123.702 Organic Chemistry
Reactions of alkenes: stereospecific reactions• Diastereospecific - reaction permits only one diastereoisomer to be formed
control relative stereochemistry not absolute stereochemistry• Electrophilic epoxidation via a concerted process is a good example...
1
PhH
PhH
Om-CPBA
syn
PhH
HPh
Om-CPBA
anti
Ph
HH
Ph(Z)
Ph
PhH
H(E)
Ph HPhH
OOOH
Ar
Note: only controlling relative
stereocheimstry NOT absolute
stereochemistry
I
Me O Osyn
OOH
Me I2
(Z)
I
Me O O H
I
Me O OantiI
Iodolactonisation• Proceeds via an iodonium species followed by intramolecular ring-opening• Geometry of alkene controls relative stereochemistry
OOHMe
I2
(E) OOHMe
I
123.702 Organic Chemistry
Stereoselective reactions• If there is a pre-existing stereogenic centre then reaction can be stereoselective• In such reactions two diastereoisomers could be formed but one is favoured
2
OOH
MeI2
O
IMe
O82% de
O
Me
OH
I2
OI
Me
O88% de
• These cyclisations are probably under thermodynamic control • This means the reactions are reversible and equilibrate• Therefore the product is the most stable compound (anti)
• Epoxidation is irreversible and the reaction is under kinetic control• So how do we explain the following observations...
Me SiMe2Ph
Me
Me SiMe2Ph
MeO
Me SiMe2Ph
MeO
m-CPBA +
>95% <5%
Me m-CPBA +
61% 39%
MeO
MeOMe Me Me
SiMe2Ph SiMe2Ph SiMe2Ph
123.702 Organic Chemistry
Conformations in allylic systems
• Arguably the lowest energy conformations have greatest separation of substituents• The control of conformation in allyl systems is called allylic strain or A(1,3) strain
3
Me
MeH
if no cis substituent then only small
energy difference
HH H
MeMe
H
HH H
HMe
Melowest energy: H
eclipses plane of alkeneslightly higher energy: Me eclipses plane of alkene
rotate bond
Me
MeMeH
cis substituent present then only
ONE conformation
MeH H
MeMe
HMeH H
HMe
Melowest energy: H
eclipses plane of alkenehigh energy: Me–Me
interaction disfavours conformation
HH H
HMe
Me
HH H
MeMe
H
H HMe
HH
Me
MeMe
HMe
Me
HX
123.702 Organic Chemistry
Stereoselective reactions of alkenes III• Apply this knowledge to the real system...
4
m-CPBA
>95%Me
Me
H SiMe2Ph
O
MeH H
HSi
Me
MeMe
Ph
OMeH H
HSi
Me
MeMe
Ph
Me
Me m-CPBA
H SiMe2Ph
m-CPBAX
lowest energy conformation
silyl group blocks approach
X
m-CPBA approaches from unhindered face
<5%Me
Me
H SiMe2Ph
O
HMe
HMe
H
Si MePh Me
m-CPBA
formation of minor diastereoisomer results
from m-CPBA approaching alkene in above conformation or
approaching passed the silyl group
123.702 Organic Chemistry
m-CPBA
m-CPBA
HMe H
MeH
SiPh
MeMe
O
39%
Me
H SiMe2Ph
OMe
HMe H
HSi
Me
MePh Me
O61%
Me
H SiMe2Ph
OMe
Me
H SiMe2Ph
Me
HMe H
HSi
Me
MePh Me
HMe H
MeH
SiPh
MeMe
Importance of A(1,3) strain
• The importance of a cis-substituent is made clear by the reduced stereoselectivity• This is explained as follows...
5
Me m-CPBA+
61% 39%
H SiMe2Ph
Me
H SiMe2Ph
OMe
H SiMe2Ph
OMe Me Me
X
m-CPBA attacks form least hindered
face
X
lowest energy conformation
gives major product HMe H
HSi
Me
MePh Me
HMe H
MeH
SiPh
MeMe
both conformations low energy -- so mixture of
products
123.702 Organic Chemistry
H2B HH2B
H CH2OBnMeH
Me
OH CH2OBn
MeHMe
O
H
H2O2NaOH
OBn
H Me
O
H Me
OH74% de
Me
OBn
H Me
O
BH3
OBn
H Me
O
H Me
H2B
Other reactions...• Epoxidation is not the only stereoselective reaction of alkenes• Below is an example of hydroboration, a useful reaction that you should be familiar
with...
