Total synthesis of (-)-martinellic acid via radical addition-cyclization- elimination reaction

Article abstract of DOI:10.1021/jo800560p

(Chemical Equation Presented) The asymmetric total synthesis of martinellic acid, the first pyrrolo[3,2-c]quinoline alkaloid found in nature, is described. Three key steps in our synthesis of (-)-martinellic acid are the Bu ₃SnH-promoted radica

Full text of DOI:10.1021/jo800560p

Total Synthesis of (-)-Martinellic Acid via Radical
Addition-Cyclization-Elimination Reaction
Atsushi Shirai,† Okiko Miyata,*,† Norimitsu Tohnai,‡ Mikiji Miyata,‡ David J. Procter,§
David Sucunza,§ and Takeaki Naito*,†
Kobe Pharmaceutical UniVersity, Motoyamakita, Higashinada, Kobe 658-8558, Japan, Graduate School of
Engineering, Osaka UniVersity, Yamadaoka, Suita, Osaka 565-0871, Japan, and School of Chemistry,
Oxford Road, The UniVersity of Manchester, Manchester, M13 9PL, United Kingdom
taknaito@kobepharma-u.ac.jp
ReceiVed December 17, 2007
The asymmetric total synthesis of martinellic acid, the first pyrrolo[3,2-c]quinoline alkaloid found in
nature, is described. Three key steps in our synthesis of (-)-martinellic acid are the Bu3SnH-promoted
radical addition-cyclization-elimination (RACE) reaction of an oxime ether with an R,ꢀ-unsaturated
ester to generate the pyrrolo[3,2-c]quinoline core, a chemoselective lactam carbonyl reduction, and
guanidinylation under Mitsunobu reaction conditions. The key radical cyclization has also been investigated
by using SmI2. (-)-Martinellic acid was synthesized from commercially available methyl 4-bromo-3-
methylbenzoate in fewer steps than previous syntheses and in an improved overall yield.
The martinella alkaloids were isolated in 1995 by Merck
Research Laboratories from the root bark of the tropical plant
Martinella iquitosensis and were found to be a new class of
pyrroloquinoline alkaloid (Figure 1).1 The structures involving
relative configurations were firmly established by the spectral
data but the absolute configurations were not determined.1 The
plant extracts have been used as an eye medication in over 13
different ethnolinguistic groups from eight South American
countries.2 These alkaloids were found to possess antibacterial
activity as well as affinity for adrenergic, muscarinic, and
bradykinin receptors. Furthermore, these are the first examples
of nonpeptidic compounds to be identified as bradykinin receptor
FIGURE 1. Martinellic acid (1a) and martinelline (1b).
antagonists.
intramolecular 1,3-dipolar cycloadditions of azomethine ylides
Over the past decade, considerable effort has been devoted
to olefins,7 Heck reactions under palladium catalysis,8 intramo-
to the synthesis of the martinella alkaloids.3–11 The pyrrolo[3,2-
lecular radical cyclizations between aryl iodides and pyrroles,9
c]quinoline core of the martinella alkaloids has been prepared
Fischer-type cycloaddition,10 and others.11
by several synthetic routes including the imino Diels-Alder
The first asymmetric total synthesis of martinellic acid (1a)
reaction of 2-pyrroline and an N-arylimine,6 the inter- and
was reported by the group of Ma,5d,e who employed a CuI-
catalyzed coupling reaction of a ꢀ-amino ester with 1,4-diiodo-
* Corresponding author. Phone: +81-78-441-7554.Fax: +81-78-441-7556.
benzene and a guanylation of a secondary amine under mild
conditions as the key steps. In 2007, Iwabuchi reported syntheses
of both enantiomers of martinellic acid (1a) and martinelline (1b)
† Kobe Pharmaceutical University.
‡ Osaka University.
§ The University of Manchester.
(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.
(2) Gentry, A.; Cook, K. J. Ethnopharmacol. 1984, 11, 337–343.
(3) Nyerges, M. Heterocycles 2004, 63, 1685-1712, and references cited
therein.
4464 J. Org. Chem. 2008, 73, 4464–4475
10.1021/jo800560p CCC: $40.75 2008 American Chemical Society
Published on Web 05/13/2008

Total Synthesis of (-)-Martinellic Acid
SCHEME 1
employing a tandem Mukaiyama-Mannich reaction/aminal cy-
clization as a key step.5f Interestingly, all the synthetic samples of
the natural product exhibit optical rotation values that are different
from that reported for the isolated natural product. More recently,
Lovely has reported the asymmetric synthesis of (-)-martinellic
acid (1a) using an intramolecular [3 + 2]azomethine ylide-alkene
cyclization as a key reaction. Again, the optical rotation of the final
product was ambiguous.5g
Aspartofourstudiesonthestannylradicaladdition-cyclization
reactions of imine derivatives,12 we have recently developed
the radical addition-cyclization-elimination (RACE) reactions
of oxime ethers with R,ꢀ-unsaturated esters.12m In this article,
(4) (a) Hadden, M.; Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J.;
Thompson, N.; Walker, D. A. Tetrahedron 2006, 62, 3977–3984. (b) Hadden,
M.; Nieuwenhuyzen, M.; Osborne, D.; Stevenson, P. J.; Thompson, N.
Tetrahedron Lett. 2001, 42, 6417–6419. (c) He, Y.; Moningka, R.; Mahmud,
H.; Lovely, C. J. Tetrahedron Lett. 2005, 46, 1251–1254. (d) He, Y.; Mahmud,
H.; Moningka, R.; Lovely, C. J.; Dias, H. V. R. Tetrahedron 2006, 62, 8755–
8769. (e) Takeda, Y.; Nakabayashi, T.; Shirai, A.; Fukumoto, D.; Kiguchi, T.;
Naito, T. Tetrahedron Lett. 2004, 45, 3481–3484. (f) Miyata, O.; Shirai, A.;
Yoshino, S.; Takeda, Y.; Sugiura, M.; Naito, T. Synlett 2006, 893–896. (g) He,
Y.; Moningka, R.; Mahmud, H.; Lovely, C. J. Tetrahedron Lett. 2005, 46, 1251–
1254.
we describe in detail an asymmetric total synthesis of martinellic
acid (1a) based on the RACE reaction of a chiral oxime ether
5b.4f
(5) (a) Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913–2916. (b) Snider,
B. B.; Ahn, Y.; O’Hare, S. M. Org. Lett. 2001, 3, 4217–4220. (c) Xia, C.; Heng,
L.; Ma, D. Tetrahedron Lett. 2002, 43, 9405–9409. (d) Ma, D.; Xia, C.; Jiang,
J.; Zhang, J. Org. Lett. 2001, 3, 2189–2191. (e) Ma, D.; Xia, C.; Jiang, J.; Zhang,
J.; Tang, W. J. Org. Chem. 2003, 68, 442–451. (f) Ikeda, S.; Shibuya, M.;
Iwabuchi, Y. Chem Commun. 2007, 504–506. (g) Badarinarayana, V.; Lovely,
C. J. Tetrahedron Lett. 2007, 48, 2607–2610.
Results and Discussion
Our retrosynthetic analysis of (-)-martinellic acid (1a) is
outlined in Scheme 1. We envisaged that martinellic acid (1a)
could be derived from pyrroloquinolines 2 and 3 by introduction
of the guanidine moiety and hydrolysis of an ester group. We
proposed that the intermediates 2 and 3 would be produced by
diastereoselective RACE reactions of oxime ethers 4 and 5, in
which the diastereroselectivity of the reactions would be
controlled by the stereocenter bearing the R2 group. The oxime
ethers 4 and 5 would be prepared by reaction of either 612m or
7 with the unsaturated esters 8.
The oxime ether 4 bearing an alkyl chain at the allylic position
was chosen for preliminary studies on the proposed RACE
reaction (Scheme 2). Benzyl alcohol 9 was prepared from
commercially available methyl anthranilate according to the
reported procedure.13 Oxidation of benzyl alcohol 9 with use
of MnO2 followed by treatment of the resulting aldehyde with
benzyloxyamine hydrochloride in the presence of sodium acetate
gave oxime ether 6.12m The Wittig reaction of 2,3-dihydroxy-
pyran 1014 with (carbethoxymethylene)triphenylphosphorane,
followed by protection of the diol intermediate with TBSCl
provided monoalcohol 11 in 60% yield for 2 steps. The
Mitsunobu reaction of sulfonamide 6 with alcohol 11 proceeded
smoothly under standard conditions15 to provide N-allyl sul-
fonamide 4 in 49% yield.
(6) (a) Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj, R. P.; Lough, A. J.
Chem Commun. 1999, 651–652. (b) Hadden, M.; Stevenson, P. J. Tetrahedron
Lett. 1999, 40, 1215–1218. (c) Hadden, M.; Nieuwenhuyzen, M.; Potts, D.;
Stevenson, P. J.; Thompson, N. Tetrahedron 2001, 57, 5615–5624. (d) Batey,
R. A.; Powell, D. A. Chem. Commun. 2001, 2362–2363. (e) Malassene, R.;
Sanchez-Bajo, L.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Synlett 2002, 1500–
1504. (f) Yadav, J. S.; Subba, R. B. V.; Sunitha, V.; Srinivasa, R. K.;
Ramakrishna, K. V. S. Tetrahedron Lett. 2004, 45, 7947–7950.
(7) (a) Lovely, C. J.; Mahmud, H. Tetrahedron Lett. 1999, 40, 2079–2082.
(b) Snider, B. B.; Ahn, Y.; Foxman, B. M. Tetrahedron Lett. 1999, 40, 3339–
3342. (c) Nyerges, M.; Fejes, I.; Toke, L. Tetrahedron Lett. 2000, 41, 7951–
7954. (d) Snider, B. B.; O’Hare, S. M. Tetrahedron Lett. 2001, 42, 2455–2458.
(e) Mahmud, H.; Lovely, C. J.; Dias, H. V. R. Tetrahedron 2001, 57, 4095–
4105. (f) He, Y.; Mahmud, H.; Wayland, B. R.; Dias, H. V. R.; Lovely, C. J.
Tetrahedron Lett. 2002, 43, 1171–11774. (g) Nyerges, M.; Fejes, I.; Toke, L.
Synthesis 2002, 1823–1828.
(8) Gurjar, M. K.; Pal, S.; Rama Rao, A. V. Heterocycles 1997, 45, 231–
234.
(9) Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287–8294.
(10) (a) Parrick, J.; Wilcox, R. J. Chem. Soc., Perkin Trans. 1 1976, 2121–
2125. (b) Khan, M. A.; da Rocha, J. F. J. Heterocycl. Chem. 1978, 15, 913–
921. (c) Park, K. K.; Rapoport, H. J. Heterocycl. Chem. 1992, 29, 1031–1032.
(d) Heidempergher, F.; Pevarello, P.; Pillan, A.; Pinciroli, V.; Della Torre, A.;
Speciale, C.; Marconi, M.; Cini, M.; Toma, S.; Greco, F.; Varasi, M. Farmaco
1999, 54, 152–160. (e) Dudouit, F.; Houssin, R.; He´nichart, J.-P. J. Heterocycl.
Chem. 2001, 38, 755–758.
(11) (a) Frank, K. E.; Aube´, J. J. Org. Chem. 2000, 65, 655–666. (b) Nieman,
J. A.; Ennis, M. D. Org. Lett. 2000, 2, 1395–1397. (c) Hamada, Y.; Kunimune,
I.; Hara, O. Heterocycles 2002, 56, 97–100. (d) Hara, O.; Sugimoto, K.; Makino,
K.; Hamada, Y. Synlett 2004, 1625–1627. (e) Hara, O.; Sugimoto, K.; Makino,
K.; Hamada, Y. Tetrahedron 2004, 60, 9381–9390. (f) Shaw, J. T.; Masse, C. E.;
Ng, P. Y. Org. Lett. 2006, 8, 3999–4002. (g) Zhang, Z.; Zhang, Q.; Yan, Z.;
Liu, Q. J. Org. Chem. 2007, 72, 9808–9810.
We next investigated the RACE reaction of 4 under standard
conditions (Scheme 3). Treatment of oxime ether 4 with Bu3SnH
and AIBN in refluxing benzene gave pyrroloquinolines 2a-c
in a 15:11:1 ratio. In all cases, the N-benzyloxy group was lost
during the cyclization.12m Isomers 2a-c were readily separated
by column chromatography.16 Unfortunately, the cyclization
(12) (a) Naito, T.; Nakagawa, K.; Nakamura, T.; Kasei, A.; Ninomiya, I.;
Kiguchi, T. J. Org. Chem. 1999, 64, 2003–2009. (b) Naito, T.; Tajiri, K.;
Harimoto, T.; Ninomiya, I.; Kiguchi, T. Tetrahedron Lett. 1994, 35, 2205–2206.
(c) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito, T. J. Org.
Chem. 1998, 63, 4397–4407. (d) Miyabe, H.; Torieda, M.; Ninomiya, I.; Kiguchi,
T.; Naito, T. Synlett 1997, 580–582. (e) Naito, T.; Torieda, M.; Tajiri, K.;
Ninomiya, I.; Kiguchi, T. Chem. Pharm. Bull. 1996, 44, 624–626. (f) Naito, T.;
Fukumoto, D.; Takebayashi, K.; Kiguchi, T. Heterocycles 1999, 51, 489–492.
(g) Miyabe, H.; Kanehira, S.; Kume, K.; Kandori, H.; Naito, T. Tetrahedron
1998, 54, 5883–5892. (h) Kiguchi, T.; Ozaki, M.; Naito, T. Heterocycles 1999,
51, 2711–2722. (i) Kiguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T. Tetrahedron
2000, 56, 5819–5833. (j) Naito, T.; Nair, J. S.; Nishiki, A.; Yamashita, K.;
Kiguchi, T. Heterocycles 2000, 53, 2611–2615. (k) Miyabe, H.; Tanaka, H.;
Naito, T. Chem. Pharm. Bull. 2004, 52, 74–78. (l) Miyabe, H.; Nishiki, A.; Naito,
T. Chem. Pharm. Bull. 2003, 51, 100–103. (m) Miyata, O.; Shirai, A.; Yoshino,
S.; Nakabayashi, T.; Takeda, Y.; Kiguchi, T.; Fukumoto, D.; Ueda, M.; Naito,
T. Tetrahedron 2007, 63, 10092–10117.
(13) (a) Hewson, A. T.; Hughes, K.; Richardson, S. K.; Sharpe, D. A.;
Wadsworth, A. H. J. Chem. Soc., Perkin Trans. 1 1991, 1565–1569. (b)
Hechavarria Fonseca, M.; Eibler, E.; Zabel, M.; Konig, B. Tetrahedron:
Asymmetry 2003, 14, 1989–1994.
(14) (a) Sweet, F.; Brown, R. K. Can. J. Chem. 1967, 45, 1007–1011. (b)
Barker, S. A.; Brimacombe, J. S.; Foster, A. B.; Whiffen, D. H.; Zweifel, G.
Tetrahedron 1959, 7, 10–18.
(15) (a) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831–5834. (b) Tsunoda, T.; Yamamoto, H.; Goda,
K.; Itoˆ, S. Tetrahedron Lett. 1996, 37, 2457–2458. (c) Henry, J. R.; Marcin,
L. R.; McIntosh, M. C.; Scola, P. M.; Davis Harris, G.; Weinreb, S. M.
Tetrahedron Lett. 1989, 30, 5709-5712, and references cited therein.
J. Org. Chem. Vol. 73, No. 12, 2008 4465

