An efficient synthetic approach to cyanocycline A and bioxalomycin β2 via [C+NC+CC] coupling

Article abstract of DOI:10.1021/ja077853c

The Ag^I catalyzed [C+NC+CC] coupling reaction of a 2,3-bisaminoaldehyde 5, l-glycyl sultam 6, and methyl acrylate provides highly functionalized pyrrolidine 7, the key intermediate in an efficient synthetic approach to the cyanocycline and biox

Full text of DOI:10.1021/ja077853c

Published on Web 11/23/2007
An Efficient Synthetic Approach to Cyanocycline A and Bioxalomycin â2 via
[C+NC+CC] Coupling
H. U¨ mit Kaniskan and Philip Garner*,†
Department of Chemistry, Case Western ReserVe UniVersity, CleVeland, Ohio 44106-7078
Received October 12, 2007; E-mail: ppg@wsu.edu
Scheme 1. Key Elements of the Synthetic Strategy
The exploitation of natural products for the treatment of disease
is often limited by availability, placing the onus on the synthetic
chemist to devise efficient and flexible approaches to specific target
families. Our group recently disclosed a set of stereocomplementary
metal-catalyzed multicomponent reactions for the synthesis of
highly functionalized pyrrolidines, which we termed [C+NC+CC]
coupling reactions.1 Herein, we illustrate how this powerful reaction
technology simplifies the synthesis of both the cyanocyclines2 and
bioxalomycins3 (Scheme 1). We are interested in developing
efficient syntheses of these natural products and structurally related
analogues because of their potential as “privileged” small molecule
scaffolds for protein interrogation and drug development.4 Previous
efforts5 include two asymmetric syntheses of cyanocycline A from
the laboratories of Evans (35 linear steps)5c and Fukuyama (32 linear
steps).5d The [C+NC+CC] reaction provides rapid access to a key
pyrrolidine intermediate (structure IV) that is converted to the target
using established chemistry, reducing the total number of steps by
one-third.
Scheme 2. Synthesis of Aldehyde 5
In our approach to the these natural products, the first order of
business involved construction of a suitably functionalized 2,3-
diamino aldehyde corresponding to I that incorporates an aromatic
precursor of the targets’ quinoid A-ring. Synthesis of the aldehyde
5 (Scheme 2) begins with a stereoselective reaction of Grignard
reagent 16 and the serinal-derived nitrone 2 to give the syn disposed
hydroxylamine 3, exclusively. The stereochemical outcome of this
addition reaction was anticipated on the basis of the precedent
provided by Merino and co-workers.7 Reduction of the hydroxyl-
amine functionality with zinc followed by N-protection with CbzCl
produced the differentially protected diamine 4. Mildly acidic
methanolysis of the oxazolidine ring released the primary alcohol,
which was oxidized by the Dess-Martin reagent to give the
required aldehyde 5 ()I) in 42% overall yield from 2.
Scheme 3. Key [C+NC+CC] Coupling Reaction
The key [C+NC+CC] coupling reaction (Scheme 3) was effected
L
by combining aldehyde 5 and L-glycylsultam 6 (X ) Oppolzer’s
L-camphorsultam)8 in methyl acrylate (solvent) with 10 mol %
AgOAc at room temperature. This reaction produced the desired
pyrrolidine 7 in 74% yield. Because of the hindered urethane
functionality present in this molecule, the relative configurations
of the newly created pyrrolidine stereocenters could not be deter-
mined using standard NMR techniques. However, the endo-si
product was expected on the basis of our earlier [3+2] cycloaddition
studies and the proposed pre-TS model (shown in inset). This
stereochemical assignment was supported by a subsequent NOE
study on a more rigid synthetic intermediate (compound 12) and
confirmed by the successful conclusion of the synthesis. Compound
7 represents the most ambitious application of our asymmetric
[C+NC+CC] coupling technology to date and essentially solves
the cyanocycline/bioxalomycin synthesis problem.
