total synthesis (±)-garcibracteatone - thieme connect · biomimetic total synthesis of...

2 0 1 3 © T H I E M E S T U T T G A R T • N E W Y O R K 1

H . P . P E P PE R , H . C . L A M , W . M . B L O C H , J . H . G E O RG E * ( U NI V E R S I T Y O F A D E L A I D E ,

A U S T R A L I A)

Biomimetic Total Synthesis of (±)-Garcibracteatone

Org. Lett. 2012, 14, 5162–5164.

Total Synthesis (±)-Garcibracteatone

Significance: Garcibracteatone (K) is the struc-turally most complex polycyclic polyprenylated acylphlorogucinol natural product that has so far been isolated. The four-step total synthesis pre-sented makes use of a biomimetic radical cas-cade reaction to build up four rings in one trans-formation. Additionally, the previously unknown relative stereochemistry at C-5 was assigned.

Comment: Precursor F for the key transformation is synthesized from phloroglucinol A in three steps by Friedel–Crafts acylation followed by subse-quent diprenylation and alkylation with (±)-lavan-dulyl iodide (E). Oxidation of F by using Mn(OAc)3–Cu(OAc)2 initiates a radical cascade, which ulti-mately leads to the formation of the natural prod-uct garcibracteatone K (14% yield) along with its C5-epimer L (8% yield). This key transformation constructs four rings and five stereocenters.

HO OH

OH

PhCOClAlCl3

47%

HO OH

OH

OPh

CKOH

34%

BrC

HO OH

OH

OPh

ENaH

29%

I

E

HO O

OH

OPh

Mn(OAc)3Cu(OAc)2

radicalcascade

HO O

O

OPh

7-endo-trig

HO O

O

OPh

5-exo-trig

5-exo-trig

HO O

O

OPh

aromatic radicalsubstitution

orsingle-electron

oxidation/Friedel–Crafts

HO O

O

OH

HO O

O

OHHO O

O

OH

H

H

+

14%Garcibracteatone (K)

8%5-epi-Garcibracteatone (L)

AB

DF

GHI

J

55

SYNFACTS Contributors: Erick M. Carreira, Stefan DiethelmSynfacts 03012013, 9(1), 0001 Published online: 17.12.20121 8 6 1 - 1 9 5 8 1 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317856; Reg-No.: C02812SF ©Georg Thieme Verlag Stuttgart · New York

Category

Synthesis of Natural Products and Potential Drugs

Key words

radical cascade

polyprenylated acylphloroglucinol

biomimetic synthesis

of the month

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2 0 1 3 © T H I E M E S T U T T G A R T • N E W Y O R K2

H . - S . O H , H . - Y . K A N G* ( C H UN G B U K N A T I O N A L U N I V E R S I T Y, R E P U B L I C O F K OR E A )

Synthesis of (–)-Oseltamivir Phosphate (Tamiflu) Starting from cis-2,3-Bis(hydroxymethyl)aziridine

J. Org. Chem. 2012, 77, 8792–8796.

Synthesis of (–)-Oseltamivir Phosphate

Significance: Oseltamivir phosphate (Tamiflu®) is a neuraminidase inhibitor that is widely prescribed for the treatment of various influenzas. The key step in this small-scale, 21-step synthesis is the enzymatic desymmetrization of the meso-diol A using Amano lipase PS. The diol A was prepared in six steps starting from cis-2-butene-1,4-diol.

Comment: For the enzymatic desymmetrization of closely related substrates, see: K. Fuji et al. Tetra-hedron Lett. 1990, 31, 6663. For a closely related strategy based on epoxide opening and ring-clos-ing metathesis, see: V. Rawat, S. Dey, A. Sudalai, Org. Biomol. Chem. 2012, 10, 3988.

A

OH

NBoc

OH

OH

NBoc

OAc

OAc

B (5.0 equiv)

Amano lipase PShexane–THF (10:1)

37 °C, 3 h68% (4.92 mmol scale)

Cer > 99:1

D

OTBS

NBoc

O

CO2Et

Br

E (3.0 equiv)

Zn (3.0 equiv)sat. aq NH4ClTHF, 0 °C, 4 h71% (dr = 3:1)

OTBS

NBoc

OH CO2Et

3 steps

71%

GH

OH

NBoc

OMs CO2Et

OTBS

NBoc

OMs CO2Et

MsCl (3.0 equiv)Et3N (3.5 equiv)

CH2Cl2, 0 °C to r.t.84%

TBAF (2.0 equiv)THF, r.t., 2 h

72%(2.62 mmol scale)

O

NBoc

OMs CO2Et

NBoc

OMs CO2Et

DMP (2.0 equiv)CH2Cl2, r.t., 2 h91% (1.89 mmol scale)

Ph3P=CH2(3.0 equiv)

THF, –20 °C, 3 h63%

J

Grubbs II (0.1 equiv)

CH2Cl2, 40 °C, 18 h55% (120 μmol scale)

CO2Et

NBoc

OMs

3-pentanol (solvent)BF3⋅OEt2 (1.5 equiv)

–8 °C, 1 h

CO2EtO

BocHN

OMs

Lmp 157 °C

84%

CO2EtO

AcHN

OMs

TFA, (20 equiv)CH2Cl2, r.t., 18 h

then Ac2OEt3N, r.t., 3 h

93% (110 μmol scale)

Mmp 137 °C

1. NaN3 (4.0 equiv) DMF, r.t., 18 h2. H2, Lindlar catalyst EtOH, r.t., 18 h

3. H3PO4, EtOH 81% (100 μmol scale)

CO2EtO

AcHN

NH2⋅H3PO4

Oseltamivir Phosphatemp 202 °C

F

I K

SYNFACTS Contributors: Philip KocienskiSynfacts 03012013, 9(1), 0002 Published online: 17.12.20121 8 6 1 - 1 9 5 81 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317719; Reg-No.: K09212SF ©Georg Thieme Verlag Stuttgart · New York

Category


Key words

oseltamivir phosphate

Tamiflu

enzymatic desymmetrization

ring-closing metathesis

aziridine ring opening

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A . K . G H O S H, * X . C H E N G , B . Z H O U ( P U R D U E U N I V E R SI T Y, WE ST L A F A Y E T T E , U S A)

Enantioselective Total Synthesis of (+)-Lithospermic Acid

Org. Lett. 2012, 14, 5046–5049.

