Total synthesis of the alkaloids martinelline and martinellic acid via a hetero Diels-Alder multicomponent coupling reaction

Article abstract of DOI:10.1021/ol026293d

(formula presented) A concise synthesis of the guanidine alkaloids, (±)-martinelline and (±)-martinellic acid, using a protic acid catalyzed 2:1 hetero Diels-Alder coupling reaction between N-Cbz 2-pyrroline and methyl 4-aminobenzoate, is described. Protic acid catalysis, rather than Lewis acid catalysis, was necessary to achieve the desired sense of diastereocontrol in the coupling reaction.

Full text of DOI:10.1021/ol026293d

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2913-2916
Total Synthesis of the Alkaloids
Martinelline and Martinellic Acid via a
Hetero Diels−Alder Multicomponent
Coupling Reaction†
David A. Powell and Robert A. Batey*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, Canada M5S 3H6
rbatey@chem.utoronto.ca
Received June 3, 2002
ABSTRACT
A concise synthesis of the guanidine alkaloids, (±)-martinelline and (±)-martinellic acid, using a protic acid catalyzed 2:1 hetero Diels−Alder
coupling reaction between N-Cbz 2-pyrroline and methyl 4-aminobenzoate, is described. Protic acid catalysis, rather than Lewis acid catalysis,
was necessary to achieve the desired sense of diastereocontrol in the coupling reaction.
Root extracts of the Martinella iquitosensis vine, found in
Amazonian lowland rainforests, are used by indigenous
peoples to treat various eye ailments, including inflammation
and conjunctivitis.1 This medicinal use may be attributed, at
least in part, to the presence of two novel guanidine alkaloids,
martinellic acid 1a and martinelline 1b, which have been
demonstrated to be modest antibiotics and micromolar
binders of several G-protein coupled receptors.2 Martinelline
in particular was identified as the first naturally occurring
nonpeptidic bradykinin B2 receptor antagonist. Beyond their
intriguing pharmacological profile, the Martinella alkaloids
have an unprecedented hexahydropyrrolo[3,2-c]quinoline
core structure with three pendant isoprenyl-derived guanidine
moieties (Figure 1).
These features have rendered the heterocyclic core of
martinelline an attractive target for synthesis,3 and there are
† Dedicated to the late Professor Richard Evans Schultes (1915-2001),
a pioneer in the field of ethnobotany.
(1) Gentry, A.; Cook, K. J. Ethnopharmacol. 1984, 11, 337-343.
(2) Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard, A. M.;
Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.; Pitzenberger, S. M.;
Varga, S. L. J. Am. Chem. Soc. 1995, 117, 6682-6685.
Figure 1. Martinella alkaloids (IUPAC numbering).
10.1021/ol026293d CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/31/2002

two recently published total syntheses of the less biologically
active martinellic acid4 from the groups of Ma and Snider.5
We now report the first total synthesis of martinelline, as
well as martinellic acid, using a hetero Diels-Alder reaction
that we believe is related to that involved in their biosyn-
thesis.
attention turned to protic acids, which have also been utilized
in Povarov reactions.11 After much experimentation, we find
that reaction of methyl 4-aminobenzoate with 2 equiv of
N-Cbz 2-pyrroline in the presence of 5 mol % camphor-
sulfonic acid (CSA) in anhydrous THF yields the corre-
sponding tricyclic triamine core 2 in 74% yield and as an
11:89 mixture of diastereomers in favor of the desired exo
product (Scheme 1). A variety of protic acids were surveyed
in the 2:1 coupling reaction as outlined in Table 1. The
Martinelline is a demanding target; its deceptively simple
heterocyclic structure belies the challenges posed by the
presence of three differentiated and polar guanidine func-
tionalities. Our initial interest in martinelline stemmed from
the use of the heterocyclic core structure as a novel
combinatorial scaffold6 and the recognition that it could be
constructed through a multicomponent “Povarov” reaction.7
This reaction couples an electron-rich alkene with an
N-arylimine (derived from an aniline and an aldehyde), a
process that may occur through a concerted inverse electron
demand hetero Diels-Alder mechanism or via a stepwise
“Mannich-like” pathway. Furthermore, we have proposed
that the Martinella alkaloids are conceivably biosynthesized
through an unprecedented enzyme-catalyzed Povarov reac-
tion.6 Thus, the N-1 and N-13 isoprenylated guanidine groups
would originate from a common intermediate, a guanidine-
substituted 2-pyrroline derivative or hydrated equivalent.
