A protecting-group-free synthesis of (+)-nephrosteranic, (+)-protolichesterinic, (+)-nephrosterinic, (+)-phaseolinic, (+)-rocellaric acids and (+)-methylenolactocin

Article abstract of DOI:10.1039/c6ob02398c

A collective synthesis of a γ-butyrolactone class of paraconic acids such as (+)-methylenolactocin, (+)-phaseolinic acid, (+)-nephrosteranic acid, (+)-nephrosterinic acid, (+)-rocellaric acid and (+)-protolichesterinic acid is described. The strategy adopted is protecting-group-free based on efficient Pd-catalyzed Suzuki-Miyaura coupling and Ru-catalyzed Sharpless oxidation to construct the core β-CO₂H-γ-butyrolactone unit to accomplish the synthesis of various paraconic acids.

Full text of DOI:10.1039/c6ob02398c

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A Protecting-Group-Free Synthesis of (+)-Nephrosteranic, (+)-
Protolichesterinic, (+)-Nephrosterinic, (+)-Phaseolinic, (+)-Rocellaric
Acids and (+)-Methylenolactocin‡
Received 00th January 20xx,
Accepted 00th January 20xx
Jothi L. Nallasivam and Rodney A. Fernandes*
DOI: 10.1039/x0xx00000x
A collective synthesis of γ-butyrolactone class of paraconic acids such as (+)-methylenolactocin, (+)-phaseolinic acid, (+)-
nephrosteranic acid, (+)-nephrosterinic acid, (+)-rocellaric acid and (+)-protolichesterinic acid is described. The strategy
adopted is protecting-group-free based on an efficient Pd-catalyzed SuzukiMiyaura coupling and Ru-catalyzed Sharpless
oxidation to construct the core β-CO2H-γ-butyrolactone unit to accomplish the synthesis of various paraconic acids.
www.rsc.org/
dihydroxylation,7s asymmetric epoxidation,7d,f,ab, asymmetric
reduction of β-keto esters,7w chiral conjugate additions,7t
Introduction
asymmetric
allylic
alkylation,7ac,ad
chemoenzymatic
γ-Butyrolactone and γ-butenolide are core structural motifs in
many natural products and pharmaceuticals possessing
potential biological activities.1 For example, the γ-
butyrolactone unit is embedded in various paraconic acids
resolution,7i use of chiral auxiliaries,7h,l,m,x,ae chiral synthons7c,e,o
and chiral pool approaches.7j,n,q,r,y While the syntheses are
competitively achieved, some suffer from large number of
steps involved and lower overall yields. Thus there is a need to
design a strategy which is step-economic and protecting-
group-free toward achieving the goal of an ideal synthesis.
(1
10, Figure 1).2 These were isolated from lichens, various
species of moss and culture filtrates of penicillium sp.3 The γ-
butyrolactones are equivalent to 4-hydroxycarbonyl
compounds4 which are functionalized at the ring carbons and
show interesting bioactivities such as antibacterial,5a,b
antiviral/antifungal,5c antibiotic,5d,e antitumor and growth
regulatory properties.5f The molecular architecture of
paraconic acids is accompanied by (a) the presence of C4-
CO2H functionality and C5-alkyl side-chain of variable length
and (b) C3-substituent, either methyl or methylene unit, which
plays prominent roles in determining the physiological
properties of a particular class of paraconic acids.5 Several new
glycosides have been isolated with paraconic acids as the
aglycon components.6 The interesting bioactivities have
prompted many researchers to devise distinct synthetic routes
toward these natural products. A number of total7 and formal8
syntheses have been reported for paraconic acids such as (+)-
methylenolactocin, (+)-phaseolinic acid, (+)-nephrosteranic
acid, (+)-nephrosterinic acid, (+)-rocellaric acid and (+)-
protolichesterinic acid in racemic as well as in enantiopure
forms. The strategies adopted for the enantioselective
synthesis of these paraconic acids include π-face
differentiation in chiral olefin-ketene [2+2] cycloaddition,5d,7b
Cu-catalyzed cyclopropanation,7p regioselective asymmetric
Figure 1. γ-Butyrolactone based paraconic acids.
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Scheme 1. Retrosynthetic route to paraconic acids.
The forward synthesis was executed with the preparation of
Recently, we reported the stereoselective synthesis of chiral alkynols 16 from ketones 17 via Midland14 reduction
paraconic acids by regioselective asymmetric dihydroxylation employing (R)-alpine borane 18 (Scheme 2). The enantiomeric
and Johnson
designing enantioselective synthetic routes to access γ- 92% ee and 16c = 93% ee by converting them into their
 =
Claisen rearrangement.9 Our interest lies in excesses of alkynols was determined for 16a = 94% ee, 16b
butyrolactone/γ-butenolide
derived
bioactive
natural respective p-nitrobenzoate derivatives.15 The alkynols 16 upon
products10 with emphasis on step-economy and protecting- Pd(PPh3)4-catalyzed hydrostannylation with nBu3SnH followed
group-free approaches. In this article, we describe an efficient
Suzuki
Miyaura coupling using the ligand11 developed in our
laboratory and an oxidative phenyl group to carboxylic acid
transformation for the collective synthesis of various paraconic
acids. The scope of SuzukiMiyaura coupling between
butenolide-derived vinyliodide and boronic acids is less
realized and application to paraconic acid synthesis is hitherto
unknown.
Results and Discussion
The retrosynthetic route to access paraconic acids is
depicted in Scheme 1. The key element of our approach is to
assemble the anti- and syn-phenyl butyrolactones 13 and 14
respectively, without involvement of protecting groups. The
phenyl group was easy to install via the Suzuki-Miyaura (SM)
coupling and serves as latent functionality to the desired -
CO2H group (Ru-mediated oxidative cleavage under Sharpless
conditions13) in the target molecules via 11 or 12. The
vinyliodide-butenolide moiety 15 for SM coupling was planned
from

