Utilization of 1-Aryl-2,2-dibromocyclopropanes in synthetic approaches to phenanthroquinolizidine and phenanthroindolizidine alkaloids

Article abstract of DOI:10.1071/CH03292

The 1-aryl-2,2-dibromocyclopropane 8 was treated with silver acetate in acetic acid to give the allylic acetate 19. Exposure of the derived chloride 26 to racemic 2-piperidinemethanol (7) then afforded the allylic amine 6, which engaged in a Pd(0)-catalyz

Full text of DOI:10.1071/CH03292

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 537–548
Utilization of 1-Aryl-2,2-dibromocyclopropanes in Synthetic
Approaches to Phenanthroquinolizidine and
Phenanthroindolizidine Alkaloids
Martin G. BanwellA,B and Magne O. SydnesA
A Research School of Chemistry, Institute of Advanced Studies, Australian National University,
Canberra ACT 0200, Australia.
B Author to whom correspondence should be addressed (e-mail: mgb@rsc.anu.edu.au).
The 1-aryl-2,2-dibromocyclopropane 8 was treated with silver acetate in acetic acid to give the allylic acetate 19.
Exposure of the derived chloride 26 to racemic 2-piperidinemethanol (7) then afforded the allylic amine 6, which
engaged in a Pd(0)-catalyzed cross-coupling reaction with arylboronate 29 to provide the cis-stilbene 25. The
chloride 4 (X = Cl) derived from compound 25 failed to cyclize in the presence of base to give the desired phenan-
throquinolizidine alkaloid julandine 1.This outcome resulted in a re-examination of the closing stages of a previously
reported synthesis of the phenanthroindolizidine alkaloid ent-septicine (ent-3). Towards this end, chloride 26 was
reacted with (S)-2-pyrrolidinemethanol (32) to give the allylic amine 33, which was cross-coupled with boronate
ester 34 to afford cis-stilbene 35. Contrary to literature reports, compound 35 was converted into the corresponding
chloride 37, rather than the expected mesylate, upon reaction with methanesulfonyl chloride in the presence of
pyridine. Moreover, chloride 37 was not converted into ent-septicine (ent-3) on exposure to sodium hydride, thus
calling into question a previously reported synthesis of this natural product.
Manuscript received: 11 November 2003.
Final version: 15 January 2004.
OMe
OMe
Introduction
MeO
MeO
MeO
MeO
1
Julandine 1[1] and its dehydro-congener cryptopleurine 2[2]
are representative members of the phenanthroquinolizidine
class of alkaloids, while septicine 3[3] belongs to the related
phenanthroindolizidine group (Scheme 1). Many of these
plant-derived natural products display notable biological
properties. For example, they show a capacity to inhibit the
growth of various human cancer cell lines, especially multi-
drug resistant ones such as KB-V1, with IC50 values in the
low nanomolar range, and are comparable, therefore, to cer-
tain clinically used drugs.[4] As such, these alkaloids have
been the subject of numerous synthetic studies most of which
have been summarized in a recent review by Huang et al.[5] Of
particular relevance to the work described here is the report
by Russel and Hunziker,[6] in which ent-septicine (namely
ent-3) was prepared by base-promoted ring closure of a C8c–
C14 seco precursor that contained a mesyloxy group at the
latter centre.
H
N
H
N
15
15
8c
8c
A
11
9
8
1
2
OMe
MeO
MeO
H
14
8c
N
MeO
3
Scheme 1.
As part of an ongoing program directed towards the
application of gem-dihalogenocyclopropanes in the total syn-
thesis of natural products,[7] we conceived of a retrosynthetic
analysis of crytopleurine 2 and its C4a–C4b-seco analogue
julandine 1 so that these readily available three-membered
carbocycles could be exploited (Scheme 2). On the basis of
previous studies conducted by other research groups,[5] it
is quite clear that target 2 could be prepared by oxida-
tive cyclization of julandine 1 using, for example, Liepa’s
reagent (VOF3).[8] Furthermore, the above-mentioned work
of Russel and Hunziker suggested that target 1 might be
accessible through base-promoted cyclization of substrate 4,
© CSIRO 2004
10.1071/CH03292
0004-9425/04/060537

538
M. G. Banwell and M. O. Sydnes
VOF3
ringsaswellasthenatureoftheheterocyclicring(specifically
pyrrolidine versus piperidine) and, therefore, has the potential
to allow access to many members of both the phenanthro-
quinolizidine and phenanthroindolizidine classes of alka-
loids. Attempts to implement these ideas are detailed below.
(Ϯ)-2
(Ϯ)-1
base
OMe
Results and Discussion
MeO
X
The foreshadowed dibromocarbene addition to styrene 9 to
generate, in an efficient manner (78%), the required 1-
aryl-2,2-dibromocyclopropane 8, was achieved by using the
well known phase-transfer catalysis conditions established by
Makosza (Scheme 3).[7i] In contrast, attempts to effect elec-
trocyclic ring-opening of adduct 8 with concomitant trapping
of the resultant allylic cation by the addition of piperidine 7
were unsuccessful. Thus, reaction of compound 8 with sil-
ver tetrafluoroborate in the presence of amine 7 afforded the
‘pseudo-dimer’ 10 (27%) as the only characterizable prod-
uct of reaction. Compound 10, which was subjected to the
usual range of spectroscopic analyses, is most likely formed
by reaction of the allylic cation generated by the cyclo-
propane ring-opening with another molecule of substrate 8
in an SEAr process. The 1,2,4,5-tetrasubstitution pattern
associated with the second aromatic ring presumably arises
in order to minimize buttressing effects around the arene
unit. This outcome highlights the significant nucleophilic
properties of the dimethoxylated arene unit associated with
compound 8. Despite examining many reaction conditions,
we were unable to obtain the required adduct 6. For example,
reactionofsubstrate8, amine7, andsilvertetrafluoroboratein
1,1,1,3,3,3-hexafluoroisopropyl alcohol, which is supposed
to be a highly ionizing but weakly nucleophilic solvent,[9]
resulted in the formation of the three solvolysis products
11, 12, and 13, the proportions of which varied depend-
ing upon the reaction conditions involved (Table 1). The
structure assigned to compound 11 must be regarded as
tentative given the limited amount of data that could be
acquired. Reaction of cyclopropane 8 with silver tosylate,
in the hope of trapping the derived allylic cation with the
tosyloxy group, was also unsuccessful. The only identifi-
able product of this process was the previously observed
compound 10 (17%). Frequently, such reaction mixtures con-
tained oligomeric materials that are presumed to arise from
sequential cyclopropane ring-cleavage/SEAr processes of the
type that lead to ‘pseudo-dimers’ 10 and 11.
N
MeO
4
X ϭ leaving group
Suzuki–Miyaura
cross-coupling
then
OH → X
OMe
MeO
OH
B(OR)2
ϩ
N
MeO
Br
5
6
Agϩ
OMe
OH
OMe
MeO
MeO
:CBr2
ϩ
HN
Br
Br
9
8
7
Scheme 2.
which should, in turn, be available via Suzuki–Miyaura cross-
coupling of arylboronic acid 5 with alkenyl bromide 6.
Compound 6 was considered to be accessible by a silver(i)-
promoted electrocyclic ring-opening of the 1-aryl-2,2-
dibromocyclopropane 8 and trapping of the resultant allylic
cation with 2-piperidinemethanol (7). The ring-opening pro-
cess was expected to be facilitated by the electron-donating
methoxy group at the remote position on the aromatic ring.
Furthermore, it was anticipated, by virtue of the operation
of the effects of A1,3-strain, that the illustrated Z-geometry
would be established. Substrate 8 itself could be prepared
in the usual way, namely by dibromocarbene addition to the
C C double bond of the commercially available styrene 9.
The modular nature of this strategy offers the possibility of
varying the substituents associated with the two aromatic
In an effort to exploit the effects of buttressing and facili-
tate cyclopropane ring-opening (Scheme 4) TMS-substituted
(where TMS refers to trimethylsilyl) styrene 16 was pre-
pared (in 71% yield) by Suzuki–Miyaura cross-coupling of
boronic acid 14 with commercially available 1-bromo-1-
trimethylsilylethylene 15. Dibromocarbene addition to the
coupled product 16 proceeded smoothly under Makosa con-
ditions to give the expected tetrasubstituted cyclopropane 17
1
in 60% yield. The H and 13C NMR spectra of this com-
poundexhibitedmanymoresignalsthanexpected, mostlikely
because it exists in multiple low-energy and slowly intercon-
verting conformations as a result of the sterically crowded
nature of the linkage between the aryl and cyclopropyl rings.

Synthetic Approaches to Phenanthroquinolizidine and Phenanthroindolizidine Alkaloids
539
OMe
CHBr3,
aq. NaOH,
TEBAC
MeO
OMe
AgBF4,
MeCN
OMe
9
8
compound 7
Br
AgBF4,
(CF3)2CHOH
added
nucleophile
Br
Br
10
OMe
MeO
OMe
OMe
OMe
OMe
Br
MeO
MeO
CF3
O
Br
ϩ
ϩ
CF3
Br
Br
O
CF3
CF3
O
F3C
CF3
11
12
Scheme 3.
13
Table 1. Distribution of solvolysis products 11–13 arising from ring-opening of cyclopropane
8 under various conditions
Entry
no.
Reaction
conditionsA
Added
nucleophile
Yield [%]
8
11
12
13
1
2
3
4
18◦C, 27 hB
7C
0
14
0
0
9
13
0
32
13
0
Sealed tube, 80◦C, 6 d
Sealed tube, 80◦C, 6 d
Sealed tube, 85◦C, 6 d
7C
13
25
61
LiClD
l-proline methyl esterE
0
8
0
A 1,1,1,3,3,3-Hexafluoroisopropyl alcohol used as reaction solvent.
B 4.3 mol. equiv. ofAgBF4
8.4 mol. equiv. used.
C
D
E
used.
2.6–2.9 mol. equiv. used.
4.3 mol. equiv. used.
OMe
Various attempts to identify the coalescence temperature for
these atropisomeric forms of cyclopropane 17 failed because
of the thermal sensitivity of the material. Moreover, the same
difficulties encountered with the ring-opening of the parent
system 8 applied to compound 17. Thus, all attempts to effect
ring-opening of the latter compound and trap the resultant
allylic cation with 2-piperidinemethanol (7) so as to gener-
ate styrene 6 after protio-desilylation failed. Indeed, the only
characterizable reaction product obtained during such stud-
ies was the solvolysis product 18 (14%), and this was only
observed when 2,2,2-trifluoroethanol was used as the solvent.
The synthetically useful cyclopropane ring-cleavage prod-
uct19wasobtainedin82%yield(Scheme5)whencompound
8 was treated with silver acetate in acetic acid under condi-
tions defined byTrost et al.[10] The geometry about the trisub-
stituted double bond within this allylic acetate was confirmed
by nOe experiments, which revealed an interaction between
the alkenyl proton and its methylenic counterparts. Cleav-
age of this acetate with potassium carbonate in methanol
gave the corresponding alcohol 20 in 99% yield. Unfortu-
nately, neither acetate 19 nor the methyl carbonate derived
MeO
OMe
B(OH)2
MeO
Pd(0),
Na2CO3
14
TMS
ϩ
TMS
Br
16
15
CHBr3,
aq. NaOH,
TEBAC
OMe
MeO
OMe
AgBF4,
CF3CH2OH
MeO
TMS
O
TMS
Br
Br
Br
CF3
18
17
Scheme 4.

