stemona alkaloids
TRANSCRIPT
Stemona Alkaloids
1
Baran Lab Tom Maimone
N
1 2
3
567
8
99a
The Stemonaceae plant family, which comprises over 30 species, produces a large class of structurally diverse alkaloids featuring a conserved pyrrolo [1,2-a] azepine = perhydroazaazulene = 4-azazaulene nucleusTheir roots have been used for centuries in traditional chinese medicince for a variety of purposes including (but not limited to): treatment of bronchitis, tuberculosis, pertussis, as well as anti-parasitic agentsOver 80 members have been discovered and many more are likely to be isolated (restriction is limited to only 8 species, mostly from the Stemona genus)
N
O
O
I. Stenine Group
N
O
O
H
HH
HH
stenine
N
O
O
H
HH
HH
H
OH O N
O
O
H
H
HOOH O
H
N
O
O
HOOH O
H
H
N
O
O
HHOH O
HH
H
H
neotuberostemonine
3
1112
10
tuberostemonine (H3 = α) tuberostemonine A (H3 = β)
tuberostemonol
didehydrotuberostemonine (H11 = β, H12 = β, Et = β)bisdehydroneotuberostemonine (H11 = α, H12 = α)
N OH O
HO
O
HHO
oxotuberostemonine
N
II. Stemoamide GroupO
NH
O
OH
H
O
stemoamide
NH
OH
H
OOH
H
O
stemonine
NH
OH
H
OO
OMe
neostemonine
N
OH
H
OO
OMe
bisdehydroneostemonine
N
OH
H
OO
OMe
HO
H
HO
protostemonine
N
OH
H
OO
OMe
HO
H
HO
protostemonine
N
OH
H
OO
OMe
OHO
didehydroprotostemonin
I. Introduction
For excellent reviews see (and references therein): Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127. Seger et al. Chemistry & Biodiversity. 2004. 1, 265-279.
Stemona Alkaloids
2
Baran Lab Tom Maimone
N
II. Stemoamide Group (Con't)
O
N
OH
HOO OH
OH
H
OMe
isoprotostemonine
N
OH
H
H
OOO
tuberstemoamide
N
OH
HOH
OH
H
OO
stemoninine
NH
OHOH
H
HO
OO
OMe
OH
stemodiol
III. Tuberostemospironine Group
NO
ON
OO
OOH
tuberstemospironine
NO
O OO
H
H
H H
R
NO
OO
H
H
O
O
NO
OO
H
H
O
O
NO
OO
H
H
O NO
OO
HO
MeOH
didehydrocroomine
stemonidine
croomine (R = H)stemospironine (R = OMe)
stemotinine isostemotinine
N
IV. Stemonamine (maistemonine) Group
OO
O
N
OO
O
OMe
Me
N
OO
O
OMe
Me
N
OO
O
OMe
Me
ON
OO
O
OMe
Me
O N
OO
O
OMe
Me
O
H
H O N
OO
O
OMe
Me
HO
O
H
H O
stemonamine isostemonamine
stemonamideisostemonamidemaistemonine oxymaistemonine
Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127.
Stemona Alkaloids
3
Baran Lab Tom Maimone
N
O
OO
H
H H
N
V. Parvistemoline
O
OOH
parvistemoline
N
O
OO
H
H H
HO
H
H O
H
parvistemonine
N
O
OO
H
H
HOH O
H
didehydroparvistemonine
VI. Miscellaneous?
NO
OR
HOO
OMe
N
O
H
OOO
OMeR
NH
O
O
OH
H
O
O
H
H O
N
O
OO
H
H
O
OH OH
ONH
O
H
H
OH
O
parvistemoamidetuberostemoninol
tuberostemononeparvistemoninine (R = H)parvistemoninol (R = OH)
stemofoline (R = H)oxystemofoline (R = OH)methoxystemofoline (R = OMe
Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127.