Synthesis of (+)-Lithospermic Acid

Significance: This elegant synthesis of the HIV in-tegrase inhibitor lithospermic acid features (1) an enantioselective intramolecular oxa-Michael reac-tion; (2) an oxidative ring contraction of the chro-manone F; and (3) an intermolecular palladium-catalyzed C–H olefination used to append acrylate ester K to J.

Comment: The enantiomeric ratio of F improved to 99:1 after one recrystallization. The presence of the two electronegative bromine atoms on chro-manone F were essential for the success of the oxidative ring contraction mediated by phenyl-iodonium bis(trifluoroacetate).

A

EMeO

OH O

O Ot-BuMeO

OH O

O Ot-Bu

Br

Br N

N H

OH

OBnO

Br

BrH

NH•HOAc

B (1.0 equiv)

C (0.05 equiv)PhH, Δ, 6 h

27% (7.9 mmol scale)

1. E (0.2 equiv) PhMe, r.t., 2 d2. TsOH (0.2 equiv) PhMe, 80 °C, 2 h97% (2.72 mmol scale)

Dmp 128 *C

O

O

OMeBr

Br

OMe

Br

Br

O

CO2Me

Fmp 136 °Cer = 95:5

PhI(O2CCF3)2 (1.1 equiv)HC(OMe)3 (0.37 equiv)

HCO2H (0.1 equiv)

H2SO4 (25 equiv)r.t., o/n

61% (1.0 mmol scale)G

IOMe

Bpin

Bpin

O

CO2Me

OBH

O

H (11 equiv)

PEPPSI (0.11 equiv)dioxane–Et3N, 110 °C, o/n


OMe

O

CO2R

O

O

1. H2O2, NaOH THF, 0 °C, 30 min

2. Me2C(OMe)2 TsOH, CHCl3, 55 °C3. Ba(OH)2, THF–MeOH 65%

O O

MeO2C

OMe

OMe

O

CO2H

OMe

O O

MeO2C

OMe

OMe

O

O

L

K (1.8 equiv)Pd(OAc)2 (0.07 equiv)Ac-Ile-OH (0.1 equiv)

O2, t-AmOH, 85 °C, 6 h89% (brsm, 0.3 mmol scale)

J

O

CO2H

OH

OHOH

O O

HO2C

OH

OH 3 steps

32%

(+)-Lithospermic Acid

K

SYNFACTS Contributors: Philip KocienskiSynfacts 03012013, 9(1), 0003 Published online: 17.12.20121 8 6 1 - 1 9 5 8 1 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317722; Reg-No.: K09512SF ©Georg Thieme Verlag Stuttgart · New York

Category


Key words

lithospermic acid

HIV integrase

organocatalysis

asymmetric oxa-Michael reaction

oxidative ring contraction

C–H activation

of the month

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J . B E L M A R , R . L . F U N K* ( P E N N S YL VA N I A ST AT E UN I V E R S I T Y, U S A)

Total Synthesis of (±)-Communesin F via a Cycloaddition with Indol-2-one

J. Am. Chem. Soc. 2012, 134, 16941–16943.

Total Synthesis of Communesin F

Significance: The stereochemically complex polycyclic structure of the communesins has attracted the interest of several researchers and led to the total syntheses of communesin A, B and F. Funk and co-worker now report an elegant and concise synthesis of the moderately cytotoxic communesin F that relies on an unusual Diels–Alder cycloaddition of indol-2-one, a reaction developed by the group. Its considerable synthet-ic utility has previously been demonstrated in the total synthesis of perophoramidine and is now fur-ther showcased by the synthesis of communesin F in only 15 steps and an overall yield of 6.7%.

Comment: Indol-2-one B was generated from bromooxindole A and underwent smooth cyclo-addition with indole C to afford E via intermediate D. Tosylation of the amide followed by methano-lysis led to formation of aminal F. Advanced tetra-cyclic intermediate G was obtained in three more steps. Heck reaction of G with alcohol H, followed by a high-yielding mercuric-triflate promoted cycli-zation to the benzazepine gave I. Cyclization to the bridged lactam J could not be achieved under thermal conditions, but exposure to trimethyl alu-minum effected the desired transformation. Syn-thetic communesin F was obtained after four more steps.

N

NH

N

Me

H

N

O

Communesin F

NH

O

Br

NO

NH

Br

NH

N

OH

N3

Br

N

HNO

Br

N3

H

Ag2CO3 (0.8 equiv)MeCN, r.t., 16 h

70%

N3

indol-2-one (B)

cycloaddition

NaH, TsCl, THF0 °C, 30 min

then MeOHr.t., 16 h

61%NH

N

CO2MeH

N3

Br

Ts

H

N

NH

Br

Me

H

BocHNHOMeO

N

NH

NBoc

Me

H

OMeO

H

N

NH

N

Me

H

OH

4 steps

3 steps

1. Pd(OAc)2

K2CO3, H2O H, DMF, 90 °C

OH2. Hg(OTf)2

CH2Cl2 r.t., 20 h

80% over2 steps

1. TBSOTf, CH2Cl2 lutidine, r.t., 3 h KF, MeOH, r.t., 1 h

2. AlMe3, CH2Cl2 0 °C, 1 h

82% over2 steps

A

C

D

EFG

IJ

H

39%

43%

SYNFACTS Contributors: Erick M. Carreira, Simon KrautwaldSynfacts 03012013, 9(1), 0004 Published online: 17.12.20121 8 6 1 - 1 9 5 81 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317850; Reg-No.: C02212SF ©Georg Thieme Verlag Stuttgart · New York

Category


Key words

communesin F

indol-2-one

Diels–Alder cycloaddition

mercuric triflate

trimethyl aluminum

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Z . S H I * E T A L . ( B R I S T O L - M Y E R S S Q U I B B C O . , N E W B R U NS W I C K A N D P R I N C E T O N , US A )

Development of a Practical Synthesis of a p38 Kinase Inhibitor via a Safe and Robust Amination

Org. Process Res. Dev. 2012, 16, 1618–1625.

Synthesis of a p38 Kinase Inhibitor

Significance: The target pyrrolotriazine is a p38 kinase inhibitor that was a lead compound for the treatment of rheumatoid arthritis. The synthesis depicted features a safe and scalable N-amination of the pyrrole F using O-(4-nitrobenzoyl)hydroxyl-amine (G). The synthesis delivered 1.6 kg of active pharmaceutical ingredient (API) in 26% overall yield.

