A convenient synthesis of 1-deoxy-8a-epi-castanospermine diastereoisomers (6R,7R,8S,8aS)-6,7,8-trihydroxyindolizidine and (6R,7R,8R,8aS)-6,7,8trihydroxyindolizidine

Article abstract of DOI:10.1002/ejoc.200200412

An efficient synthesis of (6R,7R,8S,8aS)-6,7,8-trihydroxyindolizidine and (6R,7R,8R,8aS)-6,7,8-trihydroxyindolizidine is described from readily available N-BOC-L-proline, (BOC = tert-butoxycarbonyl) which involves the addition of ethyl lithiopropiolate to the aldehyde derived from N-BOC-L-proline as a key step, then cyclization to construct indolizidine skeletons and asymmetric dihydroxylation. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200200412

FULL PAPER
A Convenient Synthesis of 1-Deoxy-8a-epi-Castanospermine Diastereoisomers
(6R,7R,8S,8aS)-6,7,8-Trihydroxyindolizidine and (6R,7R,8R,8aS)-6,7,8-
Trihydroxyindolizidine
Honglu Zhang,[a] Yi-Ke Ni,[a] Gang Zhao,*[a] and Yu Ding*[a]
Keywords: Alkaloids / Natural products / Asymmetric synthesis / Cyclization / Hydroxylation
An efficient synthesis of (6R,7R,8S,8aS)-6,7,8-trihydroxyindo- line as a key step, then cyclization to construct indolizidine
lizidine and (6R,7R,8R,8aS)-6,7,8-trihydroxyindolizidine is
described from readily available N-BOC- -proline, (BOC =
tert-butoxycarbonyl) which involves the addition of ethyl li-
skeletons and asymmetric dihydroxylation.
L
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
thiopropiolate to the aldehyde derived from N-BOC-L-pro- Germany, 2003)
Introduction
The naturally occurring polyhydroxylated indolizidine al-
kaloids, represented by (ϩ)-castanospermine (1) and (ϩ)-6-
epi-castanospermine (2), have been isolated from Castano-
spermum australe[1] and Alexa leiopetala.[2] Such indolizidine
alkaloids and their derivatives have been reported to display
glycosidase inhibition activity,[3] and are regarded as poten-
tial antiviral, antitumor, and immunomodulating agents.[4]
Because of their unique structural features and significant
bioactivity, (ϩ)-castanospermine (1), (ϩ)-6-epi-castano-
spermine (2) and their analogues have been synthesized by
many groups from different starting materials in the past
decades[5] in order to elucidate structureϪactivity relation-
ships. In our previous preparation of pumiliotoxin 251D we
developed a diastereoselective addition of ethyl lithiopropi-
olate to N-BOC--proline derivatives to elongate a three-
carbon chain.[6] As part of our continuing program, which
is directed towards a general synthesis route to hydroxylated
indolizidine alkaloids, we now report a short and practical
synthesis of 1-deoxy-epi-castanospermine 3a and 3b[7,8]
from the readily available starting material N-BOC--pro-
line. The attractive feature of this approach lies in its inher-
ent flexibility, since the key intermediates 10a and 10b can
be easily converted into a series of analogues and deriva-
tives.
Scheme 1
Scheme 2. (a) BH3·Me2S, THF, room temp., 99%; (b) (COCl)2,
DMSO, CH2Cl2, Et3N, Ϫ78 °C, 95%
ment with BH3·Me2S to afford the alcohol 5 in 99% yield,
which was followed by Swern oxidation according to a liter-
ature procedure[9] to give aldehyde 6 in 95% yield.
The addition of ethyl propiolate to aldehyde 6 using
nBuLi as base in THF at Ϫ78 °C[10] afforded a separable
mixture of 7a and 7b in a combined yield of 80%
(Scheme 3). The ratio of diastereomeric addition products
was determined by the yields of 7a and 7b isolated after
purification by column chromatography on silica gel (n-hex-
anes/ethyl acetate, 3:1). The absolute configurations of the
newly formed stereogenic centers were assigned by sub-
sequent transformation to target compounds 3a and 3b, re-
spectively. The effect of additives on the ratio of diastereo-
isomers was studied. When the reaction was conducted in
the presence of 2 equiv. of HMPA, a 2.6:1 mixture of 7a/7b
was obtained. On the contrary, in the presence of 2 equiv.
of Ti(OiPr)4 a 1:2.5 mixture of 7a/7b was produced. Unfor-
tunately, attempts to improve the stereoselectivity in the
Results and Discussion
(2S)-N-BOC-pyrrolidine-2-carboxaldehyde (6) was pre-
pared in two steps from commercially available N-BOC-
proline (4) (Scheme 2). Compound 4 was reduced by treat-
[a]
Laboratory of Modern Organic Synthetic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin lu, Shanghai, 200032, P. R. China
1918
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200200412
Eur. J. Org. Chem. 2003, 1918Ϫ1922

A Convenient Synthesis of 1-Deoxy-8a-epi-Castanospermine Diastereoisomers
FULL PAPER
presence of various Lewis acids such as [Cp2TiCl2], TiCl4,
Ti(OiPr)2Cl2 ZnBr2, Sm(OTf)3, Yb(OTf)3 or SnCl4 resulted
in either little diastereoselectivity or very low yield.
