A short synthesis of (+)-lycoricidine

Article abstract of DOI:10.1016/S0040-4020(02)00736-6

A short synthesis of (+)-lycoricidine outlined herein has been accomplished by combining asymmetric chloronitroso cycloaddition with controlled installation of the bromohydrin unit, base-promoted epoxide formation, and SnCl₄-catalyzed arene-epoxide cyclization.

Full text of DOI:10.1016/S0040-4020(02)00736-6

Tetrahedron 58 (2002) 7335–7338
A short synthesis of (1)-lycoricidine
*
Shanmugham Elango and Tu-Hsin Yan
Department of Chemistry, National Chung-Hsing University, Taichung 400, Taiwan, ROC
Received 24 May 2002; accepted 24 June 2002
Abstract—A short synthesis of (þ)-lycoricidine outlined herein has been accomplished by combining asymmetric chloronitroso
cycloaddition with controlled installation of the bromohydrin unit, base-promoted epoxide formation, and SnCl4-catalyzed arene–epoxide
cyclization. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
(þ)-Lycoricidine 1 and structurally related alkaloids like
(þ)-narciclasine 2, (þ)-pancratistatin 3, and (þ)-deoxy-
pancratistatin 4 have attracted considerable interest because
of the promising biological activity and natural scarcity.1
Unsaturated aminocyclitol such as chiral O-isopropylidene-
protected 4-aminocyclohexenol 5 is an ideal substrate in the
construction of narcissus ring skeleton as it has close
relation both structurally and stereochemically. Numerous
examples of the use of aminocyclitol derivatives like
4-((benzyloxycarbonyl)amino)cyclohexenol 6,2a,b 4-azido-
cyclohexenol 7,2c and 4-(tosylamino)cyclohexenol 82d as
key starting materials for the synthesis of (þ)-lycoricidine
have been reported.3
As part of our studies directed toward the development of
chiral nitro synthons, we devised an elegant one-pot
cycloaddition–reduction procedure for the preparation of
enantiopure 4-aminocyclohexenol 5 (86%) by employing
camphor-based chloronitroso ester 9.4 The ready avail-
ability of 5 suggested that an effective asymmetric synthesis
of (þ)-lycoricidine might emerge. Scheme 1 presents a
retrosynthetic analysis.
The successful approach to the synthesis of (þ)-lycoricidine
reported herein is predicated upon the stereocontrolled
conversion of 5 to a suitable epoxide 12 and its participation
in the desired carbon–carbon bond construction to connect
rings A and C.
The requisite epoxide 12 was prepared according to Scheme
2. Both the amino and hydroxyl functional groups of
aminocyclitol 5 were protected as N-sulfonylamide and silyl
ether, respectively to afford 10 in 78% isolated yield.
Exposure of 10 to NBS in aqueous acetone gave rise to
bromohydrins 11. During bromohydrination both the regio
Keywords: bromohydrin; cycloaddition.
*
Corresponding author. Fax: þ886-4-2285-1983;
e-mail: thyan@mail.nchu.edu.tw
Scheme 1.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00736-6

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S. Elango, T.-H. Yan / Tetrahedron 58 (2002) 7335–7338
Scheme 2. Asymmetric synthesis of lycoricidine 1.
isomers are formed and the resulting mixture was used as
such for the epoxide formation. Epoxide 12 could be derived
in one step from 11 through base-promoted epoxide
formation and piperonylation. Thus, treatment of 11 with
aqueous NaOH under phase-transfer condition followed by
exposing the mixture to piperonyl bromide led to the desired
epoxide 12 in 91% isolated yield.5
installation of the bromohydrin unit, base-promoted epoxide
formation and SnCl4-catalyzed arene–epoxide cyclization,
we have described a high yield route for the facile
construction of the typical framework of narcissus alkaloids.
