Efficient approach to 4-benzyl-5,5-dimethyldihydrofuranones: Total synthesis of (±)-solafuranone

Article abstract of DOI:10.1080/00397910601163919

A six-step general and very efficient synthesis of 4-(arylmethyl)-5,5- dialkyldihydrofuranones starting from corresponding aryl aldehyde has been developed. Solafuranone, a novel furanone isolated from the Chinese folk medicine Solanum indicum, has been a

Full text of DOI:10.1080/00397910601163919

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Efficient Approach to
4‐Benzyl‐5,5‐dimethyldihydrofuranones:
Total Synthesis of (±_bold;)‐Solafuranone
A. Srikrishna a , G. Satyanarayana a & Uday V. Desai a
a Department of Organic Chemistry , Indian Institute of Science , Bangalore,
India
Published online: 24 Feb 2007.
To cite this article: A. Srikrishna , G. Satyanarayana & Uday V. Desai (2007) Efficient Approach
to 4‐Benzyl‐5,5‐dimethyldihydrofuranones: Total Synthesis of (±_bold;)‐Solafuranone, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:6,
965-976, DOI: 10.1080/00397910601163919
To link to this article: http://dx.doi.org/10.1080/00397910601163919
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Synthetic Communicationsw, 37: 965–976, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601163919
Efficient Approach to 4-Benzyl-5,5-
dimethyldihydrofuranones: Total Synthesis
of (+)-Solafuranone
A. Srikrishna, G. Satyanarayana, and Uday V. Desai
Department of Organic Chemistry, Indian Institute of Science,
Bangalore, India
Abstract: A six-step general and very efficient synthesis of 4-(arylmethyl)-5,5-dialkyl-
dihydrofuranones starting from corresponding aryl aldehyde has been developed. Sola-
furanone, a novel furanone isolated from the Chinese folk medicine Solanum indicum,
has been accomplished starting from 2,6-dimethylbenzaldehyde in six steps in an
overall yield of 70%. Contrary to expectations, solafuranone and its analogue failed
to exhibit any significant cytotoxicity against A549 (lung adenocarcinoma) and
HL60 (leukemia cells) cell lines.
Keywords: cytotoxicity, dihydrofuranone, lycifuranones A and B, solafuranone,
Solanum indicum
The Chinese folk medicine Solanum indicum, a plant grown widely in Taiwan,
has the property of jie du (eliminating toxins) and is used as treatment for
swelling. It has been widely used in folk medicine as an analgesic for
toothache, rhinitis, and breast cancer.[1] In a search for antitumor constituents
from S. indicum, Syu and coworkers have investigated the ethanolic extract of
dried plants and fractionated based on the bioassay. The fraction that showed
cytotoxicity against OVCAR-3 cells was further chromatographed and
isolated two compounds, previously known spirosesquiterpene solavetivone
1 and a new novel dihydrofuranone, solafuranone 2a, whose structure was
Received in India August 18, 2006
Address correspondence to A. Srikrishna, Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India. E-mail: ask@orgchem.iisc.ernet.in
965

966
A. Srikrishna, G. Satyanarayana, and U. V. Desai
established from its spectral data and single crystal X-ray diffraction
analysis.[1] It was also postulated that solavetivone 1 might be biogenetically
converted into solafuranone 2a. Subsequently, isolation and structure elucida-
tion of two more members of the solafuranone family, lycifuranone A 2b and
lycifuranone B 2c, along with an acetal derivative of lycifuranone B, were
reported from the roots of Lycianthes marlipoensis.[2] However, their biologi-
cal efficacy has not been evaluated.
As a part of our interest in the synthesis of bioactive natural products,
recently, we reported an enantiospecific synthesis of solavetivone 1 from
carvone.[3] Regarding the synthetic efforts toward solafuranones, there is
only one report. Recently, Mahajan and coworkers reported the first
synthesis of (+)-solafuranone 2a.[4] In continuation of our interest in the
synthesis of natural products and their analogues for investigating their ther-
aupeutic potential, a short and efficient methodology was investigated for
the synthesis of solafuranone and their analogues. Herein we describe
results of our investigations.
We contemplated developing a general and efficient methodology for the
synthesis of dihydrofuranones 3, which could be applied to a variety of
analogues of solafuranone, and aryl aldehyde 4 was considered as a
possible starting material (Scheme 1). We thought that an aryl aldehyde 4
could be converted into 2-(arylmethyl)pent-4-enoate 5 in three steps, which
could be transformed into target molecules 3 by a Grignard reaction
followed by oxidative cleavage of the terminal olefin.
To test the feasibility of the strategy, 2,5-dimethoxybenzaldehyde 6 was
chosen as a model substrate, because the hydroxy and alkoxy groups on
aromatic ring are known to enhance the biological potential of a variety
of aryl substituted butyrolactones (e.g., lignans).[5] The sequence is
Scheme 1.

