Enantioselective route to aryl(1,3-butadien-2-yl)methanols: Formal synthesis of (-)-sporochnol a

Article abstract of DOI:10.3987/COM-08-S(F)58

Ti(IV)-promoted reaction of the chiral acetals derived from aromatic aldehydes with 1-(tri-n-butyl)stannyl-2,3-butadiene followed by removal of the chiral auxiliary gave aryl(1,3-butadien-2-yl)methanols with high enantiomeric purity (>90% ee). The synthet

Full text of DOI:10.3987/COM-08-S(F)58

HETEROCYCLES, Vol. 77, No. 1, 2009
249
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 249 - 253. © The Japan Institute of Heterocyclic Chemistry
Received, 24th July, 2008, Accepted, 27th August, 2008, Published online, 28th August, 2008.
DOI: 10.3987/COM-08-S(F)58
ENANTIOSELECTIVE ROUTE TO ARYL(1,3-BUTADIEN-
2-YL)METHANOLS:
(–)-SPOROCHNOL A†
FORMAL
SYNTHESIS
OF
Daisuke Yanagimoto, Kazuyuki Kawano, Keisuke Takahashi, Jun Ishihara,
*
and Susumi Hatakeyama
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki
852-8521, Japan. susumi@net.nagasaki-u.ac.jp
Abstract – Ti(IV)-promoted reaction of the chiral acetals derived from aromatic
aldehydes with 1-(tri-n-butyl)stannyl-2,3-butadiene followed by removal of the
chiral auxiliary gave aryl(1,3-butadien-2-yl)methanols with high enantiomeric
purity (>90% ee). The synthetic utility of this method was demonstrated by the
formal synthesis of (–)-sporochnol A, a terpene possessing a chiral benzylic
quaternary carbon center.
We have previously developed an effective method for the highly enantioselective preparation of dienol 5
via Lewis acid-promoted reaction of chiral acetal 1 with buta-2,3-dienylsilane 2.1,2 In addition, we have
demonstrated the synthetic utility of 5 as a chiral building block by utilizing it in the synthesis of natural
products.3 However, this method could not be applied to the synthesis of the compounds having aromatic
substituents 5 (R = Ar) due to the instability of 4 under the reaction conditions. We now report a highly
enantioselective route to aryl(1,3-butadien-2-yl)methanols 5 (R = Ar) through butadienylation of 1 with
buta-2,3-dienylstannane 34,5 using a mild mixed Ti(IV) reagent as a promoter.
OH
Lewis acid
1) Swern oxidn
2) aq KOH
O *
*
* OH
O *
R
*
*
X
R
R
O
•
1
4
5
2: X = SiMe3
3: X = SnBu3
Scheme 1
† Dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 1, 2009
We also demonstrate the utility of this methodology by the formal synthesis of (–)-sporochnol A, an
enantiomer of which is a fish deterrent isolated from the marine alga Sporchnus bolleanus.6,7
To establish a reliable method for the preparation of aryl(1,3-butadien-2-yl)methanols 5 (R = Ar) in high
enantiomeric purity, we examined the dienylation of chiral acetals 8a-g, prepared by acetalization of
aldehydes 6a-g with 7,8 using BF3·Et2O and 3TiCl4·Ti(O-i-Pr)4 as a promoter according to the procedure4
previously established for the reaction of dimethyl acetals (Scheme 2, Table 1). The reactions were
evaluated by HPLC analysis using a chiral column after converting 9 to 10 by Swern oxidation followed
1
by retro-Michael reaction. The absolute configurations of 10 were determined to be S by H NMR
analysis of R- and S-MTPA esters. As can be seen from Table 1, BF3·Et2O did not promote the
dienylation at all in the case of chiral acetals unlike the corresponding dimethyl acetals4 (entries 1 and 3).
On the other hand, 3TiCl4·Ti(O-i-Pr)4 was found to effectively promote the dienylation of 8a and other
acetals 8f,g having electron-withdrawing groups (entries 2, 9, and 10). However, in the case of
o-nitrophenyl derivative 8e, the desired product 9e was not produced due to the extreme insolubility of
CHO
TMSO
OTMS
O
8a: R = H, 94%; 8b: R = o-MeO, 94%
8c: m-MeO, 82%; 8d: p-MeO: 79%
8e: R = o-NO2, 95%; 8f: p-NO2, 99%
8g: R = o-Br, 97%
7
O
TMSOTf (5 mol %)
CH2Cl2
–78 °C to –40~0 °C
R
R
6a-g
OH
O
OH
1) Swern oxidn
3
8a-g
2) 7.5 M KOH
Lewis acid (1.2 equiv)
additive (1.2 equiv)
CH2Cl2, –78 °C
THF-MeOH
R
(2:1)
R
9a-g
10a-g
Scheme 2
Table 1. Lewis acid-promoted reactiona of 8 with 3 and conversion of 9 to 10.
Entry
Acetal
8a
Lewis Acid
Additive Time (h) Yield of 9 (%)b Yield of 10 (%)b Ee % of 10c,d
1
BF3·Et2O
0
––
89
––
87
92
90
91
––
93
98
––
91
––
78
90
90
90
––
98
91
21
12
8
2
8a
70
0
3TiCl4·Ti(O-i-Pr)4
BF3·Et2O
3
8b
8b
8b
8c
4
32
76
73
70
0
3TiCl4·Ti(O-i-Pr)4
3TiCl4·Ti(O-i-Pr)4
3TiCl4·Ti(O-i-Pr)4
3TiCl4·Ti(O-i-Pr)4
3TiCl4·Ti(O-i-Pr)4
3TiCl4·Ti(O-i-Pr)4
3TiCl4·Ti(O-i-Pr)4
5
5
MeCN
MeCN
MeCN
24
24
24
12
24
24
6
7
8d
8e
8
9
8f
82
81
10
8g
a The reactions were conducted at –78 °C using 8 (1 equiv), 3 (1.5 equiv), and Lewis acid (1.2 equiv) in the presence or
absence of MeCN (1.2 equiv) in CH2Cl2. b Isolated yield. c Determined by HPLC analysis using a chiral column. d The absolute
configurations were determined to be S by 1H NMR analysis of corresponding R- and S-MTPA esters.

