Asymmetrie total syntheses of (-)-renieramycin M and G and (-)-jorumycin using aziridine as a lynchpin

Article abstract of DOI:10.1021/ol9024919

"Chemical Equation Presented" By exploring the triple reactivity of two aziridines and double nucleophilicity of two aromatics, convergent and versatile syntheses of the above four natural products were developed.

Full text of DOI:10.1021/ol9024919

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5558-5561
Asymmetric Total Syntheses of
(-)-Renieramycin M and G and
(-)-Jorumycin Using Aziridine as a
Lynchpin
Yan-Chao Wu and Jieping Zhu*
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles,
CNRS, 91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
Received October 28, 2009
ABSTRACT
By exploring the triple reactivity of two aziridines and double nucleophilicity of two aromatics, convergent and versatile syntheses of the
above four natural products were developed.
Antitumor antibiotic renieramycin M (1, Figure 1) has been
isolated from the marine sponge Xestospongia sp. in 2003,1
which belongs to a growing family of bioactive tetrahy-
droisoquinoline alkaloids including renieramycin G (2),
jorumycin (3), saframycins (4), and ecteinascidin 743 (Et
743, 5) etc.2 These natural products show potent antitumor
antibiotic activities, and one of them, the Et 743 (5), has
received in 2007 marketing authorization from the European
commission for the treatment of advanced soft-tissue sar-
comas.3 The fascinating molecular architecture and potent
bioactivities of these natural products have attracted a great
deal of attention from the organic-synthesis community.4 The
synthetic efforts have not only led to the development of
new synthesis strategies but also led to the discovery of
several medicinally significant analogues such as zalypsis
that are currently in advanced human clinical trials as an
anticancer agent.5,6 Williams et al.7 have developed conver-
gent asymmetric syntheses of renieramycin G (1) and
(4) For recent total syntheses of this family of alkaloids, see: (a) Endo,
A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am.
Chem. Soc. 2002, 124, 6552–6554. (b) Ashley, E. R.; Cruz, E. G.; Stoltz,
B. M. J. Am. Chem. Soc. 2003, 125, 15000–15001. (c) Kwon, S.; Myers,
A. G. J. Am. Chem. Soc. 2005, 127, 16796–16797. (d) Chan, C.; Heid, R.;
Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.; Danishefsky, S. J. J. Am. Chem.
Soc. 2005, 127, 4596–4598. (e) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu,
J. J. Am. Chem. Soc. 2006, 128, 87–89. (f) Chen, J.; Chen, X.; Willot, M.;
Zhu, J. Angew. Chem., Int. Ed. 2006, 45, 8028–8032. (g) Chen, X.; Zhu, J.
Angew. Chem., Int. Ed. 2007, 46, 3962–3965. (h) Vincent, G.; Williams,
R. M. Angew. Chem., Int. Ed. 2007, 46, 1517–1520. (i) Kaniskan, H. U.;
Garner, P. J. Am. Chem. Soc. 2007, 129, 15460–15461. (j) Wu, Y.-C.; Liron,
M.; Zhu, J. J. Am. Chem. Soc. 2008, 130, 7148–7152. (k) Allan, K. M.;
Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 17270–17271.
(1) (a) Suwanborirux, K.; Amnuoypol, S.; Plubrukarn, A.; Pummangura,
S.; Kubo, A.; Tanaka, C.; Saito, N. J. Nat. Prod. 2003, 66, 1441–1446. (b)
Saito, N.; Tanaka, C.; Koizumi, Y.-I.; Suwanborirux, K.; Amnuoypol, S.;
Pummangura, S.; Kubo, A. Tetrahedron 2004, 60, 3873–3881.
(2) (a) Scott, J. D.; Williams, R. M. Chem. ReV. 2002, 102, 1669–1730.
(b) Siengalewicz, P.; Rinner, U.; Mulzer, J. Chem. Soc. ReV. 2008, 37, 2676–
2690.
(3) Cuevas, C.; Francesch, A. Nat. Prod. Rep. 2009, 26, 322–337.
10.1021/ol9024919 CCC: $xxxx
Published on Web 11/06/2009
 2009 American Chemical Society

