Catalytic asymmetric mercuriocyclization of γ-hydroxy-cis-alkenes

Article abstract of DOI:10.1002/anie.200461289

2-Monosubstituted tetrahydrofurans 2 are obtained with 73-95% ee through the catalytic enantioselective mercuriocyclization of Y-hydroxy-(Z)-alkenes 1 by using Hg(OAc)₂ in the presence of Hg^II complexed with tartrate-derived 4-(2-nap

Full text of DOI:10.1002/anie.200461289

Angewandte
Chemie
Oxygen Heterocycles
Catalytic Asymmetric Mercuriocyclization of
g-Hydroxy-cis-Alkenes**
Sung Ho Kang,* Mihyong Kim, and Suk Youn Kang
Conversion of prochiral olefinic double bonds into the
corresponding chiral functional groups is one of the most
influential fields of study in modern synthetic organic
chemistry, which has been realized preeminently through
asymmetric epoxidation,[1] dihydroxylation,[2] aminohydroxy-
lation,[3] hydrogenation,[4] and hydroboration.[5] Another
versatile process can be evolved from electrophile-promoted
additions.[6] Whereas few studies into intermolecular asym-
metric additions have been carried out, the intramolecular
version has been explored to some extent. The latter
asymmetric cyclizations have been achieved by substrate-
controlled means, but rarely through reagent-controlled
methods. Although the reagent-controlled approach has
been recognized as more challenging and beneficial, progress
has lagged behind owing to lack of lucid strategic clues.
Examples include organoselenylation with chiral selenium
reagents,[7] iodocyclization with iodonium ion/dihydriquinine
complexes,[8] iodocyclization with CoII–salen complexes,[9] and
mercuriocyclization with HgII–bisoxazoline complexes.[10]
Most of the aforementioned methods have some limitations
such as poor enantioselectivity, multistep synthesis of the
involved reagent, and excessive use of the expensive reagent.
Since our reported intramolecular mercurioetherification also
requires 1.2 equivalents of chiral HgII complexes, even though
the reaction itself is highly enantioselective,[10] development
of the corresponding catalytic version would no doubt have a
significant impact. Herein we describe asymmetric mercurio-
cyclization by using catalytic amounts of chiral bisoxazoline to
prepare highly enantiopure 2-substituted tetrahydrofurans.
To develop a catalytic version of asymmetric mercurio-
cyclization, we proposed the use of catalytic amounts of a
chiral bisoxazoline together with excess amounts of readily
available achiral ligand, which can hold all the existing HgII
ions tightly enough to transfer preferentially not to the
olefinic substrate but to the chiral ligand. After assaying
several kinds of additives, amine bases were found to retard
the cyclization significantly. Based on the observation,
structural tuning led us to choose oxazoline as the prospective
achiral ligand. Since our proposed relaying process was shown
experimentally to work with a complex between HgII and
oxazoline 2 (1:2), mercuriocyclization of the model substrate
1 was implemented with this complex composition in the
[*] Prof.Dr. S. H. Kang, Dr. M. Kim, Dr. S. Y. Kang
Center for Molecular Design and Synthesis
Department of Chemistry, School of Molecular Science (BK21)
Korea Advanced Institute of Science and Technology
Daejeon 305-701 (Korea)
Fax: (+82)42-869-2810
E-mail: shkang@kaist.ac.kr
[**] This work was supported by CMDS and the Brain Korea 21 Project.
Angew. Chem. Int. Ed. 2004, 43, 6177 –6180
DOI: 10.1002/anie.200461289
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6177

Communications
presence of various oxazolines to evaluate which one would
and 6 (Table 2, entries 2 and 4). The reaction conditions in
Table 2, entry 2 were applied to substrates 10–12. The
experimental data in Table 3 reveal that the enantioselectivity
be effective. Some of the results are presented in Table 1.
Although 4 and 5 promoted the cyclization to a greater extent
(Table 1, entries 3 and 4), the use of 2, 3, 6, and 7 seemed to
induce more-encouraging progress (Table 1, entries 1, 2, 5,
and 6).
