Asymmetric total synthesis of (+)-luciduline: Toward a general approach to related lycopodium alkaloids

Article abstract of DOI:10.1021/jo200745n

As part of a research program directed toward the synthesis of Lycopodium alkaloids, a multigram scale asymmetric synthesis of intermediate 11 was achieved in 11 steps from pyridine (17). In addition to our alkene metathesis strategy, a key feature of thi

Full text of DOI:10.1021/jo200745n

ARTICLE
pubs.acs.org/joc
Asymmetric Total Synthesis of (þ)-Luciduline: Toward a General
Approach to Related Lycopodium Alkaloids
Guillaume Barbe,*,†,§ Dominic Fiset,† and Andrꢀe B. Charette‡
†Merck Frosst Centre for Therapeutic Research, 16711 Route Transcanadienne, Kirkland, Quebec, Canada H9H 3L1
‡Dꢀepartement de Chimie, Universitꢀe de Montrꢀeal, P.O. Box 6128, Station Downtown, Montrꢀeal, Quꢀebec, Canada H3C 3J7
S Supporting Information
b
ABSTRACT: As part of a research program directed toward the
synthesis of Lycopodium alkaloids, a multigram scale asymmetric
synthesis of intermediate 11 was achieved in 11 steps from
pyridine (17). In addition to our alkene metathesis strategy, a
key feature of this synthetic approach consists of a Fukuyama’s
DielsꢀAlder cycloaddition between 1,2-dihydropyridine and
acrolein using MacMillan’s catalyst (18) on a 50 g scale. This led to a 12-step catalytic asymmetric synthesis of (þ)-luciduline (1). A
broader subset of Lycopodium alkaloids could also be obtained, as demonstrated by the derivatization of 11 into advanced
intermediates for the synthesis of some of these natural products.
ince 1881,1 Lycopodium alkaloids have represented an increas-
Inspired by Overman’s and Sarpong’s proposals and by
Waters’ achievements, we hypothesized that the intermediate
11 could be a common precursor to luciduline (1), lucidulinone
(2), spiroluciduline (8), and nankakurines A (3) and B (4).
Obviously, this could be achieved using the ketone functionality
as a synthetic handle, as examplified by Waters. In addition, as a
variant to Sarpong’s suggestion, we also hypothesized that this
same ketone functionality could serve as a platform for a 1-carbon
ring expansion toward the synthesis of the seven-membered ring
analogues such as lucidine A (6), oxolucidine A (7), dihydroly-
colucine (5), and lyconadins A (9) and B (10).
Herein, we describe an asymmetric multigram scale synthesis of
11 and validate its applicability for the synthesis of Lycopodium
natural products by presenting the first catalytic asymmetric total
synthesis of (þ)-luciduline (1).8 In addition, we highlight prelimi-
nary results on key chemical modifications of 11, opening the way
for a general entry into the Lycopodium “miscellaneous” subfamily.
S
ing family of structurally diverse natural products.2 The syn-
thetic challenges associated with these complex molecules have
attracted a broad interest in the scientific community.3 In addi-
tion, the biological potential associated with Lycopodium alkaloids
has motivated notable efforts.4 However, a thorough investigation
of their biological activities is still impaired by their low availability
from natural and synthetic sources. Most importantly, this supply
limitation has prohibited the chemical synthesis of analogues and
the elaboration of a structureꢀactivity relationship.
Recently, we instigated a research program directed toward the
synthesis and biological evaluation of natural product analogues,
and we became interested in the Lycopodium “miscellaneous”
subfamily (Scheme 1). More specifically, we examined the pos-
sibility for a common synthetic intermediate to allow a late-stage
divergence into a broad subset of Lycopodium natural products.
For its election, a key intermediate would have to be available in its
nonracemic form, and the synthetic sequence would have to be
flexible and scalable to multigram quantities, requirements that are
all necessary for efficient analogues syntheses.
’ RESULTS AND DISCUSSION
The search for a general strategy to access Lycopodium
alkaloids has already been discussed in the literature. In his
report on the asymmetric total syntheses of nankakurines A (3)
and B (4), Overman suggested that these two natural products
could synthetically originate from luciduline (1).5 A few years
later, this hypothesis was elegantly validated by Waters through
3- and 4-step syntheses of (()-nankakurines A (3) and B (4),
respectively, using (()-luciduline (1) as a starting material.6
Also, as a possible ramification of his total synthesis of lyconadin
A (9), Sarpong recently suggested that a ring contraction
reaction of the seven-membered ring could open the access to
the six-membered ring analogues in the family, including lucidu-
line (1) and nankakurines (3 and 4).7
Synthesis of Tandem Alkene Metathesis Precursor 15. Our
retrosynthetic analysis of 11 is outlined in Scheme 2. We
identified dione 12 as a suitable intermediate for late stage
formation of the cyclohexenone ring through an intramolecular
aldol condensation. This retrosynthetically exposed the cis-fused
hydroquinoline core of 11. For its synthesis, we elected to use
our tandem metathesis approach,9,10 thereby nominating
azabicyclo[2.2.2]octene 15 as a key intermediate. Finally, we
identified Fukuyama’s intermediate 16 as a known starting point
for our synthesis.11
Received: April 9, 2011
Published: May 20, 2011
r
2011 American Chemical Society
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ARTICLE
Scheme 1. General Strategy to Selected Lycopodium “Miscellaneous” Alkaloids
Scheme 2. Retrosynthetic Analysis of 11
Scheme 3. Synthesis of Fukuyama’s Intermediate 16
33% yield over three steps starting from 50 g of pyridine (17)
(Scheme 3). Most importantly, 51 g of 16 was thereby produced
with an enantiomeric ratio of 92:8.14
Upon the initiation of this program, our goal was primarily to
identify and synthesize a bench-stable enantioenriched azabi-
cyclo[2.2.2]octene system as a precursor to the ring-closing ring-
opening metathesis chemistry. Rapidly, we acknowledged the
asymmetric DielsꢀAlder cycloaddition using 1,2-dihydropyri-
dine as a privileged approach for accessing such a bicyclic
system.12 In this regard, we became interested in a report
published by Fukuyama’s group on the synthesis of Oseltamivir
using MacMillan’s asymmetric DielsꢀAlder methodology.13
More precisely, a footnote in that report relating to the identi-
fication of a byproduct in the DielsꢀAlder cycloaddition caught
our attention. In fact, this footnote directed the reader to the
Supporting Information’s description of the byproduct identifi-
cation method, which involved the concomitant synthesis of 16.
Although a modest yield was reported for 16 (28% over three
steps), the sequence used could produce multigram quantities
using inexpensive commercially available materials. In addition,
on the basis of previous observations from our laboratories, we
were confident that 16 would fulfill our stability requirement for
long-term storage. Finally, although the enantiomeric excess of
16 was not reported and remained to be determined, the context
of the report suggested an acceptable outcome. Thus, after minor
optimization of the reaction conditions, we were pleased to
successfully reproduce Fukuyama’s findings by obtaining 16 in
With multigram quantities of enantioenriched intermediate 16
in hand, we turned our attention to the elaboration of the tandem
metathesis precursor 15. First, oxidation of the primary alcohol
to the aldehyde followed by treatment with allylmagnesium
bromide yielded the corresponding homoallylic alcohol as a
mixture of diastereoisomers (Scheme 4). Then, as a requirement
for the metathesis sequence optimization, the free hydroxyl
group was protected as its TBS-ether 15 with an overall yield
of 61% for the 3 steps.9a,15 It is noteworthy that 15 could also be
accessed through a 4-step synthesis from pyridine (17) by direct
allylation of the aldehyde produced through the DielsꢀAlder
cycloaddition. However, although multigram quantities of 15
could still be obtained, the whole process was found to be
practically less amenable to large scale synthesis and provided
no advantage in terms of overall yield.
