Problem Session (6) - Problem 2021.4.10. Yusuke Imamura Please provide the reaction mechanisms. Values in the parentheses are the amount (eq.) of the reagent. In 3rd reaction of problem 1, please provide each reaction mechanism w/ or w/o the additive and explain the effect of the additive.
• problem 1
1. MeOH, 65 °C 95%, 1.9:1 dr, 62% desired 2. NH3, MeOH; concentration; O (CF3CO)2O (1.0), Et3N, THF, 96% MeO2C 3. NaBH3CN (2.0), additive MeOH/THF, 65 °C NH2 N HN N N N •HCl H O H H 1-11-2 O 1-31-4 (harmalane) (1.1)
additive 1-3 1-4 (harmalane)
none <20% major
71% not mentioned F3C CHO (2.6)
• problem 2
1. TsOH·H2O (1.0), MeOH, reflux; Et3N (2.0), Boc2O (3.0), rt, 65% 2. LiN(TMS)2 (2.5), PhI(OAc)2 (2.5) THF, -78 °C to rt, 65% 3. NaBH3CN (10.0), AcOH (10.0) MeOH, 0 °C; 4 M HCl in dioxane, 0 °C to rt, 70% H 4. vinylMgBr (10.0), CeCl3 (10.0) OH O THF, -78 °C, 30% (100% brsm) HN NH2 N O N H H 2-1 2-2 2-3 (racemic) (2.0)
5. CF CO H (2.0), paraformaldehyde (1.1) 3 2 O toluene/MeCN (v/v = 3:1), rt; PhIO (2.0), rt; H H 19 2 M KOH aq., rt, 59% N N 2-4 (racemic) Problem Session (6) - Answer Topic: Total Synthesis of Arborisidine 0. Introduction of Arborisidine • Isolation: from Malayan K. arborea Blume by Kam and co-workers (Wong, S.-P.; Chong, K.-W.; Lim, K.-H.; Lim, S.-H.; Low, Y.-Y.; Kam, T.-S. Org. Lett. 2016, 18, 1618−1621.) • Biosynthesis OH OH N N O X [O] N N
N N N N H H 0-4 0-5 pericine (0-1) 0-3 O O O O H H NH N N N H2O
N N N H N arborisidine (0-2) 0-8 0-7 0-6
• Biological activities Arborisidine inhibits gastric cancer in vivo when used in combination with pimelautide. (Chinese Patent CN106540237 A, 2016.) • Total syntheses of related Monoterpene Indole Alkaloids O H (+)-arborisidine: (problem 1) N Zhou, Z.; Gao, A. X.; Snyder, S. A. J. Am. Chem. Soc. 2019, 141, 1650. (-)-arborisidine (enantiomer): (problem 2) N Andres, R.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2020, 142, 14276. arborisidine (0-2)
OH
N (?)-arboridinine: Gan, P.; Pitzen, J.; Qu, P.; Snyder, S. A. J. Am. Chem. Soc. 2018, 140, 919. (+)-arboridinine: N Zhang, Z.; Xie, S.; Cheng, B.; Zhai, H.; Li, Y. J. Am. Chem. Soc. 2019, 141, 7147. arboridinine (0-9)
1. Answer for problem 1 1. MeOH, 65 °C 95%, 1.9:1 dr, 62% desired 2. NH3, MeOH; concentration; O (CF3CO)2O (1.0), Et3N, THF, 96% MeO2C 3. NaBH3CN (2.0), additive MeOH/THF, 65 °C NH2 N HN N N N •HCl H O H H 1-11-2 O 1-31-4 (harmalane) (1.1)
additive 1-3 1-4 (harmalane)
none <20% major
71% not mentioned F3C CHO (2.6)
Zhou, Z.; Gao, A. X.; Snyder, S. A. J. Am. Chem. Soc. 2019, 141, 1650.
