Progress towards the total synthesis of callipeltin A. Asymmetric synthesis of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid

Article abstract of DOI:10.1016/S0957-4166(02)00045-9

A silyl derivative of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid, a moiety present in the cyclic depsipeptide callipeltin A, was successfully synthesized from L-valine in nine steps using the Heathcock variant of the Evans aldol reaction.

Full text of DOI:10.1016/S0957-4166(02)00045-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 675–680
Progress towards the total synthesis of callipeltin A. Asymmetric
synthesis of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid
Vincent Guerlavais, Patrick J. Carroll and Madeleine M. Joullie´*
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Received 7 December 2001; accepted 15 January 2002
Abstract—A silyl derivative of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid, a moiety present in the cyclic depsipeptide
callipeltin A, was successfully synthesized from
© 2002 Published by Elsevier Science Ltd.
L
-valine in nine steps using the Heathcock variant of the Evans aldol reaction.
1. Introduction
route to a total synthesis of callipeltin A, we have
reported the synthesis of (3S,4R)-3,4-dimethylglu-
Cyclic depsipeptides have emerged as a very important
class of bioactive compounds isolated from marine
natural products.1 In 1996, Zampella et al. reported the
isolation of callipeltin A, a cyclic depsipeptide with
antiviral and antifungal properties isolated from a shal-
low water sponge of the genus Callipelta, collected in
the waters off New Caledonia (Fig. 1).2 More recently,
Luciani and co-workers have shown that callipeltin A is
a selective and powerful inhibitor of the cardiac
sodium/calcium exchanger and is therefore of great
interest as a regulator of myocardial contractility.3 En
tamine through an asymmetric Michael addition using
a camphorsultam auxiliary.4 More recently two other
groups have achieved the synthesis of this amino acid
residue.5,6 The synthesis of fully protected (2R,3R,4S)-
4,7-diamino-2,3-dihydroxyheptanoic acid has also been
reported recently.7
We now disclose a stereoselective synthesis of the silyl
ether of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic
acid 1. The synthesis involves the use of oxazolidinone
chemistry8 for both stereoselective alkylation and aldol
Figure 1. Callipeltin A and acid 1.
* Corresponding author. Fax: 215-573-9711; e-mail: mjoullie@sas.upenn.edu
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00045-9

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V. Guerla6ais et al. / Tetrahedron: Asymmetry 13 (2002) 675–680
condensation reactions.9 The retrosynthetic analysis is
shown in Fig. 2.
2).13,14 Attempts to obtain aldehyde 8 by other oxida-
tion methods (Dess–Martin periodinane,15 Collins
oxidation16) failed. The unstable aldehyde was used
without further purification in the aldol reaction. Treat-
ment with Et2AlCl in CH2Cl2 at −78°C, followed by
addition of the boron enolate of carboximide 4 pro-
duced the anti aldol product 9 in 21% yield over two
steps following crystallization. Heathcock et al.
reported that the anti aldol reaction results from the
open transition state B shown in Fig. 4, a transition
state which is favored by sterically demanding Lewis
acids such as Et2AlCl.9 The structure and stereochem-
istry of 9 were confirmed by X-ray crystallography (Fig.
5).
2. Results and discussion
The chiral auxiliary employed for the asymmetric syn-
thesis
of
(4S)-4-isopropyl-3-[(2%S)-2%,4%-dimethyl-
valeryl)]-2-oxazolidinone 6 was the Evans oxazoli-
dinone 3 (Scheme 1). Evans and co-workers repor-
ted asymmetric alkylation reactions of chiral imide
enolates as a practical approach to the enantioselec-
tive synthesis of a-substituted carboxylic acid deriva-
tives.10 Oxazolidinone 3 was prepared from
L-valine in
two steps in 62% overall yield.11,12 N-Acylation using
n-BuLi and 4-methylvaleric acid activated with pivaloyl
chloride, provided carboximide 5 in 79% yield. Methyl-
ation at the 2%-position was carried out by treatment
with LDA at −78°C, followed by alkylation with
iodomethane to afford 6 in 65% yield following crystal-
lization from hexane. The absolute configuration of 6
was established by X-ray crystallographic analysis (Fig.
