Organocatalytic asymmetric synthesis of 5-(trialkylsilyl)cyclohex-2-enones and the transformation into useful building blocks

Article abstract of DOI:10.1021/ol801392d

(Chemical Equation Presented) A simple organocatalytic approach to highly attractive chiral building blocks is presented. By the reaction of β-ketoesters with αβ-unsaturated aldehydes using a chiral IMS-protected prolinol as the catalyst, optically active 5-(trialkylsilyl) cyclohex-2-enones are formed in good yields and with 98-99% ee. The applications of 5-(trialkylsilyl)cyclohex-2-enones for the formation of 5-(hydroxy)cyclohex- 2-enones and the A-ring of 19-nor-1α,25-dihydroxyvitamin D₃ are also presented.

Full text of DOI:10.1021/ol801392d

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3753-3756
Organocatalytic Asymmetric Synthesis
of 5-(Trialkylsilyl)cyclohex-2-enones and
the Transformation into Useful Building
Blocks
Patrick Bolze, Gustav Dickmeiss, and Karl Anker Jørgensen*
Danish National Research Foundation Center for Catalysis, Department of Chemistry,
Aarhus UniVersity, DK-8000 Aarhus C, Denmark
kaj@chem.au.dk
Received June 20, 2008
ABSTRACT
A simple organocatalytic approach to highly attractive chiral building blocks is presented. By the reaction of ꢀ-ketoesters with r,ꢀ-unsaturated
aldehydes using a chiral TMS-protected prolinol as the catalyst, optically active 5-(trialkylsilyl)cyclohex-2-enones are formed in good yields
and with 98-99% ee. The applications of 5-(trialkylsilyl)cyclohex-2-enones for the formation of 5-(hydroxy)cyclohex-2-enones and the A-ring
of 19-nor-1r,25-dihydroxyvitamin D3 are also presented.
Organocatalysis is a spreading field in modern organic
synthesis.1 Various new methodologies have been developed
to construct chiral building blocks, which are employed in
the synthesis of natural products and biologically active
compounds.2
substituted cyclohexenones have been used for the synthesis
of, e.g., Sarcodictyenone3a 3 and Nicandrenone3e NIC-10 4.
The 5-hydroxy-substituted cyclohexenones4 2 have been
employed in a number of syntheses, such as 19-nor-1R,25-
(2) For a review, see: (a) Christmann, M.; Eur., J.; de Figueiredo, R. M.
Org. Chem. 2007, 2575. (b) For recent examples, see: Carpenter, J.;
Northrup, A. B.; Chung, M.; Wiener, J. J. M.; Kim, S.-G.; MacMillan,
D. W. C. Angew. Chem., Int. Ed. 2008, 47, 3568. (c) Hynes, P. S.; Stupple,
P. A.; Dixon, D. J. Org. Lett. 2008, 10, 1389. (d) Jacobs, W. C.; Christmann,
M. Synlett 2008, 247. (e) Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D.
Angew. Chem., Int. Ed. 2007, 46, 7673. (f) Kumpulainen, E. T. T.; Koskinen,
A. M. P.; Rissanen, K. Org. Lett. 2007, 9, 5043. (g) Varseev, G. N.; Maier,
M. E. Org. Lett. 2007, 9, 1461. (h) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.;
Huang, G.-F.; Su, C.-F.; Liao, J.-H. J. Org. Chem. 2007, 72, 8459. (i) Itagaki,
N.; Iwabuchi, Y. Chem. Commun. 2007, 1175. (j) Kumar, I.; Rode, C. V.
Tetrahedron: Asymmetry 2007, 18, 1975. (k) Hong, B.-C.; Nimje, R. Y.;
Yang, C.-Y. Tetrahedron Lett. 2007, 48, 1121.
Chiral 5-(trialkylsilyl)cyclohex-2-enones3 1 and 5-(hy-
droxy)cyclohex-2-enones 2 are very important building
blocks in organic synthesis (Figure 1). The trialkylsilyl-
(1) (a) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-
VCH: Weinheim, Germany, 2004. (b) Dalko, P. I., Ed. EnantioselectiVe
Organocatalysis; Wiley-VCH: Weinheim, Germany, 2007. For a review,
see: (c) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (d)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107,
5471. (e) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713.
10.1021/ol801392d CCC: $40.75
Published on Web 07/26/2008
2008 American Chemical Society

