Stereoselective synthesis of simplactone B via Prins cyclisation

Article abstract of DOI:10.1016/j.tet.2007.08.049

The synthesis of simplactone B has been achieved through a series of nine steps in 85% overall yield using Prins cyclisation as the key step with high stereochemical control.

Full text of DOI:10.1016/j.tet.2007.08.049

Tetrahedron 63 (2007) 11011–11015
Stereoselective synthesis of simplactone B via Prins cyclisation
*
M. Somi Reddy, M. Narender and K. Rama Rao
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500007, Andhra Pradesh, India
Received 25 April 2007; revised 30 July 2007; accepted 16 August 2007
Available online 22 August 2007
Abstract—The synthesis of simplactone B has been achieved through a series of nine steps in 85% overall yield using Prins cyclisation as the
key step with high stereochemical control.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
butynyl lithium in the presence of BF3$OEt2, produced
homopropargyl alcohol 4 in 90% yield.
d-Lactones are of great importance as structural components
of a large number of organic natural products and as interme-
diates in the synthesis of several drugs and natural products.
They represent important structural moieties in a large
number of bioactive natural products such as mevinolin,
compactin, pironetin, phomalactone1a and asperlin,1b
massoialactone,1c (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methyl-
undecanoic acid d-lactone,1d tetrahydro 6-(1-hydroxyun-
decyl)-2H-pyran-2-one1e (Fig. 1) and as inhibitors of
cholesterol biosynthesis.1f Hence, the synthesis of d-lac-
tones2–4 is receiving increasing attention.
Subjection of 4 to Birch reduction (Na in liq NH3 at ꢀ33 ꢁC)
for 6 h resulted in diol 5 in 85% yield, which on selective
protection of 1ꢁ hydroxy group as its benzyl ether in the pre-
sence of BnBr (1.1 equiv) and NaH in DMF produced key
intermediate 6 in 70% yield with recovery of 18% of the
starting material. Protection of the alcohol 6 as its MEM
ether by treatment of the compound with MEMCl and
DIPEA gave 7 in 99% yield. Compound 7 underwent crucial
Prins cyclisation in the presence of TFA8 to produce alcohol
8 in 59% yield. This Prins cyclisation step proceeds through
the formation of oxocarbenium ion generated in situ from
the MEM ether 7, which undergoes intramolecular cyclisa-
tion in the presence of TFA giving rise to pyranyl trifluoro-
acetate, which upon hydrolysis with K2CO3 in MeOH8 and
flash chromatography results in 8 as the only product. The
stereochemistry of 8 was assumed on the basis of extensive
previous studies8b and also through further transformation to
the known natural product B 2. Protection of 8 as MOM
ether 9 by treatment with MOMCl and DIPEA followed
by deprotection of benzylic ether linkage using Na in liquid
ammonia yielded tetrahydropyran 10 in 99% yield. Oxida-
tion of 10 using excess of PCC in refluxing conditions9 in
benzene resulted in the lactone 11 in 83% (the only isolable
isomer from column chromatography). This oxidation is
presumed to proceed as shown in Scheme 2. Deprotection
of MOM group of 11 using TFA in DCM furnished the target
product simplactone B 2 in 85% yield. The spectroscopic
(1H NMR, 13C NMR, IR, mass) and physical data of the sim-
plactone B 2 were in good agreement with the reported data.6
The d-lactones, simplactones A 1 and B 2 possessing inter-
esting cytotoxic activities were isolated from the Caribbean
sponge, Plakortis simplex; their structures were proposed
based on spectroscopic analyses and assigned as 4R,5S-5-
ethyl-4-hydroxytetrahydropyran-2-one for the former (1)
and as 4R,5R-5-ethyl-4-hydroxytetrahydropyran-2-one for
the latter (2)5 (Fig. 1).
Although a number of synthetic procedures for the construc-
tion of d-lactones have been reported,6 there is an increasing
demand for new convenient methods. We report here a new
synthetic route to simplactone B 2 utilising the highly stereo-
selective Prins cyclisation and PCC mediated over oxidation
from (R)-benzyl glycidyl ether 3.
