First asymmetric synthesis of achaetolide

Article abstract of DOI:10.1016/j.tetasy.2010.07.026

The first asymmetric synthesis of the 10-membered macrolide achaetolide is reported in this article. The main highlight of the synthetic strategy is the ring-closing metathesis (RCM) of intermediate 19, which in turn can be accessed from coupling between alcohol 11 and acid 18. The synthesis of 11 involves enzymatic kinetic resolution (EKR) coupled with a Mitsunobu inversion strategy, while 18 can be prepared by adopting a metal-enzyme combined dynamic kinetic resolution (DKR) reaction followed by functional group manipulation.

Full text of DOI:10.1016/j.tetasy.2010.07.026

Tetrahedron: Asymmetry 21 (2010) 2206–2211
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
First asymmetric synthesis of achaetolide
⇑
Tapas Das, Rajib Bhuniya, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 June 2010
Accepted 22 July 2010
The first asymmetric synthesis of the 10-membered macrolide achaetolide is reported in this article. The
main highlight of the synthetic strategy is the ring-closing metathesis (RCM) of intermediate 19, which in
turn can be accessed from coupling between alcohol 11 and acid 18. The synthesis of 11 involves enzy-
matic kinetic resolution (EKR) coupled with a Mitsunobu inversion strategy, while 18 can be prepared by
adopting a metal-enzyme combined dynamic kinetic resolution (DKR) reaction followed by functional
group manipulation.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
molecule for example, C3 and C9 are thought to be constructed by
applying a metal-enzyme combined DKR strategy and EKR/Mitsun-
Naturally occurring 10-membered ring lactones from fungal
metabolites present a wide variety of bioactive substances. Exam-
ples of 10-membered ring-containing macrolides that display
potent biological activity include aspinolide B,1 pinolidoxin,2 deca-
restrictines A–D,3–6 herbarumins I–II,7 and stagonolides A–I.8,9
Since some of these exhibit potent biological activities (cholesterol
biosynthesis inhibition activity, antimicrofilament activity and
phytotoxicity, etc), this class of lactone has received special atten-
tion from the synthetic organic chemist in recent years. Achaeto-
lide, a hydroxylated small ring macrolide, as reported by Bodo
et al.10 in 1983, was isolated from a fermentation broth of Ophiobo-
lus sp. The absolute configuration (3S,6R,7S,9R) of achaetolide was
further established by Cabellero et al.11 in 2009 by a combination
of extensive NMR analysis and GC methods. All the noneolides
mentioned above possess interesting structural features, as they
are compact and contain a properly placed olefinic moiety with
well-defined geometry; the presence of stereochemically pure
hydroxy appendages make them a very good synthetic target.
Recently we have focused our attention on the asymmetric total
synthesis of such small ring macrolides by adopting a chemoenzy-
matic strategy.12,13 Herein we report the total synthesis of such a
noneolide achaetolide. Retrosynthetic analysis of the target mole-
cule achaetolide is shown in Scheme 1. The internal double bond
between C4–C5 was thought to be a crucial disconnection as it can
be reconnected through an RCM reaction. The crucial ester linkage
between C1–C9 was planned to be constructed by an esterification
reaction of an appropriately substituted acid and alcohol. The re-
quired acid and the alcohol are constructed from the more easily
available starting materials. Two of the stereocenters in the parent
obu inversion reaction, while the two hydroxy stereocenters C6 and
C7 are assembled through an asymmetric dihydroxylation reaction.
2. Results and discussion
2.1. Synthesis of (R)-1-((4S,5R)-2,2-dimethyl-5-vinyl-[1,3]diox-
olan-4-yl)-nonan-2-ol 11
The synthesis starts from n-octanal, which upon addition with a
Grignard reagent generated from allyl bromide and Mg metal affor-
ded alcohol 2 in 86% yield. Enzymatic kinetic resolution of 2 was
attempted by using CAL-B (novozyme-435) and vinyl acetate as
the acyl donor which yielded alcohol 3 (ee = 96%, slow reacting
enantiomer) and acetate 4 (ee = 98%, with c = 49.4% and E = 422)
according to Kazlauskas empirical rule.14 Acetate 4 was hydrolyzed
with K2CO3 in methanol and the alcohol was inverted by applying a
Mitsunobu inversion strategy to give alcohol 3 (overall yield 82%
after three steps). The free hydroxy group in alcohol 3 was pro-
tected as its TBDPS (tert-butyldiphenyl silyl) ether by treatment
with imidazole and TBDPS-Cl to afford compound 5 in 89% yield.
