Stereoselective route to mitosanes via tricarbonyl η6 arene chromium complexes

Article abstract of DOI:10.1016/S0040-4039(99)02259-5

Stereoselective reduction followed by metalation of a η⁶ arene chromium tricarbonyl complex allows rapid access to substituted mitosanes, whose skeleton mimics the mitomycin family of antitumour agents. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02259-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1123–1126
Stereoselective route to mitosanes via tricarbonyl η6 arene
chromium complexes
Graham B. Jones,∗ Mustafa Guzel and Jude E. Mathews
Bioorganic and Medicinal Chemistry Laboratories, Department of Chemistry, Northeastern University,
360 Huntington Avenue, Boston, MA, 02115, USA
Received 29 October 1999; accepted 7 December 1999
Abstract
Stereoselective reduction followed by metalation of a η6 arene chromium tricarbonyl complex allows rapid
access to substituted mitosanes, whose skeleton mimics the mitomycin family of antitumour agents. © 2000
Elsevier Science Ltd. All rights reserved.
The mitomycin family of antitumour antibiotics have attracted considerable attention due to their
unique chemical structures and observed antiproliferative activity.1 Mitomycin C 1 (isolated from
Streptomyces caespitosus) is employed clinically for the treatment of a variety of solid tumors, and a
number of other closely related naturally occurring structures also display antitumoral activity, including
mitomycin K 2.2 A common feature of this interesting class is the pyrrolo[1,2-a]indole skeleton 3, and
numerous approaches for the synthesis and functionalization of this system have been explored.3 The
antiproliferative activity of the mitomycins stems from their ability to undergo covalent cross linking of
DNA, via generation of two reactive intermediates. This involves nucleophilic opening of the aziridine
ring and is then followed by side chain alkylation, which in the case of 1 results from expulsion of the
carbamate group, yielding an exomethylene iminium ion which undergoes alkylation. Both processes are
influenced by the quinone subunit, which functions as a bioreductive triggering mechanism, similar to
that found in the enediyne natural product, dynemicin A.4
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02259-5
tetl 16187

1124
Due to its strategic importance, an efficient means was thus sought to assemble and functionalize the
core unit of this important class of DNA interactive agent. Based on prior experience, we envisioned that
an appropriately functionalized η6 arene chromium carbonyl complex might serve as a versatile building
block for the construction of derivatives of 3, since they are known to undergo a range of reactions
with high levels of stereocontrol.5 Accordingly, tricyclic mitosene 5 was prepared from indole 4 via
the Katritzky metalation procedure,6 followed by intramolecular cyclization (Scheme 1).7 Reduction of
the pyrrolo vinyl group followed by direct complexation gave 6 in excellent yield. Alternatively, direct
complexation of 5 could also be effected in high yield. This complex allowed the influence of the metal
carbonyl group on the stereochemistry of allylic functionalization to be probed. Accordingly, metalation
followed by addition of methoxymethyl chloride resulted in exclusive formation of exo product 7, a
presumed consequence of the metal carbonyl group encumbering the approach of the electrophile from
the α face.8
Scheme 1. Preparation and reduction of η6 arene mitosene complexes
X-Ray determination of the tricarbonyl chromium complex of 5 was possible, and supported the ob-
served outcome of the allylic alkylation reaction.9 Furthermore, the overlay of the tricarbonyl chromium
tripod suggested that, under acidic conditions, stereoselective reduction of the indolyl C2–C3 bond may
be possible, since the associated counterion would be expected to reside anti to the metal carbonyl tripod,
encouraging endo hydride approach 10.

1125
Stereoselective reduction of the critical indolyl C2–C3 bond was thus investigated using a variety
of methods. Tandem reductions of either 7 or the tricarbonyl chromium complex of 5 gave intractable
mixtures of products; however, 6 proved an amenable substrate for study. The corresponding mitosanes
8/9 were formed in moderate to good yield and with a marked degree of stereocontrol in many cases.
As predicted by conformational analysis (10), the product of endo addition (9) predominates in most
cases (Table 1), a result consistent with the work of Pigge, who has reported a similar outcome
with substituted indoles and carbazoles.10 Optimal conditions involve sodium cyanoborohydride as
reductant and trifluoroacetic acid as proton source, with pronounced reduction in both chemical yield
and stereocontrol observed with alternate combinations. Though the origin of the endo addition product
is presumed to be a function of counterion bulk presented in iminium ion 10, no clear trend based on either
electronic or steric factors emerges, indicating the intriguing possibility of a cooperative mechanism for
hydride delivery which directly involves the metal carbonyl group.
Table 1
Stereoselective reduction of 6a
With a high yielding and stereoselective route to mitosanes developed, we wished to demonstrate the
capacity for functionalization of the skeleton (Scheme 2). Lithiation at the benzylic position, quenching
with the appropriate electrophile, followed by in situ decomplexation gave ready access to a variety
of building blocks 12 in good yield (Table 2). The exclusive anti geometry of the products was
confirmed by comparison with authentic material.11 Subsequent transformations on 12 (R_CH2OH)
lead to the formation of mitomycin K and C skeletons 13, 14.1,11 As a consequence of the planar
chirality inherent to arene chromium carbonyl complexes, the stereoselective route described could
potentially be used for enantioselective synthesis. In this regard, separation of 6 was effected using
chiral chromatography, providing access to either enantiomeric series as desired.12 The combination
of this powerful methodology, in tandem with directed metalation strategies (on e.g. 7 and 9), can now
be applied to the synthesis of mitomycin analogues, and will be reported in due course.13

1126
Scheme 2. Stereoselective functionalization of η6 arene complexed mitosene. (a) sBuLi, THF then E+; (b) hν/Et2O (>90%); (c)
PhOCOCl, NH3 (85%); (d) PhSO2Cl, lutidine (73%)
Table 2
Stereoselective functionalization of mitosanes
References
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8. Relative stereochemistry assigned. For comparison, a mixture of α/β isomers was prepared via decomplexation (hν/Et2O)
then recomplexation (CrCO6/nBu2O:THF). All new compounds gave satisfactory spectroscopic and analytical data.
9. We thank Professor William T. Pennington (Clemson University) for this determination.
10. Pigge, F. C.; Fang, S.; Rath, N. P. J. Organomet. Chem. 1998, 559, 131.
11. Dijksman, W. C.; Verboom, W.; Egberink, R. J. M.; Reinhoudt, D. N. J. Org. Chem. 1985, 50, 3791.
12. Daicel OD column, 10% IPA 90% hexanes eluent, 254 nM detection, 1.5 ml/min flow rate: ent 1 tR=20.4 min, ent 2 tR=46.8
min. [α]D: ent 1= +886° (c=0.1, CHCl3), ent 2= −813° (c=0.1, CHCl3).
13. Research supported by grants from the NIH [RO1GM57123] and PRF [33920AC-1].