Stereoselective synthesis of (-)-pinidinone

Article abstract of DOI:10.1002/hlca.201200338

A simple and efficient stereoselective linear approach to the total synthesis of (-)-pinidinone has been accomplished starting from propane-1,3-diol, and employing Maruoka asymmetric allylation and Grubbs' olefin cross-metathesis as the key steps. Copyright

Full text of DOI:10.1002/hlca.201200338

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Helvetica Chimica Acta – Vol. 96 (2013)
Stereoselective Synthesis of (ꢀ)-Pinidinone
by Gundeti Shankaraiah, Tiruvayamudi Vijaya Kumar, Guvvala Venkateswara Reddy,
Janaswamy Madhusudana Rao, and Katragadda Suresh Babu*
Division of Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Uppal Road,
Hyderabad 500607, India
A simple and efficient stereoselective linear approach to the total synthesis of (ꢀ)-pinidinone has
been accomplished starting from propane-1,3-diol, and employing Maruoka asymmetric allylation and
Grubbsꢀ olefin cross-metathesis as the key steps.
Introduction. – N-Containing heterocyclic compounds are widespread in medicinal
chemistry due to the fact that many natural and synthetic biologically active
compounds share this common architectural feature. Many of the alkaloids possess
potent and therapeutically interesting biological activities, which has led to their use as
drug candidates or as lead compounds in drug discovery [1]. Among them, 6-alkyl-2-
methylpiperidine alkaloids are prominent examples that have extensively been used as
building blocks for the synthesis of biologically active natural products [2]. In fact, the
natural alkaloids, structurally related to 2,6-disubstituted piperidines, have different
biosynthetic origins, and the stereogenic center adjacent to the N-atom can have
different configurations. Representative examples are (ꢀ)-pinidinone (1), dihydropi-
nidine (2), isosolenopsins 3, and structurally related cis-6-alkylpipecolic acids (4; Fig.).
Figure. Some naturally occurring 2,6-disubstituted piperidine alkaloids
In this class, (ꢀ)-pinidinone (1) that contains a 2,6-disubstituted piperidine skeleton
and was isolated from the needles of the Colorado blue spruce (Picea pungens En-
gelm.) was also found in the hemolymph of the Australian mealybug (Cryptolaemus
montrouzieri Mulsant), as well as the Mexican bean beetle (Epilachna varivestis
Mulsant) [3]. It was reported that (ꢀ)-pinidinone (1) serves as defensive alkaloid
because of its potent antifeedant activity against worms (Picea), ants, and spiders
(beetles) [4a]. Due to its biological importance and scarce availability from natural
sources, much effort has been devoted to the development of general methodologies
and diverse approaches for its synthesis. In this context, during the past few years, three
ꢁ 2013 Verlag Helvetica Chimica Acta AG, Zꢂrich

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991
syntheses of (ꢀ)-pinidinone were published [4a – 4c], as well as the synthesis of its
enantiomer (þ)-pinidinone [4d]. Despite reported methods, new general, efficient, and
scalable methods to access the target compounds are still highly desirable to expand the
synthetic utility of these versatile building blocks.
Among the various possible methods that allow the formation of a piperidine ring,
the intramolecular nucleophilic displacement of an activated alcohol moiety (e.g.,
tosylate, mesylate, or triflate) by an amine group is one of the most useful and reliable
ones [5]. During the past ten years, the ring-closing metathesis (RCM) reaction has
emerged as one of the most powerful synthetic tools in organic synthesis for the
preparation of both carbo- and heterocyclic ring systems [6]. It is primarily due to the
ready availability of many metathetic catalysts such as Grubbsꢀ first- [7] and second-
generation catalyst [8], Hoveydaꢀs catalyst [9], etc., and also due to their high level of
functional group tolerance. Furthermore, piperidine rings can also be constructed from
allylamines, using either chiral pool-derived cyclization precursors or stereoselective
CꢀN-bond formation such as azidization reaction, followed by the reduction of alcohols
of the appropriate configuration.
