Extremely high regio- and stereoselective C-C bond formation of substituted γ-hydroxylactams: synthesis of macronecines based on their structural duality

Article abstract of DOI:10.1016/j.tet.2009.01.085

With a view to develop a new synthetic entry for the necine bases, treatment of functionalized γ-hydroxylactams was found to undergo quite high regio- and diastereoselective carbon-carbon bond formation reactions, affording the corresponding structurally

Full text of DOI:10.1016/j.tet.2009.01.085

Tetrahedron 65 (2009) 2415–2423
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Extremely high regio- and stereoselective C–C bond formation of substituted
g
-hydroxylactams: synthesis of macronecines based on their structural duality
*
Tetsuya Sengoku, Takamasa Suzuki, Tatsuro Kakimoto, Masaki Takahashi, Hidemi Yoda
Department of Materials Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Naka-ku, Hamamatsu 432-8561, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2009
Received in revised form 21 January 2009
Accepted 22 January 2009
Available online 29 January 2009
With a view to develop a new synthetic entry for the necine bases, treatment of functionalized
g
-hydroxylactams was found to undergo quite high regio- and diastereoselective carbon–carbon bond
formation reactions, affording the corresponding structurally dualistic alkylated lactams in satisfactory
yields. The reaction was further applied to the practical and efficient synthesis of (ꢀ)-macronecine
[(1S
*
,2R
*
,7aR
*
)-1-hydroxymethyl-2-hydroxypyrrolizidine] and (ꢀ)-2-epi-macronecine [(1S
*
,2S
*
,7aR )-1-
*
hydroxymethyl-2-hydroxypyrrolizidine].
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
The necine family of the pyrrolizidine alkaloids may be di-
vided into three different classes according to their structural
features (Fig. 2). In the first class of the necines, such as lab-
urnine (1a), macronecine (1b), and hastanecine (1d), each of
these molecules bears a free hydroxyl group in their side chain.
The second class of the necine derivatives such as farfugine (1e)
possesses external ester groups, while macrocyclic lactones such
as retrorsine (1f) represent the third class of them. Their struc-
tural and stereochemical properties coupled with their diverse
and potentially useful characteristics have made them so far
inviting targets for synthesis. With these considerations in mind,
we report here the expeditiously synthetic application of the
Pyrrolizidine alkaloids, which comprise a unique family of bi-
cyclic heterocycles with diverse oxygenation patterns on the aza-
bicyclo[3.3.0]octane skeleton, are widely distributed throughout
the plant kingdom and found in the animal kingdom as well.1 Over
the past several decades, these compounds have attracted great
interest from organic chemists because of their potent mutagenic,
teratogenic, and carcinogenic activities2,3 as well as their synthetic
challenges for further elaboration of architecturally complicated
natural products.4 Noteworthy members among this class of com-
pounds are the necines, alexines,5 and the new series of hyacin-
thacines, which were recently isolated from bluebells
(Hyacinthoides non-scripta)6 and grape hyacinths (Muscari arme-
niacum)7 by Asano and co-workers as selective inhibitors of
g
-hydroxylactams to macronecine (1b)8 and 2-epi-macronecine
(1c) as well as the research of their fascinating duality for regio-
and diastereoselective carbon–carbon bond formation, which
were, in turn, prepared via the corresponding monoterpene
lactone precursor.
b
-glucosidase and b-galactosidase (Fig. 1). Among them, the com-
pounds bearing particular substituents of the C(1)-positions on the
pyrrolizidine ring systems allow us to distinguish the necines from
the others bearing the hydroxymethyl substituents at C(3)-
positions.
OH
OH
X
H
N
H
N
Y
OH
laburnine (1a)
macronecine (1b): X=OH, Y=H
7
5
1
3
2-epi-macronecine (1c): X=H, Y=OH
6
2
N
N
N
HO
OH
O
O
OH
alexine family (2)
OH
hyacinthacine family (3)
O
OH
H
necine family (1)
HO
HO
O
H
O
O
H
N
Figure 1. Structures of selected pyrrolizidine alkaloids.
N
N
farfugine (1e)
hastanecine (1d)
retrorsine (1f)
* Corresponding author. Tel./fax: þ81 53 478 1150.
Figure 2. Structures of selected necine bases.
E-mail address: tchyoda@ipc.shizuoka.ac.jp (H. Yoda).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.085

2416
T. Sengoku et al. / Tetrahedron 65 (2009) 2415–2423
OH
X
extremely predominant product.11 The hydroxylated lactone was
H
7a
N
7
subsequently protected with BnBr followed by separation of the
resulting mixture from both the minor stereoisomer and side-
products by silica gel column chromatography to give the pure
lactone 5. Ring opening reaction of 5 with p-methoxybenzylamine
(MPMNH2) proceeded smoothly to form the amide alcohol 6 in 97%
yield and the following Swern oxidation of 6 with diisopropyle-
1
3
6
2
Y
5
macronecine (1b): X=OH, Y=H
2-epi-macronecine (1c): X=H, Y=OH
OR2
O
R1O
R1O
OR2
O
thylamine gave rise to 7 without epimerization at a-position of the
aldehyde.12 Unfortunately, intramolecular cyclization of 7 did not
proceed under mild basic and acidic conditions, which employed
Et3N and p-TsOH, respectively. The use of BF3$OEt2 in THF, however,
promoted the cyclization to provide 8 in 77% yield (two steps). The
lactam 8 was subsequently converted into the imide 9a via PCC
oxidation.
H
1
2
7a
O
N
R
N
R
(III)
(IV)
OR2
R1O
HO
With the two substrates 8 and 9a in hand, regio- and diaster-
eoselective nucleophilic allylation was examined. According to our
established procedure,13 the imide 9a was treated with allyl
Grignard reagent at low temperature to give the quaternary
hydroxylactam with complete regioselectivity. Reductive de-
oxygenation of the hydroxylactam via the N-acyliminium ion in-
termediate, which was performed with Et3SiH in the presence of
BF3$OEt2, afforded the allylated lactam as the extremely diaster-
eoselective product (99:1 regioselectivity, 98% de determined by 1H
NMR). This compound was determined based on the coupling
O
N
R
(II)
R1O
O
O
OH
OH
HO
HO
O
O
dihydroxyacetone dimer
(I)
Figure 3. General retrosynthesis.
constant of 1H NMR to be the
b,g-trans-substituted lactam 10a
(JH4,H5¼3.7 Hz) shown in Scheme 1.14
Interested in this excellent regio- and diastereoselectivity, we
applied the other alkyl Grignard reagents to this type of successive
nucleophilic addition/deoxygenation reactions (Table 1). In-
terestingly, whereas the reactions with the N-larger substituted
imide 9a gave the alkylated products 10a–d predominantly to-
gether with the small amount of regioisomers (entries 1–4), the
reactions with the smaller N-methyl imide 9b afforded 10e–h with
complete regioselectivity and excellent diastereoselectivity (entries
5–8). In each case, the initial Grignard addition afforded the ad-
ducts as an approximately 1:1 mixture of diastereomers. This type
of Grignard reaction/reductive deoxygenation sequence with
mono-substituted imide has been reported.15 Both the high regio-
selectivity on Grignard addition and the trans-diastereoselectivity
on reductive deoxygenation were also observed and these selec-
tivities were attributed to the chelation between the oxygen atom
of BnO substituent and the reagents.16 Our results may support
their reaction mechanism17 and extend the utility of this strategy to
Our synthetic plan for macronecine (1b) and 2-epi-macronecine
(1c) is shown in Figure 3. We envisaged that the pyrrolizidine ring
would be constructed from lactam (IV). The stereogenic center of
C(7a) on (IV) would originate from the regio- and stereoselective
nucleophilic allylation of two different precursors, hydroxylactam
(II) and imide (III). The relative stereochemistry at C(1) and C(2)
could be constructed through sequential treatments of the mono-
terpene lactone (I) prepared from dihydroxyacetone dimer.
2. Results and discussion
As shown in Scheme 1, the starting terpene lactone 4 was pre-
pared from dihydroxyacetone dimer according to our procedure.9
The lactone 4 was oxygenated with 2-phenylsulfonyl-3-phenyl-
oxaziridine10 in the presence of lithium hexamethyldisilazide
(LiHMDS) at ꢁ78 ꢂC to give the trans-disubstituted lactone as an
DPSO
OHC
DPSO
HO
DPSO
DPSO
OBn
O
O
O
O
ref. 11
O
c
a
b
OH
OH
HO
HO
NHMPM
NHMPM
O
O
O
4
5
OBn
OBn
6
7
OBn
OH
OBn
O
OBn
DPSO
DPSO
DPSO
f
4
g
5
O
O
O
N
N
N
e
OBn
DPSO
HO
MPM
MPM
MPM
9a
10a
d
O
N
DPSO
OBn
h
MPM
8
O
N
MPM
11
Scheme 1. Reagents and conditions: (a) (i) LiHMDS, 2-phenylsulfonyl-3-phenyloxaziridine, THF, ꢁ78 ꢂC; (ii) BnBr, Ag2O, EtOAc, 46% (two steps); (b) MPMNH2, MeOH, 97%; (c)
(COCl)2, DMSO, (i-Pr)2NEt, THF, ꢁ78 ꢂC to 0 ꢂC; (d) BF3$OEt2, THF, 0 ꢂC, 96% (two steps); (e) PCC, CH2Cl2, 93%; (f) 3-bromopropene, Mg, THF, ꢁ78 ꢂC to 0 ꢂC; (g), Et3SiH, BF3$OEt2,
ꢁ78 ꢂC to 0 ꢂC, 74% (two steps); (h) allyltrimethylsilane, BF3$OEt2, CH2Cl2, ꢁ78 ꢂC to ꢁ20 ꢂC, 99%.

T. Sengoku et al. / Tetrahedron 65 (2009) 2415–2423
2417
Table 1
Regio- and diastereoselective alkylation of 9
OBn
OBn
R2
DPSO
DPSO
DPSO
R2
OBn
O
1) R2MgBr (4.0 eq), THF, -78 °C-0 °C
+
O
2) Et3SiH (3.0 eq), BF3•OEt2 (3.0 eq), CH2Cl2, -78 °C-0 °C
O
O
N
N
R1
N
R1
R1
9a: R1=MPM
10
12
9b: R1=Me
Entry
Imide (9)
R2
Yield/%a (conversion yield)b
Regioselectivity (10:12)c
Diastereoselectivity of 10/% ded
1
2
3b
4
5
6
7
8
9a
9a
9a
9a
9b
9b
9b
9b
CH2]CHCH2
Me
74
87
54 (81)
51 (61)
69
99
88
60
99:1
97:3
98:2
98 (10a)
99 (10b)
99 (10c)
99 (10d)
92 (10e)
99 (10f)
99 (10g)
99 (10h)
n-C3H7
n-C9H19
CH2]CHCH2
Me
n-C3H7
n-C9H19
99:1
100:0
100:0
100:0
100:0
a
Combined and isolated yield of 10 and 12 in two steps.
b
c
Conversion yield was calculated on the basis of the recovery of the starting material.
