Pentafulvene for the Synthesis of Complex Natural Products: Total Syntheses of (±)-

Pallambins A and B

Christian Ebner, Erick M. CarreiraAngew. Chem. Int. Ed. 2015, 54, pp–pp

Laboratorium für Organische ChemieETH Zürich, HCl H335

DOI: 10.1002/anie.201505126

Samuel Rieder, 13th Aug 2015

HH4π+2π

O Me

OH

Me

OO

HH

Me

Me

pallambin AO Me

OH

Me

OO

HH

Me

pallambin B

Me

Erick M. CarreiraBiography

2

-  1963: Born in Havana, Cuba-  1984: B.S. degree, University of Illinois, Scott Denmark-  1990: PhD degree, Harvard University, David A. Evans-  1992: Post-Doc, California Institute of Technology, Peter

Dervan-  1993: Assistant Professor, California Institute of

Technology-  1996: Associate Professor, California Institute of

Technology-  1997: Full Professor, California Institute of Technology-  1998: ETH Zurich

Research Interest-  Asymmetric synthesis of biologically active, stereochemically complex,

natural products-  Unique challenges in asymmetric bond construction-  Developing catalytic and stoichiometric reagents for asymmetric

stereocontrolhttp://www.carreira.ethz.ch/people/emc

(±)-Pallambin A and BGeneral Information

3

-  Isolated from liverwort Pallavicinia ambigua-  Cyclopropane containing diterpenoid (C19)-  Unprecedented and highly congested

tetracyclo[4.4.03,5.02,8]decane core-  Ten contiguous stereocenters, two quaternary

O Me

OH

Me

OO

HH

Me

Me

pallambin A

O Me

OH

Me

OO

HH

Me

pallambin B

Me

FulveneRule of Fulvene; Synthetic Strategy

4

HH

1956first preparation

"trapped with maleic anhydride"no yield reported

no structural characterization

this work pallambin A+

pallambin Bfirst use of pentafulvene

in complex synthesis

X

R1

R2prior work

X

R1R2sp3 hybridized

strategicallyrestricted

H

Hthis work

X

sp2 hybridizedstrategically flexibleelaboration:oxidationreductioncarbometallation

J. Thiec, J. Wiemann, Bull. Soc. Chim. Fr. 1956, 177–180

Total Synthesis from FulveneRetrosynthesis

5

O Me

OH

Me

OO

HH

Me

Me

O Me

HOH

Me

Me

OHAlkoxy-

carbonylation

O Me

MeO C–H insertion

O Me

MeO

N2

CO2Me

HH4π+2π

-  Pentafulvene not susceptible to isomerisation (≠ cyclopentadiene)-  sp2 bridge carbon atom à wide variety of transformations

Synthesis IDiels-Alder; Early Installation of Cyclopropane

6

-  Starting from fulvene-  Known to undergo facile light- or heat-induced polymerization-  Acid- and base-sensitive-  Stable in neat form only below –70 °C

B. M. Trost, R. M. Cory, J. Org. Chem. 1972, 37 (8), 1106–1110S. E. Denmark, J. P. Edwards, J. Org. Chem. 1991, 56, 6974–6981

NMe2 1. LiAlH4 (1 equiv.) Et2O, –17°C, 88%

2. MeI (1 equiv.) methyl acrylate, 0 °C then Et2AlCl (0.3 equiv.) –20 - 5 °C, 62% (d.r. 10:1)

CO2Me

CO2Me

1. ZnEt2 (2 equiv.) ClCH2I (4 equiv.) CH2Cl2, 0 °C, 85% (d.r. > 20:1)

2. [RhCl(PPh3)3] (4 mol%) H2 (1 atm) CH2Cl2, rt, 96% (d.r. > 20:1) CO2Me

MeH

-  Established cyclopropanation-protocols à low conversion, poor chemoselectivity

Synthesis IICarbene Precursor

7D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156

CO2Me

MeH LDA (2 equiv.)THF, –78 °C

then: P(OEt)3 (1 equiv.)DMPU (1 equiv.)O2 (bubbling), –90 °C 85% (d.r. 10:1)

CO2Me

MeH

HO

MeH

O Me

LDA (2.5 equiv.)THF, –78 - 0 °C

then: MeI (18 equiv.)then: NEt3 (18 equiv.)89% (d.r. 5:1)

1. TBSOTf (1.03 equiv.) NEt3 (1.5 equiv.) CH2Cl2, 0 °C

2. MeCHO (10 equiv.) BF3•Et2O (2 equiv.) CH2Cl2, –90 °C, 3x recycl.3. DMP (2 equiv.) tBuOH (2 equiv.) CH2Cl2, 0 °C, 70% (3 steps)

Me

O Me

O

Me

-  Intermediate β-hydroxy ketone unstable à Retro aldol (DM oxidation, LA nature)

-  DMP/tBuOH à increase rate of oxidation

1. LiAlH4 (0.7 equiv.) Et2O, 0 °C

2. NaIO4 (1.5 equiv.) THF/phosphate buffer (1:1) 0 °C, 97% (2 steps)

MeH

O

Synthesis IIIC-H Insertion

8R. L. Danheiser, R. F. Miller, R. G. Brisbois, S. Z. Park, J. Org. Chem. 1990, 55, 1959–1964T. J. Maimone, J. Shi, S. Ashida, Phil S. Baran J. Am. Chem. Soc., 2009, 131 (47), 17066–17067

[Rh2(OAc)4] (1 mol%)

CH2Cl2, reflux, 76%

Me

O Me

O

Me

O Me

O

Me LiHMDS (1.15 equiv.)THF, –78 °C

then: F3CCH2O2CCF3 (1.3 equiv.)NEt3 (1.5 equiv.)MsN3 (1.5 equiv.)MeCN, rt

Me

O Me

O

N2

Me

O Me

O

LDA (1.5 equiv.)then: PhNTf2 (2 equiv.)

