Stemona Alkaloids
Baran Lab
Tom Maimone
I. Introduction
2
1
9
8
7
9a N
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 nucleus
Their 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 agents
Over 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)
3
5
6
O
H
O
O
H
N
H
H
I. Stenine Group
3
N
N
H
H
O
H
H
O
O
N
H
O
O
O
H
H
N
H
O
O
H
oxotuberostemonine
tuberostemonol
H
H
N
HO
H
tuberostemonine (H3 = α)
tuberostemonine A (H3 = β)
stenine
O
HO
H
O
H
H
H
H H
O
H
H
O
O
O
O
H
O
O
H
neotuberostemonine
O
H
O 11
H
H
O
N
N
H
O
H
O
O
O
N H
O
O
stemonine
OMe
H
N
H
H
O
O
O
H
bisdehydroneostemonine
O
O
O
H
protostemonine
H
O
O
H
didehydrotuberostemonine (H11 = β, H12 = β, Et = β)
bisdehydroneotuberostemonine (H11 = α, H12 = α)
H
OMe
O
OMe
H
H
N
N
O
O
neostemonine
H
OMe
10
HO
H
O
H
stemoamide
H
H
N
O
H
II. Stemoamide Group
OMe
H
12
N
H
H
O
O
O
O
N
O
O
H
protostemonine
For excellent reviews see (and references therein): Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127.
H
O
O
H
O
O
O
H
didehydroprotostemonin
Seger et al. Chemistry & Biodiversity. 2004. 1, 265-279.
1
Stemona Alkaloids
Baran Lab
Tom Maimone
H
H
H
N
O
H
N
O
H
H
O
O
O
N
O
O
O
II. Stemoamide Group
(Con't)
N
O
O
O
O
O
H
N
tuberstemospironine
O
Me
O
H
H
O
N
O
O
O
OMe
O
O
O
H
O
N
O
O
H
O
O
O
isostemotinine
stemotinine
H
Me
OMe
O
O
O
N
H
O
O
H
N
O
H
O
O
didehydrocroomine
N
N
O
stemodiol
MeO
N
O
H
O
O
H
H
OH
HO
O
croomine (R = H)
stemospironine (R = OMe)
O
N
H
R
III. Tuberostemospironine
Group
O
O
N
O
H
H
O
O
H
stemoninine
tuberstemoamide
OH
O
O
H
O
O
H
isoprotostemonine
H
H
O
H
OMe
N
O
O
H
OMe
H
O
stemonidine
IV. Stemonamine
(maistemonine)
Group
stemonamine
O
O
OMe
O
N
O
O
OMe
O
N
O
O
OMe
H
O
N
Me
O
Me
O
Me
O
Me
O
isostemonamine
H
O
OMe
H
O
N
O
H
O
O
HO
isostemonamide
Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127.
stemonamide
maistemonine
oxymaistemonine
2
Stemona Alkaloids
Baran Lab
O
O
H
N
?
O
H
O
V. Parvistemoline
H
O
O
N
H
H
O
O
H
H
N
H
O
O
O
H
N
O
O
H
H
didehydroparvistemonine
O
OMe
H
OMe
O
H
H
O
VI. Miscellaneous
H
O
H
H
parvistemonine
parvistemoline
O
H
H
O
Tom Maimone
R
O
O
N
O
O
O
H
N
O
H
O
N
O
H
O
O
H
O
R
stemofoline
(R = H)
oxystemofoline
(R = OH)
methoxystemofoline (R = OMe
H OH
O
N
tuberostemonone
H OH
H
O
parvistemoninine (R = H)
parvistemoninol (R = OH)
H
O
O
O
O
O
H
NH
O
tuberostemoninol
Pilli et al. Nat. Prod. Rep., 2000, 17, 117-127.
parvistemoamide
3
Stemona Alkaloids
Baran Lab
Tom Maimone
II. Biosynthetic Considerations
Consider the following carbocyclic skeletons where the C5 units of presumed terpene origin are drawn in bold:
O
O
O
Me
OMe
O
O
O
O
O
O
O
O
O
O
O
N
N
N
Stemofoline
This leaves the following
fragment unaccounted for:
tuberstemonamide
stemonine
tuberostemonine
protostemonine
O
O
O
O
O
OH
N
N
O
O
O
O
O
N
tuberostemospironine
Thus the following biosynthetic picture emerges:
O
O
N
[O]
[O]
O
H2N
O
X
mannich
H
N
homospermidine
N
H2N
H
N
spermidine
O
O
O
N
N
O
N
N
N
An analagous pathway could produce the stemona alkaloids
H 2N
O
OMe
Recall pyrrolizidine biosynthesis:
NH2
OMe
O
O
[O]
O
X
O
-CO2
stemofoline
N
Seger et al. Chemistry & Biodiversity. 2004. 1, 265-279.
