Lipase-catalyzed domino kinetic resolution of α-hydroxynitrones/ intramolecular 1,3-dipolar cycloaddition: A concise asymmetric total synthesis of (-)-rosmarinecine

Article abstract of DOI:10.1039/b419426h

The title domino reactions were developed to directly provide tetrahydrofuro[3,4-c]isoxazole derivatives (5 and 9) in ≥ 90% ee from racemic α-hydroxynitrones (2 and 6), which were used in the concise asymmetric total synthesis of (-)-rosmarinecine 10. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b419426h

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COMMUNICATION
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Lipase-catalyzed domino kinetic resolution of a-hydroxynitrones/
intramolecular 1,3-dipolar cycloaddition: a concise asymmetric total
synthesis of (2)-rosmarinecine{
Shuji Akai, Kouichi Tanimoto, Yukiko Kanao, Sohei Omura and Yasuyuki Kita*
Received (in Cambridge, UK) 5th January 2005, Accepted 28th February 2005
First published as an Advance Article on the web 16th March 2005
DOI: 10.1039/b419426h
The title domino reactions were developed to directly provide
tetrahydrofuro[3,4-c]isoxazole derivatives (5 and 9) in ¢90% ee
from racemic a-hydroxynitrones (2 and 6), which were used in
the concise asymmetric total synthesis of (2)-rosmarinecine 10.
an alternative approach to the cycloadducts, free from the
6
racemization. This protocol would also be advantageous in terms
of the ready availability of racemic substrates and the shortening
of the transformation steps. However, no example of this idea has
been reported to date.
The 1,3-dipolar cycloaddition reaction of optically active nitrones
to olefins is a powerful and versatile method for preparing
polysubstituted isoxazolidines and has been extensively employed
as a key step in the asymmetric total syntheses of a variety of
biologically important compounds such as alkaloids and amino
Recently, we have developed the first domino synthesis, in
which the lipase-catalyzed kinetic resolutions of racemic dienols
with ethoxyvinyl esters having dienophilic acyl moieties were
successively followed by the intramolecular Diels–Alder reactions
of the resulting optically active esters. Tricyclic compounds bearing
multi-stereogenic carbon centres were directly obtained in high
1–4
sugars. Among these reactions, the intramolecular cyclizations of
nitrones connected to olefin moieties by tethers usually give rise to
excellent regioselectivities and diastereofacial (i.e., endo and exo)
selectivities, and the stereogenic centres in the tethers play a critical
7
yields. In this communication, the application of this domino
protocol to the acyclic, (¡)-6, and the cyclic a-hydroxynitrones,
(¡)-2, to achieve the one-pot preparation of the optically active
tetrahydrofuro[3,4-c]isoxazole derivatives (9 and 5), is reported.
Particularly, the domino reaction of (¡)-2 proceeded with
dynamic kinetic resolution, and thereby the first catalytic
asymmetric total synthesis of optically pure (2)-rosmarinecine 10
was achieved in 6 steps from commercially available racemic
1,3
role in the induction of stereogenic carbon centres in the products.
Optically active nitrones have been generally prepared from
optically active precursors, the so-called chiral pool including
3
a
3b,4
amino acid derivatives, hydroxycarboxylic acid derivatives,
3c
and sugars. However, during transformation of these precursors
into nitrones, some of them suffered racemization of their pivotal
3-hydroxypyrrolidine 11.
3a
To the best of our knowledge, there has been no precedent for
the hydrolase-catalyzed kinetic resolution of hydroxynitrones.
Therefore, our studies started with the domino reaction of a simple
stereogenic carbon centres. Scheme 1 shows an example, in
which partial racemization took place during both the deprotec-
4,5
tion of the THP ether (S)-1 to (S)-2 and its Mitsunobu reaction.
8
7b
acyclic nitrone (¡)-6 with a functionalized acyl donor 7b. After
If optically active 4a or 5a could be directly and catalytically
prepared from a racemic nitrone 2, such a method should provide
intensive screening of commercial lipases and ordinary organic
solvents, we discovered that Candida antarctica lipase, fraction B
9
CAL-B) effectively catalyzed the kinetic resolution of (¡)-6 in
(
toluene at 20 uC. The subsequent intramolecular dipolar
cycloaddition of thus generated ester (R)-8 was so fast that the
cycloadduct 9 (93% ee, 52% yield) was directly obtained as a single
diastereomer along with the recovery of (S)-6 (99% ee, 38% yield)
(Scheme 2).
