Cyclopropane-Annelated Azaoligoheterocycles by Ti-Mediated Intramolecular Reductive Cyclopropanation of Cyclic Amino Acid Amides

Article abstract of DOI:10.1002/chem.200305068

Starting from pyrrole- and indole-2-carboxylic acids 5a and 5b, the tri- and tetracyclic N,N-dibenzylcyclopropylamines 7a and 7b have been synthesized in 52 and 33% overall yield, respectively. The synthesis of the enantiopure tetracyclic diamine 10 has b

Full text of DOI:10.1002/chem.200305068

FULL PAPER
Cyclopropane-Annelated Azaoligoheterocycles by Ti-Mediated
Intramolecular Reductive Cyclopropanation of Cyclic Amino Acid Amides°
Martina Gensini and Armin de Meijere*[a]
Abstract: Starting from pyrrole- and
indole-2-carboxylic acids 5a and 5b,
the tri- and tetracyclic N,N-dibenzylcy-
clopropylamines 7a and 7b have been
synthesized in 52 and 33% overall
yield, respectively. The synthesis of the
enantiopure tetracyclic diamine 10 has
been achieved applying the established
set of reactions to N-tert-butoxycarbo-
nylindoline-2-carboxylic acid (8) in
46% overall yield. The amide 15 could
not be prepared in the same way start-
ing from the N-tert-butoxycarbonylpro-
line 11. In fact, in the allylation step
the stereogenic center was deprotonat-
ed and the doubly alkylated amide 13
was formed. However, the desired in-
termediate 15 could be obtained from
l-proline in 49% yield performing first
the N-allylation step, then the introduc-
tion of the amide function. From 15,
the cyclopropane-annelated pyrrolizi-
dine 16 was obtained in 70% yield as a
mixture of (1aS,6aS,6bR)-16 and
(1aR,6aS,6bS)-16 diastereoisomers in a
ratio of 1:2.9.
Keywords: alkaloids
¥
cyclopropanation ¥ N heterocycles ¥
titanium
Introduction
ty of employing our amide variant[11,12] of the Kulinkovich
reaction[12,13] to prepare cyclopropane-annelated pyrrolizi-
dine and indolizidine skeletons from N-alkylpyrrole and N-
alkylindole carboxamides, just as Sato et al. converted pyr-
role- and indole-2-carboxylic acid methyl esters to tri- and
tetracyclic cyclopropanols.[14] As we have previously demon-
strated, a variety of 1-amino-3-azabicyclo[3.1.0]hexane de-
rivatives can be obtained by this Ti-mediated intramolecular
reductive cyclopropanation of appropriate N,N-dialkylcar-
boxamides, which are readily available from natural amino
acids or bromoacetyl bromide by simple transforma-
tions.[15,16] Here we report the intramolecular aminocyclo-
propanation of the N-allyl group in N,N-dialkylamides of
type 3 leading to tricyclic and tetracyclic systems of type 4
as cyclopropane-annelated analogues of natural skeletons
such as in 1 and 2 (Scheme 1).
Pyrrolizidine and indolizidine heterocycles are quite
common skeletons in natural compounds.[1 7] Some examples
are the alkaloid (+)-Absouline (1; R=(E)-p-(OMe)cinna-
moyl-)[8] and the Mitomycine antibiotics, among which for
example Mitomycine C (2) is clinically used as an antitumor
agent.[9] In the last decade, many groups have been engaged
in the stereocontrolled synthesis of the heterocyclic skeleton
of such natural compounds.[7,9,10] We envisaged the possibili-
The N,N-dibenzylamides 6a and 6b were prepared from
pyrrole- and indole-2-carboxylic acids (5a and 5b) by treat-
ment with dibenzylamine, dicyclohexylcarbodiimide (DCC),
and hydroxybenzotriazole (HOBT),[17] and then with allyl
[a] Dr. M. Gensini, Prof. Dr. A. de Meijere
Institut f¸r Organische Chemie
der Georg-August-Universit‰t Gˆttingen
Tammannstrasse 2, 37077 Gˆttingen (Germany)
Fax : (+49)551-399475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[°] Cyclopropyl Building Blocks for Organic Synthesis, Part 94. Part 93
see: S. I. Kozhushkov, A. Leonov, A. de Meijere, Synthesis 2003, 956
958. Part 92: N. Moszner, F. Zeuner, U. K. Fischer, V. Rheinberger,
A. de Meijere, V. Bagutski, Macromol. Rapid Commun. 2003, 24,
269 273.
Scheme 1. Strategy for the synthesis of cyclopropane-annelated pyrrolizi-
dine and indolizidine systems.
785
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DOI: 10.1002/chem.200305068
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FULL PAPER
bromide and potassium carbonate[18] in 67 and 42% overall
yield, respectively. The amides 6a and 6b were treated with
cyclohexylmagnesium bromide (5 equiv) in the presence of
methyltitanium triisopropoxide (1.50 equiv) to give the tetra-
cyclic amines 7a and 7b in 78 and 79% yield, respectively
(Scheme 2).
When the latter was treated with allyl bromide and potassi-
um carbonate,[18] the doubly allylated amide 13 was obtained
instead of the expected 15 (Scheme 4). It is surprising that,
under the reaction conditions employed, that is with potassi-
um carbonate as a base at 608C, 12 apparently must be de-
protonated at the stereogenic center, and the allylation at
C-2 (proline numbering) occur-
red with complete racemization,
as revealed by the optical activ-
ity measurement [a]2D0 =0.0 (c=
1.0, CHCl3). Not even a trace
of the desired product 15 could
be detected. Usually, deproto-
nation at the a-position of pro-
line derivatives can only be
brought about with much stron-
Scheme 2. a) 1) 1 HNBn2, DCC, HOBT, CH2Cl2, 208C, 2 d; 2) allyl bromide, K2CO3, MeCN, 608C, 16 h.
b) cHexMgBr, [MeTi(OiPr)3], THF, 208C, 12 h.
ger bases such as lithium diiso-
propylamide.[20]
The obvious success of these reductive cyclizations led to
the idea to apply this same protocol to indoline and proline
derivatives of types 9 and 15 in order to access enantiopure
cyclopropane-annelated analogues of the alkaloid 1. Sato
and co-workers[14] reported that N-allylproline methyl ester
did not undergo intramolecular hydroxycyclopropanation,
and attributed this failure to an energetically disfavored
transition state for ring closure. Since a fused aromatic ring
in the starting material might favor the ring closure, the in-
doline derivative 9 was tested first. Applying an established
set of reactions to N-(tert-butoxycarbonyl)indoline-2-carbox-
ylic acid (8) the N-allyl-(N,N-dibenzyl)carboxamide 9 was
obtained in 76% yield. Under the conditions employed for
6a,b, the amide 9 was converted to the tetracyclic cyclopro-
pylamine 10 in 61% yield, obtained as a 1:1 mixture of dia-
stereomers, which could be separated by column chromatog-
raphy (Scheme 3).
