General strategy towards chiral methylene bis-pyrans: Synthesis of the C2-C16 fragment of phorboxazole A

Article abstract of DOI:10.1016/j.tetasy.2005.07.001

A chiral methylene bis-pyran fragment was synthesized by making efficient use of an oxy-anion intramolecular Michael addition, Brown's asymmetric allylation and Grubb's ring closing metathesis reactions in a stereoselective manner.

Full text of DOI:10.1016/j.tetasy.2005.07.001

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2722–2728
General strategy towards chiral methylene bis-pyrans:
synthesis of the C2–C16 fragment of phorboxazole AI
Jhillu Singh Yadav,* Samala Jaya Prakash and Yarrapothu Gangadhar
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 6 June 2005; accepted 4 July 2005
Available online 1 August 2005
Abstract—A chiral methylene bis-pyran fragment was synthesized by making efficient use of an oxy-anion intramolecular Michael
addition, Brownꢀs asymmetric allylation and Grubbꢀs ring closing metathesis reactions in a stereoselective manner.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
material. The strategy for constructing the bis-oxane
fragment 4, is retrosynthetically outlined in Scheme 1.
One pyran ring was constructed using an oxy anion
intramolecular Michael addition while the second was
obtained using Grubbꢀs RCM approach to complete
the methylene bis-pyran skeleton. We herein report,
the synthesis of the C2–C16 bis-oxane portion of phorb-
oxazole A.
There has been an increase in the isolation of macrolides
comprising oxygen and nitrogen heterocycles as part of
the structure. The pyran and oxazole rings are more
common in these natural products with recent examples
including halichondrin1 B 1, bryostatins2 2, phorboxaz-
oles3 3 amongst others (Fig. 1). All these natural prod-
ucts are mostly sourced from marine sponges and rare
species, thus making them difficult to be obtained from
natural sources. Accordingly, the synthesis would
ultimately allow us to obtain these bioactivities in sub-
stantial quantities for further evaluation. The methylene
bis-tetrahydropyran skeleton is present in these mole-
cules and therefore, approaches towards the properly
functionalized and enantiopure synthesis of bis-pyran
skeleton have always been a challenging and rewarding
task. As part of a major programme towards the synthe-
sis of these macrolides, we herein report a practical
approach for chirally substituted methylene bis-pyran
synthesis. This synthesis also correlates to the C2–C16
fragment of phorboxazole A, isolated in 1995 by
Searle and Molinski from the Indian Ocean sponge
Phorbas sp.4
We began with the conversion of D-glucose to the corre-
sponding ene derivative 9 in four steps (33% overall
yield) by following a literature protocol.5 Deprotection
of the acetonide of 9 was carried out using 50% aq acetic
acid and cat. H2SO4 to afford the lactol, which was fur-
ther reduced in its crude form with NaBH4 in MeOH at
0 ꢁC to give triol 10 in 67% overall yield. Selective pro-
tection of the triol afforded compound 12 in an overall
yield of 72% for two steps. Hydroboration of 12 fur-
nished the primary alcohol 13, which was oxidized to
the corresponding aldehyde and further subjected to a
two-carbon extension following the Wittig olefination
protocol to afford the a,b-unsaturated ester 14 in 89%
yield. Deprotection of the acetonide in 14, resulted in
the formation of the diol 7, which underwent an intra-
molecular oxy-anion Michael addition promoted by
NaH at ꢀ78 ꢁC to give a cis-oxane skeleton 15a with
good selectivity (20:1 cis:trans). We optimized the reac-
tion conditions for enriching the diastereoselectivity by
employing different bases such as NaHMDS, LiHMDS,
LDA and NaH (Table 1). Amongst them NaH at
ꢀ78 ꢁC was found to be appropriate for good diastereo-
selectivity (20:1) and chemical yield. The primary
hydroxyl function was protected as MOM ether 6
(Scheme 2).
2. Results and discussion
Our synthetic strategy relied on the utilization of a
natural chiral pool compound D-glucose, as starting
q IICT Communication No. 040505.
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
27160512; e-mail: yadav@iict.res.in
*
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.001

J. S. Yadav et al. / Tetrahedron: Asymmetry 16 (2005) 2722–2728
2723
H
H
H
H
H
H
H
OH
O
O
O
OAc
H
H
O
MeO2C
O
H
H
O
O
O
H
O
HO
O
O
O
X
O
O
H
O
HO
HO
O
O
H
O
OH
OH
O
O
O
OH
Halichondrin B 1
O
CO2Me
X
19
Y
N
Bryostatin 1 2a: X = Pr.CH=CH.CH=CH.CO2
Bryostatin 2 2b: X = H
13
O
O
20
CH3
24
OMe
O
O
9
5
OMe
N
O
Br
CH3 CH3
CH2
30
O
O
31
H
OH
OH
1
CH3
Phorboxazole A: X=OH, Y=H 3a
Phorboxazole B: X=H, Y=OH 3b
Figure 1.
