Enantioselective Total Synthesis of (–)-Napyradiomycin A1 ... · - One step to densely...
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Enantioselective Total Synthesis of (–)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin Snyder, S. A.; Tang, Z.-Y.; Gupta, R. J. Am. Chem. Soc. 2009, 131, 5744–5745. Tandem Asymmetric Aza-Darzens/Ring-Opening Reactions: Dual Functionality from the Silane Lewis Acid Valdez, S. A.; Leighton, J. L. J. Am. Chem. Soc. 2009, 131, 14638–14639. Mike Karney Short Literature Presentation Group Meeting 6-14-2010
Transcript of Enantioselective Total Synthesis of (–)-Napyradiomycin A1 ... · - One step to densely...
Enantioselective Total Synthesis of (–)-Napyradiomycin A1 via Asymmetric
Chlorination of an Isolated OlefinSnyder, S. A.; Tang, Z.-Y.; Gupta, R. J. Am. Chem. Soc. 2009, 131, 5744–5745.
Tandem Asymmetric Aza-Darzens/Ring-Opening Reactions: Dual Functionality
from the Silane Lewis AcidValdez, S. A.; Leighton, J. L. J. Am. Chem. Soc. 2009, 131, 14638–14639.
Mike KarneyShort Literature Presentation
Group Meeting 6-14-2010
Profs. Scott A. Snyder and James L. Leighton
Scott A. Snyder
• Undergraduate, Williams, 1995-1999 (Markgraf)
-Hetero Diels–Alder routes to Carboline Alkaloids
• Ph. D, Scripps, 1999-2004 (Nicolaou)
-Synthesis of diazonamide A
-19 publications
- Co-author of Classics in Total Synthesis II
• Post-doc, Harvard, 2004-2006, (Corey)
-Worked on dollabellane family
• Assistant Prof, Columbia, 2006-present
James L. Leighton
• Undergraduate, Yale, 1983-1987 (Danishefsky)
• Ph. D, Harvard, 1989-1994 (Evans)
-Syntheses of calyculin A and
zaragozic acid C
-5 publications
• Post-doc, Harvard, 1994-1996, (Jacobsen)
-Enantioselective epoxide opening
• Assistant Prof, Columbia, 1996-1999
• Associate Prof, Columbia, 1999-2004
• Professor, Columbia, 2004-present
HN
OO
HN
O
NH
NH
ClO
Me Me
N
Cl
HN
O
Me Me
HO
Me
Me Me
H
Me
MeOH
diazonamide A
palominol
calyculin A
zaragozic acid C
O
O
MeMe
Me
Me
MeMe
CN
OH OH
Me Me
OMe
O
O
N
NH
O
P
OH
OHO
MeOH
OHNMe2
MeO
O
O
O
O
HO2C
HO2C
OH
CO2H
OH
Ph
OMe
Me
Ph
Me
The Napyradiomycins
• Isolated from a strain of Streptomyces bacteria
• Demonstrate antibacterial properties and activity as a nonsteroidal estrogen antagonist
• Structurally similar compounds have shown antitumor potency against colon carcinoma cells
O
OH
HO
O
O
Me
Me
ClCl
OH
Me
Me
Me
Cl
O
OH
HO
O
O
Me
Me
ClCl
Me
Me
Cl
Shiomi, K.; Iinuma, H.; Hamada, M.; Naganawa, H.; Manabe, M.; Matsuki, C.; Takeuchi, T.; Umezawa, H. J. Antibiot., 1986, 39, 487–493
Hori, Y.; Abe, Y.; Shigematsu, N.; Goto, T.; Okuhara, M.; Kohsaka, M. J. Antibiot., 1993, 46, 1890–1893
Napyradiomycin A1
• Three stereocenters
• Tricyclic core with small aliphatic chain
napyradiomycin A1 napyradiomycin B1 napyradiomycin B4
O
O
OH
HO OMe
ClCl
Me
Me Me
Me
Napyradiomycin A1
Nilewski, C.; Geisser, R. W.; Carreira, E. M. Nature, 2009, 457, 573–576
Shibuya, G. M.; Kanady, J. S.; Vanderwal, C. D. J. Am. Chem. Soc., 2008, 130, 12514–12518
Schlama, T.; Gabriel, K.; Gouverneur, V.; Mioskowski, C. Angew. Chem. Int. Ed., 1997, 36, 2342–2344
OH
OH
HO
O
O
O
OH
HO
O
O
Me
Me
Johnson-Claisenrearrangement
Asymmetricchlorination
TandemKnovenagel/
6!-electrocyclization
Key Transformation
• Enantioselective chlorination to direct stereochemistry of geranyl side chain and set contiguous stereocenter
68% yieldracemicMe
CO2Et
CH2Cl2, 0 °C
Et4NCl3
MeCO2Et
Cl
Cl
Me
MeOTCA
Cl
Et4NCl3
CH2Cl2, –90 °C
Me Me
Cl
OTCA
Cl
Cl
76% yield10.5:1 dr
Stereoselective Chlorination of Natural Products
napyradiomycin A1
O
O
OH
HO OMe
ClCl
Me
Me Me
Me
O
O
OH
HO OMe
ClCl
Me
Me Me
MeO
OH
HO
O
O
Me
Me
Building the Core
Snyder, S. A.; Tang, Z.-Y.; Gupta, R. J. Am. Chem. Soc. 2009, 131, 5744–5745
napyradiomycin A1
OH OH
NaO3S SO3Na
i. NaOH, KOH, Ba(OH)2, 275 °C
ii. O2, DMF
64% over 2 steps
O
O
OH
OH
HO
O
O
OH
MOMO OMe
Me
i.
