Total synthesis of mauritines A, B, C, and F: Cyclopeptide alkaloids with a 14-membered paracyclophane unit

Article abstract of DOI:10.1002/chem.200401070

A unified strategy for the synthesis of mauritines A (5), B (6), C (7), and F (10) has been developed based on a key intramolecular nucleophilic aromatic substitution reaction (S_NAr) for the formation of the strained 14-membered paracyclophane.

Full text of DOI:10.1002/chem.200401070

Total Synthesis of Mauritines A, B, C, and F: Cyclopeptide Alkaloids with a
14-Membered Paracyclophane Unit
Pierre Cristau,[a] Taoues Temal-Laïb,[a] Michꢀle Bois-Choussy,[a] Marie-Thꢁrꢀse Martin,[a]
Jean-Pierre Vors,[b] and Jieping Zhu*[a]
Abstract: A unified strategy for the
synthesis of mauritines A (5), B (6), C
(7), and F (10) has been developed
based on a key intramolecular nucleo-
philic aromatic substitution reaction
(SNAr) for the formation of the strain-
ed 14-membered paracyclophane. It
was demonstrated that the outcome of
the cycloetherification is independent
of the stereochemistry of the peptide
backbone and that both (1R)-16 and
(1S)-16 cyclized smoothly to provide
the corresponding macrocycle. On the
other hand, dehydration of the second-
ary benzylic alcohol, via the phenylse-
lenide intermediate, is configuration
dependent. (1R)-25 underwent the two-
step syn-elimination much more easily
than (1S)-22. A modified reductive de-
amination procedure via the diazonium
intermediate was developed. A com-
plete assignment of proton and carbon
NMR spectroscopy signals for these
natural products is reported for the
first time.
Keywords: alkaloids
substitution cyclopeptides
macrocycles · mauritine
·
aromatic
·
·
Introduction
Cyclopeptide alkaloids are 13-, 14-, or 15-membered macro-
cycles widely distributed among several plants such as rham-
naceae, pendaceae, and rubiaceae.[1] Since the structure de-
termination of pandamine (1) by Païs, Goutarel, and co-
workers in 1966,[2] the cyclopeptide alkaloid family of para-
or metacyclophanes has grown rapidly and nowadays en-
compasses over 200 compounds (Scheme 1). Among these,
the 14-membered cyclophanes with an endo aryl–alkyl ether
bond represent the largest subgroup and have been the re-
search focus in the area.
Interesting biological properties such as sedative, antibac-
terial, and antifungal activities have been found for this
[a] Dr. P. Cristau, Dr. T. Temal-Laïb, Dr. M. Bois-Choussy,
Dr. M.-T. Martin, Dr. J. Zhu
Institut de Chimie des Substances Naturelles
CNRS, 91198 Gif-sur-Yvette Cedex (France)
Fax : (+33)169-077-247
Scheme 1. Representative cyclopeptide alkaloids.
E-mail: zhu@icsn.cnrs-gif.fr
[b] Dr. J.-P. Vors
class of natural products.[3] Sanjoinine A (frangufoline; 2)
and sanjoinine G1 (3) are among the most-deeply investigat-
ed compounds and the elegant work of Hanꢀs group has
convincingly demonstrated that sanjoinine A (2) is the
major bioactive component of “sanjoin”, a plant seed of
clinical importance in oriental medicine.[4] However, the re-
Bayer CropScience, 14–20 Rue Pierre Baizet
69009 Lyon (France)
Supporting information for this article (experimental procedures and
spectroscopic data for compounds (1R)-16, (1S)-16, (1R)-20, and
(1S)-20, as well as copies of H and 13C NMR spectra of mauritines A,
1
B, C, and F) is available on the WWW under http://www.chemeurj.org/
or from the author.
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DOI: 10.1002/chem.200401070
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FULL PAPER
stricted natural availability of cyclopeptide alkaloids has not
allowed systematic evaluation of their biological properties
and the lack of an efficient synthetic strategy has limited, on
the other hand, structure–activity relationship studies. This
moderately complex structure in fact represents several syn-
thetic challenges, including a) the construction of an aryl–
alkyl ether bond under mild conditions that can be tolerated
by the sensitive chiral amino acid residues; b) formation of
a sensitive Z-enamide function, and c) formation of a strain-
ed 14-membered paracyclophane. Not surprisingly, many
groups, including those of Païs,[5] Rapoport,[6] Schmidt,[7]
Joulliꢂ,[8] Lipschutz,[9] and Han,[10] as well as our own
group,[11] have been involved in the development of new
synthetic strategies.
In planning a synthesis of macrocyclic compounds, the
choice of macrocyclization site and the reaction to be em-
ployed to realize this transformation is of utmost impor-
tance. For the synthesis of cyclopeptide alkaloids, diverse
bond disconnections have been examined for the key ring-
forming process and strategies based upon macrolactamiza-
tion,[5–8,10] intramolecular aziridine-opening reaction, intra-
molecular Michael addition, intramolecular aldol condensa-
tion,[1] intramolecular amide N-alkylation,[9] and lately, intra-
molecular nucleophilic aromatic substitution (SNAr)[11] have
been investigated. However, due to the intrinsic ring strain
associated with the 14-membered paracyclophane, the cycli-
zation has turned out to be a difficult exercise. A major con-
tribution to this field came from Schmidt and co-workers,[7]
who developed a particularly efficient carboxylic acid activa-
tion method (through a pentafluorophenyl ester) for con-
ducting the key macrolactamization step. On the basis of
this methodology, they achieved the total syntheses of zizy-
phine A (4)[7c,e] and mucronine B at the beginning of the
1980s,[7f,g] followed in 1991 by the 14-membered cyclopeptide
alkaloid frangulanine.[7h] This activation methodology was
also featured in the total syntheses of nummularine F,[8b,c]
sanjoinine G1,[8f,10a] and frangufoline[8h] by the groups of
Joulliꢂ and Han. We have developed an alternative cycliza-
tion strategy based on an intramolecular SNAr reaction[12–16]
and have successfully implemented it in an efficient asym-
metric synthesis of sanjoinine G1.[17] Besides being conver-
gent, the salient feature of our approach is that two synthet-
ic challenges associated with this molecule, namely, forma-
tion of the aryl–alkyl ether bond and macrocyclization, have
been reduced to a single operation with great efficiency. In
this paper, we report in detail total syntheses of mauri-
tines A (5), B (6), C (7), and F (10; Scheme 2). We docu-
ment that, by carefully tuning the peptide sequence, the pre-
viously encountered synthetic pitfall caused by N-tert-butox-
ycarbonyl (N-Boc) deprotection is readily solved, thereby
leading to a more efficient synthesis.[18] Furthermore, all the
proton and carbon NMR spectroscopy signals of these natu-
ral products are attributed for the first time from detailed
studies.
Scheme 2. Structures of mauritines A–F (5–10, respectively).
Results and Discussion
The mauritines A–F (5–10) were isolated in 1972 and 1974
by Tschesche and co-workers, from the methanol extract of
the bark of the African trees Zizyphus mauritania Lam.[19]
The structure of these cyclopeptide alkaloids was elucidated
by chemical degradation and spectroscopic studies including
MS and NMR, UV, and IR spectroscopy. However, the
1H NMR data for these natural products were only fragmen-
tarily reported and were not attributed. The 13C NMR data
were not available in the open literature, most probably due
to the insufficient amount of natural products available
from the natural resources. Fortunately, the structure of
mauritine A (5) was determined without ambiguity by X-ray
crystal analysis.[20] Preliminary biological studies revealed
that mauritines A–F (5–10) are active against the Gram-pos-
itive bacteria Bacillus subtilis.[19b] Nevertheless, the limited
availability of these compounds hampered systematic evalu-
ation of their biological properties.[21]
Our previous synthesis of mauritine A (5) was accom-
plished in 13 steps with 2.3% overall yield.[18] The weakness
of this synthesis was the seemingly trivial N-Boc deprotec-
tion step (Scheme 3). Indeed, removal of the N-Boc function
from compound 11 under a variety of conditions failed to
give the desired compound 12. After much experimentation,
the procedure developed by Mann and co-workers (ZnBr2,
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J. Zhu et al.
group. Direct N-acylation of the proline unit of cyclophane
14 with the N-Boc-protected amino acid would provide 13.
Since the N-Boc function in compound 13 is sterically more
accessible and less prone to intramolecular hydrogen bond-
ing, its deprotection should be much easier than that of 11.
From 13, mauritines A, B, and F would be readily accessible
by coupling with the respective amino acid. The salient fea-
ture of the present strategy is its inherent convergence, since
the required acyclic precursor 16 is an intact dipeptide avail-
able in only two steps from three available building blocks:
17, 18, and 19 (Scheme 4).
Scheme 3. Removal of the N-Boc function, a pitfall in our first-genera-
tion synthesis of mauritine A. a) ZnBr2, CH2Cl2, <40%.