Shirai et al.
SCHEME 2
SCHEME 3
12 provided the benzyl dibromide in quantitative yield. The
benzyl dibromide was then treated with AgNO3 in acetone and
H2O to give aldehyde 13b, which was converted to 5b by using
a similar route to that described for the preparation of 5a. We
next carried out the RACE reaction of 5b, which proceeded
smoothly to give the desired 3aS,3bS,11bS-dipyrroloquinoline
3bA as a major product (29%) and its stereoisomers 3bB-bD
in 45% combined yield (3bA:3bB:3bC:3bD ) 7:2:1:1). Al-
though side products were obtained in addition to the desired
products 3aA and 3bA, the RACE reaction of both 5a and 5b
allowed the desired products 3aA and 3bA to be isolated easily
as colorless crystalline solids from the reaction mixture after
the radical cyclization.
The radical cyclization of 5b was also investigated with use of
20
SmI2 as an alternative to Bu3SnH. While oxime-carbonyl
proceeded with low diastereoselectivity and the desired dias-
tereomer 2b was isolated as a minor product.
cyclizations with SmI2 are well-precedented in target syn-
thesis,12c,d,h,21 oxime-alkene cyclizations have received little
attention.22 Treatment of 5b with SmI2 in THF with t-BuOH as
a proton source gave a 4:1 diastereoisomeric mixture of 3bA:
3bB in addition to minor byproduct. 3bA was isolated in 41%
yield. Thus, the cyclization with SmI2 gives an improved yield
of 3bA (41%) when compared to the Sn-mediated reaction
(29%).
We next turned our attention to the RACE reaction of oxime
ethers 5a,b bearing a 2-pyrrolidone moiety (Schemes 4 and 5).
Initially, treatment of the commercially available 2-bromoben-
zaldehyde 13a with benzyloxyamine hydrochloride in the
presence of sodium acetate gave oxime ether 7a. Palladium-
catalyzed cross-coupling17,18a,b of bromobenzene 7a with L-
pyroglutamic acid ethyl ester19 gave anilide 14a in 99% yield.
This coupling reaction proceeded in moderate yield when copper
iodide was used instead of the palladium catalyst.18c The ester
group in 14a was reduced to the corresponding alcohol followed
by Swern oxidation to give the aldehyde. The resulting aldehyde
was treated with (carbethoxymethylene)triphenylphosphorane
to give the R,ꢀ-unsaturated ester 5a in 87% yield for 3 steps.
Under standard stannyl radical reaction conditions, the RACE
reaction of 5a proceeded smoothly to provide dipyrroloquino-
lines 3aA-aD (17:6:5:3), amino ester 15a, and N-benzyloxy-
dipyrroloquinoline 16a. A major product of the reaction was
the desired 3aS,3bS,11bS-dipyrroloquinoline 3aA (33%). On the
basis of the promising preliminary results, we next investigated
the RACE reaction of oxime ether 5b bearing an ester group
on the benzene ring (Schemes 4 and 5). The preparation of the
requisite oxime ether 5b began with commercially available
methyl 4-bromo-3-methylbenzoate 12. Benzylic bromination of
The stereochemistry of the products 3aA and 3bA was
established by X-ray crystallography and that of 2b was
determined by the transformations shown in Scheme 6. Deto-
sylation of 2b with magnesium in the presence of ammonium
chloride gave 17 that was identical with the sample derived from
3aA (Scheme 6). The relative stereochemistry of the isomers
1
2a and 2c was deduced from comparison of their H NMR
spectra and NOE data with those of 2b.
The structure of the isomers 3aB-aD and 3bB-bD was
1
deduced from comparison of H NMR spectra and NOE data
with those of 3aA and 3bA.
Our explanation of the stereoselectivity of the Sn-mediated
RACE reactions is shown in Scheme 7. In the (R-stannylami-
no)benzyl radical, formed by the addition of stannyl radical to
oxime ether 4, A1,3-strain gives rise to the prefered conforma-
tions A and B, of which anti-transition structure A is favored
(20) For recent reviews on the use of SmI2, see: (a) Kagan, H. B. Tetrahedron
2003, 59, 10351–10372. (b) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem.
ReV. 2004, 104, 3371–3403.
(16) In addition to 2a-c, bicyclic amino ester (3%) was obtained by column
chromatography and characterized as shown in the Supporting Information.
(17) (a) In Transition Metals for Organic Synthesis; Beller, M., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, Germany, 2004. (b) In Palladium in Heterocyclic
Chemistry; Li, J., Gribble, G., Eds.; Elsevier: Oxford, UK, 2007, and references
cited therein.
(21) (a) Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J. Org. Chem. 1998, 63,
5877–5882. (b) de Gracia, I. S.; Bobo, S.; Martin-Ortega, M. D.; Chiara, J. L.
Org. Lett. 1999, 1, 1705–1708. (c) Bobo, S.; de Gracia, I. S.; Chiara, J. L. Synlett
1999, 1551–1554. (d) Riber, D.; Hazell, R.; Skrydstrup, T. J. Org. Chem. 2000,
65, 5382–5390. (e) Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.; Rassias,
G.; Huang, X.; Chen, D. Y.-K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003, 42,
1753-1758. See also ref 22.
(18) (a) Browning, R. G.; Badarinarayana, V.; Mahmud, H.; Lovely, C. J.
Tetrahedron 2004, 60, 359–365. (b) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2,
1101–1104. (c) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421–7428.
(22) Marco-Contelles, J.; Gallego, P.; Rodr´ıguez-Ferna´ndez, M.; Khiar, N.;
Destabel, C.; Bernabe´, M.; Mart´ınez-Grau, A.; Chiara, J. L. J. Org. Chem. 1997,
62, 7397–7412.
(19) Keusenkothen, P. F.; Smith, M. B. J. Chem. Soc., Perkin Trans. 1 1994,
2485–2492.
4466 J. Org. Chem. Vol. 73, No. 12, 2008

Total Synthesis of (-)-Martinellic Acid
SCHEME 4
SCHEME 5
SCHEME 6
(borane dimethyl sulfide complex), and disiamylborane gave
only a complex mixture. It is known that the selective reduction
of lactams to cyclic amines proceeds smoothly even in the
presence of an ester moiety. However, it seems hard to prepare
the corresponding amino alcohol by the selective reduction of
lactams carrying an ester group.
Soai23 has reported that upon treatment with LiBH4 in the
presence of MeOH in THF, primary and tertiary amides gave
the corresponding primary amines and two products of second-
ary amines and alcohols, respectively, in which the latter two
products would be formed as the result of carbon-nitrogen bond
cleavage of the hemiaminal intermediate. His group has also
reported that reduction of the secondary amides was not
observed under the same reaction conditions but esters also were
easily reduced by using LiBH4 and MeOH in Et2O. Thus, in
our case, the secondary lactam in the A-ring is not expected to
be reduced but the lactam carbonyl in the C-ring and ester
carbonyl groups would be reduced under the Soai reaction
conditions. However, we expected that the lactam carbonyl
group in the C-ring would be more activated by the ester group
in the para position to undergo C-ring opening due to higher
reactivity of the lactam carbonyl than that of the ester group.
Thus, we did a systematic study on the selective reduction of
dipyrroloquinoline 3bA bearing both ester and two types of
N-substituted lactam carbonyl groups (Scheme 10; Table 1).
Treatment of dipyrroloquinoline 3bA with LiBH4 in THF in
the presence of MeOH at room temperature gave the benzyl
alcohol 20 (67%) as a major product in addition to the desired
amino alcohol 19 (30%) (entry 1). We found that the reaction
over B, which involves unfavorable interactions between the
ester and alkoxyaminostannane. Prefered transition structure A
leads to the formation of 2a. Cyclic oxime ethers 5a,b give
3aA or 3bA as major products via prefered syn-transition
structure C as the corresponding anti-transition structure D is
disfavored due to steric repulsion between the alkoxyaminostan-
nane and pyrrolidone moiety. This interaction overrides the usual
anti-selectivity of the RACE cyclization (Scheme 7).
While the mechanism of the SmI2-mediated RACE reaction
for a benzaldehyde-derived oxime ether is unclear,22 it is
reasonable to invoke the cyclization of an R-aza radical
complexed to samarium(III) (Scheme 8).
We next investigated systematic study on the selective
reduction both of tert-N-aryllactam in the C-ring of 3bA to
amino alcohol and of sec-NH-lactam in the A ring to cyclic
amine without reduction of the ester group (Scheme 9).
Treatment of 3bA with borane reagents such as 9-BBN, BMS
(23) Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000–4005.
J. Org. Chem. Vol. 73, No. 12, 2008 4467

