Synthesis of the aziridinomitosene skeleton by application of guanidinium ylide-mediated aziridination

Article abstract of DOI:10.1002/hlca.201200510

An aziridinomitosene skeleton, a basic core of mitomycin antibiotics, was straightforwardly prepared from N-(p-toluenesulfonyl)indole-2-carboxaldehyde in 16% overall yield by successive reactions of guanidinium ylide-mediated aziridination, InCl₃-catalyzed epimerization of trans-3-(indol-2-yl) aziridine-2-carboxylate, leading to the cis-derivative, and dehydrative cyclization. Copyright

Full text of DOI:10.1002/hlca.201200510

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Synthesis of the Aziridinomitosene Skeleton by Application of Guanidinium
Ylide-Mediated Aziridination
by Hiroyuki Kojima, Chisato Takahata, David Lemin, Masato Takahashi, Takuya Kumamoto,
Waka Nakanishi, Noriyuki Suzuki, and Tsutomu Ishikawa*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675,
Japan (phone/fax: þ 81-43-226-2944; benti@faculty.chiba-u.jp)
An aziridinomitosene skeleton, a basic core of mitomycin antibiotics, was straightforwardly prepared
from N-(p-toluenesulfonyl)indole-2-carboxaldehyde in 16% overall yield by successive reactions of
guanidinium ylide-mediated aziridination, InCl3-catalyzed epimerization of trans-3-(indol-2-yl)aziridine-
2-carboxylate, leading to the cis-derivative, and dehydrative cyclization.
Introduction. – Mitomycins are antibiotics isolated from Streptomyces species [1],
and mitomycin C, among them, has clinically been used as an anticancer drug [2].
Aziridinopyrroloindole, composed of a 6-5-5-3 ring system, is the core skeleton of
mitomycin antibiotics and is generally called as either aziridinomitosane or aziridino-
mitosene depending upon the saturation of the indole unit. Many groups have
attempted at the synthesis of mitomycin antibiotics due to their interesting biological
activities, and Kishi and co-workers [3], and Fukuyama and Yang [4] have skillfully
achieved total syntheses of natural mitomycins. Although various synthetic approaches
to aziridinomitosane [5] and aziridinomitosene [6] skeletons have also been examined,
the use of bond connection between C(3) and N(4) (cf. the atom numbering of
aziridinomitosene in Scheme 1) in the final construction of the ring system has never
been reported to the best of our knowledge. We have established a unique guanidinium
ylide-mediated aziridination reaction of an aromatic [7][8] or unsaturated [9]
aldehyde, in which trans-3-(indol-2-yl)aziridine-2-carboxylate (trans-2; Scheme 1)
could be obtained, when indole-2-carboxaldehyde (1; Scheme 1) is used as an aldehyde
source. Herein, we describe a straightforward construction of a model aziridinomito-
sene skeleton from 3-(indol-2-yl)aziridine-2-carboxylate.
Results and Discussion. – Our synthetic strategy toward the aziridinomitosene
skeleton 3 or 4 is outlined in Scheme 1, in which three reactions are combined: i)
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme 1. Synthetic Strategy for Aziridinomitosenes
guanidinium ylide-mediated aziridination of N-protected (P) indole-2-carboxaldehyde
1, ii) InCl3-catalyzed epimerization of trans-aziridine trans-2 to yielding the cis-
derivative cis-2, and iii) a dehydrative C(3) and N(4) bond formation, leading to
cyclization of cis-2 for the construction of the second pyrrolo component of the
aziridinomitosene skeleton.
First, we focused on the preparation of 9-substituted aziridinomitosene, in which a
appropriate substituent could be converted to the carbamoyloxymethyl moiety present
in mitomycins. However, attempts for the aziridination between ethyl 2-formyl-1-[(4-
methylphenyl)sulfonyl]-1H-indole-3-carboxylate (7), which was prepared from ethyl
2-methyl-1-[(4-methylphenyl)sulfonyl]-1H-indole-3-carboxylate (5) [10] in two steps
as shown in Scheme 2, and a guanidinium salt 8 under standard reaction conditions,
using either tetramethylguanidine (TMG) in THF or NaH in DMF, unfortunately
failed.
