Total Synthesis of Caribenol a and Caribenol B

Literature Report 2

Total Synthesis of Caribenol A and Caribenol B

Reporter : Xiao-Yong Zhai Checker : Shubo Hu Date : 2017-04-24

Hao, H.-D.; Trauner, D. J. Am. Chem. Soc. 2017, 139, 4117. CV of Dirk Trauner

Education:  1986–1991 B.S., University of Vienna  1992–1995 M.S., Free University of Berlin  1996–1997 Ph.D., University of Vienna  1998–2000 Postdoc., Memorial Sloan Kettering Cancer Center  2001–2008 Associate Professor, University of California, Berkeley  2009-2017 Professor, University of Munich and New York University Dirk Trauner

Research:  chemical synthesis, natural product chemistry, neuroscience, cell biology and photopharmacology.

2 Contents

1 Introduction

2 Total Synthesis of Caribenol A

3 Total Synthesis of Caribenol B

4 Summary

3 Introduction

Me H H B C A HO Me Me O O

Caribenol A Pseudopterogorgia

 Isolated from the Pseudopterogorgia elisabethae in 2007;  Exhibiting biological activity against Mycobacterium tuberculosis H37Rv and plasmodium;  A caged structure and tricarbocyclic ring system with six stereocenters.

Wei, X.; Rodríguez, I. I.; Rodríguez, A. D.; Barnes, C. L. J. Org. Chem. 2007, 72, 7386.

4 Introduction

Natural products isolated from Pseudopterogorgia elisabethae

Me H Me H Me H H Me H O Me O O H Me Me O H O O O OH O Aberrarone Elisabethin A Amphilectolide

Me Me Me H H H H OH HO HO Me Me Me Me HO Me O OH O Me O O O Caribenol B Caribenol A Sandresolide B

Wei, X.; Rodríguez, I. I.; Rodríguez, A. D.; Barnes, C. L. J. Org. Chem. 2007, 72, 7386. 5 Retrosynthetic analysis of Caribenol A

O O CO Me O O O 2 Me Me Me Me Me Me TBSO Me Me A C A OH C A H C B B B H H H H H Me Me Me

Caribenol A (1) 2 3

O H Me CO2Me Me CO2Me Me + + Me O I TBSO CO Me Me Me 2

4 7 6 5

Liu, L-Z.; Han, J-C.; Yue, G-Z.; Li, C-C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 13608.

6 Total synthesis of Caribenol A

I PCC-mediated oxidative Me CO2Et rearrangement Me CO2Et o t-BuLi, Et2O, -78 C PCC, CH2Cl2, rt Me Me CO Et O then 2 (89%) (87%) Me Me Me OH Me Me O 5 8 9

o o (1) LiBEt3H, THF, -78 C (1) DIBAL-H, CH2Cl2, -78 C o Me CO2Et o (2) TBSOTf, Et3N, CH2Cl2, -78 C (2) DMP, NaHCO3, CH2Cl2, -78 C o (88%) TBSO (3) n-BuLi, THF, -78 C H CO Et Me Me 2 (72% over 3 steps) 10 HO CO2Me O CO2Me Me Me DMP, NaHCO3, CH2Cl2, rt TBSO (90%) TBSO Me Me Me Me 11 4 CO Me Intramolecular Diels-Alder O 2 Me Me reaction O 120 o 24 h TBSO BHT, toluene, C, O Me Me (92%) Me H OH 3 Me H H Me

7 PCC mediated oxidative rearrangement

Me CO2Et Me CO2Et

O Me Me Me Me OH

OH O

R R -Pyridine PCC -Hydrochloride -H2CrO3 O O Cr OH O O O Cr [3,3]-sigmatropic reaction OH R O R

8 Total synthesis of Caribenol A

I PCC-mediated oxidative Me CO2Et rearrangement Me CO2Et o t-BuLi, Et2O, -78 C PCC, CH2Cl2, rt Me Me CO Et O then 2 (89%) (87%) Me Me Me OH Me Me O 5 8 9

9 Total synthesis of Caribenol A

O CO Me o O 2 (1) Rh(PPh3)3Cl, H2, PhH, 66 C Me Me O (2) HF/Pry,THF, rt Me Me o TBSO (3) NaBH4, CeCl3•7H2O, EtOH, 0 C HO (80% over 3 steps) H H Me H 3 12 Me O O (1) KHMDS, THF (1) TPAP, NMO, 4 Å MS O O Comins -78 oC CH2Cl2, rt Me Me reagent, Me Me Pd/C, H , THF , Me Zn, THF, rt (2) 2 O (2) Pd(PPh3)4 2 Me (86 % over 2 steps) H (77 % over 2 steps) H

