Synthesis of decahydropyrrolo[2,1,5-cd ]indolizine through consecutive [2 + 3] cycloadditions and 6-exo-trig cyclization

Article abstract of DOI:10.1021/jo200601y

Azomethine ylide formed from glycine methyl ester and cinnamaldehyde adds to N-phenylmaleimide to form pyrrolidine derivative, further treatment of which with cinnamaldehyde and N-phenylmaleimide affords the second [2 + 3] cycloaddition adduct, a pyrrolizine derivative with two styrenyl groups at the 3,5-positions. Addition of ICl to the pyrrolizine derivative results in the 6-exo-trig cyclization of the styrenyl groups to form a cycl[3.2.2]azine derivative. The reactions are highly stereoselective affording 11 chiral carbons in three steps. The structure of the cycl[3.2.2]azine derivative was determined by single-crystal X-ray analysis.

Full text of DOI:10.1021/jo200601y

NOTE
pubs.acs.org/joc
Synthesis of Decahydropyrrolo[2,1,5-cd]indolizine through
Consecutive [2 þ 3] Cycloadditions and 6-Exo-Trig Cyclization
Peipei Cui,† Liang Xu,† Zhangjie Shi,*,† and Liangbing Gan*,†,‡
†Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the
Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
S Supporting Information
b
ABSTRACT: Azomethine ylide formed from glycine methyl ester and
cinnamaldehyde adds to N-phenylmaleimide to form pyrrolidine derivative,
further treatment of which with cinnamaldehyde and N-phenylmaleimide
affords the second [2 þ 3] cycloaddition adduct, a pyrrolizine derivative with
two styrenyl groups at the 3,5-positions. Addition of ICl to the pyrrolizine
derivative results in the 6-exo-trig cyclization of the styrenyl groups to form a
cycl[3.2.2]azine derivative. The reactions are highly stereoselective affording
11 chiral carbons in three steps. The structure of the cycl[3.2.2]azine derivative was determined by single-crystal X-ray analysis.
yrrolo[2,1,5-cd]indolizine or cycl[3.2.2]azine was first synthe-
sized through a two-step cyclization procedure starting from
Formation of compounds 3 and 4 follows the classical 1,3-
dipole addition mechanism. The iodochloride-induced cycli-
zation was unexpected. It probably starts from iodium addition
to the double bond trans to the ester group to form benzyl
cation A, which then adds to the other double bond to form
another benzyl cation. Finally, addition of chloride to this
second cation affords 5. The steric effect of the ester group may
be the key factor differentiating the two styrenyl groups in the
first step, i.e., regioselectivity of the ICl addition. The steric
effect of the phenyl groups and ring strain of the cycl-
[3.2.2]azine framework should be the driving force for the
stereoselectivity in the final cyclization step, forming four
chiral carbons.
P
indolizine.1 The nitrogen-doped aromatic system has attracted
much attention. A number of different synthetic methods have
been reported for its synthesis.2ꢀ4 These include the [8 þ 2]-
cycloaddition of indolizine with an electron-deficient acetylene5ꢀ7
and intramolecular condensation of 3-acyl-5-methylindolizines.8
The cyclazine family has been shown to have a wide range of
bioactivities.9 A partially hydrogenated framework was later found in
several natural products such as the myrmicarins, which were
isolated from the poison gland of the African ant species Myrmicaria
opaciventris.10 Total synthesis of myrmicarin alkaloids is a challen-
ging problem because of its complex stereochemistry and sensitivity
to air, silica gel, and alumina. So far, only the simple members have
been synthesized.11ꢀ13 In spite of numerous efforts on the synthesis
of aromatic and partially hydrogenated pyrrolo[2,1,5-cd]indolizine,
little is known about the synthesis of fully hydrogenated pyrrolo-
[2,1,5-cd]indolizine.14 In contrast, a number of methods have
been reported for the synthesis of dodecahydropyrido[2,1,
6-de]quinolizine or azaphenalene with three six-membered rings15
and octahydro-1H-pyrrolo[2,1,5-cd]pyrrolizine or azatriquinane
with three five-membered rings.16 As a continuation of our studies
of oligocyclic compounds, in particular, nitrogen-containing cyclic
compounds,17ꢀ19 here we report the formation of a fully hydro-
genated pyrrolo[2,1,5-cd]indolizine derivative.
The synthesis begins with a 1,3-dipole cycloaddition to N-
phenylmaleimide to form compound 3.20 Further treatment of 3
with cinnamaldehyde and N-phenylmaleimide yields the tetra-
cyclic compound 4. Addition of iodochloride to 4 resulted in a
6-exo-trig cyclization process to yield 5 with a decahydrocycla-
zine core. The reactions were quite stereoselective, affording
mainly one stereoisomer. Other unstable isomers may have
formed but decomposed into uncharacerizable products.
