Total Synthesis of Trioxacarcin DC-45-A2
Valentin Soulard - Group RenaudJournal Club - March, 12 2015
Nicolaou, K. C.; Cai, Q.; Qin, B.; Petersen, M. T.; Mikkelsen, R. J. T.; Heretsch, P. Angew. Chem. Int. Ed. Engl. 2015, 54, 3074–3078.
DOI : 10.1002/anie.201410369
Me OMe
O OH
OH
HOOO
OO
MeOMeO
OHH
H
> Born in Cyprus and emigrate then to England (University of London)
> PhD University of London (1972, Professors F. Sondheimer and P. J. Garratt)
> Postdoc at Columbia University (1972-1973, Professor T.J. Katz) and Harvard University(1973-1976, Professor E.J. Corey)
> Since 2013 : Professor at Rice University (Houston, Texas)
> Reasearch interest : Total synthesis of architecturally novel and biologically important natural products.
> Author or co-author of more than 725 publications, 67 patents and 6 books.
List of books :- Classics in Total Synthesis I, II, III (respectively 1993, 2003, 2011)- Molecules That Changed the World (2008)- Handbook of Combinatorial Chemistry: Drugs, Catalysts, Materials, (2002)- Selenium in Natural Products Synthesis (1984)
http://www.scripps.edu/nicolaou/kcn.html
K. C. Nicolaou
K. C. Nicolaou : Natural Product Synthesis
Taxol (1995) Vancomycin (1998)Brevetoxin B (1995)
O
OHOOAc
O
O
O
OAc
HO
NHO
O
OOHO
Cl
HOOH
O
O
OHH2N
OCl
HN
O
NH
NH
O
O
NH2
O
HN
O
NH
OHN O
OH
HN
O
HOHO
OH
HO OH
O
O
O
O
O
O
O
O O
O O
OH H H
H H H
HH
HO
H
HH
H
H H H
O
H
Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.; Couladouros, E. A.; Sorensen, E. J. J. Am. Chem. Soc. 1995, 117, 624.Nicolaou, K. C.; Liu, J. J.; Yang, Z.; Ueno, H.; Sorensen, E. J.; Claiborne, C. F.; Guy, R. K.; Hwang, C. K.; Nakada, M.; Nantermet, P. G. J. Am. Chem. Soc. 1995, 117, 634.Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Nantermet, P. G.; Claiborne, C. F.; Renaud, J.; Guy, R. K.; Shibayama, K. J. Am. Chem. Soc. 1995, 117, 645.Nicolaou, K. C.; Ueno, H.; Liu, J. J.; Nantermet, P. G.; Yang, Z.; Renaud, J.; Paulvannan, K.; Chadha, R. J. Am. Chem. Soc. 1995, 117, 653.
Nicolaou, K. C. Angew. Chem. Int. Ed. Engl. 1996, 35, 588.
Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Winssinger, N.; Hughes, R.; Bando, T. Angewandte Chemie International Edition 1999, 38, 240.
> Naturally occurring antitumor antibiotic
> Bacterial and eukaryotic cells metabolite
> Biosynthetic precursor to other biologically active member of the family
> Highly oxygenated and complex architecture
> Third synthesis of the compound
Švenda, J.; Hill, N.; Myers, A. G. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6709.Magauer, T.; Smaltz, D. J.; Myers, A. G. Nat Chem 2013, 5, 886.
