SELECTED TOTAL SYNTHESES

MACROCYCLIC STRUCTURES
 MARVELS OF THE SEA: THE SPIRASTRELLOLIDES

appreciable cytotoxicity

drive human breast cancer MCF-7 cells into

premature mitosis before causing cell cycle arrest

activity is not mediated via tubulin or actin

strong inhibition of the serine/threonine protein

phosphatase PP2A; IC50 = 1 nM

R. J. Andersen et al., JACS 2003, 125, 5296; revision: Org. Lett. 2004, 6, 2607;
stereochemistry: JACS 2007, 129, 508; JOC 2007, 72, 9842;

total synthesis of spirastrellolide A: I. Paterson et al, Angew. Chem. Int. Ed. 2008, 47, 3016 and 3021

studies towards: R. P. Hsung, C. Forsyth, J. de Brabander, S. Chandrasekhar, A. B. Smith, A. Phillips, A. Fürstner

 relative stereochemistry within the individual sectors established
ANALYSIS relationship between the sectors unknown until late 2007
absolute configuration unknown until late 2007
16 possible combinations !
NORTHERN SECTOR
for the methodology see: Kanemasa et al., JACS 1994, 116, 2324
 THE NORTHERN DOMAIN

A. F. with M. D. B. Fenster, B. Fasching, C. Godbout, K. Radkowski, Angew. Chem. Int. Ed. 2006, 45, 5510
A. F. with B. Fasching, G. W. O‘Neil, M. D. B. Fenster, C. Godbout, J. Ceccon, Chem. Commun. 2007, 3045
for the development of the „relay strategy“ see: T. Hoye et al., J. Am. Chem. Soc. 2004, 126, 10210
REVISED ANALYSIS
THE SOUTHERN SECTOR
 THE SOUTHERN SECTOR (II)

A. F. with G. W. O‘Neil, J. Ceccon, S. Benson, M.-P. Collin, B. Fasching, Angew. Chem. Int. Ed. 2009, 48, 9940
compare: A. Pfaltz et al., Organometallics 2003, 22, 1000
 COMPLETION OF THE TOTAL SYNTHESIS

A. F. with S. Benson, M.-P. Collin, G. O„Neil, J. Ceccon, B. Fasching, M. D. B. Fenster,

C. Godbout, K. Radkowski, R. Goddard, Angew. Chem. Int. Ed. 2009, 48, 9946 and 9940
 H3CO CH3 CH3 CH3 O H
O N H
N
H3C O H3C H O
OCH3 CH3 OH

H3C Iejimalide B
J. Kobayashi et al., J. Org. Chem. 1988, 53, 6147
Bioorg. Med. Chem. 2006, 14, 1063

very scarce and highly cytotoxic

(average GI50 = 13 nM)
in vivo activity (T/C = 150%)
no “COMPARE” correlation with any
standard anticancer agent
unknown mode of action
 RETROSYNTHETIC ANALYSIS

6
MeO 1 OH
O RSO2 5
Julia olefination Yamaguchi
lactonization O
11
MeO O H SO2R
6 29
O N H O H
1 N 29
5 23 HO N H
11 O H O NH2 HO
12 MeO 19 OH O
RO
20
Julia 20
peptide coupling
olefination
Heck coupling RO 12
MeO
19
X
 BUILDING BLOCKS

Pd(OAc)2 cat.
Br + N(Boc)2 MeOOC N(Boc)2
MeOOC P(o-tol)3 cat., Et3N
84%

HO
(+)-crotyl-B(Ipc)2 NHBoc
O
NHBoc
82% (95% ee)

Ts
Ph N
Ru
O Ph N OH OMe
H O
(0.6%)
SiMe3 iPrOH SiMe3 SiMe3
98% (99% ee)

1. Still-Gennari, 87%
HO
2. K2CO3, MeOH, 80% OMe

3. Cp2Zr(H)Cl (3 eq), then I2, 80% I

 PREPARATION OF THE SECO-ACID

HO HO HO
OMe NHBoc Pd(OAc)2 cat., AgOAc OMe OH
21
+ NHBoc
I DMF, RT
20
46% (+13% isomer)

MeO
COOEt
1
11
O S
N
O N
TEMPO cat., O2 O N N
OMe OH Ph
CuBr2 cat., tBuOK cat. NHBoc
NaHMDS ("Barbier"), THF
94%
57% (E:Z > 10:1)

MeO
COOR

OMe OH
NHBoc
18 23

R = Et
Me3SnOH, DCE, 94%
R=H
 MeO
MeO
O
COOH NHBoc
O
MeO
OMe OH
NHBoc
18 23

Yamaguchi
MeO
(Yonemitsu)

OR
OMe OH
NHBoc

possible mechanism:
6 1
R
Cl Cl
O
Cl Cl 6
O 1
6 R
1 O R
R N O O O
Cl N - DMAP.H
O O Cl R
O
DMAP
NMe2 NMe2
R
OH

A. Fürstner, C. Aissa, C. Chevrier, F. Teplý, C. Nevado, M. Tremblay Angew. Chem. Int. Ed. 2006, 45, 5832
 RETROSYNTHETIC ANALYSIS (II)

(intramolecular) MeO M
intermolecular 1 OH
Suzuki / Stille ? I
esterification !
O
MeO O H
6
O N H O H
N 29
7 1 HO N H
11 O H O NH2 HO
12 MeO 19 OH O
RO
20
RCM ? 20
peptide coupling I
Suzuki coupling ?
(intramolecular) MeO
19
BR2
 LITERATURE PRECEDENCE

J. Wagner et al., JACS 2003, 125, 3849; L. A. Paquette et al., Helv. Chim. Acta 2002, 85, 3033
 O
NHBoc

Pd(OAc)2 / PPh3 cat. OMs

Et2Zn
72% (dr = 7.5:1) TIPS

2nd APPROACH HO
NHBoc

TIPS
3 steps

HO
NHBoc

pinacolborane OMe
OMe I
O
B
9-BBN cat.
O Ba(OH)2.8 H2O, (dppf)PdCl2 cat.
56%
RT, 70%

HO MeO
NHBoc O
Yamaguchi NHBoc
MeO O
MeO
MeO
OH

O
73%
 2nd APPROACH

Mes N N Mes
MeO Cl Ru MeO
O Cl O
NHBoc Ph NHBoc
PCy3
O O
MeO MeO
96%

decomposition
 O
RO
N OtBu
H

X
TBSOTf, lutidine

R = Piv R = Ac

TBS
O H
PivO O O
NH2 N O
R H

O X
NHCHO EDC, HOBt
HO TBS
O O
OTBS NH
R
O OTBS
O
RO NHCHO
N
H
OTBS
N
X 95% (X = H)
O
85% (X = I) OTBS
MeO
O H
OH O
HO NH
O N
H N
MeO OTBS
DCC

MeO O H
O
O NH
N
O H
MeO OTBS

Mes N N Mes
69% Cl Ru
Cl
Ph
PCy3

MeO O H
O
A. F. with C. Nevado, M. Tremblay, C. O NH
N
Chevrier, F. Teplý, C. Aissa, M. Waser O H
MeO OR
Angew. Chem. Int. Ed. 2006, 45, 5837
R = TBS
J. Am. Chem. Soc. 2007, 129, 9150 TBAF, 80%
R=H
SCALE-UP AND MOLECULAR EDITING

>1g
 CRUENTAREN A & B

B. Kunze, H. Steinmetz, G. Höfle, M. Huss, H. Wieczorek, H. Reichenbach, J. Antibiot. 2006, 59, 664
A. F. with M. Bindl, L. Jean, Angew. Chem. Int. Ed. 2007, 46, 9275;
Chem. Eur. J. 2009, 15, 12310
 GLUTARIMIDE MACROLIDES:
POTENT TRANSLATION & CELL MIGRATION INHIBITORS
LEARNING FROM THE LITERATURE

S. J. Danishefsky et al., Angew. Chem. Int. Ed. 2007, 46, 5576

LACTIMIDOMYCIN: ANALYSIS
TOTAL SYNTHESIS OF LACTIMIDOMYCIN

A. F. with K. Micoine, J. Am. Chem. Soc. 2010, 132, 14064

 THE EPOTHILONES

R
O
S

N OH Epothilone A ( 86, R = H)

O Epothilone B ( 87, R = Me)

O OH O

R
S

N OH Epothilone C ( 88, R = H)

O Epothilone D ( 89, R = Me)

O OH O
 EPOTHILONE: BUILDING BLOCKS

[a] O O [c]
CN
HO O RO OEt
92 Br
OEt 94 R = H
[b]
93 95 R = TBDPS

OH OH O O O O O O O
[d] [e]
OEt OEt

96 97 98

[a] Zn, ultrasound, THF; then aq. HCl, 71%; [b] TBDPSCl, imidazole, DMF, 90%; [c]
[((S)-BINAP)RuCl2](NEt3) (6 mol%), H2 (65 bar), Dowex, EtOH, 80°C, 71%; [d] 2,2-
dimethoxypropane, acetone, camphorsulfonic acid cat., 92%; [e] EtMgBr, NEt3, toluene,
70°C, 68%.
 O
EPOTHILONE:
O O
[b,c]
S N
O R BUILDING BLOCKS
99 R = H 101
[a]
100 R = Me

[a] n-BuLi, THF/HMPA, MeI, 78° 

60°C, 94%; [b] LiAlH4, THF, 85%; [c]
[d] O O O OH [e]
Pr4NRuO4 cat., NMO, CH2Cl2, MS 4Å,
90%; [d] lithium enolate of ketone 98,
THF, 78°C, 70%; [e] PPTS cat., MeOH,
102
85%; [f] TBSOTf, 2,6-lutidine, 92%; [g]
camphorsulfonic acid, CH2Cl2/MeOH
OR1 O OR1 103 R 1 = R 2 = H [f] (1/1), 78%; [h] PDC, DMF, 83%.
R2O 104 R 1 = R 2 = TBS
[g]
105 R 1 = TBS, R 2 = H

[h] O OR1 O OR1

106
HO
 SYNTHESIS OF EPOTHILONES VIA RCAM

S
S
N [Mo] cat.
O OR S OR
OH N
O N O
80%
O OR O O OR O
O O O
R = TBS

O
S S

Lindlar, H2 N OR O O OH
N
CH2Cl2 O literature: 70% O

O OR O O OH O

R = TBS aq. HF
Epothilone C R=H 79% over both steps Epothilone A

A. Fürstner, Ch. Mathes, K. Grela Chem. Commun. 2001, 1057; Chem. Eur. J. 2001, 7, 5299
 AMPHIDINOLIDE X AND Y

HO O
HO O
O
O
O O O
O
O Amphidinolide Y (2)
Amphidinolide X (1) (equilibrium mixture)

HO
O O
O
HO
O

very scarce cytotoxic secondary metabolite of symbiotic dinoflagellate Amphidinium sp., cf. :
J. Kobayashi et al., JOC 2003, 68, 5339 (AX); JOC 2003, 68, 9109 (AY)
 AMPHIDINOLIDE X: RETROSYNTHETIC ANALYSIS

O
1 OH
HO
O

13 14
O M O
1 19
O O O 14 19
O
O RO

13
X
O OH
 STEREOCHEMICAL RELAY

R1 OH R1
X O R1
O 2 R2
R O [M]
19 R2
R4O
19
 IRON CATALYZED SYNTHESIS OF ALLENOLS

iPrMgCl
Fe(acac)3 (5 mol%)
O HO
toluene, -5°C, 5 min
C5H11
C5H11 94%, syn:anti = 10:1

ee = 93% ee = 93% (syn)

A. F. with M. Méndez, Angew. Chem. Int. Ed. 2003, 42, 5355

for a short review on Fe-catalyzed cross coupling, see:

B. D. Sherry, A. Fürstner, Acc. Chem. Res. 2008, 41, 1500

 TOTAL SYNTHESIS OF AMPHIDINOLIDE X

TBDPSO RO RO
1. Swern
Sharpless O O
OH 2. (MeO)2P(O)C(N2)COMe
97%
OH 67%
R2
2
LiHMDS, R =H
MeOTf, 95% R2 = Me

n-PrMgBr
RO OH
Fe(acac)3 cat. AgNO3 I
RO O O
syn:anti = 8:1 CaCO3
62% 90% PMBO
 TOTAL SYNTHESIS OF AMPHIDINOLIDE X

O O OMs OH 1. PMBCl, NaH, 94%

1. ethylene glycol, PTSA cat. O O O O
OEt O Pd(OAc)2 + PPh3 cat. 2. LiHMDS, MeI, 95%
2. Dibal-H, Et2O
Et2Zn, 65%
54% anti : syn = 4.5:1

Cp2ZrHCl, C6H6 1. DDQ, 89% I

OPMB OPMB O O
O O O O O O
I
I2, CH2Cl2 2. O
COOMe
61% HO COOMe
Yamaguchi, 96%
 FIRST TOTAL SYNTHESIS OF AMPHIDINOLIDE X

for the „9-MeO-9-BBN“ variant of the Suzuki coupling, see: O

A. Fürstner, G. Seidel, Tetrahedron 1995, 51, 11165 OMe
O
O O
I O
9-MeO-9-BBN OMe
I O
t-BuLi B O
PMBO Li (dppf)PdCl2 cat., Ph3As
PMBO
74%

