Total synthesis of leucascandrolide A

Article abstract of DOI:10.1002/1521-3773(20021104)41:21<4117::AID-ANIE4117>3.0.CO;2-4

A compound that could never be isolated again despite intensive efforts after it was first found in the sponge Leucascandra caveolata in 1996 is leucascandrolide A (1). An enantioselective, convergent total synthesis of this polyoxygenated marine macrolid

Full text of DOI:10.1002/1521-3773(20021104)41:21<4117::AID-ANIE4117>3.0.CO;2-4

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1atm. The Phe sample was purchased from Aldrich Chemical Company
and used without further purification.
must be removed constantly during the reaction to bias the
equilibrium to the product side. In particular, the direct
condensation between carboxylic acids and alcohols with a
strict 1:1 stoichiometry by use of a simple catalyst system is
very difficult to complete, although activation of the carbox-
ylic acid component with a stoichiometric amount of pro-
moter such as DCC[3] or DEAD[4] is another possible but
uneconomical choice. In this context, graphite bisulfate was
reported to catalyze esterification between equimolar reac-
tants.[5] Later, microwave irradiation coupled with p-toluene-
sulfonic acid catalyst was reported.[6] Recently, a few more
related catalysts have appeared. Although the Soxhlet
technique must be invoked, NaHSO4¥H2O[7] and
HfCl2¥2THF[8] were found to work well as a catalyst. On the
Received: May 15, 2002 [Z19307]
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other hand, Ph2NH2 OTfÀ served for the present purpose
þ
without recourse to any dehydration reagents or apparatus.[9]
The yields of all of these reactions were high (mostly > 85%)
but, unfortunately, not perfectly quantitative, except for two
cases in the HfCl2¥2THF protocol (> 99%). This is somewhat
problematic, not only in view of atom efficiency but also of
practical operation. The 1:1 stoichiometry is truly effective
only if 100% conversion is reached. In this case, the product
ester constitutes a sole organic component in the reaction
mixture, but otherwise separation of the remaining carboxylic
acid and alcohol from the product mixture is unavoidable. As
a consequence, an ideal goal of esterification would be 100%
yield by use of equimolar reactants without recourse to any
dehydration technique.
[14] L. C. Snoek, R. T. Kroemer, M. R. Hockridge, J. P. Simons, Phys.
Chem. Chem. Phys. 2001, 3, 1819.
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Chem. Phys. Lett. 2000, 319, 375.
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A 2000, 104, 4364.
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[22] S. Ullrich, G. Tarczay, X. Tong, C. E. H. Dessent, K. M¸ller-Dethlefs,
Phys. Chem. Chem. Phys. 2001, 3, 5450.
Recently, we disclosed that the fluorous biphasic trans-
esterification by use of fluoroalkyldistannoxane catalysts gave
rise to virtually 100% yields with ester and alcohol reactants
in a 1:1 ratio.[10] It was suggested in this protocol that
liberation of a lighter alcohol from the equilibrium system
as a result of its lower solubility in fluorocarbon solvents
facilitated the conversion in favor of the esters with a higher
alcohol component. Since water is much less fluorophilic than
alcohols, we postulated that the condensation between
carboxylic acids and alcohols should proceed more efficiently.
We report herein the first fluorous biphasic esterification that
achieves the above-mentioned goal. Furthermore, facile
separation of the catalyst is another notable advantage that
results from the fluorous biphasic technology.
Fluorous Biphasic Esterification Directed
towards Ultimate Atom Efficiency**
Jiannan Xiang, Akihiro Orita, and Junzo Otera*
As shown in Scheme 1, an equimolar mixture of
RCOOH
(1)
and
R’OH
(2)
together
with
Esterification technology is currently undergoing intensive
innovation to meet the rapidly increasing demands for
sustainable chemistry.[1] Since the direct reaction between a
carboxylic acid and an alcohol is innately an equilibrium
process, high atom efficiency[2] is not easy to achieve: either of
the reactants must be used in excess and/or the water formed
[{Cl(C6F13C2H4)2SnOSn(C2H4C6F13)2Cl}2] (3)[11] (5 mol%) in
FC-72 (perfluorohexanes) was heated at 1508C. After being
cooled to room temperature, toluene was added to the
RCOOR'
RCOOH
R'OH
RCOOR'
H2O
toluene
toluene
b
[*] Prof. Dr. J. Otera, J. Xiang, Dr. A. Orita
Department of Applied Chemistry, Okayama University of Science
Ridai-cho, Okayama 700-0005 (Japan)
Fax : (þ 81)86-256-4292
H2O
a
3
3
3
FC-72
FC-72
FC-72
E-mail: otera@high.ous.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan.
recycle
Scheme 1. Esterification in a biphasic system. Reagents and conditions:
a) acid (2.0 mmol), alcohol (2.0 mmol), 3 (0.1mmol), FC-72 (5 mL), 150 8C,
16 h; b) extraction with toluene (5 mL and 2 î 2 mL).
