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Total Synthesis of Longithorone A
Literature Meeting
March 11th 2008
Charette group
Angelique Fortier
2
Longithorone A
Key Concepts Biomimetic synthesis Atropisomerism Enyne metathesis Organozinc reagents Transannular Diels-Alder reactions
OO
MeH
OH
O
Me
Me
O
3
Longithorone A
Marine natural product Found on island of Palau in 1994
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4
¿Desirable synthetic target?
It’s low cytotoxicity and
lack of biological
activity is over
compensated by its
attractive
conglomeration
of rings and its
stereochemical
complexity.
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Isolate of tunicate Aplydium longithorax; sponge
OO
MeH
OH
O
Me
Me
O
5
Logistics
5x 6-, 10-, and 16 membered rings
2 types of chirality Stereogenic centers Atropisomerism
6 stereogenic centers 2 of which are
quaternary
OO
MeH
OH
O
Me
Me
***
* **
6
10
1666
6
6O
6
Biomimetics - Structural Harmony
Amalgamation of two smaller macrocyclic subunits
These subunits are comprised of Farnesyl units
conecting position 2 and 5 of
Paraquinone moiety One aspect to beware
of…
1
12
OO
MeH
OH
O
Me
Me
O
Longithorone A
1
OO
MeH
O
O
Me
Me
O
12
1
12
3 5 7 9
3
5 79
35
7
9
Generic farnesyl unit
7
Atropisomerism
Severely strained sequential 6-memered rings None can adopt the most stable chair conformation
B-ring is cis fused to with C-ring, trans fused with A-ring, and has attachment point to D-ring Forces A- and B-rings in distorted boat conformation Forces C- and D-rings in mutated half-chairs
Spacial constraints give rise to an element of chirality known as atropisomerism
OO
MeH
OH
O
Me
Me
***
* **
6
10
1666
6
6O
8
Longithorone A
First isolated in 1994
by Professor
F. J. Schmitz
and co-workers at the
University of Oklahoma
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J. Am. Chem. Soc. 1994, 116, 12125-12126
9
Schmitz’ biogenetic retrosynthetic analysis
OO
MeH
OH
O
Me
Me
(-)-Longithorone A
A B C
D
E OO
MeH
O
O
Me
Me
C
D
E
Diels-Alder reaction
Transannular
Diels-Alder reaction
OO
Me
Me
E
O
O
Me
D +
dienedienophile
O
O
O
1 2
3 4
10
Schmitz’ biogenetic retrosynthetic analysis
OO
MeH
OH
O
Me
Me
A B C
D
E OO
MeH
O
O
Me
Me
C
D
E
Diels-Alder reaction
TransannularDiels-Alder reaction
OO
Me
Me
E
O
O
Me
D +
dienedienophile
Me Me
Me
O
O
Longithorone B
O
O
O
11
Longithorone A
First chemically
synthesized in 2002
by Professor
Matthew Shair
and two of his graduate
students at Harvard
University
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J. Am. Chem. Soc. 2002, 124, 773-775
PNAS 2004, 101, 12036-12041
12
Shair’s retrosynthetic analysis
OO
MeH
OH
O
Me
Me
O
OO
MeH
O
O
Me
O
OMeTBSO
MeH
O
Me
Me
transannularDiels-Alderreaction
Quinoneformation
OTBS
MeOOMeTBSO
Me
MeO
MeO
Me
+
dienedienophile
OTBS
Me
Diels-Alderreaction
1
2
7
8
9
13
Shair’s retrosynthetic analysis
1 2
78
9
OO
MeH
OH
O
Me
Me
O
OO
MeH
O
O
Me
Me
C
D
E
O
OMeTBSO
MeH
O
Me
Me
C
D
