A Dauting Challenge in Natural Product Synthesis Vicinal ......Vicinal Quaternary Stereogenic...
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Vicinal Quaternary Stereogenic Centers: A Dauting Challenge in Natural Product Synthesis Gérald Lelais MacMillan Group Meeting October 26, 2005 Lead References: E. A. Peterson, L. E. Overman, PNAS 2004, 101, 11943-11948. K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis, VCH, Weinheim, 1996, Chapters 14, 25, 26. K. C. Nicolaou, S. A. Snyder, Classics in Total Synthesis II, Wiley-VCH, Weinheim, 2003, Chapters 11, 14, 19.
Transcript of A Dauting Challenge in Natural Product Synthesis Vicinal ......Vicinal Quaternary Stereogenic...
Vicinal Quaternary Stereogenic Centers:
A Dauting Challenge in Natural Product Synthesis
Gérald Lelais
MacMillan Group Meeting
October 26, 2005
Lead References:
E. A. Peterson, L. E. Overman, PNAS 2004, 101, 11943-11948.
K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis, VCH, Weinheim, 1996, Chapters 14, 25, 26.
K. C. Nicolaou, S. A. Snyder, Classics in Total Synthesis II, Wiley-VCH, Weinheim, 2003, Chapters 11, 14, 19.
Asymmetric Vicival Quaternary Centers Construction
! Definition of vicinal quaternary carbons:
two carbon centers attached to each other, each of them having three carbon substituents
! Contents:
" Nature's way of building vicinal quaternary stereocenters
" Biomimetic cascade cyclizations (Dammarenediol II, Secodaphniphylline)
" Diels–Alder cycloadditions (Maritimol, Colombiasin A)
" Other cycloadditions (Retigeranic acid, Valerane)
" Other pericyclic reactions (Trichodiene)
" Intramolecular Heck-cyclization (Chimonanthine)
" Intermolecular alkylation (Chimonanthine)
" Intermolecular Michael addition (Aphidicolin)
C1
C4
C3
C6C5
C2
Applied to natural product synthesis
" Decarbonylation reaction
Nature's Way of Constructing Vicinal Quaternary Stereocenters
! Quaternary carbons are a common feature of terpenes and related natural products
Me
Me
Me
MeMe
Me
MeO
HMe
Me
Me
MeMe
H
HO
Me
Me
MeH
H
squalene oxide dammaradienol
" polyene cyclizations
" cationic rearrangements
Quaternary stereocenters are biosynthetically assembled by using carbocation chemistry:
! Enzyme-catalyzed polyene cyclization:
Me
Me
MeMe
Me
MeO
H
H
H
H
Me
via:
H
Nature's Way of Constructing Vicinal Quaternary Stereocenters
squalene oxide lanosterol
! Lanosterol/cholesterol biosynthesis:
Me
H
HO
Me
Me
MeH
Me
H
Me Me
Me
H
MeMeO
HMe
MeMe
Me Me
Me
cholesterol
Eschenmoser: Helv. Chim. Acta 1955, 38, 1890-1904. Stork: JACS 1955, 77, 5068-5077.Johnson: JACS 1987, 109, 5852-5853.
