Asymmetric Synthesis of 1,3-Butadienyl-2-carbinols by the Homoallenylboration of Aldehydes with a Chiral Phosphoric Acid Catalyst

Article abstract of DOI:10.1002/anie.201501832

Asymmetric C(sp)-C(sp²) bond formation to give enantiomerically enriched 1,3-butadienyl-2-carbinols occurred through a homoallenylboration reaction between a 2,3-dienylboronic ester and aldehydes under the catalysis of a chiral phosphoric acid (CPA). A diverse range of enantiomerically enriched butadiene-substituted secondary alcohols with aryl, heterocyclic, and aliphatic substituents were synthesized in very high yield with high enantioselectivity. Preliminary density functional theory (DFT) calculations suggest that the reaction proceeds via a cyclic six-membered chairlike transition state with essential hydrogen-bond activation in the allene reagent. The catalytic reaction was amenable to the gram-scale synthesis of a chiral alkyl butadienyl adduct, which was converted into an interesting optically pure compound bearing a benzo-fused spirocyclic cyclopentenone framework.

Full text of DOI:10.1002/anie.201501832

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501832
German Edition: DOI: 10.1002/ange.201501832
Organocatalysis
Asymmetric Synthesis of 1,3-Butadienyl-2-carbinols by the
Homoallenylboration of Aldehydes with a Chiral Phosphoric Acid
Catalyst**
Yiyong Huang,* Xing Yang, Zongchao Lv, Chen Cai, Cheng Kai, Yong Pei,* and Yu Feng
Dedicated to Professor Albert S. C. Chan on the occasion of his 65th birthday
2
À
Abstract: Asymmetric C(sp) C(sp ) bond formation to give
enantiomerically enriched 1,3-butadienyl-2-carbinols occurred
through a homoallenylboration reaction between a 2,3-dienyl-
boronic ester and aldehydes under the catalysis of a chiral
phosphoric acid (CPA). A diverse range of enantiomerically
enriched butadiene-substituted secondary alcohols with aryl,
heterocyclic, and aliphatic substituents were synthesized in very
high yield with high enantioselectivity. Preliminary density
functional theory (DFT) calculations suggest that the reaction
proceeds via a cyclic six-membered chairlike transition state
with essential hydrogen-bond activation in the allene reagent.
The catalytic reaction was amenable to the gram-scale synthesis
of a chiral alkyl butadienyl adduct, which was converted into
an interesting optically pure compound bearing a benzo-fused
spirocyclic cyclopentenone framework.
T
he 1,3-butadienyl-2-carbinol motif is present in many
natural compounds.[1] Its conjugated-diene and allylic-alcohol
substructures make this unit very versatile for multistep
synthesis, as it can undergo Diels–Alder,[2] Sharpless epox-
idation,[3] and cycloaddition reactions.[4] Therefore, the con-
struction of the 1,3-butadienyl-2-carbinol scaffold,[5] espe-
cially in an asymmetric manner, is a significant task for
organic chemists. However, the catalytic asymmetric synthesis
of 1,3-butadienyl-2-carbinols has met with very limited
success. The only three existing examples of such reactions
are far from ideal,[6] as they either require a toxic tin
Scheme 1. Catalytic asymmetric synthesis of chiral 1,3-butadienyl-2-
carbinols. TMS=trimethylsilyl.
reagent[6a] or occur in only moderate yield or with moderate
enantioselectivity;[6b,c] furthermore, their scope is narrow in
terms of possible substrates (Scheme 1a,b). In this regard, the
development of a rapid and efficient route to enantiomeri-
cally enriched 1,3-butadienyl-2-carbinols is highly desirable.
