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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2010 July 22.
Published in final edited form as:
Tetrahedron Lett. 2009 July 22; 50(29): 4265–4267.
doi:  10.1016/j.tetlet.2009.05.004
PMCID: PMC2702872

Synthetic Studies Towards the Mitomycins: Construction of the Tetracyclic Core via a Reductive Aminocyclization Reaction


The tetracyclic core of the mitomycin family of natural products has been formed in one step from an acyclic precursor via a reductive aminocyclization reaction. Additionally, the 8-membered benzazocine can be prepared without the need for prior activation of the aniline. Construction of a mitomycin K analogue lacking the C9a methoxy moiety is also reported herein.

The mitomycin family of natural products (Figure 1) have been of interest to the scientific community since their isolation over 50 years ago.1 Members of this family exhibit potent activity against a variety of cancer cell lines, and were found to be particularly active against solid tumors.2 The mode of action of these compounds arises from their ability to form interstrand DNA-DNA3 as well as DNA-protein4 covalent cross-links. Mitomycin C (Figure 1) has been widely used clinically for over 40 years, and is still routinely employed today.5

Figure 1
The mitomycin family of natural products.

These molecules present a significant synthetic challenge due to their densely functionalized nature, chemical lability as well as the difficulty in maintaining the vulnerable structural elements (i.e. aziridine, quinone, exo-methylene) as the synthesis unfolds. Despite the numerous reported synthetic efforts towards the mitomycins, only Kishi6, Fukuyama7, Danishefsky8, and Jimenez9 have been successful in completing total syntheses. It is important to note that all the syntheses mentioned above delivered racemic products and there exist no enantioselective total synthesis of any of the mitomycins reported to date.

Our research program has been focused on the development of an asymmetric total synthesis of the mitomycins which was a natural out-growth of our recently completed asymmetric total synthesis of (+)-FR90048210. These efforts are fueled in part by our interest in both the biosynthesis and mode of action of these compounds.11 Herein we report efficient formation of the tetracyclic core of the mitomycins via a reductive aminocyclization reaction.

Previously, we reported the synthesis of benzazocines with the mitomycin substitution on the aromatic ring via an intramolecular Mitsunobu cyclization reaction.12 We reported that prior activation of the aniline as the corresponding sulfonamide or carbamate was requisite for Mitsunobu cyclization to occur (Scheme 1). Through this method, benzazocines and benzazocanes containing all the key elements of the mitomycins were efficiently obtained. However, conversion of these benzazocanes to the natural products proved difficult.

Scheme 1
(a) (CH3)2NCON=NCON(CH3)2 (1.5 equiv), PBu3 (1.8 equiv), toluene, rt, 6 h; 85%.

As part of our continuing efforts to access this family of natural products, a new strategy was developed. This strategy employed the use of benzyl ethers as protecting groups on the arene ring, as well as installation of the exocyclic methylene prior to cyclization (Scheme 2). The synthesis commenced by coupling of nitro arene 113 and aziridine aldehyde 214, followed by oxidation of the resultant alcohol (obtained as a 2:1 mixture of diastereomers R : S) to ketone 3. Methylenation and removal of the PMB ether with DDQ proceeded in excellent yield over two steps to provide primary alcohol 4. Conversion of alcohol 4 to the corresponding mesylate and reduction of the ketone under Luche conditions gave secondary alcohol 5 in high yield as a single diastereomer. Reduction of the nitro group using zinc dust did not provide the expected aniline 6, but rather gave benzazocine 715 in near quantitative yield as the product of a reductive aminocyclization reaction. To the best of our knowledge, this is the first example of a cyclization reaction in this family of compounds that proceeds without the need for prior activation of the aniline.

Scheme 2
(a) 1 (2.0 equiv), 2 (1.0 equiv), ZnCl2 (1.5 equiv), NaHMDS (2.0 equiv), DMF, −45 °C, 2 h, 85%; (b) Dess-Martin (1.6 equiv), CH2Cl2, rt, 2h, 98%; (c) formalin (112 equiv), LiOH (0.4 equiv), THF/water (20:3), rt, 20 h, 99%; (d) DDQ (1.3 ...

Having found an efficient method for formation of benzazocine 7, we were interested in examining the utility and scope of this transformation. Specifically, we investigated the possibility of forming the tetracyclic core of the mitomycins in one step from an acyclic precursor via this newly discovered reductive aminocyclization reaction. Accordingly, ketone 3 was transformed to bis-mesylate 8 in four straightforward steps consisting of PMB ether removal, mesylation, reduction of the ketone, and a second mesylation (Scheme 3). Treatment of bis-mesylate 8 under identical nitro reduction conditions furnished tetracyclic indoline 9 in 53% yield. Attempted conversion of indoline 9 to the mitomycins is now in progress.

