OO
Emily CherneyBaran Group Meeting Guaianes and Xanthanes
O
OO
O
farnesyl pyrophosphate
guaianeskeleton
xanthaneskeleton
xanthanolidesguaianolides
Examples: Mundane to Exotic
pseudoguaianes aromadendrane cubebane/ivaxillarane
patchoulane alerenane
1OPP
3
14
4
5 6 7 8
10
1112
13
15
92
13
14
4 5
67
810
11121315
92 13
14
45
67
810
111213
15
92
86
1212
Prevalence and Biosynthesis:
The Bioactivity...- Both groups possess activity that could treat: cancer, ulcers, inflammation, fungal infections, malaria, and leishmaniasis - Possess endoperoxides with similar antimalarial activity to artemesinin- Thapsigargin, a xantholide, currently undergoing phase I clinical trials for breast, kidney, and prostate cancer. Englerin A is a highly selective inhibitor of renal cancer cell growth.
Around the world with Guaianes and Xanthanes:
Bedfordiasalicina
Plucheadioscoridis
Inulaverbascifolia Naphthea
charboliiXanthium
strumarium
Gergeriaafricana
Xanthiumspinosum
Xanthiumcatharticum
Related but Not Discussed:
Me
MeMe
Me
guaiazulene
Me
Me CH2OO
OH
H
tamaparthin-α-peroxide
Me
O
OMe
Me
O
AcO
H
geigerin acetate
O
O
O
hypocretenolide
6
12
812
12
5
H2C
H2C OO
HO
O
H
HOR
clementein
Me
Me
H
H
O O
hanalpinol
OH
O
O
ClHOAcO
O
OO
xanthipungolide
15-chloro-2-epi-xanthanol
The Nature of the Beast:• Sesquiterpenes represent the largest class of terpenes, and guaianolides comprise of the the largest and most widely distributed groups of sesquiterpenoid lactones (JACS (1984) 8217)• Over 500 guaianes isolated by 1990 (100's more since then), dozens of dimeric guaianes (even trimers observed) • 112 xanthanes/xanthanolides, only 11 non-lactonized xanthanes and 3 known dimeric xanthanes• Synthetic challenges include: medium ring synthesis, dense stereochemical complexity on a relatively flexible skeleton, difficult levels of oxidation, NPs possess epimerizable centers and reactive moieties
Wise words from Clayton Heathcock (circa 1973):
Source: The Total Synthesis of Natural Products, Volume 2, pages 199 and 395
"the sesquiterpene field is an excellent area for the testing and refining of new synthetic methods and concepts"
"one may confidently design stereoselective syntheses in the decalin area, in which the relative stereochemistry is established by either kinetic or thermodynamic methods.
Stereoselective design in the hydroazulene area is much more difficult"
fun fact: the 1st sesquiterpene total synthesis was Ruzicka's farnesol in 1923
via:
germacrene
generallycis
generallytrans
Emily CherneyBaran Group MeetingGuaianes and Xanthanes
Photochemistry and Santonin: Synthesis of Podoandin: Blay et al. JOC (2000) 6703.
Many earlier syntheses begin with a photochemical rearrangement of Santonin based on work by Barton and co-workers (J. Chem. Soc. (1957) 929)For the true seminal work on photochemistry of santonin see: Villavecchia, Atti R. Accad. Lincei (1885) 722, Cannizzaro, et. al. ibid, (1886) 450
O
O
O
AcOH, aq.h!
O
O
O
via:
HO
O
O
OAcH
santonin "isophoto-santonic lactone"
(30-38%)
O
O
O
OAcH
OAc
Synthesis of 3-Oxa-guaianolides: Blay et al. Tetrahedron (2000) 633.
1) TsNHNH22) catecholborane
O
O
OAcH 1) O3
2) NaBH4
(68%)
O
O
O
OAcH
HO
1) MsCl2) NaPhSe3) H2O2
O
O
O
OAcH
H2C
(89%)
(73%)
O3, Ph3P
O
O
O
OAcH
O
TsOHor Al2O3
O
O
O
OH
1) LiAlH4 2) MsCl, pyr.