Table 1. Effect of additives on the reaction
Entry
Additive
Equiv.
7a/7b[a]
Total yield (7a ϩ 7b)[b]
1
2
3
none
HMPA
Ti(OiPr)4
1.2:1.0
2.6:1.0
1.0:2.5
80%
78%
74%
2
2
[a]
[b]
Determined by weight after column flash chromatography.
Isolated yield.
Scheme 4. Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2,
room temp. 12 h, 98% of 8a, 99% of 8b; (b) H2, Lindlar’s catalyst,
1 atm, quinoline, MeOH, room temp. 3 d, 96% of 9a, 98% of 9b;
Scheme 3
(c) i: TFA, CH2Cl2,
0 °C to room temp., then 1.5 h, ii:
Et3N,CH2Cl2, room temp. 2 d, 45% of 10a, 61% of 10b; (d) OsO4,
NMO, acetone/H2O (10:1), 25 °C, 8 h, 88% of 11a, 97% of 11b; (e)
i: BH3·Me2S/THF, room temp., 4 h, reflux, 1 h, ii: EtOH, reflux,
95% of 12a, 97% of 12b; (f) TBAF, THF, 25 °C 1 h, 90% of 3a,
Silylation of the alcohols 7a and 7b with TBSCl/imid-
azole[11] led to silyl ethers 8a and 8b in 98 and 99% yields,
respectively (Scheme 4).[12] Then partial cis-hydrogenation 83% of 3b
of the carbonϪcarbon triple bonds to 9a and 9b with (Z)-
double bonds was easily accomplished in the presence of
Lindlar’s catalyst. Acidic deprotection by trifluoroacetic
acid and subsequent intramolecular cyclization initiated by
Et3N in CH2Cl2 resulted in 10a (or 10b).[11] Thus, dihy-
droxylation of key intermediates 10a or 10b with OsO4/
NMO[13] (NMO ϭ N-methylmorpholine N-oxide) at room
temperature provided diols 11a or 11b in 88 and 97% yield,
respectively. Interestingly, the syn-dihydroxylations of 10a
and 10b occurred from the face of the double bond in syn
relationship to 8a-H with an exo approach as shown in Fig-
Figure 1. The syn-dihydroxylation of 10a with an exo approach
ure 1. Finally, reduction of the resulting intermediates 11a
and 11b with BH3·Me2S in THF[14] and then exposure to
TBAF yielded the two desired trihydroxyindolizidines 3a
and 3b.
The structural assignments of 3a and 3b were accomp-
1
lished by H NMR and 13C NMR spectroscopy, and from
1
2D H-1H COSY and NOESY homonuclear shift correla-
tion spectra (Figure 2 and Table 2).
The NOESY spectrum shows that 8-H and 7-H are close
to one another in 3a, and 8-H and 8a-H are close to one
another in 3b based on related cross signals. This is consist-
ent with the configurations of target compounds 3a and 3b,
which are shown in Figure 2.
Figure 2. Graphical summary of the NOESY spectrum observed
for 3a and 3b
Comparison with spectroscopic data (1H NMR) in the
literature confirmed the structural assignments. In addition,
comparison of the rotation of 3a and 3b with the literature
Table 2. Selective coupling constants J [Hz] for 3a and 3b
Isomer
J5α-5β
J5α-6
J5β-6
J6Ϫ7
J7Ϫ8
J8Ϫ8a
value confirmed the absolute stereochemistry {3a: [α]D20
ϭ
Ϫ35.8 (c ϭ 0.92, H2O); ref.[7] [α]D25 ϭ Ϫ36.3 (c ϭ 0.49,
3a
3b
10.9
10.1
5.1
5.0
11.1
10.9
2.9
3.2
2.8
3.4
10.2
1.8
H2O); 3b: [α]D20 ϭ ϩ23.8 (c ϭ 0.90, MeOH); ref.[8] [α]2D5
ϩ23 (MeOH)}.
ϭ
Eur. J. Org. Chem. 2003, 1918Ϫ1922
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1919

H. Zhang, Y.-K. Ni, G. Zhao, Y. Ding
FULL PAPER
(CHOH), 61.7 (OCH2CH3), 61.4 (NCH), 47.4 (NCH2), 28.2
[C(CH3)3], 27.9 and 23.7 (CH2CH2), 13.8 (CO2CH2CH3) ppm. MS
(EI): m/z (%) ϭ 196 (8) [M Ϫ BOC]ϩ, 70 (100), 57 (57) [C4H9ϩ].
C15H23NO5 (297.35): calcd. C, 60.59, H 7.80, N 4.71; found C
60.45, H 7.56, N 4.49.
In conclusion, we have completed a new efficient syn-
thesis of two stereoisomers 3a and 3b of 1-deoxycastano-
spermine in 16 and 23% overall yields, respectively. The mild
reaction conditions and high yield make the route attract-
ive.
Compounds 8a and 8b: TBSCl (2.42 g, 16.08 mmol) was added to a
solution of alcohol 7a (3.188 g, 10.72 mmol) and imidazole (1.83 g,
26.8 mmol) in CH2Cl2 (70 mL) at 0 °C and the resulting mixture
was warmed to 25 °C and stirred for 12 h. The reaction mixture was
diluted with CH2Cl2 (100 mL) and washed with saturated aqueous
NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried
(Na2SO4) and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography (silica gel, hex-
ane/EtOAc, 10:1) to afford TBS ether 8a (4.32 g, 98%).
