Studies toward the Synthesis of Lepadiformine A

Article abstract of DOI:10.1021/acs.joc.6b01514

Herein is described an original approach to access a tricyclic framework of the lepadiformine-type alkaloids. A Grignard/N-acylpyridinium salt reaction of a 4-methoxytetrahydroquinoline is the key carbon-carbon bond-forming step that was used to establish the desired absolute stereochemistry at the C2 position of the target alkaloid. The synthesis features an allylation reaction with an N-acyliminium ion to set the C10 quaternary stereocenter, a mild dissolving-metal cleavage of hindered phenyl carbamates, and an aminoiodocyclization to form the pyrrolidine ring. While this route does not provide the correct C10 stereochemistry, it showcases an efficient method to build analogues with the ring system of this class of alkaloids in 11 steps overall.

Full text of DOI:10.1021/acs.joc.6b01514

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Article
Studies toward the Synthesis of Lepadiformine A
Sergey V Tsukanov, Lucas R. Marks, and Daniel L. Comins
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01514 • Publication Date (Web): 14 Sep 2016
Downloaded from http://pubs.acs.org on September 16, 2016
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Studies toward the Synthesis of Lepadiformine A
†
‡
Sergey V. Tsukanov , Lucas R. Marks and Daniel L. Comins*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695ꢀ8204,
United States
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Eꢀmail: Daniel_Comins@ncsu.edu
ABSTRACT: Herein is described an original approach to access a tricyclic framework of the
lepadiformineꢀtype alkaloids. A Grignard/Nꢀacylpyridinium salt reaction of a 4ꢀmethoxy
tetrahydroquinoline is the key carbonꢀcarbon bondꢀforming step that was used to establish the
desired absolute stereochemistry at the C2 position of the target alkaloid. The synthesis features
an allylation reaction with an Nꢀacyliminium ion to set the C10 quaternary stereocenter, a mild
dissolvingꢀmetal cleavage of hindered phenyl carbamates, and an improved
aminoiodocyclization to form the pyrrolidine ring. While this route does not provide the correct
C10 stereochemistry, it showcases an efficient method to build analogs with the ring system of
this class of alkaloids in 11 steps overall.
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INTRODUCTION
A marine tunicate Clavelina lepadiformis was collected in the Mediterranean sea by Biard and
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served as a source of an azatricyclic alkaloid lepadiformine A (1a). This alkaloid belongs to a
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large family of natural products (Figure 1), and since its initial discovery by Blackman in 1990,
more than 10 different alkaloids from a variety of tunicates have been isolated and further
characterized. The structural features of this class are unique perhydropyrrolo[2,1ꢀj]quinoline or
perhydropyrido[2,1ꢀj]quinoline frameworks.
Initially it was proposed that lepadiformine A has a zwitterionic structure 1d similar to
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cylindricine with a cis relationship between the A and B ring (Figure 1); however, this structure
was proven to be incorrect since in 1999 the Weinreb group prepared this molecule and
comparison of spectroscopic data with naturally isolated material revealed distinct
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discrepancies. In the same year, Pearson and coꢀworkers accomplished the synthesis of three
different diastereomers of originally proposed compound 1d but none of the prepared
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compounds fully matched the authentic alkaloid. A year later, the structure of lepadiformine
was finally unambiguously established by the Kibayashi group who was able to furnish the
racemic synthesis of 1a and prepare a sample of its hydrochloride salt for the Xꢀray
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crystallographic analysis. The most striking structural element of the alkaloid core is an atypical
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boat conformation of the B ring that forms to avoid an unfavorable A interaction between the
pyrrolidine Cꢀring and hexyl substituent in the rigid transꢀfused 1ꢀazadecalin system. Taking into
consideration this particular structural element during the initial planning steps is crucial for
achieving any success in the synthesis of the core.
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Figure 1. Tricyclic alkaloids isolated from marine tunicates
Challenging structures of this class of alkaloids prompted significant interest from the
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scientific community. As a consequence, a multitude of successful approaches toward the total
syntheses of lepadiformine were developed. These efforts clearly underlined the difficulties in
formation of the C5 and the quaternary C10 stereocenters possessing a trans stereochemistry.
Retrosynthetically, the majority of routes were designed to introduce these key elements initially
and then build a B and C ring system later. Thus, commonly utilized strategies for the
indolizidine group members of this alkaloid family were not effective despite a presence of an
obvious indolizidine motif (B,C rings) in the lepadiformine structure. The most frequent starting
point leading to the most straightforward syntheses of the core was utilization of an amino acid
derived building block, pyroglutamic acid or its derivatives. These strategies took advantage of
the initial chirality and carbonyl functionality of the amino acid to build a Cꢀ10 quaternary center
and to form a cyclohexane A ring in a stereoselective fashion. For example, in the work of
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Kibayashi, Weinreb, and Hsung, protected lactams were used to generate Nꢀacyliminium ions
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which were cyclized to afford corresponding transꢀ5,10 spirocycles (Scheme 1). Installation of
the piperidine B ring and closing of the transꢀperhydroquinoline subunit were the finishing
elements of these syntheses.
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Kibayashi 2000, Hsung 2004
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S-pyroglutamic acid
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Renaud 2006, Zhao 2010
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our approach
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C H
6 13
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Scheme 1. Different strategies toward the lepadiformine skeleton
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Using similar bond disconnections, the Shibasaki and Kim groups utilized a Mannichꢀaza
Michael cascade and a ClaisenꢀIreland rearrangement, respectfully, to set the transꢀ5,10
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stereocenters. The Tokuyama group accomplished the same goal by application of an unusual
1,5ꢀradical migration translocationꢀcyclization reaction of an Nꢀ(2ꢀiodobenzyl) pyrollidinꢀ2ꢀone.
In another approach, the trans relationship between C5 and C10 centers was introduced
initially using manipulation of cyclohexane A ring followed by the formation of the C ring in the
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later stages of the syntheses (Scheme 1). The Funk and Rychnovsky groups introduced the
desired C5/C10 stereochemistry by synthesizing an A ring by using a DielsꢀAlder strategy with
amidoacrolein as a dienophile and a double alkylation of an aminonitrile with a chiral dibromide,
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respectfully. Craig and coꢀworkers started with an easily accessible cyclohexanone that was
converted into a unique spiroaziridine motif and further manipulated to provide the desired
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pyrrolidine C fragment. The Renaud group developed an inventive radical of exocyclic alkene
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to introduce the desired functionality. Finally, in the Zhao synthesis, addition of an allylzinc
reagent to a chiral tertꢀbutanesulfinyl imine was used to set the C10 quaternary center.
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17
Unique strategies to access lepadiformine were recently developed by the Aube group and
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by Lygo and coꢀworkers. In the first case, a Prins type reaction of 1ꢀsilyloxyꢀ1ꢀ
cyclohexylcyclopropane with an aldehyde furnished a cyclobutanone intermediate which was
subjected to Schmidt rearrangement to forge the desired framework of the natural product. In the
second approach, the tricyclic core of lepadiformine was prepared in a oneꢀstep protocol using an
intramolecular heteroꢀDielsꢀAlder reaction.
We envisioned a novel approach for the construction of the lepadiformine core using an
alternative disconnection strategy. Herein we report our attempt at accessing this alkaloid via an
unique route from inexpensive 4,7ꢀdichloroquinoline as starting material and using an A/B
system as the initial framework to install all stereocenters and the pyrrolidine ring C. Our studies
revealed interesting reactivity patterns for nucleophilic additions of organometallic reagents with
hindered bicyclic N-acylvinylogous amides. Unexpected stereochemical outcomes of these
reactions were observed that differ from anticipated results based on similar transformations of
related monocyclic dihydropyridone systems.
RESULTS AND DISCUSSION
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. Retrosynthetic Strategy. A plan was conceived where a simple quinoline would serve as a
progenitor for the A and B rings of lepadiformine. Our detailed strategy was based on this idea as
shown in Scheme 2. It was envisioned that the initial stereocenter would be installed via an
asymmetric Nꢀacylpyridinium salt reaction of 4ꢀmethoxyꢀ5,6,7,8ꢀtetrahydroquinoline 8 to
provide compound 7 having the reactive functionality for introducing the C10 quaternary
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stereocenter via conjugate addition of an organometallic species. Deprotection of the secondary
amine followed by its nucleophilic attack to open a chiral epoxide would form pyrrolidine ring
C. Desired epoxide
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would be prepared using
a
Sharpless asymmetric
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dihydroxylation/cyclization sequence starting from the alkene 6. Finally, the ketone carbonyl
would be removed at the end of the synthesis.
