Synthesis of the quinolizidine alkaloids (-)-lasubine II and (±)-myrtine by conjugate addition and intramolecular acylation of amino esters with acetylenic sulfones

Article abstract of DOI:10.1021/jo048284j

(Chemical Equation Presented) The conjugate additions of (2-piperidyl)acetate esters to acetylenic sulfones, followed by LDA-promoted intramolecular acylations, afforded cyclic enaminones that were readily converted into the corresponding 4-substituted 2-

Full text of DOI:10.1021/jo048284j

Synthesis of the Quinolizidine Alkaloids (-)-Lasubine II and
(()-Myrtine by Conjugate Addition and Intramolecular Acylation
of Amino Esters with Acetylenic Sulfones
Thomas G. Back,* Michael D. Hamilton, Vania J. J. Lim, and Masood Parvez
Department of Chemistry, University of Calgary, Calgary, Alberta, Canada T2N 1N4
tgback@ucalgary.ca
Received September 28, 2004
The conjugate additions of (2-piperidyl)acetate esters to acetylenic sulfones, followed by LDA-
promoted intramolecular acylations, afforded cyclic enaminones that were readily converted into
the corresponding 4-substituted 2-keto- or 2-hydroxyquinolizidines by stereoselective reduction and
desulfonylation. This procedure was applied to the total synthesis of (-)-lasubine II from methyl
(S)-(2-piperidyl)acetate and 2-(3,4-dimethoxyphenyl)-1-(p-toluenesulfonyl)ethyne. Similarly, methyl
(()-(2-piperidyl)acetate and 1-(p-toluenesulfonyl)propyne provided (()-myrtine.
SCHEME 1
Introduction
The chemistry of unsaturated sulfones continues to be
widely exploited in organic synthesis.1,2 For example, the
electron-withdrawing sulfone group activates adjacent
alkene, allene, and acetylene moieties in diverse conju-
gate addition and cycloaddition reactions. Moreover, the
R-protons of vinyl and alkyl sulfones are relatively acidic,
thereby permitting the generation of sulfone-stabilized
anions,3 which can in turn be alkylated or acylated with
appropriate electrophilic reagents. Finally, the sulfone
group can be removed at the end of a synthetic sequence
by a variety of reductive, alkylative, or oxidative meth-
ods.4 We have found that conjugate additions of suitably
functionalized amines to acetylenic sulfones can be used
in tandem with intramolecular alkylations or acylations,
resulting in a novel cyclization protocol that leads to a
broad range of nitrogen heterocycles (Scheme 1). This
general protocol has been employed with both cyclic and
* To whom correspondence should be addressed. Tel: (403) 220-
6256. Fax: (403) 289-9488.
(1) For a general review of sulfones, see: Simpkins, N. S. Sulphones
in Organic Synthesis; Pergamon Press: Oxford, 1993.
(2) (a) For acetylenic and allenic sulfones, see: Back, T. G. Tetra-
hedron 2001, 57, 5263. (b) For vinyl sulfones, see: Simpkins, N. S.
Tetrahedron 1990, 46, 6951. (c) For dienyl sulfones, see: Ba¨ckvall, J.-
E.; Chinchilla, R.; Na´jera, C.; Yus, M. Chem. Rev. 1998, 98, 2291.
(3) Block, E. Reactions of Organosulfur Compounds; Academic
Press: New York, 1978; Chapter 2.
acyclic secondary amines containing â- or γ-chloro sub-
stituents, leading to substituted piperidines, pyrroliz-
idines, indolizidines, and quinolizidines,5 including the
dendrobatid alkaloids indolizidines (-)-167B, (-)-209D,
(5) (a) Back, T. G.; Nakajima, K. Org. Lett. 1999, 1, 261. (b) Back,
T. G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543.
(4) Na´jera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
10.1021/jo048284j CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/12/2005
J. Org. Chem. 2005, 70, 967-972
967

Back et al.
SCHEME 2
SCHEME 3
SCHEME 4
(-)-209B, and (-)-207A5b (Scheme 1). Similarly, conju-
gate additions of amino esters to acetylenic sulfones,
followed by intramolecular acylation, have been ex-
ploited in the synthesis of both naturally occurring and
unnatural quinolones,6 as well as in the preparation of
the dendrobatid alkaloid (-)-pumiliotoxin C7 (Scheme 2).
We now report that the similar reactions of methyl
(2-piperidyl)acetate with the appropriate acetylenic sul-
fones provide a concise new route to the corresponding
4-substituted 2-keto- or 2-hydroxyquinolizidines, and
we illustrate the method by its application to the
total synthesis of the alkaloids (-)-lasubine II (1)8 and
(()-myrtine (2).