2. Results and discussion
Our synthetic approach is described in Scheme 1. Ring open-
ing of epoxide in (R)-benzyl glycidyl ether 3 (obtained via
Jacobsen’s HKR methodology),7 which on treatment with
3. Conclusion
In summary, we have achieved the stereoselective synthesis
of simplactone B via Prins cyclisation as the key step,
through a series of nine steps in 85% overall yield. This
Keywords: Prins cyclisation; d-Lactones; Simplactone B; PCC.
* Corresponding author. Tel.: +91 40 27193164; fax: +91 40 27160512;
e-mail: drkrrao@yahoo.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.049

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M. S. Reddy et al. / Tetrahedron 63 (2007) 11011–11015
HO
O
O
O
OH
O
O
OMe OH
pironetin
O
OH
O
H
O
R
(3R,4S,5S,9S)-3,5,9-trihydroxy-4-methyl
undecanoic acid d-lactone
Compactin R = H
Mevinolin R = CH3
OH
R
OH
OH
O
O
O
O
O
O
R = C14H29
simplactone A 1
simplactone B 2
(4R,5R)-tetrahydro-4-hydroxy-5-
tetradecylpyran-2-one
Figure 1.
(i)
(ii)
(iii)
OBn
OBn
OH
OBn
O
OH
OH
(vi)
OH
3
4
5
6
OMOM
OH
(v)
(iv)
OBn
OBn
OMEM
OBn
O
O
9
7
8
OMOM
OH
OMOM
(viii)
(ix)
(vii)
OH
O
O
O
O
O
11
10
2
Scheme 1. Reagents, conditions and yields: (i) n-butyne, BuLi, BF3$OEt2, THF, ꢀ78 ꢁC, 2 h, 90%; (ii) Na, liq NH3, THF, 6 h, 85%; (iii) BnBr, NaH, DMF,
0 ꢁC–rt, 6 h, 70%; (iv) (iPr)2 NEt, MEMCl, DMAP, DCM, 0 ꢁC–rt, 20 h, 99%; (v) TFA, DCM, rt, 5–6 h, then K2CO3, MeOH, rt, 1 h, 59%; (vi) (iPr)2 NEt,
MOMCl, DMAP, DCM, 0 ꢁC–rt, 15 h, 99%; (vii) Li, liq NH3, 5 min, 99%; (viii) PCC, benzene, reflux, 6 h, 83%; (ix) TFA, DCM, rt, 2 h, 85%.
OMOM
OMOM
OMOM
O
OMOM
O
PCC
O
OH
OH
O
O
O
O
Cr
O
O
OMOM
CrO2
+ HCHO
+
O
O
Scheme 2.
synthesis is a propagating proof for the utilisation of Prins
cyclisation in the natural product synthesis.
(IR) spectra were recorded on a Perkin–Elmer 683 spectro-
meter. Optical rotations were obtained on a Jasco Dip 360
digital polarimeter. Melting points are uncorrected. NMR
spectra were recorded in CDCl3 on Varian Gemini 200,
Bruker 300 or Varian Unity 400 NMR spectrometer. Chemi-
cal shifts (d) are quoted in parts per million and are refer-
enced to tetramethylsilane (TMS) as internal standard.
Coupling constants (J) are quoted in hertz. Column chroma-
tographic separations were carried out on silica gel (60–120
mesh). Mass spectra were obtained on Finnegan MAT
4. Experimental
4.1. General
Commercial reagents were used without further purification.
All solvents were purified by standard techniques. Infrared

M. S. Reddy et al. / Tetrahedron 63 (2007) 11011–11015
11013
1020B or micromass VG 70-70H spectrometer operating at
70 eV using a direct inlet system.
