Fr182877

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 HO
H Me
Cytotoxicity and Antimitotic Activity
A
Me B
! Isolation–Fujisawa Pharmaceutical Co. H H
OH
C O
Isolated from the fermentation broth of Steptomyces 2
in 1998 with IC50 = 28-75 ng/mL cytotoxicity against DO
several cell lines. Me
20
EO F H

Structurally similar natural products: Hexacyclic
Me
Acid, Macquaimicin A, and Cochleamycin A

! 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 ! Ongoing synthetic efforts
(+)-FR182877 by Sorensen in 2002 Armstrong in 2001: Model DF ring system
(–)-FR182877 by Evans in 2002 Nakada in 2002: AB bicycle
(+)-FR182877 by Sorensen in 2003 Roush in 2003: ABC tricycle
Prunet in 2004: A ring
Clarke in 2005: DEF ring system, B ring

H O O H
O Me Me O
H H H H
Me Me
HO H OH HO H OH
H H
O O
H VS. H
H Me H
H Me H
Me Me

(+)-FR182877 (–)-FR182877

A Proposed Biogenetic Synthesis of FR182877 HO
H Me

Me OH
OH Me
OH
H H
Intramolecular
Me Diels-Alder CHO
reaction
Me O CHO Me O
(IMDA)

CO2R CO2R
Knoevenagel RO Me RO Me
condenstation
HO
H
Knoevenagel
Me
condenstation
Me OH
OH Me
Transannular OH
Diels-Alder H H
Me reaction
CO2R
(TADA) O
Me O Me
Transannular
CO2R Me hetero-
HO Diels-Alder
HO Me
reaction
HO HO
H Me H Me

Me Me
OH OH
H H H H
O
Lactonization
O
O
Me H Me
O
O OR
Me
(–)-FR182877 OH
see Classics II, p. 490 Me

The Pivotal Transformation: Endo vs. Exo
HO
H Me

Me B CO2R
OH HO OH H H OH
H H Me OH
O Cascade TADA Me
B D
O H
H
DO
Me
Me O H Endo-TS Me

Me
(–)-FR182877
Me OH
OH

Me

Me O

CO2R
HO Me AcO
H Me

CO2R OH HO2C B
HO OH H OH
OH H H
Me
Me Cascade TADA H O
D
B O H
H DO
OH
Me O H
Exo-TS Me
Me
Me
Hexacyclinic Acid

Evans: A Diels-Alder Cascade Strategy

Suzuki
HO
H Me Br OR
OR
Transannular
Me Diels-Alder
OH reaction Me
H H
O
Transannular Me O
O hetero- !-ketoester alkylation
Me O H Diels-Alder
reaction CO2Et
Me TBSO Me

OR OR O O OH O
OTBDPS OTBDPS OTBDPS
(HO)2B O N H
Me Me
Bn

O OR O O OH O
MeO Me Me Me
N O N H
Me Me Br Me
OTBS OTBS
Bn
Br

Aldol Fragment Synthesis: Dibromide Fragment

O
O i. , THF
i. TBSCl, DMF, imid. Me MgBr Me
H
OH H OTBS
ii. O3/O2; PPh3 ii. triethylorthoacetate,
proprionic acid, 150°C OTBS
75%
iii. DIBAL, –78 °C
73%

O O OH i. MeNHOMe • HCl
Bu2BOTf, TEA Me3Al, THF
Me
O O O N
ii. TBSCl, DMF, imid.
88% Me
OTBS iii. TsOH:nBu4NHSO4 (1:4)
O N Bn MeOH, 0 °C
Me
82%
Bn

O OTBS i. Dess-Martin O OTBS
MeO Me Periodinane, NaHCO3 MeO Me
N N
Me
ii. CBr4, PPh3, Me Br
Me Me
OH CH2Cl2, NaHCO3

70% Br

Aldol Fragment Synthesis: Boronic Acid Fragment

OH i. nBuLi, THF
TBDPSCl O Bu2BOTf, TEA
OTBDPS
HO H O O
ii. SO3–Pyr, DMSO
CH2Cl2, TEA 89%
O N
59%
Me
Bn

