Biomedical Engineering Reference
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Me
O
Me
N
H
N
N
CH
2
CO
2
R
HO
10% Pd/C
H
2
Me
MeO
MeO
MeO
(CH
2
O)
n
CO
2
R
O
90-95%
MS 3 Å
PhMe
H
NO
2
NO
2
203a
(R = Me)
204a
(R = Me; 66%)
Horsfiline
Ph
Ph
203b
(R = )
204b
(R = ; 78%, de = 86%)
O
O
SCHEME 13.41
Palmisano and coworkers also approached the synthesis of the spirooxindole
structure through a [3
2]-cycloaddition [74]. In this case, the 1,3-dipole was
generated by condensation of formaldehyde and sarcosine followed by thermal
decarboxylation and trapping with
203a
to give
204a
in 66% isolated yield
(Scheme 13.41). Interestingly, maintenance of anhydrous conditions using a Soxhlet
extractor filled with 3 A
molecular sieves was found to be critical to the reproduc-
ibility of this result. Hydrogenation and subsequent lactam formation furnished
(
þ
)-horsfiline in 95%yield. Several chiral auxiliaries were examined, andWhitesell's
(1
S
,2
R
)-2-phenyl-1-cyclohexanol proved to be the best. In this case, heating amixture
of formaldehyde, sarcosine, and
203b
under similar conditions provided
204b
in 78%
yield and with 86% de. Hydrogenation afforded (
)-horsfiline in 90% yield.
13.2.6. Intramolecular Azomethine Ylide Cycloadditions
The intramolecular cycloaddition counterpart to these reactions serves to increase
the complexity of cycloadducts and provides access to more challenging natural
product structures [75,76]. While the most common approach to azomethine ylide
generation in these intramolecular reactions involves the condensation of an
amine with a ketone or aldehyde that is suitably appended with a dipolarophile,
some creative methods have been developed in which cascade reactions are
terminated by an intramolecular cycloaddition. This section highlights approaches
to complex natural products and particularly novel approaches to key structural
features shared by several groups of alkaloids.
13.2.6.1. Condensation Initiated Ylide Formation A group at Du Pont, led
by Confalone, developed an approach to a variety of nitrogen-containing polycyclic
scaffolds by condensing amino acid derivatives with aryl aldehydes [77]. Thus, the
ethyl ester of sarcosine
206
reacted with
205
to produce an azomethine ylide that
immediately cycloadded to the pendant alkene affording
207
in 89% yield
(Scheme 13.42). Similarly, condensation of
205
and proline methyl ester or pipe-
coline ethyl ester gave
208
or
209
in 93% and 99% yields, respectively. This method
was applied to the synthesis of
Sceletium
alkaloid
213
. Condensation of
210
and
206
in the presence of molecular sieves produced
211
in 40% yield. This reaction is
notable for the considerable congestion involved in forming the quaternary center in
the pyrrolidine ring. Hydrolysis of the ethyl ester gave acid
212
, which was
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