Supporting this hypothesis is the observation of lanthan-
ide(III)-catalyzed 2:1 couplings of substituted anilines with
2 equiv of electron-rich alkenes such as N-protected 2-pyr-
rolines and dihydrofuran to give highly functionalized
tetrahydroquinolines.6,8 Methyl 4-aminobenzoate reacts with
2 equiv of N-Cbz-2-pyrroline, for example, to provide the
hexahydropyrrolo[3,2-c]quinoline core 2 of martinelline as
an 85:15 mixture of diastereomers in favor of the undesired
endo9 product (Scheme 1). The 2-pyrroline derivative serves
Table 1. Protic Acid Catalyzed Formation of 2
protic acid (mol %)
solvent
yielda (%)
endo/exob
DL-tartaric acid (50)
AcOH (50)
TFA (50)
PPTS (50)
citric acid (50)
p-TsOH‚H2O (50)
CSA (50)
CSA (10)
CSA (10)
CSA (10)
CSA (5)
MeCN
61
62
93
69
67
65
62
92
(52)
(40)
74
(52)
(58)
82:18
84:16
74:26
57:43
39:61
35:65
30:70
32:68
52:48
49:51
11:89
39:61
82:18
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
Et2O
THF
DMF
THF/H2O (4:1)
CSA (10)
CSA (10)
a Isolated yield. Number in parentheses represents percent conversion
as determined by 1H NMR of the crude reaction mixture. b Determined by
HPLC of the crude reaction mixture. TFA ) trifluoroacetic acid, PPTS )
pyridinium p-toluenesulfononic acid, p-TsOH ) p-toluenesulfonic acid.
remarkable switchover in diastereoselection from the lan-
thanide-catalyzed reaction is not general for all protic acids
and appears to be related, at least in part, to the pKa of the
Scheme 1
(3) (a) Gurjar, M. K.; Pal, S.; Rao, A. V. R. Heterocycles 1997, 45,
231-234. (b) Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287-8294.
(c) Hadden, M.; Stevenson, P. J. Tetrahedron Lett. 1999, 40, 1215-1218.
(d) Lovely, C. J.; Mahmud, H. Tetrahedron Lett. 1999, 40, 2079-2082.
(e) Snider, B. B.; Ahn, Y.; Foxman, B. M. Tetrahedron Lett. 1999, 40,
3339-3342. (f) Kang, S. K.; Park, S. S.; Kim, S. S.; Choi, J.-K.; Yum, E.
K. Tetrahedron Lett. 1999, 40, 4379-4382. (g) Frank, K. E.; Aube´, J. J.
Org. Chem. 2000, 65, 655-666. (h) Nyerges, M.; Fejes, I.; To¨ke, L.
Tetrahedron Lett. 2000, 41, 7951-7954. (i) Escolano, C.; Jones, K.
Tetrahedron Lett. 2000, 41, 8951-8955. (j) Nieman, J. A.; Ennis, M. D.
