Facile synthesis of asymmetric quaternary centers based on diastereoselective protection of the carbonyl group at the symmetrical position

Article abstract of DOI:10.1016/j.tetlet.2010.05.010

The C2-side chain hydroxyl group of 1,3-cycloalkanedione discriminates between two ketones depending on its chirality. It chooses one ketone to form hydrogen bond with the oxygen atom of the TBDPS-oxymethyl group, but chooses the other ketone upon conversion to the isopropyl acetal. Two optically pure diastereomers, whose absolute configuration at the angular position is opposite for each other, were thus synthesized from this single chiral source through simple operations. This method may be applied for the synthesis of a variety of compounds with asymmetric quaternary centers.

Full text of DOI:10.1016/j.tetlet.2010.05.010

Tetrahedron Letters 51 (2010) 3728–3731
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of asymmetric quaternary centers based on
diastereoselective protection of the carbonyl group at the symmetrical position
*
Kou Hiroya , Yusuke Ichihashi, Yoshihiro Suwa, Tetsuro Ikai, Kiyofumi Inamoto, Takayuki Doi
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki, Aza Aoba, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The C2-side chain hydroxyl group of 1,3-cycloalkanedione discriminates between two ketones depending
on its chirality. It chooses one ketone to form hydrogen bond with the oxygen atom of the TBDPS–oxym-
ethyl group, but chooses the other ketone upon conversion to the isopropyl acetal. Two optically pure
diastereomers, whose absolute configuration at the angular position is opposite for each other, were thus
synthesized from this single chiral source through simple operations. This method may be applied for the
synthesis of a variety of compounds with asymmetric quaternary centers.
Received 17 April 2010
Revised 1 May 2010
Accepted 7 May 2010
Available online 12 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Chiral quaternary centers at the angular position are commonly
found in biologically active compounds. It is thus critical subject in
organic synthesis that general and efficient methods be devised to
prepare chiral quaternary centers.
tion that the cis-fused ring is usually more stable than the trans-
fused one in a bicyclo[4.3.0] ring system. In compound 4a, a hydro-
gen bond is expected between the hydroxyl group and the ether
oxygen atom. This bond is strong enough to retain its configura-
tion; therefore, 4a will be predominantly produced over 4b. Con-
versely, if the acetal moiety is rebuilt without steric repulsion
between side chains, 4a may yield 5b as a major product because
of the equilibrium that might occur between 4a and 4b through
3 (Fig. 2).
The substrates 11–17 were synthesized as shown in Scheme 1.
Namely, 1,3-cyclohexanedione (6) or 1,3-cyclopentanedione (7)
and (R)-2,2-dimethyl[1,3]dioxolane-4-carbaldehyde (8) were sub-
jected to cascade Knoevenagel-hydrogenation reaction developed
by Ramachary et al.5l to afford the common intermediates 9 or
10. For the compound 9, racemization during the reaction was
not observed at all, as confirmed by chiral HPLC analysis.7 The
introduction of the substituent at C2 was carried out by Michael
reaction with ethyl acrylate (for 11 and 17), alkylation with halides
in the presence of DBU9 (for 13 and 14), and Pd-catalyzed allylation
reaction (for 12, 15, and 16) (Scheme 1).