Treatment of l-N-(tert-butoxycarbonyl)proline (11) with
dibenzylamine, dicyclohexylcarbodiimide, and hydroxyben-
zotriazole,[17] followed by deprotection with trifluoroacetic
Scheme 4. a) 1) HNBn2, DCC, HOBT, CH2Cl2, 208C, 2 d; 2) TFA,
CH2Cl2, 208C, 12 h; b) Allyl bromide, K2CO3, MeCN, 608C, 16 h;
c) 1) Allyl bromide, KOH, iPrOH, 408C, 22 h; 2) HNBn2, DCC, HOBT,
CH2Cl2, 208C, 1 d; d) cHexMgBr, [MeTi(OiPr)3], THF, 208C, 12 h.
acid[19] gave the proline amide 12 in 71% overall yield.
The N-allylprolineamide 15 could, however, be prepared
by treatment of l-proline (14) with allyl bromide and potas-
sium hydroxide in 2-propanol,[21] then with dibenzylamine,
dicyclohexylcarbodiimide, and hydroxybenzotriazole[17] in
49% overall yield. The titanium-mediated intramolecular
reductive cyclopropanation of the latter afforded the tricy-
clic cyclopropylamine 16 in 70% yield as a mixture of dia-
stereoisomers (ratio 1:2.9). They could be separated by
column chromatography and assigned as (1aS,6aS,6bR)-16/
(1aR,6aS,6bS)-16 on the basis of their 1H NMR spectra
(Scheme 4).
The absolute configuration of the minor diastereoisomer
(1aS,6aS,6bR)-16 was assigned on the basis of an X-ray crys-
tal structure analysis relative to the known absolute configu-
Scheme 3. a) 1) HNBn2, DCC, HOBT, CH2Cl2, 208C, 2 d; 2) TFA,
CH2Cl2, 208C, 12 h; 3) allyl bromide, K2CO3, MeCN, 608C, 16 h;
b) cHexMgBr, [MeTi(OiPr)3], THF, 208C, 12 h.
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Chem. Eur. J. 2004, 10, 785 790

Cyclopropane-Annelated Azaoligoheterocycles
785 790
ration of the used (S)-proline (Figure 1).[22] Apparently,
(1aS,6aS,6bR)-16 has the same relative configuration as the
natural alkaloid (Æ)-Absouline (1).
N,N-Dibenzyl-1H-pyrrole-2-carboxamide:
N,N-Dibenzyl-1H-pyrrole-2-
carboxamide (1.31 g, 89%) was obtained from pyrrole-2-carboxylic acid
(5a, 556 mg, 5.00 mmol), DCC (2.60 g, 12.5 mmol), HOBT (676 mg,
5.00 mmol), and HNBn2 (2.4 mL, 12.5 mmol) according to GP 1, as a col-
orless solid. Rf (Et2O/hexane 1:1)=0.38; m.p. 140 1448C; 1H NMR
(250 MHz, CDCl3): d=11.41 (brs, 1H; NH), 7.48 7.18 (m, 10H; Har),
6.93 6.91 (m, 1H; 5-H), 6.50 6.48 (m, 1H; 3-H), 6.18 6.16 (m, 1H; 4-H),
4.89 ppm (s, 4H; CH2Ph); 13C NMR (62.9 MHz, CDCl3): d=163.6 (C=
O), 136.8 (2 Car), 128.9 (CHar), 128.8 (3 CHar), 127.5 (4 CHar), 126.9 (2
CHar), 124.1 (Car), 122.1 (CHar), 112.7 (CHar), 109.7 (CHar), 47.6 ppm (2
CH2; CH2Ph); IR (KBr): n˜ =3258, 3030, 2905, 1600, 1576, 1424,
1129 cmÀ1; MS (EI, 70 eV): m/z (%): 290 (30) [M+], 199 (70) [M+
ÀC7H7], 106 (100), 91 (52) [C7H7+]; elemental analysis calcd (%) for
C19H18N2O (290.37): C 78.59, H 6.25; found: C 78.38, H 6.42.
Preparation of N-allylheterocycles–General procedure 2 (GP 2): Allyl
bromide (0.57 mmol) was added dropwise at 08C to a suspension of the
respective azaheterocycle (0.41 mmol) and K2CO3 (0.82 mmol) in anhy-
drous MeCN (8.0 mL). After the addition was complete, the reaction
mixture was stirred at 608C for 16 h. EtOAc (5.0 mL) and saturated
aqueous NaHCO3 solution (5.0 mL) were added, the organic phase was
separated, washed with brine (10 mL), and dried over MgSO4. After
evaporation of the solvent under reduced pressure the crude product was
purified by column chromatography on silica gel.
Figure 1. Molecular structure of compound (1aS,6aS,6bR)-16 in the crys-
tal.[22]
1-Allyl-N,N-dibenzyl-pyrrole-2-carboxamide (6a): The amide 6a (1.11 g,
75%) was obtained from N,N-dibenzyl-1H-pyrrole-2-carboxamide
(1.30 g, 4.48 mmol), K2CO3 (1.24 g, 8.97 mmol), and allyl bromide
(0.50 mL, 6.27 mmol) according to GP 2 as a colorless oil. Rf (Et2O/
hexane 1:2)=0.46; 1H NMR (250 MHz, CDCl3): d=7.41 7.24 (m, 10H;
Har), 6.82 6.80 (m, 1H; 5-H), 6.42 (dd, J=1.6, 3.8 Hz, 1H; 3-H), 6.10
5.97 (m, 2H; CH=CH2, 4-H), 5.20 5.01 (m, 2H; CH=CH2), 4.95 4.91 (m,
2H; CH2CH=CH2), 4.74 ppm (s, 4H; CH2Ph); 13C NMR (62.9 MHz,
CDCl3): d=163.6 (C=O), 137.0 (2 Car), 136.4 (CH; CH=CH2), 135.3 (3
CHar), 128.7 (3 CHar), 127.4 (4 CHar), 125.9 (CHar), 124.4 (Car), 116.5
(CH2; CH=CH2), 112.6 (CHar), 107.1 (CHar), 50.7 (2 CH2), 49.0 ppm
(CH2); IR (film): n˜ =3029, 2925, 1623, 1464, 1240, 987, 734 cmÀ1; MS (EI,
70 eV): m/z (%): 330 (91) [M+], 239 (22) [M+ÀC7H7], 134 (100), 106
(61), 91 (56) [C7H7+]; HRMS (EI) calcd for C22H22N2O [M+] 330.1732,
found 330.1732.
