O
N OClO2S
O
NNH
C
N3O2SO
O
NH ON3O2S
N3
O
NHHN
O
O
NHHN
O
O
NHHN
O
O
O
ECO2Me
OH
NHHN
O
HO
CO2MeOMs
NHHN
O
MsO
G
O
ClSO2NCO
Et2O, -60oC
Et3NH+N3_
CH2Cl2, -20oC
Curtius
rearrangement
1. Na2SO3, H2O
2. Lio, EtNH2, LiNH2
1. mCPBA
2. H2O3. NaIO4
MsCl, py. 1. Na2S
2. NaOH
NHHN
S
O
CO2HH
biotin
A B
C D F
NaBH4
MeOH
Fliri, A.; Oehringen, H., Chem. Ber. 1980, 113, 607~613
Funk analysis:2 rings3 stereogenic centers1 S atom1 urea7 points = 14 steps
Synthesis of Biotin - ~without- Protecting Groups
ACIE 2009, 48, 2854
T h e m o s t e f fi c i e n t synthesis, the “ ideal synthesis,” has been defined by Hendrickson: “The ideal synthesis c r e a t e s a c o m p l e x skeleton … in a sequence o n l y o f s u c c e s s i v e construction reactions involving no intermediary refunctionalizations, and leading directly to the structure of the target, not only its skeleton but also i t s c o r r e c t l y p l a c e d functionality.”
In your presentations, identify redox steps and protecting group steps by color-coding. In the final analysis of each synthesis, summarize the total number of redox changes and the total number of protecting group steps (protecting installation = 1 step; protecting cleavage = 1 step). Identify protecting groups on the molecule structure of every intermediate in red; eg:
(DMTSF)S S
MeMe
Me
BF4
N
OSEM
N
OPMBH
H
EtS
NaCNBH3
TiCl4 (68%)86% NH
OSEM
N
OPMBH
H
EtS1. 1 N HCl, MeOH 55 oC
2. Ac2O, py.3. NaOMe, MeOH4. TIPSCl, DMF, im. 51% 4 steps
NH
OSEM
N
EtSSEt
OPMBH
H
NAc
OH
N
OTIPSH
H
EtSNiCl2, NaBH4
61%NAc
OH
N
OTIPSH
H1. SO3-py
Et3N, DMSO2. HF-Et3N N
AcO
N
H
H
HO(+)-diaboline
HO OH
N
O
N
H
HO O
NaOAc, Ac2O
1. NaOMe, MeOH
2.
O83% 2 steps
5.2 mg42% (-)-strychnine
Convergent Synthesis:
Linear Synthesis:
“Longest linear sequence” = 6 steps Actual total steps = 9 steps
Funk Analysis
N
N
O
OH
H
HH
strychnine
7 rings1 basic N1 seven-membered ring[1 alkene]1 quaternary center6 stereogenic centers
17 points = 34 steps maximum
Background: Strychnine is a poisonous alkaloid isolated from the seeds of Strychnos nux-vomica, a small climbing shrub found in Africa, Asia and South America. Strychnine is still in use today as a rodent poison and was one of the first alkaloids isolated in a pure state (1818). The complete chemical structure of strychnine was not elucidated until 1947 by Woodward, Prelog and Robinson. In 1951, the X-ray crystal structure determination confirmed the proposed structure and the complete chemical synthesis was achieved by Prof. Robert B. Woodward of Harvard University in 1954. Below, is an excerpt of the introduction to a paper (Tetrahedron, 1963, 19, 247) by Woodward on the chemical synthesis which gives some interesting insight into the importance of strychnine and the state of alkaloid research after the second World War.
