Enantioselective synthesis of an aziridinomitosane and selective functionalizations of a key intermediate

Article abstract of DOI:10.1021/jo0269013

An enantioselective synthesis of mitosane core (-)-1 has been achieved. Key steps include a rapid assembly of a key eight-membered-ring intermediate employing ring-closing metathesis. Kinetic resolution of an advanced secondary alcohol was then accomplished by using a peptide-based asymmetric acyl transfer catalyst that was discovered from a parallel screen of catalyst candidates. Optically pure material was then converted to the mitosane core, which was the subject of additional studies on the selective modification to produce several substituted compounds containing a mitosane ring system.

Full text of DOI:10.1021/jo0269013

En a n tioselective Syn th esis of a n Azir id in om itosa n e a n d Selective
F u n ction a liza tion s of a Key In ter m ed ia te
Nikolaos Papaioannou, J arred T. Blank, and Scott J . Miller*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467-3860
scott.miller.1@bc.edu
Received December 23, 2002
An enantioselective synthesis of mitosane core (-)-1 has been achieved. Key steps include a rapid
assembly of a key eight-membered-ring intermediate employing ring-closing metathesis. Kinetic
resolution of an advanced secondary alcohol was then accomplished by using a peptide-based
asymmetric acyl transfer catalyst that was discovered from a parallel screen of catalyst candidates.
Optically pure material was then converted to the mitosane core, which was the subject of additional
studies on the selective modification to produce several substituted compounds containing a mitosane
ring system.
In tr od u ction 1
related to synthesis and cancer.5-7 Synthetic studies on
the mitomycins continue to provide new insights on these
significant targets. Total syntheses of members of
the class including several mitomycins and the related
FR900482/FR66979 structures have been reported by the
Kishi,8 Fukuyama,9 Danishefsky,10 Martin,11 and Terash-
ima12 laboratories. Most recently total syntheses have
also been reported by Fukuyama,9d Williams,13 Ciufo-
lini,14 and Rapoport.15 In addition, many other important
advances have been reported.16 In this paper, we report
the results of our studies in this area in the context of
the enantioselective preparation of a mitosane core,17 as
well as further studies on the selective modification of
The application of asymmetric catalytic methods in the
context of complex molecule total synthesis constitutes
both a historic approach and a frontier for organic syn-
thesis. While the field of catalytic reaction development
strives for wide substrate generality, very often in the
context of a specific intermediate required for a total syn-
thesis, a given reaction may proceed less selectively. In
concert with a simultaneous interest in developing pro-
tocols for rapid catalyst discovery, and in the synthesis
of the mitomycin family of natural products, we em-
barked upon a synthesis of mitomycin-like molecules. Our
goal was to test catalyst discovery methodology in the
context of a target-oriented study, rather than in a more
general methodological mode.2-4 If rapid discovery pro-
tocols could be employed in this arena, this strategy could
prove useful in the context of both target-oriented and
diversity-oriented synthesis. Successful application of
such methodology could raise the possibility of introduc-
ing asymmetric catalysts at the “kit-level” such that
families of catalysts could be readily available for screen-
ing against synthetic intermediates in the context of a
variety of targets of interest.
(5) (a) Carter, S. K.; Crooke, S. T. Mitomycin C, Current Status and
New Developments; Academic Press: New York, 1979. (b) Remers, W.
A.; Iyengar, B. S. In Cancer Chemotherapeutic Agents; Foye, W. O.,
Ed.; American Chemical Society: Washington, DC, 1995; pp 584-592.
(6) Tomasz, M.; Lipman, R.; Chowdary, D.; Pawlak, J .; Verdine, G.;
Nakanishi, K. Science 1987, 235, 1204-1208.
(7) Gargiulo, D.; Musser, S. S.; Yang, L.; Fukuyama, T.; Tomasz,
M. J . Am. Chem. Soc. 1995, 117, 9388-9398.
(8) For a review of the Kishi Laboratory’s synthetic studies, see:
Kishi, Y. J . Nat. Prod. 1979, 42, 549-568.
