Diastereoselective Hydroxyethylation of β-Hydroxyketones: A Reformatsky Cyclization-Lactone Reduction Cascade Mediated by SmI2?H2O

Article abstract of DOI:10.1002/hlca.201900227

The hydroxyethylation of β-hydroxyketones allows diastereoselective access to important 1,3,5-triols. The approach exploits a SmI₂?H₂O-mediated Reformatsky cyclization-lactone reduction cascade.

Full text of DOI:10.1002/hlca.201900227

HELVETICA
chimica acta
Accepted Article
Title: Diastereoselective Hydroxyethylation of β-Hydroxyketones: a
Reformatsky Cyclization-Lactone Reduction Cascade Mediated
by SmI2-H2O
Authors: Monserrat H Garduño-Castro and David John Procter
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10.1002/hlca.201900227
Helvetica Chimica Acta
HELVETICA
Diastereoselective Hydroxyethylation of β-Hydroxyketones: a Reformatsky
Cyclization-Lactone Reduction Cascade Mediated by SmI2-H2O
Monserrat H. Garduño-Castro,a and David J. Proctera*
a Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
david.j.procter@manchester.ac.uk
Dedicated to Prof. Philippe Renaud on the occasion of his 60th birthday
The hydroxyethylation of β-hydroxyketones allows diastereoselective access to important 1,3,5-triols. The approach exploits a SmI2-H2O-mediated
Reformatsky cyclization-lactone reduction cascade.
Keywords: radical • samarium diiodide • Reformatsky • lactones • cascade
CCDC Number: 1953812). The diastereoselectivity observed in the SmI2-
Introduction
mediated Reformatksy cyclization of 2a to form lactone 3a is consistent
with that observed by Molander[30] and arises from a highly organised
The 1,3,5-triol motif is an important motif found in a number of biologically
active natural products including important polyketides (Scheme 1A).[1–5]
The motif is most often constructed by diastereoselective ketone
reduction.[6–12] Samarium diiodide (Kagan’s reagent, SmI2) is well-known for
its ability to form carbon-carbon bonds, with high diastereoselectivity,[13–15]
particularly when couplings are carried out in an intramolecular sense.
Recently, our group has expanded the synthetic reach of the reagent by
developing chemistry involving radicals generated from the carbonyl
groups of carboxylic acid derivatives. In particular, we have developed
reductions of lactones,[16,17] acyclic esters,[18] carboxylic acids,[19] nitriles,[20]
and amides,[21] using SmI2 activated by H2O.[22] This work has culminated in
the development of radical cascade reactions for the selective construction
of complex architectures.[23–29] In the case of lactone reduction, we have
described the ring size-selective reduction of six-membered lactones using
SmI2–H2O that proceeds by electron-transfer to the lactone carbonyl and
delivers the corresponding diol products (Scheme 1B).[16,17] Inspired by
Molander’s seminal work on a highly diastereoselective SmI2-mediated
intramolecular Reformatsky approach to 6-membered lactones,[30] here we
describe a diastereoselective hydroxyethylation of β-hydroxyketones that
transition structure I in which Sm(III) of the Sm(III)-enolate[31] coordinates
to the ketone carbonyl in the substrate, with the two alkyl substituents in
pseudoequatorial orientations (Scheme 2).
A. The 1,3,5-triol motif in selected, bioactive natural products
Me
zincophorin
OH OH OH
OH
HO2C
O
H
H
Me
Me Me Me
Me Me Me
Me Me Me
HO
Me
OH
O
O
OH
Me
O
O
Me
NH2
Me
Me
OH OH OH
streptenol B/D
OH
(+)-discodermolide
B. SmI2–H2O-mediated reduction of lactones
O
OH
via
R1
R2
R1
R2
R2
SmI2–H2O
THF, rt
R1
delivers 1,3,5-triols and involves
a SmI2–H2O-mediated Reformatsky
O
OH
SmIIIO
O
cyclization-lactone reduction cascade (Scheme 1C).
