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SELECTED TOTAL SYNTHESES
MACROCYCLIC STRUCTURES
MARVELS OF THE SEA: THE SPIRASTRELLOLIDES
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
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
ANALYSISrelative stereochemistry within the individual sectors established
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
NN
O
H
O
H
HOH
H3C
CH3
O
CH3
O
CH3CH3
H3C
H3CO
H3C
OCH3
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
NN
O
H
O
H
HOH
O
O
MeO
MeO
peptide coupling
YamaguchiJulia olefination
Julia
Heck coupling
HON
O
H
O
H
NH2
HO
MeO
X
RO
RO
OH
O
RSO2MeO
SO2R
O
lactonization
15
6
11
12 19
20
23
29
15
6
11
1219
20
29
olefination
BUILDING BLOCKS
MeOOCBr N(Boc)2+ MeOOC N(Boc)2
NHBocO
NHBocHO
Pd(OAc)2 cat.
P(o-tol)3 cat., Et3N
84%
(+)-crotyl-B(Ipc)2
82% (95% ee)
O
SiMe3
OH
SiMe3
NRu
NPh
Ph
Ts
H O
OMe
SiMe3
OMeHO
I
(0.6%)
iPrOH
98% (99% ee)
1. Still-Gennari, 87%
2. K2CO3, MeOH, 80%
3. Cp2Zr(H)Cl (3 eq), then I2, 80%
NHBocHO
OMeHO
I
OMeHO
OH
NHBoc
OMeO
OH
NHBoc
OMe OH
NHBoc
MeO
R = Et
R = H
20
21
18 23
COOR
+
Pd(OAc)2 cat., AgOAc
DMF, RT
46% (+13% isomer)
CuBr2 cat., tBuOK cat.
TEMPO cat., O2
94%
S
MeOCOOEt
N NN
N
O
O
Ph
1
11
NaHMDS ("Barbier"), THF
57% (E:Z > 10:1)
Me3SnOH, DCE, 94%
PREPARATION OF THE SECO-ACID
OMe OH
NHBoc
MeO
18 23
COOH NHBocO
O
MeO
MeO
OMe OH
NHBoc
MeO
OR
Yamaguchi
(Yonemitsu)
R
6O
O O
Cl
Cl
Cl
DMAP
RO
O O
Cl
Cl
Cl
N
NMe2
R
N
NMe2
O- DMAP.H
RO
R
O
1
16
6 1
R
OH
possible mechanism:
A. Fürstner, C. Aissa, C. Chevrier, F. Teplý, C. Nevado, M. Tremblay Angew. Chem. Int. Ed. 2006, 45, 5832
RETROSYNTHETIC ANALYSIS (II)
NN
O
H
O
H
HOH
O
O
MeO
MeO
peptide coupling
Suzuki / Stille ?
1
6
11
12 19
20
intermolecular
Suzuki coupling ?
7
RCM ?
HON
O
H
O
H
NH2
HO
MeO
BR2
RO
OH
O
MMeO1
19
20
29
esterification !I
I
(intramolecular)
(intramolecular)
LITERATURE PRECEDENCE
J. Wagner et al., JACS 2003, 125, 3849; L. A. Paquette et al., Helv. Chim. Acta 2002, 85, 3033
OMeOMe
B
O
O
pinacolborane
9-BBN cat.
56%
NHBocO
NHBocHO
OMs
TIPS
TIPS
NHBocHO
I
Pd(OAc)2 / PPh3 cat.
Et2Zn
72% (dr = 7.5:1)
3 steps
Ba(OH)2.8 H2O, (dppf)PdCl2 cat.
RT, 70%
NHBocO
O
MeO
MeO
OH
O
MeO
NHBocHO
MeOYamaguchi
73%
2nd APPROACH
2nd APPROACH
NHBocO
O
MeO
MeO
NHBocO
O
MeO
MeO
RuCl
Cl
PCy3Ph
N NMes Mes
96%
decomposition
NRO
H
O
OtBu
TBSOTf, lutidine
X
NH2
PivO
R = Piv
HO
O
NHCHO
OTBS
NRO
H
O
NHCHO
OTBS
EDC, HOBt
95% (X = H)
X
X
85% (X = I)
NO
H
O
O
R
O
HTBS
NHO
R
O
OTBSO
ON
OTBS
TBS
R = Ac
OH
O
MeO
NHO
MeO
O
NH
O H
OTBSH
O
O
MeO
MeO
N
O
NH
O H
OTBSH
N
N
DCC
O
O
MeO
MeO
RuCl
Cl
PCy3Ph
N NMes Mes
69%
N
O
NH
O H
ORH
R = TBS
R = HTBAF, 80%
A. F. with C. Nevado, M. Tremblay, C.
Chevrier, F. Teplý, C. Aissa, M. Waser
Angew. Chem. Int. Ed. 2006, 45, 5837
J. Am. Chem. Soc. 2007, 129, 9150
SCALE-UP AND MOLECULAR EDITING
> 1 g
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
S. J. Danishefsky et al., Angew. Chem. Int. Ed. 2007, 46, 5576
LEARNING FROM THE LITERATURE
LACTIMIDOMYCIN: ANALYSIS
TOTAL SYNTHESIS OF LACTIMIDOMYCIN
A. F. with K. Micoine, J. Am. Chem. Soc. 2010, 132, 14064
Epothilone D (89, R = Me)
Epothilone B (87, R = Me)
Epothilone C (88, R = H)
Epothilone A ( 86, R = H)
O
OH
OHO
S
N
O
OR
O
OH
OHO
S
N
O
R
THE EPOTHILONES
[e][d]
[c]
[b]
[a]
OO O
OEt
OOHOH
OEt
OO O
95 R = TBDPS
94 R = H
RO OEt
OO
BrOEt
OHOCN
92
93
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%.
EPOTHILONE: BUILDING BLOCKS
[h]
[g]
[f]
[e][d]
[b,c]
[a]
OO O OH
OOR1 OR1
R2O
OO OR1 OR1
HO
103 R1 = R2 = H
104 R1 = R2 = TBS
105 R1 = TBS, R2 = H
102
106
S NO
O R
OO
99 R = H
100 R = Me
101
[a] n-BuLi, THF/HMPA, MeI, 78°
60°C, 94%; [b] LiAlH4, THF, 85%; [c]
Pr4NRuO4 cat., NMO, CH2Cl2, MS 4Å,
90%; [d] lithium enolate of ketone 98,
THF, 78°C, 70%; [e] PPTS cat., MeOH,
85%; [f] TBSOTf, 2,6-lutidine, 92%; [g]
camphorsulfonic acid, CH2Cl2/MeOH
(1/1), 78%; [h] PDC, DMF, 83%.
EPOTHILONE:
BUILDING BLOCKS
SYNTHESIS OF EPOTHILONES VIA RCAM
A. Fürstner, Ch. Mathes, K. Grela Chem. Commun. 2001, 1057; Chem. Eur. J. 2001, 7, 5299
O
OR
ORO
S
N
O
O
OR
ORO
S
N
O
O
OH
O
OHO
S
N
O
O
OR
ORO O
S
N
OH
S
N
O
OO O
R = TBS
[Mo] cat.
80%
Lindlar, H2
CH2Cl2
R = TBS
R = H
aq. HF
Epothilone C
OO
literature: 70%
Epothilone A79% over both steps
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 AND Y
O OO
O
O
O
Amphidinolide X (1)
Amphidinolide Y (2)
(equilibrium mixture)
O
OHO
HO
O
O
OO
O
O
HO
HO
AMPHIDINOLIDE X: RETROSYNTHETIC ANALYSIS
O OO
O
O
O
HOOH
O
O
RO
OM
OH
X
O
1
13 14
19
1
13
14 19
STEREOCHEMICAL RELAY
X
R4O
O
19R2R1
O
R2
R1OH R1
O [M]R2
19
IRON CATALYZED SYNTHESIS OF ALLENOLS
C5H11
O
iPrMgCl
Fe(acac)3 (5 mol%)
toluene, -5°C, 5 min
94%, syn:anti = 10:1
ee = 93%
HO
C5H11
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
OROOHRO
RO
O
R2
RO
O
OH
TBDPSO
OH
R2 = H
R2 = Me
OI
PMBO
Sharpless
97%
1. Swern
2. (MeO)2P(O)C(N2)COMe
67%
LiHMDS,MeOTf, 95%
n-PrMgBr
Fe(acac)3 cat.
62%
syn:anti = 8:1
AgNO3
CaCO3
90%
TOTAL SYNTHESIS OF AMPHIDINOLIDE X
O O
IO O
COOMe
OEt
O O
O
OOOMs
OOOH
OOOPMB OO
OPMB
I
1. ethylene glycol, PTSA cat.
2. Dibal-H, Et2O
54%Et2Zn, 65%
Pd(OAc)2 + PPh3 cat.
anti : syn = 4.5:1
1. PMBCl, NaH, 94%
2. LiHMDS, MeI, 95%
Cp2ZrHCl, C6H6
I2, CH2Cl2
61%
1. DDQ, 89%
2.
Yamaguchi, 96%
HO COOMe
O
FIRST TOTAL SYNTHESIS OF AMPHIDINOLIDE X
OI
PMBO
B O
PMBO
OMe
Li
9-MeO-9-BBN
t-BuLi
for the „9-MeO-9-BBN“ variant of the Suzuki coupling, see:
A. Fürstner, G. Seidel, Tetrahedron 1995, 51, 11165
A. F. with O. Lepage, E. Kattnig, J. Am. Chem. Soc. 2004, 126, 15970
O OO
I
OMe
O
O
OOOO
COOMe
PMBO
O
(dppf)PdCl2 cat., Ph3As
74%
OOOO
O
O
Amphidinolide X
3 steps
AMPHIDINOLIDE Y:
STRATEGIC CONSIDERATIONS
O
OHO
HO
O
O
RO
OM
OH
XHO
O
HO
O
OH
X
OR
RO
O
X
OR
RO
O
12
1
13
18
1 6 7 12
1276
6
712
O
6
7
1,4-anti
chelate control
aldol
TOWARD AMPHIDINOLIDE Y
TBDPSO OMe
O
TBDPSO
COOMe
OAc
O
OAc
OMeP
O
O O
TBDPSO
O
O
OMe
TBDPSO
OH
O
OMe
TBDPSO
OPMB
O
Ru
P
Cl
Cl
PRu
P
ClClP
Cl
P
P= (S)-BINAP
Et2NH2
67
1. Dibal-H, 79%
2.