Tandem Alkene Metathesis Reaction of 15. With the
metathesis precursor 15 in hand, we performed a brief optimiza-
tion of the conditions for the tandem ring rearrangement
reaction. These results are shown in Table 1. Ultimately, we
found that submitting diene 15 to 2 mol % of Grubbs second
generation catalyst 2016 could afford reproducibly the desired
hydroquinoline 14 with 81% yield on a multigram scale (entry 9).
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Scheme 4. Synthesis of Metathesis Precursor 15
Table 1. Tandem Metathesis Optimizationa
Scheme 5. Synthesis of Aldol Precursor 12
entry catalyst catalyst (mol %) solvent [15] (M) time (h) yieldb (%)
1
2
3
4
5
6
7
8
9c
19
20
20
20
20
20
20
20
20
5.0
5.0
0.5
1.0
2.0
2.0
2.0
2.0
2.0
CH2Cl2 0.01
CH2Cl2 0.01
CH2Cl2 0.01
CH2Cl2 0.01
CH2Cl2 0.01
17
17
17
17
17
3
60
68
69
74
79
61
57
73
81
toluene
0.01
CH2Cl2 0.10
CH2Cl2 0.001
CH2Cl2 0.01
17
17
17
a Catalyst is added to a solution of 15 (1 mmol) in commercially available
solvent at room temperature under an argon atmosphere. b Isolated yield.
c Reaction performed on a 10 mmol scale.
Scheme 6. Intramolecular Aldol Condensation and Forma-
tion of 11
It is interesting to note that although a much faster reaction was
observed in toluene (entry 6), dimerization of the final product
became detrimental to the reaction yield. Finally, a decrease in
yield was also obtained with higher catalyst loading (entry 2) and
increased reaction concentration (entry 8).
Synthesis of Key Intermediate 11 and (þ)-Luciduline 1.
We then turned our attention toward the synthesis of dione 12
(Scheme 5). Deprotection of the alcohol followed by a 2-step
DessꢀMartin oxidation/alumina-induced alkene migration prod-
uced the enone 13 as a suitable Michael acceptor for a methyl-
cuprate addition.17 As anticipated from the cis-fused junction of
the hydroquinoline, the methyl delivery was observed uniquely
on the β-face of the bicyclic system (21). This led us to an alkene
oxidation distance from our dione target, a transformation that
occurred using Wacker oxidation conditions (12).18 This latter
result is in sharp contrast with our previous observation that the
presence of a methyl group at the 2 position, cis to the terminal
alkene, completely prohibited the formation of the ketone under
the same reaction conditions.9a,19
hydroquinolines. Indeed, in order to minimize the allylic strain
between the carbamate moiety and the cyclohexanone ring, the
system preferentially adopts a conformation such as 12-A
(Scheme 6). In fact, NMR analysis of compound 12 in d6-
acetone showed that conformer 12-A was the only one present in
solution. Therefore, we anticipated that this would impair our
desired intramolecular aldol reaction to efficiently occur.
At this point, we became concerned by the well-estab-
lished preferred conformation for N-acyl protected cis-fused
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Scheme 9. Synthetic Approach to Lyconadin A and B
Scheme 7. Synthesis of (þ)-Luciduline (1)
Scheme 8. Exploration of the Ring Expansion Strategy
of the final nitrogenꢀcarbon bond (Scheme 9).20 Thus, treat-
ment of ketone 23 with PhMe3NBr3 expectedly generated the
bromide 26 as a single diastereoisomer in good yield. We
anticipated this bromide leaving group to be suitably positioned
to participate in an intramolecular SN2 reaction with the amine
functionality. Gratifyingly, we found that treating 26 with TFA
followed by a basic workup validated this hypothesis by cleanly
producing the tetracyclic compound 27 in quantitative yield.
’ CONCLUSIONS
In conclusion, we achieved an asymmetric multigram scale
synthesis of the valuable intermediate 11. This allowed us to
conclude the first catalytic asymmetric synthesis of (þ)-lucidu-
line (1) in 12 steps from pyridine. In addition, we demonstrated
the potential for 11 to enable divergence to a broader subset of
Lycopodium alkaloids. Our efforts are currently directed toward
the optimization of the asymmetric construction of the
azabicyclo[2.2.2]octane system and its application to the synthes-
es of other Lycopodium natural products. These results will be
reported in due course.
Unfortunately, this concern was supported when dione 12 was
submitted to LiHMDS at ꢀ78 °C, and only a complex mixture of
dimers was observed by LCꢀMS analysis of the reaction mixture.
However, we then found that by simply warming the reaction to
room temperature monomers could reform via retroaldol reac-
tions. Most importantly, this temperature also allowed for an
equilibrium to occur between the two conformers, thereby
enabling the intramolecular process. After 20 h at room tem-
perature, the desired aldol condensation 11 product was ob-
tained in an isolated yield of 62%.
With enone 11 secured, we found ourselves in a suitable
position to complete the total synthesis of (þ)-luciduline (1).
Indeed, a concomitant hydrogenation of the enone, hydrogenolysis
of the Cbz protecting group, and in situ reductive amination with
formalin produced (þ)-luciduline (1) in 75% yield (Scheme 7).
Hence, this transformation concluded a 12-step catalytic asymmetric
total synthesis of (þ)-luciduline from pyridine. In addition, this
opened the door to a 15- and 16-step asymmetric formal synthesis
of nankakurine A (3) and B (4), respectively (vide supra).6
Afterward, we briefly explored the viability of our synthetic
approach toward the synthesis of other Lycopodium alkaloids.
First, we investigated a ring expansion strategy by screening
different reaction conditions on various substrates. Ultimately,
we found that treating the diazo compound 24 with a catalytic
amount of Rh2(OAc)4 gave a crude, unstable seven-membered
β-ketoester (Scheme 8). After reduction of the ketone, the stable
compound 25 could be obtained as a single regio- and diaster-
eoisomer in 61% yield over the three steps. Therefore, these
results paved the way for the asymmetric synthesis of lucidine A
(6), oxolucidine A (7), and dihydrolycolucine (5).
’ EXPERIMENTAL SECTION
General Information. Unless otherwise stated, reactions were run
under an argon atmosphere with exclusion of moisture from reagents
and glassware using standard techniques for manipulating air-sensitive
compounds. Commercial reagents and solvents were used without
purification. Analytical thin-layer chromatography was performed on
precoated, glass-backed silica gel. Visualization of the developed chro-
matogram was performed by UV and aqueous potassium permanganate.
