Synthesis of alkaloid analogues from α-amino acids by one-pot radical decarboxylation/alkylation

Article abstract of DOI:10.1002/ejoc.200500124

A mild, one-pot methodology to obtain α-substituted nitrogen heterocycles from commercial amino acids is reported. This versatile procedure has been applied to the synthesis of different alkaloid analogues in good to excellent yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500124

FULL PAPER
Synthesis of Alkaloid Analogues from α-Amino Acids by One-Pot Radical
Decarboxylation/Alkylation
Alicia Boto,*[a] Yolanda De León,[a] Juan Antonio Gallardo,[a] and Rosendo Hernández*[a]
Keywords: Alkaloids / Amino acids / Nitrogen heterocycles / Radical reactions / Spiro compounds
A mild, one-pot methodology to obtain α-substituted nitrogen
heterocycles from commercial amino acids is reported. This
versatile procedure has been applied to the synthesis of dif-
ferent alkaloid analogues in good to excellent yields.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
radical decarboxylation, which generated a carbon radical
3. This radical was oxidized in situ to an acyliminium ion
4, which could be trapped by different nucleophiles[6] to
yield the α-substituted heterocycles 2.
Introduction
Alkaloids have attracted a much interest both from the
synthetic and the pharmacological standpoints.[1] The anti-
tumour agent swainsonine[2] (Figure 1), the non-addictive
analgesic ipalbidine[3] and the poisonous histrionicotoxin[4]
exemplify the variety of structures and biological activities.
In order to study structure-activity relationships (SAR)
many alkaloid analogues have been prepared, and in many
cases new synthetic strategies have been developed.[1]
Scheme 1. Synthesis of functionalised pyrrolidines (n = 1) and pi-
peridines (n = 2) by oxidative radical decarboxylation of α-amino
acids.
Figure 1. Bioactive alkaloids.
We reasoned that the resulting α-substituted heterocycles
2 would be useful intermediates to obtain alkaloids or their
analogues. The synthesis of indolizidine and spirobicyclic
alkaloid analogues using a tandem decarboxylation/alky-
lation reaction (Nu = alkyl) as the key step is reported
herein.
In recent reports from our group, α-amino acids 1
(Scheme 1) were used as starting materials in the synthesis
of substituted nitrogen heterocycles 2.[5] The key step was a
[a] Instituto de Productos Naturales y Agrobiología CSIC,
Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tene-
rife, Spain
Results and Discussion
In recent years, many efforts have been devoted to the
synthesis of indolizidine alkaloids since several of them
Fax: +34-922-260-135
E-mail: alicia@ipna.csic.es
rhernandez@ipna.csic.es
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DOI: 10.1002/ejoc.200500124
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FULL PAPER
(such as swainsonine, Figure 1) are potent glycosidase in- yield. Treatment of 13 with base gave the 6,7-disubstituted
hibitors and possess antitumoural, antiviral or hypogluca- indolizodinone 14 in excellent yield.
emic activities.[2] However, they also have important side-
effects or limited bioavailability. In order to overcome these
problems, different synthetic analogues have been devel-
oped.
The indolizidine core can be synthesised in three steps
starting from commercial pyroglutamic acid 5 (Scheme 2).
When the amino acid 5 was treated with DIB/iodine, fol-
lowed by addition of boron trifluoride and allyltrimethylsi-
lane, the 2-allylpyrrolidinone 6[5d] was obtained in excellent
yield. N-Allylation afforded the diene 7,[7] which underwent
olefin metathesis to give the indolizidine 8[7a] in good global
yield.
Scheme 3. Synthesis of ipalbidine and septicine analogues. Rea-
Scheme 2. Synthesis of analogues of indolizidine alkaloids. Rea-
gents and conditions: (a) ClCOCH2Ph, THF/NaHCO3 (aq. satd.),
room temp., 10 h, 76%; (b) DIB, I2, CH2Cl2, 3 h; then BF3·OEt2,
isopropenyl acetate, 0 °C to room temp., 4 h, 58%; (c) tBuOK,
gents and conditions: (a) DIB, I2, CH2Cl2, 3 h; then BF3·OEt2,
allylTMS, 0 °C to room temp., 4 h, 81%; (b) NaH, DMF, 0 °C,
0.5 h; then CH2=CHCH2Br or CH2=CHCH2CH2CH2Br, 67% for
7, 63% for 9; (c) (benzylidene)dichlorobis(tricyclohexylphosphane)
tBuOH, reflux, 12 h, 99% for 14, 82% for 16; (d) DIB, I2, CH2Cl2,
3 h; then BF3·OEt2, PhC(OTMS)=CH2, 0 °C to room temp., 4 h,
ruthenium(ii) (cat.), CH2Cl2, reflux, 80% for 8, 81% for 10.
50%.
In order to obtain derivatives with different ring sizes,
In a similar way, an analogue of the seco-phenanthroline
the pyrrolidinone 6 was treated with sodium hydride and 5- alkaloid septicine[12] was readily synthesised. Thus, when
bromo-1-pentene. The resultant diene 9 underwent olefin the proline derivative 12 was treated with DIB/I2, and then
metathesis to yield the bicyclic compound 10,[7a] which con- boron trifluoride–diethyl ether and phenyl(trimethyl-
tains an eight-membered ring. Although rather unusual, the silyloxy)ethene were added, the phenone derivative 15 was
bicyclo[3.0.6] system can be found in alkaloids with potent obtained. This product underwent reaction with tBuOK in
biological activity, such as the manzamines.[8]
refluxing tBuOH to yield the septicine analogue 16[12k] in
The indolizidine core can also be found in phenan- very good yield.
throline or seco-phenanthroline alkaloids. The analgesic
It should be noted that other substituents can be intro-
ipalbidine[3] (Figure 1) has already been mentioned, and duced into the bicyclic core by using other cyclic amino
other members of this family present promising antitu- acids as substrates or by varying the amido and ketone
moural activity.[9,10] The synthesis of analogues to study the chains, thus offering a versatile route to many analogues.
