Enantioselective allyltitanation. Synthesis of (-)-slaframine

Article abstract of DOI:10.1055/s-2002-28505

An enantioselective synthesis of the indolizidine alkaloid (-)-slaframine from aldehyde 1 is reported. The stereogenic centers at C-1 and C-8a are introduced by an enantioselective allyltitanation and a Mitsunobu reaction. Reductive double cyclization of

Full text of DOI:10.1055/s-2002-28505

SPECIAL TOPIC
951
Enantioselective Allyltitanation. Synthesis of (–)-Slaframine
E
nantiosel
a
e
ctive Ally
n
ltitanation.
S
i
ynthes
n
is of (–)-Slaf
e
ramine Cossy,*a Catherine Willis,a Véronique Bellosta,a Laurent Saint-Jalmesb
a
Laboratoire de Chimie Organique associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
b
Rhodia RECHERCHES, Centre de Recherches de Lyon, 85 rue des frères Perret, 69192 Saint-Fons, France
Received 2 April 2002
derivative,9 stimulates muscarinic acetylcholine receptor
sites and may therefore have some potential in the treat-
ment of conditions arising through cholinergic dysfunc-
tions,10,11 and is a possible candidate for the alleviation of
Abstract: An enantioselective synthesis of the indolizidine alka-
loid (–)-slaframine from aldehyde 1 is reported. The stereogenic
centers at C-1 and C-8a are introduced by an enantioselective al-
lyltitanation and a Mitsunobu reaction. Reductive double cycliza-
tion of the acyclic compound (–)-10 affords the bicyclic skeleton of the symptoms of cystic fibrosis sufferers.12 The biological
(–)-slaframine.
activity of (–)-slaframine has stimulated investigations on
the structure,13 the biosynthesis,14 and the metabolism of
Key words: allyl complexes, titanium, Mitsunobu reaction, in-
this alkaloid, and several syntheses of racemic15 and
dolizidine, slaframine
enantiopure16 (–)-slaframine have been achieved.
The use of complex II applied to enantiopure aldehyde
Asymmetric C–C bond formation is an attractive synthet-
ic strategy, as the connectivity of a carbon framework and
its stereochemistry are established simultaneously. The
allylmetalation of aldehydes and ketones, leading to prod-
ucts with a maximum of two new stereocenters and versa-
tile functionality for further transformations, is an
important method for acyclic stereocontrol.1 Efficient
chirality transfer from allyl moieties has been obtained
with chiral allylboron reagents,2 allylstannanes2a,2b,3 and
allylsilanes.2a,4 Furthermore, a high enantioface differen-
tiation has been observed with allyltitanium reagents of
type I5 (Figure). In addition, complexes with alkoxy-sub-
stituted allyl groups such as II have been used to synthe-
size 1,2-diols with high diastereoselectivity and
enantioselectivity.5
(+)-1 should control the C-1 and C-8a stereogenic centers
present in (–)-slaframine. The synthesis of (–)-slaframine
is envisaged through bis-cyclization of the amino diol A,
which can be prepared from compound B by using a Mit-
sunobu reaction. This latter compound could be obtained
from the known aldehyde (+)-117 by using complex II
(Scheme 1).
OAc
NHBoc
OR
H
HO
1
8a
OH
6
N
NH2
H2N
(-)-slaframine
A
NBoc
NBoc
OR
O
O
OH
Ti
Ti
O
PMPO
Ph
Ph
Ph
Ph
O
OH
O
O
(+)-1
O
B
Ph
Ph
O
O
Ph
Ph
Scheme 1
O
O
When the (R,R)-titanium complex II was added to (+)-1 in
diethyl ether at –78 °C, the desired diol (+)-2 was isolated
in 69% yield, with excellent syn diastereoselectivity
(dr>95%). After protection of the hydroxy group of (+)-2
(TESCl, imidazole, CH2Cl2, 87%), the obtained silyl ether
(+)-3 was transformed to compounds 4 and 4 by hydro-
boration-oxidation (BH3, THF, 0 °C, then H2O2, NaOH).
The mixture of regioisomers 4 and 4 (resulting respec-
tively from anti-Markovnikov and Markovnikov addi-
tion)18 was directly treated with TBAF to produce (+)-5
and (+)-5 with an overall yield of 73% (5/5 = 83:17).19
Chromatographic separation of (+)-5 and (+)-5 led to (+)-
5 in 61% yield. At this stage, the synthetic plan called for
incorporation of the amino group by using a Mitsunobu
reaction. Therefore, compound (+)-5 was transformed to
(+)-6 in two steps. First, selective protection of the prima-
(R,R)-I
(R,R)-II
Figure
Here, we would like to report that complex II can be used
in the preparation of substituted indolizidine alkaloids
such as (–)-slaframine. (–)-Slaframine, a neurotoxic me-
tabolite isolated from the fungus Rhizoctonia leguminico-
la,6 is responsible for a disease characterized by excessive
salivation in ruminants foraging on fungus-infected red
clover hay.7,8 (–)-Slaframine, after oxidation to an active
Synthesis 2002, No. 7, 21 05 2002. Article Identifier:
1437-210X,E;2002,0,07,0951,0957,ftx,en;C01002SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

952
J. Cossy et al.
SPECIAL TOPIC
ry alcohol of (+)-5 as the tert-butyldiphenylsilyl ether transformed to N-Boc slaframine (–)-12 (Ac2O, Et3N,
(TBDPSCl, imidazole, CH2Cl2, 94%) afforded (+)-6, DMAP, THF, 92%), which was converted to (–)-slafra-
which was treated with diphenylphosphoryl azide mine in the presence of TMSI (Scheme 3).16g,21
(DPPA) (DIAD, PPh3, DPPA, THF, 0 °C r.t., 12 h) to
produce the corresponding azide (+)-7, inseparable from
DPPA (Scheme 2).
NBoc
OR
a)
O
(+)-7
OTBDPS
N3
NBoc
NBoc
OPMP
a)
O
O
(+)-8 R = H
b)
(+)-9 R = Bn
O
OR
1
(+)-2 R = H
b)
c)
(+)-3 R = TES
c)
OR1
NHBoc
OBn
H
N
d), e)
HO
OH
N3
R2HN
NBoc
OPMP
NBoc
OPMP
O
O
+
(+)-11 R1 = Bn, R2 = Boc
(-)-12 R1 = Ac, R2 = Boc
(-)-10
OH
f)
OR
d)
OR OH
g)
(-)-slaframine R1 = Ac, R2 = H
4
5
+
+
4' R = TES
5' R = H
Scheme 3 Reagents and conditions: a) CAN, CH3CN–H2O (4:1),
0 °C, 40% from (+)-6. b) NaH, BnBr, THF, 2 d, 90%. c) (i) TBAF,
THF. (ii) AcOH–THF–H2O, 5:1:1, 50 °C, 67%. d) MsCl, DMAP,
pyridine. e) H2, Pd/C, MeOH, Et3N (5 equiv), r.t. then reflux (4 h),
67%. f) (i) H2, Pd/C, MeOH–HCl. (ii) Ac2O, Et3N, DMAP, THF,
92%. g) TMSI, CDCl3, r.t., 79%.