Comment: Competing ester hydrolysis products generated in the condensation of E to the pyrrole F were minimized by adding ethyl trifluoroacetate as a water scavenger. A large-scale process for the synthesis of the crystalline O-4-(nitrobenzoyl)-hydroxylamine (G) is described.

A C

H2NO

HNOMe

NN

N

EtO

O

OH

O

EtO

O

O

EtO O

NH

OEt

O

NH

O

EtON

O

EtO

EtO

O

NH2

O

EtO

O

NMe2

Me2N–CH(OMe)2

B (1.04 equiv)

TsOH⋅H2O (0.0014 equiv)55–60 °C, 1 h

(888 mol scale)

OEt

O

NH2⋅HCl

CO2EtD (1.0 equiv)

EtOH, 45–53 °C, 30 min78% from A

Emp 70 °C

t-AmOK (2.8 equiv)F3CCO2Et (1.3 equiv)

EtOH, 60–63 °C, 1 h67% (37 mol scale)

Fmp 89 °C

O2NONH2

O

G (1.0 equiv)

t-BuOK (1.1 equiv)NMP–THF (7:3)20–32 °C, 2 h

(44.4 mol scale)

H3PO4 (0.2 equiv)HCONH2 (solvent)120–125 °C, 20 h79% from F

Imp 215 °C

POCl3 (1.23 equiv)DIPEA (1.22 equiv)

PhMe, Δ, 22 h(7 mol scale)

J (1.03 equiv)

DIPEA (1.65 equiv)DMF, 58 °C, 3 h

82% from I

⋅HCl

NN

N

EtHN

O

HNO

HNOMe

NN

N

EtO

O

HNO

HNOMe

Kmp not reported

NN

N

HO

O

HNO

HNOMe

NaOH, H2O60–65 °C, 6 h88% (5.4 mol scale)

Lmp not reported

EDAC⋅HCl, HOBtaq EtNH2 (70 wt%)

DMF, 30–35 °C, 1 h88% (4.7 mol scale)

p38 Kinase Inhibitormp not reported

H


Category


Key words

p38 kinase inhibitors

amination

O-(4-nitrobenzoyl)-hydroxylamine

pyrrolotriazines

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M . S E K I* ( M I T SU B I S HI TA N A B E PH A R M A C O R PO R A T I O N , OS A K A , JA P A N)

An Efficient C–H Arylation of a 5-Phenyl-1H-tetrazole Derivative: A Practical Synthesis of an Angiotensin II

Receptor Blocker

Synthesis 2012, 44, 3231–3237.

Synthesis of Candesartan Cilexetil

Significance: Candesartan cilexetil (Atacand®) is an angiotensin II receptor antagonist that is pre-scribed for the treatment of hypertension. It is a prodrug that is hydrolyzed to candesartan in the gut. The synthesis depicted, features an efficient protocol for ruthenium-catalyzed C–H arylation of the tetrazole A.

Comment: A significant challenge in this small-scale synthesis was the final removal of the benzyl protecting group from the tetrazole unit using transfer hydrogenation. Best results were ob-tained using a ‘thickshell’ Pd/C catalyst from Evonik.

OAc

N

NN

N Bn

Br

[RuCl2(p-cymene)]2 (0.63 mol%)Ph3P (1.25 mol%)K2CO3 (2.0 equiv)

NMP, 140 °C, 9 h80% (4.57 mmol scale)

A (1.0 equiv) B (1.1 equiv)

+

N

NN

N Bn

OAc

Cmp 73 °C

NO2

NHBoc

CO2MeN

NN

N Bn

Br

N

NN

N BnN

H

NO2

MeO O

Dmp 71 °C

E (1.03 equiv)

K2CO3 (1.5 equiv)MeCN, Δ, 9 h

81% (24 mmol scale)

HCl (3.0 equiv)

MeOH, r.t., o/n86% (19.2 mmol scale)

Fmp 115 °C

N

NN

N BnN

H

NH2

MeO O

Gamorphous solid

1. C(OEt)4 (1.3 equiv) AcOH (8 mL) 90 °C, 1 h

2. NaOH (3.0 equiv) MeOH–H2O, 90 °C, 2 h 58.5%

N

NOEt

N

NN

N BnOHO

Hmp 171 °C

88% 2 steps

SnCl2⋅2H2O (3.7 equiv)MeOH, Δ, 2 h84% (16.1 mmol scale)

N

NOEt

N

NN

N HOOOO

O

Candesartan Cilexetilmp 162 °C

HCO2NH4 (4.8 equiv) 5% Pd/C

i-PrOH–H2O (5:3)45 °C, 23 h

80%

OO

O

ClI (1.2 equiv)

K2CO3 (1.6 equiv)DMF, 65 °C, 4 h



Category


Key words

candesartan cilexetil

angiotensin II receptor antagonists

C–H arylation

ruthenium

transfer hydrogenation

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N . S H I M A D A, Y . AB E , S . YO K O S H I M A , T . F UK U Y A M A * ( T H E U N I V E R SI T Y OF TO K Y O,

J A P AN )

Total Synthesis of (–)-Lycoposerramine-S

Angew. Chem. Int. Ed. 2012, 51, 11824–11826.

Total Synthesis of (–)-Lycoposerramine-S

Significance: Fukuyama and co-workers report the first total synthesis of the caged tetracyclic Lycopodium alkaloid (–)-lycoposerramine-S. The enantioselective synthesis is centered around an impressive 1,3-dipolar cycloaddition which dia-stereoselectively constructs the central penta-substituted pyrrolidine ring utilizing a chiral morpholinone. A radical cyclization and alkylative ring closure of the nine-membered ring using a 4-nitrobenzenesulfonyl amide leads to the synthe-sis of the natural product in only 14 steps.

Comment: In a striking intramolecular 1,3-dipolar cycloaddition, condensation of aldehyde D with morpholinone E led to the diastereoselective for-mation of pyrrolidine G containing four newly con-structed contiguous stereocenters in excellent yield. The formation of the 2,5-cis relationship is thought to arise from preferential formation of Z-azomethine ylide F. Exhaustive reduction, selec-tive elimination of the resulting secondary alcohol followed by a radical annulation led to tricycle J. Finally, the medium-sized ring was assembled by use of alkylative nosyl amide chemistry previously developed by the Fukuyama group.

