This document summarizes a meeting presentation about total syntheses of the natural product FR182877. Key points include:
- FR182877 is a cytotoxic natural product isolated from bacteria in 1998. It poses synthetic challenges due to its large hexacyclic structure containing multiple stereocenters.
- Total syntheses of both enantiomers of FR182877 have been achieved by the Sorensen and Evans groups using Diels-Alder cascades.
- The presentation discusses proposed biogenetic pathways, retrosynthetic analyses, key transformations such as Suzuki couplings and macrocyclization reactions, and studies of the stereoselectivity of the Diels-Alder cascade central to the
Self explanatory really, this lecture looks at chiral auxiliaries. We will concentrate on oxazolidinones in alkylations, aldol reaction and the Diels-Alder reaction. There will be a couple examples of other auxiliaries.
The big topic of the last few years, the use of small organic molecules to catalyse enantioselective transformations. This lecture will start with proline before moving on to some of MacMillan's contributions to this field and, finally, finish with hydrogen bond catalysts and Brønsted acids.
Self explanatory really, this lecture looks at chiral auxiliaries. We will concentrate on oxazolidinones in alkylations, aldol reaction and the Diels-Alder reaction. There will be a couple examples of other auxiliaries.
The big topic of the last few years, the use of small organic molecules to catalyse enantioselective transformations. This lecture will start with proline before moving on to some of MacMillan's contributions to this field and, finally, finish with hydrogen bond catalysts and Brønsted acids.
Finishing oxidation by looking at the Baeyer-Villiger reaction and then turning our attention to reduction. Once again we will see the usual suspects with a who is who of hydride sources.
published in the journal Molecules, 2012-04; This review presents findings that indicate honey may improve oxidative stress in chronic diseases, such as in the gastrointestinal tract (GIT), liver,
pancreas, kidney, reproductive organs and plasma/serum.
Here is a brief overview of some of my work at Mayo Clinic Jacksonville, where I worked in the Organic Synthesis Core Facility for the little over two years between my undergraduate education and graduate school.
A pharmaceutical Chemist shares a view of organic chemistry and his role preparing enantiomeric drugs for clinical trials. Dr. Welch is also on the Titan Explorer team looking for signs of life on other planets
Finishing oxidation by looking at the Baeyer-Villiger reaction and then turning our attention to reduction. Once again we will see the usual suspects with a who is who of hydride sources.
published in the journal Molecules, 2012-04; This review presents findings that indicate honey may improve oxidative stress in chronic diseases, such as in the gastrointestinal tract (GIT), liver,
pancreas, kidney, reproductive organs and plasma/serum.
Here is a brief overview of some of my work at Mayo Clinic Jacksonville, where I worked in the Organic Synthesis Core Facility for the little over two years between my undergraduate education and graduate school.
A pharmaceutical Chemist shares a view of organic chemistry and his role preparing enantiomeric drugs for clinical trials. Dr. Welch is also on the Titan Explorer team looking for signs of life on other planets
2024.06.01 Introducing a competency framework for languag learning materials ...Sandy Millin
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Published classroom materials form the basis of syllabuses, drive teacher professional development, and have a potentially huge influence on learners, teachers and education systems. All teachers also create their own materials, whether a few sentences on a blackboard, a highly-structured fully-realised online course, or anything in between. Despite this, the knowledge and skills needed to create effective language learning materials are rarely part of teacher training, and are mostly learnt by trial and error.
Knowledge and skills frameworks, generally called competency frameworks, for ELT teachers, trainers and managers have existed for a few years now. However, until I created one for my MA dissertation, there wasn’t one drawing together what we need to know and do to be able to effectively produce language learning materials.
This webinar will introduce you to my framework, highlighting the key competencies I identified from my research. It will also show how anybody involved in language teaching (any language, not just English!), teacher training, managing schools or developing language learning materials can benefit from using the framework.
Macroeconomics- Movie Location
This will be used as part of your Personal Professional Portfolio once graded.
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Prepare a presentation or a paper using research, basic comparative analysis, data organization and application of economic information. You will make an informed assessment of an economic climate outside of the United States to accomplish an entertainment industry objective.
The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
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How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
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Francesca Gottschalk from the OECD’s Centre for Educational Research and Innovation presents at the Ask an Expert Webinar: How can education support child empowerment?
Honest Reviews of Tim Han LMA Course Program.pptxtimhan337
Personal development courses are widely available today, with each one promising life-changing outcomes. Tim Han’s Life Mastery Achievers (LMA) Course has drawn a lot of interest. In addition to offering my frank assessment of Success Insider’s LMA Course, this piece examines the course’s effects via a variety of Tim Han LMA course reviews and Success Insider comments.
Read| The latest issue of The Challenger is here! We are thrilled to announce that our school paper has qualified for the NATIONAL SCHOOLS PRESS CONFERENCE (NSPC) 2024. Thank you for your unwavering support and trust. Dive into the stories that made us stand out!
1. 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.
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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
25. 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
26. 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
27. 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
28. 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)
29. 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