Table 3: Mecuriocyclization with 2–HgII (1.2 equiv) in the presence of
bisoxazoline 9 (0.3 equiv) and MeOH (2.5 equiv).
Table 1: Mecuriocyclization of 1 in the presence of oxazoline–HgII
complexes (L2HgII; 1.2 equiv).
Entry
Substrate
Product
Yield (sm) [%]
ee [%][a]
1
2
3
4
1
10
11
12
8
13
14
15
72 (24)
51 (46)
63 (35)
42 (56)
90
82[b,c]
91[b,c]
75[d,e]
Entry
L
Yield [%]
Recovered starting
material [%]
[a] For the determination of the absolute configuration, see refer-
ence [10]. [b] Measured for the reductively demercurated product (LiBH4
and Et3B in THF at À788C). [c] Determined by HPLC analysis using
DAICEL OD-H. [d] Measured for the iodinated product (I2 in THFat 08C).
[e] Determined by GC analysis using CHIRALDEX B-DM. The absolute
configuration was not determined.
1
2
3
4
5
6
2
3
4
5
6
7
22
23
44
55
8
74
72
48
41
90
83
11
reached a more satisfactory level than the chemical con-
version. When the cyclization proceeded further, it became
slower, probably as a result of the gradually increasing
oxazoline concentration. All attempts to suppress the ligating
power of the generated excess oxazoline with acidic additives
proved futile.
With the promising relay ligands in hand, catalytic
asymmetric mercuriocyclization of 1 was attempted with the
corresponding HgII complexes in the presence of bisoxazoline
9. The outcomes are summarized in Table 2. As reported
To ameliorate the incomplete conversion, a different
protocol was elicited. In the second approach, 1 was treated
with the complex between 9 and HgII (1:1; 0.2 equiv) in the
presence of Hg(OAc)2 (1.0 equiv) and additive(s). The use of
MeOH (10 equiv) with or without K2CO3 resulted in moder-
ate enantioselectivity (Table 4, entries 1 and 2). The use of
allyl alcohol instead of MeOH led to improved stereo-
selectivity, notably with poorer chemical yield (Table 4,
entry 3). The best cyclization resulted when the amount of
MeOH was adjusted to 1.5 equivalents (Table 4, entry 5).
Table 2: Mecuriocyclization of 1 by using oxazoline L–HgII complexes
(L2HgII; 1.2 equiv) in the presence of bisoxazoline 9 (0.3 equiv) and
MeOH (2.5 equiv).
Entry
L
Yield (sm)[a] [%]
ee [%][b,c,d]
1[e]
2
3
4
5
2
2
3
6
7
70 (26)
72 (24)
47 (52)
72 (26)
39 (54)
89
90
89
91
72
Table 4: Mecuriocyclization of 1 with 9–HgII (0.2 equiv) in the presence
of Hg(OAc)2 (1.0 equiv) and additive(s).
Entry
Additive (equiv)
Yield (sm) [%]
ee [%]
[a] Values in parentheses refer to the recovery of starting material.
[b] Measured for the reductively demercurated product (LiBH4 and Et3B
in THF at À788C). [c] Determined by HPLC analysis using Regis Welk-O1
(R,R). [d] For the determination of the absolute configuration, see
reference [10]. [e] MeOH (10 equiv) and K2CO3 (5 equiv) were added.
1
2
3
4
5
MeOH (10), K2CO3 (5)
MeOH (10)
allyl alcohol (10)
iPrOH
84 (10)
92 ( 5)
61 (25)
77 (19)
87 (11)
54
43
74
37
91
MeOH (1.5)
before, MeOH (10 equiv) and K2CO3 (5 equiv) were
employed as additives and resulted in good chemical con-
version and remarkable stereoselectivity (Table 2, entry 1).