Org. Lett. 2000, 2, 1395-1397. (k) Snider, B. B.; O’Hare, S. M. Tetrahedron
Lett. 2001, 42, 2455-2458. (l) Hadden, M.; Nieuwenhuyzen, M.; Osborne,
D.; Stevenson, P. J.; Thompson, N. Tetrahedron Lett. 2001, 42, 6417. (m)
Batey, R. A.; Powell, D. A. Chem. Commun. 2001, 2362-2363. (n) Hamada,
Y.; Kunimune, I.; Hara, O. Heterocycles 2002, 56, 97-100. (o) He, Y.;
Mahmud, H.; Wayland, B. R.; Dias, H. V. R.; Lovely, C. J. Tetrahedron
Lett. 2002, 43, 1171-1174.
(4) 1a and 1b have binding affinities toward guinea pig bradykinin B2
of >25 and 10 mg/mL, respectively.
a dual role in this multicomponent Povarov reaction, acting
as an electron-rich dienophile and as the aldehyde component
in the formation of the Schiff base (N-arylimine). We have
categorized this as an “ABB”-type multicomponent coupling
reaction,8a in which one component serves quite different
roles in the reaction.10
While the lanthanide(III)-promoted reactions provide some
support for the biogenetic hypothesis, the wrong “endo”
diastereomer is preferentially formed. To achieve a synthesis
of the martinelline alkaloids, a catalyst that would favor
formation of the exo diastereomer was required, and our
(5) (a) Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org. Lett. 2001, 3, 2189-
2191. (b) Snider, B. B.; Ahn, Y.; O’Hare, S. M. Org. Lett. 2001, 3, 4217-
4220.
(6) Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj, R. P.; Lough, A. J.
Chem. Commun. 1999, 651-652.
(7) Povarov, L. S. Russ. Chem. ReV. 1967, 36, 656-670 and references
cited therein.
(8) (a) Batey, R. A.; Powell, D. A.; Acton, A.; Lough, A. J. Tetrahedron
Lett. 2001, 42, 7935-7939. Subsequent to this report, two other groups
have reported similar reactions. (b) Chang, J.; Li, C.-J. J. Org. Chem. 2002,
67, 3969-3971. (c) Yadav, J. S.; Reddy, B. V. S.; Sadasiv, K.; Reddy, P.
S. R. Tetrahedron Lett. 2002, 43, 3853-3856.
(9) The endo- and exo-diastereomers are defined based on the Diels-
Alder reaction where H-4 and H-3a have a cis and trans relationship,
respectively.
2914
Org. Lett., Vol. 4, No. 17, 2002

acid. With 50 mol % AcOH, TFA, or DL-tartaric acid, the
endo diastereomer is formed predominately, whereas with
the sulfonic or citric acids, the exo diastereomer is favored.
Pronounced solvent effects were also observed, with notably
THF/H2O preferentially giving the endo adduct. However,
conducting the reaction in dry THF and reducing the amount
of CSA to 5 mol % gives the optimal yield and selectivity
for exo-2.
Scheme 3a
Separation of the diastereomers by flash chromatography
through silica gel gave exo adduct 2 in 65% yield and >98%
1
d.r. as determined by H NMR. Deprotection of exo-2 with
Pearlman’s catalyst followed by acidification with HCl
yielded the triamine salt 3, which displayed 1H and 13C NMR
spectra identical to the same compound synthesized inde-
pendently by Ma and Snider5 (Scheme 2). This 2:1 coupling
Scheme 2
reaction allows for the rapid synthesis of the vital tricyclic
triamine core of the martinelline alkaloids in only two
synthetic steps and 58% overall yield. In addition, the
reaction has been carried out on relatively large scales (20
mmol) with no significant change in the yield or diastereo-
meric ratio of product.
