Aug 29, 2012 - Enantioselective Total Synthesis of Amphidinolide ... Structurally complex amphidinolide natural products ... Synthesis of common intermediate ...
Literature Report
Enantioselective Total Synthesis of Amphidinolide F Reporter: Mu-Wang Chen Checker: Ran-Ning Guo
Carter, R. G. et al. Angew.Chem. Int. Ed. 2012, 51, 7948-7951
1
Structurally complex amphidinolide natural products
Retrosynthetic analysis of amphidinolide F. O
O O
15
OH
23
H
O
OH H
H
O 6
15
macrolactonization
20
11
9
OEE 14
18
18
OTBS
25
20
H
11 29
H 1
O
OTBS H
9
3
OH
H
O
6
O
O
24 29
H OTES
3
1
OTBS OPiv
amphidinolide F (3)
4
sulfone alkylation/oxidative desulfurization
SO2Ph OEE 15
OTBS H
O
18
H
H
OTBS O
29
H
5
I
25
O
OTES
OPiv 7
OTBS 11
common intermediate for C1-C8 and C18-C25
OTBS H 8
O
H 1
OTBS 6
OPi OPiv
Synthesis of common intermediate
OBz
OPiv
OBz
OPiv
OH AD Mix
t BuOH/H2O t-BuOH/H
87%, d.r. >20:1
13
14
OTBS
OTBS OH OH TBSO
HO OH
H
O
H
AgBF4 (10 mol%) C6H6, 80 oC, 65-70%
•
BzO 15
TBSO
H
O
H
TBSO
TBSO
16
TBSO
H
o OPiv -78 C, 81%
BzO
17
OPiv
BzO
H
MeLi.LiBr, Et2O
TBSOTf, 2,6-lutidine 85%
Ag
OPiv
TBSO
O
H
OPiv O
7
Synthesis of the C1-C14 subunit
I
1) KOH, KOH EtOH/H2O, O , 36 h, h 88% CO2Me 2) LiAlH4, THF, 0 oC to 20 oC, 71%
I
I
O
CO2Me 3) MnO2, CH2Cl2, rt, 10 h, 98% a
Ph3P=CHCO2Me CH2Cl2, 0 oC, 45 min, 93%
b OH
OMe DIBAH, CH2Cl2, -78 oC to 20 oC I
O
2 h, 92%
c
d OH
(+)-DET, Ti(Oi-Pr)4 TBHP, CH2Cl2 o mol sieves,-35 , C 87%, 95% ee
I
O I e
OH O
10
e
Me
1)TBSCl, imid, 1)TBSCl imid DMAP DMF, 99% 2) Me3Al, CH2Cl2, -78 oC 95%, d. r. >20:1
Me
Al
OTBS O
Me
I
I
OTBS
OTBS
OH
TBSOTf, 2,6-Iutidine CH2Cl2, 98%
OTBS
10
f
I
10
24
I
10
Synthesis of the C15-C29 subunit
OPiv
OPiv O OTBS
H
O H OTBS
7
1) NaBH4, MeOH, 95% 2) Im2C=S, PhMe, 100 oC, 99% 3) Bu3SnH, AIBN, PhMe 90 oC, C 91%
OTBS H
H 28
OTBS
OBn OBn
OTBS + H
2) (ClCO)2, DMSO, Et3N, CH2Cl2
O
O
1) LiAlH4, Et2O, 96%
X
17
t-BuLi, THF, -78 oC
Y 8 18
OTBS
I 72% d.r. = 1.5:1 (31:32)
O H OTBS 29
30
H
O H
31 X = H, Y = OH 32 X = OH, Y = H
OTBS
11
OBn
OBn
X
17
X
17
Y
Y
18
H
18
OTBS 1) TPAP, NMO, CH2Cl2 2) L-Selectride 31:32 = 15:1 85%
O
OTBS
2) Pd/C, H2, IPA H
H 31 X = H, Y = OH 32 X = OH, Y = H
1) EtOCH=CH2, PPTS (5 mol%) CH2Cl2, 94%
O H
OTBS
31 X = H, Y = OH 32 X = OH, Y = H
OTBS
OH SO2Ph
OEE
15
OEE
18
OTBS H
H
OTBS H
OTBS
33
18
2) TPAP, NMO, MeCN, 92%
25
O
1) Ph2S2, Bu3P, THF, 78%
34
25
O H
OTBS
SO2Ph OEE .