Shirai et al.
SCHEME 7
SCHEME 8
SCHEME 10
SCHEME 9
TABLE 1. Chemoselective Reduction of 3bA
yield (%)a
entry
solvent
temp (°C)
19
20
1
2
3
THF
THF
diglyme
rt
66
90
30
76
25
67
17
19
temperature plays a critical role in the formation of the desired
product 19, which was obtained in 76% yield at 66 °C (entry
2). Unfortunately, further higher temperature (90 °C) decreased
the yield of 19 (entry 3).
a Isolated yields.
Thus, we succeeded in the reductive ring opening reaction
of the N-arylpyrrolidinone part in 3bA with LiBH4-MeOH-
THF at 66 °C, which provided selectively desired amino alcohol
19 without the reduction of an ester group.
Finally, again the selective reduction of NH-lactam in the
A-ring of 19 with BH3 ·THF gave the desired cyclic amine 18
(Scheme 11).
22b in good yield without formation of the methyl carbamate
23 (entry 3).
As methods for the introduction of the guanidine moiety
typically proceed in moderate yield and require multistep
sequences,5c–g we explored a shorter route involving a Mit-
sunobu reaction.
In our preliminary study, we used tetrahydroquinolines 24a-c
as substrates to evaluate our proposed method for introduction of
the guanidine group (Scheme 12; Table 3). The amino group of
24a, prepared by the reduction of 3,3a,4,5-tetrahydropyrrolo[1,2-
c]quinolin-1-one24 with LiBH4, was protected by the treatment with
trifluoroacetic anhydride (TFAA) or 2,2,2-trichloroethoxycarbonyl
chloride (TrocCl) to give 24b and 24c, respectively. Our first
The amino alcohol 18 was converted into the trifluoroaceta-
mide 22a5d,e and tri-Troc compound 21 under standard condi-
tions. To convert 21 into alcohol 22b, we examined selective
deprotection of the carbonate moiety (Scheme 11; Table 2). The
treatment of 21 with K2CO3 (5 equiv) in MeOH gave methyl
carbamate 23 (entry 2) while only 21 was recovered under the
acidic conditions (entry 1). The selective deprotection of the
carbonate group proceeded smoothly in the presence of K2CO3
(1.5 equiv) in MeOH:H2O (20:1) to give the desired product
(24) (a) Kocia´n, O.; Ferles, M. Collect. Czech. Chem. Commun. 1978, 43,
1413–1430. (b) Baumgarten, H. E.; Beckerbauer, R.; Debrunner, M. R. J. Org.
Chem. 1961, 26, 1539–1546.
4468 J. Org. Chem. Vol. 73, No. 12, 2008

Total Synthesis of (-)-Martinellic Acid
SCHEME 11
TABLE 2. Selective Deprotection of Troc Carbonate of 21
introduction of the guanidine moiety to alcohol 22a bearing two
trifluoroacetyl groups (Scheme 13). Trifluoroacetamide 22a was
first subjected to the Mitsunobu reaction with use of isothiourea
25b, DIAD, and Ph3P. Unfortunately, the desired product 29a
was formed in only moderate yield (44%) and N-deprotected
aniline 30a was also isolated in 17% yield (Scheme 13). The
attempted introduction of a guanidine group to aniline 30a was
unsuccessful and starting material was recovered in 61% yield.
yield (%)a
entry
reagent
solvent
MeOH
MeOH
MeOH, H2O
22b
23
21
1
2
3
TFA (1 equiv)
K2CO3 (5 equiv)
K2CO3 (1.5 equiv)
quant.
67
87
a Isolated yields.
attempt of direct preparation of 27a from 24a via the route
involving the Mitsunobu reaction using N,N′-bis(tert-butoxycar-
bonyl)-N′′-prenylguanidine 25a25 as a nucleophile was unsuccessful
and only undesired 2826 was obtained in 68% yield as a result of
intramolecular reaction (entry 1). Under the same reaction condi-
tions, 24b gave the complex mixture (entry 2).
The synthesis of (-)-martinellic acid was completed as shown
in Scheme 14. The addition-elimination reaction of isothiourea
29a with prenylamine28 proceeded to afford the N-Boc guanidine
31a in addition to 31′a. To install the second guanidine moiety
at the N(1)-position, treatment of a mixture of 31a and 31′a
with K2CO3 followed by isothiourea 32,5 in the presence of
HgCl2, gave bisguanidine 33a in excellent yield. The spectral
data of 33a were identical with those of an authentic sample
reported in the literature.5c–g Removal of one Boc group would
appear to occur during treatment with K2CO3.5a Finally,
hydrolysis of the methyl ester and removal of the two Boc
groups of 33a, followed by HPLC purification (C18 silica gel,
H2O-MeOH-CF3CO2H) gave (-)-martinellic acid (1a) as its
bistrifluoroacetate salt in 56% yield for 2 steps. The low yield
(44%) observed in conversion of 22a into 29a led us to
investigate an improved synthesis of (-)-martinellic acid using
22b, bearing Troc protection as a substrate for the introduction
of a guanidino group. The Mitsunobu reaction of N-Troc
carbamate 22b proceeded smoothly to give the desired product
29b in 96% yield (Scheme 13). The isothiourea 29b was then
converted to 33b by treatment with prenylamine,28 deprotection
of the Troc group, and introduction of the guanidino group
(Scheme 14). Finally, 33b was subjected to hydrolysis and
deprotection to give (-)-martinellic acid (1a).
Kim has reported Mitsunobu reactions using isothiourea as
a nucleophile.27 According to his procedure, treatment of 24b
with isothiourea 25b, DEAD, and Ph3P in THF at room
temperature gave 26b in 88% yield (entry 3). The subsequent
reaction of 26b with prenylamine28 proceeded at room temper-
ature to afford N-Boc-protected guanidine 27b in 93% yield.
In the case of the Mitsunobu reaction employing DIAD, a similar
chemical yield (92%) was obtained (entry 4). Furthermore, we
tested the Mitsunobu reaction of N-Troc tetrahydroquinoline 24c
and obtained 26c in moderate yield (entries 5 and 6). 26c was
also treated with prenylamine to afford N-Boc-protected guani-
dine 27c in 83% yield (Scheme 12). Quinoline compounds, such
as 27b and 27c, containing a guanidine group are known to
exhibit bradykinin antagonist activity as well as activity with
the R-adrenergic, histaminergic, and muscarinic receptors.29
On the basis of the preliminary results from our model studies,
we investigated the use of the Mitsunobu reaction for the
(25) Albrecht, C.; Barnes, S.; Bo¨ckemeier, H.; Davies, D.; Dennis, M.; Evans,
D. M.; Fletcher, M. D.; Jones, I.; Leitmann, V.; Murphy, P. J.; Rowles, R.;
Nash, R.; Stephenson, R. A.; Horton, P. N.; Hursthouse, M. B. Tetrahedron
Lett. 2008, 49, 185–188.
Ma, Iwabuchi, and Lovely have shown that the transformation
of alcohols 22 to the desired product 33a, bearing two guanidino
groups, proceeded in 28-50% yields over 5 steps.5c–g In
contrast, our synthesis of 33b was achieved in 4 steps and in
62% overall yield from 22b.
(26) Omar-Amrani, R.; Thomas, A.; Brenner, E.; Schneider, R.; Fort, Y. Org.
Lett. 2003, 5, 2311–2314.
(27) Kim, H.-O.; Mathew, F.; Ogbu, C. Synlett 1999, 193–194.
(28) Jordis, U.; Grohmann, F.; Ku¨enburg, B. Org. Prep. Proced. Int. 1997,
29, 549–560.
Synthetic martinellic acid (1a) was shown to be identical with
(29) Witherup, K. M.; Ransom, R. W.; Varga, S. L.; Pitzenberger, S. M.;
Lotti, V. J.; Lumma, W. J. U.S. Patent 5288725, 1994; Chem. Abstr. 1994, 121,
91779s.
1
natural martinellic acid by direct comparison of their H and
13C NMR spectra provided by Drs. Sheo Bux Singh and Steven
J. Org. Chem. Vol. 73, No. 12, 2008 4469

Shirai et al.
SCHEME 12
TABLE 3. Introduction of Guanidine Moiety by Using a
Mitsunobu Reactiona
methylbenzoate (12) (10 g, 43.7 mmol), NBS (23.3g, 131.1 mmol),
and AIBN (717.6 mg, 4.37 mmol) in CCl4 (437 mL) was refluxed
with stirring under a nitrogen atmosphere. After 1.5 h, AIBN (358.8
mg, 2.19 mmol) was added. After the mixture was stirred at reflux
for a further 5 h, AIBN (717.6 mg, 4.37 mmol) was added. After
the solution was refluxed for 6 h, AIBN (359.6 mg, 2.19 mmol)
was added and the mixture was refluxed for 1 h. Then the reaction
mixture was filtered to remove the resulting succinimide. The filtrate
was washed with water, dried over Na2SO4, and concentrated at
reduced pressure. The residue was recrystallized from n-hexane to
afford benzyl dibromide (16.9 g, quant.) as pale-yellow crystals.
Methyl 4-Bromo-3-(dibromomethyl)benzoate. Mp 82-83 °C
(hexane). IR ν max cm-1 1725. 1H NMR (200 MHz) δ 8.66 (1H, d,
J ) 2.0 Hz), 7.82 (1H, dd, J ) 8.5, 2.0 Hz), 7.59 (1H, d, J ) 8.5
Hz), 7.08 (1H, s), 3.96 (3H, s). 13C NMR (50 MHz) δ 165.5, 140.9,
132.9, 132.2, 131.6, 130.8, 124.8, 52.6, 38.7. HRMS m/z calcd for
C9H7Br3O2 (M+) 383.7996, found 383.8002. Anal. Calcd for
C9H7Br3O2: C, 27.94; H, 1.82. Found: C, 27.94; H, 1.95. To a
solution of benzyl dibromide (10 g, 25.8 mmol) in acetone (308
mL) and H2O (62 mL) was added AgNO3 (8.77 g, 51.6 mmol) at
room temperature. After being stirred at reflux under a nitrogen
atmosphere for 1.5 h, the reaction mixture was filtered through a
pad of Celite and the filtrate was concentrated at reduced pressure
and extracted with CHCl3. The organic phase was washed with
brine, dried with MgSO4, and concentrated at reduced pressure to
afford crude 13b. To a solution of crude 13b in pyridine (246 mL)
was added BnONH2 ·HCl (4.53 g, 28.4 mmol) at room temperature.
After being stirred at room temperature under a nitrogen atmosphere
overnight, the reaction mixture was extracted with Et2O and 2 M
HCl. The organic phase was washed with brine, dried with MgSO4,
and concentrated at reduced pressure. The residue was recrystallized
from AcOEt to afford 7b (7.19 g, 80%) as colorless crystals. Mp
entry
substrate
nucleophile
conditions
yield (%)b
c
1
2
3
4
5
6
24a
24b
24b
24b
24c
24c
25a
25a
25b
25b
25b
25b
DEAD, toluene
DEAD, toluene
DEAD, THF
DIAD, THF
DEAD, THF
DIAD, THF
-
d
-
88
92
61
66
a Reaction conditions: nucleophile (1.0 equiv), azodicarboxylate (1.5
equiv), Ph3P (1.5 equiv) in solvent at room temperature. b Isolated
yields. c Intramolecular cyclization product 28 was isolated in 68%
yield. d Complex mixture was observed. DEAD
dicarboxylate. DIAD ) diisopropyl azodicarboxylate.
) diethyl azo-
M. Pitzenberger of Merck Research Laboratories.30 However,
there is again a discrepancy between the optical rotation of the
alkaloid isolated from natural sources and our synthetic sample.
The optical rotation of our synthetic martinellic acid bistrifluo-
roacetate was [R]23D -164.8 (c 0.33, MeOH), while [R]D -8.5
(c 0.01, MeOH) was reported for the natural product.1 Recently,
Dr. Sheo Bux Singh, director and head of the Merck group,
has informed us that the natural product may have been nearly
racemic in his private communication. Our synthetic sample
and Prof. Iwabuchi’s sample exhibited almost identical optical
rotations.5f Thus, both Iwabuchi’s synthesis of both enantiomers
of martinellic acid and our synthesis of (-)-martinellic acid
determined unambiguously the absolute structure as 3aS,4S,9bS-
configuration.
Conclusion
1
58-60 °C (AcOEt). IR νmax cm-1 1723. H NMR (300 MHz) δ
The total synthesis of (-)-martinellic acid has been ac-
complished by the preparation of the chiral dipyrroloquinoline
intermediate 3bA. The three key steps in our approach are a
Bu3SnH-promoted radical addition-cyclization-elimination
reaction of oxime ether 5b, chemoselective reduction of 3bA,
and a new method for the introduction of the guanidine moiety
with use of the Mitsunobu reaction. An alternative radical
cyclization with SmI2 has also been evaluated in our approach.
Our synthetic route involves 18 steps making it the shortest of
the syntheses to date. Our synthetic strategy will allow improved
access to a variety of pyrroloquinoline structures in the future.
8.52 (1H, s), 8.51 (1H, d, J ) 2.0 Hz), 7.85 (1H, dd, J ) 8.5, 2.0
Hz), 7.63 (1H, d, J ) 8.5 Hz), 7.46-7.30 (5H, m), 5.27 (2H, s),
3.93 (3H, s). 13C NMR (50 MHz) δ 166.0, 147.5, 137.0, 133.4,
132.0, 131.4, 129.7, 128.6, 128.55, 128.49, 128.2, 77.1, 52.4. HRMS
m/z calcd for C16H14BrNO3 (M+) 347.0157, found 347.0159. Anal.
Calcd for C16H14BrNO3: C, 55.19; H, 4.05; N, 4.02. Found: C,
55.44; H, 3.97; N, 4.03.
(S)-1-[4-(Methoxycarbony)-2-[(E)-(phenylmethoxyimino)m-
ethyl]phenyl]-5-oxoproline Ethyl Ester (14b): In the Presence
of Palladium Catalyst. To 7b (1.8 g, 5.16 mmol), L-pyroglutamic
acid ethyl ester19 (971.3 mg, 6.18 mmol), Pd2(dba)3 (247.2 mg,
0.27 mmol), Xantphos (52.1 mg, 0.09 mmol), and Cs2CO3 (2.39 g,
7.32 mmol) was added 1,4-dioxane (5.16 mL) through the septum
under an Ar atmosphere at room temperature. After being stirred
at 100 °C for 8 h, the reaction mixture was filtered through a pad
of Celite and the filtrate was concentrated at reduced pressure. The
residue was purified by FCC (hexane/AcOEt 1:1) to afford 14b
(2.15 g, 98%) as colorless crystals. Mp 101-104 °C (AcOEt). IR
Experimental Section
Methyl (E)-4-Bromo-3-[(phenylmethoxyimino)methyl]ben-
zoate (7b). A solution of a mixture of methyl 4-bromo-3-
(30) The natural martinellic acid NMR is used with permission of Merck &
Co., Inc., Whitehouse Station, NJ, USA.
4470 J. Org. Chem. Vol. 73, No. 12, 2008

