Towards stereochemical control: Two approaches for the highly anti-diastereoselective construction of the spirolactone moieties of some Stemona alkaloids

Article abstract of DOI:10.1002/cjoc.201200904

Some Stemona alkaloids belonging to the tuberostemospironine group possess a spirolactone moiety with anti-configuration (C-9/C-9a). In this paper, we describe two approaches to this structural unity. By using bromine atom as a traceless directing group, the SmI₂-mediated reductive coupling of ketone 6 and β-bromomethacrylate proceeded with complete anti-diastereoselectivity. In the absence of an α-directing (chelation) group, the one-pot reaction of the ketone derived from alcohol 15 with the organozinc reagent generated from bromomethacrylate afforded spiro-α-methylene-γ-lactone derivative 16 as a single diastereomer. These two highly diastereoselective methods would find application in the synthesis of stemona alkaloids containing anti-configured spiro-lactone/ pyrrolidine moieties. In addition, on the basis of our previous work, the total synthesis of (-)-9-epi-11-demethylsessilifoliamide J (11), and an improved synthesis of (-)-9,11-di-epi-sessilifoliamide J (9) were accomplished. Completely anti-diastereoselective: This can be achieved by using bromine atom as a traceless directing group in the SmI₂-mediated reductive coupling of α,β-unsaturated ester with ketones; or by the one-pot reaction of the organozinc reagent generated from bromomethacrylate with ketone. On the basis of these results, two approaches to the spirolactone moiety with anti-configuration (C-9/C-9a) found in some Stemona alkaloids were disclosed. Copyright

Full text of DOI:10.1002/cjoc.201200904

FULL PAPER
DOI: 10.1002/cjoc.201200904
Towards Stereochemical Control: Two Approaches for the
Highly anti-Diastereoselective Construction of the Spirolactone
Moieties of Some Stemona Alkaloids†
Shichuan Tuo, Xuekui Liu, and Peiqiang Huang*
Department of Chemistry and Fujian Provincial Key Laboratory for Chemical Biology, College of Chemistry and
Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China
Some Stemona alkaloids belonging to the tuberostemospironine group possess a spirolactone moiety with
anti-configuration (C-9/C-9a). In this paper, we describe two approaches to this structural unity. By using bromine
atom as a traceless directing group, the SmI2-mediated reductive coupling of ketone 6 and β-bromomethacrylate
proceeded with complete anti-diastereoselectivity. In the absence of an α-directing (chelation) group, the one-pot
reaction of the ketone derived from alcohol 15 with the organozinc reagent generated from bromomethacrylate af-
forded spiro-α-methylene-γ-lactone derivative 16 as a single diastereomer. These two highly diastereoselective
methods would find application in the synthesis of stemona alkaloids containing anti-configured spiro-lactone/pyr-
rolidine moieties. In addition, on the basis of our previous work, the total synthesis of (−)-9-epi-11-demethyl-
sessilifoliamide J (11), and an improved synthesis of (−)-9,11-di-epi-sessilifoliamide J (9) were accomplished.
Keywords Stemona alkaloids, spirolactone, SmI2, organozinc reagent, sessilifoliamide J
Introduction
obtained over two steps, the diastereoselectivities were
poor (C-9/C-9a syn/anti＝27∶73, 11(S)/(R)＝41∶59)[8]
(Scheme 1).
Selective synthesis is one of the major pursuits in
organic synthesis.[1] Although a huge number of selec-
tive methods available,[2] the absolute control of di-
astereoselectivity is still challenging for organic chem-
ists.
γ-Butyrolactone is a motif found in many bioactive
natural products and pharmaceuticals.[3] In particular,
α-methyl-γ-butyrolactone moiety, either fused, spiral,
and/or appended to the core, is found in many Stemona
alkaloids[4] such as the tuberostemospironine group
(Figure 1). For the appended lactone/pyrrolidine moiety,
the anti-stereochemistry is characteristic, as can be seen
from Figure 1, however, both syn [e.g. sessilifoliamide
J[5] (1) and croomine (2)] and anti [e.g. tuberspironine
(3) and dehydrocroomine (4)] stereochemistries are
found in the spirolactone/pyrrolidine moieties.
H
H
H
H
9a
9
O
N
N
O
O
H
O
O
H
O
O
O
O
Sessilifoliamide J (1)
Croomine (2)
OH
H
H
H
H
O
N
O
N
O
O
H
O
H
O
O
O
Tuberospironine (3)
Dehydrocroomine (4)
Figure 1 The structures of some Stemona alkaloids of tube-
rostemospironine group.
As a part of a general program aimed at the total
synthesis of alkaloids,[6] we have recently disclosed the
total synthesis of 9-epi-sessilifoliamide J (8)[7,8] and ses-
silifoliamide J (1).[9] In those syntheses, the SmI2-medi-
ated[10] reductive coupling-lactonization method[11] has
been used for the first time for the construction of the
spirolactone moiety. Although a good yield (70%) was
In view of the presence of the spirolactone/pyr-
rolidine moiety in either syn or anti form in many Ste-
mona alkaloids, we undertook further investigations into
developing highly diastereoselective methods for the
construction of the spirolactone ring system. And the
results are reported herein.