NBoc
OPMP
e)
O
(+)-5
OTBDPS
R1
R2
By using complex II and a Mitsunobu reaction, the abso-
lute configurations of the stereogenic centers at C-1 and
C-8a of (–)-slaframine were easily controlled.
(+)-6 R1 = OH, R2 = H
(+)-7 R1 = H, R2 = N3
f)
Melting points were determined on a Kofler apparatus, and are un-
corrected. IR spectra were recorded as neat films (NaCl cell) and
KBr pellets or CHBr3 solutions for solids on a Perkin-Elmer 298. 1H
and 13C NMR spectra were respectively recorded on a Bruker AC
300 spectrometer at 300 MHz and 75 MHz. Unless otherwise spec-
ified, spectra were recorded in CDCl3, chemical shifts ( ) were ex-
pressed in ppm and coupling constant (J) in Hertz. Mass spectra
were obtained by GC/MS with electron impact ionization by using
a 5971 Hewlett- Packard instrument at 70 eV, only selected ions are
reported. HRMS and CIMS were performed at the Laboratoire de
Spectrochimie de l’Ecole Normale Supérieure in Paris. Optical ro-
tations were determined operating at the sodium D line on a Perkin
Elmer 241 MC polarimeter. Microanalyses were performed at the
Service de Microanalyse de l’Université Pierre et Marie Curie in
Paris. Unless otherwise specified, materials were purchased from
commercial suppliers and used without further purification. THF
and Et2O were distilled from sodium/benzophenone ketyl immedi-
ately before use. CH2Cl2 and Et3N were distilled from CaH2 under
argon. Moisture sensitive reactions were conducted in oven or
flame-dried glassware under an argon atmosphere. Flash chroma-
tography was carried out on Kieselgel 60 (230-400 mesh, Merck)
and analytical thin-layer chromatography was performed on Merck
precoated silica gel (60 F254). Cyclopentadienyl[(4R,trans)-2,2-
dimethyl- , , , -tetraphenyl-1,3-dioxolane-4,5-dimethanolato-
O,O ]titanium chloride5 and TMSI22 were prepared according to the
reported procedures.
Scheme 2 Reagents and conditions: a) (R,R)-II, Et2O, –78 °C, 69%.
b) TESCl, imidazole, CH2Cl2, 87%. c) (i) BH3 THF, THF. (ii) NaOH,
H2O2. d) TBAF, THF, 73% for the two steps, 5/5 = 83:17, 61% yield
of 5. e) TBDPSCl, imidazole, CH2Cl2, 94%. f) PPh3, DIAD, DPPA,
THF, 0 °C r.t., 12 h.
The azide (+)-7 was transformed to (+)-9 because a PMP
group can not be removed in the presence of an amino
group under oxidative conditions.20 This was achieved by
treating compound (+)-7 with cerium amonium nitrate
(CAN, CH3CN–H2O, 4:1, 0 °C, 40% from (+)-6). The re-
sulting alcohol (+)-8 was converted to the benzyl ether
(+)-9 (NaH, BnBr, THF) in 90% yield. Compound (+)-9
was deprotected and transformed to (–)-10 in 67% yield,
by using TBAF and heating the obtained product in a mix-
ture of AcOH–H2O–THF. After mesylation of the diol
(–)-10 (MsCl, DMAP, pyridine), hydrogenation of the re-
sulting bis-mesylate (Pd/C, H2, MeOH) in the presence of
Et3N led, after refluxing the mixture for 4 hours, to in-
dolizidine (+)-11 in 67% yield from (–)-10. A second hy-
drogenation was necessary to cleave the benzyl group (H2,
Pd/C, MeOH–HCl), and the resulting product was directly
Synthesis 2002, No. 7, 951–957 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Allyltitanation. Synthesis of (–)-Slaframine
953
(3R,4S)-1-[(4S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazoli-
din-4-yl]-4-(4-methoxyphenoxy)hex-5-en-3-ol (+)-2
Anal. Calcd for C29H49NSiO6: C, 65.02; H, 9.22; N, 2.61. Found C,
65.14; H, 9.15; N, 2.47.
To a soln of allyl p-methoxyphenyl ether (0.72 g, 4.35 mmol, 1.3
equiv) in anhyd THF (30 mL) at –78 °C, sec-BuLi (3.4 mL, 1.3M in
cyclohexane, 4.35 mmol, 1.3 equiv) was added dropwise. The or-
ange soln was stirred for 25 min at –78 °C, and was then added via
cannula to a suspension of cyclopentadienyl[(4R,trans)-2,2-dimeth-
yl- , , , -tetraphenyl-1,3-dioxolane-4,5-dimethanolato-O,O ]ti-
tanium chloride (3.3 g, 5.39 mmol, 1.6 equiv) in anhyd Et2O (10
mL) precooled to –78 °C. The red-brown mixture was stirred for 3
h at –78 °C, and a soln of 1 (0.87 g, 3.37 mmol, 1 equiv) in Et2O (10
mL) was added dropwise. The mixture was stirred for 4 h at –78 °C,
and the reaction was quenched by addition of a 45% aqueous NH4F
soln (42 mL). The mixture was stirred overnight at r.t. and then fil-
tered through Celite (Et2O, 400 mL). The organic layer was washed
with brine (380 mL), dried over MgSO4 and concentrated in vacuo.
The crude residue was diluted in pentane (150 mL), filtered to re-
move (R,R)-TADDOL and the filtrate was concentrated in vacuo. The
crude residue was purified on silica gel (petroleum ether–EtOAc,
9:1 7:3) to afford (+)-2 (0.98 g, 2.33 mmol, 69%) as a yellow oil;
Hydroboration of (+)-3
To a soln of (+)-3 (3.12 g, 5.83 mmol, 1 equiv) in THF (28 mL) at
0 °C, BH3 (17.5 mL, 1 M in THF, 17.5 mmol, 3 equiv) was added
dropwise. The soln was stirred for 2 h at 0 °C and for 2 h at r.t. The
reaction was then quenched by successive additions of H2O (5 mL),
a 3 M aq NaOH soln (6 mL) and a 30% aq H2O2 soln (6 mL). After
stirring for 2 h at r.t., the aq phase was extracted with Et2O (2 300
mL). The aq phase was acidified with a 10% aq HCl soln (pH 6–7)
and extracted with EtOAc (180 mL). The combined organic phases
were washed with brine (300 mL), dried over MgSO4 and concen-
trated in vacuo. The crude residue (5.83 g) was used without further
purification in the next step. An analytical sample of 4 can be ob-
tained by purification by flash chromatography (hexanes–EtOAc,
8:2).
(3S,4R)-6-[(4S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazoli-
din-4-yl]-3-(4-methoxyphenoxy)-4-(triethylsilyl)hexan-1-ol 4
Rf 0.15 (hexanes–EtOAc, 8:2)
20
Rf 0.20 (petroleum ether–EtOAc, 8:2); [ ]D +17.6 (c 0.9,
CHCl3).
