Asymmetric synthesis of tricyclic-cyclobutane by means of enantioselective deprotonation and intramolecular Michael-aldol reaction

Article abstract of DOI:10.1016/S0040-4039(01)01817-2

We have demonstrated the syntheses of enantiomerically enriched tricyclo[4.2.1.0^3,8]nonanes from C_s symmetric cyclohexanones by means of enantioselective deprotonation, followed by an intramolecular Michael-aldol reaction. The asymme

Full text of DOI:10.1016/S0040-4039(01)01817-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8489–8491
Asymmetric synthesis of tricyclic-cyclobutane by means of
enantioselective deprotonation and intramolecular Michael–aldol
reaction
Kiyosei Takasu,* Keiko Misawa and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama,
Sendai 980-8578, Japan
Received 12 September 2001; revised 27 September 2001; accepted 28 September 2001
Abstract—We have demonstrated the syntheses of enantiomerically enriched tricyclo[4.2.1.03,8]nonanes from Cs symmetric
cyclohexanones by means of enantioselective deprotonation, followed by an intramolecular Michael–aldol reaction. The
asymmetric deprotonation was achieved in up to 79% ee and the following Michael–aldol reaction gave the corresponding
tricyclononanes with almost the same optical purity. © 2001 Elsevier Science Ltd. All rights reserved.
We have developed
a
sequential intramolecular
cyclohexanones by means of an intramolecular
Michael–aldol reaction adopted enantioselective depro-
tonation reaction7 as an effectual asymmetric induction
method.
Michael–aldol reaction as a powerful methodology for
the formation of fused cyclobutyric skeletons.1,2
Cyclobutane derivatives have been known to be an
important and attractive class of compounds. The ring
systems are often found in natural substances,3 and also
play important roles in organic transformation as use-
ful synthetic intermediates due to their unique reactivity
originated from their high ring strain.4 However, in
spite of the usefulness, the methodology of the asym-
metric formation of cyclobutyric ring is limited in
preparative organic chemistry.5,6 Recently, we have
reported two types of asymmetric intramolecular
Michael–aldol reaction, which could easily access to
enantiomerically enriched cyclobutanes (Scheme 1).
One example was chiral auxiliary induced diastereo-
selective Michael–aldol reaction of a-substituted cy-
Koga and Simpkins have elaborated asymmetric depro-
tonation reactions of Cs symmetric ketones by the use
of chiral lithium amides to give optically active enolates
in excellent enantioselectivities.7 Recently, on the basis
of the above reaction Weinreb succeeded in enantiose-
lective intramolecular alkylation of 4-substituted cyclo-
hexanone in 80% ee.8 First, we tested direct intra-
molecular Michael–aldol reaction of 3a using lithium
amides, but no cyclobutane compounds were obser-
ved under any conditions. We modified the plan into
stepwise synthesis as follows: the chiral enolate was
trapped as the corresponded silyl enol ether, and then
the enolate equivalent was subjected to Michael–aldol
reaction conditions.
clohexanones
1
(Eq. (1)).2a,2c Another was the
enantioselective reaction of 3a mediated by a chiral
amine–silyltriflate complex, whose asymmetric induc-
tion was based on enantioselective enol silylation pro-
cess of the Cs symmetric 4-substituted cyclohexanone
3a (Eq. (2)).2b However, the resulted optical yields of 4
were not satisfactory for the synthetic needs. For fur-
ther elaboration of the asymmetric Michael–aldol reac-
tion, the more effective desymmetrization process of Cs
symmetric substrates should be crucial. In this commu-
nication, we describe the asymmetric syntheses of tri-
cyclic cyclobutane derivatives from 4-substituted
OTMS
PhMenO2C
PhMenO2C
O
TMSI
(1)
HMDS
PhMen =
(–)-8-phenylmenthyl
1
2
O
CO2Me
TBSO
MeO2C
TBSOTf
(2)
chiral amine
3a
4
* Corresponding authors. Tel.: +81-22-217-6887; fax: +81-22-217-
6877 (M.I.); e-mail: mihara@mail.pharm.tohoku.ac.jp
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01817-2

