1,4-Elimination/Br?nsted acid catalyzed aza-Ferrier reaction sequence as an entry to β-amino-β,γ-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tet.2013.01.088

The 1,4-elimination reaction of (Z)-N-Boc-2-(4-methoxy-2-alkenyloxy)amines with Br?nsted acids catalyzed aza-Ferrier reaction of the 1,4-eliminated product, thus obtained, afforded various β-amino-β,γ-unsaturated aldehydes. The scope and limitation of thi

Full text of DOI:10.1016/j.tet.2013.01.088

Tetrahedron 69 (2013) 2745e2752
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
1,4-Elimination/Brønsted acid catalyzed aza-Ferrier reaction
sequence as an entry to b-amino-b,g-unsaturated aldehydes
*
Eiji Tayama , Kouki Horikawa, Hajime Iwamoto, Eietsu Hasegawa
Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1,4-elimination reaction of (Z)-N-Boc-2-(4-methoxy-2-alkenyloxy)amines with Brønsted acids
Received 26 November 2012
Received in revised form 25 January 2013
Accepted 29 January 2013
catalyzed aza-Ferrier reaction of the 1,4-eliminated product, thus obtained, afforded various
-unsaturated aldehydes. The scope and limitation of this sequential reaction are described.
Ó 2013 Elsevier Ltd. All rights reserved.
b-amino-
b,g
Available online 8 February 2013
Keywords:
Elimination
Ferrier reaction
Acyliminium ion
Acetal
Diene
1. Introduction
The Ferrier (type-II) reaction1 of O-alkenyl O,O-acetals is
a unique synthetic transformation that converts an OeC bond into
a new CeC bond; hence, it has found wide application in the syn-
thesis of oxygen-containing heterocycles.2,3 The reaction proceeds
via the formation of an oxocarbenium ion and an enolate (or enol)
in the presence of acid catalyst. The subsequent recombination of
these species affords various types of b-alkoxy carbonyl compounds
(Scheme 1, Eq.1). The nitrogen version of the reaction, which occurs
via the formation of a N-acyliminium ion and an enolate generated
from O-alkenyl N,O-acetals (aza-Ferrier reaction), is rare (Eq. 2)4,5
because efficient preparative methods of O-alkenyl N,O-acetals
are limited. Transition metal-catalyzed4 or base-induced4c,6 isom-
erization of O-allylic N,O-acetals have been reported; however,
these methods are commonly applicable to simple O-allyl de-
rivatives that afford O-(prop-1-enyl) N,O-acetals as products.
Previously, we reported the 1,4-elimination of (Z)-N-Boc-2-(4-
methoxy-2-alkenyloxy)pyrrolidine A to give O-(1,3-dienyl) N,O-
acetal B with good 1E,3E-stereoselectivity (Scheme 2, Eq. 1, step 1).5
This method enabled us to prepare various O-alkenyl N,O-acetals
without the use of special techniques. The Brønsted acid catalyzed
Scheme 1. Ferrier (type-II) and aza-Ferrier reaction.
synthesis of pyrrolidine alkaloids.7 With this result in hand, we
tried to extend this reaction sequence to six-membered, nitrogen-
containing heterocyclic (piperidine) and acyclic derivatives, which
would afford various
b-amino-b,g-unsaturated aldehydes (Eq. 2).
aza-Ferrier reaction of B provided b-amino-b,g-unsaturated alde-
hyde C (step 2), which could be a good intermediate for the
2. Results and discussion
We selected piperidine derivatives 1aee as substrates and per-
formed the reactions to expand the scope of the synthetic protocol
* Corresponding author. Tel.: þ81 25 262 7740; fax: þ81 25 262 7741; e-mail
address: tayama@chem.sc.niigata-u.ac.jp (E. Tayama).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.088

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E. Tayama et al. / Tetrahedron 69 (2013) 2745e2752
To compare the E/Z selectivity of 1,4-elimination of six- and five-
membered nitrogen-containing heterocycles, we re-examined the
reaction of pyrrolidine derivatives 1f and 1g under the same con-
ditions (Table 1, entries 6, 7).5 A reaction of 4,4-dimethyl derivative
1f gave only 1E-2f (entry 6). The 1H NMR spectrum of 2f in DMSO-
d6 contained a pair of 1-H peaks with similar coupling constants (J1-
¼10e11 Hz) that were due to the formation of a mixture of
H, 2-H
rotamers (55/45) caused by N-Boc group.8 A reaction with 4-n-
heptyl derivative 1g gave 1E,3E-2g as a major product (entry 7,
1E,3E/1E,3Z¼90/10). The 1H NMR spectrum of 2g had two pairs of
1-H peaks with similar coupling constants (J1-H,
¼11e12 Hz)
2-H
because of the formation of a rotamer mixture (50/50). The C3eC4
stereochemistry of 2g could be determined directly (3E/3Z¼90/10)
by the coupling constant of 3-H (J3-H, 4-H¼15 Hz for 1E,3E-2g, 12 Hz
for 1E,3Z-2g).
To clarify the stereoselectivity of this 1,4-elimination, we ex-
amined the reaction with the E-isomer of 1c. The dienyl ether 2c
was obtained as a 1:1 mixture of 1Z,3E and 1Z,3Z isomer, with small
amounts of 1E isomer in a 89% combined yield (Scheme 3). All E/Z-
isomers of 2c could be identified by 1H NMR analysis.9 At present,
no reasonable explanation can be offered for the 1Z-selectivity in
1,4-elimination of E-1c. Similar 1E-to-1Z changeover was observed
in our previous work.5,10
Scheme 2. 1,4-Elimination and aza-Ferrier reaction.
(Table 1). After the treatment of the 4,4-dimethyl derivative 1a with
lithium 2,2,6,6-tetramethylpiperidide (LiTMP) in THF, the 1,4-
elimination proceeded smoothly to afford the 2-(1,3-dienyloxy)pi-
peridine 2a in a 81% yield as a single regioisomer (entry 1). 1H NMR
analysis of 2a in DMSO-d6 yielded a clear spectrum, and the C1eC2
stereochemistry was assigned as E based on the coupling constant
of 1-H (J1-H,
¼12 Hz). A reaction with the analog 1b gave the
2-H
corresponding 1,4-eliminated product 2b in a similar yield with the
same stereoselectivity (entry 2). To investigate the C3eC4 stereo-
selectivity in the 1,4-elimination, we prepared 4-mono-substituted
derivatives 1cee and performed the reactions (entries 3e5). Un-
fortunately, stereoselectivity at C3eC4 was not observed. The cor-
responding eliminated products, 2cee, were obtained in similar
yields as a mixture of 1E,3E,1E,3Z, and small amounts of 1Z isomers.
The C1eC2 stereochemistries of 2cee were determined by the
coupling constant of 1-H (J1-H, 2-H¼11e13 Hz for E, 5e7 Hz for Z).
The C3eC4 stereochemistries could not be determined directly by
the coupling constant because of multiplet peaks. These stereo-
chemistries were determined after conversion to the cyclic carba-
mate 5: the details are described in Scheme 5.
Scheme 3. 1,4-Elimination of E-1c.
The E/Z selectivity of 1,4-elimination of Z-1, though its exact
origin is unclear at present, may be rationalized as a result of the
precoordination10 of LiTMP to the oxygen of amide carbonyl to form
complex D or E (Fig. 1). The chelate complex D derived from 1c
(Table 1, entry 3, R1¼n-C7H15, R2¼H), which leads to the 1E,3E-
isomer would be preferred to form; however, the non-chelate
complex E would also be formed to avoid steric repulsion be-
tween 4-OMe and 1-H. The complex E would afford 1E,3E- and
1E,3Z-isomer without selectivity. The formation of the complex E
derived from 4,4-dialkyl derivatives 1a, 1b, and 1f (Table 1, entries
1, 2, and 6, R1¼R2¼alkyl) may be inhibited because of steric re-
pulsion between 4,4-dialkyl and 1-H. The complex D derived from
pyrrolidinyl derivatives 1f and 1g (Table 1, entries 6 and 7) would be
stabilize by its rigid five-membered ring.11
Table 1
1,4-Elimination of cyclic derivatives 1
Entry
n
R1
R2
2 (%)a
1E,3E/1E,3Z/1Z,3E/1Z,3Zb
1
2
3
4
5
6
7
2
2
2
2
2
1
1
Me
Me
a
b
c
d
e
f
81
88
87
1E only
1E only
60/32/7/1
59/33/7/1
58/33/7/2
1E only
e(CH2)5e
n-C7H15
n-C4H9
CH2CH2Ph
Me
Fig. 1. Proposed transition state of the 1,4-elimination of 1.
H
H
H
Me
H
78
81
Next, we investigated the aza-Ferrier reaction of N-Boc-2-(1,3-
dienyloxy)piperidines 2aee in the presence of pyridinium p-tolue-
nesulfonate (PPTS) (Table 2). When a reaction of 4,4-dimethyl de-
rivative 2a with PPTS was performed at 0 ꢀC for 3 h under an argon
78c
77c
n-C7H15
g
90/10/0/0
a
Isolated yield.
b
c
The ratios were determined by 1H NMR assay of the isolated product.
