Asymmetric Synthesis of Natural Products and ...

SYNTHESIS0039-78 1 437-210X © Georg Thieme Verlag Stuttgart · New York 2015, 47, A–AC review

Syn thesis

A

Review

B.-C. Hong et al.

Asymmetric Synthesis of Natural Products and Medicinal Drugs through One-Pot-Reaction Strategies Bor-Cherng Hong* Arun Raja

Department of Chemistry and Biochemistry, National Chung Cheng University, Chiayi, 621, Taiwan [email protected]

Received: 30.06.2015 Accepted after revision: 27.07.2015 Published online: 29.09.2015 DOI: 10.1055/s-0035-1560344; Art ID: ss-2015-e0407-r

Abstract One-pot synthesis has become an important subject of modern synthetic chemistry owing to its efficiency, versatility and expediency in constructing complicated polycyclic ring systems, especially with a sustainable and catalytic aspect. This review aims to highlight the recent advances in this area with specific emphasis on the asymmetric synthesis of natural products and related core structures as well as medicinal drugs via one-pot operation. 1 Introduction 2 Double Reactions 3 Triple Reactions 4 Quadruple Reactions 5 Pot-Economy Reactions 6 Conclusions

Key words asymmetric synthesis, one-pot, natural product, annulation, cascade reactions

1

Introduction

One-pot synthesis involving multiple chemical reactions in a single reaction vessel is a challenging task of contemporary organic synthesis, yet one that can exploit efficiency in establishing complex polycyclic frameworks. The multicomponent reaction, which comprises multiple chemical transformations, constitutes one of the primary motifs of the one-pot strategy.1 Among many of the one-pot syntheses, asymmetric domino/cascade catalyses stand out as particularly attractive for their efficiency, versatility and expedience in preparing highly functionalized polycycles with excellent stereoselectivities.2 Such a strategy is greatly

meritorious, since intermediates are not separated and many components can be joined in a concurrent way, generating a remarkable increase in molecular complexity. Recently, asymmetric cascade/domino reactions, catalyzed by organocatalysts,3 N-heterocyclic carbenes (NHCs),4 or metals,5 have received much attention.6 For example, the triple cascade Michael/Michael/aldol reaction of aldehydes and nitroalkenes, introduced by Enders and co-workers,7 provided the pioneering magnum opus and expanded the possibility of organocatalytic domino reactions. In this onepot process, cyclohexene derivatives with four stereogenic centres were formed in excellent diastereoselectivity and enantioselectivity. General reviews on cascade reactions as well as one-pot multi-reaction processes in natural product and drug-like scaffold synthesis,8 such as that on akuammiline alkaloid,9 have been published recently.10 Jørgensen and co-workers provided a review of organocatalytic one-pot reactions and introduced the classification, nomenclature, as well as the future prospects of this sophisticated synthetic protocol.11 To summarize practical aspects on this subject, a review highlighting the asymmetric synthesis of natural products and their analogues using a one-pot operation as the key step is organized herein by the number of bonds formed and the types of reactions involved. Considering the interesting and efficient synthetic methods achieved in one-pot processes, it is not imperative to distinguish a cascade/domino reaction and a sequential one-pot transformation (consecutive reactions or independent multiple reactions). Accordingly, the classifications take into account the outcome of the one-pot operation, and the review covers the progress of work on the topic from 2006 to June 2015, mainly focusing on work published since 2009.

© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–AC

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Vishal M. Sheth

B

2

Review

B.-C. Hong et al.

Double Reactions

2.1 2.1.1

(1) O N MeO

Formation of One C–C Bond

OMe Ph

OH

Acetal Removal/Mannich Cyclization

H

N N

1

OH H

OH

N

77%, dr = 4:1

4

H

LiAlH4, THF reflux; 87%

(2) NaBH4, MeOH

O

3

O

Recently, Koley and co-workers reported a one-pot organocatalytic acetal removal/N-acyliminium formation/Mannich cyclization strategy for the total syntheses of (–)-tashiromine, (–)-trachelanthamidine, and (–)-epilupinine (Scheme 1).12 The one-pot reaction proceeded through the intramolecular Mannich cyclization of acetals such as 1 with MacMillan’s catalyst (2) and Brønsted acid in acetone with trace amounts of water to give chiral pyrrolizidinone, indolizidinone, and quinolizidinone derivatives such as 4. The bicyclic alkaloids were reduced to the corresponding products (–)-epilupinine, (–)-tashiromine, and (–)-trachelanthamidine.

O

N

N

2 (30 mol%)

acetone, 18 °C

N O

O Ph

TfOH

N H

N

O

5 (–)-tashiromine

92% ee

OH H

OH

N (–)-trachelanthamidine

H

N (–)-epilupinine

Scheme 1

Biographical Sketch

Bor-Cherng Hong was born in Changhua (Taiwan) in 1962. He graduated from Tunghai University (Taiwan) with a BSc degree in 1984 and received his MSc from National Taiwan University in 1986 (working with Professor Jim-Min Fang). After the twoyear mandatory military service, he went to the University of Chi-

cago for graduate studies where he obtained his PhD under the guidance of Professor J. D. Winkler. Immediately after graduating, he joined the group of Professor E. J. Corey as a postdoctoral fellow at Harvard University from January 1993 to July 1994. He was appointed as an Associated Professor at Na-

tional Chung Cheng University in August 1994, established his research group, and was promoted to Full Professor in 1999. His current research interests are focused on the development of novel annulation methodologies, especially with organocatalysts or photocatalysts, and natural products synthesis.

Arun Raja was born in India in

(India) in 2008, he spent four years (2008–2012) as Research Scientist for Syngene International Ltd, India. In 2012, he began graduate studies at the National Chung Cheng Universi-

ty (Taiwan) under the guidance of Professor Bor-Cherng Hong. His current research focuses on the development of asymmetric organocatalysis reactions and their synthetic applications.

partment of organic chemistry, Indian Institute of Science Bangalore, under the guidance of the late Professor A. Srikrishna for three years. He is currently pursuing a PhD in the Department of Chemistry and Bio-

chemistry, National Chung Cheng University (Taiwan), under the supervision of Professor Bor-Cherng Hong, working on synthetic methodology and asymmetric synthesis.

1985. He received his BSc in chemistry from Thiruvalluvar University (India) in 2006. After receiving his MSc in chemistry from the University of Madras

Vishal Mohan Sheth was born in Karnataka, India in 1984. He studied in Karnatak Science University where he received his Master’s degree in 2008. He then worked as a junior research fellow in the de-



Syn thesis

C

2.2

Review

B.-C. Hong et al.

Formation of One C–C Bond and One C–N Bond

2.2.1

Iminium Ion/Enamine Aldol/Reduction

A total synthesis of (+)-ipalbidine in three steps via a one-pot process from 1-(pyrrolidin-2-yl)propan-2-one derivative 6 was achieved by Hanessian and Chattopadhyay (Scheme 2).13 The stereoselective one-pot cascade reaction started with the formation of iminium intermediate 8 from aldehyde and pyrrolidine, leading to the enamine and cyclization, followed by dehydration to give the azadienium ion 9. Finally, stereoselective reduction with sodium borohydride furnished the indolizidine alkaloid (+)-ipalbidine. Consequently, the efficient one-pot, three-step enamine– iminium ion cascade cyclization and reduction process was applied in the facile synthesis of structurally diverse azacyclic derivatives, including natural quinolizidine and indolizidine alkaloids as well as azasteroids (Scheme 3). H

(1) TFA, CH2Cl2, 0 °C to r.t., 2 h (2)

O

N

7

C6H6, 0 °C to r.t., 24 h

HO

N 6

O C

HO H

O

H N

H

N

H

DPPA (1.0 equiv) Et3N (1.5 equiv)

H

toluene, r.t., 12 h then 80 °C, 15 h; 77%

H

Cbz

H

N

H

Cbz 16

15

O HN

H

H2, Pd/C EtOH, r.t., 15 h

H

H H

94%

N

H

HN

H

O

H

Cbz

N

H

H lyconadin C

17

Scheme 4

2.3

Formation of One C–C Bond and One C–O Bond

O HO

Boc

amine, to furnish the 2-pyridone 17. After deprotection of the carbobenzyloxy group, the total synthesis of lyconadin C was achieved (Scheme 4).14

(+)-ipalbidine

2.3.1 cade

Gold-Catalyzed Cyclization/Alkoxylation Cas-

(3) NaBH4, MeOH, 0 °C to r.t., 3 h 67% for three-step one-pot process

TFA O NaBH4

HO 7 O

O

OH

H

H

N

N

N N

8

HO

HO

HO

9

HO

Scheme 2 O

Recently, Yang and co-workers revealed the synthesis of a series of cladiellin family natural products via the goldcatalyzed cascade reaction of 1,7-diynes. In their study, treatment of 1,7-diyne 18 in the presence of a gold catalyst and p-nitrobenzylic alcohol, acting as a nucleophile, provided the 6,5-bicyclic products 20 and 21 (Scheme 5).15 Furthermore, a one-pot protocol for the regio- and stereoselective double oxymercuration/reduction on the tricyclic intermediate 22, prepared from the 6,5-bicyclic products, led to the synthesis of (+)-deacetylpolyanthellin A.

H

O H +

N

N

CO2Et

Boc

[Au] O

11

10

6

HOR

(IPr)AuCl (50 mol%) AgSbF5 (5 mol%) 4-O2NC6H4CH2OH (1.5 equiv); 65%

H

OH

CO2Et

18 OMe

MeO

MeO

OR

H

H O

O

N 12 Boc

N

H

OR

OH

H H

+ R2 R1

13

H R1

CO2Et

14 R2

20

(3:1)

H

O

CO2Et

H

H

H

OH (+)-vigulariol

(–)-sclerophytin A

HO

H H

H H

(a) Hg(OAc)2

In 2013, Waters and Cheng developed an enantioselective total synthesis of the lycopodium alkaloid (–)-lyconadin C via a one-pot domino Curtius rearrangement/6π-electrocyclization of vinyl isocyanate 16, generated in situ from vinyl acid 15 with diphenylphosphoryl azide and triethyl-

O O

or H

21

R = 4-O2NC6H4CH2

Curtius Rearrangement/6π-Electrocyclization

OH

H H

OH

O

+

Scheme 3

2.2.2

19

OMe

O

AcO O

O (b) NaBH4; 52% H H

H H

Ac2O

O

O 62%

H H

O

H H

OH 22

(+)-deacetylpolyanthellin A

Scheme 5


(+)-polyanthellin A


Syn thesis

D

Syn thesis

Review

B.-C. Hong et al.

2.3.2 Cross-Dimerization/Oxonia-Cope Rearrangement

HO

CHO CHO

HO

(1) L-Pro (2 mol%)

+CF

(2) Bn2NH2

–

3O2

(2 mol%)

O

CHO 2-MeTHF, r.t., 20 h

OHC

O

t-BuCHO, BF3•OEt2 CH2Cl2, –20 °C, 6 h; 91%

O

N

24

23

(E)-25 E/Z = 82:18

+ O

Bu

O

H O

26

H

O or

BR2

t

Bu

(Z)-25

O

H (major)

O

N

O

t

R 2B

(minor)

H

27

HO

CHO

HO CO2iPr

CONHEt

Ph HO

Ph HO

OH

OH

latanoprost

bimatoprost

Scheme 7

Formation of Two C–C Bonds

2.4.1

O

O

30

29

2.4

O O

CHO

28

Cascade Double Michael Addition

A formal synthesis of α-lycorane using an enantioselective thiourea-catalyzed double Michael reaction as the key step was developed by Xu and co-workers (Scheme 8).18 The one-pot process involving malonate 31 and β-nitrostyrene 32 afforded a 95% yield of the adduct 34 with 90% ee. The cyclohexane derivative was transformed into a lycorinetype tetracyclic alkaloid, constituting the formal synthesis of α-lycorane.