CH2Cl2)[22] was found to be the method of choice in this spe-
cific case, but the yield of the corresponding deprotected cy-
clophane 12 remained moderate at best (Scheme 3). It is
worth noting that the same problem has been encountered
in previous syntheses of frangufoline.[7h,8c] It was reasoned
that the difficulty in removing this protecting group is due
either to the steric hindrance around the N-Boc carbonyl
function or to the presence of an intramolecular hydrogen
bond. Based on this consideration, a slightly modified syn-
thetic scheme was envisaged that eventually led to the de-
velopment of an efficient and unified synthesis of mauri-
tines A (5), B (6), C (7), and F (10; Scheme 4). In a forward
sense, cyclization of the linear dipeptide 16 by way of an in-
tramolecular SNAr reaction would provide first the corre-
sponding macrocycle 15 and then 14 after reductive removal
of the nitro group and hydrogenolysis of the N-benzyl
Synthesis of the 14-membered cyclophane: To determine
whether the configuration of the benzylic hydroxy group
exerts any influence on the macrocyclization and subsequent
dehydration steps, which are required for the introduction
of the corresponding enamide function, both diastereoisom-
ers of 16 were synthesized as depicted in Scheme 5. Cou-
Scheme 5. Synthesis of the linear dipeptides (1R)-16 and (1S)-16. a) N-
Boc-l-phenylalanine (18), Et3N, EDCI, HOBT, DMF, 98% yield for
(1R)-20, 93% yield for (1S)-20; b) 1. HCl, CH3CN, 2. (2S,3S)-N-benzyl-2-
hydroxyproline (19), Et3N, EDCI, HOBT, DMF, 78% yield for (1R)-16,
95% yield for (1S)-16. EDCI=3-(3-dimethylaminopropyl)-1-ethylcarbo-
diimide, HOBT=1-hydroxy-1H-benzotriazole, DMF=N,N-dimethylform-
amide.
Scheme 4. Retrosynthetic analysis of mauritines A, B, C, and F, a unified
strategy. Bn=benzyl.
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Total Synthesis of Mauritines
FULL PAPER
pling of (1R)-1-(4’-fluoro-3’-nitro)phenyl-2-amino-ethanol
(1R)-17[23] with N-Boc-l-phenylalanine (18) under classical
conditions (EDCI, HOBT, DMF, room temperature) afford-
ed (1R)-20 in a 98% yield. Subsequent N-Boc deprotection
(HCl, CH3CN) followed by acylation with (2S,3S)-N-benzyl-
2-hydroxyproline 19[24] afforded the cyclization precursor
(1R)-16 in a 78% yield. The same sequence applied to (1S)-
17 led to the formation of (1S)-16 in 88% overall yield.
The key SNAr-based cycloetherification of (1R)-16 was
performed in DMSO (concentration of substrate: 0.005m) at
608C in the presence of TBAF and powdered 4 ꢃ molecular
sieves (Scheme 6). Under these optimized reaction condi-
tions, the linear dipeptide (1R)-16 cyclized smoothly to form
the corresponding 14-membered paracyclophane in a 70%
yield as a mixture of two separable atropisomers, (aS,1R)-15
and (aR,1R)-15, in a ratio of 1:1.6. Atropisomer (aS,1R)-15
was significantly more mobile on the thin-layer chromato-
graph than its stereoisomer (aR,1R)-15. A strong NOE cor-
relation observed between protons H9 and H12 for
(aR,1R)-15 was indicative of its configuration. Similarly, cyc-
lization of (1S)-16 under identical conditions proceeded effi-
ciently to provide the paracyclophanes (aS,1S)-15 and
(aR,1S)-15 in a 70% yield and with 1:1.4 atropoenantiose-
lectivity (Scheme 6). These results showed that the SNAr-
based macrocyclization was independent from the configura-
tion of the benzylic hydroxy group and thereby expanded
further the synthetic utility of the method. The lack of atro-
podiastereoselectivity was of no consequence as the planar
chirality will disappear upon removal of the nitro group.
Reductive removal of the nitro group was carried out via
the diazonium intermediate. The transformation was initially
performed on (aS,1S)-15 in two steps, involving a) reduction
of nitro to aniline (SnCl2, MeOH)[25] and b) diazoniation/
dediazoniation with a modified Kornblum and Iffland proce-
dure (NaNO2, H3PO2, Cu2O).[26] Under these conditions, the
desired macrocycle (1S)-21 was obtained in a 43% yield. In-
terestingly, the intermediate aniline was obtained in much
higher yield when the nitro group in 15 was subjected to cat-
alytic hydrogenation (H2, Pd/C, MeOH/EtOAc), instead of
chemical reduction with stannous chloride.[27] However, the
aniline obtained by catalytic hydrogenation underwent de-
amination in only a 22% yield. Since complete removal of
tin residue by liquid–liquid extraction is known to be very
difficult, we hypothesized that trace amounts of tin contami-
nating the aniline obtained by SnCl2 reduction might have a
beneficial effect on the diazoniation/dediazoniation se-
quence. To verify this hypothesis, the deamination of aniline
obtained by hydrogenolysis was next carried out in the pres-
ence of SnCl2·H2O. To our delight, macrocycle (1S)-21 was
obtained in 70% overall yield. Application of these new
conditions (Pd/C, H2, MeOH/EtOAc, then NaNO2, H3PO2,
Cu2O, SnCl2·H2O) to (aS,1R)-15 and (aR,1R)-15 afforded
(1R)-21 in an 80% yield (Scheme 6).
Total synthesis of mauritine C: The total synthesis of mauri-
tine C is shown in Scheme 7. Hydrogenolysis of (1S)-21
under standard conditions (Pd/C, MeOH, H2) proceeded
smoothly to provide (1S)-14. Subsequent acylation of the re-
sulting secondary amine with N-Boc-N-methyl-l-valine
under Carpinoꢀs conditions (HATU, DIPEA)[28] afforded
the fully functionalized cyclophane (1S)-22 in a 71% yield
over the two steps. The enamide function was introduced
following the protocol of Joulliꢂ and co-workers. Thus, se-
quential mesylation and selenenylation (PhSeSePh, NaBH4,
EtOH) of (1S)-22 furnished (1R)-23. The latter substitution
reaction was hypothesized to proceed through an SN2 mech-
anism. Indeed, as seen from the X-ray structure of mauri-
tine A (5),[20] the benzylic carbon is out of the plane defined
by the aromatic ring due to the presence of severe ring
strain. Consequently, stabilization of the possible carbocat-
ion intermediate resulting from the SN1 mechanism is virtu-
ally nonexistent, a fact making the SN2 mechanism more
plausible. The same particular structural feature can also ex-
plain the stability of the benzylic alcohol under the hydroge-
Scheme 6. SNAr-based cycloetherification of (1R)-16 and (1S)-16.
a) TBAF, DMSO, powdered 4 ꢃ molecular sieves, 608C, 70% yield, atro-
penantioselectivity of (aS,1R)-15/(aR,1R)-15=1:1.6 and of (aS,1S)-15/
(aR,1S)-15=1/1.4; b) H2, Pd/C, MeOH/EtOAc (1:1); c) NaNO2, H3PO2,
Cu2O (0.1 equiv), SnCl2 (0.2 equiv). TBAF=tetrabutylammonium fluo-
ride, DMSO=dimethylsulfoxide.
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J. Zhu et al.
Scheme 7. Synthesis of mauritine C (7). a) H2, Pd/C, MeOH, 82%; b) N-
Boc-N-methyl-l-valine, HATU, DIEA, DMF, 87%; c) 1. MsCl, Et3N,
CH2Cl2, 2. (PhSe)2, NaBH4, EtOH, 74%; d) 1. H2O2, pyridine, CH2Cl2,
2. benzene, 608C, 48%; e) TFA, CH2Cl2, 78%. HATU=N-[(dimethyl-
amino)-1H-1,2,3-triazole[4,5-b]-pyridin-1-ylmethylene]-N-methylmethan-
aminium hexafluorophosphate, DIEA=N,N-diisopropylethylamine, Ms=
mesyl=methanesulfonyl, TFA=trifluoroacetic acid.
nation conditions. Oxidation of selenide (1R)-23 with hydro-
gen peroxide in dichloromethane afforded the correspond-
ing selenoxide, which did not undergo spontaneous syn-
elimination at room temperature. However, when a benzene
solution of the selenoxide was heated to 608C, smooth syn-
elimination occurred to provide 24 in a 48% yield. As ex-
pected and in contrast to the N-Boc deprotection of com-
pound 11 (Scheme 3), removal of the N-Boc function in 24
(TFA, CH2Cl2, room temperature) proceeded uneventfully
to provide mauritine C (7) in a 78% yield. It is noteworthy
that the enamide function is stable under such mild acidic
conditions.[29]
Scheme 8. Synthesis of mauritines A (5), B (6), and F (10). a) H2, Pd/C,
MeOH, 78%; b) N-Boc-l-valine, HATU, DIEA, DMF, 96%; c) 1. MsCl,
Et3N, CH2Cl2, 2. (PhSe)2, NaBH4, EtOH, 87%; d) H2O2, pyridine,
CH2Cl2, 60%; e) TFA, CH2Cl2; f) N,N-dimethyl-l-alanine, HATU,
DIEA, DMF, 59%; g) N,N-dimethyl-l-isoleucine, HATU, DIEA, DMF,
61%; h) N-Boc-N-methyl-l-alanine, HATU, DIEA, DMF, 79%; i) TFA,
CH2Cl2, 71%.
