Enantioselective synthesis of attenols A and B

Article abstract of DOI:10.1021/ol006905z

(Matrix presented) Enantioselective synthesis of attenols A and B was accomplished by using diastereoselective hydroboration, Lindlar reduction, and acid-catalyzed acetal formation.

Full text of DOI:10.1021/ol006905z

ORGANIC
LETTERS
2001
Vol. 3, No. 4
527-529
Enantioselective Synthesis of Attenols A
and B
Kiyotake Suenaga,* Keisuke Araki, Tetsuya Sengoku, and Daisuke Uemura
Department of Chemistry, Graduate School of Science, Nagoya UniVersity, Chikusa,
Nagoya 464-8602, Japan
uemura@chem3.chem.nagoya-u.ac.jp
Received November 21, 2000
ABSTRACT
Enantioselective synthesis of attenols A and B was accomplished by using diastereoselective hydroboration, Lindlar reduction, and acid-
catalyzed acetal formation.
Attenols A (1) and B (2) are novel ethereal compounds that
were isolated from the Chinese bivalve Pinna attenuata.1
Attenols A (1) and B (2) exhibit cytotoxicity against P388
cells with IC50 values of 24 and 12 µg/mL, respectively.
However, their natural scarcity has prevented further biologi-
cal studies. In this Letter, we report the synthesis of attenols
A (1) and B (2).
sizing attenols A and B. Since acid treatment of attenols A
(1) gave a mixture of 1 and 2 (3:1), 1 and 2 were synthesized
simultaneously by the acetal ring formation of ketone 3 in
Scheme 1. Retrosynthesis of Attenols A and B
The main structural features of 1 are a spiro acetal ring,
three contiguous stereocenters, and cis-disubstituted and
terminal olefins. Scheme 1 outlines our strategy for synthe-
10.1021/ol006905z CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/26/2001

diastereomeric mixture of secondary alcohols (78% in two
steps), which was oxidized to methyl ketone 9 (96%). Wittig
reaction of 9 with the phosphorus ylide derived from methyl
triphenylphosphonium bromide and n-butyllithium afforded
olefin 10 in 95% yield. Diastereoselective hydroboration of
10 with 9-BBN followed by oxidation with H2O2 provided
alcohol 11 (99%, R/â ) 8/1). The minor â-isomer could
be separated by chromatography at a later stage in the
synthesis. The stereochemistry of the C8 methyl group was
determined to be R on the basis of coupling constants and
NOE experiments for the derived acetonide 18 (Figure 1).
Scheme 2. Synthesis of Right-Hand Segmenta
Figure 1. Observed NOE (arrow) and coupling constants (dashed
line, in Hz) of 18.
The stereoselectivity of hydroboration can be explained
by the idea that 9-BBN approached less-hindered side of
olefin 10, which adopted the conformation shown in Figure
2 to minimize allylic strain.5 Oxidation of alcohol 11 with
a (a) TBSCl, NaH, DME, 0 °C f rt; (b) (COCl)2, DMSO,
CH2Cl2, -78 °C, then Et3N, -78 f 0 °C; (c) MeLi, CuI, Et2O,
-78 f 0 °C; (d) (COCl)2, DMSO, Et3N, -78 f 0 °C; (e)
Ph3PCH3Br, BuLi, -40 f 0 °C; (f) 9-BBN, THF, 0 °C f rt, then
H2O2, NaOAc aq; (g) Dess-Martin periodinane, CH2Cl2, rt; (h)
(EtO)2P(O)CH2COOEt, t-BuOK, THF, -78 f 0 °C; (i) H2, 5%
Rh-Al2O3, EtOAc, rt; (j) DIBAL, CH2Cl2, -78 °C; (k) NaBH4,
EtOH, 0 °C, (l) MPMCl, NaH, DMF, -20 °C; (m) Bu4NF, THF,
rt; (n) Tf2O, 2,6-di-tert-butyl-4-methylpyridine, CH2Cl2, -20 °C;
(o) 4-tert-butyldimethylsilyloxy-1-butyne, BuLi, HMPA, THF, -78
°C, then triflate, -35 °C f rt; (p) H2, Lindlar catalyst, MeOH, rt;
(q) DDQ, CH2Cl2-t-BuOH-phosphate buffer (pH 6); (r) Dess-
Martin periodinane, CH2Cl2, rt.
Figure 2.
Dess-Martin periodinane6 gave aldehyde (80%), the Hor-
ner-Emmons reaction of which with (EtO)2P(O)CH2COOEt
and t-BuOK afforded conjugated ester 12 (84%). Hydroge-
nation of 12 gave ester 13 (87%), a minor diastereomer
concerning C8 of which was separated by chromatography.
Reduction of 13 with DIBAL and then NaBH4 afforded
alcohol 14 (90% in two steps).7 Protection of the hydroxyl
group in 14 as a p-methoxybenzyl ether group (82%)
followed by desilylation with Bu4NF gave alcohol 6 (99%).
Alcohol 6 was converted into triflate, the coupling reaction
of which with 4-tert-butyldimethylsilyloxy-1-butyne gave
acetylene 15 (82% in two steps).8 Although we attempted
the coupling reaction of iodide prepared from 6, acetylene
15 was obtained in low yield (<10%). Lindlar reduction of
15 afforded cis-olefin 16 quantitatively, the MPM group of
which was removed with 2,3-dichloro-5,6-dicyano-p-ben-
zoquinone (DDQ) to give alcohol 17 (96%). Oxidation of
the final step. Ketone 3 was constructed by a Julia coupling
reaction2 between 4 and 5. The cis-disubstituted olefin was
introduced by Lindlar reduction of the disubstituted acety-
lene, which was prepared from alcohol 6 and 4-tert-
butyldimethylsilyloxy-1-butyne (7).3
Synthesis of the right-hand segment 5 began with monosi-
lylation of 2,3-O-isopropylidene-D-threitol to give silyl ether
(97%) (Scheme 2), Swern oxidation4 of which afforded
aldehyde 8. Addition of Me2CuLi to aldehyde 8 gave a
(1) Takada, N.; Suenaga, K.; Yamada, K.; Zheng, S.-Z.; Chen, H.-S.;
Uemura, D. Chem. Lett. 1999, 1025-1026.
(2) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 4833-4836.
(3) Posner, G. H.; Weitzberg, M.; Hamill, T. G.; Asirvatham, E.; He,
C.-H.; Clardy, J. Tetrahedron 1986, 42, 2919-2929.
(4) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660.
528
Org. Lett., Vol. 3, No. 4, 2001

