Asymmetric aldol reaction of allenoates: Regulation for the selective formation of isomeric allenyl or alkynyl aldol adduct

Article abstract of DOI:10.1021/acs.orglett.5b00454

A highly stereoselective synthesis of 3-butynyl-threo-aldol adducts is achieved from the reaction of allyl allenoate with a chiral bromoborane in the presence of iPr₂NEt, followed by addition of BF₃·OEt₂ as an additive to

Full text of DOI:10.1021/acs.orglett.5b00454

Letter
pubs.acs.org/OrgLett
Asymmetric Aldol Reaction of Allenoates: Regulation for the
Selective Formation of Isomeric Allenyl or Alkynyl Aldol Adduct
Jiyun Bang, Hyuna Kim, Jihyun Kim, and Chan-Mo Yu*
Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea
S
* Supporting Information
ABSTRACT: A highly stereoselective synthesis of 3-butynyl-
threo-aldol adducts is achieved from the reaction of allyl
allenoate with a chiral bromoborane in the presence of
iPr2NEt, followed by addition of BF3·OEt2 as an additive to
scavenge excess base and then aldehydes, whereas isomeric
allenyl aldol adducts are formed in the absence of a Lewis acid
additive from methyl allenoate.
Scheme 1. Design of Allenoate Aldol Routes and Targets
he discovery of efficient asymmetric methods to achieve the
T
synthesis of enantiomerically pure compounds is of
considerable interest in organic chemistry.1 In light of wide-
spread advances in asymmetric methods, aldol reactions of
carbonyl functionalities using chiral auxiliaries or catalysts led to
significant developments in the area of asymmetric synthesis.2
Numerous successful methodologies using stoichiometric
amounts of chiral reagents3 and catalytic amounts of chiral
Lewis acids,4 bases,5 and organocatalysts6 have been developed
and applied to organic synthesis. Although there have been many
reports regarding the enhancement of chemical processes for
practical use, the scope of aldol reactions is still limited to simple
systems.
In our continuous efforts to utilize allenyl functionality, we
have disclosed our discoveries of the synthetic methods for the
construction of cyclic or acyclic systems through allylic transfer
reactions to the carbonyls and imine equivalents.7 The
characteristic features of our approaches in terms of structural
aspects of the products have encouraged us to carry out more
investigations for designing new asymmetic routes using allenyl
substrates. In this regard, we became quite interested in exploring
stereo- and regioselective aldol routes starting from allenoate 1 to
a variety of products possessing versatile functional groups
(Scheme 1).8
Allenoates have been regarded as an attractive substrate for
various chemical transformations and have gained much
attention for synthetic utility because of their structural and
chemical uniqueness with facile availability.9 The most recent
notable advances are Lewis base catalyses of allenoates utilizing
amine or phosphine nucleophilic catalysts with a variety of
electrophiles, including carbonyl equivalents, to provide
structurally diverse cyclic products through formal cycloaddition
processes.10
as allenyl 2 and 3-butynyl 3 from allenoate 1.11 Furthermore,
synthetic applications can be foreseen for the products to give a
variety of bioactive substances (Scheme 1).