ethylenediamine diacetate
ii. NaH, MOMCl
O Me
Me
35% over 2 steps
H
OH
OH
1
93% yield95% ee!!!
O
MeMe
MOMO
O
OO
B
*L
B
*L
Cl
Cl
L*
L*
Cl2
O
O
OH
HO OMe
ClCl
Me
Me Me
Me
O
O
OH
MOMO OMe
Me
BH3•THF, (S)- Cl2, THF, –78 °C
O
O
OH
MOMO OMe
Me
Cl
Cl1
O
MeMe
MOMO
O
OO
B O
O
B
O
O
!-Stackinginteraction
Steric blocking
Johnson-Claisen
Snyder, S. A.; Tang, Z.-Y.; Gupta, R. J. Am. Chem. Soc. 2009, 131, 5744–5745
napyradiomycin A1
O
O
OH
HO OMe
ClCl
Me
Me Me
Me
O
O
OH
MOMO OMe
Me
Cl
Cl
i. KOAc, 18-Crown-6ii. NaH, Me2SO4
iii. Sm, I2, MeOH
O
O
OMe
MOMO OMe
Me
OH
Cl
i. CH3C(OMe)3, toluene (1:20), proprionic acid,
130 °C, 15 h
O
O
OMe
MOMO OMe
Me
Cl
CO2Me64% over 3 steps 27%, 68% r.s.m.
O
O
OMe
MOMO OMe
Me
Cl
CO2Me
O
O
OMe
MOMO OMe
Me
OH
Cl
Me
OMe
O
OH
HO
Cl
MeO
OMOM
CH3C(OMe)3Me
O
Me
O
OH
O
Cl
MeO
MeO
OMOM
Johnson-
Claisen Me
O
Me
O
O
Cl
MeO
OMOM
OMe
O
OVER THE TOP!
Endgame
Snyder, S. A.; Tang, Z.-Y.; Gupta, R. J. Am. Chem. Soc. 2009, 131, 5744–5745
napyradiomycin A1
O
O
OMe
MOMO OMe
ClH
O
HMe
(–)-napyradiomycin A1
O
O
OH
HO OMe
ClCl
Me
Me Me
Me
O
O
OMe
MOMO OMe
ClCl
Me
Me Me
Me
O
O
OH
HO OMe
ClCl
Me
Me Me
Me
O
O
OMe
MOMO OMe
Me
Cl
CO2Me
i. KHBPh3
ii. DIBAL-H
iii. Dess-
Martin
Summaryi. MgI2, 50°C; PPTS, 90 °C
• First asymmetric total synthesis of any member of the napyradiomycin family
- 15 linear steps; 0.014% overall yield
• Key Transformations
- 2-step flaviolin synthesis, highly asymmetric chlorination , Johnson-Claisen rearrangement
• Future Directions
- Asymmetric chloronium-induced cation-! cyclization
- Catalytic, enantioselective chlorination
34% over 3 steps 34%, 50% r.s.m.