O
O
OAcH
H H
HHH(97%)(91 %)
(88%)
O
O
O
OAcH
O
O
O
OAc
1) Red-Al2) TPAP, NMO
(75%)
O2, h!,methylene blue
(37%)
O
O
O
MeO
O
O
OH4 steps
6
12
6
12
AcOH, aq.h!
(85%)O
O
OH OAc
1) NaTeH2) NaBH4
(60%)
O
O
HOH OAc
H
1) POCl32) LiBr-Li2CO3
(72%)O
O
H OAc
HO
O
H
TsOH, SiO2PhMe, H2O
(85%)
podoardin
santonin
Synthesis of Absinthin: Zhang et al. JACS (2005) 18. Isolated in 1953, structure elucidated in 1985, first and only total synthesis
O
O
O
OAcH
"isophoto-santonic lactone"
1) NaBH4, MeOH2) ArSeCN, PBu33) NaIO4
(47%)
O
O
OAcH
10 days, neat, rt
(72%)
O
O
OAcH
O
O
OAc
H
H
H
O
O
HO H
O
O
HO
H
H
H
1) KOH2) SOCl2, EtN33) OsO4, NMO4) NaIO45) MeLi
(55%)
See Also: Gutekunst 2009 GM "Traditional Chinese Medicine"
Barton's proposalNote: mechansim proven to be radical
"isophoto-santonic lactone"
For Other Furanoguaianolide Studies See: Tetrahed. (2003) 1877, TL (1988) 4521, J. Chem. Soc. Perk. Trans. 1 (1990) 1601
DBU
MsO
O
1
5
12
8
absinthin
Emily CherneyBaran Group MeetingGuaianes and Xanthanes
Synthesis of (+)-Ainsliadimer: Lei et al. OL (2010) 4284.
Diversity oriented synthesis: Ando et al. J. Nat. Prod. (1994) 433.
O
O
O
OAcH
isophoto-santonic lactone
1) Pd/C, H22) NaBH43) MsCl, Pyr.
(52%)
O
O
OAcH
H
1) KOH2) SOCl2, DABCO
(93%)
O
O
H
H
1) LDA, (PhSe)22) H2O2, AcOH (85%)
O
O
H
H
m-CPBACHCl3, 0-10°C
(63%)
O
O
H
HO
1) Al(OiPr)3,
PhMe, µW
2) DMP
(32%)
O
O
H
H
O
dehydro-zaluzanin C
estafiatin
(!)-BINOL,neat, 50 °C,
60 h
Hetero-DA70%
O
O
H
H
O
OO
HH
O
HCl aq.,THF
(73%)
O
O
H
H
O
OO
HH
OOH
DBU
(89%)
O
O
H
H
OO
HH
OOH
HO
(+)-ainsliadimer
Santonin without Photochemistry:
O
O
Osantonin
12steps
(19%)
O
O
OMs0.5 M KOAcAcOH, reflux
O
O
H
H
(24%)
O
O
H
isocostuslactone
dihydrokauniolide
(32%)
mCPBA
O
O
H
H
(58%)1) LDA, PhSeCl2) H2O2
(32%)O
O
O
H
HO
estafiatin
1) LDA, (PhSe)22) H2O2
(80%)
O
O
H
H
isodehydro-costuslactone
CrO2(tBuO)2
(27%)
O
O
H
H
O
2-osodesoxyl-igustrin
1 eq.mCPBA
O
O
H
O
O
H
O
O
(36%)
(22%)
1,10-epi-arborescin
1) LDA, PhSeCl2) H2O2
(51%)
O
O
HO
3,4-epiludartin
Al(OiPr)3,
PhMe, "
(50%)
O
O
H
HO
8-deoxy-11,13-dihydrorupicolin B
1) LDA, (PhSe)22) H2O2
(27%)
O
O
H
HO
8-deoxyrupicolin B
1 starting material,15 natural products
ainsliatrimer A:OL (2008) 5517
OO
H
O
O
O
H
O
O
O
HO
HOH
+
+
Emily CherneyBaran Group MeetingGuaianes and Xanthanes
Assymetric Synthesis of Pleocarpenene: Snapper et al. JACS (2007) 486.Photochemistry without Santonin:Synthesis of Dehydrokessane: Liu et al. TL (1977) 3699.
