Stereoselective total synthesis of (+)-nephrosteranic acid and (+)-roccellaric acid through asymmetric dihydroxylation and Johnson-Claisen rearrangement

Article abstract of DOI:10.1002/ejoc.201001419

An efficient stereoselective total synthesis of (+)-nephrosteranic acid and (+)-roccellaric acid is presented. The synthetic strategy features the regioselective asymmetric dihydroxylation of the γ,δ-olefinic bond of a α,β,γ,δ-unsaturated ester and the Johnson-Claisen rearrangement as the key steps. The synthesis is achieved in 10 steps and 6.8% (nephrosteranic acid) and 7.6% (roccellaric acid) overall yield.

Full text of DOI:10.1002/ejoc.201001419

FULL PAPER
DOI: 10.1002/ejoc.201001419
Stereoselective Total Synthesis of (+)-Nephrosteranic Acid and (+)-Roccellaric
Acid through Asymmetric Dihydroxylation and Johnson–Claisen
Rearrangement
[a]
[a]
Rodney A. Fernandes* and Asim K. Chowdhury
Keywords: Diastereoselectivity / Asymmetric synthesis / Dihydroxylation / Rearrangement / Total synthesis
An efficient stereoselective total synthesis of (+)-nephroster-
anic acid and (+)-roccellaric acid is presented. The synthetic
and the Johnson–Claisen rearrangement as the key steps.
The synthesis is achieved in 10 steps and 6.8% (nephroster-
strategy features the regioselective asymmetric dihydrox- anic acid) and 7.6% (roccellaric acid) overall yield.
ylation of the γ,δ-olefinic bond of a α,β,γ,δ-unsaturated ester
Introduction
(
+)-Nephrosteranic acid (1)[1] and (+)-roccellaric acid
2)[
1g,1i,1k,2]
are trisubstituted γ-butyrolactones (Figure 1)
(
[3]
belonging to the family of paraconic acids isolated from
various species of lichens, moss, and fungus. They possess
antifungal, antibiotic, antitumor, and antibacterial
Figure 1. (+)-Nephrosteranic acid (1) and (+)-roccellaric acid (2).
[
3]
properties. Due of this pharmacological profile they have
attracted considerable interest.[
1,2]
Depending on the
distinct synthetic strategies, 1 and 2 are synthesized in
[
1d,2d,2g]
racemic
or enantiopure form by using starting mate-
[1h,2i]
Results and Discussion
rials from the chiral pool,
by using chiral auxilia-
or by applying other asymmetric methodolo-
[
1i,2f]
ries,
As part of our research program[4] aimed at the enantio-
selective synthesis of bioactive natural products employing
the Johnson–Claisen rearrangement of allyl alcohols with a
chiral vicinal diol functionality, we became interested in the
paraconic acids, specifically (+)-nephrosteranic acid (1) and
(+)-roccellaric acid (2). The retrosynthetic route to 1 and 2
is shown in Scheme 1. Removal of the free hydroxy group
in 3a and 3b, conversion of the β-vinyl bond to a carboxylic
acid group, and stereoselective α-methylation would give
title compounds 1 and 2, respectively. β,γ-Disubstituted-γ-
lactone 3a (or 3b) is the product of a stereoselective John-
son–Claisen rearrangement of allyl alcohol with vicinal chi-
ral diol functionality 4a (or 4b). Compounds 4a and 4b
could be obtained through regioselective asymmetric dihy-
droxylation of the distant olefinic bond of α,β,γ,δ-unsatu-
rated esters 5a and 5b, respectively, followed by usual aceton-
ide formation and ester group reduction. Diene 5a (or 5b)
can be obtained from the addition of ethyl propiolate to
gies.[
1b,1g,1k,1l,2b,2c,2e,2h]
Formal synthesis of these acids are
Perepogu et. al synthesized (+)-1 by em-
[
1c]
also reported.
ploying Sharpless asymmetric epoxidation, ring-closing me-
tathesis, and Gilman addition of the vinyl group as key
[
1b]
steps.
Desymmetrization of metalated 1,4-cyclohexa-
[
1e,1f]
diene have been employed by Studer and co-workers.
The synthesis by Reiser and co-workers used an asymmetric
Cu-catalyzed cyclopropanation of furan-2-carboxylic acid
IV
methyl ester and Sn or barium hydroxide mediated retro-
aldol/lactonization of cyclopropanols to synthesize γ-
[
1g,2e]
butyrolactones.
Jacobi et. al employed the Nicholas–
[
1j]
Schreiber reaction in the synthesis of both enantiomers
of 1. Takahata et. al described the synthesis of (+)-1 by
using the stereoselective iodolactonization and conjugate
addition to α,β-unsaturated lactones.
[1k,1l]
Ru-mediated
asymmetric hydrogenation was also used for the prepara-
tion of (+)-roccellaric acid (2).[2b]
aldehyde 6a (or 6b) followed by PPh -mediated “allene”-
type rearrangement. Because the creation of absolute
stereochemistry is accomplished through asymmetric dihy-
droxylation, our synthetic strategy provides the needed flex-
ibility to access both enantiomers of each of the natural
products.
3
[
a] Department of Chemistry, Indian Institute of Technology
[5]
Bombay,
Powai, Mumbai 400076, Maharashtra, India
Fax: +91-22-25767152
E-mail: rfernand@chem.iitb.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001419.
1106
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1106–1112

Total Synthesis of (+)-Nephrosteranic Acid and (+)-Roccellaric Acid
[
7]
9
b (61%, 97%ee ), respectively. Acetonide protection of
diols 9a (98%) and 9b (98%) and subsequent DIBAL-H
reduction of the ester groups provided 4a (89%) and 4b
(
90%), respectively. The stage was now set to attempt the
[
4,8]
diastereoselective Johnson–Claisen rearrangement
of all-
yl alcohols 4a and 4b with the chiral vicinal diol function-
ality. Reaction of 4a with trimethylorthoacetate in the pres-
ence of a catalytic amount of propionic acid in xylene over
4
h and the same-pot hydrolysis of the acetonide resulted in
the formation of diastereomeric lactones 3a and 10a in a
[
9]
1
.1:1 ratio. The reaction in toluene over 24 h and the
same-pot hydrolysis provided an improved ratio of 2:1 for
a/10a. These were easily separated by silica gel flash col-
3
umn chromatography in 58 and 28% yield, respectively.
Similarly, the Johnson–Claisen rearrangement of 4b and
subsequent lactonization afforded 3b (60%) and 10b (29%).
Lactones 3a and 3b have the required functionality to set
the β,γ-stereocenters of the target molecules, although the
free hydroxy group in the side chain needed to be removed.
The final transformations leading to the completion of
the total syntheses are depicted in Scheme 3. The hydroxy
groups in 3a and 3b were converted into xanthate groups to
give 11a and 11b in 62 and 64% yield, respectively. AIBN/
nBu SnH-mediated removal of the xanthate groups gave β-
3
vinyl-γ-lactones 12a and 12b in quantitative yield for both.
Ozonolytic cleavage of the vinyl bond and further oxidation
efficiently placed the desired β-carboxylic acid group, pro-
Scheme 1. Retrosynthetic analysis of 1 and 2.
The forward synthesis was initiated by assembling pre- viding 13a and 13b in good yield of 95 and 94%, respec-
cursor β,γ-disubstituted-γ-lactones 3a and 3b, as shown in tively. The α-methyl group in 13a was stereoselectively in-
Scheme 2. Addition of lithiated ethyl propiolate (7) to alde- troduced by using NaHMDS/MeI to give (+)-nephroster-
2
5
hyde 6a gave hydroxy alkynoate 8a (86%). Similarly, 6b pro- anic acid (1) in 99% yield {[α] = +26.9 (c = 0.14, CHCl3);
D
[
1k]
27
vided 8b (85%). The Ph P-mediated “allene”-type re- ref.
