Tandem hydroboration/reduction of trisubstituted β,γ-unsaturated esters for the asymmetric synthesis of chiral 1,3-diols

Article abstract of DOI:10.1016/j.tetlet.2012.10.047

Treatment of a range of trisubstituted β,γ-unsaturated esters with 2 equiv of (-)-monoisopinocampheylborane results in hydroboration of their alkene functionalities and reduction of their ester groups to afford chiral 1,3-diols containing two new vicinal

Full text of DOI:10.1016/j.tetlet.2012.10.047

Tetrahedron Letters 54 (2013) 27–31
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Tetrahedron Letters
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Tandem hydroboration/reduction of trisubstituted b,c-unsaturated esters
for the asymmetric synthesis of chiral 1,3-diols
⇑
Paul S. Fordred, Steven D. Bull
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of
a
range of trisubstituted b,
c
-unsaturated esters with 2 equiv of (ꢀ)-mono-
Received 29 June 2012
Revised 29 September 2012
Accepted 11 October 2012
Available online 22 October 2012
isopinocampheylborane results in hydroboration of their alkene functionalities and reduction of their
ester groups to afford chiral 1,3-diols containing two new vicinal b,c-(anti)-stereocentres in 67–85%
enantiomeric excess.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hydroboration
Reduction
b,c-Unsaturated ester
Chiral 1,3-diol
IpcBH2
The development of ‘one-pot’ protocols that enable reagents or
((ꢀ)-IpcBH2) 9,5 followed by oxidative work-up, gave (anti)-alcohol
10 in 81% ee (Scheme 2, Eq. ii).6 Therefore, it was decided to investi-
gate whether treatment of methyl (E)-4-aryl-pent-3-enoates 11
with excess (ꢀ)-IpcBH2 9 would result in stereoselective tandem
hydroboration/reduction reactions occurring to afford chiral 1,3-
diols 12 containing two new stereocentres in good ee (Fig. 1).
catalysts to be used to transform two different functional groups in
the same substrate represents an atom-efficient strategy. Borane
reagents have been widely used to hydroborate substituted al-
kenes with good levels of regiocontrol, which upon oxidative
work-up afford primary or secondary alcohols in good yields.1 They
may also be used to reduce the carbonyl functionalities of ester,
aldehyde and ketone groups to afford primary and secondary alco-
hols, respectively.2 Molander and Bobbitt have previously reported
A series of seven (E)-b,c-unsaturated esters 11a–g were pre-
pared via Knoevanagel-type reaction of the enolate of malonic acid
with a range of 2-arylpropionaldehydes 13a–g7 to afford their
that treatment of
a
range of allyl-ketones with dii-
respective (E)-b,c
-unsaturated acids 14a–g,8 that were then sub-
sopinocampheylborane ((ꢀ)-Ipc)2BH) 2 results in tandem hydrob-
oration/reduction reactions to afford enantiomerically enriched
chiral 1,4-diols.3 For example, treatment of allyl-ketone 1 with
1.5 equiv of (ꢀ)-Ipc)2BH 2 gave 1,4-diol 5 containing one new ste-
reocentre in 88% enantiomeric excess (ee) (Scheme 1).3 In this case,
hydroboration of the allyl group of 1 results in a trialkylborane
intermediate 3 that then undergoes stereoselective intramolecular
jected to acid catalysed esterification reactions with methanol
(Scheme 3).9 Treatment of methyl (E)-4-phenylpent-3-enoate
11a10a with 2 equiv of (ꢀ)-IpcBH2 9 at ꢀ17 ? 0 °C, followed by oxi-
dation with alkaline hydrogen peroxide, resulted in the clean for-
mation of (3S,4R)-4-phenylpentane-1,3-diol 12a10b in 60% yield
and 82% ee (Scheme 4).11 The enantiomeric excess of diol 12a
was determined via treatment with 2-formylphenylboronic acid
reduction of its ketone group (with elimination of (+)-
a-pinene) to
16 and (S)-a-methylbenzylamine 17 that gave a mixture of diaste-
afford a cyclic borinate ester 4 that on oxidative work-up affords
1,4-diol 5 (Scheme 1).