The first study focusing on the use of allenoates 112 as suitable
substrates for chemical conversions is depicted in Scheme 1. Our
initial studies were carried out with chiral borane reagents such as
Ipc2BX (4a,b)13 and 4c14 for the asymmetric aldol process. The
choice of the chiral borane reagents 4 was based on the
availability of both enantiomeric forms and their efficiency to
promote the addition of various nucleophiles to carbonyl
derivatives. Initial attempts to react 1 (R = Me) with 4a (X =
Br) in the presence of iPr2NEt at −78 °C followed by an addition
We report herein our discovery of control elements to regulate
selective formation of isomeric allenyl 2 or 3-butynyl 3 aldol
adducts from aldol reaction of allenoate 1 with aldehydes, which
allows reactions in good yields with high levels of stereo-
selectivity (Scheme 1). To the best of our knowledge, there has
been no report of stereoselective synthesis of aldol adducts such
Received: February 12, 2015
Published: March 4, 2015
© 2015 American Chemical Society
1573
DOI: 10.1021/acs.orglett.5b00454
Org. Lett. 2015, 17, 1573−1576

Organic Letters
Letter
a
Scheme 2. Allenoate Aldol Reaction of 1 (R1 = Me) to 2
of hydrocinnamaldehyde indicated that the conversion to adduct
2a could not be realized under various conditions. Replacement
of 4a with more reactive 4b (X = OTf) also turned out to be
unpromising, presumably due to geometrical difficulty of
forming a boron enolate from allenoate with structurally complex
4b. We found that 4c could be an effective chiral reagent for this
purpose. Initial experiments on the enolization of 1a with 4c in
the presence iPr2NEt at −78 °C for 1 h, followed by treatment
with hydrocinnamaldehyde at −78 °C for 2 h, afforded
encouraging but marginal results. Although aldol adduct 2a
was produced during the reaction as a single adduct, the problem
of low chemical yield (40%) remained (entry 3). After surveying
numerous conditions, we observed that the enolization time (t1)
was a crucial factor for optimal conditions (Table 1, entries 4−7).
Table 1. Optimization for the Conversion of 1 to 2
a
b
c
d
entry
4
R1
base
t1 (h)
solvent
yield (%) ee (%)
1
2
3
4
5
6
7
4a
4b
4c
4c
4c
4c
4c
Me
Me
Me
Me
Et
iPr2NEt
iPr2NEt
iPr2NEt
Et3N
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
1
1
40
21
47
23
78
90
a
For conditions, see Table 1.
1
iPr2NEt
iPr2NEt
iPr2NEt
1
88
84
92
Me
Me
1
isolate compared to 2. From a mechanistic perspective for the
formation of 2, two major events are immediately discernible in
the reaction process. The first event is presumably the
aldolization mediated by 4c and iPr2NEt between allenoate 1
and the aldehyde, which produces 3-butynyl aldol adduct 3. The
second step of the reaction would be the isomerization of alkyne
3 to allene 2. In general, the isomerization from 3 to more stable
α,β-unsaturated allenoate 2 is predictable. We reasoned that if 3
is an intermediate toward the formation of 2, then it might be
possible to isolate 3 by developing a method to prevent the
isomerization. Note that structures related to 3-butynyl aldol
adducts 3 and 5 have not been reported in the literature.
With this issue in mind, our investigations began by reducing
the amount of iPr2NEt because the isomerization was attributed
to the use of excess base during the reaction. Initial attempts for
reaction of 1 (R1 = Et) with 4c in the presence of iPr2NEt (1
equiv) under the same conditions and then with hydro-
cinnamaldehyde for 10 min at −78 °C indicated that the
conversion to the desired 3-butynyl adducts 3 and 5 turned out to
be only marginal. Reaction always produced 2 (R1 = Et) as a
major component along with the 3-butynoate aldol adducts 3
and 5 as minor products in 36% combined yields (Table 2, entry
2).
0.3
a
b
c
Using 2 equiv. Enolization time. Yields are those of products
isolated after purification by chromatography. Determined by analysis
of HPLC.
d
During optimization studies, several key findings emerged
(entry 7): (1) about 20 min of the enolization time at −78 °C
resulted in the best chemical yields; (2) iPr2NEt (2 equiv) proved
to be a suitable base compared to other bases such as Et3N and N-
methylpyrrolidine for this transformation; (3) reactions
performed in CH2Cl2 resulted in the best chemical yields in
comparison with other solvent systems including toluene; (4)
methyl allenoate is superior to ethyl allenoate in terms of
chemical yield and enantioselectivity; (5) reactions always
produced α-addition adduct 2a as a sole product. Under optimal
conditions, the reaction of 1 (R1 = Me) with hydro-
cinnamaldehyde in CH2Cl2 produced 2a in 78% yield with
92% ee.
With the notion that this approach might lead to a general and
efficient method for the synthesis of 2, we set out to explore
structurally varying aldehydes to extend the reaction scope.
