DOI: 10.1002/chem.201302220

Chiral Hypervalent Iodine Reagents: Synthesis and Reactivity Alejandro Parra*[a] and Silvia Reboredo[b]


 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2013, 19, 17244 – 17260

MINIREVIEW Abstract: Chiral hypervalent iodine chemistry has been steadily increasing in importance in recent years. This review catalogues enantioselective transformations triggered by chiral hypervalent iodineACHTUNGRE(III/V) reagents, in stoichiometric or catalytic quantities, highlighting the different reactivities in terms of yield and enantioselectivity. Moreover, the synthesis of the most remarkable and successful catalysts has been illustrated in detail. Keywords: asymmetric synthesis · hypervalent iodine · organocatalysis · oxidation dearomatization

Introduction The advance of modern chemistry is driven by social demands in order to provide solutions by optimizing the use of natural resources and minimizing waste and environmental impact. In this aspect, catalysis plays a key role. In particular, asymmetric synthesis has extensively benefited with several privileged catalysts having been designed to cover a wide range of transformations.[1] Although traditionally catalytic processes were focused on metallic and enzymatic catalysis,[2] during the last decade, organocatalysis has emerged as an important synthetic tool, and it is now a major area in organic chemistry.[3] Excellent results have been achieved in different enantioselective oxidation reactions using metals[4] and enzymes.[5] However, redox reactions have generally been limited to asymmetric reductions,[6] while metal-free asymmetric oxidations have proven to be more challenging. On the other hand, despite the fact that the first hypervalent iodine compound [(dichloroiodo)benzene] was prepared in 1886 by Willgerodt,[7] it was not until the last 30 years that this class of compounds arose as significant reagents. The attractiveness of these species is linked to their outstanding characteristics. They are mild, nontoxic (green oxidation), environmentally friendly, have easy handing, and are stable oxidants, especially compared to heavy-metal reagents.[8] Consequently, these reagents are commonly considered capable of accomplish “metal-like” transformations under ”metal-free” conditions. Moreover, given their unique variability, hypervalent iodine reagents have the potential to promote unprecedented and versatile reactions. Most of these reagents belong to two main groups: 1) iodineACHTUNGRE(III) species A (Figure 1, top left),[9] called l3-iodanes and featur-

[a] Dr. A. Parra Departamento de Qumica Orgnica (Mdulo-1) Facultad de Ciencias, Universidad Autnoma de Madrid Cantoblanco, 28049 Madrid (Spain) E-mail: [email protected] [b] Dr. S. Reboredo Departamento de Qumica Orgnica I Facultad de Ciencias Qumicas, Universidad Complutense de Madrid Ciudad Universitaria S/N, 28040 Madrid (Spain)

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Figure 1. l3-Iodane and l5-iodane structures and some representative examples.

ing a pseudo-trigonal-bipyramidal geometry and, 2) ioACHTUNGREdine(V) species B (Figure 1, top right),[10] called l5-iodanes and with a square-pyramidal geometry. Important and commercially available representatives can be found on both groups, for example, bisACHTUNGRE(acetoxy)iodobenzene (PIDA),[11a] bis(trifluoroacetate)iodobenzene (PIFA)[11b] or Dess–Martin periodinane[12] (Figure 1, bottom). The first chiral hypervalent iodine reagent, (diphenyliodonium tartrate) was discovered in 1907.[13] However, their potential as reagents in asymmetric organocatalytic oxidative protocols, has only been established over the last decades. Due to the emerging nature of the field, some excellent reviews have been published on this topic, but none of them are comprehensive.[8n–p] These precedents encouraged us to compile a more complete and thorough overview of transformations catalyzed by chiral hypervalent iodineACHTUNGRE(III or V) reagents. Along with the reactivity of these species in asymmetric synthesis, we have highlighted the different synthetic routes used to prepare the most important hypervalent iodine reagents used as catalysts and pre-catalysts.

Synthesis and Application to Asymmetric Synthesis In most of the examples described in this review, we have just shown the optimized catalyst for each transformation, although frequently a larger number of catalysts are reported in the original publications. In this sense, the reactivity of these catalytic species has also been gathered, in most of the cases as seminal works, based on the type of transformations they are involved in, independently of the iodine atom oxidation state. Thus, this survey is divided in the following five sections: 1) 2) 3) 4) 5)

Asymmetric oxidations of sulfides to sulfoxides. Dearomatization reactions. Arylation reactions. a-Functionalization of ketones. Functionalization of alkenes.

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A. Parra and S. Reboredo

Asymmetric oxidations of sulfides to sulfoxides: As already mentioned, Pribram[13] demonstrated for the first time the possibility of preparing a chiral hypervalent iodine reagent (diphenyliodonium tartrate). However, of relevance to this review was the seminal work illustrated by Imamoto et al. in 1986,[14] who pioneered the synthetically useful application of a chiral l3-iodane. They prepared the iodineACHTUNGRE(III) reagents (R,R)-3 a–c in situ by reaction of iodosylbenzene 2 and different l-tartaric anhydrides (R,R)-1 a–c in acetone at room temperature (Scheme 1), assuming a seven-membered cyclic

Scheme 1. Asymmetric oxidation of sulfides 4 to sulfoxides 5 using (R,R)3 a–c.

