Problem Seminar (2) 17/02/10 Yuki Fujimoto Please Provide Following Reaction Mechanisms O 1

Problem Seminar (2) 17/02/10 Yuki Fujimoto Please provide following reaction mechanisms O 1. piperylene O

HN Rh (OAc) (1 mol%) HN N 2 4 3 2 benzene, reflux NH slow addition of 1-1 in CH 2Cl 2, 71 %

2. 1-3 , MgI 2 (1 eq.), THF, sealed tube, 75 °C 68 % (dr = 6:1 at C3) TIPS 1-1 3. Pd(PPh 3)4 (6 mol%), NDMBA (3.2 eq.) 1-2 CH 2Cl 2, 30 °C, 86 %

O O HN N 3 N 1. Dess-Martin periodinane, CH 2Cl 2, rt 18 2. 2-3 , t- BuOK H O O CH 2Cl 2, -78 °C to rt, 64 % (2 steps) N SEM 3. [Pd (dba) ] CHCl (10 mol%) 2-2 spirotryprostatin B I 2 3 3 o + OH P( -tol) 3 (40 mol%), AcOK O O THF, 70 °C, 72 % (dr = 1:1) 4. Me AlCl, CH Cl , -78 °C to rt HN N 2 2 2 3 2-1 5. i- Pr 2NEt, MeOH, 45 °C, 93 ~ 95 % (2 steps) N 18 H O

2-2' 3,18-epi-spirotryprostatin B

EtO 2C O O 1. 3-3 , 3-4 , 3ÅMS, toluene, 60 °C, 82 % O H HN 2. H2, PdCl 2 (1 eq.), THF/EtOH, 4 atm, rt, 99 % HN N N CO 2Et 3. D-Pro-OBn, BOP, Et N, MeCN, 0 °C to rt, 74 % 3 H 4. H2, Pd/C, EtOH, rt O 5. BOP, Et 3N, MeCN, rt, 94 % (2 steps) OMe

3-1 3-2

O AcO OAc O O N I OAc P MeN NMe MeO N O MeO HN TMS O O O TIPS O H O 1-3 NDMBA Dess-Martin periodinane 2-3 SEM N O N N O HN O HN BnO PF Ph O OMe N P N 6 Ph O N

3-3 3-4 D-Pro-OBn BOP Problem Seminar (2) 17/02/10 Yuki Fujimoto Topic: total synthesis of spirotryprostatin O O H O O HN N HN N N N H H O O MeO

spirotryprostatin A spirotryprostatin B Isolation fermentation broth of Aspergillus fumigatus Osada, H. et. al. J. Antibiot. 1996 , 49 , 832. Osada, H. et. al. Tetrahedron 1996 , 52 , 12651.

Biological activity inhibition the G2/M phase of mammalian cell cycle

Structual features pentacyclic skeltone including spirooxyindole and diketopiperazine prenyl side chain

total synthesis spirotryprostatin A Danishefsky, S. J. et. al. J. Am. Chem. Soc . 1999 , 121 , 2147. Williams, R. M. et. al. Org. Lett. 2003 , 5, 3135 Horne. D. A. et. al. Org. Lett. 2004 , 6, 4249. Fukuyama, T. et. al. Chem. Sci. 2014 , 5, 904.

spirotryprostatin B Sebahar. P. R. and Williams, R. M. J. Am. Chem. Soc . 2000 , 122 , 5666. (problem 3) Wang. H. and Ganesan, A. J. Org. Chem. 2000 , 65 , 4685. Overman, L. E. and Rosen, M. D. Angew. Chem. Int. Ed . 2000 , 39 , 4596. (problem 2) von Nussbaum. F. and Danishefsky. S. J. Angew. Chem. Int. Ed. 2000 , 39 , 2175. Fuji. K. et. al. Org. Lett . 2002 , 4, 249. Meyers, C. and Carreira, E. M. Angew. Chem. Int. Ed. 2003 , 42 , 694. (problem 1) Horne, D. A. et. al. Angew. Chem. Int. Ed . 2004 , 43 , 5357. Trost, B. M. and Stiles, D. T. Org. Lett. 2007 , 9, 2763.

How to construction C3 stereocenter Danishefsky (spirotryprostatin A), Ganesan: oxidative pinacol rearrangement

Br O MeO CO Me MeO CO Me CO Me 2 2 HN 2 NBS N NBoc N NBoc NBoc H THF/H O/AcOH H OH 46 % SPh 2 SPh MeO SPh 0-1 0-2 0-3

Danishefsky, S. J. et. al. J. Am. Chem. Soc . 1999 , 121 , 2147. 1 Fuji: asymmetric nitroolefination

N O2N 0-6 OLi OMe O Ph Ph NO 2 TBSN n-BuLi, Et 2O TBSN

86 % (97 %ee)

0-4 0-5 Fuji, K. et. al. Synlett 1995 , 367 .

