Asymmetric synthesis of (3S,4R,7S)-(-)-3-hydroxy-7-methoxy-2,2,4-trimethyl- decanoic acid, a plausible polyketide fragment of halipeptin A

Article abstract of DOI:10.1016/S0957-4166(03)00622-0

The first enantioselective synthesis of (3S,4R,7S)-(-)-3-hydroxy-7-methoxy- 2,2,4-trimethyl-decanoic acid 4 in 11 steps and 6% overall yield, starting from commercially available methyl 2,2-dimethyl-3-hydroxy propionate 5 is described. The stereochemical flexible synthetic pathway involves a Brown's crotylboration reaction and a Corey-Bakshi-Shibata (CBS) oxazaborolidine-mediated reduction.

Full text of DOI:10.1016/S0957-4166(03)00622-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3371–3378
Asymmetric synthesis of
(3S,4R,7S)-(−)-3-hydroxy-7-methoxy-2,2,4-trimethyl-decanoic
acid, a plausible polyketide fragment of halipeptin A
Carmela Della Monica, Nakia Maulucci, Francesco De Riccardis* and Irene Izzo*
University of Salerno, Department of Chemistry, via S. Allende, Baronissi, I-84081 (SA), Italy
Received 16 July 2003; accepted 25 July 2003
Abstract—The first enantioselective synthesis of (3S,4R,7S)-(−)-3-hydroxy-7-methoxy-2,2,4-trimethyl-decanoic acid 4 in 11 steps
and 6% overall yield, starting from commercially available methyl 2,2-dimethyl-3-hydroxy propionate 5 is described. The
stereochemical flexible synthetic pathway involves a Brown’s crotylboration reaction and a Corey–Bakshi–Shibata (CBS)
oxazaborolidine-mediated reduction.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
In 2001 Gomez-Paloma et al. reported the isolation and
structure determination of two potent anti-inflamma-
tory cyclic depsipeptides from a marine sponge belong-
ing to the genus Haliclona which were named halipeptin
A and B 1 and 2, respectively (Fig. 1).1
Figure 2.
Accurate NMR studies allowed the partial stereochemi-
cal assignment of 1–3.1,2 The relative stereochemistry at
Figure 1.
C-3 and C-4 of the 3-hydroxy-7-methoxy-2,2,4-
trimethyl-(or 3,7-dihydroxy-2,2,4-trimethyl) decanoic
acid residues, found in the halipetins, was established to
be threo [(3S,4R) or (3R,4S)].
After 1 year a structural revision, prompted by the
isolation of third member of the halipeptins
a
(halipeptin C, 3), was reported. In particular, the het-
erocyclic portion of the molecule, incorrectly assigned
as an oxazetidine ring, was more convincingly charac-
terized as D2-thiazoline by comparison of the natural
products’ spectral data with those recorded from a
synthetic model (Fig. 2).2
In order to settle the basis for future investigations
toward halipeptin A total synthesis and with the idea to
develop a stereochemically flexible synthetic strategy for
the elaboration of its polyketide fragment, here we
report the first asymmetric synthesis of the 3-hydroxy-
7-methoxy-2,2,4-trimethyl-decanoic acid, applied for
the preparation of the (3S,4R,7S) isomer 4.
* Corresponding authors. Tel.: +39-089-965230; fax: +39-089-965296;
e-mail: dericca@unisa.it; iizzo@unisa.it
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00622-0

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C. Della Monica et al. / Tetrahedron: Asymmetry 14 (2003) 3371–3378
2. Results and discussion
Our approach to the stereodefined key intermediate,
methyl (3S,4R)-3-acetoxy-2,2,4-trimethyl-hex-5-enoate
7, was realised using the Brown’s crotylboration
reaction3 on the easily synthesized, methyl 2,2-
dimethyl-3-oxo propionate 6 (Scheme 1). This was
obtained through PDC oxidation4 of the commercially
available methyl 2,2-dimethyl-3-hydroxy propionate 5.
Highly diastereoselective alkylation with the chiral (−)-
(Z)-crotyl-Ipc2-borane and subsequent acetylation of
the crude reaction mixture, gave the expected syn
adduct 7 in 85% e.e.5 and d.r. >99%. Acetylation was
necessary for purification purposes. The observed low
yield (39%) was attributed to the steric congestion
arising from the bulky bis-methylated C-2, adversely
affecting the conformation of the stereodirecting Zim-
merman–Traxler transition state.6 Ozonolysis7 of the
terminal double bond of compound 7, gave the
required, but quite labile, methyl (3S,4S)-3-acetoxy-
2,2,4-trimethyl-5-oxo-pentanoate 8.
Scheme 2. Reagents and conditions: (a) Ts-Cl, Py, CH2Cl2, rt,
12 h, 70%; (b) Ag2O, CH3I, CH3CN, 80°C, 48 h, 91%; (c)
NaI, CH3CN, 80°C then PPh3, CH3CN, 80°C, 48 h, 33%; (d)
n-BuLi, THF, −78°C, 8, then −20°C, 18 h.
to elimination11 free alcohol 15, was planned (Scheme
3). With this alternative plan, the introduction of the
C-7 stereogenic centre had to be postponed to a later
synthetic stage.
Scheme 3. Reagents and conditions: (a) K2CO3 in MeOH,
50°C, 5 h, 89%; (b) O3, CH2Cl2, −78°C then PPh3, rt, 12 h,
80%; (c) 16, DIPEA, LiCl, CH3CN, rt, 28 h, 66% (d) Ac2O,
DMAP, CH2Cl2, rt, 1 h, 96% (e) (R)-MeCBS reagent,
BH3·THF, THF, −20°C, 1 h, 19 (66%), 20 (13%).
Scheme 1. Reagents and conditions: (a) PDC, CH2Cl2, m.s., rt,
3 h, 85%; (b) t-BuOK, n-BuLi, (Z)-2-butene, (−)-Ipc2-
B(OMe), BF3·Et2O, THF, −78°C, 7 h then NaOH, H2O2, rt,
12 h; (c) Ac2O, DMAP, Py, CH2Cl2, rt, 2 h, 39% (two steps);
(d) O3, CH2Cl2, −78°C then PPh3, −20°C, 12 h, 47%.
