Enantiopure 2,6-disubstituted piperidines bearing one alkene- or alkyne-containing substituent: Preparation and application to total syntheses of indolizidine-alkaloids

Article abstract of DOI:10.1039/b927007h

A general and efficient procedure for the preparation of 2,6-disubstituted piperidines bearing one alkene- or alkyne-containing substituent was developed by using non-racemic Betti base as a chiral auxiliary. Many chiral benzylamines are excellent auxiliaries, but they were rarely used for this purpose because of the inefficient removal of the N-benzyl auxiliary residue under non-hydrogenative conditions. We found that N,N-disubstituted Betti base derivative has a typical Mannich structure of o-naphthol. When it carried out a base-catalyzed formation of o-quinone methide, an efficient non-hydrogenative N-debenzylation was achieved, and the alkene and alkyne groups survived. To demonstrate the efficiency of the method and the versatility of the products, asymmetric total syntheses of indolizidine-alkaloids (-)-167B, (-)-195H, (-)-209D and (-)-223AB were accomplished.

Full text of DOI:10.1039/b927007h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantiopure 2,6-disubstituted piperidines bearing one alkene- or
alkyne-containing substituent: preparation and application to total syntheses
of indolizidine-alkaloids†
Hui Liu, Deyong Su, Guolin Cheng, Jimin Xu, Xinyan Wang* and Yuefei Hu*
Received 5th January 2010, Accepted 16th February 2010
First published as an Advance Article on the web 25th February 2010
DOI: 10.1039/b927007h
A general and efficient procedure for the preparation of 2,6-disubstituted piperidines bearing one
alkene- or alkyne-containing substituent was developed by using non-racemic Betti base as a chiral
auxiliary. Many chiral benzylamines are excellent auxiliaries, but they were rarely used for this purpose
because of the inefficient removal of the N-benzyl auxiliary residue under non-hydrogenative
conditions. We found that N,N-disubstituted Betti base derivative has a typical Mannich structure of
o-naphthol. When it carried out a base-catalyzed formation of o-quinone methide, an efficient
non-hydrogenative N-debenzylation was achieved, and the alkene and alkyne groups survived. To
demonstrate the efficiency of the method and the versatility of the products, asymmetric total syntheses
of indolizidine-alkaloids (-)-167B, (-)-195H, (-)-209D and (-)-223AB were accomplished.
Introduction
Indolizidines are a class of alkaloids with a nitrogen-bridged
bicyclic skeleton. Many chiral 5-substituted and 3,5-disubstituted
indolizidines were isolated from ants and amphibians,1 such as
Scheme 1
indolizidines (-)-167B (1), (-)-195H (2), (-)-209D (3) and (-)-
223AB (4) (Fig. 1). Owing to their biological importance and
novel structures,2 they have continuously been challenging targets
of total synthesis. In the past decades, a number of routes have
been reported for asymmetric total syntheses of alkaloids 1–4,3–7
partially because they also served as the excellent test cases for
new synthetic methodologies and strategies.
followed by a catalytic hydrogenation. It is noteworthy that the
hydrogenation of 6 was a three-step one-pot reaction including a
deprotection of the Cbz group, a reduction of the alkene and an
intramolecular reductive amination.
However, this synthetic strategy suffered from tedious prepara-
tion of 5 with unsatisfying enantioselectivity. When it was extended
to the synthesis of 3,5-disubstituted indolizidines, preparation of
the analogues of 5 had become a major obstacle.9 Since compound
5 and its analogues were prepared already by the best current
methods, therefore, it is necessary to find alternatives for them as
new precursors to enhance the efficiency of this synthetic strategy.
Herein, we report a general and efficient method for the prepa-
ration of enantiopure 2,6-disubstituted piperidines bearing one
alkene- or alkyne-containing substituent. As shown in Scheme 2,
we propose that (2R,6R)-2-vinyl-6-alkyl-N-Cbz-piperidine (7)
may be a very suitable precursor for the syntheses of indolizidine-
alkaloids. When 7 carries out a cross-metathesis reaction (CM),
a,b-unsaturated ketone 8 can be obtained in a singe step. Then,
the hydrogenation of 8 offers the corresponding 5-substituted or
3,5-disubstituted indolizidine depending upon the R1 group. To
display the efficiency of our proposed route, the total syntheses of
indolizidines 1–4 were demonstrated.
