catalytic asymmetric nozaki–hiyama reactions with a tridentate bis(oxazolinyl)carbazole ligand

169© 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.

Catalytic Asymmetric Nozaki–Hiyama Reactions with a Tridentate Bis(oxazolinyl)carbazole Ligand

MASAHIRO INOUE, TAKAHIRO SUZUKI, AKIHIRO KINOSHITA, MASAHISA NAKADADepartment of Chemistry and Biochemistry, Advanced School of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan

Received 28 February 2008; Accepted 25 April 2008

ABSTRACT: Nozaki–Hiyama reactions are powerful CrII-mediated C—C bond-forming reactions conducted under mild conditions that show excellent compatibility with various functional groups. Therefore, Nozaki–Hiyama reactions have been utilized for many total syntheses of complex natural products, but at least two equivalents of CrII salt are required to complete the reaction because CrII salt is a one-electron donor. In 1996, however, the quantity of CrII salts required was successfully reduced by a catalytic redox system reported by Fürstner and Shi. Since the report by Fürstner, the catalytic asymmetric Nozaki–Hiyama reactions have attracted attention because they would allow control over enantioselectivity, thereby further enhancing the versatility of Nozaki–Hiyama reactions. In this review, we describe the development of a tridentate bis(oxazolinyl)carbazole ligand for the catalytic asymmetric Nozaki–Hiyama allylation, methallylation, propargylation, and allenylation. Also described are their successful applications to the highly stereoselective construction of the side chain of calcitriol lactone, as well as structure elucidation and the enantioselective fi rst total synthesis of the potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, FR901512 and FR901516. © 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 8: 169–181; 2008: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20148

Key words: asymmetric catalysis; ligand; Nozaki–Hiyama reaction

The Chemical Record, Vol. 8, 169–181 (2008)

T H E C H E M I C A L

R E C O R D

� Correspondence to: Masahisa Nakada; e-mail: [email protected]

Introduction

The CrII-mediated C—C bond-forming reactions originally developed by Nozaki and Hiyama et al.1 have been studied extensively.2 These powerful transformations, which proceed under mild conditions and show excellent compatibility with various functional groups, have been used for many total syn-theses of complex natural products.2

Despite the noteworthy features of the Nozaki–Hiyama reactions, they were limited in the early stages by the require-ment for at least two equivalents of CrII salt to complete the reaction, because CrII salt is a one-electron donor. In 1996,

however, the catalytic redox system for the Nozaki–Hiyama reactions reported by Fürstner et al. successfully reduced the quantity of CrII salts required, making these reactions more valuable and environmentally benign.3

Since the report by Fürstner, the catalytic asymmetric Nozaki–Hiyama reactions have drawn much attention because they permit control over enantioselectivity, a feature that further enhances the versatility of these reactions. Conse-

© 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.

T H E C H E M I C A L R E C O R D

170

quently, the preparation of a chiral ligand effective for catalytic asymmetric Nozaki–Hiyama reactions has been explored.

While some chiral ligands effective for the asymmetric catalysis of Nozaki–Hiyama reactions have been developed to date, the reactions displayed unsatisfactory enantioselectivity in the early stages.4,5 Indeed, prior to our fi rst report,6,7 only limited studies on the asymmetric catalysis of Nozaki–Hiyama reactions have appeared in the literature.

In this review, we describe the development of a tridentate bis(oxazolinyl)carbazole ligand for the catalytic asymmetric Nozaki–Hiyama reactions, and present their applications to natural product synthesis.

Design and Synthesis of C2-symmetrical Chiral Tridentate Carbazole Ligand6–9

We have designed and synthesized a C2-symmetrical chiral tridentate bis(oxazolinyl)carbazole ligand 1 (Fig. 1) because:

� Takahiro Suzuki was born in 1977 in Saitama, Japan. He received his B.S. (2000), M.S. (2002), and Ph.D. (2005) degrees from Waseda University under the supervision of Prof. Masahisa Nakada. During his Ph.D. course, he was appointed assistant professor (2003–2005) and worked with Prof. Masahisa Nakada. After working as research associate (2005–2006) with Prof. Masahisa Nakada, he joined Prof. K. C. Nicolaou’s group as a postdoctoral fellow (2006–2007) at The Scripps Research Institute, La Jolla, CA, USA. In 2007, he moved to the Institute of Chemical Engineering Science, Singapore, as research fellow with Prof. K. C. Nicolaou and Dr. David Yu-kai Chen. His research interests are total synthesis of bioactive complex natural products, asymmetric catalysis, new synthetic methodology, and chemical biology. �

� Masahiro Inoue was born in 1979 in Mie, Japan. He received his B.S. (2002), M.S. (2004), and Ph.D. (2007) degrees from Waseda University under the supervision of Prof. Masahisa Nakada. During his Ph.D. course, he was appointed assistant professor (2005–2007) and worked with Prof. Masahisa Nakada. In 2007, he joined Daiichi Sankyo Co., Ltd. where he is currently a researcher. His current research interests are in the areas of medicinal chemistry. �

(i) ligand 1 fi rmly binds to chromium by three chromium–nitrogen bonds, and the Cr-ligand 1 complex formed has a very low tendency to dissociate, preventing the reaction of the ligand-free achiral organochromium reagent, (ii) ligand 1 leaves a vacant coordination site on the Cr-ligand complex at which an aldehyde can bind, and (iii) electronic and/or steric tuning of the Cr-ligand complex would be possible when an appropriate substituent is attached to the carbazole ring and/or the oxazole ring.

First, we prepared ligand 1a, but it showed relatively low solubility in some organic solvents.7 Therefore, we next prepared ligands 1b–d, which possessed phenyl groups at the carbazole ring that improved the solubility.6,8 We have also reported a new synthetic method for ligand 1 by Pd-catalyzed amidation, successfully improving the yield.9 This method offers benefi ts in preparing new variants of ligand 1 that were also inaccessible by the previous method.