Scheme 2. Retrosynthetic analysis of lepadiformine
2. N-Acylpyridinium salt reaction of 4-methoxy-5,6,7,8-tetrahydroquinoline.
Commercially available 4,7ꢀdichloroquinoline (9) was chosen as a suitable and inexpensive
starting material. The synthesis commenced with nucleophilic substitution of the C4 chlorine
with a methoxy group upon treatment with NaOMe in refluxing MeOH (Scheme 3). The
simultaneous operation of removing the C7 chlorine and reduction of the benzene ring was
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successfully accomplished using Pd/C and hydrogen
at balloon pressure.
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Scheme 3. NꢀAcylpyridinium salt reaction of 4ꢀmethoxyꢀ5,6,7,8ꢀtetrahydroquinoline
Formation of the Nꢀacylpyridinium salt with phenyl chloroformate followed by treatment with
nꢀhexyl Grignard reagent provided racemic enone 11a in excellent yield after acidic work up.
With compound 11 in hand, the possibility of a corresponding asymmetric synthesis was
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investigated. The analogous reaction using the chiral chloroformate of (ꢀ)ꢀCPC gave
octahydroquinolone 12 in an unoptimized but promising 80% yield and 50% de.
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. Introduction of the C10 quaternary stereocenter. Our efforts were now directed toward
introducing the C10 quaternary center via conjugate addition to 11. Unfortunately, multiple
attempts with a broad range of nucleophiles and Lewis acids did not result in formation of any
1,4ꢀaddition product 13 (Scheme 4).
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O
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addition
MgBr
68%, 7:1 dr
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CO2Ph
1a, R = n-Hex
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CO2Ph
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CO Ph
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84%, 9:1 dr
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CO2Ph
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CO Ph
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6a cis-
6b trans-
Scheme 4. Preliminary attempts at the C10 quaternary center formation
A sigmatropic oxyꢀCope rearrangement approach also proved to be unsuccessful. The
addition of allyl Grignard to 11b provided alcohol 14 in 68% yield as a 7:1 mixture favoring the
desired diastereomer; however, heating compound 14 in the presence of KH as a base failed to
provide the rearrangement product and only unreacted starting material was recovered. The
failure is probably due to inability of this system to reach a transition state with proper orbital
overlap necessary for the sigmatropic rearrangement.
The major barrier to the success of the conjugate addition reactions of 11 was a lack of
reactivity of the Nꢀacylvinylogous amide system due to steric and stereoelectronic reasons. To
obviate this problem, the idea of transforming 11 to a more reactive Nꢀacyliminium ion was
pursued. To this end, dihydropyridone 11a was converted into the alcohol 16 (Scheme 4) and
then treated with TMSOTf to furnish a highly reactive Nꢀacyliminium ion that was intercepted
2
0
o
by allyltributyltin at ꢀ100 C. Unfortunately, in this case the C4ꢀaddition product 17 was
isolated in a 9:1 diastereomeric ratio. The stereochemistry of the major product was confirmed
via NOE studies. Another problem with this transformation was the varying amounts of product
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8 generated from the N-acyliminium ion through a competitive isomerization. This pathway
could be minimized by conducting the reaction at low temperatures and very high concentrations
of nucleophile.
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With the reactivity problem solved, our experiments focused on finding a solution to the
regiochemistry problem. To address this issue, a bulky substituent at the C4 position was
introduced. Thus, dihydropyridone 11a was transformed into allylic alcohol 19a via addition of
dimethylphenylsilyllithium (Scheme 5). Indeed, when the allylic alcohol 19a was exposed to
TMSOTf the resulting Nꢀacyliminium ion reacted with allyltributyltin at the C10 position,
forming the desired regioisomer 20 in 56ꢀ70% yield; however, at this stage, extensive NMR
studies were not able to assign stereochemistry of the newly formed quaternary center.
Scheme 5. Allylation of Nꢀacyliminium ion with a C4 blocking group
2
1
It was also discovered that under conditions developed by Trauner and coꢀworkers,
dihydropyridone 11a would undergo a direct C10 allylation via a similar Nꢀacyliminium type
intermediate formed through reaction with triflic anhydride. Furthermore, the synthesis of
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compound 22 from both vinyl silane 20 and vinyl triflate 21 confirmed that the reaction proceeds
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in similar manner providing the same stereochemical outcome. Pdꢀmediated reduction of 21
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was conducted using formic acid and tributylamine while desilylation of 20 was realized with
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TBAF in DMSO at 80 C. Comparison of H and C NMR spectra of the both products did not
show any discrepancies.
The stereochemical assignment of C10 quaternary center was achieved upon removal of
carbamate protecting group. Due to steric hindrance of this carbamate, simple cleavage using
basic conditions was not a plausible option. Reduction was also a challenge due to a presence of
the terminal double bond. As an alternative approach, a milder reduction procedure was
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developed. Carbamate 20 was exposed to sodium metal in NH /THF at –78 C. In this case
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precise control of conditions was key and the reaction was quenched immediately upon
appearance of a blue color in order to avoid over reduction of the phenylsilyl protecting group.
Unfortunately, NOE analysis demonstrated that the C10 quaternary center possesses
stereochemistry opposite to the one found in lepadiformine A.
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a
a
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N+
N+
N+
b
b
b
CO Ph
CO Ph
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CO Ph
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H
CO Ph
2
H
H
H
CO Ph
N
2
H
CO Ph
2
H
R Si
H
N
3
R Si
3
b
b
N
H
R Si
3
H
HO
H
2
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2
4ts
25
TMS
allyltin 27
2,6-cis
SiR3
SiR3
OH
SiR3
C H
6
C H
13
C H
6
13
C H
6
6
13
13
R Si
3
2
H
N
H
10
H
N
N
H
N
CO Ph
CO Ph
2
CO Ph
2
CO Ph
2
H
H
A1,3 strain
2
1
9ts
19a
20
26
allyltin
allyltin
does not form!
2,10-trans
HO
C H
6
13
C H
6 13
4
a
C H
6
13
H
N
H
H
1
0
N
N
H
CO Ph
2
CO Ph
16
2
CO Ph
2
1
6ts
17
2
,4-cis
Scheme 6. The bifurcated reactivity of Nꢀacyliminium ion
It is worth noting that these stereochemical results were unanticipated since prior work with
the model system 24 revealed that an allyltin nucleophile attacks the Nꢀacyliminium ion mainly
from the direction cis to C2 substituent through a boat conformation generating product 25
(
Scheme 6). Moreover, it is a known that most conjugate additions of simple dihydropyridones
commonly proceed with high stereoselectivity forming cisꢀ2,6ꢀdisubstituted piperidones to avoid
a higher energy twistꢀboat transition state. Behavior of the N-acyliminium intermediate in the
bicyclic system 19 is defined by nonꢀbonding interaction between C2, C10 substituents and the
ts
carbamate group but differs from the simple dihydropyridone system 24 due to a presence of
ts
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the additional fused cyclohexane ring. Also, in the absence of a blocking substituent at the C4
position of the iminium ion (16 ), there is a significantly higher energy barrier for an attack at
ts
the C10 vs C4 positions of the iminium ion. Taking into account stereoelectronic and steric
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considerations, a reasonable outcome of this reaction is the 2,4ꢀcis compound 17 formed via
axial attack at Cꢀ4 of the iminium ion intermediate (16 ). Steric interactions with the bulky
ts
silicon group in 19 reverses the regioselectivity by forcing nucleophilic attack to occur at the
ts
C10 position. Unfortunately, in the transition state, the 1,3ꢀallylic strain interactions of the
cyclohexane ring with the phenyl carbamate, ring strain, and stereoelectronic effects combine to
force the allyl nucleophile to approach the iminium ion from the opposite face via a twistꢀboat
conformation to generate the 2,10ꢀtrans compound 20.
