Total Syntheses of FR182877 - Macmillan Group...Completed syntheses (+)-FR182877 by Sorensen in 2002...
33
Total Syntheses of FR182877 MacMillan Group Meeting October 5, 2005 Sandra Lee Key Articles: Isolation Papers: (a) Sato, B.; et. al. J. Antibiot. 2000, 53, 123; (b) Sato, B.; et. al. J. Antibiot. 2000, 53, 204; (c) Yoshimura, S.; et. al. J. Antibiot. 2000, 53, 615. Sorensen Synthesis: (a) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem. Soc. 2002, 124, 4552; (b) Vanderwal, C. D.; Vosberg, D. A.; Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393. Evans Synthesis: (a) Evans, D. A.; Starr, J. T. Angew. Chem. Int. Ed. 2002, 41, 1787; (b) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531.
Transcript of Total Syntheses of FR182877 - Macmillan Group...Completed syntheses (+)-FR182877 by Sorensen in 2002...
Total Syntheses of FR182877
MacMillan Group Meeting October 5, 2005
Sandra Lee
Key Articles:
Isolation Papers: (a) Sato, B.; et. al. J. Antibiot. 2000, 53, 123; (b) Sato, B.; et. al. J. Antibiot. 2000, 53, 204; (c) Yoshimura, S.; et. al. J. Antibiot. 2000, 53, 615.
Sorensen Synthesis: (a) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem. Soc. 2002, 124, 4552; (b) Vanderwal, C. D.; Vosberg, D. A.; Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393.
Evans Synthesis: (a) Evans, D. A.; Starr, J. T. Angew. Chem. Int. Ed. 2002, 41, 1787; (b) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531.
FR182877 : Taxol-type
! Isolation–Fujisawa Pharmaceutical Co.Me
O
HO
OH
Me
Me
HMeO
O
HH
A
B
C
D
E F
H
H
HO
HMe
OH
OH
Me
H
H
H
H
O
Me
O
Me
H
H
OH
HMe
HO
OH
Me
H
H
H
H
O
Me
O
Me
(+)-FR182877 (–)-FR182877
Isolated from the fermentation broth of Steptomyces in 1998 with IC50 = 28-75 ng/mL cytotoxicity against several cell lines.
Structurally similar natural products: Hexacyclic Acid, Macquaimicin A, and Cochleamycin A
Cytotoxicity and Antimitotic Activity
! Synthetic challenges
(a) 19-membered Hexacyclic carbomacrocycle featuring 12 stereocenters (b) Vinlogous carbonate embedded in a 6-6-7 fused ring system(c) Instability to air oxidation (C2-C21) to form a biologically inactive epoxide
! Completed syntheses
(+)-FR182877 by Sorensen in 2002 (–)-FR182877 by Evans in 2002(+)-FR182877 by Sorensen in 2003
! Ongoing synthetic efforts
Armstrong in 2001: Model DF ring systemNakada in 2002: AB bicycleRoush in 2003: ABC tricyclePrunet in 2004: A ringClarke in 2005: DEF ring system, B ring
2
20
VS.