Fig. 1
Many alkene compounds were used as key precursors in the
existing synthetic routes. Prominent among these is (S)-2-allyl-
N-Cbz-pyrrolidine (5), by which one of the shortest and most
efficient synthesis of (-)-167B (1) was achieved recently.3b It owed
its success mainly to a well-established strategy that was originally
described by Remuson et al. in a racemic synthesis of ( )-167B in
2001.8 As shown in Scheme 1, (-)-167B (1) was obtained in 35%
overall yield by a conversion of 5 into a,b-unsaturated ketone 6
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry, Tsinghua
University, Beijing, 100084, P. R. China. E-mail: wangxinyan@mail.
tsinghua.edu.cn, yfh@mail.tsinghua.edu.cn; Fax: +86-10-62771149;
Tel: +86-10-62795380
† Electronic supplementary information (ESI) available: Experiments,
characterization, and 1H and 13C NMR spectra for 14a–e, 17, 7a–r, 8a–d,
and 1–4. See DOI: 10.1039/b927007h
Scheme 2
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conditions, the expected non-hydrogenative N-debenzylation of
10 may be achieved.
Results and discussion
Preparation of enantiopure 2,6-disubstituted piperidines bearing
one alkene- or alkyne-containing substituent
Thus, the diastereopure precursor 12 was prepared by a
known procedure.12b As was expected, when 12 was treated with
=
H2C CHMgBr (13a) in THF, the alkylation occurred on C11 to
The investigation showed that a number of methods have been
reported for the preparation of the title compounds.3c,d,10,11 Al-
though each of them has some advantages, however, there remains
a great need for a highly enantioselective, efficient, convenient and
scalable procedure.
give 14a in 92% yield. As we revealed in our previous study, the
regioselectivity of this alkylation was controlled by THF solvent.
When Et2O was used as a solvent, the alkylation occurred on
both C7a and C11. As shown in Scheme 5, by using other alkene-
or alkyne-containing Grignard reagents 13b–e, the corresponding
14b–e were obtained as single diastereoisomers in excellent yields.
In our recent works, Betti base was resolved conveniently to its
non-racemic isomers on a kilogram scale by a kinetic resolution.12a
Then, a highly enantioselective and regioselective strategy was
developed for the total syntheses of (2S,6R)-dihydropinidine and
(2S,6R)-isosolenopsins.12b However, this original protocol could
not be suitable for the preparation of any alkene-containing
chain-substituted piperidines because the auxiliary residue was
removed via a hydrogenative N-debenzylation (Scheme 3). In fact,
this was a common problem for most asymmetric syntheses by
using chiral benzylamine auxiliaries. For example, non-racemic 2-
phenylglycinol is an excellent auxiliary for the preparation of chiral
piperidines,13 but it was rarely used for the preparation of alkene
compounds14 because its auxiliary residue could not be removed
efficiently via a non-hydrogenative N-debenzylation. Since the
intermediate 10 can be obtained easily by similar procedures
to that of 9,12b,15 thus, the key issue for the preparation of 2-
vinyl-6-alkyl-piperidines (11) is how to develop an efficient non-
hydrogenative N-debenzylation method.
Scheme 5
Since diastereopure precursor 12 has three chiral carbons, the
diastereomeric purity for products 14a–e can be easily measured
by their 1H and 13C NMR spectra. Therefore, the conversion of 12
to 14a has been monitored carefully by NMR measurements of the
crude product. We found that this conversion was a temperature-
controlled reaction. When the reaction proceeded below 0 ◦C,
14a was obtained as a single diastereoisomer. However, a complex
mixture was obtained when the reaction proceeded above 25 ◦C, in
which a dimer product was isolated as a major product (Scheme 6).
Scheme 3
Further investigation showed that Mannich derivatives of o-
phenol and o-naphthol are good precursors for the generation of
o-quinone methide.16 As shown in Scheme 4, this transformation is
accompanied by a N-debenzylation and usually promoted by ther-
mal initiation,17 photoirradiation18 or bases.19 Therefore, when the
intermediate 10, as a typical Mannich derivative of o-naphthol, is
converted into the corresponding o-quinone methide under those
Scheme 6
We proposed that the alkylation of 12 may be a SN2 reaction at
0 ◦C because the Bt-group was replaced with complete inversion
of configuration. The fact that 14a–e were obtained as single
diastereoisomers may result in the bulky size of Bt-group. While,
the dimmer may be obtained by an iminium salt intermediate when
the reaction proceeded at higher temperature.