[α] = +27.2 (c = 1.45, CHCl )}. Similarly, upon α-
3
D 3
[
5]
arrangement of 8a and 8b afforded all-trans dienes 5a methylation 13b provided (+)-roccellaric acid (2) in quanti-
70%) and 5b (71%), respectively. The enantio- and regiose- tative yield {[α]2 = +26.2 (c = 2.0, CHCl ); ref. [α]
5
[2i]
20
=
(
D
3
D
[6]
lective asymmetric dihydroxylation of the distant olefin +27 (c = 1.73, CHCl )}. The spectroscopic data for 1 and
bond in 5a and 5b afforded diols 9a (62%, 96%ee ) and 2 was in full agreement with the literature data.
3
[
7]
[1k]
Scheme 2. Synthesis of separable diastereomeric γ-lactones 3a, 10a, 3b, and 10b. Reagents and conditions: (i) LiHMDS (1.4 equiv.), THF,
Fe(CN) (3.0 equiv.), K CO
O (1:1), 0 °C, 12 h, 9a (62%),
CO, pTsOH (cat.), room temp., 12 h, 98% for both, (b) DIBAL-H (2.2 equiv.), CH Cl
H (cat.), reflux, 24 h, then room temp., 4 n HCl, MeOH,
–
78 °C, 1.5 h, 8a (86%), 8b (85%); (ii) Ph
3
P (1.2 equiv.), PhH, room temp., 6 h, 5a (70%), 5b (71%); (iii) K
-PHAL (1.0 mol-%), K OsO ·2H O (0.4 mol-%), MeSO NH (1.0 equiv.), tBuOH/H
C(OMe) (2.5 equiv.), Me
CMe (10.0 equiv.), toluene, EtCO
3
6
2
3
(
3.0 equiv.), (DHQ)
b (61%); (iv) (a) Me
2
2
4
2
2
2
2
9
0
1
2
2
2
2
2
,
°C, 2.5 h, 4a (89%), 4b (90%); (v) (MeO)
3
2
2 h, 3a (58%), 10a (28%), 3b (60%), 10b (29%).
Eur. J. Org. Chem. 2011, 1106–1112
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1107

R. A. Fernandes, A. K. Chowdhury
FULL PAPER
Scheme 3. Synthesis of (+)-nephrosteranic acid (1) and (+)-roccellaric acid (2). Reagents and conditions: (i) CS
1.2 equiv.), THF, 0 °C, 1 h, then MeI (7.0 equiv.), 0 °C to room temp., 2 h, 11a (62%), 11b (64%); (ii) Bu SnH (15.0 equiv.), AIBN (cat.),
toluene, reflux, 6 h, 12a (quant), 12b (quant); (iii) (a) O , CH Cl , –78 °C, 0.5 h, then Me S, –78 °C, 1 h, room temp. 2 h; (b) CrO , H SO
acetone, 0 °C, 20 min, 13a (95%), 13b (94%); (iv) NaHMDS (2.2 equiv.), THF, –78 °C, 1 h, MeI (10.0 equiv.), –78 °C, 2 h, 1 (99%), 2
quant).
2
(5.0 equiv.), NaH
(
3
3
2
2
2
3
2
4
,
(
perature. It was diluted with water and extracted with EtOAc
4ϫ50 mL). The combined organic layers were washed with water
In summary, we have demonstrated the strategic utility and brine, dried (Na SO ), and concentrated. The residue was puri-
Conclusions
(
2
4
of asymmetric dihydroxylation and the Johnson–Claisen re- fied by silica gel column chromatography (petroleum ether/EtOAc,
arrangement of allyl alcohols with a chiral vicinal diol func- 9:1) to give 8a (6.58 g, 86%) as a colorless oil. IR (CHCl ): ν˜ =
441, 3020, 2929, 2857, 2239, 1968, 1714, 1639, 1467, 1369, 1259,
3
3
1
0
1
tionality to furnish the chiral β,γ-disubstituted-γ-lactones
and their efficient conversion into the paraconic acids (+)-
nephrosteranic acid (1) and (+)-roccellaric acid (2) in 10
steps and 6.8 and 7.6% overall yield, respectively. Although
the presented strategy has been described only for one en-
antiomer of the title natural products, the choice of the suit-
able enantiomers of 9a and 9b permits control of the abso-
–
1 1
218, 1021, 933, 768, 669 cm . H NMR (400 MHz, CDCl
.87 (t, J = 6.9 Hz, 3 H, CH ), 1.0–1.40 (m, 19 H, CH , 14-, 13-,
2-, 11-, 10-, 9-, 8-, 7-H), 1.41–1.47 (m, 2 H, 6-H), 1.72–1.79 (m, 2
), 4.48 (t, J = 6.7 Hz, 1
H, 4-H) ppm. C NMR (100 MHz, CDCl ): δ = 13.9, 14.0, 22.6,
4.9, 29.0, 29.2, 29.3, 29.4, 29.5, 29.6, 31.9, 36.8, 62.0, 62.1, 76.4,
8.0, 153.5 ppm. HRMS (ESI+): calcd. for [C17 + H]
3
): δ =
3
3
H, 5-H), 4.24 (q, J = 7.1 Hz, 2 H, OCH
2
13
3
2
8
30 3
H O
lute configuration in the final products and the synthesis of 283.2274; found 283.2279.
other enantiomers can also be realized. Secondly, the syn-
Ethyl 4-Hydroxyheptadec-2-ynoate (8b): The title compound was
prepared from 6b (4.9 g, 23.07 mmol) by a procedure similar to that
described for the conversion of 6a into 8a with ethyl propiolate to
thetic strategy has significant potential for further extension
to the synthesis of other paraconic acids including those
having an α-methylene group. Efforts in this direction are
in progress in our laboratory.
give 8b (6.09 g, 85%) as a colorless oil. IR (CHCl
3
): ν˜ = 3421, 2925,
–1
2
855, 2237, 1717, 1466, 1368, 1246, 1048, 862, 752, 723, 628 cm .
1
H NMR (400 MHz, CDCl
.20–1.40 (m, 23 H, CH , 16-, 15-, 14-, 13-, 12-, 11-, 10-, 9-, 8-, 7-
H), 1.42–1.48 (m, 2 H, 6-H), 1.73–1.80 (m, 2 H, 5-H), 4.24 (q, J =
3 3
): δ = 0.88 (t, J = 7.2 Hz, 3 H, CH ),
1
3
Experimental Section
1
3
7
(
2
1
.2 Hz, 2 H, OCH
100 MHz, CDCl ): δ = 13.9, 14.1, 22.6, 24.9, 29.2, 29.1, 29.3, 29.4,
9.5, 29.6, 29.61, 29.64, 31.9, 36.8, 62.0, 62.1, 76.5, 88.0,
53.5 ppm. HRMS (ESI+): calcd. for [C19 + H] 311.2586;
2
), 4.48 (t, J = 6.7 Hz, 1 H, 4-H) ppm. C NMR
General Methods: Flasks were oven or flame dried and cooled in a
desiccator. Dry reactions were carried out under an atmosphere of
Ar or N . Solvents and reagents were purified by standard meth-
2
3
34 3
H O
ods. Thin-layer chromatography was performed on EM 250 Kiesel-
gel 60 F254 silica gel plates. Spots were visualized by staining with
found 311.2591.