enzymatic kinetic resolution,4c an enantioselective deproto-
nation strategy,4d a seven-step sequence as developed by
Nicolaou et al.,4a or as Sato et al.4i,9 have shown, in six or
seven steps starting from commercially available compounds.
As a simple alternative, we envisioned an organocatalytic,
asymmetric one-pot reaction sequence by which ꢀ-ketoesters
7 react under iminium ion catalysis with silicon-substituted
R,ꢀ-unsaturated aldehydes10 8 in a Michael addition to an
intermediate, which after acid-catalyzed decarboxylation and
aldol condensation forms the desired 5-(trialkylsilyl)cyclo-
hex-2-enones 1 (Figure 1). These products (1) (with R2 )
Ph) may then be converted by a Tamao-Fleming oxida-
tion,11 which after protection of the alcohol yields the
5-(hydroxy)cyclohex-2-enones 2. Additionally, a short syn-
thesis of the A-ring precursor4e,f,12 of 19-nor-1R,25-dihy-
droxyvitamin D3 5 is developed by an analogous strategy.
After the introduction of a second dimethylphenylsilyl
(DMPS) substituent by a 1,4-addition to the cyclohexenone
1, the Tamao-Fleming oxidation followed by alcohol
protection delivers the bishydroxylated ketone.
We started our investigations by employing the reaction
conditions for the synthesis of chiral 5-alkyl- or 5-aryl-
substituted cyclohexenones.13 Accordingly, tert-butyl ac-
etoacetate 7a was reacted with the DMPS-substituted R,ꢀ-
unsaturated aldehyde 8a in the presence of 10 mol %
(S)-2-(bis(3,5-bis(trifluoromethyl)phenyl)(trimethylsilyloxy)-
methyl)pyrrolidine14 under neat conditions to the Michael-
addition intermediate, which was converted with catalytic
amounts of p-TSA (20 mol %) to the corresponding
5-(dimethylphenylsilyl)cyclohex-2-enone by heating for 17 h
at 80 °C (Table 1). The desired product was obtained in a
low yield of 17%, but with a very good enantioselectivity
of 93% ee. This result encouraged us to investigate the
reaction conditions further.15 The first step, the Michael
reaction, usually proceeded with full conversion overnight.
Nevertheless, benzoic acid and toluene were added to
accelerate the reaction as long reaction times were observed
in some cases under neat conditions. The problematic step
turned out to be the decarboxylation-aldol condensation
sequence. In general, low yields of the desired product were
observed at long reaction times, low loadings of acid, and
high temperatures. Therefore, a fine-tuning of these param-
eters was carried out (Table 1).
Figure 1. Synthesis of chiral 5-substituted cyclohexenone deriva-
tives and their use in natural product synthesis.
dihydroxyvitamin D3 54e,f or Rugulosin 6.4a,b Furthermore,
the silyl and hydroxy group in 1 and 2, respectively, can be
used to control the stereochemistry of transformations at
adjacent double bonds.3k,5
However, to the best of our knowledge, cyclohexenones
of type 1 have so far only been synthesized by either
enzymatic,6 metal,7 or cinchonidine8 catalyzed kinetic reso-
lutions. The hydroxy derivatives 2 can be constructed by
(3) For some selected examples, see: (a) Yamazaki, T.; Ishikawa, M.;
Uemura, M.; Kanda, Y.; Takei, H.; Asaoka, M. Tetrahedron 2008, 64, 1895.
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Itahana, H.; Kosaka, T.; Takei, H. Tetrahedron 1995, 51, 3115. (j) Asaoka,
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M.; Hayashibe, S.; Sonoda, S.; Takei, H. Tetrahedron 1991, 47, 6967. (m)
Asaoka, M.; Sonoda, S.; Fujii, N.; Takei, H. Tetrahedron 1990, 46, 1541
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(4) For some selected examples, see: (a) Nicolaou, K. C.; Hwee Lim,
Y.; Piper, J. L.; Papageorgiou, C. D. J. Am. Chem. Soc. 2007, 129, 4001.
(b) Nicolaou, K. C.; Hwee Lim, Y.; Papageorgiou, C. D.; Piper, J. L. Angew.
Chem., Int. Ed. 2005, 44, 7917. (c) Kalkote, U. R.; Ghorpade, S. R.; Chavan,
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Endo, K. J. Chem. Soc., Perkin Trans. 2001, 1, 2915. (e) Hanazawa, T.;
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Hanazawa, T.; Inamori, H.; Masuda, T.; Okamoto, S.; Sato, F. Org. Lett.
2001, 3, 2205. (g) Koiwa, M.; Hareau, G. P. J.; Sato, F. Tetrahedron Lett.
2000, 41, 2389. (h) Hareau, G. P. J.; Koiwa, M.; Sato, F. Tetrahedron Lett.
2000, 41, 2385. (i) Hareau, G. P. J.; Koiwa, M.; Hikichi, S.; Sato, F. J. Am.
Chem. Soc. 1999, 121, 3640. (j) Hareau, G.; Koiwa, M.; Hanazawa, T.;
(9) (a) Hanazawa, T.; Okamoto, S.; Sato, F. Tetrahedron Lett. 2001,
42, 5455. (b) Hikichi, S.; Hareau, G. P. J.; Sato, F. Tetrahedron Lett. 1997,
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(a) Chen, Q.; Kuriyama, M.; Soeta, T.; Hao, X.; Yamada, K.-I.; Tomioka,
K. Org. Lett. 2005, 7, 4439. (b) Fleming, I.; Maiti, P.; Ramarao, C. Org.
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3754
Org. Lett., Vol. 10, No. 17, 2008

