AMMONIUM YLIDES AS BUILDING BLOCKS FOR ALKALOID SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 457

Bn

Bn

N

N

CHO

Bn

R

H CO 2 H

Br

steps MeO 2 C OH

H

N

Et 3 N, PhH
reflux
51%

N

N
H

O

O

233a (R = Br)
233b (R = I)

234 235

steps

HN

HN

NC

N

H
N

N

RO 2 C NH

H 2 N
(CF 3 ) 2 CHOH
120°C

MeO 2 C

HN H

N

N
H

N
H

CN

237 R = Me 236

NaOH
MeOH

227b R = H (62% from 236 )

SCHEME 13.47

Encouraged by the above model system, the Snider group pursued the total
synthesis of martinellic acid [84]. In this sequence of reactions, aldehyde 233a reacted
with an excess of N -benzyl glycine in boiling toluene to give tetracyclic amide 234 in
57%, along with 3% of another diastereomer (Scheme 13.47). Installation of a
carbomethoxy group on the aryl ring followed by reductive ring opening of the
pyrrolidone furnished 235 . Conversion of the alcohol into an amine and installation of
the cyanamide groups provided 236 , whichwas set for installation of the prenyl guanidine
moieties. Reaction of 236 with prenylamine at 120 C in hexafluoro-2-propanol provided
237 , and base-promoted hydrolysis afforded ( )-martinellic acid 227b in 62%yield from

248 . Lovely andBadarinarayana reported avery similar approach usingnonracemic 233b
to give (

)-martinellic acid [85].
Coldham and coworkers incorporated a [3 2]-cycloaddition of an azo-

methine ylide in their approach to manzamine alkaloids [86]. In a series of model
studies directed toward the ABCE ring system of these alkaloids, it was found that
nonenolizable aldehydes, such as 238 , reacted with sarcosine ethyl ester in the
presence of 10 mol% CSA to give, for example, 239 in 68% yield, together with a
small amount of a mixture of other diastereomers (Scheme 13.48). Heating
aldehyde 240 with sarcosine ethyl ester produced 241 asasinglediastereomerin
52% yield [87]. Tricyclic 241 has the proper relative stereochemistry and much of
the functionalization of the ABC core of manzamine A. Encouraged with these
results, themethod was applied to the synthesis of the ABCE systemby reacting 242
with N -allyl glycine ethyl ester to furnish 243 in 43% yield, along with 6% of an
epimer [88]. A palladium-mediated cleavage of the N -allyl group gave 244 in 86%
yield, and acylation of the free nitrogen atom with 245 produced 246 in 79%
yield [89]. Reduction of the ester followed by a TPAP-mediated oxidation and
olefination provided 247 in 52% yield from 246 . Ring-closing olefin metathesis
promoted by the Grubbs second generation catalyst 248 and ketal deprotection
furnished tetracycle 249 in 75% yield.

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