Enantioselective Synthesis of (-)-Englerins A and B
2010. 09. 22 (Wed)
MeMeMeMeOOO
Me HPhHirotomo Komai (M1)OOHOMe HOH PhOORO
H

R=H : Englerin B
R=Ac : Englerin B acetate(-)-Englerin AContents
0. Intrduction
1. Christmann's Total synthesis (First total synthesis)
2. Nicolaou's Total synthesis ([2+5] cycloaddition)
3. Au catalyzed Reaction
4. Echavarren's Total synthesis (Au(I) catalyzed [2+2+2] cycloaddition)

0. Introduction

Examples of making guaiane sesquiterpene skeltoneIsolationJ. A. Beutler et al. Org. Lett. 2009, 11, 57-60.
From the stem bark of the east African (Tanzania andZimbabwe) plant "Phylanthus engleri" .

First Total Synthesis((+)-Englerin A)
M. Christmann et al. Andgew. Chem., Int. Ed. 2009,
48, 9105-9108.
(Olef in metathesis using the Grubbs II catalyst)
However..... (+)-Englerin A was not natural product.

Martin E. Maier et al. Org. Lett. 2010, 12, 3418-3421.

Total Synthesis ((-)-Englerin A)
1. A.M.Echavarren Angew. Chem. Int. Ed. 2010,
49, 3517-3519.
([2+2+2] alkyne/alkene/carbonyl cycloaddition
using Au(I) catalyst.)
2. D. Ma Angew. Chem. Int. Ed. 2010, 49, 3513-3516.
(The same key reaction of Echavarren)
3. K.C. Nicolaou J . Am. Chem. Soc. 2010, 132, 8219-8222.
([5+2] cycloaddition reaction)
4. Emmanuel A. Theodorakis et al. Org. Lett.
2010, 12, 3708-3711.

A. M. Echavarren et al. Chem. Commun., 2009, 7327

Challenging
1. Construction of guaiane-type sesquiterpene that contains
uncommon oxygenated motif.
2. Tricyclic motif carrying two esters, one to a cinnamic acidand the other to a glycolic acid residue.
MeMeMeMeMeMeHguaianeMe HHOMeHOROH

Other guaiane-type sesquiterpenes

OOR'H
Skeltone of Englerin

OMe H
HOH
Orientalol EMeMeMeMeHOOOMeHOHH
Orientalol F
Pubinernoid B

1

Activity John A. Beutler et al. Org. Lett. 2008, 11, 57
Englerins A ;It demonstrated excellent
selectivity for the renalcancer cell line panel,with 5 of 8 renal lines having GI50 values
under 20 nM (Table 2, Figure 3),

Search of reason
1. Hydroxy acid containing natural productsOOOHOOH

pleuromutilin

Safaromycin R

The NCI 60-cell data
Pleuromutilin indicated no significant cytotoxicity .
Saframycin R, although quite potent, did not show
renal selectivity.

Glycolate substitution alone cannot account for therenal selectivity of Englerins A.
2. Other ester motif compounds.
MeMeO

Englerins B;

ABPhMeOH

ORO
HEnglerin B acetate showed an approximately
400-fold selectivity against the renal cell line
(A498).
This result means Englerins B is lower
activity than Englerin A.

Why?
What's difference?
MeMeOPhOMe H

It's vital to synthesize a series of englerin
analogues with different ester substitution atboth C-6 and C-9 for biological evaluation.

OROEnglerins A:
R = glicolic acidEnglerin B :R=HH

1. Glycolic acid may play a important rolein the activity.
or
2. Substitution at the C-9 position by theglycolate ester may be important for theobserved potency.

21. Christmann's Total Synthesis
1.1 Retrosynthesis
HOH

OH
PhOO
H

HO

H
H

Epoxylactone
rearrangementOH

H
allyation

OH

H

RCM

[M]OOOTBSOTBSO1: englerin A

H

HO

O

O

OH

OOO

O

H

CHO

H

trans,cis-necetalactone

OHOH

M athias Christmann et al. Angew. Chem. Int. Ed. 2009, 48, 9105-9108.