Indeed, the method turned out to be successful with structurally
various aldehydes (1°, 2 , 3 , Ar, enal, and ynal) forming
exclusively α-addition aldol products 2 in moderate to good
yields with high levels of enantioselectivity, as can be seen in
Scheme 2.
o
o
We subsequently speculated that the prevention of isomer-
ization might require a Lewis acid additive to scavenge the base
effectively. After screening reaction conditions with potent Lewis
acids such as BF3·OEt2, B(OMe)3, and Al(OEt)3, we found that
BF3·OEt2 could be a useful additive for this purpose and chose it
for systematic studies. Indeed, we observed that the utilization of
BF3·OEt2 as an additive resulted in diminishing formation of
allenyl aldol adduct 2 and increasing formation of the 3-
In an effort to expand the scope of chemical transformation in
the synthesis of 2 from allenoate 1, we have focused on the design
of a reaction pathway to produce threo-3 or erythro-5 selectively,
which are prone to isomerization and, therefore, more difficult to
1574
DOI: 10.1021/acs.orglett.5b00454
Org. Lett. 2015, 17, 1573−1576

Organic Letters
Letter
a
Table 2. Optimization for the Conversion of 1 to threo-3
Scheme 3. Chemical Pathways for 2 and 3 from 1
d
e
base
BF3·OEt2
yield
(%)
ee
b
c
entry
R1
equiv
equiv
t2
2 h
2/3/5
2 only
(%)
f
1
2
3
4
5
6
7
8
9
Me
Et
2.0
1.0
1.5
1.2
1.2
1.5
1.2
1.2
1.2
none
none
0.5
78
36
44
38
37
41
63
78
92
10 min
20 min
20 min
20 min
30 min
20 min
30 min
71:21:8
21:70:9
20:75:5
14:86:0
10:90:0
3 only
Et
Pr
0.5
81
61
64
52
54
89
Ph
Ph
tBu
tBu
allyl
0.5
1.0
0.5
1.0
3 only
1.0
15 min
3 only
62
a
b
c
Reactions were carried out in CH2Cl2. Reaction time. Determined
d
e
by 1H NMR of crude products. Isolated yields. Determined by
HPLC analysis of the benzoylated diol 8a. Enatiomeric excess value of
f
2a.
butynoate aldol adduct 3 (Table 2, entries 3−6). However, the
problem with the formation of 2 and low chemical yields needed
to be solved.
a
Scheme 4. Allenoate Aldol Reaction of 1 (R1 = Allyl) to 3
To find optimal conditions, a series of experiments was
performed with various allenoates 1. Reaction of 1 (R1 = t-butyl)
under similar conditions (t2, 30 min) indicated that the exclusive
conversion to the corresponding threo-3 (R1 = t-butyl) was
achieved in 78% yield. However, the enantioselectivity turned
out to be lower (ee = 54%) than other cases (Table 2, entry 8).
We observed that allyl allenoate 1 (R1 = allyl) could be a suitable
substrate to provide 3 in 62% yield with 89% ee (Table 2, entry
9). Under optimal conditions, a reaction was performed by
addition of BF3·OEt2 (1.0 equiv) followed by hydrocinnamalde-
hyde (2 equiv) to a resulting solution of the boron enolate
prepared from 1 (R1 = allyl) with 4c under the same conditions.
The reaction continued for 15 min at −78 °C, and then the usual
workup procedure provided 3a as a single diastereomer. Reaction
conditions were also effective for various aldehydes (Scheme 4).
Note that the reaction produced neither 2 nor 5 according to the
analysis of 1H NMR spectra of the crude products.
The preference of threo-diastereoselectivity for the larger R1
group in allenoate 1 can be explained by the formation of a boron
(E)-enolate in A from allenoate 1 (Scheme 3). Intermediate 6,
which is the result of the complexation between the lone pair of
the carbonyl oxygen of allenoate 1 and the boron of 4c, should
adopt the conformation shown in Scheme 3 due to electronic and
steric reasons.15 Subsequent enolization of complex 6 in the
presence of iPr2NEt to (E)-enolate and then addition to aldehyde
via a chairlike intermediate A provides B and C. We observed that
isomerization from 3-butynoate B to allenoate 2 during reaction
is favored by a smaller R1 over a larger R1. This phenomenon can
be accounted for by analysis of possible intermediates B and C in
Scheme 3. For the isomerization to occur from 3-butynyl to the
allenyl moiety, Ha in B and C must be acidic enough. Formation
of the allenyl aldol adduct 2 via intermediate B can be explained
by assuming that the tight coordination of the ester moiety to the
boronyl moiety provides a geometrical validity of Ha with the
carbonyl group to satisfy the isomerization with base from B to 2.