O O
3 steps
O O
O O O O O
PMBO O
O
COOMe

Amphidinolide X

A. F. with O. Lepage, E. Kattnig, J. Am. Chem. Soc. 2004, 126, 15970

 13 O
18 O
12 M O 12
HO 1 6 7
HO O X
HO 7
O 1 RO O HO OH
6
O

aldol
1,4-anti

OR
6 7 12
RO
X
O OH
chelate control
AMPHIDINOLIDE Y:
STRATEGIC CONSIDERATIONS
OR
7 12
RO
6 X
O O
 TOWARD AMPHIDINOLIDE Y

O 1. Dibal-H, 79% O
NaOMe, MeOH
OAc
TBDPSO OMe TBDPSO TBDPSO OMe
OO O COOMe 86%
O
2. P
O OMe
OAc
LiHMDS, 91%

O Cl
P P
[Ru], HCl cat., Cl
TBDPSO OMe Ru Ru Et2NH2
P P
OH Cl Cl Cl
H2 (20 bar), MeOH
92%, dr > 23:1 67
3 steps P
= (S)-BINAP
P

O
cf.: S. A. King et al., Org. Synth. 2005, 81, 178
TBDPSO
OPMB
 TOWARD AMPHIDINOLIDE Y
PMBO
1,4-anti

O
SiMe2Ph
O O OH
SiMe2Ph 1. TESCl, imidazole, 91%
TBDPSO TBDPSO
OPMB Et2BOTf, EtN(iPr)2 OPMB 2. MeMgBr, 96%

84%, dr > 4:1 major

1,3-syn
1,2-anti
(chelate-Cram (dipolar model)
model) 1. TESOTf, lutidine, 92%
HO OSiEt3 TESO OTES TMSO I
2. DDQ, 92% O SiMe2Ph
PMBO SiMe2Ph O
MeO
3. Dess-Martin, 93% COOMe
"matched"
OTBDPS OTBDPS
 I O

PMBO
TOTAL SYNTHESIS OF

tBuLi
AMPHIDINOLIDE Y
B OMe

Li
B O
MeO
TMSO I TMSO O
PMBO 1. DDQ, 75%
O O
RO 2. LiOH, then HCl/Et3N
MeO (dppf)PdCl2 cat., Ph3As MeO
COOMe COOMe
K2CO3, 79%

O
TMSO O TMSO
O O aq. HOAc HO O
Yamaguchi O O
HO HO
MeO MeO O
COO 56% (over 3 steps) O
Et3NH O

A. F. with E. Kattnig, O. Lepage J. Am. Chem. Soc. 2006, 128, 9194

for the synthesis and biological assessment of analogues, see: Chem. Eur. J. 2009, 15, 4030
 ANALOGUES BY „DIVERTED TOTAL SYNTHESIS“

for the synthesis and biological assessment of analogues, see: Chem. Eur. J. 2009, 15, 4030
 AMPHIDINOLIDE V

H O H

OH
O
O

Amphidinolide V

Isolation: J.-I. Kobayashi et al., Tetrahedron Lett. 2000, 41, 713

 TOWARDS AMPHIDINOLIDE V

OH THPO BF3K
OTBS 4-hexynoic acid RO OTBS
Br THPO OTBS
O O
Pd(OAc)2 cat., tBuNH2 OH EDC

84% 95%

Zn RO
O 2 O
O OTBS OTBS
O O O O
69%
TBSCl R=H
imidazole R = TBS
79%
 TOTAL SYNTHESIS OF AMPHIDINOLIDE V

30 mol%

80°C

A. F. with O. Larionov, S. Flügge

Angew. Chem. Int. Ed. 2007, 46, 5545;
Chem. Eur. J. 2009, 15, 4011

With: A. F. with J. Heppekausen, R. Stade, R. Goddard,

J. Am. Chem. Soc.. 2010, 132, 11045
J. Kobayashi et al., Nat. Prod. Rep. 2004, 21, 77
 very scarce

mixed polyketide biosynthesis

(very) potent cytotoxicity

interferes with actin

other biological targets?

WHAT IS THE RIGHT ORDER?
 LITERATURE PRECEDENT

G. Pattenden et al., Tetrahedron Lett. 2000, 41, 7373

other studies toward amphidinolides B, H and G were reported by

Kobayashi, Chakraborty, Nishiyama, Myles, Carter, Crews, Nelson, Marco, Kalesse, Zhao
TOWARD AMPHIDINOLIDE H

for the methodology, see: Chem. Commun. 2008, 2873

TOWARD AMPHIDINOLIDE H (II)
A. F. with L. C. Bouchez, J.-A. Funel, V. Lipins, F.-H. Porée, R. Gilmour, F. Beaufils, D. Laurich, M. Tamiya
Angew. Chem. Int. Ed. 2007, 46, 9265
PREPARED ANALOGOUSLY:

A. Fürstner et al., Chem. Eur. J. 2009, 15, 3983

 THE AMPHIDINOLIDE T FAMILY

OH O O O
O HO HO HO

O O O O
O O O O
O O O O
Amphidinolide T1 Amphidinolide T3 Amphidinolide T4 Amphidinolide T5

J. Kobayashi et al., J. Org. Chem. 2000, 65, 1349 and 2001, 66, 134.

Review: J. Kobayashi et al., Nat. Prod. Rep. 2004, 77.

 RETROSYNTHETIC ANALYSIS

OR2
R1O

Amphidinolide T
family O

O
4
5 O

syn syn OR2

OR2 R3SiO
1
RO
12 14 B X
Y

O O Cl O

O A
O O

O C
 FRAGMENT I

O O OH
1. TsCl, Et3N, 94%
(-)-Ipc2B-allyl
OMe H
2. Dibal-H, toluene, -95°C Et2O, -100°C
RO TsO 70% (over 2 steps) TsO

OH X
KCN, DMSO Dibal-H
O
99% CH2Cl2, -78°C
NC
91%

PhSO2H X = OH
CaCl2, CH2Cl2 X = SO2Ph
87%
 FRAGMENT II

O O 1. Bu2BOTf, Et3N OR O O
2. methacrolein, 90% 1. LiBH4, Et2O, 92%
N O N O
3. MOMCl, (iPr)2NEt, CH2Cl2, 93% 2. TBSCl, imidazole, DMF, 90%
Ph Ph

OMOM OMOM OMOM

O3, CH2Cl2, 86% TBSOTf, Et3N, Et2O
O TBSO
OTBS OR OTBS
91%
 FRAGMENT III

O O 1. NaHMDS, THF, -78°C O

then allyl bromide, 60%
N O OH
2. LiOH, H2O2, aq. THF, 93%
Ph
X O
EDCI, DMAP

CH2Cl2, 93%
O
tBuO O tBuO O
[((R)-binap)RuCl2]2(NEt3) cat. O
X = OtBu
H2 (10 atm), MeOH, 95°C, 84% TFA, Et3SiH, quant.
O OH X = OH
(COCl)2, quant.
ee = 98% X = Cl
 TOTAL SYNTHESIS OF AMPHIDINOLIDE T

OMOM OMOM
SO2Ph Me TBSO
OTBS O
SnCl4 O
O
OTBS
86% O
H NOE
"inside" attack

Cl O
OMOM
OMOM TBDPSO
TBDPSO O
O
12
O
I O
O Zn/Cu, TMSCl
O
Pd(0) cat., 50%
O
 O
HO

OMOM N N OMOM O
Mes Mes
TBDPSO Cl Ru TBDPSO O
O Cl Ph O Amphidinolide T4
PCy3
O O
86% OH
O O O
O O

E:Z = 6:1 O

O
Amphidinolide T1

A. Fürstner, C. Aissa, R. Riveiros, J. Ragot, Angew. Chem. Int. Ed. 2002, 41, 4763;
J. Am. Chem. Soc. 2003, 125, 15512
 OMOM N N OMOM
Mes Mes
TBDPSO Cl Ru TBDPSO

O Cl Ph O
PCy3
O O E:Z = 6:1
CH2Cl2, 40°C
O O
86%
O O

OMOM N N OMOM
Mes Mes
TBDPSO Cl Ru TBDPSO

O Cl Ph O
PCy3
O O E:Z = 2:1
toluene, 110°C
O O
82%
O O
 TOTAL SYNTHESIS OF AMPHIDINOLIDE T

OMOM OMOM OMOM

TBDPSO TBDPSO O TBDPSO
BrZn ZnBr
O O Zn
Ph3P=CH2
O O O
TiCl4
O THF, reflux, 64% O

O O
COOH
 OMOM
TBDPSO

O
 TOTAL SYNTHESIS OF AMPHIDINOLIDE T
OMOM OH
HO O

[(Me2N)3S][Me3SiF2] 1. Dess-Martin, 93%

O 2. Dowex, 52% O
84%
OMOM O O
TBDPSO O
O
Amphidinolide T1 (1)

O OH O
TBDPSO HO

1. Dess-Martin, 83%

TMSCl, Bu4NBr O O
2. HF-pyridine, 87%
85% O O
O O
Amphidinolide T4 (4)

A. Fürstner, C. Aissa, R. Riveiros, J. Ragot, Angew. Chem. Int. Ed. 2002, 41, 4763;
J. Am. Chem. Soc. 2003, 125, 15512
PROPOSED STRUCTURES OF AND BIOCHEMICAL RELATIONSHIP
BETWEEN THE LEIODOLIDES

J. S. Sandler, P. L. Colin, M. Kelly, W. Fenical, J. Org. Chem. 2006, 71, 7245-7251;

correction: J. Org. Chem. 2006, 71, 8684
A. F. with A. Larivée, J. B. Unger, M. Thomas, C. Wirtz, C. Dubost, S. Handa,
Angew. Chem. Int. Ed. 2011, 50, 304
 OTHER DIASTEREOMERS PREPARED ANALOGOUSLY

The NMR spectra of these isomers were close to those of leiodolide B reported in the literature,
but the match was not good enough to claim identity; therefore the structure of leiodlide B remains uncertain, cf:

A. F. with A. Larivée, J. B. Unger, M. Thomas, C. Wirtz, C. Dubost, S. Handa,

Angew. Chem. Int. Ed. 2011, 50, 304
 THE LATRUNCULIN FAMILY

O O O O O

O O O O O

O O O OH OH OMe O
OH OH OH
H H H H H
HN HN HN HN HN
S S S S S
O O O O O

Latrunculin A Latrunculin B 16-epi-Latrunculin B Latrunculin C Latrunculin D

isolated from various marine organisms by Kashman (1980), Scheuer (1985), Crews (1987), Jefford (1996), Hoye (2002)

previous syntheses: A. B. Smith et al., J. Am. Chem. Soc. 1992, 114, 2995; J. D. White et al., J. Org. Chem. 1992, 57, 5292

potent actin microfilament disrupting agents, cf. I. Spector et al., Science 1983, 219, 493.
 RCAM/Lindlar
Negombata magnifica
(formerly: Latrunculia magnifica)
O

O
OH Latrunculin B
H
HN
S
O

Fe-catalyzed
cross coupling

O
O
OR
O OH

Fe-catalyzed
RN
cross coupling
S
O
 TOTAL SYNTHESIS OF LATRUNCULIN B

O O MgBr
Ph-N(Tf)2 OTf O
OEt OEt
KHMDS Fe(acac)3 cat. O
61% 97% OR

R = Et NaOH, MeOH
R=H 92%

For a comprehensive study on Fe-catalyzed cross coupling reactions of enol triflates see:

B. Scheiper, M. Bonnekessel, H. Krause, A. Fürstner, J. Org. Chem. 2004, 69, 3943

 TOTAL SYNTHESIS OF LATRUNCULIN B

O OEt O OH Cl O Cl
3 steps NMe2
H 2N PMBN PMBN
SH S S
O O

O C2"
O2'

MeMgBr ee = 87% C36 C2'

RN C30
recryst. C35
Fe(acac)3 cat. ee = 99% C4
S N3
O C31
80% C34
C5

O37 O2 C2
C32 S1
C33
C38
in the absence of Fe cat.: < 30% yield

using Cu(I) in catalytic or stoichiometric amounts instead of Fe cat. leads to decomposition

 TOTAL SYNTHESIS OF LATRUNCULIN B

4-dimethylaminopyridinium
bromide perbromide, DMAP Br OMe
1. O3, then Me2S
OMe Br
2. HC(OMe)3, H+ 87%
OMe
75% OMe

OTBS
R OMe
LiHMDS 1. (Ipc)2B(allyl) X
OMe
90% 2. TBSCl, imidazole
78%
R=H BuLi, MeI X = CH2 O3, MeOH
R = Me 95% X=O then Me2S, 94%
 O