A review of the literature revealed that Martin and co-workers
had reported that treatment of cyclic b,c-unsaturated ester 6 with
excessBH3 resultedintandemalkenehydroboration/esterreduction
to afford diol 7 in a 6:1 diastereomeric ratio (dr) (Scheme 2, Eq. i).4
Furthermore, Brown and coworkers had shown that hydroboration
of trisubstituted arylalkene 8 with monoisopinocampheylborane
reomeric imino-boronate esters 18 and 19, whose 82% dr was
determined by 1H NMR spectroscopic analysis (Scheme 5).12 The
absolute configuration of (3S,4R)-4-phenylpentane-1,3-diol 12a
was determined via its two-step conversion into (2R,3S)-2-phe-
nylpentan-3-ol 1510c (½a D25
ꢁ
+6.3 (c 1.6, CHCl3); (lit.13 for (2S,3R)-
15 = ꢀ11.4 (neat)), involving mono-tosylation of its primary
alcohol group, followed by subsequent reduction with LiAlH4
(Scheme 4). This configurational assignment was consistent with
the enantiofacial selectivity previously observed for hydroboration
of the trisubstituted (E)-arylalkene functionality of (E)-trisubsti-
tuted alkene 8 with (ꢀ)-IpcBH2 9 (Scheme 2, Eq. ii).6
⇑
Corresponding author. Tel.: +44 1225 383551.
E-mail address: s.d.bull@bath.ac.uk (S.D. Bull).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.047

28
P. S. Fordred, S. D. Bull / Tetrahedron Letters 54 (2013) 27–31
Me
Me
BH
2
HO2C
CO2H
H
1.5 eq.
Ar
Ar
CO2H
Et3N, reflux, 16 h
O
2
4:1 to 10:1 mixtures of
Ipc
O
O
(E)-/(Z)-isomers
THF, 0 °C
B
R
Ipc
R
14a-g
13a-g
1
3
conc. H2SO4
a) Ar = Ph
(0.5 eq.),
(R = (CH2)4CO2Me)
(R = (CH2)4CO2Me)
b) Ar = 4-MeC6H4
c) Ar = 4-MeOC6H4
d) Ar = 4-BrC6H4
e) Ar = 2-Npth
MeOH, rt, 16 h
Me
(+)−α-pinene
Ipc
f) Ar = 2-MeOC6H4
g) Ar = 1-Npth
Ar
CO2Me
OH
(E)-isomers isolated after
B
O
OH
NaBO3.4 H2O
chromatographic purification
R
MeO2C
11a-g
94%, 88% ee
5
(R = (CH2)4CO2Me)
4
Scheme 3. Knoevanagel-type synthesis of (E)-b,
c
-unsaturated esters 11a–g.
Scheme 1. Hydroboration of allyl-ketone
followed by oxidative work-up, affords 1,4-diol 5 in 88% ee.
1
with 1.5 equiv of ((ꢀ)-Ipc)2BH 2,
(a) (−)-IpcBH2 9 (2 eq.),
THF, -17→0 °C, 16 h;
Me
Me
OH
Ph
CO2Me
Ph
(b) H2O2, NaHCO3, rt, 6 h
CO2Me
OH
12a
11a
N
Cbz
6
60%, 82% ee
Et3N (2 eq.), DMAP (0.1 eq.),
tosyl chloride (1.5 eq.),
CH2Cl2, 0 °C to rt
(a) 3eq. BH3/THF;
(i)
(b) NaBO3.4 H2O
Me
LiAlH4 (1.0 eq.),
THF, rt
Me
OH
OH
OTs
Ph
Ph
OH
OH
15
N
Cbz
N
Cbz
+
:
OH
OH
7
6
1
Scheme 4. Asymmetric synthesis of (3S,4R)-4-phenylpentane-1,3-diol 12a and its
conversion into (2R,3S)-2-phenylpentan-3-ol 15.