On the other hand, formation of threo-3 must result from a
a
Same conditions outlined in Table 2.
nonchelation intermediate C due to a steric repulsion between
the larger R1 group in ester and the N-sulfonamidyl group.
To verify the stereochemistry in products 2 and 3, we carried
out the synthesis of several compounds to compare their
spectroscopic and optical data with known compounds (Scheme
5). Cyclocarbonylation of 2d with Ru3(CO)12 (2 mol %) in the
presence of Et3N under CO atmosphere (15 atm) at 90 °C in
dioxane resulted in the formation of lactone 7 in 44% yield,16
a
methyl ester of striatisporolide A.17 Although the absolute
configuration of 7 was deduced by comparison of specific
1575
DOI: 10.1021/acs.orglett.5b00454
Org. Lett. 2015, 17, 1573−1576

Organic Letters
Letter
Scheme 5. Chemical Transformations of 2 and 3 To Prove
Their Stereochemistry
REFERENCES
■
(1) For examples, see: (a) Carreira, E. M.; Kvaerno, L. In Classics in
Stereoselective Synthesis; Wiley-VCH: Weinheim, Germany, 2009.
(b) Design and Strategy in Organic Synthesis; Hanessian, S., Giroux, S.,
Merner, B. L., Eds.; Wiley-VCH: Weinheim, Germany, 2013.
(2) For general discussions, see: (a) Modern Methods in Stereoselective
Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, Germany,
2013. (b) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600−
1632. (c) Shibasaki, M.; Matsunaga, S. Chem. Soc. Rev. 2006, 35, 269−
279.
(3) (a) Heravi, M. M.; Zadsirjan, V. Tetrahedron: Asymmetry 2014, 25,
1061−1090. (b) Heravi, M. M.; Zadsirjan, V. Tetrahedron: Asymmetry
2013, 24, 1149−1188. (c) Machajewski, T. D.; Wong, C.-H. Angew.
Chem., Int. Ed. 2000, 39, 1352−1374.
(4) (a) Kitanosonoa, T.; Kobayashi, S. Adv. Synth. Catal. 2013, 355,
3095−3118. (b) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L.
Angew. Chem., Int. Ed. 2005, 44, 4682−4698.
(5) (a) Denmark, S. E.; Wilson, T. W. Angew. Chem., Int. Ed. 2012, 51,
9980−9992. (b) Beutner, G. L.; Denmark, S. E. Angew. Chem., Int. Ed.
2013, 52, 9086−9096.
(6) (a) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int.
Ed. 2006, 45, 8100−8102. (b) Bisai, V.; Bisai, A.; Singh, V. K.
Tetrahedron 2012, 68, 4541−4580.
(7) (a) Yu, C.-M.; Youn, J.; Jung, J. Angew. Chem., Int. Ed. 2006, 45,
1553−1556. (b) Kim, S.-H.; Oh, S.-J.; Ho, P.-S.; Kang, S.-C.; Kyung-Jin,
O.; Yu, C.-M. Org. Lett. 2008, 10, 265−268. (c) Kim, J.; Kim, H.; Kim,
N.; Yu, C.-M. J. Org. Chem. 2014, 79, 1040−1046.
(8) Related carbonyl or imine addition reactions using allenoates:
(a) Xu, B.; Hammond, G. B. Angew. Chem., Int. Ed. 2008, 47, 689−692.
(b) Bhowmick, M.; Lepore, S. D. Org. Lett. 2010, 12, 5078−5080.
(c) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2007,
129, 7439−7443. (d) Cowen, B. J.; Saunders, L. B.; Miller, S. J. J. Am.
Chem. Soc. 2009, 131, 6105−6107. (e) Hashimoto, T.; Sakata, K.;
Tamakuni, F.; Dutton, M. J.; Maruoka, K. Nat. Chem. 2013, 5, 240−244.
