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Organic Synthesis workbook li - Bittner C.

Bittner C. Organic Synthesis workbook li - John Wiley & Sons, 2001. - 292 p.
ISBN: 3-527-30415-0
Download (direct link): bittnerorganicsynthesisworkbook2001.pdf
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7 Hirsutine
47 46
Lactone 15 is formed as the only product because of the high stereoselectivity of this reaction: Since the heterodiene 44 obtained from the Knoevenagel condensation is considered to react from the E-configuration at the carbon-carbon double bond (Z-heterodienes are less reactive)73,17, the sterically highly demanding BOC protecting group on the indole nitrogen favors a re-attack of the enol ether syn to the hydrogen at C-3, giving a new stereogenic center with the a-hydrogen at C-15 (see Chapter 6). The trans formation of H and H-15 is furnished with an asymmetric 1,3 induction of >1 :20. The configuration at C-20 and C-21 is not yet important since these stereogenic centers are transformed stereoconvergently in the next step. Application of ultrasound provides thorough mixing of the reaction components, and is necessary because of the poor solubility of Knoevenagel product 44 in benzene.
7 Hirsutine
First the lactone is converted into an ester by solvolysis.
The solvolysis also liberates an aldehyde.
The CBZ protecting group is labile towards hydrogenation.
How do an amine and an aldehyde react?
Finally, a double bond is hydrogenated under stereoelectronic control.
1. K2C03, MeOH, r. t., 20 min, then
2. H2, Pd/C, MeOH, r. t., 4 h 67 % (from 15)
The first step of this domino reaction opens the lactone 15 by reaction with potassium carbonate in methanol leading to hemiacetal 49. This is not stable under the reaction conditions and decomposes yielding aldehyde 50 and PMBOH 35 (see formation of acetal 40 described above).
- PMBOH 35
7 Hirsutine

H2, Pd/C
ynyh +
H, - CH3Ph
i roe
By stirring the reaction mixture under an H2 atmosphere, the CBZ-protecting group is readily cleaved leaving toluene and C02. The resulting amine 51 reacts with the carbonyl group via iminium ion 52 to enamine 53. Now, C-20 and C-21 are no longer stereogenic centers.
+ H
After the condensation, the double bond of enamine 53 is hydrogenated stereoselectively yielding enantiopure quinolizidine 16 with trans configuration of the substituents at C-15 and C-20 as the only product.
The high trans selectivity of this transformation may be explained by means of stereoelectronic effects. Therefore the attack of the hydrogen atom on enamine 53 has to proceed anti toward 15-H under formation of the 15,20- tran s-c m p u n d 16.18 Conformation 56 with pseudoequatorial orientation of the ethyl group at C-20 is assumed to be energetically most favored. An attack on C-20 anti toward 15-H proceeds via a more favorable chair-like transition state, whereas an attack syn toward 15-H results in a less favorable boat-like transition state.
7 Hirsutine
The first step removes a protecting group. What conditions are necessary?
Then a condensation is carried out.
The final step employs conditions which are suitable to convert a carboxylic acid into its methyl ester.
1. TFA,CH2C12
2. Ph3CNa, HC02Me, THF, Et20
3. 1 eq. MeOH, HC1, CH2C12
The fert-butyloxycarbonyl (BOC) group is cleaved using TFA in an aprotic solvent like CH2C12. The cleavage proceeds via protonation of the carbonyl group of carbamate 16, subsequent elimination of i
carbenium ion 58 and liberation of unstable free carbaminic acid 60 ^ H which breaks down yielding the unprotected indole 61 with loss of 58
C02. Cation 58 is deprotonated giving 2-methyl propene 59.
4 N V 0^0
HO "O 60
7 Hirsutine
cx x>
Ph3C Na 64
61 is a known key intermediate in previous reported syntheses of hirsutine.5 Interestingly, 3a-61 with different configuration at C-3 is obtained by domino-Knoevenagel-hetero-Diels-Alder reaction of the tetrahydrocarboline 62 containing an unprotected indole moiety which allows the opposite facial selectivity following solvolysis and hydrogenation as described above. 3tt-61 is a key intermediate in the synthesis of dihydrocorynantheine 2a.6
Second, methyl ester 61 is subjected to crossed ester condensation with methyl formate and triphenyl methyl sodium 64 as base.5,6 Ester
61 is deprotonated and the resulting anion 65 adds to methyl formate. The anion formed is stabilized by loss of methanolate yielding the desired product as its conjugated base. As a Claisen type ester condensation, all steps but the last are reversible since the resulting aldehydo ester 67 is more acidic than methanol; therefore the last deprotonation step occurs irreversibly. The use of LDA19 as a base is also possible for this transformation.
In the final step, hydroxymethylene ester 69 is methylated by means of one equivalent of MeOH in CH2C12 saturated with HCI gas resulting in formation of the enol ether moiety of hirsutine l.5c As a vinylogous carboxylic acid, the hydroxy group of 69 can be methylated applying esterification conditions. Thus, activation of 69 occurs by protonation, followed by addition of MeOH as a nucleophile to the double bond. Resulting intermediate 72 then undergoes rotation of the bond formed and H+-shift. Loss of water and H+ gives hirsutine (1) as the desired product.
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