H
A Proposed Biogenetic Synthesis of FR182877
Me
O
HO
OH
Me
Me
HMeO
O
HH
(–)-FR182877
H
Me
CHO
OH
OH
CO2R
O
MeRO
Me
CO2R
O
MeRO
Me
CHO
H
Me
H
HOH
HO
Me
H
Me
H
HOH
HO
Me
Me
HO
Me
O
CO2R
H
Me
H
HOH
HO
Me
O
Me
OR
O
MeOH
IntramolecularDiels-Alder
reaction
Lactonization
Knoevenagelcondenstation
Transannular hetero-
Diels-Alder reaction
see Classics II, p. 490
(IMDA)
Me
Me
OH
OH
CO2R
O
MeHO
Me
Transannular Diels-Alder
reaction
Knoevenagelcondenstation
(TADA)
Me
A Proposed Biogenetic Synthesis of FR182877
Me
O
HO
OH
Me
Me
HMeO
O
HH
(–)-FR182877
H
Me
CHO
OH
OH
CO2R
O
MeRO
Me
CO2R
O
MeRO
Me
CHO
H
Me
H
HOH
HO
Me
H
Me
H
HOH
HO
Me
Me
HO
Me
O
CO2R
H
Me
H
HOH
HO
Me
O
Me
OR
O
MeOH
IntramolecularDiels-Alder
reaction
Lactonization
Knoevenagelcondenstation
Transannular hetero-
Diels-Alder reaction
see Classics II, p. 490
(IMDA)
Me
Me
OH
OH
CO2R
O
MeHO
Me
Transannular Diels-Alder
reaction
Knoevenagelcondenstation
(TADA)
Me
Me
Me
HO
The Pivotal Transformation: Endo vs. Exo
Me
O
HO
OH
Me
Me
HMe
O
O
HH
B
D
(–)-FR182877
Me
OH
OH
CO2R
O
MeHO
Me
OH
H
Me
CO2RHH
OH
MeOH
HB O
D
Me
OH
H
OH
HOH
HO
Me
HOCO2R
Endo-TS
Exo-TS
BD
HO2C
O
AcO
OH
Me
Me
HMe
O
O
HH
H
H
OH
H
Hexacyclinic Acid
B
D
Cascade TADA
Cascade TADA
Me
Me
Me
Evans: A Diels-Alder Cascade Strategy
Me
O
HO
OH
Me
Me
HMeO
O
HH
H
Me
OR
OR
CO2Et
O
MeTBSO
Me
Transannular Diels-Alder
reaction
Transannular hetero-
Diels-Alder reaction
Br
Suzuki
!-ketoester alkylation
OTBDPS(HO)2B
OR OR
Me
OTBDPS
OH
Me
O
NO
O
Bn
OTBDPS
O
H
Me
O
H
OTBS
OH
Me
O
NO
O
Bn
Me
OTBS
OR
Me
O
N
Me
MeO Me
Br
Br
Aldol Fragment Synthesis: Dibromide Fragment
OTBS
Me
O
N
Me
MeO Me
OH
Me
O
H
OTBS
OTBS
O
HOH
i. TBSCl, DMF, imid.
ii. O3/O2; PPh3
i. , THF
ii. triethylorthoacetate,proprionic acid, 150°C
Me
O
NO
O
Bn
MgBrMe
75%iii. DIBAL, –78 °C
73%
Bu2BOTf, TEA
88%
OH
Me
O
NO
O
Bn
Me
OTBS
i. MeNHOMe • HClMe3Al, THF
ii. TBSCl, DMF, imid.
iii. TsOH:nBu4NHSO4 (1:4)
MeOH, 0 °C
82%
OTBS
Me
O
N
Me
MeO Me
Br
Br
i. Dess-MartinPeriodinane, NaHCO3
ii. CBr4, PPh3,CH2Cl2, NaHCO3
70%
Aldol Fragment Synthesis: Boronic Acid Fragment
i. nBuLi, THF
TBDPSCl
ii. SO3–Pyr, DMSOCH2Cl2, TEA
Me
O
NO
O
Bn
59%
Bu2BOTf, TEA
89%
i. MeNHOMe • HClMe3Al, THF
ii. HCCMgBr
75%
OTBDPS
(HO)2B
OTBS OTBS
Me
OTBDPS
OH
Me
O
NO
O
Bn
OTBDPS
O
HHO
OH
OTBDPS
OH
Me
O
OTBDPS
OTBS
Me
OTBS
i. DIBAL, THF, –78 °C
>20:1 dr
92%
catechol-BH, Cy2BH (10 mol%) THF; 1N NaOH
97%
ii. TBSCl, DMF, imid.
Suzuki Coupling of the "Aldol" Fragments
OTBDPS(HO)2B
OTBS OTBS
Me
5% Pd(PPh3)4Tl2CO3
THF:H2O (3:1), rt
84% desired pdt
OTBS
Me
O
N
Me
MeO Me
Br
Br
Me
O
HO
OH
Me
Me
HMeO
O
HH
H
OTBS
Me
O
N
Me
MeO Me
Br
OTBDPS
OTBS OTBS
Me
OTBS
Me
O
N
Me
MeO Me
OTBDPS
OTBS OTBS
Me
OTBDPS
OTBS
Me
TBSO
! Highly Optimized Suzuki Coupling Conditions
undesired double addition product
The coupling was sensitive to the choice of base:
(1) strong bases (i.e. hydroxides, oxides) or less halophilic cations resulted in slower rates and competitive decomposition of SM via protodeborylation, oxidation, elimination, etc.