The ratio of 10 and 12 was calculated from 1H NMR.
d
The diastereomeric excess was determined by 1H NMR.
OBn
O
OBn
O
ODPS
H
DPSO
DPSO
b
c
a
OBn
N
HO
N
N
11
13
14
MPM
MPM
O
ODPS
X
ODPS
X
OH
X
H
H
N
H
N
e
d
N
Y
Y
Y
O
15a: X=H, Y=OH
16a: X=H, Y=OH
16b: X=OH, Y=H
2-epi-macronecine (1c): X=H, Y=OH
macronecine (1b): X=OH, Y=H
f
15b: X=OH, Y=H
Scheme 2. Reagents and conditions: (a) 9-BBN, H2O2 (34.5%), 3 N NaOH, THF, 84%; (b) (i) TsCl, pyridine; (ii) CAN, MeCN/H2O¼2:1; (iii) NaH, THF, 73% (three steps); (c) Pd(OH)2/C, H2,
EtOH, 95%; (d) BH3$THF, THF, 67% (16a), 89% (16b); (e) 3% HCl/MeOH, quant. (1c), 62% (1b); (f) (i) Tf2O, pyridine, CH2Cl2; (ii) CsOAc, 18-crown-6, toluene, 70% (two steps); (iii) K2CO3,
MeOH, 93%.
the syntheses of more complicated natural products and their an-
alogs such as 1-homoaustraline.18
acetate in the presence of 18-crown-6 followed by hydrolysis,22
affording the alcohol 15b in 65% isolated yield (three steps). Finally,
two-step sequence through the same procedures for 15a allowed
the construction of (ꢀ)-macronecine (1b), which showed analytical
and spectroscopic data in complete accordance with those of au-
thentic samples.8
Since the Grignard addition/deoxygenation sequence gave 10a,
we next examined the direct allylation of the hydroxylactam 8 with
allyltrimethylsilane. Whereas the reaction employing the corre-
sponding hydroxylactams derived from tartaric acid gave the prod-
ucts with moderate cis-selectivity13c,19 or no diastereoselectivity,20
the reaction of 8 gave the trans-stereoisomer 11 in 95% yield with
complete diastereoselectivity.21 To the best our knowledge, this ex-
cellent diastereoselective reaction is the first example of the allyla-
tion with disubstituted hydroxylactam containing hydroxymethyl
and hydroxyl substituents. These results demonstrate that the allyl-
ation of the hydroxylactam 8 and the imide 9 realizes their
synthetically fascinating duality for regio- and stereocontrolled car-
bon–carbon bond formation.
With these results in hand, we attempted the formation of the
pyrrolizidine ring system toward the synthesis of 1b and 1c
(Scheme 2). Thus, 11 was regioselectively hydroborated with 9-BBN
to give the primary alcohol 13, which was, in turn, submitted to the
tosylation, deprotection of the MPM group, and the intramolecular
cyclization to provide the desired bicyclic compound 14 in 73%
yield (three steps). After hydrogenation reaction of 14 with
Pd(OH)2/C under H2 atmosphere followed by reduction of 15a,
desilylation of 16a with 3% HCl/MeOH led to the completion of the
synthesis of (ꢀ)-2-epi-macronecine (1c). In order to accomplish the
synthesis of 1b, we turn next to the preparation of 15b containing
the reverse stereochemistry at C(2). Inversion of the configuration
at C(2) was achieved via the triflate intermediate with cesium
3. Conclusions
In summary, we have completed the practical synthesis of
macronecines. Highlight of the synthesis is the efficient elaboration
of the hydroxylactam intermediate prepared from the mono-
terpene lactone precursor, which demonstrates the synthetically
fascinating duality for regio- and stereocontrolled carbon–carbon
bond formation. This synthetic strategy will find applications in the
synthesis of biologically important pyrrolizidine and/or indolizi-
dine alkaloids. Current efforts to expand the scope of synthetic
application to more complicated natural products are in progress.
4. Experimental section
4.1. General
All solvents and reagents were of reagent grade quality from
Aldrich Chemical Company, Fluka, Acros or Wako Pure Chemicals
and used without any further purification. Melting points were
measured on an automated melting point system (MPA 100, Stan-
ford Research Systems). Fourier transform infrared (FTIR) spectra

2418
T. Sengoku et al. / Tetrahedron 65 (2009) 2415–2423
were recorded on a Shimadzu FTIR-8200A spectrometer. The 1H and
13C nuclear magnetic resonance (NMR) spectra operating at the
frequencies of 300 and 75 MHz, respectively, were measured with
a JEOL JNM-AL300 spectrometer in chloroform-d (CDCl3) unless
otherwise stated. Chemical shifts are reported in parts per million
CH3), 2.88 (br s, 1H, OH), 2.15 (m, 1H, CH), 1.04 (s, 9H, C(CH3)3); 13
NMR (CDCl3) 172.1 (C), 159.0 (C), 136.6 (C), 135.5 (CH), 133.2 (C),
129.8 (CH), 129.7 (C), 129.0 (CH), 128.5 (CH), 128.3 (CH), 128.1 (CH),
127.7 (CH), 114.1 (CH), 79.2 (CH), 73.5 (CH2), 62.3 (CH2), 61.6 (CH2),
55.2 (CH), 47.1 (CH3), 42.5 (CH2), 26.8 (CH3), 19.1 (C); HRMS (ESIþ)
m/z calcd for C36H43NO5SiþNa: 620.2808, found 620.2760.
C
d
(ppm) relative to TMS as internal standard (
and CDCl3 was used as internal standard (
d
¼0 ppm) for 1H NMR,
d
¼77.0) for 13C NMR. The
coupling constants are reported in hertz (Hz). Reactions were
monitored by thin-layer chromatography (TLC) using 0.25 mm
Merck silica gel 60-F254 precoated silica gel plates by irradiation
with UV light and/or by treatment with a solution of phosphomo-
lybdic acid in methanol followed by heating. Column chromatog-
raphy was performed on Kanto Chemical silica gel 60N eluting with
the indicated solvent system. The non-crystalline compounds were
shown to be homogeneous by chromatographic methods and
characterized by NMR, IR, high resolution mass spectra (HRMS), and
microanalysis. HRMS were recorded on a JEOL JMS-T100CS spec-
trometer. Microanalyses were performed with a JSL Model JM 10.
4.2.3. (3S
*
,4S )-3-(Benzyloxy)-4-((tert-butyldiphenylsilyloxy)-
*
methyl)-5-hydroxy-1-(4-methoxybenzyl)-
pyrrolidin-2-one (8)
To a stirred solution of oxalyl chloride (0.043 mL, 0.50 mmol) in
CH2Cl2 (1.0 mL) was added DMSO (0.047 mL, 0.67 mmol) under
nitrogen at ꢁ78 ꢂC and stirred for 15 min. Then, a solution of 6
(85.0 mg, 0.142 mmol) in CH2Cl2 (1.5 mL) was added to this mixture
and further stirred for 15 min. (i-Pr)2EtN (0.19 mL, 1.4 mmol) was
added and warmed to 0 ꢂC. After stirring for 15 min, the mixture
was quenched by the addition of saturated aq NH4Cl (5 mL) and
extracted with EtOAc (3ꢃ10 mL). The combined organic extracts
were washed with brine (5 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was roughly passed
through column chromatography (silica gel, EtOAc) to give the
crude aldehyde 7 (87.7 mg), which was used without further pu-
rification. To a solution of the above aldehyde was added BF3$OEt2
(0.023 mL, 0.18 mmol) at 0 ꢂC and stirred for 30 min. It was
quenched by the addition of saturated aq NaHCO3 (5 mL) and
extracted with EtOAc (3ꢃ10 mL). The combined organic extracts
were washed with brine (5 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by column
chromatography (silica gel, hexane/EtOAc¼5:2) to give the
hydroxylactam 8 (80.9 mg, 96%) as a colorless oil. IR (NaCl) 3370
4.2. Experimental procedures
4.2.1. (3S
*
,4S )-3-(Benzyloxy)-4-((tert-butyldiphenylsilyloxy)-
*
methyl)dihydrofuran-2(3H)-one (5)
To a stirred solution of LiHMDS [prepared from hexame-
thyldisilazane (910 mg, 5.64 mmol) and n-BuLi (1.66 M in hexane,
2.5 mL, 4.23 mmol) in THF (20 mL) under nitrogen at ꢁ78 ꢂC] was
added a solution of the lactone 4 (1.00 g, 2.82 mmol) in THF
(8.0 mL). After the mixture was stirred for 10 min, a solution of 2-
phenylsulfonyl-3-phenyloxaziridine (813 mg, 3.10 mmol) was
added, and the reaction mixture was further stirred for 1 h at the
same temperature. It was quenched by the addition of saturated
aq NH4Cl (10 mL) and extracted with EtOAc (30 mL). The organic
extract was washed with brine (15 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude product was
roughly purified by column chromatography (silica gel, toluene/
EtOAc¼15:1 to 8:1). This operation was performed more two
times to give the crude product (1.88 g), which was used without
further purification. A solution of the combined crude product
(1.88 g), benzyl bromide (1.30 g, 7.59 mmol), and silver(I) oxide
(1.41 g, 6.07 mmol) in EtOAc (10 mL) was stirred for 48 h. After
filtration through a pad of Celite with EtOAc and concentration,
the crude product was purified by column chromatography (silica
gel, hexane/EtOAc¼15:1) to give 5 (1.68 g, 46%) as a colorless oil.