17 with Dess-Martin periodinane provided the right-hand
segment 5 (99%).
Synthesis of the left-hand segment 4 began with alkylation
of dithiane with 5-bromo-1-pentene to afford olefin 19 (98%)
(Scheme 3). Further alkylation of 19 with (R)-benzylglycidyl
The Julia coupling reaction between right-hand segment
5 and the carbanion generated from left-hand segment 4 gave
a diastereomeric mixture of hydroxyl sulfones, which was
oxidized and subsequently reduced with sodium amalgam
to afford ketone 3 (Scheme 4, 89% in three steps). Finally,
Scheme 4. Synthesis of Attenols A and Ba
Scheme 3. Synthesis of Left-Hand Segmenta
a (a) 4, BuLi, THF, -78 °C, then 5, -78 °C; (b) Dess-Martin
periodinane, pyridine, CH2Cl2, rt; (c) 5% Na-Hg, Na2HPO4,
MeOH, 0 °C; (d) PPTS, MeOH, rt.
removal of the protecting groups and acetal formation with
PPTS in methanol at room temperature gave attenols A (1,
65%) and B (2, 17%). Synthetic attenols A (1) and B (2)
were identical to natural 1 and 2 in all respects including
1
spectroscopic data (IR, H and 13C NMR, MS, RD).
In conclusion, enantioselective synthesis of attenols A and
B was carried out in good yield. The overall yields of attenols
A and B were 13% and 3.4%, respectively, in 22 steps.
Further biological studies on attenols are currently in
progress.
a (a) i. BuLi, ii. 5-bromo-1-pentene, THF, -78 °C f rt; (b) i.
BuLi, ii. (R)-benzylglycidyl ether, THF, -78 °C f rt; (c) CuCl2,
CuO, acetone-H2O, rt; (d) Me4NHB(OAc)3, MeCN-AcOH, -40
f -30 °C; (e) Me2C(OMe)2, CSA, acetone, rt; (f) Na, liquid NH3-
THF, -78 °C; (g) p-TsCl, pyridine, 0 °C; (h) MeSO2Ph, BuLi,
THF, reflux.
Acknowledgment. This work was supported in part by
Wako Pure Chemical Industries Ltd., by Banyu Pharmaceu-
tical Co., Ltd., and by Grants-in-Aid (11558079 and 12045235)
for Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan.
ether provided alcohol (80%), the dithian group of which
was hydrolyzed9 to give hydroxy ketone 20 (86%). Stereo-
selective reduction of hydroxy ketone 20 with tetramethy-
lammonium triacetoxyborohydride10 afforded anti-diol 21
(88%) along with syn-diol (10%). Two hydroxyl groups of
21 were protected as an acetonide (100%), the benzyl
protecting group of which was removed with sodium in liquid
ammonia to furnish alcohol 22 (99%). Alcohol 22 was
converted into a tosylate, the reaction of which with the
carbanion of methyl phenyl sulfone gave the left-hand
segment 4 (86% in two steps).
Supporting Information Available: Experimental pro-
1
cedure for compounds 11, 15, 1, and 2 and H NMR data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL006905Z
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