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S. Vassis et al. / Tetrahedron Letters 43 (2002) 2597–2600
Hesse et al. used the di-benzyloxycarbonyl (Z)-pro-
tected SPD (6), Z3-SPM (7) and the monomethyl ester
8 of 1,16-hexadecanedioic acid (Hda) to assemble
tenuilobine.6 Ester 8 was obtained from the correspond-
molar equiv. of the condensing agent bromotripyrro-
lidinophosphonium hexafluorophosphate (PyBrOP)
i
and 5 equiv. of Pr2NEt produced a mixture of the fully
protected tenuilobine 15 and the symmetric analogues
16 and 17 in the ratio of 1.5:1:1 (Scheme 2), which were
readily separated by flash column chromatography. The
SPD dimer 16 was simply prepared in 45% yield by
reacting 2 equiv. of SPD derivative 9 with 1 equiv. of
the dichloride 11 in the presence of Et3N, whereas the
SPM dimer 17 was obtained in 57% yield by reacting 2
equiv. of SPM derivative 10 with 1 equiv. of acid Hda
in the presence of 2 equiv. of PyBrOP and 5 equiv. of
iPr2NEt. On the other hand, the tenuilobine derivative
15 was assembled in 25% overall yield using the follow-
ing three-step sequence. PyBrOP-mediated coupling of
SPD derivative 9 with ester 12 gave the intermediate 18
in 60% yield. The phenacyl group was then selectively
removed with NaSPh and the acid 19 thus obtained was
coupled to 10, also in the presence of PyBrOP, to give
15. The formal synthesis of tenuilobine (1) was com-
pleted in 67% yield by routine detritylation of 15 using
a solution of CF3CO2H in CH2Cl2 (1:2), followed by
hydrogenolysis at ambient temperature and 3 atm of H2
pressure in the presence of Perlman’s catalyst to remove
both benzyl (Bn) groups.7 The synthesis of tenuilobine
was further simplified by using the alternative SPD
derivative 4 to introduce the SPD skeleton into the
molecule. Thus, PyBrOP-mediated coupling of 4 with
ester 12 gave the intermediate ester 20 in 70% yield. The
phenacyl group was then split off with NaSPh to give
acid 21 in 57% yield. Coupling of the latter to 10, also
in the presence of PyBrOP, gave the fully protected
tenuilobine 22 in 68% yield. Complete detritylation with
CF3CO2H in CH2Cl2 produced tenuilobine in 98% yield
as its corresponding pentatrifluoroacetate salt. It should
be noted that LiAlH4 reduction of the bisamide 22 in
refluxing THF gave the branched PA derivative 23 in
86% yield,11,12 which upon detritylation with CF3CO2H
in CH2Cl2 gave the fully reduced tenuilobine analogue
24 in 96% yield.
ing v-hydroxyacid through
a
two-step sequence
whereas all the aforementioned, selectively protected,
PAs were obtained through selective protection of the
primary amino functions of the parent PAs. For our
synthetic purposes, we used the SPD derivatives 43 or
97 and the novel SPM derivative 10 for the introduction
of the PA moieties and cyclic anhydrides, such as
succinic anhydride, or longer chain dicarboxylic acids,
such as Hda, or their corresponding dichlorides, e.g. 11,
or the monophenacyl esters, e.g. 12, for bridging the
PA moieties.
For the needs of this project, the SPD derivative 4 was
obtained in 47% overall yield through selective
monotritylation of a 5-fold excess of putrescine (PUT)
with TrtCl, followed by acylation of the primary amino
function with Trt-Ala-OSu8 and finally reduction of the
amide 13 thus obtained (Scheme 1) with LiAlH4. On
the other hand, the SPM derivative 10 was readily
secured in 55% yield through monotritylation of
N1,N12-Trt2-SPM (14)8,9 with 1 equiv. TrtCl, followed
by routine flash column chromatography purification.
Similarly, the ester 12 was obtained in 65% yield
through monoesterification of the commercially avail-
able Hda with 1 equiv. phenacyl bromide in the pres-
ence of iPr2NEt, also followed by flash column
chromatography purification.10 The choice of the
phenacyl group was based on its well-known property
to be readily removable under conditions (PhSNa)
which do not affect the highly hydrophobic Trt group,
whereas following the esterification (by TLC) and the
subsequent purification of the monoester from the
diester which was also formed and unreacted dicar-
boxylic acid was greatly facilitated by the presence of
its lipophilic PhCO-chromophore. Finally, the required
dichloride 11 was simply obtained in 95% yield by
treating the commercially available acid Hda with
SOCl2 at reflux in PhH.
Furthermore, side-chain-shortened tenuilobine ana-
logues can be simply assembled in one-pot reactions
using commercially available cyclic anhydrides as exem-
Condensation of equimolar amounts of the PA deriva-
tives 9 and 10 and the acid Hda in the presence of 2
Scheme 1. Synthesis of key-intermediates for the assembly of PACs. Reagents and conditions: (i) TrtCl, CH2Cl2, 0°C, 2 h; (ii)
Trt-bAla-OSu/Et3N, DMF, 0°C, 30 min then 25°C, 1 h, 73%; (iii) LiAlH4, THF, reflux 2 day, 65%; (iv) TrtCl/Et3N, CH2Cl2, 0°C,
1 h then 25°C, 1 day, FCC (EtOAc), 55%; (v) SOCl2, PhH, reflux, 2 h, 95%; (vi) PhCOCH2Br/iPr2NEt, DMF, 25°C, 1 day, FCC
(CHCl3/MeOH=98:2), 65%.