3).
Conversion of the carboximide functional group to the
desired aldehyde moiety was achieved by reduction11
with LiAlH4 followed by Swern oxidation (Scheme
Figure 3. ORTEP drawing of (4S)-4-isopropyl-3-[(2%S)-2%,4%-
dimethylvaleryl)]-2-oxazolidinone 6.
Figure 2. Retrosynthetic analysis of (2S,3R,4S)-trimethyl-3-tert-butyldimethylsiloxyheptanoic acid 1.
Scheme 1.

V. Guerla6ais et al. / Tetrahedron: Asymmetry 13 (2002) 675–680
677
Scheme 2.
solution of THF/H2O (3/1) to afford the target 1 in
76% yield (Scheme 3).
3. Conclusion
An efficient synthesis of protected (2R,3R,4S)-3-
hydroxy-2,4,6-trimethylheptanoic acid from
L-valine
has been accomplished in nine steps. The approach is
flexible and applicable to other analogues, which may
be produced by the use of a wide range of aldehydes in
the aldol condensation.
4. Experimental
All manipulations were conducted under an inert atmo-
sphere (argon or nitrogen). All solvents were reagent
grade. Tetrahydrofuran (THF) was distilled from
sodium and benzophenone ketyl. Dichloromethane
(CH2Cl2) was distilled from calcium hydride (CaH2).
Organic acids and bases were reagent grade. Triethyl-
amine and 2,6-lutidine were distilled from calcium
hydride. All other reagents were commercial com-
pounds of the highest purity available. Analytical thin-
layer chromatography (TLC) was performed on Merck
silica gel (60 F-254, plates 0.25 mm). Detection was
accomplished either with phosphomolybdic acid (7% in
ethanol) or potassium permanganate. Flash column
chromatography was carried out on Merck silica gel 60
particle size (0.040–0.063 mm). Melting points (mp)
were determined with a Thomas–Hoover capillary melt-
ing point apparatus and are uncorrected. Proton and
carbon magnetic resonance spectra (1H, 13C NMR)
were recorded on a Bruker AM-500 Fourier transform
spectrometer, and chemical shifts are expressed in parts
per million relative to tetramethylsilane (TMS, 0 ppm)
Figure 4. Heathcock’s transition state models of aldol reac-
tions.
Figure 5. ORTEP drawing of (4S)-4-isopropyl-3-[(2%R,3%S,
4%S)-2%,4%,6%-trimethyl-3%-hydroxyheptyl)]-2-oxazolidinone 9.
In order to utilize 1 in the total synthesis of callipeltin
A, acid 9 was protected as its silyl ether 10 using
tert-butyldimethylsilyl triflate17 and 2,6-lutidine in
CH2Cl2. Initial attempts to introduce the silyl group
with tert-butyldimethylsilyl chloride and imidazole
failed. The removal of the chiral auxiliary was achieved
with lithium hydroxide and 30% hydrogen peroxide in a
1
or CHCl3 as an internal reference (7.28 ppm for H and
77.0 ppm for 13C). Infrared spectra (IR) were obtained
on Perkin–Elmer Model 1600 Series FTIR spectrome-
ter. Absorptions are reported in wavenumbers (cm−1)
and the spectra were calibrated against the 1601 cm−1

678
V. Guerla6ais et al. / Tetrahedron: Asymmetry 13 (2002) 675–680
Scheme 3.
band of a polystyrene film. Optical rotations were
recorded on a Perkin–Elmer Model 341 polarimeter at
the sodium D line. High-resolution mass spectra
(HRMS) were obtained on either a VG 70–70HS [a
high-resolution double focusing mass spectrometer
using ammonia chemical ionization (CI) or electron
impact (EI)] or a ZAB-E [using fast atom bombard-
ment (FAB), CI, or EI].
