Guaianes and Xanthanes

Guaianes and Xanthanes
Baran Group Meeting
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
Emily Cherney
Examples: Mundane to Exotic
Me
Me
H
O
H2C
H
8
12
Me
Me
Me
OH
O
Wise words from Clayton Heathcock (circa 1973):
"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"
15-chloro-2-epixanthanol
O
O
O 12
Me H
Me H O
CH2
12
O
tamaparthinα-peroxide
O
5
O O
6
fun fact: the 1st sesquiterpene total synthesis was Ruzicka's farnesol in 1923
O
O
H2C H O
Me
geigerin
clementein O
acetate
Me
O
OH
H
Me
guaiazulene
O
O
AcO
OR Cl
HO
O
Me AcO
HO
O
O
hanalpinol
hypocretenolide
xanthipungolide
Around the world with Guaianes and Xanthanes:
Source: The Total Synthesis of Natural Products, Volume 2, pages 199 and 395
Prevalence and Biosynthesis:
15
5 6
4
7
2
8
3
9
3 2
1
14
14
10
OPP
11
13
12
15
4
14
9
1 10
5
15
6
11
12
farnesyl
pyrophosphate
8
7
guaiane
skeleton
2
4
13
3
8
7
6
12
11
generally
trans
generally
cis
8
6
O
O
12
O12
guaianolides
The Bioactivity...
13
xanthane
skeleton
via:
germacrene
Naphthea
charbolii
9
1 10
5
Inula
verbascifolia
Xanthium
catharticum
Xanthium
strumarium
Xanthium
spinosum
O
Pluchea
dioscoridis
Bedfordia
salicina
Related but Not Discussed:
xanthanolides
- 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.
Gergeria
africana
pseudoguaianes
aromadendrane
cubebane/
ivaxillarane
patchoulane
alerenane
Guaianes and Xanthanes
Baran Group Meeting
Synthesis of Podoandin: Blay et al. JOC (2000) 6703.
Photochemistry and Santonin:
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
OAc
via:
O
santonin
O
O
O
O
"isophotosantonic lactone"
Barton's proposal
Note: mechansim proven to be radical
O
12
O
(68%)
(89%)
H
O
O
O
OAc
MsO H
O
1) LiAlH4
2) MsCl, pyr. O
O
H
(91 %)
H
O
O
1
O
O
O
H
O
OAc
H
10 days, neat, rt
(47%)
(72%)
O
O
O
"isophotosantonic lactone"
O
O
1) KOH
2) SOCl2, EtN3
3) OsO4, NMO
4) NaIO4
5) MeLi
HO
OH
HO
HH
H
H
6
O
O 12
O
1) NaBH4, MeOH
2) ArSeCN, PBu3
3) NaIO4
OAc
H
(75%)
O
OAc
H
(73%)
H
(72%)
O
H
OAc
O
O
1) Red-Al
2) TPAP, NMO O
(37%)
O
12
(85%)
O
O
O
OAc
O2, h!,
methylene blue O
5
8
H
1) POCl3
HO
2) LiBr-Li2CO3
Isolated in 1953, structure elucidated in 1985, first and only total synthesis
O
O
OAc
H
O
H
(97%)
TsOH
or Al2O3
O
H2C
OAc
TsOH, SiO2
PhMe, H2O
Synthesis of Absinthin: Zhang et al. JACS (2005) 18.
O3, Ph3P O
O
DBU (88%)
1) MsCl
2) NaPhSe
3) H2O2
OAc
H
O
(60%) 1) NaTeH
2) NaBH4
O
H
"isophotoO
santonic lactone"
O
O
3
2) NaBH4
O
MeO
O
H
OAc
(85%)
podoardin
Synthesis of 3-Oxa-guaianolides: Blay et al. Tetrahedron (2000) 633.
HO
OAc
OAc
OAc
H
H
H
1)
O
1) TsNHNH
2
H
AcOH, aq. O
h!
6
O
2) catecholborane
OH
4
steps
santonin
O
O
H
(30-38%)
O
OAc
H
AcOH, aq.
h!
Emily Cherney
O
For Other Furanoguaianolide Studies See: Tetrahed. (2003) 1877, TL (1988) 4521, J.
Chem. Soc. Perk. Trans. 1 (1990) 1601
O
absinthin
H
(55%)
O
OAc
OAc
HH
H
O
O
O
O
See Also: Gutekunst 2009 GM "Traditional Chinese Medicine"
O
Guaianes and Xanthanes
Baran Group Meeting
Synthesis of (+)-Ainsliadimer: Lei et al. OL (2010) 4284.