to satisfy this criterion since it is potentially amenable to all
members of renieramycin/saframycin alkaloids. Compound
6 was thought to be prepared by the Pictet-Spengler reaction
of aminoester 8 and (S)-2-formyl-aziridine (9), followed by
ring-opening of aziridine with organometallic regent 10.
Aminoester 8 could in turn be synthesized by coupling of
aziridine 11 with nucleophile 12. We report herein the
realization of this strategy by developing the first total
synthesis of renieramycin M (1), as well as the syntheses of
renieramycin G (2) and jorumycin (3).
Syntheses of aziridines 9 and 11 are shown in Scheme 2.
Treatment of a 1,2-dichloroethane solution of commercially
Scheme 2. Synthesis of Aziridines 9 and 11
Figure 1. Examples of bistetrahydroisoquinoline alkaloids.
jorumycin (3) taking advantage of the latent symmetry of
these molecules.8,9 Liu et al. have very recently reported a
synthesis of (-)-renieramycin G (1) based on a similar
strategy.10 In addition, Magnus and co-workers have de-
scribed a synthesis of racemic renieramycin G (1).11 Con-
struction of the bicyclic A-B ring system followed by
N-acylation and elaboration of the central bridged C-D ring
is a common feature of these reported syntheses.7,10-12
From a structural point of view, the main differences
among these alkaloids reside on the aromatic A and E rings,
the C1 substituent (CH2OR or CH2NHR), and the C21
functionalities (carbinolamine, amionitrile vs amide). We
thought to develop a modular approach that allows the
introduction of these structural elements at the late stage of
the synthesis (Scheme 1). Tetrahydroisoquinoline 6 deemed
available N-trityl-L-serine methyl ester (13) with MsCl and
DIPEA at -78 °C followed by heating to reflux afforded
directly the aziridine 14 in 73% yield. Removal of the N-trityl
group under mild acidic conditions followed by N-tert-
butoxycabonylation afforded N-Boc aziridine 15 in 89%
overall yield, which was in turn converted to the desired (S)-
di-tert-butyl aziridine-1,2-dicarboxylate (11) (85%) by a
(5) (a) Martinez, E. J.; Owa, T.; Schreiber, S. L.; Corey, E. J. Proc.
Natl. Acad. Sci. U.S.A. 1999, 96, 3496–3501. (b) Myers, A. G.; Plowright,
A. T. J. Am. Chem. Soc. 2001, 123, 5114–5115.
Scheme 1. Retrosynthetic Analysis of Renieramycin Alkaloids
(6) Gallerani, E.; Yap, T. A.; Lopez, A.; Coronado, C.; Shaw, H.; Florez,
A.; de las Heras, B.; Corte´s-Funes, H.; de Bono, J.; Paz-Ares, L. J. Clin.
Oncol., ASCO Meeting Abstr. 2007, 25, 2517.
(7) Lane, J. W.; Chen, Y.; Williams, R. M. J. Am. Chem. Soc. 2005,
127, 12684–12690.
(8) (a) Myers, A. G.; Kung, D. W.; Zhong, B.; Movassaghi, M.; Kwon,
S. J. Am. Chem. Soc. 1999, 121, 8401–8402. (b) Myers, A. G.; Kung, D. W.
J. Am. Chem. Soc. 1999, 121, 10828–10829. (c) Myers, A. G.; Kung, D. W.
Org. Lett. 2000, 2, 3019–3022. (d) Myers, A. G.; Lanman, B. A. J. Am.
Chem. Soc. 2002, 124, 12969–12971.
(9) See also: (a) Fukuyama, T.; Yang, L.; Ajeck, K. L.; Sachleben, R. A.
J. Am. Chem. Soc. 1990, 112, 3712–3713. (b) Saito, N.; Yamauchi, R.;
Nishioda, H.; Ida, S.; Kubo, A. J. Org. Chem. 1989, 54, 5391–5395. (c)
Shawe, T. T.; Liebeskind, L. S. Tetrahedron 1991, 47, 5643–5646.
(10) Wang, X. W.; Liu, W.; Dong, W. F.; Guan, B. H.; Chen, S. Z.;
Liu, Z. Z. Tetrahedron 2009, 65, 5709–5715.
(11) Magnus, P.; Matthews, K. S. J. Am. Chem. Soc. 2005, 127, 12476–
12477.
(12) Synthesis of renieramycin A: (a) Fukuyama, T.; Linton, S. D.; Tun,
M. M. Tetrahedron Lett. 1990, 31, 5989–5992. (b) Saito, N.; Yamauchi,
R.; Kubo, A. Heterocycles 1991, 32, 1203–1206.
Org. Lett., Vol. 11, No. 23, 2009
5559