Me
Me
H
HO
Me
Me
H
MeMe
O
HMe
via:
H
Me
H
Me
Me
Me
H
MeMe
Me Me
Me
polyene
cyclization
cationic
rearrangements
H
Me Me
HO
Me Me
H
H Me
H
Me Me
Me
OH
Biomimetic Total SynthesesCascade cyclizations
! Enantioselective synthesis of Dammarenediol II Dammarenediol II
OAc
Me
Me
Me
HOHO Me
1) MsCl, Py; then K2CO3
2) MsCl, NEt3; then LiBr
Br
Me
Me
Me
MeO
(88%)
LDA, THF, –30 °C
2) AcONa–AcOH pentane–H2O
Me TBS
N Me
OMe
Me
Me
MeO
O
TBS
Me
(86%) Li
S S
I
1) , Et2O
2) ,
THF, – 78 °C
Me
Me
MeO
OTBS
Me
Me
S S
Me
O
O
Me
Me Me
HO
Me Me
H
H Me
1) MeAlCl2, CH2Cl22) HF, MeCN
3) (CF3CO2)2IPh, 0 °C
1) ,
(60%)
(42%)
Dammarenediol II
(28%)
5 steps
Corey, JACS 1996, 118, 8765-8766
96% ee
from dihydroxylation
of E,E-farnesyl acetate
Biomimetic Total Syntheses II: (–)-SecodaphniphyllineCascade cyclizations
! Retrosynthetic analysis
HNMe
MeMe
O
O
O
Me
Me
HNMe
MeMe
O
O
O
Me
Me
MeO2C
HNMe
MeMe
Cl
O
O
O
Me
Me
CO2Me
Me
MeMesqualene
(–)-Secodaphniphylline
Heathcock: JOC 1992, 57, 2566-2574.
MeO
O
H
OMe
O
H
Biomimetic Total Syntheses II: (–)-SecodaphniphyllineCascade cyclizations
! Asymmetric induction using a C2-symmetric N-acyl pyrrolidine
1) LDA, THF, –78 °C
2)
3)
Heathcock: JOC 1992, 57, 2566-2574.see also, Nicolaou: Classics in Total Synthesis, VCH, Weinheim, 1996, Chapter 26.
HNMe
MeMe
O
O
O
Me
Me
N
O
OBn
Me
Me
MeO2C
Me
Me
Me
I
O
N
MeO2C
Me
Me
Me
OBnMe
Me
H3
O
N
MeO2C
Me
Me
Me
OBnMe
Me
H3
major diastereomer minor diastereomer
H
N
O
MeMe
OBn
Li H
N
O
Me Me
BnO
Li
Re/Re-attack Si/Si-attack
repulsive interaction between the pyrrolidine
methyl and the cyclopentane ring is favored
over that with the enolate cluster
major minor
64% yield, 92:8 dr
(–)-Secodaphniphylline: Key cyclization steps
HNMe
MeMe
O
O
O
Me
Me
O
N
MeO2C
Me
Me
Me
OBnMe
Me
H31) DIBAL2) KOH, !
3) LiAlH4
Me
Me
Me
OBn
H3
HO
HO(64%)
! Preparation of the key intermediate
! Cascade cyclization with installment of vicinal quaternary stereogenic centers
Me
Me
Me
OBn
H3
HO
HO
1) Swern
2) NH3 NMe
MeMe
H
3
OBn
NMe
MeMe
H
3
OBn
AcOH
70 °C
aza-DA
HN
MeMe
3
OBn
(77%) aza-Prinscyclization
1) H2, HCl, Pd/C2) Jones
3) MeOH, H2SO4HN
MeMe
Me
CO2Me
(78% yield, 84% ee)(90% ee after recryst.)
(92:8 dr)
(–)-Secodaphniphylline
(99.6% ee)
Heathcock: JOC 1992, 57, 2566-2574.
Cycloadditions can be extremely effectivein constructing vicinal quaternary carbon arrays
Diels-Alder Cycloadditions to Assemble Contiguous Quaternary Carbons
! Retrosynthetic analysis
Me
OH
Me
Me Me
HOH
Me
MeO
MeCHO
NC
Me
MeO
MeCHO
NC
MeO2C MeO2C
NN
OPG2
Me
OPG1
OMe
I
I
O
MeO2C
SnMe3
Me
Me
H H
transannularDiels-Alder
1) Alkylation
2) Stille coupling
3) Macrocyclization
Enantioselective synthesis of (+)-Maritimol
Deslongchamps: JACS 2000, 122, 4526-4527.
Enantioselective Synthesis of (+)-Maritimol
2 steps
(70%)
! Asymmetric synthesis of the macrocycle
Me
OH
Me
Me Me
HOH
Me
CO2Et
O
Hagemann's ester
OHC
CO2EtMe
CO2Me
1) NaBH4, MeOH2) TBSCl, Im.3) NaOH, THF
4) CDI; NH(OMe)Me HCl5) DIBALH; MeOH
OMe
OTBS
OMe
(53%)
Me
TBSO
OTBDPS
I
NN
1) SAMP, PTSA2) TBDPSCl, Im.
