A new route to trans-2,6-disubstituted piperidine-related alkaloids using a novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester

Article abstract of DOI:10.1039/b601489e

A novel C₂-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester 1 was prepared by the double asymmetric allylboration of glutaldehyde followed by an aminocyclization and carbamation. On the basis of desymmetrization of 1 using iodocarbamation, one allyl group of 1 was protected and monofunctionalizations of the resulting oxazolidinone 11 were performed. The reaction of the N-methoxycarbonyl piperidine 25 employing decarbamation reagent (n-PrSLi or TMSI) as a key step gave oxazolidinone 26 or 17 including an intramolecular ring formation, which was transformed in a few steps into (-)-porantheridine (2) and (-)-2-epi-porantheridine (3), respectively. In addition, the expedient synthesis of (+)-epi-dihydropinidine (4), (2R,6R)-trans-solenopsin A (5), and precoccinelline (6), starting from 11 is described. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b601489e

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A new route to trans-2,6-disubstituted piperidine-related alkaloids using a
novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester
Hiroki Takahata,*a Yukako Saitoa and Motohiro Ichinoseb
Received 31st January 2006, Accepted 16th February 2006
First published as an Advance Article on the web 14th March 2006
DOI: 10.1039/b601489e
A novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester 1 was prepared by the double
asymmetric allylboration of glutaldehyde followed by an aminocyclization and carbamation. On the
basis of desymmetrization of 1 using iodocarbamation, one allyl group of 1 was protected and
monofunctionalizations of the resulting oxazolidinone 11 were performed. The reaction of the
N-methoxycarbonyl piperidine 25 employing decarbamation reagent (n-PrSLi or TMSI) as a key step
gave oxazolidinone 26 or 17 including an intramolecular ring formation, which was transformed in a
few steps into (−)-porantheridine (2) and (−)-2-epi-porantheridine (3), respectively. In addition, the
expedient synthesis of (+)-epi-dihydropinidine (4), (2R,6R)-trans-solenopsin A (5), and precoccinelline
(6), starting from 11 is described.
Introduction
The abundance of biologically active compounds containing
the 2,6-disubstituted piperidine ring has resulted in consider-
able synthetic efforts to prepare such systems.1 With respect
to biologically-active target molecules, an increasing interest in
the diastereo- and enantioselective synthesis of piperidines has
developed.2 The focus of our interest in this field is on the
synthetic applications of double or iterative asymmetric reactions
to achieve enantiomeric enhancement.3 We recently reported on
the asymmetric synthesis of several piperidine-related alkaloids
using a novel C2-symmetric 2,6-diallylpiperidine (1), prepared by
a double asymmetric allylboration of glutaraldehyde followed by
Fig. 1
aminocyclization as the key steps.4 In this paper, we describe the
full detail of an expedient synthesis of (−)-porantheridine (2),5 a
symmetric 2,6-diallylpiperidine 8 and meso-8 in 61 and 14% yields,
novel tricyclic alkaloid of Poranthera corymbosa, and its 2-epimer
(3), (−)-epi-dihydropinidine (4),6 a constituent of pine and spruce
species, and (2R,6R)-trans-solenopsin A (5),7 a constituent of fire-
ant venom, and precoccinelline (6),8 a ladybug defense alkaloid
starting from 1 (Fig. 1).
respectively. This success of the separation can be attributed to
both a rigid conformation and close proximity (1,3-relationship)
between the two chiral centers of 8 compared with acyclic 1,5-diols
7 (Scheme 1).
Results and discussion
We began with the synthesis of 1 as a chiral building block.
The treatment of glutaraldehyde with B-allyldiisopinocamphenyl-
borane, prepared by the reaction of B-methoxydiisocamphenyl-
borane {(−)-Ipc2BOMe} and allylmagnesium bromide, followed
by oxidation with alkaline H2O2 gave the diastereomeric and
inseparable mixture of diols 7 in 74% yield.9 The diols 7 were
successively subjected to ditosylation and aminocyclization with
benzylamine to give the diastereomeric isomers of piperidines 8,
which were fortunately separated by chromatography to yield C2-
Scheme 1
aFaculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University,
Sendai, 981-8558, Japan. E-mail: Takahata@tohoku-pharm.ac.jp; Fax: 81-
22-275-2013; Tel: 81-22-727-0144
The exchange of N-protecting groups from benzyl to carbamate
group was examined with methyl chloroformate. First, the use
of benzene and toluene as solvents under reflux resulted in the
bFaculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical
University, Toyama, 930-0194, Japan
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recovery of C2-8. However, the use of chloroform, a more polar
solvent, afforded the title carbamate 1 in 59% yield together
with the recovery of C2-8 (35%). Finally, methyl carbamate 1
was obtained in 93% yield by a reaction in a sealed tube at
Having the promising piperidine 11, the Sharpless asymmetric
dihydroxylation (AD-mix-a) of 11 was conducted to provide the
diastereomeric mixtures of diols 12 in 90% yield. Deprotection of
the oxazolidine was accomplished by the exposure of 12 to zinc in
acetic acid to give the allylpiperidine, of which N-protection was
achieved by treatment with methyl chloroformate to yield 9 and
10 in 55 and 18% from 11, respectively (Scheme 5).
◦
90 C for 48 h. On the other hand, carbamation using ethyl and
benzyl chloroformates in chloroform under the same conditions
did not proceed, resulting in the recovery of C2-8. No carbamation
with chloroformates bulkier than methyl chloroformate would
ꢀ
presumably occur due to steric effects (hindrance) of the a,a -
disubstituted allyl groups in the piperidine ring (Scheme 2).
Scheme 5
Scheme 2
Treatment of the diol 9 in a three-step sequence (1. cyclic
stannoxanation, 2. primary tosylation, 3. epoxidation) afforded
the epoxide 13 in 92% yield. Without further purification, epoxide
13 was cleaved with ethylmagnesium bromide in the presence of
CuBr–Me2S to yield the alcohol 14 in 76% yield. O-Protection of
14 with MOMCl in the presence of Hu¨nig base gave 15 in 90%
yield. Oxidative cleavage of 15 with cat. OsO4 in combination with
NaIO4 followed by the Horner–Wadsworth–Emmons reaction of
the resulting aldehyde with dimethyl 2-oxopropylphosphonate in
the presence of NaH afforded the a,b-unsaturated ketone, which
was hydrogenated with cat. Pd(OH)2 to give the ketone 16 in 84%
yield (Scheme 6).
With the C2 chiral building block 1 in hand, our synthesis began
with the selective monodihydroxylation of the diallyl appendages
in 1. Unfortunately, the dihydroxylation of 1 using AD-mix-a was
nonselective, resulting in a diasteromeric mixture of monodiols 9
and 10 and inseparable diastereomeric tetraols together with the
recovery of the starting material 1 (Scheme 3).10
Scheme 3
We hypothesized that this problem could be overcome by an
intramolecular iodocarbamation with one of the two allyl groups,
because it is impossible for a second iodocarbamation to occur
with the other one. Thus, the intramolecular iodocarbamation of 1
with iodine produced a diastereomeric and inseparable mixture of
oxazolidinones 11 in 98% yield. This desymmetrization indicates
that one of the two allyl groups was protected (Scheme 4).
Scheme 6
The decarbamation of 16 with iodotrimethylsilane11 unpre-
dictably led to the production of the oxazolidinone 17 in 50%
yield. At this stage, the stereochemistry (C3 position) of 17
remained undetermined. Acetalization of 17 gave the acetal 18,
the spectral data for which was surprisingly inconsistent with
those of Comin’s synthetic intermediate of (−)-porantheridine
19.5c From these results, the formation of 17 can be understood on
the basis of an intramolecular cyclization of the proposed reaction
intermediate 20 accompanied by an inversion of configuration at
the methoxymethyloxy-substituted carbon (Scheme 7).12
Scheme 4
We hypothesized that this problem could be overcome by an
intramolecular iodocarbamation with one of the two allyl groups,
because it is impossible for a second iodocarbamation to occur
with the other one. Thus, the intramolecular iodocarbamation of 1
with iodine produced a diastereomeric and inseparable mixture of
oxazolidinones 11 in 98% yield. This desymmetrization indicates
that one of the two allyl groups was protected.
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Scheme 7
Therefore, the epimer of 16, i.e., 21 was prepared starting
with the diol 10 according to the same procedure as was used
for the preparation of 16 (Scheme 8). Deprotection of 21 with
TMSI followed by acetalization of the resulting oxazolizinone
gave Comin’s synthetic intermediate 19, the spectral data of which
was in agreement with the reported values.5c Thus, the proposed
mechanism was verified.
