Synthesis of norsesterterpene rac- and ent-rhopaloic acid A

Article abstract of DOI:10.1039/a704563h

The stereoselective synthesis of rac- and ent-rhopaloic acid A 1 has been accomplished, via successive homologation of (2E,6E)-farnesol 2 and cyclization to form a tetrahydropyran ring, together with final introduction of an α-methylene group; the asymmet

Full text of DOI:10.1039/a704563h

View Article Online / Journal Homepage / Table of Contents for this issue
Synthesis of norsesterterpene rac- and ent-rhopaloic acid A
Ryukichi Takagi, Asami Sasaoka, Satoshi Kojima and Katsuo Ohkata*
Department of Chemistry, Faculty of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739, Japan
The stereoselective synthesis of rac- and ent-rhopaloic acid
i–iii
A 1 has been accomplished, via successive homologation of
OH
R
CO2Me
3
(2E,6E)-farnesol
2 and cyclization to form a tetra-
2
5
hydropyran ring, together with final introduction of an
iv–vii
a-methylene group; the asymmetric synthesis was achieved
viii
via
an
Evans’
asymmetric
alkylation
using
CO2Me
ix
CO2H
R
R
R
(S)-4-benzyloxazolidin-2-one as a chiral auxiliary; the syn-
thetic rhopaloic acid A, with a predicted absolute configura-
tion of (2S,5R), had a specific rotation of opposite sign to
that of the natural product, and therefore the configuration
of natural rhopaloic acid A should be assigned as (2R,5S).
4
x, xi
R
CH2OR
CO2Me
7 R = H
8 R = ButMe2Si
6
(+)-Rhopaloic acid A (+)-1, a potent cytotoxic agent, was
isolated from the marine sponge Rhopaloeides sp.1 The
interesting biological activity of the compound may be
attributed to the structurally unique feature of having a
hydrophilic pyranylacrylic acid moiety connected to a hydro-
phobic isoprenoid part.2 The acrylic acid moiety is also found in
compounds such as conconadine3a and gerin,3b and the related
2-methylene-g-lactone group is found in many bioactive natural
products. The potential of (+)-1 and its analogues as biological
probes provided the incentive for this synthetic undertaking.
Here the total syntheis of racemic rhopaloic acid A rac-1 and the
nonnatural enantiomer ent-rhopaloic acid A (2)-ent-1 is
described.
xii
CHO
xiii
R
R
OH
CH2OSiMe2But
CH2OSiMe2But
10
9
R =
Scheme 1 Reagents and conditions: i, PPh3 (1.2 equiv.), CBr4 (1.3 equiv.),
CH2Cl2, 0 °C, 3 h; ii, NaH (1 equiv.), CH2(CO2Me)2 (5 equiv.), DMF,
0–25 °C, overnight, 80% over two steps; iii, NaCl (2 equiv.), H2O (2 equiv.),
DMF, reflux, 20 h, 87%; iv, LiAlH4 (1.3 equiv.), THF, 0 °C, 1 h, 96%; v,
Ph3P (1.2 equiv.), CBr4 (1.5 equiv.), CH2Cl2, 0 °C, 1 h, 86%; vi, NaCN (2.5
equiv.), DMF, 25 °C, 1 h, 99%; vii, KOH (10 equiv.), H2O, EtOH, reflux,
30 h, 78%; viii, MeI (2 equiv.), K2CO3 (2 equiv.), 25 °C, 3 h, 98%; ix, LDA
(1.1 equiv.), THF, 278 °C, 30 min, then allyl bromide (4 equiv.), 278 to
25 °C, overnight, 83%; x, LiAlH4 (1.5 equiv.), THF, 0 °C, 3 h, 88%; xi,
ButMe2SiCl (1.1 equiv.), imidazole (2 equiv.), DMF, 3 h, 87%; xii, 9-BBN
(1.5 equiv.), THF, 0 to 25 °C, overnight, then aq. NaOH (4 equiv.), 30% aq.