OAc 1) Pd/C, H
2
H
O
OAc
H
2) NaBH4
3) MsCl, Pyr.
H
isophotosantonic lactone O
H
H
H
O
estafiatin
H
H
O (73%)
O
O
O
H
O
O
H
O (89%)
H
H
O
H
OH
HO
O
H
H
H
ainsliatrimer A:
OL (2008) 5517
O
O
O
O
H
H
(32%)
O
H
O
O
OH O
(50%)
O
O
O
1,10-epi-arborescin
+
(51%)
O
3,4-epiludartin
O
(36%)
1) LDA,
PhSeCl
2) H2O2
H
H
O
8-deoxy-11,13- O
dihydrorupicolin B
1 starting material,
15 natural products
O
Al(OiPr)3,
PhMe, "
O
H
O
dihydrokauniolide
HO
H
8-deoxyrupicolin B
O
isodehydrocostuslactone O
1) LDA,
(PhSe)2
2) H2O2
(27%)
O
O
H
1 eq.
mCPBA
H
HO
O
O
O
2-osodesoxyligustrin
O
H
H
H
(27%)
H
+
1) LDA,
(PhSe)2
2) H2O2
(80%)
O
O
DBU
OH
O
O
CrO2(tBuO)2
O
O
isocostuslactone
H
O
H
O
(24%)
(58%)
(+)-ainsliadimer
O
HCl aq.,
THF
O mCPBA
O
estafiatin
O
O
O
H
O
O
O
O
1) LDA,
PhSeCl
2) H2O2
H
H
O
(32%)
O
H
O
H
m-CPBA
CHCl3, 0-10°C
O
H
santonin
H
(63%)
AcOH, reflux
O
O
O
1) LDA, (PhSe)2
2) H2O2, AcOH (85%)
H
O
dehydrozaluzanin C O
(!)-BINOL,
neat, 50 °C, Hetero-DA
70%
60 h
steps
(19%)
O
O
1) Al(OiPr)3,
PhMe, µW
2) DMP
O
(32%)
O
Diversity oriented synthesis: Ando et al. J. Nat. Prod. (1994) 433.
OMs
12
0.5 M KOAc
H
H
(93%)
O
H
Santonin without Photochemistry:
1) KOH
2) SOCl2,
DABCO
(52%)
Emily Cherney
O
O
H
(22%)
O
O
Guaianes and Xanthanes
Baran Group Meeting
Photochemistry without Santonin:
Assymetric Synthesis of Pleocarpenene: Snapper et al. JACS (2007) 486.
1) DIBAL-H
O
PhH, h!;
Fe(CO)3
Fe(CO)3 2) MnO2
MeO2C
3)
MgBr
O Fe2(CO)9
Synthesis of Dehydrokessane: Liu et al. TL (1977) 3699.
O
O
MeO2C
PhH, h!;
TsOH
(450 w Hg Lamp,
pyrex filter)
AcO
AcO
H CO2Me
MeMgBr,
CuI,
Et2O, 0 °C
(56%)
O
H CO2Me
(64%)
H OAc
H
H
TsCl, Pyr.,
rt
(83%)
OH
H
O
O
HO
NaH, MeLi
(57%)
(61%)
H
O
H
OTIPS Cu(acac)2 (5 mol%)
EDA; NaOEt
H
H
H
HO
H
PhH, 200 °C
DBU (15 mol%)
(76%)
HO
H
O
H
(79%) (COCl)2, DMSO;
Et3N; MeMgCl
OTIPS
LiAlH4 (quant.)
dehydrokessane
EtO2C
OTIPS
HO
O
POCl3, Pyr.
CO2Me
HO
H
AcO
HO
Fe(CO)3
CAN,
acetone
(80%)
(1: 2.7 ":#)
(93%)
O
H
O
#
CO2Me
Grubbs II
2.5 mol%
(94%)
1) LiAlH4
2) TIPSCl, DMAP
(87%)
Et3N; Ac2O
H
Hg(OAc)2,
NaBH4
OMe
H
"
H OAc
H
CO2Me
H
NaH, O
Me
Me
O
O
H
H
CO2Me
HO
H OH
O
H
H CO2Me
LiAlH4
(95%)
HO
make assym.
with MnO2;
CBS reduction
1) BF3•OEt2,
SH (62%)
HS
2) Raney Ni
H
(76%)
CO2Me
H OAc
(60%)
Emily Cherney
HO
1) Raney Ni, H2
2) TBAF
3) TsCl, Et3N, DMAP (51%)
4) NaI, DBU
H
H
HO
OH
OTIPS
O
O3; DMS;
NaOMe
H
(51%)
HO
pleocarpene
HO
H
OH
H
pleocarpenone
OH
Guaianes and Xanthanes
Baran Group Meeting
Syntheses from Carvone:
Emily Cherney
Synthesis of (+)-Chinensiolide B: Hall et al. JACS (2010) 1488.
