Synthesis of isoquinuclidinones via a tandem amination/imination sequence: Application to the synthesis of (-)-mearsine

Article abstract of DOI:10.1016/j.tetlet.2010.08.052

The facile synthesis of a range of novel isoquinuclidinones from 6-acyl-cyclohex-2-enones is described, employing aqueous ammonia in a one-pot procedure involving initial conjugate addition of ammonia followed by cyclisation via intramolecular imine forma

Full text of DOI:10.1016/j.tetlet.2010.08.052

Tetrahedron Letters 52 (2011) 2024–2027
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Synthesis of isoquinuclidinones via a tandem amination/imination sequence:
application to the synthesis of (À)-mearsine
James D. Cuthbertson a, Andrew A. Godfrey b, Richard J. K. Taylor a,
⇑
a Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
b AstraZeneca, Pharmaceutical Development, Silk Road Business Park, Macclesfield, Cheshire, SK10 2 NA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 22 August 2010
The facile synthesis of a range of novel isoquinuclidinones from 6-acyl-cyclohex-2-enones is described,
employing aqueous ammonia in a one-pot procedure involving initial conjugate addition of ammonia fol-
lowed by cyclisation via intramolecular imine formation. The scope and limitations of the methodology
are described as is an efficient synthesis of the Elaeocarpus alkaloid (À)-mearsine.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Prof. Harry Wasserman in
recognition of his many seminal
achievements in organic chemistry and his
friendship over numerous years of
Tetrahedron Board Meetings.
Keywords:
Isoquinuclidinones
Mearsine
Tandem
Organocatalytic
2-Azabicyclo[2.2.2]octanes
The development of new and improved routes to nitrogen-con-
taining heterocycles represents an important and continuing chal-
lenge in organic chemistry,1 due to the prevalence of such
systems in natural products and pharmaceuticals/agrochemicals.
Recently,1b we have become interested in naturally occurring iso-
quinuclidine alkaloids such as compounds 1–3 isolated from Daph-
niphyllum,2 Securinega3 and Tabernaemontana4 species, respectively
(Fig. 1). In turn, we were attracted to the rare isoquinuclidinone
alkaloids mearsine 45 and grandisine B 56 which contain the unu-
sual 2-azabicyclo[2.2.2]oct-2-en-5-one nucleus.
Functionalised 2-azabicyclo[2.2.2]octanes have previously been
prepared via Diels–Alder cyclisations,7 thermal cyclisations of 4-
amino-cyclohexane carboxaldehyde derivatives,8 double conjugate
addition of aqueous ammonia into bifunctional Michael acceptors9
and recently via cyclisation of silyl enol ethers onto iminium
ions.10 However, to our knowledge, there are no established meth-
ods for the direct preparation of 2-azabicyclo[2.2.2]oct-2-en-5-
ones (i.e., containing both the ketone and imine functionalities).
Retrosynthetic analysis as shown in Scheme 1, based on the bio-
synthetic proposal for mearsine put forward by Bick and co-work-
ers,5 suggested that the target compounds 6 might be accessed
from 6-acyl-cyclohex-2-enones 8 by initial conjugate addition of
ammonia to give the intermediate amine 7 which might then be
expected to give the bicyclic system by intramolecular imine
formation.
In this Letter, we describe the successful implementation of the
tandem amination/imination route to isoquinuclidinones 6 as a
one-pot process, and its application in natural product synthesis.
Similar chemistry was utilised by Tamura and co-workers as part
of their recent total synthesis of grandisine B 5.11
Initial studies concentrated on the cyclisation of diketone 8a,
which bears the 5-methyl substituent found in mearsine 4 and gran-
disine B 5. This was prepared (Scheme 2) by treatment of 5-methyl-
cyclohexenone 912 with LDA in THF at À78 °C and subsequent trap-
ping with cyclohexane carboxaldehyde, followed by oxidation of the
resulting b-hydroxy ketone 1013 using Dess–Martin periodinane.
