Studies toward the total synthesis of dihydrolycolucine. Preparation of AB and CEF ring fragments

Article abstract of DOI:10.1021/jo500878v

A strategy for the synthesis of the lycopodium alkaloid dihydrolycolucine (1) has been investigated. Synthetic routes were developed based on N-acylpyridinium salt chemistry to prepare target fragments 3 and 4 that could ultimately converge to the natural

Full text of DOI:10.1021/jo500878v

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Article
Studies toward the Total Synthesis of Dihydrolycolucine.
Preparation of AB and CEF Ring Fragments.
Brandon M. Cash, Natacha Prevost, Florence F. Wagner, and Daniel L. Comins
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo500878v • Publication Date (Web): 19 May 2014
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Studies toward the Total Synthesis of
Dihydrolycolucine. Preparation of AB and
CEF Ring Fragments.
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Brandon M. Cash†, Natacha Prevost‡, Florence FévierꢀWagner§,
and Daniel L. Comins*
Department of Chemistry, North Carolina State University, Raleigh, NC 2769ꢀ8204, United
States
Corresponding Author: *Email: daniel_comins@ncsu.edu
Abstract
A strategy for the synthesis of the Lycopodium alkaloid dihydrolycolucine has been investigated.
Synthetic routes were developed based on Nꢀacylpyridinium salt chemistry to prepare target
fragments 3 and 4 that could ultimately converge to the natural product. Key reactions include
IMDA cycloadditions and retroꢀMannich ringꢀopenings to form both the AB and EF ring
fragments. The ring C precursor was prepared using pyridine substitution and directed lithiation
chemistry. A Suzuki crossꢀcoupling of rings C and EF led to the CEF ring fragment. Initial
attempts at closure of the 7ꢀmembered D ring were unsuccessful.
Introduction
Extracted from club moss Lycopodium lucidulum, the lycopodium alkaloids represent a complex family
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of heterocyclic natural products with various structural types. These alkaloids have been thoroughly
studied over the past 60 years and more than 200 members of this family have been isolated. Within the
Lycopodium family there is an abundant subclass of compounds with the general C30N3 framework
including dihydrolycolucine (1) and structurally relevelant lycolucine (2). Dihydrolycolucine, isolated in
1979 by Ayer and coworkers, represents one of the more structurally elaborate members of this alkaloid
family, and its structure has been fully characterized by crystallographic, spectroscopic, and chemical
studies. Embedded within its unique architecture are 9 sterogenic centers and a strained sevenꢀmembered
ring, both of which pose a significant synthetic challenge.1 To our knowledge, there have been no
biological or synthetic studies reported for dihydrolycolucine. Our progress toward its total synthesis is
described herein.
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Figure 1. Dihydrolycolucine and lycolucine.
Results and Discussion
Our strategy for preparation of dihydrolycolucine 1 is shown in Scheme 1. It was
envisioned that key fragments 3 and 4 would converge via a CꢀC bond forming reaction to
provide alkaloid 1. Alkyl iodide 3 would be prepared in enantiopure form via a chiral N-
acylpyridinium salt reaction. Furthermore, the tetracyclic fragment 4 would originate from a
Pd0ꢀmediated ester enolate ringꢀclosure with an appropiately functionalized pyridine. The
pyridine motif would be incorporated via a Suzuki crossꢀcoupling reaction with βꢀbromo
enecarbamate 7, furnished by starting from another chiral N-acylpyridinium salt reaction.
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Scheme 1. Retrosynthesis of Dihydrolycolucine 1
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The synthesis of the AB ring fragment 3 initiated with the in situ generation of the chiral
Nꢀacylpyridinium salt 5, from 4ꢀmethoxyꢀ3ꢀ(triisopropylsilyl)pyridine and (ꢀ)ꢀTCC
chloroformate, followed by the addition of the enantiopure Grignard 92c to yield dihydropyridone
10 upon acidic workup.2 The synthesis of compounds 10 – 15 followed our reported procedures
for preparing their enantiomers.2d Standard oneꢀpot removal of the chiral auxiliary and TIPS
group followed by reprotection of the nitrogen as the benzyl carbamate produced enantiopure
dihydropyridone 11. The terminal olefin underwent oxidative cleavage followed by a Hornerꢀ
WadsworthꢀEmmons olefination to render the trans α,βꢀunsaturated ester 12. The vinylgous
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amide carbonyl was reduced under Luche conditions, followed by dehydration of the resulting
allylic alcohol with Furukawa’s reagent, to smoothly furnish dihydropyridine 13.3,4 The triene
underwent an intramolecular DielsꢀAlder (IMDA) cycloaddition followed by hydrogenation to
simultaneously remove the Cbz group and reduce the olefin revealing amino ester 14.5 Bond
cleavage was induced through a retroꢀMannich ringꢀopening pathway5c that allowed for the
formation of bicyclic compound 15. Concomitant reduction of the enecarbamate and removal of
