Synthesis of aziridinomitosenes through base-catalyzed conjugate addition

Article abstract of DOI:10.1016/j.tet.2004.06.022

Synthesis of an aziridinomitosene core structure that relies on a facile tertiary-amine base-catalyzed azide conjugate addition is reported. Straightforward derivatization of the conjugate addition product affords the desired mitomycin ring system. Initial catalyst screens have identified peptides that afford the product with modest enantioselectivities.

Full text of DOI:10.1016/j.tet.2004.06.022

Tetrahedron 60 (2004) 7367–7374
Synthesis of aziridinomitosenes through base-catalyzed
conjugate addition
*
Kazunari Tsuboike, David J. Guerin, Steven M. Mennen and Scott J. Miller
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467-3860, USA
Received 29 April 2004; revised 27 May 2004; accepted 4 June 2004
This paper is dedicated to Professor Robert H. Grubbs on the occasion of his receiving the Tetrahedron Prize
Abstract—Synthesis of an aziridinomitosene core structure that relies on a facile tertiary-amine base-catalyzed azide conjugate addition is
reported. Straightforward derivatization of the conjugate addition product affords the desired mitomycin ring system. Initial catalyst screens
have identified peptides that afford the product with modest enantioselectivities.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The development of flexible strategies to access biologically
relevant classes of molecules is critical for the development
of tomorrow’s pharmaceuticals. As such, the complex
molecular architecture of the mitomycin family of natural
products presents a challenge to test the state-of-the-art in
Scheme 1.
synthetic chemistry. In addition, alternative strategies may
lead to new possibilities for analog generation, as well as the
growing field of diversity-oriented synthesis.1 Synthetic
studies have provided numerous approaches to these and the
related FR900482 systems, resulting in total syntheses from
the laboratories of Kishi,2 Fukuyama,3 Danishefsky,4
Martin,5 Terashima,6 Williams,7 Ciufolini8 and Rapoport.9
Numerous other approaches to various model systems have
appeared in the literature as well.10 Reported herein is the
development of a tertiary-amine catalyzed azide conjugate
addition approach towards the synthesis of an aziridino-
mitosene core system. Highlights are the facility of the
conjugate addition and efficient conversion to the core
system. In addition, we report the results of preliminary
attempts to render the sequence enantioselective, employing a
peptide-based catalytic, asymmetric azidation strategy.11,12
the asymmetric synthesis of mitomycin-like targets not
involving a resolution, we were drawn to the possibility of
developing a conjugate addition approach involving
cyclooctenone 3, a key intermediate in the synthesis of
mitosane 2 (Scheme 2). We proposed that the base-
catalyzed conjugate addition of azide14 to enone 3 could
install the nitrogen functionality required for subsequent
aziridine formation.
Recent studies in peptide-based asymmetric acyl transfer
led to the synthesis of optically pure mitosane 2, via a
kinetic resolution of racemic allylic alcohol 1 and
subsequent conversion to the desired mitosane ring system
(Scheme 1).13 In search of alternative approaches towards
Scheme 2.
2. Results and discussion
Initial studies were performed to determine if cyclooctenone
3 was a suitable substrate for conjugate addition under the
optimized conditions developed previously. However,
enone 3 proved to be sluggish towards conjugate addition.
Keywords: Aziridinomitosene; Conjugate addition; Peptide;
Organocatalyst.
*
Corresponding author. Tel.: þ1-6175523620; fax: þ1-6175522473;
e-mail address: scott.miller.1@bc.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.022

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K. Tsuboike et al. / Tetrahedron 60 (2004) 7367–7374
Treatment of 3 with TMSN3, t-BuCO2H, and Et3N
(20 mol%) did not lead to any of the desired conjugate
addition product when the reaction was carried out at
ambient temperature (Scheme 3). In fact, careful examin-
ation of the X-ray structure of 3 reveals that the carbonyl
group and the olefin are twisted approximately 100.48 out of
conjugation.15 This result is also in accordance with the
failure of previous efforts to functionalize this system under
nucleophilic epoxidation conditions. However, by simply
elevating the reaction temperature to 40 8C, quantitative
conversion to azide 4 was achieved.
alcohol 6 (Scheme 4). Conversion of the anilinic nitrogen to
the BOC-carbamate was achieved using BOC2O (NaHCO3,
dioxane/H2O). Treatment of the BOC-protected derivative
with TBSCl and imidazole affords the corresponding TBS
ether. Carbamate N-allylation (NaH, allyl bromide) fol-
lowed by desilylation using PPTS affords allylated alcohol 7
(83%, four steps). Alcohol 7 was then subjected to a one-
pot, two-step Swern oxidation/Grignard addition16 to afford
an intermediate in which the alcohol was protected as its
TBS ether to provide 8 in 71% yield (two steps). Ring-
closing metathesis of 8 using Ru-alkylidene 917 (CH2Cl2,
reflux) affords the known octacycle 10 in 90% yield.18,19
Deprotection (PPTS, MeOH) followed by Swern oxidation
delivers enone 5 in 91% yield (two steps). Indeed, enone 5
exhibits enhanced reactivity under the azidation conditions
in comparison to octacycle 3. Enone 5, when treated with
TMSN3, t-BuCO2H, and Et3N (20 mol%) delivers azide 11
in quantitative conversion (87% isolated yield) after only
3.5 h at 22 8C (Eq. 1; cf. quantitative conversion after 24 h at
40 8C, Scheme 3). In addition, enone 5 shows appreciable
reactivity at temperatures lower than 22 8C.
