Synthetic studies toward the mitomycins: construction of the tetracyclic core via a reductive aminocyclization reaction

Article abstract of DOI:10.1016/j.tetlet.2009.05.004

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 eight-membered benzazocine can be prepared without the need for prior activ

Full text of DOI:10.1016/j.tetlet.2009.05.004

Tetrahedron Letters 50 (2009) 4265–4267
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Tetrahedron Letters
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Synthetic studies toward the mitomycins: construction of the tetracyclic
core via a reductive aminocyclization reaction
Daniel A. Gubler a, Robert M. Williams a,b,
*
a Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
b University of Colorado Cancer Center, Aurora, CO 80045, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The tetracyclic core of the mitomycin family of natural products has been formed in one step from an acy-
clic precursor via a reductive aminocyclization reaction. Additionally, the eight-membered benzazocine
can be prepared without the need for prior activation of the aniline. Construction of a mitomycin K ana-
logue lacking the C9a methoxy moiety is also reported herein.
Received 4 February 2009
Revised 30 April 2009
Accepted 1 May 2009
Available online 8 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The mitomycin family of natural products (Fig. 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 partic-
ularly 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
(Fig. 1) has been widely used clinically for over 40 years, and is still
routinely employed today.5
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, and exo-methylene) as the synthesis unfolds.
Despite the numerous reported synthetic efforts toward the mito-
mycins, 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 exists 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 (+)-FR900482.10 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. How-
ever, conversion of these benzazocanes to the natural products
proved to be difficult.
O
10
9
O
OCONH2
OCONH2
OH
8
R
R
7
OMe
1
6
9a
4 N
NH
N
NMe
Me
5
Me
2
3
O
O
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 cycliza-
tion (Scheme 2). The synthesis commenced by coupling of nitro
Mitomycin A (MMA), R = OMe
Mitomycin C (MMC), R = NH2
Mitomycin B, R = OMe
Mitomycin D, R = NH2
O
OCONH2
OH
MeO
Me
OMe
NMe
OH
N
O
NH
ODEIPS
NCO2Me
OMe
ODEIPS
NCO2Me
OH
OMe
OHC
N
O
MeO
Me
MeO
Me
a
FR-900482
Mitomycin K (MMK)
NH
OMe Alloc
N
Alloc
Figure 1. The mitomycin family of natural products.
OMe
* Corresponding author. Tel.: +1 970 491 6747; fax: +1 970 491 3944.
E-mail address: rmw@lamar.colostate.edu (R.M. Williams).
Scheme 1. Reagents and conditions: (a) (CH3)2NCON@NCON(CH3)2 (1.5 equiv),
PBu3 (1.8 equiv), toluene, rt, 6 h; 85%.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.004