-hydroxy-2-alkynoate
16
by
hydrostannylation/iodination. The chiral alkynol 16 can be
prepared by chiral reduction of the corresponding keto group.
Scheme 2. Synthesis of β-iodo-butenolides 15
.
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by lactonization delivered the regioisomeric mixture of vinyl-
stannane intermediates. Interestingly, the concentration and
rate of addition of nBu3SnH could switch the regioselectivity
pattern. A dilute reaction and slow addition of nBu3SnH to
alkynol 16 furnished the α-stannane butenolide (α:β = 2−5:1)
as the major regioisomer. However, higher reaction
concentration and fast addition of nBu3SnH to alkynol 16
delivered β-stannane butenolide (α:β = 1:3) as the major
regioisomer. As an added advantage, the regioisomers could
be separated by column chromatography prior to vinyliodide
synthesis. The intermediate β-stannane was treated with
molecular I2 to provide β-iodobutenolides 15a-c (Scheme 2) in
overall 50-60% yield from 16 via the intermediate β-stannane
regioisomers.
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DOI: 10.1039/C6OB02398C
The SuzukiMiyaura coupling of β-iodobutenolides 15a-c with
PhB(OH)2 was efficiently executed under our previously optimized
procedure using the ligand L11 developed in our laboratory (Scheme
3). This delivered β-phenylbutenolides 20a-c in quantitative yields.
The reaction required only 0.5 mol% each of Pd(OAc)2 and the
ligand L. The heterogenous hydrogenation of 20a-c in the presence
of Pd-C (10% w/w) under H2 (1 atm) furnished β-
phenylbutyrolactones (13/14) in quantitative yields as anti:syn
diastereomeric mixture (anti:syn
= 1:1.2-2). Although the
Scheme 3. Synthesis of β-phenyl butyrolactones 13 and 14
.
diastereoselectivity was not satisfactory, the syn-isomer
predominates and the mixture can be separated efficiently by
column chromatography.
Scheme 4. Synthesis of (+)-nephrosteranic acid, (+)-rocellaric acid, (+)-methylenolactocin, (+)-nephrosterinic acid, (+)-protolichesterinic acid and (+)-
phaseolinic acid.
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electrospray ionization by the TOF method. The enantiomeric
excess of the alkynol was determined by HPLC method using
chiral columns, Chiralpak IA and IC at wavelength 254 nm.
Upon oxidative cleavage of β-phenyl-moiety in 13 under
Sharpless oxidative protocol13 using RuCl3.3H2O/NaIO4, it furnished
β-CO2H-γ-butyrolactones 11 in quantitative yields (Scheme 4). The
C4-phenyl group in γ-butenolides 20 thus served as latent
functionality to install β-CO2H functional group. The α-
methylation7n (NaHMDS/MeI/THF) of 11b and c delivered (+)-
nephrosteranic acid 1 and (+)-rocellaric acid 2, respectively in
quantitative yields. The α-methylenation of 11a-c (using Stiles
reagent)16 efficiently provided (+)-methylenolactocin 8, (+)-
nephrosterinic acid 9 and (+)-protolichesterinic acid 10 (Scheme 4)
respectively in good yields (60-64%). The syn-butryrolactone 14a on
oxidative cleavage of phenyl group gave the β-CO2H butyrolactone
12a quantitatively. Further α-methylation completed the synthesis
of (+)-phaseolinic acid 3 in quantitative yield.7i The spectral data of
all synthesized paraconic acids matched well with literature
data.7c,i,l,s
General procedure for the synthesis of alkynols (16a-c):14
A
solution of (R)-alpine borane 18 (6 mL, 0.5M in THF, 3.0 mmol,
2.0 equiv.) was charged into a round-bottom flask followed by
dropwise addition of a solution of acetylenic ketones 17a-c (1.5
mmol) in THF (3.0 mL) at 0 C. The solvent was removed under
vacuum to render a neat reaction mixture. The reaction flask
was flushed with N2 and stirred for 48 h at room temperature.
Excess alpine-borane was destroyed by adding freshly distilled
propionaldehyde (1.0 mmol) and stirred for 1 h at room
temperature. The reaction mixture was dissolved in THF (3.0 mL)
and then treated with aqueous 3M NaOH (2.0 mL). Then 30%
H2O2 (2.0 mL) was added dropwise at 0
C and stirred for 4 h at
40 C. The reaction mixture was extracted with Et2O (3 × 15 mL)

and the combined organic layers were dried (Na2SO4) and
concentrated. The crude residue was purified by column
chromatography using petroleum ether/EtOAc (9:1) as eluent to
afford alkynols 16a-c in good yields (68-71%).
Conclusions
General procedure for the synthesis of p-nitrobenzoate
derivatives of 16a-c: To a solution of alkynols 16a-c (0.1 mmol) in
dry CH2Cl2 (5.0 mL) were added Et3N (20.9 mg, 0.15 mmol) and p-
nitrobenzoyl chloride (22.3 mg, 0.12 mmol) at 0 C. After 30 min,
the reaction mixture was quenched with few drops of water and
concentrated to afford a brown residue. The residue was purified
by column chromatography using petroleum ether/EtOAc (20:1) as
eluent to afford p-nitrobenzoate derivatives of 16a-c.
In conclusion, we have developed a highly concise and
collective synthesis of various paraconic acids, (+)-
methylenolactocin, (+)-phaseolinic acid, (+)-nephrosteranic
acid, (+)-nephrosterinic acid, (+)-rocellaric acid and (+)-
protolichesterinic
acid
by
Pd-mediated
efficient
Suzuki Miyaura cross coupling followed by oxidative cleavage