Single-crystal X-ray structure of compound 5 was obtained
(shown in Figure 1 in the Supporting Information). The two
maleimide moieties are almost planar and trans to each other
Received: March 20, 2011
Published: April 07, 2011
r
2011 American Chemical Society
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NOTE
Scheme 1. Stereoselective Synthesis of Decahydropyrrolo-
[2,1,5-cd]indolizine 5
Compound 3. Glycine methyl ester (865 mg, 9.45 mmol) and
cinnamaldehyde (1282 mg, 9.71 mmol) were dissolved in DCM (22 mL)
and silica gel (1350 mg) was added to the solution. The solution was
stirred for 3 h at 0 °C, and then the solution was filtered to remove silica
gel, which was washed with DCM (15 mL). The filtrate was combined,
and N-phenylmaleimide (1.679 mg, 9.71 mmol) and silver acetate
(49 mg, 0.29 mmol) were added. The resulting solution was stirred at
room temperature for 6 h. The product 3 was purified by flash column
chromatography on silica gel (eluent: petroleum ether/ethyl ester, 3:1 to
1:1 v/v) as a white solid: 2284 mg (73% yield); 1H NMR (300 MHz,
CDCl3) δ 7.45ꢀ7.19 (m, 12H),6.73 (d, 1H, J = 15.9 Hz), 6.40 (dd, 1H, J
= 7.5, 6.9 Hz), 4.09 (d, 2H, J = 6.9 Hz), 3.84 (s, 3H), 3.68 (t, 1H, J = 7.8
Hz), 3.48 (t, 1H, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) all signals
represent 1C except noted 175.2, 174.2, 170.3, 136.4, 132.8, 131.7, 129.2
(2C), 128.8, 128.7(2C), 128.1, 126.8 (2C), 126.5 (2C), 125.2, 62.8,
62.7, 52.6, 49.5, 48.9; FT-IR (microscope) 3324, 3060, 3029, 2994,
2950, 2925, 2868, 1745, 1707, 1598, 1500, 1450, 1438, 1390, 1362, 1259,
1208, 1144, 1121, 975, 757, 693 cmꢀ1; ESI-HRMS m/z calcd for
C22H21N2O4 [M þ H]þ 377.1496, found 377.1504.
Compound 4. Compound 3 (1000 mg, 3.01 mmol), N-phenylma-
leimide (552 mg, 3.19 mmol), and cinnamaldehyde (421 mg, 3.19 mmol)
were dissolved in DCM (5 mL) and the solvent was evaporated to
dryness. This mixture was irradiated with a household microwave oven
(700 W at full power) for 10 min. The residue was dissolved in DCM,
and the product 4 was purified by flash column chromatography on silica
gel (eluent: petroleum ether/ethyl ester, 4:1 to 3:1 v/v) as a white solid:
1178 mg (59% yield); 1H NMR (400 MHz, CDCl3) δ 7.02ꢀ7.55 (m,
20H), 6.69 (d, 1H, J = 3.8 Hz), 6.66 (d, 1H, J = 4.0 Hz), 6.29 (dd, 1H, J =
15.4, 10.1 Hz), 6.11 (dd, 1H, J = 15.8, 7.4 Hz), 4.75 (d, 1H, J = 8.4 Hz),
4.42 (d, 1H, J = 8.4 Hz), 4.34 (t, 1H, J = 9.2 Hz), 4.22 (t, 1H, J = 8.4 Hz),
3.9 (s, 3H, J = 8.8 Hz), 3.6 (t, 1H, J = 8.8 Hz), 3.6 (t, 1H, J = 8.6 Hz); 13C
NMR (100 MHz, CDCl3) all signals represent 1C except noted δ 175.8,
174.5, 174.1, 172.9, 170.2, 136.1, 135.9, 135.8, 133.0, 131.4, 129.5 (3C),
129.1 (4C), 128.8, 128.2 (3C), 128.2 (3C), 128.0, 127.9, 127.7, 126.7
(6C), 126.4 (3C), 125.7 (3C), 122.4, 81.7, 66.9, 64.3, 53.6, 51.7, 50.2,
49.9, 47.5; FT-IR(microscope) 3060, 3026, 2954, 2923, 2851, 1778, 1710,
1598, 1498, 1380, 1192, 1177, 691 cm ꢀ1; ESI-HRMS m/z calcd for
C41H34N3O6 [M þ H]þ 664.2442, found 664.2442.