O O O

N

CF3 N

CO2Et laingolide A

S

EtO2C

CO2Me

F3C

N H

(relative stereochemistry unknown) 31

Scheme 6

N H N

(20 mol%)

33

+ toluene, r.t., 15 d; 95% NO2

O

2.3.3

OMe

H

Aldol/Acetalization

dr = 12:1

O 32

Quite recently, Aggarwal and co-workers reported a synthesis of antiglaucoma drugs, bimatoprost and latanoprost, analogues of prostaglandin PGF2α, using an organocatalytic tandem aldol reaction as a key reaction (Scheme 7).17 The one-pot strategy in providing the key bicyclic enal 30 was achieved by two amine organocatalysts, L-proline (2 mol%) and dibenzylammonium trifluoroacetate (DBA; 2 mol%). Intermolecular aldol reaction between two molecules of succinaldehyde (28) was catalyzed by L-proline, followed by the DBA-catalyzed intramolecular aldol reaction and dehydration to give bicyclic enal 30 in 14% yield and >99% ee. Subsequently, the bicyclic enal 30 was further elaborated into the two antiglaucoma drugs latanoprost and bimatoprost.

CO2Et EtO2C

lit. CO2Me

O

34

N

O

NO2

O

O

90% ee

α-lycorane

Scheme 8

2.4.2

Sequential Double Michael Addition

An enantioselective total synthesis of (–)-stenine involving a key-step strategy of one-pot enantioselective double Michael addition was reported by Zhang and coworkers (Scheme 9).19 The first enantioselective Michael reaction was achieved by the reaction of 35 and 36 with 3 mol% of Evans catalyst 37 under solvent-free conditions, whereas the second Michael addition cyclization process was accomplished in the presence of silica gel supported potassium hydroxide (KOH/SiO2) and sonication to afford



Phansavath and Pomey developed a tandem cross-dimerization/oxonia-Cope rearrangement as a crucial step in the total synthesis of laingolide A (Scheme 6).16 Treatment of pivalaldehyde and 2-(prop-1-en-2-yl)cyclohexanone (23) with boron trifluoride diethyl etherate (20 mol%) in dichloromethane at –20 °C for six hours gave a 91% yield of macrolactone product 24 as an 82:18 mixture of the E- and Z-isomers. The product mixture was transformed into the E- and Z-diastereomers of laingolide A, respectively. Since the relative configuration of natural laingolide A was elusive, this synthesis provided a definitive assignment.

THF, r.t., 20 h; 14%

E

Review

B.-C. Hong et al.

the functionalized cyclohexanone product 39 in 80% yield. The product was transformed into the stemona alkaloid (–)stenine in seven steps. Bn

Bn

(1)

Br N H CO2Et

N H

Ni

H N

O

Br

O CO2Et

HN

Bn

Bn

(3 mol%), neat, 5 °C EtO2C

OMe

37 EtO2C

OMe

NO2

35

38

+ OMe

(2) KOH/SiO2, THF sonicated at 35 °C 80%

OMe O 2N

O 36 H

O

O CO2Et

H H

H H

OMe

N

EtO2C

Three-Component Suzuki Reaction

The total synthesis of (+)-cavicularin was achieved by Beaudry and Zhao via a key step of enantioselective and regioselective Diels–Alder reactions of vinyl sulfones and αpyrone (Scheme 11).21 The Diels–Alder precursor 47, a highly substituted terphenyl, was prepared via a regioselective one-pot three-component Suzuki reaction of a dibromoarene. A solution of the Diels–Alder substrate 47 in ethyl acetate was heated in the presence of cinchona-based thiourea organocatalyst to afford the cycloaddition product 50 as a single regioisomer. The transformation involved an initial Diels–Alder cycloaddition, followed by elimination of phenylsulfinic acid and extrusion of carbon dioxide in a retro-Diels–Alder process. The product 50 was then transformed into (+)-cavicularin in two steps.

OMe

NO2

MeO TBSO

39 87% ee

(–)-stenine

2.4.4

Br

Scheme 9 B(pin)

2.4.3 Ring-Opening/Ring-Closing Metathesis (ROM/RCM) Cascade

iPrO

Pd(PPh3)4, K3PO4, KBr dioxane, H2O, 55 °C +

B(pin)

Br

63% for one pot

OMe

MeO 42

43

pin = pinacolato

A synthesis of humulanolides using a single-step metathesis cascade reaction as a key-step process was revealed by Li et al. (Scheme 10).20 The ROM/RCM cascade reaction of cyclobut-1-enecarboxylic acid derivative 40 in the presence of the Hoveyda–Grubbs II catalyst in refluxing toluene provided asteriscunolide D in 36% yield. Irradiation of the asteriscunolide D in a solution of acetonitrile and acetone (5:1 v/v) with a UV lamp (10 W, 254 nm) at ambient temperature for three hours afforded a mixture of asteriscunolides A, B, and C in 46%, 18%, and 18% yields, respectively.

MeO

MeO TBSO

TBSO

(1) Grubbs II CH2Cl2, 50 °C 44% (for two steps)

iPrO

iPrO

(2) H2, Pd/C, EtOAc 60 °C; 84%

OMe

OMe

MeO

MeO

46

45

O

OH

O

MeO

33

O

O

PhO2S

OH

EtOAc, 45 °C PhO2S

OMe

OMe MeO

O O

O

MeO

47 O

Grubbs–Hoveyda cat. II

O MeO

O

O

O

44

48

O

toluene, reflux, 36% Ru

O O (–)-asteriscunolide D

O

MeO

O MeO

O

41

40

O

O

O

O OH

OH – CO2

– PhSO2H

UV

OMe

OMe

MeCN–acetone (5:1 v/v)

+

+

O asteriscunolide A

50

49

O

O

O

MeO

MeO

O asteriscunolide B

O

HO

CF3

asteriscunolide C

S O

Scheme 10

HN

CF3

N H

N N

OH

33 HO

(+)-cavicularin

Scheme 11


MeO

cinchona alkaloid cat.


Syn thesis

F

Review

B.-C. Hong et al.

2.4.5 Dienamine Formation/Asymmetric Diels–Alder Reaction

N

N

O

Jørgensen and co-workers developed a one-pot construction of 14β-steroids 54 via the reaction of enal 51 with cyclic dienophile 52 in the presence of the Jørgensen– Hayashi catalyst (Scheme 12).22 The enantioselective reaction afforded the product in high yield and up to greater than 99% ee. The compounds prepared in this manner, including 54, were transformed into a range of naturally occurring steroids such as (+)-estrone and related steroid analogues through a series of straightforward synthetic reactions.

O O

N

N H 51 +

65%

I

O O

Ph OTMS

H

53

H

H MeCN, 0 °C, 24 h 79%

O

54

N

N O H 59

2.4.7 tion

(+)-estrone

Scheme 12

Reductive Geminal Bis-alkylation

A formal total synthesis of (±)-cephalotaxine, using a one-pot reductive gem-bis-alkylation of a tertiary lactam, was disclosed by Huang and co-workers (Scheme 13).23 The method using in situ activation of amide 55 with triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine (DTBMP), followed by successive addition of but-3-en-1-ylmagnesium bromide and vinylmagnesium bromide, gave the corresponding pyrrolidine product 58 in 65% yield. Amine 58 was transformed into the pentacyclic derivative 59 after four additional steps, which completed the formal total synthesis of (±)-cephalotaxine.

(1)

Ph N H

O

Ph OTMS

Alemán and co-workers developed an asymmetric synthesis of 3-(benzofuran-2-ylmethyl)-1H-indoles using onepot intramolecular dienamine condensation, dehydration, and Friedel–Crafts reactions (Scheme 14).24 The reaction of 2-(4-oxobut-2-enyloxy)benzaldehyde 60 was carried out with Jørgensen–Hayashi catalyst (20 mol%) in toluene at ambient temperature for 20 hours, followed by the addition of 1,4-diazabicyclo[2.2.2]octane (30 mol%) and indole, and the solution was stirred at 0 °C for 36 hours to give the diheteroarylalkanal 61 in 79% yield with 94% ee. Some of the diheteroarylalkanals prepared were found to have antiproliferative activities against certain cancer cell lines; some were found to be as cytotoxic as cisplatin.

53 (20 mol%)

NH

toluene, r.t., 20 h

(S)

(2)

CHO

O

DABCO (30 mol%), 0 °C N H

61

OAc

79%; 94% ee

NH

indole

N H

O CHO N

62

N

N

O OTMS

Ph Ph

OMe

cephalotaxine

Dienamine Condensation/Friedel–Crafts Reac-

CHO 60

H HO

O

MeO

99% ee

CHO

58

H

52

2.4.6

O

Scheme 13

H

OH

(10 mol%)

I

O

57

O

O

PhCO2H (10 mol%) MeO

O

N (3) CH2=CH2MgBr

O OH

MgBr

56

O

O Ph

(2)

I

O 55

CHO

MeO

OTf

(1) TfO2, DTBMP, CH2Cl2 I

O

O 63

OTMS

Ph Ph

64

OTMS

Ph Ph

Scheme 14


streptindole


Syn thesis

G

2.5

Review

B.-C. Hong et al.

Formation of Two C–N Bonds

2.5.1

Subsequently, the adduct 70 was further elaborated for the asymmetric total synthesis of (+)-deethylibophyllidine and (+)-limaspermidine.

Reductive Amination/Asymmetric Reduction

CF3

Turner and co-workers described a regio- and stereoselective synthesis of chiral 2,5-disubstituted pyrrolidine 67 via a one-pot enzyme-mediated reductive amination [with ω-transaminase (TA)] of 1-arylpentane-1,4-dione 65 and enzyme-mediated asymmetric reduction [with monoamine oxidase (MAO-N) and NH3·BH3] of imine intermediate 66 (Scheme 15).25 2,5-Disubstituted pyrrolidines are important scaffolds in natural products, and the one-pot multienzyme cascade process gave >99% conversion with >99% dr and >99% ee.

O

S

Boc N

O N

N

N

H

H

O

CF3

NH O

69 (10 mol%)

68 +

N

PhCl, 25 °C, 48 h; 45%

Boc

NH2

70

90% ee

OH

N H

N H H

N H O ϖ-transaminase (TA) O

N H

MAO-N/NH3•BH3

ATA113

N

conv. >99%

66

(+)-limaspermidine

2.6

Scheme 15

2.5.2

Aminolysis/Aza-Michael Addition

Formation of Two C–O Bonds

2.6.1 Double Oxidative Cyclization

Organocatalytic asymmetric total synthesis of the apocynaceae hydrocarbazole alkaloids (+)-deethylibophyllidine and (+)-limaspermidine was reported by Fan and coworkers (Scheme 16).26 The key strategy involved an asymmetric organocatalytic tandem aminolysis/aza-Michael addition reaction. The enantioselective desymmetrization cascade of spirocyclic p-dienone-imide 68 and allylamine was catalyzed by amine thiourea catalyst 69 to provide a 45% yield of the hydrocarbazole adduct 70 with 90% ee. BnO

In 2013, Donohoe and Lipinski reported a synthesis of the ABC spiroketal ring system of the naturally occurring antitumor agent pectenotoxin-4 via a cascade oxidative cyclization and hydride-shift-initiated strategy for the construction of spiroketals (Scheme 17).27 The double-oxidative-cyclization cascade was achieved by the addition of catalytic amounts of potassium osmate to 71 in an aqueous acetonitrile solution, with pyridine-N-oxide (PNO) as a reoxidant and zinc(II) triflate (50 mol%) as Lewis acid pro-

K2[OsO2(OH)4] (5 mol%) H O

CH3CN, aq. buffer; 69% 71

OPMBOH

O

O

HFIPA, 30 °C

H

OTES

N

O

O

hydride-shift-initiated spiroketalization

McO

OH O

O

OH

N

O OH

O

74

75

H

Bn O N O

OH

H O O

B O

A

H

C O

OTBS

H

OH OH

H O

O

B

A

O

H OH

H O H

C O

O

O

OTBS

H O

76

O OTBS

Bn

O

H

H

H

H O O

OH

pectenotoxin-4

Scheme 17 © Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–AC

OH O

OTBS

Bn 73

O OTBS

Bn

O

H

H

H

H

72

OH Zn(OAc)2

H

OMc

OH

OH

OTES

N

O

O

OH

cascade oxidative cyclization

O

O

H

H

BnO

Zn(OTf)2, 80 °C

OH

OH

OPMB

PNO

OH

(+)-deethylibophyllidine

Scheme 16

de > 99% ee > 99%

67

65

CO2Me

N H

H

OH


Syn thesis

H

Review

B.-C. Hong et al.

moter at 80 °C, providing the bis-tetrahydrofuranyl product 72 in 69% yield. In later steps, the hydride-shift-initiated spiroketalization was achieved by the reaction of bis-tetrahydrofuranyl intermediate 73 with zinc(II) acetate in hexafluoroisopropanol (HFIPA), allowing a one-pot hydride shift, oxygen deprotection, and spiroketalization sequence, to give product 76 with the C1–C16 fragment of the marine biotoxin pectenotoxin-4.

