A general and highly efficient synthesis of novel nonactic acid analogues

Article abstract of DOI:10.1055/s-0028-1083185

An efficient enantioselective synthesis of protected non-actic acid analogues, starting from an easily accessible β-keto ester, is described. The key steps of the strategy are asymmetric hydrogenation, chelation-controlled allylation, cis-selective etherification, and stereoselective reduction or alkylation of α-halo esters. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083185

PAPER
3389
A General and Highly Efficient Synthesis of Novel Nonactic Acid Analogues
Synthesis of
N
o
u
vel
N
onactic
d
A
cid Analo
ogues vic Coutable, Christine Saluzzo*
UMR-CNRS 6011, Unité de Chimie Organique Moléculaire et Macromoléculaire, Université du Maine, Avenue Olivier Messiaen,
72085 Le Mans Cedex 9, France
Fax +33(2)43833902; E-mail: christine.saluzzo@univ-lemans.fr
Received 8 April 2008; revised 9 July 2008
OBn
OBn
Abstract: An efficient enantioselective synthesis of protected non-
actic acid analogues, starting from an easily accessible b-keto ester,
is described. The key steps of the strategy are asymmetric hydroge-
nation, chelation-controlled allylation, cis-selective etherification,
and stereoselective reduction or alkylation of a-halo esters.
CO2Et
R3 R2
CO2Et
R1
R1
O
O
A
R2
X
B
OBn
O
O
Key words: electrophilic additions, radical reactions, ring closure,
stereselective synthesis, total synthesis
R2
R1
R1
OEt
OP
C
D
CO2Et
Scheme 1
The presence of molecules with oxygenated heterocycles
in Nature has received considerable attention as a conse-
quence of their capacity in the modification of metallic
cations for transport through lipidic membranes. Poly-
ether antibiotics isolated from various Streptomyces spe-
cies possess this property.1 As structural characteristics,
they possess a carboxylate group and 2–5 oxygen atoms
serving as ligands for complexation of the cations. Some
of them, nactins,2 feigrisolide C,3 or pamamycins4 have
been reported to exhibit a wide range of biological activity
such as antimicrobial,2–4 insecticidal,2 acaricidal,2 antipro-
tozoan,2 antiparasitic,2 and immunosuppressive2 effects.
Their precursors, nonactic acid or nonactic acid ana-
logues, possess insecticidal and plant stimulation effects.2
These chiral building blocks can be derived from the
chiral pool, or by chemical/enzymatic means from achiral
or racemic starting material.5
H
2 (50 bar)
O
O
OH
O
RuCl2[(R)-BINAP]
MeOH, 50 °C
96%, 97% ee
i-Bu
OEt
i-Bu
OEt
2
1
NH
CCl3
OBn
O
OBn
O
BnO
DIBAL-H
i-Bu
OEt
i-Bu
H
Et2O, –78 °C
90%
TfOH, Et2O
0 °C to r.t.
85%
3
4
Scheme 2
Our synthesis (Scheme 2) started with the catalytic asym-
metric reduction of ethyl 5-methyl-3-oxohexanoate (1)
obtained by transformation of Meldrum acid.6 The reduc-
tion of this b-keto ester 1, performed with the Noyori hy-
drogenation catalyst,7 gave (R)-3-hydroxy ester 2 in 96%
yield and 97% ee.8
The most efficient synthesis of methyl (benzyloxy)nonac-
tate was performed by Lee and Choi5g in seven steps (29%
overall yield) starting from (R)-3-(benzyloxy)butanal.
This approach is based on stereoselective radical cycliza-
tion for the construction of the cis-2,5-disubstituted tet-
rahydrofuran ring.
The b-hydroxy ester 2 was then protected as its benzyl
ether using benzyl 2,2,2-trichloroacetimidate in the pres-
ence of triflic acid.9 Reduction of the ester function in 3
with diisobutylaluminum hydride at –78 °C in diethyl
ether as solvent10 gave the corresponding b-(benzyl-
oxy)aldehyde 4 in 90% yield.
Herein, we report a general and highly stereoselective ac-
cess to protected analogues of nonactic acid and 2-epi-
nonactic acid in a nine-step reaction sequence starting
from a b-keto ester.
The diastereoselective allylation of 4 (Scheme 3) was per-
formed using the well-established Reetz et al. proce-
The retrosynthetic analysis of the monomer nonactic acid
analogue A is depicted in Scheme 1. A radical-mediated
dehalogenation or alkylation of the key intermediate B
was envisaged. The cis-2,5-disubstituted tetrahydrofuran
B could be obtained via Bartlett-type cyclization from the
g,d-unsaturated ether C, which could be synthesized from
b-keto ester D.
dure.11 Treatment of aldehyde
4
with either
allyltrimethylsilane or allyltributyltin, in the presence of
titanium(IV) chloride, led to anti-homoallylic alcohol 5.
In both cases, the diastereoselectivity, determined by GC
analysis of the crude reaction mixture, was in favor of the
anti diastereomer (anti/syn 98:2). Moreover, with the al-
lylsilane, the yield was 89%, in contrast to that obtained
with allyltin (quantitative yield). Then, treatment of the
alcohol 5 with sodium hydride and 2,6-dichlorobenzyl
bromide (DCBBr) in N,N-dimethylformamide, in the
presence of tetrabutylammonium iodide, afforded the cor-
SYNTHESIS 2008, No. 21, pp 3389–3396
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083185; Art ID: T05508SS
© Georg Thieme Verlag Stuttgart · New York

3390
L. Coutable, C. Saluzzo
PAPER
OBn OH
OBn ODCB
OBn
O
R3M
TiCl4,
NaH, DCBBr, n-Bu4NI
CH2Cl2, –78 °C
i-Bu
i-Bu
DMF, 0 °C to r.t.
97%
i-Bu
H
5
4
6
R3M = Me3Si
R3M = n-Bu3Sn
anti/syn > 98:2 (89%)
anti/syn = 98:2 (quant.)
1. 9-BBN-H, THF
2. H2O2, NaOAc
90%
OBn ODCB
R
OBn ODCB
OBn ODCB
1. oxidation in CH2Cl2
O
OH
i-Bu
CO2Et
i-Bu
i-Bu
2. Ph3P=C(R)CO2Et
CH2Cl2, r.t.
7
8a R = Me
8b R = H
Scheme 3
responding dibenzyl ether 6 in 97% yield.12 Subsequent ether 8a gave the desired compound 9a in 49% yield to-
hydroboration of the terminal alkene with 9-borabicyc- gether with byproducts (Table 2, entry 4), in contrast to 8b
lo[3.3.1]nonane in tetrahydrofuran followed by oxidation which furnish the cis-2,5-disubstituted tetrahydrofuran 9b
with hydrogen peroxide/sodium acetate13 furnished the in both excellent yield and diastereoselectivity (Table 2,
primary alcohol 7 in 90% yield (Scheme 3).
entry 5). When bromine was employed, the cyclization of
8a and 8b was efficient, providing the corresponding cis-
2,5-disubstituted tetrahydrofurans 10a and 10b in good
yields and with high diastereoselectivities. The latter can
be rationalized by invoking the conformational preference
of the intermediate E, similar to that proposed by
Rychnovsky and Bartlett16 (Table 2). The 2,5-cis relationship
was confirmed by NOESY analysis for compounds 9b
and 10b (Figure 1) and by X-ray analysis for 10a after de-
halogenation and transformation into 3,5-dinitrobenzoate
14 (Scheme 7). Furthermore, the antiperiplanar addition
of the oxygen to the double bond activated by the electro-
phile (IBr or Br2) results in a product with a 1,2-anti rela-
tionship between the C–X bond and the newly formed C–O
bond as in the intermediate E (Table 2).14,18 To our knowl-
edge, these are the first examples of halocyclization of
bishomoallylic ethers containing an unsaturated ester with
iodine monobromide and bromine.