of β-phenyl group to afford the advanced β-CO2H
butyrolactone intermediates. The easy installation of β-phenyl
group by Suzuki-Miyaura coupling and its subsequent
oxidation to β-CO2H group are key features in the synthesis.
The stereoselective α-methylation or methylenation
completed the syntheses of various paraconic acids. Thus, an
efficient collective protecting-group-free synthesis of various
paraconic acids in high overall yields is demonstrated. The
strategy has potential for the synthesis of other members of
the paraconic acid family, shown in Figure 1.
Alkynol 16a: Yield (211 mg, 71%); colorless oil; []
25 = 23.5 (c =
0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.89 (t, JD= 6.7 Hz, 3H),
1.10−1.40 (m, 7H), 1.40−1.60 (m, 2H), 1.70−1.90 (m, 2H), 2.09
(brs, 1H, OH), 4.24 (q, J = 7.2 Hz, 2H), 4.48 (t, J = 6.7 Hz, 1H) ppm.
13C NMR (100 MHz, CDCl3): δ = 13.9, 14.0, 22.4, 24.6, 31.3, 36.8,
62.1, 62.2, 76.5, 87.9, 153.5 ppm. IR (CHCl3): max = 3419, 2958,
2934, 2863, 2238, 1715, 1467, 1368, 1248, 1020, 861, 752, 636
cm−1. HRMS (ESI−TOF): calcd for [C11H18O3+H]+ 199.1334, found
199.1340. The alcohol was converted into p-nitrobenzoate
derivative for HPLC analysis. HPLC: Chiralpak IC, nHexane/IPA =
90:10, flow rate = 1 mL/min, tR = 11.16 min (major) min, tR =
10.58 min (minor), ee = 94%.
p-Nitrobenzoate derivative of 16a: Yield (32.9 mg, 95%); colorless
oil. 1H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 6.8 Hz, 3H), 1.24−1.38
(m, 7H), 1.51−1.58 (m, 2H), 1.96−2.02 (m, 2H), 4.21 (q, J = 7.2 Hz,
2H), 5.70 (t, J = 6.4 Hz, 1H), 8.22 (d, J = 9.2 Hz, 2H), 8.30 (d, J = 8.8
Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.85, 13.9, 22.3, 24.5,
31.1, 33.9, 62.3, 64.7, 77.4, 83.1, 123.6, 130.9, 134.6, 150.7, 152.9,
163.4 ppm. IR (CHCl3): max = 3114, 2958, 2931, 2863, 2245, 1717,
1607, 1531, 1465, 1409, 1347, 1320, 1247, 1098, 1014, 906, 872,
839, 783, 720 cm-1. HRMS (ESI−TOF): calcd for [C18H21NO6+H]+
348.1447, found 348.1450.
Experimental Section
General Information: Solvents were dried by standard
procedures. Thin-layer chromatography was performed on EM
250 Kieselgel 60 F254 silica gel plates. The spots were visualized
by staining with KMnO4 or by using UV lamp. H-NMR and 13C-
1
NMR were recorded with a spectrometer operating at 400 or
500 and 100 or 125 MHz for proton and carbon nuclei,
respectively. The chemical shifts are based on TMS peak at
0.00 pm for proton NMR and CDCl3 peak at = 77.00 ppm (t) in
carbon NMR. For other deuterated solvents the standard
chemical shifts were considered. IR spectra were obtained on an
FT-IR spectrometer. Optical rotations were measured using
Sodium D line (589 nm). HRMS were recorded using positive
 =

Alkynol 16b: Yield (288 mg, 68%); colorless oil; []
25 = 31.5 (c =
D
1
1, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 6.9 Hz, 3H),
1.0−1.40 (m, 19H), 1.41−1.47 (m, 2H), 1.72−1.79 (m, 2H), 2.02
(brs, 1H, OH), 4.24 (q, J = 7.1 Hz, 2H), 4.48 (t, J = 6.7 Hz, 1H) ppm.
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13C NMR (100 MHz, CDCl3): δ = 14.0, 14.1, 22.7, 24.9, 29.1, 29.3, (100 MHz, CDCl3): δ = 13.9, 22.3, 23.3, 31.2, 32.4, 88.0, 125.3,
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29.4, 29.5, 29.6, 31.9, 36.9, 62.1, 62.14, 76.5, 87.9, 153.4 ppm. IR 130.0, 171.1 ppm. IR (CHCl3): max = 3101, 3016, 2952, 2929,
DOI: 10.1039/C6OB02398C
(CHCl3): max = 3441, 3020, 2929, 2857, 2239, 1968, 1714, 1639, 2860, 1755, 1587, 1464, 1376, 1332, 1244, 1161, 1090, 1039,
1467, 1369, 1259, 1021, 933, 768, 669 cm−1. HRMS (ESI−TOF): 1014, 926, 880, 853, 699 cm-1. HRMS (ESI
calcd for [C17H30O3+H]+ 283.2274, found 283.2279. The alcohol [C9H13O2I+Na]+ 302.9858, found 302.9863.
was converted into p-nitrobenzoate derivative for HPLC analysis.

TOF): calcd for
25 = 13.8
HPLC: Chiralpak IA, nHexane/IPA = (90:10), flow rate = 1 mL/min,
Butenolide 15b: Yield (96.5 mg, 53%); colorless oil; []
(c = 0.3, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.85 (t, JD= 6.9 Hz,
3H), 1.25−1.43 (m, 18H), 1.53−1.65 (m, 1H), 1.99−2.07 (m, 1H),
4.94−4.97 (m, 1H), 6.51 (d, J = 1.8 Hz, 1H) ppm. 13C NMR (100
MHz, CDCl3): δ = 14.1, 22.7, 23.7, 29.1, 29.28, 29.3, 29.4, 29.6,
tR = 15.69 min (major) min, tR = 13.05 min (minor), ee = 92%.
p-Nitrobenzoate derivative of 16b: Yield (40.6 mg, 94%); colorless
oil. 1H NMR (500 MHz, CDCl3): δ = 0.84 (t, J = 6.5 Hz, 3H), 1.23−1.34
(m, 19H), 1.49−1.55 (m, 2H), 1.97−2.02 (m, 2H), 4.22 (q, J = 7.0 Hz,
2H), 5.69 (t, J = 6.5 Hz, 1H), 8.21 (d, J = 8.5 Hz, 2H), 8.28 (d, J = 8.5
Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.9, 14.0, 22.6, 24.8,
29.0, 29.3, 29.4, 29.6, 31.8, 33.9, 62.3, 64.7, 77.4, 83.1, 123.6,
130.9, 134.7, 150.7, 152.9, 163.4 ppm. IR (CHCl3): max = 3114, 2927,
2854, 2245, 1718, 1607, 1531, 1464, 1409, 1347, 1319, 1098, 1014,
872, 852, 783, 720 cm-1. HRMS (ESI−TOF): calcd for [C24H33NO6+H]+
432.2387, found 432.2392.
31.9, 32.5, 88.0, 125.3, 130.0, 171.1 ppm. IR (CHCl3):

max = 2925,
2854, 1768, 1572, 1465, 1377, 1327, 1264, 1185, 987, 705 cm-1.
HRMS (ESI
365.0987.