It had been found, that in the guanidinium ylide-mediated aziridination, aziridine
products were less effectively formed, when an aromatic aldehyde carrying a strong
electron-withdrawing group (EWG) such as CN or NO2 was subjected to the reaction
[8]. Therefore, regarding the above-mentioned results it can be speculated that the
presence of ester and Ts functionalities at C(3) and N(4), respectively, would cause
double deactivation in the reactivity of the starting aldehyde 7. Therefore, the ester
group at C(3) was changed to a CH2OH moiety. The 1H-indole-2-carboxaldehydes 11
and 12, in which the CH2OH function was protected with either a (tert-butyl)(dime-
thyl)silyl (TBDMS) or a (tert-butyl)(diphenyl)silyl (TBDPS) group, were prepared
from N-benzenesulfonyl (Bs)-substituted 3-(hydroxymethyl)-1H-indole-2-carboxalde-
hyde 10 [11] (Scheme 3). Aziridination of the TBDMS-protected 1H-indole-2-
carboxaldehyde 11 [12] with guanidinium salt 8 together with NaH in DMF, followed
by treatment with silica gel (SiO2), afforded trans-3-(3-{[(tert-butyl)dimethylsilyloxy]-
methyl}-1H-indol-2-yl)aziridine-2-carboxylate (trans-13; Bn ¼ PhCH2) in 43% yield as

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Scheme 2. Trials for Aziridination of Ethyl 2-Formyl-1H-indole-3-carboxylate 7
Scheme 3. Aziridination of (Silyloxy)methyl-Substituted 1H-Indole-2-aldehydes and Trials for Epime-
rization of the trans-Aziridines Formed
the sole isolable product, while the corresponding aziridine trans-14 was more
effectively obtained in 74% yield, when the TBDPS-protected aldehyde 12 was
subjected to the guanidinium ylide-mediated aziridination. We have observed that a
Lewis acid catalyzes a partial epimerization of trans-3-arylaziridine-2-carboxylate at
C(3) to provide a ca. 1:1 equilibrium mixture of trans- and cis-isomers, and that InCl3
was the most effective catalyst among Lewis acids examined [13]. However, application
of the InCl3-catalyzed epimerization to both the silyl-protected trans-aziridines trans-13

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and -14 was unsuccessful. The epimerization failed even in the case of a desilylated
aziridine trans-15.
We have already reported that N-Ts-protected trans-3-(1H-indol-2-yl)aziridine-2-
carboxylate trans-18, easily obtained from the aziridination of 1H-indole-2-carbox-
aldehyde 16 after N-Ts protection, was partially epimerized to cis-18 by treatment with
InCl3 (Scheme 4) [13]. Therefore, we turned our attention to the preparation of the 9-
unsubstituted aziridinomitosene skeleton (see 3 (R1 ¼ H, R2 ¼ Bn) or 4 (R1 ¼ H, R2 ¼
Bn) in Scheme 1).
Scheme 4. Trials for Cyclization to Aziridinomitosene 23

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First, the synthesis of aziridinomitosene skeleton 23 was targeted (Scheme 4). The
ester function of cis-3-{1-[(4-methylphenyl)sulfonyl]-1H-indol-2-yl)}aziridine-2-car-
boxylate (cis-18) was reduced to the corresponding alcohol with LiAlH4. The alcohol
19 was further converted to the methanesulfonate 20. These two products, 19 and 20,
were N-deprotected with Mg in MeOH to provide the corresponding (1H-indole)azir-
idines 21 and 22, respectively. However, treatment of either the aziridine-methanol 21
under Mitsunobu conditions, or the methanesulfonate 22 with Grignard reagent led to
only decomposition of the starting materials. Since it could be assumed that failure for
cyclization to the pyrroloindole skeleton was caused by its unstability under the
reaction conditions, we decided to examine next conversion of cis-aziridine cis-18 to the
known aziridinomitosenone 26 (Scheme 5) [14].
Scheme 5. Construction of Aziridinomitosenone 26
Attempts for direct cyclization of cis-18, after N-detosylation, under various basic
conditions, did not result in formation of the desired lactam 26. Gratifyingly, 26 was
prepared from cis-18 by successive N-detosylation, careful alkaline hydrolysis, and
dehydrative cyclization either through the mixed anhydride formation using pivaloyl
chloride (PivCl; Method A) or treatment with HATU (¼O-(7-azabenzotriazol-1-yl)-
N,N,N’,N’-tetramethyluronium hexafluorophosphate) (Method B; Scheme 5). Treat-
ment of (1H-indol-2-yl)aziridine 24 with 0.53m NaOH in MeOH at 268 for 4 h, which
was the hydrolysis condition optimized after careful examination of the base
concentration, gave a crude sodium carboxylate 25. Since 25 was found to decompose
after acidification, it was immediately treated with PivCl in the presence of Et3N at 08
for 1.5 h and then at 358 for 1 h to yield the aziridinomitosenone 26 in an overall yield of
37% from the cis-aziridine, cis-18. Furthermore, the cyclization step could be improved
by the use of HATU as a dehydrating agent at 08 (up to 45%).

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Successful construction of aziridinomitosenone 26, as mentioned above, encour-
aged us to apply these reaction procedures to asymmetric synthesis; however, trials for
asymmetric aziridination of N-Ts-protected indole-2-carboxaldehyde 17 using possible
chiral guanidinium salts, including the tert-butyl ester and the bromide anion [7][8],
unfortunately led to unsatisfactory combination of chemical yields (23 – 74%) and
enantioselectivities (9 – 33% ee) in the formation of aziridine trans-18.
Conclusions. – We succeeded in a straightforward preparation of aziridinomitosene
skeleton containing a lactam moiety by cyclization of cis-3-(1H-indol-2-yl)aziridine-2-
carboxylate, which was prepared by guanidinium ylide-mediated aziridination of 1H-
indole-2-carboxaldehyde, unfortunatly without success in application to chiral version.
