichloroketene afforded (R)-(-)-43 of 64% ee in 60% yield. The chirality transfer of the reaction was estimated to be >98% (Scheme  [¹6] ). The cycloaddition product 43 was obtained as a single isomer. The stereoselectivity of this transformation indicates that the cyclic structure in 42 directed the reacting ketene from the unencumbered face. [²¹]

Scheme 16

3.3 Palladium-Catalyzed S N 2 ′′ Substitution of 2-Bromo-1,3,5-trienes

The reaction of 5-bromo-7,7-dimethylocta-1,3,5-triene (44) with 33n and sodium tert-butoxide was catalyzed by a palladium species generated from Pd(dba)2 and (R)-segphos to give the conjugated vinylallene 45 selectively. The reaction was a formal SN2′′ process and proceeded via (alkylidene-π-allyl)palladium intermediate 46 and (allenyl-π-allyl)palladium intermediate 47. A dynamic process involving the two palladium intermediates played an important role in determining the selectivity of the palladium-catalyzed reaction, and the vinylallene 45 formed as the sole organic product in the reaction shown in Scheme  [¹7] . Under the reaction conditions given, the axially chiral vinylallene (R)-45 of 81% ee was obtained in 56% yield starting with the achiral substrate 44. [²²]

Scheme 17

3.4 Rhodium- or Nickel-Catalyzed Double Hydrosilylation of Conjugated Diynes

Catalytic asymmetric synthesis of axially chiral allenes was achieved by double hydrosilylation of buta-1,3-diynes 48 with dimethyl(phenyl)silane (49) using a chiral rhodium species generated in situ from [Rh(cod)Cl]2 and (2S,4S)-(-)-PPM (PPM = 4-(diphenylphosphanyl)-2-[(diphenylphosphanyl)methyl]pyrrolidine). It was found that presence of a small amount of triethylamine increased the enantioselectivity. Under the optimized conditions, the highest ee value observed in the asymmetric reaction was 27%. However, the chemical yield of the axially chiral allene 50 was only 30%, and the undesired single hydrosilylation product 51 was obtained in 54% yield (Scheme  [¹8] ). The enyne 51 was not an intermediate of the double hydrosilylation, ascertained by treatment of 51 with 49 under the same reaction conditions, which did not yield 50. [²³]

For an analogous reaction between 1,4-bis(trimethylsilyl)butadiyne and diphenylsilane, NiCl2[(-)-diop] provided the corresponding axially chiral allene in 11% ee, albeit in low yield (11%). [²³b]

Scheme 18

Scheme 19

3.5 Palladium-Catalyzed 1,4-Hydrosilylation of Conjugated Enynes

In 2001, the palladium-catalyzed asymmetric hydrosilylation of 4-substituted but-1-en-3-ynes 52 with trichlorosilane (53) was reported by Hayashi and co-workers. [²4a] A bulky, monodentate chiral phosphine, (S,R)-bisPPFOMe, was effective for the asymmetric synthesis of the axially chiral allenylsilanes (S)-54, and up to 90% enantioselectivity was achieved (Scheme  [¹9] ). The hydrosilylation of 52 is proposed to proceed through a catalytic cycle involving hydropalladation of the double bond in 52, forming a π-propargyl(silyl)palladium intermediate 55. The bulky substituent at the 4-position in 52 was essential for retarding the hydropalladation at the alkyne moiety. Indeed, the reaction of n-C6H13C≡CCH=CH2 gave a complex mixture of the hydrosilylation products containing less than 20% of the allenylsilane. More recently, Ogasawara and Hayashi­ applied a monodentate chiral phosphaferrocene, (R,R)-PhosFe*, in the same asymmetric reaction. It performed much better than (S,R)-bisPPFOMe, giving (R)-54a in higher yield (82%) with better enantioselectivity (92% ee). The sterically demanding η5-C5Me5 moiety in (R,R)-PhosFe* was important for the high performance of the chiral ligand. The use of an analogous phosphaferrocene with η5-C5H5 gave (R)-54a of 41% ee in 57% yield. [²4b] The allenyl(trichloro)silanes 54 obtained were allowed to react with benzaldehyde to give the corresponding homopropargyl alcohols, thereby transferring their axial chirality into newly formed stereogenic centers.

3.6 Palladium-Catalyzed 1,4-Hydroboration of Conjugated Enynes

The palladium-catalyzed asymmetric hydroboration of conjugated enynes 56 with catecholborane (57) was reported in 1993. [²5] A chiral monodentate phosphine (S)-MeO-mop was used as a chiral ligand in the palladium catalyst, and the axially chiral allenylboranes 58 were obtained in up to 61% ee (Scheme  [²0] ). The enantioselectivity of the asymmetric hydroboration was estimated from the enantiopurity of homopropargyl alcohols, which were obtained from the axially chiral allenylboranes and benz­aldehyde via an SE2′ pathway.

