Synthetic studies on callipeltin A: Stereoselective synthesis of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid

Article abstract of DOI:10.1016/S0957-4166(02)00178-7

An efficient and highly stereocontrolled synthesis of protected (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid, the β-hydroxy acid unit that acylates the N-terminus of callipeltin A, has been devised starting from methyl (2S)-2-methyl-3-hydroxypropion

Full text of DOI:10.1016/S0957-4166(02)00178-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 681–685
Synthetic studies on callipeltin A: stereoselective synthesis of
(2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid
Angela Zampella, Maria Sorgente and Maria Valeria D’Auria*
Dipartimento di Chimica delle Sostanze Naturali, Universita` degli Studi di Napoli ‘Federico II’, via D. Montesano 49,
80131 Naples, Italy
Received 25 January 2002; accepted 9 April 2002
Abstract—An efficient and highly stereocontrolled synthesis of protected (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid, the
b-hydroxy acid unit that acylates the N-terminus of callipeltin A, has been devised starting from methyl (2S)-2-methyl-3-hydroxy-
propionate. Comparison of NMR data with the corresponding fragment obtained from the acid hydrolysate of callipeltin A
indicates that the stereostructure of the above fragment should be revised. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
ses of the unusual amino acid (3S,4R)-3,4-dimethyl-L-
glutamine have been proposed.4 Recently, a synthesis of
(2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid, a
synthetic precursor of the (2R,3R,4S)-4-amino-7-guani-
dino-2,3-dihydroxyheptanoic acid (AGDHE) residue
also appeared in the literature.5
The novel cyclodecapeptide callipeltin A 1 and its con-
geners were isolated in our laboratories from the
marine lithistid sponge Callipelta sp.1,2 The intriguing
structure of these compounds was characterized by the
presence of several non-proteinogenic amino acid units.
Callipeltin A 1 was found to protect cells infected by
the HIV virus and, recently, it was also found to be a
selective and powerful inhibitor of the Na/Ca cardiac
exchanger.3
En route to a total synthesis of callipeltin A 1, herein
we report an asymmetric synthesis of protected
(2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid 2,
the b-hydroxy acid linked to the N-terminus of cal-
lipeltin A.
2. Results and discussion
Our retrosynthetic analysis of the protected 3-hydroxy-
2,4,6-trimethylheptanoic acid 2 is shown in Fig. 1. We
envisaged that the isopropyl terminus could be intro-
duced through a Wittig reaction on aldehyde 4. The
C(2)ꢀC(4) stereotriad in 4 would arise from a chiral
The complex structure of this natural product has
already motivated some synthetic efforts, even if no
total synthesis has been reported to date. Three synthe-
* Corresponding author. Tel.: +39-081/678-527; fax: +39-081/678-552;
e-mail: madauria@cds.unina.it
Figure 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00178-7

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A. Zampella et al. / Tetrahedron: Asymmetry 13 (2002) 681–685
from commercially available (R)-4-benzyl-3-propionyl-
oxazolidinone with protected aldehyde 5 provided an
81% isolated yield of the diastereomerically pure aldol
9. Transamidation of aldol 9 followed by treatment of
the intermediate Weinreb amide9 with TBSOTf and
2,6-lutidine yielded a mixture of degradation products.
On the basis of these results, aldol adduct 9 was
converted to primary alcohol 11 after protection of the
secondary alcoholic function as its TBS ether followed
by removal of the oxazolidinone auxiliary10 with LiBH4
in MeOH (87%, two steps). The primary alcohol was
oxidized to the corresponding aldehyde under standard
Swern conditions,7 and the unpurified aldehyde 4 was
directly subjected to Wittig reaction with isopropyli-
dene–triphenylphosphorane to give the olefin 3. Hydro-
genation of 3 in the presence of Pearlman’s catalyst11
then resulted in simultaneous reduction of the alkene
bond and hydrogenolysis of the benzyl protecting
group, producing the alcohol 12 which was easily oxi-
dized to the targeted protected b-hydroxy acid 2 using
RuCl3–NaIO4.12
Scheme 1. Reagents and conditions: (a) BTCA, TfOH, 0°C to
rt, 3 h, 94%; (b) LiBH4, dry MeOH, 2 h, 96%; (c) DMSO,
(COCl2), −78°C, 30 min, then 8, Et3N, −78°C to rt, 1 h, 97%;
(d) tert-BuOK, (Z)-2-butene, BuLi, −78 to −45°C, (+)-B-
methoxydiisopinocampheylborane, BF3·OEt2, aldehyde 5,
−78°C, 4 h, 70%.
auxiliary-controlled addition (Brown crotylboronation
or aldol addition) to the suitable protected aldehyde 5.
