Synthesis of the tetracyclic ABCD ring systems of madangamines D-F

Article abstract of DOI:10.1021/ol503586d

Synthesis of the tetracyclic cores of madangamines D-F was achieved, featuring a reductive radical process from an ethoxycarbonyldichloroacetamide to build the morphan nucleus, a Mitsunobu-type aminocyclization toward the common diazatricyclic intermediate, and ring-closing metathesis reactions for the macrocyclization step leading to the 13- to 15-membered rings.

Full text of DOI:10.1021/ol503586d

Letter
pubs.acs.org/OrgLett
Synthesis of the Tetracyclic ABCD Ring Systems of Madangamines
D−F
Faïza Diaba,*,† Climent Pujol-Grau,† Agustín Martínez-Laporta,† Israel Fernandez,‡ and Josep Bonjoch*,†
́
†Laboratori de Química Organ
‡Departamento de Química Organ
̀
̀
ica, Facultat de Farmacia, IBUB, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
́
ica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, Spain
S
* Supporting Information
ABSTRACT: Synthesis of the tetracyclic cores of madang-
amines D−F was achieved, featuring a reductive radical process
from an ethoxycarbonyldichloroacetamide to build the
morphan nucleus, a Mitsunobu-type aminocyclization toward
the common diazatricyclic intermediate, and ring-closing
metathesis reactions for the macrocyclization step leading to
the 13- to 15-membered rings.
adangamines are a group of 3-alkylpiperidine marine
Scheme 1. Retrosynthetic Strategy for Synthesis of the
Tetracyclic ABCD Rings of Madangamines
M
alkaloids embodying a pentacyclic skeleton.1 The six
madangamines isolated so far have in common a perhydro-6,4-
(iminomethano)isoquinoline core (ABC ring)2−4 and a western
macrocycle of 13 to 15 members. Madangamines A−E contain
an eastern polyunsaturated ring and madangamine F shows a
greater oxidation state in rings B and E (Figure 1). Their
Figure 1. Madangamines D−F embodying a macrocyclic saturated D-
metathesis (RCM)9 macrocyclizations of dienes 4 were required
in the range of 13- to 15-membered rings. The polyfunctional-
ized morphan10 6 was envisaged as an early stage intermediate
from which an allyl group would be selectively introduced at C9.
The nitrile at C5 and the ester at C9 stemming from the morphan
cyclization would undergo reduction for the synthesis of a useful
amino alcohol to promote the ring closure leading to 5. Morphan
6 would be accessed by the reductive radical cyclization of
alkoxycarbonyldichloroacetamide 7, thereby expanding the
scope of haloacetamides able to generate radical species for the
building of nitrogen-containing rings, either in reductive11 or
atom-transfer radical cyclizations.12 The usefulness of radical
synthetic methods for constructing valuable intermediates in
membered ring.
biological activities, coupled with a highly complex structure,
have made these alkaloids attractive synthetic targets. However,
only one member of this family, madangamine D, has been
achieved by total synthesis, in recent work by Amat and Bosch.5
Four other approaches have been developed to access the
madangamine ABC diazatricyclic core using either hydro-
isoquinolines6 or 2-azabicyclo[3.3.1]nonanes (morphans) as
intermediate platforms.7,8
Herein, we report a synthetic approach to the tetracyclic cores
of madangamines D−F from a common precursor. As depicted
in Scheme 1, the synthetic strategy we pursued toward our goal,
macrocycles 1−3, leads back, via the dienes 4, to diazatricyclic
compound 5, which served as a strategic point of divergence en
route to these targeted compounds. Overall, ring-closing
Received: December 12, 2014
© XXXX American Chemical Society
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DOI: 10.1021/ol503586d
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Letter
target-oriented natural product synthesis would thus be
enhanced.13,14
The synthesis began with the 4-(benzylamino)cyclohex-1-
encarbonitrile (8), which was available in six steps from the
monoethylene acetal of 1,4-cyclohexanedione using a protocol
without any chromatographic purification.15 This secondary
amine was acylated with 2,2-dichloro-2-ethoxycarbonylacetyl
chloride,16 and the resulting dichloroamido ester 7 was treated
with Bu3SnH to induce a reductive radical cyclization17 leading to
the bridged morphan nucleus 6 in 77% yield (Scheme 2).
