Synthesis of cylindricine C and a formal synthesis of cylindricine A

Article abstract of DOI:10.1016/j.tet.2010.05.044

This paper reports the synthesis of the alkaloid natural product (±)-cylindricine C, in addition to a formal synthesis of (±)-cylindricine A. The key step in our sequence is the (ipso) regioselective addition of an alkyl Grignard reagent to a C-2 substitu

Full text of DOI:10.1016/j.tet.2010.05.044

Tetrahedron 66 (2010) 6411e6420
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of cylindricine C and a formal synthesis of cylindricine A
y
*
Timothy J. Donohoe , Ptoton M. Brian, Gráinne C. Hargaden, Timothy J.C. O’Riordan
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper reports the synthesis of the alkaloid natural product (ꢀ)-cylindricine C, in addition to a formal
synthesis of (ꢀ)-cylindricine A. The key step in our sequence is the (ipso) regioselective addition of an
alkyl Grignard reagent to a C-2 substituted pyridinium salt to generate the dihydropyridone core of the
alkaloid targets. After cyclisation to form the A and C rings of the cyclindricines the net outcome is a short
(13 steps) synthesis of this natural product.
Received 26 February 2010
Received in revised form
7 May 2010
Accepted 13 May 2010
Available online 20 May 2010
Ó 2010 Published by Elsevier Ltd.
Dedicated to Professor Steven V. Ley on the
occasion of the 2009 Tetrahedron Prize for
Creativity in Organic Chemistry
O
O
N
O
H
H
H
1. Introduction
A
B
In 1993, Blackman et al. reported the isolation of two novel al-
kaloids from the ascidian Clavelina cylindricia, collected off the
coast of Tasmania.1 Cylindricine A, the more abundant alkaloid, was
identified as having a pyrrolo[2,1-j]quinoline ring system, while
cylindricine B (with which cylindricine A is in equilibrium via an
aziridinium ion intermediate) has a pyrido[2,1-j]quinoline ring
system (Fig. 1). Further samples were collected in the following
years, yielding alkaloids with the same skeleton as cylindricine A
but with differing functionality on the C ring side-chain, and were
named cylindricines CeG.2 Further modification of the natural
product skeleton has also been reported with the isolation of ad-
ditional members of this family, subsequently named cylindricines
HeK.3
C6H13
N
C4H9
C6H13
N
C
NCS
cylindricine G
R
Cl
R = Cl cylindricine A
OH cylindricine C
OMe cylindricine D
cylindricine B
OAc cylindricine E
SCN cylindricine F
AcO
H
H
AcO
H
C6H13
N
O
C4H9
N
C4H9
N
To date the only biological activity reported for these molecules
has been in a bioassay containing brine shrimp larvae (Artemia
salina), where they have been shown to induce 93% mortality in
24 h. Nevertheless, the tricyclic system of the cylindricines com-
prising a spirocyclic amine makes them interesting synthetic tar-
Cl
NCS
R
R = SCN cylindricine H
NCS cylindricine I
cylindricine K
cylindricine J
Figure 1. The cylindricines.
gets, with cylindricines
A and C being synthesised several
times.4e16 In terms of retrosynthetic disconnections of the natural
products, we were interested in a unique approach that started
with the six-membered B ring intact from the beginning (6, Scheme
1), and left construction of the five-membered C ring until the latter
stages of the synthesis. This approach is significantly different to
those reported in the literature, which usually rely upon late-stage
construction of the six-membered B ring.
In addition to examining a new disconnection to these targets,
our approach would also allow us to apply the recently developed
regioselective addition of Grignard reagents to electron-deficient
and substituted pyridinium salts in natural product synthesis.17 In
this case, the addition reaction would figure early in the route (see
6/5, Scheme 1), allowing us to construct a dihydropyridone,
which could then be elaborated as shown with the retrosynthesis
for cyclindricine C in Scheme 1.
* Corresponding author. Tel.: þ44 01865 27564; e-mail address: timothy.dono-
hoe@chem.ox.ac.uk (T.J. Donohoe).
y
To whom correspondence regarding X-ray crystallography should be addressed.
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.05.044

6412
T.J. Donohoe et al. / Tetrahedron 66 (2010) 6411e6420
O
N
O
H
H
TIPSO
H
C6H13
open
epoxide
HO
C6H13
N
H
C6H13
N
P
CO2Me
install
conjugate
addition
side-chain
3
1
O
2
cyclisation
OMe
N
O
O
Grignard
addition
key step
H
Br
Cl
CO2Me
N
P
N
P
CO2Me
CO2Me
P
6
5
4
Scheme 1. Retrosynthesis.
2. Results and discussion
the enol ether to generate pyridone 19 in good yield, Scheme
3).19,20 Subsequent ring closure using an unhindered base affor-
ded the core bicyclic ring system 20 in excellent yield, and the
exclusive formation of the cis-fused ring system under kinetically
controlled conditions was verified by X-ray crystallography
(Scheme 3, X-ray data is included in Supplementary data). Acti-
vation of the dihydropyridone carbonyl of 20 with a silyl triflate
was followed by regio- and stereoselective addition of hexyl
magnesium bromide to produce compound 21 in a 77:23 ratio
with the desired product, originating from nucleophilic attack
2.1. Investigation of Grignard addition reactions to N-DMB
protected pyridinium salts
Our synthesis began with the preparation of pyridine 8 from
commercially available picolinic acid 7 in a one-pot procedure
employing conditions reported by Sundberg.18 N-DMB-pyridinium
salt 9 was then prepared by reaction of pyridine 8 with 4-(bromo-
methyl)-1,2-dimethoxybenzene (Scheme 2).
OMe
OMe
SOCl2, NaBr, 85 oC
Et2O
Br
+
then MeOH, 65 oC
N
DMB
9
CO2Me
Br
99%
OMe
N
COOH
N
CO2Me
68%
OMe
7
8
Scheme 2. Preparation of DMB salt 9.
While we have previously reported the addition of Grignard
reagents to ester substituted N-methyl and N-allyl pyridinium
salts,17 we wished to extend this methodology to encompass the N-
DMB protected pyridinium salts required for application in the
synthesis of the dihydropyridone core of the cylindricines. Table 1
shows the yields from the addition of alkyl, alkenyl, aryl and
alkynyl Grignard reagents to pyridinium salt 9 to give either the C-2
or C-6 addition products, with harder nucleophiles (alkyl) adding at
position 2 and softer nucleophiles (alkenyl, aryl and alkynyl) adding
at position 6. In contrast to our previous work using N-allyl pyri-
dinium salts, it was not necessary to use organozinc reagents to
selectively add phenyl, vinyl, or 1-propynyl groups to C-6, showing
that this addition reaction is highly dependent upon the nature of
the protecting group on nitrogen. The structures of the products
from this scheme had NMR data that was consistent with that
reported in the literature. Moreover, we were able to confirm the
structures of compounds 10 and 12 by X-ray crystallography (data
not shown).
Table 1
OMe
O
O
RMgBr, CH2Cl2
then 1M HCl (aq)
R
+
N
CO2Me
R
N
CO2Me
N
DMB
9
CO2Me
Br
DMB
Regioisomer A
DMB
Regioisomer B
RMgBr
Compound
Regioisomer
Yield (%)
Ph
Me
Et
Vinyl
Homoallyl
4-Methoxyphenyl
Isopropenyl
Benzyl
10
11
12
13
14
15
16
17
18
B
A
A
B
A
B
B
A
B
77
66
72
87
83
89
93
69
72
1-Propynyl
2.2. Formation of the 6,6 ring system of the cylindricines
from the convex face of 20, as the major one.21,22 The relative
stereochemistry of these compounds was assessed by reduction of
the ester group to a CH2OH unit, and subsequent NOE experi-
ments on both diastereomers. At this point it was found to be
expedient to remove the DMB protecting group by hydrogenolysis
Our proposed synthesis relied upon the C-2 addition of 4-
chlorobutyl magnesium bromide to 9. Pleasingly, this reaction
occurred in a regioselective (ipso) manner at C-2 and generated
the desired quaternary centre (an in situ acid quench hydrolysed

T.J. Donohoe et al. / Tetrahedron 66 (2010) 6411e6420
6413
O
Cl
O
OMe
BrMg(CH2)4Cl
then H3O+
H
NaNH2, DMF
87%
64%
N
N
DMB
9
CO2Me
Br
N
CO2Me
CO2Me
DMB
DMB
19
20
TIPSOTf, PhMe
then HexylMgBr
69%
20
TIPSO
TIPSO
H
H
cat. Pd/C, H2
MeOH:EtOAc,
Hex
N
60% (after
separation
of the minor
isomer)
Hex
N
H
CO2Me
CO2Me
22
DMB
77:23 dr
21
Scheme 3. Formation of the bicyclic core.
so that the minor diastereoisomer could be separated from the
mixture to furnish compound 22.