Dihydroxylation of the terminal olefinic double bond in 5 with
OsO4 afforded the diol; oxidative cleavage of the diol with NaIO4
produced the aldehyde 6 in 80% yield. The cis-selective HWE olef-
ination of aldehyde 6 using an Ando method15 yielded Z-ester 7 in
88% yield (Z:E = 15:1). Dihydroxylation of ester 7 with AD Mix-a16
produced the required diol 8 in 78% yield. Diol 8 was protected as
its acetonide by treatment with 2,2-DMP17 (2,2-dimethoxy
propane) in the presence of a catalytic amount of CSA (camphore
sulfonic acid) to afford 9 in 92% yield. Selective reduction of the
ester functionality with DIBAL-H followed by Wittig olefination
with methyltriphenylphosphonium iodide in the presence of
LHMDS produced olefin 10 in 82% overall yield over two steps.
Deprotection of the TBDPS group in 10 was achieved by treatment
⇑
Corresponding author.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.026

T. Das et al. / Tetrahedron: Asymmetry 21 (2010) 2206–2211
2207
R
O
R
O
O
HO
O
O
OH
+
OP'
PO
OP'
HO
OH
PO
OP'
R
OH
OP'
R = nC7H15
P = TBS; P" = TBDPS
P' = acetonide
HO
OH
P"O
EtO2C
Scheme 1. Retrosynthetic analysis of achaetolide.
with TBAF in tetrahydrofuran (THF) to afford compound 11 in 88%
under Pinnic condition23 to give acid 18 in 78% yield (overall in
two steps, Scheme 3).
yield (Scheme 2).18
2.2. The synthesis of (S)-3-(tert-Butyl-dimethyl-silanyloxy)-
pent-4-enoic acid 18
2.3. Coupling of fragments 11 and 18 for the total synthesis of
achaetolide
For the synthesis of the required acid fragment, we started from
the known aldehyde 3-(4-methoxy-benzyloxy)-propionaldehyde.
Upon addition of vinylmagnesium bromide at ꢀ78 °C, racemic alco-
hol 13 was produced in 86% yield. The DKR of the secondary alcohol
functionality in compound 13 was achieved by coupling the en-
zyme-catalyzed transesterification reaction with a metal-catalyzed
(ruthenium based catalyst shown in Scheme 3) racemization meth-
od, as reported by Kim et al.19 Isopropenyl acetate was used as the
acyl donor in the DKR reaction. The DKR reaction is highly efficient
for compound 13 as it yields the corresponding acetate 14 in 92%
yield with excellent enantioselection (ee = 98%).20 The acetate
functionality was removed by treatment with K2CO3 in MeOH to
yield enantiomerically pure 15 in 94% yield. The free secondary
hydroxy group in compound 15 was protected as its TBS (tert-
butyldimethyl silyl) ether by treatment with TBS-Cl and imidazole
to produce compound 16 in 88% yield. Removal of the PMB group
was achieved with DDQ21 to afford compound 17 in 82% yield.
The primary hydroxy group in 17 was transformed to its corre-
sponding carboxylic acid by treatment with PDC in DMF to afford
18 in 78% yield. At first, compound 17 was oxidized to the corre-
sponding aldehyde by Swern oxidation,22 followed by oxidation
After the successful construction of both the required fragments
11 and 18, the remaining step was to couple the two fragments fol-
lowed by RCM strategy. The coupling of the two fragments was
successfully achieved by treating acid 18 with EDCIꢁHCl/DMAP fol-
lowed by the addition of alcohol 11 to afford the coupled ester 19
in 85% yield. The final RCM reaction seems to be crucial and prob-
lematic. After numerous conditions were attempted with Grubbs-I
and Grubbs-II22 catalyst in different solvents such as DCM, benzene
and toluene, the final outcome was same in all the cases; either
inseparable mixtures of various compounds were obtained or the
starting material had decomposed during the course of the reac-
tion. We envisioned that this may be due to the presence of a
TBS group at one end and an acetonide functionality at another
end in 19, which causes some steric crowding, hence the two ter-
minal vinyl groups cannot be in proximity to have an efficient com-
plexation with the metal catalyst, which is a prerequisite in the
RCM reaction; similar precedences have been reported before.23 Fi-
nally deprotection of the TBS and acetonide functionality was
achieved by treating compound 19 with pyridinum para toluene
sulfonate (PPTS)24 in methanol to afford triol 24 in 85% yield. Com-
pound 24, upon treatment with Grubbs second generation catalyst
R
R
R
R
d
a
b
e
PO
AcO
c
HO
HO
R-CHO
R
+
2
3
4
5
R
R
R
R
3
g
PO
h
f
PO
EtO2C
PO
i
PO
PO
CHO
EtO2C
EtO2C
6
OH
O
O
7
R
9
10
8
O
OH
O
HO
j
R = n-C7H15; P = TBDPS
O
11
O
Scheme 2. Reagents and conditions: (a) CH2@CHCH2MgBr, THF, rt, 86%; (b) CAL-B, CH2@CHOAc, DIPE (iPr2O), MS 4 Å; (c) K2CO3/MeOH, DIAD, TPP, PhCO2H, NaOH, 82%;
(d) imidazole, TBDPS-Cl, 89%; (e) OsO4, NMO, THF/H2O (1:1), NaIO4, THF/H2O (1:1), 80%; (f) (PhO)2POCH2CO2Et, NaH, 0 °C, 88%; (g) AD Mix-
a, MeSO2NH2, tBuOH/H2O (1:1),
78%; (h) 2,2-DMP, CSA, 92%; (i) DIBAL-H (1 equiv), DCM, ꢀ78 °C, Ph3P+MeIꢀ, LHMDS, THF, 0 °C, 82%; (j) TBAF, THF, 88%.

