Titanocene (III) chloride mediated radical induced synthesis of (-)-methylenolactocin and (-)-protolichesterinic acid

Article abstract of DOI:10.1016/j.tet.2010.04.058

Enantioselective synthesis of two anti-tumor antibiotics, (-)-methylenolactocin and (-)-protolichesterinic acid, has been achieved through titanocene(III) chloride mediated radical cyclization reaction starting from commercially available d-mannitol. Tita

Full text of DOI:10.1016/j.tet.2010.04.058

Tetrahedron 66 (2010) 4278e4283
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Titanocene (III) chloride mediated radical induced synthesis
of (ꢀ)-methylenolactocin and (ꢀ)-protolichesterinic acid
*
Sumit Saha, Subhas C. Roy
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India.
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective synthesis of two anti-tumor antibiotics, (ꢀ)-methylenolactocin and (ꢀ)-proto-
Received 10 March 2010
Received in revised form 8 April 2010
Accepted 13 April 2010
lichesterinic acid, has been achieved through titanocene(III) chloride mediated radical cyclization re-
action starting from commercially available
in situ from commercially available titanocene dichloride (Cp2TiCl2) and zinc dust in THF.
Ó 2010 Elsevier Ltd. All rights reserved.
D-mannitol. Titanocene(III) chloride (Cp2TiCl) was prepared
Available online 24 April 2010
Keywords:
Enantioselective
Titanocene(III) chloride
Radical
Methylenolactocin
Protolichesterinic acid
1. Introduction
sp.3,4,6f and protolichesterinic acid with antibacterial properties
was isolated from Cetrariaislandica.4,6f Both of them are effective
in inhibiting the growth of gram positive bacteria. A number of
reports has been found in the literature for the synthesis of
methylenolactocin and protolichesterinic acid in racemic5 as well
as in optically active forms.6 But most of the reported asymmetric
methods suffer from generality, use of toxic reagents, number of
steps, and moderate yield. It is noteworthy that although
(þ)-protolichesterinic acid is widely distributed in Parmelia sp.,
but both (þ) and (ꢀ) antipodes have been isolated from different
sources of Cetraria.6h
The radical chemistry in organic synthesis has become an in-
evitable tool in recent years due to the mildness and desired stereo-
chemical outcome. Due to several difficulties associated with the use
of tributyltin hydride as a radical source, titanocene(III) chloride
(Cp2TiCl) has widely been explored for the homolytic cleavage of
epoxides to generate a carbon-centered radical, which has sub-
sequently been used for the synthesis of complexorganic molecules.7
Titanocene(III) chloride (Cp2TiCl) was prepared from commercially
available titanocene dichloride and zinc dust inTHF.7a In continuation
to our studies8 toward the synthesis bioactive natural products, we
have now achieved the total synthesis (ꢀ)-methylenolactocin (1a)
and (ꢀ)-protolichesterinic (1b) through radical cyclization reaction
using titanocene(III) chloride as the radical initiator.
The a-methylene-g-butyrolactone ring system is an important
building block for a major class of biologically active natural
products.1 The biological activities of such compounds may be at-
tributed to the
as a Michael acceptor of different biological nucleophiles. Paraconic
acid2 is probably one of the simple classes of naturally occurring
a,b-unsaturated carbonyl moiety, which mainly acts
g-
butyrolactone derivative with a carboxylic acid group at C-4 posi-
tion with an exo-methylene or methyl group at C-3 position. But
substitution pattern varies at C-5 and obviously stereochemical
relationship also varies with the substituent on the adjacent car-
bon.2 Most of these densely functionalized paraconic acid mole-
cules are biologically active and some of them are isolated in both
optically active form.
Since, aforesaid compounds exhibit important biological ac-
tivities such as antifungal, anti-tumor, antibacterial etc., the
synthesis of such lactones have attracted considerable attention
to the organic chemists. Therefore, designing a general strategy
for the synthesis of such densely functionalized molecules in
both active forms is still desirable. We report here mainly the
synthesis of two paraconic acids, (ꢀ)-methylenolactocin and
(ꢀ)-protolichesterinic acid through radical cyclization reaction
starting from the easily accessible (R)-2,3-O-cyclohexylidene-
glyceraldehyde. Methylenolactocin, an isomerization prone anti-
tumor antibiotic was isolated from culture filtrate of Penicilium
2. Results and discussion
Thus, (R)-2,3-O-cyclohexylideneglyceraldehyde (2) on treat-
ment with appropriate Grignard reagent (RMgX)9 yielded the
* Corresponding author. E-mail address: ocscr@iacs.res.in (S.C. Roy).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.058

S. Saha, S.C. Roy / Tetrahedron 66 (2010) 4278e4283
4279
M
R
HOOC
M R
H
H
3
H
4
2
H
.
.
