A conjugate addition/dipolar-cycloaddition cascade sequence for the synthesis of (±)-cylindricine C

Article abstract of DOI:10.1016/j.tet.2010.03.088

An efficient stereocontrolled route to (±)-cylindricine C is described. Reaction of 9-hydroxynon-1-en-5-one oxime with 2,3-bis(phenylsulfonyl)-1,3-butadiene affords a 7-oxa-1-azanorbornane cycloadduct in high yield. The formation of the bicyclic isoxazolidine arises from conjugate addition of the oxime onto the diene to give a transient nitrone that spontaneously undergoes an intramolecular dipolar cycloaddition. The resulting cycloadduct derived from the cascade sequence was converted into (±)-cylindricine C by: (1) a reductive-cyclization to set the BC-ring skeleton, (2) a base-induced cyclization to construct the tricyclic core, and (3) an oxidation-conjugate addition of the n-hexyl side chain to complete the synthesis.

Full text of DOI:10.1016/j.tet.2010.03.088

Tetrahedron 66 (2010) 3643–3650
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A conjugate addition/dipolar-cycloaddition cascade sequence for the synthesis
of (ꢀ)-cylindricine C
Andrew C. Flick, Maria Jose Arevalo Caballero, Albert Padwa
*
´
Department of Chemistry, 1515 Dickey Drive, Emory University, Atlanta, GA 30322, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient stereocontrolled route to (ꢀ)-cylindricine C is described. Reaction of 9-hydroxynon-1-en-5-
one oxime with 2,3-bis(phenylsulfonyl)-1,3-butadiene affords a 7-oxa-1-azanorbornane cycloadduct in
high yield. The formation of the bicyclic isoxazolidine arises from conjugate addition of the oxime onto
the diene to give a transient nitrone that spontaneously undergoes an intramolecular dipolar cycload-
dition. The resulting cycloadduct derived from the cascade sequence was converted into (ꢀ)-cylindricine
C by: (1) a reductive-cyclization to set the BC-ring skeleton, (2) a base-induced cyclization to construct
the tricyclic core, and (3) an oxidation-conjugate addition of the n-hexyl side chain to complete the
synthesis.
Received 24 February 2010
Received in revised form 19 March 2010
Accepted 22 March 2010
Available online 27 March 2010
Keywords:
Alkaloid
Cylindricine C
2,3-Bis(phenylsulfonyl)-1,3-butadiene
Ó 2010 Elsevier Ltd. All rights reserved.
Oxime
Nitrone
Intramolecular dipolar cycloaddition
1. Introduction
Ciufolini and co-workers employed an oxidative spirocyclization of
a phenolic primary amine as the key step in their asymmetric
In the early 1990s, a novel family of 2,2-disubstituted piperidine
containing alkaloids were isolated by Blackman and co-workers
from the ascidian Clavelina cylindrica found off the eastern coast
of Tasmania.1 Members of this family possess either the pyrrolo or
pyrido[2,1-j]quinoline tricyclic framework.2 Among this class of
alkaloids, cylindricine C (1) represents an intriguing target.3
A structurally related alkaloid known as lepadiformine (2) was
obtained in 1994 from C. lepadiformis in the Mediterranean sea and
differs only in the cis/trans stereorelationship of the perhy-
droquinoline ring system and the functionality at C4 with cylin-
dricine C (1) (Fig. 1).4 These tricyclic marine alkaloids exhibit
a broad range of biological activity and consequently have attracted
an impressive array of synthetic efforts.5 Generally, the key
synthetic feature of the most common approaches toward cylin-
dricine C have revolved around the establishment of the sterically
congested C10-center. The most frequently implemented plan has
been the use of a double Michael addition of an amine to deliver
a critical bicyclic intermediate in one step from a dienone precursor.
This strategy has been independently used by the Molander,6
Heathcock,7 and Trost8 groups. The aza-tricyclic motif present in
cylindricine C has also been fabricated by Kibayashi9 and Hsung10
by making use of a N-acyliminium ion/diene cyclization. Finally,
synthesis of (ꢁ)-cylindricine C.11
A
5
4
10
O
B
2
C
N
13
N
HOCH2
HOCH2
C6H13
C6H13
2; lepadiformine
1; cylindricine C
Figure 1. Marine tricyclic alkaloid framework.
The essential element of our plan for the synthesis of cylin-
dricine C (1) is based on a conjugate addition/dipolar-cycloaddition
cascade strategy that we have been involved with for several years
and which readily affords 2,2-disubstituted 4-piperidin-ones of
type 6.12–15 In this cascade sequence, a bicyclic isoxazolidine 5 is
first formed by conjugate addition of an oxime with 2,3-bis(phe-
nylsulfonyl)-1,3-butadiene (3)13 to produce a transient nitrone 4
that then undergoes a further intramolecular 1,3-dipolar cycload-
dition onto the adjacent vinyl sulfone. Raney-Ni reduction of
the 7-oxa-1-azanorbornane cycloadduct 5 results in sequential
* Corresponding author. Tel.: þ1 404 727 0283; fax: þ1 404 727 6629; e-mail
address: chemap@emory.edu (A. Padwa).
nitrogen–oxygen bond cleavage followed by a subsequent
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.088

3644
A.C. Flick et al. / Tetrahedron 66 (2010) 3643–3650
desulfonylation to furnish the 2,2-disubstituted 4-piperidinone
(Scheme 1). This reaction sequence proved to be very effective for
the synthesis of several alkaloids and related nitrogen-containing
heterocyclic compounds.14,15 Thus, by using this protocol, we
have accomplished the total synthesis of yohimbenone14 as well as
2,7,8-epi-perhydrohistrionicotoxin.15 Since oximes possessing
functionalized substituent groups on the side chain are particularly
appealing substrates for the cascade sequence, we became
interested in making further use of this operation for the synthesis
of other alkaloidal skeletons. In this paper we demonstrate that the
conjugate addition/dipolar cycloaddition based methodology can be
used for a total synthesis of (ꢀ)-cylindricine C.12c
The required oxime 7 for the planned cascade was prepared by
treating -valerolactone with Me3Al and N,O-dimethylhydroxyl-
d
amine hydrochloride so as to install the Weinreb amide 11. The
hydroxyl group present in 11 was silylated with TIPS triflate to give
12 prior to treatment with 3-butenylmagnesium bromide. The
resulting ketone 13 was then converted to the corresponding oxime
7 by condensation with hydroxylamine hydrochloride (Scheme 3).
This four-step sequence proceeded in 62% overall yield from
d-valerolactone and could be used to produce gram quantities of
oxime 7 without the need for chromatographic purification.
OMe
N
O
O
MeNHOMe
Me3Al
Me
O
SO2Ph
-
RO
O
SO2Ph
H
R1
N
+
OH
R1
11; R = H; 92%
12; R = TIPS; 86%
N
+
SO2Ph
TIPSOTf
pyridine
R2
SO2Ph
R2
4
3
3-butenyl
MgBr
NOH
O
O
O
N
SO2Ph
TIPSO
H
TIPSO
Ra(Ni)
NH2OH-HCl
R1
R2
R1
SO2Ph
7; 80%
13; 98%
N
H
R2
5
Scheme 3.
6
Scheme 1.
Heating a sample of oxime 7 and bis(phenylsulfonyl)diene 3 in
CHCl3 at 90 ꢂC in a sealed tube for 12 h afforded the expected
cycloadduct 14 as a 1:1-mixture of diastereomers in 75% yield.
