Asymmetric synthesis of Goniothalesdiol A from (R)-2,3-O-cyclohexylidine glyceraldehyde

Article abstract of DOI:10.1016/j.tetasy.2009.08.005

Goniothalesdiol A 1 has been synthesized from (R)-2,3-O-cyclohexylidine glyceraldehyde with high stereoselectivity and 22% overall yield in 11 simple steps. The key features of the synthetic strategy include the stereocontrolled allylation of (R)-2,3-O-cy

Full text of DOI:10.1016/j.tetasy.2009.08.005

Tetrahedron: Asymmetry 20 (2009) 2230–2233
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of Goniothalesdiol A from
(R)-2,3-O-cyclohexylidine glyceraldehyde
*
Mallam Venkataiah, Palabindela Somaiah, Gowrisankar Reddipalli, Nitin W. Fadnavis
Biotransformation Laboratory, Indian Institute of Chemical Technology, Uppal Road, Habsiguda, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Goniothalesdiol A 1 has been synthesized from (R)-2,3-O-cyclohexylidine glyceraldehyde with high ste-
reoselectivity and 22% overall yield in 11 simple steps. The key features of the synthetic strategy include
the stereocontrolled allylation of (R)-2,3-O-cyclohexylidine glyceraldehydes; the cross-metathesis with a
Grubbs’s second generation catalyst, and the intramolecular base-catalyzed oxy-Michael addition for the
formation of the tetrahydropyran ring.
Received 23 July 2009
Accepted 6 August 2009
Available online 25 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
H
H
O
OMe
The synthesis of substituted tetrahydropyrans is of considerable
interest due to the prevalence of these structures in natural prod-
ucts and biologically active compounds. Tetrahydropyrans bearing
substituents at the 2- and 6-positions on the ring are often
observed in a large number of biologically important natural prod-
ucts, such as zampanolide,1a leucascandrolide,1b phorboxazole,1c
ratjadone,1d lasonolide,1e misakinolides,1f scytophycins,1g sorangi-
cin A,1h swinholides,1i and laulimalide.1j The stereoselective syn-
thesis of 2,6-disubstituted tetrahydropyrans is an important task
since the cis- or trans-configuration of the 2,6-substituents on the
hydropyran ring can affect the three dimensional molecular shape,
as well as the biological activity of the natural product.2 Several
strategies have already been employed for the synthesis of these
tetrahydropyran scaffolds:3 The majority of approaches involve
Prins’ cyclization,3a palladium-catalyzed cyclization of non-3-ene-
2,8-diols,3b reductive cyclizations of hydroxysulfinyl ketones,3c or
hydroxy-epoxide cyclization, and intramolecular conjugate
addition.3d
Recently, Goniothalesdiol A 1 (Fig. 1) isolated from the Gonio-
thalamus sp. has been shown to possess a 2,3,4,6-tetrasubstituted
pyran ring,4 only one synthesis based on Sharpless kinetic resolu-
tion has been reported.5 Application of the known synthetic strat-
egies for the synthesis of 1 requires the intermediates to be
prepared via a complex set of reactions. Furthermore, the kinetic
resolution strategy suffers from the drawback of a maximum
yield of 50%. We have thus devised an alternative route to 1 using
O
HO
OH
Goniothalesdiol A 1
Figure 1.
2. Results and discussion
(R)-2,3-O-Cyclohexylidine glyceraldehyde 2 can be readily pre-
pared from
-mannitol on a multi-gram scale.6 Compared to the
D
corresponding acetonide, cyclohexylidine glyceraldehyde is stable,
and provides the appropriate steric hindrance when allylation with
allyl bromide is carried out to give anti-homoallylic alcohol 3,
almost exclusively7 (91%, de 94%). The diastereomers are easily
separated by column chromatography. To obtain homoallylic alco-
hol 8 with a free primary alcohol group, compound 3 was subjected
to a series of simple protection and deprotection steps with high
yields. The secondary alcohol function was first protected by ben-
zylation to obtain 4, the cyclohexylidine protecting group was
removed with 90% TFA in water to obtain diol 5, and the primary
hydroxy group of 5 was selectively protected as a TBDMS ether fol-
lowed by protection of the resulting secondary alcohol as a benzyl
derivative. Treatment of the dibenzyl ether 7 with TBAF in THF
afforded the primary alcohol 8 (overall yield 52% from 3). The
alcohol 8 was oxidized to aldehyde by Swern oxidation protocol
and the crude aldehyde was directly used for Grignard reaction
with phenyl magnesium bromide in dry ether at ꢀ78 °C. The corre-
sponding anti-alcohol 9 was obtained in 59% yield after column
chromatography (Scheme 1).