structure for this new compound. Thus, (R,R)-3 a–c were capable of oxidizing sulfides 4 to sulfoxides 5 in moderate to good yield and up to an attractive 53 % ee (Scheme 1). The authors also used acetyl-l-lactic acid as the chiral unit, but in this case sulfoxides 5 were obtained in the racemic form (only 1 % ee), indicating that the C2-symmetry presented in (R,R)-3 a–c was critical to control the enantioselectivity. Curiously, in 1992 Koser et al.[15] published a seminal study for preparing a catalyst similar to (R,R)-3 a–c, but from bisACHTUNGRE(acetoxy)iodobenzene (6) and dibenzoyl-l-tartaric acid (7; Scheme 2). The desired catalyst 8 was isolated as

Scheme 2. Preparation and evaluation of polymeric structure 8 by Koser et al.

a white powder in 82 % yield. The authors reasoned that the T-shaped disposition proposed for (R,R)-3 a–c may present a highly energetic structure, so they decided to carry out an exhaustive NMR study to establish the real structure of the catalyst. Remarkably, all experimental evidence found by the authors highlighted that the hypervalent iodine polymer 8 was generated, instead of the previously reported cyclic structure 3. Similar yields and enantioselectivities were ob-


tained by using 8 in the Imamotos reaction, indicating that the oxidation probably involved the polymeric reagent. These authors[16] also prepared two new chiral iodinanes, (+) or ( )-10, by a ligand exchange reaction between (1 S,2 R,5 S)-(+)-menthol or (1 R,2 S,5 R)-( )-menthol and the iodineACHTUNGRE(III) derivative 9. These new reagents reacted with multiple sulfides (11), affording mixtures of diastereomers (+) or ( )-12 in very high yields (Scheme 3). After

Scheme 3. Asymmetric oxidation of sulfides 11 mediated by (+)- or ( )-10.

Alejandro Parra was born in 1980 in Toledo, Spain. He received his B.Sc. degree in Chemistry at the Universidad Autnoma de Madrid (Spain) in 2004. In 2006 he spent four months in the laboratory of Prof. Andrew Myers at Harvard University (USA) working on the chemistry of tetracyclines. He earned his Ph.D. at the Universidad Autnoma de Madrid under the supervision of Prof. Jos Luis Garca Ruano in 2009. After that, he carried out a post-doctoral stay in the Institute of Organic Chemistry, RWTH-Aachen (Germany), with Prof. Magnus Rueping (2009– 2011). In 2011, he came back to Universidad Autnoma de Madrid (Prof. Garca-Ruanos group) and his research concerns asymmetric synthesis and organocatalysis. Silvia Reboredo was born in 1983 in Alonsotegi, Bizkaia. She studied chemistry at the University of the Basque Country, where she obtained her Ph.D. for the work on organocatalytic cycloadditions in 2011, under the supervision of Prof. M. Dolores Badia and Prof. Jose Luis Vicario. During her Ph.D. she spent some time at RWTHAachen University with Prof. Magnus Rueping. Currently she is a post-doctoral researcher with Prof. Nazario Martn at Universidad Complutense de Madrid. Her present research topics include materials science and asymmetric synthesis.

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Chiral Hypervalent Iodine Reagents


separation by recrystallization, followed by basic hydrolysis, excellent optical purity was observed for chiral sulfoxides (S) or (R)-13. The method was successfully applied to other chiral alcohols. Some years later, Chen et al.[17] published the use of the chiral hypervalent iodine 15, prepared from (+)-camphorsulfonic acid previously reported by Varvoglis et al.[18] (see Scheme 20, below), to oxidize sulfides 14 to sulfoxides 16 (Scheme 4). Once again, the oxidation was stopped at the

pTolSMe). Different sulfides 17 a–f were oxidized in excellent yields and moderate ees (19 a–f, Scheme 5). The authors proposed that the coordination of the o-methoxy group with the iodine atom was essential to procure the highest enantioselectivity. Later, in 2000, the same research group,[21] obtained similar results in terms of yields and ees when they carried out this process in water using MgBr2 (20 mol %) as activator of the iodane(V). In 2000, Zhdankin et al.[22] synthesized a variety of hypervalent iodine(V) catalysts (S)-21 a–c by using amino acids (20 a–c) as chiral moieties in moderate to good yields (Scheme 6). In this case, the system formed by KBrO3/

Scheme 4. Asymmetric oxidation of sulphides 14 mediated by 15.

sulfoxide stage in good to excellent yields, but in very poor ees. In the example reported by Kita et al.[19] in 1999, a hypervalent iodine(V) compound, prepared in situ from PhIO2, was used (Scheme 5). This example is the first asymmetric Scheme 6. Preparation of catalysts (S)-21 a–c and their application to sulfur oxidation. TFA: Trifluoromethyl acetic acid.

H2SO4 was needed to oxidize the iodine atom. Then, they applied this family of catalysts to the oxidation of phenylmethylsulfide 22 giving compound 23 in excellent yields albeit in low enantioselectivities (Scheme 6). Another interesting example employing hypervalent ioACHTUNGREdine(V) was also presented by Zhdankin et al.[23] (Scheme 7). Two new proline-derived chiral reagents 27 and 28 were prepared as indicated in Scheme 7. By simple alACHTUNGREkyl-

Scheme 5. Catalytic asymmetric oxidation of sulfides 17 a–f by (S,S)-18. CTAB: Cetyl trimethylammoniun bromide.

oxidation of sulfides by using catalytic hypervalent iodine reagents.[20] The oxidation reaction was carried out in a toluene/H2O micellar system, and 20 mol % of achiral cetyl trimethylammoniun bromide (CTAB) was required as a phase-transfer agent. After testing several chiral sources, they found that 2-methoxydibenzoyl-d-tartaric acid (S,S)-18 provided the best enantioselectivities (up to 53 % ee for

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Scheme 7. Preparation of chiral hypervalent iodine(V) reagents 27 and 28. DMDO: Dimethyldioxirane.