Experimental Section
General: All reactions were conducted under Ar unless stated
otherwise and monitored by TLC on precoated silica gel HSGF254
plates (Yantai Chemical Co. Ltd.). Column chromatography was
performed on silica gel 300Ϫ400 mesh (Yantai Chemical Co. Ltd.)
and eluted with hexane and ethyl acetate mixtures. All solvents
were refluxed and distilled from sodium benzophenone ketyl (THF,
Et2O) or CaH2 (CH2Cl2). The NMR spectra (1H: 300 MHz; 13C:
75.4 MHz) were recorded with a Bruker AMX-300 spectrometer
and are reported in δ units in ppm and J values in Hz with Me4Si
as the internal standard. MS spectra (EI) were recorded with an
HP-5985-A mass spectrometer. Infrared (IR) spectra were recorded
8a: [α]2D3 ϭ Ϫ99 (c ϭ 1.06, CHCl3). Rf ϭ 0.47 (hexane/EtOAc, 3:1).
IR (film): ν˜ ϭ 2234, 1717, 1693 cmϪ1 1H NMR (300 MHz,
.
CDCl3): δ ϭ 5.15 (d, J ϭ 2.4 Hz, 0.6 H, CHOTBS), 4.90 (d, J ϭ
2.7 Hz, 0.4 H, CHOTBS), 4.29Ϫ4.19 (m, 2 H, OCH2CH3),
3.95Ϫ3.85 (m, 1 H, NCH), 3.50Ϫ3.28 (m, 2 H, NCH2), 2.27Ϫ1.73
(m, 4 H, CH2CH2), 1.48, 1.46 (2ϫs, 9 H, C(CH3)3], 1.35Ϫ1.29 (m,
3 H, OCH2CH3), 0.90 [s, 9 H, SiC(CH3)3], 0.15, 0.13, 0.08, 0.06 [4
ϫ s, 6 H, Si(CH3)2] ppm. MS (EI): m/z (%) ϭ 114 (100), 70 (87),
57 (57) [C4H9ϩ]. C21H37NO5Si (411.61): calcd. C 61.28, H 9.06, N
3.40; found C 61.12, H 9.14, N 3.40.
with a Shimadzu IR-440 or Digital FTIR and are reported in cmϪ1
Optical rotations were measured with a PerkinϪElmer 241Autopol
Polarimeter. [α]D values are reported in units of 10Ϫ1 deg cm2 gϪ1
Elemental analyses were performed with a Carlo Erba 1106 ana-
lyzer. (S)-N-(tert-butoxycarbonyl)prolinol (5) and (S)-N-(tert-bu-
toxycarbonyl)pyrrolidine-2-carboxaldehyde (6) were prepared ac-
cording to a previously described procedure.[9]
.
.
8b: [α]2D6 ϭ Ϫ98 (c ϭ 1.00, CHCl3). Rf ϭ 0.41 (hexane/EtOAc, 8:1).
IR (film): ν˜ ϭ 2241, 1717, 1696 cmϪ1 1H NMR (300 MHz,
.
CDCl3): δ ϭ 5.08 (d, J ϭ 5.0 Hz, 0.45 H, CHOTBS), 4.90 (d, J ϭ
4.9 Hz, 0.55 H, CHOTBS), 4.25 (q, J ϭ 7.1 Hz, 2 H, OCH2CH3),
3.90Ϫ3.79 (m, 1 H, NCH), 3.55Ϫ3.33 (m, 2 H, NCH2), 2.27Ϫ1.72
(m, 4 H, CH2CH2), 1.46, 1.44 [2 ϫ s, 9 H, C(CH3)3], 1.28 (t, J ϭ
7.1 Hz, 3 H, OCH2CH3), 0.87 [s, 9 H, SiC(CH3)3], 0.15, 0.13, 0.11
(3 ϫ s, 3 H, SiCH3) ppm. MS (EI): m/z (%) ϭ 298 (35), 114 (100),
70 (92). C21H37NO5Si (411.61): calcd. C 61.28, H 9.06, N 3.40;
found C 61.20, H 9.01, N 3.47.
Compounds 7a and 7b: nBuLi (9.2 mL of a 2.0  solution in hexane,
18.5 mmol) was added slowly to a stirred solution of ethyl propiol-
ate (1.88 mL, 1.814 g, 18.5 mmol) in dry THF (150 mL) at Ϫ78 °C
under Ar. The resulting solution was stirred at Ϫ78 °C for 1 h.
Then a solution of aldehyde 6 (1.844 g, 9.25 mmol) in dry THF
(10 mL) was added through a cannula under positive Ar pressure.