Scheme 3.
Although efficient conjugate addition could be carried out at
elevated reaction temperatures, we desired a room tem-
perature protocol. With this in mind we set out to prepare a
more reactive enone substrate that would afford appreciable
reactivity at ambient temperatures or below. We postulated
that removal of the ketal moiety on enone 3 might lead to a
less rigid octacycle 5 (Scheme 4), one whose conformation
would allow for the carbonyl and olefin to achieve
conjugation at lower temperatures, thereby leading to
higher reactivity under conjugate addition conditions.
ð1Þ
While our group has been successful in developing peptides
for the enantioselective azidation of a,b-unsaturated imide
substrates, we felt that it was a likely possibility that an
entirely different peptide may turn out to be optimal for
enone substrates of general structure 5. As a starting point,
we began our studies with catalysts that had been developed
previously for these imide substrates in order to obtain a
‘benchmark’ to be used for subsequent catalyst
development.
The synthesis of 5 started from the commercially available
Peptide catalyst 12a, and the rigidified peptide 12b, were
examined under optimized conditions (2.5 mol% peptide,
Fig. 1). Peptide 12a delivers azide 11 in low but measurable
ee (12%), while the b-substituted peptide 12b is slightly
more selective, affording product 11 in 21% ee. Knowing
that catalysts such as 12 were optimized for a substrate
which is significantly different structurally, we sought to
examine peptides of different structural types in hopes of
increasing selectivity. We thought that enantioselectivity
may be increased by developing peptides that incorporate
the basic t-benzyl histidine residue at an internal position,
rather than at the N-terminus. We felt that this change may
induce a more asymmetric environment around the
imidazole moiety, by more effectively surrounding it with
the chiral information of the peptide backbone. Peptide 13,
possessing the t-benzyl histidine residue at the iþ1 position,
is indeed more selective, delivering 11 in 30% ee (22 8C).
By lowering the reaction temperature, a more selective
reaction is achieved whereby 11 is obtained in 35% ee
(4 8C). Subsequent catalyst development is ongoing in our
laboratory. Small peptide libraries (,50 catalysts) based on
Scheme 4. (a) BOC2O, NaHCO3, dioxane/H2O, rt; (b) TBSCl, imid., DMF,
rt; (c) allyl bromide, NaH, DMF, 0 8C to rt; (d) PPTS, MeOH, rt;
(e) (COCl)2, DMSO, Et3N, THF; then vinyl magnesium bromide 278 8C to
rt; (f) TBSCl, imid., DMF, rt; (g) PPTS, MeOH, rt; (h) (COCl)2, DMSO,
Et3N, CH2Cl2.

K. Tsuboike et al. / Tetrahedron 60 (2004) 7367–7374
7369
We speculated that the required aziridine ring could be
constructed via a reductive ring-closure of an azido-bromide
intermediate 18 (Scheme 6). However, this reaction
sequence turned out to be capricious, and attempts to isolate
the desired aziridinomitosene 19 cleanly met with limited
success. This could be due to instability of mitosene 19
under our conditions, as this is essentially an activated form
of a mitomycin core ring system.
Scheme 6. (a) NBS, BPO, benzene, 75 8C, 3 h; then polymer-supported
PPh3, H2O, Hunig’s base, THF, rt.
To circumvent this problem, we decided to install a nitro
group on the aromatic ring in an attempt to stabilize the
aziridine ring system by decreasing the electron density of
the indole moiety. Treatment of azide 17 with copper nitrate
(Ac2O solvent) affords the desired nitrated indole 20 along
with regioisomers (regiochemistry of 20 was confirmed by
X-ray crystallography, Fig. 2). Indeed, this compound
seems to be more stable; bromination of 20 (NBS, cat.
benzoyl peroxide) allows the isolation of trans-azido
bromide 21 after conventional chromatographic purifi-
cation. Reductive cyclization of 21 under Staudinger
conditions (polymer-supported PPh3, i-Pr2NEt, THF/H2O)
Figure 1. Peptide catalysts used in initial screening.
the general structure of peptide 14 were synthesized and
screened for enantioselectivity; these catalysts were found
to be comparably or less selective than the parent peptide.
While these initial results are promising, a better under-
standing of potential substrate–catalyst interactions will be
essential to design more selective catalysts.
