Synthetic studies on homophymine A: stereoselective synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid

Article abstract of DOI:10.1016/j.tet.2009.02.069

An efficient and highly stereocontrolled synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid, the β-hydroxy acid unit that acylates the N-terminus of homophymine A, has been devised starting from iodoethane and (S,S)-pseudoephedrine propionamide in 9 steps and 36% average overall yield. Comparison of the ¹H and ¹³C NMR and optical rotation data of the resulting β-hydroxy acid with the natural fragment unambiguously verifies the configurational assignment as (2R,3R,4R,6R).

Full text of DOI:10.1016/j.tet.2009.02.069

Tetrahedron 65 (2009) 3659–3663
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic studies on homophymine A: stereoselective synthesis
of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid
*
Filomena Bellotta, Maria Valeria D’Auria, Valentina Sepe, Angela Zampella
`
Dipartimento di Chimica delle Sostanze Naturali, Universita di Napoli ‘Federico II’, via D. Montesano 49, 80131 Napoli, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and highly stereocontrolled synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic
Received 16 December 2008
Received in revised form 11 February 2009
Accepted 26 February 2009
Available online 5 March 2009
acid, the
from iodoethane and (S,S)-pseudoephedrine propionamide in 9 steps and 36% average overall yield.
Comparison of the 1H and 13C NMR and optical rotation data of the resulting
-hydroxy acid with the
natural fragment unambiguously verifies the configurational assignment as (2R,3R,4R,6R).
Ó 2009 Elsevier Ltd. All rights reserved.
b-hydroxy acid unit that acylates the N-terminus of homophymine A, has been devised starting
b
1. Introduction
2. Results and discussion
Potent HIV inhibitory cyclic depsipeptides have recently been
described from Lithistida marine sponges. Peptides in this family
include callipeltins from Callipelta sp.,1 neamphamide A from
Neamphius huxleyi,2 papuamides,3 and theopapuamides4 from the
Papua New Guinea collections of Theonella species, and mir-
abamides from the Micronesian sponge Siliquariaspongia mirabilis.5
Homophymine A (1), isolated in our laboratory from a New
Caledonian collection of the marine sponge Homophymia sp.,6
represents the latest, very recent example of this class. In addition
to antifungal and cytotoxic activities, all these compounds dis-
played potent antiviral properties.
Distinguishing structural characteristics of this family of pep-
tides include a preponderance of unusual amino acid residues, such
as (2S,3S,4R)-3,4-dimethylglutamine (diMeGln), common to all
metabolites and unique N-terminal polyketide derived moieties.
(2R,3R,4R,6R)-3-Hydroxy-2,4,6-trimethyloctanoic acid 2 (HTMOA)
is a key component of homophymine A whose structure was de-
termined by interpretation of spectroscopic data, acid hydrolysis, and
Mosher analysis.6 The HTMOA moiety, that is simply a C-1 homolog of
As a part of our efforts to total synthesis of homophymine A
herein we report an asymmetric synthesis of (2R,3R,4R,6R)-3-hy-
droxy-2,4,6-trimethyloctanoic acid 2 starting from commercially
available iodoethane.
Our retrosynthetic analysis of 3-hydroxy-2,4,6-trimethylocta-
noic acid 2 is shown in Figure 1. We envisaged that the stereo-
selective construction of the key C-2/C-3 bond would arise through
an asymmetric crotylboration on aldehyde 4. The substrate alde-
hyde (R,R)-4 could in turn be made in high enantiomeric purity
using the diastereoselective alkylation chemistry of Myers.11
The required precursor (R)-7 was made efficiently from iodo-
ethane according to Myers’s protocol. Commercial pseudoephe-
drine propionamide (S,S)-6 was alkylated with iodoethane to give
(S,S,R)-8 as a highly viscous oil in 88% yield (Scheme 1). The dia-
steroisomeric purity of amide (S,S,R)-8 was determined to be >98%
by employing Myers’ NMR-based method.12 Therefore the crude
alkylation product was subjected to cyclization with triflic anhy-
dride-pyridine and 1H NMR analysis of oxazolium product revealed
a 98% diastereomeric purity of the starting amide. Conversion of the
tertiary amide to the primary alcohol with lithium amidotrihy-
droborate13 (LAB) and subsequent treatment with iodine and tri-
phenylphosphine furnished compound 7 in 72% yield over two
steps.