Thus, deacetylation and subsequent ozonolysis7 of the
methyl hexenoate derivative 7, gave the methyl (3S,4S)-
3-hydroxy-2,2,4-trimethyl-5-oxo-pentanoate 15 in 71%
overall yield. The latter was coupled with the (2-oxo-
pentyl)-phosphonic acid diethyl ester 16, under Masa-
mune–Roush conditions12 to produce, in decent yield, a
geometrically pure (E)-a,b-unsaturated ketone 17, with-
out detectable epimerization at the C-4 stereogenic
centre. Acetylation and stereoselective reduction with
the chiral non-racemic (R)-Me-Corey–Bakshi–Shibata
[(R)-MeCBS] oxazaborolidine–borane reagent,13 used
in stoichiometric quantities, delivered to a 5:1 mixture
of the diastereomeric alcohols 19–20. The C-7 configu-
ration of the major diastereoisomer 20 was confirmed
to be (S), applying the advanced Mosher method14 to
the minor isomer 20, whose configuration proved to be
(R).
The first coupling attempt between aldehyde 8 and
racemic C3 b-methoxy ylid phosphonium reagent (2-
methoxy-propyl)-triphenylphosphonium iodide, 12, sur-
rogate of the requested C5 fragment), made use of the
Wittig reaction.8 12 was chosen as the model being
easily synthesized from 1,2-propandiol 9, as shown in
Scheme 2.
Thus, commercially available 9 was regioselectively
tosylated,9 methylated and converted in the phospho-
nium salt10 12 in 23% overall yield. Unfortunately,
repeated efforts to obtain adduct 13 failed, resulting in
an extensive decomposition of the starting materials.
To reduce the basic strength of the phosphorus stabi-
lized carbanion and with the aim to decrease the base-
sensitivity of the labile b-acetoxy aldehyde 8, a
Horner–Wadsworth–Emmons
coupling
reaction,
Finally, non-deoxygenative D5-hydrogenation,15 O-
methylation with Ag2O in refluxing acetonitrile16 and
between the b-ketophosphonate 16 and the less prone

C. Della Monica et al. / Tetrahedron: Asymmetry 14 (2003) 3371–3378
3373
KOH-mediated hydrolysis of the methyl (3S,4R,7S)-3-
4.1. 2,2-Dimethyl-3-oxo-propionic acid methyl ester 6
acetoxy-7-methoxy-2,2,4-trimethyl-decanoate 22 fur-
nished the requested 4 in 65% overall yield from 19
(Scheme 4).
To a solution of 3-hydroxy-2,2-dimethyl-propionic acid
methyl ester (2.1 g, 15.0 mmol) in dry CH2Cl2 (12.0 ml),
4 A molecular sieves (4.2 g) and PDC (11.6 g, 30.0
,
mmol) were added. The mixture was stirred at room
temperature for 3 h, then diluted with diethyl ether
(25.0 ml) and allowed to stir for additional 45 min.
Filtration through a short pad of silica gel (particle size
0.063–0.200 mm) and CaSO4 (10% in weight) afforded
a solution, which was concentrated in vacuo. The
residue was flash-chromatographed under N2 (30%
diethyl ether in petroleum ether) to afford 6 (1.7 g,
85%) as a pale yellow oil. Rf=0.45 (30% diethyl ether in
petroleum ether). 1H NMR (CDCl3): l 1.35 (6H, s,
-C(CH3)2), 3.75 (3H, s, -COOCH3), 9.66 (1H, s, -CHO).
13C NMR (CDCl3): l 19.7 (×2), 52.5, 70.7, 173.2, 199.0.
HR-EIMS m/z 130.0634 (M+) (calcd 130.0630 for
C6H10O3).
Scheme 4. Reagents and conditions: (a) H2, Pt/C, NEt3,
MeOH, 3 h, 87%; (b) Ag2O, CH3I, CH3CN, 80°C, 48 h, 80%;
(c) 10% aq. KOH, MeOH, 60°C, 8 h, 94%.
3. Conclusion
In summary, we have demonstrated a viable route for
the asymmetric synthesis of the (3S,4R,7S)-(−)-3-
hydroxy-7-methoxy-2,2,4-trimethyl-decanoic acid 4,
based on the Brown’s crotylboration and the CBS
oxazaborolidine-mediated reduction, as key steps. The
flexibility of the asymmetric approach and the choice of
the synthetic sequence allow easy elaboration of alter-
native stereochemical arrangements, necessary for the
C-3 and C-4 configuration assignment. Further studies
are underway toward the total synthesis of 1b.
4.2. (3S,4R)-3-Acetoxy-2,2,4-trimethyl-hex-5-enoic acid
methyl ester 7
A mixture of (Z)-2-butene (1.2 ml, 13.0 mmol) and
t-BuOK (1 M in THF, 7.8 ml, 7.8 mmol) was cooled to
−78°C, and n-BuLi (1.6 M in hexane, 4.9 ml, 7.8 mmol)
was added dropwise. The resultant bright yellow solu-
tion was stirred at −45°C for 15 min and recooled to
−78°C. A solution of (−)-Ipc2BOMe (2.9 g, 9.1 mmol)
in dry THF (15.0 ml) was then introduced dropwise
and the mixture was further stirred for 30 min. After
dropwise treatment with BF3·Et2O (1.2 ml, 9.8 mmol),
aldehyde 6 (0.850 g, 6.50 mmol) in dry THF (15.0 ml)
was immediately added dropwise and the mixture was
allowed to stir at −78°C for 7 h. The reaction mixture
was treated with 3N NaOH (15.0 ml) and 30% H2O2
(7.0 ml) and then it was allowed to slowly warm to
room temperature and to stir overnight. The mixture
was concentrated in vacuo to remove the excess THF
and the aqueous layer was diluted with brine followed
by extraction with diethyl ether (3×50.0 ml). The com-
bined organic phases were dried over MgSO4, filtered
and concentrated. The crude residue was dissolved in
dry CH2Cl2 (20.0 ml) under N2 at room temperature.
To this solution was added dry pyridine (9.12 ml, 118.0
mmol) followed by Ac2O (8.8 ml, 93.0 mmol) and
DMAP (0.230 g, 1.9 mmol). The resulting mixture was
stirred for 2 h at room temperature and then quenched
with 2N HCl until pH 4–5. The mixture was extracted
with CH2Cl2 (3×40.0 ml) and the combined organic
layers were washed successively with saturated
NaHCO3 and brine, dried, filtered and concentrated in
vacuo. The residue was flash-chromatographed (5–30%
diethyl ether in petroleum ether) to give pure 7 (0.568 g,
39% for two steps) as a pale yellow oil. Rf=0.5 (20%
4. Experimental
All reactions were carried out under a dry argon atmo-
sphere using freshly distilled solvents, unless otherwise
noted. Tetrahydrofuran (THF) was distilled from
LiAlH4. Toluene and methylene chloride were distilled
from calcium hydride. Glassware was flame-dried (0.05
Torr) prior to use. When necessary, compounds were
dried in vacuo over P2O5 or by azeotropic removal of
water with toluene under reduced pressure. Starting
materials and reagents purchased from commercial sup-
pliers were generally used without purification. Reac-
tion temperatures were measured externally; reactions
were monitored by TLC on Merck silica gel plates (0.25
mm) and visualized by UV light, I2, or spraying with
KMnO4, p-anysaldehyde or phosphomolybdic acid
solutions and drying.
