Stereoselective synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one

Article abstract of DOI:10.1016/j.tetasy.2007.08.020

A stereoselective synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one is reported. The strategy utilizes an olefin cross-metathesis, syn-benzylidene acetal formation and a preferential (Z)-Wittig olefination reaction and lactoniz

Full text of DOI:10.1016/j.tetasy.2007.08.020

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Tetrahedron: Asymmetry 18 (2007) 2197–2200
Stereoselective synthesis of (6S)-5,6-dihydro-6-[(2R)-
2-hydroxy-6-phenylhexyl]-2H-pyran-2-one
Palakodety Radha Krishna* and Ravula Srinivas
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
Received 10 July 2007; accepted 16 August 2007
Abstract—A stereoselective synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one is reported. The strategy
utilizes an olefin cross-metathesis, syn-benzylidene acetal formation and a preferential (Z)-Wittig olefination reaction and lactonization
as the key steps.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
alcohol with benzaldehyde to garner the requisite 1,3-syn-
polyol system. Compound 4 in turn could be derived from
5 by olefin cross-metathesis.
The a-pyrone moiety is one of the most commonly encoun-
tered structural motifs among natural product skeletons,
many of which exhibit varied pharmacological proper-
ties.1a The a-pyrone (6-substituted 5,6-dihydro-2H-pyran-
2-one or a,b-unsaturated-d-lactone) containing natural
products are most often connected through a polyoxygen-
ated chain to a lactone moiety.1b The various biological
activities shown by these compounds include antimicrobial,
antifungal, and cytotoxicity against human tumor cells.2
(6S)-5,6-Dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-
pyran-2-one,3 is one such natural product, which was
isolated from Ravensara crassifolia, the synthesis of which
was reported earlier.4 As a part of our interest in the syn-
thesis of the lactone skeleton containing bioactive natural
products,5 we herein report the stereoselective synthesis
of 1 through an olefin cross-metathesis reaction to obtain
an homoallylic alcohol, which was treated with benzalde-
hyde in presence of potassium tert-butoxide to obtain the
acetal and then its subsequent elaboration to the target
compound.
2. Results and discussion
The synthesis of 1 (Scheme 1) began from commercially
available 5-phenylpentan-1-ol 6. The known homoallyl
alcohol 55a olefin cross-metathesis with ethyl acrylate and
second generation Grubbs’ catalyst6 in dichloromethane
at 40 ꢁC led to unsaturated ester 4 (87%) as the E-isomer
exclusively. Independently, 4 was also realized through
the dihydroxylation/oxidative cleavage, followed by the
Wittig reaction in 65% yield over three steps (E:Z, 95:5
ratio). Later, homoallylic alcohol 4 was treated with benz-
aldehyde in presence of potassium tert-butoxide in THF at
0 ꢁC and pH 7 phosphate buffer to afford benzylidene
acetal 3 (57%).7 The ester function was reduced with
DIBAL–H in dry THF at ꢀ78 ꢁC to afford the aldehyde,
which was then chain-elongated via a Wittig reaction
to give the corresponding a,b-unsaturated ester
2
{(F3CCH2O)2POCH2COOMe, KHMDS, 18-crown-6,
The retrosynthetic analysis envisions that 1 could be
obtained from 2 by functional group transformations and
lactonization, while 2 could in turn be visualized from 3
by reduction and (Z)-selective Wittig olefination.
Compound 3 was obtained by the treatment of homoallyl
THF, ꢀ78 ꢁC, 76% over two steps} predominantly as the
1
Z-isomer,8 as characterized by H and 13C NMR spectro-
scopy. For example the coupling constant (J = 11.3 Hz)
of the olefinic protons confirmed the (Z)-geometry of the
olefin.