N,O-reduction of the aza-oxanorbornane adduct could be readily
accomplished by using 5% Na/Hg in a 2:1-mixture of THF/ethanol
mixture, which furnished 4-piperidinone 15 (65%). Removal of the
remaining phenylsulfonyl group in 15 was carried out using the
radical reduction conditions developed by Smith and Hale16 to give
the desired 2,2-disubstituted piperidinone 16 in 80% yield
(Scheme 4). With piperidinone 16 in hand, our next task was to
2. Results and discussion
The cylindricine C core was envisioned to evolve from the easily
accessible 4-piperidonyl B-ring precursor 9, which bears two dis-
tinguishable tethered groups at the congested C2 stereogenic center
(Scheme 2). 2,3-Bis(phenylsulfonyl)diene 3 and oxime 7 (R¼TIPS)
were considered as the two building blocks for the construction of
cycloadduct 8. Challenges to overcome in this approach would
include the construction of the remaining A- and C-rings around
the 4-piperidone periphery. There would also be the need to
leverage potential epimerization at the C5 and C13 stereocenters
within the azatricyclic core to geometries that would adopt the
energetically preferred arrangement relative to the central tetra-
substituted C10 carbon prior to the late-stage n-hexyl group
installation at the C2 position.
install the A-ring and then epoxidize the tethered p-bond in order
to induce a 5-exo trig cyclization so as to generate the core azade-
calin ring system of cylindricine C. We chose to accomplish this goal
by first converting 16 to aldehyde 19 and then subjecting it to acidic
conditions in order to induce an intramolecular aldol condensation
to produce enone 20.17 Reaction of 16 with methyl chloroformate
gave the corresponding carbamate 17 in 90% yield. Removal of the
O
O
-
SO2Ph
H
O
SO2Ph
SO2Ph
HO
NOH
+
O
5 H
10
N
+
SO2Ph
N
P
9
2
TIPSO
O
N
H
LG
SO2Ph
TIPSO
TIPSO
N
13
H
H
C6H13
3
7
10
1; cylindricine C
O
O
N
SO2Ph
H
R
SO2Ph
O
N
OH
N
H
5% Na/Hg
SO2Ph
SO2Ph
N
H
TIPSO
SO2Ph
+
SO2Ph
3
RO
RO
14 (1:1 dr); 75%
15; R = SO2Ph; 65%
16; R = H; 80%
n-Bu3SnH
8; R = TIPS
7; R = TIPS
AIBN
Scheme 2.
Scheme 4.

A.C. Flick et al. / Tetrahedron 66 (2010) 3643–3650
3645
silyl group in 17 with TBAF afforded alcohol 18 (95%) that could be
readily oxidized using Dess–Martin periodinane to furnish alde-
hyde 19 (80%). Next, the intramolecular aldol condensation-
dehydration of 19 was easily achieved using p-toluenesulfonic
acid in benzene at 50 ꢂC resulting in a 80% yield of the target
bicyclic enone 20 (Scheme 5). Heating enone 20 in the presence of
zinc dust and acetic acid gave the cis-fused azadecalone 21 as the
exclusive product and whose spectral properties were identical
with those reported by Heathcock.7 The cis-fusion selectivity can be
attributed to the protonation step, which occurs from the least
hindered face of the bicyclic system under the reducing condi-
tions.18 Preliminary attempts were made to epoxidize both 16 and
21 using a variety of oxidants (i.e., H2O2, mCPBA, trifluoroperacetic
acid, and vanadium oxidants). However, on all occasions we failed
to produce the desired epoxides, typically resulting in a return of
starting material with a 30–40% loss to decomposition. Our efforts
to remove the carbamate group from 21 also proved to be
extremely difficult, as the exceedingly hindered nitrogen atom was
surprisingly challenging to deprotect. Thus, carbamate 21 was
treated exhaustively under basic hydrolysis conditions, acidic
removal conditions, and nucleophilic cleavage conditions such as
the use of LiI/collidine or mercaptan anion/HMPA. All attempts to
remove the protecting carbamate group failed, resulting in recovery
of the starting material.
reducing agents, it was found that treating a sample of 22 with
excess zinc dust in an aqueous ammonium chloride/THF mixture21
at 70 ꢂC resulted in clean N–O bond reduction and this was
followed by the spontaneous ejection of phenylsulfenic acid to
furnish 4-piperidinone 23 as a transient intermediate. Attack of the
basic nitrogen atom of the 4-piperidinone onto the epoxide ring
proceeded rapidly and established the indolizidine ring system.22
This was followed by a further reduction of the remaining
phenylsulfonyl group in 24 to give 25 in 76% overall yield as
a 9:1-mixture of diastereomers (Scheme 6). The major isomer
coincides with the hydroxymethylene geometry at the C13 position
of the cylindricine C motif. Esterification of alcohol 25 with benzoyl
chloride gave the corresponding ester 26 and this allowed for the
ready separation of the two diastereomers by column
chromatography.
O
SO2Ph
H
O
N
H
H
Zn
aq. NH4Cl
O
H
O
SO2Ph
N
H
SO2Ph
TIPSO
TIPSO
22
23
OTIPS
O
OTIPS
O
HO
RO
Zn
O
N
O
76%
ClCO2CH3
NaHCO3
N
N
13
SO2Ph
24
N
H
BzCl
Et3N
RO
25; R = H
TIPSO
26; R = Bz
O
OCH3
16
Scheme 6.
17; R = TIPS; 90%
18; R = H; 96%
TBAF
The next challenge was to fashion the core azadecalin ring
system 30 by means of an intramolecular enolate alkylation
reaction.23 With this in mind, the desilylation of 26 was first carried
out using TBAF and this was followed by tosylation of the resulting
primary alcohol 27 to give the expected tosylate 28 in 76% overall
yield. Eventually, we determined the most effective method for the
formation of the desired tricyclic azadecalin involved treating
tosylate 28 with 2 equiv of t-BuOK in benzene followed by an
aqueous workup, which afforded 30 in 69% yield (Scheme 7). We
Dess-Martin
O
O
O
H
O
p-TsOH
Zn
AcOH
N
N
N
O
O
OCH3
OCH3
O
OCH3
H
20; 80%
21; 65%
19; 80%
Scheme 5.
OR
O
OTIPS
O
BzO
TsCl
BzO
Because of the failure in both the epoxidation and deprotection
steps using piperidinone 21, we looked to an alternate method for
generating the required pyrido[2,1-j]quinoline tricyclic framework
of cylindricine C. In a series of papers, Stack and co-workers showed
that terminal olefins can be rapidly and efficiently epoxidized using
manganese phenanthroline with commercially available peracetic
acid in CH3CN at room temperature.19 Using the Stack conditions,
we found that the alkenyl group present in cycloadduct 14 could
be successfully epoxidized producing epoxide 22 as a single
diastereomer in 26% isolated yield.20 Epoxidation of 14 proceeded
with high exo- selectivity, and this is probably a result of different
steric interactions in the transition state with the MnII complex for
the two different diastereomers. In addition, complexation of the
manganese catalyst with the N–O bond of the aza-oxanorbornane
might also help to direct the facial selectivity of the epoxidation
reaction.
TBAF
N
N
26
27; R = H; 77%
28; R = Ts; 98%
t-BuOK
C6H6
BzO
BzO
base
O
H
O
N
N
H
H
H
30; 69%
Having synthesized the desired mono-substituted epoxide 22,
we were in a position to examine the planned reductive cyclization
29
reaction. After extensive experimentation using
a
variety of
Scheme 7.