(R)-2,3-O-cyclohexylidine glyceraldehyde as
a starting chiral
template.
* Corresponding author. Fax: +91 40 27160512.
E-mail addresses: fadnavis@iict.res.in, fadnavisnw@yahoo.com (N.W. Fadnavis).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.005

M. Venkataiah et al. / Tetrahedron: Asymmetry 20 (2009) 2230–2233
OH OBn
2231
CHO
OBn
O
O
O
O
O
O
HO
a
c
b
OH
3
4
2
5
d
OH OBn
OBn
OBn
g
e, f
HO
TBDMSO
OBn
OBn
OH
8
6
9
Scheme 1. Reagents and conditions: (a) Allyl bromide, Zn, aq NH4Cl, 0 °C, 4 h, 91%; (b) NaH, BnBr, THF, 0 °C to rt, 6 h, 93%; (c) 90% CF3COOH in water, 0 °C, 2 h, 80%; (d)
TBDMSCl, imidazole, CH2Cl2, 0 °C to rt, 6 h, 82%; (e) NaH, BnBr, TBAI (cat), THF, 0 °C to rt, 6 h; (f) TBAF, THF, rt, 2 h, 85% (for steps e and f); (g) (i) (COCl)2,DMSO, Et3N, CH2Cl2,
ꢀ78 °C, 0.5 h; (ii) phenyl magnesium bromide, dry ether ꢀ78 °C, 3 h, 59%.
Cross-metathesis8 of 9 with methyl acrylate in DCM using
Grubbs’s second generation catalyst (5 mol %) gave exclusively
trans-10 in 91% yield. Base-catalyzed intramolecular oxa-Michael
addition reaction gave 11 as a single diastereomer (90%).9 The reac-
tion apparently proceeds via formation of stable chair conformer.
Finally, debenzylation of 11 using Pd–C in EtOAc gave the target
molecule 1 (98%) (Scheme 2). The stereochemistry of the substitu-
ents on the tetrahydropyran ring was confirmed by comparing the
physical and spectroscopic data of 1 with the literature data.5
4.1.1. (S)-1-((R)-1,4-Dioxaspiro[4.5]decan-2-yl)but-3-en-1-ol 3
Allyl bromide (4.96 mL, 58.82 mmol) in THF (50 mL) was added
to mixture of 2 (5.0 g, 29.41 mmol), Zn dust (3.73 g, 58.82 mmol),
and a saturated aqueous solution of NH4Cl (15 mL) dropwise over
a period of 30 min with vigorous stirring at 10 °C. The mixture was
stirred for 4 h at ambient temperature until the aldehyde was to-
tally consumed as evidenced by TLC analysis. The mixture was fil-
tered, and the precipitate was thoroughly washed with CHCl3. The
aqueous layer was separated and treated with 5% HCl to dissolve
the suspended turbid material. The clear solution was extracted
with CHCl3. The combined organic layer was washed successively
with 10% NaHCO3, water, and brine. After solvent removal under
reduced pressure, the residue was purified by column chromatog-
raphy (EtOAc–hexane, 1:9) to give 3 as a colorless oil (5.61 g, 91%).
3. Conclusion
In conclusion, we have developed a simple, convenient, and effi-
cient approach for Goniothalesdiol A 1 from a D-glyceraldehyde
template in 22% overall yield using stereoselective allylation, Grig-
nard reaction, cross-metathesis, and base-catalyzed intramolecular
oxa-Michael addition as the key steps.
½
a 2D5
ꢁ
¼ þ10:0 (c 1, CHCl3), lit7 (½a D25
ꢁ
¼ þ10:5); IR (neat, cmꢀ1): mmax
3456, 3076, 2936, 2860, 1641, 1446, 1367, 1280, 1231, 1162, 1101,
1043, 926, 846, 773; 1H NMR (300 MHz, CDCl3): d 1.40–1.69 (m,
10H), 1.85 (br s, 1H), 2.10–2.38 (m, 2H), 3.66–3.81 (m, 1H), 3.83–
4.11 (m, 3H), 5.07–5.26 (m, 2H), 5.73–5.94 (m, 1H); 13C NMR
(75 MHz, CDCl3): d 23.7, 23.9, 25.1, 34.8, 36.2, 37.6, 64.8, 70.4,
77.7, 109.6, 118.3, 134.1; EI-MS: m/z = 235 [M+Na]+.