Scheme 20

3.7 Rhodium-Catalyzed 1,6-Addition of Aryl­titanates to Conjugated Ynenones

The addition of aryltitanate reagents Li˙ArTi(Oi-Pr)4 60 to 3-alkynyl-2-en-1-ones 59 in the presence of trimethylsilyl chloride and a catalytic Rh(I)/(R)-segphos complex proceeded in a 1,6-addition fashion to give a high yield of axially chiral allenylalkenyl silyl enol ethers 61 with up to 93% ee (Scheme  [²¹] ). [²6] Because the silyl enol ethers 61 were not stable enough for chiral HPLC analyses, they were converted into the corresponding pivalate esters 62 by successive treatment with methyl lithium and pivaloyl chloride. The use of 60 and trimethylsilyl chloride at the same time was important for the present reaction, and no 1,6-addition products were detected without trimethylsilyl chloride being used. Because the spontaneous noncatalyzed 1,6-addition process (even though this was slow) was competing with the rhodium-catalyzed process, the use of a relatively large amount (˜10 mol%) of the catalyst resulted in a slightly higher enantioselectivity. The 1,6-addition was considered to proceed through an initial insertion of the carbon-carbon triple bond in 59 into the rhodium-arene bond giving 63, which isomerizes into the thermodynamically more stable oxa-π-allylrhodium intermediate 64. At this isomerization, the stereochemical outcome­ of the asymmetric 1,6-addition should be determined. The final step is the silylation and transmetalation of 64, giving 61 and regeneration of the aryl-rhodium intermediate.

Scheme 21

3.8 Kinetic Resolution of Racemic (Allenyl)methanol by Titanium-Catalyzed Oxidation

A single example of the titanium-catalyzed kinetic resolution of a racemic allenic alcohol was described briefly in 1983. [²7] Oxidation of the racemic 65 under the well-known Sharpless oxidation conditions, namely with titanium(IV) isopropoxide, (+)-diisopropyl tartrate [(+)-DIPT], and tert-butyl hydroperoxide, provided optically active (S)-(+)-65 of 40% ee; however, the relative reaction rate between the two enantiomers of 65 was not very large (Scheme  [²²] ).

Scheme 22

3.9 Kinetic Resolution of Racemic Arylallenes by Manganese-Catalyzed Oxidation

In 1998, Katsuki and co-workers demonstrated the kinetic resolution of racemic allenes 66 by way of enantiomer-differentiating manganese-catalyzed oxidation (Scheme  [²³] ). [²8] Treatment of rac-66 with 1 equivalent of iodosylbenzene (PhIO) and 2 mol% of the Mn-salen* complex in the presence of 4-phenylpyridine N-oxide resulted in partial asymmetric oxidation, which led to the recovery of enantioenriched allenes (S)-66. The relative reaction rates between the two enantiomeric allenes reached as high as 23 in 66c.

Scheme 23

3.10 Palladium-Catalyzed Dynamic Kinetic Resolution of Racemic Allenylmethyl Esters

The preparation of optically active (allenylmethyl)malonate derivatives (R)-69 by a palladium-catalyzed asymmetric alkylation of racemic allenylmethyl phosphates 67 with an appropriate malonate-derived pronucleophile 68 was reported by Imada, Murahashi, and co-workers in 2002 (Scheme  [²4] ). [²9a] Owing to the dynamic process (epimerization) of a palladium intermediate, effective asymmetric induction becomes possible even with more than 50% conversion of the substrates (dynamic kinetic resolution in a broader sense). By the use of (R)-MeO-biphep as a chiral ligand and N,O-bis(trimethylsilyl)acet­amide (BSA) as a base, the highest enantioselectivity of 90% ee was achieved for the reaction between 67d and 68m.

Scheme 24

The same authors reported that a variety of nitrogen nucleophiles, such as secondary amines (70m,n) hydroxyl­amine (70o), imides (70p,q), and sulfonamide (70r), could be applied to the preparation of axially chiral (allenylmethyl)amine derivatives 71 by an analogous palladium-catalyzed asymmetric reaction of the phosphate substrates 67. For the asymmetric amination, (R)-segphos was the chiral ligand of choice and gave excellent enan­tioselectivities, up to 97% ee (Scheme  [²5] ). [²9b] The mechanistic studies revealed that (R)-67a is consumed 4.1 to 4.2 times faster than the S-congener under these reaction conditions.

Scheme 25

A sequential double asymmetric allenylmethylation was achieved by the use of benzylamine (72) as a nitrogen nucleophile for similar palladium-catalyzed reactions (Scheme  [²6] ). [²9c] In the presence of 5 mol% of Pd/(R)-segphos or Pd/(R)-DTBM-segphos, the reaction took place as a two-step process via an initial formation of a mono(allenylmethyl)amine (R)-74, which subsequently underwent the second palladium-catalyzed allenylmethylation to afford a mixture of the chiral (R,R)-73 and the mesomeric (R,S)-73 with good diastereoselectivity. The axially chiral allenic moiety in (R)-74 had a negligible influence on the second allenylmethylation, because the chiral element in (R)-74 is located in a position sufficiently remote from the electrophilic nitrogen center. The highest enantioselectivity, 95% ee, was achieved for the reaction of 67d using the Pd/(R)-DTBM-segphos catalyst with diastereoselectivity of dl/meso = 85:15.

