Chemo- and diastereoselective control for a flexible approach to (5S,6S)-6-alkyl-5-benzyloxy-2-piperidinones

Article abstract of DOI:10.1016/j.tet.2009.03.021

Chemo- and diastereoselective transformation of the N,O-acetals and their chain tautomers (4/5), readily derived from protected 3-hydroxyglutarimide 1a, was studied. It was uncovered that while the reaction with a combination of boron trifluoride etherate

Full text of DOI:10.1016/j.tet.2009.03.021

Tetrahedron 65 (2009) 3834–3841
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journal homepage: www.elsevier.com/locate/tet
Chemo- and diastereoselective control for a flexible approach to (5S,6S)-
6-alkyl-5-benzyloxy-2-piperidinones
,
a
a,b,
*
Liang-Xian Liu a , Kai-Jiong Xiao , Pei-Qiang Huang
*
a Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, PR China
b The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Chemo- and diastereoselective transformation of the N,O-acetals and their chain tautomers (4/5), readily
derived from protected 3-hydroxyglutarimide 1a, was studied. It was uncovered that while the reaction
with a combination of boron trifluoride etherate/zinc borohydride led to cyclic products (5S,6S/R)-6-
alkyl-5-benzyloxy-2-piperidinones 3/2, and 6 in modest chemo- and diastereoselectivities, the reaction
of 4/5 with zinc borohydride led exclusively to the formation of the ring-opening products 6 in excellent
anti-diastereoselectivities. On the basis of the latter reaction, a flexible approach to (5S,6S)-6-alkyl-5-
benzyloxy-2-piperidinones 3 was disclosed.
Received 15 January 2009
Received in revised form 8 March 2009
Accepted 10 March 2009
Available online 14 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
number of methods have been developed for the synthesis of
enantio-enriched 2,6-disubstituted piperidin-3-ol alkaloids that
2,6-Disubstituted piperidin-3-ol is a framework shared by many
bioactive alkaloids.1 As can be seen from Figure 1, 6-substituted 2,3-
cis-2-methylpiperidin-3-ols constitute a subclass of piperidine
alkaloids. Both the stereochemical variation at C-2, C-3, and C-6
positions, and the interesting biological activities exhibited by
share the same ‘2,3-cis’ stereochemistry.4
Previously, we have shown that the protected (S)-3-hydroxy-
glutarimides5 1 may serve as versatile building blocks for the
asymmetric synthesis of a variety of 2,6-disubstituted 3-hydroxy-
piperidines.6 A flexible regio- and diastereoselective reductive
alkylation7 method was developed for the conversion of 1a to trans-
6-alkyl-5-benzyloxy-2-piperidinone derivatives 2 (Scheme 1, path
these alkaloids1,2 make them attractive synthetic targets.1,3
A
A).6c Although regioselective reduction–stereoselective
a-amido-
azimic acid, n = 5, R = COOH
OH
carpamic acid, n = 7, R = COOH
spectaline, n = 12, R = COCH3
alkylation of 1b and 1c allows stereoselective access to the
corresponding cis-diastereomer6a,b (Scheme 1, path B) via either
R(CH2)n
R(CH2)n
N
CH3
spectalinine, n = 12, R = CH(OH)CH3
leptophyllin A, n =10, R = CH(OH)CH2OH
intramolecular aryl/vinyl group delivery,8 or
a
-amidoallylation,6b,9
H
A
OH
spectaline, n = 12, R = COCH3
prosafrinine, n = 9, R = COCH3
cassine, n = 10, R = COCH3
carnavaline, n = 10, R = CH(OH)CH3
spicigerine, n = 10, R = CH2COOH
OP
OBn
Path A
N
CH3
O
N
PMB
1
O
O
N
PMB
2
R
1) RMgX; 2) H
(from 1a)
H
B
OH
(a. P = Bn; b. P = TBDPS
c. P = TBS)
(R = alkyl, phenyl)
spectamine A, R = COCH3, R' = Ph
spectamine B, = COCH3, R' = Me
iso-6-cassine, R = COCH3, R' = H
jurifloridine, R = CH2CH2OH, R' = H
R(CH2)10
N
CH3
Path C (This work)
1) RMgX ; 2) H
(from 1a)
1) H ; 2) Nu
Path B
R'
C
(from1b/1c)
OP
OBn
Figure 1. Some naturally occurring 2,6-disubstituted piperidin-3-ol containing
alkaloids.
O
N
R
O
N
R
PMB
3
PMB
3
* Corresponding authors. Tel.: þ86 592 2180992; fax: þ86 592 2186405 (L.-X.L.);
tel.: þ86 592 2182240; fax: þ86 592 2186405 (P.-Q.H.).
E-mail addresses: lxliu@xmu.edu.cn (L.-X. Liu), pqhuang@xmu.edu.cn (P.-Q.
Huang).
(R = phenyl, allyl)
(R = alkyl, aryl)
Scheme 1. Three approaches for the regio- and diastereoselective conversion of 1 to 2
or 3.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.021

L.-X. Liu et al. / Tetrahedron 65 (2009) 3834–3841
3835
Table 1
the alkyl groups were limited to aryl, vinyl, and allyl. We report
Reductive deoxygenation of 4/5 according to the procedure shown in Scheme 3
Entry 4/5
Yielda (%) 3/2
Diastereo-
herein a flexible approach to the cis-6-alkyl-5-benzyloxy-2-piper-
idinone derivatives 3 (Scheme 1, path C) using zinc borohydride as
a chemo- and diastereoselective control element.
6
Yielda (%) Diastereo-
selectivity
selectivity
1
2
3
4
5
6
7
8
a
b
c
d
e
f
R¼CH3
59
55
41
51
88:12b
11 (6a)
11 (6b)
42 (6c)
22 (6d)
27 (6e)
42 (6f)
35 (6g)
100:0
92:8
2. Results and discussion
R¼C2H5
87:13b
R¼n-C4H9
R¼n-C8H17
85:15c
100:0
95:5b
100:0
100:0
100:0
55:45b
In our previous approach to trans-6-alkyl-5-benzyloxy-2-
piperidinone derivatives 2, the trans-stereoselectivity was assumed
to be resulted from the reduction of the N-acyliminium ion in-
termediate10 A with triethylsilane,11 a non-chelating hydride donor
(Scheme 2). Although the origin of the trans-diastereoselectivity in
the reduction of the N-acyliminium ion intermediates A is still
unclear, it was naively envisioned that a chelating hydride donor
would allow an access to the cis-isomer 3. In view of the frequent
use of zinc borohydride12 as a powerful chelating reducing agent in
diastereoselective reductions,13 it was selected for our
investigation.
R¼n-C12H25 39
100:0
R¼BnCH2
R¼Ph
38
54
100:0
g
h
60:40b
R¼Bn
Elimination product
(7), yield: 65%
a
b
c
Isolated yield.
Ratio based on chromatography separation.
Ratio determined by 1H NMR analysis.
mixtures 4b–h/5b–h. As can be seen from Table 1, while the yields
of 2-piperidinones 3b–h/2b–h are modest or mediocre, the dia-
stereoselectivities are good to excellent except in the case of phenyl
derivatives 4g/5g, where the ratio of 3g/2g is only 60:40. Some anti-
diastereomers were also formed as minor products for the amido
diol derivatives 6b and 6c. In the case of phenyl derivative, the syn/
anti ratio is only 55:45. When R is a benzyl group (4h/5h), only the
eliminative product 7 was obtained.
These results are different with those obtained from the re-
ductive dehydroxylation with BF3$OEt2/Et3SiH, where no ring-
opening products 6 were observed.6c The difference can be
understood by taking into account of the different chelation
properties of the two systems. In the case of reductive dehydroxy-
lation with BF3$OEt2/Et3SiH, as can be seen from Scheme 2, Lewis
acid BF3$OEt2, being a irreversible hydroxyl group abstracting
agent, is capable of pushing the tautomeric equilibrium toward the
N-acyliminium ion intermediate A; while the chelating property of
OBn
OBn
BF3 OEt2
OH
R
O
N
PMB
A
R
O
N
PMB
4
BF3OH
Zn(BH4)2
Et3SiH
OBn
?
OBn
O
O
HN
PMB
R
O
N
R
O
N
PMB
3
R
OBn
PMB
2
5
Scheme 2.
The requisite 6-alkyl-5-benzyloxy-6-hydroxy-2-piperidinones
4, together with their chain tautomers 5, were prepared by
Grignard reagents addition to (S)-3-benzyloxyglutarimide 1a under
our recently improved conditions.6f Treatment of both tautomeric
and diastereomeric mixture of 4a and 5a with 1.5 mol equiv of
boron trifluoride etherate, and 3 mol equiv of Zn(BH4)2 (0.25 M in
Et2O) yielded 3a and 2a in a ratio of 88:12 (combined yield: 59%),
along with the ring-opening reduced product 6a (yield: 11%)
(Scheme 3). Although the desired 2-piperidinone was formed as
a diastereomeric mixture (3a/2a), to our surprise, only the anti-
diastereomer 6a was obtained (Table 1, entry 1). The stereochem-
istry of the major diastereomer 3a was assigned to cis according to
the observed vicinal coupling constants (J5,6¼4.5 Hz for 3a and
J5,6¼1.0 Hz for the trans-diastereomer 2a).6c
Zn(BH4)2 toward the a-keto ether in tautomers 5 as well as the
`
higher reactivity of Zn(BH4)2 vis-a-vis the activated ketone carbonyl
group (via chelation) can lead to the formation of the ring-opening
product 6. It was envisioned that an inhibition of the formation of
the tautomer 5 would decrease the amount of 6 (Scheme 4). Be-
cause it was observed that chromatographic separation on silica gel
of the Grignard adducts increased the amount of the tautomer 5 in
the tautomeric mixture, a modified procedure involving a direct
use of the crude adducts was tested. Indeed, when a crude adducts
4a/5a was directly treated with Zn(BH4)2/BF3$OEt2 in CH2Cl2
(ꢀ78 ꢁC to 0 ꢁC), the desired (5S,6S)-3a was obtained in 74% yield. In
spite of this, a further investigation on this variation was not pur-
suit because of the observed modest diastereoselectivity (4:1).
