Total synthesis of (±)-monomorine

Article abstract of DOI:10.1016/j.tetlet.2012.08.041

An efficient, two-operation synthesis of the trail ant pheromone (±)-monomorine is reported. The synthesis features an aqueous Claisen-Schmidt condensation followed by the stereocontrolled installation of the three resident stereocenters in a single operation.

Full text of DOI:10.1016/j.tetlet.2012.08.041

Tetrahedron Letters 53 (2012) 5660–5662
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of ( )-monomorine
⇑
Tri Q. Le , Robert M. Oliver III, Joel T. Arcari, Mark J. Mitton-Fry
Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, two-operation synthesis of the trail ant pheromone ( )-monomorine is reported. The synthe-
sis features an aqueous Claisen-Schmidt condensation followed by the stereocontrolled installation of the
three resident stereocenters in a single operation.
Received 12 July 2012
Revised 7 August 2012
Accepted 9 August 2012
Available online 16 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hydrogenation
Claisen-Schmidt
Monomorine
The natural product (+)-monomorine1 (1) continues to generate
substantial interest within the synthetic community. The synthesis
of this pheromone, either as the naturally-occurring enantiomer,2–4
its antipode,5,6 both enantiomers,7 or the racemic mixture,8,9
remains a popular proving ground for the development and exem-
plification of new synthetic methodology. Our interest in this mol-
ecule arises from its compact, stereochemically rich structure. We
hypothesized that a highly efficient10 synthesis could be realized
using a functionalized pyridine starting material, an atom econom-
ical11 carbon–carbon bond forming reaction, and attention to green
chemistry principles.12,13
Retrosynthetic analysis of 1 suggested the hydrogenation of a
pyridine moiety as the source of piperidine in 1 (Scheme 1). Previ-
ous syntheses of monomorine demonstrated that a highly stereo-
selective process to establish the 2,6-cis stereochemistry would
be feasible.14,15 Moreover, we believed that the pyrrolidine ring
could also be installed stereoselectively in the same reaction vessel
by the intramolecular reductive amination of an appropriately
placed ketone. Our confidence in this approach was bolstered by
Yamaguchi’s observations of high stereoselectivity in his early syn-
thesis of racemic monomorine.16,17 Given the ease of formation of
conjugated enone systems and the susceptibility of the alkene to
(3) and 2-hexanone (4) would provide expedient and atom-
economical11 access to this key intermediate.
Our exploration of the Claisen-Schmidt reaction began by
adapting conditions reported by Sinisterra and coworkers using a
partially dehydrated barium hydroxide catalyst (C-200) in Clais-
en-Schmidt condensations.19 The use of commercially available
Ba(OH)2ÁH2O as the promoter in refluxing ethanol solvent afforded
a very modest yield (entry 1, Table 1) of the desired ketone 2. The
reaction was complicated by the formation of several byproducts
(Scheme 2), including the aldol adduct 5 (ca 16%) and primary alco-
hol 7 (ca. 12%), as well as b-ethoxyketone 6 and several unidenti-
fied impurities in smaller amounts. Alcohol 7 is presumably
formed via a Cannizzaro reaction.
Moreover, the reaction mixture was highly heterogeneous, ren-
dering efficient stirring difficult. The multiple byproducts, as well
as this heterogeneity, led us to consider alternative conditions.
Recent years have seen an increasing recognition of the value of
water as a solvent for organic reactions.12,13,20–23 We believed that
water would be the ideal solvent for overcoming issues with the
precipitation of inorganic solids and opted to explore its use as a
solvent. We were pleased to find that this small change in condi-
tions resulted in an improved yield of 56% (entry 2, Table 1). Grat-
ifyingly as well, the reaction appeared to be highly regioselective,
as we did not observe the regioisomeric adduct by 1H NMR analysis
hydrogenation,
a,b-unsaturated ketone 2 presented itself as an
ideal synthetic precursor. Provided that acceptable levels of regi-
oselectivity could be achieved, a Claisen-Schmidt condensation
using commercially available 6-methylpyridine-2-carbaldehyde
N
⇑
+
Corresponding author at present address: Ohio Wesleyan University, 61 S.
Sandusky St., Delaware, OH 43015, United States. Tel.: +1 740 368 3519; fax: +1 740
368 3999.
H
N
N
1
2
3
4
O
O
O
E-mail address: mjmitton@owu.edu (M.J. Mitton-Fry).
Present address: University of Pittsburgh Graduate School of Public Health,
Pittsburgh, PA 15261, United States.