Among the reported methods for the stereoselective synthesis
of quaternary carbon centers,1 the desymmetrization of the sym-
metrical compound2 is one of useful methodologies because of
its efficiency and easy preparation of starting materials. Principal
methods of the desymmetrization for the construction of asym-
metric carbon centers which do not contain carbon–hydrogen
bonds include (1) enzymatic reaction,3 (2) catalysis by chiral me-
tal–ligand complex,4 (3) catalysis by organocatalyst,5 and (4) inter-
nal asymmetric induction.6 Many reactions promoted by chiral
metal–ligand complexes and organocatalysts have been reported,
but only limited number of reports exist on reactions by internal
asymmetric induction. Briefly, if functional group X in 1 (Fig. 1)
can discriminate the other functional groups, which are symmetric
with respect to each other, to selectively give compound 2a or 2b
under independent reaction conditions, then there might be a use-
ful method to prepare both enantiomers with a quaternary carbon
center. In this Letter, we introduce a practical and widely applica-
ble method to prepare two diastereomers having chiral quaternary
carbon center, whose absolute configuration is opposite for each
other, through the chiral discrimination of the symmetrical 2,2-
In our initial investigation, we selected the compound 11, which
has the ethoxycarbonyl-ethyl group as C2-substituent. Contrary to
expectation, hydrolysis of the acetal group yielded acetal 18 as a
disubstituted-1,3-cycloalkanedione utilizing
source at C2-side chain.
a
remote chiral
In agreement with this basic principle, we assumed that the hy-
droxyl group in 3 would discriminate two carbonyl groups depend-
ing on its chirality. Among four possible diastereomers 4a–d, axial
attack of the hydroxyl group yields 4a and 4b as major products
upon consideration of both stereoelectronic effect and the observa-
R2
R2
R1
H
R2
X
H
H
X
*
*
R1
X
R1
2b
2a
1
* Corresponding author. Tel.: +81 22 795 6867; fax: +81 22 795 6864.
E-mail address: hiroya@mail.tains.tohoku.ac.jp (K. Hiroya).
Figure 1. Representation of the chiral discrimination using a remote chiral source.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.010

K. Hiroya et al. / Tetrahedron Letters 51 (2010) 3728–3731
3729
R1
Table 1
Diastereoselectivity change induced by the hydroxymethyl group substituent10
R3
O
CO2Et
CO2Et
O
5a
O
O
R2
O
O
H
R1
aq. HCl
THF, rt
+ R3
R1
O
O
R2O
O
O
11
O
OH
18
OH
O
OH
H
O
4c
H
O
CO2Et
CO2Et
O
O
R2
O
TBDPSCl, imidazole
CH2Cl2 (entry 1)
R1
H
4a
OR2
OH
R1
TBSCl (entry 2)
Ac2O (entry 3)
PivCl (entry 4)
p-TsCl (entry 5)
Et3N, DMAP, CH 2Cl2
HO
OH
O
OH
O
O
O
O
RO
3
RO
O
H
O
H
19a−23a
19b−23b
H
R1
OR2
4b
+ R3
O
dr (a:b)a
H
Entry
Product (R)
Yield (%)
88
86
85
94
78
O
OH OR2
1
2
3
4
5
19a,b (TBDPS)
20a,b (TBS)
21a,b (Ac)
22a,b (Piv)
23a,b (Ts)
96:4
>99:1
75:25
75:25
67:33
R1
4d
OR3
4a and 4b: axial attack
4c and 4d: equatorial attack
O
O
a
Dr was determined from the integration value of the 1H NMR spectrum.
H
OR2 5b
Figure 2. General concept for chiral discrimination of synthon 3 into products 4a
and 5b.
CO2Et
δ: 1.83−1.88 (m)
: NOE
Ha
Hb
: Hydrogen Bond
O
EtO2C
Me
CO2Et
Me
δ: 4.39 (s)
O
n
OH
n
H3β
O
OHC
+
O
N
H3α
H2
O
O
, L-proline
O
H
δ: 2.68 (dd, J = 11.9, 7.6 Hz)
Si
O
O
CH2Cl2, rt, 18-20 h
Ph
O
Ph
O
6: n = 1
7: n = 0
19a
8
9: n = 1
10: n = 0
Figure 3. Summary for 1H NMR and NOESY spectra of the compound 19a.8
O
a: for 11 and 17
b: for 12 and 16
11: n =1 , R = -(CH2)2CO2Et
(48% from 6)
12: n = 1, R = allyl (75% from 6)
13: n = 1, R = Me (46% from 6)
14: n = 1, R = Bn (45% from 6)
15: n = 1, R = (E)-4-acetoxy-2-butenyl
(70% from 6)
16: n = 0, R = allyl (57% from 7)
17: n = 0, R = -(CH2)2CO2Et
(33% from 7)
R
O
n
c: for 13
d: for 14
e: for 15
Table 2
O
Diastereoselective intramolecular acetalization reactions of 12À17a
O
a: ethyl acrylate, Et3N, 80°C
b: allyl methyl carbonate, Pd(PPh3)4
THF, rt
c: MeI, DBU, DMF, rt
d: BnBr, DBU, DMF, rt
e: bisacetoxy-cis-2-butene-1,4-diol
Pd(PPh3)4, PPh3, dichloroethane, rt
Yieldb (%)
dr (a:b)c
Scheme 1. Synthesis of the substrates 11À17.