8490
K. Takasu et al. / Tetrahedron Letters 42 (2001) 8489–8491
tions, although it is generally accepted that the kinetic
abstraction of enoate’s g-proton is slower than one of
the a-proton of ketone. The reaction of 3a along with
2.4 equiv. of (R,R)-7 at −100°C gave (−)-5a in 65% ee
(run 2). The use of (S)-8a11 furnished (+)-5a in 66% ee
(run 3), whereas cyclic amide (S,S)-912 resulted in low
asymmetric induction (run 4). As was the case for the
reaction of 3a, (S)-8a gave the best result in asymmetric
deprotonation of 3b to furnish (+)-5b with 79% ee (run
6).
Asymmetric deprotonation reaction of 3a and 3b was
explored using chiral lithium amide bases in the pres-
ence of trimethylsilyl chloride (TMSCl), which was
called the ISQ (in situ quench) protocol.9 The optical
purity of 5 was determined by HPLC analysis using a
chiral column after the transformation into enone 6
(Scheme 2). The treatment of 3a with 1.3 equiv. of the
lithium amide (R,R)-7 resulted in no formation of silyl
enol ether 5a (Table 1, run 1). The use of more than 2
equiv. of base afforded the desired 5a in good yields
(runs 2–4). On the other hand, 3b10 having no acidic
proton on g-position of a,b-unsaturated ester was
transformed into silyl enol ether 5b by using only 1.3
equiv. of base (runs 5–7). Interestingly, these results
indicated that the g-proton of enoate moiety of 3a
would be preferentially abstracted rather than the a-
proton of keto-carbonyl group under the above condi-
Next, intramolecular Michael–aldol reaction of opti-
cally active 5 was performed under amine–trimethylsilyl
trifluoromethanesulfonete (TMSOTf) conditions.2b The
reaction of (+)-5a and (+)-5b afforded tricy-
clo[4.2.1.03,8]nonanes (+)-10a and (+)-10b, respectively.
However, on account of the difficulty to isolate pure 10,
full characterization was established after their trans-
formation into the corresponding diol 11. Their optical
yields were concluded by chiral HPLC analyses after
the conversion into benzoate 12 (Scheme 3). No racem-
ization was observed in the Michael–aldol reaction of
O
OTMS
O
amine, nBuLi,
TMSCl
Pd(OAc)2
CH3CN
*
*
THF
4
i
R
R
R
R
R
R
(+)-5a (66% ee) with Pr2NEt–TMSOTf at −30°C and
CO2Me
CO2Me
CO2Me
11a was obtained in 79% yield (Table 2, run 1). The
reaction of (+)-5b (79% ee) resulted in the formation of
11b with 77–78% ee,13 but the chemical yield depended
on the reaction temperature and the reagent (runs 2–4).
3a; R = H
3b; R = Me
5a; R = H
5b; R = Me
6a; R = H
6b; R = Me
Scheme 2.
Table 1. Asymmetric deprotonation reaction of 3
Ph
N
Li
Ph
Ph
N
R
Ph
Ph
N
Li
(S, S)-9
(R, R)-7
(S)-8a (R = Li)
(S)-8b (R = H)
Run
Ketone
Base (equiv.)
5
6e
% Yield
[h]2D2
% eef
Config.
1
2
3
4
5
6
3a
3a
3a
3a
3b
3b
(R,R)-7 (1.3)
(R,R)-7 (2.4)
(S)-8a (2.4)
(S,S)-9 (2.4)
(R,R)-7 (1.3)
(S)-8a (1.3)
0a
80b
84b
79b
88c
85c
–
–
–
ndd
65
66
29
61
79
R
S
S
S
R
+29.5
+19.7
−40.3
+49.2
a Reaction was carried out with 3a (1 equiv.), amine (1.3 equiv.), BuLi (1.3 equiv.) and TMSCl (5.0 equiv.) in THF at −78°C.
b 3a (1 equiv.), amine (2.4 equiv.), BuLi (2.4 equiv.) and TMSCl (5.0 equiv.) in THF at −100°C.
c 3b (1 equiv.), amine (1.3 equiv.), BuLi (1.3 equiv.) and TMSCl (5.0 equiv.) in THF at −100°C.
d Nd means not determined.
e The chemical yields of 9 ranged from 65 to 99% yield.
f All enantiomeric excesses were determined through chiral HPLC analysis using a Chiralcel AD column.
3
OTMS
OH
OH
amine,
TMSOTf
BzCl, NEt3,
DMAP (cat.)
6
i) DIBAL-H
ii) TBAF
8
OH
OBz
CO2Me
2
5a,b
R
1
CH2Cl2
CH2Cl2
R
R
R
R
R
10a; R = H
10b; R = Me
11a; R = H
11b; R = Me
12a; R = H
12b; R = Me
Scheme 3.

