Formal asymmetric synthesis of a 7-methoxyaziridinomitosene

Article abstract of DOI:10.1055/s-2006-951532

The conversion of (-)-2,3-O-isopropylidene-D-erythronolactone (14) and 2-benzyloxy-6-bromo-4-methoxy-3-methylaniline (18) into {(1R,2R)-(-)-1-azido-2, 3,5,8-tetrahydro-7-methoxy-6-methyl-2-methanesulfonyloxy-5,8-dioxo-1H-pyrrolo- [1,2-a]indol-9-yl}methyl phenyl carbonate (39) has been accomplished in 17 steps by way of the enaminone 26. Key steps included the preparation of 26 by a Reformatsky reaction on a thiolactam precursor 25, and intramolecular Heck reaction of 26 to form the indole ring. The preparation of 39 constitutes a formal synthesis of the fully functionalised 7-methoxyaziridinomitosene 12, only the second such synthesis to have been accomplished. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951532

3284
LETTER
Formal Asymmetric Synthesis of a 7-Methoxyaziridinomitosene
A
symmetr
o
ic Synthesis
s
of
a
7-Me
e
thoxyazirid
p
inomitoseneh P. Michael,* Charles B. de Koning, Theophilus T. Mudzunga, Riaan L. Petersen
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, PO Wits 2050, South Africa
Fax +27(11)7176749; E-mail: jmichael@chem.wits.ac.za
Received 8 September 2006
O
A
O
10 OCONH2
OMe
OCONH2
NY
Abstract: The conversion of (–)-2,3-O-isopropylidene-D-erythro-
nolactone (14) and 2-benzyloxy-6-bromo-4-methoxy-3-methyl-
aniline (18) into {(1R,2R)-(–)-1-azido-2,3,5,8-tetrahydro-7-
methoxy-6-methyl-2-methanesulfonyloxy-5,8-dioxo-1H-pyrrolo-
[1,2-a]indol-9-yl}methyl phenyl carbonate (39) has been accom-
plished in 17 steps by way of the enaminone 26. Key steps included
the preparation of 26 by a Reformatsky reaction on a thiolactam pre-
cursor 25, and intramolecular Heck reaction of 26 to form the indole
ring. The preparation of 39 constitutes a formal synthesis of the ful-
ly functionalised 7-methoxyaziridinomitosene 12, only the second
such synthesis to have been accomplished.
R
7
6
1
X
B
N
C
NH
N
Me
2
3
O
O
O
1 Mitomycin A R = OMe
2 Mitomycin C R = NH2
3
R1
CO2Et
CO2Et
R1
R2
N
NR3
N
NR3
Key words: antitumour agents, asymmetric synthesis, aziridines,
R2
enaminones, Heck reaction
O
4 R1 = R3 = H; R2 = NO2
5 R1 = R2 = R3 = H
7 R1 = OMe; R1 = Me; R3 = Bn
8 R1 = NH2; R2 = Me; R3 = H
9 R1 = R2 = H; R3 = Bn
6 R1 = OMe; R2 = CHO; R3 = H
The mitomycins,1 e.g. mitomycin A (1) and mitomycin C
(2), are quinone-containing antitumour antibiotics, the
biological activity of which is attributable to DNA alkyla-
tion and cross-linking.2 The unique mode of action of
these antibiotics entails initial elimination of methanol
followed by bioreduction of the quinone unit in the hy-
poxic environment of tumour cells to give a hydroquinone
(a leucoaziridinomitosene), which is the active form of the
drug. The sequence of reactions that spontaneously ensues
eventually leads to the formation of covalent bonds be-
tween DNA and the electrophilic aziridine (C-1) and car-
bamate (C-10) sites. The mitomycins can be converted
chemically into pyrrolo[1,2-a]indoles 3 (aziridinomito-
senes),3 several of which have shown substantial anti-
tumour action without the need for prior bioreductive
activation.3a,4 Considerable effort has been devoted to the
total synthesis of mitomycins and their analogues, includ-
ing the aziridinomitosenes.5 However, rarely have de
novo syntheses of the latter succeeded in incorporating all
of the reactive functionalities, namely 6,7-disubstituted
quinone, carbamate and aziridine, into the same target
structure. Thus, while aziridinomitosenes such as 4,6 5,7
6,8 7,9 810 and 911 (Figure 1), which bear a robust ester
substituent at C-9 instead of the labile carbamate, have
been synthesised; the only reported synthetic (as opposed
to semisynthetic) aziridinomitosenes bearing all three re-
active components appear to be the compounds 10, 114c
and 12.12 Of these, only compound 12, prepared by Dong
and Jimenez, also bears appropriate substituents in ring A.