PMBN
OTBS S TBSO OH O
O
O
S
TiCl4, iPrNEt2 PMBN
73% dr = 2:1 O

dr = 7:1

OH C9' C7' C5'

HCl
O4'
C4'
O C10'
C11' C9" C6'
OR C12' C8'
H
PMBN
S
O1' C3' axial !
O C36 C30 C2' O2'
C35 N3
R=H CSA, MeOH C2"
C4
R = Me 64% C38
C34 C31
C5
O2 C2
C32
O37 S1
C33

X-ray of minor isomer

 equatorial

1. Tf2O, pyridine O
OH
2. NaO O
O
OMe O O
H OMe
PMBN H
S 58% PMBN
O S
O
major isomer
 TOTAL SYNTHESIS OF LATRUNCULIN B

O O O
[Mo] cat. 1. Lindlar, quant.
O O O
CH2Cl2/toluene 2. CAN, 78%
O O O
70%
OMe OMe OH
H H H
PMBN C14" PMBN HN
C12'
S C11' S S
C14'
O C10' O O
C9" C13' C15'
C9' Latrunculin B
C2" O4' C16'
C8' O2'
C6' O16'
C38 C5'
C7'
C4'
C35 O1'
C36
C2' C3'
C4
O37 C31
C5 A. Fürstner, D. De Souza, L. Parra-Rapado, J. Jensen,
C34 N3
Angew. Chem. Int. Ed. 2003, 42, 5358
C30 S1
C33
C32 C2
O2
 PREVIOUSLY UNKNOWN DECOMPOSITION PATHWAY

R R

O O O
DCl / CDCl3
O OH OH
11 13
O O O 14
OH 15
H 16
HN HN N 17
S S S
O O HO
 EPIMERIZATION MECHANISM

d.r. = 2:1

TBSO OH O S
R S
R 11 O
11 13 H+ O + 2 H2O O O
S N HO N
PMBN - 2 H2O 13
+ PMB 13 PMB
OH
O
major

TBSO O
13 d.r. = 7:1
11
S
PMBN
OH
O 11 13
O
OH
H
PMBN
S
O
 “SECOND GENERATION” ASSEMBLY PROCESS

TBSO
O
O O O
P O
MeO
MeO P
EtO MeO
S MeO S
PMBN PMBN Ba(OH)2
BuLi, -78°C
O 60% O 75%

d.r. = 9:1

OH
TBSO O
aq. HCl O
S OR
PMBN 63% H
PMBN
O S
O
R=H MeOH, CSA
R = Me quant.
 LATRUNCULIN A

O
O
NaO
OH O

O O
OMe OMe
H H
PMBN PMBN
S S
O O

R=H O
Tf2O, pyridine
R = Tf [Mo] CAN
O decomposition
toluene/CH2Cl2 O
OMe
H
PMBN
S
O
 ENYNE-YNE METATHESIS: LATRUNCULIN A

O O
[Mo]
OH O O
toluene/CH2Cl2
O O 70% O
OMe OMe OMe
H H H
PMBN TeocN TeocN
S S S
O O O O

O
1. H2, Lindlar, 82%
2. TBAF, 62% O
OH Latrunculin A
H
3. aq. HOAc, 80% HN
S
O

L. Turet, A. Fürstner, Angew. Chem. Int. Ed. 2005, 44, 3462;

Chem. Eur. J. 2007, 13, 115
P. J. McLaughlin et al., Nature Cell Biol. 2000, 2, 376
 H
O O
O
TYR69 H GLU214
O
both epimers OH
H
(LAT B) ARG210
HN
S
ASP157 O
?
TYR186

bioactivity vanishes after N-alkylation

Lat A (16-membered) > Lat B (14-membered)
 O O O O
H H H H
RN RN RN RN
S S O O O
O O O O
OH

OH OH OH OH

O O O
O OMe OMe OMe
H H H
OTBS RN RN RN O
S S O
O O O OH

O
H H H
H H H OH
OH OH OH
H
H O O O
O OMe OMe OMe
H H H
O
OTBS RN RN RN
S O O OH
O O O
 DIVERTED TOTAL SYNTHESIS: LATRUNCULIN “LIBRARY”

O O O O O
O O O O O
O O O O O
OH OH OH OH OH
H H H H H
HN HN HN HN HN
S S S S S
O O O O O

HO O HO O O
H H
O O O OH O

O O O O O
OH OH OH OH
H H H H
HN HN HN N HN
S O O S S
O O O HO O

A. Fürstner, D. Kirk, M. Fenster, C. Aissa, D. De Souza, O. Müller, PNAS 2005, 102, 8103
 H

O HO
H
O O

O O
OH OH
H H
HN HN
S S
O LAT-B O

A. Fürstner et al., Proc. Natl. Acad. Sci. USA 2005, 102, 8103
 QM/MM CALCULATIONS

Latrunculin A / Actin Complex

refined and corrected picture of H-bonding network
importance of hydrophopic interactions

“Lat 32” / Actin Complex

different but equally strong hydrogen bond network
hydrophobic interactions optimized

with Prof. W. Thiel, Dr. T. Tuttle, Dr. C. Nevado,

Chem. Eur. J. 2007, 13, 135
SHORT SYNTHESIS OF PYRENOPHORIN
USING THE REVERSIBILITY OF RCM

A. F. with O. R. Thiel, L. Ackermann, Org. Lett. 2001, 3, 449

THE FIRST SYNTHESIS OF A TEN-MEMBERED RING BY RCM:
JASMINKETOLACTONE

A. F. with T. Müller, Synlett 1997, 1010

PHYTOTOXIC LACTONES
 CONCEPT

HO
HO
HO O O (Z)-isomer is ca. 1.5 kcal/mol more stable
HO
O O

O O
O O (Z)-isomer is ca. 3.5 kcal/mol more stable
O O
O O
 TOTAL SYNTHESIS OF HERBARUMIN I

O O
HO O
TsCl, pyridine TsO O
NaOMe, THF O H COOMe EtMgBr, CuBr

O O 77% O O 62% O O 60%

O O
O O O OH Ph3P=CH2 5-hexenoic acid
Dibal-H OH
O O O
97% 77% DCC, 84% O
O O O O
 MEDIUM SIZED RINGS: E/Z CONTROL BY “CATALYST TUNING”

N N
Mes Mes
Cl Ru
cat.
Cl Ph
PCy3 O
only (Z)
86% O O

O
O

O O

O HO
78% aq. HCl
O O O
HO
90%
PCy3 O O
Cl
Ru cat.
Cl Ph
PCy3 Herbarumin I
E : Z = 7.6 : 1

A. Fürstner, K. Radkowski, C. Wirtz, R. Goddard, C. W. Lehmann, R. Mynott, J. Am. Chem. Soc. 2002, 124, 7061
 CONFORMATIONAL RIGIDITY

O O

HO

HO O
OH
O

HO

HO O
O
O
O

overlap of x-ray structures

J. Am. Chem. Soc. 2002, 124, 7061
 AN INDEPENDENT CONFIRMATION

HO
HO
HO O O (Z)-isomer is ca. 1.5 kcal/mol more stable
HO
O O

O O

O O O (Z)-isomer is ca. 3.5 kcal/mol more stable

O
O O

TBSO TBSO
(Z)-isomer is ca. 2.5 kcal/mol less stable
TBSO O O
OTBS TBSO
OTBS
O O
 AN INDEPENDENT CONFIRMATION

Mes N N Mes

Cl Ru
Cl Ph
TBSO PCy3 RO
O O
TBSO OTBS RO OR
CH2Cl2, reflux, 85%
O O

R = TBS
TBAF
R=H

Díez, E.; Dixon, D. J.; Ley, S. V.; Polara, A.; Rodríguez, F. Helv. Chim. Acta 2003, 86, 3717
 THE PINOLIDOXIN PUZZLE

HO HO

O O HO
HO O HO O
O O O
O O HO O
O
O

proposed structure HO
de Napoli, L. et al., JOC 2000, 65, 3422 O
HO O
O excellent match with published data
O
(1H, 13C, IR, MS and [])

PINOLIDOXIN

A. Fürstner, K. Radkowski, C. Wirtz, R. Goddard, C. W. Lehmann, R. Mynott, J. Am. Chem. Soc. 2002, 124, 7061
TOTAL SYNTHESIS OF MICROCARPALIDE
MICROCARPALIDE

A. F. with T. Nagano, C. Müller, G. Seidel, O. Müller, Chem. Eur. J. 2007, 13, 1452
(-)-GLOEOSPORONE: A FUNGAL GERMINATION SELF
INHIBITING MACROLIDE

O
OH

H
O
O O

correct structure: D. Seebach, S. L. Schreiber et al., Helv. Chim. Acta 1987, 70, 281.

other syntheses: D. Seebach et al. (1987); S. L. Schreiber et al. (1988), S. Takano et al. (1988),

A. B. Holmes et al. (1991), H. Irie et al. (1992), S. V. Ley et al. (2003)

(-)-GLOEOSPORONE: RETROSYNTHETIC ANALYSIS

O O
OH

H
H O
O
O O OR O O

H H

H OR O O
OR O O
(R) (R)
H
 TOTAL SYNTHESIS OF (-)-GLOEOSPORONE

NHTf
ozonolysis (20 mol%)
MeOH, pTsOH MeO NHTf

NaHCO3, Me2S MeO O

Zn(pent)2
82% Ti(OiPr)4 (1.2 eq.)

MeO OH MeO O O
4-pentenoyl chloride
MeO MeO
DMAP, pyridine

88%, ee > 98% 91%

 TOTAL SYNTHESIS OF (-)-GLOEOSPORONE

MeO O O CF3COOH O O

MeO O
CH2Cl2:H2O (1:1)

90%

SnBu3

(S)-Binol (20 mol%), Ti(OiPr)4 (20 mol%) OR O O

molecular sieves

77%, de > 98% R=H TBDMSCl, imidazole

R = SiMe2tBu 91%
 TOTAL SYNTHESIS OF (-)-GLOEOSPORONE

[Ru] (3 mol%) Me2tBuSiO

tBuMe2SiO O O Ti(OiPr)4 (30 mol%) O O

CH2Cl2, 40°C

80%
E : Z = 2.7 : 1

O O
OH

KMnO4, Ac2O Me2tBuSiO

aq. HF H
O O
O O O O
MeCN
54%

(-)-gloeosporone

A. Fürstner, K. Langemann, J. Am. Chem. Soc. 1997, 119, 9130

 RESORYCLIC ACID MACROLIDES

RO O
HO O HO O
O
O O
HO
HO OH HO O

1 R = Me 3 4
2 R=H
H
HO O HO O N
O HO O
O O O
O OH
HO HO
O
O
5 6 7

lasiodiplodin (1), zeranol (3), zearalenone (4), resorcylide (5), monocillin I (6), salicylihalamide A (7)
 TOTAL SYNTHESIS OF (R)-(+)-LASIODIPLODIN

MeO O MeO O

O [Ru] O

MeO 94% MeO

E : Z = 2.3 : 1
MeO O
O
HO

MeO O MeO O
Lasiodiplodin
O [Ru] O

MeO MeO

A. Fürstner, N. Kindler, Tetrahedron Lett. 1996, 37, 7005.

 ZEARALENONE

N N
PCy3
Cl MeO O Cl Ru MeO O
Ru Cl
Cl Ph Ph
O PCy3 5 mol% O
PCy3
no reaction O O
MeO O MeO O
91%
(E)-isomer only !