3) LDA,
(77%)
NN
H
R
H
Li
OMe
E
Re
I
I>95:5 dr
1) Mg-monoperoxyphtalate2) Py HF; 1, PdCl2 (MeCN)23) (Cl3C)2CO, PPh3
4) Cs2CO3, CsI5) TBAF6) Dess–Martin periodinane
O
CHO
Me
Me
Me
MeO2C
CN
O
MeO2C
SnMe3
MeMe
1
Deslongchamps: JACS 2000, 122, 4526-4527.
(28%)
MeO
! Both Lewis acid-catalyzed and thermal TADA exhibit similar complete stereoface- and
diastereospecificity induced by a small remote nitril group
! Intensive decomposition was observed when demethoxycarbonylated macrocycle was subjected
to TADA reaction
Me
MeO
MeO2C CHOMe
NC
H
H
O HCN
H
Me CHOMe
Me
CO2Me
H
endo-TS1
endo-TS2
! Vicinal quaternary centers formation by transannular Diels–Alder reaction (TADA)
Enantioselective Synthesis of (+)-Maritimol
Me
OH
Me
Me Me
HOH
O
CHO
Me
Me
Me
MeO2C
CNDMSO, H2O
155 °C
MeOHC
CN
O
Me Me
(92%)
MeOHC
CN
HO
Me Me
MeO2C
MeAlCl223 °C(75%)
DMSO, H2O155 °C(92%)
(+)-Maritimol
Deslongchamps: JACS 2000, 122, 4526-4527.Deslongchamps: Tetrahedron 1999, 55, 4655-4684.
Diels–Alder Cyclization IIEnantioselective synthesis of (–)-Colombiasin A
O
OH
Me
O
Me
Me
H
Me
H
Me
Me
Me O
OMe
Me
O
H
Me
Me O
OMe
Me
O
H
SO2
Me
H
TBSO
Me
Me
Me O
Ot-Bu
Me
O
H
Me
Me
Me O
OMe
Me
O
H
MeOH
MeS2CO
Nicolaou, 2001
(first enantioselective synthesis)
Chem. Eur. J. 2001, 7, 5359-5371
Richnovsky, 2003(17 steps, 3.9% yield)
Angew. Chem. Int. Ed. 2003, 42, 1267-1270
Harrowven, 2005
(12 steps, 1.5% yield)
Angew. Chem. Int. Ed. 2005, 44, 1221-1222
Jacobsen, 2005
(12 steps, 11.5% yield)
Angew. Chem. Int. Ed. 2005, 44, 6046-6050
O
Me
Me
HO
Me
OEt
O
OMe
t-BuO
O
O
Me
OMe
Me
TBSO
O
O
Me
OMe
O
NMe
Me
Me
Ph
OH
O
O
Me
OMe
Alternative Cycloadditions: Arene-Alkene meta-CycloadditionsEnantioselective synthesis of (–)-Retigeranic acid
! Retrosynthetic analysis
H
H
Me
HMe
Me
CO2H
MeMe
H
Me
Me
R
MeMe
H
Me
Me
MeMe
Y
Me
Me Me
HMe
Me
Me
O
Me
IMDAMe
(–)-Retigeranic acid
(–)-Carvone
arene-alkenecycloaddition
Wender: Tetrahedron Letters 1990, 31, 2517-2520.Wender: Pure & Appl. Chem. 1990, 62, 1597-1602.
Only 2 cycloadducts are formed from over 100 possibilities:
! meta- vs. ortho- vs. para-cycloadditions
! regioselectivity directed by donor alkyl groups on the arene
! exo/endo-selectivity
! stereoinduction of Me-group at C9.
