Construction of successive chiral centers adjacent to a chiral tetraalkylated quaternary center using an asymmetric aldol reaction

Article abstract of DOI:10.1021/ol400556v

The aldol reaction of 2″ with a variety of different aldehydes gave the corresponding β-lactones 4 bearing successive asymmetric centers adjacent to a chiral tetraalkylated quaternary center or the (E)-alkenes 8. The use of electronically neutral or electron-deficient aldehydes led to 4 in excellent yields with high diastereoselectivities, whereas electron-rich aldehydes performed poorly and underwent decarboxylation to afford 8.

Full text of DOI:10.1021/ol400556v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Construction of Successive Chiral
Centers Adjacent to a Chiral
Tetraalkylated Quaternary Center Using
an Asymmetric Aldol Reaction
Tomoyuki Esumi,* Chihiro Yamamoto, Yuri Tsugawa, Masao Toyota,
Yoshinori Asakawa, and Yoshiyasu Fukuyama
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho,
Tokushima 770-8514, Japan
esumi@ph.bunri-u.ac.jp
Received February 28, 2013
ABSTRACT
The aldol reaction of 200 with a variety of different aldehydes gave the corresponding β-lactones 4 bearing successive asymmetric centers adjacent
to a chiral tetraalkylated quaternary center or the (E)-alkenes 8. The use of electronically neutral or electron-deficient aldehydes led to 4 in
excellent yields with high diastereoselectivities, whereas electron-rich aldehydes performed poorly and underwent decarboxylation to afford 8.
Structural units consisting of successive chiral centers
adjacent to a chiral tetraalkylated (all-carbon) quaternary
center (Figure 1) are frequently encountered in a variety of
different natural products,1 and a series of different meth-
ods aimed at providing access to structural units of this
particular type have been developed by a number of
different groups.2
(1) Selected examples for the biologically active natural products pos-
sessing successive asymmetric centers with chiral tetraalkylated quaternary
center: (a) Fukuyama, Y.; Minami, H.; Takeuchi, K.; Kodama, M.;
Kawazu, K. Tetrahedron Lett. 1996, 37, 6767–6770. (b) Tang, W.; Kubo,
M.; Harada, K.; Hioki, H.; Fukuyama, Y. Bioorg. Med. Chem. Lett. 2009,
19, 882–886. (c) Nakamura, H.; Wu, H.; Ohizumi, Y.; Hirata, Y. Tetra-
hedron Lett. 1984, 25, 2989–2992. (d) Hayashi, K.-I.; Nakanishi, Y.;
Bastow, K. F.; Cragg, G.; Nozaki, H.; Lee, K.-H. Bioorg. Med. Chem.
Lett. 2002, 12, 345–348. (e) Rudi, A.; Benayahu, Y.; Kashman, Y. Org.
Lett. 2007, 9, 2337–2340. (f) Sing, I. P.; Sidana, J.; Bharate, S. B.; Foley, W.
J. Nat. Pro. Rep. 2010, 27, 393–416. (g) Ciochina, R.; Grossman, R. B.
Chem. Rev. 2006, 106, 3963–3986. (h) Whitson, E. L.; Thomas, C. L.;
Henrich, C. J.; Sayers, T. J.; MacMahon, J. B.; Mackee, T. C. J. Nat. Prod.
2010, 73, 2013–2018. (i) Guo, D.-X.; Zhu, R.-X.; Wang, X.-N.; Wang
L.-N.; Wang, S.-Q.; Lin, Z.-M.; Lou, H.-X. Org. Lett. 2010, 12, 4404–4407.
(j) Cantrell, C. L.; Klun, J. A.; Bryson, C. T.; Kobaisy, M.; Duke, S. O.
J. Agric. Food Chem. 2005, 53, 5948–5953. (k) Song, Z.-J.; Xu, X.-M.;
Deng, W.-L.; Peng, S.-L.; Ding, L.-S.; Xu, H.-H. Org. Lett. 2011, 13, 462–
465. (l) Wang, J.-D.; Zhang, W.; Li, Z.-Y.; Xiang, W.-S.; Guo, Y.-W.;
Krohn, K. Phytochemistry 2007, 68, 2426–2431. (m) De Rosa, S.; Cristpino,
A.; De Giulio, A.; Iodice, C.; Amodeo, P.; Tancredi, T. J. Nat. Prod. 1999,
Figure 1. General structure of successive asymmetric centers
adjacent to tetraalkylated quaternary center.
