Enantio- and diastereoselective synthesis of syn -β-hydroxy-α- vinyl carboxylic esters via reductive aldol reactions of ethyl allenecarboxylate with 10-tms-9-borabicyclo[3.3.2]decane and DFT analysis of the hydroboration pathway

Article abstract of DOI:10.1021/ol4025277

An enantio- and diastereoselective synthesis of syn-β-hydroxy-α- vinyl carboxylate esters 3 via the reductive aldol reaction of ethyl allenecarboxylate (2) with 10-trimethylsilyl-9-borabicyclo[3.3.2]decane (1R) has been developed. Density functional theor

Full text of DOI:10.1021/ol4025277

ORGANIC
LETTERS
2013
Vol. 15, No. 21
5436–5439
Enantio- and Diastereoselective Synthesis
of syn-β-Hydroxy-R-vinyl Carboxylic
Esters via Reductive Aldol Reactions
of Ethyl Allenecarboxylate with 10-TMS-9-
Borabicyclo[3.3.2]decane and DFT
Analysis of the Hydroboration Pathway
Jeremy Kister,† Daniel H. Ess,‡ and William R. Roush*,†
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, United States, and
Department of Chemistry and Biochemistry, Brigham Young University, Provo,
Utah 84602, United States
roush@scripps.edu
Received September 2, 2013
ABSTRACT
An enantio- and diastereoselective synthesis of syn-β-hydroxy-R-vinyl carboxylate esters 3 via the reductive aldol reaction of ethyl
allenecarboxylate (2) with 10-trimethylsilyl-9-borabicyclo[3.3.2]decane (1R) has been developed. Density functional theory calculations
suggest that the allene hydroboration involves the 1,4-reduction of 2 with the 1R, leading directly to dienolborinate Z-(O)-8a.
syn-β-Hydroxy-R-vinyl carboxylic esters 3 and imides 5
(Figure 1) are versatile intermediates widely used in or-
ganic synthesis.1,2 Racemic 3 can be obtained with varying
degrees of diastereoselectivity by allylation of aldehydes
with γ-(alkoxycarbonyl)-substituted allyl metal reagents
(e.g., indium,3 tin,4 zinc5 and boron6 reagents). Another
approach to racemic 3 involves aldol7,8 or Reformatsky9
reactions of aldehydes with ester derived dienolates.
Given the widespread use of this structural unit in organic
synthesis,1,2 it is surprising that direct enantioselective
methods for the synthesis of the syn or anti diastereoi-
somers of β-hydroxy-R-vinyl carboxylic esters 3 have not
been reported. Both enantiomers of syn-β-hydroxy-R-vinyl
† Scripps Florida.
‡ Brigham Young University.
(2) (a) Hudlicky, T.; Frazier, J. O.; Seoane, G.; Tiedje, M.; Seoane,
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C. W.; Giroux, A.; Greidanus, G. Tetrahedron Lett. 1996, 37, 4471. (c)
Galatsis, P.; Millan, S. D.; Ferguson, G. J. Org. Chem. 1997, 62, 5048. (d)
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r
10.1021/ol4025277
Published on Web 10/18/2013
2013 American Chemical Society

