Diastereoselective synthesis of (+)-nephrosterinic acid and (+)-protolichesterinic acid

Article abstract of DOI:10.1016/j.tetasy.2011.12.012

A diastereoselective synthesis of (+)-nephrosterinic acid and (+)-protolichesterinic acid, common members of the paraconic acids is described. The synthesis is based on a diastereoselective orthoester Johnson-Claisen rearrangement of a (Z)-allyl alcohol with a vicinal dioxolane moiety as key steps. The synthesis is completed in 10 steps and with overall yields of 15.9% for (+)-nephrosterinic acid and 16.4% for (+)-protolichesterinic acid.

Full text of DOI:10.1016/j.tetasy.2011.12.012

Tetrahedron: Asymmetry 23 (2012) 60–66
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective synthesis of (+)-nephrosterinic acid
and (+)-protolichesterinic acid
⇑
Rodney A. Fernandes , Mahesh B. Halle, Asim K. Chowdhury, Arun B. Ingle
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A diastereoselective synthesis of (+)-nephrosterinic acid and (+)-protolichesterinic acid, common mem-
bers of the paraconic acids is described. The synthesis is based on a diastereoselective orthoester John-
son–Claisen rearrangement of a (Z)-allyl alcohol with a vicinal dioxolane moiety as key steps. The
synthesis is completed in 10 steps and with overall yields of 15.9% for (+)-nephrosterinic acid and
16.4% for (+)-protolichesterinic acid.
Received 15 November 2011
Accepted 22 December 2011
Available online 10 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
O
Nephrosterinic acid1 isolated from Centraria endocrocea and
protolichesterinic acid2 isolated from Cetraria islandica and Parm-
elia sinodensis are important members of the family of paraconic
acids. The latter are characterized by the presence of a highly
O
O
HO
C4H9
O
O
substituted
c-butyrolactone with a b-COOH group and an a-
(-)-methylenolactocin, 3
methyl or methylene group and display varied stereochemical
relationships of substituents on adjacent carbon atoms. These com-
pounds are known for their biological activities such as antibacte-
rial,3 antifungal,3b antitumor4 and growth-regulating effects.5 The
HO
O
n
O
n = 10, (+)-nephrosteranic acid, 1
n =12, (+)-roccellaric acid, 2
O
HO
activity arises mainly due to the a,b-unsaturated carbonyl system
C4H9
which acts as a Michael acceptor to various biological nucleophiles.
The syntheses of nephrosterinic acid6 and protolichesterinic acid7
have been reported both in racemic and either of the enantiomer
forms. In the course of studies directed toward the enantioselective
synthesis of bioactive molecules8 employing the orthoester John-
son–Claisen rearrangement (JCR)9 of allyl alcohols with a vicinal
chiral dioxolane functionality, we recently completed the synthesis
of (+)-nephrosteranic acid 1, (+)-roccellaric acid 2, (ꢀ)-methyleno-
lactocin 3, and (ꢀ)-phaseolinic acid 4 (Fig. 1).8e,f The strategy was
based on the separation of diastereomeric mixture 8/9 (or ent-8/
ent-9) obtained in a 1.1:1 to 2.5:1 ratio by the orthoester John-
son–Claisen rearrangement of (E)-7 [or (E)-ent-7, Fig. 1]. Although
the diastereomeric lactones were easily separable for further syn-
thetic exploration, the brevity was overshadowed by the poor dia-
stereoselectivity which was a major concern to us, and so we
undertook a detailed study to improve this aspect. A stereochemi-
cal feature of 7 or ent-7 available for variation apart from our
earlier work was the olefin geometry. We report here a remarkable
improvement in the diastereoselectivity in the orthoester
O
(-)-phaseolinicacid, 4
ref.8e,f
O
OH
OH
OH
H
H
O
n
n
n
JCR
+
H
O
O
H
O
O
7 or ent-7
9 or ent-9
8 or ent-8
this work
O
O
HO
n = 10, (+)-nephrosterinicacid, 5
n
n = 12, (+)-protolichesterinic acid, 6
O
⇑
Corresponding author. Tel.: +91 22 25767174; fax: +91 22 25767152.
E-mail address: rfernand@chem.iitb.ac.in (R.A. Fernandes).
Figure 1. Strategic considerations to paraconic acids.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.12.012

R. A. Fernandes et al. / Tetrahedron: Asymmetry 23 (2012) 60–66
61
Mes
Mes
Ph
N
N
O
Cl
ref.8e
O
Ru
OH
n
n
Cl
13
O
P(Cy)3
10a, n = 10
10b, n = 12
7a, n = 9
7b, n = 11
OH
O
K3Fe(CN)6, K2CO3
K2OsO4.2H2O
(DHQ)2PHAL
O
OEt
13
Grubbs-II ( , 0.2 mol%)
(MeO)2CMe2
p-TsOH
OEt
p-cresol, CH2Cl2
+
n
n
OEt
O
OH
n
acetone
rt, 12 h, 97%
MeSO4NH2
t-BuOH/H2O (1:1)
0 oC, 24 h, 92%
45 °C, 12 h, quant
11a
11b, n = 11
, n = 9
12
14a, n = 9
14b, n = 11
15a, n = 9, 98.5% ee
15b, n = 11, 96% ee
O
O
O
O
i. DIBAL-H, CH2Cl2
-78 °C, 2 h
DIBAL-H,CH2Cl2
OEt
OH
OEt
n
n
n
O
O
0 °C, 2 h, rt, 2 h, 95%
ii. Ph3P=CHCO2Et, MeOH
O
O
°
-78 C, 2 h, -40 °C,12 h
16a, n = 9
16b, n = 11
(Z)-17a (65%), (Z)-17b (67%)
7c, n = 9
7d
17a
17b
, n = 9
, n = 11
, n = 11
Scheme 1. Synthesis of allyl alcohols 7a–d.
Table 1
Diastereoselective orthoester Johnson–Claisen rearrangement of 7a or 7b
O
OH
i. MeC(OMe)3
EtCO2H (cat)
solvent, reflux
OH
OH
Hb
O
Hb
O
n
n
n
+
ii. 4N HCl
MeOH
rt, 12 h
O
Ha
O
O
Ha
7a, n = 9
7b, n = 11
8a, n = 9
9a, n = 11
8b, n = 9
9b, n = 11
Entry
Solvent (reaction time, h)
Allyl alcohol
8a:8ba (% yield)
9a:9ba (% yield)
1
2
3
4
5
6
7
8
9
Benzene (120)
’’
MeC(OMe)3 (44)
’’
Toluene (24)
’’
Xylene (4)
’’
Mesitylene (4)
’’
Decalin (2)
’’
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
7a
7b
1:1 (78)
—
1.3:1 (83)
—
1.5:1 (57)
—
2:1 (86)
—
1.1:1 (88)
—
—
1.3:1 (57)
—
2:1 (89)
—
1.1:1 (88)
—
1.2:1 (72)
—
10
11
12
1.3:1 (71)
—
1.2:1 (78)
1.1:1 (82)
—
a
Determined by 1H NMR.