Given the outcome of these experiments, it was decided to investigate the reactivity of
intermediate 19 further. It is also important to mention that despite numerous attempts, the only
nucleophile suitable for addition at the C10 position was allyltributytin. To probe reactivity with
a more functionallized organotin nucleophile, compound 27, accessed in five steps starting from
ethyl propiolate, was examined as a potential nucleophile in this system (Scheme 7).
Nucleophilic addition and TMS cleavage via protonation would provide the four carbon butenyl
side chain required to accomplish formation of the C ring of the lepadiformine system. To our
surprise, reaction of allylic alcohol 19b with 27 resulted only in an elimination product and no
C10 addition was observed. This result is in contrast to the analogous reaction previously carried
out with 24 to give 25 (Scheme 6). Allylic alcohol 19 was also successfully transformed into two
other Nꢀacyliminium ion precursors 29 and 31; however, all attempts at reacting these
compounds with a variety of organometallic reagents failed to provide any evidence of the
desired addition products.
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Ph
Ph
Ph Si OMOM
Si OH
Si
N
MOMCl, (i-Pr) NEt
PPTS, MeOH
50%
2
19b
1
9a
10
11
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KI, DMF
2%
N
R
N
CO
6
MeO
CO Ph
31
Ph
2
CO Ph 29
2
2
19a, R = n-Hex
9b, R = n-Pr
1
CO Et
2
Grignard, cuprates
LA
5
steps
LA
2
6
SnBu3
Grignard, LA
Ph
TMS
27
Ph
Si
N
Ph
Si
N
Si
N
CO Ph
CO Ph
2
28
2
30a
CO Ph
2
30b
TMS
Scheme 7. Attempts at introduction of butenyl side chain at C10
. Synthesis of the C ring and a lepadiformine analog. Although an intermediate with the
4
right configuration at the C10 quaternary center could not be accessed, it was decided to pursue
our endgame strategy and attempt to finish the C ring and potentially a diastereomer of the
natural product. To accomplish this objective it was required to add an extra carbon atom by
transforming the allyl side chain into a butenyl one. One way to achieve this goal is to perform a
threeꢀstep protocol including hydroboration, oxidation and methylenation. Previously our group
2
4
developed an efficient oneꢀstep procedure that consists of two reactions: metathesis to form an
allylic acetate or carbonate followed by a TsujiꢀTrost reduction.
nd
Unfortunately, under our original conditions, reaction of alkene 20 with Grubbs 2 generation
catalyst and the bis(carbonate) 32, or the corresponding bis(acetate), provided the required
functionalized alkene 33 only in poor yield (Scheme 8). A better result was obtained by
nd
25
switching to GrubbsꢀHoveyda 2 generation catalyst. In the second step, the TsujiꢀTrost
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reduction with Pd (dba) chloroform adduct and PPh as a ligand was generating an inseparable
2
3
3
mixture of the terminal and Z, Eꢀinternal olefins. After some experimentation, it was found that a
simple ligand exchange to PBu furnishes the desired terminal alkene 30a as a single product;
3
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0
however, in this case the two catalytic systems appeared to be incompatible and each step had to
be conducted separately. Thus, the allyl side chain was converted into a butenyl group in two
steps and 50ꢀ60% overall yield.
5
.0 equiv
Ph
Ph
Si
N
Ph
Si
N
Si
N
HCO NH , Pd (dba) CHCl ,
MeO CO
OCO Me
2
4
2
3
3
2
32
2
PBu , dioxane
Grubbs-Hoveyda 2nd Gen
3
5
0 oC,
60%, 2 steps
CO Ph
CO Ph
2
CO Ph
2
2
20
33
3
0a
OCO Me
2
Scheme 8. Synthesis of the butenyl side chain
With the side chain in place our next experiments concentrated on formation of the C ring.
Using our earlier developed method, the phenyl carbamate group of 30a was removed under
dissolvingꢀmetal conditions. In our original plan, a chiral epoxide was to be the electrophile in
the cyclization reaction to form the C ring; however, with racemic material in hand, an
1
2
aminoiodocyclization strategy was pursued based on the precedent from the Funk group
(Scheme 9). Under these conditions the tricyclic products 35 were isolated in 50ꢀ67% yield.
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Scheme 9. Iodoaminocyclization reaction of 34
Despite extensive efforts to improve on the initial result, diastereoselectivity of the process
2
6
remained low (2ꢀ5:1 dr). After screening different sources of iodine (I , NIS, ICl, I(col) ClO ) ,
2
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4
10
11
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60
Nꢀiodosuccinimide showed the best balance of reactivity and the cleanest reaction profile.
Solvents and temperature had limited influence on the overall outcome of this process. Cooling
of the reaction during the first step led to a slight improvement in diastereoselectivity. The
highest yield of the product was obtained using 1.1 equiv of NIS in methylene chloride with slow
o
o
27
warming of reaction mixture from ꢀ45 C to 0 C. Careful analysis of the reaction mixtures led
to a conclusion that low yields of the product could be a result of competing pathways. Under
similar reaction conditions cleavage of a dimethylphenylsilyl protecting group has been
2
8
reported. In the presence of base, the labile primary iodide can also undergo elimination.
Variable amounts of these alkenes were present in the crude reaction mixtures but their isolation
was not pursued.
In order to complete the analog synthesis, the dimethylphenylsilyl protecting group of 35a
was removed with TBAF, following the previously reported method by the Feringa group, to
2
3
provide alkene 36 (Scheme 10). The resulting alkene was reduced using H and Pd/C.
2
Hydrogenation proceeded selectively from the β face resulting in the cis fused ring system found
in the previously synthesized double epimer of lepadiformine (37). This confirmed the
stereochemistry of the iodoaminocyclization step. The spectral characteristics for the prepared
3
material were in accordance with the data previously reported by Weinreb .
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Ph
Si
N
H
TBAF, THF/DMSO
H , Pd/C, EtOH
2
8
0 °C
N
N
6
4%, 2 steps
3
5a
36
37
0
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7
8
9
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1
2
3
4
5
6
7
8
9
0
OH
OH
OH
Scheme 10. Synthesis of the lepadiformine C10,15 epimer
CONCLUSIONS
In summary, we have investigated a new strategy toward the synthesis of the tricyclic alkaloid
lepadiformine starting from 4,7ꢀdichloroquinoline. This approach demonstrates the power and
versatility of Nꢀacylpyridinium salt chemistry which can be successfully translated to quinoline
derivatives. This work also includes a detailed study of vinylogous amide reactivity. We were
able to show the unique nature and high reactivity of Nꢀacyliminium intermediates formed from
the bicyclic dihydropyridones, which allowed the introduction of the hindered Cꢀ10 quaternary
center using allytributyltin as a nucleophile. Alternatively, the same reaction could provide a 1,4ꢀ
addition product exclusively and stereoselectively simply by removing any blocking group at C4.
Also developed was a very mild dissolvingꢀmetal reduction procedure to cleave hindered
phenylcarbamate groups. Despite the fact that the constructed quaternary center had the opposite
stereochemistry of the alkaloid lepadiformine A, our approach showcases a distinct, original and
effective approach for the preparation of similar tricyclic systems. Finally, our pursuit of the
original endgame strategy gives some additional insight in the area of iodoaminocyclizations,
efficiency of this reaction based on the substrate, and also provided us an opportunity to prepare
the doubleꢀepimer analog 37 of the natural product with high stereoselectivity in 11 steps overall.
EXPERIMENTAL SECTION
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29
7
-Chloro-4-methoxyquinoline (10). Sodium metal (2.38 g, 103 mmol) was slowly added to
methanol (50 mL) at ꢀ30 °C with stirring. The reaction was stirred at room temperature for 18 h.
A solution of 4,7ꢀdichloroquinoline (4.04 g, 20.4 mmol) in 5 mL of methanol was added to the
sodium methoxide solution, and the mixture was heated to reflux for 24 h. The excess methanol
was removed via distillation or rotary evaporation. To the crude material was added EtOAc (50
mL) and deionized water (50 mL). The organic layer was separated, and the aqueous phase was
extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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31
32
33
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35
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37
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52
53
54
55
56
57
58
59
60
1
mL), filtered, and concentrated to afford 3.71 g (94%) of 7ꢀchloroꢀ4ꢀmethoxyquinoline. H NMR
(
CDCl , 400 MHz) δ 8.75ꢀ8.73 (d, 1H, J = 5.6 Hz), 8.13ꢀ8.11 (d, 1H, J = 8.8 Hz), 8.02ꢀ8.01 (d,
3
1H, J = 2.4 Hz), 7.45ꢀ7.42 (dd, 1H, J = 9.2, 2.0Hz). 6.73ꢀ6.72 (d, 1H, J = 5.2 Hz), 4.04 (s, 3H);
1
3
C NMR (CDCl , 100 MHz) δ 162.5, 125.7, 149.9, 135.9, 128.1, 126.7, 123.6, 120.0, 100.5,
3
56.0.