The resulting solution was stirred at Ϫ78 °C for 3 h, and the reac-
tion was monitored with TLC. Saturated aqueous NH4Cl was ad-
ded at Ϫ78 °C to quench the reaction, and then the reaction mix-
ture was warmed to room temperature and extracted with Et2O (3
ϫ 100 mL). The combined organic layers were washed with brine
and dried with Na2SO4, filtered and concentrated. Flash chromato-
Compounds 9a and 9b: Quinoline (50 µL) and reducing Lindlar’s
catalyst (99 mg) were added to
a solution of 8a (990 mg,
2.41 mmol) in MeOH (20 mL). The black suspension was stirred
under H2 for a period of 3 d at room temperature. The catalyst was
filtered off through Celite, washed with MeOH, and the filtrate was
concentrated in vacuo. Flash chromatography (silica gel, hexane/
graphy on silica gel (hexane/EtOAc, 3:1) gave 7a (1.21 g) and 7b EtOAc, 12:1) gave 9a (950 mg, 96%).
(1.02 g) in a combined yield of 80%.
9a: [α]2D6 ϭ Ϫ57.10 (c ϭ 1.35, CHCl3). Rf ϭ 0.44 (hexane/EtOAc,
8:1). IR (film): ν˜ ϭ 2959, 2932, 1722, 1697, 1652, 1473, 1392 cmϪ1
7a: [α]2D3 ϭ Ϫ123.05 (c ϭ 1.07, CHCl3). Rf ϭ 0.51 (hexane/EtOAc,
.
3:1). IR (KBr): ν˜ ϭ 3319, 2234, 1712, 1654 cmϪ1
.
1H NMR 1H NMR (300 MHz, CDCl3): δ ϭ 6.17Ϫ6.03 (m, 1 H, CHϭCH),
5.77Ϫ5.70 (m, 1 H, CHϭCH), 5.59Ϫ5.44 (m, 1 H, CHOTBS),
J ϭ 8.8 Hz, 1 H, CHOH), 4.25 (q, J ϭ 7.2 Hz, 2 H, OCH2CH3), 4.23Ϫ4.10 (m, 2 H, OCH2CH3), 3.86Ϫ3.79 (m, 1 H, NCH),
4.15Ϫ4.05 (m, 1 H, NCH), 3.56Ϫ3.53 (m, 1 H, NCHH), 3.38 (m, 3.35Ϫ3.23 (m, 2 H, NCH2), 2.04Ϫ1.76 (m, 4 H, CH2CH2), 1.48,
(300 MHz, CDCl3): δ ϭ 6.40 (d, J ϭ 9.1 Hz, 1 H, OH), 4.52 (d,
1 H, NCHH), 2.15Ϫ1.75 (m, 4 H, CH2CH2), 1.50 [s, 9 H, C(CH3)3], 1.43 [2 ϫ s, 9 H, OC(CH3)3], 1.32Ϫ1.24 (m, 3 H, OCH2CH3), 0.86
1.27 (t, J ϭ 7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR (75 MHz, [s, 9 H, SiC(CH3)3], 0.06Ϫ0.03 [m, 6 H, Si(CH3)2] ppm. MS (EI):
CDCl3): δ ϭ 157.1 [COC(CH3)3], 153.1 (CO2CH2CH3), 85.6 and m/z (%) ϭ 413 (3) [Mϩ], 314 (58), 114 (100), 70 (93), 57 (63).
80.8 (CϵC), 76.8 [OC(CH3)3], 66.8 (CHOH), 62.7 (OCH2CH3), C21H39NO5Si (413.62): calcd. C 60.98, H 9.50, N 3.39; found C
61.8 (NCH), 48.1 (NCH2), 28.9 (CH2CH2), 28.2 [C(CH3)3], 23.7
61.20, H 9.51, N 3.84.
(CH2CH2), 13.8 (CO2CH2CH3) ppm. MS (EI): m/z (%) ϭ 196 (9) 9b: [α]2D6 ϭ Ϫ25.2 (c ϭ 1.14, CHCl3). Rf ϭ 0.37 (hexane/EtOAc,
[M Ϫ BOC]ϩ, 70 (100), 57 (68) [C4H9ϩ]. C15H23NO5 (297.35): 3:1). IR (film): ν˜ ϭ 2977, 2932, 1726, 1698, 1652, 1391, 1366, 1255,
calcd. C 60.59, H 7.80, N 4.71; found C 60.88, H 8.02, N 4.65.
1188 cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 6.17Ϫ6.06 (m, 1 H,
CHϭCH), 5.75 (dd, J ϭ 0.7, 11.7 Hz, 1 H, CHϭCH), 5.58Ϫ5.46
7b: [α]2D6 ϭ Ϫ82.2 (c ϭ 1.14, CHCl3). Rf ϭ 0.43 (hexane/EtOAc,
3:1). IR (film): ν˜ ϭ 3405, 2239, 1716, 1670 cmϪ1 1H NMR (m, 1 H, CHOTBS), 4.15 (q, J ϭ 7.1 Hz, 2 H, OCH2CH3), 4.00
.