HETEROCYCLES, Vol. 77, No. 1, 2009
251
the resulting Ti(IV)-coordinated complex in the reaction media (entry 8). For the reactions of rather
sensitive acetals 8b-d having electron-donating groups, addition of 1.2 equiv of acetonitrile was found to
markedly improve the yields of 99 by attenuating the Lewis acidity of 3TiCl4·Ti(O-i-Pr)4 (entries 4-7).
Having established a highly enantioselective route to dienols 10, we then investigated the synthesis of
(–)-sporochnol A (13) using 10d10 as a chiral building block. It is of importance to provide a promising
method for the construction of chiral benzylic quaternary carbon centers, which often occur in
biologically intriguing terpenes and alkaloids.11 We envisaged that acid-promoted reaction of epoxy
alcohol 11, available from 10, would allow us to access compound 12 having a benzylic quaternary
carbon center as depicted in Scheme 3. Based on literature precedents,12 it was anticipated that this
rearrangement would take place stereoselectively with inversion of configuration of the quaternary center.
OH
OH
HO
CHO
O
HO
R
R
R
12
11
10
(–)-sporochnol A (13)
Scheme 3
According to the procedure we established previously,13 dienol 10d was subjected to VO(acac)2-catalyzed
epoxidation to give epoxide 14 as a single diastereomer in almost quantitative yield. When epoxide 14
(90% ee) was treated with PPTS (0.1 equiv) in CH2Cl2 at room temperature followed by methoxymethyl
chloride in the presence of Hünig’s base in the same flask, the desired product 15 was obtained in 50%
yield together with α,β-unsaturated aldehyde 16 (10% yield). However, the enantiomeric purity was
eroded to 80% ee from 90% ee (the enantiomeric purity of the starting epoxide 14), indicating that some
racemization took place during the transformation of 14 to 15. After considerable experimentation, we
eventually found conditions where the rearranged product could be obtained without racemization. Thus,
upon exposure of 14 to acetalization conditions8 using 1,2-di(trimethylsilyloxy)ethane and trimethyl
triflate in CH2Cl2 at –40 °C, acetal 1714 of 88% ee was produced in 65% yield. Acetal 17 was then
converted to ester 20 via 18 and 19 by a four-step sequence involving Dess-Martin oxidation,
18
Wolff-Kishner reduction, acidic hydrolysis, and Horner-Emmons olefination. The specific rotation, [α]D
+17.6 (c 1.00) [lit.7c [α]D20 +19.6 (c 1.00)], and spectral data of 20 thus obtained was identical with those
reported for the precursor of (–)-sporochnol A (13) by Fadel and Vandromme7c so that the formal
synthesis of 13 was accomplished. At this stage, it was unambiguously proved that the above-mentioned
rearrangement of 14 occurred with inversion of configuration of the quaternary center.