SAR has been undertaken by several groups.
This strategy also offers a direct route to polycyclic sys-
The direct synthesis of an ipalbidine analogue was car- tems. For instance, when proline derivative 12 was treated
ried out according to Scheme 3. Commercial proline 11 re- under the usual decarboxylation/alkylation conditions with
acted with phenylacetyl chloride to afford the proline deriv- 1-(trimethylsilyloxy)cyclohexene as nucleophile, the cyclo-
ative 12.[11] The latter was treated with DIB/I2, followed by hexyl derivatives 17 and 18 (Scheme 4) were obtained as an
addition of boron trifluoride–diethyl ether and isopropenyl inseparable diastereomer mixture (17/18 = 3:2, according to
acetate to give the ( )-norhygrine derivative 13 in good the NMR spectra at 25 °C) in 68% yield.
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Alkaloid Analogues from α-Amino Acids by One-Pot Radical Decarboxylation/Alkylation
FULL PAPER
the potent biological activities (immunosuppressant,[17]
antiinflammatory,[18] cytotoxic activities,[19] etc.) associated
with many of them.[20]
A synthetic approach to the heterobicyclic core was de-
vised using the commercial amino acid 20 (Scheme 5) as
starting material. Its methyl carbamate 21[21] was treated
under the decarboxylation/allylation conditions to generate
the tertiary N-acyliminium ion 22, which reacted with the
nucleophile to give the allyl derivative 23.
Scheme 4. Synthesis of polycyclic compounds. Reagents and condi-
tions: (a) DIB, I2, CH2Cl2, 3 h; then BF3·OEt2, 1-(trimethyl-
silyloxy)cyclohexene, 0 °C to room temp., 4 h, 68%, (17/18 = 3:2);
(b) tBuOK, tBuOH, reflux, 12 h, 81% for the isomeric olefinic mix-
ture, 21% for 19 purified from the mixture.
To confirm that compounds 17 and 18 are diastereomers
and not rotamers, the NMR spectra at 26 °C and 60 °C
were compared. Although the resolution improved on heat-
ing, no coalescence or significant shifts of the signals were
observed, and the ratio 17/18 remained constant. This be-
haviour indicates that compounds 17 and 18 are dia-
stereomers and not rotamers. According to the coupling
constants observed in the 1H NMR spectra,[13,14] the
(2R*,2ЈR*) configuration was tentatively assigned to the
major product 17, and the (2R*,2ЈS*) configuration to the
minor diastereomer 18.
Scheme 5. Synthesis of the azaspirocyclic core. Reagents and condi-
tions: (a) ClCO2Me, THF/NaHCO3 (aq. satd.), room temp., 18 h,
72%; (b) DIB, I2, CH2Cl2, room temp., 3 h, then 0 °C, allyltrimeth-
ylsilane, BF3·OEt2, 61%; (c) NaH, DMF, 0 °C, 1 h, then allyl bro-
mide, 4 h, 88%; (d) (benzylidene)dichlorobis(tricyclohexylphos-
phane)ruthenium(ii) (cat.), CH2Cl2, reflux, 94%.
To generate a polycyclic core, the mixture of dia-
stereomers 17 and 18 was submitted to an aldol condensa-
tion under thermodynamic conditions. A mixture of iso-
This reaction is remarkable since the use of tertiary acyl-
meric olefinic products was obtained (81% estimated iminium ions in synthesis has been restricted until re-
yield[15]), from which the tricyclic conjugated amide ( )-19 cently.[22] In some cases, their generation was difficult,
could be isolated (21%).
whereas in other cases the addition of nucleophiles was
The (10aS*,10bR*) configuration was assigned to pro- hampered due to steric hindrance or other problems. In our
duct 19 according to the coupling constants observed in the case, the first problem was avoided by using the acid 21 as
1H NMR spectrum, and by comparison with the J values a stable precursor of the acyliminium intermediate. To our
calculated for the minimum-energy conformations of the satisfaction, the addition of the nucleophile also proceeded
possible diastereomers.[14,16]
in good yields.
The formation of compound ( )-19 was achieved in two
The allyl derivative 23 underwent N-allylation to yield
steps from a common amino acid derivative. Other polycy- the diene 24, and subsequent ring-closing metathesis af-
clic systems could be generated by using different cyclic or forded the spirocyclic system 25 in excellent yield. This bicy-
polycyclic silyl enol ethers as nucleophiles. Although the cy- clic system is present in bioactive natural products such as
clohexanone derivatives 17 and 18 could not be separated, histrionicotoxin.[4]
in other cases separation of the decarboxylation/alkylation
By replacing the nitrogen protecting group, we can alter
products would be possible, or stereoselectivity could be in- the reaction outcome and obtain different spirocyclic com-
duced.
pounds. Thus, when the methyl carbamate in 21 was re-
Other alkaloids that have attracted much interest are the placed by a BOC group (substrate 26,[23] Scheme 6), a one-
azaspirocyclic compounds (such as histrionicotoxin,[4] Fig- pot decarboxylation/alkylation/cyclisation took place. The
ure 1), due not only to their unusual structure but also to reaction intermediate 27 evolved by nucleophilic addition
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A. Boto, Y. De León, J. A. Gallardo, R. Hernández
FULL PAPER
of the carbamate oxygen and concomitant loss of the tert-
butyl group,[24] affording the spirocyclic carbamate 28 in
61% global yield. The spirocyclic carbamates are structural
analogues of spirocyclic lactams, and both kinds of com-
pounds may be bioisosters.
Experimental Section
General Remarks: Commercially available reagents and solvents
were of analytical grade or were purified by standard procedures
prior to use. All reactions involving air- or moisture-sensitive mate-
rials were carried out under nitrogen. The spray reagents for TLC
analysis were 0.5% vanillin in H2SO4/EtOH (4:1) or 0.25% ninhyd-
rin in ethanol. Merck silica gel 60 PF was used for TLC analysis
and 0.063–0.2 mm silica gel was used for column chromatography.
