Desymmetrizing asymmetric ring expansion: Stereoselective synthesis of 7-membered cyclic β-keto carbonyl compounds with an α-hydrogen

Article abstract of DOI:10.1039/c0cc01424a

Ring expansion of symmetrically substituted cyclohexanones with N-α-diazoacetyl camphorsultam was devised as a stereoselective pathway to the functionalized 7-membered cyclic β-keto carbonyls having a kinetically stabilized α-hydrogen.

Full text of DOI:10.1039/c0cc01424a

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Desymmetrizing asymmetric ring expansion: stereoselective synthesis
of 7-membered cyclic b-keto carbonyl compounds with an a-hydrogenw
Takuya Hashimoto, Yuki Naganawa and Keiji Maruoka*
Received 15th May 2010, Accepted 28th July 2010
DOI: 10.1039/c0cc01424a
Ring expansion of symmetrically substituted cyclohexanones
with N-a-diazoacetyl camphorsultam was devised as a stereo-
selective pathway to the functionalized 7-membered cyclic b-keto
carbonyls having a kinetically stabilized a-hydrogen.
Asymmetric synthesis of acyclic b-keto carbonyl compounds
having an a-hydrogen was introduced a quarter of a century
ago by Evans and co-workers, capitalizing on the ability of a
bulky chiral ligand to kinetically stabilize the enantiomerically
enriched a-carbon established in the Claisen condensation of
acyl halides and imide enolates (Fig. 1, eq 1).1 Recently, an acid-
catalyzed reaction of aldehydes and a-substituted a-diazocarbonyl
compounds bearing a camphorsultam was developed in our
laboratory as a new tool to achieve this goal (eq 2).2–4
Fig. 1 Acid-catalyzed asymmetric ring expansion.
However, with regard to the preparation of their cyclic
counterparts, there has been no general approach to realizing
stoichiometric amount of BF3ÁEt2O as an inexpensive and
benign Lewis acid at À78 1C, cyclobutanone and cyclo-
hexanone could be successfully converted to the expected
ring-expanded products 2 and 3a with 420/1 dr as determined
by the 1H NMR of the crude mixture,8 whereas cyclopentanone
remained intact. In the case of thus-obtained 5-membered
cyclic b-keto carbonyl compound 2, a considerable loss of dr
was observed during the purification using silica gel column
chromatography by the epimerization of the a-chiral center.
On the other hand, the stereocenter at the a-carbon of
7-membered ring 3a was stable enough to be isolated without
any epimerization,9 and could only be epimerized by treating
this material with a strong base like 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU).10 The remarkably high stereoselectivity
of this ring expansion was confirmed by determining the ee
value to be 98% after the reductive detachment of the chiral
auxiliary.11 Furthermore, this asymmetric ring expansion of
cyclohexanone could also be extended to its 4-oxa-, 4-thia-,
this objective.5 This is probably due to the difficulty of directly
applying the existing intermolecular methods to an intra-
molecular variant giving cyclic b-keto carbonyl compounds
with a kinetically stabilized a-hydrogen, as well as the foreseeable
difficulty of introducing additional functionalities stereo-
selectively in the ring system.
As a reliable method for the preparation of racemic cyclic
b-keto esters having an a-hydrogen, acid-mediated ring expansion
of cyclic ketones with a-diazoacetates has been exploited for
nearly half a century.6,7 It can be envisaged that replacement
of the ester functionality of a-diazoacetates with a chiral bulky
carbonyl substituent in this reaction system would meet the
criteria for the asymmetric construction of cyclic b-keto
carbonyl compounds having an a-hydrogen (eq 3). We report
herein an investigation in this perspective, which culminated in
the discovery of a novel and reliable tactic for the asymmetric
construction of seven-membered b-keto carbonyl compounds
having a kinetically stabilized a-hydrogen and additional
stereocenters.
At the beginning of this research, asymmetric ring expan-
sion of cycloalkanones having a varying number of carbon
atoms was examined using a-diazocarbonyl compound (+)-1
to validate our hypothesis (Scheme 1). We opted for the use of
(+)-camphorsultam as an ideal chiral auxiliary, shielding one
prochiral face of the diazo carbon efficiently and imposing a
high kinetic barrier for the epimerization of thus-generated
chiral a-carbon on the basis of our previous study.2 Using a
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto, 606-8502, Japan.
E-mail: maruoka@kuchem.kyoto-u.ac.jp; Fax: +81 75-753-4041;
Tel: +81 75-753-4041
w Electronic supplementary information (ESI) available: Represen-
tative experimental methods and spectroscopic characterization of
new compounds. See DOI: 10.1039/c0cc01424a
Scheme 1 Asymmetric ring expansion of cycloalkanones.
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Scheme 2 Schematic representation of desymmetrizing asymmetric
ring expansion of substituted cyclohexanones.
4-aza- and 4-exo-methylene analogs without difficulty, giving
3b, 3c, 3d and 3e in good yields and excellent selectivities.
