Enantioselective synthesis of tarchonanthuslactone using proline-catalyzed asymmetric α-aminooxylation

Article abstract of DOI:10.1016/j.tetasy.2007.04.008

A practical enantioselective synthesis of tarchonanthuslactone 1, an important natural product with a polyol unit, is described. The sequence of synthetic reactions involves proline-catalyzed α-aminooxylation and iodine-induced electrophilic cyclization as the chiral inducing steps.

Full text of DOI:10.1016/j.tetasy.2007.04.008

Tetrahedron: Asymmetry 18 (2007) 975–981
Enantioselective synthesis of tarchonanthuslactone using
proline-catalyzed asymmetric a-aminooxylation
Shyla George and Arumugam Sudalai*
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Received 28 February 2007; accepted 11 April 2007
Abstract—A practical enantioselective synthesis of tarchonanthuslactone 1, an important natural product with a polyol unit, is
described. The sequence of synthetic reactions involves proline-catalyzed a-aminooxylation and iodine-induced electrophilic cyclization
as the chiral inducing steps.
ꢀ 2007 Elsevier Ltd. All rights reserved.
O
O
1. Introduction
OH
OH
O
O
Several natural products with 1,3-polyol/5,6-dihydro-2H-
pyran-2-one structural units have been found to exhibit a
wide range of biological activities. For instance, they act
as plant growth inhibition as well as antifeedant, anti-
fungal, antibacterial and antitumour agents.1 Tarchonan-
thuslactone 1, one of the members of this group, was
isolated2 from the leaves of Tarchonanthus tribolus in
1979 and its absolute configuration was established by syn-
thesis.4a Subsequently, Hsu et al. found that 1 lowers the
blood plasma level in diabetic rats as an important biolog-
ical activity.3 This important structural feature as well as
the biological activity of 1 made it an ideal target to devel-
op new asymmetric synthetic methodology for its construc-
tion.4 Most of the methods reported4 for the asymmetric
synthesis of 1 involve the use of stoichiometric or exotic
reagents, including toxic metal catalysts or the inherent loss
of 50% yield of chiral materials in the case of hydrolytic
kinetic resolution strategies. As part of our research efforts
aimed at developing the stereocontrolled synthesis of
bioactive molecules,5 we herein report a highly efficient
synthesis of tarchonanthuslactone 1, using proline-
catalyzed a-aminooxylation of n-butyraldehyde, as well
as iodine-induced electrophilic cyclization as the chiral
inducing steps (Scheme 2).
Tarchonanthuslactone 1
2. Results and discussion
Asymmetric organocatalysis in organic chemistry has pro-
vided several new methods for obtaining chiral compounds
in an environmentally friendly manner.6 In connection with
this, proline, an abundant, inexpensive aminoacid available
in both enantiomeric forms, has emerged as arguably the
most practical and versatile organocatalyst.7 Proline is
equally efficient for a-functionalization8 of aldehydes and
ketones. To demonstrate the synthetic utility of proline-
catalyzed a-aminooxylation for the synthesis of natural
products, we undertook the synthesis of tarchonanthuslac-
tone 1. We describe the successful application of a-func-
tionalization of aldehydes using proline followed by
diastereoselective iodine-induced electrophilic cyclization.
The retrosynthetic analysis of 1 is outlined in Scheme 1.
Evidently, alcohol 2, the key intermediate, can be obtained
from cis-olefinic ester 3. Iodocarbonate 4 is visualized to be
prepared from olefin 5 via diastereoselective iodolactoniza-
tion. The key chiral inducing step in the synthesis involves
the proline-catalyzed a-aminooxylation of readily available
n-butyraldehyde 6.
*
Corresponding author. Tel.: +91 20 25902174; fax: +91 20 25902676;
e-mail: a.sudalai@ncl.res.in
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.04.008

976
S. George, A. Sudalai / Tetrahedron: Asymmetry 18 (2007) 975–981
O
O
O
O
O
OH
OH
O
OH
O
O
O
CO2Et
3
2
1
O
O
O
O
O
BnO
CHO
I
BnO
BnO
6
4
5
Scheme 1. Retrosynthetic analysis.
The complete synthetic sequences for tarchonanthuslac-
tone 1, commencing from the monoprotected 1,4-butane
diol 7, is shown in Scheme 2. The primary alcohol function
in 7 was oxidized under IBX in DMSO to provide the
corresponding precursor aldehyde 6. The proline-catalyzed
a-asymmetric aminooxylation of aldehyde 6 involves a
two-step reaction sequence: (i) reaction of aldehyde 6 with
nitrosobenzene as the oxygen source in the presence of D-
proline in CH3CN at ꢀ20 ꢁC8a followed by treatment with
NaBH4 in MeOH gave the crude aminooxy alcohol in situ
and (ii) subsequent reduction of the crude aminoxy product
Our next task was to construct the syn-1,3-diol moiety from
epoxide 10. In order to achieve this transformation with
high diastereoselectivity, the iodine-induced carbonate
cyclization methodology, originally published by Bartlett12a
and later improved upon by Smith,12b was undertaken.
