Inoue Group - Group Meeting Problems 6/25/2016 Provide a reasonable mechanism for these reactions. 1 2-bromofuran NHAllyl CuTC*, DMEDA** O Cs2CO3 MgI2
toluene, 90 °C toluene, 120 °C N Ac N NHAc (sealed tube) Allyl 82% 60% * CuTC = copper(I) thiophene-2-carboxylate ** DMEDA = N,N'-dimethylethylenediamine
C. A. Leverett, G. Li, S. France and A. Padwa, J. Org. Chem., ASAP (2016) (doi: 10.1021/acs.joc.6b00771) 2
NHNs 1) OsO4, NMO OH OH acetone-H2O, rt 92% NNs
N 2) TFA, ClCH2CH2Cl Boc rt to 80 °C N 76%
G. Li, X. Xie and L. Zu, Angew. Chem. Int. Ed., Early View (2016) (doi: 10.1002/anie.201604770)
3 [Au(PPh3)]NTf2 (5 mol%) AgOTf (2 mol%) 2-bromopyridine N-oxide (2 eq.) MsOH (1.3 eq.), TFA (1.1 eq.) N ClCH2CH2Cl, rt; piperidine (0.4 eq.) N
N H AgOTf (1 eq.) HFIP, 150 °C ( W) N H O H NaHCO3 aq., rt 56% 74%
Y. Zhang, Y. Xue, H. Yuan and T. Luo, Chem. Sci., Advance Article (2016) (doi: 10.1039/c6sc00932h)
CO2 Me OH O O2C H Me N N H N H N NMe N N O H Me H Et O H N O CO2Me Me H Minfiensine Calophyline A Catharanthine Inoue Group - Group Meeting Problems D3 E. Yoshida
0. Monoterpene indole alkaloid 0-1. Outline of biosynthesis 6/25/2016
OHC NH OGlc N monoterpene NH + H H N 2 OGlc indole alkaloids H O MeO2C O MeO2C tryptamine (0-1) secologanin (0-2) strictosidine (0-3)
0-2. Skeletally rearranged derivatives
strictosidine (0-3)
-Glc
N N N NH N N H H H H O N H H H Me N Me CO2Me H OH MeO2C CO2Me MeO2C OH OH 0-4 geissoschizine (0-5) stemmadenine (0-6) dehydrosecodine (0-7)
N N H N N N N H H N N CO2Me CO2Me H H CO2Me CO2Me catharanthine (0-8) dehydrosecodine (0-7) tabersonine (0-9)
0-3. Classification by carbon structures
N N N H N N H N Me CO Me MeO C 2 H 2 CO2Me OH geissoschizine (0-5) catharanthine (0-8) tabersonine (0-9)
OHC
CHO
MeO2C CHO 0-10 corynanthe type (0-11) iboga type (0-12) aspidosperma type (0-13)
This carbon is sometimes removed by decarboxylation. 1 0-4. Selected examples of monoterpene indole alkaloids
N N N O O N MeN NH OH N MeO N OAc O Me O O CO2Me MeO from acetyl-CoA OMe
Gelsemine (0-14) Strychnine (0-15) Vindoline (0-16) Isoschizogamine (0-17)
corynanthe type (C10) corynanthe type(C9) aspidosperma type (C10) aspidosperma type (C9)
CO2 OH O Me N N N H N H O H Me Me Calophyline A (0-18) corynanthe type (C10) Minfiensine (0-19) corynanthe type? (C9)
0-5. Characteritics of indole chemistry
• C-3 and C-2 are easy to functionalize. • C-3 is 10^13 times more reactive to electrophiles than benzene. • C-2 is easily functionalized by lithiation.
• Indole synthesis is needed especially when C-4 to C-7 are functionalized. R Heck 4 R 5 3 Fukuyama Prefunctionalization of C-4 to C-7. 2 N 6 N Buchwald-HartwigH Fischer, aminometallation 7 H
• The asymmetric construction of C-3 quatenary center is a major synthetic challange.