3646
A.C. Flick et al. / Tetrahedron 66 (2010) 3643–3650
were pleased to find that the reaction had proceeded with excellent
stereoselectivity. This positive result can be explained by assuming
that the cyclization reaction proceeds directly to 30 or else occurs
by first forming trans-1-azadecalin 29, which then readily epi-
merizes to the thermodynamically more stable isomer 304,9b,10
possessing the stereochemistry required for the structure of
cylindricine C.24
derived from the cascade cycloaddition was converted into cylin-
dricine C by: (1) a reductive-cyclization to set the BC-ringskeleton, (2)
a base-induced cyclization to construct the tricyclic core, and (3) an
oxidation-conjugate addition of the n-hexyl side chain. The applica-
bility of the new methodology to other alkaloidal targets is currently
under study and further results will be reported in due course.
To complete the total synthesis of (ꢀ)-cylindricine C (1), oxi-
dation of 30 to the corresponding 2H-piperidonyl enone had to be
affected in order to introduce the n-hexyl side chain. A variety of
standard oxidizing agents such as IBX, CAN, and PhSeCl/NaIO4 were
examined but all failed to produce the dihydropyridinone required
for the subsequent conjugate addition step. We did have some
limited success with the oxidation of 30 when Polonovski condi-
tions were utilized (i.e., mCPBA, trifluoroacetic anhydride, and Et3N
in CH2Cl2) but the yield of 31 was never greater than 35%. The
earlier success of mercuric acetate oxidation of piperidines by
Leonard and co-workers25 led us to test the utility of this oxidizing
agent with lactam 30. We were pleased to find that when a sample
of 30 was treated with Hg(OAc)2 in the presence of EDTA,26 dihy-
dropyridinone 31 was obtained in 95% yield. The next challenge
was the conjugate addition of n-hexyl cuprate to the vinylogous
amide structure 31. Comins and co-workers had previously dem-
onstrated that the use of a Grignard reagent in the presence of
BF3$OEt2 and CuBr$Me2S provides for stereoselective attack of the
incoming alkyl group onto N-acyl vinylogous amides.27 Indeed, we
found that the organocopper addition could be successfully carried
out using n-hexylmagnesium bromide under the Comins condi-
tions. The stereochemistry of the n-hexyl side chain addition was
controlled by the tricyclic topography of 31, which facilitates
a pseudo-equatorial approach of the organometallic reagent. Thus,
conjugate addition of the n-hexyl cuprate reagent to 31 followed by
alkaline saponification28 furnished a 7:1-mixture of (ꢀ)-cylin-
dricine C (1) and (ꢀ)-2-epi-cylindricine C (32) in 94% yield
(Scheme 8).
4. Experimental
4.1. General
Melting points are uncorrected. Mass spectra were determined
at an ionizing voltage of 70 eV. Unless otherwise noted, all reactions
were performed in flame dried glassware under an atmosphere of
dry nitrogen. Solutions were evaporated under reduced pressure
with a rotary evaporator and the residue was chromatographed on
a silica gel column using an ethyl acetate/hexane mixture as the
eluent unless specified otherwise.
4.1.1. 9-Triisopropylsilanyloxy-non-1-en-5-oneoxime(7). To a stirred
solution containing 2.2 g (22.5 mmol) of N,O-dimethylhydroxyl-
amine hydrochloride in dry CH2Cl2 (5 mL) at 0 ꢂC was added
dropwise 11.2 mL (22.5 mmol, 2.0 M in hexane) of AlMe3. The
mixture was stirred for 20 min at 0 ꢂC and 1.4 mL (1.5 mmol) of
D
-valerolactone was added dropwise. After stirring at 0 ꢂC for
20 min, the mixture was diluted with 25 mL of CHCl3 and then 3 mL
of a 0.1 N HCl solution was added dropwise at 0 ꢂC. The mixture was
stirred for 1 h, dried over anhydrous MgSO4, filtered, and concen-
trated under reduced pressure to give 2.2 g (92%) of 5-hydroxy-
N,O-dimethylpentanohydroxamic acid (11) as a whiteꢁs1olid;29 mp
61–63 ꢂC; IR (CH2Cl2) 3440, 1640, 1072, and 1003 cm
;
1H NMR
(600 MHz, CDCl3)
(s, 1H), 3.63 (t, 2H, J¼6.6 Hz), and 3.67 (s, 3H).
d 1.60 (m, 2H), 1.72 (m, 2H), 2.46 (br s, 2H), 3.17
To a stirred solution containing 0.9 g (5.5 mmol) of the above
alcohol 11 and 1.4 mL (12 mmol) of 2,6-lutidine in 10 mL of dry
CH2Cl2 at 0 ꢂC was added 1.7 mL (6 mmol) of triisopropylsilyltri-
fluoromethanesulfonate. The mixture was allowed to warm to rt,
stirred for 24 h, and was then quenched with 1 mL of a 0.005 N HCl
solution. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2. The combined organic extracts were
washed with water and brine, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography to give 1.5 g (86%) of
BzO
BzO
O
Hg(OAc)2
EDTA
O
N
N
H
H
H
H
5-triisopropylsilanyloxy-N,O-dimethylpentanohydroxamic
(12) as a pale oil; IR (neat) 1674, 1463, 1415, 1383, 1105, 999, 883,
and 681 cmꢁ1; 1H NMR (400 MHz, CDCl3)
1.03–1.06 (m, 21H), 1.58
acid
30
31; 95%
1. C6H13MgBr
CuBr-DMS
d
2. 1% NaOH
MeOH
(m, 2H), 1.70 (m, 2H), 2.44 (br s, 2H), 3.16 (s, 3H), 3.66 (s, 3H), and
BF3 OEt2
.
3.69 (t, 2H, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 12.2, 18.2, 21.4,
31.9, 32.9, 61.4, 63.3, and 97.9; HRMS calcd for [C16H35NO3SiþHþ]:
318.2464. Found 318.2460.
HO
To
a solution containing 3.4 g (10.6 mmol) of the above
C6H13
HO
O
hydroxamic acid 12 in 10 mL of THF at 0 ꢂC was added dropwise
20 mL (20.2 mmol, 1.0 M in THF) of a solution of 3-butenylmagne-
sium bromide. The mixture was stirred for 1 h at 0 ꢂC and was
allowed to warm to rt and was further stirred for an additional 1 h.
At the end of this time the solution was quenched with 3 mL of
a 0.1 N HCl solution and was then diluted with ether. The organic
layer was separated and the aqueous layer was further extracted
with ether. The combined organic extracts were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was subjected to flash silica gel chromatography
to give 3.3 g (98%) of the corresponding ketone 13 as a pale yellow
O
+
N
N
H
H
C6H13
H
H
1; cylindricine C
32; 2-epi-cylindricine C
82%
12%
Scheme 8.