540
M. G. Banwell and M. O. Sydnes
OMe
MeO
MeO
OMe
MeO
Pd(0),
Na2CO3
B(OH)2
AgOAc,
AcOH
OR
8
ϩ
MeO
OR
Br
19 Rϭ Ac
20 Rϭ H
K2CO3,
MeOH
K2CO3,
MeOH
21
22 Rϭ Ac
23 Rϭ H
Swern
oxidation
OMe
OMe
MeO
MeO
MeO
OH
NaCNBH3
X
O
N
MeO
25
24
Scheme 5.
OMe
OMe
MeO
MeO
p-TsCl,
DMAP
compound 7,
Et3N, DMF
X
20
or
NCS, DMS
N
Cl
Br
Br
NaH, DMF
compound 27
6 Xϭ OH
27 Xϭ Cl
26
p-TsCl,
DMAP
OMe
MeO
O
B
Pd(0),
Na2CO3
compound 6
Cl
O
OH
HO
21
N
p-TsOH
MeO
29
28
OMe
OMe
OMe
MeO
MeO
MeO
MeO
X
OH
MsCl,
pyridine
ϩ
ϩ
25
O
N
N
H
H
4 Xϭ Cl
30
31
Scheme 6.
from alcohol 20 participated in a Pd(0)-catalyzed substitu-
tion reaction with 2-piperidinemethanol (7) to yield target
6. Instead, under such conditions, and in keeping with the
observations of Nwokogu,[11] these processes only returned
alcohol 20. However, compound 19 did engage in a Suzuki–
Miyaura cross-coupling reaction with boronic acid 21 to give
the cis-stilbene acetate 22 (12%), and this was readily con-
verted into the corresponding alcohol 23 (59%) upon reaction

Synthetic Approaches to Phenanthroquinolizidine and Phenanthroindolizidine Alkaloids
541
Table 2. Product distributions arising from Suzuki–Miyaura cross-coupling reactions of alkenyl bromide 6
with boronic acid 21 or boronate 29
Entry
no.
Coupling partner/
reaction conditions
Catalyst
used
Base
used
Yield [%]
25
30
31
1
2
3
4
5
21/EtOH, benzene, reflux, 17 h
21/DMF, 95◦C, 4 h
21/EtOH, benzene, reflux, 17 h
29/EtOH, benzene, reflux, 11 h
29/EtOH, toluene, water, reflux, 3 h
Pd(PPh3)4
2 M aq. Na2CO3
K2CO3
2 M aq. Na2CO3
2 M aq. Na2CO3
K3PO4
10
Trace
40
87
28
0
90
33
10
30
78
0
26
1
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
Pd(PPh3)4
40
with potassium carbonate in methanol. Compound 20 could
also be cross-coupled with boronic acid 21 to give the stilbene
alcohol 23 directly (58% yield). Alcohol 23 was readily oxi-
dized to the corresponding aldehyde 24 (28%) but this failed
to engage in a reductive amination process with amine 7 to
afford the required conjugate 25. As a consequence, an alter-
nate approach was adopted (Scheme 6). Thus, alcohol 20 was
treated with p-toluenesulfonyl chloride (p-TsCl) in the pres-
ence of 4-(N,N-dimethylamino)pyridine (DMAP), or with
a mixture of N-chlorosuccinimide (NCS) and dimethyl sul-
fide (DMS) to give, as expected,[12] the corresponding allylic
chloride 26 (64 and 69%, respectively). Gratifyingly, when
the latter compound was reacted with 2-piperidinemethanol
(7) in the presence of triethylamine, the long sought after
conjugate 6 was finally obtained and in 98% yield.
base-inducedcyclizationofcompound4andtherebygenerate
julandine 1 have failed.
The above-mentioned results called into question the
claims[6] of Russel and Hunziker, and prompted a reinvesti-
gation of the closing stages of their approach to ent-septicine
(Scheme 7). Towards this end, allylic chloride 26 was treated
with (S)-(+)-2-pyrrolidinemethanol 32 in the presence of
triethylamine to afford the allylic amine 33 (99%). Suzuki–
Miyaura cross-coupling of alkenyl bromide 33 with pinaco-
latoboronate 34, which itself was derived from boronic acid
14, afforded a mixture of the desired compound 35 (72%)
and the reductively debrominated product 36 (25%). These
were readily separated by flash chromatography. The Z-
configurationofthedoublebondinstilbene35wasconfirmed
usingNOESYtechniques. Conjugate35representsthepenul-
timate precursor in the (+)-septicine synthesis reported by
Russel and Hunziker, but the specific rotation {[α]D −22.1
(c 0.5 in methanol)} obtained for our enantiomerically pure
material, as judged by chiral HPLC analysis, did not match
that reported[6] {[α]D −81.4 (c 1 in methanol)} by the Swiss
workers. All the other data obtained on our sample of com-
pound 35 were fully consistent with the assigned structure,
but the lack of reported data on the material previously pre-
pared has meant that a comprehensive comparison could not
be undertaken. A further concern arose during attempts to
convert our sample of alcohol 35 into the corresponding
mesylate under conditions approximating those implied in
the Russel–Hunziker paper.[6] Thus, reaction of compound
35 with MsCl in pyridine afforded chloride 37 (approxi-
mately 100%) rather than the reported mesylate. Although
compound 37 was unstable, it could be characterized by the
usual range of spectroscopic techniques. Disappointingly, all
efforts to effect cyclization of this chloride by treating it
withsodiumhydridein DMFunder conditionsapproximating
those used[6] by Russel and Hunziker in the final step of their
synthesis of (+)-septicine (ent-3) failed to afford any char-
acterizable reaction products. Examination of several other
bases for this purpose led to the same result.
In an attempt to effect a cyclization of the type reported[6]
by Russel and Hunziker in their synthesis of ent-septicine
(see conversion 4 → 1 in Scheme 2), alcohol 6 was treated
with p-TsCl in the presence of DMAP. However, contrary to
expectations raised by the report,[6] chloride 27 (99%) rather
than the tosylate was obtained. Furthermore, when compound
27 was treated with sodium hydride in DMF, only elimina-
tion product 28 (38%) was observed. In order to prevent
this elimination process, alcohol 6 was cross-coupled with
eitherboronicacid21orthepinacolatoboronatederivative29,
which itself was prepared in 98% yield by esterification of
boronic acid 21 with pinacol using p-TsOH as catalyst and a
Dean–Stark trap to remove water.The three products obtained
from such cross-coupling reactions, which could be separated
by flash chromatography, were the desired stilbene 25 (87%)
as well as by-products 30 (10%) and 31 (approximately 1%).
Extensive efforts were made to optimize the yield of prod-
uct 25, and the results of these studies are summarized in
Table 2. The conditions defined in entry 4 represent the best
uncovered to date.
Observation of the reductive debromination product 30
is not unexpected, and co-product 31 presumably arises by
oxidative addition of Pd(0) to starting material 6 followed by
β-hydride elimination to give the corresponding amino-allene
which subsequently hydrolyzes, upon workup, to give the cin-
namaldehyde. The pivotal role of Pd(0) in the latter process
was established from control experiments, which demon-
strated that the conversion does not occur in the absence of
this catalyst. In keeping with our earlier observations (see
above), reaction of compound 25 with methanesulfonyl chlo-
ride (MsCl) in the presence of pyridine afforded chloride 4
(X = Cl) in 83% yield. Disappointingly, all efforts to effect
Summary and Conclusions
The foregoing work serves to highlight the utility of the title
cyclopropanes in the modular construction of certain seco
derivatives[e.g. 4(X = Cl), 25, 35, and37]ofvariousphenan-
throquinolizidine and phenanthroindolizidine alkaloids. The
failure of the Russel–Hunziker cyclization protocol[6] to
deliver the targeted alkaloids 1 and 3 is disappointing, and

542
M. G. Banwell and M. O. Sydnes
26
OMe
O
B
ϩ
MeO
OH
N
O
Et3N, DMF
HO
OH
ϩ
14
OH
p-TsOH
MeO
OMe
Br
HN
33
34
32
Pd(0),
Na2CO3
OMe
MeO
MeO
X
OMe
MeO
OH
X
ent-3
ϩ
N
compound 37
N
H
OMe
36
35 X ϭ OH
37 X ϭ Cl
MsCl,
pyridine
Scheme 7.
recorded on a Perkin–Elmer 1800 Series FTIR spectrometer and sam-
ples were analyzed on plates (for oils) or as KBr disks (for solids).
Low-resolution mass spectra were recorded on a Micromass–Waters
LC-ZMD single quadrupole liquid chromatograph-MS or VG Quattro
II triple quadrupole MS instrument using electron impact techniques.
High-resolution mass spectra were recorded on anAUTOSPEC spectro-
meter or a Kratos Analytical Concept ISQ instrument, the latter being
located at the University of Tasmania. Optical rotations were measured
with a Perkin–Elmer 241 polarimeter at the sodium-D line (589 nm) at
the concentrations (c, g 100 mL−1) indicated using spectroscopic grade
CHCl3 unless otherwise specified. The measurements were carried out
between 19–21◦C in a cell with a path length (l) of 1 dm. Specific rota-
tions [α]D were calculated using the equation [α]D = 100 α/(c l) and
are given in 10−1 deg cm2 g−1. Elemental analyses were performed by
the Microanalytical Services Unit at the Research School of Chemistry,
Australian National University, Canberra, Australia. Dichloromethane
was distilled from calcium hydride and THF was distilled, under an
atmosphere of nitrogen, from sodium benzophenone ketyl. Racemic
2-piperidinemethanol was purified by sublimation before use, and could
be stored for several weeks under anhydrous conditions in a sealed vial.
Whenever it was deemed necessary, reactions were performed under an
atmosphere of nitrogen, and organic extracts were dried over anhydrous
magnesium sulfate.
OMe
OMe
MeO
MeO
MeO
MeO
14
15
8c
8c
N
N
MeO
38
39
Scheme 8.
necessitates the development of alternate methods for the
formation of the central or A-ring of these natural products.
Work aimed at establishing such methods is now underway
in our laboratories. Nevertheless, a potentially useful feature
of the work detailed here is the capacity it offers to read-
ily construct C8c–C15 and C8c–C14 monoseco analogues
(e.g. 38 and 39, Scheme 8) of the title alkaloids. The out-
come of efforts directed to such ends will be reported in due
course.
4-(2ꢀ,2ꢀ-Dibromocyclopropyl)-1,2-dimethoxybenzene 8
NaOH (4.4 mL of a 50% w/v aqueous solution) was added, dropwise,
to a vigorously stirred solution of 3,4-dimethoxystyrene 9 (549 mg,
4.092 mmol, ex.Aldrich), bromoform(2.2 mL, 25.2 mmol), andtriethyl-
benzylammonium chloride (TEBAC; 9.6 mg, 0.04 mmol) in benzene
(2 mL) maintained at about 0◦C (ice–water bath). Stirring was con-
tinued at 18◦C under an atmosphere of nitrogen for 5 h, and then the
reaction mixture was poured into a mixture of water (20 mL) and hex-
ane (20 mL). The aqueous phase was extracted with hexane (3 × 30 mL)
and the combined organic fractions were washed with water (3 × 30 mL)
and brine (1 × 30 mL) before being dried, filtered, and concentrated
under reduced pressure. The ensuing light-brown oil was subjected
Experimental
Melting points were measured on a Reichert hot-stage microscope
apparatus and are uncorrected. Proton (1H) and carbon (13C) NMR
spectra were recorded on either a Varian Inova 500 spectrometer oper-
ating at 500 MHz for proton and 126 MHz for carbon, or a Gemini
300 NMR spectrometer operating at 300 MHz (for proton) and 75 MHz
(for carbon). Unless otherwise specified, spectra were acquired at
20◦C in deuterated chloroform (CDCl3) that had been filtered through
basic alumina immediately before use. Chemical shifts were recorded
as δ values in parts per million (ppm). Infrared spectra (vmax) were