Experimental Part
General. Anh. DMF and CH2Cl2 were used as purchased from Kanto Chemical, and anh. THF was
used as purchased from Wako Chemical. The org. extracts were dried (MgSO4), and solvents were
evaporated under reduced pressure. SiO2 in aziridination: Fuji Silisia FL100D. TLC: Merck Art 5715 DC-
Fertigplatten Kieselgel 60 F254. Column chromatography (CC): Kanto Chemical SiO2 60 spherical. Flash
chromatography (FC): Kanto Chemical SiO2 60 spherical for flash chromatography. M.p.: Yanagimoto
MPSI apparatus; uncorrected. IR Spectra: Attenuated Total Reflectance (ATR) system on a JASCO FT/
1
IR-300E spectrophotometer; ˜n in cmꢀ1. H- and 13C-NMR spectra: JEOL JNM-ECP-400 instrument in
CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. MS: JEOL JNM MS-GCMATE for EI-MS; in
m/z (rel. %); JEOL JNM HX-100 for HR-FAB-MS.
Ethyl 2-(Bromomethyl)-1-[(4-methylphenyl)sulfonyl]-1H-indole-3-carboxylate (6). A mixture of 2-
methyl-1H-indole (5 [10]; 0.769 g, 2.15 mmol), NBS (¼ N-bromosuccinimide; 0.384 g, 2.156 mmol), and
benzoyl peroxide (0.011 g, 0.03 mmol) in CCl4 (30 ml) was heated at reflux for 6 h, and the solvent was
evaporated. Washing the residue with hexane gave 6 (0.877 g, 93%). Pale-yellow needles (recrystallized
1
from hexane/AcOEt). M.p. 110.5 – 111.58. IR: 1705 (C¼O). H-NMR (400 MHz): 1.47 (t, J ¼ 7.1, 3 H ) ;
2.36 (s, 3 H); 4.46 (q, J ¼ 7.1, 2 H); 5.57 (s, 2 H); 7.25 (br. d, J ¼ 8.4, 2 H); 7.33 (br. t, J ¼ 7.6, 1 H); 7.38 (br.
t, J ¼ 7.7, 1 H); 7.88 (d, J ¼ 8.4, 2 H); 8.12 (d, J ¼ 8.2, 1 H); 8.13 (d, J ¼ 7.7, 1 H ) . 13C-NMR (100 MHz):
14.3; 21.6; 61.0; 113.4; 114.5; 122.5; 124.7; 126.2; 126.7; 127.2; 130.0; 135.2; 135.9; 142.4; 145.8; 163.8. EI-
MS: 437 (15), 435 (Mþ, 14), 356 (100, [M – Br]þ). Anal. calc. for C19H18BrNO4S (436.32): C 52.30, H 4.16,
N 3.21; found: C 52.05, H 3.98, N 3.08.
Ethyl 2-Formyl-1-[(4-methylphenyl)sulfonyl]-1H-indole-3-carboxylate (7). A mixture of 2-nitro-
propane (0.3 ml, 3.38 mmol) and hexane-washed NaH (0.107 g, 2.67 mmol) in anh. DMF (7 ml) was
stirred at 08 for 15 min, to which was added a soln. of 6 (0.77 g, 1.78 mmol) in anh. DMF (4 ml) at the
same temp. The mixture was stirred at 08 for 30 min and extracted with AcOEt (20 ml ꢁ 3) after addition
of H2O (10 ml). The combined org. phases was diluted with hexane (20 ml), washed with H2O (5 ml ꢁ 2)
and brine (30 ml), dried, and evaporated. CC of the residue (hexane/toluene 1:8) afforded 7 (0.557 g,
84%). Colorless needles (recrystallized from hexane/AcOEt). M.p. 122 – 1238. IR: 1709 (C¼O).
1H-NMR (400 MHz): 1.41 (t, J ¼ 7.1, 3 H); 2.38 (s, 3 H); 4.42 (q, J ¼ 7.1, 2 H); 7.30 (d, J ¼ 8.5, 2 H); 7.38
(br. t, J ¼ 7.6, 1 H); 7.49 (br. t, J ¼ 7.9, 1 H); 7.92 (d, J ¼ 8.5, 2 H); 8.10 (d, J ¼ 8.1, 1 H); 8.14 (d, J ¼ 8.6,
1 H); 10.57 (s, 1 H). 13C-NMR (100 MHz): 14.1; 21.6; 61.5; 114.4; 117.6; 123.0; 125.0; 126.2; 127.6; 127.7;
130.0; 134.7; 136.2; 139.1; 145.9; 163.0; 184.8. EI-MS: 371 (15, Mþ), 91 (100). Anal. calc. for C19H17NO5S
(371.41): C 61.44, H 4.61, N 3.77; found: C 61.40, H 4.49, N 3.73.