1 eq.
BH2
(a)
quenching with methanol at ꢀ25 °C and oxidative work-up with
alkaline H2O2, resulted in the clean formation of methyl (3S,4R)-
3-hydroxy-4-phenylpentanoate 2010d in 75% ee (Scheme 6).14,15
This demonstrates that the alkene functionality of 11a is hydrob-
orated at a significantly faster rate than its ester group is re-
duced. This implies that hydroboration of 11a occurs to afford
a chiral organoborane intermediate 21, the ester group of which
is then reduced via intramolecular hydride transfer to give a cyc-
lic borinate ester 22. Subsequent loss/addition of the methoxide
group of intermediate 22 would then occur to afford boronate-
coordinated aldehyde 23 that is then reduced by excess (ꢀ)-
IpcBH2 9 (Fig. 2).
9
THF, -25 °C
(ii)
(b) NaOH, H2O2
50 °C, 1 h
OH
81 % ee
8
10
Scheme 2. (i) Hydroboration of cyclic b,
c
-unsaturated ester 6 with excess BH3
affords diol 7 in a 6:1 dr;4 (ii) Hydroboration of (E)-2-phenyl-2-butene 8 with (ꢀ)-
IpcBH2 9 affords (2S,3R)-3-phenylbutan-2-ol 10 in 81% ee.6
Modification of the reaction conditions employed for hydrob-
oration, involving the treatment of ester 11a with 2 equiv of (ꢀ)-
IpcBH2 9 in THF at ꢀ25 °C over a period of 48 h, followed by
The remaining b,c-unsaturated esters 11b–g were then sub-
jected to our standard reaction conditions using two equivalents
of (ꢀ)-IpcBH2 9 in THF at ꢀ17 to 0 °C, over 16 h, followed by oxida-
tive work-up with H2O2/NaHCO3 to afford their corresponding chi-
ral diols 12b–g in 41–77% isolated yields and 67–85% ees (Table 1).
In conclusion, we have shown that treatment of a range of tri-
Me
Me
(-)-IpcBH2 9
OH
substituted b,c-unsaturated esters 11 with an excess of the chiral
Ar
CO2Me
Ar
Tandem
hydroborating agent (ꢀ)-IpcBH2 9 results in ‘one-pot’ hydrobora-
tion of their alkene functionalities, followed by the reduction of
their ester groups, to afford chiral 1,3-diols 12 containing two
OH
12
hydroboration/reduction?
11
new vicinal b,c-(anti)-stereocentres in 67–85% enantiomeric
excess.
Figure 1. Proposed tandem hydroboration/reduction of trisubstituted b,
rated esters 11 to afford chiral 1,3-diols 12 containing two new stereocentres.
c
-unsatu-

P. S. Fordred, S. D. Bull / Tetrahedron Letters 54 (2013) 27–31
29
Table 1
Treatment of trisubstituted b,
c
-unsaturated esters 11a–g with (ꢀ)-IpcBH2 results in formation of 1,3-diols 12a–g
(a) (−)-IpcBH2 9 (2 eq.),
Me
Me
THF, -17
0 °C, 16 h;
OH
Ar
CO2Me
Ar
(b) H2O2, NaHCO3, rt ,6 h
OH
12
11
CO2Me
OH OH
11a
12a
CO2Me
OH OH
11b
12b
CO2Me
OH OH
MeO
Br
MeO
11c
12c
CO2Me
OH OH
OH OH
Br
11d
11e
12d
12e
CO2Me
OMe
OMe
CO2Me
OH OH
11f
12f
CO2Me
OH OH
11g
12g
aIsolated yields for chromatographically purified diols.
bees determined via derivatisation with 2-formylphenylboronic acid 16 and (S)-
resultant diastereomeric imino-boronate esters (see Scheme 5).12
a
-methyl-benzylamine 17, followed by 1H NMR spectroscopic analysis of the dr of the
cLower 41% yield due to competing formation of a 10% yield of its corresponding b-hydroxy ester.