E
transannularDiels-Alderreaction
Quinoneformation
OTBS
MeOOMeTBSO
Me
MeO
MeO
Me
+
dienedienophile
OTBS
Diels-Alderreaction
14
Shair’s retrosynthetic analysis
OO
MeH
OH
O
Me
Me
O
OO
MeH
O
O
Me
Me
O
OMeTBSO
MeH
O
Me
Me
Diels-Alder reaction
transannularDiels-Alderreaction
Quinoneformation
OTBS
MeOOMeTBSO
Me
MeO
MeO
Me
+
dienedienophile
OTBS
1 2
78
9
15
Shair’s retrosynthetic analysis
It is interesting to note that the diene and dienophile are obtained from the same precursor, and is subject to similar chemistry
78
9
OMeTBSO
MeH
O
Me
Me
OTBS
MeOOMeTBSO
Me
MeO
MeO
Me
+
diene
dienophile
OTBS
OMeTBSO
Me
Me OTBSOTBS
MeO
Me
OTBSH
TBSO
Enynemetathesis
OMeTBSO
Me
Me OTBS
Diels-Alderreaction
1110
12
16
Shair’s retrosynthetic analysis
1416
15
1110 12
OMeTBSO
Me
Me OTBSOTBS
MeO
Me
OTBSH
TBSO
Enynemetathesis
Enynemetathesis
OMeTBSO
Me
Me OTBS
Asymmetricalkenylation
OMeTBSO
Me
TIPS
HO
TMS Me
I
OTBS
MeO
Me
OTBSH
TBSO
Asymmetricalkenylation
TBSO I
13
17
Shair’s retrosynthetic analysis
141615
1110
12
13
OMeTBSO
Me
Me OTBSOTBS
MeO
Me
OTBSH
TBSO
Enynemetathesis
Enynemetathesis
OMeTBSO
Me
Me OTBS
Asymmetricalkenylation
OMeTBSO
Me
TIPS
HO
TMS Me
I
OTBS
MeO
Me
OTBSH
TBSO
Asymmetricalkenylation
TBSO I
18
Ene-yne metathesis
Intramolecular ene-yne metathesis affords 1,2-disubstituted dienes
Intermolecular ene-yne metathesis affords 1,3-disubstituted dienes
What will happen for a macro-intramolecular?…
0-40-4
[Ru]
[Ru]R2 R1
R2R1
1,2-disubstituted diene
1,3-disubstituted diene
0-4
[Ru]
0-4[Ru]
0-4
[Ru] -[Ru]=
12
[Ru]R2
R1[Ru]
R1
R2
[Ru]
R1
R2
R2
-[Ru]=R2
R21
3
19
Ene-yne metathesis control
Assumed macrocyclization would resemble intermolecular reaction Hence a 1,3-disubstituted diene
Since the resulting [12]-paracyclophane is less strained than a [11]-paracyclophane (from a 1,2-disubstituted diene)
20
Ene-yne metathesis
1,3 observed especially for ring sizes of 12 and greater
Only 5 to 8 membered had been tested previously First report of macro-ene-yne RCM
But how to control which atropisomer is obtained…
21
Vancomycin
Nicolaou successfully used removable directing groups to direct an atropselective macrocyclization.
Evans group also used the same strategy Directing groups govern the transition state
adopted during enyne metathesis The A(1,3) interaction is worth several
kcal/mol more and hence will be the disfavored conformer
22
Vancomycin
Cl
OHTBSO
TIPSO
NH
HN
ONHBoc
O
OEt
O
OMe
Br
N
Br
N
N
OTBSO
TIPSO
NH
HN
ONHBoc
O
OEt
O
OMe
Br
N
Br
N
N
Cl Cu
O
TIPSO
NH
HN
ONHBoc
O
OEt
O
OMe
Br
N
Br
N
N
Cu
ClRO
HOH
TIPSO
NH
HN
ONHBoc
O
OEt
O
OMe
Br
N
Br
N
N
ClRO
23
Atropisomerism control
Strategic benzylic hydroxyl groups should favor A & C and disfavor B & D due to A(1,3) strain
Benzylic hydroxyl groups can then be removed reductively Absence of this control
group led to non-selective ring closure
OPG
OPGMe
MeO
Me
OPGMe
Me
OMe
OPG
1,3-allylic strainatropisomer control group
MeO OPG
Me
OPG
GPOH
Me
OPG
GPOH
OMe
GPO
