Asymmetric Total Synthesis of Attenol A and B

Article abstract of DOI:10.1055/s-2003-42071

The asymmetric total synthesis of attenol A (1) and B (2), which possess challenging structures and an interesting biological activity, was accomplished in a convergent and highly stereo-selective manner (de, ee ≥ 96%) with good overall yield. The short total synthesis is based on asymmetric alkylations of SAMP-hydrazones as well as a Sharpless asymmetric dihydroxylation as key steps.

Full text of DOI:10.1055/s-2003-42071

LETTER
2185
Asymmetric Total Synthesis of Attenol A and B
Asymmetric
Total
i
Synthe
e
sis of
A
tten
t
ol
A
a
e
Institut für Organische Chemie, Rheinisch Westfälische Technische Hochschule, Professor-Pirlet-Strasse 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 25 August 2003
from 2,2-dimethyl-1,3-dioxan-5-one SAMP-hydrazone
Abstract: The asymmetric total synthesis of attenol A (1) and B
(6).6 Successive alkylation of 6 with (2-bromoethoxy)-
(2), which possess challenging structures and an interesting biolog-
ical activity, was accomplished in a convergent and highly stereo-
selective manner (de, ee ≥ 96%) with good overall yield. The short
tert-butyldimethylsilane7 and 5-bromopent-1-ene gener-
ated the bisalkylated SAMP-hydrazone 8 with de ≥ 96%.
total synthesis is based on asymmetric alkylations of SAMP-hydra- Oxalic acid hydrazone cleavage gave 4 in 75% yield over
three steps and de, ee ≥ 96%.8,9
zones as well as a Sharpless asymmetric dihydroxylation as key
steps.
21
Key words: asymmetric dihydroxylation, dithianes, natural prod-
ucts, SAMP-hydrazone methodology, total synthesis
HO
O
1
Both attenol A (1) and attenol B (2, Scheme 1) are marine
natural products, which were isolated in 1999 from the
Chinese bivalve Pinna attenuata by Uemura and co-
workers.1 They are isomeric triols differing from each
other only by which hydroxyl groups are involved in the
ketal formation. This results in a 1,6-dioxa-spiro[4.5]de-
cane and a 6,8-dioxabicyclo[3.2.1]octane unit as the main
structural feature of attenol A and B, respectively. In pre-
liminary biological studies both compounds exhibited
moderate cytotoxicity against P388 cells (1: IC50 = 24 mg
mL–1; 2: IC50 = 12 mg mL–1).1 Due to their interesting bio-
logical activity and their natural scarcity, these marine
natural products have attracted considerable interest as
synthetic targets. Uemura, Suenaga et al.2a,b successfully
carried out the first total synthesis of attenol A and B fol-
lowed by Eustache, Van de Weghe et al.2c (attenol A). We
now wish to report the results of our approach leading
to a very efficient, asymmetric total synthesis of attenol
A and B, which augurs well for the future synthesis of
stereoisomers and derivatives of these compounds for
further biological studies.
O
OH
11
21
OH
1 (attenol A)
11
O
O
OH
OH
OH
1
2 (attenol B)
O
S
S
O
OTBS
O
O
3
O
O
OTBS
PMBO
+
OEt
O
O
5
4
As depicted in Scheme 1, our synthesis focused on the
generation of dithiane 3,3 which - after thioketal cleavage
and acid-catalyzed ketalization – would lead to both at-
tenol A and B.4 The anti-2,2-dimethyl-1,3-dioxan-5-one 4
and the a,b-unsaturated ester 5 were thought to be appro-
priate precursors for electrophiles required in the con-
struction of 3. It would be effective to synthesize 4 and 5
by means of asymmetric alkylation using the SAMP-hy-
drazone methodology (6 and 7, respectively), as all three
stereocenters would be generated by using a single com-
mercially available chiral auxiliary.5
OCH3
H3CO
N
O
PMBO
N
N
N
7
O
6
Scheme 1 Retrosynthetic analysis of attenol A and B.
Following the observations of Barton and McCombie10
and in addition to the knowledge acquired in our group,11
it was assumed that the most efficient way to remove the
keto group of anti-2,2-dimethyl-1,3-dioxan-5-one (4)
would be via a sequence of reduction and radical deoxy-
genation. Therefore xanthate 9 was synthesized (96%
yield over two steps, de = 23%).12
As outlined in Scheme 1 and Scheme 2, our synthesis of
the anti-2,2-dimethyl-1,3-dioxane fragment of 3 started
SYNLETT 2003, No. 14, pp 2185–2187
0
6
.1
1
.2
0
0
3
Advanced online publication: 07.10.2003
DOI: 10.1055/s-2003-42071; Art ID: G21803ST
© Georg Thieme Verlag Stuttgart · New York