(9) (a) Fukuyama, T.; Yang, L. J . Am. Chem. Soc. 1989, 111, 8303-
8304. (b) Fukuyama, T.; Yang, L. J . Am. Chem. Soc. 1987, 109, 7881-
7882. (c) Fukuyama, T.; Xu, L.; Goto, S. J . Am. Chem. Soc. 1992, 114,
383-385. (d) Suzuki, M.; Kambe, M.; Tokuyama, H.; Fukuyama, T.
Angew. Chem., Int. Ed. 2002, 41, 4686-4688.
(10) Danishefsky, S. J .; Schkeryantz, J . M. Synlett 1995, 475-490.
This paper also provides an excellent bibliography to the mitomycin
literature.
The mitomycin antitumor agents continue to be of
interest in the context of chemical and biological studies
(11) Fellows, I. M.; Kaelin, D. E., J r.; Martin, S. F. J . Am. Chem.
Soc. 2000, 122, 10781-10787.
(1) This work is taken in part from the Ph.D. Dissertation of
Nikolaos Papaioannou, Boston College, Chestnut Hill, MA 02467.
(2) J andeleit, B.; Schaefer, D. J .; Powers, T. S.; Turner, H. W.;
Weinberg, W. H. Angew. Chem., Int. Ed. 1999, 38, 2494-2532.
(3) For several recent reviews of combinatorial catalysis, see: (a)
Crabtree, R. H. Chem. Commun. 1999, 17, 1611. (b) Kuntz, K. W.;
Snapper, M. L.; Hoveyda, A. H. Curr. Opin. Chem. Biol. 1999, 3, 313-
319. (c) Fransis, M. B.; J amison, T. F.; J acobsen, E. N. Curr. Opin.
Chem. Biol. 1998, 2, 422-428.
(12) (a) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron
1997, 53, 10229-10238. (b) Yoshino, T.; Nagata, Y.; Itoh, E.; Hash-
imoto, M.; Katoh, T.; Terashima, S. Tetrahedron 1997, 53, 10239-
10252. (c) Katoh, T.; Nagata, Y.; Yoshino, T.; Nakatani, S.; Terashima,
S. Tetrahedron 1997, 53, 10253-10270.
(13) Williams, R. M.; J udd, T. C. Angew. Chem., Int. Ed. 2002, 41,
4683-4685.
(14) Ciufolini, M. A.; Ducray, R. Angew. Chem., Int. Ed. 2002, 41,
4688-4691.
(4) For reviews of catalytic kinetic resolution see: (a) Keith, J . M.;
Larrow, J . F.; J acobsen, E. N. Adv. Synth. Catal. 2001, 343, 5-26. (b)
Hoveyda, A. H.; Didiuk, M. T. Curr. Org. Chem. 1998, 2, 489-526.
(15) Paleo, M. R.; Aurrecoechea, N.; J ung, K.-Y.; Rapoport, H. J .
Org. Chem. 2003, 68, 130-138.
10.1021/jo0269013 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/25/2003
2728
J . Org. Chem. 2003, 68, 2728-2734

Enantioselective Synthesis of an Aziridinomitosane
SCHEME 1
F IGURE 1. Isatin as a starting point for synthesis.
SCHEME 2a
advanced intermediates obtained from the initial enan-
tioselective route.
Str a tegy a n d Retr osyn th etic An a lysis. To assess
the validity of our strategy, core 1 was selected as the
initial target. The retrosynthetic analysis is predicated
on the expectation that aminal-ether 1 could be accessed
through an appropriately functionalized eight-membered
ring (Scheme 1) in accord with earlier approaches.8 We
intended to obtain allylic alcohol 3 in optically pure form
from the racemate, employing an enantioselective cata-
lyst for kinetic resolution. For this purpose, the strategy
involved assembling a library of peptide catalysts for
screening against racemic alcohol (()-3.18
a
Reagents and conditions: (a) ethylene glycol, TsOH, PhH,
reflux; (b) BOC2O, DMAP, Et3N, CH2Cl2, rt; (c) NaOH, THF/H2O,
reflux; (d) allyl bromide, NaH, DMF, 0 °C to rt.
expand to the eight-membered ring and eventually form
the hemi-aminal ether.