HO O
O
HO O
Zearalenone

A. F. with O. R. Thiel, N. Kindler, B. Bartkowska J. Org. Chem. 2000, 65, 7990;

see also: A. F. with G. Seidel, N. Kindler, Tetrahedron 1999, 55, 8215
 SALICYLIHALAMIDE

H
17 N
O
HO O
1
OH
O
12

Salicylihalamide A ( 1a): 17(E)

Salicylihalamide B ( 1b): 17(Z)

K. L. Erickson, J. A. Beutler, J. H. Cardellina, M. R. Boyd, J. Org. Chem. 1997, 62, 8188

 SYNTHESIS OF SALICYLIHALAMIDE

O O 1. LHMDS O O
O
O N 2. Br O N aq. LiOH, H 2O2
X
Ph 85% Ph 99%
X = OH Cl
X = Cl NMe2

OLi
[(R)-BINAP .RuCl 2]2.NEt3 cat.
OMe O O H2, MeOH OR O
OMe OMe
81% 96%, de > 99%

R=H MOMCl, iPr 2NEt

R = MOM 90%
 SYNTHESIS OF SALICYLIHALAMIDE

OLi
[(R)-BINAP .RuCl 2]2.NEt3 cat.
OR O OtBu MOMO O O H2, MeOH
OMe OtBu
98% 93%, de > 98%

HO O
OPMB
OH HO O
MOMO OH O LiAlH 4 MOMO OH OMOM
O
OtBu 98% OR
DEAD, PPh 3
88%
R=H PMBCl, NaH (2 eq.)
R = PMB 85%
 RCM APPROACH TO SALICYLIHALAMIDE:
THE E/Z PROBLEM

N N
OPMB
RO O OPMB
Cl Ru RO O
OMOM Cl Ph
O 5 mol% OMOM
PCy3 O

toluene, 80°C

R Yield E:Z

H 69% 0 : 100
A. F. with O. R. Thiel, G. Blanda,
Org. Lett. 2000, 2, 3731
Me 93% 66 : 34

MOM 91% 68 : 32

SiMe2tBu 91% 40 : 60
 TOTAL SYNTHESIS OF SALICYLIHALAMIDE

OR O
MeO O MeO O
OMOM Dess-Martin OMOM CHI3, CrCl2
O O
87% 87%

R = PMB
DDQ, 94%
R=H

H
I N
O
R2O O H 2N HO O
OR1 O OH
O O
Cu-thiophene carboxylate
Rb2CO3

R1 = MOM, R2 = Me 57%
BBr3, 88%
R1 = R2 = H

A. Fürstner, T. Dierkes, O. R. Thiel, G. Blanda, Chem. Eur. J. 2001, 7, 5286

NON-CYCLIC POLYKETIDES
 THE CROCACINS

NH OR
O N
OMe OMe O H O

Crocacin A (R = Me)
Crocacin B (R = H)

NH2

OMe OMe O

Crocacin C

NH OMe
O N
OMe OMe O H O

Crocacin D
 NHTs
H O O O
1. TsCl, Et3N
H2N TsN
OH O OR O
2. propionyl chloride TiCl4, (iPr)2NEt
Et3N, CH2Cl2 CH2Cl2 R=H TBSOTf
82% 85% R = TBS lutidine, 97%

O OMs
I
OAc
LiBH4 AcO OAc
OH
O
THF, 89% pyridine, CH2Cl2 Pd(OAc)2 cat., PPh3 cat.
OTBS
87% OTBS Et2Zn, THF, 72%

1. TBAF, THF, 88%

2. MeOTf, CH2Cl2, 63%
OMe OMe
OR OH
R = TBS
 TOTAL SYNTHESIS OF CROCACIN C

(sia)2BH OMe OMe Bu3SnH

THF PdCl2(PPh3)2 cat.

THF, 88%

B(sia)2 SnBu3
OMe OMe OMe OMe

I OR Pd2(dba)3 cat.
Pd(PPh3)4 cat., THF
TFP cat., NMP
79% O 32%

R = (CH2)2TMS
OR
R=H
OMe OMe O
TBAF, THF
89%

A. F. with M. Besev, C. Brehm, Coll. Czech. Chem. Commun. 2005, 70, 1696
HETEROCYCLIC AND AROMATIC STRUCTURES
BERKELIC ACID

flooded former copper mine

pH ca. 2.5 (H2SO4)
Fe: 1200 ppm, Cu: 240 ppm, Al: 290 ppm, Zn: 650 ppm,
As, Cd, Co, Mn etc

habitat for extremophilic Penicillium sp.

inhibits matrix metalloproteinase 3 (GI50 = 1.87 µM)

selective inhibition of OVCAR-3 (GI50 = 91 nM)

A. A. Stierle et al. J. Org. Chem. 2006, 71, 5357

WHAT IS BERKELIC ACID ?
 BERKELIC ACID

A. F. with P. Buchgraber, T. Snaddon, C.

Wirtz, R. Mynott, R. Goddard,
Angew. Chem. Int. Ed. 2008, 47, 8450;
Chem. Eur. J. 2010, 16, 12133

see also: B. B. Snider et al., Angew. Chem. Int. Ed. 2009, 48, 1283
J. K. De Brabander et al., J. Am. Chem. Soc. 2009, 131, 11350
 ASPERCYCLIDES A-C

S. B. Singh, H. Jayasuriya, D. L. Zink, J. D. Polishook, A. W. Dombrowski, H. Zweerink,

Tetrahedron Lett., 2004, 45, 7605
 THE ASPERCYCLIDES

A. F. with C. Müller, Chem. Commun. 2005, 5583

but:

A. F. with C. Müller, J. Pospisil, Chem.

Eur. J. 2009, 15, 5956
 ASPERCYCLIDE B

A. F. with C. Müller, J. Pospisil, Chem. Eur. J. 2009, 15, 5956

 ROSEOPHILIN

MeO N

Cl NH

Roseophilin

Isolation: H. Seto et al., Tetrahedron Lett. 1992, 2701

For a review on the chemistry and biology of roseophilin see: A. Fürstner, Angew. Chem. Int. Ed. 2003, 42, 3582
 ROSEOPHILIN: RETROSYNTHETIC ANALYSIS

MeO
MeO N
O
O +
N Cl NR
O R
Cl NH
 CONCEPT

+
Pd Lx
O
O R
Nu
R OH
R

+ Nu
Pd Lx
O
O R
Nu
R OH R
R R'O N
R'O R'O
R'
 STUDIES TOWARDS ROSEOPHILIN

1. NaI
9-bromononanal
2. AgBF4,
Cl Cl S tBuMe2SiO S t-BuLi
tBuMe2SiO Cl
73% 84%

SO2Ph
SO2Ph
O COOMe , KH O
Br
tBuMe2SiO tBuMe2SiO COOMe
68%

N
O R
 STUDIES TOWARDS ROSEOPHILIN

SO2Ph Pd(0) cat.

O
tBuMe2SiO COOMe 85% PhO2S OH
MeOOC OSiMe2tBu

TBAF, NH4F Dess-Martin

63% PhO2S OH 83% PhO2S O O
O
O O

N
O R
 STUDIES TOWARDS ROSEOPHILIN

BnNH2, Pd(0) cat.

70% PhO2S
PhO2S O O OH N
O O Bn

NMe2
1.
Cl

2. SnCl4 PhO2S N
O Bn
71%
 ROSEOPHILIN: THE MACROTRICYCLIC CORE

t-BuOK
R = Bn 1. Ca, NH3
N i-PrMe2ZnMgCl N R=H 2. PCC
PhO2S
O Bn 50% O R

N N
O Bn MO R

A. Fürstner, H. Weintritt, J. Am. Chem. Soc. 1997, 119, 2944.

 MeO
MeO N
O
O +
N Cl NR
O R
Cl NH
 THE HETEROCYCLIC SEGMENT

Cl Cl 1. Cu-chromite Cl
1. Br2, HOAC, 90%
2. TsCl, NEt3, MeCN
MeOOC N 2. NaOH, H2O, 92% HOOC N Br N Br
67%
H H Ts

1. NaOH, MeOH,  O MeO OMe

OMe
2. TBDMSCl, imidazole OSiMe2tBu
X
3. K2CO3, aq. MeOH/THF NMe2
O O X = OH
52%
X = Cl Cl
 THE HETEROCYCLIC SEGMENT

1. n-BuLi, -78°C Cl
Cl
2. ZnCl2, -78°C to 0°C

Br N OSiMe2tBu
N 3. Pd(PPh3)4 cat.,
Ts O MeO OMe
Ts O MeO OMe
OSiMe2tBu 43-61%
Cl

Cl Cl
1. K2CO3, MeOH
PPTS, MeOH OMe 2. KH, TIPSCl, THF OMe
N N
76% O O
Ts 62% (iPr)3Si
 FRAGMENT COUPLING: MODEL STUDIES

1. BuLi
2. CeCl3
Cl
MeO N
3.
OMe
O
N N O
O
(iPr)3Si K
Cl NH
4. HCl

5. TBAF

analogously: N N

O O

Cl NH NH
 FRAGMENT COUPLING (I)

MeO CeCl2
N
O K
O
no reaction
Cl N Si(iPr)3
 FIRST TOTAL SYNTHESIS OF ROSEOPHILIN

MeO X
N N N
MeO MeO
O .
O SEM OH 1. TBAF HCl
SEM
O 2. aq. HCl O
Cl NSi(iPr)3 62%
76 %
Cl Cl
NSi(iPr)3 N

A. Fürstner, H. Weintritt, J. Am. Chem. Soc. 1998, 120, 2817

 ANALOGUES

MeO N N MeO N N N

O O O O O

Cl Cl NH Cl NH
N NH
N

A. Fürstner, Th. Gastner, H. Weintritt, J. Org. Chem. 1999, 64, 2361

For biochemical investigations see: A. Fürstner, E. Grabowski ChemBioChem. 2001, 706

 THE DICTYODENDRINS

OSO3Na HO OSO3Na OSO3Na HO OSO3Na

HO HO

NH NH NH NH

MeOOC OH O OH O O
O N N
N N

OH OH OH HO OH
HO HO

OH OH OH OH

Dictyodendrin A Dictyodendrin B Dictyodendrin C Dictyodendrin E

first telomerase inhibitors of marine origin, cf. N. Fusetani et al., J. Org. Chem. 2003, 68, 2765

for telomerase as a target for chemotheraphy see: S. Neidle et al., Nature Rev. 2002, 1, 383
ANALYSIS
 REDUCTIVE HETEROCYCLE SYNTHESIS

Ph
Cl Cl Ph
O "low-valent" titanium
O
NH N
O H OEt
O
OEt

Reagent Solvent Isolated Yield

TiCl3 / 2 C8K DME 93%

TiCl3 / Zn („instant“) THF 87%

TiCl3 cat., Zn, TMSCl MeCN 79%

A. Fürstner et al., JOC 1994, 59, 5215; JACS 1995, 117, 4468; Org. Synth. 1999, 76, 142

Review: A. Fürstner, B. Bogdanovic, Angew. Chem. Int. Ed. Engl. 1996, 35, 2442.
 MeO

O NO2
O NO2 1. Fe/HCl, 96%
1. TosMIC, NaH OiPr
OiPr
Br N 2. O
2.
MeO Cl
MeO OMe
OMe
83%
89%
MeO
OMe

MeO OiPr OiPr

MeO
MeO
MeO NH NH

O HN O low valent titanium hv

OMe OMe
OiPr N N
pyridine, DME Pd/C, C6H5NO2
N MeCN
93%
81%
OMe OMe

OMe OMe
MeO
 ATTEMPTED SYNTHESIS OF DICTYODENDRIN B

OMe MeO OMe

MeO
O
NH NH
Cl

MeO O
2
N N
SnCl4, DCE

OMe MeO OMe

OMe OMe

OMe OMe OMe

Cl4Sn NH MeO SnCl4 NH NH

MeO
N N 2 N
MeO

OMe OMe OMe

OMe OMe OMe

 OiPr OiPr MeO OiPr
MeO MeO

NH NH NH
1. MeLi, then BuLi
NBS
OMe OMe HO OMe
N 69% Br N CHO N
2.

MeO

OMe OMe 97% MeO OMe

OMe OMe OMe

Br
MeO OiPr

NH
CDCl3, RT

OMe
N

OMe

OMe
 TOTAL SYNTHESIS OF DICTYODENDRIN B

CCl3
O O
O S
MeO OiPr O HO OSO3 NH4
MeO
1. TPAP cat.
NH NMO, 66% NH NH
2. BCl3, 85% 1. BCl3, TBAI
HO OMe O OMe O OH
N O O N 2. Zn, HCOONH4 N
3. S
Cl O CCl3 58%

92% OH
MeO OMe MeO OMe HO

OMe OMe OH

A. F. with M. M. Domostoj, B. Scheiper

J. Am. Chem. Soc. 2005, 127, 11620; J. Am. Chem. Soc. 2006, 128, 8087

for alternative syntheses, see:

M. Iwao et al., Tetrahedron Lett. 2010, 51, 533; H. Tokuyama et al., Angew. Chem. 2010, 49, 5925
 TOTAL SYNTHESIS OF DICTYODENDRIN C

MeO OSO3CH2CCl3 OSO3CH2CCl3 HO OSO3NH4

HO

NH NH NH

1. BCl3 / TBAI 1. Zn/HCOONH4

OMe O O
N O N O N
2. H2O2, MeCN 2. O2, MeOH
57% 76%

OMe OH OH

OMe OH OH

Dictyodendrin C

A. F. with M. M. Domostoj, B. Scheiper, J. Am. Chem. Soc. 2006, 128, 8087

 DICTYODENDRIN E
MeO OiPr

NH
SnMe3 BF3 K

MeO or: MeO OMe

H N
O
or: B
O
MeO
OiPr OMe HO OSO3NH4
MeO various palladium sources

NH OMe NH

OMe O
Br N N

MgCl MeO OiPr

MeO 1. BCl3 HO OH
OMe NH
B 2. Cl3CCH2OSO2Cl
MeO OH
3.. BCl3, TBAI
OMe OMe
N 4. Zn, HCOONH4
Pd(OAc)2, S-Phos
5. DDQ
MeO B

MeO OMe
MgCl

MeO 90% OMe

for the 9-MeO-9-BBN variant see: A. Fürstner, G. Seidel Tetrahedron 1995, 51, 11165

A. Fürstner, M. M. Domostoj, B. Scheiper, J. Am. Chem. Soc. 2006, 128, 8087

DICTYODENDRIN ANALOGUES
 C27 O4
C26
C24 C31
C22
C23 C28
C5 C25
C21
C16 C6
C18 N2
O2 C29
C17
C30
C20 C7 C10
C37 C4 C11
C19 C8 C9
C36
C38
C12
C32 C3