Results and Discussion
(-)-Lasubine II and related quinolizidine alkaloids9
such as (-)-lasubine I (the 10-epi derivative of 1), and
their respective 3,4-dimethoxycinnamate esters (+)-sub-
cosine II and I, have been isolated from plants of the
Lythraceae family.10 (+)-Myrtine (2) and (-)-epimyrtine
(3) are found in Vaccinium myrtillus.11 Several earlier
syntheses of 1 and 2 and their congeners have been
reported.12,13
of Chung et al.,14 while 8 was obtained by the free-radical
selenosulfonation15 of acetylene 516 with Se-phenyl p-
tolueneselenosulfonate (6).17 The adduct 7 was then
subjected to selenoxide elimination to afford the required
acetylenic sulfone 8 (Scheme 3).
The synthesis of 1 is summarized in Scheme 4. The
conjugate addition of 4 to 5 proceeded smoothly, and the
(12) For previous syntheses of (-)-lasubine II, see: (a) Chalard, P.;
Remuson, R.; Gelas-Mialhe, Y.; Gramain, J.-C. Tetrahedron: Asym-
metry 1998, 9, 4361. (b) Ukaji, Y.; Ima, M.; Yamada, T.; Inomata, K.
Heterocycles 2000, 52, 563. (c) Davis, F. A.; Chao, B. Org. Lett. 2000,
2, 2623. (d) Ma, D.; Zhu, W. Org. Lett. 2001, 3, 3927. (e) Gracias, V.;
Zeng, Y.; Desai, P.; Aube´, J. Org. Lett. 2003, 5, 4999. For syntheses of
(()-lasubine II, see: (f) Bardot, V.; Gardette, D.; Gelas-Mialhe, Y.;
Gramain, J.-C.; Remuson, R. Heterocycles 1998, 48, 507. (g) Pilli, R.
A.; Dias, L. C.; Maldaner, A. O. J. Org. Chem. 1995, 60, 717. (h) Pilli,
R. A.; Dias, L. C.; Maldaner, A. O. Tetrahedron Lett. 1993, 34, 2729.
(i) Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am. Chem. Soc. 1988,
110, 7445. (j) Narasaka, K.; Ukaji, Y.; Yamazaki, S. Bull. Chem. Soc.
Jpn. 1986, 59, 525. (k) Hoffmann, R. W.; Endesfelder, A. Liebigs Ann.
Chem. 1986, 1823. (l) Iida, H.; Tanaka, M.; Kibayashi, C. J. Org. Chem.
1984, 49, 1909. (m) Takano, S.; Shishido, K. Chem. Pharm. Bull. 1984,
32, 3892. (n) Quick, J.; Ramachandra, R. Tetrahedron 1980, 36, 1301.
For syntheses of (-)-lasubine I, see: ref 12a and (o) Davis, F. A.; Rao,
A.; Carroll, P. J. Org. Lett. 2003, 5, 3855. (p) Comins, D. L.; LaMunyon,
D. H. J. Org. Chem. 1992, 57, 5807. (q) Ratni, H.; Kundig, E. P. Org.
Lett. 1999, 1, 1997. For syntheses of (()-lasubine I, see: ref 12f,l
and (r) Beckwith, A. L. J.; Joseph, S. P.; Mayadunne, R. T. A. J.
Org. Chem. 1993, 58, 4198. (s) Ent, H.; De Koning, H.; Speckamp, W.
N. Heterocycles 1988, 27, 237. (t) Iida, H.; Tanaka, M.; Kibayashi,
C. J. Chem. Soc., Chem. Commun. 1983, 1143. For a synthesis of
(+)-subcosine I, see ref 12p, and for a synthesis of (()-subcosine I, see
ref 12l,t. For a synthesis of (+)-subcosine II, see ref 12a.
For the synthesis of (-)-1, we required methyl (S)-(2-
piperidyl)acetate (4) as well as acetylenic sulfone 8. The
former was obtained by a minor variation of the method
(6) Back, T. G.; Parvez, M.; Wulff, J. E. J. Org. Chem. 2003, 68,
2223.
(7) Back, T. G.; Nakajima, K. J. Org. Chem. 1998, 63, 6566.
(8) Preliminary communication: Back, T. G.; Hamilton, M. D. Org.
Lett. 2002, 4, 1779.
(9) For selected reviews of quinolizidine alkaloids, see: (a) Howard,
A. S.; Michael, J. P. In The Alkaloids; Brossi, A., Ed.; Academic Press:
Orlando, 1986; Vol. 28, Chapter 3. (b) Herbert, R. B. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1987; Vol. 3, Chapter 6. (c) Kinghorn, A. D.; Balandrin, M. F. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1987; Vol. 2, Chapter 3. (d) Michael, J. P. Nat. Prod.
