Page 68 - Advanced Organic Chemistry Part B - Reactions & Synthesis

40 Scheme 1.8. (Continued)

CHAPTER 1 7 g
(CH 2 ) 2 I
Alkylation of Enolates O
and Other Carbon O H O
Nucleophiles CH 3 LiHMDS
O CH 3
THF-HMPA H
C 2 H 5 O 2 CCH 2
CH 3 O 2 C
56% 2
8 h Ar 2 O Ar
OH 1) (C 2 H 5 O) 2 PCl
CO 2 C(CH 3 ) 3
CH 3 (CH 2 ) 3 N 2) LiHMDS CH 3 (CH 2 ) 3 N
CO 2 C(CH 3 ) 3
Ar 1 Ar 1
O
Ar 1 = OTBDMS 2 O
Ar 70% on
2-kg scale
CH 3
OCH 3

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Entries 3 to 6 are examples of ester enolate alkylations. These reactions show
stereoselectivity consistent with cyclic TSs in which the hydrogen is eclipsed with the
enolate and the larger substituent is pseudoequatorial. Entries 4 and 5 involve S 2
N
substitutions of allylic halides. The formation of the six- and five-membered rings,
respectively, is the result of ring size preferences with 5 > 7 and 6 > 8. In Entry 4,
reaction occurs through a chairlike TS with the tertiary C(5) substituent controlling
the conformation. The cyclic TS results in a trans relationship between the ester and
vinylic substituents.

Cl H H
–O R
R C H O C
2
2 5
RO
CH 3 CH 3 CH
CH 3 3

Entry 6 results in the formation of a four-membered ring and shows good stereo-
selectivity. Entry 7 is a step in the synthesis of a tetracyclic lactone, quadrone, that
is isolated from a microorganism. Entry 8 is a step in a multikilo synthesis of an
endothelin receptor antagonist called cyclopentapyridine I. The phosphate group was
chosen as a leaving group because sulfonates were too reactive at the diaryl carbinol
site. The reaction was shown to go with inversion of configuration.