Thus, epoxide 10 was first treated with vinylmagnesium
bromide in the presence of CuI13 in THF at ꢀ40 ꢁC to give
homoallylic alcohol 11. The homoallylic tert-butyl carbon-
ate 5, prepared in high yields from the corresponding alco-
hol 11 on treatment with di-tert-butyldicarbonate in the
presence of DMAP13 in CH3CN, was subjected to the
diastereoselective iodolactonization using N-iodosuccini-
mide14 in CH3CN at low temperature (ꢀ40 to 0 ꢁC) to
furnish the cyclic carbonate derivative 4 in 85% yield as a
9
with 30 mol % CuSO4 yielded chiral diol 8 in 86% yield
1
and >95% ee (as determined by H NMR analysis of the
corresponding Mosher’s ester 17, see experimental section);
25
1
½aꢁD ¼ þ5:0 (c 1, CHCl3). Selective mesylation10 of the pri-
single diastereomer (as determined by H NMR analysis).
mary alcohol in 8 was achieved to afford mesylate 9, which
Iodocarbonate 4, upon exposure to basic methanolic solu-
tion,14 gave the desired syn-epoxy alcohol 12 in 90% yield.
Regioselective reduction of epoxy alcohol 12 using
on treatment with K2CO3 in MeOH10 yielded the terminal
25
25
epoxide 10; ½aꢁD ¼ ꢀ16:2 (c 3, CHCl3) {lit.11 ½aꢁD ¼ þ16:9
10
(c 2.51, CHCl3) for its antipode}.
LiAlH4 in THF furnished syn-1,3-diol 13 in 90% yield,
OH
OH
a
d
h
X
b
BnO
CHO
BnO
BnO
X = OH
7
6
8
9
c
I
X = OMs
O
OR
O
O
O
g
e
BnO
BnO
BnO
BnO
4
10
11 R = H
f
5
R = Boc
O
O
OH OH
OH
O
j
i
l
RO
BnO
13
12
14 R = Bn
k
15
R = H
O
O
O
OR
OR
O
O
O
O
O
OH
m
n
CO2Et
2
3
16 R = TBS
o
1
R = H
Scheme 2. Reagents and conditions: (a) IBX, DMSO, rt, 2 h, 95%; (b) (i) PhNO, D-proline (25 mol %), CH3CN, ꢀ20 ꢁC, 24 h then MeOH, NaBH4; (ii)
CuSO4 (30 mol %), MeOH, 0 ꢁC, 10 h, 87% (over two steps); (c) MsCl, Et3N, CH2Cl2, 0 ꢁC, 15 min, 92%; (d) K2CO3, MeOH, rt, 1 h, 95%; (e)
vinylmagnesium bromide, THF, CuI, ꢀ40 ꢁC, 1 h, 92%; (f) (Boc)2O, DMAP, CH3CN, rt, 5 h, 95%; (g) NIS, CH3CN, ꢀ40 to 0 ꢁC, 12 h, 85%; (h) K2CO3,
MeOH, 0 ꢁC to rt, 4 h, 90%; (i) LiAlH4, THF, 50 ꢁC, 6 h, 90%; (j) 2,2-dimethoxypropane, camphorsulfonic acid, rt, 4 h, 95%; (k) 10% Pd/C, H2 (1 atm),
MeOH, 12 h, 91%; (l) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC, 1 h; (ii) ethyl (di-o-tolylphosphono) acetate, NaH, THF, ꢀ78 to 0 ꢁC, 1.5 h, 80% (over
two steps); (m) pyridinium-p-toluene sulfonate, ethanol, 55 ꢁC, 12 h, 75%; (n) TBS-protected dihydrocaffeic acid, DCC, DMAP, CH2Cl2, 5 h, 81%; (o)
TBAF, PhCO2H, THF, rt, 88%.

S. George, A. Sudalai / Tetrahedron: Asymmetry 18 (2007) 975–981
977
which was then protected as its acetonide 14 on treatment
with 2,2-dimethoxypropane in the presence of catalytic
amounts of camphorsulfonic acid.15 Deprotection of the
benzyl group in 14 under catalytic hydrogenolysis condi-
tions16 [Pd/C, H2 (1 atm), MeOH] provided primary alco-
hol 15 in 91% yield.
with brine, dried over anhydrous Na2SO4 and concentrated
to give the crude material which was then purified by col-
umn chromatography on silica gel using petroleum ether/
EtOAc (7:3) to give 7 (6.8 g, 95%) as a colourless oil. IR
(CHCl3) mmax 3624, 3413, 3017, 2941, 2867, 2401, 1952,
1702, 1496, 1455, 1363, 1216, 1099, 957, 932, 850,
1
771 cmꢀ1. H NMR (200 MHz, CDCl3) d 1.62–1.73 (m,
At this stage, we turned our attention to the construction
of the pyranone functionality of tarchonanthuslactone 1.
To achieve this, we converted alcohol 15 into the corre-
sponding cis-enoate 3 as follows: alcohol 15 on Swern oxi-
dation gave the aldehyde in situ which was then subjected
to Horner–Wittig–Emmons olefination with ethyl (di-o-tol-
ylphosphono) acetate17 and NaH in THF in order to
4H), 2.41 (br s, 1H), 3.50 (t, J = 5.61 Hz, 2H), 3.61 (t,
J = 5.73 Hz, 2H), 4.50 (s, 2H), 7.27–7.33 (m, 5H). 13C
NMR (50 MHz, CDCl3) d 26.04, 29.28, 61.71, 69.91,
72.54, 127.25, 127.33, 128.02, 137.9. Elemental analysis:
C11H16O2 required C, 73.30, H, 8.95. Found: C, 73.01,
H, 9.26.