BnO
OBn
Phorboxazole A
O
O
3a
MOMO
HO
O
O
O
4
5
OBn
O
EtO
MOMO
D-Glucose
OH
O
OEt
O
OBn OH
8
6
7
Scheme 1. Retrosynthetic analysis.
Introduction of the second trans (C5/C9) oxane ring in
target 4 was intended to be accomplished via the Brown
allylation and ring closing metathesis (RCM). Accord-
ingly, compound 6 was subjected to partial reduction
using DIBAL-H at ꢀ78 ꢁC in CH2Cl2 to afford aldehyde
16 in 86% yield. The latter on treatment with Brownꢀs
(+)-allyl diisopinocampheylborane reagent6 led to the
homoallylic alcohol 17 in 78% yield. The stereochemis-
try of the newly generated hydroxy bearing carbon is as-
signed as R based on the literature precedence.7 The
chiral HPLC of this compound (chiralcel OD18) was
found to show single isomer. Compound 17, on treat-
ment with acryloyl chloride in the presence of diisoprop-
ylethylamine afforded the corresponding acryloyl ester
18 in 93% yield. The compound was set for the construc-
tion of the trans-oxane skeleton by following RCM pro-
tocol. Accordingly, compound 18 was exposed to
8
Grubbꢀs catalyst (10 mol %) in CH2Cl2 to afford d-lac-
tone 5 in 94% yield. DIBAL-H reduction of 5 at ꢀ78 ꢁC
in CH2Cl2 followed by reaction with ethanol and CSA
afforded the ethyl glycoside.9 Reaction of this ethyl ace-
tal with allyltrimethylsilane and TMSOTf as the Lewis
acid in CH2Cl2 at 0 ꢁC afforded the corresponding allyl
substituted dihydropyran 4 as a single isomer in 85%
yield (Scheme 3). This selectivity of anomeric ethoxy
group followed by allylation has precedence.10,11
Table 1.
Entry
Base
Yield (%)
cis:trans (%)
3. Conclusion
1
2
3
4
NaHMDS
LiHMDS
LDA
80
75
71
82
90:10
85:15
70:30
95:05
In conclusion, chiral methylene bis-pyran skeleton was
accomplished successfully by employing oxy-anion
Michael addition, Brownꢀs allylation and Grubbꢀs
NaH

2724
J. S. Yadav et al. / Tetrahedron: Asymmetry 16 (2005) 2722–2728
O
a, b
ref 5
c
O
OH
O
D-Glucose
OH OH
O
OH
8
O
9
10
11
d
e
HO
EtO
f,g
O
O
O
OBn
O
O
OBn
13
O
O
OBn
12
14
OBn
OBn
O
15b
trans
i
EtO
O
+
h
O
OH
HO
OH
O
OBn
HO
O
OEt
OEt
7
15a
cis
20:1
OBn
j
15a
O
MOMO
O
OEt
6
Scheme 2. Reagents and conditions: (a) 50% aq AcOH, H2SO4 (cat.), 50 ꢁC, 2 h; (b) NaBH4, MeOH, 0 ꢁC to rt, 1 h, 67% (overall yield for two steps);
(c) PTSA (cat.), acetone, rt, 3 h, 76%; (d) NaH, BnBr, THF, reflux, 8 h, 96%; (e) BH3ÆDMS, NaOH, H2O2, THF, 8 h, 80%; (f) IBX, THF, DMSO, rt,
2 h, 83%: (g) Ph3P@CH–CO2Et, benzene, rt, 12 h, 72% (overall yield for two steps); (h) CSA, MeOH, rt, 2 h, 91%; (i) NaH, THF, ꢀ78 ꢁC, 4 h, 82%;
i
(j) Pr2NEt, MOMCl, CH2Cl2, 0 ꢁC, 6 h.
OBn
OBn
O
OBn
O
b
a
MOMO
CHO
MOMO
MOMO
O
OH
O
OEt
16
17
6
OBn
O
PCh3
Ru
OBn
Cl
Cl
Ph
e
PCh3
c
MOMO
MOMO
d
O
O
O
O
O
f
5
18
OBn
O
OBn
HO
MOMO
O
O
O
OEt
4
19
Scheme 3. Reagents and conditions: (a) DIBAL-H, CH2Cl2, ꢀ78 ꢁC, 1 h, 86%; (b) (+)-allyl diisopinocampheylborane, Et3N, H2O2, 1 h, 78%;
i
(c) Pr2NEt, acryloyl chloride, CH2Cl2, 0 ꢁC to rt, 4 h, 93%; (d) Grubbꢀs catalyst (1st gene.), Ti(iOPr)4, CH2Cl2, 60 ꢁC, 6 h, 94%; (e) DIBAL-H,
CH2Cl2, ꢀ78 ꢁC, 30 min; then CSA, EtOH, 86%; (f) allyltrimethyl silane, TMSOTf, CH2Cl2, 0 ꢁC, 1 h, 85%.