4. Experimental
4.1. General
4.1.2. (R)-2-((S)-1-(Benzyloxy)but-3-enyl)-1,4-dioxaspiro[4.5]dec-
ane 4
All reagents were purchased from Aldrich. IR spectra were re-
corded on a Perkin–Elmer RX-1 FT-IR system. 1H NMR (300 MHz)
and 13C NMR (75 MHz) spectra were recorded on Bruker Avance-
300 MHz spectrometer. Optical rotations were measured with Hor-
iba-SEPA-300 digital polarimeter. Mass spectra were recorded on a
Q STAR mass spectrometer (Applied Biosystems, USA).
A solution of 3 (3.0 g, 14.15 mmol) in dry THF (20 mL) was
added dropwise to a stirred suspension of NaH (0.68 g, 28.3 mmol)
in dry THF (10 mL) at 0 °C under nitrogen atmosphere. After stir-
ring at room temperature for 15 min, benzyl bromide (1.64 mL,
14.15 mmol) was added and the reaction mixture was stirred for
N
N
Ar
Ar
Cl
Cl
Ru
PCY3
Ru-II
Ph
OH OBn
O
H
H
H
H
O
OMe
O
OMe
OMe
a
b
c
9
O
O
OBn
HO
BnO
OH
OBn
10
1
11
Scheme 2. Reagents and conditions: (a) methyl acrylate, Grubbs’s II (5 mol %), DCM, 40 °C, 4 h, 91%; (b) NaH, THF, ꢀ20 °C, 1 h, 90%; (c) H2/Pd–C, EtOAc, 4 h, 98%.

2232
M. Venkataiah et al. / Tetrahedron: Asymmetry 20 (2009) 2230–2233
1 h, quenched with saturated aq NH4Cl at 0 °C, and extracted with
ether (2 ꢂ 50 mL). The combined organic extracts were washed
with brine (30 mL), dried over anhydrous Na2SO4, concentrated
under reduced pressure, and purified by column chromatography
(EtOAc–hexane, 5:95). The benzyl-protected product 4 was ob-
The reaction mixture was stirred for 1 h at room temperature. After
completion of the reaction, the reaction mixture was quenched
with water and THF was evaporated. The residue was extracted
with CHCl3 (2 ꢂ 25 mL). The combined extracts were dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(EtOAc–hexane, 1:9) to afford 8 (1.18 g, 85% from two steps) as a
tained as a yellow oil (3.97 g, 93%). ½a D25
¼ þ27:0 (c 1, CHCl3); IR
ꢁ
(neat, cmꢀ1): mmax 3452, 3069, 3030, 2936, 2860, 1640, 1450,
1365, 1279, 1162, 1103, 1038, 925, 846, 738, 698; 1H NMR
(300 MHz, CDCl3): d 1.38–1.43 (m, 2H), 1.54–1.63 (m, 8H), 2.27–
2.46 (m, 2H), 3.52 (q, J = 5.66, 10.66 Hz, 1H), 3.78–3.86 (m, 1H),
3.95–4.05 (m, 2H), 4.61 (q, J = 11.52, 23..42 Hz, 2H), 5.05–5.14
(m, 2H), 5.79–5.93 (m, 1H), 7.12–7.32 (m, 5H); 13C NMR
(75 MHz, CDCl3): d 23.8, 24.1, 25.2, 34.9, 35.7, 36.4, 66.2, 72.5,
76.8, 79.0, 109.6, 117.5, 127.6 (ꢂ2), 127.9 (ꢂ2), 128.3, 134.3,
138.5; EI-MS: m/z = 325 [M+Na]+.