Flash column chromatography was performed using 230ꢀ400 mesh
silica. Nuclear magnetic resonance spectra were recorded on 400 and
600 MHz spectrometers (1H and 13C). Chemical shifts for H NMR
1
spectra are recorded in parts per million from tetramethylsilane with the
solvent resonance as the internal standard. Chemical shifts for 13C NMR
spectra are recorded in parts per million from tetramethylsilane using the
central peak of deuterated solvents as the internal standards. All 13C
NMR spectra were obtained with complete proton decoupling. Infrared
spectra were taken on NaCl plates (film). High resolution mass spectra
(HMRS) were performed on a high resolution magnetic sector mass
spectrometer. Optical rotation data were determined with a polari-
meter at 589 nm. All spectral data obtained for new compounds are
reported here.
Finally, we probed the formation of the tetracyclic core
structures of lyconadins A and B by evaluating the formation
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Procedure A: Benzyl Pyridine-1(2H)-carboxylate (S-1). To a
stirred solution of pyridine (50.0 g, 632 mmol) in methanol (502 mL) at
ꢀ78 °C was added sodium borohydride (26.4 g, 698 mmol). To this was
added benzyl chloroformate (108.1 g, 602 mmol) dropwise using an
addition funnel. After stirring 120 min, water and Et2O were added to
the reaction mixture. The resulting mixture was warmed to room
temperature, and the layers were separated. The aqueous layer was
extracted twice with Et2O, and the combined organic extracts were
washed with 1 N HCl, 1 N NaOH, water, and brine, dried over MgSO4,
filtered over Celite, and concentrated under reduced pressure to give
dihydropyridine S-1 as a yellow oil. The crude product was used in the
next step without further purification.
Benzyl 7-Formyl-2-azabicyclo[2.2.2]oct-5-ene-2-carboxy-
late (S-2). To a stirred solution of the dihydropyridine (123.7 g, 575
mmol) in acetonitrile (307 mL) and water (77 mL) was added
MacMillan’s catalyst 1813a (14.64 g, 57.5 mmol) and acrolein (90%,
107 mL, 1725 mmol) after which the mixture turned yellow. After
stirring overnight, the reaction mixture was diluted with DCM and
washed with water. The layers were separated, and the aqueous layer was
extracted twice with DCM. The combined organic extracts were washed
with brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure to give the aldehyde as a green foam. The crude product S-2 was
used in the next step without further purification.
concentrated under reduced pressure yielding a yellow oil. The crude
alcohol S-3 was used in the next step without further purification.
(R)-diastereoisomer: [R]20 = þ69.9 (c 0.700, CHCl3); 1H NMR
D
(acetone-d6, 400 MHz) δ 7.47ꢀ7.26 (m, 5H), 6.49ꢀ6.32 (m, 2H),
5.99ꢀ5.86 (m, 1H), 5.20ꢀ4.97 (m, 5 H), 3.83ꢀ3.74 (m 1H), 3.26 (dd,
J = 42.0, 10.0 Hz, 1H), 3.03 (br s, 3H), 2.77 (br s, 1H), 2.30 (dd, J = 16.0,
8.0 Hz, 1H), 2.14ꢀ1.97 (m, 2H), 1.77 (t, J = 12.0 Hz, 1H), 0.96ꢀ0.85 (m,
1H); 13C NMR (acetone-d6, 100 MHz) mixture of rotamers, major δ
154.6, 137.7, 135.9, 134.7, 130.8, 128.3, 127.7, 127.6, 116.1, 73.5, 65.9,
46.9, 46.6, 45.2, 38.7, 31.1, 26.9; FTIR (cmꢀ1) (neat) br3435, 3065, 2933,
2876, 1694, 1417; HRMS (ESI, Pos) calcd for C19H23NO3 [M þ H]þ:
314.1751 m/z, found 314.1766 m/z. (S)-diastereoisomer: [R]20
=
D
þ71.5 (c 0.990, CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 7.47ꢀ7.26
(m, 5 H), 6.51ꢀ6.41 (m, 1H), 6.40ꢀ6.30 (m, 1H), 6.04ꢀ5.87 (m, 1H),
5.23ꢀ4.97 (m, 4H), 4.77 (dd, J = 16.0, 4.0 Hz, 1H), 3.59 (br s, 1H), 3.27
(ddd, J = 30.0, 10.0, 4.0 Hz, 1H). 3.21ꢀ3.11 (m, 1H), 2.78 (br s, 1H),
2.46ꢀ2.32 (m, 1H), 2.26ꢀ2.14 (m, 2H), 1.85ꢀ1.74 (m, 1H), 1.50ꢀ1.40
(m, 1H); 13C NMR (acetone-d6, 100 MHz) mixture of rotamers, major δ
154.7, 137.6, 135.4, 135.1, 130.3, 128.4, 127.8, 127.7, 116.5, 73.1, 66.2,
47.5, 46.8, 45.5, 40.0, 31.2, 27.0; FTIR (cmꢀ1) (neat) br3444, 3065, 2928,
2875, 1700, 1434; HRMS (ESI, Pos) calcd for C19H23NO3 [M þ H]þ:
314.1751 m/z, found 314.1752 m/z.
Benzyl 7-(1-{[tert-Butyl(dimethyl)silyl]oxy}but-3-en-1-yl)-
2-azabicyclo[2.2.2]oct-5-ene-2-carboxylate (15). To a stirred
solution of the alcohol S-3 (188 mmol) in DMF (940 mL) were added
imidazole (25.6 g, 376 mmol) and TBS-Cl (42.5 g, 282 mmol). After
stirring for 48 h, the reaction mixture was transferred into a separation
funnel with Et2O, and the organic layer was washed with 1 N HCl, water,
and brine, dried with MgSO4, filtered, and concentrated under reduced
pressure. Flash chromatography of the brownish oily residue with EtOAc/
hexanes (20/80) afforded 49.0 g of metathesis precursor 5 (61%, 3 steps)
Benzyl 7-(Hydroxymethyl)-2-azabicyclo[2.2.2]oct-5-ene-
2-carboxylate (16). To a stirred solution of the aldehyde (575 mmol)
in ethanol (1150 mL) was added sodium borohydride (43.5 g, 575
mmol) at 0 °C at which time the mixture became yellow. After stirring
1 h, the reaction was quenched with 1 N HCl. The reaction mixture was
extracted with DCM, and the combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. Flash chromatography of the yellow oily residue with EtOAc/
hexanes (40/60) afforded 51.4 g of alcohol 16 (33%, 3 steps) as a
colorless oil (92:8 er). [R]20 = þ74.8 (c 0.500, CHCl3), lit. [R]23
as a light yellow oil. (R)-diastereoisomer: [R]20 = þ17.2 (c 0.575,
D
CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 8.06ꢀ7.89 (m, 5H),
7.15ꢀ7.08 (m, 1H), 7.04ꢀ6.92 (m, 1H), 6.63ꢀ6.49 (m, 1H),
5.79ꢀ5.57 (m, 5H), 3.96ꢀ3.79 (m, 2H), 3.65ꢀ3.52 (m, 1H), 3.40
(br s, 1H), 2.98ꢀ2.88 (m, 1H), 2.88ꢀ2.77 (m, 2H), 2.42ꢀ2.33 (m, 1H),
1.62ꢀ1.52 (m, 10H), 0.74 (dd, J = 16.0, 8.0 Hz, 6H); 13C NMR (acetone-
d6, 100 MHz) mixture of rotamers, major δ 154.2, 137.7, 135.4, 134.2,
130.5, 128.3, 127.8, 127.6, 116.9, 74.0, 65.9, 46.7, 46.7, 44.1, 37.7, 31.0,
26.8, 25.5, 17.8, 4.4, ꢀ5.4; FTIR (cmꢀ1) (neat) 3064, 2929, 2857, 1712,
1640, 1417; HRMS (ESI, Pos) calcd for C25H37NO3Si [M þ H]þ:
D
D
þ70.3 (c 1.09, CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 7.43ꢀ7.24
(m, 5H), 6.48ꢀ6.28 (m, 2H), 5.22ꢀ5.08 (m, 2H), 4.92ꢀ4.86 (m, 1H),
3.36ꢀ3.25 (m, 2H), 3.25ꢀ3.12 (m, 1H), 3.08ꢀ2.91 (m, 1H),
2.80ꢀ2.70 (m, 1H), 2.44ꢀ2.31 (m, 1H), 2.06 (br s, 1H), 1.85ꢀ1.72
(m, 1H), 0.94ꢀ0.77 (m, 1 H); FTIR (cmꢀ1) (neat) 3451 (broad), 3053,
3016, 2946, 2864, 1684, 1432, 1337; HRMS (ESI, Pos) calcd for
C16H19NO3 [M þ H]þ: 274.1438 m/z, found 274.1440 m/z.
