Asymmetric synthesis of all the known phlegmarine alkaloids

Article abstract of DOI:10.1021/jo1019688

The asymmetric synthesis of all four of the known natural phlegmarines and one synthetic derivative has been accomplished in 19-22 steps from 4-methoxy-3-(triisopropylsilyl)pyridine. Chiral N-acylpyridinium salt chemistry was used twice to set the stereoc

Full text of DOI:10.1021/jo1019688

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Asymmetric Synthesis of All the Known Phlegmarine Alkaloids
Bradley H. Wolfe, Adam H. Libby, Rima S. Al-awar, Christopher J. Foti, and
Daniel L. Comins*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204,
United States
Daniel_comins@ncsu.edu
Received October 5, 2010
The asymmetric synthesis of all four of the known natural phlegmarines and one synthetic derivative
has been accomplished in 19-22 steps from 4-methoxy-3-(triisopropylsilyl)pyridine. Chiral
N-acylpyridinium salt chemistry was used twice to set the stereocenters at the C-9 and C-20 positions
of the phlegmarine skeleton. Key reactions include the use of a mixed Grignard reagent for the second
N-acylpyridinium salt addition, zinc/acetic acid reduction of a complex dihydropyridone, and a von
Braun cyanogen bromide N-demethylation of a late intermediate. These syntheses confirmed the
absolute stereochemistry of all of the known phlegmarines.
Introduction
compound has spurred the isolation of several new Lycopodium
alkaloids having various biological activities including
cytotoxicity.3 The discovery of significant biological activ-
ities among the Lycopodium alkaloids has prompted renewed
interest in the development of new synthetic strategies for
their preparation.4 As part of our natural product synthesis
program,5,6 we have examined approaches to the phlegma-
rine alkaloids.
The lycopodiaceous plants have produced numerous and
structurally interesting alkaloids that have proven to be
challenging targets for total synthesis.1 One of the Lycopodium
alkaloids, huperzine A, is a potential therapeutic agent for
treatment of Alzheimer’s disease.2 This medicinally important
The phlegmarines are a C16N2 skeletal group of Lycopodium
alkaloids discovered by Braekman and co-workers in 1978.7a
(1) (a) Ayer, W. A.; Trifonov, L. S. In The Alkaloids; Cordell, G. A.,
Brossi, A., Eds.; Academic Press: San Diego, 1994; Vol. 45, pp 233-274. (b)
Blumenkopf, T. A.; Heathcock, C. H. Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 3,
pp 185-240. (c) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752–772.
(d) Kobayashi, J.; Morita, H. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 2005; Vol. 61, p 1. (e) Hirasawa, Y.; Kobayashi,
J.; Morita, H. Heterocycles 2009, 77, 679.
(4) (a) Comins, D. L.; Williams, A. L. Org. Lett. 2001, 3, 3217. (b)
Comins, D. L.; Brooks, C. A.; Al-awar, R. S.; Goehring, R. R. Org. Lett.
1999, 1, 229. (c) Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J.
J. Org. Chem. 1999, 64, 2184.
(2) For pertinent reviews, see: (a) Kozikowski, A. P.; Tueckmantel, W.
Acc. Chem. Res. 1999, 32, 641. (b) Ma, X.; Tan, C.; Zhu, D.; Gang, D. R.;
Xiao, P. J. Ethnopharmacol. 2007, 113, 15–34.
(5) (a) Comins, D. L.; Joseph, S. P. In Advances in Nitrogen Heterocycles;
Moody, C. J., Ed.; JAI Press Inc.: Greenwich, CT, 1996; Vol. 2, pp 251-294.
(b) Comins, D. L.; Joseph, S. P. In Comprehensive Heterocyclic Chemistry,
2nd ed.; McKillop, A., Ed.; Pergamon Press: Oxford, England, 1996; Vol. 5,
pp 37-89. (c) Comins, D. L. J. Heterocycl. Chem. 1999, 36, 1491.
(6) For recent and leading references, see: (a) Comins, D. L.; Zhang, Y.
J. Am. Chem. Soc. 1996, 118, 12248. (b) Comins, D. L.; Chen, X.; Morgan,
L. A. J. Org. Chem. 1997, 62, 7435. (c) Comins, D. L.; LaMunyon, D. H.;
Chen, X. J. Org. Chem. 1997, 62, 8182. (d) Comins, D. L.; Green, G. M.
Tetrahedron Lett. 1999, 40, 217. (e) Comins, D. L.; Zhang, Y.; Joseph, S. P.
Org. Lett. 1999, 1, 1941. (f) Kuethe, J. T.; Comins, D. L. Org. Lett. 2000, 2,
855. (g) Huang, S.; Comins, D. L.; Huang, S.; McArdle, C. L.; Ingalls, C. L.
Org. Lett. 2001, 3, 469. (h) Comins, D. L.; Sandelier, M. J.; Abad Grillo, T.
J. Org. Chem. 2001, 66, 6829.
(3) (a) Kobayashi, J.; Hirasawa, Y.; Yoshida, N.; Morita, H. J. Org.
Chem. 2001, 66, 5901. (b) Kobayashi, J.; Hirasawa, Y.; Yoshida, N.; Morita,
H. Tetrahedron Lett. 2001, 41, 9069. (c) Morita, H.; Arisaka, M.; Yoshida,
N.; Kobayashi, J. J. Org. Chem. 2000, 65, 6241. (d) Tan, C.-H.; Jiang, S.-H.;
Zhu, D.-Y. Tetrahedron Lett. 2000, 41, 5733. (e) Gao, W.-Y.; Li, Y.-M.;
Wang, B.-D.; Zhu, D.-Y. Chin. Chem. Lett. 1999, 10, 463. (f) Tan, X.-J.;
Wang, H.-Q.; Jiang, H.-L.; Zhu, W.-L.; Jiang, S.-H.; Zhu, D.-Y.; Chen,
K.-X.; Ji, R.-Y. Huaxue Xeubao 2000, 58, 1386. (g) Wang, B.-D.; Teng, N.-
N.; Zhu, D.-Y. Youji Huaxue 2000, 20, 812. (h) Gao, W.-Y.; Wang, B.-D.; Li,
Y.-M.; Jiang, S. H.; Zhu, D.-Y. Chin. J. Chem. 2000, 18, 614. (i) Gao, W.-Y.;
Li, Y.-M.; Jiang, S.-H.; Zhu, D.-Y. Planta Med. 2000, 66, 664. ( j) Morita, H.;
Hirasawa, Y.; Shinzato, T.; Kobayashi, J. Tetrahedron 2004, 60, 7015–7023.