Synthesis of Thapsivillosin F (highlights): Ley et al. ACIEE (2003) 5996.
H
1) H2O2, NaOH
THPO
2) LiCl, TFA
3) DHP, PPTS
(73%)
NaOMe THPO
(95%)
Cl
O
(S)-carvone
H
O
1) H2O2, NaOH
2) LiCl, TFA TBSO
3) TBSOTf, Pyr.
H
H
H
CO2Me
Grubbs II (2.5 mol%)
OMOM
H
3
steps TBDPSO
TBDPSO
H
OEt
OMOM
H
O
OH
H
OEt
O
H
(70%)
O
O
OH
(+)-dihydrocarvone
OAc
H
HO
6
1) OsO4, NMO,
MeSO2NH2
2) TEMPO,
NaClO, NaClO2
O
O
6
(60%)
7
O 12
OAc
OH
7
H
O
h",
AcOH
(93%)
OH
O
12
OH
OH
O
H
1) DIBAL-H;
LiEt3BH
2) MnO2
(50%)
O
OH
H
O
(71%)
deprotection/
oxidation
O
O
OH
H
PDC, TMSCl
(+)-chinensiolide B
OH
CHO
H
O
(~4:1 dr)
H
H
TBSO
H
O
OH
1) Burgess
(74%) 2) AD-mix !
tBuOH:H O
2
H
allylboration/
lactonization
1) Grubbs II
(5 mol%)
2) mCPBA
TBSO
(84%)
TBSO
DDQ
(70%)
O
CO2Me
Bpin
*yield based on Z only,
E unreactive
Studies toward Thapsigargin : Massanet et al. OL (2006) 2879.
KOH, O2
1) LiAlH4
2) (COCl)2, (76%)
DMSO, Et2N
(87%*)
O
1) TBAF, AcOH
2) p-NO2-PhSeCN,
(42%)
PBu3
3) H2O2
O
HO
O
thapsivillosin F
(see also Ley's work on thapsigargins: PNAS (2004) 12073)
O
OTBDPS
O
CO2Me
H
O
BF3•OEt2 (2.5 mol%)
OH
17 steps
H
TESO
TBDPSO
H
O
H
TBSO
(3.5:1 Z:E)
OMOM
(>19:1 dr)
OAc
O
TBDPSO
H
NaOMe
(85%)
Cl
O
(R)-carvone
TBSO
H
TESO
H
(95%)
5 steps
H
O
H
TBSO
H
O
O
Guaianes and Xanthanes
Baran Group Meeting
Making the fused 5-7 ring system Part 1:
When 5 Leads
Organoiron approach: Donaldson et al. TL (2009) 1023.
OTBDPS
Synthesis of (±)-7-epi-!-bulnesene: Ovaska et al. TL (2002) 1939.
OTMS
O
O
CsF,
Me2CuLi,
TMSCl, Et3N
TBDPSO
Mg, THF;
H2O2,
HO-
PF6
Br
(57%)
Emily Cherney
Br
MeO2C
(60%)
TBDPSO
(43%)
Fe+ Me
(CO)3
MeO2C
H
Fe
H (CO)3
MeO2C
(rel. stereochem.)
CeCl2
(57%)
PPh3
DMSO
MeLi (5 mol%)
PhOEt, 155 °C
(50%)
H
1) LiAlH4
(57%) 2) C6Me3H3,
200 °C
H
OH
(84%)
H
7
steps
O
H
O
O
OH
O
(±)-7-epi-!-bulnesene
Approach to Geigerin: Jacobi et al. JOC (1992) 6305.
O
MeO2C
1) PhSeCl
2) H2O2
O
3) ethylene glycol,
TsOH
O
(32%)
CO2Me
MeO2C
1) NaOH, aq.
2) (COCl)2,
K2CO3, DMF
3) Me-alaninate, Pyr.