6
R
R1
HS
LL R1
RS H
S = smaller groupL = larger group
R
R1
SL
HR
R1
LH
S
favoured destabilised by repulsion between C-1 & C-3 substituents or A(1,3) strain
13
13
preferred approach Selectivity in addition to cis alkenes
Attack from the least sterically demanding face of the alkene as it resides in the most favoured conformation. Followed by stereospecific oxidation
123.702 Organic Chemistry
Directed epoxidation
• A hydroxyl group can reverse normal selectivity and direct epoxidation• Epoxidation with a peracid, such as m-CPBA, is directed by hydrogen bonding and
favours attack from the same face as hydroxyl group• The reaction with a vanadyl reagent results in higher stereoselectivity as it bonds /
chelates to the oxygen
7
OHreagent
OH
O
reagent:m-CPBAt-BuO2H, VO(acac)2
OH
O+
syn9298
t::
anti82
H
OO
HO
OH
Ar hydrogen bond O
VO OO O MeMe
Me Mevanadyl acetylacetonate
O
H
OV
t-BuO O
123.702 Organic Chemistry
MeMe H
HO
Me
HOO
OH
Ar
Me Me
Me OHHm-CPBA Me Me
Me OHH
OMe Me
Me OHH
O+
95 5
Directed epoxidation in acyclic systems
• Hydroxyl group can direct epoxidation in acyclic compounds as well• Once again, major product formed from the most stable conformation• Thus the cis methyl group is very important
8
• The minor product is formed either via non-directed attack or via the less favoured...conformation
hydrogen bond
favoured conformation
O
MeMe H H
OH
HO
O
Me
Ardisfavoured
conformation
MeMe H
HOH
Me
O
123.702 Organic Chemistry
Directed epoxidation: effect of C-2 substituent
• The presence of a substituent in the C-2 position (Me) facilitates a highly diastereoselective reaction
• The preferred conformation minimises the interaction between the two Me (& Me) groups
9
• With C-2 substituent (H) there is little energy difference between conformations• Therefore, get low selectivity
H O Me
H
O
OV
t-Bu
H Me
LL
MeMe
OHH
t-BuO2HVO(acac)2 Me
MeMe
Me
O OOH OH19 1
+
:
disfavoured conformation as Me & Me eclipse
steric interaction
favoured conformation as
only Me & H eclipse
H O H
Me
O
OV
t-Bu
H Me
LL
Me Me
H OH
t-BuO2HVO(acac)2 Me Me
O OOH OH
2.5 1
+
:
Me Me H O H
Me
O
OV
t-Bu
H H
LL
H too small to differentiate
conformations
123.702 Organic Chemistry
H O H
R2
O
OV
t-Bu
H R1
LL
H O R2
H
O
OV
t-Bu
H R1
LL
versus
Substrate control in total synthesis
• Directed epoxidation from the synthesis of oleandomycin aglcon• Glycosylated version (R=sugar) is a potent antibiotic from streptomyces antibioticus• David A. Evans and Annette S. Kim, J. Am. Chem. Soc. 1996, 118, 11323
10
C13 MeNO
BnMe
O
Me
O OH
Me
OH OTIPS
MeMe
Ph
O O
MeNO
BnMe
O
Me
O OH
Me
OH OTIPS
MeMe
Ph
O O
O
VO(acac)2t-BuOOH
91%100% d.e.
