Total synthesis of (+/-)-martinellic acid.

Article abstract of DOI:10.1021/ol016884o

A 14-step synthesis of martinellic acid (1) that proceeds in 3% overall yield has been completed using the reaction of aniline 11 with Meldrum's acid-activated vinylcyclopropane 4 to give vinyl pyrrolidinone 12, condensation of aldehyde 13 with N-benzylglycine to form an azomethine ylide that cyclizes to give 14, selective reduction of 14 to amino alcohol 16 with LiBH(4) and MeOH, and guanidine formation by reaction of a cyanamide with 3-methyl-2-buten-1-amine in hexafluoro-2-propanol at 120 degrees C as key steps. [structure: see text]

Full text of DOI:10.1021/ol016884o

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4217-4220
Total Synthesis of (±)-Martinellic Acid
Barry B. Snider,* Yong Ahn, and Sean M. O’Hare
Department of Chemistry, MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received October 9, 2001
ABSTRACT
A 14-step synthesis of martinellic acid (1) that proceeds in 3% overall yield has been completed using the reaction of aniline 11 with Meldrum’s
acid-activated vinylcyclopropane 4 to give vinyl pyrrolidinone 12, condensation of aldehyde 13 with N-benzylglycine to form an azomethine
ylide that cyclizes to give 14, selective reduction of 14 to amino alcohol 16 with LiBH and MeOH, and guanidine formation by reaction of a
4
cyanamide with 3-methyl-2-buten-1-amine in hexafluoro-2-propanol at 120 °C as key steps.
Martinellic acid (1) and martinelline (2), isolated from an
organic extract of Martinella iquitosensis roots by Witherup
and co-workers in 1995, are novel non-peptide antagonists
for the bradykinin (BK) B1 and B2 receptors (Figure 1).1
synthetic interest,2 recently culminating in the first synthesis
of (-)-martinellic acid.3
We reported an efficient synthesis of the triamine core
9 lacking the carboxylic acid using an azomethine ylide
[3 + 2] dipolar cycloaddition to form the pyrroloquinoline
ring system (see Scheme 1).4 Reaction of aniline 3 with
Danishefsky’s Meldrum’s acid-activated vinylcyclopropane
45 in toluene at 65 °C for 2 d affords 56% of the
(2) (a) Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287-8294. (b)
Gurjar, M. K.; Pal, S.; Rama Rao, A. V. Heterocycles 1997, 45, 231-234.
(c) Kim, S. S.; Cheon, H. G.; Kang, S. K.; Yum, E. K.; Choi, J. K.
Heterocycles 1998, 48, 221-226. (d) Hadden, M.; Stevenson, P. J.
Tetrahedron Lett. 1999, 40, 1215-1218. (e) Batey, R. A.; Simoncic, P.
D.; Lin, D.; Smyj, R. P.; Lough, A. J. Chem. Commun. 1999, 651-652. (f)
Lovely, C. J.; Mahmud, H. Tetrahedron Lett. 1999, 40, 2079-2082. (g)
Frank, K. E.; Aube, J. J. Org. Chem. 2000, 65, 655-666. (h) Nieman, J.
A.; Ennis, M. D. Org. Lett. 2000, 2, 1395-1397. (i) Nyerges, M.; Fejes, I.;
To¨ke, L. Tetrahedron Lett. 2000, 41, 7951-7954. (j) Mahmud, H.; Lovely,
C. J.; Dias, H. V. R. Tetrahedron 2001, 57, 4095-4105. (k) Hadden, M.;
Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J.; Thompson, N. Tetrahedron
2001, 57, 5615-5624. (l) Hadden, M.; Nieuwenhuyzen, M.; Osborne, D.;
Stevenson, P. J.; Thompson, N. Tetrahedron Lett. 2001, 42, 6417-6419.
(3) Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org. Lett. 2001, 3, 2189-2191.
(4) (a) Snider, B. B.; Ahn, Y.; Foxman, B. M. Tetrahedron Lett. 1999,
40, 3339-3342. (b) Ahn, Y. Ph.D. Thesis, Brandeis University, 2000; Diss.
Abstr. Int., B 2000, 61, 1950.
Figure 1. Structures of martinellic acid and martinelline.
These alkaloids contain the unusual pyrroloquinoline ring
system, previously unobserved in natural products, and
multiple guanidine side chains. Their unusual structure and
biological activity have made them the subject of intense
(5) (a) Danishefsky, S.; Singh, R. K. J. Org. Chem. 1975, 40, 3807-
3808. (b) Danishefsky, S.; Singh, R. K. Organic Syntheses; Wiley: New
York, 1990; Collect. Vol. VII, pp 411-414. (c) Danishefsky, S. Acc. Chem.
Res. 1979, 12, 66-72. (d) Quinkert, G.; Weber, W.-D.; Schwartz, U.; Stark,
H.; Baier, H.; Du¨rner, G. Ann. Chem. 1981, 2335-2371.
(1) 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.
10.1021/ol016884o CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/29/2001