*
Finally acid catalyzed (80% aq AcOH) deprotection of
the benzylidene acetal followed by concomitant lactone
Corresponding author. Tel.: +91 40 27160123x2651; fax: +91 40
27160387; e-mail: prkgenius@iict.res.in
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.08.020

2198
P. Radha Krishna, R. Srinivas / Tetrahedron: Asymmetry 18 (2007) 2197–2200
OH
OH
a
ref 5f
CO2Et
Ph
OH
Ph
Ph
4
6
5
b
Ph
Ph
O
O
O
O
d
e
c
CO2Et
Ph
Ph
CO2Me
3
2
O
OH
O
Ph
1
Scheme 1. Reagents and conditions: (a) Ethyl acrylate, Grubbs’-II, CH2Cl2, 40 ꢁC, 12 h, 85%; (b) (i) OsO4, NMO, THF:H2O, rt, 8 h; (ii) NaIO4, NaHCO3,
CH2Cl2, rt, 6 h; (iii) Ph3P@CHCOOEt, benzene, reflux, 1 h (65% over three steps); (c) Benzaldehyde, t-BuOK, THF, pH 7 buffer; 1 h, 57%; (d) (i) DIBAL–
H, CH2Cl2, ꢀ78 ꢁC, 30 min; (ii) (F3CCH2O)2POCH2CO2Me, KHMDS, 18-crown-6, ꢀ78 ꢁC, 1 h (76% over two steps); (e) (i) 80% aq AcOH, 60 ꢁC, 3 h;
(ii) PTSA, benzene, 4 h, 61%.
cyclization with p-toluene sulfonic acid in benzene yielded
at a direct inlet system or LC/MSD Trap SL (Agilent
Technologies).
25
target compound
1
(61%). Mp 33–35 ꢁC; ½aꢁD ¼
25
ꢀ65:5 ðc 0:81; CHCl3Þ; {lit.3 mp 37 ꢁC; ½aꢁD ¼ ꢀ66:0
ðc 2:0; CHCl3Þ}. The physical and spectroscopic data of
1 were identical to the reported values of the natural
product.
4.1.1. Ethyl (E,5R)-5-hydroxy-9-phenyl-2-nonenoate 4.
A
solution of 5 (0.20 g, 0.98 mmol), ethyl acrylate (0.1 mL,
0.98 mmol) and second generation Grubbs’ catalyst
(0.04 g, 0.05 mmol) in anhydrous CH2Cl2 (15 mL) was stir-
red at reflux temperature for 12 h. After completion of the
reaction, the solvent was removed under reduced pressure
and the residue purified by column chromatography (silica
3. Conclusion
gel, EtOAc–hexane, 1:4) to afford 4 (0.204 g, 85%) as a col-
In conclusion, the stereoselective synthesis of 1 has been
accomplished by a versatile strategy wherein an olefin
cross-metathesis reaction, and a benzylidene acetal reac-
tion were effectively utilized for installing the 1,3-syn-polyol
system, followed by the preferential (Z)-Wittig olefination
and lactonization led to the target compound.
25
orless syrup. ½aꢁD ¼ ꢀ13:1 ðc 0:93; CHCl3Þ; 1H NMR
(200 MHz, CDCl3): d 7.25–7.10, (m, 5H), 6.95–6.86 (m,
1H), 5.84 (d, 1H, J 17.3 Hz), 4.18 (t, 2H, J 7.5 Hz), 2.41–
2.08 (m, 2H), 1.71–1.58 (m, 3H), 1.55–1.35 (m, 3H), 1.29
(t, 3H, J 7.5 Hz); 13C NMR (75 MHz, CDCl3): d 164.1,
146.2, 139.5, 129.7, 128.2, 128.1, 126.2, 72.9, 40.9, 36.7,
35.7, 35.5, 31.5, 24.9, 14.4; IR (thin film): 3380, 1721,
1639, 1254 cmꢀ1; LCMS; 299 [M+Na]+. Anal. Calcd for
C14H20O: C, 82.30; H, 9.87. Found: C, 82.28; H, 9.84.
4. Experimental
4.1. General methods
4.1.2. Ethyl (E,5R)-5-hydroxy-9-phenyl-2-nonenoate 4. To
a solution of 5 (0.2 g, 0.98 mmol) in acetone–water (4:1)
was added 5% OsO4 solution in toluene (0.05 mL,
0.01 mmol), after 15 min, an aqueous 50% NMO solution
(0.45 mL, 1.9 mmol) was added and the mixture was stirred
for 12 h. To the solution were added Na2SO3 and Na2SO4.