The BF3$OEt2-mediated zinc borohydride reductive de-
oxygenation reaction was then extended to other tautomeric
O
O
OBn
OH
HN
PMB
R
OBn
OH
OBn
O
N
R
OBn
RMgX
PMB
4
5
+
5
O
N
PMB
4
CH2Cl2, −20 °C
O
N
O
R
PMB
1a
(for R, see: Table 1)
Zn H
O
OH
Bn
H
O
O
B
OBn
OBn
R
H
Zn(BH4)2
HN
R
BF3 OEt2, Zn(BH4)2
H
+
PMB
OBn
Et2O, −20 °C- rt
R1
H
O
N
R
O
N
PMB
2
R
6
B
PMB
3
(R1 = (CH2)2CONHPMB)
O
OH
OBn
Ph
Scheme 4. A plausible Zn(BH4)2-controlled pathway for the chemo- and anti-dia-
stereoselective formation of 6.
+
HN
PMB
R
O
N
OBn
PMB H
7
The formation of the ring-opening products 6 in high diaster-
eoselectivity prompted us to develop an alternative approach to
piperidinones 3 based on 6 (Table 1). To this end, a switch of cyclic
6
Scheme 3.

3836
L.-X. Liu et al. / Tetrahedron 65 (2009) 3834–3841
tautomer 4 to the acyclic tautomer 5 was necessary. In view of the
interconvertibility between the two tautomers 4 and 5, and the
observed movement of the equilibrium toward 4 by the BF3$OEt2-
promoted exclusive formation of the N-acyliminium ion in-
termediates A (Scheme 2), it was envisioned that in the absence of
BF3$OEt2, formation of a chelation intermediate between Zn(BH4)2
O
C4H9-i
O
H
Ph
HN
PMB
H
HN
PMB
OBn
OBn H
10
9
Figure 2.
and the a-benzyloxy ketone tautomer 5 would enhance both the
formation and reduction of 5, and thus push the equilibrium to-
ward 5 (Scheme 4). In addition, the anti-diastereoselectivity13,14 of
the reduction could be predicted by the Cram’s five-membered
cyclic model,15as shown in the transition state B.
(Scheme 5). It is to be mentioned that using other reducing systems,
syn-selective reduction of a related system has been reported.14
Unexpectedly, the eliminative products 9 and 10 were obtained
from the iso-butyl and benzyl substituted 6j and 6h (Table 2, entries
8, 10, Fig. 2).
This turned out to be true. Indeed, when a mixture of 4a and 5a
was treated with Zn(BH4)2 in diethyl ether (ꢀ20 ꢁC to rt), the desired
product 6a was formed in 82% yield (based on the recovered starting
material, 20%) with an anti/syn diastereoselectivity of 94:6 (Scheme
5, Table 2, entry 1). Except the case of phenyl derivative 6g, reduction
of other homologues gave 6b–6j in yields ranging from 77% to 95%,
with 86:14 to 98:2 anti/syn selectivities (Table 2). The stereochem-
istryof the majordiastereomer 6awas confirmedbyconverting 6ato
(5S,6S)-6-alkyl-5-benzyloxy-2-piperidinone 3a by mesylation
(MsCl, Et3N, CH2Cl2, ꢀ20 ꢁC, 1 h) and t-BuOK-promoted cyclization
(HMPA, THF, rt, 24 h). Following this procedure, 2-piperidinones 3a–
3j were prepared and the results are displayed in Table 2.
3. Conclusion
In conclusion, we were able to demonstrate that through proper
selection of Lewis acid-reducing agent combination, both the ring-
chain tautomerism of the cyclic N,O-acetals, derived from the
protected 3-hydroxyglutarimide 1a, and the diastereoselective re-
duction can be controlled. Taking advantage of the dual role of zinc
borohydride both as a bidendate chelating Lewis acid and as a selec-
tive reducing agent, a flexible yet stepwise approach to (5S,6S)-6-
alkyl-5-benzyloxy-2-piperidinones 3 was disclosed. The present
method is complementary with the boron trifluoride etherate-
mediated diastereoselective reduction with triethylsilane, previously
developed from these laboratories, that affords (5S,6R)-6-alkyl-
5-benzyloxy-2-piperidinones 2 in excellent chemo- and diaster-
eoselectivities. Application of this method to the asymmetric
synthesis of 2,3-cis-2,6-disubstituted piperidin-3-ol alkaloids will be
reported elsewhere in due course.
O
OH
Zn(BH4)2
Et2O, −20 °C - rt
HN
PMB
R
4 + 5
OBn
6
O
OMs
R
MsCl, Et3N
CH2Cl2, −20 °C
HN
PMB
OBn
8
4. Experimental section
4.1. General methods
OBn
t-BuOK, HMPA
O
N
PMB
R
THF, rt
Melting points were determined on a Yanaco MP-500 micro
melting point apparatus and were uncorrected. Infrared spectra
were measured with a Nicolet Avatar 360 FT-IR spectrometer using
film KBr pellet techniques. 1H NMR spectra were recorded in CDCl3
on a Bruker 400 spectrometer or a Varian Unity 500 spectrometer
with tetramethylsilane as an internal standard. Chemical shifts are
3. (R = alkyl, phenyl, benzyl)
Scheme 5.
Both the exclusive formation of the ring-opening products 6
from the tautomeric mixtures 4/5, and the high anti-diastereo-
selectivities can be attributed to the formation of the presumed
chelating transition state B (Scheme 4), which not only switches the
equilibrium toward 5, but also allows the reduction to undergo
with a Cram chelation-controlled (anti-Felkin-Ahn) manner, pro-
ducing thus the anti (erythro) alcohols 6 in good to excellent yields
expressed in d (ppm) units downfield from TMS. Mass spectra were
recorded on a Bruker Dalton ESquire 3000 plus liquid chromato-
graphy–mass spectrum (direct injection). HRMS spectra were
recorded on a Bruker APEX II FT mass spectrometer, or a Shimadzu
LCMS-IT-TOF apparatus. Optical rotations were measured with
a Perkin–Elmer 341 automatic polarimeter. Silica gel (300–400
mesh) was used for flash column chromatography, eluting (unless
otherwise stated) with an ethyl acetate/petroleum ether (PE) (60–
90 ꢁC) mixture. Ether and THF were distilled over sodium benzo-
phenone ketyl under N2. Dichloromethane was distilled over
calcium hydride under N2.
Table 2
Results of the ring-opening reduction according to the procedure shown in
Scheme 5
Entry
Product 6
Yielda (%)
Diastereoselectivity
3 (% yield)f
1
2
3
4
5
6
7
8
9
10
CH3 (6a)
C2H5 (6b)
82b
89
82
95
77
87
66
85
78
81
94:6c
94:6e
91:9c
75
76
70
83
83
87
67
81
66
72
n-C4H9 (6c)
n-C8H17 (6d)
n-C12H25 (6e)
PhCH2CH2 (6f)
Ph (6g)
Bn (6h)
n-C16H33 (6i)
i-Bu (6j)
4.2. General procedure for the reductive deoxygenation
of tautomeric mixture 4/5
98:2e
90:10e
89:11e
65:35c
95:5c
86:14d
97:3e
To a cooled (ꢀ20 ꢁC) solution of tautomeric mixture 4/56c,f
(1.0 mol equiv) in THF (0.1 M) was added dropwise a solution of
boron trifluoride etherate (1.5 mol equiv) under argon atmosphere
and the mixture was stirred at ꢀ20 to ꢀ10 ꢁC for 30 min. To the
resultant mixture was added dropwise a solution of Zn(BH4)2
(0.25 M, 3 mol equiv) in Et2O. The mixture was allowed to slowly
warm to 0 ꢁC and was stirred at 0 ꢁC overnight. The reaction was
quenched with a saturated aqueous NH4Cl. After extraction with
CH2Cl2, the combined organic layers were washed with brine, dried
a
Isolated yield.
b
c
d
e
f
Based on the recovered starting material: 20%.
Ratio based on chromatography separation.
Ratio based on 1H NMR analysis.
Ratio based on HPLC analysis.
Isolated yield of 3 starting from 6.

L.-X. Liu et al. / Tetrahedron 65 (2009) 3834–3841
3837
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (eluent: EtOAc/PE¼1:1) to yield 2-piperidinones 3/2 and
the ring-opening product 6.
4.2.2.2. (4S,5R)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)heptanoyl
amide (6b) (4S,5R)-6b (major diastereomer). Rf¼0.35 (EtOAc/PE¼2:1),
25
white solid, mp: 66–67 ꢁC (EtOAc/PE¼1:1). [
a]
D
ꢀ5.1 (c 1.2, CHCl3). IR
(film) nmax: 3409, 3304, 1650, 1513, 1248 cmꢀ1 1H NMR (400 MHz,
.
