Facile synthesis of (-)-6-acetoxy-5-hexadecanolide by organocatalytic -oxygenation-allylation-RCM strategy

Article abstract of DOI:10.1055/s-0030-1258248

An asymmetric total synthesis of (-)-6-acetoxy-5-hexadecanolide has been accomplished by employing a seven-step sequence. Asymmetric α- benzoyloxylation of dodecanal followed by indium-mediated one-pot allylation produces the anti-1,2-diol. The six-membered lactone ring is constructed by RCM reaction.

Full text of DOI:10.1055/s-0030-1258248

PAPER
3627
Facile Synthesis of (–)-6-Acetoxy-5-hexadecanolide by Organocatalytic
a-Oxygenation–Allylation–RCM Strategy
F
acile Synthesis of
o
(–)-6-Aceto
u
xy-5-hexade
n
canolide gju Park, Jinsung Tae*
Department of Chemistry and Center for Bioactive Molecular Hybrids (CBMH), Yonsei University, Seoul 120-749, Korea
Fax +82(2)3647050; E-mail: jstae@yonsei.ac.kr
Received 9 July 2010; revised 10 August 2010
thesis (RCM) and hydrogenation would generate the ben-
zoyloxy derivative of 1. The overall synthetic route is
expected to be highly efficient if the initial tandem reac-
tion is successful.
Abstract: An asymmetric total synthesis of (–)-6-acetoxy-5-hexa-
decanolide has been accomplished by employing a seven-step se-
quence. Asymmetric a-benzoyloxylation of dodecanal followed by
indium-mediated one-pot allylation produces the anti-1,2-diol. The
six-membered lactone ring is constructed by RCM reaction.
O
Key words: allylation, a-benzoyloxylation, metathesis, organocat-
alysts, total synthesis
OH
RCM
O
C10H21
C10H21
OBz
OAc
In the past few years organocatalysis, complementing bio-
and metal-catalysis, has attracted much attention and it
has been employed in numerous asymmetric synthesis.1
Considerable effort has also been devoted to the develop-
ment of tandem reactions following the asymmetric orga-
nocatalytic reactions in a one-pot operation, thereby
avoiding the isolation of reaction intermediates, for the
synthesis of diverse chiral building blocks from simple
precursors. For example, a-amino aldehydes have been
further utilized in subsequent tandem reactions such as al-
dol,2 Passerini,3 Horner–Wadsworth–Emmons reactions,4
and diazomethane homologation.5 The allylation of the al-
dehyde intermediates has also been utilized to introduce
1,2-functionalized building blocks.6
Recently, the Maruoka7a and Hayashi7b groups have inde-
pendently reported the organocatalytic a-benzoyloxyla-
tion of aldehydes with benzoyl peroxide catalyzed by
pyrrolidine-type catalysts. Tandem allylation of the a-
(benzoyloxy)aldehydes could readily generate monopro-
tected 1,2-diols which could serve as key intermediates in
asymmetric synthesis. In continuation of our interest in
exploring tandem reactions of organocatalytic reactions,6b
we have developed a facile enantioselective synthesis of
(–)-(5R,6S)-6-acetoxy-5-hexadecanolide (1), the mosqui-
to oviposition attractant pheromone, which has been a
synthetic target for several decades due to its physiologi-
cal activity.8
2
(–)-6-acetoxy-5-hexadecanolide (1)
In
Br
O
N
H
O
C10H21
H
C10H21
H
BzOOBz
OBz
4
3
Scheme 1 Retrosynthetic analysis for (–)-6-acetoxy-5-hexadecano-
lide (1)
First, we screened the reaction conditions for the one-pot
a-benzoyloxylation–allylation sequence. After treating
dodecanal (4) with 5–10 mol% of (S)-59 and benzoyl per-
oxide (BzOOBz, 2 equiv) in the presence of hydroquinone