I

OTBS

O

TBSOOTBS

O

4 steps

37%

O

HN

O

H

H

A

D

E

PhMe, Δ

O

OTBS

N

OH

H

O OTBS

F

O

OTBS

N

OH

H

O OTBS

H

H

G

1. Red-Al, PhMe2. H2, Pd(OH)2/C, Boc2O, EtOAc

3. methoxyacetyl chloride, TMEDA, PhMe then ClCH2SO2Cl, TMEDA then K2CO3, MeOH, Δ

OTBS

BocN

OTBSOH

60%

1. PhOCSCl, DMAP, MeCN2. I, TMS3SiH, PhMe

69%

OH

BocN

OH

H

H

H

1. MsCl, TMEDA, CH2Cl22. K, Cs2CO3, TBAI, DMF

3. PhSH, Cs2CO3, MeCN then aq HCOH, NaBH(OAc)34. TFA, CH2Cl2

intramolecular 1,3-dipolar cycloaddition

35%

SNH2

O2N

O O

K

J

NN

NCOMe

MeOCN

V-70 (I)

HNH

NMe

(–)-Lycoposerramine-S

86%

HN

NMe

H

H

25

O

O

CB

OTBS

SYNFACTS Contributors: Erick M. Carreira, Simon BreitlerSynfacts 03012013, 9(1), 0007 Published online: 17.12.20121 8 6 1 - 1 9 5 8 1 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317853; Reg-No.: C02512SF ©Georg Thieme Verlag Stuttgart · New York

Category


Key words

lycoposerramine-S

azomethine ylides

1,3-dipolar cycloaddition

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J . WI L L W A C H E R , N . K A U S C H - B US I E S , A . F Ü R S T N E R * ( M A X - P L A NC K - I N S T I T U T F Ü R

K O H L E N F OR S C H U N G , M Ü L H E I M A N D E R R U H R, G E R M AN Y )

Divergent Total Synthesis of the Antimitotic Agent Leiodermatolide

Angew. Chem. Int. Ed. 2012, 51, 12041–12046.

Synthesis of (–)-Leiodermatolide

Significance: Leiodermatolide is an antimitotic macrolide isolated in 2011 from the deep-water sponge Leiodermatium sp. that exhibited potent and selective in vitro cytotoxicity against various human cancer cell lines (IC50 < 10 nM). Although the natural product was shown to induce cell cycle arrest at the G2/M transition, it had no effect on purified tubulin, indicating a novel mode of action. In addition to the promising biological activity, leiodermatolide posed an interesting tar-get for synthetic studies, as the segregated stereo-clusters within the macrolactone and the δ-lac-tone terminus could not be assigned unambiguously.

Comment: In order to address this issue, a strategy was chosen, in which the δ-lactone subunit F was merged with macrocycle E at a late stage of the synthesis, granting access to either conceivable diastereomer of the target. The assembly com-menced with esterification of A and B, giving diyne

C, which underwent efficient cyclization using mo-lybdenum complex D as a catalyst precursor. Suzuki–Miyaura coupling of vinyliodide E and boro-nate F gave intermediate G, which was advanced to leiodermatolide in four further steps, including Zn(Cu–Ag)-mediated enyne semi-reduction to the corresponding Z,Z-configured diene. Subtle dif-ferences in the 1H NMR data of the respective iso-mers allowed for a conclusive stereochemical as-signment of the natural product.

O

O

O

O

ROOH

O

OH2N

O

O

O

O

MOMOOH

TBSO

O

O

IMOMO

TBSO

O

O

I

MOMO

TBSOOH

I

O

O

OH

BOO

NMeOO

EDCI⋅HClDMAP

CH2Cl2, 0 °C89 %CO2H

MOMO

OR

R = TBS

A

B C

E

N MoNN t-Bu

ArAr

t-Bu t-Bu

Ar

CH2Cl2PhMe, 100 °C

72%

F

[Pd(PPh3)4] (20 mol%)Tl(OEt)THF−H2O (3:1), r.t.

0.5 M HClMTBE, r.t.

1.

2.

56 %

G

1. TBAF, 4 Å MS THF, 0 °C2. Zn(Cu–Ag) THF–MeOH–H2O (1:1.8:1.8), 50 °C

3. Cl3CC(O)NCO CH2Cl2, –78 °C then Al2O3

H (R = MOM)

(–)-Leiodermatolide (R = H)

Me2BBr, CH2Cl2–90 to –78 °C

61 %64%

ring-closingalkyne

metathesis

D (40 mol%)

alkyne semi-reduction

Suzuki–Miyaura coupling

SYNFACTS Contributors: Erick M. Carreira, Oliver F. JekerSynfacts 03012013, 9(1), 0008 Published online: 17.12.20121 8 6 1 - 1 9 5 81 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317854; Reg-No.: C02612SF ©Georg Thieme Verlag Stuttgart · New York

Category


Key words

(–)-leiodermatolide

alkyne metathesis

antitumor agents

structure elucidation

molybdenum

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Y . Z H A O* E T A L . ( TA K E D A C A L I F O R N I A, S A N D I E G O , M I L L E N I U M P H A R M A C E U T I C A L S

I N C . , C A M B R I DG E A N D I R I X PH A R M A C E U T I C A L S , G R E E N V I L L E , U S A)

Process Research and Kilogram Synthesis of an Investigational, Potent MEK Inhibitor


Synthesis of TAK-733

Significance: MEK kinases regulate the pathway that mediates proliferative and anti-apoptotic sig-naling factors that promote tumor growth and me-tastasis. TAK-733 is an MEK kinase inhibitor that entered phase I clinical trials for the treatment of cancer. A noteworthy feature of this short synthe-sis (25% yield overall) is the one-pot, three-step synthesis of the fluoropyridone D, in which the flu-orine atom is present at the outset.

Comment: The reaction of F with the nosylate G gave a mixture of N- and O-alkylation products (8:1) from which the desired N-alkylation product was isolated by crystallization. The mixture of N-methyl pyrrolidine (NMP) and methanol used in the final deprotection step, helped to ensure for-mation of the desired polymorph. The nine-step discovery synthesis (3% overall yield) is also pre-sented.

