Biomimetic Organocatalytic Approach to 4-Arylquinolizidine Alkaloids and Application in the Synthesis of (-)-Lasubine II and (+)-Subcosine II

Article abstract of DOI:10.1021/acs.orglett.9b01840

An enantioselective, biomimetic organocatalytic synthesis of 4-arylquinolizidin-2-ones, key intermediates in the synthesis of several Lythraceae alkaloids, was developed. The methodology features S-proline-mediated Mannich/aza-Michael reactions of readily available arylideneacetones and Δ¹-piperideine. The total syntheses of (-)-lasubine II and (+)-subcosine II as well as the formal syntheses of structurally related Lythraceae alkaloids were achieved. The use of Δ¹-pyrroline in the Mannich/aza-Michael reaction provides enantiomerically enriched 5-arylindolizidin-7-ones, which are precursors to nonopiate antinociceptive agents.

Full text of DOI:10.1021/acs.orglett.9b01840

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Biomimetic Organocatalytic Approach to 4‑Arylquinolizidine
Alkaloids and Application in the Synthesis of (−)-Lasubine II and
(+)-Subcosine II
Seerat Virk and Sunil V. Pansare*
Department of Chemistry, Memorial University, St. John’s, Newfoundland, Canada A1B 3X7
S
* Supporting Information
ABSTRACT: An enantioselective, biomimetic organocata-
lytic synthesis of 4-arylquinolizidin-2-ones, key intermediates
in the synthesis of several Lythraceae alkaloids, was developed.
The methodology features S-proline-mediated Mannich/aza-
Michael reactions of readily available arylideneacetones and
Δ1-piperideine. The total syntheses of (−)-lasubine II and
(+)-subcosine II as well as the formal syntheses of structurally
related Lythraceae alkaloids were achieved. The use of Δ1-
pyrroline in the Mannich/aza-Michael reaction provides
enantiomerically enriched 5-arylindolizidin-7-ones, which are
precursors to nonopiate antinociceptive agents.
he Lythraceae plant family is a rich source of
quinolizidine alkaloids (the Lythraceae alkaloids),
representative examples of which are shown in Figure 1.
macrolactone subunit that spans the 4-aryl substituent and the
C2 hydroxy group.
T
The biosynthesis7 of the Lythraceae alkaloids is known to
involve Δ1-piperideine and ring-oxygenated versions of (E)-3-
oxo-5-phenylpent-4-enoic acid which are obtained from L-
lysine and L-phenylalanine via the intermediacy of cadaverine
and cinnamic acid, respectively, as shown in Figure 2. Mannich
Figure 2. Biosynthesis of 4-arylquinolizidine alkaloids.
reaction of the phenylalanine-derived component and Δ1-
piperideine, followed by an intramolecular conjugate addition
of the piperideine intermediate A (Figure 2), provides a
quinolizidinone B which is the key biosynthetic precursor to
the 4-arylquinolizidine alkaloids. Notably, one such quinolzi-
dinone (1, Figure 1) and the alkaloids derived from it have
been isolated from the same plant.8
Despite the simplicity of the biosynthetic route, none of the
reported enantioselective syntheses of 4-arylquniolizidine
alkaloids has adopted this strategy in the sense that they do
Figure 1. Selected naturally occurring Lythraceae alkaloids.
These alkaloids incorporate the quinolizidine ring system with
an aryl substituent at C-4. A significant number of naturally
occurring 4-arylquinolizidines have the trans-decalin-type
structure in which the ring junction methine hydrogen and
the aryl substituent are trans to each other. 4-Arylquinolizidin-
2-one (1,1 Figure 1), (−)-lasubine II (2),2 (+)-subcosine II
(3),2 and (+)-abresoline (4)3 are characteristic examples of
this group. Further modification of the lasubine motif adds
structural complexity to provide provide (+)-lythrine (5),4
(+)-lyfoline (6),6 (−)-decinine (7),5 and decaline (8),5 all of
which are characterized by a 4-hydroxycinnamic acid derived
Received: May 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01840
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
not employ Δ1-piperideine and a β-aryl enone derivative as the
starting materials. Herein, we report preliminary results on a
biomimetic enantioselective synthesis of (a) representative 4-
arylquinolizidine alkaloids, (b) advanced intermediates to the
macrolactone family of Lythraceae alkaloids, and (c) advanced
intermediates to arylindolizidines with antinociceptive proper-
ties.
