Synthesis of sundiversifolide and diversifolide via a diastereoselective [3+2] nitrile oxide cycloaddition reaction

Article abstract of DOI:10.3987/COM-08-S(F)67

The enantioselective synthesis of the unnatural enantiomers (-)-sundiversifolide and (+)-diversifolide has been accomplished employing a diastereoselective intramolecular [3+2] nitrile oxide cycloaddition reaction as the key step.

Full text of DOI:10.3987/COM-08-S(F)67

HETEROCYCLES, Vol. 77, No. 2, 2009
773
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 773 - 777. © The Japan Institute of Heterocyclic Chemistry
Received, 28th July, 2008, Accepted, 9th September, 2008, Published online, 11th September, 2008
DOI: 10.3987/COM-08-S(F)67
SYNTHESIS OF SUNDIVERSIFOLIDE AND DIVERSIFOLIDE VIA A
DIASTEREOSELECTIVE [3+2] NITRILE OXIDE CYCLOADDITION
REACTION‡
Hiroyuki Sasaki,† Hiromasa Yokoe,† Mitsuru Shindo,‡ Masahiro Yoshida,†
and Kozo Shishido*†
†Graduate School of Pharmaceutical Sciences, The University of Tokushima,
1-78-1 Sho-machi, Tokushima 770-8505, Japan. ‡Institute for Materials
Chemistry and Engineering, Kyushu University, 6-1, Kasugako-en, Kasuga
816-8580, Japan
E-mail: shishido@ph.tokushima-u.ac.jp
Abstract – The enantioselective synthesis of the unnatural enantiomers
(–)-sundiversifolide and (+)-diversifolide has been accomplished employing a
diastereoselective intramolecular [3+2] nitrile oxide cycloaddition reaction as the
key step.
In our previous papers, we reported the enantioselective total synthesis1 and absolute structure
determination2 of an allelochemical sundiversifolide isolated from the exudate of Helianthus annuus L.3
Moreover, in our recent synthetic studies on the total synthesis of diversifolide,4 isolated from Tithonia T.
diversifolia (Hernsl.) A. Gray (Compositae),5 we disclosed the error of the assigned structure and
established the real structure of the natural product to be 11-epi-sundiversifolide.1 In the course of our
program directed toward the search for new lead compounds for the developments of antibacterial drugs,
particularly anti-MRSA drugs,6 and new allelochemicals, we decided to undertake the synthesis of the
unnatural enantiomers of sundiversifolide (1), diversifolide (2), as well as a wide variety of derivatives
for biological evaluation. Herein we report the synthesis of (–)-1 and (+)-2, the antipodes of the natural
products, using a diastereoselective 1,3-dipolar [3+2] cycloaddition reaction7 as the key step.
‡ This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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Approaching the synthesis from a retrosynthetic perspective, we envisioned the following scheme: (–)-1
and (+)-2 would be derived from the bicyclic lactone 3 via the synthetic route we previously developed.
The lactone 3 would be prepared from the isoxazoline 4 with the R configuration at C7 (sundiversifolide
numbering), which would be made by the 1,3-dipolar [3+2] cycloaddition of the nitrile oxide 5, via a
sequential reductive hydrolysis, stereoselective reduction of the C8 ketone and deoxygenation at C11. We
were especially interested in determining the diasteroselectivity of the construction of the isoxazoline
fused to the seven membered carbocycle during the key cycloaddition reaction.8 The nitrile oxide 5 could
be generated from an appropriate precursor, potentially synthesized from the Evans aldol product 6,
which is known in the literature.9 (Scheme 1)
H
H
H
H
O
O
O
1
O
O
O
TBSO
7
11
HO
HO
H
H
3
(–)-sundiversifolide 1
(+)-diversifolide 2
O
OH
O
INOC
diastereoselectivity?
–
+
N
O
N
BnO
N
O
O
TBSO
TBSO
CO2Et
7
Bn
H
CO2Et
6
5
4
Scheme 1. Retrosynthetic Analysis
The aldol product 6 was converted to the cyanide 7 via a standard three-step manipulation. Sequential
DIBAL reduction, acetalization, debenzylation and Dess-Martin oxidation of 7 produced the aldehyde,
which was subjected to the Wittig reaction to give 8 (4:1 inseparable mixture at the acetal carbon) in good
overall yield. Acidic hydrolysis followed by treatment of the resulting aldehyde with hydroxylamine
provided the oxime which was treated with TBSOTf to give the bis-TBS ether of alcohol and the oxime
moieties. On brief exposure to a solution of TBAF in THF, selective desilylation was carried out to
furnish 9. At this point in the synthesis, the isoxazoline fused to the cycloheptane by the key [3+2]
cycloaddition reaction of the nitrile oxide 5, generated from the oxime 9, could now be constructed.
Treatment of 9 with a 7% aqueous solution of NaOCl10 in dichloromethane at room temperature provided
the diastereoisomeric isoxazolines 10 and 11 as a chromatographically separable 7:1 mixture in 71% yield.
Although the stereochemistry of the cycloadducts could not be determined at this stage, the major adduct
was deduced to be the desired 10 with the (R) configuration at C7 from the following mechanistic point of
view. The diastereoselectivity can be explained by comparing the possible transition states T1 and T2, in
which the sterically less demanding transition state T1 might be predominant and the desired compound
10 would be generated as the major product. (Scheme 2)