the Cbz group were accomplished under standard hydrogenation procedures utilizing palladium
on carbon. The crude amine (88%) was immediately acylated with acetyl chloride to give an
unoptimized low yield of amide 16. Saponification of the methyl ester with LiOH provided the
carboxylic acid 17. Completion of fragment 3 is marked by an iododecarboxylation reaction
sequence mediated with Pb(OAc)4 and iodine (Scheme 2).6
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Scheme 2. Synthesis of the AB Ring Fragment 3
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A model study to the northern fragment 4 was initiated with the fundamental Nꢀ
acylpyridinium salt reaction albeit in a racemic fashion. Norꢀmethyl intermediates 18 – 21 were
prepared as previously reported.5d The addition of the Grignard reagent to the N-benzyloxyꢀ4ꢀ
methoxypyridinium salt followed by mild acid hydrolysis provided 18. Transformation of the
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terminal olefin to the trans α,βꢀunsaturated ethyl ester was carried out directly via a crossꢀ
metathesis reaction using excess ethyl acrylate in the presence of 0.7 mol % of 2nd generation
Grubbs catalyst7 furnishing 19 in 95% yield. With 19 in hand, reduction of the Cꢀ4 carbonyl
under standard Luche conditions3 gave the desired alcohol which was dehydrated with
Furukawa’s reagent4 to afford dihydropyridine 20. The triene underwent our intramolecular
DielsꢀAlder (IMDA) and retroꢀMannich ringꢀopening reaction sequence5c,d to provide the Nꢀ
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phenoxycarbony intermediate 22.
Through a modification of Overman’s protocol8,
enecarbamate 22 was treated with molecular bromine in the presence of excess 1,2,2’,6,6’ꢀ
pentamethylpiperidine (PMP) and 4 Å molecular sieves to provide βꢀbromo enecarbamate 23 in
93% yield.
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Scheme 3. Synthesis of βꢀBromo enecarbamate 23
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With the synthetic routes to two of the key fragments established, our attention was
directed towards the preparation of the pyridine 28 for an eventual Suzuki coupling. Initially,
2,6ꢀdichloropyridine (24) underwent two successive nucleophilic aromatic substitutions to yield
the disubstituted pyridine derivative 26. Removal of the benzyl group with catalytic
hydrogenation provided the pyridone 27 which was subsequently converted to MOMꢀprotected
pyridine 28 in 83% yield. Utilizing the MOM ether as an effective orthoꢀdirector, pyridyl
boronic ester 29 was prepared in high yield by deprotonation of 28 with n-BuLi followed
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successive treatment with trimethylborate and pinacol.9
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Scheme 4. Synthesis of Pyridyl Boronic Ester 29
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After establishing practical synthetic routes to βꢀbromo enecarbamate 23 and pyridine 29,
our attention turned towards their union. A Suzuki crossꢀcoupling reaction mediated by Pd(tꢀ
Bu3P)2 followed by mild acid hydrolysis of the MOM group of 30 with excess pyridinium pꢀ
toluenesulfonate afforded the pyridinol 31 over two steps.10 After considerable experimentation,
reduction of the enecarbamate olefin proceeded smoothly to furnish 32 in high yield as a single
diastereomer. Treatment of pyridone 32 with Tf2O in the presence of TEA afforded pyridyl
triflate 33 in 95% yield. It is worth noting that attempted conversions of the pyridone 31 into
either the iodoꢀ or bromoꢀ derivatives resulted in extensive decomposition.
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Scheme 5. Suzuki Crossꢀcoupling with Pyridyl Boronic Ester 29 and Subsequent Conversions
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With pyridyl triflate 33 readily in hand, examination of the crucial 7ꢀmembered ring
formation was addressed. Due to the sensitivity and complex nature of the substrate, we chose to
initially explore the mild Pdꢀcatalyzed arylation conditions as reported by Hartwig.11a The
silylketene acetal of 33 was prepared in situ by treatment with LDA and TMSCl. The crude
silylketene acetal was immediately exposed to crossꢀcoupling conditions mediated by
Pd(PhCN)2Cl2.11b Unfortunately, this reaction sequence proved ineffective and only starting
material was isolated. Variations of this reaction also resulted in recovered starting material or
pyridone 32. To the best of our knowledge, this is the first attempt to couple aryl triflates with
ester enolates.
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Scheme 6. Examination of 7ꢀMembered Ring Formation
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In summary, a detailed account of our progress toward Lycopodium alkaloid
dihydrolycolucine is reported utilizing an Nꢀacylꢀ2,3ꢀdihydropyridone as a building block. In
particular, the synthesis of two major fragments was accomplished leading to the examination of
the tetracylic core formation. Unfortunately, initial attempts at closing the 7ꢀmembered D ring
by way of a palladiumꢀcatalyzed esterꢀenolate crossꢀcoupling proved unfruitful. Further studies
are needed to accomplish this pivotal ringꢀclosure.