The bishomoallylic ethers 8a,b were obtained by a one-
pot oxidation/olefination protocol14 and yields ranged
from 55 to 69% (Table 1).
On treatment with tetrapropylammonium perruthenate/
N-methylmorpholine oxide (TPAP/NMO) (Table 1, entry 1)
or Dess–Martin periodinane (Table 1, entry 2), followed
by Wittig olefination with [1-(ethoxycarbonyl)eth-
ylidene]triphenylphosphorane, compound 7 gave substan-
tially lower yields of compound 8a than when using the
Swern oxidation15 (Table 1, entry 3). Similar results were
observed for the formation of bishomoallylic ether 8b us-
ing o-iodoxybenzoic acid (IBX) or Swern conditions,
followed by olefination with (ethoxycarbonylmethyl-
ene)triphenylphosphorane (Table 1, entries 4, 5). In all
cases, the undesired Z-isomer was observed, but it was
easily removed by column chromatography on silica gel.
To complete the synthesis it was necessary to form the cis-
2,5-disubstituted tetrahydrofuran ring by halocyclization.
The treatment of compounds 8a or 8b with iodine16 or
iodine/copper(II) acetate,17 in acetonitrile at room temper-
ature, was unsuccessful (Table 2, entries 1–3). Neverthe-
less, the use of better electrophiles iodine monobromide
and bromine in dichloromethane at –78 °C led to the cy-
clization. With iodine monobromide, the bishomoallylic
OBn
CO2Et
9b X = I
10b X = Br
i-Bu
O
H
H
X
NOESY correlation
Figure 1
Table 1 One-Pot Oxidation/Olefination Protocol of 7 To Give 8a,b
Entry
Oxidation conditions
R
Product
8a
Yielda (%)
Ratiob E/Z
nd
1
2
3
4
5
TPAP (0.05 equiv), NMO (1.5 equiv), 4Å MS
Dess–Martin periodinane (1.5 equiv)
Me
Me
Me
H
55
60
69
60
69
8a
nd
(COCl)2 (2.2 equiv), DMSO (2.8 equiv), Et3N (4.9 equiv)
IBX (1.5 equiv), CH2Cl2–acetone (2:1)
8a
97:3
nd
8b
(COCl)2 (2.2 equiv), DMSO (2.8 equiv), Et3N (4.9 equiv)
H
8b
93:7
a Yield of isolated product.
b Determined by 1H NMR analysis of the crude mixture; nd = not determined.
Synthesis 2008, No. 21, 3389–3396 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Nonactic Acid Analogues
3391
Table 2 Halocyclization of 8a,b
R
BnO
i-Bu
X
OBn ODCB
R
OBn
XY
CO2Et
CO2Et
O
solvent
i-Bu
CO2Et
i-Bu
O
+
Cl
R
X
–
8a R = Me
8b R = H
Br
9a X = I, R = Me
9b X = I, R = H
10a X = Br, R = Me
10b X = Br, R = H
Cl
E
Entry
R
XY
I2
Solvent, Temp
MeCN, r.t.
MeCN, r.t.
MeCN, r.t.
Product
Yielda (%)
Ratiob cis/trans
1
2
3
4
5
6
7
Me
H
–
–
–
I2
–
–
–
H
I2/Cu(OAc)2
–
–
–
Me
H
IBr
IBr
Br2
Br2
CH2Cl2, –78 °C
CH2Cl2, –78 °C
CH2Cl2, –78 °C
CH2Cl2, –78 °C
9a
9b
10a
10b
49
95
90
96
~70:30c
>98:2
>98:2
>98:2
Me
H
a Yield of isolated product (detected as a single isomer by 1H NMR analysis).
b Determined by 1H NMR analysis of the crude mixture.
c Estimated ratio, presence of byproducts.
OBn
OBn
Me2Cu(CN)Li2
X = I
CO2Et
Me Br
AIBN, R3MH
THF, –78 °C, 1 h
97%
i-Bu
i-Bu
OH
O
11
10a
OBn
CO2Et
CO2Et
CO2Et
OBn
i-Bu
O
CO2Et
X
toluene, 2 h
–25 °C or –78 °C
i-Bu
9b X = I
10b X = Br
O
AIBN
n-Bu3Sn
13
OBn
UV lamp
anti/syn = 92:8a (82%)b
anti/syn = 93:7a (85%)b
X = Br
toluene, –78 °C,
4 h, UV lamp
R3MH = n-Bu3SnH
R3MH = (Me3Si)3SiH
i-Bu
O
12
83% conv.
a
Scheme 5 Radical-mediated reduction of 10a to give 13. Deter-
syn/anti > 95:5a (65%)b
mined by H NMR analysis of the crude mixture. b Yield of isolated
1
major isomer.
Scheme 4 Formation of protected 2-epi-nonactic acid analogue 12.
a
1
Determined by H NMR analysis of the crude mixture. b Yield of
isolated major isomer.
UV irradiation (366 nm), led to the desired dehalogenated
compound 13, in 82% and 85% isolated yields, respec-
tively. In both cases, similar stereoselectivities were ob-
served.
Attempts at halogen substitution of the secondary a-iodo
ester 9b with dilithium cyanodimethylcuprate
[Me2Cu(CN)Li2]19 were unsuccessful (Scheme 4). The E-
isomer 11 resulting from the tetrahydrofuran ring-opening
reaction was formed exclusively. Then, the a-bromo ester
10b was subjected to radical-mediated allylation, accord-
ing to a modified procedure of Guindon et al.,20 i.e. UV ir-
radiation was used instead of triethylborane/air for radical
initiation. This reaction proceeded smoothly (83% con-
version after 4 h) and a ratio higher than 95:5 in favor of
the syn-isomer was observed. Thus, the first protected 2-
epi-nonactic acid analogue 12 was isolated in 65% yield.
The diastereoselectivity of the radical reactions would be
explained by considering the mechanism via the radical
intermediate F (Scheme 6).21 The conformation of this in-
termediate, which takes into consideration both steric and
electronic factors, led to the preferential approach of the
reagent to the bottom face of the p-system.
In order to confirm the stereoselectivity of the radical pro-
cesses and the relative configuration of the stereocenters,
X-ray analysis has been performed on a derivative of
compound 13 (Scheme 7). The dinitrobenzoate ester 14
was prepared by debenzylation of 13 followed by esterifi-
cation with 3,5-dinitrobenzoic acid in the presence of
N,N¢-dicyclohexylcarbodiimide and 4-(dimethylami-
no)pyridine. X-ray analysis of compound 14 confirmed
the stereochemical outcome in the reactions.