IR (NaCl) 2900 (C–H), 1788 (C]O), 1589 (C]C), 1111 (C–O), 1011
(O–H), 1690 (C]O), 1514 (C]C), 1112 (C–O), 1075 (C–O) cmꢁ1
;
1H
NMR (CDCl3) 7.63–7.60 (m, 4H, ArH), 7.50–7.15 (m, 30H, ArH), 6.87
d
(m, 2H, ArH), 6.80–6.77 (m, 2H, ArH), 5.18 (d, J¼11.3 Hz, 1H, CH2),
5.07 (m, 1H, CH), 5.06 (d, J¼11.6 Hz, 1H, CH2), 4.89 (d, J¼14.3 Hz, 1H,
CH2), 4.87 (d, J¼14.3 Hz, 1H, CH2), 4.74 (m, 1H, CH), 4.70 (d,
J¼11.6 Hz, 1H, CH2), 4.60 (d, J¼11.6 Hz, 1H, CH2), 4.39 (d, J¼8.2 Hz,
1H, CH), 4.14–3.99 (m, 6H, CH, CH2), 3.89 (dd, J¼10.6, 5.0 Hz, 1H,
CH2), 3.79 (s, 3H, CH3), 3.76 (s, 3H, CH3), 3.65–3.63 (m, 2H, OH), 2.32
(m, 1H, CH), 2.16 (m, 1H, CH), 1.04 (s, 9H, C(CH3)3), 0.93 (s, 9H, CH3);
13C NMR (CDCl3)
d 171.8 (2C), 159.0 (C), 158.9 (C), 137.5 (2C), 135.42
(2CH), 135.38 (2CH), 135.36 (CH), 135.33 (CH), 132.8 (C), 132.7 (C),
132.2 (C), 132.0 (C), 130.0 (CH), 129.9 (CH), 129.73 (CH), 129.67 (CH),
129.6 (2CH), 128.19 (CH), 128.16 (CH), 127.94 (CH), 127.87 (CH),
127.83 (CH), 127.80 (CH), 127.64 (2CH), 127.61 (2CH), 114.0 (2CH),
80.5 (CH), 80.1 (CH), 75.9 (CH), 75.1 (CH), 72.8 (CH2), 72.7 (CH2),
60.8 (CH2), 59.7 (CH2), 55.1 (CH3), 55.0 (CH3), 51.4 (CH), 45.8 (CH),
43.0 (CH2), 42.4 (CH2), 26.7 (CH3), 26.6 (CH3), 19.0 (C), 18.9 (C). Anal.
Calcd for C36H41NO5Si: C, 72.57; H, 6.94; N, 2.35. Found: C, 72.28; H,
6.61; N, 2.73.
(C–O) cmꢁ1 1H NMR (CDCl3)
; d 7.60–7.57 (m, 4H, ArH), 7.46–7.28
(m, 11H, ArH), 5.03 (d, J¼11.4 Hz, 1H, CH2), 4.65 (d, J¼11.4 Hz, 1H,
CH2), 4.37 (t, J¼8.1 Hz, 1H, CH2), 4.23 (d, J¼8.1 Hz, 1H, CH), 4.15 (t,
J¼8.7 Hz, 1H, CH2), 3.77 (dd, J¼10.5, 3.6 Hz, 1H, CH2), 3.69 (dd,
J¼10.5, 3.6 Hz, 1H, CH2), 2.69 (m, 1H, CH), 1.03 (s, 9H, C(CH3)3); 13
C
NMR (CDCl3)
d 175.2 (C), 137.0 (C), 135.5 (CH), 132.6 (C), 130.0
(CH), 128.4 (CH), 128.1 (CH), 128.0 (CH), 127.8 (CH), 73.7 (CH), 72.3
(CH2), 67.1 (CH2), 60.8 (CH2), 44.3 (CH), 26.8 (CH3), 19.2 (C); HRMS
(ESIþ) m/z calcd for C28H32O4SiþNa: 483.1968, found 483.1959.
4.2.4. (3S
methyl)-1-(4-methoxybenzyl)pyrrolidine-2,5-dione (9a)
mixture of (472 mg, 0.791 mmol), PCC (205 mg,
*
,4S
*
)-3-(Benzyloxy)-4-((tert-butyldiphenylsilyloxy)-
A
8
0.949 mmol), and MS 4 Å (300 mg) in CH2Cl2 (8.0 mL) was stirred
for 2 h. After filtration through a pad of Celite with Et2O and con-
centration, the crude product was purified by column chromato-
graphy (silica gel, hexane/EtOAc¼7:1) to give the imide 9a (438 mg,
93%) as a colorless oil. IR (NaCl) 2858 (C–H), 1713 (C]O), 1250 (C–
4.2.2. (2S
*
,3S )-2-(Benzyloxy)-4-(tert-butyldiphenylsilyloxy)-3-
*
(hydroxymethyl)-N-(4-methoxybenzyl)butanamide (6)
A solution of 5 (742 mg, 1.61 mmol) and p-methoxybenzylamine
(MPMNH2) (0.23 mL, 1.77 mmol) in MeOH (6.0 mL) was stirred for
24 h. The mixture was concentrated and chromatographed (silica
gel, hexane/EtOAc¼2:1 to 1:1) to give the amide 6 (929 mg, 97%) as
a viscous oil. IR (NaCl) 3414 (N–H), 3400 (O–H), 1651 (C]O), 1612
O), 1113 (C–O) cmꢁ1 1H NMR (CDCl3)
; d 7.55–7.27 (m, 17H, ArH),
6.79–6.74 (m, 2H, ArH), 4.99 (d, J¼11.5 Hz, 1H, CH2), 4.72 (d,
J¼11.5 Hz, 1H, CH2), 4.65 (d, J¼5.5 Hz, 2H, CH2), 4.51 (d, J¼4.4 Hz,
1H, CH), 4.19 (dd, J¼10.1, 2.6 Hz, 1H, CH2), 3.71 (s, 3H, CH3), 3.69 (dd,
J¼10.1, 2.8 Hz,1H, CH2), 2.75 (ddd, J¼4.4, 2.8, 2.6 Hz,1H, CH), 0.85 (s,
(C]C), 1249 (C–O) cmꢁ1
;
1H NMR (CDCl3)
d
7.64 (d, J¼7.3 Hz, 4H,
ArH), 7.43–7.22 (m, 9H, ArH), 7.11–7.09 (m, 4H, ArH), 6.87–6.79 (m,
3H, NH, ArH), 4.44 (d, J¼11.2 Hz, 1H, CH2), 4.37 (d, J¼11.2 Hz, 1H,
CH2), 4.37 (dd, J¼14.4, 5.1 Hz, 1H, CH2), 4.28 (dd, J¼14.4, 5.5 Hz, 1H,
CH2), 4.01 (d, J¼6.8 Hz, 1H, CH), 3.89–3.80 (m, 4H, CH2), 3.76 (s, 3H,
9H, C(CH3)3); 13C NMR (CDCl3)
d 175.6 (C), 174.8 (C), 159.2 (C), 136.9
(C), 135.5 (CH), 135.4 (C), 132.5 (C), 132.3 (C), 130.1 (CH), 129.9 (CH),
129.8 (CH), 128.5 (CH), 128.1 (2CH), 127.7 (CH), 114.0 (CH), 74.1 (CH),

T. Sengoku et al. / Tetrahedron 65 (2009) 2415–2423
2419
73.2 (CH2), 60.0 (CH2), 55.2 (CH3), 50.3 (CH), 41.8 (CH2), 26.5 (CH3),
19.0 (C); HRMS (ESIþ) m/z calcd for C36H39NO5SiþNa: 616.2495,
found 616.2463.
NH4Cl (10 mL) and extracted with EtOAc (3ꢃ10 mL). The combined
organic extracts were washed with brine (20 mL), dried over an-
hydrous Na2SO4, and concentrated in vacuo. The crude product was
roughly passed through column chromatography (silica gel, EtOAc)
to give the crude aldehyde (758 mg), which was used without
further purification. To a solution of the above aldehyde in THF
(20 mL) was added BF3$OEt2 (0.18 mL, 1.5 mmol) at 0 ꢂC and stirred
for 1 h. It was quenched by the addition of saturated aq NaHCO3
(10 mL) and extracted with EtOAc (3ꢃ10 mL). The combined or-
ganic extracts were washed with brine (20 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography (silica gel, hexane/EtOAc¼3:1
to 1:1) to give the hydroxylactam (599 mg, 91%) as a colorless oil. IR
4.2.5. (3S
*
,4S
*
,5R )-5-Allyl-4-(benzyloxy)-3-((tert-butyldiphenyl-
*
silyloxy)methyl)-1-(4-methoxybenzyl)-
pyrrolidin-2-one (10a)
To a stirred solution of 9a (260 mg, 0.438 mmol) in THF (1.0 mL)
were added magnesium (43.0 mg, 17.5 mmol) and allyl bromide
(212 mg, 1.75 mmol) in THF (0.40 mL) under nitrogen at ꢁ78 ꢂC
and gradually warmed to 0 ꢂC. The mixture was quenched by the
addition of saturated aq NH4Cl (5.0 mL) and extracted with EtOAc
(3ꢃ10 mL). The combined organic extracts were washed with brine
(10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
The crude product was roughly purified by column chromatogra-
phy (silica gel, hexane/EtOAc¼3:1) to give the crude hydrox-
ylactam (276 mg), which was used without further purification. To
a solution of the above product and Et3SiH (0.21 mL, 1.31 mmol) in
CH2Cl2 (1.5 mL) was added a solution of BF3$OEt2 (0.16 mL,
1.31 mmol) in CH2Cl2 (0.70 mL) at ꢁ78 ꢂC and gradually warmed to
0 ꢂC. Then, it was quenched by the addition of saturated aq NaHCO3
(5.0 mL) and extracted with CH2Cl2 (3ꢃ10 mL). The combined or-
ganic extracts were washed with brine (10 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography (silica gel, hexane/
EtOAc¼20:1) to give the lactam 10a (324 mg, 74%) as a colorless oil.
IR (NaCl) 2932 (C–H), 1686 (C]O), 1248 (C–O), 1113 (C–O) cmꢁ1; 1H
(NaCl) 3369 (O–H), 2858 (C–H), 1686 (C]O), 1113 (C–O) cmꢁ1
;
1H
NMR (CDCl3) 7.64–7.56 (m, 4H, ArH), 7.47–7.25 (m, 12H, ArH), 6.87
d
(m, 2H, ArH), 7.47–7.25 (m, 12H, ArH), 5.18–5.14 (m, 1H, CH), 5.11 (d,
J¼11.6 Hz, 1H, CH2), 4.98 (d, J¼11.6 Hz, 1H, CH2), 4.80 (dd, J¼10.4,
3.3 Hz, 1H, CH2), 4.65 (d, J¼11.6 Hz, 1H, CH2), 4.55 (d, J¼11.6 Hz, 1H,
CH2), 4.10–4.02 (m, 2H, CH), 3.90 (dd, J¼10.7, 5.5 Hz, 1H, CH), 3.77
(dd, J¼10.4, 4.4 Hz, 1H, CH2), 3.69 (dd, J¼10.4, 4.8 Hz, 1H, CH2), 2.93
(s, 3H, CH3), 2.87 (s, 3H, CH3), 2.75 (d, J¼10.4 Hz, 1H, OH), 2.47–2.39
(m, 1H, CH), 2.20–2.15 (m, 1H, CH), 1.05 (s, 9H, CH3), 1.01 (s, 9H,
CH3); 13C NMR (CDCl3)
d 173.2 (C), 171.8 (C), 137.5 (C), 135.6 (CH),
135.5 (3CH), 132.9 (C), 132.7 (C), 130.2 (2C), 129.9 (CH), 128.4
(CH), 128.3 (CH), 128.1 (CH), 128.0 (2CH), 127.8 (CH), 127.7 (CH), 84.2
(CH), 83.8 (CH), 74.5 (CH), 72.7 (CH2), 72.6 (CH2), 61.0 (CH2),
51.6 (CH3), 45.4 (CH), 27.3 (CH3), 26.8 (CH3), 19.2 (C), 19.1 (C). Anal.