(10 mol%) according to Maruoka’s procedure,7a the reac-
tion mixture was diluted with tetrahydrofuran–water (5:1)
and then reacted with indium powder (2 equiv) and allyl
bromide (2 equiv) at room temperature for 12 hours (see
Table 1). The initial organocatalytic transformation step
is highly enantioselective in tetrahydrofuran solution
(Table 1, entry 6). The diastereoselectivities of the allyla-
tion reactions are uniformly good under different condi-
tions and the 1,2-anti-isomer (anti/syn ~86: 14) is formed
predominantly. The anti preferences of indium-promoted
allylations to a-oxy aldehydes in tetrahydrofuran–water
solutions have been reported in the literature.6a,10 In tet-
rahydrofuran–water solution, the indium-chelation mode
is less favorable, therefore, the Felkin–Anh transition
Organocatalytic a-benzoyloxylation of dodecanal (4)
with benzoyl peroxide catalyzed by chiral pyrrolidine fol-
lowed by indium-mediated in situ allylation of the result-
ing a-(benzoyloxy)aldehyde
3
could afford the
monoprotected 1,2-diol 2 as shown retrosynthetically in
Scheme 1. Conversion of the homoallyl alcohol 2 into the
corresponding acryl ester followed by ring-closing meta-
O
R
BzO
C
In
H
H
SYNTHESIS 2010, No. 21, pp 3627–3630
Advanced online publication: 07.09.2010
x
x.
x
x
.
2
0
1
0
(R = C10H21
)
DOI: 10.1055/s-0030-1258248; Art ID: F11910SS
© Georg Thieme Verlag Stuttgart · New York
Figure 1 A proposed transition state for the allylation reaction

3628
Y. Park, J. Tae
PAPER
Table 1 One-Pot a-Benzoyloxylation and Indium-Promoted Allylation Reaction
Ph
Br
Ph
N
(2 equiv)
OTMS
H
OH
In (2 equiv)
(S)-5
C10H21
4
3
BzOOBz (2 equiv)
hydroquinone (10 mol%)
solvent
THF–H2O (5:1)
r.t., 12 h
OBz
2
Entry
Solvent (0.2 M)
1,4-dioxane
MeCN
toluene
Et2O
(S)-5 (mol%)
Temp (°C)
Time (h)
Total yield (%) eea (%) (anti isomer) dra (anti/syn)
1
2
3
4
5
6
7
8
10
10
10
10
10
5
25
0
6
6
6
6
6
6
8
8
34
7
92
89
88
90
90
95
94
95
84:16
84:16
86:14
85:15
86:14
86:14
85:15
86:14
0
6
0
20
47
44
45
34
THF
0
THF
0
THF
10
5
–20
–20
THF
a Determined using a Daicel Chiralcel IC column (1% i-PrOH–hexanes). The enantiomeric excesses of the minor syn isomers were not deter-
mined.
II catalyst (7) under dilution conditions (0.02 M in
Mes-N
Cl
N-Mes
Cl
CH2Cl2) to produce 8 in 77%.12 Catalytic hydrogenation
of the unsaturated lactone 8 furnished the benzoyloxy de-
rivative 9 in good yields. For the final conversion of 6-
OBz group into 6-OAc, both the benzoyloxy and the lac-
tone ring are hydrolyzed to give compound 10 which is
then selectively cyclized to the six-membered lactone ring
in the presence of excess acetic anhydride in pyridine so-
lution.13 The synthetic (–)-(5R,6S)-6-acetoxy-5-hexade-
canolide (1) displayed spectral data and optical rotation
O
Ru
O
Ph
(2 equiv)
Cl
PCy3
O
Et3N (2 equiv)
cat. DMAP
7 (10 mol%)
2
C10H21
CH2Cl2 (0.02 M)
reflux, 8 h
OBz
CH2Cl2, 0 °C, 5 h
73%
77%
6
25
{[a]D –35.1 (c 0.49, CHCl3)} consistent with those re-
O
O
O
ported in the literature.8
O
H2, 10% Pd/C
In summary, we have completed a facile asymmetric total
synthesis of (–)-(5R,6S)-6-acetoxy-5-hexadecanolide
starting from dodecanal in seven steps. Tandem asymmet-
ric a-benzoyloxylation and indium-mediated allylation
sequence is utilized to prepare the monoprotected 1,2-diol
intermediate for the first time. Construction of the six-
membered lactone ring is performed by RCM reaction.
