Dibromomethane as one-carbon source in organic synthesis: Formal total synthesis of (±)-nephrosteranic acid

Article abstract of DOI:10.1080/00397910701263767

A diastereoselective formal total synthesis of (±)-nephrosteranic acid (10) is described. The key step is to introduce the α-methylene group by the ozonolysis of monosubstituted alkenes followed by reaction with a preheated mixture of CH2Br2-Et2NH. The α-methyl group of compound 10 was formed from the reduction of the corresponding α-methylene precursor. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701263767

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Dibromomethane as One‐Carbon Source in
Organic Synthesis: Formal Total Synthesis of
(±)‐Nephrosteranic Acid
Yung‐Son Hon a b , Cheng‐Han Hsieh a & Hsien‐Fan Chen a
a Department of Chemistry and Biochemistry , National Chung Cheng
University , Chia‐Yi, Taiwan
b Institute of Chemistry, Academia Sinica , Nankang, Taipei, Taiwan
Published online: 22 May 2007.
To cite this article: Yung‐Son Hon , Cheng‐Han Hsieh & Hsien‐Fan Chen (2007) Dibromomethane as
One‐Carbon Source in Organic Synthesis: Formal Total Synthesis of (±)‐Nephrosteranic Acid, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:10,
1635-1651, DOI: 10.1080/00397910701263767
To link to this article: http://dx.doi.org/10.1080/00397910701263767
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Synthetic Communicationsw, 37: 1635–1651, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701263767
Dibromomethane as One-Carbon Source in
Organic Synthesis: Formal Total Synthesis
of (+)-Nephrosteranic Acid
Yung-Son Hon
Department of Chemistry and Biochemistry, National Chung Cheng
University, Chia-Yi, Taiwan and Institute of Chemistry, Academia
Sinica, Nankang, Taipei, Taiwan
Cheng-Han Hsieh and Hsien-Fan Chen
Department of Chemistry and Biochemistry, National Chung Cheng
University, Chia-Yi, Taiwan
Abstract: A diastereoselective formal total synthesis of (+)-nephrosteranic acid (10)
is described. The key step is to introduce the a-methylene group by the ozonolysis of
monosubstituted alkenes followed by reaction with a preheated mixture of CH2Br2–
Et2NH. The a-methyl group of compound 10 was formed from the reduction of the
corresponding a-methylene precursor.
Keywords: cis-nephrosterinic acid, nephrosteranic acid, a-methylenation,
a-methylene-g-butyrolactones, paraconic acids, a-substituted acrolein
INTRODUCTION
We have reported that the ozonolysis of monosubstituted alkenes 1 followed
by reacting with a preheated mixture of CH2Br2–Et2NH affords a-substituted
acroleins 2 in good yields.[1] The a-substituted acroleins 2 were easily
oxidized by NaClO2 and then treated with CH2N2 to give a-substituted
acrylate 3 in excellent yields (Scheme 1).[2] This methodology was also
Received August 15, 2006
Address correspondence to Yung-Son Hon, Department of Chemistry and
Biochemistry, National Chung Cheng University, Chia-Yi, Taiwan. E-mail:
cheysh@ccu.edu.tw
1635

1636
Y.-S. Hon, C.-H. Hsieh, and H.-F. Chen
Scheme 1.
applied to prepare the a-methylene lactones with different ring size from the
corresponding alkenol.[3]
Various bioactive a-methylene-g-butyrolactones have been isolated from
microorganisms, and some specific examples are shown in Fig. 1. The struc-
tures 4–9 contain a-methylene, b-carboxylate, and g-alkyl groups in different
chain lengths. Both the b- and g-substituents are trans to each other for
compounds 4–6 and cis to each other for compounds 7–9. We have success-
fully applied the methodology described in Scheme 1 to the total synthesis of
the (+)- and (2)-methylenolactocin (4) and (+)-canadensolide (9).[4]
Paraconic acids are a family of chiral trisubstituted g-butyrolactones with
a methyl group at the a position and a carboxylic acid at the b position,
isolated from various species of moss, lichens, and fungus. They possess
important biological activities, such as antitumor, antibiotic, antifungal, and
antibacterial properties. Because of their important potential pharmacological
applications, several total and formal total syntheses of members of this class
of compounds 10–14 (Fig. 1) have been described in both racemic and
optically active forms.[5–9]
There are two major strategies for the total synthesis of the paraconic acid
natural products A as shown in Fig. 2. First, the diastereoselective
Figure 1. Natural products with b,g-disubstituted-a-methylene-g-butyrolactone
moiety (4–9) and some typical paraconic acid natural products (10–14).

(+)-Nephrosteranic Acid
1637
Figure 2. Two major strategies to prepare the paraconic acid natural products A via
routes I and II and the retrosynthetic analysis of our total synthesis of natural product A
via route II.
a-methylation of the b-substituted-g-butyrolactone precursors B gives
compound A (route I).[5b,5c,5d,7a,10a] Second, the a-methyl group is introduced
by the hydrogenation of the a-methylene-g-butyrolactone precursors D.[9b,11]
The further epimerization at b-position of compound C is required to syn-
thesize the target molecule A (i.e., route II).[5f,7b,9a] In continuation of our
interest in using the a-methylenation methodology in natural product
synthesis,[4] we want to develop a general synthetic pathway that is applicable
to prepare paraconic acids. In this article, we describe our effort in the stereo-
selective synthesis of epinephrosteranic acid (33), which is a useful precursor
in the total synthesis of nephrosteranic acid (10).
RESULTS AND DISCUSSION
The retrosynthetic analysis of a-methyl-b-carboxyl-g-butyrolactone A is
shown in Fig. 2. Structure A could be derived from the corresponding cis,
cis-isomer C via stereoselective epimerization.[5f] The a-methyl group of
cis,cis-isomer C should be prepared from the stereoselective reduction of
the corresponding a-methylene lactone D. The g-butyrolactone D should be
easily prepared from alkenol F by our methodology as shown in Scheme 1.
The stereoselective introduction of the b- and g-stereogenic centers of
compound F from the allylation of the dianion of b-hydroxy ester G is a
well-known procedure in the literature.[12]
The b-hydroxy ester 17 was prepared from n-decanal (15) and methyl
bromoacetate (16) in the presence of activated zinc in 82% yield. The allyla-
tion of b-hydroxy ester 17 following the procedure of Frater[12b] gave the anti-
b-hydroxy ester 18 in 62% yield (Scheme 2). The hydroxy ester 18 was
reduced by diisobutylaluminum hydride to give the corresponding diol 19 in
68% yield. Selective silylation at the primary alcohol of compound 19
followed by acetylation gave the acetate 21 in excellent yield. The ozonolysis
of terminal olefin 21 followed by addition of a preheated mixture of CH2Br2

