Iminium ion cascade reactions: stereoselective synthesis of quinolizidines and indolizidines

Article abstract of DOI:10.1016/j.tet.2008.10.074

A novel iminium ion cascade reaction has been developed that allows for the stereoselective synthesis of a variety of substituted aza-fused bicycles. The combination of amino allylsilanes and aldehydes (or ketones) was used to synthesize a number of quino

Full text of DOI:10.1016/j.tet.2008.10.074

Tetrahedron 65 (2009) 3222–3231
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Tetrahedron
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Iminium ion cascade reactions: stereoselective synthesis of quinolizidines
and indolizidines
*
Shawn M. Amorde, Ivan T. Jewett, Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas at Austin, 1 University Station A5300, Austin, TX 78712-0165, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel iminium ion cascade reaction has been developed that allows for the stereoselective synthesis of
a variety of substituted aza-fused bicycles. The combination of amino allylsilanes and aldehydes (or
ketones) was used to synthesize a number of quinolizidines and indolizidines in a one-pot reaction
sequence. This technology has been used to effect the facile syntheses of several indolizidine and qui-
nolizidine natural products including (ꢀ)-epilupinine, (ꢀ)-tashiromine, and (ꢁ)-epimyrtine. Substrate
scope has been examined varying the type of amino allylsilanes (primary, secondary, and conjugated)
and carbonyl compounds (aldehydes and ketones) to give a variety of fused ring structures. Varying the
components chosen allows for the inclusion of synthetically useful functional groups at different posi-
tions on the core structure. The methodology has been used to construct the tricyclic core structures
present in the cylindricine family and halichlorine.
Received 29 September 2008
Received in revised form 13 October 2008
Accepted 23 October 2008
Available online 26 October 2008
Keywords:
Iminium ion
Cascade reaction
Alkaloid synthesis
Stereoselective
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
HO
HO
H
N
O
H
H
The quinolizidine and indolizidine ring systems comprise core
structural subunits found in a large number of natural products
ranging from simple bicyclic alkaloids such as epilupinine (1),1
tashiromine (2),2 and epimyrtine (3)3 to more complex multicyclic
molecules like halichlorine (4)4 and cylindricine B (5).5 The diverse
structures of these compounds coupled with the biological activity
exhibited by many members of these families of alkaloids have
made natural products containing these ring systems popular tar-
gets for synthesis. Consequently it does not occasion surprise that
numerous methods and strategies have been developed for the
stereoselective construction of substituted quinolizidine and
indolizidines.6
We have had a longstanding interest in developing useful and
general entries to substituted quinolizidine and indolizidines dur-
ing the normal course of our general programs in alkaloid syn-
thesis.4e,7 In that context, we recognized that imines and their
activated derivatives play pivotal roles in the synthesis of nitrogen
heterocycles via a diverse array of bond-forming reactions.8 We
therefore became intrigued by the challenge of combining some of
these different constructions and inventing new cascade reactions
involving imines and allylsilanes as the key reaction partners to
rapidly access the quinolizidine and indolizidine frameworks.
Cascade reactions are becoming increasingly attractive as synthetic
N
N
1
2
3
H
N
O
O
O
Me
Cl
N
H
Cl
C6H13
5
OH
4
tools because they involve multiple reactants and sequential bond-
forming events in which the product of one reaction is pre-
programmed to be the starting material for the next one in
a domino-like process.9 Such methods have gained popularity be-
cause they may enable the rapid assembly of complex molecular
architectures in one-pot operations that can be highly efficient.10
Our design strategy was guided by evaluating various possibil-
ities in which the different reactivity modes of imines as electro-
philes and nucleophiles might be combined in tandem with the
nucleophilic reactivity profile of allylsilanes to prepare nitrogen
heterocycles having bridgehead nitrogen atoms. The plan that
eventuated is outlined in general terms in Scheme 1 and enables
* Corresponding author. Tel.: þ1 512 471 3915; fax: þ1 512 471 4180.
E-mail address: sfmartin@mail.utexas.edu (S.F. Martin).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.074

S.M. Amorde et al. / Tetrahedron 65 (2009) 3222–3231
3223
the synthesis of a diverse array of nitrogen heterocycles 7–9 from
the cascade reactions of monoprotected dicarbonyl compounds of
the general form 6 with the amino allylsilanes 10–13, followed by
a terminating step in which the penultimate intermediate iminium
ion is trapped with a nucleophile. The ring sizes in 7–9 could be
controlled by simply varying the number of carbon atoms in the
tethers linking the reacting functional groups in 6 and 10–13.11 An
attractive feature of this entry to quinolizidines and indolizidines is
the high level of convergency wherein three components may be
integrated into a product in a single chemical operation.
give the acyclic imine 16. Although several reaction manifolds are
available to 16, acid-catalyzed expulsion of methanol would form
an intermediate oxocarbenium ion, cyclization of which onto the
imine nitrogen atom would furnish 17 that could in turn undergo
cyclization via addition of the allylsilane moiety to the iminium ion
to provide 18.8a,12 Ionization of the N,O-acetal moiety of 18 in situ
would generate another iminium ion that would be trapped with
the nucleophile, Nuꢁ, to deliver the fused bicyclic amine 15. Based
upon principles of stereoelectronic control,13 we anticipated that
the nucleophile would add from an axial direction. Notably, four
new bonds and two rings are formed from three different components
in a single chemical operation. Similar mechanistic pathways may be
set forth for the reactions of 14 with the branched allylsilane 12 and
the pentadienyl silane 13 to give 19 and 20, respectively.
H
N
H
N
O
MeO OMe
10 or 11
H+ then Nu
12
( )n
R
H+ then Nu–
( )n
Nu
( )n
Nu
( )m
R
6: R = H, alkyl, etc
R
2. Results and discussion
n = 0,1
7
8
13
H+ then Nu–
Having conceived of the iminium cascade processes outlined in
Schemes 1 and 2, the first task was to establish the feasibility of
such constructions. Toward that end, we first condensed the known
aminosilane 1114 with the monoacetal aldehyde 14, which was
prepared by the procedure of Schreiber,15 and the resulting imine
was treated directly with a number of different Brønsted and Lewis
acids to induce the desired cascade. After rather extensive experi-
mentation using different temperatures, solvents, and acids, we
eventually discovered that cyclization of the intermediate imine
proceeded best at ꢁ40 ꢂC in acetonitrile in the presence of tri-
fluoroacetic acid. After adding triethylsilane to reduce the putative
iminium ion generated in situ, the quinolizidine 22 was isolated in
75% yield as a single diastereomer (Scheme 3).
R = H, n = 1
H
N
R
Nu
9
TMS
TMS
NH2
NH2
NH2
( )
TMS
m
12
13
10: m = 0
11: m = 1
Scheme 1.
1) 4 Å sieves, CH3CN
then
TMS
H
1
The putative mechanistic underpinnings for forming bicyclic
nitrogen heterocycles related to 7 are exemplified in Scheme 2 for
the formation of 15 from the acid-catalyzed reaction of the amino
allylsilane 11 with the monoprotected dialdehyde 14, which cor-
responds to 6 (R¼H, n¼1), followed by quenching the penultimate
iminium ion intermediate with a generic nucleophile, Nuꢁ. Thus,
the sequence commences with the condensation of 11 with 14 to
TFA, CH3CN, –40 °C
9a
( )n
+
O
( )n
NH2
( )m
2) Et3SiH
N
( )m
MeO OMe
dr > 95:5
10: m = 0
11: m = 1
21: n = 0
14: n = 1
22: m = 1, n = 1 (75%)
23: m = 0, n = 1 (45%)
24: m = 1, n = 0 ( 36%)
HO
H
N
1) TFA then
H
O3
TMS
H+ then Nu–
( )n
2) LiAlH4
( )m
+
NH2
O
N
MeO OMe
1: m = 1, n = 1 (88%)
25: m = 0, n = 1 (83%)
2: m = 1, n = 0 (56%)
Nu
11
14
15
Scheme 3.
Nu–
–MeOH
–H2O
Using the standardized conditions developed for the optimized
preparation of 22, the known allyl aminosilane 1016 was allowed to
condense with the aldehyde 14, and the resultant imine was treated
sequentially with TFA and then Et3SiH to provide the indolizidine
23 as a single stereoisomer in 45% yield.1c Similarly, reaction of the
allylic aminosilane 11 with the monoprotected dialdehyde 21,15
followed by addition of TFA and then Et3SiH furnished the indoli-
zidine 24 in 36% yield as a single stereoisomer. The relative ste-
reochemistry between the two newly created stereocenters at C(1)
and C(9a) of 22 was tentatively assigned based upon the observed
coupling constant of 12.0 Hz of the trifluoroacetate salt of 22. This
assignment as well as the structural assignments for 23 and 24
were confirmed by the conversion of these intermediates into
known compounds (vide infra). Although the syntheses of indoli-
zidines via this cascade reaction were less efficient than for
TMS
TMS
H+
–TMSX
N
N
N
–MeOH
MeO OMe
OMe
OMe
16
17
18
H
N
H
N
Nu
Nu
19
20
Scheme 2.

3224
S.M. Amorde et al. / Tetrahedron 65 (2009) 3222–3231
quinolizidines, the levels of stereoselectivity were high. Un-
fortunately, preliminary efforts to extend such processes to the
preparation of pyrrolizidines have proven unsuccessful.
quinolizidine systems,21 in the major isomer was assigned based
upon examination of the 1H NMR spectrum of 31. The 1H NMR
spectrum of the minor stereoisomer, which was assigned as having
The ultimate test of any new synthetic method or strategy lies in
its applicability to the preparation of targets that may be of interest,
and it did not escape attention that compounds 22 and 24 might be
readily transformed into natural quinolizidines and indolizidines.