THF, –78 - 5 °C, 64%

Me

O Me

TfO

[Pd(PPh3)4] (5 mol%)ZnMe2 (5 equiv.)

THF, 0 °C - rt, quant.

Me

O Me

Me

Me

O Me

Me

Br2CNOH (2.5 equiv.)KHCO3 (5 equiv.)

EtOAc, rt, 91%

Me

O Me

NOMe

HBr

LiOMe (20 equiv.)

MeOH, reflux, 94%

Me

O Me

NOMe

HOMe

Synthesis IV

9S. Kim, K. H. Ahn, J. Org. Chem. 1984, 49, 1717–1724

Me

O Me

NOMe

HOMe B(OH)3 (6 equiv.)

Ra-Ni (1 equiv.)H2 (1 atm)

MeOH (aq.) (5:1), rt, 91%

Me

O Me

OHO

Me

HOMe

Me

O Me

OHO

Me

HOMe

1. DIBAl-H (3 equiv.) nBuLi (3 equiv.) THF, 0 °C then: ester THF, –60 - 0 °C, 89%

2. (COCl)2 (1.6 equiv.) DMSO (2.7 equiv.) NEt3 (5 equiv.) CH2Cl2, –78 - 0 °C, quant.

Me

O Me

OHO

Me

HH

-  DIBAl-H and nBuLi à non-Lewis-acidic Li(iBu)2(nBu)AlH

Synthesis VIntroduction of the Tetrahydrofuran and the γ-Lactone

10M. F. Semmelhack, C. Bodurow, M. Baum, Tetrahedron Lett. 1984, 25, 3171–3174Z. Li, Y. Gao, Z. Jiao, N. Wu, D. Z. Wang, Z. Yang, Org. Lett. 2008, 10, 5163–5166

-  Separation of diastereoisomers unsuccessful à mixture used

Me

O Me

OHO

Me

HH vinylmagnesium bromide (3 equiv.)

CeCl3 (3 equiv.)THF, –78 °C

then: aldehyde–78 °C - rt, 90% (d.r. 6:4)

Me

O Me

HOMe

HOH

Me

O Me

HOMe

HOH

Pd(OAc)2 (10 mol%)TMTU (10 mol%)NH4OAc (10 mol%)CuCl2 (2.5 equiv.)propylene oxide (5 equiv.)CO (1 atm)

THF, 50 °C, 26%, 55%

O Me

OH

Me

OO

HH

Me

O Me

OH

Me

OO

HH

Me+

Synthesis VISynthesis of Pallambin A and B

11

O Me

OH

Me

OO

HH

Me

1. LDA (1.4 equiv.) THF, –78 °C then: MeCHO (5.7 equiv.) THF, –78 - –40 °C

2. NEt3 (15 equiv.) DMAP (cat.) MsCl (5 equiv.) CH2Cl2, rt, 11%, 87%

O Me

OH

Me

OO

HH

Me

Me

pallambin AO Me

OH

Me

OO

HH

Me

pallambin B

Me+

-  Generation of the β-phosphonate (for HWE) failed-  Two-step aldol condensation

Conclusion

12

-  First total syntheses of pallambins A and B (3.3% overall yield, 20 steps) -  Synthetic strategy centered around use of fulvene in a DA reaction-  Highly chemo- and diastereoselective cyclopropanation

-  Efforts to expand use of the fulvene DA reaction are ongoing

Thank you for your attention

[1,5]-shift of Substituted Cyclopentadienes

13

R H [1,5] R

HH

[1,5]R

H H

[1,5]etc.

Preparation of Pentafulvene

14

NMe2LiAlH4

NMe2HAl

4

LiH2O NMe2H

NMe2HMeI

NMe3.IH Hofmannelimination

HH

Wilkinson’s Catalyst [RhCl(PPh3)3]

15

Hydroxylation with O2, P(OEt)3

16

R1

OR3

R2

Base

R1

OR3

R2

O2R1

OR3

R2O O

R1

OR3

R2

R1

OR3

R2

R1

OR3

R2O OH

P(OEt)3

R1

OR3

R2OH

DMPU, P(OEt)3, O2

Carbene, C–H insertionMechanism not well Understood, Source of Dispute

17H. M. L. Davies, T. Hansen, M. R. Churchill, J. Am. Chem. Soc. 2000, 122, 3063D. F. Taber, K. K. You, A. L. Rheingold, J. Am. Chem. Soc. 1996, 118, 547

Carbene, C–H insertionMechanism not well Understood, Source of Dispute

18Z. Li, Y. Gao, Z. Jiao, N. Wu, D. Z. Wang, Z. Yang, Org. Lett. 2008, 10, 5163–5166

OH

R

OHH

OH

R

OHH PdX2Ln

PdX2O

O PdLnH

R

O

O PdLn

O

H

RO

OO

R

H

H

CO

co-oxidant

reducedco-oxidant

base

–HX

Biosynthesis

19L.-N. Wang, J.-Z. Zhang, X. Li, X.-N. Wang, C.-F. Xie, J.-C. Zhou, H.-X. Lou, Org. Lett. 2012, 14, 1102–1105

OO

O

O

OHMe

HMe

HH

OR

R

OHMeMe

OHMeMe

OHMeMe