1.2 Key Reaction
1.2.1 Epoxylactone rearrangement
HO

Epoxylactone
rearrangement

HO
H

O

H

O
H

CHO

O

H
O

O
H
10aO
O

H
11

CHO

Scheme 1. Oxidation of nepetalactone 7 and 9.

Scheme 2. Tentative mechanism f or the ring contraction.

The oxidation of 7 with mCPBA afforded 8b (undesire)as the major isomer (d.r. 7:1).

Treatment of 10a with NaOMe led to a rapid ring contractionof the epoxylactone moiety into the formyl lactone 11.

The epoxidation of 9 installed the correct configuration
at C10 for the major isomer 10a (d.r. 1.5:1).

The rearrangement of 8a into the aldehyde 6 did not take place.

Resulting from the strain of the transbicyclo-[3.3.0]octane scaffold.

3

Tomas Hudlicky et al. Synlett. 2005, 2911-2914.
Bicyclo[3.3.0]octanones:
It is clear that only cis-f used products would be obtainedin all cases regardless of the method used to prepare them;:The average energy diff erence is 7.8 kcal/mol.
:Any trans-fused compound would isomerize
to the cis-isomer immediately.

1.2.2 Diastereoselective Barbier Reaction

This selectivity results from a minimization of dipole-dipole
interactions in the aldehydes reactive conformation.

4

1.3 Total synthesis

52. Nicolaou's Total synthesis
2.1 Retrosynthesis
O

iPrPhOBnN

iPr

SO2O

EtO2C

HO
O
O
HO

aldol
O

CO2MeOOH

K.C. Nicolaou J . Am. Chem. Soc. 2010, 132, 8219-8222.
2.2 Key Reaction

OBn~Asymmetric Synthesis version~

2.2.1 [5+2] cycloaddtion reacrion~Racemic Synthesis version~

Asymmetric cyclization used chiral auxiliaries

Bernardinelli, G. et al. Tetrahedron Lett. 1984,25, 5885.

6

2.2.2 Gold catalyzed cycloaddition
OBnOBnOH

Ph3PAuCl,AgOTfO

Bulky

The uncomplexed acrylate adopts in the crystal a strictly
antiplanar disposition of the C ,C - and the C=O bond which
in turn is out of the C-Ha-plane by an angle of about 30o.
The p lone pair on the planar nitrogen bisects the O-S-O angle;thus the surface of one cyclohexane ring is projected firmly
on top of the olefinic C -re-face.
Yuanhong Liu, Tetrahedron 2009, 65, 1839.

MsO
OBn O

OBn O

HOOOHOMs

OBn OOOO

Bulky

SO2N

2.2.3 Achmatowicz rearrangement~Mechanism~
OOH

ROH
OH

OH

O
OH

RO

R

m-CPBA

OH

O
R

O

7

2.3 Total synthesis

Crabtree cat.

8

3. Au Catalyzed Cycloaddition Reaction

The d and f orbitals are not contracted.
(higher angular momentum, seldom descend to nucleus)

3.1 Au catalyzed reaction

better shielded by contracted s and p orbitals
Instead see a weaker nuclear attraction
Expansion of d and f orbitals
Destabilization of orbital energies
Simplified form
Nucleophilic attack on the [AuL]+-activated alkyne
proceeds via complexes 1 to give trans-alkenyl goldcomplexes of type 2 as intermediates

3.2 Au catalyzed Cycloisomerizations
This high -acidity is linked to relativistic effects,
which reach a maximum in the periodic table with gold.

In the case of gold-catalyzed cycloisomerizations of enynes,
reactions proceed via complex 3.

(detail: see Itano's D2 lit.)

A.M. Echavarren et al. Chem. Rev. 2008, 108, 3326-3350
The resulting complex 3 reacts with the alkene by either the5-exo-dig or 6-endo-dig pathway to form the exo- orendocyclopropyl gold carbene 4 or 5.