DMF (15 mL) in a dropwise manner. The reaction mixture
was stirred at room temperature for 30 min and again the
mixture was cooled to 0 ꢁC. After addition of BnBr
(3.9 mL, 33.0 mmol), the reaction was brought to room tem-
perature and stirred for 6 h, cooled to 0 ꢁC and quenched
with saturated NH4Cl solution (70 mL) carefully. Then
EtOAc (150 mL) was added, organic layer was separated,
washed with H2O (3ꢂ30 mL) and brine solution (30 mL)
and dried in vacuo. Column chromatography (SiO2, 15%
EtOAc in hexane as eluent) of the crude product afforded
6 (4.62 g, 70%) along with 18% recovered starting material
5. Compound 6 was a colourless oil, Rf¼0.7.
4.2. (R)-1-(Benzyloxy)-4-heptyn-2-ol (4)
Under nitrogen atmosphere, a solution of n-butyl lithium in
hexane (71 mL, 115.2 mmol, 2.6 M solution in hexane) was
added to a solution of butyne (8.2 g, 153.6 mmol) in THF
(110 mL) at ꢀ78 ꢁC and the mixture was stirred for
15 min. Then, BF3$OEt2 (14.0 g, 99.8 mmol) was added to
the solution and stirring was continued for 15 min at
ꢀ78 ꢁC. Finally
a solution of epoxide 3 (12.6 g,
76.8 mmol) in dry THF (40 mL) was added and after stirring
the reaction mixture for 2 h at ꢀ78 ꢁC, the reaction was
quenched by adding saturated aqueous NH4Cl solution
(70 mL). The reaction mixture was extracted with ethyl ace-
tate (2ꢂ150 mL) and dried over anhydrous Na2SO4. Evapo-
ration of the solvent resulted in crude alcohol, which was
purified by column chromatography (SiO2, 15% EtOAc in
hexane as eluent) to afford pure alcohol 4 (15.0 g, 90%) as
a colourless oil, Rf¼0.45.
[a]2D5 +6.86 (c 0.51, CHCl3); IR (Neat): 3445.8, 2924.5,
2860.7, 1454.1, 1102.0 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 7.34–7.25 (m, 5H), 5.58–5.45 (m, 1H), 5.43–
5.29 (m, 1H), 4.53 (s, 2H), 3.84–3.68 (m, 1H), 3.44 (dd,
1H, J¼10.5, 5.3 Hz), 3.31 (dd, 1H, J¼10.5, 5.7 Hz), 2.18–
2.13 (m, 2H), 2.06–1.97 (m, 2H), 0.97 (t, 3H, J¼7.5 Hz);
13C NMR (CDCl3, 75 MHz): d 138.0, 135.6, 128.4, 127.7,
127.5, 124.2, 73.9, 73.3, 70.1, 36.7, 25.6, 13.7; MS
(ESIMS): m/z 253 [M+Na]+; HRMS (ESI) calcd for
C14H20O2Na [M+Na]+: 243.1360, found: 243.1368.
[a]2D5 ꢀ10.8 (c 0.51, CHCl3); IR (Neat): 3447.1, 2920.8,
2856.7, 1635.0, 1113.0 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d 7.34–7.25 (m, 5H), 4.55 (s, 2H), 3.91–3.81 (m, 1H), 3.55
(dd, 1H, J¼9.8, 4.5 Hz), 3.44 (dd, 1H, J¼9.8, 6.7 Hz),
2.39–2.35 (m, 2H), 2.18–2.07 (m, 2H), 1.10 (t, 3H,
J¼7.5 Hz); 13C NMR (CDCl3, 75 MHz): d 137.9, 128.4,
127.7, 127.6, 77.1, 74.7, 73.3, 72.9, 69.1, 23.8, 14.1, 12.3;
MS (ESIMS): m/z 241 [M+Na]+; HRMS (ESI) calcd for
C14H18O2Na [M+Na]+: 241.1204, found: 241.1197.