Scheme 9
to 2 and 3 based on n-PrSLi and TMSI-mediated oxzolidinone
ring formation of 25, respectively, in a short step.
In addition, we focused on the synthesis of 2,6-trans-dialkylpi-
peridines such as (+)-epi-dihydropinidine (4), and (2R,6R)-trans-
solenopsin A (5). OsO4-Mediated dihydroxylation of 14 followed
by an oxidative cleavage of the resulting diol with NaIO4 provided
the aldehyde, which was decarbonylated with (Ph3P)3RhCl to
afford the methyl-substituted piperidine 27 in 48% yield. Deprotec-
tion of oxazolidine occurred upon exposure of 27 to zinc in acetic
acid followed by N-protection of the resulting allylpiperidine with
Boc2O to give N-Boc-2-allyl-6-methylpiperidine 28. Transforma-
tion of 28 into 4 has been reported previously.15 The oxidative
cleavage of 28 with cat. OsO4 in combination with NaIO4 provided
the aldehyde, which was coupled by the Wittig olefination with n-
nonyltriphenylphosphonium bromide in the presence of n-BuLi,
followed by hydrogenation of the resulting olefin to give the 2,6-
disubstituted piperidine 29 in 64% yield. N-Deprotection of 29 by
treatment with trifluoroacetic acid (TFA) in CH2Cl2 provided 5 in
84% yield (Scheme 10).
Scheme 8
Next, the O-non-protected ketone 25 was synthesized from 14
in a three-step procedure in 79% yield (Scheme 9). In the ho-
mologation, the Wittig reagent (1-triphenylphosphranylidene-2-
propanone) was used in place of the Horner–Wadsworth–Emmons
reagent (dimethyl 2-oxopropylphosphonate). The decarbamation
of 25 with Corey’s reagent n-PrSLi13 fortunately provided the
desired oxazolidinone 24 in 90% yield. An intramolecular attack
of a secondary alkoxide anion, generated by n-PrSLi, to the
carbamate carbonyl had probably occurred. In addition, treatment
of 25 with TMSI gave 17 in high yield (97%). Finally, cleavage
of the oxazolidinone ring of acetal 18 with 2 M KOH in 2-
propanol at 120 ◦C in a sealed tube14 followed by an intramolecular
aminalization of the resulting amine 26 with p-TsOH afforded (−)-
2-epi-porantheridine (3) in 25% yield. Thus, 14 was transformed
Next, the transformation of 14 into precoccinelline (6) was
pursued. Wacker oxidation of 14 provided the ketone 30 in 86%
yield. By a procedure similar to that described for 28, a two-
step treatment (deprotection of the oxazolidine and N-protection)
of 30 gave the allylpiperidine 31 in 81% yield. Treatment of 32
with cat. OsO4 in combination with NaIO4 followed by the Wittig
reaction of the resulting aldehyde with (triphenylphosphoranyli-
dene)acetaldehyde afforded the a,b-unsaturated aldehyde, which
was exposed to hydrogen in the presence of cat. Pd(OH)2 in ethyl
acetate to give the keto aldehyde 32 in 59% yield. N-Deprotection
of 32 with TFA followed by an intramolecular Mannich-type
cyclization with 10-camphorsulfonic acid (CSA) gave the known
synthetic intermediate 33 for 6 in 52% yield, which constitutes a
formal synthesis of precoccinelline (Scheme 11).
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a JASCO-DIP-1000 digital polarimeter. Column chromatography
was performed on silica gel (Fuji-Division BW-200 or Merck 60
(No 9385) with a medium pressure apparatus. The extracts were
dried over Na2SO4 unless otherwise specified.
(2S,6S)-1-Benzyl-2,6-bis(2-propenyl)piperidine (C2-8). .0 M
Allylmagnesium bromide (20 mL, 20 mmol) in ether was added to
a solution of (−)-Ipc2BOMe (6.32 g, 20.0 mmol) in ether (25 mL)
at −78 ◦C. After being stirred for 15 min, the reaction was warmed
to rt. To the mixture was added a solution of glutaraldehyde
(1.0 g, 10 mmol) in ether (5 mL) at −78 ◦C. After being stirred for
1 h, the solution was warmed to rt. To the reaction mixture were
successively added 3 N NaOH (14.6 mL) and 30% H2O2 (6.0 mL)
◦
at 0 C. The mixture was refluxed for 1 h and fractionated with
a separatory funnel. The aqueous layer was extracted with ether
three times. The combined organic solvents were washed with
brine, dried, and evaporated. The residue was purified by flash
column chromatography on silica gel (n-hexane–ethyl acetate =
2 : 1) to give the diastereomeric mixture of diols (1.36 g, 74%) as
an oil. Et3N (3.48 mL, 25.0 mmol) and 4-dimethylaminopyridine
(305 mg, 2.50 mmol) were successively added to a mixture of
the diols (1.15 g, 6.25 mmol) and p-toluenesulfonyl chloride
Scheme 10
◦
(4.70 g, 25.0 mmol) at 0 C and the mixture was stirred at room
temperature for 2 d. A large amount of ether was added to the
mixture. The mixture was filtered through Celite. The filtrate
was washed with brine, dried, and evaporated. The residue was
purified by chromatography using n-hexane–ethyl acetate (5 :
1) as eluent to yield the ditosylate (2.38 g, 78%) as a yellow
oil. A solution of the tosylate in benzylamine (15.3 mL, 0.14
mol) was heated at 75 ◦C for 2 d. The reaction was diluted
◦
Scheme 11
with n-pentane (100 mL) at 0 C and 2 N NaOH (150 mL) was
added to the dilute solution. The organic layer was separated
and the aqueous layer was extracted with n-pentane (40 mL)
four times. The combined organic layers were dried over K2CO3
and evaporated. The residue was purified by medium-pressure
chromatography using n-hexane–ethyl acetate (80 : 1) as eluent
to yield C2-8 (973 mg, 61%) and meso-8 (223 mg, 14%) as
Conclusion
In conclusion, we explored the use of C2-symmetric 2,6-diallylpi-
peridine 1 as a novel chiral building block via the double
asymmetric allylboration of glutaldehyde followed by aminocy-
clization and carbamation. The formal asymmetric synthesis of
(−)-porantheridine (2) and the asymmetric synthesis of (−)-2-
epi-porantheridine (3) were demonstrated based on the distinc-
tive desymmetrization of 1 by iodocabamation including the
protection of one allyl group and n-PrSLi and TMSI-assisted
intramolecular oxazolidinone ring formation accompanied by
retention and inversion of the configuration at the 2 position
of the hydroxypentyl substituent in 25, respectively. Moreover,
the convenient synthesis of (−)-epi-dihydropinidine (4), (2R,6R)-
trans-solenopsin A (5), and precoccinelline (6), starting from 11
was achieved.
oils. C2-8: [a]26 −4.87◦ (c 1.03, CHCl3); IR (neat) 2928, 1559,
D
1
1447 cm−1; H NMR (300 MHz, CDCl3) d 1.34–1.39 (m, 2 H),
1.57–1.60 (m, 4 H), 2.13–2.24 (m, 4 H), 2.79–2.83 (m, 2 H, H-2, H-
6), 3.68, 3.82 (ABq, J = 14.3 Hz, 2 H, CH2C6H5), 4.95–5.02 (m, 4
=
=
H, 2 × CH CH2), 5.68–5.81 (m, 2 H, 2 × –CH CH2), 7.20–7.38
(m, 5 H); 13C NMR (75 MHz, CDCl3) d 20.1, 26.1, 35.7, 51.1, 54.5,
115.7, 126.5, 128.1, 128.5, 137.0, 141.3; anal. calcd for C18H25N:
C, 84.65; H, 9.87; N, 5.48. Found: C, 84.73; H, 9.74; N, 5.38.
Methyl (2S,6S)-2,6-Bis(2-propenyl)piperidinecarboxylate (1).
A solution of C2-5 (297 mg, 1.16 mmol) and methyl chloroformate
(0.45 mL, 5.81 mmol) in CHCl3 (5.2 mL) in a sealed tube was
heated at 90 ◦C for 2 d. The solution was diluted with ether. The
resulting mixture was washed with 10% HCl and H2O and dried.
