Irreversible aldolization of ketones with bisdicyclohexylboron enediolates

Article abstract of DOI:10.1016/j.tetlet.2019.151102

Unlike the reported reversible addition of ketone enolborinates to ketones, the aldolization of ketones with bisboron enediolates derived from carboxylic acids proceeds without difficulty. A variety of α,β,β-trisubstituted-β-hydroxy acids have been thus s

Full text of DOI:10.1016/j.tetlet.2019.151102

Tetrahedron Letters 60 (2019) 151102
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Irreversible aldolization of ketones with bisdicyclohexylboron
enediolates
⇑
P. Veeraraghavan Ramachandran , Barnabas Otoo
Herbert C. Brown Center for Borane Research, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2019
Revised 29 August 2019
Accepted 1 September 2019
Available online 5 September 2019
Unlike the reported reversible addition of ketone enolborinates to ketones, the aldolization of ketones
with bisboron enediolates derived from carboxylic acids proceeds without difficulty. A variety of
a,b,b-
trisubstituted-b-hydroxy acids have been thus synthesized in good to excellent yields and
diastereoselectivities.
Ó 2019 Published by Elsevier Ltd.
Keywords:
Irreversible
Diastereoselective
Enolboration
Aldolization
The presence of tert-alcohols in a large number of biologically
active molecules, such as fluconazole, bedaquiline, brassinazole,
tridihexethyl, fostriecin, venlafaxine, etc. [1–3] motivated syn-
thetic chemists to commit considerable effort in developing dia-
stereo- and enantioselective nucleophilic additions to ketones
[4–10]. Unlike the stereoselective addition of metal enolates to
aldehydes that delivers a sec-hydroxyl group b- to carbonyl func-
tionalities [11], the stereoselectivies for a similar enolate addition
to ketones yielding tert-alcohols have been subpar. This has been
attributed to the decreased electrophilicity of ketones and the
mandatory steric and/or electronic differences of their substituents
[12,13]. Another major drawback associated with the reaction of
ketone electrophiles is the complications associated with a retro-
aldol process [11,14].
this was negated by another publication from the same group
describing significant amounts of retro-aldol reaction [14]. Since
these reports, to the best of our knowledge, there has been none
on the aldolization of ketones using ketone enolborinates.
Described herein is the first boron-mediated diastereoselective
aldolization of ketones with enediolates, without any reversal, fur-
nishing a variety of
a,b,b-trisubstituted b-hydroxy acids in high
yields and diastereoselectivities.
We have recently described the generation of bisboron enedio-
lates from carboxylic acids and the subsequent stereoselective
aldolization of aldehydes [25,26]. The focal features of this reaction
are the easy purification and isolation of the product b-hydroxy
acids and their utility as valuable precursors for b-lactones and
alkenes [27]. We envisioned that extending the scope of the inves-
tigation to include ketone electrophiles will pave way for a
Additions of tin [15], cerium [16], lanthanide [17], samarium
[18], zinc [19], and titanium [16,20] enolates to ketones have been
realized with limited success due to unsatisfactory yields and
diastereoselectivities. Reported successful diastereoselective (ds)
synthesis of b,b-disubstituted b-hydroxy carbonyls via enolate
diastereoselective synthesis of
a,b,b-trisubstituted b-hydroxy
acids, provided a retro-aldol reaction is non-existent or is curtailed.
The details of our fruitful study follow.
Optimal conditions were selected by examining the effects of (i)
solvent, (ii) concentration, (iii) enolization and aldolization tem-
peratures, and (iv) amine base on the reaction. Adopting the reac-
tion conditions of bisboron enediolates with aldehydes [26],
aldolization of a representative ketone, acetophenone (2a), was
carried out in diethyl ether (0.1 M) with bisdicyclohexylboron
enediolate of propanoic acid (1) generated with B-bromodicyclo-
hexylborane (3). The corresponding aldol, 3-hydroxy-2-methyl-3-
phenylbutanoic acid 4a was obtained in 86% yield with a 94:6
diastereomer ratio. The major isomer possessed an anti-relation-
chemistry involves the addition to selected class of
a-hetero-
substituted carbonyls; e.g., the aldolization of lactate-derived alkyl
ketones with titanium enolates of
a-benzyloxyketones [21]
yielding syn-aldols (Fig. 1).
