Concise syntheses of (±)-protoemetinol and related alkaloids using radical cyclisation

Article abstract of DOI:10.1016/j.tetlet.2011.01.007

Both (±)-protoemetinol, its 3-epi-isomer and (±)-3-desmethyl protoemetinol have been prepared in five linear steps from a dihydroisoquinoline using a 6-exo-trig cyclisation of a vinyl radical in the key step. This novel and particularly short route has po

Full text of DOI:10.1016/j.tetlet.2011.01.007

Tetrahedron Letters 52 (2011) 1154–1156
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise syntheses of ( )-protoemetinol and related alkaloids using radical
cyclisation
Matthew J. Palframan a, Andrew F. Parsons a, , Paul Johnson b
⇑
a Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
b AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Both ( )-protoemetinol, its 3-epi-isomer and ( )-3-desmethyl protoemetinol have been prepared in five
linear steps from a dihydroisoquinoline using a 6-exo-trig cyclisation of a vinyl radical in the key step.
This novel and particularly short route has potential application in the synthesis of Alangium and Mit-
ragyna alkaloids.
Received 8 November 2010
Revised 10 December 2010
Accepted 4 January 2011
Available online 12 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloid
Cyclisation
Radical
Tributyltin hydride
The Alangium family of alkaloids, such as psychotrine (1) and
deoxytubulosine and Mitragyna alkaloids, including mitragynine
(2) (Fig. 1), have attracted interest due to their use as folk remedies
for numerous ailments, including dysentery.1 These types of quin-
olizidine alkaloids have been shown to exhibit potent biological
activities. For example, psychotrine (1), isolated from the root of
the Ipecacuanha plant, is a potent inhibitor of HIV-1 reverse trans-
criptase,2 while mitragynine (2) shows analgesic activity at opioid
receptors.3 As part of a programme to develop a general, efficient
and concise synthesis of these types of alkaloid, we report a novel
and particularly concise synthesis of ( )-protoemetinol (3), its 3-
epi-isomer and 3-desmethyl derivatives, which are useful starting
materials for a range of natural quinolizidines.4
Initial studies of the radical cyclisation using a model system
proved to be very encouraging (Scheme 2). Slow addition of a solu-
tion of Bu3SnH (1.2 equiv) and AIBN (0.5 equiv) in THF, to a solu-
O
O
O
N
H
H
N
N
N
H
H
H
H
H
OMe
MeO2C
The key step in the synthetic approach to ( )-protoemetinol (3)
involves the radical cyclisation of vinyl bromide 4, as illustrated in
the retrosynthetic analysis in Scheme 1. Reaction of bromide 4
with tributyltin hydride (Bu3SnH) and a radical initiator was ex-
pected to lead to a 6-exo-trig cyclisation reaction and the formation
of a 6,6,6-tricycle, which could be elaborated to 3. Although the use
of 5-exo-trig radical cyclisations to form pyrrolidine rings is preva-
lent in the literature, the use of related 6-exo-trig cyclisations to
form piperidine rings is comparatively scarce.5,6 This may partly
be explained by the relatively low rates of 6-exo-trig radical cycli-
sations and competing radical pathways such as 1,5-hydrogen
atom abstractions.
HO
OMe
2
1
Figure 1. Structures of psychotrine (1) and mitragynine (2).
O
O
O
Br
N
N
O
H
H
OMe
O
OH
4
3
⇑
Corresponding author. Tel.: +44 1904 322608; fax: +44 1904 322516.
E-mail address: andy.parsons@york.ac.uk (A.F. Parsons).
Scheme 1. Retrosynthetic analysis of ( )-protoemetinol (3).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.007

M. J. Palframan et al. / Tetrahedron Letters 52 (2011) 1154–1156
1155
O
O
O
O
O
O
Bu3SnH,
AIBN
O
O
Bu3SnH,
AIBN
Br
N
N
N
N
N
N
THF, reflux
Br
THF, reflux
16
5
22%
8, 26%
15
d.r. = 4:1
+
O
O
O
Bu3SnH,
AIBN
N
N
O
O
O
H
THF, reflux
Br
H
H
6, 44%
H
7
18, 89%
d.r. = 2.8:1
d.r. = 5:1
O
O
O
O
17
(major isomer is shown)
Scheme 4. Cyclisation of related vinyl bromides (the major isomers of the products
are shown).