3
0
4-Methoxy-5,6,7,8-tertahydroquinoline (8).
In a 1ꢀL flask were added 7ꢀchloroꢀ4ꢀ
methoxyquinoline (19.8 g, 102 mmol), lithium carbonate (9.23 g, 125 mmol), 10% palladium on
carbon (13.3 g) and 500 mL of EtOH. The reaction was charged with hydrogen gas at balloon
pressure and stirred. After 5 days, the reaction mixture was filtered through Celite with hot
methanol. The solvent was removed via rotary evaporation. The oil was purified by column
chromatography (silica gel, 5% MeOH/CH Cl ) to afford 10.2 g (60%) of compound 8. IR (neat)
2
2
ꢀ1
1
2
935, 1578, 1475, 1439, 1336, 1289, 1160, 1109, 1089, 1057, 997, 879, 808 cm ; H NMR
(
CDCl , 400 MHz) δ 8.25, (d, 1H, J = 5.6 Hz), 6.57, (d, 1H, J = 5.6 Hz), 3.84 (s, 3H), 2.87 (t,
3
1
3
2H, J = 6.0 Hz), 2.62 (t, 2H, J = 6.4 Hz), 1.80 (m, 4H); C NMR (CDCl , 100 MHz) δ 163.7,
3
+
1
58.0, 121.3, 148.0, 103.3, 55.3, 32.6, 22.9, 22.4, 22.3; HRMS calcd for C H NO ([M+H] )
10
14
164.1075, found 164.1064.
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rac-Phenyl 2-n-hexyl-4-oxo-3,4,5,6,7,8-hexahydroquinoline-1(2H)-carboxylate (11a). To a
solution of 4ꢀmethoxyꢀ5,6,7,8ꢀtetrahydroquinoline 8 (638 mg, 3.91 mmol) in 10 mL of
anhydrous THF was added dropwise phenyl chloroformate (0.54 mL, 4.32 mmol) at ꢀ42 °C. The
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o
reaction mixture was stirred at ꢀ42 C for 30 min and then cooled to ꢀ78 °C. The solution of nꢀ
hexylmagnesium bromide (0.78M in THF, 10 mL, 7.8 mmol) was transferred dropwise to the
flask containing the newly formed Nꢀacylpyridinium salt and stirring was continued at ꢀ78 °C for
3 h. The reaction mixture was quenched with 10% HCl (10 mL), warmed to rt and stirred for an
additional hour. The aqueous layer was extracted with Et O (2 × 10 mL). The combined organic
2
extracts were washed with brine (2 × 20 mL), dried over anhydrous MgSO , and concentrated in
4
vacuo. The crude product was purified by radial PLC (SiO , 4ꢀ8% EtOAc/hexanes) to yield 1.2 g
2
(87%) of the hexahydroquinolone 11a as a clear oil. IR (neat) 3044, 2930, 2858, 1725, 1666,
ꢀ1 1
1
609, 1495, 1384, 1338, 1164, 1137, 737 cm ; H NMR (CDCl , 300 MHz) δ 7.41 (m, 2H), 7.26
3
(m, 1H), 7.14 (m, 2H), 4.87 (m, 1H), 3.16 (m, 1H), 2.96 (dd, 1H, J = 5.9, 17.1 Hz), 2.47 (m, 2H),
1
3
2
.26 (m, 2H), 1.82 (m, 3H), 1.57ꢀ1.28 (m, 11H), 0.88 (t, 3H, J = 6.7 Hz); C NMR (CDCl , 75
3
MHz) δ 193.5, 152.3, 150.6, 150.4, 129.5, 125.9, 121.4, 121.3, 55.9, 42.1, 31.6, 30.8, 30.6, 28.9,
+
26.2, 22.6, 22.5, 21.6, 21.4, 14.0; HRMS calcd for C H NO [(M+H) ] 356.2220, found
2
2
30
3
356.2227.
4-Oxo-2-n-propyl-3,4,5,6,7,8-hexahydro-2H-quinoline-1-carboxylic acid phenyl ester (11b).
To a solution of 4ꢀmethoxyꢀ5,6,7,8ꢀtetrahydroquinoline 8 (12 mg, 70 ꢁmol) in 3 mL of THF at ꢀ
o
5
0 C was added phenyl chloroformate (10 ꢁL, 80 ꢁmol). After 30 min, the mixture was cooled
o
to ꢀ78 C, and a 2.0 M solution of nꢀpropylmagnesium bromide (70 ꢁL, 140 ꢁmol) in THF was
o
added dropwise. After 18 h at ꢀ55 C, 0.5 mL of 10% HCl was added, and the reaction was
warmed to room temperature. The organic layer was separated, and the aqueous phase was
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extracted with diethyl ether (3 x 10 mL). The combined organic layers were washed with water
(10 mL) and brine (10 mL). The solution was dried with magnesium sulfate, filtered through
Celite, and concentrated in vacuo. The crude product was purified by radial PLC (silica gel,
gradient 10% to 30% EtOAc/ hexanes) to yield 20 mg (87%) of compound 11b as an oil. IR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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59
60
ꢀ
1 1
(neat) 2934, 2864, 1736, 1667, 1655, 1607, 1495, 1385, 1337, 1287, 1256, 1203, 1137 cm ; H
NMR (CDCl , 300 MHz) δ 7.40 (t, 2H, J = 8.4 Hz), 7.24 (t, 1H, J = 7.5 Hz), 7.13 (d, 2H, J = 7.2
3
Hz), 4.87 (m, 1H), 3.14 (m, 1H), 2.93 (dd, 1H, J = 6.0 Hz, 17.4 Hz), 2.48 (m, 2H), 2.25 (m, 2H),
1
3
1.74ꢀ1.87 (m, 3H), 1.55ꢀ1.35 (m, 5H), 0.96 (t, 3H, J = 7.2 Hz); C NMR (CDCl , 75 MHz) δ
3
1
93.7, 152.5, 150.9, 150.6, 129.7, 126.1, 121.7, 121.6, 55.9, 42.4, 33.2, 30.8, 22.8, 21.9, 21.7,
+
1
9.8, 14.1;HRMS calcd for C H NO ([M+H] ) 314.1756, found 314.1767.
19 24
3
(2R)-2-Hexyl-4-oxo-3,4,5,6,7,8-hexahydro-2H-quinoline-1-carboxylic acid (1R,2S,4R)-4-
isopropyl-2-(1-methyl-1-phenylethyl)cyclohexyl ester (12). To a solution of 4ꢀmethoxyꢀ
5
,6,7,8ꢀtetrahydroquinoline (1.34 g, 8.2 mmol) in 3.5 mL of THF and 10.5 mL of toluene at –30
°
C was added the chloroformate of (ꢀ)ꢀ(1R,2S,4R)ꢀ2ꢀ(1ꢀmethylꢀ1ꢀphenylethyl)ꢀ4ꢀ(2ꢀ
propyl)cyclohexanol (2.74 g, 8.5 mmol) in 3.5 mL of THF and 10.5 mL of toluene. After 4 h, the
reaction was cooled to ꢀ78 °C and nꢀhexylmagnesium bromide (9 mL, 16 mmol) was added
dropwise over 1 h. After stirring the reaction for 4.5 h, 10 mL of 10% aqueous HCl was added
and the reaction was warmed to room temperature. The organic layer was separated, and the
aqueous layer was extracted with Et O (3 x 50 mL). The organic layers were combined, washed
2
with water (50 mL) and brine (30 mL), dried over magnesium sulfate, and filtered. The solvent
was removed in vacuo. The crude oil was purified via column chromatography (1%
EtOAc/hexnaes) to yield 2.57 g (60%) of the major diastereomer and 0.86 g (20%) of the minor
diastereomer (50% d.e.) as clear oils. Major isomer: IR (neat) 2931, 2860, 1709, 1665, 1605,
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ꢀ1
1
1
497, 1467, 1399, 1368, 1337, 1258, 1169, 1148, 1106, 1077, 1034, 989, 861, 766 cm ; H
NMR (CDCl , 300 MHz) δ 7.33ꢀ7.24 (m, 4H), 7.12ꢀ7.07 (t, 1H, J = 6.9 Hz), 4.79ꢀ4.73 (m, 1H),
3
1
3
3
.14ꢀ 3.06 (m, 2H), 2.43ꢀ2.24 (m, 3H), 2.16ꢀ1.67 (m, 8H), 1.47ꢀ0.85 (m, 33H); C NMR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
CDCl , 75 MHz) δ 193.9, 152.8, 152.6, 151.9, 128.5, 125.3, 125.2, 119.4, 53.6, 50.0, 43.7, 42.5,
3
39.8, 33.4, 32.7, 31.7, 30.6, 30.5, 30.2, 29.1, 27.4, 26.2, 23.2, 22.9, 22.8, 21.8, 21.6, 20.3, 19.7,
+
31
1
4.3; HRMS calcd for C H NO [(M+H) ] 522.3947, found 522.3950; [α] D: ꢀ 102 (c 1.79,
34 52 3
MeOH).
