Copper mediated scalemic organolithium reagents in alkaloid syntheses

Article abstract of DOI:10.1016/j.tet.2005.01.094

Scalemic 2-pyrrolidinylcuprates generated via asymmetric deprotonation of N-Boc-pyrrolidine followed by treatment with THF soluble CuCN·2LiCl react with ω-functionalized vinyl halides to afford 2-alkenyl-N-Boc- pyrrolidines. N-Boc deprotection and cyclization via intramolecular N-alkylation generates the pyrrolizidine or indolizidine skeletons. Subsequent functional group manipulation affords enantioenriched (+)-heliotridane, (+)-isoretronecanol, a formal synthesis of (+)-laburnine, (+)-(R)-2,3,5,7a- tetrahydro-1H-pyrrolizine, (R)-1,2,3,5,6,8a-hexahydroindolizine, (+)-ent-δ-coniceine, (+)-tashiromine and (+)-5-epitashiromine.

Full text of DOI:10.1016/j.tet.2005.01.094

Tetrahedron 61 (2005) 3221–3230
Copper mediated scalemic organolithium reagents in
alkaloid syntheses
*
R. Karl Dieter, Ningyi Chen and Rhett T. Watson
Hunter Laboratory, Department of Chemistry, Clemson University, Clemson, SC 29634-0973, USA
Received 1 October 2004; revised 15 November 2004; accepted 21 January 2005
Dedicated to Professor Amos B. Smith, III on the occasion of his 60th birthday
Abstract—Scalemic 2-pyrrolidinylcuprates generated via asymmetric deprotonation of N-Boc-pyrrolidine followed by treatment with THF
soluble CuCN$2LiCl react with u-functionalized vinyl halides to afford 2-alkenyl-N-Boc-pyrrolidines. N-Boc deprotection and cyclization
via intramolecular N-alkylation generates the pyrrolizidine or indolizidine skeletons. Subsequent functional group manipulation affords
enantioenriched (C)-heliotridane, (C)-isoretronecanol, a formal synthesis of (C)-laburnine, (C)-(R)-2,3,5,7a-tetrahydro-1H-pyrrolizine,
(R)-1,2,3,5,6,8a-hexahydroindolizine, (C)-ent-d-coniceine, (C)-tashiromine and (C)-5-epitashiromine.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
indolizidines 6–8 have all been synthesized, while pyrroli-
zine 415 and indolizine 516 have only been prepared in
racemic form. Of the nearly 50 asymmetric syntheses
involving (K)-heliotridane,5,7e–f,h (C)-ent-heliotridane
(1),6 (K)-isoretronecanol,7 (C)-isoretronecanol (2),8 (C)-
laburnine (3)7a–c,n,9 and its enantiomer (K)-trachelantha-
midine,7d,i–k,m,10 (K)-coniceine,11 (C)-coniceine,12 (C)-
tashiromine (7),7b,13,14b (K)-tashiromine14 and (C)-5-
epitashiromine (8) [or its (K) isomer]13b,17 all but six have
involved the use of chiral auxiliaries11d,f–h,12d or molecules
from the chiral pool [e.g., (S)-proline,7d,f,h,i,k,m,11a,c,e (S)-a-
methylbenzylamine,7b,g a-D-glucosamine,7l (R)-phenyl-
glycinol,12d L-glutamic acid,14a (C)-carvone,5 (S)-pyro-
glutaminol,11b (S)-ethyl pyroglutamate,7e and (K)-4-
hydroxy-L-proline7n] containing one or more of the stereo-
centers to be incorporated into the target molecules. The
reported asymmetric syntheses involving enzymatic kinetic
resolution,12a or asymmetric transformations [e.g.,
dihydroxylation,12b Heck,12b catalytic desymmetrization,7c
and iminium ion cyclization9b] are also limited by scale,
length of the synthetic route, or the enantioselectivity
achieved. An elegant asymmetric catalyzed conjugate
addition of a pyrrole moiety intramolecularly to a Michael
acceptor was recently employed in an asymmetric synthesis
of (K)-tashiromine.14a
The pyrrolizidine (1-azabicyclo[3,3]octanes)1 and indolizi-
dine (1-azabicyclo[4,3]nonanes)2 alkaloids are found in a
wide variety of plants. Pyrrolizidine alkaloids are generally
found in the genus Senecio (O1000 species) of the
Compositae family and often consist of esters between an
alkanolamine (i.e., necine base) and a necic acid.1d
Although the pyrrolizidine alkaloids function as insect
anti-feedents and insecticides, some insects sequester them
for biological purposes.1b–c Both series of alkaloids display
toxicity to mammals.3–4 Plants containing pyrrolizidine
alkaloids are the most common source of animal poisoning
and pyrrolizidine macrocyclic diesters exhibit the more
potent genotoxicity and tumorigenicity.3a The polyhydroxy
indolizidine alkaloids swainsonine and castanospermine
were shown to be agents of toxicity to grazing animals and
the isolation of these causative agents led to the discovery of
the aza sugars as glycosidase inhibitors.4b
Simple members of the two classes have been the subject of
frequent total syntheses often serving as a testing ground for
new synthetic methodology.1a,d,2 Asymmetric syntheses
abound5–14 and enantioenriched pyrrolizidines 1–3 and
Keywords: Alkaloid syntheses; a-(N-Carbamoyl)alkylcuprates; Stereo-
genic cuprates; (C)-Heliotridane; (C)-Isoretronecanol; (C)-(R)-2,3,5,7a-
Tetrahydro-1H-pyrrolizine; (R)-1,2,3,5,6,8a-hexahydroindolizine; (C)-
ent-d-Coniceine; (C)-Tashiromine; (C)-5-Epitashiromine.
* Corresponding author. Tel.: C1 864 656 5025; fax.: C1 864 656 6613;
e-mail: dieterr@clemson.edu
A potentially rapid strategy for the synthesis of enantioen-
riched pyrrolizidines 1–2, as well as indolizidines 7 and 8
(Fig. 1), could involve stereo- and regiocontrolled func-
tional group manipulation of exo-cyclic alkenes 11a and
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.094

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R. K. Dieter et al. / Tetrahedron 61 (2005) 3221–3230
2. Results and discussion
The requisite 1- or 2-halo-1-alkenes containing u-function-
alization were readily prepared from commercially avail-
able 1-alkynes (Scheme 2). Conversion of alcohol 14a into
the alkyl chloride20 followed by addition of in situ generated
HI21 to the chloro alkyne afforded vinyl iodide 10a. Similar
addition of HI to commercially available 5-chloro-1-
pentyne (14b) afforded vinyl iodide 10b. cis-Vinyl iodide
12a was prepared by iodination of alkyne 14a,22 followed
by conversion of the alcohol to the alkyl bromide23 and
diimide reduction24 of the triple bond. Silylation of alkynyl
alcohol 14c followed by 1-alkynyl iodination and diimide
reduction gave vinyl iodide 12b in good overall yield.25
Coupling of these readily prepared u-functionalized vinyl
iodides with metallated N-Boc-pyrrolidine provides all of
the carbon atoms of the alkaloid skeletons (Scheme 3).
Figure 1. Pyrrolizidine and indolizidine synthetic targets.
11b, respectively, which in turn could be constructed by
sequential vinylation of cuprate 9, generated from the
scalemic stereogenic a-lithio carbamate,18 followed by ring
annulation (Scheme 1).19 Extension of the strategy to
pyrrolizine 4, indolizine 5, and indolizidine 6 would utilize
1-halo-1-alkenes 12a–b with good leaving groups in the 3-
or 4-positions for subsequent cyclization onto the N-atom.
Variations on the strategy involving vinyl halides 13a–b
require subsequent radical cyclization of N-(2-iodo-1-
oxoethyl)-2-vinylpyrrolidine to afford, after functional
group manipulation, pyrrolizidine 3. The success of this
versatile asymmetric synthetic strategy relies upon the
stereocontrolled formation of scalemic a-lithio and a-cuprio
N-Boc-pyrrolidine and coupling of the cuprate reagent with
vinyl halides in a highly enantioselective fashion. In this full
report, we detail the rapid and efficient asymmetric
syntheses of pyrrolizidines 1–3, pyrrolizine 4, indolizine
5, and indolizidines 6–8.
Scheme 2.
The key synthetic step involves the generation of scalemic
N-Boc-2-pyrrolidinylcuprates and coupling with the vinyl
iodides 10a–b and 12a–b or vinyl halides 13a–b (Scheme 3).
Asymmetric deprotonation of N-Boc-pyrrolidine according
to Beak’s procedure26 followed by treatment with THF
soluble CuCN$2LiCl afforded either the alkyl(cyano)cup-
rate (i.e., RCuCNLi) or dialkylcuprate (i.e., R2CuLi)
reagent depending upon the equivalents of CuCN employed.