4.5. 1-[((2R,4E)-2-((2-Methoxyethoxy)methoxy)hept-4-
enyloxy)methyl]benzene (7)
To the alcohol 6 (1.76 g, 8.0 mmol) in anhydrous CH2Cl2
(20 mL) at 0 ꢁC were added diisopropylethyl amine
(6.9 mL, 40 mmol), DMAP (99 mg) and MEMCl (2.73 mL,
24 mmol) successively and the mixture was stirred for 20 h
at room temperature and then quenched by adding water
(20 mL) and extracted with CH2Cl2 (2ꢂ25 mL). The
organic extracts were washed with brine (10 mL), dried
over anhydrous Na2SO4 and concentrated under reduced
pressure to remove the solvent and the crude oil was purified
by column chromatography (SiO2, 10% EtOAc in hexane
eluent) to afford the pure product 7 (2.44 mg, 99%) as a
colourless liquid, Rf¼0.6.
4.3. (2R,4E)-4-Heptene-1,2-diol (5)
To a blue solution of sodium metal (6.5 g, 282.7 mmol) in
200 mL of NH3 was added dropwise a solution of 4 (7.6 g,
34.9 mmol) in THF (40 mL) at ꢀ78 ꢁC. During the addition
of the compound, the blue colour of the reaction mixture was
maintained by the addition of sodium metal. After addition
of the whole compound, the reaction mixture was stirred
for 6 h at ꢀ33 ꢁC. The reaction mixture was quenched
with NH4Cl (6.5 g) and the ammonia was left to completely
evaporate. The mixture was then diluted with water
(4ꢂ30 mL) and extracted with diethyl ether (250 mL). Or-
ganic layer was dried (Na2SO4) and concentrated. Column
chromatography (SiO2, 40% EtOAc in hexane as eluent)
of the crude product gave the compound 5 (3.85 g, 85%)
as a viscous liquid, Rf¼0.3.
[a]2D5 +1.88 (c 0.79, CHCl3); IR (Neat): 2926.0, 2878.2,
1454.2, 1112.6, 1041.7 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 7.33–7.26 (m, 5H), 5.55–5.42 (m, 1H), 5.39–
5.28 (m, 1H), 4.76 (d, 1H, J¼7.5 Hz), 4.72 (d, 1H,
J¼7.5 Hz), 4.50 (s, 2H), 3.83–3.73 (m, 1H), 3.70–3.60 (m,
2H), 3.49–3.43 (m, 4H), 3.34 (s, 3H), 2.31–2.11 (m, 2H),
2.06–1.94 (m, 2H), 0.95 (t, 3H, J¼7.5 Hz); 13C NMR
(CDCl3, 75 MHz): d 138.3, 134.9, 128.3, 127.8, 127.5,
124.4, 94.8, 75.8, 73.2, 71.7, 69.3, 66.9, 58.9, 35.0, 25.5,
13.6; MS (ESIMS): m/z 331 [M+Na]+; HRMS (ESI) calcd
for C18H28O4Na [M+Na]+: 331.1885, found: 331.1897.
[a]2D5 +2.83 (c 0.53, CHCl3); IR (Neat): 3421.2, 2926.0,
1644.5, 1074.2 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
;
5.60–5.49 (m, 1H), 5.44–5.29 (m, 1H), 3.72–3.58 (m, 2H),
3.39 (dd, 1H, J¼6.8, 11.3 Hz), 2.82 (br s, 1H, OH), 2.19–
2.12 (m, 2H), 2.08–1.98 (m, 2H), 0.99 (t, 3H, J¼7.5 Hz);
13C NMR (CDCl3, 75 MHz): d 135.8, 124.0, 71.7, 66.1,
36.5, 25.5, 13.6; MS (ESIMS): m/z 153 [M+Na]+; HRMS
(ESI) calcd for C7H14O2Na [M+Na]+: 153.0891, found:
153.0899.
4.6. (2R,4R,5R)-2-[(Benzyloxy)methyl]-5-ethyltetra-
hydro-2H-4-pyranol (8)
Trifluoroacetic acid (6.93 mL, 90.0 mmol) was added slowly
to a solution of compound 7 (1.85 g, 6.0 mmol) in CH2Cl2
(40 mL) at room temperature under nitrogen atmosphere.