Figure 1. Approaches to the enantioselective synthesis of syn-R-
vinyl-β-hydroxy esters 3 and imides 5.
Figure 2. Anticipated versus observed outcome of hydroboration
of allenoate 2 with borane 1R and subsequent reaction with
benzaldehyde.
imides 5 can be obtained by using enantioselective aldol
reactions of chiral crotonate imides (Figure 1). Evans’
chiral N-acyl oxazolidinones10 are widely applied for this
purpose,1 but other methods include use of Oppolzer’s
chiral sultam11 and Crimmins’ chiral oxazolidinethione
reagents.12 Here we report the development of an enan-
tio- and diastereoselective synthesis of syn-β-hydroxy-
R-vinyl carboxylate esters 3 via aldol reactions of alde-
hydes with (Z)-dienolborinate Z-(O)-8a that is generated
in situ from the hydroboration of allenyl ester 2 with
10-trimethylsilyl-9-borabycyclo[3.3.2]decane (1R, also known
as 10-TMS-9-BBD-H, and as the Soderquist borane).13,14
Density functional theory (DFT) calculations indicate
that Z-(O)-8a is generated by a kinetically controlled 1,4-
hydroboration reaction pathway.
monosubstituted allenes with the Soderquist borane 1,15
and were interested in extending these efforts to the
hydroboration of allenecarboxylic ester 2 (Figure 2). Based
on previous results,15 we were hopeful that the hydrobora-
tion reaction of 2 would occur on the terminal allene
double bond opposite to the ester moiety, leading directly
to (Z)-γ-(ethoxycarbonyl)allylborane Z-(C)-7a. Further,
it was anticipated that the reaction of allylborane Z-(C)-7a
with aldehydes such as benzaldehyde would result in an
enantioselective synthesis of anti-3a. However, this reac-
tion sequence provided syn-β-hydroxy-R-vinyl ester 3a as a
single diastereoisomer (dr >40:1) in 81% ee and in 77%
isolated yield. (See Supporting Information (SI) for stereo-
chemical assignments). 1H NMR analysis of the intermedi-
ate formed in the hydroboration step revealed the presence
of a single (Z)-dienolborinate, Z-(O)-8a, and not the
expected allylborane Z-(C)-7a (Figure 2). Based on this
insight, the formation of syn-β-hydroxy-R-vinyl carboxylic
ester3acan be rationalizedby analdol reaction ofZ-(O)-8a
with benzaldehyde via the chairlike transition state TS-1.
The optimization of several reaction variables is sum-
marized in Table 1. The use of Et2O or toluene instead
of CH2Cl2 as a reaction solvent was detrimental to both
the yield of 3a and overall reaction enantioselectivity
(entries 1À3). Increasing the reaction concentration and
the reaction time led to an increased yield of 3a, with
essentially identical results being obtained if the reactions
were performed at 0.25 or 0.5 M (entries 4, 5). However,
when the less reactive cyclohexanecarboxaldehyde was
used, 3b was obtained in 64% and 80% yield when the
reaction was performed at 0.25 or 0.5 M (entries 6,7).
The results of reductive aldol reactions of 2 with sever-
al representative aromatic, aliphatic, R,β-unsaturated, and
heteroaromatic aldehydes are presented in Scheme 1. These
reactions provided 3aÀg with >40:1 d.r. in 68À91%
We have reported studies of enantioselective allylbora-
tion reactions of reagents generated by hydroboration of
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L. D.; Colwell, B. L. J. Org. Chem. 1985, 50, 4300. (c) Orsini, F.; Leccioli,
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Lett. 1986, 27, 4957.
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Tetrahedron: Asymmetry 2007, 18, 243.
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ꢀ
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Medina, J. R.; Matos, K.; Soderquist, J. A. J. Am. Chem. Soc. 2008, 130,
9218. (b) Soderquist, J. A.; Matos, K.; Burgos, C. H.; Lai, C.; Vaquer, J.;
Medina, J. R.; Huang, S. D. ACS Symp. Ser. 2001, 783, 176.
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aldol reaction of allenic esters with aromatic ketones: Zhao, D.; Oisaki,
K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 14440.
(15) (a) Kister, J.; DeBaillie, A. C.; Lira, R.; Roush, W. R. J. Am.
Chem. Soc. 2009, 131, 14174. (b) Kister, J.; Nuhant, P.; Lira, R.; Sorg,
A.; Roush, W. R. Org. Lett. 2011, 13, 1868. (c) Nuhant, P.; Kister, J.;
Lira, R.; Sorg, A.; Roush, W. R. Tetrahedron 2011, 67, 6497.
Org. Lett., Vol. 15, No. 21, 2013
5437