(–)-Retigeranic Acid
! Preparation of the cycloaddition precursor
Me
MeO2C CO2Me
1) pig liver esterase2) Py2S, PPh3
3) p-xylyl bromide, Li, CuI
Me
Me
O Me
(86% yield, >99% ee)
1) LAH2) Pd/C, H2
3) PBu3, ArSeCN; H2O2
(78%)
CO2Me
Me
Me
Me
Me
HMe
Me
Me
HMe
Me
H
Me
Me
Me
Me
MeMe
H
H
1
23
4
5 6
78
91011
1
23
4
5 6
78
91011
1
2
3
4 5
6
7
8 9
10
11
1
2
3
45
67
8
9 10 11
h!
h!
h!
! Key photo-cycloaddition reaction
72% yield
1:2 selectivity
H
H
Me
HMe
Me
CO2H
MeMe
(–)-Retigeranic acidH
Me
Me
Me2NOC
O
H
steps
Wender: Tetrahedron Letters 1990, 31, 2517-2520.Wender: Pure & Appl. Chem. 1990, 62, 1597-1602.
Highly selective photo-cycloaddition as key step
Claisen Rearrangement/Intramolecular Diazo Ketone CyclopropanationEnantioselective synthesis of (+)-Valerane
! Retrosynthetic analysis
Me
Me
Me
Me
Me
Me
MeO
Me
Me
Me
MeMe
Me
OH
OMe
Me
CO2EtMe
Me
Me
O
N2
intramolecular
diazo ketone
cyclopropanation
orthoester Claisen
rearrangement
Combination of 2 pericyclic reactions for the stepwise construction of vicinal quaternary carbons
(R)-Carvone
Srikrishna:Tetrahedron Letters 1996, 37, 2863-2864.Srikrishna: J. Chem. Soc., Perkin Trans. 1 2000, 4321-4327.
Enantioselective Synthesis of (+)-Valerane
! Diastereoselective installment of the first quaternary carbon stereocenter
OMe
Me 1) MeMgI; PCC-SiO22) LAH
3) MeC(OEt)3, EtCO2H
HMe
H
O
OEt
Me MeMe
Me
CO2Et
Me(53%)
! Diastereoselective installment of the second quaternary carbon stereocenter
1) LAH2) PCC3) MeOCHPPh3
4) Jones5) (COCl)2; CH2N2
Me
Me
CO2Et
Me (26%)Me
Me
Me
O
N2
Me
Me
MeO
Cu–CuSO4
! Endgame
Li, NH3
(55%)Me
Me
MeO
Me
Me
MeO 1) H2, Pt/C
2) (CH2SH)2, BF3 Et2O
3) Raney NiMe
Me
Me
Me
(+)-Valerane
(R)-Carvone
(81%)
Srikrishna:Tetrahedron Letters 1996, 37, 2863-2864.Srikrishna: J. Chem. Soc., Perkin Trans. 1 2000, 4321-4327.
Other Pericyclic Reactions: Ireland–Claisen and Thio-Claisen RearrangementsEnantioselective synthesis of (–)Trichodiene
! Retrosynthetic analysis
Me
Me
Me
O
Me
Me
Me
Me
Me
Me
O
Me
N OHC
S
O
Me
Ph
OMe
N
O
O
Me
Ph
OH
Me
OR
CO2Me
Me
Me
OR
O
O
Me
Me
OR
OEt
O
Me
O
OEt
O
(–)-Trichodiene
Irland–Claisenrearrangement
diastereoselectivereduction
thio-Claisenrearrangement
Gilbert approach: JOC 1993, 58, 6255-6265.
Meyers approach: JACS 1998, 120, 5453-5457.
Other Pericyclic Reactions: Ireland–Claisen and Thio-Claisen RearrangementsEnantioselective synthesis of (–)Trichodiene
! Retrosynthetic analysis
Me
Me
Me
O
Me
Me
Me
Me
Me
Me
O
Me
N OHC
S
O
Me
Ph
OMe
N
O
O
Me
Ph
OH
Me
OR
CO2Me
Me
Me
OR
O
O
Me
Me
OR
OEt
O
Me
O
OEt
O
(–)-Trichodiene
Irland–Claisenrearrangement
diastereoselectivereduction
thio-Claisenrearrangement
Gilbert approach: JOC 1993, 58, 6255-6265.