This latter could be obtained from commercially avail-
able methyl (2S)-2-methyl-3-hydroxypropionate 6.
A first approach towards aldehyde 4 is outlined in
Scheme 1. Methyl (2S)-2-methyl-3-hydroxy propionate
6 was transformed into aldehyde 5 in a three-step
sequence (88% yield for three steps) involving the pro-
tection of the primary hydroxy group as its benzyl
ether, LiBH4 reduction of the methyl ester function of 7
followed by Swern oxidation6 of the obtained primary
alcohol 8. Unfortunately, the addition of the chiral
boron reagent derived from cis-2-butene, and (+)-
Ipc2BOMe to aldehyde 5 under Brown’s conditions,7
proceeded with unsatisfactory 65% diastereoselectivity.
To confirm the stereostructure of the naturally occur-
ring 3-hydroxy-2,4,6-trimethylheptanoic acid residue, a
sample of the acid 2 was deprotected with MeOH/HCl
1
to afford the b-hydroxy acid 13. Surprisingly, the H
NMR spectrum of the compound 13 showed some
small but significant differences in the chemical shift
values when compared with those reported for the
corresponding b-hydroxy acid isolated from the acid
hydrolysate of callipeltin A.1 Therefore, the relative
stereochemistry of the 3-hydroxy-2,4,6-trimethylhep-
tanoic acid fragment in callipeltin A 1, tentatively
assigned in our original paper on the basis of vicinal
coupling constants and molecular modeling consider-
ations, should be revised. This would require the re-iso-
lation of callipeltin A and further structural studies on
the natural 3-hydroxy-2,4,6-trimethylheptanoic acid
fragment.
Thus, we turned to the well-established Evans’ asym-
metric aldol methodology8 to set up the correct stereo-
chemistry of the three contiguous stereogenic centers
(Scheme 2). Treatment of the boron enolate derived
3. Conclusion
In summary, we have developed an efficient, highly
stereoselective synthesis (10 steps, 38% overall yield) of
protected
(2R,3R,4S)-3-hydroxy-2,4,6-trimethylhep-
tanoic acid 2 starting from commercially available
methyl (2S)-2-methyl-3-hydroxypropionate. Small dif-
ferences in the 1H NMR data of the synthetic and
natural fragments lead us to conclude that the stereo-
chemistry of the deprotected synthetic derivative 13
differs from the corresponding residue in callipeltin A 1
at one or more stereogenic centers. Further studies
devoted to the determination of the actual stereochem-
istry of the 3-hydroxy-2,4,6-trimethylheptanoic acid
fragment in callipeltin A are currently in progress in
our laboratory.
Scheme 2. Reagents and conditions: (a) Bu2BOTf, (R)-4-ben-
zyl-3-propionyl-oxazolidinone, −78°C, 1 h, then 5, −78 to
−10°C, 2 h, 81%; (b) 2,6-lutidine, TBSOTf, 0°C to rt, 2 h,
91%; (c) LiBH4, dry MeOH, 0°C, 1 h, 96%; (d) DMSO,
(COCl2), −78°C, 30 min, then 11, Et3N, −78°C to rt, 1 h, 95%;
(e) isopropyltriphenylphosphonium iodide, n-BuLi, rt 3 h,
84%; (f) H2/Pd(OH)2, 3 atm, 2 days, 90%; (g) NaIO4/
RuCl3·H2O (cat.), 84%; (h) MeOH/HCl, 25°C, 3 h, quantita-
tive.
