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Total Synthesis of (-)-Sarain AM. H. Becker, P. Chua, R. Downham, C. J. Douglas, N. K.
Garg, S. Hiebert, S. Jaroch, R. T. Matsuoka, J. A.Middleton, F. W. Ng, and L. E. Overman
J. AM. CHEM. SOC. 2007, 129, 11987-12002
Erikah EnglundCurrent Lit
Synthetic Approaches10/27/07
N N
O
H
HO
OH
Erikah Englund @ Wipf Group 1 10/29/2007
Outline
• Isolation• Biosynthesis• Syntheses from other groups• Current route• Overall picture• Conclusions
Erikah Englund @ Wipf Group 2 10/29/2007
Isolation• In 1986, Cimino isolated Sarains A-C at the Bay of Naples from the
marine sponge Reniera sarai. (Tetrahedron, 1989, 45, 3863)
• Products were characterized through MS, NMR, IR and 2D NMR:COSY, HETCOR, long range HETCOR. Structure was confirmedthrough X-ray of diacetate crystal (J. Nat. Prod. 1990, 53, 1519)
• Absolute conformation determined through Mosher ester analysis(Tetrahedron, 1996, 52, 8341)
• Sarains A-C display modest antibacterial, insecticidal and antitumoractivities (Comp.Biochem.Physiol. B, 1992, 103B, 293)
N N
O
H
HO
OHN N
O
H
R
HO
OH
Sarain B, R = -(Z)-CH2CH=CH-Sarain C, R = -(Z)-CH=CHCH2
Sarain A
Erikah Englund @ Wipf Group 3 10/29/2007
Proposed Biosynthesis
Tet. Lett. 1995, 36, 707Erikah Englund @ Wipf Group 4 10/29/2007
Previous Synthetic Efforts• Weinreb (J.O.C. 2006, 71, 2078)
• Heathcock (J.O.C. 1998, 63, 9616)
• Cha (J.O.C. 2003, 68, 2205)
• Marazano (Eur.J.O.C. 2006, 4106-4114)
NN
O
BnH
H
Bn
H
OMe
OMe NN
O
O
HTBSO
O
OMOM
N NH
OMOM
O O
O
O
NN
O
Ns
H
CO2Bn
H
CO2Me
OTBS
LHMDS
ONCO2Bn
MeO2C
NsHN OTBS
NNCO2Bn
MeO2C
OTBS
H
NNPMB
CO2Et
Boc
OTBS
O
NNPMB
CO2Et
Boc
O
O
O
NNPMB
CO2Et
OH
O
OH
O
NPh
O
NH3
Cl
NN
H
OH
Ts
TMS
NNTs
FeCl3
Erikah Englund @ Wipf Group 5 10/29/2007
Initial Retrosynthesis
Overman Communication: Angew.Chem.Int.Ed 2006, 45, 2912Erikah Englund @ Wipf Group 6 10/29/2007
First Models• Seebach chemistry
– Tet. Lett 1983, 24,3311
• Benefit: Bothenantiomers areaccessible
• Early work done withunnatural enantiomer
• Model System: Z-enoneneeded
• 71% 20:1 dr• Stereochem confirmed
via derivatization
Erikah Englund @ Wipf Group 7 10/29/2007
Model
Erikah Englund @ Wipf Group 8 10/29/2007
Model Findings
• Many Lewis Acidsscreened for cyclizationto 49– SnCl4, BF3.OEt2,
Me3Al• Further exploration
deemed necessary onreal system
• 2 Plans– Plan A
• Formmacrocyclebeforecyclization
– Plan B• Have larger C3
group on priorto cyclization
Erikah Englund @ Wipf Group 9 10/29/2007
Plan A or Plan B
N N
O
O
O
O
H
NH N
O
O
O
ORO
NBoc
N3
OH4
4
CO2Et
OBz
OTBDPS
O
N Ph
TBDPSO
EtO2C
no cyclizationunder a variety of conditions
PLAN A: macrocycle then cyclize
X
PLAN B: cyclize with large C3 side chain late stage macrocycle installation
NTos N
O
O
O
H
OTIPSR
NTos N
O
O
H
CHOR
HO
Erikah Englund @ Wipf Group 10 10/29/2007
Plan A & Problems• Macrocycle
formed prior tocyclization
• The synthesiscommencedwith:
• Converted to65 in 8 steps
Erikah Englund @ Wipf Group 11 10/29/2007
Plan B
N
CO2Et
Boc
OH
BocNTs
O
OTBDPS
1. LHMDS, allyl bromide2. 2 N HCl
3. Boc2O, DMAP (94%)
TsN
O
N
CO2Et
PhTBDPSO
OLHMDS76%
OBn
Br
6
TsN
O
N
CO2Et
PhTBDPSO
O OBn6
15 steps18%
NTs
N
O
O
O
H
OTIPSBnO6
BCl3N
NTs
N
CHO
O
O
OH
HO
6
*
NH N
O
O
H
HO
5
EtO2C OTIPS no amide formation
N N
O
O
H
OTIPS
TBSO
OGrubbs
25%Optimize!