C. This work: Hydroxyethylation of β-hydroxyketones
Results and Discussion
O
OH
OH OH
1. BrCH2C(O)Br
2. SmI2–H2O
R
Ar
O H
Ar
R
The feasibility of the hydroxyethylation process was assessed using β-
hydroxyketone 1a. After conversion to α-bromoacetate 2a (BrCH2C(O)Br,
pyridine, CH2Cl2, 72%), treatment with SmI2 at –78 °C for 30 min, followed
by addition of H2O to the pot, and warming to room temperature, gave the
1,3,5-triol product of hydroxyethylation 4a in 54% yield and lactone
intermediate 3a in 36% yield, both as single diastereoisomers. The
structure and relative stereochemistry of lactone intermediate 3a was
confirmed by X-Ray crystallographic analysis (See Supporting Information -
n high diastereocontrol n Reformatsky cyclization n lactone reduction
Scheme 1. A. Selected bioactive molecules containing the 1,3,5-triol motif. B. The
selective reduction of six-membered lactones using SmI2–H2O. C. Diastereoselective
hydroxyethylation of β-hydroxyketones.
1
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10.1002/hlca.201900227
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1. Allyl bromide, Zn, AlCl3
0 °C to rt, THF
2. NaBH4, CeCl3, EtOH
O
O
OR
SmI2 (10 eq), THF
–78 °C, 30 min
O
OH
O
O
Ph
Me
HO
Me
O
Ph
NC
N
OEt
3. N,O-Dimethylhydroxylamine
hydrochloride,
AlMe3, –20 °C to 0 °C
CH2Cl2
H
3a
5
1a R = H
2a R = C(O)CH2Br
BrCH2C(O)Br
Py, CH2Cl2, rt, 72%
82% for 3 steps
then
H2O (1000 eq)
rt, 18 h
RMgBr
Et2O
0 °C
Ar
OH OH
Me
O H
Ph
O
OH
HG-II (2 mol%)
O
OH
Ar
4a
R
54% (36% 3a recovered)
single diastereoisomer
CH2Cl2
R
X-Ray of 3a
1a R = Me, Ar = Ph, 46%
6a R = Me, 42%
6b R = Et, 19%
6c R = iBu, 25%
1b R = Me, Ar = C6H5-p-Br, 53%
1c R = Me, Ar = C6H5-p-CF3, 49%
1d R = Me, Ar = C6H5-m-CH3, 57%
1e R = Me, Ar = C6H5-o-Cl, 72%
1f R = Et, Ar = Ph, 58%
IIISm
O
OH
O
OSmIII
O
H
Me
O
Me
Ph
Ph
I
II
1g R = iBu, Ar = Ph, 76%
Scheme 2. Assessing the feasibility of the diastereoselective hydroxyethylation of β-
hydroxyketones. Samarium enolate intermediate and samarium ketyl radical
Scheme 3. Synthesis of β-hydroxyketone substrates 1a-g.
I
intermediate II. Diastereoisomeric purity was assessed by inspection of the 1H NMR
β-Hydroxyketones 1a-g were acylated using bromoacetyl bromide prior to
treatment with SmI2 and H2O (Scheme 4). By varying the aryl substituent
on the alkene we found that the presence of potentially reduceable bromo
(4b), chloro (4e), and trifluoromethyl (4c) functional groups was tolerated
in the process. Crucially, the presence of an alkene, in a position that
renders it potentially susceptible to radical cyclization, was also tolerated
(4a-g). Finally, the alkyl group of the ketone could be varied (4f, 4g). In all
cases, 1,3,5-triols products were formed as single diastereoisomers
(Scheme 4).
spectrum of the crude product mixture.
[32–38]
Addition of H2O activates SmI2
and switches on the second stage of
the process by facilitating reduction of the lactone carbonyl to give unusual
ketyl radical anion II. A sequence of further reductions and protonations
delivers 1,3,5-triol 4a as a single diastereoisomer. The conversion of 2a to
4a was optimized by varying the amount of SmI2 and the amount of H2O
employed in the cascade: Using 8 equivalents of SmI2 (a 1.3-fold excess as
the cascade requires 6-electrons) and 200 equivalents of H2O gave a 94%
isolated yield of 4a.