n
As shown in Scheme 7, when 14a was treated with PrMgBr
(15a) and quenched with saturated aq. NH4Cl, the expected 16a
was obtained in almost quantitative yield. Accidentally, when the
reaction was quenched with H2O, an N-debenzylated product
(2R,6R)-2-vinyl-6-propylpiperidine (11a) was also isolated in 18%
Scheme 4
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Table 1 (2R,6R)-2,6-Disubstituted piperidines bearing one alkene- or
alkyne-containing substituent
Scheme 7
yield. Realizing that 11a may be produced by a base-catalyzed N-
benzylation via a generation of o-quinone methide mechanism, a
group of conditional experiments were tested. We found that the
yield of 11a could be improved by increasing the concentration of
aq. NaOH, adding MeOH as a nucleophilic reagent or elevating
the reaction temperature. When the mixture of 16a in 6.0 M
aq. NaOH–MeOH–THF (1 : 2 : 2 by v/v) was heated at 60 ◦C,
16a was exhausted completely within 1 h. Although the fact
that racemic 17 was isolated in 91% yield as a by-product gave
strong evidence for our hypothesis, 11a normally was obtained
in less than 40% yield because of its high volatility. However,
this problem was resolved easily by treatment of the crude 11a
with CbzCl, by which desired (2R,6R)-2-vinyl-6-propyl-N-Cbz-
piperidine (7a) was obtained in 84% yield. Since the structural
assignments of intermediate 16a suffered from ambiguous 1H and
13C NMR spectra because of the unusual coalescence phenomenon
caused by a strong intramolecular hydrogen bonding,12b therefore,
it was directly used in the next step without purification and
characterization.
For the same reason, the NMR spectra of 16a could not be used
for the measurement of its diastereomeric purity. However, we can
use the NMR spectra of compound 7a (the derivative of 16a) to
measure its diastereomeric purity. Compound 7a has two chiral
carbons that were formed in two separated steps. Theoretically,
compound 7a should be an enantiomeric pure product when
its NMR spectra prove that it is a single product. In fact, the
NMR spectra of 7a (see the ESI†) proved that it was a single
product. In addition, we also found that the mixture of (2R,6R)-7a
and its diastereoisomer (2R,6S)-7a could not be separated under
our chromatography conditions (silica gel, EtOAc : PE = 1 : 5).
Therefore, these results indirectly proved that the conversion of
14a to 16a may be an enantiopure conversion.
forms. Based on the data of 1H and 13C NMR of 7a–r, as well as
by comparison their rotations with that of known products, we
suggested that the alkylation on C7a may go through an iminium
salt pathway because the new C–C bond was formed with retention
of configuration.
Total syntheses of natural indolizidine-alkaloids
By using our developed method, enantiopure (2R,6R)-6-propyl-
(7a), (2R,6R)-6-pentyl- (7b) or (2R,6R)-6-hexyl-2-vinyl-N-Cbz-
piperidine (7c) was prepared on a gram scale within a few hours.
According to the proposal in Scheme 2, 7a–c will be converted
into the corresponding a,b-unsaturated aldehyde or ketone. In
recent years, the conversion of alkene into a,b-unsaturated
aldehyde20,21 or ketone22 by cross-metathesis reaction (CM) is very
popular and it can be influenced by Grubbs 1st (G1) and 2nd
(G2) or Hoveyda–Grubbs (HG) catalysts. Although acrolein (18)20
was often used as an aldehyde group donor in the preparation of
a,b-unsaturated aldehyde, its CM reaction with 7a usually gave
an unseparated mixture, which may be caused by its higher self-
metathesis reactivity. However, when crotonaldehyde (19)21 was
used as an alternative, the expected product 8a was obtained in a
variable yield. As shown in Table 2, Grubbs 1st and 2nd catalysts
could not offer a satisfying yield of 8a (entries 1–5). However,
As shown in Table 1, the method was quite general and showed
high diastereoselectivity. When 14a was treated with different
RMgBr (15b–f), the corresponding 7b–f were obtained in 80–
84% yields. The long (7c), short (7e) or cycloalkyl (7d) and
benzyl (7f) substitutes gave very satisfying results. When 14b–
e were used as substrates, the novel alkene- (7g–l) or alkyne-
containing (7m–r) chain-substituted 2,6-disubstituted piperidines
were obtained smoothly. Since the diastereoselectivity of products
1
can be easily monitored by H and 13C NMR spectra, all the
final products 7a–r were confirmed to be obtained in enantiopure
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Table 2 Conversion of 7a into 8a by CM reaction
auxiliary residue was removed via a base-catalyzed generation
of o-quinone methide mechanism, by which an efficient non-
hydrogenative N-debenzylation was achieved and the alkene
and alkyne groups were survived. In total, eighteen such novel
2,6-disubstituted piperidines were prepared. By using some of
those compounds as versatile building blocks, asymmetric total
syntheses of indolizidine-alkaloids (-)-167B, (-)-195H, (-)-209D
and (-)-223AB were accomplished, respectively.
