A radical cascade reaction triggered by thiyl radical; An approach toward synthesis of tricyclic structure of platensimycin

Article abstract of DOI:10.1080/10426507.2015.1064922

The formation of oxa-tricyclic core of platensimycin was attempted. A key precursor of radical cyclization, cyclic anhydride, was readily prepared from diethylmalonate in 6 steps in good yields. Obtained precursor, diallylmethylene-δ-lactone, underwent radical cascade reaction triggered by thiyl radical, giving bicyclic ether in a stereoselective manner.

Full text of DOI:10.1080/10426507.2015.1064922

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
A radical cascade reaction triggered by thiyl
radical; an approach toward synthesis of tricyclic
structure of platensimycin
Akio Kamimura & Yusuke Kawakami
To cite this article: Akio Kamimura & Yusuke Kawakami (2016) A radical cascade
reaction triggered by thiyl radical; an approach toward synthesis of tricyclic structure of
platensimycin, Phosphorus, Sulfur, and Silicon and the Related Elements, 191:2, 259-262, DOI:
10.1080/10426507.2015.1064922
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1064922
Accepted author version posted online: 06
Oct 2015.
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Date: 18 February 2016, At: 05:27

PHOSPHORUS, SULFUR, AND SILICON
, VOL. , NO. , –
http://dx.doi.org/./..
A radical cascade reaction triggered by thiyl radical; an approach toward synthesis of
tricyclic structure of platensimycin
Akio Kamimura and Yusuke Kawakami
Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Ube, Japan
ABSTRACT
ARTICLE HISTORY
Received  May 
Accepted  June 
The formation of oxa-tricyclic core of platensimycin was attempted. A key precursor of radical cyclization,
cyclic anhydride, was readily prepared from diethylmalonate in 6 steps in good yields. Obtained precursor,
diallylmethylene-δ-lactone, underwent radical cascade reaction triggered by thiyl radical, giving bicyclic
ether in a stereoselective manner.
KEYWORDS
Radical cyclization; radical
addition; platensimycin
GRAPHICAL ABSTRACT
diallylglutaronitrile 7 via corresponding tosylate 6. Basic hydrol-
ysis of 7 afforded glutaric acid 8 which was converted to desired
cyclic anhydride 9 in good yield by treatment with acetic anhy-
dride. All of the reaction gave compounds in a very pure form
and these steps were able to be performed in a 5 gram-scale very
easily.
The next task was introduction of radical precursor at C2
position. We attempted the preparation of xanthate by adding
methyl group in various methods, but all of attempt failed
to prepare desired compound. For example, we tried to pre-
pare compound 9’ by mono addition of methyl group by
methyl Grignard reagent to compound 9, however, complex
mixture was formed. Mono reduction of 9 with LiAlH(OtBu)3
failed to provide desired hydroxylactone 9”, instead lactone
9b was formed in 75% yield. We then examined Petasis
reagent, Me2TiCp2, to introduce methylene unit at C2 car-
bon.4 Although the yield was not very good, this attempt
achieved successful conversion to methylenelactone 10, which
was expected to be an accepter for thiyl radical addition
(Scheme 3).
Treatment of compound 10 with thiophenol in the presence
of AIBN resulted in smooth consumption of compound 10 and
desired bicyclic lactone 11a in 49% yield. Use of p-thiocresol
provided an analogue 11b in 38% yield although compound 10
was recovered in 25%. As expected, in this reaction, a thiyl rad-
ical added to the C2 methylene unit of compound 10 to give α-
oxy radical, which captured one of the C4 allylic units in 5-exo
mode to give compound 11. Both products were formed as a
Introduction
Platensimaycin 11 and platencin 22 are recently found antibi-
otics that inhibit condensing enzymes FabF and FabH of fatty
acid biosynthesis. Because of this interesting bioactivity, syn-
thesis of platensimycin has been of interest and many efforts
for its total synthesis have been reported.3 A unique oxygen
atom-containing tricyclic structure fused to cyclohexene ring
in platensimycin attracted us for finding a new short synthetic
strategy based on radical cascade reaction. In this paper we
report a thiyl radical-induced cascade reaction toward the for-
mation of the polycyclic ring in one step.
