Synthesis of the heterocyclic core of martinelline and martinellic acid

Article abstract of DOI:10.1016/j.tet.2006.02.029

A Povarov reaction, between an aromatic imine derived from cinnamaldehyde and a cyclic enamide, was employed to rapidly construct the tricyclic core of the alkaloids martinelline and martinellic acid. The cycloaddition was completely regioselective though

Full text of DOI:10.1016/j.tet.2006.02.029

Tetrahedron 62 (2006) 3977–3984
Synthesis of the heterocyclic core of martinelline and
martinellic acid
*
Mark Hadden, Mark Nieuwenhuyzen, Daire Osborne, Paul J. Stevenson,
Norris Thompson and Andrew D. Walker
School of Chemistry and Chemical Engineering, The Queen’s University of Belfast, David Keir Building,
Belfast BT9 5AG, Northern Ireland, UK
Received 12 December 2005; revised 25 January 2006; accepted 10 February 2006
Available online 9 March 2006
Abstract—A Povarov reaction, between an aromatic imine derived from cinnamaldehyde and a cyclic enamide, was employed to rapidly
construct the tricyclic core of the alkaloids martinelline and martinellic acid. The cycloaddition was completely regioselective though the
exo/endo selectivity was poor. The diastereoisomers were readily separated by flash chromatography and the relative stereochemistry of the
exo-isomer confirmed by single crystal X-ray crystallography. This intermediate was converted to the central core of the aforementioned
alkaloids in five additional synthetic operations.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
There is currently much interest in identifying non-peptide
bradykinin inhibitors as potential therapeutic agents.1–7
Bioassay guided fractionation of an extract from the
medicinal plant Martinella iquitosensis led to the isolation
of the first natural product bradykinin receptor inhibitors,
martinellic acid and martinelline 1a,b, respectively,
Figure 1.8 These alkaloids are unique in that they contain
the unusual hexahydropyrroloquinoline moiety. The bio-
logical activity, coupled with the unusual heterocyclic
motif, has made these alkaloids very attractive synthetic
targets. This has prompted new methods for forming
hexahydropyrroloquinolines,9–26 culminating in four synth-
eses27–30 and three formal syntheses of these alkaloids,31–33
and the subject has been recently reviewed.34
Figure 1. Structure of martinelline and martinellic acid.
much additional chemistry once the hexahydropyrroloquino-
The major challenges in this synthesis are control of the
line is in place. We previously communicated the first
regiochemistry on the trisubstituted aromatic ring, the
approach to the heterocyclic core of martinelline 17, using a
stereochemistry at the three contiguous chiral centres and
Povarovreactionofiminesderivedfromaromaticamineswith
copingwith the labile heteroatomatC9b. On the lastpoint, itis
cyclic enamides as the key step and now report full details on
well known that heteroatoms on the 4-position of a
this study. Triamine 17 was the key intermediate in all
tetrahydroquinoline are prone to eliminate, ultimately giving
subsequent syntheses of martinellic acid.
quinolines. Therefore, methods for producing the hexahydro-
pyrroloquinoline must be mild and it is prudent not to do too
2. Results and discussion
Keywords: Martinelline; Martinellic acid; Imino Diels–Alder; Alkaloid;
Povarov reaction; Lewis acid catalysis.
Our initial strategy, Scheme 1, focussed on using a Povarov
reaction to construct the hexahydropyrroloquinoline with all
*
Corresponding author. Tel.: C44 2890974426;
e-mail: p.stevenson@qub.ac.uk
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.029

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M. Hadden et al. / Tetrahedron 62 (2006) 3977–3984
Scheme 1. Reagents and conditions: (i) indium trichloride 20%, acetonitrile 30 min 25 8C.
the carbons, bar the 8-carboxy, and nitrogens in place,
though not at the correct oxidation level for martinellic acid.
The main advantages of this approach were its convergence,
its complete regioselectivity, and the symmetry was such
that p-substituted benzenes ensured the correct regio-
chemistry of the tri-substituted aromatic ring on cyclo-
addition. The regioselectivity from this ionic stepwise
pathway was governed by the stability of the acyliminium
ion intermediate. Unfortunately, this chemistry failed with
aliphatic aldehydes and with a,b-unsaturated aldehydes
with hydrogens on the g-position, making it difficult to
introduce the required 4-substituent. However, this problem
was overcome by using (E)-3-oxo-1-propenyl cyanide35 as
the aldehyde component.
palladium led to a complex mixture of products,
suggesting that N5 may need protecting prior to
reduction of the nitrile and that the 8-bromo substituent
was also labile under these conditions. Enamide 3 was
initially chosen as the NMR spectra of the cycloadducts
derived from this were reasonably sharp and easy to
interpret. However, with compound 4, attempted removal
of the carbomethoxy group with trimethylsilyl iodide36
led to intractable material. It was clear from this initial
study that we would have to improve the yield and exo-
selectivity of the cycloaddition, use an enamide in which
the group on N1 was more easily removed than a
carbomethoxy, protect N5 before reduction of the nitrile,
and have the 8-carboxy group present before the key
cycloaddition. Incorporation of all these design features
led to the successful synthesis of the martinelline
core, 17 Scheme 2, though some convergence was
inevitably lost.
We previously reported that 3-cyanoacrolein condensed
with p-bromaniline to give an unstable imine 2, which
underwent Povarov reaction with cyclic enamide 3 to
give a 1:3 mixture of exo/endo hexahydropyrroloquino-
lines 4 and 5 in 40% combined yield. Although this
chemistry elegantly gave the gross structure of a key
martinelline intermediate in one step, the low yield and
endo-selectivity was unacceptable. Furthermore, attempts
to reduce the alkene and nitrile using hydrogen and
Imine 6, derived from cinnamaldehyde and methyl
4-aminobenzoate, was a yellow crystalline compound,
which was stable to storage at room temperature. Enamide
7, made by the literature procedure,37,38 was chosen as the
coupling partner because it was envisaged that in the later
Scheme 2. Reagents and conditions: (i) 12 mol% InCl3, CH3CN, 25 8C, 12 h; (ii) 1 mol% Y(OTf)3, CH3CN 25 8C, 2 h; (iii) 100 mol% LiBF4, CH3CN, 12 h;
(iv) trifluoroacetic anhydride, DMAP, toluene 108 8C, 24 h.