"Strychnine! The fearsome poisonous properties of this notorious substance attracted the attention of XVIth century Europe to the Strychnos species which grow in the rain forests of the Southeast Asian Archipelagos and the Coromandel Coast of India, and gained for the seeds and bark of those plants a widespread use for the extermination of rodents, and other undesirables, as well as a certain vogue in medical practice-now known to be largely unjustified by any utility. The isolation of the pure alkaloid from the beans of Strychnos ignatii in 1818 by Pelletier and Caventou was an event of some historical importance, in that it provided a convincing and elegant demonstration of the correctness of the then only recently proposed and revolutionary suggestion that acid-fixing substances are produced in the vegetable kingdom. Thus did circumstance early place ready at the hand of any interested chemist an abundant supply of a pure crystalline compound whose constitution and construction could hardly fail to excite curiosity. But organic chemistry, in its first hundred years, was scarcely equipped for the attack on so formidable an objective, and apart from the determination of the correct empirical formula of the alkaloid, and the discovery of a few simple transformations, no substantial progress was made until the commencement of the massive investigations of the present century. Then, over a period of forty years, one of the great classics of structural organic chemistry was constructed. In that effort, described in more than two hundred fifty separate communications, Robert Robinson played a brilliant and commanding role, and the extensive beautiful experimental contributions of Herman Leuchs were of definitive importance. In 1947, the task was finished and strychnine stood revealed as 1 ...It is now possible to contemplate the synthesis of the substance of which it has been said: "For its molecular size, it is the most complex substance known".."
A footnote in this paper goes on:.."It will not be lost upon the reader-nor was it on at least some of the observers of the chemical scene in the late nineteen forties- that the almost simultaneous outcomes of decades-long chemical degradative assault, and the incomparably shorter X-ray crystallographic investigations, presaged a future in which so singular an edifice as the chemical structure determination of strychnine was unlikely to find parallels. But it is worthwhile to point out here that the establishment of the structure of strychnine was accompanied by no surcease of interesting chemical developments. The elucidation and further development of the fascinating chemistry of vomicine, the dramatic establishment of the relationships between strychnine and the calabash curare alkaloids, the discovery of intricate new transformations of the strychnine skeleton, the even now rapidly unfolding exciting new chapters in the story of the biogenesis of the Strychnos and related alkaloids, and perhaps also the synthesis here recorded, may be selected as only a few high points in the continuing evolution of the chemistry of strychnine during the last fifteen years. This short history should give pause to those whose talent for despair is lavished upon an organic chemistry ornamented and supplemented- or as they fancy, burdened- by magnificent new tools which permit the establishment in days or weeks of enlightenments which once would have required months or years. While it is undeniable that organic chemistry will be deprived of one special and highly satisfying kind of opportunity for the exercise of intellectual élan and experimental skill when the tradition of purely chemical structure elucidation declines, it is true too that the not infrequent dross of such investigation will also be shed; nor is there any reason to suppose that the challenge for the hand and the intellect must be less, or the fruits less tantalizing, when chemistry begins at the advanced vantage point of an established structure. Of course, men make much use of excuses for activities which lead to discovery, and the lure of unknown structures has in the past yielded a huge dividend of unsought fact, which has been of major importance of building organic chemistry as a science. Should a surrogate now be needed, we do not hesitate to advocate the case for synthesis."
Thirteen new total syntheses of strychnine have appeared since the classical Woodward synthesis. It is quite instructive to compare and contrast a few of these syntheses. The new syntheses have been reviewed by Beifuss wherein it is stated:
“Whether the four new total syntheses (to 1994) represent a fundamental improvement over Woodward’s strychnine synthesis and the extent of this improvement can certainly be debated. However, it can not be contested that Overman et al. accomplished the first enantioselective synthesis of the natural product, and that Kuehne and Rawal with their respective 17- and 15-step syntheses devised approaches with markedly fewer reaction steps than Woodward’s 28-, Magnus’ 27- and Overman’s 25-step syntheses.”
Woodward synthesis:
N
N
O
OH
H
HH
NH
OCH3
OCH3 NH
OCH3
OCH3
N(CH3)3
NH
OCH3
OCH3
NH2H CO2Et
O
N
OCH3
OCH3
NTsCO2Et
NAc
OCH3
OCH3
NTsCO2Et
NAc
CO2CH3
CO2CH3
NTsCO2Et
N
NTsCO2Et
O
CO2CH3N
NAcCO2CH3
O
CO2CH3N
NAc
O
CO2CH3
OH
N
NAc
O
CO2CH3
H
H
N
NAc
O
HCH3
OAc N
N O
O
H
H
O
HC CNa
N
N
O
HH
OOH
N
N
O
HHHO
STRYCHNINE
1. CH2O, Me2NH
2. CH3I
NaCN, DMF
2. LiAlH4
1.