1638
Y.-S. Hon, C.-H. Hsieh, and H.-F. Chen
Scheme 2. Reagents and conditions: (i) Zn, PhH, reflux, 3 h; (ii) 2.2 equiv. LDA,
THF, 2788C, 1 h; H2C55CHCH2Br, 2788C to rt, 1 h; (iii) Dibal-H, CH2Cl2, 08C
to rt, 2 h; (iv) TBSCl, imidazole, cat. DMAP, CH2Cl2, 3 h; (v) Ac2O, cat. DMAP,
Et3N, CH2Cl2, 2 h; (vi) O3, CH2Cl2, 2788C; preheated mixture of Et2NH and
.
CH2Br2, 1.5 h; (vii) NaClO2, t-BuOH, NaH2PO4 2H2O, MeCH55CMe2, 2.5 h;
(viii) KOH, 08C to rt, MeOH, 1.5 h; (ix) o-nitrophenylsulfonyl chloride,
Na2CO3, CH2Cl2, 0.5 h; (x) Jones, reagent, acetone, 408C, 5 min; (xi) H2, 10%
Pd/C, EtOAc, 4 h.
and Et2NH afforded acrolein 22 in 78% yield. The acrolein 22 was oxidized by
sodium chlorite in the presence of a chlorine scavenger (i.e., 2-methyl-2-
butene) to give the corresponding acrylic acid 23 in 72% yield (Scheme 2).
Acrylic acid 23 was subsequently treated with CH2N2 to give the methyl
acrylate 24 in 94% yield (Scheme 3).
Scheme 3.

(+)-Nephrosteranic Acid
1639
We reported that the erythro-acrylate 25 gave the cyclized product 26 in
excellent yield under acidic conditions as shown in Eq. (1).[4a]
However, when the threo-acrylate 24 was treated with a catalytic amount of
AcCl in MeOH, a mixture of the a-methylene-g-butyrolactone 29 and 30
was obtained in a ratio of 3:2 in 88% yield (Scheme 3). Under similar
condition, acrylic acid 23 also affords a mixture of the g-butyrolactone 29
and 30 in a ratio of 1:1 in 84% yield. On the other hand, when acrylic acid
23 was treated with a catalytic amount of trifluoroacetic acid in MeOH at
08C, a mixture of the g-butyrolactone 27 and 28 was obtained in a ratio of
1:1 in 80% yield (Scheme 3). Apparently, the less acidic condition will
retain the acetate functionality to get products 27 and 28.
The possible mechanism for the formation of the lactones 29 and 30 from
acrylate 24 was proposed as follows (Fig. 3). The tert-butyldimethylsilyl ether
of compound 24 was selectively deprotected under acidic conditions to give
the primary alcohol 24a. The equilibrium occurs between compounds 24a
and 24b via 1,5-acetyl group migration. These two intermediates undergo
cyclization to give the acetoxy-lactones 27 and 28, respectively. The cycliza-
tion is disfavored from intermediate 24b because of the nonbonding
Figure 3. Proposed mechanism for the g-butyrolactone 27–30 formation via
intermediates 24a and 24b.

1640
Y.-S. Hon, C.-H. Hsieh, and H.-F. Chen
interaction of two substituents in its eclipsed conformation. If under stronger
acidic condition, further transesterification of lactones 27 and 28 occurred to
give the corresponding hydroxyl-lactones 29 and 30, respectively. In addition,
when pure compound 29 was stirring in a catalytic amount of AcCl in MeOH,
an equilibrated mixture of 29 and 30 was formed, which indicates that
compounds 29 and 30 will equilibrate with each other under acidic conditions.
To solve the problem of the lactonization, acrylic acid 23 was treated
with KOH in methanol to give the deacetylation product 31, which was
treated with o-nitrophenylsulfonyl chloride[13] in the presence of Na2CO3 to
give a-methylene-g-butyrolactone 32 in 72% yield over two steps
(Scheme 2). Finally, compound 32 was treated with Jones reagent to give
cis-nephrosteranic acid (7) in 87% yield. Catalytic hydrogenation of
compound 7 gave the all-cis isomer 33 as a sole product in 85% yield. The
b-chiral center of the epinephrostereanic acid (33) was reported previously
to give the desired natural product (10).[5f] Thus, this work constitutes a
formal total synthesis of (+)-nephrosteranic acid (10). Both (R)-17 and
(S)-17 were prepared in excellent enantioselectivity by enzymztic method-
ology.[14] Therefore, it is feasible to prepare the optical active nephrosteranic
acid (10) by our synthetic design.
CONCLUSIONS
The special features of our synthetic design are as follows. The relative
stereochemistry of b- and g-substitutents was established by the stereoselec-
tive allylation of the dianion of b-hydroxy ester 17. The a-methylene-g-
butyrolactone moiety was derived from the corresponding terminal alkene
of compound 18 by the methodology developed in our laboratory. The
stereoselectivity in the reduction of the a-methylene-g-butyrolactone 7
was controlled by its b- and g-substitutents. In conclusion, we completed
the formal total synthesis of (+)-nephrostereanic acid (10) in 11 operation
steps in 7.2% overall yield to give epinephrosteranic acid (33) starting
from n-decanal (15).
EXPERIMENTAL
All reactions were carried out under nitrogen. Unless otherwise noted,
materials were obtained from commercial suppliers and used without
further purification. Melting points were determined by using a Thomas–
Hoover melting-point apparatus and are uncorrected. The 1H and 13C
NMR spectra were recorded on a Bruker Avance DPX400 spectrometer,
and chemical shifts were given in parts per million (ppm) downfield from
tetramethylsilane (TMS). IR spectra were taken with a Perkin-Elmer 682
spectrophotometer, and only noteworthy absorptions were listed. Mass