M. Hadden et al. / Tetrahedron 62 (2006) 3977–3984
3979
stages it could be removed simultaneously with the alkene
or nitrile under reducing conditions. The main disadvantage
of using enamide 7 was that the proton NMR spectra of
the products were fairly broad and difficult to interpret due
to hindered rotation at the carbamate.
prompting an investigation of this catalyst in our system.
Initial results seemed promising and only the exo-
hexahydropyrroloquinoline 8 was formed, though the
isolated yield, 43%, was disappointingly low with the
mass balance comprising of quinoline 10. When this
reaction was repeated, and the solvent removed, proton
NMR analysis of the crude mixture revealed it was a 1:1
mixture of exo/endo isomers. Clearly this reaction is not
showing any exo-selectivity and the quinoline appears
to be selectively derived from the endo-isomer during
the aqueous work up. Presumably the mechanism for this
reaction involves isomerisation of the alkene into the
hexahydropyrroloquinoline six-membered ring, followed
by elimination of the nitrogen from C9b to give the
quinoline 10. It is not clear why the endo-isomer participates
in this isomerisation whilst the exo-isomer does not.
Initially, reaction of imine 6 with enamide 7 using 12 mol%
indium trichloride as catalyst gave a 1.1:1 mixture of exo/
endo stereoisomers 8 and 9, respectively, from which the
desired exo-isomer 8 was easily separated in 40% yield. In
our hands, indium trichloride lost its catalytic activity on
storage once the bottle was opened. Yttrium triflate proved
to be a much more reliable and robust catalyst. It did not
deteriorate on storage, much lower loadings (1%) could be
employed, and the isolated yield of the desired exo-
hexahydropyrroloquinoline 8 rose to 46%. The relative
stereochemistry of the desired exo-isomer 8 was established
by X-ray crystallography, and this is shown in Figure 2.
Interestingly, the molecule adopts a conformation, which
puts the groups at C3a and C4 trans-diaxial in the solid state.
This conformation is also the preferred one in solution and
was confirmed by NOE studies. Hence, saturation of H4 led
to a NOE of 5.5% onto H3a and no enhancement onto H9b
indicating that H4 was indeed equatorial. Unfortunately, the
peaks for H4 and H3a in the proton NMR spectrum were too
broad, due to hindered rotation, to extract J values, but in
similar compounds devoid of the CBz protecting group this
coupling constant is of the order of 2 Hz for the exo-isomer
confirming the solution conformation.
Finally, an attempt was made to recycle the unwanted endo-
isomer. We have previously shown in 1-propionyl-4-phenyl
substituted hexahydropyrroloquinolines, the Povarov
reaction is reversible and after 20 days at room temperature
in d-3-acetonitrile containing a crystal of yttrium triflate, the
endo-isomer equilibrates to a 10:7 mixture of endo/exo
isomers. As suspected the endo-isomer is slightly more
thermodynamically stable than the exo-isomer. Unfortu-
nately, the same study on the more complex tetrahydro-
pyrroloquinoline 9 was thwarted as the initial reaction was
irreversible even at 60 8C for 7 days. It is presently not clear
if it is the carbamate protecting group, the 8-carbomethoxy
group, or the more complex C4 substituent, which is
rendering this cycloaddition irreversible.
Although it was disappointing that the exo/endo selectivity
could not be improved further for the key reaction, the fact
that the starting materials were so readily available and that
the exo/endo isomers were easy to separate still made this an
attractive synthetic procedure. With 8 at hand all that
remained was elaboration of the C4 side chain.
The aromatic amine N5 was incredibly unreactive due to
conjugation to the 8-carbomethoxy group. However, forcing
conditions of refluxing toluene containing trifluoroacetic
anhydride and a catalytic quantity of 4-dimethylaminopyr-
idine for 24 h gave the trifluoroacetamides 11 and 12 in 83
and 92% yield, respectively. Ozonolysis of adduct 11
followed by a reductive work up gave aldehyde 13, which
was trapped at K78 8C with the nitrile stabilised ylide
(triphenylphosphoranylidene)acetonitrile prior to work up,
Scheme 3 Proton NMR analysis of the crude mixture
showed a 2:1 mixture of Z–E a,b-unsaturated nitriles 14a
and 14b, respectively. However, on flash chromatography
this ratio changed to 1:5 and gave the alkenes in a combined
overall yield of 74% from 11. These alkene isomers could
be separated by preparative TLC for characterisation, but
for synthetic purposes the mixture was used.
Figure 2. X-ray structure of exo-cycloadduct 8 depicting relative
configuration and unusual conformation.
In an attempt to improve the diastereoselectivity of the
cycloaddition a range of catalysts were screened. The
reaction failed completely with aluminium39 and chromium
catalysts.40 With copper chloride and triflate the reaction
proceeded smoothly but with no improvement in diaster-
eoselectivity. In order to increase the steric bulk around the
metal, chiral bisoxazole complexes were employed.41
Again, although the reaction proceeded smoothly to
completion, no increase in the diastereoselectivity was
observed. Unfortunately, conditions could not be found to
separate the enantiomers on an analytical chiral HPLC
column, but the very low optical rotation of the exo-isomer
8, strongly suggested that within the error of the
measurement it was racemic. High exo-selectivity has
previously been observed in Povarov reactions of cyclic
enol ethers, catalysed by lithium tetrafluoroborate42
At this stage, an attempt was made to incorporate the
redundant endo-isomer into the synthesis by epimerising
C4. Ma30 has recently reported that in hexahydropyrrolo-
quinolines with aldehyde functionality at C4 and an amide
at N5, an exo/endo mixture isomerises to give the exo
aldehyde. The reason for this facile isomerisation is fairly
obvious. For six-membered ring cyclic amides with

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M. Hadden et al. / Tetrahedron 62 (2006) 3977–3984
Scheme 3. Reagents and conditions: (i) CH2Cl2, O3 K78 8C then Me2S; (ii) Ph3P]CHCN; (iii) PtO2, EtOH, CHCl3, 70 8C, 45 psi, 144 h; (iv) MeOH, NH3,
25 8C, 24 h; (v) Pd(OH)2, CH3OH, 60 8C, 45 psi, 24 h.
a 2-substituent, the thermodynamically more stable con-
former is the one in which the 2-substituent is axial as this
minimises pseudo allylic 1,3-strain.43 For N5 amides
derived from hexahydropyrroloquinolines then the exo-
isomer would undoubtedly be more stable that the endo-
isomer, as this can accommodate the adjacent axial
substituent. The alkene 12 was ozonolised followed by the
addition of dimethyl sulphide and then allowed to warm to
room temperature. Proton NMR analysis of the crude
reaction mixture revealed three aldehyde peaks at d 10.03,
9.66 and 9.46 corresponding to benzaldehyde, exo-aldehyde
and endo-aldehyde, respectively, in the ratio 1:0.53:0.47.