ZAuL
R1R2LAu
R1Z

R35-exo-dig

R43ZL+Au

R3R13RZ

R2 R4R4R24AuL
R12R

6-endo-dig

R3Au+LAuLZ

R1Z

R1R33R2 4 R
R

R2 R45However, on occasion, the stronger Lewis acidity of goldcomplexes can be detrimental in terms of selectivity andbecause of their low tolerance to certain functional groups.
In these instances, the less-strongly Lewis acidic Pt(II)complexes could be the catalysts of choice.
R4Box 1 Figure 1l Calculated relativistic contraction of 6s orbital.
The relavistic and non-relavistic 6s orbital radii were determinedcompatationally, Notably, Pt, Au and Hg are markedly inf luenced.

9

3.3 Examples of this type reaction
3.3.1 Reaction 3 to 6AuL
R1R2

Z

R1Z

R34R

R2 3R
63

Standard mechanism catalyzed by Pt(II) or Ru(II)A.M. Echavarren et al. Chem. Rev. 2008, 108, 3326-3350
Compound 6 is Alder-ene cycloisomerization product thatoccasionally been found in gold-catalyzed reactions of 1,6enynes.

Oxidativeaddition

Conpound 7 and 8 are skeletal rearrangement products.
(single and double cleavage).
Compound 9 is endocyclic skeletal rearrangement
product.
Cyclobutenes 10, and products 11 of intramolecular
cyclopropanation have also been obtained.
In the presence of nucleophiles,
Compound 12-14 have been obtained in stereospecificprocesses.

More-complex transformations
starting from more-functionalized
enynes are also possible.

+A. M. Echavarren et al. J. Am. Chem. Soc, 2001, 123, 10511.
-hydrogen elimination occurs from allylic position.
Pt(II) : trans comfiguration in starting enyne
Ru(II):either trans or cis comfiguration

This type mechanism needs to coodinate to thealkene and the alkyne simultaneously
However, the [Au(PR3)]+, which is isolobal to H+,
cannot coordinate to the alkene and the alkyne
simultaneously.
We will call two fragments isolobal if the number,symmetry properties, approximate energy and shape ofthe frontier orbitals and the number of electrons in themare similar-not identical, but similar.

Hof fmann, R. Angew. Chem., Int. Ed. Engl. 1982, 21, 711.724.

Proposed Mechanism

10

3.3.2 Reaction 3 to 7 and 8(Skeletal rearrangement)

3.3.3 Reaction 3 to 9(Endocyclic Skeletalrearrangement)

1R
AuL
R12R

Z
R

4Z
2R
7R3R33R3Z
R28Z

AuL
R12R

R4R43R4R3Z

R1R32R
9R1HA. M. Echavarren et al. Angew. Chem. Int. Ed. 2005, 44, 6146.

Single cleavage rearrangement reaction

Antonio M. Echavarren et al. Chem. Eur. J. 2006, 12, 1677.
Mechanism

L+Au

L+Au

LAu
HRZ
H

H
R

AuL

Z
HHR

Double cleavage rearrangement reaction

LAu
R'R

Z

H
HR'R

Z

R
R'Z

AuL

H
H

H

In the case of 1,6-enynes,the mechanism of thisendocyclic rearrangement is just a variation of thesingle-cleavage rearrangement of 4
In the case of 1,5-enynes

Antonio M. Echavarren et al. Eur. J. Org. Chem. 2007, 4217.
Mechanism

A. M. Echavarren et al. Angew. Chem. Int. Ed. 2005, 44, 6146

Exocyclic rearangement is favorable,becouse bicyclo[2,1,0]pentane is strained. 11

3.3.4 Reaction 3 to 10 and 11(Cyclo-propane and butene)
HZAuL
R12R
3R43MeO2C
MeO2CRR1Z3Z

R2 R
10R1R34R2 R
11Scheme 5. Reactions of 23 and 24: a) 9b (2 mol%), CH2Cl2,room temp., 14 h (80%); b) 8c (2 mol%), AgSbF6 (2 mol%),
CH2Cl2, room temp., 45 min (67%); c) PtCl2 (5 mol%), MeCN,120oC, 20 h (67%).