4266
D. A. Gubler, R. M. Williams / Tetrahedron Letters 50 (2009) 4265–4267
BnO
OBn
OBn
O
O
OBn
BnO
BnO
OH
MeO
Me
MeO
Me
MeO
Me
Me
H
MeO
Me
a-b
a, b
c, d
NCO2Me
+
NCO2Me
OMs
NCO2Me
N
NCO2Me
NO2
NO2
NO2
BnO
BnO
OPMB
OBn
1
BnO
OPMB
10
2
3
5
O
OH
O
MeO
Me
MeO
Me
MeO
Me
g
H
e, f
c
NCO2Me
NCO2Me
N
NCO2Me
NO2
NO2
BnO
BnO
O
OH
OH
OMs
OH
4
5
11
BnO
BnO
Scheme 4. Reagents and conditions: (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%.
MeO
Me
MeO
Me
- MsOH
NCO2Me
NCO2Me
NH2
HN
BnO
BnO
OMs
6
7
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 bear-
ing 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 hydrogena-
tion 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.
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 mitomyc-
ins was also accomplished in a single step from an acyclic precur-
sor 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).
Scheme 2. Reagents and conditions: (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, 2 h, 98%; (c) formalin (112 equiv), LiOH (0.4 equiv), THF/
water (20:3), rt, 20 h, 99%; (d) DDQ (1.3 equiv), CH2Cl2/water (95:5), rt, 2 h, 92%; (e)
MsCl (1.3 equiv), Et3N (3.0 equiv), 0 °C, 30 min, 85%; (f) CeCl3ꢁ7H2O (5.0 equiv),
NaBH4 (3.0 equiv), 0 °C, 30 min, 92%; (g) Zn dust (5.0 equiv), NH4Cl (10.0 equiv),
acetone/water (4:1), rt, 3 h, 99%.
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 pri-
mary alcohol 4. Conversion of alcohol 4 to the corresponding mes-
ylate and reduction of the ketone under Luche conditions gave
secondary alcohol 5 in high yield as a single diastereomer. Reduc-
tion 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 which proceeds without the
need for prior activation of the aniline.
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 aminocy-
clization 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 mesy-
lation (Scheme 3). Treatment of bis-mesylate 8 under identical ni-
tro reduction conditions furnished tetracyclic indoline 9 in 53%
yield. Attempted conversion of indoline 9 to the mitomycins is
now in progress.
Acknowledgments
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.
Supplementary data
Complete experimental details and spectroscopic data for all
new compounds. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2009.05.004.
OBn
OBn
O
OMs
MeO
Me
MeO
Me
a-d
NCO2Me
OPMB
NCO2Me
OMs
NO2
NO2
References and notes
OBn
OBn
3
8
1. Hata, T.; Sano, Y.; Sugawara, R.; Matsumae, A.; Kanamori, K.; Shima, T.; Hoshi,
T. J. Antibiot. 1956, 9, 141–146.
OBn
2. Rajski, S. R.; Williams, R. M. Chem. Rev. 1998, 98, 2723–2795.
3. Iyer, V. N.; Szybalski, W. A. Proc. Natl. Acad. Sci. U.S.A. 1963, 50, 355–361.
4. Rajski, S. R.; Rollins, S. B.; Williams, R. M. J. Am. Chem. Soc. 1998, 120, 2192–
2193.
5. Bradner, W. T. Cancer Treat. Rev. 2001, 7, 35–50.
6. For a review on Kishi’s synthesis of mitomycins A, B, and C see: Kishi, Y. J. Nat.
Prod. 1979, 42, 549–568.
MeO
Me
e
N
NCO2Me
OBn
9
Scheme 3. Reagents and conditions: (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) CeCl3ꢁ7H2O
(5.0 equiv), NaBH4 (3.0 equiv), 0 °C, 30 min, 93%; (d) MsCl (1.5 equiv), Et3N
(3.0 equiv), 0 °C, 30 min, 75%; (e) Zn dust (5.0 equiv), NH4Cl (10.0 equiv), acetone/
water (4:1), rt, 3 h, 53%.
7. For a review of Fukuyama’s synthesis of mitomycins A and C see: Fukuyama, T.;
Yang, L. Studi. Nat. Prod. Chem. 1993, 13, 433–471.
8. For
a review on Danishefsky’s synthetic efforts towards the mitomycins
including the total synthesis of mitomycin
K see: Danishefsky, S. J.;
Schkeryantz, J. M. Synlett 1995, 475–490.

D. A. Gubler, R. M. Williams / Tetrahedron Letters 50 (2009) 4265–4267
4267
9. Synthesis of Mitomycin K: Wang, Z.; Jimenez, L. S. Tetrahedron Lett. 1996, 37,
6049–6052.
10: To bis-mesylate (230 mg, 0.32 mmol, 1.0 equiv) in 8.5 mL acetone/water
(4:1) were 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.
10. (a) Judd, T. C.; Williams, R. M. J. Org. Chem. 2004, 69, 2825–2830; (b) Judd, T. C.;
Williams, R. M. Angew. Chem., Int. Ed. 2002, 41, 4683–4685.
11. For a recent report of ours towards the biosynthesis of the mitomycins see:
Namiki, H.; Chamberland, S.; Gubler, D. A.; Williams, R. M. Org. Lett. 2007, 9,
5341–5344.
12. Ducept, P.; Gubler, D. A.; Williams, R. M. Heterocycles 2006, 67, 597–619.
13. Prepared according to the literature procedure: Kitahara, Y.; Nakahara, S.;
Numata, R.; Kubo, A. Chem. Pharm. Bull. 1985, 33, 2122–2128.
14. Prepared according to the literature procedure: Williams, R. M.; Rollins, S. B.;
Judd, T. C. Tetrahedron 2000, 56, 521–532.
15. Ciufolini has developed a synthesis of a fully functionalized benzazocine as
part of his strategy towards the mitomycins: Ciufolini, M. A. Il Farmaco 2005,
60, 627–641.
16. The general procedure for the reductive aminocyclization reaction is
illustrated in the conversion of bis-mesylate (from alcohol 5) to tetracycle
½
a 2D0
ꢂ
þ 14:6 (c = 2.00, CHCl3); 1H NMR (300 MHz, CDCl3) d 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); 13C NMR (75 MHz, CDCl3) d 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 cmꢀ1
498.21.
;
HRMS (FAB) m/z calcd for C30H30N2O5 (M+H)+ 498.21, found