2186
D. Enders, A. Lenzen
LETTER
OCH3
OCH3
N
N
N
O
N
a
PMBO
PMBO
PMBO
N
N
OCH3
a, b
OTBS
O
12
7
O
O
O
b
OCH3
6
8
O
c, d
c
PMBO
N
N
S
OEt
O
SCH3
OTBS
O
5
13
OTBS
d, e
e
O
O
O
O
OH
O
O
O
9
4
f
O
PMBO
PMBO
OEt
f, g
OH
OEt
14
15
OH
I
g, h
h
O
O
O
O
O
O
11
10
i
O
O
PMBO
PMBO
(de, ee ≥ 96%)
OTf
Scheme 2 Reagents and conditions: (a) t-BuLi, THF, –78 °C, then
(2-bromoethoxy)-tert-butyldimethylsilane, –100 °C → 25 °C; (b) t-
BuLi, THF, –78 °C, then 5-bromopent-1-ene, –100 °C → 25 °C;
(c) sat. oxalic acid, Et2O, 25 °C, 75% over three steps; (d) NaBH4,
MeOH, 0 °C; (e) NaH, THF, CS2, MeI, 0 °C → 25 °C, 96% over two
steps; (f) Bu3SnH, AIBN (cat.), toluene, reflux; (g) TBAF, THF,
25 °C, 91% over two steps; (h) PPh3, imidazole, I2, Et2O/CH3CN,
0 °C, 94%.
17
16
j, k, l
O
OTBS
OTBS
O
I
18
(de, ee ≥ 98%)
The radical reduction using Bu3SnH and a catalytic
amount of AIBN in refluxing toluene and subsequent
cleavage of the TBS ether yielded alcohol 10 (91% yield
over two steps).13 Iodination of this alcohol gave iodide 11
(94%), the first of the two electrophiles which had to be
coupled by the Corey–Seebach reaction.
Scheme 3 Reagents and conditions: (a) SAMP, Et2O, 0 °C to 25 °C,
95%; (b) LDA, THF, 0 °C, then MeI, –120 °C to 25 °C, 86%; (c) O3,
CH2Cl2, –78 °C; (d) Ph3PCHCO2Et, CH2Cl2, 25 °C, 71% over two
steps; (e) AD-mix b, MeSO2NH2, t-BuOH:H2O = 1:1, 0 °C, 96%;
(f) 2,2-DMP, PTSA (cat.), 25 °C, 94%; (g) LAH, Et2O, 0 °C, 95%;
(h) Tf2O, 2,6-di-tert-butyl-4-methylpyridine, CH2Cl2, –40 °C to
–30 °C; (i) tert-butylbut-3-ynyloxydimethylsilane, t-BuLi, THF,
DMPU, –78 °C, then 16, –78 °C to 25 °C, 89% over two steps; (j) H2,
Lindlar catalyst, MeOH, 25 °C, 94%; (k) DDQ, CH2Cl2, 25 °C, 99%;
(l) PPh3, imidazole, I2, Et2O/CH3CN, 0 °C, 83%.
As shown in Scheme 3, the synthesis of the second elec-
trophile 18 started from 4-(4-methoxybenzyloxy)-bu-
tyraldehyde (12).14 Condensation with SAMP, resulting in
the corresponding hydrazone 7 (95%), followed by alky-
lation with MeI yielded 13 in 86% yield and de = 96%.15
Ozonolytic cleavage of the hydrazone and Wittig olefina-
tion led to 5 with a small loss of optical purity (71%,
ee = 92%).15 Subsequent Sharpless asymmetric dihydrox-
ylation proceeded smoothly (96%) to give a mixture of
two diastereomers whose de corresponded to the ee of
the unsaturated ester 5.16 After acetonide formation with
p-toluenesulfonic acid in 2,2-dimethoxypropane (94%)
the minor diastereomer could be separated by HPLC
yielding 15 with de, ee ≥ 98%.17,18 The alcohol obtained
after reduction of the ester moiety with lithium aluminum
hydride (95%) was activated as its triflate derivative
16. Displacement with lithiated tert-butylbut-3-ynyl-
oxydimethylsilane19 gave 17 (89% yield over two steps).
Lindlar reduction, followed by the cleavage of the p-
methoxybenzyl ether with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone and iodination of the generated alcohol
afforded 18 (77% yield over three steps).
With both electrophiles 11 and 18 in hand, the synthesis
of both attenols was accomplished as shown in Scheme 4.
The alkylation of dithiane 19 with 11 proceeded cleanly in
96% yield. The second alkylation using 18 yielded 3
(84%). Copper mediated hydrolysis of this dithiane and p-
toluenesulfonic acid catalyzed ketal formation finally
gave a mixture of the title compounds 1 (57%) and 2 (9%,
each over two steps).20
In summary, we have demonstrated a very efficient and
highly stereoselective synthesis of attenol A and B em-
ploying asymmetric alkylations of SAMP-hydrazones as
well as a Sharpless asymmetric dihydroxylation as key
steps in order to install all the stereocenters apart from C-
11, which was formed in the acid catalyzed cyclization
step. The synthesis proceeded in 15 steps from 12 (longest
linear sequence) and 19% overall yield and is not only the
shortest but also the most efficient synthesis so far.
Synlett 2003, No. 14, 2185–2187 © Thieme Stuttgart · New York