Resu lts a n d Discu ssion
P r ep a r a tion of th e Rin g-Closin g Meta th esis P r e-
cu r sor . We elected to access the key eight-membered-
ring precursor (3) through catalytic ring-closing metath-
esis,20 in analogy to the method that Martin has employed
in the formal total synthesis of FR900482 and related
models.11,21 Protection of the benzylic carbonyl of isatin
was the first issue that needed to be addressed. An
ethylene glycol-based ketal was chosen for the following
reasons: (i) isatin ketal is readily synthesized in large
scale and high yields,22 (ii) the ketal protecting group is
widely used and its removal has been studied extensively
under a variety of conditions, and (iii) installation of a
ketal at the benzylic position could facilitate ring-closing
metathesis to form the eight-membered ring. Thus,
treatment of isatin with ethylene glycol and TsOH in
benzene under Dean-Stark conditions cleanly afforded
the ketal-protected isatin 4 in 99% yield (Scheme 2). The
anilinic nitrogen was then protected by treatment of
isatin-ketal 4 with BOC2O (DMAP, Et3N/CH2Cl2) to
afford ketal intermediate 5 in 86% yield.23 The BOC-
protected isatin ketal 5 was saponified (NaOH/H2O) to
afford carboxylic acid 6 (99%). Treatment of the acid with
allyl bromide in (NaH/DMF) afforded ester 7 (87%).
Isatin was selected as the ultimate starting material
due to its low cost, and since it incorporated key func-
tionality that could be elaborated to the mitosane core.19
As shown in Figure 1, isatin contains all six carbons
required for ring A, the nitrogen in the N4 position, and
functionalized carbon atoms at C9 and C9a. The carbonyl
at C9 can be used to install the hydroxy-methyl func-
tionality or the olefin found in the mitomycins. The
carbonyl at C9a and the anilinic nitrogen can be used to
(16) For example, (a) Vedejs, E.; Klapars, A.; Naidu, B. N.; Pi-
otrowski, D. W.; Tucci, F. C. J . Am. Chem. Soc. 2000, 122, 5401-5402.
(b) Lee, S.; Lee, W. M.; Sulikowski, G. A. J . Org. Chem. 1999, 64, 4224-
4225. (c) Dong, W.; J imenez, L. S. J . Org. Chem. 1999, 64, 2520-2523.
(d) Edstrom, E. D.; Yu, T. Tetrahedron 1997, 53, 4549-4560. (e) Wang
Z.; J imenez, L. S. J . Org. Chem. 1996, 61, 816-818. (f) Katoh, T.;
Yoshino, T.; Nagata, Y.; Nakatani, S.; Terashima, S. Tetrahedron Lett.
1996, 37, 3479-3482. (g) Shaw, K. J .; Luly, J . R.; Rapoport, H. J . Org.
Chem. 1985, 50, 4515-4523. (h) Ban, Y.; Nakajima, S.; Yoshida, K.;
Mori, M.; Shibasaki, M. Heterocycles 1994, 39, 657-607.
(17) Papaioannou, N.; Evans, C. A.; Blank, J . T.; Miller, S. J . Org.
Lett. 2001, 18, 2879-2882.
(20) For recent reviews of RCM, see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413-4450. (b) Fu¨rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012-3043.
(18) (a) Copeland, G. T.; Miller, S. J . J . Am. Chem. Soc. 2001, 123,
6496-6502. (b) J arvo, E. R.; Copeland, G. T.; Papaioannou, N.;
Bonitatebus, P. J .; Miller, S. J . J . Am. Chem. Soc. 1999, 121, 11638-
11643. (c) J arvo, E. R.; Evans, C. A.; Copeland, G. T.; Miller, S. J . J .
Org. Chem. 2001, 66, 5522-5527.
(21) (a) Martin, S. F.; Wagman, A. S. Tetrahedron Lett. 1995, 36,
1169-1170. (b) Miller, S. J .; Kim, S. H.; Chen, Z.-R.; Grubbs, R. H. J .