Our retrosynthetic analysis of 1 is outlined in Scheme 1. As indicated, the piperidine
framework could be constructed by reductive cyclization of 5. We then anticipated that
the olefin cross-metathesis precursors 6 and 7 would be potential and versatile
intermediates, which can be accessed from propane-1,3-diol in a three-step sequence.
The stereogenic centers C(2) and C(6) in 1 could be controlled through enantiose-
lective allylations of aldehydes. More importantly, we have successfully implemented a
strategy that minimizes protecting-group manipulation in a unique fashion, a common
and unavoidable practice in (ꢀ)-pinidinone (1) synthesis.
Scheme 1
Results and Discussion. – In our work directed towards the expedient synthesis of
polysubstituted piperidines starting from cheap and readily available starting materials,
we have recently shown that asymmetric Marouka allylation of aldehydes by the binol
complexes (R,R)-I or (S,S)-I, one-pot reductive amination, followed by the diaster-
eoselective cyclization, appear to be the method of choice for obtaining amines of high
enantiomeric excess [10]. With these considerations, as well as in continuation of our
interest in the synthesis of bioactive alkaloids, herein, we report the stereoselective
synthesis of (ꢀ)-pinidinone utilizing the Marouka allylation in combination with
Grubbsꢀ cross-metathesis as key reaction sequence.

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Helvetica Chimica Acta – Vol. 96 (2013)
Our synthetic endeavours commenced with selective protection of propane-1,3-diol
(10) as 4-methoxybenzyl (PMB) ether using PMB-Br and NaH in dry THF to give 11
[11] in 95% yield (Scheme 2). O-Iodoxybenzoic acid [12] oxidation of 11, followed by
an enantioselective Maruoka allylation using titanium complex (S,S)-I and allyl(tri-
butyl)tin furnished the homoallylic alcohol 9 [10c][13] in 84% yield with excellent
enantioselectivity of 98% ee (determined by chiral HPLC)1). The resulting
homoallylic alcohol was orthogonally protected as its tosyl ester 12 with TsCl in
pyridine/CH2Cl2 1:1 in 92% yield [14]. The treatment of 12 with NaN3 in DMF at 708
[14] afforded azido compound 13 in excellent yield. Then, oxidative removal [15] of the
PMB group by using DDQ in CH2Cl2/H2O 9 :1 provided the primary alcohol 8 in 90%
yield. Subsequent oxidation of 8 by DessꢀMartin periodinane [16] in CH2Cl2 gave an
aldehyde in quantitative yield, which was further treated with MeMgI [17] in Et2O to
afford the secondary alcohol 14 as 1:1 diastereoisomer mixture in 85% yield.
Scheme 2
a) NaH, 4-Methoxybenzyl bromide, Bu4NþIꢀ, THF, 08 – r.t., 5 h; 95%. b) i) O-Iodoxybenzoic acid,
DMSO, THF, r.t., 3 h; ii) (S,S)-I (10 mol-%), Bu3SnCH2CH¼CH2, CH2Cl2, ꢀ 158 – to 08, 24 h; 84%. c)
TsCl, Pyridine/CH2Cl2 1:1, 08 – r.t., 6 h; 92%. d) NaN3, DMF, 708, 3 h; 79%. e) DDQ (¼2,3-Dichloro-
5,6-dicyano-1,4-benzoquinone), CH2Cl2/H2O 9 :1, 08 – r.t., 1 h; 90%. f) i) DessꢀMartin periodinane,
CH2Cl2, 08, 2 h; ii) MeMgI, Et2O, 08 – r.t., 30 min; 85%. g) LiAlH4, THF, 08 – r.t., 1 h then sat. NaHCO3,
Cbz-Cl (¼ benzyloxycarbonyl chloride), 90%. h) DessꢀMartin periodinane, CH2Cl2, 08, 1 h; 90%. i)
Methyl vinyl ketone (7), Grubbsꢀ second generation catalyst (5 mol-%), CH2Cl2, 408, 1 h; 90%. j) Pd/C
(10%), H2 (ballon), AcOEt, 12 h; 72%.