-1- 1.1. mechanisms
•HCl OH MeO2C MeO2C MeO2C
NH2 NH HN N O N 2N H O H R H 1 OH2 R 1-1 1-2 1-5 1-6
O MeO2C MeO2C N MeO2C N H HN H Me H N O H sp3 A-value sp2 1-6'Me: 1.7 1-6'' O 1-7 Ac: 1.17
O O O OCOCF3 H F C OCOCF MeO NH3 N 3 3 N H HN HN N N H HN N H H H O 1-8 O 1-9 O 1-10 Step 1 Step 2-1 Pictet–Spengler reaction ester-amide exchange • reaction with additive H MeOH N BH2CN 65 °C
HN N HN N HN N H H H O 1-11 O 1-12 O 1-3 Step 2-2 Step 3-1 dehydration O HO CN CF3 CF3 MeOH H fast NC 65 °C 1-13 1-14
• reaction without additive H
CN
HN N slow N N N N H H CN H O 1-12 1-15 1-4 OH N OH Step 3-2
1.2. discussion • Screening of benzaldehyde derivertive NaBH CN 3 additive 1-3 additive NC MeOH/THF, 65 °C none <20% HN N HN N N N C6H5CHO 56% H H H 4-MeOC6H4CHO 42% 4-ClC H CHO 46% O O 6 4 1-11 1-3 1-4 (harmalane) 4-CF3C6H4CHO 69% Bezaldehydes were added as a cyanide scavenger. More electron-deficient aldehydes were effective, because it made the nucleophilic addition of cyanide faster.
-2- 2. Answer for problem 2
1. TsOH·H2O (1.0), MeOH, reflux; H Et3N (2.0), Boc2O (3.0), rt, 65% OH O 2. LiN(TMS)2 (2.5), PhI(OAc)2 (2.5) THF, -78 °C to rt, 65% HN NH 2 N 3. NaBH CN (10.0), AcOH (10.0) N H O 3 MeOH, 0 °C; H 2-1 2-2 4 M HCl in dioxane, 0 °C to rt, 70% 2-3 (racemic) (2.0) 4. vinylMgBr (10.0), CeCl3 (10.0) THF, -78 °C, 30% (100% brsm)
5. CF3CO2H (2.0), paraformaldehyde (1.1) O toluene/MeCN (v/v = 3:1), rt; PhIO (2.0), rt; H H 19 2 M KOH aq., rt, 59% N N 2-4 (racemic) Andres, R.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2020, 142, 14276. 2.1. mechanisms less hindered Me substituted O H O NH NH HN 2 N more hindered N N H O H H Et substituted OH 2-1 2-2 2 2-5 O 2-6
O O
t-BuO O Ot-Bu H HN N HN N BocN N BocN N H H H Et H O 2-7 O 2-8 O 2-9 O 2-9' racemic Step 1-1 Step 1-2 minor Pictet–Spengler reaction Boc protection
LiN(TMS)2 OAc BocN Ph I N BocN N BocN N OAc H OAc I O 2-9 O 2-10 pKa O Ph discussion 1 indole NH: 21 2-11 diastereoselectivity ketone α-H: 26
Bürgi–Dunitz angle is shielded H H H H O O O H H BH3CN BocN BocN O N N N t-Bu H N H O H 2-12 H 2-13 2-14
Step 2 Step 3-1 Oxidative cyclization Cis-fused 5/5 is generated. imine reduction (Explanation from late stage transition state) -3- shielded by Me CeCl MgBr 3 BrMg H H OH H O OH OH H H HN HN N H O - t-Bu H N N 2 N - CO2 H H H 2-15 2-3 2-16 Step 3-2 Step 4 Boc deprotection Grignard addition with CeCl3
H H H OH H OH OH H N N N N N N H discussion 2 H H 2-17 diastereoselectivity 2-18 2-18'
O H O H O H O 1,3-diaxial H I H H interaction Ph N N N N H N N H 2-19 HO I 2-20 2-21 Ph Step 5-1 Step 5-2 aza-Cope/Mannich cascade amine oxidation equatorial O O H H H KOH KOH N N N N 2-22 2-4 thermodynamic product Step 5-3 C19 epimerization 2.2. discussions • discussion 1 diastereoselectivity of oxidative enolate coupling • diastereoselectivity of enolate formation (大学院講義有機化学II p45) i-Pr Me N O OLi i-Pr Li H R= Ph, t-Bu, Ni-Pr2 R H cis-enolate R 1,3-diaxial<1,2-syn O LiNi-Pr2
R
i-Pr H N O OLi i-Pr Li H R= OMe, Ot-Bu R Me R 1,2-syn<1,3-diaxial trans-enolate -4- TMS H BocN Me O N N O R= H TMS Li BocN N H BocN H N R O 2-10 LiN(TMS)2 cis-enolate 2-12 single diastereomer BocN N H TMS O 2-9 H O H N O TMS Li BocN N H BocN Me N R O 2-10' trans-enolate 2-12' • discussion 2 not obtained diastereoselectivity of aza-Cope/Mannich cascade diastereoselecivity in aza-Cope reaction
H OH sight from arrow H
N H N N N N N OH H OH H H too far 2-17 2-17' 2-17''
H H
H OH N H N N N N N OH H OH H H 2-18'' 2-18 2-18
diastereoselecivity in Mannich reaction
H H
sight from arrow N ring flip of N H OH OH too far trans-cyclononene N HO N HN HN H 2-18 2-18 2-18'
O H O H N H N H O H
N O HN HN N N N H H 2-19' 2-19' 2-19 2-19 not obtained desired, major
-5- molecular asymmetry of trans-cycloalkene (ring flip of trans-cycloalkene)
H H H
H H H Ring flip is difficult due to transannular interaction. These cyclooctenes are enantiomers and could be separated. (Cope, A. C.; Ganellin, C. R.; Johnson, Jr., H. W.; Van Auken, T. V.; Winkler, H. J. S. J. Am. Chem. Soc. 1963, 85, 3276.)
