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Literature Report

Reporter: Mu-Wang Chen

Checker: Xiang Gao

Shen, Y. & Yang, Z. & Hao, X.

Angew. Chem. Int. Ed. 2016, 55, 7539–7543. 2016-07-05

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Peking University

Our research interests span many fields, ranging from total

synthesis of natural product, synthetic methodology,

combinatorial chemistry and small molecule based chemical

biology.

Synthesis and Chemical Biology Yang, Z.

Kunming Institute of Botany

Natural product chemistry: 1) new structure, and bioactivity,

mechanism and structure-activity relationship; 2) bioactivity

of compounds; 3) natural inhibitor of plant virus based on

the chemical defense of plants.

Isolation and Structure Determination Hao, X.

Corresponding authors

Shen, Y.

Shangdong University

Synthetic biology and chemical biology of natural products.

Synthesis, Biological Activity

Contents

1

2

Introduction

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4

Isolation and Asymmetric Total Synthesis of Perforanoid A

Summary

A Concise Total Synthesis of (±)-Cipadonoid B

3

4

Introduction

5

Introduction

Introduction

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Isolated from leaves of Harrisonia perforata Merr

Five rings, a novel BCD tricyclic ring system

Six stereocenters, one all-carbon quaternary stereocenter

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Retrosynthetic analysis of Perforanoid A (1)

Asymmetric synthesis of intermediate 7

Oshima-Utimoto reaction

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Oshima-Utimoto reaction

Fugami, K., Oshima, K.; Utimoto, K. Tetrahedron Lett. 1987, 28, 809;

Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3367.

Asymmetric synthesis of intermediate 7

10

11

Cobalt-catalyzed Pauson-Khand reaction

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Rhodium-catalyzed Pauson-Khand reaction

Jeong, N. et al. J. Am. Chem. Soc. 2000, 122, 6771.

Pauson-Khand reaction of allene 9

Entry RhI Solvent Temp.

(oC)

Conc. b

(N)

Cat.

(mol%)

Yield c

(%)

1 [Rh(CO)2Cl]2 DCE 80 0.1 10 - a

2 [Rh(CO)2Cl]2 DCE 80 0.01 10 - a

3 [Rh(CO)2Cl]2 toluene 80 0.1 10 - a

4 [Rh(CO)2Cl]2 toluene 120 0.1 10 5

5 [Rh(CO)2Cl]2 toluene 120 0.01 10 55

6 [Rh(CO)2Cl]2 toluene 120 0.008 10 84

7 [Rh(CO)2Cl]2 toluene 120 0.008 7 85

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a No reaction, recovery of starting material 9. b Concentration of allene 9. c Yield of isolated product.

Pauson-Khand reaction of allene 9

8 [Rh(CO)2Cl]2 DCM reflux 0.008 10 - a

9 [Rh(CO)2Cl]2 DCM reflux 0.008 7 - a

10 [Rh(CO)2Cl]2 CH3CN reflux 0.008 10 - a

11 [Rh(CO)2Cl]2 CH3CN reflux 0.008 7 - a

12 [Rh(CO)2Cl]2 benzene reflux 0.008 10 - a

13 [Rh(CO)2Cl]2 benzene reflux 0.008 7 - a

14 [Rh(CO)2Cl]2 toluene 120 0.005 7 75

15 [Rh(CO)2Cl]2 toluene 120 0.008 5 70

16 [Rh(CO)(dppp)Cl]2 toluene 120 0.008 10 45

17 [Rh(CO)(dppe)Cl]2 toluene 120 0.008 10 36

18 [RhCl(cod)]2 toluene 120 0.008 10 18

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Asymmetric synthesis of intermediate 7

Asymmetric synthesis of intermediates 8a/8b

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Asymmetric synthesis of intermediates 8a/8b

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Mosher’s method determine absolute stereochemistry

1H NMR and 19F NMR spectra showed that the absolute stereochemistry at

C 10 in 8a and 8b was S and R, respectively.

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Mosher’s acid 即α-甲氧基-α-三氟甲基苯基乙酸，以及其酰氯的对映异构体(R 或者S 构型)已经商业化。可以用来确定手性醇，胺，或者羧酸的绝对构型。 手性纯的二级醇分别与Mosher’s acid或其酰氯的对映异构体偶合生成一对非对映异构体(S)-MTPA ester和(R)-MTPA ester。用此法定构型有一个前提，就是生成的酯的优势构象如下图所示，其中CF3，羰基氧，和二级醇的氢共平面且同侧。摆成这样的构象后，在(S)-MTPA ester中取代基R1位于苯环上方的屏蔽区，其NMR中化学位移向高场移动，同样在(R)-MTPA ester中取代基R2位于苯环上方的屏蔽区，其化学位移向高场移动。对于R2来讲，S构型的化学位移大于R构型的，反之，对于R1，S构型的化学位移小于R构型的。

确定绝对构型-手性衍生化试 (Chiral Derivatizing Agent)

Synthesis of Perforanoid A and 10-epi Perforanoid A

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Compound HEL K562 CB3 DP17 WM9

1 6.17 4.24 3.91 25.96 11.01

25 >50 >50 >50 >50 >50

Cytotoxic assay results for perforanoid A (1) and10-epi perforanoid A (25)

against different cell lines. The results are given as IC50 values (µM)

Biological study

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A concise total synthesis of (±)-Cipadonoid B

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Faber, J. M.; Williams, C. M. Chem. Commun. 2011, 47, 2258.

Isolated from Cipadessa cinerascens (Pell.) Hand.-Mazz

in southwest China by Di and Hao et al.

Retrosynthetic approach to Cipadonoid B (1)

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Claisen rearrangement

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Synthesis of 10

25

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Synthesis of 2

Williams, C. M. et al. Tetrahedron 2006, 62, 7355.

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Synthesis of 10

Williams, C. M. et al. Tetrahedron 2006, 62, 7355.

Synthesis of Cipadonoid B

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Synthesis of Cipadonoid B

Synthesis of Cipadonoid B

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Summary

Shen, Yang, Hao’s groups: 10 steps

Key steps: Pd-catalyzed Oshima-Utimoto reaction

Rh-catalyzed Pauson-Khand reaction

Williams’ group: 12 steps

Key steps: Baylis-Hillman reaction

Ketal-Claisen rearrangement

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Limonoids are a structurally diverse family of natural

products. They have a wide range of biological activities and

are used in agricultural and medicinal applications.

Our research group is interested in Meliaceae and Sima-

roubaceae species. We have previously isolated from them a

group of limonoids featuring a polycyclic lactone fragment (2–

6), and this work, we isolated the new limonoid 1 (Figure 1).

These compounds have antifeedent, antileukemia, anticancer,

antibacterial (including against multidrug-resistant bacteria),

and antimalarial activities.

Introduction

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In summary, we isolated the novel limonoid perforanoid A

and achieved an asymmetric total synthesis in 10 steps. The

key steps in the total synthesis are chiral tertiary amino-

naphthol mediated enantioselective alkenylations of aldehydes

for the asymmetric synthesis of allylic alcohol 11, Pd-catalyzed

coupling of 11 with a vinyl ether to form the g -lactone ring, with

stereoselective construction of the C13 all-carbon quaternary

center, and formation of the cyclopentenone ring by a Rh-

catalyzed Pauson–Khand reaction. Preliminary biological

studies indicate that this type of natural product has cytotoxic

activity against HEL, K562, and CB3 tumor cell lines.

Summary