HETEROCYCLES, Vol. 77, No. 2, 2009
775
OMe
h - j
OTHP
O
NOH
CO2Et
a - c
d - g
BnO
TBSO
6
CN
O
EtO2C
7
8
9
H
N
O
TBSO
TBSO
TBSO
N
CO2Et
H
CO2Et
H
T1
k
10
CO2Et
N
O
O
N
TBSO
H
CO2Et
H
H
T2
11
Scheme 2. Reagents and Conditions: (a) DHP, PPTS, CH2Cl2, 40 °C, 4 h, 95%. (b) LiAlH4, THF, 0 °C, 1
h, 83%. (c) TsCl, Et3N, 4-DMAP, CH2Cl2, rt, 3 h, then KCN, KI, 18-Crown-6, DMSO, 60 °C, 15 h, 75%.
(d) DIBAL, benzene, 0 °C, 1 h, then H3O+. (e) PPTS, MeOH, reflux, 15 h, 70% (2 steps). (f) Li, liq. NH3,
THF, rt, 0.5 h, 92%. (g) Dess-Martin periodinane, CH2Cl2, rt, 4 h, then Ph3PCHCO2Et, benzene, reflux, 15
h, 68% (2 steps). (h) 5% HCl (aq.), THF, rt, 15 h. (i) NH2OH•HCl, NaOAc, MeOH, rt, 1 h, 70 % (2 steps).
(j) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 1 h, then TBAF, THF, rt, 5 min, 70%. (k) 7% NaOCl (aq.),
CH2Cl2, rt, 15 h, 71% (dr=7:1).
The isoxazoline 10 thus obtained was treated with trimethyl borate and Raney nickel (W2) in aqueous
methanol11 under an atmosphere of hydrogen to give the β-hydroxy ketone 12, reduced with Zn(BH4)212
and the resulting crude mixture was treated with p-TsOH to provide the α-hydroxy lactone 13 as a 4:1
mixture of diastereoisomers at C11. Upon separation by column chromatography, the stereochemistry of
the major isomer was firmly established by extensive NOESY experiments (Scheme 3). Removal of the
hydroxy group in 13 was realized by reduction with samarium iodide13 to give the bicyclic lactone 3, the
spectral properties of which are identical with those for the enantiomer we previously synthesized, except
for the sign of the optical rotation. Conversion of 3 to (+)-2 and (–)-1 was achieved according to the
procedure1 developed for the natural antipodes. Following protection of the lactone carbonyl in 3 as the
acetal, desilylation and oxidation, the seven-membered ketone was obtained and submitted to Peterson
olefination14 to provide 14 (4:1 inseparable mixture at the acetal carbon). This compound was exposed to
the methylaluminum bis(2,6-diphenylphenoxide)-mediated carbonyl ene-reaction conditions15 using
trioxane to furnish the alcohol 15. After protection of the primary hydroxy group and regeneration of the
lactone moiety, the resulting 17 was treated with lithium tetramethylpiperizide and methyl iodide to give
18 diastereoselectively. The stereochemistry at C11 was determined by NOESY spectroscopy, and turned
out to be the S configuration. Desilylation with TBAF produced (+)-diversifolide (2), which was