transesterification with lithium tert-butoxide.13 Following a
conventional three-step sequence, aziridine 14 was converted
to (S)-N-Boc-2-(hydroxymethyl) aziridine (16) in 82% overall
yield, which was then oxidized (DMP, CH2Cl2, rt) to furnish
the (S)-2-formyl-aziridine (9) in 80% yield.
Brønsted acids (HCl, HOTf, HBF4, etc.) or Lewis acids
(lanthanide triflates). Fortuitously, when the reaction was
performed in acetonitrile in the presence of a catalytic amount
of diphenylphosphoric acid [(PhO)2P(O)OH, 0.1 equiv], the
desired tetrahydroisoquinoline 20 was isolated in 27%
yield.18 Further optimization based on this observation by
varying the solvents (MeCN, PhMe, CH2Cl2), the temperature
(0 °C to rt), and the additives (molecular sieves, Na2SO4,
other acidic components) allowed us to identify the optimum
reaction conditions (cf. Supporting Information). Thus, slow
addition of a CH2Cl2 solution of 9 (1.2 equiv) to the mixture
of 8 (1.0 equiv), acetic acid (AcOH, 1.0 equiv), (PhO)2P(O)-
OH (0.1 equiv), and Na2SO4 in CH2Cl2 at room temperature
afforded 20 in 72% yield. It is interesting to note that using
acetic acid as a promoter in the absence of (PhO)2P(O)OH
under otherwise identical conditions 20 was produced in less
than 5% yield. Concurrent N- and O-benzylation of 20
furnished compound 21 in 81% yield.19 Copper bromide-
mediated coupling between Grignard reagent 22, generated
in situ from the corresponding aryl bromide, and aziridine
21 proceeded smoothly to afford compound 23 in 83% yield.
The N- and O-debenzylation and in situ N-methylation of
23 were realized under hydrogenolysis conditions [Pd(OH)2,
H2, HCHO, MeOH] to provide compound 24 in 82% yield.
The tandem N-Boc deprotection and Pictet-Spengler reac-
tion of 20 with benzyloxyacetaldehyde (25, CH2Cl2, TFA)
afforded bistetrahydroisoquinoline 26 in 64% yield.
Synthesis of bistetrahydroisoquinoline 26 is depicted in
Scheme 3. The commercially available 2,6-dimethoxytoluene
Scheme 3. Synthesis of Bistetrahydroisoquinoline 26
Syntheses of title natural products are detailed in Schemes
4 and 5. Conversion of tert-butyl ester in 26 to aldehyde
(LAH, then Swern oxidation) followed by the Strecker
reaction afforded pentacycle 27 (Scheme 3). The O-deben-
zylation of 27 was best realized in the presence of BCl3 to
afford alcohol 28 in 93% yield. Oxidation of phenol 28 with
DDQ afforded jorunnamycin A (29).20
Acylation of alcohol 29 with angelic acid under modified
Yamaguchi conditions21 provided (-)-renieramycin M (1).20
Similarly, acylation of alcohol 29 with acetic anhydride
afforded cyanojorumycin (30) that, upon treatment with silver
nitrate, was converted to (-)-jorumycin (3).20 On the other
hand, hydrolysis of the tert-butyl ester of 26 followed by
amide bond formation under carefully controlled conditions
(HATU, HOAt, DIPEA) afforded pentacycle 31 in 90% yield
(Scheme 4). Hydrogenolysis of 31 in the presence of
Pearlman’s catalyst afforded alcohol 32, which was converted
(17) was converted to aryl bromide 18 in four conventional
steps with 84% overall yield. Arylmagnesium formation from
18 under Knochel’s conditions14 followed by a copper
bromide-promoted coupling with aziridine 1115 afforded
aminoester 19 in 80% yield. Simultaneous O- and N-
deprotection of 19 under acidic conditions provided ami-
noester 8.16 The Pictet-Spengler reaction of 8 and 9 turned
out to be challenging. No reaction occurred under mild acidic
conditions (LiCl-HFIP, 2,6-di-tert-butyl-4-methyl phenol),17
while degradation was observed in the presence of stronger
(18) Chiral phosphoric-acid-catalyzed enantioselective Pictet-Spengler
reactions of tryptamine derivatives and aldehydes, see: (a) Seayad, J.;
Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086–1087. (b)
Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van Maarseveen,
J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485–7487.
(19) The 1,3-cis stereochemistry of 17 was determined based on the
observed NOE correlation between H1 and H3. See Suppoting informa-
tion.
(13) Shtrumfs, B.; Chernyak, D.; Kalvins, I.; Trapencieris, P. Chem.
Heterocycl. Compd. 2004, 40, 725–733.
(14) Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.; Gavryushin,
A.; Knochel, P. Chem.sEur. J. 2009, 15, 7192–7202.
(15) (a) Baldwin, J. E.; Farthing, C. N.; Russell, A. T.; Schofield, C. J.;
Spivey, A. C. Tetrahedron Lett. 1996, 37, 3761–3764. (b) Endo, A.; Kann,
T.; Fukuyama, T. Synlett 1999, 1103–1105. (c) Aziridines and Epoxides in
Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006.
(16) For an alternative synthesis, see :Wu, Y.-C.; Bernadat, G.; Masson,
G.; Couturier, C.; Schlama, T.; Zhu, J. J. Org. Chem. 2009, 74, 2046–
2052.
(20) The physical, spectroscopic, and spectrometric data of synthetic
materials are identical to those described for natural (-)-jorunnamycin A,
(-)-renieramycin M, (-)-jorumycin, and (-)-renieramycin G. See: (a)
Charupant, K.; Suwanborirux, K.; Amnuoypol, S.; Saito, E.; Kubo, A.; Saito,
N. Chem. Pharm. Bull. 2007, 55, 81–86. (b) Fontana, A.; Cavaliere, P.;
Wahidulla, S.; Naik, C. G.; Cimino, G. Tetrahedron 2000, 56, 7305–7308.
(c) Davidson, B. S. Tetrahedron Lett. 1992, 33, 3721–3724, and refs 1
and4a-c.
(17) (a) Chen, X. C.; Chen, J.-C.; De Paolis, M.; Zhu, J. J. Org. Chem.
2005, 70, 4397–4408. (b) Willot, M.; Chen, J.-C.; Zhu, J. Synlett 2009,
577–580.
(21) Hartmann, B.; Kanazawa, A. M.; Depres, J.-P.; Greene, A. E.
Tetrahedron Lett. 1991, 32, 5077–5080.
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Org. Lett., Vol. 11, No. 23, 2009