Am. Chem. Soc. 1995, 117, 2108-2109.
(22) Rajopadye, M.; Popp, F. D. J . Med. Chem. 1988, 31, 1001-1005.
(23) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983, 48,
2424-2426.
(19) Isatin was $0.07/g from Alfa Aesar, 2001.
J . Org. Chem, Vol. 68, No. 7, 2003 2729

Papaioannou et al.
SCHEME 3a
Con str u ction of th e Eigh t-Mem ber ed Rin g. Mar-
tin and Grubbs had previously demonstrated that mo-
lybdenum and ruthenium alkylidenes, respectively, could
be used to construct eight-membered-ring intermediates
related to compound 3 (eq 1). In contrast to the earlier
a
Reagents and conditions: (a) NaOH, THF/H2O, reflux; (b)
EDC, MeNH(OMe)‚HCl, CH2Cl2, rt; (c) MeNH(OMe)‚HCl, i-
PrMgCl, THF, -20 °C
SCHEME 4
cases where the olefinic partners were a monosubstituted
allylic alcohol and a monosubstituted alkene, the present
case involves an R,â-unsaturated ketone.28 Initial at-
tempts to construct the desired octacycle 12 with either
molybdenum catalyst 13 or ruthenium catalyst 14 met
with failure (<1% yield of product).
Since chelated intermediates such as 15 had been
proposed to be responsible for low yields in related
metatheses, we explored the use of additives as a
potential solution.29 When diene 10 was subjected to
RCM employing catalyst 14 (15 mol %, 3 × 5 mol % over
48 h, CH2Cl2 reflux) in the presence of Ti(Oi-Pr)4 (3
equiv), the desired octacycle 12 was formed in 53% yield.
As an example of the heightened activity of the IMES-
substituted Ru-alkylidene 16,30 we subsequently found
that the same reaction could be achieved in the absence
of Lewis acids with this catalyst, to deliver product 12
in improved yield (83%) within 4 h (eq 2).
Direct conversion of the allyl-ester to the Weinreb
amide with N,O-dimethylhydroxylamine in the presence
of AlMe3 was originally planned but unfortunately de-
composition of the starting material was observed with
this method.24 Alternatively, Weinreb amide 9 was suc-
cessfully obtained by a two-step sequence that involved
hydrolysis of the allyl ester (7) followed by coupling of
N,O-dimethylhydroxylamine (Scheme 3). Indeed, hy-
drolysis proceeded smoothly to afford the desired car-
boxylic acid 8 in 99% yield, although coupling with EDC,
Et3N, and N,O-dimethylhydroxylamine hydrochloride
afforded the desired Weinreb amide 9 in a modest yield
of 64% (Scheme 3, method A). Subsequently, investiga-
tions revealed that the Weinreb amide 9 could be
obtained in one step and in excellent yield (96%) by
generating the magnesium salt of the N,O,-dimethylhy-
droxylamine in the presence of allyl ester 7 (Scheme 3,
method B).25
With the desired Weinreb amide in hand, elaboration
to the metathesis precursor was undertaken (Scheme 4).26
We expected that treatment of 9 with vinylmagnesium
bromide would afford desired diene 10. Surprisingly,
exposure of 9 to vinylmagnesium bromide at 0 °C followed
by workup with aqueous NH4Cl formed Michael adduct
11 rather than diene 10. Presumably, the liberated N,O-
dimethylhydroxylamine added to the newly formed R,â-
unsaturated ketone 10 to afford 11.27 To remedy the
situation, a method to trap the expelled N,O-dimethyl-
hydroxylamine was required. To this end, quenching the
reaction with acetic anhydride provided the desired diene
10 in 99% yield.
The conformation and reactivity of cyclooctenone 12
is of note. Among the reactions we had projected for an
alternative synthesis of the mitosane core was an enan-
tioselective epoxidation of the enone. Interestingly, enone
12 was resistant to nucleophilic epoxidation, as well as
to a variety of other conjugate addition conditions.