Stemona Alkaloids
4
Baran Lab Tom Maimone
II. Biosynthetic ConsiderationsConsider the following carbocyclic skeletons where the C5 units of presumed terpene origin are drawn in bold:
N
O
O
N
O
O
O
O
O
OMe Me
O
O
N
O
O
O
N
O
O
O
O
N
O
O
O
OHN
O
OO
O
Stemofoline protostemonine tuberostemonine
O
stemonine tuberstemonamide tuberostemospironine
This leaves the following fragment unaccounted for:
N
Recall pyrrolizidine biosynthesis:
HN
H2NNH2
N
O
mannich
N
O
homospermidineAn analagous pathway could produce the stemona alkaloids
HN
H2NH2N
spermidineN
O
Thus the following biosynthetic picture emerges:
X
N
O
X
N
[O]
[O]
[O]
N
O
O
OMe
O
O
O
N
O
O
O
O
OMe
stemofoline-CO2
Seger et al. Chemistry & Biodiversity. 2004. 1, 265-279.
Stemona Alkaloids
5
Baran Lab Tom Maimone
III. Synthesis
NO
O OO
H
H
H
Croomine(D.R. Williams et al, 1989)
J. Am. Chem. Soc. 1989, 111, 1923 -1925.
MEMO
1
1) n-buLi, THF, ClCO2CH3, -78°C
MEMO
O
O MgBr
OBn
MEMO
H3CO2C
OBn
MEMO
OBn
OOH
MEMO
OBn
O
CO2CH3
MEMO
OBn
O
OBz
MEMO
OBn
OBz
HO N3
OO
N3
H
OH
Ph3POBz
OO
N3
H OBzN3
H CO2CH3
OO
(63%)CuBr DMSTMEDA, Et2O
-78°C23
2)
3) DIBAL, CH2Cl2, -78°C
4) D-DIPT, t-BuOOH, CH2Cl2 -50°C
4
5) Swern, -78°C
(83%)
(95%)
then PPh3=CHCO2CH3-78°C 25°C
(89%)
567
6) LiBH4, MeOH Et2O
5% Rh/Al2O3 H2
(60%)
7) BzCl, Et3N
8) LiN3, DMPU 110°C
(94%)
9) BF3 OEt2, O°C10) LiOH, MeOH
(79%)
11) Swern, then
8 9 10(70-81%)
12) HBF4, MeOH then LiOH, MeOH: H2O
13) Jones reagent14) CH2N2
(78%)OBn
OBn OBn
Stemona Alkaloids
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Baran Lab Tom Maimone
NO
O OO
H
H
H
Croomine(D.R. Williams et al, 1989)
N3
H CO2CH3
OO N3
H CO2CH3
OO
O
CO2CH3
OO NH
HOO N
HO
H
H O
mechanism ?
N OO
H
H
HO
H
H
O
Stemonine(D.R. Williams et al, 2003)
Org. Lett. 2003, 5, 3361-3364
A Similar iodination cascade was used here as well
O
OCH3
OOTBS N3H
TBSONH
TBSO
MeOOTBSO
H
NH
O
H
H O
TBSO
TBSO
CH3
NH
O
H
H O
O
H
H
HON
HO
H
H O
O
H
H
O
15) BCl3, CH2Cl2, -78°C
16) swern(71%)
1011
17) PPh3, 25°C then NaBH4, MeOH
(90%)18) I2, Et2O, CH2Cl2 25°C
(25°C)
prepared in many steps
1) EtPPh2, PhH, 18h, 25°C, then NaBH4, MeOH
(70%)
12
13
2) I2, Et2O:CH2Cl2, 48 h, 25°C42%
14
4) TBAF5) DMP
(69%)
15
6) Jones Reagent
(68%)
OBn
Stemona Alkaloids
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Baran Lab Tom Maimone
NO
O OO
H
H
H
Croomine(Martin et al, 1989)
