Synthesis of alkaloid analogues from β-amino alcohols by β-fragmentation of primary alkoxyl radicals

Article abstract of DOI:10.1002/ejoc.200600720

The fragmentation of primary alkoxyl radicals is usually a minor process with respect to hydrogen abstraction and other competing reactions. However, when β-amino alcohols were used as substrates, the scission proceeded in good to excellent yields and no side reactions were observed. The fragmentation can be coupled with an allylation or alkylation reaction, to give alkaloid analogues and functionalized nitrogen heterocycles. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200600720

FULL PAPER
DOI: 10.1002/ejoc.200600720
Synthesis of Alkaloid Analogues from β-Amino Alcohols by β-Fragmentation
of Primary Alkoxyl Radicals
Alicia Boto,*[a] Dácil Hernández,[a] Rosendo Hernández,*[a] Adriana Montoya,[a] and
Ernesto Suárez[a]
Keywords: Alkaloids / Amino alcohols / Radical reactions / Nitrogen heterocycles / Cleavage reactions
The fragmentation of primary alkoxyl radicals is usually a
minor process with respect to hydrogen abstraction and other
competing reactions. However, when β-amino alcohols were
used as substrates, the scission proceeded in good to excel-
mentation can be coupled with an allylation or alkylation re-
action, to give alkaloid analogues and functionalized nitro-
gen heterocycles.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
lent yields and no side reactions were observed. The frag- Germany, 2007)
Introduction
The β-fragmentation of alkoxyl radicals is useful meth-
odology to obtain a wide range of compounds such as ole-
fins, halogenated compounds, medium- and large-sized
rings, and heterocycles.[1,2] The β-scission was the key step
in the synthesis of bioactive natural products such as (–)-
CP-263,114[3a,3b] the cytotoxic chondriamides A and C,[3c]
and the antifungals deoxyvernolepin[3d,3e] and preussin.[3f]
The substrates for the scission step were alcohols or hemia-
cetals, which generated alkoxyl radicals on treatment with
reagents[1] such as (diacetoxyiodo)benzene (DIB) and io-
dine, HgO–iodine, or LTA. When tertiary alkoxyl radicals
were formed, the β-fragmentation was the major or the ex-
clusive pathway. However, the fragmentation of primary
alkoxyl radicals usually proceeded in low yields, and pro-
cesses such as intramolecular hydrogen abstraction (IHA)[4]
or addition to double bonds[5] predominated.
We reasoned that the scission of primary alkoxyl radicals
could be synthetically useful with substrates where the C-
radicals resulting from fragmentation were stabilized by ad-
jacent functionalities, such as oxygen[6] or nitrogen atoms.[7]
Moreover, if the C-radicals could be readily transformed
into other intermediates, the fragmentation would be fur-
ther favored. Hence, we decided to explore the fragmenta-
tion of β-amino alcohol derivatives 1 (Scheme 1) on treat-
ment with DIB and iodine.
Scheme 1. Fragmentation of primary alkoxyl radicals derived from
β-amino alcohols.
Many β-amino alcohols 1 are commercial products or
are readily prepared therefrom. Moreover, functionalized
amino alcohols with different stereochemistries can be ob-
tained from carbohydrates and other chiral compounds.
The β-fragmentation of substrates 1 (Scheme 1) would gen-
erate C-radical 1a stabilized by the nitrogen atom. Under
the reaction conditions, intermediate 1a would presumably
be oxidized to acyliminium ion intermediate 1b,[8] which
could be trapped by nucleophiles to afford a variety of 2-
substituted heterocycles 2,[9] which can be found in alka-
loids,[10] chiral auxiliaries,[10b,10c] and synthetic drugs.[10d]
It must be noted that competing intramolecular hydrogen
abstraction (IHA) reactions could take place. In effect, in
intermediate 1c (Scheme 2) the distance between 5-Ha and
[a] Instituto de Productos Naturales y Agrobiología CSIC,
Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna,
Tenerife, Spain
Fax: +34-922260135
E-mail: alicia@ipna.csic.es
rhernandez@ipna.csic.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 325–334
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the alkoxyl radical (2.3–2.8 Å) is optimal for IHA, and re- acylation[11] or sulfonylation of compound 3 afforded β-
sulting radical 1d would also be stabilized by a nitrogen amino alcohol derivatives 4–6 in excellent yields.
atom. The extent of IHA or other side reactions will deter-
To our satisfaction, when substrates 4–6 were treated
mine whether the β-scission is a synthetically useful process. with DIB and iodine at room temperature (Table 1, Entries
1–3), fragmentation products 7–9[8f,12] (Scheme 3) were ob-
tained in good yields, and no products derived from IHA
were isolated. These results suggested that the scission was
much faster than intramolecular H-abstraction. Since the
fragmentation is a reversible reaction, a rapid and irrevers-
ible oxidation of the C-radical to acyliminium ions 4a–6a
was also presumed. The acyliminium ion was trapped by
water during the work up.
Table 1. One-pot β-scission of primary alkoxyl radicals–oxidation–
nucleophilic addition.
Entry
Substrate
Nucleophile
Products
Global yield
[%][b]
(yield [%])[a]
1
2
3
4
5
6
4
5
6
4
5
6
H2O
H2O
H2O
allylTMS
allylTMS
allylTMS
7 (66)
8 (67)
9 (64)
66
67
64
95
86
91
7 (4), 10 (91)
8 (10), 11 (76)
9 (5), 12 (86)
[a] Conditions: See Scheme 4 and Experimental Section. [b] Yields
are given for products purified by chromatography on silica gel.
Scheme 2. Fragmentation of primary alkoxyl radicals versus intra-
molecular hydrogen abstraction in β-hydroxy amino derivatives.
The addition of carbon nucleophiles to the acyliminium
intermediate was subsequently studied. Substrates 4–6 were
treated with DIB–iodine for 2.5 h, the reaction mixture was
cooled to 0 °C, and allyltrimethylsilane and BF3·OEt2 were
added (Table 1, Entries 4–6) to afford desired allylpyrroli-
dines 10–12[12,13] in good to excellent yields.
The application of the fragmentation–allylation reaction
to the synthesis of natural products is illustrated with the
preparation of coniine methyl carbamate (13) (Scheme 4).