(+)-Nephrosteranic Acid
1641
spectra were measured on a Micromass Trio-2000 GC/MS spectrometer
(National Chiao-Tung University) by electronic impact at 70 eV (unless
otherwise indicated). High resolution mass spectroscopy (HRMS) was
measured on a Finnigan/Thermo Quest MAT mass spectrometer (National
Chung Hsing University). 3-Nitrobenzyl alcohol (NBA) was used as FAB
mass matrix.
3-Hydroxytetradecanoic Acid Methyl Ester (17)
A suspension of the activated zinc dust (3.92 g, 60 mmol) in 20 mL of
anhydrous benzene was heated up to reflux for 10 min. To the refluxing sus-
pension solution, a mixture of the n-decanal (15) (10 g, 54.25 mmol) and
methyl bromoacetate (16) (5.62 mL, 59.13 mmol) in 100 mL of benzene
was slowly added during a period of 1 h. After 2 h, the reaction mixture
was cooled to 08C, and then 1N HCl was added to work up the reaction and
extracted with ether (150 mL ꢀ 3). The combined organic extract was dried
(MgSO4), concentrated, and chromatographed on silica-gel column to give
the desired b-hydroxy ester 17 (11.5 g, 44.49 mmol) in 82% yield as a
colorless oil. TLC Rf ¼ 0.51 (hexane/EtOAc ¼ 5:1); 1H NMR (CDCl3,
400 MHz) d 3.97–4.04 (m, 1H, -CHOH), 3.71 (s, 3H), 2.83 (brd, J ¼ 4.0 Hz,
1H), 2.52 (dd, J ¼ 16.4 and 3.1 Hz, 1H, -CH2CO), 2.41 (dd, J ¼ 16.4 and
9.0 Hz, 1H, -CH2CO), 1.21–1.55 (m, 20H), 0.88 (t, J ¼ 6.8 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) d 173.4 (s), 68.0 (d), 51.6 (q), 41.1, 36.5, 31.9,
29.6, 29.57, 29.53, 29.51, 29.48, 29.3, 25.4, 22.6, 14.0 (q); IR (thin film,
NaCl plates): 3455, 2927, 2854, 1731, 1442, 1288, 1172, 914, 732 cm21; EI
mass (m/z): 258 (Mþ, 1), 103 (100), 74 (20), 71 (17), 55 (12); HRMS
calcd. for C15H30O3 258.2195; found: 258.2205.
(2Rꢁ,3Sꢁ)-2-Allyl-3-hydroxytetradecanoic Acid Methyl Ester (18)
n-Butyllithium (26.6 mL, 42.57 mmol, 1.6 M in hexane) was added to a stirring
solution of diisopropylamine (6.00 mL, 42.57 mmol) in THF (70 mL) at 2788C.
To the lithium diisopropylamide (LDA) solution, b-hydroxy ester 17 (5.0 g,
19.35 mmol) in 35 mL of THF was added at 2788C and stirred at this tempera-
ture for 1 h. At 2788C, a mixture of allyl bromide (2.02 mL, 23.18 mmol) and
hexamethylphosphoramide (HMPA) (6.7 mL) in THF (25 mL) was added to
the reaction mixture. After stirring at 2788C for 1 h, the reaction mixture was
partitioned between 40% ethyl acetate/petroleum ether and saturated aqueous
NH4Cl. The combined organic phase was dried (MgSO4), concentrated, and
chromatographed on silica-gel column to afford product 18 (3.6 g,
12.06 mmol) in 62% yield as a pale yellow oil. TLC Rf ¼ 0.62 (hexane/
EtOAc ¼ 5:1); 1H NMR (CDCl3, 400 MHz) d 5.70–5.80 (m, 1H, -CH55CH2),
5.03–5.12 (m, 2H, -CH55CH2), 3.70 (s, 3H), 3.68–3.69 (m, 1H, -CHOH),