Erikah Englund @ Wipf Group 12 10/29/2007
Cyclization Optimization
N NH
OH
PMBO
OH
1. H2 Pd/C2. HCl (TBS removal)3. PMBCl, NaHMDS (89%)
4. TAS-F5. KOH
N N
OTIPS
O
O
OTBS
1. TBSCl 2. NaBH4
3. TIPSOTf (75%)
4. Na, Naphthalene5. NaCNBH3
6. Grubbs (Gen 1>Gen2) 75-85%
NTs
N
CHO
O
O
OH
O
H
NTs
N
O
O
CHO3
1. TIPSOTf (97%)2. BCl3 85%
N
O
1. H2
2. TIPSOTf
Mechanistic studies:
Prins decomposition pathway minor diastereomer
1. O3
2. CH2=CH(CH2)3MgBr3. Swern (76%)
4. TMS(CH2)2OCH2PPH3Cl5. HF (91%
NTs
N
O
O
O
NTs
N
O
O
O
R
R=CO2Me, t-Butyl imine or N-dimethyl hydrazone
LDA,5-bromopentene
N
OO
Boc
OH
TsHN
1. DIBALH then 2 N HCl
2. NaOMe
1. DIBALH
2. NaCNBH3, HOAc (93%)
3. DMSO 130 oC
4. TBAF
5. K2CO3 (68%)
N
CO2Et
Boc
OH
BocNTs
O
OTBDPS
X
Erikah Englund @ Wipf Group 13 10/29/2007
Finale
A. HF, 1.5 h (50-60%)
B.1. HF, 10 minB.2. TMSI complex mixture
sarain AN N
O
H
PMBO
OTES
N NH
OH
PMBO
OH
N N
PMBO
OTES
SnBu3
OTES
1. 138, (86%)2. IBX, DMSO (71%)
3. 137 (68%), 3-4:1 dr4. TBAF(85%)5. TESCl (70%
O
HOTBS
BrMg
SnBu3
O
1. K2CO3, MeOH (92%)2. Dess-Martin3. 144 (76%)
N N
PMBO
OTES
SnBu3
O
I
1. Pd2. DIBALH (64%)3. Dess-Martin (70%)
PPh3Br
N N
PMBO
OH
O
I
1.Ox2. 137
messy reactionor loss of vinyl iodide
Free aminal also used
AcOH
N
OH
ON
H
I
OPMB
Erikah Englund @ Wipf Group 14 10/29/2007
Synthesis Maze
N N
O
O
O
O
H
X NH N
O
O
O
ORO
NBoc
N3
OH4
4
CO2Et
OBz
OTBDPS
O
NPh
TBDPSO
EtO2C
no cyclization
opposite enantiomer
NTosN
O
O
O
H
NTosN
O
O
O
H
MeCHO
wrong diastereomer
NTos N
O
O
O
H
BnO OTIPS6
BCl3
NTos N
O
O
H
CHO
HO6
N
HO
NH N
O
O
H
HO
5
EtO2C OTIPS
N N
O
O
H
OTIPS
TBSO
O
trace amide
X
RCM25%
NTos N
O
O
O
H
X
X
allylation of :aldehydet-butyl iminehydrazone
R
R=H
R=OMeXenolate
alkylationX=O
X=O
X=CH2
R=H
NTos N
O
O
O
H
OTIPS3
N N
O
O
H
OTIPS
TBSO
N NH
OTIPS
PMBO
OH
RCM
N N
O
PMBO
OH
I X
MgBr
SnBu3
1. Ox N N
O
H
HO
OH
N N
O
PMBO
OTES
I
SnBu3
Erikah Englund @ Wipf Group 15 10/29/2007
Conclusions• After extensive optimization, the total synthesis of sarain
A was completed in 45 steps and 0.13% overall yieldfrom diethyl D-tartrate
• Weinreb, Heathcock, Cha and Marazano haveindependently developed methadology to synthesize thecore
• The Highlights:– Seebach oxazoline chemistry sets three key stereocenters that
influence all the remainder stereocenters in the molecule– Congested core constucted via novel enoxysilane addition to N-
sulfonyliminium species– Ring closing metathesis sets western ring– Stille coupling on a sensitive substrate sets eastern ring
Erikah Englund @ Wipf Group 16 10/29/2007