N-Benzyl-N’,N’’-ethylene-N-[(methoxycarbonyl)methyl]-N’,N’’-dimethylguanidinium Hexafluoro-
phosphate (¼ N-Benzyl-N-(2-methoxy-2-oxoethyl)-1,3-dimethylimidazolidin-2-iminium Hexafluoro-
phosphate ¼ N-(1,3-Dimethyl-2-imidazolidinylidene)-N-(2-methoxy-2-oxoethyl)benzenemethanaminium
Hexafluorophosphate; 8).
A mixture of 2-(benzylimino)-1,3-dimethylimidazolidine (1.502 g,
7.39 mmol), prepared from 2-chloro-1,3-dimethylimidazolinium chloride as described in [15], and
BrCH2COOMe (0.75 ml, 8.13 mmol) in MeCN (14 ml) was stirred at r.t. for 3 h and evaporated. The

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residual yellow oil was dissolved in H2O (150 ml) and mixed with NH4PF6 (1.471 g, 9.02 mmol).
Separated precipitates were extracted with CH2Cl2 (80 ml ꢁ 3). The combined org. phases were washed
with brine (80 ml), dried, and evaporated. Washing the residual solids with hexane/Et2O 1:1 (4 ml) gave
8 (2.067 g, 65%). Colorless prisms (recrystallized from AcOEt). M.p. 126 – 1278. IR: 1747 (C¼O); 1585
(C¼N). 1H-NMR (400 MHz): 3.13 (s, 6 H); 3.74 (s, 2 H); 3.78 (s, 3 H); 3.87 (s, 4 H); 4.50 (s, 2 H); 7.28 –
7.32 (m, 2 H); 7.34 – 7.42 (m, 3 H). 13C-NMR (100 MHz): 35.6; 48.6; 49.1; 52.8; 54.5; 129.0; 129.1; 129.3;
133.7; 163.7; 168.7. EI-MS: 276 (Mþ, 10), 202 (14), 184 (17), 126 (26), 117 (21), 107 (29), 91 (100). Anal.
calc. for C15H22F6N3O2P (421.32): C 42.76, H 5.26, N 9.97; found: C 42.79, H 5.18, N 9.94.
3-({[(tert-Butyl)(dimethyl)silyl]oxy}methyl)-1-(phenylsulfonyl)-1H-indole-2-carboxaldehyde (11).
t
A mixture of 2-formyl-3-(hydroxymethyl)-1-(phenylsulfonyl)-1H-indole (10; 1.00 g, 3.18 mmol), Bu-
Me2SiCl (TBDMSCl; 0.717 g, 4.76 mmol), and 1H-imidazole (0.349 g, 5.13 mmol) in anh. CH2Cl2 (22 ml)
was stirred at r.t. for 3.5 h under Ar, and filtered through SiO2. After evaporation of the filtrate, Et2O
(20 ml) and sat. aq. NH4Cl soln. (10 ml) were added to the residue, and then the mixture was extracted
with Et2O (20 ml ꢁ 3). The combined org. phases were washed with sat. aq. NaHCO3 soln. (10 ml) and
brine (10 ml), dried, and evaporated. CC of the residue (hexane/AcOEt 10 :1) afforded 11 (1.175 g, 86%)
[12]. Pale-brown solids. M.p. 64 – 748. IR: 1670 (C¼O). 1H-NMR (400 MHz): 0.02 (s, 6 H); 0.86 (s, 9 H);
5.15 (s, 2 H); 7.30 (t, J ¼ 7.6, 1 H); 7.37 (t, J ¼ 7.9, 2 H); 7.47 – 7.58 (m, 2 H); 7.69 (d, J ¼ 8.1, 2 H); 8.04 (d,
J ¼ 8.1, 1 H); 8.21 (d, J ¼ 8.6, 1 H); 10.60 (s, 1 H). 13C-NMR (100 MHz): ꢀ 5.5; 18.2; 25.8; 58.3; 115.4;
124.57; 124.59; 126.6; 129.0; 129.2; 129.3; 131.6; 134.2; 135.2; 137.0; 137.7; 185.0.
3-({[(tert-Butyl)(diphenyl)silyl]oxy}methyl)-1-(phenylsulfonyl)-1H-indole-2-carboxaldehyde (12).
A mixture of 10 (1.50 g, 4.76 mmol), TBDPSCl (1.7 ml, 6.62 mmol), and 1H-imidazole (0.486 g,
7.13 mmol) in anh. CH2Cl2 (33 ml) was stirred at r.t. for 1 h under Ar and filtered through SiO2. After
evaporation of the filtrate, Et2O (30 ml) and sat. aq. NH4Cl soln. (10 ml) were added to the residue, and
then the mixture was extracted with Et2O (20 ml ꢁ 3). The combined org. phases were washed with sat.