IR (neat): 3400 (OH), 2950, 2880, 1690 (C=O), 1505, 1460, 1390,
1365, 1225, 1175, 1095 cm–1.
1H NMR (300 MHz, CDCl3): = 6.87–6.81 (m, 2 H), 6.81–6.75 (m,
2 H), 4.29 (br s, 1 H), 3.98–3.73 (m, 4 H), 3.74 (s, 3 H), 3.71–3.60
(m, 2 H), 2.79 (br s, 1 H), 1.99–1.82 (m, 2 H), 1.79–1.48 (m, 10 H),
1.45 (s, 9 H), 0.93 (t, 9 H, J = 7.7 Hz), 0.60 (q, 6 H, J = 7.7 Hz).
13C NMR (75.5 MHz, CDCl3), rotamers: = 153.8 (s), 152.2 (2
s), 116.7 (2 d), 114.6 (2 d), 93.6–93.1 (s), 80.0–79.4 (s), 78.5 (d),
73.6 (d), 66.8–66.5 (t), 58.7 (t), 57.4 (d), 55.5 (q), 31.7 (t), 30.6 (t),
29.1 (t), 28.3 (3 q), 27.3–26.5 (q), 24.5–23.0 (q), 6.7 (3 q), 4.9
(3 t).
IR (neat): 3450 (OH), 2980, 2930, 2870, 1790 (C=O), 1505, 1390,
1365, 1230, 1175, 1100, 1040 cm–1.
1H NMR (300 MHz, CDCl3): = 6.87–6.81 (m, 2 H), 6.81–6.75 (m,
2 H), 5.88 (m, 1 H), 5.38–5.22 (m, 2 H), 4.42 (m, 1 H), 4.03–3.65
(m, 4 H), 3.73 (s, 3 H), 3.22 (br s, 1 H), 2.51–1.64 (m, 4 H), 1.64–
1.50 (m, 6 H), 1.47 (s, 9 H).
13C NMR (75.5 MHz, CDCl3), rotamers: = 154.0 (s), 152.3–151.7
(2 s), 134.6–134.2 (d), 119.3–118.6 (t), 117.4 (2 d), 114.3 (2
d), 93.6–93.1 (s), 83.5 (d), 80.1–79.3 (s), 73.0 (d), 67.0 (t), 57.1 (d),
55.4 (q), 30.1–28.9 (2 t), 28.2 (3 q), 27.5–26.7 (q), 24.4–23.1
(q).
Desilylation of 4 + 4
EIMS (70 eV): m/z (%) = 242 (6), 213 (4), 186 (15), 142 (86), 126
To a soln of the crude mixture of 4 + 4 (5.83 g) in THF (55 mL) at
0 °C, was added TBAF (11.7 mL, 1 M in THF, 11.7 mmol, 2 equiv).
The soln was stirred overnight at r.t. and then concentrated in vacuo.
The crude residue was purified on silica gel [petroleum ether–
EtOAc, 6:4 EtOAc (100%)] to afford (+)-5 (1.56 g, 3.54 mmol,
61%) as a viscous yellow oil and (+)-5 (0.32 g, 0.72 mmol, 12%).
(18), 100 (11), 82 (8), 57 (100).
Anal. Calcd for C23H35NO6: C, 65.54; H, 8.37; N, 3.32. Found C,
65.57; H, 8.38; N, 3.17.
(3S,4R)-6-[(4S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazoli-
din-4-yl]-3-(4-methoxyphenoxy)-4-[(triethylsilyl)oxy]hex-1-ene
(+)-3
(3S,4R)-6-[(4S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazoli-
din-4-yl]-3-(4-methoxyphenoxy)hexan-1,4-diol (+)-5
Rf 0.23 (hexanes–EtOAc, 4:6); [ ]D20 +11.2 (c 1.1, CHCl3)
To a soln of (+)-2 (2.81 g, 6.68 mmol, 1 equiv) and imidazole (0.68
g, 10.0 mmol, 1.5 equiv) in CH2Cl2 (24 mL) at 0 °C, TESCl (1.68
mL, 1.51 g, 10.0 mmol, 1.5 equiv) was added dropwise. The reac-
tion mixture was stirred overnight at r.t., then diluted with CH2Cl2
(30 mL) and an aq sat. NaHCO3 soln (20 mL) was added. The aq
phase was extracted with CH2Cl2 (3 160 mL), the combined or-
ganic layers were dried over MgSO4 and concentrated in vacuo. The
crude residue was purified on silica gel (petroleum ether–EtOAc,
95:5 9:1) to afford (+)-3 (3.14 g, 5.88 mmol, 87%) as a yellow oil;
Rf 0.63 (hexanes–EtOAc, 8:2); [ ]D20 +26.5 (c 0.9, CHCl3).
IR (neat): 3400 (OH), 2970, 2930, 2870, 1680 (C=O), 1500, 1390,
1365, 1230, 1175, 1100, 1040 cm–1.
1H NMR (300 MHz, CDCl3): = 6.89–6.81 (m, 2 H), 6.81–6.74 (m,
2 H), 4.18 (m, 1 H), 3.99–3.76 (m, 5 H), 3.76–3.56 (m, 2 H), 3.73
(s, 3 H), 3.28 (br s, 1 H), 2.04–1.59 (m, 6 H), 1.59–1.46 (m, 6 H),
1.43 (s, 9 H).
13C NMR (75.5 MHz, CDCl3), rotamers: = 154.1 (s), 152.5–151.9
(2 s), 117.6 (2 d), 114.6 (2 d), 93.2 (s), 80.3 (d), 80.1–79.4 (s),
71.8 (d), 67.0 (t), 58.6 (t), 57.2–57.0 (d), 55.5 (q), 32.3–31.7 (t),
30.1–29.1 (2 t), 28.2 (3 q), 27.4–26.7 (q), 24.5–23.0 (q).
IR (neat): 2950, 2870, 1690 (C=O), 1505, 1390, 1365, 1225, 1175,
1100 cm–1.
1H NMR (300 MHz, CDCl3): = 6.87–6.76 (m, 4 H), 5.89 (m, 1 H),
5.33–5.22 (m, 2 H), 4.37 (br dd, 1 H, J = 6.6, J = 4.1 Hz), 3.95–3.86
(m, 2 H), 3.79–3.67 (m, 2 H), 3.75 (s, 3 H), 1.80–1.60 (m, 4 H),
1.60–1.51 (m, 6 H), 1.47 (s, 9 H), 0.98 (t, 9 H, J = 7.7 Hz), 0.66 (q,
6 H, J = 7.7 Hz).
13C NMR (75.5 MHz, CDCl3), rotamers: = 153.7 (s), 152.1 (2
s), 134.8 (d), 118.6 (t), 117.0 (2 d), 114.3 (2 d), 93.6–93.0 (s),
82.9 (d), 79.9–79.3 (s), 74.7 (d), 67.1–66.5 (t), 57.4 (d), 55.5 (q),
30.1–29.1 (t), 28.3 (3 q), 27.4–26.6 (q), 24.5 (t), 23.7–23.1 (q), 6.8
(3 q), 5.0 (3 t).