1
13
4
KMnO or by using a UV lamp. H NMR and C NMR were
(
2E,4E)-Ethyl Pentadec-2,4-dienoate (5a): To a solution of 8a
6.12 g, 21.67 mmol) in benzene (30 mL) was added PPh (6.82 g,
6.0 mmol, 1.2 equiv.) at room temperature, and the resulting mix-
ture was stirred for 6 h. It was diluted with petroleum ether/EtOAc
95:5, 80 mL) and filtered through a pad of silica gel. The filtrate
recorded with a Varian Mercury Plus, AS400 and a Bruker, Avance
(
3
III 400 spectrometer, and the chemical shifts are based on the TMS
2
1
peak at δ = 0.00 pm for H NMR and the CDCl
7
3
peak at δ =
7.00 ppm (t) for 13C NMR spectroscopy. IR spectra were obtained
(
with a Perkin–Elmer Spectrum One FTIR spectrometer. Optical
rotations were measured with a Jasco P-2000 digital polarimeter.
HRMS was recorded by using a Micromass:Q-Tof micro (YA-105)
spectrometer.
was concentrated, and the residue was purified by silica gel column
chromatography (petroleum ether/EtOAc, 95:5) to give 5a (4.04 g,
70%). IR (CHCl
3
): ν˜ = 3021, 2956, 2927, 2855, 1712, 1644, 1618,
1
466, 1368, 1333, 1304, 1262, 1217, 1190, 1140, 1119, 1096, 1036,
–
1 1
Ethyl 4-Hydroxypentadec-2-ynoate (8a): To a solution of ethyl pro-
piolate (7; 2.93 g, 25.86 mmol, 1.1 equiv.) in dry THF (70 mL) at
1000, 873, 759, 722, 668 cm . H NMR (400 MHz, CDCl
3
): δ =
0.88 (t, J = 6.9 Hz, 3 H, CH ), 1.10–1.50 (m, 19 H, CH , 14-, 13-,
3
3
–
1
6
78 °C was added LiHMDS (1.2 m in THF, 31.7 mL, 37.98 mmol, 12-, 11-, 10-, 9-, 8-, 7-H), 2.10–2.20 (m, 2 H, 6-H), 4.19 (q, J =
.4 equiv.), and the mixture was stirred at –78 °C for 1 h. Aldehyde
7.1 Hz, 2 H, OCH
2
), 5.77 (d, J = 15.3 Hz, 1 H, olefin-H), 6.0–6.20
a (5.0 g, 27.13 mmol) in THF (15 mL) was added at –78 °C and
(m, 2 H, olefin-H), 7.26 (dd, J = 15.3, 10.1 Hz, 1 H, olefin-H) ppm.
1
3
stirring was continued for 30 min. The reaction mixture was
quenched with sat. aq. NH Cl solution and warmed to room tem-
C NMR (100 MHz, CDCl
3
): δ = 14.0, 14.3, 22.7, 28.7, 29.2, 29.4,
4
29.5, 29.6, 29.7, 31.9, 33.0, 60.1, 119.1, 128.3, 144.8, 145.1,
1108
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1106–1112

Total Synthesis of (+)-Nephrosteranic Acid and (+)-Roccellaric Acid
67.3 ppm. HRMS (ESI+): calcd. for [C17 + H] 267.2324;
1
H
30
O
2
through a pad of silica gel. The filtrate was concentrated to give
virtually pure acetonide ester (1.51 g) as a colorless oil. This was
used directly for the next reaction without further purification.
found 267.2328.
(
2E,4E)-Ethyl Heptadec-2,4-dienoate (5b): The title compound was
prepared from 8b (8.5 g, 27.38 mmol) by a procedure similar to that
described for the conversion of 8a into 5a with PPh to give 5b
5.72 g, 71% yield) as a colorless oil. IR (CHCl ): ν˜ = 3019, 2929,
855, 1707, 1637, 1514, 1466, 1362, 1303, 1217, 1137, 1034, 1000,
2
5
α]
D 3 3
[ = –13.0 (c = 1.0, CHCl ). IR (CHCl ): ν˜ = 2985, 2927, 2856,
1
8
6
1
3
2
1
1
3
726, 1663, 1465, 1370, 1301, 1263, 1173, 1111, 1041, 979, 879,
3
–
1 1
12, 758, 721 cm . H NMR (400 MHz, CDCl
.7 Hz, 3 H, CH ), 1.0–1.80 (m, 21 H, CH , 14-, 13-, 12-, 11-,
0-, 9-, 8-, 7-, 6-H), 1.40 (s, 3 H, CH ), 1.43 (s, 3 H, CH ), 3.70–
.80 (m, 1 H, 5-H), 4.12–4.17 (m, 1 H, 4-H), 4.21 (q, J = 7.1 Hz,
H, OCH ), 6.11 (dd, J = 15.7, 1.4 Hz, 1 H, 2-H), 6.86 (dd, J =
5.7, 5.7 Hz, 1 H, 3-H) ppm. C NMR (100 MHz, CDCl
3
): δ = 0.87 (t, J =
(
3
3
3
2
9
–1 1
3
3
22, 768, 669, 626 cm . H NMR (400 MHz, CDCl
), 1.10–1.50 (m, 23 H, CH , 16-, 15-, 14-, 13-
12-, 11-, 10-, 9-, 8-, 7-H), 2.10–2.20 (m, 2 H, 6-H), 4.19 (q, J =
.1 Hz, 2 H, OCH ), 5.77 (d, J = 15.3 Hz, 1 H, olefin-H), 6.0–6.20
3
): δ = 0.88 (t,
J = 6.7 Hz, 3 H, CH
,
7
3
3
2
1
3
3
): δ =
2
4.1, 14.2, 22.7, 26.0, 26.7, 27.3, 29.3, 29.5, 29.56, 29.6 (2 C), 31.9,
2.1, 60.6, 80.2, 80.7, 109.3, 122.7, 144.2, 166.0 ppm. HRMS
(
m, 2 H, olefin-H), 7.25 (dd, J = 15.3, 10.1 Hz, 1 H, olefin-H) ppm.
1
3
C NMR (100 MHz, CDCl
3
): δ = 14.1, 14.3, 22.7, 28.7, 29.2, 29.3,
(
ESI+): calcd. for [C20
H
36
O
4
+ H] 341.2692; found 341.2698. To a
Cl
40 mL) was added DIBAL-H (1 m in hexane, 9.43 mL, 9.43 mmol,
2
1
2
9.4, 29.5, 29.5, 29.6, 29.63, 31.9, 33.0, 60.1, 119.1, 128.3, 144.8,
solution of the above acetonide ester (1.46 g, 4.29 mmol) in CH
(
2
2
45.1, 167.3 ppm. HRMS (ESI+): calcd. for [C19
95.2637; found 295.2640.
34 2
H O + H]
2.2 equiv.) dropwise at 0 °C, and the reaction mixture was stirred
(
4S,5S,E)-Ethyl 4,5-Dihydroxypentadec-2-enoate (9a): To a mixture
of K Fe(CN) (12.16 g, 36.93 mmol, 3.0 equiv.), K CO (5.10 g, potassium-sodium-tartrate and stirred vigorously at room tempera-
6.93 mmol, 3.0 equiv.), MeSO NH (1.17 g, 12.31 mmol, ture for 1 h. The solution was extracted with CH Cl (4ϫ40 mL),
.0 equiv.), (DHQ) PHAL (96 mg, 0.123 mmol, 1.0 mol-%), and
OsO ·2H O (18 mg, 0.0492 mmol, 0.4 mol-%) in tBuOH/H
1:1, 120 mL) at 0 °C was added olefin 5a (3.28 g, 12.31 mmol) in
one portion. The reaction mixture was stirred at 0 °C for 12 h and
then quenched with solid Na SO (5.0 g). Stirring was continued
for 2.5 h. It was then quenched by adding a sat. aq. solution of
3
6
2
3
3
1
K
2
2
2
2
2
and the combined organic extracts were washed with brine, dried
(Na SO ), and concentrated. The residue was purified by silica gel
2
4
2
2
O
2
4
(
flash column chromatography (petroleum ether/EtOAc, 4:1) to pro-
2
5
vide 4a (1.14 g, 89%) as a colorless oil. [α]D = –5.1 (c = 0.36,
CHCl ). IR (CHCl ): ν˜ = 3420, 2986, 2926, 2856, 1641, 1466, 1379,
2
3
3
3
–
1
1
for an additional 45 min, and the solution was extracted with
1370, 1240, 1171, 1099, 1040, 971, 877, 759, 722, 669 cm .