1. BrCH2C(O)Br
pyridine, CH2Cl2
RT, 20 min
To explore the scope of selective 1,3,5-triol synthesis, we synthesized a
range of β-hydroxyketones. Our route to substrates employed a Zn-
mediated Barbier reaction involving ethyl 2-cyanoacetate and allyl bromide,
with aluminium trichloride as a Lewis acid to activate the nitrile.[39] The
resulting ketoester was reduced under Luche conditions and the resultant
alcohol transformed to the Weinreb amide 5 using trimethyl aluminium
and N,O-dimethylhydroxylamine hydrochloride. This three-step sequence
could be carried out without purification and gave 5 in an overall yield of
82%. Treatment of 5 with three Grignard reagents delivered ketones 6a-c
in moderate yields. Finally, ketones 6 underwent olefin cross-metathesis,
using various styrenes and the Hoveyda-Grubbs 2nd generation catalyst, to
yield β-hydroxyketones 1a-g in good yield (Scheme 3).[40,41]
2. SmI2 (8 eq), THF
–78 °C, 30 min
O
OH
OH OH
R
Ar
O H
Ar
R
then
H2O (200 eq)
RT, 18 h
4a-g
1a-g
single diastereoisomer
Br
OH OH
OH OH
Me
O H
Me
O H
4a
4b
58%a, 94%b
OH OH
4c
72%a, 79%b
Me
CF3
OH OH
Me
O H
Me
O H
4d
45%a, 62%b
78%a, 92%b
Cl
OH OH
OH OH
Et
Me
O H
O H
4e
4f
69%a, 88%b
58%a, 61%b
OH OH
iBu
O H
4g
76%a, 70%b
Scheme 4. Hydroxyethylation of β-hydroxyketones using
a SmI2–H2O-mediated
cascade. Diastereoisomeric purity was assessed by inspection of the 1H NMR
spectrum of the crude product mixture. aYield for the acylation of the β-
hydroxyketone. bYield for the SmI2–H2O-mediated cascade.
2
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Conclusions
1276, 1159, 1106, 1042, 967, 795, 745, 693. HRMS calcd for C15H18O3Br [M
+ H]+: 325.0434, found 325.0427.
A two-stage, hydroxyethylation of β-hydroxyketones delivers 1,3,5-triols
with high diastereocontrol. After formation of the corresponding α-
bromoacetate, ketone hydroxyethylation proceeds through a SmI2–H2O-
mediated cascade reaction. The cascade process consists of a highly
diastereoselective SmI2-mediated Reformatsky cyclization, to give lactone
intermediates, that are then reduced to the corresponding triols, upon
addition of H2O to the reaction pot. The process shows promising
functional group compatibility and delivers important 1,3,5-triols as single
diastereoisomers in good isolated yield.
(E)-1-(4-Bromophenyl)-6-oxohept-1-en-4-yl 2-bromoacetate 2b
Prepared according to general procedure A using (E)-7-(4-bromophenyl)-4-
hydroxyhept-6-en-2-one 1b (165 mg, 0.580 mmol), pyridine (0.090 mL,
1.16 mmol) and bromoacetyl bromide (0.080 mL, 0.88 mmol) to give the
1
title compound as a yellow oil (169 mg, 0.420 mmol, 72%). H NMR (400
MHz, CDCl3) δ 2.16 (s, 3 H, CH3), 2.47 – 2.63 (m, 2 H, CH2CH=CHAr), 2.67 –
2.87 (m, 2 H, CH2C(O)), 3.77 (s, 2 H, CH2Br), 5.42 (dq, J = 7.2, 5.7 Hz, 1 H,
CH), 6.11 (dt, J = 15.8, 7.3 Hz, 1 H, CH=CHAr), 6.35 – 6.42 (m, 1 H, CH=CHAr),
7.17 – 7.23 (m, 2 H, ArCH), 7.38 – 7.45 (m, 2 H, ArCH) ppm. 13C NMR (101
MHz, CDCl3) δ 25.9 (CH2Br), 30.7 (CH3), 37.4 (CH2CH=CHAr), 46.7 (CH2C(O),
71.4 (CH), 121.4 (ArC), 124.8 (CH=CHAr), 127.9 (ArCH), 131.8 (ArCH), 132.9
(CH=CHAr), 136.0 (ArC), 166.6 (C(O)CH2Br), 204.9 (C(O)) ppm. IR νmax
(neat/cm−1): 2923, 1732, 1716, 1587, 1486, 1401, 1357, 1301, 1151, 1105,
1043, 1071, 1008, 968, 796, 731. HRMS calcd for C15H16O3Br2Na [M + Na]+:
424.9358, found 424.9345.
Experimental Section
General procedure A for the preparation of α-bromoacetates 2a-g.
β-Hydroxyketone 1 (1 equivalent) was dissolved in CH2Cl2. Pyridine (2
equivalents) was added followed by the dropwise addition of bromoacetyl
bromide (1.5 equivalent) at 0 °C. The reaction was stirred at that
temperature for 30 min and quenched with aqueous 1 M HCl. The aqueous
layer was extracted with CH2Cl2 (3 × 10 mL) and the combined organic
layers were washed with brine (10 ml), dried over MgSO4, and
concentrated in vacuo. Purification by column chromatography, eluting
with EtOAc/hexane (30:70), gave α-bromoacetates 2 as yellow oils.