Scheme 2. Radical vs Ionic Cyclization toward the Morphan
Ring
Figure 3. Computed reaction profile (uB3LYP/6-31+G(d) level) for
the radical processes from amide rotamers: (a) radical cyclization via
TS1; (b) 1,4-hydrogen translocation via TS2. Relative free energies
(ΔG298, at 298 K) are given in kcal/mol.
Notably, attempts to obtain 6 by an ionic intramolecular Michael
reaction from amido ester 9, also available from 8, gave poor
results, not only because of the overall yield but also, and even
more importantly, due to the low stereocontrol. The lack of
diastereoselectivity (6 was isolated as a 4:1 epimeric mixture at
C5, using NaH as the base) seems inherent to the process, since it
is known that the equatorial protonation of exocyclic α-cyano
cyclohexyl anions can occur, leaving an axial cyano substituent.18
Some interesting results were observed in the radical
cyclization: (i) the formation of 6 was diastereoselective, the
stereochemistry at C5 and C9 in morphan 6 being well-defined,
since the cyano group at C5 was equatorially located by a kinetic
axial delivering of the hydrogen from theBu3SnH and the ester
group at C9 has an axial disposition (Figure 2), and (ii) a
undergo radical cyclization, which underwent a 1,4-H radical
translocation20 in a more energetically demanding process (ΔG⧧
= 15.4 kcal/mol, via TS2) followed by a radical cyclization to the
normorphan nucleus (a complete profile of the process based on
density functional theory calculations is included in the
Supporting Information). Therefore, it can be concluded that
the favored formation of the morphan-cyclized compound takes
place mainly under kinetic control.21
The next step from morphan 6, involving the generation of the
quaternary stereogenic center, was the chemoselective allylation
upon the methine at C9, which took place from the top face
under a sterically controlled kinetic reaction to give exclusively
1122 (Scheme 3). The configuration in the stereogenic
quaternary center in 11 was established unequivocally from a
NOESY NMR spectrum in which a methylene proton of the side
chain at δ 2.65 give a cross-peak with the H-11 (pro-S) at δ 2.20.
In the following step, the reduction of the carbonyl lactam, nitrile,
and ester groups was carried out in only one operation by
treatment of 11 with alane, generated in situ from LiAlH4 and
AlCl3. The process gave the diamino alcohol 12 in high yield. For
the ring closure of the piperidine A ring, a Fukuyama protocol
was used involving an initial nosylation and further intra-
molecular alkylation through a Mitsunobu process. Removal of
the nosyl group rendered the secondary amine 5, which
constitutes the common advanced synthetic intermediate en
route to the three diazatetracyclic targets.
Figure 2. Fully optimized geometries (B3LYP/6-31+G(d) level) and
relative energies of morphans 6 and 6-epi (methyl esters).
Amide bond formation between secondary amine 5 and 10-
undecenoic acid chloride afforded the RCM precursor 4a in 83%
yield. The RCM of 4a was undertaken using Grubbs second-
generation catalyst in CH2Cl2 (3.3 mM) to give the cyclized
product 15a in 66% yield. Finally, adjustment of the oxidation
level by hydrogenation with a concomitant N-debenzylation gave
16a, which by reduction with LiAlH4 finally rendered the target
1. The overall yield for the synthesis of the tetracyclic ring of
madangamine F, 1, was 6.2% over 17 steps.
normorphan compound 10 was also isolated as a minor
byproduct.19 The α-amidoyl radical derived from 7 presents
two reactive conformations, namely the Z rotamer INT3 and E
rotamer INT1, the latter being required for the cyclization step
(Figure 3). Although INT3 is 5.6 kcal/mol more stable than
INT1, 6 was formed from rotamer INT1 via transition state TS1
(ΔG⧧ = 10.9 kcal/mol, from INT3). In contrast, normorphan 10
arose from the most stable radical rotamer INT3, unable to
Having achieved the first target, we pursued synthetic access to
the 14- and 13-macrocyclic ring analogues following the same
B
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Scheme 3. Synthesis of the Tetracyclic Core of Madangamine F
protocol, i.e., using the secondary amine 5 as a common
intermediate. Thus, treatment of 5 with 9-decenoic and 8-
nonenoic acid chlorides led to the amides 4b and 4c, respectively,
in good yields. RCM from 4b took place under the same reaction
conditions as used from 4a (Scheme 4). As expected, the
compounds 16b and 16c, respectively, which after reduction of
the lactam moiety rendered 2 (37% over two steps) and 3 (53%
over two steps).