Johnson–Claisen rearrangement of allyl alcohols with a vicinal chi-
ral dioxolane functionality and (Z)-olefin geometry. The results
were successfully utilized in the total synthesis of (+)-nephroster-
inic acid 5 and (+)-protolichesterinic acid 6.
14a11 and 14b,12 respectively, in quantitative yields and excellent
(E)-stereoselectivity. The asymmetric dihydroxylation of 14a and
14b afforded the diols 15a and 15b, each in 92% yields and excel-
lent enantioselectivity of 98.5%11 and 96% ee,13 respectively. The
acetonide protection of diols provided 16a and 16b, each in a
97% yield. Subsequent DIBAL-H reduction of these esters to the cor-
responding aldehydes and (Z)-selective Wittig olefination with
2. Results and discussion
Ph3P@CHCO2Et in MeOH gave (Z)-a,b-unsaturated esters 17a
We prepared the desired allyl alcohols 7a–d as shown in
Scheme 1. The allyl alcohols 7a and 7b were prepared from com-
mercially available dodecanal 10a and tetradecanal 10b as re-
ported earlier.8e The synthesis of 7c and 7d commenced from
olefins 11a and 11b which on cross-metathesis10 (using G-II, 13,
(65%) and 17b (67%).14 Further reduction of the ester groups with
DIBAL-H afforded the desired allyl alcohols 7c and 7d each in a 95%
yield.
With the four allyl alcohols 7a–d in hand, we subjected them to
orthoester Johnson–Claisen rearrangement to investigate the
0.2 mol %) with ethylacrylate 12, provided
a,b-unsaturated esters

62
R. A. Fernandes et al. / Tetrahedron: Asymmetry 23 (2012) 60–66
Table 2
Diastereoselective orthoester Johnson–Claisen rearrangement of 7c or 7d
O
i. MeC(OMe)3
EtCO2H (cat)
solvent, reflux
OH
OH
H
H
O
n
n
n
+
OH ii. 4N HCl
O
H
O
H
O
MeOH
rt, 12 h
O
7c, n = 9
7d, n = 11
8a, n = 9
9a, n = 11
8b, n = 9
9b, n = 11
diastereoselectivity based on the geometry of olefinic bond and the
presence of a chiral vicinal dioxolane moiety. The results are
shown in Tables 1 and 2. The allyl alcohol 7a with an (E)-olefinic
bond after orthoester Johnson–Claisen rearrangement in benzene
and subsequent lactonization provided 8a and 8b as a 1:1 mixture
(78%, entry 1, Table 1). The reaction was rather slow and required a
longer time (120 h) for completion. The assignment of relative ste-
reochemistry to lactones 8a and 8b comes from their 1H NMR spec-
tra. In lactone 8a the proton Ha is syn to the double bond and gets
shielded to d = 4.09 ppm, while the same proton in 8b is anti to the
double bond and appears downfield at d = 4.38 ppm. We have fur-
ther confirmation of this stereochemistry from X-ray studies of
similar lactones.8c The lactones 8a/8b or 9a/9b were easily separa-
ble by column chromatography. The allyl alcohol 7b similarly gave
9a and 9b as a 1.3:1 mixture (83%, entry 2). A neat reaction in Me-
C(OMe)3 did not improve the diastereoselectivity; and also yields
of the mixture were lower (57%, entries 3 and 4). On changing
the solvent to toluene and then to higher boiling solvents (entries
5–12), the diastereoselectivity did not change much except in tol-
uene when the mixture of diastereomeric lactones were obtained
in a 2:1 ratio (entries 5 and 6).
The allyl alcohol 7c with (Z)-olefinic bond after orthoester John-
son–Claisen rearrangement in benzene and subsequent lactoniza-
tion provided 8a and 8b as a 7:1 mixture (61%, entry 1, Table 2).
Similarly 7d gave 9a and 9b as a 5:1 mixture (60%, entry 2). The
neat reaction in MeC(OMe)3 gave similar results (entries 3 and
4). Changing the solvent to toluene, 7c provided 8a and 8b as an
8:1 mixture and in good yields of 89% (entry 5), Similarly 7d gave
9a and 9b in good diastereoselectivity of 8.7:1 and 86% yield (entry
6). With higher boiling solvents (entries 7–12), the diastereoselec-
tivity gradually decreased. Thus the reaction in toluene over 24 h
gave the best diastereoselectivity. In all cases the anti-diastereo-
mer 8a or 9a was the major product.
The observed diastereoselectivity is in accordance with the lit-
erature reports.9 Considering chairlike transition states, compound
7a giving 8a and 8b in almost equal amounts could be due to the
transition states of almost equal energy in which the chiral dioxo-
lane moiety is placed equatorial. Similar is the case with 7b giving
9a and 9b in equal amounts. However for 7c (or 7d) giving 8a (or
9a) as the major product could be due to involvement of lower en-
ergy transition state A (Scheme 2) wherein the new
r bond is
formed from the side of the smaller H atom and away from the
OMe
OMe
OH
H
O
O
new σ bond
formation
H
H
n
O
H
major
diastereomer
O
O
O
O
8a, n = 9
9a, n = 11
A
O
O
new σ bond
n
formation
OH
O
OH
n
O
O
H
H
O
H
OMe
OMe
7c
, n = 9
7d
, n = 11
minor
diastereomer
H
O
O
O
O
O
8b, n = 9
9b, n = 11
B
Scheme 2. Transition state models for orthoester Johnson–Claisen rearrangement of 7c and 7d.

R. A. Fernandes et al. / Tetrahedron: Asymmetry 23 (2012) 60–66
63
axially placed dioxolane moiety. For transition state B, the new
r
3. Conclusions
bond would be formed from the side of axially placed dioxolane
moiety which would be sterically less favored. Hence 8b or 9b
are minor products.