O3 C35 C1
C2 C14 C13
C33
C34 N1

O1
C15

for noble metal catalyzed ring closures with formation of polycyclic (hetero)arenes, see: A. F. with
V. Mamane, P. Hannen, Chem. Eur. J. 2004, 10, 4556
A. F. with P. Buchgraber, M. M. Domostoj, B.
Scheiper, C. Wirtz, R. Mynott, J. Rust,
Tetrahedron 2009, 65, 6519
 DICTYODENDRIN ANALOGUES

A. F. with P. Buchgraber, M. M. Domostoj, B. Scheiper, C. Wirtz, R. Mynott, J. Rust, Tetrahedron 2009, 65, 6519
TOTAL SYNTHESIS OF MOTUPORAMINE C

A. F. with A. Rumbo, J. Org. Chem. 2000, 65, 2608

 CITREOFURAN

O O O O

HO HO

Superposition of the X-ray structures of citreofuran (4, green)

OH O OH O and culvularin (1, blue) in an orthographic projection
1 2
A. Fürstner et al. JOC 2003, 68, 1521

O O O O H5 iv
O1 O1 iii
HO HO C17 O5
C1 H7 ii
O16 C3
O C2
O
OH O OH O9 C8
3 4 C12 C9 O7 O5 i

X-ray structure of citreofuran

A. Fürstner et al. JOC 2003, 68, 1521

 TOTAL SYNTHESIS OF CITREOFURAN

A. F. with A.-S. Castanet, K. Radkowski, C. W. Lehmann, J. Org. Chem. 2003, 68, 1521.
 (-)-BALANOL

O
O HO H
OH HO H O
O OR RO N
O OH
N
+
O OH N
HO O N O OR R1
RO O
H OR2
OH
Balanol

inhibitor of proteinkinase C (PKC) with IC50 values in the low nanomolar range
 FORMAL TOTAL SYNTHESIS OF (-)-BALANOL

(D)-(-)-DET, tBuOOH BnO

OH OR
Ti(OiPr)4 cat. allylamine, 70°C OH

O 94%
ee > 99%
N
R=H NaH, BnBr R
R = Bn 95%
R=H Boc2O, Et3N
R = Boc quant.

PCy3
Cl BnO BnO HO H
Ru 1. H2, Pd/C O
Cl Ph OH N3 N
PCy3 Mitsunobu 2. p-BnOC6H4COCl, Et3N

87% N 91% N 55% (over both steps) N

Boc Boc Boc
OBn

A. Fürstner, O. R. Thiel, J. Org. Chem. 2000, 65, 1738

 FORMAL TOTAL SYNTHESIS OF HAOUAMINE

L. Garrido, E. Zubía, M. J. Ortega and J. Salvá, J. Org. Chem., 2003, 68, 293
A. F. with J. Ackerstaff, Chem. Commun. 2008, 2870
 OMe
APORPHINE ALKALOIDS MeO

NH
MeO

from Gutteria ouregon

OMe
MeO

NH
MeO

HN
Polyalthia bullata OMe
OMe
MeO

from Polyalthia bullata

 O B(OH)2
OMe
OMe N O O
OMe MeO NR2
MeO X 1. Pd(0),
O MeO N
MeO
MeO O Pd(O)
2. Crabtree's catalyst, H2 MeO
Br O
94%
57% Br
X=H I2, Hg2O
X=I 81%

OMe OMe OMe

MeO NR2 MeO NR2 MeO
1. CBr4, PPh3, 88% InCl3 Br CuI, CsOAc NH
MeO Br MeO MeO
2. DBU, 79% 87% 71%

H2NNH2 R, R = phthalimido
from Gutteria ouregon
quant. R=H

OMe
MeO

A. Fürstner, V. Mamane, NH
MeO
CuCl2.2 H2O
Chem. Commun. 2003, 2112
tBuNH2, MeOH HN
OMe
86%
OMe
OMe

isolated from Polyalthia bullata

 CRISTATIC ACID

Zechlin, L.; Wolf, M.; Steglich, W.; Anke, T.

Liebigs Ann. Chem. 1981, 2099
A. F. with T. Gastner, Org. Lett. 2000, 2, 2467
 N-HYDROXYPYRIDONES: TMC-69 AND TMC-69-6H

HO

N O
OH TMC-69

17
HO

N O
OH TMC-69-6H

Hirano, N.; Kohno, J.; Tsunoda, S.; Nishio, M.; Kishi, N.; Okuda, T.; Kawano, K.; Komatsubara, S.;
Nakanishi, N. J. Antibiot. 2001, 54, 421, Tetrahedron 2001, 57, 1731
 O
HO O
O O
phenylacetonitrile AcO O TBSCl, Et3N, 78%
Cl O
50% Pd(0), 65% (96% ee)
Cl O X N O N O
H H
H2, Pd/C X = Cl
97% X=H
N N Ph
N
O O N S
TBSO TBSO
Me2CuLi O O
O O
LiHMDS, 69% (over 2 steps)
N OTBS N OTBS

TBSO HO
1. H2, Pd/C O
O

N OTBS 2. TBAF, 69% (over 2 steps) N O

H

1. HN(TMS)2, TMSCl
HO
2. (pyridine)MoO3(hmpa)
O
3. EDTA-Na
N O
71%
OH

A. F. with F. Feyen, H. Prinz, H. Waldmann, Angew. Chem. Int. Ed. 2003, 42, 5361;
Tetrahedron 2004, 60, 9543
 EPOHELMIN B

Y. Sakano, M. Shibuya, Y. Yamaguchi, R. Masuma, H. Tomoda, S. Omura, Y. Ebizuka, J. Antibiot. 2004, 57, 564

structure revision: B. B. Snider, X. Gao, Org. Lett. 2005, 7, 4419;

M. Shibuya, B. B. Snider, Y. Sakano, H. Tomoda, S. Omura, Y. Ebizuka, J. Antibiot. 2005, 58, 599
 TOTAL SYNTHESIS OF
EPOHELMIN B

A. F. with A. Korte, Chem. Asian J. 2008, 3, 310

 PRODIGIOSINS

N
N H
N N MeO
H H N
H H
N H
N N
N N NH
H MeO
MeO MeO
N

JACS 1998, 120, 8305 Angew. Chem., in press JOC 1999, 64, 8275

immunosuppressive – synergistic action with cyclosporin and FK506

for a review see: A. Fürstner, Angew. Chem. Int. Ed. 2003, 42, 3582
 Raphael‘s fresco „Mass of
the producing red bacteria are likely
Bolsena“ in the Vatican (1508)
responsible for the „miracles of
bleeding hosts“ reported in the
Middle Ages, e. g. in Bolsena, Italy, in
1263, commemorated until now by
the festival of Corpus Christi, cf.:
Angew. Chem. Int. Ed. 2003, 42, 3583

Agar plate with red colonies of

Serratia marescens
Orvieto Cathedral
 THE PRODIGIOSIN ALKALOIDS

R
R

N N N
H H H N
H O
N H
N H
MeO N
N
MeO
Streptorubin B

immunosuppressive – synergistic action with cyclosporin and FK506 in vivo

for a review on the chemistry and biology of the prodigions see:

A. Fürstner, Angew. Chem. Int. Ed. 2003, 42, 3582
CYCLOISOMERIZATION OF ELECTRON DEFICIENT ENYNES

Ts
N
PtCl2 (5 mol%)

toluene, 50°C, 66h

O N
Ts
79%
O

Ts
N PtCl4 (5 mol%)
MeO
toluene, 50°C, 66h
O N
Ts
COOMe 85%
 TOTAL SYNTHESIS OF STREPTORUBIN B

Bu3SnH, Pd(0) cat. 1. LiAlH4, 96%

HBF4.Et2O 2. PhOC(S)Cl, 95%

O 94% O 3. Bu3SnH, AIBN,  N

N N
Ts
Ts Ts

1. KAPA

2. H2O N 55% N
H

O
H
N
N
MeO N
A. Fürstner, H. Szillat, B. Gabor, R. Mynott H
H
J. Am. Chem. Soc., 1998, 120, 8305. N
N
MeO

Streptorubin B
 BUTYLCYCLOHEPTYLPRODIGIOSIN:
RETROSYNTHETIC ANALYSIS

N Boc
H
N N
H (HO)2B
O
H
N H
N
N
MeO
MeO O
 RETROSYNTHETIC ANALYSIS

N
H N
H
O N Pd OR N OR

O
2
O R
O R2
H
O PdLx
N Pd(0) N N N
R1 R1
R1 R1
A B C D

K. Narasaka et al., Bull. Chem. Soc. Jpn. 2002, 75, 1451

 O O

O OAc O O MeO 1. aq. DMSO, 

2. H2NOH
1. Dibal-H, 97% MeO 3. F5C6COOCl
2. Ac2O, Et3N, 97% NaH, Pd(0) cat., 74% 95%

O C 6F5
N
O
4

Pd(OAc)2 cat. KAPA

N 10 9 N
(o-tolyl)3P cat., Et3N H 65%
R
54%
Boc2O, R=H
DMAP, 69% R = Boc
 BUTYLCYCLOHEPTYLPRODIGIOSIN
1. BH3, H2O2 O
2. Dess-Martin 1. Ph3P=CHCH2CH2CH3
N
65% N 2. H2, Crabtree N
Boc Boc Boc
70%

MeO

N O
CAN H N Tf2O N
H
N
CHCl3 / H2O / DME Boc aq. NaOH, DMSO 79% H
NH N
65% 69%
O MeO MeO
O OTf

Boc
(HO)2B N
A. Fürstner, K. Radkowski, H. Peters, NH N
H
Angew. Chem. Int. Ed. 2005, 44, 2777; H
Pd(0)Ncat., LiCl N R
H N
Chem. Eur. J. 2007, 13, 1929 70% N O S N
MeO MeO
 NONYLPRODIGIOSIN

alkylation

condensation

N N
H H
MeO MeO
N N

NH NH

RCM / hydrogenation
Suzuki

Nonylprodigiosin alkylation
N. N. Gerber, Tetrahedron Lett. 1970, 809.
 N N
MeO H R
NH
R=H Boc2O, DMAP
O
R = Boc 92%

Tf2O
93%

1. N
Li
2. B(OMe) 3
N 58%
MeO
NH
O
O S CF3 (HO)2B N
O Boc

Pd(0) cat.
Na2CO3, LiCl
57%

N
H
MeO N
H
N
 Cl Cl PCy3
Cl
Ru cat.
Cl Ph
N N
H PCy3
H
MeO NH NH
O
H Me H
N 65%
N

Cl
Cl
N N
H H
RhCl(PPh 3)3 cat., H 2
MeO NH MeO NH
H 73% H
N N

(E)-isomer only ! Nonylprodigiosin.HCl

A. Fürstner, J. Grabowski, C. W. Lehmann, J. Org. Chem. 1999, 64, 8275

 Biological Evaluation: I
Cleavage of Supercoiled DNA IV
in the presence of Cu(II) II

A. Fürstner, E. J. Grabowski,
I
IV ChemBioChem 2001, 2, 706
II
III

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

N N N
H H H
MeO NH MeO NH MeO NH

O O

synthesis of analogues and studies concerning the effects of prodigiosin derivatives on the
proliferation of murine spleen cells and vacuolar acidification

A. Fürstner, J. Grabowski, C. W. Lehmann, T. Kataoka, K. Nagai, ChemBioChem 2001, 2, 60

 (-)-ISOONCINOTINE

H H
2X
N N
N N O N N O
H
H H H H H

H
OR1 Cl

N N N
H
X

Isolation from the stem bark of Oncinotis nitida by

M. Hesse et al., Helv. Chim. Acta 1968, 51, 1813
 ASYMMETRIC HYDROGENATION OF PYRIDINES

O
HX H2
N N R N N R N N R
O Pd/C H2
O H
O X O O X

H2
N R N R Pd/C N R
O H H2 H
X X
NH
O

F: Glorius et al., Angew. Chem. Int. Ed. 2004, 43, 2850

 O

O NH
OBn
BrMg
O
Cl N Cl Fe(acac)3 cat. Cl N OBn CuI cat. N N OBn
O
83% 90%

Br
H2 (120 atm) N N O H
Pd(OH)2/C cat. Ns H OH

78% N OH N
K2CO3, NaI, 73% N N O
H ee = 94% Ns H

PCy3 Ph
Cl
Ru
Cl
H PCy3 H
1. Swern, 81%

2. Ph3P=CH2, 82% N N
N N O then H2 N N O
R H 76% H H

R = Ns HSCH2COOH (-)-Isooncinotine
R=H LiOH, 84%

B. Scheiper, F. Glorius, A. Leitner, A. Fürstner, Proc. Natl. Acad. Sci. USA 2004, 101, 11960
 MUSCOPYRIDINE

X N X
M M
N N

V. Prelog et al., Helv. Chim. Acta 1946, 29, 1524

previous syntheses: G. Büchi (1957), M. Kumada (1975), H. Nozaki (1980), M. Hesse (1992), M. Ando (2000)
 6-heptenyl-MgBr N
Cl N
BrMg [Fe] cat.
[Fe] cat.
+ +
Cl N OTf

N
 „INTEGRATED„ SYNTHESIS OF MUSCOPYRIDINE

Cl
N N N
0.006 M
HCl/Et2O H2 (50 atm)
H
then
then aq. NaHCO3
PCy3 Ph
+ Cl
Ru 57% overall
Cl
PCy3 0.13 M
N

ADMET
polymer

A. Fürstner, A. Leitner, Angew. Chem. Int. Ed. 2003, 42, 308

for the preparation of the ruthenium indenylidene catalyst see: A. Fürstner et al., Chem. Eur. J. 2001, 7, 4811

since 2005 commercially available: STREM (g-quantities), UMICORE, Hanau (kg-quantities)

 HIGHLY CYTOTOXIC PHENANTHROQUINOLIZIDINE-
AND PHENATHROINDOLIZIDINE ALKALOIDS

OMe
MeO

OMe OMe OMe

MeO MeO MeO
B(OH)2
PtCl2 cat.

