Synthesis of (±)-isoretronecanol, (±)-curassanecine, (±)-heliotridane, (±)-tashiromine and (±)-5-epitashiromine via α-(N-carbamoyl)alkylcuprate chemistry

Article abstract of DOI:10.1016/S0040-4039(02)01835-X

Vinylation of N-Boc-2-pyrrolidinylcuprate reagents with functionalized vinyl iodides followed by N-Boc deprotection and cyclization affords 1-methylidine pyrrolizidine and indolizidine carbon skeletons. Functional group manipulation of the exo-cyclic olefin provides direct synthetic entries to the pyrrolizidine alkaloids (±)-isoretronecanol, (±)-curassanecine, (±)-heliotridane or the indolizidine alkaloids (±)-tashiromine and (±)-epitashiromine. This synthetic approach to pyrrolizidine and indolizidine alkaloids requires masking of the tertiary amine during functional group interconversions involving the alkene functionality.

Full text of DOI:10.1016/S0040-4039(02)01835-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7725–7728
Synthesis of ( )-isoretronecanol, ( )-curassanecine,
( )-heliotridane, ( )-tashiromine and ( )-5-epitashiromine via
a-(N-carbamoyl)alkylcuprate chemistry
R. Karl Dieter* and Rhett Watson
Department of Chemistry, Hunter Laboratory, Clemson University, Clemson, SC 29634-0973, USA
Received 13 August 2002; accepted 29 August 2002
Abstract—Vinylation of N-Boc-2-pyrrolidinylcuprate reagents with functionalized vinyl iodides followed by N-Boc deprotection
and cyclization affords 1-methylidine pyrrolizidine and indolizidine carbon skeletons. Functional group manipulation of the
exo-cyclic olefin provides direct synthetic entries to the pyrrolizidine alkaloids ( )-isoretronecanol, ( )-curassanecine, ( )-heliotri-
dane or the indolizidine alkaloids ( )-tashiromine and ( )-epitashiromine. This synthetic approach to pyrrolizidine and
indolizidine alkaloids requires masking of the tertiary amine during functional group interconversions involving the alkene
functionality. © 2002 Published by Elsevier Science Ltd.
Pyrrolizidine1 and indolizidine2 alkaloids are important
classes of biologically active natural products. Several
pyrrolizine imides display amnesia-reversal activity3
while the antineoplastic pyrrolizidine N-oxide, indicine
N-oxide, was examined in clinical trials.4 Indolizidine
alkaloids have been isolated from poison dart frogs and
many have neurological properties.5 The pyrrolizidine
alkaloids isoretronecanol (1),6 trachelanthamidine,6c,7
and heliotridane (3)8 and the indolizidines tashiromine
(+)-(4)6b,c,9 and (+)-5-epitashiromine (5)6c,9 have pro-
vided a framework for testing new synthetic method-
ologies applicable to alkaloid total synthesis. Although
several short syntheses have been devised for these
simple alkaloids, a number of annulation strategies
have involved long linear sequences. Our recent devel-
opment of a-(N-carbamoyl)alkylcuprate chemistry10
provided a synthetic methodology that could, in princi-
ple, be exploited for the rapid construction of the
bicyclic framework. The syntheses of ( )-isoretrone-
canol (1), ( )-curassanecine (2), ( )-heliotridane (3),
( )-tashiromine (4) and ( )-5-epitashiromine (5) were
undertaken to examine the utility of a-(N-car-
bamoyl)alkylcuprate chemistry in alkaloid synthesis
and to explore issues of stereocontrol resulting from
this strategy. Successful development of this approach
to alkaloids 1–5 is amenable to asymmetric synthesis
employing stereogenic a-(N-carbamoyl)alkylcuprates.11
The a-(N-carbamoyl)alkylcuprate annulation strategy
required the preparation of functionalized vinyl iodides
8 and 11 (Scheme 1). Hydroxy vinyl iodide 7, readily
prepared by addition of in situ generated HI12 to
alkynyl alcohol 6a, was converted to either the mesylate
8a or bromide 8b. Initial efforts to prepare 13 focused
on the alkylation of acetate enolates with propargyl
bromide. Although the enolate of ethyl acetate gave
complex mixtures, excellent yields of 12b (95%) were
obtained via alkylation of the enolate of tert-butyl
acetate with propargyl bromide. Addition of HI to 12b,
however, resulted in ester cleavage.
A synthetic
approach to 11 involving addition of HI to alkynyl
alcohol 6b yielded a mixture of 9 and 10, the latter
product arising via acid promoted intramolecular addi-
tion of the hydroxyl group to the triple bond followed
* Corresponding author. Tel.: 864-656-5025; fax: 864-656-6613; e-mail: dieterr@clemson.edu
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01835-X