O
O
O
R
R
O
O
5
M
O
O
O
M
R
R = C5H11, (-)-Methylenolactocin (1a)
R = C13H27, (-)-Protolichesterinic acid (1b)
anti-CRAM
CRAM
diasteromeric alcohols 3a (mixture of two isomers, ratio 2.5:1) or
3b (mixture of two isomers, ratio 3:0.8). The pure major isomer 3a1
or 3b1 was separated by column chromatography and was reacted
with propargyl bromide in the presence of NaH in HMPA/THF to
furnish the propargyl ether 4a1 or 4b1 in good yield (Scheme 1).10
The erythro-selectivity of the addition of Grignard reagent with
Figure 1.
treatment with NaH in THF furnished the epoxide 7. The epoxide 7
was subjected to radical cyclization reaction using Cp2TiCl in THF to
produce the tetrahydrofuran derivative 8 as a mixture two isomer
(trans/cis, 5:1) (Scheme 2). At this stage, two isomers could not be
separated by usual chromatographic methods. The crude cyclized
product 8 was then converted to the corresponding THP-ether 9
with dihydropyran and PPTS in CH2Cl2 in excellent yield. The crude
THP-ether 9 was then subjected to PDC oxidation in DMF to yield
the butyrolactone 10 as a mixture of two isomers in a ratio of 5:1.
Without further separating two isomers the crude lactone 10 was
treated with PTS-OH in MeOH to furnish the alcohol 11. The crude
alcohol 11 was subjected to Jones oxidation12 and the crude product
obtained after usual work-up was treated with 6 M HCl in benzene/
THF (1:1) mixture to furnish solely the trans isomer 1. Probably, in
strong acidic conditions epimerization13 took place to give the
thermodynamically more stable (ꢀ)-methyleneolactocin (1a) from
11a1 and (ꢀ)-protolicheterinic acid (1b) from 11b1 in good overall
yield. Fortunately, no trace of the isomerization of the exo double
bond was observed in the crude product under the acidic condition.
i. RMgBr
+
O
O
O
O
O
O
ii. NH4Cl
55-60%
R
R
H
H
H
OH
OH
O
3a, R=C5H11, (ratio 2.5:1)
3b, R=C13H27, (ratio 3:0.8)
2
Pure major stereomer
was separated by
column
O
O
Br
Chromatography
NaH /
R
HMPA, Δ, 4 h
OH
H
Cp2TiCl
THF
OH
O
DHP, PPTS
90%
80%
3a1, R=C5H11
R
3b1, R=C13H27
65%
H
O
R
O
HO
TsCl / Py
7a1, R = C5H11
7b1, R = C13H27
OH
Trans:Cis = 5:1
O
8a1, R = C5H11
O
aq. TFA
in DCM
Overnight
R
8b1, R = C13H27
rt, 12 h
70%
R
H
O
OTHP
OTHP
70%
H
O
TsOH
PDC / DMF
5a1, R=C5H11
5b1, R=C13H27
MeOH
4a1, R=C5H11
4b1, R=C13H27
Mol sieve 4A0
60%
85%
O
R
O
R
O
9a1, R = C5H11
O
10a1, R = C5H11
TsO
NaH / THF
at 0 0C
OH
9b1, R = C13H27
10b1, R = C13H27
R
R
OH
HOOC
H
O
rt, overnight
80%
i. Jones Oxidn
H
O
ii. 6M HCl
70 %
O
7a1, R=C5H11
7b1, R=C13H27
6a1, R=C5H11
6b1, R=C13H27
R
O
O
R
O
1a, R = C5H11, (-)Methylenolactocin
1b, R = C11H27, (-) Protolichesterinic acid
11a1, R = C5H11
Scheme 1.
11b1, R = C13H27
the aldehyde 2 to afford 3a1 or 3b1 as the major product can be
explained with the analogy reported by Mulzer et al.11 Not only the
bulky cyclohexylidene moiety but also the metal used (magnesium)
control the nucleophilic attack at Si face (Cram direction) at the
neighboring prochiral carbonyl center of 2 favoring the formation
of 3a1 or 3b1 (Fig.1). Deprotection of the cyclohexylidene group in 4
using aqueous TFA yielded the diol 5. Selective monotosylation of
the primary alcohol in 5 by TsCl and excess of pyridine in CH2Cl2
produced the tosyl derivative 6 in good yield. Compound 6 on
Scheme 2.
3. Conclusions
In conclusion, we have synthesized two anti-tumor antibiotics (ꢀ)
methylenolactocin and (ꢀ) protolichesterinic acid through radical
cyclization reaction starting from inexpensive
D-mannitol as a
chiral pool using titanocene(III) chloride as a radical initiator.
We believe that by applying the same synthetic sequences,

4280
S. Saha, S.C. Roy / Tetrahedron 66 (2010) 4278e4283
(þ)-methylenolactocin and (þ)-protolichesterinic acid can also be
synthesized starting with the minor isomer of 3a and 3b, respectively.
34.9, 36.6, 65.8, 72.4, 81.1, 109.9; HRMS calcd for C14H26O3Na
[MþNa]þ 265.178, found 265.170.