2.6.2 Wacker/Carbonylation/Methoxylation

OMe

HO

HO

OH

OMe

OMe

O

OMe

O

OMe

O

OH

OH

5-exo-trig cyclization

H2O

OMe H

HO

OH

O 84

HO

HO HO

HO

tanegool

MeO

HO

HO

OMe

HO

or FeCl3•H2O, H2O, acetone 0 °C, 3 h 59% (71% BRSM)

80

HO

OH

(1) PhI(OAc)2 (1.1 equiv) CF3CH2OH, acetone, –40 °C, 1 h

OH (2) add H2O, THF; 40%

O

Tietze et al. developed an enantioselective total syntheses of (–)-blennolide C and (–)-gonytolide C using a domino Wacker/carbonylation/methoxylation reaction (Scheme 18).28 Reaction of phenolic substrate 77 with the oxidant pbenzoquinone in the presence of chiral BOXAX ligand 78 and a catalytic amount of palladium(II) trifluoroacetate under an atmosphere of carbon monoxide in methanol for 26 hours led to a 62% yield of the chromane product 79 with >99% ee. The product was further converted into (–)-blennolide C and (–)-gonytolide C after a sequence of reactions.

H

HO

OMe

HO

OMe

OMe

83 HO

82

81

OMe

OMe HO

OMe

OH

H

OH

FeCl3•6H2O

OH

H2O, acetone, 0 °C; 48%

H O

HO

(87% BRSM)

pinoresinol MeO

HO

O

N

78

85 OMe

5-exo-trig cyclization

N

O

OMe

OH

OMe BnO

(S,S)-iPr-BOXAX (20 mol%) Pd(OTFA)2 (5 mol%) p-benzoquinone CO, MeOH, r.t., 24 h; 62%

HO 77

O

O MeO2C

O

OMe O

OMe

HO

HO

O

BnO

OH

79

>99% ee

HO

HO OMe 86

O O

O 89

HO

HO

OH

OMe

HO 5-exo-trig cyclization

OH

MeO2C

O

OMe

HO

OMe

88 OMe

HO

OMe

87

Scheme 19

(–)-gonytolide C

OH

OH

O

2.7 Formation of Two C–C Bonds and One C–N Bond

OH

O CO2Me

2.7.1

Diels–Alder/Iminium Cyclization

(–)-blennolide C

Scheme 18

2.6.3

Oxidative Ring-Opening/Cyclization

Lumb and Albertson revealed a one-pot oxidative ring opening of a diarylcyclobutane diol, resulting in a p-quinone methide system that then underwent a stereoselective cyclization, for the synthesis of tetrahydrofuran lignans (Scheme 19).29 The products were further transformed into the desired lignans, including tanegool and pinoresinol.

A nine-step enantioselective total synthesis of (–)-vincorine was achieved by MacMillan and Horning with the key step being a one-pot operation comprising a stereoselective organocatalytic Diels–Alder/iminium cyclization cascade (Scheme 20).30 The one-pot process generated the tetracyclic alkaloid core architecture with excellent stereoselectivity from the simple achiral indole 90 and enal precursors.



Syn thesis

I

Review

B.-C. Hong et al.

2.8.2

Me Me

O

N

N 90 MeO

Ph

NHBoc

2

N

HBF4

N H

CHO

(20 mol%)

H+

CO2Me

+

MeO

70%, 95% ee

NHBoc

92

CHO 91

MeO2C

NHBoc

Me

Me

Boc Me N N

N

N

N

CHO

A synthesis of the tricyclic skeleton of phomactin A involving a one-pot Prins/Conia-ene cascade cyclization was reported by Lee and co-workers (Scheme 22).33 Reaction of keto alcohol 98 and alkynal 99 with indium(III) triflate in acetonitrile in the presence of 4 Å molecular sieves provided the cascade cyclization adduct 100 in 66% yield. The 1oxadecalin product 100 was in turn converted into compound 104, with the tricyclic hydrofurochromene skeleton of phomactin A, in three steps.

CHO

CO2Me MeO

Prins/Conia-Ene

Me

MeO

CO2Me

MeO

CO2Me

(–)-vincorine

94

93

O TMS

O O

O

TMS

98

HO

O

O

In(OTf)3, MeCN

Scheme 20

O

molecular sieves 0 to 70 °C; 66%

+

H 100

OH H

99

O

2.8.1 Carbene Cyclization/Cycloaddition Cascade (CCCC)

phomactin A

Chiu and Lam used a rhodium(II)-mediated carbene cyclization–cycloaddition cascade (CCCC) for the asymmetric total synthesis of (–)-indicol (Scheme 21).31 Treatment of the α-diazo ketone 95 with a catalytic amount of rhodium(II) catalyst at 0 °C for three hours gave an 81% yield of carbocyclic products 96 and 97 in a ratio of 3:1. The major product, 96, was transformed into the secodolastane (–)-indicol after a sequence of reactions. Recently, Chiu and Leung used the same strategy of CCCC reaction as the key step to construct [5.4.0]carbocycles (Scheme 21).32 In the one-pot procedure, three σ bonds and four new stereocenters were generated. The product was further transformed into (–)-dolastatrienol. OH O

OH (–)-dolastatrienol

(–)-indicol

N2 O

O

Rh2(OAc)4 (0.5 mol%) molecular seives, CH2Cl2 0 °C, 3 h; 81%

O OTBDPS

OTBDPS

O

+

O

3:1

OTBDPS

O

97

96

95

O TBDMSO

O

vs

In3+

TMS

O

O

In3+

TMS

O

Prins O

O

O

O

O O H

101

In3+

TMS

O

O 102

O H 103

Scheme 22

2.8.3 Hetero-Diels–Alder/Mukaiyama–Michael/ Reduction Hashimoto and co-workers reported an asymmetric synthesis of diospongins A and B using a one-pot process involving a sequential hetero-Diels–Alder/Mukaiyama– Michael reaction (Scheme 23).34 The enantioselective construction of (S)-2-phenyl-2H-pyran-4(3H)-one 107 was achieved by sequential dirhodium(II) tetrakis[(S)-3-(benzofused phthalimido)-2-piperidinonate] {Rh2(S-BPTPI)4}-catalyzed enantioselective hetero-Diels–Alder and TMSOTfcatalyzed Mukaiyama–Michael reaction of benzaldehyde and diene 106. Stereoselective reduction of the diketone product 107 by K-Selectride in tetrahydrofuran afforded diospongin B in 86% yield. Treatment of diospongin B with 30% hydrochloric acid in tetrahydrofuran (1:4) at ambient temperature resulted in the formation of diospongin A in 89% yield.

TBDMSO H

OH

CHO

Conia-ene

O

104

O O

2.8 Formation of Two C–C Bonds and One C–O Bond

OMe

O

O O

H

Scheme 21



Syn thesis

J

Review

B.-C. Hong et al.

O (1) Rh2(S-BPTPI)4 (1 mol%) (3) CH2Cl2, 23 °C, 15 h

OTES H +

OMe (2) TMSOTf (10 mol%) –78 °C, 0.5 h

106

105

O

Ph

O

OMe

Ph

O

H N

Ph

Ph

O

hetero-Diels–Alder

H

Ph

O

H

diospongin B

CHO

CHO

114

113 30% aq HCl–THF (1:4) 23 °, 6 h; 89%

O

H OH

N O

O O

110

109

108

O

O

Ph

Diels–Alder

O

cat. TMSOTf O

112

111

OH

OTMS

Ph

sealed tube, 2 h; 52%

CHO

K-Selectride THF –78 °C, 2 h 86%

TFA

cat. TMSOTf

+ H

Ph

107 95% ee

SiMe3

O OTES

O

(4) TFA, –78 °C, 1 h 85%

cat. Rh2(S-BPTPI)4

toluene, 150 °C

O

O Ph , 1h Ph

O

Ph

O

OTMS

O

O

O

H

O

H

O

Rh Rh Rh2(S-BPTPI)4

Ph

O

Ph

H

O

O

diospongin A 115

O

bolivianine

Scheme 23 Scheme 24

2.9 Formation of Three C–C Bonds and One C–O Bond

O

O N

N

2.9.1 Diels–Alder/Intramolecular Hetero-Diels–Alder Reaction

MeO

A bioinspired total synthesis of bolivianine via a onepot process of Diels–Alder/intramolecular hetero-Diels– Alder cascade was achieved by Liu and co-workers (Scheme 24).35 Reaction of aldehyde 111, prepared from onoseriolide by IBX oxidation, with β-(E)-ocimene (112) in toluene and heating in a sealed tube at 150 °C for two hours gave bolivianine in 52% yield with no other isomers observed. The one-pot process comprises two cascade reactions, creating three rings, four carbon–carbon bonds, and five stereogenic centers with excellent stereoselectivities. The achievement of the total synthesis provided both confirmation of the absolute configuration of bolivianine and experimental support for a revised biosynthetic mechanism.

O

N xylene, 138 °C 44 h; 77%

N

116

H

Me

O

Me

N Me

117 (1) FeCl3, N

N H

CO2Et

N

Et

119

MeO

0.1 N HCl, CF3CH2OH 25 °C, 2 h

OH N H

Me

O

N

(2) Fe2(ox)3, NaBH4 air, 0 °C, 30 min

Me

118 OH

OH

N N N

H N H MeO2C MeO

Formation of Four C–C Bonds

H OH N Me

H O

2.10.1

O

N

N Me

2.10

MeO N

O

Diels–Alder/1,3-Dipolar Cycloaddition

120

N Me

N

N H MeO2C MeO

OH N Me

H

OAc CO2Me

vinblastine

Scheme 25

An interesting approach to the polycyclic product 117, with the construction of four new rings, four carbon–carbon bonds, and six stereocenters, was developed by Boger and co-workers using the strategy of one-pot transannular Diels–Alder/1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazole 106 (Scheme 25).36 After several steps of transformation of 117, the product 118 was subjected to iron(III)promoted coupling with catharanthine (119); subsequent in situ iron(III)/sodium borohydride air oxidation37 provided the vinblastine analogue 120 in a one-pot operation.