NMR spectra were determined in CDCl3 solution using TMS as an
internal standard, unless otherwise stated. For some compounds, a
mixture of two rotamers was observed at room temperature, which
caused broadening or splitting of the NMR signals. The rate of
rotamer interconversion usually increased on heating, and in many
cases only one rotamer could be detected at 60–70 °C. When the
NMR resolution improved significantly on heating, the spectra at
60–70 °C are described. Abbreviations: arom. = aromatic protons
or carbon atoms; BOC = tert-butyl carbamate; c.s. = complex sig-
nal; DIB = (diacetoxyiodo)benzene; DMF = dimethylformamide;
SAR = structure-activity relationship; THF = tetrahydrofuran;
TMS = trimethylsilyl; AllylTMS = allyltrimethylsilane. Com-
pounds 6,[5d] 7–10,[7a] 12[11] and 26[23] have been reported pre-
viously.
General Procedure for the Tandem Decarboxylation/Alkylation Re-
action: DIB (2.0 mmol) and iodine (1.0 mmol, unless otherwise
stated) were added to a solution of the starting acid (1.0 mmol) in
dry CH2Cl2 (15 mL) under nitrogen. The reaction mixture was
stirred at room temperature in sunlight for the time stated in the
scheme captions. Afterwards, it was cooled to 0 °C and BF3·OEt2
(2 mmol) and the nucleophile (5 mmol) were added dropwise. The
reaction mixture was allowed to reach room temperature and was
stirred for another 4 h. It was then poured into an aqueous 10%
sodium thiosulfate (Na2S2O3)/saturated NaHCO3 solution and ex-
tracted with CH2Cl2. The organic layer was washed with brine,
dried with Na2SO4, filtered and the solvents were evaporated under
vacuum. The residue was purified by chromatography on silica gel
(hexanes/EtOAc) to yield the purified reaction product(s).
Scheme 6. Synthesis of the spirocyclic carbamate 28. Reagents and
conditions: (a) DIB, I2, CH2Cl2, room temp., 3 h; then 0 °C, allyl-
trimethylsilane, BF3·OEt2, 61%.
Finally, in order to obtain other spirocyclic compounds
in one step, a new tandem decarboxylation/hetero-Diels–
Alder reaction was developed[25,26] (Scheme 7). To our satis-
faction, when the substrate 21 was treated with DIB and
iodine followed by addition of boron trifluoride and 2,3-
dimethylbutadiene, the interesting spirocyclic compound 29
was obtained in 42% yield. This variation illustrates the ver-
satility of this methodology for the synthesis of different
classes of alkaloid analogues.
1-[1-(Phenylacetyl)-2-pyrrolidinyl]acetone (13): The general decar-
boxylation/alkylation procedure with I2 (0.5 equiv.) afforded pro-
duct 13 (58%) as a syrup. IR (CHCl ): ν = 1711 cm–1. 1H NMR
˜
3
(500 MHz, 70 °C): δ = 1.70 (m, 1 H, 3-Ha), 1.86 (m, 2 H, 4-H2),
2.02 (m, 1 H, 3-Hb), 2.09 (s, 3 H, CH3CO), 2.40 (m, 1 H, 1Ј-Ha),
3.10 (d, J = 14.8 Hz, 1 H, 1Ј-Hb), 3.42 (m, 2 H, 5-H2), 3.61 (s, 2
H, CH2Ph), 4.39 (m, 1 H, 2-H), 7.24 (m, 5 H, arom.) ppm. 13C
NMR (125.7 MHz, 70 °C): δ = 24.1 (CH2, 4-C), 30.0 (CH2, 3-C),
30.4 (CH3), 42.5 (CH2, CH2Ph), 47.1 (CH2, 1Ј-C, CH2CO), 47.3
(CH2, 5-C), 54.0 (CH, 2-C), 126.7 (CH, arom.), 128.5 (2×CH,
arom.), 128.9 (2×CH, arom.), 135.0 (C, arom.), 169.5 (C, CO),
207.1 (C, CO) ppm. MS (EI, 70 eV): m/z (%) = 245 (14) [M+],
Scheme 7. One-pot decarboxylation/aza-Diels–Alder reaction. Rea-
gents and conditions: (a) DIB, I2, room temp., 2 h; then 0 °C, 2,3-
dimethylbutadiene, BF3·OEt2, 42%.
202 (27) [M+ – COCH3], 154 (20) [M+ – CH2Ph], 126 (56) [M+
–
COCH2Ph], 91 (87) [CH2Ph], 70 (100) [M+ + H – CH2COCH3 –
COCH2Ph]. HRMS (EI, 70 eV): calcd. for C15H19NO2 245.1416;
found 245.1397; calcd. for C13H16NO 202.1232; found 202.1201;
calcd. for C8H12NO2 154.0868; found 154.0858; calcd. for
C7H12NO 126.0919; found 126.0911. C15H19NO2 (245.32): calcd.
C 73.44, H 7.81, N 5.71; found C 73.59, H 8.18, N 5.93.
Conclusions
The tandem decarboxylation/alkylation reaction is a ver-
satile and efficient process to obtain key intermediates in
alkaloid synthesis. The reaction has been applied to the syn-
thesis of analogues of bioactive indolizidine and azaspiro-
cyclic alkaloids. The development of a new one-pot decar-
boxylation/Diels–Alder reaction illustrates the versatility of
this methodology.
7-Methyl-6-phenyl-2,3,8,8a-tetrahydro-5(1H)-indolizinone
(14):
tBuOK (167 mg, 1.5 mmol) was added to a solution of compound
13 (125 mg, 0.5 mmol) in dry tert-butyl alcohol (5 mL) and the re-
action mixture was refluxed under nitrogen for 8 h. It was then
partially concentrated under vacuum, poured into 10% aqueous
HCl and extracted with EtOAc. The organic layer was dried with
sodium sulfate, filtered and the solvents were evaporated under vac-
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Alkaloid Analogues from α-Amino Acids by One-Pot Radical Decarboxylation/Alkylation
FULL PAPER
uum. The residue was purified by column chromatography on silica
carboxylation/alkylation procedure with I2 (0.5 equiv.) afforded a
gel (hexanes/EtOAc, 90:10) to afford the indolizinone 14 (115 mg,
diastereomer mixture of 17 and 18 (3:2; 68%) as orange oil. IR
99%) as white crystals. M.p. 69.9–70.6 °C (from EtOAc/n-hexane).