With a mild, efficient protocol for the azidation of enone 5 in
hand, we turned our attention towards seeing if a synthesis
of an aziridinomitosene was feasible from azide 11
(Scheme 5). Azide 11, when treated with trifluoroacetic
acid (CH2Cl2, rt, 5 min) affords indole derivative 15 via
a facile tandem deprotection/transannular cyclization/
dehydration pathway. Indole 15 was then immediately
subjected to Vilsmeier conditions (POCl3, DMF) to afford
aldehyde 16. Aldehyde 16 was then oxidized (NaClO2,
NaH2PO4) to deliver an intermediate acid which was further
converted to the corresponding ethyl ester 17 (EtI, i-Pr2NEt)
in 92% yield.
Figure 2. ORTEP drawing for trans-azido bromide 21.
Scheme 5. (a) TFA/CH2Cl2 1:1, rt, 5 min; (b) POCl3, DMF, 0 8C to rt; then
aq. NaOAc; (c) NaClO2, NaH2PO4, 2-methyl-2-butene, dioxane/H2O 0 8C
to rt; (d) EtI, Hunig’s base, DMF, 50 8C.
Scheme 7. (a) Cu(NO3)2, Ac2O, 210 8C to rt; (b) NBS, BPO, benzene,
75 8C, 40 h; (c) polymer-supported PPh3, H2O, Hunig’s base, THF, rt.

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K. Tsuboike et al. / Tetrahedron 60 (2004) 7367–7374
provides aziridinomitosene 22 in 57% isolated yield. The
NMR data of 22 is complicated due to slow inversion at the
aziridine nitrogen resulting in two sets of the invertomers
(Scheme 7).20
mate according to the method of Crich.21 Protection of the
alcohol as its TBS ether 6a was accomplished using the
following procedure. To a solution of 2-(2-((tert-butoxy-
carbonyl)amino)phenyl)ethanol (0.37 g, 1.5 mmol) in
anhydrous DMF (5.0 mL) was added imidazole (0.63 g,
9.2 mmol) followed by TBSCl (0.70 g, 4.6 mmol). The
reaction was stirred for 18 h, then quenched with aqueous
NH4Cl (10 mL) and partitioned between Et2O (20 mL) and
10% NH4Cl (20 mL). The organic layer was washed with
aqueous NH4Cl (2£20 mL), dried over sodium sulfate,
filtered and concentrated to an oil that was purified by silica
gel chromatography (5% EtOAc/hexane) to provide
analytically pure 6a (quantitative yield).
3. Conclusions
In summary, we have developed a method to access
aziridinomitosene systems by employing a mild, efficient
conjugate addition of azide to an appropriately function-
alized eight-membered ring enone substrate. Introduction of
the azide functionality allows for rapid entry into mito-
mycin-like ring systems. Preliminary studies in search of an
enantioselective catalyst have identified peptides that afford
modest enantioselectivities for this conjugate addition.
Studies aimed at developing highly selective peptide
catalysts for this transformation are currently underway,
for applications in both target- and diversity-oriented
synthesis.
Data for 6a. 1H NMR (CDCl3, 400 MHz) d 8.07 (br s, 1H),
7.78 (br d, J¼9.6 Hz, 1H), 7.21 (t, J¼8.0 Hz, 1H), 7.08 (d,
J¼8.0 Hz, 1H) 7.00 (t, J¼7.2 Hz, 1H), 3.87 (t, J¼6.0 Hz,
2H), 2.82 (t, J¼5.6 Hz, 2H) 1.51 (s, 9H), 0.86 (s, 9H), 20.02
(s, 6H); 13C NMR (CDCl3, 100 MHz) d 153.3, 137.4, 130.8,
129.9, 126.9, 123.4, 121.9, 79.6, 66.0, 35.5, 28.5, 26.1, 18.5,
25.5; IR (film, cm21) 3345, 1726; TLC Rf 0.24 (10%
EtOAc/hexane). Exact mass calcd for [C19H33NO3SiNa]þ
requires m/z 374.2130. Found 374.2127 (ESI).
4. Experimental
4.1. General
4.3. Preparation of 6b
To a stirred solution of 6a (0.54 g, 1.5 mmol) in anhydrous
DMF (20 mL) was added allyl bromide (0.40 mL,
4.6 mmol). The solution was cooled to 0 8C (ice bath) and
solid NaH (0.059 g, 1.6 mmol) was added slowly in one
portion. Vigorous gas evolution ensued, and the resulting
reaction mixture was allowed to warm to room temperature
and stirred for 3 h. The reaction was quenched with 10%
aqueous NH4Cl (5 mL) and was partitioned between Et2O
(20 mL) and 10% NH4Cl (20 mL). The organic layer was
washed with aqueous NH4Cl (2£20 mL), dried over sodium
sulfate, filtered and concentrated to an oil that was purified
by silica gel chromatography (5% EtOAc/hexane) to
provide crude product which was carried on without further
purification (quantitative yield).
Proton NMR spectra were recorded on Varian 400 or 500
spectrometers. Proton chemical shifts were reported in ppm
(d) relative to internal tetramethylsilane (TMS, d, 0.0).