amounts of difficulty separable alcohol 3 resulting from
reductive cleavage of the aryl bromide. The best results were
obtained by addition of a solution of ester 10 to LAH in
THF at -78 °C and slow warming to 25 °C, which gives a
33:1 mixture of 11 and 3 from which aniline alcohol 11 can
be isolated in 81% yield (see Scheme 2).
Scheme 1. Synthesis of Model Triamine 9
Scheme 2. Synthesis of Acetoacetamide 17
vinylpyrrolidinone in a one-pot sequence involving addition
of the aniline to the allylic cyclopropane carbon, cyclization
to form the pyrrolidinone with loss of acetone, and decar-
boxylation. Oxidation of the benzylic alcohol with MnO2
gives 96% of aldehyde 5. Condensation of 5 with N-
benzylglycine provides the iminium salt which decarboxy-
lates to give azomethine ylide 6, which cyclizes to yield 68%
of the desired cis, anti adduct 7 and only 7% of the undesired
cis, syn adduct.6
Reduction of the pyrrolidinone of 7 to form amino alcohol
8 was complicated by the formation of substantial amounts
of the pyrrolidine with most reducing reagents. Optimal
results were obtained with LiBH4 and MeOH in THF,7 which
affords 67% of 8 and only 4% of the pyrrolidine. Protection
of the aniline of 8 as the trifluoroacetamide, mesylation and
immediate displacement of the mesylate with sodium azide,
cleavage of the trifluoroacetamide, and hydrogenolysis
affords triamine 9 in eight steps and 11% overall yield.
To synthesize the fully functionalized triamine ester 22
(see Scheme 3) using the sequence developed for the
synthesis of 9, we needed to introduce a carboxylic acid onto
the benzene ring. Since an ester is not compatible with the
reduction of the pyrrolidinone, we decided to introduce it
by carbonylation of an aryl bromide after the reduction.
Despite reports to the contrary,8 reduction of methyl
4-bromoanthranilate (10) or the corresponding acid to give
alcohol 11 was accompanied by formation of various
Refluxing a solution of 11 and 4 in toluene for 1 d affords
vinyl pyrrolidinone alcohol 12 in 82% yield. The reaction
proceeds more efficiently at reflux than at the lower
temperature (65 °C) used in the synthesis of 5. MnO2
oxidation of benzylic alcohol 12 gives aldehyde 13 in 87%
yield. Reaction of N-benzylglycine and aldehyde 13 in
toluene at reflux for 12-24 h provides a 10:1 mixture of
cis, anti and cis, syn fused tetracyclic lactams, 14 and 15,
respectively. Flash chromatography affords 57% of the
desired product 14 and 3% of the undesired adduct 15.
The relative stereochemistry of cis, anti fused tetracyclic
lactam 14 was assigned by analysis of the coupling constants.
The coupling constant between H5a and H2a is 4.3 Hz, which
is consistent only with a cis ring fusion. The coupling
constant between H2a and H2 is 9.8 Hz, which is consistent
1
with vicinal trans pseudoaxial hydrogens. The H NMR
spectrum and the coupling constants of 14 correspond closely
to those of model 7, whose structure was confirmed by X-ray
crystallographic structural analysis.4 The 8.0 Hz coupling
constant between H2a and H5a and the 3.1 Hz coupling
constant between H2 and H2a are consistent with those
calculated for cis, syn adduct 15 by MM2. An NOE between
H2 at δ 4.11 and H5a at δ 4.02 confirmed the stereochemistry
of 15.
(6) (a) Confalone, P. N.; Huie, E. M. J. Am. Chem. Soc. 1984, 106, 7175-
7178. (b) Kanemasa, S.; Sakamoto, K.; Tsuge, O. Bull. Chem. Soc. Jpn.
1989, 62, 1960-1968. (c) Rosini, M.; Budriesi, R.; Bixel, M. G.; Bolognesi,
M. L.; Chiarini, A.; Hucho, F.; Krogsgaard-Larsen, P.; Mellor, I. R.;
Minarini, A.; Tumiatti, V.; Usherwood, P. N. R.; Melchiorre, C. J. Med.
Chem. 1999, 42, 5212-5223.
Reductive cleavage of the pyrrolidinone without cleavage
of the bromide is also problematic. The best results are
obtained by addition of LiBH4 and MeOH to a dilute solution
(7) Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000-4005.
(8) Davis, M.; White, A. W. J. Org. Chem. 1969, 34, 2985-2988.
4218
Org. Lett., Vol. 3, No. 26, 2001