For the tertiary a-bromo ester 10a, radical-mediated
reduction20 was realized (Scheme 5). Treatment of com-
pound 10a with tributyltin hydride at –78 °C or with
tris(trimethylsilyl)silane at –25 °C, in the presence of a
catalytic amount of 2,2¢-azobis(isobutyronitrile) under
Synthesis 2008, No. 21, 3389–3396 © Thieme Stuttgart · New York

3392
L. Coutable, C. Saluzzo
PAPER
R1 = H, R2 = allyl
tallic reagent. Moreover, introduction of such an allyl
group, highly tunable, allows the preparation of a wide
range of nonactic and 2-epi-nonactic acid analogues.
CO2Et
A
O
OBn
syn-12
i-Bu
R1
O
CO2Et
H
All commercial materials were used without further purification un-
less otherwise noted. Et2O and THF were distilled over Na/ben-
zophenone ketyl. CH2Cl2, toluene, DMF, and DMSO were distilled
from CaH2. All reactions were performed under a dry argon atmo-
sphere in oven-dried glassware. Flash chromatography was per-
formed on Merck silica gel (40–63 mm). Analytical TLC was
carried out on Merck silica gel 60F254. Optical rotations were mea-
sured with a Perkin Elmer 343 polarimeter at the Na D line with a
1-dm path length, 1-mL cell. NMR spectra were recorded on a
Bruker AC400 and are referenced to TMS as internal standard. IR
spectra were recorded on a Nicolet Avatar 370 DTGS infrared spec-
trophotometer. Elemental analyses were performed by the Service
de Microanalyse de l’Institut de Chimie des Substances Naturelles,
Gif-sur-Yvette. HRMS were recorded on a Waters Micromass GCT
Premier. Chiral GC was performed on a HP 6890 with He as carrier
gas and using a Rt-bDEX cst column (30 m, 0.25 mm i.d., 0.25 mm).
Radical-mediated reactions were carried out using a Hamamatsu
UV spot light source (200 W type L8222-01).
F
R2SnBu3
A
CO2Et
R1 = Me, R2 = H
A
O
anti-13
Scheme 6
Ethyl (R)-3-Hydroxy-5-methylhexanoate (2)
(R)-BINAP (53 mg, 0.084 mmol) and [RuCl2(benzene)]2 (20 mg,
0.04 mmol) were dissolved in degassed DMF (1.4 mL) under argon.
The mixture was heated to 100 °C for 10 min. After cooling to 50
°C, the solvent was removed under vacuum to give the catalyst as
an orange-red solid. This catalyst (5 mg) was dissolved in a de-
gassed soln of 1 (1.72 g, 10 mmol) in MeOH (1.5 mL). The mixture
was transferred to an autoclave, which was then purged with H2 (3
×). The mixture was stirred overnight at 50 °C under a pressure of
50 bar. After carefully venting the H2 at r.t., the solvent was re-
moved and the residue dissolved in Et2O. The ether soln was filtered
through a pad of silica gel. Evaporation of the solvent gave the pure
2 as a colorless oil; yield: 1.67 g (96%); 97% ee (GC).
Scheme 7
[a]D20 –12.9 (c 8.00, CHCl3).
R2
O
O
OBn
Ethyl (R)-3-(Benzyloxy)-5-methylhexanoate (3)
CO2Et
Ph3P
To a stirred soln of 2 (870 mg, 5 mmol) and benzyl 2,2,2-trichloro-
acetimidate (2.53 g, 10 mmol) in Et2O (10 mL) was added, at 0 °C,
TfOH (44 mL, 0.5 mmol). The mixture was allowed to warm to r.t.
and stirred overnight. After concentration, the residue was taken up
with cyclohexane and the crystalline trichloroacetamide removed
by filtration. The filtrate was washed with brine, dried (MgSO4),
and concentrated. The crude mixture was purified by flash chroma-
tography (cyclohexane–EtOAc, 95:5) to give 3 as a colorless oil;
yield: 1.12 g (85%).
R1
OEt
R1
O
CO2Et
R3 R2
R3 MZ3
R1 = alkyl, aryl; R2 = alkyl, aryl; R3 = H
1 = alkyl, aryl; R2 = H; R3 = alkyl
G
H
(M = Si, Sn)
R
Scheme 8
[a]D20 +10.0 (c 1.00, CHCl3).
In summary, we have reported a total stereoselective syn-
thesis of two protected nonactic acid analogues from a b-
keto ester in nine steps, with 27% overall yield for
analogue 12 and 33% for 13. The key steps of the synthet-
ic sequence are asymmetric hydrogenation, chelation-
controlled allylation, cis-cyclo haloetherification, fol-
lowed by a radical-mediated allylation or dehalogenation;
all the reactions are highly stereocontrolled. Moreover,
this versatile approach offers a general access to nonactic
and 2-epi-nonactic acid analogues G and H, respectively
(Scheme 8).
IR (film): 3089, 3065, 3031, 2956, 2870, 1950, 1877, 1736, 1603,
1496, 1466, 1454, 1368, 1307, 1240, 1179, 1096, 1069, 1029, 735,
697 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (d, J = 6.6 Hz, 3 H), 0.91 (d,
J = 6.6 Hz, 3 H), 1.25 (t, J = 7.2 Hz, 3 H), 1.29 (ddd, J = 13.9, 8.1,
5.0 Hz, 1 H), 1.60 (ddd, J = 13.9, 8.0, 5.8 Hz, 1 H), 1.7–1.9 (m, 1
H), 2.46 (dd, J = 15.0, 5.7 Hz, 1 H), 2.62 (dd, J = 15.0, 6.8 Hz, 1 H),
3.9–4.0 (m, 1 H), 4.14 (q, J = 7.2 Hz, 1 H), 4.15 (q, J = 7.2 Hz, 1 H),
4.51 (d, J = 11.3 Hz, 1 H), 4.58 (d, J = 11.3 Hz, 1 H), 7.2–7.4 (m, 5
H).
13C NMR (100 MHz, CDCl3): d = 14.1, 22.2, 23.1, 24.5, 40.2, 44.1,
60.3, 71.4, 74.4, 127.5, 127.7, 128.2, 138.4, 171.7.
The structural variations come from easily accessible
building blocks: b-keto ester, ylide, and allylic organome-
Anal. Calcd for C16H24O3: C, 72.69; H, 9.15. Found: C, 72.73; H,
9.27.
Synthesis 2008, No. 21, 3389–3396 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Nonactic Acid Analogues
3393
(R)-3-(Benzyloxy)-5-methylhexanal (4)
(4R,6R)-6-(Benzyloxy)-4-(2,6-dichlorobenzyloxy)-8-methylnon-
1-ene (6)
To a stirred soln of 3 (793 mg, 3 mmol) in Et2O (6 mL) was added
dropwise, at –78 °C, 1 M DIBAL-H in toluene (4.2 mL, 4.2 mmol)
and stirring was continued at –78 °C for at least 1 h. Upon complete
consumption of the ester, the reaction was quenched with 2 M HCl
(12 mL) and the temperature allowed to warm up to r.t.. The aque-
ous phase was separated and extracted with Et2O (2 ×). The com-
bined organic extracts were washed with brine, dried (MgSO4), and
concentrated. The residue was purified by flash chromatography
(cyclohexane–EtOAc, 9:1) to give 4 as a colorless oil; yield: 596 mg
(90%).