CIMS (CH4): m/z (%) = 440 (MH+, 80), 439 (16), 384 (9), 340
(100), 326 (44), 279 (11), 225 (7).
Anal. Calcd for C23H37NO7: C, 62.85; H, 8.49; N, 3.19. Found: C,
62.69; H, 8.69; N, 3.04.
(2S,3S,4R)-6-[(4S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazo-
lidin-4-yl]-3-(4-methoxyphenoxy)hexan-2,4-diol (+)-5
Rf 0.40 (hexanes–EtOAc, 4:6); [ ]D20 = +3.9 (c 1.0, CHCl3)
IR (neat): 3400 (OH), 2960, 2920, 2860, 1675 (C = O), 1500, 1450,
1380, 1220, 1170, 1080, 1030 cm–1.
Synthesis 2002, No. 7, 951–957 ISSN 0039-7881 © Thieme Stuttgart · New York

954
J. Cossy et al.
SPECIAL TOPIC
1H NMR (300 MHz, CDCl3): = 6.92–6.85 (m, 2 H), 6.85–6.76 (m,
2 H), 4.45 (br m, 1H), 4.25–3.80 (m, 4 H), 3.76 (s, 3 H), 3.80–3.57
(m, 2 H), 3.38 (br m, 1 H), 2.07–1.45 (m, 13 H), 1.47 (s, 9 H).
CIMS (CH4): m/z (%) = 703 (MH+, 27), 675 (MH+–N2, 18), 603
(58), 511 (15), 419 (17), 295 (79), 274 (30), 239 (78), 179 (93), 125
(100).
13C NMR (75.5 MHz, CDCl3), rotamers: = 154.8 (s), 153.0–152.4
(2 s), 117.1–116.8 (2 d), 114.6 (2 d), 93.3 (s), 84.4–83.1 (d),
80.7 (s), 73.1 (d), 70.8–67.2 (d), 67.5–66.9 (t), 57.0–56.3 (d), 55.6
(q), 30.1 (t), 29.6–29.4 (t), 28.3 (3 q), 27.5–26.6 (q), 24.3 (q),
19.4–18.9 (q).
Anal. Calcd for C39H54N4SiO6: C, 66.64; H, 7.74; N, 7.97. Found:
C, 66.42; H, 7.85; N, 7.68.
(3S,4S)-4-Azido-6-[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-
oxazolidin-4-yl]-1-[(tert-butyldiphenylsilyl)oxy]hexan-3-ol (+)-
8
Anal. Calcd for C23H37NO7: C, 62.85; H, 8.49; N, 3.19. Found: C,
62.73; H, 8.68; N, 3.11.
To the crude mixture of (+)-7 and DPPA (0.29 g) in CH3CN (8 mL)
at 0 °C, a soln of CAN (1.1 g, 2.0 mmol, 5 equiv) in H2O (2 mL)
was added dropwise. After 10 min at 0 °C, the reaction was diluted
with H2O (5 mL) and EtOAc (100 mL). The aq phase was extracted
with EtOAc (2 15 mL) and the combined organic phases were
washed with an aq sat. NaHCO3 soln (5 mL), an aq sat. Na2SO3 soln
(5 mL) and brine (5 mL), then were dried over MgSO4 and concen-
trated in vacuo. The crude residue was purified on silica gel (petro-
leum ether–EtOAc, 9:1 8:2) to afford (+)-8 [95 mg, 0.16 mmol,
40% from (+)-6] as a yellow oil; Rf 0.47 (petroleum ether–EtOAc,
8:2); [ ]D20 +17.3 (c 0.9, CHCl3).
(3R,4S)-1-[(4S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazoli-
din-4-yl]-6-[(tert-butyldiphenylsilyl)oxy]-4-(4-methoxyphe-
noxy)hexan-3-ol (+)-6
To a soln of (+)-5 (202 mg, 0.46 mmol, 1 equiv) and imidazole (41
mg, 0.60 mmol, 1 equiv) in CH2Cl2 (2 mL), at 0 °C, TBDPSCl (120
L, 127 mg, 0.46 mmol, 1 equiv) was added dropwise. The mixture
was stirred overnight at r.t., then the reaction was quenched by ad-
dition of an aq sat. NaHCO3 soln (2 mL). The aq phase was extract-
ed with CH2Cl2 (3 25 mL). The combined organic phases were
dried over MgSO4 and concentrated in vacuo. The crude residue
was purified on silica gel (petroleum ether–EtOAc, 9:1 6:4) to af-
ford (+)-6 (292 mg, 0.43 mmol, 94%) as a colorless oil; Rf 0.73 (pe-
troleum ether–EtOAc, 8:2); [ ]D20 +15.1 (c 0.9, CHCl3).
IR (neat): 3460 (OH), 2940, 2850, 2100 (N3), 1690 (C=O), 1390,
1250, 1170, 1100 cm–1.
1H NMR (300 MHz, CDCl3): = 7.71–7.65 (m, 4 H), 7.50–7.36 (m,
6 H), 4.03–3.80 (m, 5 H), 3.76 (d, 1 H, J = 7.4 Hz), 3.43–3.03 (m,
2 H), 1.99–1.81 (m, 2 H), 1.75–1.51 (m, 10 H), 1.49 (s, 9 H), 1.07
(s, 9 H).
IR (neat): 3440 (OH), 2940, 2860, 1785 (C=O), 1500, 1390, 1360,
1225, 1175, 1100 cm–1.
1H NMR (300 MHz, CDCl3): = 7.72–7.58 (m, 4 H), 7.48–7.29 (m,
6 H), 6.98–6.87 (m, 2 H), 6.85–6.77 (m, 2 H), 4.42 (m, 1 H), 4.07–
3.66 (m, 6 H), 3.77 (s, 3 H), 2.03–1.50 (m, 12 H), 1.49 (s, 9 H), 1.07
(s, 9 H).
13C NMR (75.5 MHz, CDCl3), rotamers: = 154.0 (s), 152.5–151.8
(2 s), 135.4 (2 d), 135.3 (2 d), 133.4 (2 s), 129.6 (2 d),
127.6 (2 d), 127.5 (2 d), 117.5 (2 d), 114.6 (2 d), 93.6–93.2
(s), 80.1 (s), 79.4 (d), 72.2–72.0 (d), 67.1–67.0 (t), 59.9 (t), 57.2 (d),
55.6 (q), 32.3–31.9 (t), 30.2 (t), 29.4–28.8 (t), 28.3 (3 q), 27.5 (q),
26.7 (3 q), 24.4–23.2 (q), 19.0 (s).