For example, Shibasaki3 used an enantioselective Dielsꢀ
Alder reaction catalyzed by a chiral Fe3þ-pybox complex
to construct a series of chiral cyclohexane carboxylic acid
derivative (76ꢀ87% ee), whereas Carter4 reported the use
of an enantioselective Robinson annulation reaction as
€
62, 1316–1318. (n) Lamshoft, M.; Schmickler, H.; Marner, F.-J. Eur. J.
Org. Chem. 2003, 727–733. (o) Yoo, H.-D.; Cremin, P. A.; Zeng, L.; Garo,
E.; Williams, C. T.; Lee, C. M.; Goering, M. G.; O’Neil-Johnson, M.;
Eldridge, G. R.;Hu, J. J. Nat. Prod. 2005, 68, 122–124. (p) Anderson, N. R.;
Lorck, H. O. B.; Rasmussen, P. R. J. Antibiot. 1983, 36, 753–760. (q) Xu, J.;
Harrison, L. J.; Vittal, J. J.; Xu, Y. J.; Goh, S. W. J. Nat. Prod. 2000, 63,
1062–1065. (r) Gunesekera, S. P.; McCarthy, P. J.; Kelly-Borges, M.;
Lobkovsky, E.; Clardy, J. J. Am. Chem. Soc. 1996, 118, 8759–8760.
(2) Das, J. P.; Marek, I. Chem. Commun. 2011, 47, 4593–4623.
(3) Usuda, H.; Kuramochi, A.; Kanai, M.; Shibasaki, M. Org. Lett.
2004, 6, 4387–4390.
(4) Yang, H.; Carter, R. G. Org. Lett. 2010, 12, 3108–3111.
r
10.1021/ol400556v
XXXX American Chemical Society

part of a multicomponent coupling reaction process in the
presence of a chiral N-(arylsulfonyl)pyrrolidinecarbox-
amide catalyst to afford a series of chiral cyclohexene
derivatives with acceptable enantioselectivities and
high diastereoselectivities (54.6ꢀ91.8% ee, >90.4% de).
Recently, Minko et al.5 reported the successful construc-
tion of a tetraalkylated quaternary center R to a carbonyl
group via the carbocupration to the triple bonds of a series
of alkyne derivatives bearing a chiral oxazolidinone aux-
iliary, followed by oxidation and aldol reaction in one pot
(45ꢀ62%, 80ꢀ88% de). We recently reported the asym-
metric 1,4-addition reaction of (H2CdCH)2Cu(CN)Li2 to
the R,β-unsaturated carboxylic acid derivative 1 to give the
corresponding 1,4-adduct 2 bearing a chiral tetraalkylated
quaternary center β to the carbonyl group (Scheme 1).6
This reaction proceeded in excellent yield (93%) with a
high diastereoselectivity (90% de).
Table 1. Aldol Reaction of Chiral Oxazolidinone 200 with a
Variety of Different Aldehydes
Scheme 1. Asymmetric 1,4-Addition Reaction of
(H2CdCH)2Cu(CN)Li2 to an R,β-Unsaturated Carboxylic
Acid Derivative
Scheme 2. Potential One-Pot Transformation of the Chiral
Oxazolidinone Derivative 20 Involving a Tetraalkylated Carbon
entry
RCHO
CH3CHO
6:4:7:8 (%)
6 þ 4 þ 7 þ 8 (%)
1
2
3
4
5
6
7
8
0:65:7:0
0:89:0:0
0:84:0:0
0:99:0:0
0:86:0:0
0:0:0:95
0:0:0:76
0:67:33:0
72
89
84
99
86
95
76
100
(CH3)2C(H)CHO
PhCHO
p-BrPhCHO
H2CdC(H)CHO
p-CH3PhCHO
p-CH3OPhCHO
p-O2NPhCHO
the decision was made to subject 2 to an asymmetric aldol
reaction.7,8 Kende9 reported that the chiral oxazolidinone
derivative of isobutyric acid was transformed to 1,3-ox-
azine-2,6-dione by an asymmetric aldol reaction followed
by the ring-opening reaction of the oxazolidinone in one
pot. The driving force for the second step in the sequence
was reported to be the steric repulsion between the R,R-
dimethyl and isopropyl groups of the oxazolidinone.