Total syntheses of mauritines A, B, and F: The synthesis of
mauritines A (5), B (6), and F (10) was completed by start-
ing from (1R)-21 (Scheme 8). The proline N-benzyl group
was first removed under hydrogenolysis conditions (Pd/C,
H2, MeOH) and then N-Boc-l-valine was coupled (HATU,
DIEA) to give (1R)-25 in a 75% yield over two steps. Treat-
ment of (1R)-25 with mesyl chloride and triethylamine in di-
chloromethane afforded the corresponding mesylate, which
was displaced by sodium phenyl selenide to give (1S)-26 in a
87% yield. Oxidation with hydrogen peroxide gave the cor-
responding selenoxide, which underwent spontaneous syn-
elimination at room temperature to afford the desired en-
amide (27) in a 60% yield. It has previously been reported
that the two diastereomeric selenides behave differently
under the oxidation/elimination conditions.[7h,8c,8f,8h] Our re-
sults unambiguously established that the selenide (1S)-26,
which arises from the R-configured secondary alcohol (1R)-
14, undergoes syn-elimination much more readily than a
similar compound with the opposite configuration, (1R)-23,
upon conversion into the corresponding selenoxide.
Removal of the N-Boc protection in 27 (TFA, CH2Cl2,
room temperature) provided 28 in excellent yield. Coupling
of (28) with N,N-dimethyl-l-alanine or N,N-dimethyl-
(2S,3S)-isoleucine[30] afforded mauritine A (5) and mauri-
tine B (6) in 59 and 61% yields, respectively. Alternatively,
coupling of 28 with N-Boc-N-methyl-l-alanine followed by
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Total Synthesis of Mauritines
FULL PAPER
Table 1. 1H NMR and 13C NMR assignments for mauritine A (5).[a]
Conclusion
In conclusion, we have achieved
the total syntheses of mauri-
tines A (5), B (6), C (7), and F
(10) in an average overall yield
of about 10%. Our approach
featured a key intramolecular
SNAr cycloetherification for the
construction of the 14-mem-
bered paracyclophane. Since
this macrocyclization was per-
formed on an intact peptidic
precursor, the synthesis is very
convergent. Furthermore, the
synthesis was divergent at a late
stage that allowed us to develop
a unified strategy for these nat-
ural products. Additionally, new
efficient reaction conditions for
the removal of the nitro group
were developed in the course of
this study. We also demonstrat-
ed that the deprotection prob-
lem encountered in our previ-
ous synthesis can be avoided by
incorporating an additional
amino acid at the N terminus.
Finally, we have assigned, for
the first time, all proton and
carbon NMR spectroscopy sig-
nals of mauritines A (5), B (6),
C (7), and F (10) in detailed
studies.
d(1H) [ppm]
Multiplicity
No. of H atoms
Assignment
J [Hz]
d(13C) [ppm]
Assignment
7.65
7.15–7.26
6.99
6.96
6.88
6.63
6.35
6.26
6.21
5.42
4.52
4.43
4.18
4.09
3.41
3.32
2.93
2.60
2.51
2.25
2.13
1.90
1.18
0.79
0.77
d
1H
6H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
6H
1H
1H
3H
3H
3H
H24
H16, H32–36
H15
H12
H13
H2
H6
H3
H1
H9
H5
H20
H18
H8
H18’
H30
H26
H30’
H17
8.8
174.5
171.5
170.3
166.5
157.3
135.6
132.4
132.3
130.2
130.0
128.4
127.0
125.4
122.6
122.4
114.7
83.6
64.9
64.1
54.6
54.0
46.4
42.4
36.0
31.9
C25
C19
C7
C4
C11
C31
C14
C15
C13
C32, C36
C33, C35
C34
C2
C12
C16
C1
C9
C26
C8
m
dd
dd
dd
dd
d
8.4, 1.8
8.1, 2.2
8.1, 1.8
10.3, 7.7
8.4
10.3
7.7
7.0, 5.9
d
d
dt
m
dd
m
d
m
dd
q
dd
ddd
s
m
m
d
8.8, 6.6
5.9
14.0, 4.0
7.0
14.0, 5.1
12.1, 7.0, 5.5
H28, H29
H17’
H21
H27
H22, H23
H22, H23
C20
C5
C18
C28, C29
C30
7.0
6.6
6.6
d
d
C17
31.2
19.2
17.9
C21
[b]
C22
[b]
C23
12.1
C27
[a] The NMR spectra were recorded in CDCl3 on a Bruker Avance-600 (600 MHz) spectrometer. [b] The as-
signment of these two signals is interchangeable.
Experimental Section
Compounds (aS,1R)-15 and (aR,1R)-
15: A suspension of TBAF (5.45 mL,
1.0m in THF) and powdered molecu-
lar sieves (3 ꢃ, 200.0 mg, pre-dried under vacuum) in distilled DMSO
(360.0 mL) was stirred at room temperature for 4 h. A solution of com-
pound (1R)-16 (1.0 g, 1.82 mmol) in DMSO was then added in one por-
tion. After being stirred at 608C for 20 h and then cooled to room tem-
perature, the reaction mixture was diluted with water, filtered through
celite, and extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under vacuum. The
resulting crude oil was purified by flash chromatography (silica gel, hep-
tanes/EtOAc (1:1)!EtOAc/MeOH (30:1)) to afford compounds (aS,1R)-
15 (262 mg) and (aR,1R)-15 (415 mg) in a total yield of 70%. (aS,1R)-15:
Yellow solid; m.p. 98–1008C; [a]D =ꢀ155 (c=0.18 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.24 (d, J=2.0 Hz, 1H; CH arom), 7.01–7.26 (m,
12H; CH arom), 6.57 (m, 1H; NH), 5.75 (d, J=9.1 Hz, 1H; NH), 5.14
(brs, 1H; CH), 4.89 (m, 1H; CH), 4.36 (ddd, J=14.4, 10.8, 4.0 Hz, 1H;
CH2), 4.20 (q, J=8.0 Hz, 1H; CH), 3.37 (d, J=12.8 Hz, 1H; CH2), 3.02
(d, J=12.8 Hz, 1H; CH2), 2.89 (m, 1H; CH2), 2.78 (dd, J=13.4, 8.6 Hz,
1H; CH2), 2.70 (d, J=6.8 Hz, 1H; CH), 2.67 (d, J=14.4 Hz, 1H; CH2),
2.59 (dd, J=13.4, 7.0 Hz, 1H; CH2), 2.43 (m, 1H; CH2), 2.20 (m, 1H;
CH2), 1.99 ppm (m, 1H; CH2); 13C NMR (75 MHz, CDCl3): d=170.8,
169.5, 150.4, 141.6, 138.5, 137.3, 135.8, 132.0, 129.2 (2C), 129.0 (2C),
removal of the N-Boc protection provided mauritine F (10)
in 56% overall yield.[31]
Preliminary results of the biological screening against a
variety of fungal strains were disappointing, since none of
these natural products displayed exploitable antifungal ac-
tivities.
Spectroscopic analysis of mauritines A, B, C, and F: The
NMR data reported for mauritines A, B, C, and F were in-
complete.[19] Therefore, COSY, HMQC, HMBC, and
NOESY spectra were recorded to allow the assignment of
each proton and carbon NMR spectroscopy signal. The com-
plete assignment is listed in Tables 1–4 for these natural
products. This detailed NMR study also fully established the
structure of our synthetic compounds.
Chem. Eur. J. 2005, 11, 2668 – 2679
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2673

J. Zhu et al.
Table 2. 1H NMR and 13C NMR assignments for mauritine B (6).[a]
1220 cmꢀ1
;
high-resolution MS (CI):
m/z calcd: 531.2244 [M+H]+; found:
531.2235.
Compounds (aS,1S)-15 and (aR,1S)-
15: The cyclization of (1S)-16
(1.16 mmol) was performed under
identical conditions to those described
for the synthesis of (1R)-15. The crude
product was purified by flash chroma-
tography (silica gel, heptanes/EtOAc
(1:3)!CH2Cl2/MeOH (20:1)) to afford
compounds (aS,1S)-15 (179 mg) and
(aR,1S)-15 (251 mg) in a total yield of
70%. (aS,1S)-15: Yellow solid; m.p.