(2) silver bases completely decomposed products'
(3) carbonates had the best selectivity and only Tl2CO3 gave good reaction at rt
8
Synthesis of the Pivotal Macrocycle
i. DIBAL, –78 °C
70%
OTBS
Me
O
N
Me
MeO Me
TBDPSOOTBS
OTBS
Me
Br
ii. ethyldiazoacetateSnCl2
OTBS
Me
O
Me
TBDPSOOTBS
OTBS
Me
Br
EtO
O
i. TBAF, AcOH, DMF
64% (3 steps)
ii. I2, PPh3, CH2Cl2
Cs2CO3, THF (0.005M), rt
Me
TBSO
TBSO
O
Me OTBS
Me
Br
*
1:1 dr
OTBS
Me
O
Me
IOTBS
OTBS
Me
Br
EtO
O
O
EtO2
The Diels-Alder Cascade in Action
Ph2Se2O3, SO3-PyrTEA, THF, rt;
63%
hexanes, 50 °C
i. HF-MeCN
ii. Pd(dppf)Cl (10 mol%)Me3B3O3, Cs2CO3,
DMF:H2O (2:1), 100 °C
Me
TBSO
TBSO
O
Me OTBS
Me
Br
O
EtO
Me
TBSO
TBSO
EtO2C
O
Me OTBS
Me
Br
Br
O
TBSO
OTBS
Me
Me
HMe
CO2Et
HH
H
TBSO
H
single diastereomer
Me
O
HO
OH
Me
Me
HMe
CO2Et
HH
H
H63%
TMSOK, THF;
62%
N
Cl
Me
I
NaHCO3, CH2Cl2
Me
O
HO
OH
Me
Me
HMeO
O
HH
H
HO
Evans: [!]23D = -5
Fujisawa: [!]23D = -3.5
A Closer Look at the Cyclization Sequence
Me
TBSO
TBSO
EtO2C
O
Me OTBS
Me
Br
Br
O
TBSO
OTBS
Me
Me
HMe
CO2Et
HH
H
TBSO
H
H
Br
H
H OTBS
TBSO
Me
Me
OTBS
Me
OCO2Et
H
TBSO
EtO2C
O
Me OTBS
Me
Br
Me
OTBS
X O
Y
O Z
OH
O Z
OH
O
X
Y
Keq = 1-10
Moorhoff (Syn 1997, 685): 6!-cyclization to pyran tautomer
Me
TBSO
TBSO
EtO2C
O
Me OTBS
Me
Br
[O]
"
! NMR analysis shows 2H-pyran equilibrium
intermediate species were not isolable
1:1
FMO anaylsis using calculated (Spartan 5.1) Pz orbital coefficients of the HOMO and LUMO predicts B-ring cyclization to occur first.
9
12
14
153
4
5
HOMO LUMO
Atom Pz
C9 0.38C12 -0.48C14 -0.07C15 0.03
Atom Pz
C5 0.51C4 -0.26C3 -0.56O1 -0.29
B
best overlap
best overlap
! Cyclization order? The Normal-demand DA (NDA) or inverse-demand hetero DA (HDA)?
Studying the Inherent Stereoselectivity of the TADA Cascade
! The high face-selectivity of the TADA cycloaddition is conjectured to arise from C18,C19 stereocenters
O
MeTBSO
Me
CHO
H
Br
H
HOTBS
TBSO
Me
N
Me
OTBS
Me
O
N
Me
MeO Me
OOTBS
OTBS
Me
Br
OMe O
MeTBSO
Me
CHO
H
Br
H
HOTBS
TBSO
Me
N
Me
OMe
60 °C, CDCl3, 3h
37:63 dr
11
! Model IMDA study shows high endo selectivity with poor diastereofacial selectivity
Sorensen's system, the enantiomer which differs only in silyl protecting groups and the Me @ C11, also observed high endo selectivity and the opposite dr 61:31 dr.