C10H21
C10H21
Et2O, r.t., 5 h
90%
OBz
OBz
9
8
O
HO
1 M NaOH
EtOH–H2O, r.t.
OH
Ac2O (36 equiv)
C10H21
1
THF and Et2O were distilled from sodium benzophenone ketyl un-
der nitrogen prior to use. CH2Cl2 and Et3N were dried over calcium
hydride. Indium powder (~100 mesh) was purchased from Aldrich.
All reactions were performed under N2 atmosphere. All chromato-
graphic purifications were performed on silica gel (230–400 mesh)
using the indicated solvent systems. IR spectra were recorded as a
thin film. NMR spectra were recorded with reference to TMS as an
internal standard.
then 2 M HCl
75%
pyridine (0.06 M)
0 °C, 5 h
OH
71%
10
Scheme 2 Total synthesis of (–)-6-acetoxy-5-hexadecanolide (1)
state (with L = OBz) can explain the observed Cram prod-
uct as shown in Figure 1.
(4R,5S)-4-Hydroxypentadec-1-en-5-yl Benzoate (2)
To a mixture of hydroquinone (30 mg, 0.27 mmol) and (–)-(S)-a,a-
diphenylpyrrolidine-2-methanol trimethylsilyl ether [(S)-5, 44 mg,
With the monoprotected 1,2-diol 2 in hand, we next syn-
thesized the lactone ring by RCM reaction11 (Scheme 2).
Reaction of the homoallyl alcohol 2 with acryloyl chloride 0.14 mmol, 5 mol%] in THF (1 mL) was added dodecanal (4, 500
mg, 2.71 mmol) and BzOOBz (75%, remainder H2O; 963 mg, 2.98
gave the diene 6, which was treated with 10 mol% Grubbs
Synthesis 2010, No. 21, 3627–3630 © Thieme Stuttgart · New York

PAPER
Facile Synthesis of (–)-6-Acetoxy-5-hexadecanolide
3629
mmol) in THF (13 mL) at 0 °C. The mixture was stirred at 0 °C for
6 h and treated with H2O (2.7 mL), indium powder (622 mg, 5.42
mmol), and allyl bromide (0.47 mL, 5.4 mmol). The mixture was
stirred at r.t. for 12 h, quenched with sat. NaHCO3 (10 mL), and ex-
tracted with EtOAc (3 × 10 mL). The combined organic layers were
dried (anhyd MgSO4), and the residue was chromatographed (silica
gel, hexanes–EtOAc, 25:1) to give 2 (409 mg, 44%) as a colorless
oil; Rf = 0.4 (hexanes–EtOAc, 5:1). HPLC analysis: (Daicel Chiral-
cel IC, 272 nm, hexane–i-PrOH 99:1, flow rate 0.5 mL/min): tR =
21.5 (4R,5S), 24.2 min (4S,5R).
H), 4.61–4.56 (m, 1 H), 2.58–2.40 (m, 2 H), 1.85–1.81 (m, 2 H),
1.45–1.22 (m, 16 H), 0.87 (t, J = 6.8 Hz, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 165.9, 163.5, 144.8, 133.4,
129.8, 128.6, 122.5, 78.2, 74.2, 32.0, 30.1, 29.6, 29.5, 29.4, 25.6,
25.3, 22.7, 14.2.
HRMS: m/z [M + H]+ calcd for C23H33O4: 373.2301; found:
373.2372.
(S)-1-[(R)-6-Oxotetrahydro-2H-pyran-2-yl]undecyl Benzoate
(9)
[a]D25 –7.2 (c 0.89, CHCl3).