Meyers approach: JACS 1998, 120, 5453-5457.
(–)-Trichodiene: Gilbert Synthesis
bakers' yiest
40%, 47% ee
! Preparation of the Ireland–Claisen-precursor
Me
O
OEt
O
Me
OH
OEt
O
Me
Me
Me
Me
OMe
O
O
Me
1) MeI, KH2) 4N HCl
3) MsCl, NEt3,
DMAP,
Me
HO (67%, 47% ee)
! Ireland–Claisen rearrangement
Me
OR
O
O
Me
Me
OR
O
OTMS
Me
Me
OR
CO2Me
Me
1) LDA, TMSCl, NEt3, –110 °C
1) H3O+
2) CH2N2
2) reflux 76%, 92:8 dr47% ee
Z-enolate formation
No Ireland–Claisen product with R = H;
only elimination product
R = MeR = H, Me
Me
O
O
Me
elimination product
Gilbert: JOC 1993, 58, 6255-6265.
(–)-Trichodiene
MeOMe
O
TMSO
Me
Me
OR
CO2Me
Me
initially expected
+ minor diast.
A
expected
Li
MeOMe
O
TMSO
Me
B
observedMe
OMe
Me OMe
TMSO
O
OTMS
OR
R
A1,3-strain
1,3-diaxial interaction
! Howhever, A1,3-strain is responsible for rearrangement selectivity (TS-B preferred vs. TS-A)
Ireland–Claisen Rearrangement in More Detail: Gilbert Synthesis
! Ireland–Claisen rearrangement
Me
OR
CO2Me
Me
" The reaction was expected to proceed under Li-chelation of OMe- and OTMS-groups ( expected product)
Me
OMe
O
OTMS
Me
Me
OR
CO2Me
Me
92:8 dr
! Stereoselectivity rationale
Gilbert: JOC 1993, 58, 6255-6265.
" Rearrangement was expected to proceed through chair TS
" Only TS where methylcyclopentenyl group occupy an equatorial position in the product should be formed
Other Pericyclic Reactions: Ireland–Claisen and Thio-Claisen RearrangementsEnantioselective synthesis of (–)Trichodiene
! Retrosynthetic analysis
Me
Me
Me
O
Me
Me
Me
Me
Me
Me
O
Me
N OHC
S
O
Me
Ph
OMe
N
O
O
Me
Ph
OH
Me
OR
CO2Me
Me
Me
OR
O
O
Me
Me
OR
OEt
O
Me
O
OEt
O
(–)-Trichodiene
Irland–Claisenrearrangement
diastereoselectivereduction
thio-Claisenrearrangement
Gilbert approach: JOC 1993, 58, 6255-6265.
Meyers approach: JACS 1998, 120, 5453-5457.
70%, 2:1 dr
! Preparation of the rearrangement precursor
(–)-Trichodiene: Meyers SynthesisMe
Me
Me
Me
Me
N
S
O
Me
Ph
OMe
N
O
O
Me
Ph
OH
1) KH, MeI2) LDA; MeI3) (ArPS2)2, !
N
S
O
Me
Ph
OMe
Me
LDA,
Me
Br
N
S
O
Me
Ph
OMe
Me
Meonly SN2
! Thio-Claisen rearrangement
N
S
O
Me
Ph
OMe
Me
Me
solvent
T
xylene
MeCN
DME
dioxane
HMPA
DMF
DMSO
EtOH
140
80
83
101
100
90
80
78
100:0
65:35
60:40
60:40
48:52
36:64
dec
dec
T (°C)solvent SM:Prod
In DMF after 1 recycle: 60% yield
Meyers: JACS 1998, 120, 5453-5457.
! (–)-Trichodiene is synthesized in 10 steps from bicyclic lactam in 14% overall yield and >99% ee!