In summary, we have synthesized varied allyl alcohols with an
(E)- or (Z)-olefin geometry and having a chiral vicinal dioxolane
moiety and demonstrated the strategic utility of the orthoester
Johnson–Claisen rearrangement of these compounds to furnish
Thebestresultsofthisstudywerefurtherutilizedtocompletethe
total synthesis of (+)-nephrosterinic acid 5 and (+)-protolichesteri-
nic acid 6 as shown in Scheme 3. The orthoester Johnson–Claisen
rearrangementof theallylalcohol(Z)-7cwith trimethylorthoacetate
in the presence of catalytic amounts of propionic acid in toluene sol-
vent over 24 h and the same-pot hydrolysis (4 N HCl) provided a
mixture of 8a and 8b in an 8:1 ratio. Flash column chromatography
of this mixture yielded pure diastereomer 8a in 75% and 8b in 8%
yields. Similarly, (Z)-7d gave 9a (74%) and 9b (7%). The lactones were
fully characterized by spectroscopic and analytical data.8e The lac-
the chiral b,c-disubstituted-c-lactones with good diastereoselec-
tivity. These lactone diastereomers were efficiently separated and
carried forward to complete the total synthesis of paraconic acids:
(+)-nephrosterinic acid 5, and (+)-protolichesterinic acid 6 in 10
steps and 15.9% and 16.4% overall yields, respectively. Further
application of this strategy toward the synthesis of other natural
products is in progress in our laboratory.
tones 8a and 9a had the required functionality to set the b,c-stereo-
centers of the target molecules 5 and 6, respectively, while the free
4. Experimental
hydroxyl group in the side chain needs to be removed.
4.1. General information
Dry reactions were carried out under an atmosphere of Ar or N2.
Solvents and reagents were purified by standard methods. Thin-
layer chromatography was performed on EM 250 Kieselgel 60
F254 silica gel plates. The spots were visualized by staining with
KMnO4 or by a UV lamp. 1H NMR and 13C NMR were recorded on
Varian Mercury Plus, AS400 spectrometer and Bruker, AVANCE III
400 spectrometer. The chemical shifts are based on TMS peak at
d = 0.00 pm for proton NMR and CDCl3 peak at d = 77.00 ppm (t)
in carbon NMR. IR spectra were obtained on Perkin Elmer Spec-
trum One FT-IR spectrometer. Optical rotations were measured
with Jasco P-2000 polarimeter. HRMS was recorded using Micro-
mass: Q-Tof micro (YA-105) spectrometer. HPLC was performed
with JASCO-PU-2089PLUS quaternary gradient pump with MD-
2010 PLUS multiwavelength Detector.
O
OH
H
i. MeC (OMe)3, PhMe
EtCO2H (cat), reflux
24 h
n
n
OH
H O
O
O
ii. 4N HCl, MeOH
rt, 12 h
7c
7d, n = 11
, n = 9
n = 9,8b (8%)
n = 11, 9b (7%)
+
O
HO
n
OH
H
ref.8e
3 steps
H
n
O
H
O
H
O
O
8a
n = 9,
(75%)
n = 9, 18a (59%, in 3 steps)
n = 11, 18b (60%, in 3 steps)
4.1.1. (E)-Ethyl tridec-2-enoate 14a11
n = 11, 9a (74%)
A solution of dodecene 11a (1.0 g, 5.94 mmol), ethyl acrylate
(1.3 mL, 12.18 mmol, 2.05 equiv), and p-cresol (0.321 g, 2.97 mmol,
50 mol %) in CH2Cl2 (20 mL) was degassed with N2 for 20 min.
i. MeOMgOCO2Me
DMF, 135 °C, 60 h
Grubbs II catalyst (10.1 mg, 11.9 lmol, 0.2 mol %) was then added
ii. CH2O, N-methylaniline
AcOH, NaOAc, rt, 3 h
65% (two steps)
and the reaction mixture refluxed for 12 h. It was then concen-
trated and the residue purified by silica gel column chromatogra-
phy using petroleum ether/EtOAc (4:1) as eluent to afford 14a
(1.42 g, quant) as a colorless oil. IR (CHCl3):
mmax = 3019, 2930,
2858, 1711, 1656, 1471, 1366, 1274, 1125, 1044, 929, 669 cmꢀ1
.
O
HO
1H NMR (400 MHz, CDCl3): d 0.88 (t, J = 6.9 Hz, 3H, CH3), 1.24–
1.46 (m, 19H, CH3, H-5, H-6, H-7, H-8, H-9, H-10, H-11, H-12),
2.17–2.21 (m, 2H, H-4), 4.17 (q, J = 7.1 Hz, 2H, OCH2), 5.80 (dt,
J = 15.7, 1.5 Hz, 1H, H-2), 6.96 (dt, J = 15.6, 6.9 Hz, 1H, H-3). HRMS
(ESI+): Calcd for [C15H28O2+H] 241.2168. Found: 241.2174.
H
n = 9, (+)-nephrosterinic acid, 5
n = 11, (+)-protolichesterinic acid, 6
n
O
H
O
Scheme 3. Synthesis of (+)-nephrosterinic acid, 5 and (+)-protolichesterinic acid, 6.
4.1.2. (E)-Ethyl pentadec-2-enoate 14b12
Further conversion of 8a and 9a to b-carboxylic acid group con-
taining lactones 18a and 18b, respectively, was carried out as re-
ported earlier in three steps8e in a 59% overall yield for 18a and
The title compound was prepared from tetradecene 11b (1.0 g,
5.09 mmol) by a procedure similar to that described for the conver-
sion of 11a to 14a to give 14b (1.366 g, quant) as a colorless oil. IR
(CHCl3): mmax 3021, 2928, 2856, 1715, 1656, 1467, 1369, 1274,
60% for 18b. The
a-methylene group was very efficiently intro-
duced following the literature procedure.15 Thus treatment of
18a with methoxy magnesium methylcarbonate, followed by
formaldehyde and N-methylaniline gave (+)-nephrosterinic acid 5
1128, 1045, 981, 669 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.88 (t,
.