O
AcO
MeO2C
AcO
PhH, h!;TsOH
(450 w Hg Lamp,pyrex filter)
O H
H
CO2Me
OAc(60%)
MeMgBr, CuI,
Et2O, 0 °C
(56%)
O H
H
CO2Me
OAc
1) BF3•OEt2,
HSSH
2) Raney Ni
H
H
CO2Me
OAc
(62%)
LiAlH4
(95%)
H
H OH
OH
TsCl, Pyr., rt
O
H
H
(83%)
NaH,
MeO
O
OMe
O
H
H
O
OMe
NaH, MeLi
O
H
H
HO
(57%)
Hg(OAc)2, NaBH4
(61%)
O
H
H
O
LiAlH4 (quant.)
HO
H
H
OPOCl3, Pyr.O
dehydrokessane
O
O
MeO2CPhH, h!;Fe2(CO)9
(64%)
Fe(CO)3
CO2Me
1) DIBAL-H2) MnO23)
Fe(CO)3
HO
(76%)
CO2MeGrubbs II2.5 mol%
(94%)
HO
CO2Me
make assym.with MnO2; CBS reduction
CAN,acetone
(80%)HO
H CO2Me
H
HO
CO2Me
H
H
" #(1: 2.7 ":#)
1) LiAlH42) TIPSCl, DMAP Et3N; Ac2O (87%)
H
AcO
H OTIPS Cu(acac)2 (5 mol%)EDA; NaOEt
(93%) H
HO
H OTIPS
EtO2C
(COCl)2, DMSO;Et3N; MeMgCl
(79%)
H
H OTIPS
HO
HO
PhH, 200 °CDBU (15 mol%)
H
OH
HO
OTIPS
1) Raney Ni, H22) TBAF3) TsCl, Et3N, DMAP4) NaI, DBU
(51%)
(76%)
H
OH
HO
pleocarpene
O3; DMS; NaOMe
(51%)
H
H
OH
O
HOH
pleocarpenone
Fe(CO)3
MgBr
Emily CherneyBaran Group MeetingGuaianes and Xanthanes
Synthesis of (+)-Chinensiolide B: Hall et al. JACS (2010) 1488.Syntheses from Carvone:Synthesis of Thapsivillosin F (highlights): Ley et al. ACIEE (2003) 5996.
O
H
(S)-carvone
1) H2O2, NaOH2) LiCl, TFA3) DHP, PPTS
(73%)
O
HTHPO
Cl
NaOMe
(95%)
THPO
H
HCO2Me
5 steps
TBDPSO
H
H
OMOM
OH
TBDPSO
H
H
OMOM
TESO OEt
3 stepsGrubbs II (2.5 mol%)
TBDPSO
H
H
OMOM
TESOOEt
17 stepsO
H
H
OAc
HO O
O
OH
O
OO
thapsivillosin F
Studies toward Thapsigargin : Massanet et al. OL (2006) 2879.
(see also Ley's work on thapsigargins: PNAS (2004) 12073)
O
(+)-dihydrocarvone
O
KOH, O2
(70%)O
OH
O
OH
DDQ
(70%)
1) Burgess
2) AD-mix !tBuOH:H2O
(74%)
O
OH
OH
h",AcOH
(93%)
H
H
OAc
O
OH
OH
H
H
OAc
O
1) OsO4, NMO, MeSO2NH22) TEMPO, NaClO, NaClO2
O
HO
OH
O
(60%) 6 7
12
6 7
12
O
H
(R)-carvone
1) H2O2, NaOH2) LiCl, TFA3) TBSOTf, Pyr.