Scheme 26

In 2005, Trost and co-workers demonstrated that racemic allenylmethyl acetates 75 could be used in the analogous dynamic kinetic resolution catalyzed by a palladium species coordinated with the chiral ligand (S,S)-78 giving enantiomerically enriched axially chiral allenes in excellent enantioselectivity. [³0] Under the optimized conditions, the malonate-derived pronucleophiles 76 afforded the allenes (S)-77 in 86-91% ee (Scheme  [²7] ).

Scheme 27

4 Atropisomeric Axial Chirality in Biaryls

A biaryl compound, in which rotation about the aryl-aryl (sp²-sp²) single bond is restricted due to steric congestion, can, with appropriate substitution, be chiral. These biaryl molecules show helical sense chirality and possess a chiral axis through the aryl-aryl bond. A substituted biaryl becomes chiral if R¹ ¹ R² and R³ ¹ R4 (Figure  [5] ). When the interconversion through the planar conformation is slow enough, two enantiomers of a biaryl species can be isolable. This type of enantiomerism was first discovered by Christie and Kenner in 1922. [³¹]

Figure 5 Enantiomeric pair of axially chiral biaryls

4.1 Nickel- or Palladium-Catalyzed Aryl-Aryl Cross-Coupling to Axially Chiral Biaryls

Asymmetric cross-coupling between an aryl nucleophile and an aryl electrophile is a straightforward method which supplies various axially chiral biaryl compounds directly in optically active form. Early examples of this type of reaction were reported for Grignard cross-coupling (Kumada­-Tamao-Corriu coupling) using chiral nickel catalysts, [³²-³5] and, more recently, the palladium-catalyzed Suzuki coupling has been utilized successfully. [³6-45]

Initial attempts at performing this type of reaction were reported in the mid-1970s for the coupling of 2-methyl-1-naphthylmagnesium bromide (79; R¹ = Me, M = MgBr) with 1-bromo-2-methylnaphthalene (80; R² = Me, X = Br), forming 2,2′-dimethyl-1,1′-binaphthyl (81; R¹ = R² = Me) using various chiral nickel catalysts. [³²] [³³] However, the induced enantioselectivity was rather poor (2-13% ee). An early breakthrough to this problem was found through the use of (S)-(R)-ppfOMe, which is a chiral ferrocene-based monophosphine ligand containing a methoxy group on the side chain, and up to 95% ee was achieved. [³4] The first applications of the Suzuki protocol to the asymmetric aryl-aryl coupling appeared in 2000. [³6] [45] Since then, palladium species coordinated with various chiral ligands have been examined for the asymmetric reactions, [³6-46] including a palladium nanoparticle catalyst that is modified with (S)-binap. [4³] Results of some representative examples of the asymmetric reaction are listed in Scheme  [²8] .

Scheme 28

Taking advantage of the functional group tolerance of the standard Suzuki coupling conditions, researchers prepared various functionalized biaryl compounds in up to 92% ee from appropriate aryl halides and arylboronic acids (Scheme  [²9] ). [45] [46] For the success of the asymmetric reactions, the use of the biaryl-based electron-rich chiral phosphine ligand 86 was important.

Scheme 29

The protocol of the nickel-catalyzed Grignard cross-coupling was successfully extended to the asymmetric synthesis of ternaphthalenes (Scheme  [³0] ). [³5] Reaction of 1,5-dibromonaphthalene (88) with two equivalents of 87 in the presence of the nickel catalyst coordinated with (S)-(R)-ppfOMe gave a high yield of a diastereomeric mixture of ternaphthalene 89 consisting of dl and meso isomers in a ratio of 84:16. The dl isomer turned out to be 98.7% ee with the R,R-configuration. The very high enantiopurity can be rationalized by the double asymmetric induction at the first and the second cross-coupling. The reaction of 87 with 1,4-dibromonaphthalene (90) gave ternaphthalene (R,R)-91 of 95.3% ee together with a small amount of meso-91.

Scheme 30

In 2001, Miura and co-workers demonstrated that α,α-disubstituted arylmethanols could be synthetic equivalents to aryl nucleophiles in the palladium-catalyzed reactions with aryl electrophiles. [47] Treatment of 92 with 2-(1-naphthyl)propan-2-ol (93) in the presence of Pd/(R)-binap afforded the axially chiral 94 in 83% yield with 63% ee (Scheme  [³¹] ).

4.2 Enantioselective Oxidative Coupling of Naphthol Derivatives

Asymmetric homocoupling of naphthol derivatives has been developed during the last decade. Various transition-metal species, including copper, ruthenium, and vanadium, are known to catalyze the asymmetric transformation.