Minor isomer: IR (neat) 2930, 2859, 1696, 1665, 1605, 1386, 1325, 1303, 1168, 1146, 1029,
ꢀ1
1
7
61, 732 cm ; H NMR (CDCl , 300 MHz) δ 7.26ꢀ7.21 (t, 2H, J = 7.5, 6 Hz), 7.14ꢀ7.09 (t, 2H, J
3
=
7.5 Hz), 7.00ꢀ6.95 (t, 1H, J = 6.9 Hz), 4.84ꢀ4.76 (dt, 1H, J = 10.8, 4.5 Hz), 4.60ꢀ4.54 (q, 1H, J
= 6.6 Hz), 2.73ꢀ2.65 (dd, 1H, J = 17.4, 6.0 Hz), 2.38ꢀ2.27 (m, 3H), 2.20ꢀ1.84 (m, 4H), 1.76ꢀ1.60
13
(
m, 4H), 1.50ꢀ0.98 (m, 23H), 0.94ꢀ0.82 (m, 10H); C NMR (CDCl , 75 MHz) δ 194.1, 153.5,
3
1
52.2, 150.7, 128.0, 125.2, 125.0, 119.8, 55.2, 52.1, 43.7, 42.1, 39.7, 33.2, 32.7, 31.8, 31.3, 30.8,
0.5, 29.8, 29.1, 27.3, 26.3, 23.0, 22.7, 22.7, 21.6, 21.5, 20.4, 19.7, 14.2; HRMS calcd for
3
+
31
C H NO [(M+H) ] 522.3947, found 522.3947; [α] D: + 99 (c 1.25, MeOH).
34
52
3
4-Allyl-4-hydroxy-2-n-propyl-3,4,5,6,7,8-hexahydro-2H-quinoline-1-carboxylic acid
phenyl ester (14). To a solution of hexahydroquinolone 11b (79 mg, 250 ꢁmol) in 2 mL of Et O
2
at ꢀ78 °C was added dropwise a solution of 1.35 M 1ꢀpropenylmagnesium chloride (200 ꢁL, 270
ꢁ
mol) in THF. After 3 h at ꢀ78 °C, 2 mL of ammonium chloride was added and the mixture was
warmed to room temperature. The organic layer was separated, and the aqueous phase was
extracted with Et O (3 x 10 mL). The combined organic layers were washed with water (10 mL)
2
and brine (10 mL), and dried over magnesium sulfate. The mixture was filtered through Celite
and concentrated via rotary evaporation. The crude product was purified by radial PLC (silica
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gel, 10% EtOAc/hexanes) to afford 61 mg (68%) of the major diastereomer 14 as a light yellow
oil. IR (neat) 3491, 2932, 2860, 1738, 1732,1699, 1686, 1681, 1595, 1506, 1495, 1394, 1327,
ꢀ1 1
1
204, 1162, 999, 912, 751, 688 cm ; H NMR (CDCl , 300 MHz) δ 7.36 (t, 2H, J = 7.8 Hz),
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
.19 (t, 1H, J = 7.2 Hz) 7.09 (d, 2H, J = 7.5 Hz), 5.66ꢀ5.80 (m, 1H), 5.18 (s, 1H), 5.14 (d, 1H, J =
5.7 Hz), 4.90ꢀ4.35 (m, 1H), 2.98ꢀ2.93 (m, 1H), 2.42ꢀ2.23 (m, 4H), 2.14 (d, 1H, J = 17.4 Hz),
.98 (d, 1H, J = 16.5 Hz), 1.83ꢀ1.68 (m, 5H), 1.67ꢀ1.54 (m, 2H), 1.52ꢀ1.33 (m, 3H), 0.95 (t, 3H,
1
1
3
J = 6.9 Hz); C NMR (CDCl , 75 MHz) δ 153.2, 151.4, 133.5, 130.5, 129.5, 128.3, 125.5,
3
121.8, 119.5, 70.6, 51.8, 44.8, 42.4, 35.4, 29.5, 23.2, 23.2, 22.8, 20.0, 14.2; HRMS calcd for
C H NO 355.2147, found 355.2122.
22
29
3
rac-Phenyl 2-n-hexyl-4-hydroxy-3,4,5,6,7,8-hexahydroquinoline-1(2H)-carboxylate (16). To
a stirred solution of 11a (465 mg, 1.31 mmol) in MeOH (7 mL) at rt was added cerium chloride
heptahydrate (512 mg, 1.38 mmol), and the mixture was cooled to 0 °C. Sodium borohydride (98
mg, 2.62 mmol) was added and the reaction mixture was stirred for 30 min at 0 °C. The reaction
was quenched with 5 mL of water. The resulting mixture was diluted with Et O, and the organic
2
layer was separated. The aqueous layer was extracted with Et O (2 × 10 mL). The organic layers
2
were combined, washed with water (20 mL) and brine (20 mL), dried over MgSO , filtered
4
through Celite and concentrated in vacuo. The product was purified by radial PLC (SiO , 5ꢀ7.5%
2
EtOAc/hexanes) yielding 196 and 200 mg of cis/trans diastereomeric alcohols 16 (85% overall)
as clear oils.
ꢀ
2,4-Cisꢀalcohol: IR (neat) 3468, 2927, 2857, 1698, 1493, 1396, 1327, 1207, 1129, 1041, 750 cm
1
1
;
H NMR (CDCl , 300 MHz) 7.36 (m, 2H), 7.19 (m, 1H), 7.10 (m, 2H), 4.48 (m, 1H), 3.98 (bs,
3
1
H), 2.97 (m, 1H), 2.49 (m, 1H), 2.23 (dt, 1H, J = 5.8, 14.5 Hz), 2.2 (m, 2H), 1.91ꢀ1.26 (m,
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2
2
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5
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6
13
1
6H), 0.88 (t, 3H, J = 6.5 Hz); C NMR (CDCl , 75 MHz) δ 152.8, 151.2, 130.1, 129.2, 125.2,
3
123.9, 121.5, 65.2, 51.8, 37.2, 31.8, 31.7, 29.4, 29.0, 26.8, 25.9, 23.4, 22.5, 22.4, 14.0; HRMS
+
calcd for C H NO Na [(M+Na) ] 380.2196, found 380.2203.
2
2
31
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
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1
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8
9
0
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9
0
1
2
3
4
5
6
7
8
9
0
2
7
4
1
1
,4ꢀTransꢀalcohol: IR (neat) 3415, 3045, 2930, 2857, 1713, 1495, 1393, 1326, 1206, 1143, 1016,
ꢀ1 1
35 cm ; H NMR (CDCl , 300 MHz) δ 7.36 (m, 2H), 7.20 (m, 1H), 7.11 (m, 2H), 4.53 (m, 1H),
3
.10 (m, 1H), 2.91 (m, 1H), 2.49 (m, 1H), 2.20 (ddd, 1H, J = 2.8, 7.4, 13.2 Hz), 2.06ꢀ1.26 (m,
1
3
8H), 0.88 (t, 3H, J = 6.6 Hz); C NMR (CDCl , 75 MHz) δ 152.9, 151.2, 131.5, 129.3, 125.3,
3
23.1, 121.5, 66.7, 55.1, 37.7, 31.7, 30.8, 29.7, 29.0, 26.4, 25.9, 23.2, 22.5, 22.3, 14.0; HRMS
+
calcd for C H NO Na [(M+Na) ] 380.2196, found 380.2203.