Scheme 2. Cyclisation of vinyl bromide 5.
tion of vinyl bromide 57 in THF at reflux, afforded the desired 6,6,6-
tricycle 6 in 44% yield as a mixture of diastereoisomers (in an
approximately 5:1 ratio, based on the 1H NMR spectrum).8,9 The
relative stereochemistry of 6 was determined by a 1H NOESY
experiment and was consistent with that predicted from a 6-exo-
trig radical cyclisation that proceeds via chair-like transition state
7. By-products were also formed, although only one of these, 1,7-
diene 8, derived from simple reduction of 5, was isolated cleanly.
Attention then turned to the radical cyclisation of vinyl bro-
mides 4 and 11 (Scheme 3). It was envisaged that the 6-exo-trig
cyclisation of both 4 and 11 would be more efficient than that of
5. The presence of the ester substituent on the acceptor C@C bond
was expected to increase the rate of 6-exo cyclisation (for elec-
tronic reasons).
O
N
O
(i) LiAlH4, THF,
O
O
R
3, R = Me
19, R = H
0
C to r.t.,
85-87%
N
OH
+
R
(ii) H2, Pd/C,
MeOH, 82-91%
(3:epi-3 = 1:10)
(19:epi-19 = 1:6)
O
O
CO2Me
N
12, R = Me
13, R = H
Vinyl bromides 4 and 11 were prepared from dihydroisoquino-
line 10 by an N-allylation reaction,10 to give an iminium ion, which
was immediately reacted with an organozinc reagent [prepared
from methyl (2E)-4-bromobut-2-enoate (9)] that underwent
nucleophilic addition to the imine system. Pleasingly, reaction of
4 or 11 with Bu3SnH and AIBN gave the desired 6,6,6-tricycle 12
or 13, respectively, in moderate to good yields after column chro-
matography. No byproducts derived from simple reduction were
isolated. The reaction of 4 did produce a 6,6,5-tricycle 14, presum-
ably derived from a 1,5-H atom transfer/5-exo-trig cyclisation
pathway, although this was isolated in only 4% yield. Treatment
of 4 or 11 with (Me3Si)3SiH in place of Bu3SnH (under the same
conditions) gave lower yields of the desired tricycles (20–42%),
although the diastereoselectivities of the cyclisations improved to
R
epi-3, R = Me
epi-19, R = H
OH
Scheme 5. Synthesis of 3-epi-protoemetinol (epi-3) and 3-epi-3-desmethyl proto-
emetinol (epi-19).
6:1–10:1. Interestingly, in all cases, the 6-exo cyclisation of N-
but-2-enyl bromide 4 proved to be less efficient than for N-prop-
2-enyl bromide 11.11
The importance of the ester substituent on the efficiency of a 6-
exo radical cyclisation was particularly evident when the positions
of the vinyl bromide and acceptor double bond were reversed
(Scheme 4). Whereas 15 gave tricycle 16 in only 22% yield (to-
Br
(i)
R
Br
Br
O
O
O
O
Br
(i) Br
Et2O, r.t.
R
Br
N
N
Et2O, r.t.
N
N
(ii) Zn, MeCN, r.t.,
Br CO2Me
N
PMB
N
10
(ii) Zn, MeCN, r.t.,
PMB
9
CO2Me
Br
CO2Me
20, 19%
4, R = Me; 55%
11, R = H; 79%
CO2Me
9
Bu3SnH, AIBN,
THF, reflux
(iii) Bu3SnH, AIBN,
THF, reflux
O
O
N
MeO2C
+
O
O
H
H
N
N
N
+
N
PMB
N
PMB
N
R
N
MeO2C
14
PMB
12, R = Me;
44%; d.r. = 2:1
13, R = H;
CO2Me
CO2Me
CO2Me
21, 5%
22, 46%
23, 12%
78%, d.r. = 2.8:1
d.r. = 1.6:1
(major isomer shown)
Scheme 3. Cyclisation of bromides 4 and 11 (the major isomers of 12 and 13 are
Scheme 6. Synthesis of de-methoxy mitragynine analogue 22.
shown).

1156
M. J. Palframan et al. / Tetrahedron Letters 52 (2011) 1154–1156
Chuang, Y.-H.; Chang, N.-C. Tetrahedron 2008, 64, 9685–9688; (b) Takacs, J. M.;
Bolto, S. C. Tetrahedron Lett. 1995, 36, 2941–2944; (c) Tietze, L. F.; Rackelmann,
N.; Müller, I. Chem. Eur. J. 2004, 10, 2722–2731; (d) Itoh, T.; Miyazaki, M.;
Fukuoka, H.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8, 1295–1297; (e) Tietze, L.