Calcd for C29H35NO4Si: C, 71.13; H, 7.20; N, 2.86. Found: C, 71.49; H,
6.85; N, 3.12.
NMR (CDCl3)
d 7.71–7.64 (m, 4H, ArH), 7.42–7.16 (m, 13H, ArH),
6.83–6.80 (m, 2H, CH), 5.69–5.55 (m, 1H, CH), 5.05 (dd, J¼9.7,
1.5 Hz, 1H, CH2), 5.04 (dd, J¼18.0, 1.5 Hz, 1H, CH2), 4.95 (d,
J¼15.0 Hz, 1H, CH2), 4.50 (d, J¼11.7 Hz, 1H, CH2), 4.40 (d, J¼11.7 Hz,
1H, CH2), 4.15 (dd, J¼5.4, 3.7 Hz, 1H, CH), 4.09 (dd, J¼10.3, 5.3 Hz,
1H, CH2), 4.01 (d, J¼15.0 Hz, 1H, CH2), 3.93 (dd, J¼10.3, 3.5 Hz, 1H,
CH2), 3.47 (ddd, J¼7.8, 4.2, 3.7 Hz, 1H, CH), 2.75 (ddd, J¼5.4, 5.3,
3.7 Hz, 1H, CH), 2.49–2.41 (m, 1H, CH2), 2.26–2.16 (m, 1H, CH2), 1.07
A mixture of the hydroxylactam (111 mg, 0.227 mmol), PDC
(102 mg, 0.272 mmol), and MS 4 Å (170 mg) in CH2Cl2 (1.0 mL) was
stirred for 3 h. After filtration through a pad of Celite with Et2O and
concentration, the crude product was purified by column chro-
matography (silica gel, hexane/EtOAc¼5:1 to 1:1) to give the imide
9b (109 mg, 98%) as a colorless oil. IR (NaCl) 2858 (C–H), 1713
(s, 9H, C(CH3)3); 13C NMR (CDCl3)
d
172.3 (C), 158.9 (C), 137.8 (C),
(C]O), 1113 (C–O) cmꢁ1; 1H NMR (CDCl3)
d 7.51–7.57 (m, 4H, ArH),
135.7 (CH), 135.6 (CH), 133.2 (C), 132.9 (C, CH), 129.7 (CH), 129.2
(CH), 128.3 (C, CH), 127.7 (2CH), 118.6 (CH2), 114.0 (CH), 78.1 (CH),
71.4 (CH2), 62.1 (CH2), 61.7 (CH), 55.2 (CH3), 52.3 (CH), 43.7 (CH2),
26.9 (CH3), 19.3 (C). Anal. Calcd for C39H45NO4Si: C, 75.57; H, 7.32;
N, 2.26. Found: C, 75.24; H, 7.32; N, 2.28.
7.30–7.48 (m, 2H, ArH), 5.01 (d, J¼11.6 Hz, 2H, CH2), 4.75 (d,
J¼11.6 Hz, 1H, CH2), 4.49 (d, J¼3.8 Hz, 1H, CH), 4.17 (dd, J¼2.7,
10.1 Hz, 1H, CH2), 3.74 (dd, J¼2.8, 10.1 Hz, 1H, CH2), 3.05 (s, 3H, CH3),
2.76–2.79 (m, 1H, CH), 0.93 (s, 9H, C(CH3)3); 13C NMR (CDCl3):
d
175.9 (C),175.6 (C),136.9 (C),135.5 (2CH),132.6 (C),132.3 (C),130.0
(C), 129.9 (CH), 129.9 (CH), 128.6 (CH), 128.2 (CH), 127.9 (CH), 127.8
(CH), 74.3 (CH), 73.2 (CH2), 60.5 (CH2), 50.5 (CH3), 26.3 (CH3), 24.7
(CH), 19.1 (C). Anal. Calcd for C29H33NO4Si: C, 71.42; H, 6.82; N, 2.87.
Found: C, 71.39; H, 6.87; N, 3.20.
4.2.6. (3S
*
,4S )-3-(Benzyloxy)-4-((tert-butyldiphenylsilyloxy)-
*
methyl)-1-methylpyrrolidine-2,5-dione (9b)
A solution of 5 (195 mg, 0.423 mmol) and methylamine in H2O
(40%, 1.0 mL) in THF (1.0 mL) was stirred for 30 min. The mixture
was concentrated and chromatographed (silica gel, CHCl3/
MeOH¼20:1) to give the amide (194 mg, 93%) as a white powder.
Mp 116–118 ꢂC; IR (NaCl) 3456 (N–H), 3402 (O–H), 2858 (C–H),
4.2.7. General procedure for Grignard reaction/reductive
deoxygenation
To a stirred solution of 9 (0.114 mmol) in THF (0.40 mL) was
added Grignard reagent (0.456 mmol) under nitrogen at ꢁ78 ꢂC
and gradually warmed to 0 ꢂC. The mixture was quenched by the
addition of saturated aq NH4Cl (3.0 mL) and extracted with
EtOAc (3ꢃ10 mL). The combined organic extracts were washed
with brine (10 mL), dried over anhydrous Na2SO4, and concen-
trated in vacuo. The crude product was roughly purified by col-
umn chromatography (silica gel, hexane/EtOAc) to give the
crude, which was used without further purification. To a solution
of the above product and Et3SiH (0.342 mmol) in CH2Cl2
(0.60 mL) was added a solution of BF3$OEt2 (0.342 mmol) at
ꢁ78 ꢂC and gradually warmed to 0 ꢂC. Then, it was quenched by
the addition of saturated aq NaHCO3 (3.0 mL) and extracted with
CH2Cl2 (3ꢃ10 mL). The combined organic extracts were washed
with brine (10 mL), dried over anhydrous Na2SO4, and concen-
trated in vacuo. The crude product was purified by column
chromatography (silica gel, hexane/EtOAc) to give the lactam 10
as a colorless oil.
1668 (C]O), 1111 (C–O) cmꢁ1; 1H NMR (CDCl3)
d 7.66–7.63 (m, 4H,
ArH), 7.45–7.16 (m, 11H, ArH), 6.57–6.55 (m, 1H, NH), 4.49 (d,
J¼11.4 Hz, 1H, CH2), 4.40 (d, J¼11.4 Hz, 1H, CH2), 3.96 (d, J¼6.9 Hz,
1H, CH), 3.89–3.77 (m, 4H, CH, CH2, OH), 2.81 (m, 1H, CH2), 2.77 (d,
J¼5.1 Hz, 3H, CH3), 2.16–2.06 (m, 1H, CH2), 1.04 (s, 9H, C(CH3)3); 13
C
NMR (CDCl3)
d 173.0 (C), 136.8 (C), 135.6 (CH), 135.5 (C), 133.3 (C),
133.2 (C), 129.7 (CH), 128.6 (CH), 128.2 (CH), 127.9 (CH), 127.7 (CH),
79.3 (CH), 73.5 (CH2), 62.5 (CH2), 61.7 (CH2), 47.1 (CH3), 26.8 (CH3),
25.7 (CH), 19.2 (C). Anal. Calcd for C29H37NO4Si: C, 70.84; H, 7.58; N,
2.85. Found: C, 70.61; H, 7.36; N, 3.23.
To a stirred solution of oxalyl chloride (0.35 mL, 4.0 mmol) in
CH2Cl2 (7.0 mL) was added DMSO (0.38 mL, 5.4 mmol) under ni-
trogen at ꢁ78 ꢂC and stirred for 15 min. Then, a solution of the
above amide (660 mg, 1.34 mmol) in CH2Cl2 (8.0 mL) was added to
this mixture and further stirred for 15 min. (i-Pr)2EtN (1.48 mL,
10.7 mmol) was added and warmed to 0 ꢂC. After stirring for
15 min, the mixture was quenched by the addition of saturated aq

2420
T. Sengoku et al. / Tetrahedron 65 (2009) 2415–2423
4.2.7.1. (3S
*
,4S
*
,5R
*
)-4-(Benzyloxy)-3-((tert-butyldiphenylsilyloxy)-
4.2.7.5. (3S
methyl)-1,5-dimethylpyrrolidin-2-one (10f). IR (NaCl) 2858 (C–H),
1690 (C]O), 1113 (C–O) cmꢁ1 1H NMR (CDCl3):
7.68–7.62 (m,
*
,4S
*
,5R
*
)-4-(Benzyloxy)-3-((tert-butyldiphenylsilyloxy)-
methyl)-1-(4-methoxybenzyl)-5-methylpyrrolidin-2-one (10b). IR
(NaCl) 3011 (C–H), 1686 (C]O), 1248 (C–O), 1113 (C–O) cmꢁ1
1H NMR (CDCl3)
7.71–7.63 (m, 4H, ArH), 7.45–7.16 (m, 15H,
;
;
d
d
4H, ArH), 7.44–7.24 (m, 11H, ArH), 4.57 (d, J¼11.5 Hz, 1H, CH2),
4.48 (d, J¼11.5 Hz, 1H, CH2), 4.02 (dd, J¼10.3, 5.3 Hz,
1H, CH2), 3.93 (dd, J¼3.7, 3.5 Hz, 1H, CH), 3.91 (dd, J¼10.3, 3.5 Hz,
1H, CH2), 3.53 (dq, J¼6.6, 3.5 Hz, 1H, CH), 2.81 (s, 3H, CH3), 2.68
(ddd, J¼5.5, 3.7, 3.5 Hz, 1H, CH), 1.13 (d, J¼6.6 Hz, 3H, CH3), 1.04
ArH), 6.83–6.80 (m, 2H, ArH), 4.88 (d, J¼14.8 Hz, 1H, CH2), 4.51
(d, J¼11.7 Hz, 1H, CH2), 4.44 (d, J¼11.7 Hz, 1H, CH2), 4.14 (dd,
J¼10.1, 4.6 Hz, 1H, CH2), 4.04 (d, J¼14.8 Hz, 1H, CH2), 3.98 (dd,
J¼5.6, 3.3 Hz, 1H, CH), 3.92 (dd, J¼10.1, 3.3 Hz, 1H, CH2), 3.47
(dt, J¼6.6, 3.3 Hz, 1H, CH), 2.72 (dd, J¼4.6, 3.3 Hz, 1H, CH), 1.18
(d, J¼6.6 Hz, 3H, CH3), 1.05 (s, 9H, C(CH3)3); 13C NMR (CDCl3)
(s, 9H, C(CH3)3); 13C NMR (CDCl3)
d 172.2 (C), 158.9 (C), 137.9 (C),
135.7 (CH), 135.6 (CH), 133.3 (C), 133.0 (C), 129.8 (CH), 129.2 (CH),
128.5 (C), 128.4 (CH), 127.7 (CH, C), 127.5 (CH), 114.0 (CH), 78.8
(CH), 71.1 (CH2), 62.4 (CH2), 62.2 (CH), 55.2 (CH3), 52.5 (CH), 43.6
(CH2), 26.9 (CH3), 19.3 (C), 17.9 (CH2), 14.0 (CH3). Anal. Calcd for
C30H37NO3Si: C, 73.88; H, 7.65; N, 2.87. Found: C, 74.09; H, 7.36;
N, 2.94.