C1 C1 C13
C13
OHMe
O
OO
Me
OR
ORMe
O
Me
Me
Me
C1
Oleandomycin aglycon(R=H but should be a sugar)
steric interaction
123.702 Organic Chemistry
BHMe
H
H
HBH2
HMeMe Me
1. TMEDA2. BF3•OEt2
Me
1. TMEDA2. BF3•OEt2
Me
(+)-IpcBH2
H
BHMe
HH Me
B
HMeMe Me
H
H
Me
Me MeH
BH3
BH3
(–)-Ipc2BH
Me
MeMeMe
(+)-α-pinene
Stereoselective reactions of alkenes• Alkenes are versatile functional groups that, as we shall see, present plenty of scope
for the introduction of stereochemistry• Hydroboration permits the selective introduction of boron (surprise), which itself
can undergo a wide-range of stereospecific reactionsSubstrate control
11
123.702 Organic Chemistry
Hydroboration: reagent control
• The two compounds formed previously, mono- & diisopinocampheylborane are common reagents for the stereoselective hydroboration of alkenes
• Ipc2BH is very effective for cis-alkenes but less effective for trans• IpcBH2 gives higher enantiomeric excess with trans and trisubstituted alkenes
12
Me
Me
1. (–)-Ipc2BH2. H2O2 / NaOH
MeMe
OHHH
H 98.4% ee
BHMe
HH Me
(–)-Ipc2BH
Me
H
1. (+)-IpcBH22. H2O2 / NaOH
H
HOH
Me
66% eeH
BH2
HMeMe Me
(+)-IpcBH2
123.702 Organic Chemistry
P P
OMe
MeO
RhO
Me NH
CO2H
ArP P
OMe
MeO
Rh O
MeNH
HO2C
Ar
Hydrogenation: enantioselective catalysis
• One of the most important industrial reactions; above example produces amino acids• Variety of diphosphines can be used• It is essential that there is a second coordinating group (here the amide)• On coordination, two diastereoisomeric complexes are formed• The stability / ratio of each of these is unimportant• It is their reactivity we are concerned with...
13
HCO2H
NHAc
MeO
AcO
H2(g)[((S)-DIPAMP)RhL2]
L=solvent MeO
AcO
CO2H
H NHAc
H H
95% ee(S,S)-DIPAMP
P P
OMe
MeO
P P
OMe
MeOO
MeNH
HO2C
Ar
RhL L
123.702 Organic Chemistry
ArPHPh
Rh
H
PAr Ph
O
MeNH
HO2C
Ar
Mechanism for catalytic hydrogenation
14
L
PhPP
Ar
Ph Ar
Rh O
MeNH
HO2C
ArH
H
ArP P
Ph
ArPh
Rh O
MeNH
HO2C
Ar
H2slow
L
ArP P
Ph
ArPh
RhO
Me NH
CO2H
ArH
H
ArP H
Ph
Rh
H
PArPh
O
Me NH
CO2H
Ar
ArP P
Ph
ArPh
RhO
Me NH
CO2H
Ar
H2fast
O
MeNH
HO2C
ArHHH
minor enantiomer
O
Me NH
CO2H
ArHHH
major enantiomer
O
MeNH
HO2C
Ar
+ [DIPAMPRhL2]
oxidative addition fastcomplex more
reactive
oxidative addition
insertion
reductive elimination
One complex more reactive
123.702 Organic Chemistry
Enantioselective hydrogenation in action
• Used in the synthesis of candoxatril, a potent atrial natriuretic factor (ANF) potentiator (cardiovascular drug developed by Pfizer)
• Process used on a 2 metric ton-scale• Michel Bulliard, Blandine Laboue, Jean Lastennet, and Sonia Roussiasse, Org.
Process Res. Dev., 2001, 5, 438
15
MeOO
t-BuO2C CO2Na
[(R)-MeO-BIPHEP-RuBr2]60psi H2, 50°C, THF/H2O
98%e.e.