H H H H 13 Me 14 Me O O

O O O2, DMF, K2CO3 Me Me Me Me , 60 o 80 h P(OEt)3 C, Me P(OEt)3 Me O (66 %) O OH H H H H H Me Me 15 Caribenol A (1)

10 Retrosynthetic analysis of Caribenol A

Me Me Me H H H H H H cross B C B C C coupling A HO Me A A Me Me Me O O Me O furan O O O oxidation Friedel-Crafts Caribenol A (1) 2 3

Me H 14 steps

OH Me gram scale HO Me O 4 (-)-β-citronellol

Hao, H-D.; Trauner, D. J. Am. Chem. Soc. 2017, 139, 4117.

11 Total synthesis of Caribenol A

Me Me Me H H H (1) (COCl)2, DMSO then NEt3 DIBAL-H OH (92%) HO CO Me Me (2) 2 MeO2C Me Me Ph3P O (86% over two steps) O O 4 5 6

Me Me reductive Myers' allylic H Hoveyda-Grubbs || H transposition method CO2Me Ph3P, DEAD (1) TMSOK IPNBSH (63% over two steps) NEt O Me Me (2) Piv-Cl, 3 then HFIP, H2O (76% over two O NLi O CO2Me O steps) 7 8 Ph O O Me O O Me H H N CuCN, TMSCl, HMPA N O O

Ph Me (86%) Ph Me Me MgBr H O H 9 10 O HO Me Me O O 12 Myers' allylic reductive transposition method

Me Me H H

Me Me OH O O

Ph3P, DEAD IPNBSH -N2

Me Me H H

HFIP, H2O Me -acetone Me N O -ArSO2H O N O N S O HN Ar

O2N O O O S N N N OEt IPNBSH = H DEAD = EtO N O

13 Total synthesis of Caribenol A

Me Me Me H H H (1) (COCl)2, DMSO then NEt3 DIBAL-H OH (92%) HO CO Me Me (2) 2 MeO2C Me Me Ph3P O (86% over two steps) O O 4 5 6

Ph Me (86%) Ph Me Me MgBr H O H 9 10 O HO Me Me O O 14 Total synthesis of Caribenol A

O O Me , MeOH O Me H (1) Sm(OTf)3 H (2) HNMe(OMe)•HCl MeO

N Me2AlCl N (1) MgBr (94 %) O (76% over two steps) (2) H-G || (77 %) Ph Me Me O 10 O 11

Me Me Me H H H H H H tBu N tBu TMSOK

Tf2O (53 % over two steps) Me Me Me O TfO O O Me O Me O 3 12 2

Me Me Barton's protocol iodide H H for vinyl formation H CH3CO3H H (1) N2H4•H2O, Et3N NaOAc then I , TMG 2 (56 %) HO HO (72 %) (2) Me4Sn, AsPh3 Me Me Pd(PPh3)4 (33 %) O Me O Me O O O 13 Caribenol A (1)

15 Barton’s protocol for vinyl iodide formation

Me Me H H H H HO HO (1) N2H4•H2O, Et3N, then I2, TMG Me Me (2) Me4Sn, AsPh3, Pd(PPh3)4 O Me O Me O O Caribenol A (5)

N2H4•H2O I2 I C O C N C N C N N I C N N NEt NH2 3 NHI

I C I I -N2 I C Stille coupling H Me Sn, AsPh I 4 3 Me -H C Pd(PPh3)4 C C C

16 Retrosynthetic analysis of Caribenol B

Me Me H H A OH B OH

C Me Me

HO Me O Oxidation and R O aldol-type ring closure Grignard Caribenol B (14) 15 Me H Me H

Me O Me O Vilsmeler-Haack H O CHO α olefination -arylation 16 17 Me Me H H

O Me MeO2C Me H O O 18 5

17 Total synthesis of Caribenol B

Me Me Me H H H

Rh(PPh3)3Cl, H2 DIBAL-H (98 %) O MeO2C Me MeO2C Me Me O O H O 5 19 18 Ph O N O N N Me S Me H N H Bn N tBu N O (40 mol%) H •TFA LiHMDS over CAN, H2O O (26% three steps) α Me Me -Arylation of aldehyde Julia-Kocienski H O Olefination O 17 20 Me Me H H Tos-MIC, t-BuOK POCl3, DMF then MeOH (79%) Me (57%) Me Vilsmeier-Haack O Van Leusen Reaction Reaction O O CN 21 16 H

18 α-Arylation of aldehyde

Me Me H H

O O Me Me H O H O

O O O Me H O N H O

H2O t Bn N Bu H2O R1 R2 H N O R1 R2 N O

CAN

R1 R2 N O CAN

R1 R2 N O

R1 R2 N O -H H

19 Total synthesis of Caribenol B

Me Me Me H H H

20 Julia−Kocienski olefination

The Julia Olefination enables the preparation of alkenes from 1- phenyl-1H-tetrazol-5-yl sulfone and aldehydes in a single step.