We then proceeded to reduce the ester group at C-2 to an al-
dehyde to facilitate installation of the side-chain, Scheme 4. Re-
duction of 22 with DIBAL-H occurred smoothly and furnished
aldehyde 23 in 82% yield. It is noteworthy that selective partial
reduction of DMB protected amine 21 to the corresponding alde-
hyde was not an efficient process. Subsequent olefination of 23
using a HornereWadswortheEmmons phosphonate gave alkene
24 in good yield,23,24 which was hydrogenated using Pd/C to give
25. DIBAL-H reduction of the ester and olefination would then al-
low a formal synthesis of cylindricine A to be completed. However
O
O
P
OEt
EtO
OMe
DIBAL-H, -78 o
PhMe
C
TIPSO
TIPSO
H
H
NaH, THF, 60 oC
75%
82%
Hex
N
H
Hex
N
H
CHO
CO2Me
23
22
TIPSO
TIPSO
H
H2, Pd/C
MeOH:EtOAc
H
TIPSO
Hex
N
H
86%
Hex
N
H
H
CO2Me
O
25
Hex
N
H
DIBAL-H, -78 oC
PhMe
CO2Me
24
TIPSO
I
TIPSO
S
H
NaH
H
DMSO:THF
87%
66%
Hex
N
H
Hex
N
H
O
O
26
27
TIPSO
H
Hex
N
H
O
Scheme 4. Attempted side-chain homologation.

6414
T.J. Donohoe et al. / Tetrahedron 66 (2010) 6411e6420
despite repeated attempts, the partial reduction of ester 25 led only
to products of reductive amination, whereby the unprotected ni-
trogen had cyclised onto carbonyl intermediates formed during the
reduction. These adducts were themselves also prone to reduction
and the process could not be stopped, controlled or reversed. Our
attention was then turned to synthesising cyclindricine A from
ester 24 by manipulating the ester group before reduction of the E-
alkene (which would prevent any intramolecular reaction of the
nitrogen atom). Reduction of 24 using DIBAL-H to the aldehyde (26)
and subsequent reaction with the CoreyeChaykovsky reagent25
afforded epoxide 27. Unfortunately all attempts at selective
hydrogenation of the alkene failed with hydrogenolysis of the ep-
oxide being observed in each case. Therefore, we concluded that
the end-game with nitrogen unprotected was not viable and thus
we sought to remedy this problem.
completion of the syntheses. The Teoc protecting group has already
been utilised in a previous synthesis of cylindricine A and so we
added a Teoc group to form 28, knowing that it could be readily
deprotected at a later stage with a fluoride source.5 Subsequent
olefination, hydrogenation and partial reduction with DIBAL-H
afforded aldehyde 31 in good yield. Our initial aim was to complete
a formal synthesis of cylindricine A by conversion of 31 to terminal
alkene 32, followed by TBAF induced deprotection of both the Teoc
and TIPS groups. This two-step procedure gave compound 33,
which displayed spectroscopic data (1H, 13C NMR) identical to that
reported in the literature.4,5 The formation of 33 therefore consti-
tuted a formal synthesis of cylindricine A since it has been con-
verted to the natural product in two steps by both Snider4 and then
Heathcock (Scheme 5).5
Next, we sought to complete the synthesis of cylindricine C by
epoxidation of aldehyde 31, Scheme 6. This was again accom-
plished by reaction with the CoreyeChaykovsky reagent,25 which
furnished epoxide 34 (as a 1:1 mix of diastereoisomers). Note that
while these particular conditions led to deprotection of the TIPS
enol ether, they did not remove the Teoc group from the nitrogen.
2.3. Alternative protecting group strategy
Following our unsuccessful attempts at proceeding with the
unprotected amine, we proposed that N-protection would enable
TIPSO
O
P
OEt
O
H
TIPSO
TIPSO
H
H
EtO
OMe
NaH, 60 oC
Teoc-Cl, K2CO3
Hex
N
Hex
N
Teoc
Hex
N
H
CH3CN:Et2O
92%
CHO
86%
CHO
Teoc
O
MeO
23
28
29
TIPSO
H
TIPSO
TIPSO
H
H
H2, Pd/C
Ph3PCH3Br
DIBAL-H
PhMe
n-BuLi
MeOH:EtOAc
Hex
N
Hex
N
Hex
N
THF, -78 oC
O
92%
Teoc
92%
88%
Teoc
Teoc
O
MeO
30
32
31
O
H
Snider, 2 steps
TBAF, THF
99%
cylindricine A
Hex
N
H
33
Scheme 5. Formal synthesis of cylindricine A.
O
N
O
H
H
O
H
TIPSO
H
I
+
S
NaH
TBAF, THF
C6H13
C6H13
N
Hex
N
Teoc
DMSO:THF, 65%
Hex
N
99%
49%
Teoc
HO
HO
O
( )-cylindricine C
13 steps;
O
34
31
3% overall yield
Scheme 6. Synthesis of cylindricine C.

T.J. Donohoe et al. / Tetrahedron 66 (2010) 6411e6420
6415
Thus, in order to complete the synthesis, we reacted compound
34 with TBAF to effect removal of the Teoc group and encourage
in situ opening of the epoxide at the proximal position. This
protocol did indeed furnish the natural product cyclidricine C,
together with an easily separable diastereoisomer, the mixture
originating from opening of the two epoxide stereoisomers. As
expected, the synthetic cylindricine C exhibited spectroscopic data
that was a very good match with that reported in the litera-
ture.2,6,8,9 Supplementary data contains a full comparison of the
data exhibited by both compound 33 and cylindricine C with that
reported in the literature.
the conditions of electrospray ionisation (ESI). The lock-mass used
for calibration was tetraoctylammonium bromide in positive ion
and sodium dodecyl sulfate in negative ion mode. m/z values are
reported in Daltons, followed by the percentage abundance in
parentheses. Melting Points: melting points were determined us-
ing a Leica Galen III heated-stage microscope and are uncorrected.
General: all reactions were carried out under an atmosphere of
argon and performed using standard vacuum line techniques and
flame-dried glassware.
4.2. Experimental procedures
3. Conclusions
4.2.1. Methyl 4-methoxypicolinate (8)18. Picolinic acid (10.00 g,
81.00 mmol) and sodium bromide (1.00 g, 8.10 mmol) were dis-
solved in thionyl chloride (70 mL) and the mixture was heated at
reflux for 16 h. The reaction mixture was concentrated in vacuo and
cooled to 0 ꢁC. Methanol (35 mL) was added cautiously and the
reaction mixture was heated at reflux for 36 h. The solvent was
removed in vacuo and the residue was dissolved in CH2Cl2 (100 mL)
followed by addition of Na2CO3 (12.80 g, 120 mmol) and the mix-
ture stirred for 3 h. Water (100 mL) was added and the reaction
mixture was extracted with CH2Cl2 (5ꢃ50 mL). The combined or-
ganic extracts were dried (MgSO4), filtered and concentrated in
vacuo. The crude residue was purified by flash column chroma-
tography (SiO2, Et2O) and re-crystallised (hexane) to furnish the
product (9.20 g, 68%) as colourless needles. 1H NMR dH (400 MHz;
CDCl3) 8.50e8.46 (1H, m), 7.63e7.59 (1H, m), 6.94e6.90 (1H, m),
3.94 (3H, s), 3.85 (3H, s); 13C NMR dC (100 MHz; CDCl3) 166.5, 165.7,
150.9, 149.5, 113.0, 111.1, 55.5, 52.9.
In summary, we have described an efficient synthesis of
cylindricine C and a formal synthesis of cylindricine A from
a common intermediate and the synthetic utility of the regiose-
lective nucleophilic attack of Grignard reagents onto substituted
pyridinium salts has been highlighted. The dihydropyridones
formed using this methodology are furnished with considerable
functionality that can be readily manipulated to allow the syn-
thesis of natural products. In addition to a formal total synthesis
of cyclindricine A, we have also completed the synthesis of
cylindricine C, in 13 steps and 3% overall yield. Future work will
concentrate on the formation of enantiopure adducts from the
Grignard addition reaction.
4. Experimental
4.1. General
4.2.2. 1-(3,4-Dimethoxybenzyl)-4-methoxy-2-(methoxycarbonyl)
pyridinium bromide salt (9). Pyridine ester 8 (0.50 g, 3.00 mmol)
was added to a stirred solution of 3,4-dimethoxybenzyl bromide
(0.69 g, 3.00 mmol) in Et2O (5 mL) and stirred for 48 h under an
atmosphere of argon at room temperature. The solvent was re-
moved in vacuo, and the residue washed with dry THF (2ꢃ10 mL).
