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Journal Club 2012.11.8 Masashi Ugawa

Stereocontrolled Organocatalytic Synthesis of Prostaglandin PGF2α in Seven Steps Graeme Coulthard, William Erb, and Varinder K. Aggarwal

Nature 2012, 489, 278–281. 1. Introduction 1.1. Prostaglandin in Physiology

Prostaglandins are a group of compounds that act as chemical messengers and regulate many physiological activities inside the body.

Prostaglandin analogs are used as pharmaceuticals, but the syntheses require many steps. Costs time and energy; generates a large amount of wastes.

Many noble chemists developed syntheses of prostaglandins, including 17-step synthesis of the most complex prostaglandin PGF2α (1) by E. J. Corey et al.1 From Corey lactone (3), the whole family of prostaglandins can be synthesized.

Latanoprost (2), which is an analog of PGF2α, is manufactured using synthetic methods

based on Corey’s work and is a billion-dollar drug to treat glaucoma (緑内障).

Figure 1. a. General outline of Corey’s synthesis of PGF2α. b. Structure of Latanoprost.

1.2. Proline Organocatalyst

First studied by B. List.2 Enantioselective aldol reaction of aldehydes

using proline was developed by MacMillan.3

Cheap, non-toxic, and readily available in both enantiomers.

Can be easily separated due to its solubility in water.

1.3. Idea of This Work

Synthesis of PGF2α via bicyclic enal 5 (Figure 3). Upper side-chain can be connected with Wittig reaction. Lower side-chain can be stereoselectively added by Michael addition. Bicyclic enal 5 can also be intermediates for other prostaglandins.

Bicyclic enal 5 can be prepared through aldol cascade reaction of succinaldehyde (6) using proline as a catalyst. Seemingly simple reaction, but actually very difficult.

HO

HOPh

OH

CO2i-Pr

Latanoprost (2)

9 steps 8 steps

AcO

O

OH

O

Corey lactone (3)

HO

HO OH

CO2H

PGF2α (1)

a. b.

Figure 2. a. Proline-catalyzed asymmetric aldol reaction by List. b. Proline-catalyzed enatioselective aldol reaction of aldehydes by MacMillan.

O OHC

NO2

NH

CO2H

30 mol%

DMSO

O

NO2

OH

68% (76% ee)

+

20 vol%

MeO

NH

CO2H

10 mol%

DMF4 ºC, 11 h

OMe

OH

Me

2

91%anti:syn = 3:1

99% ee

a.

b.

2

Figure 3. Retrosynthesis of PGF2α (1).

2. Results and Discussion 2.1. Preparation of Key Bicyclic Enal Intermediate

Simple treatment of succinaldehyde with proline did not derive the desired compound 5 but gave oligomeric material, due to many “potential pitfalls” (Figure 4). Aldol 7 must form the less favored hemiacetal 8. However, aldol 7 can undergo further aldol reactions, leading to oligomers.

Figure 4. Potential pathway of proline-catalyzed aldol reaction of succinaldehyde (6).

Model reactions were performed to determine which of the two aldol steps was the

problem (Figure 5). Model aldehyde 9 was converted into aldol product 10 in moderate yield;

Aldehydes with a carbonyl group at the 4-position are suitable for the first step. Low conversion of model dialdehyde 11 with proline. [Bn2NH2][OCOCF3] was effective in conversion of 11.

Figure 5. Model reactions. a. Model for first step. b. Model for second step.

HO

HO OH

CO2H

PGF2α (1)

O

OH

OH

HO4

O

OH

O

OO2

6

5

aldolreaction

Wittig reaction

Michael addition

upper side-chain

lower side-chain

OO

6

NH

CO2H OH

OO

OO

OO

OHO

OH

O57 8

desired pathway

OO

O

OHO

O

O

OH

O

O

OH

O

O

+ 6–H2O

oligomers

1st step 2nd step

OO

O

NH

CO2H

(10 mol%)

THF, rt O OO

OHO O

9

1061%, 3.6:1

diastereomeric ratio

OO

OO

catalyst (20 mol%)

THF, rt, 14 h

11

O

O

O12

catalyst = (S)-proline: 5%catalyst = [Bn2NH2][OCOCF3]: 51%

a. b.