Cyclopropane

15d/ AgSbF6
MeO2C(2 mol%)
CH2Cl2, rt (67%) MeO C2HH

H

A. M. Echavarren et al. Angew. Chem. Int. Ed. 2005, 44, 6146.

For construction of cyclobutene, the anti to syn isomerizationfrom 17a to 17'a requires a rather high activation energy.
(24.7 kcalmol-1)
The initially formed anti 17a would undergo a more facile
rearrangement (9.1 kcalmol-1).

(Natural)However, an alternative pathway has been found fora more direct formation of complexes 17'a,b by a
syn-type attack of the alkene, via TS5, to the (alkyne) gold
moiety of 21a,b (Scheme 4).

(unnatural)

Antonio M. Echavarren, Chem. Eur. J. 2006, 12, 1694.

The anti attack of the alkene is more favorable, [7a] the synattack could compete if substitution at the alkene and/or
the alkyne disfavors the skeletal rearrangement.
In particular, this should be more favorable for theformation of bicyclo[3.2.0]oct-6-enes from 1,7-enynes, inaccordance with the calculations (17'b to 22b, Scheme 4).

123.4 Construct Guaiane sesquiterpene
A.M. Echavarren et al. Chem. Commun., 2009, 7327.

(+)-orientalol F

13

4. Echavarren's Total synthesis
4.1 Retrosynthetic Analysis
OAu catalyzed[2+2+2]
cycloaddition

PhOH

ROO

HO

O

OTESO
HO

HOH

OR'A. M . Echavarren, et al. Angew. Chem. Int. Ed. 2010, 49, 3517 .

4.2 Key Reaction
4.2.1 Au catalyzed [2+2+2]
alkyne/alkene/carbonyl cycloaddition
reaction

Dawei Ma et al. Angew. Chem. Int. Ed. 2010, 49, 3513.

After testing a number of protected derivatives ofaldol in gold(I)-catalyzed reactions, they f ound thatthe best results were obtained by using unprotectedaldol(67 %).

The best result is When used R = H
The exclusive formation of monocyclic products from ether
substrates 6b, 6d could be rationalized by the steric hindranceof their protecting groups, which might prevent the attack of
the carbonyl group at the cyclopropanyl ring as indicated forthe formation of intermediate C.

14

4.2.2 Stereoselective Denmark aldol reaction

4.2.4 Hydrogenation

Crabtree catalyst

Scott E. Denmark et al. J . Am. Chem. Soc. 2000, 122, 8837.

4.2.3 Reduction
HOO

WCl6(2 eq.),
nBuLi(4 eq.)

OH

HOO

OTBS

HOTBS

Andreas Pfaltza et al.Adv. Synth. Catal. 2008, 350, 174 .

K. B. Sharpless et al. J . Am. Chem. Soc. 1972, 94, 6538.

15

4.3 Total synthesis
L-(+)-diethyl tartrate
Ti(OiPr)4,
TBHP
HOHOO

CCl4, PPh3

AD-mixtBuOH/H2O

TESOTf, Et3N
CH2Cl2nBuLi (3.5 eq.), THF

O

Cl

H
R
HO

OTES

OH

OH

R:OTES
H Me
N O
P
N N
Ph H Me

OSiCl3Ph
Ph3P

NaIO4/SiO2
CH2Cl2O

CHO
OTES

CHO
OTES

benzene,reflux[IPrAuNCPh]SbF6 RO

OH O

HOO

CrO3 (2,5-dimethylpyrazole)
O

OTES

H
TBAF
TBSCl, DMAP
imidazole

H
Ph
TBAF

H

Cl

H

O

OH Cl

Ph

OTBAF

O
Cl

DMAP

H

O

H

O

CO2H
H

O

H

O
OTBS

PhO

O

O

OTBS

O
H

Phcinnamoyl chloride (3 eq.)
DMAP(3 eq.)HO

H2 (80 bar)

TBDPSOOTBS

R = TES, R' = H
R = R' = H
R = H, R' = TBS

H

O

H

OR'

HO

WCl6(2 eq.),
nBuLi(4 eq.)

O

O
H

O
OO
O

OTBDPS

OTB
SH

O
O

OH

Cl

16