The retention of the chiral oxazolidinone auxiliary in the
1,4-adduct 2 provided the opportunity for further asym-
metric induction at the position R to the carbonyl group,
and compound 2 would therefore allow for the construc-
tion of an additional asymmetric center adjacent to the
chiral tetraalkylated quaternary center. With this in mind,
(7) (a) Mahrwald, R. Modern Aldol Reactions; Wiley-VCH:
Weinheim, 2004; Vol. 1, pp 1ꢀ343. (b) Mahrwald, R. Modern Aldol
Reactions; Wiley-VCH: Weinheim, 2004; Vol. 2, pp 1ꢀ328. (c) Aya, P.;
Qin, H. Tetrahedron 2000, 56, 917–947.
(5) Minko, Y.; Pasco, M.; Lercher, L.; Botoshansky, M.; Marek, I.
Nature 2012, 490, 522–526.
(6) Esumi, T.; Shimizu, H.; Kashiyama, A.; Sasaki, C.; Toyota, M.;
(8) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127–2129.
(9) Kende, A. S.; Kawamura, K.; Orwat, M. Tetrahedron Lett. 1989,
30, 5821–5824.
Fukuyama, Y. Tetrahedron Lett. 2008, 49, 6846–6849.
B
Org. Lett., Vol. XX, No. XX, XXXX

This implied that the oxazolidinone moiety of the aldol
adduct 3a derived from 20 could be removed to give
β-lactone 4 under basic conditions, because the R-alkoxy
group of aldol adduct 3a would repel not only the alkyl
group of the oxazolidinone but also the alkyl chain bearing
the tetraalkylated quaternary center. The system would
therefore prefer to adopt conformation 3c as opposed to
3b, which would be disfavored because of steric repulsion
between the R-alkoxy group and the alkyl chain. Confor-
mation 3c would then undergo the intramolecular nucleo-
philic attack of the oxyanion on the carbonyl carbon (C1),
leading to β-lactone 4 and oxazolidinone 5 (Scheme 2).
On the basis of our prediction for this transformation,
we examined the aldol reaction of 200 under basic condi-
tions. (20R)-2-Phenyloxazolidinone derivative 200 was trea-
ted with SHMDS (1.5 equiv) in THF for 30 min at ꢀ78 °C
and then reacted with a variety of different aldehydes
(3 equiv) for 15 h at the same temperature. The results
for these reactions are shown in Table 1. The simple aldol
adducts 6 were not obtained in all of the entries, whereas
the β-lactones 4 were obtained as anticipated. When
acetoaldehyde was used, β-lactone 4a (R = CH3) and
dioxanone 7a (R = CH3) were obtained in 65 and 7%
yields, respectively (Table 1, entry 1). When bulkier al-
dehydes such as isobutylaldehyde, benzaldehyde, and
p-bromobenzaldehyde were used in the transformation,
the reactions proceeded cleanly to afford the β-lactones
4bꢀd (R = (CH3)2CH, Ph, and p-BrPh) in high yields
without the formation of any of the other stereoisomers or
dioxanone 7 (Table 1, entries 2ꢀ4). The formation of the
β-lactone 4e (R = H2CdCH) occurred via a 1,2-addition
reaction in 86% yield (Table 1, entry 5). Surprisingly, when
aromatic aldehydes bearing electron-donating substitu-
ents were used in the reaction, including p-methyl- and
p-methoxybenzaldehyde, the (E)-alkenes 8f and 8g were
formed as the sole products (R = p-CH3Ph and
p-CH3OPh) (Table 1, entries 6 and 7).10 In contrast, when
the reaction was conducted with aromatic aldehydes bear-
ing electron-deficient substituents, such as p-nitrobenzal-
dehyde, the yield of the corresponding dioxanone 7h
(p-O2NPh) was found to increase (Table 1, entry 7).
In addition, (20R)-20-phenyloxazolidinone was recovered
in quantitative yield from all of the reaction mixtures by
silica gel column chromatography. It is worthy of note that
all of our attempts to trap the enolate formed in situ
following the 1,4-addition were unsuccessful.