Table 1. Mannich/Aza-Michael Reaction of 9 and 10
We reasoned that substituted piperidines similar to B
(Figure 2) could probably be prepared by a biomimetic
reaction of Δ1-piperideine with aryl enones. Accordingly, our
synthetic approach involves an enamine/iminium ion mediated
organocatalytic Mannich−aza-Michael strategy that relies on
readily available β-aryl enones and Δ1-piperideine as the key
components (Figure 3). Notably, although Δ1-piperideine is
c
time
(h)
yield
(%)
dr
% ee of
a
b
entry cat
acid
solvent
DMF
11/12
11
1
2
3
4
5
6
7
8
C1
96
24
48
120
120
96
43
96
144
144
22
22
26
9
24
7
35
54
60
15
22
58
14
31
⩾99/1
⩾99/1
⩾99/1
0.6:1
⩾99/1
⩾99/1
⩾99/1
⩾99/1
⩾99/1
⩾99/1
2.6/1
19
8
7
TsOH
TsOH
C2
C3
DMF
DMF
20
27
96
96
96
96
82
>99
96
97
96
TsOH
TsOH
Figure 3. Organocatalytic strategy for the synthesis of 4-
arylquinolizidin-2-ones.
9
easily prepared9 from piperidine, it can be isolated only as the
minor component in a mixture with tripiperideine since it
trimerizes spontaneously. However, as shown by Bella,9a this
trimer is a convenient source of Δ1-piperideine which is
generated by dissociation in solution. Nevertheless, only a few
studies have examined the utility of Δ1-piperideine in Mannich
reactions with either acetone9a or functionalized nitro-
alkanes.9b Similarly, although reactions of enones with
dihydro-β-carbolines are known,9c,d organocatalytic reactions
of enones and Δ1-piperideine are not reported.
We chose 3,4-dimethoxybenzylidene acetone (9) as the
enone and a selection of pyrrolidine-based catalysts (C1−C5)
and S-tyrosine (C6) for exploratory reactions with tripiper-
ideine 10 (as a source Δ1-piperideine). The results of these
studies are summarized in Table 1.
10
11
12
13
14
15
16
17
18
19
20
21
22
MeOH
CH3CN
DMSO
CH2Cl2
CHCl3
THF
⩾99/1
1/0.4
0.7/1
toluene
DMF
C4
C5
C6
48
96
48
96
48
96
2
7
TsOH
TsOH
TsOH
⩾99/1
⩾99/1
⩾99/1
DMF
7
DMF
10
a
b
c
20 mol %. 20 mol %. Chiral HPLC analysis.
The proline-derived triamine C110 and the diamine C210
were examined first, either with or without the use of an acid
co-catalyst. Encouragingly, the 4-aryl quinolizidin-2-one 1111
was obtained from these reactions, albeit in low yield (20−26%
yield). Notably, neither the diastereomeric 4-aryl quinolizidin-
2-one 12 nor the amino enone (product of the Mannich
reaction) could be detected in these reactions. The diamine
C2, without an acid co-catalyst, provided a mixture of 11 and
12 (11:12 = 0.6:1) in low yield (9%). The use of TsOH as a
co-catalyst with C2 was marginally beneficial, providing only
11 in 24% yield. Interestingly, the use of S-proline (C3) as the
catalyst provided the best results (Table 1, entry 9), and 11
was obtained in 60% yield as a single diastereomer with 96%
ee. Increasing the reaction time beyond 144 h is only
marginally beneficial (yield of 11 after 240 h is 63%). Notably,
the use of TsOH acid as a co-catalyst with proline was
detrimental to the yield of the reaction (Table 1, entry 6).