* E-mail: pqhuang@xmu.edu.cn
Received September 13, 2012; accepted October 31, 2012; published online December 11, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200904 or from the author.
Dedicated to the Memory of Professor Weishan Zhou.
†
Chin. J. Chem. 2013, 31, 55—62
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55

Tuo, Liu & Huang
FULL PAPER
Scheme 1 Synthesis of (−)-9-epi and (−)-sessilifoliamide J
of SmI2 in THF (2.4 mL, 0.24 mmol). After being
stirred at the same temperature for 30 min, water (2 mL)
was added. The organic layer was separated and the
aqueous layer was extracted with EtOAc (5 mL×3).
The combined organic layers were washed with brine (2
mL), dried over anhydrous Na2SO4, filtered and con-
centrated under reduced pressure. The residue was puri-
fied by flash chromatography on silica gel eluting with
EtOAc/PE (4∶1) to afford lactones 10 and 11 (18 mg,
75%) as an inseparable diastereomeric mixture in a ratio
of 75∶25 as determined by 1H NMR. The mixture was
separated by preparative HPLC under the following
conditions: mobile phase: 10% CH3CN/H2O; flow rate
＝4 mL/min; UV detection, 210 nm; retention time:
t
r(major)＝51 min, tr(minor)＝60 min. Minor diastereomer
10: white solid. m.p. 128－130 ℃ (MeOH); [α]D20
−88 (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 1.27
(d, J＝7.1 Hz, 3H), 1.68－1.76 (m, 1H), 1.80－1.97 (m,
2H), 2.20－2.22 (m, 6H), 2.37 (ddd, J＝18.0, 8.7, 5.6
Hz, 1H), 2.43 (ddd, J＝18.0, 8.7, 6.4 Hz, 1H), 2.49－
2.74 (m, 4H), 3.87 (dd, J＝9.7, 6.3 Hz, 1H), 4.63 (ddd,
J＝8.6, 6.1, 3.4 Hz, 1H), 4.72 (ddd, J＝10.7, 5.5, 3.4 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ: 14.8 (CH3), 24.7
(CH2), 26.8 (CH2), 27.1 (CH2), 28.3 (CH2), 28.8 (CH2),
31.2 (CH2), 32.9 (CH2), 35.6 (CH), 57.7 (CH), 65.2
(CH), 79.5 (CH), 83.5 (C), 168.7 (CO), 174.9 (CO),
178.7 (CO); MS (ESI) m/z: 330 (M＋Na＋, 100%); IR
(film) vmax: 2949, 1770, 1638, 1451, 1404, 1385, 1194,
1011 cm−1. HRMS (ESI) calcd for [C16H21NO5＋Na＋]:
330.1312; found 330.1312.
Experimental
General methods
Melting points were uncorrected. Infrared spectra
were measured using film KBr pellet techniques. H
1
NMR spectra were recorded in CDCl3 with tetramethyl-
silane as an internal standard. Chemical shifts (δ) are
expressed in ppm units downfield from TMS. Silica gel
(300－400 mesh) was used for flash column chroma-
tography, eluting (unless otherwise stated) with ethyl
acetate/hexane. Ether and THF were distilled over so-
dium benzophenone ketyl under N2. Dichloromethane
was distilled over calcium hydride under N2. SmI2 was
Major diastereomer 11: white solid. m.p. 142－144
1
℃ (MeOH); [α]2D0 −40 (c 0.8, CHCl3); H NMR (500
MHz, CDCl3) δ: 1.24 (d, J＝7.1 Hz, 3H), 1.77－1.94 (m,
3H), 1.97－2.20 (m, 6H), 2.40 (ddd, J＝13.0, 8.5, 5.5
Hz, 1H), 2.49－2.74 (m, 4H), 2.50 (ddd, J＝18.2, 6.9,
1.8 Hz, 1H), 3.77 (dd, J＝8.6, 7.0 Hz, 1H), 4.62 (ddd,
J＝10.7, 5.6, 2.6 Hz, 1H), 4.67 (ddd, J＝8.5, 4.6, 2.6 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ: 14.8 (CH3), 25.0
(CH2), 25.2 (CH2), 27.9 (CH2), 28.0 (CH2), 30.0 (CH2),
32.3 (CH2), 33.4 (CH2), 35.8 (CH), 57.5 (CH), 65.6
(CH), 81.3 (CH), 81.8 (C), 168.8 (CO), 175.4 (CO),
179.2 (CO); MS (ESI) m/z: 308 (M＋H＋, 100%); IR
(film) vmax: 2923, 1765, 1640, 1453, 1405, 1372, 1195
cm−1. HRMS (ESI) calcd for [C16H21NO5 ＋ H ＋ ]:
308.1498; found 308.1497.
freshly prepared from Sm and I2 as a 0.1 mol•L－ solu-
1
tion in THF. High-resolution mass spectra were obtained
using electrospray ionization (ESI). NMO＝N-methyl-
morpholine-N-oxide; TPAP ＝ tetrapropylammonium
perruthenate.