3 Triple Reactions 3.1

Formation of One C–C Bond and One C–N Bond

3.1.1 Intramolecular Enamine/Michael Cascade Reaction and Reduction Smith and co-workers reported a total synthesis of (–)gephyrotoxin via a key step of stereoselective intramolecular enamine/Michael cascade reaction and hydroxy-direct-



Syn thesis

K

Review

B.-C. Hong et al.

ed reduction for constructing the required cis-decahydroquinoline ring system (Scheme 26).38 In their study, treatment of α,β-unsaturated ketone derivative 121 with trifluoroacetic acid in dichloromethane at room temperature for two hours resulted in the deprotection of the tertbutoxycarbonyl group. After removal of the solvent, the residue was re-dissolved in chloroform and stirred at 40 °C for 72 hours to form the tricyclic iminium cation 124 via diastereoselective intramolecular Michael addition. After removal of the solvent, the flask was charged with dichloromethane and sodium triacetoxyborohydride was added; the reaction mixture was then stirred for one hour at ambient temperature to afford the cis-decahydroquinoline 125. The one-pot process generated two rings and two stereocenters of the gephyrotoxin core.

boxylation of the ester and afforded a 67% yield of the chromanone product 131, with 80% ee. Chromanone 131 was then transformed into (–)-deguelin in two steps. CF3

(1)

O CO2tBu O

S F 3C

OH

N H

NH N

126

128 OBn

AcOH

+

(20 mol%)

MeO

O

MeO

toluene, 23 °C, 3 d

N

O N 127

O

O

O

(2) CHCl3, 40 °C, 72 h

N

CO2tBu

OH

O

O

O

(1) TFA, CH2Cl2, 2 h Boc

O

O CO2tBu

O

O

O

HN

O

OMe OMe

129

130

OMe OMe

122

121 OTBS

OH

O (2) Pd(PPh3)4, (5 mol%) TsOH (50 mol%) toluene, 80 °C, 16 h

O

O

O

H

H NBH(OAc)3

123

124 OH

H 125

OH

N

OH

OMe OMe

67%

CH2Cl2, r.t., 1 h; 79%

N

N

O

O

O

131 80% ee

dr 10:1

OMe O

O

OMe H O

O H

H (–)-deguelin H H HO

Scheme 27

N

(–)-gephyrotoxin

Scheme 26

3.2

Formation of One C–C Bond and One C–O Bond

3.2.1 Knoevenagel Condensation/Oxa-Michael/Decarboxylation The one-pot Knoevenagel condensation/oxa-Michael cyclization, developed by Scheidt and Farmer, was used for the synthesis of the anticancer rotenoid (–)-deguelin (Scheme 27).39 Reaction of keto ester 126 and bis-morpholine aminal substrate 127, an aldehyde surrogate, with acetic acid and thiourea catalyst 128 led to the Knoevenagel condensation and subsequent enantioselective intramolecular conjugate cyclization reaction to give adduct 130. Subsequent addition of palladium(0) catalyst and p-toluenesulfonic acid to 130 gave rise to both deprotection and decar-

3.2.2 Reductive Michael/Epimerization/Tishchenko List and Michrowska revealed a facile synthesis of ricciocarpin A using a one-pot, three-step, organocatalytic reductive Michael–epimerization–Tishchenko cascade of dienal 132 (Scheme 28).40 The first-step reductive Michael reaction was achieved by organocatalysis with MacMillan’s catalyst in the presence of a Hantzsch ester. Upon treatment of intermediate 135 with samarium triisopropoxide, the initially formed cis-adduct 135 was isomerized to the thermodynamically more stable trans-isomer 136. A Tishchenko reaction then gave a 48% yield of (+)-ricciocarpin A with high diastereoselectivity and excellent enantioselectivity (er = 1249, ee >99%). Several ricciocarpin analogues were synthesized in this one-pot process, and one of the ricciocarpin analogues showed significantly better molluscicidal activity compared to the naturally occurring ricciocarpin.



Syn thesis

L

Syn thesis 3.3 3.3.1

Review

B.-C. Hong et al.

Formation of Two C–C Bonds

3.4 Formation of Two C–C Bonds and One C–O Bond

Michael/Michael/Retro-Michael

(1)

O

Sorensen and co-workers reported a biomimetic total synthesis of gracilioethers B and C using a one-pot cascade aldol/transacetalization/dehydration (Scheme 30).42 Reaction of aldehyde 145 with the sodio-lithio dianion of methyl 2-oxohexanoate gave the aldol reaction intermediate 149; treatment of the solution with anhydrous hydrochloric acid (generated in situ from acetyl chloride, methanol, and excess trimethyl orthoformate) at 20 °C for 15 hours afforded the aldehyde dimethyl acetal 147 in 74% yield as a single isomer. The product was transformed into gracilioethers B and C after Horner–Wadsworth–Emmons olefination and stereoselective reduction. The relative and abso-

t

CO2tBu

BuO2C

N tBu

N H

Bn

O

N H

HCl

133 O

O

H H

O

CO2iPr OSm(OiPr)2

O O

O

OiPr

137

H

Sm

O iPrO

136

135

(+)-ricciocarpin A

iPrO

O

O

H

er = 1249; ee >99%

132

O

O

(1.1 equiv)

(2) Sm(OiPr)3, 4 h; 48%

O

O

134

(20 mol%) dioxane, 22 °C, 72 h O

H

O 138

Scheme 28

Ph CN

Cl

CN

Ph

N H

+

OTMS

53 (20 mol%) Et3N (20 mol%)

CHO

H

CHO CH2Cl2, 23 °C, 24 h; 69%

139

140 141 98% ee

CN Et3N

Cl

CN N

H CN

CN CN

Ph

TMSO Ph

C

Cl

N TMSO

N

142

Ph

N

H

C

TMSO

CN

N

N

H

Cl

TMSO

Cl

144

Ph Ph

Cl

Ph Ph

Ph

143

Scheme 29



3.4.1 Aldol/Transacetalization/Dehydration An organocatalytic, asymmetric eliminative [4+2] cycloaddition of allylidene malononitrile 139 with enal 140 for the rapid entry to cyclohexadiene-embedding polycycles such as 141 was reported by Zanardi and co-workers (Scheme 29).41 The one-pot strategy utilizes a remotely enolizable π-extended allylidenemalononitrile as an electron-rich 1,3-diene precursor in a direct eliminative [4+2] cycloaddition with an α,β-unsaturated aldehyde. The onepot asymmetric reaction comprises a domino bisvinylogous Michael/Michael/retro-Michael reaction cascade. Interestingly, a testosterone-based product prepared from this onepot process shows proliferative activity towards human smooth muscle cells.

M

Review

B.-C. Hong et al.

(1)

O

O Na

OMe

Li

O OMe

146 MeO

THF, –78 to 20 °C, 3 h MeO

CHO

O

O

CO2Me

CO2Me

74% O

O

O

(2) AcCl, CH(OMe)3, MeOH, 20 °C, 15 h

145

gracilioether B

147

148 OMe

OMe

MeO

OMe

OH

CH(OMe)3

O

MeO

O

OH

MeO

OH

AcCl, MeOH

O OH

O

OH

CO2Me

CO2Me

CO2Me 151

150

149

Scheme 30

lute configurations of the marine polyketide metabolite gracilioethers B and C were confirmed as a result of this total synthesis.

3.5 Formation of Two C–C Bonds and One C–N Bond 3.5.1

3.4.2

Diels–Alder/Amine Heterocyclization/Reduction

Ketene Generation/Trapping/Aromatization

Barrett and co-workers reported a total synthesis of aigialomycin D using a one-pot sequential ketene generation/trapping/aromatization reaction (Scheme 31).43 Heating of diketo-dioxinone 152 in toluene led to the formation of ketene 154 via a retro-Diels–Alder reaction. The ketene intermediate 154 was treated with (S)-pent-4-en-2-ol (153) and directly aromatized by reaction with cesium acetate and acetic acid to afford resorcylate product 156 in 74% yield. Ring-closing metathesis of product 156 with Grubbs– Hoveyda II catalyst, followed by deprotection with 1 M hydrochloric acid in methanol, afforded aigialomycin D.

A concise total synthesis of (+)-minfiensine, a secoiridoid indole alkaloid, was reported by MacMillan and coworkers. The key step involved a one-pot organocatalytic Diels–Alder cyclization and amine heterocyclization reaction sequence (Scheme 32).44 In their approach, reaction of 2-vinylindole 158 and three equivalents of propynal in the presence of secondary amine catalyst 160, followed by the addition of sodium borohydride, stereoselectively afforded the tricyclic alcohol 164 by way of an iminium-activated endo-selective Diels–Alder cycloaddition and a 5-exo amine heterocyclization of 162. OH

O

O

O

N

O O

O

O

OH

O

N H

C

Me

toluene

152

(+)-minfiensine

O

+

reflux, 1h

O

OH

154

O

(1)

NHBoc

O

N

OH 153 OH

OH

O

PMB

158

87% 96% ee

–40 °C, Et2O

CHO

OH

OH (2) NaBH4, CeCl3 MeOH

N N

Boc SMe

PMB

O O

O

160

+

(2) AcOH; 74% 155

t-Bu

(15 mol%)

CBr3CO2H (15 mol%)

N

(1) CsOAc, IPA–CH2Cl2 r.t., 3 h

O

OH

N H

SMe O

Me

O

159

164

endo-[4+2]

O

Grubbs–Hoveyda II (15 mol%) O

O

toluene, 100 °C; 83%

R

NHBoc

HO

HO

N

NHBoc R

156

O 157 OH

95%

O

O 161 PMB

+ HNR2 – H2O

HNR2 = cat. 160

HO OH aigialomycin D

O O N SMe N

N O

1 M HCl, MeOH

SMe

O

O

– HNR2 + H2O

Scheme 32

OH

Scheme 31


PMB

N PMB

Boc SMe

162

163


Syn thesis

N

3.5.2

Review

B.-C. Hong et al.

Domino Michael/Mannich/N-Alkylation

In the context of the total syntheses of (–)-aspidospermidine, (–)-tabersonine, and (–)-vincadifformine, the key stage for the constructing of tetrahydrocarbazole was achieved by Andrade and Zhao using an asymmetric domino Michael/Mannich/N-alkylation (Scheme 33).45 Treatment of N-sulfinylimine 165 with lithium hexamethyldisilazide in tetrahydrofuran at –78 °C generated N-sulfinyl metallodienamine 166; addition of methyl 2-ethylacrylate then triggered a Michael/Manich cascade reaction. The resulting lithium anion 168 was trapped by the subsequent addition of allyl bromide in N,N-dimethylformamide to give the tetrahydrocarbazole 169 in 90% yield (dr = 11:1). The one-pot process efficiently assembled the tetrahydrocarbazole framework of aspidosperma alkaloids, and the product was converted into (–)-aspidospermidine, (–)-tabersonine, and (–)-vincadifformine by way of a few additional transformations.

170 in conjunction with the p-toluenesulfonic acid salt of organocatalyst 172 afforded the tetracycle product 176, with excellent diastereo- and enantioselectivity, allowing for the completion of total synthesis of (–)-minovincine. Notably, with a suitable leaving group (e.g., selenium), 2-vinylindole 170 underwent a different pathway compared with its counterpart 158 (Scheme 32 and Scheme 34). O N NHBoc SeMe

O

(30 mol%)

O

tBu

S N

S

(1) LHMDS THF, –78 °C

Li

(2) tBu

N Et

173

Boc NH

SO2Ph

PhO2S

N

Boc N

N O O

167 N H

O Bu

(3)

N

CO2Me

Br

S

(–)-minovincine

91% ee tBu

Scheme 34

CO2Me

Et

Et

N

DMF, 90%

PhO2S

N

168

PhO2S

or CO2Me

(–)-aspidospermidine

N H

Metathesis/Mukaiyama–Michael/Aldol

Et or

CO2Me

(–)-tabersonine

3.6.1

N Et

Et

3.6 Formation of Two C–C Bonds and One C=C Bond

169 dr = 11:1

N

N

N H

CO2Me 176

PMB t

175

O

N

S

PMB

Et

O N

NR2

N

174

166

Li

NH

Li

S

N SO2Ph

165

Boc NR2

SeMe

PMB

CO2Me

N

SeMe

PMB

170

OMe

N

CHCl3, –30 °C; 72%

171

O

tBu

NR2

p-TsOH N

PMB

N O

NH

S

172

+

N

Boc

N H

N H

CO2Me

(–)-vincadifformine

Scheme 33

3.5.3 Diels–Alder Cycloaddition/β-Elimination/Conjugate Addition An enantioselective total synthesis of (–)-minovincine was achieved by MacMillan and co-workers. The key step of the synthesis involved a one-pot Diels–Alder cycloaddition/β-elimination/conjugate addition sequence (Scheme 34).46 In their study, employing the indole vinyl selenide

An intriguing total synthesis of (–)-aromadendranediol was developed by MacMillan and co-workers. The crucial stage of their approach involved a one-pot enantioselective synthesis of bicyclic butenolide 183 from crotonaldehyde (178), hex-5-en-2-one (177) and silyloxyfuran 180 via a metathesis/Mukaiyama–Michael/aldol cascade (Scheme 35).47 In their study, treatment of crotonaldehyde and 177 with Grubbs II ruthenium alkylidene catalyst initiated a cross-metathesis to generate 6-oxohept-2-enal (179). Silyloxyfuran 180 and MacMillan catalyst were then introduced, and the resulting Mukaiyama–Michael reaction provided the keto-aldehyde intermediate 181. Addition of L-proline to 181 then triggered the intramolecular aldol reaction to afford the butenolide product 183 in 64% yield, with 95% ee and 5:1 diastereoselectivity. Consequently, after an eight-



Syn thesis

O

Review

B.-C. Hong et al.