2208
T. Das et al. / Tetrahedron: Asymmetry 21 (2010) 2206–2211
OH
a
b
CHO
OPMB
d
OPMB
PMBO
PMBO
13
RO
12
TBSO
O
14; R = Ac
15; R = H
16
c
e
OH
f
OH
Ph
TBSO
TBSO
17
18
Ph
NHiPr
DKR catalyst
Ph
Cl
Ph
Ru
CO
CO
Scheme 3. Reagents and conditions: (a) CH2@CHMgBr, THF, ꢀ78 °C, 86%; (b) CAL-B, isopropenylacetate, chlorodicarbonyl(1-(isopropylamino)-2,3,4,5-tetraphenylcyclopen-
tadienyl) ruthenium(II), K2CO3, KOtBu 92%; (c) K2CO3, MeOH, 94%; (d) imidazole, TBS-Cl, 88%; (e) DDQ, DCM/H2O (19:1), 82%; (f) PDC, DMF, 78%.
afforded the target molecule achaetolide (Scheme 4; overall
yield = 11% from n-octanal).
light, ethanolic anisaldehyde and phosphomolybdic acid/heat as
developing agents. Silica gel 100–200 mesh was used for column
chromatography. Yields refer to chromatographically and spectro-
scopically homogeneous materials unless otherwise stated. NMR
spectra were recorded on Bruker 400 MHz spectrometers at 25 °C
in CDCl3 using TMS as an internal standard. Chemical shifts are
shown in d. 13C NMR spectra were recorded with a complete pro-
ton decoupling environment. The chemical shift value is listed as
dH and dC for 1H and 13C, respectively. Elemental analysis was
performed by using Perkin Elmer model: 2400, series II CHN ana-
lyzer. Optical rotations were measured on a JASCO P-1020 digital
polarimeter. Chiral HPLC was performed using Chiral OD-H column
(0.46 ꢂ 25 cm, Daicel industries) with Shimadzu Prominence LC-
20AT chromatograph coupled with a UV–vis detector (254 nm).
The eluting solvent used involved different ratios of hexane and
2-propanol.
3. Conclusion
In conclusion we have described an efficient asymmetric syn-
thesis of the polyhydroxylated small ring macrolide achaetolide
for the first time. Two of the stereocenters (C3 and C9) in the target
molecule have been fixed by a metal-enzyme combined DKR and
EKR strategy, whereas the other two hydroxy stereocenters (C6
and C7) have been created by asymmetric dihydroxylation reac-
tion. The RCM reaction has been successfully applied to create
the 10-membered macrolide ring in an efficient way.
4. Experimental
4.1. General
4.2. Undec-1-en-4-ol 2
Unless otherwise stated, materials were obtained from com-
mercial suppliers and used without further purification. THF and
diethyl ether were distilled from sodiumbenzophenone ketyl.
Dichloromethane (DCM), dimethylformamide (DMF) and dimeth-
ylsulfoxide (DMSO) were distilled from calcium hydride. Diiso-
propylether (DIPE) was refluxed over P2O5 and distilled prior to
use. Vinyl acetate and isopropenyl acetate were freshly distilled
prior to use. CAL-B (Candida antartica lipase-B, Novozym-435,
immobilized on acrylic resin) was obtained from Sigma and used
as obtained. Reactions were monitored by thin-layer chromatogra-
phy (TLC) carried out on 0.25 mm silica gel plates (Merck) with UV
Magnesium turnings (3.3 g) were charged with iodine and
anhydrous ethyl ether (30 mL) placed under argon in a dry,
three-necked flask equipped with a mechanical stirrer. Then allyl
bromide (4 mL, 46.2 mmol) in 10 mL of anhydrous ether was added
and stirred for few minutes until the effervescence ceased. Then
n-octanal (4 g, 31 mmol) was added and stirred for 1.5 h after
which the reaction mixture was cooled in a water-ice bath, and a
saturated aqueous ammonium chloride solution was added. The
combined organic layer was extracted with ethyl acetate and brine
and dried over MgSO4. Purification by silica gel chromatography
R
O
R
O
O
R
a
HO
b
O
OH
O
+
O
O
TBSO
TBSO
HO
OH
11
19
18
O
20
O
OH
X
c
O
R
O
R
N
N
R = nC7H15
SMe
MeS
Ph
O
O
Cl
Cl
Ru
PCy3
TBSO
HO
OH
O
O
OH
Grubbs II catalyst
21 (not obtained)
Achaetolide 1
Scheme 4. Reagents and conditions: (a) EDCIꢁHCl, DMAP, 85%; (b) PPTS, MeOH, 85%; (c) Grubbs-II (10 mol %), DCM, 62%.

