Asymmetric iodocyclization of γ-hydroxyalkenes

Article abstract of DOI:10.1055/s-2004-825593

Enantioselective intramolecular iodoetherification of disubstituted γ-hydroxyalkenes has been intended using NIS in the presence of 0.2 equivalents of (R)-Binol-Ti(IV) complex to procure the corresponding tetrahydrofurans in up to 65% ee.

Full text of DOI:10.1055/s-2004-825593

LETTER
1279
Asymmetric Iodocyclization of g-Hydroxyalkenes
A
symmetric Io
u
docyclizatio
n
n of
g
-
Hydro
g
xyalkenes Ho Kang,* Chul Min Park, Sung Bae Lee, Mihyong Kim
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)8692810; E-mail: shkang@kaist.ac.kr
Received 12 March 2004
er background reaction. The highest percentage ee was at-
Abstract: Enantioselective intramolecular iodoetherification of
tained in t-BuOMe at 0 °C, while lowering the reaction
disubstituted g-hydroxyalkenes has been intended using NIS in the
temperature and using I2 degenerated stereoselectivity and
reactivity (entries 5–7).
presence of 0.2 equivalents of (R)-Binol–Ti(IV) complex to procure
the corresponding tetrahydrofurans in up to 65% ee.
Key words: reagent-controlled, iodocyclization, g-hydroxyalk- It was found that the amount of molecular sieve as well as
enes, (R)-Binol–Ti(IV) complex, N-iodosuccinimide
its pore size were crucial in generating the active Binol–
Ti(IV) complex. The experimental data in Table 2 dis-
close that 4 Å molecular sieve (MS 4 Å) was superior to 3
Å and 5 Å species. The highest percentage ee was secured
by adding 10 mg of 4 Å molecular sieve per 3 mg of
Ti(Oi-Pr)4 (entry 2). Further improvement was attempted
by adjusting concentration of the reagents as presented in
Table 3. While the best results were reached with 26.4
mM and 52.8 mM concentration of 2 among the examined
concentrations, the cyclization proceeded faster in more
concentrated mixture (entries 2 and 3).
A variety of heterocycles are comprised in a plethora of
physiologically potent natural products. One of the most
reliable synthetic routes to the heterocycles is considered
as electrophile-promoted cycloaddition.1 While stereose-
lectivity of the cycloaddition has been mostly controlled
by the preexisting stereogenic centers of substrates,2 re-
agent-controlled asymmetric version has been relatively
little established to date. Recently, arylselenyl reagents
have been successfully designed for asymmetric seleno-
cyclization, though their preparation requires inefficient
multistep syntheses.3 A prominent enantioselective mer-
curioetherification has been also consummated using
bisoxazoline–Hg(II) complexes.4 Other reported reagent-
controlled asymmetric cycloadditions include iodolacton-
ization with amine–iodonium ion complexes5 and
oxymercuration with Hg(II) carboxylates.6 Since the
chiral reagents involved in those approaches should be
consumed by at least one-equivalent quantities, it is of
great value to accomplish the cyclizations with their cata-
lytic amounts. In this context, we have explored a catalyt-
ic asymmetric intramolecular iodoetherification of g-
hydroxyalkenes using chiral Lewis acids.7 Herein, we de-
scribe our preliminary results of the subject using (R)-
Binol–Ti(IV) complex.
Table 1 Iodocyclization of 2 in the Presence of (R)-Binol–Ti(IV)
Complexa
I
1. Ti(i-PrO)4, MS 4Åb
2. NIS
O
1
2c
solvent, r.t., 1.5 h
Ph
3
OH
OH
Ph
OH
2
1
Entry Solvent
Reaction
temp (°C) time (h)
Reaction Yield (%)d Ee (%)e,f
1
2
3
4
5
6
7h
PhMe
0
–20
0
1.5
2
94
31g
31g
57
59
65
47
9
CH2Cl2
Et2O
87
In the proposed iodocyclization, the chirality of Lewis
acid was presumed to be relayed to substrate through the
electrophile. In addition, high enantioselectivity was con-
ceived to be achieved when Lewis acid catalyzed cycliza-
tion exceeded the background reaction to a great extent.
Among several screened chiral Lewis acids, Binol–Ti(IV)
complex8 was appraised prospective. A model substrate 2
was treated with N-iodosuccinimide (NIS) in the presence
of (R)-Binol–Ti(IV) complex as shown in Table 1. The
optimal amount of the Lewis acid catalyst was determined
as 0.2 equivalents experimentally. Ethereal solvents gave
higher enantioselectivity probably in part due to the slow-
7
86
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
r.t.
0
2
90
9
93
–20
0
9
24 (71)
40 (45)
9
a 0.2 Equiv of 1, 0.2 equiv of Ti(Oi-Pr)4 and 1.2 equiv of NIS were
used.
b 10 mg per 3 mg of Ti(Oi-Pr)4 was added.
c [2] = 26.4 mM.
d Percentage of recovered sm in parenthesis.
e Determined by HPLC analysis using DAICEL OD.
f For determination of absolute configuration, see ref. 4.
g Major product was enantiomer of 3.
h I2 was used instead of NIS.
SYNLETT 2004, No. 7, pp 1279–1281
Advanced online publication: 10.05.2004
DOI: 10.1055/s-2004-825593; Art ID: U07304ST
© Georg Thieme Verlag Stuttgart · New York
0
3.
0
6.
2
0
0
4