The novel 1,3-diketone 8a exists as a mixture of diasteroisomers/
tautomers, with the trans-diastereoisomer predominating.
With the desired 1,3-diketone 8a in hand, we were in a position
to investigate the proposed cyclisation sequence (Scheme 3). Upon
treatment of diketone 8a with 35% aqueous ammonia in methanol,
rapid consumption of starting material was observed, with the for-
mation of a single product. Isolation and analysis by 1H/13C NMR
spectroscopy revealed the product to be the desired isoquinuclidi-
none 6a [characteristic bridgehead proton signals at 4.5 and
3.2 ppm; 13C NMR signals at 209.0 ppm (bridging ketone) and
179.7 ppm (imine)]. Compound 6a was obtained in excellent yield
⇑
Corresponding author. Tel.: +44 (0)1904 432606; fax: +44 (0)1904 434523.
E-mail address: rjkt1@york.ac.uk (R.J.K. Taylor).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.052

J. D. Cuthbertson et al. / Tetrahedron Letters 52 (2011) 2024–2027
2025
OH
O
O
Me
Me
N
Me
Me
MeO
N
HN
N
H
OH
2
1
3
O
O
N
N
Me
Me
Me
N
4
5
Figure 1. Isoquinuclidine and isoquinuclidinone alkaloids.
isoquinuclidinone 6g was formed but a three-day reaction time
was required (entry vii). In all cases, the reactions proceeded stere-
oselectively to give the 8b-substituted products exclusively.
Attempts were also made to prepare the ‘unsubstituted’ isoqu-
inuclidinones 6h and 6i (Scheme 4). However, treatment of precur-
sors 8h and 8i using the optimised reaction conditions did not
produce the expected isoquinuclidinones 6h and 6i but instead
gave clean conversion to the monocyclic methyl esters 12a and
12b. It seems likely that isoquinuclidinones 6h and 6i were formed
but then underwent methoxide-induced ring-opening as illus-
trated in Scheme 4 to give compounds 13.15 We assume that the
additional substitution around the isoquinuclidinone ring in com-
pounds 6a–g slows down this ring-opening process. The structural
resemblance between esters 12 and the Elaeocarpus alkaloid gran-
disine G 13, recently isolated by Carroll and co-workers,16 should
also be noted; it was proposed that grandisine G 13 results from
the corresponding methanol-induced ring-opening of grandisine
B 5.16
O
O
O
NH2
O
O
R
N
R
R1
R1
+ NH3
R1
R
6
7
8
Scheme 1. Retrosynthetic analysis of isoquinuclidinone 6.
as a single diastereoisomer (8b-Me) and the isomeric compound 11
(8 -Me) was not observed. We assume that initial, reversible 1,4-
a
addition of ammonia occurs followed by imine formation; presum-
ably, some addition of ammonia syn-to the methyl group takes
place but cyclisation to give 11 is unfavourable for steric reasons.
Having confirmed the viability of the proposed sequence, the
scope of the reaction was investigated next utilising a range of
substituted diketone substrates 8 (Table 1). The starting 1,3-dike-
tones 8 were prepared from the corresponding cyclohexenones
using the procedure outlined in Scheme 2.
As can be seen, this tandem process was compatible with a
range of aliphatic, aromatic and alkenyl substituents on the ketone
(entries i–iv). However, on increasing the steric bulk of the substit-
uents on the cyclohexenone ring, longer reaction times were re-
quired although the expected isoquinuclidinones 6e–g were
obtained in fair to excellent yield (entries v–vii). In the case of
the 5-phenyl-cyclohexenone 8f, a number of by-products were
formed in addition to isoquinuclidinone 6f (entry vi), and with
the trisubstituted carvone-derived cyclohexenone 8g the expected
In order to demonstrate the utility of this tandem amination/
imination sequence, we utilised the procedure in a short total syn-
thesis of (À)-mearsine 4 (Scheme 5). Mearsine was isolated in 1984
by Bick and co-workers from the Australian rainforest species Peri-
pentadenia mearsii,5 and subsequently the (+)-enantiomer of mear-
sine was synthesised from (+)-pulegone by Crouse and Pinder.17
The first requirement was to prepare the requisite cyclohexenone
8j and this was achieved prepared from 2,4-pentanedione and cro-
tonaldehyde via an enantioselective, organocatalytic Michael addi-
O
OH
O
O
O
LDA, CyCHO
DMP
DCM, 0 ºC to rt
98%
THF, -78 ºC
67%
9
10
8a
Scheme 2. Synthesis of cyclisation precursor 1,3-diketone 8a.
