A concise and efficient synthesis of (5r,7s)-kurzilactone and its (5s,7r)-enantiomer by the mukaiyama aldol reaction

Article abstract of DOI:10.1055/s-0029-1216936

Natural kurzilactone (5R,7S) and its (5S,7R)-enantiomer were synthesized by a convergent approach using a diastereoselective Mukaiyama aldol reaction to construct the anti diol unit. Finally, a ring-closing metathesis reaction led to the target molecule.

Full text of DOI:10.1055/s-0029-1216936

PAPER
3301
A Concise and Efficient Synthesis of (5R,7S)-Kurzilactone and Its
(5S,7R)-Enantiomer by the Mukaiyama Aldol Reaction
(
5
R
,7
S
)-Kurzilacto
o
ne and its (5
w
S
,7
R
)-enantiomer ravaram Sabitha,* Peddabuddi Gopal, C. Nagendra Reddy, Jhillu S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: gowravaramsr@yahoo.com
Received 8 May 2009; revised 22 May 2009
enantiomer (5S,7R)-1. Our strategy involves the stereose-
lective establishment of the C-7 stereogenic center by
means of a Mukaiyama aldol reaction.
Abstract: Natural kurzilactone (5R,7S) and its (5S,7R)-enantiomer
were synthesized by a convergent approach using a diastereoselec-
tive Mukaiyama aldol reaction to construct the anti diol unit. Final-
ly, a ring-closing metathesis reaction led to the target molecule.
O
O
Key words: kurzilactone, Mukaiyama reaction, aldol reaction, ring
closure, metathesis
O
OH
O
5
O
OH
7
O
5
7
Ph
Ph
(5S,7R)-1
(5R,7S)-1
The synthesis of six-membered a,b-unsaturated d-lac-
tones has generated considerable interest because of their
occurrence in large numbers of natural products that pos-
sess potent biological activities. Kurzilactone [(5R,7S)-1]1
is one such lactone isolated from the leaves of Crypto-
carya kurzii, a plant that is indigenous to Malaysia. Kurz-
ilactone exhibits a marked cytotoxicity against the KB
human carcinoma cell line (IC50 = 1 mg mL–1). Initially,
the stereogenic centers bearing hydroxy groups in the side
chain were assigned a syn-relationship through an NMR
experiment, but a corrected anti-relationship with a
(5R,7S) configuration of the C(5) and C(7) stereogenic
centers was later assigned on the basis of a total synthe-
sis.2 The structural uniqueness of kurzilactone, coupled
with its interesting bioactivity and our interest on the syn-
thesis of 6-substituted a,b-unsaturated d-lactones,3
prompted us to explore the synthesis of (5R,7S)-1 and its
Figure 1 Kurzilactone [(5R,7S)-1] and its enantiomer (5S,7R)-1
We began our synthesis of (5R,7S)-1 (Scheme 1) by treat-
ing the known epoxide4 (2S)-2 with vinylmagnesium
bromide in the presence of copper(I) cyanide in tetrahy-
drofuran at –40 °C to give the homoallylic alcohol (3R)-3
in a good yield. Alcohol (3R)-3 was esterified with acry-
loyl chloride in the presence of N,N-diisopropylethyl-
amine and
a
catalytic amount of 4-(dimethyl-
amino)pyridine to give the acryloyl ester (3R)-4 in 75%
yield. Removal of the tetrahydropyranyl group, followed
by oxidation of the resulting alcohol (3R)-5 with 2-iodo-
benzoic acid (IBX), gave the aldehyde (3R)-6. The boron
trifluoride diethyl etherate complex mediated Mukaiyama
aldol reaction of the aldehyde (3R)-6 with the trimethyl-
O
OH
O
O
a
b
THPO
THPO
RO
c
(2S)-2
(3R)-3
(3R)-4, R = THP
(3R)-5, R = H
O
d
O
O
O
g
f
O
OH
O
(5R,7S)-1
(3R)-6
OTMS
Ph
O
e
(4R,6S)-9
Ph
Ph
7
8
Scheme 1 Reagents and conditions: (a) H2C=CHMgBr, CuCN, anhyd THF, –40 °C, 90%; (b) DIPEA, acryloyl chloride, DMAP, anhyd
CH2Cl2, 0 °C to r.t, 30 min., 75%; (c) PPTS, MeOH, r.t, 12 h, 92%; (d) IBX, DMSO, anhyd CH2Cl2, 0 °C to r.t, 36 h, 95%; (e) Et3N, TMSOTf,
anhyd CH2Cl2, –10 °C, 0.5 h, 90%; (f) BF3·OEt2, anhyd CH2Cl2, –78 °C, 1 h, 92%, dr 90:10; (g) Grubbs I catalyst, anhyd CH2Cl2, r.t, 6 h, 95%.
