Classic Terpene Syntheses
Baran Lab
Tom Maimone
I. An Introduction to Terpenes
-Terpenes are an enormous class of natural products spanning well over 30,000 members
-They have been used throughout history for a broad variety of purposes including perfume, medicine, and flavoring
-Recognized early on as being composed of isoprene fragments
-Isopentyl diphosphate (IPP) and dimethyl allyl diphosphate (DMAPP) later found to be the actual building blocks
-There are 2 biosynthetic pathways for the production of IPP and DMAPP, the mevalonate pathway and the more recently
discovered deoxyxylulose pathway
Isoprene
The Chemistry of the Mevalonate Pathway:
O
O
O
Claisen
SCoA
OH O
Aldol and
Hydrolysis
SCoA
HO2C
SCoA
acetoacetyl-CoA
SCoA
H
HMG-CoA
SEnz
OH
HO2C
SCoA
mevaldic acid
hemithioacetal
O
acetyl-CoA
OH OH
NADPH HO C
2
O
mevaldic acid
O
NADPH
O
HO
-CO2
- Equilibrium
favors DMAPP
OPP
O
OH
O
ADP
OH
2xATP
HO2C
OPP
Isomerase
O
IPP
DMAPP
OPP
The Chemistry of the Deoxyxylulose Pathway:
O
NH2
OH
OP
OH
Pinacol-type
rearrangement
OH
OH
NADPH
O
OH
1. CTP
OP
OP
OH
OH
O
2. ATP
OH
OH
O
O
P
OH
N
O
O
OH
P
O
O
OH
2-C-methyl-D-erythritol 4-P
H+
OH
mevalonic acid (MVA)
P
OH
O
P
OH
HO
OH
O P O
N
O
OH
O
1-deoxy-D-xylulose 5-P
(from pyruvic acid)
OPP
DMAPP
Isomerase
OPP
IPP
steps not
fully determined OH
O
P
O
OH
OH
* For an excellent review on natural products and biosynthesis see: Dewick, P.M. Medicinal Natural Products: A Biosynthetic Approach. Wiley, 2002.
1
Classic Terpene Syntheses
Baran Lab
Tom Maimone
- All terpenes are formed through the reactions of IPP and DMAPP:
stereospecific
proton loss
OPP
OPP
DMAPP
OPP
OPP
IPP
H
H
Monoterpenes
geranyl PP (GPP)
- repeat several times:
Sesquiterpenes
Hemiterpenes (C5)
Monoterpenes (C10)
Sesquiterpenes (C15)
Diterpenes (C20)
Sesterterpenes (C25)
Triterpenes (C30)
Tetraterpenes (C40)
OPP
farnesyl PP
Diterpenes
OPP
geranylgeranyl PP
Triterpenes (Steroids)
squalene
- The interesting Chemistry involves the fate of the open-chain terpenes.
A seemingly endless number of (enzyme-mediated) carbocation cyclizations
leads to many different carbocyclic skeletons, which are often further oxidized
and rearranged.
Menthane
Type
Pinane
Type
Bornane
Type
OPP
OPP
OPP
with only 2 prenyl units:
• 7 unique skeletons
• several sites of
hydration or elimination
to terminate carbocation
Fenchane
Type
Isocamphane
type
Carane
type
Thujane Take Home Message: Complexity increases
extremely rapidly with each addition prenyl unit
type
2
Classic Terpene Syntheses
Baran Lab
Tom Maimone
II. Commercially available Terpene Building Blocks*
OH
O
OH
OH
O
OH
Carvacrol
$2.37/g
(-) carveol (isom. mix)
$1.326/g
(-) acetate $7/g
Carvone
(+) $1.76/g
(-) $0.20/g
Dihydrocarveol
(+) Dihydrocarvone
(+)-Isomenthol