relative to the cycl[3.2.2]azine ring. The piperidine moiety
adopts a twisted-boat conformation. The two hydrogen atoms
next to the piperidine nitrogen atom are in a trans configuration,
indicating that the precursor 4 should also have the same trans
configuration as depicted in Scheme 1. It is unlikely that the two
styrenyl groups switch positions in the ICl reaction. The relative
geometries of the chloro-, iodo-, and phenyl-bounded chiral
carbons are also clearly revealed from the X-ray structure. There
are four molecules in the unit cell, two of which are the same as
those drawn in Scheme 1. The other two molecules are
enantiomeric to the structure drawn for 5 in Scheme 1. Based
on the X-ray structure of 5 and spectroscopic data, structures of
other compounds can be assigned as shown in Scheme 1. The
stereochemistry of compound 3 is in agreement with well
established literature results17,18,20 including the single crystal
X-ray structure of an analogous compound prepared by similar
method.17
In summary, a fully hydrogenated pyrrolo[2,1,5-cd]indolizine
derivative is prepared through a three-step sequence, two con-
secutive azomethine ylide cycloadditions, and a ICl-induced
6-exo-trig cyclization. These reactions are highly stereoselective
affording 11 chiral centers in the final product. The final key step
involves formation and relay of a benzyl cation intermediate. This
strategy may be applied to the synthesis of other multicyclic
compounds. Further work is in progress to develop efficient
cyclization methods.
Compound 5. Compound 4 (456 mg, 0.68 mmol) was dissolved in
DCM (4 mL), and ICl (237 mg, 1.46 mmol) was added. After the
mixture was stirred at room temperature for 10 min, saturated aqueous
Na2S2O3 was added. The reaction mixture was extracted with DCM and
dried over anhydrous Na2SO4. The extract was concentrated, and the
residue was purified by flash column chromatography on silica gel
(eluent: petroleum ether/ethyl ester, 4:1 v/v) to give compound 5 as a
1
white solid: 216 mg (38% yield); H NMR (400 MHz, CDCl3) δ
7.60ꢀ7.14 (m, 20H), 5.46 (dd, 1H, J = 12.6, 8.2 Hz), 4.76 (d, 1H, J = 8.0
Hz), 4.63 (d, 2H, J = 8.7 Hz), 4.37 (t, 1H, J = 8.6 Hz), 4.02 (m, 1H), 3.92
(t, 1H, J = 5.3 Hz), 3.70 (s, 1H), 3.57(dd, 1H, J = 8.3, 6.0 Hz), 2.57 (dd,
1H, J = 7.8, 6.0 Hz), 2.35 (s, 1H); 13C NMR (100 MHz, CDCl3) all
signals represent 1C except noted δ 175.8, 173.9 (2C), 173.8, 169.6,
138.9, 138.3, 131.5, 131.4, 129.2 (3C), 129.1 (3C), 129.0, 128.8 (2C),
128.3, 128.2 (2C), 128.1, 127.7, 127.2 (2C), 126.4 (2C), 125.8 (2C),
125.2, 79.5, 72.3, 64.1, 57.7, 54.1, 49.9, 49.7, 48.1, 47.0, 46.8, 45.2, 21.6;
FT-IR (microscope) 3064, 3029, 2955, 2855, 1771, 1739, 1712, 1705,
1598; ESI-HRMS m/z calcd for C41H34ClIN3O6 [M þ H]þ 826.1175,
found 826.1171.
Single crystals were obtained from slow evaporation of 5 in DCM/
iPrOH. Crystal data for 5: C42H35Cl3IN3O6, Mw = 910.98 g molꢀ1
,
T = 173(2) K, monoclinic, space group P2(1)/n, unit cell dimensions a =
12.988(3) Å, b = 12.188(2) Å, c = 23.837(5) Å, β = 98.01(3)o, V =
3736.6(13) Å3, Z = 4, Fcalcd = 1.619 Mg m3, absorption coefficient =
1.126 mmꢀ1. Reflections collected/unique 29664/8533 [R(int) = 0.0503].
Final R indices [I > 2σ(I)] R1 = 0.0482, wR2 = 0.1116. CCDC-817229.
’ EXPERIMENTAL SECTION
All reagents were used as received. Dichloromethane (DCM) was
distilled over phosphorus pentoxide. Other solvents were used as
received. The reactions were carried out in air.
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NOTE
’ ASSOCIATED CONTENT
S
Supporting Information. Spectroscopic data for com-
b
pounds 3ꢀ5 and crystallographic data for 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: zshi@pku.edu.cn; gan@pku.edu.cn.
’ ACKNOWLEDGMENT
This work is supported by NSFC and the Major State Basic
Research Development Program.
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