3.6.2

step reaction sequence, the butenolide product was transformed into the naturally occurring sesquiterpene (–)-aromadendranediol. O

An enantioselective total synthesis of (+)-galbulin was achieved by Hong et al. using a one-pot organocatalytic domino Michael–Michael–aldol condensation as the key step. Reaction of the racemic keto-aldehyde 184 and cinnamaldehyde derivative 185 with the Jørgensen–Hayashi catalyst and acetic acid in acetonitrile, via an unusual kinetic resolution, afforded the domino Michael adduct 188 (Scheme 36).48 Treatment of the crude adduct 188 with ptoluenesulfonic acid gave an 82% yield of product 186 with >99% ee. After few steps, the product 186 was transformed into the natural lignan (+)-galbulin.

Me N

O O 177

Grubbs II catalyst (1 mol%)

Bu

133 (20 mol%) CHO

CH2Cl2, 40 to 35 °C, 2 h

+

t

N H

Ph

H2O (trace)

179

CH2Cl2, – 50 °C

CHO 178

TMSO

O

slow addition over 12 h

O

(30 mol%)

O

additional 12 h

O OH

182

OHC

EtOAc; 64%

181

OHC

O

CO2H

N H

O

180

Michael/Michael/Aldol Condensation

3.6.3 tion

H

183

Knoevenagel/Hydrogenation/Robinson Annula-

95% ee

dr = 5:1

Ramachary and Kishor reported an asymmetric synthesis of Wieland–Miescher ketone analogues using a sequential one-pot Knoevenagel/hydrogenation/Robinson annulation reaction (Scheme 37).49 Reaction of benzaldehyde, cyclohexane-1,3-dione, and Hantzsch ester 191 in dichloromethane with L-proline (20 mol%) at room temperature for three hours gave the reductive alkylation intermediate 192. After complete evaporation of the solvent, to the crude reaction mixture was added a solution of methyl vinyl ketone and L-proline (30 mol%) in N,N-dimethylforma-

OH

OH H

(–)-aromadendranediol

Scheme 35

(1)

Ph Ph

N H MeO

O

AcOH

O +

O

(20 mol%) H

OHC

185

184

OMe

OMe

MeCN, r.t., 72 h

MeO

OMe

OMe

53

OTMS

(2) p-TsOH, MeCN r.t., 5 h 82% for two steps

OMe

(+)-galbulin

186 Ph

dr >20:1; 99% ee

Ph N

OTMS H

Ph

OTMS H

Ph

H

Me

p-TsOH

O

OMe

Ar N

H

Ar (R)

N

H

O

Ph

Ph

OTMS

Ph

TS B

Ph

OMe

N H

OHC

O

OTMS Ar = C6H3(OMe)2

kS >> kR

O

H 188

Ph Ph N

H

OTMS

Ar

Ph

Ph OTMS H

H H

Ar O TS A

Ph Ph

OTMS

CHO H

H

N Ph Ph

Ar H

Me H

H (S)

O

N

H N

Me

H Ph

O

N

Ph OTMS

OTMS

OMe

O

H

187

Scheme 36



Syn thesis

P

Review

B.-C. Hong et al.

mide, and the mixture was stirred at room temperature for five days to afford a 50% yield of Wieland–Miescher ketone 193 (71% ee), along with side-products 194 and 195. O

EtO2C +

PhCHO

O

CO2Et

3.8.1 Michael Addition/Anion-Oxidative Hydroxylation/Cyclization

O

(1) L-Pro (20 mol%) CH2Cl2, r.t., 3 h

+

Ph

N H

190

O

191

189

192 (2) MVK L-Pro (20 mol%)

O

O

Ph

Ph

DMF, r.t. 5d

O

Ph O

+

+ O

O

3.8 Formation of One C–C Bond and Two C–O Bonds

O

OH

193

194

195

50%; 71% ee

30%

20%

Scheme 37

3.7 Formation of One C–C Bond and Two C–N Bonds

A total synthesis of (–)-nephrosteranic acid was accomplished by Qin and co-workers using a one-pot, three-step cascade reaction (Scheme 39).51 It began with the addition of 4.2 equivalents of lithium hexamethyldisilazide to a solution of (R)-methyl N-(tert-butylsulfinyl)propionimidate (202) and dimethyl 2-(4-methoxybenzylidene)malonate (203) in tetrahydrofuran at –78 °C. The reaction was allowed to proceed for three hours followed by the addition of 3.0 equivalents of copper(II) triflate in tetrahydrofuran, and for 48 hours to give the lactonimidate adduct 204 in 75% yield. The product 204 was transformed into the natural product (–)-nephrosteranic acid after a sequence of reactions. HO2C

3.7.1

C11H23

Conjugate Addition/C-Alkylation/N-Alkylation

O O

The Tomioka research group revealed a total synthesis of (–)-kopsinine, a plant alkaloid with anticholinergic activity, using an asymmetric one-pot [n+2+3] cyclization (Scheme 38).50 Asymmetric conjugate addition of lithium N-benzyltrimethylsilylamide 197 to tert-butyl NBoc-indole-3-propenoate (196) was achieved with the chiral di(methyl ether) ligand 198 in toluene at –65 °C for 15 hours, followed by the addition of 1-chloro-3-iodopropane in the presence of N,N′-dimethylpropyleneurea (DMPU) at –40 °C for two hours. Heating of the reaction mixture with tetrabutylammonium fluoride at 75 °C for three hours provided an 85% yield of piperidine product 201 with diastereoselectivity >99:1 and 98% ee.

(–)-nephrosteranic acid

MeO O– +

S

MeO2C +

MeO

Ph

+

N Boc

Bn

196

TMS

Ph 198

N

MeO

Li

toluene, –65 °C, 15 h

Bn

N

O

197

S

206

+S N

CO2Me

MeO

O2

Cu+2 Cu+

CO2Me

+S

CO2Me

N CO2Me

MeO

CO2Me

199

MeO

N

O

CO2Me

Cu+

CO2Me MeO

O

N

O

S

S

O

O 207

208

Scheme 39

Bn N

Bn

OMe

OMe

CO2Me

205 Cl

204

OMe O–

N Boc

N

203

O

OtBu

OMe

CO2Me O

(2) Cu(OTf)2, O2, THF –78 to 50 °C, 48 h; 75%

OMe 202

OMe

CO2tBu

CO2Me (1) LiHMDS, –78 °C, 3 h

O–

Li

TMS

CO2Me

N

NH Cl

I

TBAF

DMPU

N

–40 °C, 2 h

Boc N

N H

CO2Me

(–)-kopsinine

Scheme 38

CO2tBu

75 °C, 3 h; 85%

N Boc

200

CO2tBu 201

dr > 99:1; 98% ee

3.9 Formation of Two C–C Bonds and Two C–O Bonds 3.9.1 Intermolecular Michael Addition/Dieckmann Condensation and Spiroketalization Asymmetric total syntheses of (–)-penicipyrone and (–)-tenuipyrone were reported, by Tong and co-workers, to take place via biomimetic cascade intermolecular Michael



Syn thesis

Q

Review

B.-C. Hong et al.

addition/cycloketalization (Scheme 40).52 For the synthesis of (–)-penicipyrone, the key step of cascade intermolecular Michael addition/spiroketalization was achieved in 84% yield with exclusive diastereoselectivity via the treatment of chiral ketone derivative 209 and 4-hydroxy-6-methyl-2pyrone (210) with Amberlyst-15 in dichloromethane. Similarly, the synthesis of (–)-tenuipyrone was accomplished via the Amberlyst-15 promoted cascade reaction, although with a modified process. The first-step reaction of 210 and 212 with Amberlyst-15 in dry dichloromethane gave 16% yield of (–)-tenuipyrone and 60% yield of the undeprotected spiroketal 215. Treatment of adduct 215 with wet dichloromethane caused the desilylation of 215 and isomerization of spiroketal isomer 216 to provide (–)-tenuipyrone in 47% yield.

under the generic name orlistat and is an analogue of the naturally occurring lipstatin. The strategy started from a one-pot two-step procedure involving phosphorodiamidite coupling reaction and oxidation of (3S,5S)-hepta-1,6-diene3,5-diol (217) to afford the bicyclic phosphate 219. Subsequently, 219 was treated sequentially with Grubbs’ secondgeneration catalyst 220 (3 mol%), second-generation Hoveyda–Grubbs catalyst 222 (10 mol%) and undec-1-ene in dichloromethane, then with o-nitrobenzenesulfonyl hydrazine and triethylamine to afford the bicyclic phosphate product 224. Phosphate 224 was then transformed into THL by way of an additional seven steps.

P OH

Mes N

NiPr2

(1) O

OH

218

O

NiPr2

O

O Amberlyst-15

O

+ O

OH 209

H

(2)

O

Ph

220 (3 mol%)

MCPBA, 1 h

CH2Cl2, reflux, 2 h

219

64% yield for two-step one-pot process

OH

CH2Cl2, r.t.; 84%

Mes

PCy3

O

217

O

N Ru

Cl

P O

1H-tetrazole, MeCN, 2 h, r.t. OH

Cl

O 211

OH

210

Mes N Cl O

O

O

H

O

Mes

O

O

iPr

O P

O

Cl

P

O

N Ru

o-NBSH, Et3N

O

O

CH2Cl2, r.t., 24 h

O

OH

40% yield for three-step one-pot process

222 (10 mol%) O

O

223

221

(–)-penicipyrone CH2Cl2, reflux, 2 h

O H

NHCHO

O O

O

O

O

OTES

+

P O

O

O

O

O

O

C6H13

213

212

O

O C6H13

O

210

O O

O

O

CH2Cl2, r.t.

TBSO

OH

TBSO

Amberlyst-15

NHCHO

O

OTES

O

224

(–)-THL

(–)-lipstatin

H O H

TBSO

O

O

O

O

Scheme 41

TBSO O H

OTES

H

O

Amberlyst-15 CH2Cl2/H2O (20:1), r.t.

O

O O

214 215

HO

HO O O

O

H O H O 216

O

O 47% yield over 2 steps

H O H

O

O (–)-tenuipyrone

Scheme 40

3.10

Recently, Hanson and co-workers utilized a three-pot process for the total synthesis of antifungal natural product (+)-strictifolione and related natural products (Scheme 42). Their protocol involved two consecutive one-pot three-step procedures. A conspicuous aspect of this pot-economical synthesis is that additional protecting groups were not required.54

3.10.2 Oxidative Dearomatization and Trienamine/ Enamine Reaction

Formation of Three C–C Bonds

3.10.1 Sequential Ring-Closing Metathesis/Cross Metathesis/Hydrogenation Hanson and co-workers revealed an efficient synthesis of (–)-tetrahydrolipstatin (THL) via a one-pot sequential ring-closing metathesis/cross metathesis/hydrogenation sequence (Scheme 41).53 THL is an antiobesity drug marketed

Greck and co-workers reported a one-pot enantioselective synthesis of tricyclic ketones via a cascade oxidative dearomatization and trienamine/enamine activation reaction (Scheme 43).55 The one-pot reaction resulted in the formation of three carbon–carbon bonds and provided the tricyclic products with six contiguous stereocenters in good stereoselectivities. This tricyclic architecture has been ob-



Syn thesis

R

Syn thesis

Review

B.-C. Hong et al.