2
2
31
3
rac-Phenyl 4-allyl-2-n-hexyl-3,4,5,6,7,8-hexahydroquinoline-1(2H)-carboxylate (17). To a
solution of diastereomeric alcohols 16 (100 mg, 280 ꢁmol) in CH Cl (1 mL) at ꢀ100 °C was
2
2
added allyltributylstannane (5.0 equiv, 430 ꢁL, 1.40 mmol) followed by dropwise addition of
trimethylsilyl triflate (2.0 equiv, 100 ꢁL, 560 ꢁmol). The reaction was stirred for 1 h at ꢀ100 °C
and then 1M NaOH was added (5 mL). The reaction mixture was warmed to rt and stirred for an
additional hour. The organic layer was separated, and the aqueous layer was extracted with
CH Cl (2 × 10 mL). The combined organic layers were washed with water (10 mL) and brine
2
2
(
10 mL), dried over MgSO , filtered through Celite and concentrated in vacuo. The residue was
4
purified by radial PLC (SiO , 1ꢀ2% EtOAc/hexanes) to afford 90 mg (84%, 9:1 mixture of
2
diastereomers) of allyl product 17 as a clear oil. IR (neat) 3074, 2928, 2857, 1715, 1596, 1495,
ꢀ1 1
1
456, 1392, 1324, 1205, 1143, 993, 912 cm ; H NMR (CDCl , 300 MHz) δ 7.35 (m, 2H), 7.18
3
(
m, 1H), 7.11 (m, 2H), 5.72 (m, 1H), 5.05 (m, 2H), 4.43 (m, 1H), 2.92 (m, 1H), 2.31 (m, 2H),
1
3
2
.18ꢀ1.45 (m, 10H), 1.43ꢀ1.20 (m, 10H), 0.88 (t, 3H, J = 6.3 Hz); C NMR (CDCl , 75 MHz) δ
3
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53.2, 151.4, 136.1, 129.5, 129.2, 125.1, 121.9, 121.6, 116.6, 53.2, 37.1, 35.0, 34.1, 31.7, 31.2,
+
9.6, 29.2, 27.8, 26.4, 23.2, 22.8, 22.6, 14.1; HRMS calcd for C H NO Na [(M+Na) ]
25 35
2
04.2560, found 404.2562.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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60
(
2R*)-4-(Dimethylphenylsilanyl)-4-hydroxy-2-propyl-3,4,5,6,7,8-hexahydro-2Hquinoline-1-
carboxylic acid phenyl ester (19b). To a mixture of lithium wire (94 mg, 13.5 mmol) in 5.0 mL
of THF was added chlorodimethylphenylsilane (240 ꢁL, 1.43 mmol) all at once. The reaction
was stirred at rt for 4 h. In a separate flask was added hexahydroquinolone 11b (206 mg, 657
o
ꢁ
mol) and 5.0 mL of ether. The mixture was cooled to ꢀ78 C, and the
dimethylphenylsilyllithium was added dropwise with a syringe pump over 1 h. After 18 h at ꢀ78
o
C, 5 mL of saturated sodium bicarbonate was added and the reaction was warmed to room
temperature. The organic layer was separated, and the aqueous phase was extracted with Et O (3
2
x 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium
sulfate, and filtered through Celite. The solvent was removed via rotary evaporation, and the
crude material was purified by radial PLC (silica gel, 10% EtOAc/ hexanes) to afford 177 mg
(59%) of compound 19b as a clear oil and 41 mg (20%) of recovered starting material. IR (neat)
3
467, 2933, 2857, 2361, 1699, 1685, 1681, 1652, 1495, 1428, 1394, 1325, 1248, 1204, 1162,
ꢀ1 1
1114, 1024, 817, 775, 737, 701 cm ; H NMR (CDCl , 300 MHz) δ 6.60ꢀ7.57 (m, 2H), 7.38ꢀ
3
7
.38 (m, 5H), 7.19 (t, 1H, J = 7.5 Hz), 7.12 (d, 2H, J = 7.5 Hz), 4.32ꢀ4.24 (p, 1H), 3.03ꢀ2.97 (m,
H), 2.47ꢀ2.40 (dd, 1H, J = 13.8, 7.2 Hz), 2.22ꢀ2.16 (m, 1H), 1.96 (d, 1H, J = 16.8 Hz), 1.81ꢀ
1
1
3
1.60 (m, 5H), 1.57ꢀ1.28 (m, 7H), 0.91 (t, 3H, J = 7.2 Hz) 0.40 (s, 6H); C NMR (CDCl , 75
3
MHz) δ 151.4, 136.4, 134.6, 129.8, 129.5, 129.4, 128.1, 125.5, 121.9, 66.9, 50.8, 42.7, 36.2,
+
2
9.7, 25.3, 23.4, 22.9, 19.8, 15.9, 14.2, ꢀ4.6, ꢀ5.1; HRMS calcd for C H NO Si [(M+H) ]
27 36
3
4
49.2386, found 449.2378.
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rac-Phenyl 8a-allyl-4-(dimethyl(phenyl)silyl)-2-n-hexyl-2,3,6,7,8,8a-hexahydro-quinoline-
1
(5H)-carboxylate (20). To a solution of hexahydroquinolone 11a (115 mg, 323 ꢁmol) in dry
ether (2.5 mL) at ꢀ78 °C was added a freshly prepared solution of dimethylphenylsilyllithium
0.215M in THF, 3 mL, 646 ꢁmol) dropwise over a period of 10 min. The reaction mixture was
0
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4
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8
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7
8
9
0
(
stirred for additional 40 min, quenched with saturated NaHCO (5 mL) and warmed to rt. The
3
biphasic solution was transferred to a separatory funnel. The aqueous layer was extracted with
Et O (2 × 10 mL), the combined organic layers were washed with aqueous NaHCO (10 mL) and
2
3
brine (10 mL), dried over MgSO and filtered through Celite. The volatiles were removed in
4
vacuo and the crude product was purified by radial PLC (SiO , 7% EtOAc/3% Et N/hexanes) to
2
3
remove PhMe SiH. The resulting product 19a was immediately used in the second step without
2
additional purification due to its low stability.
To a solution of allylic alcohol 19a in CH Cl (1 mL) at ꢀ100 °C was added allyltributylstannane
2
2
(5.0 equiv, 500 ꢁL, 1.62 mmol) followed by a very slow dropwise addition of trimethylsilyl
triflate (2.0 equiv, 120 ꢁL, 646 ꢁmol) over a period of 10ꢀ15 min. The reaction was stirred for 1
h at ꢀ100 °C and then 1M NaOH was added (5 mL). The reaction mixture was warmed to rt and
stirred for an additional hour. The organic layer was separated, and the aqueous layer was
extracted with CH Cl (2 × 10 mL). The combined organic layers were washed with water (10
2
2
mL) and brine (10 mL), dried over MgSO , filtered through Celite and concentrated in vacuo.
4
The residue was purified by radial PLC (SiO , 1ꢀ6% EtOAc/hexanes) to afford 93 mg (56%, 2
2
steps) of alkene 20 as a clear oil. IR (neat) 3068, 2930, 2856, 1714, 1614, 1495, 1389, 1355,
ꢀ1 1
1
298, 1250, 1209, 1179, 1110, 813 cm ; H NMR (CDCl , 300 MHz) δ 7.54 (m, 2H), 7.36 (m,
3
5H), 7.19 (m, 1H), 7.08 (m, 2H), 5.73 (m, 1H), 5.08 (m, 2H), 4.49 (m, 1H), 3.53 (m, 1H), 2.89
(m, 1H), 2.58 (m, 1H), 2.50 (m, 1H), 2.34 (m, 1H), 2.16 (m, 2H), 1.65ꢀ1.28 (m, 15H), 0.88 (t,
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13
3
H, J = 6.2 Hz), 0.40 (s, 3H), 0.39 (s, 3H); C NMR (CDCl , 75 MHz) δ 152.6, 151.4, 149.0,
3
139.5, 134.3, 133.5, 129.1, 128.8, 127.7, 124.9, 121.9, 116.9, 63.0, 51.4, 37.1, 36.0, 33.7, 33.0,
+
3
1.7, 31.5, 29.2, 26.8, 22.8, 22.6, 14.0, ꢀ1.0, ꢀ1.1; HRMS calcd for C H NO Si [(M+H) ]
3
3
46
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
32
33
34
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40
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43
44
45
46
47
48
49
50
51
52
53
54
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57
58
59
60
5
16.3292, found 516.3291.