Rep. 2001, 18, 520; see also earlier reviews by this author in this series,
as cited therein.
(10) Fuji, K.; Yamada, T.; Fujita, E.; Murata, H. Chem. Pharm. Bull.
1978, 26, 2515.
(11) (a) Slosse, P.; Hootele´, C. Tetrahedron Lett. 1978, 397. (b) Slosse,
P.; Hootele´, C. Tetrahedron 1981, 37, 4287.
968 J. Org. Chem., Vol. 70, No. 3, 2005

Synthesis of the Quinolizidine Alkaloids (-)-Lasubine II and (()-Myrtine
SCHEME 5
SCHEME 6
SCHEME 7
adduct 9 was immediately cyclized by treatment with
LDA at -78 °C. The kinetic deprotonation and intramo-
lecular acylation of alkyl sulfones (pKa ) ca. 30)18 in the
presence of esters (pKa ) ca. 25)19 has been reported
previously.20 Similarly, the desired intramolecular acy-
lation of the sulfone-stabilized vinyl anion 12, produced
from 9, competed effectively with formation of the cor-
responding ester enolate 13 (Scheme 5), and ring closure
proceeded faster than proton transfer between 12 and
13. These considerations are significantly different from
those in Scheme 2, where a primary amine was used in
the initial conjugate addition and where subsequent
abstraction of the remaining N-H proton generated a
delocalized enamidyl anion instead of a less stable vinyl
anion. The use of excess LDA and low temperatures was
necessary in the present case to suppress undesired
proton-transfer processes between 12 and 13 and be-
tween the product 10 (which is presumably converted into
its enolate 14 in the presence of excess base) and the
anion 12. It is also worth noting that 9 was obtained as
an E/Z mixture but that both isomers reacted to afford
10, suggesting that interconversion of the geometrical
isomers is rapid under these conditions.
Both the 1H and 13C NMR spectra of 10 at room
temperature suggested that it exists as two distinct
rotamers, i.e., 10a and 10b (Scheme 6), as many of the
peaks were duplicated, most obviously the m-methoxy
peak of the aromatic ring. The rotational barrier is likely
due to steric interactions between the 3,4-dimethoxy-
phenyl and the p-toluenesulfonyl groups. Variable-tem-
perature 1H NMR experiments (see the Supporting
Information) revealed that coalescence of the twinned
signals occurred at 400 K, indicating that the energy of
the rotational barrier is 88.0 kJ/mol.21
The reduction of the enaminone moiety of 10 with
sodium borohydride proceeded selectively via the R-face
to afford 15, where the bulky aryl substituent occupies
the equatorial position. Simultaneous reduction of the
ketone occurred to afford the corresponding equatorial
alcohol 16 (Scheme 7), which possesses the 2-epi con-
figuration relative to 1. Other reduction methods, includ-
(13) For previous syntheses of (+)-myrtine, see refs 11, 12p, and (a)
Gardette, D.; Gelas-Mialhe, Y.; Gramain, J.-C.; Perrin, B.; Remuson,
R. Tetrahedron: Asymmetry 1998, 9, 1823. (b) Slosse, P.; Hootele´, C.
Tetrahedron Lett. 1979, 19, 4587. For syntheses of (()-myrtine, see:
ref 12g,h and (c) Gelas-Mialhe, Y.; Gramain, J.-C.; Louvet, A.;
Remuson, R. Tetrahedron Lett. 1992, 33, 73. (d) Comins, D. L.;
LaMunyon, D. H. Tetrahedron Lett. 1989, 30, 5053. (e) King, F. D. J.
Chem. Soc., Perkin Trans. 1 1986, 447. For syntheses of (-)-epimyrtine
see: ref 13a and (f) Davis, F. A.; Zhang, Y.; Anilkumar, G. J. Org.
Chem. 2003, 68, 8061. For syntheses of (()-epimyrtine, see: ref 13b,c,e
and (g) Comins, D. L.; Weglarz, M. A.; O′Connor, S.; Tetrahedron Lett.
1988, 29, 1751. (h) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986,
27, 4549.
(16) Pelter, A.; Ward, R. S.; Little, G. M. J. Chem. Soc., Perkin Trans.
1 1990, 2775.
(17) Back, T. G.; Collins, S.; Krishna, M. V. Can. J. Chem. 1987,
65, 38.
(18) (a) Bordwell, F. G.; Van der Puy, M.; Vanier, N. R. J. Org. Chem.