Spectral data is reported as follows: chemical shift
(multiplicity [singlet (s), doublet (d), triplet (t), quartet
(q), and multiplet (m)], coupling constants (J) [Hz],
integration). Carbon NMR spectra were recorded on a
Varian 400 MHz (100 MHz) spectrometer with complete
proton decoupling. Carbon chemical shifts are reported in
ppm (d) relative to the residual solvent signal (CDCl3, d
77.16). NMR data were collected at 25 8C, unless otherwise
indicated. Infrared spectra were obtained on a Perkin–
Elmer Spectrum 1000 spectrometer. Analytical thin-layer
chromatography (TLC) was performed using Silica Gel 60
F254 pre-coated plates (0.25 mm thickness), TLC Rf values
are reported and visualization was accomplished by
irradiation with a UV lamp and/or staining with cerium
ammonium molybdate (CAM) solutions. Flash column
Data for 6b. 1H NMR (CDCl3, 400 MHz) not fully
coalesced: d 7.28 (m, 2H), 7.19–7.02 (m, br s, 2H total),
5.93 (complex m, 1H), 5.08 (complex m, 2H), 4.37 (br m,
1H), 3.81 (complex m, 3H), 2.76 (t, J¼7.5 Hz, 2H), 1.50,
1.32 (br s, 9H total), 0.88 (br s, 9H), 0.03, 0.02 (br s, 6H
total); 13C NMR (CDCl3, 100 MHz) major peaks d 154.6,
136.5, 133.6, 130.0, 128.7, 126.9, 126.5, 117.4, 79.7, 63.3,
˚
chromatography was performed using Silica Gel 60 A
(40 mm) from Scientific Adsorbents Inc. High resolution
mass spectra were obtained from Mass Spectrometry
Facilities of Boston College (Chestnut Hill, MA). The
method of ionization is given in parentheses.
53.0, 34.5, 28.4, 26.0, 25.8, 18.4, 25.1; IR (film, cm21
)
1703, 1608, 1583; TLC Rf 0.18 (5% EtOAc/hexane). Exact
mass calcd for [C22H37NO3SiNa]þ requires m/z 414.2440.
Found 414.2450 (ESI).
All reactions were carried out under a nitrogen atmosphere
employing oven- and flame-dried glassware. Solvents
were distilled over appropriate drying reagents prior to
use.
4.4. Preparation of 7
To a stirred solution of 6b (0.60 g, 1.5 mmol) in MeOH
(10 mL) was added pyridinium p-toluenesulfonate (0.39 g,
1.5 mmol) in one portion. The reaction was stirred for 12 h,
and concentrated to a crude oil, which was partitioned
between EtOAc (20 mL) and 10% citric acid solution
(20 mL). The organic layer was washed with sat. NaHCO3
(1£20 mL), dried over sodium sulfate, and filtered.
Concentration of the filtrate provides crude product that
Caution. Organic azides are potentially explosive com-
pounds and should be handled with great care. However, we
encountered no explosive behavior during these studies.
4.2. Preparation of enone 5
4.2.1. Preparation of 6a. The anilinic nitrogen of 2-(2-
aminophenyl)ethanol 6 was protected as the BOC-carba-

K. Tsuboike et al. / Tetrahedron 60 (2004) 7367–7374
7371
was purified by silica gel chromatography to afford a clear
oil 7 (94% yield).
cm21) 3427, 1701, 1601, 1580; TLC Rf 0.26 (20% EtOAc/
hexane). Exact mass calcd for [C16H21NO3Na]þ requires
m/z 298.1420. Found 298.1419 (ESI).
Data for 7. 1H NMR (CDCl3, 400 MHz) not fully coalesced:
d 7.33–7.03 (br m, s, 4H total), 5.93 (complex m, 1H), 5.11
(br m, 2H), 4.45–4.21 (br m, 1H), 3.88 (br s, 3H), 2.87
(pentet, J¼7.0 Hz, 1H), 2.78 (br m, 1H), 1.52, 1.34 (br s, 9H
total); 13C NMR (CDCl3, 100 MHz) major peaks d 154.7,
141.2, 137.2, 136.2, 133.6, 130.2, 123.0, 128.9, 127.4,
126.9, 117.6, 80.8, 80.2, 62.7, 54.0, 53.1, 34.4, 28.5; IR
(film, cm21) 3440, 1697; TLC Rf 0.35 (30% EtOAc/
hexane). Exact mass calcd for [C16H23NO3Na]þ requires
m/z 300.1570. Found 300.1576 (ESI).
4.6. Preparation of enone 5
To a stirred solution of (COCl)2 (0.059 g, 0.45 mmol) in
anhydrous CH2Cl2 (2.5 mL) was added DMSO (0.076 g,
0.97 mmol) at 278 8C. The reaction was stirred for 15 min
at 278 8C, upon which was added a solution of substrate
10a (0.11 g, 0.39 mmol) in CH2Cl2 (1.3 mL) via cannula
(followed by a rinse 2£0.50 mL CH2Cl2). The reaction was
stirred at 278 8C for an additional 15 min, followed by the
addition of Et3N (0.32 g, 3.1 mmol) dropwise. The reaction
mixture was allowed to warm to room temperature, then
partitioned between CH2Cl2 (20 mL) and sat. NaHCO3
(20 mL). The organic layer was then dried over sodium
sulfate, filtered, and concentrated to a crude oil that was
purified by silica gel chromatography to afford enone 7 in
91% yield.