Entry
SM (n)
Product (R)
1
2
3
4
5
6
12 (1)
13 (1)
14 (1)
15 (1)
16 (0)
17 (0)
24a,b (allyl)
25a,b (Me)
26a,b (Bn)
27a,b ((E)-4-acetoxy-2-butenyl)
28a,b (allyl)
78
71
97
73
91
87
97:3
96:4
95:5
96:4
96:4
93:7
mixture of diastereomers. However, we were pleased to find that
the resulting primary hydroxyl group was converted into the cor-
responding TBDPS (tert-butyldiphenylsilyl) ether to afford 19a as
a major product (19a:19b = 96:4), observed in CDCl3 by 1H NMR
spectroscopy (Table 1, entry 1).
29a,b (–(CH2)2CO2Et)
a
b
c
Reagents and conditions: (1) aq HCl, THF, rt; (2) TBDPSCl, imidazole, CH2Cl2, rt.
Overall yield.
Since H3 and the carbonyl group at C4 in the compound 19a
a
Dr was determined by the integration value of the 1H NMR spectrum.
were almost coplanar in each, the chemical shift of H3 in 1H
a
NMR spectrum8 was observed at low-field (2.68 ppm) due to the
deshielding effect by the carbonyl group as compared with that
of H3b (1.83À1.88 ppm). The structure of 19a was determined by
NOESY spectroscopy8 and the presence of NOE between Ha and
Hb is noteworthy to support this structure (Fig. 3). The presence
of intramolecular hydrogen bond was confirmed by the sharp sin-
glet and relatively downfield (4.39 ppm) in 1H NMR spectrum,8
which corresponds to the hydroxyl proton and the chemical shift
showed essentially no change when 1H NMR spectra were mea-
sured at different concentrations in CDCl3.8 The bulkiness of the
R substituent did not affect the diastereomeric ratios (Table 1, en-
tries 1 vs 2 and 3 vs 4). However, the ratios decreased significantly
when electron-withdrawing groups, which may weaken hydrogen
bonds, were incorporated (Table 1, entries 3À5). Moreover, it was
found that compounds 19a and 24a (Table 2, entry 1) were essen-
tially single isomers, as determined by 1H and 13C NMR spectra in
CDCl3, whereas the same compounds formed diastereomer mix-
tures in CD3CN–D2O (9:1) (19a:19b and 24a:24b = 3:1).8,10 This re-
sults indicate the importance of hydrogen bond in maintaining the
configuration.
Discrimination of the carbonyl groups was found to be quite
general. Compounds with an allyl, methyl, benzyl, or (E)-4-acet-

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K. Hiroya et al. / Tetrahedron Letters 51 (2010) 3728–3731
oxy-2-butenyl group at the C3a position (24a–27a) were produced
with more than 95:5 selectivity (Table 2, entries 1À4). Five-mem-
bered analogues 28a and 29a were also afforded in high diastere-
oselectivity (Table 2, entries 5 and 6).