Scheme 31

4.2.1 Copper-Catalyzed Oxidative Coupling of Naphthol Derivatives

In a paper published in 1993, Smrčina and Kočovský briefly described the potential of the copper-catalyzed asymmetric oxidative coupling of naphthol derivatives as a route to axially chiral biaryls (Scheme  [³²] ). [48]

Scheme 32

Following this initial discovery, several research groups have developed various copper catalysts coordinated with chiral polyamine ligands and applied them to the aerobic oxidative homocoupling of naphthol derivatives (Scheme  [³³] ). [49-5¹] The mononuclear copper species, Cu/(S)-97 and Cu/(S,S)-98, showed good enantioselectivity for the homocoupling of 3-methoxycarbonyl-2-naphthol, but limited selectivity for unsubstituted 2-naphthol. [49] [50] On the other hand, the dimeric copper(II) complex 99 exhibited good enantioselectivity of up to 88% ee, even for the homocoupling of unsubstituted 2-naphthol. [5¹]

Scheme 33

The Cu/(S,S)-98 catalyst was applied in the asymmetric synthesis of highly functionalized biaryl compounds, such as 100 and 101, which are precursors to biologically active natural products or their derivatives (Figure  [6] ). [5²] [5³]

The copper-catalyzed asymmetric oxidative coupling reaction has been utilized for the preparation of optically active binaphthyl polymers as well. [54]

Figure 6

4.2.2 Ruthenium-Catalyzed Oxidative Homocoupling of Naphthol Derivatives

In 2000, Katsuki and co-workers demonstrated that a chiral Ru-salen complex was an efficient catalyst for aerobic oxidative homocoupling of various naphthols 102: the corresponding axially chiral binaphthol derivatives 103 were obtained in up to 71% ee (Scheme  [³4] ). [55]

Scheme 34

4.2.3 Vanadium-Catalyzed Oxidative Homocoupling of Naphthol Derivatives

Oxovanadium complexes with chiral Schiff bases, which are capable of promoting enantioselective oxidative coupling of 2-naphthol derivatives 104 giving 105, have been developed recently by several research groups independently (Scheme  [³5] ). [56-6³] The mononuclear vanadium catalysts, such as 106-109, were initial entries to the asymmetric reaction as catalysts; however, their enantio­selectivities were limited to moderate to fair. [56-59] More recently, Gong [60] [6¹] and Sasai [6²] [6³] developed the chiral binuclear vanadium species 110-113. These bimetallic complexes possess axially chiral binaphthyl skeletons in their backbones (with the exception of 111) and gave rise to excellent enantioselectivity of up to 98% ee in the oxidative coupling. Sasai postulated that simultaneous dual activation of two substrate molecules is important for high reaction rates as well as high enantioselectivity.

In 2004, Iwasawa demonstrated that solid-support of the monomeric chiral Schiff base vanadium complex 114 on silica gel created a self-dimerized chiral assembly on the silica gel surface. The supported vanadium material functioned as a chiral catalyst for the homocoupling of 2-naphthol to give axially chiral binaphthol, and showed excellent enantioselectivity of up to 90% ee (Scheme  [³6] ). [64]

The vanadium-catalyzed asymmetric oxidative coupling reaction has been utilized for the preparation of optically active polynaphthalene oligomers and polymers. [65-67]

Scheme 35

Scheme 36

4.3 Enantioselective [2+2+2] Cyclotrimerization of Alkynes and Related Reactions

The transition-metal-catalyzed [2+2+2] cyclotrimerization of alkynes (or other unsaturated compounds) has been intensively investigated recently as an effective synthetic route to various aromatic compounds. Catalytic asymmetric synthesis of axially chiral biaryls by the [2+2+2] cyclotrimerization was realized through the use of appropriate chiral transition-metal catalysts, which include the chiral complexes of rhodium, iridium, and cobalt.

4.3.1 Rhodium-Catalyzed [2+2+2] Cycloaddition

The first examples of rhodium-catalyzed enantioselective [2+2+2] cycloaddition of alkynes constructing axially chiral biaryl moieties were accomplished by Tanaka and co-workers in 2004, who used a cationic rhodium(I) complex (Scheme  [³7] ) [68] based on their previous studies. [69] The [2+2+2] cycloaddition between bis(alkynyl)esters 115 and monoynes 116 was effectively catalyzed by a cationic rhodium(I) species coordinated with (S)-H8-binap. In the reactions with terminal monoynes (R² = H in 116), the products were obtained as mixtures of two regioisomers 117 and 118; the axially chiral isomer, 117, obtained in up to 87% ee, were the preferred products. With symmetrical internal monoynes (R² = CH2OR¹ in 116), products 119 were obtained exclusively, and with excellent enantioselectivity (>99% ee).

Scheme 37

The same rhodium catalyst was applied to the three-component asymmetric cyclotrimerization between 120 and 121, and the axially chiral biaryl products 122 were obtained in up to 96% ee (Scheme  [³8] ). [70]

Scheme 38

Axially chiral biaryl moieties can be assembled in enan­tio­selective fashion from six alkynyl subunits by a double [2+2+2] cycloaddition in the presence of a cationic rhodium catalyst. [7¹] For these reactions, (S)-segphos was the most effective chiral ligand and the biaryl products were obtained in up to >99% ee. Two representative examples are shown in Scheme  [³9] .