T. Das et al. / Tetrahedron: Asymmetry 21 (2010) 2206–2211
2209
(3:1, hexane/EtOAc) afforded alcohol 2 in 86% yield. dH: 5.88–5.67
(m, 1H), 5.11–5.03 (m, 2H), 3.56 (m, 1H), 2.28–2.11 (m, 2H), 1.39–
1.13 (m, 12H), 0.82 (t, J = 6.8 Hz, 3H). dC: 134.9, 117.9, 70.6, 41.9,
36.7, 31.8, 29.6, 29.2, 25.6, 22.6, 14.0. Elemental Anal. Calcd for
yield Z:E isomer (15:1), which was further purified by flash chro-
matography to afford pure 7 in 88% yield. dH: 7.67 (m, 4H), 7.38
(m, 6H), 6.35 (m, 1H), 5.78 (d, J = 11.6 Hz, 1H), 4.15 (q, J = 7.0 Hz,
2H), 3.84 (m, 2H), 2.89–2.75 (m, 2H), 1.557–1.38 (m, 2H), 1.29 (t,
J = 7.0 hz, 3H), 1.22 (m, 10H), 1.10 (s, 9H), 0.87 (t, J = 6.2 Hz, 3H).
dC: 166.4, 146.7, 135.9, 134.4, 129.6, 127.5, 120.9, 72.5, 59.7,
36.8, 35.7, 31.8, 29.5, 29.2, 27.1, 25.0, 22.7, 19.4, 14.3, 14.1.
C11H22O: C, 77.58; H, 13.02. Found: C, 77.56; H, 13.09.
4.3. (R)-Undec-1-en-4-ol 3 and acetic acid (S)-1-allyl-octyl ester
4
½
a 2D9
ꢃ
¼ þ7:7 (c 1.0 MeOH).
In a typical resolution experiment, a solution of compound 2
(4.2 g, 24.8 mmol) in anhydrous diisopropyl ether (75 ml) was stir-
red with vinyl acetate (1 equiv, 1.7 mL) and powdered molecular
sieves (25 mg, 4 Å) followed by the addition of CAL-B (1 g). The
reaction mixture was stirred in an orbit shaker (250 rpm) at room
temperature for 1 h. After 50% conversion (by TLC analysis), the
reaction mixture was filtered through a pad of Celite and evapo-
rated to dryness. The alcohol and the acetate were isolated by col-
umn chromatography. Acetate 4 was deprotected and converted to
the desired alcohol 3 by Mitsunobu inversion. Compound 4; dH:
5.71–5.63 (m, 1H), 5.03–4.97 (m, 2H), 4.86 (m, 1H), 2.25 (t,
J = 6.6 Hz, 2H), 1.98 (s, 3H), 1.49 (m, 2H), 1.21 (m, 10H), 0.83 (t,
J = 6.6 Hz, 3H). Compound 4; dC: 170.6, 133.8, 117.4, 73.2, 38.6,
33.3, 31.7, 29.4, 29.1, 25.3, 22.6, 21.1, 14.0.
4.7. (2S,3S,5R)-5-(tert-Butyl-diphenyl-silanyloxy)-2,3-dihy-
droxy-dodecanoic acid ethyl ester 8
At first, t-BuOH (29 mL), H2O (29 mL) and AD-mix-
a (11.6 g)
were mixed and the mixture was stirred for 15 min. Methanesul-
fonamide (1.1 g) was then added and stirring was continued for a
further 15 min. Compound 7 (3.58 g, 8.02 mmol) was then added
in one portion. The slurry was stirred vigorously at 20 °C for
24 h. After that time, sodium sulfite (15 g) was added and stirring
was continued for a further 1 h. The reaction mixture was ex-
tracted with EtOAc. The organic layer was dried (Na2SO4) and
evaporated in vacuo. The diol was purified by flash chromatogra-
phy (3:1; hexane–EtOAc) to afford diol 8 in 78% yield. dH: 7.70
(m, 4H), 7.41 (m, 6H), 4.30–3.99 (m, 5H), 1.96–1.25 (m, 17H),
1.06 (s, 9H), 0.87 (t, J = 6.2 Hz, 3H). dC: 172.5, 135.9, 133.9, 129.8,
127.7, 74.3, 72.6, 70.1, 61.7, 36.0, 35.7, 31.7, 29.2, 29.0, 27.0,
4.4. ((R)-1-Allyl-octyloxy)-tert-butyl-diphenyl-silane 5
25.1, 22.6, 19.3, 14.2, 14.1. ½a D29
¼ ꢀ5:5 (c 1.75 MeOH).