LETTER
Asymmetric Total Synthesis of Attenol A and B
2187
Gatzweiler, W.; Jegelka, U. Synthesis 1991, 1137.
(c) Enders, D.; Jegelka, U. Synlett 1992, 999.
S
S
(7) Vader, J.; Sengers, H.; De Groot, A. Tetrahedron 1989, 45,
2131.
(8) For a review about the cleavage of N,N-dialkylhydrazones
see: Enders, D.; Peters, R.; Wortmann, L. Acc. Chem. Res.
2000, 33, 157.
19
a
S
S
(9) Since the hydrazone cleavage of 8 proceeded without
epimerisation, the ee of the anti-2,2-dimethyl-1,3-dioxan-5-
one 4 is assumed to be at least as high as its de. The absence
of epimerization can be proved on the stage of the anti-2,2-
dimethyl-1,3-dioxane 10, whose 13C NMR resonance is at
d = 100.2 in accordance to Rychnovsky’s criteria. See:
Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem.
1993, 58, 3511.
(10) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574. (b) Hartwig, W. Tetrahedron 1983, 39,
2609. (c) Motherwell, W. B.; Crich, D. Free Radical Chain
Reactions in Organic Synthesis; Academic Press: London,
1992.
O
O
20
b
O
S
S
O
OTBS
O
O
3
c, d
(11) (a) Enders, D.; Hundertmark, T.; Lampe, C.; Jegelka, U.;
Scharfbillig, I. Eur. J. Org. Chem. 1998, 2839. (b) For an
application in natural product synthesis, see: Enders, D.;
Hundertmark, T. Eur. J. Org. Chem. 1999, 751.
(12) Experiments towards higher stereoselectivities in the
reduction step were not conducted since the newly formed
stereogenic center had to be removed afterwards.
(13) A large excess of Bu3SnH was necessary to sufficiently
reduce the occuring side reactions. Under optimized
conditions 10 contained only 3 mol% of an isomerization
product in which the terminal double bond had migrated
between C-19 and C-20 (the numbering refers to the final
natural products).
attenol A (1) + attenol B (2)
(ca. 6.3 : 1)
(de, ee ≥ 96%)
Scheme 4 Reagents and conditions: (a) 19, t-BuLi, THF, DMPU,
–78 °C, then 11, 96%; (b) 20, t-BuLi, THF, HMPA, –78 °C, then 18,
–78 °C to 25 °C, 84%; (c) CuO, CuCl2, aq acetone; (d) PTSA, MeOH,
25 °C, 66% over two steps.
Acknowledgment
(14) Ishikawa, T.; Ikeda, S.; Ibe, M.; Saito, S. Tetrahedron 1998,
54, 5869.
This work was supported by the Deutsche Forschungsgemeinschaft
(Sonderforschungsbereich 380) and by the Fonds der Chemischen
Industrie. We thank the companies Degussa AG, BASF AG and
Bayer AG for the donation of chemicals.
(15) The de of 13 and the ee of 5 were verified by HPLC on chiral
stationary phase. In order to do so, the 1:1-epimeric mixture
of 13 and the racemate of 5 had to be synthesized which was
performed starting from the N,N-dimethyl-hydrazone of 12.
Alkylation with MeI and ozonolysis gave the a-alkylated
racemic aldehyde which was treated with SAMP and
Ph3PCHCO2Et to obtain the desired mixtures of compounds.
(16) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(17) The ee of 15 was verified by HPLC on chiral stationary
phase. For this, ent-15 had to be synthesized analogously to
15 starting from the RAMP-hydrazone ent-7 and performing
the Sharpless asymmetric dihydroxylation of ent-5 with the
AD-mix a.
(18) The reaction sequence leading to 15 was also conducted
starting with 5 of much lower enantiomeric purity (i.e.
ee = 83%). After HPLC, 15 (obtained in lower yield) was
still diastereomerically and enantiomerically pure (de, ee ≥
98%) which indicates the high stereoselectivity of the
Sharpless asymmetric dihydroxylation.
(19) Posner, G. H.; Weitzberg, M.; Hamill, T. G.; Asirvatham, E.;
He, C. H.; Clardy, J. Tetrahedron 1986, 42, 2919.
(20) Our synthetic material was identical in all respects with
physical and spectroscopic data provided for the natural
products. Compound 1: [a]D26 –8.2 (c 0.35, CHCl3) {(ref.2a,
[a]D28 –9.7 (c 0.35, CHCl3) and [a]D28 –8.0 (c 0.38, CHCl3)
for natural 1. Compound 2: [a]D26 37 (c 0.072, CHCl3)
{(ref.2a, [a]D29 34 (c 0.073, CHCl3) and [a]D28 31
(c 0.065, CHCl3) for natural 2}.
References
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H.-S.; Uemura, D. Chem. Lett. 1999, 1025.
(2) (a) Suenaga, K.; Araki, K.; Sengoku, T.; Uemura, D. Org.
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(3) For reviews concerning the chemistry of dithianes, see:
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1989, 89, 1617.
(5) For reviews about the SAMP/RAMP-hydrazone
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(6) Compound 6 is a versatile chiral dihydroxy acetone
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All new compounds gave satisfactory spectral data and
correct elemental analyses.
Synlett 2003, No. 14, 2185–2187 © Thieme Stuttgart · New York