H
EtOAc (5ϫ50 mL). The combined organic layers were washed with
NMR (400 MHz, CDCl ): δ = 0.86 (t, J = 6.7 Hz, 3 H, CH ), 1.0–
3
3
1
0% aqueous KOH, water, and brine, dried (Na
2
SO
4
), and concen-
1.70 (m, 18 H, 14-, 13-, 12-, 11-, 10-, 9-, 8-, 7-, 6-H), 1.39 (s, 3 H,
CH ), 1.40 (s, 3 H, CH ), 2.18 (br. s, 1 H, OH), 3.62–3.70 (m, 1 H,
trated. Silica gel column chromatography of the crude product (pe-
3
3
troleum ether/EtOAc, 7:3) gave 9a (2.29 g, 62%) as a white solid. 5-H), 4.0 (t, J = 7.9 Hz, 1 H, 4-H), 4.15 (d, J = 5.2 Hz, 2 H, 1-H),
M.p. 70–72 °C. [α]2
3
5
= –28.6 (c = 0.54, CHCl
). IR (CHCl
): ν˜ =
D
3
3
5.68 (dd, J = 15.5, 7.5 Hz, 1 H, 2-H), 5.95 (td, J = 15.5, 5.1 Hz, 1
1
3
310, 3018, 2919, 2849, 1709, 1666, 1463, 1369, 1310, 1275, 1216,
181, 1133, 1113, 1038, 978, 932, 896, 883, 834, 760, 668, 617 cm .
H, 3-H) ppm. C NMR (100 MHz, CDCl ): δ = 14.1, 22.6, 26.1,
3
–
1
1
26.9, 27.2, 29.3, 29.5, 29.54 (3 C), 29.7, 31.9, 62.6, 80.8, 81.7, 108.4,
3 3
): δ = 0.88 (t, J = 6.9 Hz, 3 H, CH ), 128.0, 134.0 ppm. HRMS (ESI+): calcd. for [C H O + H]
1
H NMR (400 MHz, CDCl
.0–1.60 (m, 21 H, CH
br. s, 2 H, OH), 3.45–3.60 (m, 1 H, 5-H), 4.08–4.17 (m, 1 H, 4-
H), 4.21 (q, J = 7.1 Hz, 2 H, OCH ), 6.14 (dd, J = 15.7, 1.8 Hz, 1
H, 2-H), 6.94 (dd, J = 15.7, 5.0 Hz, 1 H, 3-H) ppm. 13C NMR title compound was prepared from diol 9b (1.3 g, 3.96 mmol) by a
1
8
34
3
1
(
3
, 14-, 13-, 12-, 11-, 10-, 9-, 8-, 7-, 6-H), 1.98 299.2586; found 299.2581.
(4S,5S,E)-4,5-(Isopropylidenedioxy)heptadec-2-en-1-ol (4b): The
2
(
3
100 MHz, CDCl
1.9, 33.1, 60.6, 74.0, 74.1, 122.3, 147.1, 166.5 ppm. HRMS (ESI+):
calcd. for [C17 + Na] 323.2198; found 323.2204.
3
): δ = 14.1, 14.14, 22.6, 25.6, 29.3, 29.6 (4 C),
procedure similar to that described for the conversion of 9a into
4a to give the acetonide ester (1.43 g, 98%) and further DIBAL-H
reduction gave 4b (1.14 g, 90%) as a colorless oil. Data for interme-
32 4
H O
2
5
diate acetonide ester: [α]
D 3 3
= –13.9 (c = 0.4, CHCl ). IR (CHCl ):
(4S,5S,E)-Ethyl 4,5-Dihydroxyheptadec-2-enoate (9b): The title
ν˜ = 2982, 2927, 2856, 1727, 1662, 1466, 1371, 1302, 1261, 1176,
compound was prepared from 5b (3.1 g, 10.53 mmol) by a pro-
cedure similar to that described for the conversion of 5a into 9a
under asymmetric dihydroxylation conditions to give 9b (2.11 g,
–
1
1
1
113, 1036, 979, 877, 765, 668, 633 cm . H NMR (400 MHz,
CDCl ): δ = 0.87 (t, J = 6.7 Hz, 3 H, CH ), 1.0–1.80 (m, 25 H,
, 16-, 15-, 14-, 13-, 12-, 11-, 10-, 9-, 8-, 7-, 6-H), 1.41 (s, 1 H,
), 1.43 (s, 1 H, CH ), 3.70–3.80 (m, 1 H, 5-H), 4.10–4.17 (m,
), 6.11 (dd, J = 15.8,
3
3
CH
CH
1
3
1%) as a white solid. M.p. 78–80 °C. [α]2
5
= –20.9 (c = 0.28,
6
D
3
3
CHCl
1
3
). IR (CHCl
3
): ν˜ = 3275, 2918, 2847, 1717, 1708, 1665, 1465,
H, 4-H), 4.21 (q, J = 7.1 Hz, 2 H, OCH
.3 Hz, 1 H, 2-H), 6.86 (dd, J = 15.8, 5.8 Hz, 1 H, 3-H) ppm.
): δ = 14.1, 14.2, 22.7, 26.0, 26.6, 27.2,
9.3, 29.4, 29.5, 29.6, 29.63 (3 C), 31.9, 32.1, 60.6, 80.2, 80.6, 109.3,
22.7, 144.2, 166.0 ppm. HRMS (ESI+): calcd. for [C22 + H]
= –5.6 (c = 0.5,
2
–1
1
369, 1275, 1183, 1116, 1079, 1035, 974, 772 cm . H NMR
1
3
1
C
(
(
(
4
(
400 MHz, CDCl
m, 25 H, CH
br. s, 1 H, OH), 2.78 (br. s, 1 H, OH), 3.45–3.60 (m, 1 H, 5-H),
.10–4.16 (m, 1 H, 4-H), 4.20 (q, J = 7.1 Hz, 2 H, OCH ), 6.12
dd, J = 15.7, 1.3 Hz, 1 H, 2-H), 6.93 (dd, J = 15.7, 4.9 Hz, 1 H,
3
): δ = 0.87 (t, J = 6.7 Hz, 3 H, CH
3
), 1.0–1.60
NMR (100 MHz, CDCl
3
3
, 16-, 15-, 14-, 13-, 12-, 11-, 10-, 9-, 8-, 7-, 6-H), 2.42
2
1
3
40 4
H O
2
2
5
69.3005; found 369.2999. Data for 4b: [α]
). IR (CHCl
D
CHCl
1
3
3
): ν˜ = 3421, 3017, 2928, 2855, 1652, 1458, 1381,
3
2
1
3
-H) ppm. 13C NMR (100 MHz, CDCl
9.3, 29.5, 29.6, 29.61, 29.64 (3 C), 31.9, 33.1, 60.6, 74.0, 74.1,
3
): δ = 14.1, 14.2, 22.7, 25.6,
–
1
1
216, 1168, 1098, 1041, 972, 873, 759, 669 cm . H NMR
(400 MHz, CDCl
3
): δ = 0.87 (t, J = 6.7 Hz, 3 H, CH
3
), 1.0–1.70
22.4, 146.9, 166.4 ppm. HRMS (ESI+): calcd. for [C19
29.2692; found 329.2688.