(-) $14/g
isomer mixture $1.6/g isomer mixture $0.7/g $0.18/g
O
HO
Isopulegol (-) Menthone (-) Menthyl chloride
(+) $95/g
$ 0.54/g
$ 16.4/g
(-) $25/g
OH
CO2H
O
OH
OH
OH
OH
O
OH
trans-p-menth- !-terpineol
6-ene-2,8-diol (+) $38/g
$1.82/g
(-) $0.4/g
O
Limonene
(+) $0.09/g
(-) $0.23/g
Limonene oxide
(+) Menthofuran
mixture of isomers
$3.88/g
(+) $0.72/g
(-) $0.58/g
Neomenthol
Menthol
(+) 11.5/g
(+) $2.2/g
(+) and (-) acetates
(-) $0.19/g
available
many o-acetylated
derivatives available
Perillic acid
$14/g
O
OH
!-Phellandrene
$0.164/g
O
Perillyl alcohol
(+) $44/g
(-) $1.9/g
OH
NH2
O
OH
Perillaldehyde
(+) $53/g
(-) $2.88/g
Cl
OH
!-Pinene
(+) $0.28/g
(-) $0.1/g
Pinanediol
(+) $20/g
(-) $17/g
"-Pinene
(-) $0.04/g
Pinene Oxide
$0.332/g
2-Hydroxy-3-pinanone
(+) $22/g, (-) $15/g
Isoborneol
(-) Isobornylamine
$0.09g
O-acrylate $0.08/g $1360/g
OH
OH
O
CO2H
(+) Ketopinic acid
$60/g
(+) Nopinone
$31/g
(-)-Nopol
$0.13/g
Benzyl ether
available
OH
(-)-Myrtanol
$22.7/g
*Aldrich Prices (some prices are significantly lower from other suppliers)
NH2
(-)-cis-Myrtanylamine
$12.9/g
O
(-)-Myrtenal
$2.24/g
OH
(-)-Myrtenol
$2.07/g
[(1S)-endo]-(-)-Borneol
$0.31/g
3
Classic Terpene Syntheses
Baran Lab
O
OAc
NH2
OH
(+)-3-Bromocamphor-8sulfonic acid ammonium
salt $6/g
(-)-3-Bromocamphor
$4.6/g
N
O
O
4'-Bromo-cis-2',3'-epoxybutyl (1S)-camphor
sulfonate $217/g
O
Camphorquinone
(+) $12.5/g , (-) $5.14/g
O
S
O2
(+)-3-Bromocamphor10-sulfonic acid hydrate
$57/g
O
S
O2
(2-Butenoyl)-2,10-camphorsultam
(+) or (-) $45/g
O
Camphene
(+) $0.045/g
(-) $0.055/g
Camphor
(+) $0.205/g
(-) $5.49/g
CO2H
N OMe
Camphorquinone 3-oxime
(+) $126/g , (-) $86/g
O2S
Camphanic acid
Camphorsulfonamide
(+) $150/g , (-) $20/g
$24/g either ent.
(-) acid chloride $22.6/g
O
HO2C
HN
SO2NH2
2,10-Camphorsultam
(+) $59/g, (-) $32/g
O
CO2H
N
Camphoric acid
(+) $23.7/g, (-) $73.7/g
NHSO2pTs
N
SO2
Camphor p-tosylhydrazone 10-camphorsulfonyl oxaziridine
(+) $1.4/g, (-) $8.8/g
(+) $65/g, (-) $61/g
O
N
SO3H
O
O2
O S
O
O
O
O
Br
Br
Br
Br
(-) Bornyl acetate (+)-Bornylamine
$194/g
$0.18/g
(+) Borneol
$53/g
H4NO3S
Tom Maimone
(+)-2-Carene
$3.3/g
O
OH
O
SO3H
Camphor sulfonic acid
(-)-Camphorsulfonylimine (-) $0.82/g, (+) $0.32/g
(-) Ammonium salt $0.92/g
$26.80/g
sodium salt $0.25/g
(+) sulfonyl chloride $2.34/g
(-) sulfonyl chloride $10.0/g
"-Ionone
$0.24/g
!-Ionone
$0.27/g
3.7Dimethyl-3-octanol
$4.13/g
Alloocimene
$ $0.13/g
H
(-)- Cedrene
$46/g
3-Carene
$0.056/g
#-terpinene
$0.39/g
!-Copaene
$270/g
Guaiazulene
$3.1/g
(-)-Guaiol
$700/g
OH
(-)-!-Cubebene
$ 1180/g
4
Classic Terpene Syntheses
Baran Lab
Tom Maimone
H
OH
CO2H
O
Br
O
OH
H
H
(+)-8(15)-Cedren-9-ol
$288/g
(-) Carophyllene oxide Citronellyl Bromide
(+) $6/g, (-) $30/g
$2/g
Citronellic acid
(+) $16/g, (-) $78,g