8564 J. Org. Chem. 2010, 75, 8564–8570
Published on Web 11/15/2010
DOI: 10.1021/jo1019688
r
2010 American Chemical Society

Wolfe et al.
JOCArticle
SCHEME 1
FIGURE 1. Structures of the four known phlegmarine alkaloids
and derivative 1e.
All four naturally occurring members of this group (1a-d)
possess the same skeleton and differ only by their nitrogen atom
substituents.7b Synthesis and spectroscopic structure studies
carried out by Braekman’s group7a determined the basic carbon
skeleton, but it was not until the work of MacLean8 and co-
workers that the relative stereochemistry of all five stereogenic
centers of the phlegmarines was defined. The absolute stereo-
chemistry of these alkaloids was established in our laboratories
through the asymmetric total synthesis of (-)-NR-acetyl-Nβ-
methylphlegmarine (1d).4c We report herein the total synthesis
of all the known phlegmarine alkaloids 1a-d, andtheNβ-acetyl
derivative 1e (Figure 1).
with L-Selectride/BF3 OEt24c (86% yield) or more conve-
3
niently with Zn/AcOH12 to give 8 in 93% yield. Ozonolysis of
the terminal alkene of 8 provided a high yield of aldehyde 9,
which on acid-mediated cyclization13 was converted efficiently
to bicyclic enone 10.
The next step required a facial selective conjugate addition
of a nucleophile containing the latent functionality of a
hydroxymethyl group. Based on our earlier model studies,14
(dimethylphenylsilyl)methylmagnesium chloride was chosen
for use in a copper-mediated 1,4-addition to enone 10. The
resulting facial selectivity was anticipated to be high based on
conformational and stereoelectronic arguments. Due to A(1,3)
strain,15 the reactive conformation is concave as shown in
Figure 2. Stereoelectronically controlled axial attack of the
nucleophile at C-5 would afford the desired stereochemical
outcome. In the presence of copper iodide, addition of
Grignard 11 to 10 and trapping of the resulting enolate with
N-(5-(chloro-2-pyridyl)triflimide16 provided a 96% yield of
vinyl triflate 12. Since protonation of the enolate leads to the
cis-fused ring juncture,14 in situ vinyl triflate formation was
necessary to set up the eventual incorporation of the required
stereochemistry at C-10. The vinyl triflate function would
not survive the subsequent hydrolysis of the carbamate group,
so 12 was cleanly reduced to the more stable alkene 13 using
Cacchi’s conditions.17
Results and Discussion
Our strategy for synthesizing the phlegmarines is depicted
in Scheme 1. All of the alkaloid targets were to be prepared
from the common dihydropyridone intermediate 4, which
would arise from the key fragment 3 and chiral 1-acylpyr-
idinium salt 2. Fragment 3 would also be prepared from the
same antipode of 2 by a modification of our published
procedure.4c
The Grignard of (R)-5-chloro-4-methylpentene9 was added
to chiral N-acylpyridinium salt 2,preparedinsitufrom4-methoxy-
3-(triisopropylsilyl)pyridine10 and the chloroformate of
(-)-trans-2-(R-cumyl)cyclohexanol (TCC),11 to give the
crude N-acyldihydropyridone 5 in 90% yield and 88% de
(Scheme 2). Purification by recrystallization from ethanol
provided a 76% yield of the major diastereomer 5 as an
isomerically pure white solid. A one-pot reaction of 5 with
NaOMe/MeOH followed by aqueous 10% HCl furnished
dihydropyridone 6 in 95% yield with 95% recovery of the
chiral auxiliary, (-)-TCC. N-Acylation of 6 with n-BuLi and
phenyl chloroformate gave a quantitative yield of enantio-
pure carbamate 7. Conjugate reduction of 7 can be effected
Carbamate hydrolysis using KOH/2-propanol at reflux
gave a high yield of the secondary amine 14. The use of
2-propanol was essential to obtaining a clean product, for the
analogous reaction with KOH/ethanol gave a significant
amount of the corresponding ethyl carbamate via carbamate
(7) (a) Nyembo, L.; Goffin, A.; Hootele, C.; Braekman, J.-C. Can.
J. Chem. 1978, 56, 851. For the recent isolation and synthesis of related
phlegmarine-type Lycopodium alkaloids, see: (b) Tanaka, T.; Kogure, N.;
Kitajima, M.; Takayama, H. J. Org. Chem. 2009, 74, 8675 and references
cited therein.
(12) Comins, D. L.; Brooks, C. A.; Ingalls, C. L. J. Org. Chem. 2001, 66,
2181.
(8) (a) Leniewski, A.; Szychowski, J.; MacLean, D. B. Can. J. Chem. 1981,
59, 2479. (b) Leniewski, A.; MacLean, D. B.; Saunders, J. K. Ibid. 1981, 59,
2695.
(9) The chloride was prepared (NCS, Ph3P, CH2Cl2) from the known
enantiopure alcohol, see: Evans, D. A.; Bender, S. L.; Morris, J. J. Am.
Chem. Soc. 1988, 110, 2506.
(13) (a) Comins, D. L.; Dehghani, A. J. Org. Chem. 1995, 60, 794. (b)
Comins, D. L.; Dehghani, A. Chem. Commun. 1993, 1838.
(14) Comins, D. L.; Al-awar, R. S. J. Org. Chem. 1995, 60, 711.
(15) Rubiralta, M.; Giralt, E.; , Diez, A. Piperidine: Structure, Prepara-
tion, Reactivity and Synthetic Applications of Piperidine and its Derivatives;
Elsevier: New York, 1991; Chapter 7.
