M. N. Kenworthy et al. / Tetrahedron Letters 45 (2004) 6661–6664
6663
H O-MeOH
2
8:1
LiOH
Ph P( O) OC( O) R
2
O
HO
HN
HO
Ref lux
84%
NEt
THF
3
O
N
H
H N
2
OH
OH
OH
15
11
16a 70%
O
O
O
16b 72%
16c 89%
16d 74%
O
O
3 83%
Scheme 4. Synthesis of novel scyphostatin analogues.
Due to the failure of our first approach described in
Scheme 3, we investigated an alternative strategy for
the transformation of cyclic carbamate 11 into scyphost-
atin analogues. To this end, the direct hydrolysis of the
cyclic carbamate 11 was explored. We eventually found
that this could be achieved by heating 11 in aqueous
methanol with LiOH,12 delivering aminodiol 15 in 84%
yield. Direct amide formation from aminodiol 15 was
then carried out using the diphenylphosphinic chlo-
ride—derived anhydrides of various acids to give the
analogues 16a–d and 3 in good yield, with no protection
needed during the procedure. In this sequence, we used
commercially available crotonic acid, sorbic acid and
palmitic acid, along with octatrienoic acid13 and the nat-
ural scyphostatin side chain recently synthesised by our
group.3 In this way, a wide variety of side-chain struc-
tural analogues are available, from mono-unsaturated
16a to the more complex 16d and 3.14 It should be noted
that compound 3 is the first scyphostatin analogue
known, which possesses the complete southern hemi-
sphere functionality, that is, the aminodiol unit
acylated with the enantiomerically pure, natural lipo-
philic acid. These analogues will be useful in future
biological tests to understand further the effect of
structure on inhibitory activity (Scheme 4).
Acknowledgements
We gratefully acknowledge Dr. S. Handa (University of
Leicester) for unpublished experimental details. We
would also like to thank Elsevier (M.N.K.) and the Uni-
versity of York (G.D.M) for postdoctoral support.
References and notes
1. Tanaka, M.; Nara, F.; Suzuki-Konagai, K.; Hosoya, T.;
Ogita, T. J. Am. Chem. Soc. 1997, 119, 7871–7872.
2. Hoye, T. R.; Tennakoon, M. A. Org. Lett. 2000, 2,
1481–1483.
3. McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett. 2004,
45, 2551–2554.
4. (a) Gurjar, M. K.; Hotha, S. Heterocycles 2000, 50,
1885–1889; (b) Izuhara, T.; Katoh, T. Tetrahedron Lett.
2000, 41, 7651–7655; (c) Izuhara, T.; Katoh, T. Org. Lett.
2001, 3, 1653–1656; (d) Fujioka, H.; Kotoku, N.; Sawama,
Y.; Kita, Y. Tetrahedron Lett. 2002, 43, 4825–4828; (e)
Takagi, R.; Miyanaga, W.; Tamura, Y.; Ohkata, K. Chem.
Commun. 2002, 2096–2097.
5. (a) Runcie, K.; Taylor, R. J. K. Org. Lett. 2001, 3,
3237–3239; (b) Murray, L. M.; OÕBrien, P.; Taylor, R. J.
K. Org. Lett. 2003, 5, 1943–1946.
6. (a) Arenz, C.; Giannis, A. Angew. Chem., Int. Ed. 2000, 39,
1440–1442; (b) Arenz, C.; Giannis, A. Eur. J. Org. Chem.
2001, 137–140; (c) Arenz, C.; Gartner, M.; Wacholowski,
V.; Giannis, A. Bioorg. Med. Chem. 2001, 9, 2901–2904;
(d) Pitsinos, E. N.; Wacholowski, V.; Karaliota, S.; Rigou,
C.; Couladouros, E. A.; Giannis, A. Chem. Biochem. 2003,
4, 1223–1225.
7. For a recent review see: OÕBrien, P. Angew. Chem., Int. Ed.
1999, 38, 326–329.
8. Angelaud, R.; Babot, O.; Charvat, T.; Landais, Y. J. Org.
Chem. 1999, 64, 9613–9624.
In conclusion, we have applied the TA reaction of a
homo-allylic tertiary alcohol 9 to the synthesis of a model
system of the core of scyphostatin (1). In this way we
were able to obtain the correct b-amino alcohol regio-
chemistry for the natural compound. We then used this
system to investigate a strategy for incorporation of the
unsaturated amide side chain into a late-stage synthetic
intermediate. Also, using our model system, we synthe-
sised five novel scyphostatin analogues 16a–d and 3,
which could give insights into the mode of action of scyp-
hostatin in future biological tests. We are currently
extending this methodology to evaluate its use as an
end-game strategy for the synthesis of scyphostatin itself.
9. (a) Donohoe, T. J.; Johnson, P. D.; Helliwell, M.; Keenan,
M. Chem. Commun. 2001, 2078–2079; (b) Donohoe, T. J.;
Johnson, P. D.; Cowley, A.; Keenan, M. J. Am. Chem.
Soc. 2002, 124, 12934–12935; (c) Donohoe, T. J.; Johnson,
P. D.; Pye, R. J. Org. Biomol. Chem. 2003, 1, 2025–2028.