4. Experimental
NMR spectra were recorded in CDCl3 (lH=7.26 and
lC=77.0 ppm) on a Bruker 500 MHz spectrometer and

A. Zampella et al. / Tetrahedron: Asymmetry 13 (2002) 681–685
683
chemical shifts are reported in ppm. EI MS spectra
4.3. (2S)-3-Benzyloxy-2-methylpropanal 5
were performed on a VG Prospec (Fisons) mass spec-
trometer. IR spectroscopy was performed on a IFS 48
Bruker instrument. Optical rotations were measured
with a Perkin–Elmer 141 polarimeter operating at 589
nm. Methyl (2S)-(+)-3-hydroxy-2-methylpropionate
was purchased from Fluka. Solvents and reagents were
used as supplied from commercial sources with the
following exceptions. Tetrahydrofuran, toluene,
dichloromethane and triethylamine were distilled from
calcium hydride immediately prior to use. All reaction
were monitored by TLC on silica gel plates (Machery,
Nagel). Crude products were purified by column chro-
matography on silica gel 70–230 mesh. All reactions
were carried out under an argon atmosphere using dry
glassware.
DMSO (4.1 mL, 53.2 mmol) was added dropwise over
15 min to a solution of oxalyl chloride (2.3 mL, 26.6
mmol) in dry dichloromethane (50 mL) at −78°C under
argon atmosphere. After 30 min a solution of the
alcohol 8 (2.4 g, 13.3 mmol) in dry CH2Cl2 was added
via cannula and the mixture was stirred at −78°C for 1
h. Et3N (9.3 mL, 66.5 mmol) was added dropwise and
the mixture was allowed to warm to room temperature.
The reaction was quenched by addition of aqueous
NaHSO4 (1 M, 50 mL). The layers were separated and
the aqueous phase was extracted with CH2Cl2 (3×50
mL). The combined organic layers were washed with
NaHSO4, water, saturated aqueous NaHCO3 and brine.
The organic phase was then dried and concentrated to
give the corresponding aldehyde 5 (2.3 g, 97%) as a
colorless oil which was used without any further
purification.
4.1. Methyl (2S)-3-benzyloxy-2-methylpropionate 7
A solution of methyl (2S)-(+)-3-hydroxy-2-methylpro-
pionate 6 (2.0 g, 16.9 mmol) in CH2Cl2/cyclohexane
(1:2, 25 mL) was cooled to 0°C and treated with benzyl
2,2,2-trichloroacetimidate (5.1 g, 20.3 mmol) and triflic
acid (150 mL, 1.7 mmol). The reaction mixture was
allowed to stir at room temperature for 3 h and the
precipitated trichloroacetamide was filtered through a
small pad of silica gel. The filtrate was washed with
saturated NaHCO3 and water, dried (Na2SO4) and
concentrated. Silica gel chromatography (n-hex-
ane:ethyl acetate, 99:1) afforded the benzyl ether 7 as a
colorless oil (3.3 g, 94%). IR (KBr): 2999, 1725, 1200,
4.4. (4R,2%R,3%S,4%S)-4-Benzyl-3-(5%-benzyloxy-3%-
hydroxy-2%,4%-dimethylpentanoyl)-2-oxazolidinone 9
Bu2BOTf (15.5 mL, 1 M in CH2Cl2, 15.5 mmol) and
Et3N (2.3 mL, 16.8 mmol) were added to a solution of
(R)-4-benzyl-3-propionyl-oxazolidinone (3.3 g, 14.2
mmol) in dry dichloromethane (70 mL) at −78°C under
argon and the resulting pale yellow solution was stirred
