Highly diastereoselective synthesis of chiral furans with a quaternary carbon substituent at the 2-position using 8-phenylmenthol as the chiral auxiliary

Article abstract of DOI:10.1246/cl.140052

The reaction of cis-4-oxo-2-pentenal and 8-phenylmenthyl 2-oxocyclopentane-1-carboxylate in the presence of a fluorinated cosolvent afforded the corresponding furan product with a high diastereoselectivity of up to 96% de. Other cyclic β-ketoesters reacted in a likewise diastereoselective manner.

Full text of DOI:10.1246/cl.140052

CL-140052
Received: January 22, 2014 | Accepted: February 8, 2014 | Web Released: February 14, 2014
Highly Diastereoselective Synthesis of Chiral Furans with a Quaternary Carbon Substituent
at the 2-Position Using 8-Phenylmenthol as the Chiral Auxiliary
Aki Katori,1 Yoshiaki Sashihara,1 Akihisa Iwamoto,1 Satoshi Kojima,*1,2 and Yohsuke Yamamoto1
1Department of Chemistry, Graduate School of Science, Hiroshima University,
1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526
2Center for Quantum Life Sciences, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526
(E-mail: skojima@sci.hiroshima-u.ac.jp)
The reaction of cis-4-oxo-2-pentenal and 8-phenylmenthyl
2-oxocyclopentane-1-carboxylate in the presence of a fluori-
nated cosolvent afforded the corresponding furan product with
a high diastereoselectivity of up to 96% de. Other cyclic β-
ketoesters reacted in a likewise diastereoselective manner.
It used 2,5-dihydro-2,5-dimethoxyfuran (5a), a synthetic equiv-
alent of cis-4-oxo-2-pentenal.7 However, the report was on
simple diastereoselectivity and not on an asymmetric reaction.
Herein, we report on the first asymmetric reaction between cis-4-
oxo-2-enals and β-dicarbonyl compounds, which affords high
diastereoselectivity.
First, we examined catalytic asymmetric reactions using
compounds bearing either a phenolic hydroxy group or a
carboxylic acid group as the weak chiral acid moiety in the
reaction between cis-4-oxo-2-pentenal (2a) and benzyl 2-
oxocyclopentane-1-carboxylate (1). However, we obtained only
essentially racemic products in all the attempts. Therefore, we
took resort to chiral auxiliaries. Various chiral auxiliaries were
introduced to the 2-oxocyclopentane-1-carboxylic acid moiety;
the results of the reactions studied at room temperature using
benzoic acid as the weak acid are shown in Scheme 3. As
shown, reactions with amides did not proceed. However, those
with esters proceeded smoothly and those using the 8-phenyl-
menthyl group (10a), which proved useful in previously
examined reactions performed by us,8 afforded a satisfactory
preliminary selectivity of 76% de.
Furans have served as versatile four-carbon building block
units in organic synthesis.1 For example, they can be trans-
formed into various compounds such as natural and synthetic
saccharides through the Diels-Alder reaction. Therefore, adding
diversity to synthetic methods for furans is worthwhile.2
Recently, during our investigation of the Michael reaction
between cis-4-oxo-2-pentenal (2a) and β-dicarbonyl compounds
that proceeds in the presence of a base, we found that in the
absence of the base, furans with quaternary carbon centers at the
2-position form exclusively via 1,2-addition (Scheme 1).3
Further examinations showed that the reaction was accelerated
in the presence of weak Brønsted acids, and the scope of the
reaction was demonstrated using hexafluoroisopropyl alcohol
(HFIP) as the weak acid with various β-dicarbonyl compounds
capable of enolization. Because many synthetic products
obtained from furan are chiral, and our method is capable of
introducing a quaternary carbon to the 2-position of furans under
mild conditions, we decided to examine an asymmetric variant
of this reaction.
As examples of the successful introduction of asymmetry at
the 2-position of furans, while there is one recent unique
organocatalytic method based upon the Feist-Bénary reaction,4
the majority use the Friedel-Crafts reaction by either making use
of a chiral auxiliary5 or utilizing an asymmetric catalyst.6 The
reaction we developed involves nucleophilic attack of the
tautomeric enol of the β-dicarbonyl to cis-4-oxo-2-enal, a
synthetic equivalent of an oxidized furan. Therefore, our
reaction can be considered to be a formal inverse electron-
demand reaction to Friedel-Crafts-type reactions. There is a
previous example of such an electron-demand reaction furnish-
ing a furan derivative involving stereoselectivity (Scheme 2).
O
MeO
CO2Me
O
MeO
O
MeO
OMe
O
MeO
MeO
19
to
1
5a
CO2Me
ZnCl2, AcOH, H2O
O
MeO
MeO
CO2Me
O
Scheme 2.