J. Am. Chem. Soc. 1996, 118, 3299-3300.
OO OTIPSO OTIPSO Br
OO
Br
NH
CO2Me
N CO2MeMeO
Boc
BocO
O
Br
NHH
CO2MeNO
O
H
CO2H
NO
O
HOH
H
O
NO
O
HOH
H
O
NH
O
O
H
H
O
Stemoamide(Jacobi et al, 2000)
J. Am. Chem. Soc. 2000, 122, 4295-4303
racemic synthesis:
O
ClCl
N
OMeO
Cl
N
OMeO
NO
O
1) TIPSOTf, Et3N 0°C 25°C
(99%)
2) s-BuLi, TMEDA THF, 0°C
then Br(CH2)4Br
(83%)3) 5% TIPS-OTf, 0°C
1 2 3
4
5
(32%)
4) TFA
5) 3% Rh/C, H2
EtOAc:EtOH(96%)
6) NMM, DMF, Δ
(74%)7) 3M HBr, 60°CHBr
8) POCl3, DMF
OTIPSO
9) 10% Pd-C/H2
10% HCl/EtOH
(47%)
(85%)
6
7
8
1) Methyl alaninate
2) P2O5
(80%)
3) NaH, then succinimide
(97%)
1 2 3
Stemona Alkaloids
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Baran Lab Tom Maimone
N
OMeO
NO
ONH
O
O
H
H
O
Stemoamide(Jacobi et al, 2000) N
OMeO
NO
MeO
N
OMeO
NO
H
N
MeO O
NH
O
NH
O
OH
ON
H
O
OH
O
H
rationalize the following by-products formed in the IMDA cascade
NH
O
O
NH
O
OO
MeO2C
NH
O
OO
NH
O
OO
an enantioselective route was alsodeveloped using L-pyroglutamic acid
NH
O
HO2CN
O
R
NH
O
OH
O
3
4) NaBH4, MeOH, H+
(72%)
4
Sn(Bu)3
BF3 OEt2(92%)
Diethylbenzenereflux(55%)
H+
5
6
7
5)
6)
H
NiCl2
NaBH4
73%
8
Stemona Alkaloids
9
Baran Lab Tom Maimone
N
O
O
O
OMeO
N
O
O
O
OMeO
stemonamide isostemonamide
(Kende et al.)
Org. Lett. 2001. 16, 2505-2508
NO O
PMB
N OMeO
OBn
PMBN O
PMB
O
N O
PMB
O
OMe
O
HON
O
O
O
OMeO
N
O
O
O
OMeO
PMB PMBN
O
O
O
OMeO
N
O
O
O
OMeO
PMB PMB
N
O
O
O
OMeO
PMB
OPMB
N
O
O
O
OMeTMSO
PMBN
O
O
O
OMeO
PMB
OPMB OPMB
N
O
O
O
OMe
PMB
OPMB
O
N
O
O
O
OMeO
PMB
OPMB
1) BnO(CH2)3MgBr Et2O, reflux
2) PPTS, MeOH
(90%)1 2
3) H2, 5% Pd/C
O
OMe
TMSOBF3 OEt2
(82%)
3
4
4)
5) swern6) DBU, 25°C
7) swern
5 6
(70%)
1:1 mixtureof 5:6
8) TBDMSOTf, collidine, 0°C
9) Pd(OAc)2 O2, DMSO, 80°C
(93% of 7)(89% of 8)7 8
PMBO
MgBr
5% CuBr DMSTMSCl, HMPA-78°C
9 (74%) 10 (57%) 11 (32%)
10)
12 (67%) 13 (90)
11) KH, Me2N=CH2+CF3CO2
-
(for ketones)
or Me2N=CH2
+CF3CO2-
(for enol ether)
Stemona Alkaloids
10
Baran Lab Tom Maimone
N
O
O
O
OMeO
N
O
O
O
OMeO
stemonamide isostemonamide
(Kende et al.)
N
O
O
O
OMe
PMB
OPMB
O
N
O
O
O
OMeO
PMB
OPMB
NH
O
O
O
OMe
OH
O
NH
O
O
O
OMeO
NH
O
O
O
OMe
OMs
O
NH
O
O
O
OMeO
OMs
N
O
O
O
OMeO
N
O
O
O
OMeO
NH
O
O
H
Stenine(Hart et al.)
J. Org. Chem. 1990. 55, 6236-6240
O
O
OH
HO
OH
O
NHNH2
OAc
O
NHN(Me)2
12 13
12) CAN, H2O/MeCN
13) RhCl3, EtOH,H2O
(52%)14 15(53%)
OH
14) MsCl, DMAP pyr.
