Synthesis of (-)-pinidinone

Article abstract of DOI:10.1016/j.tetlet.2010.10.049

The diastereoselective PdCl₂/CuCl₂-catalysed intramolecular methoxyaminocarbonylation of N-benzyl protected alkenyl amine 4 was used as a key step in the total synthesis of the naturally occurring piperidine alkaloid (-)-pinidinone.

Full text of DOI:10.1016/j.tetlet.2010.10.049

Tetrahedron Letters 51 (2010) 6611–6614
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of (ꢀ)-pinidinone
a
b
a
a,
⇑
ˇ
Kristína Csatayová , Ivan Špánik , Veronika Durišová , Peter Szolcsányi
a Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, SK-812 37 Bratislava, Slovakia
b Department of Analytical Chemistry, Slovak University of Technology, Radlinského 9, SK-812 37 Bratislava, Slovakia
a r t i c l e i n f o
a b s t r a c t
Article history:
The diastereoselective PdCl2/CuCl2-catalysed intramolecular methoxyaminocarbonylation of N-benzyl
protected alkenyl amine 4 was used as a key step in the total synthesis of the naturally occurring piper-
idine alkaloid (ꢀ)-pinidinone. Commercially available (S)-propylene oxide was employed as starting
material, delivering the key substrate 4 in three steps and 68% overall yield. Subsequently, the influence
of various reaction parameters on the diastereoselectivity of the key cyclisation of 4 was scrutinised. Cop-
per(II) chloride proved to be the optimum reagent and/or co-catalyst for the successful aminocyclisation-
methoxycarbonylation tandem transformation of alkenyl amine 4 into the desired methyl esters 3 and 8.
The latter were subsequently transformed into the title natural product.
Received 10 September 2010
Revised 29 September 2010
Accepted 8 October 2010
Available online 14 October 2010
Keywords:
Palladium
Natural products
Heterogenous catalysis
Piperidines
Ó 2010 Elsevier Ltd. All rights reserved.
Diastereoselectivity
(ꢀ)-Pinidinone [(2R,6R)-1-(6-methyl-piperidin-2-yl)-propan-2-
one] (1) (Scheme 1) is a naturally occurring alkaloid isolated1a from
the needles of the Colorado blue spruce (Picea pungens Engelm.)
and its biosynthesis has been proposed.1b It was also found in
the hemolymph of the Australian mealybug ladybird1c (Cryptolae-
mus montrouzieri Mulsant) as well as the Mexican bean beetle1d
(Epilachna varivestis Mulsant). It is thought that (ꢀ)-pinidinone
(1) serves as an antifeedant and/or defensive alkaloid against
worms (spruce) and/or ants and spiders (beetles). To the best of
our knowledge, there are only two non-racemic1a,2 total syntheses
of 1 to date.
With the desired substrate 4 in hand, it was first subjected to
the Pd(II)-catalysed methoxyaminocarbonylation under standard
catalytic conditions in anhydrous MeOH. We obtained a diastereo-
meric mixture of easily separable piperidines 3 and 8 in the ratio
83/17 in 58% combined isolated yield (Scheme 3).
O
O
N
H
N
O
Bn
In the frame of our research programme aimed at the applica-
tion of novel palladium-catalysed aminocyclisations in the total
synthesis of alkaloids,3 we decided to apply Pd(II)-catalysed meth-
oxyaminocarbonylation4 as the key step in the synthesis of 1. Our
retrosynthetic analysis led, via the corresponding esters 3 and/or 8,
to the alkenyl amine 4 as a key substrate. This olefin could be pre-
pared from the secondary alcohol 5 which, in turn, is obtained from
commercially available (S)-propylene oxide (6) (Scheme 1).
The synthesis of 1 began from the enantiomerically pure epox-
ide 6 which underwent highly regioselective ring-opening5 with
butenylmagnesium bromide in the presence of a catalytic amount
of freshly prepared Li2CuCl4 to furnish (2S)-hept-6-en-2-ol (5) in
88% yield. Activation6 of the hydroxy group followed by treatment
of the resulting crude tosylate 7 with excess benzylamine gave, in
77% yield, the desired (R)-N-benzyl-(1-methyl-hex-5-enyl) amine
(4) over two steps (Scheme 2).