Scheme 1.
Scheme 3.

R. K. Dieter et al. / Tetrahedron 61 (2005) 3221–3230
3223
Table 1. Asymmetric deprotonation of N-Boc-pyrrolidine followed by cuprate formation and cuprate vinylation
Entry
Vinyl halide
CuCN$2LiCl (equiv)a
Product
% Yieldb
erc
1
2
3
4
5
6
7
8
9
10
10a
10a
10b
10b
12a
12a
12b
12b
13a
13b
1.0
0.5
1.0
0.5
1.0
0.5
1.0
0.5
0.5
0.5
15a
15a
15b
15b
16a
16a
16b
16b
15c
15c
71–75
73–81
79
87:13–90:10
93:7–95:5
85:15–91:9
94:6–95:5
60:40–70:30
90:10–93:7
86:14
90:10
87:13
91:9
83
64–69
51–57
81
83
61–67
73
a Deprotonation of N-Boc-pyrrolidine [(i) s-BuLi, Et2O, (K)-sparteine, K78 8C, 1 h; (ii) CuCN$2LiCl, 1.0 equivZRCuCNLi, 0.5 equivZR2CuLi].
b Based upon isolated products purified by column chromatography.
c Enantiomeric ratio determined by chiral stationary phase HPLC on a CHIRACEL OD column [cellulose tris(3,5-dimethylphenylcarbamate) on silica gel].
As previously established,26,27 high enantioselectivities
require deprotonation of N-Boc-pyrrolidine in diethyl
ether and formation of the cuprate reagents at low
temperatures. This can be achieved by addition of a THF
solution of CuCN$2LiCl to the cold solution of N-Boc-(S)-
2-lithiopyrrolidine affording the scalemic cuprate reagent in
a THF/Et2O (1:1) solvent mixture. These reaction con-
ditions afforded the N-Boc-2-alkenylpyrrolidines in modest
to good chemical yields and with very good to excellent
enantiomeric ratios as determined by chiral stationary phase
HPLC (Table 1). In all instances the two reagents gave
comparable chemical yields while the dialkylcuprate
reagent gave higher enantiomeric ratios than the alkyl-
cyanocuprate reagent. These very good to excellent
enantiomeric ratios could be achieved on 1.0 mmol and on
10 mmol scale reactions. From previous studies, it had been
established that the Li to Cu transmetallation as well as the
vinylation reactions proceeded with retention of
configuration.27 It should be noted that in principle the
opposite absolute configuration can be achieved by use of a
(C)-sparteine analogue developed by O’Brien.28
N-Boc deprotection and cyclization of 15a–b afforded
11a–b as key intermediates for the preparation of the
pyrrolizidine (i.e., 1 and 2) and indolizidine (i.e., 7 and 8)
alkaloids (Scheme 4). Although the one-pot transformation
could be achieved with either trimethylsilyl triflate
(TMSOTf) or with TMSCl/NaI/MeCN, the most convenient
procedure involved deprotection of 15a–b with TMSCl/
MeOH followed by neutralization with NaHCO3 to effect
cyclization. Simple hydrogenation of 11a afforded (C)-ent-
heliotridane (1) and its diastereomer (drZ85:15) while
hydroboration–oxidation of 11a afforded the amine–borane
complex 17 after aqueous workup. The amine–borane
complex 17 and its diastereomer (drZ85:15) were readily
1
purified by column chromatography and gave H and 13C
Scheme 4. Reagents and conditions: (a) (i) Me3SiCl, MeOH, 12 h, 25 8C; (ii) NaHCO3. (b) H2, Pd/C (10%), CH2Cl2, 12 h. (c) (i) BH3$THF (2.2 equiv), THF,
0–25 8C, 1 h, then 60 8C, 1 h; (ii) 10 M NaOH (3 equiv), H2O2 (30%, 5 equiv), 0–25 8C, 12 h, (96%). (d) (i) BH3$THF, THF, 0–25 8C, 1 h; (ii) 9-BBN
(1.0 equiv), THF, 60 8C, 1 h; (iii) 10 M NaOH (3 equiv), H2O2 (30%, 5 equiv), 0–25 8C, 12 h. (e) CF3COOH (20 equiv), CH2Cl2 (100%). (f) ClCH2COCl,
CH2Cl2, Et3N (72%). (g) NaI, CH3CN (95%).

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R. K. Dieter et al. / Tetrahedron 61 (2005) 3221–3230
NMR spectra strikingly similar to isoretronecanol.29
A
extraction with CH2Cl2, while 9-BBN hydroboration–
oxidation of 11b–BH3 complex at reflux temperatures in
THF gives an 80:20 ratio of 7:8 after BH3 decomplexation
with TMSCl/MeOH. Efforts to increase the diastereo-
selectivity with low temperature hydroboration or with
more sterically hindered boranes were not pursued. Control
experiments with one equivalent of BH3-THF did show that
amine complexation occurs before olefin hydroboration.
The BH3 complex thus facilitates isolation and purification
of these highly water soluble amino alcohols.
broad absorption peak between d 1.60 and 2.10 character-
istic of the BH3-protons was observed in the 1H NMR
spectrum. (C)-Isoretronecanol and its diastereomer (C)-
laburnine (3) were obtained as an 85:15 mixture of
diastereomers by treatment of 16 with TMSCl/MeOH.
Previous reports on the hydroboration–oxidation of the
lactam analogues of 11a have not mentioned formation of
diastereomeric mixtures of hydroxy lactams, although
reported yields were low.7e,h,29 Interestingly, hydrogenation
of 11a affords the same diastereomeric ratio as the
hydroboration reaction, consistent with the 80:20 dr
observed for hydrogenation of a lactam analogue of 11a.30
This synthetic strategy also provides a synthetic route to
(C)-laburnine (Scheme 4). Carbamate cleavage of 15c
followed by amide formation with a-chloroacetyl chloride
and Finkelstein conversion of the a-chloroamide to the
a-iodoamide afforded 18.9c The enantiomer of 18 has been
converted into (K)-trachelanthamidine which is the
enantiomer of (C)-laburnine.9c The synthesis of 18 thus
constitutes a formal total synthesis of (C)-laburnine.
Given that 1 and pseudoheliotridane are prepared from the
same intermediate (i.e., 11a) under the same reaction
conditions, the er for each diastereomer is assumed to be the
same. The specific rotation of the synthetic mixture of 1
[[a]2D5ZC57 (c 0.5, EtOH)] and pseudoheliotridane when
compared to reported values for pure 1 [(C)-heliotridane,
[a]2D5ZC86 (c 0.5, EtOH)]6a and pure pseudoheliotridane
([a]2D5ZC7.0 (c 0.5, EtOH))6b corresponds to an erZ
88.4:11.6 taking into account the 85:15 diastereomeric
ratios. The er is calculated from the expression 0.85 [axC
(1Ka)(Kx)]C0.15 [ayC(1Ka)(Ky)]ZC57 where a is
the fraction of the major enantiomer, x is the specific
rotation for pure heliotridane and y is the specific rotation
for pure pseudoheliotridane obtained from the literature.
Scalemic 2-alkenyl pyrrolidines 16a–b are also readily
converted to pyrrolizine 4 and indolizine 5. Sequential silyl
ether cleavage of 16b with H2SiF6, mesylation of the
alcohol and subsequent treatment of the mesyloxy carba-
mate with methanolic HCl followed by neutralization with
NaHCO3 yields pyrrolizine 4. The low yield was a result of
the volatility of the compound. Similar deprotection of
carbamate 16a and cyclization upon neutralization afforded
5. Hydrogenation of the indolizine 5 affords (C)-d-
coniceine (6) (Scheme 5).
Calculation of the optical purity from measured [a]mixture
/
theoretical [a]mixture gave an optical purity of 77% (i.e., an
erZ88.5:11.5) where Theoretical [a]mixtureZ(C86)(0.85)
C (C7.0)(0.15). Since the specific rotation can be non-
linear with concentration, the specific rotation of the
synthetic mixture of diastereomers was determined at
three different concentrations ([a]2D5ZC57.9 (c 1.0,
EtOH), C57.0 (c 0.5, EtOH) and C54.2 (c 0.25, EtOH)]
over a four-fold range of concentrations and showed a small
non-linearity.31 Similarly, the specific rotation of the
synthetic mixture of 2 and 3 ([a]2D5ZC60 (c 0.5, EtOH))
when compared to the reported values for 2 ([a]2D5ZC70.2
(c 5, EtOH))7n and 3 ([a]D25ZC14.6 (c 3.2, EtOH))7n
corresponds to an erZ95:5 when taking into account the
85:15 mixture of diastereomers. Consequently, within the
limits of the method, no epimerization of the stereogenic
center appears to occur during N-Boc deprotection,
cyclization or subsequent functional group manipulations.