Table 1. Optimization of the Reaction Conditions for the
Synthesis of syn-β-Hydroxy-R-vinyl Carboxylate Esters 3
Scheme 1. Diastereo- and Enantioselective Synthesis
of syn-β-Hydroxy-R-vinyl Carboxylate Esters 3aÀg
%
yieldb
%
eec
entry
RCHO
producta
solvent
d,e
1
2
3
4
5
6
7
PhCHO
3a
3a
3a
3a
3a
3b
3b
CH2Cl2
Et2Od,e
77
36
47
83
86
64
80
82
72
71
82
82
83
83
PhCHO
PhCHO
toluened,e
f,g
PhCHO
CH2Cl2
h,g
PhCHO
CH2Cl2
f,g
C6H11CHO
C6H11CHO
CH2Cl2
h,g
CH2Cl2
We have used M06-2X/6-31G(d,p)17 density functional
theory (DFT)18 to examine the hydroboration reaction
and isomerization pathways in order to rationalize the
selective formation of intermediates Z-(C)-7 or Z-(O)-8
using 9-BBN or 1R, respectively. For 1R, the direct and
stereospecific 1,4-hydroboration of allenyl ester 2 to give
Z-(O)-8a is 2À4 kcal/mol lower in energy than potentially
competitive 3,4-, and 5,4-hydroboration transition states
(Scheme 2). This concerted 1,4-addition transition state is
a A single diastereoisomer (dr >40:1) was obtained in each entry
(1H NMR analysis). b Yield of product isolated chromatographically.
c Determined by Mosher ester analysis. d Reaction concentration
0.17 M. e 12 h aldol reaction time. f Reaction concentration 0.25 M.
g 36 h aldol reaction time. h Reaction concentration 0.5 M.
yields, and with very good to excellent enantioselectivity
(73À89% ee). Either enantiomer of the syn-β-hydroxy-
R-vinyl carboxylic esters, 3 and ent-3, can be obtained by
using the appropriate enantiomer of borane 1R or 1S.13
Another variable that significantly impacts the reaction
diastereoselectivity is the borane reagent used in the hydro-
boration step (Table 2). For example, use of (lIpc)2BH as
the hydroborating agent16 resulted in an ∼1:1 mixture of
3a and anti-3a (80% ee), with benzaldehyde as the aldol
partner (entry 1). Alternatively, use of 9-BBN lead to anti-
3a exclusively in 90% yield (entry 2). While we have not
explored the full scope of the latter reaction, it is concei-
vable that this process could be developed into a general,
highlydiastereoselectivesynthesisofracemicanti-β-hydro-
xy-R-vinyl carboxylic esters.2,8
Table 2. Influence of the Borane Reagent on Reaction
Diastereoselectivity
1H NMR analysis of the hydroboration of allene 2 with
(lIpc)2BH (toluene-d8, 0 °C) revealed that a 2.3:0.05:1
mixture of Z-(O)-8b, E-(O)-8b, and Z-(C)-7b was formed.
In contrast, Z-(C)-7c was formed exclusively when 9-BBN
was used as the hydroborating agent (THF-d8, 0 °C)
(Figure 3). The exclusive formation of the anti-β-hydro-
xy-R-vinyl carboxylic ester anti-3a from the hydroboration
of 2 with 9-BBN (entry 2) is easily understood since
intermediate Z-(C)-7c (Figure 3) would be expected to
undergo allylboration reactions to give anti-3a with high
selectivity. Alternatively, a mixture of 3a and anti-3a is
produced when (lIpc)2BH is used as the hydroborating
agent (entry 1), since allylborane Z-(C)-7b should react
with benzaldehyde to give anti-3a with high selectivity,
while the dienolate Z-(O)-8bwould beexpectedtoundergo
a syn-selective aldol reaction, leading to syn aldol 3.
ratio
%
entry
R2BH
3a/anti-43
solvent
yielda
1
2
(lIpc)2BH
9-BBN
1:1
1:>40b
toluene
THF
51
90
a Isolated yield of the mixture of 3 and anti-3. b Racemic anti-3a was
the only product detected.
akinthatproposed for the formation of boron (Z)-enolates
via 1,4-hydroboration of R,β-unsaturated ketones with
alkylboranes19 or catecholborane.20,21 The alternative
(17) (a) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
(b) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
(18) (a) All calculations were carried out in Gaussian 09. (b) Frisch,
M. J.; et al. Gaussian 09, revision B.01; Gaussian, Inc.: Wallingford, CT,
2009. (c) Free energies are reported for 298 K and relative to separated
reactants. Methyl allenecarboxylate was used as a model for allenyl ester 2.
(19) Boldrini, G. P.; Bortolotti, M.; Mancini, F.; Tagliavini, E.;
Trombini, C.; Umani-Ronchi, A. J. Org. Chem. 1991, 56, 5820.
(20) Evans, D. A.; Fu, G. C. J. Org. Chem. 1990, 55, 5678.
(16) (a) Nuhant, P.; Allais, C.; Roush, W. R. Angew. Chem., Int. Ed.
2013, 52, 8703 and references therein. (b) Allais, C.; Nuhant, P.; Roush,
W. R. Org. Lett. 2013, 15, 3922.
5438
Org. Lett., Vol. 15, No. 21, 2013