A fresh aliquot was removed after 24 h and proton NMR
analysis revealed the ratio of the three aldehydes was
1:0.72:0.15. It was clear that the amount of exo-aldehyde
was not increasing as fast as the endo-aldehyde was
decreasing indicating decomposition. Finally after 48 h
proton NMR analysis showed no endo-aldehyde remaining
but the amount of exo-isomer had dropped to 30% relative
to benzaldehyde, indicating extensive decomposition. This
was supported by the observation of quinoline peaks in the
aromatic region of the proton NMR spectra. Due to the
instability of the hexahydropyrroloquinoline aldehydes
this isomerisation was not pursued further as a means of
recycling the endo-isomer.
reduction product revealed an 85:15 mixture of two
compounds, from which the major product 15 could be
isolated by flash chromatography. The aromatic proton in
the major product H6 had changed its chemical shift from d
7.57 in the starting material to 6.41 ppm in the product
strongly indicating that the trifluoroacetyl on N5 was no
longer present. However, accurate mass data and 19F NMR
spectra revealed that the compound still contained a
trifluoroacetyl group. The most likely explanation is that
the trifluoroacetyl group has migrated from the aromatic
secondary amine to the aliphatic primary amine and that the
minor component is the compound that was initially
expected. There is good literature precedent for migrations
of this type.45 Removal of the trifluoroacetyl group on the
crude mixture was accomplished with ammonia in
methanol, to give 16 in 66% for the two steps. Finally, the
carbobenzyloxo group was reductively removed using
palladium hydroxide as catalyst to give 17 in 82% yield
completing the synthesis of the tricyclic core of martinellic
acid. The triamine 17 was very polar, difficult to purify by
chromatography, did not give mass spectral data and
decomposed on storage at 0 8C. However, the 13C NMR
spectrum of the crude material was clean and was in
reasonable agreement with the published spectra,28 maxi-
mum deviation 2.6 ppm average deviation 0.9 ppm, which
can be attributed to these spectra being recorded in
d-chloroform and d-4-methanol, respectively.
Catalytic reduction of the nitrile 14a,b proved to be the most
challenging reaction in the entire sequence. Initial studies
focused on an Rh/C catalyst under a hydrogen pressure of
15–45 psi but this only resulted in hydrogenation of the
alkene. Platinum oxide was next investigated as the catalyst.
Secrist reported that in reduction of nitriles using platinum
oxide as catalyst, addition of chloroform improves the
efficiency of the process and minimises formation of
secondary amines.44 Using platinum oxide as the catalyst
under Secrist’s conditions the alkene in 14a,b was
selectively hydrogenated but the nitrile remained intact.
To get reduction of both the alkene and nitrile it was
necessary to increase the temperature to 70 8C for 6 days.
Analysis of the proton NMR spectrum of the crude
3. Conclusion
In conclusion, we have demonstrated that the Povarov
reaction can be employed to give rapid entry to hexahydro-
pyrroloquinolines with a carbomethoxy group at the
8-position and useful alkene functionality at C-4. Although
the diastereoselectivity is poor, the regioselectivity and high
convergence of this approach makes it very attractive. The
alkene functionality can be readily converted to the required
3-aminopropyl group. The overall yield for the synthesis of

M. Hadden et al. / Tetrahedron 62 (2006) 3977–3984
3981
the central core of martinellic acid was 22% from methyl
4-aminobenzoate.
Purification by flash chromatography (eluent; hexane/
diethyl ether 1:1, Rf: 0.17) afforded the titled compound
(0.36 g, 46%) as a white solid. Mp 144.5–146.0 8C. HRMS
(EI): C29H28N2O4 requires MC 468.2049, found MC
468.2049; ymax (KBr)/cmK1 3354, 1702, 1107, 966, 769,
4. Experimental
4.1. General
1
695; H NMR (500.1 MHz, CDCl3) d (ppm) (mixture of
rotamers at 25 8C) 2.05 (m, 2H), 2.51 (br, 1H), 3.41 (m, 1H),
3.59 (br, 1H), 3.82 (s, 3H), 4.00 (m, 1H), 4.50 (s, 1H), 5.23
(overlapping m, 3H) 6.23 (dd, JZ15.8, 6.9 Hz, 1H), 6.47 (d,
JZ15.8 Hz, 1H), 6.51 (d, JZ8.5 Hz, 1H), 7.21–7.36 (m,
10H), 7.73 (dd, JZ8.5, 2.0 Hz, 1H), 8.20 (br, 1H); 13C
NMR (75.4 MHz, CDCl3) d (ppm) (mixture of rotamers at
25 8C) 27.2 (br), 41.5 (br), 44.8, 51.6, 53.0, 54.0, 67.3 (br),
113.7, 119.5, 120.0 (br), 126.5 (2C), 127.9 (2C), 128.0,
128.1, 128.5 (2C), 128.6 (2C), 130.26, 130.3, 130.8, 132.5,
136.1, 136.8 (br), 145.7, 156.0 (br), 167.2; MS (EI), m/z
(%), 468 (MC, 23), 377 (11), 333 (14), 290 (71), 91 (47),
56 (100).
Melting points were recorded using a Kofler hot stage
apparatus and are uncorrected. IR spectra were recorded on
a Perkin-Elmer Model 983G instrument coupled to a Perkin-
Elmer 3700 Data Station as potassium bromide (KBr) disks,
1
or films (liquids). H nuclear magnetic resonance (NMR)
spectra were recorded at 300 MHz using Bruker DPX 300
and at 500 MHz using a Bruker DRX500 NMR spec-
trometers. Chemical shifts are given in parts per million (d
down field from tetramethylsilane as internal standard and
coupling constants are given in Hertz). Unless otherwise
stated, deuteriochloroform was used as solvent. Spectra
splitting patterns are designated as s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; br, broad. Mass spectra
were recorded using Double Focusing Triple Sector VG
Auto Spec and accurate molecular masses were determined
by the peak matching method using perfluorokerosene as
standard reference and were accurate to within C/K
0.006 amu. Analytical TLC was carried out on Merck
Kielselgel 60254 plates and the spots visualised using a
Hanovia Chromatolite UV lamp. Flash chromatography was
affected using Merck Kielselgel 60 (230–400 mesh).
