Turk et al.
sodium hydroxide (3 M, 2 mL) and hydrogen peroxide (30%, 1
mL). The partially frozen mixture was removed from the cold
bath and stirred for 18 h. The reaction was diluted with H2O
and extracted with diethyl ether. The combined organic
extracts were dried and concentrated to give a colorless oil that
was purified by flash chromatography to yield (S,R,R)-7 as a
colorless oil (400 mg, 75%, 96% de): 1H NMR (500 MHz,
CDCl3) δ 5.76 (m, 1H), 5.12 (m, 2H), 3.13 (t, J ) 6.0 Hz, 1H),
2.37 (ddq, J ) 7.0, 7.0, 7.0 Hz, 1H), 1.65 (m, 2H), 1.26 (m,
1H), 1.13 (m, 1H), 1.00 (d, J ) 6.9 Hz, 3H), 0.92 (d, J ) 6.7
Combining this fact with the conclusions drawn from the
1H NMR spectra unambiguously defines the assignment
of the 3-hydroxy-2,4,6-trimethylheptanoyl residue of cal-
lipeltin A as R,R,R.
Con clu sion
In summary, we have synthesized four diastereomers
of TMHEA (6 steps, 59% average yield), the fatty acid
fragment of callipeltin A and D, using an efficient and
flexible route. Comparison of the 1H NMR, 13C NMR, and
optical rotation data of the natural fragment with all its
diastereomers unambiguously verifies the configurational
assignment of the natural isomer as R,R,R.
Hz, 3H), 0.91 (d, J ) 6.5 Hz, 3H), 0.86 (d, J ) 6.6 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) δ 140.7, 116.2, 79.5, 41.2, 39.5, 33.0,
25.3, 24.4, 21.3, 16.9, 16.8; IR (CHCl3) 3048, 2959, 1705, 1462
cm-1; [R] +21.8 (c 0.7, CHCl3). Anal. Calcd for C11H22O‚
0.25H2O: C, 75.58; H, 12.98. Found: C, 75.32; H, 13.35.
(2R,3R,4R)-2,4,6-Tr im eth yl-3-ben zyloxyh ep ta n oic Acid
(9a ). To a stirring solution of (S,R,R)-8a (617 mg, 2.37 mmol)
in dioxane (3.5 mL) and H2O (3.5 mL) was added 4-methyl-
morpholine N-oxide (416 mg, 3.55 mmol) and osmium tetra-
oxide (4% in H2O, 302 µL, 95 µmol). After 1 h, NaIO4 (759 mg,
3.55 mmol) was added, and the suspension was stirred at room
temperature for 1.5 h. The reaction mixture was cooled to 0
°C, and sodium chlorite (857 mg, 9.48 mmol) and sulfamic acid
(920 mg, 9.48 mmol) were added, and the resulting bright
yellow mixture was removed from the cold bath and stirred
for 2 h. To the mixture was added 5% aqueous HCl, and the
resulting solution was extracted with CH2Cl2. The combined
organic extracts were washed with 5% aqueous HCl, dried over
MgSO4, concentrated, and purified by flash chromatography
to give (R,R,R)-9a as a colorless oil (634 mg, 96%): 1H NMR
(500 MHz, CDCl3) δ 7.31-7.26 (m, 5H), 4.58 (d, J ) 11.2 Hz,
1H), 4.55 (d, J ) 11.5 Hz, 1H), 3.48 (dd, J ) 4.1, 6.8 Hz, 1H),
2.77 (dq, J ) 7.1, 7.1 Hz, 1H), 1.81 (m, 1H), 1.59 (m, 1H), 1.17
(m, 2H), 1.17 (d, J ) 7.1 Hz, 3H), 0.94 (d, J ) 6.9 Hz, 3H),
0.87 (d, J ) 6.5 Hz, 3H), 0.80 (d, J ) 6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 179.9, 138.3, 128.4, 128.3, 127.7, 127.7,
127.6, 86.1, 74.5, 42.3, 40.6, 32.9, 25.2, 24.0, 21.4, 16.3, 14.7;
Exp er im en ta l Section
(R)-2,4-Dim eth ylp en ta n a l (6). A 50-mL round-bottomed
flask was charged with lithium aluminum hydride (95%, 262
mg, 6.55 mmol) and hexanes (6 mL), and the resulting
suspension was cooled to 0 °C. Ethyl acetate (960 µL, 9.83
mmol) was added dropwise over 1.5 h and the reaction mixture
was cooled to -78 °C. A solution of (S,S,R)-5 (790 mg, 2.85
mmol) in THF (3 mL) was added over 5 min, and the reaction
mixture was stirred at 0 °C for 1 h and transferred to a
vigorously stirring solution of 1 M HCl (50 mL) and TFA (2.5
mL). After the mixture was stirred for 10 min at room
temperature, 1 M HCl (65 mL) was added, and the solution
was extracted with diethyl ether. The combined organic layers
were neutralized by the slow addition of saturated aqueous
NaHCO3. The aqueous layer was separated and extracted
with diethyl ether. The combined organic layers were dried
(MgSO4), passed through a short plug of silica, and concen-
trated to give (R)-6 (280 mg, 86%) as a volatile, colorless liquid
that was used in the following step without further purifica-
tion: 1H NMR (500 MHz, CDCl3) δ 9.60 (d, J ) 1.9 Hz, 1H),
2.41 (ddq, J ) 4.2, 4.2, 4.2 Hz), 1.63 (m, 1H), 1.59 (m, 1H),
1.20 (m, 1H), 1.08 (d, J ) 6.9 Hz, 3H), 0.93 (d, J ) 6.5 Hz,
3H), 0.90 (d, J ) 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
205.4, 44.4, 39.7, 25.5, 22.9, 22.2, 20.6, 13.7.
IR (CHCl3) 3055, 2960, 1752, 1709, 1457 cm-1; [R]25 +14.9 (c
D
0.2, CHCl3). Anal. Calcd for C17H26O3‚0.5H2O: C, 71.49; H,
9.46. Found: C, 71.27, H, 9.71.
Ack n ow led gm en t. We thank Prof. Maria D’Auria
for helpful discussions and spectra of the natural
product. We also gratefully acknowledge the National
Institute of Allergy and Infectious Diseases (NIH AI-
50888) for financial support.
(3S,4R,5R)-3,5,7-Tr im eth ylocten -4-ol (7). A solution of
potassium tert-butoxide in THF (1.0 M, 4.89 mL, 4.89 mmol)
and THF (5 mL) was cooled to -78 °C, and trans-2-butene
(0.60 mL, 6.3 mmol) was added, followed by n-butyllithium
(2.50 M, 1.96 mL, 4.73 mmol). The resulting bright yellow
solution was stirred at -78 °C for 2 min and -57 °C for 10
min. The reaction was re-cooled to -78 °C, and a solution of
(-)-B-methoxydiisopinocampheylborane (1.55 g, 4.89 mmol) in
THF (3 mL) was added. The reaction was stirred for 1 h, and
BF3‚OEt2 (0.614 mL, 4.89 mmol) was added followed by a pre-
cooled (-78 °C) solution of (R)-6 (360 mg, 3.15 mmol) in THF
(3 mL). The resulting solution was stirred at -78 °C for 4 h,
and the reaction was quenched by the slow addition of aqueous
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental descriptions of transformations not included in the
Experimental Section and characterization for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O034738L
7844 J . Org. Chem., Vol. 68, No. 20, 2003