(10) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
1994, 116, 4719.
(11) (a) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656. (b)
The (+)- and (-)-TCC alcohols are available from Aldrich Chemical Co.
(16) (a) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299. (b)
Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org. Synth. 1996, 74,
77.
(17) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 4821.
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SCHEME 3
FIGURE 2. Calculated lowest energy conformation of 10 (MMFF).
SCHEME 2
carbamate 15 (78%) and the corresponding cis C-10 epimer.
The trans selectivity can be attributed to significant shielding
of the bottom face of the alkene in 14 by the axial (phenyldi-
methylsilyl)methyl group. Oxidation using Fleming’s conditions18
and subsequent lithium aluminum hydride reduction gave
amino alcohol 16 in high yield. Conversion to iodide 3 was
effected using 1,2-bis-(triphenylphosphino)ethane (17) and
I2.19 This method proved superior to the more common
procedure using triphenylphosphine/I2 due to ease of pro-
duct purification.
The key intermediate 4 was prepared as shown in Scheme 3.
The mixed Grignard reagent 18 was prepared from iodide 3,
by lithium-halogen exchange and addition of methylmagne-
sium iodide, and treated with 2 equiv of N-acylpyridinium
salt 2 to give dihydropyridone 19 in 53% yield. The five
stereocenters were correctly installed as determined by sin-
gle-crystal X-ray analysis.4c The TIPS group and TCC
auxiliary were removed from 19 in one step using our
standard procedure to afford 20, which was converted to
key intermediate 4 in high yield on lithiation and treatment
with benzyl chloroformate. With the intermediate 4 in hand,
the five target alkaloids were prepared as described below.
Nβ-Methylphlegmarine (1b) and NR-Acetyl-Nβ-methylph-
legmarine (1d). Conjugate reduction of 4 with zinc in acetic
acid gave piperidone 21 in near quantitative yield (Scheme 4).
Deprotonation with KHMDS and trapping with N-(5-chloro-
2-pyridyl)triflimide provided the vinyl triflates 22 in a 3:1
ratio favoring olefin formation at the 4,050 position. Catalytic
hydrogenation over Pearlman’s catalyst afforded the natural
product 1b, which exhibited spectral data and optical rota-
tion in agreement with its assigned structure.
exchange. Catalytic hydrogenation of 14 provided an 89/11
mixture of crude amines that were converted to Cbz
(18) Fleming, I.; Sanderson, P. E. Tetrahedron Lett. 1987, 28, 4229.
(19) Schmidt, S. P.; Brooks, D. W. Tetrahedron Lett. 1987, 48, 1313.
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SCHEME 4
SCHEME 5
SCHEME 6
The alkaloid NR-acetyl-Nβ-methylphlegmarine (1d) was
prepared in one step from 1b by simple acetylation. Although
the rotation of 1d was higher than that previously reported
for the natural product, all spectral data were in agreement
with literature values.7a
Phlegmarine (1a), NR-Methylphlegmarine (1c) and Unna-
tural NR-Methyl-Nβ-acetyl-phlegmarine (1e). To prepare the
remaining two natural phlegmarines (1a,c) and the known
synthetic derivative 1e from intermediate 4, a demethylation
of the beta nitrogen would be required toward the end of the
synthesis. The vinyl triflate mixture 22 was reduced selec-
tively via hydrogenation over platinum on carbon to afford
the benzyl carbamate 23 (Scheme 5). Initial attempts to N-
demethylate 23 with phenyl chloroformate proved prob-
lematic giving an inseparable mixture of dicarbamate 24 and
the ring-opened product 25 as determined by 1H NMR and
MS analysis. The use of other chloroformates20 led to similar
results with a poor ratio of products regardless of tempera-
ture, solvent, or the addition of additives (LiBr, LiCl). The von
Braun demethylation reaction using cyanogen bromide21
was examined next. To our delight, treatment of tertiary
amine 23 with cyanogen bromide at rt gave a near quantita-
tive conversion to cyanamide 26 (Scheme 6). When 26 was
treated with dilute HCl at reflux, both the cyanamide and
Cbz groups were hydrolyzed to the secondary amines pro-
viding natural phlegmarine (1a) in high yield. NR-Methylph-
legmarine (1c) was also prepared in excellent yield from 26 in
one step by concomitant reduction of the cyanamide and
carbamate groups with LAH. N-Acylation of 1c afforded
NR-methyl-Nβ-acetylphlegmarine (1e) in good yield. All
three of our synthetic phlegmarines (1a,c,e) exhibited char-
acterization data in agreement with literature values for the
known compounds.
(20) For a review on amine dealkylations with acyl chlorides, see: Cooley,
J. H.; Evain, E. J. Synthesis 1989, 1–7.
(21) (a) von Braun, J. Chem. Ber. 1900, 33, 1438. Review: (b) Hageman,
H. A. Org. React. 1953, 7, 198.
In summary, all four of the known phlegmarine alkaloids
and one previously reported synthetic derivative have been
synthesized enantiopure from key dihydropyridone intermediate
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Wolfe et al.
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4. These syntheses have confirmed the absolute stereochem-
istry of the phlegmarines as 20S, 5S, 7R, 9R, 10R. Our chiral
N-acylpyridinium salt chemistry was used twice during the
synthetic route to set the stereocenter at C-9 and the remote
center at C-20 of the phlegmarines. The syntheses ranged
from 19 to 22 steps and were accomplished with excellent
stereocontrol.
N-acylpyridinium salt solution. This mixture was allowed to stir for
5 h at -78 °C followed by addition of 10% HCl(aq) (4 mL). The
mixture was allowed to warm to rt and stirred for an additional
30 min. The aqueous phase was made basic with solid K2CO3 and
then extracted with EtOAc (5 ꢀ 3 mL). The combined organic
phases were washed with brine (5 mL), dried (K2CO3), filtered
(Celite), and concentrated in vacuo. The crude oil was purified by
radial PLC (SiO2, 50% EtOAc/hexanes, 1% TEA) providing 19
(198 mg, 69%) as a mixture of isomers at the newly generated
stereocenter; diasteriomeric excess was found to be 84% by HPLC.