16 17
15) NaH
1 2 3 4
1) Et2AlCl, CHCl3 85°C
(67%)
2) NH2NH2
MeOH
(87%)
3) CH3I, K2CO3
4) AcCl
Stemona Alkaloids
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Baran Lab Tom Maimone
NH
O
O
H
Stenine(David Hart et al.)
OAc
O
NHN(Me)2
OAc OH
N
H
H CO2MeHO2C
N
H
H CO2Me
N
H
H CO2MeO
O
N
H
H CO2MeHO
OH
N
H
H CO2Me
Me2N
O
N
H
H CO2Me
OH
O
I
O
N
H
H CO2Me
OH
O
O
N
H
H CO2Me
OH
O
O
4
5) Mesitiylene, Δ6) MeOH
NHCO2Me(94%)
7) 9-BBN/NaBO38) MsCl, Et3N
9) MeLi, THF(89%)
10) Jones reag. acetone
5 6
7
(83%)
11) I2, THF, H2O12) DBU
8
(91%)
13) NaBH4, MeOH t--buOH
(100%)
9
14) t-BuMe2SiCl, Et3N
15) MeC(OMe)2NMe2,
xylene, Δ
10
(93%)
16) I2, THF, H2O
11
(75%)
Sn(n-Bu)3
AIBN, PhH17)
(83%)
12
18) LDA, MeI
(87%)
13
N
H
H CO2Me
EtO2C
O
O
14
19) swern20) Ph3P=CHCO2Et
N
H
H CO2Me
EtO2C
O
O
(91%)
21) Red-Al, CuBr
15
(85%)
OSiMe2t-Bu
Stemona Alkaloids
12
Baran Lab Tom Maimone
NH
O
O
H
Stenine(David Hart et al.)
NH
O
O
H
O
NH
O
O
H
O
S
S
NH
O
O
H
S
S
SNH
O
O
Hfor a similar synthesis with anasymmetric Diels-Alder seeMorimoto et al. Angew. Chem.Int. Ed. Engl. 1996, 35, 904-906.
NH
O
O
H
Stenine(Peter Wipf et al.)
J. Am. Chem. Soc. 1995, 117, 11106-11112
HO
NHCbz
CO2H N
OH
OH
CO2Me
CbzN
OBz
H
CO2Me
CbzHO
N
H
H CO2Me
EtO2C
O
O
22) TMSI, then PhMe, Δ
(85%)
23) OsO4 (cat) NaIO4
24)
SiO2/SOCl2
HSSH
25) Lawesson's reagent
(84%)
26) Raney Ni
EtOH
(75%)
1) PhI(OAc)2, NaHCO3 MeOH, 21 40°C (55%)
15 16 17
18
2) Bz2O3) NaBH4, CeCl3
(89%)
1 2
Stemona Alkaloids
13
Baran Lab Tom Maimone
NH
O
O
H
Stenine(Peter Wipf et al.)
NH
CO2Me
CbzHO
H
NH
CO2Me
Cbz
H
O
NH
CO2Me
Cbz
H
O
(Me)2N
NH
CO2Me
Cbz
H
O
(Me)2N
TIPSO
NH Cbz
H
O
(Me)2N
NH Cbz
H
HO
O
O
N
HO
O
HN
HO
O
H
O
O
4)
N
OBz
H
CO2Me
CbzHO
2
Pd2(dba)3 CHCl3
Bu3P, HCO2H,Et3N
(68%) 3
5) TPAP, NMO
6) KHMDSA,OTf
(46%)4
7) NaBH4, CeCl38) H3CC(OMe)2NMe2, 130°C
(77%)
5
9) AD-mix β, NaIO4
10) NaBH411) TIPS-Cl, DMAP
(76%)
12) LiOH, H2O/THF13) PhOPOCl2, NEt3, PhSeH14) Bu3SnH, AIBN, 130
(70%)N
H Cbz
HO
O
OTIPSOTIPS
15) I2, pH 5.516) Allyl-SnBu3, AIBN
6
78
NH Cbz
HO
O
OTIPS
9
17) LDA, HMPA, MeI18) OsO4, NaIO419) NaBH4, -40°C20)o-(NO2)PhSeCN, Bu3P, H2O2
(47%)
O
21) HF, MeCN22) DMP, NaClO2
23) Pd(OH)2, H2
24) FDPP
10
25) Lawesson's26) Raney-Ni
(73%)(71%)
Stemona Alkaloids
14
Baran Lab Tom Maimone
NH
O
O
H
Stenine
Padwa et al.