Experimental Section
Methyl 2-((4aS,5R,7S,8aR)-1-acetyl-7-methyldecahydroquinolin-5-yl)acetate (16). A
solution of 15 (50.5 mg, 0.141 mmol) in 2 mL of ethyl acetate was hydrogenated for 4 h at rt
under balloon pressure in the presence of 5% Pd/C (23 mg). Filtration over Celite and removal
of solvent in vacuo resulted in 28.1 mg (88%) of the amine as a yellow oil. The crude amine was
dissolved in 1 mL of CH2Cl2 followed by the addition of triethylamine (25.1 µL, 0.178 mmol)
and freshly distilled acetyl chloride (11.3 µL, 0.157 mmol). The resulting mixture was stirred at
0 oC. After 30 min, distilled H2O (1 mL) was added to the reaction, and the biphasic solution
was transferred to a seperatory funnel. The aqueous layer was extracted with EtOAc (2 x 5 mL).
The organic layers were collected, washed with brine, dried over MgSO4, and filtered through a
thin pad of Celite. The volatiles were removed in vacuo and purification by chromatography
(SiO2, 5 – 10% MeOH/CH2Cl2) afforded 17.3 mg (47%) of pure 16 as a yellow oil. IR (neat)
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2926, 2869, 1737, 1644, 1434, 1266, 1172, 1035, 874 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 4.95ꢀ
4.89 (m, 1H), 4.49ꢀ4.45 (m, 1H), 3.97ꢀ3.93 (m, 1H), 3.68–3.66 (pair of s, due to rotamers, 3H),
3.60 – 3.53 (m, 1H), 3.14ꢀ3.08 (m, 1H), 2.63ꢀ2.56 (m, 1H), 2.42ꢀ2.10 (m, 3H), 2.09 and 2.06
(pair of s, due to rotamers, 3H), 1.98ꢀ1.14 (m, 7H), 1.17 and 1.10 (pair of d, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ (rotamers) 173.3, 173.2, 169.2, 168.9, 51.9, 51.8, 51.7, 46.0, 41.8,
39.7, 38.6, 38.5, 38.2, 36.4, 32.3, 31.9, 31.7, 31.5, 29.6, 28.2, 27.8, 27.4, 26.0, 25.0, 22.3, 21.5,
18.7, 18.5, 17.7, 17.6; HRMS (ESI) calcd for C15H25NO3 267.1834, found 267.1840; [α]23D ꢀ
44.6 (c 0.28, CHCl3).
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2-((4aS,5R,7S,8aR)-1-Acetyl-7-methyldecahydroquinolin-5-yl)acetic acid (17). Compound
16 (17.3 mg, 0.0647 mmol) was dissolved in 80% aqueous MeOH (5 mL) followed by the
addition of LiOH·H2O (51.9 mg, 1.23 mmol). After stirring at rt for 16 h, distilled H2O (5 mL)
was added to the mixture. The mixture was acidified with a solution of 10% HCl and extracted
with EtOAc (3 x 5 mL). The combined organic layers were washed with brine and dried over
MgSO4. After filtration through Celite, the volatiles were removed in vacuo followed by
purification (SiO2, 5 % MeOH/CH2Cl2) to give 13.8 mg (84%) of 17 as a tacky white oil. IR
(neat) 3500, 2926, 2875, 1619, 1561, 1401, 1270, 1174, 1036 cmꢀ1; 1H NMR (400 MHz, CDCl3)
δ 9.00 – 8.00 (bs, 1H), 4.95 – 4.91 (m, 1H), 4.51 – 4.46 (m, 1H), 3.99 – 3.96 (m, 1H), 3.60 –
3.56 (m, 1H), 3.16 ꢀ 3.09 (m, 1H), 2.64ꢀ2.58 (m, 1H), 2.42ꢀ2.02 (m, 5H), 2.11 and 2.08 (pair of s,
due to rotamers, 3H), 1.98ꢀ1.16 (m, 5H), 1.11 (appar t, due to rotamers, 3H); 13C NMR (100
MHz, CDCl3) δ (rotamers) 177.5, 177.1, 169.8, 169.4, 52.1, 46.3, 41.9, 39.5, 38.5, 38.4, 38.2,
36.7, 32.3, 31.9, 31.5, 31.4, 29.7, 28.2, 27.8, 27.4, 26.0, 25.0, 22.1, 21.3, 18.7, 18.5, 17.7, 17.6;
HRMS (ESI) calcd for C14H23NO3 ([M+H])+ 254.1757, found 254.1756; [α]23D ꢀ86.7 (c 0.09,
CHCl3).
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1-((4aS,5S,7S,8aR)-5-(Iodomethyl)-7-methyloctahydroquinolin-1(2H)-yl)ethan-1-one (3).