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A. Parra and S. Reboredo

ACHTUNGREation of amide derivative 24 with MeI or 4-Br-benzyl bromide, compounds 25 and 26, respectively, were generated in good yields. After oxidation of these intermediates with DMDO (dimethyldioxirane), 27 and 28 were obtained as new chiral hypervalent iodine(V) reagents in very good yields. The authors proposed a possible pseudo-bonding or coordination between IO2 and the oxygen atoms from both amide groups. That would allow the formation a sevenmembered ring therefore blocking the attack of the sulfur from one of its faces. With these compounds in hand, they evaluated the ability of controlling the enantioselectivity on the oxidation of the methylACHTUNGRE(p-tolyl)sulfide to the corresponding sulfoxide. When 28 was used in this process, they observed high yield (89 %), but only a moderate 29 % ee. Other transformations such as the kinetic resolution and the oxidation of meso-diols were also tested with similar results. More recently, Wirth et al.[24] prepared the chiral hypervalent iodine(V) reagents 29–31 (Figure 2), using the esters

Scheme 8. Synthesis of the catalyst (R)-35 by Kita et al. BINAP: 2,2’-bisACHTUNGRE(diphenylphosphino)-1,1’-binaphthyl.

Figure 2. Chiral hypervalent iodine(V) compounds 29–31 prepared by Wirth et al.

from borneol, menthol and fenchyl alcohol, respectively. Unfortunately, the authors could not determine the ees on the oxidation of phenylmethylsulfide 22, because the sulfoxide was contaminated with unidentified impurities. Dearomatization reactions: In the last years, dearomatization processes have become an important tool in organic synthesis,[25] especially in the area of total synthesis.[25e, 26c] One of the most important dearomatization reactions involves phenols to generate either dimerization or o-quinones monoketals or quinols intermediates.[26] In this context, interesting studies have appeared in the literature concerning hypervalent-iodine-mediated oxidative dearomatization of phenols.[27] However, it was 2008 when Kita et al.[28] reported the first asymmetric dearomatization using the chiral hypervalent iodineACHTUNGRE(III) (R)-35 (Scheme 8). Once the diiodine (R)-34 was prepared from 32 via intermediate 33 by means of a Pd-catalyzed amination and nitrosation sequence, the rigid spirobiindane-backbone hypervalent iodineACHTUNGRE(III) (R)-35 was readily obtained by oxidation with Selectfluor in 90 % yield. Kita et al. evaluated this catalyst in the o-spirolactonization of 4-substituted a-naphthols (36 a–d) through oxidative dearomatization (Scheme 9). Compounds 37 a–d were produced in moderate-to-good enantioselectivities and good yields. These results confirmed the importance of using a rigid structure in the catalyst, since other chiral l3-iodine reagents afforded almost racemic products. Different solvents were screened in order to gain insight into the reac-


Scheme 9. o-Spirolactonization of a-naphthols mediated by (R)-35.

tion mechanism. Polar solvents provided inferior enantioselectivities, which is consistent with an associative mechanism (Scheme 10, bottom). It was possible to decrease the amount of catalyst (to 0.15 equiv), using in this case the precatalyst (R)-34 and mCPBA as co-oxidant,[29] without detrimental effects to the ee value. Very recently, in 2013, Kita et al.[30] improved the enantioselectivity (up to 92 % ee) of this spirolactonization by using a new pre-catalyst (R)-38 derived from spirobiindane bearing o-substituents (up to 92 % ee when R = Et; Scheme 10), and determined the configuration of the final lactone as R. In addition, they proposed a plausible transition-state model to explain the observed configuration (Scheme 10). Once the pre-catalyst is oxidized to 39, the substrate can form an apical-bond between phenolic OH and the hypervalent iodineACHTUNGRE(III) atom (40). The existence of two iodineACHTUNGRE(III) atoms and an apical oxygen-bridge between them, permit the selective attack of the carboxylic group from the Re-face to give compounds 41. This model is in agreement with the experimentally observed (R)-configuration.

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Scheme 12. Asymmetric oxidation of 2-methyl-1-naphthol 46 carried out by Quideau et al. mCPBA: meta-Chloroperoxybenzoic acid.

Scheme 10. Catalyst (R)-38 and a plausible transition-state reported by Kita et al. mCBA: meta-Chlorobenzoic acid

In 2009, Birman et al.[31] reported the synthesis of a new family of chiral 2-(o-iodoxyphenyl)oxazolines (S)-43, abbreviated as CIPOs, involving in this case, chiral organoioACHTUNGREdine(V). The synthetic sequence used is outlined in Scheme 11. The corresponding chiral aminoalcohol (42) is acylated, cyclized, and oxidized with DMDO to afford the iodoarene (S)-43 in a good 50 % yield. An asymmetric ACHTUNGRE[4+2] Diels–Alder dimerization reaction of o-alkylphenols

Scheme 11. 2-(o-Iodoxyphenyl)-oxazoline (S)-43 prepared and used by Birman et al. DIC: N,N’-Diisopropylcarbodiimide. DMDO: Dimethyldioxirane.