In this communication we report a new approach to the
synthesis of 12, which has resulted in only the second, al-
O
OCONH2
NR3
R1
R2
10 R1 = R2 = H; R3 = Me
11 R1 = H; R2 = R3 = Me
12 R1 = OMe; R2 = Me; R3 = H
N
O
Figure 1
beit formal, synthesis of this fully functionalised 7-meth-
oxyaziridinomitosene, which also has proven antitumour
activity.4b
In an ongoing programme on the use of enaminones in the
synthesis of alkaloids and related compounds,13,14 we re-
cently described an asymmetric synthesis of the N-phos-
phorylated aziridinomitosene analogue 13 from (–)-2,3-
O-isopropylidene-D-erythronolactone (14) and 2-bromo-
aniline15 (Scheme 1). The key steps of the route included
a novel Reformatsky reaction of the thiolactam intermedi-
ate 15, intramolecular Heck-type cyclisation of the result-
ing enaminone 16 to form the tetracyclic product 17, and
late-stage elaboration of the aziridine ring via a cyclic
sulfite. We had previously demonstrated the versatility of
the pivotal Heck-type cyclisation in a series of model
cyclisations,16 while a similar reaction featured in an ear-
lier mitosene synthesis by Luly and Rapoport,17 who
cyclised an N-(2-bromobenzoquinone) enaminone to give
a pyrrolo[1,2-a]indole-5,8-dione system directly. We ex-
pected that our route to 13 could easily be adapted for the
preparation of 12 if we started with a suitably substituted
2-bromoaniline bearing functionality that would favour
oxidation of the ring to the quinone level found in the
target system.
SYNLETT 2006, No. 19, pp 3284–3288
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951532; Art ID: D26706ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Synthesis of a 7-Methoxyaziridinomitosene
3285
O
Br
N
Br
N
properties of which agreed with those previously report-
ed.18 Benzylation of the second hydroxy group under
more vigorous conditions yielded the doubly protected ni-
troresorcinol 22, which was reduced to a rather sensitive
aniline with hydrazine hydrate over Raney nickel in boil-
ing methanol. The crude aniline was immediately bromi-
CO2Et
O
4 steps
72%
S
i
O
90%
O
O
O
O
O
14
15
16
ii 99%
CO2Et
nated with molecular bromine in
a mixture of
dichloromethane and acetic acid to complete the synthesis
of the desired bromoaniline 18 in 77% yield over the two
steps. The entire reaction sequence from 2-methylresorci-
nol to 18 could also be performed on a scale of ca. 25
grams without purification of the intermediates in an over-
all yield of approximately 45%.
CO2Et
5 steps
39%
O
O
N
NPO(OMe)2
N
13
17
Scheme 1 Reagents and conditions: (i) Zn (5 equiv), BrCH2CO2Et
(3 equiv), I2 (0.2 equiv), THF, ultrasound, then 15, THF, reflux; (ii)
Pd(OAc)2 (0.1 equiv), PPh3 (0.4 equiv), KOAc (7.5 equiv), Bu4NBr
(2.5 equiv), DMF–MeCN–H2O (1:1:0.2), 100 °C, 5 h.
The absolute configuration of the aziridinomitosene target
is derived from the second reaction partner, (–)-2,3-O-iso-
propylidene-D-erythronolactone (14), which was pre-
pared in 77% yield by a published method that entails
oxidative cleavage of D-isoascorbic acid with hydrogen
peroxide followed by ketal exchange with 2,2-dimethoxy-
propane.19 Since we had previously found that this lactone
reacted poorly with 2-bromoaniline unless the latter was
deprotonated first, we treated a solution of 18 in tetra-
hydrofuran with ethylmagnesium chloride at –50 °C be-
fore introducing 14 and allowing the mixture to warm to
room temperature (Scheme 2). Although the alcohol in-
termediate 23 could be purified for characterisation pur-
poses, we chose to convert it directly into the lactam 24.