To a suspension of NaH (60% dispersion in mineral oil, 64 mg, 1.60
mmol) in DMF (6.5 mL) was added, at 0 °C, a soln of 5 (210 mg,
0.80 mmol) in DMF (0.7 mL). The mixture was stirred at 0 °C for
20 min and a soln of 2,6-dichlorobenzyl bromide (395 mg,
1.60 mmol) in DMF (1.3 mL) was added slowly, followed by Bu4NI
(59 mg, 0.16 mmol) at 0 °C. The resulting mixture was stirred over-
night at r.t., then quenched with sat. aq NH4Cl and diluted with
Et2O. The aqueous phase was separated and the organic layer was
washed with H2O and brine, dried (MgSO4), and concentrated. The
residue was purified by flash chromatography (cyclohexane–
EtOAc, 95:5) to give the 6 as a colorless oil; yield: 328 mg (97%).
[a]D20 +4.10 (c 24.9, CHCl3).
IR (film): 3089, 3064, 3031, 2956, 2928, 2870, 2726, 1951, 1875,
1724, 1604, 1497, 1467, 1454, 1386, 1367, 1354, 1308, 1244, 1207,
1171, 1142, 1096, 1069, 1028, 737, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.91 (d, J = 6.5 Hz, 3 H), 0.92 (d,
J = 6.5 Hz, 3 H), 1.32 (ddd, J = 13.8, 7.6, 5.7 Hz, 1 H), 1.66 (ddd,
J = 13.8, 7.5, 6.3 Hz, 1 H), 1.7–1.8 (m, 1 H), 2.59 (ddd, J = 16.2,
5.1, 2.0 Hz, 1 H), 2.67 (ddd, J = 16.2, 6.5, 2.6 Hz, 1 H), 3.9–4.1 (m,
1 H), 4.53 (d, J = 11.3 Hz, 1 H), 4.54 (d, J = 11.3 Hz, 1 H), 7.2–7.4
(m, 5 H), 9.82 (dd, J = 2.6, 2.0 Hz, 1 H).
[a]D20 –54.4 (c 0.80, CHCl3).
IR (film): 3067, 3030, 2954, 2868, 1945, 1864, 1722, 1640, 1582,
1564, 1496, 1467, 1454, 1437, 1385, 1365, 1306, 1247, 1198, 1147,
1094, 1065, 1028, 994, 914, 853, 826, 778, 767, 733, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.88 (d, J = 6.5 Hz, 3 H), 0.89 (d,
J = 6.5 Hz, 3 H), 1.26 (ddd, J = 13.6, 6.8, 6.8 Hz, 1 H), 1.53 (ddd,
J = 13.6, 6.7, 6.7 Hz, 1 H), 1.6–1.7 (m, 2 H), 1.6–1.8 (m, 1 H), 2.4–
2.5 (m, 2 H), 3.69 (m, 1 H), 3.7–3.8 (m, 1 H), 4.23 (d, J = 11.3 Hz,
1 H), 4.46 (d, J = 11.3 Hz, 1 H), 4.73 (d, J = 10.5 Hz, 1 H), 4.84 (d,
J = 10.5 Hz, 1 H), 5.08 (dm, J = 10.1 Hz, 1 H), 5.11 (dm, J = 17.1
Hz, 1 H), 5.88 (ddt, J = 17.1, 10.1, 7.1 Hz, 1 H), 7.12 (dd, J = 8.5,
7.6 Hz, 1 H), 7.2–7.4 (m, 7 H).
13C NMR (100 MHz, CDCl3): d = 22.9, 23.1, 24.6, 38.3, 40.5, 43.9,
65.1, 70.8, 74.7, 75.1, 117.3, 127.3, 127.5 (2 C), 128.2–128.3 (4 C),
129.8, 133.8, 134.4, 136.8 (2 C), 139.1.
HRMS (CI+, methane): m/z [M + H]+ calcd for C24H31Cl2O2:
421.1701; found: 421.1696.
13C NMR (100 MHz, CDCl3): d = 22.3, 22.8, 24.4, 43.8, 48.4, 71.0,
72.6, 127.5, 127.6, 128.2, 138.0, 201.4.
Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.38; H,
9.05.
(4R,6R)-6-(Benzyloxy)-8-methylnon-1-en-4-ol (5); General Pro-
cedure
To a stirred soln of 4 (1.0 equiv) in CH2Cl2 (10 mL/mmol) was add-
ed, at –78 °C, TiCl4 (freshly distilled over Cu, 1.0 equiv). After 2
min, allyl reagent (1.2 equiv) was added dropwise and stirring was
continued at –78 °C for at least 30 min. Upon complete consump-
tion of aldehyde, the mixture was quenched with sat. aq NH4Cl and
the temperature allowed to warm up to r.t. The aqueous phase was
separated and extracted with CH2Cl2 (2 ×). The combined organic
extracts were washed with brine, dried (MgSO4), and concentrated.
The residue was purified by flash chromatography (cyclohexane–
EtOAc, 95:5) to give 5 as a colorless oil.
(4R,6R)-6-(Benzyloxy)-4-(2,6-dichlorobenzyloxy)-8-methyl-
nonan-1-ol (7)
To a stirred soln of 6 (1.85 g, 4.41 mmol) in THF (20 mL) was add-
ed dropwise, at 0 °C, 0.5 M 9-BBN-H in THF (26.4 mL, 13.2
mmol). The mixture was stirred at 0 °C for 1 h and at r.t. overnight.
The mixture was cooled to 0 °C, EtOH (3.9 mL), sat. aq NaOAc
(13.4 mL) and 30% H2O2 (4.3 mL) were added in that order; stirring
was continued at 0 °C for 1 h and at r.t. for 5 h. The mixture was di-
luted with Et2O (150 mL), washed with H2O (2×), sat. aq NaHCO3
and sat. aq NH4Cl, dried (MgSO4), and concentrated. The residue
was purified by flash chromatography (cyclohexane–EtOAc, 8:2) to
give 7 as a colorless oil; yield: 1.76 g (90%).
The general procedure was used with the following reagent
amounts: 4 (980 mg, 4.45 mmol), CH2Cl2 (45 mL), TiCl4 (488 mL,
4.45 mmol), and allyltributyltin (1.65 mL, 5.34 mmol). Yield: 1.17
g (quant.).
The general procedure was used with the following reagent
amounts: 4 (3.64 g, 16.5 mmol), CH2Cl2 (165 mL), TiCl4 (1.81 mL,
16.5 mmol), and allyltrimethylsilane (3.15 mL, 19.8 mmol). Yield:
3.87 g (89%).
[a]D20 –47.2 (c 1.00, CHCl3).
IR (film): 3404, 3088, 3064, 3030, 2951, 2924, 2868, 1946, 1865,
1806, 1582, 1564, 1496, 1468, 1454, 1436, 1385, 1365, 1247, 1197,
1171, 1146, 1094, 1059, 993, 854, 826, 778, 767, 733, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.90 (d, J = 6.6 Hz, 3 H), 0.90 (d,
J = 6.6 Hz, 3 H), 1.27 (ddd, J = 13.7, 6.7, 6.7 Hz, 1 H), 1.5–1.8 (m,
9 H), 3.6–3.7 (m, 3 H), 3.7–3.8 (m, 1 H), 4.26 (d, J = 11.3 Hz, 1 H),
4.49 (d, J = 11.3 Hz, 1 H), 4.73 (d, J = 10.4 Hz, 1 H), 4.79 (d,
J = 10.4 Hz, 1 H), 7.14 (dd, J = 8.5, 7.6 Hz, 1 H), 7.2–7.4 (m, 7 H).