(+/-) $2/g
!-Citronellol
(+) $50/g, (-) $19/g
(dl) $0.13/g
!-Citronellene
(-) $1.70/g
Citronellal
(+) $16.5/g,
(-) $13/g
OH
(+)-Disparlure
$812/g
O
O
(+)-"-Longipinene
$342/g
(+) Longifolene
$10.3/g
O
(-) Linalool
$0.63/g
O
OH
OH
X
OH
nerolidol
all trans $70/g
cis/trans $0.75/g
!-Thujaplicin
$8.6/g
(-)-"-Thujone
$25/g
",!#mix $5.5/g
(S)-cis-Verbenol
$8/g
O
(-) Verbenone
$2.8/g
OH
Squalene
$0.43/g
nerolidol
all trans $70/g
cis/trans $0.75/g
OH
Farnesol
$1.1/g
(+)-Nootkatone
$18/g
trans,trans
$ 10/g (also bromide,chloride, acetate)
Br
Prenyl Bromide
$2.1/g
geraniol (X=OH)
$0.35/g
acetate $0.53/g
bromide $3.88
chloride $5.85
amine $23/g
acid $0.92/g
H
O
OH
O
O
Parthenolide
$3724/g
Totarol
$156/g
5
Classic Terpene Syntheses
Baran Lab
OH
H
H
H
OH
H
H
H
H
H
HO
Estriol
$72/g
H
Estradiol
$24.6/g
HO
OH
O
H
H
H
H
H
H
17!"Ethynylestradiol
$28.6/g
O
H
CO2H
H
HO
H
H
H
H
O
19-Hydroxy-4-androstene3,17-dione
$916/g
O
H
O
H
O
H
AcO
Hydrocortisone
$10/g
H
H
Hecogenin Acetate
$11.2/g
H
Prednisone
$13.4/g
several related
derivates available
O
O
H
H
H
H
O
H
O
H
O
OH
Ursodeoxycholic acid
$12.3/g
Ethisterone
$3.4/g
OH
H
H
O
Norgestrel
$290/g
OH
H
H
OH
OH
OH
O
H
OH
HO
H
Ergocalciferol (D2)
$15.7/g
11!-Hydroxyprogesterone
$8.3/g
Fusidic acid
$108/g
H
HO
Glycyrrhetinic acid
$5.4/g
H
O
HO
O
H
H
OAc
H
HO
HO
HO
HO
CO2Na
HO
H
O
H
HO
Estrone
$14.2/g
CO2H
OH
H
HO
Tom Maimone
H
O
H
H
SAc
Spironolactone
$26/g
H
H
H
HO
H
H
HO
Stigmasterol
$12.5/g
#-Sitosterol
$0.26/g
6
Classic Terpene Syntheses
Baran Lab
O
O
O
AcO
O
HO
HO
O
OH
H
OH
OH
OH
OH
H
O
H
O
Progesterone
$2.24/g
O
OH
OH
O
H
H
H
O
5-!-Cholestane
$60/g
O
O
H
O
MeO
OMe
Cortisone
$22/g (several derivates
available)
(-)-!-Santonin
$2.64/g
Rotenone
$4.16/g
O
O
HO
H
OH
H
H
H
HO
H
O
O
H
5-!-Cholestan-3-one
$20/g
(several unsaturated variants
available)
H
O
OH
O
O
H
OH
H
H
H
H
O
(-)-Oubain Hydrate
$75/g
H
Sclareol
$32/g
O
OBz O
Paclitaxel
$9500/g
OH
OH
O
OH
O
O
N
H
H
H
Tom Maimone
H
H
HO
H
OH
O
H
Digoxigenin
Cholesterol
$586/g
$0.30/g
(many derivatives available) (several derivatives available)
H
Dipterocarpol
$138/g
H2N
Dehydroabietylamine
(+) $0.27/g
HO
H
Cholecalciferol
$19.5/g
7
Classic Terpene Syntheses
Baran Lab
O
OH
OH
O
O
O
HO
OO
H
H
H
H
H
F
H
HO
O
H
O
H
H
O
HO
HO
OH
Chenodeoxycholic acid
$7.94/g
Betamethasone
$ 696/g
H
O
H
OH
Tom Maimone
H
OH
O
Androsterone
$45/g
Andrographolide
$175.4/g
Artemisinin
$416/g
CO2H
O
O
H
H
H
OH
H
H
H
O
1,4-androstadiene-3,17-dione
$70/g
O
4-Androstene-3,17-dione
$7.44/g
H
H
H
H
HO
H
H
Lithocholic acid
$1.24/g
H
HO
Betulin
$58.6/g
8
Classic Terpene Syntheses
Baran Lab
Tom Maimone
III. Synthesis Discussed
Disclaimer:
Natural Products
arising from mixed
biosynthetic pathways
(terpene/alkaloid, terpene/
polyketide) were not
considered.