the
b-hydroxy acid end group in callipeltin A and neamphamide
A (3-hydroxy-2,4,6-trimethylheptanoic acid, HTMHA), has already
been found as the end group of the related theopapuamide.4
Although three asymmetric syntheses of (2R,3R,4R)-HTMHA
residue have been reported,7–9 only one synthetic strategy was
explored for (2S,3S,4R,6R)-diastereomer of the fatty acid moiety of
homophymine A, found as a component of the aliphatic depside
bourgeanic acid.10
(2R)-2-Methyl-1-iodobutane 7 was transformed into aldehyde 4
in a three-step sequence (82% yield for three steps) involving al-
kylation of pseudoephedrine propionamide (S,S)-6, LAB reduction
of amide function of 5 followed by Ley oxidation of the obtained
primary alcohol (R,R)-10.14
Brown’s crotylboration15 was selected as the key step for the
assembly of the C2–C3 anti-propionate unit in b-hydroxy acid 2
(Scheme 2). Thus, aldehyde 4 was reacted with the allyl borane
derived from (ꢀ)-B-methoxydiisopinocampheyl borane and (E)-
* Corresponding author. Tel.: þ39 081678525; fax: þ39 081678552.
E-mail address: azampell@unina.it (A. Zampella).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.069

3660
F. Bellotta et al. / Tetrahedron 65 (2009) 3659–3663
NH2
peptide followed by dichloromethane extraction, unambiguously
defined the (2R,3R,4R,6R) configuration.
O
Further confirmation of the absolute stereochemistry of natural 2
was obtained from comparison of specific rotation data (synthetic 2:
OH
O
OH
O
O
H
N
O
N
H
HO
N
[a
]D¼þ21.2, c 7.3, CHCl3); natural HTMOA: [
a
]D¼þ21.8 (c 5.4, CHCl3).
H
O
NH OH
O
HN
In conclusion, the stereochemistry of the
b
-hydroxy acid unit
NH2
O
O
Orn1
HN
that acylates the N-terminus of the cyclodepsipeptide homo-
phymine A (1) was definitively confirmed by asymmetric synthesis.
Furthermore, our synthesis is short (nine steps from the commer-
cially available iodoethane and pseudoephedrine propionamide
(S,S)-6), efficient (36% overall yield), and amenable to scale-up.
O
O
NH
N
O
NH2
O
NMe
H
N
OH
NH
HO
O
HTMOA
O
O
O
MeO
3. Experimental
3.1. General
NH2
Homophymine A (1)
Brown
crotylboronation
OH
O
OH
Specific rotations were measured on a Perkin–Elmer 243 B po-
larimeter. High-resolution ESI-MS spectra were performed with
a Micromass QTOF Micromass spectrometer. ESI-MS experiments
were performed on an Applied Biosystem API 2000 triple-quad-
rupole mass spectrometer. NMR spectra were obtained on Varian
HO
CH CH
CH3
CH3CH3CH3
(S,R,R,R)-3
3
3
(R,R,R,R)-2
O
H3C
O
Inova 500 and Varian Mercury VX 400,
d (ppm), J in hertz, spectra
H
N
referred to CDCl3 as internal standards (dH¼7.26). HPLC was per-
formed using a Waters Model 510 pump equipped with Waters
Rheodine injector and a differential refractometer, model 401.
Solvents and reagents were used as supplied from commercial
sources with the following exceptions. Tetrahydrofuran, toluene,
dichloromethane and diisopropylamine were distilled from cal-
cium hydride immediately prior to use. All reactions were moni-
tored by TLC on silica gel plates (Machery, Nagel). Crude products
were purified by column chromatography on silica gel 70–230
mesh. All reactions were carried out under an argon atmosphere
using dry glassware.
CH
3CH3
(R,R)-4
OH
CH3CH3CH3
(S,S,R,R)-5
Asymmetric
alkylation
H3C
OH
O
I
N
CH
(S,S)-6
CH3
(R)-7
3
Figure 1. Retrosynthetic analysis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic
acid 2.