J = 6.8 Hz, 3H, CH3), 1.22–1.46 (m, 23H, CH3, H-5, H-6, H-7, H-8,
H-9, H-10, H-11, H-12, H-13, H-14), 2.16–2.21 (m, 2H, H-4), 4.21
(q, J = 7.1 Hz, 2H, OCH2), 5.81 (dt, J = 15.7, 1.5 Hz, 1H, H-2), 6.96
(dt, J = 15.6, 6.9 Hz, 1H, H-3). 13C NMR (100 MHz, CDCl3): d 166.8,
149.6, 121.1, 60.1, 32.2, 31.9, 29.64 (2C), 29.61, 29.5, 29.4, 29.3,
29.1, 28.0, 22.7, 14.3, 14.1. HRMS(ESI+): Calcd for [C17H32O2+H]
269.2481. Found: 269.2488.
in a 65% yield, ½a D25
ꢁ
¼ þ12:5 (c 0.1, CHCl3), lit.6b
½
a 3D2
ꢁ
¼ þ13:0 (c
0.6, CHCl3). The introduction of
a-methylene group similarly as
above in 18b provided (+)-protolichesterinic acid 6 in a 65% yield,
½
a 2D5
ꢁ
¼ þ13:9 (c 0.16, CHCl3), lit.7j
½
a 2D5
ꢁ
¼ þ14:2 (c 0.95, CHCl3). The
spectral data for 5 and 6 were in full agreement with the literature
data.6b,7j

64
R. A. Fernandes et al. / Tetrahedron: Asymmetry 23 (2012) 60–66
4.1.3. (2R,3S)-Ethyl 2,3-dihydroxytridecanoate 15a11
929, 877, 857, 669, 626 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.88
.
To a mixture of K3Fe(CN)6 (4.11 g, 12.48 mmol, 3.0 equiv),
K2CO3 (1.726 g, 12.48 mmol, 3.0 equiv), MeSO2NH2 (0.395 g,
4.16 mmol, 1.0 equiv), (DHQ)2-PHAL (32.4 mg, 0.0416 mmol,
(t, J = 6.8 Hz, 3H, CH3), 1.25–1.31 (m, 23H, CH3, H-5, H-6, H-7, H-
8, H-9, H-10, H-11, H-12, H-13, H-14), 1.44 (s, 3H, CH3), 1.47 (s,
3H, CH3), 1.63–1.80 (m, 2H, H-4), 4.10–4.20 (m, 2H, H-2, H-3),
4.22 (q, J = 7.0 Hz, 2H, OCH2). 13C NMR (100 MHz, CDCl3): d 171.0,
110.7, 79.2, 79.1, 61.2, 33.5, 31.9, 29.61 (2C), 29.6, 29.5, 29.46,
29.4, 29.3, 27.1, 25.6, 25.58, 22.6, 14.1, 14.06. HRMS (ESI+): Calcd
for [C20H38O4+H] 343.2849. Found: 343.2855.
1.0 mol %) and K2OsO4ꢂ2H2O (6.2 mg, 16.7
l
mol, 0.4 mol %) in t-
BuOH (11 mL) and water (21 mL) at 0 °C was added
a,b-unsatu-
rated ester 14a (1.0 g, 4.16 mmol) in t-BuOH (10 mL). The reaction
mixture was stirred at 0 °C for 24 h and then quenched with solid
Na2SO3 and stirred for 30 min. The solution was extracted with
EtOAc (3 ꢃ 30 mL) and combined organic layers were washed with
1 M KOH (20 mL), water (25 mL), brine, dried (Na2SO4), and con-
centrated. The residue was purified by silica gel column chroma-
tography using petroleum ether/EtOAc (1:1) as eluent to afford
4.1.7. (4S,5S,Z)-Ethyl 4,5-(isopropylidenedioxy)pentadec-2-
enoate 17a
To a solution of ester 16a (0.8 g, 2.54 mmol) in CH2Cl2 (40 mL)
at ꢀ78 °C was added DIBAL-H (1.54 mL, 2.69 mmol, 1.75 M solu-
tion in toluene, 1.06 equiv). The reaction mixture was stirred for
2 h and then quenched by adding a saturated aqueous solution of
potassium–sodium–tartarate (5 mL) and stirred for 1 h. It was then
extracted with CH2Cl2 (3 ꢃ 20 mL) and the combined organic ex-
tracts were washed with water, brine, dried (Na2SO4), and concen-
trated. The crude aldehyde was dissolved in MeOH (25 mL), cooled
to ꢀ78 °C and Ph3P@CHCO2Et (1.062 g, 3.05 mmol, 1.2 equiv) was
added. The reaction mixture was stirred at ꢀ78 °C for 2 h and then
at ꢀ40 °C for 12 h. It was warmed to room temperature and con-
centrated. The residue was purified by flash column chromatogra-
phy using petroleum ether/EtOAc (5:1) as eluent to afford 17a
15a (1.05 g, 92%) as a white solid. Mp 63–65 °C. ½a D25
¼ ꢀ9:9 (c
ꢁ
1.26, CHCl3). IR (CHCl3): mmax 3449, 3020, 2928, 2857, 1735,
1467, 1370, 1101, 1020, 930, 669 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d 0.88 (t, J = 6.8 Hz, 3H, CH3), 1.26–1.41 (m, 19H, CH3, H-5, H-6, H-7,
H-8, H-9, H-10, H-11, H-12), 1.58–1.63 (m, 2H, H-4), 3.88 (dt,
J = 6.3, 1.8 Hz, 1H, H-3), 4.09 (d, J = 2.0 Hz, 1H, H-2), 4.30 (q,
J = 7.2 Hz, 2H, OCH2). 13C NMR (100 MHz, CDCl3): d 173.7, 73.0,
72.5, 62.1, 33.8, 31.9, 29.6 (2C), 29.5, 29.48, 29.3, 25.7, 22.7, 14.1,
14.09. HRMS (ESI+): Calcd for [C15H30O4+H] 275.2223. Found:
275.2220.
4.1.4. (2R,3S)-Ethyl 2,3-dihydroxypentadecanoate 15b13
The title compound was prepared from 14b (1.3 g, 4.84 mmol)
by a procedure similar to that described for the conversion of
14a to 15a to give 15b (1.345 g, 92%) as a white solid. Mp 70–
(0.563 g, 65%) as a colorless oil. ½a D25
¼ þ37:1 (c 0.6, CHCl3). IR
ꢁ
(CHCl3): mmax 3020, 2928, 2856, 1719, 1659, 1512, 1467, 1419,
1372, 1031, 929, 876, 669 cmꢀ1 1H NMR (400 MHz, CDCl3): d
.