1
obtain the Z-unsaturated ester 3 (confirmed by H NMR
4.1.2. 4-(Benzyloxy)butanal 6. To a solution of alcohol 7
(6.48 g, 36 mmol) in DMSO (100 mL) was slowly added
IBX (11.09 g, 39.6 mmol). The reaction mixture was stirred
for 2 h at 25 ꢁC followed by quenching with cold water.
The reaction mixture was filtered and the filtrate was then
extracted with diethyl ether (3 · 100 mL). The combined
organic layers were washed with brine, dried over anhy-
drous Na2SO4 and concentrated to give the crude aldehyde
which was then purified by column chromatography over
silica gel using petroleum ether/EtOAc (7:3) to give 6
(6.1 g, 95.3%) as a colourless oil. IR (CHCl3) mmax 3032,
analysis) in 80% yield over the two steps. The deprotection
of acetonide unit in 3 followed by its cyclization was
achieved by treating 3 with pyridinium-p-toluene sulfonate
(PPTS) in ethanol at 55 ꢁC to give pyranone 2 in 75% yield.
Esterification of 15 with TBS-protected dihydrocaffeic
acid4d provided ester 16 in 85% yield. Finally, desilylation
of 16 with tetrabutyl ammonium fluoride (TBAF) and
benzoic acid4d in THF furnished tarchonanthuslactone 1
in 90% yield. The spectral data of 1 are in complete agree-
ment with the reported values.4d
2933, 2864, 1706 cmꢀ1 1H NMR (400 MHz, CDCl3) d
.
1.89 (m, 2H), 2.49 (t, J = 7.08 Hz, 2H), 3.45 (t,
J = 6.01 Hz, 2H), 4.43 (s, 2H), 7.26 (m, 5H), 9.72 (s, 1H).
13C NMR (100 MHz, CDCl3) d 22.57, 40.95, 69.13,
72.95, 127.58, 128.36, 128.39, 138.28, 202.17. Elemental
analysis: C11H14O2 required C, 74.13, H, 7.92. Found: C,
74.40, H, 7.61.
3. Conclusion
An efficient and straightforward enantioselective synthesis
of the polyketide natural product tarchonanthuslactone 1
has been described. The initial D-proline-catalyzed a-
aminooxylation of aldehydes for the introduction of chiral-
ity and the subsequent diastereoselective iodine-induced
electrophilic cyclization constitute as key reactions for
constructing syn-1,3-diol moiety. The synthetic strategy
described here has significant potential for the synthesis of
a variety of other biologically important substituted 1,3-pol-
yol/5,6-dihydropyran-2-one containing natural products.
4.1.3. (+)-(S)-4-(Benzyloxy)butane-1,2-diol 8. To a pre-
cooled (ꢀ20 ꢁC) acetonitrile (50 mL) solution of aldehyde
6 (6.05 g, 34 mmol) and nitrosobenzene (1.82 g, 17 mmol)
was added D-proline (0.49 g, 25 mol %). The reaction mix-
ture was allowed to stir at the same temperature for 24 h,
followed by the addition of MeOH (20 mL) and NaBH4
(1.94 g, 51 mmol) to the reaction mixture, which was stir-
red for 10 min. After the addition of the phosphate buffer,
the resulting mixture was extracted with EtOAc
(3 · 60 mL) and the combined organic phases were dried
over Na2SO4 and concentrated to give the crude aminooxy
alcohol, which was directly used for the next step without
purification.
4. Experimental
4.1. General
Solvents were purified and dried by standard procedures
before use; petroleum ether of boiling range 60–80 ꢁC
was used. Optical rotations were measured using sodium
D line on a JASCO-181 digital polarimeter. Infrared spec-
tra were recorded on Shimadzu FTIR-8400 spectrometer.
1H NMR and 13C NMR were recorded on Bruker AV-
200, AV-400 and BRX-500 NMR spectrometers, respec-
tively. Elemental analysis was carried out on a Carlo Erba
CHNS-O analyzer.
To a MeOH (50 mL) solution of the crude aminooxyalco-
hol was added CuSO4Æ5H2O (1.28 g, 5.1 mmol) at 0 ꢁC.
The reaction mixture was allowed to stir for 10 h at this
temperature. After the addition of the phosphate buffer,
the resulting mixture was extracted with CHCl3
(3 · 60 mL) and the combined organic phases were dried
over anhydrous Na2SO4 and concentrated to give the crude
diol, which was then purified by column chromatography
4.1.1. 4-(Benzyloxy)butan-1-ol 7. To a solution of 1,4-
butane diol (3.6 g, 40 mmol) in anhydrous DMF was
slowly added 60% NaH in oil suspension (1.42 g, 44 mmol)
followed by the addition of benzyl bromide (5.25 mL,
44 mmol). The reaction mixture was stirred at 25 ꢁC for
4 h, quenched with cold water, extracted with diethyl ether
(3 · 100 mL) and the combined organic layers were washed
over silica gel using petroleum ether/EtOAc (6:4) to give
25
8 (2.9 g, 87%) as a colourless oil. ½aꢁD ¼ þ5:0 (c 1, CHCl3).