1
)
The enantioselectivity was determined by HPLC (Waters Atlantis dC18; 150 ꢁ 4.6 mm, 5 mm, 220 nm;
eluent, MeCN/H2O 7:3, 10 ml injection volume; flow rate, 1 ml/min; tR 6.012 min).

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993
Reduction of the azide function in 14 using LiAlH4 in dry THF to give the amine [18],
followed by addition of saturated aqueous NaHCO3 and Cbz-Cl afforded the Cbz-
protected amine 15 in 90% yield. Then, the oxidation of the secondary alcohol with
DessꢀMartin periodinane provided the oxo derivative 6 in 90% yield.
Having successfully accomplished the synthesis of intermediate 6, we then shifted
our focus to conjunction of precursors 6 with methyl vinyl ketone (7) via olefin cross-
metathesis reaction. Thus, we submitted 6 and 7 to 10 mol-% of Grubbsꢀ second-
generation catalyst in refluxing CH2Cl2 [19]. As anticipated, the reaction proceeded
smoothly to afford 5 in excellent yield as a colorless crystalline solid. As premediated,
the cross-metathesis product 5 was subjected to the one-pot reductive amination,
followed by diastereoselective cyclization [20] using Pd/C (10%) to afford (ꢀ)-
pinidinone (1) in good yield. The latter was isolated and characterized as a yellow oil.
All the intermediate compounds including the (ꢀ)-pinidinone (1) were fully
characterized by means of IR, 1H- and 13C-NMR, and mass spectral data. Furthermore,
chiroptical data obtained were in complete agreement with the data reported in
literature [4a – 4c] (see Exper. Part).
Conclusions. – we have developed an efficient stereoselective protocol for the
synthesis of (ꢀ)-pinidinone (1) by employing Maruoka asymmetric allylation, Grubbsꢀ
cross-metathesis reaction, and reductive cyclization as the key reaction steps. The
presented synthetic method could be of value in the development of novel 2,6-
disubstituted piperidine-based analogues.
The authors gratefully acknowledge keen interest shown by Dr. J. S. Yadav, Director, IICT,
Hyderabad. T. V. K. and G. V. R. thank CSIR and UGC, New Delhi for financial support.
Experimental Part
General. All the reagents and solvents were reagent-grade and used without further purification
unless specified otherwise. Technical-grade AcOEt and hexanes used for column chromatography (CC)
were distilled prior to use. All the reactions were performed under N2 in flame-dried or oven-dried
glassware with magnetic stirring. The progress of the reactions was monitored by anal. TLC performed on
Merck SiO2 60 F254 plates. Flash column chromatography (FC): silica gel (SiO2; 60 – 120 mesh, unless
stated otherwise) packed in glass columns. M.p.: Bꢀchi B-545; uncorrected. Optical rotation: JASCO
DIP 300 digital polarimeter at 258 in CHCl3 or MeOH. FT-IR Spectra: Nexus FT-IR spectrometer; in
1
KBr or neat; ˜n in cmꢀ1. H- and 13C-NMR spectra: Bruker spectrometers, at 300 or 75 MHz, resp., in
CDCl3 solvent; d in ppm rel. to Me4Si as internal standard, J in Hz. LR- and HR-MS: JEOL LCmate mass
spectrometer; in m/z.
3-[(4-Methoxybenzyl)oxy]propan-1-ol (11) [11b]. To a suspension of NaH (1.21 g, 52.6 mmol) in
THF (20 ml) was added dropwise propane-1,3-diol (10; 2 g, 26.3 mmol) at 08 under inert atmosphere.
After 1 h, Bu4NþIꢀ (cat. amount) was added, followed by the addition of 4-methoxybenzyl bromide
(PMB-Br; 5.76 g, 28.9 mmol). The mixture was further stirred for 4 h at r.t. After completion (of the
reaction TLC), the mixture was diluted with H2O and extracted with AcOEt (3 ꢁ 20 ml). The combined
org. layers were separated, washed with brine, and dried (Na2SO4). The solvent was evaporated to
dryness to afford crude product, which was purified by FC (SiO2 (100 – 200 mesh); hexane/AcOEt 7:3)
to give 11 (5.3 g, 95%). Colorless liquid. IR (KBr): 3407, 2937, 2864, 1610, 1513, 1248, 1088, 820, 772.