ONs

OO

F I

H2N

N O

Me

Cl

FNC

H2NN O

Me

Cl

F

N

HN

O

N O

Me

Cl

F

N

N

O

O

O

N O

Me

F

N

N

O

O

O

F I

HN

N

N N

HO

HO

O

Me

O

F

HN

F I

Emp not reported

HCO2H (42 equiv)H2SO4 (14 equiv)

75 °C, 20 h86% (40.2 mol scale)

Fmp not reported

G (1.2 equiv)

DBU (1.6 equiv)i-PrOH, 63 °C, 63 h

66% (41.2 mol scale)H

mp not reported

I (1.0 equiv)LHMDS (1.95 equiv)THF, –5 °C to r.t., o/n93% (27 mol scale)

concd HCl

NMP–MeOH, 55 °C, 2 h84% (25 mol scale)

Jmp not reported

TAK-733mp not reported

>99.5% ee

A C

FO

OMe

OMeO

CNNC

F

OH

OMeO

NC

NC

B (1.0 equiv)

DBU (2.0 equiv)THF, r.t., 16 h(20 mol scale)

40% aq MeNH2 (6.65 equiv), r.t., 2 h

then NaOH (1.5 equiv), r.t., 5 h80% from A

N O

Me

OH

FNC

H2N

Dmp not reported

POCl3 (3.0 equiv)MeCN, Δ, 3 h

67% (16.4 mol scale)

I


Category


Key words

TAK-733

MEK inhibitors

3-fluoropyridone

cascade reaction

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J . R . D U N E T Z , * M . A . B E R L I NE R* E T AL . ( PF I Z E R WO R L D W I DE R E S E A R C H A N D

D E V E L O P M E N T , G R O T O N , U S A AN D S A N D W I C H , UK ; A S Y M C H E M L I FE S C I E N C E C O . ,

TI AN J I N , P. R . O F C H I N A )

Multikilogram Synthesis of a Hepatoselective Glucokinase Activator


Synthesis of a Glucokinase Activator

Significance: Glucokinase mediates glucose me-tabolism in the liver and insulin release in the pan-creas. The target molecule selectively activates liver glucokinase with diminished risk of hypogly-cemia. It is a lead for the treatment of type 2 dia-betes. A major challenge in the synthesis depicted was the formation of amide I by the condensation of the racemization-prone carboxylic acid G with the weakly nucleophilic 6-aminonicotinic ester H. Best results were obtained using n-propane-sulfonic anhydride (T3P) as the condensing agent.

Comment: The N-alkylation of imidazole E was studied extensively to achieve high regioselectivity with minimal racemization. Best results were ob-tained using potassium phosphate as base and ethyl acetate as solvent, in which case the regio-selectivity was 96:4. The unwanted regioisomer and epimer was removed by crystallization of the salt prepared from (R)-α-methylbenzylamine. A further complication was the hydrolytic lability of the hard-won amide bond in I.

A

C D

E

O

N

NCF3

MgBr

N

HN

CF3

H2N

N OBn

O

O

OH

O

N

NH

N OBn

O

NCF3

O

N

NCF3

OMe

O

OMe

OTf

O

OMe

OH

OOMe

B (1.1 equiv)

Li2CuCl4 (0.1 equiv)THF–Et2O, –78 to –50 °C, 30 min

65–70% (245 mmol scale)

J. Med. Chem. 2012, 55, 1318

Tf2O (1.2 equiv)2,6-lutidine (1.25 equiv)

hexanes–PhMe (4:1)–15 to 0 °C, 3 h

94% (87 mol scale)

E (1.0 equiv)K3PO4 (2.0 equiv)

EtOAc, 0 °C, 7 h90% (79 mol scale)

Fer = 98:2

NaOH (3.1 equiv)PhMe,15–20 °C, 6 h

then aq HCl to pH 3

Ger = 97:3

NH2Ph

O

N

NCF3

OH

1. (1.1 equiv) MTBE–acetone (10:1) 20 °C, 3 h

2. aq HCl to pH 3 recrystallize from MTBE–heptane 78% (from F)

Gmp 160 °Cer > 99:1

H (1.1 equiv)

T3P (2.0 equiv)py (3.375 equiv)

MeCN–EtOAc (2:1), 0 °C, 20 h88% (80 mol scale)

O

N

NH

N OH

O

NCF3

Imp 170 °C

20% Pd/CHCO2H (10% v/v) EtOAc, 55 °C, 6 h

recrystallize from heptane81% (85 mol scale)

Glucokinase Activatormp 187 °C

er > 99:1, ≤ 1 ppm Pd>110 kg from five batches

T3P = n-propanesulfonic anhydride


Category


Key words

glucokinase activators

amide bond formation

n-propanesulfonic anhydride

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ADDENDA AND ERRATA ▌1

Erratum

Synthesis of a Glucokinase ActivatorJ. R. Dunetz,* M. A. Berliner* et al. Synfacts 2013, 9, 10.

T3P was misrepresented. T3P is n-propanephosphonic acid anhydride. We apologize for this mistake.

SYNFACTS 15022013, 93, 0001Advanced online publication: 1 8 6 1 - 1 9 5 81 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1318317; Art ID: r10313sf© Georg Thieme Verlag Stuttgart · New York

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X . - F . YA NG , C . - H . D I N G , X . - H . L I , J . - Q . H UA N G , X . - L . H O U , * L . - X . D A I , P. - J . WA N G

( S H A N G H A I I N ST I T UT E OF O RG A N I C C H E M I S T R Y, P. R . O F C H I N A )

Regio- and Enantioselective Palladium-Catalyzed Allylic Alkylation of Nitromethane with Monosubstituted Allyl

Substrates: Synthesis of (R)-Rolipram and (R)-Baclofen

J. Org. Chem. 2012, 77, 8980–8985.

Synthesis of (R)-Rolipram

Significance: Rolipram is a phosphodiesterase-4 (PDE-4) inhibitor that displays potentially useful anti-inflammatory, antidepressant and antipsy-chotic effects. The key step in the micro-scale synthesis depicted is the palladium-catalyzed asymmetric allylic alkylation of nitromethane with the allylic carbonate A. High regio- and enantio-selectivities were observed using the ferrocene-based SIOCPhox chiral ligand B.

Comment: The scope of the asymmetric allylic alkylation of nitromethane was explored using eleven aryl-substituted allyl methyl carbonates giving yields of 80–92% (one exception) and enan-tiomeric excesses of 90–98%. The reaction was also applied to an asymmetric synthesis of the anti-spasmodic agent (R)-baclofen.