Trioxacarcin DC-45-A2
Me OMe
O OH
OH
HOOO
OO
MeOMeO
OHH
H
DC-45-A2
Me OMe
O OHH
OOO
OO
MeOMeO
OH
H
O
O
H
OAcMeHO Me
H
O
OH
MeOH
HMe
O
Me OMe
O OHH
OOO
OO
MeOO
OMeH
H
O
O
H
OAcMeHO Me
HOH
Me
H
Me
HO
O
OOH
Me
HO
Me
HH
Trioxacarcin A LL-D49194α1
Me OMe
O OHH
OOO
OO
MeOMeO
OMeH
H
O
O
H
OAcMeHO Me
H
DC-45-A1
Retrosynthetic analysis of Triocacarcin DC-45-A2Me OMe
O OH
OH
HOO
O
OO
MeOMeO
OHH
Hhemiketalformation
MeOMe
O OH
OH
HO
O
OHO
OMeO
MeO
O
O O
MeOMe
OOTBS
OPMB
SitBu tBu
O H
O
OTMS
MeO
MeO
H
epoxyketonerearrangement
O O
MeMeO
OOTBS
OPMB
SitBu tBu
O
TMSO
MeO
MeO
O
LA
Jørgensen epoxidation
Hauser-Kraus annulation
Baylis-Hillman reaction
Stille coupling
OOMe
OMeHO SnBu3 O
O
CNMe
MOMOI
OOTBS
OPMB
A B C D
OHOH
OsO4, NMO
acetone25°C, 72h
50%
OTBSOTBS
TBSClimidazole
DCMrt, 48h92%
OTBSOTBS
mCPBANaHCO3
cHex25°C, 17h
89%
5, nBuLi
THF0 to 25°C, 18h94% (ee 99%)O
OTBSOTBS
OH
OHOH
OPMB
1. PMBTCA, TrBF4, THF, 25°C, 1h2. TBAF, THF, 66°C, 4h TEMPO, pTSA
DCM,0°C, 45 min
74%
OOH
OPMB
OOTBS
OPMB
TBSClimidazole
DCM25°C, 1.5h
99%
84% over two steps
2 3 41
7 86 D
Ph
NHMe
Me
N
5
Synthesis of the key building block D
MeO
O
NH
CCl3
PMBTCAtetra-n-propylammonium perruthenate,
Bhuniya, D.; DattaGupta, A.; Singh, V. K. J. Org. Chem. 1996, 61, 6108.
Synthesis of the key building block C
Nicolaou, K. C.; Becker, J.; Lim, Y. H.; Lemire, A.; Neubauer, T.; Montero, A. J. Am. Chem. Soc. 2009, 131, 14812.
OH
Me
OH
O OH
Me
NEt2
OCOCl2, Et2NH•HCl Et3N, DMF
DCM or THF0 to 25 °C, 12h
74%
MOMCl, i-Pr2NEt
DMF60°C, 48h
97%
MOMO
Me
NEt2
O MOMO
Me
NEt2
O
O
1. TMEDA, t-BuLi, -78°C, 1h2. DMF, 25°C, 2h
THF95%
MOMO
MeO
O
CN
1. KCN, 18-crown-6TMSCN, 0°C, 3h
2. AcOH, 25°C, 12h
85%
OH
MeO
O
CN
deprotectionO
MOMO O
MeCN
I1. NIS, DCE, -10°C, 6h
2. MOMCl, DIPEA, DCM, 25°C, 6h
50% over two steps
MOMO HO
MeOMe
I
OTBS
OPMB
1. tBuOLi, -78°C, 0.5h2. Me2SO4, 0°C, 5h
THF69%
OOTBS
OPMB
O O
MeOMe
IO
OTBS
OPMB
SitBu tBu
1. MgBr2OEt2, THF, 0°C, 15 min2. tBu2Si(OTf)2, 2,6-lutidine, DMF, 0°C, 0.5h
85% over two steps
9 10 11 12
13 14
15 16
C D
IO
O
O
O
PIDAIodobenzene diacetate
NNSi
TMS-imidN-trimethylsilylimidazole
Synthesis of the bis-cyclization precursor epoxyketone 21
HO SnBu3B
OOMe
OMe
A
Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964.M. L. Edwards, P. J. Cox, S. Amendola, S. D. Deprets, T. A. Gillespy, A. Timothy, C. D. Christopher, A. D. Morley, C. J. Gardner, B. Pedgrift, H. Bouchard, D. Babin, L. Gauzy, A. Le Brun, T. N. Majid, J. C. Reader, L. J. Payne, N. M. Khan, M. Cherry, WO 2003035065, 2003.