H2O2 (4 equiv.), overnight, 79%; xiii, DMSO (2 equiv.), (COCl)2 (1.1
equiv.), Et3N (5 equiv.), CH2Cl2, 260 °C, 5 h, 80%
H
5S
O
11′
7′
3′
2R
CO2H
H
(+)-1
Our synthetic strategy consists of successive homologations
of (2E,6E)-farnesol 2 and cyclization to form a tetrahydropyran
ring, together with the final introduction of an a-methylene
group.
The two-carbon homologation exploited malonic esterifica-
tion starting from (2E,6E)-farnesol 2 (Scheme 1). Treatment of
farnesol with PPh3–CBr4 at 0 °C afforded farnesyl bromide.4
The bromide contained less than 5% of the (2Z,6E)-isomer and
was used for the following reaction without further purification.
Treatment of the bromide with dimethyl malonate (5 equiv.) in
the presence of NaH (1 equiv.) gave the dimethyl ester in 80%
yield.5 Demethoxycarbonylation of the dimethyl ester under
neutral conditions (NaCl in moist DMF) afforded monomethyl
ester 3 in 87% yield. Reduction of 3 with LiAlH4 afforded the
alcohol in quantitative yield. Treatment of the alcohol with
Ph3P–CBr4 gave the bromide in 86% yield. Cyanation of the
bromide with NaCN in DMF afforded the nitrile in quantitative
yield. Hydrolysis of the nitrile under basic conditions afforded
carboxylic acid 4 and esterification of 4 with MeI–K2CO36 gave
methyl ester 5 in 76% yield over two steps.
furnished 11 with only Z geometry in 57% yield as a single
isomer (Scheme 2).8† Exposure of 11 to methylation reagent
MeI–AgBF4 followed by desilylation with Bu4NF afforded
ethyl pyranylacrylate derivative 12 in 32% yield as the trans
isomer.9‡ The ester 12 contained less than 10% of the cis
isomer. Hydrolysis of 12 with aq. KOH afforded rac-1 with
CO2Et
CHO
i
R
R
CH2SPri
CH2OSiMe2But
CH2OSiMe2But
10
11
ii
O
O
CO2H
CO2Et
iii
Treatment of 5 with LDA followed by allyl bromide gave
allylated methyl ester 6 in 83% yield. Reduction of 6 with
LiAlH4 afforded alcohol 7 in 88% yield. Protection of 7 with
tert-butyldimethylsilyl chloride followed by hydroboration–
oxidation with 9-BBN–H2O2 gave primary alcohol 9 (79%).
Swern oxidation of 9 afforded aldehyde 10 (80%).
R
R
rac-1
12
Scheme 2 Reagents and conditions: i, NaH (1 equiv.), Me2CHSH (1 equiv.),
(EtO)2P(O)C(NCH2)CO2Et (1 equiv.), THF, 0 °C, 10 min, then 10, 25 °C,
overnight, 57% (Z isomer only); ii, MeI (3 equiv.), AgBF4 (1 equiv.),
CH2Cl2, 2 h, then Bu4NF (3 equiv.), THF, 16 h, 32%; iii, aq. KOH (excess),
reflux, 14 h, 34%
The modified Wittig–Horner–Emmons reaction of 10 with
(EtO)2P(O)C(NCH2)CO2Et in the presence of NaSCHMe2
Chem. Commun., 1997
1887

View Article Online
In order to investigate the structure–bioactivity relationship
of 1 and other biomechanistic problems, an alternative synthesis
of 1 and related compounds is now progress.11
Spectra of an authentic sample were kindly provided by Dr S.
Ohta (Hiroshima University). The authors thank Shiono Koryo
Kaisha, Ltd. and Kurare Co. for the gift of farnesol. NMR and
mass spectra and optical rotations were measured at the
Instrument Center for Chemical Analysis, Hiroshima Uni-
versity.
(2E,6E)-farnesol
4
2
i
Li+
O–
O
O
O
ii
R
N
O
R
N
O
Bn
O
Bn
5*
Footnotes and References
O
* E-mail: ohkata@sci.hiroshima-u.ac.jp
iii
R
R
N
O
† The product ratio changed with the reaction conditions. Only the Z isomer,
the thermodynamically stable product, was obtained when the reaction
mixture was stirred overnight at 25 °C. A ratio of Z:E = 2.4:1.0 was
obtained when the reaction mixture was stirred at 0 °C for 3 h. The relative
configuration of the product was determined with difference NOE
experiments: when 3-H of the E isomer was irradiated, the intensity of the
2-CH2S signal was enhanced by 8.2%.