for 1 h at −78°C and then at 0°C for 30 min before
re-cooling to −78°C. A solution of the aldehyde 5 (2.3
g, 12.9 mmol) in dry CH2Cl2 was cannulated to the
solution which was stirred at −78°C for 1 h and then
warmed to −10°C, stirred for 1 h and then quenched
with pH 7 potassium phosphate monobasic-sodium
hydroxide buffer (14 mL). A solution of 30% H2O2 in
MeOH (1:2, 32 mL) was added to the mixture that was
stirred overnight at room temperature and concen-
trated. The residue was diluted with CH2Cl2 and the
resulting layers separated. The aqueous phase was
extracted with CH2Cl2 (3×50 mL) and the combined
organic layers were washed with saturated aqueous
NaHCO3, water and brine. The organic phase was then
dried (Na2SO4), concentrated and chromatographed on
silica gel (n-hexane:ethyl acetate, 8:2) to give 9 as a
colorless oil (4.3 g, 81%). IR (KBr): 3540, 3000, 1780,
1700, 1200, 900, 770 cm−1; 1H NMR (500 MHz,
CDCl3): l 0.96 (d, J=6.9 Hz, 3H, CH3), 1.26 (d, J=7.2
Hz, 3H, CH3), 1.98 (m, 1H, C4%-H), 2.76 (dd, J=13.2,
9.5 Hz, 1H, benzylic CH2), 3.32 (dd, J=13.2, 2.9 Hz,
1H, benzylic CH2), 3.60 (dd, J=8.8, 4.4 Hz, 1H, C5%-
Ha), 3.88 (dd, J=8.8, 2.9 Hz, 1H, C5%-Hb), 3.94 (m,
2H, C2%-H, C3%-H), 4.16 (bs, 2H, C5-H), 4.51 (s, 2H,
benzylic CH2O), 4.66 (m, 1H, C4-H), 7.20–7.35 (m,
10H, aromatic); 13C NMR (125 MHz, CDCl3): l 9.7,
13.6, 36.0, 37.7, 40.6, 55.5, 66.1, 73.5, 74.8, 75.2, 127.3,
127.5, 128.4, 128.9, 129.4, 135.3, 137.8, 153.1, 176.2; EI
MS: m/z 411 (M+); [h]D −21.9 (c 5.6, CHCl3).
1
900, 770 cm−1; H NMR (500 MHz, CDCl3): l 1.18 (d,
J=7.2 Hz, 3H, CH3), 2.79 (m, 1H, C2-H), 3.50 (dd,
J=9.4, 6.0 Hz, 1H, C3-Ha), 3.67 (t, J=9.4, Hz, 1H,
C3-Hb), 3.69 (s, 3H, OCH3), 4.52 (s, 2H, benzylic CH2),
7.26–7.35 (m, 5H, aromatic); 13C NMR (125 MHz,
CDCl3): l 13.9, 40.1, 51.7, 72.0, 73.1, 127.5, 128.3,
138.2, 175.2; EI MS: m/z 208 (M+); [h]D +10.2 (c 3,
CHCl3).
4.2. (2R)-3-Benzyloxy-2-methyl-1-propanol 8
Dry methanol (1.4 mL, 43.2 mmol) and LiBH4 (21.6
mL, 2 M in THF, 43.2 mmol) were added to a solution
of 7 (3.0 g, 14.4 mmol) in dry THF under an argon
atmosphere and the resulting mixture was stirred for 2
h. The mixture was quenched by addition of NaOH (1
M, 30 mL) and then allowed to warm to room temper-
ature. Ethyl acetate was added and the separated
aqueous phase was extracted with ethyl acetate (3×30
mL). The combined organic phases were washed with
water, dried (Na2SO4) and concentrated. Silica gel chro-
matography (n-hexane:ethyl acetate 85:15) afforded the
alcohol 8 as a colorless oil (2.5 g, 96%). IR (KBr): 3300,
3068, 1200, 900, 770 cm−1; 1H NMR (500 MHz,
CDCl3): l 0.89 (d, J=7.7 Hz, 3H, CH3), 2.04 (m, 1H,
C2-H), 3.49 (t, J=8.6, Hz, 1H, C3-Ha), 3.54 (dd,
J=8.6, 5.0 Hz, 1H, C3-Hb) 3.60 (m, 2H, C1-H), 4.52
(s, 2H, benzylic CH2), 7.26–7.35 (m, 5H, aromatic); 13C
NMR (125 MHz, CDCl3): l 13.4, 35.5, 67.6, 73.4, 75.2,
127.5, 128.5, 138.0; EI MS: m/z 180 (M+); [h]D +11.3 (c
4.9, CHCl3).