ꢃ
The desired alcohol 3 (3.8 g, 22.3 mmol) was taken in anhydrous
DCM (50 mL) and cooled to 0 °C. Imidazole (3 g) and DMAP (cata-
lytic) were added to the reaction mixture followed by the addition
of TBDPS-Cl (7 mL, 26.76 mmol). The reaction mixture was allowed
to warm at room temperature for 6 h, after which water was added
to it and the organic layer was washed with brine and dried over
MgSO4. Evaporation and purification yielded the mono TBDPS-pro-
tected alcohol in 89% yield. dH: 7.78 (m, 4H), 7.46 (m, 6H), 5.90–5.73
(m, 1H), 5.05–4.96 (m, 2H), 3.82 (m, 1H), 2.29 (m, 2H), 1.50 (m, 2H),
1.25 (m, 10H), 1.15 (m, 9H), 0.95 (t, J = 7.2 Hz, 3H). dC: 136.0, 135.1,
134.7, 129.5, 127.5, 116.7, 72.9, 41.1, 36.1, 31.9, 29.6, 29.3, 27.2,
4.8. (4S,5S)-5-[(R)-2-(tert-Butyl-diphenyl-silanyloxy)-nonyl]-
2,2-dimethyl-[1,3]dioxolane-4-carboxylic acid ethyl ester 9
Compound 8 (4 mmol) was taken in 20 mL of dry DCM. 2,2-
Dimethoxypropane (DMP, 1.5 mL, 12 mmol) was then added fol-
lowed by the addition of a catalytic amount of CSA (0.45 mmol,
122 mg). The reaction mixture was stirred at rt overnight. The
product was purified by column chromatography (10:1; hexane–
EtOAc) to afford compound 9 in 92% yield. dH: 7.67 (m, 4H), 7.36
(m, 6H), 4.62–3.89 (m, 5H), 1.84–1.18 (m, 17H), 1.7 (s, 3H), 1.5
(s, 3H), 1.05 (s, 9H), 0.87 (t, J = 6.4 Hz, 3H). dC: 170.6, 135.9,
134.5, 129.5, 127.4, 110.5, 76.4, 74.5, 70.8, 60.9, 37.7, 37.2, 36.6,
31.7, 29.1, 27.1, 26.8, 25.6, 24.6, 22.6, 19.5, 14.3, 14.1.
24.9, 22.7, 19.5, 14.2. ½a D29
¼ ꢀ0:9 (c 1.5 MeOH).
ꢃ
4.5. (R)-3-(tert-Butyl-diphenyl-silanyloxy)-decanal 6
½
a 2D9
ꢃ
¼ ꢀ6:1 (c 0.33 MeOH).
The TBDPS-protected alcohol 5 (7.2 g, 17.84 mmol) was taken in
THF/H2O (3:1) and OsO4 (0.05 M, 7 mL) and NMO (3.1 g) was added
at room temperature and stirred for 12 h, after which a saturated
solution of NaHSO3 was added and the solution stirred for a further
1 h. The organic layer was extracted with ethyl acetate and evapo-
rated to dryness to afford the diol. The crude diol was taken in
30 mL of tetrahydrofuran and 20 mL of water, followed by the
addition of sodium periodate (4.8 g, 22.5 mmol). The mixture was
stirred for 1 h and followed by TLC to ascertain cleavage of the gly-
col. Ether (50 mL) and water (25 mL) were added, and the custom-
ary workup afforded aldehyde 6 (4.3 g). dH: 9.72 (t, J = 2.4 Hz, 1H),
7.68 (m, 4H), 7.41 (m, 6H), 4.20 (m, 2H), 2.49 (m, 2H), 1.48 (m, 2H),
1.26–1.12 (m, 10H), 1.05 (s, 9H), 0.86 (t, J = 7.0 Hz, 3H). dC: 202.5,
136.0, 134.1, 129.9, 127.8, 69.5, 50.4, 37.5, 31.8, 29.4, 29.2, 27.1,
4.9. tert-Butyl-[(R)-1-((4S,5R)-2,2-dimethyl-5-vinyl-[1,3]dioxo-
lan-4-ylmethyl)-octyloxy]-diphenyl-silane 10
Compound 8 (1.2 g, 2.8 mmol) was taken in dry toluene (10 mL)
and cooled to ꢀ78 °C. A solution of DIBAL-H (1 M in toluene,
2.8 mL) was added over 30 min. The reaction was stirred for a further
2 h at the same temperature then warmed to ꢀ20 °C and quenched
withdry methanoland stirred for a further 1.5 h, then extracted with
ethyl acetate, brine and dried over MgSO4. The organic extract was
evaporated to dryness to afford the crude aldehyde. With this crude
aldehyde, a one carbon extension via a Wittig reaction was per-
formed using LHMDS as a base. To a suspension of methyltriphenyl-
phosphonium iodide (1.7 g, 4.2 mmol) in dry ether was added
LHMDS (5 mmol) in two portions. The bright yellow mixture was
heated at reflux for 1 h. The yellow mixture was allowed to cool to
room temperature. A solution of 9 (1.0 g, 2.8 mmol) in 5 mL of Et2O
was added to the reaction mixture. The yellow suspension was stir-
red at room temperature for a further 1 h. After completion of the
reaction, as indicated by TLC, the reaction was quenched with water
and the layers were separated and extracted with 20 mL of ether,
dried with MgSO4, filtered, and the solvent was removed in vacuo.