Synthetic Approaches to Phenanthroquinolizidine and Phenanthroindolizidine Alkaloids
543
to flash chromatography (silica, 9 : 1 v/v hexane/ethyl acetate elution),
and concentration of the appropriate fractions (RF 0.3) gave the title
compound 8 (1.08 g, 78%) as a light-yellow oil that crystallized upon
standing. Recrystallization (ethyl acetate/hexane) of a portion of this
material afforded an analytically pure sample of the title compound
brine (1 × 10 mL) then dried, filtered, and concentrated under reduced
pressure to give a light-yellow oil. This material was subjected to flash
chromatography (silica, 9 : 1 to 7 : 3 v/v hexane/ethyl acetate gradient
elution) to afford fractions A–C.
Concentration of fractionA (RF 0.1 in 4 : 1 v/v hexane/ethyl acetate)
afforded a light-yellow oil that was tentatively assigned as compound 11
•
as a white crystalline solid, mp 75–77◦C (Found: C 39.3,•H 3.6, M+
•
337.9166. C11H1281Br2O2 requires C 39.3, H 3.6%, M+ 337.9163).
vmax (KBr)/cm−1 1517, 1269, 1255, 1238, 1142, 1027. δH (300 MHz,
CDCl3) 6.80 (1H, d, J 8.2), 6.76 (1H, d, J 2.0), 6.71 (1H, dd, J 2.0 and
8.2), 3.87 (3H, s), 3.84 (3H, s), 2.86 (1H, dd, J 8.0 and 10.5), 2.07 (1H,
dd, J 8.0 and 10.5), 1.92 (1H, t, J 8.0). δC (75 MHz, CDCl3) 148.4,
148.2, 128.4, 120.6, 112.1, 110.5, 55.9, 55.8, 35.6, 29.1, 27.4. m/z (EI,
70 eV) 338 (10%), 336 (20), and 334 (11, M+•); 257 (68) and 255 (68);
176 (100); 161 (39); 145 (29).
(1.5 mg, 14%) (Found: M+• 675.9892. C25H2479Br2F6O5 requires M+
675.9895). m/z (EI, 70 eV) 680 (23%), 678 (44), and 676 (21, M+•);
518 (48) and 517 (54); 254 (78) and 252 (82); 231 (100) and 229 (96);
175 (54).
Concentration of fraction B (RF 0.3 in 4 : 1 v/v hexane/ethyl acetate•)
afforded compound 12 (1 mg, 9%) as a light-yellow oil (Found: M+
423.9935. C14H1381BrF6O3 requires M+• 423.9931). vmax (KBr)/cm−1
1601, 1516, 1288, 1272, 1220, 1194, 1144, 1103, 1025. δH (300 MHz,
CDCl3) 7.38 (1H, d, J 2.0), 7.21 (1H, dd, J 2.0 and 8.4), 7.01 (1H, s),
6.86 (1H, d, J 8.4), 4.61 (2H, s), 4.21 (1H, septet, J 5.8), 3.89 (6H, s).
δC (75 MHz, CDCl3) 149.7, 148.5, 132.8, 126.7, 123.0, 115.7, 111.7,
110.6, 80.2, 74.3 (quintet), 55.9 (two signals, one of which would be
due to the CF3 group carbons, obscured or overlapping). m/z (EI, 70 eV)
424 (88%) and 422 (87, M+•); 257 (15), 256 (19), 255 (16), and 254
(17); 176 (100) and 175 (84); 161 (38); 132 (25); 99 (24); 69 (22).
Concentration of fraction C (RF 0.4 in 4 : 1 v/v hexane/ethyl acetate•)
afforded compound 13 (4 mg, 32%) as a light-yellow oil (Found: M+
421.9955. C14H1379BrF6O3 requires M+• 421.9952). vmax (KBr)/cm−1
1518, 1286, 1263, 1220, 1194, 1141, 1127, 1103, 1027. δH (300 MHz,
CDCl3) 6.96–6.85 (3H, complex m), 6.17 (1H, m), 5.77 (1H, dd, J 0.9
and 2.0), 5.22 (1H, br s), 4.12 (1H, septet, J 5.8), 3.90 (3H, s), 3.88
(3H, s). δC (75 MHz, CDCl3) 150.1, 149.4, 129.9, 126.7, 121.6, 119.4,
110.7, 110.1, 86.2, 72.3 (quintet), 55.8(8) 55.8(5) (a signal for the CF3
group carbons could not be discerned). m/z (EI, 70 eV) 424 (97%) and
422 (100, M+•); 343 (4); 317 (63); 257 (43) and 255 (44); 176 (79); 175
(42); 161 (38).
5-[(Z)-2ꢀ-Bromo-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)prop-2ꢀ-enyl]-
4-(2ꢀꢀꢀ,2ꢀꢀꢀ-dibromocyclopropyl)-1,2-dimethoxybenzene 10
Method A
AgBF4 (182 mg, 0.935 mmol) was added to a magnetically stirred solu-
tion of cyclopropane 8 (51 mg, 0.152 mmol) and 2-piperidinemethanol
(7) (77 mg, 0.67 mmol, ex. Aldrich) in acetonitrile (6 mL) maintained
under an atmosphere of nitrogen. The ensuing mixture was heated at
reflux for 72 h, while being protected from light, and was then cooled
to 18◦C, diluted with ethyl acetate (20 mL), and filtered through a pad
of Celite. The filtrate was concentrated under reduced pressure and the
residue thus obtained was subjected to flash chromatography (silica,
7 : 3 v/v hexane/ethyl acetate elution). Concentration of the appropri-
ate fractions (RF 0.3) then afforded the title compound 10 (12 mg,
27%) as a cle•ar, yellow oil (Found: M+• 591.9125. C22H2379Br81Br2O4
requires M+ 591.9106). vmax (KBr)/cm−1 1604, 1583, 1515, 1463,
1271, 1026. δH (300 MHz, CDCl3) 7.29 (1H, d, J 2.1), 7.12 (1H,
dd, J 2.1 and 8.4), 6.87 (1H, s), 6.82 (1H, d, J 8.4), 6.79 (1H, s),
6.51 (1H, s), 4.22 (1H, d, J 17.3), 3.95 (1H, d, J 17.3), 3.89 (3H,
s), 3.87 (6H, s), 3.85 (3H, s), 2.95 (1H, dd, J 7.5 and 10.4), 2.14
(1H, dd, J 7.5 and 10.4), 1.99 (1H, t, J 7.5). δC (75 MHz, CDCl3)
148.5, 148.2, 147.6, 130.7, 128.5, 128.3, 127.7, 122.8, 122.1, 113.5,
111.7, 111.6, 110.5, 56.0, 55.9(2), 55.8(8), 46.8, 34.2, 29.0, 27.3 (two
signals obscured or overlapping). m/z (EI, 70 eV) 594 (10%), 592 (23),
590 (23), and 588 (10, M+•); 513 (2), 511 (4), and 509 (2); 432 (12),
431 (19), 430 (14), and 429 (16); 351 (30), 350 (32), and 349 (22); 325
(38) and 324 (38); 231 (98) and 229 (100); 176 (44); 151 (70).
[1-(3ꢀ,4ꢀ-Dimethoxyphenyl)vinyl]trimethylsilane 16
Pd(PPh3)4 (38.5 mg) was added to a magnetically stirred mixture of
(1-bromovinyl)trimethylsilane 15 (170 µL, 1.097 mmol, ex. Fluka), 3,4-
dimethoxyphenylboronic acid 14[13] (225 mg, 1.24 mmol, ex. Aldrich),
and Na2CO3 (1.1 mL of a 2 M aqueous solution) in ethanol (0.5 mL)
and benzene (2.2 mL). The reaction mixture was then heated in a
sealed tube at 80◦C for 20 h, cooled to 18◦C, and diluted with ethyl
acetate (20 mL). The separated organic phase was washed with water
(2 × 15 mL) and brine (15 mL) then dried, filtered, and concentrated
under reduced pressure to give a light-yellow oil which was subjected
to flash chromatography (silica, 95 : 5 v/v hexane/ethyl acetate elution).
Concentration of the appropriate fractions (RF 0.2) gave the title com-
pound 16[14] (183 mg, 71%) as a light-yellow oil (Found: M+• 236.1230.
Method B
AgOTs (620 mg, 2.247 mmol) was added to a magnetically stirred solu-
tion of cyclopropane 8 (74 mg, 0.222 mmol) in acetonitrile (5 mL) and
the ensuing mixture was heated at reflux for 83 h while being protected
from light. The reaction mixture was then cooled to 18◦C, diluted with
ethyl acetate (20 mL), and filtered through a pad of Celite. The filtrate
was concentrated under reduced pressure and the residue thus obtained
was subjected to flash chromatography (silica, 7 : 3 v/v hexane/ethyl
acetate elution). Concentration of the appropriate fractions (RF 0.3)
afforded the title compound 10 (11 mg, 17%) which was identical, in all
respects, with the material obtained by method A.
•
C13H20O2Si requires M+ 236.1233). vmax (KBr)/cm−1 2953, 1600,
1511, 1463, 1254, 1247, 1210, 1171, 1139, 1029, 927, 857, 838. δH
(300 MHz, CDCl3) 6.80 (1H, d, J 8.8), 6.75–6.71 (2H, complex m),
5.80 (1H, d, J 2.9), 5.53 (1H, d, J 2.9), 3.87 (3H, s), 3.86 (3H, s), 0.17
(9H, s). δC (75 MHz, CDCl3) 152.6, 148.4, 147.6, 137.3, 126.1, 118.8,
110.8, 110.0, 55.9, 55.8, −0.6. m/z (EI, 70 eV) 236 (100%, M+•), 221
(88), 206 (21), 195 (40), 163 (37), 162 (27), 73 (66).
[2,2-Dibromo-1-(3ꢀ,4ꢀ-dimethoxyphenyl)cyclopropyl]-
trimethylsilane 17
5-[(Z)-2ꢀ-Bromo-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)prop-2ꢀ-enyl]-4-[(Z)-
2ꢀꢀꢀ-bromo-3ꢀꢀꢀ-(2ꢀꢀꢀꢀ,2ꢀꢀꢀꢀ,2ꢀꢀꢀꢀ-trifluoro-1-trifluoromethylethoxy)-
propen-1ꢀ-yl]-1,2-dimethoxybenzene 11,
NaOH (1.0 mL of a 50% w/v aqueous solution) was added, dropwise,
to a magnetically stirred solution of styrene 16 (177 mg, 0.75 mmol),
bromoform (0.50 mL, 5.725 mmol), and TEBAC (2 mg, 0.010 mmol) in
benzene (0.45 mL) maintained at 0◦C under an atmosphere of nitrogen.
The ensuing mixture was stirred vigorously at 18◦C for 18 h then poured
into a mixture of water (15 mL), hexane (7.5 mL), and ethyl acetate
(7.5 mL). The separated aqueous phase was extracted with hexane/ethyl
acetate (5 × 15 mL of a 1 : 1 v/v mixture), and the combined organic
fractions were washed with water (3 × 15 mL) and brine (15 mL) before
beingdried, filtered, andconcentratedunderreducedpressure.Theresul-
tant light-yellow oil was subjected to flash chromatography (silica, 9 : 1
v/v hexane/ethyl acetate elution), and concentration of the appropriate
fractions (RF 0.3) afforded the title cyclopropane 17 (185 mg, 60%)
4-[(Z)-2ꢀ-Bromo-3ꢀ-(2ꢀꢀ,2ꢀꢀ,2ꢀꢀ-trifluoro-1-trifluoromethylethoxy)-
propen-1ꢀ-yl]-1,2-dimethoxybenzene 12,
and 4-[2ꢀ-Bromo-1ꢀ-(2ꢀꢀ,2ꢀꢀ,2ꢀꢀ-trifluoro-1-trifluoromethylethoxy)-
propen-1ꢀ-yl]-1,2-dimethoxybenzene 13
AgBF4 (26 mg, 0.13 mmol) was added to a magnetically stirred solu-
tion of cyclopropane 8 (10 mg, 0.03 mmol) and 2-piperidinemethanol 7
(13 mg, 0.11 mmol, ex. Aldrich) in 1,1,1,3,3,3-hexafluoroisopropyl
alcohol (0.8 mL) maintained under an atmosphere of nitrogen and pro-
tected from ambient light. The ensuing mixture was stirred at 18◦C
for 27 h then diluted with ethyl acetate (15 mL) and filtered through
a plug of Celite. The filtrate was washed with water (2 × 10 mL) and