The cyclisation was accomplished by mesylation fol-
lowed by treatment with sodium hydride in a mixture of
The precursor we settled on was 2-benzyloxy-6-bromo-4-
methoxy-3-methylaniline (18), which we prepared in six
steps from 2-methylresorcinol (19). Following a proce-
dure introduced by Raphael and Ravenscroft,18 19 was
treated with sodium nitrite in acidic medium, and the re-
sulting nitroso intermediate was further oxidised to the ni-
tro product 20 with 70% concentrated nitric acid
(Scheme 2). Regioselective methylation of the less hin-
dered hydroxy group with dimethyl sulfate at ambient
temperature gave the crystalline product 3-methoxy-2-
methyl-6-nitrophenol (21), the physical and spectroscopic
HO
Me
HO
Me
MeO
Me
MeO
Me
i, ii
iv
iii
57%
78%
87%
NO2
NO2
NO2
OH
OH
OH
OBn
19
20
21
22
v, vi
77%
MeO
Br
MeO
Me
Br
N
O
MeO
Me
Br
O
viii, ix
vii
Me
N
90%
from 18
H
O
O
NH2
OBn
HO
OBn
x
O
OBn
O
24
23
18
73%
CO2Et
MeO
Me
Br
MeO
Me
Br
CO2Et
O
MeO
S
xi
xii
82%
O
O
87%
N
N
N
Me
O
OBn
OBn
OR
O
O
27 R =
xiv
92%
xiii
90%
26
Bn
25
28 R = H
Scheme 2 Reagents and conditions: (i) NaNO2, H2SO4, H2O, r.t., 45 min; (ii) HNO3 (70%), H2O, r.t., 70 h; (iii) Me2SO4, K2CO3, acetone, r.t.,
20 h; (iv) BnBr, K2CO3, acetone, reflux, 41 h; (v) NH2NH2·H2O, Raney nickel, MeOH, reflux, 1.5 h; (vi) Br2, CH2Cl2–AcOH, r.t., 6 h;
(vii) EtMgCl, THF, –50 °C, 50 min, then 14, –50 °C to r.t., 22 h; (viii) MsCl, Et3N, CH2Cl2, 0 °C to r.t., 7 d; (ix) NaH, THF–DMF, r.t., 20 h;
(x) Lawesson’s reagent, toluene, reflux, 2.5 h; (xi) BrZnCH2CO2Et (from BrCH2CO2Et, Zn, I2, THF, ultrasound), THF, reflux, 120 h; (xii)
Pd(OAc)2 (0.3 equiv), P(o-Tol)3, Et3N, DMF, MeCN, H2O, reflux, 4 h; (xiii) Pd(OAc)2 (1.6 equiv), P(o-Tol)3, Et3N, DMF, MeCN, H2O, reflux,
4 h; (xiv) 10% Pd/C, H2, EtOH, HCl (1 drop), r.t., 2 h.
Synlett 2006, No. 19, 3284–3288 © Thieme Stuttgart · New York

3286
J. P. Michael et al.
LETTER
tetrahydrofuran and N,N-dimethylformamide at room in the newly formed ring B into the carbamoyloxymethyl
temperature. The conversion of the bromoaniline into lac- substituent; and replacement of the ketal in ring C by an
tam 24 could be performed on a 20-gram scale without pu- aziridine ring with inversion of configuration at both
rification of intermediates in an overall yield of 90%. The stereogenic sites. The timing of these interconversions
product was found to exist as a 1:1 mixture of two separa- proved to be tricky. In investigating several variants in
ble rotamers that could be individually characterised, al- which the order of the reactions was altered, we either ran
though this was not necessary in view of the later into dead ends or discovered unwelcome competing pro-
convergence of these intermediates to a single product.
cesses. The most successful approach entailed initial re-
moval of the benzyl protecting group from the
pyrrolo[1,2-a]indole 27, which was efficiently accom-
plished by hydrogenolysis over 10% palladium on carbon
to give the phenol 28 in 92% yield. Thereafter, reduction
of the ester to an alcohol with lithium aluminium hydride
was immediately followed by oxidation of ring A to a
quinone, which proved to be reasonably robust in further
transformations (Scheme 3). The hydride reduction
turned out to be particularly awkward; if the reaction were
not carefully monitored by thin layer chromatography,
over-reduction occurred, giving the 3-methylindole 29 in
reasonable yield. With careful control of conditions, the
desired diol 30 could be isolated in approximately 78%
yield. However, since this compound decomposed quite
rapidly, it was oxidised without further purification with
molecular oxygen and a catalytic quantity of salcomine in
N,N-dimethylformamide at room temperature to give the
quinone 31 in a disappointing overall yield of 42%. This
process also produced a small quantity (5%) of the alde-
hyde 32.