yellow liquid. ½a D25
ꢁ
¼ þ9:5 (c 1, CHCl3); IR (neat, cmꢀ1): mmax
3434, 3067, 3031, 2875, 1718, 1640, 1454, 1395, 1274, 1209,
1096, 915, 741, 698; 1H NMR (300 MHz, CDCl3): d 2.06 (br s, 1H),
2.28–2.49 (m, 2H), 3.45 (q, J = 4.5, 10.5 Hz, 1H), 3.64 (q, J = 6.0,
11.3 Hz, 1H), 3.67–3.74 (m, 2H), 4.53–4.64 (m, 4H), 5.04–5.10 (m,
2H), 5.75–5.89 (m, 1H), 7.20–7.40 (m, 10H); 13C NMR (75 MHz,
CDCl3): d 35.2, 61.1, 72.0, 72.4, 78.6, 80.0, 117.5, 127.6, 127.7,
127.8 (ꢂ2), 127.84(ꢂ2), 128.3 (ꢂ2), 128.4 (ꢂ2), 134.3, 137.98,
138.03; EI-MS: m/z = 335 [M+Na]+. HRMS (EI): m/z calcd for
C20H24O3Na: 335.1623; found 335.1610.
4.1.3. (2R,3S)-3-(Benzyloxy)hex-5-ene-1,2-diol 5
Compound 4 (3.0 g, 9.93 mmol) was dissolved in 90% aq
CF3COOH (20 mL) at 0 °C and the mixture was stirred at the same
temperature for 2 h. The reaction mixture was then extracted with
CH2Cl2 (3 ꢂ 50 mL). The collected organic layers were combined,
washed with 10% NaHCO3 (3 ꢂ 50 mL), water, and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by sil-
ica gel column chromatography (EtOAc–hexane, 3:7) to obtain 5
4.1.6. (1R,2R,3S)-2,3-Bis(benzyloxy)-1-phenylhex-5-en-1-ol 9
At first, DMSO (0.91 mL, 12.84 mmol) was added to a stirred
solution of oxalyl chloride (0.542 mL, 6.42 mmol) in dry CH2Cl2
(20 mL) at ꢀ78 °C, and stirred for 30 min. Compound 8 (1.0 g,
3.21 mmol) in dry CH2Cl2 (10 mL), was then added to the reaction
mixture at ꢀ78 °C and stirred for 2 h at the same temperature.
Next, DIPEA (2.21 mL, 12.84 mmol) was added at ꢀ78 °C and the
reaction mixture was allowed to warm to room temperature for
30 min. The reaction mixture was then diluted with water
(20 mL) and extracted with CHCl3 (2 ꢂ 25 mL). The combined or-
ganic layers were washed with brine (20 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to afford
crude aldehyde as a yellow syrup. The crude aldehyde was dis-
solved in dry ether (20 mL) and was cooled to ꢀ78 °C. To this, phe-
nyl magnesium bromide (5.60 mL of 2 M solution in diethyl ether,
22.4 mmol) was added slowly and the reaction mixture was stirred
at the same temperature for 3 h. After completion of the reaction,
the reaction mixture was treated with saturated aqueous NH4Cl
solution (20 mL) and extracted with CH2Cl2 (2 ꢂ 30 mL). The com-
bined extracts were dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (EtOAc–hexane, 1:9) to afford 9
(1.764 g, 80%) as a syrup. ½a D25
¼ þ34:0 (c 1, CHCl3); IR (neat,
ꢁ
cmꢀ1): mmax 3445, 3076, 2936, 2860, 1641, 1446, 1367, 1280,
1162, 1099, 1042, 923, 845, 768; 1H NMR (500 MHz, CDCl3): d
1.47 (br s, 1H), 2.06 (br s, 1H), 2.32–2.51 (m, 2H), 3.56 (q, J = 5.8,
11.7 Hz, 1H), 3.64–3.60 (m, 2H), 3.68–3.74 (m, 1H), 4.56 (dd,
J = 11.71, 6.50 Hz, 2H), 5.06–5.14 (m, 2H), 5.79–5.87 (m, 1H),
7.24–7.32 (m, 5H); 13C NMR (75 MHz, CDCl3): d 35.0, 63.4, 72.4,
72.5, 80.4, 117.7, 127.8 (ꢂ3), 128.5 (ꢂ2), 134.2, 138.3; EI-MS: m/
z = 245 [M+Na]+. HRMS (EI): m/z calcd for C13H18O3Na: 245.1153;
found 245.1148.