Scheme 5. Reagents and conditions. (a) H2SiF6, THF (79%). (b) MsCl,
Et3N, CH2Cl2 (87%). (c) (i) Me3SiCl, MeOH, 12 h, 25 8C; (ii) NaHCO3.
(d) MeOH, Pd(OH)2, H2, 15 h.
Execution of the same sequence with 15b afforded 11b
which gave (C)-tashiromine (7) and (C)-5-epitashiromine
(8) in a 70:30 ratio after sequential hydroboration–oxidation
on the amine–BH3 complex with BH3–THF followed by
cleavage of the BH3-complex with TMSCl/MeOH. The two
diastereomers could be separated by flash column chroma-
tography and the measured optical rotations corresponded to
an erZ98:2 for 7 and an erZ95:5 for 8. The differences
between the two values most likely reflect errors in
measurement and/or some loss of the minor enantiomer
during sequential operations and purifications. 5-Epitashiro-
mine displayed a dextrorotatory rotation after initial
isolation which changed to a levorotatory rotation after
additional passage through a plug of silica gel as previously
observed.13b Reaction of 11b with 9-BBN followed by
oxidation gave a low yield of organic material upon
3. Summary
In summary, N-Boc-2-pyrrolidinylcuprate chemistry offers
a rapid entry into the pyrrolizidine and indolizidine carbon
skeletons via a two pot process of cuprate coupling with a
functionalized vinyl halide followed by a tandem N-Boc
deprotection–cyclization sequence. The efficient asym-
metric syntheses of (C)-ent-heliotridane, (C)-isoretrone-
canol, (C)-laburnine, (C)-4, (C)-5, (C)-ent-d-coniceine,
(C)-tashiromine and (C)-5-epitashiromine illustrate the
synthetic power of scalemic a-(N-carbamoyl)alkylcuprate
methodology and of the enantioenriched 2-lithiocarbamates
from which they are derived. Scalemic a-lithiocarbamate
methodology is thus significantly extended by copper
mediated transformations. Although this strategy for

R. K. Dieter et al. / Tetrahedron 61 (2005) 3221–3230
3225
pyrrolizidine and indolizidine synthesis, as executed,
required manipulation of functionality for elaboration and
functional group substitution patterns of the natural
products subsequent to the generation of the tertiary
bridgehead amine, these transformations can in principle
be conducted before N-Boc deprotection and cyclization.
These strongly basic, nucleophilic and easily oxidized
tertiary bridgehead nitrogen centers can be problematic in
subsequent functional group manipulations. This difficulty
can be circumvented if the nitrogen can be protected as the
amine–borane or amine–BF3 complexes.
saturated aqueous NaCl (3!20 mL), washed with H2O (2!
20 mL), and dried over anhydrous Na2SO4. A yellowish oil
(4.72 g, 90% yield) was obtained. The crude product was
used for the next reaction without further purification.
4-Hydroxy-1-iodo-1-butyne: IR (neat) 3341 (br), 2931,
1
1906 (vw), 1051, 683 cmK1; H NMR (CDCl3) d 2.01 (s,
1H), 2.61 (t, JZ6.3 Hz, 2H), 3.70 (t, JZ6.3 Hz, 2H); 13C
NMR (CDCl3) d 25.05, 60.94, 91.05, 100.03; mass spectrum
m/z (rel. intensity) EI 196 (100, MC), 166 (68), 127 (33).
To a solution of 1.96 g of 4-hydroxy-1-iodo-1-butyne
(10 mmol) in 30 mL of dry CH2Cl2 was added 3.97 g of
CBr4 (12 mmol) at K30 8C. The mixture was stirred
vigorously, and a solution of PPh3 (2.70 g, 10 mmol) in
10 mL of dry CH2Cl2 was added. The solution was stirred
for 2 h at K30 8C, warmed to 0 8C, and then stirred another
hour. The crude mixture was filtered through a thin layer of
silica gel, and concentrated in vacuo. After column
chromatography (100% Petroleum ether), 4-bromo-1-iodo-
1-butyne (2.10 g, 81% yield) was obtained: IR (neat) 2100
(vw), 1430, 1322, 1268 (vs), 1208 (vs), 1142, 656 cmK1; 1H
NMR (CDCl3) d 2.88 (t, JZ7.2 Hz, 2H), 3.41 (t, JZ7.2 Hz,
2H); 13C NMR (CDCl3) d 25.12, 28.98, 91.70, 100.06; mass
spectrum m/z (rel. intensity) EI 260 (100, MCC1), 258
(100, MCK1), 179 (38), 165 (34), 127 (13), 51 (48).
These asymmetric syntheses employing scalemic stereo-
genic N-Boc-2-pyrrolidinyl metals represent one of the most
efficient synthetic routes to these alkaloids to date and
illustrates the synthetic power and potential of scalemic
stereogenic organometallic reagents in organic synthesis.
4. Experimental
4.1. General
4.1.1. 4-Chloro-2-iodo-but-1-ene (10a). NaI (3.5 g,
23 mmol) was completely dissolved in dry acetonitrile
(20 mL). To this solution was added chlorotrimethylsilane
(TMSCl, 2.5 g, 23 mmol) which resulted in a cloudy white,
fine suspension. After 5 min, water (0.20 g, 11.5 mmol) was
added to generate anhydrous HI in situ. The mixture was
stirred another 10 min and 4-chloro-1-butyne (2.0 g,
23 mmol) was added neat by syringe. The reaction mixture
was stirred for 1 h at room temperature. Then n-pentane
(40 mL) was added along with aqueous NaHCO3 (satu-
rated). After vigorous shaking, the layers were separated.
The top organic layer was washed with sodium thiosulfate
(Na2S2O3, saturated aqueous), dried (MgSO4) and concen-
trated in vacuo to give 10a as a clear liquid (4.5 g, 92%),
which was used without further purification: IR (neat) 3003,
Dipotassium azodicarboxylate was prepared by adding 9.0 g
(77 mmol) of azodicarbonamide to a vigorously stirred 40%
aqueous potassium hydroxide solution (30 mL), cooled by
an ice water bath. After the addition was completed, the
mixture was stirred for an additional 45 min at 0 8C and then
filtered and the solid was washed with 100 mL of cold
methanol. The solid potassium salt was placed in a 500 mL
flask with 200 mL of methanol and 10 g (48 mmol) of
4-bromo-1-iodo-1-butyne was added. The mixture was
stirred vigorously while a solution of 35 mL of acetic acid
in 100 mL of methanol was added via a constant pressure
addition funnel at such a rate as to cause gentle boiling.
After the addition, the cloudy mixture turned colorless. The
reaction mixture was transferred to a separatory funnel
containing 500 mL of water and extracted with three
100 mL portions of pentane. The pentane fractions were
combined, washed with two 100 mL portions of water, dried
over anhydrous sodium sulfate, and filtered. The pentane
was removed under reduced pressure to afford 7.14 g
(57.0%) of 12a: IR (neat) 3049, 1640 (w), 1614, 1444, 1282
(s), 1256 (vs), 703, 617; 1H NMR (CDCl3) d 2.68–2.74 (m,
2H), 3.41 (t, JZ6.9 Hz, 2H), 6.24–6.31 (m, 1H), 6.38–6.41
(m, 1H); 13C NMR (CDCl3) d 30.28, 37.70, 85.20, 137.88;
mass spectrum m/z (relative intensity) EI 262 (20, MCC2),
260 (20, MC), 167 (20), 135 (89), 133 (90), 53 (100).
1
1645, 875, 740 cmK1; H NMR (CDCl3) d 2.79 (t, JZ
6.6 Hz, 2H), 3.62 (t, JZ6.5 Hz, 2H), 5.83 (m, 1H), 6.12 (m,
1H); 13C NMR (CDCl3) d 42.9, 47.7, 104.2, 125.7; mass
spectrum, m/z (rel. intensity) 218 (12, MCC2), 216 (40,
MC), 127 (48), 89 (48), 53 (100).
4.1.2. 5-Chloro-2-iodo-pent-1-ene (10b). Following the
procedure described above for 10a with 5-chloro-1-pentyne
on a 5.0 mmol scale, gave 10b as a clear liquid (0.90 g,
78%) that was used without further purification: IR (neat)
2956, 1612, 1432, 897, 766 cmK1; 1H NMR (CDCl3) d 1.96
(quint, JZ6.5 Hz, 2H), 2.55 (t, JZ6.9 Hz, 2H), 3.51 (t, JZ
6.8 Hz, 2H), 5.74 (m, 1H), 6.09 (m, 1H); 13C NMR (CDCl3)
d 31.43, 42.10, 43.09, 109.60, 127.03; mass spectrum, m/z
(rel. intensity) 232 (21, MC C2), 230 (56, MC), 168 (16),
127 (15), 103 (20), 67 (100).