O
HTBSO
Cl
NaOMe
(85%)(95%)TBSO
CO2MeH
H
1) LiAlH42) (COCl)2, DMSO, Et2N
(76%)
TBSO
CHOH
H
OTBDPS CO2Me
Bpin
BF3•OEt2 (2.5 mol%)TBSO
HO
O
TBDPSO
(87%*)*yield based on Z only,
E unreactive
(3.5:1 Z:E)
(>19:1 dr)
1) TBAF, AcOH2) p-NO2-PhSeCN,PBu33) H2O2
(42%)
TBSO
HO
O
1) Grubbs II (5 mol%)2) mCPBA
(84%)TBSO
O
H
H
O
1) DIBAL-H; LiEt3BH2) MnO2
TBSO
O
H
H
O
O
OH
(50%)
O
O
H
H
O
OH
PDC, TMSCl
(71%)
(+)-chinensiolide B
allylboration/lactonization
(~4:1 dr)
deprotection/oxidation
Emily CherneyBaran Group MeetingGuaianes and Xanthanes
Organoiron approach: Donaldson et al. TL (2009) 1023.Making the fused 5-7 ring system Part 1:When 5 Leads
Synthesis of (±)-7-epi-!-bulnesene: Ovaska et al. TL (2002) 1939.
OMe2CuLi,
TMSCl, Et3N
OTMSCsF,
Br
(57%) (60%)
O
(rel. stereochem.)
CeCl2
OH
(57%)
MeLi (5 mol%)PhOEt, 155 °C
HO
(84%)
PPh3
DMSO
H
(50%)
(±)-7-epi-!-bulnesene
Approach to Geigerin: Jacobi et al. JOC (1992) 6305.
O
CO2MeMeO2C
1) PhSeCl2) H2O23) ethylene glycol,TsOH
(32%)
CO2MeMeO2C
O
O
1) NaOH, aq.2) (COCl)2, K2CO3, DMF3) Me-alaninate, Pyr.
(60%)MeO2C
O
O
O
HN
MeO2C
1) P2O52) BF3•OEt2
HSSH
(58%)
MeO2C
S
S
NO
OMe
1) DIBAL-H
2) nBuLi,
O3) (COCl)2, DMSO4) Li
5) TBSOTf, Et3N
N
O
S
S
OTBSOMe
OMe
1) PhH, "2) TBAF3) Hydroquinone, NaHCO3, "
OOMe
OMe
O
S
S
OTBDPS
Br
Mg, THF;
Fe+
(CO)3MeMeO2C
TBDPSO
Fe(CO)3
PF6
HMeO2C
H2O2,HO-
TBDPSO
MeO2C
H
1) LiAlH42) C6Me3H3, 200 °C
(43%)
(57%)
TBDPSO
OH
H
O
O
O
H
7 steps
Synthesis of Sundiversifolide: Shindo et al. OL (2008) 1247. (continued)
Making the fused 5-7 ring system Part 2:When 7 Leads (continued)
OH
1) TBDPSCl, imid. DMAP
2) nBuLi, (CH2O)n
3) Red-Al
4) MsCl, Et3N; NaI
OTBDPS
(82%)
N O
OO
Bn LDAN O
O O
BnOTBDPS
I
(92%)
AD mix-!
MeSO2NH2tBuOH/H2O
(97%)
O
OOTBDPS
OH
O
OI
OTBS
1) TBSCl, imid. DMAP2) TBAF. AcOH3) MsCl, Et3N; NaI, Acetone
O
OTBDPSTBSO
(82%)
1) tBuLi
2) TBDPSCl,
imid. DMAP
(88%)
Emily CherneyBaran Group MeetingGuaianes and Xanthanes
Syntheses of (±)-Geigerin: Depres et al. ACIEE (2007) 6870.