126–1288C; [a]D =ꢀ151 (c=0.15 in
CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.77 (dd, J=8.5, 2.1 Hz, 1H; CH
arom), 7.71 (d, J=2.1 Hz, 1H; CH
arom), 6.98–7.26 (m, 10H; CH arom),
6.83 (m, 2H; CH arom, NH), 5.52 (d,
J=9.3 Hz, 1H; NH), 5.09–5.30 (m,
2H; CH, OH), 4.89 (m, 1H; CH), 4.46
(td, J=9.3, 7.1 Hz, 1H; CH), 3.86 (dd,
J=14.8, 5.4 Hz, 1H; CH2), 3.48 (td,
J=14.8, 6.1 Hz, 1H; CH2), 2.62–2.95
(m, 6H; CH, CH2), 2.30–2.51 (m, 2H;
CH2), 2.01 ppm (m, 1H; CH2);
13C NMR (62.5 MHz, CDCl3): d=
172.1, 170.1, 150.7, 141.7, 139.3, 137.6,
135.5, 132.0, 129.0, 128.8 (4C), 128.2
(4C), 127.4, 126.0, 124.0, 86.3, 74.5,
71.9, 57.9, 53.3, 52.1, 49.1, 36.6,
29.8 ppm; IR (CHCl3): n˜ =3625, 3420,
3011, 2976, 1928, 1667, 1534, 1495,
d(1H) [ppm]
Multiplicity
No. of H atoms
Assignment
J [Hz]
d(13C) [ppm]
Assignment
7.23–7.32
7.08
7.04
7.02
6.94
6.68
6.33
6.31
6.26
5.47
4.58
4.49
4.24
4.11
3.47
3.39
2.64
2.60
2.57
2.31
2.22
1.94
1.83
1.55
1.24
0.96
0.94
0.87
0.86
m
d
6H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
6H
1H
1H
1H
1H
1H
3H
3H
3H
3H
H16, H35–39
H24
H15
H12
H13
H2
H6
H3
H1
H9
172.4
171.5
170.6
166.4
157.4
135.6
132.4
132.3
130.3
130.2
128.4
127.0
125.4
122.5
122.2
114.7
83.6
74.8
64.3
54.9
54.0
46.3
43.4
35.9
34.6
C25
C19
C7
8.4
dd
dd
dd
dd
d
8.4, 1.9
8.2, 2.5
8.2, 1.9
10.4, 7.8
8.5
10.4
7.8
6.3, 3.7
C4
C11
C34
C14
C15
C13
C35, C39
C36, C38
C37
C2
C12
C16
C1
C9
C26
C8
d
d
dt
m
dd
m
d
m
dd
dd
d
H5
H20
H18
H8
8.4, 6.7
5.8
H18’
H33
H33’
H26
H17
H27, H28
H17’
H21
H29
H31
H31’
H32
H30
14.0, 4.1
14.0, 5.3
5.1
m
s
C20
C5
1454, 1391, 1345, 1249, 1206 cmꢀ1
;
m
m
m
m
m
t
d
d
d
high-resolution MS (CI): m/z calcd:
531.2244 [M+H]+; found: 531.2243.
(aR,1S)-15: Yellow solid; m.p. 116–
1188C; [a]D =+13 (c=0.2 in CHCl3);
1H NMR (250 MHz, CDCl3): d=7.85
(d, J=2.1 Hz, 1H; CH arom), 6.89–
7.32 (m, 12H; CH arom), 6.08 (t, J=
5.8 Hz, 1H; NH), 5.94 (d, J=9.1 Hz,
1H; NH), 5.13 (m, 1H; CH), 4.96 (m,
1H; CH), 4.54 (m, 1H; OH), 4.39 (td,
J=9.1, 7.0 Hz, 1H; CH), 3.91 (ddd,
J=14.4, 7.0, 4.1 Hz, 1H; CH2), 3.33
(dt, J=14.4, 5.6 Hz, 1H; CH2), 2.71–
2.90 (m, 5H; CH2), 2.67 (d, J=7.0 Hz,
1H; CH), 2.26–2.48 (m, 2H; CH2),
2.00 ppm (m, 1H; CH2); 13C NMR
(62.5 MHz, CDCl3): d=171.7, 170.7,
C18
C27, C28
C33
C29
C17
C21
C31
7.4
6.7
6.7
6.7
31.9
30.8
27.2
19.4
18.1
14.6
12.2
[b]
H22
H23
[b]
[c]
C22
[c]
C23
C30
C32
[a] The NMR spectra were recorded in CDCl3 on a Bruker Avance-600 (600 MHz) spectrometer. [b] The as-
signment of these two signals is interchangeable. [c] The assignment of these two signals is interchangeable.
128.5 (2C), 128.3 (2C), 127.4, 127.1, 125.1, 124.0, 85.4, 74.8, 70.7, 58.0,
54.7, 51.7, 45.9, 42.8, 29.3 ppm; IR (CHCl3): n˜ =3300, 3021, 1669, 1533,
1347, 1217, 1096 cmꢀ1; high-resolution MS (CI): m/z calcd: 531.2240
[M+H]+; found: 531.2200. (aR,1R)-15: Yellow solid; m.p. 1428C; [a]D =
ꢀ60 (c=0.27 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.75 (dd, J=
8.7, 1.9 Hz, 1H; CH arom), 7.45 (d, J=1.9 Hz, 1H; CH arom), 6.97–7.32
(m, 11H; CH arom), 6.55 (m, 1H; NH), 6.24 (d, J=9.1 Hz, 1H; NH),
5.26 (m, 1H; CH), 5.09 (d, J=3.6 Hz, 1H; CH), 4.23–4.38 (m, 2H; CH,
CH2), 3.32 (d, J=12.7 Hz, 1H; CH2), 3.01 (d, J=12.7 Hz, 1H; CH2), 2.94
(td, J=9.0, 3.5 Hz, 1H; CH2), 2.88 (d, J=7.0 Hz, 1H; CH), 2.81 (d, J=
14.0 Hz, 1H; CH2), 2.80 (dd, J=13.5, 7.4 Hz, 1H; CH2), 2.67 (dd, J=
13.5, 7.7 Hz, 1H; CH2), 2.40 (m, 1H; CH2), 2.28 (m, 1H; CH2), 1.90–
2.12 ppm (m, 1H; CH2); 13C NMR (75 MHz, CDCl3): d=170.9, 170.3,
149.9, 141.5, 137.1, 136.4, 135.7, 130.3, 129.5 (2C), 129.0 (2C), 128.5 (2C),
128.3 (2C), 127.6, 127.1, 122.7, 118.5, 82.5, 74.3, 71.3, 57.8, 54.6, 50.6, 46.8,
39.7, 28.4 ppm; IR (CHCl3): n˜ =3387, 3301, 3021, 1670, 1534, 1507, 1361,
144.1, 138.0, 137.5, 135.8, 131.4, 129.4, 129.2, 128.8 (4C), 128.2 (4C),
127.3, 121.9, 121.6, 86.1, 74.7, 72.1, 57.6, 53.7, 51.3, 48.1, 37.6, 29.8 ppm;
IR (CHCl3): n˜ =3404, 3024, 1669, 1534, 1507, 1498, 1363, 1227, 1206 cmꢀ1
;
high-resolution MS (CI): m/z calcd: 531.2244 [M+H]+; found: 531.2264.
Compound (1S)-21: Compound (aS,1S)-15 (51.2 mg, 0.097 mmol) was dis-
solved in solvent (AcOEt/MeOH (1:1); 1.5 mL), then Pd/C (10%, 5 mg)
was added. The suspension was purged three times with argon and then
three times with hydrogen. The reaction mixture was stirred vigorously
under a hydrogen atmosphere for 2.5 h at room temperature, then fil-
tered through celite and concentrated under vacuum. The resulting crude
residue was dissolved in solvent (THF/water (3:1); 1 mL) and cooled to
08C. An aqueous solution of H3PO2 (70 mL, 50%, 0.673 mmol) was
added; this was followed by successive addition of Cu2O (1.4 mg,
0.01 mmol), SnCl2 (3.6 mg, 0.019 mmol), and NaNO2 (20 mg, 0.29 mmol).
The reaction mixture was stirred at 08C for 3 h, then at room tempera-
ture for 1 h. After addition of aqueous NaOH (5%), the solution was ex-
tracted with EtOAc. The organic layer was washed with brine, dried over
2674
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2668 – 2679

Total Synthesis of Mauritines
FULL PAPER
Table 3. 1H NMR and 13C NMR assignments for mauritine C (7).[a]
(d, J=8.5 Hz, 1H; NH), 5.25 (m, 1H;
CH), 5.10 (d, J=3.5 Hz, 1H; CH),
4.16–4.29 (m, 2H; CH, CH2), 3.48 (d,
J=12.0 Hz, 1H; CH2), 3.03 (d, J=
12.0 Hz, 1H; CH2), 2.94 (m, 1H;
CH2), 2.85 (brd, J=13.8 Hz, 1H;
CH2), 2.75 (dd, J=13.3, 8.4 Hz, 1H;
CH2), 2.66 (dd, J=13.3, 6.7 Hz, 1H;
CH2), 2.55 (d, J=6.7, 1H; CH), 2.28–
2.43 (m, 2H; CH2), 1.84–1.90 ppm (m,
1H; CH2); 13C NMR (62.5 MHz,
CDCl3): d=170.9, 170.7, 157.4, 137.6,
136.1, 135.7, 129.7 (2C), 129.1 (2C),
128.3 (4C), 128.1, 127.3 (2C), 126.9,
119.5, 116.5, 81.1, 75.8, 72.1, 57.8, 54.7,
51.0, 46.9, 40.0, 29.0 ppm; IR (CHCl3):
d(1H) [ppm] Multiplicity No. of H atoms Assignment
J [Hz]
d(13C) [ppm] Assignment
7.24–7.27
7.21
7.06
7.04
6.96
6.68
6.57
6.33
6.26
5.48
4.56
4.24
3.94
3.40
3.31
3.04
2.69
m
m
5H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
1H
4H
1H
1H
3H
3H
H16, H28–29, H31–32
174.2
170.3
166.6
157.4
135.6
132.6
132.4
130.3
129.9
128.5
127.0
125.5
122.7
C19
C7
C4
H30
H15
H12
H13
H2
H6
H3
H1
H9
dd
dd
dd
dd
d
d
d
ddd
m
d
dd
ddd
dd
d
dd
ddd
m+s
m
8.4, 2.1
8.2, 2.5
8.2, 2.1
10.5, 7.8
8.4
10.5
7.8
12.6, 7.0, 5.5
n˜ =3020, 1669, 1510, 1211, 1208 cmꢀ1
;
C11
C27
C14
C15
C13
C28, C32
C29, C31
C30
C2
high-resolution MS (CI): m/z calcd:
486.2392 [M+H]+; found: 486.2396.