N N N
Boc 97%
I N Boc
Boc
Br MeO MeO MeO

Cryptopleurine
MeO

OMe OMe O
MeO MeO O
H H H
A. Fürstner, J. Kennedy,
N N N
Chem. Eur. J. 2006, 12, 7398
MeO Antofine MeO Tylophorine MeO Ficuseptine
OMe
 CRYPTOPLEURINE

OMe
MeO OMe
OMe B Li
I MeO
N
Br B(OH)2 Boc

MeO (dppf)PdCl2 (5 mol%) X

(dppf)PdCl2 (5 mol%)
LiCl, Na2CO3, DME/H2O
MeO THF, reflux
70% 82%
BuLi X = Br
then I2
X=I
82%

OMe OMe OMe

MeO MeO MeO
Boc
PtCl2 cat. aq. HCHO
N
toluene, 60°C N HCl, EtOH N
R
97% 67%
MeO MeO MeO

A. Fürstner, J. W. J. Kennedy, Chem. Eur. J. 2006, 12, 7398

 ERYPOEGIN AND ISOSOJAGOL

A. F. with E. Heilmann, P. W. Davies, Angew. Chem. Int. Ed. 2007, 46, 4760
 COMBRETASTATIN A4

Natriumacetylid, B(OMe) 3 1. BuLi

MeO Br MeO
PdCl 2(dppf) 3% 2. 9-OMe-9-BBN, PdCl 2(dppf) (3%)

3. Br
MeO MeO
OMe OMe
TBDMSO
77%
OMe

MeO OMe MeO

Lindlar
MeO OTBDMS
74% MeO
OMe
MeO OMe
66% OR
R = OTBDMS TBAF
R=H 95%

A. Fürstner, K. Nikolakis, Liebigs Ann. 1996, 2107

 2 I

ALKYLRESORCINOLS LiC CLi, THF/HMPA, 72%

HO
9-BBN (3 eq)., THF

OH
HO B B
B

OH
OH

HO 1. MeOH/HOAc (99:1)
OH 2. NaOMe (2 eq.)

OH
MeO Na
HO OH
B B
OMe
OH OH Na
HO OH MeO OTf
PdCl2(dppf) cat.
62%
OH OH OMe

RO OR

A. Fürstner, G. Seidel, J. Org. Chem. 1997, 62, 2332 OR OR

R = Me
9-Iod-9-BBN, hexane, 98%
R=H
 ALKYLRESORCINOLS: THE TURRIANES
OH
DNA-cleaving Alkylresorcinols from
HO Hakea trifurcata
OH

OH

oxidative oxidative
C-C-coupling/ C-O-coupling
O-methylation

OH
OMe OMe
OH OH O OH
OH OH
OH
OH OH

The Turrianes Robustol

isolated from Grevillea striata isolated from Grevillea robusta
 TOTAL SYNTHESIS OF TURRIANES

OH OPMB MeO OPMB

Br Br MeO CHO
+ MeO
O
OH OPMB HO
N O
OH TBDPSO
Vanilline

Mg, THF, reflux

84%
PMB OMe PMB OMe
O PMB OMe O
OPMB
O O OPMB
O
O OPMB
O O
PMB TBDPSO PMB
O
PMB
N
O
TOTAL SYNTHESIS OF TURRIANES

PCy3 Ph
OMe Cl OMe
OR Ru OR
Cl cat.
OR PCy3 OR
OR OR

84%

E : Z = 6.9 : 1

but the natural product is (Z)-configured !

 TOTAL SYNTHESIS OF TURRIANES

OMe OMe OMe

OR OR OR
OR Mo(CO)6 cat. OR OR
F3CC6H4OH
OR OR OR
76% Lindlar

or: 96%
(tBuO)3W CCMe3 cat.
61%

R = PMB BF3, EtSH

R=H 54%

turrianes are efficient DNA-cleaving agents under oxidative conditions;

for the total synthesis and biological evaluation see:

A. Fürstner, F. Stelzer, A. Rumbo, H. Krause, Chem. Eur. J. 2002, 8, 1856.

 N N N
N N N
H H H

Indolopyridocolin Flavopereirine Sempervirine

N
N N MeO N
N N
H
H H
NH MeO
N
O
Flavocorynanthyrine Villagorgine B Alstoniline
 H O
Cl N
O O Cl O O

O O Ti-graphite
NH2 89% NH 57%
N
O

O O

OH
HCl Ac2O
N N Cl N ClO 4
N N 77% N
H H H

Indolopyridocolin

Fürstner, A. Ernst, H. Krause, A. Ptock, Tetrahedron 1996, 52, 7329

 MeO OMe

MeO OMe

O
O 1. H 2, Pd/C
1. BF3.Et2O
2. NH 2OH 2. Cl O O
NH
MeO OMe 67% O O OMe O
N pyridine, DMAP O
70% OMe

MeO OMe HO OH
MeO OMe
1. KOt-Bu, H 2O
2. Ac2O, NaOAc
Ti-graphite MeOC6H4COCH2Br 3. BBr3
OMe
52% K2CO3, acetone 59% O
OMe N N
91% O
N O O
O
H

Lamellarin Q Dimethylether
OMe OH

Lamellarin O Dimethylether Lukianol A

A. Fürstner, H. Weintritt, A. Hupperts, J. Org. Chem. 1995, 60, 6637

 N S N S

TMS S o-NO2C6H4COCl HCOOH, Ac 2O O

O
N 83% NX2 87% NH
X= O H2, Pd/C H O
X= H 98%

TiCl3, Zn N
"Instant" S

71% N
H Camalexin

A. Fürstner, A. Ernst, Tetrahedron 1995, 51, 773

1. TiCl3, Zn, THF, 

NH ("Instant") NH
2. EDTA
OH
O N HN
75%

(+)-Aristotelin

A. Fürstner, A. Hupperts, A. Ptock, E. Janssen, J. Org. Chem. 1994, 59, 5215

CARBOHYDRATES AND GLYCOLIPIDS
 OH OBn OR
HO O BnO RO
RCM

HO OH BnO RO
OH OBn OR

D-glucose
R = Bn
Conduritol F R=H

catalyst time yield

PCy3
Cl Ph 60h 32% (GC)
Ru
Cl
PCy3

F3C
F3C Ph
O 1h 92%
Mo
O N
F3C
F3C
A. Fürstner et al., Tetrahedron
PCy3 2000, 56, 2195.
Cl Ph
Ru 89%
Cl
2h
R N N R
R = mesityl
 IPOMOEASSIN

Ipomoea squamosa

D. Kingston et al., J. Nat. Prod. 2005, 68, 487; Nat. Prod. Res. 2007, 21, 872
US 2006/0264383 A1
RETROSYNTHETIC ANALYSIS
 C30 C14

C10
C29 C9 O7
C28 C11

O3 C8
C26 C24 C12
O9 C7
C6
C5 O1 C13
C25
O8 C19 C1
C27 O2 C2
C15 O4
O6 C4
O5
O11 C3
C23 C22
C18
O10
C17 C16 C20

C21
REVISED RETROSYNTHETIC ANALYSIS
A. F. with T. Nagano, J. Am. Chem. Soc. 2007, 129, 1906
 for the total synthesis and biological assessment of all naturally occurring ipomoeassins and analogues, see:

A. F. with T. Nagano, J. Pospisil, G. Collet, S. Schulthoff, V. Hickmann, E. Moulin, J. Herrmann, R. Müller, Chem. Eur. J. 2009, 15, 9697

for an alternative synthesis of ipomoeassin F, see: M. H. D. Postema et al., Org. Lett. 2009, 11, 1417 (Eisai)
 WOODROSIN I

HO OH
O
HO
O OH
O
HO O
O O HO O
HO
O O O
O O HO
O
O
OH O

O
O O
HO
O O

Ipomoea tuberosa L.

K. Miyahara et al., Chem. Pharm. Bull. 1993, 41, 1925

review on the chemistry & biology of resin glycosides: A. Fürstner Eur. J. Org. Chem. 2004, 943
 O NH
O
O CCl3 OBn
O
BnO BnO O
OBn O O O
BnO
BnO O
O Ph O
BnO O O
O
Ph O RO
O O
O O
RO TMSOTf, 62%
HO R = PMB
O DDQ, 71%
O R=H
O
BnO
O O
BnO
OBn

BnO
O
O
O
O O no reaction
O
O O
O O NH
O
CCl3
O
Cl
 BnO
OBn

BnO
O
O
O
O O

O
O O
OBn O O NH
O O
BnO CCl3
BnO O
O
Ph O
O O Cl
O
RO
HO TMSOTf cat., 84%

OBn
BnO OBn BnO O
O BnO O
O
Ph O O NH
O O O O O
BnO O O
O O CCl3
O O
O O OH
BnO
O O O O no reaction
O
Cl
 PCy3 Ph
Cl
Ru O
Cl BnO OBn
OBn PCy3 OBn
BnO OBn O
BnO O cat. BnO O
O BnO O O BnO O
O BnO O
Ph O Ph O
O O O O O O O
BnO O O 94% O
O O O O
O O OO HO O O OO HO

O O
Cl Cl E:Z=9:1

HO OH
O
O NH
O HO
O O CCl3 O OH
1. BnO O
O O HO O
O O HO O
60% HO
O O O
HOTf cat. O O HO
O
O
OH O
2. deprotection, 84%
O WOODROSIN I
O O
HO
O O

A. Fürstner, F. Jeanjean, P. Razon, Angew. Chem. Int. Ed. 2002, 41, 2097; Chem. Eur. J. 2003, 9, 307 and 320
for the ruthenium indenylidene catalyst see: A. Fürstner et al., Chem. Eur. J. 2001, 7, 4811
 TRICOLORIN A

RCM
RO
6 7 O O
RO
RO
HO RO
O O RO O O
O O RO O
HO RO
O O O OH
HO RO
O O O
HO
O OH
O
O
O
O X
O
O D-glucose, D-fucose
O O O O
O O O
O O
HO
Tricolorin A O O OH
HO OH RO
RO OR

for alternative syntheses of tricolorin A via macrolactonization strategies see:

C. H. Heathcock et al., J. Org. Chem. 1997, 62, 8406; Y.-Z. Hui et al., J. Org. Chem. 1997, 62, 8400.
 TOTAL SYNTHESIS OF TRICOLORIN A

O O
O O O O
O O 6-heptenoic acid
.
OH BF3 Et2O Ph O
O O O DCC, DMAP
82% RO 71%
Ph O RO
O O
AcO O CCl3
R = Ac KOMe, MeOH
AcO NH R=H 71%

PCy3
O O
Cl
O O Ru O O
1. Cl
O R O
Ph O PCy3
O O Ph O Tricolorin A
O O O
O 2. H2, Pd/C O
OH O
O 77% OH
O

A. Fürstner, T. Müller, J. Am. Chem. Soc. 1999, 121, 7814

THE MACROCYCLIC CORE OF TRICOLORIN A

C. W. Lehmann, A. Fürstner, T. Müller, Z. Kristallogr. 2000, 215, 114

 O
O O
O
Ph O
O O O
O
n OH
O

1. RCM
2. H2, Pd/C

77% 76% 76%

O
O O O
O
O O O O O
O H O
Ph O
Ph O O O O Ph O
O O O O O
O O
O OH O
OH OH
O O O

A. Fürstner, T. Müller, J. Am. Chem. Soc. 1999, 121, 7814

 TOTAL SYNTHESIS OF TRICOLORIN G

NH
O CCl3 O
O O O O
O
BnO O
O O O O
(Bu3Sn)2O BnO Ph O
O O OAc O
O O
Ph O Ph O BnO
O O O BnBr, 57% O O
O O
HO BnO
OH OH O
BnO
BnO OAc

O
O O O
O O
O H
O O
Ph O O
Ph O O
O O O BnO
1. KOMe, MeOH BnO 1. Grubbs catalyst O Tricolorin G
O
2. 6-heptenoic acid, DCC 2. H2, Wilkinson
O O
84% BnO BnO
BnO O BnO O
O
O

A. Fürstner, T. Müller, J. Am. Chem. Soc. 1999, 121, 7814

 OH
HO O
O
HO
HO
O O
O
HO
OH
O

Sophorolipid Lactone

RCAM "Lindlar"

RCAM: A. Fürstner, G. Seidel, Angew. Chem. Int. Ed. 1998, 37, 1734
 OR
RO O
O
RO
R O OPMB
OPMB O RO
O O O O
O PMBO O
PMBO AcO O RO
O PMBO
PMBO AcO Br O RO
OH R O
O O
O
AgOTf, lutidine AcO
89% AcO

R = p-MeOC6H4-

OR OH
N Mo N O O
RO O HO O
N RO HO
RO HO
O O O O
cat. O 1. Lindlar, H2, quant O
RO HO
OR OH
CH2Cl2/toluene O 2. DDQ, 93% O
78%

A. Fürstner, K. Radkowski, J. Grabowski, C. Wirtz, R. Mynott, J. Org. Chem. 2000, 65, 8758
for the catalyst see: A. Fürstner, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc. 1999, 121, 9453
 CYCLOVIRACIN B1

OMe
O OH
25
O
OH OH
HO HO OH
OH OMe
HO 3' O OH
O O O 19
17' O O O
HO O O O OH
OMe O O
3 OH

HO OH
23' OH
HO

26 = 64 possible isomers (!)