SYNTHESIS 2009, No. 19, pp 3301–3304
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.08.2009
DOI: 10.1055/s-0029-1216936; Art ID: Z09209SS
© Georg Thieme Verlag Stuttgart · New York

3302
G. Sabitha et al.
PAPER
O
O
OH
O
a
b
d
THPO
THPO
RO
c
(2R)-2
(3S)-4, R = THP
(3S)-5, R = H
(3S)-3
O
O
e
f
O
O
OH
O
(5S,7R)-1
8
Ph
O
(3S)-6
(4S,6R)-9
Scheme 2 Reagents and conditions: (a) H2C=CHMgBr, CuCN, anhyd THF, –40 °C, 90%; (b) DIPEA, acryloyl chloride, DMAP, anhyd
CH2Cl2, 0 °C to r.t, 30 min., 75%; (c) PPTS, MeOH, r.t, 12 h, 92%; (d) IBX, DMSO, anhyd CH2Cl2, 0 °C to r.t, 36 h, 95%; (e) BF3·OEt2, anhyd
CH2Cl2, –78 °C, 1 h, 85%, dr 90:10; (f) Grubbs I catalyst, anhyd CH2Cl2, r.t, 6 h, 89%.
(3R)-1-(Tetrahydro-2H-pyran-2-yloxy)-5-hexen-3-ol [(3R)-3]
Br(CH2)2Br (2 drops) and freshly prepared H2C=CHBr (1.0 mL,
13.95 mmol) were added sequentially in a dropwise manner to Mg
turnings (0.33 g, 13.95 mmol) in anhyd THF (25 mL) at r.t. The
mixture was stirred for 0.5 h and then CuCN (10 mg) was added.
The mixture was cooled to –78 °C then a soln of epoxide (2S)-2
(1.20 g, 6.97 mmol) in THF (6 mL) was added, and the mixture to
warmed to –40 °C and stirred for 4 h. The reaction was quenched
with sat. aq NH4Cl (30 mL) and the mixture was extracted with
EtOAc (2 × 20 mL). The combined organic layers were washed
with brine (20 mL), dried (Na2SO4; 1 g), and concentrated under re-
duced pressure. The residue was purified by column chromatogra-
phy to give (3R)-3 as a yellow liquid; yield: 1.25 g (90%); Rf = 0.3
(PE–EtOAc, 7:3); [a]D25 –3.1 (c 1.0, CHCl3).
silyl enol ether 8 derived from (3E)-4-phenylbut-3-en-2-
one (7) gave the aldol adduct (4R,6S)-9 in 92% yield with
good diastereoselectivity (90:10 anti:syn). Subsequent
ring-closing metathesis of the ester in the presence of
Grubbs’ first-generation catalyst in dichloromethane at
room temperature for six hours gave the natural kurzilac-
tone [(5R,7S)-1] in 95% yield. The optical rotation of the
synthetic product (5R,7S)-1 {[a]25D +80 (c 0.2, CHCl3)}
matched the reported value.2
The (5S,7R)-enantiomer of kurzilactone5 was synthesized
in an identical manner, but starting from the known
epoxide4 (2R)-2, as shown in Scheme 2. The optical rota-
tion {[a]D25 –80 (c 0.15 CHCl3)} of the synthetic product
IR (neat): 3444, 2941, 1439, 1127, 1030 cm–1.
(5S,7R)-1 was found to be opposite to that reported for
1H NMR (300 MHz, CDCl3): d = 5.86 (m, 1 H), 5.18–5.06 (m, 2 H),
4.61 (m, 1 H, CH), 4.06–3.78 (m, 3 H), 3.69–3.47 (m, 2 H, CH2),
3.10 (br s, 1 H, OH), 2.27 (t, J = 6.9 Hz, 2 H, CH2), 1.89–1.45 (m,
8 H, 4 × CH2).
13C NMR (75 MHz, CDCl3): d = 134.9, 117.3, 98.9, 70.0, 65.9, 62.3,
41.8, 35.7, 30.5, 25.2, 19.4.