1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.32-7.28 (m, 4H),
7.12 (t, J=6.8 Hz, 1H), 4.89 (dt, J=10.8, 4.4 Hz, 1H), 2.76 (d, J=
11.6 Hz, 1H), 2.64 (m,1H), 2.31 (dd, J=15.6, 6.0 Hz, 1H), 2.19 (s,
3H), 2.05-1.99 (m, 4H), 1.88-1.74 (m, 3H), 1.61-1.19 (m, 23H),
1.06-1.01 (m, 24H), 0.71 (q, J=12.0 Hz, 1H); 13CNMR(100MHz,
CDCl3) δ 196.8, 152.8, 152.2, 147.6, 128.3, 125.2, 125.1, 110.5, 77.8,
62.8, 57.7, 51.4, 50.7, 44.1, 43.0, 39.8, 39.5, 39.1, 37.5, 34.3, 33.8,
31.0, 28.9, 26.9, 26.8, 26.2, 26.0, 24.8, 23.0, 21.6, 19.0, 18.9, 11.3.
2S-2-[(4aR,5S,7R,8aR)-1,2,3,4a,5,6,7,8,8a-Decahydroquinolin-
1,7-dimethyl-5-ylmethyl)-2,3-dihydro-4-pyridone (20).4c Improved
Procedure. Sodium methoxide (734 μL, 3.2 mmol, 4.36 M in MeOH,
10 equiv) was added to a suspension of 19 (217 mg, 320 μmol) in
methanol (20 mL). The mixture was brought to reflux affording a
homogeneous solution. The solution was refluxed for 17 h, allowed
to cool to rt, and concentrated in vacuo. The residual oil was taken
up in THF (20 mL) and then 10% HCl(aq) (2.0 mL), was added. The
mixture was allowed to stir for 3 h. The acidic mixture was carefully
quenched with K2CO3(s) (∼500 mg). Anhydrous K2CO3(s) (∼5-7g)
was then added until the solution appeared to be dry. The clumps of
K2CO3 were broken up with a glass rod, and the mixture was filtered
through Celite. The filter pad was washed with hot EtOAc (5ꢀ
20 mL), and the filtrate was concentrated in vacuo. The crude oil
was purified by radial PLC (silica gel, 50-100% EtOAc/hexanes,
1% TEA) to give the dihydropyridone 20 (86.9 mg, 98%) as an oil
that solidified upon standing, mp 141-142 °C (50% EtOAc/
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J=7.6 Hz, 1H),
5.03 (d, J=7.6 Hz, 1H), 4.72 (br s, 1H), 3.65 (m, 1H), 2.83 (br d, J=
11.2 Hz, 1H), 2.49 (dd, J=16.0, 4.4 Hz, 1H), 2.54 (d, J=16 Hz, 1H),
2.25 (s, 3H), 2.06 (m, 1H), 1.99 (m, 1H), 1.74-1.46 (m, 9H), 1.38 (m,
1H), 1.23 (m, 1H), 1.12 (dt, J=13.0, 4.0 Hz, 1H), 0.91 (d, J=6.4 Hz,
3H), 0.76 (q, J = 12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 192.9, 151.6, 98.7, 62.8, 57.6, 52.4, 44.2, 42.9, 41.5, 39.8, 38.5, 35.0,
32.1, 29.1, 26.0, 25.9, 22.9.
Experimental Section
The experimentals for compounds 5-10 and 12-17 have
been previously published.4c
2S-2-[(4aR,5S,7R,8aR)-1,2,3,4a,5,6,7,8,8a-Decahydroquinolin-
1,7-dimethyl-5-ylmethyl)-1-[(benzyloxy)carbonyl]-2,3-dihydro-4-
pyridone (4). To a cooled (-78 °C) solution of dihydropyridone
20 (58.2 mg, 211 μmol) in THF (5.0 mL) was added n-BuLi
(84 μL, 230 μmol, 1.1 equiv) dropwise. The solution immediately
turned bright yellow and became heterogeneous. After 10 min
the anion was rapidly quenched with freshly distilled benzyl
chloroformate (60 μL, 420 μmol, 2.0 equiv). The solution was
allowed to stir for an additional 2.5 h and then a 50% saturated
aqueous solution of NaHCO3 (2.0 mL) was added. The aqueous
phase was extracted with EtOAc (4 ꢀ 3.0 mL). The combined
organic phases were washed with brine (5 mL), dried (MgSO4),
filtered (Celite) and concentrated in vacuo. The crude oil was
purified by radial PLC (silica gel, 75% EtOAc/hexanes, 2%
TEA) to give 4 (82.7 mg, 96%) as a colorless oil. [R]D24 + 6.0
(c 0.81, MeOH); IR (film, NaCl) 2922, 1725 (CdO), 1672
(O-C=O), 1603 (C=C), 1327, 1192 cm-1 1H NMR (300
;
MHz, CDCl3) δ 7.79 (d, J=6.3 Hz, 1H) 7.40-7.37 (m, 5H),
5.35-5.31 (m, 2H), 5.21 (d, J=11.7 Hz, 1H), 4.55 (br s, 1H),
2.81-2.71 (m, 2H), 2.45 (d, J = 16.5 Hz, 1H), 2.21 (s, 3H),
1.98-1.89 (m, 2H), 1.79 (m, 1H), 1.63-1.28 (m, 9H), 1.13-
0.66 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 192.9, 152.5,
141.9, 135.0, 129.1, 129.0, 128.8, 107.2, 69.3, 62.7, 57.7, 52.2,
44.3, 43.0, 39.9, 38.3, 37.3, 34.5, 28.9, 26.6, 26.0, 25.6, 22.9;
HRMS calcd for C25H34N2O3 (M + H)+ 411.2648, found
411.2653.