(300 MHz, CDCl3): δ ϭ 5.45 (br., 1 H, OH), 4.50 (br., 1 H,
CHOH), 4.25 (q, J ϭ 7.1 Hz, 2 H, OCH2CH3), 4.05 (br., 1 H,
(br., 1 H, NCH), 3.50Ϫ3.21 (m, 2 H, NCH2), 2.00Ϫ1.74 (m, 4
H, CH2CH2), 1.45 [s, 9 H, OC(CH3)3], 1.25 (t, J ϭ 7.1 Hz, 3 H,
NCH), 3.34Ϫ3.46 (m, 2 H, NCH2), 2.15Ϫ1.82 (m, 4 H, CH2CH2), OCH2CH3), 0.85 [s, 9 H, Si(CH3)3], 0.06 (s, 3 H, SiCH3), 0.00 (s, 3
1.45 [s, 9 H, C (CH3)3], 1.30 (t, J ϭ 7.1 Hz, 3 H, OCH2CH3) ppm. H, SiCH3) ppm. MS (EI): m/z (%) ϭ 413 (0.01) [Mϩ], 313 (100), 57
13C NMR (75 MHz, CDCl3): δ ϭ 157.0 [COC(CH3)3], 153.1 (6). C21H39NO5Si (413.62): calcd. C 60.98, H 9.50, N 3.39; found C
(CO2CH2CH3), 86.2 and 80.7 (CϵC), 65.9 [OC(CH3)3], 61.9 61.11, H 9.44, N 3.66.
1920
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1918Ϫ1922

A Convenient Synthesis of 1-Deoxy-8a-epi-Castanospermine Diastereoisomers
FULL PAPER
(8S,8aS)-8-(tert-Butyldimethylsilyloxy)-2,3,8,8a-tetrahydro-5(1H)-indo- CDCl3): δ ϭ 4.25Ϫ4.12 (m, 3 H, 6-H, 7-H and 8-H), 3.88 (br., 1
lizinone (10a) and (8R,8aS)-8-(tert-Butyldimethylsilyloxy)-2,3,8,8a- H, 8a-H), 3.48Ϫ3.43 (m, J ϭ 5.0 Hz, 2 H, 3-H), 2.00Ϫ1.75 (m, 4
tetrahydro-5(1H)-indolizinone (10b): TFA (TFA ϭ trifluoroacetic
H, 1-H and 2-H), 0.85 [s, 9 H, SiC(CH3)3], 0.08 [s, 3 H, Si(CH3)],
acid) (8 mL) was added at 0 °C to a solution of 9b (798 mg, 0.06 [s, 3 H, Si(CH3)] ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 169.2
1.931 mmol) in CH2Cl2 (50 mL). The mixture was warmed to 25
°C and stirred for 1.5 h. The solvent was removed under reduced
pressure. A solution of Et3N (7 mL) in CH2Cl2 (30 mL) was added,
(C-5), 70.2 (C-6), 68.2 (C-7), 67.7 (C-8), 58.7 (C-8a), 44.3 (C-3),
26.6 (C-1), 25.6 [SiC(CH3)3], 22.5 (C-2), 17.9 [SiC(CH3)3], Ϫ4.8
(SiCH3), Ϫ5.2 (SiCH3) ppm. MS (EI): m/z (%) ϭ 302 (5) [M ϩ
and the reaction mixture was stirred at room temperature for 2 d. H]ϩ, 286 (2) [M Ϫ Me]ϩ, 70 (100). C14H27NO4Si (301.45): calcd.
After evaporation of solvent under reduced pressure, the residue
was purified by flash chromatography (silica gel, EtOAc/MeOH,
10:1) to afford α,β-unsaturated lactam 10b (318 mg, 61%).
C 55.78, H 9.03, N 4.65; found C 55.84, H 8.62, N 4.61.
(6R,7R,8S,8aS)-8-(tert-Butyldimethylsilyloxy)-6,7-dihydroxy-
indolizidine (12a) and (6R,7R,8R,8aS)-8-(tert-Butyldimethylsily-
loxy)-6,7-dihydroxyindolizidine (12b): To a solution of lactam 11a
10a: [α]2D0 ϭ Ϫ25.2 (c ϭ 1.01, CHCl3). Rf ϭ 0.82 (EtOAc/MeOH,
10:1). IR (film): ν˜ ϭ 1670, 1606 cmϪ1 1H NMR (300 MHz,
.
(112 mg, 0.365 mmol) in dry THF (10 mL),
a solution of
CDCl3): δ ϭ 6.35 (dd, J ϭ 10.0, 1.4 Hz, 1 H, 7-H), 5.85 (dd, J ϭ
10.0, 2.3 Hz, 1 H, 6-H), 4.35 (dd, J ϭ 11.2, 1.4 Hz, 1 H, 8-H),
3.61Ϫ3.50 (m, 2 H, 3-H), 3.39Ϫ3.30 (m, 1 H, 8a-H), 2.24Ϫ1.34
(m, 4 H, 1-H and 2-H), 0.83 [s, 9 H, SiC(CH3)3], 0.03 [s, 3 H,
Si(CH3)], 0.02 [s, 3 H, Si (CH3)] ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 162.6 (C-5), 144.8 (C-7), 124.3 (C-6), 72.4 (C-8), 62.6 (C-8a),
44.3 (C-3), 32.2 (C-1), 25.5 [SiC(CH3)3], 22.5 (C-2), 17.8
[SiC(CH3)3], Ϫ4.6 (SiCH3), Ϫ4.9(SiCH3) ppm. MS (EI): m/z (%) ϭ
267 (11) [Mϩ], 252 (4) [M Ϫ Me]ϩ, 210 (24) [M Ϫ C4H9]ϩ.