Indeed, although compound 22 was a known intermediate in
a previous synthesis of (ꢀ)-epilupinine (1),1c we developed an
improved protocol for effecting this conversion. Namely, ozonolysis
of the trifluoroacetate salt of 22, followed by reduction of the in-
termediate ozonide with LiAlH4 furnished synthetic (ꢀ)-epi-
lupinine (1), which gave 1H and 13C NMR spectral data consistent
with those reported, in 88% yield (Scheme 3).1f Compound 24 was
converted into the natural product (ꢀ)-tashiromine (2) in 56% yield
via ozonolysis of its trifluoroacetate salt followed by hydride re-
duction of the ozonide thus obtained. The synthetic 2 gave 1H and
13C NMR spectral data consistent with those reported.2a,d Similarly,
compound 23 was converted into the known indolizidine 25.1c,17
Having succeeded in preparing simple vinyl-substituted qui-
nolizidines and indolizidines, we turned our attention to trap the
penultimate iminium ion with nucleophiles other than a hydride
ion. Perhaps not unexpectedly, several initial attempts to trap the
iminium ion generated from the reaction of with organometallic
reagents such as alkyllithium and alkyl Grignard reagents formed
an unstable enamine as the major product. However, we discovered
that the intermediate iminium ion 26 could be readily trapped by
the nucleophilic addition of cyanide ion under phase-transfer
conditions to give the aminonitrile 27 as a single diastereomer in
79% overall yield (Scheme 4). As will be demonstrated in discus-
a b-CN group, the hydrogen at C(6) exhibited a large coupling
constant (J¼10.4 Hz) indicative of an axial–axial interaction and
suggesting that the cyano group was equatorial.
TMS
4 Å MS, CH3CN; then
TFA, CH3CN, –40 °C;
then NaCN (aq), CH2Cl2
O
+
R
NH2
MeO OMe
12
14: R = H
28: R = Me
29: R = Et
30: R = C CCH3
H
9a
N
6
R
CN
31: R = H (89%; 88:12)
32: R = Me (65%; >95:5)
33: R = Et (60%; >95:5)
CCH3 (75%; 3:2)
34: R = C
Scheme 5.
The nature of the monoprotected dicarbonyl component was
then extended to include the ketal aldehydes 28–30, which were
generally prepared according to the plan outlined in Scheme 6.
These aldehydes were each condensed with the branched allylsi-
lane 12, and the intermediate imines were treated with trifluoro-
acetic acid to initiate cyclization; addition of cyanide ion in the last
step then afforded the aminonitriles 32–34 (Scheme 5). Because
there was no observed NOE interaction between the bridgehead
hydrogen atom and those on the R group at C(6), these groups were
tentatively assigned as being trans to each other.22
sions that follow, it is noteworthy that a-aminonitriles such as 27
are versatile synthetic intermediates that may serve as precursors
of nucleophiles (via deprotonation)18 or electrophiles via Bruylants
reactions.19
H
4 Å MS, CH3CN;
TFA, CH3CN, –40 °C
11 + 14
N
1) MeNH(OMe) HCl
R3SiO
CF3CO2
Me3Al, CH2Cl2
26
R
O
2) R3SiCl, DMAP, CH2Cl2
3) RMgBr, THF
O
O
H
N
36: R3Si = TIPS; R = Me
37: R3Si = TBDPS; R = Et
38: R3Si = TBDPS; R = C CCH3
35
NaCN (aq), CH2Cl2
79%
6
CN
27
1) HC(OMe)3, acid, MeOH
2) (n-Bu)4NF, THF
O
Scheme 4.
R
3) IBX or PDC
We had thus established the viability of using cascade reactions
of dialdehyde monoacetals and the linear amino allylsilanes 10 and
11 for the rapid formation of indolizidine and quinolizidine alka-
loids and their precursors. At this juncture, we wished to explore
related processes involving branched amino allylsilanes and keto
aldehyde monoacetals. Toward this end, we first applied this
chemistry to the branched allylsilane 12 and the monoprotected
dialdehyde 14. In the event, condensation of 12 with 14 followed by
sequential treatment of the imine thus generated in situ with TFA
and then aqueous NaCN furnished an excellent yield of an epimeric
MeO OMe
28: R = Me
29: R = Et
30: R = C CCH3
Scheme 6.
It is noteworthy that the quinolizidines 31–34 each bear func-
tionality that might be further elaborated to give a variety of de-
rivatives. In order to illustrate the utility of this process, it was
applied to a concise, enantioselective synthesis of the quinolizidine
alkaloid (ꢁ)-epimyrtine (3) (Scheme 7). Thus, the known amino-
silane 3923 was condensed with the dialdehyde monoacetal 14 to
give an imine that was then treated sequentially with trifluoro-
acetic acid and aqueous NaCN to give a mixture of diastereomeric
mixture (88:12) of the aminonitrile 31, favoring the a-CN isomer
(Scheme 5).20 The presence of Bohlmann bands (2800–2700) in the
IR spectrum of 31 was consistent with a trans-ring fused quinoli-
zidine ring. The axial orientation of the cyano group, which is
consistent with the preferred conformation of cyano groups in

S.M. Amorde et al. / Tetrahedron 65 (2009) 3222–3231
3225
aminonitriles 40 in 90% yield. Subsequent reduction of 40 with
NaCNBH3 then provided a mixture (95:5) of epimeric quinolizi-
dines 41a,b. We were also able to reduce the intermediate bicyclic
iminium ion generated from the cascade reaction of 39 with 14
directly, but the yield of 41a,b was only about 60%. Formation of the
trifluoroacetate salt of 41a,b followed by ozonolysis of the exocyclic
olefin gave an inseparable mixture (95:5) of (ꢁ)-epimyrtine (3) and
(þ)-myrtine (42). The 1H and 13C NMR spectral data for synthetic 3
and the specific rotation for 3 were consistent with those reported.3
spectroscopy.13,25 In particular, the relative stereochemistry of the
spiro and bridgehead centers at C(9a) and C(6) in 45 was assigned
on the basis of NOE correlations observed in a GOESY experiment
performed on the TFA salt in which a strong interaction was ob-
served between the bridgehead proton at C(9a) and one of the
hydrogen atoms on the C(10) methylene group. This observation is
consistent with the cis-relationship between these protons in 45.
In order to extend this chemistry to the preparation of more
highly substituted spirocyclic quinolizidines that might better serve
as intermediates in syntheses of halichlorine and derivatives
thereof, we identified 47 as a potential target. Toward this end,
quinolizidine 34 was allowed to react with 3-butenylmagnesium
bromide to deliver quinolizidine 46 as a single diastereomer in
virtually quantitative yield (Scheme 9). The stereochemistry of 46
was assigned on the basis of a GOESY experiment in which NOE
interactions were observed between the protons at C(9a) and C(13).
The hydrochloride salt of 46 underwent facile enyne ring-closing
metathesis in the presence of Grubbs II catalyst (48) to provide 47
in 97% yield. The synthesis of 47, which comprises the tricyclic core
of halichlorine (4) is remarkable for its brevity, only three steps
from acyclic starting materials, and efficiency of 72% overall yield.
H
4 Å MS, 14, CH3CN;
TMS
then TFA, –40 °C;
N
NH2
then NaCN (aq), CH2Cl2
90%
H
CN
40
39
TFA; then
O3, CH2Cl2, MeOH
then Me2S
60%
NaCNBH3
MeOH
86%
N
41a: β-H
41b: α-H
H
N
H
N
H
N
O
MgBr
THF
>99%
9a
6
CN
13
3: -H
42: -H
34
46
H
Scheme 7.
HCl then
Grubbs II (10 mol%)
ethylene, benzene, rt
97%
9a
N
The potential utility of the
quences did not escape our attention. For example,
a
-aminonitriles formed in these se-
-aminonitriles
13
a
may be deprotonated with strong bases to generate stabilized
carbanions that may undergo reactions with a number of different
electrophiles, and they may also serve as iminium ion equivalents in
Bruylants and related processes.18a In order to exemplify the utility
47
N
N
Mes
Mes
Ph
Cl
Cl
of
a
-aminonitriles derived from our cascade reaction as precursors
-amino-
Ru
of interesting heterocyclic targets, a mixture of epimeric
a
P(Cy)3
nitriles 31 was readily transformed into the tricycle 45, which pos-
sesses a skeletal framework related to the core of halichlorine (4)
(Scheme 8). Thus, deprotonation of 31 with LDA followed by alkyl-
ation of the carbanion with the known tosylate 4324 gave 44 in good
yield. Subsequent exposure of 44 to AgOTf generated an iminium ion
in situ that underwent efficient cyclization via addition of the
allylsilane to give 45 as a single diastereomer.
48
Scheme 9.
The versatility of this cascade approach to substituted quinoli-
zidines may be further illustrated by the synthesis of the C(6)
epimer of 46 in an unoptimized, two-step sequence of reactions
H
H
N
H
LDA, Et2O; then
H
N
NC
49
Br
LDA, Et2O; then 43
N
NC
44
CN
N
50%
67%
31
CN
TMS
31
H
N
9a
2
MgBr
THF
67%
H
AgOTf, CD3CN
9a
N
10
OTs
H
10
TMS
6
110 °C
81%
43
50
Scheme 10.
45
Scheme 8.
from 31 (Scheme 10). Thus, deprotonation of 31 followed by al-
kylation with 4-bromobutane led to aminonitrile 49, which un-
derwent a Bruylants reaction with propynylmagnesium bromide to
That the cyclization to give 45 proceeded in accord with the
principles of stereoelectronic control was verified by NMR
deliver quinolizidine 50 as a
single diastereomer.18a,23 The

3226
S.M. Amorde et al. / Tetrahedron 65 (2009) 3222–3231
stereochemistry of 50 was assigned on the basis of a GOESY ex-
periment that revealed a NOE interaction between the equatorial
proton on C(2) with the C(10) proton. There was no NOE between
the protons at C(9a) and C(10).
Me Me
OH
+
Si
Et3N, DMAP
CH2Cl2
O
Si(Me)2Cl
67%
We had thus verified that the cascade processes generally out-
lined in Scheme 1 could be applied to the syntheses of quinolizi-
dines and indolizidines lacking substituents at the bridgehead
position. However, there are a number of quinolizidine alkaloids
such as cylindricine (5) that bear alkyl substituents on the bridge-
head carbon atom. In order to probe whether cascade iminium ion
reactions could be implemented to fabricate the tricyclic core of
cylindricine, the known keto acetal 5126 was first condensed with
the amino allylsilane 12. Trifluoroacetic acid was then added to the
reaction, and the resulting tricyclic iminium was trapped with cy-
anide ion to provide a mixture (2.8:1.0:1.7:1.7) of diastereomers
52a,b and 53a,b in 66% combined yield (Scheme 11). Compound
52a was isolated and crystallized, and X-ray crystallographic anal-
ysis enabled its unambiguous stereochemical assignment. When
the mixture of 52a,b and 53a,b was treated with sodium borohy-
dride, an inseparable mixture (1.1:1.0) of the two diastereomeric
tricyclic amines 54 and 55 was obtained.