Entry Catalyst (mol%) Solvent Temp./◦C Time/h Yield of 8a (%)a
Experimental section
1
2
3
4
5
6
7
G1 (5)
CH2Cl2 40
CH2Cl2 40
(CH2Cl)2 80
20
20
20
20
20
20
18
12
23
31
38
47
72
85
G2 (5)
General remarks
G2 (5)
G2 (5)
G2 (10)
HG2 (5)
HG2 (10)
PhMe
110
All melting points were determined on a Yanaco melting point
apparatus and are uncorrected. Optical rotations were recorded
on a Perkin-Elmer 343 polarimeter. IR spectra were recorded on
CH2Cl2 40
CH2Cl2 40
CH2Cl2 40
1
a Isolated yields were obtained.
a Nicolet FT-IR 5DX spectrometer with KBr pellets. H NMR
and 13C NMR spectra were recorded on a JEOL JNM-ECA 300
spectrometer in CDCl3. TMS was used as an internal reference and
the J values are given in Hz. MS were recorded on a VG-ZAB-
MS spectrometer with 70 eV. Elementary analysis data were ob-
tained on a Perkin-Elmer-241C apparatus. PE is petroleum ether
(60–90◦).
Hoveyda–Grubbs 2nd catalyst (HG2) showed very good catalytic
activity for this conversion (entry 6). When 10 mol% of HG2 was
used, 8a was obtained in 85% yield (entry 7).
By a similar procedure, 8b–c were prepared in satisfying yields by
CM reaction between 7b–c and 19. As was expected, CM reaction
between 7a and oct-2-en-4-one (20) gave desired a,b-unsaturated
ketone 8d in 92% yield. It was interesting to observed that all
Z-alkenes were obtained in 8a–d regardless of E/Z ratio of the
substrates 19 and 20 (Fig. 2).
A typical procedure for preparation of (7aR,11R,13S)-11-
vinyl-13-phenyl-7a,8,10,11-tetrahydro-9H,13H-naphtho[1,2-e]-
pyrido[2,1-b][1,3]oxazine (14a). To a cold solution (ice-water
bath) of 12 (4.32 g, 10 mmol) in dry THF (70 mL) was added
=
H2C CHMgCl (1.6 M in THF, 18.8 mL, 30 mmol) dropwise
under N2. After the reaction was stirred at 0 ◦C for 0.5 h
(monitored by TLC), a saturated aqueous solution of NH4Cl
(30 mL) was added to quench the reaction. Then, the resultant
mixture was extracted with CH2Cl2 (3 ¥ 30 mL). The combined
organic layers were washed with H2O, brine and dried over
anhydrous Na2SO4. After removal of the solvent, the residue was
purified by chromatography (silica gel, EtOAc : PE = 1 : 15) to
give product 14a (3.14 g, 92%) as a white crystal, mp 137–138 ◦C
(EtOAc–PE), [a]2D5 = +173.4◦ (c 0.2, CHCl3). IR: n 3063, 2935,
1628 cm-1; 1H NMR: d 1.43-1.50 (m, 1H), 1.65-1.74 (m, 2H), 1.85-
2.07 (m, 3H), 3.62-3.70 (m, 1H), 4.51-4.55 (m, 1H), 4.91-4.97 (m,
2H), 5.17 (s, 1H), 5.92-6.08 (m, 1H), 7.06-7.08 (m, 1H), 7.16-7.31
(m, 8H), 7.65-7.75 (m, 2H); 13C NMR: d 15.2, 29.8, 31.6, 60.2,
63.5, 81.0, 114.4, 115.3, 118.7, 122.8, 123.0, 126.1, 127.0, 128.0
(2C), 128.4, 128.6 (2C), 129.2 (2C), 131.9, 140.6, 143.1, 153.4; MS
m/z (%): 341 (M+, 6.3), 231 (100). Anal. Calcd. For C24H23NO: C,
84.42; H, 6.79; N, 4.10. Found: C, 84.20; H, 6.89; N, 4.25.
