First synthesis of (+/-)-robinlin.

Article abstract of DOI:10.1271/bbb.68.1961

The first synthesis of (+/-)-robinlin (1), a novel homo-monoterpene with strong bioactivity in the brine shrimp lethality test, was achieved by starting from 3-isobutyloxy-2,6,6-trimethyl-2-cyclohexen-1-one (2).

Full text of DOI:10.1271/bbb.68.1961

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First Synthesis of (±)-Robinlin
Hirosato TAKIKAWAa, Shintaro HOSOEa, Keiko UEDAa & Mitsuru SASAKIa
a Department of Biosystems Science, Graduate School of Science and Technology, Kobe
University
Published online: 22 May 2014.
To cite this article: Hirosato TAKIKAWA, Shintaro HOSOE, Keiko UEDA & Mitsuru SASAKI (2004) First Synthesis of (±)-
Robinlin, Bioscience, Biotechnology, and Biochemistry, 68:9, 1961-1965, DOI: 10.1271/bbb.68.1961
To link to this article: http://dx.doi.org/10.1271/bbb.68.1961
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Biosci. Biotechnol. Biochem., 68 (9), 1961–1965, 2004
First Synthesis of (Æ)-Robinlin
Hirosato TAKIKAWA,y Shintaro HOSOE, Keiko UEDA, and Mitsuru SASAKI
Department of Biosystems Science, Graduate School of Science and Technology, Kobe University,
Rokkodai 1-1, Nada-ku, Kobe 657-8501, Japan
Received May 17, 2004; Accepted June 14, 2004
The first synthesis of (Æ)-robinlin (1), a novel homo-
monoterpene with strong bioactivity in the brine shrimp
lethality test, was achieved by starting from 3-isobutyl-
oxy-2,6,6-trimethyl-2-cyclohexen-1-one (2).
report here the first synthesis of (ꢀ)-1 in detail.
Result and Discussion
Our synthetic plan for 1 is illustrated in Scheme 1.
Target compound 1 should be readily obtainable from
intermediate A by hydroxylation. To prepare A, the
following three routes were envisaged. The key process
in route A was regioselective hydration of the vinyl side-
chain. Installation of an acetate unit or its equivalent was
the key point in route B. Oxidative cleavage of the
double bond of the allyl group was the key step in route
C. All three intermediates B, C and D could be prepared
from common starting material E.
Our first choice was route A, because this was more
straightforward than the others. Starting material 22) was
converted into known dienone 33,4) according to the
reported procedure.4) We provided two options for the
crucial step, regioselective anti-Markovnikov addition
of water to the vinyl side-chain: 1) 1,6-addition of water
(3!4); 2) regioselective epoxidation and reductive
cleavage of the oxiran ring (3!5!4). Our first attempt
was the Lewis acid-promoted 1,6-addition of water
Key words: homo-monoterpene; brine shrimp test; hy-
droxylation; Robinia pseudoacacia L.
McLaughlin et al. reported in 2001 the isolation of
robinlin (1) from the black locust tree, Robinia pseu-
doacacia L. (Fabaceae),1) which is used as traditional
medicine and is also known to be poisonous. Robinlin
(1) is a structurally novel homo-monoterpene and its
skeleton has never before been reported as a natural
product isolated from plants, even though its structure
looks quite usual at the first glance. McLaughlin et al.
have also reported that 1 showed strong bioactivity in
the brine shrimp lethality test (BST), but was not
significantly cytotoxic against human solid tumor cell
lines.1) It was thus suggested that 1 may possess
pharmacological activities other than cytotoxicity. We
were interested in the construction of the novel structure
of 1 and also in clarifying its biological activities. We
Scheme 1. Structure of Robinlin (1) and Its Synthetic Plan.
y
To whom correspondence should be addressed. Tel/Fax: +81-78-803-5958; E-mail: takikawa@kobe-u.ac.jp

1962
H. TAKIKAWA et al.
reported by Majetich et al.5) Although they have
reported the successful 1,6-addition of water to 3-
vinyl-2-cyclohexen-1-one, desired adduct 4 could not be
obtained at all. One probable reason for the failure
would be the steric hindrance of three methyl groups.