CDCl3):
d
0.97 (t, J¼7.5 Hz, 3H, CH3), 1.39–1.61 (m, 2H), 1.83–1.99 (m,
4.2.1. (5S,6S)-5-Benzyloxy-1-(4-methoxybenzyl)-6-methyl-2-
piperidinone (3a)
Following the general procedure, the reductive deoxygenation
of the tautomeric mixture 4a/5a gave a diastereomeric mixture of
3a and the known 2a6c in 88:12 ratio (combined yield: 59%), along
with 6a as a single diastereomer in 11% yield.
2H), 2.22 (ddd, J¼15.0, 7.8, 7.2 Hz, 1H, H-2), 2.38 (ddd, J¼15.0, 6.8,
6.8 Hz, 1H, H-2), 2.73 (s, 1H, OH), 3.36 (ddd, J¼6.9, 4.7, 4.3 Hz, 1H), 3.67
(ddd, J¼8.5, 4.3, 4.3 Hz, 1H), 3.78 (s, 3H, OCH3), 4.26 (dd, J¼14.4, 5.7 Hz,
1H, NCH2), 4.32 (dd, J¼14.4, 5.7 Hz, 1H, NCH2), 4.45 (d, J¼11.5 Hz, 1H,
OCH2), 4.56 (d, J¼11.5 Hz, 1H, OCH2), 5.80 (br s, 1H, NH), 6.83 (d,
J¼8.7 Hz, 2H, Ar–H), 7.15 (d, J¼8.7 Hz, 2H, Ar–H), 7.22–7.34 (m, 5H, Ar–
H). 13C NMR (100 MHz, CDCl3):
d 10.4, 23.6, 25.4, 31.5, 43.0 (NCH2), 55.3
4.2.1.1. Compound (5S,6S)-3a. Rf¼0.35 (EtOAc/PE¼1:1), colorless
(OCH3), 71.5 (OCH2), 72.4 (C-4), 80.9 (C-5), 114.0 (2C), 127.8, 127.9 (2C),
128.4 (2C), 129.2 (2C), 130.4, 138.2, 159.0, 173.0 (C]O). MS (ESI): 372
(MHþ, 30), 394 (MNaþ, 100). Anal. Calcd for C22H29NO4: C, 71.13; H,
7.87; N, 3.77. Found: C, 71.03; H, 7.55; N, 3.71.
25
oil. [
a]
ꢀ51.9 (c 1.0, CHCl3). IR (film) nmax: 1638, 1512, 1450,
D
1246 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
1.21 (d, J¼6.5 Hz, 3H, CH3),
1.88–2.06 (m, 2H, H-4), 2.47 (ddd, J¼18.2, 9.4, 8.2 Hz, 1H, H-3), 2.62
(ddd, J¼18.2, 7.4, 3.8 Hz, 1H, H-3), 3.54 (m, 1H, H-6), 3.60 (ddd,
J¼10.5, 4.6, 4.6 Hz,1H, H-5), 3.79 (s, 3H, OCH3), 3.86 (d, J¼14.8 Hz,1H,
NCH2), 4.43 (d, J¼11.8 Hz, 1H, OCH2), 4.47 (d, J¼11.8 Hz, 1H, OCH2),
5.24 (d, J¼14.8 Hz, 1H, NCH2), 6.87 (d, J¼8.7 Hz, 2H, Ar–H), 7.15 (d,
J¼8.7 Hz, 2H, Ar–H), 7.22–7.26 (m, 2H, Ar–H), 7.27–7.35 (m, 3H, Ar–
4.2.3. (5S,6S)-5-Benzyloxy-6-(n-butyl)-1-(4-methoxybenzyl)-2-
piperidinone (3c)
Following the general procedure, the reductive deoxygenation
of the tautomeric mixture 4c/5c gave a diastereomeric mixture of
3c and the known 2c6c in 85:15 ratio (combined yield: 41%), and 6c
as a diastereomeric mixture in 95:5 ratio (combined yield: 42%).
H). 13C NMR (100 MHz, CDCl3):
d 13.4, 22.0, 29.2, 47.2 (NCH2), 52.4
(OCH3), 55.2 (C-6), 70.7 (OCH2), 74.1 (C-5), 113.9 (2C), 127.5 (2C),
127.7, 128.4 (2C), 129.2 (2C), 129.4, 137.8, 158.9, 169.1 (C]O). MS
(ESI): 340 (MHþ, 35), 362 (MNaþ,100). Anal. Calcd for C21H25NO3: C,
74.31; H, 7.42; N, 4.13. Found: C, 74.30; H, 7.29; N, 3.95.
4.2.3.1. Compound (5S,6S)-3c. Rf¼0.35 (EtOAc/PE¼1:1), colorless
25
oil. [
a
]
D
ꢀ40.7 (c 0.6, CHCl3). IR (film) nmax: 1642, 1512, 1456,
1247 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
0.90 (t, J¼6.9 Hz, 3H, CH3),
4.2.1.2. (4S,5R)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)hexanoyl
1.23–1.43 (m, 4H, 2ꢂCH2), 1.50–1.60 (m, 1H), 1.78–1.86 (m, 1H),
1.90–2.03 (m, 2H, H-4), 2.47 (ddd, J¼18.3, 8.1, 8.1 Hz, 1H, H-3), 2.62
(ddd, J¼18.3, 8.5, 4.8 Hz, 1H, H-3), 3.38 (ddd, J¼11.0, 5.7, 4.9 Hz, 1H,
H-6), 3.64 (ddd, J¼10.1, 4.9, 4.9 Hz, 1H, H-5), 3.74 (d, J¼14.7 Hz, 1H,
NCH2), 3.81 (s, 3H, OCH3), 4.37 (d, J¼12.7 Hz, 1H, OCH2), 4.41 (d,
J¼12.7 Hz, 1H, OCH2), 5.42 (d, J¼14.7 Hz, 1H, NCH2), 6.85 (d,
J¼8.5 Hz, 2H, Ar–H), 7.12 (d, J¼8.5 Hz, 2H, Ar–H), 7.15–7.40 (m, 5H,
amide (6a) (4S,5R)-6a (sole diastereomer). Rf¼0.35 (EtOAc/PE¼2:1),
25
white solid, mp: 52–54 ꢁC (EtOAc/PE¼1:1). [
a]
D
ꢀ4.3 (c 0.9, CHCl3).
IR (film) nmax: 3407, 3305, 1649, 1514, 1248 cmꢀ1. 1H NMR (400 MHz,
CDCl3):
d
1.19 (t, J¼6.3 Hz, 3H, CH3), 1.84 (ddd, J¼14.5, 7.4, 6.8 Hz, 1H,
H-3), 2.07 (ddd, J¼14.5, 7.4, 6.3 Hz, 1H, H-3), 2.26 (t, J¼7.4 Hz, 2H, H-
2), 2.10–2.50 (br s,1H, OH), 3.31 (dt, J¼4.5, 6.3 Hz,1H, H-5), 3.74 (ddd,
J¼6.8, 6.3, 4.5 Hz,1H, H-4), 3.78 (s, 3H, OCH3), 4.30 (dd, J¼14.5, 5.6 Hz,
1H, NCH2), 4.35 (dd, J¼14.5, 5.6 Hz, 1H, NCH2), 4.55 (d, J¼11.5 Hz, 1H,
OCH2), 4.62 (d, J¼11.5 Hz, 1H, OCH2), 5.57 (br s, 1H, NH), 6.83 (d,
J¼8.6 Hz, 2H, Ar–H), 7.18 (d, J¼8.6 Hz, 2H, Ar–H), 7.25–7.33 (m, 5H,
Ar–H). 13C NMR (100 MHz, CDCl3):
d 14.0, 22.5, 23.0, 28.7, 29.1, 29.6,
48.4 (NCH2), 55.2 (OCH3), 56.7 (C-6), 70.7 (C-5), 74.2 (OCH2), 114.0
(2C), 127.5 (2C), 127.7, 128.4 (2C), 129.4 (2C), 130.0, 137.8, 158.9,
169.6 (C]O). MS (ESI): 382 (MHþ, 100). HRESIMS calcd for
[C24H31NO3þH]þ: 382.2382; found: 382.2395.
Ar–H). 13C NMR (100 MHz, CDCl3):
d 19.0, 25.6, 31.6, 43.1 (NCH2), 55.3
(OCH3), 68.8 (OCH2), 72.6 (C-4), 82.7 (C-5), 114.1 (2C), 127.9, 127.9
(2C), 128.5 (2C), 129.2 (2C), 130.3, 138.2, 159.0, 172.3 (C]O). MS (ESI):
358 (MHþ, 100). HRESIMS calcd for [C12H23NO3þH]þ: 358.2018;
found: 358.2034.
4.2.3.2. (4S,5R)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)nonanoyl
amide (6c) (4S,5R)-6c (major diastereomer). Rf¼0.35 (EtOAc/PE¼2:1),
25
white solid, mp: 64–65 ꢁC (EtOAc/PE¼2:1). [
a]
D
ꢀ5.7 (c 0.9, CHCl3).
IR (film) nmax: 3304, 1650, 1513, 1245 cmꢀ1
.
1H NMR (500 MHz,
4.2.2. (5S,6S)-5-Benzyloxy-6-ethyl-1-(4-methoxybenzyl)-2-
piperidinone (3b)
Following the general procedure, the reductive deoxygenation
of the tautomeric mixture 4b/5b gave a diastereomeric mixture of
3b and the known 2b6c in 87:13 ratio (combined yield: 55%), and 6b
as a diastereomeric mixture in 92:8 ratio (combined yield: 11%).