HO
O O
O
H
HO2C
O
O
O
H
H
OH
O
H
O
HO
O
O
OH
Pleuromutilin
Boeckman
Qinghaosu
Hofheinz
Anisatin
Kende
OH
OH
O
HO
O
O
Cembrene
wender
Jatropholones
A.B. Smith
CO2H
Antheridium-Inducing Factor (AAn)
Corey
Some Classics not discussed:
O
O
O
O
O
HO
O
O
O
HO
HO
H
O
H
O
H
OC
HO
OH
H
Gibberellic Acid
Corey
OH
O
H
CO2H
H
O
O
Progesterone
Johnson
O
O
H
O
Ginkgolide B
Corey
O
H
Retigeranic acid
Corey
Molecules were chosen that
are not typically covered in
the synthetic organic
chemistry classes at TSRI.
The interested reader can
find many more classic
syntheses in the followiing
locations.*
OH
O
HO
Periplanone
Still
O
Picrotoxinin
Corey
Nicolaou, K.C.; Snider, S.A. Classics in Total Synthesis II. VCH, Weinheim, 2003.
* Nicolaou, K.C.; Sorensen, E.J. Classics in Total Synthesis. VCH, Weinheim, 1996.
Corey, E.J.; Chen, X. The Logic of Chemical Synthesis. Wiley, 1995.
9
Ho, T.L. Enantioselective Synthesis: Natural Products from Chiral Terpenes. Wiley, 1992.
Classic Terpene Syntheses
Baran Lab
O
OH
OH
O
Tom Maimone
OR
OTBS
OTBS
TBSO
O
i) pyrrolidine, cat. H+,!
ii) HOAc/H2O/NaOAc, !
O
O
OR
Pleuromutilin (R=C(O)CH2OH)
O
(R=H (mutilin)
LDA, THF, -23°C
O
O
(1:5) 73%
2
1
Boeckman et al. J. Am. Chem. Soc. 1989, 111, 8284-8286
OTBS
OTs
OH
93%
5
1:1 86%
KH, 18-crown-6
25°C
110°C
99%
-78°C
74%
O
OH
6
i) HOAc,H2O, THF
(CH3)2CuLi
MgBr
O
O
98%
4
3
i. PhSCl,
then P(OEt)3, MeOH, !
(70% over 2 cycles)
O
O
i. MCPBA
ii. BF3•OEt, then (CH2OH)2
O
7
ii) p-TsCl
O
89%
O
O
H
8
i. NH3/Li, THF,
then NH4Cl
ii. KH, BnBr
H
BnO
69%
O
O
i. PyH Br3
8:1
9
O
O
Br
H
10
" The relative facility of the rearrangement in the present case may
be due in part to the absence of side reactions such as retro ene
porcesses owing to the presence of the allyl unit in a rigid framework"
10
Classic Terpene Syntheses
Baran Lab
O
OH
O
OH
O
Tom Maimone
OR
O
O
OR
BnO
Br
H
i. KO-t-Bu
O
67% (2 steps)
BnO
acetone, !
H
10
Pleuromutilin (R=C(O)CH2OH)
O
1M aq. TsOH
67%
11
(R=H (mutilin)
iii. MCPBA, NaHCO3
iv. aq. TBAF
62%
OH
OMOM
ii. PCC
iii. HCl-EtOH
OH
Mutilin
80%
OMOM
i.
MgBr
ii. SOCl2
i. Li/NH3
H
OH
12
i. CH3OCH2Cl
iPr2NEt3
ii. TMSI, HMDS -20°C
10°C, then NaHCO3
Boeckman et al. J. Am. Chem. Soc. 1989, 111, 8284-8286
O
H
BnO
BnO
O
iii. CH3CuB(CH3)3
H
OMOM
15
60% (5:1)
BnO
H
OMOM
14
OH
O
i. MOM-Cl
BnO
H
OMOM
13
i. AcOCH2COOMs,
DMAP
ii. KOH, MeOH
OH
O
H
O
O
Pleuromutilin
OH
11
Classic Terpene Syntheses
Baran Lab
Tom Maimone
O
O
X
i. Me2LiCu•SMe2
O
ii. CH2N2
O
O
O
HO
HO
O
OH
O
MeO
i. 2M MMC, DMF, !
