The first stereoselective total synthesis of (6S)-5,6-dihydro-6-[(2R)-2- hydroxy-6-phenylhexyl]-2H-pyran-2-one

Article abstract of DOI:10.1016/j.tetlet.2004.10.059

Iterative asymmetric allylations and ring-closing metathesis have been effectively performed for the first stereoselective total synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one, a novel α,β-unsaturated-δ-lactone having antifu

Full text of DOI:10.1016/j.tetlet.2004.10.059

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9299–9301
The first stereoselective total synthesis of (6S)-5,6-dihydro-
6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-oneq
S. Chandrasekhar,* Ch. Narsihmulu, S. Shameem Sultana and M. Srinivasa Reddy
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 August 2004; revised 30 September 2004; accepted 8 October 2004
Abstract—Iterative asymmetric allylations and ring-closing metathesis have been effectively performed for the first stereoselective
total synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one, a novel a,b-unsaturated-d-lactone having
antifungal activity, isolated from Ravensara crassifolia.
Ó 2004 Elsevier Ltd. All rights reserved.
The 6-substituted 5,6-dihydro-2H-pyran-2-ones (a,b-
unsaturated-d-lactones) are important structural sub-
units in many biologically active natural products. These
structural units are important for a wide variety of bio-
logical activities such as plant growth inhibition as well
as antifungal, antifeedent, antibacterial, and antitumour
properties.1 Biological activity, structural uniqueness
and the challenge to synthesize them in optically pure
form have made them attractive targets for many total
syntheses. Due to the significant biological activity of
this class of natural products, several research groups
have reported the synthesis of cryptocaryalactone,2
kurizilactone,3 tetrachloranthuslactone,4 strictifoline,5
boronolide,6 and many others.7 (6S)-5,6-Dihydro-6-
[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one 1 is an
example of this class of natural product, and was iso-
lated by Hostettmann and co-workers,8 from Ravensara
crassifolia. They showed that 1 exhibited antifungal
activity against the phytopathogenic fungus Cladospo-
rium cucumarinum in a bioautographic TLC assay.
The relatively accessible skeleton, strategically fixed syn
1,3-diol system and our interest in the synthesis of bio-
active molecules9 prompted us to investigate and devel-
op a strategy for the synthesis of 1 and also to develop a
general method for installing the 1,3-diol system.
Accordingly, the enantioselective synthesis of com-
pound 1 has been achieved in just eight steps starting
from commercially available 5-phenyl-1-pentanol 2 as
retrosynthetically delineated in (Scheme 1). The asym-
metric Keck allylation10 and analogous Maruoka allyla-
tion11 in highly enantioselective fashion have been
employed including RCM to achieve the target molecule
in 28% overall yield.
The synthesis began with the oxidation of 5-phenyl-1-
pentanol 2 using 2-iodoxybenzoic acid (IBX) to give
5-phenyl-1-pentanal 3. The Maruoka asymmetric allyla-
tion of 3 with titanium complex (S,S)-I gave homoallyl
alcohol 4 in 82% yield and 97% enantiomeric exess.
O
2
1
O
OH
2'
3
4
O
6
6"
3"
5
6'
4'
5"
4"
1"
2"
1'
5'
3'
O
OMOM
Keck allylation
RCM
1
1
8
OMOM
CHO
Keywords: Maruoka asymmetric allylation; Keck asymmetric allyla-
tion; Ring-closing metathesis.
q IICT Communication No. 040816.
Oxidation
OH
6
2
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
27160512; e-mail: srivaric@iict.res.in
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.059