C14H25NO2Si (267.44): calcd. C 62.87, H 9.42, N 5.24; found C
62.92, H 9.57, N 5.13.
BH3·Me2S (0.2 mL of a 10  solution in Me2S, 2 mmol) was added
under Ar, and the reaction mixture was kept at room temperature
for 4 h and refluxed for 1 h. The excess of reducing agent was
quenched by careful addition of EtOH (2 mL) at Ϫ5 °C. The sol-
vent was evaporated and the residue was dissolved in EtOH (8 mL),
heated under reflux for 2 h, then cooled to room temperature and
concentrated under reduced pressure. The residue was purified by
flash chromatography (silica gel, EtOAc/MeOH/NH3, 10:3:0.2) to
afford 12a (102 mg, 95%).
12a: [α]2D0 ϭ Ϫ27 (c ϭ 0.99, MeOH). Rf ϭ 0.57 [EtOAc/MeOH/
aqueous NH3 (25Ϫ28%), 10:1.5:0.2]. IR (film): ν˜ ϭ 3420, 1255,
1058 cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 3.95Ϫ3.93 (m, 1 H,
7-H), 3.89Ϫ3.83 (m, 1 H,6-H), 3.52 (dd, J ϭ 9.2, 2.6 Hz, 1 H, 8-
H), 3.06 (dt, J ϭ 2.4, 8.6 Hz, 1 H, 3-H), 2.99 (dd, J ϭ 5.0, 10.1 Hz,
1 H, 5-αH), 2.64 (br., 2 H, 2OH), 2.31Ϫ2.21 (m, 3 H, 3-H, 5-βH
and 8a-H), 2.03Ϫ1.39 (m, 4 H, 1-H and 2-H), 0.90 [s, 9 H,
SiC(CH3)3], 0.09 [s, 3 H, Si(CH3)], 0.08 [s, 3 H, Si(CH3)] ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 75.1, 72.4, 69.5 (3C-OH), 62.5 (C-
8a), 53.6 (C-3), 53.1 (C-5), 28.5 (C-1), 26.0 [SiC(CH3)3], 21.5 (C-
2), 18.3 [SiC(CH3)3], Ϫ4.1 (SiCH3), Ϫ4.2 (SiCH3) ppm. MS (EI):
m/z (%) ϭ 287 (1) [Mϩ], 270 (10) [M Ϫ OH]ϩ, 70 (100). HRMS
(EIϩ): calcd. for C14H29NO3Si 287.19167; found 287.18758.
12b: [α]2D0 ϭ ϩ13.1 (c ϭ 0.96, MeOH). Rf ϭ 0.60 [EtOAc/MeOH/
aqueous NH3 (25Ϫ28%), 10:1.5:0.2]. IR (film): ν˜ ϭ 3267Ϫ3117,
10b: [α]2D0 ϭ ϩ278.4 (c ϭ 0.87, CHCl3). Rf ϭ 0.77 (EtOAc/MeOH,
10:1). IR (film): ν˜ ϭ 1656, 1602 cmϪ1 1H NMR (300 MHz,
.
CDCl3): δ ϭ 6.65 (dd, J ϭ 9.7, 5.6 Hz, 1 H, 7-H), 6.02 (d, J ϭ
9.7 Hz, 1 H, 6-H), 4.08 (dd, J ϭ 5.6, 3.6 Hz, 1 H, 8-H), 3.61Ϫ3.50
(m, 2 H, 3-H), 3.42Ϫ3.38 (m, 1 H, 8a-H), 2.10Ϫ1.75 (m, 4 H, 1-H
and 2-H), 0.83 [s, 9 H, SiC(CH3)3], 0.03 [s, 3 H, Si(CH3)], 0.02 [s,
3 H, Si(CH3)] ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 162.2 (C-5),
137.9 (C-7), 127.4 (C-6), 62.6 (C-8), 60.8 (C-8a), 44.6 (C-3), 26.8
(C-1), 25.7 [SiC(CH3)3], 22.9 (C-2), 18.1 [SiC(CH3)3], Ϫ4.1
(SiCH3), Ϫ4.8 (SiCH3) ppm. MS (EI): m/z (%) ϭ 267 (0.3) [Mϩ],
252 (5) [M Ϫ Me]ϩ, 210 (100) [M Ϫ C4H9]ϩ. C14H25NO2Si
(267.44): calcd. C 62.87, H 9.42, N 5.24; found C 62.80, H 9.42,
N 5.11.
2982, 2954, 1469, 392 cmϪ1 1H NMR (300 MHz, CDCl3): δ ϭ
.
(6R,7R,8S,8aS)-8-(tert-Butyldimethylsilyloxy)-6,7-dihydroxy-
indolizidin-5-one (11a) and (6R,7R,8R,8aS)-8-(tert-Butyldimethylsi-
lyloxy)-6,7-dihydroxyindolizidin-5-one (11b): OsO4 (27 µL of a 2.5%
solution in tBuOH) was added to a solution of α,β-unsaturated
lactam 10b (20 mg, 0.075 mmol) and NMO (22 mg, 0.188 mmol)
in acetone/H2O (10:1, 1 mL) and the reaction mixture was stirred
at 25 °C for 8 h. The reaction mixture was diluted with CH2Cl2
(50 mL) and washed with saturated aqueous NaHCO3 (5 mL) and
brine (5 mL). The organic layer was dried (Na2SO4), and the sol-
vents were removed under reduced pressure. The residue was puri-
fied by flash chromatography (silica gel, EtOAc/MeOH, 10:1) to
afford diol 11b (22 mg, 97%).