(Ϯ)-Coniine and (Ϯ)-N-methyl coniine are the active com-
ponents of hemlock poison.[14]
Results and Discussion
The synthesis of three substrates for the β-fragmentation
reaction was carried out from commercial 2-(hy-
droxymethyl)pyrrolidine (3; Scheme 3). Thus, standard
Scheme 4. Scission–allylation reaction in the synthesis of (Ϯ)-coni-
ine and (Ϯ)-n-methyl coniine. Reagents and conditions: (a) Me-
OC(O)Cl, NaHCO3 (aq.), THF, 96%; (b) DIB, I2, hν, CH2Cl2,
26 °C, then 0 °C, BF3·OEt2, allylTMS, 52%; (c) H2, Pd/C, EtOAc,
90%.
Scheme 3. β-Fragmentation of primary alkoxyl radicals and ad-
dition of nucleophiles. Reagents and conditions: (a) DIB, I2, hν,
CH2Cl2, 26 °C, then H2O; (b) DIB, I2, hν, CH2Cl2, 26 °C; then
0 °C, BF3·OEt2, allylTMS, CH2Cl2. For product yields, see Table 1.
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Alkaloid Analogues from β-Amino Alcohols
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(Ϯ)-(Hydroxymethyl)piperidine (14) was then trans-
formed into N-methyl carbamate 15, which was treated un-
der the fragmentation–allylation conditions to yield volatile
allyl derivative 16[15] in 52% yield. Reduction of the double
bond afforded (Ϯ)-coniine methyl carbamate (13)[16] in ex-
cellent yield. This product can be transformed into coniine
by hydrolysis of the methyl carbamate,[17] and into N-
methyl coniine by reduction of the protecting group with
LiAlH4.[17,18]
Another application of this methodology to the synthesis
of natural product analogues is shown in Scheme 5. The
preparation of indolizidine alkaloid analogues has been un-
dertaken by many groups because several of these alkaloids
are potent glycosidase inhibitors that present biological ac-
tivities that range from hypoglucemic to antiviral or cyto-
toxic activities.[19]
Scheme 6. Synthesis of the pyrrolizidine alkaloid core. Reagents
and conditions: (a) DIB, I2, CH2Cl2, hν, then 0 °C, BF3·OEt2,
CH2=C(CH2Cl)–CH2TMS, 70%; (b) NaH, DMF, 0 °C, 73 %.
Interestingly, when the scission–allylation reaction was
repeated with an old batch of the allyl reagent, followed by
treatment with sodium hydride, cyclization product 22 was
not formed (Scheme 7). Instead, chloroallyl derivative 23
was isolated, together with a residual amount of dia-
stereomer 24. Their stereochemistry is tentatively proposed,
by comparison with similar compounds described in the lit-
erature.[26]
Scheme 5. Synthesis of the indolizidine alkaloid core. Reagents and
conditions: (a) DIB, I2, CH2Cl2, hν, then BF3·OEt2, allylTMS,
85%; (b) NaH, THF, 0 °C, CH3C(=CH2)CH2Br, 64%; (c) Grubbs’
catalyst (2nd generation), CH2Cl2, 95%.
The starting material, commercial (Ϯ)-pyroglutamol (17;
Scheme 5), was treated under the fragmentation–allylation
conditions to afford allylpyrrolidone 18[8f] in 85% yield. Po-
tential side products derived from a nitrogen radical were
not isolated. Presumably, the formation of a nitrogen radi-
cal was slow compared to the fragmentation and subse-
quent formation of an acyliminium ion. Allylpyrrolidone 18
was then N-allylated and diene 19[20] underwent a metathe-
sis reaction[21] to give indolizidine core 20,[20] in overall
good yield.
Scheme 7. Reagents and conditions: (a) DIB, I2, CH2Cl2, hν, then
0 °C, BF3·OEt2, Cl–CH=C(CH3)–CH2TMS; (b) NaH, DMF, 0 °C;
23 (32% for the two steps) and 24 (traces).
The formation of 23 could be due to isomerization of
Other interesting alkaloids have a pyrrolizidine core[22–24] the allyl reagent before its use,[27] from 2-(chloromethyl)-3-
(Scheme 6). Some of them are hepatotoxic to animals;[23a] (trimethylsilyl)propene to 1-chloro-2-methyl-3-trimethyl-
hence, they are used by plants or insects as deterrents silylpropene. The generation of compound 23 is interesting,
against predators.[23b–23d] Other pyrrolizidines (e.g. the alex- since the replacement of the chloro group by different nu-
ines) are powerful glycosidase inhibitors[24] that display cleophiles could lead to a variety of 5-substituted pyrrol-
antiviral and retroviral activities.
idinones.
A tandem scission–alkylation reaction was also devel-
The formation of the pyrrolizidine core in just two steps
was achieved by using a fragmentation–allylation reaction oped by using silyl enol ethers as nucleophiles. When (Ϯ)-
as the key step (Scheme 6). Thus, pyroglutamol 17 was pyroglutamol (17; Scheme 8) was treated under fragmenta-
transformed into allyl derivative 21 with the use of 2-(chlo- tion conditions followed by the addition of phenyl(trimeth-
romethyl)-3-(trimethylsilyl)propene as the nucleophile. An ylsilyloxy)ethene and boron trifluoride, phenyl ketone 25
intramolecular alkylation reaction[25] was then used to gen- was formed in 73% yield. This ketone is an analogue of the
erate pyrrolizidine core 22 in good yield.
alkaloid (Ϯ)-sedamine.[28]
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Scheme 8. Tandem fragmentation–addition of silyl enol ethers.
Reagents and conditions: (a) DIB, I2, CH2Cl2, hν, then 0 °C,
BF3·OEt2, CH2=C(OTMS)–Ph, 73%.
Another interesting application of this methodology is
the formation of a hydroxylated indolizidine core, which
can be found in glycosidase inhibitors. Hence, the fragmen-
tation of prolinol derivative 5 (Scheme 9), followed by ad-
dition of methanol, afforded 2-methoxy pyrrolidine (Ϯ)-
26.[29] This product was treated with boron trifluoride and
(trimethylsilyloxy)furan to generate compounds 27 and
28,[30] which are analogues of the norpandamarilactonine
alkaloids.[31]
Scheme 10. Synthesis of functionalized pyrrolidines from the chiral
pool. Reagents and conditions: (a) DIAD, PPh3, dioxane, 80 °C,
72%; (b) LiAlH4, Et2O, reflux, 84%; (c) DIAD, PPh3, dioxane,
80 °C, 66%; (d) H2, Pd/C, MeOH, (tBuO2C)2O, 26 °C, 94 %.