1H-NMR: 7.20 (d, J ¼ 8.8, 2 H); 6.82 (d, J ¼ 7.9, 2 H); 4.42 (s, 2 H); 3.7 (s, 3 H); 3.72 (t, J ¼ 10.8, 2 H); 3.60
(t, J ¼ 11.8, 2 H); 1.84 – 1.79 (m, 2 H). 13C-NMR: 159.2; 129.9; 129.3; 113.8; 72.7; 68.3; 61.1; 55.0; 32.0.
ESI-MS: 219 ([M þ Na]þ).

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(3S)-1-[(4-Methoxybenzyl)oxy]hex-5-en-3-ol (9) [13b]. i) To a stirred soln. of O-iodoxybenzoic acid
(8.6 g, 30.6 mmol) in dry DMSO (8 ml) was added a soln. of 11 (3 g, 13.1 mmol) in dry THF (50 ml) at
r.t., and the mixture was stirred for 30 min. The reaction was quenched with Et2O (5 ml), and the mixture
was extracted with Et2O (3 ꢁ 20 ml). The org. layer was separated, washed with aq. sat. NaHCO3, and
dried (Na2SO4). The solvent was removed under vacuum. The crude product was purified by FC (SiO2;
hexane/AcOEt 9 :1) to give a yellow liquid in 90% yield (2.96 g), which was used for the next step
without purification.
ii) To a stirred soln. of 1m TiCl4 in CH2Cl2 (0.76 ml, 0.76 mmol) in CH2Cl2 (20 ml) was added dried
(iPrO)4Ti (0.67 ml, 2.28 mmol) at 08 under N2. The soln. was allowed to warm to r.t. After 1 h, Ag2O
(353 mg, 1.52 mmol) was added at r.t., and the mixture was stirred for 5 h under exclusion of direct light.
The mixture was diluted with CH2Cl2 (10 ml) and treated with (S)-binaphthol (872 mg, 3.05 mmol) at r.t.
for 2 h to furnish chiral bis-TiIV oxide (S,S)-I. The in situ generated (S,S)-I was cooled to ꢀ 208 and
treated sequentially with above aldehyde (2.96 g, 15.2 mmol) and allyl(tributyl)tin (5.14 ml, 16.78 mmol)
at ꢀ 208. The mixture was stirred for 30 min and then placed into freezer (ꢀ208) for 18 h. The mixture
was allowed to warm to 08, the reaction was quenched with aq. sat. NaHCO3 (5 ml), and the mixture
extracted with CH2Cl2 (2 ꢁ 20). The solvent was evaporated to dryness to afford crude product, which
was purified by FC (SiO2; hexane/AcOEt 8 :2) to give 9 (84%). Pale-yellow liquid. The enantiomeric
purity of the product was determined to be 98% ee by anal. HPLC analysis. [a]2D5 ¼ ꢀ5.9 (c ¼ 1.0, CHCl3).
(3S)-1-[(4-Methoxybenzyl)oxy]hex-5-en-3-yl 4-Methylbenzenesulfonate (12). To a stirred soln. of 9
(2 g, 8.47 mmol) in dry CH2Cl2 and pyridine 1:1 (20 ml) at 08 was added TsCl (2 equiv., 3.2 g, 16.9 mmol).