M. Tsunakawa et al., J. Antibiot. 1992, 45, 1467 and 1472.

 Cycloviracin B1 OMe
BnO
O OBn
BnO
O O
OBn
BnO O(NH)CCl3
OBn OMe
OMe
OBn O OBn
BnO OBn O
Y OBn
C-17' O O OBn
O O X
O O O
O O
M C-17

BnO OBn
OBn

BnO

O O(NH)CCl3
HO O OH

BnO OBn HO X
OBn
 SYNTHESIS OF THE KEY BUILDING BLOCK

O OLi tBuO O OH
O
O O
1. (PCy3)2Cl2Ru=CHPh O OtBu

2. H2, Pd/C 61%

75%

tBuO O OH HO O OTBDPS

[(R)-BINAP.RuCl2]2.NEt3 cat. HO O O
HO

H2 (15 atm), MeOH, 70°C BnO OBn

88%, ee = 98% OBn
 TEMPLATE DIRECTED CYCLODIMERIZATION

OBn
BnO OBn Cl

N N
O O Cl
OH
TBDPSO O OH
K KH, DMAP
HO O OTBDPS
HO
O O

BnO OBn OBn

OBn BnO OBn

O O
O O OR1
R 2O O O
O O

BnO OBn
OBn

71% isolated yield

A. Fürstner, M. Albert, J. Mlynarski, M. Matheu, J. Am. Chem. Soc. 2002, 124, 1168.
 STEREOCHEMICAL
ASSIGNMENT R1 = H, R2 = TBDPS, R = H: 105.3 ppm
R1 = R2 = R = H: 106.4 ppm

OH R2O(CH2)13
106.4 ppm OR
(R)
O OR
O OR
O O O O
OH
RO O
O OH O
OH OR RO
O RO (R)
O O (CH2)13OR1
O O
HO O
HO O
RO HO R1 = H, R2 = TBDPS, R = H: 100.3 ppm

R2O(CH2)13
106.4 ppm OR
Cycloviracin B1 (S)
O OR
RO O OR
O O O O
RO O
RO O
RO (S)
(CH2)13OR1
 OBn OBn
OBn
BnO BnO OMe MeO OBn
OBn
N N
H N NPh BnO OBn
O O O O
H O O
H O O
O O S
TBDPSO O O H
O O H O
H LiHMDS, DME, 61%
BnO OBn
OBn
OMe
O OBn
O
OBn OBn
BnO OBn
OBn OMe
O OBn
O O
O O O
TBDPSO O O OBn
O O
OBn

BnO OBn
OBn

A. Fürstner, J. Mlynarski, M. Albert, J. Am. Chem. Soc. 2002, 124, 10274.

 OMe
O OBn

O
OBn OBn
BnO OBn
OBn
OBn OMe Zn
O OBn
O O
O O O NHTf
O O O OBn Ti(OiPr)4
O O NHTf
OBn

BnO OBn 81%

OBn

OMe
O OBn BnO

O BnO
OBn OBn O NH
1.
BnO OBn
OBn OMe BnO O CCl3
O OBn OMe
O O (3R,19S,25R,3'R,17'S,23'R)-
O O O Cycloviracin B1
HO O O OBn 2. H2, Pd/C, 88%
O O
OBn

BnO OBn
OBn
BnO

A. Fürstner, M. Albert, J. Mlynarski, M. Matheu, E. DeClercq, J. Am. Chem. Soc. 2003, 125, 13133
 HO
HO OH

HO O
O
OH
HO
HO O O O

O
HO O
OH
TOTAL SYNTHESIS OF
O HO OH
OH
HO
OH MACROVARICIN D (BA-2836-4)
HO O O O

O OH
HO O
23 O O O OH HO HO
17 OH OH OH OH OH
OH
3
O
MeO O MeO O
O OH
O O
Macroviracin D
HO OH 25 19 HO
OH OH
O OH
O
O O
O O
HO O
Cycloviracin B1 O
HO (17S)
OH (3R) (23R)

O OH

O OMe

HO OH
OH
 TOTAL SYNTHESIS OF MACROVARICIN D (BA-2836-4)

AcO
BnO O
BnO
BnO TBDPSO O OtBu
O NH
TBDPSO O OtBu
CCl3
O
OH TMSOTf, 91% O OBn

R1O OBn
OBn

OH O OtBu
OBn OBn
O O OtBu Zn
2 O
1. TBAF, 90% 9
O OBn
O NHTf
2. PCC
, cat.
O OBn
NHTf R1 = Ac R1O OBn
OBn
analogously for R1 = Bn
R1O OBn
OBn
 BnO 1
AcO BnO OR
BnO O
BnO
BnO BnO O
O NH
OH O OtBu OtBu
O O
CCl3
OBn
OBn
O TMSOTf, 88% O
O OBn
R1 = Bn O OBn
18 R1 = Ac
d)
R1O OBn 19 R1 = H
OBn BnO OBn
OBn

BnO
BnO BnO OBn
BnO O
BnO
BnO
O NH BnO O
CCl3 O O OR1

OBn
TMSOTf, 58%
O
R1 = Bn
O OBn
16 R1 = tBu
TOWARD MACROVARICIN D 17 R1 = H
b)
BnO OBn
OBn
BnO
BnO OTBDPS
TBDPSO
BnO O
BnO
BnO
BnO O
O NH
O O OR1
CCl3
OBn

TMSOTf, 79% O
1
R = Ac O OBn
21 R1 = tBu
f)
22 R1 = H
AcO OBn
OBn
 TOTAL SYNTHESIS OF MACROVARICIN D (BA-2836-4)

BnO
BnO OAc BnO
BnO OAc

BnO O BnO O
O
O
OBn
BnO OBn
Yamaguchi BnO
19 + 22 BnO O O O 1. TBAF
BnO O O O
86% O OBn 2. TFA O OBn
BnO O BnO O
82%
O TBDPSO OBn O HO OBn
OBn
OBn OBn
COOtBu OBn
COOH
O
O
O OBn O OBn
BnO
BnO OH
BnO OBn
OBn BnO OBn
OBn
BnO O
O
OBn
1. Yamaguchi, 89% BnO
BnO O O O

2. NH3, MeOH, 86% O OBn

BnO O
O O O OBn
OBn
OBn
O

O OBn

BnO OBn
OBn
 TOTAL SYNTHESIS OF MACROVARICIN D (BA-2836-4)

BnO RO
BnO OBn RO OR

BnO BnO O RO O
BnO OH
1 O
O O OH

BnO OBn OR
O
RO
O O RO O O O

OBn O OBn O OR
BnO RO O
BnO O O O
BnO OBn O RO OR
O OBn OBn OR
BnO OR
O
RO
O O RO O O O
O OBn Yamaguchi, 74%
OBn
OBn O OR
RO O
O
O O O OR
O OBn OR
OR
O
BnO OBn
OBn
O OR
H2, Pd(OH)2 cat. R = Bn
R=H RO OR
OR

A. F. with J. Ruiz-Caro, J. Mlynarski, Chem. Eur. J. 2004, 10, 2214

 STRUCTURE DETERMINATION OF GLUCOLIPSIN
VIA TOTAL SYNTHESIS
O O O O NH
AcO
O N CCl3
O O OH BnO OBn
Ph OBn
O O N
n-Bu2BOTf, Et3N, 63% TMSOTf, MeCN, 45%
Ph Me

OR
Cl
RO OR
R1O O N N Cl Me
O O
O O O O
R 2O Me O O
KH, DMAP, CH2Cl2
BnO OBn O O
54% Me
OBn
RO OR
likely via templated
LiOH, H2O2 R 1 = auxiliary, R2 = Ac OR
cyclodimerization at a K+ center
aq. THF, 79% R 1 = R2 = H R = Bn H2, Pd(OH)2
Glucolipsin
R=H MeOH, quant.

diastereomers prepared analogously for structure determination purposes:

OR
OR
OR RO OR
RO OR
RO OR
Me
Me O O
Me O O
O O O O
O O O O
O O O O
O O O O
O O Me
O O Me
Me
RO OR
RO OR
RO OR OR
OR
OR

A. F. with J. Ruiz-Caro, H. Prinz, H. Waldmann, J. Org. Chem. 2004, 69, 459

 OH
HO OH O
HO O HO O
HO HO
O O HO HO
HO O OH O
O O
O
O O
HO O
HO HO HO HO
O O H O O HO O
HO O OH
O HO O HO O
HO O O O
O O O HO
O O
O O
OH O
O O
O HO O Sophorolipid Lactone
O HO O O
O O O HO J. Org. Chem. 2000, 65, 8758
O O Woodrosin I
O O OMe
HO O Angew. Chem. Int. Ed. 2002, 41, 2097
O OH
HO OH Tricolorin A Tricolorin G Chem. Eur. J. 2003, 9, 307 and 320
J. Am. Chem. Soc. 1999, 121, 7814 O
OH
HO
OH OMe HO OH
O OH
OH
HO O
HO OH O
OH
O
O O OH OH
HO O O HO
O O HO O O O
HO O O O OH
O
HO O
HO O HO OH
O HO OH
OMe OH Cycloviracin B1 OH
OH
J. Am. Chem. Soc. 2003, 125, 13132 HO
J. Am. Chem. Soc. 2002, 124, 10274 HO O O O

HO J. Am. Chem. Soc. 2002, 124, 1168 O OH

HO O
OH
23 O O O
HO OH OH
17 OH
OH
Me 3
O O O
O O
O O O OH
Macroviracin D
O O
Me Chem. Eur. J. 2004, 10, 2214
HO OH
Glucolipsin A HO OH OH
J. Org. Chem. 2004, 69, 459 OH
 b-MANNOPYRANOSIDES

HO OR OH OR HO OH
HO O HO O
HO O O HO O

HO O OR O HO O
HO
HO HO

(1) R = Ac "Caloporoside" (3)

(2) R = H
 OR

[a] [c]
O + CH2 =CH(CH2 )11CH2 MgBr

R=H
[b]
R = SiMe2tBu
OR OR

[d]
B
O
O OTf
O O
O O R = SiMe2 tBu
[e]
R=H

OBn
HO OH
[f] BnO O O [g,h,i] O
HO
BnO HO O
O O O
HO O
O
HO

[a] CuCl(COD) (10 mol%), THF, 86%; [b] TBDMSCl, DMF, Imidazol, 94%; [c] 9-BBN (dimer), THF; [d] NaOMe (5 eq.), KBr
(1 eq.), PdCl2(dppf) (5 mol%), 65%; [e] TBAF, THF/H2O, 92%; [f] Ulosylbromid, CH2Cl2, MS 3Å, Ag(+1) auf Alumosilikat;
[g] NaBH4, CH2Cl2, MeOH, 78% über Stufen f) und g); manno : gluco ~ 10 : 1; [h] KOH (48% in H2O), DMSO/i-PrOH, 84%;
[i] Pd(OH)2 auf Kohle („Perlman Catalyst“), H2 (1 atm), MeOH, 90%.