The resulting solid was dried under high vacuum to furnish the
Solvents and reagents: Tetrahydrofuran, dichloromethane,
methanol and toluene were dried prior to use by an alumina col-
umn. Triethylamine and diisopropylamine were dried by stirring
over and distilling from calcium hydride and were stored over
potassium hydroxide. Other solvents were used as supplied
without purification. Light petroleum refers to the fraction of pe-
troleum ether, which boils in the range 30e40 ꢁC. Reagents
obtained from Acros, Aldrich, Avocado, Fluka and Lancaster fine
chemicals suppliers were used as supplied. Chromatography:
column fractions and reactions were monitored by thin-layer
chromatography (TLC). TLC was performed on Merck Kieselgel 60
F254 0.25 mm pre-coated aluminium backed silica plates. Com-
pounds were visualised with UV light and/or by staining with basic
potassium permanganate solution. Column chromatography was
carried out according to the method described by Still et al. using
pyridinium salt (1.19 g, 99%) as
a colourless powder. Mp
101e102 ꢁC; IR nmax (film)/cmꢂ1 3417, 1743, 1517, 1263, 1143, 1020;
1H NMR dH (400 MHz; CDCl3) 10.20 (1H, d, J 7.2), 7.89 (1H, dd, J 7.2
and 3.2), 7.68 (1H, d, J 3.2), 7.17 (1H, d, J 2.0), 6.93 (1H, dd, J 8.3 and
2.0), 6.80 (1H, d, J 8.3), 6.16 (2H, s, NCH2), 4.22 (3H, s), 4.02 (3H, s),
3.90 (3H, s), 3.85 (3H, s); 13C NMR dC (100 MHz; CDCl3) 171.4, 160.2,
152.0, 149.6, 143.2, 125.6, 121.8, 117.7, 114.1, 112.3, 111.2, 60.8, 59.01,
56.5, 55.9, 54.8; MS m/z (ESI) 318 (Mþ 100%), HRMS (ESI) for
C17H20NO5 requires 318.1341 found (Mþ) 318.1336.
Merck Kieselgel 60 (40e63 mm), using head pressure by means of
head bellows. NMR Spectroscopy: 1H NMR spectra were recorded
using a Bruker AVANCE AV400 (400 MHz), a Bruker DRX500
(500 MHz) or a Bruker AV11 500 (500 MHz) spectrometer. Chem-
4.2.3. General procedure for the addition of Grignard reagents to
pyridinium salt 9. Grignard reagent (2 equiv) was added dropwise
over 5 min to a solution of pyridinium salt 9 (1 equiv) in CH2Cl2
(10 mL) at ꢂ78 ꢁC. The reaction mixture was allowed to stir for 4 h
30 min at the same temperature before adding 1 M HCl (5 mL). The
mixture was warmed slowly to room temperature and extracted
with CH2Cl2 (3ꢃ25 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo. The crude product
was purified by flash column chromatography.
ical shifts (d) are quoted in parts per million (ppm) relative to re-
sidual solvent peaks. Signal splittings are recorded as singlet (s),
doublet (d), triplet (t), quartet (q), multiplet (m), broad (br) and
apparent (app). Coupling constants (J) are given to the nearest
0.1 Hz. 13C NMR spectra were recorded on Bruker AVANCE AV400
(100 MHz), a Bruker DRX500 (125 MHz) or a Bruker AV11 500
(125 MHz) spectrometer and referenced in the same way. As-
signments of both 1H and 13C NMR were aided by COSY (correlated
spectroscopy), HMQC (heteronuclear multiple-quantum correla-
tion) and HMBC (heteronuclear multiple-bond correlation). IR
spectroscopy: Infra-red spectra were recorded on a Bruker Tensor
27 FT-IR spectrometer. Compounds were analysed as thin films on
NaCl plates or pressed into a KBr disk. Absorption maxima are
quoted in wavenumbers (cmꢂ1). Mass Spectrometry: mass spectra
(m/z) were recorded on a Fisons Platform II and accurate mass
(HRMS) on a Bruker MicroTof (resolution¼10,000 FWHM) under
4.2.4. Methyl-1-(3,4-dimethoxybenzyl)-4-oxo-6-phenyl-1,4,5,6-tet-
rahydropyridine-2-carboxylate (10). Yield 0.73 g, 77%, pale yellow
oil; IR nmax (film)/cmꢂ1 3468, 1641, 1262; 1H NMR dH (400 MHz;
CDCl3) 7.39e7.24 (5H, m), 6.84e6.82 (1H, m), 6.73e6.72 (2H, m),
5.43 (1H, s), 4.75 (1H, d, J 15.4), 4.61 (1H, t, J 6.4), 4.02 (1H, d, J 15.7),
3.91 (3H, s), 3.89 (3H, s), 3.84 (3H, s), 2.88 (1H, dd, J 16.6 and 7.0),
2.68 (1H, dd, J 16.4 and 6.1); 13C NMR dC (100 MHz; CDCl3) 199.8,
164.9, 159.0, 149.2 148.9, 137.7, 129.1, 128.5, 128.3, 126.7, 120.2, 111.1,
110.8, 101.6, 60.2, 55.9, 54.1, 53.2, 42.9; MS m/z (ESI) 404.2 (MþNaþ,

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T.J. Donohoe et al. / Tetrahedron 66 (2010) 6411e6420
65% and MþHþ 382.2, 25%), HRMS (ESI) for C22H23NNaO5 requires
404.1468, found (MþNaþ) 404.1464.
1259, 1138, 1026; 1H NMR dH (400 MHz; CDCl3) 6.86e6.80 (3H, m),
5.30 (1H, s), 5.00 (1H, s), 4.93 (1H, s), 4.73 (1H, d, J 15.4), 4.07 (1H, d,
J 15.4), 3.98 (1H, dd, J 7.5 and 4.4), 3.89 (3H, s), 3.88 (3H, s), 3.86 (3H,
s), 2.69 (1H, dd, J 16.7 and 7.6), 2.51 (1H, dd, J 16.6 and 4.2), 1.75 (3H,
s); 13C NMR dC (100 MHz; CDCl3) 191.1, 164.9, 153.3, 149.3, 148.8,
139.5, 129.1, 120.1, 114.3, 111.1, 110.7, 100.7, 61.7, 55.9, 53.9, 53.1, 39.2,
19.0; MS m/z (ESI) 368.2 (MþNaþ, 55%), HRMS (ESI) for
C19H23NNaO5 requires 368.1468, found (MþNaþ) 368.1466.
4.2.5. Methyl-1-(3,4-dimethoxybenzyl)-2-methyl-4-oxo-1,2,3,4-tet-
rahydropyridine-2-carboxylate (11). Yield 0.53 g, 66%, pale yellow
oil; IR nmax (film)/cmꢂ1 3443, 2084, 1641, 1262; 1H NMR dH
(400 MHz; CDCl3) 7.01 (1H, d, J 7.8), 6.89e6.81 (3H, m), 5.03 (1H, d, J
7.8), 4.48 (1H, d, J 15.2), 4.38 (1H, d, J 15.2), 3.90 (6H, s), 3.76 (3H, s),
2.95 (1H, d, J 16.4), 2.64 (1H, d, J 16.4), 1.55 (3H, s); 13C NMR dC
(100 MHz; CDCl3) 190.0, 173.3, 154.3, 149.4, 148.8, 129.3, 120.2,
111.3, 110.6, 99.8, 65.9, 56.0, 54.7, 53.0, 47.0, 22.5; MS m/z (ESI) 342.1
(MþNaþ, 65%), HRMS (ESI) for C17H21NaNO5 requires 342.1312,
found (MþNaþ) 342.1308.
4.2.11. Methyl-2-benzyl-1-(3,4-dimethoxybenzyl)-4-oxo-1,2,3,4-tet-
rahydropyridine-2-carboxylate (17). Yield 0.68 g, 69%, pale yellow
oil; IR nmax (film)/cmꢂ1 3449, 2083, 1642, 1516, 1260, 1026; 1H NMR
dH (400 MHz; CDCl3) 7.31e7.26 (3H, m), 7.13 (2H, dd, J 7.2 and 1.9),
6.96 (1H, d, J 7.8), 6.89e6.84 (2H, m), 6.78 (1H, s), 5.03 (1H, d, J 7.8),
4.64 (1H, d, J 15.4), 4.62 (1H, d, J 15.4), 3.89 (3H, s), 3.88 (3H, s,), 3.65
(3H, s), 3.48 (1H, d, J 13.4), 3.10 (1H, d, J 13.4), 2.86 (1H, d, J 16.4),
2.64 (1H, d, J 16.2); 13C NMR dC (100 MHz; CDCl3) 190.2, 172.2, 153.7,
149.4, 148.8, 134.1, 130.5, 129.4, 128.5, 127.5, 120.1, 111.3, 110.6, 99.9,
69.5, 55.9, 54.7, 52.7, 43.9, 40.0; MS m/z (ESI) 418.2 (MþNaþ, 65%),
HRMS (ESI) for C23H25NNaO5 requires 418.1625, found (MþNaþ)
418.1619.
4.2.6. Methyl-1-(3,4-dimethoxybenzyl)-2-ethyl-4-oxo-1,2,3,4-tetra-
hydropyridine-2-carboxylate (12). Yield 0.60 g, 72%, pale yellow oil;
IR nmax (film)/cmꢂ1 3468, 2084, 1641, 1262; 1H NMR dH (400 MHz;
CDCl3) 6.98 (1H, d, J 7.8), 6.87 (2H, s), 6.81 (1H, s), 5.00 (1H, d, J 7.8),
4.53 (1H, d, J 14.9), 4.39 (1H, d, J 14.9), 3.89 (6H, s), 3.74 (3H, s), 2.89
(1H, d, J 16.4), 2.72 (1H, d, J 16.4), 2.01 (2H, d, J 14.3 and 7.2), 1.00
(3H, t, J 7.5); 13C NMR dC (100 MHz; CDCl3) 190.6, 173.2, 154.4, 149.4,
148.8, 129.0, 120.5, 111.3, 111.0, 99.8, 69.3, 55.9, 53.7, 52.8, 43.0, 27.8,
8.4; MS m/z (ESI) 356.2 (MþNaþ, 60%), HRMS (ESI) for C18H23NNaO5
requires 356.1468, found (MþNaþ) 356.1466.