Flash chromatography was performed on Merck silica
gel (60, particle size: 0.040–0.063 mm). Yields refer to
chromatographically and spectroscopically (1H and 13C
NMR) pure materials. The NMR spectra were recorded
at room temperature on a Bruker DRX 400 spectrome-
ter (400 MHz). Chemical shifts are reported relative to
the residual solvent peak (CHCl3: l=7.26, 13CDCl3:
l=77.0; CD2HOD: l=3.34, 13CD3OD: l=49.0). Elec-
tron impact (EIMS) spectra (EI, 70 eV) were performed
on a VG TRIO 2000 mass spectrometer. Optical rota-
1
diethyl ether in petroleum ether). H NMR (CDCl3): l
0.94 (3H, d, J=6.8 Hz, -CHCH3), 1.12 (3H, s,
-C(CH3)CH3), 1.19 (3H, s, -C(CH3)CH3), 2.09 (3H, s,
O2CCH3), 2.45 (1H, m, CH2=CH-CH-), 3.61 (3H, s,
-COOCH3), 4.92 (1H, d, J=10.3 Hz, HCH=CH-), 5.02
(1H, d, J=17.1 Hz, HCH=CH-), 5.23 (1H, d, J=8.9
Hz, -CH-OOCCH3), 5.56 (1H, m, CH2=CH-). 13C
tions were measured with
polarimeter.
a
JASCO DIP-1000

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C. Della Monica et al. / Tetrahedron: Asymmetry 14 (2003) 3371–3378
NMR (CDCl3): l 17.9, 18.6, 20.7, 24.4, 40.6, 46.0, 51.5,
78.6, 115.2, 139.7, 170.5, 176.1. HR-EIMS m/z
228.1368 (M+) (calcd 228,1362 for C12H20O4). [h]2D5=
+8.5 (c 1.0, CHCl3).
NMR (CDCl3): l 1.12 (3H, d, J=6.4 Hz, CH3-
CHOCH3), 2.45 (3H, s, Ph-CH3), 3.29 (3H, s, -CH-
OCH3), 3.55 (1H, m, -CHOCH3), 3.95 (2H, bd,
TsOCH2-CHOMe), 7.34 (2H, d, J=8.1 Hz, -C6H4-),
7.78 (2H, d, J=8.1 Hz, -C6H4-). HR-EIMS m/z
244.0765 (M+) (calcd 244,0765 for C11H16O4S).
4.3. (3S,4S)-3-Acetoxy-2,2,4-trimethyl-5-oxo-pentanoic
acid methyl ester 8 and 2,2,4-trimethyl-5-oxo-pent-3-
enoic acid methyl ester 8a
4.6. (2-Methoxy-propyl)-triphenylphosphonium iodide 12
A stream of O2/O3 was bubbled through a solution of 7
(0.099 g, 0.43 mmol) in dry CH2Cl2 (20.0 ml) at −78°C
until a faint blue color persisted. A stream of argon was
then bubbled through the solution until it became
colorless. Triphenylphosphine (0.137 g, 0.52 mmol) was
added and the mixture was allowed to warm to −20°C
and to stir overnight. The solution was then concen-
trated and the residue was flash-chromatographed (20–
30% diethyl ether in petroleum ether) to give 8 (0.046 g,
47%) and 8a (0.013 g, 17%). 8: Rf=0.25 (40% diethyl
To a solution of 11 (1.05 g, 4.3 mmol) in dry acetoni-
trile (12.0 ml), under N2 at room temperature NaI
(0.873 g, 5.8 mmol) was added and the mixture was
stirred and refluxed for 24 h. After cooling the suspen-
sion was filtered washing with acetonitrile. The yellow
solution was then treated with triphenylphosphine (2.25
g, 8.6 mmol) and the mixture was allowed to warm
until reflux temperature and stirred for 20 h. After
cooling the solvent was removed under reduced pres-
sure to give a crude residue. The solid was washed with
petroleum ether and then purified by silica gel column
chromatography (5% methanol in dichloromethane) to
give 12 (0.640 g, 33% for two steps). Rf=0.4 (5%
1
ether in petroleum ether). H NMR (CDCl3): l 1.02
(3H, d, J=7.2 Hz, -CH-CH3), 1.22 (6H, s, -C(CH3)2),
2.05 (3H, s, -O2CCH3), 2.52 (1H, m, CHO-CH-), 3.66
(3H, s, -COOCH3), 5.45 (1H, d, J=4.4 Hz, -CH-
OOCCH3), 9.60 (1H, s, OHC-). 13C NMR (CDCl3): l
9.6, 20.4, 20.5, 22.6, 46.7, 47.1, 52.2, 74.7, 170.4, 175.6,
201.7. HR-EIMS m/z 230.1150 (M+) (calcd 230,1154
for C11H18O5). [h]D25=+13.1 (c 1.0, CHCl3). 8a: 1H
NMR (CDCl3): l 1.45 (6H, s, -C(CH3)2), 1.68 (3H, s,
=C(CHO)CH3), 3.72 (3H, s, COOCH3), 6.45 (1H, s,
CH=CCH3), 9.36 (1H, s, OHC-). HR-EIMS m/z
170.0947 (M+) (calcd 170,0943 for C9H14O3).
1
methanol in dichloromethane). H NMR (CD3OD): l
1.40 (3H, bdd, J=5.4, 2.6 Hz, CH3-CHOMe), 2.79 (3H,
s, -CHOCH3), 3.47 (1H, m, CH3-CHOMe), 3.61 (1H,
+ −
ddd, J=14.7, 13.5, 3.4 Hz, -HCHPPh3 I ), 3.84 (1H,
+ −
ddd, 15.7, 13.5, 11.2 Hz, -HCHPPh3 I ), 7.78 (15H, m,
-P+(C6H5)3). 13C NMR l (CD3OD): 19.4 (J=14.7 Hz),
32.5 (J=53 Hz), 56.0, 72.6 (J=5.7 Hz), 131.1 (J=13.6
Hz), 135.1 (J=9.9 Hz), 135.8. HR-EIMS m/z 461.0536
(M+) (calcd 461,0531 for C22H23IOP).