Scheme 3
(a) DDQ (1.3 equiv), CH2Cl2/water (95:5), rt, 2 h, 85%; (b) MsCl (1.5 equiv), Et3N (3.0 equiv), 0 °C, 30 min, 53%; (c) CeCl3·7H2O (5.0 equiv), NaBH4 (3.0 equiv), 0 °C, 30 min, 93%; (d) MsCl (1.5 equiv), Et3N (3.0 equiv), 0 °C, ...

With indoline 9 in hand, we decided to pursue the synthesis of mitomycin K using the same reaction, with prior installation of the C10 exocyclic olefin. Accordingly, mesylation of alcohol 5 under standard conditions provided the aminocyclization precursor bearing the exocyclic olefin (Scheme 4). Reductive aminocyclization conditions used previously did provide tetracycle 10 without any isomerization of the exocyclic olefin to the corresponding indole (mitosene) adduct.16 Treatment of tetracycle 10 under hydrogenation conditions gave quinone 11 in moderate yield. Quinone 11 comprises the core skeleton of mitomycin K, lacking only the C9a methoxy group. Installation of the requisite methoxy moiety may be accomplished by an allylic C-H activation strategy, and efforts in this vein are in progress.

Scheme 4
(a) MsCl (1.5 equiv), Et3N (3.0 equiv), 0 °C, 30 min, 53%; (b) Zn dust (5.0 equiv), NH4Cl (10.0 equiv), acetone/water (4:1), rt, 3 h, 55%; (c) 10 % Pd/C (120 wt. %), Et3N (6.0 equiv), EtOAc, H2, rt, 30 min, then O2, 50%.

In summary, benzazocines were synthesized in high yield by use of a reductive aminocyclization reaction without the need for prior activation of the aniline. The tetracyclic core of the mitomycins was also accomplished in a single step from an acyclic precursor using this methodology. This strategy was used in formation of the tetracyclic indoline compound 9, as well as the core structure of mitomycin K bearing an exocyclic olefin (i.e. 10).

Supplementary Material



This work was supported by National Institutes of Health (CA51875). D.A.G is grateful to Eli Lilly for a graduate fellowship. Mass spectra were obtained on instruments supported by the NIH Shared Instrumentation Grant GM49631. Mr. Donald Dick is acknowledged for mass spectrometric data.


Supporting Information. Complete experimental details and spectroscopic data for all new compounds.

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16. The general procedure for the reductive aminocyclization reaction is illustrated in the conversion of bis-mesylate (from alcohol 5) to tetracycle 10: To bis-mesylate (230 mg, 0.32 mmol, 1.0 equiv.) in 8.5 mL acetone/water (4:1) was added zinc dust (104 mg, 1.6 mmol, 5.0 equiv.), ammonium chloride (171 mg, 3.2 mmol, 10.0 equiv.), and then stirred at room temperature for 2 days. The reaction mixture was then concentrated, diluted (ethyl acetate), washed, (water and then brine), dried (sodium sulfate), filtered, and concentrated. Purification by column chromatography (3:1 hexanes/ethyl acetate) gave tetracycle 10 (87 mg, 55%) as a white foam. [α]20D +14.6 (c = 2.00, CHCl3); 1HNMR (300 MHz, CDCl3) δ TMS: 2.14 (3H, s), 3.28 (1H, dd, J = 4.5, 2.1 Hz), 3.36 (1H, dd, J = 12.9, 2.1 Hz), 3.42 (1H, dd, J = 4.5, 2.7 Hz), 3.65 (3H, s), 3.82 (3H, s), 4.21 (1H, d, J = 12.9 Hz), 4.58 (1H, m), 4.70 (1H, d, J = 11.4 Hz), 5.09 (1H, m), 5.28 (1H, d, J = 2.1 Hz), 5.92 (1H, d, J = 2.4 Hz), 7.57–7.35 (10H, m); 13CNMR (75 MHz, CDCl3) δ 10.0, 36.8, 44.4, 46.1, 51.1, 53.7, 60.9, 69.9, 72.2, 74.2, 120.1, 127.7, 127.9, 128.0, 128.1, 128.4, 128.5, 128.6, 128.7, 128.8, 128.9, 129.0, 137.7, 137.9, 138.6, 142.9, 145.2, 145.3, 145.5, 162.6; IR (neat) 3030, 2928, 1726, 1634, 1498, 1279 cm −1; HRMS (FAB) m/z calcd for C30H30N2O5 (M+H)+ 498.21, found 498.21