C a t a l y t i c A s y m m e t r i c N o z a k i – H i y a m a R e a c t i o n s


� Masahisa Nakada was born in 1959 in Tokyo, Japan. He received his B.S. (1982) and M.S. (1984) degrees from The University of Tokyo, and was appointed assistant professor at The Uni-versity of Tokyo during his Ph.D. course in 1987. He received his Ph.D. degree in 1988 from The University of Tokyo under the supervision of Prof. Masaji Ohno, and joined Professor Shibasaki’s group in 1991. After spending 1 year and 4 months from the beginning of FY1992 as a postdoc-toral fellow with Prof. K. C. Nicolaou at The Scripps Research Institute, he was promoted to associ-ate professor at Waseda University in 1995. Since 2000, he has been a professor in the Department of Chemistry and Biochemistry at Waseda University. His research interests include total synthesis of bioactive complex natural products, asymmetric catalysis, new synthetic reactions, and chemical biology. �

� Akihiro Kinoshita was born in 1973 in Shizuoka, Japan. He received his B.S. (1997) and M.S. (1999) degrees from Waseda University under the supervision of Prof. Masahisa Nakada. In 1999, he joined Ono Pharmaceutical Co., Ltd. where he is currently a researcher. His current research interests are in the areas of medicinal chemistry. �

Catalytic Asymmetric Nozaki–Hiyama Allylation and Methallylation6,7

Asymmetric catalysis of Nozaki–Hiyama allylation with ligand 1 was fi rst investigated. We adopted Fürstner’s conditions3 because metallic Mn was surmised to be a suitable co-reducing reagent for enantioselective allylation due to its low intrinsic reactivity.10

In the initial experiment, ligand 1a, CrCl2, and Mn were mixed in THF under an atmosphere of Ar at room temperature

in the absence of any added base. The Cr-ligand 1a complex thus prepared in situ was used for the enantioselective allylation. To the reaction mixture was added allyl bromide, and the mixture was stirred at room temperature for 30 min. Then, benzaldehyde and TMSCl were added successively to the reac-tion mixture at room temperature. After 12 h, crude products were treated with 2N HCl (or TBAF) to afford the allylated product (63%, 71% ee, Table 1, entry 1).

We optimized the reaction conditions and found that use of a base changed the yield and ee (entries 2–8). In addition, the yield and ee clearly depended on the solvent, and THF was found to be the best solvent (entries 3 and 9–11). The use of allyl bromide was also important for optimum enantioselectiv-ity because the use of allyl chloride or allyl iodide decreased the yield and/or the enantioselectivity (entries 13, 14, and 15). The low selectivity was attributed to the formation of a race-mate derived from the reaction of the achiral allylmanganese reagent formed in situ. Surprisingly, the enantioselectivity was reduced when the reaction was conducted at −10°C (entry 12) or by use of allyl iodide at 0°C (entry 15). These results are

1a (R1=H, R2=Ph)1b (R1=Ph, R2=i-Pr)1c (R1=Ph, R2=Me)1d (R1=Ph, R2=t-Bu)

NHO

N NO

R2 R2

R1 R1

Fig. 1. Structure of tridentate bis(oxazolinyl)carbazole ligand 1.



172

Table 1. Catalytic asymmetric Nozaki–Hiyama allylation of benzaldehyde with ligand 1a.

Cr

allyl

ligand 1a

1) CrCl2 (9.7 mol%) Mn (2.0 equiv) Base

Solvent, rt2) Allyl-X (2.0 equiv), rt

1) PhCHO (1.0 equiv) TMSCl (2.0 equiv)

temperature2) 2N HCl

Ligand 1a(10 mol%)

complex

Ph

OH

Entry X Base (equiv) Solvent Temp (°C) Time (h) Yield[a] (%) Ee[b] (%)

1 2 3 4 5 6 7 8 9101112131415

BrBrBrBrBrBrBrBrBrBrBrBrClII

–Py (0.2)TEA (0.2)DIPEA (0.2)NaHCO3 (0.3)K2CO3 (0.1)NaH (0.1)n-BuLi (0.1)TEA (0.2)TEA (0.2)TEA (0.2)TEA (0.2)TEA (0.2)TEA (0.2)TEA (0.2)

THFTHFTHFTHFTHFTHFTHFTHFEt2OCH3CNDMFTHFTHFTHFTHF

rtrtrtrtrtrtrtrtrtrtrt

−10rtrt0

12121212121212121212124024 1 9

6396969274938784 031[c]13[d]62647495

7169716873716261–243061416822

[a]Isolated yields.[b]See reference [7].[c]1,2-Diphenyl-1,2-ethanediol also formed, but was not isolated.[d]1,2-Diphenyl-1,2-ethanediol (57%) was isolated.

not well understood, but could arise from the reduced solu-bility of the Cr-ligand 1a complex at the low temperature and the competitive formation of the achiral allylmanganese reagent.

The Cr-ligand 1b complex with the enhanced solubility, which was prepared in situ under the same conditions as for Cr-ligand 1a, was used for the enantioselective allylation to afford alcohol 2a in 93% yield (90% ee, Table 2, entry 1).6 The ee further increased to 93% ee (entry 2) in the reaction at 0°C. Allyl chloride afforded almost the same result as allyl bromide (entry 3), but allyl iodide again gave a low ee (entry 4). Other aldehydes, including saturated and unsaturated ali-phatic aldehydes, were all allylated in high yields with 86–95% ee (entries 5–10). Furthermore, this enantioselective reaction was successfully extended to the methallylation of various aldehydes by the use of appropriate methallyl halides (entries 11–17). Thus, the highly enantioselective allylations and methallylations using ligand 1b proved their applicability to a broad range of aldehydes.

The diastereoselectivity in the reaction of benzaldehyde with crotyl bromide was somewhat lower than that observed in the reaction without ligand 1b (Scheme 1).6 The reaction

was anti-selective, with product formation refl ecting 75% ee (anti-form) and 21% ee (syn-form). Confi guration of the major enantiomer of anti-3 was (1S, 2S), showing that benzaldehyde preferentially reacted at its si-face. This si-face selectivity can be seen in Table 2 where 2d, 2f, and 2j have (R)-confi guration, and others have (S)-confi guration, revealing that all aldehydes reacted predominantly at their si-face.