3.2. (2R)-N-[(1S,2S)-2-Hydroxy-1-methyl-1-phenylethyl]-N-
methyl-2-methylbutanamide 8
butene to give the anti-homoallylic alcohol (S,R,R,R)-3. The di-
astereomeric purity of 3 was >98% as judged by the NMR spectra of
the crude reaction mixture. We encountered difficulties in sepa-
rating 3 in acceptable yield from the isopinocampheol arising from
the reaction. Thus, crude 3 was converted into the TBS-protected
derivative 11, which was easily separated from the protected iso-
pinocampheol by silica gel chromatography (92% yield of 11 from
4). Treatment of (S,R,R,R)-11 with catalytic osmium tetraoxide and
stoichiometric sodium periodate followed by in situ oxidation of
the resultant aldehyde with sodium chlorite occurred with con-
comitant removal of the silyl protecting group giving carboxylic
acid (R,R,R,R)-2 in 75% yield (Scheme 2).
A
solution of n-butyllithium in hexane (2.5 M, 17.0 mL,
42.6 mmol, 2.10 equiv) was added via cannula to a suspension of
lithium chloride (6.02 g, 142.1 mmol, 7.00 equiv) and diisopropyl-
amine (6.60 mL, 46.7 mmol, 2.30 equiv) in dry THF (20.0 mL) at
ꢀ78 ꢁC. The resulting suspension was warmed to 0 ꢁC briefly and
then was cooled to ꢀ78 ꢁC. An ice-cooled solution of amide (S,S)-6
(4.50 g, 20.3 mmol, 1.00 equiv) in dry THF (50.0 mL) was added via
cannula. The mixture was stirred at ꢀ78 ꢁC for 1 h, at 0 ꢁC for
15 min, and at 23 ꢁC for 5 min. The mixture was cooled to 0 ꢁC, and
iodoethane (6.50 mL, 81.2 mmol, 4.00 equiv) was added via can-
nula. The reaction was removed from the cold bath and stirred for
13 h at room temperature. The yellow solution was quenched by
the addition of saturated aqueous ammonium chloride solution
(30 mL), and the aqueous layer was extracted with ethyl acetate
(3ꢂ30 mL). The combined organic extracts were dried (MgSO4) and
concentrated to give a yellow oil. Purification of the residue by silica
gel chromatography (70% hexane–ethyl acetate) afforded amide
(S,S,R)-8 as a highly viscous, colorless oil (4.45 g, 88%). Rf (40%
The complete overlap of the NMR data of the synthetic de-
rivative 2 with those of the corresponding natural unit (see Ex-
perimental section), obtained through acid hydrolysis of parent
CH3
N
O
CH3
N
O
a
hexane/ethyl acetate) 0.43; [
a
]D¼ þ9.0 (c 0.9, chloroform); IR
OH CH3
(S,S)-6
b
OH CH3 CH3
(S,S,R)-8
(CHCl3): 3379, 2959, 1620 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
: 7.37–
7.31 (5H, m, Ph), 4.61 (1H, t, J 7.2 Hz, CHOH), 4.41 (1H, m, CHN), 4.09
(1H, br s, OH), 2.85 (3H, s, NMe), 2.53 (1H, m, COCHMe), 1.62 (1H, m,
CHaHbMe), 1.37 (1H, m, CHaHbMe), 1.14 (3H, d, J 6.8 Hz, NCHMe),
1.09 (3H, d, J 6.8 Hz, COCHMe), 0.84 (3H, t, J 7.4 Hz, CH2Me); 13C
c
HO
I
CH3
CH3
(R)-9
(R)-7
NMR (100 MHz, CDCl3),
142.5, 128.6
, 128.2 (ꢂ2), 127.4, 126.8
38.2, 37.5
*
denotes minor rotamer peaks,
, 126.3 (ꢂ2), 76.4, 75.4
, 11.9; HRMS (ESI):
d
: 179.1,
*
*
*
, 57.8,
Scheme 1. Reagents and conditions: (a) LDA, LiCl, THF, ꢀ78 ꢁC/rt, iodoethane, 13 h,
88%; (b) n-BuLi, DIPA, THF, ꢀ78 ꢁC/0 ꢁC, BH3$NH3, (S,S,R)-8, rt, 2 h, 85%; (c) iodine,
imidazole, triphenylphosphine, CH2Cl2, rt, 85%.