Lactone 32 was transformed into its isopropylidene ace-
tal,[34] the 5-hydroxy group was protected as its benzyl
ether,[35] and finally the lactone was opened by treatment
with benzylamine to afford compound 33. Amide 33 was
subjected to Mitsunobu conditions in order to obtain a lac-
tam, but the expected cyclization did not take place and
the 5-epimer of compound 33 was obtained instead. The
Scheme 9. Synthesis of indolizidine alkaloid analogues 29 and
30.Reagents and conditions: (a) DIB, I2, CH2Cl2, hν, then MeOH,
78%; (b) BF3·OEt2, 2-(trimethylsilyloxy)furan, 0 °C, CH2Cl2, 74%,
27/28 (10:1); (c) DIB, I2, CH2Cl2, hν, then 0 °C, BF3·OEt2, 2-(tri-
methylsilyloxy)furan, 66%, 27/28 (6:1); (d) 27/28 (10:1), H2, 10%
Pd(OH)2, MeOH, MeONa (cat), room temp., 91%, 29/30 (8:1).
The alkylation reaction proceeded in good yields and formation of 5-epimer 34 could be explained by formation
with good diastereoselectivity (27/28, dr 10:1). The one-pot of a 5-oxyphosphonium group, which is displaced by nucle-
transformation of prolinol 17 into compounds 27/28 was ophilic attack from the amide oxygen. An intermediate imi-
then carried out, and took place in 66% yield and good doate is formed, which finally undergoes hydrolysis to give
diastereomeric ratio (27/28, 6:1). The mixture of 27/28 can observed product 34. A similar reaction has been recently
be transformed into the hydroxylated indolizidine core in reported, which was applied to obtain furanolactones of
one step, by the sequential reduction of the double bond, different series.[36] In order to avoid this isomerization,
hydrogenolysis of the benzyl carbamate, and formation of amide 33 was reduced to an amine, and the latter under-
the lactam. Thus, (8aR*,8R*)-indolizidine 29[32] and went Mitsunobu cyclization to N-benzylpyrrolidine 35. The
(8aR*,8S*)-epimer 30 were obtained in excellent yield and benzyl protecting groups were then removed by hydro-
good diastereoselectivity (29/30, 8:1).
The previous examples show the versatility of the frag- butyl carbamate to afford product 31 in excellent yield.
mentation–alkylation process. Moreover, since many β- By using chiral β-hydroxy amine 31 as the substrate, the
genolysis and the amine was protected in situ as its tert-
amino alcohols can be readily prepared from sugars and fragmentation–addition reaction of nucleophiles was
other chiral compounds, their scission–alkylation could af- studied. A scission–allylation reaction was carried out first
ford a wide range of functionalized, chiral nitrogen hetero- (Scheme 11), which generated intermediate 31a by addition
cycles. For instance, fragmentation substrate 31 (Scheme 10) of the allylsilane from the less hindered face of the acylimi-
was prepared from commercially available ribonolactone nium ion. Intermediate 31a underwent loss of the TMS
(32) in six steps.[33]
group (Route a) to afford 36, or nucleophilic addition of
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Alkaloid Analogues from β-Amino Alcohols
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the carbamate oxygen followed by loss of the tert-butyl
group[37] (Route b) to give cyclic carbamates 37 and 38. The
alkylation reaction proceeded with excellent stereoselecti-
vity, and no (2S) or (4aS) products could be detected.[38]
Experimental Section
General Remarks: Commercially available reagents and solvents
were analytical grade or were purified by standard procedures prior
to use.[40] All reactions involving air- or moisture-sensitive materials
were carried out under a nitrogen atmosphere. The spray reagents
for TLC analysis were 0.5% vanillin in H2SO4/EtOH (4:1) or 0.25%
ninhydrin in ethanol. Merck silica gel 60 PF (0.063–0.2 mm) was
used for chromatography. Melting points were determined with a
hot-stage apparatus. IR spectra were recorded with a Perkin-Elmer
1600/FTIR spectrometer. NMR chemical shift values are reported
relative to 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 in-
creased on heating, and in many cases only one rotamer could be
detected at 70 °C. When the NMR resolution improved signifi-
cantly on heating, the spectra at 70 °C are described.
Preparation of 2-Hydroxy Pyrrolidines 7–9. General Procedure: 2-
(Hydroxymethyl)pyrrolidines 4–6 (1 mmol) in dry dichloromethane
(15 mL) were treated with DIB (2.5 mmol) and iodine (1 mmol)
and stirred at room temperature under a nitrogen atmosphere for
2.5 h. After that time, the mixture was poured into aqueous
NaHCO3/10% Na2S2O3 and extracted with CH2Cl2. Purification
by column chromatography on silica gel (hexanes/EtOAc) afforded
1-benzoyl-2-pyrrolidinol (7)[8f] (66%), benzyl 2-hydroxy-1-pyrroli-
dinecarboxylate (8)[8f] (67%), and 1-tolylsulfonyl-2-pyrrolidinol (9)
Scheme 11. Stereoselective fragmentation–allylation of compound
31. Reagents and conditions: (a) DIB, I2, CH2Cl2, hν, then 0 °C,
BF3·OEt2, allylTMS, 36 (41%), 37 (23%), 38 (22%).
[12]
(64%), respectively.
Standard Procedure for the Fragmentation–Allylation or Fragmenta-
tion–Alkylation Reaction: 2-(Hydroxymethyl)pyrrolidine (1 mmol)
in dry dichloromethane (15 mL) was treated with DIB (2.5 mmol)
and iodine (1 mmol) and stirred at room temperature under a nitro-
gen atmosphere for 2.5 h. After that time, the mixture was cooled
to 0 °C and BF3·OEt2 (2 equiv.) and excess nucleophile (5 equiv.;
allylsilane or silyl enol ether) were added. The reaction was allowed
to reach 26 °C and stirred for 4 h, and the mixture was then poured
into aqueous NaHCO3/10% Na2S2O3 and extracted with CH2Cl2.
The products were purified by column chromatography on silica
gel (hexanes/EtOAc).
When
phenyl(trimethylsilyloxy)ethene
was
used
as a nucleophile, the fragmentation–alkylation reaction
(Scheme 12) took place in good yield to afford (2R)-phenyl
ketone 39 (99% de).[39] No H-abstraction or oxidation
products were isolated.
2-Allyl-1-benzoylpyrrolidine (10):[13a] Compound 4 was treated un-
der the standard fragmentation–allylation conditions to afford af-
ter column chromatography (hexanes/EtOAc, 90:10), pyrrolidinol
7 (4%) and 2-allyl-1-benzoylpyrrolidine 10 (91%).
Scheme 12. Stereoselective fragmentation–alkylation. Reagents and
conditions: (a) DIB, I2, CH2Cl2, hν, then 0 °C, BF3·OEt2,
CH2=C(OTMS)Ph, 39 (64%, 99% de).
