Enantioselective Total Synthesis of(+)-Psiguadial B

L. M. Chapman, J. C. Beck, L. Wu, S. E. ReismanJ. Am. Chem. Soc. 2016, 138, 9803–9806

The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical EngineeringDivision of Chemistry and Chemical Engineering

California Institute of Technology, Pasadena, California US

Samuel Rieder, 9. Jan. 2017

MeMe

O

N2

hν, cat*, 8-AQ

tandem Wolff rearrangement/asymmetric ketene addition

MeMe

ONH N

OI

O

CHO

OHCHO

OH

MeH

HMeMe

PhH

(+)-psiguadial BHepG2 IC50 = 46 nM

+

Sarah E. Reisman

2

1997-2001 B.A. Conneticut College, New London, CTSupervisor: Prof. Timo V. Ovsaka

2001-2006 Ph.D Yale University, New Haven, CTSupervisor: Prof. John L. Wood

2006-2008 NIH Postdoctoral Fello, Harvard UniversityCambridge, MASupervisor: Prof. Eric N. Jacobson

2008-2014 Assistant Professor, CalTech, Pasadena, CA2014- Professor of Chemistry, CalTech

Research InterestNatural Product Synthesis, Methods DevelopmentNickel Catalysis

http://reismangroup.caltech.edu/index.html

(+)-Psiguadial BInformation; Biosynthesis

3

- First enantioselective total synthesis- Isolated by Shao in 2010 from Psidium guajava- Exhibits potent antiproliferative activity against human

hepatoma cells (HepG2 IC50 = 46 nM)

- Hepatoma: Cancer originating in the liver, in liver cells. More often called hepatocarcinoma or hepatocellular carcinoma.

- Biosynthesis à β-caryophyllene (sesquiterpenoid)- Key Challenges

- Bicyclo[4.3.1]decane trans-fused to cyclobutane- Synthesis of A–B–C ring system- Strategic formation of C1–C2 bond- Control of enantioselectivity

M. Shao, et al., Org. Lett. 2010, 12, 5040–5043

O

CHO

OHCHO

OH

MeH

HMeMe

PhH

C30H34O5474.60

AB

C D E

(+)-Psiguadial BBiosynthesis

4M. Shao, et al., Org. Lett. 2012, 14, 5262–5265.

SCoA

OPKS

1 x Malonyl-CoA2 x Methylmaolonyl-CoA

O

SCoA

OOO1. cyclization

2. enolization

O

HO OH

OH1. [O]

2. H+/–H2O

OHCHO

OHCHO

HOCHO

OH

CHOOH

H2Oβ-caryophyllene

a series ofhydride shifts

OHCHO

OHCHO

HO

OHCHO

OHCHO

HO O

CHO

OHCHO

OH

MeH

HMeMe

PhH

C30H34O5474.60

–H+

(+)-Psiguadial BRetrosynthetic Analysis

5

O

CHO

OHCHO

OH

MeH

HMeMe

PhH

O OH

OH

MeH

HMeMe

H

C–O bondformation OHMe

H

HMeMe

Br

OMe

MeO

ring closingmetathesis

aldol

MeMe

H

Me O

C(sp3)–Halkenylation

MeMe

ONH N

OI+prepared by

Wolffrearrangement

Synthesis IOptimisation of the Tandem Wolff Rearrangement

6M. Shao, et al., Org. Lett. 2012, 14, 5262–5265.

N

HO NH

(+)-cinchonine (C4)

OMe

MeN2

catalystNH2

N

hν (254 nm), THF, rt•

O

(S)(S)

MeMe

ONH N

Side-Discussion on KetenesHistory; Properties

7T. T. Tidwell, Ketenes II, John Wiley & Sons, Inc., Hoboken, NJ, USA, 2006.

- Hermann Staudinger

HOMO LUMO

• OC1C2

- Reactivity

• O O O

- Electrophile (at C2 or O): perpendicular to the ketene plane- Nucleophile (at C1): in ketene plane

Cl

O

Cl Ph

Ph Zn • OPh

Ph

• O

Me

Me• O

Side-Discussion on KetenesPreparation from Carboxylic Acid Derivatives

8

- α-halo carboxylic derivatives (Staudinger)- Acyl chlorides (Wedekind)

O

ClREt3N

reflux• OR

H

- Anhydrides

Et

O

O

O

Et

500 °C HO

O

MeO

Et• OMe

H

- Esters (E1cB)O

Ot-BuSiMe3

Me3SiLDA

OLi

Ot-BuSiMe3

Me3Si • OMe3Si

SiMe3

Side-Discussion on KetenesWolff Rearrangement

9W. Kirmse, Eur. J. Org. Chem. 2002, 2002, 2193.

- Ludwig Wolff (1902)

- Reactions of carbonylcarbenesthat can compete with the Wolff rearrangement

Synthesis IIC(sp3)-alkenylation; Epimerization I

10

MeMe

ONH N

Pd(OAc)2 (15 mol%)

Ag2CO3, TBME, 90 °C75% 22

55

MeMe

ONH N

O

O

I

+

(3 equiv.)