Ph Me Me N O H N H S N N O O LiHMDS Me Me H O O

Ph O O O O O Li N N S N S N (1) LiHMDS N N S O N (2) N N N O N R N O R H O R Ph Li Ph N N OLi N N N N O Li N Ph N Ph R S O R O SO2

21 Total synthesis of Caribenol B

Me Me Me H H H

22 Vilsmeier-Haack Reaction

The Vilsmeier–Haack reaction is the chemical reaction of a substituted amide with phosphorus oxychloride and an electron-rich arene to produce an aryl aldehyde or ketone . Me Me H H

POCl3, DMF Me Me O O O H

O O O Cl PO2Cl2 Cl PO2Cl2 P Cl H + P O Cl N Cl Cl Cl H N H N Cl H N

Cl Cl H Cl H O O O - H O H2O O H N N N - Me2NH2Cl H

23 Total synthesis of Caribenol B

Me Me Me H H H

24 Van Leusen Reaction

The Van Leusen Reaction allows the conversion of a ketone into a nitrile with one additional carbon atom in a single pot. Me Me H H Tos-MIC, t-BuOK then MeOH (57%) Me Me O O O CN Tos Tos N H N Tos N t-BuOK Tos N C C C O R1 R O O 1 R R1 R2 R2 2 Tos N R1 Tos -Tos R1 MeO H O • N R1 O R2 N R2 H R2 H O

R1 R1 R1 -HCO2Me H • N N N OMe R2 R2 R2 H O

25 Total synthesis of Caribenol B

Me Me H H H DMDO, K2CO3 O Me Me (77%) O O O O O CN CN CN 21

Me Me Me H H H AgNO3 K CO , O OH OH OH DMDO, 2 3 2 2,6-lutidine (54%) Me Me Me

NC O O O NC O OH 22 23 24 Me H

OH MeMgBr (45% over two steps) Me

HO Me O Caribenol B (14)

26 Summary

Me H  17 Steps, 14% overall yield; H  The first total synthesis of Caribenol A; HO  Me IMDA reaction;  Furan oxidation. Me O O Caribenol A

Liu, L-Z.; Han, J-C.; Yue, G-Z.; Li, C-C.; Yang, Z. J. Am. Chem. Soc. , 132, 13608. 2010

Me  H 17 Steps, 1.3% overall yield (Caribenol A);  12 Steps, 1.9% overall yield (Caribenol B); OH  The first total synthesis of Caribenol B; Me  Highly stereoselectivity and protecting group free; HO  Friedel−Crafts triflation; O Me  Intramolecular organocatalytic α-arylation. Caribenol B

Hao, H-D.; Trauner, D. J. Am. Chem. Soc. 2017, 139, 4117.

27 The first paragraph

Furans teeter on the edge of aromaticity and can behave both as arenes and as very electron-rich dienes. As such, they can undergo a wide variety of chemical transformations, including electrophilic substitutions, metalations, cycloadditions, and oxidations. If extended to furyl carbinols, their synthetic power is increased even more, allowing for Piancatelli rearrangements and Achmatowicz reactions with subsequent cycloadditions to access carbocyclic systems. Often associated with a significant increase in molecular complexity, these transformations have been extensively exploited in the total synthesis of complex target molecules.

28 The last paragraph

In summary, we achieved an asymmetric synthesis of caribenol A and the first total synthesis of caribenol B. Both of our syntheses are highly stereoselective and protecting group free. The nucleophilicity of furans was critical to the success of our program, as they were used in a Friedel−Crafts triflation and an intramolecular organocatalytic α- arylation. A novel strategy for the conversion of furfurals into cyclopentenones and a mild method for the hydrolysis vinyl triflates were also developed. The scope of the gold-catalyzed cycloisomeri- zation shown in Scheme 3 is under active investigation in our laboratories, and results will be reported in due course.

29 Acknowledgement