2. TsCl. pyridine
1. NaBH4
2. Ac2O pyridine
O3, HOAc HCl, CH3OH
1. HI, red Po
2. Ac2O pyridine3. CH2N2
NaOCH3
CH3OH
1. TsCl, pyridine
2. PhCH2SNa3. Ra-Nio
H2Pd-C
2. NaOH3. Ac2O pyridine
1. HCl, H2O
2. SeO2
1. , THF2. H2, Lindlar's cat.
1. LiAlH4
2. HBr, HOAc, Δ3. H2SO4
KOH, EtOH
.
I
NH
OMe
OMe
1. H2C=O, Me2NH
HOAc, diox., H2O
2. MeI
NH
OMe
OMe
NMe3I
O
H H HNMe
Me
HO NH H
Me
MeN
H H
Me Me
NH
OMe
OMe
NOMe
OMe
NMe2HB:
NH
OMe
OMe
NMe2
mechanism: step 1
NH
OMe
OMe
NMe2
H3C I
NH
OMe
OMe
NMe3I
mechanism: step 1
Woodward Strychnine synthesis 1
H+
NH
OMe
OMe
NMe3I
Woodward Strychnine synthesis 2
1. NaCN, DMF
2. LAH, THF3. Na2SO4, CHCl3 H2O
NH
OMe
OMe
NH2
NH
OMe
OMe
NMe3I
NOMe
OMe
C NNa
NH
OMe
OMe
C N
mechanism: step 1
NH
OMe
OMe
C NHAlHH
HLi
NH
OMe
OMe
NH
AlH H
H
Li
NH
OMe
OMe
NH
AlH H
Li
H
H2ONH
OMe
OMe
NH2
mechanism: step 2
NH
OMe
OMe
NH2H
O
CO2Et
benzene, Δ NOMe
OMe
1.
2. TsCl, py
Woodward Strychnine synthesis 3
NH
OMe
OMe
NH2
H
O
EtO2C
NH
OMe
OMe
NHEtO2C
OH H+
NH
OMe
OMe
NEtO2C
H
-H2O
mechanism: step 1
NTsCO2Et
NH
OMe
OMe
NTsCO2Et
Cl
NH
OMe
OMe
NEtO2C
HS
O
OCl Me
NOMe
OMe
NTsCO2Et
mechanism: step 2
N
NOMe
OMe
NTsCO2Et 1. NaBH4, EtOH, H2O
2. Ac2O, py. NAc
OMe
OMe
NTsCO2Et
H
Woodward Strychnine synthesis 4
N
NTs
ArCO2Et
BH H
HHNa
NH
OMe
OMe
NTsCO2Et
H
EtOH
mechanism: step 1
NH
OMe
OMe
NTsCO2Et
H
Me O Me
O O
NOMe
OMe
NTsCO2Et
H
MeOO
OMe
NAc
OMe
OMe
NTsCO2Et
H
-OAc
mechanism: step 2
NAc
OMe
OMe
NTsCO2Et
H NAc
CO2MeCO2Me
NTsCO2Et
H
1. O3, HOAc
Woodward Strychnine synthesis 5
OO O
OMeMeO
R [1,3]-dipolar cycloaddition
OMeMeO
R
OO
O OMeMeO
R
OO
O
primary ozonide
OMeMeO
R
O O
O
secondary ozonide
2. Na2SSO3
S SO
OONa
OMeMeO
R
O O
HO
S SO
OONa
NAc
CO2MeCO2Me
NTsCO2Et
H
ozonolysis mechanism
NAc
CO2MeCO2Me
NTsCO2Et
H
Woodward Strychnine synthesis 6
HCl, MeOH
N
NTsCO2Et
O
CO2Me
NH
NTsCO2Et
O
CO2Me
N CO2MeCO2Me
NTsCO2Et
H
Me OMeOHH+
N CO2MeCO2Me
NTsCO2Et
H
Me OHOMe
HN CO2Me
CO2Me
NTsCO2Et
H
Me OHOMe
HMeO
N
NTsCO2Et
HO
CO2Me
OMe
H+
N
NTsCO2Et
O
H O
OMeH+
N
NTsCO2Et
O
OH
OMeH+
N
NTsCO2Et
O
CO2Me
mechanism:
N
NTsCO2Et
O
CO2Me1. HI, red Po
2. Ac2O, py.
3. CH2N24. NaOMe, MeOH
N
NAc
O
CO2Me
OH
N
NCO2Et
O
CO2Me
SO
O
MeIPO
H
N
NHCO2H
O
CO2H
Woodward Strychnine synthesis 7
MeO
MeO
O
N
NCO2H
O
CO2H
MeOMeOH O
N
NAcCO2H
O
CO2H
steps 1& 2: mechanisms
I
H
HN N
diazomethane
H
H
HN N
HO
ORN
NAcCO2Me
O
CO2Me
step 3: mechanism
N
NAcCO2Me
O
CO2MeH
OMeN
NAc
O
O
OMe
OOMe
N
NAc
O
CO2Me
OOMe
N
NAc
O
CO2Me
O
H
OMe
HOMe
N
NAc
O
CO2Me
OH
step 4: mechanism
RCO2H
N
NAc
O
CO2Me
OH
N
NAc
O
CO2Me1. TsCl, py.
2. PhCH2SNa3. Ra-Ni
Woodward Strychnine synthesis 8
N
NAc
O
CO2Me
OH
SO
OCltol
N
NAc
O
CO2Me
O
SO
OCltol
N
NAc
O
CO2Me
OSO
O
tol
N
NAc
O
OSO
O
tolS
O
OMe N
NAc
O
OTs O
OMe
S
N
NAc
O
SBnO
OMe
step 1: mechanism
N
NAc
O
CO2MeRa-Ni
step 2: mechanism
N
NAc
O
CO2Me
Woodward Strychnine synthesis 9
1. H2Pd-C
2. KOH, H2O, MeOH3. Ac2O, py.
N
NAc
O
Me
OAc
N
NAc
O
CO2Me
N
NAc
O
CO2Me1. H2Pd-C
steps 1&2:
2. KOH, H2O, MeOH
N
NAc
O
CO2H
N
NAc
O
O
OH Me
O
Me
O
O
N
NAc
O
O
O
OMe
N
NAc
O
O
O
MeO
N
NAc
O
O
OH
MeO
N
NAc
O
Me
OH Me
O
Me
O
O
N
NAc
O
Me
OAc
step 3: mechanism
N
NAc
O
Me
OAc
Woodward Strychnine synthesis 10
1. HCl, H2O
2. SeO2, EtOH N
N
O
N
NAc
O
Me
O Me
OH+
OH2
N
NAc
O
Me
O Me
OH
HO N
NH
O
Me
O
step 1: mechanism
N
NH
O
O
H HH
SeO
O N
NH
O
O
HH
SeO
OH N
NH
O
O
OH
SeOH
N
NH
O
O
OH
OO
hydrolysis of acetamide
N
N
O
OOH
SeOO
N
N
O
OO Se
O
OHH
N
N
O
OO
step 2: mechanism
N
N
O
OO
1. H C C Na , THF
2. H2, Pd-BaSO4, quinoline (Lindlar's catalyst)3. LAH, ether
Woodward Strychnine synthesis 11
N
N
O
OH
N
N
O
OO
HCCNa
N
N
O
OONa
aqueous
work-up N
N
O
OOH
N
N
O
OH
2. H2, Pd-BaSO4, quinoline (Lindlar's catalyst)
O
step 1: mechanism
N
N
O
OLiO
HAlHH
H Li+
N
N
O
OLiO
AlH H
HLi+
N
N
O
OLiHAlHH
H Li+
N
N
O
OLi
H3O+
N
N
LiO
OAlH2
step 2: mechanism
H
LAH
N
N
O
OAlH
HH