69–70°C, lit,8,18 mp 71–72°C); 1H NMR (500 MHz,
CDCl3) l 0.91 (d, 3H, J=6.74 Hz), 0.97 (d, 3H, J=
6.67 Hz), 1.73 (m, 1H), 3.62 (m, 1H), 4.10 (m, 1H), 4.44
(m, 1H), 6.72 (br s, 1H); 13C NMR (125 MHz, CDCl3)
l 17.59, 17.93, 32.64, 58.36, 68.56, 160.40; IR wmax
(KBr, CHCl3) 3261, 2960, 1750, 1479, 1405, 1351, 1327,
1246, 1090, 936, 900, 770, 715 cm−1; HRMS m/z calcd
for C6H11NO2 (M+H) 130.0868, found 130.0873; [h]=
+13.3 (CHCl3, c 6.8) lit.8 +14.8 (CHCl3, c 7) and lit.18
+16.8 (CHCl3, c 17.5).
4.1. (4S)-4-Isopropyl-2-oxazolidinone 3
4.2. (4S)-4-Isopropyl-3-propionyl-2-oxazolidinone 4
Boron trifluoride diethyl etherate (22 mL, 0.17 mol)
was added over a 30 min period to a solution of
-valine (20 g, 0.17 mol) in THF (110 mL). The mixture
A solution of n-BuLi in hexanes (1.6 M, 10.7 mL, 17.12
mmol) was added dropwise over 3 min to a stirred
solution of 3 (2 g, 15.5 mmol) in anhydrous THF (30
mL) at −78°C. The mixture was stirred at this tempera-
ture for 20 min and propionyl chloride (1.48 mL, 17
mmol) was then added dropwise over 2 min. The
mixture was stirred for 30 min and then quenched with
saturated aqueous NH4Cl solution (100 mL). The solu-
tion was extracted with ethyl acetate (100 mL) and the
organic phase was washed with brine. The dried solu-
tion (Na2SO4) was concentrated in vacuo and the
residue was then purified using flash chromatography
(10% ethyl acetate in hexanes) to provide 4 as a color-
less oil (2.38 g, 83%). Rf 0.27 {ethyl acetate/hexane
(2/8)}; 1H NMR (500 MHz, CDCl3) l 0.89 (d, 3H, J=7
Hz), 0.93 (d, 3H, J=7 Hz), 1.18 (td, 3H), 2.39 (m, 1H),
2.97 (m, 2H), 4.22 (m, 1H), 4.28 (m, 1H), 4.44 (m, 1H);
13C NMR (500 MHz, CDCl3) l 8.42, 14.65, 17.93,
28.39, 29.11, 58.40, 63.37, 154.10, 174.04; IR wmax (KBr,
CHCl3) 2965, 2941, 2878, 2350, 2338, 1787, 1702, 1487,
1464, 1388, 1375, 1301, 1247, 1207, 1143, 1120, 1072,
1026, 982, 947, 806, 773, 758, 699 cm−1; HRMS m/z
calcd for C9H15NO3 (M+Na) 208.105, found 208.095;
[h]=+92 (CH2Cl2, c 1.4) lit.8 +96.8 (CH2Cl2, c 8.7) and
lit.18 +94 (CH2Cl2, c 1.75)].
L
was heated under reflux for 1 h. The reaction tempera-
ture was adjusted to below the reflux point, and
borane–dimethyl sulfide complex (17.80 mL, 0.19 mol)
was added dropwise over 2 h. During the addition,
hydrogen evolved, and methyl sulfide was allowed to
distill as it was generated. The solution was then
refluxed for 6 h and cooled to ambient temperature.
The remaining borane was quenched by careful addi-
tion of 15 mL of 1:1 THF/water. To the solution was
added 5 M aqueous NaOH solution (90 mL). The
mixture was heated at reflux for 12 h. The remaining
THF was removed in vacuo, and the resulting slurry
was extracted with CH2Cl2 (5×20 mL). The combined
organic layers were dried over Na2SO4, and concen-
trated in vacuo to give 2 as oil (12.3 g, 70%).