TOF): calcd for [C15H25O2I+H]+ 365.0978, found
Butenolide 15c: Yield (98.1 mg, 50%); colorless oil; []
25 = 11.3
(c = 0.2, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.86 (t, JD= 6.8 Hz,
3H), 1.26−1.33 (m, 22H), 1.56−1.63 (m, 1H), 1.98−2.08 (m, 1H),
4.94−4.98 (m, 1H), 6.51 (d, J = 1.8 Hz, 1H) ppm. 13C NMR (100
MHz, CDCl3): δ = 14.1, 22.7, 23.7, 29.1, 29.29, 29.3, 29.5, 29.57,
29.6, 29.7, 31.9, 32.5, 88.0, 125.3, 130.1, 171.1 ppm. IR (CHCl3):
max = 3021, 2924, 2853, 1757, 1735, 1588, 1491, 1464, 1161,
Alkynol 16c: Yield (326 mg, 70%); pale yellow oil; []
25 = 19.8 (c
D
1
= 0.25, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz,
3H), 1.25−1.33 (m, 23H), 1.42−1.48 (m, 2H), 1.73−1.81 (m, 2H),
1.98 (brs, 1H, OH), 4.21 (q, J = 7.2 Hz, 2H), 4.46 (t, J = 6.7 Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0, 14.1, 22.7, 24.9, 29.1,
29.3, 29.4, 29.5, 29.6, 29.63, 29.7, 31.9, 36.9, 62.2, 76.6, 87.8,
153.4 ppm. IR (CHCl3): max = 3421, 2925, 2855, 2237, 1717,
1466, 1368, 1246, 1048, 862, 752, 723, 628 cm−1. HRMS
(ESI−TOF): calcd for [C19H34O3+H]+ 311.2586, found 311.2591.
The alcohol was converted into p-nitrobenzoate derivative for
HPLC analysis. HPLC: Chiralpak IA, nHexane/IPA = (85:15), flow
rate = 1 mL/min, tR = 8.39 min (major) min, tR = 7.07 min (minor),
ee = 93%.
1041, 1022, 932, 911, 877, 854, 688, 669 cm-1. HRMS (ESI
calcd for [C17H29O2I+K]+ 431.0844, found 431.0848.
TOF):
General procedure for the synthesis of 4-phenylbutenolides
(20a-c) 11b
To a solution of β-iodo butenolides 15a-c (0.5 mmol)
:
in EtOH:H2O (4:1, 6.0 mL) were added sequentially PhB(OH)2 19
(90.8 mg, 0.750 mmol, 1.5 equiv.), K2CO3 (138.2 mg, 1.0 mmol,
2.0 equiv.), Pd(OAc)2 (0.56 mg, 0.0025 mmol, 0.5 mol%) and
ligand
was stirred at room temperature for 15 min and then filtered
through a small pad of celite and washed with CH2Cl2 (2 25
L (1.32 mg, 0.0025 mmol, 0.5 mol%). The reaction mixture

p-Nitrobenzoate derivative of 16c: Yield (43.7 mg, 95%); colorless
oil. 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.7 Hz, 3H), 1.25−1.32
(m, 23H), 1.51−1.57 (m, 2H), 1.98−2.04 (m, 2H), 4.21 (q, J = 7.2 Hz,
2H), 5.70 (t, J = 6.8 Hz, 1H), 8.21 (d, J = 8.8 Hz, 2H), 8.29 (d, J = 8.2
Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9, 14.1, 22.7, 24.9,
29.0, 29.3, 29.5, 29.55, 29.6, 29.63, 31.9, 34.0, 62.3, 64.8, 77.5,
mL). The filtrate was concentrated and the residue purified by
column chromatography using petroleum ether/EtOAc as eluent
to give 4-phenylbutenolides 20a-c in quantitative yields.
25
Butenolide 20a: Yield (115.1 mg, quant.); colorless oil; [
]
=
D
1
−80.2 (c = 0.6, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.81 (t, J =
7.3 Hz, 3H), 1.18−1.30 (m, 4H), 1.37–1.47 (m, 2H), 1.53–1.62 (m,
1H), 1.95–2.03 (m, 1H), 5.48–5.51 (m, 1H), 6.26 (d, J = 1.1 Hz,
1H), 7.45–7.49 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9,
22.4, 24.2, 31.3, 33.4, 82.3, 114.3, 127.1, 129.2, 130.2, 131.2,
167.8, 172.9 ppm. IR (CHCl3): max = 2926, 2851, 1755, 1599,
1492, 1448, 1338, 1275, 1118, 1026, 963, 894, 792, 694 cm-1.
HRMS (ESI−TOF): calcd for [C15H18O2+H]+ 231.1385, found
231.1390.
83.2, 123.6, 131.0, 134.7, 150.8, 152.9, 163.4 ppm. IR (CHCl3): max
=
2926, 2855, 2245, 1719, 1607, 1531, 1464, 1410, 1347, 1319, 1269,
1245, 1098, 1015, 968, 872, 853, 719 cm-1. HRMS (ESI−TOF): calcd
for [C26H37NO6+H]+ 460.2700, found 460.2694.
General procedure for the synthesis of β-iodo butenolides
(15a-c): To a solution of alkynols 16a-c (0.5 mmol) in dry THF
(5.0 mL), were added Pd(Ph3P)4 (11.6 mg, 0.01 mmol, 2.0 mol%)
and Bu3SnH (175 mg, 0.6 mmol) in one portion at room
temperature. After 20 min, the reaction mixture was
25
concentrated to afford a brown residue. The regioisomeric Butenolide 20b: Yield (157.2 mg, quant.); colorless oil; [
]
=
D
1
mixture was purified by fast column chromatography using −95.4 (c = 0.5, CHCl3). H NMR (500 MHz, CDCl3): δ = 0.86 (t, J =
petroleum ether and EtOAc (20:1) as eluent to afford β-stannane 7.0 Hz, 3H), 1.21−1.28 (m, 16H), 1.34–1.46 (m, 2H), 1.54–1.60
butenolide. To a solution of this in dry CH2Cl2 (10 mL), was added (m, 1H), 1.95–2.02 (m, 1H), 5.48–5.51 (m, 1H), 6.27 (d, J = 1.4 Hz,
I2 (152.4 mg, 0.6 mmol) in dry CH2Cl2 dropwise at room 1H), 7.44–7.50 (m, 5H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1,
temperature. The reaction was stirred for 12 h and then treated 22.7, 24.5, 29.2, 29.3, 29.32, 29.4, 29.6, 31.9, 33.5, 82.3, 114.3,
with 50% aq. KF solution (5 mL) and stirred for additional 6 h. 127.1, 129.2, 130.2, 131.2, 167.8, 173.0 ppm. IR (CHCl3): max
=
The reaction mixture was extracted with CH2Cl2 (3 × 10 mL). The 2925, 2851, 1756, 1596, 1492, 1448, 1341, 1264, 1118, 1023,
combined organic layers were dried (Na2SO4) and concentrated 963, 891, 856, 792, 694 cm-1. HRMS (ESI
to give crude vinyl iodide. The crude residue was purified by [C21H30O2+H]+ 315.2324, found 315.2321.
column chromatography using petroleum ether/EtOAc (19:1) as