1H NMR analysis in DMSO-d6 showed a mixture of rotamers (2f: 55/45,
atmosphere, the corresponding a-adduct 3a was obtained in a 89%
2g: 50/50).
yield as a mixture of diastereomers [(2S*,20R*)/(2R*,20R*)¼75/25]

E. Tayama et al. / Tetrahedron 69 (2013) 2745e2752
2747
Table 2
aza-Ferrier reaction of piperidine derivative 2
Entry
R1
R2
3 (%)a
(2S*,20R*)/(2R*,20R*)b
1
2
Me
Me
a
b
c
d
e
89
87
85
77
77
75/25
75/25
80/20
80/20
80/20
e(CH2)5e
n-C7H15
n-C4H9
CH2CH2Ph
3c
4c
5c
H
H
H
a
Isolated yield.
b
c
The ratios were determined by 1H NMR assay of the isolated product.
Mixture of E/Z-isomers depicted in Table 1.
Scheme 5. Preparation of cyclic carbamates 5.
(entry 1). The reactions of other substrates also proceeded with
similar yields and diastereoselectivities (entries 2e5). In all cases, no
identifiable amount was obtained of the
g-adducts derived by
a vinylogous aza-Ferrier reaction.
To investigate the origin of low selectivity of the relative ste-
reochemistry of 3, we examined the reaction of 1Z-2c (Scheme 4).
The product 3c was obtained in a 59% yield with the same ratio of
the relative stereoisomers that was obtained in the reaction with
1E-2c. The 1E/1Z-geometry of O-(1,3-dienyl) moiety, as in substrate
2, does not affect the relative stereochemistry of product 3. This
result would suggest that the same geometric mixture of the 1,3-
dienol is formed from 1E- and 1Z-2 under the our reaction condi-
tions and reacts with N-acyliminium ion.12
Fig. 2. Determination of relative stereochemistry of 5a.
Scheme 4. aza-Ferrier reaction of 1Z-2c.
Scheme 6. Hydrogenation of E/Z mixture of 5e.
The relative stereochemistry of 3 was determined by NMR
analysis after its conversion to the corresponding cyclic carbamate
5 (Scheme 5). The diastereomeric mixture of 3 was reduced with
sodium borohydride to give the products major-4 and minor-4.
Chromatographic separation and subsequent cyclization with so-
dium hydride afforded major-5 and minor-5. The C4eC4a relative
stereochemistry of 5a was determined by NOESY (Fig. 2). First, the
1H chemical shifts of 4-H, 4a-H, and alkenyl-H were assigned by
COSY. The NOE correlation between 4a-H and alkenyl-H was ob-
served for minor-5a but not for major-5a. The relative stereo-
chemistry of major-5a was assigned as (4S*,4aR*), and minor-5a was
assigned as (4R*,4aR*). Thus, the major isomer of 3a was de-
termined to be (2S*,20R*), and the minor isomer of 3a was de-
termined to be (2R*,20R*). The coupling constants between 4-H and
4a-H for compound 5a are 6 Hz for (4S*,4aR*) and 10 Hz for
(4R*,4aR*). These data do not contradict our previous assignment.5
The ratio of E/Z-isomer of 5e was determined by 1H NMR anal-
ysis (major-5e: E/Z¼65/35, minor-5e: E/Z¼85/15). The major isomer
of 1,3-dienyl ether 2e depicted in Table 1 is 3E.
stereochemistry of 6e was determined to be (4S*,4aR*) by
comparison to 5a. Thus, the relative stereochemistry of 3e
and 5e were also determined. The stereochemistries of 3b, 3c,
and 3d depicted in Table 2 were determined by analogy with 3a
and 3e.
To define the scope and limitation of the 1,4-elimination and
aza-Ferrier reaction sequence, we prepared acyclic substrates 1hel
and promoted the reactions to prepare acyclic
b-amino-b,g-un-
saturated aldehydes (Table 3). The 1,4-elimination of the N-methyl
and N-ethyl derivatives 1hej also proceeded (entries 1e3); how-
ever, the use of N-allyl and N-benzyl derivatives 1k and 1l lead to
the formation of unidentifiable products with the allylic isomeri-
zation or recovery of the starting materials (entries 4, 5). Depro-
tonation of the acidic proton bearing allylic or benzylic methylene,
as in 1k and 1l, may have caused unfavorable reactions.13 The aza-
Ferrier reaction of 2h with PPTS resulted in unsuccessful because of
lower conversion (3h: 50% yield, 31% recovery). The use of more
acidic Brønsted acid, such as DL-camphorsulfonic acid (CSA) was
effective for acyclic derivatives 2hej. The desired aldehydes 3 were
obtained in 65e91% yields (entries 1e3).
The relative stereochemistry of 5e was determined after
hydrogenation of an E/Z mixture of major-5e to 6e (Scheme 6).
The coupling constant between 4-H and 4a-H is 6 Hz. The relative

2748
E. Tayama et al. / Tetrahedron 69 (2013) 2745e2752
and 13C NMR spectra were measured on a Varian 400 MHz
Table 3
spectrometer (1H: 400 MHz, 13C: 100 MHz) and a 700 MHz spec-
trometer (1H: 700 MHz, 13C: 175 MHz). The splitting patterns are
denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; and br, broad peak. High-resolution mass spectra were
measured on a Thermo Fisher Scientific LC/FT-MS spectrometer.
Reactions involving air- or moisture-sensitive compounds were
conducted in appropriate round-bottomed flasks with a magnetic
stirring bar under an argon atmosphere. Tetrahydrofuran (THF) was
purchased from KANTO Chemical Co., Inc., Japan as an anhydrous
solvent. Dichloromethane was distilled from calcium hydride prior
to use. Merck thin layer chromatography (TLC) plates (silica gel 60
F254) were used for analysis. The products were purified by pre-
parative column chromatography on silica gel (silica gel 60N,
spherical neutral, KANTO Chemical Co., Inc., Japan). The 13C NMR
analysis of N-tert-butoxycarbonyl derivatives was not performed
because of the low sensitivity of the rotamers, the products mainly
obtained as a mixture of isomers, and the lack of reliability of the
data. The spectra were not improved under higher temperature
(50 ꢀC, DMSO-d6).
1,4-Elimination and aza-Ferrier reaction of acyclic derivative 1
Entry R1
R2
CH2CH2Ph Me
CHMe2 Me
2 (%)a,b 3 (%)a,b (2S*,10R*)/(2R*,10R*)c
1
2
3
4
5
h
i
j
k
l
84
91
83
0d
0e
91
65
78
d
d
85/15
75/25
80/20
d
CH2CH2Ph Et
CH2CH2Ph CH2CH]CH2
CH2CH2Ph CH2Ph
d
a
Isolated yield.
1H NMR analysis in chloroform-d showed a mixture of rotamers (2h: 50/50, 2i:
b
60/40, 2j: 65/35, 3h: 50/50, 3i:55/45, 3j: 50/50).
c
The ratios were determined by 1H NMR assay of the isolated product.
The corresponding enamide was obtained in ca. 28% by allylic isomerization.
Recovery of 1l: 57%.
d
e
3.2. Representative procedure of 1,4-elimination of 1
The relative stereochemistry of the acyclic compound 3h
was determined by the same procedures described in Scheme 5
and Fig. 2 (Scheme 7). The major-3h was assigned as (2S*,10R*)
and the minor-3h was assigned as (2R*,10R*) by NMR analysis of
the corresponding cyclic carbamates 5h. The stereochemistries
of 3i and 3j were also tentatively determined by analogy with 3h.
A solution of 2,2,6,6-tetramethylpiperidine (100 mL, 0.59 mmol)
in THF (0.7 mL) was treated with a 1.6 M hexane solution of n-
butyllithium (0.34 mL, 0.54 mmol) at 0 ꢀC under an argon atmo-
sphere and the solution was stirred for 30 min at room tempera-
ture. The solution was cooled at 0 ꢀC and a solution of 1a (112.1 mg,
0.358 mmol) in THF (0.7 mL) was added. The mixture was allowed
to warm to room temperature and stirred for 12 h. The resulting
mixture was quenched with water and extracted with ethyl acetate.
The combined extracts were washed with brine, dried over sodium
sulfate, and then concentrated. The residue was purified by chro-
matography on silica gel (hexane/ethyl acetate¼20/1 as the eluent)
to obtain 2a (81.1 mg, 81% yield) as a colorless oil.
3.2.1. (E)-N-tert-Butoxycarbonyl-2-(40-methylpenta-10,30-dien-10-
yloxy)piperidine [(1E)-2a]. Colorless oil. 1H NMR (400 MHz, DMSO-
d6)
d
6.40 (1H, d, J¼12.0 Hz, 10-H), 5.84e5.56 (1H, br, 2-H), 5.79 (1H,
dd, J¼12.0, 11.2 Hz, 20-H), 5.60 (1H, d, J¼11.2 Hz, 30-H), 3.76 (1H, br,
6-H), 2.95e2.67 (1H, br, 6-H), 1.84 (1H, d, J¼12.0 Hz, CH2), 1.75e1.29
(5H, m, CH2),1.69 (3H, s, C(CH3)2),1.62 (3H, s, C(CH3)2),1.42 (9H, s, t-
Bu); IR (film) 2912, 1682, 1616, 1362, 1335, 1244, 1140, 1106, 1035,
985, 916, 890, 866, 810, 765 cmꢁ1; HRMSeESI (m/z): [MþNa]þ calcd
for C16H27NO3Na: 304.1883. Found: 304.1879.