Evaporation left an oil, which was purified with chromatography
using n-hexane–ethyl acetate (30 : 1) as eluent to yield 1 (242 mg,
93%); [a]2D6 +6.00◦ (c 1.14, CHCl3); IR (neat) 2949, 1734, 1700,
1653, 1636, 1559, 1443, 1395 cm−1; 1H NMR (300 MHz, CDCl3) d
1.59–181 (m, 6 H), 2.1–2.25 (m, 2 H), 2.45–2.53 (m, 2 H), 3.68 (s,
3 H, COOCH3), 3.81–3.88 (m, 2 H, H-2S, H-6S), 5.03–5.08 (m,
4 H), 5.68–5.82 (m, 2 H); 13C NMR (75 MHz, CDCl3) d 13.6, 23.2,
39.1, 51.7, 52.3, 116.8, 135.9, 156.4; HRMS calcd for C13H21NO2
(M+) 223.1572, found 223.1576.
Experimental
General
Melting points are uncorrected. IR spectra were measured with
a JASCO A102 and a Perkin Elmer 1600 spectrophotometers.
1H NMR and 13C spectra were recorded on a JEOL FX 270,
Varian Gemini-300, and Varian Unity-500. MS and HRMS were
taken on a JEOL-JMS D-200 spectrometer using the electron
ionization. Elemental analyses were performed by a Perkin Elmer
2400 Elemental Analyzer. Optical rotations were measured with
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Methyl (2S,6S)-2-[(2S)-2,3-Dihydroxypropyl]-6-prop-2-enyl-
piperidinecarboxylate (9) and Methyl (2S,6S)-2-[(2R)-2,3-Dihy-
droxypropyl]-6-prop-2-enylpiperidinecarboxylate (10) from 1.
The olefin 1 (412 mg, 1.84 mmol) was added to a mixture of
AD-mix-a (2.58 g) in tert-BuOH (13 mL), and H2O (13 mL)
at 0 ◦C. After the reaction mixture was stirred for 9 h at the
same temperature, sodium sulfite (2.6 g) was added to the mixture.
After stirring for 30 min, the mixture was filtered through a Celite
pad. The filtrate was extracted with chloroform–2-propanol (5 :
1) three times. The extracts were washed with brine, dried, and
evaporated. The residue was chromatographed using n-hexane–
ethyl acetate (1 : 1) as eluent to yield 1 (78 mg, 19%), 9 (152 mg,
32%), 10 (51 mg, 11%), and the diastereomeric mixture of tetraols
(127 mg, 24%) as oils. 9; [a]2D6 −27.2◦ (c 0.98, CHCl3); IR (neat)
3415, 2947, 1673, 1453, 1396 cm−1; 1H NMR (300 MHz, CDCl3) d
1.68–1.93 (m, 8 H), 2.17–2.28 (m, 1 H), 2.44–2.51 (m, 2 H), 3.40–
3.48 (m, 1 H, H-2S or H-6S), 3.61–3.73 (m, 1 H, H-2S or H-6S),
3.71 (s, 3 H), 3.81–3.84 (m, 1 H, –CHOH), 4.00–4.07 (m, 2 H,
–CH2OH), 5.03–5.11 (m, 2 H), 5.67–5.81 (m, 1 H); 13C NMR
(75 MHz, CDCl3) d 12.8, 22.8, 24.8, 38.7, 39.7, 49.3, 51.4, 52.5,
66.8, 70.3, 116.8, 135.2, 156.7; HRMS calcd for C13H23NO4 (M+)
257.1627, found 257.1616. 10; [a]2D6 +2.34◦ (c 1.01, CHCl3); IR
organic layers were washed with brine, dried, and evaporated.
The residue was chromatographed using ethyl acetate–methanol
(10 : 1) as eluent to yield a diasteromeric mixture of the diols
12 (218 mg) as an oil. Zinc (69 mg, 1.06 mmol) was added to a
solution of the diols (218 mg, 0.59 mmol) in a mixture of THF
◦
(1.7 mL), acetic acid (70 lL), and H2O (70 lL) at 0 C and the
reaction mixture was vigorously stirred at room temperature for
1.5 h. The mixture was filtered through Celite. 1 N NaOH was
added to the filtrate. The basic solution was extracted with CHCl3
three times. The extracts were dried over K2CO3 and evaporated.
To a solution of the residue in THF (2 mL) and H2O (2 mL) were
added K2CO3 (122 mg, 0.88 mmol) and methyl chloroformate
(68 lL, 0.88 mmol). The mixture was stirred at room temperature
overnight. The mixture was acidified with 20% KHSO4 and
extracted with CH2Cl2 three times. The extracts were washed
with brine, dried and evaporated. The residue was purified by
chromatography using n-hexane–ethyl acetate (1 : 1) as eluent to
yield 9 (93 mg, 55%) and 10 (30 mg, 18%). All spectra of 9 and 10
were in accordance with those of 9 and 10 prepared from 1.
Methyl (2S,6S)-2-[(2R)-2-Hydroxypentyl]-6-prop-2-enylpiperi-
dinecarboxylate (14). n-Bu2SnO (2.3 mg, 9.41 lmol), triethy-
lamine (78.6 lL, 0.56 mmol) and p-toluenesulfonyl chloride (p-
TsCl) (108 mg, 0.56 mmol) were added to a solution of 9 (231 mg,
0.47 mmol) in CH2Cl2 (1.5 mL). The mixture was stirred for 1.5 h
at room temperature and brine (10 mL) was added to the mixture.
The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 three times. The combined organic layers
were dried and evaporated. The residue was chromatographed
using n-hexane–acetone (3 : 1) as eluent to yield the tosylate.
To a solution of the tosylate in methanol (2.0 mL) was added
K2CO3 (77 mg, 0.56 mmol) at 0 ◦C. After 1 h of stirring at
room temperature and saturated NH4Cl (5 mL) was added to
the mixture. The mixture was extracted with CH2Cl2 three times.
The extracts were dried and evaporated to yield 13 (125 mg, 92%)
as an oil. To a slurry of CuBr–SMe2 (115 mg, 0.56 mmol) in
THF (4 mL) was added ethylmagnesium bromide (1 M in THF,
1.12 mL, 1.12 mmol) at −78 ◦C with stirring. After being stirred
for 1 h at −45 ◦C, a solution of 13 in THF (1 mL) was slowly
added. The mixture was gradually warmed to −30 ◦C, stirred
for 1 h, and quenched with saturated NH4Cl. The mixture was
diluted with ether and the phases were separated. The organic
layer was washed with brine, dried, and evaporated. The residue
was chromatographed using n-hexane–acetone (7 : 1) as eluent
to give 14 (76 mg, 76%) as an oil; [a]2D6 −28.8◦ (c 1.94, CHCl3);
1
(neat) 3418, 2948, 1672, 1452, 1396, 1370, 1112 cm−1; H NMR
(300 MHz, CDCl3) d 1.40–1.48 (m, 1 H), 1.58–1.70 (m, 4 H), 1.83–
1.98 (m, 1 H), 2.09–2.20 (m, 1 H), 2.39–2.47 (m, 1 H), 3.40–3.50
(m, 2 H), 3.50–3.62 (m, 2 H, H-2S, H-6S), 3.67 (s, 3 H), 3.69–3.70
(m, 1 H, –CHOH), 4.04–4.14 (m, 2 H, –CH2OH), 4.58 (br s, 1 H),
4.98–5.23 (m, 2 H), 5.60–5.74 (m, 1 H); 13C NMR (75 MHz,
CDCl3) d 13.1, 22.1, 25.7, 38.9, 39.4, 48.3, 51.8, 52.9, 66.5, 68.4,
117.0, 135.4, 158.0; HRMS calcd for C13H23NO4 (M+) 257.1627,
found 257.1625.
(4RS,6S,10S)-1-Aza-4-(iodomethyl)-3-oxa-10-prop-2-enyl-
bicyclo[4.4.0]-decan-2-one (11). Iodine (634 mg, 2.50 mmol) was
added to a solution of 1 (279 mg, 1.25 mmol) in CH2Cl2 (10 mL)
at 0 ◦C and the reaction mixture was stirred at room temperature
overnight. The reaction was quenched with saturated Na2SO3
and the resulting mixture was extracted with CH2Cl2 three times.
The extracts were washed with brine, dried, and evaporated. The
residue was purified by chromatography using n-hexane–ethyl
acetate (3 : 1) as eluent to yield 11 (412 mg, 98%); IR (neat) 2934,
1685, 1427, 1367, 1269 cm−1; 1H NMR (300 MHz, CDCl3) d 1.09–
2.52 (m, 10 H), 3.14–3.25 (m, 1 H), 3.31–3.46 (m, 2 H), 4.00–4.08
(m, 0.6 H, H-4), 4.23–4.31 (m, 0.4 H, H-4), 4.58–4.66 (m, 1 H, H-
6S), 5.02–5.09 (m, 2 H), 5.68–5.85 (m, 1 H); 13C NMR (75 MHz,
CDCl3) d 5.05 (6.13), 19.1 (18.3), 27.3 (27.4), 32.8, 33.2, 33.4,
34.7, 35.1, 35.9, 46.5, 49.2, 50.2, 51.1, 73.2 (73.6), 117.3 (117.3),
135.2, 152.8; HRMS calcd for C12H18NO2I (M+) 335.0382, found
335.0377.
