Zirconium-catalyzed enantiotopic group-selective synthesis of hydrindanes

Article abstract of DOI:10.1016/S0040-4039(03)00780-9

When a THF solution of 12b and (S)-(EBTHI)ZrBINOL (10 mol%) was refluxed in the presence of BuMgCl (4 equiv.) for 4 h, zirconium-catalyzed enantiotopic group-selective cyclization proceeded and hydrindane 13b with 87% ee was obtained in 35% yield.

Full text of DOI:10.1016/S0040-4039(03)00780-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3797–3800
Zirconium-catalyzed enantiotopic group-selective synthesis of
hydrindanes
Miwako Mori,* Tomoko Takaki, Muneyoshi Makabe and Yoshihiro Sato
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received 3 February 2003; revised 10 March 2003; accepted 14 March 2003
Abstract—When a THF solution of 12b and (S)-(EBTHI)ZrBINOL (10 mol%) was refluxed in the presence of BuMgCl (4 equiv.)
for 4 h, zirconium-catalyzed enantiotopic group-selective cyclization proceeded and hydrindane 13b with 87% ee was obtained in
35% yield. © 2003 Published by Elsevier Science Ltd.
Zirconium-mediated or -catalyzed reaction is very useful
because carbonꢀcarbon bonds are formed between mul-
tiple bonds.1 Since Negishi and Takahashi found a
method for preparing dibutylzirconocene,2 many inter-
esting carbonꢀcarbon bond forming reactions have been
reported. These reactions have been extended to catalytic
reactions in the presence of Grignard reagent,3 and
asymmetric reactions4 using a chiral zirconium complex
have been developed.5 Asymmetric cyclization was devel-
oped by our group, and carbo- and heterocyclic com-
pounds having more than one stereo center were
synthesized in high enantiomeric excesses.6 Here we
report the synthesis of hydrindane using zirconium-cata-
lyzed enantiotopic group-selective cyclization. Our plan
is shown in Scheme 1.
The triene 5a was synthesized from 2, whose hydroxyl
group was protected by a silyl group. Deprotection of
enol ethers 3 followed by Wittig reaction gave triene 5a.
When a THF solution of triene 5a, 10 mol% of (S)-
(EBTHI)ZrBINOL (Cp*2 ZrBINOL, 1)5a and an excess
amount of BuMgCl (8 equiv.) was refluxed for 64 h,
bicyclic compounds 6a and 6b were obtained in 13 and
24% yields, respectively (Scheme 2).
Desilylation of 6a gave 6b in high yield. From an NOE
experiment of 6a, trans-fused 5-5-membered zirconacy-
cle 7a should be formed as an intermediate. After
conversion of 6a and 6b into (S)-MTPA ester 6c,
enantiomeric excesses (ee) were determined to be −12 and
1
59% ee by H NMR spectra, respectively.7 Since com-
pounds 6a and 6b had different ees, kinetic resolution
would occur during the reaction or cyclization of 5b
would occur after desilylation. The reaction was carried
out under various conditions to improve the ee and the
yield, and the results are shown in Table 1. BuMgCl,
EtMgCl, and Bu2Mg as Grignard reagents were used and
BuMgCl gave good results. Dioxane can be used as a
solvent.
When triene I is treated with zirconocene dichloride in
the presence of a Grignard reagent, for example, zircona-
cycle II and ent-II would be formed. However, if
zirconocene having a chiral ligand is used for this
reaction, enantiotopic group-selective cyclization should
proceed, and chiral cyclized compound having three
stereo centers should be produced after hydrolysis.
Scheme 1. Plan for an enantiotopic group selective cyclization.
Keywords: asymmetric synthesis; (EBTHI)ZrBINOL; enantiotopic group-selective synthesis; hydrindane; zirconacycle; zirconium-catalyzed cycliza-
tion.
* Corresponding author. E-mail: mori@pharm.hokudai.ac.jp
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00780-9