CDCl3):
d
0.91 (t, J¼6.9 Hz, 3H, CH3), 1.25–1.38 (m, 3H), 1.40–1.55 (m,
3H), 1.92–2.00 (m, 2H), 2.15 (ddd, J¼14.8, 7.4, 7.4 Hz, 1H, H-2), 2.30
(ddd, J¼14.8, 6.6, 6.6 Hz, 1H, H-2), 2.52 (s, 1H, OH), 3.39 (dt, J¼4.2,
7.3 Hz, 1H, H-5), 3.67–3.75 (m, 1H, H-4), 3.75 (s, 3H, OCH3), 4.20 (dd,
J¼14.4, 5.6 Hz, 1H, NCH2), 4.27 (dd, J¼14.4, 5.6 Hz, 1H, NCH2), 4.38 (d,
J¼11.5 Hz, 1H, OCH2), 4.51 (d, J¼11.5 Hz, 1H, OCH2), 5.65 (br s, 1H,
NH), 6.82 (d, J¼8.7 Hz, 2H, Ar–H), 7.18 (d, J¼8.7 Hz, 2H, Ar–H), 7.20–
4.2.2.1. Compound (5S,6S)-3b. Rf¼0.35 (EtOAc/PE¼1:1), colorless
7.30 (m, 5H, Ar–H). 13C NMR (125 MHz, CDCl3):
d 14.0, 22.7, 23.6,
25
oil. [
a
]
ꢀ50.9 (c 1.0, CHCl3). IR (film) nmax: 1642, 1512, 1450,
28.3, 31.6, 32.1, 43.1 (NCH2), 55.3 (OCH3), 71.0 (OCH2), 71.6 (C-4), 81.2
(C-5), 114.0 (2C), 127.8, 127.9 (2C), 128.4 (2C), 129.2 (2C), 130.4, 138.2,
159.0, 172.9 (C]O). MS (ESI): 400 (MHþ, 33), 422 (MNaþ, 100), 438
(MKþ, 5). HRESIMS calcd for [C24H33NO4þH]þ: 400.2488; found:
400.2509.
D
1246 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
0.95 (t, J¼7.5 Hz, 3H, CH3),
1.64 (ddd, J¼14.0, 7.5, 6.6 Hz, 1H), 1.82–2.05 (m, 4H), 2.48 (ddd,
J¼18.2, 8.3, 7.4 Hz, 1H, H-3), 2.63 (ddd, J¼18.2, 8.4, 5.1 Hz, 1H, H-3),
3.32 (ddd, J¼11.0, 5.8, 4.7 Hz, 1H, H-6), 3.58 (ddd, J¼9.6, 5.2, 4.7 Hz,
1H, H-5), 3.79 (d, J¼14.7 Hz, 1H, NCH2), 3.81 (s, 3H, OCH3), 4.38 (d,
J¼11.9 Hz, 1H, OCH2), 4.42 (d, J¼11.9 Hz, 1H, OCH2), 5.40 (d,
J¼14.7 Hz, 1H, NCH2), 6.85 (d, J¼8.7 Hz, 2H, Ar–H), 7.14 (d, J¼8.7 Hz,
2H, Ar–H), 7.17–7.20 (m, 2H, Ar–H), 7.25–7.33 (m, 3H, Ar–H). 13C
4.2.4. (5S,6S)-5-Benzyloxy-1-(4-methoxybenzyl)-6-(n-octyl)-2-
piperidinone (3d)
Following the general procedure, the reductive deoxygenation
of the tautomeric mixture 4d/5d gave 3d as the sole diastereomer
in 51% yield and 6d as the sole diastereomer in 22% yield.
NMR (100 MHz, CDCl3):
d 11.9 (CH3), 22.2, 22.5, 28.6, 48.3 (NCH2),
55.2 (OCH3), 58.2 (C-6), 70.6 (OCH2), 73.9 (C-5), 113.9 (2C), 127.1
(2C), 127.5, 128.2 (2C), 129.0 (2C), 129.2, 138.0, 158.7, 169.6 (C]O).
MS (ESI): 354 (MHþ, 80), 376 (MNaþ, 100). HRESIMS calcd for
[C22H27NO3þH]þ: 354.2069; found: 354.2069.
4.2.4.1. Compound (5S,6S)-3d. Rf¼0.35 (EtOAc/PE¼1:2), colorless
25
oil. [a
]
ꢀ30.4 (c 1.0, CHCl3). IR (film) nmax: 1643, 1513, 1455,
D

3838
L.-X. Liu et al. / Tetrahedron 65 (2009) 3834–3841
1248 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
0.89 (t, J¼6.9 Hz, 3H, CH3),
29.3, 29.6 (6C), 31.6, 31.9, 32.5, 43.1 (NCH2), 55.3 (OCH3), 71.1
(OCH2), 71.6 (C-4), 81.2 (C-5), 114.1 (2C), 127.8, 127.9 (2C), 128.5
(2C), 129.2 (2C), 130.4, 138.2, 159.0, 172.9 (C]O). MS (ESI): 512
(MHþ, 20), 534 (MNaþ, 100), 550 (MKþ, 10). Anal. Calcd for
C32H49NO4: C, 75.11; H, 9.65; N, 2.74. Found: C, 75.30; H, 9.40; N,
2.82.
1.20–1.45 (m, 12H), 1.49–1.58 (m, 1H), 1.78–1.87 (m, 1H), 1.90–2.03
(m, 2H, H-4), 2.46 (ddd, J¼18.3, 8.4, 7.6 Hz, 1H, H-3), 2.68 (ddd,
J¼18.3, 8.5, 4.8 Hz, 1H, H-3), 3.37 (dt, J¼4.9, 5.9 Hz, 1H, H-6), 3.54
(ddd, J¼10.0, 5.2, 4.9 Hz, 1H, H-5), 3.74 (d, J¼14.6 Hz, 1H, NCH2),
3.81 (s, 3H, OCH3), 4.36 (d, J¼12.0 Hz, 1H, OCH2), 4.41 (d, J¼12.0 Hz,
1H, OCH2), 5.41 (d, J¼14.6 Hz, 1H, NCH2), 6.85 (d, J¼8.7 Hz, 2H, Ar–
H), 7.12 (d, J¼8.7 Hz, 2H, Ar–H), 7.15–7.20 (m, 2H, Ar–H), 7.25–7.35
4.2.6. (5S,6S)-5-Benzyloxy-1-(4-methoxybenzyl)-6-phenylethyl-2-
piperidinone (3f)
(m, 3H, Ar–H). 13C NMR (100 MHz, CDCl3):
d 13.5, 21.9, 22.0, 26.8,
28.1, 28.6, 28.8 (2C), 29.3, 31.2, 47.8 (NCH2), 54.6 (OCH3), 56.1 (C-6),
70.1 (OCH2), 73.5 (C-5), 113.3 (2C), 126.9 (2C), 127.1, 127.6 (2C), 128.5
(2C), 128.8, 137.2, 158.3, 169.0 (C]O). MS (ESI): 438 (MHþ, 100).
HRESIMS calcd for [C28H39NO3þH]þ: 438.3008; found: 438.3021.
Following the general procedure, the reductive deoxygenation
of the tautomeric mixture 4f/5f gave 3f as the sole diastereomer in
38% yield, and 6f as the sole diastereomer in 42% yield.