This suggests that the C6-C8 stereotriad only modestly differentiates !-faces in the B-ring cyclization
8
6
18 19
desired cycloadduct
Me
MeO
MeO
EtO2C
O Me
Br
18 19
Me
CHO
Br
OTBS
TBSO
Me
Me
MeO
MeO
EtO2C
O
Me OMe
Me
Br
Modeling the TADA Endo Transition States H
H
BrMe
HMeO
O MeMe
OH H
HHMeO
OMe
OMe
MeOO
OMe
H H
HH
OMe
MeO
MeOH
Me Me
BrH
CO2Me
O
MeBr
Me
OMe
MeO
OMeMe
H
H
H
H
CO2Me
O
MeBr
Me
OMe
MeO
OMeMe
H
H
H
H
endo TS I
endo TS II
For each macrocycle, five energy-minimized geometries were obtained and two energy curves were generated plotting the increasing energy penalty for !-face alignment of the approaching TS ( I and II).
Nine simplified macrocycles (varied at C18 and C19) were energy-minimized (PM3) with distance
constraints (of 2.9-2.1 Å) leading to the observed natural product (via
endo TS I) or it's endo diastereomer (via endo TS II).
4.0-9.4 kcal/mol
Analysis of the Transannular Hetero Diels-Alder Cycloaddition
Experiment: R = TBS, R' = EtCalculation: R, R' = Me
CO2R'
OMe
Br
Me
OMe
MeO
OMeMe
H
H
H
H
H
CO2R'
OMe
Br
Me
OMe
MeO
OMeMe
H
H
H
H
H14
3
15
CO2R'
O
MeBr
Me
OMe
MeO
OMeMe
H
H
H
H
H
CO2R'
O
MeBr
Me
OMe
MeO
OMeMe
H
H
H
H
H
Br
O
RO
OR
Me
Me
HMe
CO2R'
HH
H
RO
H
Br
O
RO
OR
Me
Me
CO2R'
HH
H
H
Me
OR
!E =
2 kcal/mol
15
14
3
! Tricyclic intermediate has two low-energy conformations
! Application of transition state bond constraints energetically favors desired cyclization
kinetic conformation from 1st D-A required conformation for 2nd D-A
!!G = 27 kcal/mol
C3-C14: at 2.2 ÅO-C15: at 2.4 A
= –146 kcal/mol C3-C14: at 2.2 ÅO-C15: at 2.4 A
= –173 kcal/mol
X
Me
O
HO
OH
Me
Me
HMe
O
O
HH
H
(+)-FR182877(–)-FR182877
Me
O
HO
OH
Me
Me
H
O
H
O
Me
H
H
A Proposed Biogenetic Synthesis of FR182877
Me
O
HO
OH
Me
Me
HMeO
O
HH
(–)-FR182877
H
Me
CHO
OH
OH
CO2R
O
MeRO
Me
CO2R
O
MeRO
Me
CHO
H
Me
H
HOH
HO
Me
H
Me
H
HOH
HO
Me
Me
HO
Me
O
CO2R
H
Me
H
HOH
HO
Me
O
Me
OR
O
MeOH
IntramolecularDiels-Alder
reaction
Lactonization
Knoevenagelcondenstation
Transannular hetero-
Diels-Alder reaction
see Classics II, p. 490
(IMDA)
Me
Me
OH
OH
CO2R
O
MeHO
Me
Transannular Diels-Alder
reaction
Knoevenagelcondenstation
(TADA)
Me
Me
O
HO
OH
Me
Me
H
O
H
O
Me
H
H
Sorensen: Initial Retrosynthetic Strategy Towards (+)-FR182877featuring a D-A / Knoevenagel / D-A sequence
O
MeAcO
Me
CHO
H
Me
H
HOR
RO
Me
Knoevenagelcondenstation
Transannular hetero-
Diels-Alder reaction
N
O
MeAcO
Me
CHO
XOR
RO
Me
O
O
Bn
Tandem StilleCoupling-
IMDA
NO
O
Bn
Me
CHO
H
Me
H
HOR
RO
Me
O
Me
O
O
Claisen-TypeCyclization
Me
Y
X = SnBu3 or BrY = SnBu3 or I
Me
HO
OH
Me
Me
H
O
H
O
OMe
Highlighted Issues in the Initial Strategy Towards (+)-FR182877
O
MeAcO
Me
CHO
H
Me
H
H
CHO
Bu3SnOTBS
TBSO
Me
NO
O
Bn
Me
CHO
MePd2dba3 (5 mol%),Ph3As (20 mol%),
THF, reflux
N
O
MeAcO
Me
O
O
Bn
Me
Br
O
MeAcO
NO
O
Bn
OTBS
TBSO
Me
OTBS
TBSO
Me
IMDA
O
MeAcO
Me
CHO
H
Me
H
H
NO
O
Bn
OTBS
TBSO
Me
undesired endo cycloadduct
selectivity in the tandem Stille/IMDA sequence
or Cl2Pd(CN)2
DMF, rt
Highlighted Issues in the Initial Strategy Towards (+)-FR182877
O
MeAcO
Me
CHO
H
Me
H
H
NO
O
Bn
KHMDS ( 4 eq)THF, –78 °C
! Issues encountered in this approach:
The desired !-keto lactone substrate was unstable to Stille coupling, as such the acetate imide was used.