Synthesis of Sundiversifolide: Shindo et al. OL (2008) 1247. (continued)
O
OTBDPSTBSO
1)
2) 6M HCl
MgBrOH
OTBDPSHO
( 87%)
1) TPAP, NMO2) TBAF
(>99%)O
OHHO
PPh3
O
O
CF3xylene
(92%)
HOO
O
4 stepsO
OH
HO
(+)-sundiversifolide
Synthesis of Dehydrocostus Lactone: Rigby et al. JACS (1984) 8217.
O 2 eq. O
OBrMg
then NaBH4
OH
OO(85%) (96%)
NaH, MeI
OMe
OO
50% aq TFA(77%)
OMeH
H(rel. stereochem.)
O
1) Li, CH3NH22) MEMCl
(82%)
OMeH
HMEMO
mCPBA
(54%)
OMeH
HMEMO O
1) LiCH2COLi22) TMSCl, NaI(62%)
OHH
HHOO
O
1) Swern [O]2)
P
S
N(Me)2
Ph CH2Li
then MeI, Pyr.(41%)
H
HO
O
Eschenmoser'ssalt;
"quaternization/elimination"
(71%)
H
HO
Odehydrocostus
lactone
BF4
MeLi, 0! 20 °C
(83%)
Me
Cl3C
O
ClZn, ultrasound
Me
O
Cl
Cl
H
H
CH2N2;DMSO
MeH
Cl
O
(52%)2 steps
OTBSMeO
LiClO4 (cat.)
MeH
Cl
O
HO(dr at C7: 85:15)
7
H Me
CO2Me
1)
2) DMDO, -90 °CTsOH
(49%)3 steps
MeH
Cl
O
O
OMeB(OH)2, Pd(OAc)2, dpdb, K3PO4
(58%)
MeH
Me
O
O
O
LiOH, H2O/THF, CO2;I2, KI, NaHCO3
MeH
Me
O
HO
I
O
O
nBu3SnH, BEt3(53%)2 steps
MeH
Me
O
HO
O
O
Ac2O, pry.,DMAP
MeH
Me
O
AcO
O
O
(±)"geigerin
(rel. stereochem.)
(±)"geigerin acetate
Making the fused 5-7 ring system Part 2:When 7 Leads (continued)
12
6 12
8
Emily CherneyBaran Group MeetingGuaianes and Xanthanes
Synthesis of (+)-Achalensolide (highlights): Mukai et al. JOC (2008) 1061.
Studies Highlights 1: Lee et al. TL (2001) 1695.
Making the fused 5-7 ring system Part 3:Simultaneous Formations:
THPOLi
1)THPO
CHO
2) LiAlH4•
OTHP
HO
1) NaH, BnBr, TBAI (cat.)2) TsOH3) Swern [O]
•
O
BnO
O LiTBSO1)
2) VO(acac)2, tBuOOH;Ac2O, DIPEA, DMAP
O•
O
OBn
AcO
OTBS
(68%) (73%)
(52%)
DBU, DCM, rt
HO O
O
OTBS
Studies Highlights 2: Wender et al. OL (1999) 137.
Studies Highlights 3: Lee et al. OL (2010) 548.
HO
•2.5 mol% [Rh(CO)2Cl]2,
DCE, 80 °C
(76%)
HO
H
H
1) DMP2) MeMgBr
H
HHO
(+)-dictamnol
EtO
OO
O
ZnI2,Et2NH
(20%)
(See Wender's resiniferatoxin in Classics II)
(78%)
OE
H
OE=CO2Et
4 steps
H
(±)-clavukerin A
O
OO 1)nBuLi, BF3•OEt2,
2) PivCl, Pyr.TMS
O
O
OPiv
TMS
9steps
(65%)
•
OPivMOMO
10 mol% [RhCl(cod)]250 mol % dppp, 1 atm CO, PhMe, !