Compound (1S)-14: A suspension of
compound
(1S)-21
(331 mg,
0.682 mmol) and Pd/C (10%, 165 mg)
in dry MeOH (7.3 mL) was purged
three times with argon and hydrogen,
successively. The reaction mixture was
stirred at room temperature for 24 h.
The purge processes was repeated
twice and the reaction mixture was
stirred for an additional 48 h at room
temperature. The reaction mixture was
H5
H8
5.5
11.1, 8.2
12.9, 11.1, 5.3 122.6
14.2, 4.5
6.4
H18
H18’
H26
H20
H26’
H17
H24, H25
H17’
H21
C12
C16
C1
114.7
83.7
66.4
63.8
54.0
46.1
36.1
35.2
32.1
31.7
19.4
18.4
C9
C20
C8
14.2, 5.2
12.2, 7.1, 5.3
2.57
2.29–2.32
2.11
1.74
0.85
filtered through celite and concentrat-
ed under vacuum. The crude residue
was purified by flash chromatography
C5
C18
C26
C25
C17
C21
m
d
d
(silica gel, CH2Cl2/MeOH (50:1!
[b]
H22
6.7
6.7
20:1)) to afford compound (1S)-14
[b]
0.82
H23
(220 mg, 82% yield). White solid;
m.p. > 2508C; [a]D =+20.2 (c=0.23
[c]
C22
in MeOH); 1H NMR (300 MHz,
[c]
C23
CD3OD): d=7.34 (dd, J=8.8, 2.1 Hz,
1H; CH arom), 7.07–7.24 (m, 5H; CH
arom), 6.89–7.00 (m, 3H; CH arom),
[a] The NMR spectra were recorded in CDCl3 on a Bruker Avance-600 (600 MHz) spectrometer. [b] The as-
signment of these two signals is interchangeable. [c] The assignment of these two signals is interchangeable.
5.05 (dd, J=16.2, 8.1 Hz, 1H; CH),
4.56 (dd, J=10.2, 6.8 Hz, 1H; CH2),
4.04 (dd, J=9.4, 6.0 Hz, 1H; CH), 3.79
Na2SO4, filtered, and concentrated under vacuum. The crude residue was
purified by preparative TLC (silica gel, CH2Cl2/MeOH (20:1)) to afford
compound (1S)-21 (32.6 mg, 70% yield). Compound (aR,1S)-15 is simi-
larly transformed into (1S)-21. White solid; m.p. 2488C; [a]D =ꢀ77.6 (c=
(dd, J=13.0, 10.0 Hz, 1H; CH2), 3.27 (m, 1H; CH), 3.14–3.22 (m, 1H;
CH2), 2.97–3.07 (m+dd, J=12.6, 6.2 Hz, 2H; CH, CH2), 2.74 (dd, J=
13.1, 9.6 Hz, 1H; CH2), 2.61 (dd, J=13.1, 5.6 Hz, 1H; CH2), 2.38–2.49
(m, 1H; CH2), 1.96–2.09 ppm (m, 1H; CH2); 13C NMR (62.5 MHz,
CD3OD): d=172.5, 171.7, 159.2, 138.0, 137.6, 131.2, 130.3 (2C), 129.5
(2C), 128.0, 127.8, 122.0, 117.5, 84.4, 73.9, 68.1, 56.7, 46.4, 45.1, 40.3,
32.9 ppm; IR (KBr): n˜ =3404, 3296, 1642, 1545, 1437, 1374, 1281, 1224,
1074, 1033 cmꢀ1; high-resolution MS (ES+): m/z calcd: 396.1923 [M+H]+
; found: 396.1848.
1
0.12 in CHCl3); H NMR (250 MHz, CDCl3): d=7.58 (dd, J=8.3, 2.2 Hz,
1H; CH arom), 7.08–7.30 (m, 10H; CH arom), 7.05 (dd, J=8.3, 2.6 Hz,
1H; CH arom), 6.98 (dd, J=8.5, 2.6 Hz, 1H; CH arom), 6.91 (dd, J=8.5,
2.2 Hz, 1H; CH arom), 5.60 (dd, J=8.4, 4.2 Hz, 1H; CH), 5.50 (d, J=
8.7 Hz, 1H; NH), 5.13 (m, 1H; CH), 4.85 (t, J=6.0 Hz, 1H; NH), 4.31
(q, J=8.3 Hz, 1H; CH), 3.92 (ddd, J=14.2, 8.4, 5.9 Hz, 1H; CH2), 3.28
(ddd, J=14.2, 6.2, 4.2 Hz, 1H; CH2), 3.18 (d, J=12.6 Hz, 1H; CH2),
2.87–2.94 (m+d, J=12.6 Hz, 2H; CH2), 2.83 (dd, J=13.8, 7.8 Hz, 1H;
CH2), 2.64 (dd, J=13.8, 8.0 Hz, 1H; CH2), 2.59 (d, J=6.5 Hz, 1H; CH),
2.31–2.45 (m, 2H; CH2), 1.88–1.97 ppm (m, 1H; CH2); 13C NMR
(62.5 MHz, CDCl3): d=171.5, 170.4, 157.5, 137.5, 136.4, 135.9, 129.2,
128.8 (2C), 128.6 (2C), 128.2 (4C), 127.3, 127.2, 126.9, 121.63, 119.1, 84.6,
75.9, 72.9, 57.8, 54.4, 51.8, 47.8, 38.4, 29.8 ppm; IR (CHCl3): n˜ =3415,
1667, 1606, 1508 cmꢀ1; high-resolution MS (CI): m/z calcd: 486.2392
[M+H]+; found: 486.2364.
Compound (1S)-22: N-Boc-N-methyl-l-valine (143.0 mg, 0.62 mmol),
DIEA (450.0 mL, 2.58 mmol), and HATU (303.0 mg, 0.77 mmol) were
successively added to a solution of (1S)-14 (204 mg, 0.516 mmol) in dry
DMF (7.0 mL) at 08C. The reaction mixture was stirred at room temper-
ature for 17 h, then treated with a solution of NH4Cl and extracted with
EtOAc. The organic layer was washed with brine, dried over Na2SO4, fil-
tered, and concentrated under vacuum. The crude residue was purified
by flash chromatography (silica gel, CH2Cl2/MeOH (50:1!20:1)) to
afford compound (1S)-22 (274 mg, 87% yield). White solid; m.p. 150–
1528C; [a]D =ꢀ149.8 (c=0.35 in CHCl3); 1H NMR (300 MHz, CDCl3;
mixture of two rotamers (80:20)): d=7.49 (m, 1H; CH arom), 6.98–7.24
(m, 7H; CH arom), 6.85 (m, 1H; CH arom), 6.02 (d, J=8.7 Hz, 0.8H;
NH), 6.00 (d, J=8.7 Hz, 0.2H; NH), 5.46 (m, 1H; CH), 5.15 (m, 1H;
CH), 4.75 (t, J=6.0 Hz, 1H; NH), 4.45 (d, J=10.9 Hz, 0.8H; CH), 4.31
(m, 1H; CH2), 4.21 (d, J=10.9 Hz, 0.2H; CH), 3.99–4.09 (m, 1H; CH),
3.93 (d, J=6.6 Hz, 1H; CH), 3.76–3.88 (m, 1H; CH2), 3.49–3.60 (m, 1H;
Compound (1R)-21: By the same method as that described for the syn-
thesis of (1S)-21, (aS,1R)-15 and (aR,1R)-15 were converted into (1R)-21
in 80 and 85% yields, respectively. White solid; m.p. 1128C; [a]D =ꢀ35
(c=0.15 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.48 (m, 1H; CH
arom), 7.05–7.32 (m, 11H; CH arom), 7.00 (dd, J=8.3, 2.1 Hz, 1H; CH
arom), 6.82 (dd, J=8.3, 2.5 Hz, 1H; CH arom), 5.90 (m, 1H; NH), 5.76
Chem. Eur. J. 2005, 11, 2668 – 2679
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2675