IR (CHCl3) mmax 3684, 3618, 3470, 3020, 2927, 2400, 2252,
1602, 1521, 1455, 1424, 1216, 1094, 1051, 929, 850, 771,
1
669 cmꢀ1. H NMR (200 MHz, CDCl3) d 1.65–1.94 (m,
2H), 2.50 (br s, 2H), 3.45–3.72 (m, 4H), 3.87–3.98 (m,
1H), 4.53 (s, 2H), 7.29–7.37 (m, 5H). 13C NMR

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S. George, A. Sudalai / Tetrahedron: Asymmetry 18 (2007) 975–981
25
(50 MHz, CDCl3) d 32.71, 66.14, 67.13, 69.78, 72.74,
127.44, 127.49, 128.17, 137.84. Elemental analysis:
C11H16O3 required C, 67.32, H, 8.22. Found: C, 67.64,
H, 7.95.
colourless oil. ½aꢁD ¼ þ1:55 (c 1.1, CHCl3). IR (CHCl3)
mmax 3469, 3067, 3016, 2918, 2866, 2401, 1952, 1811,
1640, 1496, 1455, 1424, 1363, 1216, 1095, 1027, 921,
769 cmꢀ1. H NMR (200 MHz, CDCl3) d 1.71–1.80 (m,
1
1H), 1.86–1.94 (m, 1H), 2.16–2.28 (m, 1H), 3.26 (dd,
J = 3.45, 5.05 Hz, 1H), 3.42 (dd, J = 2.65, 5.05 Hz, 1H),
3.57–4.04 (m, 3H), 4.52 (s, 2H), 5.05–5.14 (m, 1H), 5.72–
5.93 (m, 1H), 7.27–7.35 (m, 5H). 13C NMR (50 MHz,
CDCl3) d 35.70, 41.72, 68.38, 69.74, 72.97, 117.28,
127.42, 127.54, 128.22, 134.65, 137.76. Elemental analysis:
C13H18O2 required C, 75.69, H, 8.80. Found: C, 75.33,
H, 9.01.
4.1.4. (+)-(S)-4-(Benzyloxy)-2-hydroxybutyl methanesulfo-
nate 9. A solution of diol 8 (2.94 g, 15 mmol) in CH2Cl2
(50 mL) was treated with methane sulfonyl chloride
(1.75 mL, 22.5 mmol) and Et3N (4.21 mL, 30 mmol) at
0 ꢁC. After being stirred for 15 min, the mixture was
extracted with CH2Cl2 (3 · 100 mL), washed with water
and the combined organic phases were dried over anhy-
drous Na2SO4 and concentrated to give the crude mesylate,
which was then purified by column chromatography over
4.1.7. tert-Butyl (R)-1-(benzyloxy)hex-5-en-3-yl carbonate
5. To a solution of alcohol 11 (2.06 g, 15 mmol) in aceto-
nitrile (40 mL) were added (Boc)2O (3.27 g, 15 mmol) and
DMAP (0.48 g, 4 mmol). After stirring for 5 h, the solvent
was evaporated under reduced pressure. The residue was
taken up in EtOH (30 mL) and imidazole (3.34 g, 49 mmol)
was added. The resulting mixture was stirred at 25 ꢁC for
15 min and then CH2Cl2 was added. The organic phase
was washed with 5% HCl solution (3 · 50 mL), dried over
anhydrous Na2SO4 and concentrated to give the crude
product, which was then purified by column chromatogra-
silica gel using petroleum ether/EtOAc (6:4) to give mesyl-
25
ate 9 (3.78 g, 92%) as a colourless oil. ½aꢁD ¼ þ0:4 (c 0.5,
CHCl3). IR (CHCl3) mmax 3407, 3019, 2927, 2400, 1719,
1518, 1454, 1364, 1215, 1176, 1047, 928, 756, 668 cmꢀ1
.
1H NMR (400 MHz, CDCl3) d 1.71–1.75 (m, 2H), 2.94
(s, 3H), 3.16 (br s, 1H), 3.52–3.65 (m, 2H), 3.98–4.07 (m,
2H), 4.11–4.15 (m, 1H), 4.43 (s, 2H), 7.19–7.28 (m, 5H).
13C NMR (100 MHz, CDCl3) d 32.43, 37.36, 67.59,
68.61, 73.27, 127.68, 127.84, 128.47, 137.64. Elemental
analysis: C12H18O5S required C, 52.54, H, 6.61, S, 11.69.
Found: C, 52.25, H, 6.99, S, 11.77.
phy over silica gel using petroleum ether/EtOAc (9:1) to
25
give 5 (2.75 g, 95%) as a colourless oil. ½aꢁD ¼ þ33:3 (c
4.1.5. (ꢀ)-(S)-4-(Benzyloxy)-1,2-epoxybutane 10. To a
solution of mesylate 9 (3.56 g, 13 mmol) in MeOH
(50 mL) was added K2CO3 (1.79 g, 13 mmol) and the mix-
ture was stirred at 25 ꢁC for 1 h. After the reaction was com-
pleted (monitored by TLC), the mixture was evaporated
and the residue extracted with diethyl ether (3 · 100 mL).