4.4. Toluene-4-sulfonic acid 2-hydroxy-propyl ester 10
4.7. Attempt to synthesise (3S,4R)-3-Acetoxy-7-
methoxy-2,2,4-trimethyl-oct-5-enoic acid methyl ester 13
To solution of 1,2-propandiol (1.49 g, 19.0 mmol) in
dry CH2Cl2 (25.0 ml), dry pyridine (2.4 ml, 30.0 mmol)
was added at 0°C followed by addition of tosyl chloride
(4.2 g, 22.0 mmol) over 3 h. The reaction mixture was
allowed to warm to room temperature and to stir
overnight. The reaction was treated with aq. 2N HCl
and extracted with CH2Cl2 (3×30.0 ml). The organic
layer was washed with saturated aq. NaHCO3 and
water. The combined organic phases were dried over
MgSO4, filtered and concentrated in vacuo. The residue
was flash-chromatographed (30–70% diethyl ether in
petroleum ether) to give 10 (3.06 g, 70%). Rf=0.5 (50%
A suspension of 12 (0.435 g, 0.920 mmol) in dry THF
(15.0 ml) was cooled to −78°C, under N2, and n-BuLi
(1.6 M in hexane, 0.540 ml, 0.864 mmol) was added
dropwise. The brown mixture was stirred for 1 h and
then a solution of 8 (0.103 g, 0.460 mmol) in dry THF
(5.0 ml) was slowly added via cannula. After 3 h at
−78°C, the reaction mixture was allowed to warm to
−20°C and to stir overnight. After quenching with
water (3.0 ml), the mixture was allowed to warm to
room temperature and then concentrated in vacuo to
remove the excess THF. The aqueous residue was
extracted with diethyl ether (3×5.0 ml). The combined
organic phases were dried over MgSO4, filtered and
1
ethyl acetate in petroleum ether). H NMR (CDCl3): l
1.13 (3H, d, J=6.4 Hz, CH3-CHOH-), 2.43 (3H, s,
Ph-CH3), 3.83 (1H, dd, J=9.9, 7.1 Hz, TsOCHH-),
3.96 (1H, dd, J=9.9, 3.2 Hz, TsOCHH-), 4.01 (1H, m,
-CHOH-), 7.34 and 7.78 (2×2H, 2×d, J=8.1 Hz,
-C6H4-). HR-EIMS m/z 230.0617 (M+) (calcd 230,0617
for C10H14O4S).
1
concentrated. H NMR (CDCl3) of crude yellow solid
residue did not reveal the presence of desired product
13.
4.8. (3S,4R)-3-Hydroxy-2,2,4-trimethyl-hex-5-enoic acid
methyl ester 14
4.5. Toluene-4-sulfonic acid 2-methoxy-propyl ester 11
Compound 7 (0.590 g, 2.60 mmol) was dissolved in
methanol (10.0 ml) and K2CO3 (0.018 g, 0.13 mmol)
was added. The reaction mixture was stirred for 5 h at
50°C and then quenched with CHCl3 (7.0 ml). Solvents
were concentrated in vacuo to the half of their volume.
The procedure was repeated several times to precipitate
the carbonate. The solution was concentrated in vacuo
and the residue was flash-chromatographed (10–20%
Compound 10 (0.163 g, 0.71 mmol) was dissolved in
dry acetonitrile (2.0 ml) and methyl iodide (0.624 g, 4.4
mmol) and kept in the dark. Ag2O (0.376 g, 2.2 mmol)
was added. The mixture was refluxed and stirred for 2
days then it was filtered and the filtrate was concen-
trated to afford pure 11 (0.159 g, 91%) as an oil.
Rf=0.6 (30% ethyl acetate in petroleum ether). 1H

C. Della Monica et al. / Tetrahedron: Asymmetry 14 (2003) 3371–3378
3375
diethyl ether in petroleum ether) to give 14 (0.432 g;
89%). Rf=0.3 (30% diethyl ether in petroleum ether).
1H NMR (CDCl3): l 0.99 (3H, d, J=6.7 Hz, -CHCH3),
1.20 (3H, s, -C(CH3)CH3), 1.24 (3H, s, -C(CH3)CH3),
2.36 (1H, m, CH2=CH-CH-), 3.58 (1H, d, J=5.7 Hz,
-CH-OH), 3.66 (3H, s, -COOCH3), 4.93 (1H, d, J=10.3
Hz, HCH=CH-), 4.99 (1H, d, J=17.2 Hz, HCH=CH-
), 5.74 (1H, m, CH2=CH-). 13C NMR (CDCl3): l 15.7,
22.4, 22.7, 41.1, 46.3, 51.8, 79.5, 113.9, 142.1, 178.2.
HR-EIMS m/z 186.1260 (M+) (calcd 186,1256 for
C10H18O3). [h]2D5=+12.2 (c 1.0, CHCl3).
pyridine (0.046 ml, 0.57 mmol) a catalytic amount of
DMAP and (S)-MTPA-Cl (0.021 ml, 0.11 mmol) were
added. The reaction was stirred for 1 h at room temper-
ature. The solvents were then removed under N2 stream
and the crude residue was flash-chromatographed (5–
10% diethyl ether in petroleum ether) to give 14c (0.013
1
g). H NMR (CDCl3): l 0.98 (6H, s, -C(CH3)2), 1.10
(3H, d, J=6.9 Hz -CHCH3), 2.52 (1H, m, CH2=CH-
CH-), 3.24 (1H, d, J=6.5 Hz, -CH-OBn), 3.54 (3H, s,
-OCH3), 4.07 (1H, d, J=10.6 Hz, -CHHOOC), 4.25
(1H, d, J=11.3 Hz, -CH-O-CHH-Ph), 4.29 (1H, d,
J=10.6 Hz, -CHHOOC-), 4.52 (1H, d, J=11.3 Hz,
-CH-O-CHH-Ph), 4.93 (1H, d, J=10.5 Hz, HCH=
CH), 4.98 (1H, d, J=17.2 Hz, HCH=CH), 5.85 (1H,
m, CH2=CH-), 7.40 (10H, m, -OCH2-C6H5+-OOC-C-
C6H5).
4.9.