3.2.2. (E)-N-tert-Butoxycarbonyl-2-(30-cyclohexylideneprop-10-en-
10-yloxy)piperidine [(1E)-2b]. Colorless oil. 1H NMR (400 MHz,
DMSO-d6)
d
6.43 (1H, d, J¼12.4 Hz, 10-H), 5.83 (1H, dd, J¼12.4,
Scheme 7. Determination of relative stereochemistry of 5h.
11.2 Hz, 20-H), 5.78e5.60 (1H, br, 2-H), 5.55 (1H, d, J¼11.2 Hz, 30-H),
3.74 (1H, br, 6-H), 2.94e2.66 (1H, br, 6-H), 2.13 (2H, t, J¼5.0 Hz, CH2),
2.05 (2H, t, J¼5.2 Hz, CH2), 1.83 (1H, d, J¼12.4 Hz, CH2), 1.70e1.22
(11H, m, CH2), 1.41 (9H, s, t-Bu); IR (film) 2848, 1656, 1612, 1362,
1236, 1108, 1030, 920, 864, 810, 758 cmꢁ1; HRMSeESI (m/z):
[MþNa]þ calcd for C19H31NO3Na: 344.2196. Found: 344.2193.
In conclusion, we have demonstrated that 1,4-elimination of (Z)-
N-Boc-2-(4-methoxy-2-alkenyloxy)amines (1) with LiTMP fol-
lowed by a Brønsted acids catalyzed aza-Ferrier reaction of the 1,4-
eliminated products (2) afforded the corresponding b-amino-b,g-
unsaturated aldehydes (3). The products may act as interesting
building blocks for several classes of alkaloids. Our method expands
the synthetic scope of the Ferrier reaction.
3.2.3. (1E)-N-tert-Butoxycarbonyl-2-(undeca-10,30-dien-10-yloxy)pi-
peridine [(1E)-2c]. Colorless oil. (1E,3E)/(1E,3Z)/(1Z,3E)/(1Z,3Z)¼60/
32/7/1 mixture. 1H NMR (400 MHz, DMSO-d6)
d 6.52 (0.32H, d,
J¼11.2 Hz, 10-H), 6.43 (0.60H, d, J¼12.8 Hz, 10-H), 6.26 (0.08H, dd,
J¼14.6, 11.4 Hz, 30-H), 6.16 (0.01H, d, J¼5.2 Hz, 10-H), 6.01 (0.07H, d,
J¼6.0 Hz, 10-H), 5.90e5.33 and 5.20e5.05 (3.40H, m), 5.61 (0.60H,
dd, J¼11.6, 11.6 Hz, 2-H), 3.74 (1H, br), 2.78 (1H, br), 2.08e1.93
(2H, m, 50-H), 1.90e1.77 (1H, br), 1.72e1.45 (4H, m), 1.45e1.15 (11H,
m), 1.41 (9H, s, t-Bu), 0.85 (3H, t, J¼6.8 Hz, 110-H); IR (film) 2912,
2848, 1684, 1654, 1364, 1335, 1246, 1120, 1090, 1040, 946, 864, 815,
3. Experimental
3.1. General
Infrared spectra were recorded on a Perkin Elmer Spectrum GX
FT-IR spectrometer or a HITACHI Infrared 270e30 spectrometer. 1H

E. Tayama et al. / Tetrahedron 69 (2013) 2745e2752
2749
760 cmꢁ1; HRMSeESI (m/z): [MþNa]þ calcd for C21H37NO3Na:
1050, 1030, 992, 971, 958, 930, 890, 868, 815, 770 cmꢁ1; HRMSeESI
(m/z): [MþNa]þ calcd for C21H37NO3Na: 374.2666. Found: 374.2668.
374.2666. Found: 374.2664.
3.2.4. (1E)-N-tert-Butoxycarbonyl-2-(octa-10,30-dien-10-yloxy)piperi-
3.2.9. (E)-N-tert-Butoxycarbonyl-N-methyl-1-(40-methylpenta-10,30-
dine [(1E)-2d]. Colorless oil. (1E,3E)/(1E,3Z)/(1Z,3E)/(1Z,3Z)¼59/33/
dien-10-yloxy)-3-phenylpropan-1-amine [(E)-2h]. Colorless oil. 1H
7/1 mixture. 1H NMR (400 MHz, DMSO-d6)
d
6.52 (0.33H, d,
NMR (400 MHz, CDCl3, 50/50 mixture of rotamers) d 7.33e7.25 (2H,
J¼11.6 Hz, 10-H), 6.43 (0.59H, d, J¼12.4 Hz, 10-H), 6.27 (0.08H, dd,
J¼15.0, 11.0 Hz, 30-H), 6.16 (0.01H, d, J¼5.2 Hz, 10-H), 6.01 (0.07H, d,
J¼6.0 Hz, 10-H), 5.91e5.34 and 5.20e5.04 (3.41H, m), 5.61 (0.59H,
dd, J¼11.6, 11.6 Hz, 2-H), 3.74 (1H, br), 2.95e2.65 (1H, br), 2.10e1.94
(2H, m, 50-H),1.91e1.77 (1H, br),1.74e1.46 (4H, m),1.41 (9H, s, t-Bu),
1.35e1.20 (5H, m), 0.90e0.81 (3H, m, 80-H); IR (film) 2908, 2860,
1680, 1654, 1615, 1362, 1335, 1236, 1120, 1080, 1030, 946, 864, 810,
m, Ph), 7.23e7.16 (3H, m, Ph), 6.38 (0.5H, d, J¼11.6 Hz, 10-H), 6.27
(0.5H, d, J¼12.2 Hz, 10-H), 5.91 (0.5H, dd, J¼11.6, 11.6 Hz, 20-H), 5.85
(0.5H, dd, J¼12.2 Hz, 11.6 Hz, 20-H), 5.75 (0.5H, dd, J¼6.8, 6.8 Hz, 1-
H), 5.64 (0.5H, d, J¼11.6 Hz, 30-H), 5.60 (0.5H, d, J¼11.6 Hz, 30-H),
5.46 (0.5H, dd, J¼6.6, 6.6 Hz, 1-H), 2.79e2.52 (2H, m, 3-H), 2.74
(1.5H, s, NCH3), 2.67 (1.5H, s, NCH3), 2.17e2.02 (1H, m, 2-H),
1.97e1.83 (1H, m, 2-H), 1.74 (3H, s, C(CH3)2), 1.68 (3H, s, C(CH3)2),
1.48 (4.5H, s, t-Bu), 1.42 (4.5H, s, t-Bu); IR (film) 2904, 1682, 1612,
1430, 1326, 1246, 1118, 1016, 975, 912, 875, 738 cmꢁ1; HRMSeESI
(m/z): [MþNa]þ calcd for C21H31NO3Na: 368.2196. Found: 368.2199.
760 cmꢁ1
;
HRMSeESI (m/z): [MþH]þ calcd for C18H32NO3:
310.2377. Found: 310.2375.
3.2.5. (1E)-N-tert-Butoxycarbonyl-2-(60-phenylhexa-10,30-dien-10-
yloxy)piperidine [(1E)-2e]. Colorless oil. (1E,3E)/(1E,3Z)/(1Z,3E)/
(1Z,3Z)¼58/33/7/2 mixture. 1H NMR (400 MHz, DMSO-d6)
3.2.10. (E)-N-tert-Butoxycarbonyl-N,2-dimethyl-1-(40-methylpenta-
10,30-dien-1-yloxy)propan-1-amine [(E)-2i]. Colorless oil. 1H NMR
d
7.30e7.13 (5H, m, Ph), 6.53 (0.33H, d, J¼11.2 Hz, 10-H), 6.44 (0.58H,
(400 MHz, CDCl3, 60/40 mixture of rotamers) d 6.37 (0.6H, d,
d, J¼12.0 Hz, 10-H), 6.35e6.25 (0.09H, m, 30-H), 6.16 (0.02H, d,
J¼6.0 Hz, 10-H), 6.03 (0.07H, d, J¼6.4 Hz, 10-H), 5.95e5.38 and
5.23e5.03 (3.33H, m), 5.61 (0.58H, dd, J¼11.6, 11.6 Hz, 2-H), 3.76
(1H, br), 2.95e2.70 (1H, br), 2.69e2.56 (2H, m), 2.42e2.25 (2H, m),
1.90e1.75 (1H, br), 1.75e1.15 (15H, m, CH2 and t-Bu); IR (film) 2920,
J¼12.4 Hz, 10-H), 6.29 (0.4H, d, J¼12.0 Hz, 10-H), 5.88 (0.6H, dd,
J¼11.4, 11.4 Hz, 20-H), 5.85 (0.4H, dd, J¼10.4, 10.4 Hz, 20-H), 5.65
(0.6H, d, J¼11.4 Hz, 30-H), 5.62 (0.4H, d, J¼10.4 Hz, 30-H), 5.28 (0.6H,
d, J¼9.6 Hz, 1-H), 5.03 (0.4H, d, J¼9.6 Hz, 1-H), 2.69 (1.2H, s, NCH3),
2.65 (1.8H, s, NCH3), 2.01e1.88 (1H, m, CH(CH3)2), 1.74 (1.2H, s, C]
C(CH3)2), 1.73 (1.8H, s, C]C(CH3)2), 1.68 (3H, s, C]C(CH3)2), 1.49
(3.6H, s, t-Bu), 1.47 (5.4H, s, t-Bu), 1.024 (1.8H, d, J¼6.4 Hz,
CH(CH3)2), 1.015 (1.2H, d, J¼6.4 Hz, CH(CH3)2), 0.82 (3H, d, J¼7.2 Hz,
CH(CH3)2); IR (film) 2968, 2925, 2876, 1699, 1664, 1620, 1473, 1442,
1388, 1368, 1334, 1257, 1203, 1165, 1140, 1106, 1044, 995, 941, 921,
879, 855, 771, 736, 711 cmꢁ1; HRMSeESI (m/z): [MþNa]þ calcd for
C16H29NO3Na: 306.2040. Found: 306.2034.