4.1.4. cis 3-Dimethyl(1,1-dimethylethyl)silyloxy-1-iodo-
1-propene (12b). Iodination and diimide reduction of the
tert-butyldimethylsilyl ether of propargyl alcohol as
described above for 12a gave 12b in 51% yield: IR (neat)
4.1.3. cis 4-Bromo-1-iodo-1-butene (12a). To a solution of
1.88 g of 14a (26.8 mmol) in 80 mL THF at K78 8C was
added 20 mL of 2.00 M n-BuLi (54.0 mmol). The thick
suspension was vigorously stirred at K78 8C and then
allowed to warm up to room temperature over 2 h. Then the
suspension was again cooled to K78 8C and to it was added
6.70 g (52.0 mmol) I2 in 40 mL of THF. After warming to
room temperature overnight, the mixture was quenched with
1
3420, 2996, 1642, 1455, 890 cmK1; H NMR (300 MHz,
CDCl3) d 6.58 (dt, JZ14.3, 4.4 Hz, 1H), 6.27 (dt, JZ14.5,
1.8 Hz, 1H), 4.28 (dd, JZ4.8, 1.8 Hz, 2H), 0.88 (s, 9H),
0.05 (s, 6H); 13C NMR (CDCl3) d K5.0, 18.3, 25.8, 66.8,
79.9, 142.0; mass spectrum m/z (relative intensity) 241 (100,
MC), 185 (65), 85 (90), 73 (55).

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R. K. Dieter et al. / Tetrahedron 61 (2005) 3221–3230
4.2. General procedure A: asymmetric vinylation of
N-Boc-pyrrolidine for R2CuLi
[hexane/iPrOH, 99:1 (v/v), flow rate at 0.5 mL/min,
detection at lZ210 nm]. The (R)-enantiomer (major) eluted
first with a retention time of 14.57 min followed by the (S)-
isomer (minor) at 17.17 min.
N-Boc-pyrrolidine (1.71 g, 10 mmol) was dissolved in
freshly distilled ether (30 mL) along with (K)-sparteine
(2.69 g, 11 mmol). The reaction mixture was cooled to
K78 8C under an argon atmosphere and sec-BuLi (6.9 mL,
1.6 M, 11 mmol) was added dropwise by syringe. The
resultant solution was stirred at K78 8C for 1 h. Then a
solution containing CuCN (450 mg, 5 mmol) and LiCl
(450 mg, 11 mmol) in THF (30 mL) was added portion-wise
by syringe. The mixture was allowed to stir at K78 8C for
30 min before the vinyl iodide (11 mmol) was added neat.
The reaction mixture was then allowed to warm to room
temperature overnight. It was diluted with Et2O (20 mL)
and quenched with 5% aqueous HCl (15 mL). After shaking
vigorously, the layers were separated. The organic layer was
dried (MgSO4) and concentrated in vacuo to give an oil
which was purified by column chromatography on silica gel.
4.2.3. 1,1-Dimethylethyl (2R)-2-ethenyl-1-pyrrolidine-
carboxylate (15c). Following general procedure A on a
2 mmol scale, carbamate 15c was isolated [Rf 0.65,
petroleum ether/EtOAc, 90:10, v/v] as a clear, colorless
oil (288 mg, 73%): IR (neat) 3049, 1690, 1660, 1340, 990,
892 cmK1; 1H NMR (CDCl3) d 1.36 (s, 9H), 1.56–2.10 (m,
4H), 3.12–3.37 (m, 2H), 4.10–4.30 (m, 1H), 4.85–5.10 (m,
2H), 5.62–5.80 (m, 1H);13C NMR d 23.1 (br s), 28.3, 31.2
(br s), 46.2, 58.7, 78.9, 113.7, 149.0, 154.4; mass spectrum
m/z (rel. intensity) EI 197 (0.5, MC), 141 (33), 124 (12), 96
(27).
The enantiomeric purity of 15c was determined by chiral
stationary phase HPLC on a CHIRACEL OD column
[cellulose tris(3,5-dimethylphenylcarbamate) on silica gel]
to be a 91:9 er [hexane/iPrOH, 99.5:0.5 (v/v), flow rate at
0.5 mL/min, detection at lZ210 nm]. The (R)-enantiomer
(major) eluted first with a retention time of 9.68 min
followed by the (S)-isomer (minor) at 10.15 min.
4.2.1. 1,1-Dimethylethyl (2R)-2-(3-chloro-1-methylene-
propyl)-1-pyrrolidinecarboxylate (15a). Following
general procedure A on a 10 mmol scale, carbamate 15a
was isolated [Rf 0.75, petroleum ether/EtOAc, 90:10, v/v] as
a clear, colorless oil (2.11 g, 81%): IR (neat) 2964 (s), 1703
(vs), 1658 (s), 1436 (m), 892, 888 (s) cmK1 1H NMR
;
4.2.4. 1,1-Dimethylethyl (2R)-2-[1-[(Z)-4-bromo-1-
butenyl]]-1-pyrrolidinecarboxylate 16a. Following
general procedure A on a 2 mmol scale, carbamate 16a
was isolated [Rf 0.70, petroleum ether/EtOAc, 90:10, v/v] as
a clear, colorless oil (0.420 g, 69%); IR (neat) 2967, 2873,
1703 (vs), 1651, 1385 (vs), 1169; 1H NMR (CDCl3) d 1.40
(s, 9H), 1.55–1.70 (m, 2H), 1.70–1.95 (m, 2H), 2.55–2.81
(m, 2H), 3.25–3.52 (m, 4H), 4.34–4.69 (m, 1H), 5.22–5.41
(m, 2H); 13C NMR (CDCl3) d 23.80, 28.54, 30.88, 31.50,
32.41, 46.46, 54.21, 79.16, 126.10, 134.40, 154.40.
(CDCl3) d 1.38 (s, 9H), 1.60–1.75 (m, 1H), 1.75–1.95 (m,
2H), 1.95–2.15 (m, 1H), 2.30–2.55 (m, 2H), 3.35–3.55 (m,
2H), 3.55–3.70 (m, 2H), 4.10–4.25 (m, 1H), 4.83 (br s with
shoulder, 2H); 13C NMR (CDCl3) d 22.6 (23.3), 28.4, (30.6)
31.3, 36.2, 42.6, 46.6, 61.1, 79.3, 110.2, 146.3, 154.3
(rotamers); mass spectrum, m/z (rel. intensity) 261 (0.1, MC
C2), 259 (0.5, MC), 203 (14), 186 (14), 167 (30), 114 (49),
70 (45), 57 (100).
The enantiomeric purity of 15a was determined by chiral
stationary phase HPLC on a CHIRACEL OD column
[cellulose tris(3,5-dimethylphenylcarbamate) on silica gel]
to be a 95:5 (1 mmol scale) to 90–10 (10 mmol scale) er
[hexane/iPrOH, 99:1 (v/v), flow rate at 0.5 mL/min,
detection at lZ210 nm]. The (R)-enantiomer (major) eluted
first with a retention time of 15.98 min followed by the (S)-
isomer (minor) at 18.19 min.
The enantiomeric purity of 16a was determined by chiral
stationary phase HPLC on a CHIRACEL OD column
[cellulose tris(3,5-dimethylphenylcarbamate) on silica gel]
to be a 90:10 er [hexane/iPrOH, 99.5:0.5 (v/v), flow rate at
0.5 mL/min, detection at lZ210 nm]. The (R)-enantiomer
(major) eluted first with a retention time of 13.59 min
followed by the (S)-isomer (minor) at 14.92 min.
4.2.2. 1,1-Dimethylethyl (2R)-2-(4-chloro-1-methylene-
butyl)-1-pyrrolidinecarboxylate (15b). Following general
procedure A on a 10 mmol scale, carbamate 15b was
isolated [silica gel, Rf 0.70, petroleum ether/Et2O, 50;50,
v/v] as a clear colorless oil (2.28 g, 83%): IR (neat) 2965 (s),
1702 (vs), 1680 (m), 1440 (m), 890 (s), 882 cmK1; 1H NMR
(CDCl3) d 1.39 (s, 9H), 1.60–1.75 (m, 1H), 1.75–1.90 (m,
2H), 1.90–2.10 (m, 3H), 2.10–2.25 (m, 2H), 3.35–3.50 (br s,
2H), 3.55 (t, JZ6.2 Hz, 2H), 4.15–4.35 (m, 1H), 4.77 (br s,
2H); 13C NMR (CDCl3) d 23.4, 28.4, 32.8, 33.2, 36.1, 41.9,
47.6, 61.9, 79.8, 108.9, 146.5, 155.1; mass spectrum, m/z
(rel. intensity) 275 (0.1, MCC2), 273 (0.4, MC), 238 (0.1),
217 (15), 200 (14), 181 (28), 154 (32), 114 (56), 70 (57), 57
(100).