(S)-Valinol 2 (12.3 g, 0.12 mmol), diethyl carbonate
(28.8 mL, 0.24 mol), and potassium carbonate (1.64 g,
0.012 mmol) were placed into a flask equipped with a
Dean–Stark apparatus. The magnetically stirred mix-
ture was heated at 145°C until 14 mL (11 g, 0.24 mmol)
of ethanol was collected. The resultant mixture was
cooled to room temperature and diluted with diethyl
ether (100 mL), and the resulting suspension was
filtered through a 2 cm pad of Celite to remove the
potassium carbonate. The ethereal solution was concen-
trated to a volume of 100 mL and slowly cooled to 0°C,
and the product was allowed to crystallize. Concentra-
tion of the mother liquors provided two additional
crops of crystals. The total yield of oxazolidinone 3,
obtained as white needles, was 9.59 g (62%, two steps).
Rf 0.52 {ethyl acetate/hexane (5/5)}; mp 70°C (lit.12 mp
4.3. (4S)-4-Isopropyl-3-(4%-methylvaleryl)-2-oxazolidin-
one 5
A solution of n-BuLi in hexanes (2.5 M, 11.2 mL, 28
mmol) was added dropwise to a stirred solution of 3 (3
g, 23.2 mmol) in anhydrous THF (100 mL) at −78°C.
The mixture was stirred at this temperature for 30 min.

V. Guerla6ais et al. / Tetrahedron: Asymmetry 13 (2002) 675–680
679
In a separate flask containing 4-methylvaleric acid (3.53
mL, 27.9 mmol) and THF (100 mL) at 0°C was added
triethylamine (5.51 mL, 39.6 mmol) and pivaloyl chlo-
ride (3.73 mL, 30.3 mmol). After stirring for 30 min,
the lithio-(4S)-4-isopropyl-2-oxazolidinone was added.
The mixture was warmed to room temperature over a 2
h period. The solution was extracted with EtOAc and
the organic extract was washed with saturated
NaHCO3, saturated NH4Cl solution, and brine. The
dried solution (Na2SO4) was concentrated in vacuo and
the residue was then purified using flash chromatogra-
phy (10% ethyl acetate in hexanes) to provide 5 (3.69 g,
70%) as colorless oil. Rf 0.28 {ethyl acetate/hexane
(2/8)}; 1H NMR (500 MHz, CDCl3) l 0.87 (d, 3H, J=7
Hz), 0.91 (d, 3H, J=7 Hz), 0.925 (d, 3H, J=6.5 Hz),
0.926 (d, 3H, J=6.5 Hz), 1.56 (m, 2H), 1.60 (m, 1H),
2.35 (m, 1H), 2.88 (m, 1H), 2.97 (m, 1H), 4.20 (m, 1H),
4.25 (m, 1H), 4.43 (m, 1H); 13C NMR (125 MHz,
CDCl3) l 14.6, 17.8, 22.2 (2 overlapping carbons), 27.6,
28.3, 33.2, 33.5, 58.3, 63.2, 153.9, 173.5; IR wmax (KBr,
CHCl3) 2959, 2935, 2872, 2360, 1782, 1702, 1467, 1388,
1340, 1301, 1281, 1204, 1144, 1132, 1120, 1092, 1061,
1019, 971, 774, 704, 634 cm−1; HRMS m/z calcd for
C12H21NO3 (M+Na) 250.1521, found 250.1407; [h]=
+71.2 (CHCl3, c 1).
The mixture was extracted with ether. The organic
extracts were dried (Na2SO4,) evaporated, and the
residue purified by flash chromatography (10% ethyl
acetate in hexanes) to provide 7 (1.02 g, 87%) as a
1
colorless oil. Rf 0.23 {ethyl acetate/hexane (2/8)}; H
NMR (500 MHz, CDCl3) l 0.88 (d, 3H, J=6.5 Hz),
0.919 (d, 3H, J=6.5 Hz), 0.923 (d, 3H, J=6.6 Hz), 1.03
(m, 1H), 1.21 (m, 1H), 1.4 (m, 1H), 1.69 (m, 1H), 3.41
(m, 1H), 3.51 (m, 1H); 13C NMR (125 MHz, CDCl3) l
16.7, 22.1, 23.5, 25.2, 33.4, 42.7, 68.7; IR wmax (KBr,
CHCl3) 3331, 2956, 2925, 2871, 1469, 1384, 1366, 1260,
1217, 1170, 1075, 1040, 991, 973, 939, 909, 870, 806
cm−1; [h]=−18.3 (CHCl3, c 1.12).