The crude residue was purified by flash column chromatography
to afford the compound 10 (1:40 EtOAc/hexane) in 82% yield. dH:
7.68 (m, 4H), 7.35 (m, 6H), 5.78–5.62 (m, 1H), 5.26–4.95 (m, 2H),
25.0, 22.7, 19.4, 14.2. ½a D29
¼ ꢀ12:5 (c 1.2 MeOH).
ꢃ
4.6. (Z)-(R)-5-(tert-Butyl-diphenyl-silanyloxy)-dodec-2-
enoicacid ethyl ester 7
To
a solution of ethyl (diphenylphosphono)acetate (3.4 g,
10.7 mmol) in THF (40 mL) was added NaH (60%, 513 mg,
12.84 mmol) at 0 °C; after 15 min, aldehyde 5 (4.3 g, 10.7 mmol)
in THF (10 mL) was added, and the resulting mixture was gradually
warmed to the room temperature over 1.2 h after which water was
added, extracted with ethyl acetate and brine, dried over MgSO4 to

2210
T. Das et al. / Tetrahedron: Asymmetry 21 (2010) 2206–2211
4.38 (m, 2H), 3.99 (m, 1H), 1.58 (m, 2H), 1.42 (s, 3H), 1.33 (s, 3H), 1.29
(m, 12H), 1.1 (s, 9H), 0.85 (t, J = 6.4 Hz, 3H). dC: 135.9, 134.9, 134.5,
129.4, 127.9, 117.9, 108.0, 79.8, 74.8, 71.0, 37.7, 31.9, 29.7, 29.5,
allowed to warm at room temperature for 6 h, after which water
was added and the organic layer was washed with brine and dried
over MgSO4. Evaporation and purification yielded the TBDMS-pro-
tected alcohol 16 in 88% yield. dH: 7.26 (d, J = 8.6 Hz, 2H), 6.88 (d,
J = 8.6 Hz, 2H), 5.90–5.73 (m, 1H), 5.29–5.0 (m, 2H), 4.41 (m, 2),
4.28 (m, 1H), 3.80 (s, 3H), 3.54 (m, 2H), 1.79 (m, 2H), 0.9 (s, 9H),
0.07 (s, 3H), 0.04 (s, 3H). dC: 159.1, 141.6, 130.7, 129.3, 113.7,
29.1, 28.2, 27.1, 25.5, 24.4, 22.6, 19.5, 14.1. ½a D29
¼ ꢀ7:8 (c 0.5 MeOH).
ꢃ
4.10. (R)-1-((4S,5R)-2,2-Dimethyl-5-vinyl-[1,3]dioxolan-4-yl)-
nonan-2-ol 11
72.7, 70.8, 66.4, 55.3, 38.2, 25.3, 18.2, ꢀ4.3, ꢀ4.9. ½a D29
¼ ꢀ3:5 (c
ꢃ
Compound 10 (768 mg, 1.96 mmol) was taken in dry THF
(10 mL). Next, TBAF (1 M in THF, 2 mL) was added, and the reaction
mixture was stirred for 3 h at room temperature. After that time, the
THF was evaporated, and water (4 ml) was added to it; the reaction
mixture was extracted with EtOAc (50 mL), and the organic layer
was washed with NaHCO3 and brine, and dried (Na2SO4), after which
it was purified by flash chromatography (5:1; hexane–EtOAc) to af-
ford compound 10 in 88% yield. dH: 5.88–5.70 (m, 1H), 5.34–5.20 (m,
2H), 4.58–4.41 (m, 2H), 3.83 (m, 1H), 1.57 (s, 3H), 1.47 (s, 3H), 1.45–
1.14 (m, 14H), 0.92 (t, J = 6.4 Hz, 3H). dC: 134.2, 118.9, 109.1, 80.1,
78.7, 71.6, 37.8, 37.5, 32.1, 29.9, 29.5, 28.3, 26.1, 25.8, 25.7, 22.9,
0.75 MeOH).
4.14. (S)-3-(tert-Butyl-dimethyl-silanyloxy)-pent-4-en-1-ol 17
Compound 16 (1.7 g, 4.8 mmol) was taken in 30 mL of DCM/
H2O (19:1). Next, DDQ (1.6 g, 7.2 mmol) was added to it in one por-
tion. The reaction mixture was stirred at room temperature for 1 h.
The reaction mixture was filtered off, and the filtrate was washed
with 5% NaHCO3 solution, water and brine. The organic layer was
dried (MgSO4) and evaporated. Purification by silica gel chroma-
tography (3:1, hexane/EtOAc) afforded the pure compound 17 in
82% yield. dH: 5.91–5.74 (m, 1H), 5.24–5.01 (m, 2H), 4.40 (s, 1H),
3.78 (m, 2H), 1.81 (m, 2H), 0.91 (s, 9H), 0.07 (s, 3H), 0.03 (s, 3H).