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R. K. Dieter, R. Watson / Tetrahedron Letters 43 (2002) 7725–7728
Scheme 1. Reagents and conditions: (a) Me3SiCl, NaI, CH3CN, H2O (0.5 equiv.), 25°C. (b) (i) MsCl (1.1 equiv.), Et3N (1.2 equiv.),
CH2Cl2, −40°C; (ii) NaHCO3, Et2O. (c) LiBr, DMF, reflux, 1 h.
by iodide ion cleavage of the resulting a-methylene
tetrahydrofuran intermediate. The ratio of 9:10:6b
varied as a function of HI employed [20:60:20 with 2.0
equiv. of HI and 40:30:30 with 1.0 equiv.]. Commer-
cially available 6c was easily converted to 11b by addi-
tion of HI generated in situ.
25.7)], were obtained as an 85:15 mixture by treatment
of the borane–amine complexes with TMSCl/MeOH.
Initial approaches to ( )-curassanecine envisioned uti-
lization of an epoxide derived from 16. Efforts to
epoxidize 16 with either m-chloroperbenzoic acid,14
oxone15a or peroxytrifluoroacetic acid14b were unsuc-
cessful as were attempts to effect either halohydrin
formation16 or dihydroxylation.14b,15a Ozonolysis of 16
in trifluoroacetic acid/CH2Cl2 (2:1)17 afforded ketone
1818 in excellent yield. Reaction of 18 with benzyl-
oxymethyllithium generated from the corresponding
stannane19,20 or with dimethyl sulfonium methylide21
yielded, after workup, black chloroform insoluble mate-
rials. With these carbanions, the reaction mixture
turned black immediately upon addition of ketone 18,
although the 1,2-nucleophilic addition of n-BuLi
appeared to occur uneventfully. Unable to execute 1,2-
nucleophilic addition to ketone 18, an effort to epoxi-
dize the BF3 complex of 16 was undertaken.22
Treatment of neat 16 with BF3·Et2O quantitatively
afforded 19 (Scheme 3) which upon reaction with m-
chloroperbenzoic acid (CH2Cl2, 25°C, 7 days) gave a
complex mixture after treatment with 10% aqueous
The pyrrolidinyl cuprate generated from 14 afforded
excellent yields of the vinylation products 15a or 15b
uneventfully (Scheme 2).10b,c Utilization of the alkyl-
cyanocuprate reagent (i.e. RCuCNLi) efficiently con-
serves the a-(N-carbamoyl)alkyl ligand. N-Boc depro-
tection and cyclization13 of 15a or 15b to 16 could be
effected with either trimethylsilyl triflate (TMSOTf) or
with TMSCl/NaI/MeCN. Simple hydrogenation of 16
afforded ( )-heliotridane (3) and its diastereomer
(85:15) while hydroboration–oxidation afforded amine–
borane complex 17 after aqueous work-up. The amine–
borane complex 17 and its diastereomer were readily
purified by column chromatography. ( )-Isoretrone-
canol (1) [1H NMR l 3.60 (d, J=7.3 Hz, 2H); lit.:6d
l
3.60 (d, J=7.0 Hz, 2H)] and its diastereomer, ( )-
lauburnine [13C NMR l 67.5, 64.7, 54.8, 54.2, 48.0, 32.0,
30.0, 25.0 (lit.:6b l 67.5, 64.9, 54.7, 52.7, 48.5, 32.0, 30.1,
Scheme 2. Reagents and conditions: (a) (i) sec-BuLi, THF, TMEDA, −78°C, 1.25 h; (ii) CuCN·2LiCl (1.0 equiv.), −78°C, 1 h; (iii)
8a or 8b, −78°C, 4 h. (b) TMSOTf (1.0 equiv.), CH2Cl2, under Ar, −20 to 25°C, 12 h (92%). (c) TMSCl, NaI, CH3CN (dry) (89%).
(d) H2, Pd/C (10%), CH2Cl2, 12 h (99%). (e) (i) BH3·THF, THF, 0–25°C, 1 h; (ii) 10 M NaOH (3 equiv.), H2O2 (30%, 5 equiv.),
0–25°C, 12 h, (96%). (f) MeOH, TMSCl, 1 h, 25°C. (g) CF3COOH, O3, −78°C, 20 min, (80%).