4
Stemona Alkaloids
Baran Lab
Tom Maimone
III. Synthesis
H
O
N
O
H
1) n-buLi, THF,
ClCO2CH3, -78°C
O
MEMO
O
H
(63%)
H3CO2C
MgBr
O
2)
OBn
O
CuBr DMS
TMEDA, Et2O
-78°C
(95%)
MEMO
1
2
Croomine
(D.R. Williams et al, 1989)
OBz
O
MEMO
4) D-DIPT, t-BuOOH, CH2Cl2
-50°C
(83%)
N3
HO
(94%)
OBn
OBn
5) Swern, -78°C
OBn
(60%)
OH
O
O
5% Rh/Al2O3 H2
7) BzCl, Et3N
6
7
CO2CH3
6) LiBH4, MeOH MEMO
Et2O
8) LiN3, DMPU MEMO
110°C
3
3) DIBAL, CH2Cl2, -78°C
J. Am. Chem. Soc. 1989, 111, 1923 -1925.
OBz
OBn
MEMO
MEMO
then PPh3=CHCO2CH3
-78°C 25°C
(89%)
OBn
4
5
9) BF3 OEt2, O°C
10) LiOH, MeOH
(79%)
OH
O
H
N3
O
11) Swern, then
Ph3P
8
OBn
O
O
H
N3
OBz
(70-81%)
OBz
OBn
9
12) HBF4, MeOH
then LiOH, MeOH: O
H2O
13) Jones reagent
14) CH2N2
(78%)
O
H
N3
CO2CH3
OBn
10
5
Stemona Alkaloids
Baran Lab
Tom Maimone
H
O
N
O
H
O
O
H
H
N3
O
O
H
N3
O
15) BCl3, CH2Cl2, -78°C
CO2CH3
O
CO2CH3
16) swern
Croomine
(D.R. Williams et al, 1989)
(71%)
OBn
O
11
17) PPh3, 25°C
then NaBH4, MeOH
(90%)
10
18) I2, Et2O, CH2Cl2
25°C
H
O
N
O
H
H O
O
O
(25°C)
H
mechanism ?
H
CO2CH3
NH
O
12
A Similar iodination cascade was used here as well
H
N
H
O
OTBS N3
H
O
H
O
O
O
O
H
TBSO
Stemonine
(D.R. Williams et al, 2003)
OCH3
1) EtPPh2, PhH,
18h, 25°C, then
NaBH4, MeOH
TBSO
H
O
TBSO
NH
MeO
(70%)
13
prepared in many steps
Org. Lett. 2003, 5, 3361-3364
2) I2, Et2O:CH2Cl2, 48 h, 25°C
42%
H
6) Jones Reagent
H
N
O
H
O
H
H O
O
(68%)
H
N
HO
H
O
H
15
H
CH3
H
H O
O
4) TBAF
5) DMP
(69%)
TBSO
N
H
H O
O
TBSO
14
6
Stemona Alkaloids
Baran Lab
H
O
N
O
2) s-BuLi, TMEDA
THF, 0°C
1) TIPSOTf, Et3N
0°C 25°C
H
O
H
O
O
O
TIPSO
(99%)
Tom Maimone
1
O
Croomine
(Martin et al, 1989)
N
CO2Me
Boc 4
TIPSO
then
Br(CH2)4Br
(83%)
2
MeO
Br
O
3) 5% TIPS-OTf,
0°C
3
(32%)