The asymmetric nucleophilic addition of nontoxic and
stable unsaturated organoboron reagents, such as allyl,
allenyl, and propargyl boronates, to carbonyl groups enables
access to synthetically and pharmaceutically important chiral
secondary and tertiary alcohols.[7] Basically, two types of
models involving closed and open transition states mediated
by catalysts have been demonstrated.[8] In contrast to the
popularly used allyl and allenyl boronates, the analogous
homoallenylated boronates[9] have still not been explored in
a catalytic asymmetric manner. Brown et al. showed that
noncatalytic addition reactions between aldehydes and
homoallenylated boronates generated racemic 1,3-buta-
dienyl-2-carbinols at room temperature. To suppress the
background reaction, a low temperature and asymmetric
activation of the reactive components should be efficient tools
for the development of a highly enantioselective and efficient
transformation. Inspired by the previous studies on increasing
the rate of allylboration by increasing the Lewis acidity of the
boron center,[10] we hypothesized that the protonation of the
oxygen atoms in the homoallenylated boronate 2 with
[*] Prof. Dr. Y.-Y. Huang, X. Yang, Z. Lv, C. Cai, C. Kai
Department of Chemistry, School of Chemistry, Chemical
Engineering and Life Science, Wuhan University of Technology
Wuhan 430070 (P.R. China)
E-mail: huangyy@whut.edu.cn
Prof. Dr. Y.-Y. Huang, Dr. Y. Feng
Beijing National Laboratory for Molecular Sciences (BNLMS)
Institute of Chemistry, Chinese Academy of Sciences (P.R. China)
Prof. Dr. Y. Pei
Department of Chemistry, Xiangtan University (P.R. China)
E-mail: ypnku78@gmail.com
[**] We are grateful for the financial support of this investigation by the
National Natural Science Foundation of China (21303128), the
Research Fund for the Doctoral Program of Higher Education of
China (20130143120003), and the Fundamental Research Funds for
the Central Universities (WUT: 2014-Ia-002). Y.P. is supported by the
National Natural Science Foundation of China (21422305).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501832.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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Communications
a strong chiral Brønsted acid could potentially increase the
Lewis acidity of the boron atom and enable a highly catalytic
asymmetric homoallenylation. In this study, we developed an
unprecedented catalytic asymmetric dienylboration reaction
between the pinacol (pin) ester 2 of 2,3-dienylboronic acid
and aldehydes by virtue of the bifunctional nature of chiral
phosphoric acids (CPAs; Scheme 1c).[11] A wide variety of
synthetically useful enantiomerically enriched 1,3-butadienyl-
2-carbinols were thus readily prepared.
For exploratory studies, we used the two reactive sub-
strates 2,3-dienylboronic ester 2 and benzaldehyde (1a) in
toluene at 0.2m concentration. A control experiment revealed
that the efficient background reaction between 1a and 2 at
transition state is sensitive to minute amounts of water. A
slight increase in enantioselectivity was detected when the
temperature was decreased from À25 to À508C, but a longer
reaction time was required (Table 1, entry 5). Other solvents
(THFand CH2Cl2) and chiral Brønsted acids ((R)-4b and (R)-
4c) examined at À508C did not give superior results (Table 1,
entries 6–9). To our delight, a further decrease in the temper-
ature to À608C improved the enantioselectivity significantly
(99% ee; Table 1, entry 10); this reaction temperature was
found to be the best choice. Remarkably, at a higher
concentration (0.4m of 1a) and with a slightly higher excess
of boronate 2 (1.5 equiv with respect to aldehyde 1a), 3a was
obtained in excellent yield without erosion of the enantiose-
lectivity after a shorter reaction time (99% yield, 99% ee;
Table 1, entry 12). This result could be repeated on
a 0.2 mmol scale under otherwise identical conditions, which
were used for the following investigation (Table 1, entry 13).