4.1.4. (2R,3S)-3-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)hex-
5-en-2-ol 6
To an ice cold solution of 5 (1.5 g, 6.756 mmol) in CH2Cl2
(35 mL), imidazole (0.61 g, 10.134 mmol) was added followed by
TBDMSCl (1.02 g, 6.756 mmol) and the reactants were stirred for
4 h at room temperature. The reaction mixture was then treated
with 20 mL of saturated aqueous NH4Cl solution and extracted
with CH2Cl2 (2 ꢂ 30 mL), dried over anhydrous Na2SO4, and con-
centrated under reduced pressure. The residue was purified by sil-
ica gel column chromatography (EtOAc–hexane, 15:85) to afford 6
(0.633 g, 59%) as a yellow liquid. ½a D25
¼ þ40:0 (c 1, CHCl3); IR
ꢁ
(neat, cmꢀ1): mmax 3459, 3064, 3030, 2919, 1639, 1494, 1452,
1394, 1208, 1093, 913, 742, 698; 1H NMR (300 MHz, CDCl3): d
2.37 (m, 2H), 3.09 (d, J = 6.0 Hz, 1H), 3.52 (q, J = 5.2, 10.5 Hz, 1H),
3.61–3.70 (m, 1H), 4.20–4.62 (m, 4H), 4.87 (dd, J = 3.8, 6.0 Hz,
1H), 5.00–5.12 (m, 2H), 5.74–5.92 (m, 1H), 7.10–7.38 (m,15H);
13C NMR (75 MHz, CDCl3): d 43.9, 72.3 (ꢂ2), 73.9, 78.6, 83.6,
117.5, 126.4 (ꢂ3), 127.4(ꢂ2), 127.8(ꢂ2), 128.1(ꢂ3), 128.3(ꢂ2),
128.4(ꢂ3), 134.7, 137.9, 141.3, 141.7; EI-MS: m/z = 411 [M+Na]+.
HRMS (EI): m/z calcd for C26H28O3Na: 411.1936; found 411.1949.
(1.86 g, 82%) as a liquid. ½a D25
ꢁ
¼ þ26:0 (c 1, CHCl3); IR (neat, cmꢀ1):
mmax 3466, 3071, 3031, 2930, 2859, 1640, 1464, 1392, 1254, 1212,
1097, 1004, 912, 838, 777, 740, 697; 1H NMR (300 MHz, CDCl3): d
0.06 (s, 6H), 0.90 (s, 9H), 2.28 (d, J = 4.2 Hz 1H), 2.33–2.51 (m, 2H),
3.47 (q, J = 6.0, 10.6 Hz, 1H), 3.58–3.66 (m, 2H), 3.69–3.75 (m, 1H),
4.46–4.67 (m, 2H), 5.05–5.15 (m, 2H), 5.81–5.95 (m, 1H), 7.20–7.32
(m, 5H); 13C NMR (75 MHz, CDCl3): d ꢀ5.4 (ꢂ2), 18.2, 25.8 (ꢂ3),
34.7, 63.7, 72.1, 72.4, 78.7, 117.2, 127.6, 127.8 (ꢂ2), 128.3 (ꢂ2),
134.7, 138.4; EI-MS: m/z = 337 [M+1]+. HRMS (EI): m/z calcd for
C19H32O3NaSi: 359.2018; found 359.2033.
4.1.7. (5S,6R,7R,E)-Methyl 5,6-bis(benzyloxy)-7-hydroxy-7-
phenylhept-2-enoate 10
Grubbs’s second generation catalyst (0.05 g, 5 mol %) was
placed in a two-necked flask equipped with nitrogen inlet, a mag-
netic stirring bar, and a rubber septum. A solution of 9 (0.3 g,
0.773 mmol) and methyl acrylate (0.21 mL, 2.32 mmol) in CH2Cl2
(20 mL) was introduced at 40 °C and the resultant pink solution
was stirred for 6 h. When TLC analysis indicated complete con-
sumption of 9, the reaction mixture was exposed to air and con-
centrated. The crude product was purified by column
4.1.5. (2R,3S)-2,3-Bis(benzyloxy)hex-5-en-1-ol 8
To a stirred solution of the compound 6 (1.5 g, 4.46 mmol) in
dry THF (10 mL), sodium hydride (0.214 g, 8.92 mmol), benzyl bro-
mide(0.52 mL, 4.46 mmol), and TBAI (catalytic amount) were
added at 0 °C and stirred at room temperature for 6 h. After com-
pletion of the reaction, THF was evaporated, and the residue was
extracted with CHCl3 (2 ꢂ 30 mL). The chloroform extracts were
dried over anhydrous Na2SO4 and concentrated under reduced
pressure to afford crude 7. This was dissolved in dry THF, cooled
to 0 °C, and TBAF (7.4 mL, 7.4 mmol, 1 M in THF) was added slowly.
chromatography on silica gel (EtOAc–hexane, 3:22) to give
a,b-
unsaturated ester 10 (0.314 g, 91%) as a pale yellow liquid.