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 21
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mixture. The organic layer was separated from the fluorous
layer and analyzed by GLC. The results are summarized in
Table 1. With less sterically demanding reactants, no sign of
the reactant alcohol was detected in the reaction mixture and
only a single peak attributable to the ester was observed,
indicative of virtually perfect conversions (Table 1, entries 1
13). It is safe to assume that the GLC results are normally
accurate to within Æ 1% and thus the yields are > 99%.
Notwithstanding, a higher level of precision was pursued by
calibrating our GLC machine with some representative esters
(Table 1, entries 1, 8 14). It was shown that the detection limit
was actually less than 0.1% and thus the yields could be
considered as > 99.9%. The yields of isolated products were
also consistently quantitative.[12] Furthermore, this protocol is
tolerant of various functional groups (Table 1, entries 3 7).
The catalyst was recovered from the FC-72 layer without
weight loss, but not in pure form. A portion of the catalyst was
converted into unidentifiable species, which were presumably
organotin carboxylate derivatives. Nonetheless, the recovered
material exhibited similar catalytic activity to that of the
original, and thus the FC-72 solution that contained the
organotin species could be recycled for repeated use (see
below).
(10 mmol) the product could be pipetted from the surface of
the fluorous layer, although a small amount of the ester might
have remained. This, however, is not problematic when the
same reaction is repeated [Eq. (1)]. In fact, as shown in
Table 2, quantitative yields were attained in ten runs with a
single catalyst. Notably, only little catalyst loss occurred: the
modified catalyst (491mg) was recovered from 517 mg of the
original after the 10th run. Thus, this esterification process
does not require the use of conventional organic solvents.
PhCH CH CO H þ PhCH OH 3 ð3 mol %Þ PhCH CH CO CH Ph þ H O
ƒƒƒƒƒ!
2
2
2
2
2
2
2
2
2
ð1Þ
Table 2. Esterification using recycled fluorous tin catalyst 3 [Eq. (1)].[a]
Run Yield [%]
Isolated
GC
199.8
99.9
2
3
4
5
6
7
8
9
10[b]
99.6
99.6
100.0
99.6
99.8
99.8
99.7
99.5
99.6
99.8
99.9
100.1
99.9
100.0
99.9
99.8
99.7
99.9
In the above procedure, toluene was added to the reaction
mixture to recover the ester from the FC-72 solution, simply
because the small-scale reaction did not mechanically allow
the quantitative separation of the product (3 mmol). On the
other hand, when larger amounts of reactants were used
[a] Reagents and conditions: acid (10.0 mmol), alcohol (10.0 mmol), 3
(0.3 mmol), FC-72 (50 mL), 1508C, 20 h. [b] After 10th run, 95% (491 mg)
of the catalyst was recovered.