Cmp 56 °Cer > 98:2

A

EF

O

OMe

O OMe

O

O

OMe

NO2

O

OMe

NO2OH

O

OMe

CHONO2

O

OMe

CO2HNO2

O

OMe

NOH

H

FeN

O

PNEt2

ORR = (R)-2′-hydroxy-1,1′-binaphthyl-2-yl

B (0.1 equiv)

MeNO2 (1.0 equiv)Pd2dba3⋅CHCl3 (0.05 equiv)

DABCO (1.0 equiv)THF, r.t., o/n

87% (100 μmol scale)

9-BBN (4.0 equiv)THF, r.t., 20 h

then H2O2, NaOH67% (100 μmol scale)

Dmp 72 °C

Dess–Martin oxidation71% (140 μmol scale)

NaClO2 (3.0 equiv)NaH2PO4 (2.0 equiv)

2-methyl-2-butene

t-BuOH–H2O, 0 °C, 2 h(100 μmol scale)

DCC, DMAP

MeOH, r.t.66% from E

O

OMe

CO2MeNO2

Gmp 103 °C

NiCl2⋅6H2O (1.7 equiv)NaBH4 (1.7 equiv)EtOH, 0 °C, 2 h85% (60 μmol scale)

(R)-Rolipram

Cl

CO2HH3NH

(R)-Baclofen Hydrochloride

Cl–

+


Category


Key words

(R)-rolipram

(R)-baclofen

asymmetric allylic alkylation

nitromethane

allyl carbonates

palladium

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H . - J . YU, C . S H AO , Z . C U I , C . - G . F E N G, * G. - Q . L I N * ( S H A N G HA I I N S T I T U T E O F O RG A N I C

C HE M I S T RY, P. R . O F C H I N A )

Highly Enantioselective Alkenylation of Cyclic α,β-Unsaturated Carbonyl Compounds as Catalyzed by a Rhodium–

Diene Complex: Application to the Synthesis of (S)-Pregabalin and (–)-α-Kainic Acid

Chem. Eur. J. 2012, 18, 13274–13278.

Synthesis of Pregabalin

Significance: Pregabalin (Lyrica®) is a lipophilic GABA analogue that is prescribed for the treat-ment of epilepsy. This short, small-scale synthesis of pregabalin features a highly enantioselective asymmetric conjugate addition of the alkenyl tri-fluoroborate B to the α,β-unsaturated lactam A catalyzed by a rhodium complex incorporating the chiral bicyclo[3.3.0]octa-2,5-diene ligand L.

Comment: A further 17 examples of this new vari-ant of the Hayashi–Miyaura asymmetric conjugate addition reaction are reported using six α,β-un-saturated carbonyl substrates and ten alkenyl tri-fluoroborates. The asymmetric conjugate addition was also applied to the synthesis of the potent neuroexcitatory agent α-kainic acid (seven steps, 40% overall yield).

A D

N

O

Boc N

O

Boc N

O

Boc

OH

O

NH2⋅HCl

H

H

Ph

Ph

BF3K

B (2.0 equiv)

[Rh(OH)(L)]2 (2.5 mol%)Et3N (2.0 equiv)

PhMe–H2O, r.t., 15 min97% (0.2 mmol scale)

Cer > 99:1

H2 (15.2 bar), Pd/C

MeOH, r.t., 8 h100% (1.25 mmol scale)

6 M HCl, Δ, 8 h96% yield (0.56 mmol scale)

Pregabaliner = 96:4

mp not reported

L

N

O

BocO

O O

O

O

O

N

O

Boc

99% (91% ee) 74% (93% ee) 93% (78% ee)

93% (99% ee) 78% (99% ee) 97% (99% ee)

NH

CO2H

CO2H

(–)-a-Kainic Acid

Further examples of adducts derived from the asymmetric conjugate addition reaction:


Category


Key words

pregabalin

kainic acid

Hayashi–Miyaura asymmetric conjugate addition

rhodium catalysis

alkenyl trifluoroborates

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J . L I , Y . C A I , W . C H E N , X . L I U , L . L I N , X . F E N G * ( S I C H U A N U N I VE R S I T Y, C H E N GD U ,

P. R . O F C H I N A)

Highly Enantioselective Fluorination of Unprotected 3-Substituted Oxindoles: One-Step Synthesis of BMS 204352

(Maxipost)

J. Org. Chem. 2012, 77, 9148–9155.

Synthesis of Maxipost

Significance: Maxipost is a post-stroke neuro-protective agent that acts by opening large con-ductance Ca2+-activated (maxi-K) potassium channels. Previous syntheses of maxipost by asymmetric fluorination of oxindoles required pro-tection of the oxindole nitrogen as the N-Boc de-rivative. The route depicted features the direct asymmetric catalytic fluorination of the oxindole A using N-fluorobenzenesulfinimide (B) in the pres-ence of 10 mol% of a chiral complex derived from scandium triflate and the amine oxide ligand C.

Comment: Attempts to perform the maxipost synthesis on a 3.5 mmol scale resulted in de-creased yield and enantioselectivity (53% yield, 86% ee) due to the low solubility of the substrate. By constrast, the asymmetric fluorinaton of ox-indole D on a 4.0 mmol scale gave E in 93% yield and 97% ee. The small selection of the 29 exam-ples described, showed that yields and enantio-selectivities are generally high.

N

N HOO

NO

H NO

F N

SO2Ph

SO2Ph

F3C NH

SS

F

O

Cl

MeO

F3C NH

H

O

Cl

MeO

+

rac-A (100 μmol) B (1.5 equiv)

C (0.1 equiv)

Sc(OTf)3 (0.1 equiv)Na2CO3 (1.2 equiv)

CHCl3 (2 mL), –30 °C, 3 d81% (er = 98:2)

Asymmetric fluorination of oxindole D on a gram scale:

F N

SO2Ph

SO2Ph

NH

O

+

D (4.0 mmol) B (1.2 equiv)

C (0.05 equiv)Sc(OTf)3 (0.05 equiv)Na2CO3 (1.2 equiv)

CHCl3 (10 mL), 0 °C, 3 d93% (er > 98:2)

NH

O

(S)-Maxipostmp 196 °C

OMe OMe

H F

Estereochemistry not established

NH

O

F

NH

O

F

NH

ORR

S

F

NH

O

N

F

81% (er > 97:3) 85% (er > 96:4) 90% (er > 98:2) 84% (er > 95:5)

Further examples of the asymmetric fluorination of oxindoles:


Category


Key words

maxipost

asymmetric fluorination

scandium triflate

N-fluorobenzene-sulfonimide

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J . F . B L A K E* E T A L . ( A R R A Y B I OP H A R M A I NC . , B OU L D E R A N D GE NE NT E CH I N C . , S O U T H

S A N FR A N C I S C O, U S A )

Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the

Treatment of Human Tumors

J. Med. Chem. 2012, 55, 8110–8127.

Synthesis of Akt Inhibitor GDC-0068

Significance: Akt is a kinase that controls cellular processes by phosphorylating substrates involved in apoptosis, transcription, cell cycle progression and translation. GDC-0068 is an Akt inhibitor that is in clinical trials for the treatment of cancer.