Further studies will determine whether this SnCl4-promoted
arene–epoxide cyclization will be generally useful for
construction of fused BC ring system. At present, this
reaction methodology has been applied to the asymmetric
synthesis of (þ)-narciclasine.8 Now the efforts are directed
to invert the stereochemistry of the benzylic carbon in 13 for
the saturated analogs.
Epoxide ring opening of 12 was initially attempted with
boron trifloride etherate. However, all attempts to effect
BF3-promoted arene–epoxide cyclization resulted in
deketalization or decomposition. After a good deal of
careful experimentation, we observed a facile cyclization
with a catalytic amount of SnCl4.6 Thus treatment of 12 with
20 mol% of SnCl4 in dry CH2Cl2 at room temperature for
10 min followed by addition of Ac2O led to clean
intramolecular arylation and O-acylation to give 13 in
93% isolated yield. Cleavage of the N-tosyl group of 13
proceeded under the reductive photolytic condition
(hn/NaBH4/EtOH) to generate the free amine 14 in 45%
yield,7 which upon reaction with Boc2O at room tempera-
ture for 4 h followed by immediate oxidation with RuCl3/
NaIO4 afforded 15 in 50% yield. The imide 15 possessing
the typical framework of deoxypancratistatin is lacking the
stereochemistry only at the benzylic position (carbon-10b).
In order to obtain the unsaturated alkaloid, treatment of 15
with DBU at 708C gave 16 in 97% yield. Removal of all the
protecting groups with formic acid afforded pure lycori-
cidine 1 (95%), mp 216–2188C; [a]2D5¼þ1758 (c 1.1,
MeOH). The spectral properties of 1 are in full agreement
with those of the natural product.2,3 Thus, the asymmetric
synthesis of (þ)-lycoricidine outlined herein has been
accomplished by means of a convergent approach, wherein
four steps involved aqueous condition. The overall yield of
(þ)-lycoricidine from chloronitroso 9 is 13%. By combin-
ing asymmetric chloronitroso cycloaddition with controlled
3. Experimental
3.1. General remarks
Reactions were generally conducted under a positive
pressure of dry nitrogen within oven-dried glassware. THF
and ether were distilled from sodium/benzophenone ketyl
prior to use. Methylene chloride and acetonitrile were
distilled from CaH2 prior to use. Flash chromatography was
done on E. Merck silica gel 60 (230–400 mesh) Melting
points (Pyrex capillary) are uncorrected. Concentrations for
rotation data are given as g/100 mL of solvent.
3.1.1. (1S,2S,3S,6R)-3-((t-Butyldimethylsilyl)oxy)-1,2-O-
isopropylidene-6-(N-( p-toluenesulfonyl)amino)cyclo-
hexene-1,2-diol 10. To a solution of 5 (1.85 g, 10 mmol)
and NEt3 (4.2 mL, 30 mmol) in CH3CN (20 mL) was added
p-toluenesulfonyl chloride (1.9 g, 10 mmol). After stirring
at 258C for 8 h, a solution of DBU (2.3 mL, 15 mmol) and
TBS-Cl (1.69 g, 11 mmol) in CH3CN (10 mL) was added
and the mixture was stirred further for a period of 9 h. The
reaction mixture was quenched with aqueous NaHCO3 and
CH3CN was removed under vacuum. The aqueous solution

S. Elango, T.-H. Yan / Tetrahedron 58 (2002) 7335–7338
7337
was extracted with CH2Cl2 (40 mL£3). The combined
organic extracts were washed with dilute HCl, and brine,
dried (MgSO4), concentrated in vacuo and purified by flash
chromatography (silica gel, 20% EtOAc/hexane) to give
3.58 g (78%) of 10 as a white solid: mp 130–1318C; IR
114.74, 108.81, 108.73, 107.93, 101.02, 78.51, 73.95, 70.55,
58.84, 55.28, 53.15, 50.07, 26.68, 25.69, 24.17, 21.45,
18.07, 24.87, 25.01; [a]2D5¼29.38 (c 2.2, CH2Cl2); high-
resolution MS m/e calcd for C30H41NO8SSi: 603.2341,
found: 603.2332. Anal. Calcd for C30H41NO8SSi: C, 59.67;
H, 6.79; N, 2.32. Found: C, 59.84; H, 7.00; N, 2.12.
