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