Having established a route for the tricyclic triamine core
of the Martinella alkaloids, we turned our attention to the
challenging task of installing the guanidine moieties. Initial
attempts to install both the N-1 and N-13 isoprenylguanidines
directly onto 3 were met with limited success, and we
decided to introduce each guanidine group sequentially,
beginning with the more substituted guanidine at the pyr-
rolidine nitrogen. Protection of exo-2 at both the aniline and
carbamate nitrogens by deprotonation with 3.0 equiv
KHMDS and treatment with TrocCl yielded the fully
protected triamine 4 (Scheme 3).
a Reagents and conditions: (a) (i) KHMDS (3.0 equiv), THF/
dioxane (20:1), -78 °C, 1 h, (ii) TrocCl (3.5 equiv), -78 °C, 4 h;
(b) Pd(OH)2 on C (12 mol %), H2, MeOH/AcOH (20:1), rt, 4 h;
(c) 6 (1.2 equiv), HgCl2 (1.2 equiv), Et3N (3.0 equiv), DMF, rt, 4
h; (d) Zn dust (15 equiv), THF/1.0 M aq pH ) 4 buffer (20:1), rt,
2 h; (e) 8 (2.0 equiv), MeCN, 75 °C, 16 h; (f) MeOH/0.2 M aq
NaOH (3:1), 85 °C, 16 h; (g) CH2Cl2/TFA (100:1), rt, 24 h.
amine 5 as the acetic acid salt.12 The trisubstituted guanidine
moiety at N-1 was installed through a HgCl2-promoted
guanidinylation13 with isothiourea 6 to afford guanidine 7.
The installation of the N-13 guanidine was accomplished
first by deprotection of both Troc groups using Zn dust in
THF in the presence of a pH ) 4.0 buffer. The crude primary
amine was then refluxed in the presence of isothiourea 8 to
afford the bisguanidine compound 9 in 63% yield for the
two-step procedure. Conversion to the free carboxylic acid
10 was attained by refluxing methyl ester 9 in a 3:1 mixture
The Cbz groups were then removed by hydrogenation with
Pearlman’s catalyst in 20:1 MeOH/AcOH to give the free
(10) This notation makes a distinction between “AB2” reactions, for
instance, in which one component reacts in a similar manner (e.g.,
diacylation of a diamine). Further discussions on the classification of these
types of reactions will be the subject of a future paper.
(11) (a) Nomura, Y.; Kimura, M.; Takeuchi, Y.; Tomoda, S. Chem. Lett.
1978, 267-270. (b) Grieco, P. A.; Bahsas, A.; Tetrahedron Lett. 1988, 29,
5855-5858. (c) Gregoire, P. J.; Mellor, J. M.; Merriman, G. D. Tetrahedron
Lett. 1991, 32, 7099-7102. (d) Mellor, J. M.; Merriman, G. D.; Riviere, P.
Tetrahedron Lett. 1991, 32, 7103-7106. (e) Mellor, J. M.; Merriman, G.
D. Tetrahedron 1995, 51, 6115-6132. (f) Baudelle, R.; Melnyk, P.; Deprez,
B.; Tartar, A. Tetrahedron 1998, 54, 4125-4140. (g) Posson, H.; Hurvois,
J.-P.; Moinet, C. Synlett 2000, 209-212.
(12) In accord with earlier observations, we have found that the Troc
group in not stable to hydrogenation; however, deprotection of the Cbz
groups occurs faster than the Troc group, and if the reaction is carefully
monitored, adequate yields of 5 can be obtained. Hancock, G.; Galpin, I.
J.; Morgan, B. A. Tetrahedron Lett. 1982, 23, 249-252.
(13) (a) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677-7680.
(b) Guo, Z.-X.; Cammidge, A. N.; Horwell, D. C. Synth. Commun. 2000,
30, 2933-2943. (c) Levallet, C.; Lerpiniere, J.; Ko, Y. S. Tetrahedron 1997,
53, 5291-5304.
Org. Lett., Vol. 4, No. 17, 2002
2915

of MeOH/aqueous NaOH (0.2 M) for 16 h. Hydrolysis under
these conditions resulted in the removal of one of the Boc
groups. Deprotection of the remaining two Boc groups with
TFA/CH2Cl2 followed by HPLC purification afforded (()-
martinellic acid 1a in eight steps and 14% overall yield.