Since the N-benzyl groups can easily be removed from
N,N-dibenzylcyclopropylamines such as 16,[11c] the latter
may be used to prepare a cyclopropane-annelated analogue
of the natural product. This and the other new intramolecu-
lar variants of the titanium-mediated reductive cyclopropa-
nation of amide carbonyl groups[11] once again demonstrate
the synthetic utility of this highly efficient methodology.[12]
Experimental Section
Ti-mediated intramolecular reductive cyclopropanation of N,N-dibenzyl-
carboxamides–General procedure 3 (GP 3): Cyclohexylmagnesium bro-
mide (cHexMgBr, 5.00 mmol) was added dropwise at ambient tempera-
ture to a well stirred solution of N,N-dialkylcarboxamide (1.00 mmol)
and methyltitanium triisopropoxide ([MeTi(OiPr)3], 1.50 mmol) in anhy-
drous THF (30 mL). After the addition was complete, the mixture was
stirred for 12 h, then poured into ice-cold water (10 mL), and stirred for
an additional 1 h. The mixture was filtered through Celite, the aqueous
phase was extracted with Et2O (3î50 mL), and the combined ethereal
phases were washed with saturated aqueous NaHCO3 solution (50 mL),
brine (50 mL), and dried over MgSO4. The solvent was removed and the
residue was purified by column chromatography on silica gel.
General: 1H and 13C NMR: Spectra were recorded at 250, 300 (1H), and
62.9, 75.5 [13C, additional DEPT (distortionless enhancement by polariza-
tion transfer)] MHz on Bruker AM 250 and AMX 300 instruments in
CDCl3 solution, if not otherwise specified, CHCl3/CDCl3 as internal refer-
ence; d in ppm, J in Hz. IR: Bruker IFS 66 (FT-IR) instrument, meas-
ured as KBr pellets, oils between KBr plates. MS (EI): Finnigan MAT 95
spectrometer. Optical rotations: Perkin-Elmer 241 digital polarimeter,
1 dm cell. M.p.: B¸chi 510 capillary melting point apparatus, values are
uncorrected. TLC: Macherey-Nagel precoated sheets, 0.25 mm Sil G/
UV254
. Column chromatography: Merck silica gel, grade 60, 230
400 mesh. Starting materials: Anhydrous diethyl ether and THF were ob-
tained by distillation from sodium/benzophenone, CH2Cl2 and DMF from
CaH2 and acetonitrile from P4O10. Compounds were prepared according
to published procedures. Cyclohexylmagnesium bromide was prepared
from cHexBr and Mg in Et2O, [MeTi(OiPr)3] from MeLi and
[ClTi(OiPr)3] in Et2O, [ClTi(OiPr)3] from TiCl4 and [Ti(OiPr)4] in Et2O.
All other chemicals were used as commercially available (Merck, Acrs,
BASF, Bayer, Hoechst, Degussa AG, and H¸ls AG). All reactions were
performed under an argon atmosphere. Organic extracts were dried over
MgSO4.
N,N-Dibenzyl-1,1a,2,6b-tetrahydrocyclopropa[1,2-a]pyrrolizin-6b-ylamine
(7a): The amine 7a (224 mg, 78%) was obtained from the amide 6a
(300 mg, 908 mmol), [MeTi(OiPr)3] (327 mg, 1.36 mmol) and cHexMgBr
(4.6 mL, 4.60 mmol, 1.0m solution in Et2O) according to GP 3 as a color-
less oil. Rf (hexane/Et2O 5:1)=0.74; 1H NMR (250 MHz, CDCl3): d=
7.37 7.18 (m, 10H; Har), 6.50 6.42 (m, 1H; Har), 6.25 6.20 (m, 1H; Har),
5.90 5.84 (m, 1H; Har), 4.11 (d, J=13.2 Hz, 2H; CH2Ph), 3.96 (d, J=
13.2 Hz, 2H; CH2Ph), 3.59 3.50 (m, 2H; NCH2CH), 1.38 0.84 (m, 2H;
cPr), 0.72 ppm (ps t, J=4.6 Hz, 1H; cPr); 13C NMR (62.9 MHz, CDCl3):
d=139.8 (Car), 136.0 (Car), 131.9 (Car), 129.3 (4 CHar), 128.1 (4 CHar),
126.9 (2 CHar), 113.5 (CHar), 111.2 (CHar), 99.7 (CHar), 57.7 (2 CH2;
CH2Ph), 49.7 (C; cPr), 47.9 (CH2; NCH2CH), 29.6 (CH; cPr), 23.8 ppm
(CH2; cPr); IR (film): n˜ =3028, 2924, 1530, 1392, 745 cmÀ1; MS (EI,
70 eV): m/z (%): 314 (1) [M+], 223 (14) [M+ÀC7H7], 197 (61), 106 (38),
91 (100) [C7H7+]; HRMS (EI) calcd for C22H22N2 [M+] 314.1783, found
314.1783; elemental analysis calcd (%) for C22H22N2 (314.43): C 84.04, H
7.05; found C 84.24, H 7.27.
Preparation of N,N-dibenzylcarboxamides–General procedure 1 (GP 1):
Dibenzylamine (HNBn2, 12.5 mmol) was added dropwise to a suspension
of dicyclohexylcarbodiimide (DCC, 12.5 mmol), hydroxybenzotriazole
(HOBT, 5.00 mmol), and the respective carboxylic acid (5.00 mmol) in
anhydrous CH2Cl2 (10 mL). The mixture was stirred at ambient tempera-
ture for two days. EtOAc (10 mL) was added, the mixture was filtered
through Celite, and the solvent was removed under reduced pressure.
EtOAc (10 mL) was added, the organic phase was washed with 5% aque-
ous HCl solution (10 mL), brine (10 mL), dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by column chro-
matography on silica gel.
N,N-Dibenzyl-1H-indole-2-carboxamide: N,N-Dibenzyl-1H-indole-2-car-
boxamide (1.10 g, 95%) was obtained from HNBn2 (1.6 mL, 8.55 mmol),
DCC (1.76 g, 8.55 mmol), HOBT (462 mg, 3.42 mmol), and indole-2-car-
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A. de Meijere and M. Gensini
FULL PAPER
boxylic acid (5b, 551 mg, 3.42 mmol) in CH2Cl2 (30 mL) according to GP
1 as a colorless oil, which was used for the subsequent reaction without
further purification.