Then the mixture was filtered through Celite pad, and the
filtrate was evaporated and extracted with ethylacetate
(2 · 15 mL). The combined organic layers were washed
with brine (10 mL), dried over Na2SO4, and concentrated
under reduced pressure to give a residue, which was used
directly for next reaction.
Solvents were dried over standard drying agents and
freshly distilled prior to use. Chemicals were purchased
and used without further purification. All column chro-
matographic separations were performed using silica gel
(Acme’s, 60–120 mesh). Organic solutions were dried over
anhydrous Na2SO4 and concentrated below 40 ꢁC in
vacuo. 1H NMR (200 MHz, 300 MHz, and 400 MHz)
and 13C NMR (50 MHz, 75 MHz and 100 MHz) spectra
were measured with a Varian Gemini FT-200 MHz spec-
trometer, Bruker Avance 300 MHz and Unity 400 MHz
with tetramethylsilane as internal standard for solutions
in deuteriochloroform. J values are given in Hz. IR spectra
were recorded on a Perkin–Elmer IR-683 spectrophoto-
meter with NaCl optics. Optical rotations were measured
with JASCO DIP 300 digital polarimeter at 25 ꢁC. Mass
spectra were recorded on CEC-21-11013 or Fannigan
Mat 1210 double focusing mass spectrometers operating
To a solution of the above obtained triol in CH2Cl2 was
added NaIO4 (0.42 g, 1.9 mmol) and saturated NaHCO3
solution (0.1 mL) and stirred for 6 h. Then the mixture
was added Na2SO4 (0.1 g) and concentrated in vacuo to
afford the crude aldehyde, which was used without purifica-
tion in the next reaction.

P. Radha Krishna, R. Srinivas / Tetrahedron: Asymmetry 18 (2007) 2197–2200
2199
25
To a solution of the aldehyde in benzene (2.0 mL) was
added Ph3P@CH–COOEt (0.41 g, 1.1 mmol) and stirred
at reflux for 1 h. After completion of the reaction, the sol-
vent was removed under reduced pressure and the residue
purified by column chromatography (silica gel, EtOAc–
hexane, 1:99) to afford 4 (0.156 g, 65% over three steps)
as a colorless syrup as an E/Z mixture in a 95:5 ratio.
76%) as
a
light yellow syrup. ½aꢁD ¼ ꢀ11:65
ðc 0:46; CHCl3Þ; 1H NMR (300 MHz, CDCl3): d 7.44–7.40
(m, 2H), 7.35–7.19 (m, 5H), 7.13–7.10 (m, 3H), 6.50–6.40
(m, 1H), 5.85 (d, 1H, J 11.3 Hz), 5.44 (s, 1H), 3.96–3.86
(m, 1H), 3.82–3.71 (m, 1H), 3.69 (s, 3H), 3.12–3.03 (m,
1H), 2.89–2.78 (m, 1H), 2.61 (t, 2H, J 7.5 Hz), 1.70–1.38
(m, 10H); 13C NMR (75 MHz, CDCl3): d 167.0, 146.1,
142.0, 138.7, 133.3, 129.7, 128.7, 128.6, 126.0, 125.5,
121.0, 100.6, 76.0, 74.9, 51.8, 36.7, 35.8, 35.7, 35.2, 31.4,
24.8; IR (neat): 3028, 2856, 1720, 1647, 1254 cmꢀ1; LCMS;
417 [M+Na]+. Anal. Calcd for C25H30O4: C, 76.11; H, 7.66.
Found: C, 76.12; H, 7.63.