544
M. G. Banwell and M. O. Sydnes
•
as a light-yellow oil (Found: C 41.3, H 4.9, Br 39.3, M+ 409.9554.
6.97 (1H, s), 6.83 (1H, d, J 8.3), 4.38 (2H, br s), 3.89 (6H, s), 2.00 (1H,
br s). δC (75 MHz, CDCl3) 148.9, 148.3, 127.5, 127.4, 123.3, 122.3,
111.7, 110.6, 69.7, 55.9 (one signal obscured or overlapping). m/z (EI,
70 eV) 274 (96%) and 272 (100, M+•); 243 (6) and 241 (6); 193 (24);
161 (32); 139 (41); 91 (16); 77 (22).
•
C14H2081Br2O2Si requires C 41.2, H 4.9, Br 39.2%, M+ 409.9558).
vmax (KBr)/cm−1 1515, 1463, 1410, 1250, 1163, 1139, 1073, 1028, 976,
842. δH (300 MHz, CDCl3)6.92–6.66(2.25H, complexm), 6.37(0.75H,
m), 3.93 (1.4H, s), 3.89 (0.6H, s), 3.86 (1.5H, s), 3.83 (1.5H, s), 3.81 (1H,
s), 2.71 (0.15H, d, J 10.6), 2.07 (0.35H, d, J 6.5), 2.06 (0.33H, d, J 6.5),
1.91 (0.33H, d, J 6.5), 1.89 (0.33H, d, J 6.5), 1.23 (0.5H, d, J 10.6),
0.23 (2H, s), 0.08 (4H, s), 0.07 (3H, s). δC (75 MHz, CDCl3) 148.4(4),
148.4(0), 148.3, 148.0, 147.3, 147.2, 135.0, 134.7, 129.6, 122.3, 120.4,
120.0, 113.0, 112.1, 111.5, 110.5, 55.9, 55.8(7), 55.8(4), 55.7(8), 55.7,
38.8, 35.3, 34.2, 34.1, 33.6, 31.9, 31.8, 27.6, −0.7, −0.8, −1.2. m/z (EI,
70 eV) 410 (6%), 408 (13), and 406 (6, M+•); 329 (22) and 327 (22);
225 (45) and 223 (47); 175 (86); 73 (100).
(Z)-2-Bromo-3-(3ꢀ,4ꢀ-dimethoxyphenyl)prop-2-enyl Methyl Carbonate
n-Butyllithium (30 µL of a 2.5 M solution in hexane, 0.075 mmol)
was added, dropwise, to a magnetically stirred solution of alcohol 20
(19 mg, 0.07 mmol) in THF (1.5 mL) maintained at −78◦C under an
atmosphere of nitrogen. Methyl chloroformate (12.5 µL, 0.16 mmol)
was then added rapidly and the reaction mixture was allowed to warm
to 18◦C. The resultant solution was concentrated under reduced pres-
sure and the residue subjected to flash chromatography (silica, 7 : 3 v/v
hexane/ethylacetateelution). Concentrationoftherelevantfractions(RF
4-[(E)-2ꢀ-Bromo-3ꢀ-(2ꢀꢀ,2ꢀꢀ,2ꢀꢀ-trifluoroethoxy)-1ꢀ-trimethylsilylprop-
1ꢀ-enyl]-1,2-dimethoxybenzene 18
•
0.4) gave the title carbonate (17 mg, 73%) as a yellow oil (Found: M+
•
332.0088. C13H1581BrO5 requires M+ 332.0082). vmax (KBr)/cm−1
AgBF4 (31 mg, 0.16 mmol) was added to a magnetically stirred solu-
tion of cyclopropane 17 (16 mg, 0.04 mmol) and 2-piperidinemethanol
7 (117 mg, 1.02 mmol, ex. Aldrich) in 2,2,2-trifluoroethanol (0.5 mL)
maintained under an atmosphere of nitrogen and protected from ambi-
ent light. The resultant mixture was stirred at 18◦C for 46 h then
diluted with hexane/ethyl acetate (10 mL of a 7 : 3 v/v mixture) and
filtered through a pad of Celite. The filtrate was concentrated under
reduced pressure and the ensuing light-yellow oil was subjected
to flash chromatography (silica, 95 : 5 v/v hexane/ethyl acetate elu-
tion). Concentration of the appropriate fractions (RF 0.35 in 4 : 1 v/v
hexane/ethyl acetate) afforded•the title compound 18 (2.4 mg, 14%) as
a light-yellow oil (Found: M+ 428.0449. C16H2281BrF3O3Si requires
1750, 1514, 1442, 1258, 1144, 1024, 942, 875. δH (300 MHz, CDCl3)
7.33 (1H, d, J 2.0), 7.18 (1H, dd, J 2.0 and 8.3), 7.01 (1H, s), 6.84
(1H, d, J 8.3), 4.92 (2H, s), 3.88 (6H, s), 3.81 (3H, s). δC (75 MHz,
CDCl3) 155.1, 149.2, 148.2, 131.5, 126.9, 122.7, 115.8, 111.7, 110.5,
73.5, 55.8(8), 55.8(6), 55.1. m/z (EI, 70 eV) 332 (38%) and 330 (40,
M+•); 251 (25); 176 (100); 175 (98); 161 (45).
(E)-3-(3ꢀ,4ꢀ-Dimethoxyphenyl)-2-(4ꢀꢀ-methoxyphenyl)prop-
2-enyl Acetate 22
Pd(PPh3)4 (24 mg, 0.02 mmol) was added to a magnetically stirred
solution of acetate 19 (60 mg, 0.19 mmol), 4-methoxyphenylboronic
acid 21[15] (38.0 mg, 0.250 mmol, ex. Aldrich), ethanol (1.2 mL), and
Na2CO3 (2.7 mL of a 2 M aqueous solution) in benzene (9.8 mL) main-
tained under an atmosphere of nitrogen. The resultant mixture was
heated at reflux for 4.5 days while being protected from light then cooled
to 18◦C and diluted with diethyl ether (20 mL). The separated organic
phase was washed with NaHCO3 (2 × 20 mL of a saturated aqueous
solution) and brine (1 × 20 mL) before being dried, filtered, and con-
centrated under reduced pressure. The resultant light-yellow oil was
subjected to flash chromatography (silica, 4 : 1 v/v hexane/ethyl acetate
elution), and concentration of the appropriate fractions (RF 0.4) gave the
title acetate 22 (8 mg, 12%) as a light-yellow oil (Found: M+• 342.1468.
C20H22O5 requiresM+• 342.1467). vmax (KBr)/cm−1 1737, 1606, 1512,
1463, 1242, 1161, 1142, 1026. δH (300 MHz, CDCl3) 7.15 (2H, d, J
8.4), 6.86 (2H, d, J 8.4), 6.65 (2H, s), 6.56 (1H, s), 6.46 (1H, s), 4.84
(2H, s), 3.79 (3H, s), 3.78 (3H, s), 3.47 (3H, s), 2.03 (3H, s). δC (75 MHz,
CDCl3) 170.8, 159.0, 148.1, 148.0, 134.5, 130.7, 130.1, 129.2, 129.0,
122.6, 114.2, 111.8, 110.5, 69.7, 55.7, 55.3, 55.2, 21.0. m/z (EI, 70 eV)
342 (100%, M+•), 300 (14), 283 (39), 267 (13), 252 (37), 237 (13), 167
(35), 138 (83).
•
M+ 428.0453). vmax (KBr)/cm−1 1513, 1277, 1262, 1251, 1170. δH
(300 MHz, CDCl3) 6.86–6.83 (1H, complex m), 6.77–6.75 (2H, com-
plex m), 4.38 (2H, s), 3.88 (3H, s), 3.87 (3H, s), 3.70 (2H, q, J 8.7), 0.37
(9H, s). δC (75 MHz, CDCl3) 149.2, 148.3, 148.1, 134.7, 134.2, 119.9,
111.3, 110.5, 73.9, 68.0, 55.9, 55.8, 1.1 (signal due to CF3 group carbon
could not be discerned). m/z (EI, 70 eV) 428 (66%) and 426 (62, M+•);
219 (29); 175 (100); 73 (69).
(Z)-2-Bromo-3-(3ꢀ,4ꢀ-dimethoxyphenyl)prop-2-enyl Acetate 19
A magnetically stirred mixture of cyclopropane 8 (2.53 g, 7.5 mmol)
and AgOAc (2.95 g, 17.7 mmol) in acetic acid (65 mL) was heated at
reflux while being protected from ambient light and maintained under
an atmosphere of nitrogen.After 16 h the reaction mixture was cooled to
18◦C then added to NaHCO3 (250 mL of a saturated aqueous solution)
and extracted with diethyl ether (5 × 150 mL). The combined organic
phaseswerethendried, filtered, andconcentratedunderreducedpressure
to give a light-yellow oil which was subjected to flash chromatography
(silica, 4 : 1 v/v hexane/ethyl acetate elution). Concentration of the rel-
evant fractions (RF 0.2) gave the title ace•tate 19 (1.92 g, 82%) as a
light-yellow oil (Found: C 49.6, H 5.1, M+ 316.0132. C13H1581BrO4
requires C 49.5, H 4.8%, M+• 316.0133). vmax (KBr)/cm−1 3001, 2936,
2836, 1744, 1601, 1515, 1464, 1378, 1241, 1162, 1144, 1026, 875. δH
(300 MHz, CDCl3) 7.30 (1H, d, J 2.0), 7.15 (1H, dd, J 2.0 and 8.3), 6.95
(1H, s), 6.81 (1H, d, J 8.3), 4.85 (2H, br s), 3.85 (3H, s), 3.84 (3H, s),
2.10 (3H, s). δC (75 MHz, CDCl3) 170.1, 149.1, 148.2, 131.1, 127.0,
122.6, 116.8, 111.6, 110.5, 70.4, 55.9, 55.8, 21.0. m/z (EI, 70 eV) 316
(35%) and 314 (35, M+•); 257 (6) and 255 (6); 193 (100); 175 (31);
150 (14).
(E)-3-(3ꢀ,4ꢀ-Dimethoxyphenyl)-2-(4ꢀꢀ-methoxyphenyl)prop-
2-en-1-ol 23
Method A
A magnetically stirred mixture of acetate 22 (7 mg, 0.02 mmol) and
K2CO3 (7 mg, 0.05 mmol) in methanol (1 mL) maintained under an
atmosphere of nitrogen at 18◦C for 3 h, and was then filtered through
a plug of silica that was washed with hexane/ethyl acetate (3 × 5 mL
of a 7 : 3 v/v mixture). The combined filtrates were concentrated under
reduced pressure and the residue thus obtained was subjected to flash
chromatography (silica, 3 : 7 v/v ethyl acetate/hexane elution). Concen-
tration of the appropriate fractions (RF 0.1) gave the title alcohol 23[16]
(Z)-2-Bromo-3-(3ꢀ,4ꢀ-dimethoxyphenyl)prop-2-en-1-ol 20
A magnetically stirred mixture of acetate 19 (179 mg, 0.57 mmol)
and K2CO3 (118 mg, 0.85 mmol) in methanol (6 mL) was maintained
under an atmosphere of nitrogen at 18◦C for 2 h then filtered through
a plug of silica that was subsequently washed with hexane/ethyl
acetate (3 × 10 mL of a 7 : 3 v/v mixture). The combined filtrates
were concentrated under reduced pressure to give the title alcohol 20
•
(3.6 mg, 59%) as a light-yellow oil (Found: M+ 300.1362. C18H20O4
requires M+• 300.1362). vmax (KBr)/cm−1 3469(br), 1606, 1512, 1463,
1267, 1243, 1141, 1026. δH (300 MHz, CDCl3) 7.17 (2H, d, J 8.8), 6.87
(2H, d, J 8.8), 6.65 (2H, s), 6.56 (1H, s), 6.47 (1H, s), 4.41 (2H, s), 3.80
(3H, s), 3.78 (3H, s), 3.47 (3H, s), 1.57 (1H, br s). δC (75 MHz, CDCl3)
159.0, 148.0, 147.9, 139.3, 130.9, 130.1, 129.4, 126.1, 122.3, 114.3,
111.7, 110.5, 68.8, 55.7, 55.3, 55.2. m/z (EI, 70 eV) 300 (100%, M+•),
282 (13), 181 (24), 165 (36), 151 (61), 135 (28), 121 (39).
•
(155 mg, 99%) as a clear, colourless oil (Found: C 48.5,•H 5.0, M+
274.0041. C11H1381BrO3 requires C 48.4, H 4.8%, M+ 274.0028).
vmax (KBr)/cm−1 3468(br), 1601, 1514, 1463, 1270, 1238, 1142, 1023.
δH (300 MHz, CDCl3) 7.30 (1H, d, J 2.0), 7.14 (1H, dd, J 2.0 and 8.3),

