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with tributyltin hydride and azobisisobutyronitrile (AIBN) in
refluxing benzene, furnished a mixture of the pyrrolo[1,2-
f]pyrimidines 7a and 7b in 86% yield, with ꢀ 19:1 d.r. (by
1H NMR) favoring 7a. The relative stereochemistry was
determined unequivocally by X-ray crystallographic analysis
to demonstrate the feasibility of this approach for the total
synthesis (Figure 1).
Scheme 4. Synthesis ofthe cyclic carbonate 13: a) C8H17MgCl, CuCN,
BF3·OEt2, THF, À788C; b) Me3SOTf, nBuLi, THF, À108C to RT, 68%
over 2 steps; c) 1,1’-carbonyldiimidazole, pyridine, CH2Cl2, RT to D,
90%. Tf=trifluoromethanesulfonyl.
pentadione by using the Rychnovsky protocol (Scheme 4).[9]
Treatment of 11 with the cuprate derived from octylmagne-
sium chloride and a catalytic amount of copper cyanide
afforded the secondary alcohol, which upon exposure to the
ylide prepared from trimethylsulfonium triflate, afforded the
anti-1,3-diol 12 in 68% overall yield.[10] The diol 12 was then
converted into the cyclic carbonate 13 in 90% yield using 1,1’-
carbonyldiimidazole.
The preparation of the individual fragments provided an
opportunity to examine the rhodium-catalyzed allylic amina-
tion of the cyclic carbonate 13 with the novel pronucleophile
3,4-dihydropyrimidin-2(1H)-one 10a [Eq. (2)]. Treatment of
Figure 1. X-ray crystal structure of 7a.
The total synthesis was initiated through the construction
of the requisite fragments for the key rhodium-catalyzed
allylic amination reaction. The enantiomerically enriched 3,4-
dihydropyrimidin-2(1H)-one 10a was prepared in two steps
from commercially available methyl 3,3-dimethoxypropio-
nate (8), as outlined in Scheme 3. Acid-catalyzed Biginelli
the lithium anion of 10a with 13 in the presence of trimethyl
phosphite modified Wilkinsonꢀs catalyst ([RhCl(PPh3)3]),
furnished a mixture of 14a and 14b in 84% yield, with
ꢀ 30:1 d.r. favouring 14a (branched/linear ꢀ50:1 by
HPLC).[11,12]
Scheme 5 outlines the completion of the (À)-batzella-
dine D (2) synthesis. Hydrosilylation of 14a with phenyl-
dimethylsilane in the presence of a catalytic amount of
Adams catalyst (PtO2) afforded the requisite phenyltrialkyl-
silane in 91% yield, with ꢀ 19:1 regioselectivity.[13] Interest-
ingly, the attempted hydroboration or hydrometalation of the
terminal alkene in 14a proved more challenging than
anticipated, as a result of poor regiocontrol and reactivity,
respectively. Transesterification of the methyl ester using
Oteraꢀs catalyst in refluxing toluene, followed by Mitsunobu
inversion of the residual secondary alcohol with hydrazoic
acid, furnished the diazide 15 in 82% overall yield from
14a.[14] Tamao–Fleming oxidation of 15 afforded the primary
alcohol, which was converted into alkyl iodide 16 for the free-
radical cyclization.[15] Initial attempts to promote the cycliza-
tion under standard conditions [see Eq. (1)]resulted in
competitive reduction of the azides. Gratifyingly, treatment
of 16 with tributyltin hydride and triethylborane in the
presence of air at room temperature furnished the pyrrolo-
[1,2-f]pyrimidine 17 in 80% yield, with ꢀ 19:1 d.r. (by
1H NMR).
Scheme 3. Synthesis and resolution ofthe dihydropyrimidin-2(3 H)-one
pronucleophile 10a: a) MeCHO (excess), H2NCONH2, cat. HCl, D,
84%; b) LiHMDS, THF, 08C, (1S)-(+)-10-camphorsulfonyl chloride,
70%. HMDS=hexamethyldisilazanide.
condensation of 8 with urea and acetaldehyde, furnished the
racemic dihydropyrimidin-2(3H)-one
9
in 84% yield.[7]
Regioselective sulfonylation of the dianion of 9 with (1S)-
(+)-camphorsulfonyl chloride furnished a mixture of the 3,4-
dihydropyrimidin-2(1H)-ones 10a and 10b in 70% overall
yield.[8] The diastereoisomers were then resolved by column
chromatography, and the absolute configuration of 10a was
verified by X-ray crystallography on 7a (Figure 1).
The synthesis of allylic fragment 13 commenced with the
selective ring opening of the bisepoxide 11, which is readily
available in three steps from commercially available 1,3-
The synthesis was completed by using the following four-
step sequence. Treatment of 17 with triflic acid, to remove the
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 7417 –7419