• Indoles are easily oxidized due to the electron richness. However, a protecting group of N-1 is very limited. Only Boc and ArSO2 are useful.
1. Total synthesis of (±)-Minfiensine 1-1. Retrosynthesis
Diels-Alder reaction
NH2 OH enolate O coupling alkylation; N N X O H N aminal or Heck N Me H formation Me N Minfiensine (1-1) 1-2 1-3
The ethylidene unit dramatically narrows the retrosynthesis as is often the case with corynanthe alkaloids. 2 1-2. Reaction mechanism
2-bromofuran NHAllyl CuTC*, DMEDA** O Cs2CO3 MgI2
toluene, 90 °C toluene, 120 °C N Ac N NHAc (sealed tube) Allyl 82% 1-460% 1-5 * CuTC = copper(I) thiophene-2-carboxylate ** DMEDA = N,N'-dimethylethylenediamine
Br O NHAllyl NHAllyl NHAllyl 1-7 -H O A B I N NHAc N Cu Ac Ac 1-4 1-6 1-8
NHAllyl NHAllyl O O MgII C D N N Ac Ac 1-9 Step 1 1-10
NHAllyl NHAllyl NHAllyl
O MgII O O H E N N N Ac Ac Ac H 1-11 1-12 1-13
O
N Ac N Allyl 1-5 Step 2
Buchwald-Hartiwig coupling and Diels-Alder reaction. A: Formation of copper(I) amidate. B: Formal oxidative addition and reductive elimination.* C: Diels-Alder reaction. D: Lewis-acid promotes the cleavage of the strained C-O bond. E: 1,2-hydride shift. * The mechanism is still being discussed. see: S. L. Buchwald et al., J. Am. Chem. Soc., 131, 78 (2009)
3 1-3. Asymmetric total syntheses • Asymmetric Heck Reaction
O 1-15 Ph2P N t-Bu
Me Me NHBoc N 1-16 NHBoc Me Me Me OTf Pd(OAc)2 TFA N toluene CH2Cl2 N MeO2C N 170 °C ( W); N 0 °C Boc CO2Me CO2Me 1-14 1-1775%, 99% ee 1-18
A. B. Dounay, L. E. Overman and A. D. Wrobleski, J. Am. Chem. Soc., 127, 10186 (2005)
• Organocatalytic Diels-Alder reaction
O (15 mol%) NMe 1-20 NHBoc 1-Naph N t-Bu H•HO2CCBr3 NaBH4 CHO CeCl3•7H2O OH
MeOH N SMe Et2O PMB N N SMe –50 °C –50 °C to rt Boc PMB 1-19 87%, 96% ee 1-21
S. B. Jones, B. Simmons and D. W. C. MacMillan, J. Am. Chem. Soc., 131, 13606 (2009)
• Asymmetric Tsuji-Trost reaction
NHBoc Pd2(dba)3 (2 mol%) ligand 1-24 (4.5 mol%) O O K2CO3 NH PPh2 OCO Me 2 N Ph2P HN toluene, 50 °C Ac N N Allyl H 91%, 89% ee 1-22 1-23 ligand 1-24
Z.-X. Zhang, S.-C. Chen and L. Jiao, Angew. Chem. Int. Ed., Early View (2016) (doi: 10.1002/anie.201602771)
4 2. Total synthesis of (±)-Calophyline A 2-1. Related natural products
OHC CO2Me OHC CO2Me N N 1,2-migration H H (rare) N N N N H Me MeO2C OH Rhazimal (2-2) Me The C-N bond migrates. 2-5 Me dehydrogeissoschizine (2-1) 1,2-migration (popular)
CO2Me CO2 CO2Me O MeO Me Me N N N N H N H N H O H Me Me Vincorine (2-4) 2-3 Calophyline A (2-6)
2-2. Retrosynthesis
Me Me O O2C H H aldol HO2C NH NMe N O see 1-1 N N O O H N
Calophyline A (2-6) 2-7 2-8
2-3. Reaction mechanism
NHNs 1) OsO4, NMO OH OH acetone-H2O 92% NNs
N 2) TFA, ClCH2CH2Cl Boc 23 to 80 °C N 2-976% 2-10
NHNs NHNs NHNs OH OH OH2 OsO4 OH -Boc OH A B N N N OH Boc Boc OH H 2-9 2-11Step 1 2-12
5 NHNs NsHN NsHN OH OH OH +H OH OH
N OH N N H 2-12 2-12' 2-13
NsHN NsHN NsHN OH OH OH +H OH2 C N N H N H 2-14 2-15 2-16
OH OH
NNs NNs
N N H Step 2 2-17 2-10
Aza-pinacol rearrangement. A: The bulky Boc group or the directing hydroxy group are responsible to the complete facial selectivity of osumium-catalyzed dihydroxylation. B: Aza-pinacol rearrangement. C: Conjugate addition.