1
3/8
O
NH
Bn
OH
4
5
6
Scheme 1. Retrosynthetic analysis of (ꢀ)-pinidinone (1).
a
b
c
OH
OTs
O
NH
Bn
6
5
7
4
Scheme 2. Reagents and conditions: (a) Li2CuCl4 (10 mol %), THF, ꢀ30 °C; buten-
ylmagnesium bromide, 35 min, 88%; (b) TsCl (2 equiv), pyridine (1.9 equiv), CH2Cl2,
0 °C, 18 h, 90% (crude); (c) BnNH2 (3 equiv), THF, reflux, 36 h, 86%.
⇑
Corresponding author. Tel.: +421 2 5932 5162; fax: +421 2 5249 5381.
E-mail address: peter.szolcsanyi@stuba.sk (P. Szolcsányi).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.049

6612
K. Csatayová et al. / Tetrahedron Letters 51 (2010) 6611–6614
yield (entry 9). This observation points to the dual role of CuCl2 in
a
the catalytic system being not only a re-oxidant but also an effi-
cient co-catalyst. The use of aprotic co-solvents (THF, MeCN and/
or 1,4-dioxane) along with MeOH (as the external nucleophile)
maintained the good level of both yield and dr (entries 13–15).
The best diastereoselectivity (80% dr.) was obtained with catalytic
amounts of both PdCl2 and CuCl2 under 1 atm of CO/O2 (ca. 1:1)
using oxygen as the terminal oxidant in pure MeOH (entry 16),
while the solvent mixtures performed less well (entries 17–21).
Finally, changing CuCl2 to either Cu(OAc)2 or benzoquinone as
re-oxidants furnished either a complex reaction mixture (entry
22) or undesired products (entries 23 and 24). Considering this
along with the previous result (entry 9), the indispensable role of
CuCl2 as co-catalyst in this particular transformation is clear. How-
ever, the exact structure of the true catalytic species involved in
our Pd(II)/CuCl2-catalysed cyclisation-methoxyaminocarbonyla-
tion of 4 remains elusive. We assume that due to the metal compo-
sition under the optimal reaction conditions, it inevitably should
be of a heterobimetallic nature. Such Pd/Cu-complexes in similar
transformations involving both palladium and copper salts have
been proposed and/or isolated and characterised.8
The preferential formation of the thermodynamically less stable
product 3 in all cases is noteworthy, and as such, represents one of
only a few examples where the 2,6-trans-configured piperidine
having an ester group in the b-position is formed predominately.9
This is even more interesting considering the known fact that in
protic media, including MeOH, similar compounds possessing a
carbonyl-functionality may easily epimerise to their more stable
cis-configured counterparts.10 In order to assess the origin of the
experimentally determined diastereoselectivities, we performed
control experiments to test the possible epimerisation of 3 in meth-
anol via a retro-aza-Michael addition type mechanism (Scheme 4).
+
CO2Me
CO2Me
NH
Bn
N
N
Bn
Bn
4
3
8
Scheme 3. Reagents and conditions: (a) CO (1 atm), PdCl2 (10 mol %), CuCl2
(3 equiv), AcONa (3 equiv), MeOH, 22 °C, 4 d, 3/8 (83/17), 58%.
With this promising initial result, we decided to perform exten-
sive screening of the reaction conditions in order to find the opti-
mal composition of catalytic mixture. Thus, we scrutinised the
influence of the nature of the Pd(II)-salt, co-catalyst/re-oxidant,
base and solvent on the yield of 3/8 as well as the diastereoselec-
tivity of the methoxyaminocarbonylation. The results are summa-
rised in Table 1.