*
, 33.1, 26.9, 17.6
*
, 16.9, 15.4
*
, 14.5, 12.0
*
calcd for C15H24NO2: 250.1807; found 250.1824 [MþH]þ.

F. Bellotta et al. / Tetrahedron 65 (2009) 3659–3663
3661
H3C
H3C
O
O
a
b
c
+
I
N
HO
N
CH3
OH CH3
CH3 CH3
OH CH3 CH3 CH3
(S,S)-6
(R)-7
(S,S,R,R)-5
(R,R)-10
OTBS
O
OH
OH
O
d
f
e
H
HO
CH3 CH3
(R,R)-4
CH3 CH3 CH3
CH3 CH3 CH3
CH3 CH3 CH3
(S,R,R,R)-3
(S,R,R,R)-11
(R,R,R,R)-2
Scheme 2. Reagents and conditions: (a) LDA, LiCl, THF, ꢀ78 ꢁC/rt, (R)-7, 13 h, 95%; (b) n-BuLi, DIPA, THF, ꢀ78 ꢁC/0 ꢁC, BH3$NH3, (S,S,R,R)-5, rt, 2 h, 88%; (c) TPAP, NMO, 4 Å MS,
CH2Cl2, 1 h, 98%; (d) t-BuOK, trans-2-butene, n-BuLi, ꢀ78 ꢁC/ꢀ57 ꢁC, (ꢀ)-B-methoxydiisopinocampheylborane, BF3$OEt2, (R,R)-4, ꢀ78 ꢁC, 4 h; (e) TBSCl, imidazole, DMF, 24 h, 92%,
two steps; (f) OsO4, NMO, 1 h, NaIO4, 1.5 h, NaClO2, H2NSO3H, 2 h, dioxane–H2O, 75%.
3.3. (2R)-2-Methylbutanol 9
solution of n-butyllithium in hexane (2.5 M, 27.0 mL,
3.5. (2R,4R)-N-[(1S,2S)-2-Hydroxy-1-methyl-1-phenylethyl]-
N-methyl-2,4-dimethylhexanamide 5
A
67.5 mmol, 3.90 equiv) was added to a solution of diisopropyl-
amine (10.3 mL, 72.7 mmol, 4.20 equiv) in THF (20.0 mL) at
ꢀ78 ꢁC. The resulting solution was stirred at ꢀ78 ꢁC for 10 min,
then warmed to 0 ꢁC, and held at that temperature for 10 min.
Borane–ammonia complex (2.14 g, 69.2 mmol, 4.00 equiv) was
added in one portion, and the suspension was stirred at 0 ꢁC for
15 min and then was warmed at room temperature. After 15 min,
the suspension was cooled to 0 ꢁC. A solution of amide (S,S,R)-8
(4.30 g, 17.3 mmol, 1.00 equiv) in dry THF was added via cannula,
and the reaction mixture was warmed to 23 ꢁC, held at that
temperature for 2 h, and then cooled to 0 ꢁC where excess hydride
was quenched by the careful addition of 3 N aqueous HCl (30 mL)
solution. The mixture was stirred for 2 h at 0 ꢁC and then
extracted with diethyl ether (3ꢂ30 mL). The combined organic
extracts were washed sequentially with 3 N aqueous HCl solution
(25 mL), 2 N aqueous NaOH solution (25 mL), and brine. The
combined organic extracts were dried (MgSO4) and concentrated.
