Application of Rh-catalyzed cyclization for the construction of three consecutive chiral carbons in 4,9-dimethylspiro[4.4]nonane-2,7-dione

Article abstract of DOI:10.1016/S0040-4039(00)01315-0

Asymmetric cyclization using Rh-complexes has been applied to the synthesis of 4,9-dimethylspiro[4.4]nonane-2,7-diones. The spiro[4.4]nonane skeleton bearing three consecutive chiral carbons could be stepwisely constructed from an identical starting material by the combination of a cationic Rh[(S)-BINAP]ClO₄ and a neutral RhCl(PPh₃)₃. The relationship between the stereochemistry of the spirodiketones and the Rh-complex was also discussed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01315-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7879–7883
Application of Rh-catalyzed cyclization for the construction
of three consecutive chiral carbons in
4,9-dimethylspiro[4.4]nonane-2,7-dione
Miyuki Takahashi, Masakazu Tanaka,* Eishi Sakamoto, Masanori Imai, Akiko Matsui,
Kazuhisa Funakoshi, Kiyoshi Sakai and Hiroshi Suemune*
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Received 3 July 2000; revised 27 July 2000; accepted 28 July 2000
Abstract
Asymmetric cyclization using Rh-complexes has been applied to the synthesis of 4,9-dimethyl-
spiro[4.4]nonane-2,7-diones. The spiro[4.4]nonane skeleton bearing three consecutive chiral carbons could
be stepwisely constructed from an identical starting material by the combination of a cationic Rh[(S)-
BINAP]ClO4 and a neutral RhCl(PPh3)3. The relationship between the stereochemistry of the spirodi-
ketones and the Rh-complex was also discussed. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: cyclization; spiro compounds; rhodium; asymmetric reactions.
Some spiro compounds, found as biologically active products from natural sources,1 have
been designed as chiral ligands for asymmetric syntheses,2 and prepared as new materials.
Construction of the chiral quaternary carbon in spirane skeletons continues to be a fascinating
challenge to organic chemists.3 We have previously reported the construction of spiro com-
pounds using enzymatic methods4 and stereoselective methods using cycloalkane-1,2-diols as a
chiral auxiliary.5 Here, we wish to describe the asymmetric synthesis of 4,9-dimethyl-
spiro[4.4]nonane-2,7-dione using Rh-catalyzed cyclization twice.6,7 We planned the stepwise
route using the Rh-catalyzed cyclization twice to construct 4,9-dimethylspiro[4.4]nonane-2,7-
dione. It was expected that the selection between a neutral or a cationic Rh-complex, and the
choice of proper phosphin ligands would afford the desired optically active spiro compounds
stereoselectively.
The 4-pentenal substrate 6 for the first Rh-catalyzed cyclization was prepared as follows.
Acetylacetone 1 was converted into diester 2 by dialkylation with methyl bromoacetate in 84%
* Corresponding authors. Tel: +81-92-642-6603; fax: +81-92-642-6545; e-mail: mtanaka@phar.kyushu-u.ac.jp;
suemune@phar.kyushu-u.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01315-0

