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Proposed Synthesis of Haliclonin A
Stefan Breitenlechner, Angélique Fortier, James Mousseau, Marie-Noelle Roy, Frédéric Vallée
aka: 7th Heaven
NO
N
OH
O
O
H
NO
N
OH
O
O
H
2
Retrosynthetic Analysis
NO
N
OH
O
O
H
NO
N
OH
O
O
H
NO
N
OH
PMP
NO
N
I
PMP
NO
OH
PMPHN
AcO
NO
HOOC
OB
O
O
O
O
OTIPS OTIPS
OTIPSOTIPS
OO
OO
OO
NO
N
OH
O
O
H
NO
N
OH
O
O
H
3
Diels-Alder Precursors
Br +
nBuLi/tBuOK(THF) −80 °C
Brandsma L. et al. J . Org. Chem. 1987, 52, 5261 a) BH3•SMe2, cyclohexene (DME) 0 °Cb) trimethylamine oxidec) (+)-pinanediol
OB
O
J iang B. et al. Tetrahedron 2001, 57, 2305
For a Diels-Alder reaction of electron-poor dienophils with dienes bearing a linker with a terminal alkene see:Sorensen, E. J. et al. J. Am. Chem. Soc. 2005, 127, 8612
O
O
O
O
O
O H
HB
OO
+Toluene
80 oC, 72 h
NO
N
OH
O
O
H
NO
N
OH
O
O
H
4
D-A Cascade
1,3,5-trioxolane2% H2SO4
Simoni. D. et. al. Tetrahedron Lett., 2005,46, 759
H2NOH
Zuckermann, R. N. et al. J. Med. Chem. 1994, 37, 2678 TIPSCl (DCM) rt
H2NOTIPS
O
O
O H
HB
OO+
NOTIPS
H
H
NOTIPS
H
H
H
OR
NO
O
HO
OTIPS
NO
N
OH
O
O
H
NO
N
OH
O
O
H
5
D-A Cascade
O
O
O H
HB O
O
O H
H
HN
B
O
O
O N+
HR
H
H
B
O
O
O N
HR
H
OO
OO
OO
Vaultier, M. et al., Tetrahedron Lett. 1987, 28, 4169Gao, X. et al. Tetrahedron Lett. 2003, 44, 2231Tailor, J. et al. Org. Lett. 2000, 2, 3715
NO
O
HO
OTIPS
OTIPS
Yamamoto, Y., et al. Chem. Rev. 1993, 93, 2207
NO
N
OH
O
O
H
NO
N
OH
O
O
H
6
Onward and Upward
O
O
Acetone, rt
NO
O
HO
O
OOH
OO
Murray, R.W. et al. J.Org. Chem. 1993, 61, 1830-1841
100% Yield84:16 trans:cis
NO
O
HO
For epoxidation of a cyclohexene with DMDO with a directing group bearing a linker with a terminal alkene see:Asensio, G. et al. J. Org. Chem. 1995, 60, 3692
OTIPSOTIPS
NO
N
OH
O
O
H
NO
N
OH
O
O
H
7
More Cascades
NO
O
HO
O
NO
OO
H
1) NaOH, H2O 60 oC, 30 min2) Swern
Krzysztof. K. et al. Tetrahedron : Asymmetry. 2001, 12, 455Joullié, M. M. et al.Tetrahedron : Asymmetry. 1997, 8, 3043Mohr. P. et al. Tetrahedron Lett. 1989, 30, 2513Narasaka, K. et al. J . Am. Chem. Soc. 1984, 106, 2954
3) ethane-1,2-diol TsOH
OTIPS
OO
NO
O
O
R
O
O
R
NO
R
OHEtO
O
K2CO3, EtOH
NO
R
OHEtO
O
KOEt, EtOH
Bunnage, M. E. et al. Org. Biomol. Chem. 2003, 1, 3698.