The mixture was stirred for 12 h at r.t. The reaction was quenched with aq. sat. CuSO4 (5 ml), and the
mixture was diluted with H2O, and the org. layer was extracted with CH2Cl2 (3 ꢁ 10 ml). The solvent was
removed under vacuum. The crude product was purified by FC (SiO2; hexane/AcOEt 8 :2) to give 12
(92%). Yellow liquid. [a]2D5 ¼ þ12 (c ¼ 1.0, CHCl3). IR (KBr): 2923, 2854, 1611, 1513, 1360, 1247, 1175,
1
1095, 817. H-NMR: 7.76 (d, J ¼ 8.3, 1 H); 7.31 – 7.14 (m, 5 H); 6.83 (m, 3 H); 5.71 – 5.55 (m, 1 H); 5.01
(m, 1 H); 4.83 – 4.75 (m, 1 H); 4.43 (s, 2 H); 3.79 (s, 3 H); 3.74 (t, J ¼ 12.0, 2 H); 2.67 – 2.60 (m, 2 H); 2.43
(s, 3 H); 2.40 – 2.29 (m, 1 H); 1.86 (q, J ¼ 18.8, 1 H). 13C-NMR: 159.1; 144.2; 134.6; 132.0; 129.6; 129.2;
129.1; 127.8; 118.2; 113.8; 113.7; 72.5; 65.3; 63.5; 55.1; 39.1; 34.0; 21.5. HR-MS: 413.1393 ([M þ Na]þ,
C12H26O5Sþ; calc. 413.1399).
1-({[(3R)-3-Azidohex-5-en-1-yl]oxy}methyl)-4-methoxybenzene (13). To a soln. of 12 (2 g,
5.12 mmol) in dry DMF (20 ml) were added 5 equiv. of NaN3 (1.6 g) portionwise at 708, and this
mixture was stirred for 6 h. After consumption of starting material (monitored by TLC), the mixture was
diluted with H2O and then extracted with AcOEt (3 ꢁ 30 ml). The org. layer was further washed with aq.
sat. NaHCO3 and aq. sat. NaCl, and dried (Na2SO4). The solvent was removed under vacuum. The crude
product was purified by FC (SiO2; hexane/AcOEt 9 :1) to give 13 (79%). Pale-yellow liquid. [a]2D5 ¼ ꢀ38
(c ¼ 1.0, CHCl3). IR (KBr): 2923, 2855, 2100, 1513, 1248, 772. 1H-NMR: 7.20 (d, J ¼ 8.3, 2 H); 6.82 (d, J ¼
9.0, 2 H); 5.88 – 5.72 (m, 1 H); 5.17 – 5.07 (m, 2 H); 4.41 (s, 2 H); 3.80 (s, 3 H); 3.65 – 3.46 (m, 3 H); 2.32 –
2.25 (m, 2 H); 1.88 – 1.76 (m, 1 H); 1.68 – 1.56 (m, 1 H). 13C-NMR: 159.5; 133.7; 130.2; 129.2; 118.3; 113.7;
72.9; 66.3; 59.1; 55.3; 55.1; 39.3; 34.1. HR-MS: 284.1369 ([M þ Na]þ, C14H19N3O2þ ; calc. 284.1371).
(3R)-3-Azidohex-5-en-1-ol (8). To a soln. of 13 (1 g, 3.83 mmol) in CH2Cl2/H2O 9 :1 (10 ml) was
added DDQ (0.952 g, 4.21 mmol) at 08. After stirring for 1 h, the mixture was filtered off, and the filtrate
was washed with 5% NaHCO3 soln. and brine, and dried (Na2SO4). The combined org. layers were
evaporated to dryness to afford crude product, which was purified by FC to give 8 (80%). [a]2D5 ¼ ꢀ113
1
(c ¼ 1.0, CHCl3). IR (KBr): 3457, 2923, 2853, 2098, 1462. H-NMR: 5.89 – 5.72 (m, 1 H); 5.22 – 5.14 (m,
2 H); 3.78 (t, J ¼ 10.9, 2 H); 3.64 – 3.53 (m, 1 H); 2.47 (m, 2 H); 1.84 – 172 (m, 1 H); 1.70 – 1.52 (m, 1 H).
13C-NMR: 133.6; 118.9; 59.8; 59.1; 39.1; 36.2. EI-MS: 141 (Mþ).