1976, 41, 1883. (b) Bordwell, F. G.; Bares, J. E.; Bartmess, J. E.;
Drucker, G. E.; Gerhold, J.; McCollum, G. J.; Van Der Puy, M.; Vanier,
N. R.; Matthews, W. S. J. Org. Chem. 1977, 42, 326. (c) Matthews, W.
S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.; Cornforth, F. J.;
Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum, G. J.; Vanier,
N. R. J. Am. Chem. Soc. 1975, 97, 7006.
(14) Chung, H.-K.; Kim, H.-W.; Chung, K.-H. Heterocycles 1999, 51,
2983.
(15) For thermal selenosulfonation of acetylenes, see: (a) Back, T.
G.; Collins, S.; Kerr, R. G. J. Org. Chem. 1983, 48, 3077. (b) Miura, T.;
Kobayashi, M. J. Chem. Soc., Chem. Commun. 1982, 438. For a
photochemical variation, see: (c) Back, T. G.; Krishna, M. V.; Mu-
ralidharan, K. R. J. Org. Chem. 1989, 54, 4146. For a recent review of
selenosulfonation, including descriptions of procedures, see: (d) Back,
T. G. In Organoselenium ChemistrysA Practical Approach; Back, T.
G., Ed.; Oxford University Press: Oxford, 1999; Chapter 9, pp 176-
178.
(19) Smith, M. B.; March, J. March’s Advanced Organic Chemistry,
5th ed.; Wiley: New York, 2001; p 331.
(20) (a) Grimm, E. L.; Levac, S.; Coutu, M. L. Tetrahedron Lett. 1994,
35, 5369. (b) Grimm, E. L.; Coutu, M. L. Trimble, L. A. Tetrahedron
Lett. 1993, 34, 7017.
(21) Lambert, J. B.; Mazzola, E. P. Nuclear Magnetic Resonance
Spectroscopy; Pearson Education: Upper Saddle River, NJ, 2004; pp
136-143.
J. Org. Chem, Vol. 70, No. 3, 2005 969

Back et al.
SCHEME 8
SCHEME 9
subjected to X-ray crystallography (see the Supporting
Information), thereby confirming its structure unequivo-
cally and clearly indicating the presence of an axial C-4
methyl substituent located cis to the hydrogen atom at
C-10. The observed stereochemistry was in contrast to
that observed in the reduction of enaminone 10 in
Scheme 4, where the dominant epimer contained the C-4
substituent trans to the C-10 hydrogen atom. R-Chlorina-
tions accompanying Swern oxidations have been reported
previously.24 Presumably, this process was not observed
during the preparation of 11 because of the greater steric
hindrance imposed by the bulky aryl group at C-4. Of
several other standard oxidation procedures investigated
(e.g., PDC, PCC, Dess-Martin periodinane), the Moffatt
oxidation25 afforded the best, albeit still modest, yield of
the corresponding ketone 21. Finally, reductive desulfo-
nylation of 21 with lithium 4,4′-di-tert-butylbiphenylide
(LDBB)26 produced (()-myrtine (2). Its identity was
confirmed by comparing its NMR spectra with those
reported in the literature11,13 for both myrtine (2) and
epimyrtene (3).
It is interesting to note that the stereochemical out-
come of the enaminone reduction of 19 in Scheme 8 was
the opposite to that of 10 in Scheme 4. Thus, while
incorporation of hydride at C-4 occurred predominantly
cis to the ring-fusion hydrogen at C-10 in 10, the similar
reduction of 19 resulted in trans addition. The stereo-
chemistry of nucleophilic additions to enaminones and
the corresponding iminium species has been widely
studied in other systems.27 In general, both steric and
stereoelectronic factors can play a role in determining
facial selectivity. Slosse and Hootele´11b have reported that
the reduction of the similar enaminone 22 with lithium
aluminum hydride afforded chiefly the epimyrtine de-
rivative 23 (Scheme 9), with the opposite stereochemistry
at C-4 to that observed in the reduction of 19 with sodium
borohydride to afford 24, but similar to that obtained in
the reduction of 10 shown in Scheme 4. They attributed
their observation to a preferred chairlike transition state
leading to the formation of 23. Since the principal
ing the use of sodium cyanoborohydride, various boranes,
and catalytic hydrogenation, proved less chemo- and/or
stereoselective or failed to achieve the desired transfor-
mation. Thus, alcohol 16 was subjected to a Swern oxi-
dation22 to produce the corresponding ketone, followed
by desulfonylation with lithium in liquid ammonia to
afford an 88:12 mixture of the corresponding C-4 epimers
11a and 11b (Scheme 4). Finally, reduction of 11a with
lithium tri-sec-butylborohydride (L-Selectride)23 occurred
from the â-face (equatorial approach) to produce (-)-
lasubine II (1), containing the necessary axial alcohol
(Schemes 4 and 7).