HN
N
O
OH
H
H+
1. HBr, HOAc, 120oC
2. KOH, EtOHN
N
O
OH
H
HH
STRYCHNINE
Woodward Strychnine synthesis 12
N
N
O
OH H
N
N
O
OH2
N
N
O
OH
H
N
N
O
OH
step 1: mechanism
N
N
O
OH
H H
HO
N
N
KO
OHHOEt N
N
O
OK
N
N
O
KOH
H
HH
HOEt
STRYCHNINE
step 2: mechanism
NH
NH2MeO2C CO2Me
O
+ NH
N
CO2Me
1. ClCO2CH2CCl3, CH2Cl22. NaOMe, MeOH
3. 50% aq. NaOH, CH2Cl2 ClCO2Me, BnN(Me)3Cl4. Zn, HOAc, THF
N
NH
CO2MeMeO2C
PhSCH2CO2H
BOPCl, Et3N N
N
CO2MeMeO2C
SPhO
NMeO2C
NO
SPh
HCO2Me
1. TFAA N
Me
tBu t-Bu
2. HgO, CdCO3, THF H2O N
MeO2C
NO
O
HCO2Me
1. BrCH2CH2OH DBU, tol.
2. BH3-THF3. Na2CO3, MeOH
NH
N
HCO2Me
O
OHg(OAc)2
HOAcNH
N
HCO2Me
O
O
NH
N
HCO2Me
O
OH
65%
1. Zn, H2SO4 MeOH
2. NaOMe, MeOH
NH
N
HCO2Me
O
OH 1. p-MeOC6H4SO2Cl, DMAP
EtN(i-Pr)2
2. LiBH4, THF, HN(CH2CH2OH)2–3. HClO4
N
NH
OOH
H
1. TIPSOTf, DBU CH2Cl2
2. (EtO)2P(O)CH2CN KHMDS, THF
N
NH
H
CN
OTIPS
H
1. DIBAH, CH2Cl22. NaBH4, MeOH3. 2N HCl, MeOH
4. TBDMSOTf, DBU5. SO3, py, DMSO Et3N6. HF-py.
N
NH
CHOH
OH
p-MeOC6H4O2S
p-MeOC6H4O2S p-MeOC6H4O2S
NH
NH
HO
HO
Weiland-Gumlich aldehyde
N
N
O
OH
H
HHHO OH
O O
Magnus, et al., J.Am.Chem.Soc., 1992, 114, 4403~4404.
lit.
50%
69%
1. m-CPBA CH2CL22. NaH, THF
72%
O
81%
83%84%
28% 50%
6%
Nao-anthracenide
85%70%
NaOAcAc2O
strychnine
27 steps 0.03% overall yield
NH
NHBn
CO2Me
MeO
MeO
CHO
NH CO2Me
NBnOMe
OMe NH CO2Me
NBnOMe
OMeH
NH
NBn
MeO2C
OMe
OMe
NH
NBn
MeO2C
O
HNH
NBn
MeO2C
O
SMeMe
NH
NBn
MeO2C O NH
N
HCO2Me
OH
Ph
NH
N
HCO2Me
OH
NAc
N
HCO2Me
OHN
N
O
H
OH
O
N
N
O
H
OH
OAc
N
N
O
H
O
P CO2MeO
EtO OEt
BF3-Et2O, tol. Δ
N
N
O
10% HClO4
THF
[3,3]
H
Me3SI
n-BuLi, THF
CO2Me
51% overall
DBU, MeOH
65oC
H2, Pd-C
MeOH67%,
N
N
1. NaCNBH3, HOAc
2. Ac2O, py.
O
83%
OH
LiN(TMS)2
THF
H
(Dieckman)
1. NaBH4, MeOH
2. Ac2O, py.
DIBAH, BF3-OEt2
87%
N
N
64% (3 steps)