(96%)
OMOM
OPiv
O
10 stepsO O
O
H
(+)-achalensolide
Clever Metathesis Strategies:Sesquiterpene Aklaloid Synthesis: Craig et al. Eur. JOC (2006) 3558.
6steps
(R)-citronellene
O N
OO
iPr
1) NaHMDS;
BrTBDPSO
2) HCl, MeOH
O N
OO
iPrHO(79%)
Grubbs II5 mol%
(>99%)
O N
OO
iPr
HO1) NaOMe2) DMAP, DIC
CO2H
Ts
CO2Me
O
O
Ts
KOAc, BSA, PhMe, µW, 160 C°
CO2Me
Ts
(71%) (77%)
1) O3, PPh32) NH3 in EtOH3) MeMgBr
NHO
(+)-cananodine
(46%)
[5+2]
Michael/Conia-ene
Pauson"Khand-Type
Emily CherneyBaran Group MeetingGuaianes and Xanthanes
Synthesis of Teucladiol: Vanderwal et al. JACS (2009) 15090.
Synthesis of (!)- Dihydroxanthatin: Morken et al. OL (2005) 3371.
Clever Metathesis Strategies:
HO Br
Me 8 steps TBSO
Me OH
10% Pd(OAc)2,2.5 eq Cu(OAc)2
BuO
O
Me
TBSO
OBu
O
Pd(II)BuO
MeR
Oshima-Utimoto
1) 9-BBN, H2O22) Dess-Martin
(68%)
O
Me
TBSO
OBuO
1) Ph3PCH2Br, tBuOK
2) TBAF
O
Me
HO
OBu
1) Dess-Martin
2) tBuOK
(92%)(85%)
N2 PO(OMe)2
O
Me
O
3) H2CrO4
Grubbs II (5 mol%)
O
O
Me
could not alkylate successfully
1) LDA, MeI2) Grubbs II (5 mol%) methyl vinyl ketoneO
O
MeO
(76%) 70%)
(59%)(!)-dihydroxanthatin
Synthesis of (+)-8-epi-Xanthatin: Martin et al. OL (2005) 4621.
12steps
MeO
O
OH
TIPS O
OMe
OTBSTBAF
(78%)O
Me
O
Grubbs II (5 mol%)methyl vinyl ketone (10 eq)DCM (0.005 M)
O
O
MeO
(+)-8-epi-Xanthatin
(83%)
Br
TMS
i. tBuLi; ii. CuCN;
iii. cyclopentenone
MO
TMS
iv. O
HOH
H
H
O
(60%)>10:1 dr trans-
selective
anti-aldol
Felkin-Anh
1) TESCl2) Grubbs II (5 mol%)
(77%)
O
TMS
H
TESO
O H
TESO
1) MeLi, CeCl32) TsOH
(60%)87:13 dr
HO HHO
(±)-teucladiol
Synthesis of Clavukerin: Metz et al. Eur. JOC (2010) 6145.
OHC
(S)-citronellal
O
NH
PhPh
OMe
HO
HO
CO2Et
(20%) (20%)
OHC
O
(90%)
CBr4, PPh3, DCM(94%)
O
Br
Br
Grubbs II (4 mol%)
H2C CH2
H
(!)-clavukerin A
(78%)(55%)
PPh3+CH3Br-
nBuLi
TBS
TBS
Emily CherneyBaran Group MeetingGuaianes and Xanthanes
Synthesis of (±)-7-epi-!-Bulnesene: Negishi et al. JOC (1997) 1922.
Synthesis of (+)- Cladantholide: Lee et al. JACS (1997) 8391.
Free Radical Strategies:
Synthesis of (±)-Kessane: Booker-Milburn et al. OL (2003) 3309.