Having identified S-proline as the catalyst of choice in DMF,
we conducted a brief solvent survey (Table 1, entries 10−16).
With the exception of DMSO, the yield of 11 was adversely
affected in all of the other solvents examined. Notably, the
enantiomeric excess of 11 was uniformly high (96−99% ee),
with methanol being the only exception (82% ee of 11).
However, the diastereoselectivity of the reaction was sensitive
to the solvent used, and it was particularly low in acetonitrile,
dichloromethane and chloroform (Table 1, entries 11, 13, and
14). Since there is no apparent correlation of the
diastereoselectivity and the polarity of the solvent (high
diastereoselectivity in methanol but low in acetonitrile), the
reasons for this trend in diastereoselectivity are not evident at
this time. Quinolizidinone 11 was obtained in very low yield
when hydroxyprolines C4 and C5 or S-tyrosine (C6) were
examined as catalysts.
It may be noted that S,S-11 obtained in our studies is a
direct precursor of the naturally occurring alkaloid (−)-lasu-
bine II (2, Figure 1).12 The stereoselective reduction of 11
provides (−)-lasubine II (2, 83%), and subsequent acylation of
2 with 3,4-dimethoxycinnamic acid generates (+)-subcosine II
(3, 67%, Scheme 1).13 To the best of our knowledge, these are
the shortest reported syntheses of 2 (three steps) and 3 (four
steps) from commercially available starting materials.
Scheme 1. Synthesis of (−)-Lasubine II and (+)-Subcosine
II from 11
B
DOI: 10.1021/acs.orglett.9b01840
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
As noted previously, other alkaloids share the 4-aryl
quinolizidine unit present in 1 and 2 (Figure 1). Examples
of such alkaloids include 4, a structural variant of 2, and also
the alkaloids 5−8 (Figure 1) that incorporate a macrolactone
moiety. The synthesis of these alkaloids has also been
extensively investigated. A common theme in all of these
syntheses14−18 is the multistep construction of a suitable 4-
arylquinolizidin-2-one (such as 11) as the key starting material
followed by reduction to the corresponding 4-aryl-2-hydrox-
yquinolizidine (such as 1). Elaboration to the macrolactone-
containing target is then achieved by linking the 4-aryl
substituent and the hydroxy group with the appropriate
carboxylic acid that is incorporated either directly or is
constructed in the ring-closing step (Figure 4).
Scheme 2. Synthesis of Advanced Intermediates to the
Lythraceae Alkaloids 4−7
Figure 4. Reported synthetic strategies for alkaloids 5−8.
Clearly, syntheses of 5−8 that rely on a 4-arylindolizidin-2-
one would benefit from a concise enantioselective synthesis of
this starting material. The present synthesis of 11 is relevant in
this context. We reasoned that the choice of a suitable enone
would enable a single step synthesis of advanced intermediates
to the Lythraceae alkaloids 5−8. Accordingly, the reaction of
enones 13, 14, and 15 with 10, under the reaction conditions
optimized for 11, provided the 4-arylquinolizidinones 1 (40%,
85% ee), 16 (40%, 98% ee), and 17 (32%, 98% ee),
respectively. Silylation of 1 provided 18 (77%, Scheme 2).
Notably, the diastereomeric (4S,9aR) quinolizidinone product
was not observed in any of these reactions. The conversion of
18 to (+)-abresoline (4),14 16 to (+)-dihydrolyfoline (19),15
11 to (−)-decinine (7, via 2),16 and 17 to lythrine (5)17 and
decalin (8)18 is reported.