We then attempted the second option. As already
disclosed, in an ꢀ,ꢁ-, ꢂ,ꢃ-unsaturated ketone such as 3,
regioselective epoxidation of the ꢂ,ꢃ-double bond and
reductive cleavage of the oxiran ring at the ꢂ-position
was feasible.6,7) However, in this case, the regioselective
epoxidation of 3 to 5 was troublesome. In spite of all our
efforts, we could not find out any appropriate reaction
conditions to obtain desired epoxide 5. We thus decided
to quit route A and turned to route B. In route B, for
installation of the acetate unit, 2 was exposed to such
reagents as the lithioenolate of acetate,8) Reformatsky
reagent9) and metalated ethoxyacetylene.10) However,
these trials were also not successful.
We then tried route C. Starting material 2 was first
treated with allylmagnesium chloride, before an acidic
work-up to give 7 (88%). The double bond on the side-
chain was not conjugated at this stage and was some-
what apart from the bulky cyclohexenone moiety. The
‘‘isolated’’ double bond in 7 was oxidized with OsO4 in
the presence of NMO to give corresponding diol 8,
which was subjected to oxidative cleavage with NaIO4
to furnish aldehyde 9 (80% in 2 steps). Reduction of 9
with LiAlH4 was followed by oxidation with MnO2 to
yield enone 4 (51% in 2 steps). The possible alternative
route to 4 was chemoselective reduction of the aldehyde
group of 9. This chemoselective reduction was success-
fully performed under the reported conditions11) to yield
4 (79%). The remaining step was the hydroxylation of 4
which was carried out with 2-phenylsulfonyl-3-phenyl-
oxaziridine (Davis’ reagent)12,13) to give (ꢀ)-robinlin
(1). However, the isolation yield was rather low (28%),
even after intensive investigation of the reaction
conditions. We thought that the low yield might have
been due to the presence of a free hydroxyl group in 4,
so protection of this hydroxyl group was examined. The
hydroxylation of TBS ether 10 proceeded smoothly in
this case to give 11 in a much higher yield (81%).
Finally, deprotection of the TBS group was achieved by
treating with TBAF to furnish (ꢀ)-robinlin (1). The
various spectral data for synthetic (ꢀ)-1 are in good
accordance with those of the natural product. The
overall yield was 32% in 7 steps or 16% in 5 steps based
on 2.
In conclusion, the first synthesis of (ꢀ)-robinlin (1)
was accomplished by starting from 3-isobutyloxy-2,6,6-
trimethyl-2-cyclohexenone (2). Detailed bioassays em-
ploying our synthetic samples are now in preparation.
Experimental
IR spectra were measured with a Jasco A-102
spectrometer, and 1H-NMR spectra were recorded at
300 MHz with a Jeol JNM-AL300 spectrometer. The
peak for CHCl3 in CDCl3 (at ꢃH ¼ 7:26) was used as the
internal standard. 13C-NMR spectra were recorded at
75 MHz with the Jeol JNM-AL300 spectrometer, the
peak for CDCl3 (at ꢃC ¼ 77:0) being used as the internal
standard. Mass spectra were measured with a Jeol JMS-
700 spectrometer.
3-Allyl-2,4,4-trimethyl-2-cyclohexen-1-one (7). To a
stirred mixture of iodine (a catalytic amount) and Mg
(2.50 g, 100 mmol) in ether (5 ml) was added dropwise a
solution of allyl chloride (4.7 ml, 57.7 mmol) in ether
(40 ml) at 0 ꢁC under Ar. The mixture was allowed to
warm to room temperature and then a solution of 2
(2.00 g, 9.51 mmol) in THF (30 ml) was added dropwise.