1684, 1654, 1364, 1335, 1242, 1116, 946, 885, 865, 735 cmꢁ1
;
HRMSeESI (m/z): [MþNa]þ calcd for C22H31NO3Na: 380.2196.
Found: 380.2190.
3.2.6. (E)-N-tert-Butoxycarbonyl-2-(40-methylpenta-10,30-dien-10-
yloxy)pyrrolidine [(1E)-2f]. Colorless oil. 1H NMR (400 MHz, DMSO-
d6, 55/45 mixture of rotamers)
d
6.63 (0.45H, d, J¼10.4 Hz, 10-H),
6.57 (0.55H, d, J¼10.8 Hz, 10-H), 5.70e5.56 (2H, m, 20- and 30-H),
5.49 (0.45H, s, 2-H), 5.41 (0.55H, d, J¼2.4 Hz, 2-H), 3.40e3.30 (1H,
m, 5-H), 3.27e3.14 (1H, m, 5-H), 1.96e1.80 (4H, m, CH2), 1.69 (3H, s,
C(CH3)2), 1.60 (3H, s, C(CH3)2), 1.41 (9H, s, t-Bu); IR (film) 2975,
2919, 1705, 1663, 1625, 1477, 1455, 1390, 1326, 1286, 1256, 1160,
1128, 1090, 1043, 980, 944, 917, 883, 855, 772 cmꢁ1; HRMSeESI
(m/z): [MþNa]þ calcd for C15H25NO3Na: 290.1727. Found: 290.1728.
3.2.11. (E)-N-tert-Butoxycarbonyl-N-ethyl-1-(40-methylpenta-10,30-
dien-10-yloxy)-3-phenylpropan-1-amine [(E)-2j]. Colorless oil. 1H
NMR (400 MHz, CDCl3, 65/35 mixture of rotamers) d 7.32e7.25 (2H,
m, Ph), 7.24e7.16 (3H, m, Ph), 6.38 (0.65H, d, J¼11.6 Hz, 10-H), 6.28
(0.35H, d, J¼11.6 Hz, 10-H), 5.87 (1H, dd, J¼11.6, 10.0 Hz, 20-H), 5.75
(0.65H, br, 1-H), 5.63 (1H, d, J¼10.0 Hz, 30-H), 5.46 (0.35H, br, 1-H),
3.33e3.05 (2H, br, NCH2), 2.80e2.53 (2H, m, 3-H), 2.20e2.01 (1H,
m, 2-H), 1.99e1.82 (1H, m, 2-H), 1.74 (3H, s, C(CH3)2), 1.68 (3H, s,
C(CH3)2), 1.48 (5.85H, s, t-Bu), 1.43 (3.15H, s, t-Bu), 1.20e1.06 (3H, br,
NCH2CH3); IR (film) 3027, 2973, 2929, 2872, 1695, 1622, 1453, 1409,
1368, 1336, 1293, 1254, 1223, 1202, 1165, 1141, 1124, 1091, 1044, 971,
919, 862, 795, 774, 751 cmꢁ1; HRMSeESI (m/z): [MþNa]þ calcd for
C22H33NO3Na: 382.2353. Found: 382.2351.
3.2.7. (1E)-N-tert-Butoxycarbonyl-2-(undeca-10,30-dien-10-yloxy)
pyrrolidine [(1E)-2g]. Colorless oil. (1E,3E)/(1E,3Z)/(1Z,3E)/(1Z,3Z)¼
90/10/0/0 mixture. 1H NMR (400 MHz, DMSO-d6, 50/50 mixture of
rotamers)
d
6.74 (0.05H, d, J¼10.8 Hz,10-H), 6.71e6.54 (0.05H, m, 10-
H), 6.65 (0.45H, d, J¼12.2 Hz, 10-H), 6.59 (0.45H, d, J¼12.2 Hz, 10-H),
5.84 (0.9H, dd, J¼15.2, 10.8 Hz, 30-H), 5.70 (0.1H, dd, J¼11.6, 11.6 Hz,
30-H), 5.55e5.30 (2.9H, m, 2-, 20-, and 40-H), 5.16e5.06 (0.1H, m),
3.40e3.30 (1H, m, NCH2), 3.26e3.12 (1H, m, NCH2), 2.07e1.78 (6H,
m, CH2), 1.40 (9H, s, t-Bu), 1.35e1.16 (10H, m, CH2), 0.85 (3H, t,
J¼6.8 Hz, 110-H); IR (film) 2957, 2925, 2854, 1705, 1660, 1625, 1456,
1389, 1325, 1286, 1254, 1168, 1148, 1116, 1089, 1032, 971, 943, 915,
3.3. Representative procedure of aza-Ferrier reaction of 2
A solution of 2a (112.6 mg, 0.400 mmol) and pyridinium p-tol-
uenesulfonate (10.1 mg, 0.040 mmol) in dichloromethane (2 mL)
was stirred for 3 h at 0 ꢀC under an argon atmosphere. The resulting
mixture was quenched with saturated aqueous sodium hydrogen
carbonate and extracted with ethyl acetate. The combined extracts
were washed with brine, dried over sodium sulfate, and then
concentrated. The residue was purified by chromatography on silica
gel (hexane/ethyl acetate¼5/1 as the eluent) to obtain 3a (100.7 mg,
89% yield) as a colorless oil.
884, 854, 772 cmꢁ1
C20H35NO3Na: 360.2509. Found: 360.2509.
;
HRMSeESI (m/z): [MþNa]þ calcd for
3.2.8. (1Z)-N-tert-Butoxycarbonyl-2-(undeca-10,30-dien-10-yloxy)pi-
peridine [(1Z)-2c]. Colorless oil. (1E,3E)/(1E,3Z)/(1Z,3E)/(1Z,3Z)¼3/
3/50/44 mixture. 1H NMR (400 MHz, DMSO-d6)
d 6.52 (0.03H, d,
J¼10.8 Hz, 10-H), 6.43 (0.03H, d, J¼12.4 Hz, 10-H), 6.31e6.21 (0.06H,
m, 30-H), 6.26 (0.94H, dd, J¼12.0, 12.0 Hz, 30-H), 6.15 (0.44H, d,
J¼6.0 Hz, 10-H), 6.02 (0.50H, d, J¼6.4 Hz, 10-H), 5.90e5.59 (0.94H,
br), 5.90e5.00 (0.18H, m), 5.52 (0.50H, dt, J¼15.6, 6.8 Hz, 40-H), 5.34
(0.44H, br), 5.26 (0.44H, dt, J¼10.8, 8.0 Hz, 40-H), 5.09 (0.50H, br),
3.84e3.67 (1H, br), 2.95e2.66 (1H, br), 2.11e1.93 (2H, m), 1.93e1.80
(1H, m), 1.76e1.46 (4H, m), 1.46e0.96 (11H, m), 1.40 (9H, s, t-Bu),
0.85 (3H, t, J¼6.4 Hz, 110-H); IR (film) 2926, 2854, 1701, 1656, 1616,
1603, 1454, 1404, 1365, 1338, 1318, 1272, 1255, 1238, 1162, 1088,
3.3.1. N-tert-Butoxycarbonyl-4-methyl-2-(piperidin-20-yl)pent-3-
enal (3a). Colorless oil. (2S*,20R*)/(2R*,20R*)¼75/25 mixture. 1H
NMR (400 MHz, CDCl3)
d
9.39 (0.75H, d, J¼4.0 Hz, CHO), 9.36e9.30
(0.25H, br, CHO), 5.06 (1H, br), 4.80e4.40 (1H, br), 3.99 (1H, br),
3.80e3.50 (1H, br), 2.95e2.75 (0.25H, br, 60-H), 2.52 (0.75H, t,
J¼13.0 Hz, 60-H), 1.79 (0.75H, s, C(CH3)2), 1.75 (2.25H, s, C(CH3)2),
1.70 (2.25H, s, C(CH3)2), 1.67 (0.75H, s, C(CH3)2), 1.66e1.51 (6H, m,

2750
E. Tayama et al. / Tetrahedron 69 (2013) 2745e2752
CH2), 1.47 (6.75H, s, t-Bu), 1.43 (2.25H, s, t-Bu); IR (film) 2912, 2856,
75/25 mixture. 1H NMR (400 MHz, CDCl3, 55/45 mixture of rotam-
ers)