(CHCl ): ν = 1703, 1630 cm–1. 1H NMR (500 MHz, 60 °C): Major
˜
3
1
IR (CHCl ): ν = 1650, 1612 cm–1. H NMR (500 MHz): δ = 1.62 diastereomer (2R*,2ЈR*): δ = 1.42 (ddd, J = 3.2, 11.8, 12.0 Hz, 1
˜
3
(dddd, J = 7.1, 10, 12, 12 Hz, 1 H, 1-Ha), 1.76 (s, 3 H, CH3C=),
H, 3Ј-Ha), 1.50–2.00 (c.s., 7 H, 3-Ha + 4-H2 + 5Ј-Ha + 4Ј-H2 + 3Ј-
1.80 (m, 1 H, 2-Ha), 2.00 (m, 1 H, 2-Hb), 2.22 (m, 1 H, 1-Hb), 2.35 Hb), 2.14 (ddd, J = 7.9, 7.9, 8.2 Hz, 1 H, 3-Hb), 2.17 (ddd, J = 7.8,
(ddd, J = 1.2, 13.1, 16.6 Hz, 1 H, 8-Ha), 2.40 (dd, J = 5.5, 16.5 Hz, 7.9, 8.0 Hz, 1 H, 5Ј-Hb), 2.28 (m, 2 H, 6Ј-H2), 3.30 (ddd, J = 6.9,
1 H, 8-Hb), 3.49 (ddd, J = 7.5, 9.8, 11.9 Hz, 1 H, 3-Ha), 3.60 (ddd,
7.1, 10.1 Hz, 1 H, 5-Ha), 3.37 (ddd, J = 4.8, 4.9, 11.8 Hz, 1 H, 2Ј-
J = 2.3, 9.1, 11.7 Hz, 1 H, 3-Hb), 3.77 (m, 1 H, 8a-H), 7.17 (d, J H), 3.49 (ddd, J = 6.9, 7.0, 10 Hz, 1 H, 5-Hb), 3.63 (s, 2 H, CH2Ph),
= 7.2 Hz, 2 H, arom.), 7.25 (dd, J = 7.4, 7.6 Hz, 1 H, arom.), 7.31
(dd, J = 7.2, 7.5 Hz, 2 H, arom.) ppm. 13C NMR (125.7 MHz): δ
= 21.4 (CH3, 7-Me), 23.0 (CH2, 2-C), 33.7 (CH2, 1-C), 37.2 (CH2,
4.58 (ddd, J = 4.3, 4.7, 8.4 Hz, 1 H, 2-H), 7.15–7.30 (c.s., 5 H,
arom.). Minor diastereomer (2R*,2ЈS*): δ = 1.56 (m, 1 H, 3Ј-Ha),
1.50–2.00 (c.s., 8 H, 3-H2 + 4-H2 + 5Ј-Ha + 4Ј-H2 + 3Ј-Hb), 2.24
8-C), 44.5 (CH2, 3-C), 55.3 (CH, 8a-C), 126.8 (CH, arom.), 127.6 (m, 1 H, 5Ј-Hb), 2.41 (m, 2 H, 6Ј-H2), 3.06 (ddd, J = 5.8, 5.8,
(2×CH, arom.), 130.2 (2×CH, arom.), 132.3 (C, arom.), 136.1 (C, 11.6 Hz, 1 H, 2Ј-H), 3.56 (m, 2 H, 5-H2), 3.61 (s, 2 H, CH2Ph),
6-C), 143.7 (C, 7-C), 163.7 (C, CO) ppm. MS (EI, 70 eV): m/z (%)
= 227 (96) [M+], 158 (100) [OCC(Ph)=C(Me)CH2]. HRMS (EI,
70 eV): calcd. for C15H17NO 227.1310; found 227.1283; calcd. for
C11H10O 158.0732; found 158.0745. C15H17NO (227.31): calcd. C
79.26, H 7.54, N 6.16; found C 79.25, H 7.54, N 6.14.