O
O
O
O
benzoic acid (1.0 equiv)
THF (1.0 M), rt
O
CHO
R*
O
+
R*
2a (1.2 equiv)
O
O
N
N
O2S
O
Ph
O
6
7
8
BnO2C
1,4-addition
18 h, 91%, 0% de
1 wk, no reaction
1 wk, no reaction
O
MeOC
CHO
O
O
CHO
with base
+
3
Ph
OBn
1,2-ad
ditio
n
CO2Bn
1
2a
O
O
witho
ut
b
ase
O
5 min, 89%, 22% de
O
9
10a
4
10 min, 84%, 76% de
Scheme 1.
Scheme 3.
766 | Chem. Lett. 2014, 43, 766–768 | doi:10.1246/cl.140052
© 2014 The Chemical Society of Japan

Table 1. Optimization of conditionsa
O
O
HO
R'
O
O
O
N
O
O
S
R
O
O
O
CHO
additive
NH2OH HCl
pyridine, EtOH
OR*
+
OR*
O
Ph
R
Ph
R
solvent, conditions
O
O
R'
R'
R'
2a
11a
10a
(1.2 equiv)
R* = 8-phenylmenthyl
11a (R = Me, R' = H)
11d (R = Me, R' = Me)
12a (R = Me, R' = H)
12d (R = Me, R' = Me)
12h
(R = H, R' = H)
Entry Solventa
Conditions Yield/% deb/%
11h
(R = H, R' = H)
1c
2c
3
4
5
6
7
8
THF (1.0 M)
neat
HFIP-CH2Cl2 (1:1) r.t., 10 min
HFIP-CH2Cl2 (1:1) 0 °C, 2 h
TFE-CH2Cl2 (1:1) ¹20 °C, 2 d
MeOH (1.0 M)
MeOH (1.0 M)
neat
r.t., 20 min
r.t., 10 min
84
92
93
94
84
95
79
71
76
84
84
94
96
79
86
23
Scheme 5.
r.t., 100 min
0 °C, 8 h
r.t., 1 h
aTFE: 2,2,2-trifluoroethyl alcohol, HFIP: hexafluoroisopropyl
alcohol. bThe diastereomeric ratio was determined by 1H NMR
c
of the crude product. Benzoic acid (1 equiv) was added as an
additive.
O
O
O
O
CHO
O
*
Figure 1. ORTEP drawing of 12a.
OR*
O
cosolvent
+
OR*
TFE or HFIP
R'
10a-d
2a(R' = H)
2b(R' = Me)
11a-g
R'
O
R* = 8-phenylmenthyl
Ph
O
O
O
O
O
O
H
CO2R*
O
CO2R*
CO2R*
O
CO2R*
O
front side: Si face
O
Figure 2. Assumed stable conformation of 10a.
11c
TFE, -20 °C, 8 h
90%, 92% de
11d
TFE, -20 °C, 2 d
84%, 96% de
11a
TFE, -20 °C, 2 d
84%, 96% de
11b
HFIP, 0 °C, 4 d
82%, 94% de
proceed to completion, yielding product 11f in only 28% yield.
However, even for this methyl series, the diastereoselectivity
was quite high.
O
O
O
CO2R*
CO2R*
O
CO2R*
To determine the absolute stereochemistry of the products
and thereby gain insight into the mechanism, reaction products
11a and 11d were converted to their corresponding oximes 12a
and 12d, which turned out to be crystalline (Scheme 5). X-ray
crystal structural analysis revealed that the absolute stereo-
chemistry of the quaternary carbon atoms were S, and in turn
those of the products of the furan formation reaction were R
(Figure 1).9,10 This result indicated that the formyl group of the
acceptor reacted at the Re-face of the enol carbon in the initial
step of the furan-forming reaction. This can be rationalized as
follows. The enol tautomer of the β-ketoester that reacts is in its
most stable conformation where the enol moiety forms a planar
6-membered ring structure by intramolecular hydrogen bonding,
and this plane is disposed parallel to the phenyl group of the
chiral auxiliary (Figure 2).
O
O
11g
11e
HFIP, 0 °C, 2 d
82%, 93% de
11f
HFIP, 0 °C, 2 d
28%, 87% de
HFIP, 0 °C, 2 d
99%, 91% de
Scheme 4.
In order to improve the diastereoselectivity, the reaction was
optimized (Table 1). Replacing benzoic acid with fluorinated
alcohols as cosolvents and reducing the reaction temperature to
¹20 °C resulted in diastereoselectivity exceeding 90% de. The
use of environmentally benign MeOH was slightly inferior and
carrying out the reaction neat was found to be detrimental to
selectivity.