O
O
O
O
35% aq. NH3
N
N
Me
Me
MeOH, 0 ºC to rt, 2 h
89%
Me
11
Not formed
8a
6a
Scheme 3. Synthesis of isoquinuclidinone 6a via amination/imination sequence.

2026
J. D. Cuthbertson et al. / Tetrahedron Letters 52 (2011) 2024–2027
Table 1
Scope of amination/cyclisation sequencea
Entry
Substrate 8
Product 6
Time (h)
Yieldb (%)
O
O
O
N
Me
i
2
89
Me
O
8a
6a
O
O
O
N
Me
nC5H11
ii
2
2
65
91
nC5H11
Me
O
6b
8b
8c
O
N
Me
iii
Me
O
6c
O
O
N
Me
iv
2
80c
Me
O
8d
6d
O
O
O
N
Pr
Ph
v
4
8
80
Ph
6e
Pr
O
8e
O
N
Ph
vi
ꢀ50%d
Ph
Ph
6f
Ph
O
8f
O
Me
Me
Cy
Me
O
N
vii
72
75e
Me
8g
6g
a
b
c
All reactions were performed on 0.25 mmol scale using MeOH (1 mL), 35% aq NH3 (0.5 mL) at 0 °C to rt.
Isolated yields.
Representative experimental procedure.14
d
e
An inseparable mixture of 6f (confirmed by 1H NMR/HRMS) and by-products obtained; yield estimated using NMR spectroscopy.
Dr = 3.4:1.
35% aq. NH3
O
O
O
X
N
R
R
MeOH, 0 ºC to rt
O
N
6h, R = Ph
6i, R = n-C5H11
8h, R = Ph
8i, R = n-C5H11
OMe
O
N
-OMe
N
OMe
13
O
N
R
R
12a, R = Ph (72%)
6
12b, R = n-
C5H11 (89%)
Scheme 4. Methoxide promoted ring-opening of isoquinuclidinone 6.

J. D. Cuthbertson et al. / Tetrahedron Letters 52 (2011) 2024–2027
2027
O
O
O
O
O
O
Me
O
pTSA (10 mol%)
Me
Me
Me
Me
Me
Me
Me
PhMe, 50ºC, 18 h
74%
14 (1 mol%)
Neat, rt, 24 h
91%
O
8j
15
35% aq. NH3
MeOH
0 ºC to rt
82%
CF3
CF3
N
H
O
OTMS
CF3
N
Me
Me
F3C
(-)-Mearsine 4
(81% ee)
14
Scheme 5. Synthesis of (À)-mearsine 4.
tion18 and subsequent aldol condensation. Thus, addition of 2,4-
pentanedione to crotonaldehyde mediated by Jorgensen’s catalyst
14 (1 mol %)19 gave aldehyde 15 in 91% unpurified yield. Immedi-
ate treatment of the aldehyde 15 with pTSA (10 mol %) furnished
the desired cyclohexenone 8j, which was isolated as a complex
mixture of diastereoisomers/tautomers. Treatment of diketone 8j
with 35% aqueous ammonia in methanol initiated the required
tandem amination/imination sequence to produce (À)-mearsine
4 in 82% yield;20 the melting point (mp 38–40 °C; lit.5 43–44 °C)
and spectral data for the isolated product corresponded closely to
those reported,5,17 although there was a discrepancy in the optical
5. Robertson, G. B.; Tooptakong, U.; Lamberton, J. A.; Geewananda, Y. A.;
Gunawardana, P.; Bick, I. R. C. Tetrahedron Lett. 1984, 25, 2695–2696;
Lamberton, J. A.; Geewananda, Y. A.; Gunawardana, P.; Bick, I. R. C. J. Nat.