4.1.3. Ethyl 2-[(4R,6R)-2-phenyl-6-(4-phenylbutyl)-1,3-di-
oxan-4yl]acetate 3. To a solution of alcohol 4 (0.5 g,
1.81 mmol) in THF (30 mL) at 0 ꢁC was added distilled
benzaldehyde (0.22 mL, 1.99 mmol), followed by t-BuOK
(0.02 g, 0.19 mmol). The yellow solution was stirred for
15 min at 0 ꢁC. The addition of benzaldehyde/t-BuOK
was repeated twice and allowed to warm to room temper-
ature after which the reaction was quenched with of pH
7 phosphate buffer (15 mL). The layers were separated,
and the aqueous layer was extracted with ether
(3 · 15 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo and purified by column chromato-
4.1.5. (6S)-5,6-Dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-
2H-pyran-2-one. Ester 2 (0.2 g, 0.49 mmol) was added to
acetic acid (3 mL, 80% aq AcOH) and stirred for 3 h at
60 ꢁC after which the acetic acid was removed under
reduced pressure. To this was added benzene (2 mL) and
PTSA (0.02 g, cat) and stirred for 4 h. To the reaction
mixture was quenched with aq NaHCO3 (1 mL) and the
aqueous layer was extracted with EtOAc (2 · 1 mL). The
combined organic layers were washed with brine, dried
over Na2SO4, concentrated in vacuo and purified by
column chromatography (EtOAc–hexane, 1:1) to obtain 1
graphy (silica gel, EtOAc–hexane, 1:48) to obtain 3 (0.39 g,
25
57%) as a colorless syrup. ½aꢁD ¼ ꢀ3:6 ðc 0:76; CHCl3Þ;
1H NMR (300 MHz, CDCl3): d 7.44–7.37 (m, 2H), 7.34–
7.20 (m, 5H), 7.15–7.11 (m, 3H), 5.50 (s, 1H), 4.30–4.20
(m, 1H), 4.13 (q, 2H, J 14.3, 6.7 Hz), 3.86–3.77 (m, 1H),
2.68 (dd, 1H, J 15.8, 6.9 Hz), 2.61 (t, 2H, J 7.5 Hz), 2.47
(dd, 1H, J 15.8, 6.0 Hz), 1.70–1.34 (m, 8H), 1.26 (t, 3H, J
6.7 Hz); 13C NMR (75 MHz, CDCl3): d 170.7, 142.7,
138.7, 128.4, 128.3, 128.1, 128.0, 125.9, 125.5, 100.4, 76.4,
73.1, 60.4, 40.1, 36.4, 35.7, 35.6, 31.3, 24.6, 14.1; IR (neat):
2857, 1735, 1268 cmꢀ1; LCMS; 405 [M+Na]+. Anal. Calcd
for C24H30O4: C, 75.36; H, 7.91. Found: C, 75.35; H, 7.90.
(0.08 g, 61%) as a pale yellow solid. Mp 33–35 ꢁC;
25
½aꢁD ¼ ꢀ66:5 ðc 0:81; CHCl3Þ; 1H NMR (300 MHz,
CDCl3): d 7.25–7.08 (m, 5H), 6.89–6.81 (m, 1H), 6.00 (d,
1H, J 9.4 Hz), 4.70–4.65 (m, 1H), 3.92–3.80 (m, 1H),
3.02–2.95 (br s, 1H), 2.61 (t, 2H, J 7.3 Hz), 2.42–2.34 (m,
2H), 2.10–1.60 (m, 4H), 1.60–1.40 (m, 4H); 13C NMR
(100 MHz, CDCl3): d 164.3, 145.2, 142.3, 128.3, 128.2,
125.6, 121.1, 76.5, 68.5, 41.7, 37.3, 35.6, 31.2, 29.2, 24.8;
IR (neat): 3441, 2930, 2856, 1715, 1254 cmꢀ1; LCMS; 297
[M+Na]+. Anal. Calcd for C17H22O3: C, 74.42; H, 8.08.
Found: C, 74.39; H, 8.02.
4.1.4. Methyl (Z)-4-[(4S,6R)-2-phenyl-6-(4-phenylbutyl)-
1,3-dioxan-4-yl]-2-butenoate 2. Ester 3 (0.1 g, 0.26 mmol)
was dissolved in CH2Cl2 (2 mL) and cooled to ꢀ78 ꢁC.
To the solution was added a 2 M solution of DIBAL–H
in hexane (0.08 mL, 0.17 mmol). After 30 min the reaction
was quenched with methanol and potassium sodium
tartrate (1 mL, 1:1). The layers were separated and the
aqueous layer extracted with CH2Cl2 (2 · 2 mL). The
combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated in
vacuo to give the corresponding aldehyde, which was used
directly for further reaction.
Acknowledgement
One of the authors (R.S.) thanks the UGC, New Delhi, for
financial support in the form of a fellowship.
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