1642
Y.-S. Hon, C.-H. Hsieh, and H.-F. Chen
2.52–2.56 (m, 1H, -CHCO2Me), 2.40–2.46 (m, 2H), 1.24–1.49 (m, 20H), 0.88
(t, J ¼ 6.7 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 175.1 (s), 134.8 (d), 116.9,
71.6 (d), 51.3 (q), 50.5 (d), 35.4, 33.6, 31.8, 29.48, 29.47, 29.42, 29.40, 29.36,
29.2, 25.6, 22.5, 13.9 (q); IR (thin film, NaCl plates): 3482, 2927, 2854, 1727,
1446, 1168, 914, 732 cm21; EI mass (m/z): 298 (Mþ, 1), 143 (86), 114 (100),
95 (14), 83 (41), 61 (41), 55 (46); HRMS calcd. for C18H34O3 298.2508,
found: 298.2507.
(2Rꢁ,3Sꢁ)-2-Allyltetradecane-1,3-diol (19)
To a solution of b-hydroxy ester 18 (1.8 g, 6.02 mmol) in 30 mL of CH2Cl2,
diisobutylaluminum hydride (Dibal-H, 1 M in hexane, 15.1 mL, 15.1 mmol)
was added at 08C. After the addition, the cooling bath was removed, and
the reaction mixture was stirred at ambient temperature for 2 h. To the
reaction mixture, 8 mL of ethyl acetate was added to quench the excess of
Dibal-H at 08C. The reaction mixture was then washed with 20 mL of
water. The organic layer was dried over MgSO4, concentrated, and chromato-
graphed on a silica-gel column to give diol 19 (1.11 g, 4.09 mmol) in
68% yield as a pale yellow oil. TLC Rf ¼ 0.22 (hexane/EtOAc ¼ 5:1);
1H NMR (CDCl3, 400 MHz) d 5.76–5.86 (m, 1H, -CH55CH2), 5.03–5.12
(m, 2H, -CH55CH2), 3.91–3.94 (m, 1H, -CHOH), 3.66–3.71 (m, 2H,
-CH2OH), 2.46 (br s, 1H), 2.22–2.26 (m, 3H, -CH2CH55CH2 and
-CHCH2OH), 1.22–1.60 (m, 20H), 0.88 (t, J ¼ 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) d 136.7 (d), 116.4, 75.1 (d), 63.7, 44.0 (d), 35.5, 33.4,
31.9, 29.62, 29.60, 29.57, 29.3, 25.7, 22.6, 14.0 (q); IR (thin film, NaCl
plates): 3370, 2927, 2857, 1457, 1257, 1029, 910, 732 cm21; FAB mass
(m/z): 271 (Mþ þ 1, 8), 253 (36), 235 (24), 154 (60), 136 (61), 123 (24),
95 (64), 81 (68), 69 (76), 55 (100); HRMS calcd. for C17H35O2 (Mþ þ H)
271.2637, found: 271.2635.
(4Rꢁ,5Sꢁ)-4-[(tert-Butyldimethylsilyloxy)methyl]hexadec-
1-en-5-ol (20)
To a solution of the diol 19 (800 mg, 2.96 mmol), DMAP (N,N-dimethylami-
nopyridine, 72.5 mg, 0.59 mmol) and imidazole (222 mg, 3.26 mmol) in 6 mL
of CH2Cl2, t-butyldimethylsilyl chloride (0.49 g, 3.26 mmol) was added at rt
and stirred for 3 h. The reaction is quenched with water and extracted with
ethyl acetate. The organic layer was dried over MgSO4, concentrated, and
chromatographed on a silica-gel column to give the secondary alcohol 20
(864 mg, 2.25 mmol) in 76% yield as a colorless oil. TLC Rf ¼ 0.84
1
(hexane/EtOAc ¼ 5:1); H NMR (CDCl3, 400 MHz) d 5.73–5.83 (m, 1H,
-CH55CH2), 5.02–5.09 (m, 2H, -CH55CH2), 3.91 (dd, J ¼ 10.1 and 3.5 Hz,
1H, -CH2OTBS), 3.66 (dd, J ¼ 10.2 and 5.0 Hz, 1H, -CH2OTBS),

(+)-Nephrosteranic Acid
1643
3.60–3.63 (m, 1H, -CHOH), 3.31 (d, J ¼ 6.2 Hz, 1H, OH), 2.14–2.30 (m, 3H,
-CH2CH55CH2 and CHCH2OTBS), 1.21–1.56 (m, 20H), 0.83–0.95
(m, 12H), 0.073 [s, 3H, t-BuSi(CH3)2], 0.069 [s, 3H, t-BuSi(CH3)2]; 13C
NMR (CDCl3, 100 MHz) d 136.9 (d), 116.3, 74.7 (d), 64.1, 43.7, 35.7, 33.3,
31.9, 29.8, 29.7, 29.6, 29.3, 25.9 (q), 25.8, 22.7, 18.1 (s), 14.1 (q), 25.7
(q); IR (thin film, NaCl plates): 3505, 2927, 2857, 1465, 1253, 1087, 914,
840, 732 cm21; FAB mass (m/z): 385 (Mþ þ 1, 4), 367 (4), 281 (12), 221
(20), 207 (16), 221 (16), 147 (42), 73 (100); HRMS calcd. for C23H49O2Si
(Mþ þ H) 385.3502, found: 385.3497.
(4Rꢁ,5Sꢁ)-4-[(tert-Butyldimethylsilyloxy)methyl]hexadec-1-en-5-yl
Acetate (21)
To a solution of alcohol 20 (600 mg, 1.56 mmol), DMAP (38 mg, 0.31 mmol),
and Et3N (0.33 mL, 2.3 mmol) in CH2Cl2 (3.1 mL), acetic anhydride
(0.22 mL, 2.3 mmol) was added at rt and stirred for 2 h. The reaction
mixture was concentrated and chromatographed on a silica-gel column to
afford the acetate 21 (605.8 mg, 1.42 mmol) in 91% yield as a pale yellow
1
oil. TLC Rf ¼ 0.70 (hexane/EtOAc ¼ 10:1); H NMR (CDCl3, 400 MHz)
d5.71–5.82 (m, 1H, -CH55CH2), 4.99–5.05 (m, 3H, -CH55CH2 and
-CHOAc), 3.62 (dd, J ¼ 10.2 and 5.5 Hz, 1H, -CH2OTBS), 3.54 (dd,
J ¼ 10.2 and 5.6 Hz, 1H, -CH2OTBS), 2.08–2.13 (m, 2H, -CH2CH55CH2),
2.03 (s, 3H, -COCH3), 1.77–1.85 (m, 1H, -CHCH2OTBS), 1.25–1.30
(m, 20H), 0.85–0.91 (m, 12H), 0.03 [s, 6H, t-BuSi(CH3)2]; 13C NMR
(CDCl3, 100 MHz) d 170.5(s)136.7 (d), 116.3, 74.6 (d), 61.8, 43.8 (d), 31.9,
31.8, 31.2, 29.64, 29.62, 29.58, 29.56, 29.53, 29.3, 26.0, 25.9 (q ꢀ 3), 25.6,
22.7, 21.2 (q), 18.2 (s), 14.1 (q), 25.5 (q), 25.6 (q); IR (thin film, NaCl
plates): 2927, 2857, 1739, 1465, 1245, 1099, 914, 840, 732 cm21; EI mass
(m/z): 427 (Mþ þ 1, 4), 307 (18), 289 (16), 154 (100), 136 (81), 107 (32),
77 (36); HRMS calcd. for C25H51O3Si (Mþ þ H) 427.3607, found: 427.3611.
(3Rꢁ,4Sꢁ)-3-[(tert-Butyldimethylsilyloxy)methyl]-2-
formylpentadec-1-en-4-yl Acetate (22)
A two-necked flask fitted with a glass tube to admit ozone, a CaCl2 drying
tube, and a magnetic stirring bar was charged with terminal alkene 21
(700 mg, 1.64 mmol) in CH2Cl2 (30 mL). The flask was cooled to 2788C,
and ozone was bubbled through the solution. When the solution turned blue,
ozone addition was stopped. Nitrogen was passed through the solution until
the blue color was discharged. A mixture of Et2NH (0.90 mL, 8.20 mmol)
and CH2Br2 (1.7 mL, 24.5 mmol) was heated to 558C for 1.5 h to give a
yellow solution and then cooled to rt. To a solution of ozonide in CH2Cl2
generated previously, a preheated mixture of Et2NH and CH2Br2 was added