4.19Ϫ4.13 (m, 1 H, 6-H), 3.91 (s, 2 H, 2OH), 3.13Ϫ3.02 (m, 2 H,
7-H, 8-H), 2.50Ϫ2.18 (m, 6 H), 1.88Ϫ1.60 (m, 3 H), 0.92 [s, 9 H,
SiC(CH3)3], 0.011 [s, 6 H, Si(CH3)2] ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 72.0 and 70.3 and 66.5 (3C-OH), 61.5 (C-8a), 53.6
(C-3), 52.7 (C-5), 25.9 [SiC(CH3)3], 23.8 (C-1), 21.4 (C-2), 18.2
[SiC(CH3)3], Ϫ4.7 (SiCH3), Ϫ4.8 (SiCH3) ppm. MS (EI): m/z (%) ϭ
287 (1) [Mϩ], 270 (4) [M Ϫ OH]ϩ, 230 (10) [M Ϫ C4H9]ϩ, 113 (19),
84 (31), 70 (100). HRMS (EIϩ): calcd. for C14H29NO3Si
287.19167; found 287.19336.
(6R, 7R, 8S, 8aS)-6,7,8-Trihydroxyindolizidine (3a) and (6R, 7R,
8R, 8aS)-6,7,8-Trihydroxyindolizidine (3b): nBu4NF (0.21 mL of a
11a: [α]2D0 ϭ Ϫ102.3 (c ϭ 0.84, CHCl3). Rf ϭ 0.67 (EtOAc/MeOH,
10:1). IR (film): ν˜ ϭ 3386, 1637 cmϪ1 1H NMR (300 MHz, 1  solution in THF) was added to a solution of diols 12a (50 mg,
.
CDCl3): δ ϭ 4.20 (s, 1 H, 8-H), 4.08 (s, 1 H, OH), 4.00 (s, 1 H, 0.174 mmol) in THF (5 mL) and the resulting mixture was stirred
OH), 3.74Ϫ3.71 (m, 1 H, 7-H), 3.65 (d, J ϭ 7.8 Hz, 1 H, 6-H), at 25 °C for 1 h. The solvent was removed under reduced pressure
3.50Ϫ3.45 (m, 2 H, 3-H), 2.95 (br., 1 H, 8a-H), 2.25Ϫ1.45 (m, 4 and the residue was purified by flash chromatography [silica gel,
H, 1-H and 2-H), 0.90 [s, 9 H, SiC(CH3)3], 0.11 [s, 3 H, Si(CH3)], EtOAc/MeOH/aqueous NH3 (25Ϫ28%) 8:3:0.5] to afford triol 3a
0.09 [s, 3 H, Si(CH3)] ppm. 13C NMR (75Mz, CDCl3): δ ϭ 168.5 (27 mg, 90%).
(C-5), 72.9 (C-6), 71.4 (C-7), 69.8 (C-8), 59.5 (C-8a), 44.7 (C-3),
3a: White solid, m.p.165 Ϯ0.5 °C (ref.[7] m.p. 166Ϫ168 °C). [α]2D0
ϭ
31.3 (C-1), 25.6 [SiC(CH3)3], 22.3 (C-2), 18.0 [SiC(CH3)3], Ϫ4.4 Ϫ35.8 (c ϭ 0.92, H2O) {ref.[7] [α]2D5 ϭ Ϫ36.3 (c ϭ 0.49, H2O)}. Rf ϭ
(SiCH3), Ϫ4.7 (SiCH3) ppm. MS (EI): m/z (%) ϭ 302 (0.1) [M ϩ 0.48 [CH2Cl2/MeOH/aqueous NH3 (25Ϫ28%), 8:3:0.2]. 1H NMR
H]ϩ, 286 (4) [M Ϫ Me]ϩ, 244 (100). C14H27NO4Si (301.45): calcd. (300 MHz, D2O): δ ϭ 4.02 (dd, J ϭ 2.8, 2.9 Hz, 1 H, 7-H), 3.85
C, 55.78, H 9.03, N 4.65; found C 55.74, H 8.58, N 4.65.
(ddd, J ϭ 11.1, 5.1, 2.9 Hz, 1 H, 6-H), 3.50 (dd, J ϭ 10.2, 2.8 Hz,
1 H, 8-H), 3.10Ϫ3.04 (m, 1 H, 3-H), 3.00 (dd, J ϭ 10.9, 5.1 Hz, 1
11b: [α]2D0 ϭ Ϫ104.4 (c ϭ 0.84, CHCl3). Rf ϭ 0.63 (EtOAc/MeOH,
3:1). IR (film): ν˜ ϭ 3379 (br), 1630 cmϪ1
.
1H NMR (300 MHz, H, 5-αH), 2.57Ϫ2.38 (m, 3 H, 8a-H, 3-H, 5-βH), 2.10Ϫ2.00 (m, 1
Eur. J. Org. Chem. 2003, 1918Ϫ1922
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1921

H. Zhang, Y.-K. Ni, G. Zhao, Y. Ding
FULL PAPER
H, 1-H), 1.83Ϫ1.72 (m, 2 H, 2-H), 1.48Ϫ1.35 (m, 1 H, 1-H) ppm.