‡ For 12, the assigned relative stereochemistry was confirmed by intensity
enhancement of 2-H by 10.9% upon irradiation of 6-Hax. The assignment of
6-Hax was determined by measurement of coupling constants: J5,6-ax = 11.2
Hz, J5,6-eq = 3.9 Hz.
R
CH2OH
Bn
7*
6*
CO2Et
CHO
iv
R
R
CH2SPri
CH2OSiMe2But
CH2OSiMe2But
11*
10*
§ The relative stereochemistry of rac-1 was assigned using the same
considerations as for 12 (J5,6-ax = 11.2 Hz, J5,6-eq = 3.9 Hz); when 6-Hax
was irradiated, an intensity enhancement of 2-H by 6.9% was observed.
¶ The diastereoselectivity of the allylation was evaluated by conversion of
the optical active alcohol 7* into its benzoate ester, followed by analysis
with a DAICEL CHIRALCEL-OD column (hexane–AcOEt 400:1).
v
CO2Et
CO2H
O
H
H
2S
O
vi
5R
R
R
H
H
25
∑ Selected data for (2S,5R)-1: colourless oil; [a]D 238 (c 0.315, CHCl3);
12*
(–)-ent-1
dH (270 MHz, CDCl3) 1.1–1.3 (m, 4 H, 1A-H, 3-Hax, 4-Hax), 1.3–1.6 (m, 1
H, 5-Hax), 1.60 (s, 9 H, vinyl-Me), 1.68 (s, 3 H, vinyl-Me), 1.9–2.1 (m, 12
H, 3-Heq, 4-Heq, 2A-H, 5A-H, 6A-H, 9A-H, 10A-H), 3.18 (t, J 11, 1 H, 6-Hax),
4.07 (ddd, J 12, 4, 2, 1 H, 6-Haq), 4.12 (d, J 12, 1 H, 2-H), 5.89 (s, 1 H,
a-methylene), 6.36 (br s, 1 H, a-methylene); dC (125 MHz, CDCl3) 16.0,
17.7, 24.9, 25.7, 26.6, 26.8, 30.2, 31.8, 32.4, 35.2, 39.7, 74.0, 76.4, 124.0,
124.2, 124.4, 126.7, 131.3, 135.0, 135.5, 140.7, 168.6; nmax(neat)/cm21
3500–3000, 2900, 2850, 1680, 1620, 1430, 1370, 1280, 1160, 1140, 1080,
950, 830; Calc. for C24H38O3 374.2821. Found: 374.2830.
Scheme 3 Reagents and conditions: i, Et3N (1.2 equiv.), pivaloyl chloride
(1.2 equiv.), THF, then N-lithiooxazolidin-2-one, THF, 278 °C, 15 h, 66%;
ii, LDA (1.1 equiv.), THF, 278 °C, 30 min, then allyl bromide (4 equiv.),
220 to 210 °C, 6 h, 44%; iii, LiAlH4 (3 equiv.), THF, 0 °C, 15 h, 92% iv,
NaH (1 equiv.), Me2CHSH (1 equiv.), (EtO)2P(O)(NCH2)CO2Et, THF,
0 °C, 10 min, then 10*, 25 °C, 28 h, 46% (Z isomer only); v, MeI (3 equiv.),
AgBF4 (1 equiv.), CH2Cl2, 5 h then Bu4NF (3 equiv.), THF, 25 °C, 13 h,
35%; vi, aq. KOH (excess), reflux, 18 h, 56%
1 S. Ohta, M. Uno, M. Yoshimura, Y. Hiraga and S. Ikegami, Tetrahedron
Lett., 1996, 37, 2265.
retained stereochemistry in 34% yield.§ The 1H and 13C NMR
and mass spectra of the carboxylic acid rac-1 and the ethyl ester
12 were identical with those recorded for authentic samples of
(+)-rhopaloic acid A (+)-1 and its ethyl ester derivative,
respectively.