Scheme 1. Retrosynthetic analysis.18
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.041

T. Q. Le et al. / Tetrahedron Letters 53 (2012) 5660–5662
5661
bases, most notably sodium hydroxide.24 NaOH proved superior to
Ba(OH)2ÁH2O (entry 9 versus entry 4, Table 1). With NaOH, reduc-
ing the amount of ketone to 2 or even 1.1 equiv met with reason-
able results (entries 11 and 12) and appeared slightly better than
KOH (entry 11 versus 10). Consideration of all of our results led
us to use 2 equiv of ketone as the optimal balance between yield
and atom economy. Finally, we found that pre-dissolving the base
in water before adding it to the reaction medium also had a bene-
ficial effect. Using 2 equiv of the ketone in conjunction with
0.2 equiv NaOH afforded a yield of 82% (entry 13). This reaction
was also conducted on multi-gram scale with no loss of yield.25
With an efficient and scalable synthesis of ketone 2 in hand, we
turned our attention to the alkene reduction/pyridine reduction/
reductive amination sequence. Initially, we explored the use of
Adam’s catalyst14 and were delighted to observe evidence of the
natural product from our first attempt (data not shown). Unfortu-
nately, these conditions proved somewhat capricious and also rou-
tinely led to competitive and unproductive reduction of the ketone
to a secondary alcohol (8, Scheme 3).
We qualitatively screened a number of potential alterative cat-
alysts (Pd/C, Pt/C, Rh/C, and Raney Ni) using an H-Cube™ appara-
tus. In this exercise, Rh/C18 was found to be particularly effective
at reducing the pyridine ring of 2, so we chose to examine its use
further. Reduction of 2 under strongly acidic conditions (1% HCl
in MeOH) led to chemoselective reduction of the pyridine in the
presence of the ketone but did not permit the reductive amination,
resulting instead in the formation of ketone 9 (Scheme 3). Com-
pound 9 could be converted to ( )-monomorine via a subsequent
reductive amination using either H2 in the presence of PtO2 or so-
dium triacetoxyborohydride. Notably, the use of PtO2 still resulted
in competitive reduction of the ketone to form 8 alongside the de-
sired product.
Table 1
Optimization of Claisen-Schmidt conditions for synthesis of ketone 2a
Entry
Equiv ketone
Base (equiv)
% yield
1b
2
2
2
2
4
1.2
4
1.2
5
Ba(OH)2ÁH2O (0.2)
Ba(OH)2ÁH2O (0.2)
Ba(OH)2ÁH2O (0.2)
Ba(OH)2ÁH2O (0.2)
Ba(OH)2ÁH2O (0.2)
Ba(OH)2ÁH2O (0.2)
Ba(OH)2ÁH2O (0.04)
Ba(OH)2ÁH2O (0.04)
NaOH (0.2)
28
56
0
3c
4
63
37
63
51
52
74
66
71
66
82
5
6d
7
8
9
10
11
12
13e
4
2
KOH (0.2)
2
NaOH (0.2)
1.1
2
NaOH (0.2)
NaOH (0.2)
a
General conditions: The reagents were combined in the proportions described
and heated at reflux in water for 45 min. Yields reported are after purification by
flash chromatography (heptane:ethyl acetate as eluent).
b
Reaction conducted in refluxing ethanol.
Reaction conducted in the absence of solvent.
Dropwise addition of 3 as a solution in water.
A solution of NaOH in water was used in place of solid NaOH.
c
d
e
of the crude reaction mixture. Notably, no reaction took place in
the absence of water (entry 3).
The major observed byproduct was alcohol 7. We speculated
that increasing the equivalents of ketone would help to overcome
the Cannizzaro reaction. The use of 4 equiv ketone indeed im-
proved the yield slightly (entry 4), while decreasing the ketone
to 1.2 equiv substantially reduced the yield (entry 5). Dropwise
addition of a solution of aldehyde 3 in water provided no advan-
tage (entry 6). Since the Cannizzaro side reaction is stoichiometric
in hydroxide, we also explored the use of less base. Using only
4 mol% Ba(OH)2ÁH2O, a fair yield was achieved with either 1.2 or
5 equiv ketone (entries 7 and 8). Incomplete elimination of the
hydroxyketone intermediate (5) was at least partially responsible
for the modest yield in these cases.
We reasoned that strongly acidic conditions with Rh/C catalysis
might hinder the reductive amination by preventing access to the
unprotonated secondary amine. Gratifyingly, the use of the milder
glacial acetic acid as solvent resulted in the formation of 1 as the
major product, with a lesser amount of ketone overreduction.