Purification of the residue by silica gel chromatography (99%
hexane–ethyl acetate) afforded alcohol (R)-9 as a highly viscous,
colorless oil (1.30 g, 85%). Rf (80% hexane/ethyl acetate) 0.60;
A solution of n-butyllithium in hexane (2.5 M, 8.08 mL,
20.2 mmol, 4.00 equiv) was added via cannula to a suspension of
lithium chloride (2.72 g, 64.1 mmol, 12.7 equiv) and diisopropyl-
amine (3.08 mL, 21.8 mmol, 4.31 equiv) in dry THF (10.0 mL) at
ꢀ78 ꢁC. The resulting suspension was warmed to 0 ꢁC briefly and
then was cooled to ꢀ78 ꢁC. An ice-cooled solution of amide (S,S)-6
(2.35 g, 10.6 mmol, 2.10 equiv) in dry THF (30.0 mL) was added via
cannula. The mixture was stirred at ꢀ78 ꢁC for 1 h, at 0 ꢁC for
15 min, and at 23 ꢁC for 5 min. The mixture was cooled to 0 ꢁC, and
(R)-(þ)-1-iodo-2-methylbutane (1.00 g, 5.05 mmol, 1.00 equiv) was
added via cannula. The reaction was removed from the cold bath
and stirred for 13 h at room temperature. The yellow solution was
quenched by the addition of saturated aqueous ammonium chlo-
ride solution (30 mL), and the aqueous layer was extracted with
ethyl acetate (3ꢂ30 mL). The combined organic extracts were dried
(MgSO4) and concentrated to give a yellow oil. Purification of the
residue by silica gel chromatography (70% hexane–ethyl acetate)
afforded amide (S,S,R,R)-5 as a highly viscous, colorless oil (1.40 g,
95%). Rf (50% hexane/ethyl acetate) 0.47; [
roform); IR (CHCl3): 3379, 2959, 1620 cmꢀ1
CDCl3) : 7.38–7.30 (5H, m, Ph), 4.62 (1H, t, J 6.7 Hz, CHOH), 4.38
a
]D¼ þ6.2 (c 1.2, chlo-
;
1H NMR (400 MHz,
[
a
]D¼ ꢀ9.8 (c 10.2, chloroform); 1H NMR (400 MHz, CD3OD)
d:
d
3.55 (2H, d, J 6.7 Hz, CH2OH), 1.51 (1H, m, CHMe), 1.35 (1H, m,
CHaHbMe), 1.18 (3H, d, J 6.7 Hz, CHMe), 1.00 (1H, m, CHaHbMe),
(1H, br s, OH), 4.11 (1H, m, CHN), 2.86 (3H, s, NMe), 2.70 (1H, m,
COCHMe), 1.70 (1H, m, CHMe), 1.36 (1H, m, CHaHbMe), 1.35 (1H, m,
CHaHb), 1.27 (1H, m, CHaHb), 1.15 (3H, d, J 6.5 Hz, NCHMe), 1.08 (3H,
d, J 6.8 Hz, COCHMe), 1.06 (1H, m, CHaHbMe), 0.87 (3H, t, J 7.3 Hz,
CH2Me), 0.77 (3H, d, J 6.4 Hz, CHMe); 13C NMR (100 MHz, CDCl3),
0.91 (3H, t, J 7.5 Hz, CH2Me); 13C NMR (100 MHz, CDCl3)
d: 67.9,
34.6, 18.9, 14.8, 13.5; HRMS (ESI): calcd for C5H13O: 89.0966; found
89.0952 [MþH]þ.
*
denotes minor rotamer peaks,
(ꢂ2), 127.6, 127.2 , 126.6 (ꢂ2), 76.6, 75.3
34.3, 33.5, 32.3 , 32.2, 29.9, 19.6 , 19.4, 18.9
d
: 179.3, 142.8, 141.7
, 59.2 , 58.3, 41.5
, 18.1, 15.7
*
,128.8 , 128.5
*
*
*
*
*
, 41.4,
3.4. (R)-1-Iodo-2-methylbutane 7
*
*
*
*
, 14.6, 11.5;
HRMS (ESI): calcd for C18H30NO2: 292.2277; found 292.2288
[MþH]þ.