Prod. 1983, 46, 235–247.
6. Carroll, A. R.; Arumugan, G.; Quinn, R. J.; Redburn, J.; Guymer, G.; Grimshaw, P.
J. Org. Chem. 2005, 70, 1889–1892.
7. Brooke, G. M.; Matthews, R. S.; Robson, N. S. J. Chem. Soc., Perkin Trans. 1 1980,
102–106; Babu, G.; Perumal, P. T. Tetrahedron 1998, 54, 1627–1638; McClure, C.
K.; Link, J. S. J. Org. Chem. 2003, 68, 8256–8257; Sundén, H.; Ibrahem, I.;
Eriksson, L.; Córdova, A. Angew. Chem., Int. Ed. 2005, 44, 4877–4880; Yang, H.;
Carter, R. G. J. Org. Chem. 2009, 74, 5151–5156.
8. Quirante, J.; Diaba, F.; Vila, X.; Bonjoch, J. Magn. Reson. Chem. 2005, 43, 599–
601.
9. Rassat, A.; Rey, P. Tetrahedron 1972, 28, 741–750.
10. Larouche-Gauthier, R.; Bélanger, G. Org. Lett. 2008, 10, 4501–4504.
11. Kurasaki, H.; Okamoto, I.; Morita, N.; Tamura, O. Chem. Eur. J. 2009, 15, 12754–
12763.
12. Fuchs, P. L.; Musser, A. K. J. Org. Chem. 1982, 47, 3121–3131.
13. All novel compounds were fully characterised by 1H/13C NMR spectroscopy, IR
spectroscopy and HRMS.
rotation data {lit. [
a]
D
À34.5 (c 0.495, CH2Cl2);5 synthetic 4, [
a]
D
À252.6 (c 0.51, CH2Cl2)}. For this reason, chiral HPLC analysis (Phe-
nomenex Lux Cellulose-2 column, 95:5 iso-hexane/EtOH, flow rate
1.0 mL/min) was performed which confirmed that the enantio-
meric ratio was 90.5:9.5, and conclusive evidence for the structure
and relative stereochemistry of synthetic 4 was provided by single
crystal X-ray analysis of the picrate salt (mp 208–210 °C dec; lit.5
mp 212–213 °C).
In summary, a tandem amination/imination route has been
developed to convert 6-acyl-cyclohex-2-enones 8 into isoquinuc-
lidinones 6 in a one-pot process.
The scope and limitations of the methodology have been inves-
tigated, and the utility of the sequence has been demonstrated
with an efficient synthesis of the alkaloid (À)-mearsine (the first
synthesis of the (À)-enantiomer). Applications of this new tandem
methodology in the preparation of more complex natural product
targets are currently underway.
14. Representative experimental procedure: To a stirred solution of diketone 8d
(55 mg, 0.25 mmol) in MeOH (1 mL) at 0 °C was added dropwise 35% aqueous
NH3 (0.5 mL). The resulting yellow solution was held at 0 °C for 30 min, then
warmed to rt with stirring until consumption of starting material was observed
by TLC analysis (DCM/MeOH, 95:5). The reaction mixture was then diluted
with water (5 mL) and extracted with DCM (3 Â 10 mL). The combined organic
extracts were washed with brine (10 mL), dried (MgSO4) and then
concentrated in vacuo to afford
column chromatography (SiO2, DCM/MeOH, 98:2) to give isoquinuclidinone 6d
(44 mg, 80%) as a colourless oil Rf 0.49 (DCM/MeOH, 95:5);
max/cmÀ1 (neat)
a colourless oil which was purified by
m
2930, 2868, 1731, 1576, 1340; dH (400 MHz, CDCl3) 6.41 (1H, m), 4.60 (1H,
dddd, J = 3.6, 3.6, 1.8, 1.8), 3.62 (1H, d, J = 3.1), 2.30–2.25 (2H, m), 2.21–2.15
(2H, m), 2.12 (1H, dm, J = 19.0), 2.02 (1H, dd, J = 19.0, 1.8), 2.01–1.93 (1H, m),
1.91–1.81 (1H, m), 1.67–1.54 (4H, m), 1.24 (1H, ddd, J = 12.8, 4.4, 1.8), 1.03 (3H,
d, J = 7.0); dC (100 MHz, CDCl3) 209.2 (CO), 172.2 (CN), 135.3 (C), 133.0 (CH),
55.8 (CH), 55.6 (CH), 39.8 (CH2), 32.7 (CH2), 29.2 (CH), 26.0 (CH2), 24.0 (CH2),
22.1 (CH2), 21.8 (CH2), 21.3 (CH3); m/z (ESI) 218 [MH]+; [HRMS (ESI): calcd for
C
14H20NO, 218.1539; found: MH+, 218.1540 (0.4 ppm error)].