4.6. (2S)-2,4-Dimethyl-1-pentanal 8
A solution of oxalyl chloride (0.312 mL, 3.6 mmol) in
20 mL of CH2Cl2 was cooled to −78°C and anhydrous
dimethylsulfoxide (0.275 mL, 3.9 mmol) was added.
After stirring for 30 min, a solution of 7 (350 mg, 2.9
mmol) in CH2Cl2 (4 mL) was added. The resulting
white suspension was stirred at −78°C for 30 min and
triethylamine (2.1 mL, 14.8 mmol) was then added.
After stirring for 1 h, the solution was warmed to room
temperature. The mixture was washed with 1N aqueous
HCl solution, saturated NaHCO3, and brine. The dried
solution (Na2SO4) was concentrated in vacuo to
provide 8 as an orange oil (300 mg, 91%), which was
used immediately. Rf 0.54 {ethyl cetate/hexane (2/8)};
1H NMR (500 MHz, CDCl3) l 0.91 (d, 3H, J=6.5 Hz),
0.94 (d, 3H, J=6.5 Hz), 1.09 (d, 3H, J=7 Hz), 1.21 (m,
1H), 1.62 (m, 1H), 1.68 (m, 1H), 2.42 (m, 1H), 9.61 (d,
1H, J=2.5 Hz); 13C NMR (125 MHz, CDCl3) l 13.68,
22.19, 22.87, 25.55, 39.71, 44.44, 205.34.
4.4. (4S)-4-Isopropyl-3-[(2%S)-2%,4%-dimethylvaleryl)]-2-
oxazolidinone 6
A solution of diisopropylamine (3.42 mL, 24.4 mmol)
in THF (30 mL) was cooled to −30°C and n-BuLi in
hexanes (2.5 M, 8.45 mL, 21.12 mmol) was added.
After stirring the mixture for 45 min, a solution of 5
(3.69 g, 16.25 mmol) in THF (20 mL) was added at
−78°C. The mixture was stirred at −78°C for 1 h and
iodomethane (5.06 mL, 81.3 mmol) was then added.
After stirring for 30 min, the solution was allowed to
reach room temperature. The mixture was extracted
with ether and the organic extract was washed with
saturated NH4Cl solution, saturated NaHCO3, and
brine. The dried solution (Na2SO4) was concentrated in
vacuo and the residue was purified using flash chro-
matography (5% then 10% ethyl acetate in hexanes) to
give 6 as colorless crystals (2.47 g, 63% after crystalliza-
tion from hexanes, −15°C). Rf 0.36 {ethyl acetate/hex-
4.7. (4S)-4-Isopropyl-3-[(2%R,3%R,4%S)-2%,4%,6%-trimethyl-
3%-hydroxyheptyl)]-2-oxazolidinone 9
To a solution of 4 (315 mg, 1.7 mmol) in CH2Cl2 (5
mL) at 0°C was added triethylamine (0.275 mL, 1.9
mmol). A solution of dibutylboron triflate (1 M, 2.05
mL, 2.05 mmol) in CH2Cl2 was then added, and the
mixture was stirred for 1 h at 0°C. In a separate flask,
a solution of Et2AlCl (1 M, 5.1 mL, 5.1 mmol) in
hexanes was diluted with CH2Cl2 (5 mL) and cooled to
−78°C. Aldehyde 8 (300 mg, 2.6 mmol) in CH2Cl2 (2
mL) was then added at −78°C. After stirring for 5 min,
the boron enolate solution was added via cannula. The
mixture was stirred for 5 h and then allowed to reach
room temperature over 12 h. The reaction mixture was