In summary, a 17-step approach for the construction of the
ABCD ring system of madangamines F, E, and D was successfully
developed. We have shown that radical chemistry is a powerful
tool for the stereoselective synthesis of the highly functionalized
AB ring system. The synthetic pathway gave access to the three
different ABCD fragments of madangamines from a common
intermediate. This chemistry will pave the way for the total
synthesis of madangamines.
Scheme 4. Synthesis of Tetracyclic ABCD Rings of
Madangamines D and E
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectroscopic and analytical data, and
copies of NMR spectra of new compounds. The computed
complete profile of the radical process leading to 6 and 10 and
Cartesian coordinates and energies for all the species considered.
This material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: faiza.diaba@ub.edu.
*E-mail: josep.bonjoch@ub.edu.
Notes
formation of the 13-membered ring was more difficult as a
consequence of the higher strain imposed by the double bond in
this particular macrocycle.23 Indeed, the cyclization did not
proceed when 4c in CH2Cl2 was used as a solvent, but when
toluene at 80 °C was used with 1,4-benzoquinone as an
additive,24 macrocycle 15c was isolated in 43% yield. Hydro-
genation of 15b and 15c allowed us to isolate the tetracyclic
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support of this research was provided by the Spanish MINECO
and FEDER (Project Nos. CTQ2013-41338-P and CTQ2013-
44303-P).
C
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7922−7926. See also: Klein, J. Tetrahedron 1974, 30, 3349−3353. Hoz,
S.; Azran, C.; Sella, A. J. Am. Chem. Soc. 1996, 118, 5456−5461.
(19) The reductive cyclization of the analogous trichloroacetamide of 7
(Cl atom instead of CO2Et) exclusively gave the cyclized morphan in
84% yield, with no traces of a normorphan compound being detected.
(20) For a review of 1,n-hydrogen atom transfer reactions, see: Nechab,
M.; Mondal, S.; Bertrand, M. P. Chem.Eur. J. 2014, 20, 16034−16059.
(21) The product distribution (6/10) is controlled by the difference
between the total free energy of activation for each pathway (Curtin−
Hammett principle) and is not dictated by the rotamer ratio in the
starting material 7 (Z/E = 1:4, see ref 17).
REFERENCES
■
(1) (a) Andersen, R. J.; van Soest, R. W. M.; Kong, F. Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon-
Elsevier: Oxford, 1996; Vol. 10, pp 301−355. (b) Berlinck, R. G. S.
Polycyclic Diamine Alkaloids from Marine Sponges. Topics in
Heterocyclic Chemistry; Springer: Berlin, 2007; vol. 10, pp 211−238.
(2) Madandamine, A.; Kong, F.; Andersen, R. J.; Allen, T. M. J. Am.
Chem. Soc. 1994, 116, 6007−6008.
(3) Madangamines, B.-E.; Kong, F.; Graziani, E. I.; Andersen, R. J. J.
Nat. Prod. 1998, 61, 267−271.
(4) Madangamine, F.; Oliveira, J. H. H. L.; Nascimento, A. M.;
Kossuga, M. H.; Cavalcanti, B. C.; Pessoa, C. O.; Moraes, M. O.;
Macedo, M. L.; Ferreira, A. G.; Hajdu, E.; Pinheiro, U. S.; Berlinck, R. G.
S. J. Nat. Prod. 2007, 70, 538−543.
(22) Using a reverse addition, a minor amount of the epimer at C9 was
also isolated (see the Supporting Information).
(23) As an estimation of the ring strain, we have computed the
hydrogenation heats of macrocycles 15. As shown below, the
hydrogenation of 15c is the most exothermic process, which correlates
with the higher ring strain imposed by the double bond in the thirteen-
membered ring (energy values are given in kcal/mol).
(5) (a) Ballette, R.; Per
Chem., Int. Ed. 2014, 53, 6202−6205. (b) For a preliminary ABCD ring
approach, see: Amat, M.; Ballette, R.; Proto, S.; Perez, M.; Bosch, J.
Chem. Commun. 2013, 49, 3149−3151.
́
ez, M.; Proto, S.; Amat, M.; Bosch, J. Angew.
́
(6) For approaches to the ABC tricyclic fragment of madangamines
from hydroisoquinolines (BC rings), see: (a) Matzanke, N.; Gregg, R. J.;
Weinreb, S. M.; Parvez, M. J. Org. Chem. 1997, 62, 1920−1921.
(b) Quirante, J.; Paloma, L.; Diaba, F.; Vila, X.; Bonjoch, J. J. Org. Chem.
