ROC Exam Problem 1

Transcription

1 RC Exam 2012 Problem 1 Silyl ether 1 is transformed into 2 in a two step process. Predict, through a detailed mechanistic rationale, the stereochemistry of the newly formed chiral center. TBS Si 1) Ms 2, pyridine, DMAP 2) LiCu(Me)(C) TBS Si * Me 1 2 Ms 2 = S S Problem 2 Compound 3 has been transformed into compound 4 by heating in toluene (B: the base does not participate in the reaction). Give the structure of compound 4, including absolute stereochemistry, and the mechanism of its formation. Cl 3 C 3 Me toluene, DCM, 120 o C K 2 C 3 4

2 Problem 3 Avermectin B1 is a macrolide with anti- parasitic properties. In the course of the total synthesis of avermectin B1, it was discovered that reaction of compound 5 with acb 3, Bu 3 SnCl and AIB in refluxing tert- butanol led to the predominant formation of structure 6 (compound 7 was isolated as a side product). Provide a detailed mechanism, which accounts for the formation of 6 from 5. Predict the stereochemistry at C1 and C4 in product 6. Justify your prediction. R 1 R Si 5 acb 3 Bu 3 SnCl (cat) AIB, tbu reflux R Si 6, major R 2 + R 2 R 1 Si 7, minor Problem 4 Solanoeclepin A is a substance that can be used to combat patato parasites. Recently the first total synthesis of this complex molecule was reported and depicted below are a number of steps from this synthesis. a) Give a mechanism to account for the Lewis acid mediated formation of compound 9 from 8. Predict the stereochemistry at C1 in 9 and explain your answer. b) Compound 9 is treated with DBU to give compound 10, which is transformed into 11 using C 2 =CMg and CeCl 3 (which form a hard cerium Grignard reagent). Give the structure of compound 10 and 11 and the mechanism of their formation. Account for the observed stereoselectivity. c) ext, compound 11 is treated with mcpba (~ 1 equivalent) to give 12. Give the structure of 12 and a mechanism leading to its formation. Explain the stereoselectivity of the reaction. Ac C Me 3 Al Al(Tf) 3 DCM 1 1 Ac 8 9 C DBU DCM C 2 =CMg CeCl 3, TF C mcpba, DCM DBU = 12

3 Problem 5 Chiral amide 13 was treated with dibutylboron triflate in presence of base and subsequently 5- henxenal was added to give compound 14 as the major product. Give the structure of 14 and the mechanism of its formation. Show the absolute stereochemistry of 14 and explain how it arises by evaluating the relevant transition state. 1. Bu 2 BTf, Et 3, C 2 Cl 2, 0 o C o C Problem 6 Allene 15 was treated with pyridinium bromide (a source of 2 ) and molecular sieves as an acid scavenger to give compound 16. Give the structure of 16 and show the mechanism of its formation. Give the stereochemistry of the newly formed stereogenic feature in 16 and explain your answer. 16 was heated in toluene to give 17. Give the structure of 17 and the mechanism of its formation. (B: The Lewis acid, AlMe 3, has no apparent role in this transformation). Bonus. Predict the stereochemistry at C- 5 in 17. Justify your prediction. 3 4Å mol. sieves C 2 Cl o C AlMe 3, toluene

4 Problem 7 The uncatalyzed reaction of (2E)- 2,4- pentadien- 1- ol (18) and 19 produces product 20 in one step. Give the structure of product 20. Draw the transition state of this reaction. Show all stereochemical features of 20. Explain how this stereochemistry comes about. benzene, 80 o C Me 30 h

5 Problem 1 Silyl ether 1 is transformed into 2 in a two step process. Predict, through a detailed mechanistic rationale, the stereochemistry of the newly formed chiral center. TBS Si 1) Ms 2, pyridine, DMAP 2) LiCu(Me)(C) TBS Si * Me 1 2 Ms 2 = S S Solution: rganic Letters 2012, 14,