RCM reaction effectively. Studies directed towards the
total synthesis of phorboxazole A, B, bryostatins and
halichondrins B employing this approach are currently
in progress in our group.
4.1.1. (2R,4S)-5-Hexene-1,2,4-triol 10. Ene derivative 9
(3.40 g, 170 mmol) was hydrolyzed using 50% aqueous
acetic acid (12 mL) and a catalytic amount of concd
H2SO4 (two drops) by heating at 50 ꢁC for 2 h. The reac-
tion mixture was cooled to room temperature, then ethyl
acetate was added and neutralized with saturated
sodium bicarbonate. The aqueous layer was extracted with
EtOAc (4 · 50 mL). The combined organic layers were
washed with brine and dried over Na2SO4 and concen-
trated under reduced pressure to yield the crude lactol,
which was as such used without any further purification.
The above crude lactol (2.60 g, 20 mmol) was taken in
methanol (30 mL), cooled to 0 ꢁC and NaBH4 (1.11 g,
30 mmol) then added in small portions under a nitrogen
atmosphere. After complete addition, the reaction mix-
ture was brought to room temperature and allowed to
stir for 1 h. The reaction mixture was quenched with
acidic resin (3 g) and stirred for an additional 1 h. It
was then filtered through a Celite pad and concentrated
under vacuum to yield the crude product, which was
purified by column chromatography (chloroform/
4. Experimental
4.1. General
All solvents and reagents were purified by standard
techniques. Crude products were purified by column
chromatography on silica gel of 60–120 mesh. IR spectra
were recorded on Perkin–Elmer 683 spectrometer. Opti-
cal rotations were obtained on a Jasco Dip 360 digital
1
polarimeter. H and 13C NMR spectra were recorded
in CDCl3 solution on a Varian Gemini 200, Brucker
Avance 300 or Varian Unity 400. Chemical shifts are
reported in ppm with respect to the internal TMS.
Coupling constants (J) are quoted in hertz. Mass spectra
were recorded on VG micromass-7070H (70 eV).

J. S. Yadav et al. / Tetrahedron: Asymmetry 16 (2005) 2722–2728
2725
EtOAc) to afford the pure product 10 (2.11 g, overall
taining the temperature at 0 ꢁC. The reaction mixture
was brought to room temperature and stirred for a per-
iod of 8 h. This was then treated with the very slow addi-
tion of 3 M NaOH until the reaction mixture was basic
while maintaining the temperature at 0 ꢁC. To this was
added H2O2 (30% solution in H2O, 0.82 mL, 7.25 mmol)
and the reaction mixture stirred over a period of 3 h,
and then extracted with ethyl acetate (6 · 10 mL). The
combined organic layers were washed with brine, dried
over Na2SO4, concentrated and purified by column
25
67% yield) as a colourless liquid. ½aꢁD ¼ ꢀ5.6 (c 0.75,
CHCl3); IR: 3333, 3320, 3290, 2922, 1661, 1302, 1060,
1
927 cmꢀ1; H NMR (200 MHz, D2O): d 5.96–5.77 (m,
1H), 5.36–5.15 (m, 2H), 4.30 (q, J = 7.3 Hz, 1H), 3.80–
3.71 (m, 1H), 3.58–3.40 (m, 2H), 1.70 (t, J = 4.8 Hz,
2H); 13C NMR (75 MHz, D2O): 139.1, 116.0, 70.5,
69.1, 65.3, 39.0. Anal. Calcd for C6H12O3: C, 54.53; H,
9.15. Found: C, 54.49; H, 9.11.
4.1.2.