Total Synthesis of (+)-Solafuranone
967
depicted in Scheme 2. First the aldehyde 6 was converted into 3-arylpropio-
nate 7. Thus, the Horner–Wadsworth–Emmons reaction of the aldehyde 6
with triethyl phosphonoacetate and sodium hydride in THF at room tempera-
ture quantitatively furnished the cinnamate 8, which on hydrogenation with
10% palladium on carbon as the catalyst in methanol at one atmosphere
pressure of hydrogen furnished the propionate 7 in quantitative yield. Gen-
eration of the lithium enolate with lithium diisopropylamide (LDA) at
2708C followed by reacting with allyl bromide transformed the propionate
7 into the pentenoate 9 in 81% yield. Reaction of the pentenoate 9 with an
excess of methylmagnesium iodide in ether at room temperature furnished
the tertiary alcohol 10 in 88% yield. Ozonolytic cleavage of the terminal
olefin in hexenol 10 in methanol–methylene chloride at 2708C followed
by reductive workup with dimethyl sulfide generated the hemi acetal 11 in
quantitative yield, which on oxidation with a mixture of pyridinium chlor-
ochromate (PCC) and silica gel in methylene chloride at room temperature
Scheme 2. Reagents and conditions: (a) NaH, (EtO)2P(O)CH2COOEt, THF, rt, 6 h;
(b) 10% Pd/C, EtOH, 1 atm. H2, 4 h; (c) LDA, THF, 2708C ! rt, CH255CHCH2Br,
10 and 11 h; (d) MeMgI, Et2O, 08C ! rt, 4 and 5 h; (e) O3/O2, CH2Cl2-MeOH (5:1),
2708C, Me2S, rt, 10 and 4 h; (f ) PCC, silica gel, CH2Cl2, rt, 2 h; (g) BBr3, CH2Cl2,
08C, 4 h.

968
A. Srikrishna, G. Satyanarayana, and U. V. Desai
furnished the dihydrofuranone 12a in 93% yield. The structure of the
dihydrofuranone 12a was established from its spectral data. Presence of
a carbonyl absorption band at 1774 cm21 in the IR spectrum due to a
typical g-butyrolactone revealed the formation of the product 12a.
In the 1H NMR spectrum presence of three signals, a doublet of doublet (d
6.68) and two doublets (6.74 and 6.63), due to the 1,2,5-trisubstituted
aromatic group, two singlets at 3.78 and 3.75 due to two methoxy groups,
and two singlets at 1.42 and 1.37 ppm due to two tertiary methyl groups
established the structure of the product. It was further confirmed by the
presence of a lactone carbon signal at d 175.1 ppm in the fifteen-line
13C NMR spectrum of the lactone 12a. Boron tribromide–mediated
demethoxylation of the lactone 12a in methylene chloride for 4 h
furnished the diol 12b.
After successfully demonstrating the strategy for the efficient conversion of
the aryl aldehyde 6 in to the dihydrofuranone 12 (in six steps for an overall yield
of 65%), it has been extended for the total synthesis of the novel furanone, sola-
furanone 2a, starting from 2,6-dimethylbenzaldehyde 13. Thus, Horner–
Wadsworth–Emmons reaction of the aldehyde 13 with triethyl phosphonoace-
tate and sodium hydride followed by catalytic hydrogenation of the cinnamate
14 furnished the 3-arylpropionate 15 in quantitative yield. Allylation of the ester
15 with LDA and allyl bromide in THF generated the pentenoate 16 in 84%
yield, which on Grignard reaction with an excess of methylmagnesium iodide
furnished the tertiary alcohol 17 in 90% yield. Ozonolytic cleavage of the
terminal olefin in the hexenol 17 in methanol–methylene chloride followed
by reductive workup with dimethyl sulfide generated the hemiacetal 18,
which on oxidation with a mixture of PCC and silica gel furnished solafuranone
2a in 94% yield. Synthetic solafuranone 2a exhibited 1H and 13C NMR spectral
data in acetone-d6 identical to that reported for the natural product.
Because solafuranone 2a was obtained from the fraction that exhibited
activity against the human ovarian cancer cell line OVCAR-3, after successfully
developing an efficient approach to solafuranone 2a and its analogues 12a and
12b containing two oxygen substituents on the aromatic ring, preliminary inves-
tigations were carried out to test their biological activity. The dihydrofuranones
2a, 12a, and 12b were tested for cytotoxicity on A549 (lung adenocarcinoma)
and HL60 (leukemia cells) using [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-
tetrazolium bromide] (MTT) assay. After incubation of the cells in up to 40-
mM concentration for 72 h, there was no change in the cell viability or
growth kinetics observed in comparison with DMSO (vehicle)–treated cells.
However, it is not clear whether the compounds 2a, 12a, and 12b are
inactive because of their racemic nature. Further investigations are in progress.
In conclusion, we have developed a six-step efficient methodology for the
synthesis of 4-(arylmethyl)-5,5-dialkyldihydrofuranones. Employing the
strategy, solafuranone 2a, a natural dihydrofuranone, was obtained starting
from 2,6-dimethylbenzaldehyde 13, in six steps in an overall yield of more
than 70%. Because the methodology is quite general, it is ideally suited for