An oven dried flask was charged with 17 (13.8 mg, 0.0545 mmol) and Pb(OAc)4 (31.4 mg, 0.071
mmol) in anhydrous CCl4 (1.2 mL). The mixture was stirred under N2 at reflux while being
irradiated with a tungsten 350 W lamp. Iodine (15.2 mg, 0.06 mmol) dissolved in anhydrous
CCl4 (0.8 mL) was added to the refluxing mixture. After heating for an additional 2 h, the
reaction mixture was allowed to cool to rt after which a precipitate formed. The precipitate was
filtered and washed with CCl4. The combined filtrates were washed with 10% Na2S2O3, water,
and sat. NaHCO3. The solution was dried over MgSO4, filtered, and the volatiles were removed
under reduced pressure. Purification of the crude residue by chromatography (SiO2, 0ꢀ5%
MeOH/CH2Cl2) afforded 11 mg (60%) of iodide 3 as an unstable yellow oil. 1H NMR (400
MHz, CDCl3) δ 4.92–4.85 (m, 1H), 4.52–4.47 (m, 1H), 3.94–3.90 (m, 1H), 3.61–3.56 (m, 1H),
3.17 ꢀ 3.09 (m, 4H), 2.64ꢀ2.56 (m, 1H), 2.11 and 2.06 (pair of s, due to rotamers, 3H), 1.98ꢀ1.16
(m, 7H), 1.11 (appar t, due to rotamers, 3H). LRMS calcd for C13H22INO3 335, found 335.
Phenyl (4aR*,5S*,8aS*)-5-(2-ethoxy-2-oxoethyl)-4a,5,6,7,8,8a-hexahydroquinoline-1(4H)-
carboxylate (22). A solution of lithium diisopropylamide (1.50 mmol, prepared from 0.62 mL
of 2.4 M nꢀBuLi and 0.218 mL diisopropylamine) in 5 mL of THF under N2 was cooled to ꢀ78
˚C (dry ice/acetone). Tricyclic amine 21 (0.113 g, 0.50 mmol) in THF (4 mL) was then added
and the mixture was stirred at ꢀ78 ˚C for 30 min. Trimethylsilyl chloride (0.223 mL, 1.76 mmol)
was added at ꢀ78 ˚C and mixture was warmed to rt for 15 min. Dry hexane (10 mL) was added
to cause precipitation. The mixture was filtered and concentrated under reduced pressure. This
process was repeated again to finally provide 0.190 g (103%) of the crude bisꢀsilyl intermediate
as a yellow oil. To a solution of the crude oil (0.60 g, 0.26 mmol) in 5 mL of dry CH2Cl2, under
N2 at rt, was added phenyl chloroformate (0.067 mL, 0.52 mmol). The mixture was heated to
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reflux for 12 h and then cooled to rt. A solution of 10% HCl (4 mL) was added and the mixture
was stirred for 1.5 h. Saturated NaHCO3 solution (5 mL) was added followed by ether (20 mL).
The organic phase was washed with brine (5 mL) and dried (K2CO3). The solution was filtered,
concentrated and purified by preparative layer chromatography (silica gel, EtOAcꢀhexanes, 1:5,
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three elutions) to give 0.07 g (86% from 21) of 22 as a light yellow oil. H NMR (300 MHz,
CDCl3) 7.3 δ (m, 5H), 6.8 (d, 1H), 4.8 (m, 1H), 4.2 (q, 2H), 3.9 (m, 1H), 2.9 (m, 1H), 2.9 (m,
1H), 2.2ꢀ2.5 (m, 2H), 1.1ꢀ2.2 (m, 12H); 13C NMR (75 MHz, CDCl3) 173.1 (2C), 129.2 (2C),
125.1, 121.6 (2C), 120, 115.8, 105.2, 60.8, 53.9, 47.2, 38.6 34.5, 34.0, 33.6, 24.1, 15.6, 14.3; IR
(neat) 2920, 1750, 1650, 1570 cmꢀ1.
(4aR*,5S*,8aS*)-Phenyl-3-bromo-5-(2-ethoxy-2-oxoethyl)-4a,5,6,7,8,8a-hexa-
hydroquinoline-1(4H)-carboxylate (23). To a solution of 22 (89 mg, 0.259 mmol) in CH2Cl2
(5 mL) was added 10 mg of crushed 4 Å molecular sieves followed by addition of 1,2,2’,6,6’ꢀ
o
pentamethylpiperidine (141 mg, 0.906 mmol). The mixture was cooled to 0 C and bromine
(0.518 mL, 0.259 mmol) as a 0.5 M solution in CH2Cl2 was added over 1 h via syringe pump.
Following completion of bromine addition, the reaction was warmed to rt and stirred for 1 h.