Table 1. Fluorous biphasic esterification.[a]
As is apparent from Table 1, the
Yield (RCOOR’) [%]
Entry
RCOOH
R’OH
reaction is sensitive to the steric bulk
GLC
Isolated
of the reactants (Table 1, entries 15
21). Secondary alcohols as well as
carboxylic acids with a bulky group at
the a position (except for one case,
Table 1, entry 14) did not give satis-
factory yields. Neither simple aro-
matic carboxylic acids nor a,b-unsa-
turated carboxylic acids gave good
1Ph(CH
2
3
4
5
6
7
8
9
10
11
12
13[b]
14[b]
15[b]
16[b]
17[b]
18[b]
2)2COOH (1a)
PhCH2OH (2a)
C8H17OH (2b)
TBSO(CH2)8OH
THPO(CH2)8OH
geraniol
> 99.9
> 99
> 99
> 99
> 99
> 99
> 99
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9
45
100
100
98
98
100
99
99
100
99
100
99
99
1a
1a
1a
1a
1a
1a
¼
PhCH CHCH2OH
ꢁ
PhC CCH2OH
Ph(CH2)3COOH (1b)
C7H15COOH (1c)
p-NO2C6H4COOH (1d)
C6F5COOH (1e)
p-CF3C6H4COOH (1 f)
2a
2a
2a
2a
2a
2a
2a
menthol
borneol
2a
yields
(Table 1,
entries 22 24),
whereas electron-deficient aromatic
derivatives reacted smoothly (Ta-
ble 1, entries 10 12). Such differences
in reactivity led us to carry out
competition reactions between car-
boxylic acids and either octanol or
benzyl alcohol [Eq. (2)]. As summar-
ized in Table 3, equimolar amounts of
two carboxylic acids of different re-
activity were exposed to one equiv-
alent of the alcohol. Remarkably,
complete bias was observed: the ester
(R1COOR3) derived from the reac-
tive carboxylic acid was produced in
ꢀ 100% yield whereas none of the
competing ester (R2COOR3) from
the less reactive carboxylic acid was
detected. The yield of the esters was
¼
CH2 CH(CH2)8COOH (1g)
(4-ClC6H4O)C(CH3)2COOH (1h)
98
98
44
63
1a
1a
65
3.5
14
Ph2C(CH3)COOH (1i)
1-adamantanecarboxylic acid (1j)
2a
19[b]
2a
13
20[b]
2a
16
21[b]
2a
4
22[b]
23[b]
24[b]
C6H5COOH (1n)
p-CH3C6H4COOH (1o)
2a
2a
2a
22
26
32
¼
PhCH CHCOOH (1p)
[a] Reaction conditions: acid (2.0 mmol), alcohol (2.0 mmol), 3 (0.10 mmol), FC-72 (5.0 mL), 1508C, 10 h.
[b] Reaction time: 16 h.
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Table 3. Competition between carboxylic acids in fluorous biphasic
esterification [Eq. (2)].[a]
Table 4. Selective esterification of dicarboxylic acid [Eq. (3)].
Entry
n
R
Yield (5) [%][c]
Yield (6) [%][d]
Entry R1COOH R2COOH[b] R3OH
Yield [%]
R1COOR2 R1COOR3
Isolated GLC
Ph1C1H
2
3
2CH2
100
100
100
99.9
99.7
99.8
1
4
cyclo-C6H11CH2CH2
GLC
C8H17
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1 f
1 f
1 f
1 f
1 f
1i
1j
2b
2b
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2a
2b
2b
> 99.9
> 99.9
> 99.9
> 99.9 100
> 99.9 100
> 99.9
> 99.9
> 99.9
98
98
99
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
< 0.1
[a] Reaction conditions: 4 (1.0 mmol), ROH (1.0 mmol), 3 (0.10 mmol),
FC-72 (5.0 mL), 1508C, 16 h. [b] Reaction conditions: (1.0 mmol),
Me3SiCHN2 (1.5 mmol, 2m solution in hexane, 0.75 mL), toluene
(10 mL), MeOH (5 mL), room temperature, 3 h. [c] Yield of isolated
product (column chromatography). [d] GLC yield.
5
1k
1k
1l
1m
1i
1j
1k
1l
1m
1i
1m
1n
1k
1j
1k
1l
1m
99
99
98
In summary, almost complete atom efficiency has been
realized in the fluoroalkyldistannoxane-catalyzed fluorous
biphasic esterification. This atom efficiency, in conjunction
with the facile recovery of the catalyst, holds great promise for
developing a green esterification process. The nearly perfect
stoichiometry as well as discrimination between carboxylic
acids discovered herein may pave the way to elucidate
characteristic features of kinetics in the fluorous biphasic
system. Further studies are in progress in our laboratories.
> 99.9 100
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9
> 99.9 100
> 99.9 98
> 99.9 100
> 99.9 99
99
98
97
99
97
99
[a] Reaction conditions: R1COOH (1.0 mmol), R2COOH (1.0 mmol),
alcohol (1.0 mmol), 3 (0.10 mmol), FC-72 (5.0 mL), 1508C, 16 h. [b] Un-
reacted R2COOH was quantitatively converted into the methyl ester (see
text).
Experimental Section
Typical procedure (Table 1, entry 1): A 50-mL test tube was charged with 3-
phenylpropanonic acid (1a; 300 mg, 2.0 mmol), benzyl alcohol (2a; 216 mg,
2.0 mmol), 3 (172 mg, 0.10 mmol, 5 mol%), and FC-72 (5.0 mL). The test
tube was placed in a stainless pressure bottle and heated at 1508C for 10 h.