The versatility of this diastereoselective reaction was
demonstrated by the reaction with other cyclic β-ketoester
derivatives, which afforded a similar high diastereoselectivity
(Scheme 4). As for the introduction of steric hindrance in the
cyclopentanone ring somewhat away from the enol carbon 10d,
as one might expect, the reaction became slower. However, the
high diastereoselectivity was maintained (11d). Furthermore, an
acceptor with an additional methyl group at the β-position was
also examined. As expected, as a whole, the reaction became
slower, and for the tetralone derivative, the reaction did not
In the transition state of 1,2-addition reaction, this stable
conformation is probably retained, and because the Si-face is
blocked by the phenyl group of the chiral auxiliary, the formyl
group preferentially attacks from the other side to afford the
observed product.
A consideration of the transition state of 1,2-addition
suggested that the use of a strong Lewis acid might improve
the selectivity through a tighter transition state. To this end,
Sc(OTf)3, a versatile Lewis acid catalytically usable even in
Friedel-Crafts reactions, was examined (Scheme 6).11 However,
Chem. Lett. 2014, 43, 766–768 | doi:10.1246/cl.140052
© 2014 The Chemical Society of Japan | 767

2
For representative reviews on the synthesis of furans see:
a) H. N. C. Wong, Pure Appl. Chem. 1996, 68, 335. b) X. L.
Hou, H. Y. Cheung, T. Y. Hon, P. L. Kwan, T. H. Lo, S. Y. Tong,
H. N. C. Wong, Tetrahedron 1998, 54, 1955. c) T. L. Gilchrist,
J. Chem. Soc., Perkin Trans. 1 1999, 2849. d) R. C. D. Brown,
Angew. Chem., Int. Ed. 2005, 44, 850. e) S. F. Kirsch, Org.
Biomol. Chem. 2006, 4, 2076. f) N. T. Patil, Y. Yamamoto,
ARKIVOC 2007, 121. g) G. Balme, D. Bouyssi, N. Monteiro,
Heterocycles 2007, 73, 87. h) X.-L. Hou, X.-S. Peng, K.-S. Yeung,
H. N. C. Wong, Science of Synthesis, Knowledge Updates,
Thieme, Stuttgart, 2011, pp. 261-370. i) W. J. Moran, A.
Rodríguez, Org. Prep. Proced. Int. 2012, 44, 103.
A. Iwamoto, A. Katori, Y. Sashihara, S. Kojima, Chem. Lett. 2012,
41, 1586.
Diastereoselective Friedel-Crafts reactions of furans: a) J. Jurczak,
S. Belniak, T. Kozluk, Bull. Pol. Acad. Sci. 1991, 39, 271. b) P.
Kwiatkowski, J. Majer, W. Chaładaj, J. Jurczak, Org. Lett. 2006, 8,
5045.
O
CHO
O
O
O
O
2a
O
O
Sc(OTf)3
O
Ph
CH2Cl2, 0°C
Ph
up to 77% de
Scheme 6.
R
O
O
O
O
O
MeO
OMe
O
3
4
O
Lewis acids
CH2Cl2, 0°C
O
Ph
Ph
R
5a
5b
11h
11a
(R = H)
(R = H) up to 64% de
(R = Me)
(R = Me) up to 38% de
Scheme 7.
5
6
L. Albrecht, L. K. Ransborg, B. Gschwend, K. A. Jørgensen,
J. Am. Chem. Soc. 2010, 132, 17886.
diastereoselectivity did not exceed 77% de. The advantage of
using cis-4-oxo-2-enals 2 over synthons 5 was demonstrated in
the same Sc(OTf)3-catalyzed reaction (Scheme 7). Diastereose-
lectivity was only up to 64% and 38% de, respectively, for 5a
and 5b. X-ray crystal structural analysis of oxime derivative 12h
of major product 11h from 5a, lacking the methyl group, showed
that the stereochemistry was not changed, thus suggesting that
there is no merit in using 5 over cis-4-oxo-2-enals 2.
Catalytic enantioselective Friedel-Crafts reactions of furans: a) N.
Gathergood, W. Zhuang, K. A. Jørgensen, J. Am. Chem. Soc.
2000, 122, 12517; W. Zhuang, N. Gathergood, R. G. Hazell, K. A.
Jørgensen, J. Org. Chem. 2001, 66, 1009; S. Saaby, P. Bayón, P. S.
Aburel, K. A. Jørgensen, J. Org. Chem. 2002, 67, 4352. b) K. B.
Jensen, J. Thorhauge, R. G. Hazell, K. A. Jørgensen, Angew.
