enantioselective total synthesis and structure revision of spirodihydrobenzofuranlactam 1. total...
TRANSCRIPT
Enantioselective Total Synthesis and Structure Revision of Spirodihydrobenzofuranlactam 1. Total S
ynthesis of StachybotrylactamOrg. Lett. 2003, 5, 1785
이화여대 분자생명과학부 화학전공 022LBG19 이지윤
Introductions
• A series of spirodihydrobenzofuranlactams were isolated from the cultures of two different Stachybotrys species by Roggo et al. in 1996. <J. Antibiot. 1996, 49, 13>• They have an activity as antagonists of endothelin and as inhibitors of HIV-1 protease.• These novel spirodihydrobenzofuranlactams were reported to contain the unique axial hydroxyl group at the C-19 position and the benzofuranlactam moiety.• The pseudosymmetric dimer 5 is the most potent representative of this series.• Kende’s group tried enantioselective total synthesis of structure 1 and its regioisomer 25 as well as their comparisons with natural material due to their undetermined absolute configuration and pharmacological activity.
HHO
HO
O
NO
A B
C
D
E
R
1 R = H2 R = (CH2)2OH3 R = (CH2)4COOH4 R = CH(COOH)(CH2)2COOH
H
OH
HO
ON
O
H
HO
HO
O
N
O
COOH
5
1
2
3
9
8
5
4
11
6
7
10
12
13
14
15
16
17
18
19
20
23
21
24
22
1
Retrosynthetic Analysis
2
HHO
HO
COOMe
17
O
HHO
HO
1
O
HN
O
HBnO
OH
HO
COOMe
15
HBnO
CHO
10
COOBut
OBnBnO
Br
11
+
A B
C
D
E
HBnO
O
6
O
O
(+)- Wieland- Miescher Ketone
Scheme 1. Synthesis of trans-Decalone 6 <Chem. Pharm. Bull. 1993, 41, 1698>
3
HBnO
O
HBnO
O
O
O
2- ethyl- 2- methyl- 1,3- dioxolane
p- TsOH
O
O
O
O O
O
O O
PhSH, HCHO, Et3N
O
O O
CH2SPh
O O
Li, NH3, MeI
K-Selectride 10% aq. HCl
99% 96%
HOHO
O
H H H
BnBr, NaH
(+)- Wieland- Miescher Ketone
6
Mechanisms
<J. Org. Chem. 1986, 51, 773>
O
O
p- TsOH
O
O
O
O O
2- ethyl- 2- methyl- 1,3- dioxolane
(2- butanone의 ethylene acetal 형태)
Step 1: Selective transacetalizationselective protection of the nonconjugated carbonyl group by trans- acetalization with 2- ethyl- 2- methyl- 1,3- dioxolane
H++OH
O
OH2 OH
+OH
O H OH
OH+
O
O
O
H+ +OH
O
HO
HO
O
H2O+ O
OH
O
O O
O
O
proton transfer
4
5
O
O O
O
O O
PhSH, HCHO, Et3N
CH2SPh
- O
O O
O
H H
HSPh
CH2
SPh
OH
proton transfer H+
CH2
SPh
+OH2
O
O O
H NEt3
O
O O
CH2SPhH
α,β- unsaturated carbonyl이 더 안정하기때문
O
O O
CH2SPh
Step 2: (Phenylthio)methylation
<J. Org. Chem. 1984, 49, 3685> 6
Li/liq. NH3
O
O O
H
O
O O
CH2SPh
e- - O
O O
CH2SPh
.HO
O O
CH2SPh
.HO
O O
CH2SPh
-
- O
O O
e-H
SPh
+Li- O
O O
CH2
H
.
Li/liq. NH3 NH3
proton transfer Li/liq. NH3 e-
H+
+Li- O
O O
CH3
H
CH3 I
CH3I
Step 3: Reductive alkylation
MLi/liq. NH3 M+(NH3)
...............e- (NH3)
7
O
O O O O
K-Selectride
99%
HOH H
Step 4: Selective reductiontris- sec- butyl group 매우 bulky하여 hydride attack시 sterically selective control 가능
HO
H:-K-Selectride
BH-
K+HOH
H
HBnO
O
HBnO
O
O
O
H
BnBr, NaH
Br
HH-
Step 6: Benzylation
K- Seletride(potassium tris- sec- butylborohydride)
Scheme 2. Construction of AB-Ring Segment 10
HBnO
O
HBnO
O
HBnO
CHO
HBnO
N
NH2
HBnO
I
1) LDA, TMSCl
2) MeI, BTAF82%
NH2NH2
EtOH, 84%
1) I2, DBU
2) DBU, benzene86%
t-BuLi, -78℃, DMF(5.0eq.)