1280
S. H. Kang et al.
LETTER
Table 2 Molecular Sieve Effect on Iodocyclization of 2a,b
Table 4 Iodocyclization of 2 Using Ti(IV) Complexed with 4–8a
I
I
2. NIS, 2c
1. Ti(i-PrO)4, MS 4Åb
t-BuOMe, r.t., 1.5 h
O
O
1. Ti(i-PrO)4, MS
t-BuOMe, r.t., 1.5 h
2. NIS, 2
L
1
0 °C, 9 h
0 °C, 9 h
Ph
Ph
3
3
R1
R
Entry mg of MS per 3 mg of Ti(Oi-Pr)4 Yield (%)c Ee (%)
R2
R2
OH
OH
OH
OH
OH
OH
1
2
3
4
5
5 (MS 4 Å)
10 (MS 4 Å)
20 (MS 4 Å)
10 (MS 3 Å)
10 (MS 5 Å)
72 (25)
93
52
65
64
15
29
R1
R
4 R1 = Br R2 = H
8
6 R = Ph
7 R = Br
5 R1 = H R2 = OMe
93
18 (74)
21 (71)
Entry
L
Yield (%)d
93
Ee (%)
65
1
2
3
4
5
6
1
4
5
6
7
8
a 0.2 Equiv of 1, 0.2 equiv of Ti(Oi-Pr)4 and 1.2 equiv of NIS were
17 (70)
71 (20)
90
12e
17
used.
b [2] = 26.4 mM.
c Percentage of recovered sm in parenthesis.
53
Table 3 Concentration Effect on Iodocyclization of 2a
86
26
I
43 (39)
3e
1. Ti(i-PrO)4, MS 4Åb
t-BuOMe, r.t., 1.5 h
2. NIS, 2
O
a 0.2 Equiv of 1, 0.2 equiv of Ti(Oi-Pr)4 and 1.2 equiv of NIS were
used.
1
0 °C
Ph
3
b 10 mg per 3 mg of Ti(Oi-Pr)4 was added.
c [2] = 52.8 mM.
Entry Concentration of 2 Reaction time Yield
Ee
(%)
d Percentage of recovered sm in parenthesis.
e Major product was enantiomer of 3.
(mM)
13.2
26.4
52.8
79.2
(h)
(%)c
65 (25)
93
1
2
3
4
9
46
65
65
58
Table 5 Iodocyclization of 9–14 Using (R)-Binol–Ti(IV) Complexa
9
3
93
1. Ti(i-PrO)4, MS 4Åb
2. substratec
1
3
93
t-BuOMe, r.t., 1.5 h NIS, 0 °C
a 0.2 Equiv of 1, 0.2 equiv of Ti(Oi-Pr)4 and 1.2 equiv of NIS were
used.
I
O
R
O
b 10 mg per 3 mg of Ti(Oi-Pr)4 was added.
c Percentage of recovered sm in parenthesis.
I
or
R
15 R = CH2Ph
16 R = (CH2)3OTBDPS
17 R = Et
19 R = Et
20 R = Ph
In order to investigate the effectiveness of structural vari-
ation on the asymmetric iodocyclization, (R)-Binol deriv-
atives 4–8 were prepared9 and employed in the cyclization
as chiral ligands. The outcomes in Table 4 reveal that (R)-
Binol itself was the best among the examined ligands (en-
try 1). Noticeably, phenylated (R)-Binol 6 also induced
highly enantioselective iodoetherification (entry 4).
18 R = n-Pr
OH
OH
R
R
13 R = Et
14 R = Ph
9 R = CH2Ph
10 R = (CH2)3OTBDPS
11 R = Et
12 R = n-Pr
The developed iodocyclization conditions in Table 3 (en-
try 3)10 were applied to several g-hydroxyalkenes 9–14 as
summarized in Table 5. Their enantioselectivity was not
so high as expected from 2, most of which ranged from
20% to 34% ee. The lowest percentage ee was observed
from the sterically least encumbered ethylalkene 11 (entry
4).
Entry
Substrate Reaction
Time (h)
Product
Yield (%) Ee (%)
1
2
3
4
5
6
2
9
3
18
6
3
15
16
17
18
19
93
89
84
90
95
89
65
31d
21e
13f
28f
20f
10
11
12
13
In conclusion, it has been demonstrated that catalytic
asymmetric iodocyclization can be realized by unprece-
dented use of chiral Lewis acids in a reagent-controlled
sense.
3
4
2
Synlett 2004, No. 7, 1279–1281 © Thieme Stuttgart · New York