Table 1. Screening of the Reaction Conditions for the
Decarboxylation-Aldol Reaction Step
Table 2. Scope of the Reaction
entry
R1
R2
yielda,b [%]
eec [%]
R ) Ph 1a
R ) Me 1c
1
2
3
4
5
6
7
8
7a-H
7a-H
7a-H
7a-H
7a-H
7a-H
7b-Me
7b-Me
7c-allyl
7c-allyl
7d-Ph
7d-Ph
8a-Ph
8a-Ph
8a-Ph
8b-Me
8b-Me
8b-Me
8a-Ph
8b-Me
8a-Ph
8b-Me
8a-Ph
8b-Me
1a-57
1b-55
1a-59d
1c-65
1d-69
1c-61d
1e-50
1f-42
1g-50
1h-46
1i-52
99
99 (+)
99
99
99 (+)
98
99
98
99
99
time
acid
yieldb
[%]
eec
[%]
yieldb
[%]
eec
[%]
entry acida [min] [mol %]
1
2
3
4
5
6
7
8
TSA
35
30
30
35
40
40
40
40
40
45
45
45
50
20
20
25
25
20
25
30
35
40
25
30
35
25
35
98
CSA
MSA
MSA
MSA
MSA
MSA
MSA
MSA
MSA
MSA
MSA
MSA
traces n.d.
49
50
97
99
45
43
99
99
99
99
99
99
99
97
32d
49d
60d
65d,e
55d
44
9
53
99
10
11
12
99
98
57d,e
99
1j-47
a Reaction conditions: (1) Aldehyde (1.00 mmol), ꢀ-ketoester (1.5 mmol,
1.5 equiv), catalyst (10 mol %), PhCO2H (10 mol %), toluene (c ) 2.0
mol/L), 15-17 h, rt. (2) MSA (35 mol %), toluene (c ) 0.25 mmol/mL in
total), 90 °C, 40 min. b Isolated yield after column chromatography.
c Determined by HPLC. d Reaction performed on a 10 mmol scale.
9
10
11
12
13
47d
54d
55d
42
99
99
99
98
a Reaction conditions: (1) Aldehyde (0.25), ꢀ-ketoester (0.37 mmol),
catalyst (0.25 mmol), PhCO2H (0.025 mmol), toluene (0.13 mL), 15-17
h, rt. (2) acid, toluene (0.87 mL), 90 °C. b Isolated yield after column
chromatography. c Determined by HPLC. d Reactions performed on a 1.00
mmol scale. e The isomerized products 5-(dimethyl(phenyl)silyl)cyclohex-
3-enone and 5-(trimethylsilyl)cyclohex-3-enone were observed but could
not be isolated purely after column chromatography.
the cyclohexenones was assigned by comparison of the
R-value of the literature known compounds 1a and 1c.6
The 5-(trialkylsilyl)cyclohex-2-enones are important build-
ing blocks for natural product synthesis. In recognition of
this, we wished to expand the scope of possible transforma-
tions, leading to the investigation of the copper16 catalyzed
1,4-addition of bis(pinacolato)-diboron to the synthesized
cyclohexenones (Scheme 1). Thereby trifunctionalized cy-
clohexanones of type 10 were formed in very good yields
(86-92%) and diastereoselectivities up to trans:cis > 99:1.
Interestingly, a higher diastereoselectivity was observed with
the TMS-substituted cyclohexenone in comparison to the
First, different acids were used to catalyze the second step.
The best yields were obtained with methanesulfonic acid
(MSA) in comparison to p-TSA, while only traces of the
desired product were observed with camphorsulfonic acid
(CSA) (Table 1, entries 1-3). MSA was therefore chosen
as the catalyst for further investigations. The optimizations
showed that lower yields were obtained with lower catalyst
loadings and longer reaction times (entries 4-13). In all
cases, the products were formed with an excellent enan-
tioselectivity of up to 99% ee. The best yields of 57% for
the DMPS- and 65% for the TMS-substituted R,ꢀ-
unsaturated aldehyde were in both cases obtained when
the reaction was performed for 40 min at 90 °C with 35
mol % of MSA (entry 8).
Scheme 1. Transformations of the Cylcohexenones 1
With the best conditions in hand, the scope of the reaction
was investigated (Table 2). In all cases the products 1a-j
were formed with excellent enantioselectivity of up to 99%
ee in good yields up to 69% (Table 2, entries 1-12).
Different substituted ꢀ-ketoesters 7a-d, aliphatic, allylic, and
aromatic, as well as R,ꢀ-unsaturated aldehydes 8a,b could
be used. Generally slightly better yields were obtained in
the case of the DMPS-substituted aldehyde 8a (entries 7-12).
The enantiomers 1b,d of the products 1a and 1c were
synthesized by using the enantiomer of the catalyst (entries
2 and 5). Additionally, the reaction could be performed on
a 10 mmol scale delivering the products in yields of 59%
and 61% (entries 3 and 6). The absolute configuration of
Org. Lett., Vol. 10, No. 17, 2008
3755