1
IR (neat) 3451, 2953, 1674, 1450, 1368, 1115 cm−1; H NMR
(300 MHz, CDCl3) d 0.92 (t, J = 6.9 Hz, 3 H), 1.21–1.89 (m,
12 H), 2.17–2.27 (m, 1 H), 2.45–2.53 (m, 1 H), 3.30 (br s, 1 H),
3.58–3.62 (m, 1 H), 3.71 (s, 3 H), 3.73–3.84 (m, 1 H), 4.00–4.02
(m, 1 H, H-2(2R)), 5.02–5.11 (m, 2 H), 5.68–5.82 (m, 1 H); 13C
NMR (75 MHz, CDCl3) d 13.1, 14.1, 18.8, 23.0, 24.7, 38.7, 40.1,
43.7, 49.7, 51.4, 52.3, 69.7, 116.7, 135.4, 156.6; HRMS calcd for
C15H27NO3 (M+) 269.1991, found 270.2000.
Methyl
(2S,6S)-2-[(2S)-2,3-Dihydroxypropyl]-6-prop-2-enyl-
piperidinecarboxylate (9) and methyl (2S,6S)-2-[(2R)-2,3-Dihy-
droxypropyl]-6-prop-2-enylpiperidinecarboxylate (10) from 11.
The olefin 11 (220 mg, 0.657 mmol) was added to a mixture of
AD-mix-a (1.05 g) in tert-BuOH (5 mL), and H2O (5 mL) at
(2S,6S)-Methyl 2-Allyl-6-((R)-2-(methoxymethoxy)pentyl)-
piperidine-1-carboxylate (15). To a solution of 14 (92 mg,
0.34 mmol) in CHCl3 (3 mL) were successively added N,N-
diiopropylethylamine (0.2 mL, 1.12 mmol) and chloromethyl
methyl ether (77.8 lL, 1.03 mmol) at 0 ◦C and the reaction
mixture was refluxed overnight. To the reaction mixture was
◦
0 C. After the reaction mixture was stirred for 17 h at the same
temperature, sodium sulfite (1.3 g) was added to the mixture.
After stirring for 30 min, the mixture was filtered through a
Celite pad. The organic layer was separated, and the aqueous
layer was extracted with ethyl acetate three times. The combined
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added 20% KHSO4 and the mixture was extracted with CH2Cl2
three times. The extracts were dried and evaporated. The residue
was chromatographed using n-hexane–acetone (15 : 1) as eluent
to give 15 (96 mg, 90%) as an oil; [a]2D9 −16.3◦ (c 0.98, CHCl3);
IR (neat) 2951, 1694, 1448, 1328, 1100 cm−1; 1H NMR (300 MHz,
CDCl3) d 0.92 (t, J = 7.1 Hz, 3 H), 1.26–1.76 (m, 11 H), 1.85–1.93
(m, 1 H), 2.20–2.30 (m, 1 H), 2.52–2.60 (m, 1 H), 3.39 (s, 3 H), –
OCH2OCH3, 3.53–3.62 (m, 1 H), 3.68 (s, 3 H), 3.76–3.82 (m, 1 H),
3.99–4.06 (m, 1 H), 4.63 (d, J = 7.1 Hz, 1 H, –OCH2OCH3), 4.66
(d, J = 7.1 Hz, 1 H, –OCH2OCH3), 5.01–5.10 (m, 2 H), 5.70–
5.84 (m, 1 H); 13C NMR (75 MHz, CDCl3) d 14.2, 15.0, 18.6,
24.1, 24.7, 36.6, 38.2, 38.6, 49.1, 52.0, 52.1, 55.5, 75.0, 95.1, 116.4,
135.8, 156.3; HRMS calcd for C17H31NO4 (M+) 313.2253, found
313.2250.
6.9 Hz, 3 H), 1.35–1.78 (m, 16 H), 1.85–1.95 (m, 1 H), 2.11 (s, 3 H),
2.38–2.60 (m, 2 H), 3.41–3.48 (m, 1 H), 4.17–4.21 (m, 1 H, H-4aS),
4.46–4.49 (m, 1 H, H-3S); 13C NMR (75 MHz, CDCl3) d 13.9, 18.2,
19.2, 20.0, 28.1, 28.7, 29.9, 33.0, 33.1, 36.5, 42.9, 46.8, 50.9, 72.6,
153.7, 208.6; HRMS calcd for C16H28NO3 (M+) 281.1991, found
281.2001.
(3S,4aS,8S)-Hexahydro-8-(3-(2-methyl-1,3-dioxolan-2-yl)propyl)-
3-propylpyrido[1,2-c][1,3]oxazin-1(3H)-one (18). A mixture of
17 (82 mg, 0.29 mmol), ethyleneglycol (81.3 lL, 1.46 mmol), and
p-TsOH–H2O (11 mg) in benzene (5 mL) using a Dean–Stark
apparatus was refluxed overnight. Saturated NaHCO3 was
added to the mixture. The mixture was extracted with CH2Cl2
three times. The extracts were dried and evaporated. The residue
was purified by chromatography using CHCl3 as eluent to yield
18 (87 mg, 92%) as an oil; [a]2D6 −56.3◦ (c 1.18, CHCl3); IR (neat)
(2S,6S) - Methyl 2 - ((R) - 2 - (Methoxymethoxy)pentyl) - 6 - (4 -
oxopentyl)piperidine-1-carboxylate (16). Three drops of an aque-
ous 4% OsO4 solution were added to a solution of 15 (96 mg,
0.3 mmol) in dioxane (1.5 mL) and H2O (1.5 mL) and then the
reaction mixture was stirred for 10 min at room temperature. After
NaIO4 (65 mg, 0.30 mmol) was added to mixture, the reaction
mixture was stirred for 15 min. Again NaIO4 (65 mg, 0.30 mmol)
was added to the mixture. The reaction was stirred for 1 h,
quenched with 10% sodium thiosulfate. The mixture was extracted
with CH2Cl2 three times. The extracts were dried and evaporated.
Dimethyl 2-oxopropylphosphonate (53.4 lL, 0.36 mmol) was
added to a suspension of 60% NaH (14.8 mg, 0.36 mmol) in
THF (1.5 mL) and the reaction mixture was stirred for 5 min
at room temperature. A solution of the above residue was added
to the mixture at 0 ◦C and the reaction was stirred overnight.
Saturated NH4Cl solution was added to the reaction mixture and
the mixture was extracted with CH2Cl2 three times. The extracts
were washed with brine, dried, and evaporated. The residue was
chromatographed using n-hexane–acetone (5 : 1) as eluent to give
the unsaturated ketone (91 mg, 85%) as an oil. Pd(OH)2 (20 mg)
was added to a solution of the ketone in ethyl acetate (4.5 mL) and
the suspension was stirred under hydrogen for 2 h. The mixture
was filtrated through Celite and the filtrate was evaporated. The
residue was chromatographed using n-hexane–acetone (5 : 1) as
eluent to give the saturated ketone 16 (91 mg, 99%) as an oil; [a]D26
−24.0◦ (c 0.81, CHCl3); IR (neat) 2949, 1697, 1448, 1369, 1099,
1038 cm−1; 1H NMR (300 MHz, CDCl3) d 0.92 (t, J = 7.4 Hz, 3 H,
–CH3), 1.23–1.78 (m, 15 H), 1.90–1.99 (m, 1 H), 2.14 (s, 3 H,
–COCH3), 2.45–2.49 (m, 2 H), 3.38 (s, 3 H), 3.56 (quint, J =
5.8 Hz, 1 H), 3.67 (s. 3 H), 3.74 (br s, 1 H), 3.93–3.96 (m, 1 H), 4.63
(d, J = 7.1 Hz, 1 H), 4.66 (d, J = 7.1 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) d 14.2, 15.8, 18.5, 21.1, 25.2, 25.3, 29.8, 33.1, 36.6, 38.1,
43.3, 49.2, 52.9, 52.5, 55.5, 74.9, 95.1, 156.4, 208.5; HRMS calcd
for C19H35NO5 (M+) 357.2515, found 357.2513.