The mixture was filtered through a thin pad of Celite, and the volatiles were removed under
reduced pressure. Purification by radial PLC (SiO2, 0ꢀ5% EtOAc/hexanes) afforded 101 mg
(92%) of pure 23 as a clear oil. IR (neat) 3434, 2933, 2861, 1726, 1660, 1493, 1202 cmꢀ1; H
1
NMR (300 MHz, CDCl3) δ 7.39ꢀ7.09 (m, 6H), 4.21ꢀ4.09 (m, 3H), 2.49ꢀ2.24 (m, 7H), 1.81ꢀ1.72
13
(m, 2H), 1.53ꢀ1.42 (m, 3H), 1.25 (t, J = 6.9 Hz, 3H); C NMR (75 MHz CDCl3) δ 172.4 and
173.3 (due to rotamers), 151.3 and 151.0 (due to rotamers), 150.5, 129.6, 126.0 and 125.9 (due to
rotamers), 124.6 and 124.3 (due to rotamers), 121.8, 102.1 and 101.8 (due to rotamers), 60.7,
54.0, 53.2, 38.5, 36.8 and 36.7 (due to rotamers), 36.4 and 36.1 (due to rotamers), 26.0, 25.4,
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24.5 and 24.3 (due to rotamers), 14.4; HRMS (ESI) calcd for C20H24BrNO4 421.0888, found
421.0905.
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2-Chloro-6-isopropoxypyridine (25).12 Anhydrous isopropanol (0.31 mL, 4.05 mmol) was
added to a solution of KOtꢀBu (417 mg, 3.72 mmol) in THF (3 mL) at rt. After 30 min, 2,6ꢀ
dichloropyridine (500 mg, 3.38 mmol) was added to the milky solution. The mixture was
warmed to 65 ˚C and stirred for 12 h. The solvent was removed by evaporation, water (5 mL)
was added, and the mixture was extracted with methylene chloride. The combined organic layers
were dried over K2CO3, filtered and concentrated. The crude product was purified by radial PLC
(silica gel, 2% EtOAc/hexanes) to afford 510 mg (91% yield) of 25 as a clear oil. IR (neat)
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2980, 2936, 1592, 1559, 1441, 1302, 1159, 1109, 963, 788 cmꢀ1; H NMR (400 MHz, CDCl3)
δ
7.46 (dd, J = 6.8 Hz, J = 8.0 Hz, 1H), 6.82 (d, J = 6.8 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 5.32ꢀ
5.20 (m, 1H), 1.32 (d, J = 104 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ 163.3, 148.4, 140.6,
115.9, 109.8, 69.1, 22.0.
2-Benzyloxy-6-isopropoxypyridine (26). Benzyl alcohol (0.37 mL, 3.54 mmol) was added to a
solution of KOtꢀBu (397 mg, 3.54 mmol in THF (5 mL) at rt. After 30 min, 2ꢀchloroꢀ6ꢀ
isopropoxypyridine (506 mg, 2.95 mmol) was added and the mixture was stirred at 65 ˚C for 12
h. The reaction was allowed to cool to rt, the solvent was removed by concentration, and the
residue was extracted with methylene chloride. The combined organic layers were dried over
K2CO3, filtered and concentrated. The crude product was purified by radial PLC (silica gel, 5%
EtOAc/hexanes) to afford 629 mg (87%) of 26 as a clear oil. IR (neat) 3088, 1064, 3033, 2977,
1
2936, 2876, 1596, 1579, 1444, 1371, 1312, 1237, 1140, 1115, 1041, 989, 788 cmꢀ1; H NMR
(400 MHz, CDCl3) δ 7.50ꢀ7.25 (m, 5H), 6.35 (d, J = 7.6 Hz, 1H), 6.27 (d, J = 7.6 Hz, 1H), 5.36
(s, 2H), 5.28ꢀ5.18 (m, 1H), 1.34 (d, J = 7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ
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162,4, 141.2, 137.9, 128.6, 127.9, 102.4 101.5, 68.3, 67.6, 22.3 (2C); HRMS (ESI) calcd for
C15H17NO2 ([M]+) 243.1259, found 243.1263.
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6-Isopropoxy-1-H-pyridin-2-one (27). A solution of 2ꢀbenzyloxyꢀ6ꢀisopropoxypyridine (2.11
g, 8.65 mmol) in MeOH (50 mL) was hydrogenated (balloon pressure) over 10% Pd/C (461 mg)
at rt for 12 h. The mixture was filtered through Celite and the solids rinsed with methylene
chloride. The crude product was purified by radial PLC (silica gel, 50% EtOAc/hexanes) to
afford 1.28 g (96%) of 27 as a white solid, mp 106ꢀ107 ˚C; IR (neat) 3500ꢀ2500, 1648, 1599,
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1453, 1372, 1273, 1109 cmꢀ1; 1H NMR (400 MHz, CDCl3)
δ
7.35 (dd, J = 8.8, 7.6 Hz, 1H), 6.15
13
(d, J = 8.8 Hz, 1H), 5.62 (d, J = 7.6 Hz, 1H), 4.66ꢀ4.60 (m, 1H), 1.31 (d, J = 6.4 Hz, 6H); C
NMR (100 MHz, CDCl3) δ 165.2, 157.7, 142.9, 108.6, 89.4, 71.8, 21.8; HRMS (ESI) calcd for
C8H11NO2 ([M+H]+) 154.0868, found 154.0869.