Later, it was found that the addition of 2.5 equivalents of
MeOH was sufficient to give comparable results (Table 2,
entry 2). The best cyclization was attained with oxazolines 2
A variety of Z olefinic hydroxyalkenes 10–12 and 16–22
were subjected to the developed cyclization conditions.
Under conditions A (Table 5), most of the substrates deliv-
ered good to excellent stereoselectivity; however, 10 and 12
6178
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Chemie
Table 5: Mecuriocyclization with 9–HgII in the presence of Hg(OAc)2 and
MeOH.
On the other hand, the latter produced 43% of the trans-
2,5-disubstituted tetrahydrofuran 33 with 63% ee, and 47%
of starting alcohol 32 with 61% ee [Eq. (2)].
Conditions A[a]
Conditions B[b]
Entry Substrate Product Yield (sm) ee
Yield (sm) ee
[%]
[%] [%]
[%][b,c]
1
2
3
4
5
6
7
8
9
1
10
11
16
17
18
12
19
20
21
22
8
13
14
23
24
25
15
26
27
28
29
87 (11)
71 (25)
81 (17)
79 (15)
84 (9)
72 (13)
83 (10)
83 (11)
83 (10)
87 (11)
75 (14)
91
48
91
78
93 ( 6)
80 (17)
87 (11)
72 (15)
83 (10)
68 (20)
70 (13)
80 (12)
79 (11)
80 (15)
72 (19)
94
84
95
82[d,e]
[d,e]
79
87
88
22
75
88
71
83
90[d,e]
73
In conclusion, we have established a highly enantioselec-
tive catalytic mercuriocyclization of g-hydroxy-cis-alkenes
employing Hg(OAc)2 in the presence of catalytic amounts of
the 4-(2-naphthyl)bisoxazoline–HgII (9–HgII) complex to
obtain 2-monosubstituted tetrahydrofurans with up to
95% ee.
84[d,e]
93[e,f9
82[g]
92[g]
10
11
[a] Conditions A: 0.2 equiv of 9, 0.2 equiv of Hg(tfa)2, 1.5 equiv of MeOH
and 1.0 equiv of Hg(OAc)2 were used. Conditions B: 0.3 equiv of 9,
0.2 equiv of Hg(tfa)2, 2.0 equiv of MeOH and 1.0 equiv of Hg(OAc)2 were
used. [b] For the determination of the absolute configuration, see
reference [10]. [c] Determined by GC analysis using CHIRALDEX B-DM.
[d] Measured for the iodinated product (I2 in THF at 08C). [e] The
absolute configuration was not detetermined. [f] Measured for the
reductively demercurated product (LiBH4 and Et3B in THF at À788C).
[g] Measured for the reductively demercurated alcohol, which was
produced by concomitant reductive demercuration and ester reduction
using LiBH4 and Et3B in THF at À788C.
Received: July 13, 2004
Keywords: asymmetric synthesis · cyclization ·
.
homogeneous catalysis · mercury · tetrahydrofurans
[1] a) T. Katsuki in Comprehensive Asymmetric Catalysis; Vol. 2
(Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Heidelberg, 1999, chap. 18.1; b) E. N. Jacobsen, M. F. Wu in
Comprehensive Asymmetric Catalysis, Vol. 2 (Eds.: E. N. Jacob-
sen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999,
chap. 18.2; c) R. W. Murray, Chem. Rev. 1989, 89, 1187.
[2] a) I. E. Marko, J. S. Svendsen in Comprehensive Asymmetric
Catalysis, Vol. 2 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, Heidelberg, 1999, chap. 20; b) H. C. Kolb, M. S. Van
Nieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483.
[3] a) G. Li, H.-T. Chang, K. B. Sharpless, Angew. Chem. 1996, 108,
449; Angew. Chem. Int. Ed. Engl. 1996, 35, 451; b) G. Li, H. H.
Angert, K. B. Sharpless, Angew. Chem. 1996, 108, 2991; Angew.
Chem. Int. Ed. Engl. 1996, 35, 2813.