Org. Lett. 2002, 4, 1515-1517
N
OTMS
NH
O
MeS
SMe
OAc
N
O
MeS
SMe
OAcO
CO2Me
N
H
MeO2C
O
HO
N
H
O
HN
H
MeO2C
O
H
O
O
I
N
H
O
H
O
O
N
H
H
O
O
1) LDA, then (MeS)2CHCHO, then Ac2O
(80%)1
Cl
O
CO2Me
N
OMeS
CO2Me
O
N
H
MeO2C
O
O
23
4
MeS
DMTSFEt3N
2)3)
(80%)
4) Raney-Ni5) NaBH4, CeCl3
(71%)
5
6) Crabtree's Cat, H27) MsCl, Et3N, DBU
(64%)
6
8) LiOH, H2O9) I2, MeCN
7
10) allyl-Sn(Bu)3, AIBN11) OsO4, NaIO4
O
12) ethane dithiol13) lawesson's
14) Raney-Ni15) LDA, HMPA, MeI
(60%)
(48%)
(67%)8
Stemona Alkaloids
15
Baran Lab Tom Maimone
NH
O
O
H
Stenine
Aubé et al.
J. Am. Chem. Soc. 2005, 127, 15712-15713
P
O O
OMeOMe N3 O
O
N3
N3
TMSO
O
NH
HO
NH
HO
MeO2C
NH
HO
O
NH
HO
O
O
OO
NH
O
O
H
Tuberstemonine
O
H
H O
Wipf et al from the oxidative tyrosine cyclization
N
H
HO
CO2Me
H Cbz
N
H
HO
CO2Me
H
Ph
N
H
CO2Me
H
Ph
O
NaH/ THF (92%) 1
1)2) TMSOTf
(95%)
3)
SnCl4(70% 3:1 dr)
23
4) LHMDS, then BrCH2CO2Me
(73%)
6) LHMDS, MeI
5) NaBH4
(51%)
7) Lawesson's
8) Raney Ni(83%)
8 Steps19% YieldNo PG's
1) TBDMS-Cl, imidazole DMAP2)Et3SiH, Pd(OAc)2, NEt3
3) cinnamyl bromide4) TBAF
(80%)1 23
5) TPAP, NMO6) KHMDS, allyl iodide
(58%)
Stemona Alkaloids
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Baran Lab Tom Maimone
NH
O
O
H
Tuberstemonine
O
H
H O
(Wipf et al.)
N
H
CO2Me
HO
N
H
CO2Me
HO
N
H
CO2Me
HTBDMSON
H
HTBDMSO
Br OO
OO
OOO
N
H
HHO O
H
H O
N
H
HO
H
H O
O
O
PhSe N
H
HO
H
H O
O
O
N
H
CO2Me
H
Ph
O
3
7) Grubbs
(92%)
4
8) PhSH, Et3N9) (PPh3)3RhCl, H2
10) DBU
(81%)
511) NaBH4, CeCl312) TBDMS-Cl, imid. DMAP
(56%)
6
13) (Me)(OMe)NH HCl Me2AlCl
14) LiDBB
(89%)
15) L-selectride, -78°C
16) TsOH, MeOH
(56%)78
9
17) MeC(OMe)2NMe2,
xylene, Δ18) PhSeCl, MeCN/H2O
(52%)
19) allyl-SnPh320) LDA, HMPA, MeI
21) allyltritylamine, DIEA, toluene, 110°C
(45%)10
22) Grubbs, TsOH, ethylene
23) Pd/C, H2N
H
O
O
H
O
H
H O
Stemona Alkaloids
17
Baran Lab Tom Maimone
N
O
Ac
O
O
H
MeO
NO
O
O
O
OMe
Isostemofoline(Kende et al.)