In all successful cases (entries 1–21), the predominant forma-
tion of the 2,6-trans-configured piperidine 3 was observed.7 The
catalytic system based on 10 mol % PdCl2 and excess CuCl2 with
either AcONa or Et3N worked well (entries 1 and 2), while the
employment of K2CO3 was less satisfactory (entry 3). The exclusion
of base from the reaction mixture resulted in a dramatic drop in
yield (entry 4). Similarly, a solvent change from MeOH to trimethyl
orthoformate4d had a detrimental effect on the diastereoselectivity
(entry 5). The use of Pd(OAc)2, Pd(OTFA)2 or Li2PdCl4 also gave rea-
sonable levels of diastereoselectivity, however, the combined
yields of the desired products were lower in these cases (entries
6–8). Moreover, the addition of two different chiral ligands under
these conditions did not affect the diastereoselectivity at all (en-
tries 10–12). Interestingly, a stoichiometric experiment employing
1 equiv of PdCl2 without any re-oxidant required a higher temper-
ature and longer reaction time to deliver the products, albeit in low
Table 1
Pd(II)/CuCl2-catalysed intramolecular methoxyaminocarbonylation of alkenyl amine 4
Entry
Pd salt (0.1 equiv)
Re-oxidation system
Base (3 equiv)
Solvent
Temperature, time
Ratioa3/8, yieldb
1
2
3
4
5
6
7
PdCl2
PdCl2
PdCl2
PdCl2
CuCl2 (3 equiv)
CuCl2 (3 equiv)
CuCl2 (3 equiv)
CuCl2 (3 equiv)
CuCl2 (3 equiv)
CuCl2 (3 equiv)
CuCl2 (3 equiv)
CuCl2 (3 equiv)
None
CuCl2 (3 equiv)
CuCl2 (3 equiv)
CuCl2 (3 equiv)
CuCl2 (3 equiv)
CuCl2 (3 equiv)
CuCl2 (3 equiv)
CuCl2 (0.2 equiv)/O2 (1 atm)
CuCl2 (0.2 equiv)/O2 (1 atm)
CuCl2 (0.2 equiv)/O2 (1 atm)
CuCl2 (0.2 equiv)/O2 (1 atm)
CuCl2 (0.2 equiv)/O2 (1 atm)
CuCl2 (0.2 equiv)/O2 (1 atm)
Cu(OAc)2 (3 equiv)
Benzoquinone (1 equiv)
Benzoquinone (1 equiv)
AcONa
Et3N
K2CO3
None
MeOH
MeOH
MeOH
MeOH
(MeO)3CH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH/THF (1:1)
MeOH/MeCN (1:1)
MeOH/1,4-dioxane (1:1)
MeOH
MeOH/MeCN (1:1)
MeOH/1,4-dioxane (1:1)
MeOH/DMF (1:1)
MeOH/1,4-dioxane (1:1)
MeOH/1,4-dioxane (1:1)
MeOH
22 °C, 4 d
21 °C, 2 d
22 °C, 4 d
30 °C, 2 d
40 °C, 2 d
21 °C, 2 d
21 °C, 2 d
35 °C, 3 d
60 °C, 6 d
30 °C, 2 d
30 °C, 2 d
30 °C, 2 d
30 °C, 5 d
25 °C, 3 d
23 °C, 3 d
22 °C, 24 h
30 °C, 3 d
21 °C, 2 d
21 °C, 5 d
30 °C, 4 d
40 °C, 4 d
50 °C, 2 d
36 °C, 3 d
60 °C, 17 d
83/17, 58%
78/22, 58%
70/30, 40%
61/39, 27%
59/41, 41%
76/24, 47%
79/21, 42%
85/15, 40%
80/20, 36%
80/20, 54%
80/20, 52%
83/17, 53%
79/21, 53%
84/16, 54%
75/25, 58%
90/10, 51%
72/28, 41%
69/31, 49%
70/30, 52%
63/37, 58%
69/31, 46%
—
PdCl2
None
Pd(OAc)2
Pd(OTFA)2
Li2PdCl4
PdCl2
Pd(OTFA)2
Pd(OAc)2
Pd(OTFA)2
PdCl2
PdCl2(MeCN)2
PdCl2
PdCl2
PdCl2(MeCN)2
PdCl2
PdCl2
AcONa
AcONa
AcONa
AcONa
AcONa
AcONa
AcONa
AcONa
AcONa
AcONa
None
None
None
None
None
None
None
None
AcONa
8
9c
10d
11d
12e
13
14
15
16f
17f
18f
19f
20e,f
21f
22g
23h
24h
PdCl2
PdCl2(PhCN)2
Pd(OAc)2
Pd(OAc)2
PdCl2
MeOH
MeOH
—
—
a
Diastereomeric ratios were determined by GC analysis of the crude reaction mixture using an Agilent 5890 gas chromatograph equipped with an FID detector and split/
m). The analyses were run in isothermic mode at 180 °C. (For 3: tR = 30.1 min, for 8: tR = 29.7 min.)