Intramolecular Heck Reaction vs. Intermolecular AlkylationTotal synthesis of Chimonanthine by Overman
! Retrosynthetic analysis
HNN
NH
N
Me
Me
H
H
HNN
NH
N
Me
Me
H
H
meso-Chimonanthine(–)-Chimonanthine
BnO OBn
O
HN
HN
O
I II
OBn
I
BnO
MeO2CCO2Me
BnN NBn
O
O
TfO OTf
OO
Me Me
! !BnN
O
NBn
O
ORRO
Intramolecular
Heck-Reaction
Intermolecular
Alkylation
BnN
O
NBn
O
O
Angew. Chem. Int. Ed. 2000, 39, 213-215.OL 2000, 2, 3241-3244.
JACS 1999, 121, 7702-7703.
Intramolecular Heck-Reaction Cascade:Enantioselective synthesis of Chimonanthine
LDA, THF/HMPA;
LDA, I2
! Construction of the vicinal stereogenic quaternary carbon centers
HNN
NH
N
Me
Me
H
H
I
OBn
I
BnO
MeO2CCO2Me CO2MeMeO2C
BnO OBn BnO OBn
O
HN
HN
O
I IMe3Al
2-iodoaniline
TBDMSO OTBDMS
O
HN
HN
O
I I
O O
O
HN
HN
O
I I
Me Me
10% (Ph3P)2PdCl2
NEt3, DMA, 100 °C
71% yield
10% (Ph3P)2PdCl2
NEt3, DMA, 100 °C
90% yield
TBDMSO OTBDMS
BnN NBnO O
O O
NBnO
BnN
O
Me Me
Overman: JACS 1999, 121, 7702-7703.
33% 92%
Intramolecular Heck-Reaction Cascade: Endgame
TBDMSO OTBDMS
BnN NBnO O
O O
NBnO
BnN
O
Me Me
Overman: JACS 1999, 121, 7702-7703.
HO OH
NBnO
BnN
O
HO OH
BnN NBnO O
HNN
NH
N
Me
Me
H
H
HNN
NH
N
Me
Me
H
H
meso-Chimonanthine
! Both products are formed with complete stereocontrol
! Variation in protecting group allows access to both stereogenic products
! To date, this represents the only example of catalytic asymmetric approach to vicinal quaternary stereocenters
(–)-Chimonanthine
Intramolecular Heck Reaction vs. Intermolecular AlkylationTotal synthesis of Chimonanthine by Overman
! Retrosynthetic analysis
HNN
NH
N
Me
Me
H
H
HNN
NH
N
Me
Me
H
H
meso-Chimonanthine(–)-Chimonanthine
BnO OBn
O
HN
HN
O
I II
OBn
I
BnO
MeO2CCO2Me
BnN NBn
O
O
TfO OTf
OO
Me Me
! !BnN
O
NBn
O
ORRO
Intramolecular
Heck-Reaction
Intermolecular
Alkylation
BnN
O
NBn
O
O
Angew. Chem. Int. Ed. 2000, 39, 213-215.OL 2000, 2, 3241-3244.
JACS 1999, 121, 7702-7703.
Intermolecular Transformation to Install Vicinal Quaternary Stereogenic CentersStereoselective dianion dialkylation: an alternative route to Chimonanthine
! Stereoselective dialkylation: Metal- and solvent-dependence
BnN NBn
O
O
BnN NBn
O
O
TfO OTf
OO
Me Me
NaHMDS, THF
TfO OTf
OO
Me Me
LiHMDS,7:3 THF/HMPA
92%
55%
BnNO
NBn
O
BnN
O
NBn
O
BnNO
BnN
O
NBn
OLi
OTf
NBn
O
OTf
Na
meso
C2
" The C2-symmetric derivative was obtained with very high enantio- (100:1) and good diastereoselectivity (8:1)
" This represents a rare example of high stereoselection resulting from the reaction of a prostereogenic enolate
with a chiral, sp3-hybridized electrophileOverman: Angew. Chem. Int. Ed. 2000, 39, 213-215.