LiHMDS, 91%
NaOMe, MeOH
86%
[Ru], HCl cat.,
H2 (20 bar), MeOH
92%, dr > 23:1
3 steps
cf.: S. A. King et al., Org. Synth. 2005, 81, 178
TOWARD AMPHIDINOLIDE Y
O
ITMSO
MeO
TBDPSO
OPMB
O
PMBO
SiMe2Ph
O
TBDPSO
OPMB
O
SiMe2Ph
OH
major
1,4-anti
Et2BOTf, EtN(iPr)2
84%, dr > 4:1
1. TESCl, imidazole, 91%
2. MeMgBr, 96%
PMBO SiMe2Ph
OSiEt3HO
"matched"
1,3-syn
OTBDPS
(dipolar model)1,2-anti
(chelate-Cram
model) 1. TESOTf, lutidine, 92%
2. DDQ, 92%
3. Dess-Martin, 93%
O SiMe2Ph
OTESTESO
OTBDPS
COOMe
O
ITMSO
MeOCOOMe
O
OHO
HO
O
O
PMBO
OB
MeO
Li
I
PMBO
O
OMeB
O
TMSO
MeOCOOMe
RO
O
O
TMSO
MeOCOO
HO
O
OO
O
O
TMSO
MeO
Et3NH
tBuLi
(dppf)PdCl2 cat., Ph3As
K2CO3, 79%
1. DDQ, 75%
2. LiOH, then HCl/Et3N
Yamaguchiaq. HOAc
56% (over 3 steps)
TOTAL SYNTHESIS OF
AMPHIDINOLIDE Y
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
for the synthesis and biological assessment of analogues, see: Chem. Eur. J. 2009, 15, 4030
ANALOGUES BY „DIVERTED TOTAL SYNTHESIS“
AMPHIDINOLIDE V
O
OH H
O
OH
Amphidinolide V
Isolation: J.-I. Kobayashi et al., Tetrahedron Lett. 2000, 41, 713
TOWARDS AMPHIDINOLIDE V
OH
OTBSBr
BF3KTHPO
OH
OTBSTHPOO
OTBSRO
O
O
OTBSO
O
O
Pd(OAc)2 cat., tBuNH2
84%
4-hexynoic acid
EDC
95%
O
OTBS
O
OZn
2RO
R = H
R = TBS
69%
TBSCl
imidazole
79%
TOTAL SYNTHESIS OF AMPHIDINOLIDE V
A. F. with O. Larionov, S. Flügge
Angew. Chem. Int. Ed. 2007, 46, 5545;
Chem. Eur. J. 2009, 15, 4011
30 mol%
80°C
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
A. Fürstner et al., Chem. Eur. J. 2009, 15, 3983
PREPARED ANALOGOUSLY:
THE AMPHIDINOLIDE T FAMILY
J. Kobayashi et al., J. Org. Chem. 2000, 65, 1349 and 2001, 66, 134.
O
O
OH
O
O
O
O
O
HO
O
Amphidinolide T1 Amphidinolide T3
O
O
O
HO
O
Amphidinolide T4
O
O
O
HO
O
Amphidinolide T5
Review: J. Kobayashi et al., Nat. Prod. Rep. 2004, 77.
RETROSYNTHETIC ANALYSIS
O
Y
Cl
O
O
O
X
R3SiO
OR2
A
B
C
O
O
OR2
R1O
O
45
12 14
syn syn
O
O
OR2
R1O
O
Amphidinolide T
family
FRAGMENT I
X = SO2Ph
X = OH
O
XOH
NC
OH
TsO
O
OMe
RO
1. TsCl, Et3N, 94%
2. Dibal-H, toluene, -95°C
O
H
TsO
(-)-Ipc2B-allyl
Et2O, -100°C
70% (over 2 steps)
KCN, DMSO
99%
Dibal-H
CH2Cl2, -78°C
91%
PhSO2H
CaCl2, CH2Cl2
87%
N O
Ph
OO
N O
Ph
OOOR
OTBS
OMOM
OR
OMOM
OOTBS
OMOM
TBSO
1. Bu2BOTf, Et3N
2. methacrolein, 90%
3. MOMCl, (iPr)2NEt, CH2Cl2, 93%
1. LiBH4, Et2O, 92%
2. TBSCl, imidazole, DMF, 90%
O3, CH2Cl2, 86% TBSOTf, Et3N, Et2O
91%
FRAGMENT II
FRAGMENT III
N O
Ph
OO
OH
O
O
X O
O
X = OtBu
X = OH
X = Cl
O
OtBuO
OH
tBuO O
1. NaHMDS, THF, -78°C
then allyl bromide, 60%
2. LiOH, H2O2, aq. THF, 93%
[((R)-binap)RuCl2]2(NEt3) cat.
H2 (10 atm), MeOH, 95°C, 84%
ee = 98%
EDCI, DMAP
CH2Cl2, 93%
TFA, Et3SiH, quant.
(COCl)2, quant.
TOTAL SYNTHESIS OF AMPHIDINOLIDE T
O
SO2Ph Me
O
"inside" attack
SnCl4OTBS
OMOMTBSO
O
TBDPSO
I
OMOM
NOEO
O
OTBS
OMOM
H
12
O
Cl O
O
Zn/Cu, TMSCl
Pd(0) cat., 50%
O
TBDPSO
OMOM
O
O
O
86%
O
TBDPSO
OMOM
O
O
O
Ru
PCy3
PhCl
Cl
Mes MesNN
O
O
O
OMOM
TBDPSO
O
86%
O
O
HO
O
O
O
O
O
O
OH
Amphidinolide T4
Amphidinolide T1
E:Z = 6:1
A. Fürstner, C. Aissa, R. Riveiros, J. Ragot, Angew. Chem. Int. Ed. 2002, 41, 4763;
J. Am. Chem. Soc. 2003, 125, 15512
O
TBDPSO
OMOM
O
O
O
Ru
PCy3
PhCl
Cl
Mes MesNN
O
O
O
OMOM
TBDPSO
O E:Z = 6:1
O
TBDPSO
OMOM
O
O
O
Ru
PCy3
PhCl
Cl
Mes MesNN
O
O
O
OMOM
TBDPSO
O E:Z = 2:1
toluene, 110°C
82%
CH2Cl2, 40°C
86%
TOTAL SYNTHESIS OF AMPHIDINOLIDE T
OZnBr
Zn
BrZn
O
O
O
OMOM
TBDPSO
O
O
O
OMOM
TBDPSO
O
O
OMOM
TBDPSO
O
COOH
Ph3P=CH2
TiCl4
THF, reflux, 64%
O
O
O
OMOM
TBDPSO
O
TOTAL SYNTHESIS OF AMPHIDINOLIDE T
A. Fürstner, C. Aissa, R. Riveiros, J. Ragot, Angew. Chem. Int. Ed. 2002, 41, 4763;
J. Am. Chem. Soc. 2003, 125, 15512
O
O
OMOM
TBDPSO
O
O
O
TBDPSO
O
OH
O
O
HO
O
O
Amphidinolide T4 (4)
O
O
HO
O
OMOM
O
O
O
O
OH
Amphidinolide T1 (1)
[(Me2N)3S][Me3SiF2]
84%
1. Dess-Martin, 93%
2. Dowex, 52%
TMSCl, Bu4NBr
85%
1. Dess-Martin, 83%
2. HF-pyridine, 87%
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
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.
THE LATRUNCULIN FAMILY
O
O
O
HN
S
OHH
O
O
O
O
HN
S
OHH
O
OH
O
O
OH
HN
S
H
O
OMe
O
O
O
HN
S
H
O
Latrunculin A Latrunculin B Latrunculin C Latrunculin D
O
O
O
HN
S
OHH
O
16-epi-Latrunculin B
O
O
O
HN
S
OH
H
O
Latrunculin B
RCAM/Lindlar
Fe-catalyzed
cross coupling
OR
O
S
RN
O
O
O
OH
Fe-catalyzed
cross coupling
Negombata magnifica
(formerly: Latrunculia magnifica)
TOTAL SYNTHESIS OF LATRUNCULIN B
O
OR
OEt
OO
OEt
OOTfMgBr
Fe(acac)3 cat.
97%
R = Et
R = H
NaOH, MeOH
92%
Ph-N(Tf)2
KHMDS
61%
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
in the absence of Fe cat.: < 30% yield
using Cu(I) in catalytic or stoichiometric amounts instead of Fe cat. leads to decomposition
O2S1
C2
O2'
N3
C30
C5
C2'
C4
C2"
C31
C32
C36
C33
C35
C34
O37
C38
S
RN
O
O
H2N
O OEt
SH S
PMBN
O OH
O
S
PMBN
O Cl
O
MeMgBr
Fe(acac)3 cat.
Cl
NMe23 steps
ee = 87%
ee = 99%recryst.
80%
TOTAL SYNTHESIS OF LATRUNCULIN B
OMe
OMeBr
Br
OMe
OMeR
R = H
R = Me
OTBS
X
X = CH2
X = O
OMe
OMe1. O3, then Me2S
2. HC(OMe)3, H+
75%
4-dimethylaminopyridinium
bromide perbromide, DMAP
87%
LiHMDS
90%
BuLi, MeI
95%
1. (Ipc)2B(allyl)
2. TBSCl, imidazole
78%O3, MeOH
then Me2S, 94%
O2
S1
C2
C3'
C4'
N3
O4'
C30
C5
C5'
C4
C2'
C31
C32
O2'
O1'
C6'
C36
C33
C7'
C2"
C34
C12'
C35
C11'C8'
O37
C10'
C9'
C38
C9"
OTBS
O
S
PMBN
O
O
TiCl4, iPrNEt2
73%
TBSO O
PMBNS
O
OH
dr = 2:1
HCl
CSA, MeOH
64%
O
PMBN
S
OH
O
ORH
dr = 7:1
R = H
R = Me
X-ray of minor isomer
axial !
O
PMBN
S
OH
O
OMeH
O
PMBN
S
O
O
OMeH
O1. Tf2O, pyridine
2. NaO
O
58%
major isomer
equatorial
TOTAL SYNTHESIS OF LATRUNCULIN B
C9"
C7'
C9'
C5'
C10'C11'
C8'
C12'
C2"
C4'
O4'
O1'
C16'
C13'
C3'
C15'
O16'
C14'
C14"
C30
C2'
O2
N3
C36
O2'
C31
C2
C4
C6'
C35
C32
S1
C5
C34
C33
C38
O37
O
PMBN
S
O
O
OMeH
O[Mo] cat.
CH2Cl2/toluene
70%O
PMBN
S
O
O
OMeH
O
O
O
O
HN
S
OHH
O
Latrunculin B
1. Lindlar, quant.
2. CAN, 78%
A. Fürstner, D. De Souza, L. Parra-Rapado, J. Jensen,
Angew. Chem. Int. Ed. 2003, 42, 5358
PREVIOUSLY UNKNOWN DECOMPOSITION PATHWAY
O
O
OH
HN
S
R
O
O
O
OH
N
S
R
HO
14
1516
17
11 13
O
O
O
HN
S
OHH
O
DCl / CDCl3
EPIMERIZATION MECHANISM
TBSO O
PMBNS
O
OH
O
PMBN
S
OH
O
OHH
TBSO O
PMBNS
O
OR
N
S
O
PMB
O
OH
R
HO N
S
O
PMB
+ 2 H2O
d.r. = 2:1
d.r. = 7:1
13
11 13
13 13
13
11
11
11
H+
- 2 H2O +
major
“SECOND GENERATION” ASSEMBLY PROCESS
O
PMBN
S
OH
O
ORH
TBSO O
PMBNS
O
EtO
O
PMBNS
O
O
PMBNS
O
PMeO
O
MeO
R = H
R = Me
O
P
MeOMeO
BuLi, -78°C
60%
TBSO
O
Ba(OH)2
75%
aq. HCl
63%
MeOH, CSA
quant.
d.r. = 9:1
LATRUNCULIN A
O
PMBN
S
O
O
OMeH
O
O
O
O
PMBN
S
OMeH
O
O
PMBN
S
OH
O
OMeH
R = H
R = TfTf2O, pyridine
[Mo]
toluene/CH2Cl2
O
NaO
decompositionCAN
ENYNE-YNE METATHESIS: LATRUNCULIN A
L. Turet, A. Fürstner, Angew. Chem. Int. Ed. 2005, 44, 3462;
Chem. Eur. J. 2007, 13, 115
O
PMBN
S
OH
O
OMeH
O
TeocN
S
O
O
OMeH
O[Mo]
toluene/CH2Cl2
70%
O
O
O
HN
S
OHH
O
Latrunculin A
O
O
O
TeocN
S
OMeH
O
1. H2, Lindlar, 82%
2. TBAF, 62%
3. aq. HOAc, 80%
P. J. McLaughlin et al., Nature Cell Biol. 2000, 2, 376
bioactivity vanishes after N-alkylation
Lat A (16-membered) > Lat B (14-membered)
O
H
H GLU214
O
OO
HN
S
OHH
O
TYR69
ARG210
TYR186
ASP157
both epimers
(LAT B)
?