4.22 (ddd, J = 6.1, 6.1, 7.5 Hz, 1 H, 2-H), 7.15–7.30 (c.s., 5 H,
arom.) ppm. 13C NMR (125.7 MHz, 60 °C; mixture of two dia-
stereomers, the signals for each diastereomer could not be assigned,
since they are of similar intensity): δ = 24.2/24.4 (CH2, 4-C or 4Ј-
C), 24.7/24.8 (CH2, 4-C or 4Ј-C), 26.8/26.9 (CH2, 3-C or 5Ј-C or
3Ј-C), 26.8/27.2 (CH2, 3-C or 5Ј-C or 3Ј-C), 27.4/27.9 (CH2, 3-C
or 5Ј-C or 3Ј-C), 41.8/42.5 (CH2, 6Ј-C), 42.5/42.8 (CH2, CH2Ph),
47.7/48.0 (CH2, 5-C), 51.4/52.2 (CH, 2Ј-C), 56.9/57.8 (CH, 2-C),
126.6/126.7 (CH, arom.), 128.4 (2×CH, arom.), 128.9 (2×CH,
arom.), 135.1/135.2 (C, arom.), 169.8 (C, CO), 211.0/211.2 (C, CO)
2-Phenyl-1-[1-(phenylacetyl)-2-pyrrolidinyl]ethanone (15): General
decarboxylation/alkylation procedure (50%); syrup. IR (CHCl ): ν
˜
3
= 1678, 1632, 1599 cm–1. H NMR (500 MHz): δ = 1.83 (m, 1 H,
1
3-Ha), 1.88 (m, 1 H, 4-Ha), 1.90 (m, 2 H, 3-Hb + 4-Hb), 2.71 (dd,
J = 10.3, 14.7 Hz, 1 H, CHaHbCOPh), 3.44 (ddd, J = 7.8, 8.1,
9.3 Hz, 1 H, 5-Ha), 3.50 (m, 1 H, 5-Hb), 3.67 (s, 2 H, COCH2Ph),
3.90 (dd, J = 3.0, 15.0 Hz, 1 H, CHaHbCOPh), 4.58 (m, 1 H, 2-H),
7.26 (dd, J = 8.2, 8.5 Hz, 1 H, arom.), 7.28 (d, J = 7.4 Hz, 2 H,
arom.), 7.33 (dd, J = 7.4, 7.4 Hz, 2 H, arom.), 7.45 (dd, J = 7.5,
7.9 Hz, 2 H, arom.), 7.54 (dd, J = 7.4, 7.4 Hz, 1 H, arom.), 8.10
(d, J = 7.2 Hz, 2 H, arom.) ppm. 13C NMR (125.7 MHz): δ = 23.8
(CH2, 4-C), 29.3 (CH2, 3-C), 42.1 (CH2, CH2COPh), 42.4 (CH2,
COCH2Ph), 47.2 (CH2, 5-C), 54.7 (CH, 2-C), 126.7 (CH, arom.),
128.3 (2×CH, arom.), 128.5 (4×CH, arom.), 128.9 (2×CH,
arom.), 133.0 (CH, arom.), 134.6 (C, arom.), 136.5 (C, arom.),
169.6 (C, CO), 198.8 (C, CO) ppm. MS (EI, 70 eV): m/z (%) = 307
(8) [M+], 202 (11) [M+ – COPh], 188 (73) [M+ – COCH2Ph], 105
(100) [PhCO], 91 (65) [PhCH2]. HRMS (EI, 70 eV): calcd. for
C20H21NO2 307.1572; found 307.1585; calcd. for C12H14NO
188.1075; found 188.1091; calcd. for C7H5O 105.0340; found
105.0357. C20H21NO2 (307.39): calcd. C 78.15, H 6.89, N 4.56;
found C 78.26, H 7.12, N 4.40.
ppm. MS (EI, 70 eV): m/z (%) = 285 (13) [M+], 188 (10) [M+
–
cyclohexanone], 166 (30) [M+ – COCH2Ph], 91 (92) [CH2Ph], 70
(100) [M+ + H – cyclohexanone – COCH2Ph]. HRMS (EI, 70 eV):
calcd. for C18H23NO2 285.1729; found 285.1691; calcd. for
C12H14NO 188.1075; found 188.1013; calcd. for C10H16NO
166.1232; found 166.1187; calcd. for C7H7 91.0548; found 91.0498;
calcd. for C4H8N 70.0657; found 70.0617. C18H23NO2 (285.39):
calcd. C 75.76, H 8.12, N 4.91; found C 75.59, H 8.44, N 4.61.
(10aS*,10bR*)-6-Phenyl-2,3,7,8,9,10,10a,10b-octahydropyrrolo-
[2,1-a]isoquinoline-5(1H)-one (19): Same procedure as for com-
pound 17. Starting from a 3:2 mixture of diastereomers 17/18
(142 mg, 0.50 mmol), a mixture of isomeric tricyclic compounds
was obtained (108 mg, 81%) from which pure compound 19
(28 mg, 21%) was isolated as a syrup by Chromatotron chromatog-
raphy (toluene/EtOAc, 98:2). IR (CHCl ): ν = 1719, 1641 cm–1. 1H
˜
3
NMR (500 MHz): δ = 1.65 (m, 3 H, 1-Ha + 2-Ha + 8-Ha), 1.76 (m,
1 H, 8-Hb), 1.83 (m, 3 H, 7-Ha + 9-H2), 2.05 (m, 3 H, 2-Hb + 10-
H2), 2.31 (m, 2 H, 10a-H + 1-Hb), 2.51 (d, J = 15.2 Hz, 1 H, 7-
Hb), 3.41 (ddd, J = 5.6, 10.9, 11.7 Hz, 1 H, 10b-H, CHN), 3.52
(ddd, J = 8, 10, 10 Hz, 1 H, 3-Ha), 3.68 (dd, J = 9.2, 9.6 Hz, 1 H,
3-Hb), 7.15 (d, J = 7.1 Hz, 2 H, arom.), 7.26 (dd, J = 7.1, 7.6 Hz,
1 H, arom.), 7.34 (dd, J = 7.5, 7.6 Hz, 2 H, arom.) ppm. 13C NMR
(100.6 MHz): δ = 22.8 (CH2, 2-C), 24.3 (CH2, 8-C) 25.3 (CH2, 9-
C), 30.3 (CH2, 7-C), 30.8 (CH2, 10-C), 32.7 (CH2, 1-C), 42.6 (CH,
10a-C), 44.9 (CH2, 3-C), 61.5 (CH, 10b-C), 126.8 (CH, arom.),
127.7 (2×CH, arom.), 130.3 (2×CH, arom.), 131.2 (C, 6-C), 136.2
(C, arom.), 149.0 (C, 6a-C), 163.7 (C, CO) ppm. MS (EI, 70 eV):
m/z (%) = 267 (100) [M+], 198 (35) [M+ – pyrrolidine]. HRMS (EI,
70 eV): calcd. for C18H21NO 267.1623; found 267.1635; calcd. for
C14H14O 198.1045; found 198.1071. C18H21NO (267.37): calcd. C
80.86, H 7.92, N 5.24; found C 80.43, H 8.03, N 5.19.