1-[2,2-Dimethyl-(4R)-1,3-dioxolan-4-yl]-(2S)-3-
chromatography to yield alcohol 13 (810 mg, 80%) as
25
buten-2-ol 11. To compound 10 (1.320 g, 10 mmol) in
anhydrous acetone (20 mL) at room temperature was
added a catalytic amount of p-toluenesulfonic acid in
one portion. The mixture was stirred at room tempera-
ture for 3 h, then solid sodium hydrogen carbonate
was added in one portion and the mixture stirred for
20 min. The mixture was filtered and the filtrate concen-
trated in vacuo to leave a light blue oil. Purification by
column chromatography, using ethyl acetate–petroleum
a colourless liquid. ½aꢁD ¼ þ18.1 (c 0.85, CHCl3); IR:
3485, 2988, 1380, 1266, 1056, 738 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 7.38–7.22 (m, 5H), 4.52 (Abq, J =
11.8 Hz, 2H), 4.21–4.08 (m, 1H), 3.95 (t, J = 7.4 Hz,
1H), 3.82–3.68 (m, 3H), 3.45 (t, J = 7.4 Hz, 1H), 2.05–
1.90 (m, 1H), 1.88–1.65 (m, 3H), 1.38 and 1.30 (2s,
6H); 13C NMR (75 MHz, CDCl3): 137.9, 128.3, 127.7,
127.6, 108.5, 75.0, 72.6, 70.8, 69.4, 59.9, 37.1, 35.9,
26.8, 25.5. Mass (FAB): m/z 281 (M++1): HRMS: Calcd
for C16H25O4 (M++1): 281.1752. Found: 281.1755.
ether as eluent, gave the acetonide 11 (1.30 g, 76% yield)
25
as a colourless oil. ½aꢁD ¼ ꢀ7.6 (c 2.35, CHCl3); IR:
3457, 2924, 1644, 1370, 1247, 1054 cmꢀ1
;
1H NMR
4.1.5. Ethyl 5-benzyloxy-6-[2,2-dimethyl-(4R)-1,3-dioxo-
lan-4-yl]-(E,5R)-2-hexenoate 14. To a well-stirred solu-
tion of IBX (1.12 g, 4 mmol) in DMSO (1 mL) was
added alcohol 13 (0.56 g, 2 mmol) dropwise in THF
(15 mL). The reaction mixture was stirred for 3 h at
room temperature. The solid materials were filtered
through a sintered funnel. The resulting filtrate was
extracted with diethyl ether. The combined organic
layers were washed with brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure to
yield the crude aldehyde, which was used as such with-
out any further purification. The above crude aldehyde
was taken in benzene (15 mL) and carboethoxy methyl-
enetriphenylphosphorane (1.39 g, 4 mmol) then added
with the resulting solution stirred for 12 h at room tem-
perature. The solvent was removed under vacuum, the
residue was diluted with dichloromethane and washed
with water, brine, dried over Na2SO4 and concentrated.
The residue was purified by column chromatography to
(200 MHz, CDCl3): d 5.97–5.80 (m, 1H), 5.30 (d,
J = 10.4 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.22–4.11
(m, 2H), 4.10 (t, J = 7.4 Hz, 1H), 3.58 (t, J = 7.4 Hz,
1H), 2.95 (br s, 1H), 1.71–1.68 (m, 2H), 1.42 and 1.38
(2s, 6H); 13C NMR (75 MHz, CDCl3): 141.5, 116.0,
110.5, 76.0, 72.6, 71.0, 41.8, 28.5, 27.2. Mass (EI): m/z
172 (M+). Anal. Calcd for C9H16O3: C, 62.77; H, 9.36.
Found: C, 62.81; H, 9.35.
4.1.3. 4-[2-Benzyloxy-(2S)-3-butenyl]-2,2-dimethyl-(4R)-
1,3-dioxolane 12. To a well-stirred suspension of
freshly activated NaH (0.8 g, 20 mmol, 60% w/v disper-
sion in mineral oil) in anhydrous THF (20 mL), a solu-
tion of alcohol 11 (1.72 g, 10 mmol) in dry THF (5 mL)
was added dropwise at 0 ꢁC. After 30 min, benzyl bro-
mide (1.43 mL, 12 mmol) was added and the reaction
mixture brought to room temperature and refluxed for
8 h. Then the solid ice pieces were added to quench
the reaction and the THF layer separated with the aque-
ous layer extracted with ether (3 · 20 mL). The com-
bined organic layers were washed with water and brine
and dried over Na2SO4. After removing the volatiles
under reduced pressure, crude benzyl ether was purified
by column chromatography with 10% EtOAc in hexane
yield the a,b-unsaturated ester 14 (0.61 g, 72% overall
25
yield from alcohol) as a colourless oil. ½aꢁD ¼ ꢀ20.1 (c
2.7, CHCl3); IR: 2975, 1713, 1656, 1263, 1053 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 7.40–7.30 (m, 5H),
7.05–6.90 (m, 1H), 5.90 (d, J = 18.6 Hz, 1H), 4.55
(Abq, J = 11.8 Hz, 2H), 4.28–4.12 (m, 3H), 3.95 (t,
J = 7.4 Hz, 1H), 3.65 (m, 1H), 3.50 (t, J = 7.4 Hz,
1H), 2.50 (t, J = 6.5 Hz, 2H), 2.00–1.85 (m, 1H), 1.75–
1.60 (m, 1H), 1.40 (s, 3H), 1.32–1.21 (m, 6H); 13C
NMR (50 MHz, CDCl3): 166.7, 144.6, 138.2, 128.7,
127.8, 124.0, 108.8, 99.8, 75.0, 72.8, 71.2, 69.5, 60.5,
37.8, 36.5, 27.0, 25.8, 14.2. Mass (FAB): m/z 349
(M++1). HRMS: Calcd for C20H29O5 (M++1):