13C NMR (75.5 MHz, CDCl3), rotamers: = 152.5–151.7 (s),
135.4–135.3 (4 d), 132.7 (2 s), 129.8 (2 d), 127.7 (4 d), 93.7–
93.2 (s), 80.0–79.6 (s), 73.5–72.4 (d), 66.9 (t), 66.3–66.0 (d), 62.8
(t), 57.1–56.9 (d), 35.4 (t), 30.7–29.8 (t), 28.3 (3 q), 27.5 (q), 26.7
(3 q), 26.4 (t), 24.4–23.1 (q), 18.9 (s).
CIMS (CH4): m/z (%) = 597 (MH+, 43), 569 (MH+–N2, 10), 497
(100), 405 (17), 313 (21), 255 (34), 235 (96), 135 (73), 79 (91).
HRMS (CI, CH4): m/z calcd for C32H49N4SiO5 (MH+): 597.3472;
found: 597.3478.
Anal. Calcd for C39H55NSiO7: C, 69.10; H, 8.18; N, 2.07. Found: C,
69.10; H, 8.28; N, 1.97.
(3S,4S)-3-Azido-4-benzyloxy-1-[(4S)-3-(tert-butoxycarbonyl)-
2,2-dimethyloxazolidin-4-yl]-6-[(tert-butyldiphenylsi-
lyl)oxy]hexane (+)-9
(3S,4S)-3-Azido-1-[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-
oxazolidin-4-yl]-6-[(tert-butyldiphenylsilyl)oxy]-4-(4-methoxy-
phenoxy)hexane (+)-7
To a suspension of NaH (86 mg, 60% in oil, 2.15 mmol, 2 equiv) in
THF (2 mL), at 0 °C, a soln of (+)-8 (639 mg, 1.07 mmol, 1 equiv)
in THF (10 mL) was added via cannula. After 10 min at 0 °C, benzyl
bromide (191 L, 275 mg, 1.61 mmol, 1.5 equiv) was added drop-
wise. The reaction mixture was stirred for 2 days at r.t., then an aq
sat. NH4Cl soln (12 mL) was added. The aq phase was extracted
with EtOAc (3 50 mL) and the combined organic phases were
washed with H2O (10 mL), brine (10 mL), dried over MgSO4 and
concentrated in vacuo. The crude residue was purified on silica gel
(petroleum ether–EtOAc, 95:5) to afford (+)-9 (665 mg, 0.97 mmol,
90%) as a slightly yellow oil; Rf 0.47 (petroleum ether–EtOAc,
9:1); [ ]D20 +0.6 (c 1.2, CHCl3).
To a soln of (+)-6 (0.27 g, 0.40 mmol, 1 equiv) and PPh3 (0.14 g,
0.52 mmol, 1.3 equiv), at 0 °C, were added DIAD (0.10 mL, 0.10 g,
0.52 mmol, 1 equiv) and DPPA (0.11 mL, 0.14 g, 0.52 mmol, 1.3
equiv). The mixture was allowed to warm to r.t. overnight and then
concentrated in vacuo. The crude residue was purified on silica gel
(petroleum ether–EtOAc, 95:5 6:4) to afford a mixture of (+)-7
and DPPA (0.29 g) as a colorless oil which was directly engaged in
the next step; Rf 0.71 (petroleum ether–EtOAc, 8:2); [ ]D20 +3.3
(c 1.0, CHCl3)
IR (neat): 2940, 2850, 2100 (N3), 1690 (C=O), 1500, 1385, 1360,
1220, 1175, 1100 cm–1.
IR (neat): 2920, 2850, 2100 (N3), 1690 (C=O), 1450, 1385, 1360,
1250, 1170, 1100 cm–1.
1H NMR (300 MHz, CDCl3): = 7.72–7.66 (m, 2 H), 7.66–7.59 (m,
2 H), 7.50–7.33 (m, 6 H), 7.04–6.96 (m, 2 H), 6.87–6.80 (m, 2 H),
4.63 (br s, 1 H), 4.05–3.81 (m, 4 H), 3.79 (s, 3 H), 3.69 (m, 1 H),
3.36 (br m, 1 H), 2.04–1.87 (m, 2 H), 1.77–1.60 (m, 4 H), 1.60–1.50
(m, 6 H), 1.50 (s, 9 H), 1.10 (s, 9 H).
13C NMR (75.5 MHz, CDCl3), rotamers: = 154.2 (s), 152.7–151.7
(2 s), 135.4 (4 d), 133.3 (2 s), 129.7 (2 d), 127.7 (2 d),
127.6 (2 d), 116.9 (2 d), 114.6 (2 d), 93.7–93.2 (s), 79.9–79.6
(s), 77.6–77.4 (d), 66.9 (t), 63.9 (d), 59.7 (t), 57.0–56.8 (d), 55.6 (q),
34.1–33.8 (t), 31.0–30.1 (t), 28.3 (3 q), 27.5 (q), 26.8 (3 q), 26.6
(t), 24.4–23.1 (q), 19.1 (s).
1H NMR (300 MHz, CDCl3): = 7.71–7.64 (m, 4H), 7.49–7.35 (m,
6 H), 7.35–7.26 (m, 5 H), 4.61 (br s, 2 H), 4.03–3.72 (m, 5 H), 3.69
(d, 1 H, J = 7.7 Hz), 3.27 (m, 1 H), 1.97–1.76 (m, 2 H), 1.68–1.51
(m, 10 H), 1.50 (s, 9 H), 1.09 (s, 9 H).
13C NMR (75.5 MHz, CDCl3), rotamers: = 152.4–151.9 (s), 138.1
(s), 135.4 (4 d), 133.4 (2 s), 129.6 (2 d), 128.2 (2 d), 127.7
(3 d), 127.6 (4 d), 93.7–93.2 (s), 79.9–79.5 (s), 78.1 (d), 72.9 (t),
66.9 (t), 64.6 (d), 60.0 (t), 57.1 (d), 33.8 (t), 30.9–30.2 (t), 28.3 (3
q), 27.5 (q), 26.8 (3 q), 26.6 (t), 24.4–23.1 (q), 19.1 (s).
Synthesis 2002, No. 7, 951–957 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Allyltitanation. Synthesis of (–)-Slaframine
955
Anal. Calcd for C39H54N4SiO5: C, 68.19; H, 7.92; N, 8.16. Found:
C, 68.13; H, 7.97; N, 7.99.
13C NMR (75.5 MHz, CDCl3): = 155.3 (s), 138.4 (s), 128.2 (2
d), 127.4 (2 d), 127.3 (d), 78.8 (d), 78.7 (s), 70.9 (t), 68.5 (d), 57.7
(t), 53.0 (t), 44.8 (d), 29.9 (t), 28.7 (t), 28.3 (3 q), 20.5 (t).
(2S,5S,6S)-5-Azido-6-benzyloxy-2-[(tert-butoxycarbonyl)ami-
no]octan-1,8-diol (–)-10
EIMS (70 eV): m/z (%) = 346 (M, 1), 289 (M–tBu, 2), 273 (M–
tBuO, 27), 255 (M–Bn, 30), 240 (36), 229 (85), 199 (100), 181 (68),
166 (28), 155 (61), 138 (50), 91 (55).