(S)-N,N-Dibenzyl-1-allyl-2,3-dihydroindole-2-carboxamide
amide 9 (1.13 g, 90%) was obtained from (S)-N,N-dibenzyl-2,3-dihydro-
1H-indole-2-carboxamide (1.12 g, 3.27 mmol), K2CO3 (940 mg,
(9):
The
6.80 mmol), and allyl bromide (0.40 mL, 4.75 mmol) according to GP 2 as
a
1-Allyl-N,N-dibenzyl-1H-indole-2-carboxamide (6b): Compound 6b
(545 mg, 44%) was obtained from N,N-dibenzyl-1H-indole-2-carbox-
amide (1.10 g, 3.23 mmol), allyl bromide (0.40 mL, 4.79 mmol), and
K2CO3 (945 mg, 6.84 mmol) according to GP 2 as a colorless solid. Rf
(Et2O/hexane 1:2)=0.53; m.p. 121 1288C; 1H NMR (250 MHz, CDCl3):
d=7.56 7.07 (m, 14H; Har), 6.70 (s, 1H; 3-H), 6.09 5.94 (m, 1H; CH=
CH2), 5.13 4.91 (m, 4H; CH2Ph, CH2CH=CH2), 4.73 ppm (s, 4H;
CH2Ph, CH2CH=CH2); 13C NMR (62.9 MHz, CDCl3): d=165.1 (C=O),
137.6 (Car), 136.6 (Car), 136.1 (CH; CH=CH2), 134.1 (2CHar), 131.0 (Car),
128.8 (2 Car), 127.6 (3 CHar), 126.4 (2CHar), 123.5 (2 CHar), 121.7 (2
CHar), 120.4 (2 CHar), 116.5 (CH2; CH=CH2), 110.3 (CHar), 103.7 (CH;
C-3), 47.0 (CH2), 46.6 ppm (2CH2); IR (KBr): n˜ =3064, 3029, 2917, 1630,
1523, 1451, 1244, 962 cmÀ1; MS (EI, 70 eV): m/z (%): 380 (100) [M+],
196 (17), 184 (81), 157 (55), 91 (62), 56 (29); elemental analysis calcd
(%) for C26H24N2O (380.49): C 82.07, H 6.36; found: C 81.86, H 6.59.
colorless oil. Rf (Et2O/hexane 1:2)=0.31; [a]2D0 =À36.0 (c=0.35,
CHCl3); 1H NMR (250 MHz, CDCl3): d=6.98 (m, 12H; Har), 6.68 6.51
(m, 2H; Har), 5.91 5.75 (m, 1H; CH=CH2), 5.25 5.10 (m, 2H; CH=CH2),
4.83 (d, J=14.5 Hz, 1H; CH2Ph), 4.65 4.49 (m, 4H, 2-H; CH2Ph), 3.98
(dd, J=5.0, 15.7 Hz, 1H; 3-H), 3.73 (dd, J=7.4, 15.7 Hz, 1H; 3-H), 3.27
3.04 ppm (m, 2H; CH2CH=CH2); 13C NMR (62.9 MHz, CDCl3): d=
172.9 (C=O), 156.4 (Car), 151.1 (Car), 137.2 (Car), 136.4 (Car), 133.4 (CH;
CH=CH2), 129.0 (2 CHar), 128.7 (2 CHar), 128.5 (2 CHar), 127.8 (2 CHar),
127.6 (CHar), 126.6 (CHar), 126.5 (CHar), 124.1 (CHar), 118.3 (CHar), 117.9
(CH2; CH=CH2), 107.4 (CHar), 63.6 (CH; C-2), 50.1 (CH2; CH2Ph), 49.4
(CH2; CH2Ph), 48.7 (CH2; CH2CH=CH2), 34.1 ppm (CH2; C-3); IR
(film): n˜ =3030 cmÀ1, 2925, 1657, 1453, 1208, 747; MS (EI, 70 eV): m/z
(%): 382 (8) [M+], 270 (10), 158 (100), 117 (20); elemental analysis calcd
(%) for C26H26N2O (382.51): C 81.64, H 6.85; found: C 81.58, H 6.97.
(1aS,8aS,8bR)- and (1aR,8aS,8bS)-N,N-Dibenzyl-8,8a-dihydroindo-
lo[1,2-a]cyclopropa-[1,2-c]pyrrolidin-8b-ylamine (10): The amine 10
(223 mg, 61%) was obtained from the amide 9 (382 mg, 1.00 mmol), Me-
Ti(OiPr)3 (361 mg, 1.50 mmol) and cHexMgBr (5.0 mL, 5.00 mmol, 1.0m
solution in Et2O) according to GP 3 in a (1aS,8aS,8bR)-10/(1aR,8aS,8bS)-
10 ratio of 1:1.
(1aS,8aS,8bR)-10: Colorless oil; Rf (Et2O/hexane 1:5)=0.66; [a]2D0 =À7.7
(c=0.35, CHCl3); 1H NMR (250 MHz, CDCl3): d=7.37 6.97 (m, 12H;
Har), 6.65 (t, J=7.1 Hz, 1H; Har), 6.34 (d, J=8.1 Hz, 1H; Har), 4.74 (ddd,
J=1.5, 5.2, 8.8 Hz, 1H; 2-H), 3.97 (d, J=13.5 Hz, 2H; CH2Ph), 3.80 (d,
J=13.5 Hz, 2H; CH2Ph), 3.32 3.28 (m, 2H; 1-H), 3.15 (dd, J=3.5,
11.3 Hz, 1H; 6-H), 3.00 (d, J=11.3 Hz, 1H; 6-H), 1.03 0.97 (m, 1H;
cPr), 0.64 0.58 (m, 1H; cPr), 0.18 ppm (ps t, J=5.0 Hz, 1H; cPr);
13C NMR (62.9 MHz, CDCl3): d=143.2 (Car), 139.9 (2 Car), 130.1 (Car),
128.9 (4 CHar), 128.1 (4 CHar), 127.5 (CHar), 127.0 (2 CHar), 124.4 (CHar),
118.5 (CHar), 109.2 (CHar), 60.8 (CH; C-2), 57.1 (2 CH2; CH2Ph), 55.3
(C; cPr-C), 53.1 (CH2; C-6), 33.1 (CH2; C-1), 28.1 (CH; cPr), 14.0 ppm
(CH2; cPr); IR (film): n˜ =3026, 2920, 1480, 1263, 1028, 749 cmÀ1; MS (EI,
70 eV): m/z (%): 366 (47) [M+], 275 (100) [M+ÀC7H7], 170 (48), 91 (84)
[C7H7+]; HRMS (EI): calcd for C26H26N2 [M+] 366.2096, found 366.2096.
