asymmetric*total*synthesis*of*(+)6danicalipin*accc.chem.pitt.edu/wipf/current...
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Asymmetric Total Synthesis of (+)-‐Danicalipin A Yoshimitsu, T.; Nakatani, R.; Kobayashi, A.; Tanaka, T. Org. Le<. ASAP
Current literature Yongzhao Yan February 26th 2011
C6H13OSO3
-Cl OSO3
-
Cl ClCl
ClCl
C6H13 OTBS
Cl OTBS
Cl
ClClO2N
C6H13OSO3
-Cl OSO3
-
Cl
ClCl
NO
( )7
C6H13OSO3
-Cl
OSO3-
Cl ClCl
ClCl
2
1
C6H13OSO3
-Cl OSO3
-
Cl ClCl
ClCl
Chlorosulfolipids
Chlorosulfolipids was first reported in 1969 and ignored by syntheMc chemists for the ensuing 40 years.
Danicalipin A (1) was isolated by Haines and Block from Ochromaonas danica. It is a key component of algal membranes.1
Malhamensilipin A (2) is isolated in 1994 from alga O. malhamensis. It displays acMvity in kinase assay.2
Ciminiello and Fa<orusso reported isolaMon of 3-‐5 from AdriaMc mussels. These lipids were deemed to be the causaMve agents in seafood poisoning.3
-‐Heavily chlorinated linear hydrocarbon moMfs -‐Complicated stereochemical structures -‐Toxicity mechanism
1. T. H. Haines, M. Pousada, B. Stern and G. L. Mayers, Biochem. J.,1969, 113, 565–566. 2. J. L. Chen, P. J. Proteau, M. A. Roberts, W. H. Gerwick, D. L. Slateand R. H. Lee, J. Nat. Prod., 1994, 57, 524–527. 3. P. Ciminiello, C. Dell’Aversano, E. Fa<orusso, M. Forino, S. Magno,M. Di Rosa, A. Ianaro and R. Polec, J. Am. Chem. Soc., 2002, 124,13114–13120.
Danicalipin A
In Ochromaonas danica cells, the total sulfolipid fracMon consMtutes about 15% of the lipids and 3% of dry weight.
The structure of the monochloride diol 6 was determined by mass-‐spectroscopy.
The planar structure of the major chlorosulfolipid is elucidated by a strategy using 36Cl-‐labeled chlorosulfolipid.1
These compounds were revisited in 2009 by Vanderwal by synthesis and J-‐based configuraMonal analysis.2
C6H13OSO3
-OSO3
-
ClC6H13
OSO3-
Cl OSO3-
Cl ClCl
ClCl
6
1. J. Elovson and P. R. Vagelos, Proc. Natl. Acad. Soc. USA, 1969, 62,957–963. 2. T. Kawahara, Y. Kumaki, T. Kamada, T. Ishii and T. Okino, J. Org.Chem., 2009, 74, 6016–6024.
ElucidaMon of relaMve configuraMon of chlorosulfolipid
Carreira et al., applied Murata’s approach for the configuraMonal assignment adjacent of hydroxy/alkoxy-‐ subsMtuted carbons into chlorosulflipid.1
This approach also provides important imformaMons about their soluMon structures.
1. C. Nilewski, R. W. Geisser, M.-‐O. Ebert and E. M. Carreira, J. Am. Chem. Soc., 2009, 131, 15866–15876.
Biosynthesis and biological relavance
Haines group demonstrated that the hydrocarbon chain is first constructed via the normal fa<y acid biosyntheMc pathway, and later funcMonalized with the polar subsMtuents.
Enzyme-‐mediated transfer of the sulfate group of PAPS to the diol was postulated to be the final step in the biosynthesis of sulfolipid 6.
Few details is known about the chlorinaMon. The chlorinaMon is happened in step-‐wise fashion. And it does not follow a linear path. A new class of non-‐heme iron halogenases is found to be able to halogenate unacMvated methyl group via free-‐radical process.
1. G. Thomas and E. I. Mercer, Phytochemistry, 1974, 13, 797–805. 2. J. Elovson, Biochemistry, 1974, 13, 3483–3487. 3. F. H. Vaillancourt, J. Yin and C. T. Walsh, Proc. Natl. Acad. Soc.USA, 2005, 102, 10111–10116.