13C NMR (75 MHz, D2O): δ ϭ 74.3 and 73.5 and 70.0(3C-OH),
63.8 (C-8a), 55 (C-3), 52.6 (C-5), 29.2 (C-1), 22.9 (C-2).
3b: [α]2D0 ϭ ϩ23.5 (c ϭ 0.90, MeOH) {ref.[8] [α]2D5 ϭ ϩ23 (MeOH)}.
Rf ϭ 0.70 [CH2Cl2/MeOH/aqueous NH3 (25Ϫ28%), 8:3:0.2]. 1H
NMR (400 MHz, CD3OD): δ ϭ 4.20 (ddd, J ϭ 10.9, 5.0, 3.2 Hz,
1 H, 6-H), 4.11 (dd, J ϭ 3.3, 3.4 Hz, 1 H, 7-H), 3.90 (dd, J ϭ 3.4,
1.8 Hz, 1 H, 8-H), 3.22Ϫ3.17 (m, 1 H, 3-H), 3.10 (dd, J ϭ 10.1,
5.0 Hz, 1 H, 5-αH), 2.73Ϫ2.69 (m, 1 H, 8a-H), 2.52 (dd, J ϭ 10.1,
10.9 Hz, 1 H, 5-βH), 2.45Ϫ2.38 (m, 1 H, 3-H), 2.08Ϫ1.95 (m, 3 H,
1-H and 2-H), 1.87Ϫ1.84 (m, 1 H, 1-H) ppm. 13C NMR (75 MHz,
CD3OD): δ ϭ 72.8 and 70.3 and 67.5 (3C-OH), 62.9 (C-8a), 54.9
(C-3), 54.2 (C-5), 24.5 (C-1), 22.7 (C-2) ppm.
[4] [4a]
A. D. Elbein, R. J. Molyneux, in Alkaloids: Chemical and
Biological Perspectives (Ed.: S. W. Pelletier), Wiley, New York,
[4b]
1987, vol. 5, pp. 1Ϫ54.
N. Asano, R. J. Nash, R. J. Moly-
neux, G. W. J. Fleet, Tetrahedron: Asymmetry 2000, 11,
1645Ϫ1680.
[5]
[6]
[7]
N. T. Patil, J. N. Tilekar, D. D. Dhavale, Tetrahedron Lett. 2001,
42, 747Ϫ749 and references cited therein.
Y. Ni, G. Zhao, Y. Ding, J. Chem. Soc., Perkin Trans. 1 2000,
3264Ϫ3266.
[7a] H. Setoi, H. Takeno, M. Hashimoto, Heterocycles 1986, 24,
[7b]
1261Ϫ1264.
H. Setoi, H. Takeno, M. Hashimoto, J. Org.
Chem. 1985, 50, 3948Ϫ3950.
K. H. Aamlid, L. Hough, A. C. Richardson, Carbohydr. Res.
1990, 202, 117Ϫ129.
P. Z. Reed, J. A. Katzenellenbogen, J. Org. Chem. 1991, 56,
2624Ϫ2634.
[8]
[9]
[10]
[11]
P. Garner, J. M. Park, J. Org. Chem. 1990, 55, 3772Ϫ3787.
K. C. Nicolaou, H. J. Mitchell, K. C. Fylaktakidou, R. M.
Rodriguez, H. Suzuki, Chem. Eur. J. 2000, 6, 3116Ϫ3148.
Stable conformation isomers exist of 8a, 8b, 9a and 9b, which
form because of steric hindrance between C-2 of the pyrrolid-
ine ring and the propargyl carbon atom after the hydroxy
group has been protected with the large tBuMe2Si group. Their
1H NMR spectra show that the isomeric ratio is 40:60 in 8a
and 45:55 in 8b.
Acknowledgments
[12]
We thank the National Natural Sciences Foundation for funding
this work.
[1]
L. D. Hohenschutz, E. A. Bell, P. J. Jewess, D. P. Leworthy, R.
J. Pryce, E. Arnold, J. Clardy, Phytochemistry 1981, 20,
[13] [13a]
811Ϫ814.
N. Cabezas, J. Thierry, P. Potier, Heterocycles 1989, 28.
[2]
R. J. Nash, L. E. Fellows, J. V. Dring, C. H. Stirton, D. Carter,
607Ϫ610. [13b] N. M. Carpenter, G. W. J. Fleet, I. Cencidi Bello,
B. Wichester, L. E. Fellows, R. J. Nash, Tetrahedron Lett. 1989,
30, 7261Ϫ7264.
M. P. Hegarty, E. A. Bell, Phytochemistry 1988, 27, 1403Ϫ4.
[3] [3a]
E. W. Baxter, A. B. Reitz, J. Org. Chem. 1994, 59,
[3b]
[14]
3175Ϫ3185.
1171Ϫ1202.
L. M. Sinnott, Chem. Rev. 1990, 90,
C. Paolucci, L. Mattioli, J. Org. Chem. 2001, 66, 4787Ϫ4794.
Received July 22, 2002
1922
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1918Ϫ1922