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44 a–c was catalyzed by (S)-43 in good yields, but with moderate enantioselectivities (Scheme 11). In 2009, Quideau et al.[32] published the asymmetric oxidation of 2-methyl-1-naphthol (46) mediated by an in situ generated l5-iodane (Scheme 12). After they unsuccessfully evaluated a variety of chiral iodine derivatives and oxidants for creating a new chiral l5-iodane, the authors turned out their attention to the use of chiral iodoarenes and in situ generation of the hypervalent iodine (mCPBA as co-oxidant). In this way, the best candidate was (R)- or (S)-49 to afford the dearomatization product 47 in good yield and moderate enantioselectivity. By using excess of co-oxidant, the epoxidized product 48 was obtained in 90 % yield and in a modest 29 % ee (Scheme 12). Additional mechanistic studies suggested the participation of the l5-iodane species in the reaction. Later, several C2-symmetric chiral catalysts were designed and prepared by Ishihara et al.[33a] Coupling between 2-iodoresorcinol (50) and ethyl lactate ((R)-51) under Mitsunobu conditions, provided the corresponding iodoarene (R,R)52 in good yields. Acyl chloride formation (to give 53) followed by amidation, afforded the new pre-catalyst (R,R)-54 (Scheme 13). This family of C2-symmetric chiral pre-catalysts was examined in the oxidative o-lactonization of naphthols, similar to that reported by Kita et al.[28a] (Scheme 9) using only 10 mol % of chiral (R,R)-54 and 1.2–1.5 equiv of mCPBA as

Scheme 13. Synthesis of the pre-catalyst (R,R)-54 by Ishihara et al. DIAD: Diisopropyl azodicarboxylate.

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A. Parra and S. Reboredo

Scheme 15. Synthesis of pre-catalyst 61 by Harned et al.

Scheme 14. Asymmetric spirolactonization reported by Ishihara et al. mCPBA: meta-Chloroperoxybenzoic acid.

co-oxidant for the in situ generation of iodaneACHTUNGRE(III) catalyst (Scheme 14). The products (56 a–f) were obtained in very good yields and enantiomeric excesses with a variety of anaphthols (55 a–f). The authors believed that both the intramolecular n–s* interactions between iodineACHTUNGRE(III) atom and the two oxygen atoms at the carbonyl groups, and the hydrogen-bonding interactions between the iodineACHTUNGRE(III) ligands and the NH from the amide groups are responsible for generating the suitable chiral environment (see 57, Scheme 14). In order to identify the real catalytic species, they isolated the hypervalent iodineACHTUNGRE(III) catalyst from chiral iodoarene (R,R)-54. In terms of ee and yield, similar results were obtained in comparison to the catalytic version, justifying the presence of this iodineACHTUNGRE(III) intermediate in the present transformation. The same research group studied the scope for this spirolactonization. Additionally, a one-pot spirolactonization/epoxidation sequence was also reported in good yields and diastereselectivities.[33b] Very recently, Harned et al.[34] prepared a new chiral hypervalent iodineACHTUNGRE(III) pre-catalyst 61 by reaction of iodotetACHTUNGREralone dimethylacetal (58) and (+)-dimethyl L-tartrate ((R,R)-59) under scandium catalysis, and subsequent amidation with mesytil aniline in good yield (Scheme 15). They demostrated that the pre-catalyst 61, with 2.2 equivalents of mCPBA as co-oxidant for in situ generation of the l3-iodane intermediate, was able to carry out the asymmetric oxidation of a wide range of phenols (62 a–g) to p-quinols (63 a–g) in moderate to good yields (Scheme 16). Despite the low ees found by the authors, this was the first time that a chiral hypervalent iodineACHTUNGRE(III) was applied on this asymmetric transformation.


Scheme 16. Asymmetric synthesis of p-quinols mediated by 61/mCPBA system. mCPBA: meta-Chloroperoxybenzoic acid.

Arylation reactions: A seminal work concerning the first chiral hypervalent iodinesACHTUNGRE(III) carrying chiral carbon moieties was reported by Ochiai et al.[35a] In this context, the authors synthesized the reagents 64–67 shown in Figure 3. Different studies carried out on the catalysts (especially by NMR spectroscopy) showed that, unfortunately, these struc-

Figure 3. Different catalysts reported by Ochiai et al.

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tures displayed low configurational stability, since they experienced pseudorotation on the diacetoxyiodinane moiety. In 1997, Kitamura et al.[35b] reported the first synthesis of chiral alkynylACHTUNGRE(aryl)iodonium salts and their application to the preparation of diarylacetilenes by cross-coupling reaction. Later, in order to develop asymmetric arylation reactions, Ochiai et al.[35c] synthesized several chiral diaryliodonium salts, 1,1’-binaphtyl-2-ylACHTUNGRE(phenyl)iodonium tetrafluoroborates, from (R)-64 and (R)-68 by means of a tin–iodaneACHTUNGRE(III) exchange reaction catalyzed by BF3 (Scheme 17).

and control the stereochemistry of the reaction. Once the process is finished, the reoxidation of the chiral iodoarene would provide the initial chiral salt. Tuning the reactivity, asymmetric induction and chemoselectivity of the arylation reactions would be influenced by the following factors: 1) the electron-richness of the aryl moiety, 2) the aliphatic chains improving the solubility of the salts, and 3) the number of substituents in the aromatic ring. The synthesis of these salts 73–75 was achieved by different procedures (Scheme 19). The reaction of the 2-iodo-

Scheme 17. Diaryliodonium salts prepared by Ochiai et al.

When the indanone 71 was treated with the diaryliodonium salts (R)-69 and (R)-70, instead of the expected binaphthyl group reported to that moment, the a-phenylated indanone 72 was yielded with high regioselectivity (C vs. O) in moderate to good yield (30–68 %), with a variable degree of induction (up to 53 % ee) (Scheme 18). That was a break-

Scheme 19. Synthesis of diaryliodonium salts 73–75. NMP: N-Methyl-2pyrrolidone.