4.5. Preparation of 7a
Compound 7 was subjected to a one-pot, two step Swern
oxidation/Grignard addition sequence according to the
method of Martin16 to afford 7a after silica gel chromato-
graphy (5% EtOAc/hexane, 71% yield).
Data for 7a. 1H NMR (CDCl3, 400 MHz) not fully
coalesced: d 7.42–7.02 (br m, 4H), 6.00–5.86 (overlapping
m, 2H), 5.30 (br m, 1H), 5.15–5.06 (br m, 3H), 4.43 (br m,
2H), 4.25–3.50 [4.19 (m), 3.95 (br m), 3.79 (dd, J¼15.4,
6.6 Hz), 3.57 (m), 3H total], 2.93–2.62 [2.89 (br m), 2.76
(br m), 2.67 (dd, J¼13.6, 8.8 Hz), 3H total], 1.51, 1.34 (br s,
9H total); 13C NMR (CDCl3, 100 MHz) major peaks d
155.0, 141.4, 140.5, 136.6, 135.6, 133.5, 130.2, 129.3,
128.4, 127.3, 117.7, 114.6, 113.8, 81.2, 80.4, 73.2, 72.0,
54.2, 53.2, 39.3, 39.0, 28.5; IR (film, cm21) 3465, 1709,
1600, 1579; TLC Rf 0.31 (20% EtOAc/hexane). Exact mass
calcd for [C18H25NO3Na]þ requires m/z 326.1735. Found
326.1732 (ESI).
Data for 5. 1H NMR (CDCl3, 400 MHz) not fully coalesced:
d 7.31 (br pentet, J¼7.6 Hz, 2H), 7.26 (br t, J¼8.0 Hz, 1H),
7.16 (br s, 1H), 5.88 (br d, J¼12.4 Hz, 1H), 5.68 (br m, 1H),
4.37 (br m, 1H), 3.81 (br m, 3H), 1.49, 1.34 (br s, 9H total);
13C NMR (CDCl3, 100 MHz) major peaks d 203.8, 153.9,
140.2, 135.6, 132.4, 129.9, 129.0, 128.9, 128.3, 127.4, 81.2,
50.7, 48.4, 28.6; IR (film, cm21) 1702, 1501; TLC Rf 0.24
(20% EtOAc/hexane). Exact mass calcd for
[C16H19NO3Na]þ requires m/z 296.1267. Found 296.1263
(ESI).
4.7. Conversion of enone 5 to ester 17
4.7.1. Preparation of azide 11. To a stirred solution of
enone 7 (0.023 g, 0.084 mmol) in anhydrous toluene
(0.50 mL) was added azidotrimethylsilane (0.048 g,
0.42 mmol) dropwise, followed by solid trimethyl acetic
acid (0.013 g, 0.13 mmol). To this was added a stock
solution of Et3N in CH2Cl2 (0.050 mL, 0.017 mmol). The
reaction was allowed to stir at room temperature for 3.5 h,
upon which TLC indicated reaction was complete. The
crude reaction mixture was applied directly to a short silica
gel plug, and filtered using 50% EtOAc/hexane as the
eluent. Concentration of the filtrate delivers azide 11 in 87%
yield.
4.5.1. Preparation of 8. TBS protection of substrate 7a was
performed in an analogous manner to that described above
to afford 8 which was purified by silica gel chromatography
(5% EtOAc/hexane, quantitative). Structural characteriz-
ation for this compound has been reported previously by
Grubbs and Miller.18
4.5.2. Preparation of 10. To a solution of 8 (0.19 g,
0.45 mmol) in CH2Cl2 (130 mL) was added ruthenium
catalyst 9 (0.038 g, 0.045 mmol) in one portion. The
solution was heated under reflux for 24 h. The reaction
was cooled to room temperature, then concentrated to a
crude oil that was purified by silica gel chromatography (5%
EtOAc/hexane) to give the known octacycle 10 in 90%
yield.18
Data for 11. 1H NMR (CDCl3, 400 MHz) not fully
coalesced: d 7.33 (br pentet, J¼7.8 Hz, 2H), 7.22 (m, 1H),
7.13 (d, J¼7.2 Hz, 1H), 4.40 (br m, 1H), 4.26 (br m, 1H),
3.79 (dd, J¼37.0, 18.0 Hz, 1H), 3.59 (d, J¼18.0 Hz, 1H),
2.91–2.64 [2.87 (br t, J¼4.4 Hz), 2.71 (m), 2H total], 2.46
(br d, J¼12.0 Hz, 1H), 1.32, 1.24 (s, 9H total); 13C NMR
(CDCl3, 100 MHz) major peaks d 204.0, 134.5, 130.3,
130.1, 129.2, 129.0, 128.3, 128.1, 127.6, 60.3, 54.0, 48.9,
42.9, 28.3, 27.1; IR (film, cm21) 2112, 1709; TLC Rf 0.45
(20% EtOAc/hexane). Exact mass calcd for
[C16H20N4O3Na]þ requires m/z 339.1418. Found
339.1433 (ESI).
