Synthesis of the alkaloids (±)-oxomaritidine and (±)-epimaritidine using an orchestrated multi-step sequence of polymer supported reagents

Article abstract of DOI:10.1039/a901798d

The concise synthesis of the alkaloids (±)-oxomaritidine 1 and (±)-epimaritidine 2 in high yield are described, which employs a sequence of five- and six-step reactions respectively, using solely polymer supported reagents in an orchestrated successive ma

Full text of DOI:10.1039/a901798d

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Synthesis of the alkaloids ( )-oxomaritidine and ( )-epimaritidine
using an orchestrated multi-step sequence of polymer supported
reagents
Steven V. Ley,*a Olivier Schucht,a Andrew W. Thomasa and P. John Murrayb
a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW
b GlaxoWellcome Cambridge Chemistry Laboratory, University Chemical Laboratories,
Lensfield Road, Cambridge, UK CB2 1EW
Received (in Cambridge) 8th March 1999, Accepted 24th March 1999
The concise synthesis of the alkaloids ( )-oxomaritidine 1 and ( )-epimaritidine 2 in high yield are described,
which employs a sequence of five- and six-step reactions respectively, using solely polymer supported reagents
in an orchestrated successive manner.
We have recently challenged the current dogma of preparing
compound libraries on solid supports preferring instead to
combine the advantages of solution phase chemistry with the
versatility and convenience of polymer supported reagents.1
Here, we demonstrate that these concepts are readily adapted to
natural product synthesis, by effecting the clean and efficient
preparation of the alkaloids ( )-oxomaritidine 1 and ( )-epi-
maritidine 2. These compounds were obtained, in a linear
sequence of reactions, using five and six polymer supported
reagents respectively, with work-up simply involving filtration
followed by evaporation of solvent. To the best of our knowl-
edge, this report and the following paper2 constitute the first
total syntheses of natural products using a sequence of polymer
supported reagents.
Following a modification of a route recently described by
Kita,3 which allowed access to galanthamine-type amaryl-
lidaceae alkaloids, we have devised a complementary route
using polymer supported reagents in order to accomplish these
syntheses. The first step (Scheme 1) employed polymer sup-
ported perruthenate (PSP) reagent4 which converted the alco-
hol 3 into the aldehyde 4 in essentially quantitative yield. This
aldehyde was reacted with the primary amine 5 under reductive
amination conditions to generate the norbelladine derivative 6
in excellent yield, any by-product or unreacted materials, in this
step, being absorbed onto the polymer which was simply filtered
off at the end of the reaction. Optimum conditions for this step
involved adding the polymer supported borohydride5 reagent
to a solution of the pre-formed imine. Alternatively, performing
reactions using polymer supported cyanoborohydride,6 under
conditions we had developed previously,1c resulted in similar
clean and quantitative conversions to the secondary amine 6.
Subsequently, trifluoroacetylation of this amine 6 was effected
by treatment with trifluoroacetic anhydride using polymer
bound aminomethyl pyridine7 to give the amide 7 in 99% yield.
The intramolecular phenolic oxidative cyclisation of 7 to the
spirodienone 8 was best achieved using polymer supported
(diacetoxyiodo)benzene8 in trifluoroethanol, although reactions
with polymer supported [bis(trifluoroacetoxyiodo)]benzene9
reagent gave comparable results. This oxidation reaction gave
the desired regioisomeric para–paraЈ coupled product 8 in 70%
yield with no other products being detected by LC-MS fol-
lowing filtration and evaporation. Finally, treatment of the
trifluoroacetamide 8 with polymer supported carbonate10 in
methanol resulted in rapid deprotection and spontaneous
intramolecular 1,4-addition to give ( )-oxomaritidine 1 as a
crystalline product in 98% yield which was identical to the
previously prepared material11 by mp, NMR and MS
analysis. Reduction of the carbonyl group in 1 using polymer
supported borohydride, in the presence of a catalytic quantity
of NiCl2ؒ6H2O or Cu(SO4)2ؒ5H2O12 in methanol, provided
access to the natural product ( )-epimaritidine 2 in high
yield, also identical to authentic material11 by NMR and MS
analysis.
The route described above could be readily modified to pre-
pare other novel analogues of 1 and 2 or alternatively scaled-up
to give material which would be highly suitable for further
combinatorial change. In addition, we have prepared two other
members of the amaryllidacae family of alkaloids, and in the
process confirmed the stereochemical outcome of the reduction
step in the transformation of ( )-1 into ( )-2. Initially, catalytic
hydrogenation of 1 provided ( )-dihydrooxomaritidine 9 in 95%
yield. This was further reduced with polymer supported boro-
hydride in methanol to afford ( )-epidihydromaritidine 10. Sub-
sequent catalytic hydrogenation of 2 followed by filtration
through a small pad of Celite, as in the transformation from 1
to 9, gave the same product 10. Spectroscopic data were con-
sistent with those previously published13 and the relative
stereochemistry of the hydroxy group was confirmed by NOE
measurements.
In the following paper2 a longer and more elaborate reaction
sequence is described which opens up even greater opportun-
ities for the use of polymer supported reagents in organic
synthesis.
In summary, the preparation of two natural products ( )-
oxomaritidine 1 and ( )-epimaritidine 2 has been achieved in
excellent overall yields and high purity. The reaction sequences,
which provided these compounds, were conducted entirely
using polymer supported reagents without recourse to con-
ventional work up procedures or the need for chromatographic
purification. Moreover this approach has considerable potential
for the preparation of other members of the amaryllidaceae
family and following our linear route ( )-dihydrooxomaritidine
9 and ( )-epidihydromaritidine 10 were prepared in six and
seven steps respectively without chromatography.
J. Chem. Soc., Perkin Trans. 1, 1999, 1251–1252
1251