The synthesis of the myrtine-epimyrtine system was
approached in a similar manner, with the expectation
that epimyrtine (3) would be the dominant stereoisomer,
by analogy to the formation of 1 in Scheme 4. In this case,
amino ester (()-4 (arbitrarily shown as the R-enan-
tiomer) was added to 1-(p-toluenesulfonyl)propyne (17),
followed by intramolecular acylation of 18 with excess
LDA (Scheme 8). The sulfone 17 was prepared by a
protocol similar to that shown in Scheme 3, except that
a chloroform solution of 6 was saturated with propyne,
followed by irradiation with UV light. In contrast to
Scheme 4, where deprotonation of 9 produced a vinyl
anion, the methyl-substituted adduct 18 presumably
underwent acylation via the corresponding allyl anion.
The enaminone 19 was then reduced with sodium boro-
hydride to furnish 94% of a single diastereomer of a
saturated alcohol product with undetermined stereo-
chemistry at C-3 and C-4. The alcohol was subjected to
a Swern oxidation (as in the preparation of 11 in Scheme
4) to afford 20, in which the expected ketone underwent
a subsequent R-chlorination at C-3. Product 20 was
(24) For example, see: Beck, B. J.; Aldrich, C. C.; Fecik, R. A.;
Reynolds, K. A.; Sherman, D. H. J. Am. Chem. Soc. 2003, 125, 12551.
(25) (a) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963, 85,
3027. (b) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1965, 87,
5661. (c) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1965, 87,
5670.
(26) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924. (b) Manthorpe, J. M.; Gleason, J. L. J. Am. Chem. Soc. 2001,
123, 2091.
(27) For reviews of stereoelectronic effects in additions to enami-
nones and related iminium species, see: (a) Deslongchamps, P.
Stereoelectronic Effects in Organic Chemistry; Pergamon Press: Oxford,
1983; pp 211-221. (b) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289.
(22) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(23) Quick, J.; Meltz, C.; Ramachandra, R. Org. Prep. Proc. Int. 1979,
11, 111.
970 J. Org. Chem., Vol. 70, No. 3, 2005

Synthesis of the Quinolizidine Alkaloids (-)-Lasubine II and (()-Myrtine
The pure (S)-enantiomer of 4 was prepared by a variation
difference in the structures of 22 and 19 is the presence
of the sulfone substituent at C-3 in the latter, this group
may play a role in determining the stereochemistry. It
has also been reported that myrtine and epimyrtine
equilibrate under both acid- and base-catalyzed condi-
tions, most probably via retro-Michael and/or retro-
Mannich processes followed by recyclization.11b Since
these processes are likely to be facilitated by the presence
of the sulfone moiety at C-3, similar isomerizations of
the initial reduction products of 10 and 19 might also
affect the stereochemistry found in their respective
products. The greater steric bulk of the C-4 aryl group
in 10 compared to the methyl substituent in 19 is
consistent with its greater propensity to occupy the
equatorial position in the reduced product.28 Because the
above equilibration experiments demonstrated that
epimyrtine is thermodynamically favored over myrtine,11b
it is plausible that the myrtine analogue 24 is the kinetic
product of reduction of 19, while the similar reduction of
10 is under thermodynamic control, thereby resulting in
the opposite stereochemistry at C-4. However, the con-
formational mobility of quinolizidinones such as myrtine
and epimyrtine,11b,13a as well as uncertainty about the
precise effect of the sulfone group upon the stereochem-
istry, precludes more precise conclusions at this time.
In summary, the quinolizidine alkaloid (-)-1 was
obtained with high stereoselectivity in just six steps and
24% overall yield from amino ester 4 and acetylenic sul-
fone 5, as shown in Scheme 4. Since (-)-1 has been pre-
viously converted into (+)-subcosine II,12a this also rep-
resents a formal synthesis of the latter product. Similarly,
despite a relatively low overall yield of 12%, the synthesis
shown in Scheme 8 comprises a concise approach to (()-2
from (()-4 and acetylenic sulfone 17 in five steps. The
different C-4 stereochemistry that was obtained in prod-
ucts 1 and 2 from enaminones 10 and 19 by very similar
synthetic procedures is also noteworthy.
of the procedure of Chung et al.14 These authors resolved the
N-Cbz-protected parent carboxylic acid derivative by forming
an amide with a chiral oxazolidinone, followed by hydrolytic
cleavage of the resolving agent. In the present case, cleavage
of the resolving agent was achieved with sodium methoxide
in methanol to afford the methyl ester (S)-4 directly.
