Total Synthesis of Indolizidine Alkaloid (—)-209D: Overriding Substrate Bias in the Asymmetric Rhodium-Catalyzed [2+2+2] Cycloaddition Wipf Group Saturday Morning Meeting Current Literature Abstracts & Reports Robert T. Yu, Ernest E. Lee, Guillaume Malik, Tomisav Rovis* Angewandte Chemie International Addition, 2009, 48, 2379-2382. Department of Chemistry, Colorado State University, Fort Collins, CO Robert B. Lettan II April 11, 2009 n-Hex H N C O + Rh(I)/L* N O H Me N H Me Rob Lettan @ Wipf Group Page 1 of 11 5/2/2009
Transcript
Total Synthesis of Indolizidine Alkaloid (—)-209D:Overriding Substrate Bias in the Asymmetric
Rhodium-Catalyzed [2+2+2] Cycloaddition
Wipf Group Saturday Morning MeetingCurrent Literature Abstracts & Reports
Robert T. Yu, Ernest E. Lee, Guillaume Malik, Tomisav Rovis*
Angewandte Chemie International Addition, 2009, 48, 2379-2382.
Department of Chemistry, Colorado State University, Fort Collins, CO
Robert B. Lettan IIApril 11, 2009
n-Hex
H
NC
O
+
Rh(I)/L*N
OH
Me
N
H
Me
Rob Lettan @ Wipf Group Page 1 of 11 5/2/2009
Indolizidine Alkaloids
N
HHO
HO
R1,R2,R3 = H: lentiginonsine
R1 = OH; R2,R3 = H: swainsonine
R1,R2 = OH; R3 = H: castanospermine
R1,R2,R3 = OH: uniflorine
hydroxylated indolizidines
R1
R2
R3
N
H
Me
Me
(—)-dendroprimine
N
H
(+)-pumiliotoxin
HO Me
Me R
N
H
Me
(+)-monomorine
Me
N
Me
MeH
HHMe
(—)-alkaloid 205B
Alkaloids from ants and amphibians
N
O
OR
polygonatum alkaloids
N
NH
X
NH
Me
HO
HO
Me10
8
prosopis alkaloids
N
X = O, H2
HMe
HO
(+)-ipalbidine
N
Q
R2O
OMe
R3
tylophoridicines
N
O
n-C6H13 OR
(+)-cylindricines
N
OMe(HO)2OPO
HO
MeHNFR901483
NO
H
OH
H
H
O
(—)-secu'amamine A
Michael, J. P. Nat. Prod. Rep. 2008, 25, 139-165.
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Rovis' Initial Approach towards Indolizidines
R1
R2
NC
O
5 mol % [Rh(ethylene)2Cl]2,10 mol % P(4-OMePh)3
toluene, 80-110 °C
N N
R2
R1
O
O
R1
R2
A B
substituted phenyl
1-cyclohexene1-cylopentene
3-furyl2-thiophene
n-propyln-butyl
n-butyl
nnn
(CH2)2OTBS
(CH2)2OTBS
R1/R2
R1 = Me, R2 = Ph
Yield (%) Selectivity (A:B)
60-72
6672
7550
607056
6256
R1 = Et, R2 = Ph6063
n
1
11
11
111
22
11
>20:1
1.1 : 11.3 : 1
>20:1>20:1
>1:201:6
>1:20
1:3.5>20:1
6063
1 2
Proposed Mechanism
1 + 2
RhLn
N
O
R1
R2
NLnRh
O
N
LnRh
O
N
A
B
LnRh
R2
R1O
PathB
PathA
PathB'
N
LnRh
R1
R2
O Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782.
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Application to Terminal Alkynes with Chiral Ligands
H
R
NC
O
5 mol % [Rh(ethylene)2Cl]2,10 mol % Ligand
N N
R
O
O
Rtoluene, 110 °C
major (>20:1 to 1.5:1)when R = aryl50-96% yield81-98% ee
major (>20:1 to 1.2:1)when R = alkyl46-82% yield76-87% ee
electron deficientsubstituents give poor selectivity
Steric factorsinfluence selectivity
Total Synthesis of (+)-Lasubine II
MeO
MeO
H
NC
O
N
O
Ar Ar side product (20%)
quinolizinone
H H
O
P
OO
O
Ph Ph
PhPh
NMe
MeLigand
5 mol % [Rh(ethylene)2Cl]2,10 mol % Ligand
toluene, 110 °C
N
OH
OMe
MeO
62% yield, 98% ee(+)-Lasubine II
N
HOH
OMe
MeO
62% yield, 98% ee
1) Pd/C, H2, MeOH 80% yield, >20:1 dr
2) PPh3, DEAD, p-NO2PhCO2H; then K2CO3, MeOH 64% yield
Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370.