F.; Rackelmann, N.; Sekar, G. Angew. Chem., Int. Ed. 2003, 42, 4254–4257; (f)
Ihara, M.; Yasui, K.; Taniguchi, N.; Fukumoto, K. Tetrahedron Lett. 1988, 29,
4963–4966; (g) Ihara, M.; Tasui, K.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc.,
Perkin Trans. 1 1990, 1469–1476; (h) Takano, S.; Hatakeyama, S.; Ogasawara, K.
Tetrahedron Lett. 1978, 19, 2519–2522.
gether with various by-products), unsaturated ester 17 gave 18 in
excellent 89% yield.
Tricycles 12 and 13 were then converted into predominantly 3-
epi-protoemetinol (epi-3) and 3-epi-3-desmethyl protoemetinol
(epi-19), respectively, by reduction of the ester groups followed
by catalytic hydrogenation of the C@C bonds (Scheme 5). In each
case, a face-selective hydrogenation using Pd/C as the catalyst
was observed to give predominantly the epi isomers. However,
investigations on the use of alternative catalysts, found that Crab-
tree’s catalyst12 afforded a moderate excess of both ( )-protoemet-
inol (3) and the ( )-desmethyl analogue 19. For example, catalytic
hydrogenation using Crabtrees’ catalyst, in dichloromethane at rt,
afforded a 1.1:1.0 ratio of 3:epi-3 (54% yield) and a 1.4:1.0 ratio
of 19:epi-19 (96% yield).
5. See for example: (a) Gandon, L. A.; Russell, A. G.; Güveli, T.; Brodwolf, A. E.;
Kariuki, B. M.; Spencer, N.; Snaith, J. S. J. Org. Chem. 2006, 71, 5198–5207; (b)
Lee, E.; Jeong, E. J.; Min, S. J.; Hong, S.; Lim, J.; Kim, S. K.; Kim, H. J.; Choi, B. G.;
Koo, K. C. Org. Lett. 2000, 2, 2169–2171; (c) Koreeda, M.; Wang, Y.; Zhang, L.
Org. Lett. 2002, 4, 3329–3332; (d) Katritzky, A. R.; Luo, Z.; Fang, Y.; Feng, D.;
Ghiviriga, I. J. Chem. Soc., Perkin Trans. 2 2000, 1375–1380; (e) Parsons, A. F.;
Pettifer, R. M. J. Chem. Soc., Perkin Trans. 1 1998, 651–660; (f) Ishibasi, H.;
Inomata, M.; Ohba, M.; Ikeda, M. Tetrahedron Lett. 1999, 40, 1149–1152; (g)
Kaoudi, T.; Miranda, L. D.; Zard, S. Z. Org. Lett. 2001, 3, 3125–3127; (h) Quirante,
J.; Escolano, C.; Bosch, J.; Bonjoch, J. J. Chem. Soc., Chem. Commun. 1995, 2141–
2142; (i) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.; Liao, X.;
Cook, J. M. J. Org. Chem. 2003, 68, 7565–7581; (j) Kuehne, M. E.; Wang, T.;
Seraphin, D. J. Org. Chem. 1996, 61, 7873–7881; (k) Wang, T.; Cook, J. M. Org.
Lett. 2000, 2, 2057–2059; (l) Eichberg, M. J.; Dorta, R. L.; Lamottke, K.; Vollhardt,
K. P. C. Org. Lett. 2000, 2, 2479–2481; (m) Kuehne, M. E.; Wang, T.; Seraphin, D.
Synlett 1995, 557–558.
6. For a related 6-exo cyclisation of an indole bearing an unsaturated malonate,
see: Takayama, H.; Watanabe, F.; Kitajima, M.; Aimi, N. Tetrahedron Lett. 1997,
38, 5307–5310.
7. Compound 5 was prepared from 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
using the following four-step procedure: (1) Boc2O, Et3N, CH2Cl2, rt (85%); (2)
sBuLi, THF, À78 °C then allyl bromide, À78 °C to rt (68%); (3) TFA, CH2Cl2, rt
then aq NaOH (88%); (4) 2,3-dibromopropene, K2CO3, Et3N, DMF, rt (67%).
8. All new compounds gave consistent spectral and high-resolution mass
spectrometry data.