3

Authors developed a sequenced addition method of the two catalysts (Table 1). Low yield due to oligomerization but high enantioselectivity (98% ee). Timing to add the second catalyst depended on the amount of proline; must be

added before trialdehyde 7 increases too much and oligomerization increases. Removal of oligomeric material lead to relatively pure crude; easy work-up. Diastereomeric isomers were consumed by oligomerization. Can be conducted with low loading of catalyst and under high concentration (2 M).

Table 1. Effect of catalyst loading and time delay on yield.

Figure 6. Proposed transition state structure that leads to the observed enantioselectivity.

2.2. Total Synthesis of PGF2α

Using the developed preparation of bicyclic enal 5, total synthesis of PGF2α was performed (Figure 7). Succinaldehyde (6) was prepared by heating 2,5-dimethoxytetrahydrofuran (13) in

water. Hemi-acetal 5 was subsequently converted into methoxy acetal 14.

Lower side-chain was added by conjugate addition of mixed vinyl cuprate 15 to methoxy acetal 14, followed by treatment with TMSCl, leading to silyl enol ether 16. Then controlled ozonolysis of 16 and treatment with NaBH4 yielded alcohol 17. Mixed cuprate 15 is prepared with only 1 eq of vinyl substrate. 2 steps with complete stereoselectivity.

Upper side-chain was added to 17 by simultaneous deprotection of acetal and silyl ether followed by Wittig reaction with phosphonium salt 18.

ON

O H OO

O

OHO

OH

OO

O

7

=HO O

(S)-proline (mol%) Time (h) Yield (%) 10 2 14 5 2 16 5 4 19 2 0 ~2 2 4 10 2 6 16 2 10 20 2 24 20 1 24 18

‘Time’ refers to the time before [Bn2NH2][OCOCF3] was added.

OO

6

NH

CO2HO

OH

O5

i)

THF, rt

ii) [Bn2NH2][OCOCF3] (2 mol%)THF, rt, 14 h

4

Figure 7. Complete Synthesis of PGF2α

3. Conclusion

Total synthesis of prostaglandin PGF2α was achieved in 7 steps with a total yield of 3%. Less time, energy, and waste compared to prior methods.

Key step is organocatalytic aldol dimerization of succinaldehyde in high enantioselectivity. Yield is low, but purification is easy and can be performed on multi-gram scale.

Bicyclic enal 5 can be used as a cost-effective starting material for prostaglandin-based drugs and can lead to rapid exploration of other prostaglandin analogs.

4. References 1. Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675–

5677. 2. List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396. 3. Northrup, A. B.; MacMillan D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–6799.

OO OH2O, 70 ºC, 4 h

OO

669%

NH

CO2HO

OH

O5

i)

THF, rt, 20 h

ii) [Bn2NH2][OCOCF3] (2 mol%)THF, rt, 14 h

(2 mol%)

MeOH (2 eq)amberlyst 15

MgSO4

CH2Cl2, rt, 14 h

O

O

O14

14% (2 steps)99:1 enantiomeric ratio

13

S

Li2(NC)CuOTBDMS

i) (1.1 eq)

THF, –78 ºC, 1 h

ii) Me3SiCl (5 eq)Et3N (6 eq)

15 O

OTBDMS

O

16OSiMe3

i) O3CH2Cl2 / MeOH (3:1)

–78 ºC

ii) NaBH4 (2 eq)–78 ºC to rt

O

OTBDMS

O

HO17

60% (2 steps)

O

OH

OH

HO4

HCl

H2O / THF (3:2)rt, 16 h

BrPh3P CO2H18

t-BuONa (12 eq)

THF, 0 ºC to rt, 1 h

HO

HO OH

CO2H

PGF2α (1)57% (2 steps)

(6 eq)