4.2.6.1. Compound (5S,6S)-3f. Rf¼0.35 (EtOAc/PE¼1:2), colorless
25
4.2.4.2. (4S,5R)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)tridecanoyl
oil. [
a]
ꢀ16.5 (c 1.2, CHCl3). IR (film) nmax: 1642, 1512, 1455,
D
amide (6d). Rf¼0.35 (EtOAc/PE¼1:1), white solid, mp: 83–84 ꢁC (EtOAc/
1247 cmꢀ1 1H NMR (400 MHz, CDCl3):
. d 1.80–1.90 (m, 1H, H-4),
PE¼2:1). [a 2D5
]
ꢀ6.7 (c 0.8, CHCl3). IR (film) nmax: 3409, 3314, 1638, 1513,
1.92–2.06 (m, 2H), 2.22 (ddd, J¼14.1, 7.8, 4.9 Hz, 1H, H-4), 2.48
(ddd, J¼18.2, 8.3, 7.8 Hz, 1H, H-3), 2.65 (ddd, J¼18.2, 8.2, 4.9 Hz,
1H, H-3), 2.68 (d, J¼8.0 Hz, 1H, PhCH2), 2.72 (d, J¼8.0 Hz, 1H,
PhCH2), 3.42 (ddd, J¼6.2, 4.9, 1.0 Hz, 1H, H-6), 3.58 (ddd, J¼10.0,
5.1, 4.9 Hz, 1H, H-5), 3.68 (d, J¼14.6 Hz, 1H, NCH2), 3.80 (s, 3H,
OCH3), 4.36 (d, J¼11.9 Hz, 1H, OCH2), 4.42 (d, J¼11.9 Hz, 1H, OCH2),
5.36 (d, J¼14.6 Hz, 1H, NCH2), 6.80 (d, J¼8.7 Hz, 2H, Ar–H), 7.10 (d,
J¼8.7 Hz, 2H, Ar–H), 7.12–7.15 (m, 2H, Ar–H), 7.18–7.22 (m, 2H, Ar–
1
1249 cmꢀ1. H NMR (400 MHz, CDCl3):
d
0.88 (t, J¼6.8 Hz, 3H, CH3),
1.20–1.35 (m, 11H), 1.40–1.52 (m, 3H), 1.93 (m, 2H, H-3), 2.22 (ddd,
J¼15.2, 7.4, 7.4 Hz, 1H, H-2), 2.38 (ddd, J¼15.2, 8.2, 6.6 Hz, 1H, H-2), 2.61
(d, J¼3.1 Hz, 1H, OH), 3.35 (ddd, J¼7.0, 4.4, 4.4 Hz, 1H, H-5), 3.70–3.75
(m, 1H, H-4), 3.78 (s, 3H, OCH3), 4.26 (dd, J¼14.4, 5.5 Hz, 1H, NCH2), 4.33
(dd, J¼14.4, 5.5 Hz, 1H, NCH2), 4.45 (d, J¼11.5 Hz, 1H, OCH2), 4.57 (d,
J¼11.5 Hz, 1H, OCH2), 5.72 (br s, 1H, NH), 6.84 (d, J¼8.7 Hz, 2H, Ar–H),
7.15 (d, J¼8.7 Hz, 2H, Ar–H), 7.25–7.38 (m, 5H, Ar–H). 13C NMR
H), 7.26–7.35 (m, 6H, Ar–H). 13C NMR (100 MHz, CDCl3):
d 22.4,
(100 MHz, CDCl3):
d
14.1, 22.6, 23.6, 26.1, 29.3, 29.5, 29.7, 31.6, 31.9, 32.4,
28.7, 31.1, 33.3, 48.2 (NCH2), 55.2 (OCH3), 55.9, 70.8 (OCH2), 74.2
(C-5), 113.9 (2C), 126.1, 127.5 (2C), 127.7, 128.4 (2C), 128.5 (4C),
129.2, 129.4 (2C), 137.8, 141.4, 158.9, 169.6 (C]O). MS (ESI): 430
(MHþ, 100). HRESIMS calcd for [C28H31NO3þH]þ: 430.2382;
found: 430.2392.
43.1 (NCH2), 55.3 (OCH3), 71.0 (OCH2), 71.6 (C-4), 81.2 (C-5), 114.0 (2C),
127.8, 127.9 (2C), 128.5 (2C), 129.2 (2C), 130.3, 138.2, 159.0, 173.0 (C]O).
MS (ESI): 456 (MHþ, 100). Anal. Calcd for C28H41NO4: C, 73.81; H, 9.07;
N, 3.07. Found: C, 73.87; H, 8.77; N, 3.06.
4.2.5. (5S,6S)-5-Benzyloxy-6-(n-dodecyl)-1-(4-methoxybenzyl)-2-
piperidinone (3e)
Following the general procedure, the reductive deoxygenation
of the tautomeric mixture 4e/5e gave 3e as the sole diastereomer in
39% yield, and 6e as the sole diastereomer in 27% yield.
4.2.6.2. (4S,5R)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)-7-phenyl-
heptanoyl amide (6f). Rf¼0.35 (EtOAc/PE¼1:1), white solid, mp: 71–
73 ꢁC (EtOAc/PE¼1:1). [a 2D0
]
11.5 (c 1.8, CHCl3). IR (film) nmax: 3403,
3305,1645,1513,1248 cmꢀ1.1H NMR (500 MHz, CDCl3):
d 1.75–1.96 (m,
2H), 2.03 (ddd, J¼13.8, 7.2, 6.8 Hz, 1H, H-3), 2.21 (ddd, J¼15.3, 9.5,
6.8 Hz, 1H, H-2), 2.38 (ddd, J¼15.3, 7.2, 6.6 Hz, 1H, H-2), 2.67 (ddd,
J¼13.8, 9.5, 6.6 Hz, 1H, H-3), 2.85–2.95 (m, 2H), 3.38 (dt, J¼4.3, 7.1, 1H,
H-5), 3.68–3.75 (m,1H, H-4), 3.80 (s, 3H, OCH3), 4.28 (dd, J¼14.5, 5.6 Hz,
1H, NCH2), 4.35 (dd, J¼14.5, 5.6 Hz, 1H, NCH2), 4.46 (d, J¼11.5 Hz, 1H,
OCH2), 4.54 (d, J¼11.5 Hz, 1H, OCH2), 5.72 (br s, 1H, NH), 6.83 (d,
J¼8.7 Hz, 2H, Ar–H), 7.18 (d, J¼8.7 Hz, 2H, Ar–H), 7.20–7.40 (m, 10H, Ar–
4.2.5.1. Compound (5S,6S)-3e. Rf¼0.35 (EtOAc/PE¼1:2), colorless
25
oil. [
a]
ꢀ27.0 (c 0.9, CHCl3). IR (film) nmax: 1642, 1513, 1455,
D
1245 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
0.89 (t, J¼6.8 Hz, 3H, CH3),
1.18–1.45 (m, 20H), 1.48–1.59 (m, 1H), 1.77–1.88 (m, 1H), 1.88–2.05
(m, 2H, H-4), 2.46 (ddd, J¼18.2, 8.4, 7.7 Hz, 1H, H-3), 2.62 (ddd,
J¼18.2, 8.5, 4.9 Hz, 1H, H-3), 3.37 (dt, J¼4.9, 5.9 Hz, 1H, H-6), 3.54
(ddd, J¼9.8, 4.9, 4.9 Hz, 1H, H-5), 3.73 (d, J¼14.7 Hz, 1H, NCH2), 3.81
(s, 3H, OCH3), 4.36 (d, J¼12.0 Hz, 1H, OCH2), 4.40 (d, J¼12.0 Hz, 1H,
OCH2), 5.41 (d, J¼14.7 Hz, 1H, NCH2), 6.84 (d, J¼8.7 Hz, 2H, Ar–H),
7.12 (d, J¼8.7 Hz, 2H, Ar–H), 7.15–7.20 (m, 2H, Ar–H), 7.23–7.32 (m,
3H, Ar–H). 13C NMR (100 MHz, CDCl3): 14.1, 22.5, 22.6, 27.5, 28.7,
29.3, 29.4, 29.5, 29.6 (4C), 29.9, 31.9, 48.4 (NCH2), 55.2 (OCH3), 56.7
(C-6), 70.7 (OCH2), 74.2 (C-5),113.8 (2C),127.5 (2C),127.7,128.3 (2C),
129.2 (2C), 129.4, 137.8, 158.9, 169.6 (C]O). MS (ESI): 494 (MHþ,
100). Anal. Calcd for C32H47NO3: C, 77.85; H, 9.60; N, 2.84. Found: C,
78.12; H, 9.71; N, 3.08.
H). 13C NMR (125 MHz, CDCl3):
d 23.5, 31.2, 32.3, 34.2, 43.1 (NCH2), 55.2
(OCH3), 70.2 (OCH2), 71.6 (C-4), 81.1 (C-5), 114.0 (2C), 125.7, 127.8, 127.9
(2C), 128.4 (4C), 128.5, 129.2 (2C), 129.4, 130.3, 138.2, 142.1, 159.0, 172.9
(C¼O). MS (ESI): 448 (MHþ, 100). HRESIMS calcd for [C28H33NO4þH]þ:
448.2488; found: 448.2493.
4.2.7. (5S,6S)-5-Benzyloxy-1-(4-methoxybenzyl)-6-phenyl-2-
piperidinone (3g)
Following the general procedure, the reductive deoxygenation
of the tautomeric mixture 4g/5g gave a diastereomeric mixture of
3g and the known 2g6c in 60:40 ratio (combined yield: 54%), and 6g
as a diastereomeric mixture in 55:45 ratio (combined yield: 35%).