4.2.12. Methyl-1-(3,4-dimethoxybenzyl)-4-oxo-6-(prop-1-ynyl)-
1,4,5,6-tetrahydropyridine-2-carboxylate (18). Yield 0.62 g, 72%,
yellow oil; IR nmax (film)/cmꢂ1 3447, 2955, 2837, 2250, 1558; 1H
NMR dH (400 MHz; CDCl3) 6.93e6.83 (3H, m), 5.47 (1H, s), 4.74 (1H,
d, J 14.9), 4.29 (1H, d, J 15.2), 4.23 (1H, m), 3.89 (3H, s), 3.88 (3H, s),
3.86 (3H, s), 2.62 (1H, dd, J 16.2 and 6.1), 2.48 (1H, dd, J 16.0 and 4.4),
1.82 (3H, d, J 2.3); 13C NMR dC (100 MHz; CDCl3) 191.2, 164.6, 152.1,
149.3, 148.9, 128.7, 120.6, 111.1, 111.0, 102.5, 82.2, 74.2, 55.9, 53.8,
53.0, 48.9, 41.7, 3.6; MS m/z (ESI) 366.2 (MþNaþ, 80%), HRMS (ESI)
for C19H21NNaO5 requires 366.1312, found (MþNaþ) 366.1315.
4.2.7. Methyl-1-(3,4-dimethoxybenzyl)-4-oxo-6-vinyl-1,4,5,6-tetra-
hydropyridine-2-carboxylate (13). Yield 0.72 g, 87%, pale yellow oil;
IR nmax (film)/cmꢂ1 3444, 2063, 1731, 1644, 1516, 1259, 1138, 1065,
1026; 1H NMR dH (400 MHz; CDCl3) 6.87 (1H, s), 6.84 (2H, s), 5.84
(1H, ddd, J 17.2, 10.4 and 6.8), 5.34 (1H, s), 5.28 (1H, d, J 17.2), 5.22
(1H, d, J 10.4), 4.71 (1H, d, J 15.4), 4.16 (1H, d, J 15.4), 4.07e4.00 (1H,
m), 3.89 (6H, s), 3.86 (3H, s), 2.72 (1H, dd, J 16.6 and 6.7), 2.37 (1H,
dd, J 16.4 and 3.8); 13C NMR dC (100 MHz; CDCl3) 191.1, 164.8, 152.4,
149.3, 148.9, 132.2, 129.2, 120.2, 118.4, 111.1, 110.7, 101.0, 59.2, 55.9,
53.8, 53.1, 40.4; MS m/z (ESI) 354.1 (MþNaþ, 55% and MþHþ 332.2,
25%), HRMS (ESI) for C18H21NaNO5 requires 354.1312, found
(MþNaþ) 354.1309.
4.2.13. Methyl-2-(4-chlorobutyl)-1-(3,4-dimethoxybenzyl)-4-oxo-
1,2,3,4-tetrahydropyridine-2-carboxylate (19). Freshly prepared 4-
chlorobutyl magnesium bromide in THF was added dropwise over
5 min to a solution of pyridinium salt 9 (0.25 g, 0.63 mmol) in
CH2Cl2 (1.5 mL) cooled at ꢂ30 ꢁC. The reaction mixture was stirred
for 4 h 30 min at the same temperature before the addition of 1 M
HCl (5 mL). The reaction mixture was warmed to room tempera-
ture and extracted with CH2Cl2 (3ꢃ25 mL). The combined organic
layers were dried (Na2CO3), filtered and concentrated in vacuo.
The crude product was purified by column chromatography (SiO2,
Et2O followed by Et2O:CH2Cl2 7:3) to furnish the product (0.16 g,
64%), as a colourless oil; IR nmax (film)/cmꢂ1 2954, 1735, 1645,
1587, 1516, 1462, 1262, 1140, 1025; 1H NMR dH (400 MHz; CDCl3)
6.96 (1H, d, J 7.8), 6.86 (2H, s), 6.81 (1H, s), 4.88 (1H, d, J 7.8), 4.47
(1H, d, J 14.7) 4.37 (1H, d, J 14.7), 3.88 (6H, s), 3.73 (3H, s), 3.49
(2H, m), 2.88 (1H, d, J 16.4), 2.72 (1H, d, J 16.4), 1.98e1.93 (2H, m),
1.80e1.65 (2H, m), 1.60e1.49 (2H, m); 13C NMR dC (100 MHz;
CDCl3) 190.2, 172.9, 154.1, 149.4, 148.9, 128.7, 120.0, 111.3, 111.1,
99.9, 68.9, 55.9, 53.9, 52.9, 44.3, 43.5, 33.8, 32.3, 21.3; MS m/z (ESI)
396.00 (MþHþ 100%), HRMS (ESI) for C20H27Cl35NO5 requires
396.1572, found (MþHþ) 396.1572 (Using 10 g of 9 we obtained 19
in a yield of 62%.).
4.2.8. Methyl-2-(but-3-enyl)-1-(3,4-dimethoxybenzyl)-4-oxo-
1,2,3,4-tetrahydropyridine-2-carboxylate (14). Yield 0.90 g, 83%,
colourless oil; IR nmax (film)/cmꢂ1 3447, 3059, 2954, 2837, 1734,
1644, 1516, 1027, 857, 734; 1H NMR dH (400 MHz; CDCl3) 6.97 (1H,
dd, J 7.8 and 1.4), 6.87 (2H, s), 6.80 (1H, s), 5.76e5.67 (1H, m),
5.01e4.97 (3H, m), 4.50 (1H, d, J 14.9), 4.38 (1H, d, J 14.9), 3.80 (6H,
s), 3.73 (3H, s), 2.91 (1H, d, J 16.3), 2.72 (1H, dd, J 16.3 and 1.3),
2.18e1.96 (4H, m); 13C NMR dC (100 MHz; CDCl3) 190.2, 172.9, 154.1,
149.4, 148.9, 136.4, 128.9, 120.6, 115.8, 111.4, 111.0, 68.8, 56.0, 53.8,
52.9, 43.5, 33.8, 28.0; MS m/z (ESI) 382 (MþNaþ, 40%), HRMS (ESI)
for C20H25NNaO5 requires 382.1625, found (MþNaþ) 382.1625.
4.2.9. Methyl-1-(3,4-dimethoxybenzyl)-6-(4-methoxyphenyl)-4-oxo-
1,4,5,6-tetrahydropyridine-2-carboxylate (15). Yield 0.92 g, 89%,
pale yellow oil; IR nmax (film)/cmꢂ1 3442, 2062, 1732, 1643, 1463,
1253, 1138, 1026; 1H NMR dH (400 MHz; CDCl3) 7.17 (2H, m, J 8.8),
6.88 (2H, m, J 8.8), 6.83e6.81 (1H, m), 6.72e6.71 (2H, m), 5.39 (1H,
s), 4.70 (1H, d, J 15.4), 4.54 (1H, t, J 6.6), 4.01 (1H, d, J 15.4), 3.89 (6H,
s), 3.84 (3H, s), 3.81 (3H, s), 2.82 (1H, dd, J 16.6 and 6.7), 2.64 (1H,
dd, J 16.4 and 6.6); 13C NMR dC (100 MHz; CDCl3) 191.1, 165, 159.5,
154.0, 149.2, 148.8, 129.7, 128.7, 128.1, 120.2, 114.4, 111.1, 110.7, 101.5,
59.8, 55.9, 53.8, 53.3, 53.2, 43.2; MS m/z (ESI) 434.2 (MþNaþ, 85%),
HRMS (ESI) for C23H25NNaO6 requires 434.1574, found (MþNaþ)
434.1577.