Imidazole (1.39 g, 20.4 mmol, 1.5 equiv) and iodine (4.66 g,
18.4 mmol, 1.35 equiv) were added sequentially to a solution of
triphenylphosphine (4.28 g, 16.3 mmol, 1.20 equiv) in CH2Cl2
(20 mL) at 23 ꢁC. A solution of alcohol (R)-9 (1.20 g, 13.6 mmol,
1.00 equiv) in CH2Cl2 (5 mL) was added to the resulting fine
suspension via cannula. After 2 h, dichloromethane was re-
moved in vacuo. Purification of the residue by silica gel chro-
matography (95% hexane–ethyl acetate) afforded iodide (R)-7 as
a highly viscous, colorless oil (2.29 g, 85%); Rf (hexane) 0.99;
3.6. (2R,4R)-2,4-Dimethylhexanol 10
A
solution of n-butyllithium in hexane (2.5 M, 6.96 mL,
17.4 mmol, 3.90 equiv) was added to a solution of diisopropylamine
(2.65 mL, 18.7 mmol, 4.20 equiv) in THF (5 mL) at ꢀ78 ꢁC. The
resulting solution was stirred at ꢀ78 ꢁC for 10 min, then warmed to
0 ꢁC, and held at that temperature for 10 min. Borane–ammonia
complex (550 mg, 17.8 mmol, 4.00 equiv) was added in one portion,
and the suspension was stirred at 0 ꢁC for 15 min and then was
warmed at room temperature. After 15 min, the suspension was
cooled to 0 ꢁC. A solution of amide (S,S,R,R)-5 (1.30 g, 4.46 mmol,
1.00 equiv) in dry THF was added via cannula, and the reaction
[
a
]D¼ ꢀ8.6 (c 12.3, CDCl3); 1H NMR (400 MHz, CDCl3)
d: 3.20
(2H, m, CH2I), 1.39 (2H, m, CHMe, CHaHbMe), 1.26 (1H, m,
CHaHbMe), 0.97 (3H, d, J 7.4 Hz, CHMe), 0.89 (3H, t, J 7.4 Hz,
CH2Me); 13C NMR (100 MHz, CDCl3)
d: 36.3, 29.1, 20.1, 17.5, 11.3;
HRMS (ESI): calcd for C5H12I: 198.9984; found 198.9972
[MþH]þ.

3662
F. Bellotta et al. / Tetrahedron 65 (2009) 3659–3663
mixture was warmed to 23 ꢁC, held at that temperature for 2 h, and
then cooled to 0 ꢁC where excess hydride was quenched by the
careful addition of 3 N aqueous HCl solution. The mixture was
stirred for 2 h at 0 ꢁC and then extracted with diethyl ether
(3ꢂ25 mL). The combined organic extracts were washed sequen-
tially with 3 N aqueous HCl solution (25 mL), 2 N aqueous NaOH
solution (25 mL), and brine. The combined organic extracts were
dried (MgSO4) and concentrated. Purification of the residue by
silica gel chromatography (99% hexane–ethyl acetate) afforded al-
cohol (R,R)-10 as a highly viscous, colorless oil (510 mg, 88%). Rf (5%
in vacuo and the residue was purified by column chromatography
on silica gel (100% hexane) to give the desired silylether derivative
(S,R,R,R)-11 (1.03 g, 92% over two steps) as colorless solid. Rf (hex-
ane) 0.99; [
a
]D¼ þ13.0 (c 9.8, CDCl3); 1H NMR (400 MHz, CDCl3)
d:
5.77 (1H, m, CH2]CH), 4.97 (2H, m, CH2]CH), 3.36 (1H, m, CHOSi),
2.34 (1H, m, ]CHCHMe), 1.70 (1H, m, OCHCHMe), 1.53 (1H, m,
CH2CHMe), 1.37 (2H, m, CH2), 1.32 (1H, m, CHaHbMe), 1.03 (1H, m,
CHaHbMe), 0.98 (3H, d, J 6.7 Hz, ]CHCHMe), 0.90 (9H, s, Me3CSi),
0.86 (6H, s, CHMe), 0.83 (3H, t, J 7.4 Hz, CH2Me), 0.03 (6H, s, Me2Si);
13C NMR (100 MHz, CDCl3)
d: 142.5, 113.6, 79.5, 42.8, 42.1, 33.9, 31.7,
ethyl acetate/hexane) 0.33; [
(400 MHz, CDCl3)
a
]D¼ þ4.0 (c 8.7, CDCl3); 1H NMR
28.7, 26.2, 19.8, 18.5, 17.6, 15.5, 11.2, ꢀ3.7; HRMS (ESI): calcd for
d
: 3.52 (1H, dd, J 5.1, 10.4 Hz, CHaHbOH), 3.37 (1H,
C18H39OSi: 299.2770; found 299.2750 [MþH]þ.
