Post on 18-Apr-2018
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
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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
Synthesis of Natural Products and Potential Drugs
Key words
oseltamivir phosphate
Tamiflu
enzymatic desymmetrization
ring-closing metathesis
aziridine ring opening
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 3
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
57% (1.0 mmol scale)
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
Synthesis of Natural Products and Potential Drugs
Key words
lithospermic acid
HIV integrase
organocatalysis
asymmetric oxa-Michael reaction
oxidative ring contraction
C–H activation
of the month
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 K4
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
Synthesis of Natural Products and Potential Drugs
Key words
communesin F
indol-2-one
Diels–Alder cycloaddition
mercuric triflate
trimethyl aluminum
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 5
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
SYNFACTS Contributors: Philip KocienskiSynfacts 03012013, 9(1), 0005 Published online: 17.12.20121 8 6 1 - 1 9 5 8 1 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317723; Reg-No.: K09612SF ©Georg Thieme Verlag Stuttgart · New York
Category
Synthesis of Natural Products and Potential Drugs
Key words
p38 kinase inhibitors
amination
O-(4-nitrobenzoyl)-hydroxylamine
pyrrolotriazines
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 K6
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
100% (7.0 mmol scale)
SYNFACTS Contributors: Philip KocienskiSynfacts 03012013, 9(1), 0006 Published online: 17.12.20121 8 6 1 - 1 9 5 81 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317726; Reg-No.: K09912SF ©Georg Thieme Verlag Stuttgart · New York
Category
Synthesis of Natural Products and Potential Drugs
Key words
candesartan cilexetil
angiotensin II receptor antagonists
C–H arylation
ruthenium
transfer hydrogenation
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 7
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
Synthesis of Natural Products and Potential Drugs
Key words
lycoposerramine-S
azomethine ylides
1,3-dipolar cycloaddition
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 K8
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
Synthesis of Natural Products and Potential Drugs
Key words
(–)-leiodermatolide
alkyne metathesis
antitumor agents
structure elucidation
molybdenum
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 9
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
Org. Process Res. Dev. 2012, 16, 1652–1659.
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
SYNFACTS Contributors: Philip KocienskiSynfacts 03012013, 9(1), 0009 Published online: 17.12.20121 8 6 1 - 1 9 5 8 1 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317725; Reg-No.: K09812SF ©Georg Thieme Verlag Stuttgart · New York
Category
Synthesis of Natural Products and Potential Drugs
Key words
TAK-733
MEK inhibitors
3-fluoropyridone
cascade reaction
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 K10
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
Org. Process Res. Dev. 2012, 16, 1635–1645.
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
SYNFACTS Contributors: Philip KocienskiSynfacts 03012013, 9(1), 0010 Published online: 17.12.20121 8 6 1 - 1 9 5 81 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317724; Reg-No.: K09712SF ©Georg Thieme Verlag Stuttgart · New York
Category
Synthesis of Natural Products and Potential Drugs
Key words
glucokinase activators
amide bond formation
n-propanesulfonic anhydride
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 11
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–
+
SYNFACTS Contributors: Philip KocienskiSynfacts 03012013, 9(1), 0011 Published online: 17.12.20121 8 6 1 - 1 9 5 8 1 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317720; Reg-No.: K09312SF ©Georg Thieme Verlag Stuttgart · New York
Category
Synthesis of Natural Products and Potential Drugs
Key words
(R)-rolipram
(R)-baclofen
asymmetric allylic alkylation
nitromethane
allyl carbonates
palladium
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 K12
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:
SYNFACTS Contributors: Philip KocienskiSynfacts 03012013, 9(1), 0012 Published online: 17.12.20121 8 6 1 - 1 9 5 81 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317717; Reg-No.: K09012SF ©Georg Thieme Verlag Stuttgart · New York
Category
Synthesis of Natural Products and Potential Drugs
Key words
pregabalin
kainic acid
Hayashi–Miyaura asymmetric conjugate addition
rhodium catalysis
alkenyl trifluoroborates
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 13
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:
SYNFACTS Contributors: Philip KocienskiSynfacts 03012013, 9(1), 0013 Published online: 17.12.20121 8 6 1 - 1 9 5 8 1 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317721; Reg-No.: K09412SF ©Georg Thieme Verlag Stuttgart · New York
Category
Synthesis of Natural Products and Potential Drugs
Key words
maxipost
asymmetric fluorination
scandium triflate
N-fluorobenzene-sulfonimide
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 K14
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
87% (51.4 mmol scale)
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
SYNFACTS Contributors: Philip KocienskiSynfacts 03012013, 9(1), 0014 Published online: 17.12.20121 8 6 1 - 1 9 5 81 8 6 1 - 1 9 4 XDOI: 10.1055/s-0032-1317718; Reg-No.: K09112SF ©Georg Thieme Verlag Stuttgart · New York
Category
Synthesis of Natural Products and Potential Drugs
Key words
GDC-0068
serine/threonine kinase
Akt inhibitor
Favorskii ring contraction
Noyori asymmetric transfer hydrogenation
pyrimidine N-oxide rearrangement
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 15
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
Synthesis of Natural Products and Potential Drugs
Key words
dispegatrine
sarpagine alkaloids
carbonyl vinylation
thallium
oxidative biaryl coupling
dimerization
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 K16
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
Synthesis of Natural Products and Potential Drugs
Key words
bromoetherification
ring expansion
lauroxocanes
haloethers
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.
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 17
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
Synthesis of Natural Products and Potential Drugs
Key words
nitro-Mannich reaction
ring-closing metathesis
Michael addition
alkaloids
Thi
s do
cum
ent w
as d
ownl
oade
d fo
r pe
rson
al u
se o
nly.
Una
utho
rized
dis
trib
utio
n is
str
ictly
pro
hibi
ted.