Synthetic Approaches to Phenanthroquinolizidine and Phenanthroindolizidine Alkaloids
545
Method B
dropwise, with dimethyl sulfide (0.015 mL, 0.204 mmol). The reac-
tion mixture was stirred at 0◦C for 10 min, then cooled to −10◦C and
treated, dropwise, with a solution of alcohol 20 (41 mg, 0.15 mmol) in
dichloromethane (1.0 mL). After addition was complete, the reaction
mixture was warmed to 0◦C and stirred at this temperature for 1.5 h.
It was then warmed to 18◦C and stirred at this temperature for 16 h,
after which time it was poured into chilled (approximately 0◦C) brine
(10 mL). The separated aqueous phase was extracted with hexane/ethyl
acetate (3 × 15 mL of a 1 : 1 v/v mixture), and the combined organic
phases were then washed with chilled brine (2 × 20 mL) before being
dried, filtered, and concentrated under reduced pressure. The resultant
light-yellow oil was subjected to flash chromatography (silica, 4 : 1 v/v
hexane/ethyl acetate elution), and concentration of the appropriate frac-
tions (RF 0.3) gave chloride 26 (30.0 mg, 69%) which was identical, in
all respects, with the material obtained by method A.
Pd(PPh3)4 (41 mg, 0.04 mmol) was added to a magnetically stirred solu-
tion of alcohol 20 (100 mg, 0.37 mmol), 4-methoxyphenylboronic acid
21[15] (69 mg, 0.45 mmol), ethanol (2.25 mL), and Na2CO3 (5.2 mL
of a 2 M aqueous solution) in benzene (18.7 mL) maintained under an
atmosphere of nitrogen and protected from ambient light. The resultant
mixture was heated at reflux for 12 h, and cooled to 18◦C and diluted
with diethyl ether (20 mL). The separated organic phase was washed
with NaHCO3 (2 × 20 mL of a saturated aqueous solution) and brine
(1 × 20 mL) before being dried, filtered, and concentrated under reduced
pressure. The residue thus obtained was subjected to flash chromatogra-
phy (silica, 70 : 25 : 5 v/v/v hexane/ethyl acetate/benzene elution), and
concentration of the appropriate fractions (RF 0.1) gave the title alcohol
23 (64 mg, 58%) which was identical, in all respects, with the material
obtained by method A.
{1-[(Z)-2ꢀ-Bromo-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)prop-
2ꢀ-enyl]piperidin-2-yl}methanol 6
(E)-3-(3ꢀ,4ꢀ-Dimethoxyphenyl)-2-(4ꢀꢀ-methoxyphenyl)propenal 24
A solution of oxalyl chloride (14.5 mg 0.11 mmol) in dichloromethane
(0.5 mL) maintained under an atmosphere of nitrogen at −60◦C
was treated with a solution of DMSO (12 µL, 0.17 mmol) in
dichloromethane (0.1 mL). The ensuing mixture was stirred at −60◦C
for 2 min, and then a solution of alcohol 23 (21 mg, 0.07 mmol) in
dichloromethane (1.0 mL) was added over 5 min. After a further 0.25 h,
triethylamine (0.05 mL) was added to the reaction mixture, and after
a further 5 min the mixture was allowed to warm to 18◦C. It was
then diluted with dichloromethane (10 mL) and water (10 mL), and the
separated aqueous phase extracted with dichloromethane (2 × 10 mL).
The combined organic phases were washed with HCl (2 × 10 mL of a
0.3 M aqueous solution), water (2 × 10 mL), Na2CO3 (2 × 10 mL of a
5% w/v aqueous solution), water (2 × 10 mL), and brine (1 × 10 mL)
before being dried, filtered, and concentrated under reduced pressure.
The residue thus obtained was subjected to flash chromatography (silica,
7 : 3 v/v hexane/ethyl acetate elution), and concentration of the appropri-
atefractions(RF 0.3)gavethetitlealdehyde24[17] (6 mg, 28%)asaclear,
A magnetically stirred solution of chloride 26 (515 mg, 1.77 mmol) in
DMF (4 mL) maintained under an atmosphere of nitrogen was treated
with 2-piperidinemethanol (7) (220 mg, 1.91 mmol), and then triethyl-
amine (250 µL, 1.79 mmol) was added dropwise. After the resultant
mixture had been heated at 70◦C for 16 h, it was cooled to 18◦C, diluted
with ethyl acetate (50 mL), washed with brine/water (5 × 30 mL of a 1 : 1
v/v mixture) and then brine (1 × 30 mL) before being dried, filtered,
and concentrated under reduced pressure to afford the title alcohol 6
(641 mg, 98%) as a light-yellow and viscous oil (Found: C 55.4, H 6.7,
N 3.7, M+• 371.0913. C17H2481BrNO3 requires C 55.1, H 6.5, N 3.8%,
M+• 371.0919). vmax (KBr)/cm−1 3435, 2933, 1601, 1582, 1514, 1261,
1143, 1026, 804. δH (300 MHz, CDCl3) 7.34 (1H, d, J 2.1), 7.15 (1H,
dd, J 2.1 and 8.5), 6.86 (1H, s), 6.83 (1H, d, J 8.5), 3.89 (3H, s), 3.88
(3H, s), 3.86–3.75 (2H, complex m), 3.52 (1H, dd, J 4.6 and 11.0),
3.21 (1H, d, J 14.6), 3.07–3.00 (1H, complex m), 2.80 (1H, br s), 2.52
(1H, m), 2.28–2.20 (1H, complex m), 1.76–1.32 (6H, complex m). δH
(300 MHz, CD3OD) 7.37 (1H, d, J 2.0), 7.19 (1H, ddd, J 0.6, 2.0, and
8.3), 7.04 (1H, s), 6.92 (1H, d, J 8.3), 3.91 (1H, dd, J 1.2 and 14.8), 3.82
(6H, s), 3.71 (1H, dd, J 4.8 and 11.3), 3.60 (1 H, dd, J 5.3 and 14.1), 3.29
(1H, dd, J 0.9 and 14.8), 3.01–2.93 (1H, complex m), 2.52–2.43 (1H,
complex m), 2.29–2.20 (1H, complex m), 1.79–1.26 (6H, complex m).
δC (75 MHz, CDCl3) 148.8, 148.2, 129.0, 127.8, 123.1, 122.3, 111.7,
110.5, 63.5, 62.0, 60.2, 55.9(2), 55.8(9), 49.8, 26.8, 23.8, 23.2. m/z (EI,
70 eV) 371 (2%) and 369 (2, M+•); 340 (71) and 338 (72); 290 (24);
257 (92) and 255 (92); 176 (100); 161 (37); 145 (34); 115 (26).
•
•
yellow oil (Found: M+ 298.1209. C18H18O4 requires M+ 298.1205).
vmax (KBr)/cm−1 1676, 1596, 1508, 1463, 1270, 1247, 1144, 1088,
1023. δH (300 MHz, CDCl3) 9.69 (1H, s), 7.26 (1H, s), 7.14 (2H, d,
J 8.8), 6.95 (3H, m), 6.76 (1H, d, J 8.4), 6.67 (1H, d, J 2.0), 3.85 (3H,
s), 3.80 (3H, s), 3.47 (3H, s). δC (75 MHz, CDCl3) 194.1, 159.5, 150.9,
150.2, 148.4, 139.6, 130.8, 127.1, 125.9, 125.7, 114.4, 112.4, 110.6,
55.9, 55.3, 55.2. m/z (EI, 70 eV) 298 (100%, M+•), 283 (7), 270 (19),
255 (25), 165 (23), 138 (18).
(Z)-4-(2ꢀ-Bromo-3ꢀ-chloroprop-1ꢀ-enyl)-1,2-dimethoxybenzene 26
1-[(Z)-2ꢀ-Bromo-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)prop-2ꢀ-enyl]-
2-chloromethylpiperidine 27
Method A
p-TsCl (910 mg, 4.773 mmol) and DMAP (700 mg, 5.729 mmol) were
added to a magnetically stirred solution of alcohol 20 (750 mg,
2.748 mmol) in dichloromethane (25 mL) maintained at 18◦C under an
atmosphere of nitrogen. After 50 min the reaction mixture was diluted
with hexane/ethyl acetate (60 mL of a 1 : 1 v/v mixture), and was then
washed with water (2 × 30 mL) and brine (1 × 30 mL) before being
dried, filtered, and concentrated under reduced pressure. The residue
thus obtained was subjected to flash chromatography (silica, 4 : 1 v/v
hexane/ethyl acetate elution), and concentration of the appropriate frac-
tions (RF 0.3) gave the title chloride 26 (515 mg, 64%) •as a white,
crystalline solid, mp 49–51◦C (Found: C 45.5, H 4.2, M+ 293.9669.
Method A
p-TsCl (24 mg, 0.12 mmol) and DMAP (17 mg, 0.14 mmol) were added
to a magnetically stirred solution of alcohol 6 (23 mg, 0.06 mmol) in
dichloromethane (1.0 mL) maintained under an atmosphere of nitro-
gen. After the ensuing mixture was stirred at 18◦C for 16 h, it was
poured into water (10 mL) and the separated aqueous phase was
extracted with hexane/ethyl acetate (3 × 20 mL of a 1 : 1 v/v mixture).
The combined organic fractions were washed with water (2 × 20 mL)
and brine (1 × 20 mL) then dried, filtered, and concentrated under
reduced pressure. The yellow oil thus obtained was poured onto a pad
of TLC-grade silica that was subsequently washed with a 95 : 5 v/v
dichloromethane/methanol solution containing a few drops of ammo-
nia (15% aqueous solution). Concentration of the filtrate under reduced
pressure gave chloride 27 (24 mg, 99%) as a light-yellow oil (Found:
•
C11H1281Br37ClO2 requires C 45.3, H 4.2%, M+ 293.9659). vmax
(KBr)/cm−1 1600, 1514, 1463, 1258, 1241, 1144, 1025. δH (300 MHz,
CDCl3) 7.34 (1H, d, J 2.1), 7.17 (1H, ddd, J 0.6, 2.1, and 8.4), 7.03 (1H,
br s), 6.84 (1H, d, J 8.4), 4.45 (2H, d, J 0.6), 3.88(9) (3H, s), 3.88(7)
(3H, s). δC (75 MHz, CDCl3) 149.3, 148.3, 131.3, 126.9, 122.7, 118.2,
111.6, 110.5, 55.8(8), 55.8(6), 52.8. m/z (EI, 70 eV) 294 (13%), 292
(55), and 290 (41, M+•); 257 (32) and 255 (33); 176 (100); 161 (38);
145 (29); 89 (15).
•
•
M+ 391.0559. C17H2381Br37ClNO2 requires M+ 391.0551). vmax
(KBr)/cm−1 2933, 1601, 1582, 1514, 1463, 1270, 1143, 1027. δH
(300 MHz, CDCl3) 7.32 (1H, d, J 1.9), 7.14 (1H, dd, J 1.9 and 8.5), 7.00
(1H, s), 6.83(1H, d, J 8.5), 3.88(3H, s), 3.87(3H, s), 3.70(1H, d, J 15.4),
3.65 (2H, d, J 5.2), 3.37 (1H, d, J 15.4), 2.91–2.84 (1H, complex m),
2.82–2.73 (1H, complex m), 2.37 (1H, m), 1.85–1.22 (6H, complex m).
δC (75 MHz, CDCl3) 148.6, 148.2, 128.1, 122.2, 111.8, 110.5, 64.4,
61.0, 55.8(8), 55.8(5), 50.8, 45.0, 28.6, 25.2, 22.2 (two signals obscured
Method B
A magnetically stirred solution of N-chlorosuccinimide (22 mg,
0.17 mmol) in dichloromethane (0.5 mL) maintained at 0◦C was treated,