Thus, in terms of enantioselectivity and catalytic efficiency,
the optimal reaction parameters include a 0.4m concentration
of the aldehyde 1 in toluene with 1.5 equivalents of boronate
2, a temperature of À608C, and 5 mol% loading of catalyst
(R)-4a. A lower loading of the chiral catalyst (2.5 mol%) was
also evaluated and led to comparable results (Table 1,
entry 14).
room temperature through
a facile 1,3-rearrangement
(Table 1, entry 1) was completely avoided at low temperature
(a trace amount of adduct 3a was detected by TLC at À258C
after 24 h), whereas the (R)-binol-derived CPA (R)-4a could
catalyze the reaction to provide the (R)-(1,3-butadien-2-
yl)methanol derivative 3a exclusively even at very low
temperature. The absolute configuration of 3a was assigned
as R by analogy with established cases.[6a] The use of 4 ꢀ
molecular sieves as an additive was critical to the formation of
the product with a high ee value (Table 1, entry 3 versus
entry 2); the high yield was preserved under these conditions.
We reason that the hydrogen bonding in the hypothesized
Under the optimized conditions, a wide array of aromatic,
heteroaromatic, a,b-unsaturated, and aliphatic aldehydes 1a–
v were screened, and respectable ee values of 95– > 99% and
yields were observed for all except two cases, in which alkyl
aldehydes were used (Table 2). In the case of phenyl-
substituted aldehydes, electron-donating and electron-with-
drawing groups at the para position were all tolerated, and the
desired products were formed in consistently excellent yield
(ꢀ 96%) and enantioselectivity (ꢀ 98% ee) within 24 h
(Table 2, entries 2–9). When a bromo or methoxy group was
introduced at the 3-position of the aromatic ring of benz-
aldehyde, or a methyl group at the 2-position, the yield and
ee value of the product were extremely high (Table 2,
entries 10–12). Both 1- and 2-naphthyl-substituted aldehydes
were converted into the corresponding addition adducts with
very satisfactory results (Table 2, entries 13 and 14), as was 9-
anthryl aldehyde (Table 2, entry 15). Moreover, heterocyclic
aldehydes also underwent the reaction with excellent con-
version and enantiomeric induction (Table 2, entries 16 and
17), although a solvent mixture containing cyclohexane was
required for 2-thiophenecarboxaldehyde. Furthermore, the
effect of various two-carbon-atom linkers between the phenyl
ring and the carbonyl group of the aldehyde was investigated.
a,b-Unsaturated aldehydes bearing a triple or double bond
were smoothly converted into the desired products with a 1,4-
enyne or triene motif with uniformly satisfactory results
(Table 2, entries 18–20). By tuning the reaction conditions
and using a 1:1 mixture of cyclohexane and CCl4 as the
solvent, we observed a synthetically acceptable level of
Table 1: Optimization of the catalytic asymmetric dienylation of benz-
aldehyde (1a).[a]
Entry
Catalyst
Solvent
T [8C]
t [h]
Yield [%][b]
ee [%][c]
1[d]
2[d]
3
4
5
6
7
8
9
10
11[e]
12[e,f]
13[f,g]
14[f,g,h]
none
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
CH2Cl2
toluene
toluene
toluene
toluene
toluene
25
À25
À25
À40
À50
À50
À50
À50
À50
À60
À60
À60
À60
À60
24
24
24
24
48
48
48
48
48
48
48
24
24
24
86
90
90
88
92
85
91
60
84
90
92
99
99
98
0
81
93
94
96
3
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4b
(R)-4c
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
84
3
88
99
99
99
99
98
[a] Reaction conditions, unless otherwise specified: 1a (0.10 mmol), 2
(0.12 mmol), solvent (0.5 mL), catalyst (5 mol%). [b] Yield of the
isolated product. [c] The ee value was determined by HPLC analysis on
a chiral stationary phase. [d] The reaction was conducted in the absence
of 4 ꢀ MS. [e] The reaction was conducted in 0.25 mL of toluene. [f] The
reaction was conducted with 1.5 equivalents of 2. [g] Reaction condi-
tions: 1a (0.20 mmol), 2 (0.30 mmol), toluene (0.5 mL). [h] Catalyst
loading: 2.5 mol%. Tf=trifluoromethanesulfonyl.