MeMe

ONH N

O

DBU

CH2Cl2, 60 °C64%

- Undesired enantiomer is obtained- (–)-cinchonine did not help

- Pseudoenantiomeric catalyst ent-product with 58% ee

1. ethylene glycol CH(OMe)3, p-TsOH PhMe, 80 °C, 86%

2. Cp2Zr(H)Cl, THF; then, Ph3P=CH2; then, 5 M HCl 58% (two steps)

MeMe

O

D. J. A. Schedler, J. Li, B. Ganem, J. Org. Chem. 1996, 61, 4115–4119.

Synthesis IIIC(sp3)-alkenylation; Epimerization II

11

MeMe

ONH N

I

+

(2 equiv., 8:1)

OO Pd(OAc)2 (15 mol%)

Ag2CO3, TBME, 90 °C72% 22

55

MeMe

ONH N

O

O

Ph3P=CH2;then, 5 M HCl

88%

MeMe

O

- Desired enantiomer obtained- Acetal as coupling partner à elimination of linear protection step

1. Cp2Zr(H)Cl, THF

2. KOH, MeOH, rt70% (2 steps)

MeMe

O

O

O

H

D. J. A. Schedler, J. Li, B. Ganem, J. Org. Chem. 1996, 61, 4115–4119.

Synthesis IVCompletion of the Synthesis I

12

O

Br OMe

OMe

+KOH

MeOH, 80 °C92%

MeMe

OH

Me

Br

MeO

MeO

vinyllithiumTHF, –78 °C

80%, dr 2:154% single diasteroisomer

MeMe

OH

HMe

Br

MeO

MeO

Grubbs-II (10 mol%)1,4-BQ

benzene, 80 °C93%

MeMe

OH

HMe

Br

MeO

MeO

- Gilman’s reagent furnished product in moderate yield (dr 3:1)

- Extensive experimentation to improve drunsuccessful

O

OP

Ph

PhMe

Me

MeMe

O

CuTC (15 mol%)L1 (30 mol%)Me3Al, Et2O, –35 °C

94%, dr 19:1

MeMe

OH

Me

Synthesis VCompletion of the Synthesis II

13

MeMe

OH

HMe

Br

MeO

MeO

Crabtree's cat. (5 mol%)H2 (34 bar)

CH2Cl2, rt90%

MeMe

OH

HMe

Br

MeO

MeO H

CuI2,2'-bipy (20 mol%)KOt-Bu

DMF, 120 °C75%

O OMe

OMe

MeH

HMeMe

H

DDQEtO(CH2)2OH

MeCN/CH2Cl2, 0 °C to rt60%, dr 4.8:1, 2 cycles

O OMe

OMe

MeH

HMeMe

H OEtO

Synthesis VICompletion of the Synthesis III

14

O OMe

OMe

MeH

HMeMe

H OEtO

Ph2Cu(CN)Li2BF3•OEt2–78 °C to –45 °C

90%, dr 2:1O OMe

OMe

MeH

HMeMe

H Ph

1. pyr•HCl, 200 °C 62%, 1 dia

2. MeOCHCl2, TiCl4 CH2Cl2, –78 °C to rt 50%

O OH

OH

MeH

HMeMe

H PhCHO

CHO

(+)-psiguadial

Conclusion

15

- (+)-psiguadial obtained in 15 steps from diazoketone

- Spectroscopically identical with natural sample reported by Shao

- De novo construction of trans-fused cyclobutane ring

- Pd-catalyzed C(sp3)–H alkenylation

- Expansion of sequence scope to other cyclobutanes ongoing

Thank you for your attention

Backup-Slide IScreened Catalysts for the Wolff Rearrangement

16

Backup-Slide IIAsymmetric Catalysis of Amide Formation

17

Backup-Slide IIICoupling with Pd(OAc)2

18G. He, G. Chen, Angew. Chem. Int. Ed. 2011, 50, 5192–5196V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2005, 127, 13154–13155.

Backup-Slide IVSchwartz Reduction

19D. J. A. Schedler, J. Li, B. Ganem, J. Org. Chem. 1996, 61, 4115–4119.

R1

O

NH

R2 Cp2Zr(H)Cl

R1

O

N R2

ZrCp2Cl

Cp2Zr(H)Cl

R1

H

N R2–Cp2Zr=O

H2O

R1

H

O

Backup-Slide VCopper Catalyzed Alkylation

20J. Westermann, K. Nickisch, Angew. Chem. Int. Ed. 1993, 32, 1368–1370M. d’Augustin, L. Palais, A. Alexakis, Angew. Chem. Int. Ed. 2005, 44, 1376–1378

- stronger coordinating solvents are used than with dialkylzinc reagents (Et2O or THF instead of toluene or CH2Cl2) as this allows the cleavage of the AlR3 dimeric species, thus increasing its reactivity

- 18 h at –30 °C; more rapidly at higher temperatures but decrease in ee

Backup-Slide VICrabtree’s Catalyst

21T. L. Church, P. G. Andersson, Coord. Chem. Rev. 2008, 252, 513–531

Backup-Slide VIICopper Catalyzed O-arylation; Ullmann

22I. P. Beletskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004, 248, 2337–2364.