Overman: OL 2000, 2, 3241-3244.
OO OO
OO OO
Me Me Me Me
Me MeMe Me
56:1 dr
Intermolecular Michael ReactionEnantioselective synthesis of Aphidicolin
! Retrosynthetic analysis
OH OH
H H
O
Me
Me
HO
OH
RO
Me
Me
OR
O
OO
Me
X
O
O
OMe
Me
Me
MeO O
S
Me
O
Me
Me
TBSO
O
Tol
Aphidicolin
intermolecularMichael addition
Intermolecular Michael Reaction: Total Synthesis of Aphidicolin
LDA, THF
! Vicinal quaternary stereocenter construction
OH OH
H
Me
Me
HO
OH
TBSO
Me
O
Me
O O
S
Me
O
Tol
Me
TBSO O
MeO
Me
S O
Tol
O
75% yield, 7.4:1 dr
O
O
S
Me
OTol
TBSO
Me
Me
O Li
Holton: JACS 1987, 109, 1597-1600.
" The Michael addition may be carried out under aprotic conditions,
provided that the enolate formed in the addition reaction is more
stabilized than that of which acts as the nucleophilic addend
Two electron-withdrawing groups attached to the Michael acceptor
are enough to compensate the steric bulk originated by the formation
of the vicinal quaternary carbons
Intermolecular Michael Reaction: Total Synthesis of Aphidicolin
LDA, THF
! One-pot procedure for the construction of the core system of aphidicolin
OH OH
H
Me
Me
HO
OH
TBSO
Me
O
Me
O O
S
Me
O
Tol
Me
TBSO O
MeO
Me
S O
Tol
O
Holton: JACS 1987, 109, 1597-1600.
Me
O
MeO
Me
S O
Tol
O
Me
O
MeO
Me
O
Li1)
2) HF, MeOH
NaOMe, MeOH
traces H2OS(O)Tol
45% yield
>98% ee
Aphidicolin
! A robust crystal lattice is needed to ensure stereochemistry transfer from reactant to product
! Reaction relies on the high energy content of the ketone n,!* excited state (ca. 80 kcal/mol)
! Reaction relies on the effects of the !-substituents, which lower the bond dissociation energies of the two !-bonds
! Substituents with radial-stabilizing energies (RSE) > 12–15 kcal/mol should enable the solid-state reaction
(e.g., crystalline ketones with secondary, tertiary, and quaternary !-carbons bearing phenyl, carbonyl, dialkoxy,
and !-alkenyl groups)O
Me
Me
O
Me
! Applied to the total synthesis of (±)-Herbertenolide
Green Chemistry Strategies: Decarbonylation ReactionsPhotochemical crystal-to-crystal reactions
h!, 25 °C
CRYSTAL
! Proof of concept
O
MeMe
CO2 NH3BnBnH3N O2C
>97% yield
Me Me
BnH3N O2C CO2 NH3Bn
" Reaction run on 1.5 g scale: microcrystals suspended in hexane and irradiated with a medium-pressure Hg lamp
using a pyrex jacket (" ! 290 nm) for 12 h. Product was simply collected by filtration.
(mp = 187-189 °C)
Garcia-Garibay: OL 2004, 6, 645-647.Garcia-Garibay: OL 2005, 7, 371-374.
Garcia-Garibay: JACS 2005, 127, 7994-7995.
Conclusions
! At present, only limited number of chemical synthesis strategies have been devised
for directly assembling vicinal quaternary carbon centers
! To date, only one diastereoselective catalytic reaction has been developed (Heck-reaction) and no catalytic asymmetric approach has been disclosed!
! Mainly intramolecular approaches such as biomimetic polyene cycloadditions,
cycloaddition reactions, and sigmatropic rearrangements have been used to control
the stereochemistry of adiacent quaternary centers
! Only two types of intermolecular transformations have been realized. In both cases, the alkylation
diastereoselectivity results from the union of a chiral electrophile with an achiral nucleophile
(extremely rare!)
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