Total Synthesis of (+)-Solafuranone
969
generation of a library of dihydrofuranones (having diversification at two
places, aryl group and Grignard reagent) to evaluate their biological
potential and is being investigated currently.
EXPERIMENTAL
Melting points were recorded using a Mettler FP1 melting-point apparatus in
capillary tubes and are uncorrected. IR spectra were recorded on Jasco FTIR
410 spectrophotometer. 1H (300-MHz) and 13C (75-MHz) NMR spectra were
recorded on JNM l-300 spectrometer. Unless otherwise specified, a 1:1
mixture of CDCl3 and CCl4 was used as solvent for preparing the NMR
samples. The chemical shifts (d ppm) and coupling constants (Hz) are
reported in the standard fashion with reference to either internal tetramethyl-
1
silane (for H) or the central line (77.0 ppm) of CDCl3 (for 13C). In the
13C NMR spectra, the nature of the carbons (C, CH, CH2, or CH3) was deter-
mined by recording the DEPT-135 spectra and is given in parentheses. High-
resolution mass spectra (HRMS) were recorded using a Micromass Q-TOF
micromass spectrometer using electrospray ionization.
Ethyl E-3-(2,5-Dimethoxyphenyl)prop-2-enoate (8)
A suspension of sodium hydride (241 mg, 60% dispersion in oil, 6.0 mmol) in
hexanes under nitrogen atmosphere was magnetically stirred for 10 min, and
the solvent was syringed out. The oil-free NaH was then suspended in dry THF
(3 ml) and cooled in an ice bath. Triethyl phosphonoacetate (1.19 ml,
6.0 mmol) was added dropwise, and the reaction mixture was stirred for 30 min
at room temperature. To the reaction mixture, a solution of the aldehyde 6
(500 mg, 3.01 mmol) in dry THF (2 ml) was added dropwise and stirred for 6 h
at rt. The reaction was then quenched by careful addition of saturated aqueous
NH4Cl solution and extracted with ether (4 ꢀ 4 ml). The combined ether
extract was washed with brine and dried (Na2SO4). Evaporation of the solvent
and purification of the residue over a silica-gel column using ethyl acetate–
hexane (1:20) as eluent furnished the cinnamate 8 (710 mg, 100%) as oil. IR
1
(neat): nmax/cm21 1714, 1633, 1496. H NMR (300 MHz, CDCl3 þ CCl4): d
7.91 (1H, d, J 16.2 Hz, H-3), 7.00 (1H, d, 2.4 Hz, H-60), 6.84 (1H, dd, J 8.7 and
2.4 Hz, H-40), 6.79 (1H, d, J 8.7 Hz, H-30), 6.44 (1H, d, J 16.2 Hz, H-2), 4.24
(2H, q, J 7.2 Hz, OCH2CH3), 3.82 (3H, s) and 3.75 (3H, s) [2 ꢀ OCH3], 1.33
(3H, t, J 7.2 Hz, OCH2CH3). 13C NMR (75 MHz, CDCl3 þ CCl4): d 166.8
(C, OC55O), 153.5 (C), 152.6 (C), 139.6 (CH, C-3), 124.0 (C, C-10), 118.9
(CH, C-2), 116.8 (CH), 113.1 (CH), 112.2 (CH), 60.0 (CH2, OCH2CH3), 55.8
(CH3) and 55.4 (CH3) [2 ꢀ OCH3], 14.4 (CH3, OCH2CH3). HRMS: m/z calcd.
for C13H16O4Na (M þ Na): 259.0946. Found: 259.0945.