The anti-selectivity noted earlier is not high enough to indicate a cyclic Zimmermann–Traxler-type transition state, which may account for the si-face selectivity. Thus, an acyclic transition state cannot be ruled out.

Recycling the Cr-ligand Complex6

We expected that the Cr-ligand 1b complex would be recycled because of its predicted stability. As shown in Table 3, the Cr-ligand 1b complex recovered after the reaction was successfully recycled twice. It is worth noting that the ee of the products in the recycling experiments were almost unchanged from the values in entry 2 (93% ee) and entry 8 (94% ee) of Table 2, respectively.



Table 2. Catalytic asymmetric Nozaki–Hiyama allylations and methallylations of aldehydes with ligand 1b.

Cr

allyl

ligand 1b

1) CrCl2 (10 mol%) Mn (2.0 equiv) DIPEA (30 mol%)

THF, rt2) R1-X (2.0 equiv), rt

1) R2CHO (1.0 equiv) TMSCl (2.0 equiv), rt

2) TBAF

Ligand 1b(10 mol%)

complex

R2 R1

OH

2a-j

Entry Product R1 X R2 Time (h) Yield[a] (%) Ee[b] (%)

1 2a Allyl Br Ph 12 93 90(S)2[c] 2a Allyl Br Ph 12 89 93(S)3 2a Allyl Cl Ph 16 95 89(S)4 2a Allyl I Ph 12 52 64(S)5 2b Allyl Br p-BrPh 12 87 92(S)6 2c Allyl Br PhCH:CH 12 87 95(S)

86(R)7[c] 2d Allyl Br PhCH2CH2 12 918 2e Allyl Br c-C6H11 12 95 94(S)9 2e Allyl Cl c-C6H11 12 88 93(S)

10 2f Allyl Br n-C5H11 12 83 92(R)11 2g Methallyl Br Ph 16 77 46(S)12 2g Methallyl Cl Ph 16 96 95(S)13 2h Methallyl Cl PhCH:CH 16 50 90(S)14 2i Methallyl Br c-C6H11 16 96 96(S)15 2i Methallyl Cl c-C6H11 16 98 95(S)16 2j Methallyl Br n-C5H11 16 65 79(R)17 2j Methallyl Cl n-C5H11 16 83 96(R)

[a]Isolated yields.[b]See reference [6].[c]Reaction carried out at 0°C.

Ph

OHanti-3

anti , 75% ee (1S, 2S); syn, 21% ee (1R, 2S)anti / syn = 73 / 27, 38%

without ligand 1anti / syn = 86 / 14, 48%

Ph

OHsyn-3

+

12

12Cr

crotyl

ligand 1b

1) CrCl2, Mn DIPEA, THF, rt

2) crotyl bromide, rt

1) PhCHO TMSCl

rt, 16 h2) TBAF

Ligand 1b(10 mol%)

complex

Scheme 1. Enantioselective crotylation of benzaldehyde with ligand 1b.

Catalytic Asymmetric Nozaki–Hiyama Propargylation8

Encouraged by the successful results in the catalytic asym-metric Nozaki–Hiyama allylations and methallylations, we examined the enantioselective propargylation of benzaldehyde with ligand 1b. As shown in Table 4, the reaction was complete after 18 h to provide the propargylated (S)-product in 80% yield with −28% ee (entry 1).

Propargylation with the Cr-ligand 1c complex, prepared in situ by the same method as for the Cr-ligand 1b complex,

also afforded the (S)-product (94%, −26% ee, entry 3). We found that formation of the Cr-ligand 1d complex was slow and left a considerable amount of unreacted CrCl2, probably due to the steric hindrance of t-butyl groups. Therefore, the Cr-ligand 1d complex that formed was isolated and used. The reaction with the isolated Cr-ligand 1d complex required a longer reaction time (60 h) to provide (R)-product (75%, 71% ee, entry 5). This result surprised us because not only was the ee increased, but also the enantioselectivity was reversed, in contrast to the enantioselective allylation, which generally produced (S)-products (Tables 1–3).



174

Table 4. Catalytic asymmetric Nozaki–Hiyama propargylation of benzaldehyde with ligands 1b–d.

1) Mn (2.0 equiv) DIPEA (30 mol%), THF, rt

2) propargyl bromide (2.0 equiv), rt

1) PhCHO (1.0 equiv) TMSCl (2.0 equiv), rt

2) TBAF

Cr-ligand 1complex

(10 mol%)

Ph

OH

4

Entry Ligand Time (h) Yield[a] (%) Ee[b] (%)

1 1b 18 80 −28(S)2 1b[c] 24 74 −24(S)3 1c 16 94 −26(S)4 1c[c] 16 78 −24(S)5 1d[c] 60 75 71(R)

[a]Isolated yields.[b]See reference [8].[c]Isolated Cr-ligand 1 complex was used.

Table 5. Solvent effect on the enantioselective propargylation with ligand 1d.

1) Mn (2.0 equiv) DIPEA (30 mol%) solvent, rt


1) PhCHO (1.0 equiv) TMSCl (2.0 equiv), rt

2) TBAF

Cr-ligand 1dcomplex

(10 mol%)

Ph

OH

4

Entry Solvent Time (h) Yield[a] (%) Ee[b] (%)

1 THF 60 75 712 CH3CN 18 93 563 C2H5CN 12 92 284 DMF 96 20[c] 17[d]5 1,4-dioxane 36 33 716 Diglyme 16 62 717 DME 12 93 788[e] DME 48 NR9[f] DME 120 Trace

10 CH2Cl2 48 55 621112

(CH2Cl)2

Toluene4848

TraceTrace

[a]Isolated yields.[b]See reference [8].[c]Combined yield of 4 and the corresponding allenic alcohol.[d]Ee of 4.[e]Reaction carried out at 0°C.[f]Propargyl chloride was used instead of propargyl bromide.