OO
OO
KOEt, EtOH
NO
OHEtO2COO
OTIPS
1) LiBH4 2) DMP, CH2Cl2
NO
OHC OOO
OTIPS
NO
N
OH
O
O
H
NO
N
OH
O
O
H
8
Aziridination
NO
OHC O
i) p-anisidine, 4 Å MS CH2Cl2ii) Me3SI/n-BuLi, THF −78 °C to r.t.
NO
OPMPN
Reetz, M. T., Lee, W. K. Org. Lett. 2001, 3, 3119-3120.
OOOO
OTIPSOTIPSLBH, 0 °C
DCM
NO
OHPMPHN
Hu, X. E. Tetrahedron. 2004, 60, 270
OO
OTIPS
OPG
OH
NO
nN
PMP
M
H
H
H H
OTIPS
OAc
OAc
NO
OH
PMPHN
AcO
Grubbs I (CH2Cl2)reflux +
Grubbs, R. H. et al. Tetrahedron Lett. 1998, 39, 7427
OO
OTIPS
NO
N
OH
O
O
H
NO
N
OH
O
O
H
9
Towards the End
1) Swern
2)
Ph3P I
I-
NaHMDS
NO
NPMP
I
OO
OTIPS
O CrCl3 (10 mol%)Ligand (10 mol%)NEt3 (20 mol%)
Mn (3 equiv)Me3SiCl (1.5 equiv)
THF
Berkessel, A. et al. Angew. Chem. Int. Ed. 2003, 42, 1032
NO
NPMP
OH
OO
OTIPS
Ligand =
NN
HOOH
tBu
tBu
tBu
tBu
O
HOI+
Satoh, M. et al. Chem Pharm. Bull. 2001, 49, 18-22
HCl (EtOH) rt
NO
NPMP
OH
OH
O
2) H2 (1 atm), 10% Pd/C EtOH, rt NO
N
OH
NO
OH
PMPHN
AcO
PMP
Trost, B. M. et al. J. Am. Chem. Soc. 1982, 104, 6881
1) Pd(Ph3)4, dppb(THF) reflux
OOO
O
OTIPSOTIPS
NO
N
OH
O
O
H
NO
N
OH
O
O
H
10
Cyclization/Endgame
1)TEMPO, NCS TBACl (H2O/CH2Cl2)
Snapper, M. L. et al. J. Am. Chem. Soc. 2002, 124, 10998
NO
NPMP
OH
O
2)NO
NPMP
OH
OH
O
Cp2TiCl
AlMe2
−40 °C (THF/toluene)
Schreiber, S. L. et al. J . Am. Chem. Soc. 1997, 119, 4353
1) Lindlar's Catalyst
2) Grubbs II or Shrock
NO
NPMP
OH
ON
O
N
O
Hoveyda, A. et al. J. Am. Chem. Soc. 1997, 119, 10302-10316 (12)Pandit, U. K. et al. Tetrahedron Lett. 1994, 35, 3191-3194 (13)
OH
OH
NO
NOHC
OH
1) CAN, DCM, H2O2) HCO2H, DCC, Pyr 0 ºC
O
Johansson, R. et al. J. Chem. Soc. Perkin Trans. I. 1984, 2371Atkinson, R. S. et al. J. Chem. Soc. Chem. Commun. 1996, 1051
Farina, V. et al. Org. Proc. Res. Dev. 2009, 13, 250 (15)
NO
N
OH
O
O
H
NO
N
OH
O
O
H
11
Summary
• 25 linear steps
• 2 ‘Cascade’ reactions
• Projected overall yield: 98.2%
• Actual overall yield: 85.4%
• Manuscript in preparation
NO
N
OH
O
O
H
NO
N
OH
O
O
H
12
Proof
![Descendants of Antoine Fortier [#2] & Marie …arslanmb.org/fortier/Descendants-2.pdfJean Baptiste FORTIER (male, of father's second marriage) B. 2 Jun 1758 @ St-Laurent, Ile-d'Orleans,](https://img.pdfslide.us/doc/110x75/5ec5616436fb713fcc38febe/descendants-of-antoine-fortier-2-marie-jean-baptiste-fortier-male-of.jpg)