d
172.0 (C), 158.9 (C), 137.8 (C), 135.7 (CH), 135.6 (CH), 133.3 (C),
132.9 (C), 129.7 (CH), 128.6 (CH), 127.7 (CH), 127.4 (CH), 114.0
(CH), 81.2 (CH), 71.7 (CH2), 61.8 (CH), 58.0 (CH), 55.2 (CH3), 43.4
(CH2), 26.9 (CH3), 19.3 (C), 18.7 (CH3). /INS> Anal. Calcd for
C37H43NO4Si: C, 74.84; H, 7.30; N, 2.36. Found: C, 74.95; H, 7.12;
N, 2.36.
4.2.7.6. (3S
methyl)-1-methyl-5-propylpyrrolidin-2-one (10g). IR (NaCl) 2858
(C–H), 1693 (C]O), 1113 (C–O) cmꢁ1; 1H NMR (CDCl3):
7.68–7.62
*
,4S
*
,5R
*
)-4-(Benzyloxy)-3-((tert-butyldiphenylsilyloxy)-
4.2.7.2. (3S
methyl)-1-(4-methoxybenzyl)-5-propylpyrrolidin-2-one (10c). IR
(NaCl) 2992 (C–H), 1682 (C]O), 1248 (C–O), 1113 (C–O) cmꢁ1 1H
NMR (CDCl3) 7.70–7.64 (m, 4H, ArH), 7.43–7.39 (m, 5H, ArH),
*
,4S
*
,5R
*
)-4-(Benzyloxy)-3-((tert-butyldiphenylsilyloxy)-
d
;
(m, 4H, ArH), 7.45–7.24 (m, 11H, ArH), 4.58 (d, J¼11.7 Hz, 1H, CH2),
4.43 (d, J¼11.7 Hz, 1H, CH2), 3.99 (dd, J¼3.3, 3.1 Hz, 1H, CH), 3.95 (d,
J¼4.6 Hz, 1H, CH2), 3.94 (d, J¼5.5 Hz, 1H, CH2), 3.42 (dt, J¼8.8,
3.1 Hz, 1H, CH), 2.81 (s, 3H, CH3), 2.72 (ddd, J¼5.5, 4.6, 3.3 Hz, 1H,
CH), 1.74–1.60 (m, 1H, 2CH2), 1.41–1.23 (m, 3H, 2CH2), 1.05 (s, 9H,
d
7.38–7.15 (m, 6H, ArH), 6.83–6.80 (m, 2H, ArH), 4.92 (d,
J¼15.0 Hz, 1H, CH2), 4.51 (d, J¼11.6 Hz, 1H, CH2), 4.38 (d,
J¼11.6 Hz, 1H, CH2), 4.09–4.03 (m, 2H, CH, OH), 3.96 (d, J¼15.0 Hz,
1H, CH2), 3.95 (dd, J¼10.4, 3.7 Hz, 1H, CH2), 3.77 (s, 3H, CH3), 3.37
(dt, J¼9.0, 3.3 Hz, 1H, CH), 2.78–2.74 (m, 1H, CH), 1.67–1.58 (m,
1H, 2CH2), 1.40–1.15 (m, 3H, 2CH2), 1.06 (s, 9H, C(CH3)3), 0.84 (t,
C(CH3)3), 0.92 (t, J¼6.8 Hz, 3H, CH3); 13C NMR (CDCl3)
d 171.9 (C),
137.8 (C), 135.7 (CH), 135.6 (CH), 133.2 (C), 133.0 (C), 129.7 (CH),
128.4 (CH), 127.7 (2CH), 127.5 (CH), 79.0 (CH), 71.1 (CH2), 65.4
(CH), 62.6 (CH2), 52.3 (CH3), 33.9 (CH2), 26.9 (CH3), 19.3 (C), 18.1
(CH2), 14.1 (CH2). Anal. Calcd for C32H41NO3Si: C, 74.52; H, 8.01; N,
2.72. Found: C, 74.36; H, 7.76; N, 2.67.
J¼7.2 Hz, 3H, CH3); 13C NMR (CDCl3)
d 171.8 (C), 137.8 (C), 135.7
(CH), 135.6 (CH), 133.3 (C), 132.9 (C), 129.7 (CH), 128.4 (CH), 127.7
(2CH), 127.5 (CH), 81.2 (CH), 72.4 (CH2), 62.2 (CH2), 60.8 (CH2),
52.1 (CH3), 26.8 (CH3), 19.3 (CH), 18.6 (C). Anal. Calcd for
C39H47NO4Si: C, 75.32; H, 7.62; N, 2.25. Found: C, 75.47; H, 7.55;
N, 2.29.
4.2.7.7. (3S
methyl)-1-methyl-5-nonylpyrrolidin-2-one (10h). IR (NaCl) 2856
(C–H), 1690 (C]O), 1113 (C–O) cmꢁ1; 1H NMR (CDCl3):
7.67–7.62
*
,4S
*
,5R
*
)-4-(Benzyloxy)-3-((tert-butyldiphenylsilyloxy)-
d
4.2.7.3. (3S
methyl)-1-(4-methoxybenzyl)-5-nonylpyrrolidin-2-one
(NaCl) 2993 (C–H), 1688 (C]O), 1248 (C–O), 1113 (C–O) cmꢁ1
NMR (CDCl3) 7.71–7.64 (m, 4H, ArH), 7.45–7.41 (m, 13H, ArH),
*
,4S
*
,5R
*
)-4-(Benzyloxy)-3-((tert-butyldiphenylsilyloxy)-
(10d). IR
1H
(m, 4H, ArH), 7.45–7.25 (m, 11H, ArH), 4.58 (d, J¼11.7 Hz, 1H, CH2),
4.43 (d, J¼11.7 Hz, 1H, CH2), 3.95 (d, J¼5.3 Hz, 1H, CH2), 3.94 (d,
J¼4.2 Hz, 1H, CH2), 3.41 (dt, J¼8.8, 3.1 Hz, 1H, CH), 2.81 (s, 3H, CH3),
2.73–2.69 (m, 1H, CH), 1.71–1.68 (m, 1H, CH2), 1.39–1.26 (m, 15H,
CH2), 1.04 (s, 9H, C(CH3)3), 0.89 (t, J¼6.7 Hz, 3H, CH3); 13C NMR
;
d
6.84–6.79 (m, 2H, ArH), 4.91 (d, J¼14.9 Hz, 1H, CH2), 4.52 (d,
J¼11.6 Hz, 1H, CH2), 4.38 (d, J¼11.6 Hz, 1H, CH2), 4.11–4.05 (m, 2H,
2CH), 3.97 (d, J¼14.9 Hz, 1H, CH2), 3.95 (dd, J¼10.3, 3.5 Hz, 1H, CH2),
3.77 (s, 3H, CH3), 3.36 (dt, J¼9.2, 3.5 Hz, 1H, CH), 2.77–2.73 (m, 1H,
CH), 1.71–1.64 (m, 1H, CH2), 1.31–1.19 (m, 15H, CH2), 1.06 (s, 9H,
(CDCl3) d 172.0 (C), 137.8 (C), 135.7 (CH), 135.6 (CH), 133.2 (C), 133.0
(C), 129.8 (CH), 128.4 (CH), 127.7 (2CH), 127.6 (CH), 78.8 (CH), 71.1
(CH2), 65.5 (CH), 62.6 (CH2), 52.3 (CH3), 31.9 (CH2), 31.7 (CH2),
29.6 (CH2), 29.5 (CH2), 29.3 (CH2), 27.7 (CH2), 26.9 (CH3), 24.8 (CH2),
22.7 (CH2), 19.3 (C), 14.1 (CH3). Anal. Calcd for C38H53NO3Si: C,
76.08; H, 8.90; N, 2.33. Found: C, 75.98; H, 8.79; N, 2.44.
C(CH3)3), 0.89 (t, J¼6.8 Hz, 3H, CH3); 13C NMR (CDCl3)
d 172.0 (C),
158.9 (C), 137.8 (C), 135.7 (CH), 135.6 (CH), 133.2 (C), 132.9 (C), 129.8
(CH), 129.2 (CH), 128.5 (CH), 128.3 (CH), 127.7 (2CH), 127.5 (C),
114.0 (CH), 78.5 (CH), 71.2 (CH2), 62.4 (CH2), 62.3 (CH), 55.2 (CH3),
52.4 (CH), 43.6 (CH2), 31.8 (CH2), 31.3 (CH2), 29.5 (3CH2), 29.3 (CH2),
26.9 (CH3), 24.5 (CH2), 22.6 (CH2), 19.3 (C), 14.1 (CH3). Anal. Calcd for
C45H59NO4Si: C, 76.55; H, 8.42; N, 1.98. Found: C, 76.49; H, 8.45; N,
2.04.