Scheme 18. a-Phenylation of cyclic b-keto ester 71.

through in this area, becoming the first example of an asymmetric a-phenylation of cyclic b-keto esters. More recently, Olofsson et al.[36] focused their investigations on the design of diaryliodonium salts 73–75 (Figure 4). They proposed that catalysts containing aryl groups with different stereoelectronic properties could allow the transfer of the more electron-deficient aryl group to the nucleophile

Figure 4. Target diaryliodonium salts 73–75.

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phenol (76) and the mesylated alcohol (R)-77, followed by subsequent treatment with nBuLi, and vinyliodonium triflate 79, yielded the desirable diaryliodonium triflate 73 (Scheme 19). For the synthesis of the target triflate 74, the same synthetic procedure was used, but starting from 2-bromoresorcinol (80; Scheme 19). Finally, the tosylate salt 75 was readily prepared by nucleophilic aromatic substitution of 1,3,5-trifluorobenzene (82) with the chiral alcohol (R)-83, followed by treatment with Kosers reagent 85 (Scheme 19). a-Functionalization of ketones: In 1990, inspired by the precedents of Koser,[37] Varvoglis et al.[18] evaluated the incorporation of a chiral partner on a new hypervalent iodine reagent 15 (Scheme 20). The stable (hydroxyl-{[(+)-10-camphorsulfonyl]oxy}iodo)benzene (15) was prepared from [bisACHTUNGRE(acetoxy)iodo]benzene (6) and (+)-camphorsulfonic acid in very good 80 % yield. Then, they tested this catalyst in the a-oxidation of ketones, observing better regioselectivity in nonsymmetric ketones than with catalysts bearing less bulky groups such as p-tolyl and methyl. Nevertheless, for the examined cases, the stereoselectivity was low.

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A. Parra and S. Reboredo

Scheme 20. Synthesis of hypervalent iodineACHTUNGRE(III) reagent 15 by Varvoglis et al.


More than ten years later, Wirth et al. focused on the identification of the best enantiopure iodoarene that would allow the a-oxytosylation of ketones employing mCPBA as the stoichiometric oxidant. Among the set of synthesized iodoarene pre-catalysts, including ethers, esters, binaphthyl derivatives or naphthalene-based catalysts, 6-ethyl-substituted iodoarene (S)-87 (Scheme 21), gave the highest ees values

Scheme 22. Chiral hypervalent iodineACHTUNGRE(III) pre-catalyst (S)-92 prepared by Wirth et al. DCCI: N,N-Dicyclohexylmethanediimine. DMAP: 4-Dimethylaminopyridine.

enantiomerically pure alcohols 90: dimethyl and diethyl tartrate, 1-phenylethanol, 2-bromobenzyl alcohol, hydroquinine as well as an indane derivative (Scheme 22Pre-catalyst (S)92 provided the best enantioselectivity (up to 26 %) in 70 % yield in the model a-oxytosylation of propiophenone. Further investigations by using (S)-92 as the catalyst in the lactonization reaction shown in the Scheme 23 revealed that non-enantioselectivity was observed in the reaction of 5-oxo-5-phenylpentanoic acid (93) to give compound 94, even when high yields were achieved.

Scheme 23. Lactonization of 5-oxo-5-phenylpentanoic acid 93 developed by Wirth et al. mCPBA: meta-Chloroperoxybenzoic acid.

Scheme 21. a-Tosyloxylation of ketones 86 a–d by using chiral pre-catalyst (S)-87. mCPBA: meta-Chloroperoxybenzoic acid.

(up to 28 % for 88 b). Propiophenone derivatives 86 a–d afforded variable yields depending on the electronic demand. The reaction was also valid for cyclic ketones, such as indanone 86 c (79 % yield and 21 % ee) and a tetralone derivative, obtained in this case as a nearly racemic mixture. The same authors[39] have also carried out an extensive study of the same process evaluating a series of chiral ethers, iodoarenes, as well as the nature of the nucleophile. The experiments revealed the importance of the presence of an oxygen atom as a part of the catalyst that fixes the hypervalent intermediate as a rigid structure. This fact, together with a chiral moiety in the same o-position to the iodine, allowed the moderate enantioselectivity of the process. The catalyst and the nucleophiles play an important role in the yield and selectivity of the reaction, with ( )-camphorsulfonic acid being the most successful. Afterwards,[40] more catalysts 91 were prepared by esterification of various iodobenzoic acids 89 from the following


Later, in 2012, Moran et al.[41] prepared iodoarenes 95 and 96, bearing a chiral norephedrine and pseudo-ephedrine moieties, from the corresponding carboxylic acids by amidation in 72 % and 75 % yield, respectively (Figure 5). The pre-catalyst 95 (using mCPBA as co-oxidant) was later applied to a-tosylation of propiophenone in 67 % yield albeit in a low 18 % ee, (Figure 5). A better result was obtained for the cyclization of 93 catalyzed by pre-catalyst 96 and mCPBA. The lactone was achieved in 47 % yield and in an improved 51 % ee, the highest enantioselectivity reported up to date for this transformation (compare results with those in Scheme 23).

Figure 5. Pre-catalysts 95 and 96 reported by Moran et al.