À
enantiomeric induction (92% ee) for aldehyde 1u with a
À
CH2CH2 linkage (Table 2, entry 21). Both the yield and
ee value reached 90% for the challenging substrate 1v when
CCl4 was used as the solvent (Table 2, entry 22). In all cases
the regioselectivity of the reaction was perfect: no b-allenol
adducts were detected.
2
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Chemie
Table 2: Asymmetric dienylation of various aldehydes.[a]
Entry
R
Product Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17[d]
18
19
20
21[e]
22[f]
Ph(1a)
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
99
99
98
96
97
96
98
98
97
99
99
99
98
99
96
95
98
98
98
95
96
92
99
99
99
>99
98
99
98
98
>99
>99
>99
98
99
>99
97
97
98
99
98
96
92
4-MeC6H4 (1b)
4-MeOC6H4(1c)
4-FC6H4 (1d)
4-ClC6H4 (1e)
4-BrC6H4 (1 f)
4-CO2MeC6H4 (1g)
4-NO2C6H4 (1h)
4-CF3C6H4 (1i)
3-BrC6H4 (1j)
3-MeOC6H4 (1k)
2-MeC6H4 (1l)
1-naphthyl (1m)
2-naphthyl (1n)
9-anthryl (1o)
2-furyl (1p)
Scheme 2. Proposed transition structures based on DFT studies.
2-thienyl (1q)
ꢁ
PhC C (1r)
=
=
(E)-PhCH CH (1s)
3s
3t
3u
3v
(E)-PhCH C(CH3) (1t)
PhCH2CH2 (1u)
c-C6H11 (1v)
90
[a] Reaction conditions, unless otherwise specified: 1 (0.20 mmol), 2
(0.3 mmol), toluene (0.5 mL). [b] Yield of the isolated product. [c] The
ee value was determined by HPLC analysis on a chiral stationary phase.
[d] The reaction was conducted in toluene/cyclohexane (1:1). [e] The
reaction was conducted in cyclohexane/CCl4 (1:1) at À208C. [f] The
reaction was conducted in CCl4 at À208C.
To shed light on the mode of activation and the origin of
enantiomeric induction, we calculated (DFT) several possible
transition states based on previous studies by other research
groups (see the Supporting Information for details).[12] To
reduce the calculating time, we considered a biphenol-derived
phosphoric acid in the model, with methyl groups in place of
the isopropyl groups in (R)-4a. In the resulting privileged
chairlike transition state (TS-1Re; Scheme 2), the bifunc-
tional phosphoric acid moiety captures the two reactive
components through two hydrogen bonds. The energy barrier
for the formation of the R stereoisomer is smaller by
1.70 kcalmolÀ1 than that for the S isomer. This difference is
attributed to steric repulsions between the large substituent at
one of the 3-positions of the biphenyl group in (R)-4a and the
pinacol methyl groups of 2 in the transition state TS-1Si
(shortest carbon–carbon distance: 4.11 versus 3.92 ꢀ) and
would be expected to lead to the formation of the product
with approximately 96% ee at À608C. This value is consistent
with the experimental value of 99% ee.
We next focused our attention on the synthetic application
of the alkyl (1,3-butadien-2-yl)methanol product 3u
(Scheme 3). First, a gram-scale reaction between 1u and 2
provided the enantiomerically pure adduct (S)-3u (1.10 g) in
97% yield with 92% ee), a result comparable to that in
entry 21 of Table 2. Selective monoepoxidation directed by
the hydroxy group in 3u then readily gave the erythro a-epoxy
alcohol 5, frequently presented as a structural core in natural
Scheme 3. Gram-scale synthesis of 3u and further transformations
showing its synthetic utility. acac=acetylacetonate, DCC=
N,N’-dicyclohexylcarbodiimide, DMAP=4-dimethylaminopyridine,
TBS=tert-butyldimethylsilyl, TES=triethylsilyl, Ts=p-toluenesulfonyl.