N,N-Dibenzylindolo[1,2-a]cyclopropa[1,2-c]pyrrolidin-8b-ylamine (7b):
The amine 7b (204 mg, 79%) was obtained from the N,N-dibenzylamide
6b (270 mg, 710 mmol), [MeTi(OiPr)3] (256 mg, 1.06 mmol) and
cHexMgBr (3.5 mL, 3.50 mmol, 1.0m solution in Et2O) according to GP 3
as a colorless oil. Rf (hexane/Et2O 10:1)=0.55; 1H NMR (250 MHz,
CDCl3): d=7.66 7.62 (m, 1H; Har), 7.36 7.12 (m, 13H; Har), 6.33 (s, 1H;
Har), 4.15 (d, J=13.0 Hz, 2H; CH2Ph), 4.03 (d, J=13.0 Hz, 2H; CH2Ph),
3.70 (d, J=10.1 Hz, 1H; NCHHCH), 3.61 (dd, J=5.0, 10.0 Hz, 1H;
NCHHCH), 1.59?1.49 (m, 1H; cPr), 1.37 1.32 (m, 1H; cPr), 0.85 ppm
(ps t, J=5.0 Hz, 1H; cPr); 13C NMR (62.9 MHz, CDCl3): d=143.2 (Car),
139.6 (2 Car), 132.7 (Car), 132.6 (Car), 129.2 (4 CHar), 128.1 (4 CHar), 127.1
(2 CHar), 120.5 (CHar), 120.4 (CHar), 119.2 (CHar), 108.9 (CHar), 93.4
(CHar), 57.8 (2 CH2; CH2Ph), 49.6 (CH2; NCH2CH), 45.8 (C; cPr), 30.6
(CH; cPr), 24.2 ppm (CH2; cPr); IR (film): n˜ =3024, 2928, 1510, 1398,
1114 cmÀ1; MS (EI): m/z (%): 364 (1) [M+], 273 (100), 168 (6), 91 (32);
elemental analysis calcd (%) for C26H24N2 (364.49): C 85.68, H 6.64;
found: C 85.44, H 6.50.
(S)-N,N-Dibenzyl-1-(tert-butoxycarbonyl)-2,3-dihydroindole-2-carboxa-
mide: (S)-N,N-Dibenzyl-1-(tert-butoxycarbonyl)-2,3-dihydroindole-2-car-
boxamide (1.50 g, 89%) was obtained from the acid
8 (1.00 g,
3.80 mmol), DCC (1.96 g, 9.50 mmol), HOBT (513 mg, 3.80 mmol), and
HNBn2 (1.8 mL, 9.50 mmol) according to GP 1 as a colorless oil. Rf
(hexane/Et2O 2:1)=0.35; [a]2D0 =À72.0 (c=1.0, CHCl3); 1H NMR
(250 MHz, CDCl3, observed as a major/minor rotamer mixture): d=7.23
6.80 (m, 14H; Har), 5.28 5.10 (m, 1H; 2-H), 4.90 4.64 (m, 2H; CH2Ph),
4.58 4.41 (m, 2H; CH2Ph), 3.25 2.91 (m, 2H; 3-H), 1.63 [s, 9H, major;
C(CH3)3], 1.41 ppm [s, 9H, minor; C(CH3)3]; 13C NMR (62.9 MHz,
CDCl3): d=175.5 (C=O), 157.2 (Car), 155.3 (C=O), 137.1 (2 Car), 130.2
(Car), 129.8 (2 CHar), 129.2 (2 CHar), 129.0 (2 CHar), 128.6 (2 CHar), 127.7
(CHar), 127.3 (2 CHar), 126.8 (CHar), 122.2 (CHar), 114.8 (CHar), 79.7
[C(CH3)3], 59.1 (CH; C-2), 50.1 (CH2; CH2Ph), 49.8 (CH2; CH2Ph), 49.2
(CH2; C-3), 28.4 ppm [3 CH3; C(CH3)3]; MS (EI, 70 eV): m/z (%): 442
(14) [M+], 342 (15), 224 (7), 118 (100), 91 (23) [C7H7+].
(1aR,8aS,8bS)-10: Colorless oil, Rf (Et2O/hexane 1:5)=0.33; [a]D20 =À3.3
(c=0.3, CHCl3); 1H NMR (250 MHz, CDCl3): d?=7.08 7.34 (m, 12H;
Har), 6.87 (t, J=7.4 Hz, 1H; Har), 6.69 (d, J=7.7 Hz, 1H; Har), 3.71 (s,
2H; CH2Ph), 3.69 (s, 2H; 2 CH2Ph), 3.56 (dd, J=7.8, 16.0 Hz, 1H; 1-H),
3.90 (dd, J=8.2 Hz, 1H; 2-H), 3.22 3.28 (m, 2H; 6-H), 2.83 (dd, J=9.0,
16.0 Hz, 1H; 1-H), 1.82 1.90 (m, 1H; cPr), 1.30 (dd, J=4.8, 9.1 Hz, 1H;
cPr), 0.75 ppm (ps t, J=4.7 Hz, 1H; cPr); 13C NMR (62.9 MHz, CDCl3):
d=154.3 (Car), 140.1 (2 Car), 133.1 (Car), 128.7 (3 CHar), 128.2 (4 CHar),
127.4 (CHar), 126.9 (3 CHar), 124.4 (CHar), 121.2 (CHar), 113.9 (CHar),
72.7 (CH; C-2), 56.9 (2 CH2; CH2Ph), 56.4 (CH2; C-6), 55.0 (C; cPr), 33.1
(CH2; C-1), 28.6 (CH; cPr), 21.0 ppm (CH2; cPr); IR (film): n˜ =
3016 cmÀ1, 2919, 1462, 1257, 1027, 769; MS (EI, 70 eV): m/z (%): 366
(24) [M+], 275 (100) [M+ÀC7H7], 170 (48), 130 (47), 91 (84) [C7H7+];
HRMS (EI) calcd for C26H26N2 [M+] 366.2096, found 366.2096.
(S)-N,N-Dibenzyl-2,3-dihydro-1H-indole-2-carboxamide: Trifluoroacetic
acid (1.3 mL, 17.0 mmol) was added dropwise to a well-stirred solution of
(S)-N,N-dibenzyl-1-(tert-butoxycarbonyl)-2,3-dihydroindole-2-carboxamide
(1.50 g, 3.39 mmol) in CH2Cl2 (20 mL) at ambient temperature. The reac-
tion mixture was stirred at ambient temperature for 12 h, then cooled in
an ice bath while a saturated aqueous NaHCO3 solution (20 mL) was
carefully added. The organic phase was separated, washed with saturated
aqueous NaHCO3 solution (2î20 mL), brine (20 mL), and dried over
MgSO4. The product (1.12 g, 95%) was obtained as a colorless oil, which
was used without further purification. [a]2D0 =À64.0 (c=1.0, CHCl3); 1H
NMR (250 MHz, CDCl3): d?=7.45 7.12 (m, 12H; Har), 6.81 6.76 (m,
2H; Har), 4.98 (d, J=14.6 Hz, 1H; CHHPh), 4.75 4.65 (m, 2H, 2-H;
CHHPh), 4.42 4.25 (m, 3H, NH; CH2Ph), 3.44 (dd, J=10.6, 15.7 Hz,
1H; 3-H), 3.25 ppm (dd, J=6.4, 15.7 Hz, 1H; 3-H); 13C NMR (62.9 MHz,
CDCl3): d=174.1 (C=O), 156.1 (2 Car), 136.9 (CHar), 135.7 (2 Car), 128.8
(3 CHar), 128.4 (CHar), 127.9 (2 CHar), 127.6 (CHar), 127.3 (CHar), 126.7
(2 CHar), 124.3 (CHar), 119.9 (CHar), 111.5 (CHar), 58.2 (CH; C-2), 49.1
(CH2; CH2Ph), 48.2 (CH2; CH2Ph), 35.5 ppm (CH2; C-3); MS (EI,
70 eV): m/z (%): 342 (8) [M+], 270 (29), 189 (19), 155 (28), 118 (100), 90
(48).