Boron enolates have been widely used for directed aldol synthe-
sis for over four decades [22,23]. Yet, a boron-mediated cross-
aldolization of ketones was reported only recently [24]. However,
⇑
Corresponding author.
E-mail address: chandran@purdue.edu (P.V. Ramachandran).
ship between the
a-methyl and b-hydroxy substituents (Table 1,
https://doi.org/10.1016/j.tetlet.2019.151102
0040-4039/Ó 2019 Published by Elsevier Ltd.

2
P.V. Ramachandran, B. Otoo / Tetrahedron Letters 60 (2019) 151102
absence of any reversal that afflicts the ketone aldol reactions
[14]. The aldol (4b) from cyclohexanone was isolated in 99% yield
(Scheme 1).
The optimized protocol for the aldolization of ketones with the
enediolate of 1 (Table 1, entry 3) was then successfully extended to
include representative examples of different classes of ketones. The
results are summarized in Table 2. Substitution of 2a with a bro-
mine atom at the para-position (2c) provided similar ds for the
hydroxy acid 4c in 83% yield (entry 3). An
a-haloketone, 2-
chloroacetophenone (2d), provided the aldol 4d in 90% yield, also
with 94:6 diastereomer ratio (dr). A b-ketoester, ethyl benzoylac-
etate (2e) provided the aldol 4e in 57% yield and 89:11 dr (entries
4–5). An
a-keto ester, ethyl pyruvate 2f provided the correspond-
ing aldol, 4f in 60% yield and 93% anti-selectivity (entry 6). An
a,b-
unsaturated ketone, (E)-4-phenylbut-3-en-2-one 2g was aldolized
to provide the corresponding hydroxy acid 4g in a much decreased
54% yield and 85:15 dr favouring the anti-isomer (entry 7). No
decrease in yield was observed with ethyl benzoylacrylate (2h),
aldolized to 4h in 89% yield and 89:11 dr (entry 8).
The diastereoselectivity appears to depend on the sterics on
either side of the carbonyl group. For example, the aldolization of
4-methoxybenzophenone 2i with bisdicyclohexylboron enediolate
of 1a provided the corresponding aldol in very high (95%) yield,
with no diastereoselectivity (1:1 dr) (entry 9). A similar dr (1:1)
was also observed for the aldolization of 3-hexanone (2j) (entry
10). The dr improved to 86:14 for 2-butanone (2k) and 76:24 for
3-methyl-2-butanone (2l) (entries 11–12). Further increasing the
bulk of the ketone to 3,3-dimethyl-2-butanone (2m) provided
essentially diastereopure anti-isomer of 4m in 73% yield (entry 13).
The sterics and electronics of a trifluoromethyl group has been
of interest to organic and biological chemists [29–31]. Given the
Fig. 1. Irreversible boron-mediated aldol reaction of ketones.
entry 1), confirmed by comparing with the reported 1H NMR spec-
trum [28]. The anti-stereochemistry of all of the aldols produced
during this study is assigned on the basis of reported structures
of anti-aldols 4a, 13a and 13k (see below).
Diluting the reaction (0.066 M instead of 0.1 M) was necessary
for consistency of the results. Increasing the aldolization time to
4 h at 0 °C, furnished an improved 92% yield of 4a in 94% anti-selec-
tivity (entry 3). Similar to the aldolization of aldehydes, changing
the enolizing agent from 3 to the corresponding B-chlorodicyclo-
hexylborane 5 decreased both the yield and selectivity (54%,
80:20, entry 4). Switching from triethylamine to the bulkier N,N-
diisopropylethylamine also produced a deleterious effect on the
yield, while the ds was maintained (35% yield, 91:9 dr, entry 5).
Surprisingly, no aldol product was isolated when either THF or
dichloromethane was used as the solvent for the reaction.
Aiming to probe the lack or presence of reversibility in the
aldolization of ketones with bisboron enediolates, 1 was subjected
to enolization, followed by aldolization of an equiv. of cyclohex-
anone (2b) for 3 h. The choice of the ketone was based on the
retro-aldol reaction reported [14]. An equiv. of benzaldehyde was
then added to the aldolate mixture and monitored for 12 h by 1H
NMR spectroscopy. Gratifyingly, none of the 3-hydroxy-2-
methyl-3-phenylpropanoic acid resulting from sequential retro-
keto-aldol-aldehyde aldol reaction was observed, verifying the
Scheme 1. Non-reversible addition of bisboron enediolate of propanoic acid to
cyclohexanone.
