The first total synthesis of mauritine-A

Article abstract of DOI:10.1016/S0040-4039(00)01335-6

Total synthesis of mauritine-A is accomplished featuring a key cycloetherification reaction based on an intramolecular S(N)Ar reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01335-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7645–7649
The first total synthesis of mauritine-A
Taoues La¨ıb, Miche`le Bois-Choussy and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 12 July 2000; accepted 2 August 2000
Abstract
Total synthesis of mauritine-A is accomplished featuring a key cycloetherification reaction based on an
intramolecular SNAr reaction. © 2000 Elsevier Science Ltd. All rights reserved.
Cyclopeptide alkaloid is a family of 13-, 14- and 15-membered cyclophanes widely distributed
among plants of the Rhamnaceae.1 Since the first structural determination of pandamine by
Goutarel and Pa¨ıs in 1966,2 this family of natural product has grown rapidly and encompasses
nowadays a group of over 200 compounds. Although various bioactivities have been identified,1
their limited availability from natural sources has hampered extensive pharmacological investi-
gations and, consequently, their biological profile has not yet been well defined. Nevertheless,
sanjoinine-A (frangufoline) (1) has been identified as the major bioactive component, responsible
for the sedative properties of ‘Sanjoin’, a plant seed of clinical importance in oriental medicine.3
Synthesis of cyclopeptide alkaloids has been investigated by a number of groups and various
ingenious approaches have been investigated.4 A seminal contribution results from Schmidt’s
group who discovered that activation of a carboxyl group via a pentafluorophenyl ester is
particularly effective for the ring closure reaction. Based on this methodology, the same group
has accomplished the first total synthesis of zizyphine-A,5 mucronin-B6 and finally frangulanine,
* Corresponding author. Fax: 33 1 69 07 72 47; e-mail: zhu@icsn.cnrs-gif.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01335-6

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a 14-membered para-cyclophane in 1991.7 Subsequently, other natural products have been
synthesized in Joullie´’s8 and Han’s9 groups employing the same macrolactamization strategy.
Despite these impressive achievements, there is still a need for developing a more practical and
efficient synthetic route to this class of natural products. Toward this end, we have developed
a novel cycloetherification methodology10 and have recently achieved an asymmetric total
synthesis of sanjoinine G1.11 In this letter, we describe the first total synthesis of mauritine-A
(2),12 isolated by Tschesche from the root bark of Ziziphus mauritiana Lam.13 Formation of an
arylꢀalkyl ether bond with concomitant ring closure based on an intramolecular SNAr reaction14
is the key feature of the present synthesis.
The cyclization precursor 3 was prepared by two conventional peptide coupling steps starting
from (1R)-1-(4%-fluoro-3%-nitro)phenyl-2-aminoethanol,15
L
-N-Boc phenyl ala and (2S,3S)-N-
benzyl-2-hydroxy proline.16 Cyclization of dipeptide 3 under the optimal conditions (TBAF,
DMSO, 60°C) afforded 14-membered cyclophane in 75% yield as a mixture of two atropisomers
4 and 5 in a 1/1.5 ratio. A strong NOE correlation observed between protons Ha and Hb is
indicative of the atropstereochemistry of compound 5. Steric repulsion between a nitro group
and an N-benzyl residue of proline in compound 4 may be responsible for the preferential
formation of the atropisomer 5. The fact that compounds 4 and 5 are two atropisomers was
confirmed by their subsequent transformation to the common product 6 via a straightforward
two-step sequence (Scheme 1).
Scheme 1.
To verify if the stereochemistry of benzylic alcohol can exert any influence on the macrocy-
clization reaction and the subsequent dehydration reaction at the benzylic carbon, compound 7,
an epimer of 3, was synthesized and was transformed into cyclophane 8 following the identical
synthetic scheme. The same efficiency observed indicated that neither the cyclization nor the
post-manipulations of nitro groups were sensitive to the stereochemistry of the tether chain.
Prior to the introduction of the enamide function, the N-protective group of proline residue
needed to be readjusted. This was realized by a one-step transprotection procedure. Thus,
hydrogenolysis of compound 6 over Pearlmans catalyst in the presence of Boc2O gave the

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corresponding N-Boc derivative (9).17 The benzylic hydroxyl function was stable under these
conditions (Scheme 2). Mesylation of alcohol followed by its displacement with sodium phenyl
selenide gave compound 10. This substitution reaction was hypothesized to proceed via an SN2
mechanism. In fact, as seen from the X-ray structure of mauritine-A,18 the benzylic carbon was
out of the plane defined by the aromatic ring due to the presence of severe ring strain.
Consequently, stabilization of the possible carbon cation intermediate by the benzene ring was
virtually non-existent rendering the SN2 reaction more plausible. This particular structural
property can also explain the stability of benzylic alcohol under the hydrogenation conditions.
Oxidation of phenyl selenide with hydrogen peroxide in CH2Cl2 in the presence of pyridine gave
the corresponding selenoxide, which was found to be unstable and underwent the desired
syn-elimination to afford directly the enamide 11 at room temperature. In contrast, the
phenylselenoxide resulting from the oxidation of R configured selenide 12 was more stable and
heating in benzene was required to effect the desired syn-elimination.7,8 Our results unambigu-
ously established that the R configured secondary alcohol 9 is much easier to undergo
syn-elimination via phenylselenoxide than the S configured alcohol 8.
t
Scheme 2. Reagents and conditions: (a) Pd(OH)2, H2, Boc2O, BuOH, 90%; (b) (i) MsCl, Et3N, CH2Cl2, −10°C, (ii)
diphenyl diselenide, NaBH4, 5°C, then 80°C, 72%; (c) H2O2, Py., CH2Cl2, 25°C, 60%; (d) H2O2, Py., CH2Cl2, then
benzene, 60°C, 55%
To reach the mauritine-A, a two-step sequence involving N-deprotection and peptide coupling
was required. These seemingly trivial transformations were found to be more difficult than it
might suggest. Joullie´8c has previously identified Ohfune’s procedure (TMSOTf, 2,6-dimethyl
lutidine) for the removal of the N-Boc function.19 However, only degradation was observed
when these conditions were applied to compound 11. After surveying various conditions, the
procedure developed by Mann (ZnBr2, CH2Cl2)20 was found to be the most suitable in this case.
Coupling of 13 with dipeptide N,N-dimethyl-
to the racemization at the valine a-carbon, probably via the mu¨nchnone intermediate 15. Model
coupling between -proline methyl ester and dipepetide 14 revealed that HATU (O-(7-azabenzo-
L
-alanyl-
-valine (14)12 posed another problem due
L
L
triazol-1-yl)-N,N,N%,N%-tetramethyluronium hexafluorophosphate) in DMF in the presence of
K2CO3 was optimal.8,21 Applying these two optimized deprotection–coupling conditions to
compound 10, mauritine-A was obtained in 20–40% yield (Scheme 3).

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Scheme 3.
In conclusion, we achieved the first total synthesis of mauritine-A using cycloetherification
technology. Two difficult synthetic steps, namely, arylꢀalkyl ether bond formation and macro-
cyclization associated with the synthesis of 14-membered cyclopeptide alkaloids were reduced
into a single operation with high efficiency. Since the cyclization was performed on an intact
peptidic precursor, the synthesis became very convergent. Furthermore, no tedious separation of
diastereomers was required in contrast to previous syntheses.
Acknowledgements
A Doctoral fellowship from ‘Ligue Nationale Contre le Cancer’ to Dr. T. La¨ıb is gratefully
acknowledged.
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