Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. Seiple Baran Group Meeting3/17/2007

tiglianedaphnane ingenane

Daphnanes: - Triciclic diterpenes with a tricyclo[9.3.0.0]tetradecane ring system - Obtained from the extracts of seeds and sap of Euphorbiaceae species (shrub) - Several members shown to exhibit cytotoxic, irritant, analgesic activity - Resiniferatoxin is the most potent irritant known in the literature at over a thousand times more potent than capsaicin - Only total synthesis reported of any daphnane was by Wender in 1997

Tiglianes: - Identical triciclo[9.3.0.0]tetradecane ring system as daphnanes, with additional gem-dimethyl cyclopropane appended to the 6-membered ring - Isolated as a mix of many esters from Euphorbia and Thymelaeaceae - Most famous: Phorbol (named in 25 BC by King Juba II of Mauritania) - Used for 2000 years in traditional medicine for tumors, migraines, parasites, venereal diseases, and as purgatives - Tetradodecanoyl phorbol acetate is the most potent tumor promoter (co-carcinogen) known - Acts on Protein Kinase C (PKC), which plays a role in regulating cellular growth and differentiation - Paradoxically, C12 deoxy derivatives inhibit tumor formation - Two total syntheses completed by Wender (one formal), and one by Cha (formal)

12Ingenanes: - Bicyclo[4.4.1]undecane ring system with in – out stereochemistry - Ingenol esters found in Euphorbiaceae, and used traditionally to treat tumors, migraines, parasites, gingivitis, and also as purgatives. - Derivatives have shown HIV-1 inhibition - Derivatives have also shown tumor-promoting and anti-tumor-promoting activities. - Racemic total syntheses reported by Winkler and Tanino/Kuwajima, asymmetric by Wood and Kigoshi (formal)lathyrane

Lathyranes: - Triciclic diterpenes with an 11-membered macrocycle and a cyclopropane - Obtained from Euphorbiaceae species (shrub) (W. Australia) - Various proinflammatory and tumor-promoting activities - Only one total synthesis reported of bertyadionol in 1986 (Smith III) - Stable to mild acid, base and UV-light

Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. SeipleBaran Group Meeting

3/17/2007

Tiglianes: Approaches to the Core12

Rigby Approaches: Hydroazulene Precursors

O TBSO

O

OOMeO

MeO MeO2C

OOMeO

MeO CO2Me

2:1 desired, 60%

8 kbar

O

O

1. TBAF2. Swern

O

O

1. LDA, F-, A

2. KOt-Bu

56% A =

O

TMS

Rigby, TL, 1989, 30, 5073

Shibasaki Asymmetric Approach: Tapping the Chiral Pool

H

H(+)-3-carene

20 stepsH

H

HO

O2N

p-ClC6H4NCOEt3N

65%

H

H

HO

O

N

Heterocycles, 1992, 33, 161TL 1992, 33, 4937

H

H

TBSO

HO

O

Steps

Me CeCl2H

H

TBSO

HO

HO

H

H

TBSO4 steps

O

Similar approaches with C12 oxygenationand C20 installation (but not both)

H

H

HO2C H

H

98%

OAcO

EtO2C

O

N2

H

H

O

O

CO2Et

H

H

OAcDauben/McMills Approach:

major

Rh2(OAc)2

86%

Dauben JOC 1993, 58, 7635McMills TL 1994, 35, 8311

OH

H

O

O1. KH, 18C62. m-CPBA

HO

LDA

1:1 dr

H

H

O

H

H

H

H

H

H

Paquette: Oxy-Cope Ring Expansion/Contraction

Ovaska: Chiral Pool to Tandem Cyclization Paquette T 1994, 50, 4071

Br 1. t–BuLi, CeCl32. B

OB =

OH

cat. MeLi

OH

H

185 ºC76%

Ovaska Org. Lett. 2001, 3, 115Wender: Why not a [4 + 2] ... or 3

MeO

O

CO2Et

8 steps O

O

OBn

heat

O

O

MeOMeO

MeO OMe 1. Wittig

2. H+

OO

OBn

OBnO

OBnO

TBSO

EtO

OEt

OTBS

ZnI2

18 stepsHO

OHHOHO

J. Am. Chem. Soc. 1987, 109, 4390

OH

Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. SeipleBaran Group Meeting

3/17/2007

Tiglianes: Total Synthesis (Wender's Game)

O

OTBS

HOAcO

O

AcO

OAc

OTBS

O

1. m-CPBA2. Ac2O DMAP

O

O

OTBS

AcO

DBU, 92%2:1

O

OTBS

AcO

O

O

OTBS

HO

OHC

1. TMSCN, ZnI22. DIBAL

O

OTBS

HO

OTMSON

1. NH2OH2. NaOCl

OTMS

52%8 steps

5 steps78%

46%4 steps 15:1

O

OTBS

O

OO

OAc1. m–CPBA2. P(OEt)33. Ph2SC(Me)24. DIBAL

O

OTBS

HO

OO

O

OTBS

OH

O OTMS

1. H2, RaNi, H2O2. Bz2O, DMAP3. DBU

9 steps37% ov.