To a soln of 8 (84 mg, 0.22 mmol) in Et2O (1 mL) was added 10%
Pd/C (10 mg, 0.09 mmol). The mixture was stirred for 5 h under a
H2 atmosphere (1.01 bar) at r.t. The mixture was filtered through a
short pad of Celite and the residue was chromatographed (silica gel,
hexanes–EtOAc, 6:1) to give 9 (74 mg, 90%) as a colorless oil:
Rf = 0.5 (hexanes–EtOAc, 2:1).
IR (film) 3480, 3073, 2924, 2854, 1718, 1644, 1602, 1452, 1315,
1273, 1176, 1113, 1069, 1026 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.07–8.05 (m, 2 H), 7.60–7.44 (m,
3 H), 5.92–5.81 (m, 1 H), 5.19–5.12 (m, 3 H), 3.90–3.86 (m, 1 H),
2.42–2.22 (m, 2 H), 1.86–1.68 (m, 2 H), 1.35–1.23 (m, 16 H), 0.87
(t, J = 6.8 Hz, 3 H).
[a]D25 –11.5 (c 0.85, CHCl3).
13C NMR (100.6 MHz, CDCl3): d = 166.7, 134.5, 134.3, 133.2,
130.3, 129.8, 128.5, 118.5, 77.7, 72.3, 37.3, 32.0, 29.8, 29.7, 29.6,
29.4, 25.6, 22.8, 14.2.
HRMS: m/z [M + H]+ calcd for C22H35O3: 347.2508; found:
347.2579.
IR (film) 2921, 2855, 1714, 1601, 1585, 1491, 1452, 1315, 1272,
1176, 1109, 1069, 1026 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.07–8.04 (m, 2 H), 7.60–7.43 (m,
3 H), 5.26–5.22 (m, 1 H), 4.52–4.46 (m, 1 H), 2.65–2.42 (m, 2 H),
2.03–1.68 (m, 6 H), 1.43–1.28 (m, 16 H), 0.87 (t, J = 6.8 Hz, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 171.0, 166.1, 133.3, 130.0,
129.9, 129.8, 128.6, 80.8, 75.0, 32.0, 29.79, 29.76, 29.65, 29.64,
29.5, 29.4, 25.4, 24.0, 22.8, 18.4, 14.2.
HRMS: m/z [M + H]+ calcd for C23H35O4: 345.2457; found:
375.2431.
(4R,5S)-4-(Acryloyloxy)pentadec-1-en-5-yl Benzoate (6)
To a stirred soln of 2 (379 mg, 1.04 mmol) and DMAP (27 mg, 0.22
mmol) in CH2Cl2 (3 mL) was added Et3N (221 mg, 2.18 mmol) and
acryloyl chloride (198 mg, 2.18 mmol) at 0 °C. The mixture was
stirred at 0 °C for 5 h, quenched with sat. NH4Cl (10 mL), and ex-
tracted with CH2Cl2 (3 × 10 mL). The combined organic layers were
dried (anhyd MgSO4), and the residue was chromatographed (silica
gel, hexanes–EtOAc, 99:1) to give 6 (319 mg, 73%) as a colorless
oil; Rf = 0.7 (hexanes–EtOAc, 5:1).
(–)-(5R,6S)-Acetoxy-5-hexadecanolide (1)
A soln of 7 (34 mg, 0.090 mmol) in EtOH (0.69 mL) and H2O (0.15
mL) with 1 M aq NaOH (0.45 mL) was stirred at r.t. for 5 h. The
mixture was quenched with 2 M HCl (0.45 mL) and stirred for 1 h
at r.t. The white solids were collected by filtration to give 10 (19 mg,
0.067 mmol, 75%). A soln of dried 10 (19 mg, 0.067 mmol) in py-
ridine (1.12 mL) and Ac2O (0.23 mL, 2.4 mmol) was stirred at 0 °C
for 5 h. The mixture was quenched with sat. NH4Cl (10 mL) and ex-
tracted with EtOAc (3 × 10 mL) The combined organic layers were
washed with sat. CuSO4, NaHCO3, H2O, and brine, and dried (an-
hyd MgSO4). The residue was chromatographed (silica gel, hex-
anes–EtOAc, 4:1) to give 1 (15 mg, 71%) as a colorless oil; Rf = 0.4
(hexanes–EtOAc, 2:1).