[4] a) R. Noyori, Angew. Chem. 2002, 114, 2108; Angew. Chem. Int.
Ed. 2002, 41, 2008; b) W. S. Knowles Angew. Chem. 2002, 114,
2096; Angew. Chem. Int. Ed. 2002, 41, 1998.
[5] a) F. Y. Kwong, Q. Yong, T. C. W. Mak, A. S. C. Chan, K. S.
Chan, J. Org. Chem. 2002, 67, 2769, and references therein; b) K.
Burgess, W. A. Van der Donk in Advanced Asymmetric Synthesis
(Ed.: G. R. Stephenson), Champman & Hall, London, 1996,
p. 181.
[6] a) G. Rousseau, S. Robin, Tetrahedron 1998, 54, 13681; b) K. E.
Harding, T. H. Tinger in Comprehensive Organic Synthesis,
Vol. 4 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991,
p. 463; c) J. Mulzer in Organic Synthesis Highlights (Eds.: J.
Mulzer, H. J. Altenbach, M. Braun, K. Krohn, H. U. Reissig),
Wiley-VCH, Weinheim, 1991, p. 157.
[7] a) T. G. Back, B. P. Dyck, S. Nan, Tetrahedron 1999, 55, 3191;
b) Y. Nishibayashi, S. K. Srivastava, H. Takada, S.-I. Fukuzawa,
S. Uemura, J. Chem. Soc. Chem. Commun. 1995, 2321; c) T.
Wirth, Angew. Chem. 1995, 107, 1872; Angew. Chem. Int. Ed.
resulted in poor enantioselectivity (Table 5, entries 2 and 7).
To overcome the inferior asymmetric induction, it was
necessary to maintain the concentration of the free HgII ion
as low as possible. As a consequence, the cyclization
conditions were optimized by increasing the amount of 9 to
0.3 equivalents with 2.0 equivalents of MeOH (Table 5, con-
ditions B). The enantioselectivity under the established con-
ditions was improved considerably from 48 to 84% ee for 13
and from 22 to 73% ee for 15 (Table 5, entries 2 and 7). Most
of the remaining substrates also underwent cyclization with
significant enantiomeric enhancement.[11] Scrutiny of the data
suggests that not only the steric bulk of the substituent but
also the distance of the bulky region from the olefinic double
bond seem to be greatly influential. It is possible that the two
factors are involved in forming the tight coordination bond
between the substrate and 9–HgII complex, which is thought
to be crucial for high facial selectivity.
Finally, the newly developed cyclization conditions were
employed for the asymmetric mercurioetherification of the
trans alkene 30 (isomeric to 1) and the racemic terminal
alkene (Æ )-32 as a kinetic resolution experiment. The former
proceeded somewhat more sluggishly to afford the expected
tetrahydrofuran 31 in 74% yield with 73% ee (15% of
recovered 30) [Eq. (1), tfa = trifluoroacetate].
Angew. Chem. Int. Ed. 2004, 43, 6177 –6180
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Communications
Engl. 1995, 34, 1726; d) R. Dꢀziel, S. Goulet, L. Grenier, J.
Bordeleau, J. Nernier, J. Org. Chem. 1993, 58, 3619; e) K.-I.
Fujita, M. Iwaoka, S. Tomoda, Chem. Lett. 1992, 1123.
[8] a) R. B. Grossman, R. J. Trupp, Can. J. Chem. 1998, 76, 1233;
b) H. B. Vardhan, R. D. Bach, J. Org. Chem. 1992, 57, 4948.
[9] S. H. Kang, S. B. Lee, C. M. Park, J. Am. Chem. Soc. 2003, 125,
15748.
[10] S. H. Kang, M. Kim, J. Am. Chem. Soc. 2003, 125, 4684.
[11] When the cyclization of 1 was scaled up from 0.2 to 2.0 mmol, the
enantioselectivity decreased to 90% ee. However, the addition
of 1 by a syringe pump over 8 h instead of in one portion restored
it to the initial level (93% ee).
6180
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