O
RN
S
OH
O
OMeH
RN
S
O
H
O
OTBS
O
OTBS
O
HH
RN
S
O
H
O
RN
O
O
H
O
RN
O
O
H
O
O
RN
S
OH
O
OMeH
O
RN
O
OH
O
OMeH
O
RN
S
OH
O
OMeH
HH
O
RN
O
OH
O
OMeH
HH
O
RN
O
OH
O
OMeH
HH
O
OH
O
OH
O
OH
O
OH
O
OH
DIVERTED TOTAL SYNTHESIS: LATRUNCULIN “LIBRARY”
O
O
O
HN
S
H
OHH
O
O
O
O
HN
S
OHH
O
O
HN
S
O
O
OHH
O
O
O
O
HN
S
OHH
O
O
O
O
HN
S
H
OHH
O
H
H
O
O
O
HN
O
OHH
O
O
O
OH
N
S
HO
O
O
O
HN
S
OHH
O
O
O
O
HN
S
OHH
O
O
O
O
HN
O
OHH
O
HH
A. Fürstner, D. Kirk, M. Fenster, C. Aissa, D. De Souza, O. Müller, PNAS 2005, 102, 8103
O
O
O
HN
S
OHH
O LAT-B
O
O
O
HN
S
H
OHH
O
H
H
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
O
O
O
O
O
O
O
O
(Z)-isomer is ca. 3.5 kcal/mol more stable
CONCEPT
O
O
HO
HO
O
O
HO
HO
(Z)-isomer is ca. 1.5 kcal/mol more stable
O
O
O
O
OHO
OO
OO
OHO
OO
O
TsO O
O O
OCOOMe
OO
O HHO O
O O
O
TsCl, pyridine
77%
NaOMe, THF
62%
EtMgBr, CuBr
60%
Dibal-H
97%
Ph3P=CH2
77%
5-hexenoic acid
DCC, 84%
TOTAL SYNTHESIS OF HERBARUMIN I
MEDIUM SIZED RINGS: E/Z CONTROL BY “CATALYST TUNING”
O
O
O
O
N NMesMes
O
O
O
O
Ru
PCy3
PhCl
Cl
O
O
HO
HO
PCy3
Ru
PCy3
Cl
Cl Ph
O
O
O
O
cat.
cat.
86%only (Z)
E : Z = 7.6 : 1
78% aq. HCl
90%
Herbarumin I
A. Fürstner, K. Radkowski, C. Wirtz, R. Goddard, C. W. Lehmann, R. Mynott, J. Am. Chem. Soc. 2002, 124, 7061
CONFORMATIONAL RIGIDITY
OO
O
O
OHO
HO
O
OH
OHO
HO
O
O
O
overlap of x-ray structures
J. Am. Chem. Soc. 2002, 124, 7061
O
O
O
O
O
O
O
O
(Z)-isomer is ca. 3.5 kcal/mol more stable
AN INDEPENDENT CONFIRMATION
O
O
HO
HO
O
O
HO
HO
(Z)-isomer is ca. 1.5 kcal/mol more stable
(Z)-isomer is ca. 2.5 kcal/mol less stableO
O
TBSO
TBSO
OTBSO
O
TBSO
TBSO
OTBS
AN INDEPENDENT CONFIRMATION
R = TBS
O
O
TBSO
TBSO
OTBSO
O
RO
RO
OR
R = H
N N MesMes
Ru
PCy3
PhCl
Cl
CH2Cl2, reflux, 85%
TBAF
Díez, E.; Dixon, D. J.; Ley, S. V.; Polara, A.; Rodríguez, F. Helv. Chim. Acta 2003, 86, 3717
THE PINOLIDOXIN PUZZLE
A. Fürstner, K. Radkowski, C. Wirtz, R. Goddard, C. W. Lehmann, R. Mynott, J. Am. Chem. Soc. 2002, 124, 7061
O
O
HO
HO O
O
proposed structure
de Napoli, L. et al., JOC 2000, 65, 3422
O
O
HO
HO O
O
O
O
HO
HO O
O
O
O
HO
HO O
O
PINOLIDOXIN
excellent match with published data
(1H, 13C, IR, MS and [])
TOTAL SYNTHESIS OF MICROCARPALIDE
A. F. with T. Nagano, C. Müller, G. Seidel, O. Müller, Chem. Eur. J. 2007, 13, 1452
MICROCARPALIDE
(-)-GLOEOSPORONE: A FUNGAL GERMINATION SELF
INHIBITING MACROLIDE
OO
H
OH
H
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
(R) (R)
O OORO
H
H
OOR
OO
H
H
O
OOROO
H
OH
H
O
O
TOTAL SYNTHESIS OF (-)-GLOEOSPORONE
82%
91%
DMAP, pyridine
4-pentenoyl chloride
MeO
MeO O O
88%, ee > 98%
MeO
MeO OH
Ti(OiPr)4 (1.2 eq.)
(20 mol%)
Zn(pent)2
NHTf
NHTf
OMeO
MeO
NaHCO3, Me2S
MeOH, pTsOH
ozonolysis
TOTAL SYNTHESIS OF (-)-GLOEOSPORONE
91%
TBDMSCl, imidazole77%, de > 98%
90%
R = SiMe2tBu
R = H
O OOR
molecular sieves
(S)-Binol (20 mol%), Ti(OiPr)4 (20 mol%)
SnBu3
O
O O
CH2Cl2:H2O (1:1)
CF3COOH
MeO
MeO O O
TOTAL SYNTHESIS OF (-)-GLOEOSPORONE
54%
(-)-gloeosporone
MeCN
aq. HF
O OO
O
H
OH
KMnO4, Ac2O
O O
Me2tBuSiO
O
O
E : Z = 2.7 : 1
80%
O O
Me2tBuSiO
CH2Cl2, 40°C
Ti(OiPr)4 (30 mol%)
[Ru] (3 mol%)
O OtBuMe2SiO
A. Fürstner, K. Langemann, J. Am. Chem. Soc. 1997, 119, 9130
7
OHO
H
O
HO ON
4
O
OHO
HO O
65
3
O
OHO
HO
O
O
O
OHO
HO
O
O
OHO
HO OH
2 R = H
1 R = Me
O
ORO
HO
RESORYCLIC ACID MACROLIDES
lasiodiplodin (1), zeranol (3), zearalenone (4), resorcylide (5), monocillin I (6), salicylihalamide A (7)
TOTAL SYNTHESIS OF (R)-(+)-LASIODIPLODIN
Lasiodiplodin
[Ru]
MeO
MeO O
OO
MeO
MeO O
94%
[Ru]
MeO
MeO O
OO
MeO
MeO O
O
OMeO
HO
E : Z = 2.3 : 1
A. Fürstner, N. Kindler, Tetrahedron Lett. 1996, 37, 7005.
ZEARALENONE
(E)-isomer only !
no reactionO
OMeO
MeOO
O
PCy3
Ru
PCy3
Cl
Cl Ph 5 mol%
N N
Ru
PCy3
Cl
Cl Ph
O
OHO
HO O
Zearalenone
O
OMeO
MeOO
O
91%
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
HO
O
O
OH
NH
O17
Salicylihalamide A ( 1a): 17(E)
Salicylihalamide B ( 1b): 17(Z)
12
1
SALICYLIHALAMIDE
K. L. Erickson, J. A. Beutler, J. H. Cardellina, M. R. Boyd, J. Org. Chem. 1997, 62, 8188
SYNTHESIS OF SALICYLIHALAMIDE
R = MOM
R = H
OR
OMe
OO
OMe
O
Cl
NMe2X = Cl
X = OH
X
O
NO
Ph
O O
NO
Ph
O O 1. LHMDS
2. Br
85%
aq. LiOH, H2O2
99%
OLi
OMe
81%
[(R)-BINAP .RuCl2]2.NEt3 cat.
H2, MeOH
96%, de > 99%
MOMCl, iPr2NEt
90%
SYNTHESIS OF SALICYLIHALAMIDE
OR
OMe
O MOMO O
OtBu
O
MOMO OH
OtBu
O MOMO OH
OR
R = H
R = PMB
OLi
OtBu
98%
[(R)-BINAP .RuCl2]2.NEt3 cat.
H2, MeOH
93%, de > 98%
LiAlH4
98%
PMBCl, NaH (2 eq.)
85%
HO O
OH
DEAD, PPh 3
88%
HO
O
O
OMOM
OPMB
RCM APPROACH TO SALICYLIHALAMIDE:
THE E/Z PROBLEM
RO
O
O
OMOM
OPMB
RO
O
O
OMOM
OPMBRu
PCy3
Cl
Cl Ph
N N
5 mol%
toluene, 80°C
R Yield E : Z
H 69% 0 : 100
Me 93% 66 : 34
MOM 91% 68 : 32
SiMe2tBu 91% 40 : 60
A. F. with O. R. Thiel, G. Blanda,
Org. Lett. 2000, 2, 3731
TOTAL SYNTHESIS OF SALICYLIHALAMIDE
HO
O
O
OH
NH
O
R1 = R2 = H
R1 = MOM, R2 = Me
R2O
O
O
OR1
I
MeO
O
O
OMOM
O
R = H
R = PMB
MeO
O
O
OMOM
OR
DDQ, 94%
Dess-Martin
87%
CHI3, CrCl2
87%
BBr3, 88%
H2N
O
Cu-thiophene carboxylate
Rb2CO3
57%
A. Fürstner, T. Dierkes, O. R. Thiel, G. Blanda, Chem. Eur. J. 2001, 7, 5286
NON-CYCLIC POLYKETIDES
NHO
OMe OMe O
NOR
OH
Crocacin A (R = Me)
Crocacin B (R = H)
NH2
OMe OMe O
Crocacin C
NHO
OMe OMe O
NOMe
O
Crocacin D
H
THE CROCACINS
OR
O
O
NHTs
O
O
O
TsN
H
OHH2N
2. propionyl chloride
1. TsCl, Et3N
Et3N, CH2Cl2
82%
TiCl4, (iPr)2NEt
CH2Cl2
85%
R = H
R = TBS
TBSOTf
lutidine, 97%
LiBH4
THF, 89%OTBS
OH
O
I
O
AcOOAc
OAc
pyridine, CH2Cl2
87% OTBS
O
OMs
Et2Zn, THF, 72%
Pd(OAc)2 cat., PPh3 cat.
OR OH
1. TBAF, THF, 88%
2. MeOTf, CH2Cl2, 63%OMe OMe
R = TBS
OMe OMe
OR
O
OMe OMe
SnBu3
OMe OMe Bu3SnH
PdCl2(PPh3)2 cat.