Vanderwal’s diastereoselecMve dichlorinaMon
3 groups – Vanderwal’s, Carreira’s and Yoshimitsu/Tanaka’s have been acMvely engaged in the development of methodologies and strategies for chlorosulfolipid synthesis in the past few years.
DichlorinaMon of (Z)-‐allylic trichloroacetates efficiently and stereoselecMvely generates the syn-‐syn hydroxydichloride.
H
O
Cl
1.2. H2, Pd/CaCO3/Pb3. (Cl3CO)2O
Li n-Bu
ca. 30:1 d.r.Cl
O Et4NCl3, DCM, -90°C76%, 10.5:1 d.r.
O
Cl3C
Cl
O
O
Cl3C
Cl
Cl
1. G. M. Shibuya, J. S. Kanady and C. D. Vanderwal, J. Am. Chem.Soc., 2008, 130, 12514–12518.
Yoshimitsu/Tanaka deoxydichlorinaMon of epoxide
1. T. Yoshimitsu, N. Fukumoto and T. Tanaka, J. Org. Chem., 2009, 74,696–702.
OTBDPSO
NCS, PPh3,PhMe, 45°C
90% OTBDPS
Cl
Cl
OTBDPSBnOO O
NCS, PPh3,PhMe, 90°C
42%OTBDPSBnO
Cl
Cl Cl
Cl
The Yoshimitsu group expanded the use of NCS/PPh3 system to acyclic system.
Their methodology included outstanding examples of stereospecific diepoxide to tetrachloride conversions.
The combinaMon of this reacMon with the Sharpless asymmetric epoxidaMon of allylic alcohols presents a valuable entry into enanFoenriched polychlorides.
These two methodologies provide important tools to approach the chlorosulfolipid.
Carreira’s synthesis of (±)-‐hexachlorosulfolipid
Cl
Cl
O
OTBS( )64 steps from the starting ester, 2%
TMSClCl
Cl OTBS( )6
OH
Cl43%
Et4NCl310:1 d.r. 93%
Cl
Cl
OTBS( )6
OH
Cl
Cl
Cl
4 steps46%
Cl
Cl( )6
OSO3-
Cl
Cl
Cl
Cl
(±)-hexachlorosulfolipid
1. C. Nilewski, R. W. Geisser and E. M. Carreira, Nature, 2009, 457,573–577.
CO2EtEt4NCl3 CO2Et
Cl
Cl68%
1. DIBAL-H2. TBSCl3. OsO4, NMO
Cl
ClOTBS63%, 3 steps
5.6:1 d.r. OH
OH 1. Tf2O, DABCO2. CSA, MeOH
91%, 2 steps
Cl
Cl
O
OH
Ph3P OTBSBr- ( )6
2. n-BuLi1. Swern Ox.
Cl
Cl
O
OTBS( )6
TMSClCl
Cl
OTMSR
Cl
Cl OTMSR+H H
Cl
Cl OTBS( )6
OH
Cl
39%, 4% epimer, 10% SN2 mixture, 31% SM.62%, 2 steps
Yoshimitsu/Tanaka’s synthesis of (+)-‐hexachlorosulfolipid
PivO OTBDPSO
1. NCS, PPh32. DIBAH-H81%, 2 steps
HO OTBDPS
Cl
Cl
( )6 ( )6
1. DMP, NaHCO32. BF3 etherate TMS
72%, 2 steps, 3.8:1 d.r OH
OTBDPS
Cl
Cl
( )6
1. NaH2. PPh3, NCS OTBDPS
Cl
Cl
( )6Cl
SeO2, t-BuOOH OTBDPS
Cl
Cl
( )6Cl
OH
49%, 3:5 syn:anti68%, 2 steps
1. DMP2. NaBH4, CeCl381%, 2 steps
OTBDPS
Cl
Cl
( )6Cl
OHGrubbs' 2nd
58%KMnO4, BnEt3NCl, TMSCl
38%, 36% diastereomersOTBDPS
Cl
Cl
( )6Cl
OH
Cl
Cl 6 steps50%
Cl
Cl( )6
OSO3-
Cl
Cl
Cl
Cl
(+)-hexachlorosulfolipid
1. T. Yoshimitsu, N. Fujumoto, R. Nakatani, N. Kojima and T. Tanaka, J. Org. Chem., 2010, 75, 5425–5437.
Vanderwal’s total synthesis of chlorosulfolipid
1. D. K. Bedke, G. M. Shibuya, A. Pereira, W. H. Gerwick, T. H.Haines and C. D. Vanderwal, J. Am. Chem. Soc., 2009, 131, 7570–7572. 2. D. K. Bedke, G. M. Shibuya, A. R. Pereira, W. H. Gerwick and C. D. Vanderwal, J. Am. Chem. Soc., 2010, 132, 2542–2543.