(S)-N,N-Dibenzyl-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxamide: (S)-
N,N-Dibenzyl-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxamide (2.85 g,
72%) was obtained from proline 11 (2.15 g, 10.0 mmol), DCC (5.16 g,
25.0 mmol), HOBT (1.35 g, 10.0 mmol), and HNBn2 (4.8 mL, 25.0 mmol)
according to GP 1 as a colorless solid. Rf (cyclohexane/EtOAc 1:1)=
1
0.42; m.p. 128 1318C; [a]2D0 =+28.8 (c=1.0, CHCl3); H NMR (250 MHz,
CDCl3, observed as a major/minor rotamer mixture): d=7.37 7.20 (m,
10H; Har), 4.89 4.80 (m, 1H; 2-H), 4.74 4.60 (m, 2H; CH2Ph), 4.50 4.40
(m, 2H; CH2Ph), 3.66 3.41 (m, 2H; 5-H), 2.04 1.81 (m, 4H; 3,4-H), 1.50
[s, 9H, minor; C(CH)3)3], 1.38 ppm [s, 9H, major; C(CH)3)3]; 13C NMR
(62.9 MHz, CDCl3, observed as a major/minor rotamer mixture): d=
174.0 (C=O), 155.3 (C=O), 137.2 (Car), 136.5 (Car), 128.9 (2 CHar), 128.8
(2 CHar), 128.5 (CHar), 127.9 (CHar), 127.5 (CHar), 126.8 (CHar), 126.7 (2
CHar), 79.9 [C, major; C(CH)3)3], 79.4 [C, minor; C(CH)3)3], 56.4 (CH,
minor; C-2), 56.0 (CH, major; C-2), 50.2 (CH2, major; CH2Ph), 49.7
(CH2, minor; CH2Ph), 49.0 (CH2, major; CH2Ph), 48.8 (CH2, minor;
CH2Ph), 47.0 (CH2; C-5), 31.5 (CH2, minor; C-3), 30.2 (CH2, major; C-3),
28.5 [CH3, major; C(CH3)3], 28.4 [CH3, minor; C(CH3)3], 24.5 (CH2,
major; C-4), 23.4 ppm (CH2, minor; C-4); IR (KBr): n˜ =3030, 2973, 1684,
788
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 785 790

Cyclopropane-Annelated Azaoligoheterocycles
785 790
1651, 1403, 1164, 706 cmÀ1; MS (EI, 70 eV): m/z (%): 394 (2) [M+], 303
(21) [M+ÀC7H7], 170 (36), 114 (100), 91 (83) [C7H7+], 70 (96); elemental
analysis calcd (%) for C24H30N2O3 (394.52): C 73.07, H 7.67; found: C
72.83, H 7.46.
CH2Ph), 49.0 (CH2; CH2CH=CH2), 48.1 (CH2; C-5), 29.6 (CH2),
22.8 ppm (CH2); IR (film): n˜ =3030, 2972, 1651, 1453, 1211, 732 cmÀ1; MS
(EI, 70 eV): m/z (%): 334 (2) [M+], 110 (100), 91 (10), 41 (33); elemental
analysis calcd (%) for C22H26N2O (334.46): C 79.00, H 7.84; found: C
78.89, H 7.64.
(S)-N,N-Dibenzyl-2-pyrrolidinecarboxamide (12): Trifluoroacetic acid
(0.50 mL, 6.34 mmol) was added dropwise to a well stirred solution of
(S)-N,N-dibenzyl-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxamide
(480 mg, 1.22 mmol) in CH2Cl2 (20 mL) at ambient temperature. The re-
action mixture was stirred at ambient temperature for 12 h, then cooled
in an ice bath while a saturated aqueous NaHCO3 solution (20 mL) was
carefully added. The organic phase was separated, washed with a saturat-
ed aqueous NaHCO3 solution (2î20 mL), brine (20 mL), and dried over
MgSO4. The product (355 mg, 99%) was obtained as a colorless oil,
which was used without further purification. [a]2D0 =À77.0 (c=0.50,
CHCl3); 1H NMR (250 MHz, CDCl3): d=7.34 7.15 (m, 10H; Har), 4.91
(d, J=14.8 Hz, 1H; CHHPh), 4.58 (d, J=23.5 Hz, 1H; CHHPh), 4.34 (d,
J=23.5 Hz, 1H; CHHPh), 4.25 (d, J=14.8 Hz, 1H; CHHPh), 3.99 3.94
(m, 1H; 2-H), 3.29 3.19 (m, 1H; 5-H), 2.91 (s, 1H; NH), 2.86 2.77 (m,
1H; 5-H), 2.08 1.98 (m, 1H), 1.84 1.69 ppm (m, 3H); 13C NMR
(62.9 MHz, CDCl3): d=174.8 (C=O), 137.0 (Car), 136.0 (Car), 129.0 (2
CHar), 128.6 (2 CHar), 128.1 (2 CHar), 127.8 (CHar), 127.4 (CHar), 126.6 (2
CHar), 58.5 (CH; C-2), 49.1 (CH2; CH2Ph), 48.1 (CH2; CH2Ph), 47.9
(CH2; C-5), 31.4 (CH2; C-3), 26.6 ppm (CH2; C-4).
