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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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OTMS
H
18
|Nal, m-CPBA TMS- j
\
21
1. , AIBN, C6H6, reflux,
Si(CH3)2Ph j Q2 o/o
TMS
Problem
In this radical cyclization a five-membered ring is favored over a Hints six-membered one.
First an iodine atom is abstracted.
The resulting exo-radical reacts to build a second ring.
182
11 (+)-Paniculatine
Solution
H
7
Discussion
NC N=N^CN
22
AIBN
Bu3SnH
23
-N2
AIBN
CN
CN + Bu3Sn 24 25
Treatment of 6 with a benzene solution of tributyl tin hydride 23 and azobisi'sobutyronitrile (AIBN) 22, introduced slowly with a syringe pump at reflux, provided the tricyclic ketone 7 in 82 % yield. Overall only traces of AIBN as radical initiator and not more than a slight excess of Bu3SnH are needed.
This tandem radical cyclization9 starts with formation of Bu3Sn- 25 initiated by thermal decomposition of unstable AIBN. Next 25 abstracts an iodine atom from the weak -I bond resulting in alkyl-radical 26. After 5-exo-dig cyclization giving 27, 5-exo-trig cyclization occurs, affording 7 after hydrogen abstraction from tributyltin hydride. Formed Bu3Sn- then reenters the catalytic cycle. Both cyclizations take place from the -face of the molecule, according to the stereochemistry of the alkene/alkyne bearing side chains. To use peroxide as a radical starter in this transformation would lead to side reactions as result of uncontrolled hydrogen abstraction through the highly active RO- radical.
11 (+)-Paniculatine
183
The abbreviations to describe the ring forming processes were established by Baldwin in 1976.10
- The prefixed number specifies the size of the generated ring.
- The words exo or endo are used to picture if the breaking bond is exo- or endo-cyclic to the smallest ring so formed.
- The suffixes tet, trig or dig indicate the geometry of the carbon atom undergoing the ring closure reaction [tet = tetragonal (sp3), trig = trigonal (sp2), dig - digonal (sp)].
In this publication the author describes the phenomenon that most times the thermodynamically less stable product (see 29) of the two possible rings (e.g. 5-exo and 6-endo) is formed. Today looking at the
5-exo cyclization it is known that, although the generated primary radical is less stable than a secondary one, stereoelectronic effects favor reaction to the kinetically controlled product. According to MO-calculations, for a successful cyclization, an angle of 70 of the incoming radical to the plane of the alkene-/alkyne-bond is necessary.11
1. Li, NH3/THF/ EtOH (3:2:2),
-78 C, 30 min
2.TBAF, THF, r.t., 1 h;
MeOH, KHCO3, 30 % H202) r. t 4 h
52 % (over two steps) -> 8
3.TBSCI, imidazole, DMF, r.t.,
30 min, 93 %
The phenyldimethylsilyl group is used as surrogate for an alcohol functionality.
Under Birch reaction conditions not only reduction of the carbonyl occurs.
With TBAF a strong Si-F bond is formed.
Using TBSCI one alcohol is selectively protected.
OTBS
H
7
6-endo-trig
30
Problem
Hints
Solution
11 (+)-Paniculatine
According to the method of Taber12 compound 7 is first reduced with lithium in a liquid ammonia/THF/EtOH mixture at -78 C. This leads to 33 with concomitant formation of the alcohol at the six-membered ring and the 1,4-cyclohexadiene from the aromatic ring.
Dissolving elementary lithium or sodium in liquid ammonia gives an intense blue solution, indicating solvated electrons. In a Birch reaction these conditions are used for reduction. With time the blue color fades, the electrons reacting slowly with ammonia to form NH2~ and elemental hydrogen. For this reason a better electron acceptor will get reduced in preference. In this example the electron is transferred via SET (single electron transfer) into the LUMO of the benzene ring. The radical anion 32 is very basic and picks up a proton from the ethanol that is present in the reaction mixture. Next a further electron and finally a proton are received, leading to the 1,4-cyclohexadienyl species 33.
Then 33 is exposed in a one-pot reaction to tetrabutylammonium fluoride (TBAF), forming 34. Driving force of this reaction is the higher bond energy of an Si-F bond (467 KJ/mol) compared with that of the Si-C bond (251 KJ/mol). The following oxidation with aqueous hydrogen peroxide in the presence of potassium bicarbonate gives exclusively the diol 35.
The reaction sequence is terminated by protection of the primary alcohol as TBS ether using the standard protocol TBSCl/imidazole.
11 (+)-Paniculatine
185
OTBS
OTBS
Problem
Which reaction sequence inverts a stereogenic center?
Oxidation of the free alcohol is followed by selective reduction.
Hints
1. PCC, CH2C12, r. t 2 h, 88 %
2. L-Selectride 38, THF, 0 C
Solution
At this stage in order to invert the /?-OH to the -configuration, 8 is first oxidized within 2 h with pyridinium chlorochromate (PCC) at room temperature. PCC is a versatile oxidizing agent for many functional groups and is often used to convert primary or especially secondary alcohols to aldehydes or ketones. Overoxidations are rare. But chromium makes it a suspected cancer agent and thus it should be handled carefully. With compounds bearing acid-sensitive groups milder pyridinium dichromate (PDC) should be used, which is advantageous over PCC in this point.13
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