4. Experimental
4.1. General
4.1.2. Synthesis of 4a1 and 4b1. To a stirred suspension of sodium
hydride (595 mg, 60% dispersion, 24.8 mmol) in a mixture of dry
THF (25 mL) was added dropwise a solution of alcohol 3a1 (1.5 g,
6.2 mmol) in dry THF (25 mL) at 0 ꢁC under N2. Then HMPA (0.5 mL)
was added to the reaction mixture. Then, a solution of propargyl
bromide (950 mg, 8.06 mmol) in dry THF (20 mL) was added
dropwise at 0 ꢁC over 30 min. The reaction mixture was refluxed for
4 h and then stirred overnight at room temperature. The reaction
mixture was then carefully quenched with ice-water. After removal
of most of THF under reduced pressure, the resulting residue was
extracted with diethyl ether (3ꢂ30 mL). The combined ether ex-
tract was washed with water (10 mL), brine (5 mL), and finally
dried (Na2SO4). Removal of the solvent under reduced pressure
afforded a viscous liquid, which was purified by column chroma-
tography over silica gel (5% ethyl acetate/light petroleum, Rf¼0.76)
Melting points were determined in open capillary tubes and are
uncorrected. 1H NMR and 13C NMR spectra were recorded in CDCl3
with Bruker DPX 300 and Bruker AVANCE III 500 spectrometer
using tetramethyl silane as the internal standard. IR spectra were
recorded on Shimadzu FT IR-8300. Column chromatography was
performed on silica gel (60e120 mesh) and preparative TLC was
performed using pre-coated silica 60 F 254 plates (0.2 mm). High-
resolution mass spectra were obtained using a Qtof Micro YA263
instrument. Diethyl ether and tetrahydrofuran were freshly dis-
tilled from sodium. Methylene chloride was freshly distilled over
calcium hydride. Light petroleum of boiling range 60e80 ꢁC was
used for chromatography. Elemental analyses were done in the
Inorganic Chemistry Department of this Institute using 2400 Series
II CHNS analyzer.
to furnish 4a1 (1.4 g, 80%) as a viscous liquid. [
a]
25.0 þ1.24 (c, 6.07 in
D
CHCl3); IR (neat): 3310, 2935, 2115, 1448, 1163, 1101 cmꢀ1; 1H NMR
(300 MHz, CDCl3):
d
0.87 (t, J¼6.7 Hz, 3H), 1.30e1.63 (m, 18H), 2.41
(t, J¼2.4 Hz, 1H), 3.60e3.65 (m, 1H), 3.88e3.97 (m, 1H), 3.99e4.08
4.1.1. Synthesis of 3a1 and 3b1. To a stirred solution of Grignard
reagent at ꢀ50 ꢁC [prepared by the treatment of the halide (RX)
(0.075 mol) with a suspension of Mg (1.92 g, 0.08 g equiv) in THF
(100 mL)] was added 2 (5.1 g, 0.03 mol) in THF (60 mL) over a pe-
riod of 1 h. The mixture was stirred at ꢀ50 ꢁC for 3 h at room
temperature overnight. Saturated aqueous NH4Cl was added to the
reaction mixture followed by extraction with ether (3ꢂ10 mL). The
combined organic layer was washed with water (10 mL) and brine
(5 mL), and finally dried (Na2SO4). The solvent was evaporated
under reduced pressure and the residue was purified by column
chromatography over silica gel (15% ethyl acetate/light petroleum,
(m, 2H), 4.29 (d, J¼2.4 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 14.2,
22.7, 24.0, 24.2, 24.9, 25.3, 31.2, 32.1, 35.1, 36.3, 58.1, 65.7, 74.1, 77.6,
78.5, 80.5, 109.7; HRMS calcd for C17H28O3Na [MþNa]þ 303.1936,
found 303.1937.
Compound 4b1 (72%) was prepared from 3b1 following the
similar procedure described for the 4a1. Rf¼0.50 (2% ethyl acetate/
27.1
light petroleum); [
a
]
¼þ2.51 (c, 4.95 in CHCl3); IR (neat): 3312,
D
2926, 2852, 2115, 1464, 1448, 1101 cmꢀ1
CDCl3):
0.81 (t, J¼6.5 Hz, 3H), 1.19e1.56 (m, 35H), 2.34 (t, J¼2.4 Hz,
1H), 3.53e3.56 (m, 1H), 3.81e3.99 (m, 2H), 4.21 (d, J¼2.4 Hz, 2H);
13C NMR (75 MHz, CDCl3):
14.1, 22.7, 23.8, 24.0, 25.1, 25.2, 29.3,
;
1H NMR (300 MHz,
d
d
Rf¼0.70) to afford resulting in separation of the pure major isomer
29.5, 29.6, 29.6, 31.1, 31.9, 34.9, 36.1, 58.0, 65.5, 73.9, 77.5, 78.3, 80.4,
109.5; HRMS calcd for C25H44O3Na [MþNa]þ 415.3188, found
415.3187.
25.7
3a1 (3.0 g, 43%) as a viscous oil. [
a]
ꢀ8.70 (c, 4.32 in CHCl3); IR
D
(neat): 3491, 2900, 1464, 1448, 1043 cmꢀ1
CDCl3):
0.81 (t, J¼6.5 Hz, 3H), 1.12e1.57 (m, 18H), 3.64e3.72 (m,
2H), 3.80e3.90 (m, 1H), 3.94e4.09 (m, 1H); 13C NMR (125 MHz,
;
1H NMR (500 MHz,
d
4.1.3. Synthesis of 5a1 and 5b1. Compound 4a1 (1.0 g, 3.6 mmol)
was stirred with wateretrifluoroacetic acid (1:2) for 12 h at room
temperature. The reaction mixture was extracted with ethyl acetate
(3ꢂ30 mL) and the combined organic layer was washed with brine
(5 mL) then dried over Na2SO4. Solvent was removed under re-
duced pressure and the residue obtained was chromatographed
over silica gel (50% ethyl acetate/light petroleum, Rf¼0.44) to fur-
CDCl3): d 14.0, 22.6, 23.8, 23.9, 25.0, 25.2, 25.6, 25.8, 31.8, 32.7, 34.9,
36.2, 64.2, 70.8, 78.4, 109.5; HRMS calcd for C14H26O3Na [MþNa]þ
265.178, found 265.178.