A. Fürstner, I. Konetzki Tetrahedron 1996, 52, 15071

 D-gluco D-manno
O O

O OTf
RO
7
O [a]
RO O O
OR O O
[c] O
4 RO
RO O O
5 R=H epoxide
[b] RO O OR O
6 R = SiMe2t-Bu RO opening
RO

tBuMe2SiO
Suzuki reaction
O O [d]

O
CALOPOROSIDE
8

RO

BnO O
[a] 13-tetradecenylmagnesium bromide, CuCl(COD) (10 mol%),
BnO THF, -78°Cr.t., overnight, 86%; [b] TBDMSCl, imidazole, DMF,
r.t., 94%; [c] (i) [9-H-9-BBN]2 (0.5 eq.) THF; (ii) NaOMe (1 eq.),
9 R = SiMe2t-Bu KBr (1.1 eq.), PdCl2(dppf) (2.5 mol%), THF, reflux, overnight,
10 R = H
[e] 86%; [d] (i) BnOH, NaH, DMF, 3h, r.t., 92%; (ii) BnBr, K2CO3,
DMF, 4h, reflux, 93%; [e] TBAF, THF, r.t., 89%.
 OAc OR

AcO
O [a] RO O CALOPOROSIDE
AcO RO
AcO O
Br O
11 OEt
12 R = Ac [a] Bu4NBr, s-collidine, EtOH, 85%; [b] BnBr, KOH, THF, 81%; [c]
[b]
13 R = Bn 2N HCl, THF; [d] K2CO3, MeOH, 1h, r.t., 87% over two steps

OBn
[c,d] BnO O
BnO
OH OH
14

OBn OBn
[a] O [b] O
14 BnO BnO [a] (ClCH2CO)2O, pyridine, -20°-10°C, 1.5 h, 85%; [b]
BnO BnO
HBr/HOAc, CHCl3, 0°Cr.t., 3 h, 95%.
RO OR O
Br

15 R = C(O)CH2Cl O
16
Cl
 BnO OH
[a] [b]
14 OH
BnO
HO OBn
17 CALOPOROSIDE
OMe

OMe

BnO O [d]
O [a] NaBH4, THF/H2O, 0°Cr.t., 2h, 96%; [b] 3,4-
BnO dimethoxybenzaldehyde, H2SO4 cat., MS 3Å,
RO OBn CH2Cl2, 3.5 h, 84%; [c] tBuMe2SiCl, imidazole, DMF,
18 R = H 15 h, r.t., 91%; [d] BH3.THF, THF, reflux, 2 h, 20
[c] (62%) + 21 (32%); [e] (i) Swern oxidation; (ii)
19 R = tBuMe 2Si
NaClO2, HSO3NH2, THF/H2O, r.t., 10 min, 93%.

BnO OR BnO OH
OH + OR
BnO BnO
tBuMe2SiO OBn tBuMe2SiO OBn

20 21

BnO OR
[e] OH
BnO
tBuMe2SiO OBn O

22 (R = 3,4-dimethoxybenzyl)
 Cl

BnO OR
NMe2
24 Cl
22 BnO
tBuMe2SiO OBn O
23

CALOPOROSIDE
BnO OR
O
BnO
BnO O tBuMe2SiO OBn O
[a]
BnO

[a] 10, DMAP, CH2Cl2, 0°Cr.t., 16 h; [b] DDQ,

25 R = CH2C6H3(OMe)2
[b] CH2Cl2/H2O, 0°Cr.t., 3.5 h, 74% (over last three
26 R = H steps steps); [c] triflic anhydride, CH2Cl2/pyridine, 0°C,
[c]
27 R = SO2CF 3 15 min; [d] KOAc, DMF, r.t., 1 h, 75%; [e] KOAc, DMF,
0°Cr.t., 30 (75%) + 28 (18%); [f] BF3.Et2O, CH2Cl2,
0°Cr.t., 1.5 h, 83%
BnO OAc
O
BnO
BnO O RO OBn O

BnO

28 R = tBuMe 2Si
[d] [f]
29 R = H

BnO
OBn
BnO
O
O
[e]
BnO O O

BnO

30
 BnO O
BnO O
OBn O
CALOPOROSIDE
16 BnO O O
[a]
+ BnO O RO OBn O
29 BnO
BnO

31 R = C(O)CH2Cl [a] Ag+ on silica/alumina, MS 3Å, CH2Cl2, -5°C, 45

[b]
min, 74%; [b] thiourea, Na2CO3, EtOH/CH2Cl2,
32 R = H
[c] reflux, 4 h, 75%; [c] triflic anhydride, pyridine, r.t.,
33 R = SO2CF3 45 min, 78%; [d] Bu4NOAc, toluene, ultrasound, 16
h, 95%; [e] H2 (1 atm), Pd/C (5%), MeOH + HOAc
(1%), 22 h, 96%.

RO O O
OR O O
RO O
RO O O
[d]
RO O OR O
RO
A. Fürstner, I. Konetzki, J. Org. Chem.
RO
1998, 63, 3072
34 R = Bn
[e]
1 R=H
 HIGHER SUGARS

H2N OH
OH
HO
O
H2N N O
O OH OH OH OH OH
H H
N O OH HO O OH
1
OH OH OH OH
HO NH2 HO NH2
OH OH

Hikizimycin Hikosamine
 O
O R O
O
O TMSCHN2, BuLi OH 1. TBSOTf, lutidine, 95% I O
O O
O OTBS
65% O O 2. NIS, AgNO3, 92%
OH
O O
R=H
K2CO3, MeOH
R = TMS

O
O 1. LiAlH4, 94% O Swern, 76% O OTBS
OMe OTBS
O OMe OH O
2. TBSCl, NaH, 71% O
O O
 O
O
I O CrCl2 (1 eq.), 82%
O OH
OTBS OTBS O
or: O H2, Pd/C, EtOAc
O + OTBS
O O CrCl2 cat., Mn, LiCl, TMSCl, Bu4NCl, 88% O
O 89%
O O
TBSO

OH O OTBS O O O
N OTBS 1. HF/pyridine, 98%
O phthalimide, DEAD
O O O
O O 2. Swern, 75%
O PPh3, 62% O O
O
TBSO
TBSO

O O
RuCl3 cat., FeCl2(H2O)4 cat. H OH O O OH O O
O O H
O O O HO O O
O OTBS NaIO4, 57%
O O OTBS O OTBS
NR2 O O
O NR2 NR2
O O
-NR2 = phthalimido

orthogonally protected hikosamine

A. F. with M. Wuchrer, Chem. Eur. J. 2006, 12, 76

LIPIDS, OXYLIPINS AND PROSTAGLANDINS
 MARINE OXYLIPINS

M. Kurada et al., Chem. Lett. 1989, 267; W. H. Gerwick et al., J. Nat. Prod. 1994, 57, 171;
K. Kosuaka et al., J. Nat. Prod. 2003, 66, 1318
A. Fürstner et al. Chem. Eur. J. 2001, 7, 4811
now commercially available from Umicore and Evonik
PROTECTING GROUP FREE TOTAL SYNTHESIS OF ECKLONIALACTONE A

A. F. with V. Hickmann, M. Alcarazo, J. Am. Chem. Soc. 2010, 132, 11042

 ANCEPSENOLIDES

O O

O O

Ancepsenolide

O O

O O

Dehydrohomoancepsenolide

moderately cytotoxic marine „acetogenins“, cf. F. J. Schmitz et al., Tetrahedron Lett. 1966, 7,
97; J. Org. Chem. 1971, 36, 719; G. Cimino et al., J. Nat. Prod. 1999, 62, 1194;
for a previous synthesis of ancepsenolide by Ru-catalyzed Alder-ene reaction see: B. M. Trost
et al., J. Am. Chem. Soc. 1994, 116, 4985
 TOTAL SYNTHESIS OF DEHYDROHOMOANCEPSENOLIDE

O
O
DEAD, PPh3
OH O Br
+ HO Br
71%
1

1. CuCN (1 eq.)
2. I O O (tBuO)3W
3. ester 1 O [Ru] cat. cat.
X X O
70% 70% 75%
X=I
Zn
X = ZnI

O O O O
Lindlar
O O O O
96%

A. Fürstner, Th. Dierkes Org. Lett. 2000, 2, 2463.

PROSTAGLANDIN LACTONES FROM Tethys fimbria

O O

O O
O O
HO AcO

HO O

O O
O O
HO

G. Cimino et al., Experientia 1991, 47, 56; J. Org. Chem. 1991,

56, 2907; Tetrahedron Lett. 1989, 3589.

first and only example of “in vivo storage” of prostaglandins

 PROSTAGLANDIN LACTONE E2

MO
1. TESCl, imidazole Bu3Sn OTES 1. BuLi
OH OTES
2. Bu3SnH, AIBN cat. 2. Me2Zn
I
O
73% TBSO
3.

TBSO

OR 5-heptynoic acid O Mo[N(tBu)(Ar)]3 cat.

iPrN=C=NiPr, DMAP CH2Cl2/toluene
TBSO O
94% O 73%
TBSO
R = TES HOAc
R=H 74% (overall)

O O O
1. H2, Lindlar, 86% pig liver esterase
O COOH
O
O 2. HF, MeCN, 88% O
TBSO HO HO OH
PGE2

A. Fürstner et al., Angew. Chem. Int. Ed. Engl. 2000, 39, 1234, J. Am. Chem. Soc. 2000, 122, 11799
 SOME PGE2 LACTONE ANALOGUES

O O

O O
O O
HO HO

O O O O
O
O O O
O O O O
HO HO HO HO O

PGE2-lactone

A. Fürstner, K. Grela, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc. 2000, 122, 11799.
 ALKYNE CROSS METATHESIS

MeO O
O O
O OMe
COOMe
OTES
[Mo] cat., CH2Cl2, toluene, 80°C
TBSO TBSO OTES
51%

O
COOH
PGE2

HO OH

A. Fürstner, C. Mathes Org. Lett. 2001, 3, 221.

TERPENOIDS
 TOTAL SYNTHESIS OF DACTYLOL

COOMe Previous Syntheses: (a) Gadwood,

O
Paquette et al, 1987 R. C.; Lett, R. M.; Wissinger, J. E. J.
Harmata et al., 2000
(16 steps)
(17 steps) Am. Chem. Soc. 1986, 108, 6343. (b)
Paquette, L. A.; Ham, W. H. J. Am.
O Chem. Soc. 1987, 109, 3025. (c)
HO MeO Feldman, K. S.; Wu, M.-J.; Rotella, D.
P. J. Am. Chem. Soc. 1990, 112,
8490. (d) Molander, G. A.;
Eastwood, P. R. J. Org. Chem. 1995,
Gadwood et al., 1986
Dactylol 60, 4559. (e) Hayasaka, K.; Ohtsuka,
Shirahama et al., 1985 (20 steps)
T.; Shirahama, H.; Matsumoto, T.
(9 steps)
Tetrahedron Lett. 1985, 873. (f) M.
Harmata, P. Rashatasakhon, Org.
HO Lett. 2000, 2, 2913.

Feldman et al, 1990 O Molander et al, 1995

(12 steps) (13 steps)
 O
O O
O OM H
MeLi, CuI, Bu3P OH MesylCl, DMAP

77% 85%

RO 1. [Mo] (3%) HO
2. TBAF

92%

Bu3SnH MgCl
O R=H (TMS)2NH
ZnCl2, Pd(0) cat.
CeCl3
R = SiMe3 MeCOCl, 93%
83%
80%

RO 1. [Mo] (3%) HO
2. TBAF

6 steps, overall yield ca. 21% (Dactyol) + 85%

18% (epimer)
R=H (TMS)2NH
A. Fürstner, K. Langemann, J. Org. Chem.
1996, 61, 8746. R = SiMe3 MeCOCl, 95%
 SYNTHESIS OF SABINOL

O
HO
SiMe3
PtCl2 (5 mol%)

BF3 toluene, 80°C, 2h

78%

O OH
NaBH4, CeCl3

65%

sabinone trans-sabinol

V. Mamane, T. Greß, H. Krause, A. Fürstner J. Am. Chem. Soc. 2004, 126, 8654

see also: M. Malacria et al., JACS 2004, 126, 8656; F. D. Toste et al., JACS 2004, 126, 10858
 CUBEBENE

O O PtCl2 cat.

O toluene, 80°C
92% AcO H H

MeMgBr
Fe(acac)3 cat.
-cubebene
90%
TfO H H Me H H

Review on Iron Catalyzed Cross Coupling:

A. Fürstner et al., Chem. Lett. 2005, 34, 624

A. Fürstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006

see also: A. Fürstner et al., Chem. Commun. 2004, 2546 (sesquicarene).

PROPARGYL ACETATES AS SYNTHETIC EQUIVALENTS FOR
α-DIAZOKETONES

O OAc O O
O N2
 TWO CONCEIVABLE PATHWAYS

path I O

O
M
O

O
M OAc
O

O
path II M
 O PtCl2 cat.
single isomer
O toluene, 80°C
92% AcO H H

O PtCl2 cat.
+
O toluene, 80°C
79% AcO H H AcO H H

1:1

A. Fürstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006

 THE MOST LIKELY PATHWAY

path I O

O
M
O

O
M OAc
O

O
path II M

A. Fürstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006

for a computational study see: J. Marco-Contelles et al., Organometallics 2005, 24, 3182
 EPOXYSESQUITHUJENE AND CONGENERS

analogously:

A. Fürstner, A. Schlecker, Chem. Eur. J. 2008, 14, 9181