6,7-Diphenyl-2,3,8,8a-tetrahydro-5(1H)-indolizinone (16): The same
procedure as reported for compound 17 afforded the indolizinone
16 (82%) as a colourless oil. IR (CHCl ): ν = 1651 cm–1. 1H NMR
˜
3
(500 MHz): δ = 1.73 (m, 1 H, 1-Ha), 1.89 (m, 1 H, 2-Ha), 2.09 (m,
1 H, 2-Hb), 2.29 (ddd, J = 5.3, 5.5, 12.0 Hz, 1 H, 1-Hb), 2.77 (dd,
J = 13.2, 16.4 Hz, 1 H, 8-Ha), 2.83 (dd, J = 5.1, 16.4 Hz, 1 H, 8-
Hb), 3.60 (m, 1 H, 3-Ha), 3.71 (dd, J = 10.4, 11.3 Hz, 1 H, 3-Hb),
3.97 (m, 1 H, 8a-H), 7.01 (m, 2 H, arom.), 7.09 (m, 2 H, arom.),
7.13 (m, 6 H, arom.) ppm. 13C NMR (100.6 MHz): δ = 23.2 (CH2,
2-C), 33.7 (CH2, 1-C), 37.5 (CH2, 8-C), 44.7 (CH2, 3-C), 55.7 (CH,
8a-C), 126.7 (CH, arom.), 127.4 (CH, arom.), 127.5 (2×CH,
arom.), 127.9 (2×CH, arom.), 128.3 (2×CH, arom.), 131.1
(2×CH, arom.), 133.2 (C, arom.), 135.9 (C, arom.), 140.3 (C, 6-C),
145.2 (C, 7-C), 163.9 (C, CO) ppm. MS (EI, 70 eV): m/z (%) = 289
(60) [M+], 288 (100) [M+ – H], 220 (66) [OCC(Ph)=C(Ph)CH2].
HRMS (EI, 70 eV): calcd. for C20H19NO 289.1467; found
289.1503; calcd. for C20H18NO 288.1388; found 288.1420; calcd.
for C16H12O 220.0888; found 220.0914. C20H19NO (289.38): calcd.
C 83.01, H 6.62, N 4.84; found C 83.08, H 6.96, N 4.77.
1-[(Methoxycarbonyl)amino]cyclohexanecarboxylic Acid (21): Com-
mercial 1-aminocyclohexanecarboxylic acid (20) (1.35 g, 10 mmol)
was added to a biphasic mixture of THF (15 mL) and a saturated
aqueous NaHCO3 solution (15 mL) at 0 °C. Methyl chloroformate
was then injected dropwise (1.0 mL, 1.22 g, 13 mmol). The reaction
mixture was allowed to reach room temperature and was then
Mixture of Diastereomers (2R*,2ЈR*)- and (2R*,2ЈS*)-2Ј-[1-(Phen- stirred for 18 h, after which it was carefully acidified with 2 m aque-
ylacetyl)-2-pyrrolidinyl]cyclohexanone (17 and 18): The general de- ous HCl and extracted with EtOAc. The organic layer was dried
Eur. J. Org. Chem. 2005, 3461–3468
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3465

A. Boto, Y. De León, J. A. Gallardo, R. Hernández
FULL PAPER
with sodium sulfate, filtered and the solvents were evaporated un-
ganic layer was dried and concentrated as usual, and the residue
was purified by column chromatography on silica gel (hexanes/
der vacuum to yield acid 21 (1.47 g, 72%) as a white crystalline
solid. M.p. 178–179 °C. IR (CHCl ): ν = 3441, 1723 cm–1. 1H EtOAc, 90:10) to afford the azaspiro compound 25 (74 mg, 94%)
˜
3
NMR (500 MHz, CD3OD): δ = 1.27 (m, 1 H, 4-Ha), 1.49 (m, 4 H, as a syrup. IR (CHCl ): ν = 1696.1 cm–1. H NMR (500 MHz): δ
1
˜
3
3-H2 + 5-H2), 1.55 (m, 1 H, 4-Hb), 1.75 (ddd, J = 4.1, 11.4, 13.6 Hz,
2 H, 2-Ha + 6-Ha), 1.95 (m, 2 H, 2-Hb + 6-Hb), 3.55 (s, 3 H, OMe)
ppm. 13C NMR (100.6 MHz, CD3OD): δ = 22.4 (2×CH2, 3-C +
= 1.25–1.40 (m, 3 H, 7-Ha + 11-Ha + 9-Ha), 1.40–1.70 (m, 5 H, 9-
Hb + 8-H2 + 10-H2), 2.13 (m, 2 H, 5-H2), 2.52 (m, 2 H, 7-Hb
11-Hb), 3.64 (s, 3 H, OMe), 4.00 (dd, J = 2.5, 2.5 Hz, 2 H, 2-H2),
+
5-C), 26.5 (CH2, 4-C), 33.5 (2×CH2, 2-C + 6-C), 52.2 (CH3, OMe), 5.66 (m, 1 H, 3-H or 4-H), 5.70 (m, 1 H, 3-H or 4-H) ppm. 13C
60.1 (C, 1-C), 158.5 (C, CO), 178.5 (C, CO) ppm. MS (EI, 70 eV):
m/z (%) = 169 (4) [M+ – HOMe], 156 (100) [M+ – COOH]. HRMS
(EI, 70 eV): calcd. for C8H11NO3 169.0739; found 169.0746; calcd.
for C8H14NO2 156.1025; found 156.0990. C9H15NO4 (201.22):
calcd. C 53.70, H 7.52, N 6.96; found C 53.61, H 7.68, N 6.83.
NMR (100.6 MHz): δ = 22.5 (2×CH2, 8-C + 10-C), 26.3 (CH2, 9-
C), 35.3 (2×CH2, 7-C + 11-C), 36.0 (CH2, 5-C), 43.4 (CH2, 2-C),
51.9 (CH3, OMe), 57.2 (C, 6-C), 125.0 (CH, 3-C or 4-C), 125.2
(CH, 3-C or 4-C), 156.6 (C, CO) ppm. MS (EI, 70 eV): m/z (%) =
209 (92) [M+], 194 (30) [M+ – Me], 166 (100) [M+ – H –
CH2CH2CH2]. HRMS (EI, 70 eV): calcd. for C12H19NO2 209.1416;
found 209.1405; calcd. for C11H16NO2 194.1181; found 194.1209;
calcd. for C9H12NO2 166.0868; found 166.0866. C12H19NO2
(209.29): calcd. C 68.87, H 9.15, N 6.69; found C 68.90, H 9.47, N
7.05.