[a]D20 –25.6 (c 2.00, CHCl3).
IR (film): 3443, 3067, 3031, 2955, 2928, 2869, 1948, 1826, 1641,
1605, 1497, 1467, 1454, 1433, 1385, 1366, 1308, 1246, 1207, 1170,
1147, 1090, 1068, 1028, 997, 914, 868, 845, 816, 735, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.90 (d, J = 6.3 Hz, 6 H), 1.2–1.4
(m, 1 H), 1.58 (ddd, J = 14.7, 6.5, 2.4 Hz, 1 H), 1.6–1.8 (m, 2 H),
1.76 (ddd, J = 14.7, 9.6, 3.5 Hz, 1 H), 2.2–2.3 (m, 2 H), 2.88 (d,
J = 3.0 Hz, 1 H), 3.78 (m, 1 H), 3.9–4.1 (m, 1 H), 4.56 (s, 2 H), 5.09
(dm, J = 10.5 Hz, 1 H), 5.10 (dm, J = 16.8 Hz, 1 H), 5.83 (ddt,
J = 16.8, 10.5, 7.1 Hz, 1 H), 7.2–7.4 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 22.9, 23.1, 24.6, 27.9, 30.2, 40.3,
43.8, 63.0, 65.1, 70.8, 74.9, 75.6, 127.3, 127.6 (2 C), 128.2–128.4
(4 C), 129.8, 133.7, 136.8 (2 C), 138.9.
Anal. Calcd for C24H32Cl2O3: C, 65.60; H, 7.34. Found: C, 65.54; H,
7.31.
13C NMR (100 MHz, CDCl3): d = 22.8, 22.9, 24.7, 39.4, 42.2, 42.9,
67.7, 71.1, 75.5, 117.4, 127.7, 127.9 (2 C), 128.4 (2 C), 134.9,
138.3.
Oxidation/Olefination Reaction; General Procedure
To a stirred soln of oxalyl chloride (2.2 equiv) in CH2Cl2 (15 mL/
mmol) was added dropwise, at –78 °C, DMSO (2.8 equiv), then the
resulting mixture was stirred for 30 min. Subsequently, a soln of 7
(1 equiv) in CH2Cl2 (4 mL/mmol) was added over 5 min giving a
Anal. Calcd for C17H26O2: C, 77.82; H, 9.99. Found: C, 77.77; H,
9.94.
Synthesis 2008, No. 21, 3389–3396 © Thieme Stuttgart · New York

3394
L. Coutable, C. Saluzzo
PAPER
white precipitate. After stirring at –78 °C for 10 min, Et3N (4.9
equiv) was added. After 15 min, the mixture was allowed to warm
up to 0 °C and stirred for 1 h. Then, the ylide (1.5 equiv) was added
at 0 °C, and the resultant mixture stirred at r.t. overnight. The mix-
ture was diluted with Et2O (10 mL/mmol), washed with H2O (2 ×)
and brine, then dried (MgSO4), and concentrated. The residue was
taken up with cyclohexane and filtered. The filtrate was evaporated
to afford a yellowish oil. Purification by flash chromatography (cy-
clohexane–EtOAc, 95:5) gave the pure (E)-bishomoallylic ether 8.
CH2Cl2, 1.4–1.5 equiv). The resulting brown soln was stirred in the
dark at –78 °C. After complete consumption of the starting material,
the mixture was quenched with sat. aq Na2S2O3 soln and diluted
with Et2O. The aqueous phase was separated and extracted with
Et2O (2 ×). The combined organic extracts were washed with brine,
dried (MgSO4), and concentrated. The residue was purified by flash
chromatography (cyclohexane–EtOAc, 95:5) to give the a-iodotet-
rahydrofuran 9.
Method B: To a stirred soln of 8 (1.0 equiv) in CH2Cl2 (50 mL/
mmol) was added slowly, at –78 °C, a 1.0 M soln of Br2 in CH2Cl2
(freshly prepared, 1.4–2.0 equiv). The resulting brown soln was
stirred in the dark at –78 °C. After complete consumption of the
starting material, the mixture was quenched with sat. aq Na2S2O3
and diluted with Et2O. The aqueous phase was separated and ex-
tracted with Et2O (2 ×). The combined organic extracts were
washed with brine, dried (MgSO4), and concentrated. The residue
was purified by flash chromatography (cyclohexane–EtOAc, 95:5)
to give the a-bromotetrahydrofuran 10.
Ethyl (2E,6R,8R)-8-(Benzyloxy)-6-(2,6-dichlorobenzyloxy)-
2,10-dimethylundec-2-enoate (8a)
Following the general procedure using oxalyl chloride (1.51 mL,
17.6 mmol), DMSO (1.59 mL, 22.4 mmol), 7 (3.52 g, 8.00 mmol),
Et3N (5.40 mL, 38.9 mmol), CH2Cl2 (150 mL), and
Ph3P=C(Me)CO2Et (4.35 g, 12.0 mmol) gave 8a as a colorless oil;
yield: 2.86 g (69%).
[a]D20 –28.9 (c 1.10, CHCl3).
IR (film): 3088, 3064, 3030, 2954, 2928, 2869, 1947, 1865, 1712,
1650, 1582, 1564, 1496, 1466, 1454, 1437, 1386, 1366, 1273, 1261,
1196, 1135, 1094, 1075, 1029, 993, 918, 855, 826, 779, 767, 736,
697 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.90 (d, J = 6.6 Hz, 3 H), 0.91 (d,
J = 6.6 Hz, 3 H), 1.2–1.4 (m, 1 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.5–1.7
(m, 2 H), 1.6–1.8 (m, 4 H), 1.84 (s, 3 H), 2.2–2.4 (m, 2 H), 3.6–3.8
(m, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.27 (d, J = 11.3 Hz, 1 H), 4.49
(d, J = 11.3 Hz, 1 H), 4.72 (d, J = 10.4 Hz, 1 H), 4.78 (d, J = 10.4
Hz, 1 H), 6.77 (tm, J = 7.4 Hz, 1 H), 7.14 (dd, J = 8.5, 7.5 Hz, 1 H),
7.2–7.4 (m, 7 H).
Ethyl (2S)-2-{(2S,5R)-5-[(2R)-2-(Benzyloxy)-4-methylpen-
tyl]tetrahydrofuran-2-yl}-2-iodopropanoate (9a)
Following the general procedure, method A, using 8a (261 mg, 0.50
mmol) and IBr soln (1.5 mL, 0.75 mmol) gave 9a as a colorless oil;
yield: 120 mg (49%).