MOMO O
MeOMe
IO
OTBS
OPMB
SitBu tBu
B, Pd(PPh3)4CuTC
DMF:THF 1:185°C, 12h
74%
O O
MeOMe
OOTBS
OPMB
SitBu tBu
HOTEMPO, PIDA
DCM25°C, 4h
89%
urea•H2O2
DCM:H2O 20:125°C, 7h
O O
MeOMe
OOTBS
OPMB
SitBu tBu
O
H
O O
MeOMe
OOTBS
OPMB
SitBu tBu
O
H O
O O
MeOMe
OOTBS
OPMB
SitBu tBu
O
A, DABCO4-nitrophenol
THF25°C, 12h
OH
OMeO
OMe
TMS-imid
DCM25°C, 0,5h
36% over three steps
O O
MeOMe
OOTBS
OPMB
SitBu tBu
O
OTMS
OMeO
OMe
16 17 18
19 20
21
NH Ph
PhOTMS
O O
MeMeO
OOTBS
OPMB
SitBu tBu
O
OTMS
OMeO
OMe
MeO
MeOO
OTMS
ArO
Sn ClClCl Cl
MeOMeO O
TMSO
ArO
H
MeOMeO O
TMSO
HO
Ar
H
H
steric congestion
retention at C6 O
OMe
MeO
O
OTBSPMBO
SitBu
tBu
∗∗
O H
O
OTMSMeO
MeO
H
MeO
MeOO
OTMS
ArO
BF
FF
O
HO
OTMS
HArMeO
MeO OOMe
MeO
O
OTBSPMBO
SitBu
tBu
∗∗
O HO
OTMSMeO
MeO
H
BF3•OEt2DCM,
-78°C, 3h72%
SnCl4DCM,
-78°C, 3h37%
21, (+C4-epi-21, d.r. ca. 3:1)
1
23
45
6
1
23
45
6
1
23
4
5
61
2
3 4
5
6
12
5 6
12
5 6
12
56
12
4
56
∗∗
inversion at C6
J5,6 = 3.0 Hz (17a), 3.6 Hz (17b)
22a (54%), 22b (C4-epi-22b, 18%)
23 (+C4-epi-23 : d.r. ca. 13:1 37%)
J5,6 = 0 Hz
Bis-cyclization of precursor epoxyketone 21
Completion of the total synthesis of trioxacarcin DC-45-A2
OOMe
MeO
O
OTBSPMBO
SitBu
tBuO H
OMeO
MeO
H
OOMe
MeO
O
OTBSPMBO
SitBu
tBuO H
O
OHMeO
MeO
H
TFA
THF:H2O 5:125°C, 6h
65% (recovered X : 24%)
1. OsO4, NMO, acetone, 25°C, 12h2. TsCl, Et3N, DMAP, DCM, 0°C to 25°C, 5h3. K2CO3, MeOH, 0°C, 3h
82% over three steps
OOMe
MeO
O
OTBSPMBO
SitBu
tBuO H
O
OHMeO
MeO
H
O
TPAPNMO•H2O
DCM0°C, 2h
93%
OOMe
MeO
O
OTBSPMBO
SitBu
tBuO H
O
OMeO
MeO
H
O
MeOMe
O OTBS
OPMB
HO
O
OHO
OMeO
MeO
O
CH3CN25°C, 15 min
88%
Et3N•3HF
HOTBS
J5,6 = 3.0 Hz
J4,5 = 4.8 Hz
56
4
22a 24
25 26 27
Completion of the total synthesis of trioxacarcin DC-45-A2
Me OMe
O OTBS
OPMB
HOO
O
OO
MeOMeO
OHH
H
Me OMe
O OH
OH
HOO
O
OO
MeOMeO
OHH
H
Me OMe
O OTBS
OH
HOO
O
OO
MeOMeO
OHH
H
DDQ
DCM:H2O 10:125°C, 1h
93%
Et3N•3HF
CH3CN25°C, 13h
86 %
Trioxacarcin DC-45-A2
MeOMe
O OTBS
OPMB
HO
O
OHO
OMeO
MeO
O
28 28
29
Conclusion
> Novel Lewis acid-‐induced cascade rearrangement of epooxyketone to forge the polyoxygenated2,7-‐dioxabicyclo(2.2.1)heptane core
> Provide a rapid access to the trioxacarcin DC-‐45-‐A2
> Application in the construction of designed analogues
Thank you for your attention
Bhuniya, D.; DattaGupta, A.; Singh, V. K. J. Org. Chem. 1996, 61, 6108.