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HETEROCYCLES, Vol. 77, No. 1, 2009
In conclusion, the present work provides a highly enantioselective method for the preparation of
aryl(1,3-butadien-2-yl)methanols and demonstrates an effective methodology for the construction of a
chiral benzylic quaternary carbon center.
OH
OH
PPTS (10 mol %)
CH2Cl2
VO(acac)2 (16 mol %)
t-BuOOH (4 equiv)
O
4A molecular sieves
CH2Cl2, –30 °C
then
MeO
MeO
MOMCl, i-Pr2EtN
10d
14
96%
90% ee
CHO
MOMO
CHO
+
HO
HO
15 (50%)
80% ee
16 (10%)
Dess-Martin
periodinane
HO
OHC
NH2NH2·H2O
TMSO
OTMS
O
O
14
CH2Cl2
90%
triethyle glycol
120 °C
TMSOTf (1 equiv)
CH2Cl2, –40 °C
O
O
MeO
MeO
18
17
88% ee
80%
65%
1) 5% HCl, THF
ref. 7c
CO2Et
O
O
(–)-sporochnol A (13)
2) (EtO)2P(O)CH2CO2Et
n-BuLi, THF, –78 °C
MeO
MeO
19
20
89%
Scheme 4
ACKNOWLEDGEMENTS
We are grateful to Professor Meiming Luo (Sichuan University) for his contribution as a postdoctoral
fellowship of the Japan Promotion of Science in the early stage of this work.
REFERENCES (AND NOTES)
1. S. Hatakeyama, K. Sugawara, M. Kawamura, and S. Takano, Tetrahedron Lett., 1991, 32, 4509.
2. For other enantioselective approaches to dienols 5, see: a) R. Soundararajan, G. Li, and H. C. Brown,
J. Org. Chem., 1996, 61, 100. b) C.-M. Yu, S.-J. Lee, and M. Jeon, J. Chem. Soc., Perkin Trans. 1,
1999, 3557. c) J. A. Smulik and S. T. Diver, Org Lett., 2000, 2, 2271.
3. For a review, see: S. Hatakeyama, J. Synth. Org. Chem. Jpn., 1997, 55, 793.
4. M. Luo, Y. Iwabuchi, and S. Hatakeyama, Chem. Commun., 1999, 267.
5. M. Luo, Y. Iwabuchi, and S. Hatakeyama, Synlett, 1999, 1109.