THF, 88%
(sia)2BH
OMe OMe
B(sia)2
OR
O
IPd(PPh3)4 cat., THF
79%
Pd2(dba)3 cat.
TFP cat., NMP
32%
R = (CH2)2TMS
R = H
THF
TBAF, THF
89%
TOTAL SYNTHESIS OF CROCACIN C
A. F. with M. Besev, C. Brehm, Coll. Czech. Chem. Commun. 2005, 70, 1696
HETEROCYCLIC AND AROMATIC STRUCTURES
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
BERKELIC ACID
WHAT IS 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
BERKELIC ACID
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, J. Pospisil, Chem.
Eur. J. 2009, 15, 5956
A. F. with C. Müller, Chem. Commun. 2005, 5583but:
A. F. with C. Müller, J. Pospisil, Chem. Eur. J. 2009, 15, 5956
ASPERCYCLIDE B
ROSEOPHILIN
N
O
NH
MeO
Cl
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
N
O R
N
O
NH
MeO
Cl
O
NR
MeO
Cl+
CONCEPT
R
O
R
O
Pd+Lx
RNu
OH
N
R'
R
Nu
R
O
R'OR
O
R'O
Pd+Lx
RNu
OHR'O
STUDIES TOWARDS ROSEOPHILIN
RO
N
tBuMe2SiOBr
O
tBuMe2SiO ClCl Cl
tBuMe2SiO
O
COOMe
SO2Ph
S
1. NaI
2. AgBF4,
73%
tBuMe2SiO S
9-bromononanal
t-BuLi
84%
COOMe
SO2Ph
68%
, KH
STUDIES TOWARDS ROSEOPHILIN
83%
Dess-Martin
63%
TBAF, NH4F
85%
Pd(0) cat.
tBuMe2SiO
O
COOMe
SO2Ph
PhO2S OHO
O
OSiMe2tBu
PhO2S OHMeOOC
PhO2S O
OO
RO
N
STUDIES TOWARDS ROSEOPHILIN
PhO2S
BnO
N
OHO
PhO2S
Bn
NPhO2S O
OO
71%
2. SnCl4
1.
NMe2
Cl
70%
BnNH2, Pd(0) cat.
ROSEOPHILIN: THE MACROTRICYCLIC CORE
A. Fürstner, H. Weintritt, J. Am. Chem. Soc. 1997, 119, 2944.
2. PCC
1. Ca, NH3
R = H
R = Bn
RO
NPhO2S
BnO
N i-PrMe2ZnMgCl
t-BuOK
50%
BnO
N
RMO
N
N
O R
N
O
NH
MeO
Cl
O
NR
MeO
Cl+
THE HETEROCYCLIC SEGMENT
NMe2
ClX = Cl
X = OH
XOSiMe2tBu
O MeO OMe
52%
3. K2CO3, aq. MeOH/THF
2. TBDMSCl, imidazole
1. NaOH, MeOH,
OO
OMe
N
H
MeOOC
Cl
N
Ts
Cl
Br
1. Br2, HOAC, 90%
2. NaOH, H2O, 92% N
H
HOOC
Cl
Br
1. Cu-chromite
2. TsCl, NEt3, MeCN
67%
THE HETEROCYCLIC SEGMENT
62%
2. KH, TIPSCl, THF
1. K2CO3, MeOH
76%
PPTS, MeOH
Cl
Ts
NO
OMe
OSiMe2tBu
Cl
Ts
N
O MeO OMe
43-61%
3. Pd(PPh3)4 cat.,
2. ZnCl2, -78°C to 0°C
1. n-BuLi, -78°C
ClOSiMe2tBu
O MeO OMe
N
Ts
Cl
Br
Cl
(iPr)3Si
NO
OMe
FRAGMENT COUPLING: MODEL STUDIES
Cl
(iPr)3Si
NO
OMe
1. BuLi
2. CeCl3
3.
4. HCl
5. TBAF
N
O
K
N
ClHN
O
MeO
N
ClHN
O
N
HN
O
analogously:
FRAGMENT COUPLING (I)
CeCl2
ClSi(iPr)3N
O
MeO
O
N
K
no reaction
FIRST TOTAL SYNTHESIS OF ROSEOPHILIN
A. Fürstner, H. Weintritt, J. Am. Chem. Soc. 1998, 120, 2817
62%
N
O
NSi(iPr)3
MeO
Cl
SEMOHO
NSi(iPr)3
MeO
Cl
X
1. TBAF
2. aq. HCl
76 %
N
SEMO
N
O
N
MeO
Cl
. HCl
ANALOGUES
A. Fürstner, Th. Gastner, H. Weintritt, J. Org. Chem. 1999, 64, 2361
For biochemical investigations see: A. Fürstner, E. Grabowski ChemBioChem. 2001, 706
N
O
N
MeO
Cl
N
ClHN
O
MeO N
ClHN
O
N
HN
O
N
O
N
THE DICTYODENDRINS
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
N
N
MeOOC
HO OSO3Na
H
OH
OH
OH
HO
N
N
O
HO OSO3Na
H
O
OH
OH
Dictyodendrin A Dictyodendrin C
N
N
O
HO OSO3Na
H
OH
OH
OH
HO
Dictyodendrin B
N
N
HO OSO3Na
H
O
OH
OH
HO
Dictyodendrin E
ANALYSIS
REDUCTIVE HETEROCYCLE SYNTHESIS
O
Ph
NH
O
OEt
O
Cl
NO
OEt
Ph
H
Cl"low-valent" titanium
A. Fürstner et al., JOC 1994, 59, 5215; JACS 1995, 117, 4468; Org. Synth. 1999, 76, 142
Reagent Solvent Isolated Yield
TiCl3 / 2 C8K DME 93%
TiCl3 / Zn („instant“) THF 87%
TiCl3 cat., Zn, TMSCl MeCN 79%
Review: A. Fürstner, B. Bogdanovic, Angew. Chem. Int. Ed. Engl. 1996, 35, 2442.
NO2
OiPr
O
MeO
1. TosMIC, NaH
2.
MeO
Br
83%
NO2
OiPr
O
N
MeO
MeO
1. Fe/HCl, 96%
2. O
Cl
OMeOMe
89%
HN
OiPr
O
N
MeO
MeO
O
MeO
OMe
low valent titanium
pyridine, DME
93%
N
N
MeO OiPr
H
OMe
OMe
OMehv
Pd/C, C6H5NO2
MeCN
N
N
MeO OiPr
H
OMe
OMe
OMe
81%
ATTEMPTED SYNTHESIS OF DICTYODENDRIN B
N
NH
OMe
OMe
MeO OMe
N
NHCl4Sn
OMe
OMe
OMe
N
NH
OMe
OMe
OMe
MeO
MeON
NHSnCl4
OMe
OMe
OMe
MeO
2
MeO
O
Cl
SnCl4, DCE
N
NH
OMe
OMe
MeO OMe
O
MeO
2
N
NH
OMe
OMe
MeO OiPr
CHO
MeO
N
NH
OMe
OMe
MeO OiPr
HO
MeO
1. MeLi, then BuLi
2.N
NH
OMe
OMe
MeO OiPr
Br
NBS
69%
97%
OMe OMe OMe
N
NH
OMe
OMe
MeO OiPrBr
CDCl3, RT
OMe
TOTAL SYNTHESIS OF DICTYODENDRIN B
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
N
NH
OMe
OMe
MeO OiPr
HO
MeO
1. TPAP cat.
NMO, 66%
2. BCl3, 85%
ClS
O CCl3
O O3.
92%
N
NH
OMe
OMe
MeO O
O
MeO
SO
O
O
CCl3
1. BCl3, TBAI
2. Zn, HCOONH4
58%
N
NH
OH
OH
HO OSO3 NH4
O
HO
OMe OMe OH
TOTAL SYNTHESIS OF DICTYODENDRIN C
A. F. with M. M. Domostoj, B. Scheiper, J. Am. Chem. Soc. 2006, 128, 8087
N
N
O
HO OSO3NH4
H
O
OH
OH
Dictyodendrin C
N
N
MeO OSO3CH2CCl3
H
OMe
OMe
OMe
N
N
HO OSO3CH2CCl3
H
OH
OH
OO
1. BCl3 / TBAI
2. H2O2, MeCN
1. Zn/HCOONH4
57%
2. O2, MeOH
76%
DICTYODENDRIN E
N
NH
OMe
OMe
MeO OiPr
MeOMgCl
MeO
MeO
B
MgCl
BMeO
MeO
Pd(OAc)2, S-Phos
90%
OMe
N
NH
OH
OH
HO OSO3NH4
HO
O
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
1. BCl3
2. Cl3CCH2OSO2Cl
4. Zn, HCOONH4
5. DDQ
3.. BCl3, TBAI
SnMe3
MeO
BF3 K
MeO
B
MeOO
O
or:
or:N
NH
OMe
OMe
MeO OiPr
H
various palladium sources
OMe
N
NH
OMe
OMe
MeO OiPr
BrOMe
DICTYODENDRIN ANALOGUES
C38
O3
C36
C35
C37
C34
C15
C32
O1
C33
C2
N1
C3
C1C13C14
C20C4
C12
C19 C8
O2
C16
C9
N2
C21
C7C11
C10
C18
C24
C17
C5
C22
C6
C23
C26
C25
C27
C30
C28
C29
O4
C31
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
O O
O
OH
HO
O
OH
HO
O
O O
OH
HO
O
O
1 2
3
O
OH
HO
O
O
O
4
C17
O1
O16 C2
C1
O1
C3
O5
O9
H5
C8
H7
C12 C9 O7O5
iv
ii
iii
i
Superposition of the X-ray structures of citreofuran (4, green) and culvularin (1, blue) in an orthographic projection
A. Fürstner et al. JOC 2003, 68, 1521
X-ray structure of citreofuran
A. Fürstner et al. JOC 2003, 68, 1521
CITREOFURAN
A. F. with A.-S. Castanet, K. Radkowski, C. W. Lehmann, J. Org. Chem. 2003, 68, 1521.
TOTAL SYNTHESIS OF CITREOFURAN
(-)-BALANOL
inhibitor of proteinkinase C (PKC) with IC50 values in the low nanomolar range
Balanol
OH
HO OO
HO
OH
O
OH
OH
N
O
H
N
+
OR
RO OO
RO
OR
O
OH
OR2
OH
N
R1
N
HO
FORMAL TOTAL SYNTHESIS OF (-)-BALANOL
A. Fürstner, O. R. Thiel, J. Org. Chem. 2000, 65, 1738
87%
Ph
PCy3
Ru
PCy3
Cl
Cl
55% (over both steps)
2. p-BnOC6H4COCl, Et3N
1. H2, Pd/C
91%
Mitsunobu
quant.
Boc2O, Et3N
94%
allylamine, 70°C
95%
NaH, BnBr
ee > 99%
Ti(OiPr)4 cat.