9.43 (0.41H, d, J¼4.0 Hz, CHO), 9.41 (0.34H, d, J¼3.6 Hz, CHO),
2700, 1672, 1405, 1390, 1362, 1305, 1242, 1142, 1050, 990, 915, 830,
d
758 cmꢁ1
282.2064. Found: 282.2059.
;
HRMSeESI (m/z): [MþH]þ calcd for C16H28NO3:
9.34 (0.11H, d, J¼3.2 Hz, CHO), 9.26 (0.14H, d, J¼4.8 Hz, CHO),
5.15e5.06 (0.25H, m, 3-H), 4.97 (0.41H, dqq, J¼9.6, 1.4, 1.4 Hz, 3-H),
4.88 (0.34H, dqq, J¼9.6, 1.4, 1.4 Hz, 3-H), 4.42e4.09 (1H, m),
3.53e3.38 (1H, m), 2.69 (0.33H, br, NCH3), 2.66 (0.42H, s, NCH3), 2.64
(1.02H, s, NCH3), 2.60 (1.23H, s, NCH3), 2.00e1.65 (7H, m, C]C(CH3)2
and CH(CH3)2),1.48 (3.06H, s, t-Bu),1.47 (0.99H, s, t-Bu),1.45 (3.69H,
s, t-Bu),1.44 (1.26H, s, t-Bu), 0.96 (0.66H, d, J¼6.8 Hz, CH(CH3)2), 0.95
(0.84H, d, J¼6.8 Hz, CH(CH3)2), 0.91 (2.46H, d, J¼6.4 Hz, CH(CH3)2),
0.88 (2.04H, d, J¼6.8 Hz, CH(CH3)2); IR (film) 2970, 2925, 2876, 2812,
2708,1718,1692,1473,1444,1388,1366,1338,1305,1255,1147,1049,
982, 939, 877, 835, 771, 704 cmꢁ1; HRMSeESI (m/z): [MþNa]þ calcd
for C16H29NO3Na: 306.2040. Found: 306.2037.
3.3.2. N-tert-Butoxycarbonyl-3-cyclohexylidene-2-(piperidin-20-yl)
propanal (3b). Colorless oil. (2S*,20R*)/(2R*,20R*)¼75/25 mixture.
1H NMR (400 MHz, CDCl3)
d
9.41 (0.75H, d, J¼3.6 Hz, CHO), 9.36
(0.25H, br, CHO), 4.99 (1H, br), 4.85e4.37 (1H, br), 4.20e3.60 (2H,
br), 2.95e2.75 (0.25H, br, 60-H), 2.52 (0.75H, t, J¼13.2 Hz, 60-H),
2.23e2.05 (4H, m, CH2), 1.75e1.23 (12H, m, CH2), 1.46 (9H, s, t-Bu);
IR (film) 2908, 2848, 2696, 1670, 1385, 1360, 1306, 1242, 1138, 1070,
1025, 985, 915, 840, 758 cmꢁ1; HRMSeESI (m/z): [MþNa]þ calcd for
C19H31NO3Na: 344.2196. Found: 344.2194.
3.3.3. N-tert-Butoxycarbonyl-2-(piperidin-20-yl)undec-3-enal
3.3.8. N-tert-Butoxycarbonyl-2-(10-(ethylamino)-30-phenylpropyl)-
4-methylpent-3-enal (3j). White solid. (2S*,10R*)/(2R*,10R*)¼80/20
mixture. 1H NMR (400 MHz, CDCl3, 50/50 mixture of rotamers)
(3c). Colorless oil. (2S*,20R*,E)/(2S*,20R*,Z)/(2R*,20R*,E)/(2R*,20R*,Z)¼
50/30/15/5 mixture. 1H NMR (400 MHz, CDCl3)
d 9.51 (0.50H, d,
J¼3.6 Hz, CHO), 9.43 (0.30H, d, J¼3.6 Hz, CHO), 9.42 (0.15H, br, CHO),
9.38 (0.05H, br, CHO), 5.78e5.61 (0.20H, m, 4-H), 5.71 (0.30H, dt,
J¼10.8, 8.0 Hz, 4-H), 5.66 (0.50H, dt, J¼15.2, 7.2 Hz, 4-H), 5.30 (1H, br),
4.85e4.40 (1H, br), 4.20e3.65 and 3.65e3.30 (2H, br), 2.95e2.70 and
2.70e2.45 (1H, br), 2.13e1.97 (2H, m, CH2), 1.78e1.20 (25H, m, CH2
and t-Bu), 0.91e0.85 (3H, m, 11-H); IR (film) 2912, 2848, 2696, 1672,
1390, 1362, 1306, 1242, 1140, 1030, 968, 862, 750 cmꢁ1; HRMSeESI
(m/z): [MþNa]þ calcd for C21H37NO3Na: 374.2666. Found: 374.2653.
d
9.40 (0.1H, s, CHO), 9.35 (0.8H, d, J¼4.0 Hz, CHO), 9.31 (0.1H, d,
J¼4.8 Hz, CHO), 7.33e7.23 (2H, m, Ph), 7.23e7.13 (3H, m, Ph),
5.03e4.88 (0.2H, m, 3-H), 5.00 (0.4H, d, J¼9.6 Hz, 3-H), 4.91 (0.4H, d,
J¼9.2 Hz, 3-H), 4.50e4.33 (0.5H, m), 3.53e3.38 (0.5H, m), 3.27e2.76
(2H, m), 2.76e2.50 (2H, m), 2.00e1.55 (9H, m), 1.51e1.43 (9H, m, t-
Bu), 1.17 (1.5H, t, J¼7.0 Hz, NCH2CH3), 1.12 (1.5H, t, J¼7.0 Hz,
NCH2CH3); IR (KBr) 3059, 3025, 2973, 2933, 2862, 2734, 1722, 1677,
1601, 1475,1453, 1413,1366, 1334,1284,1243,1212, 1175, 1149, 1093,
1044, 991, 943, 910, 862, 833, 798, 777, 753, 701 cmꢁ1; HRMSeESI
(m/z): [MþNa]þ calcd for C22H33NO3Na: 382.2353. Found: 382.2346.
3.3.4. N-tert-Butoxycarbonyl-2-(piperidin-20-yl)oct-3-enal
(3d). Colorless oil. (2S*,20R*,E)/(2S*,20R*,Z)/(2R*,20R*,E)/(2R*,20R*,Z)¼
50/30/15/5 mixture.1H NMR (700 MHz, CDCl3)
d
9.51 (0.50H, s, CHO),
3.4. Representative procedure of the reduction of 3 with so-
dium borohydride
9.43 (0.30H, s, CHO), 9.42 (0.15H, br, CHO), 9.37 (0.05H, br, CHO),
5.77e5.61 (1H, m, 4-H), 5.45e5.15 (1H, br), 4.85e4.40 (1H, br),
4.20e3.65 and 3.60e3.30 (2H, br), 2.95e2.45 (1H, br), 2.14e1.98 (2H,
m, 5-H),1.77e1.24 (19H, m, CH2 and t-Bu), 0.93e0.85 (3H, m, 8-H); IR
(film) 2912, 2852, 2700,1672,1390,1362,1308,1246,1140,1030, 970,
862, 752 cmꢁ1; HRMSeESI (m/z): [MþNa]þ calcd for C18H31NO3Na:
332.2196. Found: 332.2184.
Sodium borohydride (0.20 g, 0.53 mmol) was added to a solution
of 3a (145.3 mg, 0.516 mmol) in methanol (2.6 mL) at 0 ꢀC, and the
mixture was stirred for 3 h at room temperature. The resulting
mixture was diluted with saturated aqueous ammonium chloride
and extracted with ethyl acetate. The combined extracts were
washed with brine, dried over sodium sulfate, and concentrated. The
residue was purified by chromatography on silica gel (hexane/ethyl
acetate¼2/1 as the eluent) to obtain major-4a (106.8 mg, 73% yield)
as a colorless oil and minor-4a (30.4 mg, 21% yield) as a white solid.
3.3.5. N-tert-Butoxycarbonyl-6-phenyl-2-(piperidin-20-yl)hex-3-enal
(3e). Colorless oil. (2S*,20R*,E)/(2S*,20R*,Z)/(2R*,20R*,E)/(2R*,20R*,Z)¼
50/30/15/5 mixture. 1H NMR (400 MHz, CDCl3)
d 9.48 (0.50H, d,
J¼2.8 Hz, CHO), 9.38 (0.15H, br, CHO), 9.34 (0.05H, d, J¼5.2 Hz, CHO),
9.26 (0.30H, br, CHO), 7.32e7.24 (2H, m, Ph), 7.22e7.12 (3H, m, Ph),
5.81e5.62 (0.20H, m, 4-H), 5.74 (0.30H, dt, J¼10.8, 7.6 Hz, 4-H), 5.68
(0.50H, dt, J¼15.6, 6.8 Hz, 4-H), 5.33 (1H, br), 4.85e4.35 (1H, br),
4.15e3.80 (1H, br), 3.80e3.25 (1H, br), 2.90e2.49 (3H, m), 2.48e2.26
(2H, m), 1.69e1.32 (15H, m, CH2 and t-Bu); IR (film) 2920, 2848, 2704,
1670,1390,1358,1306,1244,1142,1030, 970, 862, 725cmꢁ1;HRMSeESI
(m/z): [MþNa]þ calcd for C22H31NO3Na: 380.2196. Found: 380.2188.