Wender: The First Total Synthesis of a Tigliane

SPh

72%

OH

OH

HO

OO

OPiv

5 Steps45%

1. PCC2. NaBH(OAc)3

OH

HO

OO

OPiv

OH

BzO

OO

OBz

DIBAL; Bz2OSeO2, tBuO2H

OH

OH

BzO

OO

OBz

1. SOCl2, propylene oxide2. AgOBz, KOBz

OBz

OH

BzO

O OTMS

OBz

OBz

1. HClO42. SO3•pyr3. CF3CON(Me)TMS4. KN(TMS)2; TMSCl, NBS5. LiBr, Li2CO3

34% ov.58%

1. TsOH2. KCN 86%

OH

HO

O OH

OH

OH

(±)-phorbol52 steps

0.16% yield

JACS 1989, 111, 8954JACS 1989, 111, 8957

Wender's Formal Asymmetric

O

TBSOCHO

O N

O O

Ph

13 stepsMe

OAc

O

OTBS

H12% ov.

Me

O

O

OTBS

H

OTMSPh

O

Me

OAc

O

OTBS

HTMSO

Ph

PhCCLiLiBr, TMSCl

Cp2ZrCl2n–BuLi, HOAc;PCC, NaOAc

Me

O

O

OTBS

H

OTMSPh

1. LDA; TMSCl, PhSCl2. Pb(OAc)23. m–CPBA4. P(OEt)35. Ph2S(C(Me)2

1. HF2. O3; DMS3. Tf2O, pyr4. n–Bu4NI5. Zn, EtOH

OAc

Steps

phorbol36 steps

1.2% yield

16 steps9% ov.

For another formal asymmetric synthesis see Cha, JACS 2001, 123, 559043 steps, 0.4% overall

JACS 1997, 119, 7897

Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. SeipleBaran Group Meeting

3/17/2007

Ingenanes: Approaches to the Core

Me

Me

HOHO

HO

O

OH

Me

Me

H

Me

Me

HOHO

HO

O

OH

Me

Me

H

ingenol isoingenol

- ingenol is 5.9 kcal/mol higher in energy than isoingenol- the "in-out" stereochemistry of ingenol is essential to bioactivity- see Funk JACS 1988, 110, 2097

MeO

O 1. KNH2, NH32.

Cl Cl

MeO

O

3. KH32%

O

ORsteps

O

hv

RO

OHO

steps

O

ROHO

HOOH

R = palmitate

Derivative completely devoid of biological activity.

JACS, 1988, 110, 6192

Paquette: out-out Analogue

(+)-3-carene

10 steps

O

Me

O

MeO2C H

O

1. LiHMDS TBSCl2. PhMe, 95 ºC

O

Me

MeO2C H

HO2C3. HF

88%

Funk Delivers the In-Out

Rigby: Another in-out TechniqueJOC 1993, 58, 5873

O

O

OR

ROROR = MOM

1. Pd(OAc)2 (20%) TEA, PPh32. KH, 18C6

55%

O

O

OR

ROROOrg. Lett. 2002, 4, 799

O

O

OR

RORO

1. OsO42. m–CPBA3. thiocarbonyl- diimidazole4. P(OMe)3

H

Ingenanes: Total Syntheses of IngenolWinkler: First Total Synthesis

O11 steps

23%O

O

O

H

Cl

1. hv, MeCN2. K2CO3, MeOH

O

H

Cl

CO2Me

1. LAH2. DBU3. TBSCl

O

HOTBS

O

HOTBS

1. CHBr3, NaOH Et3N(Bn)Cl2. MeLi, CuSCN MeI

72%

35%

27 steps

rac–ingenol43 steps0.0068%

JACS, 2002, 124, 9726

O

OMe

Br

OTES

11 steps

OMeOTIPS

Co(CO)3

Co

OAc

OMeOTIPS

MeOH

Co(CO)3

Co

MeAl(OAr)2

OMeOTIPS

Me

OHO

1. Li, NH32. CHBr3, -OH BnEt3NCl3. Me3CuLi2, MeI4. Ti(Oi-Pr)4, TBHP

AlMe3

MeO

Me

Me

H

MeO

HO

OTIPS

34%5 steps

18 stepsrac–ingenol45 steps

0.03%

Tanino and Kuwajima: Improvement (?)