1
(neat) 3291, 1598, 1328, 1157 cm21; H NMR (400 MHz,
CDCl3) d 7.71 (d, J¼8.4 Hz, 2H), 7.26 (d, J¼8.4 Hz, 2H),
5.95 (dd, J¼10.0, 5.2 Hz, 1H), 5.77 (dd, J¼10.0, 5.6 Hz,
1H), 5.53 (d, J¼10.0 Hz, 1H), 4.37 (d, J¼2.8 Hz, 1H), 4.35
(d, J¼3.2 Hz, 1H), 4.27 (dd, J¼6.8, 2.4 Hz, 1H), 4.12 (dd,
J¼5.2, 2.8 Hz, 1H), 3.89–3.84 (m, 1H), 2.40 (s, 3H), 1.22
(s, 6H), 0.89 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H); 13C NMR
(75.5 MHz, CDCl3) d 143.27, 138.27, 132.30, 130.76,
129.61, 127.08, 108.35, 78.41, 77.32, 66.45, 49.93, 26.16,
25.73, 24.36, 21.48, 17.94, 24.78, 24.91; [a]2D5¼247.68 (c
1.4, CH2Cl2); high-resolution MS (FABþ) m/e calcd for
C22H35NO5SSi: 454.2079, found: 454.2081. Anal. Calcd for
C22H35NO5SSi: C, 58.25; H, 7.78; N, 3.09. Found: C, 58.31;
H, 7.76; N, 3.07.
3.1.4. (1R,2R,3S,4R,4aR,10bS )-1-Acetoxy-2-((t-butyl-
dimethylsilyl)oxy)-3,4-(isopropylidenedioxy)-8,9-
(methylenedioxy)-5-( p-toluenesulfonyl)-1,1a,2,3,4,4a,6-
heptahydrophenanthridine 13. To a solution of epoxide
12 (1.81 g, 3.0 mmol) in CH2Cl2 (45 mL) was added SnCl4
(1.0 M in CH2Cl2, 0.6 mL). After being stirred at 258C for
20 min, K2CO3 (1.73 g, 12.5 mmol) was added to the
reaction mixture followed by the addition of a solution of
DMAP (0.13 g, 1.0 mmol), pyridine (30 mmol), and acetic
anhydride (1.4 mL, 15 mmol) in CH2Cl2. Stirring was
continued for 6 h and the reaction mixture was diluted
with water (20 mL). The organic layer was washed with
dilute HCl and brine. Concentration and purification by
flash chromatography (silica gel, 17% EtOAc/hexane) to
afford 1.82 g (93%) of 13 as a white solid: mp 115–1168C;
3.1.2. (1S,2S,3S,4S,5S,6S)-5-Bromo-3-((t-butyldimethyl-
silyl)oxy)-1,2-O-isopropylidene-6-(N-( p-toluenesulfon-
yl)amino)cyclohexane-1,2,4-triol and (1S,2S,3R,4S,
5R,6R )-4-bromo-3-((t-butyldimethylsilyl)oxy)-1,2-O-iso-
propylidene-6-(N-( p-toluenesulfonyl)amino)cyclohex-
ane-1,2,5-triol 11. To a solution of 10 (4.53 g, 10.0 mmol)