TOF): calcd for
25
eluent to deliver β-iodo butenolides 15a-c in 50−60% yield (two
steps).
Butenolide 20c: Yield (171.2 mg, quant.); colorless oil; [
]
=
D
1
−138.3 (c = 0.35, CHCl3). H NMR (500 MHz, CDCl3): δ = 0.86 (t, J
= 6.8 Hz, 3H), 1.37−1.14 (m, 20H), 1.42–1.46 (m, 2H), 1.54–1.61
Butenolide 15a: Yield (84.0 mg, 60%); colorless oil; [
]
25 = 12.8 (m, 1H), 1.95–2.02 (m, 1H), 5.48–5.51 (m, 1H), 6.27 (d, J = 1.4 Hz,
D
1
13
(c = 0.25, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 6.9 1H), 7.44–7.49 (m, 5H) ppm. NMR (125 MHz, CDCl3): δ = 14.1,
Hz, 3H), 1.30−1.42 (m, 6H), 1.55−1.64 (m, 1H), 1.99−2.07 (m, 22.7, 24.5, 29.2, 29.3, 29.4, 29.6, 29.61, 29.63, 31.9, 33.5, 82.3,
1H), 4.94−4.97 (m, 1H), 6.51 (d, J = 1.6 Hz, 1H) ppm. 13C NMR 114.4, 127.0, 127.1, 129.2, 130.2, 131.2, 167.8, 172.9 ppm. IR
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Journal Name
 = 14.1, 22.7, 25.8, 29.2, 29.3, 29.3V3ie,w2A9r.ti4cl,e 2O9nl.i5ne,
TOF): calcd for 29.6, 31.1, 31.9, 35.8, 44.6, 84.3, 127.6, 127.8, 128.7, 138.1,
176.9 ppm. IR (CHCl3): max = 3014, 29D2O6,I: 1208.15073,9/1C767O9B,021349686C,
1362, 1187, 1043, 920, 674 cm-1. HRMS (ESI−TOF): calcd for
[C21H32O2+Na]+ 339.2295, found 339.2298.
(CHCl3): max = 2929, 1761, 1649, 1590, 1447, 1122, 1078, 1040, MHz, CDCl3):
946, 856, 709, 666 cm-1. HRMS (ESI
[C23H34O2+Na]+ 365.2451, found 365.2448.

General procedure for the synthesis of 4-phenylbutyrolactones,
(13a-c) and (14a-c): To a solution of 20a-c (0.3 mmol) in absolute
EtOH (5.0 mL) was added 10% Pd-C (3.0 mg, 10 mol%) and the
reaction mixture stirred under H2 (1 atm, balloon pressure) for 1
h at room temperature. The reaction mixture was then filtered
25
Butyrolactone 14c: Yield (48.6 mg, 47%); colorless oil; [

]
=
D
1
28.1 (c = 0.25, CHCl3). H NMR (CDCl3, 500 MHz):
 = 0.86 (t, J =
7.0 Hz, 3H), 1.12−1.45 (m, 24H), 2.74 (dd, J = 17.5, 4.9 Hz, 1H),
2.94 (dd, J = 17.5, 8.6 Hz, 1H), 3.70−3.74 (m, 1H), 4.68−4.72 (m,
1H), 7.12−7.26 (m, 2H), 7.29−7.34 (m, 3H) ppm. 13C NMR (125
through a small pad of celite and washed with EtOAc (3
 5 mL).
The filtrate was concentrated under vacuo to afford the
diastereomeric mixture 13a-c/14a-c (anti:syn = 1:1.2-2) in
quantitative yield in each case. The diastereomeric mixture was
separated by column chromatography using petroleum
ether/EtOAc (19:1) as eluent to furnish pure anti-butyrolactones
MHz, CDCl3):
 = 14.1, 22.7, 25.8, 29.2, 29.3, 29.4, 29.5, 29.6,
29.64, 31.1, 31.9, 35.8, 44.6, 84.3, 127.6, 127.8, 128.7, 138.1,
176.9 ppm. IR (CHCl3): max = 3014, 2926, 2857, 1779, 1468,
1357, 1187, 1038, 1027, 669 cm-1. HRMS (ESI−TOF): calcd for
[C23H36O2+Na]+ 367.2608, found 367.2605.
(13a-c) and syn-butyrolactones (14a-c).
Butyrolactone 13a: Yield (21 mg, 30%); colorless oil; []
25 = 22.3
General procedure for the synthesis of butyrolactones 11a-c
(c = 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.83 (t, JD= 6.8 Hz,
3H), 1.21−1.34 (m, 5H), 1.48−1.52 (m, 1H), 1.65−1.70 (m, 2H),
2.71 (dd, J = 17.7, 10.5 Hz, 1H), 2.91 (dd, J = 17.6, 8.7 Hz, 1H),
3.26−3.33 (m, 1H), 4.42−4.47 (m, 1H), 7.23−7.39 (m, 5H) ppm.
13C NMR (100 MHz, CDCl3): δ = 13.9, 22.4, 25.3, 31.5, 34.1, 37.6,
47.7, 87.1, 127.2, 127.7, 129.1, 139.1, 175.7 ppm. IR (CHCl3):
max = 3019, 2927, 2855, 1779, 1423, 1264, 1044, 928, 778, 669
cm-1. HRMS (ESI−TOF): calcd for [C15H20O2+Na]+ 255.1356, found
255.1352.
and 12a under Sharpless oxidation conditions 13
. To a solution of
13a-c or 14a (0.1 mmol) in CCl4 (1 mL), CH3CN (1 mL) and H2O (2
mL) were added sequentially NaIO4 (321 mg, 1.5 mmol, 15
equiv) and RuCl3.3H2O (1.44 mg, 0.0055 mmol, 5.5 mol%) under
vigorous stirring. After 48 h, the reaction mixture was diluted
with CH2Cl2 (10 mL) and filtered through a pad of celite and
washed with CH2Cl2 (3 × 5 mL). The filtrate was concentrated to
afford virtually pure butyrolactones 11a-c or 12a respectively.
Carboxylic acid 11a: Yield (20 mg, quant.); white solid; m.p =
25
100−102