1644
Y.-S. Hon, C.-H. Hsieh, and H.-F. Chen
at 2788C. After the addition, the cooling bath was removed, and the reaction
mixture was stirred at rt. The reaction was completed in 1.5 h, and the reaction
mixture was concentrated. To the crude mixture, ether was added, and most of
the ammonium salts were precipitated out. After filtration, the filtrate was con-
centrated and chromatographed on the silica-gel column to give the desired
acrolein 22 (564 mg, 1.28 mmol) as a colorless oil in 78% yield. TLC
Rf ¼ 0.43 (hexane/EtOAc ¼ 10:1); 1H NMR (CDCl3, 400 MHz) d 9.50
(s, 1H, CHO), 6.40 (s, 1H, -C55CH2), 6.16 (s, 1H, -C55CH2), 5.15 (td,
J ¼ 8.1 and 3.7 Hz, 1H, -CHOAc), 3.74 (dd, J ¼ 10.0 and 6.3 Hz, 1H, -
CH2OTBS), 3.61 (dd, J ¼ 10.0 and 4.4 Hz, 1H, -CH2OTBS), 3.10–3.15
(m, 1H), 2.03 (s, 3H, -COCH3), 1.22–1.56 (m, 20H), 0.80–0.90 (m, 12H),
20.01 [s, 3H, t-BuSi(CH3)2], 20.02 [s, 3H, t-BuSi(CH3)2]; 13C NMR
(CDCl3, 100 MHz)d 193.9 (s), 170.3 (s), 148.5 (s), 136.4, 72.8 (d), 61.5,
41.9 (d), 31.9, 31.8, 29.6, 29.5, 29.4, 29.3, 25.8 (q ꢀ 3), 25.0, 22.6, 21.0
(q), 18.1 (s), 14.1 (q), 25.6 (q), 25.7 (q); IR (thin film, NaCl plates): 2927,
2857, 1739, 1697, 1465, 1369, 1241, 1106, 948, 840, 779 cm21; FAB Mass
(m/z): 441 (Mþ þ 1, 4), 307 (28), 289 (16), 154 (100), 136 (81), 107 (32),
89 (32); HRMS calcd. for C25H49O4Si (Mþ þ H) 441.7395, found: 441.7397.
(3Rꢁ,4Sꢁ)-4-Acetoxy-3-[(tert-butyldimethylsilyloxy)methyl]-
2-methylenepentadecanoic Acid (23)
To a solution of acrolein 22 (200 mg, 0.45 mmol), t-butyl alcohol (2.3 mL), and
2-methyl-2-butene (0.15 mL, 95.2 mg, 1.36 mmol), a solutionof sodium chlorite
(94.4 mg, 1.04 mmol) and sodium dihydrogenphosphate dihydrate (139.4 mg,
0.91 mmol) in 0.7 mL of water was added dropwise. The pale yellow reaction
mixture was stirred at rt for 2.5 h. The reaction mixture was concentrated, the
residue was dissolved in 1.3 mL of water, and this was extracted with 5 mL of
hexane. The aqueous layer was acidified to pH 3 with 2N HCl and extracted
with two 4.2-mL portions of ether. The combined ether layers were washed
with 5 mL of water, dried with Na2SO4, and concentrated to give the crude car-
boxylic acid. The residue was chromatographed on a silica-gel column to give
acrylic acid 23 (149.1 mg, 0.33 mmol) as a colorless oil in 72% yield. TLC
1
Rf ¼ 0.18 (hexane/EtOAc ¼ 10:1); H NMR (CDCl3, 400 MHz) d 6.39 (s),
1H, -C55CH2), 5.66 (s, 1H, -C55CH2), 5.20 (td, J ¼ 8.0 and 3.6 Hz, 1H,
-CHOAc), 3.76 (dd, J ¼ 10.0 and 6.5 Hz, 1H, -CH2OTBS), 3.71 (dd, J ¼ 10.0
and 4.8 Hz, 1H, -CH2OTBS), 3.02–3.07 (m, 1H), 2.03 (s, 3H, -OCOCH3),
1.16–1.29 (m, 20H), 0.85–0.91 (m, 12H), 0.01 [s, 6H, t-BuSi(CH3)2]; 13C
NMR (CDCl3, 100 MHz) d 171.5 (s), 170.8 (s), 139.5 (s), 127.8, 73.5 (d), 62.1,
46.0 (d), 31.9, 29.62, 29.61, 29.57, 29.51, 29.3, 25.8 (q ꢀ 3), 22.7, 21.1 (q),
18.1 (s), 14.1 (q), 25.57 (q), 25.61 (q); IR (thin film, NaCl plates): 3455,
2927, 2857, 1735, 1461, 1249, 1164, 1103, 840, 732 cm21; FAB mass (m/z):
439 (Mþ-17, 2), 397 (Mþ-59, 2), 365 (4), 117 (24), 73 (100); HRMS calcd. for
C25H47O4Si (Mþ-OH) 439.3244, found: 439.3241.