4.2.8. (3S
*
,4S
*
,5R )-5-Allyl-3-(benzyloxy)-4-((tert-butyldiphenyl-
*
silyloxy)methyl)-1-(4-methoxybenzyl)pyrrolidin-2-one (11)
To a stirred solution of 8 (927 mg, 1.56 mmol) and allyl-
trimethylsilane (0.99 mL, 6.2 mmol) in CH2Cl2 (15 mL) was
added a solution of BF3$OEt2 (0.77 mL, 6.2 mmol) at ꢁ78 ꢂC
and gradually warmed to ꢁ20 ꢂC. The mixture was quenched
by the addition of saturated aq NaHCO3 (5 mL) and extracted
with EtOAc (3ꢃ10 mL). The combined organic extracts were
washed with brine (5 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by
column chromatography (silica gel, hexane/EtOAc¼4:1) to give
11 (959 mg, 99%) as a colorless oil. IR (NaCl) 1693 (C]O), 1514
4.2.7.4. (3S
silyloxy)methyl)-1-methylpyrrolidin-2-one (10e). IR (NaCl) 2858
(C–H), 1690 (C]O), 1113 (C–O) cmꢁ1 1H NMR (300 MHz, CDCl3):
7.68–7.62 (m, 4H, ArH), 7.44–7.24 (m, 11H, ArH), 5.75–5.61 (m, 1H,
*
,4S
*
,5R
*
)-5-Allyl-4-(benzyloxy)-3-((tert-butyldiphenyl-
;
d
CH), 5.11–5.06 (m, 2H, CH2), 4.57 (d, J¼11.6 Hz, 1H, CH2), 4.45 (d,
J¼11.6 Hz, 1H, CH2), 4.09 (t, J¼3.6 Hz, 1H, CH), 3.96–3.93 (m, 2H,
CH2), 3.54 (dt, J¼8.2, 3.6 Hz, 1H, CH), 2.84 (s, 3H, CH3), 2.74–2.69 (m,
1H, CH), 2.53–2.45 (m, 1H, CH2), 2.29–2.19 (m, 1H, CH2), 1.05 (s, 9H,
(C]C), 1113 (C–O) cmꢁ1 1H NMR (CDCl3)
; d 7.50–7.47 (m, 4H,
ArH), 7.44–7.23 (m, 11H, ArH), 7.13–7.10 (m, 2H, ArH), 6.79–6.76
(m, 2H, ArH), 5.44 (m, 1H, CH), 5.13–4.99 (m, 4H, CH2), 4.77 (d,
J¼11.7 Hz, 1H, CH2), 4.23 (d, J¼5.5 Hz, 1H, CH), 3.86 (d,
J¼14.8 Hz, 1H, CH2), 3.75 (s, 3H, CH3), 3.64 (dd, J¼10.6, 4.7 Hz,
1H, CH2), 3.51 (dd, J¼10.7, 4.2 Hz, 1H, CH2), 3.29 (m, 1H, CH),
2.26–2.23 (m, 2H, CH2, CH), 2.15 (m, 1H, CH2), 0.95 (s, 9H,
C(CH3)3); 13C NMR (CDCl3)
d 172.1 (C), 137.8 (C), 135.7 (CH), 133.2
(CH), 129.7 (CH), 128.4 (CH), 127.69 (CH), 127.68 (CH), 127.67 (CH),
118.7 (CH2), 78.3 (CH), 71.3 (CH2), 64.7 (CH), 62.3 (CH2), 52.2 (CH3),
35.9 (CH2), 27.8 (CH3), 26.8 (CH3), 19.2 (C). Anal. Calcd for
C32H39NO3Si: C, 74.81; H, 7.65; N, 2.73. Found: C, 74.50; H, 7.45; N,
2.70.
C(CH3)3); 13C NMR (CDCl3)
d 172.7 (C), 159.0 (C), 138.1 (C),

T. Sengoku et al. / Tetrahedron 65 (2009) 2415–2423
2421
135.5 (CH), 133.0 (C), 132.8 (C), 132.5 (CH), 129.80 (CH), 129.3
(CH), 128.3 (CH), 128.02 (CH), 127.67 (CH), 127.6 (CH), 118.9
(CH2), 114.1 (CH), 76.8 (CH), 72.5 (CH2), 61.3 (CH2), 55.2 (CH3),
54.3 (CH), 45.5 (CH), 43.4 (CH2), 35.9 (CH2), 26.8 (CH3), 19.1
(C); HRMS (ESIþ) m/z calcd for C39H45NO4SiþNa: 642.3016,
found 642.3057.
J¼7.9, 1.7 Hz, 4H, ArH), 7.47–7.22 (m, 11H, ArH), 5.09 (d, J¼11.7 Hz,
1H, CH2), 4.64 (d, J¼11.7 Hz, 1H, CH2), 4.32 (d, J¼10.1 Hz, 1H, CH2),
3.81 (dd, J¼10.7, 3.1 Hz, 1H, CH2), 3.73 (dd, J¼10.7, 6.1 Hz, 1H, CH2),
3.67–3.54 (m, 2H, CH2), 3.07 (m,1H, CH), 2.20 (m,1H, CH), 2.07–1.93
(m, 3H, CH2, CH2), 1.41 (m, 1H, CH2), 1.04 (s, 9H, C(CH3)3); 13C NMR
(CDCl3) d 172.7 (C), 138.0 (C), 135.5 (CH), 133.2 (C), 129.8 (CH), 128.3
(CH), 128.0 (CH), 127.8 (CH), 127.6 (CH), 79.5 (CH), 72.5 (CH2), 62.0
(CH2), 59.5 (CH), 52.9 (CH), 41.3 (CH2), 31.6 (CH2), 26.8 (CH3), 26.0
(CH2), 19.2 (C). Anal. Calcd for C31H37NO3Si: C, 74.51; H, 7.46; N,
2.80. Found: C, 74.62; H, 7.39; N, 3.19.
4.2.9. (3S
*
,4S
*
,5R )-3-(Benzyloxy)-4-((tert-butyldiphenyl-
*
silyloxy)methyl)-5-(3-hydroxypropyl)pyrrolidin-2-one (13)
To a solution of 11 (834 mg, 1.34 mmol) in THF (10 mL) was
added 9-BBN (0.5 M solution in THF, 3.0 mL, 1.5 mmol) under
nitrogen and stirred for 1 h. After the mixture was quenched by
the addition of 3 N aq NaOH (10 mL) and hydrogen peroxide
solution (34.5 wt % in H2O, 10 mL) was added dropwise at 0 ꢂC
and stirred for further 3 h at room temperature. The mixture was
quenched by the addition of saturated aq Na2S2O3 (20 mL) and
extracted with EtOAc (3ꢃ30 mL). The combined organic extracts
were washed with water (10 mL) and brine (10 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, hexane/
acetone¼2:1 to 3:2) to give the primary alcohol 13 (719 mg, 84%)
as a colorless oil. IR (NaCl) 3210 (O–H), 1682 (C]O), 1514 (C]C),
4.2.11. (1S
*
,2S
*
,7aR )-1-((tert-Butyldiphenylsilyloxy)methyl)-2-
*
hydroxytetrahydro-1H-pyrrolizin-3(2H)-one (15a)
A mixture of 14 (78.9 mg, 0.158 mmol) and Pearlman’s catalyst
(31.2 mg) in EtOH (9.0 mL) was stirred under hydrogen atmosphere
for 23 h. The mixture was filtered through a pad of Celite with EtOH
and concentrated. The residue was purified by column chromatog-
raphy (silica gel, hexane/EtOAc¼1:1 then CHCl3/MeOH¼15:1) to give
15a (61.8 mg, 95%) as a white powder. Mp 119–120 ꢂC; IR (NaCl) 3281
(O–H), 1684 (C]O), 1113 (C–O), 1057 (C–O) cmꢁ1 1H NMR (CDCl3)
;
d
7.66–7.63 (m, 4H, ArH), 7.46–7.26 (m, 6H, ArH), 4.44 (d, J¼9.9 Hz,1H,
CH), 3.95 (dd, J¼10.4, 3.7 Hz, 1H, CH2), 3.84 (dd, J¼10.4, 6.8 Hz, 1H,
CH2), 3.66–3.54 (m, 2H, CH), 3.29 (br s,1H, OH), 3.07 (m,1H, CH), 2.18–
1112 (C–O) cmꢁ1 1H NMR (CDCl3)
; d 7.51–7.47 (m, 4H, ArH), 7.51–
7.25 (m, 11H, ArH), 7.11 (d, J¼8.5 Hz, 2H, ArH), 6.76 (d, J¼8.5 Hz,
2H, ArH), 5.09 (d, J¼11.7 Hz, 1H, CH2), 5.00 (d, J¼14.6 Hz, 1H,
CH2), 4.75 (d, J¼11.7 Hz, 1H, CH2), 4.16 (d, J¼5.5 Hz, 1H, CH), 3.84
(d, J¼14.6 Hz, 1H, CH2), 3.74 (s, 3H, CH3), 3.59 (dd, J¼10.2, 5.1 Hz,
1H, CH2), 3.51–3.47 (m, 3H, CH2), 3.25 (m, 1H, CH), 2.11 (m, 1H,
CH), 1.62–1.55 (m, 2H, CH2), 1.38–1.20 (m, 2H, CH2), 0.95 (s, 9H,
1.93 (m, 4H, CH2, CH2, CH),1.47 (m,1H, CH2),1.07 (s, 9H, C(CH3)3); 13
C
NMR (CDCl3) d 173.8 (C), 135.5 (CH), 133.2 (C), 129.8 (CH), 127.8 (CH),
73.9 (CH), 62.6 (CH2), 60.3 (CH), 55.0 (CH), 41.5 (CH2), 31.5 (CH2), 26.9
(CH3), 26.2 (CH2), 19.2 (C). Anal. Calcd for C24H31NO3Si: C, 70.38; H,
7.63; N, 3.42. Found: C, 70.58; H, 7.53; N, 3.42.
C(CH3)3); 13C NMR (CDCl3)
d
172.5 (C), 158.9 (C), 138.0 (C), 135.5
4.2.12. (1S
*
,2S
*
,7aR )-2-Hydroxy-1-(hydroxymethyl)tetrahydro-
*
(CH), 133.0 (C), 132.8 (C), 129.8 (CH), 129.3 (CH), 128.3 (CH), 128.1
(CH), 127.9 (CH), 127.7 (CH), 114.0 (CH), 77.2 (CH), 72.5 (2CH2),
62.4 (CH2), 61.9 (CH2), 55.19 (CH), 55.16 (CH3), 45.6 (CH), 43.4
(CH2), 27.4 (CH2), 26.7 (CH3), 19.1 (C). Anal. Calcd for
C39H47NO5Si: C, 73.43; H, 7.43; N, 2.20. Found: C, 73.59; H, 7.57;
N, 2.59.
1H-pyrrolizin-3(2H)-one (16a)
To a solution of 15a (40.4 mg, 0.0986 mmol) in THF (1.2 mL) was
added borane–tetrahydrofuran complex (0.99 M solution in THF,
0.97 mL, 0.96 mmol) and stirred for 18 h. The mixture was
quenched by the addition of MeOH (5 mL) and concentrated. To the
residue was added MeOH (10 mL) and stirred under reflux for 4 h.