25
natural (5R,7S)-kurzilactone {[a]D
CHCl3)}.
+84 (c 0.231
In conclusion, we have achieved a short and convergent
synthesis of both natural kurzilactone [(5R,7S)-1] and its
enantiomer (5S,7R)-1. The highlight of the total synthesis
is in the use of the Mukaiyama aldol reaction, which gives
the requisite C(7) stereochemistry directly.
HRMS (ESI): m/z [M + Na]+ calcd for C11H20O3Na: 223.131; found:
223.1313 (ppm error: +1.2798).
(3S)-1-(Tetrahydro-2H-pyran-2-yloxy)-5-hexen-3-ol [(3S)-3]
Compound (3S)-3 was similarly obtained as a liquid from (2S)-2;
yield: 90%; [a]D25 +3.0 (c 1.0, CHCl3).
Reactions were conducted under N2 in anhyd solvents such as
CH2Cl2, THF, and EtOAc. All reactions were monitored by TLC
(silica-coated plates, visualization by UV irradiation). Hexane (bp
60–80 °C) was used. Yields refer to chromatographically and spec-
troscopically (1H and 13C NMR) homogeneous materials. Air-sensi-
tive reagents were transferred by syringe or double-ended needle.
Solvents were evaporated at reduced pressure on a Buchi rotary
evaporator. 1H and 13C NMR spectra of samples in CDCl3 were re-
corded on Varian FT-200MHz (Gemini) or Bruker UXNMR FT-
300MHz (Avance) spectrometers. The chemical shift d is reported
relative to TMS (d = 0.0) as an internal standard. Mass spectra were
recorded under EI conditions at 70 eV on an LC-MSD (Agilent
Technologies) spectrometer. All high-resolution spectra were re-
corded on a QSTAR XL hybrid MS/MS system (Applied Biosys-
tems/MDS Sciex, Foster City, USA) equipped with an ESI source
(IICT, Hyderabad). Column chromatography was performed on sil-
ica gel (60–120 mesh) supplied by Acme Chemical Co., India. TLC
was performed on Merck 60 F-254 silica gel plates. Optical rota-
tions were measured with a Jasco DIP-370 polarimeter at 20 °C.
(3R)-1-(Tetrahydro-2H-pyran-2-yloxy)hex-5-en-3-yl Acrylate
[(3R)-4]
Acryloyl chloride (0.34 g, 3.75 mmol) was added dropwise under
N2 to a soln of alcohol (3R)-3 (0.75 g, 3.75 mmol), DIPEA (0.70
mL, 5.62 mmol), and DMAP (0.05 mmol) in anhyd CH2Cl2 (10
mL). The mixture was stirred at r.t. for 30 min until the reaction was
complete (TLC). The mixture was then poured into brine and ex-
tracted with CH2Cl2 (2 × 20 mL). The organic phases were washed
with 1 M aq HCl (5 mL) and brine (8 mL), dried (Na2SO4; 1 g), and
evaporated under reduced pressure.
The crude product was purified by column chromatography to give
(3R)-4 as a liquid; yield: 0.71 g (75%); Rf = 0.5 (PE–EtOAc, 9:1);
[a]D25 –15.3 (c 1.0, CHCl3).
IR (neat): 2944, 1724, 1406, 1195, 1037 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.39 (td, J = 1.1, 17.1 Hz, 1 H),
6.17–6.04 (m, 1 H), 5.86–5.70 (m, 2 H), 5.17 (m, 1 H, CH), 5.14–
5.04 (m, 2 H), 4.56 (td, J = 3.5, 15.4 Hz, 1 H, CH), 3.89–3.73 (m, 2
Synthesis 2009, No. 19, 3301–3304 © Thieme Stuttgart · New York

PAPER
(5R,7S)-Kurzilactone and Its (5S,7R)-Enantiomer
3303
H, CH2), 3.54–3.34 (m, 2 H, CH2), 2.49–2.32 (m, 2 H, CH2), 1.97–
1.44 (m, 8 H, 4 × CH2).