An isomeric product was also isolated (eluent; hexane/
diethyl ether 1:1, Rf: 0.31) (0.36 g, 46%) as a white solid.
Mp 164–165 8C. HRMS (FAB): C29H28N2O4 requires MC
468.2049, found MC 468.2070; ymax (KBr)/cmK1 3348,
1
1701, 1280, 1098, 772; H NMR (500.1 MHz, CDCl3) d
(ppm) (mixture of rotamers at 25 8C) 1.96–2.06 (m, 2H),
2.50 (m, 1H), 3.40 (m, 1/2H), 3.41 (m, 1/2H), 3.49 (q, JZ
9.6 Hz, 1/2H), 3.58 (q, JZ9.7 Hz, 1/2H), 3.80 (s, 3H), 4.23
(br s, 1H), 4.27 (br, 1H), 5.29–5.34 (overlapping m, 3H),
6.19 (dd, JZ15.9, 7.6 Hz, 1H), 6.50 (d, JZ8.5 Hz, 1H),
6.66 (dd, JZ15.9, 4.4 Hz, 1H), 7.26–7.39 (overlapping m,
9H), 7.50 (d, JZ7.3 Hz, 1H), 7.72 (d, JZ8.3 Hz, 1H), 8.19
and 8.30 (br, 1H); 13C NMR (125.8 MHz, CDCl3) d (ppm)
(mixture of rotamers at 25 8C) 22.1 and 23.1, 41.8 and 42.4,
44.8 and 44.9, 52.0, 54.3, 55.7 and 55.9, 67.0 and 67.5,
113.9, 119.9, 120.2 and 120.9, 126.4 (2C), 127.7, 127.8,
128.0 and 128.1, 128.2 and 128.3, 128.4 and 128.5, 128.6
(2C) 130.0, 132.1 and 132.4, 132.3 and 132.5, 136.1, 136.5
and 136.9, 147.0, 155.5 and 156.5, 167.1; MS (FAB), m/z
(%), 469 (MCC1, 36), 468 (MC, 35), 437 (22), 377 (10),
333 (23), 290 (12), 154 (100), 136 (75); Anal. calcd for
C29H28N2O4: C 74.3, H 6.0, N 5.9. Found: C 74.0, H 5.8, N
6.0.
4.1.1. 4-(3-Phenyl-allylideneamino)-benzoic acid methyl
ester 6. trans-Cinnamaldehyde (0.81 g, 6.13 mmol) and
methyl 4-aminobenzoate (0.92 g, 59.5 mmol) were dis-
˚
solved in dry methylene chloride (30 ml). Activated, 4 A
molecular sieves were then added and the reaction vessel
was flushed with nitrogen for 5 min and the mixture was
stirred for 6 h. The molecular sieves were removed by
filtration and the methylene chloride was removed under
reduced pressure and the residue was crystallised from
hexane/ethyl ethanoate 9:1 to yield the titled product
(1.45 g, 90%) as yellow needles. Mp 134–135 8C. HRMS
(EI): C17H15NO2 requires MC 265.1103, found MC
265.1090; ymax (KBr)/cmK1 1716, 1628, 1279, 735, 696;
1H NMR (500.1 MHz, CDCl3) d (ppm) 3.92 (s, 3H), 7.11
(dd, JZ16.0, 8.8 Hz, 1H), 7.18 (d, JZ8.7 Hz, 2H), 7.21 (d,
JZ16.0 Hz, 1H), 7.38–7.44 (overlapping m, 3H), 7.55 (d,
JZ8.3 Hz, 2H), 8.06 (d, JZ8.8 Hz, 2H), 8.25 (d, JZ
8.7 Hz, 1H); 13C NMR (125.8 MHz, CDCl3) d (ppm) 52.1,
120.8 (2C), 127.5, 127.7 (2C), 128.3, 129.0 (2C), 130.0,
130.9 (2C), 135.4, 145.4, 155.9, 163.0, 166.8; MS (EI), m/z
(%), 265 (MC, 38), 264 (100), 129 (3), 103 (15), 77 (26).
4.1.3. 3-(2-Benzyloxycarbonylamino-ethyl)-2-phenethyl-
quinoline-6-carboxylic acid methyl ester 10. Imine 6
(69 mg, 0.26 mmol) and ene–carbamate 7 (51 mg,
0.25 mmol) were dissolved in dry acetonitrile (10 ml)
under a nitrogen atmosphere, lithium tetrafluoroborate
(24 mg, 0.26 mmol) was then added and the mixture stirred
at room temperature for 12 h. The solvent was removed
under reduced pressure and the residue was dissolved in
methylene chloride (30 ml) and washed with aqueous
saturated sodium bicarbonate (20 ml) and water (20 ml).
The organic phase was dried over magnesium sulfate and
concentrated under reduced pressure. Purification by
preparative TLC (eluent; ethyl ethanoate/hexane 3:7, Rf:
0.30) afforded the titled product (48 mg, 41%) as a yellow
oil. HRMS (FAB): C29H29N2O4 requires MC(C1)
469.2127, found MC(C1) 469.2106; ymax (KBr)/cmK1
4.1.2. exo-4-Styryl-2,3,3a,4,5,9b-hexahydro-pyrrolo[3,2-
c]quinoline-1,8-dicarboxylic acid 1-benzyl ester
8-methyl ester 8. Imine 6 (0.45 g, 1.70 mmol) and ene–
carbamate 7 (0.34 g, 1.66 mmol) were dissolved in dry
acetonitrile (30 ml) and a catalytic amount of yttrium triflate
(0.01 g, 1 mol%) was added and the reaction stirred for 2 h
under nitrogen. The solvent was removed under reduced
pressure and the residue was dissolved in methylene
chloride (40 ml), washed with saturated aqueous sodium
bicarbonate (20 ml), water (20 ml), dried over magnesium
sulfate and concentrated under reduced pressure.