K2PtCl4 + K PtCl3 + KCl …(1)
NH2 K PtCl3 + PtCl2 + KCl …(2) Ph H N Ph (-)-α-methylbenzylamine 2
(+)-trans-cyclooctene (-)-trans-cyclooctene
PtCl2 + (±)-trans-cyclooctene PtCl2 + PtCl2 + …(3) H2N Ph H2N Ph H2N Ph
insolube solube -> crystallization
(+)-trans-cyclooctene NH2 PtCl2 + 4KCN +K Pt(CN) + 2KCl + (+)-trans-cyclooctene …(4) Ph 2 4 H2N Ph (-)-α-methylbenzylamine
These procedures were applied for trans-cyclononene and trans-cyclodecene. However, several optimizations to suppress the racemization were needed for the isolation of optically active trans- cyclononene, and trans-cyclodecene was not able to be isolated. And also, thermal stability of isolated trans-cyclooctene and trans-cyclononene were tested. (Cope, A. C.; Pawson, B. A. J. Am. Chem. Soc. 1965, 87, 3649. Cope, A. C.; Banholzer, K.; Pawson, B. A.; Whang, J. J.; Winkler, H. J. S. J. Am. Chem. Soc. 1965, 87, 3644.)
activation energy half-life time
cyclooctene 35.6±0.9 kcal/mol 122 h (132.7 °C), 15 h (156.4 °C), 1h (183.9 °C)
cyclononene 20±2 kcal/mol 4 min (0 °C), 20 s (20 °C), 6 s (30 °C)
N H ring flip of N trans-cyclononene OH HO HN HN
2-18 2-18' The ring flip of 2-18 is fast enough for the aza-Cope/Mannich cascade reaction.
-6- Appendix • Pictet-Spengler reaction from C2 or C3
MeO2C MeO2C 1-7 HN HN 2N N R H H R1 Ac 1-6 A1 Nucleophilic attack from indole C3 position can be possible. However, construction of adjacent tetrasubstituted olefin seems to be difficult in this situation. In different situation, C3 attack are reported. ref. Zheng, C.; Xia, X.-L.; You, S. L. Chem. 2018, 4, 1952. (mechnistic study) Gabriel, P.; Gregory, A. W.; Darren, D. J. Org. Lett. 2019, 21, 6658. (selective example of interrupted P-S reaction)
IrCl(CO)(PPh3)2 (1 mol%) TMDS (3 eq.) O N CH2Cl2, -15 °C, 1h N 90% 96:4 dr N N 25 examples H H A2 A3 Construction of continuous tetrasubstituted carbon was not reported.
• Alternative mechanism for oxidative cyclization
2-12 BocN N BocN N OAc Ph I O O OAc I A4 Ph OAc 2-10 Aromatic interaction between indole and PIDA might not such large. More nucleophilic oxygen might react with PIDA.
• Vinyl Grignard addition
CeCl3 CeCl2 H Cl2Ce H O OH
HN HN H N N H 2-15 2-3 Electrostatic repulsion might also exist. • Thermodynamic explanation of aza-Cope/Mannich cascade
N H N H N N aza-Cope ring flip OH O HO HO HN HN HN HN
2-17 2-18 2-18' 2-19 thermodynamic product
2-19 might be thermodynamically yielded from 2-17. i.e. 2-17, 2-18, 2-18' are in equilibrium and reaction from 2-18' to 2-19 is irreversible.