(E)-6-Oxo-1-(4-(trifluoromethyl)phenyl)hept-1-en-4-yl
2-
bromoacetate 2c
Prepared according to general procedure A using (E)-4-hydroxy-7-(4-
(trifluoromethyl)phenyl)hept-6-en-2-one 1c (118 mg, 0.430 mmol),
pyridine (0.070 mL, 0.86 mmol) and bromoacetyl bromide (0.060 mL, 0.65
mmol) to give the title compound as a yellow oil (76.3 mg, 0.190 mmol,
45%). 1H NMR (500 MHz, CDCl3) δ 2.17 (d, J = 1.9 Hz, 3 H, CH3), 2.58 – 2.63
(m, 2 H, CH2CH=CHAr), 2.78 – 2.85 (m, 2 H, CH2C(O)), 3.77 (d, J = 1.9 Hz, 2 H,
CH2Br), 5.45 (p, J = 6.1 Hz, 1 H, CH), 6.19 – 6.28 (m, 1 H, CH=CHAr), 6.48 (d,
J = 15.8 Hz, 1 H, CH=CHAr), 7.42 (d, J = 8.1 Hz, 2 H, ArCH), 7.55 (d, J = 8.0 Hz,
2 H, ArCH) ppm. 13C NMR (126 MHz, CDCl3) δ 25.8 (CH2Br), 30.7 (CH3), 37.4
(CH2CH=CHAr), 46.7 (CH2C(O)), 71.2 (CH), 123.2 (ArC), 125.6 (ArCH), 126.5
(ArCH), 126.9 (CH=CHAr), 132.7 (CH=CHAr), 140.4 (ArC), 166.6 (C(O)CH2Br),
197.4 (C(O)) ppm (CF3 not observed). IR νmax (neat/cm−1): 2953, 1735, 1718,
1615, 1414, 1323, 1278, 1161, 1110, 1066, 1045, 971, 908, 857, 730, 649.
HRMS calcd for C16H16O3BrF3Na [M + Na]+: 415.0127, found 415.0112.
General procedure B for the preparation of 1,3,5-triols 4a-g. To a
solution of SmI2 (8 equivalents, 0.1 M in THF), under N2, at –78 °C, was
added α-bromoacetate 2 (1 equivalent) in THF (0.5 mL), dropwise and the
resulting mixture stirred for 30 min. The reaction was then allowed to
slowly warm to room temperature and degassed H2O (200 equivalents)
was added. The reaction was stirred at room temperature for 18 h before
being quenched by opening to air, followed by the addition of saturated
aqueous Rochelle’s salt. The aqueous layer was extracted with Et2O (3 × 5
mL) and the combined organic layers were washed with brine (10 mL),
dried over MgSO4, and concentrated in vacuo. Purification by column
chromatography, eluting with EtOAc/hexane (50:50), gave the 1,3,5-triols
as single diastereoisomers and as colourless oils.
(E)-6-Oxo-1-phenylhept-1-en-4-yl 2-bromoacetate 2a
(E)-6-Oxo-1-(m-tolyl)hept-1-en-4-yl 2-bromoacetate 2d
Prepared according to general procedure
A using (E)-4-hydroxy-7-
Prepared according to general procedure A using (E)-4-hydroxy-7-(m-
tolyl)hept-6-en-2-one 1d (146 mg, 0.670 mmol), pyridine (0.110 mL, 1.34
mmol) and bromoacetyl bromide (0.09 mL, 1 mmol) to give the title
compound as a yellow oil (178 mg, 0.520 mmol, 78%). 1H NMR (400 MHz,
CDCl3) δ 2.16 (s, 3 H, CH3), 2.34 (s, 3 H, ArCH3), 2.48 – 2.62 (m, 2 H,
CH2CH=CHAr), 2.67 – 2.87 (m, 2 H, CH2C(O)), 3.79 (s, 2 H, CH2Br), 5.43 (dq, J
= 7.5, 5.8 Hz, 1 H, CH), 6.10 (dt, J = 15.8, 7.3 Hz, 1 H, CH=CHAr), 6.42 (dd, J =
15.8, 1.5 Hz, 1 H, CH=CHAr), 7.03 – 7.07 (m, 1 H, ArCH), 7.12 – 7.23 (m, 3 H,