Table 3. Recycling the recovered Cr-ligand 1b complex.[a]

1) Mn (2.0 equiv) DIPEA (30 mol%)

THF, rt2) allyl Br (2.0 equiv), rt

1) RCHO (1.0 equiv) TMSCl (2.0 equiv)

rt2) TBAF

recoveredCr-ligand 1bcomplex(10 mol%)

R

OH

2a, 2e

Cr

allyl

ligand 1bcomplex

Entry Product R Time (h) Yield[b] (%) Ee[c] (%) Recycling

1[d] 2a Ph 24 86 92(S) First time2[d] 2a Ph 24 79 93(S) Second time3 2e c-C6H11 16 84 95(S) First time4 2e c-C6H11 16 90 94(S) Second time

[a]The Cr-ligand 1b complex remained on the base line of the preparative TLC was eluted with CH2Cl2/ethyl acetate = 1/1. The eluate was evaporated to afford a pale yellow oil, which was dissolved in CH2Cl2, washed with water, dried over Na2SO4, evaporated, dried under vacuum, and used for the recycling experiments.[b]Isolated yields.[c]See reference [6].[d]Reaction carried out at 0°C.

Although the Cr-ligand 1b and 1c complexes were iso-lated and utilized for the propargylation, almost the same results as in entries 1 and 3 were obtained (entries 2 and 4, respectively), suggesting that the preparation method of the Cr-ligand 1 complex is not a major factor in the observed change of enantioselectivity.

It should be noted that no allenic alcohol was obtained in the reactions in Table 4, despite the fact that a mixture of the homopropargylic alcohol and the allenic alcohol is usually formed in the Nozaki–Hiyama propargylation.2

The reaction in acetonitrile or propionitrile (Table 5, entries 2 and 3) was fast, and provided the product in high yield; however, the ee decreased. In DMF, not only was the reaction slow, but also both the yield and ee were low (entry 4). Moreover, a small amount of the allenic alcohol was formed in DMF (homopropargylic alcohol/allenic alcohol = 14/1). In

the case of 1,4-dioxane or diglyme, the ee was comparable to the ee obtained in THF (entries 5 and 6). Finally, DME was found to be the best solvent for this propargylation with respect to reaction time, yield, and ee (entries 1–7 and 10–12). Inter-estingly, no product was obtained at 0°C (entry 8) or by use of propargyl chloride (entry 9).



Table 6. Enantioselective propargylation of various aldehydes with ligand 1d.

1) Mn (2.0 equiv) DIPEA (30 mol%) DME, rt


1) RCHO (1.0 equiv) TMSCl (2.0 equiv), rt

2) TBAF

Cr-ligand 1dcomplex

(10 mol%)

R

OH

4-10

Entry R (product no.) Time (h) Yield[a] (%) Ee[b] (%)

1 Ph (4) 12 93 782 2-Naphthyl (5) 20 95 743 (E)-PhCH:CH (6) 16 91 734 PhCH2CH2 (7) 16 20 515 CH3(CH2)4 (8) 16 55 586 c-C6H11 (9) 16 86 827 t-Bu (10) 16 41 98

[a]Isolated yields.[b]See reference [8].

Table 7. Catalytic propargylation of benzaldehyde without ligand 1.[a]

+

2 equiv1 equiv

+PhCHO BrPh

OH

Ph

OH1) conditions

2) TBAF

4a 4b

Entry Solvent CrCl2 (mol %)

DIPEA (mol %)

Time (h)

Yield[b] (%; 4a/4b)

1234

DMEDMEDMEDMF

10 0 0 0

3030 0 0

12121696

93; 15/1 0 0 6; 3.5/1

[a]TMSCl (2.0 equiv) and Mn (2.0 equiv) were used in all reactions.[b]Combined isolated yields of 4a and 4b.

Various aldehydes were successfully propargylated under the optimized conditions (Table 6). The reactions of 2-naphthaldehyde (entry 2) and (E)-cinnamaldehyde (entry 3) with ligand 1d afforded the (R)-products (95%, 74% ee; 91%, 73% ee, respectively). The (R)-product preferentially formed in the reactions of hydrocinnamaldehyde (entry 4) and also n-hexanal (entry 5). However, the yield and ee were somewhat low (20%, 51% ee; 55%, 58% ee, respectively). In contrast, the reactions of bulky aliphatic aldehydes showed high ee; thus, cyclohexylaldehyde (entry 6) was propargylated in 86% yield (82% ee). In the case of pivalaldehyde, the most bulky alde-hyde in Table 6, the ee of the product increased to 98% ee.

The allenylchromium(III) intermediate was shown to be in equilibrium with the propargylchromium(III) intermediate, and their ratio was dependent on their structure and/or the additives used.11 Consequently, these intermediates usually afford a mixture of homopropargylic alcohol and allenic alcohol. However, no allenic alcohol was formed in entries 1–7.

We carried out the propargylation without ligand 1 and found that the allenic alcohol was formed as a minor product in DME (Table 7, entry 1). The exclusive formation of the propargylated alcohol with ligand 1 cannot yet be clearly explained, but ligand 1 could stabilize the allenylchromium intermediate or accelerate its preferential formation, thus favoring the propargylation.11

The reactions without CrCl2 and ligand 1 in the presence (entry 2) or absence (entry 3) of DIPEA provided no product in DME. These results suggested that formation or reaction of the organomanganese could be ruled out in DME.

The homopropargylic and allenic alcohols formed in the reaction without CrCl2 and ligand 1 in DMF (entry 4, the

ratio = 3.5/1). Hence, we surmised that the allenyl- and propargylmanganese intermediates would form in DMF and competitively react with benzaldehyde to give the homo-propargylic alcohol and the allenic alcohol, respectively.

The reversal of the enantioselectivity by changing the substituent of ligand 1 and the increment of the re-face selec-tivity with the increasing bulkiness of aldehyde could be ratio-nally explained by the proposed models, A and B, in Figure 2. When the substituent of ligand 1 is small, the aldehyde coor-dinates at the equatorial position and favors the reaction at the si-face under the infl uence of the asymmetric circumstance (model A). In contrast, when the substituent of ligand 1 is bulky, steric strain between the aldehyde and the oxazoline substituents would be large and, therefore, the bulky aldehyde would preferentially coordinate at the apical position, making the re-face reaction of the aldehyde dominant (model B).