The reaction mixture was stirred for 5–6 h, and then satu-
rated aqueous sodium hydrogen carbonate solution (60 mL)
was added and pH was adjusted to >7 by addition of triethyl-
amine. The layers were separated, the aqueous layer was
extracted with CH2Cl2 (4ꢂ30 mL), the organic layers were
4.4. (2R,4E)-1-(Benzyloxy)-4-hepten-2-ol (6)
To a suspension of NaH (4.2 g, 105.0 mmol) in dry DMF
(30 mL) at 0 ꢁC was added diol 5 (3.9 g, 30.0 mmol) in

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M. S. Reddy et al. / Tetrahedron 63 (2007) 11011–11015
combined, washed with brine (10 mL) and the solvent was
removed under reduced pressure. The residue was dissolved
in methanol (20 mL) and stirred with potassium carbonate
(1.65 g) for 0.5 h. Methanol was then removed under re-
duced pressure and water (15 mL) was added. The mixture
was extracted with dichloromethane (3ꢂ20 mL), washed
with brine (6 mL) and the combined organic layers were
dried (Na2SO4) and the solvent was removed under reduced
pressure. Column chromatography (SiO2, 25% EtOAc in
hexane as eluent) of the crude afforded 8 (0.89 g, 59%) as
a colourless oil, Rf¼0.35.
purification by column chromatography (SiO2, 30% EtOAc
in hexane as eluent) of the crude product afforded alcohol 10
(303 mg, 99%) as a colourless liquid, Rf¼0.25.
[a]2D5 ꢀ50.52 (c 0.48, CHCl3); IR (Neat): 3448.4, 2926.3,
1
1038.0 cmꢀ1; H NMR (CDCl3, 300 MHz): 4.70 (d, 1H,
J¼7.0 Hz), 4.53 (d, 1H, J¼7.0 Hz), 4.01 (dd, 1H, J¼4.7,
11.5 Hz), 3.61–3.28 (m, 7H, including s for OMe), 3.07 (t,
1H, J¼11.4 Hz), 1.94 (ddd, 1H, J¼1.9, 6.6, 12.4 Hz), 1.85–
1.72 (m, 1H), 1.58–1.43 (m, 1H), 1.39–1.24 (m, 1H), 1.14–
0.97 (m, 1H), 0.91 (t, 3H, J¼7.4 Hz); 13C NMR (CDCl3,
50 MHz): d 95.2, 77.4, 76.7, 70.2, 65.9, 55.5, 43.8, 33.9,
20.8, 11.1; MS (ESIMS): m/z 227 [M+Na]+; HRMS (ESI)
calcd for C10H20O4Na [M+Na]+: 227.1259, found:
227.1251.
[a]2D5 +8.33 (c 0.54, CHCl3); IR (Neat): 3442.0, 2923.4,
2856.9, 1455.2, 1373.1, 1102.7, 1065.7 cmꢀ1 1H NMR
;
(CDCl3, 300 MHz): d 7.31–7.25 (m, 5H), 4.53 (s, 2H),
3.99 (dd, 1H, J¼4.5, 11.3 Hz), 3.55–3.31 (m, 4H), 3.01 (t,
1H, J¼11.3 Hz), 1.92 (ddd, 1H, J¼1.5, 6.0, 12.1 Hz), 1.85–
1.71 (m, 1H), 1.46–1.23 (m, 3H, including OH), 1.15–
0.98 (m, 1H), 0.94 (t, 3H, J¼7.5 Hz); 13C NMR (CDCl3,
75 MHz): d 138.1, 128.2, 127.6, 127.4, 75.7, 73.3, 72.9,
72.0, 69.9, 45.7, 37.9, 20.9, 11.4; MS (ESIMS): m/z 273
[M+Na]+; HRMS (ESI) calcd for C15H22O3Na [M+Na]+:
273.1466, found: 273.1472.