4.5. (4R,2%R,3%S,4%S)-4-Benzyl-3-(5%-benzyloxy-3%-(tert-
butyldimethylsilyloxy)-2%,4%-dimethyl-pentanoyl)-2-oxazo-
lidinone 10
2,6-Lutidine (2.9 mL, 25.5 mmol) and TBSOTf (3.9
mL, 17 mmol) were added sequentially to a solution of

684
A. Zampella et al. / Tetrahedron: Asymmetry 13 (2002) 681–685
the alcohol 9 (3.5 g, 8.5 mmol) in dry CH2Cl2 at 0°C
under an argon atmosphere. The mixture was allowed
to warm at room temperature where stirring was con-
tinued for 2 h. Saturated NaHCO3 was added and the
organic phase was washed with water, dried (MgSO4)
and then concentrated in vacuo. Purification by column
chromatography on silica gel using n-hexane:EtOAc
(98:2) as eluent gave the silyl ether 10 as a colorless oil
(4.0 g, 91%). IR (KBr): 3540, 3000, 1780, 1700, 1200,
layers were separated and the aqueous phase was
extracted with CH2Cl2 (3×30 mL). The combined
organic layers were washed with NaHSO4, water, satu-
rated aqueous NaHCO3, and brine. The organic phase
was then dried (Na2SO4), concentrated to give the
corresponding aldehyde 4 (1.8 g, 95%) as a colorless oil
which was used without any further purification.
4.8. (2S,3R,4S)-1-O-Benzyl-3-(tert-butyldimethylsilyl-
oxy)-2,4,6-trimethyl-5-hepten-1,3-diol 3
1
1100, 900, 800, 770 cm−1; H NMR (500 MHz, CDCl3):
l 0.06 (s, 6H, Si-CH3), 0.90 (s, 9H, Si-C(CH3)3), 1.02
(d, J=7.0 Hz, 3H, CH3), 1.24 (d, J=7.2 Hz, 3H, CH3),
1.98 (m, 1H, C4%-H), 2.70 (dd, J=13.2, 9.6 Hz, 1H,
benzylic CH2), 3.20 (m, 2H, benzylic CH2, C5%-Ha),
3.57 (dd, J=8.8, 5.9 Hz, 1H, C5%-Hb), 3.69 (t, J=8.8,
Hz, 1H, C5-Ha), 3.99 (m, 2H, C2%-H, C5-Hb), 4.04 (d,
J=7.3 Hz, C3%-H), 4.42 (m, 1H, C4-H), 7.20–7.35 (m,
10H, aromatic); 13C NMR (125 MHz, CDCl3): l −4.0,
14.7, 18.3, 26.0, 37.6, 38.9, 41.5, 55.4, 65.7, 72.0, 72.9,
75.2, 127.3, 128.3, 128.9, 129.4, 135.4, 138.4, 152.8,
176.1; EI MS: m/z 525 (M+); [h]D −13.0 (c 1.2, CHCl3).
n-BuLi (15.9 mL, 1.6 M in hexane, 25.5 mmol) was
added dropwise to
a
suspension of isopropyl-
triphenylphosphonium iodide (11.2 g, 26 mmol) in dry
THF (70 mL) at room temperature. The resulting red
solution was stirred at room temperature for 30 min. A
solution of the aldehyde 4 (1.8 g, 5.1 mmol) in dry THF
(10 mL) was introduced via cannula. The solution
immediately became yellow. After 2 h the reaction was
diluted with ethyl acetate and washed with saturated
NaHCO3, water, dried (Na2SO4) and concentrated. The
residue was chromatographed on SiO2 eluting with
995:5 hexane:ethyl acetate to afford 3 (1.6 g, 84%). IR
4.6. (2S,3R,4S)-5-Benzyloxy-3-(tert-butyldimethylsilyl-
oxy)-2,4-dimethyl-1-pentanol 11
1
(KBr): 3000, 1660, 1200, 1100, 900, 800, 770 cm−1; H
NMR (500 MHz, CDCl3): l 0.07 (s, 6H, Si-(CH3)2),
0.93 (s, 9H, Si-C(CH3)3), 0.94 (d, J=7.1 Hz, 3H, CH3),
1.02 (d, J=7.0 Hz, 3H, CH3), 1.60 (s, 3H, CH3), 1.68
(s, 3H, CH3), 2.05 (m, 1H, C2-H), 2.56 (m, 1H, C4-H),
3.29 (t, J=8.8 Hz, 1H, C1-Ha), 3.46 (t, J=5.1 Hz, 1H,
C3-H), 3.57 (dd, J=8.8, 5.1 Hz, 1H, C1-Hb), 4.50 (s,
2H, benzylic CH2), 4.98 (d, J=9.7 Hz, C5-H), 7.34–
7.37 (m, 5H, aromatic); 13C NMR (125 MHz, CDCl3):
l −3.9, 14.8, 17.1, 17.9, 18.4, 25.8, 26.2, 35.9, 38.5, 72.9,
78.5, 127.9, 127.3, 128.2, 128.5, 128.7, 129.4, 129.7,
133.7, 133.8, 138.9; EI MS: m/z 376 (M+); [h]D −5.9 (c
2.6, CHCl3).