2 R. L. Letsinger, S. K. Chaturvedi, F. Farooqui and M. Salunkhe, J. Am.
Chem. Soc., 1993, 115, 7535; W. Ding and G. A. Ellestad, J. Am. Chem.
Soc., 1991, 113, 6617; U. S. Singh, R. T. Scannell, H. Au, B. J. Carter
and S. M. Hecht, J. Am. Chem. Soc., 1995, 117, 12691; S. B. Singh,
D. L. Zink, J. M. Liesch, M. A. Goetz, R. G. Jenkins, M. Nallin-
Omstead, K. C. Silverman, G. F. Bills, R. T. Mosley, J. B. Gibbs, G.
Albers-Schonberg and R. B. Lingham, Tetrahedron, 1993, 49, 5917.
Asymmetric synthesis of ent-rhopaloic acid A was carried out
by way of the Evans’ asymmetric alkylation as shown in
Scheme 3. The auxiliary moiety, (S)-4-benzyloxazolidin-2-one,
was introduced into 4 (66%) to give 5*. The lithium enolate of
5* was treated with allyl bromide at 220 to 210 °C to give 6*
as the pure diastereoisomer (44% yield, 99% de).7,10¶ Con-
sideration of the chelation model of the enolate intermediate
predicted the stereochemistry at the C2 position of 6* to be
2R.10 Following removal of the chiral auxiliary by LiAlH4
reduction (92%) and protection (79%) of the alcohol 7* with a
tert-butyldimethylsilyl group, silyl ether 8* was subjected to
regioselective hydroboration with 9-BBN followed by oxida-
tion with H2O2 to give 9* (68%). Swern oxidation of 9* gave
10* in 80% yield. The modified Wittig–Horner–Emmons
reaction of 10* afforded a,b-unsaturated ester 11* (46%),
which was cyclized into 12* (35%). Hydrolysis of 12* gave the
optically pure (2S,5R)-ent-1∑ in 9% overall yield from 10*. The
3
J. M. Muller, H. Fuhrer and J. Gruner, Helv. Chim. Acta, 1976, 2506;
E. Rodriguez, B. Sanchez, P. A. Grieco, G. Majetich and T. Oguri,
Phytochemistry, 1979, 18, 1741.
4 J. P. Schaefer and J. Higgins, J. Org. Chem., 1967, 32, 1607.
5 M. J. Kates and J. H. Schauble, J. Org. Chem., 1996, 61, 4164.
6 Y. Harada, M. Shibata, T. Sugiura, S. Kato and T. Shioiri, J. Org.
Chem., 1987, 52, 1252.
7 W. He, E. Pinard and L. A. Paquette, Helv. Chim. Acta, 1995, 78,
391.
8 M. F. Semmelhack, J. C. Tomesch, M. Czany and S. Boettger, J. Org.
Chem., 1978, 43, 1259; M. F. Semmelhack, A. Yamashita, J. C.
Tomesch and K. Hirotsu, J. Am. Chem. Soc., 1978, 100, 5565.
9 N. D. Smith, P. J. Kocienski and S. D. A. Street, Synthesis, 1996, 652;
A. T. F. Edmunds and W. Trueb, Tetrahedron Lett., 1997, 38, 1009.
10 D. A. Evans, T. C. Briton, J. A. Ellman and R. L. Dorow, J. Am. Chem.
Soc., 1990, 112, 4011; P. P. Waid, G. A. Flynn, E. W. Huber and J. S.
Saabol, Tetrahedron Lett., 1996, 37, 4091.
25
specific rotation of ent-1 was [a]D 237.6 (c 0.315, CHCl3),
11 M. Tokumasu, A. Sasaoka, R. Takagi, Y. Hiraga and K. Ohkata, Chem.
Commun., 1997, 875.
which was of opposite sign to that of the natural product (+)-1.
Therefore, it is presumed that the configuration of natural
rhopaloic acid A {[a]D25 + 40 (c 0.47, CHCl3)}1 is 2R,5S.
Received in Cambridge, UK, 30th June 1997; 7/04563H
1888
Chem. Commun., 1997