Procedure B: Benzyl 7-Formyl-2-azabicyclo[2.2.2]oct-5-
ene-2-carboxylate (S-2). To a stirred solution of oxalyl chloride
(26.2 g, 207 mmol) in DCM (611 mL) was slowly added DMSO (33.0 g,
423 mmol) in DCM (50 mL) at ꢀ78 °C. After 15 min of stirring, a
solution of alcohol 16 (51.4 g, 188 mmol) in DCM (135 mL) was added
at ꢀ78 °C. After 20 min of stirring, triethylamine (97.0 g, 958 mmol)
was added, and the reaction mixture was stirred for 20 min at ꢀ78 °C
followed by warming to room temperature and stirring an additional
10 min. Saturated NH4Cl aqueous solution was carefully added to the
reaction mixture, the layers were separated, and the aqueous layer was
extracted twice with DCM. The combined organic layers were dried with
MgSO4, filtered, and concentrated under reduced pressure, yielding the
aldehyde S-2 as an orange oil. The crude product was used in the next
step without further purification.
Benzyl 7-(1-hydroxybut-3-en-1-yl)-2-azabicyclo[2.2.2]oct-
5-ene-2-carboxylate (S-3). The crude aldehyde S-2 (188 mmol)
was dissolved in DCM (1880 mL), and the solution was cooled to
ꢀ78 °C. Allylmagnesium bromide (282 mL of a 1.0 M solution in Et2O,
282 mmol) was then added dropwise, and the thick reaction mixture was
brought to room temperature. The heterogeneous solution was stirred for
2 h, and saturated NH4Cl aqueous solution was carefully added to the
reaction mixture. The solution was transferred into a separation funnel,
the layers were separated, and the aqueous layer was extracted twice with
DCM. The combined organic layers were dried with MgSO4, filtered, and
428.2616 m/z, found 428.2617 m/z. (S)-diastereoisomer: [R]20
=
D
þ56.7 (c 0.580, CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 7.45ꢀ7.26
(m, 5H), 6.50ꢀ6.42 (m, 1H), 6.40ꢀ6.30 (m, 1H), 6.01ꢀ5.82 (m, 1H),
5.25ꢀ4.96 (m, 4H), 4.77 (dd, J = 20.0, 8.0 Hz, 1H), 3.43ꢀ3.34 (m, 1H),
3.26 (ddd, J = 34.0, 10.0, 2.0 Hz, 1H), 3.01ꢀ2.89 (m, 1H), 2.80 (br s, 1H),
2.40ꢀ2.18 (m, 3H), 1.84ꢀ1.73 (m, 1H), 1.37ꢀ1.23 (m, 1H), 0.92 (d, J =
4.0 Hz, 9H), 0.08 (t, J = 8.0 Hz, 6H); 13C NMR (acetone-d6, 100 MHz)
mixture of rotamers, major δ 154.5, 137.7, 134.9, 134.1, 130.6, 128.3,
127.9, 127.6, 117.2, 74.5, 66.0, 46.9, 46.5, 44.6, 39.5, 31.2, 27.5, 25.5, 17.8,
4.4, ꢀ5.1; FTIR (cmꢀ1) (neat) 3066, 2953, 2857, 1699, 1642, 1416;
HRMS (ESI, Pos) calcd for C25H37NO3Si [M þ H]þ: 428.2616 m/z,
found 428.2610 m/z.
Alternative Route for the Synthesis of Metathesis Pre-
cursor: Procedure C. The crude aldehyde S-2 obtained from
Procedure A (25.0 mmol) was dissolved in DCM (250 mL), and the
solution was cooled to ꢀ78 °C. Allylmagnesium bromide (37.5 mL of a
1.0 M solution in Et2O, 37.5 mmol) was then added dropwise, and the
thick reaction mixture was brought to room temperature. The hetero-
geneous solution was stirred for 2 h, and saturated NH4Cl aqueous
solution was carefully added to the reaction mixture. The solution was
transferred into a separation funnel, the layers were separated, and the
aqueous layer was extracted twice with DCM. The combined organic
layers were dried with MgSO4, filtered, and concentrated under reduced
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pressure yielding a yellow oil. Crude product was dissolved in Et2O, and
5% sodium bisulfite aqueous solution was added. After stirring over-
night, the layers were separated, and the aqueous layer was extracted
with Et2O. The combined organic layer were dried with MgSO4, filtered
over Celite, and concentrated under reduced pressure to yield 4.70 g of
alcohol S-3 as a yellowish oil.
To a stirred solution of the alcohol S-3 (4.70 g, 15.0 mmol) in DMF
(75 mL) were added imidazole (2.04 g, 30.0 mmol) and TBS-Cl (3.39 g,
22.5 mmol) at room temperature. After stirring for 48 h, the reaction
mixture wastransferredinto aseparationfunnelwithEt2O, and the organic
layer was washed with 1 N HCl, water, and brine, dried with MgSO4,
filtered, and concentrated under reduced pressure. Flash chromatography
of the brownish oily residue with EtOAc/hexanes (20/80) afforded 2.49 g
of metathesis precursor 15 (22%, 4 steps) as a light yellow oil.