O
59%
1. DBU, diox., H2O, Δ
2. Swern ox.
OH
1. KHMDS, THF
2. hν
isostrychnine
KOH, EtOH
85oC H
strychnine
H
28%Kuehne, M.E.; Xu, F., J.Org.Chem., 1993, 58, 7490~7497
17 steps~2% overall yield
H+
Kuehne: short, convergent total synthesis - [3,3]/Mannich
OAc
OAc
OH
OAct-BuO
O
CO2Et
AcOCO2Et
O Ot-Bu
HAcO
CO2Et
OH
H
Ot-Bu
OOTIPS
Ot-Bu
AcOCO2Et
Ot-Bu
OTIPS
Ot-Bu
Me3Sn
MeN
N
NMe
O
I
OTIPS
Ot-Bu
ON
OTIPS
Ot-Bu
ON
O OH
Ot-Bu
NONMe
MeNNMeMeN
O ONMe
MeN
O
NHCOCF3
Ot-Bu
NO
NMeMeN
OOt-Bu
HN
N NMe
MeN OO R
Ot-Bu
N
N NMe
MeN OHO
H
Ot-Bu
N+
N NMe
MeN O
meso
acetylcholine
esterase
HO
1. ClCO2Me, py.
2. NaH, 1% Pd2(dba)3
NaCNBH3
TiCl4
Ot-Bu
N+
N NMe
MeN O
63%
1. L-selectridePhNTf2, THF
2. Me6Sn2, LiClPd(PPh3)4, THF
1. DIBAH
2. TIPSCl, NMP TMG3. Jones ox.
DCC, CuCl
80oC, PhH98%
88%
HO
+
Pd2(dba)3, NMP
Ph3As, CO, LiCl
N
O
Ot-Bu
N
MeN
MeN
O
80%63%
t-BuOOH
triton B
H
91%
1. Ph3P=CH2 (92%)
2. TBAF (97%)
1. MsCl, LiCl
2. CF3CONH2 NaH
NaH, 100oC
75%
KOH
EtOH
NH
N
CO2Me
75%
OH
(CH2O)n, Na2SO4
MeCN, D
HMannich 1. LDA, NCCO2Me
2. HCl, MeOH, Δ
aza-Cope
NCCO2Me = methylcyanoformate(Mander's reagent)
98%
NH
N
CO2MeOHH N
H
N
CO2MeOHH N
H
N
HO OH
H
HN
N
O OH
1. Zn, 10% H2SO4
2. NaOMe, MeOH
58%
H
H
DIBAH
CH2Cl2
Wieland-Gumlich aldehyde
NaOAc, Ac2O
CH2(CO2H)2HOAc, 110oC
51%
Knight, S.D.; Overman, L.E.; Pairaudeau, G., J.Am.Chem.Soc., 1995, 117, 5776~5788 25 steps~3% overall yield
(-)-strychnine
Mechanism of the Fisher Indole Synthesis
N
Me
NHNH2
OMe
*1. HOAc, Δ
NAc H
MeO
aspidospermidine
N
O
Me+
N
N
Me
NH
OMe
N
NH
Me
NH
OMe
[3,3]N
NH2
MeNH2
MeO
N
MeNH NH2
MeO
-NH3N
MeNMeO
1. LAH
2. Ac2O
OO
AlOO
Li
OCO2Me
CO2Me
0.1 mol%
0.09 mol% KOt-BuO
CO2Me
CO2MeH
91%, > 99% ee; > 1 Kgno chromatography
Shibasaki: catalytic, asymmetric Michael-type reaction
Shibasaki, et al., J.Am.Chem.Soc. 2002, 124, 14546-14547
Shibasaki, et al., J.Am.Chem.Soc. 2002, 124, 14546-14547
OO
AlOO
Li
O CO2Me
CO2Me
0.1 mol%
0.09 mol% KOt-BuO
CO2Me
CO2MeH
91%, > 99% ee; > 1 Kgno chromatography
CO2MeH
OO
O
O
MeEt
TsOH
1.