546
M. G. Banwell and M. O. Sydnes
or overlapping). m/z (EI, 70 eV) 391 (0.4%), 389 (2), and 387 (1.7,
M+•); 354 (1.8) and 352 (1.9); 340 (15) and 338 (16); 257 (63) and 255
(65); 176 (98) and 175 (100); 161 (23); 145 (19); 91 (27).
oil. This material was subjected to flash chromatography [silica, 95 : 5
v/v dichloromethane/methanol and a trace of ammonia (15% aqueous
solution)] to afford fractions A–C.
Concentration of the fraction A [RF 0.0(7)] gave compound 30
•
(1.3 mg, 10%) as a light-yellow solid, mp 89–91◦C (Found: M+
Method B
291.1840. C17H25NO3 requires M+•, 291.1834). vmax (KBr)/cm−1
3369(br), 2933, 1602, 1584, 1515, 1464, 1264, 1158, 1138, 1026. δH
(300 MHz, CDCl3) 6.91 (1H, d, J 2.0), 6.87 (1H, dd, J 2.0 and 8.2),
6.78 (1H, d, J 8.2), 6.44 (1H, d, J 15.7), 6.11 (1H, ddd, J 2.0, 6.8, and
15.7), 3.87 (3H, s), 3.84 (3H, s), 3.83 (1H, dd, J 4.1 and 11.0), 3.60
(1H, ddd, J 1.4, 5.8 and 14.0), 3.51 (1H, dd, J 3.6 and 11.0), 3.16 (1H,
dd, J 7.9 and 14.6), 3.03 (1H, dt, J 3.9 and 11.8), 2.68 (1H, br s), 2.44
(1H, sextet, J 4.1), 2.29 (1H, ddd, J 2.9, 10.4 and 11.9), 1.76–1.21 (6H,
complex m). δC (75 MHz, CDCl3) 149.0, 148.8, 132.8, 129.9, 124.0,
119.4, 111.1, 108.6, 62.4, 60.7, 55.9, 55.8, 55.7, 51.4, 27.6, 24.3, 23.4.
m/z (EI, 70 eV) 291 (2%, M+•), 260 (49), 178 (36), 177 (100), 146 (38).
Concentration of fraction B [RF 0.1(4)] gave alcohol 25 (15.4 mg,
MsCl (40 µL, 0.517 mmol) was added, dropwise, to a magnetically
stirred solution of alcohol 6 (105 mg, 0.284 mmol) in pyridine (3.0 mL)
maintained at 0◦C under an atmosphere of nitrogen. After the reaction
mixture had stirred at 0◦C for 1.5 h, it was poured into water (15 mL)
and the separated aqueous phase was extracted with dichloromethane
(4 × 25 mL). The combined organic phases were then dried, filtered,
and concentrated under reduced pressure. The residue thus obtained
was subjected to flash chromatography (silica, 85 : 15 v/v hexane/ethyl
acetate elution), and concentration of the appropriate fractions (RF 0.2)
gave the title chloride 27 (60 mg, 54%) as a light-yellow oil which was
identical, in all respects, with the material obtained by method A.
•
87%) as a yellow oil (Found: M+ 397.2254, C 69.1, H 8.1, N 3.3.
2-Chloromethyl-1-[3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)prop-
•
C24H31NO4 requires M+ 397.2253. C24H31NO4 · H2O requires C
2ꢀ-ynyl]piperidine 28
69.4, H 8.0, N 3.4%). vmax (KBr)/cm−1 3436(br), 2931, 1606, 1511,
1463, 1267, 1243, 1141, 1027. δH (300 MHz, CD3OD) 7.14 (2H, d,
J 8.8), 6.89 (2H, d, J 8.8), 6.72 (1H, d, J 8.4), 6.62 (1H, dd, J 1.9 and
8.4), 6.54 (1H, s), 6.43 (1H, d, J 1.9), 3.93 (1H, d, J 13.4), 3.77 (3H,
s), 3.74 (3H, s), 3.59 (1H, dd, J 4.7 and 11.1), 3.53 (1H, dd, J 5.3 and
11.1), 3.40 (3H, s), 3.20 (1H, d, J 13.4), 3.09–3.02 (1H, complex m),
2.38 (1H, br s), 2.23 (1H, t, J 9.7), 1.74–1.26 (6H, complex m). δC
(75 MHz, CD3OD) 160.4, 149.4, 149.2, 139.1, 134.2, 131.6, 131.3,
129.9, 123.7, 115.2, 113.4, 112.3, 64.0, 63.6, 63.5, 56.3, 55.7(2), 55.7(0),
52.7, 29.1, 25.8, 24.4. m/z (EI, 70 eV) 397 (3%, M+•), 366 (56), 283
(100), 252 (47), 237 (17), 128 (32).
NaH (5 mg of a 60% dispersion in mineral oil, 0.13 mmol) was added
to a magnetically stirred solution of chloride 27 (25 mg, 0.06 mmol) in
DMF (1 mL) maintained at 18◦C under an atmosphere of nitrogen.After
the ensuing mixture had stirred at 18◦C for 16 h, it was diluted with ethyl
acetate (15 mL) and washed with brine (6 × 10 mL) before being dried,
filtered, and concentrated under reduced pressure to give a light-yellow
oil.This material was subjected to flash chromatography (silica, 4 : 1 v/v
hexane/ethyl acetate elution) to afford, after concentration of the appro-
priate fractions (RF 0.15), alkyne 28 (7.6 mg, 38%) as a light-yellow oil
(Found: M+• 309.1317. C17H2237ClNO2 requires M+• 309.1310). vmax
(KBr)/cm−1 2935, 2219, 1599, 1578, 1513, 1462, 1267, 1242, 1206,
1168, 1137, 1027. δH (300 MHz, CD3OD) 7.00 (1H, dd, J 1.9 and 8.3),
6.95 (1H, d, J 1.9), 6.87 (1H, d, J 8.3), 3.88 (1H, d, J 17.7), 3.83 (1H,
partially obscured m), 3.81 (3H, s), 3.80 (3H, s), 3.66 (1H, dd, J 2.3 and
11.6), 3.53 (1H, d, J 17.7), 2.90–2.82 (1H, complex m), 2.74–2.67 (1H,
complex m), 2.62 (1H, dd, J 3.5 and 11.6), 1.83–1.52 (5H, complex m),
1.45–1.26 (1H, complex m). δC (75 MHz, CD3OD) 151.0, 150.0, 126.1,
116.4, 115.9, 112.6, 87.6, 81.6, 60.9, 56.5, 56.4, 54.5, 47.1, 44.4, 30.3,
26.5, 24.9. m/z (EI, 70 eV) 309 (3%) and 307 (9, M+•); 272 (5); 258
(65); 175 (100); 131 (20); 129 (19).
Concentration of fraction C (RF 0.8) gave a white solid, which
was recrystallized (benzene/hexane) to afford aldehyde 31[19] (vari-
able quantities—see Table 2) as white needles, mp 82–84◦C (lit.[19]
•
•
83–84◦C) (Found: M+ 192.0790. C11H12O3 requires M+ 192.0786).
vmax (KBr)/cm−1 2935, 1672, 1621, 1597, 1512, 1270, 1126, 1023. δH
(300 MHz, CDCl3) 9.63 (1H, d, J 7.8), 7.39 (1H, d, J 15.8), 7.14 (1H,
dd, J 1.9 and 8.2), 7.05 (1H, d, J 1.9), 6.88 (1H, d, J 8.2), 6.58 (1H, dd,
J 7.8 and 15.8), 3.91 (3H, s), 3.90 (3H, s). δC (75 MHz, CDCl3) 193.6,
152.9, 151.9, 149.3, 127.0, 126.7, 123.4, 111.0, 109.7, 56.0, 55.9. m/z
(EI, 70 eV) 192 (100%, M+•), 177 (42), 161 (83), 149 (41), 121 (34),
91 (39), 78 (31), 77 (43).
2-(4ꢀ-Methoxyphenyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane 29
2-Chloromethyl-1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)-
2ꢀ-(4ꢀꢀꢀ-methoxyphenyl)prop-2ꢀ-enyl]piperidine 4 (X = Cl)
p-TsOH · H2O (20 mg, 0.11 mmol) was added to a magnetically stirred
solution of 4-methoxyphenylboronic acid 21[15] (263 mg, 1.73 mmol)
and pinacol hexahydrate (1.14 g, 5.04 mmol) in benzene (15 mL), and
the resultant mixture was heated at reflux for 16 h in an apparatus incor-
porating a Dean–Stark trap. The cooled reaction mixture was washed
with water (2 × 10 mL) and brine (1 × 10 mL) then dried, filtered, and
concentrated under reduced pressure to give boronate 29[18] (398 mg,
98%) as a light-yellow solid, mp 26–28◦C. δH (300 MHz, CDCl3) 7.73
(2H, d, J 8.8), 6.87(2H, d, J 8.8), 3.80(3H, s), 1.31(12H, s). δC (75 MHz,
CDCl3) 162.1, 136.5, 113.3, 83.5, 55.1, 24.8 (one signal obscured or
overlapping). m/z (EI, 70 eV) 234 (100, M+), 219 (69), 148 (66), 135
(85), 134 (90).
MsCl (5 µL, 0.06 mmol) was added to a magnetically stirred solution
of alcohol 25 (7.6 mg, 0.02 mmol) in pyridine (0.5 mL) maintained at
0◦C under an atmosphere of nitrogen. After 1 h at 0◦C the reaction
mixture was diluted with dichloromethane (15 mL) then washed with
Na2CO3 (2 × 10 mL of a 2 M aqueous solution) and HCl (2 × 10 mL of
a 2 M aqueous solution) before being dried, filtered, and concentrated
under reduced pressure to give chloride 4 (X = Cl) (6.6 mg, 83%) as an
unstable, yellow oil. vmax (KBr)/cm−1 2930, 1729, 1606, 1580, 1512,
1464, 1266, 1243, 1028, 805. δH (300 MHz, CD3OD) 7.14 (2H, d, J 8.8),
6.88 (2H, d, J 8.8), 6.72 (1H, d, J 8.4), 6.62 (1H, dd, J 1.9 and 8.4),
6.53 (1H, s), 6.43 (1H, d, J 1.9), 3.81 (1H, d, J 15.2), 3.77 (3H, s), 3.75
(1H, d, J 15.2), 3.74 (3H, s), 3.64 (1H, m), 3.42 (1H, d, J 6.3), 3.40
(3H, s), 2.96–2.89 (1H, complex m), 2.63–2.56 (1H, complex m), 2.34–
2.26 (1H, complex m), 1.71–1.27 (6H, complex m). m/z (EI, 70 eV) 417
(15%) and 415 (41, M+•); 380 (14); 366 (49); 307 (53); 283 (100); 252
(53); 199 (46); 177 (35); 146 (72).
{1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-Dimethoxyphenyl)-2ꢀ-(4ꢀꢀ-methoxyphenyl)prop-
2ꢀ-enyl]piperidin-2-yl}methanol 25,
{1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)prop-2ꢀ-enyl]piperidin-2-yl}-
methanol 30,
and (E)-3-(3ꢀ,4ꢀ-dimethoxyphenyl)propenal 31
A magnetically stirred mixture of alcohol 6 (16 mg, 0.04 mmol),
boronate ester 29 (21 mg, 0.09 mmol), ethanol (280 µL), and Na2CO3
(0.63 mL of a 2 m aqueous solution) in benzene (2.25 mL) was treated
with PdCl2(dppf) (2.4 mg, 0.003 mmol) then heated at reflux for 11 h
under an atmosphere of nitrogen while being protected from light. The
cooled reaction mixture was diluted with diethyl ether (20 mL), and the
separated organic phase was washed with NaHCO3 (2 × 10 mL of a
saturated aqueous solution) and brine (1 × 10 mL) before being dried,
filtered, and concentrated under reduced pressure to give a light-yellow
{(S)-1-[(Z)-2ꢀ-Bromo-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)prop-2ꢀ-enyl]-
pyrrolidin-2-yl}methanol 33
A magnetically stirred solution of chloride 26 (41 mg, 0.14 mmol) in
DMF (1.0 mL) maintained at 18◦C under an atmosphere of nitrogen was
treated with (S)-(+)-2-pyrrolidinemethanol (32) (15 µL, 0.15 mmol, ex.
Aldrich)andtriethylamine(20 µL, 0.143 mmol).Aftertheresultantmix-
ture had been heated at 70◦C for 16 h, it was cooled to 18◦C then diluted
with ethyl acetate (20 mL), washed with brine/water (5 × 15 mL of a