970
A. Srikrishna, G. Satyanarayana, and U. V. Desai
Ethyl 3-(2,5-Dimethoxyphenyl)propinoate (7)
To 10% Pd-C (50 mg), a solution of the cinnamate 8 (700 mg, 2.966 mmol) in
methanol (5 ml) was added. The reaction mixture was stirred for 4 h at rt in an
atmosphere of hydrogen, created by evacuative replacement of air (balloon),
and then the catalyst was filtered off. Evaporation of the solvent furnished
the saturated ester 7 (705 mg, 100%) as oil. IR (neat): nmax/cm21 1734,
1
1502, 1224. H NMR (300 MHz, CDCl3 þ CCl4): d 6.70 (1H, d, J 9.0 Hz,
H-30), 6.69 (1H, brs, H-60), 6.64 (1H, dd, J 9.0 and 2.7 Hz, H-40), 4.10 (2H,
q, J 7.2 Hz, OCH2CH3), 3.76 (3H, s) and 3.72 (3H, s) (2 ꢀ OCH3), 2.87
(2H, t, J 7.8 Hz), 2.55 (2H, t, J 7.8 Hz), 1.23 (3H, t, J 7.2 Hz, OCH2CH3).
13C NMR (75 MHz, CDCl3 þ CCl4): d 172.8 (C, OC55O), 153.5 (C), 151.7
(C), 130.0 (C, C-10), 116.3 (CH), 111.5 (CH), 110.9 (CH), 60.1 (CH2,
OCH2CH3), 55.6 (CH3), 55.4 (CH3), 34.3 (CH2), 26.3 (CH2), 14.3 (CH3,
OCH2CH3). HRMS: m/z calcd. for C13H18O4Na (M þ Na): 261.1103.
Found: 261.1096.
Ethyl 2-(2,5-Dimethoxybenzyl)pent-4-enoate (9)
To a cold (2708C), magnetically stirred solution of LDA [prepared from dii-
sopropylamine (0.35 ml, 2.52 mmol) and BuLi (1.7 M in hexane, 1.38 ml,
n
2.35 mmol)] in dry THF (3 ml), a solution of the ester 7 (200 mg,
0.84 mmol) in dry THF (1 ml) was added and the resulting reaction mixture
stirred for 45 min at the same temperature. The enolate thus formed was
treated with allyl bromide (0.22 ml, 2.52 mmol) and stirred for 10 h at rt. It
was then diluted with water and extracted with ether (3 ꢀ 5 ml). The
combined ether extract was washed with 3 N aq. HCl followed by brine and
dried (Na2SO4). Evaporation of the solvent and purification of the residue
over a silica-gel column using ethyl acetate–hexane (1:50) as eluent
furnished the ester 9 (190 mg, 81%) as oil. IR (neat): nmax/cm21 1732, 1502,
1224. 1H NMR (300 MHz, CDCl3 þ CCl4): d 6.80–6.50 (3H, m, Ar-H), 5.74
(1H, ddt, J 17.4, 10.2 and 6.9 Hz, CH55CH2), 5.05 (1H, d, J 17.4 Hz), and
5.00 (1H, d, J 10.2 Hz), (CH55CH2), 4.03 (2H, q, J 7.2 Hz, OCH2CH3), 3.77
(3H, s), and 3.71 (3H, s) [2 ꢀ OCH3], 3.00–2.80 (3H, m), 2.50–2.20 (2H,
m), 1.14 (3H, t, J 7.2 Hz, OCH2CH3). 13C NMR (75 MHz, CDCl3 þ CCl4): d
174.8 (C, OC55O), 153.3 (C), 151.9 (C), 135.5 (CH, CH55CH2), 128.7 (C),
117.0 (CH), 116.7 (CH2, CH55CH2), 111.8 (CH), 110.9 (CH), 59.9 (CH2,
OCH2CH3), 55.7 (CH3), 55.4 (CH3), 45.1 (CH, C-2), 36.4 (CH2), 33.0 (CH2),
14.3 (CH3, OCH2CH3). HRMS: m/z calcd. for C16H22O4Na (M þ Na):
301.1416. Found: 301.1402.
3-(2,5-Dimethoxybenzyl)-2-methylhex-5-en-2-ol (10)
To a cold (08C), magnetically stirred solution of methylmagnesium iodide
(2.16 mmol) [prepared from magnesium (52 mg, 2.16 mmol), methyl iodide

Total Synthesis of (+)-Solafuranone
971
(0.16 ml, 2.59 mmol), and a catalytic amount of iodine in 3 ml of dry ether], a
solution of the ester 9 (60 mg, 0.22 mmol) in dry ether (2 ml) was added. The
reaction mixture was slowly warmed up to rt and stirred for 4 h. It was then
poured into cold saturated aq. NH4Cl solution and extracted with ether
(3 ꢀ 3 ml). The ether extract was washed with brine and dried (Na2SO4). Evap-
oration of the solvent and purification of the residue on a silica-gel column
using ethyl acetate–hexane (1:7) as eluent furnished the tertiary alcohol 10
(50 mg, 88%) as oil. IR (neat): nmax/cm21 3454, 1500, 1223. 1H NMR
(300 MHz, CDCl3 þ CCl4): d 6.72 (1H, d, J 9.0 Hz, H-30), 6.70 (1H, d, J
3.0 Hz, H-60), 6.64 (1H, dd, J 9.0 and 3.0 Hz, H-40), 5.79 (1H, ddt, J 17.4,
10.2 and 6.9 Hz, H-5), 5.00 (1H, d, J 17.1 Hz), and 4.94 (1H, d, J 10.2 Hz)
[H-6], 3.79 (3H, s) and 3.74 (3H, s) [2 ꢀ OCH3], 2.90 (1H, dd, J 13.5 and
4.2 Hz), 2.40 (1H, dd, J 13.5 and 8.4 Hz), 2.40–1.98 (3H, m), 1.93–1.80
(1H, m), 1.23 (3H, s), and 1.21 (3H, s) [2 ꢀ tert-CH3]. 13C NMR (75 MHz,
CDCl3 þ CCl4): d 153.5 (C), 151.6 (C), 139.0 (CH, C-5), 131.3 (C), 117.5
(CH), 115.6 (CH2, C-6), 111.2 (CH), 111.0 (CH), 74.0 (C, C-2), 55.8 (CH3),
55.5 (CH3), 50.0 (CH, C-3), 35.3 (CH2), 30.6 (CH2), 27.9 (CH3), 27.0 (CH3).
HRMS: m/z calcd. for C16H24O3Na (M þ Na): 287.1623. Found: 287.1627.
4-(2,5-Dimethoxybenzyl)-5,5-dimethyltetrahydrofuran-2-ol (11)
A precooled (2708C) mixture of ozone in oxygen was passed through a cold
(2708C) solution of the hexenol 10 (40 mg, 0.15 mmol) and a catalytic
amount of NaHCO3 in methanol (2 ml) and CH2Cl2 (8 ml) for 40 s. The
reaction mixture was flushed off with oxygen, and dimethyl sulfide (0.11 ml,
1.52 mmol) was added to the reaction mixture. It was then slowly warmed up
to rt and magnetically stirred for 10 h. Evaporation of the solvent under
reduced pressure and purification of the residue on a silica-gel column using
ethyl acetate–hexane (1:3) as eluent furnished a diastereomeric mixture of the
lactol 11 (40 mg, 99%) as a colorless solid, which was recrystallized from a
mixture of CH2Cl2 and hexane. Mp: 112–1148C. IR (neat): nmax/cm21 3392,
1500, 1223. 1H NMR (300 MHz, CDCl3 þ CCl4): d 6.80–6.40 (3H, m, Ar-H),
5.36 (1H, d, J 4.2 Hz, H-2), 3.76 (3H, s) and 3.73 (3H, s) [2 ꢀ OCH3], 3.63
(1H, brs, OH), 2.75–2.05 (4H, m), 2.00–1.60 (1H, m), 1.34 and 1.29 (3H, s),
and 1.10 and 1.23 (3H, s) (2 ꢀ tert-CH3). 13C NMR (75 MHz, CDCl3 þ
CCl4): d 153.5 and 153.4 (C), 151.7 and 151.6 (C), 130.3 (C), 116.7 (CH),
111.2 and 111.0 (CH), 111.1 (CH), 97.3 and 96.4 (CH), 84.1 and 83.2 (C),
55.6 (CH3) and 55.5 (CH3) (2 ꢀ OCH3), 45.8 and 48.7 (CH), 39.4 and 39.7
(CH2), 30.5 and 30.8 (CH2), 29.5 and 28.0 (CH3), 23.5 and 23.7 (CH3).
HRMS: m/z calcd. for C15H22O4Na (M þ Na): 289.1416. Found: 289.1408.
4-(2,5-Dimethoxylbenzyl)-5,5-dimethyldihydro-2(3H)-furanone (12a)
To a magnetically stirred solution of the lactol 11 (25 mg, 0.09 mmol) in 1 ml
of dry CH2Cl2, a homogeneous mixture of PCC (101.3 mg, 0.47 mmol) and