Benzyl 2-Allyl-1-pyrrolidinecarboxylate (11):[13b] Compound 5 was
treated under the standard fragmentation–allylation conditions to
afford after column chromatography (hexanes/EtOAc, 90:10) ben-
zyl 2-hydroxy-1-pyrrolidinecarboxylate (8) (10%) and benzyl 2-al-
lyl-1-pyrrolidinecarboxylate (11) (76%).
2-Allyl-1-(tolylsulfonyl)pyrrolidine (12):[12] Compound 6 was treated
under the standard fragmentation–allylation conditions to afford
after column chromatography (hexanes/EtOAc, 90:10) N-tolylsul-
Conclusions
fonyl-2-pyrrolidinol
9
(5%) and 2-allyl-N-(tolylsulfonyl)-
pyrrolidine 12 (86%).
The fragmentation of primary alkoxyl radicals has been
scarcely used in synthesis since other competing processes
(such as H-abstraction) usually predominate. However,
when β-amino alcohols were used as substrates, the scission
took place in good to excellent yields. Tandem scission–
allylation, or –alkylation reactions were subsequently devel-
oped. This one-pot methodology was applied to the synthe-
sis of alkaloid analogues and functionalized, chiral nitrogen
heterocycles.
Methyl 2-Allyl-1-piperidinecarboxylate (16):[15] Compound 15 was
treated under the standard fragmentation–allylation conditions, but
with the use of iodine (0.5 equiv.), to afford after column
chromatography (hexanes/EtOAc, 90:10) 2-allylpiperidine 16
(52%).
Methyl 2-Propyl-1-piperidinecarboxylate (13):[16] To a solution of
allyl derivative 16 (20 mg) in EtOAc (10 mL) was added 10% Pd/
C (50 mg), and the solution was stirred at 26 °C under a hydrogen
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A. Boto, D. Hernández, R. Hernández, A. Montoya, E. Suárez
atmosphere (1 atm) for 18 h. The reaction mixture was filtered 84.0449; found 84.0451. C8H12ClNO (173.64): calcd. C 55.34, H
FULL PAPER
through a celite column which was eluted with EtOAc. The organic
layer was evaporated under vacuum to yield product 13 (18 mg,
90%).
6.97, N 8.07; found C 55.66, H 7.05, N 7.82.
6-Methylenehexahydro-3H-pyrrolizin-3-one (22): Compound 21
(25 mg, 0.14 mmol) in dry THF (2 mL) was cooled to 0 °C and
treated with 60% NaH (15 mg, 2.5 mmol). The solution was stirred
overnight at room temperature, then poured into H2O, and ex-
tracted with EtOAc. Column chromatography as usual gave prod-
uct 22 (14 mg, 73%). Compound 22 was previously reported,[25]
but its physical and spectroscopic data were not described. Color-
5-Allyl-2-pyrrolidinone (18):[8f] Compound 17 was treated under the
standard fragmentation–allylation conditions to afford after col-
umn chromatography (hexanes/EtOAc, 90:10) product18 (85%).
5-Allyl-1-(2-methyl-2-propenyl)-2-pyrrolidinone (19):[20] To a solu-
tion of allylpyrrolidinone 18 (200 mg, 1.6 mmol) in dry DMF
(5 mL) at 0 °C, was added sodium hydride (60% dispersion in min-
eral oil, 160 mg, 3.2 mmol). The reaction mixture was stirred at
0 °C for 1 h and then ClCH2C(Me)=CH2 (240 µL, 2.4 mmol) was
added dropwise. After stirring at 0 °C for 30 min, the reaction mix-
ture was allowed to reach room temperature (26 °C) and stirred for
another 16 h. The mixture was then cooled to 0 °C and methanol
(1 mL) was added dropwise to destroy excess sodium hydride. Af-
terwards, the reaction mixture was poured into a saturated sodium
hydrogen carbonate solution and extracted with diethyl ether. The
organic layer was washed with brine, dried on sodium sulfate, and
the solvents evaporated under vacuum. The residue was purified by
column chromatography on silica gel (hexanes/EtOAc, 95:5) to af-
ford product 19 (192 mg, 64%).
less oil. IR (film): ν = 3085, 1681, 1236, 897 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 1.77 (dddd, J = 2.6, 2.9, 10.0, 10.3 Hz, 1
H, 1-Ha), 2.15 (m, 1 H, 7-Ha), 2.36 (dddd, J = 2.3, 6.9, 9.3, 12.8 Hz,
1 H, 1-Hb), 2.43 (ddd, J = 2.3, 9.7, 16.7 Hz, 1 H, 2-Ha), 2.68 (m,
2 H, 2-Hb + 7-Hb), 3.58 (ddd, J = 1.7, 1.9, 15.9 Hz, 1 H, 5-Ha),
3.99 (dddd, J = 6.5, 6.9, 6.8, 10.0 Hz, 1 H, 7a-H), 4.22 (br. d, J =
15.9 Hz, 1 H, 5-Hb), 4.99 (m, 1 H, =CHaHb), 5.04 (m, 1 H,
=CHaHb) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 27.1 (CH2, C-
1), 34.1 (CH2, C-2), 40.2 (CH2, C-7), 46.1 (CH2, C-5), 61.2 (CH,
C-7a), 108.2 (CH2, =CH2), 147.2 (C, C-6), 174.3 (C, C-3) ppm. MS
(EI, 70 eV): m/z (%) = 137 (99) [M]+, 82 (100) [M – COCH2CH2]+.
HRMS (EI, 70 eV): calcd. for C8H11NO 137.0842; found 137.0835;
calcd. for C5H8N 82.0419; found 82.0421. C8H11NO (137.18):
calcd. C 70.04, H 8.08, N 10.21; found C 70.01, H 8.03, N 10.41.
6-Methyl-1,5,8,8a-tetrahydro-3(2H)-indolizinone (20):[20] To a solu-
tion of compound 19 (110 mg, 0.6 mmol) in dry dichloromethane
(20 mL) was added a catalytic amount (10 mg) of Grubbs’ catalyst
2nd generation {benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imid-
azolidinylidene]dichloro(tricyclohexylphosphane)ruthenium}, and
the solution was heated at reflux for 3 h. The reaction mixture was
then cooled to room temperature, poured into a saturated aqueous
NaHCO3 solution, and extracted with dichloromethane. The or-
ganic layer was dried and evaporated as usual, and the residue was
purified by column chromatography on silica gel (hexanes/EtOAc,
95:5) to afford indolizinone 20 (88 mg, 95%).