J. Am. Chem. Soc. 1996, 118, 3299-3300.
O
N
O
H
8) POCl3, DMF
CO2H 6) NMM, DMF, Δ
HBr
7) 3M HBr, 60°C
4) TFA
O
O
N
H H
(74%)
(47%)
CO2Me
O
5) 3% Rh/C, H2
EtOAc:EtOH
(96%)
7
TIPSO
O
N
CO2Me
Boc
Br
Br
O
H
5
6
H
O
N
O
H
O
O
H
10% HCl/EtOH
(85%)
8
H
O
H
N
H
O
O
H
1) Methyl
alaninate
O
H
O
O
racemic synthesis:
N
O
H
O 9) 10% Pd-C/H2
Cl
Cl
Stemoamide
(Jacobi et al, 2000)
MeO
O
2) P2O5
N
(80%)
1
O
Cl
N
3) NaH, then
succinimide
(97%)
MeO
O
O
N
2
3
J. Am. Chem. Soc. 2000, 122, 4295-4303
7
Stemona Alkaloids
Baran Lab
H
O
O
MeO
N
N
H
O
O
H
Stemoamide
(Jacobi et al, 2000)
4) NaBH4,
MeOH, H+
O
O
MeO
(72%)
N
O
O
N
H
BF3 OEt2
MeO
H
O
O
H
8
N
H
O
N
5
Diethylbenzene
6) reflux
(55%)
4
H
73%
O
Sn(Bu)3
N
N
O
5)
(92%)
N
O
H
O
O
MeO
3
H
Tom Maimone
O
O
NaBH4
NiCl2
H+
N
N
H
H
O
O
MeO
H
O
N
7
6
rationalize the following by-products
formed in the IMDA cascade
an enantioselective route was also
developed using L-pyroglutamic acid
O
NH
HO2C
O
O
O
N
H
O
N
MeO2C
O
N
H
O
R
O
O
N
H
O
O
N
H
O
O
8
Stemona Alkaloids
Baran Lab
Tom Maimone
O
O
OO
OO
OMe
1) BnO(CH2)3MgBr
Et2O, reflux
OMe
O
O
O
O
PMB
3
OBn
1
O
N
PMB
(90%)
stemonamide
3) H2, 5% Pd/C
O
N
2) PPTS, MeOH
PMB
N
N
O
N
MeO
2
OMe
isostemonamide
4) BF3 OEt2
(Kende et al.)
TMSO
(82%)
O
Org. Lett. 2001. 16, 2505-2508
O
O
OO
OMe
OO
8) TBDMSOTf,
collidine, 0°C
OMe
O
O
PMB
PMB
7
OO
OMe
(93% of 7)
(89% of 8)
8
OO
O
PMB
PMB
O
O
N
7) swern
(70%)
N
N
5
5) swern
6) DBU, 25°C
OMe
O
9) Pd(OAc)2
O2, DMSO, 80°C
N
N
OMe
O
O
PMB
HO
1:1 mixture
of 5:6
6
O
4
MgBr
10)
PMBO
5% CuBr DMS
TMSCl, HMPA
-78°C
O
OO
OMe
O
N
O
TMSO O
OMe
9 (74%)
OO
OMe
O
N
PMB
PMB
OPMB
O
O
OPMB
10 (57%)
O
N
PMB
OPMB
11 (32%)
11) KH, Me2N=CH2+CF3CO2(for ketones)
or
Me2N=CH2+CF3CO2(for enol ether)
O
OO
OMe
OO
OMe
O
N
PMB
O
N
PMB
OPMB
OPMB
12 (67%)
13 (90)
9
Stemona Alkaloids
Baran Lab
OO
OO
OMe
O
O
O
O
OMe
OO
OO
OMe
12
(Kende et al.)
O
OPMB
OPMB
isostemonamide
OMe
O
N
H
13) RhCl3, EtOH,H2O
PMB
OO
OMe
O 12) CAN, H2O/MeCN
PMB
stemonamide
O
OO
OMe
N
N
N
N
O
O
O
O
Tom Maimone
N
H
OH
13
OH
14 (53%)
15 (52%)
14) MsCl, DMAP
pyr.
O
O
O
OO
OO
OMe
OMe
O
OO
15) NaH
N
N
OMe
O
O
O
OO
OMe
O
N
H
N
H
OMs
OMs
16
17
3) CH3I, K2CO3
NHN(Me)2
O
O
H
N
H
1) Et2AlCl, CHCl3
85°C
O
O
(67%)
H
H
O
Stenine
(Hart et al.)