½
a 2D5
ꢁ
¼ þ11:0 (c 1, CHCl3); IR (neat, cmꢀ1): mmax 3466, 3061, 3030,
2920, 1721, 1654, 1450, 1395, 1322, 1270, 1209, 1168, 1092,
746, 699; 1H NMR (400 MHz, CDCl3): d 2.48–2.54 (m,2H), 2.98

M. Venkataiah et al. / Tetrahedron: Asymmetry 20 (2009) 2230–2233
2233
(br s, 1H), 3.55 (q, J = 5.8, 10.9 Hz, 1H), 3.62–3.67 (m, 1H), 3.72 (s,
3H), 4.25–4.50 (m, 4H), 4.82 (br s, 1H), 5.80 (d, J = 14.7 Hz, 1H),
6.86–6.94 (m, 1H), 7.15–7.38 (m, 15H); 13C NMR (75 MHz, CDCl3):
d 33.4, 51.5, 70.4, 72.3, 72.4, 74.2, 83.8, 123.2, 126.3, 126.7, 127.1,
127.6, 127.7, 127.8, 127.9, 128.0, 128.12, 128.26, 128.32, 128.38,
128.5(ꢂ3), 131.0, 137.5, 145.5, 145.9, 166.0; EI-MS: m/z = 469
[M+Na]+. HRMS (EI): m/z calcd for C28H30O5Na: 469.1990; found
469.2010.
13.6 Hz, 1H), 2.10 (ddd, J = 2.2, 3.0, 13.6 Hz, 1H), 2.44 (dd, J = 6.0,
15.1 Hz, 1H), 2.60 (dd, J = 6.9, 15.1 Hz, 1H), 3.48 (dd, J = 3.0, 9.8,
Hz, 1H), 3.65 (s, 3H), 4.20–4.23 (m,1H), 4.33–4.44 (m, 1H), 4.53
(d, J = 9.8, Hz, 1H), 7.28–7.40 (m, 5H); 13C NMR (75 MHz, CDCl3):
d 37.1, 40.3, 51.6, 67.0, 68.4, 72.6, 77.7, 127.3, 128.2, 128.4,
139.2, 171.2; EI-MS: m/z = 289 [M+Na]+. HRMS (EI): m/z calcd for
C14H18O5Na: 289.1051; found 289.1062.
Acknowledgment
4.1.8. Methyl 2-((2R,4S,5S,6R)-4,5-bis(benzyloxy)-6-phenyltetra-
hydro-2H-pyran-2-yl)acetate 11
We are thankful to CSIR-New Delhi, and UGC-New Delhi for
financial assistance.
Sodium hydride (60% dispersion in mineral oil, 15 mg) was
added to a solution of compound 10 (0.25 g, 0.56 mmol) in 15 mL
dry THF at ꢀ20 °C. The reaction mixture was allowed to reach room
temperature while stirring, and then stirred at room temperature
for 1 h. The reaction mixture was then cooled in ice and quenched
with 2 mL saturated NH4Cl solution. The solvent was evaporated
under reduced pressure, after which the residue was extracted
with EtOAc (2 ꢂ 15 mL) and dried with anhydrous Na2SO4. After
evaporation of ethyl acetate, the residue was chromatographed
over silica gel (EtOAc–hexane, 15:85) yielding 11 (0.375 g, 90%)
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as a colorless oil. ½a D25
ꢁ
¼ þ28:5 (c 1, CHCl3); IR (neat, cmꢀ1): mmax
3450, 3031, 2922, 2854,1737, 1636, 1452, 1266, 1169, 1077, 748,
697; 1H NMR (300 MHz, CDCl3): d 1.44–1.56 (m, 1H), 2.07–2.17
(m, 1H), 2.39 (dd, J = 6.6, 15.3 Hz, 1H), 2.57 (dd, J = 6.5, 15.3 Hz,
1H), 3.21 (dd, J = 2.6, 9.4 Hz, 1H), 3.65 (s, 3H), 3.89–3.95 (m, 1H),
3.96–4.06 (m, 2H), 4.32–4.44 (m, 1H), 4.67–4.76 (m, 2H), 4.80 (d,
J = 9.7, Hz, 1H), 6.81–6.92 (m, 2H), 7.06–7.18 (m, 2H), 7.19–7.33
(m, 9H), 7.35–7.44 (m, 2H); 13C NMR (75 MHz, CDCl3): d 35.2,
40.5, 51.6, 68.5, 71.4 (ꢂ2), 71.5, 76.6, 80.6, 127.4, 127.5, 127.6
(ꢂ3), 127.7, 127.8 (ꢂ2), 128.0 (ꢂ2), 128.1 (ꢂ2), 128.3 (ꢂ2),
128.5, 137.9, 138.6, 140.3, 171.4; EI-MS: m/z = 469 [M+Na]+. HRMS
(EI): m/z calcd for C28H30O5Na: 469.1990; found 469.1999.