Combined isolated yield of 3+8 after flash liquid chromatography (silica gel, toluene/EtOAc, 8:1 with 1% w/w NH4OH).
splitless injector on a HP-5 column (50 m ꢁ 0.32 mm ꢁ 0.52
l
b
c
d
e
f
Stoichiometric amount of PdCl2 was used.
3aR-[2(30aR*,80aS*),30ab,80ab]-(+)-2,20-methylene-bis[3a,8a-dihydro-8H-indeno-[1,2-d]oxazole] (0.12 equiv) was used as a chiral ligand.
(ꢀ)-Sparteine (0.12 equiv) was used as a chiral ligand.
3 Å molecular sieves were added.
g
h
Full conversion of 4 with concomitant formation of a complex mixture of unidentified products.
Full conversion of 4 without formation of piperidines 3 and/or 8.

K. Csatayová et al. / Tetrahedron Letters 51 (2010) 6611–6614
6613
O
OH
MeOH
N
OMe
NH
Bn
N
OMe
Bn
Bn
O
OMe
3 (kinetic product)
OH
O
N
OMe
N
OMe
Bn
Bn
8
(thermodynamic product)
Scheme 4. The possible epimerisation of 3 into 8 in MeOH via a retro-aza-Michael type addition at elevated temperature.
We found that neither standing pure 3 in neat MeOH nor stir-
ring its methanolic solution containing the Pd/Cu-catalytic system
led to any observable epimerisation by TLC. However, raising the
temperature above 60 °C resulted in slow but steady formation of
8 from 3. As all our successful methoxyaminocarbonylations of 3
took place well below the critical temperature, we are confident
that the observed diastereoselectivity is a result of the Pd/Cu-cata-
lysed cyclisation only, and without any contribution from back-
ground epimerisation.
the alkenyl amine 4 was subjected to the broad reaction screening
of the Pd(II)/CuCl2-catalysed methoxyaminocarbonylation to
furnish the desired cyclic esters 3/8. The influence of the nature
of the palladium and copper salts, the re-oxidant, the base and sol-
vent on the yield of 3/8 as well as the diastereoselectivity was ex-
plored. We found that CuCl2 was the optimum reagent for this
transformation and acts not only as the re-oxidant, but also as an
efficient co-catalyst in the presence of molecular oxygen as the ter-
minal oxidant. The methyl ester 3 was subsequently used as a key
intermediate in the total synthesis of the naturally occurring piper-
idine alkaloid (ꢀ)-pinidinone (1).
Having established reaction conditions11 for the preparation of
the desired piperidines 3/8, we next focused on completion of the
synthesis of 1. The initially attempted direct conversion12 of major
ester 3 into ketone 9 using MeMgBr in the presence of Et3N led
only to complex mixtures. Therefore, we turned to the established
methodology.13a Thus, treatment of 3 with Weinreb’s reagent gave
the crude N-methoxyamide, which was immediately treated13b
with excess methylmagnesium bromide to yield a mixture of
inseparable ketones 9 and 10 in a 1:2 ratio after flash liquid chro-
matography (FLC) using silica gel.14 To check whether the epimer-
isation at C-2 during the Weinreb protocol/Grignard addition of 3
could be suppressed, we changed the order of the transformations.
Thus, we first deprotected ester 3 using Pearlman’s catalyst to ob-
tain the piperidine 11 in 62% yield.15 However, the subsequent
transformation of 2,6-trans-disubstituted ester 11 into the corre-
sponding ketone proceeded with complete epimerisation at C-2
after FLC using silica gel and furnished the 2,6-cis-configured nat-
urally occurring alkaloid (ꢀ)-pinidinone 11a,2 (Scheme 5).
Acknowledgements
We thank Professor Tibor Gracza and Professor František Pova-
ˇ
zanec for helpful discussions. We are grateful to Mrs. Mária Kraj-
ˇ
ˇ
círová for technical assistance, to Dr. Nada Prónayová for NMR
ˇ
spectra, to Dr. Pavel Cepec (Tau-Chem Ltd) for MS analyses and
to Dr. Peter Zálupsky´ for proof-reading the manuscript. This work
was supported by the Science and Technology Assistance Agency
under contracts no. APVV-0164-07 and VMSP-P-0130-09 and the
Scientific Grant Agency under contract no. VEGA 1/0340/10.
References and notes
1. (a) Tawara, J. N.; Blokhin, A.; Foderaro, T. A.; Stermitz, F. R.; Hope, H. J. Org.