30
P. S. Fordred, S. D. Bull / Tetrahedron Letters 54 (2013) 27–31
Me
OH
Me
Me
Ph
OH
Ph
Ph
(3S,4R)-12a, 82% ee
O
O
O
O
B
H
Me
Ph
B
H
Me
Ph
MgSO4,
+
+
HO
OH
N
CDCl3, rt,
10 min
N
B
O
Me
H
H2N
Ph
91
18
:
9
16
(1.1 eq.)
17
19
(1.2 eq.)
Ratio determined by 1H NMR
spectroscopic analysis
Scheme 5. The ee of diol 12a was determined via 1H NMR spectroscopic analysis of the dr of iminoboronate ester derivatives 18 and 19.
(a) (−)-IpcBH2 9 (2 eq.),
THF, -25 °C, 48 h;
Me
Me
18.3 mmol) was heated at reflux for 16 h. The crude reaction mixture was
Ph
CO2Me
Ph
CO2Me
cooled to rt, acidified to pH 1.0, extracted with Et2O (3 ꢂ 30 mL) and the
combined organic phases washed with NaCl(aq), dried (MgSO4) and the solvent
removed under reduced pressure. The resultant crude product was dissolved in
0.1 M aqueous NaOH solution, washed with Et2O (2 ꢂ 30 mL), acidified to pH
1.0 and the precipitated acid extracted with CH2Cl2 (4 ꢂ 30 mL). The combined
organic solvent was dried (MgSO4) and removed under reduced pressure to
afford the desired 4-arylpent-3-enoic acid 14. Step 2: 98% H2SO4 (0.5 equiv)
was added dropwise to a rapidly stirred solution of 4-arylpent-3-enoic acid 14
in MeOH (0.5 M), and the resulting solution stirred at rt for 16 h. The solution
was neutralised by the addition of solid NaHCO3 and the solvent evaporated
under reduced pressure. The crude product was partitioned between H2O and
CH2Cl2, the aqueous layer re-extracted with CH2Cl2, the combined organic
layers dried (MgSO4) and solvent removed under reduced pressure. The
resultant mixture of (E)/(Z)-isomers was purified via chromatography (petrol/
Et2O (9:1), SiO2) to afford the desired methyl (E)-4-arylpent-3-enoate 11.
10. Spectroscopic data for selected compounds: (a) Methyl (E)-4-phenylpent-3-
enoate 11a: 1H NMR (300 MHz, CDCl3) d 7.21–7.44 (5H, m, ArH), 5.95 (1H, tq,
J = 7.1 and 1.4 Hz, C@CH), 3.72 (3H, s, OCH3), 3.27 (2H, d, J = 7.1 Hz, CH2), 2.05–
2.08 (3H, m, CH3); 13C NMR (75 MHz, CDCl3) d 172.4, 143.1, 138.1, 128.3, 127.1,
125.8, 119.2, 52.0, 34.3, 16.2; IR (neat): 1730 (C@O), 1160 (C–O) cmꢀ1; (b)
(b) Add MeOH at-25 °C;
(c) H2O2 ,NaHCO3, rt, 6 h
OH
20
11a
75% ee
Scheme 6. Hydroboration of b,
c
-ester 11a to afford (3S,4R)-b-hydroxy ester 20.