(2S,3'S,8a'R/S)-3'-[(2S,4S)-4-Methyl-5-oxotetrahy-
drofran-2-yl]tetrahydro-1'H,3H-spiro[furan-2,8'-
indolizine]-5,5'(4H,8a'H)-dione (−)-11-demethylsessi-
lifoliamide J (10) and (−)-9-epi-11-demethylsessilifoli-
amide J (11)
To a solution of alcohol 5 (20 mg, 0.079 mmol) in
CH2Cl2 (2 mL) were added 4 Å molecular sieves (33
mg), NMO (14 mg, 0.12 mmol) and TPAP (2 mg, 0.006
mmol). The resultant mixture was stirred at room tem-
perature for 50 min. The mixture was concentrated un-
der reduced pressure and the residue was filtered
through an Al2O3 pad eluting with ether. The solvent
was removed under reduced pressure to afford the crude
ketone, which was used in the next step without further
purification. To a cooled solution (0 ℃) of the above
mentioned crude ketone in THF (1 mL) were added
successively methyl acrylate (119 mg, 0.67 mmol),
t-BuOH (0.037 mL, 0.40 mmol), and 0.1 mol/L solution
Methyl (E)-3-{(3S,8R,8aS)-8-hydroxy-3-[(2S,4S)-4-
methyl-5-oxotetrahydrofuran-2-yl]-5-oxooctahydro-
indolizin-8-yl}-2-methylacrylate (12)
To a solution of alcohol 5 (17 mg, 0.067 mmol) in
CH2Cl2 (2 mL) were added 4 Å molecular sieves (35
mg), NMO (12 mg, 0.10 mmol) and TPAP (2 mg, 0.006
mmol). The resultant mixture was stirred at room tem-
perature for 50 min. The mixture was concentrated un-
der reduced pressure and the residue was filtered
through an Al2O3 pad eluting with ether. The solvent
was removed under reduced pressure to afford the crude
ketone, which was used in the next step without further
56
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Chin. J. Chem. 2013, 31, 55—62

Two Approaches for the Highly anti-Diastereoselective Construction of the Spirolactone Moieties
Methyl (E)-3-[(2S,3R)-2-ethyl-3-hydroxy-1-(4-meth-
oxybenzyl)-6-oxopiperidin-3-yl]-2-methylacrylate
(14)
purification. To a cooled solution (0 ℃) of the above
mentioned crude ketone in THF (1 mL) were added
successively methyl (E)-3-bromo-2-methacrylate (119
mg, 0.67 mmol) and a 0.1 mol•L－ solution of SmI2 in
1
To a solution of alcohol 13 (490 mg, 1.86 mmol) in
CH2Cl2 (11 mL) was added 4 Å molecular sieves (930
mg), NMO (327 mg, 2.79 mmol) and TPAP (32 mg,
0.093 mol). After being stirred at room temperature for
50 min, the mixture was concentrated under reduced
pressure. The residue was filtered through an Al2O3 pad
eluting with ether and the solvent was removed under
reduced pressure to afford the crude ketone, which was
used in the next step without further purification. To a
cooled solution (0 ℃) of the above crude ketone in
THF (4 mL) were added successively methyl (E)-3-
bromo-2-methacrylate (3311 mg, 18.6 mmol) and a 0.1
mol•L－1 solution of SmI2 in THF (74.5 mL, 7.45 mmol).
After being stirred at the same temperature for 30 min,
the mixture was allowed to warm to room temperature
and stirred for 30 min, then quenched with water. The
organic layer was separated and the aqueous layer was
extracted with EtOAc (10 mL×3). The combined or-
ganic layers were washed with brine (2 mL), dried over
anhydrous Na2SO4, filtered and concentrated under re-
duced pressure. The residue was purified by flash chro-
matography on silica gel eluting with EtOAc/PE (2∶1)
to afford compound 14 as a colorless oil (527 mg, 78%).
[α]2D0 −113 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3)
δ: 1.11 (t, J＝7.6 Hz, 3H), 1.62－1.67 (m, 1H), 1.83 (d,
J＝1.5, 3H), 1.85 (s, 1H, OH, D2O exchangeable), 1.92
－2.09 (m, 2H), 2.15 (ddd, J＝13.3, 10.0, 8.6, 1H), 2.47
(ddd, J＝18.8, 10.0, 8.6, 1H), 2.58 (ddd, J＝18.8, 8.6,
2.0, 1H), 3.19 (dt, J＝1.7, 5.7 Hz, 1H), 3.56 (d, J＝14.3
Hz, 1H), 3.66 (s, 3H), 3.79 (s, 3H), 5.53 (d, J＝14.3 Hz,
1H), 6.52 (q, J＝1.5 Hz, 1H), 6.77－6.80 (m, 2H), 7.14
－7.16 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 13.3
(CH3), 13.6 (CH3), 24.0 (CH2), 28.6 (CH2), 29.6 (CH2),
48.6 (CH2), 51.9 (CH3), 55.2 (CH3), 63.8 (CH), 71.6
(qC), 113.8 (CH), 128.4 (qC), 130.5 (qC), 132.3 (CH),
142.0 (CH), 159.1 (qC), 168.1 (CO), 168.6 (CO); MS
(ESI) m/z: 384 (M＋Na＋, 100%); IR (film) vmax: 3346,
2957, 1715, 1618, 1509, 1459, 1252, 1030 cm−1. HRMS
(ESI) calcd for [C20H27NO5＋Na＋]: 384.1787; found
384.1782.
