Case study #1: Strychnine · Case study #1: Strychnine N N O O H H H H STRYCHNINE LD50 = 0.16 mg/kg...

Case study #1: Strychnine

N

N

O

OH

H

HH

STRYCHNINE

LD50 = 0.16 mg/kg (rats)

Nature Chemistry 2009, 1, 193-205

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.

Strychnos nux vomica

seeds: 1.5% strychnine

Biosynthesis of Strychnine

"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".."

Sir Robert Robinson & Robert Burns Woodward Tetrahedron Publications

India

< Coromandel Coast

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."

Curare: alkaloid arrow poison extracts Central and South America

Strychnos toxifera

Calabash gourd

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


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


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


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


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


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


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


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


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


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


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


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

Shibasaki, et al., J.Am.Chem.Soc. 2002, 124, 14546-14547

Shibasaki: 31 steps

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



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


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%


2. Swern ox.

OH

1. KHMDS, THF

2. hν

isostrychnine

KOH, EtOH

85oC H

strychnine

H



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%


2. Swern ox.

OH

1. KHMDS, THF

2. hν

isostrychnine

KOH, EtOH

85oC H

strychnine

H



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

review: John Andraos Pure Appl. Chem., 2011, 83, 1361–1378.

Case study #1: Strychnine · Case study #1: Strychnine N N O O H H H H STRYCHNINE LD50 = 0.16 mg/kg...

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Transcript of Case study #1: Strychnine · Case study #1: Strychnine N N O O H H H H STRYCHNINE LD50 = 0.16 mg/kg...