Next, we challenged the inversion of absolute configuration at
the angular position. As expected, the ratios of produced diastereo-
mers changed according to the size of alcohols during acetal for-
mation. The highest yield of 32b was obtained with 2-propanol
and triisopropyl orthoformate, and Ce(OTf)3 as a catalyst11 (Table 3,
entry 3). The chemical shifts of H3 in 1H NMR spectra of the com-
a
pounds 32a and 32b were observed again at low-field (32a:
2.79 ppm, 32b: 2.93 ppm) as compared with those of H3b (32a:
1.52 ppm, 32b: 1.89 ppm) and the stereochemistry of the both
compounds were determined by NOESY spectroscopy shown in
Figure 4.8
Under identical reaction conditions, quasi-similar degrees of
diastereoselectivity inversion were observed for compounds 19a
(Table 3, entry 4) and 25a–27a (Table 3, entries 5À7), which have
different R1. We therefore confirmed that the inversion would be
applied to a wide variety of substrates possessing different func-
tional group at C3a (R1).
Figure 4. Summary for 1H NMR and NOESY spectra of the compound 32a and 32b.8
In conclusion, we have established a simple, efficient method to
synthesize two types of diastereomers 19a, 24a–29a, and 32b–36b
with opposite absolute configurations at the angular position from
a single chiral source in high selectivity.12 Expensive chiral sources
are thus not required and it can be applied to a variety of 1,3-cyclo-
hexanedione and 1,3-cyclopentanedione derivatives because dia-
stereoselectivity is independent on the C2 substituent in the
starting material.
Because desymmetrization reactions based on carbon–carbon
bond formation are irreversible, it seems likely that synthesizing
the chiral center having different absolute configuration from single
chiral molecule requires the special devices. Desymmetrization reac-
tions of 3,3-disubstituted-1,4-cyclohexadiene derivatives2d,6b–e,g–i by
catalytic reaction or chiral induction have been reported. However,
the fundamental difference between our method and those examples
is reversibility. Our method is based on a carbon–oxygen bond forma-
tion and can be regarded as the diastereoselective protection of the
carbonyl group at the symmetrical position. The protected carbonyl
group reverts back to the carbonyl group when necessary and is
transformed to another functional group. Although the diastereose-
lectivity in the most examples by internal asymmetric induction
were achieved by kinetic control, it is noteworthy that the
diastereoselectivity at hemiacetal synthesis in our method was
controlled by the thermodynamic stability among the possible
compounds. This method may be applied to the synthesis of a wide
variety of compounds with asymmetric quaternary carbon centers.
Further applications of this method to the synthesis of biologically
active compounds are under investigation in our laboratory.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Re-
search (C) 19590001 and 21590001 from the Japan Society for
the Promotion of Science (JSPS).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.010.
References and notes
Table 3
Diastereoselectivity inversion through intermolecular acetalization reactions
1. (a) For recent reviews see: Quaternary Stereocenters: Challenges and Solutions for
Organic Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
Germany, 2005; (b) Bella, M.; Gasperi, T. Synthesis 2009, 1583–1614; (c)
Trost, B. M.; Jiang, C. Synthesis 2006, 369–396; (d) Douglas, C. J.; Overman, L. E.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363–5367; (e) Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105–10146; (f) Christoffers, J.; Mann, A. Angew. Chem.,
Int. Ed. 2001, 40, 4591–4597.
R1
R1
R1
OR2
R2O
HO
O
O
O
O
O
O
TBDPSO
TBDPSO
TBDPSO
H
H
H
24a, 19a, 25a−27a
30a−36a
30b−36b
2. (a) Atodiresei, I.; Schiffers, I.; Bolm, C. Chem. Rev. 2007, 107, 5683–5712; (b)
Rovis, T. In New Frontiers in Asymmetric Catalysis; Mikami, K., Mark, L., Eds.;
John Wiley & Sons Inc.: Hoboken, USA, 2007; pp 275–311; (c) García-Urdiales,
E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313–354; (d) Studer, A.; Schleth,
H. Synlett 2005, 3033–3041; (e) Rahman, N. A.; Landais, Y. Curr. Org. Chem.
2002, 6, 1369–1395; (f) Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765–
1784.