By using a similar procedure, the intermediates 14b–e were
prepared (see the ESI†).
Fig. 2
Finally, the three-step one-pot hydrogenation of 8a–d proceeded
smoothly over Pd–C catalyst to give the target alkaloids 1–4
in high yields (Scheme 8). No surprise, the formation of 4 was
accompanied by 9% of (3R)-diastereomer. Since alkaloids 1–4
were known products and their stereochemistries have been well
established in the literature, therefore, the stereochemistry of 7a–r
and the mechanisms of alkylations in the preparation of 7a–r were
re-confirmed.
A typical procedure for preparation of (2R,6R)-benzyl 2-vinyl-
6-propyl-piperidine-1-carboxylate (7a). To a stirred solution of
n-PrMgBr made from Mg (1.22 g, 50 mmol) and n-PrBr (3.69 g,
30 mmol) in dry Et2O (15 mL) was added a solution of 14a (3.41 g,
Scheme 8
◦
10 mmol) in dry Et2O (70 mL) within 20 min at 0 C under N2.
After the resultant mixture was stirred for another 10 min, it was
quenched by addition of a saturated aqueous solution of NH4Cl
(40 mL). The organic layer was separated and the aqueous layer
was extracted by Et2O (3 ¥ 30 mL). The combined organic layers
were washed with brine (3 ¥ 30 mL) and dried over Na2SO4. The
solvent was removed to give crude 16a as an oil residue.
Conclusion
A general and efficient method for the preparation of enan-
tiopure 2,6-disubstituted piperidines bearing one alkene- or
alkyne-containing substrate was established by using non-racemic
Betti base as a chiral auxiliary. The key step is that the
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The residue (crude 16a) was diluted by a solution of THF
(10 mL), CH3OH (10 mL) and aq. NaOH (6.0 M, 5 mL), and
was refluxed for 1 h. Then it was cooled to room temperature
and quenched by addition of CH2Cl2 (50 mL). The resultant
mixture was extracted by aq. HCl (6.0 M, 3 ¥ 20 mL) and the
combined aqueous layers were neutralized by aq. NaOH (6.0 M).
The alkaline solution was extracted with CH2Cl2 (3 ¥ 20 mL) again
and the combined organic layers were washed with brine (20 mL)
and dried over Na2SO4.
After Na2SO4 was filtered off, the filtrate containing free amine
11a was treated with CbzCl (3.41 g, 20 mmol) and Na2CO3 (5.3 g,
50 mmol). The mixture was stirred for 4 h at room temperature
and the solid was filtrated off. Then the solvent was evaporated
in vacuum and the residue was purified by chromatography (silica
gel, EtOAc : PE = 1 : 30) to give product 7a (2.45 g, 84%) as a
colorless oil, [a]2D5 = +24.7◦ (c 1.8, CHCl3). IR: n 2939, 1691,
1408 cm-1; 1H NMR: d 0.87 (t, J = 7.2, 3H), 1.15-1.92 (m, 10H),
4.15-4.30 (m, 1H), 4.75-4.85 (m, 1H), 5.02-5.20 (m, 4H), 5.85-6.05
(m, 1H), 7.25-7.41 (m, 5H); 13C NMR: d 14.0, 14.5, 202, 27.7, 27.8,
36.3, 50.9, 51.7, 66.9, 114.8, 127.8 (3C), 128.4 (2C), 137.0, 139.7,
156.0; MS m/z (%): 287 (M+, 4.58), 200 (100). Anal. Calcd. For
C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C, 75.50; H, 8.72;
N, 4.85.
6.17 (dq, J = 1.8 and 7.6, 1H), 6.83 (dd, J = 14.5 and 7.8, 1H),
7.25-7.45 (m, 5H), 9.53 (d, J = 7.8, 1H); 13C NMR: d 14.0, 14.5,
22.5, 26.9, 27.3, 27.4, 29.1, 31.7, 33.9, 50.6, 51.1, 67.4, 128.0 (2C),
128.1, 128.5 (2C), 131.6, 136.4, 155.8, 158.8, 193.5; MS m/z (%):
357 (M+, 2.70), 91 (100). Anal. Calcd. For C22H31NO3: C, 73.91;
H, 8.74; N, 3.92. Found: C, 73.87; H, 8.95; N, 4.02.