then cooled to −78°C, and a mixture of methanol (6
mL) and of 30% aqueous H2O2 (2 mL) was added. The
mixture was allowed to warm to 0°C. The mixture was
extracted with ether and the organic extract was washed
with saturated NaHCO3, saturated NH4Cl solution,
and brine. The solution was dried (Na2SO4), concen-
trated in vacuo, and the residue was then purified using
flash chromatography (10% ethyl acetate in hexanes) to
provide 9 as colorless crystals (98 mg, 21% from two
steps and crystallization from hexanes, −15°C). Rf 0.25
{ethyl acetate/hexane (2/8)}; mp 61–62°C; 1H NMR
(500 MHz, CDCl3) l 0.84–0.92 (m, 15H), 1.10 (d, 3H,
J=6.7 Hz), 1.16 (m, 1H), 1.25 (m, 1H), 1.65 (m, 1H),
1
ane (2/8)}; mp 42°C; H NMR (500 MHz, CDCl3) l
0.89–0.94 (m, 12H), 1.21 (d, 3H, J=6.5 Hz), 1.25 (m,
1H), 1.59 (m, 1H), 1.68 (m, 1H), 2.37 (m, 1H), 3.88 (m,
1H), 4.21 (m, 1H), 4.28 (m, 1H), 4.46 (m, 1H); 13C
NMR (125 MHz, CDCl3) l 14.7, 17.9, 18.2, 22.4, 22.8,
25.8, 28.4, 35.6, 42.00, 58.4, 63.2, 153.6, 177.5; IR wmax
(KBr, CHCl3) 2960, 2933, 2874, 2359, 2341, 1781, 1699,
1488, 1459, 1386, 1300, 1249, 1225, 1203, 1120, 1092,
1058, 1023, 991, 968, 774, 688 cm−1; HRMS m/z calcd
for C13H23NO3 (M+Na) 241.168, found 241.158; [h]=
+83 (CHCl3, c 1.05).
4.5. (2S)-2,4-Dimethyl-1-pentanol 7
Lithium aluminum hydride (1.15 g, 30.3 mmol) was
added to a solution of 6 (2.44 g, 10.1 mmol) in THF (20
mL) at 0°C. After 10 min, excess LiAlH4 was neutral-
ized by addition of saturated aqueous NH4Cl solution.

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V. Guerla6ais et al. / Tetrahedron: Asymmetry 13 (2002) 675–680
1.74 (m, 1H), 2.4 (m, 1H), 3.56 (m, 1H), 4.03 (m, 1H),
4.30 (m, 2H), 4.42 (m, 1H); 13C NMR (125 MHz,
CDCl3) l 12.44, 14.57, 14.78, 17.99, 22.34, 23.07, 25.02,
28.56, 32.36, 40.58, 43.29, 59.12, 63.42, 78.00, 152.00,
177.13; IR wmax (KBr, CHCl3) 3530, 2959, 1779, 1670,
1464, 1385, 1301, 1204, 1142, 1109, 1056, 986, 775, 709
cm−1; HRMS m/z calcd for C16H29NO4 (M+Na)
322.1994, found 322.1978; [h]=+57.5 (CHCl3, c 1.02).
14.34, 15.00, 18.34, 21.76, 23.65, 25.23, 26.04 (3 over-
lapping carbons), 34.15, 42.23, 44.08, 78.10, 180.47; IR
wmax (KBr, CHCl3) 2960, 2933, 2873, 1781, 1699, 1487,
1465, 1386, 1299, 1284, 1249, 1225, 1203, 1092, 1058,
992, 774, 701 cm−1; HRMS m/z calcd for C16H34O3Si
(M+Na) 325.2175, found 325.2160; [h]=−13.55
(CHCl3, c 1.07).
Crystallographic data (excluding structure factors) for
the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 175153 & 175154.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44 (0) 1223–336033 or e-mail:
deposit@ccdc.cam.ac.uk.