4.1.1.1. Minor isomer of 3a. Yield 17%. Rf¼0.79 (15% ethyl ace-
tate/light petroleum); [
a
]
D
26.0 þ6.2 (c, 1.60 in CHCl3); IR (neat): 3462,
3316, 2950, 1454, 1272, 1109 cmꢀ1
;
1H NMR (300 MHz):
d
0.88 (t,
nish the diol 5a1 (535 mg, 75%) as a viscous oil. [
in CHCl3); IR (neat): 3408, 3308, 2955, 2860, 2115, 1456, 1261,
a]
27.8 þ21.41 (c,1.66
D
J¼6.7 Hz, 3H), 1.25e1.42 (m, 24H), 1.59e1.84 (m, 13H), 3.54e3.60
(m, 1H), 3.71e3.87 (m, 2H), 3.93e4.03 (m, 1H); 13C NMR (75 MHz):
1089 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
0.88 (t, J¼7 Hz, 3H),
d
14.2, 22.8, 23.9, 24.0, 24.0, 25.9, 26.8, 29.5, 29.6, 29.7, 29.8, 32.0,
1.27e1.36 (m, 6H), 1.42e1.62 (m, 2H), 2.45 (t, J¼2.3 Hz, 1H), 2.56 (br
32.8, 35.0, 36.8, 37.1, 62.4, 76.6, 81.3, 109.2; HRMS calcd for
s, 2H), 3.61e3.61 (m, 1H), 3.68e3.75 (m, 3H), 4.20 (dd, J¼2.5, 16 Hz,
C22H42O3Na [MþNa]þ 337.3032, found 337.3030.
1H), 4.29 (br d, J¼16 Hz, 1H); 13C NMR (125 MHz, CDCl3):
d 14.1,
Compound 3b1 (43.4%) was prepared following the same pro-
cedure described for 3a1: Rf¼0.40 (5% ethyl acetate/light petro-
22.7, 25.1, 30.4, 32.1, 57.9, 63.3, 72.8, 74.7, 80.2, 81.0; HRMS calcd for
C11H20O3Na [MþNa]þ 223.131, found 223.1312.
leum); [
a
]
26.2 ꢀ5.45 (c, 1.91 in CHCl3); IR (neat): 3454, 3300, 2900,
Compound 5b1 prepared from 4b1 following the similar pro-
cedure described for 5a1 (70%) as a crystalline solid. Rf¼0.24 (30%
D
1464, 1448, 1280, 1101 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
0.89 (t,
J¼6.5 Hz, 3H), 1.26e1.44 (m, 26H), 1.45e1.65 (m, 8H), 3.77e3.81 (m,
ethyl acetate/light petroleum). Mp 53e55 ꢁC (ethyl acetate/light
1H), 3.87e3.90 (m, 1H), 3.94e3.96 (m, 1H), 4.01e4.04 (m, 1H); 13C
petroleum); [
a
]
þ9.12 (c, 7.10 in CHCl3); IR (KBr): 3367, 3265,
25.7
D
NMR (75 MHz, CDCl3):
d
14.2, 22.8, 23.9, 24.1, 25.3, 25.9, 29.5, 29.6,
2918, 2125, 1462, 1091 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
0.81 (t,
29.7, 29.8, 32.0, 32.7, 35.0, 36.3, 64.2, 70.8, 78.4, 109.5; HRMS calcd
J¼7 Hz, 3H),1.16e1.23 (m, 21H),1.38e1.40 (m, 3H), 2.39 (t, J¼2.5 Hz,
for C22H42O3Na [MþNa]þ 377.3032, found 377.3035.
1H), 3.56e3.72 (m, 4H), 4.14 (dd, J¼2.5 Hz, 16 Hz, 1H), 4.23 (dd,
J¼2.5 Hz, 16 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 14.2, 22.8, 25.4,
4.1.1.2. Minor isomer of 3b. Yield 11.6%. Rf¼0.48 (5% ethyl ace-
29.1, 29.4, 29.6, 29.7, 29.9, 29.9, 30.1, 30.3, 32.0, 45.0, 57.8, 62.0, 63.3,
72.9, 74.6, 80.7; HRMS calcd for C19H36O3Na [MþNa]þ 335.2562,
found 335.2565.