HRMS (CI, CH4): m/z calcd for C20H31N2O3 (MH+): 347.2335;
To a soln of (+)-9 (738 mg, 1.08 mmol, 1 equiv) in THF (8 mL) at
0 °C, TBAF (2.15 mL, 1 M in THF, 2.15 mmol, 2 equiv) was added
dropwise. The mixture was stirred for 4 h at r.t. and concentrated in
vacuo. The crude residue was dissolved in a mixture of AcOH–
THF–H2O (5:1:1, 16.8 mL). The soln was heated at 55–60 °C for 12
h, concentrated in vacuo and diluted with H2O (5 mL) and EtOAc
(75 mL). The aq phase was extracted with EtOAc (2 25 mL), the
combined organic phases were washed with brine (10 mL), dried
over MgSO4 and concentrated in vacuo. The crude residue was pu-
rified on silica gel [petroleum ether–EtOAc 3:7 EtOAc (100%)] to
afford (–)-10 (295 mg, 0.72 mmol, 67%) as a white oil; Rf 0.28 (pe-
troleum ether–EtOAc, 2:8); [ ]D20 –31.4 (c 1.1, CHCl3).
found: 347.2339.
(1S,6S,8aS)-1-Acetoxy-6-[(tert-butoxycarbonyl)amino]octahy-
droindolizidine (-)-12
A mixture of (+)-11 (90 mg, 0.26 mmol, 1 equiv) and 10% Pd/C (28
mg, 0.03 mmol, 0.1 equiv) in MeOH–HCl (50:1, 5.1 mL) was
stirred under H2 (1 atm) for 1 h, and then filtered through Celite
(EtOAc, 100 mL). The filtrate was washed with an aq sat. NaHCO3
soln (3 10 mL), dried over MgSO4 and concentrated in vacuo. The
resulting yellow crystals (ca. 70 mg) were dissolved in THF (12
mL) at 0 °C, Et3N (0.18 mL, 0.13 g, 1.3 mmol, 5 equiv), Ac2O (49
mL, 53 mg, 0.52 mmol, 2 equiv) and a catalytic amount of DMAP
were successively added. After 2 h of stirring under Ar at r.t., the
mixture was concentrated in vacuo. The crude residue was purified
on silica gel (CH2Cl2–MeOH–EtOAc, 96.2:2) to afford (–)-12 (71
mg, 0.24 mmol, 92%) as a yellow oil; Rf 0.89 (CH2Cl2–MeOH–
IR (neat): 3460 (OH), 2920, 2100 (N3), 1680, 1510, 1360, 1250,
1165, 1050 cm–1.
1H NMR (300 MHz, CDCl3): = 7.39–7.28 (m, 5 H), 4.81 (br d,
1 H, J = 8.5 Hz), 4.64 (s, 2 H), 3.74 (t, 2H, J = 5.9 Hz), 3.71–3.59
(m, 2 H), 3.59–3.49 (m, 2 H), 3.45 (m, 1 H), 2.49 (br s, 2 H), 1.90–
1.79 (m, 2 H), 1.71–1.52 (m, 4 H), 1.44 (s, 9 H).
13C NMR (75.5 MHz, CDCl3): = 156.3 (s), 137.8 (s), 128.4 (2
d), 127.9 (2 d), 127.8 (d), 79.7 (s), 79.1 (d), 72.8 (t), 65.4 (t), 63.8
(d), 59.1 (t), 51.6 (d), 33.2 (t), 28.2 (3 q), 28.1 (t), 26.6 (t).
20
EtOAc, 6:2:2); [ ]D –16.2 (c 1.1, CHCl3).
IR (neat): 3440 (NH), 2940, 2795, 1770, 1720 (C=O), 1490, 1365,
1240, 1165 cm–1.
CIMS (CH4): m/z (%) = 409 (MH+, 19), 381 (MH+–N2, 9), 353 (30),
1H NMR (300 MHz, CDCl3): = 5.37 (br d, 1 H, J = 8.5 Hz), 5.22
(m, 1 H), 3.88 (m, 1 H), 3.11–2.97 (m, 2 H), 2.25 (m, 1 H), 2.13 (dd,
1 H, J = 11.4, J = 2.2 Hz), 2.08 (s, 3 H), 2.05–1.50 (m, 7 H), 1.45 (s,
9 H).
13C NMR (75.5 MHz, CDCl3): = 170.7 (s), 155.1 (s), 78.8 (s), 74.7
(d), 67.2 (d), 57.7 (t), 52.9 (t), 44.8 (d), 30.4 (t), 28.5 (t), 28.3 (3 q),
21.0 (q), 20.4 (t).
325 (26), 309 (MH+–NBoc, 100), 264 (24), 202 (3), 107 (7).
HRMS (CI, CH4): m/z calcd for C20H33N4O5 (MH+): 409.2451;
found: 409.2453.
Formation of the indolizidine ring
To a soln of (–)-10 (184 mg, 0.45 mmol, 1 equiv) in pyridine (2
mL), at 0 °C, were added DMAP (17 mg, 0.14 mmol, 0.3 equiv) and
MsCl (105 L, 155 mg, 1.35 mmol, 3 equiv). After 2 h at 0 °C, the
mixture was diluted with Et2O (50 mL), washed with H2O (10 mL),
and with an aq sat. CuSO4 soln (2 10 mL) and then with H2O (7
mL). The organic phase was dried over MgSO4 and concentrated in
vacuo. The crude dimesylate was diluted in MeOH (5 mL). Et3N
(315 L, 228 mg, 2.26 mmol, 5 equiv) and 10% Pd/C (24 mg, 0.02
mmol, 0.05 equiv) were added. The mixture was stirred under H2 (1
atm) overnight, then refluxed under Ar for 4 h and filtered through
Celite (EtOAc, 90 mL). The resulting filtrate was concentrated in
vacuo and the crude residue was purified on silica gel (CH2Cl2–
MeOH–EtOAc, 96:2:2) to afford (+)-11 (104 mg, 0.30 mmol, 67%).
EIMS (70 eV): m/z (%) = 298 (M, 1), 255 (M–Ac, 1), 238 (4), 225
(M–tBuO, 18), 181 (100), 164 (8), 155 (9), 138 (6), 121 (67), 95
(12).
HRMS (CI, CH4): m/z Calcd for C15H27N2O4 (MH+): 299.1971;
found: 299.1967.