1
2936, 2872, 1682, 1433, 1375, 1284, 1229, 1120, 1059 cm−1; H
NMR (300 MHz, CDCl3) d 0.94 (t, J = 6.3 Hz, 3 H), 1.30 (s, 3 H,
–C–CH3), 1.25–1.72 (m, 17 H), 1.85–1.96 (m, 1 H), 3.42–3.48 (m,
1 H), 3.92 (s, 4 H. –OCH2CH2O–), 4.19 (m, 1 H), 4.50 (m, 1 H);
13C NMR (75 MHz, CDCl3) d 14.1, 18.5, 19.5, 21.0, 24.0, 28.0,
29.8, 33.4, 36.8, 39.2, 47.0, 51.7, 64.8, 72.8, 110.0, 153.8; HRMS
calcd for C18H31NO4 (M+) 325.2253, found 325.2246.
(2S,6S)-Methyl 2-Allyl-6-((S)-2-hydroxypentyl)piperidine-1-
carboxylate (22). According to the same procedure described for
preparation of 14, 22 was prepared from 10 in 61% yield. An oil;
[a]2D8 −28.8◦ (c 0.96, CHCl3); IR (neat) 3452, 2953, 1675, 1450,
1
1368, 1115 cm−1; H NMR (300 MHz, CDCl3) d 0.90 (t, J =
6.9 Hz, 3 H, –CH3), 1.24–1.93 (m, 12 H), 2.15–2.26 (m, 1 H),
2.49–2.53 (m, 1 H), 3.47–3.49 (m, 1 H), 3.68–3.78 (m, 1 H), 3.72 (s,
3 H), 4.16–4.20 (m, 2 H, –CHOH), 5.02–5.09 (m, 2 H), 5.66–5.80
(m, 1 H); 13C NMR (75 MHz, CDCl3) d 13.8, 14.5, 189.5, 22.8,
26.3, 38.9, 39.4, 43.7, 48.9, 52.0, 52.9, 67.5, 117.0, 135,8, 158.0;
HRMS calcd for C15H27NO3 (M+) 269.1991, found 270.1988.
(2S,6S)-Methyl 2-Allyl-6-((S)-2-(methoxymethoxy)pentyl)-
piperidine-1-carboxylate (23). According to the same procedure
described for preparation of 15, 23 was prepared from 22 in 80%
yield. An oil; [a]2D9 −17.1◦ (c 1.02, CHCl3); IR (neat) 2949, 1698,
1446, 1327, 1100 cm−1; 1H NMR (300 MHz, CDCl3) d 0.92 (t, J =
7.1 Hz, 3 H), 1.26–1.93 (m, 12 H), 2.20–2.30 (m, 1 H), 2.50–2.58
(m, 1 H), 3.38 (s, 3 H, –OCH2OCH3), 3.53–3.60 (m, 1 H), 3.68
(s, 3 H), 3.73–3.80 (m, 1 H), 3.99 (m, 1 H), 4.62–4.68 (m, 2 H,
–OCH2OCH3), 5.01–5.10 (m, 2 H), 5.70–5.83 (m, 1 H); 13C NMR
(75 MHz, CDCl3) d 14.2, 15.1, 18.2, 24.3, 25.6, 37.1, 38.5, 38.9,
50.1, 52.0, 52.2, 55.5, 76.5, 95.9, 116.4, 135.7, 156.3; HRMS calcd
for C17H31NO4 (M+) 313.2253, found 313.2260.
(2S,6S) - Methyl 2 - ((S) - 2 - (Methoxymethoxy)pentyl) - 6 - (4-
oxopentyl)piperidine-1-carboxylate (21). According to the same
procedure described for preparation of 16, 21 was prepared from
23 in 79% yield. An oil; [a]2D6 −27.0◦ (c 0.97, CHCl3); IR (neat)
(3S,4aS,8S)-Hexahydro-8-(4-oxopentyl)-3-propylpyrido[1,2-
c][1,3]oxazin-1(3H)-one (17). Iodotrimethylsilane (61.3 lL,
0.43 mmol) was added to a solution of 16 (35 mg, 0.10 mmol)
in CH3CN (3.5 mL) at 0 ◦C and the solution was stirred
for 2 h. After the reaction was quenched with 10% sodium
thiosulfate, the mixture was extracted with CH2Cl2 three times.
The extracts were dried over K2CO3 and evaporated. The residue
was chromatographed using CHCl3 as eluent to give the 17 (14 mg,
50%) as an oil; [a]2D6 −57.6◦ (c 0.68, CHCl3); IR (neat) 2934, 1681,
1431, 1363, 1274 cm−1; 1H NMR (300 MHz, CDCl3) d 0.92 (t, J =
1
2949, 1697, 1447, 1368, 1099, 1039 cm−1; H NMR (300 MHz,
CDCl3) d 0.92 (t, J = 7.1 Hz, 3 H), 1.18–1.76 (m, 15 H), 1.88–1.96
(m, 1 H), 2.14 (s, 3 H, –COCH3), 2.44–2.47 (m, 2 H), 3.38 (s, 3 H),
3.51–3.62 (m, 1 H), 3.66 (s, 3 H), 3.71 (m, 1 H), 3.87 (m, 1 H),
4.63–4.70 (m, 2 H); 13C NMR (75 MHz, CDCl3) d 14.5, 16.0,
18.5, 21.4, 25.5, 26.4, 30.2, 33.4, 37.4, 39.0, 43.6, 50.3, 52.2, 52.8,
55.8, 76.7, 96.1, 156.7, 208.8; HRMS calcd for C19H35NO5 (M+)
357.2515, found 357.2513.
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(3R,4aS,8S)-Hexahydro-8-(4-oxopentyl)-3-propylpyrido[1,2-
c][1,3]oxazin-1(3H)-one (24) from 21. According to the same
procedure described for preparation of 17, 24 was prepared from
21 in 48% yield. An oil; [a]2D6 +9.67◦ (c 0.73, CHCl3); IR (neat)
THF (2 mL) was added to the mixture at 0 ◦C and the mixture was
stirred at room temperature for 5 d. 28% NH3 solution was added
to the reaction mixture and the mixture was extracted with ether
ten times. The extracts were dried over K2CO3 and evaporated. The
residue was purified by chromatography using CHCl3 as eluent to
yield 24 (63 mg, 90%) as an oil; [a]2D6 +9.67◦ (c 0.74, CHCl3). All
spectra were in accordance with those of 24 prepared from 21.
1
2936, 2870, 1708, 1674, 1433, 1363, 1289, 1129 cm−1; H NMR
(300 MHz, CDCl3) d 0.93 (t, J = 6.9 Hz, 3 H), 1.09–1.80 (m, 16 H),
2.04 (dd, J = 13.4, 5.5 Hz, 1 H), 2.13 (s, 3 H), 2.42–2.58 (m, 2 H),
3.37–3.47 (m, 1 H), 4.07–4.12 (m, 1 H, H-4aS), 4.58–4.61 (m, 1
H, H-3R); 13C NMR (75 MHz, CDCl3) d 13.9, 17.9, 18.2, 19.9,
27.7, 29.1, 30.0, 33.6, 35.8, 36.9, 42.8, 49.1, 49.9, 74.4, 153.9, 208.5;
HRMS calcd for C16H28NO3 (M+) 281.1991, found 281.2000.
(3S,4aS,8S)-Hexahydro-8-(4-oxopentyl)-3-propylpyrido[1,2-
c][1,3]oxazin-1(3H)-one (17) from 25. Iodotrimethylsilane (71 lL,
0.5 mmol) was added to a solution of 25 (71 mg, 0.23 mmol) in
CH3CN (6 mL) at 0 ◦C and the solution was stirred for 2 h. After
the reaction was quenched with 10% sodium thiosulfate, the mix-
ture was extracted with CH2Cl2 three times. The extracts were dried
over K2CO3 and evaporated. The residue was chromatographed
using CHCl3 as eluent to give 17 (62 mg, 97%) as an oil. All spectra
were in accordance with those of 17 prepared from 16.