With both rings A and C in place, the next task was to
complete the construction of the pyrrolo[1,2-a]indole
skeleton by means of the tandem Reformatsky–Heck se-
quence that we had successfully used in preparing the
model system 13. To this end, the rotameric mixture of
lactams was thionated with Lawesson’s reagent in boiling
toluene to yield the thiolactam 25, also as a mixture of rot-
amers, in 73% yield. Not surprisingly, when the lactam
rotamers were separated and individually subjected to
thionation, both produced rotameric mixtures of the thi-
olactam. Conversion of 25 into the vinylogous urethane
26 was achieved by extended reaction in boiling tetrahy-
drofuran with an excess of the organozinc reagent formed
by sonicating activated zinc powder with ethyl bromoac-
etate in the presence of iodine as catalyst.20 The product,
yet again a mixture of two rotamers, was obtained in re-
producibly good yields of above 85% yield on scales as
large as five grams. The crucial intramolecular Heck cy-
clisation reaction was then achieved by adapting condi-
tions devised by Tietze and Petersen21 in which a carefully
balanced combination of solvent, base, ligand and addi- At this point, problems with the sensitive hydroxymethyl
tives was employed. In this case, the reactant was heated substituent necessitated its protection. Acetylation of 31
at reflux with palladium(II) acetate (0.3 equiv), tri-o- under standard conditions afforded 33 in 97% yield. How-
tolylphosphine and triethylamine in the mixed solvent ever, the subsequent hydrolysis of the acetonide proved to
system of N,N-dimethylformamide, acetonitrile and water be surprisingly difficult to accomplish. We eventually
(5:5:1) to give 27 in 82% yield.22 In one case, when an ex- succeeded by treating 33 with a mixture of acetic acid,
cess of palladium acetate (1.6 equiv) was used, the benzyl tetrahydrofuran and water at 65 °C;23 but diol 34 was
protecting group was also lost, giving the free phenol 28 obtained in only 46% yield. The formation of the aziridine
in 90% yield.
ring by the double SN2 displacement of the diol was then
envisaged by the method we had previously used in mak-
ing the aziridinomitosene model 13.15 Reaction of 34 with
thionyl chloride and triethylamine in dichloromethane
produced a 1:1 mixture of the two separable cyclic sulfite
Three tasks remained in converting the advanced interme-
diate 27 into the desired aziridinomitosene target: oxida-
tion of ring A to the quinone level; conversion of the ester
O
O
OH
OH
CHO
MeO
Me
MeO
MeO
Me
iii
ii
O
O
O
O
O
O
+
28
N
N
N
42% + 5%
from 28
Me
OH
O
O
O
31
32
30
i
61%
iv 97%
OAc
O
O
OAc
Me
MeO
Me
MeO
Me
MeO
Me
v
O
O
OH
OH
O
O
46%
N
N
N
O
OH
29
33
34
Scheme 3 Reagents and conditions: (i) LiAlH4 (3 equiv), THF, 0 °C to r.t., 50 h; (ii) LiAlH4 (3 equiv), THF, 0 °C to r.t., 25 h; (iii) Salcomine,
DMF, O2, r.t., 3 h; (iv) Et3N, Ac2O, CH2Cl2, r.t., 18 h; (v) AcOH, THF, H2O, 65 °C, 48 h.
Synlett 2006, No. 19, 3284–3288 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of a 7-Methoxyaziridinomitosene
3287
O
O
O
O
OAc
OAc
OH
MeO
Me
MeO
Me
MeO
Me
ii, iii
iv
i
O
O
N3
N3
34
O
78%
79%
68%
S
N
N
N
OH
OH
O
O
35
36
37
v
87%
O
O
OCONH2
NH
O
O
O
O
OCO2Ph
OCO2Ph
MeO
Me
MeO
Me
MeO
ref. 12
vi
98%
N3
N3
N
N
N
Me
OMs
OH
12
39
38
Scheme 4 Reagents and conditions: (i) SOCl2, Et3N, THF, –15 °C to r.t., 1 h; (ii) NaN3, DMF, 55 °C, 2 h; (iii) H2SO4, THF, H2O, r.t., 2 h;
(iv) K2CO3, MeOH, r.t., 1 h; (v) PhOCOCl, pyridine, CH2Cl2, 0 °C to r.t., 3 h; (vi) MsCl, Et3N, CH2Cl2, r.t., 22 h.
diastereomers 35 in 78% yield (Scheme 4). As in our ear- References and Notes
lier studies, conversion of the sulfite into the more reac-
tive sulfate was not necessary for further reaction with
(1) (a) Franck, R. W. Fortschr. Chem. Org. Naturst. 1978, 38,
1. (b) Remers, W. A.; Dorr, R. T. In Alkaloids: Chemical
azide ion; simply treating the mixture of sulfite diastereo-
mers with sodium azide in N,N-dimethylformamide at 55
°C followed by treatment with aqueous sulfuric acid gave
the azido alcohol 36 as a single regioisomer in 68% yield.