The observed high stereoselectivity and robustness of the
thus-generated a-chiral center then prompted us to merge this
foundation and our recent discovery on the stereochemical
prediction model of ring-expansions using symmetrically sub-
stituted cyclohexanones and a-substituted a-diazoacetates.12
According to this model, it is assumed that the use of
symmetrically substituted cyclohexanones 4 with (+)-1 would
initially form the intermediate I via the equatorial attack of
(+)-1 while the chiral auxiliary shields one prochiral face
of the diazo carbon (Scheme 2).13 From this intermediate
orienting the bulky carbonyl moiety in an axial fashion to
reduce the steric repulsion, migration of the alkyl group occurs
through the inversion of the chiral center at the diazonium
carbon. As such, symmetrically substituted cyclohexanones
would be converted to homologated chiral cycloheptanones 5
with a kinetically stabilized a-hydrogen, while desymmetrizing
residual substituents to create additional stereogenic centers.
To prove the validity of this principle, the asymmetric
ring expansion of 4-methylcyclohexanone using (+)-1 was
implemented under identical reaction conditions as above
(Scheme 3). Consequently, the expected cycloheptanone 5a
bearing methyl and the carbonyl groups in a trans relationship
was obtained as a single diastereomer in 81% yield. Prompted
by this result, we then examined other cyclohexanones bearing
t-butyl, phenyl, and N-phthalimido groups as 4-substituent. In
all cases, this desymmetrizing asymmetric ring expansion
proceeded with high stereoselectivities, giving 5b, 5c and 5d,
respectively. In contrast to these 4-substituents which are
oriented in an equatorial position of the cyclohexanone, a
4-siloxy moiety is known to be in an axial position.14 Due to
this fact, the ring expansion of 4-(tert-butyldimethylsiloxy)-
cyclohexanone with (+)-1 furnished the product 5e, projecting
the carbonyl and siloxy groups in a cis fashion. By building on
this dichotomy, cyclohexanones having both alkyl and siloxy
groups as 4-substituents could be stereoselectively converted
to 5f, 5g and 5h, incorporating chiral tertiary alcohol in the
7-membered ring. Furthermore, the same strategy could be
applied to cis-3,5-dimethylcyclohexanone and its oxa-analogue to
give seven-membered rings 5i and 5j having 1,3,5-tertiary-tertiary-
tertiary stereogenic centers in an expected stereochemistry.
Since the state-of-the-art asymmetric catalysis provides us
with facile access to a variety of almost enantiomerically pure
Scheme
3
Desymmetrizing asymmetric ring expansion of
cyclohexanones.
3-substituted cyclohexanones,15 we looked into the application
of our asymmetric ring expansion to one such compound (R)-
3-methylcylohexanone 6 (Scheme 3, in dashed rectangle). In
accordance with the mechanistic model in Scheme 2, the ring
expansion with (+)-1 led to the stereoselective formation of
the cycloheptanone 7a. On the other hand, use of the antipode
(À)-1 gave rise to the regioisomeric product 7b exclusively. It
should be noted that the simple ring expansion of 6 with ethyl
diazoacetate resulted in a mixture of four isomers composed of
two regioisomers derived from nonselective ring expansion
and two diastereomers stemming from the labile chirality at
the a-carbon.
The regio- and stereoselective nature of this ring expansion
with regard to chiral nonracemic cyclohexanones further
prompted us to employ a chiral polycyclic system which has
a cyclohexanone moiety harnessed in a chair conformation.
In this context, TBS-protected dihydrotestosterone 8 was
subjected to the conditions optimized for this specific reaction,
giving the ring-expanded product 9 as a single isomer in 70%
yield (Scheme 4). The nearly quantitative recovery of the
unreacted substrate indicated clean conversion (96% yield
based on recovered starting material). As polycyclic systems
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functionalized 7-membered ring systems in almost enantio-
merically pure form. This strategy could be further extended to
regio- and stereoselective ring expansion of chiral nonracemic
cyclohexanones.
This work was partially supported by a Grant-in-Aid for
Scientific Research from MEXT (Japan). T.H. and Y.N. thank
a Grant-in Aid for Young Scientists (B) and the Research
Fellowships of JSPS for Young Scientists, respectively. We are
grateful to Dr Hiroyasu Sato (Rigaku) for X-ray analysis.
Notes and references
1 D. A. Evans, M. D. Ennis, T. Le, N. Mandel and G. Mandel,
J. Am. Chem. Soc., 1984, 106, 1154.
2 T. Hashimoto, H. Miyamoto, Y. Naganawa and K. Maruoka,
J. Am. Chem. Soc., 2009, 131, 11280.
3 For the original work and recent advance on acid-catalyzed
Scheme 4 Ring expansion of TBSO-dihydrotestosterone with (+)-1.