1-(p-Toluenesulfonyl)propyne (17). Acetylenic sulfone 17
was prepared by a modification of the general selenosulfona-
tion procedure described previously.15d Propyne was bubbled
through a solution of Se-phenyl p-tolueneselenosulfonate (4.34
g, 14.0 mmol) in chloroform (40 mL) at 0 °C for 10 min. The
solution was irradiated in a Rayonet reactor containing six
300 nm lamps for 1.5 h. The solvent was removed in vacuo,
and the residue was chromatographed over silica gel using 15%
ethyl acetate-hexane to afford the corresponding â-(phenylse-
leno)vinyl sulfone as a white solid (4.35 g, 89%). The latter
product (1.70 g, 4.84 mmol) in dichloromethane (30 mL) was
stirred with K2CO3 (0.81 g, 5.9 mmol) and purified m-CPBA31
(0.94 g, 5.5 mmol) for 20 min. The solution was then washed
with water, 1.0 M K2CO3 solution, and brine. It was dried and
concentrated in vacuo to give the corresponding crude sele-
noxide as a yellow oil, which was dissolved in chloroform (125
mL) and refluxed under Ar for 3.5 h. The solvent was removed
in vacuo, and chromatography over silica gel (25% ethyl
acetate-hexane) provided 17 as a pale yellow solid (600 mg,
64%): mp 97-99 °C (lit.32 mp 96-97 °C); IR (film) 2203, 1324,
1
1150 cm-1; H NMR (300 MHz) δ 7.88 (d, J ) 8.2 Hz, 2 H),
7.37 (d, J ) 8.2 Hz, 2 H), 2.47 (s, 3 H), 2.03 (s, 3 H); 13C NMR
(75 MHz) δ 145.3, 139.1, 130.0, 127.5, 93.3, 77.9, 21.8, 4.4.
(()-4-Methyl-3-(p-toluenesulfonyl)-3,4-dehydroquino-
lizidin-2-one (19). Amino ester (()-4 (1.428 g, 9.10 mmol) and
acetylenic sulfone 17 (0.872 g, 4.49 mmol) were dissolved in
dry MeOH (45 mL) and stirred at room temperature for 20 h.
The solvent was removed in vacuo to give the crude enamine
18 as a yellow oil, which was used directly in the next step.
The above enamine was dissolved in dry THF (20 mL) and
added to a solution of LDA (11 mmol) in dry THF (30 mL) at
-78 °C over 5 min. The dark red solution was filtered through
neutral alumina, which was subsequently washed with THF
(30 mL) and acetone (30 mL). The dark red filtrate was
concentrated in vacuo and chromatographed over silica gel
(50% acetone-hexanes) to give enaminone 19 as a yellow oil
(599 mg, 42%): IR (film) 1641, 1279, 1136 cm-1; 1H NMR (300
MHz) δ 7.84 (d, J ) 8.2 Hz, 2 H), 7.20 (d, J ) 8.2 Hz, 2 H),
4.09 (br d, J ) 14.0 Hz, 1 H), 3.57-3.44 (m, 1 H), 3.07 (br t, J
) 11.8 Hz, 1 H), 2.64-2.54 (m, 1 H), 2.61 (s, 3 H), 2.34 (s, 3
H), 2.20 (dd, J ) 16.6, 7.4 Hz, 1 H), 1.88-1.77 (m, 2 H), 1.65-
1.47 (m, 4 H); 13C NMR (75 MHz) δ 185.0, 165.6, 142.6, 141.8,
129.0, 127.2, 112.5, 58.3, 49.8, 42.1, 30.6, 26.1, 23.3, 21.6, 17.9;
mass spectrum m/z (relative intensity) 319 (M+, 1), 275 (4),
254 (100).
Experimental Section
Experimental procedures for the synthesis of (-)-lasubine
II (1) via Schemes 3 and 4 are available in the Supporting
Information accompanying our preliminary communication.8
Se-Phenyl p-tolueneselenosulfonate (6)17 was prepared by a
literature procedure.
Methyl (()-(2-Piperidyl)acetate (4). 2-(2-Piperidyl)etha-
nol was converted to (2-piperidyl)acetic acid by Jones oxida-
tion.29 The product (1.83 g, 12.8 mmol) in HCl-saturated
methanol (20 mL) was refluxed for 2 h and stirred at room
temperature for 16 h. The solvent was removed in vacuo to
give the hydrochloride salt of 4 as a fine white powder. This
solid was dissolved in saturated NaHCO3 solution (10 mL) and
was extracted with dichloromethane. The combined, dried, and
concentrated organic extracts gave (()-430 as a pale yellow
liquid (2.05 g, quantitative): 1H NMR (200 MHz) δ 3.67 (s, 3
H), 3.11-2.84 (m, 2 H), 2.65 (dt, J ) 11.5 and 3.2 Hz, 1 H),
2.40-2.34 (m, 2 H), 2.04 (br s, 1 H), 1.85-1.05 (m, 6 H); mass
spectrum (ESI) m/z (relative intensity) 158 (M+ + 1, 100), 96
(80), 84 (81).