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Almost simultaneously, Legault et al.[42a] reported a new pre-catalyst iodoarene 98 bearing a chiral oxazoline ring moiety, using for its synthesis the experimental procedure developed by Birman et al. (for synthesis of an analogous hypervalent iodine(V), see Scheme 11). Then, they evaluated the a-tosyloxylation of propiophenone 97 a as a model reaction (Scheme 24) with catalytic amounts of 98 and

Figure 6. Chiral hypervalent iodineACHTUNGRE(III) compounds 100 a–c prepared by Wirth et al.

pound 101 via intermediate 102) introducing a methoxy group ortho to the iodineACHTUNGRE(III) atom (Scheme 25). This species slightly improved the enantioselectivity previously obtained on the dioxytosylation of styrene (104) to give comopund 105, and the a-oxidation of propiophenone (97 a),

Scheme 24. a-Tosyloxylation of ketones 97 a–c by using iodoaryloxazoline pre-catalyst 98. mCPBA: meta-Chloroperoxybenzoic acid.

mCPBA as co-oxidant. The reactivity of the reaction was linked to the presence of an alkyl group ortho to the iodineACHTUNGRE(III) atom, making the association of the iodine atom with the oxazoline ring difficult.[42b] On the other hand, catalysts bearing a stereogenic centre (responsible for the stereoinduction) a to the oxygen present in the oxazoline turned out to be the optimal in terms of enantioselectivity, in particular for 98 (Scheme 24). The process tolerated various alkyl chains on propiophenones, as well as electronwithdrawing groups at aromatic ring leading to the formation of 99 a and c. However, electron-donating groups as well as ortho substitution at aromatic ring, did not yield the corresponding adduct. For cyclic ketones, indanone (97 b) and tetralone, opposite behaviour was detected, the latter being a substrate not valid for this process (Scheme 24). Functionalization of alkenes: In a seminal work in 1997, Wirth et al.,[43] investigated the synthesis of three different chiral hypervalent iodineACHTUNGRE(III) compounds 100 a–c (Figure 6), following the principles related to the previously obtained results with selenium electrophiles.[44] Firstly, they tested these catalysts 100 a–c in the a-oxyACHTUNGREtosylation of ketones, observing a moderate yield in a promising 15 % ee. On the other hand, sulfide oxidation and iodo lactonization gave almost racemic products. Alkenes were also treated under similar conditions affording dioxytosylated compounds in up to 21 % ee. Shortly after, the same research group[45a] synthesized catalyst (S)-103 (from com-

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Scheme 25. Dioxytosylation and a-oxytosylation using catalyst (S)-103. Icp: Isopinocampheyl. TMEDA: Tetramethylethylenediamine.

probably due to an interaction between the oxygen in the omethoxy and the iodaneACHTUNGRE(III). The study also revealed that the addition of a small amount of p-TsOH monohydrate increased the reaction rate by attack to the double bond. The study was complemented with the synthesis of more catalysts that were subsequently subjected to DFT calculations,[45b] corroborating the beneficial effect of the ortho substituent on the enantioselectivity of the process. The proposed model, despite being limited, was a breakthrough in the field. In 2003, using 4-aryl-4-pentenoic acid 106, Wirth et al.[46] were able to access to the lactone 109, via the phenonium ion 108, in moderate yield (56 %), but only in 4 % ee when chiral hypervalent iodineACHTUNGRE(III) reagent (S)-107 (prepared in a similar manner to that indicated in Scheme 25) was employed (Scheme 26). In 2004, Zhdankin et al.[47] synthesized several amino acid derived iodobenzene dicarboxylates (S,S)-111 a–e by an ex-

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A. Parra and S. Reboredo

Scheme 28. Synthesis of hypervalent iodineACHTUNGRE(III) reagents (S)-119 a,b. DIAD: Diisopropyl azodicarboxylate.

Scheme 26. Lactonization of the unsaturated carboxylic acid 106 mediated by (S)-107.

change reaction of various N-protected amino acids (S,S)110 a–e with (diacetoxyiodo)benzene (6). Interestingly, these reagents worked properly on the iodocarboxylation reaction of cyclohexene 112 and dihydropyran 114 (Scheme 27). This process yielded b-iodocarboxylates 113 a–e and 115 as a mixture of 1:1 diastereomers in moderate to good yield (Scheme 27).

121 a–c, respectively, with a variable, but always small amount of oxo-butyl benzoate 122 (treatment with pTsOH reduces the ketone amount favouring the tetrahydrofuran). The substituents present in the double bond of the substrates control the enantioselectivity of the process, directing the electrophilic addition of the iodaneACHTUNGRE(III) toward to the olefin (Scheme 29). Shortly after, the same authors im-

Scheme 29. Tetrahydrofuranylation of but-3-enyl carboxylates (Z/E)120 a–c.

Scheme 27. Iodocarboxylation of cyclohexene 112 and dihydropyran 114.

Fujita et al.[48a] prepared two optically active hypervalent iodineACHTUNGRE(III) reagents (S)-119 a,b by Mitsunobu reaction of 116 with methyl lactate (S)-117 and subsequent oxidation with sodium perborate (Scheme 28). The tert-butyl ester derivate (R)-118 b was prepared by an ester-exchange reaction from (R)-118 a. The reaction of a series of (Z)- and (E)-but-3-enyl benzoates (Z/E)-120 a–c catalyzed by these reagents (S)-119 a,b, stereospecifically yielded the trans- or cis-tetrahydrofurans


proved the diastereoselectivity of the process using a double asymmetric induction with the same hypervalent iodineACHTUNGRE(III) reagent (S)-119 a,b and (1 S)-camphanate (R1, Scheme 29) as a chiral auxiliary at the ester–alkene substrate.[48b] While searching for a method for the synthesis of gymnasatin F, Lupton et al.[49] figured out a mild route for the achlorination or bromination of a,b-unsaturated carbonyls without using traditional strong oxidants, such as oxone or mCPBA. Benzyl 2-(o-iodoxyphenyl)oxazoline derivate ((R)124; prepared following the Birmans procedure, Scheme 11) and the pyridine hydrochloride salt at room temperature in CH2Cl2, allowed the halogenation of b-methylstyrene (123) in very good 82 % yield (Scheme 30). Unfortunately, non-asymmetric induction was observed, leading to the dibromide 125 with very low enantioselectivity. Fujita et al.[50] prepared, following the previously reported procedure by Ishihara et al.[32] (Scheme 13), a new family of catalysts (R)-126 a–e and (R,R)-127 (Figure 7). In this case, chiral ester derivatives instead of chiral amides were used. Going further in the investigation of the reaction mechanism catalyzed by these optically active hypervalent io-