1,3-allylic strainatropisomer control group
A B
C D
24
Negishi-type cross-coupling
Directing group installed via asymmetric alkenylation of an aldehyde Can then be removed by hydride displacement or acid-
mediated lysis
This starting material was derived from a Negishi-type Pd cross-coupling reaction
OMeTBSO
Me
TIPS
HO TMS
I
OMeMeO
Me
TIPS
Br
BrMeO
OMeBr
Me
Pd-mediatedcross-coupling
25
Total Synthesis
TIPS
Me
IOH
TIPSOH
EtMgCl,THF, Δ, 12h;
TIPSCl, Δ, 6h(94%)
1. Dess-Martin [O]
2. THF,
(47% overall)3839 40 Ph3P I
Me
OO
MeH
OH
O
Me
Me
O
protectionoxidation
Z selective Wittig via unstabalized ylide
26
Total Synthesis OO
MeH
OH
O
Me
Me
O
Halogen metal exchange
quench
reduction
Exchange of BzOH for Br
Conversion to zinc bromide species
Pd-Negishi cross-coupling reaction
MeO
Br
Br
OMe
n-BuLi, Et2O,0°C, 10 min;
then DMF(81%)
MeO
Br OMe
1. NaBH4MeOH
2. PBr3DCM(95% overall)
H
O
MeO
Br OMe
Br
Zn, THF,0°, 30 min
MeO
Br OMe
ZnBrPd(PPh3)4,THF, 25°C(98% overall)
MeO
Br OMe
Me
TIPS
n-BuLi, Et2O,-78°C, 45 min;
then DMF(94%)
MeO
OMe
Me
TIPS
H
OLA
BBr3, DCM-78→ 25°C, 16 h HO
OMe
Me
TIPS
H
O
TBSOTf,i-Pr2NEt,
DCM, 0°C(88% overall)
TBSO
OMe
Me
TIPS
H
O
41 42 37
43
38
3644
45 14 TIPS
Me
I38
Usually nearly impossible! …but aldehyde can coordinate with L.A. catalyst, directing it to its’ adjacent methyl ether hence activating it for preferential cleavage!!!
Aryl lithiation
quench
Differentiation of two aryl methoxy groups!!!
reprotection
Also, increases the electronic effect. The lone pair of the adjacent oxygen can be delocalized into aldehyde
27
Total Synthesis OO
MeH
OH
O
Me
Me
O
Lithiation
Lithium alkoxide serves as highly competent chiral auxiliarly
Stereoselectively orchestrates the uniion of aldehyde 14 and nucleophilic vinylzinc
transmetallation
Stable complex with lithium trans to Ar
Transition state: aldehyde coordinates to lithium trans to the distal pphenyl ring. Alkenyl transfer occurs via 6-membered transition state. -recovery of auxiliary via extraction. Completion achieved with equimolar aldehyde and bromozinc hence material economy
TMS, TBS selective deprotection
Partial reduction: hydrogenation via Lindlar’s catalyst selective for terminal alkyne, TIPS deprotection
TBS protection
TMS Me
It-BuLi, Et2O,-78°C, 1 h;
ZnBr2, 0°C, 1 hTMS Me
ZnBr
Me
NMe2LiO
Ph
then toluene, 0°C
H
MeNH
Zn
TMS
Me
Me
MeO Li
O
Ar
HBr
(91% overall)(95% ee)
TIPS
Me
TBSO
OMeMeTMS OH
TBAF,THF, 0°C
(98%)TIPS
Me
HO
OMeMe OH
14
1. H2, Pd/BaSO4,hexane/MeOH (1:1)2. TBAF, THF, 25°C
3. TBSCl, imid, DMF(63% overall)
Me
TBSO OMe
MeOTBS
13 46
47
484912
TBSO
OMe
Me
TIPS
H
O 14
28
Total Synthesis OO
MeH
OH
O
Me
Me
O
Complete selectivity for both olefin geometry and atropisomerism. 42% yield due to formation of major byproduct.
TBS deprotection
Major by-product…loss of 1 carbon -propene formed with carbene
Hydride displacement via NaBH3CN using TFA as benzylic alcohol activation into a good
leaving group followed by reprotection.