Dry methanol (585 mL, 18.3 mmol) and LiBH4 (9.1
mL, 2 M in THF, 18.3 mmol) were added to a solution
of the amide 10 (3.2 g, 6.1 mmol) in dry THF at 0°C
under argon and the resulting mixture was stirred for 1
h at 0°C. The mixture was quenched by addition of
NaOH (1 M, 30 mL) and then allowed to warm to
room temperature. Ethyl acetate was added and the
separated aqueous phase was extracted with ethyl ace-
tate (3×30 mL). The combined organic phases were
washed with water, dried (Na2SO4) and concentrated.
Purification by silica gel (n-hexane:EtOAc, 85:15) gave
the alcohol 11 as a colorless oil (2.0 g, 96%). IR (KBr):
4.9. (2S,3R,4S)-3-(tert-Butyldimethylsilyloxy)-2,4,6-
trimethylheptan-1-ol 12
1
3540, 3000, 1200, 1100, 900, 800, 770 cm−1; H NMR
(500 MHz, CDCl3): l 0.04 (s, 3H, Si-CH3), 0.07 (s, 3H,
Si-CH3), 0.87 (d, J=7.0 Hz, 3H, CH3), 0.90 (s, 9H,
Si-C(CH3)3), 0.98 (d, J=7.0 Hz, 3H, CH3), 1.88 (m,
1H, C2-H), 2.02 (m, 1H, C4-H), 3.31 (t, J=8.8 Hz, 1H,
C5-Ha), 3.47 (dd, J=10.3, 5.8 Hz, 1H, C1-Ha), 3.54
(dd, J=8.8, 1.0 Hz., 1H, C5-Hb), 3.57 (dd, J=10.3, 5.1
Hz, 1H, C1-Ha), 3.76 (dd, J=5.5, 2.9 Hz, 1H, C3-H),
4.51 (s, 2H, benzylic CH2), 7.32 (m, 5H, aromatic); 13C
NMR (125 MHz, CDCl3): l −4.3, 11.7, 15.0, 26.0, 37.6,
38.9, 66.1, 72.9, 73.1, 74.7, 127.5, 127.6, 128.3, 138.5; EI
MS: m/z 352 (M+); [h]D −1.2 (c 3.5, CHCl3).
A solution of 3 (950 mg, 2.5 mmol) in ethanol was
hydrogenated in the presence of a Pearlman’s catalyst
(100 mg) for 2 days in a Parr apparatus (3 atm). The
mixture was filtered through Celite and the filtrate was
concentrated in vacuo. Purification by column chro-
matography on silica gel using n-hexane:EtOAc (97:3)
gave 12 as a colorless oil (654 mg, 90%); IR (KBr):
1
1200, 1100, 800 cm−1; H NMR (500 MHz, CDCl3): l
0.07 (s, 3H, Si-CH3), 0.10 (s, 3H, Si-CH3), 0.83 (d,
J=7.0 Hz, 3H, CH3), 0.86 (d, J=7.3 Hz, 3H, CH3),
0.89 (d, J=6.9 Hz, 3H, CH3), 0.91 (s, 9H, Si-C(CH3)3),
0.94 (d, J=7.0 Hz, 3H, CH3), 1.09 (m, 1H, C5-Ha),
1.21 (m, 1H, C5-Hb), 1.59 (m, 1H, C6-H), 1.69 (m, 1H,
C4-H), 1.85 (m, 1H, C2-H), 3.46 (t, J=5.1 Hz, 1H,
C3-H), 3.59 (t, J=6.0 Hz, 2H, C1-H); 13C NMR (125
MHz, CDCl3): l −4.1, −4.0, 15.0, 16.2, 18.2, 21.7, 23.8,
25.3, 26.1, 35.5, 37.9, 42.6, 66.1, 81.1; EI MS: m/z 288
(M+); [h]D −16.6 (c 1, CHCl3).