Chem., Int. Ed. 2001, 40, 160. c) D. A. Evans, K. R. Fandrick,
H.-J. Song, J. Am. Chem. Soc. 2005, 127, 8942. d) Y. Huang,
A. M. Walji, C. H. Larsen, D. W. C. MacMillan, J. Am. Chem.
Soc. 2005, 127, 15051. e) P. Kwiatkowski, E. Wojaczyńska,
J. Jurczak, Tetrahedron: Asymmetry 2003, 14, 3643. f) P.
Kwiatkowski, E. Wojaczyńska, J. Jurczak, J. Mol. Catal. A:
Chem. 2006, 257, 124. g) D. Uraguchi, K. Sorimachi, M. Terada,
J. Am. Chem. Soc. 2004, 126, 11804. h) S. Yamazaki, S. Kashima,
T. Kuriyama, Y. Iwata, T. Morimoto, K. Kakiuchi, Tetrahedron:
Asymmetry 2009, 20, 1224. i) S. Adachi, F. Tanaka, K. Watanabe,
T. Harada, Org. Lett. 2009, 11, 5206. j) S. Adachi, F. Tanaka, K.
Watanabe, A. Watada, T. Harada, Synthesis 2010, 2652.
Diastereoselective furan formation using 2,5-dihydro-2,5-dimeth-
oxyfuran: O. Duval, A. Rguigue, L. M. Gomés, Heterocycles
1994, 38, 2709.
a) R. Takagi, J. Kimura, Y. Shinohara, Y. Ohba, K. Takezono, Y.
Hiraga, S. Kojima, K. Ohkata, J. Chem. Soc., Perkin Trans. 1
1998, 689. b) Y. Shinohara, Y. Ohba, R. Takagi, S. Kojima, K.
Ohkata, Heterocycles 2001, 55, 9. c) R. Takagi, M. Nakamura, M.
Hashizume, S. Kojima, K. Ohkata, Tetrahedron Lett. 2001, 42,
5891. d) S. Kojima, K. Fujitomo, Y. Shinohara, M. Shimizu, K.
Ohkata, Tetrahedron Lett. 2000, 41, 9847. e) R. Takagi, M.
Hashizume, M. Nakamura, S. Begum, Y. Hiraga, S. Kojima, K.
Ohkata, J. Chem. Soc., Perkin Trans. 1 2002, 179. f) S. Kojima, K.
Hiroike, K. Ohkata, Tetrahedron Lett. 2004, 45, 3565. g) S.
Kojima, K. Fujitomo, Y. Itoh, K. Hiroike, M. Murakami, K.
Ohkata, Heterocycles 2006, 67, 679. h) S. Matsumura, R. Takagi,
S. Kojima, K. Ohkata, M. Abe, Heterocycles 2010, 81, 2479.
The configurations of the oximes and the ketone are same, but
differ in stereochemical symbols due to a change in the preference
order of the substituents.
In summary, the reactions of cis-4-oxo-2-pentenals 2a and
2b with cyclic β-ketoesters using the 8-phenylmenthyl group as
a chiral auxiliary afforded furan products with diastereoselec-
tivities of up to 96% de. X-ray analysis of the oxime derivatives
allowed the assignment of absolute stereochemistry, and it was
in good agreement with an assumed transition state in which the
β-ketoester enol assumes a conformation with a cyclic hydrogen-
bonded 6-membered ring and attack of the formyl group occurs
to the side of this enol unblocked by the phenyl group of the
chiral auxiliary. The advantage of using cis-4-oxo-2-enals over
their cyclic synthons was also demonstrated. This is the first
asymmetric furan-forming reaction involving an aldol-type first
step, and can be considered to be a formal inverse electron-
demand reaction to Friedel-Crafts-type reactions. It should also
be noted that the asymmetric Friedel-Crafts reactions are limited
to the introduction of either asymmetric secondary or tertiary
carbons, whereas our method allows the incorporation of an
asymmetric quaternary carbon. Thus, our reaction should be
valuable as a complementary reaction toward chiral furans.
Modifications to encompass a wider range of substrates are
currently underway.
7
8
This work was supported by a Grant-in-Aid for Science
Research (No. 24550055) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
9
References and Notes
1
For representative reviews on the use of furans as synthetic
intermediates see: a) B. H. Lipshutz, Chem. Rev. 1986, 86, 795.
b) C. O. Kappe, S. S. Murphree, A. Padwa, Tetrahedron 1997, 53,
14179. c) H. N. C. Wong, P. Yu, C.-Y. Yick, Pure Appl. Chem.
1999, 71, 1041. d) H.-K. Lee, K.-F. Chan, C.-W. Hui, H.-K. Yim,
X.-W. Wu, H. N. C. Wong, Pure Appl. Chem. 2005, 77, 139.
10 See the Supporting Information section for other ORTEP drawings
and details of the X-ray analysis. Supporting Information is
available electronically on the CSJ-Journal Web site, http://www.
csj.jp/journals/chem-lett/index.html.
11 T. Tsuchimoto, K. Tobita, T. Hiyama, S.-i. Fukuzawa, J. Org.
Chem. 1997, 62, 6997.
768 | Chem. Lett. 2014, 43, 766–768 | doi:10.1246/cl.140052
© 2014 The Chemical Society of Japan