4.5.3. Preparation of 10a. TBS ether cleavage of substrate
10 followed the same procedure using pyridinium p-toluene-
sulfonate as described above to afford 10a, which was carried
on without further purification (quantitative).
Data for 10a. 1H NMR (CDCl3, 400 MHz) not fully
coalesced: d 7.27–7.16 (m, 3H), 7.05 (br s, 1H), 5.53 (br
m, 1H), 5.29 (br m, 1H), 5.02 (br m, 1H), 3.86–3.40 [3.80
(br m), 3.60 (br m), 3.46 (br m), 3H total], 1.90 (br s, 1H),
1.53, 1.35 (br s, 9H total); 13C NMR (CDCl3, 100 MHz)
major peaks d 154.5, 139.3, 138.0, 135.7, 130.7, 128.2,
127.5, 127.2, 124.0, 80.3, 67.5, 48.6, 42.7, 28.6; IR (film,
4.8. Preparation of indole 15
To a stirred solution of azide 11 (0.12 g, 0.38 mmol) in

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CH2Cl2 (1.0 mL) was added trifluoroacetic acid (1.0 mL).
The reaction mixture was allowed to stir at room
temperature for no more than 5 min. During this time, the
solution changed from colorless to a dark purple solution.
The reaction was slowly quenched with sat. NaHCO3 until
gas evolution ceased, and the aqueous layer was pH 8 (pH
paper). The organic layer was dried over sodium sulfate,
filtered, and concentrated to an oil that solidified on high
vacuum to give indole derivative 15 (92% yield) that was
carried on immediately to the next step (product begins to
slowly decompose at room temperature).
organic extracts were then washed with 10% citric acid
solution, which was then immediately extracted with
copious amounts of CH2Cl2. The combined organic extracts
were dried over sodium sulfate, filtered, and concentrated to
afford a crude solid 16a that was used to the next step
without further purification.
4.9.2. Preparation of ester 17. To a stirred solution of 16a
(0.050 g, 0.21 mmol) in anhydrous DMF (1.0 mL) was
added Hunig’s base (0.13 g, 1.0 mmol) and ethyl iodide
(0.16 g, 1.0 mmol). The reaction was heated at 50 8C for
24 h. The reaction was then cooled to room temperature, and
partitioned between 10% NH4Cl and Et2O. The organic
layer was washed with additional 10% NH4Cl, dried over
sodium sulfate, filtered, and concentrated to a crude solid
that was purified by silica gel chromatography (20% EtOAc/
hexane) to deliver 17 in 92% yield.
Data for 15. 1H NMR (CDCl3, 400 MHz) d 7.56 (d,
J¼8.0 Hz, 1H), 7.23 (d, J¼8.0 Hz, 1H), 7.15 (t, J¼7.2 Hz,
1H), 7.09 (t, J¼7.2 Hz, 1H), 6.24 (s, 1H), 4.77 (septet,
J¼4.0 Hz, 1H), 4.33 (dd, J¼10.8, 6.6 Hz, 1H), 4.06 (dd,
J¼10.8, 4.0 Hz, 1H), 3.40 (dd, J¼16.8, 7.2 Hz, 1H), 3.13
(dd, J¼16.8, 4.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d
140.1, 132.6, 132.4, 120.6, 120.4, 119.4, 109.2, 93.8, 63.0,
49.3, 31.4; IR (film, cm21) 2106, 1709; TLC Rf 0.60 (20%
EtOAc/hexane). Exact mass calcd for [C11H10N4Na]þ
requires m/z 221.0806. Found 221.0803 (ESI).
1
Data for 17. H NMR (CDCl3, 400 MHz) d 8.17 (m, 1H),
7.32–7.28 (m, 3H), 4.89 (septet, J¼3.6 Hz, 1H), 4.42 (q,
J¼13.2, 7.6 Hz, 2H), 4.39 (dd, J¼11.8, 6.8 Hz, 1H), 4.14
(dd, J¼11.2, 3.6 Hz, 1H), 3.68 (dd, J¼18.2, 7.0 Hz, 1H),
3.47 (dd, J¼17.8, 3.8 Hz, 1H), 1.47 (t, J¼7.0 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) d 164.7, 148.2, 146.9, 132.4,
130.3, 122.1, 121.7, 121.4, 109.6, 62.3, 59.5, 50.3, 33.3,
14.7; IR (film, cm21) 2099, 1690; TLC Rf 0.33 (20%
EtOAc/hexane). Exact mass calcd for [C14H14N4O2Na]þ
requires m/z 293.1014. Found 293.1004 (ESI).