2R-2-[(R)-2-Methyl-4-pentenyl]-1-(phenoxycarbonyl)-2,3,5,6-
tetrahydro-4-pyridone (8).4c Improved procedure. To a rapidly
stirred solution of dihydropyridone 7 (1.25 g, 4.18 mmol) in
glacial acetic acid (38 mL) was added zinc powder (5.5 g,
84 mmol, 20 equiv) in small portions, to prevent the zinc from
clumping. The mixture was allowed to stir for 17 h, filtered
(Celite) and then concentrated in vacuo. The heterogeneous oil
was purified by radial PLC (silica gel, 10-20% EtOAc/hexanes)
to provide piperidone 8 (1.17 g, 93%) as a colorless oil. Spectral
data is identical to that previously reported.
2S-2-[(4aR,5S,7R,8aR)-1,2,3,4a,5,6,7,8,8a-Decahydroquinolin-
1,7-dimethyl-5-ylmethyl)-1-[(1R,2S)-2-((1-methyl-1-phenyl)ethyl)-
cyclohexyloxyl-oxycarbonyl]-5-(triisopropylsilanyl)-2,3-dihydro-
4-pyridone (19).4c Improved procedure. The chiral N-acylpyridinium
salt was prepared in situ by adding (-)-TCC chloroformate (253 mg,
901 μmol, 2.1 equiv) to a cooled (- 45 °C) solution of 3-(triisopro-
pylsilyl)-4-methoxypyridine (241 mg, 901 μmol, 2.1 equiv) in
toluene (27 mL). The solution was allowed to stir at -45 °C for
45 min followed by cooling to -78 °C before addition of the
organometallic. The organometallic was prepared by dropwise
addition of t-BuLi (559 μL, 944 μmol, 1.7 M in pentane, 2.2 equiv)
to a cooled (-78 °C) solution of (4aR,5S,7R,8aR)-5-iodomethyl-
1,7-dimethyl-1,2,3,4a,5,6,7,8,8a- decahydroquinoline4c (17) (132 mg,
429 μmol) in ether (9.0 mL). The solution was stirred for 45 min
at -78 °C and then warmed to -42 °C (dry ice/acetonitrile) for
45 min. To the solution was added methylmagnesium iodide
(154 μL, 429 μmol, 2.85 M in ether, 1.0 equiv), and the solution
was allowed to stir for an additional 10 min. This solution was
added dropwise via cannula over 3 min to the cooled (-78 °C)
2S-2-[(4aR,5S,7R,8aR)-1,2,3,4a,5,6,7,8,8a-Decahydroquinolin-
1,7-dimethyl-5-ylmethyl)-1-[(benzyloxy)carbonyl]-4-piperidone (21).
Zinc powder was added slowly to a rapidly stirred solution of 4
(24.6 mg, 60 μmol) in glacial acetic acid (1.0 mL). The reaction
mixture was allowed to stir for 11 h, and then filtered through
Celite, and the filter pad was washed with methanol (5 mL). The
filtrate was concentrated in vacuo. The resulting amorphous
solid was suspended in dichloromethane (5 mL) and passed
through a plug of basic alumina (activity 2). The plug was
washed with a 10% solution of methanol in dichloromethane
(5 ꢀ 5 mL). The solution was concentrated in vacuo to provide a
colorless oil. The crude material was purified by flash chroma-
tography on silica gel (50% EtOAc/hexanes, 1% TEA) to
23
provide 21 (24.6 mg, 99%) as a colorless oil. [R]D -49
(c 0.69, CHCl3); IR (film, NaCl) 2925, 2775 (N-Me), 1721
1
(CdO), 1698 (O-C(dO)N), 1422, 1233, 1104, 1005 cm-1; H
NMR at 50 °C (300 MHz, CDCl3) δ 7.37-7.31 (m, 5H), 5.24 (d,
J=9.0 Hz, 1H), 5.13 (d, J=9.0 Hz, 1H), 4.59 (br s, 1H), 4.38 (dd,
J=9.6, 6.0 Hz, 1H), 3.33 (ddd J = 11.2, 8.5, 2.9 Hz, 1H), 2.81 (br
d, J =8.4 Hz, 1H), 2.60 (dd, J = 10.8, 4.8 Hz, 1H), 2.50 (ddd, J=
11.5, 8.5, 5.2 Hz, 1H), 2.34 (br d, J = 10.8 Hz, 1H), 2.22 (s, 3H),
2.04-1.94 (m, 2H), 1.64-1.42 (m, 9H), 1.30 (m, 1H), 1.20-1.12
(m, 1H), 1.03 (m, 1H), 0.83 (d, J = 4.2 Hz, 3H), 0.70 (q, J=
9.0 Hz, 1H); 13C NMR at 50 °C (100 MHz, CDCl3) δ 207.5,
155.5, 136.7, 128.8, 128.5, 128.4, 68.0, 63.1, 57.9, 52.3, 44.6 (2C,
8568 J. Org. Chem. Vol. 75, No. 24, 2010

Wolfe et al.
JOCArticle
determined by 13C NMR at 70 °C in benzene-d6 δ 45.5, 44.3),
43.0, 40.8, 40.1, 39.4, 39.1, 35.7, 31.2, 29.3, 26.2 (2C, determined
by 13C NMR at 70 °C in benzene-d6 δ 26.9, 26.4), 22.9; HRMS
calcd for C25H36N2O3 (M + H)+ 413.2804, found 413.2797.