(3 mM)9 of 14 in THF at reflux, with periodic addition of
more LiBH4 and MeOH over several days to give 91% of
the desired amino alcohol 16, 2% recovered 14a, and no 8
or pyrrolidine.7,10 The absence of the pyrrolidine is probably
due to the electron-withdrawing effect of the bromine group,
which favors cleavage of the tetrahedral intermediate to the
aldehyde and retards formation of the imine that is the
pyrrolidine precursor.
Scheme 3. Synthesis of Triamine Ester 22
p-Bromoaniline was used to optimize methoxycarbonyl-
ation conditions. Reaction of p-bromoacetanilide, Pd(OAc)2
(4%), PPh3 (16%), CO (60 psi), and NaOAc (5 equiv) in
MeOH at 120-130 °C for 24 h gives 80% of the desired
methyl ester. A similar reaction of p-bromotrifluoroacet-
anilide affords 95% of p-bromoaniline and <1% of the
desired methyl ester, indicating that the trifluoroacetamide
is not stable to carbonylation conditions. p-Bromoaniline is
also not methoxycarbonylated under these conditions. We
therefore attempted to acetylate amino alcohol 16.
Reaction of 16 with AcCl (3 equiv) and Et3N (5 equiv) in
CH2Cl2 only acetylates the alcohol. However, reaction of
16, AcCl (10 equiv), and Et3N (20 equiv) in CH2Cl2 affords
79% of acetoxy acetoacetamide 17 as a mixture of keto and
enol tautomers. The structure of 17 was verified by aceto-
acetylation of the acetate of 16 with diketene in CH2Cl2,
which yields the identical material in lower yield. Reaction
of AcCl and Et3N is known to give diketene, and products
of addition of diketene have occasionally been isolated from
reactions with AcCl and Et3N.11 The aniline nitrogen of 16
is very hindered and does not react with acetyl chloride but
is acylated with the unhindered diketene. This result is similar
to the observation that the side chain of taxol can be
introduced more easily by acylation with a â-lactam than
an acid chloride.12
Reaction of 17, Pd(OAc)2 (10%), PPh3 (40%), CO (60
psi), and NaOAc (5 equiv) in dry MeOH at 120-130 °C
for 3 d provides a 3:1 mixture of amino alcohol 18 and the
corresponding acetate. Hydrolysis of the acetate is completed
by heating the crude mixture and 5 equiv of NaOAc in dry
MeOH at 120 °C for 24 h to give amino alcohol 18 in 72%
yield (see Scheme 3). Conversion of the bromide of 17 to a
methyl ester makes the aniline a better leaving group, so
NaOAc cleaves the acetoacetamide under the reaction
conditions after carbonylation.
MsCl and pyridine in CH2Cl2 affords the crude mesylate,
which is treated with 10 equiv of NaN3 in dry DMF to give
54% of crude trifluoroacetamide azide 20. Hydrolysis of
trifluoroacetamide 20 with NaOMe in dry CH2Cl2 provides
pure aniline 21 in 44% yield from 19. Hydrogenation and
hydrogenolysis of 21 over Pd(OH)2 under H2 (1 atm) in 20:1
MeOH/concentrated HCl gives 84% of the hydrochloride salt
of 22 that is 90-95% pure.13 The synthesis of fully
functionalized tricyclic triamine 22 was accomplished in 11
steps in 5% overall yield from methyl 2-amino-5-bromo-
benzoate (10).
Introduction of the guanidine onto the hindered secondary
amine of 22 is difficult, and the standard methods fail. In
his synthesis of martinellic acid, Ma developed a novel
AgNO3-catalyzed reaction with N-(Boc)-N-(3-methyl-2-
butenyl)-S-methylisothiourea.3 We recently reported a general
new method for the preparation of hindered guanidines.14
Treatment of a hindered amine with cyanogen bromide and
NaHCO3 in EtOH gives the cyanamide in virtually quantita-
tive yield. Reaction with a second amine in the polar, non-
nucleophilic solvent hexafluoro-2-propanol in a sealed tube
at 90-120 °C forms the guanidine in >80% yield.
Reaction of amino alcohol 18, TFAA, and Et3N in CH2-
Cl2 as in the protection of 8 provides trifluoroacetamide 19
in low yield presumably due to ester hydrolysis catalyzed
by Et3N. Reaction of 18, 10 equiv of TFAA, and 20 equiv
of the weaker base pyridine in CH2Cl2 for 12 h yields 74%
of trifluoroacetamide alcohol 19 after hydrolysis of the
trifluoroacetate ester during workup. Treatment of 19 with
This sequence works well on triamine 22. Reaction with
NaHCO3 (25 equiv) and cyanogen bromide (2.2 equiv) in
MeOH for 1 h at 0 °C yields bis cyanamide 23 quantitatively
(see Scheme 4). As expected the hindered aniline does not
react. Heating 23 (2 × 10-2 M) and 3-methyl-2-buten-1-
amine15 (2 equiv) in hexafluoro-2-propanol at 120 °C for
32 h provides crude methyl martinellate (24). Hydrolysis of
the methyl ester cannot be carried out under acidic conditions
since the prenyl double bonds are reactive.14 Hydrolysis in
(9) Both 8 and the pyrrolidine are formed at higher concentrations.
(10) Reduction with LiNH2BH3 was less effective: Myers, A. G.; Yang,
B. H.; Kopecky D. J. Tetrahedron Lett. 1996, 37, 3623-3626.
(11) Maujean, A.; Chuche, J. Tetrahedron Lett. 1976, 2905-2908.
(12) (a) Holton, R. A.; Kim, H.-B.; Somoza, C.; Liang, F.; Biediger, R.
J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.;
Suzuki, Y.; Tao. C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L.
N.; Liu, J. H. J. Am. Chem. Soc. 1994, 116, 1599-1600. (b) Ojima, I.;
Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk, S. Tetrahedron
Lett. 1993, 34, 4149-4152.
(13) The free triamino ester is unstable and readily forms polymeric
amides. This compound is best stored and characterized as the hydrochloride
salt.
(14) Snider, B. B.; O’Hare, S. M. Tetrahedron Lett. 2001, 42, 2455-
2458.
(15) Jordis, U.; Grohmann, F.; Ku¨enburg, B. Org. Prep. Proced. Int.
1997, 29, 549-560.
Org. Lett., Vol. 3, No. 26, 2001
4219