2. Reviews including the synthesis of hydropyrans: (a) Yeung, K. S.; Paterson, I.
Chem. Rev. 2005, 105, 4237–4313; (b) Mulzer, J.; Ohler, E. Chem. Rev. 2003, 103,
3753–3786.
3. (a) (i) Yadav, J. S.; Reddy, B. V. S.; Reddy, Y. J.; Reddy, N. S. Tetrahedron Lett. 2009,
50, 2877–2880; (ii) Kok-Ping, C.; Teck-Peng, L.; Org. Lett. 2005, 7, 4491–4494;
(iii) Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 12216–12217.; (b)
Nobuyuki, K.; Jean-Marie, L.; Masashi, O.; Jun’ichi, U. J. Org. Chem. 2006, 71,
4530–4537; (c) Carreno, M. C.; Mazery, D. S.; Urbano, A.; Colobert, F.; Solladie, F.
J. Org. Chem. 2003, 68, 7779–7787; (d) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M.
E.; Nugiel, D. A.; Abe, Y.; Reddy, K. Bal; DeFrees, S. A.; Reddy, D. R.; Awartani, R.
A.; Conley, S. R.; Rutjes, F. P. J. T.; Theodorakis, E. A. J. Am. Chem. Soc. 1995, 117,
10227–10238.
4. Lan, Y.-H.; Chang, F.-R.; Yang, Y.-L.; Wu, Y.-C. Chem. Pharm. Bull. 2006, 54, 1040–
1043.
5. Yadav, J. S.; Rami reddy, N.; Harikrishna, V.; Subba Reddy, B. V. Tetrahedron Lett.
2009, 50, 1318–1320.
4.1.9. Methyl 2-((2R,4S,5S,6R)-4,5-dihydroxy-6-phenyltetrahy-
dro-2H-pyran-2-yl)acetate 1
A solution of 11 (0.12 g, 0.269 mmol) in ethyl acetate (10 mL)
was stirred with 20 mg of 10% Pd/C under a hydrogen atmosphere
for 4 h. The reaction mixture was filtered and the filtrate was con-
centrated. The crude product was purified on silica gel column
chromatography (EtOAc–hexane, 3:9) to obtain 1 as a white solid
6. Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem. 1995, 60, 585–587.
7. Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104–6107.
8. Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140.
9. (a) For recent examples of the oxy-Michael reaction, see: Reddipalli, G.;
Venkataiah, M.; Mishra, M.K.; Fadnavis, N.W. Tetrahedron: Asymmetry 2009.
doi:10.1016/j.tetasy.2009.07.004.; (b) Edward, A. I. P.; Stephen, M. A.; Jong Ho
Lim, D. J. G.; Moessner, C. Chem. Commun. 2007, 1852–1854; (c) Kigoshi, H.; Kita,
M.; Ogawa, S.; Itoh, M.; Uemura, D. Org. Lett. 2003, 5, 957–960; (d) Kubota, T.;
Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3, 1363–1366; (e) Honda, T.; Ishikawa, F.
J. Org. Chem. 1999, 64, 5542–5546.
(70 mg, 98%). Mp: 90 °C (lit.5 mp. 92 °C); ½a D25
¼ ꢀ28:0 (c 0.5,
ꢁ
CHCl3), lit.5
½
a 2D5
ꢁ
¼ ꢀ27:2 (c 0.3, CHCl3); IR (neat, cmꢀ1): mmax
3432, 2922, 2853, 1733, 1441, 1344, 1286, 1170, 1078, 918, 859,
757, 700, 515; 1H NMR (400 MHz, CDCl3): d 1.74 (ddd, J = 2.2, 3.0,