Our retrosynthetic analysis is as follows (Scheme 1). Desired
tricyclic structure A should be formed by a cascade cyclization
of radical D via intermediates B and C. The radical D should be
generated from a precursor provided from compound E, which
should be readily prepared from malonic ester 3. Thus, this strat-
egy could provide a new short synthetic route to the tricyclic
structure of platensimycin 1. In this paper we report our attempt
to prepare the polycyclic structure via radical cascade process
triggered by thiyl radical addition.
Result and discussion
Our synthesis started from diethylmalonate 3 (Scheme 2). Dial-
lylation of malonate 3 was carried out in the presence of NaH as
a base to give diallylmalonate 4 in 96% yield. LiAlH4 reduction
of the esters 4 quantitatively gave diol 5, which was converted to
CONTACT Akio Kamimura
, Japan.
ak@yamaguchi-u.ac.jp
Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Ube -
©  Taylor & Francis Group, LLC

260
A. KAMIMURA AND Y. KAWAKAMI
Scheme . Plausible reaction pathway.
single isomer, thus indicated that the radical cascade process
progressed in a highly stereoselective manner. Unfortunately,
neither of isomers gave good crystal samples suitable for X-
ray analyses. We then performed NMR studies for determin-
ing stereochemistry of compound 11a. NOESY spectrum for
11a indicated a cross peak between C1-CH2SPh and C7 methyl
group. Indeed an irradiation of the CH2SPh enhanced a sig-
nal from the methyl group by 3% (Scheme 3), which reflects
that the methyl group at C7 position should occupy the cis-
position to phenylthiomethyl group at C1 position. This is an
opposite stereoselectivity we expected, but probably steric effect
from the lactone system in compound 10 could cause repul-
sive effect on the allylic unit serving as a radical acceptor. As a
result, the double bond may be orientated to phenylthiomethyl
group and compound 11 was formed (Scheme 4). Thus, the
radical cascade reaction from compound 10 progressed in a
highly stereoselective manner although these were undesir-
able products toward the synthesis of the multicyclic core of
platensimycin.
Scheme . Retrosynthetic analysis of platensimycin.
We have performed an examination of radical addi-
tion/cyclization cascade to give bicyclic ether 11 in highly
stereoselective manner. The preparation was simple and the
cyclization precursor was prepared in short steps from com-
mercially available compounds. Although this strategy gave an
opposite stereoisomers we desired, we think our results may
give information to explore a new route for the synthesis of
platensimycin.
Scheme . Synthesis of precursor .
Experimental
General
1
All H and 13C NMR spectra were recorded on a JEOL GSX-
270 (270 MHz for 1H and 67.5 MHz for 13C) or a JNM-ECA500
1
Delta2 (500 MHz for H and 126 MHz for 13C) spectrome-
ter. High-resolution mass spectrometry was performed on JEOL
JMS-T100 LP spectrometer.
Preparation of diethyl 2,2-diallylmalonate 4
Diethylmalonate (57.11 g, 353.4 mmol) in THF was slowly
added to a suspension of NaH (29.02 g, 60%, 725.5 mmol,
washed with hexane for three times) in THF (400 mL) at 0°C
over 1 h, and the resulting solution was stirred at room tem-
perature for 1 h. The reaction mixture was then cooled at 0°C
again and allyl bromide (108.6 g, 883.5 mmol) was added to
the solution over 40 min. The reaction mixture was allowed to
stir at room temperature for additional 2.5 h. Saturated NH4Cl
(50 mL) was added to the reaction mixture and resulting bipha-
sic mixture was extracted with EtOAc (7 × 100 mL). The
organic phase was combined, washed with brine (1 × 10 mL)
Scheme . Radical cyclization of compound .