THF (2.7 mL, 0.27 mmol). After being stirred at the
same temperature for 30 min, the mixture was allowed
to warm to room temperature and stirred for 30 min.
The reaction was quenched by addition of water (2 mL).
The organic layer was separated and the aqueous layer
was extracted with EtOAc (5 mL×3). The combined
organic layers were washed with brine (2 mL), dried
over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by flash
chromatography on silica gel eluting with EtOAc/PE
(4∶1) to afford compound 12 (14 mg, 60%) as a color-
1
less oil. [α]2D0 −200 (c 0.4, CHCl3); H NMR (500
MHz, CDCl3) δ: 1.25 (d, J＝7.0 Hz, 3H), 1.70－1.92 (m,
3H), 1.77 (br s, 1H), 1.96－2.17 (m, 4H), 2.14 (d, J＝
1.6 Hz, 3H), 2.37 (ddd, J＝12.9, 8.6, 5.6 Hz, 1H), 2.47
(ddd, J＝18.3, 7.2, 1.5 Hz, 1H), 2.58 (ddd, J＝18.3,
11.4, 7.2 Hz, 1H), 2.61－2.68 (m, 1H), 3.71 (dd, J＝7.7,
7.7 Hz, 1H), 3.76 (s, 3H), 4.66 (ddd, J＝8.7, 5.0, 3.3 Hz,
1H), 4.74 (ddd, J＝10.6, 5.6, 3.3 Hz, 1H), 6.64 (q, J＝
1.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ: 13.5 (CH3),
14.9 (CH3), 24.9 (CH2), 25.7 (CH2), 27.4 (CH2), 32.5
(CH2), 32.9 (CH2), 35.6 (CH), 52.2 (CH3), 57.9 (CH),
66.5 (CH), 71.5 (C), 80.3 (CH), 131.6 (C), 141.1 (CH),
168.5 (CO), 169.5 (CO), 179.2 (CO); MS (ESI) m/z:
374 (M＋Na＋, 100%); IR (film) vmax: 3384, 2986, 2910,
1760, 1712, 1617, 1407, 1384, 1260, 1113, 1022 cm−1.
HRMS (ESI) calcd for [C18H25NO6＋Na＋]: 374.1580;
found 374.1569.
(−)-9-epi-Sessilifoliamide J (8) and (−)-9,11-di-epi-
sessilifoliamide J (9)
To a suspension of 10% Pd/C (6 mg) in EtOAc (1
mL) was added a solution of compound 12 (6 mg, 0.017
mmol) in EtOAc (0.5 mL). The mixture was stirred un-
der an atmosphere of H2 for 10 h at room temperature.
The solid was filtered through a Celite pad and washed
with methanol, and the filtrate was concentrated under
reduced pressure. To the residue were added THF (1 mL)
and 3 mol•L－ HCl (0.5 mL). The solution was stirred
1
overnight and extracted with EtOAc (2 mL×3). The
combined organic layers were washed with brine (1 mL),
dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by
flash chromatography on silica gel eluting with EtOAc/
PE (4∶1) to afford a mixture of two diastereomers 8
and 9 (5 mg, 91%, dr＝52∶48) as a white solid that
was separated by preparative HPLC under the following
conditions: mobile phase: 12% CH3CN/H2O; flow rate
＝4 mL/min; UV detection, 210 nm; retention time: trA6
＝30 min, trA2＝39 min. The physical and spectroscopic
data of 8 and 9 are identical with those we reported pre-
viously.[7]
(2R,3'S,8a'S)-3'-((tert-Butyldiphenylsilyloxy)methyl)-
4-methylenetetrahydro-1'H,3H-spiro[furan-2,8'-in-
dolizine]-5,5'(4H,8a'H)-dione (16)
To a solution of hydroxyindolizidone derivative 15
(423 mg, 1.0 mmol) in CH2Cl2 (10 mL) were added 4 Å
molecular sieves (423 mg), NMO (292 mg, 2.5 mmol)
and TPAP (35.1 mg, 0.1 mmol). The resultant mixture
was stirred at room temperature for 50 min. The mixture
was concentrated under reduced pressure and the resi-
due was filtered through an Al2O3 pad eluting with ether.