JACS 2003, 125, 1498

Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. SeipleBaran Group Meeting

3/17/2007

Daphnane Diterpenes

OEt

TIPSO

OMe

Li

OTBS

OEt

TIPSO

OMe

OHOTBSHO

O

1. Co2(CO)82. TBAF

Carreira: Tricyclic Rearrangement

TIPSO

OEt1. H2/Pd2. MsCl3. TBAF

MsO

HO

OEt

O

OEt

OH

OH

1. KOtamyl2. OsO4

O

EtO MeO

1. hv, TFA pentane

OOH

MeO

MeO MeO

HO

MeO

OH O

OH

OMeMeO

H

HH

Wender: Sugar to BC Rings + C12 Oxygenation

O

OH

OHHO

OH13 steps

9% ov.O

TBSO

OH

Me

OAc

OBn

OBn

1. VO(acac)2 t-BuOOH2. Ac2O, py.3. DBU

OAc

OBn

OBnO

OTBS

O

H

Angew. Chem. Int. Ed. 2001, 40, 2694

Wender: Total Synthesis of Resiniferatoxin

O

OBn

via kinetic resolution

1. Li-ethoxyacetylide2. p–TsOH

OO

OBnMe

OO

OTBS

H

OAc

OBn10 steps

See Classics II for more info

Org. Lett. 2006, 8, 5373

OMe

OOR

MeMe

H

HO

O

O

H

Ph

Resiniferatoxin

Lathyrane Diterpenes

Lathyrane IngenaneTigliane

Daphnane

HOOCcis-chrysanthemic acid

H

H

1. (COCl)22. CH2N23. hv, MeOH

H

HMeO2C

1. SeO22. HS(CH2)3SH BF3•OEt23. (EtO)2(O)PCLiHMe

H

H

S

S

O

(EtO)2(O)P

1. NaH, BuLi2. A; HCl

O

O

O

= A

H

H

O

(EtO)2(O)P

SS

O

6 steps

HOS

S

O

H

H

OCOPhO

H

H

OH

9 steps

O

(–)-bertyadionolJACS 1986, 108, 3110

Lathyrane diterpenes have been proposed as biosynthetic precursors for tigliane, ingenane, daphnane, jatrophane, and jatrapholane skeletons by Adolf et. al. (Isr. J. Chem. 1977, 16, 75). Groups have attempted to convert Lathyrane-type skeletons into the more complex cyclized products, but thusfar there has been no success.

Smith III: The First and Only Synthesis of a Lathyrane

Daphnane, Tigliane, Ingenane and Lathyrane DiterpenesI.B. SeipleBaran Group Meeting

3/17/2007

Ingenanes: Total Syntheses of Ingenol

Kigoshi: Formal Asymmetric Approach via RCM

MeO2C

O

HH

MeO2C

O

HH

THPO

INaH +

OTHPO

HH

Cl

75%

1. LiI2. PPTS3. CCl4, PPh3

O

HH

H

Et3CONa53%

O

HH

H

LDA

I

1. Grubbs 22. SeO2

O

HO

H

74%

H

formally36 Steps

0.01%

Me

Me

O

Wood: ROMRCM to VictoryMe

Me

O

Me

Me

O

Me

Me

OOPMB

O

O

Grubbs

59% 98%

3 steps

Grubbs II

76%

HS O

Me

Me

H

H

OPMB

O

O17 steps

37 steps0.002%

Org. Lett. 2001, 3, 1563JACS, 2004, 126, 16300

JOC 2004, 69, 7802

Lathyranes Continued

CHCl2

MeOOMe O

1. n–BuLi; MeI2. HClO4

+

I

O

O

CrCl2 (4.0 eq)NiCl2 (5%)

H

H

H

HO

O

HO

CCMe

from (+)-3-carene 1. LiEt3BH2. CP2Zr(H)Cl3. I2

O

O

HO

I

1. HCl2. CrCl2, NiCl2

HO

OH

O

O

IBX

Yamamura: Cr-Ni Coupling to the Core

TL 2000, 41, 2189