(5S*,1ЈR*)-5-(1-Chloro-2-methyl-2-propenyl)-2-pyrrolidinone (23)
and
(5S*,1ЈS*)-5-(1-Chloro-2-methyl-2-propenyl)-2-pyrrolidinone
(24): Fragmentation–allylation as described to obtain product 21,
but using 1-chloro-2-methyl-3-trimethylsilyl-1-propene as the nu-
cleophile. The crude reaction product was treated with NaH in
DMF as described to obtain product 22. Usual purification af-
forded product 23 (32% for both steps) and traces of diastereomer
24. Compound 23: Crystalline solid. M.p. 115–117 °C (from
EtOAc/n-hexane). IR (film): ν = 3430, 3088, 1700, 1260, 917 cm–1.
˜
1H NMR (500 MHz, CDCl3): δ = 1.78 (m, 1 H, 4-Ha), 1.80 (s, 3
H, 2Ј-CH3), 2.17 (m, 1 H, 4-Hb), 2.33–2.45 (m, 2 H, 3-H2), 3.92
(ddd, J = 7.5, 7.9, 8.4 Hz, 1 H, 5-H), 4.20 (d, J = 9.3 Hz, 1 H, 1Ј-
H), 5.05 (s, 1 H, =CHaHb), 5.11 (s, 1 H, =CHaHb), 6.04 (br. s, 1
H, NH) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 17.5 (CH3, 2Ј-
CH3), 24.5 (CH2, C-4), 30.1 (CH2, C-3), 57.5 (CH, C-5), 70.7 (CH,
C-1Ј), 117.3 (CH2, =CH2), 140.6 (C, C-2Ј), 177.0 (C, C-2) ppm.
MS (EI, 70 eV): m/z (%) = 176/174 (2.7/8.2) [M + H]+, 138 (15)
[M – Cl]+, 84 (100) [M – CH(Cl)C(Me)=CH2]+. HRMS (EI,
70 eV): calcd. for C8H1337ClNO/C8H1335ClNO 174.0656/174.0686;
found 174.0650/174.0692; calcd. for C4H6NO 84.0449; found
84.0447. C8H12ClNO (173.64): calcd. C 55.34, H 6.97, N 8.07;
found C 55.69, H 7.16, N 7.66. Compound 24: Minor diastereomer
24 could not be purified from its mixture with major diastereomer
5-[(2-Chloromethyl)-2-propenyl]-2-pyrrolidinone (21): To a solution
of pyroglutamol (17, 57.5 mg, 0.5 mmol) in dry CH3CN (7 mL)
under a nitrogen atmosphere was added I2 (63.5 mg, 0.25 mmol)
and DIB (322 mg, 1.0 mmol), and the resulting mixture was stirred
at 25 °C, under irradiation with visible light (80 W tungsten-fila-
ment lamp) for 3 h. The reaction mixture was cooled to 0 °C; after-
wards 2-chloromethyl-3-trimethylsilyl-1-propene (272 µL, 244 mg,
1.5 mmol) and BF3·OEt2 (127 µL, 141.9 mg, 1.0 mmol) were added
dropwise. The mixture was allowed to reach room temperature and
stirred for 3 h. The mixture was then poured into a solution of
Na2S2O3 (10% aq.)/NaHCO3 (saturated aq.) and extracted with
CH2Cl2. The organic layers were dried (Na2SO4) and the solvents
evaporated under vacuum. Silica gel chromatography (hexanes/
EtOAc, 70:30) gave compound 21 (36.5 mg, 70%). Compound 21
was previously reported,[25] but its physical and spectroscopic data
were not described. Crystalline solid. M.p. 60–62 °C (from EtOAc/
1
23. H NMR (500 MHz, CDCl3): δ = 1.82 (s, 3 H, 2Ј-CH3), 2.03
(m, 1 H, 4-Ha), 2.15 (m, 1 H, 4-Hb), 2.31–2.45 (m, 2 H, 3-H2), 3.90
(m, 1 H, 5-H), 4.12 (d, J = 8.8 Hz, 1 H, 1Ј-H), 5.05 (s, 1 H,
=CHaHb), 5.09 (s, 1 H, =CHaHb), 6.18 (br. s, 1 H, NH) ppm. 13C
NMR (125.7 MHz, CDCl3): δ = 17.5 (CH3, 2Ј-CH3), 25.1 (CH2,
C-4), 29.8 (CH2, C-3), 56.6 (CH, C-5), 68.4 (CH, C-1Ј), 117.3 (CH2,
=CH2), 141.2 (C, C-2Ј), 177.9 (C, C-2) ppm.
n-hexane). IR (film): ν = 3431, 3087, 1694, 1260, 925 cm–1. 1H
˜
NMR (500 MHz, CDCl3): δ = 1.75 (m, 1 H, 4-Ha), 2.26–2.44 (m,
5 H, 3-H2 + 4-Hb + CH2C=), 3.89 (dddd, J = 6.5, 6.6, 6.7, 6.9 Hz,
1 H, 5-H), 4.01 (d, J = 11.8 Hz, 1 H, CHaHbCl), 4.04 (d, J =
11.6 Hz, 1 H, CHaHbCl), 5.03 (s, 1 H, =CHaHb), 5.25 (s, 1 H,
5-(2-Oxo-2-phenylethyl)-2-pyrrolidinone (25): The general fragmen-
tation–alkylation procedure with the use of 1-phenyl-1-(trimethyl-
=CHaHb), 6.37 (br. b., 1 H, NH) ppm. 13C NMR (125.7 MHz, silyloxy)ethene as the nucleophile, afforded compound 25 (73%).