56
57
58
Me Me
Si
O
Grubbs II-Hoveyda
ethylene, CH2Cl2
40 °C
MeMgBr
THF, 0 °C
58%
60
1) DPPA, DIAD
Ph3P, Et2O
TMS
TMS
2) LiAlH4, Et2O
49%
OH
61
NH2
13
N
N
Mes
Mes
Cl
Cl
Ru
O
OMe
OMe
TMS
O
4 Å MS, CH3CN, 70 °C;
then TFA, –40 °C to rt;
+
+
then NaCN (aq), CH2Cl2
66%
NH2
59
Scheme 12.
51
12
Gratifyingly, we found that condensation of 13 with the monop-
rotected dialdehyde 14, followed by the addition of trifluoroacetic
acid and subsequent nucleophilic trapping with cyanide furnished
a separable mixture (18:82) of aminonitriles 62a,b in 32% combined
yield (Scheme 13). The relative chemistry between C(5a) and C(9)
was assigned based upon the observation of NOE interactions be-
tween the protons at these positions in a GOESY experiment with
the minor diastereoisomer 62a. Despite the modest yield in this
reaction, the result is noteworthy as it represents the first example
of the use of a conjugated dienylsilane in an intramolecular Man-
nich-like reaction.28
NaBH4, MeOH
0 to 50 °C
60%
N
N
CN
52a: β-CN
52b: α-CN
CN
53a: β -CN
53b: α -CN
H
N
54: β-H
55: α-H
O
Scheme 11.
+
H
NH2
TMS
MeO OMe
As foreshadowed in the introductory discussion of our general
approach to polycyclic nitrogen heterocycles via the iminium ion
cascade reactions outlined in Scheme 1, we were also intrigued by
the possibility of using amino dienylsilanes 13 as reacting partners
to allow access to more highly functionalized products. Because 13
was unknown, it was necessary to devise a means for its synthesis.
Toward this end propargyl alcohol (56) was treated with allyl
chlorodimethylsilane (57) in the presence of base to give silyloxy
ether 58 (Scheme 12). Ring-closing enyne metathesis of 58 using
3 mol % of the Grubbs II–Hoveyda catalyst 59 under an ethylene
atmosphere gave the volatile cyclic silyloxy ether 60, which was not
isolated by rather treated directly with methylmagnesium bromide
to yield the hydroxy allylsilane 61 in 58% yield over two steps.27 The
hydroxyl group of the allylsilane 61 was converted into an azide
function via a Mitsunobu reaction that surprisingly proceeded to
give a mixture (3:1) of E- and Z-isomer. Preliminary efforts to avoid
forming a mixture of geometric isomers were unsuccessful. Be-
cause the obtention of a mixture of geometric isomers was pre-
sumably inconsequential for the purpose at hand, we did not
attempt to separate the isomers. Subsequent reduction of the azide
gave the desired amino E-/Z-dienylsilanes 13.
13
14
H
4 Å MS, CH3CN; then
TFA, CH3CN, –40 °C;
then NaCN (aq), CH2Cl2
32%
5a
N
9
CN
62a: -CN
62b: -CN
Scheme 13.
3. Conclusion
In summary we have developed a number of related cascade
reactions in which iminium ions are generated and trapped by
allylsilanes and other nucleophiles such as cyanide ion and hydride
donors to give functionalized quinolizidines and indolizidines
according to the general plan set forth in Scheme 1. This novel
cascade sequence features
a one-pot process involving the

S.M. Amorde et al. / Tetrahedron 65 (2009) 3222–3231
3227
formation of two rings and four new bonds from simple acyclic
starting materials. A variety of amino allylsilanes and monop-
rotected dicarbonyl compounds may serve as inputs in these re-
actions. The practical utility of this new entry to polycyclic nitrogen
heterocycles was convincingly demonstrated by its application to
the facile syntheses of a number of quinolizidine and indolizidine
alkaloids including (ꢀ)-epilupinine, (ꢁ)-epimyrtine, and
(ꢀ)-tashiromine as well as the tricyclic core structures of the more
complex alkaloids halichlorine and cylindricine. Significantly, the
amino nitrile function that may be obtained in some of these cas-
cade reactions serves as a convenient functional handle for the
introduction of a variety of other substituents onto the heterocyclic
framework. Further applications of these processes to the prepa-
ration of targets of biological interest are under active investigation,
and the results will be reported in due course.
NaOH saturated with NaCl (15 mL) and extracted with Et2O
(3ꢃ15 mL). The combined organic layers were dried (K2CO3) and
concentrated under reduced pressure (300 mmHg). The crude
residue was purified by flash chromatography eluting with pen-
tane/EtOH (60:1). An aliquot of the fractions containing pure 22
was concentrated under reduced pressure (300 mmHg) to give an
analytical sample for characterization. The remaining fractions
containing pure 22 were combined, CF3CO2H (1.5 mL) was added,
and the mixture was concentrated under reduced pressure to give
444 mg (75%) of the trifluoroacetate salt of 22 as a single di-
astereomer as a pale yellow oil. 1H NMR (500 MHz, CD3CN)
d 5.60
(ddd, J¼17.5,10.0, 9.0 Hz,1H), 4.99 (ddd, J¼17.5, 2.0,1.0 Hz,1H), 4.94
(dd, J¼10.0, 2.0 Hz, 1H), 2.76–2.69 (comp, 2H), 2.00–1.93 (comp,
2H), 1.85 (app tdd, J¼11.0, 9.0, 3.0 Hz, 1H), 1.74 (app dp, J¼13.0,
2.5 Hz, 1H), 1.74–1.64 (comp, 2H), 1.63–1.54 (comp, 4H), 1.54–1.46
(m, 1H), 1.23–1.13 (comp, 2H), 1.04 (app dq, J¼10.5, 3.5 Hz, 1H); 13C
4. Experimental
4.1. General
NMR (125 MHz) d 142.2, 114.8, 66.5, 57.2, 56.9, 48.3, 32.5, 31.3, 26.4,
25.6, 25.2; IR (neat) 3400, 3079, 2953, 2869, 2723, 2627, 2584, 1738,
1671, 1448, 1201 cmꢁ1; mass spectrum (CI) m/z 166.1591 [C11H20
(Mþ1) requires 166.1596], 164, 194, 248, 327, 329, 341, 399, 401.
N
Tetrahydrofuran, dimethylformamide, acetonitrile, and toluene
were dried according to the procedure described by Grubbs.29 All
solvents were determined to contain less than 50 ppm H2O by Karl
Fischer coulometric moisture analysis. Triethylamine was distilled
from calcium hydride prior to use. Reactions involving air or
moisture sensitive reagents or intermediates were performed un-
der an inert atmosphere of nitrogen or argon in glassware that was
flame dried. Thin layer chromatography was run on pre-coated
silica gel plates with a 0.25 mm thickness containing 60F-254 in-
dicator (Merck), and the plates were visualized by staining with
AMCAN (ammonium molybdate/cerium ammonium nitrate), po-
tassium permanganate, or p-anisaldehyde. Flash chromatography
was performed using the indicated solvent system on 230–400
mesh silica gel (E. Merck reagent silica gel 60) according to Still’s
protocol.30 Melting points are uncorrected. Infrared (IR) spectra
were obtained as solutions in the solvent indicated. Proton nuclear
magnetic resonance spectra (1H NMR) were obtained in CDCl3 so-
lutions, and chemical shifts are reported in parts per million (ppm)
referenced to the solvent. Coupling constants (J) are reported in
hertz (Hz) and the splitting abbreviations used are: s, singlet; d,
doublet; t, triplet; app t, apparent triplet; q, quartet; m, multiplet;
comp, complex multiplet; br, broad. Carbon nuclear magnetic res-
onance spectra (13C NMR) were obtained using CDCl3 as the in-
ternal reference.
4.3. (1S
*
,8aS )-1-Vinyloctahydroindolizine (23)
*
Prepared in 45% yield in accordance with the representative
procedure. 1H NMR (500 MHz, CD3CN)
d
5.70 (ddd, J¼17.0, 10.5,
8.0 Hz, 1H), 5.18 (ddd, J¼17.0, 1.5, 1.0 Hz, 1H), 5.18 (ddd, J¼10.5, 1.5,
1.0 Hz, 1H), 3.62–3.56 (comp, 2H), 3.05–2.97 (m, 1H), 2.86–2.74
(comp, 2H), 2.64 (app p, J¼8.5 Hz, 1H), 2.20 (app ddt, J¼11.5, 9.5,
7.5 Hz, 1H), 2.04–1.94 (m, 1H), 1.90–1.80 (comp, 3H), 1.73–1.64 (m,
1H), 1.55–1.40 (comp, 2H); 13C NMR (125 MHz)
d 137.9, 118.7, 70.7,
53.4, 52.7, 47.2, 27.6, 27.1, 23.8, 22.8. The spectral data are in ac-
cordance with reported spectra for 23.1c
4.4. (8S
*
,8aS )-8-Vinyloctahydroindolizine (24)
*
Prepared in 36% yield in accordance with the representative
procedure. 1H NMR (500 MHz, CD3CN)
d
5.71 (ddd, J¼17.0, 10.0,
8.0 Hz, 1H), 5.23 (d, J¼17.0 Hz, 1H), 5.13 (d, J¼10.0 Hz, 1H), 3.70–
3.60 (comp, 2H), 3.07–2.88 (comp, 2H), 2.39–2.33 (m, 1H), 2.28–
2.22 (m, 1H), 2.06–2.00 (comp, 3H), 1.92–1.82 (comp, 2H), 1.75–1.67
(m, 1H), 1.52–1.44 (m, 1H); 13C NMR (125 MHz)
d 138.3, 117.7, 70.4,
54.1, 52.3, 45.7, 30.1, 28.4, 24.0, 20.0; IR (neat) 2923,1454,1376, 725;
mass spectrum (CI) m/z 152.143559 [C10H17N (Mþ1) requires
152.143925], 371, 222, 152 (base), 97.