4.9. Preparation of aldehyde 16
To a stirred round-bottom flask containing anhydrous DMF
(0.44 mL) under nitrogen was added POCl3 (0.18 g,
1.2 mmol) dropwise at 0 8C. Let stir for 30 min at 0 8C.
To this was added a solution of substrate 15 in CH2Cl2/
pyridine (4:1, 2.8 mL) by cannula (followed by a rinse of the
same solvent, 3£0.70 mL). The reaction was allowed to
slowly warm to room temperature and stirred for an
additional 5 h. The reaction was then quenched with
aqueous sat. NaOAc (10 mL) at 0 8C, and stirred for 12 h.
The reaction mixture was then partitioned between CH2Cl2
(30 mL) and brine (30 mL). The organic layer was dried
over sodium sulfate, filtered, and concentrated to a crude oil
which was purified by silica gel chromatography (30%
EtOAc/hexane) to deliver 16 as a reddish solid (71% yield),
that was immediately carried on to the next step.
4.9.3. Synthesis of peptides. Peptide catalysts were
prepared employing standard solution phase coupling
techniques, utilizing commercially available amino acid
derivatives with EDC (1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimidehydrochloride) as the coupling agent and
HOBt (1-hydroxybenzotriazole) as a racemization suppres-
sant. The resulting peptides were then purified by silica gel
flash column chromatography (2–5% MeOH/CH2Cl2).
Data for 12a,b. Characterization data for these compounds
has been reported previously.11
1
Data for 16. H NMR (CDCl3, 400 MHz) d 10.0 (s, 1H),
Data for 13. 1H NMR (CDCl3, 400 MHz) d 8.08 (d,
J¼8.5 Hz, 1H), 7.81 (br m, 1H), 7.77 (d, J¼8.0 Hz, 1H),
7.71 (d, J¼7.9 Hz, 1H), 7.55 (br m, 1H), 7.51–7.36 (m, 5H),
7.29–7.26 (m, 2H), 7.21–7.06 (m, 5H), 7.01 (br s, 1H), 6.94
(br m, 1H), 6.82 (br m, 1H), 6.32 (br s, 1H), 5.92 (pentet,
J¼7.0 Hz), 4.97 (br m, 1H), 4.71 (d, J¼15.0 Hz, 1H), 4.60–
4.51 (br m, 2H), 4.43 (br m, 1H), 4.21 (d, J¼8.7 Hz, 1H),
3.01–2.98 (br m, 2H), 2.90 (dd, J¼7.6, 13.9 Hz, 1H), 2.76
(dd, J¼7.0, 14.8 Hz, 1H), 1.58 (d, J¼6.7 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) d 170.9, 170.8, 169.0, 155.1, 138.9,
137.6, 136.5, 136.2, 135.6, 133.7, 130.8, 129.2, 128.8,
128.6, 128.3, 128.1, 127.9, 127.3, 126.6, 126.2, 125.6,
125.2, 123.3, 122.5, 117.2, 79.8, 61.4, 55.4, 53.6, 50.7, 44.8,
38.9, 34.7, 31.0, 28.5, 27.0, 21.7; IR (film, cm21) 3298,
2973, 1698, 1674, 1660, 1638; TLC Rf 0.25 (5% MeOH/
CH2Cl2). Exact mass calcd for [C45H54N6O5Na]þ requires
m/z 781.4053. Found 781.4051 (ESI).
8.19 (br d, J¼7.2 Hz, 1H), 7.33–7.27 (m, 3H), 4.94 (septet,
J¼3.6 Hz, 1H), 4.38 (dd, J¼11.0, 6.4 Hz, 1H), 4.13 (dd,
J¼11.4, 3.8 Hz, 1H), 3.65 (dd, J¼18.4, 7.2 Hz, 1H), 3.42
(dd, J¼18.0, 3.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d
182.9, 150.8, 132.7, 129.2, 123.1, 122.8, 121.1, 110.7,
109.9, 62.4, 50.3, 31.8; IR (film, cm21) 2099, 1659; TLC Rf
0.41 (50% EtOAc/hexane). Exact mass calcd for
[C12H10N4ONa]þ requires m/z 249.0760. Found 249.0752
(ESI).
4.9.1. Preparation of acid 16a. To a stirred suspension of
16 (0.15 g, 0.67 mmol) in dioxane (13 mL) and 2-methyl-2-
butene (1.0 mL) was added a solution of NaClO2 (0.54 g)
and NaH2PO4 (0.54 g) in H2O (5.0 mL) over 10 min at 0 8C.