(2R,6R,E)-Benzyl
2-(3-oxohept-1-enyl)-6-propylpiperidine-1-
carboxylate (8d). It is a yellowish oil (92%), [a]2D5 = +67.9◦ (c
0.48, CHCl3). IR: n 2936, 1951, 1686, 1408 cm-1; H NMR: d
1
0.78-0.95 (m, 6H), 1.15-2.00 (m, 13H), 2.50 (t, J = 7.2, 3H),
4.15-4.30 (m, 1H), 4.90-5.00 (m, 1H), 5.15 (s, 2H), 6.15 (dd, J =
14.5 and 1.8, 1H), 6.81 (dd, J = 14.5 and 7.8, 1H), 7.25-7.45 (m,
5H); 13C NMR: d 13.8, 13.9, 14.5, 20.1, 22.3, 26.1, 27.5, 27.7,
36.2, 40.1, 50.4, 50.8, 67.2, 127.9 (2C), 128.0, 128.4 (2C), 129.4,
136.6, 146.7, 155.8, 200.5. MS m/z (%): 371 (M+, 13.65), 284
(100). Anal. Calcd. For C23H33NO3: C, 74.36; H, 8.95; N, 3.77.
Found: C, 74.45; H, 8.95; N, 3.61.
A
typical procedure for the preparation of (-)-(5R,9R)-
indolizidine 167B (1). A suspension of 8a (420 mg, 1.33 mmol)
and 10% Pd–C (105 mg, 25 wt%) in anhydrous MeOH (20 mL) was
stirred under hydrogen atmosphere (55 psi) at room temperature
for 12 h. After the Pd–C catalyst was filtered off, solvent was
removed on a rotary evaporator. The residue was purified by
chromatography (silica gel, EtOAc–MeOH = 10 : 1) to give 184 mg
(83%) of product 5a as a yellowish oil, [a]2D5 = -104.4◦ (c 0.44,
CH2Cl2) [lit.3d [a]D22 = -109◦ (c 1.32, CH2Cl2); lit.5c [a]2D0 = -106.9◦
(c 1.10, CH2Cl2)]. 1H NMR: d 0.91 (t, J = 7.0, 3H), 1.10-2.05 (m,
16H), 2.05 (q, J = 8.6, 1H), 3.31 (dt, J = 2.1 and 8.6, 1H); 13C
NMR: d 14.4, 19.0, 20.2, 24.4, 30.3, 30.4, 30.5, 36.5, 51.2, 63.7,
65.2.
By a similar procedure, the compounds 7a–r were prepared from
14a–e and different R1MgBr (15a–h) (see the ESI†).
A typical procedure for the preparation of (2R,6R,E)-benzyl
2-(3-oxoprop-1-enyl)-6-propylpiperidine-1-carboxylate (8a). To a
boiling solution of 7a (500 mg, 1.75 mmol) and crotonaldehyde
(19, 370 mg, 5.25 mmol) in CH2Cl2 was added Hoveyda–Grubbs
catalyst [2nd generation (HG2), 110 mg, 0.525 mmol] with bubble
of N2 at the bottom of solution. After the reaction system was
refluxed for 18 h, the solvent was evaporated in vacuum. The
residue was purified by chromatography (silica gel, EtOAc : PE =
By using a similar procedure, the target products 2–4 were
prepared.
1 : 5) to give product 8a (460 mg, 85%) as a yellowish oil, [a]D25
=
+92.9◦ (c 0.4, CHCl3). IR: n 2954, 1686, 1406 cm-1; 1H NMR: d
0.86 (t, J = 7.2, 3H), 1.15-2.05 (m, 10H), 4.15-4.30 (m, 1H), 5.03-
5.22 (m, 3H), 6.18 (qd, J = 7.6 and 1.8, 1H), 6.83 (dd, J = 14.5
and 7.8, 1H), 7.25-7.41 (m, 5H), 9.53 (d, J = 7.8, 1H); 13C NMR:
d 13.9, 14.5, 20.1, 27.3, 36.1, 50.7, 50.9, 67.4, 128.0 (2C), 128.1
(2C), 128.5 (2C), 131.7, 136.4, 155.8, 158.8, 193.6; MS m/z (%):
315 (M+, 1.83), 91 (100). Anal. Calcd. For C19H25NO3: C, 72.35;
H, 7.99; N, 4.44. Found: C, 72.27; H, 8.05; N, 4.38.