in acetone (10 mL) and water (40 mL) was added NBS
(2.67 g, 15 mmol). After stirring at 258C for 10 h, the
reaction mixture was diluted with CH2Cl2 (150 mL),
washed with water, dried (MgSO4), concentrated in vacuo
and purified by flash chromatography (silica gel, 17%
EtOAc/hexane) to give 5.4 g (98%) of 11 as a sticky solid:
(two regio isomers, found by 400 MHz 1H NMR to be an 1:1
IR (neat) 2930, 1747, 1237 cm21 1H NMR (400 MHz,
;
CDCl3) d 7.63 (d, J¼8.4 Hz, 2H), 7.13 (d, J¼8.4 Hz, 2H),
6.64 (s, 1H), 6.31 (s, 1H), 5.83 (s, 2H), 5.08 (t, J¼8.4 Hz,
1H), 4.53 (d, J¼16.8 Hz, 1H), 4.40 (t, J¼6.4 Hz, 1H), 4.33
(t, J¼6.4 Hz, 1H), 4.30 (d, J¼16.8 Hz, 1H), 4.00 (t,
J¼6.4 Hz, 1H), 3.90 (dd, J¼8.8, 7.2 Hz, 1H), 2.33 (s, 3H),
1.95 (s, 3H), 1.50 (s, 3H), 1.28 (s, 3H), 0.81 (s, 9H), 0.10 (s,
3H), 0.05 (s, 3H); 13C NMR (75.5 MHz, CDCl3) d 169.54,
146.77, 146.43, 143.37, 136.09, 129.23, 127.65, 126.36,
125.69, 109.15, 108.02, 106.29, 100.94, 78.36, 74.50, 73.68,
73.57, 53.27, 44.39, 40.95, 27.68, 25.60, 25.52, 21.35,
21.09, 17.90, 24.37, 24.87; [a ]2D5¼233.18 (c 0.2, CH2Cl2);
high-resolution MS (FABþ) m/e calcd for C32H43NO9SSi:
645.2432, found: 645.2430.
1
ratio): IR (neat) 3484, 3279 cm21; H NMR (400 MHz,
CDCl3) d 7.75 (d, J¼8.4 Hz, 2H), 7.28 (d, J¼8.4 Hz, 2H),
5.66 (d, J¼12.0 Hz) and 5.51 (d, J¼11.6 Hz) (1H total),
4.48–3.52 (m, 6H), 2.41 (s, 3H), 1.42, 1.39, 1.27, and 1.22
(4s, 6H total), 0.90 and 0.88 (2s, 9H total), 0.18 and 0.13 (2s,
6H total); Anal. Calcd for C22H36BrNO6SSi: C, 47.99; H,
6.59; N, 2.54. Found: C, 47.78; H, 6.50; N, 2.63.
3.1.5. (1R,1aS,2R,3S,4R,4aR )-1-Acetoxy-2-((t-butyl-
dimethylsilyl)oxy)-3,4-(isopropylidenedioxy)-8,9-
(methylenedioxy)-1,1a,2,3,4,4a,5,6-octahydrophenan-
thridine 14. A solution of 13 (0.5 g, 0.77 mmol), NaBH4
(0.45 g, 11.9 mmol), and anisole (0.5 g, 4.6 mmol) in 90%
EtOH (67 mL) was put into a Pyrex column (100 mL,
OD¼20 mm) and degassed by bubbling nitrogen through
the solution for 15–20 min. The column was placed ca.