4.2.14. (4aS,8aR)-Methyl-1-(3,4-dimethoxybenzyl)-4-oxo-
1,4,4a,5,6,7,8,8a-octahydroquinoline-8a-carboxylate (20). Dihydro-
pyridone 19 (8.20 g, 20.76 mmol) was dissolved in DMF (40 mL)
and cooled to ꢂ40 ꢁC before addition of NaNH2 (2.03 mL, 60%
suspension in PhMe, 31.14 mmol). The reaction mixture was then
allowed to warm slowly to 0 ꢁC over 20 min before quenching with
saturated NH4Cl solution in H2O (5 mL). The aqueous layer was
extracted with CH2Cl2 (3ꢃ30 mL) and the combined organic layers
were washed with H2O (5ꢃ50 mL), dried (MgSO4) and the crude
product purified by flash column chromatography (SiO2, Et2O/
4.2.10. Methyl-1-(3,4-dimethoxybenzyl)-4-oxo-6-(prop-1-en-2-yl)-
1,4,5,6-tetrahydropyridine-2-carboxylate (16). Yield 0.80 g, 93%,
pale yellow oil; IR nmax (film)/cmꢂ1 3444, 2063, 1731, 1644, 1516,

T.J. Donohoe et al. / Tetrahedron 66 (2010) 6411e6420
6417
EtOAc 1:1) to furnish the product (6.50 g, 87% yield) as a colourless
oil; mp 141e143 ꢁC; IR nmax (KBr)/cmꢂ1 2949,1732,1644,1587,1513,
1238; 1H NMR dH (400 MHz; CDCl3) 6.93 (1H, d, J 7.8) 6.88 (2H, m),
6.84 (1H, d, J 1.4), 4.90 (1H, dd, J 7.8 and 1.3), 4.49 (1H, d, J 14.2), 4.40
(1H, d, J 14.2), 3.88 (3H, s), 3.87 (3H, s), 3.70 (3H, s), 2.70 (1H, dd, J
3.6 and 1.0), 2.29 (1H, m), 1.86e1.66 (4H, m), 1.53e1.33 (3H, m); 13C
NMR dC (100 MHz; CDCl3)194.5, 173.9, 153.5, 149.3, 148.8, 128.5,
121.3, 111.6, 111.4, 99.2, 68.9, 55.9, 52.8, 52.5, 50.3, 30.8, 26.4, 24.3,
21.7; MS m/z (ESI) 360.3 (MþHþ, 100%), HRMS (ESI) for
C20H25NNaO5 requires 382.1627, found (MþNaþ) 382.1625.
s), 2.44 (1H, dd, J 11. 8 and 4.4), 1.97 (1H, dd, J 12.6 and 2.5),
1.72e1.47 (8H, m), 1.35e1.24 (10H, m), 1.17e1.04 (21H, m),
0.89e0.86 (3H, m); 13C NMR dC (100 MHz; CDCl3) 177.7,153.4, 102.0,
61.7, 51.6, 50.8, 41.8, 38.2, 36.3, 31.9, 29.6, 28.6, 25.5, 25.4, 22.6, 20.8,
18.0, 14.1, 12.7; MS m/z (ESI) 452.30 (MþHþ, 95%), HRMS (ESI) for
C26H50NO3Si requires 452.3554, found (MþHþ) 452.3552.
4.2.17. (2R,4aS,8aR)-2-Hexyl-4-(triisopropylsilyloxy)-
1,2,4a,5,6,7,8,8a-octahydroquinoline-8a-carbaldehyde (23). DIBAL-H
(12.2 mL, 1 M in hexanes, 12.27 mmol) was added dropwise to
a solution of 22 (3.69 g, 8.18 mmol) in PhMe (30 mL) at ꢂ78 ꢁC
under an atmosphere of argon and stirred for 1 h. MeOH (20 mL)
was added to the reaction mixture and stirring continued for
15 min before the addition of H2O (20 mL) and stirring for a further
15 min. The reaction mixture was warmed to room temperature
and the aqueous layer extracted with Et2O (3ꢃ10 mL). The com-
bined organic extracts were washed with NaOH (20 mL, 1 M in
H2O) and brine (20 mL) before being dried (Na2SO4), filtered and
concentrated in vacuo. Purification of the crude product via flash
column chromatography (SiO2, 9:1 petrol/Et2O) furnished 23
(2.82 g, 82%) as a colourless oil; IR nmax (film)/cmꢂ1 3444, 2930,
1729, 1665, 1466, 1205; 1H NMR dH (400 MHz; CDCl3) 9.54 (1H, s),
4.69 (1H, dd, J 2.3 and 11.0), 3.50e3.45 (1H, m), 2.50 (1H, br s),
1.95e1.78 (2H, m), 1.77 (2H, ddd, J 13.0, 9.0 and 4.6), 1.60 (2H, ddd, J
13.4, 8.8 and 4.0), 1.50e1.26 (14H, m), 1.20e1.15 (4H, m), 1.10e1.06
(15H, m), 0.90e0.87 (3H, m); 13C NMR dC (100 MHz; CDCl3) 204.5,
150.7, 103.9, 62.2, 50.6, 38.8, 38.3, 31.8, 29.3, 28.5, 26.1, 25.4, 22.6,
22.5, 22.1, 18.1, 17.7, 14.1, 12.7; MS m/z (ESI) 422.34 (MþHþ, 100%),
HRMS (ESI) for C25H48NO2Si requires 422.3455, found (MþHþ)
422.3467.
4.2.15. (2R,4aS,8aR)-Methyl-1-(3,4-dimethoxybenzyl)-2-hexyl-4-(trii-
sopropylsilyloxy)-1,2,4a,5,6,7,8,8a-octahydroquinoline-8a-carboxylate
and (2S,4aS,8aR)-methyl-1-(3,4-dimethoxybenzyl)-2-hexyl-4-(triiso-
propylsilyloxy)-1,2,4a,5,6,7,8,8a-octahydroquinoline-8a-carboxylate
(21). Triisopropylsilyl
trifluoromethanesulfonate
(4.10 mL,
15.32 mmol) was added to a solution of 20 (2.80 g, 7.66 mmol) in
PhMe (40 mL) under an atmosphere of argon and stirred for 45 min.
The mixture was cooled to 0 ꢁC before the dropwise addition of n-
hexyl magnesium bromide (5.80 mL, 2 M in Et2O, 11.49 mmol). The
reaction mixture was stirred for 4 h 30 min before the addition of
NH4Cl (20 mL, saturated aqueous solution). The aqueous layer was
extracted with Et2O (3ꢃ30 mL) and the combined organic extracts
were washed with brine (30 mL), dried (MgSO4), filtered and con-
centrated in vacuo. The crude residue was purified via flash column
chromatography (SiO2, gradient of neat petrol to petrol/Et2O 9:1) to
furnish the mixture of products (3.18 g, 69% yield) as an oil; IR nmax
(film)/cmꢂ1 3442, 2062, 1732, 1643, 1463, 1253, 1138, 1026; 1H NMR
dH (400 MHz; CDCl3) 7.10 (1H, m), 7.02 (1H, m, ArH), 6.93e6.90 (1H,
m), 6.88e6.86 (1H, m), 6.81e6.80 (1H, m), 6.79e6.77 (1H, m), 4.66
(1H, d, J 2.8), 4.58 (1H, d, J 2.8), 4.34 (1H, d, J 15.4), 3.96 (1H, d, J
15.1), 3.87 (12H, s), 3.74 (1H, d, J 17.9), 3.70e3.68 (1H, m), 3.64 (3H,
s), 3.60 (3H, s), 3.51e3.40 (2H, m), 3.14 (1H, d, J 7.6), 2.45e2.41 (1H,
m), 2.18e1.92 (2H, m), 1.78e1.72 (4H, m), 1.62e1.56 (4H, m),
1.51e1.42 (6H, m), 1.35e1.65 (62H), 0.95e0.82 (6H, m); 13C NMR dC
(100 MHz; CDCl3) 177.8, 151.5, 141.3, 132.3, 129.4, 128.5, 125.8, 118.5,
110.7, 102.1, 68.2, 65.0, 55.9, 55.7, 52.9, 51.3, 47.6, 43.5, 42.1, 37.4,
37.1, 34.4, 34.1, 31.9, 31.8, 29.6, 29.5, 28.4, 26.4, 25.9, 24.3, 22.8, 22.5,
22.4, 18.7, 17.7, 14.1, 12.8, 12.7, 12.3 (for clarity we have normalised
the ratio of the two diastereomers as 1:1); MS m/z (ESI) 602.4
(MþHþ, 100%), HRMS (ESI) for C35H60NO5Si requires 602.4235,
found (MþHþ) 602.4234.
4.2.18. (E)-Methyl-3-((2R,4aS,8aS)-2-hexyl-4-(triisopropylsilyloxy)-
1,2,4a,5,6,7,8,8a-octahydroquinolin-8a-yl)acrylate (24). To solution
of trimethyl phosphonoacetate (0.14 mL, 0.88 mmol) in dry THF
(5 mL) at room temperature was added NaH (44.0 mg, 1.07 mmol,
60% suspension in mineral oil), which caused vigorous evolution of
gas. The solution was stirred for 20 min before addition of a solu-
tion of 23 (0.18 g, 0.43 mmol) in THF (3 mL). The reaction mixture
was stirred for 1 h at room temperature before cautiously adding
H2O (3 mL). The mixture was extracted with Et2O (3ꢃ5 mL). The
combined organic extracts were washed with brine (5 mL), dried
(Na2SO4), filtered and the solvent removed in vacuo. The residue
was purified via flash column chromatography (SiO2, 8:2 petrol/
Et2O), which furnished the product (0.15 g, 75%) as a colourless oil;
IR nmax (film)/cmꢂ1 3444, 2929, 1729, 1666, 1205; 1H NMR dH
(400 MHz; CDCl3) 7.20 (1H, d, J 16.2), 6.04 (1H, d, J 15.9), 4.75 (1H,
s), 3.75 (3H, s), 3.46 (1H, br s), 2.31 (1H, br s), 2.18 (1H, d, J 12.6),
2.05e1.97 (1H, m), 1.65e1.60 (2H, m), 1.49e1.16 (17H, m), 1.10e1.07
(18H, m), 0.90e0.87 (3H, m); 13C NMR dC (100 MHz; CDCl3) 167.5,
154.8, 149.7, 119.2, 104.7, 55.7, 51.6, 49.7, 43.3, 37.6, 31.8, 30.8, 29.4,
25.8, 24.4, 22.9, 22.6, 21.6, 18.1, 14.1, 12.8; MS m/z (ESI) 478.3
(MþHþ, 100%), HRMS (ESI) for C28H52NO3Si requires 478.3711,
found (MþHþ) 478.3699.