O
2) NH2NH2
MeOH
NHNH2
(87%)
O
OH
1
2
3
4) AcCl
O
OAc
4
J. Org. Chem. 1990. 55, 6236-6240
10
Stemona Alkaloids
Baran Lab
Tom Maimone
H
H
O
H
O
NHN(Me)2
N
7) 9-BBN/NaBO3
8) MsCl, Et3N
5) Mesitiylene, Δ
6) MeOH
NHCO2Me
(94%)
O
N
H
9) MeLi, THF
CO2Me
4
6
5
O
O
H
16) I2, THF, H2O
(75%)
H
14) t-BuMe2SiCl, Et3N
N
H
CO2Me
OH 11
CO2Me
15) MeC(OMe)2NMe2,
xylene, Δ
(93%)
H
13) NaBH4, MeOH
t--buOH
(100%)
CO2Me
N
HO
H
OH
OSiMe2t-Bu
CO2Me
7
H
Me2N
N
I
HO2C
11) I2, THF, H2O
12) DBU
(91%)
(David Hart et al.)
O
H
OH
OAc
OAc
H
N
(83%)
(89%)
H
Stenine
10) Jones reag.
acetone
N
O
H
O
9
CO2Me
8
10
Sn(n-Bu)3
17)
AIBN, PhH
(83%)
O
H
O
18) LDA, MeI
N
H
OH
12
O
O
O
H
O
19) swern
20) Ph3P=CHCO2Et
N
(87%)
H
CO2Me
OH
O
H
O
21) Red-Al, CuBr
N
(91%)
H
CO2Me
13
EtO2C
H
14
CO2Me
N
(85%)
H
EtO2C
CO2Me
15
11
Stemona Alkaloids
Baran Lab
Tom Maimone
O
O
O
O
H
H
O
N
H
N
H
CO2Me
22) TMSI,
then PhMe,
Δ
O
EtO2C
23) OsO4 (cat)
NaIO4
H
24)
N
(85%)
H
Stenine
(David Hart et al.)
O
15
O
HS
S
SH
H
O
S
N
H
SiO2/SOCl2
O
17
16
25) Lawesson's
reagent
(84%)
O
for a similar synthesis with an
asymmetric Diels-Alder see
Morimoto et al. Angew. Chem.
Int. Ed. Engl. 1996, 35, 904-906.
O
H
O
26) Raney Ni
N
H
EtOH
(75%)
S
H
O
S
N
H
S
18
O
O
H
OH
NHCbz
N
H
HO
Stenine
(Peter Wipf et al.)
CO2H
1) PhI(OAc)2, NaHCO3
MeOH, 21
40°C
CO2Me
O
(55%)
N
H
1
Cbz
OBz
2) Bz2O
3) NaBH4, CeCl3
(89%)
CO2Me
HO
N
H
Cbz
2
J. Am. Chem. Soc. 1995, 117, 11106-11112
12
Stemona Alkaloids
Baran Lab
Tom Maimone
O
H
H
O
H
OBz
CO2Me
HO
N
H
Bu3P, HCO2H,
Et3N
(68%)
N
H
5) TPAP, NMO
4) Pd2(dba)3 CHCl3
Cbz
2
CO2Me
HO
O
6) KHMDSA,
N
H
CO2Me
OTf
Cbz
H
7) NaBH4, CeCl3
8) H3CC(OMe)2NMe2,
130°C
(77%)
Stenine
(Peter Wipf et al.)
O
O
H
12) LiOH, H2O/THF
(Me)2N
13) PhOPOCl2, NEt3, PhSeH
14) Bu3SnH, AIBN, 130
H
15) I2, pH 5.5
16) Allyl-SnBu3, AIBN
N
O
O
(Me)2N
H
O
Cbz
4
(46%)
3
N
N
Cbz
H
OTIPS
8
CO2Me
H
TIPSO
CO2Me
10) NaBH4
11) TIPS-Cl, DMAP
N
Cbz
N
H
Cbz
(76%)
5
6
OTIPS
H
9) AD-mix β, NaIO4
(70%)
Cbz
(Me)2N
H
7
17) LDA, HMPA, MeI
18) OsO4, NaIO4
19) NaBH4, -40°C
20)o-(NO2)PhSeCN, Bu3P, H2O2
(47%)
O
O
H
O
N
H
H
23) Pd(OH)2, H2
O
O
H
25) Lawesson's
24) FDPP
Cbz
OTIPS
9
O
21) HF, MeCN
22) DMP, NaClO2
O
N
H
HO
O
Cbz
(71%)
H
26) Raney-Ni
(73%)
N
H
O
O
O
N
H
10
13
Stemona Alkaloids
Baran Lab
Tom Maimone
CO2Me
O
H
O
O
TMS
N
N
1) LDA, then
(MeS)2CHCHO,
OAc O
MeS
NH
then Ac2O
H
2)
Cl
CO2Me
3) DMTSF
Et3N
OAc O
MeS
SMe
(80%)
CO2Me
O
N
O
(80%)
MeS
O
N
Stenine
O
SMe
1
2
Padwa et al.