CO2Me
THPO
(4 steps from carvone)
1) DIBAL-H2)
MgBr THPO
HO
Br
OEt
Br Et3N,DMAP
THPO
O Br
OEt
nBu3SnH,
AIBNTHPO
O
H
OEt
H5-exo;7-endo
1) TsOH2) PCC
O
O
H
OEt
H
1) LDA, TMSCl2) DMDO
(77%) (98%)
(99%)(80%)
(79%)
O
O
H
OEt
H
HO 1) TsNHNH22) MeLi3) Jones [O]4) LDA, MeI
(18%)O
H
O
H
O
(+)- Cladantholide
Synthesis of (±)-Alismol: Lange et al. JOC (1999) 6738.
O
MeO2C
OO
h"
(53%)
H
H
CO2Me
H OO
O
1) iPrMgBr
2) LiAlH4
3) I2, PPh3
(50%)
H
H HO
O
I
OH
MeLi; CS2;MeI
(90%)
H
H HO
O
I
OCS2Me
nBu3SnH,
AIBNH
HO
O(92%)
1) Acetone, H+
2) MeMgBr, CeCl3
(50%)
H
HOH
(±)-alismol
(nBu)2ZrCp2ZrCp2
H
1) nBuNC
2) I23) HCl
(68%)
H
H
I
O
1)
2) PCC
TMS MgBr
H
I
O
TMS
nBu3SnH,
AIBN
H OTMS
(78%)
1) KH, H2O
2) iPr=PPh3
H
(46%3 steps)
(±)-7-epi-!-bulnesene
O
HO1) TMSCl, DMPU,
MgBrthen Et3N2) Et2Zn, CH2I2
(76%)
OTMS
HO
Fe(NO3)3
H
H O
1) Ph3P
2) BH3•THF; PCC3) Cp2TiCl2,AlMe3
(54%)
H
H
OH
OH
(#:! 1:2.5)
with the #$epimer:
NISH
H
O
I
Pd/C, H2
H
H
O(67%
2 steps)
(±)-kessane
For an interesting synthesis of bulnesene from patchoulol see: TL (1975) 4495
Emily CherneyBaran Group MeetingGuaianes and Xanthanes
Christmann Synthesis Highlights: ACIEE (2009) 9105.
The Battle of Englerin A :Quick stats: Isolated in 2009 [OL (2009)p.57] and promptly patented; selectively inhibits renal cancer cell lines selectively with GI50 values of 1-87 nM; 4 total synthesis to date 1 in 2009 and 3 in 2010, 1 formal synthesis in 2010.
O
Me H O
H CHO2 steps from
cis-nepetalactone
1)BrZn
2) LiAlH4
Me H
H
OH
OH
OH4
steps
(85%)
Me H
H
Me
OO
Grubbs II(20 mol%)
Me H
H
Me
OO
3 steps
Me H
H
Me
HOO
O
O
OTBS
!
MeH
HMe
O
O
HO
O
OTBS
(99%)
2 steps
(+)-
en
gle
rin
A
Me H
HMe
O
O
O
O
OH
O
Ph
(")-englerin A
Ma Synthesis Highlights: ACIEE (2010) 3513.
OHC
5steps
OH
O
AuCl, DCM, rt
(48%)
15 steps10.9% overall
Me
HMe
O
OH
(")-englerin A
10steps
16 steps8.1% overall
Echavarren Synthesis Highlights: ACIEE (2010) 3517.
OH
(R)-citronellal
geraniol
8steps
OH
O
OTES
[iPrAuNCPh]SbF6
Me
HMe
O
OH
OTES9
steps
(")-e
ng
lerin
A
18 steps7% overall
Nicolaou/Chen Synthesis Highlights: JACS (2010) 8220.
O
OBn O
Me
MsCl, DIPEA;
CO2Et
Me
O
CO2Et
OBnO
(7 steps)
14steps
(")-englerin A
22 steps2.6% overall
Theodorakis Formal Synthesis Highlights: OL (3708) 3708.
O
O
O
O
O
N2
TBSO
Rh2(Ooct)4(2 mol%)
(90%)
Me
O
TBSO
O
O
O
O14
steps Ma'sintermed.
7steps
(")-englerin A
22 stepsoverall yield
???
if completed as depicted:
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