Mixture of Enol Triflate Isomers (22). To a cooled (-78 °C)
solution of piperidone 21 (10.8 mg, 26.3 μmol) and 2-(5-chlor-
opyridyl)triflimide (33 mg, 84 μmol, 3.2 equiv) in THF (2.0 mL)
was added potassium bis(trimethylsilyl)amide (3 ꢀ 56 μL, 84 μmol,
0.5 M in toluene, 3 equiv) dropwise in three portions. The reaction
mixture was allowed to stir at -78 °C for 30 min, saturated
aqueous NaHCO3 (1 mL) was rapidly added, and the mixture
was allowed to warm to rt. The aqueous phase was diluted with
water until it became homogeneous (1 mL). The aqueous phase
was extracted with EtOAc (5 ꢀ 1 mL). The combined organic
phases were washed with brine (1 mL), dried (Na2SO4), filtered
(Celite), and concentrated in vacuo. The crude oil was purified
by flash column chromatography with basic alumina (activity 2,
elution with 5% MeOH/CH2Cl2), and then a second column
with silica gel (elution with 50% EtOAc/hexanes) to afford the
product (13.8 mg, 96%) as an inseparable mixture of enol triflate
isomers 22 (ratio of 3,4- to 4,5-enol triflate found to be 1.0 to 3.1
by 1H NMR). 1H NMR at 50 °C (400 MHz, CDCl3) δ 7.33 (br s,
5H, mixture of isomers), 5.81 (s, 1H, minor isomer), 5.75 (s, 1H,
major isomer), 5.25-5.07 (m, 2H, mixture of isomers), 4.57-
4.38 (m, 2H, mixture of isomers), 3.08 (m, 1H, minor isomer),
2.80 (d, J = 10 Hz, major isomer), 2.74-2.61 (m, 1H, mixture of
isomers), 2.22-2.02 (m, 7H, mixture of isomers), 2.01-1.94 (m,
4H, mixture of isomers), 1.65-1.02 (m, 22H, mixture of isomers),
0.88-0.67 (m, 7H, mixture of isomers); HRMS calcd for
C26H35F3N2O5S (M + H)+ 545.2297, found 545.2310.
51.3, 49.7, 43.9, 39.6, 39.2, 38.4, 35.2, 27.9, 26.9, 26.6, 26.0, 25.6,
25.2, 22.5, 18.8; TLC Rf=0.21 (30% EtOAc/hexane); HRMS
calcd for C25H35N3O2 (M + H)+ 410.2808, found 410.2814.
Phlegmarine (1a). A mixture 26 and 6 M HCl(aq) (1.0 mL) was
heated at reflux for 3 h. The solution was cooled to rt and then
extracted with ether (3 ꢀ 0.5 mL). The organic phase was
discarded and the aqueous phase was made basic by careful
addition of solid K2CO3. More potassium carbonate was added
until the solution became saturated. The aqueous phase was
then extracted with EtOAc (14 ꢀ 1.0 mL) until the extracts no
longer contained product by TLC. The crude solid was purified
by flash chromatography (basic alumina (activity 2), MeOH)
providing 1a as a solid. The solid was then taken up in hexanes
(1.0 mL) and passed through a plug of cotton providing
24
phlegmarine (1a) (4.8 mg, 96%) as a solid. [R]D -29 (c 0.39,
CHCl3); IR (film, NaCl) 3230 (N-H), 2923, 2852, 1120, 743
cm-1; 1H NMR (400 MHz, CDCl3) δ 3.08-2.99 (m, 2H), 2.63 (dt,
J=11.8, 2.7 Hz, 1H), 2.56 (dt, J=11.9, 2.5 Hz, 1H), 2.45-2.35
(m, 2H), 1.86-1.46 (m, 11H), 1.45-1.23 (m, 5H), 1.07 (tt, J=
11.2, 3.8 Hz, 1H), 1.05 (dt, J = 12.4, 4.0 Hz, 1H), 0.99-0.90 (m,
2H), 0.88 (d, J=6.0 Hz, 3H), 0.80 (q, J=13.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 56.1, 55.5, 47.5, 47.0, 46.1, 43.2, 39.7, 35.5,
35.2, 32.5, 28.9, 27.6, 27.0, 26.1, 25.0, 22.8; LRMS: 250 (M+, 7),
235 (5) 167 (12), 150 (14), 124 (6), 110 (9), 97 (24), 84 (100), 70
(90) 56 (10), 44 (80) m/z; HRMS calcd for C16H30N2 (M + H)+
251.2487, found 251.2485.
Nβ-Methylphlegmarine (1b). A solution of the mixed enol
triflates 22 (17.7 mg, 32.5 μmol) and 20% palladium hydroxide
on carbon (17.7 mg) in ethanol (1.0 mL) was stirred under an
atmosphere of hydrogen gas for 6 h. The solution was filtered
(Celite) and solid K2CO3 (100 mg) was added to the filtrate. The
suspension was allowed to stir for 1 h, again filtered (Celite), and
concentrated in vacuo. The residual oil was purified by flash
chromatography (basic alumina (activity 2), 2% MeOH/
CH2Cl2) to provide Nβ-methylphlegmarine (1b) (7.7 mg, 90%)
2S-2-[(4aR,5S,7R,8aR)-1,2,3,4a,5,6,7,8,8a-Decahydroquinolin-
1,7-dimethyl-5-ylmethyl)-1-[(benzyloxy)carbonyl]piperidine (23).
A solution of the mixed triflates 22 (13.8 mg, 25 μmol), 5% platinum
on carbon (14 mg) and lithium carbonate (18 mg, 240 μmol) in
EtOAc was stirred under an atmosphere of hydrogen gas for
5.75 h. The solution was filtered through a plug of Celite and
then concentrated in vacuo. The crude oil was purified by flash
column chromatography (silica gel, 50% EtOAc/hexanes, 1%
TEA) providing piperidine 23 (8.3 mg, 84%) as a colorless oil.
22
as a colorless oil. [R]D -65 (c 0.39, CHCl3); IR (film, NaCl)
3276 (N-H), 2925, 2774 (N-Me), 1455, 1331, 1118, 1006 cm-1
;
1H NMR (400 MHz, CDCl3) δ 3.06 (br d, J=11.6 Hz, 1H) 2.82
(br d, J=11.2 Hz, 1H), 2.63 (dt, J=11.6, 2.8 Hz, 1H), 2.41 (m,
1H), 2.24 (s, 3H), 2.06-2.00 (m, 2H), 1.80-1.58 (m, 9H), 1.45
(m, 8H), 1.04 (dt, J=12.7, 4.6 Hz, 1H), 0.96 (m, 1H), 0.89 (d, J=
6.8 Hz, 3H), 0.72 (q, J=11.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 63.0, 57.7, 56.1, 47.4, 44.6, 42.9, 39.9, 39.2, 35.5, 35.4,
32.3, 29.1, 26.8 (two carbons), 26.1, 24.9, 23.4; TLC Rf=0.13
(5% MeOH/CH2Cl2, basic alumina); LRMS: 264 (M+, 20), 249
(22), 207 (16), 180 (12), 166 (55), 164 (44), 150 (10), 124 (40), 111
(38), 97 (28), 84 (100), 44 (68) m/z; HRMS calcd for C17H32N2
(M + H)+ 265.2644, found 265.2654.
