Stereoselective construction of 3a-methylhydrindanes starting from 2,7-enynol derivatives based on Ti(II)-mediated cyclization and Ru-catalyzed ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2006.05.030

The Ti(II)-mediated cyclization of 3-methyloct-2-en-7-yn-1-ol derivatives 2 proceeded stereoselectively to afford 1-methyl-2-(1-alkylbut-3-enylidene)-1-vinylcyclopentanes 3 after treatment of the resulting alkenyltitaniums with allylbromide in the presenc

Full text of DOI:10.1016/j.tetlet.2006.05.030

Tetrahedron Letters 47 (2006) 5181–5185
Stereoselective construction of 3a-methylhydrindanes starting
from 2,7-enynol derivatives based on Ti(II)-mediated
cyclization and Ru-catalyzed ring-closing metathesis
Mutsumi Ohkubo, Wataru Uchikawa, Hitomi Matsushita, Aiko Nakano,
Takayuki Shirato and Sentaro Okamoto*
Department of Applied Chemistry, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
Received 3 April 2006; revised 1 May 2006; accepted 8 May 2006
Abstract—The Ti(II)-mediated cyclization of 3-methyloct-2-en-7-yn-1-ol derivatives 2 proceeded stereoselectively to afford 1-methyl-
2-(1-alkylbut-3-enylidene)-1-vinylcyclopentanes 3 after treatment of the resulting alkenyltitaniums with allylbromide in the
presence of CuCN, which was readily converted to 3a-methyl-2,3,3a,6-tetrahydro-1H-indenes 1 by the Ru-catalyzed ring-closing
metathesis.
Ó 2006 Elsevier Ltd. All rights reserved.
Construction of the 3a-methylhydrindane skeleton that
is widely present in natural compounds such as steroids,
vitamin D, higher terpenes, and related natural products
has received a great deal of attention.1 Recently, metal-
promoted or -catalyzed reactions have attracted interest
as a selective means for synthesis of 3a-methylhydrin-
dane from acyclic starting compound(s).2 Herein we re-
port an efficient two-step method for the synthesis from
acyclic unsaturated starting compounds.
Our synthetic plan for synthesizing 3a-methyl-2,3,3a,6-
tetrahydro-1H-indene (1) is summarized in Scheme 1
(R3 = Me), which involves divalent titanium-mediated
enyne-cyclization (intramolecular allyltitanation of
alkyne) of enyne 2 followed by copper-catalyzed allylation
of the resulting alkenyltitanium compound 4 and the
subsequent Ru-catalyzed ring-closing metathesis reac-
tion of the resulting triene 3. Regarding the first step
of Scheme 1, we already reported that the reaction of
2 (R3 = H) with a divalent titanium reagent, Ti(O-i-
Pr)4/2i-PrMgCl,3 proceeds in an intramolecular allyltit-
anation pathway to provide the corresponding cyclized
product type 4 (R3 = H) in excellent yield.4 With the re-
sults, we expected that we could find appropriate condi-
tions to control 1,2-diastereoselection of the reaction of
compound 2 (R3 = Me) with Ti(O-i-Pr)4/2i-PrMgCl.5
Scheme 1. Synthetic plan.
First, we carried out the Ti(II)-mediated cyclization of
enynes 2 (R3 = Me) having a different leaving group X
such as OAc, OP(O)(OEt)2, OCO2Et, or Cl, and the fol-
lowing copper-catalyzed allylation of the resulting
alkenyltitanium 4 to see the efficiency. Thus, to a solu-
tion of 2 (1.0 equiv) and Ti(O-i-Pr)4 (1.3 equiv) in ether
was added dropwise i-PrMgCl (2.6 equiv, 1.3 M in
ether) at À40 °C. After being stirred for 1.5 h at this
temperature, to the resulting solution of alkenyltitanium
4 were added allylbromide (1.5 equiv) and a THF
solution of CuCN–2LiCl (5 mol %) at 0 °C.4i After
warming to room temperature over 3 h, usual aqueous
*
Corresponding author. Tel.: +81 45 481 5661; fax: +81 45 413
9770; e-mail: okamos10@kanagawa-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.030