Scheme 39

The Rh/(S)-segphos catalytic system was found to be useful for the asymmetric [2+2+2] cycloaddition between 1,2-bis(arylpropiolyl)benzene 123 and monoalkyne 124 to give the anthraquinone derivative 125, in which two axially chiral units are incorporated into a single molecule, in good enantio- and diastereoselectivity (Scheme  [40] ). [7²]

Scheme 40

The rhodium-catalyzed cycloaddition protocol shown above was applied to the asymmetric synthesis of various functionalized axially chiral biaryls, including mono- and diphosphonates (126 and 127) and a dicarboxylate (128), with excellent enantioselectivity (Scheme  [4¹] ). [7³] [74]

Scheme 41

The use of isocyanates as a component of the [2+2+2] cyclotrimerization in place of a monoalkyne furnished axially chiral pyridones. The reaction of unsymmetrical 1,6-diynes 129 with isocyanates 130 in the presence of a cationic Rh(I)/(R)-DTBM-segphos complex gave the sterically demanding and axially chiral pyridones 131 as the sole products in high yields and with high enantioselectivity (Scheme  [4²] ). [75]

Scheme 42

The preparation of some axially chiral heterocycles, namely bipyridine 134 and bipyridone 136, was achieved by the double [2+2+2] cycloaddition between a tetrayne 132 and ethyl cyanoformate (133) or butyl isocyanate (135) as shown in Scheme  [4³] . [7¹]

Scheme 43

4.3.2 Iridium-Catalyzed [2+2+2] Cycloaddition

An enantioselective [2+2+2] cycloaddition has been attained using an iridium catalyst. The iridium complex coordinated with Me-Duphos was found to be extremely effective for the asymmetric reactions between diynes 137 and alkynes 138 giving the C 2-symmetric axially chiral teraryl products 139, which possess two axially chiral subunits in a single molecule, with excellent enantio- and diastereoselectivity (Scheme  [44] ). [76] The diastereoselectivity was generally very high and most of the teraryl products 139 were obtained as exclusively as the dl-isomers. The protocol can be applied to the preparation of unsymmetrical (i.e., C 1-symmetric) teraryl compounds as well.

Scheme 44

Taking advantage of the high enantio- and diastereoselectivities of the iridium-catalyzed reactions, the double [2+2+2] cycloaddition of tetraynes 140 with two equivalents of monoynes 141 gave the linearly connected polyaryl products 142, which possess four consecutive axially chiral units in a single molecule, in nearly enantiomerically pure form (Scheme  [45] ). In the same way, a polyaryl species with eight consecutive axial chiralities was prepared from an octayne and a monoyne (4 equiv) in >99% ee. [77]

Scheme 45

With an appropriate arrangement of alkyne units in a cycloaddition substrate, the iridium-catalyzed asymmetric cycloaddition takes place in an intramolecular fashion to produce various axially chiral molecules with high enantioselectivity. As shown in Scheme  [46] , triyne 143 was cyclized in the presence of the Ir/Me-Duphos complex to give ortho-diarylbenzene 144 in 94% ee with good diastereoselectivity. [78] In the same way, the Ir/xyl-binap complex catalyzed the intramolecular double cycloaddition of hexaynes 145 to give the corresponding axially chiral biaryls 146 in up to 98% ee. [79]

Scheme 46

A formal [4+2] cycloaddition between biphenylene (147) and alkynes 148, which is closely related to the above-mentioned [2+2+2]-cycloaddition reactions, proceeded enantioselectively in the presence of an Ir/Me-BPE complex to give axially chiral biaryls 149 in up to 95% ee. In this reaction, 147 furnished a biphenyl component via the activation of a strained carbon-carbon bond (Scheme  [47] ). [80]

Scheme 47

4.3.3 Cobalt-Catalyzed [2+2+2] Cycloaddition

The asymmetric [2+2+2] cycloaddition of nitriles and alkynes in the presence of a catalytic amount of modified chiral cobalt(I) complexes bearing an η5-2-(+)-neomenthylindenyl ligand was reported in 2004 by Gutnov and Heller. [8¹] As shown in Scheme  [48] , the cycloaddition of 1-naphthonitrile 150 and alkynes (2 equiv) or diynes (1 equiv) catalyzed by 154 or 155 afforded the axially chiral 2-arylpyridines 151 in moderate enantioselectivity and modest yields. In contrast, analogous reactions between naphthyldiynes 152 and nitriles gave axially chiral pyridines 153 with much higher enantioselectivity (up to 93% ee) and in better yields. [8¹a]

Scheme 48

The cobalt-catalyzed reaction was applied to the cross-cyclotrimerization of alkynes to give axially chiral biaryls bearing a phosphoryl moiety. [8¹b] In the example shown in Scheme  [49] , the chiral phosphine oxide 156 was obtained in 82% ee; the enantiopurity was further improved to >99% ee by simple recrystallization.

Scheme 49

4.4 Palladium-Catalyzed Enantioposition-Selective Cross-Coupling of Biaryl Ditriflates

The enantioposition-selective asymmetric cross-coupling was realized in the preparation of axially chiral biaryl molecules using a Pd/(S)-phephos or Pd/(S)-alaphos catalyst (Scheme  [50] ). [8²] [8³] Reaction of achiral ditriflate 157 with excess phenylmagnesium bromide in the presence of lithium bromide and catalytic PdCl2[(S)-phephos] gave the monophenylated product (S)-158 in 87% yield with 93% ee and the achiral diphenylated product 159 in 13% yield. [8²] The enantiomeric purity of (S)-158 was dependent on the yield of 159, since a kinetic resolution took place at the second cross-coupling that formed 159. The minor enantiomer from the first cross-coupling, that is (R)-158, was consumed approximately five times faster than the major enantiomer (S)-158 at the second cross-coupling; this resulted in the increase of enantiomeric purity of (S)-158 observed as the amount of 159 increased. Addition of lithium bromide to the reaction mixture was essential for achieving both high enantioselectivity and good reactivity.