The reaction was warmed to room temperature, and stirred
for an additional 5 h. The reaction mixture was then charged
with an additional 0.34 g each of NaClO2 and NaH2PO4,
and stirred for an additional 12 h at room temperature. The
reaction mixture was partitioned between aqueous 5%
NaOH (40 mL) and CH2Cl2 (40 mL). The aqueous layer
was washed with CH2Cl2 (2£20 mL). The combined
4.10. Conversion of ester 17 to aziridinomitosene 22
4.10.1. Preparation of nitrated indole 20. To a stirred
solution of 17 (0.050 g, 0.185 mmol) in anhydrous Ac2O

K. Tsuboike et al. / Tetrahedron 60 (2004) 7367–7374
7373
(1.8 mL) was added cupric nitrate (0.045 g, 0.185 mmol) at
210 8C. The reaction was allowed to slowly warm to room
temperature and stirred for 16 h. The reaction mixture was
partitioned between sat. NaHCO3 (20 mL) and EtOAc
(40 mL). The aqueous layer was extracted with EtOAc
(2£15 mL). The combined organic extracts were dried over
sodium sulfate, filtered, and concentrated to a crude mixture
of nitrated compounds that was purified by silica gel
chromatography (20% EtOAc/hexane) to afford nitrated
indole 20 in 36% yield. Recrystallization from Et2O gave an
analytical sample.
then concentrated to a crude product that was purified by
silica gel chromatography (50% EtOAc/hexane to 80%
EtOAc/hexane) to afford aziridinomitosene 22 in 57% yield.
1
Data for 22. H NMR (CDCl3, 500 MHz) d 8.16 (br d,
J¼8.8 Hz, 1H), 8.14 (br d, J¼1.7 Hz, 1H), 8.10 (br d,
J¼8.8 Hz, 1H), 4.44 (qd, J¼7.1, 10.6 Hz, 1H), 4.42 (qd,
J¼7.1, 10.6 Hz, 1H), 4.33 (br d, J¼10.9 Hz, 1H), 4.21 (br d,
J¼10.9 Hz, 1H), 4.10 (br s, 0.6H), 3.84 (br s, 0.4H), 3.77 (br
s, 0.6H), 3.62 (br s, 0.4H), 1.51 (br s, 0.6H), 1.45 (t,
J¼7.1 Hz, 3H), 0.75 (br s, 0.4H); 13C NMR (CDCl3,
100 MHz) d 163.9, 154.0, 143.4, 134.5, 131.7, 121.9, 117.2,
116.9, 106.2, 60.2, 48.0, 40.4, 38.9, 33.3, 32.8, 14.7; IR
(film, cm21) 1696, 1514, 1342; TLC Rf 0.27 (EtOAc). Exact
mass calcd for [C14H14N3O4]þ requires m/z 288.0984.
Found 288.0980 (ESI).
Data for 20. 1H NMR (CDCl3, 400 MHz) d 8.23 (d,
J¼2.0 Hz, 1H), 8.20 (d, J¼8.9 Hz, 1H), 8.14 (dd, J¼2.0,
8.9 Hz, 1H), 4.95 (septet, J¼3.3 Hz, 1H), 4.46 (dd, J¼6.4,
11.4 Hz, 1H), 4.40 (q, J¼7.1 Hz, 2H), 4.22 (dd, J¼3.2,
11.4 Hz, 1H), 3.70 (dd, J¼7.0, 18.4 Hz, 1H), 3.50 (dd,
J¼3.6, 18.4 Hz, 1H), 1.44 (t, J¼7.1 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) d 163.9, 153.4, 143.1, 135.2, 131.2,
121.5, 117.1, 106.6, 102.0, 62.4, 60.3, 51.2, 34.0, 14.8; IR
(film, cm21) 2114, 1692, 1513, 1337; TLC Rf 0.49 (50%
EtOAc/hexane). Exact mass calcd for [C14H13N5O4Na]þ
requires m/z 338.0865. Found 338.0861 (ESI).
Acknowledgements
This research is supported by National Science Foundation
(CHE-0236591). In addition, we are grateful to support
from Ube Industries, Ltd (Japan) for support of K. T. S. J. M.
thanks the Merck Chemistry Council and Pfizer Global
Research for support. S. J. M. is a Fellow of the Alfred
P. Sloan Foundation and a Camille Dreyfus Teacher-
Scholar. The authors wish to thank T. J. Paxton for critical
assistance in the preparation of intermediates.
4.10.2. Preparation of bromide 21. To a stirred solution of
20 (0.074 g, 0.235 mmol) in anhydrous benzene (6.0 mL)
was added N-bromosuccinimide (0.125 g, 0.705 mmol)
followed by a catalytic amount of benzoyl peroxide. The
reaction was heated at 75 8C for 17.5 h. An additional
catalytic amount of benzoyl peroxide was added and the
reaction was heated at 75 8C for an additional 13.5 h. The
reaction mixture was then charged with an additional
0.042 g of N-bromosuccinimide and a catalytic amount of
benzoyl peroxide, and heated at 75 8C for an additional
8.5 h. The reaction was cooled to room temperature, and
partitioned between sat. NaHCO3 (40 mL) and CH2Cl2
(30 mL). The aqueous layer was extracted with CH2Cl2
(2£15 mL). The combined organic extracts were dried over
sodium sulfate, filtered, and concentrated to a crude product
that was purified by silica gel chromatography to afford
bromide 21 in 36% yield. Recrystallization from hexane/
EtOAc gave an analytical sample for X-ray crystallographic
analysis.
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Data for 21. 1H NMR (CDCl3, 400 MHz) d 8.30 (d,
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