1
3359, 1717, 1262, 1099, 750, 699; H NMR (500.1 MHz,
CDCl3) d (ppm) 2.93 (t, JZ6.7 Hz, 2H), 3.20 (t, JZ8.2 Hz,
2H), 3.30 (t, JZ8.2 Hz, 2H), 3.43 (q, JZ6.4 Hz, 2H), 3.98
(s, 3H), 4.82 (br, 1H), 5.08 (s, 2H), 7.17–7.33 (overlapping

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M. Hadden et al. / Tetrahedron 62 (2006) 3977–3984
m, 10H), 7.89 (s, 1H), 8.07 (d, JZ8.8 Hz, 1H), 8.23 (dd, JZ
8.8, 1.9 Hz, 1H), 8.46 (s, 1H); 13C NMR (125.8 MHz,
CDCl3) d (ppm) 32.9, 35.5, 37.8, 41.3, 52.7, 67.2, 126.5,
127.9, 128.5 (2C), 128.6, 128.83, 128.89 (2C), 128.9 (2C),
129.0 (2C), 129.1, 129.3, 130.7, 131.7, 136.8, 137.2, 142.0,
(6:4 hexane/ethyl acetate); (C31H27F3N2O5 requires MC
564.1872, found MC 564.1870); ymax (KBr)/cmK1 2952,
1699, 1410, 1271, 1207, 767, 737, 696; dH (500 MHz,
CDCl3) (mixture of rotamers, 25 8C) 1.52 (br m, 1H), 1.89
(dq, JZ5.7, 15.9 Hz, 1H), 3.40 (br, 1H), 3.50 (br, 1H), 3.61
(br, 1H), 3.92 (s, 3H), 4.97 (br, 1H), 5.25 (overlapping m,
3H), 5.64 (br, 1H), 6.65 (d, JZ15.6 Hz, 1H), 7.18–7.27 (m,
5H), 7.31–7.37 (m, 5H), 7.39 (br, 1H), 7.67 (d, JZ8.6 Hz,
1H), 8.04–8.14 (br m, 1H); dC (125 MHz, CDCl3) (mixture
of rotamers at 25 8C) 27.1 (br), 43.6 (br), 44.6 (br), 46.4,
52.2, 55.9 (br), 67.3, 114.9, 117.2, 119.6, 122.5, 125.4 (br),
126.3 (2C), 127.8, 128.2 (br), 128.4 (2C), 128.5 (2C),
128.6–129.1 (q), 129.6, 130.7, 133.6, 134.5, 135.2, 136.2
(br), 137.4, 155.2 (q, JZ38.1 Hz), 165.9; 19F (282 MHz,
CDCl3) K67.5 (3F, s, C]OCF3); MS (EI), m/z (%), 564
(MC, 36), 489 (100), 473 (51), 466 (25), 369 (12), 152 (28),
91 (100), 57 (30).
149.1, 156.7, 163.7, 167.2; MS (FAB), m/z (%), 469 (MC1
,
100), 468 (MC, 15), 377 (11), 318 (10), 304 (11), 147 (41),
105 (43).
4.1.4. exo-4-Styryl-5-(2,2,2-trifluoro)-2,3,3a,4,5,9b-hexa-
hydro-pyrrolo[3,2-c]quinoline-1,8-dicarboxylic acid
1-benzyl ester 8-methyl ester 11. Anhydrous pyridine
(0.17 ml, 2.10 mmol), 4-dimethylaminopyridine (8 mg,
17 mol%), and trifluoroacetic anhydride (0.11 ml,
0.79 mmol) were added sequentially to a stirred solution
of amine 8 (181 mg, 0.39 mmol) in anhydrous toluene
(15 ml) under a nitrogen atmosphere. The reaction was then
refluxed for 24 h and the solvent was removed under
reduced pressure. The residue was dissolved in methylene
chloride (30 ml) and washed with 9% aqueous HCl (15 ml),
saturated sodium bicarbonate (15 ml) and water (15 ml).
The organic phase was dried over magnesium sulfate and
concentrated under reduced pressure. Purification by flash
chromatography (eluent; hexane/diethyl ether 35:65, Rf:
0.45) afforded the titled compound (182 mg, 83%) as a
cream foam. HRMS (EI): C31H27F3N2O5 requires MC
564.1872, found MC 564.1873; ymax (KBr)/cmK1 2954,
1708, 1699, 1409, 1277, 1196, 770, 736, 696; 19F NMR
(282.3 MHz, CDCl3) d (ppm) K67.6 (s, 3F); 1H NMR
(500.1 MHz, CDCl3) d (ppm) (mixture of rotamers at 25 8C)
1.92 (dq, JZ12.7, 8.9 Hz, 1H), 2.23 (br, 1H), 2.89 (dtd, JZ
9.6, 7.4, 2.4 Hz, 1H), 3.46 (br, 1H), 3.62 and 3.75 (br, 1H),
3.89 (br s, 3H), 5.18 (overlapping, 3H), 5.33 (br, 1H), 5.95
(br, 1H), 6.56 (d, JZ15.9 Hz, 1H), 7.19–7.26 (overlapping
m, 5H), 7.30–7.36 (overlapping m, 5H), 7.67 (br, 1H), 7.96
(d, JZ8.4 Hz, 1H), 8.38 and 8.64 (br, 1H); 13C NMR
(75.4 MHz, CDCl3) d (ppm) (mixture of rotamers at 25 8C)
27.9 (br), 42.8 (br), 45.4, 52.3, 54.7, 58.6 (br), 67.4 (br),
110.8–122.3 (q, JZ288.8 Hz), 124.3, 124.7, 126.6 (2C),
127.9, 128.1, 128.5 (2C), 128.7 (2C), 128.9, 129.4, 130.8,
132.7, 132.9, 133.9, 135.3, 136.5 (br), 137.3 (br), 156.4,
156.8 (q, JZ36.7 Hz), 166.1; MS (EI), m/z (%), 564 (MC,
1.5), 533 (1), 473 (5), 429 (8), 279 (29), 149 (100), 91 (74),
57 (42).
4.1.6. exo-4-(2-Cyano-vinyl)-5-(2,2,2-trifluoro)2,3,3-
a,4,5,9b-hexahydro-pyrrolo[3,2-c]quinoline-1,8-dicar-
boxylic acid 1-benzyl ester 8-methyl ester 14. Alkene 11
(1.26 g, 2.23 mmol) was dissolved in anhydrous methylene
chloride (60 ml) and the solution was cooled to K78 8C
under a nitrogen atmosphere. Ozone was then bubbled
through the system at a rate of 1 l/min for 30 min. The
reaction solution changed from colourless to a deep blue hue
during the course of the reaction. While maintaining the
system at K78 8C, the residual ozone was removed by
slowly bubbling nitrogen gas through the reaction mixture.