Scheme 3. Enantioselective Synthesis of 5-Arylindolizidin-7-
ones
The present one-step syntheses of 11, 16, and 17 and the
two-step synthesis of 18 compare favorably with the shortest
multistep syntheses of these quinolizidinones reported to date
(11: five steps from 2-pyrrolidone, 40% overall,12e or five steps
from methyl 5-chloropenanoate, 30% overall;12a 16: five steps
from piperidine, 14.7% overall;15 17: six steps from piperidine,
2% overall;17 18: 12 steps from 3-(benzyloxy)-4-methoxyben-
zaldehyde, 14.8% overall14). In addition, with the exception of
18, the reported syntheses require separation of the undesired
diastereomeric 4-arylquinolizidin-2-one products that are
invariably obtained and their subsequent isomerization to the
diastereomers that are required for the natural product targets.
Preliminary results on the extension of this methodology to
the synthesis of arylindolizidinones are promising, and the
reaction of 1-pyrroline19 with selected enones under proline
catalysis provided 5-arylindolizidin-7-ones20 with good enan-
tioselectivity (Scheme 3). The reasons for the low yields
observed in these reactions are not clear at this time. It may be
noted that arylindolizidines and arylquinolizidines, which can
be easily obtained by reduction of the corresponding
indolizidinones and quinolizidinones,21 are of interest as
nonopiate antinociceptive agents.21
asymmetric induction is provided in Figure 5. Addition of the
enamine derived from proline and the enone to the re face of
the imine generates the iminium ion D. Intramolecular
conjugate addition of the amine to the si face of the iminium
ion generates the enamine E, which provides the observed
(S,S) diastereomer of the 4-arylquinolizidin-2-one or the 5-
arylindolizidin-7-one. The intramolecular aza-Michael reaction
is also a component in other syntheses of 4-arylquinolizidine
alkaloids.12c,d,f,g,22 However, the diastereoselectivity of C−N
bond formation in the other syntheses is low (dr for required
diastereomer = 1.2:1,12c 7:1,12e and 0.7:112g). In addition,
opposite diastereoselectivity is observed when the aza-Michael
reaction is mediated by a bifunctional catalyst (4S,9aR
quinolizidinone is obtained)22 and when β-alkyl enones,9c,d
A plausible mechanism that explains the stereoselectivity of
the Mannich−conjugate addition reaction and the sense of
C
DOI: 10.1021/acs.orglett.9b01840
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Contribution to the Chemotaxonomy. Chem. Pharm. Bull. 1978, 26,
2515.
(3) Horhammer, R. B.; Schwarting, A. E.; Edwards, J. M. Structure
of Abresoline. J. Org. Chem. 1975, 40, 656.
(4) Blomster, R. N.; Schwarting, A. E.; Bobbitt, J. M. Alkaloids of
Heimia salicifolia. I. A Preliminary Report. Lloydia 1964, 27, 15.
(5) Ferris, J. P. Lythraceae Alkaloids. I. Isolation and Structural
Studies of the Alkaloids of Decodon Verticillatus (L.) Ell. J. Org.
Chem. 1962, 27, 2985.
(6) Appel, H.; Rother, A.; Schwarting, A. E. Alkaloids of Heimia
salicifolia. II. Isolation of Nesodine and Lyfoline and their correlation
with other Lythraceae Alkaloids. Lloydia 1965, 28, 84.
(7) (a) Rother, A.; Schwarting, A. E. Phenylalanine as a Precursor
for Cryogenine Biosynthesis in Heimia salicifolia. Phytochemistry 1972,
11, 2475. (b) Rother, A.; Schwarting, A. E. Biosynthesis of
Cryogenine. J. Chem. Soc. D: Chem. Commun. 1969, 1411. (c) Koo,
S. H.; Comer, F.; Spenser, I. D. Biosynthesis of the Lythraceae
Alkaloids: Mode of Incorporation of Phenylalanine. J. Chem. Soc. D
1970, 897. (d) Koo, S. H.; Gupta, R. N.; Spenser, I. D.; Wrobel, J. T.