Alternative explanations are possible for the change of enantioselectivity. For example, the possibilities that the reac-tion proceeds in an intermolecular fashion and that the Cr-ligand 1 complex is a dinuclear complex12 cannot be ruled out.

1b (i-Pr), 1c (Me)

1d (t-Bu)

A > B

A << B

CrLL L

O

X

re-faceattack

R

H

B

CrLL L

O R

H

X

si-faceattack

A

L=Ligand ; X=halogen

Fig. 2. Proposed models A and B.



176

Table 8. Catalytic asymmetric Nozaki–Hiyama allenylation of benzaldehyde with ligand 1.

Ph

OH

R

Ligand(10 mol%)

1) CrCl2 (10 mol%), Mn (2.0 equiv) base (30 mol%), solvent, rt2) RCCCH2Br, rt

3) PhCHO, TMSCl (2.0 equiv), temperature4) dil. HCl

Entry Ligand Solvent Temperature (°C) Base R[a] Time (h) Yield[b] (%) Ee[c] (%)

1 1b THF rt DIPEA TMS 8 92 522 1c THF rt DIPEA TMS 6 90 643 1d THF rt DIPEA TMS 12 92 −29[d]4[e] 1c THF rt DIPEA TMS 8 85 475 1c DME rt DIPEA TMS 12 72 616 1c CH3CN rt DIPEA TMS 12 74 607 1c EtCN rt DIPEA TMS 12 83 718 1c CH2Cl2 rt DIPEA TMS 24 49 579 1c DMF rt DIPEA TMS 48 56[f] 74[g]

10 1c EtCN 0 DIPEA TMS 16 80 7611[h] 1c EtCN 0 DIPEA TMS 20 81 7612 1c EtCN 0 K2CO3 TMS 16 72 7613 1c EtCN 0 γ-Collidine TMS 16 65 7614 1c EtCN 0 Pyridine TMS 30 64 6515 1c EtCN 0 DIPEA TES 24 81 7416 1c EtCN 0 DIPEA TIPS 30 49 6617 1c EtCN 0 DIPEA DMPS 24 66 7318 1c EtCN 0 DIPEA MDPS 30 79 7319 1c EtCN 0 DIPEA DMS 16 81 80

[a]TES, triethylsilyl; TIPS, triisopropylsilyl; DMPS, dimethylphenylsilyl; MDPS, methyldiphenylsilyl; DMS, dimethylsilyl.[b]Isolated yields.[c]See reference [13].[d]The minus sign indicates that the enantioselectivity of the reaction was reversed in this case to afford the (S)-product.[e]1-Trimethylsilyl-3-chloropropyne was used instead of 1-trimethylsilyl-3-bromopropyne.[f]A mixture of allenic alcohol and homopropargylic alcohol (1.8 : 1) was obtained and the combined yield is given.[g]The ee value of the allenic alcohol as determined from the corresponding α-methoxy-α-(trifl uoromethyl)phenylacetyl (MTPA) ester. The ee value of the homo-propargylic alcohol was 4%.[h]Molecular sieves 4A (200 wt %) were added.

Ph CHO +

2.0 equiv

1) CrCl2 (10 mol%) Mn (2.0 equiv) DIPEA (30 mol%) TMSCl (2.0 equiv) THF, rt

2) dil. HCl, 85 %

Ph

OH

TMS

TMSCCCH2Br

Scheme 2. Catalytic Nozaki–Hiyama allenylation without ligand.

Catalytic Asymmetric Nozaki–Hiyama Allenylation13

Allenylation with CrII and a propargyl halide is particularly useful due to the ease of operation, high chemoselectivity, and excellent compatibility with various functional groups.14 In the reaction of CrII with a propargylic halide, the allenylchromium(III) and propargylchromium(III) intermedi-ates exist in equilibrium, and the ratio of these intermediates depends on their structure and/or additives.2,13,14 However,

allenylations of carbonyl compounds with CrII and the termi-nally substituted propargyl halides afford allenic alcohols as the major products.2,8,13,14 Hence, we surmised that the terminally silylated propargyl halide would generate 2-silylated secondary allenic alcohol, which can easily be desilylated15 and can also be used as allenylsilane. Therefore, we focused our attention on the study of the asymmetric catalysis of the Nozaki–Hiyama allenylation with terminally silylated propargyl halides.

First, a CrII-mediated reaction of commercially available 1-trimethylsilyl-3-bromopropyne with benzaldehyde was carried out in the absence of the chiral ligand under catalytic conditions6–8 (Scheme 2). The reaction was complete after 4 h, affording the allenic alcohol as the sole product in 85% yield.

Subsequently, a CrII/chiral-ligand-mediated reaction of 1-trimethylsilyl-3-bromopropyne with benzaldehyde was carried out. The reaction with ligand 1b took 8 h to fi nish and gener-ated the (R)-product in 92% yield with 52% ee (Table 8, entry



1). The reaction with ligand 1c was complete after 6 h, gener-ating the (R)-product in 90% yield with 64% ee (entry 2). Interestingly, the enantioselectivity in the reaction with ligand 1d was reversed to afford the (S)-product in 92% yield with 29% ee after 12 h (entry 3). It is noteworthy that the least bulky ligand 1c gave the best result and that only allenic alco-hols were generated in entries 1–3. Reaction with propargyl chloride and ligand 1c did not improve the result (entry 4; 85%, 47% ee).

Next, the reaction was carried out in various solvents with ligand 1c and propargyl bromide. The reactions in DME (entry 5) and acetonitrile (entry 6) required 12 h for comple-tion, and the ee values were slightly decreased. Although the reaction time was not shortened, propionitrile increased the ee value to 71% (entry 7). Other solvents gave unrewarding results. For example, the reaction in CH2Cl2 required much more time, and both the yield and ee were markedly decreased (entry 8; 24 h, 49%, 57% ee). DMF generated the allenic alcohol (56%, 74% ee) along with the propargylic alcohol (20%, 4% ee).

The reaction at 0°C prolonged the reaction time (16 h); however, the ee was increased to 76% ee (entry 10). Therefore, all further reactions were carried out at 0°C. Use of molecular sieves did not affect the ee and merely extended the reaction time (entry 11).