4.9. (4R,5R)-5-Ethyltetrahydro-4-(methoxymethoxy)-
2H-2-pyranone (11)
˚
Powdered molecular sieves (3 A, 600 mg) were heated under
N2 at 320 ꢁC with a Bunsen burner for 1 h. It was allowed to
come to room temperature and pyridinium chlorochromate
(1.39 g, 7.0 mmol) and dry benzene (10 mL) were added. To
this mixture was added a solution of 10 (285 mg, 1.4 mmol)
in benzene (4 mL) and stirred under reflux for 6 h. Then, it
was cooled to room temperature, diethyl ether (20 mL)
was added and the reaction mixture was filtered through
a short pad of Celite and silica gel (1:1). The filter cake
was washed thoroughly with ether (2ꢂ8 mL) and the filtrate
was concentrated under vacuo. The residue after flash chro-
matography (SiO2, 20% EtOAc in hexane as eluent) afforded
the lactone 11 (218 mg, 83%) as a colourless liquid, Rf¼0.4.
4.7. (2R,4R,5R)-2-[(Benzyloxy)methyl]-5-ethyltetra-
hydro-4-(methoxymethoxy)-2H-pyran (9)
To the alcohol 8 (500 mg, 2.0 mmol) in anhydrous CH2Cl2
(10 mL) at 0 ꢁC were added diisopropylethyl amine
(1.38 mL, 8.0 mmol), DMAP (20 mg) and MOMCl
(0.75 mL, 6.0 mmol) successively and the mixture was
stirred for 15 h at room temperature and then quenched by
adding water (6 mL) and extracted with CH2Cl2 (2ꢂ15 mL).
The organic extracts were washed with brine (4 mL), dried
over anhydrous Na2SO4 and concentrated under reduced
pressure to remove the solvent and the crude was purified
by column chromatography (SiO2, 10% EtOAc in hexane
as eluent) to afford the pure product 9 (582 mg, 99%) as
a colourless liquid, Rf¼0.6.
[a]2D5 ꢀ18.6 (c 0.1, CHCl3); IR (Neat): 2966.0, 2929.0,
1743.0, 1244.0, 1038.0 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d 4.65 (d, 1H, J¼7.1 Hz), 4.63 (d, 1H, J¼7.1 Hz), 4.45 (dd,
1H, J¼11.4, 4.3 Hz), 3.96 (dd, 1H, J¼11.4, 7.2 Hz), 3.84–
3.76 (m, 1H), 3.36 (s, 3H), 2.77 (dd, 1H, J¼5.2, 17.2 Hz),
2.6 (dd, 1H, J¼5.1, 17.2 Hz), 1.91–1.79 (m, 1H), 1.66–
1.51 (m, 1H), 1.45–1.25 (m, 1H), 1.02 (t, 3H, J¼7.5 Hz);
13C NMR (CDCl3, 75 MHz): d 170.7, 95.6, 73.5, 69.2,
55.9, 40.7, 35.6, 21.9, 11.5; MS (ESIMS): m/z 211
[M+Na]+; HRMS (ESI) calcd for C9H16O4Na [M+Na]+:
211.0946, found: 211.0954.
[a]2D5 ꢀ36.58 (c 0.51, CHCl3); IR (Neat): 2924.7, 2855.9,
1
1458.0, 1373.5, 1103.3, 1039.4 cmꢀ1; H NMR (CDCl3,
300 MHz): d 7.34–7.22 (m, 5H), 4.70 (d, 1H, J¼7.0 Hz),
4.55 (s, 2H), 4.53 (d, 1H, J¼7.0 Hz), 4.01 (dd, 1H, J¼4.7,
11.7 Hz), 3.54–3.25 (m, 7H, including s for OMe), 3.04 (t,
1H, J¼11.4 Hz), 2.04–1.98 (m, 1H), 1.86–1.68 (m, 1H),
1.60–1.39 (m, 1H), 1.36–1.25 (m, 1H), 1.14–0.95 (1H),
0.90 (t, 3H, J¼7.4 Hz); 13C NMR (CDCl3, 75 MHz):
d 138.1, 128.3, 127.7, 127.6, 95.1, 75.6, 73.4, 73.2, 70.4,
63.1, 55.5, 32.8, 31.9, 22.6, 14.0; MS (ESIMS): m/z 317
[M+Na]+; HRMS (ESI) calcd for C17H26O4Na [M+Na]+:
317.1728, found: 317.1723.