R. K. Dieter, R. Watson / Tetrahedron Letters 43 (2002) 7725–7728
7727
Scheme 3. Reagents and conditions: (a) (i) BF3·Et2O (2.0
equiv.), 12 h; (ii) high vacuum, remove excess BF3·Et2O
(100%). (b) m-CPBA (2.0 equiv.), CH2Cl2, 25°C, 7 days. (c)
10% aq. HCl, 12 h. (d) 6 M HCl, 2 h (46–50%). (e) CsF,
CH3CN, reflux, 12 h.
Scheme 4. Reagents and conditions: (a) (i) sec-BuLi, THF,
TMEDA, −78°C, 0.75–1.25 h; (ii) CuCN·2LiCl (1.0 equiv.),
−78°C, 1 h; (iii) 11a or 11b, −78°C, 4 h. (b) TMSOTf,
CH2Cl2, −40°C, 12 h. (c) (i) BH3·THF, THF, 0–25°C, 1 h; (ii)
10 M NaOH (3 equiv.), H2O2 (30%, 5 equiv.), 0–25°C, 12 h.
(d) MeOH, TMSCl, 1 h, 25°C.
HCl in contrast to literature suggestions of low epoxi-
dation yields.22 The 13C NMR spectrum of this mixture
displayed 32 absorption peaks. Further treatment of
this material with 6 M HCl afforded material that
displayed 16 absorption peaks in the 13C NMR spec-
trum while the 19F NMR spectrum indicated the con-
tinued presence of an amine–borane complex. These
results are consistent with the initial formation of a
mixture of diastereomeric epoxides and diols (four com-
pounds each with eight carbon atoms) which are con-
verted to the two diastereomeric diols upon treatment
with 6 M HCl. DEPT, COSY, NOESY and difference
NOE NMR experiments on the two component sample
supported structural assignments as the BF3-complexes
of ( )-curassanecine 20 and its diastereomer 21. Efforts
to cleave the BF3-complexes with 10% NaOH (80°C, 30
min) or concentrated NH4OH (80°C, 12 h) yielded only
recovered complex.23 Treatment of the 20+21 mixture
with CsF in acetonitrile gave ( )-2 [13C NMR l 80.1,
70.5, 68.1, 55.7, 53.3, 39.1, 27.8, 25.3 (lit.:24 l 80.3, 70.8,
68.3, 55.7, 53.3, 39.2, 27.8, 25.4)] and recovered ( )-21
[19F NMR l −150.5 and identical 13C NMR absorp-
tions as before treatment with CsF] as a 75:25–80:20
mixture, respectively.
reflux temperatures in THF gives a 66:34 ratio of 4:5
after BH3 decomplexation with TMSCl/MeOH. The
BH3 complex thus facilitates isolation and purification
of these highly water soluble amino alcohols. Addi-
tional efforts to maximize this stereoselectivity were not
made.
In summary, a-(N-carbamoylalkyl)cuprate chemistry
offers
a rapid entry into the pyrrolizidine and
indolizidine carbon skeletons via a two pot process of
cuprate coupling with a functionalized vinyl iodide
followed by a tandem N-Boc deprotection–cyclization
sequence. This strategy requires manipulation of func-
tionality for elaboration of the stereochemistry and
functional group substitution patterns of the natural
products subsequent to the generation of the tertiary
bridgehead amine. 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
complex or as a salt by reaction with a strong protic
acid or with a Lewis acid such as BH3 or BF3·Et2O.
The amine–borane complexes are quite useful for the
isolation and characterization of reaction products and
can be easily converted to the free amines by treatment
with either TMSCl–MeOH or CsF. The a-(N-car-
bamoylalkyl)cuprate is particularly attractive because
the cuprate coupling reaction can be achieved with high
enantioselectivity.11
The same strategy can be employed for construction of
the indolizidine skeleton (Scheme 4). Vinylation of the
cuprate generated from 14 with 11a or 11b affords 22a
or 22b, respectively, both of which undergo N-Boc
deprotection and cyclization to give 23 in excellent
yields. Hydroboration–oxidation of 23 with BH3·THF
gives a 70:30 mixture of ( )-tashiromine (4) [1H NMR
l 3.62 (dd, J=10.7, J=4.6 Hz, 1H), 3.48 (dd, J=10.8,
J=6.1 Hz, 1H); lit.:6c l 3.61 (dd, J=10.9, J=4.7 Hz,
1H), 3.44 (dd, J=10.9, J=6.5 Hz, 1H)] and ( )-5-epi-
tashiromine (5) [1H NMR l 4.15 (dd, J=10.9, J=4.1
Hz, 1H), 3.71 (bd, J=9.7, 1H); lit.:6c l 4.18 (dd,
J=10.7, J=4.0 Hz, 1H), 3.74 (dd, J=10.7, 1H)] after
cleavage of the initially formed amine–borane com-
plexes [i.e. ( )-4-BH3 and ( )-5-BH3]. Reaction of 23
with 9-BBN followed by oxidation gave a low yield of
organic material upon extraction with CH2Cl2 while
9-BBN hydroboration–oxidation of 23-BH3 complex at
Acknowledgements
This work was generously supported by the National
Institutes of Health (GM-60300-01). Support of the

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R. K. Dieter, R. Watson / Tetrahedron Letters 43 (2002) 7725–7728
NSF Chemical Instrumentation Program for purchase
of a JEOL 500 MHz NMR instrument is gratefully
acknowledged (CHE-9700278).
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