9. Typical experimental procedure for the radical cyclisation: A solution of bromide 5
(0.70 g, 2.0 mmol) in THF (25 mL) was stirred at reflux while AIBN (16 mg,
0.10 mmol) was added, followed by the slow addition of a solution of Bu3SnH
(0.75 mL, 2.80 mmol) and AIBN (150 mg, 0.90 mmol) in THF (20 mL) by a
syringe pump over a period of 4 h. Following the complete addition of the
Bu3SnH solution, the reaction mixture was maintained at reflux for a further
2 h, after which the solution was cooled to rt. The reaction mixture was
concentrated in vacuo, until approximately 10 mL of solvent remained, which
was then stirred with KF/silica for 10 min. The resulting slurry was loaded onto
a short KF/silica column, and flushed with petrol then EtOAc, and the EtOAc
fraction was concentrated in vacuo to afford a yellow gum. The gum was
purified by flash silica chromatography, elution gradient 3:1 petrol/EtOAc to
EtOAc, the pure fractions were then concentrated in vacuo to afford compound
6 (0.24 g, 44%) and compound 8 (0.14 g, 26%), both as yellow gums.
10. 1,2-Dibromobut-2-ene was prepared in four-steps from crotonaldehyde. The
stereochemistry of the C@C bond was tentatively assigned as Z on the basis of a
1H NOESY experiment.
The synthesis of a de-methoxy mitragynine analogue 22 was
also explored (Scheme 6). Treatment of the vinyl bromide 20 with
tributyltin hydride afforded a mixture of products, including the
direct reduction diene 21, the desired cyclised product, octahydro-
quinolizine 22 and an unexpected pentacyclic-bridged system 23.
The pentacyclic-bridged system is proposed to occur via a 5-exo
cyclisation of the initial vinyl radical onto the indole ring, followed
by a second 5-exo cyclisation onto the a
,b-unsaturated ester.13
It has been shown that ( )-protoemetinol (3), its 3-epi-isomer
epi-3 and 3-desmethyl derivatives 19 and epi-19 can be prepared
in just five linear steps from dihydroisoquinoline 10. This repre-
sents the quickest reported approach to these compounds, which
are isolated in good to moderate yield. For example, 3-epi-3-desm-
ethyl protoemetinol (epi-19) was isolated in an excellent overall
yield of 32%. Also, because we found that resolution of ( )-bromide
11 could be achieved using chiral HPLC,14 it was possible to use
this approach to access both enantiomeric series of the alkaloids.
Acknowledgements
We thank AstraZeneca and the EPSRC for the funding.
References and notes
1. (a) Fuji, T.; Ohba, M.; Yoshifuji, S. Heterocycles 1988, 27, 1009–1033; (b)
Michael, J. P. Nat. Prod. Rep. 1994, 17–39.
2. Tan, G. T.; Kinghorn, A. D.; Hughes, S. H.; Pezzuto, J. M. J. Biol. Chem. 1991, 266,
23529–23536.
3. (a) Takayama, H.; Ishikawa, H.; Kurihara, M.; Kitajima, M.; Aimi, N.; Ponglux,
D.; Koyama, F.; Matsumoto, K.; Moriyama, T.; Yamamoto, L. T.; Watanabe, K.;
Murayama, T.; Horie, S. J. Med. Chem. 2002, 45, 1949–1956; (b) Takayama, H.
Chem. Pharm. Bull. 2004, 52, 916–928; (c) Takayama, H.; Kitajima, M.; Kogure,
N. Curr. Org. Chem. 2005, 9, 1445–1464; (d) Matsumoto, K.; Takayama, H.;
Ishikawa, H.; Aimi, N.; Ponglux, D.; Watanabe, K.; Horie, S. Life Sci. 2006, 78,
2265–2271; (e) Ma, J.; Yin, W.; Zhou, H.; Cook, J. M. Org. Lett. 2007, 9, 3491–
3494.
11. The lower yield of 12 may be explained by a competing 1,5-H transfer reaction
of the radical formed on 6-exo cyclisation. Reduction of the resulting allylic
radical could produce a terminal alkene, which is supported by the presence of
new signals between 5 and 6 ppm in the 1H NMR spectrum of the crude
product.
12. Crabtree, R. Acc. Chem. Res. 1979, 12, 331–337.
13. For the synthesis of mitragynine 2, see: Takayama, H.; Maeda, M.;
Ohbayashi, S.; Kitajima, M.; Sakai, S-i.; Aimi, N. Tetrahedron Lett. 1995,
36, 9337–9340.
14. HPLC was carried out at AstraZeneca, Alderley Park, by Michael Hatton on a
Rainin prep (200 ml heads) instrument with a Merck 100 mm 20
lm Chiralpak
AS column, using IsoHex/IPA/Et3N 80/20/0.1 as the mobile phase.
4. For the synthesis of protoemetinol (3) and related compounds, and the use of
these compounds in alkaloid synthesis, see: (a) Chang, J.-K.; Chang, B.-R.;