The solvent was removed under reduced pressure to
afford the crude ketone, which was used in the next step
without further purification. To a stirred solution of the
Chin. J. Chem. 2013, 31, 55—62
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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57

Tuo, Liu & Huang
FULL PAPER
above obtained ketone in dry THF (8 mL) under N2 at-
mosphere, Zn (195 mg, 3.0 mmol) was added. The
mixture was heated to reflux, and a solution of ethyl-
2-bromomethacrylate (0.2 mL, 1.5 mmol) in dry THF (2
mL) was added. After 1 h of refluxing, the ketone dis-
appeared as indicated by TLC analysis. The mixture was
filtered through Celite and the filtrate was concentrated
under vacuum. The residue was dissolved in CH2Cl2 (10
mL) and washed with a saturated NH4Cl solution. The
aqueous phase was extracted with CH2Cl2 (5 mL×2).
The combined organic layers were dried over anhydrous
Na2SO4, filtered and concentrated in vacuum. Purifica-
tion of the crude material by flash column chromatog-
raphy on silica gel eluting with EtOAc/PE (2∶1) af-
forded compound 16 (445 mg, yield: 91%) as a white
solid. m.p. 120－128 ℃ (MeOH); [α]2D0 −71 (c 1.0,
calcd for [C13H17NO4＋Na＋]: 274.1050; found 274.1053.
((2R,3'S,8a'S)-4-Methylene-5,5'-dioxooctahydro-1'H,
3H-spiro[furan-2,8'-indolizine]-3'-yl)methyl-4-nitro-
benzenesulfonate (18)
To an ice-bath cooled solution of 17 (30 mg, 0.13
mmol) in CH2Cl2 (6 mL) were added successively
DMAP (cat.), 4-nitrobenzene-1-sulfonyl chloride (86
mg, 0.39 mmol) and Et3N (0.07 mL, 0.52 mmol). After
being stirred at room temperature overnight, the reaction
was quenched with a saturated aqueous NaHCO3 (2 mL)
and water (1 mL) at 0 ℃. The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2
(3 mL×3). The combined organic layers were dried
over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by flash
chromatography on silica gel eluting with EtOAc/PE
(6∶1) to afford compound 18 (50 mg, yield 96%) as a
white solid. m.p. 160－161 ℃ (MeOH); [α]2D0 −56 (c
0.4, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 1.82－1.95
(m, 2H), 1.55－1.66 (m, 1H), 1.97－2.16 (m, 3H), 2.38
(dd, J＝18.4, 6.2 Hz, 1H), 2.56 (ddd, J＝18.4, 12.0, 7.4
Hz, 1H), 2.80 (dt, J＝17.5, 2.7 Hz, 1H), 2.88 (dt, J＝
17.5, 2.8 Hz, 1H), 3.66 (dd, J＝10.9, 5.0 Hz, 1H), 4.18
(dd, J＝10.1, 2.3 Hz, 1H), 4.21－4.30 (m, 1H), 4.63 (dd,
J＝10.1, 3.9 Hz, 1H), 5.72 (t, J＝2.5 Hz, 1H), 6.30 (t,
J＝2.8 Hz, 1H), 8.05－8.10 (m, 2H), 8.36－8.41 (m,
2H); 13C NMR (125 MHz, CDCl3) δ: 24.2 (CH2), 25.0
(CH2), 28.1 (CH2), 33.4 (CH2), 36.4 (CH2), 56.1 (CH),
35.1 (CH2), 65.7 (CH), 71.2 (CH2), 78.5 (C), 124.1
(CH2), 124.6 (CH), 129.3 (CH), 133.1 (C), 141.4 (C),
151.0 (C), 168.1 (CO), 168.8 (CO); IR (film) vmax: 3104,
2963, 2917, 2847, 1759, 1640, 1630, 1530, 1451, 1404,
1352, 1271, 1185, 1095 cm−1. HRMS (ESI) calcd for
[C19H20N2O8S＋Na＋]: 459.0833; found 459.0836.
1
CHCl3); H NMR (500 MHz, CDCl3) δ: 1.05 (s, 9H),
1.59－1.69 (m, 1H), 1.83－1.92 (m, 2H), 1.97－2.10
(m, 4H), 2.37 (dd, J＝18.2, 6.3 Hz, 1H), 2.57 (ddd, J＝
18.2, 12.5, 7.0 Hz, 1H), 2.73 (dt, J＝17.4, 3.0 Hz, 1H),
2.83 (dt, J＝17.4, 2.8 Hz, 1H), 3.65 (dd, J＝10.7, 5.6
Hz, 1H), 3.76 (dd, J＝10.3, 2.3 Hz, 1H), 4.15 (dd, J＝
10.3, 4.0 Hz, 1H), 4.23—4.30 (m, 1H), 5.69 (t, J＝2.6
Hz, 1H), 6.29 (t, J＝3.0 Hz, 1H), 7.33—7.42 (m, 6H),
7.58—7.62 (m, 1H); 13C NMR (125 MHz, CDCl3) δ:
19.4 (C), 24.0 (CH2), 25.3 (CH2), 27.0 (CH), 28.2 (CH2),
30.0 (CH2), 33.6 (CH2), 36.6 (CH2), 58.4 (CH), 64.3
(CH2), 66.0 (CH), 78.8 (C), 123.6 (CH2), 127.69 (CH),
127.71 (CH), 129.7 (CH), 129.8 (CH), 133.5 (C), 133.6
(C), 135.49 (CH), 167.1 (CO), 169.0 (CO); IR (film)
v
max: 3070, 2959, 2930, 1769, 1582, 1426, 1267, 1066
cm−1. HRMS (ESI) calcd for [C29H35NO4Si＋Na＋ ]:
512.2228; found 512.2230.