36 4
H O + H]
(
m, 22 H, 16-, 15-, 14-, 13-, 12-, 11-, 10-, 9-, 8-, 7-, 6-H), 1.40 (s, 3
), 1.41 (s, 3 H, CH ), 3.60–3.75 (m, 1 H, 5-H), 4.01 (t, J =
H, CH
3
3
(
4S,5S,E)-4,5-(Isopropylidenedioxy)pentadec-2-en-1-ol (4a): To a
7.9 Hz, 1 H, 4-H), 4.18 (d, J = 5.0 Hz, 2 H, 1-H), 5.70 (dd, J =
15.3, 7.5 Hz, 1 H, 2-H), 5.97 (td, J = 15.3, 5.0 Hz, 1 H, 3-H) ppm.
solution of diol 9a (1.36 g, 4.53 mmol) in acetone (40 mL) was
added pTsOH (cat.) and 2,2-dimethoxypropane (1.4 mL, 1.18 g,
1
3
C NMR (100 MHz, CDCl
3
): δ = 14.1, 22.7, 26.1, 26.9, 27.3,
11.32 mmol, 2.5 equiv.), and the reaction mixture was stirred at
29.31, 29.5, 29.54, 29.6, 29.63 (3C), 29.7, 31.9, 62.6, 80.8, 81.7,
room temperature for 12 h. NaHCO (0.2 g) was added, and the
mixture was stirred for an additional 30 min and then filtered
3
108.4, 127.9, 134.1 ppm. HRMS (ESI+): calcd. for [C20
327.2900; found 327.2905.
H
38
O
3
+ H]
1109
Eur. J. Org. Chem. 2011, 1106–1112
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

R. A. Fernandes, A. K. Chowdhury
FULL PAPER
(
4R,5S)-5-[(S)-1-Hydroxyundecyl]-4-vinyl-4,5-dihydrofuran-2(3H)-
H, CH
3
), 1.19–1.31 (m, 20 H, 12Ј-, 11Ј-, 10Ј-, 9Ј-, 8Ј-, 7Ј-, 6Ј-, 5Ј-,
one (3a) and (4S,5S)-5-[(S)-1-Hydroxyundecyl]-4-vinyl-4,5-dihy-
drofuran-2(3H)-one (10a): To a solution of allyl alcohol 4a (1.19 g,
4Ј-, 3Ј-H), 1.36–1.75 (m, 3 H, 2Ј-H, OH), 2.58 (dd, J = 17.3, 9.0 Hz,
1 H, 3-H ), 2.69 (dd, J = 17.5, 9.0 Hz, 1 H, 3-H ), 3.20–3.24 (m,
A
B
3
.99 mmol) in toluene (25 mL) was added trimethylorthoacetate 1 H, 4-H), 3.70–3.80 (m, 1 H, 1Ј-H), 4.37 (dd, J = 7.9, 2.7 Hz, 1
(
4.79 g, 39.9 mmol, 10.0 equiv.) and EtCO H (catalytic), and the H, 5-H), 5.20 (d, J = 11.3 Hz, 1 H, vinyl-H), 5.21 (d, J = 15.9 Hz, 1
2
1
3
solution was heated at reflux for 24 h. After cooling to room tem-
perature, the volatile material was removed under reduced pressure,
and the residue (1.42 g) was used directly for the next reaction with-
H, vinyl-H), 5.85–6.0 (m, 1 H, vinyl-H) ppm. C NMR (100 MHz,
CDCl ): δ = 14.1, 22.6, 25.5, 29.3, 29.4, 29.5, 29.51, 29.6, 29.61 (2
C), 31.9, 33.3, 34.7, 42.8, 71.0, 84.3, 118.7, 134.6, 177.0 ppm.
3
1
out further purification. Analysis of the crude methyl ester by H
HRMS (ESI+): calcd. for [C19
311.2591.
34 3
H O + H] 311.2586; found
NMR indicated ca. 2:1 diastereomer mixture. To a solution of
crude methyl ester in MeOH (30 mL) was added 4 n HCl (5 mL),
and the mixture was stirred for 12 h at room temperature. It was
S-Methyl O-(S)-1-[(2S,3R)-5-Oxo-3-vinyltetrahydrofuran-2-yl]un-
decyl Carbonodithioate (11a): To a mixture of lactone 3a (0.130 g,
3
then quenched with powdered NaHCO (1.0 g) and filtered. The
0
.46 mmol) and CS
THF (8 mL) was added in portions NaH (13.2 mg, 0.55 mmol,
.2 equiv.) at 0 °C, and the reaction mixture was stirred at 0 °C for
2
(0.20 mL, 0.245 g, 3.22 mmol, 7.0 equiv.) in
filtrate was concentrated, and the residue was purified by silica gel
flash column chromatography (petroleum ether/EtOAc, 9:1) to pro-
vide 10a (0.315 g, 28%) as a colorless oil. Further elution gave 3a
(
0
1
(
(
2
1
2
5
1 h. MeI (0.20 mL, 0.457 g, 3.22 mmol, 7.0 equiv.) was added, and
the mixture was stirred at room temperature for 2 h. The reaction
0.653 g, 58%) as a colorless oil. Data for 3a: [α]
D
= +36.8 (c =
.4, CHCl
316, 1268, 1217, 1167, 1020, 928, 763, 669 cm
): δ = 0.87 (t, J = 6.5 Hz, 3 H, CH
m, 16 H, 10Ј-, 9Ј-, 8Ј-, 7Ј-, 6Ј-, 5Ј-, 4Ј-, 3Ј-H), 1.38–1.71 (m, 3 H,
3 3
). IR (CHCl ): ν˜ = 3436, 2927, 2856, 1778, 1644, 1467,
–
1
1
was quenched with sat. aq. NH
EtOAc (15 mL). The solution was extracted with EtOAc
4ϫ30 mL), and the combined organic layers were washed with
brine, dried (Na SO ), and concentrated. The residue was purified
by silica gel flash column chromatography (petroleum ether/EtOAc,
5:5) to provide xanthate 11a (0.106 g, 62 %) as a colorless oil.
4
Cl solution and diluted with
.
H NMR
400 MHz, CDCl
3
3
), 1.25–1.38
(
2
4
Ј-H, OH), 2.46 (dd, J = 17.7, 10.3 Hz, 1 H, 3-H
A
), 2.77 (dd, J =
7.7, 8.9 Hz, 1 H, 3-H ), 3.22–3.25 (m, 1 H, 4-H), 3.58–3.61 (m, 1
1
B
9
H, 1Ј-H), 4.09 (d, J = 8.3 Hz, 1 H, 5-H), 5.17 (d, J = 10.7 Hz, 1
2
5
D 3 3
[α] = –58.9 (c = 0.16, CHCl ). IR (CHCl ): ν˜ = 3392, 2929, 2858,
H, vinyl-H), 5.21 (d, J = 17.4 Hz, 1 H, vinyl-H), 5.72–5.78 (m, 1
H, vinyl-H) ppm. 1 C NMR (100 MHz, CDCl
3
1855, 1794, 1661, 1547, 1465, 1405, 1377, 1284, 1229, 1177, 1045,
3
): δ = 14.0, 22.6,
–
1 1
9
26, 870, 825, 766, 728, 670, 617 cm
.