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Scheme 30. Dihalogenation of alkenes reported by Lupton et al.

d-lactone was selectively formed in high yield and enantioselectivity. Varying the substrate to the methyl ester derivatives 128 a–c along with the nucleophile, d-lactones 129 a– c were again preferentially observed, depending the enantioselectivity on the employed catalyst (Scheme 31). Encouraged by these results, the authors later proposed a plausible mechanism, with two nucleophilic displacements taking place with inversion of configuration, yielding selectively the corresponding syn product. According to this mechanism, the alkene is attacked on the Si face by the catalyst. Additionally, some of the iodaneACHTUNGRE(III) reagents were studied in solution by mass spectroscopy, suggesting that the enantioselectivity of the process might be controlled by the interaction between the lactate moiety and the hypervalent iodineACHTUNGRE(III) atom (see Scheme 14 for a similar intermediate structure described by Ishihara et al.).[32] Finally, the method was applied to the asymmetric synthesis of the biologically active compound 130 in 73 % yield and 95 % ee using the antipodal enantiomer (S)-126 a (Scheme 31). In 2011, the same authors[51] developed an interesting variant for the preparation of optically active 1,3-dioxolan-2-yl cation, employing it in Prvost and Woodward reactions (Scheme 32). The enantioselective oxylactonization of al-

Figure 7. Chiral hypervalent iodineACHTUNGRE(III) compounds (R)-126 a–e and (R,R)-127 prepared by Fujita et al.

dineACHTUNGRE(III) reagents, the authors studied the oxylactonization of o-alkenylbenzoates 128 a–c more thoroughly (Scheme 31). The endo selectivity of the process, the role of the nucleophile and the substrate, as well as the efficiency of various catalysts were studied. When 2-ethenylbenzoic acid was exposed to oxidative cyclization conditions, the corresponding

Scheme 32. Switchover on enantioselectivity diacetoxylation of alkenes 131.

Scheme 31. endo-Selective oxylactonization reported by Fujita et al.

Chem. Eur. J. 2013, 19, 17244 – 17260

kenes 131 mediated by lactate-derived aryl-l3-iodanes (R)132 a,b or (R,R)-127 was subsequently followed by a nucleophilic attack that allowed the selective formation of a specific adduct according to the nature of the nucleophile. The syn products (syn-133) were formed due to the addition of water at the 2-position of the cation intermediate 134 with retention of configuration. In contrast, the anti products, anti-133, were a consequence of a SN2 attack of acetic acid to the 4-position of 134 with inversion of configuration (Scheme 32). This switchover of the stereochemical course of the reaction was also observed with styrene derivatives, yielding S and R enantiomers in good yields and excellent

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A. Parra and S. Reboredo

Scheme 33. Intermolecular enantioselective diamination of styrenes 135 a–c reported by MuÇiz et al. Scheme 34. Aziridination of allylic carbamate 139 mediated by (S)-138.

ees. The results derived from the use of ketene silyl acetal and trimethylsilyl bromide as alternative nucleophiles did not afford the desired products, but confirm the formation of the proposed intermediate. In 2011, MuÇiz et al.[52] solved the traditional problem of the challenging deamination of nonfunctionalized alkenes in an enantioselective version using Fujitas catalyst (R,R)-127 (Scheme 33). Under the mild optimized conditions, two nitrogen atoms (methysulfonyl groups are susceptible of removal under reductive reaction conditions) were transferred to the styrene derivatives 135 a–c giving the products 136 a– c in moderate to good yields and high ees (Scheme 33). When other alkenes were evaluated, the corresponding diACHTUNGREamine derivatives were yielded in good yields albeit in lower ees. This oxidation process is in agreement with the previously reported mechanism,[53] highlighting an aziridinium intermediate participation which rationalizes the high enantiomeric excesses obtained. Later, Xu, Che et al.[54] achieved the intramolecular aziridination of several allylic carbamates in very good to excellent yields mediated by PhIO. Since the products were sensitive to the water, the presence of molecular sieves was crucial to observe the desired transformation. The replacement of PhIO with the chiral binaphthyl iodaneACHTUNGRE(III) (S)-138 (Scheme 34), which was prepared by using a modified Kitas methodology from compound 127,[27] made the enantioselective aziridination reaction of 139 possible to give 140, followed by subsequent in situ opening, providing 141 derivative in a promising 16 % ee. Wirth et al.[55] investigated the stereoselective oxyaminations of tosyl-substituted homoallylic urea derivatives 142 using Ishiharas reagent[32] (R,R)-54 (Scheme 13), which triggered off the synthesis of bicyclic compounds 143 (Scheme 35) in good yields and excellent ees. After testing several hypervalent iodineACHTUNGRE(III) compounds, the authors figured out that the first cyclization took place after the activation of the double bond with the iodine reagent (activated in part by TMSOTf) followed by the first nucleophilic attack. The subsequent substitution of the hypervalent iodine moiety, which transformed into an excellent leaving group, yielded the desired heterocycles. The method was sat-