(()-3-Chloro-4-methyl-3-(p-toluenesulfonyl)quinolizi-
din-2-one (20). Enaminone 19 (294 mg, 0.922 mmol) and
sodium borohydride (178 mg, 4.68 mmol) were stirred in
methanol (20 mL) at room temperature for 30 min and then
concentrated in vacuo to afford a solid foam. This was
partitioned between dichloromethane and 1 M KOH solution.
The aqueous portions were combined and extracted with
dichloromethane. The organic portions were combined, dried,
and concentrated in vacuo to give the corresponding amino
alcohol, which was used directly in the next step.
Oxalyl chloride (121 µL, 1.39 mmol) was added to dry
dichloromethane (20 mL) under Ar and cooled to -78 °C.
DMSO (196 µL, 2.76 mmol) was added, and the solution was
stirred at -78 °C for 30 min. A solution of the above amino
alcohol in dichloromethane (8 mL) was added, and the mixture
was stirred at -78 °C for 30 min. Triethylamine (866 µL, 6.22
(28) The differences in the conformational energies of axial and
equatorial substituents are reflected in their A values, which are 1.74
and 2.8 kcal mol-1 for methyl and phenyl groups, respectively: Eliel,
E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley: New York, 1994.
(29) Marshall, W. D.; Nguyen, T. T.; MacLean, D. B.; Spenser, I. D.
Can. J. Chem. 1975, 53, 41.
(30) Kawakami, T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada,
Y.; Murahashi, S. Bull. Chem. Soc. Jpn. 2000, 73, 2423.
(31) MCPBA was purified by washing with a pH 7.5 buffer and was
assumed to be 100% pure; see: Schwartz, N. N.; Blumbergs, J. H. J.
Org. Chem. 1964, 29, 1976.
(32) McDowell, S. T.; Stirling, C. J. M. J. Chem. Soc. B 1967, 351.
J. Org. Chem, Vol. 70, No. 3, 2005 971

Back et al.
mmol) was added, and the resulting solution was stirred at
room temperature for 18 h. The mixture was partitioned
between ether and 1 M KOH solution, and the aqueous layer
was extracted with dichloromethane. The combined organic
layers were dried and concentrated in vacuo to a yellow oil.
Chromatography over silica gel (10% ethyl acetate-hexanes)
afforded the R-chloro-â-keto sulfone as a pale yellow solid (178
mg, 54%): mp 130-132 °C (from ethyl acetate-hexanes); IR
(film) 1725, 1324, 1143 cm-1; 1H NMR (400 MHz) δ 7.69 (d, J
) 8.1 Hz, 2 H), 7.32 (d, J ) 8.1 Hz, 2 H), 3.78 (q, J ) 6.8 Hz,
1 H), 3.09 (m, 1 H), 2.82-2.73 (m, 3 H), 2.51-2.44 (m, 1 H),
2.45 (s, 3 H, Me), 1.79-1.65 (m, 4 H), 1.55-1.42 (m, 1 H), 1.23-
1.14 (m, 1 H), 1.09 (d, J ) 6.8 Hz, 3 H); 13C NMR (100 MHz)
δ 196.3, 145.4, 133.7, 130.3, 129.3, 92.9, 63.7, 52.2, 51.7, 47.0,
33.7, 25.5, 23.4, 21.7, 7.8; mass spectrum m/z (relative inten-
sity) 355 (M+, 32), 200 (100), 185 (22), 164 (30), 124 (38), 110
(70), 91 (46), 55 (39); exact mass calcd for C17H2235ClNO3S
355.1009, found 355.0997. For X-ray crystallographic data for
20, see the Supporting Information.
tetrahydrofuran (10 mL) and adding finely cut pieces of lithium
metal (43 mg, 6.2 mmol). The mixture was stirred under Ar
until it turned dark green, at which point it was cooled to 0
°C and stirring was continued for 4 h. The LDBB solution was
added dropwise via syringe to a solution of keto sulfone 21
(117 mg, 0.364 mmol) in dry tetrahydrofuran (10 mL) until
the green color persisted. After 2 min, the reaction was
quenched by adding saturated ammonium chloride to give a
yellow solution. The mixture was partitioned between ethyl
acetate and 0.5 M KOH solution. The aqueous phase was
extracted with ethyl acetate, and the combined organic por-
tions were dried and concentrated in vacuo to give a white
residue. Chromatography over silica gel (ethyl acetate) gave
(()-myrtine (2) as a pale yellow residue (41 mg, 67%): IR (film)
1
1718 cm-1; H NMR (400 MHz) δ 3.39 (d of quintets, J ) 6.4
and 1.9 Hz, 1 H), 2.90-2.76 (m, 2 H), 2.70-2.61 (m, 1 H), 2.48
(dt, J ) 11.4, 2.8 Hz, 1 H), 2.30-2.16 (m, 3 H), 1.79-1.55 (m,
4 H), 1.40-1.17 (m, 2 H), 0.97 (d, J ) 6.8 Hz, 3 H); 13C NMR
(100 MHz) δ 209.4, 57.1, 53.5, 51.4, 48.6, 48.0, 34.2, 25.8, 23.4,
11.1; mass spectrum m/z (relative intensity) 167 (M+, 40), 152
(100).