CDCl3): δ = 27.1 (CH2, C-4), 30.1 (CH2, C-3), 40.6 (CH2, C-1Ј), Crystalline solid. M.p. 125–127.5 °C (from EtOAc/n-pentane). IR
48.0 (CH2, CH2Cl), 52.2 (CH, C-5), 117.6 (CH2, =CH2), 141.4 (C,
=C), 178.0 (C, C-2) ppm. MS (EI, 70 eV): m/z (%) = 176/174 (3.8/
11.8) [M + H]+, 138 (13) [M – Cl]+, 84 (100) [M – ClCH2C(=CH2)-
CH2]+. HRMS (EI, 70 eV): calcd. for C8H1337ClNO/C8H1335ClNO
176.0656/174.0686; found 176.0651/174.0694; calcd. for C4H6NO
(CHCl ): ν = 3432, 1697, 1682 cm–1. 1H NMR (500 MHz, CDCl ):
˜
3 3
δ = 1.80 (m, 1 H, 4-Ha), 2.40 (m, 3 H, 3-H2 + 4-Hb), 3.11 (dd, J =
8.9, 17.8 Hz, 1 H, 1Ј-Ha), 3.27 (dd, J = 4.0, 17.8 Hz, 1 H, 1Ј-Hb),
4.20 (m, 1 H, 5-H), 6.53 (br. s., 1 H, NH), 7.45 (dd, J = 7.7, 7.7 Hz,
2 H, arom.), 7.57 (dd, J = 7.3, 7.4 Hz, 1 H, arom.), 7.91 (d, J =
330
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 325–334

Alkaloid Analogues from β-Amino Alcohols
FULL PAPER
7.7 Hz, 2 H, arom.) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 26.8 (100.6 MHz, CDCl3, 26 °C): δ = 25.0 [CH3, C(Me)CH3], 26.9 [CH3,
(CH2, C-4), 29.5 (CH2, C-3), 45.2 (CH2, C-1Ј), 50.0 (CH, C-5), C(Me)CH3], 28.4 [3ϫCH3, OC(CH3)3], 36.0/35.3 (CH2, C-1Ј),
127.8 (2ϫCH, arom.), 128.6 (2ϫCH, arom.), 133.5 (CH, arom.),
136.1 (C, arom.), 177.8 [C, C(O)N], 198.2 (C, CO) ppm. MS (EI,
70 eV): m/z (%) = 203 (31) [M]+, 175 (26) [M – CO]+, 105 (100)
[PhCO], 84 (90) [M – CH2COPh]+. HRMS (EI, 70 eV): calcd. for
C12H13NO2 203.0946; found 203.0907; calcd. for C7H5O 105.0340;
found 105.0341. C12H13NO2 (203.24): calcd. C 70.90, H 6.45, N
6.89; found C 70.79, H 6.60, N 6.82.
51.4/52.0 (CH2, C-5), 62.6/63.1 (CH, C-2), 78.6/79.3 (CH, C-4),
79.7 [C, OC(CH3)3], 83.2/84.0 (CH, C-3), 111.6 [C, OC(Me)3],
118.2 (CH2, C-3Ј), 133.8 (CH, C-2Ј), 154.3 (C, CO) ppm. MS (EI,
70 eV): m/z (%) = 268 (4) [M – Me]+, 242 (7) [M – CH2CH=CH2]
+, 186 (22) [M + H – CH2CH=CH2 – CMe3]+, 142 (100) [M +
H – CH2CH=CH2 – CO2CMe3]+. HRMS (EI, 70 eV): calcd. for
C14H22NO4 268.1549; found 268.1592; calcd. for C7H12NO2
142.0868; found 142.0872. C15H25NO4 (283.37): calcd. C 63.58, H
8.89, N 4.94; found C 63.60, H 8.86, N 4.78. Compound 37: White
crystals. M.p. 101.5–103.5 °C (from EtOAc/n-pentane), [α]D = +62
Benzyl
2-Methoxy-1-pyrrolidinecarboxylate
(26):[29]
2-(Hy-
droxymethyl)pyrrolidine 5 (250 mg, 1.06 mmol) in CH2Cl2 (7 mL)
was treated with I2 (135 mg, 0.53 mmol) and DIB (685 mg,
2.13 mmol), and stirred under irradiation with visible light for 3 h.
Dry MeOH (0.5 mL) was then added, and the solution was stirred
for other 30 min. Work up and purification, as previously de-
scribed, afforded product 26 (193 mg, 78%).
(c 0.25, CHCl ). IR (CHCl ): ν = 1686, 1441, 1376 cm–1. 1H NMR
˜
3
3
(500 MHz, CDCl3): δ = 0.08 [s, 9 H, Si(CH3)3], 0.94 (dd, J = 7.7,
14.5 Hz, 1 H, TMSCHaHb), 1.17 (dd, J = 6.8, 14.5 Hz, 1 H,
TMSCHaHb), 1.34 [s, 3 H, C(Me)CH3], 1.40 (ddd, J = 11.4, 11.5,
13.4 Hz, 1 H, 4-Ha), 1.53 [s, 3 H, C(Me)CH3], 2.31 (ddd, J = 2.0,
4.6, 13.5 Hz, 1 H, 4-Hb), 3.46 (dd, J = 2.3, 13.3 Hz, 1 H, 7-Ha),
3.51 (ddd, J = 5.1, 6.4, 11.5 Hz, 1 H, 4a-H), 4.18 (dd, J = 6.4,
13.2 Hz, 1 H, 7-Hb), 4.24 (dd, J = 6.3, 6.3 Hz, 1 H, 5-H), 4.36
(dddd, J = 1.9, 6.8, 7.0, 12.8 Hz, 1 H, 3-H), 4.75 (ddd, J = 2.5, 6.3,
6.3 Hz, 1 H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = –0.9
[3ϫCH3, Si(CH3)3], 24.4 (CH2, TMSCH2), 25.5 [CH3, C(Me)
CH3], 27.7 [CH3, C(Me)CH3], 34.7 (CH2, C-4), 50.3 (CH2, C-7),
60.9 (CH, C-4a), 76.0 (CH, C-3), 77.6 (CH, C-6), 84.4 (CH, C-5),
113.8 [C, C(Me)2], 152.2 (C, C-1) ppm. MS (EI, 70 eV): m/z (%) =
299 (1) [M]+, 284 (31) [M – Me]+, 258 (46) [M + H – CMe2]+, 214
(2R*,5ЈR*)- (27)[30a] and (2R*,5ЈS*)-Benzyl 2-(5-Oxo-2,5-dihydro-2-
furanyl)-1-pyrrolidinecarboxylate (28):[30a] Method A: To a solution
of compound 26 (43.8 mg, 0.2 mmol) in dry CH2Cl2 (4 mL) at 0 °C
under N2 was added 2-(trimethylsilyloxy)furan (168 µL, 156 mg,
1 mmol), and BF3·OEt2 (51 µL, 56 mg, 0.4 mmol) was then injected
dropwise. The solution was stirred at room temperature for 1 h,
poured into a saturated aqueous NaHCO3 solution, and extracted
with CH2Cl2. Usual drying, evaporation, and chromatography af-
forded products 27 and 28 (40.2 mg, 74%) as a diastereoisomeric
mixture [27 (threo)/28 (erythro), 10:1]. Method B: 2-(Hy-
droxymethyl)pyrrolidine (5) underwent the standard fragmenta-
tion–alkylation procedure with the use of 2-(trimethylsilyloxy)furan
as the nucleophile to give products 27 and 28 (66%) as a diastereo-
isomeric mixture (27/28, 6:1).