Scheme 35. Oxyamination of alkenes-ureas promoted by (R,R)-54.

isfactorily applied to different substrates (e.g., 144 giving 145), including those bearing substituents different from tosyl on the nitrogen atom (e.g., 146 giving 147; Scheme 35). It must be taken into account that the Lewis acid as well as the solvent, played a key role in the reaction course. Recently, Fujita et al.[56] demonstrated how valid their previously developed method[50] (Scheme 31) was by extending the process to the synthesis of various 4-oxyisochroman-1one polyketide metabolites 148–150 (Figure 8). For the compound 148, the aforementioned conditions (Scheme 31) followed by a hydrolysis process, were applied on the corresponding alkene-ester yielding 4-hydroxymellein in 61 % yield. For the preparation of the remaining target compounds 149 and 150, a common transformation using 151 as starting material provided both precursors 152 and 153, respectively, in moderate yields and excellent enantioselectivities (Scheme 36). By simple hydrolysis of the acetate groups, the desirable fusarentin 149 as well as the epimer of monocerion epi-150 were obtained.

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Figure 8. Target metabolites synthesized by Fujita et al.

Scheme 37. Aminofluorination of alkenes developed by Nevado et al. Scheme 36. Preparation of 149 and 150.

At essentially the same period, Nevado et al.[57] studied the aminofluorination of alkenes mediated by a new catalyst (R,R)-155 (Scheme 37). Using the successful analogous chiral Ishiharas iodoarenes[32] (R,R)-154 (Scheme 13) and, under treatment with Selectfluor/Et3N.HF, they were able to obtain (R,R)-155 in excellent yields (Scheme 37). This new reagent catalyzed the intramolecular aminofluorination of pentenamines 156 a–f. Notably, total regioselectivity for the 6-endo-cyclization products 157 a–f was observed. In most cases good yields and ees were obtained. The enantiomeric purity of the compounds was improved with a simple recrystallization (ee > 99 %). Next, the same authors investigated this reaction on hexenamines for giving the corresponding b-fluorinated azepanes. In this case, a combination of the hypervalent iodine reagent (R,R)-155 and a gold complex ([2-PicAuNTf2]) was crucial to carry out the cyclization, because the 7-endo-trig cyclization is a less favorable route. The yields and enantioselectivities were similar to those found for the six-membered rings. Recently, MuÇiz et al.[58] described the enantioselective intermolecular diamination of styrene 104 (Scheme 38) through the in situ generation of new hypervalent iodineACHTUNGRE(III) species derived from Ochiais catalyst 66[34] (Figure 3). The asymmetric induction was dependent on the substituents at the sulfonyl moiety on the nitrogen atom, providing in both cases 158 a and 158 b with moderate enantioselectivities (Scheme 38). Although the isolation of the involved active hypervalent iodineACHTUNGRE(III) species was not accomplished, they proposed (R)-159 as a possible intermedi-

Chem. Eur. J. 2013, 19, 17244 – 17260

Scheme 38. Styrene diamination protocol reported by MuÇiz et al.

ate, since similar catalysts were prepared and isolated for carrying out the achiral version. Very recently, Wirth et al.[59a] employed aryl-substituted alkenes (160 a–e) in an interesting oxidative rearrangement. They observed that both the yield and the enantioselectivity depended on the substitution at the aromatic ring (Scheme 39). Taking into account the need for previous activation of the hypervalent iodineACHTUNGRE(III) reagent,[59b] a wide range of reaction conditions were evaluated. They found that the hypervalent iodine compound (R,R)-54 together with TMSOTf as the activating Lewis acid were the best conditions to study the scope of the reaction (Scheme 39). The reaction was compatible with a wide range of substrates giving the products 161 a–e in moderate to good yields and excellent ees. To gain insight into the mechanism, more experiments were conducted, observing that the reaction proceeded by means of an aryl ring migration.

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A. Parra and S. Reboredo

Scheme 39. Oxidative rearrangement catalyzed by (R,R)-54.

Summary and Outlook In the last century, hypervalent iodine chemistry has emerged as an important synthetic tool in organic synthesis. In this field, the use of chiral molecules containing hypervalent iodine atoms has successfully been utilized in asymmetric synthesis. In this review, we have summarized enantioselective transformations that can be triggered off by these reagents, in stoichiometric as well as in a catalytic versions. The reactivity has been divided into different sections, always specifying the oxidation state of the iodine (III or V). On the other hand, we have also illustrated the synthesis of the most significant catalysts or pre-catalysts, with the aim of clarifying the structure and the design of the most successful chiral l3/l5-organoiodanes. We believe that the generation of new families of chiral compounds containing polyvalent iodine (III/V) atoms will open up the development of important challenges and their application to other disciplines, such as total synthesis or pharmaceutical chemistry. Although noteworthy contributions such as the seminal works introduced by Koser, Kita, Ishihara, and Wirth, among others, have inspired remarkable studies, considerable efforts are needed to search new reactivities, recycle the catalysts and improve the enantiocontrol of these processes.

Acknowledgements The authors thank Dr. Mariola Tortosa and Dr. Jos Alemn for revising the manuscript. A.P. and S.R. are indebted to Prof. J. L. Garca Ruano and Prof. N. Martn, respectively, for their support.

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 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Published online: November 22, 2013

Chem. Eur. J. 2013, 19, 17244 – 17260

Chiral hypervalent iodine reagents: synthesis and reactivity.

Chiral hypervalent iodine chemistry has been steadily increasing in importance in recent years. This review catalogues enantioselective transformation...
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