3. Conclusion
oil; IR (neat) 1716, 1674, 1463, 1105, 996, 882, and 680 cmꢁ1
;
1H
In summary, the total synthesis of (ꢀ)-cylindricine C (1) starting
from 9-hydroxynon-1-en-5-one oxime (7) and bis(phenylsulfo-
nyl)diene 3 has been accomplished. The resulting cycloadduct 14
NMR (400 MHz, CDCl3)
d
1.02–1.20 (m, 21H), 2.29 (dd, 2H, J¼13.8
and 6.6 Hz), 2.42 (t, 2H, J¼7.2 Hz), 2.47 (t, 2H, J¼7.2 Hz), 3.66 (t, 2H,
J¼6.3 Hz), 4.94 (d, 1H, J¼10.2 Hz), 4.99 (d, 1H, J¼17.1 Hz), and 5.77

A.C. Flick et al. / Tetrahedron 66 (2010) 3643–3650
3647
(m, 1H); 13C NMR (100 MHz, CDCl3)
41.9, 42.9, 63.3, 115.4, 137.4, and 210.5; HRMS calcd for
[C18H36O2SiþHþ]: 313.2563. Found 313.2559.
d
12.2, 18.2, 20.6, 28.0, 32.6,
n-butyltin hydride in 50 mL of toluene at reflux was added 0.2 g
(1.3 mmol) of AIBN followed by the addition of a further 0.1 g
(0.8 mmol) of AIBN after heating for 5 min. The mixture was further
heated at reflux for an additional 2 h and the solvent was removed
under reduced pressure. The crude residue was purified by flash
silica gel to give 0.5 g (80%) of piperidone 16 as a pale yellow oil; IR
To a stirred solution containing 1.0 g (1.5 mmol) of hydroxyl-
amine hydrochloride and 2.4 g (3.0 mmol) of sodium acetate in
50 mL of water was added the above ketone 13 (1.0 g, 5 mmol). The
mixture was heated at reflux for 8 h, cooled to rt and extracted with
CH2Cl2. The organic extracts were washed with a saturated solution
of NaHCO3, NaCl, dried over anhydrous MgSO4, and concentrated
under reduced pressure. The residue was subjected to flash silica
gel chromatography to give 0.9 g (80%) of oxime 7 as a 1:1-mixture
of the syn and anti diastereomers; IR (neat) 1642, 1461, 1106, 996,
(neat) 1709, 1640, 1381, 1070, 883, and 658 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
d
0.91 (t, 1H, J¼6.4 Hz), 0.94–1.07 (m, 21H),
1.22–1.63 (m, 6H), 1.98 (m, 2H), 2.24 (s, 2H), 2.31 (t, 2H, J¼6.0 Hz),
3.10 (t, 2H, J¼6.0 Hz), 3.65 (t, 2H, J¼6.4 Hz), 4.92 (br d, 1H, J¼10 Hz),
4.99 (br d, 1H, J¼16.8 Hz), and 5.76 (m, 1H); 13C NMR (100 MHz,
CDCl3)
d 12.2, 18.2, 19.3, 27.5, 33.5, 35.9, 36.8, 40.8, 42.6, 52.9, 59.2,
and 680 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
0.98–1.15 (m, 21H), 1.57
63.1, 114.9, 138.4, and 210.2; HRMS calcd for [C22H43NO2SiþHþ]:
(m, 4H), 2.20 (t, 1H, J¼7.4 Hz), 2.27 (m, 3H), 2.36 (t, 1H, J¼7.7 Hz),
2.42 (t, 1H, J¼7.7 Hz), 3.68 (m, 2H), 4.97 (br d, 1H, J¼10 Hz), 5.04 (br
d, 1H, J¼18 Hz), 5.81 (m, 1H), and 8.87 (br s, 1H); 13C NMR
382.3141. Found: 382.3137.
4.1.5. 2-(3-Butenyl)-2-(4-tri-isopropylsilanyloxybutyl)-4-piperidone-
1-carboxylic acid methyl ester (17). To a solution containing 0.3 g
(0.8 mmol) of piperidone 16 and 0.1 g (1.6 mmol) of NaHCO3 in
CH3CN (8 mL) at 0 ꢂC was slowly added methyl chloroformate
(0.09 mL, 1.2 mmol). The mixture was allowed to warm to rt and
was stirred overnight. A saturated aqueous ammonium chloride
solution (10 mL) was added and the resulting mixture was extrac-
ted with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous MgSO4, and concentrated under reduced
pressure. The residue was subjected to flash silica gel column
chromatography to give 0.3 g (90%) of carbamate 17 as a colorless
(100 MHz, CDCl3)
d 12.2, 18.2, 22.2, 22.8, 27.1, 27.5, 29.8, 30.5, 32.7,
33.2, 33.5, 34.3, 63.1, 63.2, 115.2, 115.4, 137.7, 137.9, and 161.2; HRMS
calcd for [C18H37NO2SiþHþ]: 328.2672. Found: 328.2667.
4.1.2. 2-(3-Butenyl)-2-(4-tri-isopropylsilanyloxybutyl)-4,5-bis(phen-
ylsulfonyl)-7-oxa-1-azabicyclo[2.2.1]heptane (14). A solution con-
taining 2.5 g (7.2 mmol) of 2,3-bis(phenylsulfonyl)-1,3-butadiene
(3)13 and 1.5 g (6 mmol) of oxime 7 in 100 mL of CHCl3 was placed
in a Pyrex tube equipped with a stir bar. The tube was sealed and
the mixture was heated at 90 ꢂC for 12 h in a sandbath. The mixture
was cooled and the solvent was removed under reduced pressure.
The residue was purified by silica gel chromatography (15% EtOAc
in hexane) to give 3.5 g (75%) of a 1:1-diastereomeric mixture of
cycloadduct 14 as a pale yellow oil: IR (neat) 2942, 2864, 1447, 1331,
oil; IR (neat) 1727, 1697, 1381, 1102, 883, and 658 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) 0.98–1.08 (m, 21H), 1.27 (m, 2H), 1.45–1.72
d
(m, 4H), 1.96 (dd, 2H, J¼16.1 and 7.0 Hz), 2.14 (m, 2H), 2.43 (t, 2H,
J¼6.0 Hz), 2.59 (d, 1H, J¼15.6 Hz), 2.64 (d, 1H, J¼15.6 Hz), 3.64
(t, 2H, J¼6.4 Hz), 3.68 (s, 3H), 3.89 (m, 2H), 4.92 (br d, 1H, J¼10 Hz),
4.98 (br d, 1H, J¼17.2 Hz), and 5.73 (m, 1H); 13C NMR (100 MHz,
1153, 1100, 720, 686, and 614 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
0.92–1.10 (m, 42H), 1.91 (m, 6H), 1.92 (m, 8H), 2.99 (d, 2H,
J¼12.8 Hz), 3.53 (m, 1H), 3.63 (t, 4H, J¼12.4 Hz), 3.70 (m, 1H), 3.95
(dd, 2H, J¼12.8 and 5.6 Hz), 4.32 (ddd, 2H, J¼10.8, 5.2 and 2.2 Hz),
4.80 (br d, 2H, J¼10 Hz), 5.02 (br d, 2H, J¼16.4 Hz), 5.52 (m, 1H),
5.82 (m, 1H), 7.50 (t, 4H, J¼7.6 Hz), 7.78–7.60 (m, 12H), and 7.97
CDCl3) d 12.2, 18.2, 20.4, 28.5, 33.4, 38.9, 39.5, 39.7, 41.3, 48.7, 52.6,
61.4, 63.3, 115.1, 138.1, 155.7, and 210.2; HRMS calcd for
[C24H45NO4SiþHþ]: 440.3190. Found: 440.3188.