6-Isopropoxy-2-(methoxymethoxy)pyridine (28). A solution of 27 (75 mg, 0.489 mmol) in
DMF (1 mL) was added to a solution of KOtꢀBu (60 mg, 0.538 mmol) in DMF (2 mL) at 0 ˚C.
After 20 min at 0 ˚C, the mixture was warmed to rt and stirred for 2 h. The mixture was then
cooled back down to 0 ˚C and MOMCl (0.04 mL, 0.59 mmol) was added dropwise. After 5 min
at 0 ˚C, the mixture was warmed to rt and stirred overnight (15 h). The reaction was quenched
with water, and the mixture was extracted with methylene chloride. The combined organic
layers were dried over K2CO3, filtered and concentrated. The crude product was purified by
radial PLC (silica gel, 5% EtOAc/hexanes) to afford 80 mg (83% yield) of 28 as a clear oil. IR
1
(neat) 2978, 2936, 1600, 1580, 1447, 1312, 1236, 1158, 1141, 1114, 1009, 970 cmꢀ1; H NMR
(300 MHz, CDCl3) δ 7.47 (t, J = 7.9 Hz, 1H), 6.34ꢀ6.27 (m, 2H), 5.45 (s, 2H), 5.19 (septet, J =
6.0 Hz, 1H), 3.50 (s, 3H), 1.32 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ
162.4, 161.4,
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141.4, 103.7, 101.4, 68.3, 57.0, 22.2; HRMS (ESI) calcd for C10H15NO3 ([M+H]+) 198.1130,
found 198.1127.
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Isopropoxy-2-methoxymethoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine
(29). To a solution of pyridine 28 (355 mg, 1.80 mmol) in freshly distilled THF (10 mL) was
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added nꢀBuLi at ꢀ42 C (2.36 M in hexanes, 1.21 mL, 2.85 mmol), and the mixture was stirred
for 30 min at ꢀ42 oC. The solution was slowly warmed to rt and stirred for an additional 30 min.
After cooling to ꢀ78 oC, neat trimethylborate (0.41 mL, 3.60 mmol) was quickly added and after
15 min the solution was warmed to rt. Stirring was continued at rt for 1 h, and then pinacol (490
mg, 4.14 mmol) was added in one portion. After 2 h, the reaction mixture was filtered through a
thin pad of Celite with a diethyl ether (10 mL) wash. Concentration of the filtrate under reduced
pressure provided the crude product. Purification by radial PLC (SiO2, 2% Et3N/10ꢀ20%
EtOAc/hexanes) gave 517 mg (83 %) of boronic ester 29 as a pale yellow oil. IR (neat) 2978,
1595, 1566, 1370, 1111, 963 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 8.1 Hz, 1H), 6.28
13
(d, J = 8.1 Hz, 1H), 5.54 (s, 2H), 5.20 (m, 1H), 3.53 (s, 3H), 1.32 (s, 18H); C NMR (75 MHz,
CDCl3) δ 203.7, 165.6, 164.6, 149.1, 103.7, 91.5, 83.5, 68.7, 56.8, 25.0, 22.2; HRMS (ESI)
[(M+Na)+] Calcd for C16H26BNO5 346.1796, Found 346.1803.
(4aR*,5S*,8aS*)-Phenyl-5-(2-ethoxy-2-oxoethyl)-3-(6-isopropoxy-2-(methoxymethoxy)-
pyridin-3-yl)-4a,5,6,7,8,8a-hexahydroquinoline-1(4H)-carboxylate (30). In a 15 mL roundꢀ
bottom flask containing boronate ester 29 (44 mg, 0.137 mmol) was added 1 mL of degassed
DME:EtOH (20:0.5). The boronate ester solution was added to a 15 mL flask containing vinyl
bromide 23 (34 mg, 0.081 mmol) followed by the addition of 1 mL DME:EtOH (20:1). To the
combined solution was added aqueous 2.0 M Na2CO3 (0.081 mL, 0.161 mmol). With good
stirring, the solution was degassed for 10 min and then Pd(tꢀBu3P)2 (2.1 mg, 0.004 mmol) was
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added in one portion. The flask was quickly fitted with a reflux condenser and purged with N2
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for 2 min. The reaction was heated to 100 C for 4 h or until disappearance of starting material
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by TLC. Once complete, the reaction vessel was cooled to rt and the contents were filtered
through Celite with a CH2Cl2 wash. The volatiles were removed under reduced pressure.