OH
i. MeNHOMe • HCl
O O O OH
Me3Al, THF i. DIBAL, THF, –78 °C
O N
ii. HCCMgBr ii. TBSCl, DMF, imid.
Me OTBDPS Me OTBDPS
75% >20:1 dr
Bn
92%

catechol-BH,
OTBS OTBS Cy2BH (10 mol%) OTBS OTBS
THF; 1N NaOH
(HO)2B
97%
Me OTBDPS Me OTBDPS

Suzuki Coupling of the "Aldol" Fragments HO
H Me
O OTBS
MeO Me Me
OH
N H H
O
Me Me Br 5% Pd(PPh3)4
Tl2CO3 O
Me O H
Br THF:H2O (3:1), rt
Me
84% desired pdt
OTBS OTBS
OTBDPS
(HO)2B 8

Me

O OTBS
MeO Me
N OTBS OTBS
Me Me OTBDPS

Br Me

undesired double
addition product
! Highly Optimized Suzuki Coupling Conditions
O OTBS
The coupling was sensitive to the choice of base:
MeO Me
(1) strong bases (i.e. hydroxides, oxides) or less halophilic N OTBS OTBS
cations resulted in slower rates and competitive Me Me OTBDP
decomposition of SM via protodeborylation, oxidation, S
elimination, etc. Me
OTBS
(2) silver bases completely decomposed products' OTBDPS
TBSO
(3) carbonates had the best selectivity and only Tl2CO3
Me
gave good reaction at rt

Synthesis of the Pivotal Macrocycle

O OTBS O O OTBS
MeO Me Me
N EtO
Me Me Me

Br i. DIBAL, –78 °C Br

ii. ethyldiazoacetate
OTBS SnCl2 OTBS
TBDPSO 70% TBDPSO
OTBS OTBS
Me Me

O O OTBS
Me O Me OTBS
EtO EtO
2
Me
Cs2CO3, *
i. TBAF, AcOH, DMF THF (0.005M), rt O Me
Br

ii. I2, PPh3, CH2Cl2 1:1 dr Me
OTBS
64% (3 steps)
I TBSO
OTBS Br
TBSO
Me

The Diels-Alder Cascade in Action

TBSO
O Me OTBS Me OTBS H Me
EtO EtO2C
Br
Ph2Se2O3, SO3-Pyr O Me OTBS
O Me H H
TEA, THF, rt;
CO2Et
Me hexanes, 50 °C Me
TBSO
63% Me O H
TBSO TBSO
Br H
TBSO Br TBSO Me

single diastereomer

HO HO
H Me H Me

i. HF-MeCN Me TMSOK, THF; Me
OH OH
H H H H
ii. Pd(dppf)Cl (10 mol%) CO2Et NaHCO3, CH2Cl2 O
Me3B3O3, Cs2CO3, O
DMF:H2O (2:1), 100 °C HO
Me H Cl 62% Me H
O O
N I
63% H
Me Me Me

Evans: [!]23D = -5
Fujisawa: [!]23D = -3.5

A Closer Look at the Cyclization Sequence
intermediate species were not isolable
TBSO
Me OTBS TBSO
Me OTBS H Me
EtO2C H Me
EtO2C
Br B
O Me [O] 15
H OTBS Br
3 O Me H H OTBS
H H
4 14
Me " CO2Et
5 Me CO2Et
12
Me O TBSO
TBSO 9 Me O H
Br TBSO Me
TBSO Br H
TBSO
Me
OTBS

! NMR analysis shows 2H-pyran equilibrium
O Z
1:1
X O
! Cyclization order? The Normal-demand DA (NDA)
Y OH Me OTBS
or inverse-demand hetero DA (HDA)?
EtO2C
Keq = FMO anaylsis using calculated (Spartan 5.1) Pz orbital
1-10 coefficients of the HOMO and LUMO predicts B-ring
O Me
cyclization to occur first.
O
OTBS

