Preparation of advanced intermediates for the synthesis of both methyllycaconitine and racemulsonine via a common intermediate

Article abstract of DOI:10.1016/j.tetlet.2004.12.092

Polycyclic precursors to 1 and 2 have been prepared via a common intermediate. The key steps include the intramolecular alkylation of a phenol and a selective metal-ammonia reduction.

Full text of DOI:10.1016/j.tetlet.2004.12.092

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1111–1113
Preparation of advanced intermediates for the synthesis
of both methyllycaconitine and racemulsonine via
a common intermediate
George A. Kraus* and Sarathy Kesavan
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 29 November 2004; revised 15 December 2004; accepted 17 December 2004
Available online 11 January 2005
Abstract—Polycyclic precursors to 1 and 2 have been prepared via a common intermediate. The key steps include the intramolecular
alkylation of a phenol and a selective metal–ammonia reduction.
Ó 2004 Elsevier Ltd. All rights reserved.
Methyllycaconitine (1) is a novel hexacyclic alkaloid iso-
lated from tall larkspur.1 It has been shown to be a
potent nicotinic acetylcholine receptor antagonist.2
Researchers have proposed that methyllycaconitine or
analogs thereof could be useful for the treatment of
diseases affecting memory or for antiepileptic drug
development.3 Racemulsonine (2), a novel C20 diterpene
alkaloid containing an azabicyclo[3.2.1]octane subunit,
was recently isolated by Wang et al.4
of a tetracyclic ABEF ring analog, the most complex
subunit generated to date, by a route that is distinctly
different from all previous approaches.
Our synthesis began with aldehyde 3, readily available in
three steps from 3-aminophenol.11 Although the TBS
protecting group was crucial for the regioselective instal-
lation of the carboxaldehyde, the condensation of 3 with
dimethyl malonate led to a mixture of products. There-
fore, the TBS group was replaced with a methoxymethyl
protecting group (TBAF; MeOCH2Cl, i-Pr2NEt). Con-
densation of aldehyde 5 with dimethyl malonate and
piperidine in boiling ethanol provided a lactam, presum-
ably via a diester that cyclized to form the lactam before
BOC deprotection. Selective N-alkylation using anhy-
drous potassium carbonate and ethyl iodide produced
lactam 7 in 73% overall yield from 5.
OMe
A
CONH2
C
OMe
OMe
B
E
N
H
OH
O
D
O
F
H
OH
OH
OH
OMe
N
O
Me
N
1
2
O
Dimethyl
malonate
OHC
MeO2C
O
As a consequence of the biological activity and its novel
structure, 1 has been the synthetic objective of several
research groups. Brimble and co-workers,5 Kraus
et al.,6 and Whiting and co-workers7 have reported the
preparation of tricyclic analogs of 1. Analogs bearing
the AE bicyclic unit and the E ring subunit have also
been reported.8 Additionally, Kraus and Dneprovskaia9
and Blagbrough et al.10 have reported procedures for
attaching the methylsuccinimidobenzoate unit to meth-
yllycaconitine analogs. We report herein the synthesis
BOC-N
OR
N
R
OMOM
piperidine
3: R = TBS
4: R = H
6: R = H
7: R = Et
TBAF
K2CO3, EtI
MOMCl
5: R = MOM
Conjugate addition with vinyl magnesium bromide and
copper iodide/dimethyl sulfide and alkylation with 1,3-
dibromopropane furnished 8a in 51% yield.12 The
cis-relationship of the vinyl and ester groups were deter-
mined by 2D NOESY NMR. Reaction of 7 with vinyl
*
Corresponding author. Tel.: +1 5152947794; fax: +1 5152940105;
e-mail: gakraus@iastate.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.092