The combined organic phases were dried over anhydrous
Na2SO4 and concentrated to give the crude product which
was then purified by column chromatography over silica
0.6, CHCl3). IR (CHCl3) mmax 3686, 3625, 3019, 2983,
2870, 2401, 1737, 1644, 1455, 1395, 1370, 1280, 1216,
1
1160, 1093, 926, 770 cmꢀ1. H NMR (200 MHz, CDCl3)
d 1.47 (s, 9H), 1.90 (dd, J = 6.5, 12.89 Hz, 2H), 2.34–2.41
(m, 2H), 3.53 (t, J = 6.41 Hz, 2H), 4.49 (s, 2H), 4.83–4.96
(m, 1H), 5.04–5.15 (m, 2H), 5.69–5.86 (m, 1H), 7.28–7.35
(m, 5H). 13C NMR (50 MHz, CDCl3) d 27.60, 33.70,
38.77, 66.30, 72.89, 73.66, 81.43, 117.78, 127.35, 127.45,
128.16, 133.20, 138.20, 153.05. Elemental analysis:
C18H26O4 required C, 70.56, H, 8.55. Found: C, 70.89,
H, 8.29.
gel using petroleum ether/EtOAc (8:2) to give epoxide 10
25
(2.2 g, 95%) as a colourless oil. ½aꢁD ¼ ꢀ16:2 (c 3, CHCl3)
25
{lit.11 ½aꢁD ¼ þ16:9 (c 2.51, CHCl3) for its antipode}. IR
(CHCl3) mmax 3477, 3015, 2925, 2864, 2402, 1725, 1496,
4.1.8.
(ꢀ)-(4S,6S)-4-[2-(Benzyloxy)ethyl]-6-(iodomethyl)-
1455, 1362, 1217, 1102, 1028, 910, 831, 766 cmꢀ1
.
1H
1,3-dioxan-2-one 4. To a stirred solution of 5 (2.76 g,
9 mmol) in acetonitrile (60 mL) was added N-iodosuccini-
mide (4.05 g, 18 mmol) at ꢀ40 ꢁC. The mixture was then
warmed up and stirred at 0 ꢁC for 12 h. After the reaction
was completed (monitored by TLC), 50 mL aqueous
sodium thiosulfate solution was added, followed by
50 mL of aq NaHCO3. The reaction mixture was then ex-
tracted with EtOAc (3 · 60 mL) and the combined organic
phases were dried over anhydrous Na2SO4 and concen-
trated to give the crude product, which was then purified
by flash column chromatography using petroleum ether/
NMR (200 MHz, CDCl3) d 1.62–1.97 (m, 2H), 2.50 (dd,
J = 2.7, 5.06 Hz, 1H), 2.76 (dd, J = 4.06, 4.94 Hz, 1H),
3.01–3.10 (m, 1H), 3.58–3.64 (m, 2H), 4.52 (s, 2H), 7.29–
7.35 (m, 5H). 13C NMR (50 MHz, CDCl3) d 32.76, 46.68,
49.68, 66.76, 72.79, 127.32, 128.13, 128.80, 138.11. Elemen-
tal analysis: C11H14O2 required C, 74.13, H, 7.92. Found: C,
74.46, H, 7.69.
4.1.6. (+)-(R)-6-(Benzyloxy)-1-hexen-4-ol 11. Vinyl bro-
mide (6.44 M in THF, 7.76 mL, 50 mmol) was added
slowly to Mg (0.61 g, 25 mmol) in THF (25 mL) at 0 ꢁC
and the mixture was stirred for 10 min; then cooled to
ꢀ40 ꢁC and CuI (0.34 g, 15 mol %) was added. The result-
ing reaction mixture was stirred for 30 min at ꢀ40 ꢁC and a
solution of epoxide 10 (2.14 g, 12 mmol) in THF (30 mL)
was added. After being stirred for 1 h, the mixture was
quenched with saturated NH4Cl solution, extracted with
diethyl ether (3 · 100 mL), washed with brine and the com-
bined organic phases were dried over anhydrous Na2SO4
and concentrated to give the crude product, which was then
purified by column chromatography over silica gel using
petroleum ether/EtOAc (8:2) to give 11 (2.27 g, 92%) as a
EtOAc (7:3) to give 4 (2.87 g, 85%) as a colourless oil.
25
½aꢁD ¼ ꢀ3:1 (c 1.3, CHCl3). IR (CHCl3) mmax 3019, 2400,
1751, 1523, 1399, 1216, 1104, 988, 770, 669 cmꢀ1 1H
.
NMR (400 MHz, CDCl3) d 1.65–1.76 (m, 1H), 1.92–2.04
(m, 2H), 2.40 (dt, J = 3.03, 14.36 Hz, 1H), 3.25 (dd,
J = 7.37, 10.53 Hz, 1H), 3.38 (dd, J = 4.42, 10.52 Hz,
1H), 3.59–3.64 (m, 1H), 3.67–3.73 (m, 1H), 4.39–4.45 (m,
1H), 4.47–4.55 (m, 2H), 4.64–4.71 (m, 1H), 7.28–7.38 (m,
5H). 13C NMR (100 MHz, CDCl3) d 5.95, 32.96, 34.87,
64.71, 72.79, 75.48, 76.68, 127.40, 127.44, 128.13, 137.67,
148.09. Elemental analysis: C14H17IO4 required C, 44.70,
H, 4.55, I, 33.73. Found: C, 44.45, H, 4.77, I, 33.65.