4.2.5. 1,1-Dimethylethyl (2R)-2-[1-[(Z)-3-[dimethyl(1,1-
dimethylethyl)silyloxy]-1-propenyl]]-1-pyrrolidinecar-
boxylate (16b). Following general procedure A on a
2 mmol scale, carbamate 16b was isolated [Rf 0.75,
petroleum ether/EtOAc, 90:10, v/v] as a clear, colorless
oil (0.566 g, 83%): IR (neat) 2967, 1688 (vs), 1376 (vs),
1
1253, 1161, 1100, 843, 770; H NMR (CDCl3) d K0.8 (s,
6H), 0.81 (s, 9H), 1.35 (s, 9H), 1.50–1.61 (m, 1H), 1.65–
1.87 (m, 2H), 1.92–2.06 (m, 1H), 3.22–3.42 (m, 2H), 4.23
(br s, 2H), 4.39 (br s, 1H), 5.21–5.32 (m, 1H), 5.34–5.48 (m,
1H); 13C NMR (CDCl3) d K4.90, 18.15, 23.59, 25.83,
28.42, 33.33, 46.26, 54.33, 59.30, 76.72, 128.60, 132.50,
154.35; mass spectrum m/z (rel. intensity) 341 (1, MC),
268 (7), 228 (48), 184 (46), 153 (74), 110 (100), 75 (59), 57
(81).
The enantiomeric purity of 15b was determined by chiral
stationary phase HPLC on a CHIRACEL OD column
[cellulose tris(3,5-dimethylphenylcarbamate) on silica gel]
to be a 95:5 (1 mmol scale) to 90:10 (10 mol scale) er
The enantiomeric purity of 16b was determined by chiral
stationary phase HPLC on a CHIRACEL OD column
[cellulose tris(3,5-dimethylphenylcarbamate) on silica gel]

R. K. Dieter et al. / Tetrahedron 61 (2005) 3221–3230
3227
to be a 90:10 er [hexane/iPrOH, 99:1 (v/v), flow rate)
0.5 mL/min, detection at lZ210 nm]. The (R)-enantiomer
(major) eluted first with a retention time of 9.17 min
followed by the (S)-isomer (minor) at 10.58 min.
1 mmol) was dissolved in THF (3 mL) and cooled to 0 8C
under an inert argon atmosphere. Then a 1.0 M solution of
BH3$THF in THF (1 mL, 1 mmol) was added and the
reaction mixture was allowed to slowly warm to room
temperature over 1 h. 9-BBN (2.0 mL, 1.0 mmol) was
added dropwise. The reaction mixture was then heated at
reflux for 1 h, cooled to 0 8C, and treated with 10 M NaOH
(1.0 mL). H2O2 (1.0 mL, 30% aq) was added and stirring
continued for 1 h while allowing the reaction mixture to
warm to room temperature. The crude mixture was then
diluted with Et2O and the layers separated. The organic
layer was dried (MgSO4) and concentrated in vacuo.
Column chromatography on silica gel (petroleum ether/
ether, 80:20, v/v) afforded the amine–borane complexes 17
as a 85:15 mixture of diastereomers: IR (neat) 3415 (s),
2976 (s), 2881 (s), 2365 (vs), 2314 (vs), 2271 (vs), 1634 (w),
4.2.6. (R)-Hexahydro-1-methylene-1H-pyrrolizine (11a).
Carbamate 15a (259 mg, 1.0 mmol) was dissolved in
methanol (5.0 mL) at 25 8C, and trimethylsilylchloride
(TMSCl, 540 mg, 5.0 mmol) was added dropwise by
syringe. The mixture was stirred at room temperature
overnight then quenched with saturated aqueous NaHCO3
until pHO8. The mixture was diluted with methylene
chloride, two layers were separated, and the organic layer
was extracted three times with methylene chloride, and
dried (MgSO4). Concentration in vacuo afforded a clear
yellow oil which was purified by Kugelrohr distillation
(100 8C, 20 mm Hg) to give 11a as a clear, colorless liquid
(0.113 g, 92%): [a]2D2ZC53 (c 1.0, HCCl3); IR (neat) 3400
1
1453 (s), 1170 (vs), 1015 (s) cmK1; H NMR (CDCl3) d
1.30–2.10 (vbr s, BH3, 3H), 1.50–1.65 (m, 2H), 1.70–1.90
(m, 2H), 1.90–2.05 (m, 3H), 2.62–2.78 (m, 2H), 2.90–2.98
(m, 1H), 3.10–3.21 (m, 1H), 3.30–3.40 (m, 1H), 3.58–3.75
(m, 3H); 13C NMR (CDCl3). Major diastereomer: d 24.4,
26.3, 26.6, 42.6, 61.6, 62.7, 64.1, 74.6. Minor diastereomer:
d 24.6, 28.0, 31.8, 49.0, 63.1, 64.0, 65.6, 76.2; mass
spectrum, m/z (rel. intensity) 141 (28, MC), 124 (14), 110
(9), 97 (3), 83 (100), 70 (10), 55 (48).
1
(vs), 2950 (m), 1660 (m), 1642, 1420 (w) cmK1; H NMR
(CDCl3) d 1.48–1.60 (m, 1H), 1.60–1.80 (m, 2H), 1.90–2.15
(m, 1H), 2.35–2.50 (m, 2H), 2.50–2.60 (m, 2H), 2.80–3.10
(m, 2H), 3.77 (t, JZ6.6 Hz, 1H), 4.75 (dd, JZ1.5, 2.0 Hz,
1H), 4.87 (dd, JZ1.5, 2.0 Hz, 1H); 13C NMR (CDCl3) d
25.5, 32.2, 32.5, 52.6, 54.1, 67.4, 104.6, 154.5; mass
spectrum, m/z (rel. intensity) 123 (28, MC), 122 (44), 108
(5), 95 (100), 80 (15), 67 (22), 55 (19).
Decomposition of the amine–borane complexes 17 with
methanolic HCl (chlortrimethylsilane in methanol) afforded
2 and its epimer (C)-laburnine (3) as a mixture of
diastereomers (85:15, 80%): [a]2D5ZC60 (c 0.5, EtOH),
[lit.7n (C)-isoretronecanol [a]2D5ZC70.2 (c 5, EtOH) and
its epimer (C)-laburnine [a]2D5ZC14.6 (c 3.2, EtOH);7n
calculated [a]mixtureZ(C70.2)(0.85)C(C14.6)(0.15)Z
C62 corresponding to an eeZ90% or an erZ95:5 assuming
4.2.7. (C)-ent-Heliotridane (1). Alkene 11a (123 mg,
1 mmol) was dissolved in methylene chloride (10 mL) and
10% palladium on carbon (30 mg) was added. The round
bottom flask (50 mL) was capped with a rubber septum, and
sealed with parafilm. A balloon filled with hydrogen gas was
attached via a syringe and the reaction mixture was stirred
overnight at room temperature. Afterwards, the catalyst was
removed by filtration through a thin layer of celite, and
methylene chloride removed in vacuo to give a light brown
oil which was purified by Kugelrohr distillation (100 8C,
20 mm Hg) to give (C)-ent-heliotridane (1) and its epimer
(C)-pseudoheliotridane as a mixture of diastereomers
(85:15, 99%): [a]D25ZC57 (c 0.5, EtOH), [lit.:6a (C)-
heliotridane, [a]2D5ZC86 (c 0.5, EtOH); lit.6b epimer (C)-
pseudoheliotridane, [a]D25ZC7.0 (c 0.5, EtOH); calculated
[a]mixtureZ(C86)(0.85)C(C7.0)(0.15)ZC74 corre-
sponding to an eeZ77% or an erZ88.5:11.5 assuming
both diastereomers have the same er]; IR (neat) 3408 (vs),
1
both diastereomers have the same er]; H NMR (CDCl3)
1.35–1.55 (m, 2H), 1.55–2.20 (m, 6H), 2.40–2.75 (m, 2H),
3.00–3.15 (m, 1H), 3.15–3.30 (m, 1H), 3.59 (d, JZ7.4 Hz,
2H), 5.25–6.50 (br s, 1H); 13C NMR (CDCl3) d 25.8, 26.4,
27.0, 44.1, 53.8, 55.5, 62.8, 66.5. (C)-Laburnine. 13C NMR
d 25.6, 29.5, 31.7, 47.9, 54.4, 54.7, 64.5, 68.0; [lit.7n 13C
NMR (CDCl3) d 24.9, 30.0, 31.9, 48.3, 52.5, 54.6, 64.9, 67.5
and for the enantiomer (K)-trachelanthamide13b d 25.7,
29.8, 31.8, 48.1, 54.5, 54.8, 65.6, 68.0].