(60%)
CO2Me
Making the fused 5-7 ring system Part 2:
When 7 Leads (continued)
O
Synthesis of Sundiversifolide: Shindo et al. OL (2008) 1247. (continued)
O
HN
OH
1) DIBAL-H
2) nBuLi,
O
S
O
1) PhH, "
2) TBAF
3) Hydroquinone,
S
NaHCO3, "
O
N
OTBS
OMe
OMe
OMe
OMe
I
N
OTBDPS
O
O
O
N
Bn LDA
(92%)
O
Bn
OTBDPS
1) P2O5
(58%) 2) BF3•OEt2
SH
HS
(97%)
O
3) (COCl)2,
DMSO
S
Li
4)
5) TBSOTf, Et3N S
S
(82%)
O
O
1) TBDPSCl, imid. DMAP
2) nBuLi, (CH2O)n
3) Red-Al
4) MsCl, Et3N; NaI
O
MeO2C
MeO2C
S
TBDPSO
O
MeO2C
O
1) tBuLi
2) TBDPSCl, I
imid. DMAP
(88%)
O
O
AD mix-!
MeSO2NH2
tBuOH/H O
2
1) TBSCl, imid. DMAP
2) TBAF. AcOH
3) MsCl, Et3N;
NaI, Acetone OTBDPS
(82%)
O
O
N
OMe
TBSO
OTBDPS
OTBS
OH
Guaianes and Xanthanes
Baran Group Meeting
Making the fused 5-7 ring system Part 2:
When 7 Leads (continued)
Syntheses of (±)-Geigerin: Depres et al. ACIEE (2007) 6870.
O
Me
Synthesis of Sundiversifolide: Shindo et al. OL (2008) 1247. (continued)
O
MgBr
2) 6M HCl
1) TPAP, NMO
2) TBAF
(>99%)
( 87%)
OTBDPS
TBSO
OTBDPS
HO
Cl
Cl H
BF4
O
(rel. stereochem.)
(52%) CH2N2;
2 steps DMSO
OH
HO
1) MeO
O
(92%)
HO
4
steps
O
O
O
2 eq.
BrMg
then NaBH4
(49%)
3 steps
Cl
OH
OMe
O
(85%)
O
O
NaH, MeI
(96%)
O
OMe
H
MEMO H
O
OMe
1) Li, CH3NH2
2) MEMCl
(54%)
(82%)
MEMO H
HO H
OH
1) Swern [O]
2) S
Ph P CH2Li
N(Me)2
O
then MeI, Pyr.
(41%)
O
HO
H
O
H
OMe
Me
LiOH, H2O/THF, CO2;
I2, KI, NaHCO3
H
Eschenmoser's
salt;
"quaternization/
elimination"
(71%)
O
O
H
Me
O 12
Me
H
Ac2O, pry.,
DMAP
O
(±)"geigerin acetate
O
O
HO
(53%)
2 steps
Me AcO
dehydrocostus
O
lactone
O
12
O
O
I
8
O
O
O
H
Cl
6
(rel. stereochem.)
H
O
CO2Me
Me
H
1) LiCH2COLi2
(62%) 2) TMSCl, NaI
H
Cl
Me
H
Me
H
(77%) 50% aq TFA
mCPBA
O
7
Me
H
O
MeB(OH)2,
Pd(OAc)2,
(58%)
dpdb,
K3PO4
O
H
O
OTBS
LiClO4 (cat.)
2) DMDO, -90 °C
(dr at C7: 85:15)
Synthesis of Dehydrocostus Lactone: Rigby et al. JACS (1984) 8217.
O
TsOH
O
(+)-sundiversifolide H
Me
H
Me
H
O
PPh3
CF3 O
xylene
O
HO
Me
H
O
Cl3C Cl
Zn, ultrasound
MeLi,
0! 20 °C
(83%)
OH
1)
Emily Cherney
nBu
3SnH,
BEt3
Me
H
O
O
Me
HO
(±)"geigerin
O
Guaianes and Xanthanes
Baran Group Meeting
Synthesis of (+)-Achalensolide (highlights): Mukai et al. JOC (2008) 1061.
OPiv
MOMO OPiv
O 1)nBuLi, BF3•OEt2,
O
O
TMS
9
Making the fused 5-7 ring system Part 3:
Simultaneous Formations:
Studies Highlights 1: Lee et al. TL (2001) 1695.
1)
THPO
Li 2) LiAlH
4
THPO
1) NaH, BnBr, TBAI (cat.)
2) TsOH
3) Swern [O]
(73%)
CHO
•
HO
(68%)
Emily Cherney
steps
2) PivCl, Pyr.