3. (a) Chênevert, R.; Lévesque, C.; Morin, P. J. Org. Chem. 2008, 73, 9501–9503; (b)
Fuhshuku, K.-i.; Tomita, M.; Sugai, T. Adv. Synth. Catal. 2003, 345, 766–774; (c)
Wei, Z.-L.; Li, Z.-Y.; Lin, G.-Q. Synthesis 2000, 1673–1676; (d) Fuhshuku, K.-i.;
Funa, N.; Akeboshi, T.; Ohta, H.; Hosomi, H.; Ohba, S.; Sugai, T. J. Org. Chem.
2000, 65, 129–135.
4. (a) Deschamp, J.; Riant, O. Org. Lett. 2009, 11, 1217–1220; (b) Kusakabe, T.;
Kato, K.; Takaishi, S.; Yamamura, S.; Mochida, T.; Akita, H.; Peganova, T. A.;
Vologdin, N. V.; Gusev, O. V. Tetrahedron 2008, 64, 319–327. and references
cited therein; (c) Kim, H. C.; Youn, J.-H.; Kang, S. H. Synlett 2008, 2526–2528;
(d) Machotta, A. B.; Straub, B. F.; Oestreich, M. J. Am. Chem. Soc. 2007, 129,
13455–13463; (e) Jung, B.; Hong, M. S.; Kang, S. H. Angew. Chem., Int. Ed. 2007,
46, 2616–2618.
Entry SM (R1)
Product (R2) Yield (%) dr (a:b)d
1a
2a
3b
4c
5c
6c
7c
24a (allyl)
24a (allyl)
24a (allyl)
19a (–(CH2)2CO2Et)
25a (Me)
30a,b (Me)
31a,b (Et)
32a,b (i-Pr)
33a,b (i-Pr)
34a,b (i-Pr)
35a,b (i-Pr)
quant.
98
91
84
83
20:80
12:88
8:92
8:92
9:91
26a (Bn)
92
13:87
9:91
27a ((E)-4-acetoxy-2-butenyl) 36a,b (i-Pr)
79
Reagents and conditions: a HC(OR2)3 (3.0 equiv), Ce(OTf)3 (10 mol %), R2OH–toluene
(1:1), rt, 3 h (entry 1: R2 = Me, entry 2: R2 = Et).
b
HC(Oi-Pr)3 (3.0 equiv), Ce(OTf)3 (10 mol %), i-PrOH–toluene (1:1), rt for 3 h, then
70 °C for 1.5 h.
HC(Oi-Pr)3 (3.0 equiv), Ce(OTf)3 (10 mol %), i-PrOH–toluene (1:1), 70 °C for 1 h
c
(entries 4 and 5), for 16 h (entry 6), and for 1.5 h (entry 7).
Dr was determined from the integration value of the 1H NMR spectrum.
d

K. Hiroya et al. / Tetrahedron Letters 51 (2010) 3728–3731
3731
5. (a) Ema, T.; Oue, Y.; Akihara, K.; Miyazaki, Y.; Sakai, T. Org. Lett. 2009, 11, 4866–
4869; (b) de Arriba, A. L. F.; Simón, L.; Raposo, C.; Alcázar, V.; Morán, J. R.
Tetrahedron 2009, 65, 4841–4845; (c) You, Z.; Hoveyda, A. H.; Snapper, M. L.