Chem. 1993, 58, 4813–4818; (b) Stermitz, F. R.; Tawara, J. N.; Boeckl, M.;
Pomeroy, M.; Foderaro, T. A.; Todd, F. G. Phytochemistry 1994, 35, 951–953; (c)
Brown, W. V.; Moore, B. P. Aust. J. Chem. 1982, 35, 1255–1261; (d) Attygalle, A.
B.; Xu, S.-Ch.; McCormick, K. D.; Meinwald, J. Tetrahedron 1993, 49, 9333–9342.
2. Fréville, S.; Delbecq, P.; Thuy, V. M.; Petit, H.; Célérier, J.-P.; Lhommet, G.
Tetrahedron Lett. 2001, 42, 4609–4611.
Starting from commercially available (S)-propylene oxide (6),
we have prepared (R)-benzyl-(1-methyl-hex-5-enyl)-amine (4) as
a key substrate in three steps in 68% overall yield. Subsequently,
3. (a) Szolcsányi, P.; Gracza, T.; Koman, M.; Prónayová, N.; Liptaj, T. Chem.
Commun. 2000, 471–472; (b) Szolcsányi, P.; Gracza, T.; Koman, M.; Prónayová,
N.; Liptaj, T. Tetrahedron: Asymmetry 2000, 11, 2579–2597; (c) Szolcsányi, P.;
Gracza, T. Chem. Commun. 2005, 3948–3950; (d) Szolcsányi, P.; Gracza, T.
Tetrahedron 2006, 62, 8498–8502; (e) Szolcsányi, P.; Gracza, T.; Špánik, I.
O
a, b
CO2Me
ˇ
Tetrahedron Lett. 2008, 49, 1357–1360; (f) Kubizna, P.; Špánik, I.; Kozíšek, J.;
N
N
Bn
Szolcsányi, P. Tetrahedron 2010, 66, 2351–2355.
Bn
4. (a) Tamaru, Y.; Hojo, M.; Yoshida, Z. J. Org. Chem. 1988, 53, 5731–5741; (b)
Tamaru, Y.; Hojo, M.; Higashimura, H.; Yoshida, Z. J. Am. Chem. Soc. 1988, 110,
3994–4002; (c) Tamaru, Y.; Tanigawa, H.; Itoh, S.; Kimura, M. Tetrahedron Lett.
1992, 33, 631–634; (d) Tamaru, Y.; Kimura, M. Synlett 1997, 749–757; (e)
Gallagher, A.; Davies, I. W.; Jones, S. W.; Lathbury, D.; Mathon, H. F.; Molloy, K.
C.; Shaw, R. W.; Vernon, P. J. Chem. Soc., Perkin Trans. 1 1992, 433–440.
5. Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem. Soc., Perkin Trans. 1 2000, 2385–2394.
6. (a) Kabalka, G. W.; Varma, M.; Varma, R. S. J. Org. Chem. 1986, 51, 2386–2388;
(b) Fürstner, A.; Langemann, K. Synthesis 1997, 792–803.
3
9 (cis) / 10 (trans)
c
c
O
d, e
CO2Me
N
H
7. The relative 2,6-trans-configuration of major product 3 was determined on the
basis of 1D NOESY experiments.
N
H
8. (a) Fenton, D. M.; Steinwand, P. J. J. Org. Chem. 1974, 39, 701–704; (b)
Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J. Am. Chem. Soc. 1981, 103,
2318–2323; (c) Karandin, A.; Gusevskaya, E. V.; Likhobolov, V. A.; Stepanov, A.
G.; Talzi, E. P. Kinet. Catal. 1990, 31, 506–510; (d) Zargarian, D.; Alper, H.
Organometallics 1991, 10, 2914–2921; (e) Hosokawa, T.; Nomura, T.;
Murahashi, S.-I. J. Organomet. Chem. 1998, 551, 387–389; (f) Kawamura, Y.;
Kawano, Y.; Matsuda, T.; Ishitobi, Y.; Hosokawa, T. J. Org. Chem. 2009, 74, 3048–
3053.