The synthetic end game (Scheme 4) begins with Pd-catalyzed
hydrogenolysis of 7 to give a phenolic lactam. This multistep
operation effected concomitant removal of the benzyl ether and
Cbz groups, followed by δ-lactam formation. At this point, Cbz
protection of the pyrrolidine amine and removal of the Boc group
led to the phenolic amine 8, which was subjected to a Pictet-
Spengler reaction with benzyloxyacetaldehyde to produce the
tetrahydroisoquinoline 9 in 75% overall yield. The (9R) stereo-
chemistry was tentatively assigned on the basis of Fukuyama’s
precedent and confirmed later by correlation with cyanocycline A.
† Current address: Department of Chemistry, Washington State University,
Pullman, WA 99164-4630.
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J. AM. CHEM. SOC. 2007, 129, 15460-15461
10.1021/ja077853c CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. The Cyanocycline A/Bioxalomycin â2 Endgame
(2) Zaccardi, J.; Alluri, M.; Ashcroft, J.; Bernan, V.; Korshalla, J. D.; Morton,
G. O.; Siegel, M.; Tsao, R.; Williams, D. R.; Maiese, W.; Ellestad, G. A.
J. Org. Chem. 1994, 59, 4045. This paper established that the originally
proposed structure of naphthyridinomycin was likely the G-ring hydroly-
sate and that the natural product is, in fact, bioxalomycin â2.
(3) For, a comprehensive review of the chemistry and biology of the
saframycin, quinocarcin, and naphthyridinomycin families of tetrahy-
droisoquinoline antibiotics, see: Scott, J. D.; Williams, R. M. Chem. ReV.
2002, 102, 1669.
Reprotection of the free phenol gave 10, which was reduced with
LiAlH4 to give the primary alcohol 11 in 54% yield. This reaction
not only released the chiral auxiliary but also converted the urethane
moiety to the required N-methyl group.9 Swern oxidation and
aminonitrile formation afforded compound 12, which was amenable
to NOESY experiments to confirm its structure (Supporting
Information). The F-oxazolidine was introduced using methodology
developed by Pelletier that proceeds via stable imine 13.10 Finally,
14 was deprotected with BCl3 (hydrogenolysis was ineffective) to
give diol 15. This compound corresponded to an advanced
intermediate that Fukuyama had converted to cyanocycline A
(reference 5, parts b and d). Since cyanocycline A is convertable
to bioxalomycin â2 through the agency of AgI (references 5e and
2), attainment of 15 constitutes an efficient formal synthesis of this
natural product as well.
Our formal synthesis of cyanocycline A proceeded in 22 linear
steps from 2,6-dimethoxytoluene (19 steps from the commercially
available serinal precursor of 2). This represents the most efficient
synthetic approach yet to these complex natural products. The
successful application of our [C+NC+CC] coupling technology
to the cyanocycline/bioxalomycin problem augers well for the
synthesis of other members of this natural product family (dnacins,
for example) as well as structurally related unnatural products.
Improved access to this natural product family will enable their
biological and biochemical evaluation with an eye on discovering
previously unrecognized protein targets.11
(4) While the tetrahydroisoquinoline antibiotics were originally believed to
act as DNA-damaging, cytotoxins, there is increasing evidence that these
molecules also interact with therapeutically relevant proteins: (a) dnacin
inhibits dual specificity phosphatase cdc25B: Horiguchi, T.; Nishi, K.;
Hakoda, S.; Tanida, S.; Nagata, A.; Okayama, H. Biochem. Pharmacol.
1994, 48, 2139. (b) DX-52-1 inhibits radixin: Kahsai, A. W.; Zhu, S.;
Wardrop, D. J.; Lane, W. S.; Fenteany, G. Chem. Biol. 2006, 13, 973. (c)
ET-743 inhibits DNA repair proteins: D’Incalci, M.; Erba, E.; Damia,
G.; Gallera, E.; Carrassa, L.; Marchini, S.; Mantovani, R.; Tognon, G.;
Fruscio, R.; Jimeno, J.; Faircloth, G. T. The Oncologist 2002, 7, 210.