The effect of the base was also surveyed. Potassium car-bonate (entry 12) and bulky γ-collidine (entry 13), which would not coordinate to chromium, gave results comparable with those obtained by the use of DIPEA. However, pyridine (entry 14) gave diminished results in all respects (reaction time, yield, and ee), probably due to its strongly coordinating nature.

We found that the silyl group of the propargyl halide affected the enantioselectivity. While silyl groups bulkier than the TMS group (TES, TIPS, DMPS, and MDPS) did not improve the enantioselectivity (entries 15–18), the smaller DMS group (entry 19) afforded the best result (81%, 80% ee).

As the ee of the allenic alcohol was high (74% ee) in the reaction in DMF (Table 8, entry 9), the reaction in the pres-ence of an additive possessing a polar functional group was examined. The additives possessing an oxygen–phosphine bond (Table 9, entries 1–4) or oxygen–sulfur bond (entry 5) had no effect on the enantioselectivity; however, some ureas improved the ee value. Thus, the reaction in the presence of DMPU afforded the product in 91% yield with 82% ee (entry 6). The reaction in the presence of DMI gave the best enanti-oselectivity (entry 7; 97%, 83% ee). Other ureas (entries 8–11) did not improve the result given in entry 7.

Under the optimized conditions (Table 9, entry 7), various aldehydes were successfully allenylated with high enantioselec-tivity, thereby revealing the generality of this catalytic asym-metric allenylation (Table 10).

The absolute confi gurations of the products13 disclosed that all the aldehydes were allenylated predominantly at the si-face. Compared with the propargylation,8 in which the aldehydes showed re-face selectivity (Table 6), the enantioface

Table 9. Effect of additive on the enantioselective allenylation of benzaldehyde.

Ph

OH

DMS

Ligand 1c(10 mol%)

1) CrCl2 (10 mol%), Mn (2.0 equiv) DIPEA (30 mol%), EtCN, rt2) DMSCCCH2Br, rt

3) PhCHO, TMSCl (2.0 equiv), 0 oC4) dil. HCl

Entry Additive[a] (1.0 equiv)

Time (h) Yield[b] (%) ee[c] (%)

1 2 3 4 5 6 7 8 91011

HMPAPh3P(O)nBu3P(O)(PhO)3P(O)DMSODMPUDMIDMId

TMUDEDPUDTBI

2424364830242436483616

7569232073919717[e]21[f]7173

7680775579828373677581

[a]HMPA, hexamethyl phosphoramide; DMSO, dimethylsulfoxide, DMPU, N,N ′-dimethylpropylene urea; DMI, 1,3-dimethyl-2-imidazolidinone; TMU, N,N,N ′,N ′-tetramethylurea; DEDPU, N,N ′-diethyl-N,N ′-diphenylurea; DTBI, 1,3-di-tert-butyl-2-imidazolidinone.[b]Isolated yields.[c]See reference [13].[d]10 equivalents of DMI were used.[e]A large amount of pinacol coupling product was formed (52% yield).[f ]Homopropargylic alcohol was identifi ed by 1H NMR spectroscopy; the ratio of products was allenic alcohol: homopropargylic alcohol = 50 : 1.

Table 10. Enantioselective allenylation of various aldehydes with ligand 1c.

R

OH

DMS

Ligand 1c(10 mol%)

1) CrCl2 (10 mol%), Mn (2.0 equiv) DIPEA (30 mol%), EtCN, rt2) DMSCCCH2Br, rt

3) RCHO, TMSCl (2.0 equiv), 0 oC4) dil. HCl

Entry R Time (h) Yield[a] (%) ee[b] (%)

12345

p-MeOPhp-ClPhPhCH2CH2

c-C6H11

n-C5H11

3624242424

9091999581

8082727475

[a]Isolated yields.[b]See reference [13].



178

selectivity in the allenylation is reversed. This reversal is well explained, as shown in Figure 3. Thus, when the terminally silylated propargyl group was positioned at the less hindered apical position of the asymmetric catalyst, the aldehyde coor-dinated at the equatorial position and was allenylated from the si-face under the infl uence of the asymmetric circumstances. However, several other explanations for the enantioselectivity are possible. For example, the possibilities of the reaction pro-ceeding intermolecularly12 or the Cr-complex 1c being a dinu-clear complex cannot be ruled out.

The product obtained through this asymmetric catalysis would be a good synthetic intermediate because the silyl group can easily be desilylated. For example, as shown in Scheme 3, the allenylated product was easily desilylated in 100% yield without diminishing the ee.

Application of Catalytic Asymmetric Nozaki–Hiyama Reactions: Highly Stereoselective Construction of the Side Chain of Calcitriol Lactone, a Metabolite of Vitamin D3

6

The catalytic asymmetric Nozaki–Hiyama methallylation with ent-ligand 1b has been successfully utilized for the stereoselec-tive construction of the side chain of calcitriol lactone (Fig. 4), which is a metabolite of vitamin D3. The chiral aldehyde 11 gave the methallylated product 12 (97% de), which is a key intermediate in calcitriol lactone synthesis.16 This diastereose-lective reaction is apparently a chiral catalyst-controlled reac-tion because without ent-ligand 1b, almost no diastereoselectivity was observed (−3% de), and high diastereoselectivity (−94% de) was also obtained with ligand 1b. In the earlier synthesis, the stereoselective construction of the C23 stereogenic center in the side chain required numerous steps.16 The catalytic asymmetric Nozaki–Hiyama methallylation with ent-ligand 1b successfully provided the desired product 12 with high yield and de in a one-pot procedure by use of readily accessible reagents, successfully reducing the steps.

Structure Elucidation and Enantioselective Total Synthesis of the Potent 3-Hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitor FR90151217

FR901512 (13) and FR901516 (14) (Fig. 5) are new specifi c and strong inhibitors of HMG-CoA reductase (IC50 values of 0.95 and 14.0 nM, respectively) isolated from the fermenta-tion broth of agonomycete strain no. 14919.18 FR901512 (13) inhibits cholesterol synthesis from [14C]-acetate in Hep G2 cells with an IC50 of 1.0 nM. Single oral administration of 13 strongly inhibits sterol synthesis in rats, and daily oral admin-istration of 13 to beagle dogs decreased plasma cholesterol

CrN

N N

O

O

O R

H

Ph

Ph

si-face attackX

DMS

Fig. 3. Proposed model for the catalytic asymmetric Nozaki–Hiyama allenylation.