24
[R]D -20.6 (c 0.65, MeOH); IR (film, NaCl) 2930, 1694
(CdO), 1422, 1259 cm-1 1H NMR (300 MHz, CDCl3)
;
δ 7.35-7.25 (m, 5H), 5.18 (d, J = 12.3 Hz, 1H), 5.07 (d, J =
12.3 Hz, 1H), 4.23 (br s, 1H), 4.06 (br d, J = 13.2 Hz, 1H),
2.23-2.80 (m, 2H), 2.23 (s, 3H), 2.03-1.95 (m, 2H), 1.75-
1.22 (m, 17H), 0.97 (dt, J=13.4, 3.9 Hz, 1H), 0.82 (d, J=6.0 Hz,
3H), 2.75 (q, J=11.9 Hz, 1H); 13C NMR at 50 °C (75 MHz,
CDCl3) δ 155.7, 137.2, 128.7, 128.2, 128.1, 67.2, 63.0, 57.8, 49.9,
44.7, 43.1, 40.1, 39.6, 38.5, 35.6, 29.2, 27.2, 27.0, 26.3, 26.0, 25.7,
23.1, 18.8; TLC Rf=0.26 (30% EtOAc/hexanes, basic alumina);
HRMS calcd for C25H38N2O2 (M + H)+ 399.3012, found
399.3010.
Nr-Methylphlegmarine (1c). Lithium aluminum hydride (400 μL,
400 μmol, 1.0 M in THF, 12 equiv) was added dropwise slowly into
a solution of 26 (13.7 mg, 33.5 μmol) in THF (6.0 mL). The solution
was then heated at reflux for 3 h, cooled to 0 °C, and water (10 μL)
was added carefully followed by a 25% solution of NaOH (20 μL).
The solution was warmed to rt and Celite (0.5 g) was added. After
stirring for 1.5 h, the mixture was filtered through Celite, and the
filter cake was washed with hot EtOAc (3 ꢀ 10 mL). Concentration
of the filtrate gave a crude heterogeneous oil which was purified by
flash column chromatography (basic alumina (activity 2), stepwise
gradient from 75 to 100% EtOAc/hexanes then 5% MeOH/
CH2Cl2) to afford NR-methylphlegmarine (1c) (8.4 mg, 94%) as
an oil. [R]D22 -77 (c 0.42, CHCl3); IR (film, NaCl) 3364 (N-H),
2926, 2777 (N-Me), 2852, 1455, 1371, 1026 cm-1; 1H NMR (300
MHz, CDCl3) δ 3.01 (br d, J=12.2 Hz, 1H), 2.83 (br d, J=11.4 Hz,
1H), 2.57 (dt, J=12.2, 2.5 Hz, 1H), 2.42 (dt, J=10.6, 3.6 Hz, 1H),
2.27 (s, 3H), 2.11 (dt, J=11.4, 5.2 Hz, 1H), 1.84-1.4 (m, 15H),
1.39-1.05 (m, 4H), 1.00 (br t, J=10 Hz, 1H), 0.89 (d, J=6.4 Hz,
3H), 0.81 (q, J=11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 62.2,
57.3, 55.5, 47.1, 46.4, 43.4, 43.3, 38.4, 35.2, 30.7, 29.3, 28.9, 27.8,
2S-2-[(4aR,5S,7R,8aR)-1,2,3,4a,5,6,7,8,8a-Decahydroquinolin-
1-cyano-7-methyl-5-ylmethyl)-1-[(benzyloxy)carbonyl]piperidine
(26). To a cooled (0 °C) solution of 23 (8.3 mg, 21 μmol) and
lithium carbonate (2.1 mg, 21 μmol, 1 equiv) in chloroform
(1.0 mL) was added cyanogen bromide (10 μL, 31 μmol, 3 M
solution in CH2Cl2, 1.5 equiv). The solution was allowed to stir
at 0 °C for 30 min, warmed to rt, and concentrated in vacuo. The
crude oil was purified by flash column chromatography (silica
gel, 20% EtOAc/hexanes) to give 26 (8.2 mg, 96%) as a colorless
23
oil. [R]D -30 (c 0.79, CHCl3); IR (film, NaCl) 2929, 2205
(CtN), 1693 (CO), 1454, 1422, 1262 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.38-7.26 (m, 5H), 5.19 (d, J = 12.0 Hz, 1H), 3.05 (d,
J = 12.0 Hz, 1H), 4.22 (br s, 1H), 4.07 (br d, J = 13.2 Hz, 1H),
3.41 (br d, J = 12.8 Hz, 1H), 2.95 (td, J = 11.4, 3.6 Hz, 1H), 2.85
(t, J = 12.8 Hz, 1H), 2.69 (br s, 1H), 2.01 (br d, J = 9.2 Hz, 1H),
1.67-1.25 (m, 16H), 1.07-0.85 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 155.6, 137.0, 128.7, 128.3 (br s, 2C), 117.1, 67.3, 57.1,
J. Org. Chem. Vol. 75, No. 24, 2010 8569

Wolfe et al.
JOCArticle
26.2, 25.9, 24.3, 23.0; TLC Rf = 0.18 (5% MeOH/CH2Cl2, basic
alumina); LRMS: 264 (M+, 0.07), 249 (0.5), 150 (5), 134 (1), 122(1),
110 (3), 98 (100), 82 (2), 70 (4), 54 (2), 44 (23) m/z; HRMS calcd for
C17H32N2 (M + H)+ 265.2644, found 265.2643.