11
1
Scheme 5. Reagents and conditions: (a) 3 equiv MeNHOMeꢂHCl, 1.6 equiv Me3Al,
THF, 0 °C to rt, 18 h; (b) 2.3 equiv MeMgBr, THF, ꢀ78 °C to rt, 1 h, FLC (SiO2), 30%, 9/
10 (1:2); (c) H2 (1 atm), Pd(OH)2 (14 mol %), MeOH, rt, 18 h, FLC (SiO2), 11 (62%), 1
(71%); (d) 3 equiv MeNHOMeꢂHCl, 3 equiv Me3Al, THF, 0 °C to rt, 2.5 h, 74% crude;
(e) 2.2 equiv MeMgBr, THF, ꢀ78 °C to rt, 1 h, FLC (SiO2), 58%.

6614
K. Csatayová et al. / Tetrahedron Letters 51 (2010) 6611–6614
9. (a) Adams, D. R.; Carruthers, W.; Crowley, P. J. J. Chem. Soc., Chem. Commun.
1991, 1261–1263; (b) Banwell, M. G.; Bui, Ch. T.; Pham, H. T. T.; Simpson, G. W.
J. Chem. Soc., Perkin Trans. 1 1996, 967–969; (c) Banwell, M. G.; Bissett, B. D.;
Bui, Ch. T.; Pham, H. T. T.; Simpson, G. W. Aust. J. Chem. 1998, 51, 9–18; (d) Lee,
E.; Jeong, E. J.; Min, S. J.; Hong, S.; Lim, J.; Kim, S. K.; Kim, H. J.; Choi, B. G.; Koo, K.
Ch. Org. Lett. 2000, 2, 2169–2172; (e) Bargiggia, F. C.; Murray, W. V. Tetrahedron
Lett. 2006, 47, 3191–3193.
10. It is reported that (+)-2-epipinidinone slowly epimerises to 2,6-cis-configured
(ꢀ)- pinidinone (1) even on standing in MeOH at room temperature for a few
days (see Ref. 1a). Such solution epimerisation was also reported for other
piperidine alkaloids of similar structures, see, for example Fodor, G. B.;
Colasanti, B. In Alkaloids Chemical and Biological Perspectives; Pelletier, S. W.,
Ed.; John Wiley and Sons: New York, 1985; Vol. 3, pp 49–73.
11. Typical procedure for the Pd(II)-catalysed aminocarbonylation: a suspension of
aminoalkene 4 (200 mg, 0.984 mmol), PdCl2 (17 mg, 0.0984 mmol, 0.1 equiv),
CuCl2 (397 mg, 2.95 mmol, 3 equiv) and AcONa (242 mg, 2.95 mmol, 3 equiv)
in anhydrous MeOH (9.8 mL) was stirred under a CO atmosphere (balloon) at
22 °C over 4 d, while the colour of reaction mixture changed from turquoise to
green. After evaporation, the residue was partitioned between AcOEt (20 mL)
and 2% NH4OH (20 mL). The aqueous layer was extracted with AcOEt
(3 ꢁ 20 mL). The combined organic extracts were washed with brine
(2 ꢁ 30 mL), dried over MgSO4 and concentrated in vacuo. The brown oily
residue was purified by careful flash liquid chromatography (SiO2, toluene-
AcOEt, 40:1 with 1% w/w NH4OH) to furnish [(2S,6R)-1-benzyl-6-methyl-
piperidin-2-yl]-acetic acid methyl ester (3) (109 mg, 42%) as a pale yellow oil
OCH3), 3.81 (d, J = 14.4 Hz, 1H, CH2Ph), 7.18–7.35 (m, 5H, Ph); 13C NMR
(150 MHz, CDCl3): = 18.9 (q, CH3), 19.6 (t, C-4), 28.0 (t, C-3), 31.6 (t, C-5), 34.2
(t, CH2CO), 50.2 (d, C-6), 51.4 (q, OCH3), 52.7 (t, CH2Ph), 53.1 (d, C-2), 126.5
(d, Cp-Ph), 128.1 (d, Co,m-Ph), 141.2 (s, Cq-Ph), 173.4 (s, C@O).