IR (film): 3088, 3064, 3030, 2955, 2869, 1949, 1873, 1732, 1604,
1585, 1564, 1497, 1467, 1454, 1385, 1366, 1298, 1259, 1212, 1173,
1088, 1067, 1029, 910, 862, 806, 736, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.88 (d, J = 6.6 Hz, 6 H), 1.2–1.3
(m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.4–1.6 (m, 2 H), 1.6–1.8 (m, 3
H), 1.84 (s, 3 H), 1.9–2.3 (m, 3 H), 3.5–3.7 (m, 1 H), 4.0–4.2 (m, 1
H), 4.24 (q, J = 7.1 Hz, 2 H), 4.42 (dd, J = 8.0, 5.7 Hz, 1 H), 4.51 (s,
2 H), 7.2–7.4 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 12.3, 14.3, 22.9, 23.1, 24.0, 24.6,
32.7, 40.4, 43.9, 60.3, 65.1, 70.8, 74.8, 75.3, 127.3, 127.6 (2 C),
128.0, 128.2–128.4 (4 C), 129.8, 133.7, 136.8 (2 C), 138.9, 141.8,
168.1.
Ethyl (2S)-2-{(2S,5R)-5-[(2R)-2-(Benzyloxy)-4-methylpen-
tyl]tetrahydrofuran-2-yl}-2-iodoacetate (9b)
Following the general procedure, method A, using 8b (135 mg, 0.27
mmol) and IBr soln (740 mL, 0.37 mmol) gave 9b as a colorless oil;
yield: 120 mg (95%).
Anal. Calcd for C29H38Cl2O4: C, 66.79; H, 7.34. Found: C, 66.77; H,
7.25.
Ethyl (2E,6R,8R)-8-(Benzyloxy)-6-(2,6-dichlorobenzyloxy)-10-
methylundec-2-enoate (8b)
Following the general procedure using oxalyl chloride (1.83 mL,
21.4 mmol), DMSO (1.93 mL, 27.2 mmol), 7 (4.27 g, 9.70 mmol),
Et3N (6.54 mL, 47.2 mmol), CH2Cl2 (180 mL), and Ph3P=CHCO2Et
(5.08 g, 14.6 mmol) gave 8b as a colorless oil; yield: 3.42 g (69%).
[a]D20 –69.0 (c 1.00, CHCl3).
IR (film): 3062, 3030, 2953, 2870, 1952, 1877, 1736, 1606, 1459,
1366, 1300, 1260, 1195, 1129, 1088, 1065, 1035, 929, 894, 857,
804, 740, 698 cm–1.
[a]D20 –27.0 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.88 (d, J = 6.6 Hz, 3 H), 0.89 (d,
J = 6.6 Hz, 3 H), 1.2–1.4 (m, 1 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.53
(ddd, J = 13.6, 6.8, 6.8 Hz, 1 H), 1.59 (m, 1 H), 1.6–1.8 (m, 3 H),
1.94 (m, 1 H), 1.9–2.1 (m, 1 H), 2.22 (m, 1 H), 3.5–3.7 (m, 1 H),
4.15 (d, J = 9.2 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 4.1–4.3 (m, 1 H),
4.27 (ddd, J = 9.2, 7.3, 5.1 Hz, 1 H), 4.51 (s, 2 H), 7.2–7.4 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.8, 22.8, 23.0, 24.6, 26.1, 31.1,
31.4, 42.2, 44.3, 61.7, 71.5, 75.2, 78.6, 79.7, 127.4, 127.8 (2 C),
128.3 (2 C), 138.9, 170.0.
IR (film): 3063, 3030, 2952, 2928, 2871, 1949, 1870, 1718, 1654,
1572, 1442, 1363, 1311, 1268, 1201, 1167, 1095, 1064, 986, 854,
774, 736, 700 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.90 (d, J = 6.6 Hz, 3 H), 0.91 (d,
J = 6.6 Hz, 3 H), 1.2–1.4 (m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.5–1.7
(m, 2 H), 1.6–1.8 (m, 4 H), 2.2–2.4 (m, 2 H), 3.6–3.8 (m, 2 H), 4.19
(q, J = 7.1 Hz, 2 H), 4.29 (d, J = 11.3 Hz, 1 H), 4.50 (d, J = 11.3 Hz,
1 H), 4.70 (d, J = 10.3 Hz, 1 H), 4.75 (d, J = 10.3 Hz, 1 H), 5.84
(dm, J = 15.6 Hz, 1 H), 6.98 (dt, J = 15.6, 6.9 Hz, 1 H), 7.14 (dd,
J = 8.5, 7.5 Hz, 1 H), 7.2–7.4 (m, 7 H).
HRMS (CI+, methane): m/z [M + H]+ calcd for C21H32IO4:
475.1345; found: 475.1352.
13C NMR (100 MHz, CDCl3): d = 14.3, 22.9, 23.1, 24.6, 27.4, 32.2,
40.4, 43.9, 60.1, 65.1, 70.8, 74.8, 75.1, 121.4, 127.4, 127.6 (2 C),
128.3–128.4 (4 C), 129.9, 133.6, 136.8 (2 C), 138.9, 148.9, 166.6.
Anal. Calcd for C21H31IO4: C, 53.17; H, 6.59. Found: C, 53.11; H,
6.61.
Ethyl (2S)-2-{(2S,5R)-5-[(2R)-2-(Benzyloxy)-4-methylpen-
tyl]tetrahydrofuran-2-yl}-2-bromopropanoate (10a)
Following the general procedure, method B, using 8a (2.86 g, 5.49
mmol) and Br2 soln (7.69 mL, 7.69 mmol) gave 10a as a colorless
oil; yield: 2.18 g (90%).
Anal. Calcd for C28H36Cl2O4: C, 66.27; H, 7.15. Found: C, 66.37; H,
7.16.
Electrophilic Cyclization; General Procedure
Method A: To a stirred soln of 8 (1.0 equiv) in CH2Cl2 (50 mL/
mmol) was added slowly, at –78 °C, 0.5 M IBr in CH2Cl2 (freshly
prepared by mixing equimolar quantities of I2 and Br2 in anhyd
[a]D20 –26.4 (c 1.00, CHCl3).
Synthesis 2008, No. 21, 3389–3396 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Nonactic Acid Analogues
3395
IR (film): 3088, 3064, 3030, 2955, 2869, 1949, 1875, 1739, 1604,
1460, 1366, 1263, 1213, 1173, 1070, 963, 910, 862, 806, 735, 698
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.88 (d, J = 6.6 Hz, 6 H), 1.26
(ddd, J = 13.6, 7.3, 6.2 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.4–1.6
(m, 2 H), 1.6–1.8 (m, 3 H), 1.84 (s, 3 H), 1.9–2.1 (m, 2 H), 2.0–2.2
(m, 1 H), 3.5–3.7 (m, 1 H), 4.11 (m, 1 H), 4.24 (q, J = 7.1 Hz, 2 H),
4.42 (dd, J = 8.0, 5.6 Hz, 1 H), 4.51 (s, 2 H), 7.2–7.4 (m, 5 H).
Ethyl (2R)-2-{(2S,5R)-5-[(2R)-2-(Benzyloxy)-4-methylpen-
tyl]tetrahydrofuran-2-yl}pent-4-enoate (12)
To a stirred and degassed soln of 10b (200 mg, 0.47 mmol) and
AIBN (15 mg, 0.09 mmol) in anhyd toluene (4.7 mL) was added
dropwise, at –78 °C, allyltributyltin (150 mL, 0.94 mmol). The mix-
ture was irradiated for 4 h with a UV lamp (366 nm) and then
quenched with sat. aq NH4Cl soln and diluted with EtOAc. The
aqueous phase was separated and the organic layer was dried
(MgSO4) and concentrated. The residue was purified by flash chro-
matography (cyclohexane–EtOAc, 95:5) to give 12 as a colorless
oil; yield: 119 mg (65%).