O
O
(65%)
•
TMS
OTHP
1) TBSO
O
Pauson" 10 mol% [RhCl(cod)]2
mol % dppp,
(96%)
Khand-Type 50
1 atm CO, PhMe, !
Li
O
OBn 2) VO(acac)2, tBuOOH;
DBU, DCM, rt
O
AcO
•
H
•
Ac2O, DIPEA, DMAP
(52%)
BnO
O
O
OTBS
OTBS
10
steps
O
O
Clever Metathesis Strategies:
Sesquiterpene Aklaloid Synthesis: Craig et al. Eur. JOC (2006) 3558.
1) NaHMDS;
TBDPSO
6
steps
O
Studies Highlights 2: Wender et al. OL (1999) 137.
H
2.5 mol% [Rh(CO)2Cl]2,
DCE, 80 °C
•
(76%)
[5+2]
HO
H
1) DMP
2) MeMgBr
ZnI2,
Et2NH
EtO
(78%)
Michael/
Conia-ene
O
(79%)
O
O
HO
E
(+)-dictamnol
Ts
O
KOAc, BSA,
PhMe, µW, 160 C°
Ts
H
O
(±)-clavukerin A
1) NaOMe
2) DMAP, DIC HO
CO2H
Ts
O
(71%)
O
H
E=CO2Et
O
(>99%) Grubbs II
5 mol%
H
4 steps
N
O
(20%)
HO H
iPr
HO
N
O
(R)-citronellene
O
Studies Highlights 3: Lee et al. OL (2010) 548.
O
Br
2) HCl, MeOH
iPr
(See Wender's resiniferatoxin in Classics II)
O
OPiv
(+)-achalensolide
O
HO
OMOM
O
iPr
(77%)
CO2Me
(46%)
CO2Me
N
O
1) O3, PPh3
2) NH3 in EtOH
3) MeMgBr
O
N
(+)-cananodine
HO
O
Guaianes and Xanthanes
Baran Group Meeting
Emily Cherney
Synthesis of Teucladiol: Vanderwal et al. JACS (2009) 15090.
Clever Metathesis Strategies:
Synthesis of (!)- Dihydroxanthatin: Morken et al. OL (2005) 3371.
Me
HO
8
Br steps
Me
10% Pd(OAc)2,
2.5 eq Cu(OAc)2
OH
BuO
OshimaUtimoto
TBSO
MO
Me
Pd
(II)
H
i. tBuLi; ii. CuCN;
iii. cyclopentenone
Br
R
O
BuO
iv. O
(60%)
>10:1 dr
TMS
TMS
O
transselective
H
TMS
(68%)
1) Ph3PCH2Br,
Me
tBuOK
2) TBAF
TBSO
O
(85%)
1) 9-BBN, H2O2
2) Dess-Martin TBSO
(92%)
OBu
1) TESCl
(77%) 2) Grubbs II
(5 mol%)
Me
TBS
O
OBu
(±)-teucladiol
1) Dess-Martin
2) tBuOK
N2
PO(OMe)2
3) H2CrO4
OBu
(76%)
O
HO
O
O
TBS
Synthesis of Clavukerin: Metz et al. Eur. JOC (2010) 6145.
Me
O
N
H
(20%)
O
O
(59%)
O
(!)-dihydroxanthatin
O H
TESO
70%)
1) LDA, MeI
2) Grubbs II (5 mol%)
methyl vinyl ketone
O
(60%)
87:13 dr
HO H
HO
Grubbs II
(5 mol%)
could not alkylate
successfully
Me
O
Me
TESO
O H
1) MeLi, CeCl3
2) TsOH
O
Me
H
anti-aldol
FelkinOH
Anh
OHC
HO
Ph
Ph HO
OMe
CO2Et
O
(20%)
OHC
(90%)
Synthesis of (+)-8-epi-Xanthatin: Martin et al. OL (2005) 4621.
MeO
OH
O
OMe
TBAF
(78%)
TIPS
O
O
Me
O
(94%) CBr4, PPh3, DCM
O
O
H
Grubbs II (5 mol%)
methyl vinyl ketone (10 eq)
DCM (0.005 M)
(83%)
O
(+)-8-epi-Xanthatin
(S)-citronellal
Me
OTBS
12
steps
Grubbs II
(4 mol%)
H2C CH2
(55%)
O
PPh3+CH3BrnBuLi
(78%)
Br
Br
(!)-clavukerin A
Guaianes and Xanthanes
Baran Group Meeting
Emily Cherney
Synthesis of (±)-7-epi-!-Bulnesene: Negishi et al. JOC (1997) 1922.