PHOSPHORUS, SULFUR, AND SILICON
261
and dried over Na2SO4. After filtration, the filtrate was con- × 100 mL). The organic phase was combined, washed with
centrated in vacuo to give compound 4 in 96% yield (81.86 g, water (20 × 20 mL) and brine (2 × 50 mL), and dried over
340.7 mmol). Obtained product was sufficiently pure and used Na2SO4. After filtration, the filtrate was concentrated in vacuo
for the next step without further purification. Pale yellow oil; 1H to give crude residue, which was purified through flash chro-
NMR (270 MHz, CDCl3) δ 5.66 (ddt, J = 18.3, 9.1, 7.4 Hz, 2H), matography (silica gel/hexane-EtOAc 8:1 v/v) to give compound
1
5.19–5.01 (m, 4H), 4.19 (q, J = 7.2 Hz, 4H), 2.64 (d, J = 7.4 Hz, 7 in 97% yield (31.15 g, 73.5 mmol). Colorless oil; H NMR
4H), 1.25 (t, J = 7.1 Hz, 6H); 13C NMR (67.5 MHz, CDCl3) δ (270 MHz, CDCl3) δ 5.87–5.65 (m, 2H), 5.38–5.20 (m, 4H),
170.7 (2C), 132.4 (2C), 119.0 (2C), 61.0 (2C), 57.1, 36.6 (2C), 2.43 (s, 4H), 2.31 (d, J = 7.4 Hz, 4H); 13C NMR (67.5 MHz,
13.9 (2C).
CDCl3) δ 130.6 (2C), 120.6 (2C), 116.3 (2C), 39.9 (2C), 37.6, 24.7
(2C); HRMS (ESI M + H) m/z 175.1230. Calcd for C11H15N2
175.1235.
Preparation of 2,2-diallylpropane-1,3-diol 5
Compound 4 (4.806 g, 20.0 mmol) in ether (50 mL) was added
slowly to a suspension of LiAlH4 (2.125 g, 56 mmol) in ether
Preparation of 3,3-diallylpentanedioic Acid 8
(50 mL) at 0°C and the resulting suspension was heated to A solution of compound 7 (4.90 g, 28.1 mmol) in MeOH
refluxing temperature for 13 h. The reaction mixture was then (170 mL) was added to aqueous NaOH (35%, 70 g) and the reac-
cooled to 0°C and saturated NH4Cl (2 mL) and 30% NaOHaq tion mixture was heated at 90°C for 13 h. MeOH was removed
(4 mL) were slowly added. The resulting suspension was heated under reduced pressure. Water (50 mL) was added to the residue
to the refluxing temperature for 18 h. After cooled, the reaction and the resulting solution was refluxed for 5 h. Cooled reac-
mixture was filtered and the precipitate was washed with ether tion mixture was acidified to pH 2 by adding conc. HCl and
(200 mL). The filtrate was concentrated in vacuo to give com- the resulting biphasic mixture was extracted with EtOAc (5 ×
pound 5 in 100% yield (3.112 g, 19.9 mmol). Obtained prod- 100 mL). The organic phase was combined, washed with water
uct was sufficiently pure and used for the next step without fur- (5 × 10 mL), and dried over Na2SO4. After filtration, the fil-
ther purification. Pale yellow oil; 1H NMR (270 MHz, CDCl3) trate was concentrated in vacuo to give compound8 in 97% yield
δ 5.93–5.71 (m, 2H), 5.19–4.96 (m, 4H), 3.70–3.57 (br, 2H), (5.79 g, 27.3 mmol). White solid; mp 111°C; 1H NMR (270 MHz,
3.53 (d, J = 5.0 Hz, 4H), 2.05 (d, J = 7.5 Hz, 4H); 13C NMR CDCl3) δ 11.59–11.15 (m, 2H), 6.04–5.65 (m, 2H), 5.33–4.94
(67.5 MHz, CDCl3) δ 133.9 (2C), 118.1 (2C), 67.5 (2C), 41.9, (m, 4H), 2.53 (d, J = 4.3 Hz, 4H), 2.28 (d, J = 7.3 Hz, 4H); 13
C
35.7 (2C).
NMR (67.5 MHz, CDCl3) δ 178.4 (2C), 133.2 (2C), 119.7 (2C),
41.0 (2C), 40.1 (2C), 38.0.