Table 1
Optimization of anti-selective aldolization of acetophenone with bisdicyclohexylboron enediolate of propanoic acid (1).
Entry
Chx2BX
Cond.a
Solvent
Yield (%)b
anti:sync
#
X
1
2
3
4
5e
6
7
3
3
3
5
5
3
3
Br
Br
Br
Cl
Cl
Br
Br
A
B
C
C
C
C
C
Et2O
Et2O
Et2O
Et2O
Et2O
THF
86d
85
92
54
35
–
94:6
94:6
94:6
80:20
91:9
–
CH2Cl2
–
–
a
Reaction conditions: A = concentration of 1: 0.1 M, enolization: 0 °C, 1 h; aldolization: À78 °C, 0.5 h, 0 °C, 1 h. B = concentration of 1: 0.066 M, enolization: 0 °C, 1 h,
aldolization: À78 °C, 0.5 h, 0 °C, 1 h. C = concentration of 1: 0.066 M, enolization: 0 °C, 1 h, aldolization: À78 °C, 0.5 h, 0 °C, 3 h.
b
Combined yields of syn and anti-isomers.
c
syn and anti ratios were determined by 1H NMR analysis of the crude reaction mixture.
d
Yields varied between 40% and 95%.
i-Pr2NEt was used as the base.
e

P.V. Ramachandran, B. Otoo / Tetrahedron Letters 60 (2019) 151102
3
Table 2
Addition of ketones to bisboron enediolates of propanoic acid.
Entry
Ketone
#
Aldol
#
R1
R2
Yielda
anti:synb
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
C6H5
Me
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
92
99
83
90
57
60
54
89
95
84
60
62
73
56
94:6
–
–(CH2)5–
p-BrC6H4
C6H5
Me
94:6
94:6
89:11
93:7
85:15
89:11
50:50
50:50
86:14
76:24
99:1
93:7
CH2Cl
CH2CO2Et
Me
C6H5
CO2Et
C6H6CHCH
C6H5
p-CH3OC6H4
n-Pr
Et
i-Pr
t-Bu
CF3
Me
CHCHCO2Et
C6H5
Et
Me
Me
9
10
11
12
13
14
Me
Et
a
Combined yields of syn and anti-isomers.
syn- and anti-ratios were determined by 1H NMR, occasionally 13C NMR and where applicable 19F NMR spectroscopy.
b
importance of fluoroorganic molecules in medicinal chemistry
[32,33], as well as our longstanding interest in fluoroorganic syn-
thesis via boranes [34,35], 1,1,1-trifluoro-2-butanone (2n) was
subjected to the aldolization when the corresponding aldol, 3-
hydroxy-2-methyl-3-(trifluoromethyl)pentanoic acid (4n) was iso-
lated in 56% yield and 93:7 dr (entry 14).
ing differing steric and electronic environments (Table 3). The reac-
tion conditions were modified, as necessary, based on previously
optimized protocols of the bisboron endiolates of these acids with
aldehydes [25,26].
The optimal conditions for the enolization-aldolization with
chloroacetic acid (6) and phenylacetic acid (8) were the same as
that of 1. 4-Methoxyphenylacetic acid (10), on the other hand, eno-
lized under similar conditions but required higher temperature (rt)
for aldolization. Enolization of but-3-enoic acid (12) and subse-
quent aldolization were carried out at À78 °C for optimal results.
The bisboron enediolate from 6 provided aldols in 83% yield and
99:1 dr with 2a (Table 3, entry 1) and 75% yield and 85:15 dr with
To further validate the non-reversible nature of the reaction and
to verify the effect of the enediolates on the diastereoselectivity,
additional
a-substituted acetic acids were included in the study.
The aldolization of representative aromatic and aliphatic ketones,
2a and 2k, respectively, were carried out using bisdicyclohexyl
boron enediolates derived from four representative acids possess-
Table 3
Addition of representative ketones to bisboron enediolates of selected substituted acetic acids.
Entry
Acid
Ketone
Aldol
#
R
2
R1
#
Yielda
anti:synb
1
2
3
4
5
6
7
8
6c
Cl
2a
2k
2a
2k
2a
2k
2a
2k
C6H5
Et
C6H5
Et
C6H5
Et
C6H5
Et
7a
7k
9a
9k
11a
11k
13a
13k
83
75
95
85
80
75
80
87
99:1
85:15
99: 1
86:14
94:6
85:15
99:1
8c
C6H5
10d
12e
p-CH3OC6H4
CH@CH2
82:18
a
b
c
Combined yields of syn and anti-isomers.
syn and anti ratios were determined by 1H NMR spectroscopy.