aq. NaHCO3 soln. (10 ml) and brine (10 ml), dried, and evaporated. Washing the residue with hexane
afforded 12 (2.34 g, 89%). Pale-brown solids (recrystallized from hexane/AcOEt). M.p. 124 – 1258. IR:
1
1684 (C¼O). H-NMR (400 MHz): 1.01 (s, 9 H); 5.14 (s, 2 H); 7.24 – 7.38 (m, 7 H); 7.41 (br. t, J ¼ 7.4,
2 H); 7.45 – 7.55 (m, 2 H); 7.55 – 7.61 (m, 4 H); 7.66 (br. d, J ¼ 7.3, 2 H); 8.09 (d, J ¼ 7.9, 1 H); 8.21 (d, J ¼
8.4, 1 H); 10.26 (s, 1 H). 13C-NMR (100 MHz): 19.2; 26.8; 58.5; 115.3; 124.3; 124.6; 126.6; 127.6; 128.9;
129.1; 129.3; 129.8; 132.1; 132.8; 134.0; 134.1; 135.5; 136.9; 137.5; 184.1. FAB-MS: 554 ([M þ H]þ). Anal.
calc. for C32H31NO4SSi (553.74): C 69.41, H 5.64, N 2.53; found: C 69.32, H 5.43, N 2.48.
Methyl rac-(2R,3R)-3-[3-({[(tert-Butyl)(dimethyl)silyl]oxy}methyl)-1-(phenylsulfonyl)-1H-indol-2-
yl]-1-(phenylmethyl)aziridine-2-carboxylate (trans-13). A mixture of NaH (60% in mineral oil, 0.156 g,
3.91 mmol) and 8 (1.02 g, 2.42 mmol) in anh. DMF (2.7 ml) was stirred at ꢀ 208 for 20 min under Ar. To
the mixture, a soln. of 11 (0.798 g, 1.86 mmol) in anh. DMF (2 ml) was slowly added, and the mixture was
stirred at ꢀ 208 for 3 h. After addition of SiO2 (12 g) and MeCN (40 ml), the resulting suspension was
stirred at r.t. further 19 h and filtered. After evaporation of the filtrate, the residue was diluted with
AcOEt (51 ml) and hexane (17 ml), washed with H2O (2 ml ꢁ 5) and brine (10 ml), dried, and
evaporated. FC of the residue (hexane/AcOEt 10 :1) afforded trans-13 (0.470 g, 43 %). Colorless needles
(recrystallized from hexane). M.p. 126 – 1278. IR: 1736 (C¼O). 1H-NMR (400 MHz) of a major
invertomer: ꢀ 0.05, ꢀ 0.01 (2s, 3 H); 0.83 (s, 9 H); 2.94 (d, J ¼ 2.6, 1 H); 3.71 (s, 3 H); 3.74 (d, J ¼ 2.6,
1 H); 4.07, 4.54 (2d, J ¼ 13.6, 1 H); 4.89, 4.94 (2d, J ¼ 12.4, 1 H); 7.20 – 7.36 (m, 7 H); 7.41 (t, J ¼ 7.8, 2 H);
7.53 (t, J ¼ 7.4, 1 H); 7.65 (d, J ¼ 7.5, 1 H); 7.86 (d, J ¼ 7.5, 2 H); 8.11 (d, J ¼ 8.4, 1 H). 1H-NMR (400 MHz)
of a minor invertomer: 2.75 (d, J ¼ 13.5, 1 H); 3.17 (br. s, 1 H); 3.77 (s, 3 H); 4.76, 4.82 (2d, J ¼ 11.9, 1 H);
7.60 (d, J ¼ 7.7, 1 H); 8.28 (d, J ¼ 8.2, 1 H). EI-MS: 590 (1, Mþ), 449 (73), 399 (24), 299 (13), 259 (16), 199
(47), 135 (100). Anal. calc. for C32H38N2O5SSi (590.81): C 65.05, H 6.48, N 4.74; found: C 64.89, H 6.46, N
4.73.