OH Me
HOMO LUMO
X
O Z TBSO Br Atom Pz Atom Pz
Y
best overlap
C9 0.38 C5 0.51
best overlap
C12 -0.48 C4 -0.26
C14 -0.07 C3 -0.56
C15 0.03 O1 -0.29
Moorhoff (Syn 1997, 685): 6!-cyclization to pyran tautomer

Studying the Inherent Stereoselectivity of the TADA Cascade

! 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

O OTBS TBSO TBSO
MeO Me H Me H Me
N 8
6
Me Me Br Br 11
OTBS OTBS
Br
60 °C, CDCl3, 3h H H H H
CHO CHO
37:63 dr
OTBS Me O OMe Me O OMe
O N N
OTBS
Me 18 19 Me
Me
TBSO Me TBSO Me

desired cycloadduct

! The high face-selectivity of the TADA cycloaddition is conjectured to arise from C18,C19 stereocenters

OMe Me OMe
Modeling the TADA Endo Me CO2Me
Transition States H
H O
Me
MeO
H
H Me

HH H O OMe H
MeO OMe
MeO O
H H
H
endo TS I Br Br
Me Me
Nine simplified macrocycles (varied
Me OMe
at C18 and C19) were energy-
CO2Me
minimized (PM3) with distance MeO H H MeO H
H Me
constraints (of 2.9-2.1 Å) leading to O Me MeO
Me
the observed natural product (via H H OMe
Br O OMe O
endo TS I) or it's endo MeO Me
H H
diastereomer (via endo TS II).
H Br
endo TS II H
Me

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).
18 19 Me OMe
EtO2C
EtO2C

O Me OTBS
Me O Me
CHO
Me
Me
TBSO Me
MeO
Br Br MeO
MeO
MeO Br

4.0-9.4 kcal/mol

Analysis of the Transannular Hetero Diels-Alder Cycloaddition

! Tricyclic intermediate has two low-energy conformations

Me OMe Me OMe
H CO2R'
Me H CO2R'
H !E = H Me
MeO MeO
H Me O OMe H OMe
HO
2 kcal/mol
H H
Br H Br Me

kinetic conformation from 1st D-A required conformation for 2nd D-A

! Application of transition state bond constraints energetically favors desired cyclization

Me OMe Me OMe
H CO2R' H
3 Me CO2R'
H H 3
Me
MeO MeO
H Me O OMe H HO OMe

X 15 14 RO
RO H 14 H Me
15 H
H Me Br H Br Me

C3-C14: at 2.2 Å = –146 kcal/mol C3-C14: at 2.2 Å = –173 kcal/mol Br
Br OR
OR O-C15: at 2.4 A O-C15: at 2.4 A H H
H H
OR CO2R'
CO2R'
!!G = 27 kcal/mol RO
Me Me O H
Me O Experiment: R = TBS, R' = Et H
H Calculation: R, R' = Me Me

HO HO
H Me Me

Me Me
OH H OH
H H
O H O O

O H
H
Me O H Me O
Me
Me

(–)-FR182877 (+)-FR182877

Sorensen: Initial Retrosynthetic Strategy Towards (+)-FR182877
featuring a D-A / Knoevenagel / D-A sequence

RO
H Me

HO HO
Me Me Me
Transannular OR
H H
hetero- CHO
Me Diels-Alder Me Knoevenagel
H OH reaction H OH
condenstation
H O O O O Me
H
H H O
Me O Me O
Me O
Me Me

O

RO RO
H Me Me
Y
Me Me X
OR Tandem Stille OR
H H
Claisen-Type Coupling- CHO
Cyclization CHO
IMDA
Bn Bn
Me O Me O
N N
O O
X = SnBu3 or Br
AcO Me O AcO Me O Y = SnBu3 or I

Highlighted Issues in the Initial Strategy Towards (+)-FR182877
selectivity in the tandem Stille/IMDA sequence

TBSO TBSO
Me Me
Br
Bu3Sn Pd2dba3 (5 mol%), Me
Me OTBS OTBS
Ph3As (20 mol%),
THF, reflux IMDA
CHO CHO
Bn
Bn or
Me O
Me O Cl2Pd(CN)2
DMF, rt N
N O
O
AcO Me O
AcO Me O