15 cm from a light source and then NaBH4 (0.19 g,
5.0 mmol) was added. After irradiating with 300 nm light
for 6 h, the reaction mixture was concentrated in vacuo. The
residue was taken in water (20 mL) and extracted with
CH2Cl2. The organic layer was washed with aqueous NH4Cl
and brine. The organic layer was dried, concentrated, and
purified by flash chromatography (silica gel; 10, 15, then
20% EtOAc/hexane) to give 0.18 g (45%) of 14 as a white
solid: mp 147–1488C; IR (neat) 3409, 1748 cm21; 1H NMR
(400 MHz, CDCl3) d 6.54 (s, 1H), 6.44 (s, 1H), 5.86 (s, 2H),
5.15 (t, J¼10.0 Hz, 1H), 4.16–4.09 (m, 2H), 4.07 (d,
J¼16.0 Hz, 1H), 4.02 (d, J¼16.0 Hz, 1H), 3.80 (dd, J¼9.2,
6.0 Hz, 1H), 3.47 (dd, J¼1.6, 1.2 Hz, 1H), 2.79 (dd, J¼10.4,
3.2 Hz, 1H), 1.94 (s, 3H), 1.54 (s, 3H), 1.36 (s, 3H), 0.81 (s,
9H), 0.12 (s, 3H), 0.05 (s, 3H); 13C NMR (75.5 MHz,
CDCl3) d 169.47, 146.69, 145.51, 127.98, 126.72, 109.71,
108.56, 106.17, 100.71, 80.29, 78.26, 76.25, 74.52, 53.88,
48.43, 39.49, 28.17, 26.23, 25.66, 21.34, 17.93, 24.20,
3.1.3. (1S,2S,3S,4R,5R,6S )-3-((t-Butyldimethylsilyl)oxy)-
4,5-epoxy-1,2-O-isopropylidene-6-(N-piperonyl-N-( p-
toluenesulfonyl)amino)cyclohexane-1,2-diol 12. To
a
solution of 11 (2.75 g, 5.0 mmol) and Bu4NHSO4 (50 mg)
in CH2Cl2 (75 mL) was added 50% aqueous NaOH
(45 mL). After stirring at room temperature for 8 h,
piperonyl bromide (1.1 g, 5.0 mmol) was added and the
mixture was stirred for a further 7 h. The reaction mixture
was diluted with CH2Cl2 (80 mL), washed with water,
aqueous NH4Cl, and brine, dried (MgSO4), concentrated in
vacuo and purified by flash chromatography (silica gel, 15%
EtOAc/hexane) to give 2.8 g (91%) of 12 as a white solid:
1
mp 45–468C; IR (neat) 2930, 1598, 1244 cm21; H NMR
(400 MHz, CDCl3) d 7.74 (d, J¼8.0 Hz, 2H), 7.26 (d,
J¼8.0 Hz, 2H), 6.87 (d, J¼1.6 Hz, 1H), 6.79 (dd, J¼8.0,
1.6 Hz, 1H), 6.68 (d, J¼8.0 Hz, 1H), 5.90 (s, 2H), 4.40 (d,
J¼16.0 Hz, 1H), 4.24 (d, J¼16.0 Hz, 1H), 4.18 (dd, J¼7.6,
6.0 Hz, 1H), 3.99 (dd, J¼8.0, 5.2 Hz, 1H), 3.86 (dd, J¼4.8,
2.8 Hz, 1H), 3.08 (t, J¼3.2 Hz, 1H), 3.01 (t, J¼3.2 Hz, 1H),
2.39 (s, 3H), 1.30 (s, 3H), 1.14 (s, 3H), 0.85 (s, 9H), 0.07 (s,
6H); 13C NMR (75.5 MHz, CDCl3) d 147.82, 147.11,
143.47, 137.36, 130.87, 129.56, 127.59, 127.49, 121.57,

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S. Elango, T.-H. Yan / Tetrahedron 58 (2002) 7335–7338
24.86; [a ]2D5¼þ27.78 (c 0.35, CH2Cl2); high-resolution MS
m/e calcd for C25H37NO7Si: 491.2330, found: 491.2335.
Anal. Calcd for C25H37NO7Si: C, 61.07; H, 7.58; N, 2.85.
Found: C, 61.22; H, 7.54; N, 2.71.