The most effective strategy from this point onwards in-
volved hydrolysis of the acetate with potassium carbonate
in methanol (79%), and selective acylation of the primary
alcohol of product 37 with phenyl chloroformate (87%).
Finally, treatment of the carbonate 38 with methanesulfo-
nyl chloride and triethylamine in dichloromethane afford-
ed the mesylate 39 in 98% yield. The spectroscopic data
recorded on this compound24 agreed with those reported
by Dong and Jimenez,12 who obtained the same interme-
diate by a quite different route. These authors completed
the synthesis of 12 by treating 39 with gaseous ammonia
to make the carbamate, followed by Staudinger reaction
of the azide with triphenylphosphine and intramolecular
displacement of the mesylate by the intermediate imino-
phosphorane.
and Biological Perspectives, Vol. 6; Pelletier, S. W., Ed.;
John Wiley & Sons: New York, 1988, 1–74.
(2) Reviews: (a) Tomasz, M. Chem. Biol. 1995, 2, 575.
(b) Rajski, S. R.; Williams, R. M. Chem. Rev. 1998, 98,
2723. (c) Wolkenberg, S. E.; Boger, D. L. Chem. Rev. 2002,
102, 2477. (d) Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju,
J.; Thorson, J. S.; Shen, B. Chem. Rev. 2005, 105, 739.
(3) (a) Patrick, J. B.; Williams, R. P.; Meyer, W. E.; Fulmor, W.;
Cosulich, D. B.; Broschard, R. W.; Webb, J. S. J. Am. Chem.
Soc. 1964, 86, 1889. (b) Danishefsky, S.; Egbertson, M. J.
Am. Chem. Soc. 1986, 108, 4648. (c) Han, I.; Kohn, H. J.
Org. Chem. 1991, 56, 4648.
(4) (a) Iyengar, B.; Remers, W.; Bradner, W. J. Med. Chem.
1986, 29, 1864. (b) Li, V.-S.; Choi, D.; Tang, M.-S.; Kohn,
H. J. Am. Chem. Soc. 1996, 118, 3765. (c) Vedejs, E.;
Naidu, B. N.; Klapars, A.; Warner, D. L.; Li, V.-S.; Na, Y.;
Kohn, H. J. Am. Chem. Soc. 2003, 125, 15796.
(5) Reviews: (a) Kasai, M.; Kono, M. Synlett 1992, 778.
(b) Danishefsky, S. J.; Schkeryantz, J. M. Synlett 1995, 475.
(c) See also: Coleman, R. S.; Felpin, F.-X.; Chen, W. J. Org.
Chem. 2004, 69, 7309; and references cited therein.
(6) Tsuboike, K.; Guerin, D. J.; Mennen, S. M.; Miller, S. J.
Tetrahedron 2004, 60, 7367.
(7) Vedejs, E.; Little, J. D. J. Org. Chem. 2004, 69, 1794.
(8) Kim, M.; Vedejs, E. J. Org. Chem. 2004, 69, 7262.
(9) Shaw, K. J.; Luly, J. R.; Rapoport, H. J. Org. Chem. 1985,
50, 4515.
Our preparation of 39 thus constitutes a formal synthesis
of the target 7-methoxyaziridinomitosene 12. Attempts
are currently under way to improve the yields of the trou-
blesome oxidation and ketal deprotection steps, and to ap-
ply the new methodology to the synthesis of additional
analogues of 12 for biological evaluation.
(10) Edstrom, E.; Yu, T. Tetrahedron 1997, 53, 4549.
(11) Vedejs, E.; Piotrowski, D. W.; Tucci, F. C. J. Org. Chem.
2000, 65, 5498.
(12) Dong, W.; Jimenez, L. J. Org. Chem. 1999, 64, 2520.
(13) Review: Michael, J. P.; de Koning, C. B.; Gravestock, D.;
Hosken, G. D.; Howard, A. S.; Jungmann, C. M.; Krause, R.
W. M.; Parsons, A. S.; Pelly, S. C.; Stanbury, T. V. Pure
Appl. Chem. 1999, 71, 979.