8a-allyl-2-n-hexyl-4-(trifluoromethylsulfonyloxy)-2,3,6,7,8,8a-hexahydroqui-
noline-1(5H)-carboxylate (21). To a solution of enone 11 (68 mg, 191 ꢁmol) in CH Cl (2 mL)
rac-Phenyl
2
2
at ꢀ78 °C was added allyltributylstannane (5.0 equiv, 290 ꢁL, 956 ꢁmol) followed by dropwise
addition of trifluoromethanesulfonic anhydride (2.0 equiv, 60.0 ꢁL, 382 ꢁmol). The reaction was
stirred for 1 h at ꢀ78 °C and then 1M NaOH was added (5 mL). The reaction mixture was
warmed to rt and stirred for an additional hour. The organic layer was separated, and the aqueous
layer was extracted with CH Cl (2 × 10 mL). The combined organic layers were washed with
2
2
water (10 mL) and brine (10 mL), dried over MgSO , filtered through Celite and concentrated in
4
vacuo. The residue was purified by radial PLC (SiO , 1ꢀ2% EtOAc/hexanes) to afford 65 mg
2
(64%) of allyl product 21 as clear oil. IR (neat) 3077, 2932, 2859, 1720, 1594, 1495, 1417, 1364,
ꢀ1 1
1299, 1208, 1142, 1007, 961, 901 cm ; H NMR (CDCl , 300 MHz) δ 7.37 (m, 2H), 7.20, (m,
3
1H), 7.06 (m, 2H), 5.69 (m, 1H), 5.12 (m, 2H), 4.69 (m, 1H), 3.49 (m, 1H), 2.90 (m, 3H), 2.61
(
(
m, 1H), 2.23 (dd, 1H, J = 1.3, 16.5 Hz), 2.12 (tt, 1H, J = 4.7, 14.6 Hz), 1.86 (m, 1H), 1.80ꢀ1.26
1
3
m, 14H), 0.87 (t, 3H, J = 6.6 Hz); C NMR (CDCl , 75 MHz) δ 13.9, 22.4, 22.5, 24.3, 25.4,
3
26.8, 29.0, 31.5, 31.6, 34.2, 35.8, 37.6, 52.6, 63.1, 118.2, 118.3 (q, CF ), 118.5, 121.8, 125.3,
3
+
129.3, 130.0, 132.5, 139.1, 151.0, 152.6; HRMS calcd for C H F NO S [(M+H) ] 530.2183,
2
6
35
3
5
found 530.2172.
rac-Phenyl 8a-allyl-2-n-hexyl-2,3,6,7,8,8a-hexahydroquinoline-1(5H)-carboxylate (22).
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Method I. To a solution of vinyl silane 20 (35 mg, 68 ꢁmol) in anhydrous DMSO (2 mL) at rt
was added TBAF (1M in THF, 1.0 mL, 1.0 mmol) and the reaction mixture was heated at 80 °C
for 1 h. The mixture was cooled to rt, diluted with Et O (10 mL) and washed with water (3 × 10
2
0
1
2
3
4
5
6
7
8
9
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1
2
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4
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6
7
8
9
0
mL) and brine (10 mL), dried over MgSO , filtered through Celite and concentrated in vacuo.
4
The residue was purified by radial PLC (SiO , 2% EtOAc/hexanes) to afford 20 mg (77%) of
2
alkene 22 as a clear oil.
Method II. To a degassed solution of triflate 21 (40 mg, 76 ꢁmol) in anhydrous DMF (2 mL) at
rt was added tributylamine (5.0 equiv, 90.0 ꢁL, 377 ꢁL), formic acid (4.0 equiv, 10.0 ꢁL, 304
ꢁ
mol) and Pd(PPh ) (OAc) (0.1 equiv, 6.0 mg, 8.0 ꢁmol), and the reaction mixture was stirred
3 2 2
at rt for 5 h. The reaction mixture was diluted with Et O (10 mL). The resulting mixture was
2
washed with 1% HCl (10 mL), water (10 mL), and brine (10 mL), dried over MgSO , filtered
4
through Celite and concentrated in vacuo. The residue was purified by radial PLC (SiO , 2%
2
EtOAc/hexanes) to afford 20 mg (70%) of alkene 22 as a clear oil.
IR (neat) 3073, 2930, 2856, 1717, 1596, 1495, 1455, 1389, 1350, 1297, 1207, 1168, 1207, 1114,
ꢀ
1 1
9
1
1
1
89, 912 cm ; H NMR (CDCl , 300 MHz) δ 7.38 (m, 2H), 7.18 (m, 1H), 7.07 (m, 2H), 5.69 (m,
3
H), 5.58 (d, 1H, J = 7.4 Hz), 5.03 (m, 2H), 4.51 (q, 1H, J = 6.1 Hz), 3.43 (bs, 1H), 2.85 (m,
H), 2.59 (m, 1H), 2.97 (m, 3H), 1.97 (dd, 1H, J = 7.7, 17.1 Hz), 1.78 (d, 1H, J = 13.5 Hz), 1.65ꢀ
13
.25 (m, 14H), 0.87 (t, 3H, J = 6.6 Hz); C NMR (CDCl , 75 MHz) δ 152.6, 151.4, 138.4,
3
134.4, 129.2, 124.9, 122.0, 117.7, 116.7, 62.5, 52.0, 36.7, 35.9, 34.5, 33.1, 31.8, 29.7, 29.3, 27.2,
+
2
7.0, 23.2, 22.6, 14.1; HRMS calcd for C H NO [(M+H) ] 382.2741, found 382.2742.
2
5
36
2
rac-8a-Allyl-4-(dimethyl(phenyl)silyl)-2-n-hexyl-1,2,3,5,6,7,8,8a-octahydroquinoline
(23).
Phenyl carbamate 20 (50 mg, 96.9 ꢁmol) was dissolved in a mixture of anhydrous THF (1.5 mL)
and freshly distilled liquid ammonia (5.5 mL) at ꢀ78 °C. Anhydrous tꢀbutanol (5 ꢁL) was added
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followed by a slow addition of sodium (7.0 equiv, 16 mg, 0.68 mmol) in small portions until a
deep blue color persisted. The reaction was immediately quenched with solid NH Cl and then
4
warmed to rt. The resulting solution was filtered through Celite and concentrated in vacuo. The
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crude product was purified by radial PLC (SiO 1ꢀ12% EtOAc/hexanes) to yield 28.5 mg (74%)
2
of the free amine 23 as a clear oil. IR (neat) 3068, 2925, 2856, 1636, 1607, 1454, 1428, 1247,
ꢀ1
1
1
110, 912, 814 cm ; H NMR (CDCl , 300 MHz) δ 7.51 (m, 2H), 7.32 (m, 3H), 5.80 (m, 1H),
3
5.13 (m, 2H), 2.83 (m, 1H), 2.57 (dd, 1H, J = 6.6, 14.0 Hz), 2.42 (dd, 1H, J = 8.5, 14.3 Hz), 2.30
(m, 1H), 2.09 (m, 1H), 1.96ꢀ1.83 (m, 2H), 1.76 (dq, 1H, J = 2.3, 13.1 Hz), 1.57ꢀ1.05 (m, 15H),
13
0
.88 (t, 3H, J = 6.6 Hz), 0.35 (s, 3H), 033 (s, 3H); C NMR (CDCl , 75 MHz) δ 153.6, 140.2,
3
133.8, 133.6, 128.6, 127.6, 124.6, 118.5, 57.4, 46.9, 38.2, 37.7, 37.6, 37.1, 32.0, 29.6, 27.2, 26.0,
+
2
2.6, 22.2, 14.1, ꢀ0.7, ꢀ1.1; HRMS calcd for C H NSi [(M+H) ] 396.3081, found 396.3085.