(1aS,6aS,6bR)- and (1aR,6aS,6bS)-N,N-Dibenzylperhydrocyclopropa[1,2-
a]pyrrolizin-6b-ylamine (16): The amine 16 (224 mg, 70%) was obtained
from (S)-N,N-dibenzyl-1-allyl-2-pyrrolidinecarboxamide (15, 334 mg,
1.00 mmol), [MeTi(OiPr)3] (370 mg, 1.54 mmol), and cHexMgBr (5.0 mL,
5.00 mmol, 1.0m solution in Et2O) according to GP 3 in a (1aR,6aS,6bS)-
16/(1aS,6aS,6bR)-16 ratio of 2.9:1. (1aR,6aS,6bS)-16: Colorless oil; Rf
(CH2Cl2/MeOH 20:1)=0.25; [a]2D0 =À21.6 (c=0.80, CHCl3); 1H NMR
(250 MHz, CDCl3): d=7.34 7.15 (m, 10H; Har), 4.90 (m, 1H; 6a-H), 3.83
(d, J=13.3 Hz, 2H; CH2Ph), 3.66 (d, J=13.3 Hz, 2H; CH2Ph), 3.56 3.52
(m, 1H; 4-H), 3.46 3.40 (m, 1H; 2-H), 2.60 (d, J=12.3 Hz, 1H; 2-H),
2.50 2.04 (m, 4H; 4,5,6-H), 1.89 1.80 (m, 1H; 6-H), 1.17 1.10 (m, 1H;
cPr), 1.00 0.94 (m, 1H; cPr), 0.59 ppm (ps t, J=5.3 Hz, 1H; cPr); 13C
NMR (250 MHz, CDCl3): d=139.4 (2 Car), 128.9 (4 CHar), 128.2 (4
CHar), 127.1 (2 CHar), 62.4 (CH; C-6a), 57.0 (2 CH2; CH2Ph), 55.2 (CH2;
C-4), 54.3 (CH2; C-2), 53.5 (C; cPr), 30.1 (CH; cPr), 29.4 (CH2; C-6),
27.7 (CH2; C-5), 19.3 ppm (CH2; cPr); IR (film): n˜ =3020, 2910, 1465,
1241, 1032 cmÀ1; MS (EI, 70 eV): m/z (%): 318 (6) [M+], 250 (10), 227
(100) [M+ÀC7H7], 124 (60), 91 (80) [C7H7+]; HRMS (EI) calcd for
C22H26N2 [M+] 318.2096, found 318.2096; elemental analysis calcd (%)
for C22H26N2 (318.46): C 82.97, H 8.23; found: C 82.73, H 8.08.
(Æ)-N,N-Dibenzyl-1,2-diallyl-2-pyrrolidinecarboxamide (13): Compound
13 (1.32 g, 33%) was obtained from the amine 12 (3.15 g, 10.7 mmol),
K2CO3 (3.00 g, 21.7 mmol), and allyl bromide (1.40 mL, 16.1 mmol) ac-
(1aS,6aS,6bR)-16: Colorless solid; Rf (CH2Cl2/MeOH 20:1)=0.10; m.p.
148 1518C; [a]2D0 =À40.0 (c=0.25, CHCl3); 1H NMR (250 MHz, CDCl3):
d=7.35 7.18 (m, 10H; Har), 4.24 (t, J=7.3 Hz, 1H; 6a-H), 3.79 (d, J=
13.3 Hz, 2H; CH2Ph), 3.70 (d, J=13.3 Hz, 2H; CH2Ph), 3.03 2.89 (m,
2H; 2,4-H), 2.42 2.28 (m, 2H; 2,4-H), 2.24 2.22 (m, 1H; 5-H), 1.96 1.57
(m, 3H; 5,6-H), 1.04 0.97 (m, 1H; cPr), 0.80 0.71 (m, 1H; cPr),
0.26 ppm (t, J=4.9 Hz, 1H; cPr); 13C NMR (250 MHz, CDCl3): d=140.1
(2 Car), 128.9 (4 CHar), 128.0 (4 CHar), 126.8 (2 CHar), 61.4 (CH; C-6a),
57.9 (C; cPr), 57.1 (2 CH2; CH2Ph), 55.1 (CH2; C-4), 54.3 (CH2; C-2),
30.5 (CH; cPr), 29.8 (CH2; C-6), 28.0 (CH2; C-5), 19.1 ppm (CH2; cPr);
IR (film): n˜ =3018 cmÀ1, 2912, 1468, 1235, 1022; MS (EI, 70 eV): m/z
(%): 318 (5) [M+], 250 (1), 227 (100) [M+ÀC7H7], 123 (18), 91 (75)
[C7H7+]; HRMS (EI) calcd for C22H26N2 [M+] 318.2096, found 318.2096.
cording to GP 1 as a colorless oil. Rf (hexane/Et2O 10:1)=0.48; [a]D20
=
0.0 (c=1.0, CHCl3); 1H NMR (300 MHz, C2D2Cl4 at 1008C): d=7.38
7.15 (m, 10H; Har), 6.11 5.97 (m, 1H; NCH2CH=CH2), 5.78 5.63 (m,
1H; CCH2CH=CH2), 5.19 4.98 (m, 6H; CH2Ph, CCH2CH=CH2,
NCH2CH=CH2), 4.60 (d, J=18.5 Hz, 2H; CH2Ph), 3.56 3.45 (m, 1H),
3.21 3.09 (m, 2H), 2.90 (dd, J=7.3, 13.1 Hz, 1H), 2.70 2.61 (m, 1H;
CCHHCH=CH2), 2.39 2.20 (m, 2H; 3-H, CCHHCH=CH2), 2.18 2.03
(m, 1H), 1.84 1.78 ppm (m, 2H); 13C NMR (75.5 MHz, C2D2Cl4 at
1008C): d=174.6 (C=O), 137.6 (2 Car), 136.5 (CH; NCH2CH=CH2), 136.2
(CH; CCH2CH=CH2), 128.2 (4 CHar), 127.2 (4 CHar), 126.7 (2 CHar),
116.8 (CH2; NCH2CH=CH2), 115.7 (CH2; CCH2CH=CH2), 65.2 (C; C-2),
51.9 (2 CH2), 50.0 (CH2), 49.7 (CH2; NCH2CH=CH2), 37.1 (CH2;
CCH2CH=CH2), 32.3 (CH2; C-3), 21.7 ppm (CH2; C-4); IR (film): n˜ =
3067, 2977, 2812, 1633, 1413, 1190, 916 cmÀ1; MS (EI, 70 eV): m/z (%):
374 (<1) [M+], 150 (100), 91 (14) [C7H7+].