1112
G. A. Kraus, S. Kesavan / Tetrahedron Letters 46 (2005) 1111–1113
magnesium bromide/copper iodide followed by alkyla-
tion with 1,2-dibromoethane provided 8b in 68% yield.
of both 1215 and 13. The stereochemistry of compound
12 should facilitate the stereoselective appendage of
the remaining two rings.
MeO2C
References and notes
1. CH2=CH-MgBr,
CuI
Br
( )n
7
1. Manske, R. H. F. Can. J. Res. 1938, 16B, 57–60;
Schramm, L. C. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; J. Wiley and Sons: New
York, 1984; Vol. 2, pp 205–462; Yunusov, M. S. Nat.
Prod. Rep. 1993, 10, 471–486.
O
N
Et
OMOM
2. NaH, Br(CH2) Br
n
8a: n = 1
8b: n = 0
2. Alkondon, M.; Pereira, E.; Wonnacott, S. Mol. Pharma-
col. 1992, 41, 802–808.
3. Loscher, W.; Potschka, H.; Wlaz, P.; Danysz, W.;
Parsons, C. G. Eur. J. Pharmacol. 2003, 466, 99–111.
4. Wang, F. P.; Peng, C. S.; Yu, K.-B. Tetrahedron 2000, 56,
7443–7446.
5. Barker, D.; Brimble, M. A.; McLeod, M. D.; Savage, G.
P. Org. Biomol. Chem. 2004, 2, 1659–1669; Barker, D.;
McLeod, M. D.; Brimble, M. A.; Savage, G. P. Tetrahe-
dron Lett. 2002, 43, 6019–6022.
6. Kraus, G. A.; Andersh, B.; Su, Q.; Shi, J. Tetrahedron
Lett. 1993, 34, 1741–1744.
Oxidative cleavage of the alkene in 8a and subsequent
acetal formation/removal of the MOM protecting group
(PTSA, MeOH, 25 °C) gave a phenol that underwent
intramolecular cyclization with sodium hydride and
18-crown-6 in THF at 75 °C to generate dienone 9 in
72% isolated yield.13 Interestingly, the phenol produced
from 8a by removing the MOM protecting group under-
went cyclization to 10 in only 43% yield and required
high dilution conditions (NaH, 15-crown-5, 0.0005 M
in THF).
7. Baillie, L. C.; Bearder, J. R.; Li, W.-S.; Sherringham, J. A.;
Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1998, 4047–
4056, and references therein.
1. O3
2. MeOH
1. 4N HCl
2. NaH,
MeO2C
MeO
MeO2C
O
OMe
8a
8. Ismail, K. A.; Bergmeier, S. C. Eur. J. Med. Chem. 2002,
37, 469–474; Bergmeier, S. C.; Lapinsky, D. J.; Free, R. B.;
McKay, D. B. Bioorg. Med. Chem. Lett. 1999, 9, 2263–
2266; Grangier, G.; Trigg, W. J.; Lewis, T.; Rowan, M.
G.; Potter, B. V. L.; Blagbrough, I. S. Tetrahedron Lett.
1998, 39, 889–892; Davies, A. R. L.; Hardick, D. J.;
Blagbrough, I. S.; Potter, B. V. L.; Wolstenholme, A. J.;
Wonnacott, S. Biochem. Soc. Trans. 1997, 25, 545S; Callis,
D. J.; Thomas, N. F.; Pearson, D. P. J.; Potter, B. V. L. J.
Org. Chem. 1996, 61, 4634–4640; Coates, P. A.; Blag-
brough, I. S.; Rowan, M. G.; Pearson, D. P. J.; Lewis, T.;
Potter, B. V. L. J. Pharm. Pharmacol. 1996, 48, 210–213.
9. Kraus, G. A.; Dneprovskaia, E. Tetrahedron Lett. 1998,
39, 2451–2454.
O
N
Et
O
N
Et
O
3. NaH,
18-crown-6
15-crown-5
0.0005 M
9
10
Hydrogenation of 9 followed by hydrolysis of the ester
with lithium hydroxide in THF–methanol and metal–
ammonia reduction (5 equiv Li, 2 equiv t-BuOH in
NH3/THF) of the dienone gave diketo acid 11 as a 3:1
mixture of diastereomers with the isomer shown pre-
dominating in 47% yield. Esterification and acid cata-
lyzed (4 N HCl) acetal hydrolysis/aldol condensation
afforded ketol 12 in 58% yield. The structure of the
methyl ester of 11 was determined by X-ray
crystallography.14
10. Blagbrough, I. S.; Coates, P. A.; Hardick, D. J.; Lewis, T.;
Rowan, M. G.; Wonacott, S.; Potter, B. V. L. Tetrahedron
Lett. 1994, 35, 8705–8708.
11. Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997,
62, 6507–6511.
12. Dowd, P.; Choi, S. C. Tetrahedron 1989, 45, 77–90.
13. Murphy, W. S.; Wattanasin, S. Chem. Soc. Rev. 1983, 12,
213–250.
1. Pd/C, H2
1. CH2N2
MeO2C
O
2. LiOH
HO2C
9
MeO
O
OMe
H
2. 4N HCl
O
3. Li/NH3
N
Et
12
O
N
Et
H
OH
11
14. X-ray structure of the methyl ester of 11:.
The key intermediate for the synthesis of 2 was gener-
ated from 8b by hydrolysis of the phenol protecting
group with 4 N HCl followed by cyclization to 13 with
sodium hydride in 82% yield. In this case, the cyclization
could be conducted in boiling THF at lower dilution
than for the phenol derived from 8a.
1. 4N HCl
2. NaH,
MeO2C
O
8b
N
Et
O
18-crown-6
0.005 M
13
82%
Our B-BE-ABE ring building strategy allows for consid-
erable flexibility in the introduction of the A ring. Com-
pound 7 is a common intermediate for the preparation

G. A. Kraus, S. Kesavan / Tetrahedron Letters 46 (2005) 1111–1113
1113
1
15. Spectral data for 12: H NMR (400 MHz, CDCl3) d 4.83
1.7–1.9 (4H, m), 1.2 (3H, t, J = 7.2 Hz). 13C NMR
(75 MHz, CDCl3) d 209.6, 172.7, 166.6, 75.2, 68.7, 62.2,
57.4, 55.6, 53.0, 41.7, 41.4, 35.9, 34.9, 33.8, 33.4, 20.1, 12.8;
HRMS m/z for C17H23O5N calcd 321.1576, found
321.1581.
(1H, dd, J = 7.2 Hz, 4.0 Hz), 3.90–4.00 (1H, m), 3.80
(3H, s), 3.39 (1H, d, J = 2.8 Hz), 3.08 (1H, d, J = 7.6 Hz),
2.70–2.84 (2H, m), 2.42 (1H, d, J = 4 Hz), 2.27–2.33
(2H, m), 2.17 (1H, d, J = 2.8 Hz), 1.90–2.04 (2H, m),