ArCH). 13C NMR (101 MHz, CDCl3) δ 21.5 (ArCH3), 25.9 (CH2Br), 30.7 (CH3),
37.4 (CH2CH=CHAr), 46.6 (CH2C(O)), 71.6 (CH), 123.5 (ArCH), 123.6
(CH=CHAr), 127.0 (ArCH), 128.5 (ArCH), 128.6 (ArCH), 134.2 (CH=CHAr),
137.0 (ArC), 138.3 (ArC), 166.6 (C(O)CH2Br), 205.0 (C(O)) ppm. IR νmax
phenylhept-6-en-2-one 1a (356 mg, 1.74 mmol), pyridine (0.280 mL, 3.48
mmol) and bromoacetyl bromide (0.230 mL, 2.61 mmol) to give the title
1
compound as a yellow oil (406 mg, 1.00 mmol, 58%). H NMR (400 MHz,
CDCl3) δ 2.17 (s, 3 H, CH3), 2.57 (dtd, J = 7.5, 6.0, 1.4 Hz, 2 H, CH2CH=CHAr),
2.68 – 2.88 (m, 2 H, CH2C(O)), 3.78 (s, 2 H, CH2Br), 5.44 (dq, J = 7.3, 5.8 Hz,
1 H, CH), 6.12 (dt, J = 15.6, 7.3 Hz, 1 H, CH=CHAr), 6.46 (dt, J = 15.8, 1.4 Hz,
1 H, CH=CHAr), 7.20 – 7.25 (m, 1 H, ArCH), 7.28 – 7.37 (m, 4 H, ArCH) ppm.
13C NMR (101 MHz, CDCl3) δ 25.9 (CH2Br), 30.7 (CH3), 37.4 (CH2CH=CHAr),
46.6 (CH2C(O)), 71.6 (CH), 123.9 (CH=CHAr), 126.3 (ArCH), 127.7 (ArCH),
128.7 (ArCH), 134.1 (CH=CHAr), 137.0 (ArC), 166.6 (C(O)CH2Br), 205.1
(C(O)) ppm. IR νmax (neat/cm−1): 3025, 1732, 1715, 1495, 1421, 1378, 1357,
3
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(neat/cm−1): 2922, 1735, 1716, 1602, 1485, 1421, 1378, 1357, 1276, 1159,
1106, 1042, 967, 774, 732, 694. HRMS calcd for C16H19O3BrNa [M + Na]+:
361.0410, found 361.0392.
(CH3)2CHCH2), 71.6 (CH), 124.0 (CH=CHAr), 126.3 (ArCH), 127.7 (ArCH),
128.7 (ArCH), 134.0 (CH=CHAr), 137.1 (ArC), 166.6 (C(O)CH2Br), 207.1
(C(O)) ppm. IR νmax (neat/cm−1): 2958, 2254, 1737, 1405, 1367, 1277, 1166,
1107, 967, 907, 694, 649. HRMS calcd for C18H23O3BrNa [M + Na]+:
389.0723, found 389.0706.
(E)-1-(2-Chlorophenyl)-6-oxohept-1-en-4-yl 2-bromoacetate 2e
Prepared according to general procedure A using (E)-7-(2-chlorophenyl)-4-
hydroxyhept-6-en-2-one 1e (176 mg, 0.740 mmol), pyridine (0.120 mL,
1.47 mmol) and bromoacetyl bromide (0.10 mL, 1.1 mmol) to give the title
compound as a yellow oil (183 mg, 0.510 mmol, 69%). 1H NMR (400 MHz,
CDCl3) δ 2.17 (s, 3 H, CH3), 2.52 – 2.67 (m, 2 H, CH2CH=CHAr), 2.70 – 2.90
(m, 2 H, CH2C(O)), 3.79 (s, 2 H, CH2Br), 5.41 – 5.50 (m, 1 H, CH), 6.10 (ddd, J
= 15.7, 7.9, 7.0 Hz, 1 H, CH=CHAr), 6.75 – 6.85 (m, 1 H, CH=CHAr), 7.14 –
7.25 (m, 2 H, ArCH), 7.33 (dd, J = 7.8, 1.5 Hz, 1 H, ArCH), 7.47 (dd, J = 7.6,
1.9 Hz, 1 H, ArCH) ppm. 13C NMR (101 MHz, CDCl3) δ 25.9 (CH2Br), 30.7
(CH3), 37.6 (CH2CH=CHAr), 46.7 (CH2C(O)), 71.3 (CH), 127.0 (2 × ArCH,
CH=CHAr), 128.7 (ArCH), 129.7 (ArCH), 130.3 (CH=CHAr), 132.8 (ArC), 135.2
(ArC), 166.6 (C(O)CH2Br), 204.9 (C(O)) ppm. IR νmax (neat/cm−1): 2962, 1733,
1716, 1591, 1470, 1423, 1357, 1275, 1150, 1105, 1034, 967, 751, 694.