9300
S. Chandrasekhar et al. / Tetrahedron Letters 45 (2004) 9299–9301
O
OH
OH
b
H
a
complex (S ,S )-I
4
3
2
OMOM
OMOM
O
c
H
d
e
6
5
O
OMOM OH
OMOM
O
g
f
7
8
O
O
OiPr
O
OH
O
O
OMOM O
Ti
O
h
O
Ti
iPrO
O
9
1
complex (S ,S )-I
Scheme 2. Reagents, conditions, and yields: (a) IBX, DMSO–THF, rt, 4h, 88%; (b) TiCl4 (5mol%), Ti(OiPr)4 (15mol%), rt, 1h, Ag2O (10mol%), rt,
5h, S-BINNOL (20mol%), rt, 2h, allyltrinbutyltin, 0°C, 12h, 82%; (c) MOMCl, DIPEA, CH2Cl2, 3h, 0°C, 90%; (d) (i) OsO4 (0.5mol%), NMO,
acetone–H2O, rt, 4h, (ii) NaIO4, rt, 2h; (e) Ti(OiPr) (10mol%) S-BINOL (20mol%) S-BINOL (20mol%), rt, 1h, allyltrinbutyltin, CH2Cl2, rt, 12h,
72%; (f) acryolyl chloride, DIPEA, CH2Cl2, rt, 3h, 85%; (g) GrubbsÕ catalyst, (5mol%), DCM, rt, 18h, 80%; (h) 6N HCl–THF–H (1:2:1), rt, 24h,
90%.
The hydroxy functionality of 4 was protected as its
methoxymethyl (MOM) ether 5. The MOM protection
played a crucial role in further transformation as other
protecting groups viz., TBDMS and MPM ethers gave
unsatisfactory results.12 The MOM protecting group
also turned out to be a superior group for the later Keck
allylation. After the dihydroxylation–oxidative cleavage
of MOM ether 5 with OsO4/NMO and NaIO4, the
resulting aldehyde 6 was subjected to asymmetric Keck
allylation to furnish the homoallyl alcohol 7 in an over-
all yield of 72% with a 9:1 syn:anti diastereomeric ratio
resulting over the two steps. The relative stereochemis-
tries of the stereogenic centers at C(20) and C(6) were
deduced from 13C NMR analysis of the corresponding
acetonide derivative.13 The syn relative configuration
of the hydroxy groups was confirmed by analysis of
the 13C NMR spectra which showed signals at 30.2
and 19.7ppm for the two-methyl groups and 98.5ppm
for the quaternary center of the acetonide. The MOM
protected homoallyl alcohol 7 was converted to its
acryolyl ester 8 and subsequent ring closing metathesis
(RCM) using the first-generation GrubbsÕ catalyst14
yielded lactone 9. Finally, deprotection with 1:2:1 (6N
HCl–THF–H2O) gave the target molecule 1. The spect-
1 in eight steps with an overall yield of (28%) (Scheme
2).
Spectral data for selected compounds: compound 4:
25
D
½aꢀ +9.42 (c 0.9, CHCl3); 1H NMR (200MHz, CDCl3):
d 7.28–7.06 (m, 5H), 5.90–5.66 (m, 1H), 5.11 (d, 2H,
J = 11.8Hz), 3.66–3.52 (m, 1H), 2.61 (t, 2H,
J = 7.4Hz), 2.34–2.00 (m, 2H), 1.72–1.34 (m, 6H). 13C
NMR (75MHz, CDCl3): d 142.2, 134.5, 128.0, 127.9,
125.3, 117.6, 70.2, 41.6, 36.2, 35.5, 31.1, 24.9. MS (EI):
m/z M+ 204, 145, 117, 104, 91, 65, 55, and 41.
25
D
Compound 7: ½aꢀ ꢁ26.54 (c 1.2, CHCl3); 1H NMR
(200MHz, CDCl3): d 7.27–7.08 (m, 5H), 5.88–5.72 (m,
1H), 5.08 (d, 2H,J = 15.1Hz), 4.72–4.56 (m, 2H), 3.86–
3.70 (m, 2H), 3.37 (d, 3H, J = 14.2Hz), 2.70–2.55 (m,
2H), 2.24-2.16 (m, 2H), 1.91–1.82 (m, 2H), 1.72–1.50
(m, 5H), 1.41–1.22 (m, 2H). 13C NMR (75MHz,
CDCl3): d 142.3, 134.7, 128.1, 125.8, 117.4, 95.1, 96.9,
70.0, 55.7, 42.0, 40.8, 35.7, 34.1, 30.7, 31.4, and 24.4.
MS (FAB): m/z M+ 292, 261 (M+ꢁOCH3), 233, 189,
171, 155, 137, 109, 95, 81, 69, and 55.
25
Compound 1: ½aꢀ ꢁ58.85 (c 0.65, CHCl3), (lit.
D
25
D
roscopic data (IR, MS, H, and 13C NMR) and [a]D
½aꢀ ꢁ66); 1H NMR (200MHz, CDCl3): d 7.24–7.10
1
were identical to those reported.
(m, 5H), 6.85–6.83 (m, 1H), 5.98 (d, 1H, J = 9.7Hz),
4.73–4.69 (m, 1H), 4.00–3.96 (m, 1H), 2.62 (t, 2H,
J = 7.5Hz), 2.34–2.30 (m, 2H), 1.88–1.71 (m, 2H),
1.65–1.56 (m, 2H), 1.48–1.36 (m, 4H). 13C NMR
(75MHz, CDCl3): d 164.3, 145.3, 142.3, 128.3, 128.2,
In conclusion, we have completed the first total synthesis
of the biologically active natural product (6S)-5,6-dihy-
dro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one

S. Chandrasekhar et al. / Tetrahedron Letters 45 (2004) 9299–9301
9301
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