Total Synthesis of (-)-Martinellic Acid
SCHEME 13
SCHEME 14
ν
max cm-1 1721. 1H NMR (300 MHz) δ 8.46 (1H, d, J ) 2.0 Hz),
11.0 Hz), 5.16 (1H, d, J ) 11.0 Hz), 4.17 (1H, br s), 3.93 (3H, s),
3.59 (1H, dd, J ) 12.0, 3.0 Hz), 3.42 (1H, dd, J ) 12.0, 3.0 Hz),
2.41 (2H, t, J ) 8.0 Hz), 2.27-2.06 (2H, m). 13C NMR (75 MHz)
δ 174.7, 165.7, 146.9, 139.1, 137.0, 131.3, 131.0, 130.0, 129.4,
128.4, 128.1, 128.0, 127.1, 76.3, 62.2, 62.1, 52.4, 31.1, 20.8. HRMS
8.20 (1H, s), 8.04 (1H, dd, J ) 8.5, 2.0 Hz), 7.43-7.32 (6H, m),
5.24 (2H, s), 4.59-4.55 (1H, m), 4.14-4.03 (2H, m), 3.93 (3H,
s), 2.71-2.61 (1H, m), 2.53-2.40 (2H, m), 2.23-2.12 (1H, m),
1.16 (3H, t, J ) 7.0 Hz). 13C NMR (50 MHz) δ 173.8, 170.2, 164.9,
144.9, 138.5, 136.2, 130.2, 129.03, 128.98, 128.8, 127.5, 127.2,
127.1, 127.0, 75.6, 61.6, 60.8, 51.4, 28.7, 22.6, 13.0. HRMS m/z
calcd for C23H24N2O6 (M+) 424.1633, found 424.1647. Anal. Calcd
for C23H24N2O6: C, 65.08; H, 5.70; N, 6.60. Found: C, 65.18; H,
m/z calcd for C21H22N2O5 (M+) 382.1528, found 382.1530. [R]27
D
+23.2 (c 1.35, CHCl3). To a solution of DMSO (2.75 mL, 38.8
mmol) in CH2Cl2 (60 mL) was added dropwise a solution of TFAA
(2.69 mL, 19.4 mmol) in CH2Cl2 (30 mL) under a nitrogen
atmosphere at -65 °C. After being stirred at -65 °C for 20 min,
a solution of the above-mentioned alcohol (4.93 g, 12.9 mmol) in
CH2Cl2 (30 mL) was added dropwise. After being stirred at -65
°C for 3.5 h, the reaction mixture was warmed briefly to -30 °C
(10 min) and cooled to -65 °C. Et3N (5.22 mL, 37.5 mmol) was
added dropwise at this temperature and the reaction mixture was
stirred at -65 °C for 30 min and warmed to room temperature.
The reaction mixture was diluted with H2O and extracted with
CHCl3. The organic phase was washed with brine, dried over
MgSO4, and concentrated at reduced pressure to give the crude
aldehyde. To a solution of the crude aldehyde in THF (258 mL)
was added (carbethoxymethylene)triphenylphosphorane (6.76 g,
19.4 mmol) under a nitrogen atmosphere at room temperature. After
being stirred overnight, the reaction mixture was diluted with H2O
and extracted with Et2O. The organic phase was washed with brine,
dried over MgSO4, and concentrated at reduced pressure. The
residue was purified by FCC (hexane/AcOEt 1:1) to afford 5b (5.46
g, 94%) as a colorless oil. IR νmax cm-1 1720. 1H NMR (300 MHz)
δ 8.42 (1H, d, J ) 2.0 Hz), 8.14 (1H, s), 8.02 (1H, dd, J ) 8.5, 2.0
Hz), 7.44-7.30 (5H, m), 7.16 (1H, d, J ) 8.5 Hz), 6.66 (1H, dd,
J ) 15.5, 8.5 Hz), 5.74 (1H, dd, J ) 15.5, 0.5 Hz), 5.24 (2H, s),
4.57 (1H, br q, J ) 8.0 Hz), 4.12 (2H, q, J ) 7.0 Hz), 3.92 (3H,
s), 2.62-2.28 (3H, m), 1.98-1.86 (1H, m), 1.24 (3H, t, J ) 7.0
5.63; N, 6.65. [R]28 -9.06 (c 1.035, CHCl3).
D
In the Presence of Copper Catalyst. To 7b (1.35 g, 3.89 mmol),
L-pyroglutamic acid ethyl ester19 (757.5 mg, 4.82 mmol), CuI (38.1
mg, 0.20 mmol), N,N′-dimethylethylenediamine (0.04 mL, 0.4
mmol), and K2CO3 (1.11 g, 8.04 mmol) was added 1,4-dioxane
(2.0 mL) through the septum under an Ar atmosphere at room
temperature. After being stirred at 130 °C for 5 h, the reaction
mixture was filtered through a pad of Celite and the filtrate was
concentrated at reduced pressure. The residue was purified by FCC
(hexane/AcOEt 1:1) to afford 14b (1.01 g, 61%).
Methyl 4-[(5S)-5-[(E)-3-Ethoxy-3-oxo-1-propenyl]-2-oxo-1-pyr-
rolidinyl]-3-[(1E)-(phenylmethoxyimino)methyl]benzoate (5b). To
a solution of 14b (199.5 mg, 0.47 mmol) in MeOH (7.0 mL) was
added NaBH4 (106.7 mg, 2.82 mmol) under a nitrogen atmosphere at
room temperature. After being stirred for 40 min, the reaction mixture
was diluted with 2 M HCl at 0 °C and extracted with CHCl3. The
organic phase was washed with brine, dried over MgSO4, and
concentrated at reduced pressure. The residue was purified by FCC
(AcOEt) to afford alcohol (179.7 mg, quant.) as a colorless oil.
Methyl 4-[(5S)-5-(Hydroxymethyl)-2-oxo-1-pyrrolidinyl]-3-
[(E)-(phenylmethoxyimino)methyl]benzoate. IR νmax cm-1 3375,
1723. 1H NMR (300 MHz) δ 8.26 (1H, d, J ) 2 Hz), 8.22 (1H, s),
8.04 (1H, dd, J ) 8.5, 2 Hz), 7.41-7.25 (6H, m), 5.17 (1H, d, J )
J. Org. Chem. Vol. 73, No. 12, 2008 4471