349.2014. Found: 349.2011.
as an eluent to furnish 12 (2.51 g, 96% yield) as a colour-
25
less liquid. ½aꢁD ¼ ꢀ32.9 (c 3.15, CHCl3); 1H NMR
(200 MHz, CDCl3): d 7.28–7.16 (m, 5H), 5.82–5.66 (m,
1H), 5.28 (dd, J = 14.2, 1.1 Hz, 2H), 4.58 (d,
J = 13.4 Hz, 1H), 4.30 (d, J = 13.4 Hz, 1H), 4.05 (m,
1H), 3.98–3.80 (m, 2H), 3.48 (t, J = 8.6 Hz, 1H), 2.10–
1.95 (m, 1H), 1.76–160 (m, 1H), 1.37 and 1.30 (2s,
6H); 13C NMR (50 MHz, CDCl3): 138.0, 128.2, 127.5,
127.4, 117.7, 115.2, 108.3, 72.7, 70.0, 69.7, 69.4, 39.1,
26.8, 25.7. Mass (FAB): m/z 263 (M++1); HRMS: Calcd
for C16H23O3 (M++1): 263.1647. Found: 263.1644.
4.1.6. Ethyl 5-benzyloxy-7,8-dihydroxy-(E,5R,7R)-2-oct-
enoate 7. Camphor-10-sulfonic acid (23 mg, 0.1 mmol)
was added in one portion to a stirred solution of the ace-
tonide compound 14 (348 mg, 1 mmol) in methanol
(10 mL) at 0 ꢁC under nitrogen atmosphere. The mix-
ture was warmed to room temperature and stirred at this
temperature for 12 h before it was quenched with a
4.1.4. 3-Benzyloxy-4-[2,2-dimethyl-(4R)-1,3-dioxolan-4-
yl]-(3R)-butan-1-ol 13. To compound 12 (950 mg,
3.625 mmol) in dry THF was added BH3ÆDMS (0.413
g, 5.438 mmol) for over a period of 15 min while main-

2726
J. S. Yadav et al. / Tetrahedron: Asymmetry 16 (2005) 2722–2728
25
saturated aqueous solution of sodium hydrogen carbon-
ate (5 mL). The methanol was removed in vacuo and the
remaining aqueous layer was then extracted with ethyl
acetate (3 · 10 mL). The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo to leave a yel-
low oil. Purification by column chromatography, using
80% ethyl acetate–petroleum ether, increasing to ethyl
90%) as a colourless liquid. ½aꢁD ¼ ꢀ7.6 (c 0.3, CHCl3);
IR: 2924, 1736, 1452, 1341, 1112, 1041 cmꢀ1; H NMR
1
(200 MHz, CDCl3): d 7.39–7.25 (m, 5H), 4.64 (s, 2H),
4.55 (Abq, J = 8.1 Hz, 2H), 4.32–4.23 (m, 1H), 4.18–
4.02 (m, 3H), 3.94–3.88 (m, 1H), 3.53 (d, J = 3.6 Hz,
2H), 3.35 (s, 3H), 2.60 (dd, J = 15.3, 8.1 Hz, 1H), 2.48
(dd, J = 15.3, 8.1 Hz, 1H), 2.02–1.96 (m, 1H), 1.86–
1.74 (m, 1H), 1.68–1.59 (m, 2H), 1.28 (t, J = 7.4 Hz,
3H); 13C NMR (75 MHz, CDCl3): 171.1, 138.6, 128.3,
127.8, 127.3, 96.4, 71.8, 70.7, 70.1, 69.8, 68.8, 60.1,
55.2, 41.3, 34.8, 31.8, 14.1. Mass (FAB): 353 (M++1);
HRMS: Calcd for C19H29O6 (M++1): 353.1964. Found:
353.1968.