Inspection of the X-ray structure of compound 12 (Figure
2) revealed that the carbonyl group and the olefin are
twisted approximately 100.4° out of conjugation. Also of
(28) For two related examples of enone metathesis to form eight-
membered rings, see: (a) Paquette, L. A.; Schloss, J . D.; Efremov, I.;
Fabris, F.; Gallou, F.; Andino, J . M.; Yang, J . Org. Lett. 2000, 2, 1259-
1261. (b) Paquette, L. A.; Efremov, I. J . Am. Chem. Soc. 2001, 123,
4492-4501.
(29) For one such example, see: Fu¨rstner, A.; Langemann, K. J .
Am. Chem. Soc. 1997, 199, 9130-9136.
(30) (a) Scholl, M.; Trnka, T. M.; Morgan, J . P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247-2250. (b) Trnka, T. M.; Grubbs, R.
H. Acc. Chem. Res. 2001, 34, 18-29.
(24) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
48, 4171-4174.
(25) Williams, J . M.; J obson, R. B.; Yasuda, N.; Marchesini, G.
Tetrahedron Lett. 1995, 36, 5461-5464.
(26) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818.
(27) Gomtsyan, A. Org. Lett. 2000, 2, 11-13.
2730 J . Org. Chem., Vol. 68, No. 7, 2003

Enantioselective Synthesis of an Aziridinomitosane
the X-ray crystal structure allowed the assignment of
absolute configuration (eq 5).
F IGURE 2. X-ray crystal structure of 12.
Recyclin g of th e Un d esir ed En a n tiom er . Although
catalyst 18 exhibits acceptable selectivity (krel ) 27), little
doubt remains that kinetic resolution is inherently inef-
ficient with half of the material not targeted for use in
the synthetic direction. Therefore, we wished to demon-
strate that the other enantiomer could be recycled.
Initially, we wished to invert the stereogenic center of
the product through a hydrolysis/Mitsunobu reaction
sequence (Scheme 5). The undesired acetate 3-Ac was
efficiently hydrolyzed (K2CO3, MeOH/H2O) to yield alco-
hol 3 (96%). When the free alcohol was subjected to
Mitsunobu conditions, none of the desired p-NO2-benzoyl
ester was produced but instead a transannular cycliza-
tion occurred to produce a desmethoxymitosane 20
(Scheme 5). Upon inspection of the X-ray crystal struc-
tures of 3-Ac, a hypothesis to explain this reaction is
apparant. The anilinic nitrogen is aligned directly with
the transannular C-O σ* orbital; upon activation, trans-
annular cyclization occurs.
As an alternative to inversion, we next considered
oxidation of the undesired enantiomeric alcohol to reform
enone 12. One potential pitfall of this strategy is that
the eight-membered ring is itself chiral by virtue of its
conformation. That is, if the barrier to inversion by ring-
flip were too high, optical activity could be retained in
the enone.34 Such an event, although intriguing, could
preclude the possibility of recycling the material and
would be an obstacle for future plans involving dynamic
resolution.35 To assess whether the barrier to inversion
of octacycle 12 is sufficiently low, optically pure alcohol
(-)-3 was converted to enone 12 and then subjected to
the established reduction conditions (Scheme 6). Fortu-
itously the oxidation/reduction sequence effectively elimi-
nated the chirality of optically pure alcohol (-)-3, sug-
gesting that the barrier to inversion of ketone 12 is
indeed adequetly low. Therefore, recycling the material
via this process is viable and holds promise for future
attempts to render the resolution process dynamic.
Ela bor a tion to a Mitosa n e Cor e. With access to
optically pure (-)-3 and with a method to recycle the
undesired enantiomer, we turned our attention to con-
version of the eight-membered ring to a mitosane-like
molecule (Scheme 7). Substrate-directed epoxidation of
allylic alcohol (-)-3 in the presence of dimethyldioxirane
led to the production of epoxide 21 with high diastereo-
note is the fact that the anilinic nitrogen is slightly
pyramidalized, and is oriented at an angle of 112° (N-
CdO) with respect to the transannular carbonyl (N-C
distance ) 2.59 Å). These parameters are reminiscent of
a Burgi-Dunitz interaction in the solid state, and
foreshadow the projected transannular cyclization (vide
infra).31
Id en tifica tion of P ep tid e Ca ta lyst for Resolu tion .