The synthesis of the allylic alcohol side chain 11 required
for martinelline synthesis was accomplished through a five-
step sequence14 beginning with N-Boc glycine methyl ester
(Scheme 4). The ester was reduced to the aldehyde with
Scheme 5
Scheme 4a
In conclusion, the total synthesis of guanidine-containing
alkaloids (()-martinelline and (()-martinellic acid has been
achieved, with the heterocyclic core synthesized using a 2:1
multicomponent coupling of a substituted aniline with 2
equiv of an endocyclic enamine. We propose that this process
is the first example of a biomimetic Povarov reaction.
Selectivity in favor of the exo-diastereomer could only be
achieved using protic acid catalysis under clearly defined
conditions, with Lewis acid catalysis favoring the endo-
diastereomer. Other key steps in the synthesis include a
Hg(II)-promoted guanidinylation to install the sterically
hindered N-1 pyrrolidine guanidine and a BOP-Cl-mediated
coupling to install the ester side chain. This approach allows
for the rapid synthesis of (()-martinellic acid and the
biologically more significant (()-martinelline in nine steps
(from the longest linear sequence) and 10% overall yield.
a Reagents and conditions: (a) DIBAL (1.5 equiv), CH2Cl2, -78
°C, 1 h; (b) Ph3PdC(CH3)CO2Et (1.0 equiv), CH2Cl2, rt, 4 h; (c)
DIBAL (3 equiv), CH2Cl2, -78 °C, 2 h; (d) 1 M aq HCl, rt, 2 h;
(e) 14 (1.2 equiv), HgCl2 (1.2 equiv), Et3N, DMF, rt, 4 h.
DIBAL and immediately reacted with the commercially
available Wittig reagent to give a greater than 10:1 mixture
of diastereomers in favor of the desired E-R,â-unsaturated
ester 12. Reduction of the ester to the alcohol and depro-
tection of the Boc group, under acidic conditions, gave the
ammonium salt 13, which was guanidinylated with di-Boc-
protected methyl isothiourea 1413b to afford the protected side
chain 11 in 39% overall yield.
Acknowledgment. AstraZeneca, the Natural Science and
Engineering Research Council (NSERC) of Canada, and the
Ontario Research and Development Challenge Fund sup-
ported this work. D.A.P. acknowledges receipt of an Ontario
Graduate Scholarship. We thank Dr. A. B. Young for MS
analyses and Dr. T. Burrow for help with NMR analysis.
Finally, we thank Dr. Sandor Varga and Dr. Steven M.
Pitzenberger of Merck for providing copies of the original
spectroscopic information on 1.
Coupling of fragments 10 and 11 was more difficult than
originally anticipated possibly due to the reduced nucleo-
philicity of the allylic alcohol 11 and/or steric hindrance at
the aromatic carboxylic acid. Many commonly employed
ester coupling reagents, including EDCI/HOBt/DMAP, SOCl2,
CDI, CH3SO2Cl, DEAD/PPh3, BOP reagent, and Mukaiya-
ma’s reagent, gave only starting material or a complex
mixture of products. This reaction was finally achieved using
BOP-Cl and Hu¨nig’s base, providing protected martinelline
15 in 78% yield (Scheme 5). Global deprotection of the Boc
groups with TFA in CH2Cl2 followed by reversed-phase
preparative HPLC gave (()-martinelline 1b, which displayed
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds as
well as spectroscopic information for 1a and 1b. This
information is available free of charge via the Internet at
http://pubs.acs.org.
1
identical H and 13C spectra to the original compound.2
(14) Evidente, A.; Piccialli, G.; Sisto, A.; Ohba, M.; Honda, K.; Fujii,
T. Chem. Pharm. Bull. 1992, 40, 1937-1939.
OL026293D
2916
Org. Lett., Vol. 4, No. 17, 2002