Scheme 1
{
Electronic supplementary information (ESI) available: determination of
the optical purity and absolute structure of (S)-2, 5a,b, (S)-6, 9 and 14
and typical procedures for the lipase-catalyzed domino reaction (Table 1,
entry 5) and the one-pot synthesis of 5b (entry 7). See http://www.rsc.org/
suppdata/cc/b4/b419426h/
*kita@phs.osaka-u.ac.jp
Scheme 2
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With these successful results in hand, our next attention focused
on the domino reaction of the cyclic nitrone (¡)-2 with the acyl
donors 7a,b aimed at the effective asymmetric total synthesis of
Table 1 Lipase-catalyzed domino reactions of (¡)-2 and 7a,b in
MeCN
Amount of
CAL-B
a
(
2)-rosmarinecine 10, a typical necine-base-portion of some
Entry
7
Conditions
5
(S)-2
10
natural alkaloids such as rosmarinine (Scheme 3). In contrast
b
1
7a 150 wt%
7a 150 wt%
7b 150 wt%
7b 300 wt%
7b 300 wt%
7b 300 wt%
7b 300 wt%
30 uC, 12 h 5a 89% ee, 27% trace
to the case of 6, the reaction of (¡)-2 was somewhat problematic.
b
c
2
0 uC, 12 h 5a 92% ee, 53% 73% ee, 43%c
0 uC, 8 h 5b 94% ee, 49% 77% ee, 33%
10 uC, 17 h 5b 86% ee, 69% trace
5 uC, 12 h 5b 91% ee, 60% 96% ee, 28%
5 uC, 11 h 5b 90% ee, 60% 99% ee, 30%c
5 uC, 11 h 5b 92% ee, 58% 95% ee, 23%
b
b
First, although a similar reaction of (¡)-2 with 7a in toluene, as
i
3
b
4
well as other solvents such as THF and Pr O, at 30 uC gave the
2
b
5
expected cycloadduct 5a as a single diastereomer, the enantios-
electivity was low (up to 60% ee). Second, the decomposition of 2
was observed, probably via its competitive intermolecular dipolar
cycloaddition to 7a. These problems were solved using MeCN at
d
6
d
7
a
Weight% of commercial CAL-B to (¡)-2. Carried out using
purified 7 (1.5 equiv.). Substrate amount was 50 mg.
yield. Carried out by the one-pot procedure; for details, see ESI.
Substrate amount was 40 mg for entry 6 and 1.0 g for entry 7.
c 1
H NMR
d
0
uC. Thus, the enantioselectivity was improved (Table 1, entry 1)
and the side reactions were sufficiently depressed at 0 uC to give 5a
92% ee, 53% yield) and the recovered (S)-2 (entry 2). In a similar
(
identical reaction conditions using the same ratio of (¡)-2, 3b,
CAL-B, and the solvent, the reactions of (¡)-2 (40 mg and 1.0 g)
afforded similar results (entries 6 and 7).
manner, the reaction of (¡)-2 with the ethyl ester 7b afforded 5b
with a slightly better enantioselectivity (94% ee, 49% yield)
(entry 3).
Finally, the asymmetric total synthesis of (2)-rosmarinecine 10
was attained as follows: a recrystallization of 5b (92% ee) from a
mixture of hexanes and EtOAc afforded the optically pure 5b [43%
yield from (¡)-2]. Hydrogenolysis of 5b gave 14 (.99% ee based
To our surprise, partial racemization of the remaining (S)-2 was
observed during these reactions. Thus, the optical purity of (S)-2
should be almost the same as that of the products 5 at about 50%
conversion; however, it was always lower (entries 2 and 3). Among
the intensive studies to achieve the domino reaction with a
dynamic kinetic resolution by changing the temperature, the
amount of the lipase, and some additives, the reaction using CAL-
B (300 wt%) at 10 uC for 17 h afforded 5b (86% ee, 69% yield)
23
on chiral HPLC analysis using Daicel Chiralpak AD-H), [a]
4a
D
2
7
+
89.4 (c 5 0.36, abs. EtOH) [lit. [a] +94.2 (c 5 0.31, abs.
D
EtOH)]. The Red-Al reduction of 14 (.99% ee), according to
4a
Goti’s paper, afforded (2)-rosmarinecine 10 in 90% yield. The
1
physical properties and the H and C NMR data of the
13
(entry 4) and that at 5 uC for 12 h gave 5b (91% ee, 60% yield)
synthesized 10 showed good agreement with those of the natural
10
(entry 5). Similar to the above-mentioned studies using pure 7a,b,
24
compound: mp 167–170 uC, [a]D 2117.7 (c 5 0.98, EtOH) [lit.
the more convenient one-pot procedure, including the preparation
21
mp 168–170 uC, [a]D 2119.8 (c 5 1.01, EtOH)]. Because we
prepared (¡)-2 from commercially available (¡)-11 (45% overall
11
of 7b from 3b and the enzymatic domino reaction of (¡)-2, gave
5b with the same optical and chemical yields (entry 6). This
yield) in 3 steps, the total synthesis of (2)-10 was achieved in
method was scarcely affected by the reaction scale and was suitable
for multigram synthesis of chiral products. For instance, under
6
steps with a 9.6% overall yield from (¡)-11 (Scheme 3).
Although the asymmetric total synthesis of (2)-10 had already
been reported by three groups, all of them used optically active
substrates as either the starting material or as a chiral
4,10,12
auxiliary.