(1S,6S,8aS)-1-Acetoxy-6-aminooctahydroindolizidine,
(–)-Slaframine
To a soln of (–)-12 (33 mg, 0.11 mmol, 1 equiv) in CDCl3 (1 mL)
was added TMSI (32 L, 44 mg, 0.22 mmol, 2 equiv). After 10 min
at r.t., the reaction was quenched by addition of MeOH (2 mL) and
the soln was concentrated in vacuo. The crude residue was purified
on alumina (CH2Cl2–MeOH, 97:3) to afford (–)-slaframine (17.3
mg, 0.09 mmol, 79%) as a pale yellow oil. 1H NMR spectrum was
in accordance with those kindly provided by Prof. W. H. Pearson
and Dr. A. E. Greene. The other physical and spectral data are iden-
tical to those previously reported;16c,n Rf 0.23 (CH2Cl2–MeOH–
NH4OH, 120:20:1) on an alumina plate; [ ]D20 –45.2 (c 1.0, CHCl3)
(2S,5S,6S)-5-Azido-6-benzyloxy-2-[(tert-butoxycarbonyl)ami-
no]-1,8-[(methylsulfonyl)oxy]octane
Rf 0.71 (petroleum ether–EtOAc, 2:8)
1H NMR (300 MHz, CD3OD): = 7.42–7.24 (m, 5 H), 4.87 (br s, 1
H), 4.63 (br s, 2 H), 4.35 (t, 2 H, J = 6.1 Hz), 4.23–4.11 (m, 2 H),
3.82 (m, 1 H), 3.69 (m, 1 H), 3.42 (m, 1 H), 3.10 (s, 3 H), 3.07 (s, 3
H), 2.13–1.90 (m, 2 H), 1.75–1.52 (m, 4 H), 1.42 (s, 9 H).
20
{lit.16a [ ]D –38 (c 0.16, CHCl3)}.
IR (neat): 3350, 2930, 2780, 1730, 1570, 1440, 1375, 1250, 1110
cm–1.
1H NMR (300 MHz, CDCl3): = 5.22 (ddd, 1 H, J = 7.4, J = 4.8,
J = 2.2 Hz), 3.13–2.99 (m, 3 H), 2.24 (m, 1 H), 2.14 (dd, 1 H,
J = 11.0, J = 2.2 Hz), 2.08 (s, 3 H), 2.01 (m, 1 H), 1.89–1.80 (m, 2
H), 1.84 (br s, 2 H), 1.80–1.63 (m, 2 H), 1.61–1.46 (m, 2 H).
13C NMR (75.5 MHz, CDCl3): = 170.8 (s), 74.9 (d), 67.5 (d), 60.0
(t), 53.0 (t), 45.6 (d), 31.3 (t), 30.4 (t), 21.0 (q), 19.6 (t).
EIMS (70 eV): m/z (%) = 198 (M+, 8), 180 (3), 155 (74), 142 (65),
138 (100), 122 (20), 111 (28), 100 (24), 96 (32), 94 (34), 82 (23), 70
(46), 56 (11).
(1S,6S,8aS)-6-[(tert-Butoxycarbonyl)amino]-1-benzyloxyoc-
tahydroindolizidine (+)-11
Rf 0.74 (CH2Cl2–MeOH–EtOAc, 6:2:2); [ ]D20 +11.4 (c 1.2,
CHCl3).
IR (neat): 3430 (NH), 2920, 2850, 2780, 1705 (C=O), 1490, 1360,
1240, 1165, 1120, 1090 cm–1.
1H NMR (300 MHz, CDCl3): = 7.35–7.24 (m, 5 H), 5.79 (br d,
1H, J = 8.5 Hz), 4.60 (d, AB system, 1 H, J = 12.1 Hz), 4.43 (d, AB
system, 1 H, J = 12.1 Hz), 3.96–3.82 (m, 2 H), 3.21–3.03 (m, 2 H),
2.16 (m, 1H), 2.11–1.78 (m, 7 H), 1.65 (m, 1 H), 1.43 (s, 9 H).
Synthesis 2002, No. 7, 951–957 ISSN 0039-7881 © Thieme Stuttgart · New York

956
J. Cossy et al.
SPECIAL TOPIC
(14) (a) Guengerich, F. P.; Broquist, H. P. Bioorganic Chemistry,
Vol. 2; van Tamelen, E. E., Ed.; Academic Press: New York,
1978, Chap. 4. (b) Clevenstine, E. C.; Broquist, H. P.;
Harris, T. M. Biochemistry 1979, 18, 3659. (c) Clevenstine,
E. C.; Walter, P.; Harris, T. M.; Broquist, H. P. Biochemistry
1979, 18, 3663. (d) Schneider, M. J.; Ungemach, F. S.;
Broquist, H. P.; Harris, T. M. J. Am. Chem. Soc. 1982, 104,
6863. (e) Harris, C. M.; Schneider, M. J.; Ungemach, F. S.;
Hill, J. E.; Harris, T. M. J. Am. Chem. Soc. 1988, 110, 940.
(15) (a) Cartwright, D.; Gardiner, R. A.; Rinehart, K. L. Jr. J. Am.
Chem. Soc. 1970, 92, 7615. (b) Gensler, W. J.; Hu, M. W. J.
Org. Chem. 1973, 38, 3848. (c) Gobao, R. A.; Bremmer, M.
L.; Weinreb, S. M. J. Am. Chem. Soc. 1982, 104, 7065.
(d) Schneider, M. J.; Harris, T. M. J. Org. Chem. 1984, 49,
3681. (e) Dartmann, M.; Flitsch, W.; Krebs, B.; Pandl, K.;
Westfechtel, A. Liebigs Ann. Chem. 1988, 695. (f) Shono,
T.; Matsumura, Y.; Katoh, S.; Takeuchi, K.; Sasaki, K.;
Kamada, T.; Shimizu, R. J. Am. Chem. Soc. 1990, 112,
2368. (g) Wasserman, H. H.; Vu, C. B. Tetrahedron Lett.
1994, 35, 9779.
Acknowledgements
One of us (C. W.) thanks Rhodia for a grant. We are indebted to Pr.
W. H. Pearson (University of Michigan) and Dr. A. E. Greene (Uni-
versity of Grenoble) for spectra of (–)-slaframine and N-acetyl-
slaframine.
References
(1) (a) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1982, 21,
555. (b) Yamamoto, Y.; Maruyama, K. Heterocycles 1982,
18, 357. (c) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl.
1987, 26, 489. (d) Hoppe, D. Angew. Chem., Int. Ed. Engl.
1984, 23, 932. (e) Mulzer, J.; Kattner, L.; Strecker, A. R.;
Schröder, C.; Buschmann, J.; Lehmann, C.; Luger, P. J. Am.
Chem. Soc. 1991, 113, 4218.
(2) For reviews see: (a) Yamamoto, Y.; Asao, N. Chem. Rev.
1993, 93, 2207. (b) Roush, W. R. In Comprehensive
Organic Chemistry, Vol. 2; Trost, B. M., Ed.; Pergamon
Press: Oxford, 1991, 1–53. (c) Roush, W. R. In Houben-
Weyl: Methods of Organic Chemistry, Vol. E21b;
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995, 1410–1486.
(3) For reviews see: (a) Marshall, J. A. Chem. Rev. 1996, 96,
31. (b) Thomas, E. J. In Houben-Weyl: Methods of Organic
Chemistry, Vol. E21b; Helmchen, G.; Hoffmann, R. W.;
Mulzer, J.; Schaumann, E., Eds.; Thieme: Stuttgart, 1995,
1508–1540.