7880
yield. Olefination ofthe 1,3-dicarbonylfunction in2 with Nysted reagent {cyclodibromodi-m-methyl-
ene[m-(tetrahydrofuran)]trizinc}8 afforded diene 3 in 30% yield. The diester 3 was reduced to diol
4 (99%), and the diol 4 was converted to the 4-pentenal 6 by monoacetylation and subsequent
oxidation with PCC in 62% overall yield.
†
The cyclization by the cationic Rh[(S)-BINAP]ClO4 (0.05 equiv.) in CH2Cl2 at room
temperature afforded cyclopentanone (+)-7 in 94% yield. The ratio of cis and trans in the
obtained (+)-7 was 1 (cis) to 99 (trans). The relative stereochemistry of product (+)-7 was
1
unambiguously determined by the NOESY H–1H NMR spectrum. Correlation between the
methyl proton signals l 1.06 (d, J=7.3 Hz, 3H) and the methylene signals l 2.41–2.50 (m, 2H)
1
was observed. The enantiomeric excess of (+)-7 was determined to be 95% ee by the H and 13C
NMR spectra, after conversion of (+)-7 into the (R,R)-butane-2,3-diol acetal. Furthermore, the
relative and absolute stereochemistries of (+)-7 were correlated with those of (3R,4R)-3,4-
dimethyl-3-isopropenylcyclopentanone (−)-10 which was obtained by the Rh[(S)-BINAP]ClO4-
catalyzed cyclization.7 Therefore, the absolute stereochemistry of (+)-7 cyclized by the cationic
Rh[(S)-BINAP]ClO4 should be 3R,4R. Cyclization by the neutral Rh[(S)-BINAP]Cl did not
proceed at all, due to the low catalytic activity of the neutral Rh-complex and the bulkiness of
the BINAP ligand. The obtained cyclopentanone (+)-7 was converted into 4-pentenal (+)-8 by
solvolysis of the acetyl function and subsequent oxidation of primary alcohol in 98% overall
yield, as shown in Scheme 1.
Scheme 1. Reagents and conditions: (i) BrCH2COOCH3, NaH; (ii) BrCH2COOCH3, t-BuOK; (iii) Nysted reagent,
TiCl4; (iv) LiAlH4; (v) Ac2O, 4-DMAP, pyridine; (vi) PCC; (vii) Rh[(S)-BINAP]ClO4; (viii) K2CO3, MeOH; (ix)
Rh-complexes
The results of the second cyclization by the Rh-complexes are summarized in Table 1. The
cyclization of (+)-8 by the neutral Rh[(R)- or (S)-BINAP]Cl did not proceed at all (entries 3, 4)
because of the bulky quaternary carbon at the C(3)-position and the low reactivity of the neutral
Rh[(R)- or (S)-BINAP]Cl complex. The cyclization by the cationic Rh[(R)-BINAP]ClO4 did not
proceed (entry 1), but the cyclization by the cationic Rh[(S)-BINAP]ClO4 proceeded to afford
spirodiketone (−)-9a in 94% yield (entry 2). The cyclization of (+)-8 by the achiral RhCl(PPh3)3
afforded (−)-9b in 90% yield. The spectroscopic data of (−)-9a and (−)-9b were apparently
different.
† Rh[(S)-BINAP]ClO4 was prepared in situ from Rh[(NBD)(S)-BINAP]ClO4 by hydrogenation.

7881
Table 1
The second cyclization of (+)-8 by the Rh-complexesa)
The spirodiketones 9 contain three consecutive chiral carbons, and the C2-axis at the
quaternary carbon C(5) exists in some spirodiketones; therefore, three pairs of enantiomers exist.
The 13C NMR spectrum of (−)-9a showed six peaks, while those of (−)-9b showed eleven peaks.
These results indicate that the C2-symmetry exists in the structures 9a but not in 9b. In the
NOESY H–1H NMR spectrum of (−)-9a, correlation between the methyl proton signals l 1.08
(d, J=6.9 Hz, 6H) at the C(4 and 9)-position and the methylene signals l 2.31 (d, J=17.6 Hz,
2H) at the C(1 and 6)-position was observed. In the spectrum of (−)-9b, the correlation between
the methyl proton signals l 1.14 (d, J=6.9 Hz, 3H) at the C(9)-positon and the methine signals
l 2.34 (m, 1H) at the C(4)-position and also the methyl signals l 1.03 (d, J=6.9 Hz, 3H) at the
C(4)-position and the methylene signals l 2.50 (d, J=18.0 Hz, 1H) at the C(6)-position were
observed (Fig. 1). Moreover, it is already reported that the stereochemistry of 3,4-substituted
cyclopentanones cyclized from 4-pentenal by the RhCl(PPh3)3 is 3,4-cis. Based on these results,
we concluded the stereochemistry of (−)-9a as 4R,5S,9R, and (−)-9b as 4R,5S,9S.9
1
Figure 1. Correlations observed in the NOESY H–1H NMR spectra (only relevant correlations were depicted)