972
A. Srikrishna, G. Satyanarayana, and U. V. Desai
silica gel (101 mg) were added and stirred vigorously for 2 h at rt. The reaction
mixture was then filtered through a small silica-gel column and eluted the
column with an excess of CH2Cl2. Evaporation of the solvent and purification
of the residue over a silica-gel column using ethyl acetate–hexane (1:20 to
1:10) as eluent furnished the lactone 12a (23 mg, 93%) as an oil. IR (neat):
1
nmax/cm21 1774, 1500. H NMR (300 MHz, CDCl3 þ CCl4): d 6.74 (1H,
d, J 8.7 Hz, H-30), 6.68 (1H, dd, J 8.7 and 3.0 Hz, H-40), 6.63 (1H, d, J
3.0 Hz, H-60), 3.78 (3H, s) and 3.75 (3H, s) [2 ꢀ OCH3], 2.76 (1H, d, J
8.4 Hz), 2.70–2.48 (2H, m), 2.48–2.20 (2H, m), 1.42 (3H, s) and 1.37 (3H,
s) (2 ꢀ tert-CH3). 13C NMR (75 MHz, CDCl3 þ CCl4):
d
175.1
(C, OC55O), 153.5 (C), 151.4 (C), 128.5 (C, C-10), 116.8 (CH), 111.5 (CH),
111.1 (CH), 86.2 (C, C-5), 55.6 (CH3) and 55.5 (CH3) [2 ꢀ OCH3], 45.8
(CH, C-4), 34.8 (CH2), 30.5 (CH2), 27.4 (CH3) and 21.9 (CH3) [2 ꢀ tert-
CH3]. HRMS: m/z calcd. for C15H20O4Na (M þ Na): 287.1259. Found:
287.1255.
4-(2,5-Dihydoxylbenzyl)-5,5-dimethyldihydro-2(3H)-
furanone (12b)
A solution of BBr3 (1 M in CH2Cl2, 0.85 ml, 0.85 mmol) was added dropwise
to a solution of the ether 12a (40 mg, 0.17 mmol) in CH2Cl2 (3 ml) at 08C; the
reaction mixture slowly warmed up to rt and stirred for 4 h at rt. It was
quenched with saturated aqueous NaHCO3 solution and extracted with
CH2Cl2 (3 ꢀ 5 ml). The combined organic layer was washed with brine and
dried (Na2SO4). Evaporation of the solvent and purification of the residue
over a silica-gel column using ethyl acetate–hexane (1:2) as eluent
furnished the phenol 12b (30 mg, 74%) as yellow color oil. IR (neat): nmax
/
cm21 3371, 1739, 1506. 1H NMR (300 MHz, D2O): d 6.50 (1H, d, J
8.4 Hz), 6.64–6.40 (2H, m), 2.70–2.20 (5H, m), 1.28 (3H, s) and 1.25 (3H,
s) [2 ꢀ tert-CH3]. 13C NMR (75 MHz, D2O): d 181.0 (C, OC55O), 149.7
(C), 147.9 (C), 128.7 (C), 118.0 (CH), 117.7 (CH), 115.0 (CH), 90.8
(C, C-5), 45.8 (CH, C-4), 35.3 (CH2), 30.0 (CH2), 27.1 (CH3) and 21.7
(CH3) [2 ꢀ tert-CH3]. HRMS: m/z calcd. for C13H16O4Na (M þ Na):
259.0946. Found: 259.0958.
Ethyl E-3-(2,6-Dimethylphenyl)prop-2-enoate (14)
A suspension of sodium hydride (210 mg, 60% dispersion in oil, 5.25 mmol) in
hexanes under nitrogen atmosphere was magnetically stirred for 10 min, and
the solvent was syringed out. The oil-free NaH was then suspended in dry
THF (2 ml) and cooled in an ice bath. Triethyl phosphonoacetate (0.98 ml,
4.95 mmol) was added dropwise, and the reaction mixture was stirred for
30 min at room temperature. To the reaction mixture, a solution of the