2. LiCl, DMSOH2O 140 oC97% 2 steps
LDA
O
NMe
O
MeO
OMe
CO2MeH
OO
OPMBO
72%
1. NaBH3CN, TiCl4
2. DCC, CuCl, PhHheat 70% 2 steps
CO2MeH
OO
OPMBE:Z 15.7:1
1. DIBAl-H
2. TIPSOTf, Et3N3. CSA, acetone61% 3 steps
H
OPMB
O1. TMSCl
NMe
MeMe
Me
Li
H
OPMB
TMSO
>6:1
Pd(dba)3-CHCl3
OTIPS
OTIPSdi-allylcarbonate
90% 2 stepsH
OPMB
O OTIPS
1. LDA, TMSCl
2. HCHO 20 mol%Yb(OTf)33. DBU57% 3 steps
H
OPMB
O OTIPS
HO
I2, DMAP
H
OPMB
O OTIPS
HO
I
NO2
SnMe3
Pd(dba)3, Ph3As, CuI H
OPMB
O OTIPS
HO
NO2
>99%
1. SEMCl, DIPEA (99%)
2. HF-Et3N3. Tf2O, DIPEA;
EtS
EtS NH2
H
OPMB
O
SEMO
NO2
HN
SEtSEt
Zno-MeOH
NH4Cl77% 2 steps
NH
OSEM
N
EtSSEt
OPMBH
H
Shibasaki: 31 steps
Shibasaki, et al., J.Am.Chem.Soc. 2002, 124, 14546-14547
12/31 steps = protecting group manipulations
(DMTSF)S S
MeMe
Me
BF4
N
OSEM
N
OPMBH
H
EtS
NaCNBH3
TiCl4 (68%)86% NH
OSEM
N
OPMBH
H
EtS1. 1 N HCl, MeOH 55 oC
2. Ac2O, py.3. NaOMe, MeOH4. TIPSCl, DMF, im. 51% 4 steps
NH
OSEM
N
EtSSEt
OPMBH
H
NAc
OH
N
OTIPSH
H
EtSNiCl2, NaBH4
61%NAc
OH
N
OTIPSH
H1. SO3-py
Et3N, DMSO2. HF-Et3N N
AcO
N
H
H
HO(+)-diaboline
HO OH
N
O
N
H
HO O
NaOAc, Ac2O
1. NaOMe, MeOH
2.
O83% 2 steps
5.2 mg42% (-)-strychnine
7/31 steps = redox changes19 “wasted” steps for PG & redox manipulations
N
N
O
OH
H
HH
NH
OCH3
OCH3 NH
OCH3
OCH3
N(CH3)3
NH
OCH3
OCH3
NH2H CO2Et
O
N
OCH3
OCH3
NTsCO2Et
NAc
OCH3
OCH3
NTsCO2Et
NAc
CO2CH3
CO2CH3
NTsCO2Et
N
NTsCO2Et
O
CO2CH3N
NAcCO2CH3
O
CO2CH3N
NAc
O
CO2CH3
OH
N
NAc
O
CO2CH3
H
H
N
NAc
O
HCH3
OAc N
N O
O
H
H
O
HC CNa
N
N
O
HH
OOH
N
N
O
HHHO
STRYCHNINE
1. CH2O, Me2NH
2. CH3I
NaCN, DMF
2. LiAlH4
1.
2. TsCl. pyridine
1. NaBH4
2. Ac2O pyridine
O3, HOAc HCl, CH3OH
1. HI, red Po
2. Ac2O pyridine3. CH2N2
NaOCH3
CH3OH
1. TsCl, pyridine
2. PhCH2SNa3. Ra-Nio
H2Pd-C
2. NaOH3. Ac2O pyridine
1. HCl, H2O
2. SeO2
1. , THF2. H2, Lindlar's cat.
1. LiAlH4
2. HBr, HOAc, Δ3. H2SO4
KOH, EtOH
.