The solution was concentrated to give the crude amine, which was
purified by column chromatography (silica gel, hexane/acetone¼
3:1) to give 16a (26.2 mg, 67%) as a colorless oil. IR (NaCl) 3500 (O–
4.2.10. (1S
*
,2S
*
,7aR )-2-(Benzyloxy)-1-((tert-butyldiphenylsilyloxy)-
*
methyl)tetrahydro-1H-pyrrolizin-3(2H)-one (14)
To a solution of 13 (71.1 mg, 0.111 mmol) in pyridine (1.3 mL)
was added p-toluenesulfonyl chloride (117 mg, 0.613 mmol) at 0 ꢂC
and stirred for 6 h. The mixture was quenched by the addition of 3%
HCl (5 mL) and extracted with EtOAc (2ꢃ5 mL). The combined or-
ganic extracts were washed with brine (5 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude product was
roughly purified by column chromatography (silica gel, hexane/
EtOAc¼3:1 to 1:1) to give the crude tosylate (98.6 mg), which was
used without further purification. A solution of this tosylate and
CAN (243 mg, 4.44 mmol) in MeCN/H2O¼2:1 (6.0 mL) was stirred
for 2 h. The mixture was quenched by the addition of water and
extracted with EtOAc (3ꢃ5 mL). The combined organic extracts
were washed with brine (5 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was roughly purified by
column chromatography (silica gel, hexane/EtOAc¼2:1 to 1:2) to
give the crude deprotected amide (57.9 mg), which was used
without further purification. To a solution of this amide in THF
(3.0 mL) was added NaH (55 wt %, 48.4 mg, 1.11 mmol) under ni-
trogen at 0 ꢂC and stirred for 30 min under the same temperature.
After the solution was warmed to room temperature and stirred for
20 min, it was quenched by the addition of water (5 mL) and
extracted with EtOAc (3ꢃ5 mL). The combined organic extracts
were washed with water (5 mL) and brine (5 mL), dried over an-
hydrous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography (silica gel, hexane/EtOAc¼3:1
to 1:1) to give 14 (40.6 mg, 73%) as a colorless oil. IR (NaCl) 1701
H), 1113 (C–O) cmꢁ1 1H NMR (CDCl3)
; d 7.68–7.64 (m, 4H, ArH),
7.49–7.38 (m, 6H, ArH), 4.47 (dt, J¼8.3, 6.6 Hz, 1H, CH), 3.77 (d,
J¼6.2 Hz, 2H, CH2), 3.56 (dd, J¼10.5, 6.3 Hz, 1H, CH2), 3.48 (m, 1H,
CH2), 3.16–3.07 (m, 2H, CH, CH2), 2.76 (dd, J¼10.1, 9.2 Hz, 1H, CH2),
2.19–1.82 (m, 5H, CH2, CH2, CH, OH), 1.65 (m, 1H, CH2), 1.07 (s, 9H,
C(CH3)3); 13C NMR (CDCl3)
d 135.6 (CH), 132.9 (C), 130.0 (CH), 127.9
(CH), 74.1 (CH), 72.5 (CH), 67.7 (CH2), 64.6 (CH2), 63.9 (CH2), 55.4
(CH), 31.1 (CH2), 26.9 (CH3), 24.2 (CH2), 19.1 (C). Anal. Calcd for
C24H33NO2Si: C, 72.86; H, 8.41; N, 3.54. Found: C, 72.68; H, 8.22; N,
3.63.
4.2.13. (1S
*
,2S
*
,7aR )-1-(Hydroxymethyl)hexahydro-1H-pyrrolizin-
*
2-ol (2-epi-macronecine) (1c)
A solution of 16a (15.3 mg, 0.0387 mmol) in 3% HCl/MeOH
(2.0 mL) was stirred for 1.5 h. After concentration, the residue was
dissolved in 3% HCl (5.0 mL) and washed with EtOAc (5 mL). The
water extract was concentrated and the residue was passed
through Dowex 50WX-8 (Hþ form), which was first eluted with
water (20 mL), and then 0.3 M NH4OH (20 mL) followed by 0.7 M
NH4OH (20 mL). Alkaline fractions were concentrated in vacuo to
give 1c (6.2 mg, quant.) as a white powder. Mp 94–96 ꢂC; IR (NaCl)
3300 (O–H), 2910 (O–H), 1112 (C–O) cmꢁ1 1H NMR (CDCl3)
; d 4.33
(m, 1H, CH), 3.80 (dd, J¼11.1, 3.9 Hz, 1H, CH2), 3.64 (dd, J¼11.1,
5.1 Hz, 1H, CH2), 3.42–3.30 (m, 2H, CH, CH2), 2.94 (m, 1H, CH2), 2.68
(m, 1H, CH2), 2.47 (t, J¼9.3 Hz, 1H, CH2), 2.01–1.86 (m, 2H, CH, CH2),
1.82–1.56 (m, 3H, CH2); 13C NMR (CD3OD)
d 74.7 (CH), 67.7 (CH),
(C]O), 1113 (C–O), 1074 (C–O) cmꢁ1
;
1H NMR (CDCl3)
d
7.61 (dd,
63.0 (CH2), 61.9 (CH2), 56.4 (CH2), 56.2 (CH), 33.3 (CH2), 26.3 (CH2).

2422
T. Sengoku et al. / Tetrahedron 65 (2009) 2415–2423
Anal. Calcd for C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C, 61.36;
H, 9.93; N, 9.06.
4.2.16. (1S
*
,2R
*
,7aR )-1-(Hydroxymethyl)hexahydro-1H-
*
pyrrolizin-2-ol (macronecine) (1b)
Mp 109–110 ꢂC; IR (NaCl) 3363 (O–H), 2933 (O–H), 1038 (O–
4.2.14. (1S
*
,2R
*
,7aR
*
)-1-((tert-Butyldiphenylsilyloxy)methyl)-2-
H) cmꢁ1
;
1H NMR (CDCl3)
d
4.50 (t, J¼3.9 Hz, 1H, CH), 3.91 (dd,
hydroxytetrahydro-1H-pyrrolizin-3(2H)-one (15b)
J¼11.4, 4.8 Hz, 1H, CH2), 3.84 (dd, J¼11.4, 6.9 Hz, 1H, CH2), 3.59 (m,
1H, CH), 3.22 (d, J¼11.4 Hz, 1H, CH2), 3.00 (dt, J¼10.8, 6.6 Hz, 1H,
CH2), 2.71 (dd, J¼11.4, 3.9 Hz, 1H, CH2), 2.60 (dt, J¼10.8, 6.3 Hz,
1H, CH2), 1.97 (m, 1H, CH), 1.90–1.77 (m, 3H, CH2, CH2), 1.54 (m, 1H,
To a solution of 15a (6.7 mg, 0.0164 mmol) and pyridine
(0.050 mL, 0.65 mmol) in CH2Cl2 (1.0 mL) was added tri-
fluoromethanesulfonic anhydride (0.050 mL, 0.26 mmol) at 0 ꢂC
and stirred for 1 h at room temperature. It was quenched by the
addition of water (5 mL) and extracted with EtOAc (3ꢃ10 mL). The
combined organic extracts were washed with brine (5 mL), dried
over anhydrous Na2SO4, and concentrated to give the crude triflate,
which was used without further purification. To a solution of the
above product and 18-crown-6 (4.0 mg, 0.015 mmol) in toluene
(0.5 mL) was added CsOAc (4.0 mg, 0.21 mmol) and stirred for 1 h.
The reaction was quenched by the addition of water (5 mL) and
extracted with EtOAc (10 mL). The combined organic extracts were
washed with water (5 mL) and brine (5 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude product was purified
by column chromatography (silica gel, hexane/acetone¼3:1 to 2:1)
to give the acetate (5.7 mg, 70%). IR (NaCl) 1736 (C]O),1703 (C]O),
CH2); 13C NMR (CDCl3)
d 75.6 (CH), 64.5 (CH), 62.8 (CH2), 60.8 (CH2),
54.7 (CH2), 52.2 (CH), 31.0 (CH2), 25.5 (CH2). Anal. Calcd for
C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C, 61.09; H, 9.70; N, 9.05.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific
Research from Japan Society for the Promotion of Science. We ac-
knowledge Nanotechnology Network Project (Kyushu-area Nano-
technology Network) of the Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
1232 (C–O), 1113 (C–O) cmꢁ1 1H NMR (CDCl3)
; d 7.65–7.60 (m, 4H,
References and notes
ArH), 7.48–7.36 (m, 6H, ArH), 5.50 (d, J¼9.6 Hz, 1H, CH), 3.82 (dd,
J¼10.5, 6.3 Hz, 1H, CH2), 3.78 (m, 1H, CH), 3.63 (dd, J¼10.5, 8.4 Hz,
1H, CH2), 3.53 (dt, J¼12.3, 7.5 Hz, 1H, CH2), 3.14 (m, 1H, CH2), 2.35
(dq, J¼13.2. 7.5 Hz, 1H, CH2), 2.19–2.02 (m, 3H, CH2, CH2, CH), 1.37
1. For reviews of pyrrolizidine alkaloids, see: (a) Warren, F. L. In The Alkaloids:
Chemistry and Physiology; Manske, R. H. F., Ed.; Academic: New York, NY, 1970;
Vol. 12, Chapter 4; (b) Robins, D. J. Adv. Heterocycl. Chem. 1979, 24, 247; (c)
´
Wrobel, J. T. In The Alkaloids: Chemistry and Physiology; Brossi, A., Ed.; Academic:
(m, 1H, CH2), 1.05 (s, 9H, C(CH3)3); 13C NMR (CDCl3)
d 169.5 (C),
Orlando, FL, 1985; Vol. 26, Chapter 7; (d) Despinoy, X. L. M.; McNab, H. Tetra-
hedron 2000, 56, 6359; (e) Asano, N. In Modern Alkaloids: Structure, Isolation,
Synthesis and Biology; Fattorusso, E., Taglialatela-Scafati, O., Eds.; Wiley-VCH:
Weinheim, 2008; Chapter 5.
2. (a) Hartwell, J. Cancer Treat. Rep. 1976, 60, 1031; (b) Atal, C. K. Lloydia 1978, 41,
312; (c) Smith, L. W.; Culvenor, C. C. J. J. Nat. Prod. 1981, 44, 129; (d) Letendre, L.;
Smithson, W. A.; Gilchrist, G. S.; Bergert, E. O., Jr.; Hoagland, C. H.; Ames, M. M.;
Powis, G.; Kovach, J. S. Cancer 1981, 47, 437.
169.2 (C),135.5 (CH),133.0 (C),129.9 (CH),127.8 (CH), 76.2 (CH), 64.2
(CH), 61.0 (CH2), 47.8 (CH), 41.1 (CH2), 31.5 (CH2), 27.1 (CH2), 26.8
(CH3), 20.5 (CH3), 19.1 (C). Anal. Calcd for C26H33NO4Si: C, 69.14; H,
7.36; N, 3.10. Found: C, 69.12; H, 7.14; N, 3.27.