(4R)-4-Azidohept-6-en-2-ol (14). i) To a soln. of 8 (0.500 g, 3.546 mmol) in 15 ml of CH2Cl2 at 08
were added NaHCO3 (1.489 g, 17.73 mmol) and DessꢀMartin periodinane (3 g, 7.09 mmol). The mixture
was stirred at 08 for 2 h, and then ca. 10 ml of a 5 :1 aq. sat. NaHCO3 and aq. sat. Na2S2O3 soln. were
added. The mixture was diluted with Et2O and stirred at r.t. until separation of the layers (45 min). The
mixture was extracted with Et2O (2 ꢁ 20 ml), and the combined org. layers were washed with cold 1m
NaHSO4 and dried (anh. Na2SO4). The solvent was removed under vacuum to obtain the crude aldehyde
which was used for the next step without purification.

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ii) In a 100-ml two-neck round-bottom flask 0.34 g (14.1 mmol), activated Mg was taken in dry Et2O
(5 ml), and MeI (0.8 ml, 14.18 mmol) was added, and the mixture was stirred for 30 min at r.t. After
keeping this mixture at 08, and the above crude aldehyde was added, the reaction was monitored by TLC.
The reaction was quenched with aq. sat. NH4Cl (3 ml), and the mixture was diluted with H2O and
extracted with AcOEt (2 ꢁ 20 ml). The solvent was removed under vacuum. The crude product was
purified by FC (SiO2; hexane/AcOEt 8 :2) to give 6 (85%). Yellow liquid. [a]2D5 ¼ ꢀ86 (c ¼ 1.0, CHCl3).
IR (KBr): 3381, 2923, 2854, 2106, 1460, 1254. 1H-NMR: 5.88 – 5.74 (m, 1 H); 5.15 (m, 2 H), 4.03 (m, 1 H);
3.72 – 3.47 (m, 1 H); 2.41 – 2.27 (m, 2 H); 1.65 – 1.41 (m, 2 H); 1.23 (d, J ¼ 6.0, 3 H). 13C-NMR: 133.8;
118.9; 64.5; 59.2; 42.9; 38.6; 24.2. EI-MS: 155 (Mþ).
Benzyl [(4R)-6-Hydroxyhept-1-en-4-yl]carbamate (15). Into a oven-dried 100-ml two-neck round-
bottom flask, 2 equiv. of LiAlH4 (0.092 g) were placed. To this ash-colored solid in dry THF (5 ml) was
added a soln. of 14 (0.3 g, 1.9 mmol in dry THF (5 ml) over a period of 5 min at 08. After stirring for 1 h,
and reaction was quenched with aq. sat. NaHCO3 (5 ml) soln. at 08, 2 equiv. of Cbz-Cl (0.55 ml,
3.8 mmol) were added, and the mixture was stirred for 1 h. Then, the mixture was diluted with H2O and
extracted with AcOEt. The org. layer was washed with brine soln., dried (Na2SO4), and concentrated to
obtain the crude product, which was purified by FC (SiO2; hexane/AcOEt 7:3) to give 15 (0.330 g; 90%).
Yellow liquid. [a]D25 ¼ ꢀ30 (c ¼ 1.0, CHCl3). IR (KBr): 3325, 2965, 2925, 1694, 1534, 1262, 1074, 697.
1H-NMR: 7.36 – 7.25 (m, 5 H); 5.84 – 5.66 (m, 1 H); 5.10 (m, 4 H); 3.98 – 3.65 (m, 2 H); 2.28 – 2.14 (m,
2 H); 1.50 (m, 1 H); 1.32 (m, 1 H); 1.13 (d, J ¼ 6.0, 3 H). 13C-NMR: 157.2; 136.4; 134.1; 128.5; 128.1;
118.2; 66.9; 63.4; 47.7; 45.1; 39.6; 22.9. HR- MS: 286.1413 ([M þ Na]þ, C15H21NO3þ ; calc. 286.1411).
Benzyl [(4R)-6-Oxohept-1-en-4-yl]carbamate (6). To a soln. of 15 (0.200 g, 0.760 mmol) in 10 ml of
CH2Cl2 were added NaHCO3 (0.319 g, 3.802 mmol) and DessꢀMartin periodinane (0.644, 1.520 mmol) at
08. The mixture was stirred at 08 for 1 h, and then ca. 5 ml of a 5 :1 mixture of aq. sat. NaHCO3 and aq. sat.
Na2S2O3 soln. were added. The mixture was diluted with Et2O and stirred at r.t. until separation of the
layers (30 min). The mixture was extracted three times with Et2O, and the combined org. layers were
washed with cold 1m NaHSO4 and dried (anh. Na2SO4). The solvent was removed under vacuum. The
crude product was purified by FC (SiO2; hexane/AcOEt 8 :2) to give 6 (90%). White solid. M.p. 66 – 688.