NLi
N
O
H
Ph
MeH
TBSO
OTBS
NLi
N
O
H
Ph
Me
OTBS
TBSOH
H
OTBSOTBS
Ph
NHMeN
Me , n-BuLi
THF0 to 25°C, 18h94% (ee 99%)O
OTBSOTBS
OH
H
Supplementary information : Regioselective opening of the epoxyde
Supplementary information : Tempo Oxydation
NO
N+
O
N+
O-O R
HH
NOH
OHR
OR
H
O O
Li, X.-‐Q.; Zhang, C. Synthesis 2009, 2009, 1163. Banwell, M. G.; Bridges, V. S.; Dupuche, J. R.; Richards, S. L.; Walter, J. M. J. Org. Chem. 1994, 59, 6338.
Supplementary information : Up-John dihydroxylation
OsO
OO
O
OsOO O
OR
R'OHHO
R R'
2 H2O
N+
O
Me O-
N
O
Me
OsO
OO
R R'
OHOH
OsO4, NMO
acetone25°C, 72h
50%
MOMOI
MeO
O
CN
MOMOI
MeO
O
NC
OOTBS
OPMB
MOMO HO
MeOMe
I1. tBuOLi, -78°C, 0.5h2. Me2SO4, 0°C, 5h
THF69%
OOH
OPMB
Li
OOTBS
OPMB
MOMOI
Me
O
O
NC
OOTBS
OPMB
Li MOMOI
MeO
O
CN
OHOTBS
OPMB
Li
MOMOI
MeOH
OH OOTBS
OPMB
MOMOI
MeMeO
OH OOTBS
OPMB
Me2SO4, 0°C, 5h
THF0°C, 5h
Supplementary information : Hauser-Kraus annulation
Mal, D.; Pahari, P. Chem. Rev. 2007, 107, 1892.
Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964.
R1
R2 O
H R1
R2 O
HO
urea•H2O2
CHCl3:H2O 20:125°C, 7h
NH
Ph
PhOTMS
R1
R2 O
H
R1 R2
H
NPh
OTMSPh
O HRO
R1R2
H
NPh
OTMSPh
ORO
H
NPh
OTMSPh
NH Ph
OTMSPh
R1 R2
O
H2O
H2O
R1
R2 O
HO
Supplementary information : Jørgensen epoxidation
Supplementary information : Baylis-Hillman reaction
O O
MeOMe
OOTBS
OPMB
SitBu tBu
O
H O
O O
MeOMe
OOTBS
OPMB
SitBu tBu
O
DABCO4-nitrophenol
THF25°C, 12h
OH
OMeO
OMe
O
OMe
OMe
NR
R R
O
O-
N+R R
R
R'
O
H
R'
O- O
HN+
R R
R
R'
O- O
R'
OH O
N+
RR R
H
NR R
R
NR R
R
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
M. L. Edwards, P. J. Cox, S. Amendola, S. D. Deprets, T. A. Gillespy, A. Timothy, C. D. Christopher, A. D. Morley, C. J. Gardner, B. Pedgrift, H. Bouchard, D. Babin, L. Gauzy, A. Le Brun, T. N. Majid, J. C. Reader, L. J. Payne, N. M. Khan, M. Cherry, WO 2003035065, 2003.