J. Zhu et al.
Table 4. 1H NMR and 13C NMR assignments for mauritine F (10).[a]
lution (2.0 mL) of mesylated com-
pound was next added dropwise (very
slowly) at 08C to the solution of
PhSeNa. The reaction mixture was
stirred at 808C for 2 h, then cooled at
room temperature and concentrated
under vacuum. Water was added and
the mixture was extracted with
EtOAc. The organic layer was washed
with brine, dried over Na2SO4, filtered,
and concentrated under vacuum. The
crude solid was purified by preparative
TLC (silica gel, heptanes/EtOAc (1:2))
to afford compound (1R)-23 (55 mg,
74% yield). White solid; [a]D =ꢀ44.0
d(1H) [ppm]
Multiplicity
No. of H atoms
Assignment
J [Hz]
d(13C) [ppm]
Assignment
7.74
7.20–7.30
7.03
7.00
6.92
6.67
6.37
6.30
6.25
5.47
4.53–4.59
4.18
4.12
3.45
3.38
3.09
2.64
2.55
d
m
d
dd
d
dd
d
1H
6H
1H
1H
1H
1H
1H
1H
1H
1H
2H
1H
1H
1H
1H
1H
1H
1H
3H
1H
1H
3H
3H
3H
H24
H16, H32–36
H15
H12
H13
H2
H6
H3
H1
H9
8.9
175.1
171.4
170.4
166.4
157.4
135.6
132.5
132.4
130.3
130.1
128.5
127.1
125.4
122.6
122.4
114.7
83.6
64.2
60.5
54.3
54.0
46.4
36.0
35.2
31.9
C25
C19
C7
(c=0.25
in
CHCl3);
1H NMR
(300 MHz, CDCl3; mixture of two ro-
tamers (70:30)): d=7.45 (m, 2H; CH
arom), 7.29 (m, 1H; CH arom), 7.00–
7.21 (m, 8H; CH arom), 6.88 (m, 2H;
CH arom), 6.80 (m, 1H; CH arom),
5.87 (d, J=8.7 Hz, 1H; NH), 5.12 (m,
1H; CH), 4.55 (m, 1H; NH), 4.41 (d,
J=11.1 Hz, 1H; CH), 4.14–4.26 (m,
2H; CH, CH2), 3.91 (dd, J=12.2,
5.6 Hz, 1H; CH2), 3.72–3.79 (m+d,
J=6.8 Hz, 2H; CH), 3.53 (m, 1H;
CH2), 2.97 (dd, J=12.2, 5.8 Hz, 1H;
CH2), 2.68–2.77 (m+s, 5 H; CH2,
CH3), 2.43 (m, 1H; CH2), 2.06–2.19
(m, 2H; CH, CH2), 1.43 (s, 2.7H;
CH3), 1.40 (s, 6.3H; CH3), 0.73–
0.78 ppm (m, 6H; CH3); 13C NMR
(62.5 MHz, CDCl3): d=170.2 (2C),
169.0, 157.6, 156.4, 136.6, 135.0 (3C),
134.5, 131.5, 129.2 (4C), 128.3 (3C),
128.1, 126.5, 121.7, 117.8, 82.9, 79.9,
66.1, 59.8, 56.4, 45.8, 45.1 (2C), 39.0,
31.4, 29.5, 28.3 (3C), 27.7, 18.8,
18.4 ppm; IR (CHCl3): n˜ =3429, 3016,
2964, 2930, 1673, 1508, 1454, 1440,
8.4
8.1, 2.1
8.1
10.4, 7.8
8.4
10.4
C4
C11
C31
C14
C15
C13
C32, C36
C33, C35
C34
C2
C12
C16
C1
C9
C8
d
d
7.8
10.1, 6.7
dt
m
m
d
m
dd
q
dd
m
s
m
m
d
H5, H20
H18
H8
5.7
H18’
H30
H26
H30’
H17
H29
H17’
H21
H27
14.1, 3.9
6.9
14.1, 5.3
2.46
2.16
1.95
1.32
0.83
0.81
C26
C20
C5
6.9
6.8
6.8
C18
C30
C29
C17
C21
C27
[b]
d
d
H22
H23
[b]
31.2
19.9
19.2
17.6
1383, 1368, 1227, 1215, 1154 cmꢀ1
;
[c]
C22
high-resolution MS (ES+): m/z calcd:
771.2637 [M+Na]+; found: 771.2639.
[c]
C23
[a] The NMR spectra were recorded in CDCl3 on the Bruker Avance-600 (600 MHz) spectrometer. [b] The as-
signment of these two signals is interchangeable. [c] The assignment of these two signals is interchangeable.
Compound 24: Pyridine (26 mL,
0.321 mmol) and H2O2 (39 mL, 30%,
0.382 mmol) were added successively
to
a solution of compound (1R)-23
(22.6 mg, 0.0302 mmol) in dry CH2Cl2
(1.1 mL) cooled to 08C. The reaction mixture was stirred at 08C for
20 min, then at room temperature for 1 h. The solution was cooled at
08C and dimethyl sulfide (67.0 mL, 0.912 mmol) was added. The reaction
mixture was stirred at 08C for 1.5 h and concentrated under vacuum. The
crude product was dissolved in benzene (1.5 mL), heated at 608C for 2 h,
concentrated under vacuum, and purified by preparative TLC (silica gel,
CH2Cl2/MeOH (30:1)) to afford compound 24 (8.5 mg, 48% yield). Col-
orless oil; [a]D =ꢀ266 (c=0.36 in CHCl3); 1H NMR (300 MHz, CD3OD;
mixture of two rotamers (60:40)): d=7.12–7.24 (m, 6H; CH arom), 7.00–
7.03 (m, 3H; CH arom), 6.67 (d, J=7.4 Hz, 1H; CH), 6.11 (d, J=7.4 Hz,
1H; CH), 5.25 (dt, J=10.3, 6.6 Hz, 1H; CH), 4.46 (d, J=11.0 Hz, 0.6H;
CH), 4.28–4.34 (m, 1.4H; CH), 4.21 (t, J=9.2 Hz, 0.6H; CH2), 4.00–4.08
(m+d, J=6.6 Hz, 1.4H; CH, CH2), 3.53–3.67 (m, 1H; CH2), 2.77–2.85
(m+s, 5 H; CH2, CH3), 2.49–2.62 (m, 1H; CH2), 2.09–2.24 (m, 2H; CH,
CH2), 1.50 (s, 3.6H; CH3), 1.48 (s, 5.4H; CH3), 0.79–0.86 ppm (m, 6H;
CH3); 13C NMR (75 MHz, CD3OD; mixture of two rotamers): d=172.7,
171.4, 170.7, 158.9, 158.1, 157.1, 138.3, 133.4, 132.3, 130.8, 130.5, 129.4,
127.7, 126.8, 122.6, 119.9, 83.9, 83.8, 82.3, 81.6, 66.8, 62.9, 61.7, 56.4, 46.7,
46.5, 39.2, 32.7, 32.6, 30.8, 30.2, 29.2, 28.9, 28.7, 19.6, 19.1, 18.9 ppm; IR
(CHCl3): n˜ =3690, 3396, 3024, 3016, 2966, 2932, 1683, 1626, 1505, 1439,
CH2), 3.18–3.26 (m, 1H; CH2), 2.91 (dd, J=13.4, 10.2 Hz, 1H; CH2), 2.81
(s, 3H; CH3), 2.71 (dd, J=13.4, 4.5 Hz, 1H; CH2), 2.45–2.54 (m, 1H;
CH2), 2.07–2.22 (m, 2H; CH, CH2), 1.48 (s, 1.8H; CH3), 1.46 (s, 7.2H;
CH3), 0.81 (d, J=6.6 Hz, 3H; CH3), 0.75 ppm (d, J=6.6 Hz, 3H; CH3);
13C NMR (75 MHz, CDCl3; mixture of two rotamers): d=171.2, 171.1,
170.4, 169.5, 157.5, 156.4, 137.1, 136.6, 129.1, 128.8, 128.4, 127.2, 127.0,
126.7, 121.6, 118.8, 118.5, 83.4, 83.1, 80.5, 80.1, 72.7, 65.7, 65.6, 61.5, 60.0,
55.7, 55.5, 47.2, 45.6, 44.9, 38.2, 31.6, 31.4, 29.6, 29.1, 28.5, 28.4, 27.8, 19.2,
18.9, 18.5, 18.4 ppm; IR (CHCl3): n˜ =3416, 3025, 3016, 2966, 2934, 1672,
1510, 1441, 1383, 1368, 1154 cmꢀ1; high-resolution MS (ES+): m/z calcd:
631.3108 [M+Na]+; found: 631.3106.
Compound (1R)-23: Et3N (82.0 mL, 0.593 mmol) and MsCl (31.0 mL,
0.4 mmol) were added to a solution of compound (1S)-22 (60.0 mg,
99.0 mmol) in dry CH2Cl2 (5.0 mL) cooled to ꢀ158C. The reaction mix-
ture was stirred for 1 h, then concentrated under vacuum to yield the me-
sylated compound as a yellow solid. In a separate flask, PhSeSePh
(93.0 mg, 0.297 mmol) was dissolved in dry EtOH (2 mL), and NaBH4
(34.0 mg, 0.89 mmol) was added at 08C. The resulting suspension was
stirred at 08C until the yellow solution became colorless. The EtOH so-
2676
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2668 – 2679

Total Synthesis of Mauritines
FULL PAPER
1392, 1383, 1368, 1315, 1154 cmꢀ1; high-resolution MS (ES+): m/z calcd:
613.3002 [M+Na]+; found: 613.3004.