Biosynthesis of the Lythraceae Alkaloids: Incorporation of Lysine. J.
Chem. Soc. D 1970, 396. (e) Gupta, R. N.; Horsewood, P.; Koo, S. H.;
Spenser, I. D. The Biosynthesis of the Lythraceae Alkaloids I. The
Lysine-Derived Fragment. Can. J. Chem. 1979, 57, 1606. (f) Horse-
wood, P.; Golebiewski, W. M.; Wrobel, J. T.; Spenser, I. D.; Cohen, J.
F.; Comer, F. The Biosynthesis of the Lythraceae Alkaloids I. The
Phenylalanine-Derived Fragments. Can. J. Chem. 1979, 57, 1615.
(g) Hedges, S. H.; Herbert, R. B.; Wormald, P. C. Biosynthesis of
Lythraceae Alkaloids. Incorporation of DL-(4,5-13C2,6-14C) Lysine
and Cis-and Trans-4-(3,4-Dihydroxyphenyl)-Quinolizidin-2-one Into
Vertine and Lythrine. J. Nat. Prod. 1993, 56, 1259.
Figure 5. Proline-catalyzed Mannich/aza-Michael reaction of cyclic
imines and arylideneacetones.
and enones with a β-aryl group lacking electron-rich
substituents9d are employed.
While it is likely that formation of the C4 stereocenter in the
4-arylquinolizidinones is thermodynamically controlled, it
should be mentioned that the diastereomer 12 was not
observed at any time during the reaction of 9 and 10 under the
optimized conditions. However, rapid equilibration of E and D
via a retro-aza-Michael process, and the resultant conversion of
12 to 11 under thermodynamic control, cannot be ruled out.23
A similar process may also be operative in the 5-
arylindolizidinone synthesis.
In conclusion, we have developed a stereoselective
biomimetic synthesis of (−)-lasubine II and (+)-subcosine II.
The methodology also provides the shortest enantioselective
route to several 4-arylquinolizidin-2-ones that are key
intermediates in the synthesis of macrolactone-containing
Lythraceae alkaloids. Current efforts focus on extension of the
methodology to β-alkyl enones as well as 3-alkyl/aryl-but-2-
enones and related ketones.
(8) Rother, A.; Schwarting, A. E. The Phenylquinolizidines of the
Seedlings of Heimia salicifolia. Lloydia 1975, 38, 477.
(9) (a) Monaco, M. R.; Renzi, P.; Scarpino Schietroma, D. M.; Bella,
M. Biomimetic Organocatalytic Asymmetric Synthesis of 2-
Substituted Piperidine-Type Alkaloids and Their Analogues. Org.
Lett. 2011, 13, 4546. (b) Jakubec, P.; Cockfield, D. M.; Helliwell, M.;
Raftery, J.; Dixon, D. Stereoselective, Nitro-Mannich/Lactamisation
Cascades for the Direct Synthesis of Heavily Decorated 5-Nitro-
piperidin-2-Ones and Related Heterocycles. Beilstein J. Org. Chem.
2012, 8, 567. (c) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.;
Ohsawa, A. Total Synthesis of ent-Dihydrocorynantheol by Using a
Proline-Catalyzed Asymmetric Addition Reaction. Org. Lett. 2006, 8,
1533. (d) Lalonde, M. P.; McGowan, M. A.; Rajapaksa, N. S.;
Jacobsen, E. N. Enantioselective Formal Aza-Diels-Alder Reactions of
Enones with Cyclic Imines Catalyzed by Primary Aminothioureas. J.
Am. Chem. Soc. 2013, 135, 1891.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01840.
1
Experimental methods, spectroscopic data, and H and
13C data for all compounds (PDF)
(10) Pansare, S. V.; Pandya, K. Simple Diamine- and Triamine-
Protonic Acid Catalysts for the Enantioselective Michael Addition of
Cyclic Ketones to Nitroalkenes. J. Am. Chem. Soc. 2006, 128, 9624.