C. [

]
= 40.2 (c = 0.3, CHCl3); lit.7s m.p = 105
C,
25
[

]
25 = 53.7 (c =D1.82, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.90
Butyrolactone 13b: Yield (42.8 mg, 45%); colorless oil; [

]
=
D
1
D
18.2 (c = 0.45, CHCl3). H NMR (500 MHz, CDCl3):
 = 0.79 (t, J =
(t, J = 6.6 Hz, 3H), 1.11−1.56 (m, 6H), 1.65−1.85 (m, 2H), 2.81 (dd,
J = 18.0, 9.6 Hz, 1H), 2.94 (dd, J = 18.0, 8.6 Hz, 1H), 3.05−3.15 (m,
1H), 4.57−4.65 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9,
22.4, 24.8, 31.3, 32.0, 35.3, 45.4, 81.9, 174.4, 176.0 ppm. IR
(CHCl3): max = 3467, 3020, 2930, 2856, 1779, 1746, 1461, 1021,
910, 770, 669 cm-1 HRMS (ESI−TOF): calcd for [C10H16O4+H]+
201.1127, found 201.1131.
6.0 Hz, 3H), 1.26−1.42 (m, 18H), 1.49−1.62 (m, 2H), 2.65 (dd, J =
17.2, 10.9 Hz, 1H), 2.85 (dd, J = 17.6, 8.7 Hz, 1H), 3.19 (dd, J =
17.5, 8.8 Hz, 1H), 4.36 (dd, J = 12.5, 6.0 Hz, 1H), 7.17−7.31 (m,
5H) ppm. 13C NMR (125 MHz, CDCl3):
 = 14.1, 22.7, 25.6, 29.27,
29.3, 29.4, 29.5, 29.6, 31.9, 34.1, 37.6, 47.7, 87.1, 127.2, 127.7,
129.1, 139.1, 175.7 ppm. IR (CHCl3): max = 3018, 2927, 2855,
1777, 1541, 1445, 1236, 1119, 1043, 928, 775, 669 cm-1. HRMS
(ESI−TOF): calcd for [C21H32O2+Na]+ 339.2295, found 339.2295.
Carboxylic acid 11b: Yield (28.4 mg, quant.); white solid; m.p =
25
25
= 44.0 (c = 0.2, CHCl3), lit.7n
[
]
= 44.8 (c =
25
116−118

C. [

]
D
D
Butyrolactone 13c: Yield (46.5 mg, 45%); colorless oil; [

]
=
D
1
1
0.25, CHCl3). H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 6.9 Hz,
3H), 1.10−1.60 (m, 18H), 1.65−1.85 (m, 2H), 2.82 (dd, J = 17.9,
9.8 Hz, 1H), 2.94 (dd, J = 17.9, 8.6 Hz, 1H), 3.06−3.13 (m, 1H),
4.58−4.65 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1,
22.7, 25.2, 29.2, 29.3, 29.4, 29.5, 29.6, 31.9, 35.4, 45.4, 81.8,
174.4, 175.9 ppm. IR (CHCl3): max = 3437, 3020, 2928, 2856,
1779, 1717, 1602, 1521, 1424, 1019, 929, 845, 669, 626 cm-1.
HRMS (ESI−TOF): calcd for [C16H28O4+H]+ 285.2066, found
285.2068.
19.8 (c = 0.2, CHCl3). H NMR (500 MHz, CDCl3):
 = 0.86 (t, J =
6.8 Hz, 3H), 1.22−1.54 (m, 22H), 1.45−1.69 (m, 2H), 2.72 (dd, J =
17.7, 10.5 Hz, 1H), 2.92 (dd, J = 17.7, 8.8 Hz, 1H), 3.26 (dd, J =
18.9, 8.6 Hz, 1H), 4.42 (dd, J = 14.2, 6.2 Hz, 1H), 7.23−7.38 (m,
5H) ppm. 13C NMR (125 MHz, CDCl3):
 = 14.1, 22.7, 25.7, 29.3,
29.34, 29.4, 29.5, 29.57, 29.6, 29.7, 31.9, 34.1, 37.6, 47.7, 87.1,
127.2, 127.7, 129.1, 139.1, 175.7 ppm. IR (CHCl3): max = 3019,
2927, 2854, 1771, 1555, 1442, 1222, 1043, 928, 876, 669 cm-1.
HRMS (ESI−TOF): calcd for [C23H36O2+Na]+ 367.2608, found
367.2608.
Carboxylic acid 11c: Yield (31.2 mg, quant.); white solid; m.p =
25
= 38.8 (c = 0.35, CHCl3), for enantiomer lit.7s
25
104−106