90%
Me Me
PPh3 Me
I
2
i. , n -BuLi
ii. KHMDS, NCS
2
Darzens Reaction
Aza-Darzens Variants
Darzens, G. Compt. rend., 1911, 151, 883–884
Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem. Int. Ed. Engl., 1995, 34, 676–678
Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc., 1999, 121, 5099–5100
Ph N
H
Ph OEt
O
N2
10 mol % Cu(I) cat.,
CH2Cl2 N
Ph
H
H CO2Et
Ph N
Ph
CO2Et
HH
Ph
N
EtO2C
CO2Et
CO2Et
Ph
Ph
1
OEt
O
N2
10 mol %
CH2Cl2
Ph NCHPh2
N
Ph CO2Et
CHPh2NH
Ph
CO2EtH
Ph2HCNH
H
CO2EtPh
Ph2HC
S-VAPOL-B
1
S-VAPOL
Me Me
N N
O O
Ph Ph
OH
Ph
Ph
OH
77% yield>50:1 dr97% ee
37% yield4:1 dr
44% ee 35% ee
RO
O
R1
X
H
Base
RO
O
R1
X
R2
O
R3
O
XR1 R3
RO2C R2
O
XR1 R2
RO2C R3
R1 R3
RO2C R2
R1 R2
RO2C R3O
O
Leighton!s Approach
Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc., 2004, 126, 5686–5687
Shirakawa, S.; Berger, R.; Leighton, J. L. J. Am. Chem. Soc., 2005, 127, 2858–2859
Shirakawa, S.; Lombardi, P. J.; Leighton, J. L. J. Am. Chem. Soc., 2005, 127, 9974–9975
Notte, G. T.; Leighton, J. L. J. Am. Chem. Soc., 2008, 130, 6676–6677
• Chiral silane Lewis acid previously used in a number of acyl hydrazone nucleophilic addition manifolds
- Mannich-type reactions with silyl enol ethers
- [3+2] cycloadditions
- Friedel–Crafts alkylations
- Allylations
What other nucleophiles can
be added to hydrazones??
N
Si
O Ph
ClMe
Ph
Me
84% yield97% ee!!!
• Ring opened product obtained as single regioisomer and diastereomer
Ph
N
H
NH
O Ph
Ph2SOEt
O
BF4
i - Pr2NEt, 1
PhMe/CH2Cl2, 0 °CPh OEt
O
NHNHBz
Cl
1
One-Pot Procedure
Valdez, S. C.; Leighton, J. L. J. Am. Chem. Soc., 2009, 131, 14638–14639
Ar
N
H
NH
O Ph
1 mol% Rh2(OAc)4, Ph2S4:1 PhMe:CH2Cl2, 0 °C
Ar OEt
O
NHNHBz
ClO
OEt
N2
1.3 equiv (S,S)-1
1
N
Si
O Ph
ClMe
Ph
Me
OEt
O
NHNHBz
Cl
OEt
O
NHNHBz
Cl
O2N
OEt
O
NHNHBz
Cl
F3C
OEt
O
NHNHBz
Cl
Me
OEt
O
NHNHBz
ClBr
OEt
O
NHNHBz
ClMe
OEt
O
NHNHBz
Cl
Br
OEt
O
NHNHBz
Cl
F
OEt
O
NHNHBz
Cl
Two equiv of ethyl diazoacetate and diphenyl sulfide needed because of dimerization
88% yield 76% yield 82% yield>20:1 rr95% ee
>20:1 rr94% ee
6:1 rr94% ee
83% yield9:1 rr
97% ee
85% yield
82% yield
84% yield81% yield17:1 rr91% ee
11:1 rr91% ee
10:1 rr93% ee
81% yield6:1 rr
86% ee
7:1 rr89% ee
Alternate Ring-Opening Nucleophiles
Valdez, S. C.; Leighton, J. L. J. Am. Chem. Soc., 2009, 131, 14638–14639
1
N
Si
O Ph
ClMe
Ph
MeAr1
N
H
NH
O Ph
1 mol% Rh2(OAc)4, Ph2S4:1 PhMe:CH2Cl2, 0 °C
Ar1 OEt
O
NHNHBz
Ar2O
OEt
N2
1.3 equiv (S,S)-1 Ar2H
Si OO
Ph
N
NN
Ph
HH
Ar1
EtO2C
Ph
Me
Me
Si OO
Ph
N
HNN
Ph
Ph
Me
Me
EtO2CAr1
Cl
HCl
22% yield92% ee
ZnCl2
80% yield94% ee
• Addition of electron rich arenes sluggish (72 h reaction times) and low yielding
• Brief survey of substrates showed good scope
- Products obtained in good to moderate (50–80%) yields
- Single regioisomers and diastereomers obtained with excellent enantioselectivity (>90% ee)
- Diastereochemical outcome implied equilibrium between two intermediates
- Addition of a Lewis acid should favor aziridine intermediate
Applications and Conclusions
• General and highly efficient procedure to access !-chloro-"-hydrazido esters through an activated aziridine intermediate
- One step to densely functionalized heterocycles
• Treatment with secondary nucleophiles access differentially substituted amino acid derivatives
Ph OEt
O
NHNHBz
Cl
DMSO, 55 °C PhNCS, PhMe, 75 °C
i. Acroleinii. 10 mol% NHC
O
NH
N
N
SN
Ph
Ph
CO2Et
NPh
NHBz
Ph
CO2Et
O
BzHN
CO2Et
Ph
• Future Directions
- Expanding nucleophile scope