24.4
tate/light petroleum); [
a]
þ11.4 (c, 1.00 in CHCl3); IR (neat):
D
3450, 2933, 2860, 1448, 1280, 1101 cmꢀ1
0.82 (t, J¼6.6 Hz, 3H), 1.14e1.34 (m, 8H), 1.36e1.80 (m, 10H),
3.41e3.62 (m, 1H), 3.64e3.70 (m, 2H), 3.87e3.96 (m, 1H); 13C NMR
(75 MHz): 14.0, 22.5, 23.8, 24.0, 24.3, 25.1, 25.6, 26.8, 31.8, 33.3,
;
1H NMR (300 MHz):
d
4.1.4. Synthesis of 6a1 and 6b1. To a stirred solution of 5a1 (930 mg,
4.65 mmol) and excess of pyridine (3 ml) in dry CH2Cl2 (20 mL) at
d

S. Saha, S.C. Roy / Tetrahedron 66 (2010) 4278e4283
4281
0 ꢁC was added p-toluenesulfonyl chloride (1.06 g, 5.58 mmol) in
portions during 1 h. After stirring for 12 h at room temperature, the
mixture was poured into ice-water. The organic layer was sepa-
rated, and the aqueous portion was extracted with CH2Cl2
(3ꢂ30 mL). The combined organic extract was washed successively
with aqueous 2 M HCl (5 mL), water (5 mL), brine (5 mL), and fi-
nally dried (Na2SO4). Removal of the solvent under reduced pres-
sure followed by column chromatography of the residue obtained
over silica gel (20% ethyl acetate/light petroleum) afforded the
monotosylated derivative 6a1 (1.2 g, 75%) as a viscous liquid.
(360 mg, 5.5 mmol) for 1 h under argon (activated zinc dust was
prepared by washing 20 g of commercially available zinc dust with
60 mL of 4 M HCl and thorough washing with water and finally with
dry acetone and then drying in vacuo). The resulting green solution
was then added dropwise to a stirred solution of the epoxide 7a1
(200 mg, 1.1 mmol) in dry THF (25 ml) at room temperature under
argon during 1 h. The reaction mixture was stirred for overnight and
was decomposed with 10% H2SO4 (10 mL). Most of the solvent was
removed under reduced pressure, and the residue was extracted
with diethyl ether (4ꢂ30 mL). The combined ether layer was washed
with saturated NaHCO3 (2ꢂ25 mL) and finally dried (Na2SO4). After
removal of the solvent under reduced pressure the crude residue was
purified by column chromatography over silica gel (20% ethyl ace-
tate/light petroleum, Rf¼0.30) to afford the cyclized alcohol 8a1
(mixture of two isomers in 1:5 ratio) as a viscous liquid (130 mg,
Rf¼0.25 (10% ethyl acetate/light petroleum); [
a
]
26.9 þ12.61 (c, 3.65
D
in CHCl3); IR (neat): 3524, 3504, 3286, 2955, 2929, 2117, 1359, 1176,
1095 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
0.87 (t, J¼6.6 Hz, 3H),
1.25e1.39 (m, 6H), 1.42e1.50 (m, 2H), 2.42 (t, J¼2.4 Hz, 1H), 2.44 (s,
3H), 3.54e3.56 (m, 1H), 3.87e3.88 (m, 1H), 4.04e4.24 (m, 4H), 7.35
(d, J¼8 Hz, 2H), 7.80 (d, J¼8 Hz, 2H); 13C NMR (75 MHz, CDCl3):
65%). IR (neat): 3400, 2955, 2931, 1458, 1039 cmꢀ1
(300 MHz):
0.88 (t, J¼6.5 Hz, 3H), 1.24e1.37 (m, 6H), 1.45e1.57 (m,
2H), 2.45e2.48 (m, 1H), 3.63e3.73 (m, 2H), 3.84 (m, 2H), 4.23e4.39
(m, 2H), 5.00e5.04 (m, 2H); 13C NMR (75 MHz):
14.2, 22.7, 25.8,
;
1H NMR
d
14.1, 21.8, 22.6, 24.6, 29.9, 31.9, 57.7, 71.0, 71.5, 74.7, 79.2, 80.0,
d
128.1, 130.1, 132.8, 145.2; HRMS calcd for C18H26O5SNa [MþNa]þ
377.1399, found 377.1395.
d
Compound 6b1 (75%) was prepared from 5b1 following similar
32.0, 34.6, 51.6, 63.3, 70.5, 80.3, 82.3, 105.2, 149.6; Anal. Calcd for
C11H20O2: C, 71.70; H, 10.94. Found: C, 71.52; H, 10.70.