Nr-Methyl-Nβ-acetylphlegmarine (1e). To a cooled (0 °C)
solution NR-methylphlegmarine (1c) (8.4 mg, 32 μmol) and
pyridine (8.6 μL, 110 μmol, 3.5 equiv) in dichloromethane (1.0 mL)
was added acetyl chloride (7.5 μL, 110 μmol) dropwise. The
solution was allowed to stir for 30 min at 0 °C and then warmed
to rt for an additional 30 min. Saturated NaHCO3 (1.0 mL)
was added and the phases were separated. The aqueous phase
was extracted with dichloromethane (5 ꢀ 1 mL), and the
combined organic phases were washed with brine (1.0 mL),
dried (Na2SO4), filtered (Celite) and concentrated in vacuo.
The crude oil was purified by flash column chromatography
(basic alumina (activity 2), stepwise elution with 50-100%
EtOAc/hexanes then 10% MeOH/CH2Cl2) providing NR-
methyl-Nβ-acetylphlegmarine (1e) (8.2 mg, 84%) as a colorless
oil. [R]D23 -192 (c 0.40, CHCl3); IR (film, NaCl) 2928, 2777 (N-
Nr-Acetyl-Nβ-methylphlegmarine (1d). To a cooled solution
(0 °C) of Nβ-methylphlegmarine (1b) (6.9 mg, 26 μmol) and
pyridine (6.3 μL, 78 μmol) in dichloromethane (1.0 mL) was
added acetyl chloride (5.6 μL, 78 μmol) dropwise. The solution
was stirred at 0 °C for 30 min, warmed to rt for an additional
30 min, and then saturated NaHCO3 (0.5 mL) was added. The
aqueous phase was extracted with EtOAc (5 ꢀ 0.5 mL), and then
the combined organic phases were concentrated in vacuo to give
a colorless oil. The crude material was purified by flash chro-
matography over basic alumina (activity 2, 2% MeOH/CH2Cl2)
providing NR-acetyl-Nβ-methylphlegmarine (1d) (7.6 mg, 95%)
as a colorless oil. [R]D23 -75 (c 0.37, CHCl3); lit.7 [R]D -11 (c 0.7,
CHCl3) ; IR (film, NaCl) 2929, 2776 (NCH3), 1643 (CdO),
1424, 1263, 1005 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.75 and
3.80 (2 br s due to rotamers, total 1H), 4.54 and 3.59 (2 br d due
to rotamers, J=13.0 Hz, total 1H), 3.15 and 2.63 (2 tt due to
rotamers, J=3.2, 13.2 Hz, total 1H) 2.83 (br d, J=8.4 Hz, 1H),
2.25 and 2.23 (2 s due to rotamers, total 3H), 2.08 and 2.07 (2 s
due to rotamers, total 3H), 2.02-1.90 (m, 3H), 1.68-1.24 (m,
18H), 1.09 and 1.02 (2 dt due to rotamers, J=13.0, 3.8 Hz, total
1H), 0.92 (apparent t due to rotamers, J=5.8 Hz, 3H), 0.75 and
0.71 (2 q due to rotamers, J=11.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 169.0, 63.1, and 63.0 (doubled due to rotamers), 57.9
and 57.7 (doubled due to rotamers), 52.8 and 47.1 (doubled due
to rotamers), 44.7 and 44.6 (doubled due to rotamers), 43.1,
42.3, 40.1, and 38.9 (doubled due to rotamers), 38.4 and 36.9
(doubled due to rotamers), 36.0 and 35.8 (doubled due to
rotamers), 29.2, 27.3, and 27.2 (doubled due to rotamers),
26.8, 26.4, and 26.3 (doubled due to rotamers), 26.3 and 26.0
(doubled due to rotamers), 26.2 and 25.5 (doubled due to
rotamers), 23.2 and 23.0 (doubled due to rotamers), 22.4 and
21.8 (doubled due to rotamers), 19.0 and 18.9 (doubled due to
rotamers); TLC Rf=0.23 (2.5% MeOH/CH2Cl2, basic alumi-
na); LRMS: 306 (M+, 10), 291(7), 264 (1), 263 (4), 250 (2), 249
(11), 206 (3), 181 (1), 180 (6), 167 (13), 166 (100), 164 (7), 127 (3),
126 (32), 124 (5), 123 (4), 98 (2), 97 (10), 96 (8); HRMS calcd for
C19H34N2O (M + H)+ 307.2749, found 307.2750.
1
Me), 1640 (CdO), 1439, 1247, 1027 cm-1; H NMR at 50 °C
(400 MHz, CDCl3) δ 3.71 (br m, 2H), 3.11 (br m, 1H), 2.82 (dt,
J=11.6, 3.4 Hz, 1H), 2.27 (s, 3H), 2.13 (dt, J=11.6, 6.8 Hz,
1H), 2.05 (s, 3H), 2.03 (m, 1H), 1.92-1.55 (m, 13H), 1.42 (m,
1H), 1.35-1.02 (m, 6H), 0.94-0.85 (m, 1H), 0.91 (d, J=6.4 Hz,
3H); 13C NMR at 50 °C (100 MHz, CDCl3) δ 169.9, 62.2, 56.8,
54.8, 43.2, 41.5, 39.6, 38.6, 37.9, 35.4, 30.7, 28.5, 26.8, 25.9,
24.1, 23.1, 23.0, 22.5, 22.1; TLC Rf = 0.29 (2.5% MeOH/
CH2Cl2, basic alumina); LRMS: 306 (M+, 0.96), 291 (0.41),
263 (1.6), 207 (1.9), 192 (1.3), 150 (5.2), 110 (2.8), 98 (100), 70
(5.1), 55 (3.0), 44 (49) m/z;HRMScalcdforC19H34N2O(M+H)+
307.2749, found 307.2747.
Acknowledgment. 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. CHE-0078253).
Supporting Information Available: Characterization data
sheets for 1a,b and comparison data tables for 1c-e. NMR
spectra for 1, 8, 19-23, and 26. This material is available free of
charge via the Internet at http://pubs.acs.org.
8570 J. Org. Chem. Vol. 75, No. 24, 2010