C. [
]
D
Butyrolactone 14a: Yield (41.8 mg, 60%), colorless oil; [

]
=
D
25
1
1
[
]
= −42.8 (c = 1.72, CHCl3). H NMR (500 MHz, CDCl3): δ =
0.8D8 (t, J = 6.9 Hz, 3H), 1.10−1.60 (m, 22H), 1.65−1.85 (m, 2H),
2.82 (dd, J = 17.8, 8.4 Hz, 1H), 2.94 (dd, J = 17.8, 8.4 Hz, 1H),
3.06−3.13 (m, 1H), 4.58−4.65 (m, 1H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 14.1, 22.7, 25.2, 29.2, 29.3, 29.4, 29.5, 29.6, 29.62,
29.7, 31.9, 32.0, 34.1, 35.4, 45.4, 81.9, 174.5, 175.6 ppm. IR
(CHCl3): max = 3451, 3018, 2923, 1657, 1534, 1221, 1062, 894,
856, 809, 772, 686, 628, 541 cm-1. HRMS (ESI−TOF): calcd for
[C18H32O4+H]+ 313.2379, found 313.2376.
28.1 (c = 0.2, CHCl3). H NMR (400 MHz, CDCl3):
 = 0.79 (t, J =
7.0 Hz, 3H), 1.13−1.33 (m, 7H), 1.37−1.46 (m, 1H), 2.74 (dd, J =
17.4, 4.9 Hz, 1H), 2.93 (dd, J = 17.5, 8.5 Hz, 1H), 3.69−3.74 (m,
1H), 4.68−4.73 (m, 1H), 7.11−7.14 (m, 2H), 7.27−7.36 (m, 3H)
ppm. 13C NMR (100 MHz, CDCl3):
 = 13.9, 22.4, 25.5, 31.1, 31.4,
35.8, 44.6, 84.3, 127.6, 127.8, 128.8, 138.1, 176.9 ppm. IR
(CHCl3): max = 3014, 2930, 2852, 1779, 1463, 1365, 1187, 1043,
1024, 920, 671 cm-1. HRMS (ESI−TOF): calcd for [C15H20O2+Na]+
255.1356, found 255.1354.
25
Carboxylic acid 12a: Yield (20 mg, quant.); white solid; m.p =
Butyrolactone 14b: Yield (42.7 mg, 45%); colorless oil; [

]
=
D
25
29
= 44.0 (c = 0.14, CHCl3); lit.7y [

]
= 54.08 (c
1
101−103

C. [
]
D
D
24.2 (c = 0.35, CHCl3). H NMR (500 MHz, CDCl3):
 = 0.86 (t, J =
1
= 0.51, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 7.1 Hz,
3H), 1.25−1.75 (m, 8H), 2.71 (dd, J = 17.7, 8.5 Hz, 1H), 2.90 (dd, J
= 17.7, 5.1 Hz, 1H), 3.42−3.52 (m, 1H), 4.67 (dd, J = 13.7, 7.1 Hz,
7.0 Hz, 3H), 1.13−1.42 (m, 20H), 2.75 (dd, J = 17.5, 4.9 Hz, 1H),
2.94 (dd, J = 17.5, 8.6 Hz, 1H), 3.69−3.74 (m, 1H), 4.68−4.72 (m,
1H), 7.12−7.14 (m, 2H), 7.27−7.35 (m, 3H) ppm. 13C NMR (125
6 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9, 22.4, 25.5, 31.2, methylaniline (1.0 mL) and NaOAc (0.12 g)] and stirVrieewdAfroticrle3Ohnlianet
31.3, 31.9, 44.1, 80.3, 174.9, 175.1 ppm. IR (CHCl3): max = 3645, room temperature. Brine solution (10 mLD, OcoI:n1t0a.1in03in9g/C16OmBL02c3o9n8cC.
3019, 2926, 2855, 1770, 1469, 1443, 1161, 1040, 971, 928, 669 HCl) was added and the aqueous layer extracted with Et2O (5 ×
cm-1. HRMS (ESI−TOF): calcd for [C10H16O4+H]+ 201.1127, found 15 mL). The combined organic layers were washed with brine,
201.1130.
dried (Na2SO4) and concentrated. The residue was purified by
silica gel flash column chromatography (CH2Cl2/EtOAc, 19:1) to
provide 8-10 respectively in 60-64% yield.
General procedure for α-methylation of acids 11b, 11c or 12a
to 1-3 respectively.7n To a solution of 11b
,
11c or 12a (0.10
mmol) in THF (4 mL) at –78
0.22 mmol, 1.0 M solution in THF, 2.2 equiv) and stirred for 1.5 = 81−83
h. MeI (62 L, 1.0 mmol, 10.0 equiv) was added and the reaction 1.46, CH3OH). H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 6.7 Hz,
mixture stirred at –78 C for 2 h and then allowed to warm to – 3H), 1.11−1.58 (m, 6H), 1.65−1.81 (m, 2H), 3.62−3.64 (m, 1H),
20 C. 2N HCl (1.0 mL) was added and the mixture extracted 4.78−4.83 (m, 1H), 6.02 (d, J = 2.8 Hz, 1H), 6.47 (d, J = 2.8 Hz, 1H)
with EtOAc (5 × 15 mL). The combined organic layers were dried ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9, 22.4, 24.4, 31.3, 35.7,
C was added NaHMDS (0.22 mL, (+)-Methylenolactocin (8): Yield (13.6 mg, 64%); white solid; m.p
25
25

C. [

]
= 6.8 (c = 0.2, CH3OH), lit.7s
[

]
= 2.25 (c =
D
D
1



(Na2SO4) and concentrated. The residue was purified by silica gel 49.4, 78.8, 125.8, 132.4, 168.2, 173.8 ppm. IR (CHCl3): max
=
flash column chromatography (petroleum ether/EtOAc, 1:1) as 3352, 3020, 2930, 1763, 1720, 1115, 1025, 929, 669 cm-1. HRMS
eluent to provide 1-3 respectively as white solids in quantitative (ESI−TOF): calcd for [C11H16O4+H]+ 213.1127, found 213.1135.
yields.
(+)-Nephrosterinic acid (9): Yield (19 mg, 64%); white solid; m.p
32
(+)-Nephrosteranic acid (1): Yield (29.8 mg, quant.); white solid; = 80

82

C. D25 = 12.6 (c = 0.5, CHCl3), lit. 7l
[

]
= 13.0 (c =
D
25
1
m.p = 94−96

C. [
]
= 26.9 (c = 0.14, CHCl3); lit.7c m.p = 96−98 0.66, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 6.8 Hz,
D
27
1
C, [
]
= 27.2 (c = 1.45, CHCl3). H NMR (400 MHz, CDCl3): δ = 3H), 1.10–1.60 (m, 18H), 1.65–1.80 (m, 2H), 3.61
0.88 (tD, J = 6.8 Hz, 3H), 1.02−1.61 (m, 18H), 1.37 (d, J = 7.3 Hz, 4.81