(11) The stereochemistry of 11 and 12 was determined by
comparison of their 1H NMR data with those reported. The absolute
configuration of 11 was assigned as (S,S) by comparison of the sign of
its optical rotation to that reported12d for (S,S)-11. This assignment
was subsequently confirmed by the optical rotation of (−)-lasubine II
that was obtained by the reduction of 11. The absolute configuration
of 12 is based on the assumption that both 11 and 12 are derived
from the β-amino enone obtained from the initial Mannich reaction.
The stereochemistry of 1, 16, and 17 is assigned by analogy to 11.
(12) Selected enantioselective syntheses of lasubine II: (a) Lahosa,
A.; Yus, M.; Foubelo, F. Enantiodivergent Approach to the Synthesis
of cis-2,6-Disubstituted Piperidin-4-ones. J. Org. Chem. 2019, 84,
7331. (b) Formal synthesis: Mohamed Aslam, N. F.; Simon, O.;
Bates, R. W. Studies on the Synthesis of the Lasubine Alkaloids.
Tetrahedron 2018, 74, 5032. (c) Reddy, A. A.; Reddy, P. O.; Prasad,
K. R. Synthesis of β-Amino-Substituted Enones by Addition of
Substituted Methyl Enones to Sulfinimines: Application to the Total
Synthesis of Alkaloids (+)-Lasubine II and (+)-241D and the Formal
Total Synthesis of (−)-Lasubine I. J. Org. Chem. 2016, 81, 11363.
(d) Trost, B. M.; Hung, C.-I. Broad Spectrum Enolate Equivalent for
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: spansare@mun.ca.
ORCID
Sunil V. Pansare: 0000-0002-0100-5343
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
These investigations were supported by the Natural Sciences
and Engineering Research Council of Canada and the Canada
Foundation for Innovation.
REFERENCES
■
(1) Rother, A.; Schwarting, A. E. A New Phenylquinolizidol of
Heimia salicifolia. Experientia 1974, 30, 222.
(2) Fuji, K.; Yamada, T.; Fujita, E.; Murata, H. Lythraceous
Alkaloids X. Alkaloids of Lagerstroemia subcosta and L. favriei. A
D
DOI: 10.1021/acs.orglett.9b01840
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Catalytic Chemo-, Diastereo-, and Enantioselective Addition to N-
Boc Imines. J. Am. Chem. Soc. 2015, 137, 15940. (e) Shi, S.-L.; Wei,
X.-F.; Shimizu, Y.; Kanai, M. Copper(I)-Catalyzed Enantioselective
Incorporation of Ketones to Cyclic Hemiaminals for the Synthesis of
Versatile alkaloid Precursors. J. Am. Chem. Soc. 2012, 134, 17019.
(f) Lim, J.; Kim, G. Synthetic Study of Lasubine II via Sequential
Cyclization Process. Tetrahedron Lett. 2008, 49, 88. (g) Synthesis of
racemic lasubine II via Mannich/Michael reaction of a cyclic iminium
ion and 2-silyloxybutadiene: Pilli, R. A.; Dias, L. C.; Maldaner, A. O.
One-pot Preparation of Quinolizidin-2-one and Indolizidin-7-one
Ring Systems. Concise Total Syntheses of ( )-Myrtine, ( )-Lasu-
bine-II, and ( )-Indolizidine 223AB. J. Org. Chem. 1995, 60, 717.
(13) Enantioselective syntheses of subcosine II: (a) Cui, L.; Li, C.;
Zhang, L. A Modular, Efficient, and Stereoselective Synthesis of
Substituted Piperidin-4-ols. Angew. Chem., Int. Ed. 2010, 49, 9178.
(b) Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J.-C.
Asymmetric Synthesis of Quinolizidine Alkaloids (−)-Lasubine I,
(−)-Lasubine II and (+)-Subcosine II. Tetrahedron: Asymmetry 1998,
9 (c), 4361.