(4) For a review see: Thomas, E. J. In Houben-Weyl: Methods of
Chemistry, Vol. E21b; Helmchen, G.; Hoffmann, R. W.;
Mulzer, J.; Schaumann, E., Eds.; Thieme: Stuttgart, 1995,
1491–1507.
(16) (a) Choi, J.-R.; Han, S.; Cha, J. K. Tetrahedron Lett. 1991,
32, 6469. (b) Pearson, W. H.; Bergmeier, S. C. J. Org.
Chem. 1991, 56, 1976. (c) Pearson, W. H.; Bergmeier, S. C.;
Williams, J. P. J. Org. Chem. 1992, 57, 3977. (d) Knapp,
S.; Gibson, F. S. J. Org. Chem. 1992, 57, 4802. (e) Sibi, M.
P.; Christensen, J. W.; Li, B.; Renhowe, P. A. J. Org. Chem.
1992, 57, 4329. (f) Knight, D. W.; Sibley, A. W.
Tetrahedron Lett. 1993, 34, 6607. (g) Hua, D. H.; Park, J.-
G.; Katsuhira, T.; Bharathi, S. N. J. Org. Chem. 1993, 58,
2144. (h) Gmeiner, P.; Junge, D. J. Org. Chem. 1995, 60,
3910. (i) Szeto, P.; Lathbury, D. C.; Gallagher, T.
Tetrahedron Lett. 1995, 36, 6957. (j) Knight, D. W.; Sibley,
A. W. J. Chem. Soc., Perkin Trans. 1 1997, 2179. (k) Sibi,
M. P.; Christensen, J. W. J. Org. Chem. 1999, 64, 6434.
(l) Comins, D. L.; Fulp, A. B. Org. Lett. 1999, 1, 1941.
(m) Carretero, J. C.; Arrayas, R. G. Synlett 1999, 49.
(n) Pourashraf, M.; Delair, P.; Rasmussen, M. O.; Greene, A.
E. J. Org. Chem. 2000, 65, 6966.
(5) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-
Streit, P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114,
2321.
(6) (a) Rainey, D. P.; Smalley, E. B.; Crump, M. H.; Strong, F.
M. Nature (London) 1965, 205, 203. (b) Aust, S. D.;
Broquist, H. P. Nature (London) 1965, 205, 203.
(7) (a) Byers, J. H.; Broquist, H. P. J. Dairy. Sci. 1960, 43, 873.
(b) Byers, J. H.; Broquist, H. P. J. Dairy. Sci. 1961, 44, 1179.
(8) For general reviews see: (a) Broquist, H. P. Annu. Rev. Nutr.
1985, 5, 391–409. (b) Howard, A. S.; Michael, J. P. In The
Alkaloids, Vol. 28; Brossi, A., Ed.; Academic Press: New
York, 1986, 183–308. (c) Elbein, A. D.; Molyneux, R. J. In
Alkaloids: Chemical and Biological Perspectives, Vol. 5;
Pelletier, S. W., Ed.; Wiley: New York, 1987, 1–54.
(d) Broquist, H. P.; Snyder, J. J. In Microbial Toxins, Vol. 7;
Ajl, S. J.; Kadis, S.; Montie, T. C., Eds.; Academic Press:
New York, 1971, 317. (e) Molyneux, R. J.; James, L. F. In
Mycotoxins and Phytoalexins; Sarma, R. P.; Salunkhe, D.
K., Eds.; CRC Press: Boca Raton FL, 1991, 637–656.
(9) Guengerich, F. P.; Aust, S. D. Mol. Pharmacol. 1977, 13,
185.
(17) Feng, X.; Edstrom, E. Tetrahedron: Asymmetry 1999, 10,
99.
(18) For a study on the hydroboration of homoallylic alcohols
see: Jung, M. E.; Karama, U. Tetrahedron Lett. 1999, 40,
7907.
(19) The direct hydroboration of alcohol (+)-2 without silylation
of the homoallylic alcohol function (BH3 THF then H2O2,
NaOH) led to the formation of 5 and 5 with an overall yield
of 50% and a 60/40 ratio of 5/5 . See ref.18
(20) Compound (+)-11 was synthesized according to a strategy
similar to the one used for obtaining (+)-11 However the
deprotection of the PMP group by using CAN produced the
decomposition of 11 .
(21) (–)-Slaframine was transformed into the more stable N-
acetylslaframine (Ac2O pyridine): [ ]D20 –13.3 (c 0.8,
EtOH) {lit.16c [ ]D20 –11.2 (c 1.45, EtOH)}; mp 138–140 °C
(10) General review: Croom, W. J.; Hagler, W. M.; Froetschel,
M. A.; Johnson, A. D. J. Anim. Sci. 1995, 73, 1499.
(11) (a) Froetschel, M. A.; Amos, H. E.; Evans, J. J.; Croom, W.
J. Jr.; Hagler, W. M. Jr. J. Anim. Sci. 1989, 76, 827.
(b) Jacques, K.; Harmon, D. L.; Cromm, W. J. Jr.; Hagler,
W. M. Jr. J. Dairy. Sci. 1989, 72, 443.
OH
OPMP
H
N
H
CAN
X
CH3CN/H2O
N
BocHN
BocHN
(12) (a) Aust, S. D. Biochem. Pharmacol. 1969, 18, 929.
(b) Aust, S. D. Biochem. Pharmacol. 1970, 19, 427.
(13) Gardiner, R. A.; Rinehart, K. L. Jr.; Snyder, J. J.; Broquist,
H. P. J. Am. Chem. Soc. 1968, 90, 5639; and references cited
therein.
(+)-11'
Scheme 4
(lit.16c mp 139–141 °C); IR (CHCl3): 3300, 1730, 1650,
1545, 1440 cm–1; 1H NMR (CDCl3, 300 MHz) = 6.62 (br
m, 1 H), 5.25 (ddd, 1 H, J = 7.4, 4.8, 2.2 Hz), 4.21 (dt, 1 H
J = 8.5, 2.9 Hz), 3.14–3.02 (m, 2 H), 2.29 (m, 1 H), 2.19 (dd,
Synthesis 2002, No. 7, 951–957 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Allyltitanation. Synthesis of (–)-Slaframine
957
1 H, J = 11.4, 2.6 Hz), 2.08 (s, 3 H), 2.00 (s, 3 H), 2.07-1.87
21.0 (q), 20.3 (t). The physical and spectral data are identical
to those reported.16c,n
(22) Groutas, W. C.; Felker, D. Synthesis 1980, 861.
(m, 2 H), 1.81 (m, 1 H), 1.65–1.56 (m, 2 H), 1.48 (m, 1 H);
13C NMR (CDCl3, 75 MHz) = 170.5 (s), 169.3 (s), 74.4 (d),
67.4 (d), 57.4 (t), 52.9 (t), 43.6 (d), 30.3 (t), 28.0 (t), 23.2 (q),
Synthesis 2002, No. 7, 951–957 ISSN 0039-7881 © Thieme Stuttgart · New York