5.82ꢀ5.64 (m, 2H), 5.40 (d, J = 8.0 Hz, 1H), 5.25ꢀ4.96 (m, 5H),
4.15ꢀ3.88 (m, 3H), 2.57 (dt, J = 44.0, 12.0 Hz, 1H), 2.30 (d, J = 20.0 Hz,
1H), 2.20ꢀ1.99 (m, 3H), 1.59 (d, J = 12.0 Hz, 1H), 1.12 (q, J = 12.0 Hz,
1H); 13C NMR (acetone-d6, 100 MHz) mixture of rotamers, major δ
155.1, 140.1, 137.6, 128.4, 127.7, 127.6, 126.9, 126.6, 114.0, 68.2, 66.4,
47.9, 45.0, 39.8, 39.1, 29.7, 29.6; FTIR (cmꢀ1) (neat) br 3443, 3027,
2923, 1682, 1427, 1261, 1120, 911; HRMS (ESI, Pos) calcd for
C19H23NO3 [M þ Na]þ: 336.1570 m/z, found 336.1569 m/z
Benzyl (3S,4aS,8aS)-3-Ethenyl-5-oxo-3,4,4a,5,6,8a-hexa-
hydroquinoline-1(2H)-carboxylate (13). To a stirred solution
of the alcohol S-4 (3.98 g, 12.7 mmol) were added DessꢀMartin
periodinane (8.08 g, 19.1 mmol) and a drop of water. The reaction
mixture was stirred for 4 h, diluted with Et2O, and poured into a
saturated NaHCO3 aqueous solution (100 mL) containing Na2S2O3
(25 g). This heterogeneous solution was stirred until the solid was
completely dissolved. The layers were separated, and the organic layer
was washed with saturated NaHCO3 aqueous solution and water, dried
over MgSO4, filtered over Celite, and concentrated under reduced
pressure. The resulting yellowish oil was dissolved in ethyl acetate
(127 mL), and alumina was added (20 g). The mixture was stirred
overnight, then filtered over Celite, and concentrated under reduced
pressure. The crude enone 13 was used to the next step without any
Benzyl (3S,4aS,8aS)-5-{[tert-Butyl(dimethyl)silyl]oxy}-3-
ethenyl-3,4,4a,5,6,8a-hexahydroquinoline-1(2H)-carboxy-
late (14). Metathesis precursor 15 (4.28 g, 10.0 mmol) was dissolved in
DCM (1000 mL), and Grubbs’ catalyst second generation (20) (0.170 g,
0.200 mmol) was added. After stirring 17 h, the reaction mixture was
quenched with the addition of ethyl vinyl ether (excess), and the solution
was concentrated under reduced pressure. Flash chromatography of the
brownish oil with EtOAc/hexane (20/80) afforded 3.48 g of metathesis
further purification. [R]20 = ꢀ41.1 (c 0.730, CHCl3); 1H NMR
product 14 (81%) as a colorless oil. (R)-diastereoisomer: [R]20
=
D
D
þ56.9 (c 0.520, CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 7.45ꢀ7.29
(m, 5H), 5.85ꢀ5.71 (m, 2H), 5.39ꢀ5.29 (m, 1H), 5.23ꢀ4.98 (m, 4H),
4.91 (br s, 1H), 4.20ꢀ3.98 (m, 2H), 2.53 (dt, J = 44.0, 12.0 Hz, 1H),
2.32ꢀ2.19 (m, 1H), 2.19ꢀ1.98 (m, 3H), 1.88 (d, J = 12.0 Hz, 1H), 1.22
(q, J = 12.0 Hz, 1H), 0.92 (s, 9H), 0.12 (d, J = 8.0 Hz, 6H); 13C NMR
(acetone-d6, 100 MHz) mixture of rotamers, major δ 154.9, 140.3,
137.4, 128.4, 127.8, 127.7, 127.6, 127.3, 114.1, 69.1, 66.5, 51.7, 45.1, 39.8,
39.7, 31.0, 25.4, 24.8, 17.7, ꢀ5.4; FTIR (cmꢀ1) (neat) 3029, 2953, 2895,
2857, 1699, 1423, 1272, 1113, 837, 776; HRMS (ESI, Pos) calcd for
C25H37NO3Si [M þ Na]þ: 450.2435 m/z, found 450.2455 m/z.
(acetone-d6, 400 MHz) δ 7.48ꢀ7.28 (m, 5H), 7.13ꢀ7.01 (m, 1H),
6.03ꢀ5.93 (m, 1H), 5.88ꢀ5.71 (m, 1H), 5.24ꢀ5.02 (m, 4H),
4.82ꢀ4.72 (m, 1H), 4.13 (dd, J = 20.0, 16.0 Hz, 1H), 2.97ꢀ2.69 (m,
2H), 2.60ꢀ2.46 (m, 1H), 2.45ꢀ2.31 (m, 1H), 2.25 (br s, 1H),
1.79ꢀ1.68 (m, 1H), 1.49 (q, J = 12.0 Hz, 1H); 13C NMR (acetone-d6,
100 MHz) mixture of rotamers, major δ 199.3, 154.7. 148.4, 139.3, 137.2,
128.5, 128.3, 127.9, 127.8, 115.0, 66.8, 49.4, 47.6, 43.6, 39.3, 28.7, 24.5;
FTIR (cmꢀ1) (neat) 3063, 3033, 2930, 1681, 1498, 1417, 1263; HRMS
calcd for C19H21NO3 [M þ H]þ: 312.1594 m/z, found 312.1586 m/z.
Benzyl (3S,4aS,7S,8aS)-3-Ethenyl-7-methyl-5-oxooctahydro-
quinoline-1(2H)-carboxylate (21). To a stirred suspension of
copper iodide (7.26 g, 38.1 mmol) and THF (80 mL) was added
methyllithium (47.60 mL of a 1.0 M solution in Et2O, 47.60 mmol) at
0 °C. After the reaction mixture stirred for 30 min at 0 °C followed by an
additional 15 min at room temperature, the solution became colorless.
The reaction mixture was cooled to ꢀ78 °C and stirred 10 min. A
solution of enone 13 (12.7 mmol) in THF (80 mL) was added dropwise,
and the reaction mixture was stirred for 3 h at ꢀ78 °C. The reaction was
quenched at ꢀ78 °C by addition of saturated aqueous NH4Cl, removed
from the ice bath, and allowed to warm to room temperature. The
heterogeneous solution was diluted with water and extracted with Et2O.
The combined organic layers were dried over MgSO4, filtered over
Celite, and concentrated under reduced pressure. Flash chromatography
of the yellowish oil with EtOAc/hexanes (25/75) afforded 3.38 g of
ketone 21 (81%, 3 steps) as a light yellow oil. [R]20D = ꢀ52.2 (c 0.720,
CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 7.47ꢀ7.27 (m, 5H),
5.87ꢀ5.70 (m, 1H), 5.28ꢀ5.00 (m, 4H), 4.78ꢀ4.62 (m, 1H),
4.18ꢀ4.00 (m, 1H), 2.76 (dd, J = 16.0, 4.0 Hz, 2H), 2.61ꢀ2.51 (m
1H), 2.46ꢀ2.32 (m, 2H), 2.25ꢀ2.12 (m, 1H), 2.01 (d, J = 12.0 Hz, 1H),
1.79 (q, J = 13.3 Hz, 1H), 1.71ꢀ1.61 (m, 1H), 1.50 (d, J = 12.0 Hz, 1H),
0.99 (d, J = 4.0 Hz, 3H); 13C NMR (acetone-d6, 100 MHz) δ 210.4,
154.5, 139.4, 137.3, 128.4, 127.8, 127.7, 114.9, 66.6, 51.3, 47.7, 43.3, 43.2,
39.4, 29.2, 28.1, 27.1, 18.6; FTIR (cmꢀ1) (neat) 2952, 2929, 2865, 1694,
1420, 1263, 1222; HRMS (ESI, Pos) calcd for C20H25NO3 [M þ H]þ:
328.1907 m/z, found 328.1902 m/z.