procedure described for 6a1. Rf¼0.60 (20% ethyl acetate/light pe-
25.7
troleum). [
a
]
þ10.34 (c, 4.55 in CHCl3); IR (neat): 3545, 3290,
Compound 8b1 was synthesized from 7b1 following similar
procedure described for 8a1. Rf¼0.37 (20% ethyl acetate/light pe-
D
2924, 2117, 1458, 1359, 1176, 1097 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
0.87 (t, J¼7 Hz, 3H), 1.21e1.31 (m, 24H), 2.40 (t, J¼2.0 Hz, 1H), 2.4
troleum). Yield 64%; IR (neat): 3400, 2924, 1465, 1041 cmꢀ1 1H
;
(s, 3H), 3.5e3.57 (m, 2H), 3.87e3.90 (m, 1H), 4.05e4.23 (m, 3H),
7.54 (d, J¼8 Hz, 2H), 7.80 (d, J¼9 Hz, 2H); 13C NMR (75 MHz, CDCl3):
NMR (500 MHz):
d
0.88 (t, J¼7 Hz, 3H), 1.21e1.29 (m, 20H),
1.46e1.49 (m, 2H), 1.55e1.59 (m, 3H), 2.45e2.48 (m, 1H), 3.67 (dd,
J¼5.5, 11 Hz, 1H), 3.74 (dd, J¼6, 11 Hz, 1H), 3.86 (dd, J¼6.5, 12.5 Hz,
1H), 4.26e4.39 (2 AB br d, J¼13.5 Hz, 2H), 5.02e5.04 (m, 2H); 13C
d
14.2, 21.8, 22.8, 25.1, 26.4, 28.6, 29.5, 29.7, 29.8, 29.8, 30.0, 32.1,
44.2, 57.7, 69.7, 71.1, 71.5, 74.7, 79.3, 80.0, 128.0, 130.0, 132.9, 145.0;
HRMS calcd for C26H42O5S [MþH]þ 467.2831, found 467.2973.
NMR (75 MHz): d 14.2, 22.8, 26.8, 29.5, 29.7, 29.7, 29.7, 32.1, 34.7,
51.6, 63.3, 70.6, 82.3, 105.2, 149.7; calcd for C19H36O2: C, 76.96; H,
12.24. Found: C, 76.45; H, 11.96.
4.1.5. Synthesis of 7a1 and 7b1. To a stirred suspension of sodium
hydride (80 mg, 60% dispersion, 4 mmol) in dry THF (20 mL) at 0 ꢁC
was added dropwise a solution of mono tosylate derivative 6a1
(400 mg, 1.13 mmol) in dry THF (10 mL) under N2 for 30 min. The
reaction mixture was stirred for 1 h at 0 ꢁC at room temperature for
overnight. It was then carefully quenched with ice-water. After
removal of most of THF under reduced pressure, the resulting
residue was extracted with diethyl ether (3ꢂ30 mL). The combined
ether extract was washed with water (10 mL) and brine (5 mL), and
finally dried (Na2SO4). Removal of the solvent under reduced
pressure afforded a viscous liquid, which was purified by column
4.2.1. Synthesis of 9a1 and 9b1. A solution of the alcohol 8a1
(120 mg,
0.65 mmol),
3,4-dihydro-2H-pyran
(120.5 mg,
1.43 mmol), and pyridinium-p-toluenesulfonate (10 mol %) in dry
CH2Cl2 (15 mL) was stirred for 5 h at room temperature under N2.
The resulting reaction mixture was diluted with CH2Cl2 (15 mL),
washed with saturated NaHCO3 (3ꢂ25 mL), and dried (Na2SO4).
After evaporation of the solvent under reduced pressure, the crude
residue was purified by column chromatography over silica gel (2%
ethyl acetate/light petroleum) to afford 9a1 (165 mg, 95%) as a vis-
cous liquid. IR (neat): 3074, 2941, 2866, 1444, 1350, 1222 cmꢀ1; 1H
chromatography over silica gel (5% ethyl acetate/light petroleum,
26.8
Rf¼0.65) to furnish 7a1 (175 mg, 85%) as a viscous liquid. [
a
]
NMR (300 MHz, CDCl3):
d
0.82 (t, J¼6.5 Hz, 3H), 1.19e1.31 (m, 6H),
D
þ27.92 (c, 1.23 in CHCl3); IR (neat): 3308, 2956, 2860, 2115, 1464,
1.46e1.52 (m, 8H), 1.54e1.67 (m, 2H), 3.41e3.46 (m, 2H), 3.63e3.81
1261, 1087 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
0.82 (t, J¼6.6 Hz,
(m, 3H), 4.16e4.33 (m, 2H), 4.88e4.97 (m, 2H); 13C NMR (75 MHz,
3H), 1.19e1.28 (m, 4H), 1.30e1.38 (m, 1H), 1.41e1.9 (m, 1H),
1.50e1.57 (m, 2H), 2.35 (t, J¼2.5 Hz, 1H), 2.70e2.74 (m, 2H),
2.82e2.85 (m, 1H), 3.31e3.34 (m, 1H), 4.16 (ABq, further coupled
with acelylenic proton, J¼15.5, 2 Hz, 2H); 13C NMR (125 MHz,
CDCl3): d 14.2, 19.3, 19.6, 22.7, 22.7, 25.6, 25.8, 30.7, 30.8, 32.0, 32.0,
34.7, 34.8, 48.7, 49.1, 62.0, 62.3, 68.9, 69.1, 70.7, 70.8, 83.5, 83.8, 98.8,
99.3, 104.8, 105.0, 149.9, 150.0; HRMS calcd for C16H28O3Na
[MþNa]þ 291.1936, found 291.1938.
CDCl3):
d
13.0, 21.5, 23.7, 30.8, 31.6, 44.4, 52.1, 56.4, 73.2, 76.4, 79.0;
Compound 9b1 (90%) was prepared from 8b1 following similar
HRMS calcd for C11H18O2Na [MþNa]þ 205.1204, found 205.1201.