83%A B
6 7 8
9 10
8
<J. Org. Chem. 1984, 49, 3685>
9
Mechanisms
Step 7: Methylation
HBnO
O
HBnO
O
1) LDA, TMSCl 2) MeI, BTAFH :B
CH3
SiH3C
CH3
Cl
HBnO
O
HBnO
TMS
H3C I
desilylation에는 aqueous acid 또는 fluoride ion 사용
N+
F-
BTAF(benzyltrimethylammoniumfluoride)
10
HBnO
+OH
HBnO
N
NH2
NH2NH2
Step 8: Hydrazination
HBnO
H2N NH2
HO
+
proton transfer
HBnO
HN NH2
H2O+
Step 9
HBnO
I
HBnO
N
NH2
HBnO
N
- NH
base
HBnO
N
NI I
base
H :B
N
N
DBU (1,8- diazabicyclo [5,4,0] undec- 7- ene)
I
-N 2
11
HBnO
CHO
HBnO
I
t-BuLi, -78℃,
DMF(5.0eq.)
83%A B
9 10
Step 10
HBnO
Li N
O N
DMF
N,N- dimethylformamide
H
O
HBnO
CHO
HBnO
I
t-BuLi
Scheme 3. Attemped Spiroannulation of C- and D-Rings
HBnO
CHO
10
COOBut
OBnBnO
Br
HBnO11
t-BuLi,THF, -78℃
85%OBn
BnO
COOBut
HBnO
OBn
BnO
COOBut
HBnO
OBn
BnO
COOMe
+HO
NaBH3CN, ZnI2
DCM, 83%
SOCl2, MeOH
reflux, 89%
HBnO
OH
HO
COOMe
Raney Ni, H2
THF.H2O, 94%
12
13 1415
12
<J. Org. Chem. 1996, 41, 4572>
HBnO
CH
10
COOBut
OBnBnO
Br
HBnO11
t-BuLi,THF, -78℃
OBn
BnO
COOBut
+
HO
12
COOBut
OBnBnO
Li
O
Step 11: Bromine- lithium exchange
13
Mechanisms
<J. Org. Chem. 1986, 51, 3038>
HBnO
OBn
BnO
COOBut
O
12H
BnO
OBn
BnO
COOBut
13
NaBH3CN, ZnI2
DCM, 83%
H +OH
H2B
HNC
H2O+
H-
Step 12: Removal of the sec- benzylic hydroxyl grp
Step 13
HBnO
OBn
BnO
COBut
13
O
Cl S Cl
O
OBn
BnO
C
O
S O
Cl
O CH3
+OButH
HBnO
OBn
BnO
COOMe
14
14
HBnO
OBn
BnO
COOMe
HBnO
OH
HO
COOMe
Raney Ni, H2
THF.H2O, 94%
1415
Step 14: Selective hydrogenolysis
10% Pd/C 또는 Pd(OH)2 사용시 하나에서 세개까지의 benzyl grp cleavage 일어난 mixture 형성; Raney nickel 사용하니 benzene ring에 있는 benzyl grp만 선택적으로 제거
Ch2 O
H H
COOMe
OBn
CH3
COOMe
OH
HO+
debenzylation에 catalytic hydrogenolysis 이용
15
Scheme 3. Attemped Spiroannulation of C- and D-Rings
HBnO
OH
HO
COOMe
15
HHO
OH
HO
COOMe
16
HHO
HO
COOMe
17
10% Pd/C, EtOH, H2
100%Amberlyst 15, DCM
O
HHO
HO
COOMe
O
18
+
rt 12hrs 4 : 5 overall yield, 90%0℃, 3days 1.7(60%) : 1 95%
HHO
HO
COOMe
16a
O
Amberlyst 15, rt
DCM. 3days
acid- catalyzed spiro- heteroannulation시도하였으나 실패
. Corey's method(THF/ethylene glycol, 2N HCl) J ACS 1982, 104, 5551
. McMurry's method(Amberlyst 15/DCM) J ACS 1985, 107, 2712
. other acidic condition(TFA/CHCl3; Hg(OCOCF3)2/THF; PTS/benzene)
시도하였으나 모두 실패
A B
C
D
16
17
X-ray structure of cpd 15
18
HBnO
OH
HO
COOMe
15
HHO
OH
HO
COOMe
16
10% Pd/C, EtOH, H2
100%
H2C OR
Pd0CH2PdOR CH2PdOR
H
H
CH3
HORPd0+ +
Step 15: Debenzylation
H2
Mechanism
Scheme 4. Construction of E-Ring
HHO
HO
COOMe
17
O
HHO
HO
COOMe
19
ONBS, DCM, rt, 82% BnBr, K2CO3, CH3CN, 95%
Br
HHO
BnO
COOMe
20
O
Br
HHO
BnO
COOMe
21
O
NC
HHO
HO
1
O
CuCN, DMF, 100℃� 92% 1) H2, PtO2, EtOH, CHCl3