4.2. Representative procedure for the reductive cascade
4.5. ( )-Epilupinine (1)
reaction: synthesis of (1S
*
,9aS )-1-vinyloctahydro-1H-
*
quinolizine (22)
The trifluoroactetate salt of 22 (75 mg, 0.27 mmol) was dis-
solved in Et2O (3 mL) and ozone was passed through the stirred
solution at ꢁ78 ꢂC until the solution turned blue. Air was then
passed through the reaction mixture for 5 min. A solution of LiAlH4
(51 mg, 1.5 mmol) in THF (2 mL) was added, the dry ice bath was
removed, and the suspension was stirred at room temperature for
12 h. H2O (0.05 mL), 5% NaOH (0.05 mL), and H2O (0.15 mL) were
added dropwise sequentially with stirring, and the mixture was
stirred until the suspension turned white. The solids were removed
by vacuum filtration and washed with Et2O. The combined filtrate
and washings were concentrated under reduced pressure to give
40 mg (88%) of 1 as a colorless oil. Recrystallization of the crude
product from pentane provided a white solid; (mp 79–80 ꢂC; lit.1f
Freshly prepared amine 11 (363 mg, 2.12 mmol) was added
dropwise to a suspension of freshly prepared aldehyde 14 (310 mg,
2.12 mmol) and molecular sieves (4 Å, 0.50 mg) in CH3CN (2.0 mL)
at 0 ꢂC. The ice bath was removed, and the mixture was stirred for
2 h at which time the solution was transferred via syringe to a flame
dried round-bottom flask. Additional CH3CN (30 mL) was added,
and the mixture was cooled to 0 ꢂC with stirring. Freshly distilled
CF3CO2H (2.4 g, 1.6 mL, 21.2 mmol) was added dropwise, and the
reaction mixture was stirred for 2 h. The ice bath was removed, and
the solution was stirred at room temperature for 12 h. Neat Et3SiH
(2.5 g, 3.2 mL, 21.2 mmol) was then added dropwise, and the
mixture was heated under reflux for 24 h. The reaction mixture was
cooled to room temperature, and the solvents were removed under
reduced pressure. The crude residue was dissolved in Et2O (15 mL),
and a solution of 2 N HCl (15 mL) was added dropwise. The layers
were separated, and the aqueous layer was extracted with Et2O
(3ꢃ15 mL). The aqueous layer was made basic with a solution of 5%
78–79 ꢂC). 1H NMR (500 MHz, MeOD)
d
3.55 (dd, J¼11.0, 3.5 Hz,1H),
3.50 (dd, J¼11.0, 5.5 Hz, 1H), 2.83–2.74 (comp, 2H), 2.10–2.01
(comp, 2H), 1.98–1.94 (m, 1H), 1.84–1.54 (comp, 7H), 1.37–1.23
(comp, 3H), 1.16 (app tdd, J¼13.5, 11.0, 4.0 Hz, 1H); 13C NMR
(125 MHz) d 65.8, 64.4, 57.9, 57.7, 44.9, 30.4, 29.3, 26.3, 25.8, 25.4; IR
(neat) 3382, 2940, 2850, 2800, 2750, 2681, 2540, 2252, 2070, 1819,

3228
S.M. Amorde et al. / Tetrahedron 65 (2009) 3222–3231
1795, 1467, 1379, 1298, 1121, 1094 cmꢁ1; mass spectrum (CI) m/z
170.1537 [C10H19NO (Mþ1) requires 170.1545], 170 (base), 168, 152.
These spectral data are in accordance with reported spectra for
(ꢀ)-epilupinine.1f
1.20 (comp, 13H); 13C NMR (100 MHz)
d 146.8, 121.1, 108.3, 63.6,
56.2, 55.8, 42.4, 34.8, 33.2, 31.7, 23.5 cmꢁ1; mass spectrum (CI) m/z
177.1400 [C11H16N2 (Mþ1) requires 177.1391], 150 (base), 177.
4.8. (1R
*
,6R
*
,9aS )-1-Vinyl-6-cyanoquinolizidine (27)
*
4.6. ( )–Tashiromine (2)
Prepared in 79% yield in accordance with the representative
procedure. 1H NMR (500 MHz)
The trifluoroactetate salt of 24 (142 mg, 0.57 mmol) was dis-
solved in Et2O (5 mL) and ozone was passed through the stirred
solution at ꢁ78 ꢂC until the solution turned blue. Air was then
passed through the reaction mixture for 5 min. A solution of LiAlH4
(215 mg, 4.46 mmol) in THF (3 mL) was added, the dry ice bath was
removed, and the suspension was stirred at room temperature for
12 h. H2O (0.2 mL), 5% NaOH (0.2 mL), and H2O (0.6 mL) were added
dropwise sequentially with stirring, and the mixture was stirred
until the suspension turned white. The solids were removed by
vacuum filtration and washed with Et2O. The combined filtrate and
washings were concentrated under reduced pressure to give 44 mg
d
5.64 (ddd, J¼17.0, 10.0, 9.0 Hz, 1H),
5.02 (ddd, J¼17.0, 2.0, 1.0 Hz, 1H), 4.97 (dd, J¼10.0, 2.0 Hz, 1H), 3.88
(app t, J¼3.0 Hz, 2H), 2.67 (app dp, J¼11.0, 2.0 Hz, 2H), 2.33 (app dt,
J¼11.0, 1.0 Hz, 1H), 1.86–1.44 (comp, 10H), 1.28–1.20 (m, 1H), 1.07–
0.99 (m,1H); 13C NMR (125 MHz)
d 142.1,115.9, 99.2, 61.2, 56.2, 54.7,
49.0, 32.3, 31.2, 25.7, 21.5; IR (neat) 3075, 2935, 2858, 2814, 2747
(Bohlmann bands), 2221, 1641, 1442 cmꢁ1; mass spectrum (CI) m/z
191.1539 [C12H19N2 (Mþ1) requires 191.1548], 164 (base), 191, 220,
236, 263.
4.9. (4R
*
,9aR )-4-Methyl-8-methyleneoctahydro-1H-
*
(56%) of 2 as a colorless oil. 1H NMR (500 MHz, CD3CN)
d
3.46 (dd,
quinolizine-4-carbonitrile (32)
J¼11.0, 5.0 Hz,1H), 3.30 (dd, J¼11.0, 7.0 Hz,1H), 2.98 (app dp, J¼11.0,
2.0 Hz, 1H), 2.93 (app dt, J¼9.0, 2.5 Hz, 1H), 1.98 (app q, J¼9.0 Hz,
1H), 1.91–1.78 (comp, 3H), 1.70–1.48 (comp, 5H), 1.40–1.28 (comp,
Prepared in 65% yield in accordance with the representative
procedure. 1H NMR (500 MHz, C6H6)
d 4.57–4.55 (m, 2H), 3.10–3.07
2H), 1.04–0.90 (m, 1H); 13C NMR (125 MHz)
d
67.3, 65.4, 54.8, 53.4,
45.6, 29.9, 28.6, 26.1, 21.5; IR (neat) 3622, 3100 (broad peak), 2928,
2876, 2789, 2760, 2755, 2241, 2171, 1459, 1442, 1386, 1329 cmꢁ1
(m, 1H), 2.18–2.05 (comp, 5H), 1.91–1.86 (m, 1H), 1.82–1.79 (m, 1H),
1.61–1.51 (comp, 4H), 1.40 (s, 1H), 1.20–1.15 (m, 1H); 13C NMR
;
(125 MHz) d 144.9, 119.1, 107.7, 59.2, 49.4, 42.1, 38.5, 34.4, 33.2, 21.2;
mass spectrum (CI) m/z 156.1391 [C9H18NO (Mþ1) requires
156.1388], 156 (base). The spectral data are in accordance with
reported spectra for (ꢀ)-tashiromine.2a,d
IR (neat) 2976, 2938, 2860, 2814, 1659, 1444, 1371, 1281, 1228, 1198,
1122, 1096, 1036, 890 cmꢁ1; mass spectrum (CI) m/z 191.1544
[C12H19N2 (Mþ1) requires 191.1548], 191, 164 (base).
4.7. Representative procedure for the cascade reaction with
4.10. (4R
*
,9aR )-4-Ethyl-8-methyleneoctahydro-1H-
*
cyanide-trapping: synthesis of (4R
*
,9aR
*
)-8-methylene-
quinolizine-4-carbonitrile (33)
octahydro-1H-quinolizine-4-carbonitrile (31)
Prepared in 60% yield in accordance with the representative
Freshly prepared amine 12 (696 mg, 4.4 mmol) was added
dropwise to a mixture of freshly prepared 14 (642 mg, 4.4 mmol)
and molecular sieves (4 Å, 0.70 mg) in CH3CN (2.0 mL) at 0 ꢂC. The
ice bath was removed, and the mixture was stirred at room tem-
perature for 2 h. The supernatant was transferred via syringe to
another round-bottom flask, and additional CH3CN (50 mL) was
added. The mixture was cooled to ꢁ40 ꢂC, and freshly distilled
CF3CO2H (2.5 g, 1.7 mL, 22.0 mmol) was added dropwise. The re-
action mixture was stirred at ꢁ40 ꢂC for 4 h, whereupon the cooling
bath was removed and the mixture stirred at room temperature for
2 h. The solvents were removed under reduced pressure and the
residue was dissolved in CH2Cl2 (2.2 mL) at 0 ꢂC. A solution of NaCN
(1.0 g, 20.4 mmol) in H2O (3 mL) was added to the reaction, the ice
bath was removed, and the reaction mixture stirred at room tem-
perature for 12 h. CH2Cl2 (10 mL) and 0.5 M NaOH saturated with
NaCl were added, and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (3ꢃ25 mL), and the combined organic
layers were dried (K2CO3), and concentrated under reduced pres-
sure (300 mmHg). The crude residue was purified by flash chro-
matography eluting with pentane/Et2O (10:1). The fractions were
combined and concentrated under reduced pressure (300 mmHg)
to give 690 mg (89%) of an epimeric mixture (88:12) of 31 as a pale
procedure. 1H NMR (500 MHz)
d 4.64–4.63 (m, 2H), 3.10 (app dt,
J¼10.7, 3.8 Hz, 1H), 2.26–2.17 (m, 4H), 2.12–2.06 (m, 1H), 1.98 (app t,
J¼1.4 Hz, 1H), 1.88–1.81 (m, 3H), 1.72–1.60 (m, 4H), 1.28–1.18 (m,
2H), 0.97 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz)
d 145.1, 119.1, 107.5,
62.2, 59.2, 48.9, 42.3, 34.5, 33.8, 33.2, 30.8, 21.0, 7.4; IR (neat) 2880,
2838, 2817, 1660, 1444, 1382, 1281, 1186, 1098, 891 cmꢁ1; mass
spectrum (CI) m/z 205.1707 [C13H21N2 (Mþ1) requires 205.1705],
205, 178 (base).