With the eight-membered ring in hand, we now turned
our attention to catalytic kinetic resolution. Enone 12 was
converted to racemic allylic alcohol 3 with LAH (Et2O, 0
°C, 5 min) in quantitative yield. Since secondary alcohol
3 did not bear resemblance to the substrates previously
studied for peptide-catalyzed kinetic resolution, we de-
cided to screen a diverse set of catalysts. In this vein,
152 peptides were prepared with the general structure
17 (Figure 3). Screening of the unpurified catalysts at
room temperature for the kinetic resolution of alcohol 3
resulted in selectivity factors that ranged from 1 to 10
(Figure 3).32 Catalyst 18 proved to be promising, and was
therefore purified to homogeneity for further study.
After purification, rescreening of catalyst 18 under the
conditions in Figure 3 yielded identical results. However,
when the reaction was performed at 0 °C (2.0 mol % of
18, 6 equiv of Et3N, 5 equiv of Ac2O, PhCH3), selectivity
improved (krel ) 27, conv ) 53%). In addition, a single
recrystallization afforded alcohol (-)-3 in >99% ee
(eq 4).
To establish the absolute configuration of the slow
reacting enantiomer, recovered starting material (>99%
ee) was converted to Mosher ester 19 employing the acid
chloride derived from (R)-Mosher’s acid;33 inspection of
(31) (a) Procter, G.; Doyle, B.; Dunitz, J . D. Helv. Chim. Acta 1981,
64, 471-477. (b) Schweizer, W. B.; Procter, G.; Kaftory, M.; Dunitz, J .
D. Helv. Chim. Acta 1978, 61, 2783-2808.
(34) Cope, A. C.; Pawson, B. A. J . Am. Chem. Soc. 1965, 87, 3649-
3651.
(32) Kagan, H. B.; Fiaud, J . C. Top. Stereochem. 1988, 18, 249-
(35) For reviews of dynamic kinetic resolution see: (a) Noyori, R.;
Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. J pn. 1995, 68, 36-56.
(b) Strauss, U. T.; Felfer, U. Tetrahedron: Asymmetry. 1999, 10, 107-
117. (c) El Gihani, M. T.; Williams, J . M. J . Curr. Opin. Chem. Biol.
1999, 3, 11-15.
330.
(33) (a) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969,
34, 2543-2549. (b) Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991,
32, 7165-7166.
J . Org. Chem, Vol. 68, No. 7, 2003 2731

Papaioannou et al.
F IGURE 3. (a) Library of 152 catalysts for kinetic resolutions of 3, and the optimum member of the library, 18. (b) Distribution
of s-factors for the library observed for screening of substrate 3 (reactions conducted at 25 °C).
SCHEME 5
SCHEME 7a
a
Reagents and conditions: (a) oxone, NaHCO3 acetone/H2O (3:
1); (b) BzCl, Et3N, CH2Cl2; (c) (ClCO)2, Et3N, DMSO, CH2Cl2.
SCHEME 8 a
a
Reagents and conditions: (a) TBDMSOTf, Et3N, CH2Cl2,
SCHEME 6a
-78f0 °C; (b) 20 mol % of Sm(Oi-Pr)3, TMSN3, CH2Cl2; (c) MsCl,
Et3N, various conditions.
Our initial attempt to induce transannular cyclization
paralleled literature precedent employing Lewis acid
catalysis (Scheme 8).37 Thus, treatment of epoxide 23
with TBDMSOTf in the presence of Et3N afforded tetra-
cycle TBDMS-protected aminal 24 (80%). However, con-
version of the epoxide to the aziridine proved difficult in
this series. Exposure of epoxide 24 to a range of condi-
tions afforded only limited amounts of ring-opened
product 25.38 Furthermore, all attempts to convert the
alcohol to the corresponding mesylate as a prelude to
a
Reagents and conditions: (a) (ClCO)2, Et3N, DMSO, CH2Cl2;
(b) LAH, Et2O, 0 °C.
selectivity (>98:2, quantitative yield).36 The assignment
of the anti-stereochemistry was secured by X-ray crystal-
lographic analysis of the derived benzoate 22. Swern
oxidation afforded epoxyketone 23 in 94% yield.