Methyl rac-(2R,3R)-3-[3-({[(tert-Butyl)(diphenyl)silyl]oxy}methyl)-1-(phenylsulfonyl)-1H-indol-2-
yl]-1-(phenylmethyl)aziridine-2-carboxylate (trans-14). A mixture of NaH (60% in mineral oil, 0.304 g,
7.60 mmol) and 8 (1.98 g, 4.70 mmol) in anh. DMF (5 ml) was stirred at ꢀ 208 for 30 min under Ar. To the
mixture, a soln. of 12 (2.00 g, 3.61 mmol) in anh. DMF (4.1 ml) was slowly added, and the mixture was
stirred at ꢀ 208 for 3.5 h. After addition of SiO2 (18 g) and MeCN (60 ml), the resulting suspension was
stirred at r.t. further 22 h and filtered. After evaporation of the filtrate, the residue was diluted with

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AcOEt (120 ml) and hexane (40 ml), washed with H2O (3 ml ꢁ 6) and brine (30 ml), dried, and
evaporated. FC of the residue (hexane/CH2Cl2 1:1 ! hexane/AcOEt 10 :1) afforded trans-14 (1.90 g, 74
%). Yellow solids (recrystallized from hexane). M.p. 36 – 418. IR: 1732 (C¼O). 1H-NMR (400 MHz) of a
major invertomer: 0.97 (s, 9 H); 2.72 (d, J ¼ 2.4, 1 H); 3.54 (d, J ¼ 2.4, 1 H); 3.61 (s, 3 H); 3.80, 3.95 (2d,
J ¼ 13.7, 1 H); 5.01, 5.07 (2d, J ¼ 12.6, 1 H); 6.96 – 7.17 (m, 2 H); 7.13 – 7.45 (m, 13 H); 7.49 (t, J ¼ 7.1, 1 H ) ;
7.55 – 7.65 (m, 5 H); 7.82 (d, J ¼ 8.1, 2 H); 8.15 (d, J ¼ 8.4, 1 H). 1H-NMR (400 MHz) of a minor
invertomer: 2.88 (d, J ¼ 13.7, 1 H); 3.33 (s, 1 H); 3.70 (s, 3 H); 4.74, 4.90 (2d, J ¼ 11.9, 1 H); 7.09 (t, J ¼ 7.9,
1 H); 7.68 (d, J ¼ 7.9, 2 H); 8.25 (d, J ¼ 8.2, 1 H). 13C-NMR (100 MHz) of a major invertomer: 19.1; 26.6;
41.6; 42.8; 52.1; 53.9; 57.3; 114.3; 121.0; 122.8; 123.5; 125.0; 126.3; 126.8; 127.57; 127.60; 128.1; 128.2; 129.1;
129.58; 129.64; 129.7; 132.1; 133.2; 133.3; 133.6; 135.5; 136.3; 138.3; 138.9; 168.9. HR-FAB-MS: 715.2662
([M þ H]þ, C42H43N2O5SSiþ; calc. 715.2662).
Methyl rac-(2R,3R)-3-[3-(Hydroxymethyl)-1-(phenylsulfonyl)-1H-indol-2-yl]-1-(phenylmethyl)-
aziridine-2-carboxylate (trans-15). A 1m soln. of TBAF in THF (2.16 ml, 21.6 mmol) was added to a
soln. of trans-14 (0.700 g, 0.98 mm) in anh. THF (1 ml). The mixture was stirred at r.t. for 0.5 h, the
reaction was quenched with sat. NH4Cl aq. soln. (3 ml), and the mixture was extracted with AcOEt
(10 ml ꢁ 3). The combined org. phases were washed with H2O (10 ml) and brine (10 ml), dried, and
evaporated. FC of the residue (hexane/AcOEt 3 :1 ! 2 :1) afforded trans-15 (0.424 g, 91%). A yellow
oil, solidified on keeping in the refrigerator. M.p. 42 – 478. IR: 3362 (OH); 1732 (C¼O). 1H-NMR
(400 MHz): 2.75 (br. d, J ¼ 2.9, 1 H); 3.80 (s, 3 H); 3.91 (d, J ¼ 2.9, 1 H); 4.16, 4.46 (2d, J ¼ 12.8, 1 H); 4.28
(d, J ¼ 13.2, 1 H); 4.45 (br. d, J ¼ 13.0, 1 H); 4.85 (br. s, 1 H); 7.20 – 7.27 (m, 1 H); 7.28 – 7.37 (m, 6 H); 7.41
(t, J ¼ 7.8, 2 H); 7.48 (t, J ¼ 7.9, 1 H); 7.53 (t, J ¼ 7.5, 1 H); 7.75 (d, J ¼ 7.3, 2 H); 8.15 (d, J ¼ 8.4, 1 H).
13C-NMR (100 MHz): 41.8; 43.2; 52.6; 53.4; 55.0; 114.2; 119.0; 123.5; 123.7; 125.4; 126.2; 127.8; 128.67;
128.72; 129.0; 129.3; 133.1; 133.9; 135.9; 136.9; 138.7; 168.2. HR-FAB-MS: 477.1469 ([M þ H]þ,
C26H25N2O5Sþ; calc. 477.1484).
rac-[(2R,3S)-3-{1-[(4-Methylphenyl)sulfonyl]-1H-indol-2-yl}-1-(phenylmethyl)aziridin-2-yl]meth-
anol (19). A suspension of LiAlH4 (0.186 g, 4.90 mm) in anh. THF (3 ml) was added to a soln. of cis-18
(0.564 g, 1.22 mm) in anh. THF (5 ml) at 08 under Ar, and the mixture was stirred at the same temp. for
0.5 h. After successive addition of H2O (2 ml), 20% NaOH (2 ml), H2O (2 ml), and a 8 :1 mixed soln. of
CH2Cl2/MeOH (27 ml), the resulting mixture was stirred at 08 for 1 h and filtered through Celite. The
filtrate was washed with brine (50 ml ꢁ 2), dried, and evaporated to give 19 (0.462 g, 87%). Colorless
prisms (recrystallized from hexane/benzene). M.p. 156 – 1578. IR: 3232 (OH). 1H-NMR (400 MHz): 2.33
(m, 1 H); 2.36 (s, 3 H); 3.10 – 3.28 (m, 2 H); 3.33 (d, J ¼ 6.2, 1 H); 3.70, 3.80 (2d, J ¼ 13.2, 1 H); 6.63 (s,
1 H); 7.16 – 7.41 (m, 9 H); 7.44 (t, J ¼ 7.5, 1 H); 7.69 (d, J ¼ 8.4, 2 H); 8.13 (d, J ¼ 8.2, 1 H). 13C-NMR
(100 MHz): 21.5; 41.3; 60.1; 64.1; 110.8; 114.1; 120.7; 123.5; 124.4; 126.4; 127.4; 128.1; 128.5; 129.0; 129.9;
136.0; 136.4; 137.2; 138.4; 144.0. EI-MS: 432 (11, Mþ). Anal. calc. for C25H24N2O3S (432.54): C 69.42, H
5.59, N 6.48; found: C 69.33, H 5.33, N 6.49.