(D)-(-)-DET, tBuOOHOH OR
O
R = H
R = Bn
N
R
OH
BnO
R = H
R = Boc
N
Boc
OH
BnO
N
Boc
N3
BnO
OBn
OH
N
Boc
N
HO
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
APORPHINE ALKALOIDSOMe
MeO
MeONH
OMe
MeO
MeONH
HN
OMe
OMe
MeO
from Polyalthia bullata
from Gutteria ouregon
Polyalthia bullata
OMe
MeO
MeO
Br
X
X = H
X = I
OMe
MeO
MeO
Br
N
O
O
OMe
MeO
MeO
NR2
Br
R, R = phthalimido
R = H
OMe
MeO
MeONH
OMe
MeO
MeO
NR2
O
OMe
MeO
MeO
NR2
Br
N
O
O
1. Pd(0),
2. Crabtree's catalyst, H2
B(OH)2
O
57%
Pd(O)
94%
I2, Hg2O
81%
1. CBr4, PPh3, 88%
2. DBU, 79%
InCl3
87%
H2NNH2quant.
CuI, CsOAc
71%
from Gutteria ouregon
OMe
MeO
MeONH
HN
OMe
OMe
OMe
CuCl2.2 H2O
tBuNH2, MeOH
86%
isolated from Polyalthia bullata
A. Fürstner, V. Mamane,
Chem. Commun. 2003, 2112
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
OH
HO
O
O
TMC-69
N
OH
HO
O
O
TMC-69-6H
17
N-HYDROXYPYRIDONES: TMC-69 AND 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
A. F. with F. Feyen, H. Prinz, H. Waldmann, Angew. Chem. Int. Ed. 2003, 42, 5361;
Tetrahedron 2004, 60, 9543
N
H
O
O
O
O
N
H
HO
OX
O
O
AcO
O
O
Cl
Cl
N
TBSO
OTBS
O
O
X = Cl
X = H
N
TBSO
OTBS
O
O
N
TBSO
OTBS
O
N
H
HO
O
O
phenylacetonitrile
50%
H2, Pd/C
97%
Pd(0), 65% (96% ee)
TBSCl, Et3N, 78%
Me2CuLi
S
NN
NN
Ph
O O
LiHMDS, 69% (over 2 steps)
1. H2, Pd/C
2. TBAF, 69% (over 2 steps)
2. (pyridine)MoO3(hmpa)
3. EDTA-Na
1. HN(TMS)2, TMSCl
71%N
OH
HO
O
O
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
EPOHELMIN B
TOTAL SYNTHESIS OF
EPOHELMIN B
A. F. with A. Korte, Chem. Asian J. 2008, 3, 310
PRODIGIOSINS
for a review see: A. Fürstner, Angew. Chem. Int. Ed. 2003, 42, 3582
immunosuppressive – synergistic action with cyclosporin and FK506
N
NN
H
H
MeO
NN
H
MeO
NH
H
NMeO
NH
N
N
N
NMeO
H
H
JACS 1998, 120, 8305 JOC 1999, 64, 8275Angew. Chem., in press
Agar plate with red colonies of Serratia marescens
Raphael‘s fresco „Mass of Bolsena“ in the Vatican (1508)
Orvieto Cathedral
the producing red bacteria are likely 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
THE PRODIGIOSIN ALKALOIDS
for a review on the chemistry and biology of the prodigions see:
A. Fürstner, Angew. Chem. Int. Ed. 2003, 42, 3582
immunosuppressive – synergistic action with cyclosporin and FK506 in vivo
NN
H
MeO
NH
Streptorubin B
N
NN
H
MeO
ON
R
H
R
NHH
CYCLOISOMERIZATION OF ELECTRON DEFICIENT ENYNES
NTs
O
79%
toluene, 50°C, 66h
PtCl2 (5 mol%)N
Ts
O
85%
toluene, 50°C, 66h
PtCl4 (5 mol%)N
Ts
COOMe
MeO
NTs
O
NN
H
MeO
NH
Streptorubin B
NTs
O
NN
H
MeO
O
2. H2O 55%
1. KAPA
3. Bu3SnH, AIBN,
2. PhOC(S)Cl, 95%
1. LiAlH4, 96%
94%
HBF4.Et2O
Bu3SnH, Pd(0) cat.
NTs
NN
H
NTs
O
TOTAL SYNTHESIS OF STREPTORUBIN B
A. Fürstner, H. Szillat, B. Gabor, R. Mynott
J. Am. Chem. Soc., 1998, 120, 8305.
BUTYLCYCLOHEPTYLPRODIGIOSIN:
RETROSYNTHETIC ANALYSIS
N
NN
H
H
MeO
NH
O(HO)2B
N
Boc
N
MeO O
H
RETROSYNTHETIC ANALYSIS
NH
O
NH
N Pd OR N OR
K. Narasaka et al., Bull. Chem. Soc. Jpn. 2002, 75, 1451
R1
NO
R2O
R1
NPdLx
O
O
R2
NR1 NR1
H
Pd(0)
A B C D
O OAc
OO
MeO
NO
O
C6F5
NH
N
R
R = H
R = Boc
4
910
1. Dibal-H, 97%
2. Ac2O, Et3N, 97%
OO
MeO
NaH, Pd(0) cat., 74%
1. aq. DMSO,
2. H2NOH
3. F5C6COOCl
95%
Pd(OAc)2 cat.
(o-tolyl)3P cat., Et3N
54%
KAPA
65%
Boc2O,
DMAP, 69%
N
Boc
NBoc
O
NH
N
MeO O
H
N
N
MeO OTf
H
N
Boc
(HO)2B
NBoc
O
NBoc
1. BH3, H2O2
2. Dess-Martin
65%
1. Ph3P=CHCH2CH2CH3
2. H2, Crabtree
70%
CAN
CHCl3 / H2O / DME
65%
N O
MeO
H
aq. NaOH, DMSO
69%
Tf2O
79%
N
NN
H
H
MeO
Pd(0) cat., LiCl
70%
A. Fürstner, K. Radkowski, H. Peters,
Angew. Chem. Int. Ed. 2005, 44, 2777;
Chem. Eur. J. 2007, 13, 1929
BUTYLCYCLOHEPTYLPRODIGIOSIN
HN
N
NH
MeOO S
RN
N. N. Gerber, Tetrahedron Lett. 1970, 809.
Nonylprodigiosin
H
NMeO
NH
NH
NMeO
NH
N
Suzuki
alkylation
alkylation
condensation
RCM / hydrogenation
NONYLPRODIGIOSIN
57%
Na2CO3, LiCl
Pd(0) cat.
N
N
N
MeO
H
H
N
Boc
(HO)2B
58%
2. B(OMe)3
N
Li
1.
92%
Boc2O, DMAP
R = Boc
R = H
N
R
93%
Tf2O
NH
N
O
H
MeO
N
N
MeO
O
H
S CF3
O
O
N
NH
N
MeO
H
H
Cl
ClCl
N
N
N
MeO
H
HH
N
NH
HO
HN
Me
N
N
N
MeO
H
HH
Ph
PCy3
Ru
PCy3
Cl
Clcat.
65%
RhCl(PPh3)3 cat., H2
73%
Cl
Nonylprodigiosin.HCl(E)-isomer only !
A. Fürstner, J. Grabowski, C. W. Lehmann, J. Org. Chem. 1999, 64, 8275
I
II
III
IV
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
IVI
II
N
NH
O
MeO
HN
NH
O
MeO
HN
NHMeO
H
Biological Evaluation:
Cleavage of Supercoiled DNA
in the presence of Cu(II)
A. Fürstner, E. J. Grabowski, ChemBioChem 2001, 2, 706
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
NN
H
N O
HH
NN
H
N O
HHH
H
2 X
N
H
HN
Cl
X
N
OR1
Isolation from the stem bark of Oncinotis nitida by
M. Hesse et al., Helv. Chim. Acta 1968, 51, 1813
ASYMMETRIC HYDROGENATION OF PYRIDINES
NO
N R
O
N
O
N R
OH
X
H2
Pd/CN
O
N R
O X
X
N R
X
N R N RPd/C
HX H2
NHO
O
H2
H H2 H
F: Glorius et al., Angew. Chem. Int. Ed. 2004, 43, 2850
B. Scheiper, F. Glorius, A. Leitner, A. Fürstner, Proc. Natl. Acad. Sci. USA 2004, 101, 11960
NCl Cl
NHO
O
BrMgOBn
NCl OBn NO
N
O
OBn
N
H
OHN
N
H
N O
HNs
OH
NN
H
N O
HR
R = Ns
R = H
NN
H
N O
HH
Ph
Ru
PCy3
PCy3
Cl
Cl
ee = 94%
Fe(acac)3 cat.
83%
CuI cat.
90%
H2 (120 atm)
Pd(OH)2/C cat.
78%
NBr
N O
HNs
K2CO3, NaI, 73%
1. Swern, 81%
2. Ph3P=CH2, 82%
HSCH2COOH
LiOH, 84%
then H2
76%
(-)-Isooncinotine
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)
MUSCOPYRIDINE
N NM M
N XX
NCl OTf
Cl N
N
BrMg
[Fe] cat.+ +
N6-heptenyl-MgBr
[Fe] cat.
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)
N
N
PhPCy3
Ru
PCy3
Cl
Cl
HCl/Et2O
then
+
0.006 M N
H
Cl
H2 (50 atm)
then aq. NaHCO3
N
57% overall
0.13 M
ADMET
polymer
„INTEGRATED„ SYNTHESIS OF MUSCOPYRIDINE
HIGHLY CYTOTOXIC PHENANTHROQUINOLIZIDINE-
AND PHENATHROINDOLIZIDINE ALKALOIDS
OMe
MeO
B(OH)2
I
Br
MeO
NBoc N
Boc
MeO
OMe
MeO
PtCl2 cat.
MeO
OMe
MeO
NBoc
97%
MeO
OMe
MeO
N
Cryptopleurine
A. Fürstner, J. Kennedy,
Chem. Eur. J. 2006, 12, 7398AntofineMeO
OMe
MeO
N
H
TylophorineMeO
OMe
MeO
N
H
OMe
FicuseptineMeO
N
H
O
O
MeO
I
Br
OMe
MeO
MeO
X
B(OH)2
OMe
MeO
X = Br
X = I
(dppf)PdCl2 (5 mol%)
LiCl, Na2CO3, DME/H2O
70%
BuLi
then I2
82%
N
Boc
OMe
B Li
MeO
OMe
MeO
N
Boc
MeO
OMe
MeO
N
MeO
OMe
MeO
RN
(dppf)PdCl2 (5 mol%)
THF, reflux
82%
PtCl2 cat.
toluene, 60°C
97%
aq. HCHO
HCl, EtOH
67%
A. Fürstner, J. W. J. Kennedy, Chem. Eur. J. 2006, 12, 7398
CRYPTOPLEURINE
ERYPOEGIN AND ISOSOJAGOL
A. F. with E. Heilmann, P. W. Davies, Angew. Chem. Int. Ed. 2007, 46, 4760
2. 9-OMe-9-BBN, PdCl 2(dppf) (3%)
1. BuLi
77%
MeO
MeO
OMe
PdCl2(dppf) 3%
Natriumacetylid, B(OMe) 3MeO
MeO
OMe
Br
3. Br
TBDMSO
OMe
OTBDMS
OMe
MeO
MeO
MeO MeO
MeO
OMe
OR
OMe
R = OTBDMS
R = H
66%
Lindlar
74%
TBAF
95%
COMBRETASTATIN A4
A. Fürstner, K. Nikolakis, Liebigs Ann. 1996, 2107
ALKYLRESORCINOLS
HO
OH
OH
HO
HO
OH
OH
OH
OH
OH
OH
HO
OH
OHOH
HO
Na
B B
OMe
MeO
I2
B BB
RO
OR OR
OR
R = Me
R = H
Na
LiC CLi, THF/HMPA, 72%
9-BBN (3 eq)., THF
1. MeOH/HOAc (99:1)
2. NaOMe (2 eq.)
OTfMeO
OMe
PdCl2(dppf) cat.