1
[a]2D5 ¼ ꢀ25.8 (c ¼ 1.0, CHCl3). IR (KBr): 2922, 2953, 1699, 1532, 1259, 738. H-NMR: 7.35 – 7.21 (m,
5 H); 5.79 – 5.62 (m, 1 H); 5.21 – 4.99 (m, 4 H); 3.95 (m, 1 H); 2.78 – 2.53 (m, 2 H); 2.39 – 2.26 (m, 2 H);
2.12 (s, 3 H). 13C-NMR: 206.7; 155.6; 136.6; 134.2; 128.5; 128.0; 118.3; 66.6; 47.5; 46.4; 38.6; 30.4. HR-MS:
262.1148 ([M þ H]þ, C15H19NOþ3 ; calc. 262.1438).
Benzyl [(4R,6E)-2,8-Dioxonon-6-en-4-yl]carbamate (5). In a two-neck flask equipped with N2 inlet,
a magnetic stirring bar, and a rubber septum, was placed Grubbsꢀ second-generation catalyst (0.016 g,
5 mol-%). A soln. of 6 (0.1 g, 0.386 mmol) and methyl vinyl ketone (0.081 g, 1.158 mmol) in CH2Cl2
(2 ml) were introduced at 408, and the resulting pink soln. was stirred for 1 h. When TLC analysis
indicated complete consumption of 6, the mixture was exposed to air and concentrated to give the crude
product, which was purified by FC (SiO2; hexane/AcOEt 6 :4) to give 5 (90%). Brown solid. M.p. 73 –
758. [a]2D5 ¼ ꢀ8.5 (c ¼ 1.0, CHCl3). IR (KBr): 2925, 2854, 1711, 1533, 1257, 741. 1H-NMR: 7.34 – 7.21 (m,
5 H); 6.74 – 6.58 (m, 1 H); 6.03 (d, J ¼ 16.6, 1 H); 5.03 (s, 2 H); 4.13 – 3.93 (m, 1 H); 2.77 – 2.34 (m, 4 H);
2.14 (s, 3 H); 2.10 (s, 3 H). 13C-NMR: 206.6; 197.7; 155.7; 142.9; 136.3; 133.5; 128.4; 128.0; 127.9; 66.6;
47.7; 46.8; 37.5; 30.4; 26.8. HR-MS: 326.1124 ([M þ Na]þ, C17H21NO4þ ; calc. 326.1363).
1-[(2R,6R)-6-Methylpiperidin-2-yl]propan-2-one (¼(ꢀ)-Pinidinone; 1). To a stirred soln. of
5
(0.050 g) in AcOEt (5 ml) was added 10% Pd/C, and hydrogenation was performed under 1 atm pressure
of H2 at r.t. for 12 h. The mixture was filtered through Celite, and the filtrate was concentrated to obtain
the crude product, which was purified by FC (SiO2; CH2Cl2/MeOH 8 :2) to give 1 (72%). Yellow oil.
[a]2D5 ¼ ꢀ3.6 (c ¼ 0.5, MeOH). IR (KBr): 3397, 2925, 2853, 1744, 1459, 1383, 1219. 1H-NMR: 3.94 – 3.83
(m, 1 H); 3.45 – 3.38 (m, 1 H); 2.79 (d, J ¼ 6.0, 2 H); 2.09 (s, 3 H); 1.72 – 1.45 (m, 4 H); 1.36 – 1.28 (m,
2 H); 1.11 (d, J ¼ 2.0, 3 H). 13C-NMR: 206.8; 55.1; 54.6; 54.3; 31.5; 30.1; 29.2; 23.5; 19.8. EI-MS: 155
(Mþ).

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Received July 2, 2012