The IMDA was not diastereoface-selective and gave 2 endo cycloadducts (separable by chromatography)
The Knoevenagel condensation to form the tetracycle ring was unsuccessful
OTBS
TBSO
Me
Me
CHO
H
Me
H
HOTBS
TBSO
Me
O
Me
O
O
Knoevenagel
Sorensen: Org. Lett. 1999, 1, 645 + JACS 2003, 125, 5393
forming the !-keto lactone and Knoevenagel condensation
Me
HO
OH
Me
Me
H
O
H
O
OMe
5
revise strategy to an intermolecular Knoevenagel condensation
Me
HO
OH
Me
Me
H
O
H
O
OMe
A Revised Retrosynthetic Strategy Towards (+)-FR182877featuring a Knoevenagel / RCM approach
Ring-ClosingOlefin Metathesis
Transannular hetero-
Diels-Alder reaction
IntermolecularCondenstation
Me
RO
OR
Me
H
H
H
CHO
O
O
O
Me Me
Me
O
RO
OR
Me
H
Me
Me
O
HO
OH
Me
Me
H
O
H
O
Me
H
H
Me
H
O OH
H
Highlighted Issues in the Revised Strategy Towards (+)-FR182877
i. TBAF, THF
Me
TESO
OTES
Me
H
H
H
CHO
Me
TESO
OTES
Me
Me
TESO
OTES
Me
H
H
H
CHO
ii. Dess-Martin Periodinane, NaHCO3
iii. NMP, rt
O
O
Me
Me
O
N
Me
OMe
Me
TESO
OTES
Me
H
H
H
Br
O
O
Me
Me
O
N
Me
OMeBr
P
O
Me
Me
1.9:1 dr
53%
ii. Ba(OH)2, THF,
iii. TESCl, TEA, DMAP
6.5:1 Z:E
65%
i. Et3N•3HF
undesired product
Br
Me
TESO
OTES
Me
H
H
H
O O
Me
Me
O
N
Me
OMe
unfruitful condensation reactions are circumvented via a HWE
OTES
for IMDA rxn: Yamamoto's BLA and MacMillan's catalysts were also tried
undesired product
Highlighted Issues in the Revised Strategy Towards (+)-FR182877an unexpected olefin geometry in alkylidene formation
t-BuLi, THF, –78 °C
! Issues Encountered in this Approach:
O
O
Me
Me
O
N
Me
OMe
Me
TESO
OTES
Me
H
H
H
IMDA to form the first fragment was moderately diastereoface-selective (1.9:1 desired:undesired)
The desired !-keto lactone and the acyclic !-keto ester were not amenable to the Knoevenagel condensation
Isomerization to the needed E geometry of alkylidene ketolactone was not realized though various methods
O
O
Me
TESO
OTES
Me
H
H
H
Br
Me
O
Me
>90%H O
OR
E
Br
Me
TESO
OTES
Me
H
H
H
O O
Me
Me
O
N
Me
OMe transient lithium allenoate
undesired Z-olefin geometry
revise strategy to form E-geometry alkylidene dicarbonyl
Li
A Re-revised Retrosynthetic Strategy Towards (+)-FR182877
H-W-ECondensation
Transannular hetero-
Diels-Alder reaction
OR
RO
Me
Me
CHO
Me
O
MeRO
Me
O
MeO
N
Me
OR
OR
Me
O
P
Br
OMeO
OMe
OMe
Me
CHO
Me
O
MeRO
N
Me
OR
RO
Me
OMe