Comment: Key steps in the synthesis depicted are (1) the use of a Favorskii ring contraction in the conversion of (R)-pulegone (A) to the ester B and (2) the Noyori asymmetric transfer hydrogenation of ketone J.

B

OOEt

OH

Ac2O (14 equiv)100 °C, 2 h

89%126 mmol scale

1. Br2 (1.02 equiv) NaHCO3 (0.5 equiv) Et2O, 0 °C

2. NaOEt (2.2 equiv) EtOH, 0 °C to r.t. 64% (3.94 mol scale)

Favorskii reaction

1. O3, EtOAc then Zn, AcOH

2. NH4OAc, MeOH 86% C

NH2

OEt

O

N

N

OHHCO2NH4H2N–CHO

150 °C, 24 h66%

EN

N

N

N

Boc

N

N

ClNH

N

Boc

F (1.05 equiv)

DIPEA (3.0 equiv)t-BuOH, Δ, 16 h

81%Gmp not reported

N

N

N

N

Boc

O–

MCPBA NaHCO3

CHCl3, r.t., 4.5 h100%

H

N

N

N

N

Boc

AcO Icis/trans = 3:2

N

N

N

N

Boc

ON

N

N

N

Boc

HO

Cl

N

O

N

N

N

N

HO

Cl

NH

O

N

N

N

N

HO

Boc

Cl

N

O

OH

Boc

RuCl(p-cymene)(R,R)-TsDPEN(0.005 equiv)

HCO2H (1.23 equiv)

Et3N (1.06 equiv)CH2Cl2, r.t., o/n


J Kmp not reported

er = 97:3

N

N

N

N

H

HO

HCl (14 equiv)dioxane–CH2Cl2

0 °C to r.t.89% (34.4 mmol scale)

⋅2HCl

Lmp not reported

M (1.0 equiv)

HBTU (1.0 equiv)DIPEA (3.0 equiv)

CH2Cl2, 4 h87% (6.5 mmol scale)

Nmp not reported

HCl (20 equiv)

dioxane, r.t., o/n90% (4.5 mmol scale)

⋅2HCl

GDC-0068mp not reported

Noyori asymmetrictransfer hydrogenation

POCl3DCE, Δ48%

2 steps70%

A D


Category


Key words

GDC-0068

serine/threonine kinase

Akt inhibitor

Favorskii ring contraction

Noyori asymmetric transfer hydrogenation

pyrimidine N-oxide rearrangement

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C . R . E DW A N K AR , R . V . E D W A N KA R , J . R . D E S C H A M P S , J . M . C O OK * ( U NI VE R S I T Y O F

WI SC O N SI N- M I L W A U K E E A N D N AV A L R E S E A R C H L A B O R A T OR Y, WA S H I NG T O N , D . C . ,

U S A)

Nature-Inspired Stereospecific Total Synthesis of P-(+)-Dispegatrine and Four Other Monomeric Sarpagine Indole

Alkaloids

Angew. Chem. Int. Ed. 2012, 51, 11762–11765.

Total Synthesis of the Dimeric Sarpagine Indole Alkaloid P-(+)-Dispegatrine

Significance: Reported in this work is the first total synthesis of P-(+)-dispegatrine, a complex dimeric sarpagine indole alkaloid, which has been shown to exhibit anti-hypertensive activity due to its affinity to both the α1 and α2 adrenoreceptors. In addition to an efficient asymmetric route, the synthetic efforts toward this natural product have also led to the determination of the absolute con-figuration around the biaryl axis, which had previ-ously been left unassigned by the isolation group.

Comment: The most notable feature in the syn-thetic route presented above is a thallium-mediated oxidative dimerization of (+)-lochnerine (E) which re-gioselectively delivers the desired dimer F. Thereby, the rigid chiral framework of the monomer dictates atroposelection during the dimerization reaction, leading exclusively to the naturally occuring atro-podiastereomer (P-isomer). This and similar re-sults from an earlier semi-synthetic study led to the proposal that the biaryl coupling might closely parallel the biosynthetic route.

NNH

H

H

MeO

NNH

H

H

MeO

O

I

NH

MeO

NH2

CO2HH 6 steps

Pd(PPh3)4 (6 mol%)PhOH, t-BuOK, THF

75 °C, 8 h

73%

NNH

H

H

MeO

OR

NNH

H

H

MeO

OH

NHN

H

H

OMe

HO

NNH

H

H

HO

OH

NHN

H

H

OH

HO

Me

Me

Cl

Cl

MeOCH2PPh3Cl, t-BuOK PhH; then 2 M HCl–THF, Δ

90%

1. BBr3, CH2Cl2, –78 °C to r.t.2. MeI–MeOH, 40 °C; then AgCl, MeOH, r.t., 2 d

56%

Tl(OAc)3 (0.65 equiv)BF3⋅OEt2 (3 equiv), MeCN

–40 to –10 °C, 90 min

53%

A B

C

E R = CH2OH: (+)-Lochnerine

P-(+)-Dispegatrine

analogous to:J. M. Cook and co-workers

J. Org. Chem. 2003, 68, 6279.

D R = CHO: (+)-MethoxyvellosimineNaBH4, EtOH90%

F

thallium-mediatedoxidative biaryl coupling

observed as single atropodiastereomer

palladium-catalyzedcarbonyl vinylation

–

+

+

–

SYNFACTS Contributors: Erick M. Carreira, Nikolas HuwylerSynfacts 03012013, 9(1), 0015 Published online: 17.12.20121 8 6 1 - 1 9 5 8 1 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317855; Reg-No.: C02712SF ©Georg Thieme Verlag Stuttgart · New York

Category


Key words

dispegatrine

sarpagine alkaloids

carbonyl vinylation

thallium

oxidative biaryl coupling

dimerization

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S . A . SN Y D E R , * A . P . B R U C K S , D . S . TRE I T L E R , I . M O G A ( C OL UM B I A U N I V E R S I T Y, NE W

YOR K , U S A )

Concise Synthetic Approaches for the Laurencia Family: Formal Total Syntheses of (±)-Laurefucin and (±)-E- and

(±)-Z-Pinnatifidenyne

J. Am. Chem. Soc. 2012, 134, 17714–17721.

Formal Syntheses of (±)-Laurefucin and (±)-E- and (±)-Z-Pinnatifidenyne

Significance: (±)-Laurefucin and (±)-E- and (±)-Z-pinnatifidenyne are oxocanes belonging to the class of Laurencia haloethers. The authors imple-ment a previously developed bromoetherification–ring-expansion sequence to obtain the stereo-chemically rich medium-sized rings present in the natural products.