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M. Ohkubo et al. / Tetrahedron Letters 47 (2006) 5181–5185
work-up afforded 3. As can be seen from Table 1 sum-
marizing the results, all reactions predominantly pro-
duced the cyclized compound 3 with syn configuration
regarding the methyl and R2 groups.6 Although the
reaction of Z-2a having an OAc or OCO2Et moiety as
a leaving group resulted in poor yield and/or low stereo-
selectivity (entries 2 and 4), high selectivity and good
yield of syn-3a were attained by using 2a having
OP(O)(OEt)2 or Cl, irrespective of the olefin geometry
of the starting 2a (entries 5–8). Similarly, the reaction
of enynes 2b–d having other alkyne substituents yielded
the corresponding triene syn-3 selectively. The enynol
derivative 2e with a secondary alkyl group as R2 could
also be converted to syn-3e with nearly complete selec-
tivity, where a mixture of E- and Z-isomers was em-
ployed as the substrate.
B and D (indicated by gray circles in Scheme 2) may
cause their instability. Use of a better leaving group
(X) enhanced the rate of the b-elimination reaction of
the titanacycle intermediates. Accordingly, it could in-
crease the overall reaction rate and efficiency of the for-
mation of 4. The rate enhancement of the b-elimination
reaction from A or C by use of the better leaving group
may be larger than that for B or D, respectively, and it
may favorably effect predominant formation of syn-4.
With these results in hand, we next carried out the
Ru-catalyzed ring-closing metathesis reaction8,9 of the
resulting triene 3 to 1 (Scheme 3). Thus, the triene 3
was treated with the first-generation Grubbs catalyst,
Cl2(Cy3P)2Ru@CHPh, (3–5 mol %) in CH2Cl2 at room
temperature and the following purification by column
chromatography to provide 16 in good isolated yield.
To explain the diastereoselectivity observed in Table 1,
we carried out MM2 calculations7 using simplified mod-
els A–D for the possible titanacyclopentene intermedi-
ates derived from (E)- and (Z)-2, where R2, X, R1 in 2
and O-i-Pr moieties on the titanium atom were replaced
by O-t-Bu, OMe, Me, and OMe groups, respectively
(Scheme 2). As shown in Scheme 2, it was revealed that
models A and C which can provide the product of the
type syn-4, that is, syn-3, are more stable in ꢀ2 kcal/
mol than the corresponding isomers B and D. The pseu-
do-axial orientation of the R2 group (O-t-Bu) in models
2,7-Enynol derivatives 2a–d (R2 = Me, R3 = OTBS)
thus utilized were synthesized according to the proce-
dure summarized in Scheme 4. Thus, diynes 8 were ob-
tained by the reaction of the alkynyllithium compound,
derived from the propynoic acid ethyl ester and LDA,
with the corresponding alkynylaldehydes 5 and the fol-
lowing silylation of the resulting alcohols. Treatment
of 6 with Me2CuLi provided 7,10 which was converted
to 2 by the reduction with DIBAL and the following
esterification or halogenation.
Table 1. Ti(II)-mediated cyclization and the following allylation of 2 to 3
Entry
2a
syn:anti
Yield (%)
X
Geometry
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
OAc
OAc
E
95:5
93:7
96:4
76:24
97:3
98:2
99:1
98:2
92:8
92:8
98:2
93
34
72
25
87
90
82
72
84
98
83
86
Z
OCO2Et
OCO2Et
OP(O)(OEt)2
OP(O)(OEt)2
Cl
E
Z
E
Z
E
Cl
Z
9
OP(O)(OEt)2
OAc
OP(O)(OEt)2
OP(O)(OEt)2
E
10
11
12
E
E
Mix.b
>99:1
a The structure is shown above.
b E:Z = 90:10.
cA 1:1 mixture of diastereoisomers.