Additional optimization led to the use of 3:1 MeOH:acetic acid as
a solvent mixture.
Despite these improvements, the overall yield was still subopti-
mal. We next explored the use of other readily available hydroxide
conditions
H
+
+
2 +
N
N
N
O
O
O
OR
OH
3
4
5: R=H
7
6: R=Et
Scheme 2. Initial Claisen-Schmidt condensation of 3 and 4 in ethanol.
Frequently observed side products
N
H
N
OH
Various
8
conditions
N
2
1
O
N
H
O
9
Scheme 3. Reduction/reductive amination results.

5662
T. Q. Le et al. / Tetrahedron Letters 53 (2012) 5660–5662
Table 2
References and Notes
Optimization of one-pot synthesis of monomorine from enone 2a
1. Ritter, F. J.; Rotgans, I. E. M.; Talman, E.; Verwiel, P. E. J.; Stein, F. Experientia
1973, 29, 530.
Entry
Catalyst
Ratio 1:8
% yieldb
1
2
3
5% Rh/aluminac
5% Rh/Cd
60:40
80:20
75:25
80:20
70:30
ND
ND
ND
ND
ND
ND
52
2. Kim, G.; Jung, S-d; Lee, E-j; Kim, N J. Org. Chem. 2003, 68, 5395.
3. Davis, F. A.; Zhang, J.; Wu, Y. Tetrahedron Lett. 2011, 52, 2054.
4. Reddy, C. R.; Latha, B. Tetrahedron Asymm. 2011, 22, 1849.
5. Zhang, S.; Xu, L.; Miao, L.; Shu, H.; Trudell, M. L. J. Org. Chem. 2007, 72, 3133.
6. Reddy, C. R.; Latha, B.; Rao, N. N. Tetrahedron 2012, 68, 145.
7. Toyooka, N.; Zhou, D.; Nemoto, H. J. Org. Chem. 2008, 73, 4575.
8. Lapointe, G.; Schenk, K.; Renaud, P. Chem. Eur. J. 2011, 17, 3207.
9. Iska, V. B. R.; Verdolino, V.; Wiest, O.; Helquist, P. J. Org. Chem. 2010, 75, 1325.
10. Gaich, T.; Baran, P. J. Org. Chem. 2010, 75, 4657.
11. Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
12. Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301.
13. Sheldon, R. A. Green Chem. 2005, 7, 267.
14. Oliver, J. E.; Sonnet, P. E. J. Org. Chem. 1974, 39, 2662.
15. Sonnet, P. E.; Oliver, J. E. J. Heterocycl. Chem. 1975, 12, 289.
16. Yamaguchi, R.; Hata, E-i; Matsuki, T; Kawanisi, M. J. Org. Chem. 1987, 52, 2094.
17. Other authors have also confirmed the high stereoselectivity in this
transformation. See: (a) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J.
J. Org. Chem. 2003, 68, 1919; (b) Ref.4; For a related stereoselective reductive
amination in the synthesis of (+)-trifluoromethyl monomorine, see: (c) Kim, G.;
Kim, N. Tetrahedron Lett. 2005, 46, 423.
4.5% Pd/C:0.5% Rh/Ce
4.5% Pd/C:0.5% Rh/Cf
5% Rh/aluminac
5% Rh/Cd
4
5g
6h
a
General conditions: Reactions were carried out on 50 mg 2 using an Endeavor™
catalyst screening system under ca. 45 psi H2 in 2 mL volume of 3:1 methanol:
acetic acid unless otherwise noted.
b
Isolated yield after flash chromatography; ND = not determined.
Aldrich.
Johnson Mathey (JM) #34.
JM #20.
c
d
e
f
JM #21.
g
Reaction was run in 1:1 methanol: trimethylorthoformate as solvent.
300 mg 2 were used, and a Parr shaker was used to conduct the reaction (45 psi
h
H2).
18. In this context, it should be noted that a similar approach to a series of
octahydroindolizine analgesics has been reported in the patent literature. See:
Carmosin, R. J.; Carson, J. R. U.S. Patent 4,582,836, April 15, 1986.
19. Sinisterra, J. V.; Garcia-Raso, A.; Cabello, J. A.; Marinas, J. M. Synthesis 1984, 502.
20. Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2005, 44, 3275.