62%
9-Iod-9-BBN, hexane, 98%
A. Fürstner, G. Seidel, J. Org. Chem. 1997, 62, 2332
isolated from Grevillea robustaisolated from Grevillea striata
The Turrianes
Hakea trifurcata
DNA-cleaving Alkylresorcinols from
Robustol
HO
OH
OH
OH
OMe
OH
OH
OHOMe
OH
OH
OH O
OH
OH
OH
oxidative
C-O-coupling
oxidative
C-C-coupling/
O-methylation
ALKYLRESORCINOLS: THE TURRIANES
TOTAL SYNTHESIS OF TURRIANES
Br
OH
OH
OH
O
Br
OPMB
OPMB
TBDPSO
CHOMeO
HO
OPMBMeO
MeO
ON
NO
O
OPMB
OMeOMe
O
O
O
TBDPSO
PMB
PMB
Mg, THF, reflux
84%
+
Vanilline
O
OPMB
OMeOMe
O
O
OPMB
PMB
O
OPMB
OMeOMe
O
O
OPMB
PMB
TOTAL SYNTHESIS OF TURRIANES
OMe
OR
OR
OROMe
OR
OR
ORRu
PCy3
PCy3
Cl
Cl
Ph
cat.
84%
E : Z = 6.9 : 1
but the natural product is (Z)-configured !
A. Fürstner, F. Stelzer, A. Rumbo, H. Krause, Chem. Eur. J. 2002, 8, 1856.
turrianes are efficient DNA-cleaving agents under oxidative conditions;
for the total synthesis and biological evaluation see:
OMe
OR
OR
OR
76%
F3CC6H4OH
Mo(CO)6 cat.
OMe
OR
OR
OROMe
OR
OR
OR
Lindlar
96%
R = PMB
R = H
BF3, EtSH
54%
or:
(tBuO)3W CCMe3 cat.
61%
TOTAL SYNTHESIS OF TURRIANES
Alstoniline
NN
H
MeO
O
MeO
Villagorgine B
NN
H
N
NH
Flavocorynanthyrine
NN
H
Sempervirine
NN
H
Flavopereirine
NN
H
Indolopyridocolin
NN
H
O
O
O
NH2
NCl
OH
ClO
O
O
NH
ON
OO
H
NN
H
NN
ClO4
89%
Ti-graphite
57%
H
NN
OH
Cl
HClAc2O
77%
Indolopyridocolin
Fürstner, A. Ernst, H. Krause, A. Ptock, Tetrahedron 1996, 52, 7329
Lamellarin O Dimethylether Lukianol A
3. BBr3
2. Ac2O, NaOAc1. KOt-Bu, H 2O
K2CO3, acetone
MeOC6H4COCH2BrTi-graphite
pyridine, DMAP
Cl
O OMe
O2.
1. H2, Pd/C
2. NH2OH1. BF3
.Et2O
OH
O
O
HO OH
NN
OMeMeO
O
OMe
O
OMe
N
OMeMeO
HO
OMe
ONH
OMeMeO
O
OMe
OO
N
OMeMeO
OO
OMeMeO67%
70%
52%
91%
59%
Lamellarin Q Dimethylether
A. Fürstner, H. Weintritt, A. Hupperts, J. Org. Chem. 1995, 60, 6637
71%
Camalexin
N S
O
NX2N
STMS
N
S
N
H
NH
O
SN
OHX = O
X = H
o-NO2C6H4COCl
83%
H2, Pd/C
98%
HCOOH, Ac 2O
87%
TiCl3, Zn
"Instant"
A. Fürstner, A. Ernst, Tetrahedron 1995, 51, 773
NH
HN
NH
HNO
O
1. TiCl3, Zn, THF, ("Instant")
2. EDTA
75%
(+)-Aristotelin
A. Fürstner, A. Hupperts, A. Ptock, E. Janssen, J. Org. Chem. 1994, 59, 5215
CARBOHYDRATES AND GLYCOLIPIDS
time
Conduritol F
RCM
R = H
R = Bn
OR
OR
RO
RO
D-glucose
OH
OH
HO
HO
O
OH
OBn
OBn
BnO
BnO
PCy3
RuCl
Cl
Ph
PCy3
MoO
O N
PhF3CF3C
F3CF3C
R = mesityl
PCy3
RuCl
Cl
Ph
RNNR
A. Fürstner et al., Tetrahedron2000, 56, 2195.
catalyst yield
60h 32% (GC)
1h 92%
2h 89%
IPOMOEASSIN
D. Kingston et al., J. Nat. Prod. 2005, 68, 487; Nat. Prod. Res. 2007, 21, 872
US 2006/0264383 A1
Ipomoea squamosa
RETROSYNTHETIC ANALYSIS
C14
O7
C11
C12
C10
C13
C9
C8
C7
O3
C6
O1
C27 C1
C26
C5C25
O2O4
C2
C3
C24
C4
C28
O9
O6 O5
C19
C29
C15
C30
O8
C16
C18
C17O10
C23O11
C20
C21
C22
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)
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
WOODROSIN I
Ipomoea tuberosa L.
O
O
O
OHHO
HO
O
O
O
OHO
HO
OH
HOHO
O
OO
OO
OH
O
O
O
O
OOHO
OO
O
OO
HO
RO
Ph
OO
O
BnOBnO
OBn
O NH
OO
BnOO O
O CCl3
OO
BnOO O
O
OBn
BnOBnO
O
OO
Ph
ROO
OO
O
R = PMB
R = H
O
O
O
O
BnO
BnO
O
O
O O
O
O
O
Cl
O
OBn
CCl3
NH
no reaction
TMSOTf, 62%
DDQ, 71%
O
OO
HO
RO
Ph
OO
O
BnOBnO
OBn
O NH
OO
BnOO O
O CCl3
O
O
O
O
BnO
BnO
O
O
O O
O
O
O
Cl
O
OBn
CCl3
NH
O
O
O
BnO
BnO O
O O
O
O
O
O
OBn
O
Cl
OBn
BnOBnO
O
OO
Ph
OOH
OO
O
no reaction
TMSOTf cat., 84%
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
cat.
Ph
Ru
PCy3
PCy3
Cl
Cl
OO O
O
O
O O
Cl
OBn
BnOBnO
O
OO
Ph
OHO
OOO
OBn
OBnO
BnO
O
O
O
94%
1.
O
O
O
OHHO
HO
O
O
O
OHO
HO
OH
HOHO
O
OO
OO
OH
O
O
O
O
OOHO
OO
O NHO
OBnO
O O
O CCl3
2. deprotection, 84%WOODROSIN I
O
O
O
BnO
BnO O
O O
O
O
O
O
OBn
O
Cl
OBn
BnOBnO
O
OO
Ph
OHO
OOO
E : Z = 9 : 1
60%HOTf cat.
TRICOLORIN A
O
O
HO
HO
OH
O
O
O
O
O
HOHO
O
O
O
O
O
HO
HOO
O
Tricolorin A OH
O
O
OH
RO
ROO
RO
RO
O O
O
O
O
OH
RO
ROO
RO
RO
O O
O
D-glucose, D-fucose
RCM
O
O
RO
RO
O
O
O
O
O
X
OR
67
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
OH
R = H
R = Ac
OO
RO
O
RO
PhO
O
O
O
O
OO
AcO
O
AcO
Ph
NH
CCl3O
OO
OH
O
O
O
O
O
O
O
O
PhO
O
OH
O
O
PhO
O
O
O
O
O
BF3.Et2O
82%
KOMe, MeOH
71%
6-heptenoic acid
DCC, DMAP
71%
Ru
PCy3
RCl
Cl
PCy3
1.
2. H2, Pd/C
77%
Tricolorin A
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
OO
OH
O
O
O
O
O
O
O
O
Ph Ph
O
O
O
O
O
O
O
O
OH
OO
n
OO
OH
O
O
PhO
O
O
O
O
O
OO
OH
O
O
O
O
O
O
O
PhH
O
1. RCM
2. H2, Pd/C
77% 76% 76%
A. Fürstner, T. Müller, J. Am. Chem. Soc. 1999, 121, 7814
TOTAL SYNTHESIS OF TRICOLORIN G
A. Fürstner, T. Müller, J. Am. Chem. Soc. 1999, 121, 7814
OO
OH
O
HO
PhO
O
O
O
O
BnO
O
O
O
O
OPh
O
OH
OO
BnO
BnO
OAc
O
O
NH
CCl3
BnO
BnO
O
O
O
O
O
O
BnO
O
O
O
O
O
O
H
Ph
O
O
OBnO
BnO
BnO
O
O
O
O
OPh
O
O
OO
(Bu3Sn)2O
BnBr, 57%
OAc
OBnO
BnO
BnO
O
O
O
O
OPh
O
O
OO
1. KOMe, MeOH
2. 6-heptenoic acid, DCC
84%
1. Grubbs catalyst
2. H2, Wilkinson
Tricolorin G
RCAM: A. Fürstner, G. Seidel, Angew. Chem. Int. Ed. 1998, 37, 1734
OO
O
HOHO
OH
HO
OHO
OH
O
O
Sophorolipid Lactone
RCAM "Lindlar"
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
OO
OH
PMBOPMBO
OPMB
RO
RO
ORO
O
OO
O
RORO
OR
O
OO
O
RORO
OR
RO
ORO
OR
O
O
OO
O
HOHO
OH
HO
OHO
OH
O
O
NNN
Mo
R
AcO
AcO
OO
O
BrR
AcO
AcO
OO
O
OO
O
PMBOPMBO
OPMB
R = p-MeOC6H4-
AgOTf, lutidine
89%
cat.
CH2Cl2/toluene
78%
1. Lindlar, H2, quant
2. DDQ, 93%
CYCLOVIRACIN B1
26 = 64 possible isomers (!)
M. Tsunakawa et al., J. Antibiot. 1992, 45, 1467 and 1472.
O
O O
O
O O
OOO
O
HO
O
O
O
O
OH
OH
HO
OH
OH
HO OH
OHHO
OH
OMe
OH
OMe
OMe
HO
HO
OH
OH
3
19
25
3'
17'
23'
O
O O
O
O O
OOO
O
HO
O
O
O
O
OH
OH
HO
OH
OH
HO OH
OHHO
OH
OMe
OH
OMe
OMe
HO
HO
OH
OH
3
19
25
17'
23'
O
O O
O
O O
OO
OBn
OBn
BnO OBn
OBnBnO
OX
O(NH)CCl3
O
BnO
OMe
BnO
BnO
BnO
M
Y
O
O
O
O
OBn
OBn
OBn
OMe
OBn
OMe
OBn
OBn
Cycloviracin B1
O O(NH)CCl3
OBn
OBnBnO
HO
HO
O OH
X
C-17'
C-17
SYNTHESIS OF THE KEY BUILDING BLOCK
O
O
O
OBn
O
BnO OBn
HO
OHO OTBDPS
HO
OtBuO OH
O
OtBuO OHOLi
OtBu
61%
O
O
1. (PCy3)2Cl2Ru=CHPh
2. H2, Pd/C
75%
[(R)-BINAP.RuCl2]2.NEt3 cat.