Comment: Treatment of highly functionalized tet-rahydrofuran substrates D and O with bromonium source E, induces a haloetherification giving oxo-nium intermediates F and P. Subsequent intramo-lecular trapping by an internal nucleophile pro-vides previously reported cyclic ethers G and R.

O

O

H

HO

Br

O

Cl

H

BrMe

OH

OH

O CHO

BocO

O

BocO

HMsO

O

HMsO

Br

OO

Ot-Bu

O

H

OMs

OO

O

BrO

O

H

HO

Br

H

Cl

OHTBS

HO Cl

OH

O

ClTBS

Br

HO

O

ClTBS

O

Cl

H

Br

O

Cl

H

Br

6 steps

17%

1. BF3⋅OEt2, CH2Cl2 then C, –78 to –20 °C2. MsCl, Et3N, CH2Cl2

81%

TMS

Csingle diastereomerFelkin–Anh product S

Br

EtEt–SbCl5Br

E

E, MeNO2

–25 °C to r.t.

72%

bromo-etherification

ring-expansion

DIBALHPhMe

–78 °C to r.t.

46%

Kim et al.Org. Lett. 2005, 7, 75.

A

B D

G

F

H(±)-Laurefucin

OTHP

OH

EtO

OEtEtO

EtO

OCl

O

TBS H

H

Br

3 steps

44%

EtO OEt

NBS, AcOH Ph3PS, CH2Cl2

I J M N

OP

Q (25%)

R (61%)

55% from J

E, MeNO2–CH2Cl2 (1:1)

–25 °C

O

bromo-etherification

ring-expansion

O

O

E- and Z-Pinnatifidenyne

Kim et al.J. Am. Chem. Soc.2003, 125, 10238.

3 steps 33%

+

1. K, py, Et2O2. TBSH, L, THF 40 °C, then TBAF, 0 °C

Si Cl

K

O

Si

SiPt

L

directed alkyne hydrosilylation

H

H

HH

+

+

S

Br

EtEt–SbCl5Br

E

+

+

SYNFACTS Contributors: Erick M. Carreira, Julian EggerSynfacts 03012013, 9(1), 0016 Published online: 17.12.20121 8 6 1 - 1 9 5 81 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317851; Reg-No.: C02312SF ©Georg Thieme Verlag Stuttgart · New York

Category


Key words

bromoetherification

ring expansion

lauroxocanes

haloethers

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P . J A KU B E C , A . H A W KI NS , W . FE L Z M A N N , D . J . D I X ON * ( U NI V E R S I T Y O F O X F O R D , U K )

Total Synthesis of Manzamine A and Related Alkaloids

J. Am. Chem. Soc. 2012, 134, 17482–17485.

Total Synthesis of Manzamine A and Related Alkaloids

Significance: Manzamine A (N) is a highly struc-turally complex alkaloid with a wide range of bio-logical activities. The total synthesis reported is the shortest to date, accessing manzamine A (N) in 20 linear steps from commercially available starting materials. The key feature of the synthesis is the use of nitro groups as handles to construct two rings of the manzamine core by nitro-Mannich reactions.

Comment: The total synthesis of manzamine A (N) starts with a Michael addition onto nitroolefin A. A series of two nitro-Mannich reactions delivers I, which undergoes ring-closing metathesis to con-struct the 13-membered ring incorporating a Z-double bond. Palladium-catalyzed coupling reac-tions on vinyl triflate L produce manzamine A (N) or the related alkaloids P–Q, alternatively.

O O

O2N

N

O

MeO2C

7 steps from D-pyroglutaminol

NO

OO

O2N

MeO2CH

N

OO

N

O2N

O O

N

OO

N

O

NO2

N

OO

NH

NO2

N

NH

OTfH

OTMSN

N

OTfH

OH

H

N

N

H

OH

H

N NH

N NH

SnBu3

N

N

RH

OH

H

+

KHMDS18-crown-6

–94 °C65%

dr = 7:3

NH2

CH2O, E

Δ88%

nitro-Mannich/lactamizationMichael

addition

Ti(Oi-Pr)4Ph2SiH2

81%dr = 4:1 at C(3)3

Angew. Chem. Int. Ed.1996, 35, 1515.

nitro-Mannich

M

73%Z/E = 7:3

PCy3

Ru

PhPCy3

Cl

Cl

Grubbs I (M)

1) AIBN, Bu3SnH, 77%2) TMSCl, KI, 81%3) AgNO2, 63%4) DIBALH, 74%

2) J, CeCl3 then HCl, 91%3) TMSOTf, Et3N, 72%4) K, KHMDS, 90%

ring-closingmetathesis

MgBr

N

NTf2Cl

E

OPd(PPh3)4 (12 mol%)

52%Stille coupling

O

TiCl3

56%

reductiveNef reaction

N

OO

NH

O

J

K

for PPd(OAc)2 (18 mol%)

PPh3, CO, MeOH78%or

for QPd(PPh3)4 (10 mol%)

CO, LiCl, Bu3SnH58%

P R = CO2Me (Methyl Ircinate)Q R = CH2OH (Ircinol A)R R = CHO (Ircinal A)

DIBALH, 82%

Manzamine A (N)

A

B

C D

FGH

IL

carbonylation

SYNFACTS Contributors: Erick M. Carreira, Stefan DiethelmSynfacts 03012013, 9(1), 0017 Published online: 17.12.20121 8 6 1 - 1 9 5 8 1 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317852; Reg-No.: C02412SF ©Georg Thieme Verlag Stuttgart · New York

Category


Key words

nitro-Mannich reaction

ring-closing metathesis

Michael addition

alkaloids

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total synthesis (±)-garcibracteatone - thieme connect · biomimetic total synthesis of...

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