HRMS calcd for C15H16O3BrClNa [M + Na]+: 380.9864, found 380.9850.
rac-(3R,5S,E)-3-Methyl-8-phenyloct-7-ene-1,3,5-triol 4a
Prepared according to general procedure B using SmI2 (2.46 mL, 0.25 mmol,
0.1 M in THF), ethyl (E)-6-oxo-1-phenylhept-1-en-4-yl 2-bromoacetate 2a
(0.01 mg, 0.03 mmol) and H2O (0.11 mL, 6.14 mmol) to give the title
compound as a colourless oil (7.20 mg, 0.03 mmol, 94%). 1H NMR (400
MHz, CDCl3) δ 1.35 (s, 3 H, CH3), 1.51 – 1.63 (m, 1 H, CquatCHaHbCH), 1.75 (tt,
J = 5.2, 2.3 Hz, 2 H, CquatCH2CH2OH), 1.87 – 1.92 (m, 1 H, CquatCHaHbCH), 2.41
(ddd, J = 7.4, 6.1, 1.4 Hz, 2 H, CH2CH=CH), 3.03 (s, 1 H, OH), 3.29 (s, 1 H, OH),
3.92 (t, J = 5.5 Hz, 2 H, CH2OH), 4.20 (ddt, J = 7.9, 6.0, 3.0 Hz, 1 H, CH), 4.27
(s, 1 H, OH), 6.16 – 6.28 (m, 1 H, CH=CHAr), 6.49 (dd, J = 15.8, 3.3 Hz, 1 H,
CH=CHAr), 7.20 – 7.25 (m, 1 H, ArCH), 7.31 (dd, J = 7.6, 7.6 Hz, 2 H, ArCH),
7.37 (dt, J = 5.8, 1.4 Hz, 2 H, ArCH) ppm. 13C NMR (101 MHz, CDCl3) δ 26.4
(CH3), 42.2 (CH2CH=CH), 43.8 (CquatCH2CH2OH), 45.8 (CquatCH2CH), 59.8
(CH2OH), 69.0 (CH), 74.5 (Cquat), 125.7 (CH=CHAr), 126.3 (ArCH), 127.5
(ArCH), 128.7 (ArCH), 133.6 (CH=CHAr), 137.2 (ArC) ppm. IR νmax
(neat/cm−1): 3341, 2934, 2042, 1665, 1426, 1259, 1117, 1053, 967, 744.
HRMS calcd for C15H21O3 [M - H]-: 249.1496, found 249.1498.
(E)-6-Oxo-1-phenyloct-1-en-4-yl 2-bromoacetate 2f
Prepared according to general procedure
A using (E)-5-hydroxy-8-
phenyloct-7-en-3-one 1f (62.0 mg, 0.280 mmol), pyridine (0.050 mL, 0.57
mmol) and bromoacetyl bromide (0.040 mL, 0.43 mmol) to give the title
compound as a yellow oil (55.5 mg, 0.160 mmol, 58%). 1H NMR (400 MHz,
CDCl3) δ 0.97 (t, J = 7.3 Hz, 3 H, CH3), 2.36 (qd, J = 7.3, 1.9 Hz, 2 H, CH3CH2),
2.50 (dtd, J = 7.5, 5.8, 1.4 Hz, 2 H, CH2CH=CHAr), 2.58 – 2.78 (m, 2 H,
CH2C(O)), 3.71 (s, 2H, CH2Br), 5.39 (ddt, J = 13.4, 7.7, 5.9 Hz, 1 H, CH), 6.05
(dtd, J = 15.8, 7.3, 4.8 Hz, 1 H, CH=CHAr), 6.38 (dd, J = 15.8, 1.6 Hz, 1 H,
rac-(3R,5S,E)-8-(4-Bromophenyl)-3-methyloct-7-ene-1,3,5-triol 4b
Prepared according to general procedure B using SmI2 (6.00 mL, 0.60 mmol,
0.1 M in THF), (E)-1-(4-bromophenyl)-6-oxohept-1-en-4-yl 2-bromoacetate
2b (30.3 mg, 0.075 mmol) and H2O (0.27 mL, 15 mmol) to give the title
1
compound as a colourless oil (19.6 mg, 0.059 mmol, 79%). H NMR (500
CH=CHAr), 7.12 – 7.19 (m, 1 H, ArCH), 7.21 – 7.31 (m, 4 H, ArCH) ppm. 13