Methyl 1-Allylcyclohexylcarbamate (23): The general decarboxyl-
ation/alkylation procedure with I2 (0.5 equiv.) afforded product 23
(61%) as a syrup. IR (CHCl ): ν = 3441, 1723, 1509 cm–1. 1H NMR
˜
3
(400 MHz): δ = 1.15–1.60 (m, 8 H, 2-Ha + 6-Ha + 4-H2 + 3-H2 +
5-H2), 1.93 (m, 2 H, 2-Hb + 6-Hb), 2.44 (d, J = 7.3 Hz, 2 H,
CH2C=C), 3.56 (s, 3 H, OMe), 4.46 (br. s, 1 H, NH), 5.02 (m, 2
H, 3Ј-H2), 5.73 (m, 1 H, 2Ј-H) ppm. 13C NMR (100.6 MHz): δ =
21.5 (2×CH2, 3-C + 5-C), 25.6 (CH2, 4-C), 34.7 (2×CH2, 2-C +
6-C), 42.5 (CH2, 1Ј-C), 51.4 (CH3, OMe), 54.4 (C, 1-C), 117.9
(CH2, 3Ј-C), 133.7 (CH, 2Ј-C), 155.1 (C, CO) ppm. MS (EI, 70 eV):
m/z (%) = 197 (Ͻ1) [M+], 156 (100) [M+ – CH2CH=CH2]. HRMS
(EI, 70 eV): calcd. for C11H19NO2 197.1416; found 197.1455; calcd.
for C8H14NO2 156.1025; found 156.1071. C11H19NO2 (197.28):
calcd. C 66.97, H 9.71, N 7.10; found C 66.61, H 10.01, N 7.30.
4-[(Trimethylsilyl)methyl]-3-oxa-1-azaspiro[5.5]undecan-2-one (28):
General decarboxylation/alkylation procedure (61%). White solid;
m.p. 139.6–141.4 °C (from EtOAc/n-hexane). IR (CHCl ): ν =
˜
3
3427, 1691 cm–1. 1H NMR (500 MHz): δ = 0.07 (s, 9 H, SiMe3),
0.92 (dd, J = 8.2, 14.5 Hz, 1 H, CHaHbTMS), 1.18 (dd, J = 6.4,
14.5 Hz, 1 H, CHaHbTMS), 1.40–1.70 (m, 11 H), 1.97 (d, J =
14 Hz, 1 H), 4.41 (m, 1 H, 4-H, CHO), 5.78 (br. s, 1 H, NH) ppm.
13C NMR (100.6 MHz): δ = –0.9 [3×CH3, Si(CH3)3], 21.9
(2×CH2, 8-C + 10-C), 24.1 (CH2, CH2TMS), 25.1 (CH2, 9-C), 37.8
(CH2, 5-C or 7-C or 11-C), 40.2 (CH2, 5-C or 7-C or 11-C), 40.5
(CH2, 5-C or 7-C or 11-C), 52.6 (C, 6-C), 72.6 (CH, 4-C), 154.8
(C, CO) ppm. MS (EI, 70 eV): m/z (%) = 255 (11) [M+], 240 (5)
[M+ – CH3], 214 (49) [M+ – CH2CH=CH2], 168 (100) [M+ – H –
CO2 – CH2CH2CH2]. HRMS (EI, 70 eV): calcd. for C13H25NO2Si
255.1655; found 255.1710; calcd. for C12H22NO2Si 240.1439; found
240.1438; calcd. for C10H20NO2Si 214.1263; found 214.1324; calcd.
for C9H18NSi 168.1209; found 168.1206. C13H25NO2Si (255.43):
calcd. C 61.13, H 9.87, N 5.48; found C 60.97, H 10.22, N 5.23.
Methyl N-Allyl-N-(1-allylcyclohexyl)carbamate (24): A solution of
the allyl derivative 23 (100 mg, 0.51 mmol) in dry DMF (3 mL) was
added dropwise to a suspension of NaH (50% dispersion in mineral
oil, 72 mg, 1.5 mmol) in dry DMF (3 mL) at 0 °C. The reaction
mixture was stirred at 0 °C for 0.5 h and then allyl bromide (60 μL,
88 mg, 0.73 mmol) was slowly injected. The solution was allowed
to reach room temperature and stirring was continued for another
4 h. The mixture was then cooled to 0 °C and methanol (0.5 mL)
was added dropwise to destroy unreacted NaH. The solution was
poured into aqueous saturated sodium hydrogencarbonate and ex-
tracted with Et2O. The organic layer was dried and concentrated
as usual, and the residue was purified by column chromatography
on silica gel (hexanes/EtOAc, 95:5) to afford the diene 24 (105 mg,
Methyl 3,4-Dimethyl-1-azaspiro[5.5]undec-3-ene-1-carboxylate (29):
DIB (805 mg, 2.5 mmol) and iodine (127 mg, 0.5 mmol) were
added to a solution of acid 21 (200 mg, 1.0 mmol) in dry CH2Cl2
(15 mL) under nitrogen. The reaction mixture was stirred at room
temperature in sunlight for 2 h. Afterwards, it was cooled to 0 °C
and 2,3-dimethylbutadiene (1.13 mL, 0.82 g, 10 mmol) and
BF3·OEt2 (0.25 mL, 0.28 g, 1.97 mmol) were added dropwise. The
reaction mixture was allowed to reach room temperature and was
stirred for another 4 h. It was then poured into an aqueous 10%
sodium thiosulfate (Na2S2O3)/saturated NaHCO3 solution and ex-
tracted with CH2Cl2. The organic layer was dried and concentrated
as usual and the residue was purified by chromatography on silica
gel (hexanes/EtOAc, 98:2) to yield the azaspiro compound 29
88%) as a syrup. IR (CHCl ): ν = 1693 cm–1. 1H NMR (500 MHz):
˜
3
δ = 1.32 (m, 1 H, 4-Ha), 1.40–1.60 (m, 5 H, 4-Hb + 3-H2 + 5-H2),
1.82 (ddd, J = 3.0, 10.0, 12.7 Hz, 2 H, 2-Ha + 6-Ha), 1.99 (m, 2 H,
2-Hb + 6-Hb), 2.64 (d, J = 7.4 Hz, 2 H, 1Ј-H2), 3.64 (s, 3 H, OMe),
3.89 (d, J = 5.5 Hz, 2 H, 1ЈЈ-H2, NCH2C=C), 5.03 (m, 4 H, 3Ј-H2