13C NMR (75 MHz, CDCl3): d = 165.6, 133.2, 130.4, 128.6, 117.8,
98.7, 70.9, 63.6, 61.9, 38.7, 33.5, 30.5, 25.3, 19.3.
HRMS (ESI): m/z [M + Na]+ calcd for C14H22O4Na: 277.1415;
found: 277.1418 (ppm error: +0.7969).
soln was stirred at –78 °C for 1 h. The reaction was quenched by ad-
dition of sat. aq NaHCO3 (3 mL), and the mixture was extracted
with CHCl3 (2 × 20 mL). The combined organic extracts were dried
(Na2SO4; 1 g), filtered, and concentrated. The residue was purified
by column chromatography to give (4R,6S)-9; yield: 0.257 g (92%);
Rf = 0.3 (PE–EtOAc, 3:2); [a]D25 –15.0 (c = 1, CHCl3).
IR (neat): 3478, 1717, 1646, 1609, 1576, 1406, 1273, 1198, 1050
cm–1.
(3S)-1-[2-(Tetrahydro-2 H-2-pyranyloxy)ethyl]-3-butenyl
Acrylate [(3S)-4]
1H NMR (300 MHz, CDCl3): d = 7.60–7.48 (m, 3 H), 7.42–7.33 (m,
3 H), 6.68 (dd, J = 5.2, 16.6 Hz, 1 H), 6.40 (ddd, J = 1.5, 9.0, 17.3
Hz, 1 H), 6.16–6.03 (m, 1 H), 5.86–5.68 (m, 2 H), 5.27–5.03 (m, 3
H), 4.16 (m, 1 H), 3.41 (br s, 1 H, OH), 2.99–2.66 (m, 2 H), 2.52–
2.35 (m, 2 H), 1.97–1.66 (m, 2 H).
Compound (1S)-4 was similarly obtained as a liquid from (3S)-3;
yield: 75%; [a]D25 +15.0 (c 1.0, CHCl3).
(3R)-1-Hydroxyhex-5-en-3-yl Acrylate [(3R)-5]
A catalytic amount of PPTS was added to a stirred soln of ester
(3R)-4 (0.61 g, 2.4 mmol) in MeOH (20 mL) under N2, and the mix-
ture was stirred for 12 h at r.t. The reaction was quenched with solid
NaHCO3 (1 g), and the mixture was filtered. The solvent was re-
moved under reduced pressure and the residue was purified by silica
gel column chromatography to give compound (3R)-5 as a pale yel-
low liquid; yield: 0.37 g (92%); Rf = 0.4 (PE–EtOAc, 7:3); [a]D
–17.0 (c = 1, CHCl3).
IR (neat): 3427, 1721, 1407, 1295, 1197, 1052 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.42 (dd, J = 1.5, 17.3 Hz, 1 H),
6.16–6.05 (m, 1 H), 5.88–5.68 (m, 2 H), 5.20–5.08 (m, 2 H), 5.06
(m, 1 H), 3.67–3.45 (m, 2 H), 2.47 (br s, 1 H, OH), 2.39 (m, 2 H),
1.94–1.82 (m, 1 H), 1.75–1.63 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 200.0, 166.0, 143.6, 134.1, 133.2,
131.0, 130.7, 130.6, 128.9, 128.3, 126.2, 118.1, 70.7, 64.6, 46.6,
40.5, 38.9.
HRMS (ESI): m/z [M + Na]+ calcd for C19H22O4Na: 337.1415;
found: 337.1405 (ppm error –3.200).
25
(4S,6R,9E)-6-Hydroxy-8-oxo-10-phenyldeca-1,9-dien-4-yl
Acrylate [(4S,6R)-9]
Compound (4S,6R)-9 was similarly obtained as a liquid from (3S)-
6; yield: 85%; [a]D25 +15.8 (c = 1, CHCl3).
(6R)-6-[(2S,5E)-2-Hydroxy-4-oxo-6-phenylhex-5-en-1-yl]-5,6-
dihydro-2H-pyran-2-one [Kurzilactone; (5R,7S)-1]
Grubbs’ first-generation catalyst (0.033 g, 0.0415 mmol) was added
to a soln of (4R,6S)-9 (0.132 g, 0.415 mmol) in anhyd CH2Cl2 (15
ml) at 0 °C, and the mixture was allowed to warm to r.t. over 6 h.