MeOO
t-BuO2C CO2Na
MeOO
HN
OCO2H
O
O
candoxatril
MeOMeO
PP
PhPh
PhPh
(R)-MeO-BIPHEP
123.702 Organic Chemistry
N
Ar
H
N
t-BuBn
O Me
HMe
N NH
ArMe
H
PhMe
OH
Me MeMe
NMe
i-PrE
EH
H
Hδ–
δ+
N
Ar Me
H
N
t-BuBn
O Me
Me
H
O
NC
NH2
N
Bnt-Bu
OMe
Cl3CO2
NH
MeO2C
Me i-Pr
CO2MeH H
H
O
NC
H Me
89%; 96% ee
catalyst 10%hydrogen source 1eq
Organocatalytic hydrogenation
• A recent development is the use of small organic molecules to achieve hydrogenation• Inspire by nature• Based on the formation of a highly reactive iminium ion (this is the basis of many
organocatalytic reactions)
16
123.702 Organic Chemistry
Me
Me
MeOH
Me
OH
(–)-DET, Ti(Oi-Pr)4, TBHPMe
Me
MeOH
O
>90% ee
(+)-DIPT, Ti(Oi-Pr)4, TBHP Me
OHO
92% ee
Me
Me
MeOH
Me
OH
Sharpless Asymmetric Epoxidation (SAE)
• Sharpless asymmetric epoxidation was the first general asymmetric catalyst• There are a large number of practical considerations that we will not discuss• Suffice to say it works for a wide range of compounds in a very predictable manner
17
EtO2CCO2Et
OH
OH(–)-DET
i-PrO2CCO2i-Pr
OH
OH(+)-DIPT
Me O
MeMe
OH
TBHP
• Compounds must be allylic alcohols• Second example shows that this limitation allows highly selective reactions
must be allylic alcohol
123.702 Organic Chemistry
OTi
Ot-BuLL
OO
Ot-Bu
OTi
LL
O
t-BuO
OTi
LL
OTi
OLL
Ot-BuTiL4
TBHP+
+
HO
Sharpless Asymmetric Epoxidation II
• SAE is highly predictable -- the mnemonic above is accurate for most allylic alcohols• To understand where this comes from we must look at the mechanism• A simplified version of the basic epoxidation is given below
18
if you want “O” on top its on your kNuckles so you
use Negative (–)-DET
if you want “O” on top its on your Palm so you use
Positive (+)-DET
using your left hand, the index finger is
the alkene and your thumb the alcohol
R1
R2 R3
OHO
Ti(Oi-Pr)4TBHP
R1
R2 R3
OHO
Ti(Oi-Pr)4TBHP
R3
R1
R2
OH
D-(–)-DET unnatural isomer
“O”
“O”D-(+)-DET
natural isomer
place alkene vertical and
alcohol in bottom right corner
activation of peroxide
123.702 Organic Chemistry
E
OO
O
TiO
O O
O
O
TiO
O
CO2Et
CO2Et
i-Pr
i-Pr
EtOt-Bu
R
HO
RO E
OO
O
TiO
O O
O
O
TiO
O
CO2Et
CO2Et
i-Pr
i-Pr
EtOt-Bu
R
HO
R
t-BuO2H CO2Et
OO
O
TiO
O O
O
O
TiO
O
CO2Et
CO2Et
i-Pri-Pr
i-Pr
EtOt-Bu
OO
O
TiO
O O
O
O
TiO
O
CO2Et
CO2Et
i-Pri-Pr
i-Pr
i-Pr
OEt
EtO
Ti(Oi-Pr)4 +(+)-DET
Mechanism of SAE
19
Active species thought to be 2 x Ti bridged by 2 x tartrate
Reagents normally left to ‘age’ before addition of substrate thus allowing clean formation of dimer
must deliver “O” from lower face
123.702 Organic Chemistry
• SAE works for a wide range of allylic alcohols
• Only cis di-substituted alkenes appear to be problematic
20
R2 OHR2 OH
R1good substrates
high yields and ee's >90%
OHR1
R3
R2 OHR1
R3normally good
ee's >90%few examples
OH
R3 problematicslow reactionsmoderate ee's,
especially with bulky R3
OHO
O
MeMe
OHO
O
MeMe
OHO
O
MeMe
O O
conditions
t-BuO2H, VO(acac)2t-BuO2H, Ti(Oi-Pr)4, (+)-DETt-BuO2H, Ti(Oi-Pr)4, (–)-DET
+
2.3199
:::
1221
• Example below shows that SAE can over-ride the inherent selectivity of a substrate• Furthermore, it demonstrates the concept of matched & mismatched • When the catalyst & substrate reinforce each other spectacular (or matched) results are achieved
123.702 Organic Chemistry
MeNH2
Ph NHMe
OH1. NaH2. ArCl
MsCl
Ph OMs
OH
Red-Al[NaAlH2(OCH2CH2OMe)2]
Ph OHH
OHSAE(+)-DIPT
89%>98%e.e.