(3R,4aS,8S)-Hexahydro-8-(3-(2-methyl-1,3-dioxolan-2-yl)-
propyl)-3-propylpyrido[1,2-c][1,3]oxazin-1(3H)-one (19). Accor-
ding to the same procedure described for preparation of 18, 19
was prepared from 24 in 99% yield. An oil; [a]2D6 +10.0◦ (c 0.25,
CHCl3), lit.5c [a]D23 +10.3◦ (c 1.96, CHCl3); IR (neat) 2934, 1682,
1
1429, 1372, 1286, 1229, 1120, 1059 cm−1; H NMR (300 MHz,
(S)-1-((2S,6S)-6-(3-(2-Methyl-1,3-dioxolan-2-yl)propyl)piperidin-
2-yl)pentan-2-ol (26). A solution of 18 (65 mg, 0.20 mmol) in
2 M KOH of 2-propanol (2.1 mL) was heated in a sealed tube for
3 d at 120 ◦C. After addition of H2O to the reaction mixture, the
mixture was extracted with CHCl3 three times. The extracts were
dried over K2CO3 and evaporated. The residue was purified by
chromatography using CHCl3–MeOH (5 : 1) as eluent to yield 26
(51 mg, 85%) as an oil; [a]2D6 +1.22◦ (c 1.31, CHCl3); IR (neat)
CDCl3) d 0.93 (t, J = 6.6 Hz, 3 H), 1.30 (s, 3 H, –CCH3), 1.07–
1.80 (m, 17 H), 2.02 (dd, J = 13.5, 5.2 Hz, 1 H), 3.34–3.43 (m,
1 H), 3.92 (s, 4 H, –OCH2CH2O–), 4.04–4.10 (m, 1 H), 4.59 (m,
1 H); 13C NMR (75 MHz, CDCl3) d 13.9, 17.9, 18.2, 20.7, 23.8,
27.2, 29.8, 33.7, 35.8, 36.9, 38.8, 49.2, 50.4, 64.5, 74.3, 109.7, 153.8;
HRMS calcd for C18H31NO4 (M+) 325.2253, found 325.2240.
Methyl (2S,6S) - 2 - [(2R) - 2 - Hydroxypentyl] - 6 - (4 - oxopentyl)
piperidinecarboxylate (25). Three drops of 4% OsO4 solution
were added to a solution of 14 (77 mg, 0.29 mmol) in a mixture of
dioxane (1.5 mL) and H2O (1.5 mL) and the solution was stirred
at room temperature for 10 min. NaIO4 (61 mg, 0.29 mmol) was
added to the solution, which was stirred for 15 min. NaIO4 (61 mg,
0.29 mmol) was again added to the mixture. After 1 h, 10% sodium
thiosulfate was added, and extracted with CH2Cl2 three times. The
extracts were dried and the mixture was evaporated to leave the
aldehyde. 1-Triphenylphosphranylidene-2-propanone (182 mg,
0.57 mmol) was added to a solution of the aldehyde in CH2Cl2
(3 mL). After being refluxed for 15 h, the mixture was evaporated.
The residue was diluted with ether and the resulting mixture was
filtered through Celite. The filtrated was evaporated. The residue
was purified by chromatography using n-hexane–ethyl acetate (3 :
1) as eluent to yield the ketone. A suspension of the ketone and
Pd(OH)2 (20 mg) in ethyl acetate (4 mL) was stirred under a
hydrogen atmosphere at room temperature for 1 h. The mixture
was filtered through Celite and the filtrate was evaporated. The
residue was purified with chromatography using n-hexane–ethyl
acetate (3 : 1) as eluent to yield 25 (71 mg, 79%) as an oil; [a]D26
−39.2◦ (c 0.74, CHCl3); IR (neat) 3445, 2950, 2870, 1677, 1452,
1
3385, 2932, 2871, 1456, 1375, 1219, 1127, 1061 cm−1; H NMR
(300 MHz, CDCl3) d 0.91 (t, J = 6.9 Hz, 3 H), 1.20–1.65 (m,
17 H), 1.30 (s, 3 H), 1.77–1.86 (m, 1 H), 2.89–2.90 (m, 2 H),
3.20–3.36 (m, 1 H, H-2 or H-6), 3.83–3.88 (m, 1 H, –CHOH),
3.92 (s, 4 H); 13C NMR (75 MHz, CDCl3) d 14.5, 19.5, 19.9, 21.2,
24.0, 30.7, 31.7, 33.6, 38.9, 39.4, 39.9, 47.8, 50.9, 64.8, 69.5, 110.1;
HRMS calcd for C17H33NO4 (M+) 299.2460, found 299.2449.
(2S,3aS,6aS,9aS)-Decahydro-9a-methyl-2-propyl-2H -[1,3]-
oxazino[4,3,2-de]quinolizine {(−)-2-epi-poranthredine} (3).
A
mixture of 26 (51 mg, 0.17 mmol) and p-TsOH–H2O (39 mg,
0.20 mmol) in benzene (3 mL) was refluxed for 3 h. After
addition of saturated NaHCO3 to the reaction mixture, the
mixture was extracted with CHCl3 three times. The extracts were
dried over K2CO3 and evaporated. The residue was purified by
chromatography using ethyl acetate–MeOH (10 : 1) as eluent
to yield 3 (12 mg, 30%) as an oil; [a]2D6 −42.9◦ (c 0.36, CHCl3);
1
IR (neat) 2931, 2867, 1453, 1375, 1254, 1131 cm−1; H NMR
(300 MHz, CDCl3) d 0.93 (t, J = 7.1 Hz, 3 H, –CH2CH3), 1.15–
1.83 (m, 17 H), 1.49 (s, 3 H, CH3-9aS), 2.35–2.46 (m, 1 H), 2.96 (t,
J = 11.3 Hz, 1 H, H-6aS), 3.74–3.78 (m, 1 H, H-3aS), 4.01–4.07
(m, 1 H, H-2); 13C NMR (75 MHz, CDCl3) d 14.5, 19.6, 20.2,
20.3, 24.4, 29.0, 30.9, 34.1, 34.4, 40.2, 41.6, 44.5, 50.0, 71.5, 86.1;
HRMS calcd for C15H27NO (M+) 237.2093, found 237.2102.
1
1370, 1190, 1115 cm−1; H NMR (300 MHz, CDCl3) d 0.92 (t,
J = 7.1 Hz, 3 H), 1.25–1.96 (m, 16 H), 2.14 (s, 3 H, –COCH3),
2.47 (t, J = 5.5 Hz, 2 H), 3.19 (br s, 1 H), 3.58–3.60 (m, 1 H),
3.69 (s, 3 H), 3.76–3.77 (m, 1 H), 3.92–3.96 (m, 1 H); 13C NMR
(75 MHz, CDCl3) d 13.9, 14.1, 18.8, 20.9, 23.9, 25.0, 29.9, 33.2,
40.1, 43.2, 43.4, 49.6, 51.8, 52.3, 69.6, 156.5, 208.4; HRMS calcd
for C17H31NO4 (M+) 313.2253, found 313.2249.
(4RS,6S,10S)-1-Aza-4-(iodomethyl)-3-oxa-10-methyl-2-enyl-
bicyclo-[4.4.0]decan-2-one (27). Three drops of 4% OsO4 solution
were added to a solution 14 (89 mg, 0.27 mmol) in a mixture of
dioxane (2 mL) and H2O (2 mL) and the mixture was stirred at
room temperature for 10 min. NaIO4 (57 mg, 0.27 mmol) was
added to the mixture, which was stirred for 15 min. NaIO4 (57 mg,
0.27 mmol) was again added to the mixture, which was stirred for
1 h. The reaction was quenched with 10% sodium thiosulfate, and
the resulting mixture was extracted with CH2Cl2 three times. The
extracts were dried and evaporated. To a solution of the residue
(4R,6S,10S)-1-Aza-3-oxa-10-(4-oxopentyl)-4-propylbicyclo-
[4.4.0]decan-2-one (24) from 25. n-BuLi (1.6 M solution in
hexane) (1.58 mL, 2.52 mmol) was added to a solution n-PrSH
(0.27 mL, 3.03 mmol) in HMPA (1.0 mL) at 0 ◦C and the mixture
was stirred for 30 min. A solution of 22 (79 mg, 0.25 mmol) in
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[a]2D6 −26.3◦ (c 1.58, CHCl3); IR (neat) 2927, 2855, 1690, 1461,
in toluene (3 mL) was added RhCl(PPh3)3 (270 mg, 0.3 mmol).
The reaction mixture was refluxed overnight and filtered through
Celite. The filtrate was evaporated. Ethanol was added to the
residue and the mixture was filtered through Celite. The filtrate was
evaporated to leave an oil, which was purified by chromatography
using n-hexane–ethyl acetate (3 : 1) as eluent to yield 27 (39 mg,
48%) as a diasteromeric mixture; IR (neat) 2936, 1686, 1428, 1290,
1
1369 cm−1; H NMR (300 MHz, CDCl3) d 0.88 (t, J = 6.5 Hz,
3 H, –(CH2)10CH3), 1.22–126 (m, 23 H), 1.46 (s, 9 H), 1.49–1.85
(m, 6 H), 3.78–3.79 (m, 1 H, H-2R or H-6R), 3.91–3.93 (m, 1 H,
H-2R or H-6R); 13C NMR (75 MHz, CDCl3) d 13.7, 14.1, 20.8,
22.6, 23.1, 26.8, 27.1, 28.5, 29.3, 29.59, 29.63, 31.8, 34.3, 46.8,
51.6, 78.5, 155.0; HRMS calcd for C22H43NO2 (M+) 353.3294,
found 353.3306.