(d, 4H, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d
12.2, 18.2, 20.0, 21.2,
4.1.6. 2-(3-Butenyl)-2-(4-hydroxybutyl)-4-piperidone-1-carboxylic
acid methyl ester (18). To a solution containing 0.1 g (0.3 mmol) of
carbamate 17 in 5 mL of dry THF at 0 ꢂC was added 2 g of 4 Å
molecular sieves and 0.3 mL (0.3 mmol) of tetrabutylammonium
fluoride. The mixture was allowed to warm to room temperature,
stirred for 4 h, and then filtered through a pad of Celite. The solu-
tion was diluted with 10 mL of water and extracted with EtOAc. The
organic layer was washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue was
subjected to flash silica gel column chromatography to give 0.08 g
(95%) of alcohol 18 as a colorless oil; IR (neat) 1727, 1692, 1384,
27.8, 29.1, 30.4, 30.9, 33.4, 33.5, 37.2, 37.8, 53.3, 62.9, 63.2, 66.7, 75.0,
114.6, 115.5, 129.1, 129.5, 130.5, 134.5, 134.7, 134.9, 137.7, 138.1, and
139.4; Anal. Calcd for C34H51NO6S2Si: C, 61.69; H, 7.77; N, 2.12; S,
9.69. Found: C, 61.89; H, 7.51; N, 2.21; S, 9.54.
4.1.3. 2-(3-Butenyl)-2-(4-tri-isopropylsilanyloxybutyl)-5-phenyl-
sulfonyl-4-piperidone (15). A solution containing 2.0 g (3 mmol) of
cycloadduct 14 and 2.1 g (15.2 mmol) of sodium phosphate in
a 2:1-THF/EtOH mixture (21 mL total volume) at 0 ꢂC was charged
with 3.5 g (7.6 mmol) of 5% Na/Hg in two portions. The mixture was
stirred at this temperature for 5 h and was then filtered through
a pad of Celite. The solvent was removed under reduced pressure
and the residue was purified by silica gel chromatography to give
1.0 g (65%) of a 1:1-diastereomeric mixture of piperidone 15 as
a pale yellow oil; IR (neat) 1711, 1642, 1463, 1104, 883, and
1229, 998, 914, and 772 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 1.28
(m, 2H), 1.59 (m, 4H), 1.98 (m, 2H), 2.16 (m, 3H), 2.44 (t, 2H,
J¼6.4 Hz), 2.60 (d, 1H, J¼15.6 Hz), 2.65 (d, 1H, J¼15.6 Hz), 3.62
(t, 2H, J¼6.8 Hz), 3.69 (s, 3H), 3.90 (m, 2H), 4.93 (br d, 1H,
J¼10.4 Hz), 4.99 (m, 1H, J¼17 Hz), and 5.74 (m, 1H); 13C NMR
629 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
0.98–1.12 (m, 21H),
(100 MHz, CDCl3) d 20.1, 28.5, 32.7, 38.8, 39.1, 39.6, 41.4, 48.6, 53.0,
1.30–1.62 (m, 8H), 1.95–2.03 (m, 3H), 2.43 (d, 1H, J¼13.6 Hz), 2.77
(dd, 1H, J¼13.6 and 2.8 Hz), 3.30–3.35 (m, 1H), 3.65–3.67 (m, 2H),
3.71 (t, 1H, J¼6 Hz), 3.85 (dd, 1H, J¼4.0 and 1.3 Hz), 3.89 (dd, 1H,
J¼4.0 and 1.6 Hz), 4.95–5.10 (m, 2H), 5.85–5.95 (m, 1H), 7.57 (t, 2H,
J¼7.6 Hz), 7.60–7.68 (t, 1H, J¼7.2 Hz), and 7.84 (d, 2H, J¼7.6 Hz); 13C
61.4, 62.5, 115.2, 138.0, 155.8, and 210.1; HRMS calcd for
[C15H25NO4þHþ]: 284.1856. Found: 284.1856.
4.1.7. 2-(3-Butenyl)-2-(4-oxobutyl)-4-piperidone-1-carboxylic acid
methyl ester (19). To a solution containing 0.05 g (0.2 mmol) of
alcohol 18 in 2 mL of dry CH2Cl2 at 0 ꢂC was added Dess–Martin
periodinane reagent (0.09 g, 0.2 mmol) in one portion. The mixture
was allowed to warm to rt over 12 h, diluted with ether, and
washed with a saturated solution of sodium bisulfite and sodium
bicarbonate. The aqueous layer was extracted with ether and the
combined organic extracts were washed with brine, dried over
anhydrous MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography to give
NMR (100 MHz, CDCl3)
d 12.2, 18.2, 18.3, 19.3, 19.4, 27.3, 27.5, 33.4,
33.5, 33.7, 34.6, 38.6, 39.4, 42.1, 52.5, 52.6, 60.5, 63.1, 72.3, 114.9,
115.2, 128.6, 128.7, 129.6, 134.6, 137.8, 138.1, 138.3, 200.9, and 201.0;
HRMS calcd for [C28H47NO4SSiþHþ]: 522.3073. Found: 522.3064.
4.1.4. 2-(3-Butenyl)-2-(4-tri-isopropylsilanyloxybutyl)-4-piperidone
(16). To a solution containing 1.0 g (1.9 mmol) of the above phe-
nylsulfonyl substituted piperidone 15 and 2.1 mL (7.7 mmol) of tri-

3648
A.C. Flick et al. / Tetrahedron 66 (2010) 3643–3650
0.04 g (80%) of aldehyde 19 as a colorless oil; IR (neat) 2954, 1724,
1693, 1382, 1089, and 772 cmꢁ1 1H NMR (400 MHz, CDCl3)
3.6 Hz), 2.92–2.97 (m, 1H), 3.10 (d, 1H, J¼12.8 Hz), 3.52–3.55
(m, 2H), 3.61–3.69 (m, 2H), 3.97 (dt, 1H, J¼12.4 and 4.7 Hz),
4.29–4.37 (m, 1H), 7.52 (t, 2H, J¼7.6 Hz), 7.61–7.79 (m, 6H), and
;
d
1.49–1.73 (m, 4H), 1.97 (dd, 2H, J¼16 and 6.8 Hz), 2.15 (m, 2H),
2.44 (m, 4H), 2.65 (s, 2H), 3.69 (s, 3H), 3.90 (dt, 2H, J¼6.2 Hz), 4.93
(br d, 1H, J¼10.4 Hz), 4.99 (m, 1H, J¼16.8 Hz), 5.73 (m, 1H) and 9.73
7.97–8.00 (m, 2H); 13C NMR (CDCl3, 300 MHz)
d 7.8, 13.9, 15.3, 22.4,
23.0, 23.4, 24.0, 29.0, 33.6, 34.3, 42.7, 43.1, 47.5, 47.8, 49.0, 58.8, 62.3,
70.3, 99.9, 124.6, 124.7, 125.1, 125.2, 126.1, 130.1, 130.4, 130.6, and
135.0; HRMS calcd for [C34H51NO7S2SiþHþ]: 678.2949. Found:
678.2940.
(br s, 1H); 13C NMR (100 MHz, CDCl3)
d 16.6, 28.5, 38.6, 38.9, 39.6,
41.4, 43.9, 48.5, 52.7, 61.3,115.3,137.8,155.7, 201.9, and 209.8; HRMS
calcd for [C15H23NO4þHþ]: 282.1701. Found: 282.1699.