3.10.3 Conjugate Addition/Friedel–Crafts Alkylation/Cyclization

(1) Cl

N

Mes 222

Ru

(6 mol%)

Cl O

O

O

O

CH2Cl2

O

iPr

P O

O (2)

Ph

O

(2) MeSO4, THF

Ph

60 °C, 3 h

DCE, 60 °C, 2 h

225

(1) Pd(OAc)2, HCO2H Ph3P, CsCO3 THF, 50 °C, 1 h

O P

226

Ph (3)

o-NBSH, Et3N, DCE, r.t. 52% for three-step one pot process

O

OH

OMe P

O

OH

(3) LiAlH4, THF, 0 °C

O

65% for three-step one pot process

Ph

Ph 228

227

N

Mes Cl

N

Mes

H

Ru

O

222

Cl iPr

The Hong research group recently reported a one-pot biomimetic total synthesis of yuehchukene using the organocatalytic Friedel–Crafts alkylation of indole to the sterically encumbered α-alkyl enal 236 as a key step (Scheme 44).56 (±)-Yuehchukene is an uncommon dimeric indole alkaloid that was isolated as a racemate from the roots of several Murraya species. The one-pot process of the synthesis of yuehchukene from indole and the naturally occurring αalkyl enal 236 may mimic the biosynthetic pathway. In addition, the observation of racemization during the cyclization steps of reaction intermediate 240 to yuehchukene (241) provides a possible explanation as to why yuehchukene is present in nature as a racemate.

OH

O

OH

N H

Ar

O

H

(6 mol%) O O O

O

241

P

Ph

CH2Cl2, 40 °C; 77%

O

(+)-strictifolione

OH

N H

237 (20 mol%)

229

Ar

Ar

Ar = 3,5-(CF3)2C6H3

O

Scheme 42

O

served in disparate natural products, including atropurpuran, penicillone A and valeriananoid A, isolated from microorganisms and plants.

237 Ar = 3,5-(CF3)2C6H3 (20 mol%) OMe

indole, CH2Cl2 73%; 21% ee

N

Ph

OHC +

O

Ph

N H

OTBS

OHC

(10 mol%)

OH

230

238 N

N H

O

N H H O

232 OHC

Ph

Ph

CHCl3–EtOAc; 25%

anti: 88% ee 239

Ph

(40 mol%)

OTBS

OTBS

O

+

O

N

N

H

O H

235

234

233

1,3-H shift N H O

HO

OH

CHO atropurpuran

243

241

O

O

N H H

H

O

HO

N H chirality retention

N H

H

N H

H

242 N H and

O

H H

penicillone A

racemized

valeriananoid A

N

Scheme 43

H O

240 anti/syn = 63:37

OH

O

236 O

O P

97% ee 231

Ph

H

(20 mol%)

+

PhI(OAc)2, CHCl3 55 °C; 53%

OH

Ar

NH2

OH

O P

CH2Cl2; 26%; 5% ee

N H (±)-241

H

N

H N

N H

(racemate)

244

H

achiral compound no proper sites for asymmetric induction

Scheme 44


H

H 242

N H


Mes N

S

Review

B.-C. Hong et al.

3.10.4 Michael Addition/Claisen Condensation/Reductive Coupling

46).58 The one-pot process assembled three heterocyclic rings and a spiroacetal center, with the relative stereochemistry at the quaternary center required for the synthesis of ascospiroketal A. The studies also established the full stereochemistry for the ascospiroketal family of natural products.

A library synthesis of sexually deceptive chiloglottones was attained by Ramachary and Madhavachary using onepot three-component reductive coupling reactions (Scheme 45).57 Treatment of pent-3-en-2-one and diethyl malonate with potassium tert-butoxide in refluxing tetrahydrofuran followed by hydrolysis with 20% aqueous sodium hydroxide and decarboxylation with concentrated hydrochloric acid afforded 5-methylcyclohexane-1,3-dione (249) via a domino Michael addition/Claisen condensation. The aqueous layer of the reaction was removed, and the crude product 249 was treated with butyraldehyde and Hantzsch ester in the presence of catalytic proline in acetonitrile at room temperature to give chiloglottone analogue 247 in 66% yield. EtO2C

O

4 4.1

Rodriguez and co-workers reported an enantioselective cascade formal reductive insertion of allylic alcohols into the C(O)–C bond of 1,3-diketone 254 via a one-pot process of iron-catalyzed oxidation, iminium-catalyzed Michael reaction, iron-catalyzed reduction and retro-Claisen fragmentation to afford the chiral ester 257 (Scheme 47).59 In this cascade dual iron/amine catalysis and acyl transfer process, the allylic alcohol was activated by iron cyclopentadienone as a ‘borrowing hydrogen’ complex and trimethylamine N-oxide to generate the active iron catalyst by liberating carbon monoxide and trimethylamine. Later, the application of this redox, step- and atom-economic process was demonstrated in the transformation of the chiral esters into the key fragments of biologically active natural products or odorant molecules.

O N H

(2) 20% NaOH, H2O, 90 °C, 3 h

+

nPrCHO,

(3) concd aq HCl, 90 °C, 1 h EtO2C

191

proline (20 mol%)

O

MeCN, 25 °C, 1 h; 66%

CO2Et

247

246 Hantzsch ester

O

O

O n

PrCHO, cat. Pro

O

O

O

CO2Et 249

248

250

4.2

Scheme 45

3.11

Formation of Two C–N Bonds

4.2.1 Hydrogenation/Deprotection/Cyclization/ Trifluoroacetylation

Formation of Three C–O Bonds

3.11.1

Formation of One C–C Bond

4.1.1 Oxidation/Michael/Reduction/Retro-Claisen

CO2Et

(1) tBuOK, THF, 85 °C, 12 h

245

Quadruple Reactions

Silver(I)-Promoted Cyclization Cascade

Arimoto and co-workers reported a total synthesis of pinnaic acid and halichlorine using a one-pot, four-step hydrogenation–cyclization reaction for the stereoselective cyclization of the spirocyclopentane (Scheme 48).60 The onepot reaction comprised reduction of the olefin, deprotec-

Britton and co-workers reported a total synthesis of the naturally occurring octaketide ascospiroketal A using a silver(I)-promoted cyclization cascade strategy (Scheme

O O

OH

H

O

O

Ag2O, AgBF4, THF 20–50 °C; 82%

TMS

OH

H O

+ (1:1)

O H

TMS

Cl

OH

TMS

O H

OH O

O

O H

252

248

H O H

OH O

H 253

O

CO2H H

ascospiroketal A H

O O

OH

O

OH

HO

TMS

H

H OH

Cl 249

TMS

O Cl

O HO 250

AgI

O

TMS

H

O

AgI 251

Scheme 46



Syn thesis

T

Review

B.-C. Hong et al.

derivatives 269 with acetaldehyde and a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene gave the β-hydroxyaldehydes 270; subsequent dehydration under acidic conditions afforded enal derivatives 271 in very good yield. Organocatalytic asymmetric Michael addition of nitromethane with the 2-oxoindoline-3-ylidene acetaldehydes 271 gave intermediates 272, and reduction with zinc and cyclization gave spiropyrrolidines 273, which were methylated by aqueous formaldehyde to afford products 274. Reductive deprotection of the benzyl group (Na, liquid NH3) afforded (–)-coerulescine and (–)-horsfiline in 77% and 80% yield, respectively, resulting in 46% and 33% overall yields for the three one-pot operations.

other fragments of biologically active natural products prepared: O

OH tBu

Ph

TBDMSO

HO

O

261

most odorant isomer of doremox

263

262

(1) LiAlH4, Et2O, r.t. (2) CF3SO3H, CH2Cl2

apratoxin A fragment

lyconadin A fragment

0 °C; 83%, dr = 10:1 TMS O OH

O

O 255

O +

Ph

Ph

Ph (OC)3Fe

254

TMS

(6.5 mol%)

O

Me3NO (8 mol%)

Fe

Ph

H2 Ar Im

N H

O

Ar OTMS

O

256

257

Ar = 3,5-(CF3)2C6H3 (13 mol%)

80% ee

toluene, 26 °C; 96%

O R

retro-Claisen

O

OHC HO

N O

O

Fe

Ph

O

O

Ph 258

O

269

H2 O

Ph

O

OH

O

H2SO4

DBU (10 mol%)

R=H R = OMe

Ph H

Ph

AcOH–H2O (3:1) reflux, 1 h

THF, –25 °C, 12 h 270

Bn

N 271

Bn

R = H; 89% R = OMe; 90%

O

260

259

H

Scheme 47

Ar

tion of the Cbz group, intramolecular cyclic imine (enamine) formation, stereoselective reduction of the imine (enamine) intermediate, and trifluroacetylation of the amine. Subsequently, spiroamine 265 was transformed into (+)-halichlorine through a sequence of reactions.

N H

Ar = 3,5-(CF3)2C6H3 Ar 256

H N

NO2

OTMS

CHO R

(20 mol%)

i-PrOH, r.t., 42 h

272

Bn

273

N R Na, NH3

O N 274

THF, –78 °C

Bn

Scheme 49

H

CbzHN

TFA

N

O

(2) TFAA; 80% TBDPSO

TBDPSO

N

O

MOMO

(1) H2, Pd(OH)2/C

H

Cl

H 265

264 H2

– Cbz

H2

MOMO O

MOMO

MOMO

H 266

HN

N

HN TBDPSO

OH (+)-halichlorine

TFAA

TBDPSO

H 267

O N H

R = H, (–)-coerulescine; 77%; three one-pot processes: 46% R = OMe, (–)-horsfiline; 80%; three one-pot processes: 33%

R = H; 69% R = OMe; 46%

O

MOMO

Bn

Me

R

1h

Hayashi and co-workers reported the synthesis of (–)horsfiline and (–)-coerulescine using three one-pot operations as the key steps (Scheme 49).61 Aldol reaction of isatin

N

r.t., 1 h

N

Michael/Reduction/Cyclization/Methylation

O

AcOH–H2O (1:1)

Me

37% aq formaldehyde

R

Zn O N

MeNO2, H2O

4.3 Formation of One C–C Bond and Two C–N Bonds 4.3.1

O

O N

+

Ph

CHO R

R

Bn

TBDPSO

H 268

Scheme 48



Syn thesis

U

Review

B.-C. Hong et al.

4.4 Formation of Two C–C Bonds and One C–N Bond 4.4.1

Michael/Acetalization/Mannich/Rearrangement

Paixão’s research group recently reported a highly stereoselective synthesis of natural-product-like hybrids using a one-pot organocatalytic/multicomponent reaction sequence (Scheme 50).62 The one-pot strategy started from an organocatalytic Michael–acetalization of 1,3-cyclohexadione 275 to α,β-unsaturated aldehyde 276, followed by an intramolecular three-component reaction of a primary amine and an isocyanide. The one-pot process resulted in the rapid assembly of four different types of molecules, and the strategy combined the enantioselectivity of organocatalysis with the diverse nature of multicomponent reactions. The protocol was applied in the synthesis of structurally unique peptidomimetics including lipidic, heterocyclic, and sugar moieties.

of the Jørgensen–Hayashi catalyst to give the conjugate addition intermediate. Treatment with acetyl chloride or benzoyl chloride then initiated a sequence of lactol ring opening, enol ether formation, hemiaminal formation, and acidcatalyzed N-acyliminium ion cyclization to afford the thermodynamically controlled and kinetically controlled products 284 and 285, respectively. Quinolizidines 284 and 285 were transformed into a series of corynantheine and ipecac alkaloids, including (–)-corynantheol and (+)-hirsutinol. N H N H (1)

(–)-corynantheol

Ph

53

O

OTMS

N

(20 mol%) N H

CH2Cl2, –20 °C, 72 h 282

HO

(2) AcCl; 85%

H 284

thermodynamic control

+

O

H

dr >95:5; 99% ee

N H N H

O Ar

O

N H

O

OTMS

Ar = 3,5-(CF3)2C6H3

275

(1)

O

256

Ar

tBuNH

(10 mol%)

Ar

H N

N

NC

2,

O

N H

CH2Cl2, TFE microwave; 59%

CHO

OTMS

N

CH2Cl2, –20 °C, 72 h

N H

(2) BzCl; 70%

277

OH

O

(20 mol%)

Ar = 3-indolyl

H

(+)-hirsutinol

Ph 53

N H 283

H

Ph

O

+

CH2Cl2, 10 °C

H OH

Ph N H

CHO

H

O

H H 285

kinetic control

dr >99:1; 97% ee

dr 18:82; 95% ee

276 O H N NH

H N

O

O N

N H

O N

O O HN

H

N H

O

281 286

H O

OH

HO O

O CN

O

O

tBuNH

NH

2

O O

278

OH

O

N

N H

280

279

O H 288

287

Scheme 51

4.6 Formation of One C–C Bond, Two C–N Bonds, and One C–O Bond 4.6.1 Aminoacetal Formation/Stille–Migita Coupling/ Azaelectrocyclization/Intramolecular Aminoacetal Formation

Scheme 50

4.5 Formation of Two C–C Bonds, One C–N Bond, and One C–O Bond 4.5.1 Michael/Enol Ether Formation/Hemiaminal Formation/Mannich Cyclization Franzén and co-workers developed a stereodivergent strategy for the synthesis of corynantheine and ipecac alkaloids. The total syntheses of (–)-dihydrocorynantheol, (–)corynantheol, (–)-protoemetinol, (–)-corynantheal and (–)protoemetine were achieved via a one-pot quinolizidine synthesis (Scheme 51).63 β-Keto amides 283 were allowed to react with α,β-unsaturated aldehyde 282 in the presence

The first asymmetric total synthesis of (–)-hippodamine was reported by Katsumura and co-workers, who used a one-pot asymmetric 6π-azaelectrocyclization (Scheme 52).64 The protocol began with the addition of (1S,2S)-1amino-2,3-dihydro-7-isopropyl-1H-inden-2-ol (289) and (Z)-ethyl 3-formyl-2-iodoacrylate (290) in N,N-dimethylformamide to vinylstannane 291 in the presence of a palladium(0) catalyst at 80 °C, affording the tetracyclic aminal product 292 in 81% yield as a single stereoisomer. The cisaminoindanol derivative 292 here not only acted as a chiral auxiliary but also served to introduce a nitrogen atom for this asymmetric azaelectrocyclization. The four-bond-



Syn thesis

V

Review

B.-C. Hong et al.