The absolute configuration of 4e was determined to be
(2S,3S,10S) following analysis of the nuclear Overhauser
Scheme 3. Determination of the Absolute Configuration of 4e
Figure 2. Assertion of absolute configuration for β-lactones
4aꢀd and 4h and the dioxanones 7a and 7h.
Scheme 4. Proposed Mechanism for the Induction of Stereochemistry for the Aldol Reaction and the Generation of 4 and (E)-Alkene 7
Org. Lett., Vol. XX, No. XX, XXXX
C

effect spectroscopy (NOESY) correlation spectrum of
cyclopentene derivative 9, which was prepared by LiAlH4
reduction of 4e followed by a ring closing metathesis
reaction catalyzed by Grubbs’ reagent (first generation)
(Scheme 3).
Scheme 5. Proposed Mechanism for the Formation of 4g
The absolute configuration of the other compounds,
4aꢀd and 4h (R = CH3, (CH3)2CH, Ph, p-BrPh, p-O2NPh)
and 7a and 7h (R = p-CH3Ph, p-CH3OPh), were assumed
by comparison of their NMR spectra with that of 4e and
NOESY correlation experiments (Figure 2).
Based on these results, we proposed a mechanism for the
induction of the stereochemistry of the aldol reaction and
the generation of the dioxanone 7 and (E)-alkene 8 pro-
ducts, as shown in Schemes 4 and 5. Treatment of 200 with
SHMDS leads to the formation of a six-membered cyclic
chelate with Naþ. The (E)-enolate 10a would then be
formed because of steric repulsion between the alkyl chain
carrying the tetraalkylated quaternary center and the
oxazolidinone moiety. Given that the R-face of the
(E)-enolate 10a would be blocked by the phenyl group of
the oxazolidinone, the aldehyde would approach from the
β-face and the aldol reaction would then proceed via a
six-membered chair transition state. The alkyl group of
aldehyde in the cyclic transition state would then be placed
in a pseudoaxial orientation because of steric repulsion
between the alkyl chain of the tetraalkylated quaternary
center and the alkyl groupofthe aldehyde, and the reaction
would therefore proceed via transition state 11a and adopt
configuration 3. Furthermore, the bulky tetraalkylated
quaternary center would force the oxyanion close to
the carbonyl carbon (C1), resulting in the formation of
the β-lactone 4. The use of a small or electrophilic alkyl
group on the aldehyde, however, such as a methyl or a
p-nitrophenyl group, respectively, would allow the oxya-
nion to attack another aldehyde, leading to the formation
of dioxanone. In contrast, for aromatic aldehydes bearing
electron-donating substituents on their aromatic ring such
as p-methoxyphenyl, the resulting β-lactone ring would be
opened through the donation of electrons, resulting in the
formation of quinone methylide 12, which would be con-
verted to arylalkene 8g together with the elimination of
CO2, with the electron being pushed back to the electron-
deficient aromatic ring.
Inconclusion, wehavedevelopedanefficient method for
constructing successive chiral centers adjacent to chiral
tetraalkylated quaternary centers using a sequential asym-
metric 1,4-addition/aldol reaction. The aldol reaction be-
tween the 1,4-adduct200 and a varietyofdifferent aldehydes
except for aromatic aldehydes bearing electron-donating
substituents afforded the β-lactones 4aꢀe and 7h and
the dioxanones 7a and 7h with excellent stereocontrol.
To the best of our knowledge, the current work represents
the first report describing the construction of successive
chiral centers adjacent to a quaternary carbon in one
pot. In addition, the reaction producing an aryl alkene
could be used as an alternative CꢀC bond formation
reaction. The scope and limitations of these reactions
and their application to the syntheses of a variety of
different natural products are currently being investigated
in our laboratory.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology of
Japan (23590035).
Supporting Information Available. Experimental pro-
cedures and characterization of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Example for CO2-elimination from β-lactone by thermolysis: (a)
Adam, W.; Baeza, J.; Liu, J.-C. J. Am. Chem. Soc. 1972, 94, 2000–2006.
(b) Mulzer, J.; Speck, T. Tetrahedron Lett. 1995, 36, 7643–7646.
The authors declare no competing financial interest.
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