(+)-Nephrosteranic Acid
1645
(3Rꢁ,4Sꢁ)-4-Acetoxy-3-[(tert-butyldimethylsilyloxy)methyl]-
2-methylenepentadecanoic Acid Methyl Ester (24)
To a solution of a-substituted acrylic acid 23 (149.1 mg, 0.33 mmol) in 1 mL of
CH2Cl2, a solution of CH2N2 in ethyl ether was added at rt. The progress of the
reaction should be monitored carefully by thin-layer chromatography (TLC).
Excess of the CH2N2 will cause further 1,3-dipolar cycloaddition on the
double bond. The reaction mixture was concentrated, and the residue was chro-
matographed on a silica-gel column to give methyl acrylate 24 (144.5 mg,
0.31 mmol) as a pale yellow oil in 94% yield. TLC Rf ¼ 0.43 (hexane/
1
EtOAc ¼ 10:1); H NMR (CDCl3, 400 MHz) d 6.34 (s, 1H, -C55CH2), 5.65
(s, 1H, -C55CH2), 5.16 (td, J ¼ 8.0 and 3.7 Hz, 1H, -CHOAc), 3.76 (s, 3H,
OCH3), 3.73 (dd, J ¼ 9.9 and 6.7 Hz, 1H, -CH2OTBS), 3.68 (dd, J ¼ 9.9 and
4.9 Hz, 1H, -CH2OTBS), 3.06–3.11 (m, 1H), 2.03 (s, 3H, -OCOCH3), 1.23–
1.29 (m, 20H), 0.85–0.89 (m, 12H), 20.008 [s, 3H, t-BuSi(CH3)2], 20.01
[s, 3H, t-BuSi(CH3)2]; 13C NMR (CDCl3, 100 MHz) d 170.4 (s), 167.3 (s),
138.8 (s), 127.1, 73.3 (d), 62.1, 51.9 (q), 46.0 (d), 31.9, 29.6, 29.5, 29.43,
29.39, 29.28, 25.7 (q ꢀ 3), 25.0, 22.6, 21.0 (q), 18.1 (s), 14.0 (q), 25.6 (q),
25.7 (q); IR (thin film, NaCl plates): 2927, 2857, 1735, 1461, 1373, 1241,
1106, 948, 840, 779 cm21; EI Mass (m/z): 439 (Mþ-31, 2), 413 (11), 353
(100), 327 (20), 117 (79), 89 (47), 75 (31), 57 (12), 55 (10); HRMS calcd.
for C26H51O5Si (Mþ þ H) 471.3506, found: 471.3518.
(Sꢁ)-1-[(Rꢁ)-4-Methylene-5-oxotetrahydrofuran-3-yl]dodecyl
Acetate (27) and [(2Sꢁ,3Rꢁ)-4-Methylene-5-oxo-2-
undecyltetrahydrofuran-3-yl] Methyl Acetate (28)
To a mixture of acetoxy–acrylic acid 23 (20.2 mg, 0.044 mmol) in 1 mL of
MeOH, a catalytic amount of trifluoroacetic acid was added and stirred at rt
for 0.5 h. The reaction mixture was concentrated and chromatographed on a
silica-gel column to give the a-methylenelactone 27 (5 mg, 0.015 mmol) in
40% yield and a-methylenelactone 28 (5 mg, 0.015 mmol) in 40% yield.
1
Compound 27, pale yellow oil; TLC Rf ¼ 0.36 (hexane/EtOAc ¼ 5:1); H
NMR (CDCl3, 400 MHz) d 6.36 (d, J ¼ 2.6 Hz, 1H, -C55CH2), 5.72
(d, J ¼ 2.6 Hz, 1H, -C55CH2), 5.17–5.21 (m, 1H, -CHOAc), 4.41 (dd,
J ¼ 9.0 and 9.0 Hz, 1H, -CH2OCO), 4.30 (dd, J ¼ 9.0 and 5.4 Hz, 1H,
-CH2OCO), 3.29–3.34 (m, 1H), 2.03 (s, 3H, -OCOCH3), 1.21–1.60
(m, 20H), 0.88 (t, J ¼ 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 170.4
(s), 170.1 (s), 134.5 (s), 124.0, 73.3, 66.3 (d), 42.0 (d), 31.9, 31.4, 29.6,
29.5, 29.4, 29.3, 25.5, 22.6, 20.8 (q), 14.1 (q); IR (thin film, NaCl plates):
2927, 2854, 1762, 1461, 1373, 1234, 1118, 1041, 817, 728 cm21; EI mass
(m/z): 325 (Mþ þ 1, 1), 252 (39), 140 (25), 127 (33), 109 (42), 98
(100), 81 (28), 69 (28), 55 (48); HRMS calcd. for C19H32O4 324.2301,
found: 324.2294. Compound 28, pale yellow oil; TLC Rf ¼ 0.45