7882
The diastereomeric ratio of spirodiketones 9 in entry 2 was determined to be 97 (9a) to 3 (9b)
by the ratio of methyl proton signals of 9a at l 1.08 (d, 6H), and the signal of 9b at l 1.14, 1.03
1
(each d, total 6H), in the H NMR spectrum, and that in entry 5 was 5 (9a) to 95 (9b).
The stereoselectivity for the first cyclization was consistent with the previous experiments.6,7
The outcome in the stereochemistry of spirodiketones 9 could be explained as follows: First, the
stereochemistry of C(4)- and C(5)-carbons in the spirodiketones was derived from the C(4)- and
C(3)-carbons of cyclopentanone 7 with retention of its chirality, respectively. Thus, the stereo-
chemistry of the C(9)-carbon in spirodiketones 9 was newly constructed by the second
Rh-catalyzed cyclization.
The second cyclization by the neutral RhCl(PPh3)3 would be explained by considering the
plausible acyl-rhodium intermediates. Intermediate (a) would be less stable than intermediate (b)
because the repulsion between the methyl function at the C(4)-position and the rhodium metal
exists in the intermediate (a). Consequently, the spirodiketone (−)-9b (Table 1, entry 5) was
obtained as a major product by way of the stable intermediate (b), as shown in Fig. 2. The
relative stereochemistry of (−)-9b was cis between the methyl function at the C(9)-position and
the C(4)-carbon of the spirane skeleton. The second cyclization by the cationic Rh-complex gave
the opposite stereochemistry at the C(9)-position to that by the neutral Rh-complex. This
phenomenon has already been observed in the Rh-catalyzed cyclization of 4-pentenals.7 The
cyclization of (+)-8 by Rh[(S)-BINAP]ClO4 proceeded to afford (−)-9a, but use of Rh[(R)-
BINAP]ClO4 was not effective. This result would be attributed to the fact that the absolute
stereochemistry of (3R,4R)-(+)-8 accorded with that of Rh[(S)-BINAP]ClO4.
Figure 2. Plausible mechanism for the stereoselection of the second cyclization by the RhCl(PPh3)3
The Rh-catalyzed cyclization was applied to construct the optically active spiro[4.4]nonane-
2,7-dione skeleton. Spiro[4.4]nonanes (−)-9a,b bearing a chiral quaternary carbon, could be
constructed in diastereoselective and enantioselective manners by using the Rh-complex twice.
The strategy described here would be useful for the construction of spirane skeletons.
References
1. (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C. T. The Total Synthesis of
Sesquiterpines; ApSimon, J., Ed.; Wiley: New York, 1983, Vol. 5, pp. 264–313. (b) Crimmins, M. T.; Wang, Z.;
McKerlie, L. A. J. Am. Chem. Soc. 1998, 120, 1747–1756.

7883
2. (a) Srivastava, N.; Mital, A.; Mumar, A. J. Chem. Soc., Chem. Commun. 1992, 493–494. (b) Jiang, Y.; Xue, S.; Li,
Z.; Deng, J.; Mi, A.; Chan, A. C. Tetrahedron: Asymmetry 1998, 9, 3185–3189.
3. Sannigrahi, M. Tetrahedron 1999, 55, 9007–9071 and references therein.
4. Fujita, T.; Tanaka, M.; Norimine, Y.; Sakai, K.; Suemune, H. J. Org. Chem. 1997, 62, 3824–3830.
5. (a) Suemune, H.; Maeda, K.; Kato, K.; Sakai, K. J. Chem. Soc., Perkin Trans. 1 1994, 3441–3447. (b) Yamada,
S; Karasawa, S.; Takahashi, Y.; Aso, M.; Suemune, H. Tetrahedron 1998, 54, 15555–15566.
6. (a) Sakai, K. J. Synth. Org. Chem. Jpn. 1993, 51, 733–743. (b) Fujio, M.; Tanaka, M.; Wu, X. M.; Funakoshi, K.;
Sakai, K.; Suemune, H. Chem. Lett. 1998, 881–882 and references therein.
7. (a) Tanaka, M.; Imai, M.; Fujio, M.; Sakamoto, E.; Takahashi, M.; Eto-Kato, Y.; Wu, X.-M.; Funakoshi, K.;
Sakai, K.; Suemune, H. J. Org. Chem., in press. (b) Takahashi, M.; Tanaka, M.; Sakamoto, E.; Imai, M.;
Funakoshi, K.; Sakai, K.; Suemune, H. Chem. Pharm. Bull., in press.
8. Nysted reagent is commercially available from Aldrich Co.: Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett
1998, 313–315.
9. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York, 1994; pp. 1138–1142.
.
.