H NMR (400 MHz,
), 1.0–1.50 (m, 16 H,
2
1
2
5.6, 29.2, 29.4 (2 C), 29.5 (2 C), 31.8, 34.1, 35.2, 41.2, 70.7, 86.4,
CDCl
3
): δ = 0.87 (t, J = 6.6 Hz, 3 H, CH
3
18.0, 136.1, 176.1 ppm. HRMS (ESI+): calcd. for [C17
H
30
O
3
+ H]
83.2273; found 283.2268. Data for 10a: [α]2
5
10Ј-, 9Ј-, 8Ј-, 7Ј-, 6Ј-, 5Ј-, 4Ј-, 3Ј-H), 1.72–1.82 (m, 1 H, 2Ј-H), 1.86–
.96 (m, 1 H, 2Ј-H), 2.44 (dd, J = 17.7, 8.4 Hz, 1 H, 4-H ), 2.60
(s, 3 H, S-CH ), 2.76 (dd, J = 17.7, 9.0 Hz, 1 H, 4-H ), 2.90–3.10
m, 1 H, 3-H), 4.36 (dd, J = 6.2, 1.5 Hz, 1 H, 2-H), 5.17 (d, J =
D
= +38.9 (c = 0.3,
1
A
CHCl
466, 1414, 1312, 1216, 1177, 1020, 967, 925, 759, 667 cm .
NMR (400 MHz, CDCl ): δ = 0.87 (t, J = 6.8 Hz, 3 H, CH ), 1.19–
.31 (m, 16 H, 10Ј-, 9Ј-, 8Ј-, 7Ј-, 6Ј-, 5Ј-, 4Ј-, 3Ј-H), 1.36–1.75 (m,
H, 2Ј-H, OH), 2.58 (dd, J = 17.2, 9.2 Hz, 1 H, 3-H ), 2.69 (dd,
), 3.20–3.24 (m, 1 H, 4-H), 3.70–3.80
m, 1 H, 1Ј-H), 4.37 (dd, J = 8.1, 2.9 Hz, 1 H, 5-H), 5.20 (d, J =
3 3
). IR (CHCl ): ν˜ = 3458, 3082, 3018, 2927, 2855, 1772, 1644,
–
1
1
3
B
1
H
(
3
3
1
5
0.6 Hz, 1 H, vinyl-H), 5.18 (d, J = 14.7 Hz, 1 H, vinyl-H), 5.70–
1
3
1
3
.80 (m, 1 H, vinyl-H), 5.90–6.0 (m, 1 H, 1Ј-H) ppm. C NMR
): δ = 14.1, 19.2, 22.6, 25.0, 29.2, 29.3, 29.4 (2
C), 29.5, 30.8, 31.8, 34.6, 41.0, 80.8, 84.0, 118.3, 135.6, 175.2,
16.2 ppm. HRMS (ESI+): calcd. for [C19 + H] 373.1871;
found 373.1874.
A
(100 MHz, CDCl
3
J = 17.2, 9.2 Hz, 1 H, 3-H
B
(
2
32 3 2
H O S
1
6
1
7
5.8 Hz, 1 H, vinyl-H), 5.21 (d, J = 11.4 Hz, 1 H, vinyl-H), 5.85–
.01 (m, 1 H, vinyl-H) ppm. 13C NMR (100 MHz, CDCl
): δ =
3
4.0, 22.6, 25.5, 29.2, 29.4, 29.42, 29.5, 29.51, 31.8, 33.2, 34.7, 42.8,
0.9, 84.4, 118.6, 134.7, 177.0 ppm. HRMS (ESI+): calcd. for
S-Methyl O-(S)-1-[(2S,3R)-5-Oxo-3-vinyltetrahydrofuran-2-yl]tri-
decyl Carbonodithioate (11b): The title compound was prepared from
[C
17
H
30
O
3
+ H] 283.2273; found 283.2269.
3b (0.168 g, 0.54 mmol) by a procedure similar to that described
for the conversion of 3a into 11a to afford 11b (0.139 g, 64%) as a
(
4R,5S)-5-[(S)-1-Hydroxytridecyl]-4-vinyl-4,5-dihydrofuran-2(3H)-
25
colorless oil. [α]
D
= –36.9 (c = 0.14, CHCl
3 3
). IR (CHCl ): ν˜ = 3432,
one (3b) and (4S,5S)-5-[(S)-1-Hydroxytridecyl]-4-vinyl-4,5-dihy-
drofuran-2(3H)-one (10b): The title compounds were prepared from
allyl alcohol 4b (1.13 g, 3.46 mmol) by a procedure similar to that
described for the conversion of 4a into 10a and 3a. The reaction
2
8
924, 2853, 1787, 1645, 1466, 1322, 1216, 1156, 1057, 969, 923,
–1
1
67, 764, 672, 626 cm . H NMR (400 MHz, CDCl
), 1.0–1.50 (m, 20 H, 12Ј-, 11Ј-, 10Ј-, 9Ј-,
Ј-, 7Ј-, 6Ј-, 5Ј-, 4Ј-, 3Ј-H), 1.68–1.81 (m, 1 H, 2Ј-H), 1.83–1.97 (m,
H, 2Ј-H), 2.40 (dd, J = 17.7, 8.4 Hz, 1 H, 4-H ), 2.51 (s, 3 H, S-
), 2.70 (dd, J = 17.7, 9.0 Hz, 1 H, 4-H ), 2.80–3.0 (m, 1 H, 3-
H), 4.29 (dd, J = 7.0, 2.1 Hz, 1 H, 2-H), 5.09–5.20 (m, 2 H, vinyl-
3
): δ = 0.81 (t,
J = 6.8 Hz, 3 H, CH
8
1
3
afforded 10b (0.312 g, 29%) and 3b (0.644 g, 60%) as colorless oils.
A
Data for 3b: [α]2
5
= +37.1 (c = 0.28, CHCl
). IR (CHCl
): ν˜ =
D
3
3
CH
3
B
3
9
6
7
=
H
429, 3020, 2928, 2856, 1777, 1646, 1467, 1309, 1217, 1163, 1046,
–
1 1
29, 761, 669 cm . H NMR (400 MHz, CDCl
.9 Hz, 3 H, CH ), 1.19–1.31 (m, 20 H, 12Ј-, 11Ј-, 10Ј-, 9Ј-, 8Ј-,
Ј-, 6Ј-, 5Ј-, 4Ј-, 3Ј-H), 1.36–1.75 (m, 3 H, 2Ј-H, OH), 2.46 (dd, J
3
): δ = 0.87 (t, J =
13
H), 5.60–5.80 (m, 1 H, vinyl-H), 5.80–6.0 (m, 1 H, 1Ј-H) ppm.
NMR (100 MHz, CDCl ): δ = 14.1, 19.2, 22.7, 25.1, 29.3, 29.5,
9.6, 29.61 (3 C), 29.7, 30.8, 31.9, 34.6, 41.0, 80.8, 84.0, 118.4,
35.6, 175.3, 216.2 ppm. HRMS (ESI+): calcd. for [C21
C
3
3
2
1
17.7, 10.1 Hz, 1 H, 3-H
A
), 2.77 (dd, J = 17.4, 8.9 Hz, 1 H, 3-
36 3 2
H O S +
B
), 3.21–3.24 (m, 1 H, 4-H), 3.56–3.62 (m, 1 H, 1Ј-H), 4.10 (dd,
H] 401.2184; found 401.2182.