(14) Recent examples: (a) Michael, J. P.; de Koning, C. B.; San
Fat, C.; Nattrass, G. L. ARKIVOC 2002, (ix), 62.
(b) Michael, J. P.; de Koning, C. B.; Malefetse, T. J.; Yillah,
I. Org. Biomol. Chem. 2004, 2, 3510. (c) Michael, J. P.; de
Koning, C. B.; van der Westhuyzen, C. W. Org. Biomol.
Chem. 2005, 3, 836. (d) Michael, J. P.; de Koning, C. B.;
Pienaar, D. P. Synlett 2006, 383; and references cited
therein.
Acknowledgment
This work was supported by grants from the National Research
Foundation, Pretoria (grant number 2053652), the UK/SA Science
and Technology Fund, the Mellon Postgraduate Mentoring
Programme (sponsored by the Andrew W. Mellon Foundation), and
the University of the Witwatersrand. T.T.M. thanks the National
Research Foundation for a Post-Doctoral Fellowship. We are grate-
ful to Mr R. Mampa and Mr T. van der Merwe for recording NMR
spectra and mass spectra, respectively.
Synlett 2006, No. 19, 3284–3288 © Thieme Stuttgart · New York

3288
J. P. Michael et al.
LETTER
(15) Michael, J. P.; de Koning, C. B.; Petersen, R. L.; Stanbury,
T. V. Tetrahedron Lett. 2001, 42, 7513.
(16) Michael, J. P.; Chang, S.-F.; Wilson, C. Tetrahedron Lett.
1993, 34, 8365.
(17) Luly, J. R.; Rapoport, H. J. Org. Chem. 1984, 49, 1671.
(18) Raphael, R. A.; Ravenscroft, P. J. Chem. Soc., Perkin Trans.
1 1988, 1823.
120.12 (arom C), 112.21 (O2CMe2), 111.12 (arom C), 85.04
(=CHCO2Et), 80.03 (C-3a), 76.00 (OCH2Ph), 75.19 (C-6a),
58.82 (OCH2CH3), 57.68 (C-6), 55.93 (ArOCH3), 24.85,
26.75 (2 × CH3), 14.40 (OCH2CH3), 9.45 (ArCH3).
(21) Tietze, L. F.; Petersen, S. Eur. J. Org. Chem. 2000, 11, 1827.
(22) Synthesis of (–)-Ethyl (3aR,10bS)-6-Benzyloxy-8-
methoxy-2,2,7-trimethyl-3a,10b-dihydro-4H-
(19) Cohen, N.; Banner, B. L.; Laurenzano, A. J.; Carozza, L.
Org. Synth. 1985, 63, 127.
(20) Synthesis of (–)-Ethyl (2E)-{(3aR,6aS)-5-[2-(Benzyloxy)-
6-bromo-4-methoxy-3-methyphenyl]dihydro-2,2-
dimethyl-3aH-[1,3]dioxolo[4,5-c]pyrrol-6 (5H)-
[1,3]dioxolo-[4¢,5¢:3,4]pyrrolo[1,2-a]indole-10-
carboxylate (27): A solution of the vinylogous urethane 26
(N-Ar rotameric mixture, 5.62 g, 10.6 mmol, 1.0 equiv) in a
mixture of DMF (70 mL), MeCN (70 mL) and H2O (15 mL)
was thoroughly degassed with nitrogen for 10 min.
ylidene}acetate (26): To a solution of ethyl bromoacetate
(6.70 mL, 60.4 mmol, 5 equiv) in THF (250 mL) was added
activated zinc powder (11.9 g, 181.9 mmol, 15 equiv) at r.t.
After 5 min of stirring, iodine (2.15 g, 8.47 mmol, 0.7 equiv)
was added in one portion, resulting in spontaneous reflux of
the reaction mixture for a period of 5–10 min. The resulting
greyish suspension was allowed to cool to r.t. over 1 h and
then subjected to sonication for 1 h at 45 °C under an
atmosphere of nitrogen. The mixture was allowed to cool to
r.t. over 30 min, after which thiolactam 25 (rotameric
mixture, 5.79 g, 12.1 mmol, 1 equiv) was added in one
portion. The mixture was subsequently heated at reflux for
48 h, and then cooled to r.t. A further portion of organozinc
reagent, prepared on the same scale as described above, was
added, after which the mixture was heated again under reflux
for 72 h. The reaction mixture was allowed to cool to r.t., and
an ice–water mixture (200 mL) was added, which resulted in
precipitation of inorganic solids. The organic material was
extracted into Et2O, which was dried (MgSO4) and
evaporated to yield a crude orange oil. Purification by
column chromatography on silica gel using EtOAc–hexane
(3:17, then 2:8) as eluent gave an inseparable mixture of
vinylogous urethane rotamers 26 (5.62 g, 87%, 4:5 mixture
of N-Ar rotamers by NMR spectroscopy; vide infra) as a
viscous yellow oil–foam; Rf 0.41 (EtOAc–hexane 3:7);
[a]D23 –67.5 (c = 0.46, CHCl3). IR (CHCl3): 2981 (w), 1697
(s, C=O), 1476 (m), 1233 (w), 1134 (s), 735 (s) cm–1. HRMS
(EI): m/z [M+] calcd for C26H30NO679Br: 531.1257; found:
531.1266.
