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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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Ziegler reaction 124
Zimmerman-Traxler transition state 42
zinc chloride 274
zirconium 38
Zn(CH2I)2 46
ZnEt2 79
Organic Synthesis Workbook II
C. Bittner, A. S. Busemann, U. Griesbach, F. Haunert, W.-R. Krahnert, A. Modi, J. Olschimke, P. L. Steck
Copyright 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30415-0 (Softcover); 3-527-60013-2 (Electronic)
1

(+)-Asteriscanolide (Paquette 2000)
1.1 Introduction
The sesquiterpene (+)-asteriscanolide 1 was first isolated from Asteriscus aquaticus L and characterized by San Feliciano in 1985.1 It has captured the attention of organic chemists mainly because of its uncommon bicyclo[6.3.0]undecane ring system bridged by a butyrolactone fragment. The only prior enantioselective synthesis of 1 has been described by Wender in 1988 featuring an Ni(0)-promoted [4 + 4]-cycloaddition.2 Booker-Milburn and co-workers described the sequential application of intramolecular [2 + 2]-photocycloaddition, Curtius rearrangement, and oxidative fragmentation to produce the 7-desmethyl derivative in 1997.3
This problem is based on the work of Paquette published in 2000.4
(+)-asteriscanolide
2
1 (+)-Asteriscanolide
1.2 Overview
n
1. nBuLi, THF, -78 C, 3.5 h; (S)-(-)-menthyl
0r p-toluenesulfinate, 77 %
2. CSA, acetone/H20, r. t., 15 h, quant.
1.
1.10 bar H2/Raney Ni, THF/MeOH, r. t 4 h, 88 %
2. KHMDS, PhNTf2, THF -78 C, 3 h, 98 %
Tol n
'/ ^
1. LiAIH4, THF,
20 C, 30 min, 94 %
2. MsCI, Et3N, 0 C, 1.5 h, Nal, NaHC03, acetone, 20 C, 15 h, 79%
6
7
1
(+)-Asteriscanolide
3
1.
ci,jCy3
1.20 mol% Ru=\
Cl^l Ph
PCy3
CH2CI2, reflux, 33 h, 93 %
11
1. Dess-Martin periodinane, CH2CI2, r.t., 0.5 h 2.21 bar H2, 10% Pd/C, EtOH, r.t.,1h
67 % (over two steps)
1.

12
1
4
1 (+)-Asteriscanolide
1.3 Synthesis
Problem
Hints
Solution
Discussion
1. nBuLi, THF, -78 C, 3.5 h;
(S)-(-)-menthyl p-toluenesulfinate, 77 %
-> 3
2. CSA, acetone/H20, r. t., 15 h, quant.
The first step is a halogen-metal exchange.
(S)-(-)-menthyl p-toluenesulfinate:

ii
13

";.. V
Tol
3
The synthesis of 3 was initiated by reaction of wBuLi with the protected cyclopentenone 2 generating the corresponding vinyllithium reagent by halogen-metal exchange. Subsequent condensation with (S)-(-)-menthyl para-toluenesulfinate (13) provides the enantiodefined sulfoxide substituent in 3.5 Since thermal equilibration of chiral sulfoxides at room temperature is slow, the large sulfur atom is a preferred reaction site in synthetic intermediates to introduce chirality into carbon compounds.
The second step is the deprotection of the ketone functionality. Acid-catalyzed hydrolysis is the most common method for deprotection of
1 (+)-Asteriscanolide
5
acetals or ketals. However, Lewis acids can also be used to effect deacetalization.
3 is a Michael-system.
3 reacts with methyl-4-hydroxy-2-butynoate (14).
The ester 14 reacts as an oxygen-centered hetero-nucleophile with the Michael-system.
The reaction is a twofold Michael reaction with a second stage intramolecular conjugate addition.
1. Methyl-4-hydroxy-2-butynoate (14), K2C03, THF, r. t., 5 h, 38 %
This domino6 Michael-Michael reaction sequence is one of the key steps in this synthesis and proceeds with complete asymmetric induction, which could be confirmed by X-ray crystallographic analysis. The two five-membered rings in the target molecule are thereby generated in a single step.
The butynoate 14 adds to the chiral enone 3 from the ee-surface with asymmetric induction probably rationalized by the chelate model 15. The initial product 16 of the 1,4-conjugate addition is capable of another intramolecular Michael addition to the triple bond resulting in conversion of 16 to 4.
Problem
Hints
/ GOpMe
HO
14
Solution
Discussion
4
C02Me
3
16
6
1
(+)-Asteriscanolide
Problem
Tol, Q
s' /fC02Me 1.10 bar H2/Raney Ni,
V THF/MeOH, r. t 4 h, 88 %
2. KHMDS, PhNTf2, THF, -78 C, 3 h, 98 %
Hints Two equivalents of H2 are consumed.
Reductive desulfurization as well as reduction of the double bond take place.
KHMDS (potassium hexamethyldisilazide) is a strong non-nucleophilic base.
An enol triflate is generated.
Discussion
: H
The most common application of Raney nickel is the desulfurization of a wide range of compounds including thioacetals, thiols, sulfides, disulfides, sulfoxides, and sulfur-containing heterocycles. In addition it can be used to reduce benzylic nitrogen and oxygen atoms. Hydrogenation of 4 in the presence of Raney nickel results in carbon-sulfur bond cleavage concomitant with saturation of the olefinic bond in 88 % yield. The configuration of the newly generated stereogenic centers was proved by facile overreduction. An increase of hydrogen pressure up to 70 bar was sufficient to reduce the ketone as well. The following intramolecular cyclization gives lactone 17 which could not take place if a different diastereomer had been initially produced. Potassium hexamethyldisilazide is a strong non-nucleophilic base which deprotonates in -position to the ketone. The resulting enolate can be captured as the enol triflate 5 by reaction with /V-phenyl triflimide (PhNTf2) and is directly used in the next reaction step.7
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