GrubbsMe
TBSO OMe
MeOTBS
Enynemetathesis(>20:1 atropselectivity)
(50 mol %),H2C=CH2, DCM
40°C, 21 h
Me
OMe
Me OTBS
TBSO
TBAF, THF
(42% overall)
Me
OMe
Me OH
HO
1. NaBH3CN,TFA, DCM
2. TBSOTf,i-Pr2NEt,DCM, 0°C(52% overall)
Me
OMe
Me
TBSO
12
18
10 50 8
RuPh
PCy3
PCy3
Cl
Cl
18
Me
OMe
Me OTBS
TBSO
51
29
Total Synthesis OO
MeH
OH
O
Me
Me
O
Install vinyl iodide side chain as before
Lithiation, transmetallation, stable complex
Alcohol protection, allylation
Global desilylation, followed by alcohol protection
Macrocyclization provide exclusively the 1,3 disubstituted diene product
However, less atropselective (less steric differentiation) and failed to completely control endocyclic olefin geometry
Ionic type reduction of benzylic directing group via H- (silane) H+
(TFA), PPTS deprotects alcohol
oxidation
Thermally stable up to 100°C …implies can activate Diels Alder reaction at higher temperatures
HO TBSO I1. TBSCl,imid, DMF
2. AllylMgCl,CuBr2•Me2S,THF, -45°C; I2(56%)
TIPSMe
TBSO
OMeOH
OTBS
t-BuLi, Et2O,-78°C, 45 min;ZnBr2, 0°C, 1 h;
(97%, 90% ee)
Me
LiO
Ph
NMe2
; 14
1. TBAF, THF, 25°C2. TBSCl, imid, DMF
(99%)
OTBS
MeO
Me
OTBS
HTBSOOTBS
MeO
Me
OTBSH
TBSO
Ru
PCy3
PCy3Cl
Cl
Ph
18: 40 mol %H2C=CH2, toluene,45°C, 40 h(31%)
1. Et3SiH, TFA, 25°C, 15 min2.PPTS, MeOH, 45°C, 1.5 h
(46% overall)
OH
MeO
Me
OTBS
Dess-Martin [O]
(99%)O
MeO
Me
OTBS
52
1653
1511
57 9
TBSO
OMe
Me
TIPS
H
O 14
30
Total Synthesis OO
MeH
OH
O
Me
Me
O
First attempt failed. 15 h at RT, heating and LA’s also did not work
After much screening, reaction conditions were found giving complete endo selectivity but not facially selective, giving rise to both diastereomers (aldehyde and H down) favoring the non-natural configuration -this supports possibility of enzymatic assistance proposed by Schmitz
Desilylation of 2 phenolic TBS groups, followed by oxidation with iodosylbenzene to give rise to bis quinone
Amazingly, adduct started to slowly convert into Longithorine A at RT without being isolated
Ie.diels-alderase
MeO
Me
OTBSMe
OMe
Me
TBSO
O
MeO
Me
OTBSMe
OMe
Me
TBSO
H
O
Me2AlCl,DCM,-20°C, 5 h
(70%)(1:1.4 ratio of diastereomers
1. TBAF, THF, 0°C2. PhI(O),MeCN/H2O (3:1)
O
Me
OMe
O
Me
O
H
O
25°C, 40 h
(90% overall)
OO
MeH
OH
O
Me
Me
O
9
8
7
21
(−)-Longithorone A
31
Summary
Total synthesis 32 operations overall 19 steps in the longest linear sequence
Unique example of chirality transfer in complex molecule synthesis Stereogenic centers are used to control planar chirality
Removal of chiral centers
Planar chirality is then in return used to regenerate stereogenic centers
OO
MeH
OH
O
Me
Me
O
32
Summary
Challenges overcome Biosynthesis is feasible Atropselectivity acheived Macrocyclic ring closing enyne metathesis gave
disubstituted 1,3 diene (first example) Diels-Alder reaction gave endo product only
But was not facially selective (hence 2 diastereoisomers)
Benzylic alcohols were installed highly enantioselectively via vinylzinc additions
OO
MeH
OH
O
Me
Me
O
33
Thank you
OO
MeH
OH
O
Me
Me
O