0.88 (t, J = 6.9 Hz, 3H, CH3), 1.25–1.50 (m, 19H, CH3, H-7, H-8, H-
9, H-10, H-11, H-12, H-13, H-14), 1.42 (s, 3H, CH3), 1.43 (s, 3H,
CH3), 1.58–1.65 (m, 2H, H-6), 3.68–3.73 (m, 1H, H-5), 4.18 (q,
J = 7.1 Hz, 2H, OCH2), 5.27 (dt, J = 8.5, 1.0 Hz, 1H, H-4), 5.94 (dd,
J = 11.8, 1.0 Hz, 1H, H-2), 6.13 (dd, J = 11.7, 8.8 Hz, 1H, H-3). 13C
NMR (100 MHz, CDCl3): d 165.4, 145.4, 123.1, 109.1, 81.1, 76.1,
60.4, 32.0, 31.9, 29.7, 29.6, 29.55, 29.5, 29.3, 27.3, 27.1, 26.1,
22.7, 14.2, 14.1. HRMS (ESI+): Calcd for [C20H36O4+H] 341.2693.
Found: 341.2688.
71 °C. ½a 2D5
¼ ꢀ7:8 (c 1.4, CHCl3). IR (CHCl3): mmax 3514, 3020,
ꢁ
2928, 2856, 1732, 1524, 1467, 1446, 1422, 1390, 1102, 1029,
. d 0.88 (t,
929, 669, 626 cmꢀ1 1H NMR (400 MHz, CDCl3):
J = 6.8 Hz, 3H, CH3), 1.26–1.42 (m, 23H, CH3, H-5, H-6, H-7, H-8,
H-9, H-10, H-11, H-12, H-13, H-14), 1.57–1.64 (m, 2H, H-4), 1.85
(br s, 1H, OH), 3.05 (br s, 1H, OH), 3.89 (dt, J = 6.8, 1.9 Hz, 1H, H-
3), 4.08 (d, J = 2.0 Hz, 1H, H-2), 4.29 (q, J = 7.1 Hz, 2H, OCH2). 13C
NMR (100 MHz, CDCl3): d 173.7, 73.0, 72.5, 62.1, 33.8, 31.9, 29.64
(2C), 29.61, 29.55, 29.53, 29.5, 29.3, 25.7, 22.7, 14.1, 14.08. HRMS
(ESI+): Calcd for [C17H34O4+H] 303.2536. Found: 303.2542.
4.1.8. (4S,5S,Z)-Ethyl 4,5-(isopropylidenedioxy)heptadec-2-
enoate 17b
4.1.5. (2R,3S)-Ethyl 2,3-(isopropylidenedioxy)tridecanoate 16a
To a solution of diol 15a (0.84 g, 3.06 mmol) in acetone (25 mL)
was added p-TsOH (catalytic) and 2,2-dimethoxypropane (0.94 mL,
7.65 mmol, 2.5 equiv) and the reaction mixture stirred at room
temperature for 12 h. NaHCO3 (0.2 g) was added to the reaction
mixture and stirred for additional 30 min and then filtered through
a pad of silica gel. The filtrate was concentrated and the residue
purified by silica gel column chromatography using petroleum
ether/EtOAc (3:2) as eluent to afford 16a (0.933 g, 97%) as a color-
The title compound was prepared from 16b (0.9 g, 2.63 mmol)
by a procedure similar to that described for the conversion of
16a to 17a to give acetonide ester 17b (0.65 g, 67%) as a colorless
oil. ½a 2D5
¼ þ32:6 (c 0.4, CHCl3). IR (CHCl3): mmax 2986, 2927,
ꢁ
2855, 1725, 1657, 1466, 1418, 1380, 1371, 1193, 1047, 929, 874,
826, 668 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.88 (t, J = 6.9 Hz,
.
3H, CH3), 1.27–1.50 (m, 23H, CH3, H-7, H-8, H-9, H-10, H-11, H-
12, H-13, H-14, H-15, H-16), 1.42 (s, 3H, CH3), 1.43 (s, 3H, CH3),
1.60–1.65 (m, 2H, H-6), 3.68–3.74 (m, 1H, H-5), 4.18 (q,
J = 7.1 Hz, 2H, OCH2), 5.27 (dt, J = 8.5, 1.0 Hz, 1H, H-4), 5.94 (dd,
J = 11.8, 1.1 Hz, 1H, H-2), 6.13 (dd, J = 11.7, 8.8 Hz, 1H, H-3). 13C
NMR (100 MHz, CDCl3): d 165.4, 145.5, 123.1, 109.1, 81.1, 76.1,
60.4, 32.0, 31.9, 29.7, 29.63 (3C), 29.6, 29.5, 29.3, 27.4, 27.1, 26.1,
22.7, 14.2, 14.1. HRMS (ESI+): Calcd for [C22H40O4+H] 369.3006.
Found: 369.3011.
less oil. ½a 2D5
¼ ꢀ14:6 (c 0.6, CHCl3). IR (CHCl3): mmax 2988, 2928,
ꢁ
2857, 1755, 1660, 1466, 1382, 1373, 1216, 1099, 1034, 861,
668 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.88 (t, J = 6.8 Hz, 3H,
.
CH3), 1.27–1.36 (m, 19H, CH3, H-5, H-6, H-7, H-8, H-9, H-10, H-
11, H-12), 1.48 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.63–1.87 (m, 2H,
H-4), 4.11–4.13 (m, 2H, H-2, H-3), 4.24 (q, J = 7.0 Hz, 2H, OCH2).
13C NMR (100 MHz, CDCl3): d 171.0, 110.7, 79.2, 79.1, 61.3, 33.5,
31.9, 29.6, 29.54, 29.5, 29.46, 29.3, 27.2, 25.64, 25.6, 22.7, 14.2,
14.1. HRMS (ESI+): Calcd for [C18H34O4+H] 315.2536. Found:
315.2545.
4.1.9. (4S,5S,Z)-4,5-(Isopropylidenedioxy)pentadec-2-en-1-ol 7c
To a solution of the acetonide ester 17a (0.41 g, 1.204 mmol) in
CH2Cl2 (20 mL) was added DIBAL-H (1.51 mL, 2.65 mmol, 1.75 M
solution in toluene, 2.2 equiv) dropwise at 0 °C. The reaction mix-
ture was stirred for 2 h and warmed to room temperature and stir-
red for 2 h. It was then quenched by adding a saturated aqueous
solution of potassium–sodium–tartarate (5 mL) and stirred for
2 h. It was then extracted with CH2Cl2 (3 ꢃ 20 mL) and the com-
bined organic extracts were washed with water, brine, dried
(Na2SO4), and concentrated. The residue was purified by flash col-
umn chromatography using petroleum ether/EtOAc (3:2) as eluent
4.1.6. (2R,3S)-Ethyl 2,3-(isopropylidenedioxy)pentadecanoate
16b
The title compound was prepared from 15b (1.2 g, 3.96 mmol)
by a procedure similar to that described for the conversion of
15a to 16a to give acetonide ester 16b (1.32 g, 97%) as a colorless
oil. ½a 2D5
¼ ꢀ10:8 (c 0.74, CHCl3). IR (CHCl3): mmax 3020, 2991,
ꢁ
2928, 2856, 1749, 1657, 1523, 1467, 1383, 1374, 1099, 1031,

R. A. Fernandes et al. / Tetrahedron: Asymmetry 23 (2012) 60–66
65
to afford 7c (0.34 g, 95%) as a colorless oil. ½a D25
ꢁ
¼ þ2:1, (c 0.54,
74%) as colorless oils. Data for 9a: ½a D25
ꢁ
¼ þ37:6 (c 0.22, CHCl3).