1
2936 (m), 1642 (w), 1461 (w) cmK1; H NMR (CDCl3) d
4.2.9. 2,3,5,7a-Tetrahydro-1H-pyrrolizine (4). To the
solution of 16b (341 mg, 1.0 mmol) in THF (10 mL) was
added H2SiF6 (1.0 mL, 2.2 mmol) under an Argon atmo-
sphere. After addition was complete, the mixture was stirred
for 12 h at room temperature. The reaction mixture was
diluted with Et2O (20 mL) and quenched with brine
(15 mL). After shaking vigorously, the layers were
separated. The organic layer was dried (MgSO4) and
concentrated in vacuo to give a colorless oil (179 mg,
79%) which was purified by column chromatography on
silica gel (petroleum ether/EtOAc, 70:30, v/v) to give pure
N-Boc-2-(Z)-3-hydroxy-1-propenyl)pyrrolidine: IR (neat)
1.04 (d, JZ6.8 Hz, 3H), 1.55–1.80 (m, 2H), 1.80–2.20 (m,
4H), 2.40–2.55 (m, 1H), 2.65–2.75 (m, 1H), 2.90–3.10 (m,
1H), 3.50–3.70 (m, 1H), 3.80–4.00 (m, 1H), 4.15–4.25 (m,
1H); 13C NMR (CDCl3) d 13.4, 25.7, 25.9, 30.7, 34.7, 53.6,
56.5, 69.9; mass spectrum, m/z (rel. intensity) 125 (19, MC),
108 (4), 97 (10), 83 (100), 55 (52). Pseudoheliotridane: 13C
NMR d 16.5, 24.9, 29.1, 34.1, 39.8, 54.51, 54.54, 72.9.
Heliotridane–BH3 complex. 13C NMR (CDCl3) d 13.80,
24.92, 27.40, 31.40, 34.76, 63.60, 65.02, 76.91 [lit.1e 13C
NMR d 13.76, 24.88, 27.36, 31.37, 34.74, 63.54, 64.97,
76.88]. Pseudoheliotridane–BH3 complex. 13C NMR
(CDCl3) d 17.63, 24.46, 30.99, 33.03, 41.60, 63.76, 65.02,
80.18 [lit.:1e 13C NMR d 17.60, 24.43, 30.07, 33.01, 41.60,
63.73, 64.27, 80.18].
1
3360 (br), 1688 (vs), 1460 (s), 992, 890 cmK1; H NMR
(CDCl3) d 1.44 (s, 9H), 1.63–1.76 (m, 1H), 1.76–1.98 (m,
2H), 2.08–2.22 (m, 1H), 3.29–3.53 (m, 2H), 4.05–4.16 (m,
1H), 4.32 (br s, 1H), 4.50–5.61 (m, 1H), 5.49–5.71 (m, 2H);
13C NMR (CDCl3) d 23.86, 28.51, 32.99, 39.34, 46.48,
53.80, 79.51, 124.76, 136.57, 154.46.
4.2.8. (C)-Isoretronecanol (2). Alkene 11a (123 mg,

3228
R. K. Dieter et al. / Tetrahedron 61 (2005) 3221–3230
Treatment of the alcohol (0.114 g, 0.5 mmol) with triethyl-
amine (0.076 g, 0.75 mmol) and mesyl chloride (0.069 g,
0.60 mmol) in dry CH2Cl2 at K30 8C for 2 h followed by
the NaHCO3 work up afforded crude mesylate (0.133 g,
87%) which was used without further purification. The
crude mesylate was dissolved in methanol (3 mL) and
TMSCl (0.295 g, 2.5 mmol) was added slowly at room
temperature and the mixture was stirred for 6 h followed by
NaHCO3 workup. The crude product was distilled under
low pressure (30 mm Hg, 50 8C) to afford 4 (0.049 g, 31%):
[a]2D5ZC2.1 (c 1.5, CHCl3); IR (neat) 3058 (vs), 1649 (w),
685 (br) cmK1; 1H NMR 1.75–2.04 (m, 4H), 2.10–2.29 (m,
2H), 2.87–2.98 (m, 1H), 3.61 (m, 2H), 4.40 (m, 1H), 4.83–
4.93 (m, 1H); 13C NMR 24.6, 29.9, 56.9, 61.4, 73.4,
124.3, 129.0; mass spectrum m/z (rel. intensity), EI 110 (5,
MCC1), 109 (49, MC), 108 (42), 107 (25), 106 (42), 94 (5),
81 (100), 80 (94), 79 (18), 67 (11), 54 (28).
NaHCO3 until pHO8. The mixture was diluted with
methylene chloride, two layers were separated and the
organic layer extracted three times with methylene chloride,
and dried (MgSO4). Concentration in vacuo afforded a clear
yellow oil which was purified by Kugelrohr distillation
(100 8C, 20 mm Hg) to give 11b as a clear colorless liquid
(116 mg, 85%): [a]2D2ZC79 (c 0.30, HCCl3); IR (neat)
3395 (vs), 2955 (m), 1655 (m), 1644 (m), 1410 (w) cmK1
;
1H NMR (CDCl3) d 1.53–1.80 (m, 6H), 1.96 (td, JZ5.2,
14.8 Hz, 1H), 2.00–2.20 (m, 2H), 2.20–2.30 (m, 1H), 2.30–
2.45 (m, 1H), 3.08–3.20 (m, 2H), 4.68 (dd, JZ1.6, 1.6 Hz,
1H), 4.72 (dd, JZ1.5, 1.5 Hz, 1H); 13C NMR (CDCl3) d
20.2, 26.0, 26.7, 33.3, 52.7, 54.6, 66.6, 106.0, 147.1; mass
spectrum, m/z (rel. intensity) 137 (58, MC), 136 (96), 122
(100), 109 (98), 94 (23), 81 (44), 67 (28), 54 (28).
4.2.12. (C)-Tashiromine (7) and (C)-5-epitashiromine
(8). Indolizidine olefin 11b (137 mg, 1 mmol) was dissolved
in THF (5 mL) and a 0.5 M solution of 9-BBN in THF
(2.0 mL, 1.0 mmol) was added. The mixture was heated for
1 h at 60 8C and then cooled to room temperature before the
addition of BH3$THF (1.0 mL, 1.0 mmol). After stirring for
30 min, the mixture was cooled to 0 8C and treated with
10 M NaOH (1.0 mL). Then H2O2 (35% aq, 1.0 mL) was
added dropwise and allowed to stir for 1 h. The white cloudy
reaction mixture was diluted with Et2O, the combined ether
phase was washed with NaHCO3 twice, the combined
organic phase was dried over Na2SO4, and concentrated in
vacuo to afford a mixture of the BH3-complexes of (C)-
tashiromine and (C)-5-epitashiromine. Flash column
chromatography (Rf 0.5, diethyl ether, 100%) gave a
mixture of the BH3-complexes. (C)-Tashiromine–BH3
complex: 13C NMR (CDCl3) d 18.74, 19.99, 20.92, 21.75,
35.43, 52.04, 64.28, 65.23, 66.82. (C)-epitashiromine–
BH3-complex: 13C NMR (CDCl3) d 19.05, 20.44, 24.38,
28.11, 38.65, 55.30, 56.77, 64.69, 66.70.
4.2.10. (C)-Coniceine (6). Carbamate 16a (0.304 g,
1.0 mmol) was dissolved in methanol (5 mL) and TMSCl
(0.540 g, 5.0 mmol) was added slowly at room temperature.
The reaction mixture was stirred for 6 h followed by the
addition of NaHCO3 until pHO8, stirred for another 2 h at
room temperature. The crude material was extracted three
times with 15 mL CH2Cl2, the combined organic phase was
dried over Na2SO4, and concentrated in vacuo to afford (R)-
5 (0.106 g, 86%): IR (neat) 3073 (vs), 2995, 2315, 1639 (w),
1434; 1H NMR (CDCl3) d 1.44–1.56 (m, 1H), 1.75–1.86 (m,
2H), 1.96–2.03 (m, 2H), 2.19–2.32 (m, 1H), 2.72–2.81 (m,
2H), 2.85–2.95 (m, 2H), 3.31–3.42 (m, 1H), 5.62–5.74 (m,
2H); 13C NMR (CDCl3) d 22.23, 22.74, 29.50, 46.07, 51.40,
59.26, 124.77, 128.38; mass spectrum m/z (rel. intensity) EI
123 (MC, 51), 122 (100), 95 (47), 80 (24), 67 (27).