(3S,4R)-3-Benzyloxy-2,2,4-trimethyl-hex-5-enoic
acid methyl ester 14a
Compound 14 (0.100 g, 0.540 mmol) was dissolved in
dry acetonitrile (2.0 ml) and benzyl bromide (0.260 g,
1.60 mmol) in a reacti-vial in the dark. Ag2O (0.174 g,
0.80 mmol) was added. The mixture was refluxed and
stirred overnight, then filtered and concentrated. Flash
chromatography of the residue (1–30% diethyl ether in
4.12. Mosher ester 14d
To a solution of 14b (0.006 g, 0.023 mmol) in dry
pyridine (0.046 ml, 0.57 mmol) a catalytic amount of
DMAP and (R)-MTPA-Cl (0.021 ml, 0.11 mmol) were
added. The reaction was stirred for 1 h at room temper-
ature. The solvents were then removed under N2 stream
and the crude residue was flash-chromatographed (5–
10% diethyl ether in petroleum ether) to give 14d (0.013
g). 1H NMR (CDCl3): l 0.97 (3H, s, -C(CH3)CH3), 0.98
(3H, s, -C(CH3)CH3), 1.09 (3H, d, J=6.9 Hz,
-CHCH3), 2.51 (1H, m, CH2=CH-CH-), 3.23 (1H, d,
J=6.5 Hz, -CH-OBn), 3.53 (3H, s, -OCH3), 4.16 (1H,
d, J=10.6 Hz, -CHHOCO), 4.25 (1H, d, J=11.3 Hz,
-CH-O-CHH-Ph), 4.32 (1H, d, J=10.6 Hz,
-CHHOCO-), 4.57 (1H, d, J=11.3 Hz, -CH-O-CHH-
Ph), 4.93 (1H, d, J=10.5 Hz, HCH=CH), 4.98 (1H, d,
J=17.2 Hz, HCH=CH), 5.85 (1H, m, CH2=CH-),
7.40 (10H, m, -OCH2-C6H5+-OOC-C-C6H5).
1
petroleum ether) gave 14a (0.046 g, 31%) as an oil. H
NMR (CDCl3): l 1.13 (3H, d, J=6.7 Hz, -CHCH3),
1.19 (3H, s, -C(CH3)CH3), 1.28 (3H, s, -C(CH3)CH3),
2.43 (1H, m, CH2=CH-CH-), 3.60 (3H, s, -COOCH3),
3.66 (1H, d, J=6.5 Hz, -CH-OBn), 4.54 (1H, d, J=
12.9 Hz, -CH-O-CHH-Ph), 4.67 (1H, d, J=12.9 Hz,
-CH-O-CHH-Ph), 4.91 (1H, d, J=10.2 Hz, HCH=
CH-), 5.00 (1H, d, J=17.2 Hz, HCH=CH), 5.71 (1H,
m, CH2=CH-), 7.36 (5H, m, -OCH2-C6H5). HR-EIMS
m/z 276.1730 (M+) (calcd 276,1725 for C11H18O5).
4.10. (3S,4R)-3-Benzyloxy-2,2,4-trimethyl-hex-5-en-1-ol
14b
To a solution of 14a (0.046 g, 0.17 mmol) in dry THF
(1.0 ml), at 0°C, LiAlH4 (1 M in THF, 0.510 ml, 0.510
mmol) was added dropwise. The reaction mixture was
stirred at the same temperature for 1 h and the
quenched with ethyl acetate. The solution was then
treated with 30% aq. NH4OH (2.0 ml). The suspension
was filtered on a pad of Celite® washing with ethyl
acetate. Solvents were removed in vacuo and the
residue was flash-chromatographed (10–30% diethyl
ether in petroleum ether) to give 14b (0.017 g, 41%).
Rf=0.4 (30% diethyl ether in petroleum ether). 1H
NMR (CDCl3): l 0.92 (3H, s, -C(CH3)CH3), 0.99 (3H,
s, -C(CH3)CH3), 1.17 (3H, d, J=6.9 Hz, -CHCH3), 2.58
(1H, m, CH2=CH-CH-), 3.33 (1H, d, J=10.9 Hz,
-CHHOH), 3.35 (1H, d, J=6.5 Hz, -CH-OBn), 3.55
(1H, d, J=10.9 Hz, -CHHOH), 4.45 (1H, d, J=11.1
Hz, -CH-O-CHH-Ph), 4.65 (1H, d, J=11.1 Hz, -CH-O-
CHH-Ph), 4.98 (1H, d, J=10.5 Hz, HCH=CH-), 5.04
(1H, d, J=17.2 Hz, HCH=CH), 5.96 (1H, m, CH2=
CH-), 7.30 (5H, m, -OCH2-C6H5). 13C NMR (CDCl3):
l 15.0, 20.9, 23.7, 38.5, 40.5, 71.3, 74.7, 89.6, 112.8,
127.7 (×3), 128.4 (×2), 138.1, 145.2. HR-EIMS m/z
248.1780 (M+) (calcd 248,1776 for C16H24O2). [h]2D5=
+29.8 (c 1.0, CHCl3).
4.13. (3S,4S)-3-Hydroxy-2,2,4-trimethyl-5-oxo-
pentanoic acid methyl ester 15
A stream of O2/O3 was bubbled through a solution of
14 (0.290 g, 1.50 mmol) in dry CH2Cl2 (40.0 ml) at
−78°C until a faint blue color persisted. A stream of
argon was then bubbled through the solution until it
became colorless. Triphenylphosphine (0.490 g, 1.90
mmol) was added and the mixture was allowed to warm
to room temperature and stir overnight. The solution
was then concentrated and the residue was flash-chro-
matographed (30–70% diethyl ether in petroleum ether)
to give 15 (0.226 g, 80%). Rf=0.20 (50% diethyl ether in
petroleum ether). 1H NMR (CDCl3): l 1.04 (3H, d,
J=7.1 Hz, -CHCH3), 1.18 (3H, s, -C(CH3)CH3), 1.28
(3H, s, -C(CH3)CH3), 2.51 (1H, m, CHO-CH-), 3.45
(1H, d, J=7.9 Hz, -OH), 3.68 (3H, s, COOCH3), 4.13
(1H, dd, J=7.9, 3.5 Hz, -CH-OH), 9.61 (1H, s, OHC-).
13C NMR (CDCl3): l 7.9, 21.7, 24.0, 45.8, 48.6, 52.2,
74.9, 178.0, 203.6. HR-EIMS m/z 188.1045 (M+) (calcd
188,1049 for C9H16O4). [h]2D5=13.8 (c 1.0, CHCl3).