3798
M. Mori et al. / Tetrahedron Letters 44 (2003) 3797–3800
cyclized compound 6b was obtained in high yield, it
was almost racemic (Scheme 3). Since the amount of a
Grignard reagent affects the ee of the product in zirco-
nium-catalyzed asymmetric cyclization,6 the amounts of
a Grignard reagent were changed (Table 2). It was
interesting that a decrease in the amount of BuMgCl
resulted in an increase in the ee of 6b, although the ees
were moderate (runs 1–5). When 1.2 equiv. of BuMgCl
was used for this reaction, 6b with 54% ee was obtained
in 46% yield (run 6). The reaction proceeded in a
similar manner when 5b was treated with BuLi or NaH,
and in each case, the different ee was obtained (runs
7–8).
Scheme 3. Reaction of 5b with 1.
The possible reaction course is shown in Scheme 4.
Treatment of triene 5 with 1 gives tricyclic zirconacycle
7 (route a). In the presence of BuMgCl, it is converted
into ate-complex 8 (route b), which is in a state of
equilibrium with 9 or 9% (routes c and c%) From 9 or 9%,
b-hydrogen elimination occurs to give 10 or 10%. After
hydrolysis, each complex affords hydrindane 6. Accord-
ing to this scheme, the reaction of 5 with 1 also affords
ent-7, which should give ent-6.
Scheme 2. Zirconium-catalyzed cyclization of triene 5.
The protecting groups of the hydroxyl group were
changed to TBDPS (SitBuPh2), benzyl, and methyl
groups, but good results were not obtained. Next,
compound 5b was used as a substrate. Although the
Table 1. Enantioselective zirconium-catalyzed cyclization
Entry
RMgX (equiv.)
Solvent
Time (h)
6a (%)
6b (%)
ee
5a (%)
Yield
ee
Yield
1
2
3
4
5
6
BuMgCl (8)
EtMgBr (8)
Bu2Mg (4)
BuMgCl (8)
BuMgCl (8)
BuMgCl (8)
THF
THF
64
91
87.5
15.5
40
13
19
11
37
–
−12
24
30
19
23
45
13
59
41
30
25
47
53
33
5
9
–
–
14
25
32
THF/heptaneb
Bu2Oa
–
–
THF/THPa,c
THF/dioxanea,c
63.5
41
–
a Reaction temp., 80°C.
b Ratio of 3 to 2.
c Ratio of 2 to 3.
Table 2. Results for different amounts of BuMgCl
Entry
R
BuMgCl (equiv.)a
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
MgCl
MgCl
MgCl
MgCl
MgCl
MgCl
Lic
5c
5c
5c
5c
5c
5c
5d
5e
15
8
7
4
2
1.2
8
8
1.5
13
10
11.5
16
48
85
83
95
98
88
46b
77
90
−9
0
12
17
34
54
−21
−19
12.5
3
Nac
a Since 1 equiv. of BuMgCl is consumed by the hydroxyl group, the other amount of BuMgCl was described.
b 5b was recovered in 23% yield.
c 1 equiv. of BuLi or NaH was added and the reaction was carried out.

M. Mori et al. / Tetrahedron Letters 44 (2003) 3797–3800
3799
Scheme 4. Possible reaction course.
It was thought that the reaction proceeds through
either route c or c%. To determine the route, compound
5b was treated with rac-1 in a similar manner in the
presence of BuMgCl, and then the formed magnesium
complex was treated with oxygen to give compound 11
in 70% yield (Scheme 5). This means that the reaction
proceeds via route c. When the reaction of 5d with a
stoichiometric amount of (S)-1 was carried out at room
temperature for 48 h, 6b was obtained in 57% yield with
−36% ee after hydrolysis. In a catalytic reaction, 6b
with −21% ee was obtained from 5d (Table 2, run 7).
These results indicate that enantioselection should
occur at both steps, i.e. when zirconacycle is formed
(step a) and when ate-complex 8 is formed by RMgX
(step b). The effects of protecting group, including
metals, on the hydroxyl group are not clear at this
stage.
Scheme 6. Synthesis of hydrindane using zirconium-catalyzed
asymmetric cyclization.
Subsequently, triene 12 was used as a substrate. When
a THF solution of triene 12a, 10 mol% of (S)-1, and
BuMgCl (8 equiv.) was refluxed for 5 h, cyclized com-
pounds 13a and 13b were obtained in 22 and 15%
yields, respectively. Treatment of the former compound
with Bu4NF afforded compound 13b in high yield. The
results of an NOE experiment of benzoate 13d,
obtained from 13b, indicate that trans-fused 5-5-mem-
bered zirconacycle 14 was formed. The ees were deter-
mined by HPLC using a chiral column to be 78 and
80%, respectively.8,9 The effects of protecting groups
were examined, and the results are shown in Table 3. In
the case of a TBDPS group, the desired compound 13c
with 78% ee was obtained in 48% yield, and in the case
of a hydroxyl group, 13b with 87% ee was obtained in
35% yield. Compound 12b was treated in a similar
manner followed by treatment with oxygen to give diol
15 with 85% ee in 35% yield. This means that b-hydro-
gen elimination10 from 16 should occur during the
reaction to give 17 (Scheme 6).
The results indicate that functionalized hydrindane hav-
ing a high ee can be obtained using zirconium-catalyzed
enantiotopic group-selective cyclization, although the
yield is moderate. Further studies are in progress.
Scheme 5. Confirmation of the reaction course.
Table 3. Reaction of 12 with (S)-1 in the presence of BuMgCl
Run
R
BuMgCl (equiv.)
Time (h)
13
13b
Yield (%)
ee (%)
Yield (%)
ee (%)
1
2
3
4
TBDMS
TBDMS
TBDPSa
H
12a
12a
12c
12b
8
4
4
5
5
10
23.5
4
22
23
48
–
78
75
78
–
15
10
–
80
78
–
35
87
a SitBuPh2.