(37) (a) Ban, Y.; Nakajima, S.; Yoshida, K.; Mori, M.; Shibasaki, M.
Heterocycles 1994, 39, 657-607. (b) Nakajima, S.; Yoshida, K.; Mori,
M.; Ban, Y.; Shibasaki, M. J . Chem. Soc., Chem. Commun. 1990, 468-
470.
(36) Wang, Z. X.; Miller, S. H.; Anderson, O. P.; Shi, Y. J . Org. Chem.
1999, 64, 6443-6458.
(38) See: Martinez, L. E.; Cartsen, D. H.; J acobsen, E. N. J . Am.
Chem. Soc. 1995, 117, 5897-5898 and references therein.
2732 J . Org. Chem., Vol. 68, No. 7, 2003

Enantioselective Synthesis of an Aziridinomitosane
SCHEME 9
SCHEME 10a
a
Reagents and conditions: (a) 50 mol % of Sm(O-iPr)3, TMSN3,
aziridine formation failed. Danishefsky and co-workers
had encountered similar difficulties in mesylating a
hydroxyl group at C1; this is most likely due to the
concave nature of the molecule that renders the alcohol
sterically encumbered.39
CH2Cl2; (b) AcCl/MeOH; (c) MsCl, Et3N, CH2Cl2; (d) resin-bound
PPh3, Hunig’s base, THF/H2O.
SCHEME 11
The inefficiency of both the epoxide opening and the
requirement for a deprotection step led to reevaluation
of the cyclization strategy. Given the precedent for
thermal BOC group cleavage, we subjected neat epoxyke-
tone 23 to thermolytic conditions in a sealed tube (185
°C) and found that ring-closed hydroxy-epoxide 26 was
formed in 52% yield (eq 6). Furthermore, the efficiency
of the reaction improved at lower temperature in the
presence of catalytic acid (HNO3/MeOH, 5 mol %, sealed
tube, 135 °C). Removal of the protecting ketal with
concomitant cyclization delivered epoxide 27 in a single
step (81%). X-ray analysis of epoxide 27 revealed the anti-
orientation between the epoxide and the methoxy group
(eq 7).
ture of epimers (86% combined yield).40 Activation of 31
toward aziridine formation was accomplished by conver-
sion to the mesylate. Reductive cyclization was effected
by resin-bound Ph3P to afford aziridinomitosane (-)-1 in
42% yield (2 steps) with the trans-configuration, corre-
sponding to the natural stereochemistry (Scheme 10).
Selective Fu n ction alization s of th e Mitosan e Cor e.
At this stage, we wished to evaluate the prospects for
converting the mitosane core into intermediates that
could resemble a mitosane with a functionalized aromatic
nucleus (e.g., Scheme 11, 33). Certainly one approach to
extending these findings to a total synthesis of a mito-
mycin could involve repeating the sequence from a
suitably functionalized isatin precursor. An alternative,
more aggressive strategy became apparent while syn-
thesizing the aziridinomitosane core (-)-1. The stability
of epoxymitosane 27 under harsh thermal and acidic
conditions suggested that aromatic substitution of this
intermediate may be possible, allowing access to the
desired substitution of the mitomycins. Furthermore,
successful substitution of such an advanced intermediate
could bode well for analogue synthesis.
Removal of the ketal under these conditions was
fortuitous since it had proven difficult under a range of
other conditions. Of particular note, when model ketal
28 was subjected to acidic deprotection conditions, in-
stead of the desired ketone 29, an unexpected dimer 30,
whose structure was secured by X-ray analysis, was
produced as the major product. This observation focused
attention on the pyrolytic route as the method of choice
for both transannular cyclization and deprotection.