4.11. 8-Methylene-4-(prop-1-ynyl)octahydro-1H-quinolizine-
4-carbonitrile (34)
Prepared in 75% yield in accordance with the representative
procedure. 1H NMR (500 MHz, CD3CN)
d
4.66 (ddt, J¼11.3, 1.8,
1.7 Hz, 2H), 3.61 (ddd, J¼10.6, 4.7, 4.5 Hz, 1H), 2.36–2.28 (m, 2H),
2.27–2.17 (m, 4H), 2.10–1.95 (m, 2H), 1.85 (s, 3H), 1.73–1.62 (m, 3H),
1.34–1.24 (m, 1H); 13C NMR (125 MHz)
d 144.7, 115.4, 108.2, 82.2.
75.6, 58.4, 56.8, 51.8, 41.9, 38.4, 34.3, 32.5, 20.5, 3.6; IR (neat) 2939,
2868, 2819, 2360, 1658, 1442, 1284, 1207, 1106, 1018 cmꢁ1; mass
spectrum (CI) m/z 215.1552 [C14H19N2 (Mþ1) requires 215.1548],
219 (base), 215, 205.
yellow oil: For
a
-H: 1H NMR (500 MHz, CD3CN)
d
4.71–4.67 (comp,
4.12. (4R)-2-Methylenyl-4-methyl-6-cyanoquinolizidine (40)
2H), 3.90 (app t, J¼3.4 Hz, 1H), 2.82–2.78 (m, 1H), 2.30–2.20 (comp,
5H), 2.07 (app tt, J¼11.0, 3.0 Hz, 1H), 1.92–1.85 (m, 1H), 1.78 (app
ddt, J¼11.0, 4.5, 4.0 Hz, 1H), 1.72–1.62 (comp, 2H), 1.54 (app qt,
Prepared in 90% yield in accordance with the representative
procedure. 1H NMR (500 MHz, CD3CN)
d
4.70 (app t, J¼2.0 Hz, 2H),
J¼13.5, 3.5, 1H), 1.50–1.28 (m, 1H); 13C NMR (125 MHz)
d
146.0,
4.35 (app t, J¼3.5 Hz, 1H), 2.35–2.18 (comp, 4H), 2.07–1.95 (comp,
117.0, 107.8, 58.2, 55.1, 54.9, 41.7, 34.3, 32.8, 28.8, 20.4 4; IR (neat)
3H), 1.82–1.70 (comp, 3H), 1.59 (app qt, J¼12.0, 1.5 Hz, 1H), 1.31–
3061, 2925, 2812, 2223, 1653, 1438, 1279, 1172, 1115, 889 cmꢁ1
;
1.23 (m, 1H), 1.14 (d, J¼6.0 Hz, 1H); 13C NMR (125 MHz)
d 146.3,
mass spectrum (CI) m/z 177.1400 [C11H16N2 (Mþ1) requires
117.4, 107.8, 59.3, 58.3, 50.7, 43.7, 42.8, 33.9, 29.6, 21.3, 20.3; IR
(neat) 3074, 2939, 2868, 2825, 2736, 2221, 1778, 1726, 1659, 1444,
177.1391], 150 (base), 177.
For
b
-H: 1H NMR (500 MHz, CD3CN)
d
4.71–4.67 (comp, 2H),
1379, 1328, 1182 cmꢁ1; mass spectrum (CI) m/z 191.1541 [C15H23
(Mþ1) requires 191.1548], 220, 191, 164 (base).
N
3.40 (app dt, J¼10.4, 3.2 Hz, 1H), 3.06 (app dd, J¼11.6, 3.2, 1H), 2.34–

S.M. Amorde et al. / Tetrahedron 65 (2009) 3222–3231
3229
4.13. 7-Vinyl-1,3,4,6,9,9a-hexahydro-2H-quinolizine-4-
carbonitriles (62a, 62b)
1H), 1.30–1.20 (m, 1H), 1.17 (d, J¼5.5 Hz, 3H); 13C NMR (125 MHz)
d 208.4, 62.1, 59.3, 51.0, 49.8, 48.7, 34.2, 25.9, 23.9, 20.7; IR (neat)
2929, 2846, 2788, 2741, 1718, 1442, 1336, 1283, 1166 cmꢁ1; mass
spectrum (CI) m/z 168.1388 [C10H18NO (Mþ1) requires 168.1388],
240, 196, 168 (base), 152. The spectral data were in accordance with
reported values for (ꢁ)-epimyrtine.3
Prepared in 79% yield in accordance with the representative
procedure. (
b
-CN) 1H NMR (500 MHz)
d
6.27 (dd, J¼17.8, 10.9 Hz,
1H), 5.27 (s, 1H), 5.06 (d, J¼17.8 Hz, 1H), 4.96 (d, J¼10.9 Hz,1H), 4.00
(d, J¼15.5 Hz, 1H), 3.08 (dd, J¼12.1, 3.1 Hz, 1H), 2.81 (dd, J¼15.1,
2.6 Hz, 1H), 2.20–2.08 (comp, 4H), 1.98–1.90 (m, 1H), 1.84–1.81 (m,
1H), 1.76–1.73 (m, 1H), 1.37–1.29 (comp, 2H); 13C NMR (125 MHz)
4.16. 6-Cyano-6-(30-methyltrimethylsilyl-30-butenyl)-2-
methylenylquinolizidine (44)
d
136.6, 132.2, 125.7, 119.3, 111.0, 57.0, 55.8, 52.7, 33.9, 32.2, 30.7,
22.9; IR (neat) 2867, 2817, 2787, 2356, 1661, 1611, 1440, 1370, 1310,
1249, 1165, 1119, 1044, 994, 894, 853 cmꢁ1; mass spectrum (CI) m/z
189.1397 [C12H17N2 (Mþ1) requires 189.1392], 252, 217, 189, 163
A solution of n-butyllithium in hexanes (0.21 mL of 2.5 M,
0.44 mmol) was added dropwise to a solution of diisopropylamine
(101 mg, 0.07 mL, 0.44 mmol) in Et2O (3 mL) at 0 ꢂC. The solution
was stirred for 0.5 h at which time 31 (60 mg, 0.35 mmol) was
added dropwise. The reaction mixture was stirred for 0.5 h, and 43
(215 mg, 0.69 mmol) was added dropwise. The ice bath was re-
moved, and the mixture was stirred for 1 h. A solution of 0.5 M
NaOH saturated with NaCl (5 mL) was added, and the layers were
separated. The aqueous layer was extracted with Et2O (3ꢃ10 mL),
and the combined organic layers were dried (K2CO3) and concen-
trated under reduced pressure. The crude residue was purified by
flash chromatography eluting with pentane/Et2O (95:5) to give
67 mg (62%) of 44 as a pale yellow oil. 1H NMR (500 MHz, CD3CN)
(base); (
a
-CN) 1H NMR (500 MHz)
d
6.28 (dd, J¼11.01, 17.9 Hz, 1H),
5.71 (s, 1H), 5.01 (d, J¼17.3 Hz, 1H), 4.95 (d, J¼11.0 Hz, 1H), 3.97 (app
t, J¼3.4 Hz, 1H), 3.31 (comp, 2H), 2.55–2.52 (m, 1H), 2.26 (d,
J¼16.7 Hz, 1H), 2.07–1.80 (m, 4H), 1.84–1.81 (m, 1H), 1.77–1.71 (m,
2H), 1.27–1.21 (comp, 1H); 13C NMR (125 MHz)
d 136.7, 132.9, 125.4,
117.1, 110.8, 54.9, 52.0, 51.2, 33.9, 32.9, 28.8, 20.3; IR (neat) 2870,
2849, 2822, 2361, 1657, 1144, 1440, 1267, 1127, 852, 837, 738 cmꢁ1
;
mass spectrum (CI) m/z 189.1391 [C12H17N2 (Mþ1) requires
189.1392], 189, 162 (base).
4.14. (4R)-2-Methylenyl-4-methylquinolizidine (41)
d
4.67–4.54 (comp, 4H), 3.14 (app dq, J¼11.0, 2.5 Hz, 1H), 2.29–1.15
(comp, 16H), 1.57 (s, 3H), 0.02 (s, 9H); 13C NMR (125 MHz)
d
148.0,
Acetic acid (276 mg, 4.6 mmol) was added dropwise to a solu-
tion of NaBH3CN (145 mg, 2.3 mmol) in CH3CN (2 mL) with stirring,
whereupon 18 (88 mg, 0.46 mmol) was added dropwise for 2 min.
The solution was stirred for 24 h at room temperature, and then
CH2Cl2 (5 mL) and a solution of 2 N HCl (5 mL) were added. The
layers were separated, and the aqueous layer was made basic with
a solution of 5% NaOH saturated with NaCl and extracted with
CH2Cl2 (3ꢃ15 mL). The combined organic layers were dried
(K2CO3), CF3CO2H (60 mg) was added dropwise, and the crude
mixture was concentrated under reduced pressure to give 111 mg
(86%) of 40 as an inseparable mixture (95:5) of diastereomers
(based on GC/MS and 1H NMR) as a pale yellow oil. Major isomer:
146.9, 119.8, 107.8, 107.8, 62.6, 60.5, 50.2, 27.4, ꢁ1.3, 42.9, 37.0, 35.2,
35.0, 33.8, 31.5, 21.9; IR (neat) 3067, 2939, 2820, 2726, 2358, 2213,
1658, 1632, 1440, 1239 cmꢁ1; mass spectrum (CI) m/z 317.2408
[C19H32NSi (Mþ1) requires 317.2413], 290 (base), 154, 218, 274, 317.