(S)-diastereoisomer: [R]20 = þ59.8 (c 0.660, CHCl3), 1H NMR
D
(acetone-d6, 400 MHz) δ 7.46ꢀ7.29 (m, 5H), 5.80ꢀ5.64 (m, 2H),
5.47ꢀ5.38 (m, 1H), 5.23ꢀ4.97 (m, 5H), 4.16ꢀ3.99 (m, 2H), 2.58 (dt, J
= 41.3, 13.0 Hz, 1H), 2.32 (d, J = 20 Hz, 1H), 2.15 (br s, 1H), 1.99 (d, J =
12.0 Hz, 2H), 1.62 (d, J = 12.0 Hz, 1H), 1.12 (q, J = 14.0 Hz, 1H),
0.94ꢀ0.88 (m, 9H), 0.14ꢀ0.10 (m, 6H); 13C NMR (acetone-d6, 100
MHz) δ 154.9, 140.0, 137.4, 128.4, 127.7, 127.6, 127.1, 126.2, 114.1, 69.7,
66.5, 48.0, 44.9, 39.9, 39.7, 30.2. 29.5, 25.4, 17.7, ꢀ5.4; FTIR (cmꢀ1
)
(neat) 3028, 2927, 2890, 2856, 1699, 1424, 1259, 1072, 951, 837, 775;
HRMS (ESI, Pos) calcd for C25H37NO3Si [M þ Na]þ: 450.2435 m/z,
found 450.2442 m/z.
Benzyl (3S,4aS,8aS)-3-Ethenyl-5-hydroxy-3,4,4a,5,6,8a-
hexahydroquinoline-1(2H)-carboxylate (S-4). To a stirred solu-
tion of metathesis product 14 (5.95 g, 13.9 mmol) in THF (27.8 mL)
was added TBAF (27.8 mL of a 1.0 M solution in THF, 27.8 mmol).
After stirring overnight, the mixture was extracted with DCM. The
combined organic extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. Flash chromatography
of the brownish oily solid with EtOAc/hexane (40/60) afforded 4.03 g
of the alcohol S-4 (92%) as a brownish oil. (R)-diastereoisomer: [R]20
D
= þ49.0 (c 0.300, CHCl3); 1H NMR (acetone-d6, 400 MHz) δ
7.45ꢀ7.29 (m 5H), 5.85ꢀ5.68 (m, 2H), 5.39ꢀ5.29 (m, 1H),
5.21ꢀ4.97 (m, 4H), 4.90ꢀ4.87 (m, 1H), 4.13ꢀ3.93 (m, 3H), 2.53
(dt, J = 44.0, 12.0 Hz, 1H), 2.34ꢀ2.21 (m, 1H), 2.18ꢀ1.95 (m, 3H),
1.89 (d, J = 16.0 Hz, 1H), 1.24ꢀ1.14 (m, 1H); 13C NMR (acetone-d6,
100 MHz) mixture of rotamers, major δ 155.0, 140.3, 137.4, 128.4,
127.8, 127.8, 127.7, 127.3, 114.0, 67.7, 66.5, 51.9, 45.1, 39.7, 39.5, 30.2,
24.6; FTIR (cmꢀ1) (neat) br 3438, 3029, 2923, 1697, 1427, 1274, 1116,
917; HRMS (ESI, Pos) calcdfor C19H23NO3 [M þ Na] þ: 336.1570 m/z,
Benzyl (3S,4aS,7S,8aS)-3-Acetyl-7-methyl-5-oxooctahydro-
quinoline-1(2H)-carboxylate (12). A stirred suspension of ketone
21 (4.83 g, 14.8 mmol), copper(II) chloride (0.146 g, 1.48 mmol), and
palladium(II) chloride (0.262 g, 1.48 mmol) in THF (118 mL) and
water (29.5 mL) was stirred under an oxygen atmosphere overnight.
Additional amounts of copper(II) chloride (0.146 g, 1.48 mmol) and
found 336.1568 m/z. (S)-diastereoisomer: [R]20 = þ58.5 (c 0.525,
D
CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 7.47ꢀ7.27 (m, 5H),
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ARTICLE
palladium(II) chloride (0.262 g, 1.48 mmol) were added, and the
reaction mixture was stirred an additional 4 h under an oxygen atmo-
sphere. The reaction was quenched with a saturated aqueous NH4Cl
solution, and the mixture was extracted with DCM. The combined
organic extracts were dried over MgSO4, filtered over Celite, and
concentrated under reduced pressure. Flash chromatography of the
brown oil with EtOAc/hexanes (40/60) afforded 3.97 g of diketone 12
(30.7 mL) was stirred under a hydrogen atmosphere. After stirring for
4 h, the mixture was filtered over silica gel eluting with EtOAc, and the
solution was concentrated under reduced pressure. Flash chromatogra-
phy of the colorless oil with EtOAc/hexanes (20/80) afforded 0.785 g
(87%) of N-protected ketone 23 as a colorless oil. [R]20 = þ123.3
D
(c 0.520. CHCl3); 1H NMR (CDCl3, 400 MHz) δ 4.05 (d, J = 16.0 Hz,
1H) 3.48 (s, 1H), 3.20 (d, J = 16.0 Hz, 1H), 3.00 (dd, J = 12.0, 4.0 Hz,
1H), 2.70 (t, J = 14.0 Hz, 1H), 2.49 (s, 1H), 2.29 (dd, J = 16.0, 8.0 Hz,
1H), 2.22ꢀ2.12 (m, 1H), 1.92 (s, 2H), 1.90ꢀ1.79 (m, 1H), 1.76 (s, 1H),
1.54 (d, J = 12.0 Hz, 1H), 1.43 (s, 9H), 1.30 (td, J = 13.0, 5.3 Hz, 1H),
1.02 (t, J = 12.0 Hz, 1H), 0.91 (d, J = 4.0 Hz); 13C NMR (CDCl3, 100
MHz): 213.5, 156.8, 80.1, 55.9, 48.6, 45.0, 44.9, 39.9, 39.6, 37.0, 35.3,
33.3, 28.4, 22.0, 20.8; FTIR (cmꢀ1) (neat) 2929, 2859, 1717, 1700,
1455, 1152, 1071; HRMS (ESI, Pos) calcd for C17H27NO3 [M þ Na]þ:
316.1883 m/z, found 316.1878 m/z.