products,[13] in 83% yield with high diastereoselectivity
(> 20:1).[14] The configuration of 3u and 5 was assigned on
the basis of reported data.[15] An initial attempt at the TES
protection of 5 with a stoichiometric amount of TESOTf[16]
led to an unexpected 6-exo-tet epoxy–arene cyclization to
give (1S,2S)-6’. This result inspired us to synthesize the
optically pure diol 6 by using Zn(NTf2)2 as a Lewis acid
catalyst[17] and to carry out the total synthesis of 11. As
expected, compound 6 was accessed exclusively in excellent
yield with preservation of the ee value (92% ee). The absolute
configuration of 6 was determined by mechanistic consider-
ations and a 2D NOESY NMR spectroscopic study of its
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Communications
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derivative 8 (see the Supporting Information for details);
these analyses indicated that the two adjacent stereocenters
have a cis relative configuration. The tetrahydronaphthalene
6 contains a functionality-rich 1,3-diol motif and a quaternary
stereocenter bearing a vinyl group. These features facilitated
the total synthesis of 11, which shares the benzo-fused chiral
spirocyclic cyclopentenone moiety present in a molecular
probe for DNA bulges,[18] via 7, 8, 9, and 10 by selective
protection of the secondary alcohol, Dess–Martin oxidation,
allylation of the aldehyde, a second Dess–Martin oxidation,
and a final olefin-metathesis reaction in satisfactory yields.
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In summary, we have described an enantioselective
2
À
C(sp) C(sp ) bond-forming reaction that occurs through the
noncovalent activation of an allene reagent by a chiral
Brønsted acid catalyst.[19] This environmentally benign and
straightforward metal-free process avoids toxic reagents and
metal leaching. A broad range of useful enantiomerically
enriched butadiene-substituted secondary alcohols were
available in consistently high yields (92–99%) with excellent
regio- and enantioselectivity (90- > 99% ee). One such adduct
was transformed in a practical manner into the previously
unreported interesting chiral compound 11. DFT calculations
were found to be beneficial in the elucidation of the transition
state, which involves essential noncovalent activation of the
allene reagent, and prediction of the high level of enantio-
selectivity. Further exploration of the use of 2,3-dienylboronic
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Keywords: allylic alcohols · asymmetric dienylation · boron ·
enantioselectivity · organocatalysis
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Lett. 2006, 16, 2895 – 2899.
2
À
[19] For asymmetric C(sp) C(sp ) bond formation relying on the
activation of the electrophile instead of the allene reagent by
a Brønsted acid catalyst, see: a) J. Yu, L. He, X.-H. Chen, J. Song,
W.-J. Chen, L.-Z. Gong, Org. Lett. 2009, 11, 4946 – 4949; b) C.-S.
Wang, R.-Y. Zhu, J. Zheng, F. Shi, S.-J. Tu, J. Org. Chem. 2015,
80, 512 – 520.
[6] a) C.-M. Yu, S.-J. Lee, M. Jeon, J. Chem. Soc. Perkin Trans.
1 1999, 3557 – 3558; b) M. Durꢃn-Galvꢃn, B. T. Connell, Eur. J.
Received: February 26, 2015
Published online: && &&, &&&&
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Organocatalysis
Y.-Y. Huang,* X. Yang, Z. Lv, C. Cai, C. Kai,
Y. Pei,* Y. Feng
&&&& — &&&&
Asymmetric Synthesis of 1,3-Butadienyl-
2-carbinols by the Homoallenylboration
of Aldehydes with a Chiral Phosphoric
Acid Catalyst
That important first step: The ability of
chiral phosphoric acids to interact
simultaneously with a 2,3-dienylboronic
ester and an aldehyde through hydrogen
synthetic intermediates. A chiral alkyl
butadienyl adduct formed in this way on
a gram scale was transformed into an
optically pure benzo-fused spirocyclic
cyclopentenone derivative (see scheme).
À
bonding enabled enantiospecific C(sp)
C(sp2) bond formation to give versatile
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!