CHCl3). IR (CHCl3): mmax 3682, 3613, 3448, 3019, 2989, 2929,
1H NMR (400 MHz, CDCl3): d = 0.87 (t, J = 6.9 Hz, 3H, CH3), 1.18–
1.30 (m, 20H, H-30, H-40, H-50, H-60, H-70, H-80, H-90, H-100, H-110,
H-120), 1.35–1.75 (m, 3H, H-20, OH), 2.47 (dd, J = 17.7, 10.1 Hz,
1H, HA-3), 2.78 (dd, J = 17.4, 8.9 Hz, 1H, HB-3), 3.21–3.25 (m, 1H,
H-4), 3.56–3.61 (m, 1H, H-10), 4.10 (dd, J = 8.3, 2.4 Hz, 1H, H-5),
5.18 (d, J = 10.7 Hz, 1H, H-vinyl), 5.22 (d, J = 17.1 Hz, 1H, H-vinyl),
2856, 1602, 1523, 1466, 1381, 1372, 1164, 1042, 930, 876, 669,
626 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.87 (t, J = 6.8 Hz, 3H,
.
CH3), 1.15–1.70 (m, 18H, H-6, H-7, H-8, H-9, H-10, H-11, H-12, H-
13, H-14), 1.41 (s, 3H, CH3), 1.42 (s, 3H, CH3), 3.65–3.70 (m, 1H,
H-5), 4.11–4.21 (m, 1H, H-4), 4.31–4.36 (m, 2H, H-1), 5.48–5.54
(m, 1H, H-2), 5.85–5.92 (m, 1H, H-3). 13C NMR (100 MHz, CDCl3):
d 134.2, 128.5, 108.6, 80.9, 76.7, 58.6, 31.9, 31.7, 29.7, 29.54,
29.5, 29.4, 29.3, 27.3, 27.0, 26.0, 22.6, 14.1. HRMS (ESI+): Calcd
for [C18H34O3+H] 299.2587. Found: 299.2594.
5.72–5.79 (m, 1H, H-vinyl). Data for 9b: ½a D25
¼ þ34:2 (c 0.38,
ꢁ
CHCl3). 1H NMR (400 MHz, CDCl3): d 0.87 (t, J = 6.7 Hz, 3H, CH3),
1.19–1.33 (m, 20H, H-30, H-40, H-50, H-60, H-70, H-80, H-90, H-100,
H-110, H-120), 1.36–1.76 (m, 3H, H-20, OH), 2.59 (dd, J = 17.3,
9.0 Hz, 1H, HA-3), 2.69 (dd, J = 17.5, 9.0 Hz, 1H, HB-3), 3.20–3.24
(m, 1H, H-4), 3.71–3.80 (m, 1H, H-10), 4.38 (dd, J = 7.9, 2.7 Hz, 1H,
H-5), 5.21 (d, J = 11.3 Hz, 1H, H-vinyl), 5.22 (d, J = 15.9 Hz, 1H, H-vi-
nyl), 5.85–6.01 (m, 1H, H-vinyl). Other spectral data and analysis
for 9a and 9b are same as reported earlier.8e
4.1.10. (4S,5S,Z)-4,5-(Isopropylidenedioxy)heptadec-2-en-1-ol
7d
The title compound was prepared from 17b (0.5 g, 1.36 mmol)
by a procedure similar to that described for the conversion of
17a to 7c to give allyl alcohol 7d (0.42 g, 95%) as a colorless oil.
½
a 2D5
ꢁ
¼ þ2:9 (c 0.6, CHCl3). IR (CHCl3): mmax 3684, 3616, 3432,
3019, 2928, 2856, 1687, 1603, 1523, 1468, 1422, 1382, 1047,
929, 877, 669, 626 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.87 (t,
4.1.13. (2R,3S)-4-Methylene-5-oxo-2-undecyltetrahydrofuran-
3-carboxylic acid/(+)-nephrosterinic acid 5
.
Methoxy magnesium methylcarbonate (Stiles reagent, 4.3 mL,
8.64 mmol, 38.0 equiv, 2 M solution in DMF) was added under an
inert atmosphere to 18a (64.5 mg, 0.227 mmol) and the solution
stirred at 135 °C for 60 h. After cooling the reaction mixture was
acidified with dropwise addition of cold 10% HCl (15 mL) at 0 °C.
Then CH2Cl2 (25 mL) was added to the mixture and stirred for
0.5 h. The aqueous layer was extracted with CH2Cl2 (4 ꢃ 30 mL).
The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated. The residue was treated with 3 mL
of a freshly prepared stock solution [HOAc (10 mL), 37% formalde-
hyde in water (7.5 mL), N-methylaniline (2.6 mL) and NaOAc
(0.3 g)] and stirred for 3 h at room temperature. Brine solution
(20 mL, containing 2 mL conc. HCl) was added and the aqueous
layer extracted with Et2O (5 ꢃ 20 mL). The combined organic lay-
ers were washed with brine, dried (Na2SO4), and concentrated.