J. Am. Chem. Soc. 1999. 121, 7431-7432
OH
OH
O
OMOM
O
OMOM
NN
N
OMOM
Boc
N
OMOM
MeO2C
TBSO
BocN Boc
OMOMO
N Boc
OMOMO
O
N Boc
MOMO
O
O
N Boc
MOMO
O
O
OTIPS N Boc
MOMO
OTIPS
OO
N Boc
MOMO
OTs
OO
1) aq. NaOCl, HOAc
2) MOMCl, EtN(i-Pr)2
(60%)1 2
ON
NMe2
KOEt(80%)
3)
4) Na2S2O4, EtOH, H2O, 90°C5) BOC2O, DMAP
(25%)
4
6)
CO2Me
N2
OTBS
Rhodium octanoate dimer
5
7) Bu4NF8) H2, Pd/C, MeOH,9) H2O, DMSO, 150°C
(90%)
(52%)
6
OO
NaOH, MeOH(90%)
7
8
10)
11) LHMDS, DMPU allyl iodide
(91%)
12) K2OsO4, NaIO4, H2O13) Zn(BH4)2, THF, -10°C14) TIPSCl, imid., DMF
(48%)
15) MeLi (2.2 eq.) DMPU, Et2O -40 °C
16) Bu4NF, THF
17) TsCl, pyr, CHCl3
(85%)
9 10 11(81%)
Stemona Alkaloids
18
Baran Lab Tom Maimone
N
O
O
O
O
H
MeO
NO
O
O
O
OMe
Isostemofoline(Kende et al.)
N Boc
MOMO
OTs
OO
N Boc
MOMO
OTs
O
HO2C
N Boc
MOMO
OTs
OO
N Boc
MOMO
OTs
O
O
OH
OOMe
N Boc
MOMO
OTs
O
OO
OMe
OH
N
O
OO
OMe
H
O
OH
NO
O
O
O
OMe
NO
O
O
11
18) O3, DMS
(65%)
12
19) i-BuOCOCl, NMM20) NaBH4, MeOH21) DMP
13
22)
OLiO
OMe
14
23) DMP, CH2Cl2
(61%) (56%)
24) CF3CO2H then NaHCO3 (67%)
15
16
25) Tf2O
(12%) (14%)
?
Stemona Alkaloids
19
Baran Lab Tom Maimone
NO
O
ODidehydrostemofoline (Asparagamine A)
NO
O
O
O
OMeO
OMe
Isodidehydrostemofoline
(Overman et al.)
J. Am. Chem. Soc. 2003. 125, 15284-15285
N
Boc
OMe
OH
BocN
OMe
O2N
OHEtO2C
BocN
OMeOTIPSHO
BocN
OMeOTIPS
O
HN
OMeOTIPS
OH
HIN
MeO
O OTIPS
N
MeO
O
N
MeO
O
MeO2CNMeO2C
O
TMSONOHC
O
TMSO N
O
HO
OMeO
O
HOH
1 2 3
456
7
8 10
1)
CO2Et
O2N
2) H2, Pd/C
3) DBU, then H2, Pd/C4) TIPSOTf, 2,6-lutidine5) DIBAL, PhMe, -78°C
(73%)
6) DMP7) TIPSOTf, Et3N8) O3, DMS
(37%)
9) VinylMgBr, CeCl3
10) TMSI
(85%)
11) (CH2O)n, PhMe/ MeCN,
(94%)
12) TBAF13) SO3 Py, Et3N, DMSO14) Julia olefination
(70%)
15) LDA, ICH2CO2Et16) DBU, PhMe, 130°C
(54%)
17) BBr3; aq. NaOH
18) TMS-imid., 130°C
11 12
19) DIBAL, -78°C20) DMP
21) SiO2 (epim.)54%
O OLi
MeO
then aq. HCl
22)
N
O
O
OMeO
O
H
23) IBX, DMSO
HO
13
N
O
O
O
O
OS
MeOO
N
O
O
O
O
OS
MeOO
25) P(OMe)3Didehydrostemofoline +Isodidehydrostemofoline (65%)
24) CSCl2 DMAP
3.5 : 1
50°C