Dimethyl sulphide (1.8 ml, 24 mmol) was added dropwise
and the solution was stirred for another hour at K78 8C.
(Triphenylphosphoranylidene)acetonitrile
(1.90 g,
6.31 mmol) in methylene chloride (3 ml) was introduced
and the solution maintained at K78 8C for a further 2 h,
after which it was allowed to warm to room temperature
overnight. The methylene chloride solution was washed
with saturated aqueous sodium bicarbonate (15 ml), water
(15 ml), dried over magnesium sulfate and concentrated
under reduced pressure. The titled compound was obtained
as a mixture of cis and trans isomers by flash chromato-
graphy (eluent; diethyl ether/hexane 8:2) as a white powder
(0.85 g, 74%). A small sample was separated by preparative
TLC Rf: 0.37 (diethyl ether/hexane 8:2) and crystallised
from methanol to give the trans product 14b as prisms. Mp
69–72 8C. HRMS (EI): C26H22F3N3O5 requires MC
513.1512, found MC 513.1518; ymax (KBr)/cmK1 2211,
1703, 1411, 1292, 1198; 19F NMR (282.3 MHz, CDCl3) d
4.1.5. endo-4-Styryl-5-(2,2,2-trifluoro)-2,3,3a,4,5,9b-hexa-
hydro-pyrrolo[3,2-c]-quinoline-1,8-dicarboxylic acid
1-benzyl ester 8-methyl ester 12. Anhydrous pyridine
(0.16 ml, 1.98 mmol), dimethyl aminopyridine (7.7 mg,
17 mol%) and trifluoroacetic anhydride (0.11 ml,
0.76 mmol) were added to a stirred solution of endo-4-
styryl-2,3,3a,4,5,9b-hexahydro-pyrrolo[3,2-c]quinoline-
1,8-dicarboxylic acid 1-benzyl ester 8-methyl ester 9
(174 mg, 0.37 mmol) in dry toluene (40 ml) and the
resulting solution was refluxed for 24 h. The solvent was
removed under reduced pressure and the residue was
dissolved in dichloromethane (40 ml), washed with 9%
aqueous hydrochloric acid (20 ml), saturated sodium
bicarbonate solution (20 ml) and water (20 ml). The organic
phase was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. Purification by flash
chromatography (6:4 hexane/ethyl acetate), afforded 12 as a
light brown powder (193 mg, 92%). Mp 69–70 8C. Rf: 0.66
1
(ppm) K67.69 (s, 3F); H NMR (500.1 MHz, CDCl3) d
(ppm) (mixture of rotamers at 25 8C) 1.90 (dq, JZ12.7,
8.2 Hz, 1H), 2.24 (td, JZ12.5, 7.5 Hz, 1H), 2.83 (ddd, JZ
16.4, 7.2, 2.1 Hz, 1H), 3.43 (br, 1H), 3.65 (br, 1H), 3.91 (br
s, 3H), 5.20 (overlapping m, 4H), 5.45 (d, JZ15.1 Hz, 1H),
6.46 (br, 1H), 7.27–7.36 (m, 5H), 7.57 (br, 1H), 8.00 (d, JZ
7.8 Hz, 1H), 8.32 and 8.61 (br, 1H); 13C NMR (125.8 MHz,
CDCl3) d (ppm) (mixture of rotamers at 25 8C) 27.3 (br),
40.9 (br), 44.3 (br), 51.4, 53.6 (br), 56.8 (br), 66.5 and 67.0
(br), 102.9, 111.7–118.6 (q, JZ288.8 Hz), 114.4, 123.4,
126.9, 127.2 (2C overlapping), 127.5 (2C), 128.6 (br), 128.9
(2C), 129.3 (br), 132.2 (br), 135.3 (br), 147.5, 155.1 (br),
155.9 (q, JZ37.2 Hz), 164.7; MS (EI), m/z (%), 513 (MC,
1.1), 482 (1.6), 407 (1.4), 378 (15), 277 (30), 148 (6), 91
(100), 77 (18).

M. Hadden et al. / Tetrahedron 62 (2006) 3977–3984
3983
cis Product 14a. Rf: 0.29 (diethyl ether/hexane 8:2)
crystallised from methanol as prisms. Mp 66–69 8C.
HRMS (EI): C26H22F3N3O5 requires MC 513.1512, found
MC 513.1527; ymax (KBr)/cmK1 2955, 2275, 2224, 1698,
1409, 1197, 770, 732, 698; 19F NMR (282.3 MHz, CDCl3) d
pressure. Purification by flash chromatography (eluent;
methylene chloride/methanol 95:5, Rf: 0.43) afforded the
titled product (53 mg, 66% from 14) as a clear oil. HRMS
(FAB): C24H29N3O4 requires MC 423.2158, found MC
423.2146; ymax (KBr)/cmK1 3354, 2948, 1698, 770, 736,
1
1
(ppm) K67.69 (s, 3F); H NMR (500.1 MHz, CDCl3) d
698; H NMR (500.1 MHz, CDCl3) d (ppm) (mixture of
(ppm) (mixture of rotamers at 25 8C) 2.03 (br m, 1H), 2.33
(td, JZ12.5, 7.3 Hz, 1H), 2.89 (ddd, JZ14.2, 9.1, 2.4 Hz,
1H), 3.46 (br, 1H), 3.66 (br, 1H), 3.91 (br s, 3H), 5.13–5.25
(overlapping m, 4H), 5.48 (br, 1H), 6.26 (br, 1H), 7.30–7.36
(m, 5H), 7.64 (br, 1H), 7.99 (d, JZ7.9 Hz, 1H), 8.38 and
8.61 (s, 1H); 13C NMR (125.8 MHz, CDCl3) d (ppm)
(mixture of rotamers at 25 8C) 27.4 (br), 42.5 and 43.4 (br),
44.3 (br), 51.4, 53.7 (br), 56.3 (br), 66.5 (br), 101.8, 111.8–
118.5 (q, JZ288.5 Hz), 113.1, 123.9 (br), 126.9, 127.2,
127.5 (2C), 128.7 (2C), 129.7, 129.8 (br), 132.0 (br), 132.0
(br), 135.3 (br), 147.3, 155.2 (br), 155.6 (q, JZ36.5 Hz),
164.8 (br); MS (EI), m/z (%), 513 (MC, 0.4), 482 (0.3), 378
(2), 277 (65), 122 (75), 105 (100).