A mixture of the acetate (41.3 mg, 0.0826 mmol) and K2CO3
(40.0 mg) in MeOH (3.0 mL) was stirred for 45 min. The mixture
was roughly purified by silica gel column chromatography (hexane/
acetone¼2:1) and concentrated. The residue was purified by col-
umn chromatography (silica gel, hexane/acetone¼3:1 to 2:1) to
give 15b (31.4 mg, 93%) as colorless needles. Mp 162–164 ꢂC; IR
3. (a) Mattocks, A. R. Chemistry and Toxicology of Pyrrolizidine Alkaloids; Academic:
London, 1986; (b) McLean, E. K. Pharmacol. Rev. 1970, 22, 429.
4. For reviews, see: (a) Robins, D. J. Nat. Prod. Rep. 1992, 9, 313; (b) Robins, D. J. Nat.
Prod. Rep. 1995, 12, 413; (c) Liddell, J. R. Nat. Prod. Rep. 1996, 13, 187; (d) Ca-
siraghi, G.; Zanardi, F.; Rassu, G.; Pinna, L. Org. Prep. Proceed. Int. 1996, 28, 643;
(e) Liddell, J. R. Nat. Prod. Rep. 1998, 15, 363; (f) Liddell, J. R. Nat. Prod. Rep. 1999,
16, 499; (g) Liddell, J. R. Nat. Prod. Rep. 2000, 17, 455; (h) Liddell, J. R. Nat. Prod.
Rep. 2001, 18, 441; (i) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773; (j) Hudlicky´, T.;
Reed, J. W. The Way of Synthesis; Wiley-VCH: Weinheim, 2007; Chapter 4. and
references cited therein.
5. The first pyrrolizidine alkaloid found with a carbon substituent at C-3; (a)
Isolation: Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.; Derome, A. E.;
Hamor, T. A.; Scofield, A. M.; Watkin, D. J. Tetrahedron Lett. 1988, 29, 2487; (b)
Synthesis: Fleet, G. W. J.; Haraldsson, M.; Nash, R. J.; Fellows, L. E. Tetrahedron
Lett. 1988, 29, 5441.
(NaCl) 3330 (O–H), 1680 (C]O), 1111 (C–O), 1072 (C–O) cmꢁ1
;
1H
NMR (CDCl3)
d
7.66 (dd, J¼7.7, 1.7 Hz, 4H, ArH), 7.46–7.35 (m, 6H,
ArH), 4.35 (br d, J¼5.9 Hz, 1H, CH), 4.20 (br s, 1H, OH), 4.01–3.90 (m,
2H, CH2), 3.83 (m, 1H, CH), 3.45 (dt, J¼11.3, 7.9 Hz, 1H, CH2), 3.10 (m,
1H, CH2), 2.20–1.97 (m, 4H, CH2, CH), 1.32 (m, 1H, CH2), 1.06 (s, 9H,
C(CH3)3); 13C NMR (CDCl3)
d 173.4 (C), 135.6 (CH), 133.3 (C), 129.8
(CH), 127.8 (CH), 76.5 (CH), 64.5 (CH), 61.7 (CH2), 49.1 (CH), 40.6
(CH2), 31.5 (CH2), 27.1 (CH2), 26.9 (CH3), 19.1 (C). Anal. Calcd for
C24H31NO3Si: C, 70.38; H, 7.63; N, 3.42. Found: C, 70.10; H, 7.42; N,
3.52.
The same procedure gave the pyrrolizidine 16b and (ꢀ)-mac-
ronecine (1b) from the corresponding amide 15b (yields are given
in Scheme 2). The spectral data of synthetic 1b thus obtained were
identical in all respects with those of the natural and synthesized
compound.8
6. Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae, T.; Kizu, H.; Kameda, Y.;
Watson, A. A.; Nash, R. J.; Wormald, M. R.; Fleet, G. W. J.; Asano, N. Carbohydr.
Res. 1999, 316, 95.
7. Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson,
A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1. Recently, the
research in the same group for hyacinthacines in the Hyacinthaceae has led to
the isolation from Scilla socialis bulbs of new 11 hyacinthacines, see: Kato, A.;
Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.; Kuriyama, C.; Ikeda, K.; Asano,
N.; Nash, R. J. J. Nat. Prod. 2007, 70, 993 and references cited therein.
8. Isolation and synthesis of macronecine, see: (a) Danilova, A.; Utkin, L.; Mas-
sagetov, P. J. Gen. Chem. USSR 1955, 25, 797; (b) Aasen, A. J.; Culvenor, C. C. J.
J. Org. Chem. 1969, 34, 4143; (c) Ito, H.; Ikeuchi, Y.; Taguchi, T.; Hanzawa, Y.;
Shiro, M. J. Am. Chem. Soc. 1994, 116, 5469; (d) Denmark, S. E.; Hurd, A. R. J. Org.
Chem. 1998, 63, 3045; (e) Ha, D.-C.; Ahn, J.-B.; Kwon, Y.-E. Bull. Korean Chem.
Soc. 1998, 19, 514; (f) Sarkar, T. K.; Hazra, A.; Gangopadhyay, P.; Panda, N.;
Slanina, Z.; Lin, C.-C.; Chen, H.-T. Tetrahedron 2005, 61, 1155.
4.2.15. (1S
*
,2R
*
,7aR )-2-Hydroxy-1-(hydroxymethyl)tetrahydro-
*
1H-pyrrolizin-3(2H)-one (16b)
IR (NaCl) 3474 (O–H), 1112 (C–O), 1078 (C–O) cmꢁ1 1H NMR
;
9. Yoda, H.; Mizutani, M.; Takabe, K. Synlett 1998, 855.
(CDCl3)
d
7.65 (d, J¼7.3 Hz, 4H, ArH), 7.44–7.37 (m, 6H, ArH),
10. (a) Jefford, C. W.; Wang, J. B.; Lu, Z.-H. Tetrahedron Lett. 1993, 47, 7557; (b) Davis,
F. A.; Stringer, O. D. J. Org. Chem. 1982, 47, 1774.
4.35 (m, 1H, CH), 4.02 (dd, J¼10.4, 7.0 Hz, 1H, CH2), 3.74 (dd,
J¼10.4, 6.7 Hz, 1H, CH2), 3.64–3.53 (m, 2H, 2CH2), 3.21 (d,
J¼9.7 Hz, 1H, OH), 3.15–2.91 (m, 3H, CH, 2CH2), 2.20–1.97 (m,
3H, CH, CH2), 1.86–1.68 (m, 2H, CH2), 1.06 (s, 9H, C(CH3)3); 13C
11. Only trace amounts of minor stereoisomer were detected by 1H NMR.
12. Substantial epimerization has been observed upon the reaction employing Et3N
(triethylamine) instead of (i-Pr)2NEt under the same conditions.
13. The addition of Grignard reagents to chiral imide derivatives from tartaric acid,
followed by the reduction with text-cited reagents has been extensively studied
and applied in the syntheses of some indolizidine alkaloids in our laboratory,
see: (a) Yoda, H.; Shirakawa, K.; Takabe, K. Chem. Lett. 1991, 489; (b) Yoda, H.;
Shirakawa, K.; Takabe, K. Tetrahedron Lett. 1991, 32, 3401; (c) Yoda, H.; Ki-
tayama, H.; Yamada, W.; Katagiri, T.; Takabe, K. Tetrahedron: Asymmetry 1993, 4,
1451; (d) Yoda, H.; Kitayama, H.; Katagiri, T.; Takabe, K. Tetrahedron: Asymmetry
NMR (CDCl3)
d 135.6 (CH), 133.2 (C), 129.9 (CH), 127.8 (CH), 75.5
(CH), 73.1 (CH), 70.3 (CH2), 65.6 (CH2), 62.2 (CH2), 53.8 (CH),
30.8 (CH2), 26.8 (CH3), 24.4 (CH2), 19.1 (C). Anal. Calcd for
C24H33NO2Si: C, 72.86; H, 8.41; N, 3.54. Found: C, 72.76; H, 8.52;
N, 3.57.

T. Sengoku et al. / Tetrahedron 65 (2009) 2415–2423
2423
1993, 4, 1455; (e) Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996, 37,
5531; (f) Yoda, H.; Shimojo, T.; Takabe, K. Tetrahedron Lett. 1999, 40, 1335.
14. To determine the stereochemistry of allylated lactam 10a unambiguously, we
prepared the compound A and B under the same reaction conditions, providing
almost non-stereoselective results as described below. The coupling constants
of these compounds were indicated to be 4.7 (trans-form) and 6.6 (cis-
form) Hz, respectively.
16. In Ref. 15, they suggest that the regioselectivity on Grignard addition is con-
trolled by both the complex induced proximity effects (cis-directing effect)
between benzyloxy group and Grignard reagent and steric effects (trans-di-
recting effect). They also explained that the diastereoselectivity on reductive
deoxygenation is influenced by the chelation between the benzyloxy group on
N-acyliminium ion intermediate and the triethylsilane supporting the syn-
addition (see below).
DPSO
OTBS
Bn
SiEt3
O
R'
H
1) MeMgCl (4.0 eq), THF
N
R
O
O
O
2) Et3SiH (3.0 eq), BF •OEt2 (3.0 eq), CH2Cl2
N
3
H
MPM
Hb
Hb
N
OTBS
Ha
OTBS
Me
DPSO
DPSO
17. As shown in Ref. 14, we observed the similar regioselectivity on the reaction of
the imide containing TBS protecting group, which is generally recognized as
+
a
non-chelation substituent. This result indicates that the regioselectivity
O
O
Me
Ha
N
would be controlled by not only the complex induced proximity effects but also
some other unclarified factors.
MPM
(Ha, Hb) = 4.7 Hz
MPM
(Ha, Hb) = 6.6 Hz
A
B
18. Socha, D.; Pasniczek, K.; Jurczak, M.; Solecka, J.; Chmielewski, M. Carbohydr. Res.
2006, 341, 2005.
J
J
19. Vieira, A. S.; Ferreira, F. P.; Fiorante, P. F.; Guadagnin, R. C.; Stefani, H. S. Tetra-
hedron 2008, 64, 3306.
20. Klitzke, C. F.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 5605.
21. Although the exact mechanism of this reaction is still unknown, the protecting
groups of hydroxyl groups may play an important role in this reaction.
22. Torisawa, Y.; Okabe, H.; Ikegami, S. Chem. Lett. 1984, 1555.
74% yield
97:3 regioselectivity, 8% de (cis-selective)
15. Huang, P. Q.; Wang, S. L.; Ye, J. L.; Ruan, Y. P.; Huang, Y. Q.; Zheng, H.; Gao, J. X.
Tetrahedron 1998, 54, 12547.