4.17. 6-(20-Methenylcyclopentyl)-2-methylenylquin-
olizidine (45)
Silver triflate (55 mg, 0.22 mmol) was added to a suspension of
4 Å molecular sieves (0.10 mg) in CH3CN (0.5 mL) at room tem-
perature. The suspension was wrapped in tin foil and a solution of
cyanoamine 44 (62 mg, 0.20 mmol) in CH3CN (0.5 mL) was added
dropwise. The resulting mixture was stirred at room temperature
for 1 h, at which time the suspension was filtered through a cotton
plug and washed with CH3CN (2 mL). The combined supernatant
was heated at 120 ꢂC (oil bath) with stirring for 24 h. The mixture
was cooled to room temperature, and Et2O (10 mL) was added. A
solution of 2 N HCl (5 mL) was added, and the layers were sepa-
rated. The aqueous layer was washed with Et2O (3ꢃ5 mL) and then
made basic with a solution of 5% NaOH saturated with NaCl. The
mixture was then extracted with Et2O (3ꢃ5 mL). The combined
organic layers were dried (K2CO3) and concentrated under reduced
pressure to give 34 mg (81%) of 45 as a single diastereomer (based
1H NMR (500 MHz, CD3CN)
d
4.85 (app t, J¼2.0, Hz, 2H), 3.77–3.70
(m, 1H), 3.06 (app ttd, J¼10.0, 6.5, 3.5 Hz, 1H), 2.95 (app tdt, J¼12.0,
9.0, 3.0 Hz, 1H), 2.65 (app tdd, J¼13.0, 10.0, 3.0 Hz, 1H), 2.54–2.33
(comp, 4H), 1.92–1.89 (comp, 2H), 1.81–1.70 (comp, 2H), 1.49 (app
tdd, J¼17.0, 7.0, 4.0 Hz, 1H), 1.36 (d, J¼6.5 Hz, 1H); 13C NMR
(125 MHz) d 140.9, 111.8, 66.6, 63.7, 52.3, 40.6, 39.3, 31.7, 24.3, 22.6,
17.8; IR (CH2Cl2) 2943, 2869, 2263, 1785, 1673, 1453, 1415, 1198,
1131 cmꢁ1; mass spectrum (CI) m/z 166.1591 [C11H20N (Mþ1) re-
quires 166.1596], 107, 150, 166 (base), 224. The spectral data were in
accordance with reported values.3b
4.15. (L)-Epimyrtine (3a)
on 1H NMR) as a colorless oil. 1H NMR (500 MHz, CD3CN)
d 4.77
(app p, J¼2.0 Hz, 1H), 4.74 (app p, J¼2.0 Hz, 1H), 4.59–4.56 (m, 1H),
4.56 (br s, 1H), 3.00 (app dt, J¼9.0, 3.0 Hz, 1H), 2.48 (d, J¼16.5 Hz,
1H), 2.31–2.11 (comp, 6H), 2.10–1.98 (comp, 2H), 1.86 (dddd, J¼11.5,
9.5, 2.0, 1.5 Hz, 1H), 1.55–1.40 (comp, 5H), 1.32–1.25 (m, 1H); 13C
The trifluoroacetate salt of 19 (115 mg, 0.41 mmol) was dis-
solved in a mixture of CH2Cl2 (3 mL) and MeOH (0.5 mL) and ozone
was bubbled through the solution at ꢁ78 ꢂC until a blue color
persisted (5 min). Air was passed through the reaction mixture for
5 min. Methyl sulfide (128 mg, 0.15 mL, 2.06 mmol) was added
dropwise, the dry ice bath was removed, and the reaction mixture
stirred at room temperature for 12 h. A solution of 5% NaOH satu-
rated with NaCl (1 mL) was added dropwise with stirring. The
layers were separated, and the aqueous layer was extracted with
Et2O (3ꢃ15 mL). The combined organic layers were dried (K2CO3)
and concentrated under reduced pressure (300 mmHg). The resi-
due was purified by flash chromatography eluting with hexanes/
EtOH (10:1) to give 40 mg (60%) of a mixture (95:5) of 3a and 3b as
NMR (125 MHz)
d 153.7, 148.1, 107.0, 106.0, 66.9, 58.9, 47.9, 43.5,
39.2, 37.9, 36.0, 35.6, 33.0, 31.6, 21.8; IR (CH2Cl2) 2943, 2872, 2249,
1672, 1443, 1414, 1196 cmꢁ1; mass spectrum (CI) m/z 218.1904
[C15H23N (Mþ1) requires 218.1908], 250, 218 (base), 152, 109.
4.18. 2-Methylenyl-6-cyano-6-butenylquinolizidine (49)
A solution of n-butyllithium in hexanes (0.74 mL of 2.5 M,
1.40 mmol) was added dropwise to a solution of i-Pr2NEt (0.17 mL,
1.40 mmol) in Et2O (5 mL) at 0 ꢂC. The solution was stirred for 0.5 h
and then was cooled to ꢁ78 ꢂC. Cyanoamine 31 (211 mg,
1.20 mmol) was added dropwise with stirring and the dry-ice/ac-
etone bath was replaced with an ice-water bath. The mixture was
23
20
a pale yellow oil. [
a
]
ꢁ18.0 (c 0.4, CDCl3); [lit.3b
[
a
]
ꢁ17.4 (c 0.7,
D
D
23
CHCl3); [
a]
ꢁ19.0 (c 0.4, CHCl3)]. 1H NMR (500 MHz)
d 3.30–3.26
D
(m, 1H), 2.40–2.12 (comp, 6H), 1.83–1.52 (comp, 5H), 1.41–1.33 (m,

3230
S.M. Amorde et al. / Tetrahedron 65 (2009) 3222–3231
stirred for 0.5 h at 0 ꢂC and then cooled to ꢁ78 ꢂC. 4-Bromobutene
(186 mg, 0.14 mL, 1.4 mmol) was added dropwise, and the dry-ice/
acetone bath was again replaced with an ice-water bath. The
mixture was stirred for 1 h at 0 ꢂC, whereupon a solution of 0.5 M
NaOH (10 mL) was added dropwise. The ice bath was removed, and
the mixture was stirred for 15 min. The layers were separated, and
the aqueous layer was extracted with Et2O (3ꢃ10 mL). The com-
bined organic layers were dried (K2CO3) and concentrated under
reduced pressure (300 mmHg). The crude residue was purified by
flash chromatography eluting with pentane/Et2O (9:1) to give
137 mg (50%) of 49 as a single diastereomer of a pale yellow oil. 1H
35.7, 34.5, 30.0, 26.7, 19.3, 3.6; IR (neat) 2934, 2863, 2812, 1656,
1450, 1091, 885 cmꢁ1; mass spectrum (CI) m/z 244.2066 [C17H26
(Mþ1) requires 244.2065], 269, 244 (base), 243.
N
4.21. Spirocycle 47
A solution of 46 (121 mg, 0.50 mmol) in 3% HCl/MeOH (5 mL)
was stirred at room temperature for 15 min and then concentrated.
The resulting salt was dissolved in benzene (10 mL) that had been
sparged with ethylene, and a solution of Grubbs II catalyst (34 mg,
0.04 mmol) in benzene (2 mL) was added. The mixture was stirred
at room temperature under ethylene for 36 h, whereupon 3 M
NaOH in saturated brine (10 mL) was added. The mixture was
extracted with Et2O (3ꢃ20 mL), and the combined organic layers
were washed with brine (15 mL), dried (MgSO4), filtered, and
concentrated. The crude material was purified by silica gel column
chromatography eluting with a 5–10% gradient of ether/pentane to
NMR (500 MHz, CD3CN)
d
5.84 (ddt, J¼17.0, 10.0, 6.5 Hz, 1H), 5.07
(dq, J¼17.0, 2.0 Hz, 1H), 4.97 (ddt, J¼10.0, 2.0, 1.5 Hz, 1H), 4.65 (dp,
J¼8.0, 2.0 Hz, 2H), 3.15 (ddd, J¼10.0, 4.5, 2.5 Hz, 1H), 2.27–2.06
(comp, 6H), 2.10 (app tt, J¼11.0, 2.5 Hz, 1H), 2.00–1.91 (comp, 3H),
1.86–1.80 (comp, 2H), 1.75 (app dt, J¼13.5, 4.0 Hz, 1H), 1.68–1.61
(comp, 2H), 1.56 (app tdd, J¼17.5, 8.0, 4.0 Hz, 1H), 1.20 (app tdd,
J¼15.0, 11.0, 4.0 Hz, 1H); 13C NMR (125 MHz)
d
146.9, 138.8, 119.7,
yield 118 mg (97%) of 47 as a colorless oil. 1H NMR (500 MHz)
d 6.19
115.6, 107.8, 62.6, 60.5, 50.2, 42.9, 37.7, 35.1, 35.0, 33.8, 27.6,
(d, J¼3.3 Hz, 1H), 5.71 (t, J¼2.7 Hz, 1H), 4.92 (s, 1H), 4.56–4.55 (m,
2H), 2.74 (ddd, J¼11.3, 4.1, 3.0 Hz, 1H), 2.26–2.22 (m, 2H), 2.16–2.01
(m, 6H), 1.96 (td, J¼10.7, 4.5 Hz, 1H), 1.90–1.86 (m, 1H), 1.89 (s 3H),
1.69–1.50 (m, 5H), 1.34–1.29 (m, 1H), 1.29–1.24 (m, 1H); 13C NMR
21.9 cmꢁ1; mass spectrum (CI) m/z 204 (base), 231.
4.19. 6-(10-Propynyl)-6-(30-butenyl)-2-methylenyl-
quinolizidine (50)
(125 MHz)
d 148.6, 148.3, 138.1, 128.8, 113.4, 105.9, 74.2, 57.8, 48.9,
43.9, 35.6, 35.2, 35.0, 29.9, 24.6, 23.3, 21.3; IR (neat) 2934, 2859,
1655,1444,1374,1100,1026, 907, 884 cmꢁ1; mass spectrum (CI) m/z
244.2066 [C17H26N (Mþ1) requires 244.2065], 244, 243 (base), 242.