Compound 7b1 (75%) was prepared from 6b1 following similar
procedure described for 7a1. Rf¼0.38 (5% ethyl acetate/light petro-
procedure described for 9a1. IR (neat): 2926, 1456, 1201, 1033 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
0.87 (t, J¼6.9 Hz), 1.25 (m, 18H),
1.52e1.82 (m, 12H), 2.5 (m, 1H), 3.48e3.53 (m, 1H), 3.71e3.86 (m,
leum); [
a
]
27.2 ꢀ15.68 (c, 3.91 in CHCl3); IR (neat): 3310, 2924, 2115,
3H), 4.27e4.35 (m, 2H), 4.58e4.64 (m, 1H), 4.95e5.04 (m, 2H); 13C
D
1458,1267 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
0.81 (t, J¼10 Hz, 3H),
NMR (75 MHz, CDCl3): d 14.2, 19.3, 22.8, 25.6, 26.1, 26.2, 29.5, 29.7,
1.19e1.07 (m, 20H), 1.49e1.58 (m, 4H), 2.34 (t, J¼2.4 Hz, 1H),
2.71e2.72 (m, 2H), 2.81e2.84 (m, 1H), 3.29e3.33 (m, 1H), 4.10e4.16
29.8, 29.8, 30.6, 30.7, 32.1, 34.7, 48.9, 62.2, 68.9, 70.7, 83.6, 98.9,
105.1, 150.0; HRMS calcd for C24H44O3Na [MþNa]þ 403.3188, found
403.3186.
(m, 2H); 13C NMR (75 MHz, CDCl3):
d 14.1, 22.7, 25.0, 29.3, 29.5, 29.6,
29.6, 29.7, 31.9, 32.6, 45.4, 53.1, 57.4, 74.2, 80.0; HRMS calcd for
C19H34O2Na [MþNa]þ 317.2457, found 317.2456.
4.2.2. Synthesis of 10a1 and 10b1. To a stirred solution of compound
9a1 (90 mg, 0.33 mmol) in dry DMF (4 mL) was added molecular
sieves (4 A) (50 mg) and pyridinium dichromate (1.4 g, 3.3 mmol)
portion-wise at room temperature during 1 h. The reaction mixture
was further stirred for 24 h, diluted with water (5 mL), and
extracted with ethyl acetate (4ꢂ25 mL). The combined organic
layer was washed with saturated NaHCO3 (10 mL), water (4ꢂ5 mL),
ꢀ
4.2. General procedure for Cp2TiCl mediated radical
cyclization of 7a1. Synthesis of 8a1
A solution of titanocene dichloride (564 mg, 2.2 mmol) in dry THF
(25 mL, not deoxygenated) was stirred with activated zinc dust

4282
S. Saha, S.C. Roy / Tetrahedron 66 (2010) 4278e4283
and finally dried (Na2SO4). The solvent was removed under reduced
pressure, and the residue obtained was chromatographed over
silica gel (20% ethyl acetate/light petroleum) to furnish the lactone
10a1 (60 mg, 65%) as a light yellow viscous liquid. IR (neat): 2926,
was dissolved in THFebenzene (1:1, 5 mL) and was heated at 70 ꢁC
with dil HCl (0.5 mL) for 3 h. It was extracted with CH2Cl2
(2ꢂ25 mL) and the combined organic layer was washed with brine
(5 mL) and then dried (Na2SO4). Evaporation of the solvent under
reduced pressure afforded the pure acid 1a as a crystalline solid
(30 mg, 70%) the NMR spectra of which were identical3 with
2854, 1764, 1512, 1269, 1033 cmꢀ1 1H NMR (500 MHz, CDCl3):
;
d
0.88 (t, J¼6.5 Hz, 3H), 1.24e1.39 (m, 6H), 1.40e1.47 (m, 2H),
1.50e1.61 (m, 5H), 1.64e1.77 (m, 3H), 2.93e2.96 (m, 1H), 3.47e3.52
(m, 2H), 3.75e3.89 (m, 2H), 4.33e4.37 (m, 1H), 4.58e4.61 (m, 1H),
5.69e5.70 (m, 1H), 6.29e6.30 (m, 1H); 13C NMR (75 MHz, CDCl3):
(ꢀ)-methylenolactocin reported in the literature. Mp 82e84 ꢁC
24.0
(ethyl acetate/petroleum ether); [
a
]
ꢀ17.13 (c, 1.96 in CHCl3),
D
24.0
reported [
a
]
ꢀ18.80 (c, 1.34 in CHCl3);6c IR (KBr): 3444, 3099,
D
d
13.9, 13.9, 19.2, 19.4, 22.5, 24.6, 24.6, 25.3, 25.6, 30.4, 30.4, 31.4,
2955, 1743, 1716, 1255 cmꢀ1; 1H NMR (500 MHz):
d
0.90 (t, J¼7 Hz,
31.5, 36.0, 36.0, 44.7, 44.9, 68.7, 68.9, 81.2, 81.2, 98.7, 99.3, 123.1,
123.2, 136.6, 136.7, 170.0; HRMS calcd for C16H26O4Na [MþNa]þ
305.1729, found 305.1724.