(65) [M + H – CMe2 – CO2]+, 142 (37) [M – CO2 – TMSCH2
–
CH=CH2]+, 73 (100) [TMS]. HRMS (EI, 70 eV): calcd. for
C14H25NO4Si 299.1552; found 299.1577; calcd. for C3H9Si 73.0473;
found 73.0459. C14H25NO4Si (299.44): calcd. C 56.16, H 8.42, N
4.68; found C 56.08, H 8.77, N 4.68. Compound 38: Oil. [α]D
=
(8aR*,8R*)- (29)[32a] and (8aR*,8S*)-8-Hydroxyhexahydro-5-(1H)-
indolizinone (30):[32b] To a solution of diastereomers 27/28 (10:1)
(40 mg, 0.15 mmol) in MeOH (3 mL) was added Pd(OH)2/C
(20 mg) and a catalytic amount of MeONa (5 mg), and the re-
sulting mixture was stirred at room temperature under a hydrogen
atmosphere (1 atm) overnight. The suspension was filtered through
a silica gel–celite (1:1) path and the organic layers were concen-
trated under vacuum to yield products 29 and 30 (21 mg, 91%; dr
8:1).
+8 (c 0.17, CHCl ). IR (CHCl ): ν = 1683, 1441 cm–1. 1H NMR
˜
3
3
(500 MHz, CDCl3): δ = 0.09 [s, 9 H, Si(CH3)3], 0.88 (dd, J = 7.0,
14.5 Hz, 1 H, TMSCHaHb), 1.21 (dd, J = 8.8, 14.6 Hz, 1 H,
TMSCHaHb), 1.36 [s, 3 H, C(Me)CH3], 1.55 [s, 3 H, C(Me)CH3],
1.81 (ddd, J = 4.7, 11.2, 13.4 Hz, 1 H, 4-Ha), 2.15 (ddd, J = 2.2,
4.9, 13.5 Hz, 1 H, 4-Hb), 3.49 (dd, J = 2.2, 13.2 Hz, 1 H, 7-Ha),
3.58 (ddd, J = 5.5, 5.7, 11.0 Hz, 1 H, 4a-H), 4.21 (dd, J = 6.4,
13.3 Hz, 1 H, 7-Hb), 4.28 (dd, J = 6.4, 6.4 Hz, 1 H, 5-H), 4.61 (m,
1 H, 3-H), 4.75 (ddd, J = 2.3, 6.2, 6.2 Hz, 1 H, 6-H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = –1.1 [3ϫCH3, Si(CH3)3], 22.5
(CH2, TMSCH2), 25.5 [CH3, C(Me)CH3], 27.7 [CH3, C(Me)CH3],
31.8 (CH2, C-4), 50.4 (CH2, C-7), 57.1 (CH, C-4a), 74.8 (CH, C-
3), 77.4 (CH, C-6), 84.6 (CH, C-5), 113.9 [C, C(Me)2], 151.6 (C, C-
1) ppm. MS (EI, 70 eV): m/z (%) = 284 (16) [M – Me]+, 258 (26)
[M + H – CMe2]+, 214 (41) [M + H – CMe2 – CO2]+, 142 (49)
[M – CO2 – TMSCH2CH=CH2]+, 73 (100) [TMS]. HRMS (EI,
70 eV): calcd. for C13H22NO4Si 284.1318; found 284.1297; calcd.
for C3H9Si 73.0474; found 73.0471. C14H25NO4Si (299.44): calcd.
C 56.16, H 8.42, N 4.68; found: C 56.11, H 8.48, N 4.77.
Tandem Fragmentation–Allylation of Compound 31: The reaction
was carried out according to the standard procedure to afford tert-
butyl (2R,3R,4S)-2-allyl-3,4-O-isopropylidene-1-pyrrolidinecarbox-
ylate (36) (41%), (3S,4aR,5R,6S)-5,6-dioxy-3-[(trimethylsilyl)-
methyl]hexahydropyrrolo[1,2-c][1,3]oxazin-1-one (37) (23%), and
(3R,4aR,5R,6S)-5,6-dioxy-3-[(trimethylsilyl)methyl]hexahydropyr-
rolo[1,2-c][1,3]oxazin-1-one (38) (22%) (global yield 86%). Com-
pound 36: Two rotamers at 26 °C (1:1), one rotamer at 70 °C. Oil.
1
[α]D = –64 (c 0.64, CHCl ). IR (CHCl ): ν = 1687, 1409 cm–1. H
˜
3
3
NMR (500 MHz, CDCl3, 26 °C): δ = 1.29 [s, 3 H, C(Me)CH3], 1.44
[s, 3 H, C(Me)CH3], 1.45 [s, 9 H, OC(CH3)3], 2.20/2.33 (m/m, 2 H,
1Ј-H2), 3.33 (dd, J = 5.2, 13.0 Hz, 1 H, 5-Ha), 3.75/3.86 (d, J =
12.9 Hz/d, J = 13.0 Hz, 1 H, 5-Hb), 4.02/4.15 (dd, J = 5.8, 6.4 Hz/
Tandem Fragmentation–Alkylation of Compound 31: The reaction
was carried out according to the standard procedure to afford tert-
m, 1 H, 2-H); 4.45 (d, J = 5.9 Hz, 1 H, 3-H), 4.67 (m, 1 H, 4-H), butyl (2R,3R,4S)-2-(2-oxo-2-phenylethyl)-3,4-O-isopropylidene-1-
5.09 (d, J = 11.1 Hz, 1 H, 3Ј-Ha), 5.10 (d, J = 16.3 Hz, 1 H, 3Ј-
pyrrolidinecarboxylate (39) (64%, 99% de). Two rotamers at 26 °C
Hb), 5.75 (m, 1 H, 2Ј-H) ppm. 1H NMR (500 MHz, CDCl3, 70 °C): (1:1), one rotamer at 70 °C. Colorless crystals. M.p. 103.5–105.5 °C
δ = 1.30 [s, 3 H, C(Me)CH3], 1.46 [s, 3 H, C(Me)CH3], 1.47 [s, 9 (from EtOAc/n-pentane). [α]D = –16 (c 0.24, CHCl3). IR (CHCl3):
1
H, OC(CH3)3], 2.21 (ddd, J = 7.7, 7.7, 15.1 Hz, 1 H, 1Ј-Ha), 2.31
(m, 1 H, 1Ј-Hb), 3.33 (dd, J = 5.2, 13.0 Hz, 1 H, 5-Ha), 3.81 (d, J
ν = 1686, 1597, 1406 cm–1. H NMR (500 MHz, CDCl , 26 °C): δ
˜
3
= 1.30 [s, 3 H, C(Me)CH3], 1.41/1.42 [s/s, 9 H, OC(CH3)3], 1.45 [s,
= 13.0 Hz, 1 H, 5-Hb), 4.10 (m, 1 H, 2-H), 4.45 (d, J = 5.9 Hz, 1 3 H, C(Me)CH3], 3.18 (m, 1 H, CHaHbCOPh), 3.29/3.44 (dd, J =