TBSO TBSO
H Me H Me

Me Me
OTBS OTBS
H H H H
CHO CHO
Bn Bn
Me O Me O
N N
O O

AcO Me O AcO Me O

undesired endo cycloadduct

Highlighted Issues in the Initial Strategy Towards (+)-FR182877
forming the !-keto lactone and Knoevenagel condensation

TBSO TBSO
H Me H Me

Me Me
OTBS 5 OTBS
H H KHMDS ( 4 eq) H H
CHO THF, –78 °C CHO Knoevenagel
Bn
Me O Me
N
O
O
AcO Me O Me O

O

HO ! Issues encountered in this approach:
Me
The desired !-keto lactone substrate was unstable to Stille coupling, as such the
acetate imide was used.
Me
H OH
The IMDA was not diastereoface-selective and gave 2 endo cycloadducts
O O (separable by chromatography)

H The Knoevenagel condensation to form the tetracycle ring was unsuccessful
Me O
Me revise strategy to an intermolecular Knoevenagel condensation

Sorensen: Org. Lett. 1999, 1, 645 + JACS 2003, 125, 5393

A Revised Retrosynthetic Strategy Towards (+)-FR182877
featuring a Knoevenagel / RCM approach

HO HO
Me Me
Transannular
Me hetero- Me
H OH Diels-Alder H OH Ring-Closing
H O
reaction O Olefin Metathesis
O O

H
H H
Me O Me O
Me Me

RO
H Me
RO
Me Me
H OR
H
O
Me CHO
H OR Intermolecular
H Condenstation
O O
O
H
O
H
O Me Me
Me
Me

Highlighted Issues in the Revised Strategy Towards (+)-FR182877
unfruitful condensation reactions are circumvented via a HWE

TESO i. TBAF, THF TESO TESO
Me ii. Dess-Martin H Me H Me
Periodinane, NaHCO3
Me Me Me
OTES H OTES H OTES
iii. NMP, rt H H
OTES CHO CHO
1.9:1 dr
53% undesired
product

O O
for IMDA rxn: Yamamoto's BLA and MacMillan's i. Et3N•3HF
Me
catalysts were also tried P
ii. Ba(OH)2, THF, Me O O
Br OMe
iii. TESCl, N
TEA, DMAP
Me Me
6.5:1 Z:E
Me
TESO 65%
H Me
TESO
H Me
Me
H OTES
H
Me
Br H OTES
H O

O O O O O
OMe Br OMe
N N
Me Me Me Me

Me Me undesired product

Highlighted Issues in the Revised Strategy Towards (+)-FR182877
an unexpected olefin geometry in alkylidene formation

TESO TESO
H Me H Me

Me Me t-BuLi,
H OTES OTES THF, –78 °C
H H H OR
O
Br >90%
H O Li
O O
Br OMe E
O O O N
OMe Me Me transient lithium allenoate
N
Me Me Me

Me

TESO
H Me ! Issues Encountered in this Approach:

Me IMDA to form the first fragment was moderately diastereoface-selective (1.9:1
H OTES desired:undesired)
H

The desired !-keto lactone and the acyclic !-keto ester were not amenable to the
O O
Knoevenagel condensation
O Isomerization to the needed E geometry of alkylidene ketolactone was not
Me
realized though various methods
Me
revise strategy to form E-geometry alkylidene dicarbonyl
undesired Z-olefin geometry

A Re-revised Retrosynthetic Strategy Towards (+)-FR182877
OR
Me

Me
OR
H H
HO RO
Me Me CHO
Transannular
hetero-
Diels-Alder H-W-E Me O OMe
Me Me Condensation
reaction
H OH H OR N
H O O O O Me
O Me
H
H H Br
Me O Me O O
Me Me P OMe
reductive C-acylation O
OMe

RO
RO
Me Me

Intramolecular Me
Diels-Alder Me OR
OR
reaction
Me3Sn OTES
CHO OAc
!-allyl Stille coupling
Me O OMe
N Me O OMe
Me N
RO Me Me
RO Me

Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877
IMDA and the HWE sequence

TESO TESO O O
Me Me MeO P
OH
MeO
Me Me Br
OTES OTES
i. TBAF, THF, 0 °C H H i. DCC, NaHCO3
OTES CHO
ii. MnO2, DMF, rt ii. Et3N•3HF, CH2Cl2
Me O OMe Me O OMe
65% (2 steps) 77%
N N
Me 1.6:1dr Me acylation yielded 4 spots
(chromatographic separation
HO Me HO Me of desired endo product)

HO TESO
Me Me

Me Me
OH OTES
H H i. Ba(OH)2, THF/H2O H
CHO Me Br OMe
H N
ii. TESCl, imid., DMAP O
Me O OMe Me O
O
N
Me Me
O Me
Br
O
*
P OMe
O
OMe

Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877
haunted by the formation of the E-alkylidene

TESO TESO HO
Me Me Me

Me Me Me
H OTES i. t-BuLi, THF, –78 °C H OTES H OH
1
Me Br OMe H OMe H
H Me 19 O
N ii. PPTS, MeOH N
O OLi O
Me O 64% (4 steps) Me O Me
O O
O
Me
Me Me

undesired Z olefin geometry
confirmed by X-ray

! 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

revise strategy in forging the C1-C19 bond and forming the !-keto lactone

Sorensen: Org. Lett. 2001, 3, 4307 + JACS 2003, 125, 5393

Sorensen: The Retrosynthetic Strategy that Worked
featuring tandem TADA reactions

RO OR
HO
Me
Me lactonization Me O OMe

Me O
Me OR
tandem RO OTMS O O
H OH t-BuO
TADAs
H O TMSO O
O
OP
H H Me Me Me
H Me O
Me O !-allyl Stille coupling
Me
Me
Tsuji-Trost
allylic alkylation

OR
Me OR OR
O O OR Me OR
OR O O
O N OMe
P RO HWE
Me O OMe H I
Bn Me
SnMe3
Me

OTMS O O TMSO O O
AcO
N AcO OMe
O
N
Me Me Me Me Me
Ph

Synthesis of !-allyl Stille Coupling Fragment

MeNHOMe • HCl
O O O OH
Bu2BOTf, TEA Me3Al, THF
OTBS OTBS
H O N
O O 75% (2 steps)
Me
(2 steps from diol)
O N Bn
Me
Bn

OTMS
i. TMSCl, DMAP,
O OH Me OTBS
imid, CH2Cl2
MeO OTBS
N
ii. LiCH2P(O)(OMe)2, O
Me Me THF, –78 °C OMe
P
O OMe

OH OTES
i. Ba(OH)2, THF; Me OH i. Et2BOMe, NaBH4 Me OTES
THF/H2O, 0 °C THF/MeOH

O ii. TESCl, DMAP, TESO
I O
imid., CH2Cl2
Me I Sn(Me3)
Me iii. Me3SnSnMe3, Me
ii. PPTS, MeOH, rt Pd(Ph3P)4, Hünigs,
79% (4 steps) PhH, 80 °C

83% (3 steps)

The !-allyl Stille Coupling of the Aldol Fragments

O O OH
i. MeNHOMe • HCl
O Bu2BOTf, TEA Me3Al, THF
OAc OAc
H O N
O O ii. TMSCl, DMAP,
Me Me Me
imid, CH2Cl2
O N Ph
87% (4 steps)
"known aldehyde" Me
Tetrahedron, 1972, 28, 2622 Ph

O OTMS
MeO OAc
N OTES

Me Me Me OTES
Pd2dba3, LiCl, NMP
Hünig's base, 40 °C
TESO OTMS O
85% OMe
OTES N
Me OTES Me Me Me Me

TESO

Sn(Me3)
Me

Fr182877

Recomendados

Recomendados

Mais conteúdo relacionado

Mais procurados

Mais procurados (16)

Mais de ORmeetinggroup

Mais de ORmeetinggroup (7)

Último

Último (20)

Fr182877