o
1) TF Pyr, THF, 0 C, 80%
O
2) DMSO, (ClCO)2, Et3N, CH2Cl2 H
25
O 35
H OTBS
12
13
Total synthesis of amphidinolide F I 14
SO2Ph OTBS
OEE
15
LHMDS THF, LHMDS, THF HMPA +
TBSO
H
O
H
-10 oC to rt, 2.5 h, 74%
24
H
O H
OTBS 6
OTES 5
OPiv
SO2Ph OEE 14
15
OTBS H
O
TBSO H
O
H
H OTES 1
OTBS 38
OPiv
14
SO2Ph 14
PhO2S
OEE
LDA, DMPU, THF TMSOOTMS -50 to -35 oC
15
OTBS H H
O
4+39: 65% (1.8:1 4:39) (94% brsm)
O
TBSO
14
H
H
O
OEE
OTBS H H
O
H
H OTES 1
OTBS
OTBS
OPiv
OPiv
O OEE 15
OTBS H
O
TBSO H
O
H
OTBS
H OTES R
4 R= CH2OPiV (42%) DMSO, (ClCO)2 CH2Cl2, Et3N, 83%
O
TBSO 1
14
Nu
15
OTES
38
SiMe3
39 R= CH2OH (23%) 40 R R= CHO
1) LAH, Et2O 2) DMSO, (ClCO)2 CH2Cl2, Et3N, 83%
O
O OEE
OEE
NaClO2, 2-Me-2-butene NaH2PO4.H2O t-BuOH/H2O, 85%
15
OTBS H
O
TBSO H
O
OTBS
H
H H
O
TBSO H
OTES
O
H
CHO
OTBS
OTBS
1
40 PPTS MeOH
O OEE ArCOCl, Et3N PhMe/THF DMAP, 65%
OTBS H
O
TBSO Cl
H
Cl
Ar =
O
24
H
H 1
O
Cl
OTBS
O 43
41 P = TES 42 P = H
H OP CO2H 1
Over 30 members of the diverse amphidinolide family of biologically active macrolides have been isolated from the dinoflagellate Amphidinium sp. p From this family, y amphidinolides p C ((1–2)) and F(3) ( ) are among g the most complex and densely functionalized members . These natural products 1– 3 contain eleven stereogenic centers embedded within a 25-membered macrolactone including two trans trans-disposed disposed tetrahydrofuran ring systems, a 1,4-diketone motif, and a highly substituted diene moiety at C9–C11. In addition to the sizable structural challenges present in 1–3, these macrolides have shown significant cytotoxic activity. activity Consequently, Consequently compounds 1–3 have attracted considerable synthetic attention from numerous laboratories, including our own. Despite these sizable endeavors neither amphidinolide C nor amphidinolide F have been endeavors, successfully synthesized in the more than 20 years since their isolation. It should be noted that the stereochemical assignment of compound 3 is b based d on analogy l to compound d 1 and d isolation i l i from f the h same organism. i Herein, we disclose the first total synthesis of amphidinolide F (3), and thus confirm both the absolute and relative stereochemistry of the natural product.
In summary, the total synthesis of amphidinolide F has been accomplished in 34 steps (longest linear sequence). sequence) Highlights of the synthetic sequence include a silvercatalyzed dihydrofuran formation, use of common intermediate 7 to access both the C1–C8 and C18–C25 fragments, regioselective hydrostannylation of enyne 25, di t diasteroselective l ti addition dditi off a 2-lithio-1,3-diene 2 lithi 1 3 di species i to aldehyde 22, and the sulfone alkylation/oxidative desulfurization sequence to couple the major subunits and incorporate the carbonyl moiety at C15.