For comparison, the following IR, NMR, and mass spectral
data for (()-myrtine (2) were reported in the literature:12g IR
(film) 1714 cm-1; 1H NMR (300 MHz) δ 3.39 (dqt, J ) 6.3, 2.4
Hz, 1 H), 2.90-2.74 (m, 2 H), 2.72-2.62 (m, 1 H), 2.49 (dt, J
) 11.5, 3.0 Hz, 1 H), 2.31-2.16 (m, 3 H), 1.90-1.55 (m, 4 H),
1.45-1.15 (m, 2 H), 0.97 (d, J ) 6.8 Hz, 3 H); 13C NMR (75.2
MHz) δ 210.0, 57.2, 53.6, 51.5, 48.8, 48.1, 34.3, 25.9, 23.5, 11.1;
mass spectrum m/z (relative intensity) 167 (M+, 39), 152 (100).
Similarly, the following spectra were reported for (-)-epimyr-
tine (3):13a IR 1750 cm-1; 1H NMR (400 MHz) δ 3.34 (br d, J )
11.0 Hz, 1 H), 2.50-2.25 (m, 4 H), 2.24-2.12 (m, 1 H), 1.90-
1.55 (m, 6 H), 1.50-1.25 (m, 2 H), 1.20 (d, J ) 5.7 Hz, 3 H);
13C NMR (100 MHz) δ 208.7, 62.4, 59.6, 51.3, 50.0, 49.0, 34.4,
26.2, 24.2, 21.0.
(()-4-Methyl-3-(p-toluenesulfonyl)quinolizidin-2-one
(21). Enaminone 19 (282 mg, 0.884 mmol) was reduced with
sodium borohydride (138 mg, 3.63 mmol) as in the preceding
procedure to afford the corresponding amino alcohol as a beige
solid foam (268 mg, 94%), which was used directly in the next
step.
The above product and DCC (694 mg, 3.37 mmol) were
dissolved in benzene (4 mL). To this solution were added
DMSO (0.7 mL, 10 mmol) and pyridine (94 µL, 1.16 mmol).
The mixture was cooled to 0 °C, trifluoroacetic acid (45 µL,
0.58 mmol) was added, and the resulting solution was stirred
at room temperature for 18 h. The mixture was filtered, and
the resulting dark orange solution was concentrated in vacuo
and subjected to column chromatography over silica gel (35%
ethyl acetate-hexanes) to afford keto sulfone 21 as a slightly
yellow oil (117 mg, 44%): IR (film) 1718, 1318, 1285, 1143
cm-1; 1H NMR (400 MHz) δ 7.73 (d, J ) 8.0 Hz, 2 H), 7.33 (d,
J ) 8.0 Hz, 2 H), 3.94 (q, J ) 6.9 Hz, 1 H), 3.61 (d, J ) 1.4 Hz,
1 H), 2.75 (d, J ) 11.0 Hz, 1 H), 2.69-2.59 (m, 2 H), 2.46-
2.30 (m, 2 H), 2.43 (s, 3 H), 1.71-1.55 (m, 4 H), 1.24-1.11 (m,
2 H), 0.98 (d, J ) 6.9 Hz, 3 H); 13C NMR (100 MHz) δ 200.7,
145.0, 136.4, 129.7, 129.0, 80.2, 57.2, 52.3, 51.2, 46.8, 34.1, 25.7,
23.4, 21.6, 10.0; mass spectrum m/z (relative intensity) 321
(M+, 18), 306 (84), 165 (100); exact mass calcd for C17H23NO3S
321.1399, found 321.1396.
Acknowledgment. We thank the Natural Sciences
and Engineering Research Council of Canada (NSERC)
and Merck Frosst (Canada) Ltd. for financial support.
Supporting Information Available: 1H and 13C NMR
spectra of 19, 20, 21, and 2, variable-temperature NMR spectra
of 10, and X-ray crystallographic data for 20. This material is
available free of charge via the Internet at http://pubs.acs.org.
(()-Myrtine (2). A solution of LDBB was prepared by
dissolving di-tert-butylbiphenyl (1.45 g, 5.44 mmol) in dry
JO048284J
972 J. Org. Chem., Vol. 70, No. 3, 2005