DMPS derivative. This may be due to interactions of the
bulky DPEphos ligand with the DMPS group in the transition
state.
a Tamao-Fleming oxidation18 followed by protection in a
yield of 54% over three steps without loss of enantiopurity.
In conclusion, we have developed the first asymmetric
synthesis which is not based on kinetic resolution of
5-(trialkylsilyl)cyclohex-2-enones in good yields with excel-
lent enantioselectivities. Moreover, silicon-substituted R,ꢀ-
unsaturated aldehydes were introduced to organocatalysis for
the first time which might give rise to further interesting
transformations. Finally, the synthesized cyclohexenone
derivatives were transformed into interesting and important
building blocks in shorter sequences than previously seen.
Then, the short synthesis of the A-ring precursor 9 of
19-nor-1R,25-dihydroxyvitamin D3 5 was developed. The
copper17 catalyzed conjugated addition of bis(dimeth-
ylphenylsilyl)zinc resulted in formation of the disubstituted
cyclohexanone 11 in a yield of 75% with a very good
diastereoselectivity of trans:cis ) 98:2. The cyclohex-
anone 11 was converted by a two-step Tamao-Fleming
oxidation18 to the corresponding diol and protected to
bissilanolether ent-9 in 31% over three steps without loss
of enantiopurity to deliver the A-ring precursor.
Finally, the cyclohexenone 1a was transformed into the
corresponding protected 5-hydroxycyclohex-2-enone 12 by
Acknowledgment. This work was made possible by
support from the Danish National Research Foundation and
OChemSchool.
Supporting Information Available: Experimental pro-
cedures and spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) See Supporting Information for more details.
(16) Mun, S.; Lee, J.-E.; Yun, J. Org. Lett. 2006, 8, 4887.
(17) Oestreich, M.; Weiner, B. Synlett 2004, 2139.
(18) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
E. J. J. Chem. Soc., Perkin Trans. 1 1995, 317.
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