Ph OHO
Use of SAE in synthesis
• Fluoxetine is a commercial anti-depressant (better known as Sarafem® or Prozac®)• Can be synthesized in a number of methods• One involves the use of the SAE reaction...• Y. Gao and K. B. Sharpless, J. Org. Chem., 1988, 53, 4081• Yun Gao, Robert M. Hanson, Janice M. Klunder, Soo Y. Ko, Hiroko Masamune, and
K. Barry Sharpless, J. Am. Chem. Soc., 1987, 109, 5165
21
Ph OH
Ph NHMe
O
CF3
fluoxetine
123.702 Organic Chemistry
R2 OHR1
R3 RO
R
R3
R1
R2
OHH
H
R3
R1
R2
OHR
R2 OHR1
R3 R
(–)-DET, Ti(Oi-Pr)4, TBHP
Kinetic resolution
• Both enantiomers should be epoxidised from same face• But rate of epoxidation is different• If sufficient rate difference then stop the reaction at 50% conversion
22
R2 OHR1
R3 R
if allylic alcohol is desired use 0.6eq TBHPif epoxy alcohol is desired use 0.45eq TBHP
slowsteric hindrance fast
racemic mixture
if reaction goes to 100% completion you
get a 1:1 mixture of diastereoisomers
123.702 Organic Chemistry
H
OH
Kinetic resolution II
• Kinetic resolution normally works efficiently• The problem with kinetic resolution is that is can only give a maximum yield of 50%• Desymmetrisation of a meso compound allows 100% yield• Effectively, the same as two kinetic resolutions, first desymmetrises compound
second removes unwanted enantiomer• ee of desired product increases with time (84% ee 3hrs ➔ >97% 140hrs)
23
Me3Si
C5H11
OH
(+)-DIPT, Ti(Oi-Pr)4, TBHP
Me3Si
C5H11
OH
Me3Si
C5H11
OH+O
>95% ee (R) >95% ee(R/S)
rate of epoxidation (S) : (R) ~700 : 1
OH
O
OH(–)-DIPT
FAST
FASTslow
slow
OH
O wanted
OH
O Omesoreadily
removed
OHH
H
OH
O
slow
OHH
O
FASTslowFAST
123.702 Organic Chemistry
OH
OBnOBn
(–)-DIPT, Ti(Oi-Pr)4, TBHP
1hr = 93%e.e.2hr = 95%e.e.
3hr = >97%e.e.
OH
OBnOBnO
O
OBnOBnO
O
NHPhPhNCO
pyr
BF3•OEt2
HOOBn
OO
O
OBn
O
OH
OHOH
OH
HO2C
HO
KDO
Desymmetrisation in synthesis
• Desymmetrisation has been used in many elegant syntheses• Here is the synthesis of KDO, a key component of the cell wall lipopolysaccharide
(LPS) of Gram-negative bacteria forming the necessary linkage between the polysaccharide and lipid A regions
• David B. Smith, Zhaoyin Wang and Stuart L. Schreiber, Tetrahedron, 1990, 46, 4793.• Stuart L. Schreiber, Thomas S. Schreiber, and David B. Smith, J. Am. Chem. Soc.,
1987, 109, 1525
24
123.702 Organic Chemistry
Jacobsen-Katsuki epoxidation• SAE is a marvelous reaction but suffers certain limitations
substrate must be an allylic alcoholcis-disubstituted alkenes are poor substrates
• (salen)Mn catalysts with bleach (NaOCl) are good for these substrates
25
NNMn
OOt-Bu
t-Bu t-Bu
t-Bu
HHCl
(S,S)-Mn(salen)
H
H
NN
O OMn
O
manganese(IV) oxo species active oxidant
L S
L = larger groupS = smaller group
(S,S)-cat (2-15%) NaOCl, pH 11 L S
O
O
OO
Ph CO2Me
O
O CNMe
MeO
94% ee ≥95% ee 97% ee
123.702 Organic Chemistry
Jacobsen-Katsuki oxidation in synthesis
• This example demonstrates the industrial potential of such catalytic systems• Indinavir is an HIV protease inhibitor marketed by Merck as Crixivan®• "Industrial Syntheses of the Central Core Molecules of HIV Protease Inhibitors"
Kunisuke Izawa and Tomoyuki Onishi, Chem. Rev., 2006, 106, 2811
26
(salen)Mn catNaOCl, R3N+–O–
O2000kg scale
H2SO4MeCN OH
OH
N CMe
N
O
Me
OH
NH2
H2O
MeCN
N
NN
HN
OH CHBn
CONHt-Bu
OH
O