(5) Synthesis of rac-cyanocycline A: (a) Evans, D. A.; Illig, C. A.; Saddler,
J. C. J. Am. Chem. Soc. 1986, 108, 2478. (b) Fukuyama, T.; Li, L.; Laird,
A. A.; Frank, R. K. J. Am. Chem. Soc. 1987, 109, 1587. (c) Illig, C. R.
Ph.D. Dissertation, Harvard University, Cambridge, MA, 1987. (d) Li, L.
Ph.D. Dissertation, Rice University, Houston, TX, 1989. (e) Synthesis of
(+)-naphthyridinomycin: Fukuyama, T. AdV. Heterocycl. Chem. 1992,
2, 189. Other synthetic efforts: (f) Danishefsky, S.; O’Neill, B. T.;
Taniyama, E.; Vaughn, K. Tetrahedron Lett. 1984, 25, 4199. (g)
Danishefsky, S.; O’Neill, B. T.; Springer, J. T. Tetrahedron Lett. 1984,
25, 4203. (h) Garner, P.; Cox, P. B.; Anderson, J. T.; Protasiewicz, J.;
Zaniewski, R. J. Org. Chem. 1997, 62, 493. (i) Movassaghi, M. Ph.D.
Dissertation, Harvard University, Cambridge, MA, 2001. (j) Herberich,
B.; Kinugawa, M.; Vazquez, A.; Williams, R. M. Tetrahedron Lett. 2001,
42, 543. (k) Mori, K.; Rikimaru, K.; Kan, T.; Fukuyama, T. Org. Lett.
2004, 6, 3095.
(6) The bromide corresponding to 1 was prepared by benzylation of the known
5-bromo-2,4-dimethoxy-3-methylphenol: Marques, M. M.; Pichlmair, M.
M. B.; Martin, H. J.; Mulzer, J. Synthesis 2002, 2766.
(7) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahedron:
Asymmetry 1998, 9, 629.
Acknowledgment. This research was supported by a grant from
the National Science Foundation (Grant CHE-0553313). Thanks
to Chris Parker and Yu Zhang for their technical assistance.
(8) This compound was conveniently prepared by acylation of Oppolzer’s
L-camphorsultam with bromoacetyl bromide followed by displacement
by azide and hydrogenolysis. See: Kaniskan, H. U¨ . Ph.D. Dissertation,
Case Western Reserve University, Cleveland, OH, 2007.
(9) (a) Pallavicini, M.; Moroni, B.; Bolchi, C.; Cilia, A.; Clementi, F.;
Fumagalli, L.; Gotti, C.; Meneghetti, F.; Riganti, L.; Vistoli, G.; Valoti,
E. Bioorg. Med. Chem. Lett. 2006, 16, 5610. (b) McManus, H. A.;
Fleming, M. J.; Lautens, M. Angew. Chem., Int. Ed. 2007, 46, 433.
(10) Pelletier, S. W.; Nowacki, J.; Mody, N. V. Synth. Commun. 1979, 9, 201.
(11) Compound 12 has been found to inhibit cell migration, like DX-52-1,
and has target overlap with DX-52-1 but has far greater selectivity for
one target over another: Fenteany, G. Personal communication. This
finding supports our hypothesis that this natural product familysnow
readily accessible using the strategy disclosed hereinswill be useful for
protein interrogation and drug development.
Supporting Information Available: Experimental details and
characterization data for compounds 2 through 15. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) AgI-catalyzed endo selective [C+NC+CC] coupling: Garner, P.;
Kaniskan, H. U¨ .; Hu, J.; Youngs, W. J.; Panzner, M. Org. Lett. 2006, 8,
3647. (b) CuI-catalyzed exo selective [C+NC+CC] coupling: Garner,
P.; Hu, J.; Parker, C. G.; Youngs, W. J.; Medvetz, D. Tetrahedron Lett.
2007, 48, 3867.
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