Synthetic Approaches to Phenanthroquinolizidine and Phenanthroindolizidine Alkaloids
547
1 : 1 v/v mixture) and brine (1 × 15 mL) before being dried, filtered, and
concentrated under reduced pressure to give the title alcohol 33 (50 mg,
99%) as a light-yellow oil, [α]D −44.3 (c 0.8 in CHCl3) (Found: C 53.7,
detected using a UV cell set at 240 nm. For the purposes of this anal-
ysis, an authentic sample of ( )-35 was prepared under the conditions
detailed above by treating ( )-2-pyrrolidinemethanol with compound
26, and then cross-coupling the amine ( )-33 so formed with boronate
34 [Rt (S-enantiomer) 23.6 min, (R-enantiomer) 26.8 min].
•
H 6.1, N 3.8, M+ 355.0783. C16H2279BrNO3 requires C 53.9, H 6.2,
N 3.9%, M+• 355.0783). vmax (KBr)/cm−1 3500(br), 1601, 1514, 1463,
1269, 1143, 1026. δH (300 MHz, CD3OD) 7.36 (1H, d, J 2.0), 7.19 (1H,
dd, J 2.0 and 8.5), 6.98 (1H, s), 6.88 (1H, d, J 8.5), 3.80 (3H, s), 3.79
(3H, s), 3.78 (1H, d, J 14.5), 3.55 (1H, dd, J 4.2 and 10.8), 3.46 (1H,
dd, J 6.0 and 10.8), 3.34 (1H, d, J 14.5), 3.09 (1H, m), 2.70 (1H, m),
2.34 (1H, m), 1.93 (1H, m), 1.79–1.62 (3H, complex m). δC (75 MHz,
CD3OD) 150.3, 149.7, 130.1, 129.6, 123.7, 113.5, 112.2, 66.7, 65.8,
65.2, 56.3 (2C), 55.3, 29.2, 24.1 (one resonance obscured or overlap-
ping). m/z (EI, 70 eV) 357 (0.8%) and 355 (0.9, M+•); 326 (39) and 324
(38); 257 (81) and 255 (79); 176 (100).
Concentration of fraction B (RF 0.07) gave the debrominated mate-
rial 36 (7 mg, 25%) as a light-yellow oil, [α]D +30.0 (c 0.2 in CHCl3)
•
•
(Found: M+ 277.1675. C16H23NO3 requires M+ 277.1678). vmax
(KBr)/cm−1 3369(br), 2958, 2934, 2873, 2836, 1602, 1584, 1515, 1464,
1418, 1264, 1158, 1139, 1026, 968, 735. δH (300 MHz, CD3OD) 7.03
(1H, d, J 1.9), 6.95 (1H, dd, J 1.9 and 8.3), 6.88 (1H, d, J 8.3), 6.54
(1H, d, J 15.7), 6.20 (1H, ddd, J 6.4, 7.7, and 15.7), 3.83 (3H, s), 3.81
(3H, s), 3.73 (1H, m), 3.65 (1H, dd, J 4.9 and 11.1), 3.53 (1H, dd, J 6.1
and 11.1), 3.26–3.11 (2H, complex m), 2.77 (1H, m), 2.47 (1H, m),
2.04–1.95 (1H, complex m), 1.88–1.63 (3H, complex m). δC (75 MHz,
CD3OD) 150.6, 150.5, 131.5, 120.9, 112.8, 110.6, 66.7, 64.7, 58.5, 56.4,
55.4, 28.9, 23.5 (three signals obscured or overlapping). m/z (EI, 70 eV)
277 (3%, M+•), 246 (44), 177 (100), 146 (37).
2-(3ꢀ,4ꢀ-Dimethoxyphenyl)-4,4,5,5-tetramethyl[1,3,2]-
dioxaborolane 34
p-TsOH · H2O (12.0 mg, 0.0631 mmol) was added to a magneti-
cally stirred solution of 3,4-dimethoxyphenylboronic acid 14 (315 mg,
1.73 mmol) and pinacol hexahydrate (1.18 g, 5.22 mmol) in benzene
(15 mL) maintained under an atmosphere of nitrogen, and the resultant
mixture was heated at reflux for 16 h in an apparatus incorporating a
Dean–Stark trap.The reaction mixture was cooled to 18◦C, then washed
with water (2 × 10 mL) and brine (1 × 10 mL) before being dried, fil-
tered, and concentrated under reduced pressure to give the title boronate
34[20] (452 mg, 99%) as a light-yellow solid, mp 75–76◦C (lit.[20] 74–
77◦C). δH (300 MHz, CDCl3) 7.40 (1H, dd, J 1.4 and 8.0), 7.26 (1H, d,
J 1.4), 6.85 (1H, d, J 8.0), 3.89 (3H, s), 3.87 (3H, s), 1.31 (12H, s). δC
(75 MHz, CDCl3) 151.5, 148.3, 128.5, 116.5, 110.4, 83.6, 55.8, 55.7,
24.8 (one signal obscured or overlapping). m/z (EI, 70 eV) 264 (100%)
and 263 (48, M+); 249 (28); 179 (33) and 178 (40); 165 (63) and 164
(74); 149 (22) and 148 (9); 121 (17); 77 (24).
(S)-2-Chloromethyl-1-[(E)-2ꢀ,3ꢀ-bis(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)-
prop-2ꢀ-enyl]pyrrolidine 37
Mesyl chloride (10 µL, 0.13 mmol) was added, dropwise, to a mag-
netically stirred solution of alcohol 35 (10 mg, 0.02 mmol) in pyridine
(1.0 mL) maintained at 0◦C under an atmosphere of nitrogen. After
1 h the reaction mixture was diluted with dichloromethane (15 mL),
then washed with Na2CO3 (2 × 10 mL of a 2 M aqueous solution) and
HCl (2 × 10 mL of a 2 M aqueous solution) before being dried, fil-
tered, and concentrated under reduced pressure to give a light-yellow
and unstable oil (11 mg), [α]D −8.9 (c 0.44 in MeOH). This mate-
rial, which contained traces of pyridine (as judged by 300 MHz 1H
NMR analysis), was subjected to flash chromatography [silica, 95 : 5 v/v
dichloromethane/methanol and a trace of ammonia (15% aqueous solu-
tion)] to afford, after concentration of the appropriate fractions (RF 0.7),
the title chloride 37 (2 mg, 19%) as a unstable and light-yellow oil. vmax
(KBr)/cm−1 2960, 2930, 1601, 1581, 1514, 1464, 1259, 1141, 1024.
δH (300 MHz, CD3OD) 6.92 (1H, d, J 8.2), 6.84 (1H, d, J 1.9), 6.79
(1H, dd, J 1.9 and 8.2), 6.74 (1H, d, J 8.3), 6.65 (1H, dd, J 2.0 and
8.3), 6.51 (1H, s), 6.47 (1H, d, J 2.0), 3.97 (1H, m), 3.81 (3H, s), 3.74
(3H, s), 3.70 (3H, s), 3.42 (3H, s), 3.33 (2H, dd, J 1.1 and 4.6), 3.08
(1H, m), 2.78 (1H, br d, J 10.7), 2.32 (1H, t, J 8.1), 2.21–2.04 (2H,
complex m), 1.85–1.72 (1H, complex m), 1.64–1.46 (2H, complex m).
δC (75 MHz, CD3OD) 151.3, 151.2, 150.7, 149.8, 130.8, 130.2, 129.5,
128.8, 124.6, 123.3, 114.2, 113.7, 113.5, 112.3, 70.1, 64.4, 56.5, 56.3,
56.0, 55.9, 52.8, 43.4, 29.1, 23.1. m/z (EI, 70 eV) 433 (28%) and 431
(70, M+•); 396 (20); 314 (70); 313 (47); 134 (45); 132 (100).
{(S)-1-[(E)-2ꢀ,3ꢀ-Bis(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)prop-2ꢀ-enyl]-
pyrrolidin-2-yl}methanol 35
and {(S)-1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-Dimethoxyphenyl)prop-2ꢀ-enyl]-
pyrrolidin-2-yl}methanol 36
PdCl2(dppf) (11.4 mg, 0.0139 mmol) was added to a magnetically
stirred solution of bromide 33 (37.5 mg, 0.11 mmol), boronate ester
34 (64 mg, 0.24 mmol), ethanol (660 µL), and Na2CO3 (1.5 mL of a
2 M aqueous solution) in benzene (5.34 mL). After the ensuing mixture
had been heated at reflux for 13 h while being protected from ambi-
ent light, it was cooled to 18◦C and diluted with diethyl ether (20 mL).
The separated organic phase was washed with NaHCO3 (2 × 10 mL
of a saturated aqueous solution) and brine (1 × 10 mL) then dried,
filtered, and concentrated under reduced pressure. The ensuing light-
yellow oil was subjected to flash chromatography [silica, 95 : 5 v/v
dichloromethane/methanol and a few drops of ammonia (15% aqueous
solution)] to afford fractions A and B.
Acknowledgments
We thank the Institute of Advanced Studies for financial
support and the provision of a PhD Scholarship to M.O.S.,
Mr Tony Herlt (RSC, ANU) for expert assistance with the
operation of HPLC instrumentation, and Mr Chris Blake
(RSC, ANU) for help with the acquisition of certain NMR
data.
Concentration of fraction A (RF 0.14) gave the title compound
35[6] (31 mg, 72%) as a clear, colourless oil, [α]D −22.1 (c 0.5 in
MeOH), [lit.[6] −81.4 (c 1 in MeOH)] (Found: C 66.7, H 7.6, N 3.1,
M+• 413.2201. C24H31NO5 requires M+• 413.2202. C24H31NO5 · H2O
requires C 66.8, H 7.7, N 3.3%). vmax (KBr)/cm−1 3439(br), 2926, 2851,
2836, 1601, 1581, 1513, 1464, 1255, 1163, 1139, 1026. δH (500 MHz,
CD3OD) 6.92 (1H, d, J 8.0), 6.83 (1H, d, J 2.0), 6.81 (1H, dd, J 2.0
and 8.0), 6.74 (1H, d, J 8.3), 6.65 (1H, dd, J 2.0 and 8.3), 6.55 (1H, s),
6.49 (1H, d, J 2.0), 3.91 (1H, d, J 13.2), 3.81 (3H, s), 3.74 (3H, s), 3.69
(3H, s), 3.49 (1H, dd, J 4.0 and 10.7), 3.43 (3H, s), 3.41 (1H, dd, J 6.0
and 10.7), 3.25 (1H, d, J 13.2), 3.11 (1H, m), 2.66 (1H, br s), 2.35 (1H,
m), 1.93 (1H, m), 1.75–1.59 (3H, complex m). δC (75 MHz, CD3OD)
150.6, 149.8, 149.5, 149.3, 139.8, 134.7, 131.5, 129.3, 123.7, 122.6,
114.2, 113.5, 113.2, 112.3, 66.3, 64.9, 64.8, 56.5, 56.4, 56.3, 55.8, 55.4,
29.2, 24.0. m/z (EI, 70 eV) 413 (3%, M+•), 382 (26), 313 (100), 282
(39), 267 (12), 175 (19), 114 (29).
References
[1] N. K. Hart, S. R. Johns, J. A. Lamberton, Aust. J. Chem. 1968,
21, 2579.
[2] (a) E. Gellert, N. V. Riggs, Aust. J. Chem. 1954, 7, 113.
(b) E. Gellert, Aust. J. Chem. 1956, 9, 489.
[3] J. H. Russel, Naturwissenschaften 1963, 50, 443.
[4] D. Stærk, A. K. Lykkeberg, J. Christensen, B. A. Budnik, F. Abe,
J. W. Jaroszewski, J. Nat. Prod. 2002, 65, 1299, and references
therein. doi:10.1021/NP0106384
[5] Z. Li, Z. Jin, R. Huang, Synthesis 2001, 2365, and references
therein. doi:10.1055/S-2001-18703
The enantiomeric excess of compound 35 was >95% as determined
by HPLC analysis using a 4.6 by 250 mm Diacel Chiralcel OD column
and 20 : 79.95 : 0.05 v/v/v isopropyl alcohol/hexane/triethylamine as the
eluting solvent (flow rate of 0.3 mL min−1). Eluted compounds were