CO2MeC6H13
1. Et4NCl32. OsO4, NMO47%, 2 steps
CO2MeC6H13
OH
OH
Cl
Cl
1. NsCl, py2. K2CO3, MeOH3. DIBAL-H
48%, 3 stepsCHO
C6H13
OCl
Cl 63%, 2.5:1 Z:E
PPh3ClCl
TBSO ( )7
C6H13
OCl
ClClCl
OTBS( )7
BF3 etherateEt4NCl
48% from Z/E mixture
C6H13
OHCl
ClClCl
OTBS( )7Cl
1. ICl 2.Bu3SnH, Et3B, O2
30%, 2 steps1.8:1 d.r.
C6H13
OHCl
Cl
ClClOTBS( )7
Cl Cl
1. Et3N 3HF2. ClSO3H; NaHCO3
57%, 2 stepsC6H13
OSO3-Cl
Cl
ClClOSO3
-( )7
Cl Cl(±)-danicalipin A
CO2MeC6H13 Et4NCl3, DCM CO2MeC6H13
Cl
Cl83%, 10:1 d.r.
4 steps, 25% C6H13
OHCl
ClClCl
OTBS( )7Cl
1. Et4NCl32. ClSO3H; NaHCO3
C6H13
OSO3-
Cl
Cl
Cl
OSO3-
( )7Cl Cl
Cl
OH
ONs ONs
OH
(+)-malhamensilipin A
72%, 2 steps 8:1 d.r.
LDA, THF, 26%
Title paper: total synthesis of (+)-‐danicalipin A
OMe( )8
1. NCS2. TFA3. t-BuNH2, NCS
( )8Nt-Bu
Cl Cl 1. 3 N HCl2. NaBH4
63% ( )8OH
Cl Cl
1. TBSOTf, 2,6-lutidine2. O3, PPh33. NaBH4, MeOH
80%, 3 steps HO ( )8OTBS
Cl Cl 1. I2, PPh32. NaNO2, DMF
O2N ( )8OTBS
Cl Cl
59%
C6H13
OPiv
O 1. NCS, PPh32. DIBAL-H
C6H13 OH
Cl
Cl82%, 2 steps
1. DMP, NaHCO32. MgBranti:syn = 1.7:167%, 2 steps
C6H13
OHCl
Cl80% ee
Lipase PS IM Amano
99% ee
TBSOTf, 2,6-lutidine
98% C6H13
OTBSCl
Cl
1. Yoshimitsu, T.; Nakatani, R.; Kobayashi, A.; Tanaka, T. Org. Le<. ASAP
Title paper: total synthesis of (+)-‐danicalipin A
1. Yoshimitsu, T.; Nakatani, R.; Kobayashi, A.; Tanaka, T. Org. Le<. ASAP
O2N ( )8OTBS
Cl Cl PhNCO, Et3N, PhMe, 90°CC6H13
OTBSCl
Cl
+ C6H13OTBS
Cl OTBS
Cl
ClCl
NO60%, 7.3:1 d.r
1. Mo(CO)6, MeCN/H2O 81%
2. Me4NHB(OAc)384%, 6:1 d.r.
C6H13OTBS
Cl OTBS
Cl
ClCl
OHOH
NCS, Ph3P
38%C6H13OTBS
Cl OTBS
Cl
ClCl
ClCl
1. AcCl, MeOH2. SO3, Py, DMF
91% C6H13OSO3
-Cl OSO3
-
Cl ClCl
ClCl
(+)-danicalipin A
3 steps, 42%
OTBSH ClCl
OBnHO
HH
O
C6H13
Unanswered quesMons
1. D. K. Bedke, C. D. Vanderwall, Nat. Prod. Rep., 2011, 28, 15
The mechanism of toxicity of the mussel-‐derived lipid is unknown.
In O. danica, chlorosulfolipid is 90 mol% of its polar lipid and appeared to be very important component of membrane.
The mechanism of chlorinaFon is poorly understand.