Towards the total synthesis of tangutorine by intramolecular Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2005.09.058

The syntheses of 3,5-disubstituted-2-sulfolenes, and their participation in Pictet-Spengler reactions to give precursors of tangutorine, are described.

Full text of DOI:10.1016/j.tetlet.2005.09.058

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8053–8056
Towards the total synthesis of tangutorine by intramolecular
Diels–Alder reaction
James A. Wilkinson,a,* Nicolas Ardes-Guisot,a Sylvie Duckia and John Leonardb
aCentre for Drug Design, Biosciences Research Institute, Cockcroft Building, University of Salford, Salford M5 4WT, UK
bAstraZeneca Process R+D, Silk Road, Macclesfield, Cheshire SK10 2NG, UK
Received 29 June 2005; revised 1 September 2005; accepted 9 September 2005
Available online 26 September 2005
Abstract—The syntheses of 3,5-disubstituted-2-sulfolenes, and their participation in Pictet–Spengler reactions to give precursors of
tangutorine, are described.
Ó 2005 Elsevier Ltd. All rights reserved.
Tangutorine is an alkaloid isolated from the leaves of
Nitraria tangutorum, a Chinese plant with some impor-
tance in local medicine.1 Significant biological activity
has recently been reported.2 It has been the subject of
some synthetic attention including total synthesis.3
made to extrude SO2 in one pot.4 Pictet–Spengler dis-
connection of 2/3 gives a tryptophan ester and either
aldehyde 4 or 5. The stereochemistry of the Diels–Alder
reaction was difficult to predict with any degree of con-
fidence as literature precedent is in short supply and
simple models were inconclusive. It is well known
that the stereochemistry of the carboline 1-position
can be adjusted if necessary and it was felt that the first-
formed product, an unsaturated ester would also allow
epimerisation of the c-hydrogen with base to give the
desired trans ring junction.5
H
N
Tangutorine
N
H
H
OH
H
Our route for the synthesis of 2/3 involved forming a
tryptophan derivative bearing a masked enamine substi-
tuent and using this in the Pictet–Spengler reaction. We
chose a sulfoxide as a leaving group since this could be
eliminated with base to give an enamine, as has been
demonstrated by IshibashiÕs group, but is not so reactive
as to cause problems in earlier steps.6
Here, we report progress towards achieving a total syn-
thesis of this molecule via an inverse electron demand
intramolecular Diels–Alder (IMDA) protocol. A retro-
synthetic analysis is shown (Scheme 1). After a trivial
functional group interconversion to an ester and recon-
nection of the tryptophan-derived carboxylate, the six-
membered carbocycle disconnects by the key IMDA
step to give an electron-deficient diene and an enamine
in 1. It was felt that a direct Pictet–Spengler disconnec-
tion of 1 would lead to a diene aldehyde, which would be
difficult to synthesise and work with and hence the next
retrosynthetic step gives a sulfolene (2 or 3). 3-Carbome-
thoxy-3-sulfolenes are known to extrude sulfur dioxide
giving a geometrically predictable diene on heating while
3-carbomethoxy-2-sulfolenes can be isomerised and
Reaction of tryptophan methyl ester with (2-chloro-
ethyl)-phenyl sulfide7 provided 6 in poor yield (Scheme
2).8 Conditions were found, which gave a 45% yield of
recovered starting material and virtually no doubly
alkylated product. We first carried out a model study
using benzaldehyde in order to test the feasibility of
carrying out the Pictet–Spengler reaction followed by
enamine formation. Recent work by the groups of Bai-
ley and Cook has allowed the Pictet–Spengler reaction
to be carried out with high degrees of stereoselectivity.9
Reaction of 6 with benzaldehyde gave a single diastereo-
mer 7 in 75% yield. The product was assigned as 7 by
literature precedent, since the conditions used were
Keywords: Tangutorine; Intramolecular Diels–Alder; Sulfolene; Tetra-
hydrothiophene; Xanthate radical transfer.
*
Corresponding author. Tel.: +44 161 295 4046; fax: +44 161 295
5111; e-mail: j.a.wilkinson@salford.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.058