After stirring for 10 min, this reaction mixture was
quenched with saturated aq. NH4Cl, and extracted with
EtOAc. The extract was successively washed with water
and brine, dried (MgSO4) and concentrated under
reduced pressure. The residue was chromatographed
on SiO2 to give 7 (1.50 g, 8.41 mmol, 88%) as an oil. IR
ꢄ
max (film) cmꢂ1: 1650 (s, C=O), 1600 (m, C=C). NMR
ꢃH (CDCl3): 1.15 (6H, s, 4-Me), 1.75 (3H, s, 2-Me), 1.82
(2H, t, J ¼ 6:9 Hz, 5-H), 2.48 (2H, t, J ¼ 6:9 Hz, 6-H),
3.01 (2H, d, J ¼ 6:0 Hz, 10-H), 5.03 (1H, d, J ¼ 16:8 Hz,
30-H) 5.08 (1H, brd, J ¼ 10:8 Hz, 30-H), 5.76 (1H, tdd,
16.8, 10.8, 6.0 Hz, 20-H). NMR ꢃC (CDCl3): 11.4, 26.7,
34.2, 34.4, 36.3, 37.2, 116.4, 132.0, 134.1, 161.4, 198.9.
HREIMS m/z (Mþ): calcd. for C12H18O, 178.1358;
found, 178.1360.
Scheme 2. Routes A and B.
Reagents and conditions: (a) TiCl4, H2O, THF; (b) i) monop-
erphthalic acid, CHCl3 or ii) m-CPBA, CH2Cl2, etc; (c) i) LDA,
t
3-(2,3-Dihydroxypropyl)-2,4,4-trimethyl-2-cyclohex-
en-1-one (8). To a stirred solution of 7 (1.02 g,
CH3CO2 Bu, THF, ii) BrZnCH2CO2Et, toluene, iii) LiCꢃCOEt,
THF, etc.

First Synthesis of (ꢀ)-Robinlin
1963
Scheme 3. Route C for Synthesis of (ꢀ)-1.
Reagents and conditions: (a) allylmagnesium chloride, Et2O (88%); (b) OsO4, NMO, t-BuOH, aq. acetone (86%); (c) NaIO4, aq. CH2Cl2
(93%); (d) LiAlH4, THF (91%); (e) MnO2, CHCl3 (56%); (f) NaBH4, EtOH, CH2Cl2, ꢂ78 ꢁC (79%); (g) Davis’ reagent, KHMDS, THF (28%);
(h) TBSCl, imidazole, DMF (84%); (i) Davis’ reagent, NaHMDS, THF (81%); (j) TBAF, THF (85%).
5.72 mmol) in acetone (20 ml) and water (10 ml) were
added OsO4 (0.01 g/ml in t-BuOH, 3 ml) and NMO
(1.34 g, 11.4 mmol). After stirring overnight at room
temperature, the reaction mixture was diluted with water
and extracted with EtOAc and then with CHCl3. The
combined extract was successively washed with water
and brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was chromatographed
on SiO2 to give 8 (0.975 g, 4.92 mmol, 86%) as an oil.
IR ꢄmax (film) cmꢂ1: 3400 (s, O–H), 1660 (s, C=O),
1640 (s, C=O), 1600 (m, C=C). NMR ꢃH (CDCl3): 1.14
(3H, s, 4-Me), 1.16 (3H, s, 4-Me), 1.75 (3H, s, 2-Me),
1.79 (2H, t, J ¼ 6:9, 5-H), 2.34 (1H, dd, J ¼ 4:5, 13.5,
10-H), 2.44 (2H, t, J ¼ 6:9 Hz, 6-H), 2.51 (1H, dd,
J ¼ 8:7, 13.5 Hz, 10-H), 3.33 (2H, brs, –OH), 3.47 (1H,
dd, J ¼ 7:2, 11.1 Hz, 30-H), 3.64 (1H, dd, J ¼ 3:0,
11.1 Hz, 30-H), 3.96 (1H, m, 20-H). NMR ꢃC (CDCl3):
12.6, 26.9, 27.5, 34.16, 34.20, 36.3, 37.3, 66.6, 71.4,
132.7, 161.9, 199.6. HREIMS m/z (Mþ): calcd. for
C12H20O3, 212.1412; found, 212.1423.