H2 (15 atm), MeOH, 70°C
88%, ee = 98%
TEMPLATE DIRECTED CYCLODIMERIZATION
A. Fürstner, M. Albert, J. Mlynarski, M. Matheu, J. Am. Chem. Soc. 2002, 124, 1168.
O
OBn
O
BnO OBn
OHO OTBDPSHO
O
OBn
O
OBnBnO
O OHTBDPSOOH
K
NN
Cl
Cl
O
O O
O
O O
OO
OBn
OBn
BnO OBn
OBnBnO
OR1
R2O
KH, DMAP
71% isolated yield
STEREOCHEMICAL
ASSIGNMENT
106.4 ppm
O
HO
HOHO O
O
O
O
O
O OHOH
OH
O
OH
OR
RO
RO
106.4 ppm
(CH2)13OR1
O
RORO
RO O
O
O
O
O
O OROR
OR
O
R2O(CH2)13
(CH2)13OR1
O
RORO
RO O
O
O
O
O
O OROR
OR
O
R2O(CH2)13
(R)
(S)
(R)
(S)
R1 = H, R2 = TBDPS, R = H: 105.3 ppm
R1 = R2 = R = H: 106.4 ppm
R1 = H, R2 = TBDPS, R = H: 100.3 ppm
Cycloviracin B1
O
O O
O
O O
OO
OBn
OBn
BnO OBn
OBnBnO
STBDPSO
NPh
NN
N
O
O
HH
H
H
H
H
O
O O
O
O O
OOTBDPSO
O
O
O
OOBn
OBn
OBn
OBn
BnO OBn
OBnBnO
OBn
OMe
OBn
OMe
OBn
OBn
OO
OBn
MeO OBn
OBnO O
OBn
OMeBnO
BnO
O
LiHMDS, DME, 61%
A. Fürstner, J. Mlynarski, M. Albert, J. Am. Chem. Soc. 2002, 124, 10274.
Zn
OBn
NHTf
NHTf
O
O
BnO
OMe
BnO
BnO
CCl3
NH
O
O O
O
O O
OOO
O
O
O
OOBn
OBn
OBn
OBn
BnO OBn
OBnBnO
OBn
OMe
OBn
OMe
OBn
OBn Zn
OBn
Ti(OiPr)4
O
O O
O
O O
OOHO
O
O
O
OOBn
OBn
OBn
OBn
BnO OBn
OBnBnO
OBn
OMe
OBn
OMe
OBn
OBn
BnO
81%
Cycloviracin B1
1.
2. H2, Pd/C, 88%
Zn
OBn
NHTf
NHTf
O
O
BnO
OMe
BnO
BnO
CCl3
NH
(3R,19S,25R,3'R,17'S,23'R)-
O
O O
O
O O
OOO
O
O
O
OOBn
OBn
OBn
OBn
BnO OBn
OBnBnO
OBn
OMe
OBn
OMe
OBn
OBn Zn
OBn
Ti(OiPr)4
O
O O
O
O O
OOHO
O
O
O
OOBn
OBn
OBn
OBn
BnO OBn
OBnBnO
OBn
OMe
OBn
OMe
OBn
OBn
BnO
81%
1.
2. H2, Pd/C, 88%
A. Fürstner, M. Albert, J. Mlynarski, M. Matheu, E. DeClercq, J. Am. Chem. Soc. 2003, 125, 13133
TOTAL SYNTHESIS OF
MACROVARICIN D (BA-2836-4)
O
O
OMe
OHOH
HO
O O
O
OH
OHOHO
OH
O OHOH
HO
O
O
O
MeO
OHHO
OH
O
O
MeO
OHHO
OH
OO
(3R) (17S) (23R)
O
HOHO
HO
O
O
O
HOHO
HO
O
OH
O
O
OH
OHOH
HO
OH
O
O
O
OH
OHOH
HO
O
O
OH
OHOH
O
HOHO
HO
O
O
OH
OO
OH
O
1925
3
17
23
Macroviracin D
Cycloviracin B1
NHTf
NHTf
Zn
OBn
9
O
BnOBnO
BnO
AcO
O
CCl3
NH
OH
TBDPSO OtBuO
O
O
OBn
OBnOBn
R1O
TBDPSO OtBuO
O
O
OBn
OBnOBn
R1O
O OtBuO
O
O
OBn
OBnOBn
R1O
OH
OBn
OtBuO
NHTf
NHTf
, cat.
Zn
OBn
29
TMSOTf, 91%
1. TBAF, 90%
2. PCC
R1 = Ac
analogously for R1 = Bn
TOTAL SYNTHESIS OF MACROVARICIN D (BA-2836-4)
O
O
OBn
OBnOBn
R1O
OH
OBn
OtBuO
O
O
OBn
OBnOBn
BnO
O
BnOBnO
BnO
OR1
O
OBn
OtBuO
18 R1 = Ac
19 R1 = H
O
O
OBn
OBnOBn
AcO
O
BnOBnO
BnO
OTBDPS
O
OBn
OR1O
21 R1 = tBu
22 R1 = H
O
O
OBn
OBnOBn
BnO
O
BnOBnO
BnO
OBn
O
OBn
OR1O
16 R1 = tBu
17 R1 = H
OBnOBnO
BnO
TBDPSO
O
CCl3
NH
b)
d)
f)
TMSOTf, 88%
R1 = Bn
TMSOTf, 58%
R1 = Bn
TMSOTf, 79%
R1 = Ac
OBnOBnO
BnO
AcO
O
CCl3
NH
OBnOBnO
BnO
BnO
O
CCl3
NH
TOWARD MACROVARICIN D
O
BnOBnO
BnO
O
OAc
O
O
OBn
OBnOBn
BnO
O
O
OBn
OBnOBn
O
BnOBnO
BnO
O
O
OBn
TBDPSO
OBn
O
COOtBu
19 + 22
O
BnOBnO
BnO
O
OH
O
O
OBn
OBnOBn
BnO
O
O
OBn
OBnOBn
O
BnOBnO
BnO
O
O
OBn
O
OBn
O
O
Yamaguchi
86%
1. TBAF
2. TFA
82%
O
BnOBnO
BnO
O
OAc
O
O
OBn
OBnOBn
BnO
O
O
OBn
OBnOBn
O
BnOBnO
BnO
O
O
OBn
HO
OBn
O
COOH
1. Yamaguchi, 89%
2. NH3, MeOH, 86%
TOTAL SYNTHESIS OF MACROVARICIN D (BA-2836-4)
TOTAL SYNTHESIS OF MACROVARICIN D (BA-2836-4)
A. F. with J. Ruiz-Caro, J. Mlynarski, Chem. Eur. J. 2004, 10, 2214
O
BnOBnO
BnO
O
OH
O
O
OBn
OBnOBn
BnO
O
O
OBn
OBnOBn
O
BnOBnO
BnO
O
O
OBn
O
OBn
O
O
O
RORO
RO
O
O
O
RORO
RO
O
OR
O
O
OR
OROR
RO
OR
O
O
O
OR
OROR
RO
O
O
OR
OROR
O
RORO
RO
O
O
OR
OO
OR
O
R = Bn
R = HH2, Pd(OH)2 cat.
O
O
OBn
OBnOBn
BnO
O
BnOBnO
BnO
OBn
O
OBn
OH1O
Yamaguchi, 74%
O
n-Bu2BOTf, Et3N, 63%
N
O
O
O
Ph Me
OH
N
O
O
O
Ph
O O
OBn
OBn
NH
CCl3
AcO
BnO
TMSOTf, MeCN, 45%
O O
OBn
R1O
Me
O
BnO
OBn
R2O
R1 = auxiliary, R2 = Ac
R1 = R2 = H
LiOH, H2O2
aq. THF, 79%
O O
OR
OO
Me
O
O
RO
OMe
O
RO
OR
OR
OR
NN
Cl
Cl
KH, DMAP, CH2Cl2
54%
R = Bn
R = H
H2, Pd(OH)2
MeOH, quant.
likely via templated
cyclodimerization at a K+ center
Glucolipsin
STRUCTURE DETERMINATION OF GLUCOLIPSIN
VIA TOTAL SYNTHESIS
O O
OR
OO
Me
O
O
RO
OMe
O
RO
OR
OR
OR
O O
OR
OO
Me
O
O
RO
OMe
O
RO
OR
OR
OR
O O
OR
OO
Me
O
O
RO
OMe
O
RO
OR
OR
OR
diastereomers prepared analogously for structure determination purposes:
A. F. with J. Ruiz-Caro, H. Prinz, H. Waldmann, J. Org. Chem. 2004, 69, 459
O O
OH
OO
Me
O
O
HO
OMe
O
HO
OH
OH
OH
O
O
OH
OH
O
O
OH
OH
OMe
OMe
OH
OH
O O
OH
OO O
O
HO
O
O
HO
OH
OH
OH
O
HO
O
HO
HO
HO
OMe
O
O
O
OHHO
HO
O
O
O
OHO
HO
OH
HOHO
O
OO
OO
OH
O
O
O
O
OOHO
OO
Cycloviracin B1
J. Am. Chem. Soc. 2003, 125, 13132
J. Am. Chem. Soc. 2002, 124, 10274
J. Am. Chem. Soc. 2002, 124, 1168
Angew. Chem. Int. Ed. 2002, 41, 2097
Chem. Eur. J. 2003, 9, 307 and 320
Woodrosin I
Glucolipsin A
J. Org. Chem. 2004, 69, 459
O
O
HOHO
HO
HO
HO
O
OO
OHO
HOO
O
H
O
O
HO
HO
OH
O
O
O
O
O
HOHO
O
O
O
O
O
HO
HOO
O
Tricolorin A Tricolorin G
J. Am. Chem. Soc. 1999, 121, 7814
OO
O
HOHO
OH
HO
OHO
OH
O
O
Sophorolipid Lactone
J. Org. Chem. 2000, 65, 8758
O
HOHO
HO
O
O
O
HOHO
HO
O
OH
O
O
OH
OHOH
HO
OH
O
O
O
OH
OHOH
HO
O
O
OH
OHOH
O
HOHO
HO
O
O
OH
OO
OH
O
3
17
23
Macroviracin D
Chem. Eur. J. 2004, 10, 2214
HO O
HO
O
OR
OR
OHO
HOHO
HO
HO
O O
OR
(1) R = Ac "Caloporoside"
(2) R = H
O
HOHO
HO
O
OH
HO
OHO
(3)
b-MANNOPYRANOSIDES
[e]
[d]
[c]
[b]
[a]
OTf
OO
O
OR
OO
O
OR
B
OR
R = SiMe2tBu
R = H
+ CH2=CH(CH2)11CH2MgBrO
R = SiMe2tBu
R = H
OBnOBnO
OBn
O
OO
O
O
[f]
O
OHO
HO
HO
HOHO O
OH[g,h,i]
[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
10
9
8
7
4
OO
O
tBuMe2SiO
O
R = H
R = SiMe2t-Bu
OTf
OO
O
R = SiMe2t-Bu
R = H
[b]
[c]
[e]
5
6
RO
OBnO
BnO
RO
[a]
[d]
[a] 13-tetradecenylmagnesium bromide, CuCl(COD) (10 mol%),
THF, -78°Cr.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.),
KBr (1.1 eq.), PdCl2(dppf) (2.5 mol%), THF, reflux, overnight,
86%; [d] (i) BnOH, NaH, DMF, 3h, r.t., 92%; (ii) BnBr, K2CO3,
DMF, 4h, reflux, 93%; [e] TBAF, THF, r.t., 89%.