4.14. (2-Oxo-pentyl)-phosphonic acid diethyl ester 16
4.11. Mosher ester 14c
To a stirred solution of diethylmethylphosphonate (1.30
To a solution of 14b (0.006 g, 0.023 mmol) in dry
g, 8.30 mmol) in dry THF (2.0 ml) at −78°C, under N2,

3376
C. Della Monica et al. / Tetrahedron: Asymmetry 14 (2003) 3371–3378
4.16.
(3S,4R)-3-Acetoxy-2,2,4-trimethyl-7-oxo-dec-5-
was added n-BuLi (1.6 M in hexane, 6.10 ml, 9.70
mmol) dropwise. The resultant yellow solution was
stirred for 45 min before a solution of butyric aldehyde
(0.500 g, 6.90 mmol) in dry THF (3.0 ml) was added
slowly via cannula. The solution was stirred for an
additional 2 h. Brine (10.0 ml) was added, and the
mixture was allowed to warm to room temperature.
THF was removed in vacuo and the aqueous residue
was extracted with ethyl acetate (3×10.0 ml). The com-
bined organic phases were dried over Na2SO4, filtered
and concentrated. The crude residue was dissolved in
enoic acid methyl ester 18
To a solution of 17 (0.126 g, 0.492 mmol) in dry
CH2Cl2 (5.0 ml) under N2 at room temperature was
added DMAP (0.240 g, 1.97 mmol) followed by Ac2O
(0.200 ml, 1.72 mmol). The resulting mixture was
stirred for 1 h at room temperature and then quenched
with 0.1 N aq. HCl. The mixture was extracted with
CH2Cl2 (3×10.0 ml) and the combined organic layers
were washed successively with saturated NaHCO3 and
brine, dried, filtered and concentrated in vacuo. The
residue was flash-chromatographed (30–40% diethyl
ether in petroleum ether) to give pure 18 (0.141 g, 96%)
as an oil. Rf=0.5 (40% diethyl ether in petroleum
,
dry CH2Cl2 (8.0 ml) and 4 A molecular sieves (3.1 g)
and PDC (5.2 g, 13.8 mmol) were added. The mixture
was stirred at room temperature for 2 h, then diluted
with diethyl ether (8.0 ml) and allowed to stir for
additional 45 min. Filtration with ethyl acetate through
a short pad of silica gel (particle size 0.063–0.200 mm)
and CaSO4 (10% in weight) afforded a solution which
was concentrated in vacuo. The crude oil was flash-
chromatographed (80–100% ethyl acetate in petroleum
ether and then 10% methanol in ethyl acetate) to give
16 as a yellow oil (0.921 g, 50% for two steps). Rf=0.45
1
ether). H NMR (CDCl3): l 0.89 (3H, t, J=7.4 Hz,
CH3-CH2-), 0.98 (3H, d, J=6.8 Hz, CH3-CH-), 1.09
(3H, s, -C(CH3)CH3), 1.15 (3H, s, -C(CH3)CH3), 1.62
(2H, m, CH3-CH2-CH2-), 2.07 (3H, s, O2CCH3), 2.45
(2H, m, -CH2CO), 2.57 (1H, m, CH3CH-), 3.56 (3H, s,
-COOCH3), 5.26 (1H, d, J=8.6 Hz, -CH-OAc), 6.02
(1H, d, J=15.9 Hz, OC-CH=CH-), 6.56 (1H, dd,
J=15.9 Hz and J=9.7 Hz, OC-CH=CH-). 13C NMR
(CDCl3): l 13.7, 17.2, 17.3, 18.6, 20.6, 24.3, 39.3, 42.2,
46.1, 51.9, 77.8, 130.0, 146.6, 170.3, 175.7, 200.3. HR-
EIMS m/z 298.1775 (M+) (calcd 298,1780 for
C16H26O5). [h]2D5=+30.6 (c 1.0, CHCl3).
1
(ethyl acetate). H NMR (CDCl3): l 0.85 (3H, t, J=7.3
Hz, CH3CH2CH2C=O), 1.27 (6H, t, J=7.1 Hz,
CH3CH2O-), 1.55 (2H, m, CH3CH2CH2C=O), 2.54
(2H, t, J=7.2 Hz, CH3CH2CH2C=O), 3.00 (2H, d,
J=22.8 Hz, O=C-CH2-P=O), 4.08 (4H, m,
CH3CH2O-). 13C NMR (CDCl3): l 13.4, 16.2 (×2),
16.8, 42.3 (J=126 Hz), 45.8, 62.4, 62.5, 202.0. HR-
EIMS m/z 222.1025 (M+) (calcd 222,1021 for
C9H19O4P).
4.17. (3S,4R,7S)-3-Acetoxy-7-hydroxy-2,2,4-trimethyl-
dec-5-enoic acid methyl ester 19 and (3S,4R,7R)-3-ace-
toxy-7-hydroxy-2,2,4-trimethyl-dec-5-enoic acid methyl
ester 20
(R)-Me-CBS reagent (1 M in toluene, 0.470 ml, 0.470
mmol) and BH3·THF (1 M in THF, 0.700 ml, 0.700
mmol) were mixed, under N2 and at room temperature,
and allowed to stir for 15 min. The mixture was cooled
at −20°C and a solution of 18 (0.141 g, 0.470 mmol)
dissolved in dry THF (5.0 ml) was then added via
cannula. The reaction mixture was stirred for 1 h.
