LETTER
A Concise Synthesis of Tashiromine
2529
In summary, we have developed a six-step synthesis of
tashiromine from succinimide (19% overall yield). The
key finding in this synthesis is that olefin cross-metathesis
is a useful route to nitrogen-containing functionalised al-
lylsilanes. This approach should not only find utility as an
alternative to linear allylsilane precursors such as 5 but
also in the preparation of more highly substituted variants
which have found use in synthesis.23 Further applications
of this chemistry from our own laboratory will be reported
in due course.
O
O
NH
O
i
N
O
7
ii
O
H
iv
N
Me3Si
N
Y
X
8 X,Y = O
4 X = H, Y = OH
2
O
iii
Scheme 2 Reagents and conditions: i, NaH, 5-bromopent-1-ene,
DMF, r.t., 98%; ii, 5% [(H2Imes)(Pcy3)Cl2Ru=CHPh], 4 equiv 6,
CH2Cl2, reflux, 73%; iii, NaBH4, EtOH, 2 N HCl, 86%; iv, TFA,
CH2Cl2, r.t., 85%
Synthesis of Compound 8
1-Pent-4-enylpyrrolidine-2,5-dione (7. 0.74 g, 4.4 mmol) was dis-
solved in anhyd degassed CH2Cl2 (70 mL, 0.063 M) and was heated
to reflux for 30 min. Allyltrimethylsilane (6, 2.8 mL, 17.7 mmol)
was added via
a syringe followed by the addition of
[(H2Imes)(Pcy3)Cl2Ru=CHPh] (0.19 g, 0.22 mmol, 5 mol%). The
solution became a rose colour and was heated to reflux for 20 h by
which time the colour had changed to a golden brown. The reaction
vessel was opened to air and stirred for 3 h. The volume of solvent
was reduced in vacuo to 2 mL and this solution flushed through a
plug of silica gel with CH2Cl2 (50 mL) and 16% EtOAc in hexane
(100 mL). The solvents were removed in vacuo and the residue pu-
rified by column chromatography (petrol ether–EtOAc, 6:4) to yield
8 (0.82 g of an inseparable 3:1 mixture of E- and Z-isomers, 73%)
as a colourless oil.
H
N
SiMe3
2
H
O
Figure 2 Model for transition-state for cyclisation leading to 2
With 2 in hand, we turned our attention to its conversion
to tashiromine (1). Initial attempts at oxidative cleavage
of the vinyl group to give aldehyde 9, either by ozonolysis
(with either triphenylphosphine or dimethyl sulfide work
up) or dihydroxylation–periodate cleavage were unsuc-
cessful, yielding complex mixtures in which 9 was at best
a minor component. Aldehyde 9 is potentially subject to
decomposition through retro-Mannich pathways, and so
instead we elected to employ a reductive (sodium borohy-
dride) work up to the ozonolysis reaction, which success-
fully provided alcohol 10 (Scheme 3). Lithium aluminium
hydride reduction of crude 10 provided tashiromine (1) in
36% yield over the two steps. The spectral data were in ac-
cord with those reported in the literature7–17 and, further,
differ considerably from the known diastereomeric epi-
tashiromine.14
Analytical Data
IR (film): 2952, 2899 (m, aliphatics), 1775, 1701 (CO–NH–CO)
cm–1.
NMR data for the major E-stereoisomer: 1H NMR (300 MHz,
CDCl3): d = 5.45 (1 H, dtt, J = 14.8, 7.2, 1.5 Hz), 5.22 (1 H, m), 3.51
(2 H, t, J = 7.7 Hz), 2.71 (4 H, s), 2.01 (2 H, q, J = 7.2 Hz), 1.62 (2
H, quintet, J = 7.7 Hz), 1.42 (2 H, d, J = 7.2 Hz), 0.00 (9 H, s). 13
C
NMR (75 MHz, CDCl3): d = 179.3, 129.3, 129.0, 40.5, 32.1, 30.1,
29.8, 24.7, 0.0.
1
NMR signals for the minor Z-stereoisomer: H NMR (300 MHz,
CDCl3): d = 3.56 (2 H), 2.70 (4 H, s), 1.47 (2 H, d, J = 8.7 Hz), 0.01
(9 H, s). 13C NMR (75 MHz, CDCl3): d = 128.6, 127.7, 40.6, 29.6,
26.4, 24.7, 20.5, 0.2.
LRMS (ES): m/z (%) = 253.9 (12) [M + H]+, 241.8 (33), 209.8
(100). Data for Z-isomer corresponds to that quoted in the litera-
ture.18
O
H
N
H
N
Acknowledgment
i or ii
We thank the EPSRC for a studentship (ADM) and Pfizer and
Merck for generous unrestricted research funding.
O
2
9
O
iii
References
(1) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97,
2063.
HO
HO
H
N
(2) (a) Cassidy, J. H.; Marsden, S. P. Synlett 1997, 1411.
(b) Miles, S. M.; Marsden, S. P.; Leatherbarrow, R. J.;
Coates, W. J. J. Org. Chem. 2004, 69, 6874. (c) Akindele,
T.; Marsden, S. P.; Cumming, J. G. Org. Lett. 2005, 7, 3685.
(3) Miles, S. M.; Marsden, S. P.; Leatherbarrow, R. J.; Coates,
W. J. Chem. Commun. 2004, 2292.
H
iv
N
O
10
1
Scheme 3 Reagents and conditions: i, O3, MeOH–CH2Cl2, then
either Me2S or PPh3; ii, K2OsO4·2H2O, NMO, acetone–H2O, then
NaIO4, THF, phosphate buffer; iii, ozone, MeOH–CH2Cl2, then
NaBH4; iv) LiAlH4, THF, reflux, 36% over two steps
Synlett 2005, No. 16, 2528–2530 © Thieme Stuttgart · New York