I
Woodward strychnine synthesis: 1 PG for +2 steps
Kuehne strychnine synthesis: 2 PG for + 4 steps
NH
NHBn
CO2Me
MeO
MeO
CHO
NH CO2Me
NBnOMe
OMe NH CO2Me
NBnOMe
OMeH
NH
NBn
MeO2C
OMe
OMe
NH
NBn
MeO2C
O
HNH
NBn
MeO2C
O
SMeMe
NH
NBn
MeO2C O NH
N
HCO2Me
OH
Ph
NH
N
HCO2Me
OH
NAc
N
HCO2Me
OHN
N
O
H
OH
O
N
N
O
H
OH
OAc
N
N
O
H
O
P CO2MeO
EtO OEt
BF3-Et2O, tol. Δ
N
N
O
10% HClO4
THF
[3,3]
H
Me3SI
n-BuLi, THF
CO2Me
51% overall
DBU, MeOH
65oC
H2, Pd-C
MeOH67%,
N
N
1. NaCNBH3, HOAc
2. Ac2O, py.
O
83%
OH
LiN(TMS)2
THF
H
(Dieckman)
1. NaBH4, MeOH
2. Ac2O, py.
DIBAH, BF3-OEt2
87%
N
N
64% (3 steps)
O
59%
1. DBU, diox., H2O, Δ
2. Swern ox.
OH
1. KHMDS, THF
2. hν
isostrychnine
KOH, EtOH
85oC H
strychnine
H
28%Kuehne, M.E.; Xu, F., J.Org.Chem., 1993, 58, 7490~7497
17 steps~2% overall yield
H+
NH
NHBn
CO2Me
MeO
MeO
CHO
NH CO2Me
NBnOMe
OMe NH CO2Me
NBnOMe
OMeH
NH
NBn
MeO2C
OMe
OMe
NH
NBn
MeO2C
O
HNH
NBn
MeO2C
O
SMeMe
NH
NBn
MeO2C O NH
N
HCO2Me
OH
Ph
NH
N
HCO2Me
OH
NAc
N
HCO2Me
OHN
N
O
H
OH
O
N
N
O
H
OH
OAc
N
N
O
H
O
P CO2MeO
EtO OEt
BF3-Et2O, tol. Δ
N
N
O
10% HClO4
THF
[3,3]
H
Me3SI
n-BuLi, THF
CO2Me
51% overall
DBU, MeOH
65oC
H2, Pd-C
MeOH67%,
N
N
1. NaCNBH3, HOAc
2. Ac2O, py.
O
83%
OH
LiN(TMS)2
THF
H
(Dieckman)
1. NaBH4, MeOH
2. Ac2O, py.
DIBAH, BF3-OEt2
87%
N
N
64% (3 steps)
O
59%
1. DBU, diox., H2O, Δ
2. Swern ox.
OH
1. KHMDS, THF
2. hν
isostrychnine
KOH, EtOH
85oC H
strychnine
H
28%Kuehne, M.E.; Xu, F., J.Org.Chem., 1993, 58, 7490~7497
17 steps~2% overall yield
H+
Kuehne Synthesis: 4 changes in oxidation state
CN
NO2
Br Br CN
NO2
CHO
NO2NO2
NBn
NO2
N Bn
NO2
NBn
ITMS
NH2
NCO2MeMeO2C CHO
Me N
NCO2Me
CO2MeMeO2C
N
NCO2Me
CO2MeMeO2C
N
NH
O
N
N
O
BrI OTBS
NaOH, n-Bu4NBrMeCN
I OTBS
96%
1. BnNH2, Et2O
2. TMSCl, NaI, DMF
DIBAH
tol.
N
N
O
1. ClCO2Me, acetone
2. Pd/C, HCO2NH4, MeOH
OHH
+benzene
185oC
1. neat
2. ClCO2Me PhNEt2 99%
TMS-I
CHCl3
N
N
90%
O74%K2CO3, DMF, acetone
OH
1. Pd(OAc)2, K2CO3
Bu4NCl, DMF2. 2N HCl, THF
71%isostrychnine
Kuehne/Woodward H
H
strychnine
Rawal, V.H.; Iwasa, S., J.Org.Chem., 1994, 59, 2685~268615 steps~10% overall yield
Me3SiClI
Rawal: Shortest Synthesis on Record - IMDA & Heck Reactions
N
N
O
OH
H
HH
strychnine
7 rings1 basic N1 seven-membered ring1 alkene1 quaternary center6 stereogenic centers
17 points = 34 steps maximum
Funk Analysis
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