(-)-(5R,9R◦)-Indolizidine 195H (2)5a. It is a yellowish oil (86%),
[a]2D5 = -95.6 (c 1.1, CH2Cl2). 1H NMR: d 0.89 (t, J = 6.8, 3H),
1.05-1.95 (m, 20H), 1.97 (q, J = 8.8, 1H), 3.25 (dt, J = 2.1 and
8.6, 1H); 13C NMR: d 14.0, 20.4, 22.6, 24.7, 25.5, 30.5, 30.8, 31.0,
32.3, 34.6, 51.5, 63.9, 65.0.
(-)-(5R,9R)-Indolizidine 209D (3). It is a yellowish oil (85%),
[a]2D5 = -77.1◦ (c 0.34, CH2Cl2) [lit.5c [a]1D9 = -84.9◦ (c 0.98,
◦
1
CH2Cl2); lit.5f [a]D25 = -80.4 (c 1.0, CH2Cl2)]. H NMR: d 0.88
(t, J = 6.6, 3H), 1.05-1.95 (m, 22H), 1.97 (q, J = 8.6, 1H), 3.26
(dt, J = 2.1 and 8.6, 1H); 13C NMR: d 14.1, 20.4, 22.6, 24.7, 25.8,
29.7, 30.5, 30.8, 31.0, 31.8, 34.6, 51.5, 63.9, 65.0.
By using a similar procedure, the products 8b–d were prepared.
(2R,6R,E)-Benzyl
2-(3-oxoprop-1-enyl)-6-pentylpiperidine-1-
carboxylate (8b). It is a yellowish oil (88%), [a]2D5 = +88.3◦ (c
0.2, CHCl3). IR: n 2933, 1684, 1406 cm-1. H NMR: d 0.84 (t,
1
J = 7.2, 3H), 1.15-2.05 (m, 14H), 4.15-4.30 (m, 1H), 5.03-5.22
(m, 3H), 6.17 (dq, J = 1.8 and 7.6, 1H), 6.83 (dd, J = 14.5 and
7.8, 1H), 7.25-7.45 (m, 5H), 9.53 (d, J = 7.8, 1H); 13C NMR: d
14.0, 14.5, 22.5, 26.5, 27.3, 31.5, 33.9, 50.6, 51.1, 67.4, 128.0 (2C),
128.1 (2C), 128.5 (2C), 131.6, 136.4, 155.8, 158.8, 193.5; MS m/z
(%): 343 (M+, 2.84), 91 (100). Anal. Calcd. For C21H29NO3: C,
73.44; H, 8.51; N, 4.08. Found: C, 73.05; H, 8.48; N, 4.00.
(-)-(3S,5R,9R)-Indolizine 223AB (4). It is a yellowish oil
(91%), [a]2D5 = -82.0◦ (c 0.8, MeOH), [lit.3c [a]2D5 = -11.1◦ (c 0.2,
MeOH)]. 1H NMR: d 0.80-0.95 (m, 6H), 1.05-1.50 (m, 16H), 1.50-
1.85 (m, 4H), 2.16-2.00 (m, 2H), 2.45-2.57 (m, 1H); 13C NMR: d
14.1, 14.5, 19.3, 22.8, 24.9, 29.3, 29.8, 30.5, 31.0, 31.8, 38.0, 39.9,
62.1, 65.1, 67.4.
(2R,6R,E)-Benzyl 2-(3-oxoprop-1-enyl)-6-hexylpiperidine-1-car-
boxylate (8c). It is a yellowish oil (81%), [a]2D5 = +101.2◦ (c 0.5,
CHCl3). IR: n 2931, 1686, 1408 cm-1. 1H NMR: d 0.86 (t, J = 7.2,
3H), 1.15-2.05 (m, 16H), 4.15-4.30 (m, 1H), 5.03-5.22 (m, 3H),
Acknowledgements
This work was supported by NNSFC (30600779, 20672066) and
the CFKSTIP from Education Ministry of China (706003).
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 1899–1904 | 1903
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1904 | Org. Biomol. Chem., 2010, 8, 1899–1904
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