1646
Y.-S. Hon, C.-H. Hsieh, and H.-F. Chen
1
(hexane/EtOAc ¼ 5:1); H NMR (CDCl3, 400 MHz) d 6.32 (d, J ¼ 2.4 Hz,
1H, -C55CH2), 5.69 (d, J 55 2.4 Hz, 1H, -C55CH2), 4.55–4.61
(m, 1H, -CHOCO), 4.17–4.27 (m, 2H, -CH2OAc), 3.36–3.38 (m, 1H), 2.08
(s, 3H, -OCOCH3), 1.21–1.62 (m, 20H), 0.88 (t, J ¼ 6.8 Hz, 3H);
13C NMR (CDCl3, 100 MHz) d 170.4 (s), 169.3 (s), 136.3 (s), 123.1, 79.3
(d), 62.2, 41.5 (d), 31.8, 30.4, 29.5, 29.4, 29.3, 29.2, 25.7, 22.5, 20.6 (q),
14.0 (q); IR (thin film, NaCl plates): 2927, 2857, 1766, 1747, 1461, 1373,
1234, 1114, 1022, 914, 813, 732 cm21; EI mass (m/z): 325 (Mþ þ 1, 3),
264 (12), 140 (97), 125 (16), 98 (100), 81 (25), 69 (35), 55 (72); HRMS
calcd. for C19H32O4 324.2301, found: 324.2309.
(Sꢁ)-4-[(Rꢁ)-1-Hydroxydodecyl]-3-methylenedihydrofuran-2(3H)-
one (29) and (4Rꢁ,5Sꢁ)-4-(Hydroxymethyl)-3-methylene-5-
undecyldihydrofuran-2(3H)-one (30)
Method One (in CF3CO2H in MeOH)
To a mixture of acetoxy–acrylate 24 (130 mg, 0.28 mmol) in 2 mL of MeOH,
a catalytic amount of acetyl chloride (2 mL, 29 mmol) was added and stirred at
rt for 0.5 h. The reaction mixture was concentrated and chromatographed on
a silica-gel column to give a-methylenelactone 29 (41 mg, 0.14 mmol) in 52%
yield and 30 (28 mg, 0.10 mmol) in 36% yield.
Method Two (in CH3COCl in MeOH)
To a mixture of acetoxy–acrylate 23 (137 mg, 0.30 mmol) in 2 mL of MeOH,
a catalytic amount of acetyl chloride (2.1 mL, 30 mmol) was added and stirred
at rt for 0.5 h. The reaction mixture was concentrated and chromatographed
on a silica-gel column to give the a-methylenelactone 29 (35.6 mg,
0.13 mmol) in 42% yield and 30 (35.7 mg, 0.13 mmol) in 42% yield.
Compound 29, pale yellow solid; mp 67.4–68.88C; TLC Rf ¼ 0.20
(hexane/EtOAc ¼ 5:1); 1H NMR (CDCl3, 400 MHz)
d
6.40 (d,
J ¼ 2.6 Hz, 1H, -C55CH2), 5.71 (d, J ¼ 2.6 Hz, 1H, -C55CH2), 4.44 (dd,
J ¼ 9.2 and 4.9 Hz, 1H, -CH2OCO), 4.36 (dd, J ¼ 9.2 and 9.2 Hz, 1H,
-CH2OCO), 3.82–3.85 (m, 1H, -CHOH), 3.11–3.16 (m, 1H), 1.66 (brd,
J ¼ 4.2 Hz, 1H), 1.26–1.52 (m, 20H), 0.88 (t, J ¼ 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) d 170.9 (s), 136.0 (s), 123.4, 72.4, 66.6 (d), 44.4 (d),
34.0, 31.9, 29.6, 29.50, 29.49, 29.42, 29.3, 25.7, 22.6, 14.1 (q); IR (thin
film, NaCl plates): 3444, 2919, 2854, 1747, 1465, 1268, 1064, 817,
736 cm21; FAB mass (m/z): (283, Mþ þ 1, 1), 98 (100), 83 (22), 69 (48),
55 (48); HRMS calcd. for C17H31O3 (Mþ þ 1) 283.2273, found: 283.2270.
Compound 30, white solid; mp 67.1–69.38C; TLC Rf ¼ 0.11 (hexane/
EtOAc ¼ 5:1); 1H NMR (CDCl3, 400 MHz) d 6.30 (d, J ¼ 2.2 Hz, 1H,
-C55CH2), 5.69 (d, J ¼ 2.2 Hz, 1H, -C55CH2), 4.55–4.60 (m, 1H,

(+)-Nephrosteranic Acid
1647
-CHOCO), 3.83–3.89 (m, 1H, -CH2OH), 3.74–3.80 (m, 1H, -CH2OH), 3.22–
3.28 (m, 1H), 1.54–1.68 (m, 4H), 1.26–1.34 (m, 16H), 0.89 (t, J ¼ 6.8 Hz,
3H); 13C NMR (CDCl3, 100 MHz) d 170.3 (s), 137.1 (q), 122.9 (t), 80.3
(d), 60.9 (t), 44.6 (d), 31.9 (t), 30.2 (t), 29.6 (t), 29.5 (t), 29.4 (t), 29.33 (t),
29.29 (t), 26.0 (t), 22.6 (t), 14.1 (q); IR (thin film, NaCl plates): 3413, 2923,
2857, 1751, 1461, 1346, 1272, 1052, 817, 736 cm21; EI mass (m/z): 282
(Mþ, 1), 252 (23), 127 (27), 109 (11), 98 (100), 81 (20), 69 (36), 55 (39);
HRMS calcd. for C17H30O3 282.2195, found: 282.2196.
(4Rꢁ,5Sꢁ)-4-[(tert-Butyldimethylsilyloxy)methyl]-3-methylene-
5-undecyldihydrofuran-2(3H)-one (32)
To mixture of acetoxy–acrylic acid 23 (40 mg, 0.087 mmol) in MeOH
(0.5 mL), a solution of KOH (4.9 mg, 0.087 mmol) in MeOH (0.5 mL) was
added and stirred at 08C for 1.5 h. The reaction mixture was concentrated,
diluted with water, and extracted with CH2Cl2. The combined organic
extracts were dried (Na2SO4), filtered, and concentrated to give a crude
product of compound 31, which can be used directly for the further
reaction. To a solution of compound 31 in CH2Cl2 (1 mL), Na2CO3
(93.1 mg, 0.88 mmol) was added. After 15 min, o-nitrobenzenesulfonyl
chloride (29 mg, 0.131 mmol) was added, and the mixture was left to stir at
room temperature for 15 min water was added to the mixture and extracted
with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered,
and concentrated. Purification by silica-gel column chromatography
(hexane/EtOAc ¼ 98:2) provided 32 as a colorless oil (25.3 mg, 73%). TLC
1
Rf ¼ 0.82 (hexane/EtOAc ¼ 3:1); H NMR (CDCl3, 400 MHz) d 6.24 (d,
J ¼ 2.2 Hz, 1H, -C55CH2), 5.61 (d, J ¼ 2.2 Hz, 1H, -C55CH2), 4.50–4.56
(m, 1H, -CHOCO), 3.70–3.78 (m, 2H, -CH2OTBS), 3.13–3.18 (m, 1H, -
CHCO2H), 1.25–1.67 (m, 20H), 0.83–0.88 [m, 12H, -CH2CH3 and -
(CH3)3CSiMe2], 0.05 [s, 3H, t-BuSi(CH3)2], 0.04 [s, 3H, t-BuSi(CH3)2]; 13C
NMR (CDCl3, 100 MHz) d 170.2 (s), 137.6 (s), 122.2, 80.3 (d), 61.8, 44.9
(d), 31.9, 30.2, 29.6, 29.5, 29.41, 29.36, 29.30, 26.0, 25.7 (q ꢀ 3), 22.7,
18.1 (s), 14.1 (q), 25.6 (q), 25.7 (q); IR (thin film, NaCl plates): 2954,
2926, 2855, 1769, 1464, 1256, 1113, 940, 814, 723 cm21; EI mass (m/z):
397 (Mþ þ 1, 1), 339 (100), 309 (37), 73 (26), 55 (27); HRMS calcd. for
C23H44O3Si 396.3060, found: 396.3068.
(2Sꢁ,3Sꢁ)-4-Methylene-5-oxo-2-undecyltetrahydrofuran-
3-carboxylic Acid (7)
To a solution of silyl ether 32 (50 mg, 0.13 mmol) in acetone (1 mL) at 408C,
Jones reagent was added dropwise until the orange color persisted, and the