4.2.5.2. (4S,5R)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)hepta-
decanoyl amide (6e). Rf¼0.35 (EtOAc/PE¼1:1), white solid, mp: 66–
4.2.7.1. Compound (5S,6S)-3g (major diastereomer). Rf¼0.35
25
25
68 ꢁC (EtOAc/PE¼2:1). [
a
]
ꢀ3.5 (c 2.2, CHCl3). IR (film) nmax: 3306,
(EtOAc/PE¼1:2), colorless oil. [
a
]
ꢀ76.4 (c 0.9, CHCl3). IR (film)
D
D
1638, 1514, 1250, 1092 cmꢀ1. 1H NMR (500 MHz, CDCl3):
d
0.81 (t,
nmax: 1644, 1512, 1246 cmꢀ1 1H NMR (400 MHz, CDCl3):
. d 1.60–
J¼6.9 Hz, 3H, CH3), 1.10–1.25 (m, 19H), 1.30–1.50 (m, 3H), 1.80–1.92
(m, 2H, H-3), 2.16 (ddd, J¼14.8, 7.4, 7.4 Hz, 1H, H-2), 2.30 (ddd,
J¼14.8, 8.0, 6.6 Hz, 1H, H-2), 2.52 (s, 1H, OH), 3.26–3.32 (m, 1H, H-
5), 3.63–3.68 (m, 1H, H-4), 3.75 (s, 3H, OCH3), 4.21 (dd, J¼14.4,
5.5 Hz, 1H, NCH2), 4.27 (dd, J¼14.4, 5.5 Hz, 1H, NCH2), 4.39 (d,
J¼11.5 Hz, 1H, OCH2), 4.51 (d, J¼11.5 Hz, 1H, OCH2), 5.65 (s, 1H, NH),
6.79 (d, J¼8.7 Hz, 2H, Ar–H), 7.10 (d, J¼8.7 Hz, 2H, Ar–H), 7.18–7.30
1.76 (m, 2H, H-4), 2.58 (ddd, J¼18.3, 9.5, 8.7 Hz, 1H, H-3), 2.78
(ddd, J¼18.3, 5.4, 5.2 Hz, 1H, H-3), 3.32 (d, J¼14.4 Hz, 1H, NCH2),
3.75–3.82 (m, 1H, H-5), 3.80 (s, 3H, OCH3), 4.43 (d, J¼11.8 Hz, 1H,
OCH2), 4.48 (d, J¼11.8 Hz, 1H, OCH2), 4.57 (d, J¼4.9 Hz, 1H, H-6),
5.50 (d, J¼14.4 Hz, 1H, NCH2), 6.82 (d, J¼8.7 Hz, 2H, Ar–H), 7.05 (d,
J¼8.7 Hz, 2H, Ar–H), 7.12 (dd, J¼7.8, 1.8 Hz, 2H, Ar–H), 7.19 (dd,
J¼7.8, 1.8 Hz, 2H, Ar–H), 7.23–7.29 (m, 3H, Ar–H), 7.34–7.40 (m,
(m, 5H, Ar–H). 13C NMR (125 MHz, CDCl3):
d
14.1, 22.7, 23.6, 26.2,
3H, Ar–H). 13C NMR (100 MHz, CDCl3):
d 22.5, 29.6, 47.4 (NCH2),

L.-X. Liu et al. / Tetrahedron 65 (2009) 3834–3841
3839
55.3 (OCH3), 61.4, 71.0 (OCH2), 74.4 (C-5), 114.0 (2C), 127.3 (2C),
127.6, 128.0, 128.2 (2C), 128.4 (2C), 128.7 (2C), 129.0, 129.6 (2C),
136.2, 137.9, 159.0, 169.9 (C]O). MS (ESI): 402 (MHþ, 100), 424
(MNaþ, 30). HRESIMS calcd for [C26H27NO3þH]þ: 402.2069;
found: 402.2086.
2.22 (ddd, J¼15.2, 7.4, 7.4 Hz, 1H, H-2), 2.41 (ddd, J¼15.2, 7.5,
6.6 Hz, 1H, H-2), 2.60 (s, 1H, OH), 2.73 (dd, J¼13.8, 8.8 Hz, 1H, H-6),
2.90 (dd, J¼13.8, 3.6 Hz, 1H, H-6), 3.38–3.45 (m, 1H, H-5), 3.80 (s,
3H, OCH3), 3.90–3.98 (m, 1H, H-4), 4.25 (dd, J¼14.5, 5.6 Hz, 1H,
NCH2), 4.33 (dd, J¼14.5, 5.6 Hz, 1H, NCH2), 4.46 (d, J¼11.5 Hz, 1H,
OCH2), 4.58 (d, J¼11.5 Hz, 1H, OCH2), 5.65 (br s, 1H, NH), 6.82 (d,
J¼8.7 Hz, 2H, Ar–H), 7.15 (d, J¼8.7 Hz, 2H, Ar–H), 7.20–7.50 (m,
4.2.7.2. (4S,5R)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)-5-phenyl-
pentanoyl amide (6g) (major diastereomer). Rf¼0.35 (EtOAc/PE¼1:1),
10H, Ar–H). 13C NMR (125 MHz, CDCl3):
d 24.0, 31.4, 39.1, 43.1
white solid, mp: 76–78 ꢁC (EtOAc/PE¼2:1). [a 2D5
]
ꢀ2.4 (c 1.9, CHCl3). IR
(NCH2), 55.4 (OCH3), 71.6 (OCH2), 72.6 (C-4), 80.4 (C-5), 114.0 (2C),
126.3, 127.8, 127.9 (2C), 128.4 (4C), 129.1 (2C), 129.3 (2C), 130.3,
138.1, 138.7, 159.0, 172.8 (C]O). MS (ESI): 434 (MHþ, 100). Anal.
Calcd for C27H31NO4: C, 74.80; H, 7.21; N, 3.23. Found: C, 74.46; H,
7.35; N, 3.25.
(film) nmax: 3414, 3315, 1650, 1513, 1248 cmꢀ1 1H NMR (400 MHz,
.
CDCl3):
d
1.81 (dddd, J¼14.5, 7.4, 7.0, 3.9 Hz,1H, H-3),1.92 (dddd, J¼14.5,
7.4, 7.1, 1.2 Hz, 1H, H-3), 2.14 (ddd, J¼14.9, 7.4, 7.4 Hz, 1H, H-2), 2.29
(ddd, J¼14.9, 7.1, 7.0 Hz,1H, H-2), 3.00–3.20 (s,1H, OH), 3.59 (ddd, J¼5.1,
3.9, 1.2 Hz, 1H, H-4), 3.77 (s, 3H, OCH3), 4.23 (dd, J¼14.5, 5.6 Hz, 1H,
NCH2), 4.27 (dd, J¼14.5, 5.6 Hz, 1H, NCH2), 4.41 (d, J¼11.5 Hz, 1H, OCH2),
4.46 (d, J¼11.5 Hz, 1H, OCH2), 4.80 (d, J¼5.1 Hz, 1H, H-5), 5.68 (br s, 1H,
NH), 6.82 (d, J¼8.7 Hz, 2H, Ar–H), 7.12 (d, J¼8.7 Hz, 2H, Ar–H), 7.24–7.36
4.4.2. (4S,5R)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)-
heneicosanoyl amide (6i) (4S,5R)-6i (major diastereomer)
Rf¼0.35 (EtOAc/PE¼1:2), white solid, mp: 85–86 ꢁC (EtOAc/
25
(m, 10H, Ar–H). 13C NMR (100 MHz, CDCl3):
d
24.5, 31.9, 43.0 (NCH2),
PE¼1:1). [
a]
ꢀ3.4 (c 1.1, CHCl3). IR (film) nmax: 3306, 1637, 1514,
D
55.3 (OCH3), 72.1 (OCH2), 73.8 (C-4), 82.1 (C-5), 114.0 (2C), 126.5 (2C),
127.5, 127.8, 128.0 (2C), 128.2 (2C), 128.4 (2C), 129.2 (2C), 130.3, 138.0,
140.8, 159.0, 172.9 (C]O). MS (ESI): 420 (MHþ, 15), 442 (MNaþ, 100).
Anal. Calcd for C26H29NO4: C, 74.44; H, 6.97; N, 3.34. Found: C, 74.70; H,
7.04; N, 3.51.
1467, 1250 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
0.91 (t, J¼6.9 Hz, 3H,
CH3), 1.18–1.35 (m, 27H), 1.42–1.55 (m, 3H), 1.88–1.98 (m, 2H, H-3),
2.27 (ddd, J¼14.6, 7.4, 7.4 Hz, 1H, H-2), 2.41 (ddd, J¼14.6, 8.2, 6.6 Hz,
1H, H-2), 2.65 (br s, 1H, OH), 3.36 (dt, J¼4.5, 6.5 Hz, 1H, H-5), 3.70–
3.76 (m, 1H, H-4), 3.79 (s, 3H, OCH3), 4.27 (dd, J¼14.4, 5.5 Hz, 1H,
NCH2), 4.35 (dd, J¼14.4, 5.5 Hz, 1H, NCH2), 4.45 (d, J¼11.5 Hz, 1H,
OCH2), 4.58 (d, J¼11.5 Hz, 1H, OCH2), 5.65 (br s, 1H, NH), 6.84 (d,
J¼8.7 Hz, 2H, Ar–H), 7.18 (d, J¼8.7 Hz, 2H, Ar–H), 7.8–7.40 (m, 5H,
4.3. General procedure for the reductive ring-opening of the
tautomeric mixture 4/5
Ar–H). 13C NMR (100 MHz, CDCl3):
d 14.1, 22.7, 23.5, 26.2, 29.4, 29.6
To a cooled (ꢀ20 ꢁC) solution of the tautomeric mixture 4/5
(1 mol equiv) in Et2O (0.1 M) was added dropwise a solution of
Zn(BH4)2 in Et2O (3 mol equiv) under argon atmosphere. The mix-
ture was allowed to slowly warm to room temperature and was
stirred at that temperature overnight. The reaction was quenched
with saturated NH4Cl. After extraction with CH2Cl2, the combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
EtOAc/PE¼1:1) to yield 6 as a white solid.
(2C), 29.7 (8C), 31.6, 31.9, 32.5, 43.1 (NCH2), 55.3 (OCH3), 71.0
(OCH2), 71.6 (C-4), 81.1 (C-5), 114.0 (2C),127.8,127.9 (2C),128.5 (2C),
129.2 (2C), 130.3, 138.2, 159.0, 172.9 (C¼O). MS (ESI): 568 (MHþ, 25),
590 (MNaþ, 100). Anal. Calcd for C36H57NO4: C, 76.15; H, 10.12; N,
2.47. Found: C, 76.26; H, 9.81; N, 2.39.
4.4.3. (4S,5R)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)-7-
methyloctanoyl amide (6j) (4S,5R)-6j (major diastereomer)
Rf¼0.35 (EtOAc/PE¼2:3), white solid, mp: 56–58 ꢁC (EtOAc/
25
PE¼2:1). [
a
]
ꢀ5.3 (c 1.4, CHCl3). IR (film) nmax: 3415, 3305, 1650,
D
Following the general reductive ring-opening procedure, 6a and
its diastereomer were obtained in 94:6 diastereomeric ratio and in
82% combined yield. Compound 6b and its diastereomer were
obtained in 94:6 diastereomeric ratio and in 89% combined yield.