Scheme 50

The reaction was extended to an enantioposition-selective alkynylation. [8³] For the alkynylation, (S)-alaphos ligand was much more effective than (S)-phephos in terms of enantioselectivity. For example, the reaction of 157 with (triphenylsilyl)ethynylmagnesium bromide in the presence of the palladium catalyst coordinated with (S)-alaphos gave the corresponding monoalkynylated product (S)-160 (92% ee). In the same way, axially chiral biaryls, such as 161 (84% ee) and 162 (99% ee), were prepared from the respective ditriflates.

4.5 Palladium-Catalyzed Ring-Opening Cross-Coupling of Dinaphthothiophene

The nickel-catalyzed asymmetric reactions of dinaphthothiopene (163) with Grignard reagents gave axially chiral binaphthyl derivatives 164, where the axial chirality was generated at the cleavage of the carbon-sulfur bond in the thiophene ring (Scheme  [5¹] ). [84] Thiophene 163 is practically an achiral molecule because of the rapid flipping of the strained binaphthyl moiety at ambient temperature, and it is expected to become axially chiral once the thiophene ring undergoes the ring opening. For the reactions with arylmagnesium bromides, the phosphinooxazoline (S)- i Pr-phox was the ligand of choice and the ring-opened cross-coupling products (S)-164 were obtained in 93-95% ee. In contrast, (S)-H-mop was the best ligand for the reaction with methylmagnesium iodide and the corresponding product, of R-configuration, was obtained in 68% ee.

Scheme 51

4.6 Cobalt-Catalyzed Ring-Opening Reduction of Biaryl Lactones

The atropo-enantioselective borohydride reduction of biaryl lactones 165 was catalyzed by an chiral β-ketoiminatocobalt(II) complex 167, and a dynamic kinetic resolution took place to afford ring-opened optically active biaryl compounds 166 in high enantioselectivity of up to 93% ee (Scheme  [5²] ). [85] While a lower reaction temperature enhanced the proper kinetic discrimination between the two enantiomers in 165, higher temperatures resulted in a faster equilibrium between the two enantiomers. Thus, running the reaction at the appropriate temperature was crucial for achieving both good enantioselectivity and high chemical yields.

Scheme 52

4.7 Kinetic Resolution of Racemic 2,2 ′ -Dihydroxy-1,1 ′ -biaryl Derivatives by Palladium-Catalyzed Alcoholysis

In 2005, Tokunaga and Tsuji developed a highly enantio­selective kinetic resolution of racemic axially chiral 2-vinyloxy-2′-acyloxy-1,1′-biaryls 168 by palladium-catalyzed asymmetric alcoholysis (Scheme  [5³] ). [86] The alcoholysis of the vinyl ethers 168 was facilitated in the presence of a palladium species coordinated with the chiral secondary diamine 170. Under the conditions shown in Scheme  [5³] , the S-enantiomers of 168 were preferentially converted into the corresponding 2-hydroxy-biaryls 169 with good enantioselectivity (k rel = 12.1-35.8). The bulkiness of the acyl group at the 2′-position was important for the high enantioselectivity of the kinetic resolution. [86a] [b] Although methanol was the best reagent in this alcoholysis in terms of reactivity, the k rel values improved to 41.2 (for 168a) and 39.8 (for 168c) upon use of 2-chloroethanol in place of methanol. The palladium-catalyzed alcoholytic kinetic resolution was applied to phosphoryl esters (171) and sulfonyl esters (172) of binaphthol derivatives as well. [86c]

Scheme 53

Figure 7 Nonbiaryl atropisomeric axially chiral compounds

5 Atropisomeric Axial Chirality about Carbon­-Nitrogen or Carbon-Carbon Single Bonds in Nonbiaryl Systems

Atropisomerism is a ubiquitous phenomenon in organic chemistry. Although the biaryl system is by far the best known framework in this category, other classes of compounds shown in Figure  [7] are also known to display atropisomeric­ axial chirality.

5.1 Palladium-Catalyzed N-Allylation of Anilides

N-Alkyl anilides bearing a sterically bulky ortho substituent are axially chiral and often exist as pairs of stable atropisomeric­ enantiomers at ambient temperatures. For persistent axial chirality in the anilides, three substituents should exist on the nitrogen. In 2002 and 2003, two research groups independently reported analogous asymmetric reactions, namely the palladium-catalyzed asymmetric N-allylation of achiral anilides 173 bearing an N-H group (Scheme  [54] ). While Taguchi and co-workers used diallyl carbonate as an allyl proelectrophile, [87] Curran employed allyl acetate and butyllithium instead. [88] In both cases, enantioselectivity remained modest, and the enan­tio­meric purity of the axially chiral anilides 174 was in the range of 32-44% ee and 12-56% ee, respectively.