Preparation of 2,2-diallylpropane-1,3-diyl
bis(4-methylbenzenesulfonate) 6
Preparation of 4,4-diallyldihydro-2H-pyran-2,6(3H)-dione
9
KOH (crashed, 49.52 g, 750.2 mmol) was suspended in THF
(300 mL). Compound 5 (11.64 g, 74.5 mmol) in THF (75 mL) A solution of compound 8 (0.2725 g, 1.28 mmol) in Ac2O (5 mL)
was added to this suspension at 0°C. Then TsCl (51.08 g, was heated at refluxing temperature for 10 h. After the reaction,
262.6 mmol) was added to the reaction mixture and the result- remaining Ac2O and acetic acid were azeotropically removed
ing solution was stirred at 0°C for 2 h and at room temperature with toluene in vacuo to give compound 9 in 99% yield (0.2477 g,
for 6.5 h. THF was removed under reduced pressure and ice- 1.28 mmol). Colorless oil; 1H NMR (270 MHz, CDCl3) δ 5.73
water (200 mL) was added to the residue. The resulting aque- (ddt, J = 16.7, 10.1, 7.5 Hz, 2H), 5.25 (dd, J = 9.3, 1.6 Hz, 2H),
ous solution was extracted with CH2Cl2 (5 × 120 mL). The 5.16 (dt, J = 16.9, 1.4 Hz, 2H), 2.61 (s, 4H), 2.14 (dt, J = 7.6,
organic phase was combined, washed with brine (2 × 150 mL) 1.1 Hz, 4H); 13C NMR (67.5 MHz, CDCl3) δ 166.5 (2C), 131.1
and dried over Na2SO4. After filtration, the filtrate was con- (2C), 121.0 (2C), 41.7 (2C), 39.3 (2C), 35.0; HRMS (ESI M + H)
centrated in vacuo to give compound 6 in 99% yield (31.15 g, m/z 195.1023. Calcd for C11H15O3 195.1021.
73.5 mmol). Obtained product was sufficiently pure and used for
the next step without further purification. White solid; mp 71°C;
Preparation of
1H NMR (270 MHz, CDCl3) δ 7.74 (d, J = 8.4 Hz, 4H), 7.35 (d,
4,4-diallyl-6-methylenetetrahydro-2H-pyran-2-one 10
J = 8.2 Hz, 4H), 5.68–5.43 (m, 2H), 5.11–4.90 (m, 4H), 3.76 (s,
4H), 2.44 (s, 6H), 2.00 (d, J = 7.3 Hz, 4H); 13C NMR (67.5 MHz, Under nitrogen atmosphere, a solution of compound 10
CDCl3) δ 145.2 (2C), 132.5 (2C), 131.0 (2C), 130.1 (4C), 128.0 (0.7883 g, 4.0 mmol) and titanocenedimethyl (2.421 g,
(4C), 120.2 (2C), 70.2 (2C), 40.7, 34.7 (2C), 21.5 (2C); HRMS 8.86 mmol) in toluene (4 mL) was heated at 70°C for 20 h. The
(ESI M + Na) m/z 487.1219. Calcd for C23H28NaO6S2 487.1225. reaction mixture was concentrated in vacuo and the residue was
passed through florisil column (eluted with CH2Cl2-pentane
1:9). The eluent was concentrated and the residue was purified
through florisil flash chromatography to give compound 10
Preparation of 3,3-diallylpentanedinitrile 7
1
A mixture of compound 6 (19.89 g, 42.8 mmol) and NaCN in 28% yield (0.2175 g, 1.13 mmol). Pale yellow oil; H NMR
(25.0 g, 510 mmol) in DMSO (340 mL) was stirred at 75°C (270 MHz, CDCl3) δ 5.92–5.59 (m, 2H), 5.25–5.02 (m, 4H),
for 34 h. Cold water (500 mL) was added to the reaction mix- 4.74 (d, J = 1.4 Hz, 1H), 4.31 (d, J = 1.3 Hz, 1H), 2.45 (s, 2H),
ture, and the aqueous solution was extracted with ether (20 2.34 (s, 2H), 2.17–1.99 (m, 4H); 13C NMR (67.5 MHz, CDCl3) δ

262
A. KAMIMURA AND Y. KAWAKAMI
168.0, 153.6, 132.3 (2C), 119.8 (2C), 95.5, 41.4 (2C), 40.1, 36.3,
34.8; HRMS (ESI M + H) m/z 193.1238. Calcd for C12H17O2
193.1229.