Free Radical Strategies:
1) nBuNC
2) I2
3) HCl
Synthesis of (+)- Cladantholide: Lee et al. JACS (1997) 8391.
THPO
Br Et N,
3
OEt
DMAP
(98%)
THPO
H
AIBN
(99%)
5-exo;
7-endo
O
H
(79%)
O
OEt
H
MeO2C
h"
(53%)
1) TMSCl, DMPU,
MgBr
then Et3N
2) Et2Zn, CH2I2
HO
O
O
I
H
H
HO
(50%)
O
OH H
H
OTMS
(54%)
H
(50%)
H
OH
(±)-alismol
H
H
I
O
AIBN
(92%)
O
O
H
H
O
OH H
OCS2Me
with the
#$epimer:
NIS
H
(±)-kessane
Pd/C, H2
(67%
2 steps)
O
H
I
O
1) Ph3P
OH
H
nBu SnH,
3
OH
H
MeLi; CS2;
(90%) MeI
1) Acetone, H+
2) MeMgBr,
CeCl3
O
Fe(NO3)3
O
OH H O
H
OTMS
(76%)
3) I2, PPh3
O
TMS
Synthesis of (±)-Kessane: Booker-Milburn et al. OL (2003) 3309.
O
Synthesis of (±)-Alismol: Lange et al. JOC (1999) 6738.
1) iPrMgBr
I
3SnH,
AIBN
For an interesting synthesis of bulnesene from patchoulol see: TL (1975) 4495
H
H CO2Me 2) LiAlH4
nBu
(±)-7-epi-!-bulnesene
(+)- Cladantholide O
OEt
1) KH, H2O
2) iPr=PPh3
(46%
3 steps)
Br
O H
(18%)
O
MgBr
2) PCC
1) TsNHNH2
2) MeLi
3) Jones [O]
4) LDA, MeI
1) LDA, TMSCl O
2) DMDO
O
TMS
THPO
OEt
HO H
H
O
1)
OEt
O
H
H
nBu SnH,
3
THPO
(80%)
H
H
(68%)
(78%)
H
O
ZrCp2
I
HO
(4 steps from carvone)
1) TsOH
2) PCC
(nBu)2ZrCp2
Br
1) DIBAL-H
2)
MgBr
(77%)
CO2Me
2) BH3•THF;
PCC
3) Cp2TiCl2,
AlMe3
H
OH
H
(#:! 1:2.5)
Guaianes and Xanthanes
Baran Group Meeting
O
The Battle of Englerin A :
Ph
Echavarren Synthesis Highlights: ACIEE (2010) 3517.
OTES
OH
O
Me
H
O
(")-englerin A
Christmann Synthesis Highlights: ACIEE (2009) 9105.
1) BrZn
Me H O
Me H OH
4
steps
OH
2) LiAlH4
O
H
Me
H
CHO
2 steps from
cis-nepetalactone
H
Me
geraniol
H
OH
(+)-englerin A
2
steps
Me
H
3
steps
!
O
H
Me
O
Me
O
O
Nicolaou/Chen Synthesis Highlights: JACS (2010) 8220.
OBn
OBn O
O
MsCl, DIPEA;
14
steps
CO2Et
O
O
15 steps
10.9% overall
O
H
HO
O
O
H
O
O
Rh2(Ooct)4
(2 mol%)
O
OTBS
(R)-citronellal
O
O
H
Me
10
steps
OH
O
TBSO
O
O
O
O Me
14
steps
Ma's
intermed.
7
steps
(")-englerin A
if completed as
depicted:
Me
AuCl,
DCM, rt
(48%)
O
O
N2
O
(90%)
O
Ma Synthesis Highlights: ACIEE (2010) 3513.
OH
22 steps
2.6% overall
Theodorakis Formal Synthesis Highlights: OL (3708) 3708.
TBSO
OHC
(")-englerin A
Me
OTBS
5
steps
CO2Et
Me
(7 steps)
H
Me
O
18 steps
7% overall
Me
Me
HO
H
OH
O
(99%) Grubbs II
(20 mol%)
Me
9
steps
O
OH
H
(85%)
H
[iPrAuNCPh]SbF6
O
O
OH
Me
Me OTES
8
steps
(")-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.
Emily Cherney
(")-englerin A
16 steps
8.1% overall
22 steps
overall yield
???