Palladium(II) acetate (710 mg, 3.16 mmol, 0.3 equiv), P(o-
tolyl)3 (5.15 g, 16.9 mmol, 1.6 equiv) and Et3N (14.7 mL,
105 mmol, 10 equiv) were added in succession and the
resulting orange mixture was heated at reflux for 4 h. The
dark brown reaction mixture was cooled to r.t., diluted with
H2O (200 mL) and stirred vigorously for 1 h. The mixture
was extracted with CH2Cl2, which was then dried (MgSO4)
and evaporated to afford a dark brown oil. Purification by
column chromatography on silica gel with EtOAc–hexane
(1:9 then 2:8) as eluent gave the pyrrolo[1,2-a]indole 27
(3.92 g, 82%) as a pale yellow solid. Recrystallisation from
EtOAc–hexane yielded a colourless crystalline solid; mp
90–91 °C; Rf 0.49 (EtOAc–hexane, 3:7); [a]D23 –85.5 (c =
0.57, abs. EtOH). IR (CHCl3): 2982 (w), 1697 (s, C=O),
1570 (m), 1454 (m), 1433 (m), 1275 (s), 1206 (m), 1129 (s),
747 (w) cm–1. 1H NMR (300 MHz, CDCl3): d = 7.33–7.41
(m, 6 H, 9-H, CH2Ph), 5.77 (s, J = 6.2 Hz, 1 H, 10b-H), 5.22
(br t, J ≈ 5.8 Hz, 1 H, 3a-H), 4.96 (d, J = 11.4 Hz, 1 H,
OCHaHbPh), 4.90 (d, J = 11.4 Hz, 1 H, OCHaHbPh), 4.40 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 4.15–4.27 (m, 2 H, NCH2), 3.91
(s, 3 H, ArOCH3), 2.27 (s, 3 H, ArCH3), 1.26, 1.44 (2 × s, 6
H, 2 × CH3), 1.42 (t, J = 7.1 Hz, 3 H, OCH2CH3). 13C NMR
(75 MHz, CDCl3): d = 164.82 (C=O), 155.28 (C-10), 146.45,
143.40, 136.70, 130.16, 128.65, 128.28, 127.74, 121.57,
115.68 (arom C), 112.61 (O2CMe2), 101.73 (C-10a), 98.09
(C-9), 81.60 (C-3a), 76.92 (OCH2Ph), 76.41 (C-10b), 59.53
(OCH2CH3), 55.82 (ArOCH3), 53.30 (C-4), 26.97, 25.59
(2 × CH3), 14.48 (OCH2CH3), 9.61 (ArCH3). HRMS
(EI): m/z calcd for C26H29NO6: 451.1995; found: 451.2006.