martinellic acid (1) in 62% yield for the three-step sequence
1
from 22 with H and 13C NMR spectral data in DMSO-d6
Scheme 4. Introduction of the Guanidines of 1
identical to those reported.1
In conclusion, we have developed a 14-step synthesis of
martinellic acid that proceeds in 3% overall yield. Key steps
include the reaction of aniline 11 with Meldrum’s acid-
activated vinylcyclopropane 4 to give vinyl pyrrolidinone
12, condensation of aldehyde 13 with N-benzylglycine to
form an azomethine ylide that cyclizes to give 14, selective
reduction of 14 to amino alcohol 16 with LiBH4 and MeOH,
and guanidine introduction by formation of the cyanamide
and reaction with 3-methyl-2-buten-1-amine in hexafluoro-
2-propanol at 120 °C.
Acknowledgment. We thank the NIH (GM-50151) for
generous financial support and Daryl A. Bosco for assistance
with NMR experiments.
4:1 MeOH/0.15 M aqueous NaOH at reflux for 14 h and
neutralization with 1% TFA in MeOH affords crude marti-
nellic acid (1) as the bis trifluoroacetate salt. Reverse phase
chromatography eluting with water to MeOH in 20%
increments removes the sodium trifluoroacetate and organic
impurities. Elution with 0.05% TFA in MeOH affords pure
Supporting Information Available: Full experimental
procedures for the conversion of 10 to martinellic acid (1).
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL016884O
4220
Org. Lett., Vol. 3, No. 26, 2001