Scheme 54

5.2 Palladium-Catalyzed N-Arylation of Anilides

Enantiomerically enriched axially chiral N-aryl anilides 176, the structures of which are closely related to those of 174, were prepared from 175 by a palladium-catalyzed asymmetric N-arylation (Scheme  [55] ). [89] In the presence of catalytic Pd(OAc)2/(R)-DTBM-segphos species, N-arylation (aromatic amination) of various o-tert-butylanilides with p-iodonitrobenzene proceeded with high enantioselectivity to give the corresponding 176 with 88-96% ee in good yields. The application of this catalytic enantioselective N-arylation to an intramolecular cyclization of 177 gave atropisomeric axially chiral lactam derivatives 178 of high enantiomeric purity (70-98% ee).

Scheme 55

5.3 Rhodium-Catalyzed 1,4-Addition of Arylboronic Acids to N-Arylmaleimides

The catalytic asymmetric construction of chiral C-N axes was developed through a rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to N-arylmaleimides 179 by Shintani and Hayashi in 2007 (Scheme  [56] ). [¹¹] The rhodium-catalyzed 1,4-addition simultaneously produced both carbon-central chirality and C-N axial chirality. A rhodium complex coordinated with a chiral diene ligand (R,R)-Ph-bod* promoted the 1,4-addition reactions to give 180 with high diastereoselectivity (dr = 91:9 to 98:2) and excellent enantioselectivity of up to 99% ee.

Scheme 56

5.4 Rhodium-Catalyzed [2+2+2] Cycloaddition Constructing Chiral C-N Axes

The rhodium-catalyzed asymmetric [2+2+2]-cycloaddition protocol (see Section 4.3.1) was found to be effective for the preparation of enantiomerically enriched axially chiral anilides as well.

Tanaka and co-workers demonstrated that intermolecular [2+2+2] cyclotrimerization of 1,6-diynes 181 with trimethylsilylynamides 182 in the presence of a cationic Rh/(S)-xyl-binap complex provided the axially chiral amides 183 with high enantioselectivity (79-98% ee), albeit in relatively low yield (Scheme  [57] ). [90] The presence of the trimethylsilyl group in 182 was important and no reaction was observed in the case of a terminal ynamide.

Scheme 57

The use of ortho-substituted phenyl isocyanates 185 in place of 182 in the [2+2+2] cycloaddition with 1,6-diynes 184 afforded N-aryl-2-pyridones 186, which are atropisomeric with respect to the carbon-nitrogen bonds (Scheme  [58] ). [9¹] For this reaction, a Rh(I)/(R)-binap complex was the catalyst of choice, and enantioselectivity of the reaction was in the range of 30 to 87% ee.

Scheme 58

Concurrent assembly of both the C-C and the C-N axial chirality in a single molecule was reported in 2007 by Hsung and co-workers to take place by an analogous rhodium-catalyzed [2+2+2] cycloaddition. [9²] A representative example is shown in Scheme  [59] : both diastereomeric products were obtained with extremely high enantiopurity (99% ee) and modest diastereoselectivity (dr = 1:6).

Scheme 59

5.5 Rhodium-Catalyzed [2+2+2] Cycloaddition Constructing Chiral C-C Axes

It is known that 2,6-disubstituted N,N-dialkylbenzamides exist as pairs of atropisomers due to the high rotational barrier about the aryl-carbonyl single bond. The application of an asymmetric [2+2+2] cycloaddition catalyzed by a cationic rhodium(I) catalyst realized the highly enantio­selective (>99% ee) synthesis of axially chiral N,N-dialkylbenzamides 189 from 1,6-diynes 187 and N,N-dialkylalkynylamides 188 in high yields (Scheme  [60] ). [9³]

Scheme 60

The reaction of an N,N-dialkylalkynylamide bearing a 2-substituted phenyl group at an alkyne terminus with a 1,6-diyne constructed both the aryl-carbonyl and the aryl-aryl axial chiralities in a single step in a high yield with excellent enantio- and diastereoselectivity; an example is shown in Scheme  [6¹] . [9³]

Scheme 61

The cationic Rh(I)/(S)-segphos complex catalyzed an intermolecular [2+2+2] cycloaddition of enynes 190, possessing an ortho-substituted aryl group on the alkyne terminus, with alkynes 191 to give the corresponding cyclohexadienylarenes 192, which have both a chiral axis and a stereogenic carbon, in a highly diastereo- and enantioselective fashion with up to >99% ee (Scheme  [6²] ). [94]

Scheme 62

5.6 Kinetic Resolution of Racemic Atropisomeric Amides by Osmium-Catalyzed Sharpless Asymmetric Dihydroxylation

Kinetic resolution of the racemic benzoylamide derivatives 193, which possess an olefinic tether, was conducted under Sharpless asymmetric dihydroxylation (AD) reaction conditions using the commercially available AD-mix-α [with (DHQ)2-PHAL] or AD-mix-β [with (DHQD)2-PHAL]. [95] The relative reaction rates between the two enantiomers in 193 were estimated from the conversions of 193 and the ee values of the remaining substrates. Low-to-excellent levels of kinetic enantioselection with k rel up to 32 were realized, and the results are summarized in Figure  [8] . For example, enantiomerically enriched 193d of 98% ee was obtained at 57% conversion.