J=8.1, 2.3 Hz, 1H; CH arom), 5.79 (d, J=8.7 Hz, 1H; NH), 5.45 (dd, J=
7.5, 4.5 Hz, 1H; NH), 5.16 (m, 1H; CH), 5.12 (d, J=8.9 Hz, 1H; NH),
4.71 (t, J=6.8 Hz, 1H; CH), 4.18 (dd, J=8.9, 6.2 Hz, 1H; CH), 3.99–4.09
(m, 3H; CH, CH2), 3.87 (d, J=6.8 Hz, 1H; CH), 3.52 (m, 1H; CH2), 2.99
(ddd, J=14.5, 6.8, 4.5 Hz, 1H; CH2), 2.85 (dd, J=13.4, 10.2 Hz, 1H;
CH2), 2.59 (dd, J=13.4, 4.3 Hz, 1H; CH2), 2.46 (m, 1H; CH2), 2.16 (m,
1H; CH2), 1.81 (m, 1H; CH), 1.36 (s, 9H; CH3), 0.74–0.83 ppm (m, 6H;
CH3); 13C NMR (75 MHz, CDCl3): d=171.7, 170.0, 169.2, 157.2, 155.8,
136.5, 134.9 (2C), 134.6, 131.0, 130.0, 129.2 (4C), 128.4 (2C), 128.3, 128.2,
126.6, 121.1, 119.6, 82.8, 79.7, 65.8, 56.2, 55.3, 45.8, 45.6, 44.3, 38.1, 31.5,
31.4, 28.4 (3C), 19.1, 17.5 ppm; IR (CHCl3): n˜ =3687, 3422, 3032, 3018,
3011, 2965, 2931, 2401, 2360, 2340, 1702, 1671, 1507, 1437, 1232, 1199,
1166, 1044, 927 cmꢀ1; high-resolution MS (ES+): m/z calcd: 757.2480
[M+Na]+; found: 757.2451.
Mauritine C (7): TFA (200.0 mL, 2.6 mmol) was added to a solution of
compound 24 (12.5 mg, 0.0212 mmol) in dry CH2Cl2 (2.0 mL) cooled to
08C. The reaction mixture was stirred at 08C for 20 min, then at room
temperature for 1 h. The solvent was removed under vacuum and the
crude residue was dissolved in EtOAc. The organic layer was washed
with a saturated solution of Na2CO3 and with brine, dried over Na2SO4,
filtered, and concentrated under vacuum. The crude oil was purified by
flash chromatography (silica gel, CH2Cl2/MeOH (20:1)) to afford mauri-
tine C (7; 8.1 mg, 78% yield). White solid; m.p. 70–738C (literature
value:[13]: not measured); [a]D =ꢀ168.7 (c=0.11 in MeOH; literature
value:[13] ꢀ224, c=0.11 in MeOH); 1H NMR and 13C NMR data: see
Table 3; IR (CHCl3): n˜ =3396, 3024, 3018, 2960, 2930, 2875, 2855, 1689,
1626, 1505, 1229, 1215, 1212, 1204, 1098, 1083, 863, 836 cmꢀ1; high-resolu-
tion MS (ES+): m/z calcd: 491.2658 [M+H]+; found: 491.2640.
Compound 27: Pyridine (230 mL, 2.84 mmol) and an aqueous solution of
H2O2 (350.0 mL, 30%, 3.43 mmol) were added successively to a solution
of compound (1S)-26 (193.0 mg, 0.26 mmol) in dry CH2Cl2 (8.2 mL)
cooled at 08C. The reaction mixture was stirred for 1 h at 08C, then
Me2S (380.0 mL, 5.17 mmol) was added at 08C. The reaction mixture was
stirred at room temperature for 4 h, then a large volume of EtOAc was
added. The organic layer was washed with brine, dried over Na2SO4, fil-
tered, and concentrated under vacuum. The crude residue was purified
by flash chromatography (silica gel, heptanes/EtOAc (1:1)) and then by
preparative TLC (silica gel, CH2Cl2/MeOH (40:1)) to afford compound
27 (90.4 mg, 60% yield). White solid; [a]D =ꢀ181.5 (c=0.24 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.15–7.23 (m, 6H; CH arom), 6.86–7.02
(m, 3H; CH arom), 6.62 (dd, J=10.3, 7.7 Hz, 1H; CH), 6.36 (d, J=
8.1 Hz, 1H; NH), 6.25 (d, J=10.3 Hz, 1H; NH), 6.22 (d, J=7.7 Hz, 1H;
CH), 5.41 (td, J=10.3, 6.6 Hz, 1H; CH), 5.05 (d, J=8.8 Hz, 1H; NH),
4.51 (td, J=9.0, 5.0 Hz, 1H; CH), 4.20 (dd, J=8.8, 7.0 Hz, 1H; CH),
4.02–4.12 (m+d, J=5.9 Hz, 2H; CH, CH2), 3.38 (m, 1H; CH2), 3.28 (dd,
J=14.0, 4.4 Hz, 1H; CH2), 2.61 (dd, J=14.0, 5.1 Hz, 1H; CH2), 2.51 (m,
1H; CH2), 2.11 (m, 1H; CH2), 1.79 (m, 1H; CH), 1.39 (s, 9H; CH3),
0.77 ppm (d, J=6.6 Hz, 6H; CH3); 13C NMR (75 MHz, CDCl3): d=170.3,
169.4, 166.5, 157.4, 154.0, 135.6, 132.6, 132.4, 130.2, 129.9 (2C), 128.6
(2C), 127.1, 125.4, 122.6, 122.5, 114.8, 83.8, 75.9, 64.1, 56.2, 54.0, 46.4,
36.2, 31.9, 31.5, 28.4 (3C), 19.2, 17.6 ppm; IR (CHCl3): n˜ =3395, 3018,
2930, 1692, 1626, 1502, 1369, 1163, 908, 864 cmꢀ1; high-resolution MS
(ES+): m/z calcd: 599.2846 [M+Na]+; found: 599.2850.
Compound (1R)-14:
A suspension of compound (1R)-21 (1.16 g,
2.39 mmol) and Pd/C (10%, 580 mg) in dry MeOH (26 mL) was purged
three times with argon and hydrogen, successively. The reaction mixture
was stirred under a hydrogen atmosphere at room temperature for 24 h
during which time the system of purging was repeated twice. The suspen-
sion was filtered through celite, concentrated under vacuum, and purified
by flash chromatography (silica gel, CH2Cl2/MeOH (20:1)) to afford com-
pound (1R)-14 (736 mg, 78% yield). White solid; [a]D =+39.5 (c=0.102
in DMSO); 1H NMR (250 MHz, CD3OD): d=7.38 (dd, J=8.8, 2.4 Hz,
1H; CH arom), 7.06–7.24 (m, 5H; CH arom), 7.03 (dd, J=8.8, 2.4 Hz,
1H; CH arom), 6.95 (dd, J=8.5, 2.4 Hz, 1H; CH arom), 6.79 (dd, J=8.5,
2.4 Hz, 1H; CH arom), 5.05 (dd, J=16.4, 8.1 Hz, 1H; CH), 5.01 (m, 1H;
CH), 4.17 (dd, J=9.1, 6.1 Hz, 1H; CH), 4.09 (dd, J=14.2, 4.6 Hz, 1H;
CH2), 3.28–3.35 (m under CD3OD, 1H; CH2), 3.12–3.25 (m+d, J=
7.8 Hz, 2H; CH, CH2), 2.79–3.05 (m, 1H; CH2), 2.75 (dd, J=13.2, 9.3 Hz,
1H; CH2), 2.62 (dd, J=13.2, 6.1 Hz, 1H; CH2), 2.35–2.49 (m, 1H; CH2),
1.97–2.08 ppm (m, 1H; CH2); 13C NMR (75 MHz, [D6]DMSO): d=172.4,
169.7, 156.7, 137.2, 135.9, 129.0 (2C), 127.8 (2C), 127.4, 126.5, 126.0,
119.3, 116.6, 83.5, 70.6, 66.6, 53.3, 46.7, 44.0, (1C under [D6]DMSO),
31.9 ppm; IR (KBr): n˜ =3328, 3069, 3027, 2917, 2893, 2103, 1638, 1542,
1516, 1440, 1378, 1278, 1232, 1182, 1085, 1033, 854 cmꢀ1; high-resolution
MS (ES+): m/z calcd: 396.1923 [M+H]+; found: 396.1906.
Compound (1R)-25: N-Boc-l-valine (256 mg, 1.18 mmol), DIEA
(935.0 mL, 5.35 mmol), and HATU (630.0 mg, 1.66 mmol) were added
successively to a solution of compound (1R)-14 (423.0 mg, 1.07 mmol) in
dry DMF (15.0 mL) cooled at 08C. The reaction mixture was stirred at
room temperature for 17 h, then treated with a solution of NH4Cl and ex-
tracted with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under vacuum. The crude oil was pu-
rified by flash chromatography (silica gel, CH2Cl2/MeOH (50:1!10:1))
to afford compound (1R)-25 (611 mg, 96% yield). Pale-yellow solid;
[a]D =ꢀ121.1 (c=0.19 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.39
(dd, J=8.7, 1.8 Hz, 1H; CH arom), 7.01–7.19 (m, 6H; CH arom), 6.97
(dd, J=8.5, 2.1 Hz, 1H; CH arom), 6.85 (dd, J=8.4, 2.4 Hz, 1H; CH
arom), 6.01 (d, J=8.8 Hz, 1H; NH), 5.70 (m, 1H; NH), 5.32 (d, J=
9.2 Hz, 1H; NH), 5.24 (m, 1H; CH), 5.04 (brs, 1H; CH), 4.06–4.25 (m,
3H; CH, CH2), 3.94 (m, 1H; CH), 3.82 (d, J=7.2 Hz, 1H; CH), 3.59 (m,
1H; CH2), 3.15 (m, 1H; OH), 2.83 (m, 1H; CH2), 2.65–2.72 (m, 2H;
CH2), 2.40 (m, 1H; CH2), 2.21 (m, 1H; CH2), 1.95 (m, 1H; CH), 1.43 (s,
9H; CH3), 0.93 (d, J=6.8 Hz, 3H; CH3), 0.88 ppm (d, J=6.8 Hz, 3H;
CH3); 13C NMR (75 MHz, CDCl3): d=171.7, 170.8, 169.2, 157.4, 155.9,
136.4, 135.5, 129.3 (2C), 128.3 (2C), 127.4, 127.0, 126.6, 119.9, 116.8, 80.9,
79.7, 72.1, 66.5, 56.3, 56.2, 46.9, 45.5, 39.2, 31.4 (2C), 28.4 (3C), 19.15,
17.7 ppm; IR (CHCl3): n˜ =3413, 3307, 3028, 3013, 2983, 2933, 2876, 1702,
1661, 1508, 1435, 1368, 1169, 1085, 1049 cmꢀ1; high-resolution MS (ES+):
m/z calcd: 617.2951 [M+Na]+; found: 617.2967.