4.2.16. (2R,4aS,8aR)-Methyl-2-hexyl-4-(triisopropylsilyloxy)-
1,2,4a,5,6,7,8,8a-octahydroquinoline-8a-carboxylate and (2S,4aS,8aR)-
methyl-2-hexyl-4-(triisopropylsilyloxy)-1,2,4a,5,6,7,8,8a-octa-
hydroquinoline-8a-carboxylate (22). Palladium on carbon (0.24 g,
10% loading) was added to a solution of 21 (1.60 g, 2.6 mmol) in
EtOAc/MeOH (1:5, 30 mL) under an atmosphere of hydrogen. The
reaction mixture was stirred for 2 h before filtration through Celite.
The mixture was concentrated and the crude residue was purified
via flash column chromatography (SiO2, 95:5 petrol/Et2O) to fur-
nish the deprotected compound 22 (720 mg, 60%) and its minor
diastereomer (210 mg, 18%) in a ratio of 3.4:1 with an overall yield
of 78%. Both compounds were isolated as colourless oils.
4.2.19. Methyl-3-((2R,4aS,8aS)-2-hexyl-4-(triisopropylsilyloxy)-
Major: IR nmax (film)/cmꢂ1 3441, 2930, 2865, 1731, 1667, 1463,
1205; 1H NMR dH (400 MHz; CDCl3) 4.64 (1H, s), 3.67 (3H, s), 3.44
(1H, m), 2.71 (1H, br s), 2.02e1.98 (1H, m), 1.84e1.72 (1H, m),
1.71e1.38 (5H, m),1.37e1.25 (11H, m),1.18e1e15 (4H, m),1.07e1.04
(17H, m), 0.86e0.83 (3H, m); 13C NMR dC (100 MHz; CDCl3) 176.1,
150.7, 103.3, 61.2, 51.9, 50.5, 40.7, 37.4, 31.7, 30.4, 29.3, 25.9, 25.4,
22.8, 22.5, 22.3, 18.0, 14.1, 12.8; MS m/z (ESI) 452.30 (MþHþ, 95%),
HRMS (ESI) for C26H50NO3Si requires 452.3554, found (MþHþ)
452.3552.
1,2,4a,5,6,7,8,8a-octahydroquinolin-8a-yl)propanoate
(25). Palla-
dium on carbon (7.0 mg, 10% loading) was added to a solution of 24
(0.14 g, 0.30 mmol) in MeOH/EtOAc 1:4 under an atmosphere of
hydrogen gas. The mixture was stirred for 2 h before filtering
through Celite. The solvent was removed in vacuo and the crude
product purified by flash column chromatography (SiO2, 8:2 petrol/
Et2O) to furnish the product (0.12 g, 86%) as a colourless oil; IR nmax
(film)/cmꢂ1 3441, 2930, 1729, 1665, 1203, 853; 1H NMR dH
(400 MHz; CDCl3) 4.72 (1H, s), 3.67 (3H, s), 3.35 (1H, br s), 2.41 (2H,
m), 2.35e2.31 (1H, d, J 13.1), 2.08e2.05 (1H, m), 2.00e1.97 (1H, m),
1.82 (2H, td, J 13.0 and 4.3), 1.55 (1H, m), 1.42.1.28 (15H, m),
Minor: IR nmax (film)/cmꢂ1 3444, 2930, 1729, 1665, 1466, 1205;
1H NMR dH (400 MHz; CDCl3) 4.40 (1H, m), 3.63 (3H, s), 3.52 (1H, br

6418
T.J. Donohoe et al. / Tetrahedron 66 (2010) 6411e6420
1.23e1.06 (21H, m), 0.89 (3H, t, J 6.8); 13C NMR dC (100 MHz; CDCl3)
175.2, 150.1, 105.0, 54.4, 51.6, 49.0, 43.6, 33.3, 31.8, 29.5, 29.2, 28.0,
25.7, 23.7, 22.7, 22.6, 21.8, 18.2, 18.1, 14.1, 12.8; MS m/z (ESI) 480.4
(MþHþ, 95%), HRMS (ESI) for C28H54NO3Si requires 480.3867, found
(MþHþ) 480.3857.
Et2O/petrol) to furnish the product (3.58 g, 92%) as a colourless oil; IR
nmax (film)/cmꢂ1 2950, 1678, 1250, 838; 1H NMR dH (400 MHz;
CDCl3) 9.62 (1H, br s), 4.98 (1H, dd, J 6.14 and 2.2), 4.21e4.13 (3H, m),
2.80 (1H, br s), 2.44 (1H, d, J 13.8), 2.13 (1H, d, J 14.0), 1.86e1.83 (1H,
m), 1.76 (1H, br s), 1.53e1.39 (6H, m), 1.28e1.21 (9H, m), 1.17e1.09
(20H, m), 1.03e0.93 (2H, m), 0.90e0.87 (3H, m), 0.03 (9H, s); 13C
NMR dC (100 MHz; CDCl3) 199.6, 157.1, 151.0, 101.1, 66.0, 64.2, 52.6,
38.0, 31.8, 29.1, 25.9, 25.9, 23.0, 22.6, 22.2, 21.3, 18.1, 18.0, 17.8, 14.1,
12.8, ꢂ1.6; MS m/z (ESI) 566.4 (MþHþ, 100%), HRMS (ESI) for
C31H59NNaO4Si2 requires 588.3862, found (MþNaþ) 588.3862.
4.2.20. (E)-3-((2R,4aS,8aS)-2-Hexyl-4-(triisopropylsilyloxy)-
1,2,4a,5,6,7,8,8a-octahydroquinolin-8a-yl)acrylaldehyde
(26). To
a solution of 24 (0.12 g, 0.24 mmol) in dry PhMe (5 mL) at ꢂ78 ꢁC
was added DIBAL-H (0.36 mL, 1 M in hexanes, 0.36 mmol) slowly
over 10 min. The reaction mixture was stirred at ꢂ78 ꢁC for
45 min before addition of MeOH (5 mL) and stirring for 15 min.
H2O (5 mL) was added and the mixture was stirred for a further
15 min before allowing it to warm slowly to room temperature.
The reaction mixture was extracted with Et2O (3ꢃ15 mL) and the
combined organic extracts were washed with brine (15 mL), dried
(Na2SO4) and the solvent removed in vacuo. The crude product
was purified via flash column chromatography (SiO2, 0.5% MeOH
in CH2Cl2) to furnish 26 (70 mg, 66%), as a yellow oil; IR nmax
(film)/cmꢂ1 3441, 2930, 1729, 1665, 1466, 1205, 873; 1H NMR dH
(400 MHz; CDCl3) 9.57 (1H, d, J 7.8), 7.00 (1H, d, J 16.2), 6.30 (1H
dd, J 15.9 and 7.8), 4.75 (1H, s), 3.48 (1H, br s), 2.35 (1H, br s),
2.17 (1H, d, J 2.2), 2.04 (1H, td, J 12.3 and 2.8), 1.65 (2H, m),
1.47e1.35 (11H, m), 1.28e1.05 (23H, m), 0.88 (3H, t, J 6.6); 13C
NMR dC (100 MHz; CDCl3) 194.5, 164.2, 149.6, 130.6, 104.6, 56.1,
49.9, 43.2, 37.7, 31.8, 30.9, 29.4, 25.9, 24.7, 22.9, 22.6, 21.7, 18.1,
14.1, 12.8; MS m/z (ESI) 448.3 (MþHþ, 100%), HRMS (ESI) for
C27H50NO2Si requires 448.3533, found (MþHþ) 448.3532.
4.2.23. (2R,4aS,8aS)-2-(Trimethylsilyl)-ethyl-2-hexyl-8a-((E)-3-me-
thoxy-3-oxoprop-1-enyl)-4-(triisopropylsilyloxy)-4a,5,6,7,8,8a-hexahy-
droquinoline-1(2H)-carboxylate (29). Trimethyl phophonoacetate
(0.36 mL, 1.59 mmol) was dissolved in dry THF (15 mL) and NaH
(70.0 mg, 1.75 mmol, 60% suspension in oil) was added. The re-
action mixture was stirred for 20 min at room temperature. A
solution of 28 (0.45 g, 0.80 mmol) in dry THF (5 mL) was then
added and the reaction flask placed in a preheated oil bath at
60 ꢁC. The reaction mixture was allowed to stir for 2 h before
addition of H2O (5 mL) to quench. The mixture was extracted
with Et2O (3ꢃ20 mL). The combined organic extracts were then
washed with brine, dried (MgSO4) and concentrated in vacuo.