3H), 1.32e1.33 (m, 4H), 1.41e1.63 (m, 2H), 1.71e1.77 (m, 2H),
3.62e3.64 (m, 1H), 4.79e4.83 (m, 1H), 6.02 (d, J¼2.5 Hz, 1H), 6.46
(d, J¼2.5 Hz, 1H); 13C NMR (75 MHz):
d 14.0, 22.6, 24.6, 31.5, 35.8,
49.7, 79.1, 126.1, 132.6, 168.4, 174.4; HRMS calcd for C11H16O4Na
Compound 10b1 (60%) was prepared from 9b1 following similar
procedure described for 10a1. IR (neat): 2924, 1766, 1465, 1271,
[MþNa]þ 235.0946, found 235.0944.
1033 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
0.80 (t, J¼6.5 Hz, 3H),
(ꢀ)-Protolichesterinic acid (1b) was prepared from 11b1 in 70%
yield following the similar procedure described for 1a. Mp
1.08e1.22 (m, 23H), 1.31e1.40 (m, 2H), 1.40e1.58 (m, 6H), 1.61e1.70
(m, 2H), 2.87e2.88 (m, 1H), 3.32e3.46 (m, 2H), 3.70e3.82 (m, 2H),
4.27e4.29 (m, 1H), 4.51e4.54 (m, 1H), 5.62e5.64 (m, 1H), 6.22e6.23
98e100 ꢁC; [
a]
26.9 ꢀ12.24 (c, 1.23 in CHCl3), reported [
a]
32.0 ꢀ10.40
D
D
(c, 0.46 in CHCl3);6f IR (KBr): 3091, 2920, 2849, 1743, 1715, 1407,
(m,1H); 13C NMR (75 MHz, CDCl3):
d
19.4, 22.8, 25.0, 25.1, 29.4, 29.5,
1254, 1199 cmꢀ1
;
1H NMR (500 MHz):
d
0.88 (t, J¼6.5 Hz, 3H),
29.6, 29.7, 29.8, 30.5, 30.6, 30.7, 32.0, 36.2, 44.8, 45.0, 62.3, 62.5,
68.8, 69.0, 81.4, 81.4, 98.9, 99.4, 123.2, 123.4, 136.7, 136.9, 170.2;
HRMS calcd for C24H42O4Na [MþNa]þ 417.2981, found 417.2983.
1.22e1.33 (m, 17H), 1.72e1.75 (m, 5H), 3.62e3.63 (m, 1H),
4.80e4.82 (m, 1H), 6.02 (d, J¼2.5 Hz,1H), 6.46 (d, J¼3, 1H); 13C NMR
(75 MHz):
d 14.2, 22.8, 25.1, 29.3, 29.5, 29.5, 29.6, 29.7, 29.8, 29.8,
32.0, 35.9, 49.6, 79.0, 125.9, 132.7, 168.3, 173.5; HRMS calcd for
4.2.3. Synthesis of 11a1 and 11b1. To a stirred solution of lactone
10a1 (60 mg, 0.2 mmol) in methanol (4 mL) was added p-toluene-
sulfonic acid monohydrate (10 mol %), and the reaction mixture
was stirred for 3 h at room temperature. Most of the solvent was
removed in vacuo and water (3 mL) was added to it. It was
extracted with ethyl acetate (3ꢂ20 mL). The combined ethyl ace-
tate extract was washed with saturated NaHCO3 (5 mL), brine
(5 mL), and finally dried (Na2SO4). After removal of the solvent
under reduced pressure, the residue obtained was purified by col-
umn chromatography over silica gel (25% ethyl acetate/light pe-
troleum) to afford the hydroxy lactone 11a1 (35 mg, 85%) as viscous
C19H32O4Na [MþNa]þ 347.2198, found 347.2198.
Acknowledgements
We thank Department of Science and Technology, New Delhi, for
financial assistance. S.S. thanks CSIR, New Delhi, for awarding
fellowship.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.058. These data include
MOL files and InChiKeys of the most important compounds
described in this article.
oil. IR (neat): 3500, 3013, 2955, 2929, 1750, 1271 cmꢀ1
(500 MHz, CDCl3):
;
1H NMR
d
0.84 (t, J¼6.5 Hz, 3H), 1.17e1.37 (m, 4H),
1.41e1.48 (m, 2H), 1.56e1.7 (m, 3H), 2.80 (m, 1H), 3.66e3.72 (m,
2H), 4.31e4.35 (m,1H), 5.65 (d, J¼2 Hz,1H), 6.27 (d, J¼3 Hz,1H); 13C
NMR (75 MHz, CDCl3): d 14.1, 22.6, 24.8, 30.4, 36.2, 47.1, 64.1, 123.5,
References and notes
137.4, 170.1; HRMS calcd for C11H18O3Na [MþNa]þ 221.1154, found
221.1152.
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freshly prepared Jones reagent at room temperature until a persis-
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propanol was added and the reaction mixture was diluted with
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solvent was removed and the residue was dissolved in toluene
(5 mL) and extracted with 10% of aqueous NaHCO3 (3ꢂ3 mL).
Aqueous bicarbonate layer was acidified with dil HCl and was
extracted with CH2Cl2 (2ꢂ25 mL). The combined organic layer was
washed with brine (5 mL) and then dried (Na2SO4). Evaporation of
the solvent under reduced pressure afforded a crude mass, which
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