K. Takasu et al. / Tetrahedron Letters 42 (2001) 8489–8491
Table 2. Intramolecular Michael–aldol reaction of nonracemic 5
8491
Run
Substrate (% ee)
Michael–aldol conditions
Temperature
11
Reagentsa
% Yieldb
% eec
1
2
3
4
(+)-5a (66)
(+)-5b (79)
(+)-5b (79)
(+)-5b (79)
iPr2NEt, TMSOTf
NEt3, TMSOTf
NEt3, TMSOTf
(S)-8b, TMSOTf
−30°C
−30°C
rt
79
29
54
89
66
78
78
77
rt
a Reaction was carried out with 5 (1 equiv.), amine (3.2 equiv.), TMSOTf (3 equiv.) in CH2Cl2.
b Overall yields from 5 in three steps.
c All enantiomeric excesses were determined through chiral HPLC analysis using a Chiralcel OJ column after transformation into 12.
The best result was accomplished by the use of amine
(S)-8b along with TMSOTf at room temperature (run
4).
3. (a) Bandaranayake, W. M.; Banfield, J. E.; Black, D. S.
C. J. Chem. Soc., Chem. Commun. 1980, 902–903; (b)
Leimner, J.; Marschall, H.; Meier, N.; Weyerstahl, P.
Chem. Lett. 1984, 1769–1772; (c) De Jesus, A. E.; Gorst-
Allman, C. P.; Steyn, P. S.; Van Heerden, F. R.; Vleg-
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4. For recent examples, see: (a) Haque, A.; Ghatak, A.;
Ghosh, S.; Ghoshal, N. J. Org. Chem. 1997, 62, 5211–
5214; (b) Winkler, J. D.; Doherty, E. M. J. Am. Chem.
Soc. 1999, 121, 7425–7426; (c) Nishimura, T.; Ohe, K.;
Uemura, S. J. Am. Chem. Soc. 1999, 121, 2645–2646.
5. Methods of Organic Chemistry (Houben–Weyl); De Mei-
jere, A., Ed.; Thieme: Stuttgart, 1997; Vol. E17e.
6. (a) Narasaka, K.; Hayashi, Y.; Shimadzu, H.; Niihata, S.
J. Am. Chem. Soc. 1992, 114, 8869–8885; (b) Yoshida,
M.; Ismail, M. A.-H.; Nemoto, H.; Ihara, M. J. Chem.
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Chang, V.; Cai, X.; Duesler, E.; Mariano, P. S. J. Am.
Chem. Soc. 2001, 123, 6433–6434.
The absolute configurations of 5a and 10a were deter-
mined by correlation with one of the known compound
12a after the derivatization.2b In consequence, the chi-
ralities of (+)-5a and (+)-10a were assigned as (4S) and
(1S,2S,3R,6S,8S), respectively. The predominance of
the introduced chirality during enantioselective depro-
tonation reaction of 3a was consistent with the estab-
lished rules by Simpkins.7a According to this, the
absolute configurations of (+)-5b and (+)-10b might be
(4R) and (1S,2S,3R,6R,8S), respectively.14
In summary, we have demonstrated the asymmetric
syntheses of tricyclo[4.2.1.03,8]nonanes from Cs symmet-
ric cyclohexanones by means of enantioselective depro-
tonation, followed by intramolecular Michael–aldol
reaction. It is worth mentioning that five stereogenic
centers of 10 could be constructed with up to 78% ee in
the above operations.
7. For reviews, see: (a) Simpkins, N. S. Tetrahedron: Asym-
metry 1991, 2, 1–26; (b) Koga, K.; Shindo, M. J. Synth.
Org. Chem. Jpn. 1995, 53, 1021–1032; (c) O’Brien, P. J.
Chem. Soc., Perkin Trans. 1 1998, 1439–1457.
8. Kropf, J. E.; Weinreb, S. M. Chem. Commun. 1998,
2357–2358.
Acknowledgements
9. (a) Shirai, R.; Tanaka, M.; Koga, K. J. Am. Chem. Soc.
1986, 108, 543–545; (b) Bunn, B. J.; Cox, P. J.; Simpkins,
N. S. Tetrahedron 1993, 49, 207–218.
This work was partly supported by Grant-in-Aid for
Encouragement of Young Scientists (No. 12771347)
from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan.
10. Compound 3b was synthesized according to the reported
procedures with minor modifications.1b
11. Izawa, H.; Shirai, R.; Kawasaki, H.; Kim, H.-D.; Koga,
K. Tetrahedron Lett. 1989, 30, 7221–7224.
12. Aldous, D. J.; Dutton, W. M.; Steel, P. G. Tetrahedron:
Asymmetry 2000, 11, 2455–2462.
References
1. Racemic version: (a) Ihara, M.; Ohnishi, M.; Takano,
M.; Makita, K.; Taniguchi, N.; Fukumoto, K. J. Am.
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Yamada, M.; Tokunaga, Y.; Fukumoto, K. Tetrahedron
Lett. 1995, 36, 8071–8074.
2. Asymmetric version: (a) Takasu, K.; Ueno, M.; Ihara, M.
Tetrahedron Lett. 2000, 41, 2145–2148; (b) Takasu, K.;
Misawa, K.; Yamada, M.; Furuta, Y.; Taniguchi, T.;
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13. Spectral data for 11b; colorless prisms: mp 56.5–57.5°C
1
(as the racemate); H NMR (CDCl3) l: 0.91 (3H, s), 1.01
(3H, s), 1.54–1.77 (8H, m), 2.16–2.24 (1H, m), 2.40–2.75
(1H, br s), 2.64 (2H, dd, J=12.1, 4.9 Hz), 3.75 (1H, dd,
J=11.0, 4.4 Hz), 3.90 (1H, dd, J=11.0, 8.0 Hz); 13C
NMR (CDCl3) l: 19.5, 20.3, 27.7, 30.5, 30.8, 40.0, 41.7,
43.7, 45.3, 47.5, 64.4, 74.2; HRMS calcd for C12H20O2
196.1462 (M+), found 196.1443.
14. Although the absolute configurations of (+)-5a and (+)-5b
would be the same stereochemical sense, the (R) and (S)
symbols are defined as opposite to each other according
to the IUPAC rule. Similarly, the RS designations of 10a
and 10b are not identical.