(s, C=O), 1610 (w, C=C). NMR ꢃH (CDCl3): 1.11 (6H,
s, 4-Me), 1.72 (3H, s, 2-Me), 1.87 (2H, t, J ¼ 6:9 Hz, 5-
H), 2.50 (2H, t, J ¼ 6:9 Hz, 6-H), 3.39 (2H, s, 10-H),
9.64 (1H, brs, 20-H). NMR ꢃC (CDCl3): 12.1, 26.4, 34.1,
35.9, 36.7, 45.6, 133.9, 154.2, 197.2, 198.1.
3-(2-Hydroxyethyl)-2,4,4-trimethyl-2-cyclohexen-1-
one (4).
Method A:To a stirred solution of 9 (0.74 g, 4.1 mmol)
in THF (15 ml) was carefully added LiAlH4 (0.20 g,
5.3 mmol) portionwise at 0 ꢁC. The reaction mixture was
quenched with water and then with 15% aq. NaOH. This
was filtered, and the resulting filtrate was extracted with
EtOAc. The extract was successively washed with water
and brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was chromatographed
on SiO2 to give the corresponding diol, 3-(2-hydrox-
yethyl)-2,4,4-trimethyl-2-cyclohexen-1-ol, (0.69 g, 3.7
mmol, 91%) as an oil. IR ꢄmax (film) cmꢂ1: 3300 (s,
O–H). NMR ꢃH (CDCl3): 0.92 (3H, s, 4-Me), 1.00 (3H,
s, 4-Me), 1.23–1.37 (1H, m, 5-H), 1.52–1.86 (3H, m, 5-
H, 6-H2), 1.74 (3H, s, 2-Me), 2.17–2.42 (2H, m, 10-H)
2.81 (2H, br, –OH) 3.57 (2H, brt, J ¼ 7:2 Hz, 20-H), 3.84
(1H, t, J ¼ 4:2 Hz, 1-H). NMR ꢃC (CDCl3): 17.3, 27.0,
28.4, 32.1, 34.3, 35.1, 61.7, 69.9, 130.8, 137.7. HREIMS
m/z (Mþ): calcd. for C12H20O2, 184.1463; found,
184.1483.
2,4,4-Trimethyl-3-(2-oxoethyl)-2-cyclohexen-1-one
(9). To a stirred mixture of 8 (0.13 g, 0.66 mmol) in ether
(5 ml) and water (2.5 ml) was added NaIO4 (0.13 g,
0.86 mmol) at 0 ꢁC. After stirring for 1 hr, the reaction
mixture was diluted with water and extracted with
EtOAc. The extract was successively washed with water
and brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was chromatographed
on SiO2 to give 9 (0.11 g, 0.61 mmol, 93%) as an oil. IR
ꢄmax (film) cmꢂ1: 2650 (w, CHO), 1720 (s, C=O), 1660
To a stirred solution of 3-(2-hydroxyethyl)-2,4,4-
trimethyl-2-cyclohexen-1-ol (0.69 g, 3.7 mmol) in
CHCl3 (30 ml) was added MnO2 (11 g, 0.13 mol). After
stirring at room temperature for 43 hr, the reaction

1964
H. TAKIKAWA et al.
mixture was diluted with EtOAc, filterd, and concen-
trated under reduced pressure. The residue was chroma-
tographed on SiO2 to give 4 (0.37 g, 2.1 mmol, 56%) as
an oil. IR ꢄmax (film) cmꢂ1: 3400 (s, O–H), 1660 (s,
C=O), 1600 (w, C=C). NMR ꢃH (CDCl3): 1.16 (6H, s,
4-Me), 1.79 (3H, s, 2-Me), 1.79 (2H, t, J ¼ 6:9 Hz, 5-H),
2.03 (1H, d, J ¼ 5:1, -OH), 2.45 (2H, t, J ¼ 6:9 Hz, 6-
H), 2.57 (2H, t, J ¼ 8:1 Hz, 10-H) 3.70 (2H, t,
J ¼ 8:1 Hz, 20-H). NMR ꢃC (CDCl3): 11.9, 26.8, 34.2,
34.3, 36.1, 37.1, 61.0, 132.3, 160.3, 199.0. HREIMS m/z
(Mþ): calcd. for C11H18O2, 182.1307; found, 182.1307.