Danishefsky (spirotryprostatin B), Horne: Mannich type cyclization

Br TrocN Br 1. O Br 2. CO 2Me CO 2Me Cl HN HN CO 2Me 0-8 HN NH 2 0-10 NH 2 + N O

0-7 0-7' Br Br 0-7 0-7' Br Br : = 3:4 Cl 0-9 O CO 2Me CO 2Me CO 2Me HN TrocN N TrocN HN TrocN Cl H O N N 2 N H H H O O O Br Br Br O O 0-11 H 0-12 0-13 HN N 3. Zn, MeOH N overall 56 % (3 steps) H O Horne. D. A. et. al. Org. Lett. 2004 , 6, 4249. Br 0-14 Trost: Asmmetric Allylic Alkylation

Pd (dba) CHCl 2 3 3 Pd (10 mol%) O O O O OO O O O O ligand (12 mol%) HN N HN N HN N HN HN toluene, 60 °C HN H H 89 %, dr = 16:1 H O O O + 0-18 0-16 0-15 (S)(S) O O O O Pd NH HN HN N Ph Ph 0-19 HN P P H Ph Ph O ligand

0-20 Trost, B. M. and Stiles, D. T. Org. Lett. 2007 , 9, 2763. 2 Fukuyama: Heck reaction Problem 1: Carreira's synthesis Retrosynthetic analysis

O O O Julia-Kocienski O CO Me 2 HN BocN HN N olefination HN BocN N N N condensation H H H O O O O TIPS spirotryprostatin B 1-4 1-5

O O HN condensation C-H insertion HN NH N2 ring expansion

TIPS rac-1-2 rac-1-1

O 1. piperylene O

HN Rh (OAc) (1 mol%) HN N 2 4 3 2 benzene, reflux NH slow addition of 1-1 in CH 2Cl 2, 71 %

2. 1-3 , MgI 2 (1 eq.), THF, sealed tube, 75 °C 68 % (dr = 6:1 at C3) TIPS 1-1 3. Pd(PPh 3)4 (6 mol%), NDMBA (3.2 eq.) 1-2 CH 2Cl 2, 30 °C, 86 % N

TIPS

1-3

Meyers, C. and Carreira, E. M. Angew. Chem. Int. Ed. 2003 , 42 , 694.

1. C-H insertion

O O O O O O Rh II Rh II II II Rh 2(OAc) 4 Rh Rh O O O O 1-6

3 O O O HN HN HN N N

O O 1-11 1-10 Rh II Rh II 1-1

1-6

O O N O O N O O HN HN RhIII Rh I RhIII Rh I

1-9 1-7

O O O HN RhIII Rh I

2. ring expansion N2 proposed by author (path A) 1-8 piperilene

IMg IMg O O O MgI I HN HN HN

1-11 1-12 1-13 N IMg IMg O O O 1-3-( E) TIPS MgI HN HN HN I R N N stoichiometric MgI 2 R = TIPS 1-14 1-15TIPS 1-16 IMg IMg O O O

HN N H2O HN N N N

TIPS TIPS TIPS 1-17 1-18 1-16 4 3. removal of allyl group O O HN N MeN NMe 0 Pd L4 O O coordination TIPS decomplexation 1-16 1-20 oxidative addition

O O MeN NMe HN O O N Pd

PdL 4 1-17 TIPS 1-19 ligand exchange nucleophilic attack O O PdL 2 HN 1-18 MeN NMe NH O OH Discussion NDMBA another passway of ring expansion (path B) TIPS

N 1-2 IMg O O I O HN 1-3-( E) TIPS HN HN I N N

1-14 TIPS 1-21 TIPS 1-2 my proposal of stereoselectivity

path A O

Allyl N TIPS HN OMgI N H bulky TIPS group avoid benzene ring NH

1-15 TIPS 1-2'

path B TIPS O R HN N Allyl 6-membered TS make stereochemistry of 1-2 O Mg N N I ring expansion would proceed via pass B H

1-14, 1-3 TIPS 1-2 R = I 5 5-endo-trig VS 5-exo-tet path A path B IMg O O I HN HN R N N