3800
M. Mori et al. / Tetrahedron Letters 44 (2003) 3797–3800
6b into (S)-MTPA ester using DCC. The methylene
References
protons connected to the acyloxy group on a 1H NMR
spectrum of a mixture of (S)-MTPA esters of 6a and
ent-6a appeared at 4.16 and 4.11 ppm for 6 and ent-6,
respectively, as 1H protons of quartets of AB type. The ee
was determined from the ratio of the area. Since the
absolute configuration was not determined, the ee
obtained from 4.16 ppm is shown as a positive value and
that obtained from 4.11 ppm is shown as a negative
value.
1. (a) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.
J. Am. Chem. Soc. 1985, 107, 2508; (b) Negishi, E.;
Holmes, S. J.; Tour, J. M.; Miller, J. A.; Ceberaum, F.
E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc.
1989, 111, 3336; (c) Nugent, W. A.; Calabrese, J. C. J.
Am. Chem. Soc. 1984, 106, 6422.
2. Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetra-
hedron Lett. 1986, 27, 2829.
3. (a) Dzhemilev, U. M.; Vostrikova, O. S. J. Organomet.
Chem. 1985, 285, 43; (b) Takahashi, T.; Seki, T.; Nitto,
Y.; Saburi, M.; Rousset, C. J.; Negishi, E. J. Am. Chem.
Soc. 1991, 113, 6266; (c) Knight, K. S.; Waymouth, R.
M. J. Am. Chem. Soc. 1991, 113, 6268; (d) Hoveyda, A.
H.; Xu, Z. J. Am. Chem. Soc. 1991, 113, 5079.
8. The ees were determined by HPLC using DAICEL
CHIRALCEL OD eluted with hexane/2-propanol=95/5.
9. 13b was converted into 19, and the absolute configuration
was determined using the CD exciton chirality method.11
Since the CD spectrum of 19 showed first the negative
Cotton effect at 273 nm and secondly the positive Cotton
effect at 247 nm, the absolute configuration of 19 was
determined to be S as shown in Scheme 7.
4. (a) Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. J. Am.
Chem. Soc. 1993, 115, 6997; (b) Bell, L.; Whitby, R. J.;
Jones, R. V. H.; Standen, M. C. H. Tetrahedron Lett.
1996, 37, 7139; (c) Kondakov, D. Y.; Negishi, E. J. Am.
Chem. Soc. 1995, 117, 10771; (d) Kondakov, D. Y.;
Negishi, E. J. Am. Chem. Soc. 1996, 118, 1577; (e)
Morken, J. P.; Didiuk, M. T.; Visser, M. S.; Hoveyda, A.
H. J. Am. Chem. Soc. 1994, 116, 3123; (f) Didiuk, M. T.;
Johannes, C. W.; Mroken, J. P.; Hoveyda, A. H. J. Am.
Chem. Soc. 1995, 117, 7097; (g) Hoveyda, A. H.; Morken,
J. P. Angew. Chem., Int. Ed. Engl. 1996, 35, 1262.
5. (a) Wild, F. R. W. P.; Wasiucionek, M.; Huttner, G.;
Brintzinger, H. H. J. Organomet. Chem. 1985, 288, 63; (b)
Collins, S.; Kuntz, B. A.; Taylor, N. J.; Ward, D. G. J.
Organomet. Chem. 1988, 342, 21; (c) Grossman, R. B.;
Davis, W. M.; Buchwald, S. L. J. Am. Chem. Soc. 1991,
113, 2321.
Scheme 7. Determination of absolute configuration.
10. In some cases, b-hydrogen elimination occurred at the
stage of the hydrolysis: Uesaka, N.; Mori, M.; Okamura,
K.; Date, T. J. Org. Chem. 1994, 59, 4542.
11. Harada, N.; Nakanishi, K. Circular Dichroic Spec-
troscopy—Exciton Coupling in Organic Stereochemistry;
University Science Books: Mill Valley, CA and Oxford
University Press: Oxford, 1983.
6. (a) Yamaura, Y.; Hyakutake, M.; Mori, M. J. Am.
Chem. Soc. 1997, 119, 7615; (b) Yamaura, Y.; Mori, M.
Tetrahedron Lett. 1999, 40, 3221; (c) Yamaura, Y.; Mori,
M. Heterocycles 2000, 52, 595.
7. The ees of 6a and 6b were determined by conversion of