A solution of propynylmagnesium chloride in Et2O (3.4 mL of
0.5 M, 1.7 mmol) was added dropwise to a solution of cyanoamine
49 (137 mg, 0.60 mmol) in THF (3.0 mL) at room temperature. The
solution was stirred for 5 h, at which time a solution of 2 N HCl
(5 mL) was added dropwise. The layers were separated, and the
aqueous layer was extracted with Et2O (3ꢃ5 mL). The aqueous layer
was made basic with a solution of 5% NaOH saturated with NaCl and
extracted with Et2O (3ꢃ5 mL). The combined organic layers were
dried (K2CO3) and concentrated under reduced pressure to give
116 mg (80%) of 50 as a single diastereomer (based on 1H NMR) as
4.22. 2-Methylenedodecahydropyrido[1,2-j]quinoline-6-
carbonitrile (52a, 52b, 53a, 53b)
A solution of 2-(3,3-dimethoxypropyl)cyclohexanone (76 mg,
0.38 mmol) in CH3CN (2 mL) was added to a solution of 3-((tri-
methylsilyl)methyl)but-3-en-1-amine (60 mg, 0.36 mmol) in
CH3CN (1 mL) with 4 Å molecular sieves (5 beads). The mixture was
heated under reflux for 4 h under nitrogen. The mixture was
cooled, and stirring was continued for 2 h at room temperature. The
4 Å molecular sieves were removed, the mixture was cooled to
ꢁ40 ꢂC, and CF3CO2H (3 mL, 40 mmol) was added. The mixture was
allowed to warm to room temperature for 3 h and then stirred at
room temperature for 21 h. The mixture was concentrated under
reduced pressure, and the residue was dissolved in CH2Cl2 (5 mL).
The solution was cooled to 0 ꢂC, aqueous NaCN (1.9 mL of a 2 M
solution) was added, the ice bath was removed, and the reaction
mixture was stirred at room temperature for 4 h. The solution was
cooled to 0 ꢂC, saturated K2CO3 (5 mL) was added, and the mixture
was extracted with Et2O (3ꢃ5 mL). The combined organic layers
were washed with brine (10 mL), dried (K2CO3), filtered, and con-
centrated under reduced pressure. The crude material was purified
by silica gel chromatography eluting with a 10–20% gradient of
ether/pentane to yield 66 mg (68%) of 52a, 52b, 53a, and 53b as
a (2.8:1:1.7:1.7) mixture of isomers. The major isomer 52a was
crystallized from ether/pentanes. For 52a: 1H NMR (400 MHz)
a colorless oil. 1H NMR (500 MHz, CD3CN)
d
5.84 (ddt, J¼17.0, 10.5,
6.5 Hz, 1H), 5.02 (dq, J¼17.0, 1.5 Hz, 1H), 4.92 (dq, J¼9.0, 1.0 Hz, 1H),
4.58 (dd, J¼4.0, 2.5 Hz, 2H), 3.00 (ddd, J¼11.0, 4.5, 3.0 Hz, 1H), 2.21–
2.06 (comp, 6H), 2.00 (app td, J¼11.0, 4.0 Hz, 1H), 1.87 (app t,
J¼12.5 Hz, 1H), 1.79 (s, 3H), 1.76 (ddd, J¼16.5, 14.0, 5.5 Hz, 1H), 1.70–
1.60 (comp, 2H), 1.59–1.49 (comp, 4H), 1.14 (app dtd, J¼15.5, 13.5,
4.0 Hz, 1H); 13C NMR (125 MHz)
d 148.4, 140.2, 114.6, 106.8, 82.0,
80.1, 59.4, 59.2, 49.3, 43.5, 40.6, 37.1, 35.6, 34.8, 30.9, 28.3,
21.8 cmꢁ1; mass spectrum (CI) m/z 244.2074 [C17H25N (Mþ1) re-
quires 244.2065], 244 (base), 204, 188.
4.20. (6R,9aR)-6-(But-3-enyl)-2-methylene-6-(prop-1-
ynyl)octahydro-1H-quinolizine (46)
4-Bromobutene (0.23 mL, 2.27 mmol) was added to a suspen-
sion of Mg (48 mg, 1.98 mmol) in THF (3 mL), and the mixture was
heated to 70 ꢂC for 1.5 h. A portion of the solution (1 mL) was added
to 34 (14 mg, 0.07 mmol) in CH2Cl2 (0.40 mL) at ꢁ78 ꢂC. The mix-
ture was allowed to warm to room temperature with stirring for
8 h. The solution was cooled to 0 ꢂC, and 2.9 N HCl (3 mL) was
added. The mixture was washed with Et2O (3ꢃ4 mL). The aqueous
layer was cooled to 0 ꢂC, 6 N NaOH (5 mL.) was added, and the
mixture was extracted with Et2O (3ꢃ3 mL). The combined organic
extracts were concentrated under reduced pressure to yield 17 mg
(100%) of 46 as a single diastereomer of a clear oil. 1H NMR
d
4.79 (app dd, J¼3.5, 1.6 Hz, 1H), 4.66 (app dd, J¼3.9, 2.0 Hz, 1H),
3.77–3.75 (m, 1H), 3.10 (td, J¼11.9, 3.9 Hz, 1H), 2.88 (dd, J¼13.1,
3.2 Hz, 1H), 2.54 (ddd, J¼11.5, 6.3, 1.8 Hz, 1H), 2.38–2.20 (m, 2H),
2.12–1.71 (m, 6H), 1.60 (m, 1H), 2.37–2.22 (m, 2H), 1.69–1.50 (m,
5H), 1.50–1.37 (m, 2H); 13C NMR (100 MHz)
d 143.5, 120.7, 109.9,
58.1, 50.1, 48.6, 43.5, 41.9, 34.1, 29.2, 28.2, 22.7, 22.2, 20.5; IR (neat)
2932, 2863, 2360, 1652, 1456, 888 cmꢁ1; mass spectrum (CI) m/z
231.1861 [C15H23N2 (Mþ1) requires 231.1858], 243, 231 (base), 230.
(500 MHz)
d
5.89–5.81 (comp, 1H), 5.04–5.00 (ddt, J¼17.2, 1.8,
1.7 Hz, 1H), 4.94–4.91 (ddt, J¼10.2, 1.4, 1.0 Hz, 1H), 4.59–4.56 (m,
2H), 3.50–3.48 (m, 1H), 2.34–2.29 (app tt, J¼10.9, 3.1 Hz, 1H), 2.25–
2.12 (m, 5H), 2.03–1.86 (m, 3H), 1.81 (s, 3H), 1.76–1.70 (app td,
J¼12.8, 5.4 Hz, 1H), 1.64–1.55 (m, 5H), 1.50–1.45 (m, 1H), 1.40–1.32
(app qt, J¼13.3, 3.3 Hz, 1H), 1.28–1.20 (m, 1H); 13C NMR (125 MHz)
4.23. 2-Methylenedodecahydropyrido[1,2-j]quinolines
(54, 55)
Solid NaBH4 (27 mg, 0.71 mmol) was added to a solution of 53a–
d (32.4 mg, 0.14 mmol) in MeOH (5 mL) at 0 ꢂC. The mixture was
d
147.9, 139.5, 114.2, 106.5, 84.0, 78.6, 58.5, 55.9, 49.6, 43.7, 35.8,

S.M. Amorde et al. / Tetrahedron 65 (2009) 3222–3231
3231
warmed to room temperature and then heated at 50 ꢂC (oil bath)
for 3 h. The reaction mixture was cooled to room temperature, HCl
(1 M, 2 mL) was added, and the mixture was washed with Et2O
(3ꢃ4 mL). Aqueous NaOH (2.5 M, 3 mL) was added, and the mixture
was extracted with Et2O (3ꢃ3 mL). The combined ethereal extracts
were concentrated under reduced pressure to yield 17 mg (60%) of
an inseparable mixture (1.1:1.0) of 54 and 55. 1H NMR of the mix-
Kuramochi, A.; Ohshima, T.; Shibasaki, M. Heterocycles 2007, 72, 421–438; (j)
Flick, A. C.; Caballero, M. J.; Padwa, A. Org. Lett. 2008, 10, 1871–1874.
6. For leading reviews of quinolizidine and indolizidine alkaloids, see: (a) Daly, J.
W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556–1575; (b) Michael,
J. P. Nat. Prod. Rep. 2007, 24, 191–222.
7. (a) Williamson, S. A.; Gist, R. P.; Smith, K. M.; Martin, S. F. J. Org. Chem. 1983, 47,
5170–5180; (b) Grzejszczak, S.; Wiliamson, S. A.; Rueger, H.; Martin, S. F. J. Am.
Chem. Soc. 1987, 109, 6124–6134; (c) Martin, S. F.; Yang, C. P.; Laswell, W. L.;
Rueger, H. Tetrahedron Lett. 1988, 29, 6685–6688; (d) Martin, S. F.; Campbell, C.
L. J. Org. Chem. 1988, 53, 3184–3190; (e) Martin, S. F.; Liao, Y.; Chen, H.-J.;
Paetzel, M.; Ramser, M. N. Tetrahedron Lett. 1994, 35, 6005–6008; (f) Martin, S.
F.; Bur, S. K. Tetrahedron 1999, 55, 8905–8914; (g) Deiters, A.; Martin, S. F. Org.
Lett. 2002, 4, 3243–3245; (h) Reichelt, A.; Bur, S. K.; Martin, S. F. Tetrahedron
2002, 58, 6323–6328; (i) Deiters, A.; Chen, K.; Eary, C. T.; Martin, S. F. J. Am.
Chem. Soc. 2003, 125, 4541–4550; (j) Dieters, A.; Pettersson, M.; Martin, S. F.
J. Org. Chem. 2006, 71, 6547–6561.
8. For reviews of N-alkyl iminium ions, see: (a) Blumenkopf, T. A.; Overman, L. E.
Chem. Rev. 1986, 86, 857–874; (b) Kleinman, E. F.; Volkmann, R. A. In Compre-
hensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, NY,
1991; Vol. 2, pp 975–1006; (c) Overman, L. E. Aldrichimica Acta 1995, 28, 107–
120; (d) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311–2352; For
reviews of N-acyl iminium ions, see: (e) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817–3856; (f) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.;
Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431–1628; For a review of
vinylogous Mannich reactions, see: Martin, S. F. Acc. Chem. Res. 2002, 35,
895–904.
ture (400 MHz, CDCl3)
5.2 Hz, 1H), 3.38–3.21 (m, 1H), 2.87–2.83 (m, 1H), 2.70–2.38 (comp,
6H), 2.28–1.16 (comp, 29H); 13C NMR (100 MHz)
145.0, 143.4,
d
4.77–4.61 (comp, 4H), 4.08 (dd, J¼12.1,
d
120.3, 109.6, 108.8, 58.7, 57.0, 49.7, 49.2, 47.0, 45.3, 44.4, 43.2, 41.8,
34.4, 34.1, 31.2, 28.5, 28.0, 27.9, 27.6, 25.9, 25.8, 25.7, 25.6, 22.0, 21.9,
20.5; IR (neat) 2928, 2862, 2810, 1650, 1454, 1352, 1120 cmꢁ1; mass
spectrum (CI) m/z 206.19146 [C14H24N (Mþ1) requires 206.1909],
204, 206 (base).
