ORGANIC
LETTERS
2
007
Vol. 9, No. 7
359-1362
Synthesis of the Oxygenated
Pactamycin Core
1
Spencer Knapp* and Younong Yu
Department of Chemistry & Chemical Biology, RutgerssThe State UniVersity of
New Jersey, 610 Taylor Road, Piscataway, New Jersey 08854
Received January 31, 2007
ABSTRACT
Pactamycin, one of the most complex and densely functionalized aminocyclitol antibiotics known, presents synthetic challenges that include
reactivity and sterics, relative and absolute stereochemistry, and functional group compatibility and protection. An approach is reported that
features four different types of (cyclopentane) face selective functionalization reactions and results in a polyfunctionalized and appropriately
protected intermediate that incorporates all the core carbons and the oxygenated functionality of the target.
Pactamycin (1), isolated from a fermentation broth of
Streptomyces pactum var pactum,1 exhibits potent broad-
range cytotoxicity both in vitro and in vivo. It interacts with
the smaller ribosomal subunit4 and functions as a potent
Functionalization of cyclohexenes and cyclohexanones can
often be carried out by relying on preferential pseudoaxial
approach of electrophiles and nucleophiles. Cyclopentenes
and cyclopentanones, however, enjoy no such general
conformational preferences, and so other stereoselective
methods for reliably introducing or modifying functionality
must be employed. These could include such tactics as the
use of a bulky reagent that approaches from the less-hindered
cyclopentane face, use of a chiral reagent with inherent
enantioface selectivity, use of a coordinating or hydrogen-
-3
,5
6
and universal inhibitor of translocation. The unique struc-
7
8
ture, elucidated crystallographically in 1972, features a nine-
carbon core bearing seven vicinally related functionalities
(three amino and four hydroxyl), three of which are modified
by further N/O substitution, and six stereogenic carbons (all
five of the cyclopentane and one off ring). The total synthesis
of 1, arguably among the most complex aminocyclitol
assemblages known, can be taken as a challenge to existing
and new methods of cyclopentane ring functionalization and
amino/hydroxyl protection and manipulation.9-12
13
bonding syn-directing group, and use of a tethered nucleo-
1
4
phile. We present an approach to the synthesis of 1 that
includes stereoselective reactions belonging to each of these
(8) Duchamp, D. J. Abstracts, American Crystallographic Association
Winter Meeting, Albuquerque, NM, 1972; p 23.
(
1) Bhuyan, B. K.; Dietz, A.; Smith, C. G. Antimicrob. Agents Chemother.
962, 184-190.
2) Argoudelis, A. D.; Jahnke, H. K.; Fox, J. A. Antimicrob. Agents
Chemother. 1962, 191-197.
3) Brodasky, T. F.; Lummis, W. L. Antimicrob. Agents Chemother. 1962,
(9) Vicinal amino alcohol review: Bergmeier, S. C. Tetrahedron 2000,
56, 2561-2576.
(10) Aminocyclopentitol review: Bericibar, A.; Grandjean, C.; Siriwar-
dena, A. Chem. ReV. 1999, 99, 779-844.
(11) An earlier synthetic approach to pactamycin: Tsujimoto, T.;
Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005, 433-436.
(12) Ganem, B. In Carbohydrate Mimics; Chapleur, Y., Ed.; Wiley-
VCH: New York, 1998; pp 239-258.
(13) Substrate-directed reactions: Hoveyda, A. H.; Evans, D. A.; Fu,
G. C. Chem. ReV. 1993, 93, 1307-1370. Donohoe, T. J.; Blades, K.; Moore,
P. R.; Waring, M. J.; Winter, J. J. G.; Helliwell, M.; Newcombe, N. J.;
Stemp, G. J. Org. Chem. 2002, 67, 7946-7956.
(14) Tethered nitrogen delivery: Knapp, S. Chem. Soc. ReV. 1999, 28,
61-72.
1
(
(
1
98-204.
(
327-1335.
4) Cohen, L. B.; Goldberg, I. H.; Herner, A. E. Biochemistry 1969, 8,
1
(5) Brodersen, D. E.; Clemons, W. M., Jr.; Carter, A. P.; Morgan-Warren,
R. J.; Wimberly, B. T.; Ramakrishnan, V. Cell 2000, 103, 1143-1154.
6) Dinos, G.; Wilson, D. N.; Teraoka, Y.; Szaflarska, W.; Fucini, P.;
Kalpaxis, D.; Niewhaus, K. H. Mol. Cell 2004, 13, 113-124.
7) Wiley, P. F.; Jahnke, H. K.; MacKellar, F.; Kelly, R. B.; Argoudelis,
A. D. J. Org. Chem. 1970, 35, 1420-1425.
(
(
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0.1021/ol0702472 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/06/2007