1
1234, 1136 cm−1; H NMR (300 MHz, CDCl3) d 1.19–1.22 (m,
3 H, –CH3), 1.38–2.2.38 (m, 8 H), 3.15–3.72 (m, 3H, H-6S, –
CH2I), 4.08–4.71 (m, 1 H, H-4), 13C NMR (75 MHz, CDCl3) d
5.34, 6.27, 15.9, 16.4, 18.1, 19.1, 29.7, 29.9, 30,8, 33.1, 33.3, 33.4,
33.6, 35.9, 44.5, 45.1, 46.3, 46.9, 47.8, 48.8, 72.3, 72.5, 73.9, 152.3;
HRMS calcd for C10H16NO2I (M+) 309.0226, found 309.0222.
(−)-Solenopsin A (6). Trifluoroacetic acid (1 mL) was added
to a solution of 29 (35 mg, 0.10 mmol) in CH2Cl2 (1 mL) and
the reaction mixture was stirred at room temperature for 2 h. The
mixture was evaporated and the residue was diluted with 2 N
NaOH. The basic solution was extracted with CH2Cl2 three times.
The extracts were dried over K2CO3 and evaporated. The residue
was purified with chromatography using CHCl3–methanol (5 : 1)
as eluent to yield 6 (21 mg, 84%) as an oil; [a]2D6 −1.3◦ (c 0.94,
CH3OH), lit.7c [a]D20 −1.3◦ (c 1.3, CH3OH); IR (neat) 2924, 2853,
tert-Butyl (2R,6S)-2-Methyl-6-(2-propenyl)piperidinecarboxy-
late (28). Zinc (55 mg, 0.842 mmol) was added to a solution
of 27 (48 mg, 0.15 mmol) in a mixture of THF (1 mL), acetic
acid (40 lL), and H2O (40 lL) at 0 ◦C. The reaction mixture was
stirred at room temperature for 5 h and filtered through Celite. 2 N
NaOH was added to the filtrate. To the basic solution was added
Boc2O (0.16 mL, 0.70 mmol). The mixture was stirred at room
temperature overnight. 20% KHSO4 was added to the reaction
mixture and the mixture was extracted with CH2Cl2 three times.
The extracts were dried and evaporated. The residue was purified
by chromatography using n-hexane–ethyl acetate (60 : 1) as eluent
to yield 28 (28 mg, 80%); [a]2D6 −24.2◦ (c 0.23, CHCl3), lit.15 [a]2D6
−24.67◦ (c 3.1, CHCl3); IR (neat) 2944, 1689, 1368, 1176 cm−1; 1H
NMR (300 MHz, CDCl3) d 1.22 (d, J = 6.6 Hz, 3 H, CH3-6S),
1.47 (s, 9 H), 1.53–1.91 (m, 6 H), 2.13–2.24 (m, 1 H), 2.42–2.47
(m, 1 H), 3.83–3.87 (m, 1 H, H-2 or H-6), 3.97 (m, 1 H, H-2 or
H-6), 5.00–5.09 (m, 2 H), 5.70–5.82 (m, 1 H); 13C NMR (75 MHz,
CDCl3) d 13.3, 21.2, 22.6, 26.8, 28.8, 39.4, 47.1, 51.2, 79.1, 116.6,
136.3, 155.2; HRMS calcd for C14H25NO2 (M+) 239.1885, found
239.1885.
1
1460 cm−1; H NMR (300 MHz, CDCl3) d 0.88 (t, J = 6.5 Hz,
3 H, –(CH2)10CH3), 1.07 (d, J = 6.5 Hz, 3 H), 1.19–1.64 (m,
26 H), 2.85–2.89 (m, 1 H, H-2R or H-6R), 3.03–3.08 (m, 1 H,
H-2R or H-6R); 13C NMR (75 Hz, CDCl3) d 14.1, 19.5, 21.2, 22.7,
26.4, 29.3, 29.6, 29.7, 30.7, 31.9, 32.9, 34.0, 45.7, 50.7.
tert-Butyl (2S,6S)-8-(2-Oxopropyl)-2-prop-2-enylpiperidine-
carboxylate (31). A suspension of PdCl2 (4 mg, 23.6 lmol)
and CuCl (23 mg, 0.23 mmol) in a solution of DMF and H2O
(7 : 1) (0.3 mL) was stirred under oxygen atmosphere at room
temperature for 1 h. A solution of 14 (79 mg, 0.24 mmol) in
DMF and H2O (7 : 1) (0.1 mL) was added to the reaction mixture.
After being stirred at room temperature overnight, the mixture was
quenched with 20% KHSO4 and extracted with ether three times.
The extracts were successively washed with saturated NaHCO3
and brine, dried, and evaporated. The residue was purified by
chromatography using n-hexane–ethyl acetate (3 : 1) as eluent to
yield 30 (71 mg, 86%). Zinc (22 mg, 0.337 mmol) was added to a
solution of 30 (66 mg, 0.19 mmol) in a mixture of THF (0.5 mL),
acetic acid (20 lL), and H2O (20 lL) at 0 ◦C and the reaction
mixture was vigorously stirred at room temperature for 1 h. The
mixture was filtered through Celite. 2 N NaOH was added to the
filtrate. The basic solution was extracted with CH2Cl2 three times.
The extracts were dried over K2CO3 and evaporated. To a solution
of the residue in THF (1 mL) and H2O (1 mL) were added K2CO3
(35 mg, 0.27 mmol) and Boc2O (79 lL, 0.34 mmol). The mixture
was stirred at room temperature overnight. 20% KHSO4 was
added to the reaction mixture and the mixture was extracted with
CH2Cl2 three times. The extracts were washed with brine, dried and
evaporated. The residue was purified by chromatography using n-
hexane–ethyl acetate (10 : 1) as eluent to yield 31 (43 mg, 81%) as
an oil; [a]2D9 +19.4◦ (c 1.07, CHCl3); IR (neat) 2942, 1687, 1389,
1253, 1172, 1116 cm−1; 1H NMR (300 MHz, CDCl3) d 1.44 (s, 9 H),
1.61–1.79 (m, 6 H), 2.16 (s, 3 H. –COCH3), 2.18–2.21 (m, 1 H),
2.24–2.48 (m, 1 H), 2.59 (dd, J = 15.9, 9.1 Hz, 1 H), 2.87–2.94 (m,
1 H), 3.86–3.88 (m, 1 H), 4.17–4.21 (m, 1 H), 4.99–5.08 (m, 2 H),
5.74–5.76 (m, 1 H); 13C NMR (75 MHz, CDCl3) d 14.3, 23.6, 25.4,
28.7, 30.4, 38.7, 47.7, 48.8, 51.9, 79.6, 116.7, 135.8, 155.0, 207.0;
HRMS calcd for C16H27NO3 (M+) 281.1991, found 281.1990.
tert-Butyl
(2R,6R)-2-Methyl-6-undecylpiperidinecarboxylate
(29). Two drops of 4% OsO4 solution were added to a solution
of 28 (49 mg, 0.21 mmol) in a mixture of dioxane (1.5 mL) and
H2O (1.5 mL) and the reaction was stirred at room temperature
for 10 min. NaIO4 (44 mg, 0.21 mmol) was added to the mixture,
which was stirred for 15 min. NaIO4 (44 mg, 0.21 mmol)
was again added to the mixture, which was stirred for 1 h.
The reaction was quenched with 10% sodium thiosulfate, and
the resulting mixture was extracted with CH2Cl2 three times.