4.7. (2R,3S,4S)-5-Benzyloxy-3-(tert-butyldimethylsilyl-
oxy)-2,4-dimethyl-pentanal 4
DMSO (1.7 mL, 21.6 mmol) was added dropwise over
15 min to a solution of oxalyl chloride (5.4 mL, 2 M in
CH2Cl2, 10.8 mmol) in dry dichloromethane (25 mL) at
−78°C under an argon atmosphere. After 30 min a
solution of the alcohol 11 (1.9 g, 5.4 mmol) in dry
CH2Cl2 was added via cannula and the mixture was
stirred at −78°C for 1.5 h. Et3N (3.7 mL, 27.5 mmol)
was added dropwise and the mixture was allowed to
warm to room temperature. The reaction was quenched
by addition of aqueous NaHSO4 (1 M, 25 mL). The
4.10. (2R,3R,4S)-3-(tert-Butyldimethylsilyloxy)-2,4,6-
trimethyl-heptanoic acid 2
To a stirred solution of 12 (620 mg, 2.1 mmol) in CCl4
(4 mL), CH3CN (4 mL) and water (6 mL) were added

A. Zampella et al. / Tetrahedron: Asymmetry 13 (2002) 681–685
685
sodium meta-periodate (1.8 g, 8.6 mmol) and
Acknowledgements
RuCl3·H2O (10.8 mg, 0.04 mmol) sequentially. The
mixture was stirred at 25°C for 2 h. Diethyl ether (20
mL) was added and the stirring was continued for 20
min to precipitate black RuO2. The reaction mixture
was dried and filtered through Celite and the solid
residue was washed with ether. The combined organic
phases were concentrated and chromatographed (n-
hexane:EtOAc, 9:1) to give the carboxylic acid 2 (546
This work was supported by grants from MURST
(PRIN 2001) ‘Sostanze naturali ed analoghi sintetici
ad attivita` antitumorale’ Rome, Italy. Mass spectra
were provided by the CRIAS Centro Interdipartimen-
tale di Analisi Strumentale, Faculty of Pharmacy,
University of Naples. The staff are acknowledged. We
acknowledge the ungraduated students Rosa D’Orsi
and Erminia Lauro for their kind assistance. The
NMR spectra were recorded at CRIAS Centro Inter-
dipartimentale di Analisi Strumentale, Faculty of
Pharmacy, University of Naples.
1
mg, 84%); IR (KBr): 1725, 1200, 1100, 800 cm−1; H
NMR (500 MHz, CDCl3): l 0.05 (s, 3H, Si-CH3),
0.08 (s, 3H, Si-CH3), 0.83 (d, J=6.9 Hz, 3H, CH3),
0.85 (d, J=7.0 Hz, 3H, CH3), 0.87 (d, J=7.5 Hz,
3H, CH3), 0.89 (s, 9H, Si-C(CH3)3), 1.09 (m, 1H, C5-
Ha), 1.16 (d, J=7.0 Hz, 3H, CH3), 1.20 (m, 1H,
C5-Hb), 1.61 (m, 1H, C6-H), 1.71 (m, 1H, C4-H),
2.65 (m, 1H, C2-H), 3.78 (dd, J=6.6, 2.9 Hz, 1H,
C3-H); 13C NMR (125 MHz, CDCl3): l −4.5, −4.0,
14.2, 14.7, 18.3, 21.7, 23.5, 25.1, 26.0, 33.9, 42.3, 44.2,
77.9, 180.6; EI MS (relative intensity): m/z 245 (M+−
54, 100), 229 (20), 217 (24), 131 (45); HREI MS: for
C12H25SiO3 found 245.1577, calcd. 245.1573; [h]D
–12.4 (c 2.3, CHCl3).
References
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4.11. (2R,3R,4S)-3-Hydroxy-2,4,6-trimethylheptanoic
acid 13
A solution of HCl in MeOH (2N, 5 mL) was added
to a solution of 2 (35 mg, 0.12 mmol) in methanol (1
mL) at room temperature. The reaction was stirred
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