4.1.8. 8a-(3-Butenyl)-3,4,6,7,8a-hexahydro-2H-quinolin-4-one-1-
carboxylic acid methyl ester (20). To a solution containing 0.05 g
(0.2 mmol) of the above aldehyde 19 in 2 mL of benzene was added
0.03 g (0.2 mmol) of p-toluenesulfonic acid monohydrate and the
mixture was stirred at 50 ꢂC for 8 h. The solution was allowed to
cool to rt and was quenched with 15 mL of a saturated NaHCO3
solution. The aqueous phase was extracted with ether and the
combined organic extracts were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography to give 0.04 g (80%) of enone 20 as a colorless oil; IR (neat)
4.1.11. 3-Hydroxymethyl-8a-(4-tri-isopropylsilanyloxybutyl)-
hexahydroindolizin-7-one (25). To a round bottom flask charged
with 2.4 g (3.5 mmol) of epoxide 22 in 220 mL of a saturated NH4Cl/
H2O/THF (1:1:1) solution was added 11.6 g (177 mmol) of zinc dust.
The reaction mixture was vigorously stirred and then heated to
70 ꢂC for 12 h, cooled to rt, and filtered through a pad of Celite. The
filtered solid was washed with an aqueous NaHCO3 solution and
the filtrate was collected, and extracted with ether. The combined
organic layer was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. Purification of the residue by
silica gel chromatography provided 1.07 g (68%) of the major
diastereomer of 25 as a pale yellow oil: IR (CH2Cl2) 3454, 2940,
1694, 1623, 1386, 1252, 1093, and 771 cmꢁ1
;
1H NMR (400 MHz,
CDCl3) 1.61–1.82 (m, 5H), 1.97 (m, 1H), 2.28 (m, 2H), 2.36 (t, 1H,
d
2864, 1701, 1459, and 1104 cmꢁ1
;
1H NMR (CDCl3, 600 MHz)
J¼2.4 Hz), 2.41 (t, 1H, J¼2.4 Hz), 2.60 (m, 2H), 3.11 (dt, 1H, J¼13.6
and 2.4 Hz), 3.70 (s, 3H), 4.35 (br d, 1H, J¼12.8 Hz), 4.90 (br d, 1H,
J¼10.4 Hz), 4.95 (br d, 1H, J¼17.2 Hz), 5.70 (m, 1H), and 6.62 (t, 1H,
d 1.03–1.05 (m, 21H),1.34–1.39 (m, 4H),1.49–1.52 (m, 4H),1.83–1.91
(m, 2H), 2.04–2.08 (m, 2H), 2.20 (dd, 1H, J¼13.6 and 2.1 Hz), 2.34
(d, 1H, J¼13.6 Hz), 2.50–2.54 (m, 1H), 3.05–3.10 (m, 1H), 3.21 (ddd,
1H, J¼14.4, 6.6, and 1.7 Hz), 3.34 (d, 1H, J¼9.0 Hz), 3.44 (dd, 1H,
J¼10.8 and 1.8 Hz), and 3.64–3.69 (m, 3H); 13C NMR (CDCl3,
J¼4.0 Hz); 13C NMR (100 MHz, CDCl3)
d 18.2, 24.8, 28.9, 31.1, 38.9,
39.8, 39.9, 52.6, 60.4, 115.1, 138.2, 138.4, 141.6, 157.9, and 193.2;
HRMS calcd for [C15H21NO3þHþ]: 264.1594. Found: 264.1595.
300 MHz) d 7.8, 13.9, 15.9, 20.4, 29.1, 31.2, 31.9, 33.1, 38.4, 43.5, 55.7,
58.2, 58.9, 64.8, and 205.8; HRMS calcd for [C22H43NO3SiþHþ]:
4.1.9. cis-8a-(3-Butenyl)octahydro-4-quinolin-4-one-1-carboxylic
acid methyl ester (21). To a solution containing 0.05 g (0.2 mmol) of
enone 20 in 4 mL of acetic acid was added 0.2 g of zinc dust and the
mixture was stirred overnight at 120 ꢂC. Water was added and the
mixture was extracted with CH2Cl2. The organic extracts were
washed with water, an aqueous solution of NaHCO3 and brine. The
organic layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure to give 0.03 g (65%) of the cis-fused deca-
lone 21 as a colorless oil: IR (CH2Cl2) 2940, 2864, 1686, 1448, and
398.3046. Found: 398.3085.
The minor diastereomer (9%) could not be fully separated from
the major diastereomer but showed characteristic 1H NMR peaks at
d
1.03–1.05 (m, 21H),1.34–1.39 (m, 4H),1.49–1.52 (m, 2H),1.83–1.91
(m, 2H), 2.04–2.08 (m, 1H), 2.20–2.30 (m, 2H), 2.45–2.58 (m, 2H),
2.62 (t, 1H, J¼9.6 Hz), 2.67 (dd, 1H, J¼13.6 and 2.1 Hz), 2.83 (dt, 1H,
J¼9.6 and 3.6 Hz), 2.88–2.96 (m, 1H), 3.05–3.10 (m, 1H), 3.43–3.46
(m, 1H), and 3.64–3.69 (m, 3H); 13C NMR (CDCl3, 300 MHz)
d 12.2,
18.2, 21.4, 26.4, 27.5, 33.8, 34.6, 40.3, 52.1, 59.6, 61.5, 63.1, 66.4, and
210.3.
883 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 1.38–1.57 (m, 6H), 2.05
(m, 3H), 2.15 (m, 1H), 2.36 (m, 1H), 2.45 (m, 2H), 2.58 (m, 1H), 2.89
(br s,1H), 3.48 (dt,1H, J¼13.6 Hz), 3.70 (s, 3H), 4.40 (ddd,1H, J¼14.2,
5.2, and 3.6 Hz), 4.96 (br d,1H, J¼10.4 Hz), 5.04 (br d,1H, J¼17.2 Hz),
4.1.12. Benzoic acid 7-oxo-8a-(4-tri-isopropylsilanyloxybutyl)octa-
hydroindolizin-3-yl methyl ester (26). To a round bottom flask
charged with 1.0 g (2.4 mmol) of the above alcohol 25 in 24.4 mL of
CH2Cl2 was added 0.7 mL (4.9 mmol) of Et3N, 0.4 mL (2.9 mmol) of
benzoyl chloride, and a catalytic amount of DMAP, sequentially. The
reaction mixture was stirred at rt for 2 h, and was then partitioned
between CH2Cl2 and aqueous NaHCO3. The organic layer was
extracted with ether, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. Purification of the residue by
silica gel chromatography provided 1.2 g (97%) of the titled com-
pound as a pale yellow oil: IR (CH2Cl2) 2942, 2856, 1722, 1269, 1108,
and 5.80 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 21.3, 22.1, 22.2, 28.1,
30.0, 33.0, 35.7, 39.7, 40.8, 49.9, 52.5, 61.6, 115.1, 138.3, and 210.8.