4.7 Formation of Two C–C Bonds and Two C–N Bonds

forming reaction also controlled the stereochemistry at the two asymmetric centers. The one-pot three-component reaction provided a powerful strategy for the synthesis of chiral piperidines, namely azaphenalene-type alkaloids. For example, 292 was transformed into (–)-hippodamine after a series of reactions. Similar strategies were applied in the stereocontrolled synthesis of (–)-dendroprimine, (+)-7-epidendroprimine, (+)-5-epidendroprimine, (+)-5,7-epidendroprimine,65 (–)-20-epiuleinevia,66 and (–)-dendroprimine.67

4.7.1 tion

Hong and co-workers reported a facile and highly stereoselective synthesis of ‘inside yohimbane’ analogues using a one-pot organocatalytic enantioselective domino doubleMichael reaction and Pictet–Spengler/lactamization reaction as key step (Scheme 53).68 The one-pot process started from the reaction of nitroalkenoate 297 and cinnamaldehyde (298) with the Jørgensen–Hayashi catalyst and 1,4-diazabicyclo[2.2.2]octane in dichloromethane. Subsequently, after the completion of the double Michael reaction, the toluene, tryptamine and trifluoroacetic acid were added. The one-pot process afforded a 77% yield of the pentacyclic benzindolo-quinolizine product 300 with >99% ee, and the protocol provided a facile entry to the dodecahydrobenz[a]indolo[3,2-h]quinolizines with five contiguous stereogenic centers.

O H

H

O

N HN

O H

296

(–)-hippodamine

OH + NH2

OHC I

SnBu3 CO2Et

+

O O

291

N

LiCl, MS 4 A

290

289

O

Pd2(dba)3 (2-furyl)3P

CO2Et

DMF, 80 °C 20 min; 81%

292 O

O

293

N

N

CO2Et

CO2Et

Tang and co-workers reported a biomimetic synthesis of rubialatin A using a one-pot protocol of tandem ring contraction/Michael addition/aldol reaction/oxidation (Scheme 54).69 Treatment of naphthalene-1,4-dione (305) and keto ester 304 with sodium hydride in dichloromethane under

295

294 O

4.8.1 Tandem Ring Contraction/Michael Addition/ Aldol Reaction/Oxidation

OH

CO2Et I

4.8 Formation of Two C–C Bonds and Two C–O Bonds

O

OH

N H

Michael/Michael/Pictet–Spengler/Lactamiza-

O

O

O

Scheme 52

(1)

Ph 53 N H

CO2Et

O2N

Ph

DABCO

OTMS

CH2Cl2, r.t.

297

O

(0.2 equiv) H

H

N

+ (2)

H

NH2

CHO

299 (1.5 equiv)

N H

298

HN

NO2 300

TFA (1.4 equiv) toluene–CH2Cl2 (21:1), reflux EtO CO2Et

EtO2C

H2N

CHO N H H+

NO2 301

H

O

NH

H N H

H N H

H

HN

H H

H

NO2 302

O 2N

Scheme 53


303


Syn thesis

W

Review

B.-C. Hong et al.

an argon atmosphere for 40 minutes followed by exposure to molecular oxygen for half an hour afforded rubialatin A and isorubialatin A in 23% and 20% yield, respectively. O CO2Me

HO

O

O

O

304 +

CO2Me

O O

O

(2) O2, 0.5 h

O

CO2Me

O

(1) NaH (1.2 equiv) CH2Cl2, r.t., Ar 40 min

O O

+

HO

HO O

O isorubialatin A

rubialatin A

20%

23%

O

tetrabutylammonium fluoride led to isomerization of 315 to 314 and provided 316 in 63% yield with 99% ee. Later, the three-step reaction sequence was completed in a one-pot operation: addition of the tetrahydrofuran into the freshly prepared mixture of 314 and 315 in chloroform, followed by the addition of tetrabutylammonium fluoride at room temperature for 20 hours, provided 316 in 25% yield, starting from 311 and 312. Alternatively, evaporation of chloroform from the freshly prepared reaction mixture of 314 and 315, followed by the addition of tetrahydrofuran, 1,8-diazabicyclo[5.4.0]undec-7-ene (3.6 equiv), and tetrabutylammonium fluoride (3.6 equiv), afforded 316 in 47% yield, starting from 311 and 312.

305

4.10 Formation of Three C–C Bonds and One C–O Bond

NaH O

O

CO2Me

O

CO2Me

O

O

OH

O

O OH

CO2Me HO

HO HO O

O

O2

O O

O

CO2Me

O

O CO2Me

O

CO2Me

O

O

O

O

O OH

HO

HO O

O

O

307

309

Scheme 54

4.9 Formation of Three C–C Bonds and One C=C Bond 4.9.1

Oxa-Michael/Michael/Michael/Aldol Condensa-

O 310

308

306

4.10.1 tion

Hong and co-workers revealed the first total synthesis of the marine meroterpene (+)-conicol via quadruple cascade three-component organocatalysis (Scheme 56).71 The key step involved a one-pot, organocatalytic oxa-Michael/ Michael/Michael/aldol condensation cascade of (E)-2-(2-nitrovinyl)benzene-1,4-diol (319) and two different α,β-unsaturated aldehydes. In their study, reaction of 319, 3methylbut-2-enal (320) and (E)-4,4-dimethoxybut-2-enal (321) in the presence of the Jørgensen–Hayashi catalyst (20 mol%) at ambient temperature for 36 hours afforded a 55% yield of tricyclic product 322. This was then used for the completion of the total synthesis of (+)-conicol, and the absolute configuration of (+)-conicol was consequently assigned.

Michael/Michael/Aldol/Henry

Hong and co-workers reported a synthesis of steroids with six contiguous stereogenic centers using a one-pot enantioselective organocatalytic Michael–Michael–Aldol– Henry reaction as key step (Scheme 55).70 Reaction of 311 and 312 with the Jørgenson–Hayashi catalyst (20 mol%) and diisopropylethylamine (20 mol%) at 10 °C in chloroform for 48 hours, followed by the addition of p-toluenesulfonic acid, and reaction for an additional 24 hours at ambient temperature afforded a 56:44 ratio of enones 314 and 315 in 75% yield, with 98% and 99% ee, respectively. Reaction of the nitro ketone 314 with 1,8-diazabicyclo[5.4.0]undec-7ene at room temperature for 24 hours led to the formation of Henry product 316 in 89% yield. Nevertheless, owing to the steric bulk of isomer 315, exposure of nitro ketone 315 to 1,8-diazabicyclo[5.4.0]undec-7-ene under the same reaction conditions gave no reaction after many days. However, treatment of the mixture of nitro ketones 314 and 315 with

4.11 Formation of Four C–C Bonds and One C–O Bond 4.11.1 Friedel–Crafts Alkylation/Michael/Michael/ Acetalization George and Spence developed a biomimetic total synthesis of ent-penilactone A and penilactone B using a onepot Friedel–Crafts alkylation/Michael/Michael/acetalization cascade of tetronic acid (324) and 4-methyl-6-acetylresorcinol (323) (Scheme 57).72 The efficient five-component cascade reaction generated four carbon–carbon bonds, one carbon–oxygen bond and two stereocenters for the one-pot synthesis of ent-penilactone A in 46% yield. Alternatively, the three-component cascade reaction of 331 and a precursor of o-quinone methide, 2-methyleneacetoxy-4-methyl6-acetylresorcinol (330), provided 86% yield of penilactone B.



Syn thesis

X

Syn thesis

Review

B.-C. Hong et al.

O H

Me O

O2N H

TBAF (4 equiv) CHCl3–THF, r.t., 20 h

CH3 H

H

O

H

HO

25% for three steps from 312

O

H

or O (1) DBU (3.6 equiv), THF, r.t., 2 h (2) TBAF (3.6 equiv), THF, 0 °C, 20 h

314 TBAF

NO2

H

316

H

DBU (1.5 equiv), THF

O

O H

r.t., 24 h; 89% from 314 CH3

H

or TBAF (1.0 equiv)

H NO2

315

THF, –10 °C, 1.5 h 63% from 314 and 315

O

O

53

+

O CHCl3, r.t., 24 h 75% for two steps

(20 mol%)

DIPEA (20 mol%) CHCl3, 10 °C, 48 h

O

O2N

CHO

OTMS

NO2 O

dr 56:44

313

312

Ph N

O

p-TsOH (1.8 equiv)

Ph

N H

311

O

Ph

OHC

O

H

O

NO2

H

314: β-NO2; 315: α-NO2

Ph OTMS

H NO2 H

H

R CHO

R H

H

H 317

O

p-TsOH

+

H NO2 H

– H 2O H

H H

R CHO

H

O

O

R=

NO2 H

H2C 318

O

O

Scheme 55

H

HO H O (+)-conicol

NO2

N H

CHO

53

CHO

HO

+

+

MeO OMe

OH 320

319

Ph Ph OTMS

321

AcOH

MeO

OMe

O 2N

CHO H

HO

(20 mol%)

H

CHCl3, 25 °C 36 h, 55%

O 322 dr >20:1; >99% ee

oxa-Michael N

MeO OMe

O2N NO2

Ph

OTMS

MeO OTMS Ph

OMe

O 2N N

N Ph

Ph Michael

N

Ph

Michael

O

O O

O

Ph Ph

OTMS

Scheme 56


OTMS Ph


47% for three steps from 312

O

Y

O

Review

B.-C. Hong et al.

HO

O

OH

+ OH

HCHO, NaOAc, AcOH 90 C, 16 h, then

O HO

323

O O

OH

O

110 °C, 24 h; 46%

OH

O

324

O OH

HCHO, NaOAc, AcOH 325

O

ent-penilactone A

OH OAc

O

OH OH 326 O O O

O

HO

O

OH O

OH

OH

O

O

OH

O

OH

O OH

O

OH HO

O

329

328

327

formation was achieved by the treatment of azide 339 with acetic acid in acetic anhydride at ambient temperature. Reduction of nitroalkane 340 to amine 341 was accomplished with zinc and chlorotrimethylsilane in ethanol. After bubbling of ammonia into the reaction mixture, and thus formation of the inactive zinc(II)–ammonia complex, the crude product was treated with potassium carbonate to promote the retro-Michael reaction of the thiol and thereby generate the enoate ester, namely oseltamivir, in 82% yield. The total synthesis of (–)-oseltamivir with an overall yield of 57% comprised nine reactions, three separate one-pot operations, and one purification by column chromatography before the isolation of the final product. The process was later optimized, by the same research group, into two one-pot reaction sequences, mainly by replacing sodium azide with trimethylsilyl azide and pyridine.74 This process provides a tour-de-force example of onepot synthesis and shows that the present procedure used in this context is suitable for large-scale preparation.