rotamers at 25 8C) 1.53 (overlappping m, 4H), 1.96 (br m,
2H), 2.36 (dtd, JZ9.2, 8.3, 2.1 Hz, 1H), 2.69 (m, 2H), 3.25
(m, 1H), 3.38 (m, 1H), 3.53 (br, 1H), 3.80 (s, 3H), 5.04 and
5.12 (br, 1H), 5.24 (s, 2H), 6.44 (d, JZ8.5 Hz, 1H), 7.24–
7.50 (overlapping m, 5H), 7.68 (dd, JZ8.5, 2.0 Hz, 1H),
8.19 (br, 1H); 13C NMR (125.8 MHz, CDCl3) d (ppm)
(mixture of rotamers at 25 8C) 26.9 and 27.8 (br), 30.0, 33.6
(br), 40.6 and 41.4 (br), 41.7, 44.7, 51.5, 51.6, 53.0, 67.0 and
67.5, 113.7, 118.9 (br), 127.7, 128.0 (2C), 128.5 (2C),
130.2, 132.4 (br), 137.0, 137.2, 145.6, 156.7, 167.2; MS
(FAB), m/z (%), 424 (MC1, 100), 423 (MC, 26), 393 (21),
365 (46), 275 (32), 257 (18).
4.1.9. exo-4-(3-Amino-propyl)-2,3,3a,4,5,9b-hexahydro-
1H-pyrrolo[3,2-c]quinoline-8-carboxylic acid methyl
ester 17. Tricycle 16 (11 mg, 0.02 mmol) was dissolved
in methanol (5 ml) in a glass Parr hydrogenation flask.
A catalytic quantity of 20% w/w palladium hydroxide on
carbon (5 mg, 20 mol%) was suspended in methanol (1 ml)
and then added to the hydrogenation flask. The system was
hydrogenated (45 psi 60 8C) for 24 h. The reaction solution
was filtered through Hyflo-Supercel and the solvent was
removed under reduced pressure. The residue was
dissolved in methylene chloride (20 ml) and washed with
2 M sodium hydroxide (10 ml), water (10 ml), dried over
magnesium sulfate and concentrated under reduced
pressure to give the titled compound (6.2 mg, 82%) as a
clear oil. Due to the high polarity of 17 further purification
was not attempted. ymax (KBr)/cmK1 1770, 1470, 1192,
866, 769, 644; 1H NMR (500.1 MHz, CDCl3) d (ppm)
1.44–1.63 (5H overlap), 1.89 (m, 1H), 1.99 (m, 1H), 2.60–
2.74 (overlapping m, 3H), 2.80 (m, 1H), 3.01 (m, 1H), 3.70
(s, 3H), 3.77 (d, JZ6.5 Hz, 1H), 6.41 (d, JZ8.5 Hz, 1H),
7.58 (dd, JZ8.5, 2.1 Hz, 1H), 7.85 (d, JZ2.0 Hz, 1H); 13C
NMR (125.8 MHz, CDCl3) d (ppm) 29.5, 29.7, 31.0, 41.0,
42.0, 44.7, 51.5, 52.2, 57.7, 113.6, 118.6, 121.0, 129.9,
132.6, 148.8, 167.3. Mass spectral data were not secured
due to the high polarity and presumably involatility of the
sample. The sample also proved to be very unstable and
decomposed after days on storage at 0 8C.
4.1.7. exo-4-[3-(2,2,2-Trifluoro-acetylamino)-propyl]-
2,3,3a,4,5,9b-hexahydro-pyrrolo[3,2]quinoline-1,8-di-
carboxylic acid 1-benzyl ester 8-methyl ester 15.
Platinum oxide (4.5 mg, 10 mol%) was added to a solution
of alkenes 14a,b (100 mg, 0.19 mmol) in methanol (10 ml).
Three drops of chloroform were then added and the reaction
mixture was hydrogenated (50 psi) at the elevated tempera-
ture of 70 8C for 144 h. The mixture was filtered through
Hyflo-Supercel and the solvent was removed in vacuo. The
residue was dissolved in methylene chloride (30 ml) and
washed with 2 M sodium hydroxide (15 ml), water (15 ml),
dried over magnesium sulfate and concentrated under
reduced pressure. An analytical sample was purified by
flash chromatography (eluent; chloroform/methanol 95:5,
Rf: 0.49) afforded the titled compound as a clear oil. HRMS
(FAB): C26H29F3N3O5 requires MC1 520.2059, found MC1
520.2068; ymax (KBr)/cmK1 3367, 2949, 1701, 1609, 1436,
1280, 1187, 769; 19F NMR (282.3 MHz, CDCl3) d (ppm)
K76.2 (s, 3F); 1H NMR (500.1 MHz, CDCl3) d (ppm)
(mixture of rotamers at 25 8C) 1.47 (m, 1H), 1.55 (m, 1H),
1.67 (m, 2H), 1.95 (br m, 2H), 2.32 (m, 1H), 3.31
(overlapping m, 4H), 3.51 (br, 1H), 3.80 (s, 3H), 4.75 (br,
1H), 5.12 (br, 1H), 5.29 (s, 2H), 6.41 (d, JZ8.5 Hz, 1H),
6.98 and 7.15 (br, 1H), 7.26–7.40 (overlapping m, 5H), 7.66
(dd, JZ8.5, 2.0 Hz, 1H), 8.18 (br, 1H); 13C NMR
(125.8 MHz, CDCl3) d (ppm) (mixture of rotamers at
25 8C) 25.7, 26.8 and 27.7 (br), 32.9 (br), 39.6, 40.4 and 41.1
(br), 44.7, 51.0, 51.6, 52.9 (br), 67.1 and 67.7, 112.4–119.3
(q, JZ287.8 Hz), 113.7, 118.9, 119.6 (br), 127.7, 128.0
(2C), 128.5 (2C), 130.2, 132.4 (br), 136.8 (br), 145.4, 156.7,
157.5 (q, JZ36.9 Hz), 167.4; MS (FAB), m/z (%), 520
(MC, 15), 461 (11), 341 (29), 281 (76).
Acknowledgements
We would like to thank The Department of Education
Northern Ireland (DENI) and Department of Education and
Learning (DEL) for studentships (M.H.) (A.W.), respect-
ively, and Queens University for support.