After completion of the reaction (TLC), the solvent was removed
under reduced pressure and the residue was purified by column
chromatography to give (5R,7S)-1 as a solid; yield: 0.114 g (95%);
mp 74–76 °C; Rf = 0.4 (PE–EtOAc, 1:4); [a]D25 +80 (c 0.2, CHCl3).
13C NMR (75 MHz, CDCl3): d = 166.4, 133.1, 131.0, 128.2, 117.8,
70.7, 58.2, 38.7, 36.6.
HRMS (ESI): m/z [M + Na]+ calcd for C9H14O3Na: 193.0840;
found: 193.0849 (ppm error +4.3287).
(3S)-1-Hydroxyhex-5-en-3-yl Acrylate [(3S)-5]
Compound (3S)-5 was similarly obtained as a liquid from (3S)-4;
yield: 92%; [a]D25 +17.0 (c = 1, CHCl3).
IR (neat): 3447, 1712, 1652, 1606, 1386, 1253, 1178, 1051 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.58 (d, J = 16 Hz, 1 H), 7.54–7.39
(m, 5 H), 6.90 (m, 1 H), 6.73 (d, J = 16 Hz, 1 H), 6.00 (dd J = 2, 10
Hz, 1 H), 4.77 (m, 1 H), 4.5 (m, 1 H), 3.52 (br s, 1 H, OH), 2.93 (dd,
J = 2.8, 17.4 Hz, 1 H), 2.81 (dd, J = 8.8, 17.5 Hz, 1 H), 2.39 (m, 2
H), 1.88 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 200.4, 164.2, 145.1, 144.0, 134.1,
130.9, 129.0, 128.5, 126.1, 121.5, 75.0, 64.2, 46.9, 41.7, 30.0.
(3R)-1-Oxohex-5-en-3-yl Acrylate [(3R)-6]
A soln of alcohol (3R)-5 (0.3 g, 1.76 mmol) in anhyd CH2Cl2 (8 mL)
was added to an ice-cooled soln of 2-iodoxybenzoic acid (0.71 g,
1.65 2.64 mmol) in anhyd DMSO (2.0 mL). The mixture was stirred
at r.t. for 12 h then filtered through a pad of Celite that was subse-
quently washed with Et2O (10 mL). The combined organic filtrates
were washed with H2O (2 × 5 mL) and brine (5 mL), dried (Na2SO4;
1 g), and concentrated in vacuo. The residue was purified by column
chromatography to give (3R)-6; yield: 0.281 g (95%); Rf = 0.5 (PE–
EtOAc, 9:1).
HRMS (ESI): m/z [M + Na]+ calcd for C17H18O4Na: 309.1102;
found: 309.1094 (ppm error –2.8435).
(6S)-6-[(2R,5E)-2-Hydroxy-4-oxo-6-phenylhex-5-en-1-yl]-5,6-
dihydro-2H-pyran-2-one [(5S,7R)-1]
IR (neat): 1722, 1407, 1191, 985 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.75 (m, 1 H, CHO), 6.39 (dd,
J = 1.3, 17.3 Hz, 1 H), 6.09 (dd J = 10.3, 17.1 Hz, 1 H), 6.0–5.8 (m,
2 H), 5.25–5.12 (m, 3 H), 3.22 (d, J = 6.9 Hz, 2 H, CH2), 2.83 (t,
J = 6.4 Hz, 2 H, CH2).
13C NMR (75 MHz, CDCl3): d = 205.3, 165.9, 130.9, 129.9, 128.1,
119.2, 59.2, 47.9, 40.8.
Compound (5S,7R)-1 was similarly obtained as a liquid from
(4S,6R)-9; yield: 89%; [a]25D –78 (c 0.2, CHCl3).
Acknowledgment
P.G. thanks CSIR, and C.N.R. thanks UGC, New Delhi, for awards
of fellowships.
+
MS (ESI, 70 eV): m/z 186 [M + NH4 ].
(3S)-1-Oxohex-5-en-3-yl Acrylate [(3S)-6]
Compound (3S)-6 was similarly obtained as a liquid from (3S)-5;
yield: 95%.
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Synthesis 2009, No. 19, 3301–3304 © Thieme Stuttgart · New York