Compound 6c and its diastereomer were obtained in 91:9 di-
astereomeric ratio and in 82% combined yield. Compound 6d and
its diastereomer were obtained in 98:2 diastereomeric ratio and in
95% combined yield. Compound 6e and its diastereomer were
obtained in 90:10 diastereomeric ratio and in 77% combined yield.
Compound 6f and its diastereomer were obtained in 89:11 di-
astereomeric ratio and in 87% combined yield. Compound 6g and
its diastereomer were obtained in 65:35 diastereomeric ratio and in
66% combined yield. Compound 6h and its diastereomer were
obtained in 95:5 diastereomeric ratio and in 85% combined yield.
Compound 6i and its diastereomer were obtained in 86:14 di-
astereomeric ratio and in 78% combined yield. Compound 6j and its
diastereomer were obtained in 97:3 diastereomeric ratio and in 81%
combined yield.
1513, 1248 cmꢀ1. 1H NMR (500 MHz, CDCl3):
d
0.89 (d, J¼6.7 Hz, 3H,
CH3), 0.94 (d, J¼6.7 Hz, 3H, CH3), 1.22 (ddd, J¼9.5, 9.0, 3.3 Hz, 1H),
1.39 (ddd, J¼9.5, 5.1, 4.4 Hz, 1H), 1.75–1.84 (m, 1H), 1.87–1.98 (m,
2H), 2.22 (ddd, J¼15.2, 7.4, 7.4 Hz, 1H, H-2), 2.37 (ddd, J¼15.2, 6.8,
6.8 Hz, 1H, H-2), 2.52 (s, 1H, OH), 3.33 (dt, J¼4.2, 6.0 Hz, 1H, H-5),
3.76 (ddd, J¼9.5, 4.2, 3.8 Hz, 1H, H-4), 3.78 (s, 3H, OCH3), 4.26 (dd,
J¼14.4, 5.8 Hz, 1H, NCH2), 4.33 (dd, J¼14.4, 5.8 Hz, 1H, NCH2), 4.45
(d, J¼11.6 Hz,1H, OCH2), 4.58 (d, J¼11.6 Hz,1H, OCH2), 5.80 (br s,1H,
NH), 6.78 (d, J¼8.5 Hz, 2H, Ar–H), 7.15 (d, J¼8.5 Hz, 2H, Ar–H), 7.25–
7.40 (m, 5H, Ar–H). 13C NMR (125 MHz, CDCl3):
d 22.0, 23.6, 23.7,
24.8, 31.8, 41.4, 43.1 (NCH2), 55.3 (OCH3), 69.0 (OCH2), 71.7 (C-4),
81.6 (C-5), 114.1 (2C), 127.8, 127.9 (2C), 128.5 (2C), 129.2 (2C), 130.4,
138.3, 159.0, 173.0 (C]O). MS (ESI): 400 (MHþ, 40), 422 (MNaþ,
100), 438 (MKþ, 15). HRESIMS calcd for [C24H33NO4þH]þ:
400.2484; found: 400.2482.
4.5. General procedure for the synthesis of (5S,6S)-2-
piperidinones 3 via the cyclization of 6
4.4. The physical and spectral data of 6h–6j
To a cooled (ꢀ20 ꢁC) solution of a mixture of 6 (1.0 mol equiv)
and Et3N (2.0 mol equiv) in CH2Cl2 was added dropwise MsCl
(1.2 mol equiv) under nitrogen atmosphere. The mixture was stir-
red at ꢀ20 to ꢀ10 ꢁC for 2 h. Water was added and the aqueous
layer was separated and extracted with CH2Cl2. The combined or-
ganic layers were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (eluent: EtOAc/
PE¼1:2) to yield the mesylates 8, which are unstable and were used
immediately in the subsequent step.
The physical and spectral data of 6a–6g are shown in the pre-
vious sections, those of 6h–6j in the following sections.
4.4.1. (4S,5R)-4-Benzyloxy-5-hydroxy-N-(4-methoxybenzyl)-6-
phenylhexanoyl amide (6h) (4S,5R)-6h (major diastereomer)
Rf¼0.35 (EtOAc/PE¼2:3), white solid, mp: 75–76 ꢁC (EtOAc/
25
PE¼2:1). [
a
]
ꢀ5.6 (c 1.7, CHCl3). IR (film) nmax: 3408, 3306, 1645,
D
1513, 1248 cmꢀ1 1H NMR (500 MHz, CDCl3): 2.04 (m, 2H, H-3),
.

3840
L.-X. Liu et al. / Tetrahedron 65 (2009) 3834–3841
To a solution of mesylate 8 (1 mol equiv) in THF (0.1 M) and
100), 454 (MKþ, 10). Anal. Calcd for C27H29NO3: C, 78.04; H, 7.03; N,
3.37. Found: C, 78.41; H, 7.11; N, 3.36.
HMPA (2.0 mol equiv) was added dropwise a solution of potassium
tert-butoxide (1.2 mol equiv) in THF at 0 ꢁC under nitrogen atmo-
sphere. The mixture was allowed slowly to warm to room tem-
perature and was stirred for 48 h. The reaction was quenched with
saturated NH4Cl at 0 ꢁC. The aqueous layer was separated and
extracted with CH2Cl2. The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash chro-
matography on silica gel (eluent: EtOAc/PE¼1:2) to yield (5S,6S)-2-
piperidinones 3 in 66–87% yields (Table 2). The reaction of 8h gave
9 in 81% yield. The reaction of 8j gave 10 in 72% yield.
Acknowledgements
The authors are grateful to the NSF of China (grant numbers:
20772099; 20832005) and the program for Innovative Research
Team in Science & Technology (University) in Fujian Province for
financial support.
References and notes
1. For reviews on the piperidine alkaloids, see: (a) Angle, S. R.; Breitenbucher, J. G.
Recent Progress in the Synthesis of Piperidine and Indolizidine Alkaloids. In
Studies in Natural Products Chemistry; 1995; Vol. 16, Part 10, pp 453–502; (b)
Schneider, M. Pyridine and Piperidine Alkaloids: An Update. In Alkaloids:
Chemical and Biochemical Perspectives; Pelletier, S. W., Ed.; Elsevier Science:
Oxford, 1996; Vol. 10, pp 155–299; (c) Ojima, I.; Iula, D. M. New Approaches to
the Syntheses of Piperidine, Pyrrolizidine, and Quinazoline Alkaloids by Means
of Transition Metal Catalyzed Carbonylations. In Alkaloids: Chemical and
Biological Perspectives; Elsevier Science: Oxford, 1999; Vol. 13, pp 371–412; (d)
Michael, J. P. Nat. Prod. Rep. 1999, 16, 675–696.
4.5.1. The physical and spectral data of (5S,6S)-2-piperidinones
3a–3g
The physical and spectral data of (5S,6S)-2-piperidinones 3a–3g
are shown in the previous sections.
4.5.2. (5S,6S)-5-Benzyloxy-6-(n-hexadecyl)-1-(4-methoxybenzyl)-
2-piperidinone (3i)
25
Colorless oil. [
a
]
ꢀ18.9 (c 0.7, CHCl3). IR (film) nmax: 1644, 1512,
2. (a) Brown, E.; Dhal, R. Bull. Soc. Chim. Fr. 1972, 11, 4292–4303; (b) Bolzani, V. D. S.;
Gunatilaka, A. A. L.; Kingston, D. G. I. Tetrahedron 1995, 51, 5929–5934; (c) San-
D
1464, 1248 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
0.88 (t, J¼6.8 Hz, 3H,
´
sores-Peraza, P.; Rosado-Vallado, M.; Brito-Loeza, W.; Mena-Rejon, G. J.; Quijano, L.
CH3), 1.18–1.43 (m, 28H), 1.48–1.60 (m, 1H), 1.77–1.88 (m, 1H), 1.88–
2.05 (m, 2H, H-4), 2.48 (ddd, J¼18.2, 8.1, 8.1 Hz, 1H, H-3), 2.62 (ddd,
J¼18.2, 8.3, 5.0 Hz, 1H, H-3), 3.37 (dt, J¼4.8, 5.9 Hz, 1H, H-6), 3.54
(ddd, J¼9.9, 5.1, 4.8 Hz, 1H, H-5), 3.74 (d, J¼14.6 Hz, 1H, NCH2), 3.81
(s, 3H, OCH3), 4.37 (d, J¼12.2 Hz, 1H, OCH2), 4.40 (d, J¼12.2 Hz, 1H,
OCH2), 5.41 (d, J¼14.6 Hz, 1H, NCH2), 6.85 (d, J¼8.5 Hz, 2H, Ar–H),
7.13 (d, J¼8.5 Hz, 2H, Ar–H), 7.15–7.20 (m, 2H, Ar–H), 7.25–7.32 (m,
Fitoterapia 2000, 71, 690–692; (d) Viegas, C., Jr.; Bolzani, V. S.; Pimentel, L. S. B.;
Castro, N. G.; Cabral, R. F.; Costa, R. S.; Floyd, C.; Rocha, M. S.; Young, M. C. M.;
Barreiro, E. J.; Fraga, C. A. M. Bioorg. Med. Chem. 2005, 13, 4184–4190; (e) Viegas, C.,
Jr.; Silva, D. H. S.; Pivatto, M.; de Rezende, A.; Castro-Gamboˆa, I.; Bolzani, V. S.; Nair,
M. G. J. Nat. Prod. 2007, 70, 2026–2028; (f) Viegas, C., Jr.; Alexandre-Moreira, M. S.;
Fraga, C. A. M.; Barreiro, E. J.; da Silva Bolzani, V.; de Miranda, A. L. P. Chem. Pharm.