8054
J. A. Wilkinson et al. / Tetrahedron Letters 46 (2005) 8053–8056
H
OH
N
N
H
H
H
CO2Me
MeO2C
CO2Me
N
N
CO2Me
N
O
S
H
O2
N
H
4
1
O2S
2
CO2Me
CO2Me
R = H, CO2Me
MeO2C
N
N
O
S
H
O2
5
O2S
CO2Me
3
Scheme 1.
CO2Me
N
CO2Me
NH2
CO2Me
HN
b
a
SPh
N
H
N
Ph
N
SPh
H
H
7
6
c
CO2Me
N
CO2Me
N
d
SOPh
N
H
Ph
N
Ph
H
9
8
Scheme 2. Reagents and conditions: (a) NaHCO3, (2-chloroethyl)-phenyl sulfide, MeOH, rt, 18 h, 26%; (b) PhCHO, CHCl3/AcOH 5:1, reflux, 18 h,
75%; (c) m-CPBA, CH2Cl2, 0 °C, 1 h, 66%; (d) NaHCO3, toluene, reflux, 45% conversion after 24 h.
those of Cook, which are known to give high stereo-
selectivity for trans-products when Nb is substituted,
though this particular substituent has not previously
been investigated.10 This compound was oxidised with
m-CPBA in reasonable yield to give a mixture of sulf-
oxides 8. The ratio was approximately 1.25:1 but no
attempt has been made to identify the diastereomers. On
treatment with NaHCO3 in refluxing toluene, proton and
carbon, NMR studies indicated clean conversion of the
sulfoxides to the enamine 9. The enamine was not purified.
Purification of 10 proved difficult, accounting for the
low yield. A number of alkenes were used for the addi-
tion step with the aldehyde masked as a hydroxy
group, variously protected. Generally the radical addi-
tion, under ZardÕs standard conditions, proceeded well
with good yields of products 11a and 11b obtained and
a reasonable yield of the acetate 11c. The products
were then subjected to cleavage of the xanthate and
acid-catalyzed cyclisation, which provided the dihydro-
thiophenes 12a–c. As might have been expected, the
acetate group performed poorly in this sequence but
we were slightly surprised to obtain only 49% of 12b.
It appeared that the silyl protection was largely lost
after cyclisation had occurred since an 18% yield of
alcohol 13 was also recovered. With our best protecting
group established as pivaloyl, we took 12a and gently
cleaved with methoxide to give 13, oxidised to the sul-
folene and performed a Swern oxidation to obtain our
target aldehyde 5, in just under 25% yield from the
starting olefin.
Our efforts towards the synthesis of compound 4 will be
detailed in a full paper. The methodology adopted for
the synthesis of 5 was ZardÕs xanthate radical transfer
protocol.11 This has been shown to be an excellent method
for the preparation of xanthate-substituted acetals,
themselves good precursors for 3,4-dihydrothiophenes.
The xanthate precursor 10 was prepared from methyl
methoxyacrylate in 37% overall yield (Scheme 3).

J. A. Wilkinson et al. / Tetrahedron Letters 46 (2005) 8053–8056
8055
MeO2C
O
MeO2C
O
CO2Me
a
b
S
S
Br
O
O
O
O
10
OR
c
CO2Me
CO2Me
CO2Me
O
O
O
f
d
RO
S
S
O
S
S
RO
OEt
O
12a R = Piv
89%
5
12b R = TBDPS 49%
11a R = Piv
93%
e
12c R = Ac
13 R = H
15%
11b R = TBDPS 88%
11c R = Ac
65%
Scheme 3. Reagents and conditions: (a) NBS, MeOH, 0 °C; (b) (i) NaI, Et2O, rt, 1 h; (ii) KSC(S)OEt, Et2O, 0 °C to rt, 18 h, 37% for three steps; (c)
dilauryl peroxide (16 mol %), 1,2-DCE, reflux, 2 h; (d) (i) ethylenediamine, EtOH, rt, 1 h; (ii) TFA, CH2Cl2, rt, 1 h; (e) NaOMe, MeOH, 0 °C to rt,
20 h, 70%; (f) (i) oxone, MeOH, H2O, 0 °C, 15 min, 55%; (ii) oxalyl chloride, DMSO, CH2Cl2, triethylamine, À78 °C to rt, 90%.
Pictet–Spengler reaction of 6 with aldehyde 5 gave a very
poor yield of 14 (a single diastereomer was obtained), one
problem being that the methyl ester in 5 was cleaved
under the reaction conditions (Scheme 4). The methyl
ester would also have been problematic for the later
stages of the proposed synthesis, since it would have
had to be differentiated from the tryptophan-derived ester.
but there were some idiosyncracies. While the radical
addition of the xanthate took place in very high yield,
the cleavage/cyclisation protocol was much more diffi-
cult to achieve. Conditions were found, which cleaved
the xanthate and the pivaloyl protecting group, giving
the trifluoroacetate ester of the desired product in mod-
erate yield after cyclisation. Cleavage of the trifluoroac-
etate, and oxidation to a sulfolene were straightforward
but Swern oxidation gave only a 37% isolated yield of
the aldehyde 15, which was found to be a fairly unstable
compound and had to be used immediately.
To avoid using the ester, we prepared the 3-cyano-2-sul-
folene derivative 15 (Scheme 5). The Zard chemistry fol-
lowed much the same route as for the preparation of 5
CO2Me
CO2Me
CO2Me
a
N
HN
O
S
N
H
N
SPh
SPh
H
O
O
5
6
O2S
CO2Me
14
Scheme 4. Reagents and conditions: (a) AcOH, 70 °C, 24 h, 7%.
CN
O
NC
CN
a, b
c
S
S
O
S
S
O
O
O
OPiv
PivO
O
S
OEt
CN
d
CN
O
e
F3C(OC)O
O
S
O
15
Scheme 5. Reagents and conditions: (a) NIS, MeOH, 0 °C to rt, 3 h, 88%; (b) KSC(S)OEt, Et2O, 0 °C to rt, 22 h, 47%; (c) dilaurylperoxide
(16 mol %), 1,2-DCE, reflux, 6 h, 90%; (d) (i) NaOMe, MeOH, 0 °C to rt, 24 h; (ii) Amberlite-H 120; (iii) TFA, CH2Cl2, rt, 1 h, 41% over three steps;
(e) (i) KOH, MeOH/H2O, 0 °C, 1 h, 63%; (ii) oxone, MeOH/H2O, 0 °C, 1 h, 65%; (iii) oxalyl chloride, DMSO, CH2Cl2, triethylamine, À78 °C to rt,
37%.