Scheme 2. M06-2X Free Energies (kcal/mol) for Hydroboration
of Methyl Allenylcarboxylate with 1R (series a) and 9-BBN
(series b; data in parentheses are for 9-BBN)18c
Figure 3. Intermediates formed in the hydroboration of allene 2
with (lIpc)2BH (left) and 9-BBN (right).
3,4- and 5,4-hydroboration pathways also require either a
single 1,5-boratropic shift or multiple 1,3-boratropic shifts
in order to produce Z-(O)-8a. We have previously shown
that the steric bulk of the 10-TMS group in products of
hydroboration reactions of 1R retards the 1,3-boratropic
rearrangement transition state.22 Here also, the 10-TMS
group provides large kinetic stability to intermediate
Z-(O)-8a with >20 kcal/mol free energy barriers for 1,3-
and 1,5-rearrangement pathways. In addition, Z-(O)-8a is
8À10 kcal/mol more stable than Z-(C)-7a and E-(C)-7a.23
For the 9-BBN hydroboration sequence, 1,4-addition
also provides the lowest energy hydroboration transition
state. However, inthiscasethereisa low free energybarrier
(9 kcal/mol) for the 1,5-boratropic shift to directly convert
Z-(O)-8c to Z-(C)-7c. To our knowledge, this is the first
prediction of a 1,5-boratropic shift. Importantly, Z-(C)-7c
is 5 kcal/mol more stable than Z-(O)-8c and 9 kcal/mol
more stable than E-(C)-7c due to intramolecular coordina-
tion of boron by the ester carbonyl. In Z-(C)-7a this
interaction is prevented due to the steric bulk of the
10-TMS group. The alternative route via two 1,3-boratropic
shifts requires >6 kcal/mol higher free energy barriers than
the direct 1,5-boratropic shift pathway.
Figure 4. Studies concerning the origin of 7 and the proposed
equilibration of 8 and 7.
Additional experiments were performed to explore the
origin of 7 and the proposed equilibria between 8 and 7
(Figure 4). First, 1H NMR studies demonstrated that the
2.3:0.05:1 mixture of Z-(O)-8b, E-(O)-8b, and Z-(C)-7b
generated by the hydroboration of 3 with (lIpc)2BH (see
Figure 3 and SI) did not change over time, suggesting that
this is the equilibrium mixture. Second, treatment of ethyl
but-3-enoate (10) with (lIpc)2BCl and Et3N in toluene-d8,
conditions known to generate ester enolborinates,24 pro-
vided after 10 min a 2.7:0.7:1 mixture of Z-(O)-8b, E-(O)-
8b, and Z-(C)-7b that over a ca. 2 h period isomerized to
a 2.3:0.1:1 mixture that remained constant over a 12 h
period. Finally, treatment of 10 with B-iodo-9-BBN and
Et3N in THF-d6 provided Z-(C)-7c exclusively, with no
change observed over a 1 h monitoring period. These data
are consistent with our proposal that allylborane Z-(C)-7
can arise by isomerization of dienolborinate 8 as suggested
by the computational studies (Scheme 2). These observations
may also be relevant to understanding the ‘unusual’ stereo-
chemical course of the ‘aldol’ reactions of ethyl but-3-enoate
and di(bicyclo[2.2.1]heptan-2-yl)chloroborane recently re-
ported by Ramachandran.8
In conclusion, hydroboration of allenecarboxylate 2
with borane 1R provides stereoselective formation of
(Z)-dienolborinate Z-(O)-8a, which upon treatment with
aldehydes provides syn R-vinyl-β-hydroxy esters 3aÀg in
68À91% yields with excellent diastereoselectivities (dr >40:1)
and with good to excellent enantioselectivity (73À89% ee).
DFT calculations and NMR evidence support the proposed
1,4-hydroboration pathway.
Acknowledgment. Financial support provided by the
NIH (GM038436) is gratefully acknowledged. D.H.E. thanks
BYU and the Fulton Supercomputing Lab for support.
Supporting Information Available. Experimental pro-
cedures and tabulated spectroscopic data for new com-
pounds. Full ref 18b and xyz coordinates for the calcu-
lations summarized in Scheme 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Citations of other methods for reductive aldol reactions are
provided in ref 16.
(22) Ess, D. H.; Kister, J.; Chen, M.; Roush, W. R. Org. Lett. 2009,
11, 5538.
(23) A 3,4-addition pathway has been proposed for the borylcupra-
tion of allenamides: Yuan, W.; Zhang, X.; Yu, Y.; Ma, S. Chem.;Eur.
J. 2013, 19, 7193.
(24) Ganesan, K.; Brown, H. C. J. Org. Chem. 1994, 59, 2336.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 21, 2013
5439