3.1.8. (1)-Lycoricidine 3. To a solution of 16 (0.10 g,
0.18 mmol) in THF was added 60% HCOOH (8 mL) at
258C. After heated at 608C for 1 h, the solvent was
evaporated and the residue was purified by flash chroma-
tography (silica gel, 15% EtOAc/hexane) to give 0.05 g
(98%) of 3 as a white solid: mp 216–2188C [lit.2c mp 217–
3.1.6. (1R,1aS,2R,3S,4R,4aR )-1-Acetoxy-5-(t-butoxycar-
bonyl)-2-((t-butyldimethylsilyl)oxy)-3,4-(isopropylidene-
dioxy)-8,9-(methylenedioxy)-1,1a,2,3,4,4a-pentatahydro-
phenanthridone 15. A solution of 14 (0.25 g, 0.5 mmol)
and di-t-butyl dicarbonate (0.14 g, 0.6 mmol) in CH3CN
(9 mL) was stirred at 258C till the starting amine
disappeared on TLC (ca. 4 h). To this vigorously stirred
solution was added CCl4 (9 mL) followed by aqueous
solution of NaIO4 (0.45 g in 13.5 mL H2O) and RuCl3
(55 mg, 0.29 mmol). After being stirred for 8 h, the reaction
mixture was diluted with CH2Cl2 (30 mL) and the aqueous
phase was extracted with CH2Cl2 (15 mL£3). The com-
bined organic extracts were dried and concentrated in
vacuo. The residue was diluted with ether (20 mL), filtered
through a celite pad, concentrated, and purified by flash
chromatography (silica gel; 6, 10 and 15% EtOAc/hexane)
to afford 0.16 g (50%) of 15 as a white solid: mp 83–848C;
2218C; lit.3c mp 224–2268C]; IR (neat) 3390, 1679 cm21
;
1H NMR (400 MHz, CD3OD) d 7.29 (s, 1H), 7.06 (s, 1H),
6.07 (dd, J¼4.0, 2.8 Hz, 1H), 5.97 (d, J¼1.2 Hz, 1H), 5.95
(d, J¼1.2 Hz, 1H), 4.29 (dt, J¼9.2, 1.6 Hz, 1H), 4.15 (dt,
J¼4.4, 2.0 Hz, 1H), 3.85–3.81 (m, 2H); 13C NMR
(75.5 MHz, CDCl3) d 166.53, 153.44, 150.11, 133.41,
132.63, 123.34, 122.83, 107.71, 104.40, 103.56, 74.37,
70.94, 53.90; [a]D25¼1758 (c 1.1, MeOH) [lit.2b
[a ]D25¼þ1708 (c 1.0, MeOH); lit.2c [a ]2D5¼þ2048 (c 0.21,
pyridine); lit.3c [a ]D25¼þ1808 (c 0.21, pyridine)].
Acknowledgments
National Science Council of the Republic of China provides
generous support of this program (NSC 88-2113-M-005-
006).
IR (neat) 1747, 1723, 1698 cm21 1H NMR (400 MHz,
;
CDCl3) d 7.56 (s, 1H), 7.13 (s, 1H), 5.99 (s, 2H), 5.32 (dd,
J¼8.0, 3.2 Hz, 1H), 4.93 (dd, J¼8.8, 5.2 Hz, 1H), 4.15 (dd,
J¼8.8, 7.2 Hz, 1H), 3.99 (t, J¼7.6 Hz, 1H), 3.79 (t,
J¼7.6 Hz, 1H), 3.41 (dd, J¼4.8, 4.0 Hz, 1H), 2.10 (s, 3H),
1.56 (s, 9H), 1.47 (s, 3H), 1.18 (s, 3H), 0.83 (s, 9H), 0.07 (s,
3H), 0.04 (s, 3H); 13C NMR (75.5 MHz, CDCl3) d 170.12,
161.56, 152.60, 152.15, 147.43, 133.07, 123.37, 109.78,
109.18, 106.13, 101.96, 83.61, 77.57, 75.65, 75.07, 72.82,
53.50, 41.74, 27.97, 27.27, 25.64, 25.03, 21.22, 17.97,
24.44, 24.89; [a]2D5¼þ10.28 (c 1.9, CHCl3); high-
resolution MS (FABþ) m/e calcd for C30H43NO10Si:
References
1. (a) Pettit, G. R.; Gaddamidi, V.; Cragg, G. M.; Herald, D. L.;
Sawaga, Y. J. Chem. Soc., Chem. Commun. 1984, 1693.
(b) Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.;
Cragg, G. M.; Schmidt, J. M.; Boettner, F. E.; Williams, M.;
Sawaga, Y. J. Nat. Prod. 1986, 49, 995.