S. George, A. Sudalai / Tetrahedron: Asymmetry 18 (2007) 975–981
979
4.1.9. (+)-(2S,4S)-6-(Benzyloxy)-1,2-epoxyhexan-4-ol 12.
To a stirred solution of 4 (2.6 g, 7 mmol) in MeOH
(50 mL) was added K2CO3 (4.83 g, 35 mmol) at 0 ꢁC. The
mixture was then warmed up and stirred at 25 ꢁC. After
the reaction was completed (monitored by TLC), 50 mL
aq NaHCO3 was added and the reaction mixture was then
extracted with EtOAc (3 · 60 mL). The combined organic
phases were dried over anhydrous Na2SO4 and concen-
trated to give the crude product, which was then purified
by flash column chromatography using petroleum ether/
4.1.12. (ꢀ)-(4S,6R)-2-(2,2,6-Trimethyl-1,3-dioxan-4-yl)eth-
anol 15. To a solution of 14 (0.53 g, 2 mmol) in MeOH
(20 mL) was added a catalytic amount of 10% Pd/C and
the resulting heterogeneous mixture was stirred for 12 h
at 25 ꢁC. The reaction mixture was then filtered through
a pad of Celite and the solvent removed under reduced
pressure to give the crude product, which was then purified
by column chromatography over silica gel using petroleum
ether/EtOAc (5:5) to give 15 (0.32 g, 91%) as a colourless
25
oil. ½aꢁD ¼ ꢀ15 (c 0.4, CHCl3). IR (CHCl3) mmax 3502,
EtOAc (6:4) to give 12 (1.39 g, 89.7%) as a colourless oil.
3054, 2930, 2103, 1734, 1541, 1427, 1382, 1265, 1201,
25
½aꢁD ¼ þ8:0 (c 1.25, CHCl3). IR (CHCl3) mmax 3682, 3491,
1111, 1051, 951, 866, 739 cmꢀ1 1H NMR (200 MHz,
.
3019, 2922, 2400, 2258, 1733, 1479, 1455, 1424, 1362,
CDCl3) d 1.13–1.23 (m, 4H), 1.37 (s, 3H), 1.44 (s, 3H),
1.53–1.74 (m, 3H), 3.05 (br s, 1H), 3.71–3.81 (m, 2H),
3.96–4.14 (m, 2H). 13C NMR (100 MHz, CDCl3) d 19.81,
22.08, 30.87, 38.38, 44.66, 60.76, 65.03, 69.21, 98.56. Ele-
mental analysis: C9H18O3 required C, 62.04, H, 10.41.
Found: C, 62.36, H, 10.12.
1216, 1093, 927, 770, 669 cmꢀ1 1H NMR (200 MHz,
.
CDCl3) d 1.59–1.88 (m, 4H), 2.48 (dd, J = 2.64, 5.06 Hz,
1H), 2.75 (dd, J = 4.22, 4.96 Hz, 1H), 3.04–3.15 (m, 2H),
3.59–3.78 (m, 2H), 3.99–4.11 (m, 1H), 4.52 (m, 2H), 7.26–
7.35 (m, 5H). 13C NMR (50 MHz, CDCl3) d 36.34, 39.70,
46.31, 49.70, 68.41, 68.82, 73.11, 127.49, 127.58, 128.28,
137.78. Elemental analysis: C13H18O3 required C, 70.24,
H, 8.16. Found: C, 70.59, H, 7.89.
4.1.13. (ꢀ)-(5S,7R,2Z)-Ethyl-5,7-(isopropylidenedioxy)octe-
noate 3. To a precooled (ꢀ78 ꢁC) solution of (COCl)2
(0.11 mL, 1.2 mmol) in CH2Cl2 (5 mL) was added DMSO
(0.17 mL, 2.4 mmol) in CH2Cl2 (5 mL). The reaction mix-
ture was stirred at ꢀ78 ꢁC for 15 min, then alcohol 15
(0.1 g, 0.6 mmol) was added. The reaction mixture was stir-
red for 40 min at ꢀ78 ꢁC followed by the addition of Et3N
(0.5 mL, 3.6 mmol). The mixture was allowed to warm to
0 ꢁC. After 30 min, the reaction was diluted with water
and extracted with CH2Cl2 (3 · 25 mL). The combined
organic phases were dried over anhydrous Na2SO4 and
concentrated to give the crude aldehydes, which were
immediately used in the next step.
4.1.10. (+)-(2R,4S)-6-(Benzyloxy)hexane-2,4-diol 13.