J = 8.3, 2.4 Hz, 1 H, 5-H), 5.18 (d, J = 10.7 Hz, 1 H, vinyl-H),
.21 (d, J = 17.1 Hz, 1 H, vinyl-H), 5.72–5.78 (m, 1 H, vinyl- (4R,5R)-5-Undecyl-4-vinyl-4,5-dihydrofuran-2(3H)-one (12a): A
5
1
3
H) ppm. C NMR (100 MHz, CDCl
3
): δ = 14.1, 22.6, 25.6, 29.3,
9.4, 29.5, 29.52, 29.6, 29.61 (2 C), 31.9, 34.2, 35.2, 41.3, 70.7, 86.4,
18.1, 136.1, 175.9 ppm. HRMS (ESI+): calcd. for [C19 + H]
= +33.6 (c = 0.28,
): ν˜ = 3459, 3081, 3018, 2926, 2855, 1774, 1644,
3
mixture of 11a (50 mg, 0.134 mmol), Bu SnH (0.54 mL, 0.586 g,
2
1
3
2.01 mmol, 15.0 equiv.), and AIBN (catalytic amount) in toluene
(15 mL) was stirred under reflux for 6 h. It was then concentrated,
and the residue was purified by silica gel flash column chromatog-
raphy (petroleum ether/EtOAc, 95:5) to provide 12a (36 mg,
34 3
H O
11.2586; found 311.2589. Data for 10b: [α]2
). IR (CHCl
5
D
CHCl
1
6
3
3
2
5
467, 1414, 1377, 1311, 1216, 1175, 1138, 1022, 967, 925, 847, 759, quant.) as a colorless oil. [α]
D
= +61.4 (c = 0.32, CHCl
3
). IR
–1 1
67 cm . H NMR (400 MHz, CDCl
110
3
): δ = 0.87 (t, J = 6.7 Hz, 3
(CHCl ): ν˜ = 3020, 2928, 2854, 1774, 1646, 1465, 1216, 1022, 929,
3
1
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1106–1112

Total Synthesis of (+)-Nephrosteranic Acid and (+)-Roccellaric Acid
–
1
1
–1 1
7
6
4
(
(
60, 669, 621 cm . H NMR (400 MHz, CDCl
.8 Hz, 3 H, CH ), 1.0–1.80 (m, 20 H, 10Ј-, 9Ј-, 8Ј-, 7Ј-, 6Ј-, 5Ј-, H), 1.10–1.60 (m, 22 H, 11Ј-, 10Ј-, 9Ј-, 8Ј-, 7Ј-, 6Ј-, 5Ј-, 4Ј-, 3Ј-,
Ј-, 3Ј-, 2Ј-, 1Ј-H), 2.44 (dd, J = 17.2, 10.6 Hz, 1 H, 3-H ), 2.67 2Ј-, 1Ј-H), 1.65–1.85 (m, 2 H, 1Ј-H), 2.82 (dd, J = 17.8, 8.4 Hz, 1
), 2.72–2.82 (m, 1 H, 4-H), 4.13 H, 4-H ), 2.94 (dd, J = 17.8, 8.4 Hz, 1 H, 4-H ), 3.06–3.13 (m, 1
dt, J = 8.4, 3.7 Hz, 1 H, 5-H), 5.15 (d, J = 9.9 Hz, 1 H, vinyl-H), H, 3-H), 4.58–4.65 (m, 1 H, 2-H) ppm. C NMR (100 MHz,
.17 (d, J = 17.2 Hz, 1 H, vinyl-H), 5.60–5.78 (m, 1 H, vinyl- CDCl ): δ = 14.1, 22.7, 25.2, 29.2, 29.3, 29.4, 29.5, 29.6, 29.62, 29.7
(3 C), 31.9, 35.4, 45.3, 81.8, 174.4, 175.7 ppm. HRMS (ESI+):
9.4, 29.5 (3 C), 29.6, 31.9, 33.6, 35.5, 46.3, 84.8, 118.0, 135.8, calcd. for [C18 + H] 313.2379; found 313.2374.
75.8 ppm. HRMS (ESI+): calcd. for [C17 + H] 267.2324;
3 3
): δ = 0.87 (t, J = 541 cm . H NMR (400 MHz, CDCl ): δ = 0.88 (t, J = 6.9 Hz, 3
3
A
dd, J = 17.2, 8.4 Hz, 1 H, 3-H
B
A
B
1
3
5
3
13
3
H) ppm. C NMR (100 MHz, CDCl ): δ = 14.1, 22.6, 25.7, 29.3,
2
1
32 4
H O
30 2
H O
(
2R,3S,4S)-4-Methyl-5-oxo-2-undecyltetrahydrofuran-3-carboxylic
Acid, (+)-Nephrosteranic Acid (1): To a solution of 13a (60 mg,
.21 mmol) in THF (2.5 mL) at –78 °C was added NaHMDS (1.0 m
found 267.2319.
0
(
4R,5R)-5-Tridecyl-4-vinyl-4,5-dihydrofuran-2(3H)-one (12b): The
in THF, 0.46 mL, 0.46 mmol, 2.2 equiv.), and the mixture was
stirred for 1 h. MeI (0.131 mL, 0.298 g, 2.1 mmol, 10.0 equiv.) was
added, and the mixture was stirred at –78 °C for 2 h and then
warmed to –20 °C. 2 n HCl (1.0 mL) was added, and the mixture
was extracted with EtOAc (5ϫ15 mL). The combined organic lay-
title compound was prepared from 11b (0.1 g, 0.25 mmol) by a pro-
cedure similar to that described for the conversion of 11a into 12a
to give 12b (73.5 mg, quant.) as a colorless oil. [α]2
5
D
= +35.5 (c =
0
1
.12, CHCl
440, 1216, 1097, 1026, 947, 769, 667, 565 cm
): δ = 0.87 (t, J = 6.7 Hz, 3 H, CH
m, 24 H, 12Ј-, 11Ј-, 10Ј-, 9Ј-, 8Ј-, 7Ј-, 6Ј-, 5Ј-, 4Ј-, 3Ј-, 2Ј-, 1Ј-H),
3 3
). IR (CHCl ): ν˜ = 3016, 2929, 2846, 1781, 1665, 1534,
–
1
1
.
H NMR
ers were dried (Na
by silica gel flash column chromatography (petroleum ether/EtOAc,
:1) to provide 1 (62 mg, 99%) as a white solid. M.p. 95–96 °C
2 4
SO ) and concentrated. The residue was purified
(400 MHz, CDCl
3
3
), 1.0–1.80
(
1
2
1
.44 (dd, J = 17.3, 10.5 Hz, 1 H, 3-H
A
), 2.68 (dd, J = 17.3, 8.3 Hz,
[
1k]
25
[1k]
(
ref.
M.p. 96–98 °C). [α]
= +27.2 (c = 1.45, CHCl
2928, 2855, 1773, 1716, 1464, 1216, 1022, 761, 669 cm . H NMR
D
= +26.9 (c = 0.14, CHCl
3
) {ref.
H, 3-H ), 2.70–2.82 (m, 1 H, 4-H), 4.13 (dt, J = 8.3, 3.6 Hz, 1
B
2
7
[α]
D
3
)}. IR (CHCl ): ν˜ = 3356, 3020,
3
H, 5-H), 5.15 (d, J = 9.9 Hz, 1 H, vinyl-H), 5.17 (d, J = 17.0 Hz,
–
1 1
H, vinyl-H), 5.60–5.78 (m, 1 H, vinyl-H) ppm. 1 C NMR
100 MHz, CDCl ): δ = 14.1, 22.7, 25.7, 29.3, 29.32, 29.4, 29.5,
9.6, 29.61, 29.64 (2 C), 31.9, 33.6, 35.5, 46.3, 84.8, 118.0, 135.7,
75.8 ppm. HRMS (ESI+): calcd. for [C19 + H] 295.2637;
3
1
(
2
1
(400 MHz, CDCl
3 3
): δ = 0.88 (t, J = 6.8 Hz, 3 H, CH ), 1.02–1.61
3
(
m, 18 H, 10Ј-, 9Ј-, 8Ј-, 7Ј-, 6Ј-, 5Ј-, 4Ј-, 3Ј-, 2Ј-H), 1.37 (d, J =
3
7.3 Hz, 3 H, 4-CH ), 1.62–1.76 (m, 1 H, 1Ј-H), 1.76–1.83 (m, 1 H,
34 2
H O
1
Ј-H), 2.72 (dd, J = 11.3, 9.5 Hz, 1 H, 4-H), 2.97–3.01 (m, 1 H, 3-
found 295.2637.