8056
J. A. Wilkinson et al. / Tetrahedron Letters 46 (2005) 8053–8056
2. Liu, B. P. L.; Chong, E. Y. Y.; Cheung, F. W. K.; Duan,
CO2Me
HN
CO2Me
N
J.-A.; Che, C.-T.; Liu, W. K. Biochem. Pharmacol. 2005,
70, 287–299.
a
3. Luo, S. J.; Zhao, J. R.; Zhai, H. B. J. Org. Chem. 2004, 69,
4548–4550; Luo, S. J.; Zificsak, C. A.; Hsung, R. P. Org.
Lett. 2003, 5, 4709–4712; Putkonen, T.; Tolvanen, A.;
Jokela, R. Tetrahedron 2003, 59, 8589–8595, and references
cited therein.
4. 3-Sulfolenes: (a) Leonard, J.; Fearnley, S. P.; Hague, A. B.
Tetrahedron Lett. 1997, 38, 3071–3074, and references
cited therein; Lathbury, D. C.; Parsons, P. J.; Pinto, I. J.
Chem. Soc., Chem. Commun. 1988, 81–82; 2-sulfolenes: (b)
Lusinchi, M.; Stanbury, T. V.; Zard, S. Z. Chem.
Commun. 2002, 1532–1533.
N
H
N
H
SPh
SPh
O2S
CN
16
Scheme 6. Reagents and conditions: (a) 15, CHCl3/AcOH, 5:1, reflux,
18 h, 78%.
5. Many conditions are available for this type of epimerisa-
tion. Recent examples include: Berner, M.; Tolvanen, A.;
Jokela, R. Tetrahedron Lett. 1999, 40, 7119–7122; Cox, E.
D.; Hamaher, L. K.; Li, J.; Yu, P.; Czerwinski, K. M. J.
Org. Chem. 1997, 62, 44–61; Waldmann, H.; Schmidt, G.;
Jansen, M.; Geb, J. Tetrahedron 1994, 50, 11865–11884.
6. Ishibashi, H.; Kato, I.; Takeda, Y. Chem. Commun. 2000,
1527–1528; Kato, I.; Higashimoto, M.; Tamura, O.;
Ishibashi, H. J. Org. Chem. 2003, 68, 7983–7989.
7. Russavaskaya, N. V.; Korchevin, N. A.; Alekminskaya,
O. V.; Sukhamazova, E. N.; Levanova, E. P.; Deryagina,
E. N. Russ. J. Org. Chem. 2002, 38, 1445–1448.
8. All products gave satisfactory spectral data including
accurate mass measurements of molecular ions.
9. Alberch, L.; Bailey, P. D.; Clingan, P. D. Eur. J. Org.
Chem. 2004, 1887–1890, and references cited therein; Yu,
S.; Berner, O. M.; Cook, J. M. J. Am. Chem. Soc. 2000,
122, 7827–7828.
10. Cox, E. D.; Hamaker, L. K.; Li, J.; Yu, P.; Czerwinski, K.
M.; Deng, L.; Bennett, D. W.; Cook, J. M.; Watson, W.
H.; Krawiec, M. J. Org. Chem. 1997, 62, 44–61. This gives
the required stereochemistry for the natural product at the
newly formed chiral centre.
In contrast to ester 5 the use of 15 in the Pictet–Spengler
reaction (Scheme 6) gave a 78% yield of the desired
products 16 (1.1:1 ratio of diastereomers, again a trans
stereochemistry at the carboline ring has been assumed
with a mixture of epimers at the sulfolene 5-position).
Work is ongoing to complete the synthesis via the
IMDA reaction.
Acknowledgements
We thank the EPSRC for a project studentship (N.G.).
We thank the EPSRC mass spectrometry service for
provision of accurate mass spectral data. We would also
like to thank Professor Samir Zard for helpful conversa-
tions and provision of experimental detail.
References and notes
1. Duan, J.-A.; Williams, I. D.; Che, C.-T. Tetrahedron Lett.
1999, 40, 2593–2596.
11. See Ref. 4b, also: Binot, G.; Zard, S. Z. Tetrahedron Lett.
2003, 44, 7703–7706, and references cited therein.