Conversion of epoxide 27 to an aziridinomitosane
commenced with a Lewis acid-promoted ring-opening
(Sm(O-iPr)3, TMSN3) to produce hydroxy azide 31 (Scheme
10), which upon acidic workup was converted to a mix-
(39) Danishefsky, S.; Berman, E. M.; Ciufolini, M.; Etheredge, S.
J .; Segmuller, B. E. J . Am. Chem. Soc. 1985, 107, 3891-3898.
(40) Martinez, L. E.; Leighton, J . L.; Cartsen, D. H.; J acobsen, E.
N. J . Am. Chem. Soc. 1995, 117, 5897-5898 and references therein.
J . Org. Chem, Vol. 68, No. 7, 2003 2733

Papaioannou et al.
Ar om atic Su bstitu tion of th e Epoxym itosan e Cor e.
Given that epoxymitosane 27 was formed during the one-
pot deprotection/cyclization mediated by catalytic nitric
acid (c.f., eq 7), we anticipated that nitration of the
aromatic ring was plausible. Mild nitration of 27 (Cu-
(NO3)2‚3H2O, Ac2O)41 thus proceeded to deliver nitrated
products 34 and 35 as a 2.3:1 mixture (99% combined
yield). Both of the isomers proved to be crystalline
enabling regioisomeric assignments by crystallographic
analysis (eq 8).
(eq 9). Subjection of 40 to Cu(NO3)2‚3H2O/Ac2O results
in ipso substitution of a bromide with a nitro group,
affording compound 41 (20%, eq 10). These studies set
the stage for additional late-stage functionalizations of
the mitosane core.
Con clu sion s
A concise synthesis of an optically pure aziridinomi-
tosane has been accomplished. Enantioselectivity was
achieved in rapid fashion by screening a moderately sized
peptide library of acylation catalysts for kinetic resolution
of a key intermediate. In synthesizing the aziridinomi-
tosane, a point of divergence has been identified for
analogue synthesis. An optically pure late-stage inter-
mediate was found to be stable to aromatic substitution
under a variety of conditions providing precedent for
further elaboration to the desired natural products.
Furthermore, substitution of a late-stage intermediate
introduces the possibility of using such intermediates as
a starting place for libraries of mitosane-like compounds.
Studies along these lines are currently ongoing in our
group.
Nitrated epoxymitosane 34 was subjected to hydroge-
nation conditions in the presence of BOC2O to afford the
corresponding BOC-protected aniline 36 (98%, Scheme
12). Encouraged by these results, a second nitration was
performed on the BOC-protected compound and afforded
nitrated mitosane 37 in 93% yield. Further reduction
with (Pd/C, H2) afforded aniline 38 in 68% yield.
SCHEME 12a
Ack n ow led gm en t. The authors wish to thank Ms.
Catherine A. Evans and Mr. J ames P. J ewell for
assistance in the preparation of catalysts and interme-
diates. This research is supported by the National
Science Foundation (CHE-0236591). In addition, we are
grateful to DuPont and the Merck Chemistry Council
for research support. S.J .M. is a Fellow of the Alfred P.
Sloan Foundation, a Cottrell Scholar of Research Cor-
poration, and a Camille Dreyfus Teacher-Scholar.
a
Reagents and conditions: (a) Pd/C H2, BOC2O, MeOH/EtOAc;
(b) Cu(NO3)2‚3H2O, Ac2O; (c) Pd/C H2, MeOH/EtOAc.
In addition to nitration, halogenation was performed
to further probe the reactivity and relative stability of
epoxymitosane 27 to aromatic substitution conditions.
Treatment of 27 with differing quantities of NBS affords
either the monobromo- (39) or dibromo-epoxymitosane 40
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and product characterization for all new compounds
synthesized; X-ray structures referred to in the text whose sole
role is to confirm identity (compounds 1, 9, 19, 22, 27, 30, 34,
35, and 41, in addition to 3-Ac and 12). This material is
available free of charge via the Internet at http://pubs.acs.org.
(41) Boger, D. L.; Garbaccio, R. M. J . Org. Chem. 1999, 64, 8350-
8362.
J O0269013
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