Total Synthesis of (+)-Solafuranone
973
aldehyde 13 (220 mg, 1.64 mmol) in dry THF (1 ml) was added dropwise and
stirred for 6 h at rt. The reaction was then quenched by careful addition of
saturated aqueous NH4Cl solution and extracted with ether (4 ꢀ 4 ml). The
combined ether layer was extracted with brine and dried (Na2SO4). Evapor-
ation of the solvent and purification of the residue over a silica-gel column
using ethyl acetate–hexane (1:20) as eluent furnished the cinnamate 14
1
(334 mg, 100%) as oil. IR (neat): nmax/cm21 1716, 1639, 1174. H NMR
(300 MHz, CDCl3 þ CCl4): d 7.80 (1H, d, J 16.5 Hz, H-3), 7.20–6.90 (3H,
m, Ar-H), 6.03 (1H, d, J 16.5 Hz, H-2), 4.26 (2H, q, J 7.2 Hz, OCH2CH3),
2.34 (6H, s, 2 ꢀ ArCH3), 1.34 (3H, t, J 7.2 Hz, OCH2CH3). 13C NMR
(75 MHz, CDCl3 þ CCl4): d 166.3 (C, OC55O), 143.2 (CH, C-3), 136.4
(2 C, C, C-20 and 60), 134.0 (C, C-10), 128.2 (3 C, CH), 123.9 (CH, C-40), 60.3
(CH2, OCH2CH3), 21.1 (2 C, CH3, 2 ꢀ ArCH3), 14.4 (CH3, OCH2CH3).
HRMS: m/z calcd. for C13H16O2Na (M þ Na): 227.1048. Found: 227.1044.
Ethyl 3-(2,6-Dimethylphenyl)propinoate (15)
To 10% Pd-C (25 mg), a solution of the cinnamate 14 (300 mg, 1.47 mmol) in
ethanol (3 ml) was added. The reaction mixture was stirred for 4 h at rt in an
atmosphere of hydrogen, created by evacuative replacement of air (balloon),
and then the catalyst was filtered off. Evaporation of the solvent furnished
the saturated ester 15 (302 mg, 100%) as oil. IR (neat): nmax/cm21 1736,
1
1180, 769. H NMR (300 MHz, CDCl3 þ CCl4): d 6.95 (3 H, brs, Ar-H),
4.14 (2H, q, J 7.2 Hz, OCH2CH3), 2.94 (2H, t, J 8.1 Hz), 2.40 (2H, t, J
8.1 Hz), 2.32 (6H, s, 2 ꢀ CH3), 1.27 (3H, t, J 7.2 Hz, OCH2CH3). 13C
NMR (75 MHz, CDCl3 þ CCl4): d 172.7 (C, OC55O), 137.1 (C, C-10),
135.9 (2 C, C, C-20 and 60), 128.3 (2 C, CH, C-30 and 50), 126.2 (CH, C-40),
60.3 (CH2, OCH2CH3), 33.5 (CH2), 25.1 (CH2), 19.8 (2 C, CH3), 14.4
(CH3, OCH2CH3). HRMS: m/z calcd. for C13H18O2Na (M þ Na):
229.1204. Found: 229.1212.
Ethyl 2-(2,6-Dimethylbenzyl)pent-4-enoate (16)
To a cold (2708C) magnetically stirred solution of LDA [prepared from dii-
sopropylamine (0.46 ml, 3.26 mmol) and BuLi (2.3 M in hexane, 1.27 ml,
n
2.91 mmol)] in dry THF (4 ml), a solution of the ester 15 (240 mg,
1.16 mmol) in dry THF (2 ml) was added, and the resulting reaction
mixture was stirred for 45 min at the same temperature. The enolate thus
formed was treated with allyl bromide (0.30 ml, 3.49 mmol) and stirred for
11 h at rt. It was then diluted with water and extracted with ether
(3 ꢀ 5 ml). The combined ether extract was washed with 3 N aq. HCl
followed by brine and dried (Na2SO4). Evaporation of the solvent and purifi-
cation of the residue over a silica-gel column using ethyl acetate–hexane