Acknowledgements
We thank the National Institutes of Health (GM 25439), the
Robert A. Welch Foundation, Pfizer, Inc., Merck Research Laborato-
ries, and Boehringer Ingelheim Pharmaceuticals for their generous
support of this research. We are also grateful to Dr. Richard Pederson
(Materia, Inc.) for catalyst support. We additionally thank Dr. Vin-
cent Lynch (The University of Texas) for X-ray crystallography data
and Dr. Andrew S. Judd (Abbott Laboratories) for helpful discussions.
9. For some reviews, see: (a) Ho, T. L. Tandem Organic Reactions; Wiley: New York,
NY, 1992; (b) Tietze, L. F. Chem. Rev. 1996, 96, 115–136; (c) Padwa, A. Pure Appl.
Chem. 2003, 75, 47–62; (d) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004,
76, 1967–1983.
10. For some leading references, see: (a) Nicolaou, K. C.; Edmonds David, J.; Bulger
Paul, G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186; (b) Chapman, C. J.; Frost, C.
G. Synthesis 2007, 1–21; (c) Enders, D.; Grondal, C.; Huettl, M. R. M. Angew.
Chem., Int. Ed. 2007, 46, 1570–1581.
11. For a preliminary account of some of these results, see: Amorde, S. M.; Judd, A.
S.; Martin, S. F. Org. Lett. 2005, 2031–2033.
Supplementary data
12. For leading examples of related cyclizations, see: (a) Cellier, M.; Gelas-Mialhe, Y.;
Husson, H. P.;Perrin, B.; Remuson, R. Tetrahedron: Asymmetry 2000,11, 3913–3919;
(b) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org. Chem. 2002, 67, 2424–2428.
13. (a) Ziegler, F. E.; Spitner, E. B. J. Am. Chem. Soc. 1973, 95, 7146–7149; (b) De-
slongchamps, P. Stereoelectronic Effects in Organic Chemistry. Organic Chemistry
Series; Pergamon Press: New York, NY, 1983; Vol. 1, pp 211–221; (c) Maruoka,
K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.; Hattori, K.; Yamamoto, H.
J. Am. Chem. Soc. 1983, 105, 2831–2843; (d) Stevens, R. V. Acc. Chem. Res. 1984,
17, 289–296.
14. Wasserman, H. H.; Vu, C. B.; Cook, J. D. Tetrahedron 1992, 48, 2101–2112.
15. Schreiber, S. L.; Claus, R. E.; Reagan, J. Tetrahedron Lett. 1982, 23, 3867–3870.
16. Mooiweer, H. H.; Hiemstra, H.; Fortgens, H. P.; Speckamp, W. N. Tetrahedron
Lett. 1987, 28, 3285–3288.
17. Bertrand, S.; Hoffmann, N.; Pete, J. P. Tetrahedron Lett. 1999, 40, 3173–3174.
18. (a) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359–373; (b) Enders, D.;
Thiebes, C. Synlett 2000, 1745–1748; (c) Agami, C.; Couty, F.; Evano, G. Org. Lett.
2000, 2, 2085–2088; (d) Meyer, N.; Opatz, T. Synlett 2003, 1427–1430; (e)
Wolckenhaur, S. A.; Rychnovsky, S. D. Org. Lett. 2004, 6, 2745–2748; (f) Werner,
F.; Blank, N.; Opatz, T. Eur. J. Org. Chem. 2007, 23, 3911–3915; (g) Liermann, J.
C.; Opatz, T. J. Org. Chem. 2008, 73, 4526–4531.
19. (a) Bruylants, P. Bull. Soc. Chim. Belg. 1924, 33, 467–478; (b) Bernardi, L.; Bonini,
B. F.; Capito, E.; Dessole, G.; Fochi, M.; Comes-Franchini, M.; Ricci, M. Synlett
2003, 1778–1782; (c) Reimann, E.; Ettmayer, A. Monatsh. Chem. 2004, 135,
1289–1295; (d) Beaufort-Droal, V.; Pereira, E.; Thery, V.; Aitken, D. J. Tetrahe-
dron 2006, 62, 11948–11954.
Experimental procedures for the preparation of 13, 28–30, 58, and
61. Copies of 1H NMR spectra for all new compounds, as well as 1H and
13C NMR spectra of epilupinine (1), tashiromine (2), and epimyrtine (3)
and a CIF file for 52a. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2008.10.074.
References and notes
1. For representative syntheses of epilupinine, see: (a) Comins, D. L.; Brown, J. D.
Tetrahedron Lett. 1986, 27, 2219–2222; (b) Morley, C.; Knight, D. W.; Share, A. C.
J. Chem. Soc., Perkin Trans. 1 1994, 2903–2907; (c) Pandey, G.; Reddy, G. D.;
Chakrabarti, D. J. Chem. Soc., Perkin Trans. 1 1996, 219–224; (d) Naidu, B. N.;
West, F. G. Tetrahedron 1997, 53, 16565–16574; (e) Mangeney, P.; Hamon, L.;
Raussou, S.; Urbain, N.; Alexakis, A. Tetrahedron 1998, 54, 10349–10362; (f) Ma,
S.; Ni, B. Chem.dEur. J. 2004, 10, 3286–3300; (g) Ahari, M. H.; Perez, A.; Menant,
C.; Vasse, J.-L.; Szymoniak, J. A. Org. Lett. 2008, 10, 2473–2476.
2. For representative syntheses of tashiromine, see: (a) Kim, S. H.; Kim, S. I.; Lai, S.;
Cha, J. K. J. Org. Chem. 1999, 64, 6771–6775; (b) Olivier, D.; Bellec, C.; Fargeau-
Bellassoued, M. C.; Lhommet, G. Heterocycles 2001, 55, 1689–1701; (c) Bates, R.
W.; Boonsombat, J. J. Chem. Soc., Perkin Trans. 1 2001, 654–656; (d) Dieter, R. K.;
Watson, R. Tetrahedron Lett. 2002, 43, 7725–7728; (e) McElhinney, A. D.;
Marsden, S. P. Synlett 2005, 2528–2530; (f) Belanger, G.; Larouche-Gauthier, R.;
Menard, F.; Nantel, M.; Barabe, F. J. Org. Chem. 2006, 71, 704–712; (g) Pohma-
kotr, M.; Prateeptongkum, S.; Chooprayoon, S.; Tuchinda, P.; Reutrakul, V. Tet-
rahedron 2008, 64, 2339–2347.
20. The products 30 (
matography. The ratio of the two compounds appears to be thermodynamic as
30 ( -CN) equilibrated to a mixture (87:13) 30 ( -CN) and 30 ( -CN) upon
a-CN) and 30 (b-CN) were readily separable by flash chro-
b
a
b
standing in CD3CN or upon heating in the presence of basic alumina.
21. Husson, H.-P.; Roulland, E.; Cecchin, F. J. Org. Chem. 2005, 70, 4474–4477.
22. In this context it is significant that an NOE interaction was observed between
the hydrogen atom at C(9a) and the hydrogen atoms on the pendant butenyl
group at C(10) in 45.
23. Monfray, J.; Gelas-Mialhe, Y.; Gramain, J.-C.; Remuson, R. Tetrahedron Lett. 2003,
44, 5785–5787.
24. Rubiralta, M.; Diez, A.; Miguel, D.; Remuson, R.; Gelas-Mialhe, Y. Synth. Com-
mun. 1992, 22, 359–367.
25. Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990, 55, 4688–4693.
26. (a) Heathcock, C. J. Org. Chem. 2001, 66, 7751–7756; (b) Overman, L. E. J. Org.
Chem. 1997, 62, 6379–6387.
27. For a related route to similar dienyl silanes, see: (a) Barrett, E. Org. Lett. 2003, 7,
671–672; (b) Yaun, H. J. Am. Chem. Soc. 2001, 123, 2964–2969.
28. For an intermolecular example, see: Larsen, S. D.; Grieco, P. A.; Fobare, W. F.
J. Am. Chem. Soc. 1986, 108, 3512–3515.
29. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518–1520.
30. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.
3. For representative syntheses of epimyrtine, see: (a) Slosse, P.; Hootele, C. Tet-
rahedron 1981, 37, 4287–4294; (b) Gardette, D.; Gelas-Mialhe, Y.; Gramain, J. C.;
Perrin, B.; Remuson, R. Tetrahedron: Asymmetry 1998, 9, 1823–1828; (c) Davis, F.
A.; Zhang, Y.; Anilkumar, G. J. Org. Chem. 2003, 68, 8061–8064.
4. For a recent review, see: Clive, D. L.; Yu, M.; Wang, J.; Yeh, V. S.; Kang, S. Chem.
Rev. 2005, 105, 4483–4514; For representative syntheses of halichlorine, see: (a)
Trauner, D.; Schwartz, J. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1999, 38,
3542–3545; (b) Christie, H. S.; Heathcock, C. H. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 12079–12084; (c) Matsumura, Y.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2004, 6,
965–968; (d) Zhang, H.-L.; Zhao, G.; Ding, Y.; Wu, B. J. Org. Chem. 2005, 70,
4954–4961; (e) Andrade, R.; Martin, S. F. Org. Lett. 2005, 7, 5733–5735.
5. For a recent review, see: (a) Weinreb, S. M. Chem. Rev. 2006, 106, 2531–2549; For
representative syntheses of cylindricines, see: (b) Snider, B. B.; Liu, T. J. Org. Chem.
1997, 62, 5630–5633; (c) Molander, G. A.; Roen, M. J. Org. Chem. 1999, 64, 5183–
5187; (d) Liu, J. F.; Heathcock, C. H. J. Org. Chem.1999, 64, 8263–8266; (e) Trost, B.
M.; Rudd, M. T. Org. Lett. 2003, 5, 4599–4602; (f) Arai, T.; Abe, H.; Ayogai, S.; Ki-
bayashi, C. Tetrahedron Lett. 2004, 45, 5921–5924; (g) Canesi, S.; Bouchu, D.;
Ciufolini, M. A. Angew. Chem., Int. Ed. 2004, 43, 4336–4338; (h) Liu, J.; Hsung, R. P.;
Peters, S. D. Org. Lett. 2004, 6, 3989–3992; (i) Mihara, H.; Shibuguchi, T.;