HH
IntramolecularDiels-Alder
reaction
!-allyl Stille coupling
reductive C-acylation
Me
Me3Sn
N
Me
OMe
OAc
Me
O
HO
OH
Me
Me
H
O
H
O
Me
H
H
Me
RO
OR
Me
Me
H
O
H
O
OMe
OTES
Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877
Me
Me
CHO
Me
O
MeHO
N
Me
OTES
TESO
Me
OMeMe
Me
O
MeHO
N
Me
OTES
TESO
Me
OMe
HH
Me
CHO
Me
O
MeO
N
Me
OH
HO
Me
O
P
Br
OMeO
OMe
OMe
HH
N
Me
TESO
OTES
Me
H
H
O
O
Me
O
OMe
i. TBAF, THF, 0 °C
ii. MnO2, DMF, rt
65% (2 steps)
1.6:1dr
i. DCC, NaHCO3
ii. Et3N•3HF, CH2Cl2
77%
Br
Me
MeO
P
O
MeO
Br
O
i. Ba(OH)2, THF/H2O
ii. TESCl, imid., DMAP
OH
IMDA and the HWE sequence
OTES
acylation yielded 4 spots(chromatographic separation
of desired endo product)
*
Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877
haunted by the formation of the E-alkylidene
Me
! Issues Encountered in this Approach:
IMDA gave poor diastereofacial selectivity (1.6:1 of desired:undesided cycloadduct)
Key reductive lithiation cyclization step resulted in the formation of an undesired Z alkylidene dicarbonyl tetracycle. It was conjectured that the geometrical constraints of the 12-membered ring would had favored the Z isomer
N
Me
TESO
OTES
Me
H
H
O
O
Me
O
OMe
Me
HO
OH
Me
H
H
O
ON
Me
TESO
OTES
Me
H
H
O
OLi
Me
O
OMe
i. t-BuLi, THF, –78 °C
Sorensen: Org. Lett. 2001, 3, 4307 + JACS 2003, 125, 5393
ii. PPTS, MeOH
64% (4 steps) Me
Br
Me
Me
Me
undesired Z olefin geometryconfirmed by X-ray
revise strategy in forging the C1-C19 bond and forming the !-keto lactone
1
19
O
Me
Sorensen: The Retrosynthetic Strategy that Workedfeaturing tandem TADA reactions
lactonization
Tsuji-Trostallylic alkylation
OMe OMe
O
OR
Me Me
OP
OTMS
Me
O ORO
!-allyl Stille coupling
ORMe
OR
SnMe3
Me
RO
ORMe
OR
P
O
O OMe
OMe
OR
Me
O
NO
O
Bn
Me
N
TMSO
Me
O O
Me
OMeAcO
Me
OTMS
Me
O
AcON O
O
Ph
Me
O
HO
OH
Me
Me
H
O
H
O
Me
H
H
Me
H
TMSO
OMe
Me
RO
OR
Me
O
t-BuOtandemTADAs
OR
HWEI
O
Me
H
Synthesis of !-allyl Stille Coupling Fragment
OTBSMe
OTMS
P
O
O OMe
OMe
OTBS
OH
Me
O
NO
O
Bn
OTBS
OTBS
OH
Me
O
N
Me
MeO
H
O
Me
O
NO
O
Bn
Bu2BOTf, TEAMeNHOMe • HCl
Me3Al, THF
75% (2 steps)
i. TMSCl, DMAP,imid, CH2Cl2
ii. LiCH2P(O)(OMe)2,THF, –78 °C
i. Ba(OH)2, THF;THF/H2O, 0 °C
O
Me
I
OHMe
OH
O
Me
I
i. Et2BOMe, NaBH4THF/MeOH
ii. TESCl, DMAP,imid., CH2Cl2
ii. PPTS, MeOH, rt
79% (4 steps)
OTESMe
OTES
TESO
Me
Sn(Me3)iii. Me3SnSnMe3,