[a]D27 –3.1 (c 0.65, CHCl3).
IR (film) 2924, 2854, 1725, 1639, 1602, 1452, 1405, 1273, 1190,
1108, 1069 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.04–8.03 (m, 2 H), 7.57–7.42 (m,
3 H), 6.40–6.35 (m, 1 H), 6.14–6.07 (m, 1 H), 5.84–5.73 (m, 2 H),
5.36–5.32 (m, 1 H), 5.28–5.24 (m, 1 H), 5.13–5.05 (m, 2 H), 2.51–
2.47 (m, 2 H), 1.79–1.67 (m, 2 H), 1.42–1.23 (m, 16 H), 0.86 (t,
J = 6.8 Hz, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 166.0, 165.5, 133.3, 133.1,
131.1, 130.3, 129.8, 128.5, 118.1, 74.5, 73.7, 34.5, 32.0, 30.1, 29.7,
29.6, 29.5, 29.4, 25.5, 22.8, 14.2.
[a]D25 –35.1 (c 0.49, CHCl3).
IR (film) 2928, 2854, 1730, 1464, 1373, 1240, 1052 cm–1.
HRMS: m/z [M + H]+ calcd for C25H37O4: 401.2614; found:
401.2695.
1H NMR (400 MHz, CDCl3): d = 4.99–4.95 (m, 1 H), 4.36–4.31 (m,
1 H), 2.63–2.40 (m, 2 H), 2.07 (s, 3 H), 1.98–1.87 (m, 2 H), 1.85–
1.77 (m, 1 H), 1.65–1.57 (m, 3 H), 1.37–1.21 (m, 16 H), 0.87 (t,
J = 6.8 Hz, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 171.0, 170.7, 80.7, 74.5, 32.0,
29.8, 29.7, 29.6, 29.5, 25.4, 23.7, 22.8, 21.2, 18.4, 14.3.
(S)-1-[(R)-6-Oxo-3,6-dihydro-2H-pyran-2-yl]undecyl Benzoate
(8)
A mixture of 6 (319 mg, 0.796 mmol) and Grubbs II catalyst (7; 68
mg, 0.080 mmol, 10 mol%) in CH2Cl2 (400 mL, 0.02 M) was re-
fluxed for 8 h. The mixture was evaporated and the residue was
chromatographed (silica gel, hexanes–EtOAc, 12:1) to give 8 (228
mg, 77%) as a colorless oil (The minor syn diastereomer was sepa-
rated in 15% (45 mg) as a colorless oil); Rf = 0.1 (hexanes–CH2Cl2,
1:1).
HRMS: m/z [M + H]+ calcd for C18H33O4: 313.2301; found:
313.2381.
Supporting Information for this article is available online at
http://www.thieme-connect.de/ejournals/toc/synthesis.
[a]D25 +19.4 (c 0.92, CHCl3).
IR (film) 2920, 2854, 1727, 1637, 1601, 1585, 1452, 1381, 1314,
1270, 1110, 1069 cm–1.
Acknowledgment
1H NMR (400 MHz, CDCl3): d = 8.05–8.03 (m, 2 H), 7.59–7.42 (m,
3 H), 6.91–6.87 (m, 1 H), 6.04–6.01 (m, 1 H), 5.34 (q, J = 5.6 Hz, 1
This work was supported by the Center for Bioactive Molecular Hy-
brids (MOST/KOSEF) at Yonsei University.
Synthesis 2010, No. 21, 3627–3630 © Thieme Stuttgart · New York

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Y. Park, J. Tae
PAPER
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Synthesis 2010, No. 21, 3627–3630 © Thieme Stuttgart · New York