M. Ohkubo et al. / Tetrahedron Letters 47 (2006) 5181–5185
5183
Scheme 3. Ru-catalyzed ring-closing metathesis of 3 to 1.
Scheme 4. Preparation of 2a–d.
Scheme 2. Postulated reaction mechanism and MM2 calculation of
models of titanacycle intermediates: aEnergy calculated as RO, R1, R2
and X are MeO, Me, O-t-Bu, and MeO, respectively.
was racemic, an optically active compound can be
prepared by starting from optically active 9.11
Closely related reaction conditions to those for the
synthesis of 3a-methylhydrindanes 2 were subsequently
utilized for synthesis of a variety of 1,4-cyclohexadienes
(Table 2), which are useful intermediates as a precursor
Meanwhile, 2e was prepared by the procedure depicted
in Scheme 5. Thus, diynol derivative 8 was treated with
Ti(O-i-Pr)4/2i-PrMgCl to generate the corresponding
allenyltitanium,3 addition of ethylidene malonate to
which provided the Michael addition product 9 in 80%
yield with a high diastereomeric ratio (94:6).11 The
resulting diester 9 was converted to benzyl ether 10 by
decarboxylation and the following reduction, desilyla-
tion, and benzylation. The 1-alkyne 11 was carboxylated
by treatment with n-BuLi and then ClCO2Et to give 11,
which was isolated as a single diastereomer. After meth-
ylation of 11 was performed by treatment with Me2Cu-
Li, reduction of the resulting b-methyl-a,b-unsaturated
ester with DIBAL afforded alcohol 12, the TIPS group
of which was replaced by a TMS moiety to give 13.
Esterification of 13 with ClP(O)(OEt)2 provided 2e
(E/Z = 90:10). Although compound 2e thus synthesized
of the arene ligand in organometallic compounds,12
a
substrate of ene and/or Diels–Alder reactions13 and oxi-
dation to the corresponding benzene derivatives. Table 2
summarizes representative results of the synthesis of 1,4-
cyclohexadienes 15 from acyclic unsaturated starting
materials by the intra- or intermolecular Ti(II)-mediated
allyltitanation/Cu-catalyzed allylation and the following
Ru-catalyzed ring-closing metathesis reactions of the
resulting trienes 14. Entry 4 exemplified preparation of
disubstituted 1,4-cyclohexadienes through the inter-
molecular Ti(II)-mediated bis-allylation of alkynes.
In summary, we have developed an efficient two-
step method for diastereoselective construction of

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M. Ohkubo et al. / Tetrahedron Letters 47 (2006) 5181–5185
3-substituted 3a-methyl-2,3,3a,6-tetrahydro-1H-indenes
from acyclic unsaturated compound by the tandem
Ti(II)-mediated cyclization/Cu-catalyzed allylation and
Ru-catalyzed ring-closing metathesis reactions. Further
investigation including preparation of optically active
compounds11 of the type 1 and their application to
natural product synthesis is in progress.
Acknowledgments
We thank the Ministry of Education, Culture, Sports,
Science and Technology (Japan) for financial support.
We thank Professor Raymond J. Giguere, Skidmore
College, for valuable comments and discussion.
References and notes
Scheme 5. Preparation of 2e. Reagents and conditions: (i) Ti(O-i-Pr)4
(1.5 equiv), i-PrMgCl (3.0 equiv), ether, À40 °C, 3 h; (ii) LiCl
(2.7 equiv), DMSO–H2O, 135 °C, 10 h; (iii) DIBAL (2 equiv), ether,
À20 °C, 1 h; (iv) cat. K2CO3, MeOH, rt, 2 h; (v) BnBr (1.5 equiv), NaH
(1.5 equiv), THF–DMF, rt, 10 h; (vi) n-BuLi (1.5 equiv) then ClCO2Et
(1.8 equiv), THF, À78 °C, 0.5 h; (vii) CuI (1.4 equiv), MeLi
(2.8 equiv), THF, À40 °C, 0.5 h; (viii) TBAF (1.5 equiv), THF, rt,
3 h; (ix) n-BuLi (2.3 equiv) then TMSCl (2.3 equiv), THF, 0 °C, and
then 1 M HCl–MeOH, rt, 0.5 h; (x) ClP(O)(OEt)2 (2 equiv), pyridine,
rt, 0.5–1 h.
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a Stereochemistry was not confirmed.
b Reaction was carried out in toluene at 70 °C for 3 days.

M. Ohkubo et al. / Tetrahedron Letters 47 (2006) 5181–5185
5185
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was
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´
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