Using these conditions, we undertook the final optimization of
the conversion of 2 to 1 using a variety of Rh-based catalysts
(Table 2). We consistently observed the formation of alcohol 8 as
the principal byproduct. By conducting the hydrogenation at
50 °C using commercially available 5% Rh/C as catalyst, we were
able to achieve an 80:20 ratio of 1:8 (entry 2). Using this method-
ology, we obtained a 52% yield of the desired product on 300 mg
scale (entry 6).26 1H and 13C NMR spectra were consistent with
the literature values,7 and a series of NMR experiments (COSY,
HSQC, HMBC, NOESY, ROESY, HSQC-TOCSY) also confirmed the
relative stereochemistry (see Supplemental data).
By using an atom-economical aqueous Claisen-Schmidt con-
densation and a stereoselective triple-reduction sequence, we have
developed a highly efficient synthesis of racemic monomorine (1)
in two operations from commercially available aldehyde 3. Related
approaches may also prove useful to the synthesis of other indo-
lizidine natural products.27
21. Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725.
22. Wang, Y.; Ye, J.; Liang, X. Adv. Synth. Catal. 2007, 349, 1033.
23. Mohrig, J. R.; Hammond, C. N.; Schatz, P. F.; Davidson, T. A. J. Chem. Educ. 2009,
86, 234.
24. Ref.18 also made use of NaOH as a base but utilized methanol as a solvent,
stoichiometric amounts of base, reduced temperatures, and acetophenone
derivatives as the ketone partner.
25. (E)-1-(6-methylpyridin-2-yl)hept-1-en-3-one
(2):
6-methylpyridine-2-
carbaldehyde (3.00 g, 24.8 mmol, 1.0 equiv) and 2-hexanone (4.86 g,
48.5 mmol, 2.0 equiv) were combined and stirred until the aldehyde
dissolved fully.
A solution of sodium hydroxide (0.200 g, 5.0 mmol,
0.20 equiv) in water (20 mL) was then added and the resulting mixture
heated at reflux with vigorous stirring for 45 min under N2. After cooling to
room temperature, the reaction was extracted twice with ether, and the
organic phases were combined, dried over MgSO4, filtered, and concentrated.
The residue was purified by flash column chromatography on silica gel using a
0–50% gradient of ethyl acetate in heptane to afford the desired product
(4.25 g) as an oil. In this instance, the desired product was contaminated with
7.5 mol% of heptane, so a corrected mass of 4.1 g was used in calculating a yield
of 82%. 1H NMR (400 MHz, CDCl3): d 7.62 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 16.0 Hz,
1H), 7.30 (d, J = 7.8 Hz, 1H), 7.12–7.22 (m, 2H), 2.67–2.75 (m, 2H), 2.60 (s, 3H),
1.62–1.73 (m, 2H), 1.32–1.44 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 200.98, 158.91, 152.60, 141.17, 136.93, 129.39, 124.02,
121.34, 40.89, 26.29, 24.51, 22.40, 13.85; HRMS (ESI): calcd for C13H18NO
(M+H)+: 204.1383, found 204.1379.
Acknowledgments
The authors wish to thank the Pfizer summer internship pro-
gram for support (T.L.). The authors would particularly like to
acknowledge Andrew Butler for support in 2D NMR experiments
and analysis. Patrick Mullins is recognized for his diligence in
byproduct identification. Thuy Hoang is gratefully acknowledged
for experimental assistance, as are Drs. Matthew Brown and Tarek
Sammakia for helpful discussions.
26. ( )-monomorine (1): Compound 2 (0.300 g, 1.48 mmol) was dissolved in 40 mL
of methanol/glacial acetic acid (3/1, v/v). The solution was degassed with
nitrogen, and the catalyst (0.150 g, Johnson Mathey 5% Rh/C, #34, catalog
number C101023-5) was added. The reaction mixture was placed in a Parr
shaker under H2 (45 psi) for 24 h at 50 °C. The catalyst was removed by
filtration through celite, and the filtrate was concentrated in vacuo. To the
residue was added a saturated aqueous solution of NaHCO3 (20 mL), resulting
in pH of ca. 8-9. This solution was extracted twice with ethyl acetate, and the
combined organic phases were dried over Na2SO4, filtered and concentrated.
Purification by flash chromatography on silica gel (hexanes: ethyl acetate,
gradient from 90:10–0:100) afforded the title compound as a light tan oil
(0.150 g, 52%). Spectral and analytical data were consistent with literature
values.7
Supplementary data
Supplementary data (1H and 13C NMR spectra for compounds 1
and 2. COSY, HSQC, HMBC, NOESY, ROESY, and HSQC-TOCSY spec-
tra for compound 1) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
08.041.
27. Michael, J. P. Nat. Prod. Rep. 2005, 22, 603.