(78%) as a white solid, mp 118ꢀ120 °C. [R]20 = þ67.5 (c 0.810,
D
CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 7.45ꢀ7.28 (m, 5H), 5.17
(q, J = 13.3 Hz, 2H), 4.77ꢀ4.65 (m, 1H), 4.27 (dd, J = 12.0, 4.0 Hz, 1H),
2.98ꢀ2.93 (m, 1H), 2.75 (dd, J = 18.0, 6.0 Hz, 1H), 2.69ꢀ2.51 (m, 2H),
2.44ꢀ2.31 (m, 2H), 2.19 (s, 3H), 2.09ꢀ1.82 (m, 3H), 1.54ꢀ1.44 (m,
1H), 0.99 (d, J = 8.0 Hz, 3H); 13C NMR (acetone-d6, 100 MHz) δ 210.3,
207.6, 154.6, 137.2, 128.4, 127.9, 127.7, 66.7, 50.7, 48.0, 47.6, 43.5, 39.6,
28.5, 27.6, 27.1, 25.8, 18.6; FTIR (cmꢀ1) (neat) 3028, 2952, 2871, 1717,
1700, 1426, 1350, 1258; HRMS (ESI, Pos) calcd for C20H25NO4 [M þ
H]þ: 344.1856 m/z, found 344.1846 m/z.
tert-Butyl (1S,3R,4aS,7R,8aR)-6-(1-Diazo-2-ethoxy-2-oxo-
ethyl)-6-hydroxy-3-methyldecahydro-1,7-(epiminomethano)-
naphthalene-10-carboxylate (24). To a stirred solution of ketone
23 (0.583 g, 1.987 mmol) in THF (24.84 mL) at ꢀ78 °C was added
dropwise a cold solution of lithium di-isopropylamide (prepared from
the addition of n-butyllithium (2.092 mL of a 1.52 M solution in hexanes,
3.18 mmol) to di-isopropylamine (0.481 mL, 3.38 mmol)), and then
ethyl diazoacetate (0.309 mL, 2.98 mmol) was added. After stirring for
1 h at ꢀ78 °C, the reaction was quenched by the rapid addition of
saturated NH4Cl aqueous solution. The reaction mixture was extracted
with Et2O and washed with a saturated NaHCO3 aqueous solution
followed by a brine solution. The combined organic layers were dried
over MgSO4, filtered over silica gel eluting with Et2O, and concentrated
under reduced pressure to yield diazo 24 as a yellow oil. The crude
product was used in the next step without further purification.
11-tert-Butyl 6-Ethyl (1S,3R,4aS,7R,8R,9aR)-3-Methyl-7-oxo-
decahydro-1H-1,8-(epiminomethano)benzo[7]annulene-6,11-
dicarboxylate (S-5). A solution of diazo 24 (0.810 g, 1.987 mmol) and
rhodium(II) acetate dimer (8.78 mg, 0.020 mmol) in DCM (39.7 mmol)
was stirred at room temperature. After stirring 90 min, the solvent was
removed under reduced pressure yielding the β-ketoester S-5 as a light
greenish oil. The crude product was used in the next step without further
purification.
Benzyl (1S,3R,7R,8aR)-3-Methyl-6-oxo-1,2,3,4,6,7,8,8a-
octahydro-1,7-(epiminomethano)naphthalene-10-carbox-
ylate (11). To a stirred solution of diketone 12 (3.97 g, 11.6 mmol) in
THF (116 mL) at ꢀ78 °C was added LiHMDS (12.7 mL of a 1.0 M
solution in hexanes, 12.7 mmol) after which the solution became
turquoise. After stirring for 1 h at ꢀ78 °C, the reaction mixture was
warmed to room temperature and stirred overnight. The yellowish
reaction mixture was diluted in Et2O and 1 N HCl. The layers were
separated, and the aqueous layer was extracted with Et2O. The com-
bined organic extracts were dried over MgSO4, filtered over Celite, and
concentrated under reduced pressure. Flash chromatography of the
colorless oil with EtOAc/hexanes (40/60) afforded 2.25 g of enone 11
(60%) as a colorless oil. [R]20D = þ307.7 (c 0.740. CHCl3); 1H NMR
(acetone-d6, 400 MHz) δ 7.42ꢀ7.27 (m, 5H), 5.96 (s, 1H), 5.12 (d, J =
12.0 Hz, 1H), 5.01 (d, J = 12.0 Hz, 1H), 4.06 (dt, J = 13.3, 2.0 Hz, 1H),
3.77ꢀ3.72 (m, 1H), 3.16 (dd, J = 16.0, 4.0 Hz, 2H), 2.57ꢀ2.53 (m, 1H),
2.46 (ddd, J = 10.4, 4.0, 0.8 Hz, 1H), 2.41ꢀ2.35 (m, 1H), 2.25ꢀ2.18
(m, 1H), 2.07ꢀ1.98 (m, 1H), 1.91 (dt, J = 13.3, 3.0 Hz, 1H), 1.85ꢀ1.69
(m, 1H), 1.38ꢀ1.27 (m, 1H), 0.94 (d, J = 8.0 Hz, 3H); 13C NMR
(acetone-d6, 100 MHz) δ 198.7, 165.8, 156.3, 137.1, 128.4, 127.9, 127.8,
124.8, 66.4, 58.3, 46.9, 44.7, 41.8, 40.3, 39.4, 33.9, 29.6, 21.4; FTIR(cmꢀ1
)
(neat) 3030, 2956, 2858, 1719, 1672, 1403, 1295, 1209;HRMS(ESI, Pos)
calcd for C20H23NO3 [M þ H]þ: 326.1751 m/z, found 326.1744 m/z.
(þ)-Luciduline (1): (1S,3R,4aS,7R,8aR)-3,10-Dimethylocta-
hydro-1,7-(epiminomethano)naphthalen-6(2H)-one. A solu-
tion of enone 11 (0.200 g, 0.615 mmol) and 10% palladium on carbon
(0.131 g, 0.123 mmol) in ethanol (6.15 mL) was stirred under a
hydrogen atmosphere. After 1 h of stirring, formaldehyde (0.229 mL
of a solution 37% in water, 3.07 mmol) was added, and the reaction
mixture was stirred an additional 3 h under the hydrogen atmosphere.
The mixture was filtered and concentrated under reduced pressure.
Flash chromatography of the colorless oil with EtOAc/hexanes (25/75)
11-tert-Butyl 6-Ethyl (1S,3R,4aS,7R,8R,9aR)-7-Hydroxy-3-
methyldecahydro-1H-1,8-(epiminomethano)benzo[7]annu-
lene-6,11-dicarboxylate (25). To a stirred solution of the crude
β-ketoester S-5 (0.754 g, 1.987 mmol) in ethanol (19.9 mL) at 0 °C was
added sodium borohydride (0.150 g, 3.97 mmol), and the mixture
became yellow. After stirring overnight from 0 °C to room temperature,
the reaction was quenched with the slow addition of 1 N HCl. The
reaction mixture was extracted with DCM, and the combined organic
layers were washed with brine, dried over MgSO4, filtered, and con-
centrated under reduced pressure. Flash chromatography of the yellow
oily residue with EtOAc/hexanes (20/80) afforded 0.464 g of alcohol 25
(61%, 3 steps) as a yellowish oil. [R]20D = þ51.7 (c 0.755. CHCl3); 1H
NMR (acetone-d6, 400 MHz) δ 4.50 (td, J = 8.0, 4.0 Hz, 1H), 4.16ꢀ4.02
(m, 3H), 3.85 (d, J = 8.0 Hz, 1H), 3.60ꢀ3.55 (m, 1H), 3.16 (dd, J = 14.0,
6.0 Hz, 1H), 2.82 (dd, J = 10.0, 3.0 Hz, 1H), 2.58 (br d, J = 16.0 Hz, 1H),
2.50ꢀ2.41 (m, 1H), 2.11ꢀ2.04 (m, 2H), 1.95ꢀ1.77 (m, 5H),
1.73ꢀ1.61 (m, 2H), 1.47 (s, 9H), 1.34ꢀ1.27 (1H), 1.22 (t, J = 8.0 Hz,
3H), 1.14ꢀ1.04 (m, 1H), 0.88 (d, J = 8.0 Hz, 3H); 13C NMR (acetone-
d6, 100 MHz) δ 173.7, 154.7, 79.2, 71.7, 59.6, 56.6, 49.6, 45.7, 42.2, 39.8,
39.6, 37.0, 35.5, 29.8, 29.1, 27.8, 23.4, 22.2, 13.7; FTIR (cmꢀ1) (neat) br
3435, 2927, 17.37, 16.44, 1455, 1250, 1160; HRMS (ESI, Pos) calcd for
C21H35NO5 [M þ H]þ: 382.2588 m/z, found 382.2599 m/z.