Shirai et al.
Hz). 13C NMR (50 MHz) δ 174.4, 165.7, 165.1, 145.6, 144.8, 139.1,
137.1, 131.0, 130.0, 129.8, 129.7, 128.4, 128.1, 128.0, 124.3, 76.5,
61.6, 60.6, 52.3, 30.2, 25.8, 14.0. HRMS m/z calcd for C25H26N2O6
(3H, s), 3.22-3.15 (1H, m), 2.70-2.57 (2H, m), 2.38-2.25 (3H,
m), 1.87-1.78 (1H, m). 13C NMR (125 MHz) δ 175.7, 174.0, 166.1,
139.0, 130.6, 129.9, 126.4, 126.2, 119.0, 56.9, 53.0, 52.2, 38.9,
31.6, 28.7, 21.8. HRMS m/z calcd for C16H16N2O4 (M+) 300.1109,
found 300.1111. NOE was observed between 3b-H (δ 4.17) and
11b-H (δ 4.86) in NOESY spectroscopy. The coupling constant of
8.0 Hz was observed between 3a-H and 11b-H.
Ethyl (3aS,4S,5S)-3,3a,4,5-Tetrahydro-7-methoxycarbonyl-1-
oxo-5-[(phenylmethoxy)-amino]-1H-pyrrolo[1,2-a]quinoline-4-
acetate (15b). A pale-yellow oil. IR νmax cm-1 3261, 1718. 1H NMR
(500 MHz) δ 8.90 (1H, d, J ) 9.0 Hz), 8.04 (1H, d, J ) 2.0 Hz),
7.94 (1H, dd, J ) 9.0, 2.0 Hz), 7.34-7.24 (5H, m), 5.48 (1H, d, J
) 3.5 Hz), 4.62 (1H, d, J ) 11.5 Hz), 4.54 (1H, d, J ) 11.5 Hz),
4.32 (1H, br t, J ) 3.0 Hz), 4.20-4.06 (3H, m), 3.89 (3H, s), 2.71
(1H, dd, J ) 16.5, 10.0 Hz), 2.64-2.48 (3H, m), 2.34-2.20 (2H,
m), 1.76-1.66 (1H, m), 1.24 (3H, t, J ) 7.0 Hz). 13C NMR (125
MHz) δ 174.3, 171.1, 166.4, 140.6, 136.9, 132.1, 130.4, 128.5,
128.4, 128.0, 124.8, 123.9, 117.8, 75.9, 60.7, 58.3, 57.0, 52.0, 39.1,
32.5, 32.2, 24.6, 14.2. HRMS m/z calcd for C25H28N2O6 (M+)
452.1945, found 452.1929. The absolute configuration of 15b was
determined by leading to the formation of 16b by the reaction with
p-TsOH·H2O.
(M+) 450.1789, found 450.1789. [R]28 -3.17 (c 1.105, CHCl3).
D
Radical Cyclization of 5b with Bu3SnH and AIBN. To a
boiling solution of 5b (604.4 mg, 1.34 mmol) in benzene (7.0 mL)
was added a solution of Bu3SnH (0.72 mL, 2.68 mmol) and AIBN
(44.3 mg, 0.27 mmol) in benzene (6.4 mL) by syringe pump for
10 min under a nitrogen atmosphere. After being stirred at reflux
for 3.0 h, a solution of Bu3SnH (0.72 mL, 2.68 mmol) and AIBN
(44.3 mg, 0.27 mmol) in benzene (6.4 mL) was added by syringe
pump for 10 min. After being stirred at reflux for 1.5 h, the reaction
mixture was cooled to room temperature and then stirred at room
temperature overnight to precipitate 3bA. The reaction mixture was
filtered through a glass filter to give 3bA as colorless crystals (100.6
mg, 25%). The filtrate was extracted with hexane/MeCN. The
MeCN phase was concentrated at reduced pressure to give the
residue, which was purified by FCC (hexane/AcOEt 1:1) to afford
3bA (16 mg, 4%; total 29%), 3bB (32.2 mg, 8%), 3bC (16 mg,
4%), 3bD (16 mg, 4%), 15b (48.5 mg, 8%), and 16b (10.1 mg,
2%).
Methyl (3aS,3bS,11bS)-1,3a,3b,4,5,11b-Hexahydro-2,6-dioxo-
3H-dipyrrolo[1,2-a:3′,2′-c]quinoline-10-carboxylate (3bA). Col-
orless crystals. Mp 165-168 °C (acetone, MeOH). IR νmax cm-1
3428, 1702. 1H NMR (500 MHz) δ 8.65 (1H, d, J ) 8.5 Hz), 8.02
(1H, dd, J ) 8.5, 2.0 Hz), 7.96 (1H, d, J ) 2.0 Hz), 5.84 (1H, br
s), 4.84 (1H, d, J ) 5.5 Hz), 3.91 (3H, s), 3.75 (1H, td, J ) 11.0,
7.5 Hz), 2.80 (1H, dd, J ) 17.0, 7.5 Hz), 2.72-2.57 (2H, m),
2.54-2.43 (2H, m), 2.23 (1H, d, J ) 17.0 Hz), 1.81-1.73 (1H,
m). 13C NMR (125 MHz) δ 174.6, 173.8, 166.2, 139.8, 131.1, 130.7,
125.7, 123.5, 119.6, 55.8, 53.2, 52.3, 40.3, 34.0, 31.4, 23.1. HRMS
m/z calcd for C16H16N2O4 (M+) 300.1109, foun: 300.1128. Anal.
Calcd for C16H16N2O4: C, 63.99; H, 5.37; N, 9.33. Found: C, 63.85;
Methyl (3aS,3bS,11bS)-2,3,3a,3b,4,5,6,11b-Octahydro-2,6-di-
oxo-1-(phenylmethoxy)-1H-dipyrrolo[1,2-a:3′,2′-c]quinoline-10-
carboxylate (16b). Colorless crystals. Mp 230-233 °C (AcOEt).
1
IR νmax cm-1 1711. H NMR (300 MHz) δ 8.72 (1H, d, J ) 8.5
Hz), 8.23 (1H, d, J ) 2.0 Hz), 8.07 (1H, dd, J ) 8.5, 2.0 Hz),
7.30-7.18 (5H, m), 4.92 (1H, d, J ) 9.5 Hz), 4.64 (1H, d, J ) 5.5
Hz), 4.54 (1H, d, J ) 9.5 Hz), 3.93 (3H, s), 3.68 (1H, td, J ) 10.0,
8.5 Hz), 2.75-2.52 (3H, m), 2.50-2.25 (2H, m), 2.29 (1H, br d,
J ) 17.5 Hz), 1.82-1.65 (1H, m). 13C NMR (125 MHz) δ 173.7,
170.6, 166.2, 140.1, 134.0, 133.7, 131.3, 130.0, 128.9, 128.3, 125.3,
120.4, 119.1, 78.4, 56.8, 56.4, 52.2, 34.4, 31.5, 30.7, 23.5. HRMS
m/z calcd for C23H22N2O5 (M+) 406.1527, found 406.1526. Anal.
Calcd for C23H22N2O5 ·1/2H2O: C, 66.50; H, 5.58; N, 6.74. Found:
C, 66.90; H, 5.45; N, 6.64. NOE was observed between 3-H (δ
2.29) and 3b-H (δ 3.68) in NOESY spectroscopy. The coupling
constant of 5.5 Hz was observed between 3a-H and 11b-H.
Sammarium-Mediated Reaction of 5b. To a stirred solution
of SmI2 (0.1 M in THF, 17.2 mL, 1.72 mmol) at 0 °C was added
t-BuOH (4.0 mL) and the resulting solution was stirred for 10 min.
A solution of oxime ether 5b (155 mg, 0.34 mmol) in THF (3.0
mL) was then added and the resulting solution was stirred at 0 °C
for 3 h. The reaction was quenched by opening to the air, followed
by the addition of saturated NaHCO3. The aqueous layer was
separated and extracted with Et2O. The combined organic extracts
were dried over MgSO4 and concentrated in vacuo to give the crude
product mixture containing 3bA and 3bB (4:1 by 1H NMR).
Purification by column chromatography (silica gel, EtOAc/MeOH/
NEt3 89:10:1) gave 3bA (42 mg, 41%).
H, 5.25; N, 9.25. [R]28 +100.7 (c 0.235, CHCl3).
D
Methyl (3aS,3bS,11bR)-1,3a,3b,4,5,11b-Hexahydro-2,6-dioxo-
3H-dipyrrolo[1,2-a:3′,2′-c]quinoline-10-carboxylate (3bB). Col-
orless crystals. Mp 227-230 °C (acetone, MeOH). IR νmax cm-1
3426, 1711. 1H NMR (500 MHz) δ 8.97 (1H, d, J ) 8.5 Hz), 7.97
(1H, dd, J ) 8.5, 2.0 Hz), 7.78 (1H, br s), 6.76 (1H, br s), 4.51
(1H, d, J ) 10.5 Hz), 4.21 (1H, td, J ) 11.0, 5.5 Hz), 3.92 (3H, s),
2.73-2.57 (3H, m), 2.36-2.20 (3H, m), 1.90-1.80 (1H, m). 13C
NMR (125 MHz) δ 177.0, 174.7, 166.4, 139.5, 130.4, 124.9, 124.7,
124.0, 118.1, 62.6, 57.7, 52.2, 43.6, 34.0, 32.9, 25.5. HRMS m/z
calcd for C16H16N2O4 (M+) 300.1109, found 300.1108. Anal. Calcd
for C16H16N2O4: C, 63.99; H, 5.37; N, 9.33. Found: C, 63.80; H,
5.45; N, 9.13. NOE was observed between 3b-H (δ 4.21) and 11b-H
(δ 4.51) in NOESY spectroscopy. The coupling constant of 10.5
Hz was observed between 3a-H and 11b-H.
Methyl (3aR,3bS,11bS)-1,3a,3b,4,5,11b-Hexahydro-2,6-dioxo-
3H-dipyrrolo[1,2-a:3′,2′-c]quinoline-10-carboxylate (3bC). Col-
orless crystals. Mp 105-109 °C (acetone, MeOH). IR νmax cm-1
3424, 1704. 1H NMR (500 MHz) δ 8.06 (1H, dd, J ) 8.0, 2.0 Hz),
7.88 (1H, br s), 7.79 (1H, d, J ) 8.0 Hz), 6.70 (1H, br s), 4.22-4.17
(1H, ddd, J ) 11.5, 7.5, 4.5 Hz), 4.14 (1H, d, J ) 10.5 Hz), 3.93
(3H, s), 2.74-2.67 (1H, m), 2.59-2.46 (4H, m), 2.21-2.16 (1H,
m), 2.08-2.01 (1H, m). 13C NMR (125 MHz) δ 177.0, 173.7, 166.5,
137.4, 132.8, 129.4, 126.9, 124.0, 122.6, 56.4, 53.5, 52.4, 45.8,
32.6, 32.1, 24.2. HRMS m/z calcd for C16H16N2O4 (M+) 300.1109,
found 300.1104. Anal. Calcd for C16H16N2O4: C, 63.99; H, 5.37;
N, 9.33. Found: C, 63.95; H, 5.48; N, 9.19. NOE was observed
between 4-H (δ 2.08-2.01) and 11b-H (δ 4.14) in NOESY
spectroscopy. The coupling constant of 10.5 Hz was observed
between 3a-H and 11b-H.
Methyl (3aR,3bS,11bR)-1,3a,3b,4,5,11b-Hexahydro-2,6-dioxo-
3H-dipyrrolo[1,2-a:3′,2′-c]quinoline-10-carboxylate (3bD). Col-
orless crystals. Mp 231-234 °C (acetone, MeOH). IR νmax cm-1
3428, 1704. 1H NMR (500 MHz) δ 8.65 (1H, d, J ) 8.0 Hz), 7.89
(1H, dd, J ) 8.0, 2.0 Hz), 7.83 (1H, d, J ) 2.0 Hz), 6.64 (1H, br
s), 4.86 (1H, d, J ) 8.0 Hz), 4.17 (1H, td, J ) 7.5, 3.0 Hz), 3.89
Chemoselective Reduction of 3bA. (a) Table 1, Entry 1. To a
solution of 3bA (9 mg, 0.03 mmol) in THF (3 mL) and MeOH
(0.3 mL) was added LiBH4 (0.6 mg, 0.03 mmol) under a nitrogen
atmosphere at room temperature. More LiBH4 (0.6 mg, 0.03 mmol)
was added to the solution every 24 h. After being stirred at room
temperature for 7 days, the reaction mixture was acidified with 1
M HCl at 0 °C and basified with 10% NaOH at 0 °C. The mixture
was extracted with CHCl3. The organic phase was washed with
brine, dried over Na2SO4, and concentrated at reduced pressure.
The residue was purified by PTLC (CHCl3/MeOH 10:1) to afford
19 (2.7 mg, 30%) and 20 (5.5 mg, 67%).
(b) Table 1, Entry 2. To a boiling solution of 3bA (99.1 mg,
0.33 mmol) in THF (6 mL) and MeOH (0.6 mL) was added LiBH4
(21.6 mg, 0.99 mmol) under a nitrogen atmosphere. After being
stirred at reflux for 15 min, LiBH4 (21.6 mg, 0.99 mmol) was added.
After being stirred at reflux for 10 min, the reaction mixture was
acidified with 1 M HCl at 0 °C and basified with 10% NaOH at 0
°C. The mixture was extracted with CHCl3. The organic phase was
washed with brine, dried over Na2SO4, and concentrated at reduced
4472 J. Org. Chem. Vol. 73, No. 12, 2008