rac-[(2R,3S)-3-{1-[(4-Methylphenyl)sulfonyl]-1H-indol-2-yl}-1-(phenylmethyl)aziridin-2-yl]methyl
Methanesulfonate (20). A soln. of methanesulfonyl chloride (MsCl; 10 ml, 0.133 mmol) in anh. CH2Cl2
(0.1 ml) and a soln. of Et3N (19 ml, 0.137 mmol) in anh. CH2Cl2 (0.1 ml) was successively added to a soln.
of 19 (0.0413 g, 0.095 mmol) in anh. CH2Cl2 (0.1 ml) at 08, and the mixture was stirred at the same temp.
for 0.5 h. After addition of sat. aq. NaHCO3 soln. (2 ml), the mixture was extracted with CH2Cl2 (10 ml ꢁ
3). The combined org. phases were washed with sat. aq. NH4Cl soln. (5 ml ꢁ 2), H2O (10 ml), and brine
(10 ml), dried, and evaporated to give 20 (0.484 g, quant.) as a pale-yellow oil, which was used for the
next step without any purification. 1H-NMR (400 MHz): 2.35 (s, 3 H); 2.41 (dt, J ¼ 6.6, 6.2, 1 H); 2.71 (s,
3 H); 3.48 (d, J ¼ 6.2, 1 H); 3.71 (d, J ¼ 6.6, 2 H); 3.74, 3.79 (2d, J ¼ 13.2, 1 H); 6.66 (s, 1 H); 7.18 – 7.42 (m,
9 H); 7.45 (d, J ¼ 7.7, 1 H); 7.67 (d, J ¼ 8.2, 2 H); 8.12 (d, J ¼ 8.2, 1 H). 13C-NMR (100 MHz): 21.5; 37.3;
40.3; 44.4; 63.7; 68.5; 110.8; 114.1; 120.9; 123.7; 124.6; 126.4; 127.4; 128.3; 128.4; 128.7; 130.0; 135.6; 135.9;
137.3; 137.9; 145.4. EI-MS: 510 (4, Mþ), 91 (100).
rac-[(2R,3S)-3-(1H-Indol-2-yl)-1-(phenylmethyl)aziridin-2-yl]methanol (21). A mixture of 19
(0.092 g, 0.212 mmol) and Mg turnings (0.259 g, 10.7 mmol) in dry MeOH (7 ml) was stirred at 08 for
2 h under Ar, and the reaction was quenched with sat. aq. NH4Cl soln. (4 ml) and H2O (1 ml). After
dissolving the precipitates under microwave irradiation, the mixture was extracted with AcOEt (20 ml ꢁ
3). The combined org. phases were washed with sat. aq. NaHCO3 soln. (20 ml) and brine (20 ml), dried,

Helvetica Chimica Acta – Vol. 96 (2013)
387
and evaporated to give 21 (0.059 g, quant.) as a brown oil, which was used for the next step without any
purification. IR: 3000 (OH); 1700 (C¼O). 1H-NMR (400 MHz): 2.24 (q-like, J ¼ 6.2, 1 H); 3.01 (d, J ¼
6.2, 1 H); 3.47 (dd, J ¼ 11.9, 6.2, 1 H); 3.54 (dd, J ¼ 11.9, 5.7, 1 H); 3.66, 3.71 (2d, J ¼ 13.4, 1 H); 6.43 (s,
1 H); 7.06 (t, J ¼ 7.3, 1 H); 7.11 (t, J ¼ 6.8, 1 H); 7.15 – 7.23 (m, 1 H); 7.24 – 7.38 (m, 5 H); 7.52 (d, J ¼ 7.5,
1 H); 8.71 (br. s, 1 H).
rac-[(2R,3S)-3-(1H-Indol-2-yl)-1-(phenylmethyl)aziridin-2-yl]methyl Methanesulfonate (22). A
mixture of 20 (0.032 g, 0.063 mmol) and Mg turnings (0.037 g, 1.51 mmol) in dry MeOH (2 ml) was
stirred at 08 for 2 h under Ar, and the reaction was quenched with sat. aq. NH4Cl soln. (2 ml) and H2O
(1 ml). After dissolving the precipitates under microwave irradiation, the mixture was extracted with
AcOEt (10 ml ꢁ 3). The combined org. phases were washed with sat. aq. NaHCO3 soln. (10 ml) and brine
(10 ml), dried, and evaporated to give 22 (0.021 g, quant.) as a brown oil, which was used for the next step
without any purification. IR: 3000 (OH); 1700 (C¼O). 1H-NMR (400 MHz): 1.78 – 1.90 (m, 1 H); 1.88 (s,