The residue was purified by silica gel flash column chromatogra-
phy (CH2Cl2/EtOAc, 19:1) to furnish 5 (43.7 mg, 65%) as a white so-
J = 6.7 Hz, 3H, CH3), 1.15–1.80 (m, 22H, H-6, H-7, H-8, H-9, H-10,
H-11, H-12, H-13, H-14, H-15, H-16), 1.41 (s, 3H, CH3), 1.42 (s,
3H, CH3), 3.64–3.70 (m, 1H, H-5), 4.16–4.21 (m, 1H, H-4), 4.31–
4.36 (m, 2H, H-1), 5.50–5.56 (m, 1H, H-2), 5.85–5.92 (m, 1H, H-
3). 13C NMR (100 MHz, CDCl3): d 134.1, 128.5, 108.6, 80.9, 76.7,
58.6, 31.9, 31.7, 29.7, 29.62 (2C), 29.6, 29.5, 29.46, 29.3, 27.3,
27.0, 26.0, 22.6, 14.1. HRMS (ESI+): Calcd for [C20H38O3+H]
327.2900. Found: 327.2908.
4.1.11. (4R,5S)-5-[(S)-1-Hydroxyundecyl]-4-vinyl-4,5-
dihydrofuran-2(3H)-one 8a and (4S,5S)-5-[(S)-1-
hydroxyundecyl]-4-vinyl-4,5-dihydrofuran-2(3H)-one 8b
To a solution of allyl alcohol 7c (0.6 g, 2.01 mmol) in toluene
(15 mL) were added trimethylorthoacetate (2.41 g, 20.10 mmol,
10.0 equiv) and EtCO2H (catalytic), and the solution refluxed for
24 h. After cooling to room temperature, the volatile material
was removed under reduced pressure and the residue (0.72 g)
was dissolved in MeOH (30 mL). To this was added 4 N HCl
(5 mL) and stirred for 12 h at room temperature. It was then
quenched with powdered NaHCO3 (1.0 g) and filtered. The filtrate
was concentrated and the residue purified by silica gel flash col-
umn chromatography (petroleum ether/EtOAc, 9:1) to provide 8b
(45 mg, 8%) as a colorless oil. Further elution gave 8a (426 mg,
lid. Mp 82–84 °C, ½a D25
ꢁ
¼ þ12:5 (c 0.1, CHCl3); lit.6b Mp 86–88 °C,
½
a 3D2
ꢁ
¼ þ13:0 (c 0.66, CHCl3). IR (CHCl3): mmax 3684, 3020, 2958,
2928, 2856, 1763, 1719, 1602, 1523, 1475, 1423, 1117, 1018,
929, 850, 669, 626 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 0.87 (t,
.
J = 6.8 Hz, 3H, CH3), 1.11–1.60 (m, 18H, H-20, H-30, H-40, H-50, H-60,
H-70, H-80, H-90, H-100), 1.65–1.80 (m, 2H, H-10), 3.58–3.64 (m, 1H,
H-3), 4.78–4.82 (m, 1H, H-2), 6.01 (d, J = 3.0 Hz, 1H, H-vinyl), 6.45
(d, J = 3.0 Hz, 1H, H-vinyl). 13C NMR (CDCl3, 100 MHz): d 172.2,
168.2, 132.7, 125.6, 78.9, 49.4, 35.7, 31.9, 29.7, 29.6, 29.5, 29.4,
29.3, 29.2, 24.8, 22.7, 14.1. HRMS (ESI+): Calcd for [C17H28O4+H]
297.2066. Found: 297.2072.
75%) as a colorless oil. Data for 8a: ½a D25
¼ þ37:0 (c 0.32, CHCl3).
ꢁ
1H NMR (400 MHz, CDCl3): d 0.87 (t, J = 6.5 Hz, 3H, CH3), 1.25–
1.39 (m, 16H, H-30, H-40, H-50, H-60, H-70, H-80, H-90, H-100), 1.38–
1.74 (m, 3H, H-20, OH), 2.46 (dd, J = 17.7, 10.3 Hz, 1H, HA-3), 2.78
(dd, J = 17.7, 8.9 Hz, 1H, HB-3), 3.21–3.25 (m, 1H, H-4), 3.58–3.61
(m, 1H, H-10), 4.09 (d, J = 8.3 Hz, 1H, H-5), 5.16 (d, J = 10.7 Hz, 1H,
H-vinyl), 5.21 (d, J = 17.4 Hz, 1H, H-vinyl), 5.71–5.78 (m, 1H, H-vi-
nyl). Data for 8b: ½a D25
ꢁ
¼ þ40:1 (c 0.28, CHCl3). 1H NMR (400 MHz,
4.1.14. (2R,3S)-4-Methylene-5-oxo-2-tridecyltetrahydrofuran-3-
carboxylic acid/(+)-protolichesterinic acid (6)
CDCl3): d = 0.87 (t, J = 6.8 Hz, 3H, CH3), 1.18–1.31 (m, 16H, H-30, H-
40, H-50, H-60, H-70, H-80, H-90, H-100), 1.36–1.77 (m, 3H, H-20, OH),
2.59 (dd, J = 17.2, 9.2 Hz, 1H, HA-3), 2.69 (dd, J = 17.2, 9.2 Hz, 1H,
HB-3), 3.21–3.25 (m, 1H, H-4), 3.71–3.80 (m, 1H, H-10), 4.38 (dd,
J = 8.1, 2.9 Hz, 1H, H-5), 5.20 (d, J = 15.8 Hz, 1H, H-vinyl), 5.22 (d,
J = 11.4 Hz, 1H, H-vinyl), 5.85–6.02 (m, 1H, H-vinyl). Other spectro-
scopic data and analysis for 8a and 8b are the same as reported
earlier.8e
The title compound was prepared from 18b (55 mg,
0.176 mmol) by a procedure similar to that described for the con-
version of 18a to 5 to give 6 (37.1 mg, 65%) as a white solid. Mp
101–103 °C, ½a 2D5
ꢁ
¼ þ13:9 (c 0.16, CHCl3); lit.7j Mp 103–104 °C,
½
a 2D5
ꢁ
¼ þ14:2 (c 0.95, CHCl3). IR (CHCl3): mmax 3682, 3020, 2927,
2855, 1759, 1714, 1602, 1516, 1466, 1378, 1109, 1023, 929, 669,
626 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 0.87 (t, J = 6.7 Hz, 3H,
.
CH3), 1.08–1.62 (m, 22H, H-20, H-30, H-40, H-50, H-60, H-70, H-80, H-
90, H-100, H-110, H-120), 1.65–1.81 (m, 2H, H-10), 3.59–3.63 (m,
1H, H-3), 4.78–4.82 (m, 1H, H-2), 6.01 (d, J = 2.9 Hz, 1H, H-vinyl),
6.45 (d, J = 2.9 Hz, 1H, H-vinyl). 13C NMR (CDCl3, 100 MHz): d
172.9, 168.3, 132.7, 125.6, 79.0, 49.6, 35.7, 31.9 (2C), 29.6, 29.5
(3C), 29.4, 29.3, 29.2, 24.8, 22.7, 14.1. HRMS (ESI+): Calcd for
[C19H32O4+H] 325.2379. Found: 325.2386.