Data for 8: Rf = 0.63 (toluene–AcOEt, 8:1 with 1% w/w NH4OH); ½a D25
ꢀ1.54 (c
ꢃ
0.13, CHCl3); 1H NMR (300 MHz, CDCl3): d = 1.02 (d, JMe,6 = 6.4 Hz, 3H, CH3),
1.23–1.52 (m, 4H, H-3, H-5), 1.54–1.62 (m, 2H, H-4), 2.17 (dd, JA,X = 9.5,
JA,B = 15.1 Hz, 1H, A of ABX, CH2CO), 2.59 (dd, JB,X = 3.9, JA,B = 15.1 Hz, 1 H, B of
ABX, CH2CO), 2.68–2.72 (m, 1H, H-6), 2.95–3.09 (m, 1H, H-2), 3.58 (s, 3H,
OCH3), 3.71 (d, J = 17.0 Hz, 1H, CH2Ph), 3.78 (d, J = 17.0 Hz, 1H, CH2Ph), 7.12–
7.42 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3): = 21.4 (q, CH3), 22.9 (t, C-4), 30.4
(t, C-3), 32.6 (t, C-5), 40.3 (t, CH2CO), 51.4 (d, C-6), 53.7 (q, OCH3), 57.5 (t,
CH2Ph), 59.6 (d, C-2), 126.2 (d, Cp-Ph), 127.9 (d, Co,m-Ph), 142.3 (s, Cq-Ph), 172.9
(s, C@O).
12. (a) Kikkawa, I.; Yorifuji, T. Synthesis 1980, 877–880; (b) Chenevert, R.;
Thiboutot, S. Can. J. Chem. 1986, 64, 1599–1601.
13. (a) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989–993; (b)
Munchhof, M. J.; Meyers, A. I. J. Am. Chem. Soc. 1995, 117, 5399–5400.
14. The 1H NMR spectra of the crude reaction mixture showed the formation of
2,6-trans-configured ketone 10 only. However, after purification of this
material by flash liquid chromatography (SiO2, toluene–AcOEt, 8:1 with 1%
w/w NH4OH) partial epimerisation of 10 into thermodynamically more stable
9 was observed.
15. Data for 11: ½a D25
ꢃ
+12.9 (c 0.29, CHCl3); 1H NMR (600 MHz, CDCl3): = 1.08 (d,
JMe,6 = 6.4 Hz, 3H, CH3), 1.18–1.23 (m, 1H, H-5A), 1.26–1.35 (m, 1H, H-3A),
1.49–1.56 (m, 1H, H-4A), 1.59–1.65 (m, 2H, H-4B, H-5B), 1.66–1.73 (m, 1H, H-
3B), 1.85 (br s, 1H, exchange with D2O, NH), 2.39 (dd, JA,X = 5.1, JA,B = 15.5 Hz,
1H, A of ABX, CH2CO), 2.64 (dd, JB,X = 8.8, JA,B = 15.5 Hz, 1H, B of ABX, CH2CO),
and [(2R,6R)-1-benzyl-6-methyl-piperidin-2-yl]-acetic acid methyl ester
8
(40 mg, 16%) as a pale yellow oil.
Data for 3: Rf = 0.73 (toluene–AcOEt, 8:1 with 1% w/w NH4OH); ½a D24
ꢀ3.9 (c
ꢃ
0.62, CHCl3); 1H NMR (600 MHz, CDCl3): = 1.03 (d, JMe,6 = 6.5 Hz, 3H, CH3),
1.25–1.35 (m, 1H, H-5A), 1.38–1.44 (m, 1H, H-3A), 1.56–1.63 (m, 3H, H-4, H-
5B), 1.66–1.70 (m, 1H, H-3B), 2.43 (dd, JA,X = 8.6, JA,B = 14.2 Hz, 1H, A of ABX,
CH2CO), 2.63 (dd, JB,X = 5.5, JA,B = 14.2 Hz, 1H, B of ABX, CH2CO), 2.81–2.87 (m,
1H, H-6), 3.25–3.30 (m, 1H, H-2), 3.55 (d, J = 14.4 Hz, 1H, CH2Ph), 3.60 (s, 3H,
3.02–3.07 (m, 1 H, H-6), 3.44 (dt, J2;CH
¼ 5:1, J2,3A = J2,3B = 9.5 Hz, 1H, H-2),
2CO
3.69 (s, 3H, OCH3); 13C NMR (125 MHz, CDCl3): = 19.5 (t, C-4), 21.3 (q, CH3),
30.5 (t, C-3), 32.8 (t, C-5), 38.2 (t, CH2CO), 45.6 (d, C-6), 48.1 (d, C-2), 51.5 (q,
OCH3), 173.1 (s, C@O). The relative 2,6-trans-configuration of 11 was confirmed
on the basis of 1D NOESY experiments.