3 H); 2.44 (d, J ¼ 6.2, 1 H); 3.20, 3.27 (2d, J ¼ 13.5, 1 H); 3.69 (dd, J ¼ 11.2, 5.7, 1 H); 3.87 (dd, J ¼ 11.4, 7.1,
1 H); 6.41 (s, 1 H); 6.90 – 7.40 (m, 8 H); 7.55 – 7.65 (m, 1 H); 7.83 (br. s, 1 H).
Methyl rac-(2R,3S)–3-(1H-Indol-2-yl)1-(phenylmethyl)aziridine-2-carboxylate (24). A mixture of
cis-18 (0.061 g, 0.133 mmol) and Mg turnings (0.078 g, 3.19 mmol) in dry MeOH (2.5 ml) was stirred at 08
for 2 h, and the reaction was quenched with sat. aq. NH4Cl soln. (2 ml) and H2O (1 ml). After dissolving
the precipitates under microwave irradiation, the mixture was extracted with CH2Cl2 (10 ml ꢁ 2). The
combined org. phases were washed with sat. aq. NaHCO3 soln. (10 ml) and brine (10 ml), dried, and
evaporated to give 24 as a brown oil, which was used for the next step without any purification. IR: 3400
(OH), 1736 (C¼O). 1H-NMR (400 MHz): 2.69 (d, J ¼ 6.4, 1 H); 3.23 (d, J ¼ 6.4, 1 H); 3.62 (s, 3 H); 3.81
(s, 2 H); 6.54 (d, J ¼ 1.3, 1 H); 7.06 (br. t, J ¼ 7.5, 1 H); 7.14 (br. t, J ¼ 7.6, 1 H); 7.24 – 7.40 (m, 6 H); 7.53 (d,
J ¼ 7.9, 1 H); 9.05 (br. s, 1 H).
rac-(1aR,8bS)-1a,8b-Dihydro-1-(phenylmethyl)azireno[2’,3’:3,4]pyrrolo[1,2-a]indol-2(1H)-one
(26). Method A. A mixture of crude 24 (0.0264 g, 0.086 mmol) and NaOH (0.0112 g, 0.280 mmol) in anh.
THF (0.5 ml) was stirred at r.t. for 2 h. After addition of Et3N (46 ml, 0.33 mmol) and pivaloyl chloride
(PivCl; 36 ml, 0.292 mmol) at 08, the mixture was stirred at the same temp. for 1.5 h and then at 358 for
1 h, and diluted with Et2O (10 ml). After filtration, the filtrate was washed with sat. aq. NH4Cl soln.
(10 ml). The org. soln. was washed with brine (10 ml), dried, and evaporated. FC of the residue (hexane/
AcOEt 3 :1), followed by washing with hexane/Et2O, afforded 26 (0.87 g, 37%). Pale-brown solids. M.p.
121 – 1228 (lit. [14] m.p. 121 – 1238). IR: 1742 (C¼O). 1H-NMR (400 MHz) of major invertomer: 3.18 (d,
J ¼ 4.4, 1 H); 3.39 (d, J ¼ 4.4, 1 H); 3.69, 3.75 (2d, J ¼ 13.5, 1 H); 6.47 (s, 1 H); 7.22 (ddd, J ¼ 7.5, 7.5, 1.3,
1 H); 7.28 – 7.34 (m, 2 H); 7.36 (br. d, J ¼ 4.4, 4 H); 7.47 (br. d, J ¼ 7.7, 1 H); 7.90 (d, J ¼ 7.5, 1 H). 1H-NMR
(400 MHz) of minor invertomer: 3.29 (d, J ¼ 13.4, 1 H); 3.59 – 3.60 (m, 2 H); 3.63 – 3.64 (m, 1 H); 3.88 (d,
J ¼ 2.7, 1 H); 6.59 (s, 1 H); 7.20 – 7.34 (m, 3 H); 7.53 (d, J ¼ 7.9, 1 H); 7.96 (d, J ¼ 7.9, 1 H). HR-FAB-MS:
274.1107 (Mþ, C18H14N2Oþ; calc. 274.1106).
Method B. A mixture of crude 24 (0.0213 g, 0.0695 mmol) and NaOH (0.0086 g, 0.215 mmol) in anh.
THF (0.2 ml) was stirred at r.t. for 1.5 h and evaporated. After dissolving the residue in anh. DMF
(0.7 ml), the resulting soln. was added to HATU (0.0491 g, 0.129 mmol), stirred at 08 for 1.5 h under Ar,
and evaporated. FC of the residue (hexane/CH2Cl2 1:1), followed by washing with hexane/Et2O,
afforded 26 (0.086 g, 45%) as yellow solid, which was identical to the product obtained by Method A.
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Received September 7, 2012