4.1.12. (4R,5S)-5-[(S)-1-Hydroxytridecyl]-4-vinyl-4,5-
dihydrofuran-2(3H)-one 9a and (4S5S)-5-[(S)-1-
hydroxytridecyl]-4-vinyl-4,5-dihydrofuran-2(3H)-one 9b
The title compounds were prepared from 7d (0.5 g, 1.53 mmol)
by a procedure similar to that described for the conversion of 7c to
8a and 8b. The reaction afforded 9b (33 mg, 7%) and 9a (352 mg,

66
R. A. Fernandes et al. / Tetrahedron: Asymmetry 23 (2012) 60–66
1997, 53, 17335; (f) Mandal, P. K.; Maiti, G.; Roy, S. C. J. Org. Chem. 1998, 63,
Acknowledgements
2829; (g) Chen, M.-J.; Liu, R.-S. Tetrahedron Lett. 1998, 39, 9465; For chiral
synthesis, see: (h) Murta, M. M.; de Azevedo, M. B. M.; Greene, A. E. J. Org. Chem.
1993, 58, 7537; (i) Sibi, M. P.; Deshpande, P. K.; La Loggia, A. J. Synlett 1996,
343; (j) Martín, T.; Rodríguez, C. M.; Martín, V. S. J. Org. Chem. 1996, 61, 6450;
(k) Masaki, Y.; Arasaki, H.; Itoh, A. Tetrahedron Lett. 1999, 40, 4829; (l) ref. 6b.;
(m) Chhor, R. B.; Nosse, B.; Sörgel, S.; Böhm, C.; Seitz, M.; Reiser, O. Chem. Eur. J.
2003, 9, 261; (n) Braukmüller, S.; Brückner, R. Eur. J. Org. Chem. 2006, 2110; (o)
Saha, S.; Roy, S. C. Tetrahedron 2010, 66, 4278.
The authors are indebted to the IRCC, IIT-Bombay and the
Department of Science and Technology, New Delhi (Grant No. SR/
S1/OC-25/2008) for financial support. M.B.H., A.K.C., and A.B.I. are
grateful to the Council of Scientific and Industrial Research (CSIR)
New Delhi for a research fellowship.
8. (a) Fernandes, R. A.; Ingle, A. B. Tetrahedron Lett. 2009, 50, 1122; (b) Fernandes,
R. A.; Dhall, A.; Ingle, A. B. Tetrahedron Lett. 2009, 50, 5903; (c) Fernandes, R. A.;
Chowdhury, A. K. J. Org. Chem. 2009, 74, 8826; (d) Fernandes, R. A.; Ingle, A. B.;
Chavan, V. P. Tetrahedron: Asymmetry 2009, 20, 2835; (e) Fernandes, R. A.;
Chowdhury, A. K. Eur. J. Org. Chem. 2011, 1106; (f) Fernandes, R. A.; Chowdhury,
A. K. Tetrahedron: Asymmetry 2011, 22, 1114.
9. For the Johnson–Claisen rearrangement see: (a) Johnson, W. S.; Werthemann,
L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-T.; Faulkner, D. J.; Peterson, M. R. J. Am.
Chem. Soc. 1970, 92, 741; (b) Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A.
C., Jr.; Saucy, G. J. Org. Chem. 1976, 41, 3497; (c) Hiyama, T.; Kobayashi, K.;
Fujita, M. Tetrahedron Lett. 1984, 25, 4959; (d) Ziegler, F. Chem. Rev. 1988, 88,
1423; (e) Agami, C.; Couty, F.; Evano, G. Tetrahedron Lett. 2000, 41, 8301; (f)
Brenna, E.; Fuganti, C.; Gatti, F. G.; Passoni, M.; Serra, S. Tetrahedron: Asymmetry
2003, 14, 2401.
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Yakugaku Zasshi 1980, 100, 755; Chem. Abstr. 1980, 93, 179563f
10. For similar cross-metathesis with acrylates to generate a,b-unsaturated esters,
see: (a) Forman, G. S.; Tooze, R. P. J. Organomet. Chem. 2005, 690, 5863; (b)
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360; (c) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783.
11. Olefin 14a is known in literature and prepared by Wittig olefination, see:
Gurjar, M. K.; Pramanik, C.; Bhattasali, D.; Ramana, C. V.; Mohapatra, D. K. J.
Org. Chem. 2007, 72, 6591. Compound 15a is also known in the above paper.
12. Olefin 14b is known in the literature and prepared by Wittig-Horner
olefination, see: (a) Bonini, C.; Federici, C.; Rossi, L.; Righi, G. J. Org. Chem.
1995, 60, 4803; (b) Chun, J.; Byun, H.-S.; Bittman, R. . J. Org. Chem. 2003, 68, 348.
13. Asymmetric dihydroxylation of 14b was similar to that reported for the
preparation of ent-15b.12 Enantiomeric excess was determined by chiral HPLC.
14. The (Z)-selective Wittig olefination was carried out similar to literature reports,
see: Reddy, D. K.; Shekhar, V.; Prabhakar, P.; Babu, D. C.; Ramesh, D.;
Siddhardha, B.; Murthy, U. S. N.; Venkateswarlu, Y. Bio. Org. Med. Chem. Lett.
2011, 21, 997. 1H NMR indicated ca.17:83 (E/Z) mixture. The pure (Z) isomer
was isolated by column chromatography.
5. Huneck, S.; Schreiber, K. Phytochemistry 1972, 11, 2429.
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Org. Chem. 1976, 41, 4065; For chiral synthesis, see: (b) Kongsaeree, P.;
Meepowpan, P.; Thebtaranonth, Y. Tetrahedron: Asymmetry 2001, 12, 1913; (c)
Jongkol, R.; Choommongkol, R.; Tarnchompoo, B.; Nimmanpipug, P.;
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7. For a synthesis of racemic protolichesterinic acid see: (a) van Tamelen, E. E.;
Bach, S. R. J. Am. Chem. Soc. 1958, 80, 3079; (b) Martin, J.; Watts, P. C.; Johnson,
F. J. Org. Chem. 1974, 39, 1676; (c) Ref. 6a.; (d) Damon, R. E.; Schlessinger, R. H.
Tetrahedron Lett. 1976, 17, 1561; (e) Ghatak, A.; Sarkar, S.; Ghosh, S. Tetrahedron
15. de Azevedo, M. B. M.; Murta, M. M.; Greene, A. E. J. Org. Chem. 1992, 57, 4567.