2
6
42
4-(Dimethylphenylsilanyl)-4-hydroxy-2-isobutyl-3,4-dihydro-2H-pyridine-1-carboxylic
acid phenyl ester (24). To a solution of lithium wire (50 mg, 9.8 mmol) in 5.0 mL of THF was
added chlorodimethylphenylsilane (180 ꢁL, 1.07 mmol) all at once. The reaction was stirred at rt
for 4 h. In a separate flask was added dihydropyridone (201 mg, 730 ꢁmol) in 1.5 mL of THF
and 9.0 mL of ether. The mixture was cooled to ꢀ78 °C, and the dimethylphenylsilyllithium was
added dropwise via a syringe pump over 1 h. After 8 h at ꢀ78 °C, 2 mL of saturated aqueous
sodium bicarbonate was added and the reaction was warmed to room temperature. The organic
layer was separated, and the aqueous phase was extracted with Et O (3 x 10 mL). The combined
2
organic layers were washed with brine (10 mL), dried over K CO , and filtered through Celite.
2
3
The solvent was removed by rotary evaporation and the crude material was purified by radial
PLC (silica gel, 10% EtOAc/ hexanes) to afford 162 mg (54%) of compound 24 as a clear oil and
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0 mg (20%) of recovered starting material. IR (neat) 3436, 2855, 2927, 2856, 1688, 1453, 1427,
ꢀ1
1
1404, 1366, 1329, 1250, 1171, 1135, 1113, 1020, 832, 816, 772 cm ; H NMR (CDCl , 300
3
MHz) δ 7.62ꢀ7.60 (m, 2H), 7.40ꢀ7.35 (m, 5H), 7.25ꢀ7.22 (d, 1H J = 9.9 Hz), 7.19ꢀ7.14 (d, 2H, J
16.5 Hz), 6.96ꢀ6.93 (d, 1H, J = 7.2 Hz), 5.17ꢀ5.08 (dd, 1H, J = 17.4, 8.1 Hz), 4.46 (m, 1H),
0
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9
0
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7
8
9
0
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0
1
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8
9
0
1
2
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8
9
0
=
1
3
2.1ꢀ1.95 (m, 2H), 1.70ꢀ1.55 (m, 4H), 1.27ꢀ1.18 (m , 2H), 0.91 (br s, 6H), 0.38 (s, 6H) ; C NMR
(CDCl , 100 MHz) δ 151.8, 151.2, 135.6, 134.9, 129.8, 129.6, 128.1, 125.8, 125.2, 124.5, 121.8,
3
1
21.7, 111.8, 110.5, 61.5, 48.0, 40.4, 34.9, 25.6, 23.2, 22.5, ꢀ5.8, ꢀ6.1; HRMS calcd for
+
C H NO Si [(M+H) ] 410.2151, found 410.2142.
24
32
3
4
-(Dimethylphenylsilanyl)-2-isobutyl-6-(4-trimethylsilanyl-but-2-enyl)-3,6-dihydro
pyridine-1-carboxylic acid phenyl ester (25). To a solution of silyl alcohol 24 (75 mg, 183
mol) in 5 mL of CH Cl at ꢀ78 °C was added compound 27 (135 mg, 323 ꢁmol). After 10 min,
2H-
ꢁ
2
2
BF ·OEt (50.0 ꢁL, 0.405 ꢁmol) was added dropwise. After 2.5 h, the reaction was quenched
3
2
with saturated NaHCO (2 mL) and warmed to room temperature. The organic layer was
3
separated and the aqueous phase was extracted with CH Cl (3 x 10 mL). The combined organic
2
2
layers were washed with water (10 mL) and dried over K CO . Filtration and concentration
2
3
afforded the crude product which was purified by radial PLC (silica gel, 1% TEA, 5% EtOAc/
hexanes) to give 59 mg (63%) of compound 25 as a light yellow oil. IR (neat) 2954, 2360, 2340,
ꢀ1 1
1715, 1494, 1406, 1389, 1360, 1333, 1300, 1248, 1207, 1162, 958, 835, 773, 733, 687 cm ; H
NMR (CDCl , 300 MHz) δ 7.52ꢀ7.51 (m, 2H), 7.38ꢀ7.33 (m, 5H), 7.21ꢀ7.08 (m, 3H), 6.30ꢀ6.16
3
(m, 2H), 5.62ꢀ5.55 (m, 1H), 5.16ꢀ4.98 (m, 2H), 4.19 (br s, 2H), 3.16 (br s, 1H), 2.33ꢀ2.07 (m,
1
3
2H), 1.43ꢀ1.26 (m, 4H), 0.88ꢀ0.81 (m, 4H), 0.72ꢀ0.54 (m, 5H), 0.39 (s, 6H), ꢀ0.03 (s, 9H) ; C
NMR (CDCl , 75 MHz) δ 154.6, 151.8, 141.8, 137.7, 136.6, 134.2, 129.5, 128.1, 126.2, 122.0,
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16.8, 60.1, 53.5, 50.4, 47.3, 43.1, 31.2, 28.8, 26.4, 25.7, 24.1, 24.0, 23.6, 23.2, 21.4, 20.0, 19.1,
+
ꢀ0.48, ꢀ1.7, ꢀ3.7; HRMS calcd for C H NO Si [(M+H) ] 520.3067, found 520.3066.
31 46
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rac-Phenyl 4-(dimethyl(phenyl)silyl)-2-n-hexyl-8a-methoxy-2,3,6,7,8,8a-hexahydroquino-
line-1(5H)-carboxylate (29). To a solution of allylic alcohol 19a (55.0 mg, 112 ꢁmol) in MeOH
(dry, 1 mL) at rt was added PPTS (1.0 equiv, 29.0 mg, 112 ꢁmol), and the mixture was stirred
for 10ꢀ15 min. The reaction was quenched with saturated NaHCO . The organic layer was
3
separated, and the aqueous layer was extracted with CH Cl (2 × 10 mL). The combined organic
2
2
layers were washed with water (10 mL) and brine (10 mL), dried over MgSO , filtered through
4
Celite and concentrated in vacuo. The residue was purified by radial PLC (SiO , 1% EtOAc/1%
2
Et N/hexanes) to afford 20 mg (35%) of ether 29 as a clear oil. IR (neat) 2929, 2856, 1732, 1703,
3
ꢀ1
1
1
495, 1389, 1335, 1209, 1163, 1109, 815 cm ; H NMR (CDCl , 300 MHz) δ 7.52 (m, 2H), 7.36
3
(m, 5H), 7.17 (m, 1H), 7.11 (m, 2H), 4.54 (m, 1H), 3.13 (s, 3H), 2.98 (m, 1H), 2.40 (m, 2H),
2
9
.23 (dd, 1H, J = 1.7, 17.1 Hz), 2.03 (tt, 1H, J = 4.1, 13.8 Hz), 1.78ꢀ1.53 (m, 6H), 1.30ꢀ1.12 (m,
1
3
H), 0.88 (t, 3H, J = 6.6 Hz) 0.44 (s, 3H), 0.42 (s, 3H); C NMR (CDCl , 75 MHz) δ 151.3,
3
145.2, 139.0, 133.5, 129.1, 129.0, 127.9, 125.0, 121.8, 87.4, 52.6, 48.3, 33.2, 32.3, 31.8, 31.1,
+
2
9.3, 27.0, 22.6, 22.4, 14.1, ꢀ1.1, ꢀ1.3; HRMS calcd for C H NO SiNa [(M+Na) ] 528.2904,
3
1
43
3
found 528.2897.
rac-Phenyl 8a-(but-3-enyl)-4-(dimethyl(phenyl)silyl)-2-n-hexyl-2,3,6,7,8,8a-hexahydroqui-
noline-1(5H)-carboxylate (30a). To a degassed solution of 20 (157 mg, 304 ꢁmol) in 5 mL of
anhydrous methylene chloride was added (Z)ꢀbutꢀ2ꢀeneꢀ1,4ꢀdiyl diacetate (314 mg, 1.83 mmol)
nd
followed by addition of GrubbsꢀHoveyda 2 Gen catalyst (9.50 mg, 15 ꢁmol). The mixture was
heated at reflux for 2 h, cooled, and filtered through a silica gel pad with a methylene chloride
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