A
solution of epoxy alcohol 12 (1.33 g, 6 mmol) in THF
(30 mL) was added to a stirred slurry of LiAlH4 (0.47 g,
12 mmol). After being stirred for 6 h at 50 ꢁC, the reaction
was carefully quenched with water. The reaction mixture
was then extracted with EtOAc (3 · 50 mL) and the com-
bined organic phases were dried over anhydrous Na2SO4
and concentrated to give the crude product, which was then
purified by flash column chromatography using petroleum
ether/EtOAc (5:5) to give diol 13 (1.2 g, 89.6%) as a colour-
25
less oil. ½aꢁD ¼ þ3:0 (c 1, CHCl3). IR (CHCl3) mmax 3616,
3461, 3019, 2934, 2400, 1519, 1454, 1378, 1215, 1095,
A solution of ethyl (di-o-tolylphosphono)acetate (0.23 g,
0.66 mmol) in THF (5 mL) was treated with NaH (17 mg,
0.72 mmol) at ꢀ78 ꢁC for 15 min. To the above mixture
was added a freshly prepared aldehyde in THF (3 mL)
and the resulting mixture was stirred at ꢀ78 ꢁC. After
TLC showed completion of the starting material, the reac-
tion was quenched with saturated NH4Cl solution and ex-
tracted with EtOAc (3 · 20 mL) and the combined organic
phases were dried over anhydrous Na2SO4 and concen-
trated to give the crude product, which was then purified
by column chromatography over silica gel using petroleum
1
930, 758, 668 cmꢀ1. H NMR (200 MHz, CDCl3) d 1.19
(d, J = 6.53 Hz, 3H), 1.54 (t, J = 3.62 Hz, 2H), 1.71–1.88
(m, 2H), 2.99 (br s, 2H), 3.62–3.78 (m, 2H), 4.01–4.15
(m, 2H), 4.52 (s, 2H), 7.29–7.40 (m, 5H). 13C NMR
(50 MHz, CDCl3) d 23.66, 36.94, 44.58, 68.31, 71.71,
73.13, 127.57, 127.64, 128.33, 137.72. Elemental analysis:
C13H20O3 required C, 69.61, H, 8.99. Found: C, 69.99,
H, 7.54.
4.1.11. (+)-(4S,6R)-4-[2-(Benzyloxy)ethyl]-2,2,6-trimethyl-
1,3-dioxane 14. To a solution of diol 13 (0.68 g, 3 mmol)
in 2,2-dimethoxypropane (6 mL) was added camphorsulf-
onic acid (69 mg, 0.3 mmol) and the reaction mixture was
stirred at 25 ꢁC for 4 h. The organic layer was concentrated
under reduced pressure to afford the crude product, which
was then purified by column chromatography over silica
ether/EtOAc (9:1) to give 3 (0.12 g, 80%) as a colourless oil.
25
½aꢁD ¼ ꢀ23:5 (c 0.17, CHCl3). IR (CHCl3) mmax 2995, 2940,
2401, 1713, 1645, 1417, 1381, 1216, 1185, 1035, 995, 826,
755, 667 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.16 (d,
.
J = 6.09 Hz, 3H), 1.29 (t, J = 7.31 Hz, 3H), 1.36 (d,
J = 1.49 Hz, 1H), 1.40 (s, 3H), 1.44 (s, 3H), 1.50 (dt,
J = 2.49, 13.05 Hz, 1H), 2.69–2.77 (m, 1H), 2.88–2.96 (m,
1H), 3.92–4.02 (m, 2H), 4.17 (q, J = 7.29 Hz, 2H), 5.85
(dt, J = 1.54, 11.49 Hz, 1H), 6.35 (dt, J = 7.25, 11.46 Hz,
1H). 13C NMR (100 MHz, CDCl3) d 14.26, 19.83, 22.16,
30.23, 35.50, 38.27, 59.86, 65.05, 68.41, 98.56, 121.06,
145.82, 166.37. Elemental analysis: C13H22O4 required C,
64.44, H, 9.15. Found: C, 64.11, H, 9.39.
gel using petroleum ether/EtOAc (9:1) to give 14 (0.75 g,
25
94.9%) as a colourless oil. ½aꢁD ¼ þ4:0 (c 0.5, CHCl3). IR
(CHCl3) mmax 3610, 3019, 2400, 1716, 1646, 1523, 1456,
1381, 1215, 1097, 929, 758, 669 cmꢀ1
.
1H NMR
(500 MHz, CDCl3) d 1.14 (d, J = 5.89 Hz, 3H), 1.36 (s,
3H), 1.42 (s, 3H), 1.53–1.64 (m, 1H), 1.69–1.77 (m, 3H),
3.50–3.60 (m, 2H), 3.92–4.01 (m, 2H), 4.48 (s, 2H), 7.25–
7.34 (m, 5H). 13C NMR (125 MHz, CDCl3) d 19.92,
22.30, 30.34, 36.61, 38.89, 65.11, 65.95, 66.18, 73.00,
98.41, 127.54, 127.63, 128.35, 138.56. Elemental analysis:
C16H24O3 required C, 72.69, H, 9.15. Found: C, 73.01,
H, 7.21.
4.1.14. (ꢀ)-(5S,7R)-7-Hydroxy-5-(oct-2-enolide) 2. To a
solution of 3 (0.11 g, 0.45 mmol) in EtOH (5 mL) was
added pyridinium-p-toluene sulfonate (10 mg, 10 mol %)
and stirred for 12 h at 55 ꢁC. The solvent was then evapo-

980
S. George, A. Sudalai / Tetrahedron: Asymmetry 18 (2007) 975–981
rated and the residue extracted with EtOAc (3 · 20 mL).
The combined organic phases were dried over anhydrous
Na2SO4 and concentrated to give the crude product, which
was then purified by column chromatography over silica
C17H20O6 required C, 63.74, H, 6.29. Found: C, 63.41,
H, 6.52.