Figure 8

6 Axial Chirality in Spiro Compounds

Spiro compounds with the appropriate substitution can be chiral despite their possessing no stereogenic centers. Two representative examples of such non-centrochiral spiro compounds are shown in Figure  [9] . The element of chirality in both compounds can be regarded as axial chirality.

Figure 9 Examples of axially chiral spiro compounds

6.1 Rhodium-Catalyzed Intramolecular Double C-H Insertion Cyclization

An efficient one-pot construction of an axially chiral spiro compound, 1,1′-spirobi(indan-3,3′-dione) derivative 197, was achieved in 80% ee by an exploitation of the intramolecular double C-H insertion reaction of bis(diazocarboxylate) 194 under the influence of the chiral dirhodium(II) complex, Rh2[(S)-PTTL]4, as a catalyst (Scheme  [6³] ). [96] The crude double C-H insertion product 196 was transformed into 197 by demethoxycarbonylation in aqueous dimethylsulfoxide at 120 ˚C, and the total yield for the two-step sequence was 78%. In keeping with the accepted fact that a methine carbon-hydrogen bond is generally more reactive than a methylene carbon-hydrogen bond in the C-H insertion reaction, the first insertion product, 195, was not detected during the course of the reaction.

Scheme 63

6.2 Rhodium-Catalyzed Intramolecular Double [2+2+2] Cycloaddition of Bis(diynyl)malononitrile

The rhodium-catalyzed asymmetric [2+2+2] cycloaddition of two alkynyl moieties with a nitrile (see Scheme  [4³] , top) was also utilized in the enantioselective creation of spiro chiral molecules. Treatment of bis(diynyl)malononitrile derivatives 198 with a catalytic cationic rhodium(I) complex coordinated with (R)-segphos or (R)-H8-binap promoted the double [2+2+2] cycloaddition in an enantioselective fashion to give C 2-symmetric spiranes 199 with up to 71% ee (Scheme  [64] ). [97] The cycloaddition preferentially proceeded intramolecularly and the yields of 199 were generally very high (up to 99%).

Scheme 64

7 Helical Chirality in ortho -Fused Polycyclic Aromatic Compounds

Helical structures are very common in many biological materials. A notable example is the double helices in DNA molecules. In ortho-fused polycyclic aromatic compounds (or related compounds), the helicity is inherent in the molecular framework. For example, the helical structures in [6]helicene, shown in Figure  [¹0] , are persistent at ambient temperature and the two helical enantiomers are separable.

Figure 10 Enantiomeric pair of helically chiral [6]helicene

7.1 Nickel-Catalyzed Intramolecular [2+2+2] Cycloaddition

In 1999, Stará and Star described the transition-metal-catalyzed synthesis of tetrahydro derivatives of [5]-, [6]-, and [7]helicenes by intramolecular [2+2+2] cycloaddition. [98a] Since the helical sense chirality is installed at the cycloaddition step, the use of an appropriate chiral metal catalyst was predicted to induce the helical chirality in the helicene-like products. Indeed, Ni/(S)-MeO-mop and Ni/(S)-bop species catalyzed the cycloaddition of 200 to give the tetrahydro[6]helicene (+)-201 with moderate enantioselectivities of 42-48% ee (Scheme  [65] ). [98]

Scheme 65

7.2 Rhodium-Catalyzed Intramolecular [2+2+2] Cycloaddition

Tanaka and co-workers found a way to apply the powerful rhodium(I)-catalyzed asymmetric [2+2+2]-cycloaddition reaction for composing helicene-like molecules (Scheme  [66] ). [99] The trialkynyl compounds 202 were cyclized intramolecularly in the presence of a cationic Rh(I)/(R,R)-Me-Duphos complex to give the corresponding helically chiral products 203 in 71-80% yields with 71-85% ee.

Scheme 66

8 Conclusions

Despite the increasing importance of compounds with non-centrochirality in various asymmetric reactions, including those that are catalytic, the preparative methods for their optically active congeners are limited. As seen in this review article, the ‘transition-metal-catalyzed enantioselective synthesis of non-centrochiral compounds’ is still a relatively new and underachieved area in synthetic organic chemistry. Although some interesting examples have been developed in the last decade, additional examples are clearly desired, and would certainly enhance the synthetic usefulness of these compounds with non-centrochirality.

Note Added In Proof

Since the submission of this manuscript in early 2009, the following two additional papers have been published. One is the preparation of planar-chiral paracyclophanes by palladium-catalyzed asymmetric Sonogashira coupling, [¹00] and the other is the preparation of axially chiral spirobilactams via palladium-catalyzed intramolecular double N-arylation. [¹0¹]

Acknowledgment

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Figure 1 Representative examples of useful chiral compounds with non-centrochirality: planar-chiral ferrocenyl phosphines 1 and 2, and axially chiral biaryl-based phosphines 3 and 4

Figure 2 Representative examples of non-centrochiral compounds

Figure 3 Examples of planar-chiral molecules

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Figure 4 Enantiomeric pair of axially chiral allenes

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Figure 5 Enantiomeric pair of axially chiral biaryls

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Figure 7 Nonbiaryl atropisomeric axially chiral compounds

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Figure 9 Examples of axially chiral spiro compounds

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Figure 10 Enantiomeric pair of helically chiral [6]helicene

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