LETTER
Asymmetric Iodocyclization of g-Hydroxyalkenes
1281
Table 5 Iodocyclization of 9–14 Using (R)-Binol–Ti(IV) Complexa
(continued)
References
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34, 1726. (d) Fujita, K.-I.; Iwaoka, M.; Tomoda, S. Chem.
Lett. 1992, 1123.
1. Ti(i-PrO)4, MS 4Åb
2. substratec
1
t-BuOMe, r.t., 1.5 h NIS, 0 °C
I
O
R
O
I
or
R
15 R = CH2Ph
16 R = (CH2)3OTBDPS
17 R = Et
19 R = Et
20 R = Ph
18 R = n-Pr
OH
OH
R
R
(4) Kang, S. H.; Kim, M. J. Am. Chem. Soc. 2003, 125, 4684.
(5) (a) Hass, J.; Piguel, S.; Wirth, T. Org. Lett. 2002, 4, 297.
(b) Grossman, R. B.; Trupp, R. J. Can. J. Chem. 1998, 76,
1233.
13 R = Et
14 R = Ph
9 R = CH2Ph
10 R = (CH2)3OTBDPS
11 R = Et
12 R = n-Pr
(6) (a) Grundon, M. F.; Stewart, D.; Watts, W. E. J. Chem. Soc.,
Chem. Commun. 1973, 573. (b) Carlson, R. M.; Funk, A. H.
Tetrahedron Lett. 1971, 27, 3661.
(7) Kang, S. H.; Lee, S. B.; Park, C. M. J. Am. Chem. Soc. 2003,
51, 15748.
Entry
7
Substrate Reaction
Time (h)
Product
Yield (%) Ee (%)
34g
14
10
20
82
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Nakamura, Y. Micropor. Mesopor. Mater. 1998, 21, 461.
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Chem. 1981, 46, 393. (b) Hu, Q.; Vitharana, D.; Pu, L.
Tetrahedron: Asymmetry 1995, 6, 2123. (c) Qian, C.;
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1998, 2097. (d) Cram, D. J.; Helgeson, R. C.; Peacook, S.
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(10) General Procedure for the Asymmetric Iodocyclization.
To a mixture of (R)-Binol (17 mg, 0.06 mmol) and 4Å
molecular sieve (57 mg) in t-butyl methyl ether (3.5 mL) was
added Ti(Oi-Pr)4 (17 mg, 0.06 mmol) in t-butyl methyl ether
(0.7 mL) at r.t., and the resulting mixture was stirred at that
temperature for 1.5 h. After cooling the generated (R)-
Binol–Ti(IV) complex to 0 °C, the substrate 2 (57 mg, 0.3
mmol) in t-butyl methyl ether (1.5 mL) and N-iodo-
succinimide (81 mg, 0.36 mmol) were added in sequence.
The iodocyclization was allowed to proceed at 0 °C for 3 h,
and then quenched with 10% aq Na2S2O3 (3 mL). The
reaction mixture was extracted with Et2O (3 × 5 mL), and
subsequently the organic layer was filtered through celite.
Evaporation of the volatile materials in vacuo followed by
silica gel column chromatography (Et2O–hexane = 1:15)
yielded tetrahydrofuran 3 (89 mg, 93%).
a 0.2 Equiv of (R)-Binol, 0.2 equiv of Ti(Oi-Pr)4 and 1.2 equiv of NIS
were used.
b 10 mg per 3 mg of Ti(Oi-Pr)4 was added.
c [Substrate] = 52.8 mM.
d Determined by HPLC analysis using DAICEL OD-H.
e Determined by HPLC analysis of the corresponding benzoate using
DAICEL OD, which was prepared from 16 via desilylation followed
by benzoylation.
f Determined by GC analysis using CHIRALDEX B-DM.
g Determined by HPLC analysis using DAICEL OD.
Finally, the iodoetherification of terminal olefinic alcohol
( )-21, as a kinetic resolution experiment, was imple-
mented to engender trans-2,5-disubstituted tetrahydro-
furan trans-22 in 52% ee and 42% yield along with 41%
of recovered 21 having 54% ee (Scheme 1).
n
Ti(O-i-Pr)4, MS 4Å
t-BuOMe, r.t., 1.5 h
NIS, 0 °C, 3 h
1
_
(+)-21
Ph
OH
Ph
O
I
+
22
21
Scheme 1
Acknowledgment
This work was supported by CMDS and the Brain Korea 21 Project.
Synlett 2004, No. 7, 1279–1281 © Thieme Stuttgart · New York