HETEROCYCLES, Vol. 77, No. 1, 2009
253
6. Y.-C. Shen, P. I. Tsai, W. Fenical, and M. E. Hay, Phytochemistry, 1993, 32, 71.
7. For the enantioselective syntheis of sporochnol, see: a) M. Takahashi, Y. Shioura, T. Murakami, and
K. Ogasawara, Tetrahedron: Asymmetry, 1997, 8, 1235. b) T. Kamikubo, M. Shimizu, and K.
Ogasawara, Enantiomer, 1997, 2, 297. c) A. Fadel and L. Vandromme, Tetrahedron: Asymmetry,
1999, 10, 1153. d) C. A. Luchaco-Cullis, H. Mizutani, K. E. Murphy, and A. H. Hoveyda, Angew.
Chem. Int. Ed., 2001, 40, 1456. e) Y. Kita, A. Furukawa, J. Futamura, K. Ueda, Y. Sawama, H.
Hamamoto, and H. Fujioka, J. Org. Chem., 2001, 66, 8779. f) S. Ohira, A. Kuboki, T. Hasegawa, T.
Kikuchi, T. Kutsukake, and M. Nomura, Tetrahedron Lett., 2002, 43, 4641. g) R. Alibés, F. Busqué,
G. G. Bardají, P. de March, M. Figueredo, and J. Font, Tetrahedron: Asymmetry, 2006, 17, 2632.
8. T. Tsunoda, M. Suzuki, and R. Noyori, Tetrahedron Lett., 1980, 21, 1357.
20
1
9. Compound 9d: [α]D −118.8° (c 2.68, CHCl3); FTIR (neat) 3438, 1610, 1510, 1250, 1036 cm−1; H
NMR (300 MHz, CDCl3) δ 7.29 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.26 (dd, J = 11.1,
17.7 Hz, 1H), 5.39 (brd, J = 1.2 Hz, 1H), 5.29 (brs, 1H), 5.23 (dd, J = 1.2, 18.0 Hz, 1H), 5.10 (s, 1H),
5.00 (d, J = 10.5 Hz, 1H), 4.11-4.01 (m, 1H), 3.87-3.70 (m, 1H), 3.79 (s, 3H), 2.55 (d, J = 3.0 Hz,
13
1H), 1.66-1.51 (m, 2H), 1.24 (d, J = 6.3 Hz, 3H), 1.09 (d, J = 6.0 Hz, 3H); C NMR (75 MHz,
CDCl3) δ 159.3, 146.5, 136.1, 132.2, 128.7, 115.4, 114.9, 113.9, 78.1, 70.2, 64.2, 55.2, 44.5, 23.3,
19.1; HRMS calcd for C17H24O3 (M+) 276.1725, found 276.1725.
22
1
10. Compound 10d: [α]D −85.4° (c 0.61, CHCl3); FTIR (neat) 3417, 1610, 1512, 1252, 1034 cm−1; H
NMR (300 MHz, CDCl3) δ 7.31 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.31 (dd, J = 11.4,
18.0 Hz, 1H), 5.44 (s, 1H), 5.44 (d, J = 3.6 Hz, 1H), 5.33 (s, 1H), 5.17 (d, J = 17.6 Hz, 1H), 5.03 (d,
J = 11.1 Hz, 1H), 3.80 (s, 3H), 1.91 (dd, J = 1.7, 3.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 159.3,
147.7, 136.0, 134.3, 128.3, 115.4, 113.9, 73.5, 55.3; HRMS calcd for C12H14O2 (M+) 190.0994, found
190.1004.
11. For reviews, see: a) S. F. Martin, Tetrahedron, 1980, 36, 419. b) K. Fuji, Chem. Rev., 1993, 93,
2037.
12. For reviews, see: a) K. Suzuki, J. Synth. Org. Chem. Jpn., 1988, 46, 365. b) H. Fujioka, Y. Yoshida,
and Y. Kita, J. Synth. Org. Chem. Jpn., 2003, 61, 133.
13. S. Hatakeyama, K. Sugawara, and S. Takano, Tetrahedron Lett., 1991, 32, 4513.
14. Compound 17: [α]D19 −15.8° (c 2.10, CHCl3); FTIR (neat) 3506, 2887, 1601, 1508, 1246, 1028 cm−1;
1H NMR (300 MHz, CDCl3) δ 7.38 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 6.05 (dd, J = 11.1,
18.0 Hz, 1H), 5.42 (dd, J = 1.2, 11.1 Hz, 1H), 5.31 (s, 1H), 5.25 (dd, J = 1.1, 17.9 Hz, 1H), 4.07 (ddd,
J = 6.0, 11.1, 18.3 Hz, 2H), 3.91-1.86 (m, 4H), 3.80 (s, 3H), 2.34 (t, J = 6.3 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 158.4, 138.4, 131.4, 129.6, 117.7, 113.6, 107.2, 65.5, 65.2, 55.2, 53.1; HRMS calcd
for C14H18O4 (M+) 250.1205, found 250.1200.