Acknowledgments
(S)-1-Allylproline hydrochloride: Amixture of l-proline (14, 20.0 g,
174 mmol) and KOH (29.2 g, 521 mmol) in isopropanol (100 mL) was
heated at 408C for 30 min, then allyl bromide (18 mL, 208 mmol) was
added and the solution stirred at the same temperature for 19 h. Hydro-
chloric acid (22 mL of a 37% aq. solution) and CHCl3 (100 mL) were
added, the mixture was stirred for 3 h and then filtered. After removal of
the solvent under reduced pressure a yellow solid was obtained and
washed several times with acetone. The product (18.3 g, 55%) was ob-
This work was supported by the Deutsche Forschungsgemeinschaft (SFB
416 Project A3), the Fonds der Chemischen Industrie, Bayer AG, and
EPSRC (UK). The authors are grateful to the companies BASF AG,
Chemetall GmbH, and Degussa AG for generous gifts of chemicals. They
are indebted to Dr. Dimitri S. Yufit and Prof. Judith A. K. Howard at the
University of Durham, UK, for carrying out the X-ray crystal structure
analysis of compound (1aS,6aS,6bR)-16. They gratefully acknowledge the
careful proofreading of the final manuscript by Dr. Burkhard Knieriem,
Gˆttingen.
tained as
a
colorless solid. M.p. 205 2098C; [a]2D0 =À60.2 (c=1.0,
1
MeOH); H NMR (250 MHz, CD3OD): d=5.84 5.67 (m, 1H; CH=CH2),
5.41 5.26 (m, 2H; CH=CH2), 3.94 (dd, J=6.7, 9.5 Hz, 1H; 2-H), 3.78
3.58 (m, 2H; CH2CH=CH2), 3.52 3.42 (m, 1H; 5-H), 3.08 2.96 (m, 1H;
5-H), 2.35?2.24 (m, 1H), 2.01 1.70 ppm (m, 3H); 13C NMR (62.9 MHz,
CD3OD): d=172.0 (C==O), 128.8 (CH; CH=CH2), 125.8 (CH2; CH=
CH2), 68.1 (CH; C-2), 58.3 (CH2), 55.5 (CH2), 29.8 (CH2), 23.9 ppm
(CH2); IR (KBr): n˜ =3480, 3004, 2849, 1734, 1444, 1226, 953 cmÀ1; MS
(EI, 70 eV): m/z (%): 155 (2) [M+], 110 (100), 70 (18), 41 (33).
[1] R. W. Franck, in Progress in the Chemistry of Organic Natural Prod-
ucts (Eds.: W. Herz, H. Grisebach, G. W. Kirby), Springer, Wien,
1979, Vol. 38, pp. 1 45.
[2] H.-P. Husson in The Alkaloids, Vol. 26 (Ed.: A. Brossi), Academic
Press, London, 1985, Chapter 1, 1 51.
[3] M. Lounasmaa, P. Somersalo in Progress in the Chemistry of Organ-
ic Natural Products, Vol. 50, (Eds.: W. Herz, H. Grisebach, G. W.
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[4] W. A. Remers, R. T. Dorr, in Alkaloids: Chemical and Biological
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74.
(S)-N,N-Dibenzyl-1-allyl-2-pyrrolidinecarboxamide (15): The amide 15
(4.65 g, 89%) was obtained from (S)-1-allylproline hydrochloride (3.00 g,
15.6 mmol), DCC (3.40 g, 16.5 mmol), HOBT (2.22 g, 16.4 mmol), and
HNBn2 (4.5 mL, 23 mmol) according to GP 1 as a colorless oil. Rf
(Et2O)=0.30; [a]2D0 =À75.0 (c=1.0, CHCl3); 1H NMR (250 MHz,
CDCl3): d=7.39 7.12 (m, 10H; Har), 5.98 5.85 (m, 1H; CH=CH2), 5.16
4.97 (m, 2H; CH=CH2), 4.74 (d, J=14.6 Hz, 1H; CH2Ph), 4.49 4.41 (m,
4H; CH2Ph, 2-H), 3.50 3.34 (m, 2H; CH2CH=CH2), 3.25 3.18 (m, 1H;
5-H), 3.01 (dd, J=7.3, 13.1 Hz, 1H; 5-H), 2.35 2.25 (m, 1H), 2.04?1.87
(m, 2H), 1.76 1.71 ppm (m, 1H); 13C NMR (62.9 MHz, CDCl3): d=173.8
(C=O), 137.3 (Car), 136.6 (Car), 135.8 (CH; CH=CH2), 128.7 (2 CHar),
128.4 (2 CHar), 128.3 (2 CHar), 127.4 (CHar), 127.2 (CHar), 126.3 (2 CHar),
116.8 (CH2; CH=CH2), 63.5 (CH; C-2), 57.3 (CH2; CH2Ph), 53.1 (CH2;
[5] a) C. Szµntay in The Alkaloids, Vol. 50 (Ed.: G. A. Cordell), Aca-
demic Press, London, 1998, Chapter 10, 377 414; b) D. J. Robins in
The Alkaloids, Vol. 46 (Ed.: G. A. Cordell), Academic Press,
London, 1995, Chapter 1, 1 61.
789
Chem. Eur. J. 2004, 10, 785 790
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

A. de Meijere and M. Gensini
FULL PAPER
[6] M. Lounasmaa, P. Hanhinen, M. Westersund in The Alkaloids,
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[7] C. Christine, K. Ikhiri, A. Ahond, A. Al Mourabit, C. Poupat, P.
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[9] a) S. J. Danishefsky, J. M. Schkeryantz, Synlett 1995, 475 490; b) F.
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1977, 99, 8115 8116; c) T. Fukuyama, F. Nakatsubo, A. J. Cocuzza,
Y. Kishi, Tetrahedron Lett. 1977, 4295 4298.
USSR (Engl. Transl.) 1991, 27, 250 253; c) O. G. Kulinkovich, S. V.
Sviridov, D. A. Vasilevski, Synthesis 1991, 234.
[14] S. Okamoto, M. Iwakubo, K. Kobayashi, F. Sato, J. Am. Chem. Soc.
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[15] M. Gensini, S. I. Kozhushkov, D. S. Yufit, J. A. K. Howard, M. Es-
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[16] The first examples of such an intramolecular aminocyclopropanation
of an N-allyl group in an N-allyl-a-amino acid N,N-dialkylcarbox-
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collected on
a Bruker CCD SMART 1 K diffractometer using
graphite-monochromated MoKa radiation. The structure solutions
and refinements on F2 were performed with the Bruker SHELXTL
program suite. (1aS,6aS,6bR)-16: C22H26N2, crystal size 0.33î0.07î
0.04 mm3,
orthorhombic,
a=6.1990(3),
b=14.5497(8),
c=
20.0989(11) ä, V=1812.79(17) ä3, Z=4, space group P212121, T=
120(2) K, 1=1.167 gcmÀ3, intensities measured: 13907 (2qmax =508),
independent: 3194 (Rint =0.1604), 217 parameters refined, R1 (all
data)=0.1363, wR2 (all data)=0.1082, Gof=0.976, maximum and
minimum residual electron density 0.180 and À0.222 eäÀ3. CCDC-
206103 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via www.ccdc.cam.
ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(+44)1223 336033; or email: deposit@ccdc.cam.ac.uk.
Received: April 24, 2003
Revised: October 10, 2003 [F5068]
790
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www.chemeurj.org
Chem. Eur. J. 2004, 10, 785 790