dd, J 6.8, 10.4 Hz, CHaHbOH), 1.71 (1H, m, HOCH2CHMe), 1.54 (1H,
m, CHMe), 1.42 (1H, m, CHaHb), 1.36 (1H, m, CHaHb), 1.31 (1H, m,
3.10. (2R,3R,4R,6R)-3-Hydroxy-2,4,6-trimethyloctanoic acid (2)
CHaHbMe), 1.05 (1H, m, CHaHbMe), 0.92 (3H, d,
HOCH2CHMe), 0.87 (3H, t, J 7.3 Hz, CH2Me), 0.86 (3H, d, J 6.4 Hz,
CHMe); 13C NMR (100 MHz, CDCl3)
: 68.6, 40.5, 33.1, 31.5, 29.0,
J 6.7 Hz,
To
a stirring solution of (S,R,R,R)-11 (500 mg, 1.68 mmol,
d
1.00 equiv) in dioxane (3.00 mL) and H2O (3.00 mL) was added 4-
methylmorpholine N-oxide (295 mg, 2.52 mmol, 1.50 equiv) and
osmium tetraoxide (2% in H2O, 432 mL, 0.034 mmol, 0.02 equiv).
19.8, 17.3, 11.1; HRMS (ESI): calcd for C8H19O: 131.1436; found
131.1448 [MþH]þ.
After 1 h, NaIO4 (539 mg, 2.52 mmol, 1.50 equiv) was added, and
the suspension was stirred at room temperature for 1.5 h. The re-
action mixture was cooled to 0 ꢁC, and sodium chlorite (608 mg,
6.72 mmol, 4.00 equiv) and sulfamic acid (652 mg, 6.72 mmol,
4.00 equiv) 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 (20 mL), and the resulting solution was
extracted with CH2Cl2 (3ꢂ20 mL). The combined organic extracts
were washed with 5% aqueous HCl (20 mL), dried over MgSO4,
concentrated, and purified by HPLC (Macherey, Nagel; ET 200/4
3.7. (2R,4R)-2,4-Dimethylhexanal 4
To a stirred solution of (R,R)-10 (500 mg, 3.84 mmol, 1.00 equiv),
N-methylmorpholine-N-oxide (899 mg, 7.68 mmol, 2.00 equiv),
and 4 Å molecular sieves (1.92 g) in dry CH2Cl2 (4.00 mL), a catal-
ytic amount of tetrapropylammonium perruthenate (67.5 mg,
0.19 mmol, 0.05 equiv) was added. After stirring the reaction mix-
ture at room temperature for 1 h, it was filtered through Celite
washing with diethyl ether to obtain 481 mg of aldehyde (R,R)-4
(98%), immediately used for Brown’s reaction. Rf (20% ethyl acetate/
Nucleosil 100-5, 5
m
, 250ꢂ4.6 mm) with hexane/AcOEt (75:25, with
hexane) 0.43; 1H NMR (400 MHz, CDCl3)
d: 9.57 (1H, d, J 2.5 Hz,
0.05% TFA) to give pure (R,R,R,R)-2 (tR¼4.0 min, 254 mg, 75%).
CHO), 2.43 (1H, m, COCHMe), 1.72 (1H, m, CHMe), 1.42 (1H, m,
CHaHb), 1.36 (1H, m, CHaHb), 1.36 (1H, m, CHaHbMe), 1.08 (3H, d, J
6.8 Hz, COCHMe), 1.05 (1H, m, CHaHbMe), 0.89 (3H, d, J 7.0 Hz,
[
a
]D¼ þ21.2 (c 7.3, chloroform); 1H NMR (500 MHz, CDCl3)
d: 3.49
(1H, t, J 5.8 Hz, CHOH), 2.74 (1H, quintet, J 7.1 Hz, COCHMe), 1.74
(1H, m, HOCHCHMe), 1.44 (1H, m, CHaCHbMe), 1.40 (1H, m,
CH2CHMe), 1.27 (3H, d, J 7.1 Hz, COCHMe), 1.06 (2H, m, CHaCHbMe
and CHaHb),1.03 (1H, m, CHaHb), 0.97 (3H, d, J 6.8 Hz, HOCHCHMe),
0.91 (3H, d, J 6.2 Hz, CH2CHMe), 0.88 (3H, t, J¼7.3 Hz, CH2Me); 13C
CHMe), 0.88 (3H, t, J 7.4 Hz, CH2Me); 13C NMR (100 MHz, CDCl3)
d:
205.5, 44.1, 37.8, 31.9, 29.1, 19.2, 14.1, 11.1; HRMS (ESI): calcd for
C8H17O: 129.1279; found 129.1290 [MþH]þ.