Reaction conditions: concentration of acid: 0.66 M, enolization: 0 °C, 1 h; aldolization: À78 °C, 0.5 h, 0 °C, 3 h.
Reaction conditions: concentration of acid: 0.66 M, enolization: rt, 1 h; aldolization: 0 °C, 0.5 h, rt, 3 h.
Reaction conditions: concentration of 0.66 M: enolization: À78 °C, 1 h; aldolization: À78 °C, 4 h.
d
e

4
P.V. Ramachandran, B. Otoo / Tetrahedron Letters 60 (2019) 151102
2k (entry 2). Acid 8 provided near perfect diastereoselectivity (99:1
dr) in 95% yield with 2a (entry 3) and 86:14 dr in 85% yield with 2k
(entry 4). The enolization of p-methoxyphenylacetic acid, followed
by aldolization of 2a and 2k provided the aldols in 80% and 75%
yields, respectively (entries 5–6). The aromatic ketone revealed a
dr of 94:6, whereas the aliphatic ketone showed only a dr of
85:15. But-3-enoic acid provided essentially diastereopure anti-
aldol in 80% yield with 2a. However, an 87% yield and a dr of
82:18 was observed with 2k (entries 9–10). The anti- relationship
References
[1] E.J. Corey, A. Guzman-Perez, Angew. Chem. Int. Ed. 37 (1998) 388–401.
[2] K. Fuji, Chem. Rev. 93 (1993) 2037–2066.
[3] J.G. de Vries (Ed.), Quaternary Stereocenters, Wiley-VCH Verlag GmbH & Co.
KGaA, Weinheim, FRG, 2006, pp. 25–50.
[4] D.A. Evans, C.S. Burgey, M.C. Kozlowski, S.W. Tregay, J. Am. Chem. Soc. 121
(1999) 686–699.
[5] K. Oisaki, D. Zhao, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 128 (2006) 7164–
7165.
[6] P.I. Dosa, G.C. Fu, J. Am. Chem. Soc. 120 (1998) 445–446.
[7] F. Langer, L. Schwink, A. Devasagayaraj, P.-Y. Chavant, P. Knochel, J. Org. Chem.
61 (1996) 8229–8243.
[8] J.L. Stymiest, V. Bagutski, R.M. French, V.K. Aggarwal, Nature 456 (2008) 778–
782.
[9] D.J. Ramón, M. Yus, Angew. Chem. Int. Ed. 44 (2005) 1602–1634.
[10] P.V. Ramachandran, H. Liu, M.V.R. Reddy, H.C. Brown, Org. Lett. 5 (2003) 3755–
3757.
between the
a-vinyl and b-hydroxy groups was confirmed based
on the 1H NMR spectrum of 13a and 13k reported in the literature
[36]. It is noteworthy that in all of the cases the aldols from the
representative arylalkyl ketones possessed higher diastereoselec-
tivity compared to those from dialkyl ketones.
In conclusion, the aldolization of various ketones with bisdicy-
clohexylboron enediolates of a series of substituted acetic acids
have been achieved to provide b,b-disubstituted b-hydroxy acids,
generally, in very good yields and high anti-selectivity. Unlike
the aldolization of ketones with enolborinates derived from
ketones [14], there is no retro-aldol reaction with the boron enedi-
olates. Further studies to expand the scope of this reaction are
under way.
[11] R. Mahrwald, Aldol Reactions, Springer, Dordrecht, 2009.
[12] M. Hatano, K. Ishihara, Synthesis (Stuttg) 2008 (2008) 1647–1675.
[13] D.J. Ramón, M. Yus (Eds.), Quaternary Stereocenters, Wiley-VCH Verlag GmbH
& Co. KGaA, Weinheim, FRG, 2006, pp. 207–241.
[14] K.M. Cergol, P. Jensen, P. Turner, M.J. Coster, Chem. Commun. (2007) 1363–
1365.
[15] J.-I. Matsuo, M. Murakami, Angew. Chem. Int. Ed. 52 (2013) 9109–9118.
[16] G. Bartoli, M. Bosco, E. Marcantoni, M. Massaccesi, S. Rinaldi, L. Sambri,
Tetrahedron Lett. 42 (2001) 6093–6096.