The extracts were dried and evaporated to leave the aldehyde.
n-BuLi (0.19 mL, 0.31 mmol) was added to a mixture of
n-nonyltriphenylphosphonium bromide (193 mg, 0.41 mmol) in
THF (1.5 mL) at 0 ◦C and the mixture was stirred at the same
temperature for 30 min. A solution of the aldehyde in THF (1 mL)
was added to the mixture. After being stirred at room temperature
for 5 h, the mixture was quenched with saturated NH4Cl at 0 ◦C
and extracted with CH2Cl2 three times. The extracts were dried
and evaporated. The residue was purified by chromatography
using n-hexane–ethyl acetate (100 : 1) as eluent to yield olefin
(48 mg, 66%). A suspension of the olefin (36 mg, 0.1 mmol)
and Pd(OH)2 (10 mg) in methanol (2 mL) was stirred under a
hydrogen atmosphere at room temperature for 1 h. The mixture
was filtered through Celite and the filtrate was evaporated. The
residue was purified with chromatography using n-hexane–ethyl
acetate (100 : 1) as eluent to yield 29 (35 mg, 97%) as an oil;
tert-Butyl (2S,6S)-8-(2-Oxopropyl)-2-(4-oxobutyl)piperidine-
carboxylate (32). Two drops of 4% OsO4 solution were added
1594 | Org. Biomol. Chem., 2006, 4, 1587–1595
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to a solution of 31 (68 mg, 0.24 mmol) in a mixture of dioxane
(1.5 mL) and H2O (1.5 mL) and the mixture was stirred at
room temperature for 10 min. NaIO4 (52 mg, 0.24 mmol) was
added to the mixture, which was stirred for 15 min. NaIO4
(52 mg, 0.24 mmol) was again added to the mixture. After 1 h,
sodium thiosulfate was added, and the mixture was extracted
with CH2Cl2 three times. The extracts were dried and evaporated
to leave the aldehyde. (Triphenylphosphranylidene)acetaldehyde
(147 mg, 0.482 mmol) was added to a solution of the aldehyde
in toluene (2.5 mL.). After being refluxed for 9 h, the mixture
was evaporated. The residue was diluted with ether and the
resulting solution was filtered through Celite. The filtrated was
evaporated. The residue was purified by chromatography using
n-hexane–ethyl acetate (5 : 1) as eluent to yield a,b-unsaturated
aldehyde (45 mg, 60%). A suspension of the aldehyde (45 mg,
0.15 mmol) and Pd(OH)2 (10 mg) in ethyl acetate (2 mL) was
stirred under a hydrogen atmosphere at room temperature for
1 h. The mixture was filtered through Celite and the filtrate was
evaporated. The residue was purified by chromatography using
n-hexane–ethyl acetate (5 : 1) as eluent to yield 32 (44 mg, 98%)
as an oil; [a]2D8 +0.68◦ (c 0.98, CHCl3); IR (neat) 2935, 2865, 1717,
1685, 1367, 1252, 1171 cm−1; 1H NMR (300 MHz, CDCl3) d 1.43
(s, 9 H), 1.48–1.78 (m, 10 H), 2.15 (s, 3 H), 2.40–2.50 (m, 2 H),
2.56–2.64 (m, 1 H), 2.96–3.01 (m, 1 H), 3.88–3.91 (m, 1 H), 4.07
(m, 1 H), 9.75–9.77 (m, 1 H, –CHO); 13C NMR (75 MHz, CDCl3)
d 19.4, 22.3, 25.5, 26.8, 28.7, 30.4, 32.7, 43.8, 47.7, 48.4, 52.5, 79.6,
155.2, 202.5, 206.9; HRMS calcd for C17H29NO4 (M+) 311.2097,
found 311.2094.
istry of Education, Culture, Sports and, Sciences and Technology
of Japan.
References and notes
1 (a) G. B. Fodor and B. Colasanti, in Alkaloids: Chemical and Biological
Perspectives, ed. W. W. Pelletier, John Wiley and Sons, New York,
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and Biological Perspectives, ed. W. W. Pelletier, Elsevier, New York,
1996, vol. 10, pp. 247–255; (c) J. W. Daly, H. M. Garraffo and
T. F. Spande, in Alkaloids: Chemical and Biological Perspectives, ed.
W. W. Pelletier, Elsevier, New York, 1999,Vol. 13, pp. 92–95; (d) M.
Rubiralta, E. Giralt and A. Diez, Piperidine: Structure, Preparation,
Reactivity and Synthetic Applications of Piperidine and its Derivatives,
Elsevier: Amsterdam, 1991; (e) G. M. Struntz and J. A. Findlay, in
The Alkaloids, vol. 26, ed. A. Brossi, Academic, New York, 1985,
pp. 89–193.
2 For a recent reviews, see: (a) F.-X. Felpin and J. Lebreton, Curr. Org.
Synth., 2004, 1, 83–109; (b) S. Knauer, B. Kranke, L. Krause and H.
Kunz, Curr. Org. Chem., 2004, 8, 1739–1761; (c) S. Laschat and T.
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J.-C. Gramain and R. Remuson, Tetrahedron: Asymmetry, 2005, 16,
1025–1034; (e) C. Shu and L. S. Liebeskind, J. Am. Chem. Soc., 2003,
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3 (a) Takahata, S. Takahashi, S. Kouno and T. Momose, J. Org. Chem.,
1998, 63, 2224–2231; (b) H. Takahata, Y. Yotsui and T. Momose,
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4 H. Takahata, H. Ouchi, M. Ichinose and H. Nemoto, Org. Lett., 2002,
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Lamberton, A. Mc L. Mathieson and H. Suares, Tetrahedron Lett.,
1972, 13, 1767–1770; (b) Synthesis: M. David, H. Dhimane, C. Vanucci-
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Comins and H. Hong, J. Am. Chem. Soc., 1993, 115, 8851–8852.
6 (a) J. N. Tawara, A. Blokhin, T. A. Foderaro, F. R. Stermitz and H.
Hope, J. Org. Chem., 1993, 58, 4813–4818; (b) M. F. A. Adamo, V. K.
Aggarwal and M. A. Sage, Synth. Commun., 1999, 29, 1747–1756.
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13-Azatricyclo[7.3.1.0ꢀ5,13ꢁ]tridecan-3-one (33). Trifluoro-
acetic acid (1.5 mL) was added to a solution of 32 (62 mg,
0.20 mmol) in CH2Cl2 (1.5 mL) and the reaction mixture was
stirred at room temperature for 1 h. The mixture was evaporated
and the residue was diluted with saturated NaHCO3. The
resulting basic solution was extracted with CH2Cl2 three times.
The extracts were dried and evaporated. A mixture of the residue
and CSA (139 mg, 0.60 mmol) in toluene (9 mL) was refluxed for
2 h. Saturated NaHCO3 was added to the mixture. The mixture
was extracted with CH2Cl2 three times. The extracts dried and
evaporated. The residue was purified by chromatography using
CHCl3–methanol (30 : 1) as eluent to ◦yield 33 (20 mg, 52%) as
8 (a) C. Yue, F. Nicolay, J. Royer and H. P. Husson, Tetrahedron, 1994,
50, 3139–3148; (b) R. V. Stevens and A. W. M. Lee, J. Am. Chem. Soc.,
1979, 101, 7032–7035.
9 V. P. Ramachandran, G.-M. Chen and H. C. Brown, Tetrahedron Lett.,
1997, 38, 2417–2420. Brownreported a double asymmetric allylboration
of gultaldehyde to provide C2-symmetric 1,5-diol in 90% de and >98%
ee.
10 All attempts such as hydroboration, dihydroxylation, and the
Wacker oxidation of 1 non-selectively resulted in mono- and di-
functionalization and recovery of starting material 1.
11 S. Raucher, B. L. Bray and R. F. Lawrence, J. Am. Chem. Soc., 1987,
109, 442–446.
◦
a solid; mp. 80–81 C, lit.8a mp. 81–83 C; IR (KBr) 2931, 2866,
1708, 1435, 1336, 1253 cm−1; 1H NMR (300 MHz, CDCl3) d
1.19–2.05 (m, 14 H), 2.79 (t, J = 13.1 Hz, 3 H), 3.24 (br d, J =
12.4 Hz, 2 H); 13C NMR (75 MHz, CDCl3) d 19.2, 30.1, 34.1, 40.7,
48.4, 58.9, 211.1; HRMS calcd for C12H19NO (M+) 193.1467,
found 193.1460.
12 H. Zhao and A. Thurkauf, SYNLETT, 1999, 1280–1282. This paper
described an unexpected intramolecular cyclization by treatment of N-
butoxycarbonyl b-amino alcohols with diethylaminosulfur trifluoride
occurred to provide the oxazolidinone.
13 E. J. Corey, L. O. Weigel, D. Floyd and M. G. Bock, J. Am. Chem. Soc.,
1978, 100, 2916–2918.
Acknowledgements
14 The use of EtOH in place of 2-propanol as a solvent resulted in the
recovery of the starting material 15.
This work was supported in part by a Grant-in-Aids for High
Technology Research Program and Scientific Research from Min-
15 H. Takahata, M. Kubota, S. Takahashi and T. Momose, Tetrahedron:
Asymmetry, 1996, 7, 3047–3054.
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The Royal Society of Chemistry 2006
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