13C NMR (100 MHz, CDCl3): d = 13.8, 22.6, 22.7, 22.8, 24.5, 28.3,
31.9, 41.0, 44.2, 61.8, 61.9, 71.3, 75.1, 78.0, 81.9, 127.3, 127.7 (2
C), 128.1 (2 C), 138.8, 170.3.
[a]D20 –33.5 (c 0.40, CHCl3).
Anal. Calcd for C22H33BrO4: C, 59.86; H, 7.54. Found: C, 59.88; H,
7.52.
IR (film): 3065, 3030, 2955, 2870, 1949, 1876, 1732, 1642, 1605,
1497, 1465, 1454, 1368, 1340, 1304, 1259, 1181, 1156, 1069, 1029,
996, 915, 855, 804, 735, 698 cm–1.
Ethyl (2S)-2-{(2S,5R)-5-[(2R)-2-(Benzyloxy)-4-methylpen-
tyl]tetrahydrofuran-2-yl}-2-bromoacetate (10b)
Following the general procedure, method B, using 8b (519 mg, 1.02
mmol) and Br2 soln (2.05 mL, 2.05 mmol) gave 10b as a colorless
oil; yield: 420 mg (96%).
1H NMR (400 MHz, CDCl3): d = 0.89 (d, J = 6.6 Hz, 3 H), 0.90 (d,
J = 6.6 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.28 (ddd, J = 13.6, 7.3,
6.0 Hz, 1 H), 1.4–1.6 (m, 2 H), 1.6–1.7 (m, 2 H), 1.7–1.8 (m, 2 H),
1.9–2.1 (m, 2 H), 2.4–2.6 (m, 3 H), 3.6–3.7 (m, 1 H), 3.9–4.1 (m, 2
H), 4.13 (q, J = 7.1 Hz, 1 H), 4.13 (q, J = 7.1 Hz, 1 H), 4.54 (s, 2 H),
5.00 (ddd, J = 10.2, 1.8, 1.2 Hz, 1 H), 5.07 (ddd, J = 17.1, 1.8, 1.6
Hz, 1 H), 5.78 (dddd, J = 17.1, 10.2, 7.2, 6.4 Hz, 1 H), 7.2–7.4 (m,
5 H).
13C NMR (100 MHz, CDCl3): d = 14.3, 22.8, 23.0, 24.6, 29.3, 31.5,
34.2, 41.9, 44.4, 51.7, 60.2, 71.5, 75.4, 76.5, 78.9, 116.5, 127.4,
127.9 (2 C), 128.3 (2 C), 135.4, 139.0, 173.4.
HRMS (CI+, methane): m/z [M + H]+ calcd for C24H37O4: 389.2692;
found: 389.2709.
[a]D20 –49.7 (c 1.00, CHCl3).
IR (film): 3088, 3064, 3030, 2954, 2867, 1950, 1877, 1747, 1604,
1586, 1497, 1465, 1454, 1385, 1368, 1305, 1266, 1197, 1145, 1067,
1028, 939, 893, 853, 806, 736, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (d, J = 6.6 Hz, 6 H), 1.26
(ddd, J = 13.6, 7.1, 6.3 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.53 (ddd,
J = 13.6, 6.7, 6.7 Hz, 1 H), 1.5–1.7 (m, 1 H), 1.6–1.8 (m, 3 H), 1.9–
2.1 (m, 2 H), 2.1–2.3 (m, 1 H), 3.5–3.7 (m, 1 H), 4.00 (d, J = 8.9
Hz, 1 H), 4.1–4.3 (m, 1 H), 4.23 (q, J = 7.1 Hz, 1 H), 4.24 (q, J = 7.1
Hz, 1 H), 4.37 (ddd, J = 8.8, 7.3, 4.6 Hz, 1 H), 4.50 (d, J = 11.4 Hz,
1 H), 4.51 (d, J = 11.4 Hz, 1 H), 7.2–7.4 (m, 5 H).
Ethyl (2S)-2-{(2S,5R)-5-[(2R)-2-(Benzyloxy)-4-methylpen-
tyl]tetrahydrofuran-2-yl}propanoate (13); General Procedure
To a stirred and degassed soln of 10a (1.0 equiv) and AIBN (0.02–
0.15 equiv) in anhyd toluene (10 mL/mmol) was added dropwise, at
–78 °C, R3MH (1.5–2.0 equiv). The mixture was irradiated for 2 h
with a UV lamp (366 nm) and then concentrated. The residue was
taken up with cyclohexane (10 mL/mmol) and treated with 1 M
TBAF in THF (2.5 equiv) at r.t. for 5 min. After filtration of the
mixture through a short pad of silica gel and solvent removal, a res-
idue was obtained and subsequently purified by flash chromatogra-
phy (cyclohexane–EtOAc, 95:5) to yield, as a colorless oil, the
major isomer 13.
13C NMR (100 MHz, CDCl3): d = 13.9, 22.8, 22.9, 24.5, 29.4, 31.3,
42.0, 44.3, 47.9, 61.8, 71.4, 75.2, 78.2, 79.0, 127.4, 127.8 (2 C),
128.2 (2 C), 138.8, 168.5.
Anal. Calcd for C21H31BrO4: C, 59.02; H, 7.31. Found: C, 59.01; H,
7.23.
Ethyl (2E,6R,8R)-8-(Benzyloxy)-6-hydroxy-10-methylundec-2-
enoate (11)
In a dry Schlenk flask was placed CuCN (41 mg, 0.46 mmol). The
vessel was flushed with argon and then evacuated under high vacu-
um; the process being repeated three times. Anhyd THF (2 mL) was
introduced and the slurry cooled to –78 °C. To this slowly stirring
suspension was added dropwise 1.6 M MeLi in THF (575 mL, 0.92
mmol). The heterogeneous mixture was allowed to warm up gradu-
ally until complete dissolution and was then recooled to –78 °C. A
soln of 10b (98 mg, 0.23 mmol) in THF (1 mL) was introduced and
the resulting mixture was stirred at –78 °C for 1 h. The reaction was
quenched with a mixture composed of 10% concd NH4OH–90%
sat. aq NH4Cl soln and diluted with Et2O. The aqueous phase was
separated and the organic layer was washed with brine, dried
(MgSO4), and concentrated to give 11 as a colorless oil; yield:
77 mg (97%).
The general procedure was used with the following reagent
amounts: 10a (673 mg, 1.52 mmol), AIBN (5 mg, 0.03 mmol),
toluene (15 mL), and n-Bu3SnH (819 mL, 3.04 mmol). Yield: 450
mg (82%).
The general procedure was used with the following reagent
amounts: 10a (221 mg, 0.50 mmol), AIBN (12 mg, 0.08 mmol),
toluene (5 mL), and (Me3Si)3SiH (233 mL, 0.75 mmol). Yield: 153
mg (85%).
[a]D20 –9.30 (c 1.00, CHCl3).