A suspension of (R)-5 (123 mg, 1.0 mmol) and palladium
hydroxide (35 mg) in methanol (5.0 mL) was stirred under a
hydrogen atmosphere (50 psi) for 15 h. The catalyst was
removed through Celite by filtration. After conc. HCI
(0.20 mL) was added to the filtrate, the organic solvent was
evaporated to yield a hydrochloride salt. The salt was
treated with 10% K2CO3, and the mixture was extracted
with diethyl ether twice. The combined ether extract was
washed with brine, and dried over Na2SO4. After the solvent
was removed, picric acid in EtOH was added. After slight
heating, the mixture was cooled to room temperature and
the solid was precipitated to yield the picrate salt (315 mg,
89%) of (C)-coniceine (6): [a]2D5ZC1.60 (c 0.1, EtOH) for
the picrate salt corresponding to an 80% ee or an erZ90:10,
Treatment of the BH3 complexes of 7 and 8 with methanolic
HCl (chlortrimethylsilane in methanol) afforded (C)-
tashiromine (7) and its epimer (C)-5-epitashiromine (8)
as a mixture of diastereomers (70:30, 85%). The two
diastereomers were separated by column chromatography
(flash silica gel, CH2Cl2/MeOH/NH4OH, 95:4.75:0.25).
(C)-Tashiromine (7): [a]2D2ZC41.9 (c 1.1, EtOH) [lit.13b
([a]2D0ZC42.9 (c 1.1, EtOH)]; IR (neat) 3560 (br),
2950 cmK1 1H NMR (CDCl3) d 3.62 (dd, JZ10.7,
;
4.6 Hz, 1H), 3.48 (dd, JZ10.8, 6.1 Hz, 1H); 3.15–3.02
(m, 2H), 2.09–2.01 (m, 1H), 2.05–1.80 (m, 3H), 1.74–1.37
(m, 7H), 1.23–1.15 (m, 1H); 13C NMR (CDCl3) d 20.8, 24.9,
27.4, 28.9, 44.3, 52.6, 53.5, 65.6, 65.6; [lit.1e 13C NMR d
20.2, 24.6, 27.1, 28.5, 44.1, 52.1, 53.6, 65.0, 65.8].
1
[lit.11f K2.0 (c 0.35, EtOH) for the enantiomer]; H NMR
(CDC13) d 1.38–2.15 (10H, m), 2.50–2.67 (2H, m), 3.75–
3.95 (3H, m), 10.38 (br s 2H), 10.88 (br s 1H); 13C NMR
(CDC13) d 19.8, 22.9, 23.0, 27.3, 28.3, 53.7, 69.1, 126.6,
129.4, 142.3, 161.9; [lit.12b 13C NMR d 19.8, 23.0, 23.1,
27.3, 28.1, 53.6, 68.6, 126.8, 128.3, 141.8, 162.1]; mass
spectrum (neat) m/z (rel. intensity) EI 125 (MC, 51), 124
(100), 97 (94), 96 (96), 83 (61), 69 (67).
(C)-5-Epitashiromine (8). [a]2D2ZC1.48 (c 1.5, EtOH) [lit.
[a]2D0ZC1.1 (EtOH),13b [a]DZK0.96 (c 0.31, EtOH);14a
1
IR (neat) 3450, 2952 cmK1; H NMR (CDCl3) d 4.15 (dd,
JZ10.9, 4.1 Hz, 1H), 3.71 (br d, JZ9.7 Hz, 1H), 3.11–3.05
(m, 1H), 3.03–2.91 (m, 1H), 2.36–2.24 (m, 1H), 2.12–1.93
(m, 3H), 1.90–1.61 (m, 6H), 1.60–1.42 (m, 2H); 13C NMR
(CDCl3) d 20.8, 23.2, 25.7, 30.5, 35.3, 54.0, 54.4, 66.5, 66.8;
[lit.1e 13C NMR d 20.8, 23.3, 25.8, 30.6, 35.3, 53.5, 54.5,
65.7, 66.8]. A sample of 8 taken from the column
chromatography gave [a]2D2ZC1.48 (c 1.5, EtOH) and
this sample upon passage through a pipette with a small
4.2.11. (R)-8-Methyleneoctahydroindolizine (11b).
Carbamate 15b (259 mg, 1.0 mmol) was dissolved in
methanol (5 mL) at 25 8C and trimethylsilylchloride
(TMSCl, 540 mg, 5.0 mmol) was added dropwise by
syringe. The mixture was stirred at room temperature
overnight and then quenched with saturated aqueous

R. K. Dieter et al. / Tetrahedron 61 (2005) 3221–3230
3229
amount of silica gel gave [a]2D2ZK0.87 (c 1.5, EtOH). This
change in the sign of rotation as a function of sample history
was previously noted.13b
heliotridane see: Coldham, I.; Hufton, R.; Snowden, D. J.
J. Am. Chem. Soc. 1996, 118, 5322–5323.
7. (K)-Isoretronecanol: (a) Bertrand, S.; Hoffmann, N.; Pete,
J.-P. Eur. J. Org. Chem. 2000, 2227–2238. (b) David, O.; Blot,
J.; Bellec, C.; Fargeau-Bellassoued, M.-C.; Haviari, G.;
Celerier, J.-P.; Lhommet, G.; Gramain, J.-C.; Gardette, D.
J. Org. Chem. 1999, 64, 3122–3131. (c) Konno, H.; Kishi, M.;
Hiroya, K.; Ogasawara, K. Heterocycles 1998, 49, 33–37. (d)
Knight, D. W.; Share, A. C.; Gallagher, P. T. J. Chem. Soc.,
Perkin Trans. 1 1997, 2089–2097. (e) Keusenkothen, P. F.;
Smith, M. B. J. Chem. Soc., Perkin Trans. 1 1994, 2485–2492.
(f) Le Coz, S.; Mann, A.; Thaueau, F.; Taddei, M.
Heterocycles 1993, 36, 2073–2080. (g) Haviari, G.; Celerier,
J. P.; Petit, H.; Lhommet, G. Tetrahedron Lett. 1993, 34,
1599–1600. (h) Knight, J. G.; Ley, S. V. Tetrahedron Lett.
1991, 32, 7119–7122. (i) Knight, D. W.; Share, A. C.;
Gallagher, P. T. J. Chem. Soc., Perkin Trans. 1 1991,
1615–1616. (j) Knight, D. W.; Share, A. C.; Gallagher, P. T.
Gazz. Chim. Ital. 1991, 121, 49–50. (k) Moriwake, T.;
Hamano, S.; Saito, S. Heterocycles 1988, 27, 1135–1139. (l)
Tatsuta, K.; Takahashi, H.; Amemiya, Y.; Kinoshita, M. J. Am.
Chem. Soc. 1983, 105, 4096–4097. (m) Rueger, H.; Benn, M.
Heterocycles 1982, 19, 1677–1680. (n) Robins, D. J.;
Sakdarat, S. J. Chem. Soc., Perkin Trans. 1 1981, 909–913.
8. (C)-Isoretronecanol: Ledoux, S.; Marchalant, E.; Celerier,
J.-P.; Lhommet, G. Tetrahedron Lett. 2001, 42, 5397–5399.
9. (C)-Laburnine: (a) Arai, Y.; Kontani, T.; Koizumi, T.
J. Chem. Soc., Perkin Trans. 1 1994, 15–23. (b) Tankano,
S.; Ogawa, N.; Ogasawara, K. Heterocycles 1981, 16,
915–919. For the synthesis of (K)-trachelanthamidine (the
enantiomer of laburnine see: (c) Jolly, R. S.; Livinghouse, T.
J. Am. Chem. Soc. 1988, 110, 7536–7538.
Acknowledgements
This work was generously supported by the National
Institutes of Health (GM-60300-01) and the National
Science Foundation (CHE-0132539). Support of the NSF
Chemical Instrumentation Program for purchase of a JEOL
500 MHz instrument is gratefully acknowledged (CHE-
9700278). We are thankful to Professor Martin Banwell of
the Australian National University (Canberra) for helpful
suggestions.
Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tet.2005.
01.094. General experimental information, description of
materials and 1H and 13C NMR spectra for compounds 1–5,
7–8, 2–BH3 (i.e., 17)/3–BH3, 7–BH3/8–BH3, 11a–b, 15a–c,
and 16a–b are available.
References and notes
10. Nagao, Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi, S.; Fujita, E.
J. Am. Chem. Soc. 1988, 110, 289–291.
´
1. (a) Wrobel, J. T. In Brossi, A., Ed.; The Alkaloids: Chemistry
11. (K)-Coniceine: (a) Park, S. H.; Kang, H. J.; Ko, S.; Park, S.;
Chang, S. Tetrahedron: Asymmetry 2001, 12, 2621–2624. (b)
Costa, A.; Najera, C.; Sansano, J. M. Tetrahedron: Asymmetry
2001, 12, 2205–2211. (c) Arisawa, M.; Takahashi, M.;
Takezawa, E.; Yamaguchi, T.; Torisawa, Y.; Nishida, A.;
Nakagawa, M. Chem. Pharm. Bull. 2000, 48, 1593–1596. (d)
Groaning, M. D.; Meyers, A. I. J. Chem. Soc., Chem. Commun.