acetate as eluent, gave the diol 7 (280 mg, 91%) as a pale
25
yellow oil. ½aꢁD ¼ ꢀ16.2 (c 0.4, CHCl3); IR: 3446, 3424,
1733, 1647, 1216, 758 cmꢀ1
;
1H NMR (200 MHz,
CDCl3): d 7.35–7.24 (m, 5H), 6.98–6.82 (m, 1H)), 5.85
(d, J = 15.6 Hz, 1H), 4.69 (d, J = 11.1 Hz, 1H), 4.46
(d, J = 11.1 Hz, 1H), 4.18 (q, J = 7.4 Hz, 2H), 3.86–
3.78 (m, 2H), 3.50 (dd, J = 11.1, 5.9 Hz, 1H), 3.35 (dd,
J = 11.1, 5.9 Hz, 1H), 2.52 (t, J = 6.7 Hz, 2H), 1.58–
1.43 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3): 166.0, 143.9, 137.2, 128.7, 128.1,
127.8, 124.0, 77.6, 77.2, 71.1, 66.4, 60.5, 37.0, 36.5,
14.2. Mass (FAB): m/z 331 (M++23), 309 (M++1);
HRMS: Calcd for C17H25O5 (M++1): 309.1701. Found:
309.1705.
4.1.9. 2-[4-Benzyloxy-6-methoxymethoxymethyl-(2S,4R,
6R)-dihydro-4H-2-pyranyl]acetaldehyde 16. To a solu-
tion of 6 (200 mg, 0.568 mmol) in dry dichloromethane
at ꢀ78 ꢁC under a nitrogen atmosphere was added DI-
BAL-H (1 M solution in hexane, 0.568 mmol). The mix-
ture was stirred at ꢀ78 ꢁC for 1 h, and then 1 mL of
CH3OH added slowly, while maintaining the tempera-
ture at ꢀ78 ꢁC for an additional 30 min. A mixture of
3 mL of EtOAc and 12 mL of saturated aqueous sodium
potassium tartarate was added to the mixture and the
temperature allowed to rise to 23 ꢁC. The aqueous layer
was extracted with CH2Cl2 and the combined organic
extracts washed with brine, dried over Na2SO4 and con-
centrated. The crude product was purified by column
chromatography (petroleum ether/EtOAc) to afford 16
(150 mg) as a viscous liquid in 86% yield. IR: 2924,
4.1.7. Ethyl 2-[4-benzyloxy-6-hydroxymethyl-(2S,4R,6R)-
dihydro-4H-2-pyranyl]acetate 15a. To a suspension of
NaH (160 mg, 4 mmol, 60% w/v dispersion in mineral
oil) in dry THF (20 mL) at ꢀ78 ꢁC was added slowly
compound 7 (308 mg, 1 mmol) in THF (3 mL). The
reaction was stirred for 4 h, after which TLC showed
complete conversion. Then solid ice pieces were added
to quench the reaction and then the THF layer was sep-
arated and the aqueous layer was extracted with ether
(3 · 20 mL). The combined organic layers were washed
with water, brine, dried over Na2SO4 and concentrated
under vacuum to yield the crude product, which was
purified by column chromatography (hexane/EtOAc)
1706, 1453, 1339, 1112, 1041 cmꢀ1
;
1H NMR
(200 MHz, CDCl3): d 9.79–9.77 (m, 1H), 7.35–7.22 (m,
5H), 4.58 (s, 2H), 4.55 (s, 2H), 4.40–4.28 (m, 1H),
4.08–3.98 (m, 1H), 3.95–3.88 (m, 1H), 3.48 (d,
J = 6.5 Hz, 2H), 3.36 (s, 3H), 2.65–2.38 (m, 2H), 1.88
(t, J = 12.0 Hz, 2H), 1.46 (t, J = 12.0 Hz, 2H).
to afford the pure product 15a (252 mg, 82% yield) as
25
a colourless liquid. ½aꢁD ¼ ꢀ9.5 (c 1.15, CHCl3); IR:
1
3504, 2865, 1733, 1417, 1288, 1184, 905, 737 cmꢀ1; H
4.1.10. 1-[4-Benzyloxy-6-methoxymethoxymethyl-(2R,4R,
A
NMR (200 MHz, CDCl3): d 7.32–7.28 (m, 5H), 4.52
(Abq, J = 8.2 Hz, 2H), 4.30–4.22 (m, 1H), 4.14 (q,
J = 7.4 Hz, 2H), 3.98–3.90 (m, 1H), 3.89–3.85 (m, 1H),
3.56 (dd, J = 7.6, 5.3 Hz, 1H), 3.40 (dd, J = 7.6,
5.3 Hz, 1H), 2.49 (dd, J = 10.6, 4.7 Hz, 1H), 2.35 (dd,
J = 10.6, 4.7 Hz, 1H), 1.99–1.91 (m, 1H), 1.75–1.68
(m, 1H), 1.55–1.43 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H);
13C NMR (75 MHz, CDCl3): 170.8, 138.2, 128.2,
127.6, 127.1, 72.6, 70.5, 70.0, 68.8, 65.8, 60.5, 41.2,
34.9, 31.0, 14.2. Mass (FAB): m/z 331 (M++Na);
HRMS: Calcd for C17H24O5Na (M++Na): 331.1521.