Mauritine A (5): TFA (200.0 mL, 2.6 mmol) was added to a solution of
compound 27 (70.0 mg, 0.12 mmol) in dry CH2Cl2 (1.5 mL) cooled to
08C. The reaction mixture was stirred at 08C for 20 min, then at room
temperature for 1 h. Solvent was removed under vacuum and the result-
ing crude oil was dissolved in dry DMF (1.5 mL). The solution was next
cooled to 08C and N,N-dimethyl-l-alanine (16.0 mg, 0.13 mmol), DIEA
(106.0 mL, 0.61 mmol), and HATU (71.0 mg, 0.19 mmol) were added suc-
cessively. The reaction mixture was stirred at room temperature for 2 h,
then treated with a solution of NH4Cl and extracted with EtOAc. The or-
ganic layer was washed with brine, dried over Na2SO4, filtered, and con-
centrated under vacuum. The resulting crude residue was purified by
flash chromatography (silica gel, CH2Cl2/MeOH (20:1)) to afford mauri-
tine A (5; 40.9 mg, 59% yield). White solid; m.p. 87–908C (literature
value:[13] 1048C); [a]D =ꢀ287.7 (c=0.333 in MeOH; literature value:[13]
ꢀ315, c=0.33 in MeOH); 1H NMR and 13C NMR data: see Table 1; IR
(CHCl3): n˜ =3393, 3027, 3022, 3015, 2992, 2963, 2939, 2873, 2834, 2790,
1732, 1689, 1626, 1599, 1505, 1434, 1373, 1246, 1099 cmꢀ1; high-resolution
MS (ES+): m/z calcd: 576.3186 [M+H]+; found: 576.3155.
Mauritine B (6): TFA (200.0 mL, 2.6 mmol) was added to a solution of
compound 27 (41.0 mg, 71.0 mmol) in dry CH2Cl2 (1.8 mL) cooled to 08C.
The reaction mixture was stirred at 08C for 20 min, then at room temper-
ature for 1 h. Solvent was removed under vacuum and the resulting crude
oil was dissolved in dry DMF (1.5 mL). The solution was next cooled at
08C and N,N-dimethyl-l-isoleucine (14.0 mg, 85.0 mmol), DIEA (62.0 mL,
35.5 mmol), and HATU (42.0 mg, 0.11 mmol) were added successively.
The reaction mixture was stirred at room temperature for 2 h, then treat-
ed with a solution of NH4Cl and extracted with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, filtered, and concentrat-
ed under vacuum. The resulting crude residue was purified by flash chro-
Compound (1S)-26: Following the procedure described for the synthesis
of compound (1R)-23, (1S)-26 was prepared starting from compound
(1R)-25 in 87% yield (purification by flash chromatography: silica gel,
heptanes/EtOAc (1:1)). White solid; [a]D =ꢀ176.4 (c=0.62 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.42–7.45 (m, 2H; CH arom), 6.99–7.23
(m, 10H; CH arom), 6.95 (dd, J=8.3, 2.1 Hz, 1H; CH arom), 6.80 (dd,
Chem. Eur. J. 2005, 11, 2668 – 2679
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ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2677

J. Zhu et al.
matography (silica gel, CH2Cl2/MeOH (20:1)) to afford mauritine B (6;
26.7 mg, 61% yield). Colorless oil; [a]D =ꢀ229 (c=0.332 in MeOH; liter-
ature value:[13] ꢀ151, c=0.44 in MeOH); 1H NMR and 13C NMR data:
see Table 2; IR (CHCl3): n˜ =3691, 3390, 3017, 3013, 2965, 2931, 1730,
1688, 1626, 1505, 1433, 1374 cmꢀ1; high-resolution MS (ES+): m/z calcd:
618.3655 [M+H]+; found: 618.3654.
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Compound 29: TFA (150.0 mL, 1.95 mmol) was added to a solution of
compound 27 (20.0 mg, 0.035 mmol) in dry CH2Cl2 (1.5 mL) cooled to
08C. The reaction mixture was stirred at 08C for 20 min, then at room
temperature for 1 h. Solvent was removed under vacuum and the result-
ing crude oil was dissolved in dry DMF (0.8 mL), then N-Boc-N-methyl-
l-alanine (8.0 mg, 0.038 mmol), DIEA (31.0 mL, 0.18 mmol), and HATU
(21.0 mg, 54.0 mmol) were added successively at 08C. The reaction mix-
ture was stirred at room temperature for 4 h, then treated with a solution
of NH4Cl and extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under vacuum. The
resulting crude residue was purified by preparative TLC (silica gel, hep-
tanes/EtOAc (1:1)) to afford compound 29 (18.1 mg; 79% yield). White
1
solid; [a]D =ꢀ161.2 (c=0.60 in CHCl3); H NMR (300 MHz, CDCl3): d=
7.15–7.28 (m, 6H; CH arom), 6.87–7.01 (m, 3H; CH arom), 6.63 (dd, J=
10.3, 7.7 Hz, 1H; CH), 6.37 (m, 1H; NH), 6.25 (d, J=10.3 Hz, 1H; NH),
6.22 (d, J=7.7 Hz, 1H; CH), 5.40 (m, 1H; CH), 4.67 (m, 1H; CH), 4.48
(m, 2H; CH), 4.06–4.16 (m+d, J=5.5 Hz, 2H; CH, CH2), 3.38 (m, 1H;
CH2), 3.30 (dd, J=14.0, 4.0 Hz, 1H; CH2), 2.74 (s, 3H; CH3), 2.60 (dd,
J=14.0, 5.1 Hz, 1H; CH2), 2.49 (m, 1H; CH2), 2.11 (m, 1H; CH2), 1.83
(m, 1H; CH), 1.40 (s, 9H; CH3), 1.28 (d, J=7.0 Hz, 3H; CH3), 0.74 ppm
(d, J=6.6 Hz, 6H; CH3); 13C NMR (75 MHz, CDCl3): d=171.6, 171.1,
170.3, 166.5, 157.4 (2C), 135.4, 132.5, 132.4, 130.2, 129.9 (2C), 128.6 (2C),
127.1, 125.4, 122.5, 122.4, 114.9, 83.8, 80.7, 64.4, 64.2, 54.7, 54.0, 46.4, 36.2,
31.9, 31.5, 29.8, 28.4 (3C), 19.2, 17.7, 13.4 ppm; IR (CHCl3): n˜ =3395,
3017, 2969, 2933, 1685, 1626, 1505, 1436, 1392, 1369, 1324, 1221, 1205,
1160, 909 cmꢀ1; high-resolution MS (ES+): m/z calcd: 684.3373 [M+Na]+;
found: 684.3391.
Mauritine F (10): Following the procedure described for the synthesis of
mauritine C (7), mauritine F (10) was prepared from compound 29 in
71% yield. White solid; m.p. 220–2228C (literature value:[13] 222–2258C);
[a]D =ꢀ234 (c=0.149 in MeOH; literature value:[13] ꢀ285, c=0.15 in
1
MeOH); H NMR and 13C NMR data: see Table 4; IR (CHCl3): n˜ =3651,
3394, 3024, 3018, 2991, 2966, 1689, 1626, 1505, 1227, 1208 cmꢀ1; high-reso-
lution MS (ES+): m/z calcd: 584.2849 [M+Na]+; found: 584.2845.
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Acknowledgements
We thank CNRS, Bayer CropScience, and “Ligue Nationale Contre le
Cancer” for financial support. Doctoral fellowships to P.C. from Bayer
CropScience and to T.L. from “Ligue Nationale Contre le Cancer” are
gratefully acknowledged.
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2678
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www.chemeurj.org
Chem. Eur. J. 2005, 11, 2668 – 2679

Total Synthesis of Mauritines
FULL PAPER
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[24] Prepared in three steps from the commercially available (2S,3S)-2-
hydroxyproline.
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558C) has been reported; see ref. [10b].
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[31] The purities of our synthetic compounds are greater than 95% from
NMR spectroscopy analysis. However, there is a discrepancy be-
tween the natural products and our synthetic compounds in the [a]D
1
value. Because H NMR spectra of the natural products are unavail-
able, we are unable to make any comment on this point.
[27] Competitive N-debenzylation of the proline unit was avoided by
careful TLC monitoring and by using the bi-solvent system AcOEt/
MeOH.
Received: October 20, 2004
Published online: February 24, 2005
Chem. Eur. J. 2005, 11, 2668 – 2679
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2679