ORTEP diagram of 9 drawn at 50% thermal ellipsoids with H atoms,
TBS group, camphorsultam and a solvent molecule omitted for clarity.
reaction
between
diazo
esters
and
aldehydes,
see:
(a) C. R. Holmquist and E. J. Roskamp, J. Org. Chem., 1989,
54, 3258; (b) W. Li, J. Wang, X. Hu, K. Shen, W. Wang, Y. Chu,
L. Lin, X. Liu and X. Feng, J. Am. Chem. Soc., 2010, 132, 8532.
4 For the phase-transfer catalyzed asymmetric alkylation of
malonamic esters, see: M.-b. Kim, S.-h. Choi, Y.-J. Lee, J. Lee,
K. Nahm, B.-S. Jeong, H.-g. Park and S.-s. Jew, Chem. Commun.,
2009, 782.
5 For a crystallization induced second-order asymmetric transfor-
mation, see: C. P. Decicco and R. N. Buckle, J. Org. Chem., 1992,
57, 1005.
6 (a) T. Ye and M. A. McKervey, Chem. Rev., 1994, 94, 1091;
(b) M. P. Doyle, T. Ye and M. A. McKervey, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds, John Wiley
& Sons, New York, 1998.
7 For recent reviews on the use of diazo compounds, see: (a) Y. Zhang
and J. Wang, Chem. Commun., 2009, 5350; (b) J. N. Johnston,
H. Muchalski and T. L. Troyer, Angew. Chem., 2010, 122, 2340;
Angew. Chem., Int. Ed., 2010, 49, 2290.
8 The reaction of (+)-1 and cyclohexanone in the presence of
20 mol% BF3ÁEt2O resulted in the formation of the desired product
in 49% yield, leaving a substantial amount of (+)-1 unconsumed.
9 The stereochemistries of 3a, 5a, 5e, 5f, 5i, 7a, 7b and 10 were
unambiguously determined by X-ray crystallographic analysis. See
ESIw for details.
10 Treatment of 3a with 1 equiv. of DBU in CH2Cl2 at 0 1C for 4 h
led to the predominant formation of the opposite diastereomer
(dr = 1 : 4.6).
having a 7-membered ring are abundant in nature, this strategy
would provide a new, appealing tool in the arsenal of 7-membered
ring constructions applicable in a complex setting.16
Finally, we re-investigated the ring expansion of cyclobuta-
none briefly in an attempt to pave a new way to functionalized
chiral cyclopentanes (Scheme 5). As the generated a-stereocenter
eroded during purification, we decided to trap the ring-expanded
product 2 with a nucleophilic reagent sequentially in one pot.
To this end, the reaction solution containing 2 was directly
treated with NaBH4 to give cis-cyclopentanol 10 in 44% yield
(unoptimized). By taking advantage of the Lewis acidic reac-
tion conditions, a one-pot ring expansion/Mukaiyama aldol
reaction sequence was also implemented to generate the
cyclopentanol 11 bearing a tertiary alcohol moiety in moderate
yield as an essentially single isomer.
In summary, we have demonstrated herein the viability of acid-
catalyzed ring expansion using N-a-diazoacetyl camphorsultam 1
as a means to afford cyclic b-keto carbonyl compounds with a
kinetically stabilized a-hydrogen stereoselectively. Combination
of this finding with our stereochemical prediction model of ring-
expansions using symmetrically substituted cyclohexanones led to
the establishment of a reliable system, providing rigorously
11 See ESIw for details.
12 T. Hashimoto, Y. Naganawa and K. Maruoka, J. Am. Chem. Soc.,
2009, 131, 6614.
13 For the discussion on the effect of the chiral auxiliary, see ESIw.
14 (a) Y. Nagao, M. Goto, M. Ochiai and M. Shiro, Chem. Lett.,
1990, 1503; (b) G. Baghdasarian and K. A. Woerpel, J. Org.
Chem., 2006, 71, 6851.
15 For reviews on the use of transition metal catalysis, see:
(a) T. Hayashi and K. Yamazaki, Chem. Rev., 2003, 103, 2829;
(b) R. Shintani and T. Hayashi, Aldrichim. Acta, 2009, 42, 31;
(c) S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard
and B. L. Feringa, Chem. Rev., 2008, 108, 2824; (d) T. Jerphagnon,
M. G. Pizzuti, A. J. Minnaard and B. L. Feringa, Chem. Soc. Rev.,
2009, 38, 1039; (e) J. Wencel, M. Mauduit, H. He
and A. Alexakis, Aldrichim. Acta, 2009, 42, 43; organocatalysis,
see: (f) D. Alma-si, D. A. Alonso and C. Najera, Tetrahedron:
Asymmetry, 2007, 18, 299; (g) J. L. Vicario, D. Badıa and
´
non, S. Kehrli
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L. Carrillo, Synthesis, 2007, 2065; (h) S. B. Tsogoeva, Eur. J.
Org. Chem., 2007, 1701.
16 For a recent review, see: D. A. Foley and A. R. Maguire, Tetra-
hedron, 2010, 66, 1131.
Scheme 5 One-pot asymmetric ring expansion/functionalization of
cyclobutanone. Reaction conditions: (a) NaBH4 (3 equiv.), MeOH,
À78 1C, 18 h; (b) H2CQC(OMe)OTBS (2 equiv.), À20 1C, 16 h.
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6812 Chem. Commun., 2010, 46, 6810–6812
This journal is The Royal Society of Chemistry 2010