Ph

OH

DMS

TBAF, THF

-78 oC, 15 minPh

OH

H

100 % (single isomer)ee %38ee %38

Scheme 3. Desilylation of the product.

CHO

BnOH

BnOH

OH

-3% de, 27% (41% conv.) (rt, 30h, without ligand) 97% de, 91% (rt, 18h, with ent-ligand 1b)-94% de, 97% (rt, 18h, with ligand 1b)

2111H

HO OH

OO

OH

calcitriol lactone

23

Fig. 4. Structure of calcitriol lactone and application of the catalytic asymmetric Nozaki–Hiyama methallylation to the steroid side chain synthesis.



levels. Consequently, 13 is expected to have a hypolipidemic effect in humans.

Compared with the previously reported naturally occur-ring HMG-CoA reductase inhibitors,19 13 and 14 possess a unique tetralin core with two stereogenic centers instead of the hexahydronaphthalene ring found in mevastatin and lovastatin.20 Furthermore, the side chain, 3,5-dihydroxy-6-heptenoic acid in both compounds, differs from 3,5-dihydroxyheptanoic acid, which is found in mevastatin and lovastatin.

The potent bioactivity and unique structural features of 13 make this compound an attractive target, but the absolute structure of 13 has not been elucidated,18a and only a limited amount of 13 was available. Hence, we decided to elucidate the structure of 13 through enantioselective total synthesis utilizing the catalytic asymmetric Nozaki–Hiyama reactions developed by us.

Aldehyde 16 was prepared from readily available bromide 1521 via lithiation and formylation (Scheme 4). The catalytic asymmetric Nozaki–Hiyama methallylation of aldehyde 16 successfully provided homoallylic alcohol 17 with excellent yield and enantioselectivity (93%, 92% ee). We employed Grubbs’s second-generation catalyst22 for the ring-closing metathesis of homoallylic alcohol 17 to generate the trisubsti-tuted alkene 18 (96%). The hydroxyl group directed hydroge-nation of alkene 18 with Crabtree’s catalyst23 in DME-produced saturated alcohol 19 in 94% yield (dr ≥ 50/1). The regioselec-tive lithiation of alcohol 19 and subsequent formylation were crucial, providing aldehyde 20 in 43% yield under the opti-mized conditions. Acetylation of aldehyde 20 above 0°C was low yielding due to the formation of an unidentifi ed by-product, but performing the acetylation at −78°C improved the yield (94%, 74% conv). The diastereomeric acetate 24 was successfully prepared from alcohol 19 via 22.

Comparison of the 1H-NMR spectra of acetates 21, 24, and 13 clearly indicated that the relative confi guration of the tetralin moiety of 13 would be trans. Furthermore, alcohol 20 was gratifyingly transformed to crystalline p-bromobenzoate 25 via 3 steps (Scheme 5), and its X-ray crystallographic analy-

sis established its absolute structure as shown in Scheme 5. At the same time, we succeeded in preparing diol 26 and aceton-ide 27 from 13, and the diol prepared by reduction of aldehyde 20 with NaBH4 was spectroscopically identical to diol 26 in all respects, while the absolute structure of acetonide 27 was determined by comparison with known ent-27.24 Conse-quently, we elucidated the entire structure of FR901512 (13) as shown in Figure 5.

Further synthetic studies were continued from acetate 21 (Scheme 6). While all the attempts to assemble the side chain moiety of 13 with acetate 21 failed, reaction of acetate 21 with

O

O

O

O

HO

FR901512 (13) FR901516 (14)

O

OHCO2H

O

HO

Fig. 5. Structure of FR901512 (13) and FR901516 (14).

R1

b

15 (R1=Br)16 (R1=CHO)

a

OH

c

NH

Ph Ph

ON N

O

17

1b

18

OH

d

19

OH

22

OH

g,h

e

R2O

i

R2O

CHO

CHO

20 (R2=H)21 (R2=Ac)

f

23 (R2=H)24 (R2=Ac)

j

Scheme 4. Reagents and conditions: (a) n-BuLi, THF, −78°C; DMF, 96%; (b) methallyl chloride, CrCl2 (5 mol %), 1b (6 mol %), Mn, DIPEA, TMSCl, THF, rt, 93%, 92% ee; (c) Cl2(Cy3P)(IMes)Ru:CHPh (3 mol %), PhMe (0.03 M), 50°C, 96%; (d) H2, [Ir(cod)PCy3Py]PF6 (4 mol %), DME, 0°C, 94%, dr ≥ 50/1; (e) s-BuLi, TMEDA, hexane, −10°C; DMF, THF, −40 to 0°C, 43%; (f) Ac2O, DMAP, THF, −78°C, 70% (94% brsm); (g) Dess–Martin periodinane, CH2Cl2, 0°C; (h) NaBH4, CeCl3⋅7H2O, MeOH, −78°C, 100% (two steps), dr ≥ 50/1; (i) s-BuLi, TMEDA, hexane, −10°C; DMF, THF, −40 to 0°C; (j) Ac2O, DMAP, THF, −78°C, 13% (14% conv, two steps).

FR901512 (13)d

26OH

OTBS

O

O+

HO OH

27

HO CHO

20 a

3,5-(NO2)2BzOOBz-Br-p

25

a-c

Scheme 5. Reagents and conditions: (a) NaBH4, MeOH, 0°C, 100%; (b) p-bromobenzoyl chloride, DIPEA, CH2Cl2, 10°C; (c) 3,5-dinitrobenzoyl chloride, NEt3, DMAP, CH2Cl2, 75% (two steps); (d) see reference [17].