R = TIPS 1-15 TIPS 5-endo-trig (disfavored) 1-21 5-exo-tet (favored) example of 5-endo-trig Br Cl CO 2Me CO 2Me HN TrocN N TrocN 5-endo-trig cyclization seems to be allowed. N N But overlap of orbital is not good. H H O O Br Br 0-11 0-12 Problem 2: Overman's synthesis Retrosynthetic analysis O O Heck, Tsuji-Trost O O Horner-Wadsworth- O cascade reaction Emmons reaction HN N N N N O SEM SEM N I HN I H H O O

spirotryprostatin B (2-2 ) 2-4 2-5 O O

condensation MeO OAc MeO

2-6 2-7

O O 1. Dess-Martin periodinane, CH 2Cl 2, rt 2. 2-3 , t- BuOK HN N O 3 CH 2Cl 2, -78 °C to rt, 64 % (2 steps) N 18 N H SEM O I 3. [Pd 2(dba) 3] CHCl 3 (10 mol%) OH P( o-tol) 3 (40 mol%), AcOK THF, 70 °C, 72 % (dr = 1:1) 2-2 spirotryprostatin B 4. Me 2AlCl, CH 2Cl 2, -78 °C to rt O O 2-1 5. i- Pr 2NEt, MeOH, 45 °C, 93 % (2 steps) HN N O O 3 P N MeO N 18 MeO H HN O H O 2-2' 2-3 3,18-epi-spirotryprostatin B Overman, L. E. and Rosen, M. D. Angew. Chem. Int. Ed . 2000 , 39 , 4596. 6 1. Dess-Martin oxidation AcO OAc I OAc O V O O O

N O N AcOH N SEM SEM SEM I I I OH AcO O H O AcOH OAc OAc I III V 2-1 O I 2-5 O O 2. Horner-Wadsworth-Emmons reaction 2-8 O

O O O O H P t- BuO P MeO N MeO N O MeO MeO O HN HN N SEM H H I R H O O O 2-3 2-6 2-5 K O O O MeO P MeO N R H HN fast H slow O K 2-5 2-6 K O O O O MeO P MeO P MeO N MeO N O O HN HN R H H H R H O O 2-7- Z 2-7- E

K K O O O O

R N R N O O N HN P P MeO OMe H MeO OMe H O O 2-8- Z 2-8- E

OH OH O OMe O OMe P OMe P OMe R N R N O O HN HN H H O 2-9- Z O 2-9- E

O O O R O R N N N SEM N HN I HN HN H H O O H 7 2-4- Z (single isomer) O 2-4- E 3. Heck, Tsuji-Trost cascade reaction O O O O SEMN N SEMN N N N O O H H O O N N SEM 0 I HN 2-14 2-14' Pd L2 H O oxidative 2-4- Z decomplexation L = P(o-tol) 3 addition

O O O O O O SEMN N SEMN N O O N N N N SEM Pd 0Ln H Pd 0Ln H I Pd L HN L H O 2-13 2-13' 2-10

nucleophilic attack carbopalladation

H anti to Pd O O O O AcOK SEMN N SEMN N O O AcOH HN HN Pd II Ln H Pd II Ln H I 2-12 2-11 formation of allyl O O O O SEMN N SEMN N O O HN I HN Pd II Ln H Pd II Ln H I 2-12' 2-11' 4. transformation of SEM group to hydroxy methyl group

O O O O Si Me AlCl Si Cl O N N 2 O N N N Me 2Al N TMSCl H H ethylene O O

2-14 2-15 8 O O O O

O N N H2O HO N N Me 2Al N N H H O O

2-16 2-17 5. removal of hydroxy methyl group O O O O HO N N HN N N N H OH H O O H H 2-17 spirotryprostatin B (2-2 ) i-Pr 2NEt Discussion HCHO regioselectivity of Heck reaction

in generally, exo is favored than endo in 5, 6 or 7 membered ring formation.

5-exo O O 6-exo N N SEM I Pd L HN L 7-exo H O 2-10

7-exo: 7-membered ring containing trans olefin 5-exo (favored)

HN O

O N large ligand has steric repulsion to methyl group of prenyl group. Pd HN L H O 2-18-5-exo

6-exo (disfavored)

HN O Pd O N L large ligand has steric repulsion to diketopiperazine ring. HN the other ligand which is located over Pd was omitted for clarity. H O 2-18-6-exo

9 Problem 3: Williams' synthesis Retrosynthetic analysis EtO 2C EtO 2C O O O O O H O H decarboxylation diketopiperazine HN N HN N formation HN O N N N Ph H H O O Ph OMe OMe

spirotryprostatin 3-2 3-5 O O 1,3-dipolar cycloaddition HN O

CO 2Et HN Ph O OMe 3-1Ph 3-3 3-4

EtO 2C O O 1. 3-3 , 3-4 , 3ÅMS, toluene, 60 °C, 82 % O H HN 2. H2, PdCl 2 (1 eq.), THF/EtOH, 4 atm, rt, 99 % HN N N CO 2Et 3. D-Pro-OBn, BOP, Et N, MeCN, 0 °C to rt, 74 % 3 H 4. H2, Pd/C, EtOH, rt O OMe 5. BOP, Et 3N, MeCN, rt, 94 % (2 steps) O 3-1 3-2 O HN O OMe Ph 3-4 Ph 3-3 Sebahar. P. R. and Williams, R. M. J. Am. Chem. Soc . 2000 , 122 , 5666.