́
2008, 73, 768−771. (c) Amat, M.; Perez, M.; Proto, S.; Gatti, T.; Bosch,
J. Chem.Eur. J. 2010, 16, 9438−9441.
(7) For approaches from 2-azabicyclo[3.3.1]nonanes (AB rings), see:
(a) Yamazaki, N.; Kusanagi, T.; Kibayashi, C. Tetrahedron Lett. 2004, 45,
́ ́
6509−6512. (b) Tong, H. M.; Martin, M.-T.; Chiaroni, A.; Benechie,
M.; Marazano, C. Org. Lett. 2005, 7, 2437−2440.
(8) For the synthesis of the ACE rings, see: (a) Yoshimura, Y.; Inoue, J.;
Yamazaki, N.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 2006, 47,
(24) 1,4-Benzoquinone acts as scavenger of ruthenium hydride species
that might be formed during the reaction and cause decomposition:
(a) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2005, 127, 17160−17161. (b) Toya, H.; Satoh, T.; Okano, K.;
Takasu, K.; Ihara, M.; Takahashi, A.; Tanaka, H.; Tokuyama, H.
Tetrahedron 2014, 70, 8129−8141.
3489−3492. (b) Proto, S.; Amat, M.; Per
́
ez, M.; Ballette, R.; Romagnoli,
F.; Mancinelli, A.; Bosch, J. Org. Lett. 2012, 14, 3916−3919.
A
preliminary work on madangamine alkaloids field has been presented:
(c) Dixon, D. J. Abstracts of Papers, 244th ACS National Meeting,
Philadelphia, 2012; American Chemical Society: Washington, DC,
2012; ORG-105.
́
(9) (a) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45,
6086−6101. (b) Wang, C.; Yu, M.; Hoveyda, A. H.; Kyle, A. F.; Jakubec,
P.; Dixon, D. J.; Schrock, R. R. Chem.Eur. J. 2013, 19, 2726−2740 and
references cited therein.
(10) For a review of 2-azabicyclo[3.3.1]nonanes and their application
to natural product synthesis, see: Bonjoch, J.; Diaba, F.; Bradshaw, B.
Synthesis 2011, 993−1018.
(11) (a) Quirante, J.; Escolano, C.; Merino, A.; Bonjoch, J. J. Org.
Chem. 1998, 63, 968−976. (b) Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-
B.; Zard, S. Z. Tetrahedron Lett. 1998, 39, 8995−8998. (c) Cassayre, J.;
Zard, S. Z. Synlett 1999, 501−503.
(12) (a) Hirai, Y.; Hagiwara, A.; Terada, T.; Yamazaki, T. Chem. Lett.
1987, 2417−2418. (b) Seijas, J. A.; Vaz
́
quez-Tato, M. P.; Castedo, L.;
Estevez, R. J.; Onega, M. G.; Ruiz, M. Tetrahedron 1992, 48, 1637−1642.
́
(c) Li, Q.; Li, G.; Ma, S.; Feng, P.; Shi, Y. Org. Lett. 2013, 15, 2601−
2603. (d) Diaba, F.; Martínez-Laporta, A.; Bonjoch, J. J. Org. Chem.
2014, 79, 9365−9372.
(13) For a classical review, see: Jasperse, C. P.; Curran, D. P.; Flevig, T.
L. Chem. Rev. 1991, 91, 1237−1286.
(14) (a) Quiclet-Sire, B.; Zard, S. Z. Beilstein J. Org. Chem. 2013, 9,
557−576. (b) Bonjoch, J.; Bradshaw, B.; Diaba, F. In Stereoselective
Synthesis of Drugs and Natural Products; Andrushko, V., Andrushko, N.,
Eds.; Wiley-VCH: New York, 2013; pp 733−768.
(15) Compound 8 was prepared in a six-step sequence on a 3-g scale
without any intermediate purification step (86% overall yield).
(16) Castelfranchi, G.; Perrotti, E. Ann. Chim. (Rome) 1957, 47, 1201−
1224.
(17) Treatment of dichloro ester 7 under atom-transfer radical
cyclization conditions gave a mixture of compounds: Diaba, F.;
Martínez-Laporta, A.; Bonjoch, J. Eur. J. Org. Chem. 2014, 2371−2378.
(18) For protonation of cyclohexyl anions, see: Luning, U.;
̈
Baumgartner, H.; Manthey, C.; Meynhardt, B. J. Org. Chem. 1996, 61,
D
DOI: 10.1021/ol503586d
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