Methanol (10.0 ml) was then added and the solution
was stirred for an additional hour and allowed to warm
to room temperature. The solvents were then removed
in vacuo and the crude was flash-chromatographed
(40–100% diethyl ether in petroleum ether) to give 19
(0.093 g; 66%) and 20 (0.018 g, 13%). 19: Rf=0.55 (50%
4.15. (3S,4R)-3-Hydroxy-2,2,4-trimethyl-7-oxo-dec-5-
enoic acid methyl ester 17
To a mixture of LiCl (dried overnight at 140°C at 0.5
Torr, 0.022 g, 0.48 mmol) and 16 (0.100 g, 0.45 mmol)
in dry acetonitrile (3.0 ml) at room temperature under
N2 dry diisopropylethylamine (0.072 ml, 0.415 mmol)
was added. The resultant yellow solution was stirred for
15 min before a solution of 15 (0.065 g, 0.346 mmol) in
dry acetonitrile (3.0 ml) was added via cannula. After
the reaction mixture was stirred for 28 h, it was diluted
with ethyl acetate, washed with 1N aq. HCl, H2O and
brine. The organic phase was dried on Na2SO4, filtered
and concentrated in vacuo. The residue was flash-chro-
matographed (30–50% diethyl ether in petroleum ether)
to give 17 (0.058 g, 66%). Rf=0.40 (50% diethyl ether in
petroleum ether). 1H NMR (CDCl3): l 0.92 (3H, t,
J=7.3 Hz, CH3CH2-), 1.04 (3H, d, J=6.8 Hz,
-CHCH3), 1.19 (3H, s, -C(CH3)CH3), 1.24 (3H, s,
-C(CH3)CH3), 1.61 (2H, m, CH3CH2-), 2.50 (3H, m,
CH3CH2CH2CO+=CH-CH-, overlapped), 2.99 (1H, d,
J=7.9 Hz, -OH), 3.64 (1H, d, J=7.9, 5.9 Hz, -CHOH),
3.65 (3H, s, COOCH3), 6.05 (1H, d, J=15.8 Hz, OC-
CH=), 6.76 (1H, dd, J=15.8, 8.7 Hz, OC-CH=CH).
13C NMR (CDCl3): l 13.8, 15.2, 17.5, 22.6, 22.7, 39.9,
42.0, 46.3, 52.1, 79.1, 129.3, 149.6, 178.0, 200.8. HR-
EIMS m/z 256.1680 (M+) (calcd 256,1675 for
C14H24O4). [h]2D5=+12.1 (c 1.0, CHCl3).
1
diethyl ether in petroleum ether). H NMR (CDCl3): l
0.88 (3H, t, J=6.7 Hz, -CH2CH3), 0.90 (3H, d, J=6.6
Hz, -CHCH3), 1.07 (3H, s, -C(CH3)CH3), 1.13 (3H, s,
-C(CH3)CH3), 1.25–1.44 (4H, m, -CH2 overlapped),
1.83 (1H, bs, -OH), 2.05 (3H, s, -Ac), 2.39 (1H, m,
-CHCH3), 3.63 (3H, s, -OCH3) 3.96 (1H, m, -CHOH),
5.19 (1H, d, J=8.8 Hz, -CHOAc), 5.36 (1H, dd, J=
15.5, 9.2 Hz, HOCHCH=CH), 5.50 (1H, dd, J=15.5,
5.9 Hz, HOCHCH=CH). 13C NMR (CDCl3): l 14.0,
18.2, 18.5 (×2), 20.7, 24.5, 39.0, 39.4, 46.1, 51.7, 71.5,
78.8, 131.2, 134.3, 170.6, 176.3. HR-EIMS m/z
300.1941 (M+) (calcd 300,1937 for C16H28O5). [h]2D5=
+24.2 (c 1.0, CHCl3). 20: Rf=0.45 (50% diethyl ether in
petroleum ether). 1H NMR (CDCl3): l 0.90 (3H, t,
J=6.7 Hz, -CH2CH3), 0.92 (3H, d, J=6.6 Hz,
-CHCH3), 1.09 (3H, s, -C(CH3)CH3), 1.18 (3H, s,
-C(CH3)CH3), 1.24–1.42 (3H, m, -CH2CHHCHOH

C. Della Monica et al. / Tetrahedron: Asymmetry 14 (2003) 3371–3378
3377
overlapped), 1.54 (1H, m, -CH2CHHCHOH over-
lapped), 2.10 (3H, s, -Ac), 2.24 (1H, bs, -OH), 2.42 (1H,
m, -CHCH3), 3.68 (3H, s, -OCH3) 3.88 (1H, m,
-CHOH), 5.20 (1H, dd, J=15.3, 10.0 Hz, HOCHCH=
CH), 5.23 (1H, d, J=9.7 Hz, -CHOAc), 5.20 (1H, dd,
J=15.3, 8.0 Hz, HOCHCH=CH). 13C NMR (CDCl3)
l 14.0, 17.5, 18.3, 18.5, 20.8, 25.1, 38.6, 40.1, 46.0, 51.8,
73.2, 78.4, 131.9, 134,9, 170.7, 177.5. HR-EIMS m/z
300.1941 (M+) (calcd 300,1937 for C16H28O5). [h]2D5=
−1.8 (c 0.6, CHCl3).
4.20. (3S,4R,7S)-3-Hydroxy-7-methoxy-2,2,4-trimethyl-
decanoic acid 4
To a solution of 22 (0.050 g, 0.160 mmol) in methanol
(3.0 ml), 10% aqueous KOH was added (0.360 ml,
0.640 mmol) and the mixture was stirred at 60°C for 8
h. The reaction was then treated with aqueous 1 M HCl
until pH 4 and then extracted with ethyl acetate (3×5.0
ml). The organic phase was dried on Na2SO4, filtered
and concentrated in vacuo. The residue was flash-chro-
matographed (50–70% ethyl acetate in petroleum ether)
to give 4 (0.039 g, 94%). Rf=0.4 (50% ethyl acetate in
petroleum ether). 1H NMR (CDCl3): l 0.82 (3H, d,
J=6.8 Hz, -CHCH3), 0.90 (3H, t, J=7.3 Hz,
-CH2CH3), 1.15 (3H, s, -C(CH3)CH3), 1.34 (3H, s,
-C(CH3)CH3), 1.35–1.49 (8 H, m, CH2 overlapped),
1.69 (1H, m, -CHCH3), 3.16 (1H, m, -CHOCH3), 3.31
(3H, s, -CHOCH3), 3.53 (1H, bs, -CHOH). 13C NMR
(CDCl3): l 12.9, 14.3, 18.5, 21.6, 25.6, 30.8 (×2), 34.6,
35.4, 45.1, 56.3, 79.9, 81.1, 181.9. HR-EIMS m/z
260.1984 (calcd 260,1988 for C14H28O4). [h]2D5=−31.8 (c
1.0, CHCl3).
4.18. (3S,4R,7S)-3-Acetoxy-7-hydroxy-2,2,4-trimethyl-
decanoic acid methyl ester 21
To a solution of 19 (0.430 mmol, 0.129 g) in methanol
(6.0 ml) triethylamine (0.006 ml, 0.04 mmol) and a
catalytic amount of 5% platinum on carbon were
added. The flask was evacuated (50 Torr) and flushed
three times with hydrogen. The reaction mixture was
then stirred vigorously under hydrogen for 3 h. It was
filtered through a pad of Celite® and concentrated.