H, 3-H), 4.66 (dd, J = 5.4, 5.5 Hz, 1 H, 4-H), 5.09 (dd, J = 1.5, 3.4, 16.6 Hz/dd, J = 7.3, 16.9 Hz, 1 H, CHaHbCOPh), 3.45/3.50
9.3 Hz, 1 H, 3Ј-Ha), 5.11 (dd, J = 1.0, 18.3 Hz, 1 H, 3Ј-Hb), 5.76 (dd, J = 5.2, 12.9 Hz/dd, J = 5.2, 12.6 Hz, 1 H, 5-Ha), 3.71/3.91 (d,
(dddd, J = 7.0, 7.1, 10.4, 17.2 Hz, 1 H, 2Ј-H) ppm. 13C NMR
J = 12.6 Hz/d, J = 12.9 Hz, 1 H, 5-Hb), 4.43 (m, 1 H, 2-H), 4.61/
Eur. J. Org. Chem. 2007, 325–334
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331

A. Boto, D. Hernández, R. Hernández, A. Montoya, E. Suárez
FULL PAPER
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4.70 (d, J = 5.9 Hz/d, J = 6.0 Hz, 1 H, 3-H), 4.82/4.87 (dd, J = 5.4,
5.4 Hz/dd, J = 5.5, 5.4 Hz, 1 H, 4-H), 7.44/7.46 (dd, J = 7.6, 7.7 Hz/
dd, J = 7.6, 7.6 Hz, 2 H, arom.), 7.55/7.57 (dd, J = 5.6, 7.4 Hz/dd,
J = 6.6, 7.4 Hz, 1 H, arom.), 7.94/7.96 (d, J = 7.0 Hz/d, J = 7.2 Hz,
2 H, arom.) ppm. 1H NMR (500 MHz, CDCl3, 70 °C): δ = 1.30 [s,
3 H, C(Me)CH3], 1.42 [s, 9 H, OC(CH3)3], 1.44 [s, 3 H, C(Me)-
CH3], 3.21 (m, 1 H, CHaHbCOPh), 3.35 (m, 1 H, 5-Ha), 3.46 (m,
1 H, CHaHbCOPh), 3.78 (m, 1 H, 5-Hb), 4.43 (dd, J = 5.7, 6.1 Hz,
1 H, 2-H), 4.68 (m, 1 H, 3-H), 4.83 (dd, J = 5.3, 5.3 Hz, 1 H, 4-
H), 7.44 (dd, J = 7.8, 7.7 Hz, 2 H, arom.), 7.54 (dd, J = 7.4, 7.4 Hz,
1 H, arom.), 7.95 (d, J = 7.6 Hz, 2 H, arom.) ppm. 13C NMR
(100.6 MHz, CDCl3, 26 °C): δ = 24.8 [CH3, C(Me)CH3], 26.9 [CH3,
C(Me)CH3], 28.3 [3ϫCH3, OC(CH3)3], 39.4/40.1 (CH2, C-1Ј),
51.7/52.8 (CH2, C-5), 60.9 (CH, C-2), 78.8/79.6 (CH, C-4), 79.8/
80.1 [C, OC(Me)3], 83.9/84.7 (CH, C-3), 111.6 [C, C(Me)2], 128.2
(2ϫCH, arom.), 128.6/128.7 (2ϫCH, arom.), 133.3/133.5 (CH,
arom.), 136.6 (C, arom.), 153.8/154.1 [C, C(O)N], 197.6/198.6 (C,
CO) ppm. MS (EI, 70 eV): m/z (%) = 361 (3) [M]+, 288 (8) [M –
OCMe3]+, 261 (10) [M – CO2CMe3]+, 186 (100) [M – CH2COPh –
CMe3]+, 105 (64) [COPh], 57 (79) [CMe3]. HRMS (EI, 70 eV):
calcd. for C20H27NO5 361.1889; found 361.1914; calcd. for
C8H12NO4 186.0766; found 186.0771. C20H27NO5 (361.44): calcd.
C 66.46, H 7.53, N 3.88; found C 66.26, H 7.92, N 3.67.
Supporting Information (see footnote on the first page of this arti-
cle): The synthesis of substrates 4–6, 15, 31, 33–35, and 40–42, and
the spectroscopic data for the new or partially described products
(4, 6, 15, 31, 33–35, and 42). The 1H- and 13C NMR spectra for
fragmentation substrate 31 and its precursors 33–35 and 42. The
1H- and 13C NMR spectra for the following fragmentation prod-
ucts or compounds derived therefrom: products 21–23, 25, 29/30,
and 36–39. This material is available on the WWW under
http://www.eurjoc.org or from the author.
[3]
[4]
Acknowledgments
This work was supported by the Investigation Programs PPQ2000-
0728 and PPQ2003-01379 (Plan Nacional de I+D, Ministerios de
Ciencia y Tecnología and Educación y Ciencia, Spain) and Pro-
yecto Intramural del CSIC 2004-8-0E211. We also acknowledge
financial support from FEDER funds. D. H. thanks the Ministerio
de Educación y Cienciafor an FPU fellowship. A. M. thanks the
C.S.I.C. for an I3P fellowship.
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333

A. Boto, D. Hernández, R. Hernández, A. Montoya, E. Suárez
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[39] The assigned stereochemistry for compound 43 was also sup-
ported by NOESY experiments. Spatial correlations were ob-
served for 2-H (δH 4.43) and Meb (δH 1.45), for CHaHbCOPh
(δH 3.18)/3-H (δH 4.70), for 3-H (δH 4.70)/Mea (δH 1.30)/4-H
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1.30)/4-H (δH 4.66); Compound 41: Spatial correlations were
observed for: 3-H (δH 4.36)/4a-H (δH 3.51) and 4-Ha (δH 1.40)/
5-H (δH 4.24); Compound 42: Spatial correlations were ob-
served for: CH2TMS (δH 1.21 and 0.88)/4a-H (δH 3.58), for 4a-
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Received: August 16, 2006
Published Online: November 6, 2006
334
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Eur. J. Org. Chem. 2007, 325–334