1
OMe
MMC
CO2Me
SiMe3
i. MeMgBr
ii. MeOH, HCl
60%
3
ii. KOH, EtOH, !
Deoxyanisatin (X=H)
O
O
41%
2
Mg
X=OH (Anisatin)
Kende et al. J. Am. Chem. Soc. 1985, 107, 7184-7186
O
O
O
i. LiAlH4
O
ii. KIO4, cat. KMnO4
K2CO3, t-BuOH/H2O
MeO2C
iii.
p-TsOH (cat), !
OBn
5
6
33%
OBn
cat. MeSO3H 75%
!
O
i. BBr3
70%
OBn
7
5:4
4
i. CF3CO3H
37%
O OH
O
O
O
OH
O
76%
OH
OO
10
O
OH
OH
OH
OH
11
O
HO
LiOH, MeOH
O
PhSO2Cl
O
O
O OH
O
O
HO
i. NaClO2
100%
OH
9
O
HO
O
O
O
8
O
O
i. OsO4 (1.1 eq)
ii. PDC
CO2Me
CO2Me
O
O
BnOCH2Cl
87%
OBn
O
O
LDA
OBn
OH
13
OH
90%
HO2C
OH
OH
OH
12
12
Classic Terpene Syntheses
Baran Lab
Tom Maimone
OH
O
O
i. H2SO4
LDA
F3CSO2Cl
95%
38%
OMe
(-)-3Z-Cembrene A
3.7:1
2
1
O
i. Li
Cl
ii. Li
-78 °C
!
iii. LiAlH4, O°C
(one pot)
OMe
OMe
57-61%
KH, 18-crown-6
rt
48-55 %
Wender et al. J. Am. Chem. Soc. 1985, 107, 7771-7772
O
OH
OH
AcOMs
i. Ac2O, pyr:
H2, PtO2
NaBH4
34%
ii. Li, EtNH2
74%
Hexane/EtOAc
59%
CeCl3
91%
OMe
OMe
7
OMe
6
3
OMe
5
4
H
O O
O
H
i. MOMCl, PhN(CH3)2
H
H2O2
MOMO
80%
O
Qinghaosu
O O
HO
1
ii. HCl, MeOH
iii. PCC
73%
O
I
Me3Si
LDA
62%
H
BnO
O
H
BnO
3
2
TMS
OMe
89%
Li
O
ii. HCOOH, 0°C
O
Me3Si
Hofheinz. et al. J. Am. Chem. Soc. 1983, 105, 624-625
(Hoffman-la Roche)
O
i. 1O2 methylene
blue, MeOH, -78°C
H
O
H
Isopulegol
H
O
H
ii. B2H6
HO
O
i. BnBr, KH
30 %
Bu4NF
H
O
HO2C
7
95%
Me3Si
MeO
Si O
O
6
mcpba;
TFA
72%
MeO
i. Li/NH3
Si O
O
H
5
ii. PCC
75%
Me3Si
HO
MeO
H
TMS
4 OBn
13
Classic Terpene Syntheses
Baran Lab
Tom Maimone
H
O
N
H
HO2C
EtAlCl2
O
PhH, !
CHO
Retigeranic Acid
i. LiAlH4
Corey et al. J. Am. Chem. Soc. 1985, 107, 4339-4341.
Ph
Ph
P
Rh
i.
MgBr
O
H
80%
6
P
CrO3, H2SO4
ii. KHSO4
Ph
93%
H
5
H
OHC
61%
H
H
3
O
O
CO2Me
11
O
O
2
O
O
H
CO2Me
i. LAH
ii. o-NO2C6H4SeCN,
(n-Bu)3
MCPBA; DMS
80%
7
H
O
O
O
H
75%
H
80%
OH
ii. KOH
99%
OH
O
(Ph)3P
[2+2]
H
i. PPh3, DEAD
PhCOOH
Ph
89%
4
CHO
(CH2)4 BF4
H2, 950 psi
OH
CO2Me
!
1
racemic
H
H
O
•
O
H
8
H
CO2H
9
I. H2SO4
II. NaOH
i. (COCl)2
ii. Et3N
H
H
10
14
Classic Terpene Syntheses
Baran Lab
Tom Maimone
H
SMe
H
O
i. Li
HO2C
OH
H
SMe
SMe
Me
H
73%
11
H
H
12
i. CuOTf, Et3N
ii. NaIO4, aq. Dioxane
iii. Al/Hg, H2O
65%
Retigeranic Acid
Corey et al. J. Am. Chem. Soc. 1985, 107, 4339-4341.