Bull. 2008, 56, 407–412; (g) Castro, N. G.; Costa, R. S.; Pimentel, L. S. B.; Danuello, A.;
Romeiro, N. C.; Viegas, C., Jr.; Barreiro, E. J.; Fraga, C. A. M.; Bolzani, V. S.;Rocha, M. S.
Eur. J. Pharmacol. 2008, 580, 339–349.
3. For reviews on the syntheses of piperidines, see: (a) Nadin, A. J. Chem. Soc.,
Perkin Trans. 1 1998, 3493–3514; (b) Ciufolini, M. A.; Hermann, C. Y. W.; Dong,
Q.; Shimizu, T.; Swaminathan, S.; Xi, N. Synlett 1998, 105–114; (c) Zhou, W. S.;
Lu, Z. H.; Xu, Y. M.; Liao, L. X.; Wang, Z. M. Tetrahedron 1999, 55, 11959–11983;
(d) Laschat, S.; Dickner, T. Synthesis 2000, 1781–1813; (e) Toyooka, N.; Nemoto,
H. Drugs Future 2002, 27, 143–158; (f) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953–2989; (g) Felpin, F.-X.; Lebreton,
J. Eur. J. Org. Chem. 2003, 3693–3712; (h) Buffat, M. G. P. Tetrahedron 2004, 60,
1701–1729.
3H, Ar–H). 13C NMR (100 MHz, CDCl3):
d 14.1, 22.5, 22.7, 27.5, 28.7,
29.3, 29.4, 29.5, 29.6 (3C), 29.7 (5C), 30.0, 31.9, 48.4 (NCH2), 55.2
(OCH3), 56.7 (C-6), 70.7 (OCH2), 74.2 (C-5), 114.0 (2C), 127.5 (2C),
127.7, 128.4 (2C), 129.3 (2C), 129.4, 137.9, 158.9, 169.6 (C]O). MS
(ESI): 550 (MHþ, 30), 572 (MNaþ,100). Anal. Calcd for C36H55NO3: C,
78.64; H, 10.08; N, 2.55. Found: C, 78.26; H, 9.92; N, 2.85.
4.5.3. trans-4-Benzyloxy-N-(4-methoxybenzyl)-7-methyl-4-
4. For selected examples on the synthesis of 2,3-cis-piperidin-3-ols, see: (a) Lu, Z.-H.;
Zhou, W.-S. Tetrahedron 1993, 49, 4659–4664; (b) Kiguchi, T.; Shirakawa, M.;
Ninomiya, I.; Naito, T. Chem. Pharm. Bull. 1996, 44, 1282–1284; (c) Kiguchi, T.;
Shirakawa, M.; Honda, R.; Ninomiya, I.; Naito, T. Tetrahedron 1998, 54, 15589–
15606; (d) Kumar, K. K.; Datta, A. Tetrahedron 1999, 55, 13899–13906; (e) Sato, T.;
Aoyagi, S.; Kibayashi, C. Org. Lett. 2003, 5, 3839–3842; (f) Lee, H. K.; Chun, J. S.; Pak,
C. S. Tetrahedron 2003, 59, 6445–6454; (g) Ma, D.; Ma, N. Tetrahedron Lett. 2003, 44,
3963–3965; (h) Randl, S.; Blechert, S. Tetrahedron Lett. 2004, 45, 1167–1169; (i)
Lemire, A.; Charette, A. B. Org. Lett. 2005, 7, 2747–2750; (j) Leverett, C. A.; Cassidy,
M. P.; Padwa, A. J. Org. Chem. 2006, 71, 8591–8601; (k) Liu, R.-H.; Fang, K.; Wang, B.;
Xu, M.-H.; Lin, G.-Q. J. Org. Chem. 2008, 73, 3307–3310.
heptenoylamide (9)
Colorless oil. IR (film) nmax: 1642, 1512, 1246 cmꢀ1
.
1H NMR
(400 MHz, CDCl3):
d
0.87 (d, J¼6.7 Hz, 6H, 2ꢂCH3), 1.55 (ddd,
J¼13.3, 6.7, 6.7 Hz, 1H), 1.89 (dd, J¼7.5, 6.7 Hz, 2H), 2.41 (t, J¼7.4 Hz,
2H, H-3), 2.55 (t, J¼7.4 Hz, 2H, H-2), 3.78 (s, 3H, OCH3), 4.25 (dd,
J¼14.4, 5.6 Hz, 1H, NCH2), 4.31 (dd, J¼14.4, 5.6 Hz, 1H, NCH2), 4.52
(t, J¼7.5 Hz, 1H), 4.63 (d, J¼12.1 Hz, 1H, OCH2), 4.67 (d, J¼12.1 Hz,
1H, OCH2), 5.80 (br s, 1H, NH), 6.82 (d, J¼8.5 Hz, 2H, Ar–H), 7.13 (d,
J¼8.5 Hz, 2H, Ar–H), 7.25–7.35 (m, 5H, Ar–H). 13C NMR (100 MHz,
5. Ruan, Y.-P.; Wei, B.-G.; Xu, X.-Q.; Liu, G.; Yu, D.-S.; Liu, L.-X.; Huang, P.-Q.
Chirality 2005, 17, 595–599.
6. (a) Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett. 2003, 5, 1927–1930;
(b) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003, 1663–1667; (c) Liu, L.-X.;
Ruan, Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem. 2004, 69, 6001–6009; (d) Wei,
B.-G.; Chen, J.; Huang, P.-Q. Tetrahedron 2006, 62, 190–198; (e) Liu, L.-X.; Peng,
Q.-L.; Huang, P.-Q. Tetrahedron: Asymmetry 2008, 19, 1200–1203; (f) Yu, D.-S.;
Xu, W.-X.; Liu, L.-X.; Huang, P.-Q. Synlett 2008, 1189–1192.
7. For reductive alkylation of symmetric tartarimide, see: Yoda, H.; Kitayama, H.;
Yamada, W.; Katagiri, T.; Takabe, K. Tetrahedron: Asymmetry 1993, 4, 1451–1454
and 1455–1456.
CDCl3):
d 22.2 (2C), 26.2, 29.5, 34.3, 35.7, 43.1 (NCH2), 55.3 (OCH3),
68.6 (OCH2), 98.4 (C-5),114.0 (2C),127.4 (2C),127.7,128.4 (2C),129.2
(2C), 130.5, 137.5, 154.1 (C-4), 159.0, 172.3 (C]O). MS (ESI): 382
(MHþ, 100). HRESIMS calcd for [C24H31NO3þH]þ: 382.2382; found:
382.2377.
4.5.4. trans-(S)-4-Benzyloxy-N-(4-methoxybenzyl)-6-
8. (a) Morgan, I. R.; Yazici, A.; Pyne, S. G. Tetrahedron 2008, 64, 1409–1419; See
also: (b) Morgan, I. R.; Yazici, A.; Pyne, S. G.; Skelton, B. W. J. Org. Chem. 2008,
73, 2943–2946; (c) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am.
Chem. Soc. 2001, 123, 12510–12517.
phenylhexanoyl amide (10)
25
Colorless oil. [
a
]
D
ꢀ61.1 (c 1.1, CHCl3). IR (film) nmax: 3303, 1645,
1512, 1248 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
2.02 (dddd, J¼13.7,
9. For reviews on
181–212.
a-amidoalkylation, see: Zaugg, H. E. Synthesis 1984, 85–110 and
7.1, 6.6, 0.9 Hz, 2H, H-3), 2.33 (dt, J¼0.9, 7.1 Hz, 2H, H-2), 3.78 (s, 3H,
OCH3), 3.96 (ddd, J¼8.0, 7.1, 6.6 Hz,1H, H-4), 4.25 (dd, J¼14.4 5.5 Hz,
1H, NCH2), 4.33 (dd, J¼14.4, 5.5 Hz, 1H, NCH2), 4.34 (d, J¼11.8 Hz,
1H, OCH2), 4.62 (d, J¼11.8 Hz, 1H, OCH2), 5.75 (br s, 1H, NH), 6.11
(dd, J¼16.0, 8.0 Hz, 1H, H-5), 6.55 (d, J¼16.0 Hz, 1H, H-6), 6.83 (d,
J¼8.7 Hz, 2H, Ar–H), 7.14 (d, J¼8.7 Hz, 2H, Ar–H), 7.23–7.40 (m, 10H,
10. For reviews on the N-acyliminium ions, see: (a) Speckamp, W. N.; Hiemstra, H.
Tetrahedron 1985, 41, 4367–4416; (b) Speckamp, W. N.; Moolenaar, M. J. Tet-
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Ar–H). 13C NMR (100 MHz, CDCl3):
d 31.4, 32.6, 43.0 (NCH2), 55.3
(OCH3), 70.2 (OCH2), 79.1 (C-4), 114.0 (2C), 126.5 (2C), 127.6, 127.8
(2C), 127.9 (2C), 128.4 (2C), 128.6 (2C), 129.2, 129.6 130.4, 132.8,
136.3, 138.4,159.0,172.4 (C]O). MS (ESI): 416 (MHþ, 5), 438 (MNaþ,
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