The crude was purified via flash column chromatography (SiO2,
Et2O/petrol 5:95) to furnish the product (0.43 g, 86%) as a col-
ourless oil; IR nmax (film)/cmꢂ1 3440, 2947, 1648, 1250, 837; 1H
NMR dH (400 MHz; CDCl3) 7.44 (1H, d, J 16.2), 5.90 (1H, d, J 16.7),
4.97 (1H, d, J 6.1), 4.32 (1H, ddd, J 10.2, 6.4 and 3.4), 4.11e4.06
(2H, m), 3.74 (3H, s), 2.57 (1H, br s), 2.25 (1H, d, J 12.9), 1.93e1.91
(2H, m), 1.80e1.76 (2H, m), 1.64 (1H, s), 1.58e1.37 (7H, m),
1.32e1.17 (12H, m), 1.11e1.05 (15H, m), 0.99e0.94 (2H, m),
0.90e0.88 (3H, m), 0.02 (9H, s); 13C NMR dC (100 MHz; CDCl3)
167.5, 155.5, 155.1, 150.8, 118.3, 101.0, 63.2, 61.1, 53.5, 51.5, 45.2,
38.1, 31.8, 29.1, 26.9, 24.2, 22.6, 18.1, 18.0, 17.8, 17.7, 14.1, 12.7, 12.3,
ꢂ1.6; MS m/z (ESI) 644.4 (MþNaþ, 100%), HRMS (ESI) for
C34H63NNaO5Si2 requires 644.4143, found (MþNaþ) 644.4129.
4.2.21. (2R,4aS,8aS)-2-Hexyl-8a-((E)-2-(oxiran-2-yl)vinyl)-4-(triiso-
propylsilyloxy)-1,2,4a,5,6,7,8,8a-octahydroquinoline (27). To a sus-
pension of trimethylsulfonium iodide (73.0 mg, 0.36 mmol) in dry
THF (5 mL) at room temperature was added NaH (29.0 mg, 60%
suspension in oil, 0.72 mmol) and the reaction mixture was stirred
for 15 min before the addition of a solution of 26 (80.0 mg,
0.18 mmol) in THF (3 mL). The reaction mixture was warmed to
60 ꢁC in an oil bath and stirred for 2 h before cooling to 0 ꢁC and H2O
(5 mL) was carefully added. The mixture was extracted with Et2O
(3ꢃ10 mL). The combined organic extracts were washed with brine
and concentrated in vacuo. Flash column chromatography (SiO2,
CH2Cl2/MeOH 99:1) afforded the product (72 mg, 87%) as a colour-
less oil, 1:1 mixture of diastereomers. This compound contained an
4.2.24. (2R,4aS,8aS)-2-(Trimethylsilyl)-ethyl-2-hexyl-8a-(3-me-
thoxy-3-oxopropyl)-4-(triisopropylsilyloxy)-4a,5,6,7,8,8a-hexahydro-
quinoline-1(2H)-carboxylate (30). Palladium on carbon (10.0 mg,
10% loading) was added to a solution of 29 (0.20 g, 0.32 mmol) in
EtOAc/MeOH (1:5, 5 mL) under an atmosphere of hydrogen. The
reaction mixture was stirred for 1 h before filtration through a pad
of Celite. The mixture was concentrated and the crude residue was
purified via flash column chromatography (SiO2, 95:5 petrol/Et2O)
to furnish the product (172 mg, 88%) as a colourless oil; IR nmax
(film)/cmꢂ1 3441, 1644, 1249; 1H NMR dH (400 MHz; CDCl3) 4.76
(1H, d), 4.41e4.37 (1H, m), 4.15e4.10 (2H, m), 3.66 (3H, s), 2.66 (1H,
br s), 2.50e2.24 (4H, m), 2.05 (2H, br s), 1.80e1.77 (2H, m),
1.65e1.52 (4H, m), 1.38e1.15 (13H, m), 1.12e1.08 (18H, m),
1.03e0.98 (2H, m), 0.90e0.87 (3H, m), 0.04 (9H, s); 13C NMR dC
(100 MHz; CDCl3) 174.6, 156.1, 150.9, 98.5, 62.9, 60.5, 53.5, 51.5,
45.2, 37.9, 34.2, 31.7, 29.1, 27.0, 24.2, 22.5, 18.1, 18.0, 17.8, 14.1 12.8,
ꢂ1.5; MS m/z (ESI) (MþHþ, 624.05), HRMS (ESI) for C34H65NNaO5Si2
requires 646.4293, found (MþNaþ) 646.4306.
impurity, which caused the region
d 1.47e1.07 to integrate for an
extra 9H in the 1H NMR spectrum; IR nmax (film)/cmꢂ1 3442, 2895,
1724, 1466, 1205; 1H NMR dH (400 MHz; CDCl3) 6.16 (1H, dd, J 15.9
and 12.9), 5.37 (1H, ddd, J 16.0, 8.2 and 2.9), 4.76e4.74 (1H, m), 3.44
(1H, m), 3.40e3.36 (1H, m), 2.98 (1H, td, J 4.6 and 1.6), 2.69 (1H, td, J
3.0 and 1.8), 2.32 (1H, br s), 2.23e2.21 (1H, m), 2.01e1.94 (1H, m),
1.68 (3H, m), 1.47e1.15 (24H, m), 1.10e1.07 (20H, m), 0.90 (3H, m);
13C NMR dC (100 MHz; CDCl3) 149.9, 149.8, 143.0, 126.7, 126.5, 104.7,
104.6, 55.5, 52.8, 52.8, 49.5, 49.4, 48.9, 48.8, 43.7, 43.4, 37.5, 31.8,
30.6, 30.1, 29.7, 29.4, 25.8, 24.1, 23.1, 22.6, 21.5, 21.4, 18.2, 18.1, 14.1,
12.8; MS m/z (ESI) 462.4 (MþHþ,100%), HRMS (ESI) for C28H52NO2Si
requires 462.3762, found (MþHþ) 462.3776.
4.2.22. (2R,4aS,8aR)-2-(Trimethylsilyl)-ethyl-8a-formyl-2-hexyl-4-
(triisopropylsilyloxy)-4a,5,6,7,8,8a-hexahydroquinoline-1(2H)-car-
boxylate (28). To a solution of 23 (2.90 g, 6.89 mmol) in CH3CN/Et2O
4:1 (20 mL) at room temperature was added K2CO3 (3.70 g,
27.56 mmol), followed by Teoc-Cl (2.48 g, 13.28 mmol). The slurry
was stirred at room temperature for 48 h, then the solution was
transferred to a separating funnel containing CH2Cl2 (20 mL) and
saturated aqueous solution of NaHCO3 (20 mL). The aqueous layer
was extracted with CH2Cl2 (2ꢃ20 mL). The combined organic ex-
tracts were then dried (MgSO4), filtered and concentrated in vacuo.
The crude was purified via flash column chromatography (SiO2, 5:95
4.2.25. (2R,4aS,8aS)-2-(Trimethylsilyl)-ethyl-2-hexyl-8a-(3-oxo-
propyl)-4-(triisopropylsilyloxy)-4a,5,6,7,8,8a-hexahydroquinoline-1
(2H)-carboxylate (31). A solution of 30 (0.50 g, 0.80 mmol) in PhMe
(15 mL) was cooled to ꢂ78 ꢁC before the slow addition of DIBAL-H
(0.96 mL, 1 M in hexanes, 0.61 mmol). The solution was stirred at
ꢂ78 ꢁC for 1 h before the addition of MeOH (5 mL) and further
stirring for 15 min. H2O (5 mL) was added and the reaction mixture
was stirred for a further 15 min. The reaction mixture was allowed
to warm slowly to room temperature before extracting with EtOAc
(3ꢃ15 mL). The combined organic extracts were washed with brine,

T.J. Donohoe et al. / Tetrahedron 66 (2010) 6411e6420
6419
dried (MgSO4), filtered and concentrated in vacuo. The crude
product was purified via flash column chromatography (SiO2, 95:5
petrol/Et2O), to furnish the product (0.44 g, 92%) as a colourless oil;
IR nmax (film)/cmꢂ1 3453, 2953, 2094, 1644, 1250; 1H NMR dH
(400 MHz; CDCl3) 9.80 (1H, t, J 1.5), 4.76 (1H, d, J 4.55), 4.39 (1H, m),
4.13 (2H, m), 2.61 (2H, m), 2.38 (3H, m), 2.05 (2H, br s), 1.76 (2H, br
s), 1.63e1.57 (6H, m), 1.35e1.16 (13H, m), 1.11e1.08 (16H, m),
1.03e0.99 (2H, m), 0.89 (3H, t, J 7.0), 0.05 (9H, s); 13C NMR dC
(100 MHz; CDCl3) 202.6, 156.1, 150.9, 99.4, 63.0, 63.0, 53.5, 41.3,
39.2, 38.2, 34.2, 31.8, 29.1, 27.0, 22.5, 22.5, 18.1, 17.8, 12.7, ꢂ1.5; MS
m/z (ESI) 594.5 (MþHþ, 50%), HRMS (ESI) for C33H63NNaO4Si2 re-
quires 616.4208, found (MþNaþ) 616.4208.