3.4.1. (2S*,20R*)-N-tert-Butoxycarbonyl-4-methyl-2-(piperidin-20-yl)
pent-3-en-1-ol (major-4a). Colorless oil. 1H NMR (700 MHz, CDCl3)
d
4.96 (1H, d, J¼10.5 Hz, 3-H), 4.16 (1H, br), 3.93 (1H, br), 3.56 (1H,
br), 3.32 (1H, dd, J¼10.9, 8.1 Hz), 2.94 (1H, br), 2.65 (1H, br), 1.74
(3H, d, J¼0.7 Hz, C(CH3)2), 1.69 (3H, d, J¼1.4 Hz, C(CH3)2), 1.68e1.53
(6H, m), 1.49e1.38 (1H, m), 1.45 (9H, s, t-Bu); IR (film) 3446, 2973,
2932, 2865, 1688, 1664, 1475, 1421, 1366, 1316, 1272, 1252, 1163,
1066, 1014, 993, 919, 870, 845, 815, 766, 736 cmꢁ1; HRMSeESI (m/
z): [MþH]þ calcd for C16H30NO3: 284.2220. Found: 284.2218.
3.3.6. N-tert-Butoxycarbonyl-4-methyl-2-(10-(methylamino)-30-phe-
nylpropyl)pent-3-enal (3h). Colorless oil. (2S*,10R*)/(2R*,10R*)¼85/
15 mixture. 1H NMR (400 MHz, CDCl3, 50/50 mixture of rotamers)
3.4.2. (2R*,20R*)-N-tert-Butoxycarbonyl-4-methyl-2-(piperidin-20-yl)
d
9.37 (0.425H, d, J¼3.2 Hz, CHO), 9.36 (0.425H, d, J¼4.0 Hz, CHO),
pent-3-en-1-ol (minor-4a). White solid. 1H NMR (700 MHz, CDCl3)
9.32e9.26 (0.075H, br, CHO), 9.28 (0.075H, d, J¼5.2 Hz, CHO),
7.32e7.23 (2H, m, Ph), 7.22e7.13 (3H, m, Ph), 5.06e4.87 (0.15H, m,
3-H), 5.03 (0.425H, d, J¼10.0 Hz, 3-H), 4.91 (0.425H, d, J¼10.0 Hz, 3-
H), 4.65e4.30 (0.575H, br, 10-H), 4.60 (0.425H, ddd, J¼10.0, 10.0,
3.2 Hz, 2-H), 3.42e3.20 (0.575H, br, 10-H), 3.31 (0.425H, ddd, J¼10.0,
10.0, 4.0 Hz, 2-H), 2.83e2.45 (5H, m, 30-H and NCH3), 1.91e1.54 (8H,
m, 20-H and C(CH3)2), 1.51e1.40 (9H, m, t-Bu); IR (film) 2908, 2700,
1672,1426,1380,1332,1246,1128, 826, 738 cmꢁ1; HRMSeESI (m/z):
[MþH]þ calcd for C21H32NO3: 346.2377. Found: 346.2376.
d
5.22 (1H, d, J¼8.4 Hz, 3-H), 4.17 (1H, br), 3.99 (1H, d, J¼11.2 Hz),
3.53e3.36 (2H, br), 2.79e2.68 (1H, m), 2.72 (1H, ddd, J¼13.0, 13.0,
2.8 Hz),1.76 (3H, s, C(CH3)2),1.72e1.54 (4H, m),1.67 (3H, s, C(CH3)2),
1.54e1.36 (3H, m), 1.47 (9H, s, t-Bu); IR (film) 3444, 2933, 2861,
1684, 1658, 1424, 1366,1343, 1316,1275, 1252, 1160, 1074, 1032, 996,
977, 919, 866, 843, 813, 771 cmꢁ1; HRMSeESI (m/z): [MþNa]þ calcd
for C16H29NO3Na: 306.2040. Found: 306.2037.
3.4.3. (2S*,20R*)-N-tert-Butoxycarbonyl-6-phenyl-2-(piperidin-20-yl)
hex-3-en-1-ol (major-4e). Colorless oil. E/Z¼65/35 mixture. 1H
3.3.7. N-tert-Butoxycarbonyl-4-methyl-2-(20-methyl-10-(methyl-
amino)propyl)pent-3-enal (3i). Colorless oil. (2S*,10R*)/(2R*,10R*)¼
NMR (400 MHz, CDCl3) d 7.32e7.25 (2H, m, Ph), 7.22e7.13 (3H, m,
Ph), 5.64 (0.35H, dt, J¼11.2, 7.4 Hz, 4-H), 5.56 (0.65H, dt, J¼14.8,

E. Tayama et al. / Tetrahedron 69 (2013) 2745e2752
2751
6.8 Hz, 4-H), 5.27e5.14 (1H, m, 3-H), 4.13 (1H, br), 3.89 (1H, br), 3.49
(1H, br), 3.32e3.20 (1H, m), 2.80e2.50 (4H, m), 2.50e2.25 (2H, m),
1.64e1.49 (6H, br), 1.45 (5.85H, s, t-Bu), 1.44 (3.15H, s, t-Bu),
1.34e1.23 (1H, m); IR (film) 3449, 3062, 2933, 2863, 1687, 1661,
1604, 1470, 1449, 1421, 1366, 1314, 1272, 1163, 1063, 975, 914, 869,
13.0, 13.0, 4.2, 4.2 Hz, 6-H), 1.12 (1H, dddd, J¼13.0, 13.0, 11.6, 4.2 Hz,
5-H); 13C NMR (175 MHz, CDCl3)
153.4, 138.0, 119.4, 67.7, 59.9,
45.1, 39.7, 31.8, 25.9, 25.0, 23.7, 18.5; IR (KBr) 2932, 2857, 1676, 1478,
1443, 1390, 1364, 1347, 1320, 1304, 1262, 1229, 1177, 1137, 1104,
1049, 1010, 967, 951, 923, 853, 756 cmꢁ1; HRMSeESI (m/z): [MþH]þ
calcd for C12H20NO2: 210.1489. Found: 210.1486.
d
813, 745, 700 cmꢁ1
;
HRMSeESI (m/z): [MþNa]þ calcd for
C22H33NO3Na: 382.2353. Found: 382.2349.
3.5.3. (4S*,4aR*)-4-(40-Phenylbut-10-enyl)hexahydropyrido[1,2-c]
3.4.4. (2R*,20R*)-N-tert-Butoxycarbonyl-6-phenyl-2-(piperidin-20-yl)
[1,3]oxazin-1(3H)-one (major-5e). Yellow oil. E/Z¼65/35 mixture.
hex-3-en-1-ol (minor-4e). Colorless oil. 1H NMR (400 MHz, CDCl3)
1H NMR (700 MHz, CDCl3)
d 7.30e7.25 (2H, m, Ph), 7.22e7.13 (3H, m,
d
7.32e7.24 (2H, m, Ph), 7.22e7.13 (3H, m, Ph), 5.53 (2H, br, 3-H and
Ph), 5.66 (0.35H, dt, J¼10.5, 7.7 Hz, 20-H), 5.59 (0.65H, dt, J¼15.4,
7.0 Hz, 20-H), 5.27 (0.65H, dd, J¼15.4, 8.4 Hz, 10-H), 5.20 (0.35H, dt,
J¼10.5, 1.4 Hz, 10-H), 4.42e4.34 (1H, m, 8-H), 4.09e4.05 (1.3H, m, 3-
H), 3.90 (0.35H, dd, J¼10.7, 8.8 Hz, 3-H), 3.79 (0.35H, dd, J¼10.7,
3.5 Hz, 3-H), 3.24 (0.65H, ddd, J¼12.1, 6.2, 2.3 Hz, 4a-H), 2.96e2.90
(0.35H, m), 2.88 (0.35H, ddd, J¼11.6, 6.0, 2.5 Hz, 4a-H), 2.78e2.65
(2.65H, m), 2.65 (0.65H, ddd, J¼12.6, 12.6, 2.8 Hz), 2.58 (0.35H, ddd,
J¼13.0, 13.0, 2.8 Hz), 2.46e2.32 (2H, m), 1.89e1.81 (1H, m),
1.67e1.59 (1H, m), 1.47e1.21 (3.35H, m), 1.15 (0.65H, dddd, J¼12.5,
4-H), 4.15 (1H, br), 3.96 (1H, br), 3.55e3.20 (2H, br), 2.85e2.60 (3H,
m), 2.55e2.30 (3H, m), 1.75e1.20 (7H, m), 1.46 (9H, s, t-Bu); IR (film)
3440, 3062, 2933, 2859, 1687, 1656, 1476, 1423, 1366, 1317, 1275,
1252, 1161, 1075, 1033, 996, 974, 918, 867, 812, 746 cmꢁ1; HRMSeESI
(m/z): [MþNa]þ calcd for C22H33NO3Na: 382.2353. Found: 382.2349.
3.4.5. N-tert-Butoxycarbonyl-4-methyl-2-(10-(methylamino)-30-phe-
nylpropyl)pent-3-en-1-ol (4h). Colorless oil. (2S*,10R*)/(2R*,10R*)¼
85/15 mixture. 1H NMR (400 MHz, CDCl3, 80/20 mixture of
12.5, 12.5, 3.5 Hz); 13C NMR (175 MHz, CDCl3)
d 153.0, 152.9, 141.2,
rotamers)
d
7.32e7.25 (2H, m, Ph), 7.22e7.13 (3H, m, Ph), 5.19
141.1, 134.0, 133.3, 128.6, 128.4, 128.22, 128.16, 126.0, 125.7, 124.5,
123.3, 67.4, 67.0, 57.9, 57.5, 46.11, 46.09, 39.5, 35.32, 35.26, 34.22,
34.19, 29.7, 27.9, 27.5, 25.2, 25.1, 24.04, 23.98; IR (film) 3059, 3024,
2936, 2855,1693,1602,1475,1430,1371,1316,1296,1247,1176,1142,
1112, 1084, 1015, 974, 910, 855, 833, 819, 752, 700 cmꢁ1; HRMSeESI
(m/z): [MþH]þ calcd for C18H24NO2: 286.1802. Found: 286.1796.