3
Org. Lett. 2002, 4, 1515-1517
O
MeO2C
H
O
O
I
H
8) LiOH, H2O
9) I2, MeCN
N
O
HO
H
O
N
H
7
4) Raney-Ni
5) NaBH4, CeCl3
(71%)
O
H
O
N
MeS
5
6
4
10) allyl-Sn(Bu)3, AIBN
11) OsO4, NaIO4
(48%)
O
6) Crabtree's Cat, H2
7) MsCl, Et3N, DBU
(64%)
N
(60%)
H
MeO2C
MeO2C
O
H
O
12) ethane dithiol
13) lawesson's
O
H
O
N
O
H
8
14) Raney-Ni
15) LDA, HMPA,
MeI
(67%)
N
H
14
Stemona Alkaloids
Baran Lab
Tom Maimone
N3
O
O
O
H
O
P
OMe
OMe
N
H
3)
O
1)
N3
2) TMSOTf
O
N3
NaH/ THF
(92%)
(95%)
1
H
O
O
N
SnCl4
(70% 3:1 dr)
TMSO
H
O
3
Stenine
4) LHMDS, then
BrCH2CO2Me
(73%)
2
Aubé et al.
J. Am. Chem. Soc. 2005, 127, 15712-15713
O
O
8 Steps
19% Yield
No PG's
O
H
7) Lawesson's
N
MeO2C
H
O
8) Raney Ni
(83%)
H
6) LHMDS, MeI
N
H
H
O
5) NaBH4
O
N
H
(51%)
O
O
O
H
H
N
H
H
Tuberstemonine
Wipf et al
1) TBDMS-Cl, imidazole
DMAP
H
O
CO2Me
O
HO
N
H
1
Cbz
from the oxidative
tyrosine cyclization
H
2)Et3SiH, Pd(OAc)2, NEt3
3) cinnamyl bromide
4) TBAF
(80%)
CO2Me
HO
N
(58%)
H
2
5) TPAP, NMO
6) KHMDS, allyl
iodide
Ph
H
CO2Me
O
N
H
Ph
3
15
Stemona Alkaloids
Baran Lab
Tom Maimone
O
H
O
H
N
H
CO2Me
O
O
O
H
N
7) Grubbs
8) PhSH, Et3N
9) (PPh3)3RhCl, H2
CO2Me
(92%)
H
3
H
Ph
CO2Me
N
O
10) DBU
N
O
H
(81%)
4
Tuberstemonine
(Wipf et al.)
H
H
N
H
13) (Me)(OMe)NH HCl
Me2AlCl
15) L-selectride, -78°C
O
O
16) TsOH, MeOH
H
N
TBDMSO
H
O
O O
(56%)
14) LiDBB
O
Br
7
8
5
11) NaBH4, CeCl3
12) TBDMS-Cl, imid.
DMAP
(56%)
H
H
HO
H
H
H
CO2Me
N
TBDMSO
H
O
O
O
6
(89%)
17) MeC(OMe)2NMe2,
xylene, Δ
18) PhSeCl, MeCN/H2O
(52%)
O
O
PhSe
O
O
H
19) allyl-SnPh3
20) LDA, HMPA, MeI
H
N
H
9
H
O
O
21) allyltritylamine, DIEA,
toluene, 110°C
(45%)
O
H
22) Grubbs, TsOH,
ethylene
H
N
H
H
O
O
23) Pd/C, H2
O
H
H
N
H
H
O
O
10
16
Stemona Alkaloids
Baran Lab
Tom Maimone
O
Ac
OH
MeO
O
O
1) aq. NaOCl, HOAc
OH
O
OMOM
2) MOMCl, EtN(i-Pr)2
N
O
NMe2
KOEt
(80%)
2
(60%)
1
H
3)
O
N
O
OMe
N
O
O
OMOM
O
Isostemofoline
(Kende et al.)