14.3.
½
a 2D9
ꢃ
¼ ꢀ3:6 (c 1.0 MeOH). Elemental Anal. Calcd for
C16H30O3: C, 71.07; H, 11.18. Found: C, 71.12; H, 11.19.
dC: 140.6, 114.3, 73.0, 39.2, 25.8, 18.1, -4.4, -5.0. ½a D29
¼ ꢀ5:65 (c
ꢃ
4.11. 5-(4-Methoxy-benzyloxy)-pent-1-en-3-ol 13
0.5 MeOH).
Aldehyde 12 (2.4 g, 11.6 mmol) was taken in 40 mL of anhy-
drous THF. A solution of vinylmagnesium bromide (1 M, 17.4 mL,
17.4 mmol) was then added at ꢀ78 °C. The reaction mixture was
kept at the same temperature for 1 h, after which time saturated
NH4Cl solution was added. The solution was extracted with EtOAc,
and the organic layer was washed with water and brine. The organ-
ic layer was dried (MgSO4) and evaporated. Purification by silica
gel chromatography (3:1, hexane/EtOAc) afforded alcohol 13 in
86% yield. dH: 7.27 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H),
5.96–5.79 (m, 1H), 5.31–5.08 (m, 2H), 4.45 (s, 2H), 4.30 (m, 1H),
3.77 (s, 3H), 3.64 (m, 2H), 1.87 (m, 2H). dC: 159.4, 140.7, 130.1,
129.5, 114.5, 114.0, 73.1, 72.1, 68.2, 55.4, 36.4. Elemental Anal.
Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.26; H, 8.23.
4.15. (S)-3-(tert-Butyl-dimethyl-silanyloxy)-pent-4-enoic acid
18
Compound 17 (588 mg, 2.4 mmol) was taken in anhydrous DMF
(8 mL). Next, pyridinium dichromate (PDC, 3.2 g, 8.5 mmol) was
added to the reaction mixture and the reaction mixture was stirred
at room temperature until all the starting material had been con-
sumed as indicated by TLC. Water was added to the reaction mix-
ture, and the water layer was extracted three times with EtOAc
followed by washing with an aq KHSO4 solution. The organic sol-
vent was dried (MgSO4) and evaporated. The crude acid was puri-
fied by silica gel chromatography (1:1, hexane/EtOAc) to afford
pure 18 in 78% yield. dH: 5.93–5.77 (m, 1H), 5.30–5.10 (m, 2H),
4.59 (m, 1H), 2.56 (d, J = 6.2 Hz, 2H), 0.88 (s, 9H), 0.08 (s, 6H). dC:
4.12. Acetic acid (S)-1-[2-(4-methoxy-benzyloxy)-ethyl]-allyl
ester 14
174.7, 139.3, 115.4, 70.6, 42.8, 25.7, 18.0, ꢀ4.4, ꢀ5.1. ½a D29
¼
ꢃ
ꢀ4:95 (c 2.0 MeOH).
In a 50 mL round-bottomed flask attached with a grease free high
vacuum stopcock, chlorodicarbonyl(1-(isopropylamino)-2,3,4,5-
tetraphenylcyclopentadienyl) ruthenium(II) [DKR catalyst, 84 mg,
0.136 mmol] was added. The flask was successively charged with
alcohol 13 (0.86 g, 3.4 mmol) in 10 mL dry toluene, Na2CO3
(3.4 mmol), CAL-B (25 mg) and KOtBu (0.17 mmol) followed by iso-
propenyl acetate (5 mmol). The reaction mixture was stirred at
room temperature under an argon atmosphere. After that time the
reaction mixture was filtered off and the solution was evaporated
to afford the crude acetate 14, which was subsequently purified by
silica gel chromatography (10:1, hexane/EtOAc) to give the pure ace-
tate 14 in 92% yield. dH: 7.23 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz,
2H), 5.83–5.66 (m, 1H), 5.39 (m, 1H), 5.32–5.09 (m, 2H), 4.38 (s,
2H), 3.76 (s, 3H), 3.43 (t, J = 6.4 Hz, 2H), 2.0 (s, 3H), 1.85 (m, 2H).
dC: 170.2, 159.1, 136.3, 130.3, 129.3, 116.6, 113.7, 72.6, 72.1, 65.8,
4.16. (S)-3-(tert-Butyl-dimethyl-silanyloxy)-pent-4-enoic acid
(R)-1-((4S,5R)-2,2-dimethyl-5-vinyl-[1,3]dioxolan-4-ylmethyl)-
octyl ester 19
Carboxylic acid 18 (90 mg, 0.42 mmol) was taken in dry DCM
(4 mL). Dimethylaminopropyl-3-ethylcarbodiimide hydrochloride
(EDCIꢁHCl, 81 mg, 0.42 mmol), DMAP (cat amount) and (R)-1-
((4S,5R)-2,2-dimethyl-5-vinyl-[1,3]dioxolan-4-yl)-nonan-2-ol 11
(75 mg, 0.28 mmol) was sequentially added to the reaction mix-
ture. The reaction mixture was kept at room temperature for 3 h.