IR (film): 3088, 3064, 3030, 2954, 2870, 1948, 1876, 1732, 1604,
1497, 1455, 1368, 1332, 1300, 1259, 1188, 1157, 1067, 1029, 952,
905, 862, 806, 736, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.88 (d, J = 6.5 Hz, 3 H), 0.90 (d,
J = 6.5 Hz, 3 H), 1.11 (d, J = 7.0 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H),
1.27 (ddd, J = 13.6, 7.5, 5.9 Hz, 1 H), 1.4–1.8 (m, 6 H), 1.9–2.1 (m,
2 H), 2.50 (dq, J = 8.2, 7.0, 1 H), 3.5–3.7 (m, 1 H), 4.0–4.1 (m, 2 H),
4.15 (q, J = 7.1 Hz, 1 H), 4.15 (q, J = 7.1 Hz, 1 H), 4.51 (d, J = 11.3
Hz, 1 H), 4.53 (d, J = 11.3 Hz, 1 H), 7.2–7.4 (m, 5 H).
IR (film): 3493, 3089, 3064, 3031, 2954, 2869, 1949, 1877, 1807,
1709, 1654, 1497, 1466, 1454, 1386, 1367, 1269, 1183, 1132, 1094,
1069, 1029, 914, 849, 745, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.90 (d, J = 6.1 Hz, 6 H), 1.2–1.4
(m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.5–1.9 (m, 6 H), 2.1–2.5 (m, 2
H), 3.03 (br s, 1 H), 3.7–4.0 (m, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.54
(s, 2 H), 5.83 (dm, J = 15.6 Hz, 1 H), 6.98 (dt, J = 15.6, 6.9 Hz, 1
H), 7.2–7.4 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 13.3, 14.2, 22.7, 23.0, 24.6, 28.6,
31.5, 41.8, 44.5, 45.6, 60.2, 71.6, 75.4, 76.5, 80.3, 127.3, 127.8 (2
C), 128.2 (2 C), 139.0, 174.9.
Synthesis 2008, No. 21, 3389–3396 © Thieme Stuttgart · New York

3396
L. Coutable, C. Saluzzo
PAPER
Anal. Calcd for C22H34O4: C, 72.89; H, 9.45. Found: C, 72.68; H,
9.43.
(5) (a) Fleming, I.; Ghosh, S. K. Stud. Nat. Prod. Chem. 1996,
18, 229. (b) Ferraz, H. M. C.; Payret-Arrúa, M. E. Quim.
Nova 1998, 21, 597. (c) Kiyota, H.; Abe, M.; Ono, Y.;
Oritani, T. Synlett 1997, 1093. (d) Mandville, G.; Girard,
C.; Bloch, R. Tetrahedron 1997, 53, 17079. (e) Meiners,
U.; Cramer, E.; Frohlich, R.; Wibbeling, B.; Metz, P. Eur. J.
Org. Chem. 1998, 2073. (f) Ahmar, M.; Duyck, C.;
Fleming, I. J. Chem. Soc., Perkin Trans. 1 1998, 2721.
(g) Lee, E.; Choi, S. J. Org. Lett. 1999, 1, 1127. (h) Wang,
Y.; Metz, P. Tetrahedron: Asymmetry 2000, 11, 3995.
(i) Fraser, B.; Perlmutter, P. J. Chem. Soc., Perkin Trans. 1
2002, 2896. (j) Jeong, J. W.; Woo, B. Y.; Ha, D. C.; No, Z.
Synlett 2003, 393. (k) Wu, Y.; Sun, Y.-P. Org. Lett. 2006, 8,
2831.
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1978, 43, 2087. (b) Houghton, R. P.; Lapham, D. J.
Synthesis 1982, 451.
(7) (a) Noyori, R.; Ohkuma, T.; Kitamura, M. J. Am. Chem. Soc.
1987, 109, 5856. (b) Noyori, R.; Ohkuma, T. Angew. Chem.
Int. Ed. 2001, 40, 40.
Ethyl 2-(5-{2-[3,5-Dinitrobenzyloxy]-4-methylpentyl}tetrahy-
drofuran-2-yl)propanoate (14)
A mixture of the 13 (110 mg, 0.30 mmol) and 10% Pd-C (64 mg) in
MeOH (3 mL) was stirred at r.t. for 4 h under H2 (1 bar). The solid
was filtered off and washed with EtOAc. The filtrate was evaporat-
ed under reduced pressure. To a soln of this crude alcohol (27 mg,
0.10 mmol), 3,5-dinitrobenzoic acid (25 mg, 0.12 mmol), and
DMAP (24 mg, 0.20 mmol) in CH2Cl2 (1 mL) was added slowly, at
0 °C, a soln of DCC (23 mg, 0.11 mmol) in CH2Cl2 (0.5 mL). The
mixture was allowed to warm up to r.t. and stirred overnight, then
concentrated. The residue was taken up with Et2O, filtered, and con-
centrated. Flash chromatography (cyclohexane–EtOAc, 95:5) af-
forded 14 as white crystals; yield: 30 mg (64%); mp 48–50 °C.
IR (film): 3105, 2959, 2873, 1731, 1629, 1598, 1548, 1462, 1345,
1277, 1172, 1075, 921, 825, 773, 730, 722 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.96 (d, J = 6.5 Hz, 6 H), 1.08 (d,
J = 7.0 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.4–1.7 (m, 4 H), 1.75
(ddd, J = 13.7, 8.2, 5.8 Hz, 1 H), 1.8–2.1 (m, 4 H), 2.45 (dq, J = 8.2,
7.0 Hz, 1 H), 3.9–4.1 (m, 2 H), 4.13 (q, J = 7.1 Hz, 2 H), 5.4–5.5 (m,
1 H), 9.1–9.3 (m, 3 H).
(8) (a) Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. M.
Tetrahedron 2004, 60, 7345. (b) Baraldi, P. T.; Zarbin, P. H.
G.; Vieira, P. C.; Corrêa, A. G. Tetrahedron: Asymmetry
2002, 13, 621.
13C NMR (100 MHz, CDCl3): d = 13.3, 14.2, 22.3, 22.9, 24.8, 28.4,
31.4, 41.0, 43.8, 45.5, 60.3, 74.3, 75.8, 80.7, 122.1, 129.4 (2 C),
134.5, 148.6 (2 C), 162.0, 174.7.
HRMS (FI): m/z [M]+ calcd for C22H30N2O9: 466.1951; found:
466.1949.
(9) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O.
Tetrahedron Lett. 1988, 29, 4139.
(10) Enders, D.; von Berg, S.; Jandeleit, B. Org. Synth., Coll. Vol.
X; John Wiley & Sons: London, 2002, 177.
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25, 729.
(12) White, J. D.; Wang, G.; Quaranta, L. Org. Lett. 2003, 5,
4109.
(13) Suenaga, K.; Araki, K.; Sengoku, T.; Uemura, D. Org. Lett.
Acknowledgment
We are grateful to Dr. Karim Adil for carrying out the crystal struc-
ture determination of compound 14. The authors thank the CNRS
for financial support and the Ministère de la Recherche for L. C.
graduate fellowship.
2001, 3, 527.
(14) Guindon, Y.; Soucy, F.; Yoakim, C.; Ogilvie, W. W.;
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Chem. 2002, 67, 1982.
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Synthesis 2008, No. 21, 3389–3396 © Thieme Stuttgart · New York