4.1.17. Preparation of Mosher’s ester of (+)-(S)-4-(benzyl-
oxy)butane-1,2-diol 17. A two-neck 10 mL flask equipped
with septum was charged with (49 mg, 0.24 mmol) N,N0-
dicyclohexylcarbodiimide (DCC), a catalytic amount of
4-dimethylaminopyridine (DMAP) and CH2Cl2 (2 mL)
under an argon atmosphere. The flask was allowed to cool
at 0 ꢁC for 10 min and a solution of diol 8 (40 mg, 0.2 mmol)
in CH2Cl2 (2 mL) was introduced through a syringe. This
was allowed to stir for an additional 10 min, followed by
dropwise addition of (R)-a-methoxy-a-trifluoromethyl-
phenyl acetic acid (51 mg, 0.22 mmol) in CH2Cl2 (2 mL).
This reaction mixture was then stirred at 0 ꢁC for an
additional 1 h and then at room temperature overnight.
The reaction mixture was diluted with CH2Cl2 (50 mL),
washed with saturated sodium bicarbonate solution
(50 mL), dried over anhydrous Na2SO4 and then concen-
gel using petroleum ether/EtOAc (5:5) to give 2 (49 mg,
25
75%) as a colourless oil. ½aꢁD ¼ ꢀ108 (c 0.13, CHCl3). IR
(CHCl3) mmax 3550, 2958, 1718, 1472, 1380, 1255,
1216 cmꢀ1
.
1H NMR (400 MHz, CDCl3) d 1.25 (d,
J = 6.28 Hz, 3H), 1.71 (br s, 1H), 1.74–1.79 (m, 1H), 2.01
(dt, J = 8.07, 14.4 Hz, 1H), 2.38–2.41 (m, 2H), 4.06–4.12
(m, 1H), 4.60–4.67 (m, 1H), 6.02 (dt, J = 1.73, 9.81 Hz,
1H), 6.88 (dt, J = 4.3, 8.52 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 23.76, 29.53, 43.58, 65.36, 76.85,
121.30, 145.12, 163.91. Elemental analysis: C8H12O3
required C, 61.52, H, 7.74. Found: C, 61.85, H, 7.43.
4.1.15. TBS-protected tarchonanthuslactone 16. To a solu-
tion of alcohol 2 (47 mg, 0.3 mmol) in CH2Cl2 (2 mL) was
added
TBS-protected
hydrocaffeic
acid
(0.14 g,
trated under reduced pressure to give Mosher’s ester 17
0.33 mmol), dicyclohexylcarbodiimide (77 mg, 0.33 mmol)
and DMAP (16 mg, 0.13 mmol). The reaction mixture
was stirred for 3 h. Ether was added to the solution, and
the mixture filtered through a pad of Celite. Removal of
solvent under reduced pressure provided the crude product,
which was then purified by column chromatography over
25
(47 mg, 75%) as a thick syrup. ½aꢁD ¼ þ36 (c 0.5, CHCl3);
IR (CHCl3) mmax 3484, 3019, 2856, 2401, 1749, 1496, 1453,
1363, 1266, 1216, 1171, 1106, 1021, 928, 759, 668 cmꢀ1. 1H
NMR (400 MHz, CDCl3) d 1.74–1.80 (m, 2H), 2.88 (br s,
1H), 3.56 (s, 3H), 3.60–3.71 (m, 2H), 4.08–4.14 (m, 1H),
4.26–4.35 (m, 2H), 4.50 (s, 2H), 7.29–7.40 (m, 8H), 7.53–
7.55 (m, 2H). 13C NMR (100 MHz, CDCl3) d 32.76,
55.47, 67.87, 68.56, 69.50, 73.34, 84.58, 127.38, 127.69,
127.84, 128.43, 128.49, 129.66, 132.17, 137.72, 166.49. Ele-
mental analysis: C21H23F3O5 required C, 61.16, H, 5.62, F,
13.82. Found: C, 61.49, H, 5.43, F, 13.60.
silica gel using petroleum ether/EtOAc (8:2) to give 16
25
(0.13 g, 81%) as a colourless oil. ½aꢁD ¼ ꢀ44 (c 1.2, CHCl3).
IR (CHCl3) mmax 1723, 1505, 1255, 900, 840 cmꢀ1 1H
.
NMR (200 MHz, CDCl3) d 0.18 (s, 6H), 0.19 (s, 6H),
0.98 (s, 9H), 0.99 (s, 9H), 1.26 (d, J = 6.5 Hz, 3H), 1.78–
1.85 (m, 1H), 2.13–2.29 (m, 1H), 2.30–2.35 (m, 2H),
2.52–2.60 (m, 2H), 2.78–2.86 (m, 2H), 4.36–4.50 (m, 1H),
5.06–5.15 (m, 1H), 6.01 (d, J = 9.5 Hz, 1H), 6.61–6.85
(m, 4H). 13C NMR (125 MHz, CDCl3) d ꢀ4.23, 18.28,
20.14, 25.82, 28.98, 30.10, 36.09, 40.66, 67.00, 74.79,
120.77, 120.94, 121.02, 121.19, 133.31, 144.75, 145.07,
146.48, 163.88, 172.36. Elemental analysis: C29H48O6Si2
required C, 63.46, H, 8.81, Si, 10.23. Found: C, 63.74, H,
8.60, Si, 10.01.
Acknowledgements
S.G. thanks CSIR, New Delhi, for the award of research
fellowships. The authors are thankful to Dr. B. D. Kul-
karni, Head, CEPD, for his support and encouragement.
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