(2R,3'S,8a'S)-3'-(Hydroxymethyl)-4-methylenetetra-
hydro-1'H,3H-spiro[furan-2,8'-indolizine]-5,5'(4H,
8a'H)-dione (17)
Results and Discussion
To a cooled solution (0 ℃) of compound 16 (110
mg, 0.23 mmol) in anhydrous THF (2 mL) under N2
was added Py•HF (0.21 mL, 2.3 mmol) dropwise. After
being stirred at room temperature for 24 h, the mixture
was concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel
eluting with EtOAc/MeOH (15∶1) to afford compound
17 (52 mg, yield: 92%) as a white solid. m.p. 145－146
The SmI2-mediated[10] reductive coupling-lactoniza-
tion method[11] was first investigated. The hydroxyin-
dolizidinone core 5[7] found in sessilifoliamide J was
chosen as a model substrate, which was converted to
ketone 6 by Ley oxidation[12] (TPAP/NMO/4 Å MS). To
confirm the syn/anti diastereoselectivity (C-9/C-9a)[8] in
the subsequent spirolactonization, the SmI2-mediated
coupling of ketone 6 with methyl acrylate was first un-
dertaken. The 11-demethyl derivative of sessilifoliamide
J was obtained as a diastereomeric mixture (10 and 11)
1
℃ (MeOH); [α]2D0 −42 (c 0.5, CHCl3); H NMR (500
MHz, CDCl3) δ: 1.34－1.44 (m, 1H), 1.55－1.66 (m,
1H), 1.83 (td, J＝12.1, 6.1 Hz, 1H), 1.98－2.14 (m, 3H),
2.51 (ddd, J＝18.5, 5.4, 3.0 Hz, 1H), 2.62 (ddd, J＝18.5,
11.7, 7.8 Hz, 1H), 2.79 (dt, J＝17.5, 2.7 Hz, 1H), 2.87
(dt, J＝17.5, 2.7 Hz, 1H), 3.50 (dd, J＝11.6, 7.7 Hz,
1H), 3.63 (dd, J＝11.5, 5.1 Hz, 1H), 3.68 (d, J＝11.5 Hz,
1H), 5.35 (s, 1H), 5.70 (t, J＝2.5 Hz, 1H), 6.28 (t, J＝
2.8 Hz, 1H), 7.58－7.62 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ: 24.8 (CH), 25.4 (CH), 28.1 (CH), 33.2 (CH),
36.4 (CH), 62.0 (CH2), 66.0 (CH2), 67.0 (CH), 60.0
(CH), 78.6 (C), 123.0 (CH), 133.2 (C), 168.8 (CO),
170.3 (CO); IR (film) vmax: 3407, 2917, 2849, 1767,
1620, 1452, 1414, 1289, 1215, 1069 cm−1. HRMS (ESI)
1
in a ratio of 25∶75 (determined by H NMR) (Scheme
2). The two diastereomers could be separated by prepa-
rative HPLC. The stereochemistries of the two diastereo-
mers were determined by NOESY experiments. The
observed NOESY correlations between H10β↔H9a↔
H10α in compound 11 (Figure 2) allowed an unambigu-
ous assignment of the stereochemistry of 11 as anti
(C-9/C-9a). Thus the major diastereomer is 9-epi-11-
demethylsessilifoliamide J (11) and the minor di-
astereomer is 11-demethylsessilifoliamide J (10). The
results are in agreement with our previous observation
58
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 55—62

Two Approaches for the Highly anti-Diastereoselective Construction of the Spirolactone Moieties
(cf. Scheme 1).[7]
8 and 9 in a ratio of 52∶48. Use of other reducing con-
ditions such as catalytic hydrogenation by Crabtree's
catalyst,[14] and NiCl2/NaBH4 in MeOH[15] did not im-
prove the diastereoselectivity at C-11. Comparing the
1H and 13C NMR spectra of two products with those we
reported previously[7] came to a conclusion that the
products are actually (−)-9-epi-sessilifoliamide J (8) and
(−)-9,11-di-epi-sessilifoliamide J (9), respectively. Al-
though we were unable to establish the syn-stereochem-
istry (C-9/C-9a) of sessilifoliamide J, the anti-stereo-
chemistry (C-9/C-9a) found in other Stemona alkaloids
could be established in excellent diastereoselectivity by
using bromine atom as a directing element.