2. (a) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992, 114,
9694. (b) Hudlicky, T.; Olivo, H. F.; McKibben, B. J. Am.
Chem. Soc. 1994, 116, 5108. (c) Chida, N.; Ohtsuka, M.;
Ogawa, S. J. Org. Chem. 1993, 58, 4441. (d) McIntosh, M. C.;
Weinreb, S. M. J. Org. Chem. 1993, 58, 4823.
606.2718,
found:
606.2726.
Anal.
Calcd
for
C30H43NO10Si: C, 59.48; H, 7.15; N, 2.31. Found: C,
59.51; H, 7.19; N, 2.49.
3.1.7. (2S,3S,4R,4aR )-5-(t-Butoxycarbonyl)-2-((t-butyl-
dimethylsilyl)oxy)-3,4-(isopropylidenedioxy)-8,9-
(methylenedioxy)-2,3,4,4a-tetrahydrophenanthridone
16. To a solution of 15 (0.3 g, 0.5 mmol) in benzene (3 mL)
was added DBU (0.75 mL, 5 mmol). After being heated at
708C for 40 h, the reaction mixture was cooled, diluted with
ether (15 mL), and washed with aqueous NaHCO3 followed
by brine. Drying, solvent evaporation, and silica gel
chromatography (elution with 15% EtOAc/hexane) gave
0.26 g (97%) of 16 as a white solid: mp 58–598C; IR (neat)
3. For some other syntheses of (þ)-lycoricidine, see: (a) Keck,
G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc. 1999,
121, 5176. (b) Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron
Lett. 1991, 32, 4525. (c) Paulsen, H.; Stubbe, M. Tetrahedron
Lett. 1982, 23, 3171. Paulsen, H.; Stubbe, M. Liebigs Ann.
Chem. 1983, 535.
4. For precursors 5 and 9, see: Elango, S.; Wang, Y.-C.; Cheng,
C.-L.; Yan, T.-H. Tetrahedron Lett. 2002, 43, 3757.
5. The more hindered epoxide can usually be prepared by
bromohydrin formation and base-promoted closure, see:
Hanselaer, R.; Samson, R.; Vandewalle, M. Tetrahedron
1978, 34, 2393.
1
1756, 1667 cm21; H NMR (400 MHz, CDCl3) d 7.56 (s,
1H), 6.99 (s, 1H), 6.20 (t, J¼3.2 Hz, 1H), 6.01 (s, 2H), 4.78
(dt, J¼8.4, 2.8 Hz, 1H), 4.36 (dt, J¼5.6, 2.4 Hz, 1H), 4.12
(t, J¼8.8 Hz, 1H), 4.01 (dd, J¼8.0, 5.6 Hz, 1H), 1.58 (s,
9H), 1.46 (s, 3H), 1.29 (s, 3H), 0.93 (s, 9H), 0.14 (s, 6H); 13C
NMR (75.5 MHz, CDCl3) d 161.02, 153.61, 152.16, 148.59,
128.39, 127.15, 126.78, 120.62, 111.48, 107.88, 101.96,
100.89, 84.01, 79.86, 79.56, 73.55, 58.38, 27.69, 26.96,
25.87, 25.13, 18.22, 24.48, 25.00; [a ]2D5¼214.88 (c 0.7,
CH2Cl2); high-resolution MS m/e calcd for C28H39NO8Si:
545.2445, found: 545.2448.
6. During the preparation of this manuscript Hudlicky reported the
total synthesis of epi-7-deoxypancratistatin via Me2AlCl-
assisted cyclization of 12, which in turn was derived from the
base-assisted aza-Payne rearrangement of tosylaziridine:
Rinner, U.; Siengalewicz, P.; Hudlicky, T. Org. Lett. 2002, 4,
115.
7. Hamada, T.; Nishida, A.; Yonemitsu, O. J. Am. Chem. Soc.
1986, 108, 140.
8. Elango, S.; Yan, T.-H. Submitted for publication.