Indinavir(Merck / HIV treatment)
123.702 Organic Chemistry
Organocatalytic epoxidations
• As with most chemical reactions, epoxidation has seen a move towards ‘greener’ chemistry and the use of catalytic systems that do not involve transition metals
• A number of systems exist, notably the catalysts of Shi & Armstrong• Most are based on the in situ conversion of ketones to the active, dioxirane
species, that actually performs the epoxidation
27
PhMe
cat.oxone, K2CO3
DME / H2O, –15°CPh
MeO
100%; 86% ee
O
F
F
cat.F
F
OO
RH
H
OO
RR
H
HO
R
123.702 Organic Chemistry
Organocatalytic epoxidations in synthesis
• Tanabe Seiyaku Co. utilise organocatalysis in the synthesis of diltiazem-L®, a blood pressure reducing agent
• T. Furutani, R. Imashiro, M. Hatsuda and M. Seki, J. Org. Chem. 2002, 67, 4599
28
MeO
OMe
O cat (5mol%), oxone (1eq), NaHCO3,
dioxane/H2O
89%77% ee MeO
OMe
OO
O
O
O
O
O
NS
AcO O
NMe2MeO
diltiazem
123.702 Organic Chemistry
Sharpless Asymmetric Dihydroxylations (SAD)
• Looks complicated but isn’t too bad...• The active, catalytic, oxidant is K2OsO2(OH)4 - OsO4 is too volatile & toxic• K3Fe(CN)6 is the stoichiometric oxidant• K2CO3 & MeSO2NH2 accelerate the reaction • Normally use a biphasic solvent system• And the two ligands are...
29
C5H11CO2Et
K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH,
H2O, 0°C, (DHQD)2-PHALC5H11
CO2EtOH
OH99% ee
• Ligands are pseudo-enantiomers (only blue centres are inverted; red are not)• They act if they were enantiomers (see slide 26)• Coordinate to the metal via the green nitrogen
N
HO
N
MeO
EtN
HO
N
OMe
EtNN
(DHQD)2-PHAL
N
HO
N
OMe
N
HO
N
MeO
N NEt Et
(DHQ)2-PHAL
123.702 Organic Chemistry
Sharpless Asymmetric Dihydroxylation II
• Reaction works on virtually all alkenes• Exact mechanism not known but...• It is relatively predictable (but not as predictable as the SAE)
30
PhPh
PhPh
OH
OHPh
PhOH
OH98.8% ee >99.5% ee
K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH,
H2O, 0°C, (DHQ)2-PHAL
K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH,
H2O, 0°C, (DHQD)2-PHAL
small steric barrier
large steric barrier
attractive area - attracts flat, aromatic substituents or large, hydrophobic aliphatic
groups
H
MS
L
OsO4
(DHQD)2PHAL
OsO4(DHQ)2PHAL
123.702 Organic Chemistry
Me
OO
Me OsO4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH, H2O,
0°C, (DHQD)2-PHAL Me
OO
Me
HO
OH
96%95% ee
TsOH
90% O
O
Me
Me
exo-Brevicomin
Sharpless asymmetric dihydroxylation in synthesis
• The simple example above shows the power of the SAD reaction in synthesis• exo-Brevicomin is the aggregation pheromone of several timber beetles• Interestingly, endo-brevicomin inhibits the aggregation of the southern pine beetle• John A. Soderquist and Anil M. Ranel, Tetrahedron Lett., 1993, 34, 5031
31
123.702 Organic Chemistry
The Sharpless aminohydroxylation reaction
• A variant has now been developed that permits aminohydrodroxylation• Used in the semi-synthesis of paclitaxel (Taxol®), an anti-carcinogen• G. Li and K.B. Sharpless, Acta Chem. Scand., 1996, 50, 649
32
Ph Oi-Pr
O
Ph Oi-Pr
OAcNH
OHregioselectivity >20:1
94% ee
Ph Oi-Pr
OHCl.NH2
OH
HCl, H2O
AcNHBr, LiOH, K2OsO2(OH)4, (DHQ)2-PHAL
ONH
Ph
O OPh
OH
Me
OBz
Me
Me
AcO OHMe
H OAcO
O
HOtaxol
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