N
4) Na2S2O4, EtOH, H2O, 90°C
5) BOC2O, DMAP
J. Am. Chem. Soc. 1999. 121, 7431-7432
N
(25%)
10)
O
N Boc
O
O
O
NaOH, MeOH
(90%)
MOMO
7
N Boc
O
7) Bu4NF
8) H2, Pd/C, MeOH,
9) H2O, DMSO, 150°C
(52%)
MOMO
OMOM
MeO2C
N Boc
(90%)
6)
TBSO
6
OMOM
5
N
OTBS
Boc
CO2Me
4
N2
Rhodium octanoate dimer
11) LHMDS, DMPU
allyl iodide
(91%)
O
N Boc
O
12) K2OsO4, NaIO4, H2O
13) Zn(BH4)2, THF, -10°C
14) TIPSCl, imid., DMF
(48%)
MOMO
8
OTs
OTIPS
O
O
OTIPS
N Boc
15) MeLi (2.2 eq.)
DMPU, Et2O
-40 °C
(85%)
MOMO
9
N Boc
O
O
MOMO
10
16) Bu4NF, THF
17) TsCl, pyr,
CHCl3
(81%)
N Boc
O
O
MOMO
11
17
Stemona Alkaloids
Baran Lab
Tom Maimone
O
OTs
O
MeO
O
O
N Boc
O
O
H
OMe
N
18) O3, DMS
O
N Boc
HO2C
(65%)
O
N
O
OTs
O
MOMO
MOMO
19) i-BuOCOCl, NMM
20) NaBH4, MeOH
21) DMP
Isostemofoline
(Kende et al.)
OTs
OTs
H
O
N Boc
OH
23) DMP, CH2Cl2
O
O
(61%)
O
OMe MOMO
12
11
O
N Boc
OMe
22)
LiO
OTs
N Boc
O
O
O
O
(56%)
O
OMe MOMO
15
O
MOMO
13
14
24) CF3CO2H
then NaHCO3
(67%)
H
O
O
OH
N
25) Tf2O
O
O
O
N
O
OMe
16
O
OMe
O
O
(12%)
N
O
O
?
(14%)
18
Stemona Alkaloids
Baran Lab
OMe
O
O
O
O
1) O2N
Boc
N
N
O2N
CO2Et
2) H2, Pd/C
(73%)
OMe
O
Isodidehydrostemofoline
1
OMe
OH
EtO2C
3
2
6) DMP
7) TIPSOTf, Et3N
8) O3, DMS
(37%)
J. Am. Chem. Soc. 2003. 125, 15284-15285
N
O
12) TBAF
13) SO3 Py, Et3N, DMSO
14) Julia olefination
N
OTIPS
O
(70%)
MeO
9) VinylMgBr, CeCl3
10) TMSI
(94%)
OH
6
15) LDA, ICH2CO2Et
16) DBU, PhMe, 130°C
Boc
N
H
N HI
11) (CH2O)n, PhMe/
MeCN,
MeO
7
OMe
OTIPS
O
(85%)
O
17) BBr3; aq. NaOH MeO2C
18) TMS-imid., 130°C
MeO
N
TMSO
4
O
N
TMSO
54%
O
(54%)
H
HO
OLi
O
then aq. HCl
O
N
HO
O
11
10
O
MeO
19) DIBAL, -78°C
OHC
20) DMP
21) SiO2 (epim.)
8
OMe
OTIPS
5
22) MeO
N
OMe
OTIPS
HO
(Overman et al.)
MeO2C
Boc
N
3) DBU, then H2, Pd/C
4) TIPSOTf, 2,6-lutidine
5) DIBAL, PhMe, -78°C
O
OMe
O
Didehydrostemofoline
(Asparagamine A)
Boc
N
OH
N
O
Tom Maimone
12
O
MeO
MeO
Didehydrostemofoline
+
Isodidehydrostemofoline
25) P(OMe)3
(65%)
O
O
O
O
O
S
N
O
O
O
O
S
3.5 : 1
N
24) CSCl2
DMAP
O
O
23) IBX, DMSO
50°C
O
MeO
O
H
HO
N
O
O
13
19