Me
Me
H
(−)-IpcBH2
OMe
Ph
Ipc
11a
Ph
OMe
B
O
B
O
H
Ipc
21
22
(3S,4R)-4-Phenylpentane-1,3-diol 12a: 82% ee; ½a D25
ꢁ
+6.4 (c 4.6, CHCl3); 1H
Me
Me
Ipc
NMR (300 MHz, CDCl3) d 7.21–7.38 (5H, m, ArH), 3.77–3.97 (3H, m, CH2(OH)
and CH(OH)), 2.79 (app. p, J = 7.0 Hz, CHCH3), 2.17 (2H, br s, 2 ꢂ OH), 1.82–1.95
(1H, m, CHAHB), 1.58–1.74 (1H, m, CHAHB), 1.28 (3H, d, J = 7.0 Hz, CH3); 13C
NMR (75 MHz, CDCl3) d 143.0, 128.8, 128.1, 126.9, 76.8, 61.9, 46.6, 35.6, 17.6;
IR (neat): 3350 (O–H) cmꢀ1; HRMS (ES): m/z [C11H16NaO2]+ requires 203.1043,
H2O2/
H
H
(−)-IpcBH2
Ph
NaHCO3
Ph
H
12a
B
O
B
O
Ipc
OMe
23
found 203.1052; (c) (2R,3S)-2-Phenylpentan-3-ol 15: 82% ee; ½a D25
ꢁ
+6.3 (c 1.6,
CHCl3), (lit.13
½
a 2D5
ꢁ
for (2S,3R)-15 = ꢀ11.4(neat)); 1H NMR (300 MHz, CDCl3) d
7.12–7.30 (5H, m, ArH), 3.52 (1H, ddd, J = 8.2, 7.1 and 3.5 Hz, CH(OH)), 2.69
(app. p, J = 7.1 Hz, CH3CH), 1.49–1.65 (1H, m, CHAHB), 1.44 (1H, br s, OH), 1.24-
1.38 (1H, m, CHAHB), 1.21 (3H, d, J = 7.1 Hz, CHCH3), 0.92 (3H, t, J = 7.3 Hz,
CH2CH3); 13C NMR (75 MHz, CDCl3) d 143.6, 128.6, 128.2, 126.7, 77.4, 45.7,
Figure 2. Proposed mechanism for the tandem hydroboration/reduction of b,
unsaturated ester 11a.
c-
27.3, 18.0, 10.0; IR (neat): 3387 (O–H), 1602 cmꢀ1
; HRMS (ES): m/z
[C11H16NaO]+ requires 187.1099, found 187.1092; (d) Methyl (3S,4R)-3-
Acknowledgment
hydroxy-4-phenylpentanoate 20: 75% ee;
½
a 2D5
ꢁ
ꢀ11.7 (c 3.9, CHCl3); 1H
NMR (300 MHz, CDCl3) d 7.13–7.30 (5H, m, ArH), 4.11 (1H, ddd, J = 9.4, 6.2 and
3.0 Hz, CH(OH)), 3.61 (3H, s, OCH3), 2.78 (1H, app. p, J = 7.0 Hz, CHCH3), 2.97
(1H, dd, J = 16.0 and 3.0 Hz, CHAHB), 2.29 (1H, dd, J = 16.0 and 9.6 Hz, CHAHB),
1.25 (3H, d, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) d 173.4, 142.6, 128.5, 128.2,
P.S.F. gratefully acknowledges the EPSRC for the award of a
Ph.D. scholarship.
126.8, 72.3, 51.8, 45.2, 38.8, 17.2; IR (neat): 3657 (O–H), 1727 (C@O) cmꢀ1
HRMS (ES): m/z [C12H16NaO3]+ requires 231.0997, found 231.0999.
;
References and notes
11. General procedure for the asymmetric hydroboration/reduction of b,c-unsaturated
esters 11a–g: BF3.OEt2 (2.0 equiv, 5.26 mmol, 0.65 mL) was added dropwise to a
solution of 2IpcBH2.TMEDA16 (1.05 equiv, 2.76 mmol, 1.15 g) in dry THF
(3.8 mL). The resulting solution was stirred at rt for 3 h and then cooled to
ꢀ17 °C (MeOH/finely crushed ice). A solution of ester 11 (1.0 equiv, 2.63 mmol)
in THF (1.0 mL) was then added dropwise and the reaction mixture allowed to
warm to 0 °C overnight. The resultant solution was then treated with 30%
aqueous H2O2 (13.8 mL) and saturated NaHCO3 solution (84 mL), followed by
stirring at rt for 6 h. The reaction mixture was then extracted with Et2O, the
combined organics washed with water, dried (MgSO4) and the solvent
removed under reduced pressure to afford a crude product that was purified
via chromatography (petrol/Et2O (1:1), SiO2) to afford the desired 4-
arylpentane-1,3-diol 12.
