total synthesis of (-)-okilactomycinccc.chem.pitt.edu/wipf/current literature/josh_5.pdf · josh...
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O
O
OH
O
O
O
Total Synthesis of (-)-Okilactomycin
Amos B. Smith, III, Kallol Basu and Todd BosanacJACS ASAP (11/13/2007)
Wipf Group Current Literature Joshua Pierce - 11/24/07
Josh Pierce @ Wipf Group 1 2/17/2008
Isolation and Structure Determination
Isolated in 1987 from bioactive filtrate of Streptomyces griseoflavus
Exhibits cytotoxicity against human cell lines P388 and lymphoid leukemia L1210
(IC50 = 0.09, 0.037 µg/mL)
Structure contains functionalized cyclohexane with spirocenter, 2,6-cis-
tetrahydropyranone and 13 membered ring
Initially assigned by NMR, later confirmed by X-ray analysis. Absolute stereochemistyremained unknown until present work.
Josh Pierce @ Wipf Group 2 2/17/2008
Previous Synthetic Studies
O
O
OH
O
O
O
O
O
OMe
O
O
O
OPMB
Knoevenagel-Michael
O
O
OMe
OR
O
O
OPMB
OHC
Metathesis
O
O
OMe
OR
O
O
OPMB
OHCAldol
CO2Me
OO
O
ORO O
OPMB
+
Okilactomycin
Ot-Bu
OOTBSO
OPMB
13 steps
ClHO
BnO
O
N
O2S
7 steps
Paquette et al., Synthesis, 2002, 888-894. Paquette et al., Synthesis, 2002, 895-900.Josh Pierce @ Wipf Group 3 2/17/2008
O
O
OH
O
O
O
O
O
OH
O
O
O
O
OBn
O
O
O
OR
OBn
O
O
OH
O
OH
OR
OBn
O
O
+
Petasis-Ferrier
Union/Rearrangement
RCM
Retrosynthetic Analysis
Josh Pierce @ Wipf Group 4 2/17/2008
Synthesis of Acid Fragment
N
O
OH
N
O
OH
OTBDPS OTBDPS
O OH
O
OH
N O
O O
Bn
Confirmed by X-ray analysis
I OTBDPS
LDA, LiCl, THF
(95%)
1. LDA, BH3•NH3 (94%)
2. SO3•Pyr, DMSO, Et3N (90%)3. PPh3CH3Br, n-BuLi (96%)Myers pseudoephedrine-derived
auxiliary
Parikh-Doering Oxidation
Wittig Olefination
1. TBAF (97%)
2. SO3•Pyr, DMSO, Et3N (93%)
Parikh-Doering Oxidation
1.
Bu2BOTf, Et3N (93%)
2. LiOH, H2O2 (97%)
Evans-Aldol8 steps, 63% yield
Josh Pierce @ Wipf Group 5 2/17/2008
OTBS
N
Ph
Ph
MeO
O
N
OTBS
OH
Ph
Ph
O
OBn
OTf
OBn
OH
OBn
OBn
O-
OMe
OBn
ONap
O
O
OBn
1. PhMe (88%)
2. LiAlH4 (97%)
1. NaHMDS, BnBr
2. 10% HF-MeCN (90%, 2 steps)
L-Selectride
then PhNTf2(82%)
1. Pd(PPh3)4, LiCl, CO Bu3SnH (87%)
2.
TsNB
NTs
Ph Ph (71%)
KH, 18-C-6
Me2SO4
96%
1. MCPBA, MeOH (91%)
2. NaH, NapBr (96%)
Rawal Diels-Alder
anion acceleratedoxy-Cope rearrangement
Corey Allylation
Rubottom-like oxidation
Synthesis of Cyclohexyl Fragment
Josh Pierce @ Wipf Group 6 2/17/2008
Petasis-Ferrier Union/Rearrgangement
Petasis-Ferrier Reaction (1995):
O
O
OCH2
R
H
AlR3O
CH2
H
R
R3Al
O
CH2
O
R
H
R3Al
RR
R
Ketone reduction occurs ifethyl or isopropyl groupsemployed
H H
O
OTIPS
HO
O OTIPSOH
1. HMDS, then TMSOTf
2. Cp2TiMe2
H H
OTIPS
O O
OTIPS
Me2AlCl
H H
OTIPS
H2C O
O OTIPS
Smith has utilized coupling of complex fragments via acetalization followed by P-F rearrangement:
Petasis et al. JACS, 1995, 117, 6394.
Smith et al. JACS, 2001, 123, 10942.Smith et al. OL, 2006, 8, 3315,
Josh Pierce @ Wipf Group 7 2/17/2008
Petasis-Ferrier Union/Rearrgangement Applied
ONap
O
O
OBn
ONap
O
O
OBn
PhSe
1. Cp2ZrHCl then NBS (90%)
2. PhSeH, Cs2CO3 (96%)
Bromide did not functionwell in Petasis-Ferrier
Schwartz Hydrozirconation
OH
O
OH
1. TMSOTf
2. Cp2TiMe23. Me2AlCl (42-46%, 3 steps)
ONap
OBn
O
O
PhSe
Petasis-Ferrier Union/Rearrangement
1. Davis Oxaziridine (94%)
2. DDQ (84%)OH
OBn
O
O KHMDS, MeOCOCl(99%)
OCO2Me
OBn
O
O1. NaOMe
2. MeI, K2CO3 (88%)
O
OBn
O
O
O
First example with bulky quaternary center! to acetal
Josh Pierce @ Wipf Group 8 2/17/2008
O
OBn
O
O
O
1. Hoveyda-Grubbs II then air
2. H2, Pd/C (80-85%, 2 steps) O
OH
O
O
O
Grubbs Ring Closing Metathesis
1. NaClO2, NaOCl TEMPO
2. TMSCHN2 (87%, 2 steps)
O
O
O
O
O
O
LHMDS (4 eq)PhSeCl (10 eq)
(99%) O
O
O
O
O
O
SePh
NO SELENIDE!
Ring Closing Metathesis
Josh Pierce @ Wipf Group 9 2/17/2008
O
OH
O
O
O
Confirmed by X-ray analysisof Iodide
O
O
O
O
ArSeCN, Bu3P
Pyr., H2O2 (90%)
Grieco-Nishizawa Elimination
1. SeO2, t-BuO2H (62% brsm)
2. SOCl2 (74%)
O
O
O
O
Cl
1. NaHMDS, PhSeCl (83%)
2. Me3NO, DMSO (65%)
O
O
O
O
O
SePh
Ganem Oxidation
1. NaIO4, THF/H2O (90%)
2. NaClO2, NaH2PO4 2-methyl-2-butene THF:t-BuOH:H2O (3:3:1) (80%)
O
O
OH
O
O
O
Pinnick Oxidation
(-)-okilactomycin
Synthetic Material: [!]20D = = -37 (c = 0.03, MeOH)
Natural Product: [!]20D = = +34 (c = 1, MeOH)
Completion of the Synthesis
Josh Pierce @ Wipf Group 10 2/17/2008
Conclusions
First total synthesis of okilactomycin has been achieved in 29 steps (longest linear sequence).
Synthesis establishes absolute configuration through formation of incorrect enantiomer.
Utilization of a variety of classical reaction in conjunction of effective Petasis-Ferrier union/rearrangement provided access to the functionalized core.
Biological evaluation and analog development should provide insight into the potential of this compound as a therapeutic agent.
Josh Pierce @ Wipf Group 11 2/17/2008
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