SCHEME 2. Oxidation of Tetrahydrofuran 4b into
Furanonea
SCHEME 4. Synthesis of Amphiasterin B4 from 6d
a Reagents and conditions: (a) TBDMS-Cl (4.2 equiv), imidazole
(3 equiv), DMF, rt (80%). (b) PCC/Celite, Ph-H, ∆ (70%). (c) HF·pyr,
CH3CN, rt, 12h (71%).
SCHEME 3. Formation of Malonate 6d
tetrahydrofurans represents a new example of desymmetrization
of tris(hydroxymethyl)methane derivatives.22
To access the core structure of amphiasterins, the tetrahy-
drofuran subunit was selectively oxidized to 2-furanone. Com-
pound 4b was used as a model and the two hydroxy groups
were first protected as TBDMS ether by using a well-established
method.23 A large number of oxidants already have been
reported for the formation of butyrolactones from the parent
cyclic ethers.24-27 Among all of them, PCC adsorbed on Celite25
led to the expected structure 10b in 70% yield. Treated with an
excess of HF ·pyr in acetonitrile, the TBDMS ether was cleaved
to furnish the fully deprotected structure 3b in an acceptable
yield (Scheme 2).
were separated by chromatography on silica. Deprotection of
the silyl ethers delivered amphiasterin 1c and its epimer 1c′.
In conclusion, we have achieved the first total synthesis of
amphiasterin B4 in 10 steps from propionaldehyde and with a
3.3% overall yield. The strategy was based on a highly regio-
and stereoselective cyclization of epoxydiols, the reaction
proceeding with desymmetrization of the starting material. Work
is now underway to complete the enantioselective synthesis of
other members of this family of natural products.
Experimental Section
The above sequence was next applied to the first synthesis
of amphiasterin B4. The R,ꢀ-unsaturated diester 6d was prepared
according to Scheme 3. Hydrazone 11 obtained by condensation
of N,N-dimethylhydrazine with propionaldehyde was conve-
niently alkylated28 with commercially available 1-bromopen-
tadecane and hydrolyzed under acidic conditions into 13.29 This
aldehyde reacted with diethylmalonate under conditions already
used for 6a-c to deliver the corresponding diester 6d.
The irradiation of diester 6d under conditions as described
above furnished an unseparable 1:1 mixture of (E) and (Z)-ꢀ,γ-
isomers 7d/7d′. 1,3-Diols 8d-d′ were obtained by reduction
with LiAlH4 in ether. Epoxidation of the double bond was
conveniently achieved by treatment with m-CPBA. The transient
oxiranes led smoothly to an unseparable 1:1 mixture of the two
tetrahydrofurans 4d and 4d′ in 63% yield (Scheme 4). As
mentioned before, the two hydroxy groups were etherified under
standard conditions. By treatment with PCC on Celite, the two
diastereoisomers 9d/9d′ were oxidized into the corresponding
butyrolactones 10d and 10d′. Fortunately, these two substances
Formation of tetrahydrofurans 4d/4d′: To a solution of diols
8d/8d′ (0.052 g, 0.16 mmol) in dichloromethane (5 mL) was added
at 0 °C m-CPBA (0.090 g, 0.51 mmol). After stirring overnight at
rt, the resulting mixture was hydrolyzed and extracted with ethyl
acetate. The organic layers were washed with brine and dried over
MgSO4. Solvents were removed by concentration. After flash-
chromatography on silica (eluent: methanol/dichloromethane 5/95),
an unseparable 1:1 mixture of tetrahydrofurans 4d and 4d′ (0.034
1
g, 0.10 mmol) was obtained. Yield ) 63%. H NMR (300 MHz,
CDCl3) δ 0.85 (3H, t, J ) 6.7 Hz, H22), 1.13 (1.5H, s, isomer 4d′),
1.27 (1.5H, s, isomer 4d), 1.28-1.59 (28H, m), 2.40-2.49 (1H,
m), 3.45 (1H, dd, J ) 8.6 and 19.5 Hz), 3.70-3.86 (3H, m), 3.97
(1H, dd, J ) 8.6 et 17.1 Hz); 13C NMR (75 MHz, CDCl3) δ 14.5
(CH3), 19.3 (CH3), 23.0, 27.3, 29.7-30.8, 32.3, 33.6 (CH2, C20),
40.4, 48.9, 64.8, 65.9, 81.4, 83.5; HRMS (CI) m/z calcd for
C21H42O3 + H 343.3212, found 343.3208.
Amphiasterin B (1c): 1H NMR (300 MHz, CDCl3) δ 0.90
(3H, t, J ) 6.9 Hz), 1.17-1.34 (24H, m), 1.37 (3H, s), 1.40-1.50
(2H, m), 1.68-1.79 (2H, m), 2.85 (1H, dt, J ) 9.9 and 4.9 Hz),
3.98 (1H, dd, JAB ) 11.3 Hz, J ) 4.6 Hz), 4.06 (1H, dd, JAB
)
11.3 Hz, J ) 5.0 Hz), 4.34 (1H, d, J ) 9.9 Hz); 13C NMR (75
MHz, CDCl3) δ 14.5, 19.4, 23.1, 23.9, 29.8-30.3 (10CH2), 32.3,
40.3, 49.8, 59.7, 75.1, 87.4, 174.6; HRMS (ES) m/z calcd for
C21H40O4 + Na 379.2824, found 379.2820; IR ν 3377, 2914, 1759,
(22) (a) Guanti, G.; Banfi, L.; Narisano, E. J. Org. Chem. 1992, 57, 1540.
(b) Guanti, G.; Riva, R. Tetrahedron Lett. 2003, 44, 357.
(23) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
(24) Jung, M. E.; Karama, U.; Marquez, R. J. Org. Chem. 1999, 64, 663.
(25) Piancatelli, G. In Handbook of reagents for organic synthesis-Oxidizing
and reducing agents; Burke, S. D., Danheiser, R. L., Eds.; Wiley,: Chichester,
UK, 1999.
1469, 1265, 1099, 936, 739 cm-1
.
Acknowledgment. H.S. thanks the Syrian Government for
a Ph.D. grant. We are indebted to Professor A. Zampella
(26) Cornely, J.; Ham, L. M. S.; Meade, D. E.; Dragojlovic, V. Green Chem.
2003, 5, 34.
J. Org. Chem. Vol. 74, No. 5, 2009 2259