Pd(Ph3P)4, Hünigs,PhH, 80 °C
83% (3 steps)
(2 steps from diol)
The !-allyl Stille Coupling of the Aldol Fragments
OH
Me
O
NO
O
Ph
OAc
OAc
OTMS
Me
O
N
Me
MeO
Me
O
NO
O
Ph
Bu2BOTf, TEAi. MeNHOMe • HCl
Me3Al, THF
Pd2dba3, LiCl, NMPHünig's base, 40 °C
OTESMe
OTES
TESO
Me
Sn(Me3)
85%
Me
H
O
Me
OAc
"known aldehyde"Tetrahedron, 1972, 28, 2622
ii. TMSCl, DMAP, imid, CH2Cl2
87% (4 steps)
OTESMe
OTES
Me Me
NOMe
OTMS
Me
OTESO
Me
Trost-Tsuji Coupling to the 19-Membered Macrocycle
i. LDA, t-BuOAc, THF
ii. TBAF, THF
70%
OTESMe
OTES
Me Me
NOMe
OTMS
Me
OTESO
Me
OHMe
OTES
Me Me
OH
Me
OTESO
Ot-Bu
O
i. MeOCOCl, pyridine
ii. TMS, imid, CH2Cl2
88%
OMe
OTES
Me Me
OTMS
Me
OTESO
Ot-Bu
O
OMe
O
Pd2dba3 (10 mol%) THF (0.005 M), 40 °C
80%
Me
OTES
Me Me
OTMS
Me
OTESO
Ot-Bu
O
PdL2
Me
H
TMSO
OMe
Me
TESO
OTES
Me
O
t-BuO
single diastereomer(configuration at C19 was not determined)
*
CO2, OMe
TMSO
Me
Tandem Diels-Alder Sequence
KHMDS, PhSeBr
91%
mCPBA, CH2Cl2;
40%
3:1 dr
*
NaHCO3, CHCl340 °C, 4h
Me
O
TESO
OTES
Me
H
Me
Me
O
TESO
OTES
Me
Me
Me
O
TESO
OTES
Me
H
H
H
Me
TESO
OTES
Me
Me elimination yields an inseparable
mix of olefin geometries
"two byproducts...the majority of the mass balance, are
presumably formed from the Z-isomer"
Me
H
TMSO
OMe
Me
TESO
OTES
Me
O
t-BuO
Me
HO
O
t-BuO
PhSe
Me
H
TMSOO
t-BuO
Me
H
TMSOO
t-BuO
Me
H
OTMSCO2
t-Bu
H
Me
Me
O
TESO
OTES
Me
H
H
H
Me
H
OTMSCO2
t-Bu
H
Completion of the Synthesis of (+)-FR182877
i. PPTS, MeOH, rtEDC, DMAP,
CH2Cl2, rt
63% (3 steps)ii. TFA:CH2Cl2 (1:9)
Me
O
HO
OH
Me
H
Me
H
H
! Demonstrated the gram scale synthesis of the natural enantiomer (–)-FR182877
Limitation of this synthesis was the undesired Z-isomer in the selenium-based desaturation
60g of dienyl stannane and 47g the allylic acetate were used to synthesize 3.2g of the natural product
Sorensen: [!]23D = +5.7
Fujisawa : [!]23D = –3.5
Me
H
HOO
t-BuO
Me
O
HO
OH
Me
Me
H
O
H
O
Me
H
H
Adventures in Synthesis: Comparative Syntheses of FR182877
! Both successful strategies included a casade Diels-Alder sequence to yield the hexacyclic frame of the natural product
Evans Synthesis
17 linear steps6.04% yield
84.8% avg.yield/step
Sorensen Synthesis
22 linear steps2.09% yield
83.9% avg.yield/step
Me
O
HO
OH
Me
Me
HMeO
O
HH
H
(+)-FR182877(–)-FR182877
Me
O
HO
OH
Me
Me
H
O
H
O
Me
H
H