(0.12H, d, J¼10.4 Hz, 3-H), 4.98 (0.03H, d, J¼10.4 Hz, 3-H), 4.89
(0.17H, d, J¼10.4 Hz, 3-H), 4.79 (0.68H, d, J¼10.8 Hz, 3-H), 4.35
(0.68H, br, 10-H), 4.20e3.85 (0.32H, br, 10-H), 3.60 (0.17H, dd, J¼11.0,
5.4 Hz), 3.48 (0.12H, dd, J¼11.4, 4.2 Hz), 3.43e3.27 (1.71H, m),
2.80e2.42 (1.64H, m), 2.71 (3H, s, NCH3), 2.57 (1.36H, t, J¼8.0 Hz, 30-
H), 1.94e1.57 (4.92H, m), 1.71 (2.04H, s, C(CH3)2), 1.64 (2.04H, s,
C(CH3)2),1.49 (7.2H, s, t-Bu),1.45 (1.8H, s, t-Bu); IR (film) 3440, 3061,
3026, 2972, 2928, 2866, 1689, 1666, 1603, 1480, 1452, 1394, 1365,
1346,1254, 1153,1057, 980, 874, 770, 749, 700 cmꢁ1; HRMSeESI (m/
z): [MþNa]þ calcd for C21H33NO3Na: 370.2353. Found: 370.2346.
3.5.4. (4R*,4aR*)-4-(40-Phenylbut-10-enyl)hexahydropyrido[1,2-c]
[1,3]oxazin-1(3H)-one (minor-5e). Colorless oil. E/Z¼85/15 mixture.
1H NMR (700 MHz, CDCl3)
d 7.30e7.26 (2H, m, Ph), 7.21e7.13 (3H, m,
Ph), 5.70e5.64 (0.15H, m, 20-H), 5.67 (0.85H, dt, J¼15.6, 7.2 Hz, 20-H),
5.11 (0.85H, dd, J¼15.6, 8.8 Hz, 10-H), 5.05 (0.15H, ddt, J¼10.2, 10.2,
1.4 Hz, 10-H), 4.47e4.41 (1H, m, 8-H), 4.00 (0.85H, dd, J¼11.0, 4.2 Hz,
3-H), 3.86 (0.85H, dd, J¼11.0, 11.0 Hz, 3-H), 3.73 (0.15H, dd, J¼10.9,
10.9 Hz, 3-H), 3.63 (0.15H, dd, J¼10.9, 4.6 Hz, 3-H), 2.90 (0.85H, ddd,
J¼11.6, 9.1, 2.5 Hz, 4a-H), 2.87 (0.15H, ddd, J¼11.2, 8.8, 2.8 Hz, 4a-H),
2.75e2.58 (2.15H, m), 2.63 (0.85H, ddd, J¼13.0, 13.0, 2.8 Hz),
2.46e2.33 (3H, m), 1.84e1.75 (2H, m), 1.70e1.63 (1H, m), 1.49e1.38
(0.15H, m), 1.45 (0.85H, ddddd, J¼13.2, 13.2, 13.2, 3.7, 3.7 Hz),
1.35e1.24 (0.15H, m), 1.31 (0.85H, ddddd, J¼13.2, 13.2, 13.2, 3.7,
3.7 Hz), 1.06 (0.85H, dddd, J¼13.2, 13.2, 11.8, 3.7 Hz), 0.97 (0.15H,
3.5. Representative procedure of the cyclization of 4
Sodium hydride (60 wt % in oil,17 mg, 0.43 mmol) in THF (1.8 mL)
was added to a solution of major-4a (101.7 mg, 0.359 mmol) at 0 ꢀC.
After stirring for 2 h at 0 ꢀC and 15 h at room temperature, the
resulting mixture was quenched with saturated aqueous ammo-
nium chloride at 0 ꢀC. Extractive workup and purification of the
residue by chromatography on silica gel (ethyl acetate as the eluent)
afforded major-5a (42.7 mg, 57% yield) as a white solid.
dddd, J¼13.2, 13.2, 11.8, 3.7 Hz); 13C NMR (175 MHz, CDCl3)
d 153.3,
3.5.1. (4S*,4aR*)-4-(20-Methylprop-10-enyl)hexahydropyrido[1,2-c]
153.2,141.2,141.0,134.9,134.4,128.5,128.4,128.3,128.2,126.1,125.9,
125.7, 125.0, 67.9, 67.4, 59.4, 59.1, 45.2, 45.0, 43.6, 38.8, 35.5, 35.4,
34.3, 31.6, 29.9, 24.91, 24.88, 23.63, 23.59; IR (film) 3059, 3025, 2935,
2855,1694,1602,1474,1432,1388,1368,1343,1313,1293,1251,1225,
1169,1124,1095,1050,1008, 971, 907, 849, 758, 700 cmꢁ1;HRMSeESI
(m/z): [MþNa]þ calcd for C18H23NO2Na: 308.1621. Found: 308.1617.
[1,3]oxazin-1(3H)-one (major-5a). White solid. 1H NMR (700 MHz,
CDCl3)
d
4.99 (1H, dqq, J¼9.8, 1.4, 1.4 Hz, 10-H), 4.45e4.41 (1H, m, 8-
H), 4.08 (1H, dd, J¼10.7, 9.3 Hz, 3-H), 4.02 (1H, dd, J¼10.7, 3.7 Hz, 3-
H), 3.30 (1H, ddd, J¼12.3, 5.6, 2.5 Hz, 4a-H), 3.05 (1H, dddd, J¼9.8,
9.3, 5.6, 3.7 Hz, 4-H), 2.68 (1H, ddd, J¼12.8, 12.8, 3.2 Hz, 8-H),
1.95e1.90 (1H, m, 6-H), 1.75 (3H, d, J¼1.4 Hz, C(CH3)2), 1.70e1.62
(2H, m, 5-H and 6-H), 1.69 (3H, d, J¼1.4 Hz, C(CH3)2), 1.52e1.40 (2H,
m, 7-H), 1.36 (1H, ddd, J¼12.3, 12.3, 3.9 Hz, 5-H); 13C NMR
3.5.5. (4R*,5S*)-3-Methyl-5-(20-methylprop-10-enyl)-4-phenethyl-
1,3-oxazinan-2-one (major-5h). Colorless oil. 1H NMR (700 MHz,
(100 MHz, CDCl3)
d
153.1, 137.0, 117.4, 67.5, 57.9, 46.3, 35.2, 27.7,
CDCl3)
d
7.31 (2H, dd, J¼7.7, 7.7 Hz, Ph), 7.22 (1H, t, J¼7.4 Hz, Ph), 7.16
25.9, 25.4, 24.2, 18.3; IR (KBr) 2948, 2859, 1705, 1691, 1479, 1448,
1383, 1355, 1339, 1302, 1258, 1223, 1198, 1175, 1157, 1133, 1092,
1049,1016, 953, 922, 858, 831, 745 cmꢁ1; HRMSeESI (m/z): [MþH]þ
calcd for C12H20NO2: 210.1489. Found: 210.1488.
(2H, d, J¼7.4 Hz, Ph), 4.94e4.90 (1H, m, 10-H), 4.15 (1H, dd, J¼10.9,
10.2 Hz, 6-H), 4.10 (1H, ddq, J¼10.9, 4.9, 1.1 Hz, 6-H), 3.24 (1H, td,
J¼5.8, 4.9 Hz, 4-H), 3.12 (1H, dddd, J¼10.2, 10.2, 4.9, 4.9 Hz, 5-H),
2.97 (3H, s, NCH3), 2.68 (2H, t, J¼8.4 Hz, CH2Ph), 1.97e1.85 (2H, m,
CH2CH2Ph), 1.77 (3H, s, C(CH3)2), 1.71 (3H, d, J¼1.4 Hz, C(CH3)2); 13
C
3.5.2. (4R*,4aR*)-4-(20-Methylprop-10-enyl)hexahydropyrido[1,2-c]
NMR (175 MHz, CDCl3) d 153.2, 140.8, 137.8,128.5,128.1, 126.2, 117.4,
[1,3]oxazin-1(3H)-one (minor-5a). White solid. 1H NMR (700 MHz,
67.7, 59.5, 36.8, 35.5, 33.4, 32.3, 25.9, 18.3; IR (film) 3060, 3025,
2929, 1709, 1684, 1602, 1482, 1452, 1406, 1385, 1318, 1243, 1226,
1177, 1145, 1080, 1040, 1033, 1002, 983, 930, 909, 841, 755,
701 cmꢁ1; HRMSeESI (m/z): [MþNa]þ calcd for C17H23NO2Na:
296.1621. Found: 296.1618.
CDCl3)
d
4.81 (1H, dqq, J¼9.5, 1.4, 1.4 Hz, 10-H), 4.49e4.44 (1H, m, 8-
H), 3.97 (1H, dd, J¼10.9, 4.6 Hz, 3-H), 3.84 (1H, dd, J¼10.9, 10.9 Hz,
3-H), 2.95 (1H, ddd, J¼11.6, 9.5, 2.5 Hz, 4a-H), 2.68 (1H, dddd,
J¼10.9, 9.5, 9.5, 4.6 Hz, 4-H), 2.66 (1H, ddd, J¼13.2, 13.2, 2.8 Hz, 8-
H), 1.88e1.81 (2H, m, 5-H and 7-H), 1.74 (3H, d, J¼1.4 Hz, C(CH3)2),
1.71e1.66 (1H, m, 6-H), 1.70 (3H, d, J¼1.4 Hz, C(CH3)2), 1.47 (1H,
ddddd, J¼13.0, 13.0, 13.0, 4.2, 4.2 Hz, 7-H), 1.35 (1H, ddddd, J¼13.0,
3.5.6. (4R*,5R*)-3-Methyl-5-(20-methylprop-10-enyl)-4-phenethyl-
1,3-oxazinan-2-one (minor-5h). Pale yellow solid. 1H NMR

2752
E. Tayama et al. / Tetrahedron 69 (2013) 2745e2752
(700 MHz, CDCl3)
d
7.30 (2H, dd, J¼7.6, 7.6 Hz, Ph), 7.22 (1H, t,
Supplementary data
J¼7.6 Hz, Ph), 7.16 (2H, d, J¼7.6 Hz, Ph), 5.03e5.00 (1H, m,10-H), 4.16
(1H, dd, J¼10.9, 4.2 Hz, 6-H), 3.91 (1H, dd, J¼10.9, 7.7 Hz, 6-H), 3.15
(1H, ddd, J¼7.0, 7.0, 2.8 Hz, 4-H), 2.96 (3H, s, NCH3), 2.87 (1H, dddd,
J¼8.4, 7.7, 7.0, 4.2 Hz, 5-H), 2.61 (2H, t, J¼8.4 Hz, CH2Ph), 1.99 (1H,
dtd, J¼15.1, 8.4, 2.8 Hz, CH2CH2Ph), 1.90 (1H, ddt, J¼15.1, 8.4, 7.0 Hz,
CH2CH2Ph), 1.75 (3H, d, J¼1.4 Hz, C(CH3)2), 1.71 (3H, d, J¼0.7 Hz,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.01.088.
References and notes
C(CH3)2); 13C NMR (175 MHz, CDCl3)
d
154.6, 140.8, 136.8, 128.6,
1. (a) Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779e2831; (b) Ferrier, R. J.
J. Chem. Soc., Perkin Trans. 1 1979, 1455e1458.
128.1, 126.2, 120.7, 67.4, 61.9, 35.2, 34.7, 33.1, 30.3, 25.8, 18.3; IR
(KBr) 3061, 3028, 2975, 2933, 2872, 1695, 1664, 1487, 1454, 1429,
1403, 1385, 1349, 1324, 1291, 1272, 1240, 1226, 1190, 1145, 1097,
1073, 1037, 846, 761, 701 cmꢁ1; HRMSeESI (m/z): [MþNa]þ calcd
for C17H23NO2Na: 296.1621. Found: 296.1618.
2. For reviews: (a) Nasveschuk, C. G.; Rovis, T. Org. Biomol. Chem. 2008, 6,
240e254; (b) Meek, S. J.; Harrity, J. P. A. Tetrahedron 2007, 63, 3081e3092.
3. Previous examples of Ferrier reaction of O-alkenyl O,O-acetals: (a) Tayama, E.;
Hashimoto, R. Tetrahedron Lett. 2007, 48, 7950e7952; (b) Tayama, E.; Isaka,
W. Org. Lett. 2006, 8, 5437e5439; (c) Frein, J. D.; Rovis, T. Tetrahedron 2006,
62, 4573e4583; (d) Inui, M.; Hosokawa, S.; Nakazaki, A.; Kobayashi, S. Tet-
rahedron Lett. 2005, 46, 3245e3248; (e) Shenoy, S. R.; Woerpel, K. A. Org. Lett.
2005, 7, 1157e1160; (f) Zhang, Y.; Rovis, T. Tetrahedron 2003, 59, 8979e8987;
(g) Suzuki, T.; Inui, M.; Hosokawa, S.; Kobayashi, S. Tetrahedron Lett. 2003, 44,
3713e3716; (h) Zhang, Y.; Reynolds, N. T.; Manju, K.; Rovis, T. J. Am. Chem.
Soc. 2002, 124, 9720e9721; (i) Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem. Soc.,
Perkin Trans. 1 2000, 2385e2394; (j) Petasis, N. A.; Lu, S.-P. Tetrahedron Lett.
1996, 37, 141e144; (k) Petasis, N. A.; Lu, S.-P. J. Am. Chem. Soc. 1995, 117,
6394e6395; (l) Adam, S. Tetrahedron Lett. 1988, 29, 6589e6592; (m)
Takahashi, M.; Suzuki, H.; Moro-oka, Y.; Ikawa, T. Tetrahedron Lett. 1982, 23,
4031e4034; (n) Takahashi, M.; Suzuki, H.; Moro-oka, Y.; Ikawa, T. Tetrahedron
Lett. 1982, 23, 1079e1082.
3.6. Hydrogenation of major-5e
A mixture of major-5e (35.0 mg, 0.123 mmol) and palladium on
activated carbon (loading: 10 wt %, 2 mg) in ethyl acetate (1.5 mL)
was stirred for 3 h at room temperature under a hydrogen atmo-
sphere. The resulting mixture was filtered through a pad of Celite,
and the filtrate was concentrated to obtain major-6e (34.9 mg, 99%
yield) as a colorless oil.
4. (a) Koziol, A.; Grzeszczyk, B.; Koziol, A.; Staszewska-Krajewska, O.; Furman, B.;
Chmielewski, M. J. Org. Chem. 2010, 75, 6990e6993; (b) Terada, M.; Toda, Y. J. Am.
Chem. Soc. 2009, 131, 6354e6355; (c) Arenz, T.; Frauenrath, H.; Raabe, G.; Zorn,
M. Liebigs Ann. Chem. 1994, 931e942; (d) Frauenrath, H.; Arenz, T.; Raabe, G.;
Zorn, M. Angew. Chem., Int. Ed. Engl. 1993, 32, 83e85.
3.6.1. (4S*,4aR*)-4-(40-Phenylbutyl)hexahydropyrido[1,2-c][1,3]ox-
azin-1(3H)-one (major-6e). Colorless oil. 1H NMR (400 MHz, CDCl3)
d
7.31e7.25 (2H, m, Ph), 7.22e7.14 (3H, m, Ph), 4.45e4.38 (1H, m, 8-
5. Tayama, E.; Otoyama, S.; Isaka, W. Chem. Commun. 2008, 4216e4218.
6. Arenz, T.; Frauenrath, H. Angew. Chem., Int. Ed. Engl. 1990, 29, 932e933.
7. O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435e446.
H), 4.03e3.96 (2H, m, 3-H), 3.25 (1H, ddd, J¼12.4, 5.9, 2.3 Hz, 4a-H),
2.67 (1H, ddd, J¼12.4, 12.4, 2.8 Hz, 8-H), 2.62 (2H, t, J¼7.8 Hz, 40-H),
2.24e2.13 (1H, m, 4-H), 2.02e1.88 (1H, m), 1.70e1.20 (11H, m); 13C
8. 1H NMR analysis of the oxygen analog, 2-(1,3-dienyloxy) tetrahydrofuran does
not form a mixture of rotamers. See, Ref. 3b and its Supplementary data (Copies
of NMR spectrum).
NMR (100 MHz, CDCl3)
d 153.0, 142.0, 128.2, 125.7, 66.8, 57.7, 46.8,
9. A representative copy of 1H NMR spectrum of 2c: see, Supplementary data.
10. Our previous studies on the 1,4-elimination of E-isomer and precoordination
transition state: (a) Tayama, E.; Sugai, S. Tetrahedron Lett. 2007, 48, 6163e6166;
(b) Tayama, E.; Sugai, S. Synlett 2006, 849e852 See, also Ref. 3a.
11. When we examined the 1,4-elimination of 4-mono-substituted acyclic
derivatives 1, similar E/Z-selectivity with the piperidinyl derivatives 1cee were
obtained.
35.5, 35.1, 31.3, 26.4, 26.3, 25.7, 25.4, 24.4; IR (film) 3059, 3024,
2931, 2856, 1688, 1602, 1477, 1431, 1361, 1314, 1296, 1241, 1177, 1150,
1105, 1085, 1012, 950, 917, 855, 834, 821, 754, 700 cmꢁ1; HRMSeESI
(m/z): [MþH]þ calcd for C18H26NO2: 288.1958. Found: 288.1954.
Acknowledgements
12. Similar results were obtained in the previous studies on aza-Ferrier reaction
(Refs. 4a, 4c, and 4d). However, Terada and Toda reported regiospecific reaction.
The reaction of the geometry pure (1E or 1Z) of O-alkenyl N,O-acetals catalyzed
chiral phosphonic acid proceeds with high regiospecifically to give the almost
single relative stereoisomer (Ref. 4b).
This work was supported by MEXT KAKENHI Grant Number
18037021 (Grant-in-Aid for Scientific Research on Priority Areas
‘Advanced Molecular Transformations of Carbon Resources’).
13. The unidentifiable products were observed by TLC analysis.