The spectral data for this compound is identical to that reported in
the literature.8
4.1.10. 4,5-Bis-benzenesulfonyl-2-(2-oxiranylethyl)-2-(4-tri-iso-
propylsilanyloxybutyl)-7-oxa-1-aza-bicyclo[2.2.1]heptane (22). To
a round bottom flask charged with 11.0 g (16.6 mmol) of cyclo-
adduct 14 in 80 mL of MeCN/AcOH (97:3) at ꢁ15 ꢂC was slowly
added 16.6 mL (0.4 mmol) of a 2.5 M solution of manganese phe-
nanthroline in MeCN/AcOH (97:3). To this mixture was added
5.9 mL (25 mmol) of a 32 wt % solution of aqueous peracetic acid
over the course of 20 min. The solution was allowed to stir for
10 min while being warmed to 0 ꢂC. The reaction mixture was then
transferred to a separatory funnel and was partitioned between
aqueous NaHCO3 and ethyl acetate. The organic layer was washed
twice with water, once with brine, dried over Na2SO4, and
concentrated under reduced pressure. Purification of the residue by
silica gel column chromatography provided 3.0 g (26%) of the titled
compound as a pale yellow oil that consisted primarily of a single
diastereomer: IR (CH2Cl2) 2943, 2865, 1329, 1153, 1100, and
and 712 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 1.03–1.06 (m, 21H),
1.25–1.35 (m, 4H), 1.41–1.55 (m, 4H), 1.76–1.83 (m, 1H), 1.90–1.98
(m, 1H), 2.04–2.10 (m, 1H), 2.12–2.18 (m, 1H), 2.19 (dd, 1H, J¼13.6
and 2.1 Hz), 2.33 (d, 1H, J¼13.6 Hz), 2.51–2.60 (m, 1H), 3.07–3.15
(m, 1H), 3.41 (ddd, 1H, J¼14.4, 6.4, and 1.9 Hz), 3.52–3.56 (m, 1H),
3.59 (t, 2H, J¼6.8 Hz), 4.24–4.33 (m, 2H), 7.44 (t, 2H, J¼7.6 Hz), 7.56
(t, 1H, J¼7.4 Hz), and 8.03 (dd, 2H, J¼7.4 and 1.4 Hz); 13C NMR
(CDCl3, 300 MHz)
d 12.2, 18.2, 20.1, 25.5, 33.5, 34.9, 36.7, 37.3, 44.3,
48.2, 58.5, 63.3, 68.1, 69.2, 128.6, 129.8, 133.2, 166.8, and 210.7;
HRMS calcd for [C29H47NO4SiþHþ]: 502.3347. Found: 502.3342.
4.1.13. Benzoic acid 7-oxo-decahydropyrrolo[2,1-j]quinolin-3-yl methyl
ester (30). An oven-dried round bottom flask was charged with
0.96 g (1.92 mmol) of the starting silyl ether 26, 4 Å molecular sieves
and 19 mL of anhydrous THF and the mixture was cooled to 0 ꢂC
603 cmꢁ1
; d 1.03–1.06 (m, 21H),
1H NMR (CDCl3, 400 MHz)
1.20–1.30 (m, 4H), 1.46–1.56 (m, 3H), 1.89 (dq, 1H, J¼6.3 and 2.2 Hz),
2.00–2.05 (m, 2H), 2.51 (q, 1H, J¼2.4 Hz), 2.78 (dd, 1H, J¼5.2 and

A.C. Flick et al. / Tetrahedron 66 (2010) 3643–3650
3649
under an argon atmosphere. To this mixture was added 2.3 mL
(2.3 mmol) of a 1.0 M solution of TBAF in THF over the course of
30 min. The solution was allowed to stir for an additional 1.5 h while
being warmed to rt. The reaction mixture was filtered through a pad
of Celite and the collected solid was rinsed with ether. The filtrate
was then partitioned between ether and aqueous NaHCO3 and the
organic layer was extracted, washed with brine, dried with Na2SO4,
and concentrated under reduced pressure. Purification of the residue
by silica gel chromatography provided 0.51 g (77%) of alcohol 27 as
the solution was partitioned between aqueous NH4Cl and CH2Cl2.
The organic layer was extracted with ether, washed with brine,
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure to provide 4.7 mg (95%) of 31 as a pale yellow oil: IR (CH2Cl2)
2926, 2854, 1721, 1633, 1579, 1269, 1211, and 1111 cmꢁ1
;
1H NMR
(CDCl3, 600 MHz)
d 1.25–1.34 (m, 4H), 1.45–1.48 (m, 1H), 1.65–1.71
(m, 1H), 1.76–1.82, (m, 1H), 1.88–1.96 (m, 1H), 2.03–2.07 (m, 1H),
2.27 (p, 1H, J¼6.9 Hz), 2.43 (dd, 1H, J¼12.3 and 6.9 Hz), 2.50 (br s,
1H), 2.53 (br s, 1H), 4.09 (br t, 1H, J¼13.5 Hz), 4.31 (dd, 1H, J¼12.0
and 6.0 Hz), 4.55 (dd, 1H, J¼12.0 and 4.6 Hz), 4.95 (d, 1H, J¼7.2 Hz),
7.22 (d,1H, J¼7.2 Hz), 7.47 (t, 2H, J¼7.6 Hz), 7.60 (t,1H, J¼7.4 Hz) and
a colorless oil: IR (CH2Cl2) 3361, 2918,1717,1271,1146, and 713 cmꢁ1
1H NMR (CDCl3, 400 MHz)
1.22–1.29 (m, 4H), 1.38–1.54 (m, 4H),
;
d
1.78–1.83 (m, 2H), 1.89–1.96 (m, 1H), 2.04–2.06 (m, 1H), 2.10–2.14
(m, 1H), 2.16 (d, 1H, J¼7.6 Hz), 2.32 (d, 1H, J¼9.2 Hz), 2.50–2.57
(m, 1H), 3.05–3.12 (m, 1H), 3.39 (ddd, 1H, J¼9.4, 4.2, and 0.8 Hz),
3.49–3.54 (m, 1H), 4.23 (dd, 1H, J¼7.4 and 3.0 Hz), 4.35 (dd, 1H, J¼7.4
and 3.8 Hz), 7.4 (t, 2H, J¼7.6 Hz), 7.55 (dt, 1H, J¼7.4 and 0.4 Hz) and
8.03 (d, 2H, J¼7.4 Hz); 13C NMR (CDCl3, 300 MHz)
d 22.1, 22.9, 24.6,
27.4, 27.8, 30.3, 35.6, 51.1, 60.0, 66.8, 97.6, 129.2, 130.0, 130.2, 134.0,
147.1, 166.7, and 193.6; HRMS calcd for [C20H23NO3þHþ]: 326.1750.
Found: 326.1750.
8.01 (dd, 2H, J¼7.4 and 1.4 Hz); 13C NMR (CDCl3, 300 MHz)
d
20.7,
4.1.15. (ꢀ)-Cylindricine C (1). An oven-dried round bottom flask
was charged with 11 mg (53 mmol) of copper bromide-dimethyl
sulfide and 0.3 mL of dry THF. The flask was degassed with argon
and immersed in an ice bath. To the resulting slurry was added
dropwise 0.3 mL (18.4 mmol) of a 37.0 M solution of 31 in dry THF
over the course of 30 min at 0 ꢂC. The reaction mixture was cooled
to ꢁ78 ꢂC and 8.2 mL (65 mmol) of BF3$OEt2 was added dropwise
over the course of 10 min. To this reaction mixture was added
dropwise 28.7 mL (53 mmol) of a 1.86 M solution of n-hexyl-
magnesium bromide in ether over the course of 30 min at ꢁ78 ꢂC.