4.8. (4S)-4-Isopropyl-3-[(2%R,3%R,4%S)-2%,4%,6%-trimethyl-
3%-tert-butyl-dimethylsilylo-xyheptyl)]-2-oxazolidinone
10
2,6-Lutidine (0.1 mL, 0.86 mmol) and tert-
butyldimethyltrifluoromethane sulfonate (0.104 mL,
0.46 mmol) were added to a solution of 9 (90 mg, 0.3
mmol) in CH2Cl2 (1 mL). The solution was stirred for
1.5 h at room temperature and then poured into a
mixture of ether and saturated aqueous NaHCO3. The
organic phase was separated and washed with saturated
brine, dried (Na2SO4), and evaporated. The residue was
then purified using flash chromatography (10% ethyl
acetate in hexanes) to provide the silyl ether 10 as a
white solid (89 mg, 65%). Rf 0.28 {ethyl acetate/hexane
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1
(1/9)}; mp 76–78°C; H NMR (500 MHz, CDCl3) l
0.07 (s, 3H), 0.12 (s, 3H), 0.83–0.95 (m, 24H), 1.14–1.20
(m, 5H, including d, 3H, J=6.7 Hz), 1.62 (m, 1H), 1.67
(m, 1H), 2.4 (m, 1H), 4.04 (m, 1H), 4.11 (m, 1H), 4.24
(m, 2H), 4.44 (m, 1H); 13C NMR (125 MHz, CDCl3) l
−4.57, −4.07, 13.50, 13.83, 14.46, 18.22, 18.44, 21.81,
23.6, 25.1, 26.17 (3 overlapping carbons), 28.43, 33.18,
44.06, 44.44, 58.87, 62.72, 75.07, 153.66, 175.23; IR wmax
(KBr, CHCl3) 2956, 2929, 1782, 1698, 1464, 1386, 1372,
1300, 1250, 1226, 1204, 1120, 1088, 1058, 1015, 990,
838, 776 cm−1; HRMS m/z calcd for C22H43NO4Si
(M+Na) 436.2859, found 436.2856; [h]=−7.0 (CHCl3, c
1.02).
6. Okamoto, N.; Hara, O.; Makino, K.; Hamada, Y. Tetra-
hedron: Asymmetry 2001, 12, 1353–1358.
7. Chandrasekhar, S.; Ramanchandar, T.; Rao, V. B. Tetra-
hedron: Asymmetry 2001, 12, 2315–2321.
8. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
4.9. (2R,3R,4S)-2,4,6-Trimethyl-3-tert-butyldimethyl-
silyloxyheptanoic acid 1
1981, 103, 2127–2129.
9. Walker, F. J.; Heathcock, C. H. J. Org. Chem. 1991, 56,
5747–5750.
10. Evans, D. A.; Ennis, M. D.; Mathre, D. J. Am. Chem.
Soc. 1982, 104, 1737–1739.
11. Smith, G. A.; Gawley, R. E. Org. Synth. 1984, 63,
136–139.
A solution of 10 (90 mg, 0.22 mmol) in THF–H2O (3/1,
1 mL) was treated at 0°C with H2O2 (6 equiv., 0.15 mL
of 30% aqueous H2O2) and LiOH (11 mg, 0.46 mmol).
The resulting mixture was stirred at 0°C for 3 h, and
then warmed to room temperature and stirred for 12 h.
Excess peroxide was quenched at 0°C by the addition
of 1.5N aqueous Na2SO3 (1 mL). The solution was
poured into a mixture of ether and 1N aqueous HCl.
The organic phase was separated and washed with
saturated brine, dried (Na2SO4), and concentrated in
vacuo. The residue was then purified using flash chro-
matography (10% ethyl acetate in hexanes+1% acetic
acid) to give 1 as a colorless oil (50 mg, 76%). Rf 0.57
12. Evans, D. A.; Mathre, D. J. Org. Chem. 1985, 1830–
1835.
13. Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
14. Tidwell, T. T. Synthesis 1990, 857–870.
15. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
16. Arrick, R. E.; Baker, D. C.; Horton, D. Carbohydr. Res.
1973, 26, 441–447.
1
{ethyl acetate/hexane (1/9)+1% AcOH}; H NMR (500
17. Corey, E. J.; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetra-
MHz, CDCl3) l 0.05 (s, 3H), 0.08 (s, 3H), 0.81–0.89 (m,
18H), 1.09 (m, 1H), 1.15–1.19 (m, 4H, including d, 3H,
J=7.1 Hz), 1.6 (m, 1H), 1.7 (m, 1H), 2.64 (m, 1H), 3.76
(m, 1H); 13C NMR (125 MHz, CDCl3) l −4.44, −4.04,
hedron Lett. 1981, 22, 3455–3458.
18. Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991,
56, 2489–2498.