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subjected to kinetic protonation conditions using LDA and phenol as a proton source at –78 °C to give a
chromatographically separable mixture of (–)-sundiversifolide (1) and (+)-2 in a ratio of 2:1 in 85% yield.
The spectral properties of the synthetic 2 {[α]D +31.4 (c 0.70, CHCl3)} and 1 {[α]D –34.4 (c 0.51, CHCl3);
lit.2 [α]D –33.7 (c 0.46, CHCl3)} were identical with those for the natural products except for the sign of
optical rotations {enantiomer of 2: [α]D –30.5 (c 0.10, CHCl3)1 and [α]D –32.4 (c 0.37, CHCl3)4;
enantiomer of 1: [α]D +34.0 (c 0.40, CHCl3)1}.
H
O
H
H
a
O
b
c
OH
TBSO
H
10
O
3
TBSO
H
TBSO
H
CO2Et
O
H
O
O
H
12
OH
13
OH
NOESY of 13
H
H
H
O
O
h, i
O
n
d - g
j - m
OMe
(–)-1
OMe
3
RO
R1O
H
H
H
R2
14
15 R=H
16 R=TBDPS
17 R1=TBDPS, R2=H
18 R1=TBDPS, R2=Me
(+)-2 R1=H, R2=Me
Scheme 3. Reagents and Conditions: (a) H2, (MeO)3B, Raney-Ni (W2), MeOH, H2O, rt, 15 h, 95%. (b)
Zn(BH4)2, Et2O, –20 °C, 2 h then p-TsOH, CH2Cl2, rt, 2 h, 61%. (c) SmI2, HMPA, ethylene glycol, THF,
rt, 1 h, 90%. (d) DIBAL, CH2Cl2, –78 °C, 0.5 h. (e) p-TsOH, MeOH, reflux, 15 h, 70% (2 steps). (f)
Dess-Martin periodinane, CH2Cl2, rt, 1 h, 88%. (g) TMSCH2MgCl, Et2O, 0 °C, 2 h then KH, THF, reflux,
1 h, 90% (2 steps). (h) trioxane, Me3Al, 2,6-diphenylphenol, CH2Cl2, –78 ~ 0 °C, 0.5 h, 70%. (i)
TBDPSCl, imidazole, 4-DMAP, CH2Cl2, rt, 0.5 h. (j) AcOH, acetone, H2O, rt, 5 h. (k) TPAP, NMO, 4A
MS, CH2Cl2, rt, 1 h, 89% (3 steps). (l) n-BuLi, tetramethylpiperidine, HMPA, THF, –78 °C, 2 h then MeI,
THF, –78 ~ –40 °C, 2 h, 83%. (m) TBAF, THF, rt, 2 h, 92%. (n) LDA, THF, –78 °C, 0.5 h then phenol,
85% (2:1=1:2).
In summary, we have completed the enantiocontrolled total synthesis of ent-diversifolide, which is the
first one reported, and ent-sundiversifolide using a diastereoselective intramolecular [3+2] nitrile oxide
cycloaddition reaction as the key step. The wide variety of compounds prepared here will be submitted
for biological evaluation in the search for new antibacterial drug and allelochemical leads.
ACKNOWLEDGEMENTS
This work was supported financially by a Grant-in-Aid for Scientific Research (A) (No. 16209001) from
the Japan Society for the Promotion of Science.

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