NMR (125 MHz, CDCl3) d: 180.5, 78.3, 42.3, 37.5, 33.2, 31.5, 27.7,
3.8. (3S,4R,5R,7R)-3,5,7-Trimethyl-1-nonen-4-ol 3
20.4, 16.9, 14.8, 11.0; HRMS (ESI): calcd for C11H23O3: 203.1647;
found 203.1665 [MþH]þ.
A solution of potassium tert-butoxide in dry THF (10.5 mL,
10.5 mmol, 2.80 equiv) was cooled to ꢀ78 ꢁC, and trans-2-butene
(1.35 mL, 15.0 mmol, 4.00 equiv) was added, followed by n-butyl-
lithium (2.5 M, 4.21 mL, 10.5 mmol, 2.80 equiv). The resulting bright
yellow solution was stirred at ꢀ78 ꢁC for 2 min and at ꢀ45 ꢁC for
20 min. The reaction was re-cooled to ꢀ78 ꢁC, and a solution of (ꢀ)-B-
methoxydiisopinocampheylborane (3.79 g, 12.0 mmol, 3.20 equiv) in
dry THF was added. The reaction was stirred for 35 min, and BF3$OEt2
(1.47 mL, 12.0 mmol, 3.20 equiv) was added followed by a pre-cooled
(ꢀ78 ꢁC) solution of (R,R)-4 (481 mg, 3.76 mmol, 1.00 equiv) in dry
THF (5.00 mL). The resulting solution was stirred at ꢀ78 ꢁC for 4 h. The
reaction was diluted with saturated aqueous solution of NaCl (40 mL)
and extracted with ethyl acetate (3ꢂ40 mL). The combined organic
extracts were dried (MgSO4) and concentrated to give a dark liquid
(3.80 g) that was used in the following step without further
purification.
Data for natural 3-hydroxy-2,4,6-trimethyloctanoic acid
(HTMOA): [
CDCl3)
a
]D¼ þ21.8 (c 5.4, chloroform); 1H NMR (500 MHz,
d
: 3.48 (1H, t, J 5.8 Hz, CHOH), 2.74 (1H, quintet, J 7.1 Hz,
COCHMe), 1.72 (1H, m, HOCHCHMe), 1.46 (1H, m, CHaCHbMe), 1.40
(1H, m, CH2CHMe), 1.29 (3H, d, J 7.1 Hz, COCHMe), 1.06 (2H, m,
CHaCHbMe and CHaHb), 1.03 (1H, m, CHaHb), 0.97 (3H, d, J 6.8 Hz,
HOCHCHMe), 0.91 (3H, d, J 6.2 Hz, CH2CHMe), 0.87 (3H, t, J¼7.3 Hz,
CH2Me); 13C NMR (125 MHz, CDCl3)
d: 180.5, 78.3, 42.1, 37.7, 33.4,
31.5, 27.7, 20.4, 16.9, 14.8, 11.0.
Acknowledgements
This work was supported by grants from MIUR (PRIN 2007)
‘Sostanze Naturali ed Analoghi Sintetici con Attivita Antitumorale’
Rome, Italy. NMR spectra were provided by the CSIAS, Centro
Interdipartimentale di Analisi Strumentale, Faculty of Pharmacy,
University of Naples. The staff is acknowledged.
3.9. (3S,4R,5R,7R)-4-O-(tert-Butyl-dimethylsilyl)-3,5,7-
trimethyl-1-nonen-4-ol 11
References and notes
To a stirred solution of homoallylic alcohol 3 (3.80 g) in dry DMF
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imidazole (3.36 g, 49.4 mmol, 2.40 equiv) and the mixture was
stirred at room temperature for 24 h. The mixture was diluted with
water (30 mL), and the aqueous layer was extracted with ethyl
acetate (3ꢂ30 mL). The combined organic layer was concentrated
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