+ 3ЈЈ-H2), 5.70 (m, 1 H, 2Ј-H), 5.84 (m, 1 H, 2ЈЈ-H) ppm. 13C NMR
(100.6 MHz): δ = 22.6 (2×CH2, 3-C + 5-C), 25.6 (CH2, 4-C), 34.7
(2×CH2, 2-C + 6-C), 38.6 (CH2, 1Ј-C), 47.0 (CH2, 1ЈЈ-C), 51.9
(CH3, OMe), 61.7 (C, 1-C), 114.9 (CH2, 3Ј-C or 3ЈЈ-C), 117.5 (CH2,
3Ј-C or 3ЈЈ-C), 134.6 (CH, 2Ј-C), 137.5 (CH, 2ЈЈ-C), 156.7 (C, CO)
(99 mg, 42%) as a syrup. IR (CHCl ): ν = 1697 cm–1. 1H NMR
˜
3
(500 MHz): δ = 1.29 (m, 2 H, 7-Ha + 11-Ha), 1.47 (m, 6 H, 8-H2
+ 9-H2 + 10-H2), 1.59 (s, 3 H, Mea-C=), 1.62 (s, 3 H, Meb-C=),
2.05 (s, 2 H, CCH2C=), 2.45 (m, 2 H, 7-Hb + 11-Hb), 3.61 (s, 3 H,
OMe), 3.79 (br. s, 2 H, 2-H2, NCH2C=) ppm. 13C NMR
(125.7 MHz): δ = 15.9 (CH3), 18.9 (CH3), 22.8 (2×CH2, 8-C + 10-
C), 26.0 (CH2, 9-C), 34.6 (2×CH2, 7-C + 11-C), 41.2 (CH2, 5-C,
CCH2C=), 47.7 (CH2, 2-C, NCH2C=), 51.9 (CH3, OMe), 57.8 (C,
6-C), 124.1 (C, 3-C or 4-C), 124.7 (C, 3-C or 4-C), 156.3 (C, CO)
ppm. MS (EI, 70 eV): m/z (%) = 237 (5) [M+], 236 (32) [M+
–
H], 196 (100) [M+ – CH2CH=CH2]. HRMS (EI, 70 eV): calcd. for
C14H23NO2 237.1729; found 237.1704; calcd. for C14H22NO2
236.1651; found 236.1662; calcd. for C11H18NO2 196.1338; found
196.1333. C14H23NO2 (237.34): calcd. C 70.85, H 9.77, N 5.90;
found C 70.74, H 9.75, N 5.76.
Methyl 1-Azaspiro[5.5]undec-3-ene-1-carboxylate (25): A catalytic
amount (20 mg) of (benzylidene)dichlorobis(tricyclohexylphos-
phane)ruthenium(ii) was added to a solution of diene 24 (90 mg,
0.38 mmol) in dry CH2Cl2 (5 mL), and the reaction mixture was
heated under reflux for 2 h. It was then poured into a saturated
aqueous NaHCO3 solution and extracted with CH2Cl2. The or-
ppm. MS (EI, 70 eV): m/z (%) = 237 (100) [M+], 222 (32) [M+
–
Me]. HRMS (EI, 70 eV): calcd. for C14H23NO2 237.1729; found
237.1736; calcd. for C13H20NO2 222.1494; found 222.1496.
C14H23NO2 (237.34): calcd. C 70.85, H 9.77, N 5.90; found C
70.86, H 10.01, N 6.03.
3466
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 3461–3468

Alkaloid Analogues from α-Amino Acids by One-Pot Radical Decarboxylation/Alkylation
FULL PAPER
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This work was supported by the Research Programmes PPQ2000-
0728 and PPQ2003-01379 of the Plan Nacional de Investigación
Científica, Desarrollo e Innovación Tecnológica, Dirección Gene-
ral de Investigación, Ministerio de Ciencia y Tecnología, Spain.
We also acknowledge financial support from FEDER funds. Y. R.
thanks the Gobierno de Canarias for a fellowship. We thank Dr.
Ezequiel Quintana Morales for his help with molecular modelling.
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Selected experimental coupling constants for compound 17 are
J2,2Ј = 4.5 Hz, and J2,3 = 4.7, 8.2 Hz, and for compound 18
J2,2Ј = 6.0 Hz, and J2,3 = 6.1, 7.5 Hz. The J values were also
calculated for the minimum-energy conformations of both dia-
stereomers. For instance, the coupling constants for the
(2R,2ЈR) diastereomer are J2,2Ј = 3.6 Hz, and J2,3 = 6.5,
10.7 Hz, and for the (2R, 2ЈS) diastereomer J2,2Ј = 11.1 Hz,
and J2,3 = 8.0, 9.1 Hz. It must be taken into account that free
rotation around the C2–C2Ј bond is possible, and hence the
experimental constants may not completely match those calcu-
lated for the minimum-energy conformations.
[13]
[14]
[15]
Theoretical coupling constants were calculated over the mini-
mised structures (MMFF force field) for all possible isomers,
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The elemental analysis of the mixture and the elemental analy-
sis of the pure tricyclic compound 19 corresponded to an em-
pirical formula C18H21NO. The 13C NMR spectrum of the
mixture resembles that of compound 19, and shows olefinic
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A. Boto, Y. De León, J. A. Gallardo, R. Hernández
FULL PAPER
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Received: February 18, 2005
Published Online: June 28, 2005
3468
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www.eurjoc.org
Eur. J. Org. Chem. 2005, 3461–3468