Anal. Calcd for C26H29NO6·0.5H2O: C, 67.81; H, 6.57; N,
3.04. Found: C, 67.99; H, 6.56; N, 3.19.
Minor Rotamer: 1H NMR (300 MHz, CDCl3): d = 7.26–
7.44 (m, 5 H, CH2Ph), 6.92 (s, 1 H, 5-H), 5.65 (d, J = 6.3 Hz,
1 H, 3a-H), 4.86 (d, J = 11.4 Hz, 1 H, OCHaHbPh), 4.67 (d,
J = 11.4 Hz, 1 H, OCHaHbPh), 4.56 (td, J ≈ 2.0, 6.2 Hz, 1 H,
6a-H), 4.38 (s, 1 H, =CHCO2Et), 4.13 (q, J = 7.0 Hz, 2 H,
OCH2CH3), 3.82 (s, 3 H, ArOCH3), 3.77 (dd, J = 6.3, 10.8
Hz, 1 H, NCHaHb), 3.50 (dd, J = 1.8, 10.8 Hz, 1 H, NCHaHb),
2.12 (s, 3 H, ArCH3), 1.41, 1.56 (2 × s, 6 H, 2 × CH3), 1.22
(t, J = 7.0 Hz, 3 H, OCH2CH3). 13C NMR (75 MHz, CDCl3):
d = 167.78 (C=O), 160.73 (C-4), 158.63, 156.40, 136.86,
128.57, 128.21, 127.97, 124.84, 121.45, 120.76 (arom C),
112.28 (O2CMe2), 111.12 (arom C), 84.46 (=CHCO2Et),
80.29 (C-3a), 75.93 (OCH2Ph), 75.01 (C-6a), 58.79
(OCH2CH3), 57.61 (C-6), 55.96 (ArOCH3), 27.15, 25.33
(2 × CH3), 14.42 (OCH2CH3), 9.59 (ArCH3).
(23) Wiegerinck, P. H. G.; Flucks, L.; Hammink, J. B.; Mulders,
S. J. E.; de Groot, F. M. H.; van Rozendaal, H. L. M.;
Scheeren, H. W. J. Org. Chem. 1996, 61, 7092.
(24) {(1R,2R)-(–)-1-Azido-2,3,5,8-tetrahydro-7-methoxy-6-
methyl-2-methanesulfonyloxy-5,8-dioxo-1H-
pyrrolo[1,2-a]indol-9-yl}methyl Phenyl Carbonate (39):
Rf 0.13 (EtOAc–hexane, 3:7); [a]D23 –121.6 (c = 1.02,
CHCl3). IR (CHCl3): 3018 (m), 2939 (m), 2108 (s, N3), 1761
(s, ester C=O), 1647 (s, quinone C=O), 1507 (m), 1365 (s),
1319 (s), 1246 (br s), 1210 (s), 1176 (s), 1106 (s), 960 (s) cm–
1. 1H NMR (300 MHz, CDCl3): d = 7.18–7.41 (m, 5 H, arom
H), 5.56 (d, J = 13.4 Hz, 1 H, CHaHbOCO2Ph), 5.50 (d, J =
13.4 Hz, 1 H, CHaHbOCO2Ph), 5.47 (br dd, J ≈ 2.4, 4.2 Hz,
1 H, H-2), 5.28 (d, J = 1.2 Hz, 1 H, H-1), 4.50–4.64 (m, 2 H,
NCH2), 4.06 (s, 3 H, OCH3), 3.07 (s, 3 H, OSO2CH3), 1.97
(s, 3 H, ArCH3). 13C NMR (75 MHz, CDCl3): d = 178.79,
178.63 (2 × quinone C=O), 157.46 (C-10), 153.47
(carbonate C=O), 150.99 (arom C), 135.95 (C-7), 129.50,
128.15, 127.51, 126.19, 124.22, 120.97 (3 × arom C, C-4, C-
6, C-9), 114.53 (C-10), 84.25 (C-2), 61.99, 61.78 (C-1,
CH2OCO2Ph), 61.29 (quinone OCH3), 51.71 (C-3), 38.71
(OSO2CH3), 8.49 (quinone CH3). LRMS (FAB): m/z = 517
[MH+].
Major Rotamer: 1H NMR (300 MHz, CDCl3): d = 7.26–
7.44 (m, 5 H, CH2Ph), 6.90 (s, 1 H, arom H), 5.93 (d, J = 6.6
Hz, 1 H, H-3a), 5.07 (d, J = 11.1 Hz, 1 H, OCHaHbPh), 4.94
(td, J = 2.4, 6.3 Hz, 1 H, H-6a), 4.71 (d, J = 11.1 Hz, 1 H,
OCHaHbPh), 4.43 (s, 1 H, =CHCO2Et), 4.13 (q, J = 7.0 Hz,
2 H, OCH2CH3), 3.83–3.89 (m, 2 H, NCH2), 3.84 (s, 3 H,
ArOCH3), 1.99 (s, 3 H, ArCH3), 1.36, 1.44 (2 × s, 6 H, 2 ×
CH3), 1.22 (t, J = 7.0 Hz, 3 H, OCH2CH3). 13C NMR (75
MHz, CDCl3): d = 167.97 (C=O), 160.56 (C-4), 158.61,
156.21, 136.74, 128.31, 127.97, 127.48, 124.80, 121.47,
Synlett 2006, No. 19, 3284–3288 © Thieme Stuttgart · New York