974
A. Srikrishna, G. Satyanarayana, and U. V. Desai
(1:50) as eluent furnished the ester 16 (240 mg, 84%) as oil. IR (neat): nmax
/
cm21 1732, 1163, 769. 1H NMR (300 MHz, CDCl3 þ CCl4): d 6.95 (3H, brs,
Ar-H), 5.72 (1H, ddt, J 17.1, 10.2, and 6.9 Hz, H-3), 5.05 (1H, d, J, 17.1 Hz)
and 5.01 (1H, d, J, 10.2 Hz) [H-4], 4.01 (2H, q, J, 7.2 Hz, OCH2CH3), 2.99
(1H, dd, J 14.1 and 7.2 Hz), 2.82 (1H, dd, J 14.1 and 7.2 Hz), 2.76–2.60
(1H, m), 2.58–2.45 (1H, m), 2.40–2.10 (1H, m), 2.32 (6H, s, 2 ꢀ ArCH3),
1.10 (3H, t, J 7.2 Hz, OCH2CH3). 13C NMR (75 MHz, CDCl3 þ CCl4): d
175.0 (C, OC55O), 136.6 (2 C, C, C-20 and 60), 135.9 (C, C-10), 135.5 (CH,
C-3), 128.4 (2 C, CH, C-30 and 50), 126.2 (CH, C-40), 117.0 (CH2, C-4),
60.1 (CH2, OCH2CH3), 45.1 (CH, C-2), 36.3 (CH2), 32.1 (CH2), 20.4 (2 C,
CH3), 14.2 (CH3, OCH2CH3). HRMS: m/z calcd. for C16H22O2Na
(M þ Na): 269.1517. Found: 269.1529.
3-(2,6-Dimethylbenzyl)-2-methylhex-5-en-2-ol (17)
To a cold (08C), magnetically stirred solution of methylmagnesium iodide
(9.1 mmol) [prepared from magnesium (218 mg, 9.1 mmol), methyl iodide
(0.66 ml, 10.58 mmol), and a catalytic amount of iodine in 3 ml of dry ether]
was added a solution of the ester 16 (186 mg, 0.76 mmol) in dry ether (2 ml).
The reaction mixture was slowly warmed up to rt and stirred for 5 h. It was
then poured into saturated aq. NH4Cl solution and extracted with ether
(3 ꢀ 3 ml). The ether extract was washed with brine and dried (Na2SO4). Evap-
oration of the solvent and purification of the residue on a silica-gel column
using ethyl acetate–hexane (1:10 to 1:5) as eluent furnished the tertiary
1
alcohol 17 (157 mg, 90%) as oil. IR (neat): nmax/cm21 3452, 767. H NMR
(300 MHz, CDCl3 þ CCl4): d 6.98 (3 H, brs, Ar-H), 5.72–5.52 (1H, m, H-5),
4.87 (1H, d, J 18.0 Hz) and 4.82 (1H, d, J 9.9 Hz) [H-6], 2.87 (1H, dd, J 13.5
and 4.2 Hz) and 2.58 (1H, dd, J 13.5 and 10.5 Hz) [ArCH2], 2.35 (6H, s,
2 ꢀ ArCH3), 2.25–2.15 (1H, m), 2.10–1.90 (2H, m), 1.70 (1H, s, OH), 1.32
(3H, s) and 1.29 (3H, s) [2 ꢀ tert-CH3]. 13C NMR (75 MHz, CDCl3 þ CCl4):
d 139.9 (CH, C-5), 137.7 (C, C-10), 136.6 (2 C, C, C-20 and 60), 128.4 (2 C,
CH, C-30 and 50), 125.9 (CH, C-40), 115.0 (CH2, C-6), 74.5 (C, C-2), 48.9
(CH, C-3), 34.1 (CH2), 30.3 (CH2), 27.9 (CH3) and 26.9 (CH3) [2 ꢀ tert-
CH3], 20.9 (2 C, CH3, 2 ꢀ ArCH3). HRMS: m/z calcd. for C16H24ONa
(M þ Na): 255.1725. Found: 255.1735.
4-(2,6-Dimethylbenzyl)-5,5-dimethyltetrahydrofuran-2-ol (18)
A precooled (2708C) mixture of ozone in oxygen was passed through a cold
(2708C) solution of the olefin 17 (70 mg, 0.30 mmol) and a catalytic amount
of NaHCO3 in methanol (2 ml) and CH2Cl2 (8 ml) for 1 min. The reaction
mixture was flushed off with oxygen, and dimethyl sulfide (0.11 ml,
1.51 mmol) was added to the reaction mixture. It was then slowly warmed