4.10. (4R,5R)-5-Ethyltetrahydro-4-hydroxy-2H-2-
pyranone (2)
Compound 11 (113 mg, 0.6 mmol) was dissolved in CH2Cl2
(2 mL) and then TFA (0.185 mL, 4 mmol) was added drop-
wise at room temperature. After stirring the mixture at room
temperature for 2 h, the reaction mixture was quenched with
saturated NaHCO3 solution (6 mL) and extracted with
CH2Cl2 (2ꢂ6 mL). The combined organic extracts were
washed with brine (6 mL), concentrated in vacuo and the
residue was subjected to column chromatography (SiO2,
40% EtOAc in hexane as eluent) to afford the alcohol 2
(73 mg, 85% yield) as a semisolid, Rf¼0.3.
4.8. [(2R,4R,5R)-5-Ethyltetrahydro-4-(methoxy-
methoxy)-2H-2-pyranyl]methanol (10)
To a solution of lithium (52.5 mg, 7.5 mmol) in liq NH3
(10 mL) was added compound 9 (440 mg, 1.5 mmol) in
dry THF (3 mL). The mixture was stirred for 5 min and
quenched with solid NH4Cl (406 mg). Ammonia was
allowed to evaporate and the residual mixture was taken in
diethyl ether (20 mL) and washed with water (2ꢂ4 mL), brine
(1ꢂ4 mL) and dried (Na2SO4). Removal of the solvent and
[a]2D5 ꢀ23.0 (c 0.45, CHCl3) (lit.6b [a]2D5 ꢀ23.1 (c 1.0,
CHCl3)); IR (Neat): 3474.9, 2968.9,
2924.7,
1717.9,1273.9, 1004.0 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d 4.45 (dd, 1H, J¼4.5, 11.9 Hz), 4.01–3.88 (m, 2H), 2.82

M. S. Reddy et al. / Tetrahedron 63 (2007) 11011–11015
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(dd, 1H, J¼5.2, 17.1 Hz), 2.53 (dd, 1H, J¼5.9, 17.1 Hz),
2.29 (br s, OH), 1.86–1.52 (m, 2H), 1.46–1.25 (m, 1H),
1.02 (t, 3H, J¼8.2 Hz); 13C NMR (CDCl3, 75 MHz):
d 170.7, 69.8, 67.1, 43.2, 39.2, 19.9, 11.5; MS (ESIMS):
m/z 145 [M+H]+; HRMS (ESI) calcd for C7H13O3
[M+H]+: 145.0864, found: 145.0860.
4. For the synthesis of prelactone C, see: (a) Yamashita, Y.; Saito,
S.; Ishitani, H.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125,
3793; (b) Chakraborty, T. K.; Tapadar, S. Tetrahedron Lett.
2001, 42, 1375; (c) Esumi, T.; Fukuyama, H.; Oribe, R.;
Kawazoe, K.; Iwabuchi, Y.; Irie, H.; Hatakeyama, S.
Tetrahedron Lett. 1997, 38, 4823.
Acknowledgements
M.S.R. and M.N. thank CSIR, New Delhi, India for the
award of research fellowships.
5. Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O.; Di Rosa, M.;
Ianaro, I. Tetrahedron 1999, 55, 13831.
6. (a) Sato, M.; Nakashima, H.; Hanada, K.; Hayashi, M.;
Honzumi, M.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett.
2001, 42, 2833; (b) Ravi Kumar, A.; Sudhakar, N.; Rao, B. V.;
Raghunandan, N.; Venkatesh, A.; Sarangapani, M. Bioorg.
Med. Chem. Lett. 2005, 15, 2085.
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