1648
Y.-S. Hon, C.-H. Hsieh, and H.-F. Chen
resulting solution was stirred at this temperature for 5 min. After cooling to
08C, isopropanol was added to quench the excess of Jones reagent. The
mixture was partitioned between CH2Cl2 and water. The organic phase was
dried (MgSO4) and evaporated in vacuo. The residual oil was chromato-
graphed on a silica-gel column to give a white solid 7 (32.5 mg,
0.11 mmol) in 87% yield. Mp 65.4–66.78C; TLC Rf ¼ 0.34 (hexane/
EtOAc ¼ 1:1); 1H NMR (CDCl3, 400 MHz) d 6.45 (d, J ¼ 2.2 Hz,
1H, -C55CH2), 5.89 (d, J ¼ 2.2 Hz, 1H, -C55CH2), 4.67 (td, J ¼ 8.0 and
5.4 Hz, 1H, -CHOCO), 4.01–4.04 (m, 1H), 1.25–1.76 (m, 20H), 0.88
(t, J ¼ 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 173.9 (s), 168.8 (s),
133.2 (s), 125.6, 78.0 (d), 48.8 (d), 31.9, 31.4, 29.6, 29.5, 29.4, 29.3, 29.2,
25.5, 22.7, 14.1 (q); IR (thin film, NaCl plates): 3309, 2923, 2854, 1756,
1465, 1268, 1168, 819, 721 cm21; EI Mass (m/z): 296 (Mþ, 17), 251 (100),
155 (44), 141 (28), 123 (26), 95 (25), 81 (23), 69 (37), 57 (74), 55 (58);
HRMS calcd. for C17H28O4 296.1988, found: 296.1992.
(2Sꢁ,3Sꢁ,4Rꢁ)-4-Methyl-5-oxo-2-undecyltetrahydrofuran-3-
carboxylic Acid (33)
Under a hydrogen atomosphere in a ballon, a mixture of compound 10 (20 mg,
0.067 mmol) and 10% Pd/C (7.3 mg, 0.007 mmol) in 2 mL of EtOAc was
stirred at room temperature for 4 h. The reaction mixture was filtered
through Celitew, and the filtrate was concentrated. The crude mixture was
chromatographed on a silica-gel column to give a white solid 33 (17.2 mg,
0.057 mmol) in 85% yield. Mp 101.3–102.98C, (100–1028C[5f]); TLC
1
Rf ¼ 0.44 (hexane/EtOAc ¼ 3:1); H NMR (CDCl3, 400 MHz) d 4.43 (td,
J ¼ 8.7 and 5.2 Hz, 1H, -CHOCO), 3.34 (dd, J ¼ 7.4 and 5.2 Hz, 1H,
-CHCO2H), 2.94 (quint. J ¼ 7.4 Hz, 1H, -CHCH3), 1.81–1.90 (m, 1H),
1.63–1.71 (m, 1H), 1.32 (d, J ¼ 7.1 Hz, 3H), 1.26–1.59 (m, 18H), 0.88
(t, J ¼ 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 176.8 (s), 174.1 (s),
78.8 (d), 50.3 (d), 39.1 (d), 31.9, 30.9, 29.6, 29.5, 29.4, 29.3, 29.2, 25.9,
22.7, 14.1 (q), 10.3 (q); IR (thin film, NaCl plates): 3496, 3054, 2923, 2854,
1781, 1716, 1463, 1265, 1186, 1002, 966, 738 cm21; EI Mass (m/z): 298
(Mþ, 4), 253 (42), 225 (37), 114 (59), 97 (71), 87 (59), 81 (51), 69 (94), 55
(100); HRMS calcd. for C17H30O4 298.2144, found: 298.2145.
ACKNOWLEDGMENT
We are grateful to the National Science Council, National Chung Cheng
University, and Academia Sinica for financial support.

(+)-Nephrosteranic Acid
1649
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(+)-Nephrosteranic Acid
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