Purification by flash chromatography (Florisil, 0ꢀ5% EtOAc/hexanes, 2% Et3N) afforded 36 mg
(80%) of pure 30 as a clear oil. IR (neat) 3403, 2359, 2329, 2090, 1642, 1460, 1308, 1202 cmꢀ1;
1H NMR (300 MHz, CDCl3) δ 7.48ꢀ7.12 (m, 7H), 6.34ꢀ6.28 (m, 1H), 5.59ꢀ5.52 (m, 2H), 5.20ꢀ
5.11 (m, 1H), 4.31ꢀ4.10 (m, 3H), 3.54ꢀ3.51 (m, 3H), 2.51ꢀ2.32 (m, 6H), 1.87ꢀ1.50 (m, 6H), 1.37ꢀ
1.23 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 172.7, 160.5, 157.6, 151.4 and 151.3 (due to
rotamers), 140.2, 129.6, 125.8, 122.9, 122.6, 121.8, 113.5 and 113.1 (due to rotamers), 103.2,
92.2 and 92.0 (due to rotamers), 68.6, 60.6, 57.4, 54.4, 53.7, 38.8, 37.1 and 36.9 (due to
rotamers), 35.1 and 34.8 (due to rotamers), 29.9, 26.2, 24.6 and 24.5 (due to rotamers), 22.2, 21.9
and 21.7 (due to rotamers), 14.5; HRMS (ESI) calcd for C30H38N2O7 538.2679, found 538.2670.
(4aR*,5S*,8aS*)-Phenyl-5-(2-ethoxy-2-oxoethyl)-3-(2-hydroxy-6-isopropoxypyridin-3-yl)-
4a,5,6,7,8,8a-hexahydroquinoline-1(4H)-carboxylate (31). To a stirred solution of 30 (45 mg,
0.083 mmol) in MeOH (5 mL) cooled to 0 oC was added solid pyridinium paraꢀtoluenesulfonate
(1.42 mmol, 357 mg) in portions. After stirring for 15 min at 0 oC, the temperature was raised to
rt, and the mixture was stirred for 48 h or until complete by TLC analysis. The MeOH was
removed under reduced pressure, and the residue was redissolved in CH2Cl2 (5 mL) followed by
the addition of deionized H2O (5 mL). The mixture was transferred to a seperatory funnel and
extracted with CH2Cl2 (3 x 10 mL). Combined organic layers were washed with saturated
aqueous NaHCO3, dried over MgSO4, and filtered through Celite. The volatiles were removed in
vacuo and purification by flash chromatography (Florisil, 10% EtOAc/hexanes to 50%
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EtOAc/MeOH) afforded 35 mg (87%) of pure 31 as a clear oil. IR (neat) 3436, 2933, 2866,
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6
7
1
1716, 1630, 1605, 1402, 1356, 1274, 1201, 1111 cmꢀ1; H NMR (300 MHz, CDCl3) δ 8.07 and
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7.66 (bs, 1H), 7.39 (m, 6H), 5.56 (d, J = 8.40 Hz, 1H), 4.56 (m, 1H), 4.25 (m, 1H), 4.12 (q, J =
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7.2 Hz, 2H), 2.32ꢀ1.49 (m, 11H), 1.31ꢀ1.22 (m, 11H); C NMR (75 MHz, CDCl3) δ 172.9 and
172.7 (due to rotamers), 162.3, 154.9 and 154.5 (due to rotamers), 151.7 and 151.5 (due to
rotamers), 138.5 and 137.0 (due to rotamers), 129.4, 125.6, 122.6, 122.1, 121.8, 114.2 and 112.8
(due to rotamers), 87.7 and 87.3 (due to rotamers), 72.4, 60.6, 54.4, 53.7, 38.9, 37.0, 35.2 and
34.8 (due to rotamers), 29.9, 26.1 and 25.6 (due to rotamers), 24.6 and 24.4 (due to rotamers),
21.8, 21.0, 14.5; HRMS (ESI) [(M+Na)+] calcd for C28H34N2O6 517.2315, found 517.2313.
(3S*,4aR*,5S*,8aS*)-Phenyl-5-(2-ethoxy-2-oxoethyl)-3-(2-hydroxy-6-isopropoxypyridin-3-
yl)octahydroquinoline-1(2H)-carboxylate (32). A 15 mL roundꢀbottom flask was charged
with pyridinol 31 (21 mg, 0.042 mmol), a mixture of acetic acid:MeOH:CH2Cl2 (1:2:2, 3 mL),
and 10 mg of Pd(OH)2. The flask was fitted with a balloon containing hydrogen gas. Using an
aspirator, the mixture was purged two times. The heterogenous mixture was stirred for 3 h or
until the disappearance of starting material by TLC. Once complete, the mixture was filtered
through Celite and concentrated under reduced pressure. Purification by radial PLC (30ꢀ50%
EtOAc/hexanes) gave 18 mg (85%) of 32 as a clear oil. IR (neat) 3855, 3423, 1626, 1524, 1025,
696, 460 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.37ꢀ7.09 (m, 7H), 5.57ꢀ5.54 (m, 1H), 4.60 (sep, J
= 5.6 Hz, 1H), 4.32ꢀ4.08 (m, 4H), 3.25 (t, J = 12.4 Hz, 1H), 2.90ꢀ2.83 (m, 1H), 2.30ꢀ1.46 (m,
13
12H), 1.34 (d, J = 6.0 Hz, 6H), 1.24 (t, J = 9.6 Hz, 3H); C NMR (100 MHz, CDCl3) δ 173.0,
162.9, 155.7, 154.0, 151.8, 139.8 and 139.6 (due to rotamers), 129.3, 125.2, 122.6, 122.0, 88.0
and 87.8 (due to rotamers), 72.2, 60.5, 54.5 and 53.7 (due to rotamers), 43.7 and 42.9 (due to
rotamers), 39.6, 39.1 and 38.8 (due to rotamers), 38.3 and 38.0 (due to rotamers), 37.7 and 37.5
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(due to rotamers), 26.5, 25.0, 24.3, 23.7 and 23.4 (due to rotamers), 21.9, 14.4; HRMS (ESI)
calcd for C28H36N2O6 496.2578, found 496.2576.