Total Synthesis of (+)-Solafuranone
975
up tortand magnetically stirred for 4 h. Evaporationof the solventunder reduced
pressure and purification of the residue on a silica-gel column using ethyl
acetate–hexane (1:10 to 1:3) as eluent first furnished the lactol 18 (70 mg,
99%) as colorless solid, which was recrystallized from a mixture of CH2Cl2
1
and hexane. Mp: 71–738C. IR (neat): nmax/cm21 3399, 1030, 769. H NMR
(300 MHz, CDCl3 þ CCl4): d 6.96 and 6.90 (3H, m, Ar-H), 5.32 (1H, d, J
4.8 Hz, H-2), 2.70–2.45 (4H, m), 2.31 and 2.30 (6H, s, 2 ꢀ ArCH3), 2.20–
1.90 (m) and 1.90–1.65 (m) [2H], 1.44 and 1.32 (3H, s), and 1.12 and 1.30
(3 H, s) [2 ꢀ tert-CH3]. 13C NMR (75 MHz, CDCl3 þ CCl4): d 137.2 (C),
135.8 (2 C, C), 128.4 (2 C, CH), 125.8 (CH), 96.1 and 97.1 (CH, C-2), 83.9
and 82.9 (C, C-5), 45.7 and 49.1 (CH, C-4), 38.8 and 39.3 (CH2), 29.1 and
27.6 (CH3), 28.8 and 29.0 (CH2), 23.2 and 23.3 (CH3), 20.3 (2 C, CH3).
HRMS: m/z calcd. for C15H22O2Na (M þ Na): 257.1517. Found: 257.1528.
4-(2,6-Dimethylbenzyl)-5,5-dimethyldihydro-2(3H)-furanone
(solafuranone 2a)
To a magnetically stirred solution of the lactol 18 (55 mg, 0.24 mmol) in 3 ml
of dry CH2Cl2, a homogeneous mixture of PCC (253 g, 1.17 mmol) and silica
gel (253 mg) was added which was stirred vigorously for 2 h at rt. The reaction
mixture was then filtered through a small silica-gel column and eluted with an
excess of CH2Cl2. Evaporation of the solvent and purification of the residue
over a silica-gel column using ethyl acetate–hexane (1:20 to 1:10) as eluent
furnished solafuranone1 2a (51 mg, 94%). IR (neat): nmax/cm21 1772,
1
1120, 771. H NMR (300 MHz, acetone-d6): d 7.01 (3H, brs, Ar-H), 2.90–
2.70 (2H, m), 2.70–2.40 (2H, m), 2.40–2.10 (1H, m), 2.34 (6H, s,
2 ꢀ ArCH3), 1.55 (3H, s) and 1.43 (3H, s) [2 ꢀ tert-CH3]. 1H NMR
(300 MHz, CDCl3): d 7.02 (3H, brs, Ar-H), 2.85–2.65 (2H, m), 2.55–2.25
(3H, m), 2.32 (6H, s, 2 ꢀ ArCH3), 1.56 (3H, s) and 1.43 (3H, s) [2 ꢀ tert-
CH3]. 13C NMR (75 MHz, acetone-d6): d 175.1 (C, OC55O), 137.2 (C,
C-10), 137.0 (2 C, C, C-20 and 60), 129.3 (2 C, CH, C-30 and 50), 126.9 (CH,
C-40), 86.6 (C, C-5), 46.3 (CH, C-4), 34.8 (CH2), 29.1 (CH2), 27.1 (CH3)
and 21.7 (CH3) [2 ꢀ tert-CH3], 20.4 (2 C, CH3, 2 ꢀ ArCH3). 13C NMR
(75 MHz, CDCl3): d 175.2 (C, OC55O), 135.9 (C, C-10), 135.6 (2 C, C,
C-20 and 60), 128.7 (2 C, CH, C-30 and 50), 126.3 (CH, C-40), 86.5 (C, C-5),
45.7 (CH, C-4), 34.4 (CH2), 28.5 (CH2), 26.9 (CH3) and 21.5 (CH3)
[2 ꢀ tert-CH3], 20.2 (2 C, CH3, 2 ꢀ ArCH3). HRMS: m/z calcd. for
C15H20O2Na (M þ Na): 255.1361. Found: 255.1347.
ACKNOWLEDGMENTS
We thank the Department of Biotechnology, New Delhi for the financial
support, Council of Scientific and Industrial Research, New Delhi, for the

976
A. Srikrishna, G. Satyanarayana, and U. V. Desai
award of a research fellowship to G.S. and Indian Academy of Sciences,
Bangalore, for providing a summer fellowship to U.D. We are also grateful
to Dr. Kondaiah and C. K. Aravinda, Department of Molecular Reproduction,
Development and Genetics, Indian Institute of Science, for carrying out the
biological evaluation of solafuranone and its analogues.
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3. Srikrishna, A.; Ramasastry, S. S. V. Tetrahedron Lett. 2005, 46, 7373.
4. Mahajan, V. A.; Borate, H. B.; Wakharkar, R. D. Tetrahedron 2006, 62, 1258.
5. (a) Rao, C. B. S. Chemistry of Lignans; Andhra Uiversity Press: Waltair, 1978;
(b) Ward, R. S. Chem. Soc. Rev. 1982, 11, 75; (c) Ward, R. S. Tetrahedron 1990,
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