Scheme 2 Ley oxidation-SmI2-mediated tandem reductive cou-
pling-lactonization
H
o
H
(1) TPAP, 4 A MS, NMO, CH2Cl2
HO
N
H
(2) SmI2, t-BuOH, THF, 0 oC
O
O
O
CO2Me
5
75% over 2 steps
H
H
1
H
H
3
11
9a N
+
N
9
H
O
H
O
O
O
O
O
O
O
O
O
10
11
(dr = 25:75)
Scheme 3 Ley oxidation-SmI2-mediated reductive coupling and
subsequent lactonization
O
(1) TPAP, NMO
O
H
o
H
4 A MS, CH2Cl2
HO
O
N
O
H
3
H
H
H
O
(2) SmI2, THF
β
2
9a
O
N
5
Br
H10α
CO2Me
H10β
60%
O
CO2Me
H
O
(1) 10% Pd/C, H2, EtOAc
11
O
N
HO
O
H
(2) 3 mol L-1 HCl, THF, 91%
H
.
Figure 2 Observed key NOE correlations of the major di-
astereomer 11.
O
12
(Single diastereomer)
To improve the diastereoselectivity in the spirolac-
tonization reaction, a stereochemical control by intro-
ducing bromine atom as the stereodirecting group was
envisaged. In the Evans asymmetric aldol methodol-
ogy,[13] haloacetyloxazolidinone or methylthioacetyl-
oxazolidinone has been used to overcome the low di-
astereoselectivity of the aldol reaction of acetyloxazo-
lidinone. In those asymmetric aldol-type reactions, ei-
ther chlorine or bromine atom or methylthio group
served as a stereodirecting group and could be removed
after the reaction. Herein we adopted the same tactic to
improve the diastereoselectivity at C-9. Methyl (E)-3-
bromo-2-methacrylate was thus selected as the coupling
reagent. It was expected that the bromo atom served
firstly as a stereodirecting group in the coupling reaction
with ketone 6, then β-elimination occurred spontane-
ously to give a butenolide, which in turn could be sub-
jected to asymmetric hydrogenation to establish the
stereogenic centre at C-11.
H
H
H
1
H
11
3
O
O
9a
+
9
N
N
O
O
H
O
H
O
O
O
O
O
8
:
9
(52 48)
To further test the bromo-directed diastereoselective
reductive coupling reaction, 6-ethyl-5-hydroxypiperi-
din-2-one 13 was oxidized with the Ley reagent and the
resulting ketone was subjected to the SmI2-mediated
reductive coupling with methyl (E)-3-bromo-2-meth-
acrylate. trans-Diastereomer 14 was obtained again as a
single diastereomer (Scheme 4).
Scheme 4 Ley oxidation-SmI2-mediated reductive coupling of
compound 13
o
OH
(1) TPAP, NMO, 4 A MS, CH2Cl2
(2)
O
N
Br
To our delight, Ley oxidation of compound 5 fol-
lowed by treatment of the resulting ketone with SmI2
and methyl (E)-3-bromo-2-methacrylate afforded com-
pound 12 as a single diastereomer (Scheme 3). The ge-
ometry of the olefin could not be determined by NO-
ESY due to an overlap of the signals, however, it could
be deduced to be E-form based on the fact of failing to
form the butenolide under the reaction conditions.
Catalytic hydrogenation [10% Pd/C, H2 (1 atm), EtOAc]
followed by treatment of the reduction product with a
CO2Me
SmI2, THF, 78%
PMB
13
OH
CO2Me
O
N
PMB
14
The role of the bromine atom in the diastereoselec-
tive reductive coupling reaction deserves comment. For
the SmI2-mediated coupling of aldehydes and α,β-unsa-
－
1
solution of HCl in THF (3 mol•L ) gave diastereomers
Chin. J. Chem. 2013, 31, 55—62
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
59

Tuo, Liu & Huang
FULL PAPER
turated esters leading to γ-butyrolactones, mechanisms
involving either the first reduction of an aldehyde to a
ketyl-radical anion A (mechanism a)[16] or the first re-
duction of an α,β-unsaturated ester to a radical-anionic
intermediate B (mechanism b)[17] have been postulated,
respectively, by Procter (Scheme 5).
ketyl-radical anions B1/B2 or D/D2, respectively. The
subsequent addition of the ketyl-radical anion to
α,β-unsaturated esters gives E1/E2 or F1/F2, respec-
tively (mechanism a). Alternatively, due to the higher
reactivity of both methyl (E)-methacrylate and methyl
(E)-3-bromo-2-methacrylate, the SmI2-mediated cou-
pling reaction might pass through a sequential single
electron transfer manner to give directly E1/E2 or
F1/F2 (mechanism c). The conformations A1,2/B1,2
featured the disposition of the olefin moiety at the
equatorial position are less congested (and are thus more
stable) comparing with C1,2/D1,2. This can account for
the formation of epimers 8/9 as the major diastereomers.