The ester was purified by flash chromatography to afford 19 in
85% yield. dH: 5.97–5.77 (m, 2H), 5.38–5.21 (m, 3H), 5.09 (m, 2H),
4.63 (m, 2H), 4.25 (m, 1H), 2.53 (m, 2H), 1.77–11.63 (m, 4H), 1.58
(s, 3H), 1.49 (s, 3H), 1.37 (m, 10H), 0.91 (br, 12H), 0.1 (s, 3H), 0.08
(s, 3H). dC: 170.4, 140.3, 134.2, 118.4, 114.6, 108.3, 79.5, 74.9,
72.3, 70.6, 43.7, 35.2, 34.8, 31.8, 29.6, 29.4, 29.1, 28.2, 25.8, 25.7,
55.2, 34.3, 21.1. ½a D29
¼ þ8:65 (c 1.0 MeOH). Elemental Anal. Calcd
ꢃ
for C15H20O4: C, 68.16; H, 7.63. Found: C, 68.22; H, 7.69.
25.0, 22.6, 18.1, 14.1, -4.4, -4.9. ½a D29
¼ ꢀ6:1 (c 0.33 MeOH).
ꢃ
4.13. tert-Butyl-{(S)-1-[2-(4-methoxy-benzyloxy)-ethyl]-
4.17. (S)-3-Hydroxy-pent-4-enoic acid (R)-1-((2S,3R)-2,3-
allyloxy}-dimethyl-silane 16
dihydroxy-pent-4-enyl)-octyl ester 20
The desired alcohol 15 (1.5 g, 6 mmol) was taken in anhydrous
DCM (30 mL) and cooled to 0 °C. Imidazole (820 mg) and DMAP
(catalytic) were added to the reaction mixture followed by the
addition of TBDMS-Cl (1.4 g, 9 mmol). The reaction mixture was
Coupled ester 19 (70 mg, 0.15 mmol) was taken in methanol
(4 mL) after which pyridinium para-toluenesulfonate (PPTS, 9 mg,
0.045 mmol) was added. The solution was kept stirring overnight
at the same temperature, after which it was purified through silica

T. Das et al. / Tetrahedron: Asymmetry 21 (2010) 2206–2211
2211
gel chromatography to afford the triol 20 in 85% yield. dH: 5.95–
References
5.77 (m, 2H), 5.34–5.06 (m, 5H), 4.56 (m, 1H), 4.05 (m, 1H), 3.65
(m, 1H), 3.17 (br, 3H, –OH), 2.52 (m, 2H), 1.63–1.52 (m, 4H), 1.23
(m, 10H), 0.85 (t, J = 6.8 Hz, 3H). dC: 172.9, 138.9, 136.0, 117.3,
115.4, 75.8, 72.3, 69.9, 69.2, 41.8, 36.5, 34.8, 31.7, 29.3, 29.1,
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25.4, 22.6, 14.1. ½a D29
¼ ꢀ16:3 (c 0.5, MeOH). Elemental Anal. Calcd
ꢃ
for C18H32O5: C, 65.82; H, 9.82. Found: C, 65.92; H, 9.86.
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hexahydro-oxecin-2-one (achaetolide)
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refluxed for 8 h. The solution was evaporated and the content of
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lide in 62% yield. IR (film)
mmax = 3452 (O–H), 3256 (O–H), 1710
(O–C@O) cmꢀ1
.
dH: 5.92 (dd, J = 15.2, 8.4 Hz, 1H), 5.39 (d,
J = 15.2 Hz, 1H), 4.73 (m, 1H), 4.53 (m, 2H), 3.72 (m, 1H), 2.75
(m, 1H), 2.42 (m, 1H), 2.35 (m, 1H), 1.53–1.25 (m, 13H), 0.87 (t,
J = 6.4 Hz, 3H). dC: 171.0, 130.8, 135.2, 75.4, 73.3, 73.3, 67.2, 43.8,
36.9, 36.8, 31.7, 29.4, 29.1, 25.0, 22.6, 14.0. ½a D29
¼ ꢀ27:8 (c 0.5
ꢃ
MeOH); Literature value, ½a D23
ꢃ
¼ ꢀ27 (c 0.52 MeOH).11 Elemental
Anal. Calcd for C16H28O5: C, 63.97; H, 9.40. Found: C, 63.92; H. 9.36.
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Acknowledgements
We are thankful to CSIR (New Delhi, India; Grant No: 01-2109/
07/EMR-II) for providing financial support. We are also thankful to
DST (New Delhi) for providing the departmental NMR facility un-
der the DST-IRPHA programme. Two of the authors RB and TD
are thankful to CSIR (New Delhi, India) for a research fellowship.
24. Prakash, S.; Saleh, A.; Blair, A. I. Tetrahedron Lett. 1989, 30, 19.