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_
CHO
+
OH
NMe3RuO4
MeO
MeO
HO
HO
CH2Cl2
100%
OMe
OMe
_
+
N
N
NMe3BH4
4
3
N
H
N
HO
MeOH
90%
(CF3CO)2O
99%
MeO
O
CF3
MeO
OMe
OMe
H2N
6
7
5
O
I (OCOCX3)2
OH
_
+
O
+
NEt3((CO3)2–
)
NMe3BH4
1
2 MeO
MeO
MeO
X = H or F
MeO
MeO
H
H
CuSO4 or NiCl2
MeOH
CF3CH2OH
70%
MeOH
100%
N
N
N
MeO
CF3
80%
O
(±)-1
(±)-2
8
H2 / Pd / C
MeOH
H2 / Pd / C
MeOH
95%
99%
OH
O
_
+
NMe3BH4
MeO
MeO
MeO
MeO
H
H
MeOH
98%
N
N
(±)-9
(±)-10
Scheme 1
6 R. O. Hutchins. N. R. Natale and I. M. Taffer, J. Chem. Soc., Chem.
Commun., 1978, 1088.
7 S. Shinkai, H. Tsuji, Y. Hara and O. Manabe, Bull. Chem. Soc. Jpn.,
1981, 54, 631.
8 (a) S. V. Ley, A. W. Thomas and H. Finch, J. Chem. Soc., Perkin
Trans. 1, 1999, 669; (b) H. Toga, G. Nogami and M. Yokoyama,
Synlett, 1998, 535.
Acknowledgements
We gratefully acknowledge financial support from the BP
endowment and the Novartis Research Fellowship (to S. V. L.)
and Glaxo Wellcome (for a Postdoctoral Fellowship to
A. W. T.).
9 S. V. Ley, O. Schucht and A. W. Thomas, personal communication.
10 Macroporous triethylammonium methylpolystyrene carbonate resin
(‘carbonate on polystyrene’) was purchased from Argonaut
Technologies. The trimethylammonium carbonate resin has been
prepared and used in synthesis; G. Cardillo, M. Orena, G. Porzi and
S. Sandri, Synthesis, 1981, 793.
References
1 (a) B. Hinzen and S. V. Ley, J. Chem. Soc., Perkin Trans. 1, 1998, 1;
(b) F. Haunert, M. H. Bolli, B. Hinzen and S. V. Ley, J. Chem. Soc.,
Perkin Trans. 1, 1998, 2235; (c) S. V. Ley, M. H. Bolli, B. Hinzen,
A.-G. Gervois and B. J. Hall, J. Chem. Soc., Perkin Trans. 1, 1998,
2239; (d) M. H. Bolli and S. V. Ley, J. Chem. Soc., Perkin Trans. 1,
1998, 2243; (e) J. Habermann, S. V. Ley and J. S. Scott, J. Chem. Soc.,
Perkin Trans. 1, 1998, 3127; ( f ) M. Caldarelli, J. Habermann and
S. V. Ley, J. Chem. Soc., Perkin Trans. 1, 1999, 107.
11 M. A. Schwartz and R. A. Holton, J. Am. Chem. Soc., 1970, 92,
1090.
12 T. B. Sim and N. M. Yoon, Bull. Chem. Soc. Jpn., 1997, 70, 1101; in
this paper cyclohexenone was reported to be reduced to cyclo-
hexanol but in our case the double bond of 1 remained unaffected
after a reaction time of 30 min.
2 J. Habermann, S. V. Ley and J. S. Scott, following paper.
3 Y. Kita, M. Arisawa, M. Gyoten, M. Nakajima, R. Hamada,
H. Tohma and T. Takada, J. Org. Chem., 1998, 63, 6625.
13 J. B. P. A. Wunberg and W. N. Speckamp, Tetrahedron, 1978, 34,
2579.
4 (a) B. Hinzen and S. V. Ley, J. Chem. Soc., Perkin Trans. 1, 1997,
1907; (b) R. Lenz and S. V. Ley, J. Chem. Soc., Perkin Trans. 1, 1997,
3291; (c) B. Hinzen, R. Lenz and S. V. Ley, Synthesis, 1998, 977.
5 H. W. Gibson and F. C. Bailey, J. Chem. Soc., Chem. Commun.,
1977, 815.
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J. Chem. Soc., Perkin Trans. 1, 1999, 1251–1252