2000, 1027–1028. (e) Sibi, M. P.; Christensen, J. W. J. Org.
Chem. 1999, 64, 6434–6442. (f) Munchhof, M. J.; Meyers,
A. I. J. Org. Chem. 1995, 60, 7084–7085. (g) Waldmann, H.;
Braun, M. J. Org. Chem. 1992, 57, 4444–4451. (h) Waldmann,
H.; Braun, M.; Draeger, M. Angew. Chem., Int. Ed. Engl. 1990,
29, 1468–1471.
and Pharmacology; Academic: San Diego, 1985; Vol. 26,
p 327. (b) Hartmann, T.; Witte, L. Alkaloids: Chem. Biol.
Perspect. 1995, 9, 155–233. (c) Hartmann, T. Chemoecology
1995, 5/6(3/4), 139–146. (d) Swan, G. A. An Introduction to
the Alkaloids; Blackwell: Oxford, 1967, p 20. (e) Kim, S.-K.;
Kim, S.-I.; Lai, S.; Cha, J. K. J. Org. Chem. 1999, 64, 6771 and
references cited therein.
2. (a) Michael, J. P. In Cordell, G. A., Ed.; The Alkaloids:
Chemistry and Pharmacology; Academic: San Diego, 2001;
Vol. 55, Chapter 2 and references cited therein, p 91. (b)
Takahata, H.; Momose, T. In Cordell, G. A., Ed.; The
Alkaloids: Chemistry and Pharmacology; Academic: San
Diego, 1993; Vol. 44, Chapter 3 and references cited therein,
p 189. (c) Howard, A. S.; Michael, J. P. In Brossi, A., Ed.; The
Alkaloids: Chemistry and Pharmacology; Academic: San
Diego, 1986; Vol. 28, Chapter 3 and references cited therein,
p 183.
12. (C)-(S)-Coniceine: (a) Sanchez-Sancho, F.; Herradon, B.
Tetrahedron: Asymmetry 1998, 9, 1951–1965. (b) Takahata,
H.; Kubota, M.; Takahashi, S.; Momose, T. Tetrahedron:
Asymmetry 1996, 7, 3047–3054. (c) Sato, Y.; Nukui, S.;
Sodeoka, M.; Shibasaki, M. Tetrahedron 1994, 50, 371–382.
(d) Arseniyadis, S.; Huang, P. Q.; Husson, H. P. Tetrahedron
Lett. 1988, 29, 631–634.
3. For pyrrolizidine toxicity see: (a) Fu, P. P.; Xia, Q.; Lin, G.;
Chou, M. W. Drug Metab. Rev. 2004, 36, 1–55. (b) Stewart,
M. J.; Steenkamp, V. Ther. Drug Monitor. 2001, 23, 698–708.
4. (a) Colegate, S. M.; Dorling, P. R. Bioactive Indolizidine
Alkaloids In Handbook of Plant and Fungal Toxicants 1997 pp
1–18. (b) Fellows, L. E.; Kite, G. C.; Nash, R. J.; Simmonds,
M. S. J.; Scofield, A. M. In Recent Advances in Phyto-
chemistry, 1989; Vol. 23, pp 395–427.
13. (C)-Tashiromine: (a) David, O.; Bellec, C.; Fargeau-
Bellassoued, M.-C.; Lhommet, G. Heterocycles 2001, 55,
1689–1701. (b) Ha, D.-C.; Park, S.-H.; Choi, K.-S.; Yun, C.-S.
Bull. Kor. Chem. Soc. 1998, 19, 728–730.
14. (K)-Tashiromine: (a) Banwell, M. G.; Beck, D. A. S.; Smith,
J. A. Org. Biomol. Chem. 2004, 2, 157–159. (b) Gage, J. L.;
Branchaud, B. P. Tetrahedron Lett. 1997, 38, 7007–7010.
15. Viola, A.; Collins, J. J.; Filipp, N.; Locke, J. S. J. Org. Chem.
1993, 58, 5067–5075.
5. (K)-Heliotridane: Honda, T.; Yamane, S.-I.; Naito, K.;
Suzuki, Y. Heterocycles 1995, 40, 301–310.
6. (C)-Heliotridane: (a) Dener, J. M.; Hart, D. J. Tetrahedron
1988, 44, 7037–7046. (b) For a synthesis of (C)-pseudo-

3230
R. K. Dieter et al. / Tetrahedron 61 (2005) 3221–3230
16. Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107,
1768–1769.
Shimizu, H.; Nakai, T. J. Organomet. Chem. 2001, 624,
364–366. (e) Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2002,
4, 119–122.
17. For
a racemic synthesis of 5-epi-tashiromine see: (a)
Paulvannan, K.; Stille, J. R. J. Org. Chem. 1994, 59,
1613–1620. For (K)-5-epi-tashiromine see: (b) Agami, C.;
´
Dechoux, L.; Hebbe, S.; Menard, C. Tetrahedron 2004, 60,
5433–5438.
28. (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P.; O’Brien, P.
J. Am. Chem. Soc. 2002, 124, 11870–11871. (b) Hermet,
J.-P.R.; Porter, D. W.; Dearden, M. J.; Harrison, J. R.; Koplin,
T.; O’Brien, P.; Parmene, J.; Tyurin, V.; Whitwood, A. C.;
Gilday, J.; Smith, N. M. Org. Biomol. Chem. 2003, 1,
3977–3988. (c) Dearden, M. J.; McGrath, M. J.; O’Brien, P.
J. Org. Chem. 2004, 69, 5789–5792.
18. Beak, P.; Johnson, T. A.; Kim, D. D.; Lim, S. H. In Hodgson,
D. M., Ed.; Organolithiums in Enantioselective Synthesis;
Springer: Berlin, 2003; Vol. 5, p 139.
19. For a preliminary account involving racemic syntheses of 1–2,
4 and 7–8 see: Dieter, R. K.; Watson, R. Tetrahedron Lett.
2002, 43, 7725–7728.
29. White, J. D.; Amedio, J. C., Jr.; Gut, S.; Ohira, S.; Jayasinghe,
L. R. J. Org. Chem. 1992, 57, 2270–2284.
30. Mori, M.; Kanda, N.; Oda, I.; Ban, Y. Tetrahedron 1985, 41,
5465–5474.
20. Roberts, J. D.; Mazur, R. H. J. Am. Chem. Soc. 1951, 73,
2509–2520.
31. The specific rotation can vary with concentration, temperature,
solvent and the presence of soluble impurities in the sample.
The optical and enantiomeric purities may be nonequivalent
(Horeau effect), although this is generally a small effect
observed in weakly polar solvents that disappears in polar
solvents. All these effects must be kept in mind when
attempting to determine optical purity by polarimetry and
rotations should be measured at the same concentration,
temperature and in the same solvent when making compari-
sons with literature values. The 85:15 mixture of 1 (c 0.45) and
pseudoheliotridane (c 0.07) were measured at cZ0.5 (EtOH)
giving the concentrations shown in parentheses for each
species. Thus the concentration of 1 is close to the reported
literature concentration of cZ0.5 and pseudoheliotridane is at
1/6th the concentration of the reported value (i.e., c 0.5). See:
Eliel, E. L.; Whilen, S. H. Stereochemistry of Organic
Compounds; Wiley-Interscience: New York, 1994; pp 217–
221 and 1071–1080.
21. Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675–676.
22. Montierth, J. M.; DeMario, D. R.; Kurth, M. J.; Schore, N. E.
Tetrahedron 1998, 54, 11741–11748.
23. Nicolaou, K. C.; Ramphal, J. Y.; Abe, Y. Synthesis 1989,
898–901.
24. Stille, J. K.; Simpson, J. H. J. Am. Chem. Soc. 1987, 109,
2138–2152.
25. Yenjai, C.; Isobe, M. Tetrahedron 1998, 54, 2509–2520.
26. Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc.
1994, 116, 3231–3239.
27. (a) Dieter, R. K.; Topping, C. M.; Chandupatla, K. R.; Lu, K.
J. Am. Chem. Soc. 2001, 123, 5132–5133. (b) Dieter, R. K.;
Oba, G.; Chandupatla, K. R.; Topping, C. M.; Lu, K.; Watson,
R. T. J. Org. Chem. 2004, 69, 3076–3086. (c) Kocienski, P.;
Bell, R.; Bourque, E.; Christopher, J. A.; Cooksey, J.; Gunn,
A.; Kuhl, A.; Li, Y.; Uppal, S.; Yuen, J. Pure Appl. Chem.
2004, 76, 477–494. For asymmetric deprotonation of O-alkyl-
carbamates and cuprate formation see: (d) Tomooka, K.;