6 Problem 2 Compound 3 has been transformed into compound 4 by heating in toluene (B: the base does not participate in the reaction). Give the structure of compound 4, including absolute stereochemistry, and the mechanism of its formation. Cl 3 C 3 Me toluene, DCM, 120 o C K 2 C 3 4 Solution: rganic Letters 2010, 12, (S) Cl 3 C 3 Me Cl 3 C R (S) CCl 3 (S) favored t.s. Cl 3 C PMB CCl 3 R

7 Problem 3 Avermectin B1 is a macrolide with anti- parasitic properties. In the course of the total synthesis of avermectin B1, it was discovered that reaction of compound 5 with acb 3, Bu 3 SnCl and AIB in refluxing tert- butanol led to the predominant formation of structure 6 (compound 7 was isolated as a side product). Provide a detailed mechanism, which accounts for the formation of 6 from 5. Predict the stereochemistry at C1 and C4 in product 6. Justify your prediction. R 1 R Si 5 acb 3 Bu 3 SnCl (cat) AIB, tbu reflux R Si 6, major R 2 + R 2 R 1 Si 7, minor Solution: rganic Letters 2008, 10,

8 Problem 4 Solanoeclepin A is a substance that can be used to combat patato parasites. Recently the first total synthesis of this complex molecule was reported and depicted below are a number of steps from this synthesis. a) Give a mechanism to account for the Lewis acid mediated formation of compound 9 from 8. Predict the stereochemistry at C1 in 9 and explain your answer. b) Compound 9 is treated with DBU to give compound 10, which is transformed into 11 using C 2 =CMg and CeCl 3 (which form a hard cerium Grignard reagent). Give the structure of compound 10 and 11 and the mechanism of their formation. Account for the observed stereoselectivity. c) ext, compound 11 is treated with mcpba (~ 1 equivalent) to give 12. Give the structure of 12 and a mechanism leading to its formation. Explain the stereoselectivity of the reaction. Ac C Me 3 Al Al(Tf) 3 DCM 1 1 Ac 8 9 C DBU DCM C 2 =CMg CeCl 3, TF C mcpba, DCM DBU = 12 Solution: ature Chemistry 2011, 3,

9 C C C C Ac LA Ac Ac LA migration of underneath the ring LA Ac C 10 Attack from front C Me Cl 2 Ce Ac C Me DBU C C Me mcpba: oxidation of most substituted C=C, guided by : epoxidation underneath the ring C

10 Problem 5 Chiral amide 13 was treated with dibutylboron triflate in presence of base and subsequently 5- henxenal was added to give compound 14 as the major product. Give the structure of 14 and the mechanism of its formation. Show the absolute stereochemistry of 14 and explain how it arises by evaluating the relevant transition state. 1. Bu 2 BTf, Et 3, C 2 Cl 2, 0 o C o C Solution: rganic Letters 2007, 9, Bu 2 BTf, Et 3, C 2 Cl 2, 0 o C 13 Bu B Bu Z-enolate (borone triflate gives Z) o C Bu B Bu Bu Bu B C 3 C 3 Disfavored Favored after work up C 3 C 3 C 3 C 3 major 14

11 Problem 6 Allene 15 was treated with pyridinium bromide (a source of 2 ) and molecular sieves as an acid scavenger to give compound 16. Give the structure of 16 and show the mechanism of its formation. Give the stereochemistry of the newly formed stereogenic feature in 16 and explain your answer. 16 was heated in toluene to give 17. Give the structure of 17 and the mechanism of its formation. (B: The Lewis acid, AlMe 3, has no apparent role in this transformation). Bonus. Predict the stereochemistry at C- 5 in 17. Justify your prediction. 3 4Å mol. sieves C 2 Cl o C AlMe 3, toluene Solution: rganic Letters pyridine 16 2 disrotary and rotate away from

12 Problem 7 The uncatalyzed reaction of (2E)- 2,4- pentadien- 1- ol (18) and 19 produces product 20 in one step. Give the structure of product 20. Draw the transition state of this reaction. Show all stereochemical features of 20. Explain how this stereochemistry comes about. benzene, 80 o C Me 30 h Solution: Angewandte Chemie 2002, 41, (p. 1673) highest LUM coeffient most electron poor double bond: lowest LUM Me highest M coeffient Me endo Me Me