HO O

O O

OH

O OAc

O +

O

Ph

OH O

Et

dioxane, 110 °C

HO

O

5 h; 86%

OH

OH

Et

tBuO

ClCH2CO2H (20 mol%)

NO2

2C

tBuO

(2) evaporation

Et

Et

O

TolSH, EtOH

CO2Et

tBuO

2C

NO2

CO2Et

(1) TFA, CH2Cl2, 2 h (2) evaporation

–15 °C, 36 h; 70% tBuO

STol

Et

O

2C

NO2

336

337

purified by chromatography

Et Et STol

Et O

Hayashi and co-workers reported a synthesis of the anti-influenza neuramidase inhibitor (–)-oseltamivir by three one-pot operations (Scheme 58).73 The reaction sequence started from the organocatalytic enantioselective Michael reaction of aldehyde 332 and nitroalkene 333 followed by the subsequent Michael reaction of vinylphosphonate 335 and the intramolecular Horner–Wardsworth– Emmons reaction with the formyl group to provide ethyl cyclohexenecarboxylate 336. The reactive enoate group was protected as ethyl cyclohexanecarboxylate 337 by temporary introduction of the p-toluenethiol group. After purification of 337 by column chromatography, the tert-butyl ester was deprotected with trifluoroacetic acid. Excess reagents were evacuated under reduced pressure, and the crude carboxylic acid was transformed into the acyl azide 339 by addition of first oxalyl chloride, then sodium azide in aqueous acetone. A Curtius rearrangement and amide

(3) EtOH, r.t., 15 min

96% ee

Et

Pot-Economy Reactions

5.1.1 Michael/Michael/Horner–Wardsworth– Emmons/Thio-Michael and Curtius Rearrangement/ Reduction/Elimination

335

NO2

2C

334

333

5.1 Formation of One C=C Bond, Two C–C Bonds and One C–N Bond

(EtO)2P(O)

CHO

CH2Cl2, r.t., 40 min

Scheme 57

5

O

Cs2CO3, 0 °C, 3 h

+

CO2H

EtO2C

Et

Et

OTMS

(5 mol%)

332

331 penilactone B

(1)

Ph 53

N H

CHO

O

HO2C 330

OH

CO2Et

(1) (COCl)2, cat. DMF CH2Cl2, 1 h

NO2

338

O

CO2Et

N3O2C

(3) NaN3, H2O–acetone 0 °C, 20 min

NO2

339

without purification

Et

Et STol

Et O

CO2Et

Zn, TMSCl, EtOH 70 °C, 2 h

STol

Et O

CO2Et

AcHN

AcHN NO2

340

NH2

Et (1) bubble NH3 for quenching Zn by forming Zn(II)-NH3 (2) K2CO3, EtOH, 6 h

Et

57% for three one-pot processes

CO2Et

O AcHN

82%

NH2 (–)-oseltamivir

Scheme 58


(1) AcOH, Ac2O r.t., 49 h (2) evaporation

(2) evaporation HO2C

STol

Et

341


Syn thesis

Z

Review

B.-C. Hong et al.

5.1.2 Michael/Michael/Horner–Wadsworth–Emmons/ Epimerization/Amidation/Reduction

Ph

NO2

F

Hayashi and co-workers developed a high-yielding onepot synthesis of the DPP4-selective inhibitor ABT-341 by a four-component coupling reaction (Scheme 59).75 The onepot operation consisted of six reactions with only one isolation process at the final step to give 63% total yield of ABT341. The sequence started with the asymmetric Michael reaction of nitrostyrene 342 and acetaldehyde, catalyzed by the Jørgensen–Hayashi catalyst, followed by evaporation under reduced pressure to remove the excess acetaldehyde. Treatment of the residue with vinyl phosphonate 344 and cesium carbonate in dichloromethane resulted in a Michael reaction; this was followed by an intramolecular Horner– Wadsworth–Emmons reaction, promoted by the addition of ethanol to the reaction mixture at room temperature, affording the cyclohexene product 347. Quenching of the cesium carbonate, by the addition of chlorotrimethylsilane in ethanol at –40 °C, was followed by the addition of diisopropylethylamine to epimerize the nitro group. After evaporation of the volatile reagents and solvent, trifluoroacetic acid and dichloromethane were added to hydrolyze the ester into the corresponding carboxylic acid 349. The subsequent coupling reaction of acid 349 with 350 was achieved by the addition of tetrahydrofuran, O-(benzotriazol-1-yl)N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), diisopropylethylamine and the amine. The final step of the nitro group reduction proceeded with zinc and acetic acid in ethyl acetate, followed by acid–base extraction and only one column chromatography purification, to provide ABT341 in 63% isolated yield. With the elaborate choice of solvents and the reagent design, this high-yielding enantioselective one-pot operation, comprising six reactions with only one purification step, constitutes a milestone in the field of one-pot synthetic strategy.

5.2

Miscellaneous Reactions

5.2.1 Michael/Henry/Horner–Wadsworth–Emmons/ Dehydration/Alkene Isomerization/Epoxidation/Reduction Hayashi and Umemiya reported an efficient enantioselective synthesis of prostaglandin A1 (PGA1) and E1 (PGE1) methyl esters via a pot-economic process (Scheme 60).76 The sequence of eight reactions was accomplished with a three-pot operation, including three isolations and three chromatographic purifications, to give PGE1 methyl ester in 14% total yield. Similarly, the pot-economy approach afforded PGA1 methyl ester in 25% total yield. The merits of this pot-economic process include the reduction of the amount

O F

Ph

N H

53

OHC

OTMS

(10 mol%)

NO2

F

+

F

H

1,4-dioxane 0 °C to r.t., 5 h evaporation

342

F

F

343

O P(OEt)2

OHC

344 F

(1.2 equiv)

tBu

CO2

P((O)OEt)2

F

Cs2CO3 (2 equiv)

F

NO2 CO2tBu 345

CH2Cl2, 0 °C, 4 h

OH

CO2tBu

P((O)OEt)2 CO2tBu

EtOH

F

F r.t., 15 min F

F

NO2

F

NO2

F

347

346

CO2tBu (1) TMSCl, –40 °C, 5 min

TFA, CH2Cl2 F –40 °C to r.t., 4 h

(2) DIPEA, EtOH, r.t., 48 h F

evaporation

CO2H

F

F

O N F F

349

N

N

TBTU, DIPEA, THF

NO2

N

N

350 CF3

F

evaporation

348

N

HN N

F

NO2

F

CF3

NO2 351

0 °C to r.t., 18 h O (1) nPrNH2, r.t., 30 min (2) evaporation

N

N

(1) Zn, AcOH, EtOAc –40 to 0 °C, 48 h

F

(2) NH4OH

F

N F

N CF3

NH2 ABT-341

Scheme 59

of solvent necessary and waste formed, as well as the omission of functional group protection and deprotection. The sequence started with the organocatalytic Micheal reaction of nitroalkene 352 and succinaldehyde (353) followed by a Henry reaction, facilitated by diisopropylethylamine, and the subsequent addition of a Horner–Wadsworth–Emmons reagent to afford the product 357 having the prostaglandin skeleton. The three-reaction one-pot protocol gave 81% yield of the product. Diastereoselective reduction of ketone 357 with (–)-diisopinocampheyl chloroborane (DIPCl) provided alcohol 358 in 68% yield and with a diastereomeric ratio of 96:4. Dehydration of 358 with acidic alumina at 60 °C for 48 hours was followed by isomerization of the double bond to give 2-nitrocyclopentene with 1,4-diazabicyclo[2.2.2]octane and diisopropylethylamine. The reaction medium was neutralized by the addition of chlorotrimethylsilane; base-mediated epoxidation in methanol at –45 °C then gave epoxy ketone 359, which was treated with zinc to provide PGE1 methyl ester. The four-reaction one-pot process afforded a 25% yield of the product.



Syn thesis

AA

Syn thesis

Review

B.-C. Hong et al.

Ph O2N

CO2Me 352

N H

Ph

53 O2N

OTMS

4-O2NC6H4OH (5 mol%)

+

CO2Me

O CHO

MeCN, r.t., 18 h

CHO

with 11 contiguous stereocenters and five all-carbon quaternary stereocenters, giving an average 92% yield for each carbon–carbon bond-formation reaction. O

354

Me

OHC

N

353

N H

O OMe

P

MeO iPr

2NEt 0 °C, 30 min

O 2N

CO2Me

LiCl, iPr2NEt

356

HO

CN

(1) slow addition of Cu(OTf)2 (2.5 equiv) NaTFA (2.0 equiv) and TFA (3.0 equiv) in i-PrCN and 344 (30 mol%) in i-PrCN–DME (1:2) over 7 h

OMe

MeCN, THF CHO

0 °C to r.t., 6 h

355

160

CN

OMe

362

CHO

(2) r.t., 17 h; 63%

81% for three-step one-pot process OMe O 2N

CO2Me

CN

O2N

CO2Me CN

(–)-DIPCl HO

HF, –40 °C 12 h; 68%

HO H

O

HO

H CHO

358 357

dr = 76:17:7

dr = 96:4

Al2O3 O 2N

CO2Me

Cl(CH2)2Cl

Al2O3 Cl(CH2)2Cl 60 °C 48 h; 75%

HO

DABCO, 6 h iPr

2NEt,

360

DABCO, 6 h

MeCN, 0 °C

iPr

TMSCl, MeOH then evaporation

2NEt,

24 h

NaOH H2O2, MeOH

MeCN, 0 °C

60 °C, 48 h evaporation

–45 °C, 48 h TMSCl (5 equiv)

24 h O

O 2N

CO2Me

CO2Me O HO HO

359

361 Zn aq NH4Cl

73%

O

CO2Me

HO PGA1 methyl ester three-pot process for PGA1 methyl ester, total yield 25%

MeOH, Et2O r.t., 12 h

O

CO2Me

HO HO PGE1 methyl ester four-reaction one-pot, yield 25% three-pot process for PGE1 methyl ester, total yield 14%

Scheme 60

5.2.2

Organo-SOMO-Catalyzed Polyene Cyclization

MacMillan and Rendler reported a singly occupied molecular orbital organocatalysis (organo-SOMO) polyene cyclization for the one-pot synthesis of steroidal and terpenoidal frameworks (Scheme 61).77 For example, the reaction of polyene aldehyde 362 was triggered by copper(II) triflate, sodium trifluoroacetate (NaTFA) and MacMillan catalyst 160 to give the polycyclic product 363. In this optimal example, six new carbon–carbon bonds were formed

H

OMe

H

363

93% ee

Scheme 61

6 Conclusions Many successful and imaginative applications of the one-pot strategy in natural product and medicinal drug synthesis have been described above. Moreover, many other interesting one-pot approaches to cyclic frameworks with natural-product-like systems or drug-like scaffolds have also been reported.78 The examples described herein delineate the merit of one-pot processes in assembling complex molecules and secure their position in future syntheses of natural products and medicinal drugs. It is conceivable that the combination of cooperative multicatalytic methods and other state-of-the-art technologies, such as flow chemistry, would further enhance the pot-economic processes. In summary, one-pot strategies for the synthesis of valuable complex molecules will continue to assume a key role in chemical synthesis for decades to come.

Acknowledgment Financial support from the Ministry of Science and Technology (MOST), Taiwan, R.O.C., is gratefully acknowledged.

References (1) (a) Multicomponent Reactions; Zhu, J.; Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005. (b) Multicomponent Reactions: Concepts and Applications for Design and Synthesis; Herrera, R. P.; Marquess-Lopez, E., Eds.; John Wiley & Sons: New York, 2015. (c) Multicomponent Reactions in Organic Synthesis; Zhu, J.; Wang, Q.; Wang, M.-X., Eds.; Wiley-VCH: Weinheim, 2015. (d) Science of Synthesis: Multicomponent Reactions; Vol. I and II; Müller, T. J. J., Ed.; Georg Thieme: Stuttgart, 2014.



O

AB

(2)

(3)

(4) (5) (6)

(7) (8)

(9) (10)

(11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27)

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Syn thesis