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(3S*,4aR*,5S*,8aS*)-Phenyl-5-(2-ethoxy-2-oxoethyl)-3-(6-isopropoxy-2-(trifluoro-
methylsulfonyloxy)pyridin-3-yl)octahydroquinoline-1(2H)-carboxylate (33). To a solution
of pyridone 32 (10 mg, 0.02 mmol) in CH2Cl2 (1 mL) was added triethylamine (0.026 mmol)
from a 1 M stock solution in CH2Cl2. The solution was cooled to ꢀ78 oC and to it was added Tf2O
(0.022 mmol) as a 0.5 M stock solution in CH2Cl2. Once the addition was complete, the
temperature was slowly raised to rt. After 30 min, saturated aqueous NaHCO3 (3 mL) was
added, and the biphasic solution was transferred to a seperatory funnel. The aqueous layer was
extracted with CH2Cl2 (3 x 5 mL), and the organics were collected, dried over MgSO4, and
filtered through a thin pad of Celite. The volatiles were removed in vacuo and purification by
radial PLC (SiO2, 10ꢀ30% EtOAc/hexanes) afforded 11.3 mg (90%) of pure 33 as a clear oil. IR
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(neat) 3436, 3054, 2985, 2935, 2306, 1710, 1625, 1421, 1265, 705 cmꢀ1; H NMR (400 MHz,
CDCl3) δ 7.62 (m, 1H), 7.40ꢀ7.09 (m, 5H), 6.74 (m, 1H), 5.16 (sep, J = 6.0 Hz, 1H), 4.37ꢀ4.12
(m, 4H), 3.1ꢀ2.93 (m, 2H), 2.24ꢀ1.48 (m, 12H), 1.33 (d, J = 6.0 Hz, 6H), 1.25 (t, 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 172.0, 161.2, 153.6, 151.6, 141.2 and 140.8 (due to rotamers),
129.5, 125.5, 122.0, 119.3, 112.1, 70.3, 60.6, 54.2 and 53.3 (due to rotamers), 44.4 and 43.4 (due
to rotamers), 39.2 and 38.8 (due to rotamers), 37.3, 32.1, 29.8, 26.4, 25.5, 24.8, 24.1, 23.3, 22.9,
21.8, 14.4; HRMS (ESI) calcd for C29H35F3N2O8S ([M+H])+ 629.2139, found 629.2140.
Acknowledgments. This work was supported in part by the National Institutes of Health
(Grant No. GM 34442). NMR and mass spectra were obtained at NCSU instrumentation
laboratories, which were established by grants from the North Carolina Biotechnology Center
and the National Science Foundation (Grant No. CHEꢀ0078253).
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Supporting Information: Copies of H NMR spectra for 3 and 22, and H and 13C NMR
spectra for 16ꢀ17, 23, and 26ꢀ33. This material is available free of charge via the Internet at
http://pubs.acs.org.
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Corresponding Author: Daniel L. Comins
*Eꢀmail: daniel_comins@ncsu.edu
Present Addresses:
† (B.M.C.)
804 Virginia Pine Lane
Clover, SC 29710, USA
‡ (N.P.)
44 rue du Poumpidou
Le Piccadilly D28
34990 JUVIGNAC, France
§ (F.F.ꢀW.)
4 Old Country Path
Ashland, MA 01721, USA
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Kobayashi, J.; Morita, H. Heterocycles, 2009, 77, 679. (d) Nyembo, L.; Goffin, A.; Hootele,
C.; Braekman, J. C. Can. J. Chem. 1978, 56, 851.
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Evans, D. A.; Bender, S. L.; Morris. J. J. Am. Chem. Soc. 1988, 110, 2506. (d) Comins, D. L.,
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Brooks, C. A.; Alꢀawar, R. S.; Goehring, R. R. Org. Lett. 1999, 1, 229.
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5.(a) Comins, D. L.; Abdullah, A. H.; Mantlo, N. B. Tetrahedron Lett. 1984, 25, 4867. (b) Krow,
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