Flash chromatography of the residue (50–90% diethyl
ether in petroleum ether) gave 21 (0.113 mg, 87%) as a
colorless oil. (Found: C, 63.1; H, 10.1. C16H30O5
requires: C, 63.5; H, 10.0). Rf=0.45 (60% diethyl ether
Acknowledgements
1
in petroleum ether). H NMR (CDCl3): l 0.80 (3H, d,
This work has been supported by the MIUR (‘PRIN:
Chimica dei Composti Organici di Interesse Biologico’)
and by the Universita` degli Studi di Salerno.
J=6.7 Hz, CH3CH-), 0.87 (3H, t, J=6.8 Hz, CH3CH2-),
1.11 (3H, s, -C(CH3)CH3), 1.13 (3H, s, -C(CH3)CH3),
1.21–1.42 (8H, m, CH3CH2CH2CH(OH)CH2CH2-,
overlapped), 1.65 (1H, m, CH3CH-), 1.82 (1H, bs,
-CHOH), 2.02 (3H, s, OCCH3), 3.48 (1H, m, -CHOH),
3.61 (3H, s, COOCH3), 5.08 (1H, d, J=3.5 Hz,
-CHOAc). 13C NMR (CDCl3): l 14.1, 15.3, 18.8, 20.3,
20.7, 23.1, 31.4, 34.2, 34.8, 39.6, 46.7, 51.9, 71.3, 79.0,
170.7, 176.5. HR-EIMS m/z 302.2098 (M+) (calcd
302,2093 for C16H30O5). [h]2D5=+17.2 (c 1.0, CHCl3).
References
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promising antitumor activity, being cytotoxic against
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4.19. (3S,4R,7S)-3-Acetoxy-7-methoxy-2,2,4-trimethyl-
decanoic acid methyl ester 22
Compound 21 (0.079 g, 0.260 mmol) was dissolved in
dry acetonitrile (1.0 ml) and methyl iodide (0.405 ml,
6.50 mmol) was added, in a reacti-vial in the dark.
Ag2O (0.180 g, 0.780 mmol) was added. The mixture
was refluxed and stirred for 2 days then it was filtered
and concentrated. The residue was flash-chro-
matographed (20–40% diethyl ether in petroleum ether)
to afford 22 (0.066 g, 80%) as an oil. (Found: C, 64.8;
H, 10.5. C17H32O5 requires: C, 64.5; H, 10.2). Rf=0.7
(50% diethyl ether in petroleum ether). 1H NMR
(CDCl3): l 0.82 (3H, d, J=6.9 Hz, CH3CH-), 0.87 (3H,
t, J=6.8 Hz, CH3CH2-), 1.13 (3H, s, -C(CH3)CH3),
1.15 (3H, s, -C(CH3)CH3), 1.18–1.47 (8H, m,
CH3CH2CH2CH(OH)CH2CH2-, overlapped), 1.64 (1H,
m, CH3CH-), 2.04 (3H, s, OCCH3), 3.05 (1H, bs,
-CHOCH3), 3.26 (3H, s, -CHOCH3), 3.63 (3H, s,
-COOCH3), 5.10 (1H, d, J=3.8 Hz, -CHOAc). 13C
NMR (CDCl3): l 14.3, 15.4, 18.4, 20.3, 20.7, 23.1, 31.0,
31.1, 34.5, 35.6, 46.7, 51.8, 56.4, 79.1, 80.6, 170.6, 176.4.
HR-EIMS m/z 316.2245 (M+) (calcd 316,2250 for
C17H32O5). [h]2D5=+12.9 (c 1.0, CHCl3).
3. Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem.
1989, 54, 1570–1576. This reaction was chosen for its
flexibility: it is possible to prepare, in principle, the four
C-3 and C-4 stereoisomers reacting the aldehyde 6 with
the (E)- and (Z)-enantiomeric crotyl boranes.
4. Herscovici, J.; Antonakis, K. J. Chem. Soc., Chem. Com-
mun. 1980, 561–562.
5. The e.e. of compound 7 was evaluated through deacetyla-
tion to give 14 (reported later) and transformation of the
ester according the reported synthetic sequence (see Sec-
tion 4), because of the very low reactivity of the C-3
secondary alcohol of 14 toward the MTPA chlorides
(Scheme 5).
6. In an attempt to increase the crotylboration’s yields we
chose the supposed sterically less demanding 3-[(tert-
butyl-diphenylsilyl)-oxy]-2,2-dimethyl-propanal 5c (syn-
thesized through the reported reaction sequence).
However, also in this case, the yields of the crotylbora-
tion step were low (25–35%) (Scheme 6).
7. Urbanek, R. A.; Sabes, S. F.; Forsyth, C. J. J. Am.
Chem. Soc. 1998, 120, 2523–2533 (ozonolysis of 7 gave

3378
C. Della Monica et al. / Tetrahedron: Asymmetry 14 (2003) 3371–3378
8. (a) Amemiya, S.; Kojima, K.; Sakai, K. Chem. Pharm.
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gave no elimination byproducts.
12. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A.
P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron
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Scheme 5. Reagents and conditions: (a) Ag2O, BnBr, CH3CN,
80°C, 12 h, 31%; (c) LiAlH4, THF, 0°C, 1 h, 41%; (d)
(R)-MTPA-Cl or (S)-MTPA-Cl, Py, DMAP, rt, 1 h, quant.
13. (a) Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry
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Kitahara, T. Tetrahedron 2001, 57, 3899–3908. Substoi-
chiometric amounts of (R)-MeCBS reagent gave lower
yields of diastereomeric alcohols; lower temperatures
(−40°C) did not increase the d.r.
14. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092–4096. The Dl values for
the protons at C-4 and C-6 were, respectively, −0.05 and
−0.13; while for the protons at C-10 it was 0.05, confirm-
ing a (R) configuration for the stereogenic centre at C-7
for 20.
Scheme 6. Reagents and conditions: (a) 2.0 equiv. of LiAlH4,
THF, 0°C, 1 h; (b) 0.9 equiv. of TBDPS-Cl, 1.4 equiv. of
DBU, CH2Cl2, 0°C, 1 h; (c) 2.0 equiv. of PDC, m.s., CH2Cl2,
60% (three steps).
15. Kinney, W. A.; Zhang, X.; Williams, J. I.; Johnston, S.;
Michalak, R. S.; Deshpanade, M.; Dostal, L.; Rosazza, J.
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also some a,b-unsaturated aldehyde 8a, see experimental
part)
16. Finch, N.; Fitt, J. J.; Hsu, I. H. S. J. Org. Chem. 1975,
40, 206–215.