Angew. Chem., Int. Ed. 2009, 48, 547–550; (d) Purohit, V. C.; Matla, A. S.; Romo,
D. J. Am. Chem. Soc. 2008, 130, 10478–10479; (e) Kennedy, J. W. J.; Vietrich, S.;
Weinmann, H.; Brittain, D. E. A. J. Org. Chem. 2008, 73, 5151–5154; (f)
Ramachary, D. B.; Kishor, M. Org. Biomol. Chem. 2008, 6, 4176–4187; (g)
Lanfranchi, D. A.; Baldovini, N.; Hanquet, G. Synthesis 2008, 3775–3778; (h)
Zhang, X.-M.; Wang, M.; Tu, Y.-Q.; Fan, C.-A.; Jiang, Y.-J.; Zhang, S.-Y.; Zhang, F.-
M. Synlett 2008, 2831–2835; (i) Ramachary, D. B.; Sakthidevi, R. Org. Biomol.
Chem. 2008, 6, 2488–2492; (j) Hayashi, Y.; Sekizawa, H.; Yamaguchi, J.; Gotoh,
H. J. Org. Chem. 2007, 72, 6493–6499; (k) Kanger, T.; Kriis, K.; Laars, M.; Kailas,
T.; Müürisepp, A.-M.; Pehk, T.; Lopp, M. J. Org. Chem. 2007, 72, 5168–5173; (l)
Ramachary, D. B.; Kishor, M. J. Org. Chem. 2007, 72, 5056–5068. and references
cited therein; (m) Nagamine, T.; Inomata, K.; Endo, Y.; Paquette, L. A. J. Org.
Chem. 2007, 72, 123–131; (n) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552–
2553.
Elliott, M. C.; El Sayed, N. N. E.; Paine, J. S. Org. Biomol. Chem. 2008, 6, 2611–
2618; (f) Headley, C. E.; Marsden, S. P. J. Org. Chem. 2007, 72, 7185–7189; (g)
Barradas, S.; Carreño, M. C.; González-López, M.; Latorre, A.; Urbano, A. Org.
Lett. 2007, 9, 5019–5022; (h) Butters, M.; Elliott, M. C.; Hill-Cousins, J.; Paine, J.
S.; Walker, J. K. E. Org. Lett. 2007, 9, 3635–3638; (i) Lertpibulpanya, D.;
Marsden, S. P.; Rodriguez Garcia, I.; Kilner, C. Angew. Chem., Int. Ed. 2006, 45,
5000–5002; (j) Lebeuf, R.; Robert, F.; Schenk, K.; Landais, Y. Org. Lett. 2006, 8,
4755–4758.
7. HPLC condition; column: Daicel Chemical Industries, Ltd CHIRALCELÒ OJ-H
[0.46 cm (I.D.) Â 25 cm (L.)], solvent: hexaneÀ2-propanol (9:1 v/v). The detail
conditions were shown in Supplementary data.
8. 1H NMR spectra of 19a [in CDCl3, difference concentration in CDCl3, and in
CD3CNÀD2O (9:1)] and 24a [in CDCl3 and CD3CNÀD2O (9:1)], and NOESY
spectra of 19a, 32a, and 32b are available in Supplementary data.
9. Maini, P. N.; Sammes, M. P.; Katritzky, A. R. J. Chem. Soc., Perkin Trans. 1 1988,
161–168.
10. Structures of minor diastereomers 19b and 21b–23b were estimated by
6. (a) Tuan, L. A.; Kim, G. Tetrahedron Lett. 2010, 51, 2354–2355; (b) Elliott, M. C.;
Paine, J. S. Org. Biomol. Chem. 2009, 7, 3455–3462. and references cited therein;
(c) Butters, M.; Elliott, M. C.; Hill-Cousins, J.; Paine, J. S.; Westwood, A. W. J.
Tetrahedron Lett. 2008, 49, 4446–4448; (d) Butters, M.; Beetstra, D. J.; Elliott, M.
C.; Hill-Cousins, J.; Kariuki, B. M. Org. Biomol. Chem. 2008, 6, 4426–4434; (e)
analogy to the 1H and 13C NMR spectra of 32b.
11. Ono, F.; Takenaka, H.; Eguchi, Y.; Endo, M.; Sato, T. Synlett 2009, 487–489.
12. Examples of the reversal of enantioselectivity using a single chiral source were
reviewed recently. See: Tanaka, T.; Hayashi, M. Synthesis 2008, 3361–3376.