[17] G. Desimoni, G. Faita, F. Piccinini, M. Toscanini, Eur. J. Org. Chem. 2006 (2006)
5228–5230.
A typical experimental procedure is as follows: All operations
were carried out in a nitrogen atmosphere. B-bromodicyclohexylb-
orane (Chx2BBr) (4.8 mmol) was transferred to a 50 mL round-bot-
tom flask and dissolved in anhydrous ether (30 mL) followed by
dropwise addition of triethylamine (0.67 mL, 4.8 mmol) to the stir-
red solution at 0 °C. The acid (2.0 mmol) dissolved in 2 mL of anhy-
drous Et2O was then added, dropwise, to the above solution at 0 °C.
The reaction mixture was stirred at 0 °C for 1 h, cooled to À78 °C, fol-
lowed by the dropwise addition of the ketone (2.4 mmol). The reac-
tion mixture was stirred for 1 h at the same temperature (À78 °C),
warmed to 0 °C and stirred for 3 h. The reaction was then quenched
by the addition of a saturated aqueous solution of sodium bicarbon-
ate (5 mL) and stirred for 1 h at room temperature. After separation
of the layers, the organic phase was treated with additional satu-
rated aqueous sodium bicarbonate solution. The combined aqueous
layers were washed with ether, acidified with 6 M HCl, saturated
with NaCl, and extracted with ether (3 Â 10 mL). The combined
ether layer was dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo to obtain the anti-aldol products.
[18] L. Lu, H.-Y. Chang, J.-M. Fang, J. Org. Chem. 64 (1999) 843–853.
[19] Y. Ding, G. Zhao, J. Chem. Soc., Chem. Commun. (1992) 941–942.
[20] Y. Yoshida, R. Hayashi, H. Sumihara, Y. Tanabe, Tetrahedron Lett. 38 (1997)
8727–8730.
[21] S. Alcoberro, A. Gómez-Palomino, R. Solà, P. Romea, F. Urpí, M. Font-Bardia,
Org. Lett. 16 (2014) 584–587.
[22] D.S. Matteson, Stereodirected Synthesis with Organoboranes, Springer-Verlag,
1995.
[23] C.J. Cowden, I. Paterson (Eds.), Organic Reactions, John Wiley & Sons Inc,
Hoboken, NJ, USA, 1997, pp. 1–200.
[24] K.M. Cergol, P. Turner, M.J. Coster, Tetrahedron Lett. 46 (2005) 1505–1509.
[25] P.V. Ramachandran, P.B. Chanda, B. Otoo, Tetrahedron Lett. 55 (2014) 1289–
1291.
[26] P.V. Ramachandran, B. Otoo, P.B. Chanda, Tetrahedron Lett. 56 (2015) 3019–
3022.
[27] P.V. Ramachandran, B. Otoo, Chem. Commun. 51 (2015) 12388–12390.
[28] D. Seebach, L. Widler, Helv. Chim. Acta 65 (1982) 1972–1981.
[29] P.V. Ramachandran, B. Gong, A.V. Teodorovic’, H.C. Brown, Tetrahedron:
Asymmetry 5 (1994) 1061–1074.
[30] D. Seebach, Angew. Chem. Int. Ed. Engl. 29 (1990) 1320–1367.
[31] D. O’Hagan, H.S. Rzepa, Chem. Commun. (1997) 645–652.
[32] J. Wang, M. Sánchez-Roselló, J.L. Aceña, C. del Pozo, A.E. Sorochinsky, S.
Fustero, V.A. Soloshonok, H. Liu, Chem. Rev. 114 (2014) 2432–2506.
[33] I. Ojima (Ed.), Fluorine in Medicinal Chemistry and Chemical Biology, John
Wiley & Sons Ltd, Chichester, UK, 2009.
[34] P.V. Ramachandran, A. Chatterjee, Org. Lett. 10 (2008) 1195–1198.
[35] H.C. Brown, G.-M. Chen, M.P. Jennings, P.V. Ramachandran, Angew. Chem. Int.
Ed. 38 (1999) 2052–2054.
Acknowledgment
[36] L.A. Wessjohann, H. Wild, L.A. Ferreira, H.S. Schrekker, Appl. Organomet. Chem.
30 (2016) 674–679.
The authors acknowledge the financial assistance from the Her-
bert C. Brown Center for Borane Research.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151102.