Found: 331.1520.
6R)-dihydro-4H-2-pyranyl]-(2R)-4-penten-2-ol
17.
solution of (+)-allyldiisopinocampheylborane (162 mg,
0.5 mmol) in dry diethyl ether was cooled to ꢀ78 ꢁC
and aldehyde 16 (154 mg, 0.5 mmol) in anhydrous
diethyl ether was added dropwise over 5 min under a
nitrogen atmosphere. The reaction mixture was stirred
at the same temperature for 1 h and then brought to
room temperature (ꢂ1 h). This was then treated with a
very slow addition of TEA (0.278 mL, 2 mmol), and
hydrogen peroxide (0.113 mL, 30% w/v dispersion in
H2O, 1 mmol) successively while maintaining the tem-
perature at 0 ꢁC. Then the reaction mixture was allowed
to warm to room temperature and stirred for 12 h. The
organic layer was separated and washed with water,
brine and dried over Na2SO4, concentrated and purified
by column chromatography to yield the homoallyl alco-
4.1.8. Ethyl 2-[4-benzyloxy-6-methoxymethoxymethyl-
(2S,4R,6R)-dihydro-4H-2-pyranyl]acetate 6. To alco-
hol 15a (280 mg, 0.909 mmol) in anhydrous CH2Cl2
(10 mL) at 0 ꢁC was added diisopropylethylamine
(234 mg, 1.818 mmol) and MOMCl (109 mg,
1.363 mmol) successively and the mixture stirred for
6 h. The reaction mixture was quenched by adding water
(4 mL) and extracted with CH2Cl2. The organic extracts
were washed with brine, dried over anhydrous Na2SO4
and concentrated under vacuum to yield the crude prod-
uct, which was purified by column chromatography
(hexane/EtOAc) to afford the pure product 6 (287 mg,
hol 17 (136 mg, 78% yield) as a colourless oil.
25
½aꢁD ¼ ꢀ9.8 (c 1.0, CHCl3); IR: 3437, 2928, 1450,
1341, 1041 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d
7.38–7.25 (m, 5H), 5.89–5.75 (m, 1H), 5.14–4.98 (m,
2H), 4.60 (s, 2H), 4.51 (s, 2H), 4.18–3.98 (m, 2H),
3.96–3.83 (m, 2H), 3.47 (d, J = 4.9 Hz, 2H), 3.33 (s,
3H), 2.31–2.20 (m, 2H), 1.90–1.74 (m, 2H), 1.57–1.40
(m, 4H). Mass (FAB): m/z 351 (M++1); HRMS: Calcd
for C20H31O5 (M++1): 351.2171. Found: 351.2173.

J. S. Yadav et al. / Tetrahedron: Asymmetry 16 (2005) 2722–2728
2727
4.1.11.
1-[4-Benzyloxy-6-methoxymethoxymethyl-
1046 cmꢀ1 1H NMR (200 MHz, CDCl3) d 7.36–7.32
;
(2S,4R,6R)-dihydro-4H-2-pyranylmethyl]-(1R)-3-butenyl
acrylate 18. To an ice-cold solution of alcohol 17
(155 mg, 0.442 mmol) and diisopropylethylamine (0.381
mL, 2.21 mmol) in CH2Cl2 (10 mL) was added a solu-
tion of acryloyl chloride (119 mg, 1.328 mmol) in
CH2Cl2 (2 mL) dropwise. After 4 h of stirring at 0 ꢁC,
the solution was diluted with saturated NaHCO3, the
organic layer separated and the aqueous layer extracted
twice with CH2Cl2. The combined organic layers were
dried over Na2SO4 and concentrated to afford a residue,
which was purified by column chromatography on silica
(m, 5H), 6.02–5.96 (m, 1H), 5.76–5.71 (m, 1H), 4.95
(d, J = 9.6 Hz, 1H), 4.64 (s, 2H), 4.55 (Abq,
J = 11.8 Hz, 2H), 4.24–4.19 (m, 1H), 4.12 (q,
J = 5.9 Hz, 2H), 3.95–3.82 (m, 2H), 3.58–3.48 (m, 3H),
3.34 (s, 3H), 2.02–1.90 (m, 4H), 1.58–1.54 (m, 4H),
1.26 (t, J = 5.9 Hz, 3H). Mass (ESIMS): m/z 429
(M++Na); HRMS: Calcd for C23H34O6Na (M++Na):
429.2253. Found: 429.2252.
4.1.14. 4-Benzyloxy-2-[2-ethoxy-(2S,6R)-2H,5H-6-pyran-
ylmethyl]-6-methoxymethoxymethyl-(2R,4R,6R)-2H,3H,
4H,5H-pyran 4. A solution of 19 (30 mg, 0.73 mmol)
in anhydrous CH2Cl2 (5 mL) was cooled to 0 ꢁC. To
the cooled solution was added allyltrimethylsilane
(16 mg, 0.147 mmol) in dichloromethane. After stirring
for 10 min, trimethylsilyl triflate (3 mg, 0.014 mmol) in
dichloromethane was added to the reaction mixture.