Total Synthesis of (-)-Martinellic Acid
pressure. The residue was purified by FCC (CHCl3/MeOH 10:1)
to afford 19 (76.3 mg, 76%) and 20 (15.3 mg, 17%).
of rotamers precluded a comprehensive assignment of all proton
and carbon resonances.
(c) Table 1, Entry 3. To a solution of 3bA (20.4 mg, 0.068 mmol)
in Diglyme (1.5 mL) and MeOH (0.1 mL) was added LiBH4 (1.5
mg, 0.068 mmol) at 90 °C under a nitrogen atmosphere. After being
stirred at 90 °C for 1.5 h, LiBH4 (1.5 mg, 0.068 mmol) was added.
After being stirred at 90 °C for 4 h, LiBH4 (1.5 mg, 0.068 mmol)
was added. After being stirred at 90 °C for 1 h, the reaction mixture
was acidified with 1 M HCl at 0 °C and basified with 10% NaOH
at 0 °C. The mixture was extracted with CHCl3. The organic phase
was washed with brine, dried over Na2SO4, and concentrated at
reduced pressure. The residue was purified by PTLC (CHCl3/MeOH
10:1) to afford 19 (5.2 mg, 25%) and 20 (3.5 mg, 19%).
Methyl (3aS,3bS,11bS)-2,3,3a,4,5,9b-Hexahydro-4-(3-hydrox-
ypropyl)-2-oxo-1H-pyrrolo[3,2-c]quinoline-8-carboxylate (19).
Colorless crystals. Mp 170-175 °C (benzene, MeOH). IR νmax cm-1
3341, 1695, 1683. 1H NMR (500 MHz, d6-DMSO) δ 8.22 (1H, br
s), 7.77 (1H, d, J ) 1.5 Hz), 7.55 (1H, dd, J ) 8.5, 1.5 Hz), 6.67
(1H, d, J ) 8.5 Hz), 6.64 (1H, br s), 4.56 (1H, d, J ) 7.0 Hz), 4.43
(1H, t, J ) 5.0 Hz), 3.74 (3H, s), 3.39 (2H, br q, J ) 5.5 Hz),
3.00-2.98 (1H, m), 2.46-2.38 (1H, m), 2.35 (1H, dd, J ) 16.5,
8.5 Hz), 2.02 (1H, dd, J ) 16.5, 6.0 Hz), 1.64-1.52 (2H, m),
1.52-1.38 (2H, m). 13C NMR (125 MHz, d6-DMSO) δ 175.4,
166.2, 148.6, 132.4, 129.5, 119.2, 116.3, 113.8, 60.7, 51.2, 50.6,
50.2, 37.1, 34.2, 29.5, 28.5. HRMS m/z calcd for C16H20N2O4 (M+)
304.1422, found 304.1427. Anal. Calcd for C16H20N2O4: C, 63.14;
H, 6.62; N, 9.20. Found: C, 62.94; H, 6.43; N, 9.21. [R]29D -19.4
(c 0.785, MeOH).
(3aS,3bS,11bS)-1,3a,3b,4,5,11b-Hexahydro-2,6-dioxo-10-hy-
droxymethyl-3H-dipyrrolo[1,2-a:3′,2′-c]quinoline (20). Colorless
crystals. Mp >260 °C (MeOH). IR νmax (KBr) cm-1 3445, 3377,
3211, 1709, 1684, 1661. 1H NMR (500 MHz, CD3OD) δ 8.36 (1H,
d, J ) 8.5 Hz), 7.39 (1H, br s), 7.31 (1H, dd, J ) 8.5, 1.5 Hz),
4.84 (1H, d, J ) 6.0 Hz), 4.58 (2H, s), 3.67 (1H, tt, J ) 7.5, 7.5
Hz), 2.82 (1H, dd, J ) 17, 8.0 Hz), 2.70-2.62 (1H, m), 2.60-2.50
(2H, m), 2.50-2.40 (1H, m), 2.17 (1H, d, J ) 17.0 Hz), 1.84-1.74
(1H, m). 13C NMR (125 MHz, CD3OD) δ 178.3, 176.0, 139.0,
135.9, 129.8, 128.4, 126.0, 120.8, 64.6, 57.8 55.0, 41.5, 35.1, 32.2,
23.6. HRMS m/z calcd for C15H16N2O3 (M+) 272.1160, found 272.
1160.
Methyl (3aS,3bS,9bS)-1,5-Bis(2,2,2-trichloroethoxycarbonyl)-
4-[3-(2,2,2-trichloroethoxycarbonyloxy)propyl]-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[3,2-c]quinoline-8-carboxylate (21). To a
solution of 19 (240.4 mg, 0.79 mmol) in THF (20 mL) was added
slowly BH3 ·THF (0.9 M in THF, 4.4 mL, 3.95 mmol) under an
Ar atmosphere at room temperature. After being stirred for 20 min,
the reaction mixture was heated to reflux. After being stirred at
reflux for 1.5 h, 6 M HCl (4.0 mL) was added at 0 °C. After being
stirred at room temperature for 2.5 h, the reaction mixture was
basified with 10% NaOH and extracted with CHCl3. The organic
phase was washed with brine, dried over Na2SO4, and concentrated
at reduced pressure to afford crude 18. To a solution of crude 18
in CH2Cl2 (10 mL) were added pyridine (0.22 mL, 2.8 mmol),
DMAP (48.9 mg, 0.4 mmol), and 2,2,2-trichloroethyl chloroformate
(0.39 mL, 2.8 mmol) under a nitrogen atmosphere at room
temperature. After being stirred at room temperature overnight, the
reaction mixture was diluted with saturated NH4Cl. The mixture
was extracted with CHCl3. The organic phase was washed with
brine, dried over MgSO4, and concentrated at reduced pressure.
The residue was purified by FCC (AcOEt/hexane 1:3) to afford 21
(522.5 mg, 81%) as a white solid. IR νmax cm-1 2956, 1761, 1739,
1
1714. H NMR (300 MHz) δ 8.54 (2/3H, s), 8.42 (1/3H, s), 7.93
(1H, d, J ) 8.5 Hz), 7.73 (1H, d, J ) 8.5 Hz), 5.28 (1H, d, J ) 8.0
Hz), 5.05 (1H, d, J ) 12.0 Hz), 4.90-4.70 (6H, m), 4.30-4.10
(2H, m), 3.88 (3H, s), 3.80-3.60 (1H, m), 3.60-3.48 (2/3H, m),
2.80-2.58 (1H, m), 2.32-2.12 (1H, m), 2.0-1.5 (5H, m). 13C NMR
(125 MHz) δ 166.3, 154.8, 153.8, 153.3, 138.1, 137.5, 132.4, 132.0,
129.6, 129.4, 128.7, 127.3, 124.6, 95.7, 95.0, 94.3, 75.4, 75.0, 68.1,
56.1, 55.6, 54.8, 52.2, 52.1, 45.7, 45.4, 41.7, 28.8, 28.4, 27.9, 25.4.
HRMS m/z calcd for C25H25Cl9N2O9 (M+) 811.8755, found
811.8766. [R]21D -18.5 (c 1.245, CHCl3). The presence of rotamers
precluded a comprehensive assignment of all proton and carbon
resonances.
General Procedure for Selective Deprotection of Troc Car-
bonate of 21 [Table 2]. To a solution of 21 in solvent (0.01 mmol/
mL) (MeOH:H2O ) 20:1) was added TFA or K2CO3 at room
temperature. After being stirred overnight, the reaction mixture was
diluted with H2O and extracted with CHCl3. The organic phase
was washed with brine, dried over MgSO4, and concentrated at
reduced pressure. The residue was purified by PTLC to afford 22b,
23, or 21 in yields shown in Table 2.
Methyl (3aS,3bS,9bS)-1,5-Bis(trifluoroacetyl)-2,3,3a,4,5,9b-
hexahydro-4-(3-hydroxypropyl)-1H-pyrrolo[3,2-c]quinoline-8-
carboxylate (22a). To a solution of 19 (10 mg, 0.033 mmol) in
THF (2 mL) was added slowly BH3 ·THF (1 M in THF, 0.165 mL,
0.165 mmol) under an Ar atmosphere at room temperature. After
being stirred for 10 min, the reaction mixture was heated to reflux.
After being stirred at reflux for 1.5 h, 6 M HCl (1.0 mL) was added
at 0 °C. After being stirred at 0 °C for 1 h, the reaction mixture
was basified with 10% NaOH and extracted with CHCl3. The
organic phase was washed with brine, dried over Na2SO4, and
concentrated at reduced pressure to afford crude 18. To a solution
of crude 18 in CH2Cl2 (2 mL) was added Et3N (0.02 mL, 0.116
mmol), DMAP (0.4 mg, 0.003 mmol), and TFAA (0.02 mL, 0.116
mmol) under a nitrogen atmosphere at room temperature. After
being stirred at room temperature overnight, saturated NaHCO3 (0.5
mL) was added at 0 °C. After being stirred at 0 °C for 0.5 h, the
reaction mixture was extracted with CHCl3. The organic phase was
washed with brine, dried over Na2SO4, and concentrated at reduced
pressure. The residue was purified by FCC (AcOEt/hexane 1:1) to
afford 22a5d,e (12.6 mg, 79%) as a colorless oil. IR νmax (neat)
Methyl (3aS,3bS,9bS)-1,5-Bis(2,2,2-trichloroethoxycarbonyl)-
2,3,3a,4,5,9b-hexahydro-4-(3-hydroxypropyl)-1H-pyrrolo[3,2-
c]quinoline-8-carboxylate (22b). A colorless oil. IR νmax (neat)
cm-1 3509, 2953, 1715. 1H NMR (300 MHz) δ 8.54 (2/3H, s), 8.42
(1/3H, s), 7.93 (1H, d, J ) 8.5 Hz), 7.74 (1H, d, J ) 8.5 Hz), 5.28
(1H, d, J ) 8.0 Hz), 5.06 (1H, d, J ) 11.5 Hz), 4.86 (1H, br s),
4.83 (1H, s), 4.76 (1H, s), 4.72 (1H, s), 3.88 (3H, s), 3.80-3.44
(7/2H, m), 3.44-3.30 (1 2H, m), 2.74-2.58 (1H, m), 2.28-2.10 (1H,
/
m), 2.00-1.80 (1H, m), 1.80-1.30 (4H, m). 13C NMR (75 MHz)
δ 166.4, 154.8, 153.3, 137.8, 132.3, 132.0, 129.3, 128.8, 127.1,
124.5, 95.7, 95.0, 77.2, 75.4, 75.0, 62.0, 55.9, 54.8, 52.1, 45.4, 41.7,
29.7, 29.2, 29.1, 28.7, 27.9. HRMS m/z calcd for C22H24Cl6N2O7
(M+) 637.9713, found 637.9725. [R]25 -17.9 (c 1.015, CHCl3).
D
The presence of rotamers precluded a comprehensive assignment
of all proton and carbon resonances.
Methyl (3aS,3bS,9bS)-1-(2,2,2-Trichloroethoxycarbonyl)-
2,3,3a,4,5,9b-hexahydro-4-(3-hydroxypropyl)-5-methoxycarbo-
nyl-1H-pyrrolo[3,2-c]quinoline-8-carboxylate (23). A colorless
oil. IR νmax (neat) cm-1 3501, 1723, 1695. 1H NMR (300 MHz) δ
8.51 (2/3H, s, 9-H), 8.40 (1/3H, s, 9-H), 7.89 (1H, d, J ) 8.5 Hz,
7-H), 7.62 (1H, d, J ) 8.5 Hz, 6-H), 5.27 (1H, d, J ) 8 Hz, 9b-H),
1
cm-1 3526, 1695. H NMR (500 MHz) δ 8.43 (1H, d, J ) 1.5
Hz), 8.02 (1H, dd, J ) 8.5, 1.5 Hz), 7.40 (1H, br s), 5.36 (1H, br
s), 4.74 (1H, br s), 3.92 (4H, br s), 3.64-3.50 (3H, m), 2.74-2.68
(1H, m), 2.34-2.24 (1H, m), 2.18-2.08 (1H, m), 1.66-1.48 (4H,
m). 13C NMR (125 MHz) δ 165.8, 157.1 (q, COCF3), 137.8, 133.6,
130.4, 129.9, 125.3, 116.5 (q, COCF3), 116.2 (q, COCF3), 61.9,
58.6, 57.7, 52.4, 46.0, 30.8, 30.1, 29.7, 28.6. HRMS m/z calcd for
4.87 (2 5H, s, Troc), 4.83 (3/5H, s, Troc), 4.72-4.62 (1H, m, 4-H),
/
3.87 (3H, s, CO2Me), 3.83 (3H, s, H3COCON), 3.80-3.46 (7/2H,
m, 2-H1, 3′-H2), 3.42-3.28 (1/2H, m, 2-H1), 2.70-2.54 (1H, m,
3a-H), 2.24-2.10 (1H, m, 3-H1), 1.92-1.48 (5H, m, 3-H1, 1′-H2,
2′-H2). 13C NMR (75 MHz) δ 166.4, 155.7, 154.7, 138.5, 132.2,
C20H20F6N2O5 (M+) 482.1275, found 482.1273. [R]16 +64.0 (c
D
0.99, CHCl3) [lit. [R]20D +65.1 (c 0.97, CHCl3)].5d,e The presence
J. Org. Chem. Vol. 73, No. 12, 2008 4473