C
MHz, CDCl3) δ 1.34 (s, 3 H, CH3), 1.48 – 1.54 (m, 1 H, CquatCHaHbCH), 1.65 –
1.78 (m, 2 H, CquatCH2CH2OH), 1.85 – 1.92 (m, 1 H, CquatCHaHbCH), 2.38 (dd, J
= 7.3, 7.3 Hz, 2 H, CH2CH=CH), 3.08 (s, 1 H, OH), 3.59 (s, 1 H, OH), 3.92 (t, J =
5.7 Hz, 2 H, CH2OH), 4.19 (dq, J = 16.0, 9.6, 8.0 Hz, 1 H, CH), 4.33 (s, 1 H,
OH), 6.17 – 6.29 (m, 1 H, CH=CHAr), 6.41 (d, J = 15.8 Hz, 1 H, CH=CHAr),
7.15 – 7.24 (m, 2 H, ArCH), 7.42 (dd, J = 8.5, 1.9 Hz, 2 H, ArCH) ppm. 13C
NMR (126 MHz, CDCl3) δ 26.3 (CH3), 42.1 (CH2CH=CH), 43.7 (CquatCH2CH2OH),
45.7 (CquatCH2CH), 59.8 (CH2OH), 68.8 (CH), 74.6 (Cquat), 121.1 (ArCH), 126.9
(CH=CHAr), 127.8 (ArCH), 131.7 (CH=CHAr), 132.2 (ArC), 136.2 (ArC) ppm.
IR νmax (neat/cm−1): 3347, 2930 1651, 1486, 1401, 1378, 1117, 1071, 1008,
968, 908, 798, 733, 648. HRMS calcd for C15H21O3BrNa [M + Na]+: 351.0566,
found 351.0554.
NMR (101 MHz, CDCl3) δ 7.6 (CH3), 25.9 (CH2Br), 36.7 (CH3CH2), 37.4
(CH2CH=CHAr), 45.4 (CH2C(O)), 71.7 (CH), 123.9 (CH=CHAr), 126.3 (ArCH),
127.6 (ArCH), 128.7 (ArCH), 134.0 (CH=CHAr), 137.0 (ArC), 166.6
(C(O)CH2Br), 207.7 (C(O)) ppm. IR νmax (neat/cm−1): 2975, 1732, 1714, 1449,
1410, 1378, 1277, 1165, 1109, 966, 910, 751, 701. HRMS calcd for
C16H19O3BrNa [M + Na]+: 361.0410, found 361.0394.
(E)-8-Methyl-6-oxo-1-phenylnon-1-en-4-yl 2-bromoacetate 2g
Prepared according to general procedure A using (E)-6-hydroxy-2-methyl-
9-phenylnon-8-en-4-one 1g (33.1 mg, 0.13 mmol), pyridine (0.02 mL, 0.27
mmol) and bromoacetyl bromide (0.02 mL, 0.20 mmol) to give the title
1
compound as a yellow oil (37.4 mg, 0.10 mmol, 76%). H NMR (500 MHz,
rac-(3R,5S,E)-3-Methyl-8-(4-(trifluoromethyl)phenyl)oct-7-ene-
CDCl3) δ 0.89 (d, J = 6.1 Hz, 3 H, CH3), 0.91 (d, J = 6.1 Hz, 3 H, CH3), 2.06 –
2.17 (m, 1 H, (CH3)2CH), 2.29 (dd, J = 7.0, 2.4 Hz, 2 H, (CH3)2CHCH2), 2.51 –
2.62 (m, 2 H, CH2CH=CHAr), 2.63 – 2.83 (m, 2 H, CH2C(O)), 3.78 (s, 2 H,
CH2Br), 5.45 (dq, J = 7.4, 5.8 Hz, 1 H, CH), 6.14 (tt, J = 15.3, 7.3 Hz, 1 H,
CH=CHAr), 6.45 (d, J = 15.8 Hz, 1 H, CH=CHAr), 7.21 – 7.25 (m, 1 H, ArCH),
7.28 – 7.35 (m, 4 H, ArCH) ppm. 13C NMR (126 MHz, CDCl3) δ 22.6 (2 × CH3),
24.6 ((CH3)2CH), 25.9 (CH2Br)), 37.4 (CH2CH=CH2), 46.2 (CH2C(O)), 52.5
1,3,5-triol 4c
Prepared according to general procedure B using SmI2 (4.00 mL, 0.40 mmol,
0.1 M in THF), (E)-6-oxo-1-(4-(trifluoromethyl)phenyl)hept-1-en-4-yl 2-
