Diastereoselective synthesis of (2S*,3R*)- and (2R*,3R*)-2,6-dimethyl-2-homoprenylchroman-3-ol

Article abstract of DOI:10.1055/s-1998-1751

Diastereoselective synthesis of (2S*,3R*)- and (2R*,3R*)-2,2-dialkylchroman-3-ols was achieved by stereoselective epoxide-opening cyclization of ortho-(2,3-epoxyalkyl)phenols which were prepared by the coupling of p-cresol and (2R*,3R*)- and (2R*,3S*)-2,3-diacetoxyalkyl isopropyl sulfides, which were in turn derived from geraniol and nerol, respectively.

Full text of DOI:10.1055/s-1998-1751

June 1998
SYNLETT
679
Diastereoselective Synthesis of (2S*,3R*)- and (2R*,3R*)-2,6-Dimethyl-2-homoprenyl-
chroman-3-ol
Seiichi Inoue,* Masatoshi Asami, Kiyoshi Honda, Kedar Shanker Shrestha, Masaaki Takahashi, Takashi Yoshino
Department of Synthetic Chemistry, Faculty of Engineering, Yokohama National University, Tokiwadai, Hodogayaku, Yokohama 240-8501, Japan
Fax 045-339-3970; inoue@syn.synchem.bsk.ynu.ac.jp
Received 29 March 1998
Abstract: Diastereoselective synthesis of (2S*,3R*)- and (2R*,3R*)-
2,2-dialkylchroman-3-ols was achieved by stereoselective epoxide-
opening cyclization of ortho-(2,3-epoxyalkyl)phenols which were
prepared by the coupling of p-cresol and (2R*,3R*)- and (2R*,3S*)-2,3-
diacetoxyalkyl isopropyl sulfides, which were in turn derived from
geraniol and nerol, respectively.
silica gel afforded desired product 6 in 80% yield. Acetyl groups in 6
were deprotected by the action of LiAlH , and the isopropylthio group
4
was removed by hydrogenolysis with freshly prepared Raney Ni (W4) in
ethanol at room temperature to give triol 7. The cyclization of 7 was
effected in the presence of p-toluenesulfonic acid in benzene at reflux to
furnish 2,2,5-trimethylchroman-3-ol (8) (Scheme 2).
2,2-Dialkylchroman-3-ol skeleton (1) is found in naturally occurring
1
2
bioactive compounds, such as NG-121, stachybotrins A and B, and
3
stachybotrin C. Effective methods for their stereoselective construction
are highly needed to develop an effective path for the total synthesis of
such bioactive natural products.
We have extensively studied on the ortho-alkylation of phenols via
4
[2,3]sigmatropic rearrangement reaction under mild conditions and
previously reported their application to the stereoselective synthesis of
Scheme 2
4a,4b
4c,5
2,2-dialkylchroman
and others.
As a part of our continuing
study on the stereoselective synthesis of polysubstituted chromans, we
here report an effective diastereoselective synthesis of (2S*,3R*)- and
(2R*,3R*)-2,6-dimethyl-2-homoprenylchroman-3-ol.
1
8
According to H-NMR data, coupling constants between the proton at
C-3 and two protons at C-4 position are 5.0 and 5.3 Hz. These indicate
that the hydroxyl group is probably axially oriented. This was confirmed
9
by X-ray crystallographic analysis and it was found that two molecules,
For a preliminary study, synthesis of 2,2,5-trimethylchroman-3-ol (8)
was investigated. 2-Methyl-3-buten-2-ol (2) was subjected to Sharpless
epoxidation to give epoxy alcohol, which was treated with isopropyl
(3R)-8 and (3S)-8 are united by a hydrogen bond (Figure 1) and four
molecules are in a unit-cell. The conformations of the two molecules are
slightly different to one another. The notable difference between the two
conformers is in bond angle of C(4)-C(3)-O by 3°.
6
mercaptan in the presence of sodium hydride to give 1-(1-
methylethylthio)-3-methylbutan-2,3-diol (3). The same diol 3 was also
obtained from 2,3-epoxy-3-methyl-1-butanol by the reaction with
7
sodium isopropyl mercaptide under Payne rearrangement conditions.
Diol 3 was converted to diacetate 4 in good yield.
Next we examined the diastereoselective synthesis of 2,6-dimethyl-2-
homoprenylchroman-3-ol. For this propose, first we prepared diol
sulfide 11 of the defined relative stereochemistry from trans-allylic
6
alcohol, geraniol (9), by selective Sharpless epoxidation followed by
Scheme 1
the action of sodium isopropyl sulfide under Payne rearrangement
7
conditions. Then it was converted to (2R*,3R*)-2,3-diacetoxy-1-(1-
methylethylthio)-3,7-dimethyl-6-octene (12) for ortho-alkylation
reaction (Scheme 3).
The ortho-alkylation of p-cresol (5) with sulfide 4 was effected by
[2,3]sigmatropic
rearrangement
of
phenoxysulfonium
ylide
intermediate. Thus, a mixture of 4 and 5 in dichloromethane was treated
with sulfuryl chloride at –50 °C, followed by addition of triethylamine
in dichloromethane. The reaction mixture was allowed to warm to room
temperature and usual work-up followed by column chromatography on
p-Cresol (5) and sulfide 12 were reacted as before to give ortho-
alkylated product 13 in good yield. It is noteworthy that relatively bulky
group was transferred to the ortho position of phenol via
[2,3]sigmatropic rearrangement of phenoxysulfonium ylide. The