afforded 95 mg (75%) of (þ)-luciduline (1) as a light yellow oil. [R]20
:
D
þ87.3 (c 0.495, MeOH), lit.8b [R]22D þ87 (c 2.05, MeOH); 1H NMR
(CDCl3, 400 MHz) δ 3.05 (dd, J = 16.0, 12.0 Hz, 1H), 2.83 (d, J = 8.0
Hz, 1H), 2.42 (br s, 1H), 2.38ꢀ2.28 (m, 2H), 2.24 (br s, 1H), 2.21ꢀ2.11
(m, 4H), 2.08ꢀ2.04 (m, 1H), 2.03ꢀ1.92 (m, 1H), 1.91ꢀ1.80 (m, 2H),
1.69 (br s, 1H), 1.55ꢀ1.51 (m, 1H), 1.25 (td, J = 12.0, 4.0 Hz, 1H), 0.99
(t, J = 14.0 Hz, 1H), 0.90 (d, J = 4.0 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 215.9, 62.7, 58.8, 46.6, 46.4, 42.3, 39.8, 38.5, 36.6, 35.0, 33.8,
22.3, 20.1; FTIR (cmꢀ1) (neat) 2915, 2861, 2856, 1693, 1458, 1293,
1197, 1133, 909; HRMS (ESI, Pos) calcd for C13H21NO [M þ H]þ:
208.1696 m/z, found 208.1690 m/z.
tert-Butyl (1S,3R,4aS,7R,8aR)-3-Methyl-6-oxodecahydro-
1,7-(epiminomethano)naphthalene-10-carboxylate (23). A
solution of enone 11 (1.00 g, 3.07 mmol), 10% palladium on carbon
(0.654 g, 0.615 mmol), and Boc2O (1.01 g, 4.61 mmol) in ethanol
tert-Butyl (1S,3R,4aS,5R,7R,8aR)-5-Bromo-3-methyl-6-ox-
odecahydro-1,7-(epiminomethano)naphthalene-10-carbox-
ylate (26). To a stirred solution of ketone 23 (0.785 g, 2.68 mmol) in
THF (31.5 mL) at 0 °C was slowly added phenyltrimethylammonium
5360
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ARTICLE
tribromide (1.006 g, 2.68 mmol). The reaction mixture was stirred at
0 °C for 15 min followed by an additional 15 min at room temperature.
The solution became white and cloudy. Water and Et2O were added, the
layers were separated, and the aqueous layer was extracted with Et2O.
The combined organic extracts were dried over MgSO4, filtered over
Celite, and concentrated under reduced pressure. Flash chromatography
of the gray solid with EtOAc/hexanes (15/85) afforded 0.820 g of
’ REFERENCES
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bromoketone 26 (82%) as a white solid, mp 168ꢀ171 °C. [R]20
=
D
þ129.9 (c 0.535. CHCl3); 1H NMR (CDCl3, 400 MHz) δ 5.14 (d, J =
12.0 Hz, 1H), 4.10 (dt, J = 13.3, 2.0 Hz, 1H), 3.50ꢀ3.47 (m, 1H),
3.32ꢀ3.26 (m, 1H), 3.02 (dd, J = 16.0, 4.0 Hz, 1H), 2.88 (br s, 1H),
2.43ꢀ2.36 (m, 1H), 2.29ꢀ2.21 (m, 1H), 2.07ꢀ1.77 (m, 4H), 1.47 (s,
9H), 1.35ꢀ1.26 (m, 1H), 1.13ꢀ1.04 (m, 1H), 0.98 (d, J = 8.0 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 203.3, 156.8, 80.8, 60.3, 56.0, 48.2, 48.2,
45.9, 39.9, 38.2, 38.2, 33.3, 28.4, 21.8, 20.7; FTIR (cmꢀ1) (neat) 2929,
2867, 1709, 1366, 1297, 1158; HRMS (ESI, Pos) calcd for
C17H26BrNO3 [M þ H]þ: 372.1169 m/z, found 372.1182 m/z.
(3R,4aR,5S,7R,8aR)-7-Methyloctahydro-1,5,3-(azanetriyl-
methano)naphthalen-2(1H)-one (27). To a stirred solution of
bromoketone 26 (1.42 g, 3.81 mmol) in DCM (9.54 mL) at 0 °C was
added trifluoroacetic acid (9.54 mL). The reaction mixture was stirred
1 h at 0 °C and was then slowly added to a 500 mL erlenmeyer flask
equipped with a stir bar and containing 150 mL of DCM and 150 mL of
10% Na2CO3 aqueous solution. The mixture was stirred for 30 min, the
layers were separated, and the aqueous layer was extracted with DCM.
The combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure yielding 0.730 g of tetracycle 27
(99%) as a beige solid, mp 44ꢀ47 °C. [R]20D = þ58.4 (c 0.640. CHCl3);
1H NMR (CDCl3, 400 MHz) δ 3.38 (d, J = 4.4 Hz, 1H), 3.30 (d, J = 14.0
Hz, 2H), 3.17 (d, J = 12.0 Hz, 1H), 2.55 (br s, 1H), 2.29 (d, J = 2.4 Hz,
1H), 2.07 (d, J = 13.2 Hz, 1H), 2.00 (br s, 1H), 1.98ꢀ1.89 (m, 1H),
1.89ꢀ1.81 (m, 2H), 1.79ꢀ1.65 (m, 1H), 1.11 (t, J = 13.2 Hz, 1H), 0.99
(t, J = 12.0 Hz, 1H), 0.91 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 216.7, 71.0, 70.1, 60.2, 55.0, 45.2, 43.7, 40.3, 38.2, 35.7, 25.4,
21.3; FTIR (cmꢀ1) (neat) 2924, 2870, 1756, 1456, 1025, 958, 733;
HRMS (ESI, Pos) calcd for C12H17NO [M þ Na]þ: 214.1202 m/z,
found 214.1213 m/z.
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’ ASSOCIATED CONTENT
1
Supporting Information. H NMR, 13C NMR, and HPLC
S
b
chromatograms for the determination of the enantiomeric ratio
16. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: guillaume.barbe@novartis.com.
Present Addresses
§Novartis Institutes for Biomedical Research, 100 Technology
Square, Cambridge, MA 02139.
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’ ACKNOWLEDGMENT
We thank Merck Frosst Canada for financial support to D.F.
during his undergraduate work terms. We also thank Dan
Sorensen for NMR and Ravi Sharma and Serge Plamondon for
analytical support. Finally, we thank Dr. Martine Gravelle and
Vincent Lindsay for revision of the manuscript.
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(14) See Supporting Information for more details.
(15) Using our optimized conditions from Table 1, 100% conversion
of the homoallylic alcohol to its corresponding terminal alkene dimers
was observed.
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(19) Unpublished results.
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