1
3
H), 4.46–4.50 (m, 1 H, 2-H) ppm. C NMR (100 MHz, CDCl
14.1, 14.5, 22.7, 25.3, 29.2, 29.3, 29.4, 29.5, 29.6 (2 C), 31.9,
4.9, 39.8, 53.8, 79.3, 175.1, 176.6 ppm. HRMS (ESI+): calcd. for
+ H] 299.2222; found 299.2217.
3
): δ
(2R,3S)-5-Oxo-2-undecyltetrahydrofuran-3-carboxylic Acid (13a): A
=
3
solution of vinyl lactone 12a (50 mg, 0.0.19 mmol) in CH Cl
25 mL) was cooled to –78 °C and a stream of O /O was bubbled
through the reaction mixture until the blue color of unreacted O
appeared (0.5 h). The reaction was quenched with Me S (0.5 mL)
2
2
(
3
2
17 30 4
[C H O
3
(
2R,3S,4S)-4-Methyl-5-oxo-2-tridecyltetrahydrofuran-3-carboxylic
2
Acid, (+)-Roccellaric Acid (1): The title compound was prepared
from 13b (20 mg, 0.064 mmol) by a procedure similar to that de-
scribed for the conversion of 13a into 1 to provide 2 (21 mg, quant.)
and stirred for 1 h at –78 °C and for a further 2 h at room tempera-
ture. The mixture was concentrated to give the crude aldehyde
(
55 mg), which was used directly for the next reaction. To a solution
of the crude aldehyde in acetone (10 mL) at 0 °C was dropwise
added the Jones reagent [0.5 mL; Jones reagent: CrO (1.33 g) dis-
solved in H O (3 mL). To this solution was added conc. H SO
1.2 mL) at 0 °C, and finally H O (1 mL) was added to get a trans-
[
2i]
25
as a white solid. M.p. 99–100 °C (ref. M.p. 109 °C). [α]
D
= +26.2
= +27.0 (c = 1.73, CHCl )}. IR
): ν˜ = 3434, 3019, 2923, 2857, 1778, 1748, 1602, 1456, 1216,
2i]
27
(
(
1
0
1
4
c = 2.0, CHCl
CHCl
3
) {ref.[ [α]
D
3
3
3
2
2
4
–
1 1
127, 1017, 925, 769, 669 cm . H NMR (400 MHz, CDCl
.87 (t, J = 6.8 Hz, 3 H, CH ), 1.03–1.64 (m, 22 H, 12Ј-, 11Ј-,
0Ј-, 9Ј-, 8Ј-, 7Ј-, 6Ј-, 5Ј-, 4Ј-, 3Ј-, 2Ј-H), 1.36 (d, J = 7.0 Hz, 3 H,
-CH ), 1.65–1.76 (m, 1 H, 1Ј-H), 1.77–1.85 (m, 1 H, 1Ј-H), 2.69
3
): δ =
(
2
3
parent orange solution]. The reaction mixture was stirred at 0 °C
for 20 min and then the excess amount of the Jones reagent was
destroyed by adding 2-propanol (1 mL). The volatiles were removed
under reduced pressure, brine solution (5 mL) was added, and the
reaction mixture was extracted with EtOAc (5ϫ 30 mL). The com-
3
(
dd, J = 11.3, J = 9.5 Hz, 1 H, 4-H), 2.95–3.02 (m, 1 H, 3-H), 4.43–
.50 (m, 1 H, 2-H) ppm. C NMR (100 MHz, CDCl ): δ = 14.1,
3
4.5, 22.7, 25.3, 29.2, 29.3, 29.4, 29.5 (2 C), 29.6 (2 C), 29.7, 31.9,
4.9, 39.8, 53.8, 79.4, 174.5, 176.6 ppm. HRMS (ESI+): calcd. for
1
3
4
1
3
2 4
bined organic layers were dried (Na SO ) and concentrated. The
residue was purified by silica gel flash column chromatography (pe-
[C
19
H
34
O
4
+H] 327.2535; found 327.2529.
troleum ether/EtOAc, 1:1) to provide 13a (51 mg, 95%) as a white
solid. M.p. 119–120 °C. [α]2
5
= +44.9 (c = 0.18, CHCl
). IR
Supporting Information (see footnote on the first page of this arti-
D
3
1
13
(
1
CHCl
216, 1019, 929, 845, 759, 669, 626 cm . H NMR (400 MHz,
CDCl ): δ = 0.88 (t, J = 6.9 Hz, 3 H, CH ), 1.10–1.60 (m, 18 H,
0Ј-, 9Ј-, 8Ј-, 7Ј-, 6Ј-, 5Ј-, 4Ј-, 3Ј-, 2Ј-H), 1.65–1.85 (m, 2 H, 1Ј-H),
.82 (dd, J = 17.9, 9.8 Hz, 1 H, 4-H ), 2.94 (dd, J = 17.9, 8.6 Hz,
H, 4-H ), 3.06–3.13 (m, 1 H, 3-H), 4.58–4.65 (m, 1 H, 2-H) ppm.
C NMR (100 MHz, CDCl ): δ = 14.1, 22.7, 25.1, 29.2, 29.3, 29.4,
9.5, 29.6 (3 C), 31.9, 35.4, 45.3, 81.8, 174.3, 176.0 ppm. HRMS
+ H] 285.2066; found 285.2070.
3
): ν˜ = 3437, 3020, 2928, 2856, 1779, 1717, 1602, 1521, 1424, cle): H NMR and C NMR spectra for selected compounds.
–
1 1
3
3
Acknowledgments
1
2
1
A
Financial support by the Industrial Research and Consultancy
Centre (IRCC), Indian Institute of Technology Bombay, and De-
partment of Science and Technology (DST) New Delhi is gratefully
acknowledged. A.K.C. thanks the Council of Scientific and Indus-
trial Research (CSIR) New Delhi for a Senior Research Fellowship.
B
1
3
3
2
(
ESI+): calcd. for [C16
28 4
H O
(
2R,3S)-5-Oxo-2-tridecyltetrahydrofuran-3-carboxylic Acid (13b):
The title compound was prepared from 12b (80 mg, 0.272 mmol)
by a procedure similar to that described for the conversion of 12a
[
1] Isolation: a) Y. Asahina, M. Yanagita, Y. Sakurai, Ber. Dtsch.
Chem. Ges. 1937, 70B, 227–235; synthesis: b) A. K. Perepogu,
D. Raman, U. S. N. Murty, V. J. Rao, Synth. Commun. 2010,
40, 686–696; c) C. B. Barreto Jr., V. L. P. Pereira, Tetrahedron
Lett. 2009, 50, 6389–6392; d) S. Bazin, L. Feray, N. Vanthuyne,
into 13a to give 13b (80 mg, 94 %) as a white solid. M.p. 107–
5
1
3
08 °C. [α]2
D
= +39.3 (c = 0.32, CHCl
3
). IR (CHCl
3
): ν˜ = 3451,
018, 2923, 1657, 1534, 1221, 1062, 894, 856, 809, 772, 686, 628,
Eur. J. Org. Chem. 2011, 1106–1112
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1111

R. A. Fernandes, A. K. Chowdhury
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1112
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Eur. J. Org. Chem. 2011, 1106–1112