For conformations A2 and B2, further stabilization ef-
fect gains from orbital interaction between perpenticu-
larly oriented C－Br bond (σ*-orbital) and C＝O
(π-orbital) bond or •C－O− bond. In addition, the per-
penticularly disposed dipole of C－Br bond and the ni-
trogen lone pair might provide yet additional stabili-
zation effect to the conformations A2/B2; while such
beneficial effects do not exist in conformations A1/B1,
C1,2/D1,2. Consequently, compound 12 was obtained
as the sole observable diastereomer, while the C-9
epimer of 12 was no observed.
Scheme 5 Two mechanisms proposed by Procter
Mechanism a
Sm3+
(Me) H
O
O
OH
R2
CO2Me
SmI2
R1
R1
R1
R2
R2
CO2Me
A
H(Me)
Mechanism b
(Me) H
O
SmI2
R1
(Me) H
R2
CO2Me
CO2Me
B
R1, R2 = H, alkyl, aryl
It occurs to us that a chelation enhanced sequential
single electron transfer mechanism (mechanism c) can
not be excluded. On the basis of these considerations, a
plausible stereochemical course of the diastereoselective
coupling reactions (Schemes 2 and 3) is depicted in
Scheme 6. The initial chelating conformers could be
represented by A1 (X＝H)/A2 (X＝Br) versus C1 (X＝
H)/C2 (X＝Br), which are valuable for mechanisms a－
c (mechanism b no shown in Scheme 6). The first single
electron transfer from SmI2 gives the corresponding
We next investigated the organozinc reagent-based
one-pot lactonization method.[18] The hydroxyindolizi-
dinone 15,[9] which was easily available from (S)-pyro-
glutamic acid via the vinylogous Mannich reaction
(VMR),[19] was oxidized by the Ley oxidation. The fol-
lowing reaction of the resulting ketone with zinc re-
Scheme 6 Plausible stereochemical course of the diastereoselective coupling reaction
Mechanism a
Mechanism a
H
H
H
H
H
H
H
H
O
O
O
O
X
X
H
I
H
N
N
N
N
OMe
OMe
X
O
X
H
H
O
O
I
I
I
I
O
O
O
MeO
MeO
Sm
Sm
Sm
Sm
O
O
I
I
I
A1 (X = H)
A2 (X = Br)
B1 (X = H)
B2 (X = Br)
C1 (X = H)
C2 (X = Br)
D1 (X = H)
D2 (X = Br)
Mechanism c
SmI2
SmI2
H
H
H
O
H
O
X
I
N
lactonization (from E1, F1)
-HBr (from E2, F2)
N
X
O
Sm
O
I
O
I
I
MeO
:
73 27
O
Sm
OMe
E1 (X = H)
E2 (X = Br)
F1 (X = H)
F2 (X = Br)
8/9 (from E1)
12 (from E2)
1/7 (from F1)
C-9 epimer of 12 (from F2), not observed
60
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Chin. J. Chem. 2013, 31, 55—62

Two Approaches for the Highly anti-Diastereoselective Construction of the Spirolactone Moieties
agent generated from methyl bromomethacrylate gave
the spiro-α-methylene-γ-lactone 16 as the only observ-
able diastereomer in 91% over two steps. Desilylation
(Py•HF 10 equiv., THF, r.t.) of silyl ether 16 gave com-
pound 17 in 92% yield. Treatment of alcohol 17 with
p-NO2C6H4SO2Cl (TEA, DMAP, CH2Cl2) gave crystal-
line compound 18, which was subjected to single crystal
X-ray diffraction analysis (Figure 3). The stereochemis-
try of spiro-α-methylene-γ-lactones 16 and 17 was thus
established as anti. Although this complete facial selec-
tive lactonization method has been reported in the syn-
thesis of the putative structure of Stemona alkaloid ste-
monidine,[20] the result is still remarkable because a
substrate without any stereodirecting group such as an
α-methoxy group[20] or an α-hydroxyl group is in-
volved.[21]
Figure 3 X-ray structure of compound 18.
Scheme 7 Organozinc reagent-based one-pot lactonization
pyrrolidine moieties of some Stemona alkaloids with
anti-configuration.
(1) TPAP, NMO, DCM
H
o
4 A MS, 0 oC－r.t.
HO
N
In addition, on the basis of our previous work,[7,9] we
have accomplished the total synthesis of (−)-9-epi-11-
demethylsessilifoliamide J (11) and an improved syn-
thesis of (−)-9,11-di-epi-sessilifoliamide J (9).
H
(2) Zn, THF, reflux
OTBDPS
O
CO2Me
Br
15
91% over 2 steps
H
Acknowledgement
1
.
10
Py HF
3
O
8a
8
N
O
The authors are grateful for financial support from
the National Basic Research Program (973 Program) of
China (Grant No. 2010CB833200), the NSF of China
(21072160; 20832005), the Fundamental Research
Funds for the Central Universities of China (Grant No.
201112G001).
THF, r.t., 92%
H
OTBDPS
O
16
Single diastereomer
H
OH
p-NO2-C6H4SO2Cl
O
O
N
N
O
O
TEA, DMAP, CH2Cl2
96%
H
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O
17
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Chin. J. Chem. 2013, 31, 55—62