(f) Mbofana, C.; Miller, S. J. Am. Chem. Soc. 2014, 136, 3285−3292.
(9) (a) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev. 2009, 38, 3102−3116.
(b) Ma, S. Acc. Chem. Res. 2009, 42, 1679−1688.
(10) (a) Wang, Z.; Xub, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927−
2940. (b) Pei, C.-K.; Shi, M. Chem.Eur. J. 2012, 18, 6712−6716.
(11) Racemic 2 was prepared by propargylic indium with carbonyls:
Park, C.; Lee, P. H. Org. Lett. 2008, 10, 3359−3362. The related
enantioselective Mannich reaction with allenoate has been reported; see
refs 8d−f.
(12) Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong, J.; Wang,
M.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Guo, H.; Kwon, O. J.
Am. Chem. Soc. 2011, 133, 13337−13348.
rotation with literature values,18 optical purity of 7 was
diminished to 71% ee starting from 91% ee (4d), presumably
due to a partial epimerization under harsh reaction conditions.
Diols 8a−f were cleanly prepared by LiAlH4 reduction of 3a−f in
good yields. The stereochemical assignment for threo-3 was
based on the magnitude of the vicinal coupling constant of six-
membered ring protons in the 1,3-dioxane 9 obtained from 8f.
Conversion of 8a to 10 was achieved by catalytic hydrogenation
on Pd/C in MeOH in 83% yield. Finally, relative and absolute
configurations of 10 were proven by comparison of NMR and
specific rotation to the literature.19
In summary, this paper describes highly selective synthetic
routes to allenoate 2 and threo-3-butynoate 3 from an aldol
reaction of allenoate 1 with aldehydes in a general and efficient
way that promises to be synthetically useful. We observed that
Lewis acid additive BF3·OEt2 plays a crucial role in the formation
of 3 to prevent an isomerization by scavenging excess amine base.
Studies are in progress for the extension of methods to other
aldol routes, especially the γ-addition process, and their
applications to natural product synthesis.
(13) (a) Joshi, N. N.; Brown, H. C. J. Am. Chem. Soc. 1988, 110, 6246−
6248. (b) Roy, C. D.; Brown, H. C. Aust. J. Chem. 2007, 60, 835−842.
(14) (a) Corey, E. J.; Yu, C.-M.; Lee, D.-H. J. Am. Chem. Soc. 1990, 112,
878−879. (b) Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc. 1989,
111, 5495−5496. (c) Choi, J.; Lee, B.; Yu, C.-M. Chem. Commun. 2011,
47, 3811−3813.
ASSOCIATED CONTENT
* Supporting Information
■
S
(15) Ooi, T.; Maruoka, K. In Modern Carbonyl Chemistry; Otera, J., Ed.;
Wiley-VCH: Weinheim, Germany, 2000; pp 1−32.
Detailed experimental procedures and full spectroscopic data for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) (a) Yoneda, E.; Kaneko, T.; Zhang, S.-W.; Onitsuka, K.;
Takahashi, S. Org. Lett. 2000, 2, 441. (b) Kang, S.; Kim, K.; Yu, C.-
M.; Hwang, J.; Do, Y. Org. Lett. 2001, 3, 2851−2853.
AUTHOR INFORMATION
Corresponding Author
(17) (a) Stewart, M.; Capon, R. J.; Lacey, E.; Tennant, S.; Gill, J. H. J.
Nat. Prod. 2005, 68, 581−584. (b) Desk, J.; Backvall, J.-E. Org. Biomol.
Chem. 2009, 7, 3379−3381.
■
*E-mail: cmyu@skku.edu.
Notes
(18) Drioli, S.; Felluga, F.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin,
E. J. Org. Chem. 1998, 63, 2385−2388.
(19) Kano, T.; Sugimoto, H.; Maruoka, K. J. Am. Chem. Soc. 2011, 133,
18130−18133.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Research Foundation,
Korea (2012R1A1A2006930), for generous financial support of
this research.
1576
DOI: 10.1021/acs.orglett.5b00454
Org. Lett. 2015, 17, 1573−1576