The reaction mixture was allowed to stir for an additional 90 min at
ꢁ78 ꢂC and was then warmed to rt and partitioned between ether
and aqueous NH4Cl. The organic layer was extracted with ether,
washed with water, brine, dried with Na2SO4, and concentrated
under reduced pressure. The crude residue was purified by flash
silica chromatography. The major fraction was immediately added
to 5 mL of a 1% NaOH in methanol solution. The mixture was stirred
at rt for 2 h and then concentrated under reduced pressure. The
residue was partitioned between CH2Cl2 and 1 N NaOH. The organic
layer was extracted with ether, washed with water, brine, dried
over Na2SO4, and concentrated under reduced pressure to give
4.1 mg (82%) of (ꢀ)-cylindricine C (1) as a colorless oil that
exhibited spectroscopic data identical to that described in the
literature:10 IR (CH2Cl2) 2926, 2854, 1724, 1633, 1462, 1024, and
26.0, 33.8, 35.6, 37.4, 37.8, 45.0, 48.9, 59.3, 63.5, 68.5, 69.9, 129.3,
130.4,131.1, 133.9,167.4, and 211.5; HRMS calcd for [C20H27NO4þHþ]:
346.2019. Found: 346.2007.
To a round bottom flask charged with 42 mg (0.12 mmol) of
alcohol 27 was added 1.2 mL of CH2Cl2 and 0.025 mL (0.27 mmol)
of pyridine, sequentially. The reaction mixture was cooled to 0 ꢂC
prior to the addition of 49 mg (0.26 mmol) of p-tosyl chloride.
The solution was allowed to stir for 1 h while being warmed to rt.
The reaction mixture was then partitioned between CH2Cl2 and
aqueous NaHCO3. The organic layer was extracted with ether,
washed with water, brine, dried over Na2SO4, and concentrated
under reduced pressure. The crude residue was purified by flash
silica chromatography to give 60 mg (98%) of the reactive tosy-
late 28 as a pale yellow oil that was taken up in 4 mL of dry
benzene and immediately subjected to the following reaction
conditions.
An oven-dried round bottom flask equipped with a stir bar and
4 Å molecular sieves was degassed with argon. To this flask was
added 2 mL of dry benzene and 0.25 mL (0.25 mmol) of a 1.0 M
solution of potassium tert-butoxide in THF. The mixture was
cooled to 0 ꢂC and 4 mL (0.12 mmol) of a 0.03 M solution of
tosylate 28 in benzene was added dropwise over the course of
30 min. After stirring for an additional 30 min, the reaction
mixture was warmed to rt and was stirred for an additional 1 h
and then filtered through a pad of Celite. The filtrate was
concentrated under reduced pressure and then partitioned
between ethyl acetate and aqueous NaHCO3. The organic layer was
extracted with ether and washed with brine, dried over Na2SO4,
and then concentrated under reduced pressure. Purification of the
residue by silica gel chromatography provided 27 mg (69%) of the
titled compound 30 as a pale yellow oil: IR (CH2Cl2) 2923, 1717,
804 cmꢁ1
;
1H NMR (CDCl3, 600 MHz)
d
0.88 (t, 3H, J¼7.0 Hz),
1.22–1.65 (m, 19H), 1.83 (dd, 1H, J¼13.0 and 8.5 Hz), 2.13 (dd, 1H,
J¼12.5 and 8.0 Hz), 2.23 (dd, 2H, J¼13.0 and 3.0 Hz), 2.30 (t, 2H,
J¼11.4 Hz), 2.88 (br s, 1H), 3.26–3.32 (m, 1H), 3.43 (t, 1H, J¼9.3 Hz),
and 3.54 (m, 2H); 13C NMR (CDCl3, 300 MHz)
d 14.6, 22.4, 23.1, 23.3,
24.9, 27.7, 29.3, 30.3, 32.2, 35.8, 36.5, 37.0, 43.1, 50.8, 55.9, 57.1, 58.1,
71.3, and 197.0; HRMS calcd for [C19H33NO2þHþ]: 308.2584. Found:
308.2578.
The minor diastereomer (12%) could not be fully separated
from the major diastereomer but exhibited spectroscopic data
identical to 2-epi-(ꢀ)-cylindricine C (32) as reported in the
literature:10 IR (CH2Cl2) 2926, 2854, 1724, 1633, 1462, 1024, and
1459, 1271, and 1104 cmꢁ1
;
1H NMR (CDCl3, 600 MHz)
d
1.25–1.51
(m, 8H), 1.67 (d, 1H, J¼10.4 Hz), 1.74–1.84 (m, 2H), 2.07–2.10
(m, 1H), 2.14–2.18 (m, 2H), 2.23–2.26 (m, 1H), 2.40 (d, 1H,
J¼4.2 Hz), 2.59 (ddd, 1H, J¼13.5, 12.0, and 5.4 Hz), 3.30 (ddd, 1H,
J¼14.4, 11.7, and 3.5 Hz) 3.38 (ddd, 1H, J¼14.4, 6.3, and 3.3 Hz),
3.60 (dt, 1H, J¼9.6 and 3.6 Hz), 4.29 (dd, 1H, J¼11.4 and 6.0 Hz),
4.30 (dd, 1H, J¼11.4 and 5.9 Hz), 7.46 (t, 2H, J¼7.6 Hz), 7.57 (dt, 1H,
J¼7.4 and 1.2 Hz), and 8.03 (dd, 2H, J¼7.4 and 1.4 Hz); 13C NMR
804 cmꢁ1
;
1H NMR (CDCl3, 600 MHz)
d
0.88 (t, 3H, J¼7.0 Hz),
1.22–1.65 (m, 19H), 2.02–2.07 (m, 2H), 2.17 (dd, 1H, J¼16.0 and
6.0 Hz), 2.26 (d, 1H, J¼10.5 Hz), 2.52–2.53 (m, 1H), 2.65 (dd, 1H,
J¼15.3 and 5.7 Hz), 2.86 (br s, 1H), 3.22 (dt, 1H, J¼6.6 and 1.8 Hz),
3.26–3.32 (m, 1H), 3.36–3.41 (m, 1H), and 3.52–3.57 (m, 1H); 13C
(CDCl3, 300 MHz) d 21.8, 22.8, 24.5, 25.6, 35.5, 36.5, 37.5, 44.4, 50.9,
59.0, 68.5, 69.4, 128.6, 129.7, 130.4, 133.2, 166.8, and 211.1; HRMS
NMR (CDCl3, 300 MHz) d 14.6, 22.4, 23.1, 23.3, 24.9, 27.7, 29.3,
calcd for [C20H25NO3þHþ]: 328.1907. Found: 328.1901.
29.9, 32.3, 35.8, 36.5, 37.0, 43.1, 50.8, 55.9, 57.1, 58.1, 66.9, and
197.0; HRMS calcd for [C19H33NO2þHþ]: 308.2584. Found:
308.2579.
4.1.14. Benzoic acid 7-oxo-2,3,7,7a,8,9,10,11-octahydro-1H-pyrrolo-
[2,1-j]quinolin-3-yl methyl ester (31). To a round bottom flask
charged with 4.8 mg (14.4 mmol) of the above tricyclic compound
30 dissolved in 1.0 mL of a 2:1-EtOH/H2O mixture at rt was added
5.8 mg (15.5 mmol) of EDTA and 4.9 mg (15.5 mmol) of mercuric
acetate. The mixture was heated at 80 ꢂC for 1.5 h, cooled to rt and
Acknowledgements
The financial support provided by the National Science Foun-
dation (CHE-0742663) is greatly appreciated.

3650
A.C. Flick et al. / Tetrahedron 66 (2010) 3643–3650
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