Scheme 4
.
Syntheses of (-)-Renieramycin M and
(-)-Jorumycin
Scheme 5. Synthesis of (-)-Renieramycin G
in the bond forming processes for the effective construction
of 27 and 31 (Figure 2). All transformations were highly
Figure 2. Full exploitation of the serine-derived aziridines.
to (-)-renieramycin G (2)20 by selective acylation of the
primary alcohol with angelic acid followed by DDQ oxida-
tion.
diastereoselective, and no epimerization and stereochemical
correction were required in these syntheses. We are currently
exploiting this strategy for the syntheses of other members
of bistetrahydroisoquinoline alkaloids as well as analogues
for detailed structural-activity relationship studies.
In conclusion, we described efficient syntheses of four
natural products: renieramycin M (17 steps in the longest
linear sequence from 2,6-dimethoxytoluene with 3.9% overall
yield), renieramycin G (16 steps with 6.4% overall yield),
jorumycin (18 steps with 5.8% overall yield), and jorunna-
mycin A (16 steps with 10.9% overall yield) using highly
functionalized bistetrahydroisoqinoline 26 as a common
intermediate. The key feature of the present syntheses is the
use of (S)-serine-derived aziridines 9 and 11 as lynchpins to
connect the left and right part of the molecules. It is
interesting to note that three out of four C and N atoms of
aziridines 9 and 11, except for the chiral carbon, participated
Acknowledgment. Financial support from CNRS and
ICSN is gratefully acknowledged.
Supporting Information Available: Experimental details
and compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL9024919
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