548
M. G. Banwell and M. O. Sydnes
[6] J. H. Russel, H. Hunziker, Tetrahedron Lett. 1969, 4035.
[9] F. L. Schadt, P. v. R. Schleyer, T. W. Bentley, Tetrahedron Lett.
1974, 2335. doi:10.1016/S0040-4039(01)92248-8
[10] B. M. Trost, J. D. Oslob, J. Am. Chem. Soc. 1999, 121, 3057.
doi:10.1021/JA983617D
doi:10.1016/S0040-4039(01)88607-X
[7] (a) M. G. Banwell, R. W. Gable, B. Halton, J. R. Phyland,
Aust. J. Chem. 1994, 47, 1879.
(b) M. G. Banwell, R. W. Gable, S. C. Peters, J. R. Phyland,
J. Chem. Soc., Chem. Commun. 1995, 1395.
(c) M. Banwell, A. Edwards, J. Harvey, D. Hockless,
A. Willis, J. Chem. Soc., PerkinTrans. 1 2000, 2175. doi:10.1039/
B002525I
(d) M. G. Banwell, J. E. Harvey, D. C. R. Hockless, A. W. Wu,
J. Org. Chem. 2000, 65, 4241. doi:10.1021/JO991791U
(e) M. G. Banwell, W. Ebenbeck, A. J. Edwards, J. Chem. Soc.,
Perkin Trans. 1 2001, 114. doi:10.1039/B008146I
(f) M. G. Banwell, J. E. Harvey, K. A. Jolliffe, J. Chem. Soc.,
Perkin Trans. 1 2001, 2002. doi:10.1039/B106369N
For reviews see (g) M. Fedoryn´ski, Chem. Rev. 2003, 103,
1099. doi:10.1021/cr0100087
[11] G. C. Nwokogu, J. Org. Chem. 1985, 50, 3900.
[12] C. K. Hwang, W. S. Li, K. C. Nicolaou, Tetrahedron Lett. 1984,
25, 2295. doi:10.1016/S0040-4039(01)80237-9
[13] M. G. Banwell, B. D. Bissett, S. Busato, C. J. Cowden,
D. C. R. Hockless, J. W. Holman, R. W. Read, A. W. Wu,
J. Chem. Soc., Chem. Commun. 1995, 2551.
[14] T. K. Vinod, H. Hart, Tetrahedron Lett. 1988, 29, 885.
doi:10.1016/S0040-4039(00)82473-9
[15] M. G. Banwell, B. L. Flynn, E. Hamel, D. C. R. Hockless,
Chem. Commun. 1997, 207.
[16] G. Gonzalez Trigo, J. Alvarez-Builla, M. M. Sollhuber Kretzer,
Anales de Quimica 1978, 74, 523 [Chem. Abstr. 1978, 89,
163824].
(h) R. M. Taylor, Aust. J. Chem. 2003, 56, 631. doi:10.1071/
CH02223
(i) M. G. Banwell, M. E. Reum, in Advances in Strain in
Organic Chemistry (Ed. B. Halton) 1991, Vol. 1, pp. 19–64
(JAI Press: Greenwich, CT).
[17] T. Kobayashi, S. Ogura, K. Sakurai, K. Shiroyama, T. Hagiwara,
Jpn Kokai Tokkyo Koho 2002, JP 2002053527 [Chem. Abstr.
2002, 136, 189101].
[18] T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem. 1995, 60,
7508.
[8] (a) A. J. Liepa, R. E. Summons, J. Chem. Soc., Chem. Commun.
1977, 826.
[19] S. Li, K. Lundquist, Acta Chem. Scand. 1995, 49, 64.
[20] M. K. Tse, J.-Y. Cho, M. R. Smith III, Org. Lett. 2001, 3, 2831.
doi:10.1021/OL0162668
(b) A. J. Liepa, Chem. Aust. 1999, 66, 25.