1. Brown, H. C. Boranes in Organic Chemistry; Cornell University Press: Ithaca, New
York, 1972.
2. (a) Patra, P. K.; Nishide, K.; Fuji, K.; Node, M. Synthesis 2004, 1003–1006; (b)
Andrews, G. C. Tetrahedron Lett. 1980, 21, 697–700.
3. Molander, G. A.; Bobbitt, K. L. J. Org. Chem. 1994, 59, 2676–2678.
4. Simila, S. T. M.; Reichelt, A.; Martin, S. F. Tetrahedron Lett. 2006, 47, 2933–2936.
5. Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem. 1995, 500, 1–19.
6. (a) Mandal, A. K.; Jadhav, P. K.; Brown, H. C. J. Org. Chem. 1980, 45, 3543–3544;
(b) Brown, H. C.; Yoon, N. M. J. Am. Chem. Soc. 1977, 99, 5514–5516.
7. 2-Arylpropionaldehydes 13a–g were prepared from their corresponding
acetophenones via a two-step Wittig C1-homologation/enol ether hydrolysis
protocol, see: Pelphrey, P. M.; Popov, V. M.; Joska, T. M.; Beierlein, J. M.; Bolstad,
E. S. D.; Fillingham, Y. A.; Wright, D. L.; Anderson, A. C. J. Med. Chem. 2007, 50,
940–950.
12. For a detailed discussion of how to determine the ee of diols using this
derivatisation method, see: (a) Kelly, A. M.; Pérez-Fuertes, Y.; Arimori, S.; Bull,
S. D.; James, T. D. Org. Lett. 2006, 8, 1971–1974; (b) Kelly, A. M.; Pérez-Fuertes,
Y.; Fossey, J. S.; Yeste, S. L.; Bull, S. D.; James, T. D. Nat. Protoc. 2008, 3, 215–219.
13. Cram, D. J. J. Am. Chem. Soc. 1952, 74, 2159–2165.
14. The ee of b-hydroxy-ester 20 was determined via reduction with LiAlH4 to
afford 1,3-diol 12a whose ee was then determined using the 1H NMR
derivatisation method described in Scheme 5.
8. (a) Garnier, J. M.; Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2007, 3281–3291; (b)
Kumar, H. M. S.; Reddy, B. V. S.; Reddy, E. J.; Yadav, J. S. Tetrahedron Lett. 1999,
40, 2401–2404.
9. General procedure for the two-step synthesis of b,c-unsaturated esters 11a–g.
Step 1: A mixture of dry Et3N (1.5 equiv, 27.5 mmol, 3.9 mL), malonic acid
(1.0 equiv, 18.3 mmol, 1.90 g) and 2-aryl-propionaldehyde 13 (1.0 equiv,

P. S. Fordred, S. D. Bull / Tetrahedron Letters 54 (2013) 27–31
31
15. For related studies describing rhodium-catalysed asymmetric hydroboration
reactions of trisubstituted b, -unsaturated amides using pinacolborane that
16. (a) Brown, H. C.; Mandal, A. K.; Yoon, N. M.; Singaram, B.; Schwier, J. R.; Jadhav,
P. K. J. Org. Chem. 1982, 47, 5069–5074; (b) Brown, H. C.; Jadhav, P. K.; Mandal,
A. K. J. Org. Chem. 1982, 47, 5074–5083.
c
gave chiral b-hydroxy amides in good yields and high ee, see: (a) Smith, S. M.;
Takacs, J. M. J. Am. Chem. Soc. 2010, 132, 1740–1741; (b) Smith, S. M.; Takacs, J.
M. Org. Lett. 2010, 12, 4612–4615.