Rob Lettan @ Wipf Group Page 4 of 11 5/2/2009
Additional Applications
H
R1
NC
O
2.5 mol % [Rh(ethylene)2Cl]2,5 mol % Ligand
N N
Aryl
O
O
Alkyltoluene, 110 °C
major (12:1 to 2:1)
when R1 = aryl
Ligand I
87-94% ee
major (>20:1 to 3:1)
when R1 = alkyl
Ligand II
91-95% ee
R2 R2
O
P
OO
O
Ar Ar
ArAr
NR2
Me
Me
Ligand
R2
I: Ar = Ph, R = MeII: Ar = 3,5-xylyl, NR2 =
III: Ar = 3-xylyl, NR2 =
N
N R2 = Me, n-Bu, i-Bu, Bn, i-Pr,
cy, CH2OBn, n-butene
H
R
NC
N
3 mol % [Rh(ethylene)2Cl]2,6 mol % Ligand III
NN
R
N
N
Rtoluene, 110 °CHH
Ar
Synthesis of Bicyclic Amidines
Formation of Quaternary Stereocenters
up to >19:143-82% yield88-99% ee
Ar
Ar
Lee, E. E..; Rovis, T. Org. Lett. 2008, 10, 1231.Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 3262.
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Overriding Substrate Bias
N
O
n-C6H13 OR
(+)-cylindricines
N
O
n-C6H13
(—)-209D
H
N
Alkyl
dialkylated indolizidines
HMe
NPMB
(HO)2OPO
HO
MeHN
FR901483
NO
H
OH
H
H
O
(—)-secu'amamine A
H
Alkyl
NC
O
N
O
AlkylR2
R2
Rh(I)/L
Previous Work (A)
Topic Paper(B)
orN
Alkyl
OR2
Ligand Screening (alkyl = n-Hex; R2 = H)
Ligand A:B Yield of B (%) ee of B (%)
O
P
OO
O
Ph Ph
PhPh
NMe
MeMe
Me
O
OP N
Me
Me
O
OP N
Me
Me
Me
Me
Me
Me
O
OP N
Me
Me
SiMe3
SiMe3
R
R
R = SiMe3
R = t-Bu
3.2 : 1
1 : 2.2
1 : 3.8
1 : 3.5
1 : 6.2
20
22
60
50
75
73
72
96
94
91
Rob Lettan @ Wipf Group Page 6 of 11 5/2/2009
Revisiting the Mechanism
H
Alkyl
NC
O
N
O
AlkylR
Rh(I)/L
Previous Work (A)
Topic Paper(B)
orN
Alkyl
OR
Proposed Mechanism
RhLn
N
O
Alkyl
NLnRh
O
N
LnRh
O
N
B
A
LnRh
Alkyl
O
PathA
PathB
PathA'
N
LnRh
Alkyl
O
1 2
1
1
1
PathB
COmigration
Previously, Path A is favored, presumably due to relatively low steric interactions between the alkyl side chain of the alkyne and the taddol-derived ligand on the Rhodium catalyst. Product A is generated.
Previously, when the steric interaction is increased (aryl or branched alkyl acetylenes) Path B becomes more favorable, leading to product B.
When the catalyst is modified to the binol-derived phosphoramidites (especially the 3/3' subsituted variants) the increase in steric interactions due to the catalyst overrides the substrate bias, leading to Path B and the formation of product B.
Additional substitution on the olefin (R) does not appear to play a part in the mechanistic pathway.
NC
O
RhLn
R
R
R
RR
R R
Rob Lettan @ Wipf Group Page 7 of 11 5/2/2009
Synthesis of Indolizidine Alkaloid (—)-209D
N
R
H
R = n-hexyl, (—)-209DR = n-propyl, (—)-167B
Part of a family of 22 natural products referred to as the gephyrotoxins.
Isolated from the skin secretions of neotropical frogs.
These 2 alkaloids have only been isolated in minute quantities.
Multiple syntheses (>12) in literature aimed to both prepare in greater quantities and to validate methodologies.
NC
ON
OHMe
H
2.5 mol % [Rh(C2H4)2Cl]2,5 mol %
toluene, 110 °C66% yield91% ee
Me
MeMe
Me
OO
P NMe
Me
t-Bu
t-Bu
Me
N
HOH
Me
Pd/C, H2, MeOH
82%1 diastereomer
1) (Im)2CS, DMAP neat, 50 °C, 77%
2) AIBN, n-Bu3SnH, PhMe, 100 °C, 71%
Barton-McCombie
deoxygenation
N
H
Me
(—)-209D
Shortest synthesis of (—)-209D reported to date:5 steps (22%) from 5-hexenoic acid.
Utilizing a Rhodium (I) catalyzed process in the presence of chiral ligands the Rovis group has developed a method for the product selective and enantioselective process for the synthesis of Indolizidine alkaloids.
This methodology has been applied to the synthesis of the efficient enantioselective synthesis natural products (+)-lasubine II and alkaloid (—)-209D.
This route can be enivisioned to access other more-complex 5-substituted indolizidine alkaloids, including FR901483, the cylindricines, and derivatives of these compounds.
An improvement on the selective synthesis of corresponding quinolzinones is still necessary.
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