Our method features the first catalytic asymmetric
total synthesis of (2)-10 starting from the commercially available
racemic material (¡)-11, the fewest steps, and the highest overall
yield. The acceleration of the racemization of the alcohol (S)-2 to
attain more effective dynamic kinetic resolution is now under
13
investigation in our laboratory.
This work was supported by Grants-in-Aid for Scientific
Research, (S) 13853010 and (C) 15590005, from the Ministry of
Education, Culture, Sports, Science, and, Technology, Japan.
Roche Diagnostics K. K., Japan is thanked for the generous gift of
the lipase.
Shuji Akai, Kouichi Tanimoto, Yukiko Kanao, Sohei Omura and
Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6,
Yamadaoka, Suita, Osaka 565-0871, Japan.
E-mail: kita@phs.osaka-u.ac.jp; Fax: (+81) 6-6879-8229
Notes and references
1
For recent reviews, see: K. V. Gothelf and K. A. Jørgensen, Chem. Rev.,
1998, 98, 863; H. M. Osborn, N. Gemmell and L. M. Harwood,
J. Chem. Soc., Perkin Trans. 1, 2002, 2419.
t
Scheme 3 Reagents and conditions: a, Me
Na WO , H , Et NCl, CH Cl –H
tylene, [RuCl (p-cymene)] (0.5 mol%), acetone; ii) CAL-B, MeCN; e,
Pd(OH) , H , MeOH; f, Red-Al, THF.
2
BuSiCl, imidazole, MeCN; b,
2
4
2
O
2
4
2
2
2
O; c, CsF, MeOH; d, i) ethoxyace-
2
For some examples of the asymmetric total syntheses of biologically
important compounds, see: (a) H. Ooi, A. Urushibara, T. Esumi,
Y. Iwabuchi and S. Hatakeyama, Org. Lett., 2001, 3, 953; (b)
2
2
2
2
2
370 | Chem. Commun., 2005, 2369–2371
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K. Nagasawa, A. Georgieva, H. Koshino, T. Nakata, T. Kita and
Y. Hashimoto, Org. Lett., 2002, 4, 177.
8 W. Kliegel and G. Lubkowitz, Can. J. Chem., 1992, 70, 2809.
9 CAL-B [Chirazyme L-2, c.-f. C2, dry (12900 U/g lyo.)], a lipase
1
3
4
For some examples, see: (a) H. G. Aurich and J.-L. R. Quintero,
Tetrahedron, 1994, 50, 3929; (b) T. Ishikawa, T. Kudo, K. Shigemori
and S. Saito, J. Am. Chem. Soc., 2000, 122, 7633; (c) O. Tamura,
A. Toyao and H. Ishibashi, Synlett, 2002, 1344.
(a) A. Goti, M. Cacciarini, F. Cardona, F. M. Cordero and A. Brandi,
Org. Lett., 2001, 3, 1367; (b) see also: F. M. Cordero, F. Pisaneschi,
M. Gensini, A. Goti and A. Brandi, Eur. J. Org. Chem., 2002, 1941; (c)
F. Pisaneschi, F. M. Cordero and A. Brandi, Synlett, 2003, 1889.
We also observed the complete racemization of the stereogenic chiral
centre of the optically pure 2 during its Mitsunobu reaction with 3 and
its treatment with p-TsOH.
We have discovered that the acetate of (S)-2 is stable against
racemization under common basic conditions as well as acidic
conditions at room temperature.
(a) S. Akai, T. Naka, S. Omura, K. Tanimoto, M. Imanishi, Y. Takebe,
M. Matsugi and Y. Kita, Chem. Eur. J., 2002, 8, 4255; (b) S. Akai,
K. Tanimoto and Y. Kita, Angew. Chem. Int. Ed., 2004, 43, 1407.
immobilized on a polymer support, was used, which is commercially
available from Roche Diagnostics GmbH. The same lipase is also on
sale from Novozymes Inc. by the name NOVOZYM 435 . The
commercial lipase was dried (1 mmHg, room temperature, overnight)
prior to use.
1
10 S. E. Denmark, A. Thorarensen and D. S. Middleton, J. Am. Chem.
Soc., 1996, 118, 8266.
11 The oxidation of (¡)-12 to (¡)-13 was based on: H. Ohtake, Y. Imada
and S. Murahashi, Bull. Chem. Soc. Jpn., 1999, 72, 2737.
12 K. Tatsuta, H. Takahashi, Y. Amemiya and M. Kinoshita, J. Am.
Chem. Soc., 1983, 105, 4096.
5
6
7
13 Preliminary studies have found that the treatment of (S)-2 (99% ee) with
7
b
2 2 3
[RuCl (mesitylene)] (4 mol% equiv.) and Et N (1 equiv.) in either
acetone or MeCN caused racemization; however, its combination
with the enzymatic domino reaction of (¡)-2 resulted in an
unsatisfactory yield (ca. 30%) mainly due to the Ru-catalyzed
decomposition of 5.
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Chem. Commun., 2005, 2369–2371 | 2371