hexahydroquinoline-1(2H)-carboxylate (34). To a mixture of trime-
thylsulfonium iodide (0.15 g, 0.75 mmol) and NaH (27.0 mg, 60%
suspension in oil, 0.68 mmol) at ꢂ5 ꢁC was added THF/DMSO 1:1
(10 mL) and stirred until evolution of hydrogen gas was finished. A
solution of the 31 (0.20 g, 0.34 mmol) in THF/DMSO 1:1 (10 mL)
was then added slowly. The reaction mixture was stirred for 45 min
before the addition of H2O (10 mL). The reaction mixture was
extracted with EtOAc (3ꢃ10 mL). The combined organic extracts
were washed with H2O (5ꢃ20 mL), brine (20 mL) and dried
(MgSO4). The mixture was filtered and concentrated in vacuo. Flash
column chromatrography (SiO2, petrol/Et2O 9:1) gave the product
as a mixture of diastereomers in a ratio of 1:1 (100 mg, 65%) as
colourless oil’ IR nmax (film)/cmꢂ1 3442, 2094, 1643; 1H NMR dH
(400 MHz; CDCl3) 4.33 (1H, br s), 4.19e4.14 (2H, m), 2.97e2.92 (1H,
m), 2.78 (2H, dt, J 12.1 and 4.3), 2.69e2.64 (2H, m), 2.64e2.55 (1H,
m), 2.48 (1H, dt, J 5.0 and 2.5), 2.42 (1H, d, J 13.2), 2.13 (1H, m), 1.94
(1H, m), 1.66 (1H, m), 1.60e1.43 (7H, m), 1.37e1.25 (12H, m),
1.06e1.00 (2H, m), 0.88 (3H, t, J 6.8), 0.06 (9H, s); 13C NMR dC
(100 MHz; CDCl3) 209.3, 156.1, 63.4, 61.4, 61.2, 52.4, 52.1, 51.1, 48.6,
47.4, 41.4, 37.5, 37.4, 35.7, 31.7, 29.8, 29.6, 29.3, 28.9, 27.9, 27.9, 27.0,
26.9, 22.5, 22.3, 22.1, 22.1, 21.9, 21.2, 14.0, ꢂ1.5; MS m/z (ESI) 474.3
(MþNaþ, 100%), HRMS (ESI) for C25H45NNaO4Si requires 474.3016,
found (MþNaþ) 474.3019.
4.2.26. (2R,4aS,8aS)-2-(Trimethylsilyl)-ethyl-8a-(but-3-enyl)-2-
hexyl-4-(triisopropylsilyloxy)-4a,5,6,7,8,8a-hexahydroquinoline-1
(2H)-carboxylate (32). Methyltriphenylphosphonium bromide salt
(0.27 g, 0.76 mmol) was dried at 60 ꢁC for 30 min under high vac-
uum before the addition of dry THF (5 mL) and cooled to 0 ꢁC. To the
suspension was added n-BuLi (0.39 mL, 1.6 M in hexanes,
0.63 mmol) and the mixture was stirred for 30 min, which gave
a bright orange colour. The solution was then cooled to ꢂ78 ꢁC
before the slow addition of a cooled solution of 31 (0.15 g,
0.25 mmol) in dry THF (2 mL). After 1 h H2O (3 mL) was added and
the mixture was allowed to warm to room temperature. The
aqueous layer was separated and extracted with Et2O (3ꢃ5 mL).
The combined organic extracts were washed with water (10 mL),
brine (10 mL) and dried (MgSO4). The solvent was removed in
vacuo and the crude mixture purified via flash column chroma-
tography (SiO2, Et2O/petrol 5:95) to furnish the product (136 mg,
92%) as a colourless oil; IR nmax (film)/cmꢂ1 3439, 2945, 1640, 1249;
1H NMR dH (400 MHz; CDCl3) 5.81 (1H, ddt, J 16.9, 10.4 and 6.4),
4.99 (1H, d, J 17.3), 4.92 (1H, d, J 10.1), 4.75 (1H, d, J 4.4), 4.39 (1H, dt,
J 10.4 and 3.5), 4.15e4.11 (2H, m), 2.77 (1H, br s), 2.15e2.14 (1H, m),
2.06e1.97 (3H, m), 1.67e1.66 (1H, m), 1.58e1.51 (8H, m), 1.42e1.16
(12H, m), 1.10e1.07 (18H, m), 1.03e0.99 (2H, m), 0.89 (3H, t, J 6.9),
ꢂ0.05 (9H, s); 13C NMR dC (100 MHz; CDCl3) 156.1,151.0,139.1,113.9,
98.4, 62.7, 60.8, 53.6, 45.6, 37.9, 37.1, 36.8, 34.4, 31.8, 29.1, 28.1, 27.1,
24.5, 22.7, 22.6, 18.1, 17.8, 14.1, 12.7, ꢂ1.5; MS m/z (ESI) 592.5 (MþHþ,
85%, MþNaþ, 614.4 100%), HRMS (ESI) for C34H66NO3Si2 requires
591.4576, found (MþHþ) 592.4573.
4.2.29. (ꢀ)-Cylindricine C. To a solution of 34 (0.06 g, 0.13 mmol) in
dry THF (5 mL) at 0 ꢁC was added TBAF (0.16 mL, 1 M in THF,
0.16 mmol) and the reaction mixture was stirred for 50 min at this
temperature before addition of water. The reaction mixture was
transferred into a separating funnel containing 6 M NaOH aqueous
solution (5 mL) and Et2O (5 mL). The mixture was shaken and layers
separated. The aqueous layer was extracted with Et2O (3ꢃ10 mL)
and the combined organic extracts dried (MgSO4), filtered and
concentrated under reduced pressure. The crude product was pu-
rified via flash column chromatography (SiO2, gradient of neat
petrol to 8.5:1.5 petrol/Et2O) to furnish (ꢀ)-cylindricine C (20 mg,
49%) and epi-(ꢀ)-cylindricine C (20 mg, 49%) as colourless oils.
(ꢀ)-Cylindricine C: 1H NMR dH (400 MHz; CDCl3) 3.54 (2H, m),
3.43 (1H, d J 9.8), 3.29 (1H, m), 2.89 (1H, br s), 2.33 (2H, m), 2.24
(2H, dd, J 13.2, 2.5), 2.12 (1H, dd, J 12.1, 8.0), 1.84 (1H, dd, J 12.6, 9.1),
1.71e1.61 (5H, m), 1.49 (1H, m), 1.42e1.26 (13H, m); 13C NMR dC
(100 MHz; CDCl3) 210.5, 70.7, 66.4, 56.5, 55.3, 50.3, 42.5, 36.4, 35.9,
35.2, 31.7, 29.3, 28.7, 27.1, 24.3, 22.7, 21.9, 14.0.
4.2.27. (2R,4aS,8aS)-8a-(But-3-enyl)-2-hexyloctahydroquinolin-4
(1H)-one (33). A solution of 32 (0.07 g, 0.12 mmol) in THF (2 mL)
was cooled to 0 ꢁC before adding TBAF (0.35 mL, 1 M in THF,
0.35 mmol). The solution was stirred at room temperature for
50 min, then H2O (2 mL) was added and the mixture was trans-
ferred to a separating funnel containing 6 M aqueous NaOH (3 mL)
and Et2O (3 mL). The mixture was shaken and the layers were
separated. The aqueous layer was extracted with Et2O (3ꢃ5 mL)
and the combined organic layers were dried (Na2SO4), filtered and
concentrated in vacuo to yield an oil. Flash column chromatography
(SiO2, EtOAc/CH2Cl2 5:95) afforded the product (35 mg, 99%) as
a colourless oil; 1H NMR dH (400 MHz; CDCl3) 5.88 (1H, ddt, J 17.0,
10.3 and 6.5), 5.07 (1H, dd, J 17.0 and 1.5), 4.99 (1H, dd, J 10.0 and
1.8), 3.13 (1H, ddd, J 11.8, 6.0 and 2.8), 2.38 (1H, dd, J 13.5 and 2.8),
2.26 (1H, m), 2.24e2.08 (2H, m), 1.97 (1H, t, J 12.4), 1.82 (1H, ddd, J
14.2, 11.5 and 5.4), 1.70 (1H, ddd, J 14.0, 11.5 and 5.3), 1.59 (2H, td, J
13.0 and 3.6), 1.51e1.36 (6H, m), 1.34e1.26 (10H, m), 0.88 (3H, t, J
6.9); 13C NMR dC (100 MHz; CDCl3) 210.9, 138.9, 114.7, 58.2, 53.7,
49.9, 48.8, 37.7, 37.6, 31.6, 29.3, 27.2, 25.6, 22.6, 22.5, 21.4, 14.1; MS
m/z (ESI) 292.26 (MþHþ, 100%), HRMS (ESI) for C19H34NO requires
292.2635, found (MþHþ) 292.2641.
Acknowledgements
We would like to thank the Rhodes Trust for funding this project
and Dr. Dale Johnson for performing some preliminary experi-
ments. We also thank the Oxford Chemical Crystallography Service
for use of their instrumentation. Akshat Rathi and Cedric Callens
are thanked for their assistance with X-Ray analysis.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.05.044.
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