Shirai et al.
1
129.1, 128.3, 126.3, 124.5, 124.3, 95.7, 77.2, 74.9, 62.0, 55.6, 55.2,
54.8, 53.4, 52.0, 45.6, 45.4, 41.5, 30.8, 29.0, 28.6, 27.6. HRMS
m/z calcd for C21H25Cl3N2O7 (M+) 522.0726, found 522.0755.
[R]26D -38.8 (c 1.07, CHCl3). The presence of rotamers precluded
a comprehensive assignment of all proton and carbon resonances.
Mitsunobu Reaction of 22a. To a solution of 22a (48.2 mg,
0.10 mmol) in THF (1.0 mL) were added 25b (87.1 mg, 0.3 mmol),
Ph3P (39.3 mg, 0.15 mmol), and DIAD (2.2 M in toluene, 0.07
mL, 0.15 mmol) under an Ar atmosphere at room temperature. After
being stirred for 1.0 h, the reaction mixture was concentrated at
reduced pressure. The residue was purified by FCC (AcOEt/hexane
1:2) to afford 29a (33.2 mg, 44%) and 30a (6.6 mg, 17%).
Methyl (3aS,3bS,9bS)-4-{3-[N-(tert-Butoxycarbonyl)-N-[(tert-
butoxycarbonylimino)(methylthio)methyl]amino]propyl}-1,5-
bis(trifluoroacetyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quin-
oline-8-carboxylate (29a). A colorless oil. IR νmax (neat) cm-1
ylate (31a). A colorless oil. IR νmax (neat) cm-1 1694. H NMR
(300 MHz) δ 8.43 (1H, d, J ) 1.5 Hz), 8.04 (1H, dd, J ) 7.0, 1.5
Hz), 7.42 (1H, br s), 5.31 (1H, br s), 5.18 (1H, br t, J ) 7.0 Hz),
4.71 (1H, br s), 3.93 (3H, s), 4.00-3.84 (1H, m), 3.71 (2H, d, J )
6.5 Hz), 3.65-3.40 (3H, m), 2.80-2.62 (1H, m), 2.22-2.40 (1H,
m), 2.24-2.04 (1H, m), 1.75 (3H, s), 1.66 (3H, s), 1.49 (9H, s),
1.45 (9H, s), 1.80-1.40 (4H, m). 13C NMR (75 MHz) δ 165.7,
156.8 (q, COCF3), 137.8, 133.5, 130.4, 129.6, 125.3, 118.5, 116.1
(q, COCF3), 82.6, 79.3, 77.2, 52.3, 46.5, 45.9, 41.7, 28.2, 28.1,
25.6, 25.0, 17.9. SIMS calcd for C36H48F6N5O8 (M + H) 792.3404,
found 792.3415. [R]29 +20.4 (c 0.93, CHCl3). The presence of
rotamers precluded a comprehensive assignment of all proton and
carbon resonances.
D
Methyl (3aS,3bS,9bS)-4-{3-[1,2-Di(tert-butoxycarbonyl)-3-(3-
methylbut-2-enyl)guanidino]propyl}-1-trifluoroacetyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[3,2-c]quinoline-8-carboxylate (31′a). A
colorless oil. IR νmax (neat) cm-1 3366, 1705. 1H NMR (300 MHz)
δ 9.38 (1H, br s), 7.96 (1H, s), 7.71 (1H, dd, J ) 8.5, 1.5 Hz),
6.61 (1H, d, J ) 8.5 Hz), 5.88-5.72 (1H, m), 5.55 (1H, d, J ) 7.0
Hz), 5.23 (1H, br t, J ) 6.0 Hz), 3.82 (3H, s), 3.90-3.60 (3H, m),
3.60-3.36 (3H, m), 2.35 (1H, br q, J ) 9.0 Hz), 2.14 (2H, br q, J
) 9.0 Hz), 1.75 (3H, s), 1.67 (3H, s), 1.50 (9H, s), 1.49 (9H, s),
1.90-1.30 (4H, m). 13C NMR (75 MHz) δ 167.1, 157.2 (q, COCF3),
146.0, 137.9, 131.9, 130.6, 118.8, 118.6, 116.6, 116.4 (q, COCF3),
114.1, 83.0, 79.4, 77.2, 54.1, 51.5, 49.5, 46.1, 44.6, 42.0, 39.8, 31.8,
28.2, 28.1, 27.5, 25.6, 24.8, 18.0. SIMS calcd for C34H49F3N5O7
1
1695. H NMR (300 MHz) δ 8.43 (1H, d, J ) 1.0 Hz), 8.03 (1H,
dd, J ) 8.0, 1.0 Hz), 7.40 (1H, br s), 5.33 (1H, br s), 4.71 (1H, br
s), 3.93 (4H, br s), 3.60-3.48 (1H, m), 3.44 (2H, br t, J ) 7.0 Hz),
2.74-2.64 (1H, m), 2.35 (4H, br s), 2.14 (1H br s), 1.65 (4H, m),
1.49 (9H, s), 1.43 (9H, s). 13C NMR (125 MHz) δ 165.8, 162.3,
157.8, 156.8 (q, COCF3), 151.8, 137.7, 133.5, 130.4, 129.6, 125.4,
116.3 (q, COCF3), 116.0 (q, COCF3), 82.5, 82.0, 58.3, 52.4, 47.6,
46.0, 30.4, 29.7, 28.00, 27.96, 24.9, 15.5. HRMS m/z calcd for
C32H40F6N4O8S (M+) 754.2468, found 754.2497. [R]21 +27.9 (c
D
1.51, CHCl3). The presence of rotamers precluded a comprehensive
assignment of all proton and carbon resonances.
(M + H) 696.3581, found 696.3571. [R]29 -294.23 (c 0.52,
CHCl3). The presence of rotamers precluded a comprehensive
assignment of all proton and carbon resonances.
D
Methyl (3aS,3bS,9bS)-1-Trifluoroacetyl-2,3,3a,4,5,9b-hexahy-
dro-4-(3-hydroxypropyl)-1H-pyrrolo[3,2-c]quinoline-8-carboxy-
late (30a). A colorless oil. IR νmax (neat) cm-1 3627, 3441, 1687.
1H NMR (300 MHz) δ 7.98 (1H, s), 7.73 (1H, d, J ) 8.5 Hz), 6.47
(1H, d, J ) 8.5 Hz), 5.56 (1H, d, J ) 7.0 Hz), 3.83 (3H, s),
3.80-3.60 (4H, m), 3.45-3.30 (1H, m), 2.40 (1H, br q, J ) 9.0
Hz), 2.13 (1H, br q, J ) 6.5 Hz), 1.80-1.50 (5H, m). 13C NMR
(125 MHz) δ 167.0, 157.2 (q, COCF3), 145.6, 132.0, 130.8, 119.6,
117.2, 116.6 (q, COCF3), 114.0, 62.6, 54.1, 51.7, 51.2, 44.6, 39.8,
32.7, 29.7, 29.1, 27.5. HRMS m/z calcd for C18H21F3N2O4 (M+)
386.1452, found 386.1433.
Methyl (3aS,4S,9bS)-1-[N′-(tert-Butoxycarbonyl)-N-(3-meth-
ylbut-2-enyl)carbamimidoyl]-4-{3-[2-(tert-butoxycarbonyl)-3-(3-
methylbut-2-enyl)guanidino]propyl}-2,3,3a4,5,9b-hexahydro-
1H-pyrrolo[3,2-c]quinoline-8-carboxylate (33a). To a solution of
31a:31′a (1.6:1, 89.8 mg, 0.119 mmol) in MeOH (3.0 mL) was
added K2CO3 (98.7 mg, 0.714 mmol) under a nitrogen atmosphere
at room temperature. After being stirred at room temperature
overnight, K2CO3 (49.3 mg, 0.357 mmol) was added. After being
stirred at room temperature for 8 h, the reaction mixture was diluted
with H2O and extracted with CHCl3. The organic phase was washed
with brine, dried over Na2SO4, and concentrated at reduced pressure
to afford crude amine. To a solution of the crude amine in DMF
(3.0 mL) were added isothiourea 325 (36.9 mg, 0.143 mmol) and
Et3N (0.05 mL, 0.357 mmol) under a nitrogen atmosphere at room
temperature. After being stirred at room temperature for 10 min,
HgCl2 (38.8 mg, 0.143 mmol) was added. After being stirred at
room temperature for 2 h, the reaction mixture was diluted with
H2O and extracted with Et2O. The organic phase was washed with
brine, dried over Na2SO4, and concentrated at reduced pressure.
The residue was purified by PTLC (CHCl3/MeOH 10:1) to afford
33a5d–g (73.5 mg, 87%) as a white foam. IR νmax (neat) cm-1 3294,
Methyl (3aS,3bS,9bS)-4-{3-[N-(tert-Butoxycarbonyl)-N-[(tert-
butoxycarbonylimino)(methylthio)methyl]amino]propyl}-1,5-
bis(2,2,2-trichloroethoxycarbonyl)-2,3,3a,4,5,9b-hexahydro-1H-
pyrrolo[3,2-c]quinoline-8-carboxylate (29b). According to the
procedure given for the Mitsunobu reaction of 22a, reaction of 22b
(34.6 mg, 0.054 mmol) with 25b (47.0 mg, 0.162 mmol), Ph3P
(21.2 mg, 0.081 mmol), and DIAD (2.2 M in toluene, 0.04 mL,
0.081 mmol) gave 29b (47.4 mg, 96%) as a colorless oil. IR νmax
1
(neat) cm-1 2981, 1715, 1615. H NMR (300 MHz) δ 8.54 (2/3H,
s), 8.42 (1/3H, s), 7.93 (1H, d, J ) 8.5 Hz), 7.77 (1H, d, J ) 8.5
Hz), 5.27 (1H, d, J ) 8.0 Hz), 5.12-4.90 (1H, m), 4.86 (1H, br s),
4.83 (1H, s), 4.77 (1H, s), 4.73 (1H, s), 3.88 (3H, s), 3.80-3.30
(2H, m), 3.47 (2H, t, J ) 7.0 Hz), 2.72-2.56 (1H, m), 2.33 (3H,
s), 2.26-2.10 (1H, m), 2.00-1.80 (1H, m), 1.82-1.60 (4H, m),
1.48 (9H, s), 1.42 (9H, s). 13C NMR (75 MHz) δ 166.3, 162.5,
157.7, 154.7, 153.2, 151.8, 137.8, 132.3, 131.9, 129.3, 128.8, 127.0,
124.6, 95.7, 95.0, 82.3, 81.9, 77.2, 75.4, 75.0, 55.6, 54.8, 52.1, 47.9,
45.4, 41.6, 29.6, 29.4, 29.2, 28.00, 27.96, 27.85, 25.5, 21.9, 21.7,
15.6. SIMS calcd for C34H45Cl6N4O10S (M + H) 911.0984, found
911.0978. [R]26D -22.6 (c 0.55, CHCl3). The presence of rotamers
precluded a comprehensive assignment of all proton and carbon
resonances.
1
2977, 1696, 1608. H NMR (300 MHz) δ 7.98 (1H, s), 7.65 (1H,
d, J ) 8.5 Hz), 7.07 (1H, br s), 6.60 (1H, d, J ) 8.5 Hz), 5.72 (1H,
d, J ) 7.0 Hz), 5.38-5.24 (1H, m), 5.24-5.12 (1H, m), 3.95-3.60
(4H, m), 3.81 (3H, s), 3.50-3.20 (4H, m), 3.25-3.05 (1H, m),
2.40-2.20 (1H, m), 2.15-1.90 (2H, m), 1.73 (3H, s), 1.72 (3H,
s), 1.67 (3H, s), 1.65 (3H, s), 1.52 (9H, s), 1.49 (9H, s), 1.80-1.40
(4H, m). 13C NMR (75 MHz) δ 167.4, 163.9, 161.9, 161.4, 160.1,
146.5, 137.0, 131.7, 130.0, 120.3, 119.5, 118.2, 117.7, 113.7, 78.0,
77.6, 77.2, 53.3, 51.3, 50.5, 46.7, 42.5, 40.0, 39.42, 39.36, 31.9,
28.44, 28.38, 28.0, 27.9, 26.5, 25.6, 17.9. SIMS calcd for
C38H60N7O6 (M + H) 710.4602, found 710.4594. [R]25 -179.2
Guanylation Reaction of 29a. To a solution of 29a (113.2 mg,
0.15 mmol) in THF (3.0 mL) was added 3-methyl-2-buten-1-
amine28 (127.7 mg, 1.50 mmol) at room temperature. After being
stirred for 5.0 h, the reaction mixture was concentrated at reduced
pressure. The residue was purified by PTLC (Et2O) to afford 31a
(60.6 mg, 51%) and 31′a (38.6 mg, 37%).
Methyl (3aS,3bS,9bS)-4-{3-[1,2-Di(tert-butoxycarbonyl)-3-(3-
methylbut-2-enyl)guanidino]propyl}-1,5-bis(trifluoroacetyl)-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-8-carbox-
D
(c 1.20, CHCl3) [lit. [R]28D -179.1 (c 0.80, CHCl3),5f [R]20D -94.2
(c 0.28, CHCl3),5d,e [R]D -95.2 (c 0.58, CHCl3)5g].
(-)-Martinellic Acid (1a). To a solution of 33a (51.1 mg, 0.072
mmol) in MeOH (8.0 mL) was added 0.2 M NaOH (2.76 mL) under
a nitrogen atmosphere at room temperature. After being stirred at
reflux for 14 h, the reaction mixture was diluted with saturated
NH4Cl and extracted with CHCl3. The organic phase was washed
with brine, dried over Na2SO4, and concentrated at reduced pressure
4474 J. Org. Chem. Vol. 73, No. 12, 2008