1. 1,3-dipolar cycloaddition O O O H O O O + HN O OMe MeO N MeO N Ph Ph Ph 3-4 Ph OH Ph Ph 3-3 3-6 3-7 EtO 2C O O O O H HN + O HN O MeO N N CO 2Et Ph Ph Ph Ph OMe 3-1 3-7 3-5

10 2. removal of chiral auxiliary group Pd II Cl +H Pd 0+2HCl EtO 2C 2 2 EtO 2C O O O H O H OH HN HN O N N Ph Ph Ph Ph H OMe OMe 2 Pd 0 3-10 3-7

reductive elimination oxidative addition

EtO C EtO C 2 O 2 O O H O H O O HN HN H II Pd II Pd N H N H Ph Ph Ph Ph OMe OMe

3-9 3-8

EtO 2C EtO 2C O O O H O OH C-N bond cleavage HN HN OH N NH Ph Ph OMe OMe 3-10 3-11 N N 3. condensation of Proline N BOP N O N EtO 2C EtO 2C N P N EtO 2C N O O O O O O N OH Et 3N N H P HOBt HN O HN O HN O N N NH NH N NH O N N P N N OMe OMe OMe N OH 3-11 3-12 HOBt 3-13 HMPA

HN EtO 2C EtO 2C O N N O O BnO O H N HN O O HN N NH N NH N BnO O OMe N OMe OH HOBt 3-14 3-15 11 4. removal of Bn group EtO 2C EtO 2C O O O H O H HN N Pd/C HN N NH NH

BnO O HO O OMe OMe 3-15 3-16 N 5. formation of diketopiperazine N N EtO 2C EtO 2C EtO 2C O O O O O H O H O H Et 3N N P N HN N HN N HN N N NH NH NH NMe 2 H P O O O O O O NMe 2 OMe OMe OMe NMe 2 3-16 3-17 3-18 N N EtO 2C N O EtO 2C O H O O OH H HOBt HN N HN N NH N N O N N N N H Me 2N P NMe 2 O O OMe N O NMe 2 OH OMe HOBt HMPA 3-19 3-2 Discussion stereoselectivity of 1,3-dipolar cycloaddition dipolar formation O O

O O MeO N (Z) N Ph Ph allylic strain would make (E)-ylide (E) Ph MeO Ph H 3-7-( E) 3-7-( Z)

oxindole approaches to iminiumcation from face to avoid Ph groups.

Ph O Ph O Ph O Ph O O O O O Ph Ph Ph Ph N N N N R R R R H H N H H NH O EtO 2C O CO 2Et TS-1O TS-2EtO 2C TS-3 TS-4 CO 2Et O N HN H H H EtO 2C EtO 2C N N O O O H O H O O HN O HN O O O EtO C O EtO C O N N 2 N 2 N Ph Ph Ph Ph R R R R Ph Ph Ph Ph 12 3-5-R (major) 3-20 (not obtained) 3-21 (not obtained) 3-22 (minor) EtO C 2 O O O O H HN HN O O toluene + + N CO Et HN O R 2 Ph Ph MS3Å R Ph Ph

3-1 3-3 3-4-R 3-5-R

entry R temp. 3-5-R 3-22 3-23 1 a) H reflux 28 11 0

2 BzOCH 2 reflux 44 14 0

3 BzOCH 2 60 °C 54 8 0 4 i-Pr reflux 43 11 5 5 i-Pr 60 °C 74 6 trace 6 i-Bu reflux 84 1 0 7 i-Bu 60 °C 86 0 0 b) 8 (Me) 2(OMe)CCH 2 reflux 29 0 0 c) 9 (Me) 2(OMe)CCH 2 60 °C 82 1 0 10 p-MeOPh reflux 60 0 0

a) 3-21 was obtained (9 %) Sebahar, P. R. and Williams, R. M. Heterocycles , 2002 , 58 , 563. b) 3-24 was obtained (59 %) c) 3-24 was obtained (6 %)

EtO 2C EtO 2C O O O H O H HN O HN O N N Ph Ph R Ph Ph

3-23 (generate from 3-7-( Z)) 3-24

bulkiness of R dominantly influenced on regioselectivity steric repulsion between CO 2Et and R would be dominant.