(14) Atobe, N.; Yamazaki, N.; Kibayashi, C. Asymmetric Synthesis
of (+)-Abresoline. Tetrahedron Lett. 2005, 46, 2669.
(15) Mei, R.; Xu, D.; Hu, H.; Song, D.; Zhang, H.; Ma, D.; Xie, X.;
She, X. Biomimetic Total Syntheses of (+)-Dihydrolyfoline and
(−)-5-epi-Dihydrolyfoline. Org. Lett. 2015, 17, 2230.
(16) Shan, Z.-H.; Liu, J.; Xu, L.-M.; Tang, Y.-F.; Chen, J.-H.; Yang,
Z. Total Synthesis of (+-) Decinine via an Oxidative Biaryl Coupling
with Defined Axial Chirality. Org. Lett. 2012, 14, 3712.
̀
́
́
(17) Chausset-Boissarie, L.; Arvai, R.; Cumming, G. R.; Guenee, L.;
Kundig, P. E. Asymmetric Synthesis of (+)-Vertine and (+)-Lythrine.
̈
Org. Biomol. Chem. 2012, 10, 6473.
(18) Hanaoka, M.; Ogawa, N.; Arata, Y. Synthetic Studies on
Lythraceae Alkaloids. III. Stereoselective Total Synthesis of
(+-)-Decaline. Chem. Pharm. Bull. 1975, 23, 2140.
(19) (a) 1-Pyrroline was prepared by oxidation of pyrrolidine; see:
Nomura, Y.; Ogawa, K.; Takeuchi, Y.; Tomoda, S. One-Step Synthesis
and Structural Confirmation of 1-Pyrroline. Chem. Lett. 1977, 6, 693.
The crude product was purified by precipitation; see: (b) Baker, J. D.;
Heath, R. R.; Millar, J. G. An Equilibrium and Stability Study of Δ1-
Pyrroline. J. Chem. Ecol. 1992, 18, 1595.
(20) Selected reports on the synthesis of 9-aryindolizidinones:
(a) Trost, B. M.; Biannic, B. Redox Cycloisomerization Approach to
1,2-Dihydropyridines. Org. Lett. 2015, 17, 1433. (b) Pearson, W. H.;
Walavalkar, R. A Schmidt Route to 1-azabicyclo[x.y.0]alkanes: A
Comparison of Carbocation Stabilizing Groups. Tetrahedron 2001,
57, 5081. (c) Pearson, W. H.; Gallagher, B. M. The Intramolecular
Schmidt Reaction of Azides with Tertiary Alcohols: Synthesis of 5-(α-
Naphthyl) and 5-(β-naphthyl)indolizidines as Potential Dopamine
Analogs and Non-Opiate Antinociceptive Agents. Tetrahedron 1996,
52, 12039.
(21) Carson, J. R.; Carmosin, R. J.; Vaught, J. L.; Gardocki, J. F.;
Costanzo, M. J.; Raffa, R. B.; Almond, H. R. 2-Substituted 1-
Azabicycloalkanes, A New Class of Non-Opiate Antinociceptive
Agents. J. Med. Chem. 1992, 35, 2855.
(22) Hirama, T.; Umemura, T.; Kogure, N.; Kitajima, M.;
Takayama, H. Synthetic Study of Biphenylquinolizidine Alkaloids.
Asymmetric Total Synthesis of Lasubine I Featuring Organocatalyzed
Asymmetric Intramolecular aza-Michael Addition. Tetrahedron Lett.
2017, 58, 223.
(23) In preliminary studies, enones lacking electron-donating groups
in the aryl substituent provided a mixture of diastereomeric
quinolizidinones, presumably due the greater reactivity of the iminium
ion D at the β-position.
E
DOI: 10.1021/acs.orglett.9b01840
Org. Lett. XXXX, XXX, XXX−XXX