4.1.8. exo-4-(3-Amino-propyl)-2,3,3a,4,5,9b-hexahydro-
pyrrolo[3,2-c]quinoline-1,8-dicarboxylic acid 1-benzyl
ester 8-methyl ester 16. Trifluoroacetamide 15 (103 mg,
0.20 mmol, crude from previous step) was added to a
saturated solution of ammonia in methanol (6 ml) and the
reaction was stirred for 3 days at room temperature. The
solvent was removed under reduced pressure and the residue
dissolved in methylene chloride (20 ml) and washed with
2 M sodium hydroxide (10 ml), water (10 ml), dried over
magnesium sulfate and concentrated under reduced
References and notes
1. Sawada, Y.; Kayakiri, H.; Abe, Y.; Mizutani, T.; Inamura, N.;
Asano, M.; Hatori, C.; Aramori, I.; Oku, T.; Tanaka, H. J. Med.
Chem. 2004, 47, 2853–2863.

3984
M. Hadden et al. / Tetrahedron 62 (2006) 3977–3984
24. Lovely, C. J.; Mahmud, H. Tetrahedron Lett. 1999, 40,
2. Sawada, Y.; Kayakiri, H.; Abe, Y.; Mizutani, T.; Inamura, N.;
Asano, M.; Aramori, I.; Hatori, C.; Oku, T.; Tanaka, H. J. Med.
Chem. 2004, 47, 2667–2677.
2079–2082.
25. Hadden, M.; Stevenson, P. J. Tetrahedron Lett. 1999, 40,
1215–1218.
3. Sawada, Y.; Kayakiri, H.; Abe, Y.; Imai, K.; Mizutani, T.;
Inamura, N.; Asano, M.; Aramori, I.; Hatori, C.; Katayama, A.;
Oku, T.; Tanaka, H. J. Med. Chem. 2004, 47, 1617–1630.
4. Howl, J.; Payne, S. J. Expert Opin. Ther. Targets 2003, 7,
277–285.
26. Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287–8294.
27. Ma, D. W.; Xia, C. F.; Jiang, J. Q.; Zhang, J. H. Org. Lett.
2001, 3, 2189–2191.
28. Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913–2916.
29. Snider, B. B.; Ahn, Y.; O’Hare, S. M. Org. Lett. 2001, 3,
4217–4220.
5. Heitsch, H. Expert Opin. Investig. Drugs 2003, 12, 759–770.
6. Heitsch, H. Curr. Med. Chem. 2002, 9, 913–928.
7. Heitsch, H. Drug News Perspect. 2000, 13, 213–225.
8. Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard,
A. M.; Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.;
Pitzenberger, S. M.; Varga, S. L. J. Am. Chem. Soc. 1995, 117,
6682–6685.
30. Xia, C. F.; Heng, L. S.; Ma, D. W. Tetrahedron Lett. 2002, 43,
9405–9409.
31. He, Y.; Moningka, R.; Lovely, C. J. Tetrahedron Lett. 2005,
46, 1251–1254.
32. Takeda, Y.; Nakabayashi, T.; Shirai, A.; Fukumoto, D.;
Kiguchi, T.; Naito, T. Tetrahedron Lett. 2004, 45, 3481–3484.
33. Hadden, M.; Nieuwenhuyzen, M.; Osborne, D.; Stevenson,
P. J.; Thompson, N. Tetrahedron Lett. 2001, 42, 6417–6419.
34. Nyerges, M. Heterocycles 2004, 63, 1685–1712.
35. Nudelman, A.; Keinan, E. Synthesis 1982, 687–689.
36. Lott, R. S.; Chauhan, V. S.; Stammer, C. H. Chem. Commun.
1979, 495–496.
9. Testa, M. L.; Lamartina, L.; Mingoia, F. Tetrahedron 2004,
60, 5873–5880.
10. Poornachandran, M.; Raghunathan, R. Tetrahedron Lett. 2005,
46, 7197–7200.
11. Yadav, J. S.; Reddy, B. V. S.; Sunitha, V.; Reddy, K. S.;
Rarnakrishna, K. V. S. Tetrahedron Lett. 2004, 45, 7947–7950.
12. Hara, O.; Sugimoto, K.; Hamada, Y. Tetrahedron 2004, 60,
9381–9390.
37. Oliveira, D. F.; Miranda, P.; Correia, C. R. D. J. Org. Chem.
1999, 64, 6646–6652.
13. Hara, O.; Sugimoto, K.; Makino, K.; Hamada, Y. Synlett 2004,
1625–1627.
38. MacDonald, S. J. F.; Spooner, J. E.; Dowle, M. D. Synlett
1998, 1375–1377.
14. Viranyi, A.; Nyerges, M.; Blasko, G.; Toke, L. Synthesis 2003,
2655–2660.
39. Maruoka, K.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc.
1992, 114, 1089–1090.
15. Nyerges, M.; Fejes, I.; Toke, L. Synthesis 2002, 1823–1828.
16. Malassene, R.; Sanchez-Bajo, L.; Toupet, L.; Hurvois, J. P.;
Moinet, C. Synlett 2002, 1500–1504.
40. Ruck, R. T.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
2882–2883.
17. Hadden, M.; Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J.;
Thompson, N. Tetrahedron 2001, 57, 5615–5624.
18. Mahmud, H.; Lovely, C. J.; Dias, H. V. R. Tetrahedron 2001,
57, 4095–4105.
41. Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.;
Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63,
4541–4544.
42. Yadav, J. S.; Reddy, B. V. S.; Madhuri, C. R.; Sabitha, G.
Synthesis 2001, 1065–1068.
19. Escolano, C.; Jones, K. Tetrahedron Lett. 2000, 41, 8951–8955.
20. Nieman, J. A.; Ennis, M. D. Org. Lett. 2000, 2, 1395–1397.
21. Frank, K. E.; Aube, J. J. Org. Chem. 2000, 65, 655–666.
22. Snider, B. B.; Ahn, Y.; Foxman, B. M. Tetrahedron Lett. 1999,
40, 3339–3342.
43. Johnston, F. Chem. Rev. 1968, 68, 375–413.
44. Secrist, J. A.; Logue, M. W. J. Org. Chem. 1972, 37, 335–336.
45. MacDonald, S. J. F.; Clarke, G. D. E.; Dowle, M. D.; Harrison,
L. A.; Hodgson, S. T.; Inglis, G. G. A.; Johnson, M. R.; Shah,
P.; Upton, R. J.; Walls, S. B. J. Org. Chem. 1999, 64,
5166–5175.
23. Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj, R. P.; Lough,
A. J. Chem. Commun. 1999, 651–652.