CALOPOROSIDE
D-mannoD-gluco
opening
epoxide
Suzuki reaction
RO O
RO
O
O
OR
ORO
RORO
RO
RO
O O
O O O
14
11
O
BrAcO
AcOAcO
OAc
O
OO
RORO
OR
OEt
12 R = Ac
13 R = Bn
O
OH
BnOBnO
OBn
OH
[a]
[b]
[c,d]
[a] Bu4NBr, s-collidine, EtOH, 85%; [b] BnBr, KOH, THF, 81%; [c]
2N HCl, THF; [d] K2CO3, MeOH, 1h, r.t., 87% over two steps
[b][a]
15 R = C(O)CH2Cl
O
RO
BnOBnO
OBn
OR
O
O
BnOBnO
OBn
Br
O
Cl
14
16
[a] (ClCH2CO)2O, pyridine, -20°-10°C, 1.5 h, 85%; [b]
HBr/HOAc, CHCl3, 0°Cr.t., 3 h, 95%.
CALOPOROSIDE
22 (R = 3,4-dimethoxybenzyl)
2120
17
14
BnO
tBuMe2SiO
BnO
OBn
OR
O
OH
BnOOR
tBuMe2SiO
BnO
OBn
OH
BnOOH
tBuMe2SiO
BnO
OBn
OR
19 R = tBuMe2Si
18 R = H
BnOO
RO
BnO
OBn
O
OMe
OMe
BnOOH
HO
BnO
OBn
OH
+
[a] [b]
[c]
[d]
[e]
[a] NaBH4, THF/H2O, 0°Cr.t., 2h, 96%; [b] 3,4-
dimethoxybenzaldehyde, H2SO4 cat., MS 3Å,
CH2Cl2, 3.5 h, 84%; [c] tBuMe2SiCl, imidazole, DMF,
15 h, r.t., 91%; [d] BH3.THF, THF, reflux, 2 h, 20
(62%) + 21 (32%); [e] (i) Swern oxidation; (ii)
NaClO2, HSO3NH2, THF/H2O, r.t., 10 min, 93%.
CALOPOROSIDE
24
27 R = SO2CF3
26 R = H
25 R = CH2C6H3(OMe)2
BnO
tBuMe2SiO
BnO
OBn
OR
O
O
BnO O
BnO
Cl
NMe2
23
BnO
tBuMe2SiO
BnO
OBn
OR
O
Cl
[a]
[b]
[c]
[e]
[f][d]29 R = H
28 R = tBuMe2Si
O
O
BnO O
BnO
O
OBnBnO
BnO
BnO
RO
BnO
OBn
OAc
O
O
BnO O
BnO
30
22
[a] 10, DMAP, CH2Cl2, 0°Cr.t., 16 h; [b] DDQ,
CH2Cl2/H2O, 0°Cr.t., 3.5 h, 74% (over last three
steps steps); [c] triflic anhydride, CH2Cl2/pyridine, 0°C,
15 min; [d] KOAc, DMF, r.t., 1 h, 75%; [e] KOAc, DMF,
0°Cr.t., 30 (75%) + 28 (18%); [f] BF3.Et2O, CH2Cl2,
0°Cr.t., 1.5 h, 83%
CALOPOROSIDE
[e]
[d]
[c]
[b]
[a]
1 R = H
34 R = Bn
33 R = SO2CF3
32 R = H
31 R = C(O)CH2Cl
RO O
RO
O
O
OR
ORO
RORO
RO
RO
O O
O O O
BnO O
BnO
O
O
OBn
OBnO
BnOBnO
BnO
BnO
O O
RO
O
16
29
+
[a] Ag+ on silica/alumina, MS 3Å, CH2Cl2, -5°C, 45
min, 74%; [b] thiourea, Na2CO3, EtOH/CH2Cl2,
reflux, 4 h, 75%; [c] triflic anhydride, pyridine, r.t.,
45 min, 78%; [d] Bu4NOAc, toluene, ultrasound, 16
h, 95%; [e] H2 (1 atm), Pd/C (5%), MeOH + HOAc
(1%), 22 h, 96%.
CALOPOROSIDE
A. Fürstner, I. Konetzki, J. Org. Chem.
1998, 63, 3072
O
O
OHON
N OH2N
HO NH2
HOH
OH
OH
OH
OH
HO
OHH2N
OH
OH
OHOHO
HO NH2
HOH
OH
OH
OH
OH
1
HikosamineHikizimycin
HIGHER SUGARS
O
O
OO O
OHOO
OH
O
OR
R = H
R = TMS
OO
OTBS
O
OITMSCHN2, BuLi
K2CO3, MeOH
65%
1. TBSOTf, lutidine, 95%
2. NIS, AgNO3, 92%
OMe
OMe
O
O
O
O
OH
OTBS
O
O OTBS
O
O
O
1. LiAlH4, 94%
2. TBSCl, NaH, 71%
Swern, 76%
OTBS
O
O
OOO
OTBS
O
OICrCl2 (1 eq.), 82%
or:
CrCl2 cat., Mn, LiCl, TMSCl, Bu4NCl, 88%
+
O
O
OH
TBSOOO
OTBS
O
O
O
O
OH
TBSO
O
O
OTBS
O
O
H2, Pd/C, EtOAc
89%
N OO
O
O
TBSO
O
O
OTBS
O
O
phthalimide, DEAD
PPh3, 62%
O
O
OTBS
O
OO
O
ONR2
OH
O
HO
O
OTBS
O
O
O
ONR2
O
O
O
OTBS
O
OHO
O
ONR2
OH
O
H
1. HF/pyridine, 98%
2. Swern, 75%
-NR2 = phthalimido
RuCl3 cat., FeCl2(H2O)4 cat.
NaIO4, 57%
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
O
OO
O
O
O
O
O
Ancepsenolide
Dehydrohomoancepsenolide
ANCEPSENOLIDES
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
A. Fürstner, Th. Dierkes Org. Lett. 2000, 2, 2463.
96%
Lindlar
75%
cat.
(tBuO)3W
70%
[Ru] cat.
70%
1
3. ester 1
I2.
1. CuCN (1 eq.)
ZnX = ZnI
X = I
O
O
O
O
X X
O
OO
O O
OO
O
71%
DEAD, PPh3OHBrHO
O
+BrO
O
PROSTAGLANDIN LACTONES FROM Tethys fimbria
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
O
O
HO
OO
O
AcO
O
O
HO
HO
OO
O
O
PROSTAGLANDIN LACTONE E2
O
O
TBSO
O
O
O
TBSO
O
R = H
R = TES
OR
O
TBSO
IOTES
MO
TBSO
Bu3Sn OTES
O
TBSO
O
O
HO
O
OH1. TESCl, imidazole
2. Bu3SnH, AIBN cat.
73%
1. BuLi
2. Me2Zn
3.
HOAc
74% (overall)
5-heptynoic acid
94%
iPrN=C=NiPr, DMAP
Mo[N(tBu)(Ar)]3 cat.
CH2Cl2/toluene
73%
1. H2, Lindlar, 86%
2. HF, MeCN, 88%
PGE2
COOH
OHHO
O
pig liver esterase
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
HO
O
O
HO
O
O
OO
O
HO
O
PGE2-lactone
O
O
HO
OO
O
HO
O
O
O
HO
O
A. Fürstner, K. Grela, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc. 2000, 122, 11799.
ALKYNE CROSS METATHESIS
A. Fürstner, C. Mathes Org. Lett. 2001, 3, 221.
PGE2
COOH
OHHO
O
51%
COOMe
O
TBSO OTES[Mo] cat., CH2Cl2, toluene, 80°C
OMe
MeO O
O
OTES
O
TBSO
TERPENOIDS
TOTAL SYNTHESIS OF DACTYLOL
HO
DactylolShirahama et al., 1985
(9 steps)
O
MeO
Gadwood et al., 1986
(20 steps)
O
Paquette et al, 1987
(17 steps)
HO
Feldman et al, 1990
(12 steps)
O Molander et al, 1995
(13 steps)
OCOOMe
Harmata et al., 2000
(16 steps)
Previous Syntheses: (a) Gadwood,R. C.; Lett, R. M.; Wissinger, J. E. J.Am. Chem. Soc. 1986, 108, 6343. (b)Paquette, L. A.; Ham, W. H. J. Am.Chem. Soc. 1987, 109, 3025. (c)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. 1995,60, 4559. (e) Hayasaka, K.; Ohtsuka,T.; Shirahama, H.; Matsumoto, T.Tetrahedron Lett. 1985, 873. (f) M.Harmata, P. Rashatasakhon, Org.Lett. 2000, 2, 2913.
RO
RO
O
OO
OH
OMO
R = H
R = SiMe3
HO
HO
MeLi, CuI, Bu3P
H
O
77%
MesylCl, DMAP
85%
Bu3SnH
83%
MgCl
CeCl3
80%
(TMS)2NH
MeCOCl, 93%
1. [Mo] (3%)
2. TBAF
92%
R = H
R = SiMe3
(TMS)2NH
MeCOCl, 95%
1. [Mo] (3%)
2. TBAF
85%
ZnCl2, Pd(0) cat.
6 steps, overall yield ca. 21% (Dactyol) + 18% (epimer)
A. Fürstner, K. Langemann, J. Org. Chem. 1996, 61, 8746.
SYNTHESIS OF SABINOL
V. Mamane, T. Greß, H. Krause, A. Fürstner J. Am. Chem. Soc. 2004, 126, 8654
HO
O
PtCl2 (5 mol%)
toluene, 80°C, 2h
NaBH4, CeCl3
OH
trans-sabinol
65%
sabinone
78%
O
SiMe3
BF3
see also: M. Malacria et al., JACS 2004, 126, 8656; F. D. Toste et al., JACS 2004, 126, 10858
CUBEBENE
A. Fürstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006
see also: A. Fürstner et al., Chem. Commun. 2004, 2546 (sesquicarene).
Review on Iron Catalyzed Cross Coupling:
A. Fürstner et al., Chem. Lett. 2005, 34, 624
HAcOH
HTfOH
HMeH
O
O
PtCl2 cat.
MeMgBr
Fe(acac)3 cat.
90%
-cubebene
O
toluene, 80°C
92%
PROPARGYL ACETATES AS SYNTHETIC EQUIVALENTS FOR
α-DIAZOKETONES
O
N2
OOAc
O
O
TWO CONCEIVABLE PATHWAYS
M
O
O
O
OM OAc
M
O
O
path I
path II
HAcOH
O
O
PtCl2 cat.
toluene, 80°C
92%
HAcOH
O
O
PtCl2 cat.
toluene, 80°C
79%
+
HAcOH
1 : 1
single isomer
A. Fürstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006
THE MOST LIKELY PATHWAY
M
O
O
O
OM OAc
M
O
O
path I
path II
A. Fürstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006
for a computational study see: J. Marco-Contelles et al., Organometallics 2005, 24, 3182
A. Fürstner, A. Schlecker, Chem. Eur. J. 2008, 14, 9181
analogously:
EPOXYSESQUITHUJENE AND CONGENERS