2-4. Another application
Me NNs I 1) OsO4, NMO 1) ClCO2Me acetone-H2O, rt NsN I NaH, THF, rt O OH 94% O 83% I N 2) p-TsOH•H2O 2) PhSH, MeCN, rt; MeO C N Me N benzene, 85 °C 2 Boc p-TsOH•H2O, 85 °C 81% 67% N 2-18 2-19 2-18 Minfiensine precursor Y. Yu, G. Li, L. Jiang and L. Zu, Angew. Chem. Int. Ed., 54, 12627 (2015)
3. Formal synthesis of Catharanthine 3-1. Retrosynthesis
known 1,2-rearrangement H N conversion N (Stevens rearrangement) O HN N N N H Et H CO2Me O Catharanthine (3-1) 3-2 3-3
N N
N O N O 6 H H 3-2. Reaction mechanism
[Au(PPh3)]NTf2 (5 mol%) AgOTf (2 mol%) 2-bromopyridine N-oxide (2 eq.) MsOH (1.3 eq.), TFA (1.1 eq.) N ClCH2CH2Cl, rt; piperidine (0.4 eq.) N
N H AgOTf (1 eq.) HFIP, 150 °C ( W) N H O H NaHCO3 aq., rt 3-456% 3-2 74%
3-6 N Br H O N N
N H AN H B H H 3-4 3-5 AuI
Br H H N N N OMs O O N H C N H H H AuI 3-7Au 3-8
H N H O +H N -H O N H H OMs N H H OMs 3-9Au 3-10
Ag O MsO N O O N D N N H H OMs N H N H H H 3-11 3-12 3-13 Step 1
N N +piperidine see 3-2 hydrolysis N N 3-2 E H N N H H 3-14 3-15 Step 2
Stevens rearrangement. A: Protonation of amine under the acidic conditions. B: Nucleophilic attack to the more cationic site. C: Generation of gold(I) carben. D: Silver(I) activates the methansulfonate.* E: Enamine- catalyzed Stevens rearrangement. * The counteranion is not determined. 7 3-3. Discussion on 1,2-rearrangement
H N N 1,2-rearrangement N N HN unknown mechanism H N
3-14 3-15
• Concerted pathway (theoretically denied)
H H N N N N N HN HN N H N
3-14 3-15 retention of stereochemistry
1,2-carbanion rearrangement* is symmetrically forbidden. *2 pairs of (4n+2) electrons participate in the reaction, and both of C-N -bond and enamine 6e- are supra. So there are even number of (4n+2)s electrons, and such reaction is denied by Woodward-Hoffmann rules.
• Biradical pathway (proposed by authors, standard mechanism of Stevens rearrangement)
H H H N N N HN N HN N HN N
3-14 3-16 3-17
H H N N HN N HN N
3-18 3-15
• Cationic pathway (proposed by authors)
H H H N N N HN N HN HN HN N
stabillized cation 3-14 3-19 3-15
8