Method B: To a stirred mixture of NaBH4 (0.18 g,
4.8 mmol, 4.3 eq) in EtOH (5 ml) and CH2Cl2 (14 ml)
was added a solution of 9 (0.20 g, 1.1 mmol) in CH2Cl2
(1 ml) dropwise at ꢂ78 ꢁC under Ar. After stirring for
15 min, acetaldehyde (distilled, 2 ml) was added, and the
reaction mixture was allowed to warm to room temper-
ature. The resulting mixture was diluted with water and
then extracted with CHCl3. The extract was successively
washed with saturated aq. NaHCO3 and brine, dried
(MgSO4), and concentrated under reduced pressure. The
residue was chromatographed on SiO2 to give 4 (0.16 g,
0.87 mmol, 79%) as an oil.
(4.3 mg, 0.022 mmol, 85%) as colorless needles. This
product was identical to (ꢀ)-1 which had been synthe-
sized from 4 in all aspects.
3-[2-(tert-Butyldimethylsilyloxy)ethyl]-2,4,4-trimeth-
yl-2-cyclohexen-1-one (10). To a stirred solution of 4
(0.18 g, 0.97 mmol) in DMF (5 ml) were added imid-
azole (0.15 g, 1.9 mmol) and TBSCl (0.25 g, 1.7 mmol).
After stirring for 1 hr, the reaction mixture was
quenched with saturated aq. NH4Cl and then extracted
with EtOAc. The extract was successively washed with
water and brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was chromatographed on
SiO2 to give 10 (0.24 g, 0.82 mmol, 84%) as an oil. IR
ꢄmax (film) cmꢂ1: 1660 (s, C=O), 1600 (w, C=C), 1240
(m, Si-Me). NMR ꢃH (CDCl3): 0.07 (6H, s, SiMe), 0.90
(9H, s, t-Bu), 1.15 (6H, s, 4-H), 1.79 (3H, s, 2-Me), 1.79
(2H, t, J ¼ 6:9 Hz, 5-H), 2.45 (2H, t, J ¼ 6:9 Hz, 6-H),
2.52 (2H, t, J ¼ 8:1 Hz, 10-H), 3.65 (2H, t, J ¼ 8:1 Hz,
20-H). NMR ꢃC (CDCl3): ꢂ5.3, 12.0, 18.3, 25.9, 26.8,
34.2, 34.6, 36.1, 37.2, 61.4, 132.2, 160.6, 199.0.
HREIMS m/z (Mþ): calcd. for C17H32O2Si, 296.2172;
found, 296.2168.
6-Hydroxy-3-(2-hydroxyethyl)-2,4,4-trimethyl-2-cy-
clohexen-1-one, robinlin (1).
3-[2-(tert-Butyldimethylsilyloxy)ethyl]-6-hydroxy-2,4,
4-trimethyl-2-cyclohexen-1-one (11). NaHMDS (1.0 M
in THF, 0.25 ml, 0.25 mmol) was added to dry THF
(1 ml) at ꢂ78 ꢁC under Ar. To this solution, 10 (50 mg,
0.17 mmol) in THF (1 ml) was slowly added dropwise.