180

Nagata’s reagent25 provided aldehyde 28 in excellent yield (88%). Although a rather reactive benzylic acetate was incor-porated in aldehyde 28, the catalytic asymmetric Nozaki–Hiyama allylation of aldehyde 28 fortunately provided homoallylic alcohol 29 with excellent yield and stereoselectiv-ity (99%, 90% de).

The ring-closing metathesis of the acrylate of 29 with Grubbs’s fi rst-generation catalyst26 afforded α,β-unsaturated lactone 30 in 100% yield. The chemoselective and diastereose-lective epoxidation of α,β-unsaturated lactone 30 was well achieved with TBHP and Triton B in toluene, affording epoxide 31 as the sole product.27 Epoxide 31 was reacted with diphenyl diselenide, NaBH4, and acetic acid28 in THF/EtOH, providing 14 in 100% yield with complete regioselectivity. Methanolysis of 14 and subsequent cleavage of the resultant methyl ester furnished 13. The synthesized 13 and 14 were spectroscopically identical to natural FR901512 and FR901516, respectively.18a

The structure elucidation and enantioselective total syntheses of FR901512 (13) and FR901516 (14) were accomplished starting from commercially available 2-bromo-4-methylbenzaldehyde in 16.3% overall yield (15 steps, 89% average yield). The catalytic asymmetric Nozaki–Hiyama reac-tions developed by us proved their applicability and reliability through this work, enabling concise, effi cient, and protecting-group-free enantioselective total syntheses of these new statins.

Conclusion

Increasing numbers of the catalytic asymmetric Nozaki–Hiyama reactions have been reported.29,30 However, the chief studies are limited to allylation, propargylation, and allenyl-ation. That is, the asymmetric catalysis of other Nozaki–Hiyama reactions (alkenylation, alkylation, arylation, and so on) has been left undeveloped. As mentioned in the Introduc-tion, Nozaki–Hiyama reactions are practical CrII-mediated C—C bond-forming reactions performed by readily available halides with carbonyl compounds under mild conditions, showing excellent compatibility with various functional groups and with a wide range of applications. Consequently, further development of various catalytic asymmetric Nozaki–Hiyama reactions is being awaited. Obviously, the design and synthesis of new chiral ligands would be a key achievement in achieving asymmetric catalysis.

REFERENCES

[1] (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J Am Chem Soc 1977, 99, 3179; (b) Okude, Y.; Hiyama, T.; Nozaki, H. Tetrahedron Lett 1977, 18, 3829.

[2] Recent reviews: (a) Takai, K.; Nozaki, H. Proc Jpn Acad Ser B 2000, 76B(8), 123; (b) Fürstner, A. Chem Rev 1999, 99, 991; (c) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1, 1; (d) Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios, J. C. Chem Soc Rev 1999, 28, 169.

[3] (a) Fürstner, A.; Shi, N. J Am Chem Soc 1996, 118, 12349; (b) Fürstner, A.; Shi, N. J Am Chem Soc 1996, 118, 2533.

[4] (a) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Morganti, S.; Umani-Ronchi, A. Org Lett 2001, 3, 1153; (b) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Pure Appl Chem 2001, 73, 325; (c) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Tetrahedron 2001, 57, 835; (d) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Polyhedron 2000, 19, 537; (e) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Angew Chem Int Ed 2000, 39, 2327; (f) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Morganti, S.; Umani-Ronchi, A. Angew Chem Int Ed 1999, 38, 3357.

[5] Asymmetric allylations not via a catalytic process: (a) Sugi-moto, K.; Aoyagi, S.; Kibayashi, C. J Org Chem 1997, 62, 2322; (b) Chen, C.; Tagami, K.; Kishi, Y. J Org Chem 1995, 60, 5386; (c) Cazes, B.; Verniere, C.; Goré, J. Synth Commun 1983, 13, 73.

[6] Inoue, M.; Suzuki, T.; Nakada, M. J Am Chem Soc 2003, 125, 1140.

[7] Suzuki, T.; Kinoshita, A.; Kawada, H.; Nakada, M. Synlett 2003, 570.

[8] Inoue, M.; Nakada, M. Org Lett 2004, 6, 2977. [9] Inoue, M.; Nakada, M. Heterocycles 2007, 72, 133.[10] (a) Cahiez, G.; Chavant, P. Y. Tetrahedron Lett 1989, 30,

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21

28

AcO

CHO

a bAcO

OH

29

AcO

O

O

c,d

fAcO

O

O

e

O

FR901512 (13)

g,h

30 31

FR901516 (14)

Scheme 6. Reagents and conditions: (a) (EtO)2P(O)CH2CH:N-cHex, KHMDS, THF, −78 to −30°C; aq. oxalic acid, 88%; (b) allyl bromide, CrCl2 (15 mol %), 1b (16 mol %), Mn, DIPEA, TMSCl, THF, 3°C, 99%, 90% de; (c) acryloyl chloride, DIPEA, CH2Cl2, 10°C, 94%; (d) Cl2(Cy3P)2Ru:CHPh (10 mol %), CH2Cl2 (0.005M), refl ux, 100%; (e) TBHP, Triton B, PhMe, 0°C, 70%; (f) PhSeSePh, NaBH4, AcOH, THF/EtOH, 0°C, 100%; (g) MeOH, PhMe, rt; (h) TMSOK, THF, 0°C, 95% (two steps).



[11] (a) Le Doussal, B.; Le Coq, A.; Gorgues, A.; Meyer, A. Tetrahedron 1983, 39, 2185; (b) Cazes, B.; Vernière, C.; Gorè, J. Tetrahedron Lett 1982, 23, 3501.

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[20] To the best of our knowledge, 13 and 14 are the fi rst naturally occurring statins possessing a tetralin core. An early review: Rosen, T.; Heathcock, C. H. Tetrahedron 1986, 42, 4909.

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395.[24] Nicolaou, K. C.; Daines, R. A.; Uenishi, J.; Li, W. S.;

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[26] Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.

[27] For the precedent synthesis of the β-hydroxy-δ-lactone moiety, see: Ghosh, A. K.; Lei, H. J Org Chem 2000, 65, 4779.

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catalytic asymmetric nozaki–hiyama reactions with a tridentate bis(oxazolinyl)carbazole ligand

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