The resulting mixture was stirred for 1 h and diluted
with water and extracted with dichloromethane. The
combined organic extracts were dried over anhydrous
Na2SO4 and the solvent evaporated. The residue was
gel (hexane/EtOAc) to furnish ester 18 (166 mg, 93%) as
25
a colourless liquid. ½aꢁD ¼ ꢀ14.6 (c 1.0, CHCl3); IR:
2924, 1722, 1197, 1046, 771 cmꢀ1
;
1H NMR
(200 MHz, CDCl3): d 7.30–7.21 (m, 5H), 6.41–6.30 (m,
1H), 6.15–6.03 (m, 1H), 5.82–5.71 (m, 2H), 5.25–5.11
(m, 1H), 5.10–5.01 (m, 2H), 4.61 (s, 2H), 4.50 (s, 2H),
3.92–3.78 (m, 3H), 3.48 (d, J = 4.9 Hz, 2H), 3.32 (s,
3H), 2.41–2.32 (m, 2H), 2.00–1.89 (m, 1H), 1.85–1.55
(m, 5H). Mass (ESIMS): m/z 427 (M++Na); HRMS:
Calcd for C23H32O6Na (M++Na): 427.2096. Found:
427.2093.
purified by column chromatography to give 4 (22 mg,
25
85%) as a colourless liquid. ½aꢁD ¼ ꢀ8.23 (c 1.15,
4.1.12.
6-[4-Benzyloxy-6-methoxymethoxymethyl-
CHCl3); IR: 3480, 2922, 1384, 1061, 772 cmꢀ1 1H
;
(2S,4R,6R)-2H,3H,4H,5H-2-pyranylmethyl]-(6R)-2H,5H-2-
pyranone 5. To a solution of ester 18 (100 mg,
0.247 mmol) in CH2Cl2 (20 mL) were added Ti(iOPr)4
(21 mg, 0.074 mmol) in CH2Cl2 (5 mL) and Cl2(PCy3)2-
Ru@CHPh (20 mg, 0.024 mmol) in CH2Cl2 (5 mL)
successively. The mixture was refluxed at 60 ꢁC (oil bath
temperature) overnight, and then concentrated to afford
a residue, which was purified by column chromato-
NMR (200 MHz, CDCl3): d 7.36–7.32 (m, 5H), 5.88–
5.78 (m, 2H), 5.73–5.67 (m, 1H), 5.10–5.02 (m, 2H),
4.54 (Abq, J = 11.8 Hz, 2H), 4.21–4.16 (m, 1H), 4.14–
4.08 (m, 1H), 3.94–3.84 (m, 3H), 3.60 (dd, J = 11.1,
5.9 Hz, 1H), 3.42 (dd, J = 11.1, 5.9 Hz, 1H), 2.44–
2.38 (m, 1H), 2.35–2.31 (m, 1H), 2.26–2.21 (m, 1H),
2.08–2.00 (m, 1H), 1.97–1.90 (m, 4H), 1.56–1.52 (m,
2H). Mass (ESIMS): m/z 381 (M++Na). Anal. Calcd
for C22H30O4: C, 73.72; H, 8.44. Found: C, 73.75; H,
8.46.
graphy on silica gel (hexane/EtOAc) to furnish lactone
25
5 (87 mg, 94% yield) as a viscous liquid. ½aꢁD ¼ ꢀ10.7
1
(c 1.0, CHCl3); IR: 2920, 1732, 1219, 1061 cmꢀ1; H
NMR (200 MHz, CDCl3): d 7.31–7.22 (m, 5H), 6.86–
6.83 (m, 1H), 5.98 (d, J = 12.5 Hz, 1H), 4.66–4.61 (m,
1H), 4.58 (s, 2H), 4.51 (s, 2H), 4.08–3.88 (m, 2H),
3.86–3.82 (m, 1H), 3.48 (d, J = 5.3 Hz, 2H), 3.32 (s,
3H), 2.40–2.27 (m, 2H), 1.86–1.69 (m, 4H), 1.35–1.30
(m, 2H). Mass (FAB): m/z 399 (M++Na). HRMS:
Calcd for C21H28O6Na (M++Na): 399.1783. Found:
399.1784.
Acknowledgements
Two of us (S.J.P. and Y.G.) thank CSIR, New Delhi,
for financial assistance.
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25

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