3.65 (m, 1H),

4.83 (m, 1H), 6.01 (d, J = 3.0 Hz, 1H, ), 6.45 (d, J = 3.0 Hz,
3H), 1.62−1.83 (m, 2H), 2.72 (dd, J = 11.3, 9.5 Hz, 1H), 2.97–3.01 1H), ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7, 24.8, 29.2,
(m, 1H), 4.46–4.50 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 29.3, 29.4, 29.5, 29.6, 29.7, 31.9, 35.7, 49.4, 78.9, 125.6, 132.7,
14.1, 14.5, 22.7, 25.3, 29.2, 29.3, 29.4, 29.5, 29.6, 31.9, 34.9, 168.2, 172.2 ppm. IR (CHCl3): max = 3684, 3020, 2957, 2928,
39.8, 53.8, 79.3, 175.1, 176.6 ppm. IR (CHCl3):
2928, 2855, 1773, 1716, 1464, 1022, 669 cm-1. HRMS (ESI−TOF): 1018, 929, 850, 669, 626 cm-1. HRMS (ESI−TOF): calcd for
calcd for [C17H30O4+H]+ 299.2222, found 299.2217. [C17H28O4+H]+ 297.2066, found 297.2072.
max = 3356, 3020, 2856, 2433, 2400, 1763, 1719, 1602, 1523, 1475, 1423, 1117,
(+)-Rocellaric acid (2): Yield (32.6 mg, quant.); white solid; m.p = (+)-Protolichesterinic acid (10): Yield (19.5 mg, 60%); white
25
25
98−100

C. [
]
= 26.9 (c = 2.0, CHCl3); lit.7s
D
[

]
= 23.6 (c = solid; m.p. = 102

104

C; D25 = 13.1 (c = 0.4, CHCl3) lit.7s m.p. =
D
1.60, CHCl3), lit. 7c
[
]
25 = 27 (c = 0.87, CHCl3), 1H NDMR (400 MHz, 104

105

C; *α+D = 13.6 (c = 1.72, CHCl3). H NMR (400 MHz,
25
1
CDCl3): δ = 0.87 (t, J = 6.8 Hz, 3H), 1.03–1.64 (m, 22H), 1.36 (d, J CDCl3): δ = 0.87 (t, J = 6.7 Hz, 3H), 1.10–1.60 (m, 22H), 1.65–1.80
= 7.0 Hz, 3H), 1.65–1.85 (m, 2H), 2.69 (dd, J = 11.3, 9.5 Hz, 1H), (m, 2H ), 3.613.63 (m, 1H), 4.804.84 (m, 1H), 6.01 (d, J = 2.8
2.95–3.02 (m, 1H), 4.43–4.50 (m, 1H) ppm. 13C NMR (100 MHz, Hz, 1H), 6.45 (d, J = 2.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):
CDCl3): δ = 14.1, 14.5, 22.7, 25.3, 29.2, 29.3, 29.4, 29.5, 29.6, δ = 14.1, 22.7, 24.8, 29.2, 29.3, 29.4, 29.5, 29.6, 31.9, 35.7, 49.6,
29.7, 31.9, 34.9, 39.8, 53.8, 79.4, 174.5, 176.6 ppm. IR (CHCl3): 79.0, 132.7, 125.6, 168.3, 172.9 ppm. IR (CHCl3): max = 3682,
max = 3434, 3019, 2923, 2857, 1778, 1748, 1602, 1456, 1127, 3020, 2927, 2855, 2400, 1759, 1714, 1602, 1516, 1466, 1109,
1017, 925, 769, 669 cm-1. HRMS (ESI−TOF): calcd for 1024, 929, 669, 626 cm-1. HRMS (ESI−TOF): calcd for
[C19H34O4+H]+ 327.2535, found 327.2529.
[C19H32O4+H]+ 325.2379, found 325.2386.
(+)-Phaseolinic acid (3): Yield (21.4 mg, quant.); white solid; m.p
= 137−139

C. *α+D25 = 115 (c = 0.2, CHCl3), lit.7i *α+D25 = 111.4 (c =
Acknowledgements
1
0.22, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 7.0 Hz,
3H), 1.21–1.57 (m, 6H), 1.33 (d, J = 7.1 Hz, 3H), 1.57–1.67 (m,
2H), 3.0–3.09 (m, 1H), 3.22 (dd, J = 9.6, 8.2, 1H), 4.69−4.73 (m,
1H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9, 14.4, 22.4, 25.3,
We thank the Department of Science and Technology, New
Delhi, (Grant No. SB/S1/OC-42/2013) and Board of Research in
Nuclear Sciences (BRNS), Government of India (Basic Sciences,
Grant No. 2013/37C/59/BRNS/2443) for financial support.
J.L.N thanks Council of Scientific and Industrial Research (CSIR),
New Delhi for research fellowship.
31.0, 31.3, 36.4, 51.6, 77.4, 174.8, 177.5 ppm. IR (CHCl3): max
=
3021, 2959, 2930, 2861, 1775, 1717, 1524, 1459, 1420, 1382,
1017, 984, 669, 625 cm−1. HRMS (ESI−TOF): calcd for
[C11H18O4+H]+ 215.1283, found 215.1289.
General procedure for α-methylenation of acids 11a-c to 8-10
respectively.16 Methoxy magnesium methylcarbonate (Stiles References
reagent, 1.9 mL, 3.80 mmol, 38.0 equiv., 2 M solution in DMF)
was added under inert atmosphere to 11a-c (0.1 mmol) and the
1
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mixture was acidified with dropwise addition of cold 10% HCl (7
mL) at 0 C. Then CH2Cl2 (10 mL) was added to the mixture and
stirred for 0.5 h. The aqueous layer was extracted with CH2Cl2 (4
× 15 mL). The combined organic layers were washed with brine,
dried (Na2SO4) and concentrated. The crude compound was
used directly for the next reaction.
C for 60 h. After cooling, the reaction
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Organic & Biomolecular Chemistry
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