15. Lowering the reaction temperature or reducing the reaction time failed to
prevent the undesired ring opening but instead gave incomplete conversion of
the starting material.
16. Katavic, P. L.; Venables, D. A.; Forster, P. I.; Guymer, G.; Carroll, A. R. J. Nat. Prod.
2006, 69, 1295–1299.
Acknowledgements
We are grateful to the EPSRC and AstraZeneca for studentship
support (JDC).
17. Crouse, J. R.; Pinder, A. R. J. Nat. Prod. 1989, 52, 1227–1230.
18. Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628–13630.
19. Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jorgensen, K. A. Angew. Chem., Int. Ed.
2005, 44, 794–797.
References and notes
m
max/cmÀ1 (neat) 2957, 1729, 1633,
1. (a)Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ed.; Elsevier, 2008;
Vols. 1–15, For recent publications in this area from our group see: (b) Pugh, D.
S.; Klein, J. E. M. N.; Perry, A.; Taylor, R. J. K. Synlett 2010, 934–938; Catozzi, N.;
Edwards, M. G.; Raw, S. A.; Wasnaire, P.; Taylor, R. J. K. J. Org. Chem. 2009, 74,
8343–8354; Millemaggi, A.; Perry, A.; Whitwood, A. C.; Taylor, R. J. K. Eur. J. Org.
Chem. 2009, 2947–2952; Donald, J. R.; Taylor, R. J. K. Synlett 2009, 59–62;
Bromley, W. J.; Gibson, M.; Lang, S.; Raw, S. A.; Whitwood, A. C.; Taylor, R. J. K.
Tetrahedron 2007, 63, 6004–6014.
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4. de Souza, J. J.; Mathias, L.; Braz-Filho, R.; Vieira, I. J. C. Helv. Chim. Acta 2010, 93,
422–429.
20. (À)-Mearsine 4: Rf 0.45 (DCM/MeOH, 9:1);
1379; dH (400 MHz, CDCl3) 4.50 (1H, dddd, J = 3.5, 3.5, 1.9, 1.9), 3.13 (1H, d,
J = 2.9), 2.17–2.08 (1H, m), 2.12 (3H, s), 2.01 (1H, dd, J = 19.0, 1.8), 1.97 (2H, m),
1.22 (1H, m), 1.04 (3H, d, J = 6.9); dC (100 MHz, CDCl3) 208.4 (CO), 173.7 (CN),
61.4 (CH), 55.5 (CH), 39.5 (CH2), 32.4 (CH2), 28.8 (CH), 24.5 (CH3), 21.0 (CH3);
m/z (ESI) 152 [MH]+; [HRMS (ESI): calcd for C9H14NO, 152.1070; found: MH+,
152.1070 (0.1 ppm error)]; HPLC Analysis [Phenomenex Lux Cellulose-2
column, 95:5 iso-hexane/EtOH, flow rate 1.0 mL/min; RT = 9.51 (minor, 9.5%)
and 10.62 (major, 90.5%)]. Picrate salt mp 208–210 °C dec (lit.5 mp 212–
213 °C).