Total Synthesis of (-)-Martinellic Acid
to afford crude acid. To a solution of the crude acid in CH2Cl2
(5.0 mL) was added TFA (0.07 mL) under a nitrogen atmosphere
at room temperature. After being stirred at room temperature for
24 h, further TFA (0.035 mL) was added. After being stirred at
room temperature for 24 h, the reaction mixture was concentrated
at reduced pressure. The residue was purified by preparative HPLC
through a COSMOSIL 5C18-PAQ (20 × 250 mm) eluting with
80:20 H2O/MeOH (with 0.1% TFA) to 60:40 H2O/MeOH (with
0.1% TFA) as a gradient over 80 min and with a flow rate of 5
mL/min. The detector was set to 330 nm and the major fraction
had a retention time of 67.6 min. This fraction was concentrated at
reduced pressure to afford 1a (27.8 mg, 56%) as a white powder.
IR νmax (neat) cm-1 3318, 3198, 1659, 1610. 1H NMR (500 MHz,
d6-DMSO) δ 7.73 (1H, br s), 7.67 (1H, br s), 7.63 (1H, br s), 7.53
(1H, dd, J ) 8.5, 1.5 Hz), 7.45 (2H, br s), 7.36 (2H, br s), 7.03
(1H, br d, J ) 3.0 Hz), 6.56 (1H, d, J ) 8.5 Hz), 5.32-5.26 (1H,
m), 5.23 (1H, d, J ) 6.5 Hz), 5.18-5.12 (1H, m), 3.96-3.90 (1H,
m), 3.88-3.80 (1H, m), 3.71 (2H, br t, J ) 5.5 Hz), 3.40-3.30
(2H, m), 3.30-3.22 (1H, m), 3.18-3.06 (2H, m), 2.46-2.38 (1H,
m), 2.10-2.02 (1H, m), 1.73 (3H, s), 1.69 (3H, s), 1.68 (3H, s),
1.63 (3H, s), 1.70-1.50 (3H, m), 1.42-1.36 (2H, m). 13C NMR
(125 MHz, d6-DMSO) δ 167.2, 155.4, 154.3, 146.3, 136.0, 135.6,
130.4, 130.0, 119.6, 119.2, 117.1, 115.7, 113.3, 53.0, 49.2, 45.8,
40.7, 39.9*, 39.4*, 39.0*, 33.4, 26.3, 25.4, 25.30, 25.28, 17.9, 17.8.
(3 peaks observed at 39.9, 39.4, and 39.0 by Witherup and co-
workers1 could not be unequivocally assigned as they were
underneath the DMSO peak, but these 3 peaks could be detected
in the DEPT data we carried out on synthetic 1a). MS (SIMS,
3-nitrobenzyl alcohol) m/z 722 (100, [M - H + 2CF3CO2H]), 608
(75, [M - H + CF3CO2H]), 494 (6, [M - H]). HRMS (SIMS,
3-nitrobenzyl alcohol) calcd for C27H40N7O2 (M - H, free guani-
(10.5 mg, 0.16 mmol) and saturated NH4Cl (0.3 mL) under a
nitrogen atmosphere at room temperature and the resulting mixture
was stirred at room temperature. Zn powder (50.0 mg, 0.76 mmol)
was added every 1 h during 6 h. After being stirred at room
temperature for 6 h, the reaction mixture was filteted through a
pad of Celite and filtrate was diluted with 10% NaOH and extracted
with CHCl3. The organic phase was washed with brine, dried over
MgSO4, and concentrated at reduced pressure to afford crude amine.
To a solution of the crude amine in DMF (2.0 mL) were added
isothiourea 325 (12.4 mg, 0.048 mmol) and Et3N (0.02 mL, 0.12
mmol) under a nitrogen atmosphere at room temperature. After the
mixtue was stirred at room temperature for 10 min, HgCl2 (13.0
mg, 0.048 mmol) was added. After being stirred at room temper-
ature for 2 h, the reaction mixture was diluted with H2O and
extracted with Et2O. The organic phase was washed with brine,
dried over MgSO4, and concentrated at reduced pressure. The
residue was purified by PTLC (AcOEt) to afford 33b (21.1 mg,
65%) as a sticky oil. IR νmax (neat) cm-1 3310, 2977, 2932, 1709,
1
1609. H NMR (500 MHz) δ 7.99 (1H, d, J ) 2.0 Hz), 7.66 (1H,
dd, J ) 9.0, 2.0 Hz), 6.54 (1H, d, J ) 9.0 Hz), 5.70 (1H, d, J )
7.5 Hz), 5.54-5.48 (1H, br s), 5.27 (1H, br t, J ) 7.0 Hz), 5.22
(1H, br t, J ) 7.0 Hz), 3.87 (1H, dd, J ) 14.0, 7.5 Hz), 3.82-3.76
(1H, m), 3.80 (3H, s), 3.76-3.70 (2H, m), 3.70-3.60 (1H, m),
3.54-3.44 (1H, m), 3.44-3.30 (3H, m), 2.36-2.28 (1H, m),
2.10-1.80 (2H. m), 1.74 (3H, s), 1.70 (3H, s), 1.66 (3H, s), 1.64
(3H, s), 1.80-1.60 (4H, m), 1.51 (9H, s), 1.49 (9H, s), 1.47 (9H,
s). 13C NMR (125 MHz) δ 167.4, 162.1, 161.7, 146.2, 137.8, 137.0,
131.9, 130.0, 120.4, 118.7, 118.5, 118.3, 113.7, 82.8, 79.3, 77.5,
53.2, 51.4, 50.0, 46.7, 42.5, 41.9, 39.7, 32.2, 30.3, 29.7, 28.5, 28.2,
28.1, 28.0, 25.61, 25.58, 24.9, 18.0, 17.97. SIMS calcd for
C43H67N7O8 (M + H) 810.5125, found 810.5121. [R]28 -125.9
D
dine) 494.3241, found 494.3267. [R]23 -164.8 (c 0.33, MeOH)
D
(c 0.52, CHCl3).
[lit. natural [R]D -8.5 (c 0.01, MeOH),1 [R]29 -164.3 (c 0.14,
D
(-)-Martinellic Acid (1a). According to the procedure given
for hydrolysis and deprotection of 33a, 33b (33.2 mg, 0.041 mmol)
was converted into 1a (15.8 mg, 56%).
MeOH),5f [R]20 -122.7 (c 0.31, MeOH)5d,e].
D
Methyl (3aS,3bS,9bS)-4-{3-[1,2-Di(tert-butoxycarbonyl)-3-(3-
methylbut-2-enyl)guanidino]propyl}-1,5-bis(2,2,2-trichloroet-
hoxycarbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quin-
oline-8-carboxylate (31b). According to the procedure given for
the guanylation reaction of 29a, reaction of 29b (51.1 mg, 0.056
mmol) with 3-methyl-2-buten-1-amine28 (71.5 mg, 0.84 mmol) gave
31b (53.2 mg, quant.) as a colorless oil. IR νmax (neat) cm-1 3423,
2980, 1715, 1643, 1615. 1H NMR (300 MHz) δ 9.31 (1H, s), 8.53
(2/3H, s), 8.42 (1/3H, s), 7.92 (1H, d, J ) 8.5 Hz), 7.75 (1H, d, J )
8.5 Hz), 5.30-5.20 (1H, m), 5.20-5.10 (1H, m), 5.10-5.00 (1H,
m), 4.90-4.68 (4H, m), 3.88 (3H, s), 3.80-3.30 (7H, m), 2.72-2.54
(1H, m), 2.26-2.10 (1H, m), 2.00-1.80 (1H, m), 1.75 (3H, s),
1.65 (3H, s), 1.49 (9H, s), 1.43 (9H, s), 1.70-1.40 (4H, m). 13C
NMR (75 MHz) δ 166.3, 154.7, 153.2, 137.8, 132.3, 131.9, 129.4,
128.7, 127.1, 124.4, 118.6, 95.7, 95.1, 82.5, 79.3, 77.2, 75.3, 75.0,
55.6, 54.7, 53.8, 52.1, 46.8, 45.7, 45.4, 41.7, 29.7, 29.5, 28.2, 28.1,
27.9, 25.7, 25.6, 18.0. SIMS calcd for C38H51Cl6N5O10 (M + H)
Acknowledgement. We are grateful to acknowledge the
research Grants-in-Aid for Scientific Research (B) (to T.N.) and
(C) (to O.M.) from the Japan Society for the Promotion of
Science (JSPS) and Scientific Research on Priority Areas (A)
(to T.N.) from the Ministry of Education, Culture, Sports, and
Technology. We also acknowledge a research grant from the
Science Research Promotion Fund of the Japan Private School
Promotion Foundation. We particularly thank Drs. Sheo Bux
Singh, Steven M. Pitzenberger, and Nobuyoshi Yasuda of Merck
1
Research Laboratories for providing H NMR and 13C NMR
spectra of natural martinellic acid and their helpful suggestions.
Supporting Information Available: Experimental proce-
dures, compound characterizations except for the Experimental
Section, copies of 1H NMR and 13C NMR spectra for selected
compounds and natural martinellic acid, copies of MASS for
5b and 20, X-ray crystallographic data, and CIF files. This
material is available free of charge via the Internet at
http://pubs.acs.org.
948.1842, found 948.1827. [R]25 -32.3 (c 0.51, CHCl3). The
D
presence of rotamers precluded a comprehensive assignment of all
proton and carbon resonances.
Methyl (3aS,4S,9bS)-1-[N′-(tert-Butoxycarbonyl)-N-(3-meth-
ylbut-2-enyl)carbamimidoyl]-4-{3-[1,2-di(tert-butoxycarbonyl)-
3-(3-methylbut-2-enyl)guanidino]propyl}-2,3,3a4,5,9b-hexahydro-
1H-pyrrolo[3,2-c]quinoline-8-carboxylate (33b). To a solution of
31b (38.0 mg, 0.04 mmol) in THF (3.0 mL) were added Zn powder
JO800560P
J. Org. Chem. Vol. 73, No. 12, 2008 4475