H
i. TsNHNH2
i. H2, Pd/C, Pyr
ii. catechol borane
iii. (n-Bu)4NOAc
15
H
H
H
H
H
H
SMe
O
H
83%
ii. NaOMe, -78 °C
HOAc
74%
14
O
H
13
i. OsO4, py, NaHSO3
ii. Pb(OAc)4
iii. neutral Al2O3, 4-A MS
69%
H
H2O/t-BuOH
H
16
CHO
H
NaClO2, NaH2PO4
85%
H
COOH
Retigeranic Acid
15
Classic Terpene Syntheses
Baran Lab
Tom Maimone
OH
O
O
H
OMe
i. Cl
O
N
O
O
H
ii. H2O
iii. KOH/MeOH
OH
2
1
Jatropholones
i. p-TsOH (-H2O)
OAc
O
ii. LDA, HMPA, Me2SO4
57% (overall)
O
5 kbar
80 %
A.B Smith et al. J. Am. Chem. Soc. 1986, 108, 3040-3048
O
4
3
OTES
OTES
OMe
OTES
3,5-dimethyl
pyrazole/CrO3
H
H
i. HCl
H
ii. CH2=P(Ph)3
iii. TESCl
(34%)
O
H
H
H
7
1:6
57%
6
HH
O
H
O
H
5
i.LDA, MeI
ii. TBAF
OMe
OH
OH
O
H
H
OBn
O
O
H
Jatropholone A
can also be employed in place
of 3, although the ensuing
Diels Alder step is problematic
24:76
H
Jatropholone B
16
Classic Terpene Syntheses
Baran Lab
Tom Maimone
OH
i. Na/NH3, t-BuOH, -78 °C
MeI (xs)
I
HO
Ni
MeO
Ni
80%
Br
CO2H
O
DMF, 35°C
Br
O
85%
MeO
CO2Me
CO2Me
1
Antheridium-Inducing Factor (AAn)
2
Corey et al. J. Am. Chem. Soc. 1985, 107, 5574-5576
N
Cu
O
O
H
N
O
TBDMSO
PhCH3, !
84%
H
i. DIBAL
O
CHN2
5
H
i. ZnBH4
ii. TsNH=CHCOCl
PhNMe2
iii. Et3N
91%
TBDMSO
CO2Me
4
ii. TBDMSOTf
69%
O
CO2Me
3
8:1
H
O
i. Br2, O°C
TBDMSO
H
6
O
O
ii. DBU, DMF,
63% BRSM
72%
80%
O
O
OTBDMS
O
O
O
9
8
LiNEt2
79%
O
OH
O
TFAA
pyr
90%
OTBDMS
13
MeCO3H
OTBDMS
7
O
CHO
H
O
O
F3C
Et2AlCl, 0°C
TBDMSO
CO2Me
OTBDMS
CHO CO2Me
12
O2N
OH
i. KOH
ii. K2S2O8, RuCl3,
t-BuOH/H2O OTBDMS
OH
NO2
OTBDMS
iii. CH2N2
68%
O
O
11
H
N
76%
O
O
10
17
Classic Terpene Syntheses
Baran Lab
O
O
OH
F3C
F3C
O
O
DBU
OTBDMS
O
CO2H
90%
CHO
Antheridium-Inducing Factor (AAn)
O
i. NaClO2, NaH2PO4
H2O/t-BuOH
O
O
O
HO
Tom Maimone
OTBDMS
CHO
CO2Me
ii. 2,6-lutidine
CF2CF3OH
CO2Me
OTBDMS
95%
13
O
CO2Me
O
14
i. Et3N, TMSCL, LDA
ii. (i-Pr)2NEt, MeI
Corey et al. J. Am. Chem. Soc. 1985, 107, 5574-5576
H2C
N
O
I
iii. aq. K2CO3
HF-Py
HO
O
O
60%
HO
HO
OTBDMS
CO2Me
NaBH4
O
16
Originally Proposed
structure (methyl ester)
OTBDMS
O
91%
CO2Me
O
O
O
CO2Me
15
i. HF-Py
ii. PDC
iii. NaBH4
iv. LiOH
HO
HO
O
O
CO2H
Antheridium-Inducing Factor (AAn)
18