2) 10% NaOH, H2O, 80%
HN
O
SpirodihydrobenzofuranlactamThe structure of cpd 1 was confirmed by single-crystalX-ray analysis
19
Step 17: Regioselective aromatic bromination
HO
COOMe
EWG: meta directing grp(moderately deactivating)
EDG: ortho- para directing grp(strong activating)
HO
COOMe
Br+
HO
COOMeHBr
HO
COOMeHBr
HO
COOMe
+
+
HO
COOMeHBr
+
Br
O
O
N
O
O
BrN
O
O
HCH2
H
CH2Br
NBS는 Br. (radical) 로 작용하여 benzylic position에 bromination되기도 함
.Br
.Br
+ +
NBS(N- Bromosuccinimide)
ROOR
CCl4
20
Mechanisms
<J. Am. Chem. Soc. 1982, 104, 5551>
<Tetrahedron Lett. 1998, 39, 4347>
HHO
BnO
COOMe
20
O
Br
HHO
BnO
COOMe
21
O
NC
CuCN, DMF, 100℃� 92%
- :C N
Step 20: Hydrogenation of nitrile group using Adam's catalyst
MeOOC
CN
H H
OBn
H2, PtO2 H2, PtO2
C
CH2
HN
O
O
:- OH
H10% NaOH, H2O
OMe
HN
O
Bn HO21 1
Step 19: Cyanation
21
Scheme 5. Synthesis of Regioisomer 25
HHO
HO
COOMe
17
O
HHO
TBDPSO
COOMe
22
OTBDPSCl, imidazole
1) NBS, Silica gel, DCM, rt, 45%2) TBAF, THF, rt3) BnBr, K2CO3, CH3CN, 92%
HHO
BnO
COOMe
23
O
HHO
BnO
COOMe
24
O
HHO
HO
25
O
CuCN, DMF, 100℃� 94% 1) H2, PtO2, EtOH, CHCl3
2) 10% NaOH, H2O, 85%
DCM, rt, 95%
Br CN
NH
O
isolated in 1995 by Jarvis et al.[α]20
D =-21.3 (c 1.10, MeOH)
Stachybotrylactam
22
Conclusions
• A series of spirodihydrobenzofuranlactams were isolated from the cultures of two different Stachybotrys species by Roggo group in 1996.
• The enantioselective total synthesis of spirodihydrobenzofuranlactam 1 was achieved via 20 steps in 5.1% overall yield from the optically pure (+)-Wieland-Miescher ketone. And its regioisomer 25 stachybotrylactam was also synthesized.
• The structures of compound 1, 10, 13, 15, 17, 20, 21, and 23-25 were confirmed by 1H and 13C NMR spectra.
• The 1H and 13C NMR spectra of the synthetic compound 1 were not identical to those reported for the natural spirodihydrobenzofuranlactam 1 revealed by Roggo.
• Comparisons of 1H and 13C NMR spectra of the synthetic 25 with the natural spirolactam isolated by Roggo et al. and with stachybotrylactam isolated by Jarvis reported to have structure 1.
• The absolute configuration of the natural lactam could not be established because neither the Roggo group nor the Jarvis laboratories has reported its optical rotation.
• A very closely related spirobenzofuranlactam N-ethanol derivative reported by Jarvis has the negative sign of optical rotation ([α]20
D= -16, c 0.1, MeOH), which is very similar to that of the synthetic lactam 25 ([α]20
D= -21.3, c 1.10, MeOH). Thus, the absolute configuration of natural stachybotrylactam is most likely represented by stereoformula 25.
23