After stirring for 30 min, a solution of Davis’ reagent
(66 mg, 0.25 mmol) in THF (1 ml) was added dropwise,
and the mixture was stirred for 1hr. The reaction mixture
was quenched with saturated aq. NH4Cl at ꢂ78 ꢁC and
extracted with EtOAc. The extract was successively
washed with water and brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was
chromatographed on SiO2 to give 11 (43 mg, 0.14 mmol,
81%) as an oil. IR ꢄmax (film) cmꢂ1 : 3450 (s, O–H),
1660 (s, C=O), 1600 (w, C=C), 1250 (s, Si-Me). NMR
ꢃH (CDCl3): 0.07 (6H, s, SiMe), 0.89 (9H, s, t-Bu), 1.19
(3H, s, 4-Me), 1.25 (3H, s, 4-Me), 1.73 (1H, t, J ¼
13:2 Hz, 5-H), 1.85 (3H, s, 2-Me), 2.13 (1H, dd, J ¼ 5:4,
13.2 Hz, 5-H), 2.46 (1H, ddd, J ¼ 6:6, 9.6, 12.6 Hz, 10-
H), 2.59 (1H, ddd, J ¼ 6:6, 9.6, 12.6 Hz, 10-H), 3.63
(1H, ddd, J ¼ 6:6, 9.6, 11.4 Hz, 20-H), 3.66 (1H, ddd,
J ¼ 6:6, 9.6, 11.4 Hz, 20-H), 4.28 (1H, dd, J ¼ 5:4,
13.8 Hz, 6-H). NMR ꢃC (CDCl3): ꢂ5.3, 12.1, 18.3, 25.3,
25.9, 29.5, 34.6, 37.3, 45.2, 61.2, 69.2, 129.3, 161.9,
200.1. HRFABMS m/z (Mþ + H): calcd. for
C17H33O3Si, 313.2199; found, 313.2199.
Method A: KHMDS (0.5 M in THF, 5.0 ml, 2.5 mmol)
was added to dry THF (15 ml) under Ar at ꢂ78 ꢁC. To
this solution, 4 (0.20 g, 1.1 mmol) in THF (1 ml) was
slowly added dropwise. After stirring for 30 min, a
solution of Davis’ reagent (0.37 g, 1.4 mmol) in THF
(2 ml) was added dropwise, and the mixture was stirred
for 1 hr. The reaction mixture was quenched with
saturated aq. NH4Cl at ꢂ78 ꢁC and extracted with
EtOAc. The extract was successively washed with water
and brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was chromatographed
on SiO2 to give (ꢀ)-1 (61 mg, 0.31 mmol, 28%) as
colorless needles, mp 79.5–81.5 ꢁC. IR ꢄmax (nujol)
cmꢂ1: 3300 (s, O–H), 1660 (s, C=O), 1600 (w, C=C).
NMR ꢃH (CDCl3): 1.16 (3H, s, 4-Me), 1.23 (3H, s, 4-
Me), 1.70 (1H, t, J ¼ 13:2 Hz, 5-H), 1.82 (3H, s, 2-Me),
2.09 (1H, dd, J ¼ 5:7, 12.6 Hz, 5-H), 2.48 (2H, ddd,
J ¼ 6:0, 9.3, 12.6 Hz, 10-H), 2.60 (1H, ddd, J ¼ 6:0, 9.3,
12.6 Hz, 10-H), 3.11 (2H, br, –OH), 3.64 (1H, ddd,
J ¼ 6:6, 10.5, 12.0 Hz, 20-H), 3.67 (1H, ddd, J ¼ 6:6,
10.5, 12.0 Hz, 20-H) 4.25 (1H, dd, J ¼ 5:7, 13.8 Hz, 6-
H). NMR ꢃC (CDCl3): 12.0, 25.2, 29.4, 34.1, 37.2, 45.1,
60.7, 69.1, 129.3, 161.6, 200.1. HREIMS m/z (Mþ):
calcd. for C11H18O3, 198.1256; found, 198.1274.
Method B: To a stirred solution of 11 (8.0 mg,
0.026 mmol) in THF (1 ml) was added tetrabutylammo-
nium fluoride (1.0 M in THF, 38 ꢅl, 0.038 mmol). After
stirring overnight, the reaction mixture was diluted with
water and then extracted with EtOAc. The extract was
successively washed with water and brine, dried
(MgSO4), and concentrated under reduced pressure.
The residue was chromatographed on SiO2 to give (ꢀ)-1
Acknowledgment
We are grateful to Otsuka Chemical Co., Ltd., for the
generous support.

First Synthesis of (ꢀ)-Robinlin
(1972).
1965
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