680
LETTERS
SYNLETT
Scheme 3
phenolic hydroxyl group of 13 was protected by methoxymethyl group,
then acetyl groups were deprotected to give 14. The isopropylthio group
was cleaved by the action of Raney Ni (W4) to give the compound 15.
Similar to the model compound 7, cyclization of 15 was attempted by
refluxing the benzene solution of the demethoxymethylated 15 in the
presence of p-toluenesulfonic acid, resulting in the recovery of the
starting material. Then, in order to activate the diol moiety for
cyclization and to carry out the cyclization stereospecifically, 15 was
converted into an epoxide. The secondary hydroxyl group in 15 was
selectively mesylated, then the resulting mesylate was converted to
epoxide 16 by treating with saturated potassium carbonate. After several
efforts were devoted to effect cyclization of 16 to chroman-3-ol by
nucleophilic epoxide-opening reaction, (2S*,3R*)-2,6-dimethyl-2-
homoprenylchroman-3-ol (17) was obtained stereoselectively as a single
isomer when 16 was treated with 10N formic acid in ethyl acetate at
room temperature.
Scheme 4
Scheme 5
1
Structure and stereochemistry of 17 was determined by H-NMR
10
spectra and NOE experiments and it was found that 3-hydroxyl group
and homoprenyl carbon chain were oriented at the axial position. The
chemical shift of a three-proton singlet of the methyl protons at C-2 (δ
1.32) was very close to that of the equatorial methyl protons in 8 (δ
1.35), and irradiation of the axial proton at C-4 (δ 3.01) gave a 3.4%
enhancement of the α-protons of the homoprenyl group at C-2 (Figure
2).
The formation of the sole cyclization product of (2S*,3R*)
configuration indicates that intramolecular cyclization proceeded by
nucleophilic attack of phenolic oxygen to tertiary carbon of the epoxide
ring in spite of less favorable 5-endo-mode according to Baldwin’s
11
rule.
stage of the synthesis by a proper choice of the starting alcohol, (3)
optically active compounds would be prepared by using Katsuki-
Sharpless asymmetric epoxidation at an earlier stage.
On the other hand, diastereomer of 17, (2R*,3R*)-2,6-dimethyl-2-
homoprenylchroman-3-ol (20), was successfully synthesized
stereoselectively using diastereomeric (2R*,3S*) sulfide 19, which was
prepared from cis-allylic alcohol, nerol (18), by a similar method
12
In conclusion, the present study provides the first example of efficient
diastereoselective synthesis of (2S*,3R*)- and (2R*,3R*)-2,6-dimethyl-
2-homoprenylchroman-3-ols. Further synthetic applications of this
methodology is currently under progress.
1
(Scheme 5). Structure of 20 was similarly determined by H-NMR
10
spectra and NOE, which showed that 3-hydroxyl group was oriented
at the axial position and 2-homoprenyl carbon chain was at equatorial
position. Irradiation of the axial proton at C-4 (δ 3.01) gave a 3.36%
enhancement of axial oriented methyl protons at C-2 (δ 1.25) (Figure 2).
Acknowledgement
This work was supported by a Grant-in-Aid for Scientific Research (No.
09450339) from the Ministry of Education, Science, Sport, and Culture
of Japan. We thank Dr. Tomomi Ota and Mr. Keita Matsumoto of Taisho
Pharmaceutical Co. Ltd., Japan for X-ray crystallographic analysis of 8.
To our knowledge, this is the first effective method for the
diastereoselective synthesis of chroman-3-ol derivatives with a terpene
chain at C-2. This method has several advantages: (1) desired
diastereomer can be synthesized merely starting from trans or cis allylic
alcohol, (2) desired side chain at C-2 can be introduced at the initial

June 1998
SYNLETT
681
ax
eq
References and Notes
3H, CH -2 ), 1.35 (s, 3H, CH -2 ), 2.26 (s, 3H, CH -6), 2.75
3
3
3
eq
(dd, J=16.5, 5.3 Hz, 1H, H-4 ), 3.07 (dd, J=16.5, 5.0 Hz,1H, H-
4 ), 3.79 (dd, J=5.3, 5.0 Hz, 1H, H-3 ), 6.90–6.91 (m, 3H, Ar-
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1
3
90.12(2)°, β = 91.63(1)°, γ = 76.31(1)°, V = 1092.9(3) Å , Z = 4,
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-1
1390, 1300, 1270, 1240, 1140, 1065, 1030, 970, 900, 820 cm ;
1
eq
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3
3
CH -5’), 1.66 (s, 3H, CH -5“), 1.78 (m, 2H, CH -1’), 2.12 (m,
3
3
2
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2
3
eq
ax
H-4 ), 3.01 (dd, J=17.17, 4.95 Hz, 1H, H-4 ), 3.84 (dd, J=5.45,
4.95 Hz, 1H, H-3 ), 5.06 (tt, 1H, olefinic H), 6.73 (d, 1H, Ar-H),
6.88 (d, 1H, Ar-H), 6.95 (d, 1H, Ar-H). 20: H-NMR (270 MHz,
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eq
1
ax
3
3
3
CH -5“), 1.73 (m, 2H, CH -1’), 2.11 (m, 2H, CH -2’), 2.25 (s,
3
2
2
eq
3H, CH -6), 2.75 (dd, J=17.16, 4.62 Hz, 1H, H-4 ), 3.01 (dd,
J=17.16, 4.95 Hz, 1H, H-4 ), 3.82 (dd, J=4.62, 4.95 Hz, 1H, H-
3 ), 5.13 (tt, 1H, olefinic H), 6.73 (d, 1H, Ar-H), 6.86 (d, 1H, Ar-
3
ax
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6136.
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1587, 1497, 1450, 1389, 1300, 1262, 1223, 1183, 1144, 1065,
-1
1
960, 849, 817, 570 cm ; H-NMR (270 MHz, CDCl ) δ 1.29 (s,
3