After the pressure bottle had been cooled, toluene (5.0 mL) was added to
the reaction mixture. The toluene and FC-72 layers were separated, and the
latter was extracted with toluene (2 î 2.0 mL). GC analysis of the combined
organic layer showed a quantitative yield of benzyl 3-phenylpropanoate.
confirmed to be > 99.9% on the basis of GLC, which was
carefully calibrated as described already. Furthermore, the
organic layer was separated from the reaction mixture and
treated with trimethylsilyldiazomethane (1.5 equiv) to con-
vert the unreacted carboxylic acids into the methyl esters, the
yield of which was found to be more than 99.9%.[13] Notably,
such perfect discrimination is rather surprising because
reaction of the less reactive carboxylic acids actually takes
place, though to a lesser extent, under noncompetitive
conditions, which is suggestive of the involvement of some
unique kinetic effects.
Received: July 3, 2002 [Z19660]
[1] J. Otera, Angew. Chem. 2001, 113, 2099; Angew. Chem. Int. Ed. 2001,
40, 2044.
[2] a) B. M. Trost, Science 1991, 254, 1471; b) R. A. Sheldon, Chem. Ind.
(London) 1997, 1 2.
[3] DCC ¼ dicyclohexylcarbodiimide; a) A. Buzas, C. Egnell, P. Frÿon,
C. R. Acad. Sci. 1962, 255, 945; b) B. Neises, W. Steglich, Angew.
Chem. 1978, 90, 556; Angew. Chem. Int. Ed. Engl. 1978, 17, 522; c) A.
Hassner, V. Aleranian, Tetrahedron Lett. 1978, 4475.
[4] DEAD ¼ diethylazodicarboxylate; O. Mitsunobu, Synthesis 1981, 1 .
[5] G. A. Olah, G. Liand, J. Staral, J. Am. Chem. Soc. 1974, 96, 8113.
[6] A. Loupy, A. Petit, M. Ramdani, C. Yvanaeff, M. Majdoub, B. Labiad,
A. Villemin, Can. J. Chem. 1993, 71, 90.
R1COOH þ R2COOH þ R3OH 3 ð10 mol %Þ R1COOR3 þ R2COOR3
ƒƒƒƒƒƒ!
ð2Þ
The differentiation between aliphatic and aromatic carbox-
ylic acids was highlighted with substrates 4 [Eq. (3); Table 4].
[7] Y.-Q. Li, Synth. Commun. 1999, 29, 3901.
[8] K. Ishihara, S. Ohara, H. Yamamoto, Science 2000, 290, 1140.
[9] K. Wakasugi, T. Misaki, K. Yamada, Y. Tanabe, Tetrahedron Lett.
2000, 41, 5249.
[10] a) J. Xiang, S. Toyoshima, A. Orita, J. Otera, Angew. Chem. 2001, 113,
3782; Angew. Chem. Int. Ed. 2001, 40, 3670; b) J. Xiang, A. Orita, J.
Otera, Adv. Synth. Catal. 2002, 344, 84.
COOH
COOH
COOCH3
a
b
(3)
[11] J. Xiang, A. Orita, J. Otera, J. Organomet. Chem. 2002, 648, 246.
[12] The yields given in this paper were the best among more than two
trials and are accurate within Æ 1%.
O(CH2)nCOOH
O(CH2)nCOOR
O(CH2)nCOOR
4
5
6
[13] The control experiments disclosed that the ester formation with
trimethylsilydiazomethane proceeds quantitatively (> 99.9% yield)
on the basis of GLC, the detection limit of which was found to be
0.1% for the methyl esters .
Exposure of these substrates to an alcohol resulted in the
exclusive esterification of the aliphatic alcohol to furnish the
single products 5 in quantitative yields. The complete
discrimination of the two carboxylic acid functions was
further confirmed by transformation of 5 into methyl ben-
zoate derivatives 6. GLC analysis revealed quantitative
formation of the methyl ester without contamination by any
other products.[14]
[14] The differentiation of primary alcohols from secondary and aromatic
alcohols with HfCl4¥2THF was previously reported: K. Ishihara, M.
Nakayama, S. Ohara, H. Yamamoto, Synlett 2001, 1 1 1 7.
Angew. Chem. Int. Ed. 2002, 41, No. 21
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