Acknowledgments
The authors are grateful to Dr. Tsuyoshi Arai and Dr. Yousuke Oota,
UBE Scientific Analysis Laboratory Inc. for their NMR analyses of several
compounds. We also thank Koichiro Miyazaki for measurements of high-
resolution mass spectrometry.
Radical addition/cyclization of compound 11
A solution of thiophenol (0.188 g, 1.707 mmol), AIBN (0.1926 g,
1.138 mmol) and compound 10 (0.2187 g, 1.138 mmol) in
toluene (40 mL) was heated at 80°C for 8 h. The reaction mix-
ture was concentrated in vacuo and the residue was subjected
to flash chromatography (silica gel/hexane then hexane/EtOAc
1:1) to give compound 11a in 49% yield (0.1671 g, 0.5525
mmol).
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(1S∗,5S∗,7S∗)-5-allyl-7-methyl-1-((phenylthio)methyl)-
2-oxabicyclo[3.2.1]octan-3- one 11a
Pale yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 7.1 Hz,
2H), 7.28 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 5.72 (ddt,
J = 17.4, 10.2, 7.4 Hz, 1H), 5.12 (dd, J = 10.1, 2.1 Hz, 1H), 5.07
(dd, J = 17.0, 1.7 Hz, 1H), 3.28 (d, J = 13.2 Hz, 1H), 3.22 (d,
J = 13.2 Hz, 1H), 2.50 (dd, J = 18.2, 3.0 Hz, 1H), 2.42 (dd, J
= 18.2, 2.3 Hz, 1H), 2.50 – 2.42 (m, 1H), 2.17 (d, J = 7.6 Hz,
1H), 2.15 (d, J = 7.6 Hz, 1H), 2.06 (ddd, J = 13.7, 8.7, 2.0 Hz,
1H), 1.87 (dt, J = 12.8, 2.0 Hz, 1H), 1.71 (dd, J = 12.8, 2.3 Hz,
1H), 1.29 (ddd, J = 13.7, 5.3, 3.0 Hz, 1H), 0.99 (d, J = 7.3 Hz,
3H); 13C NMR (126 MHz, CDCl3) δ 170.8, 137.0, 133.3, 130.0
(2C), 129.1 (2C), 126.5, 119.0, 92.8, 44.9, 44.2, 43.7, 42.7, 41.1,
40.7, 39.9, 19.9; HRMS (ESI M + Na) m/z 325.1233. Calcd for
C18H22NaO2S 325.1238.
(1S∗,5S∗,7S∗)-5-allyl-7-methyl-1-((4-
methylphenylthio)methyl)-2-oxabicyclo[3.2.1]octan-3-
one 11b
1
Pale brown oil; H NMR (270 MHz, CDCl3) δ 7.38–7.29 (m,
2H), 7.16–7.05 (m, 2H), 5.81–5.62 (m, 1H), 5.21–5.00 (m, 2H),
3.26 (d, J = 13.2 Hz, 1H), 3.17 (d, J = 13.3 Hz, 1H), 2.47 (dd, J =
7.9, 2.4 Hz, 3H), 2.32 (s, 3H), 2.17 (d, J = 7.2 Hz, 1H), 2.08–2.00
(m, 1H), 1.89 (d, J = 12.6 Hz, 2H), 1.70 (dd, J = 12.8, 2.1 Hz, 1H),
1.35–1.25 (m, 1H), 0.98 (d, J = 7.3 Hz, 3H); 13C NMR (68 MHz,
CDCl3) δ 170.6, 136.5, 133.2, 130.7 (2C), 129.7 (2C), 118.7, 92.7,
44.7, 44.0, 43.4, 42.5, 40.9, 40.4, 40.4, 23.1, 20.8, 19.6. HRMS (ESI
M + Na) m/z 339.1387. Calcd for C19H24NaO2S 339.1395.
4. (a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392-6394;
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