bromoacetate 2c (19.6 mg, 0.05 mmol) and H2O (0.18 mL, 0.01 mmol) to
give the title compound as a colourless oil (9.86 mg, 0.031 mmol, 62%). 1H
NMR (400 MHz, CDCl3) δ 1.35 (s, 3 H, CH3), 1.45 – 1.52 (m, 1 H,
4
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CquatCHaHbCH), 1.69 – 1.78 (m, 2 H, CquatCH2CH2OH), 1.79 – 1.91 (m, 1 H,
CquatCHaHbCH), 2.43 (ddd, J = 7.4, 4.8, 3.1 Hz, 2 H, CH2CH=CH), 2.87 (s, 1 H,
OH), 3.62 (s, 1 H, OH), 3.93-4.05 (m, 3 H, CH2OH, OH), 4.18 – 4.29 (m, 1 H,
CH), 6.35 (dt, J = 15.9, 7.2 Hz, 1 H, CH=CHAr), 6.51 (d, J = 15.9 Hz, 1 H,
rac-(3R,5S,E)-3-Ethyl-8-phenyloct-7-ene-1,3,5-triol 4f
Prepared according to general procedure B using SmI2 (6.50 mL, 0.65 mmol,
0.1 M in THF), (E)-6-oxo-1-phenyloct-1-en-4-yl 2-bromoacetate 2f (27.7 mg,
0.08 mmol) and H2O (0.29 mL, 16.3 mmol) to give the title compound as a
colourless oil (13.3 mg, 0.05 mmol, 61%). 1H NMR (400 MHz, CDCl3) δ 0.84
(t, J = 7.6 Hz, 3 H, CH3), 1.55 – 1.67 (m, 2 H, 1 H from CquatCH2CH, 1 H from
CquatCH2CH2OH), 1.69 – 1.85 (m, 4 H, 2 H from CH3CH2, 1 H from CquatCH2CH,
1 H from CquatCH2CH2OH), 2.40 (tt, J = 6.9, 1.6 Hz, 2 H, CH2CH=CH), 3.21 (s, 1
H, OH), 3.45 (s, 1 H, OH), 3.79 – 3.97 (m, 2 H, CH2OH), 4.06 – 4.18 (m, 1 H,
CH), 4.34 (s, 1 H, OH), 6.21 (dt, J = 15.4, 7.3 Hz, 1 H, CH=CHAr), 6.48 (d, J =
15.8 Hz, 1 H, CH=CHAr), 7.19 – 7.25 (m, 1 H, ArCH), 7.30 (dd, J = 7.6, 7.6 Hz,
2 H, ArCH), 7.36 (d, J = 7.2 Hz, 2 H, ArCH) ppm. 13C NMR (101 MHz, CDCl3) δ
9.1 (CH3), 31.5 (CH3CH2), 39.6 (CquatCH2CH2OH), 42.2 (CH2CH=CH,
CquatCH2CH), 59.6 (CH2OH), 68.7 (CH), 77.0 (Cquat), 125.7 (CH=CHAr), 126.3
(ArCH), 127.5 (ArCH), 128.7 (ArCH), 133.5 (CH=CHAr), 137.3 (ArC) ppm. IR
νmax (neat/cm−1): 3344, 3026, 2940, 1598, 1495, 1432, 1329, 1108, 1051,
966, 908, 852, 692, 648. HRMS calcd for C16H24O3Na [M + Na]+: 287.1618,
found 287.1604.
CH=CHAr), 7.45 (d, J = 8.1 Hz, 2 H, ArCH), 7.53 (d, J = 8.8 Hz, 2 H, ArCH). 13
C
NMR (101 MHz, CDCl3) δ 26.3 (CH3), 42.1 (CH2CH=CH), 43.7 (CquatCH2CH2OH),
45.9 (CquatCH2CH), 59.8 (CH2OH), 68.8 (CH), 74.6 (Cquat), 125.4 (ArCH), 126.4
(ArCH), 128.6 (CH=CHAr), 129.0 (ArC), 132.0 (CH=CHAr), 140.8 (ArC) ppm
(CF3 not observed). IR νmax (neat/cm−1): 3322, 2936, 1615, 1415, 1352,
1163, 1120, 1067, 1017, 908, 856, 732, 649. HRMS calcd for C16H22O3F3 [M
+ H]+: 319.1516, found 319.1512.
rac-(3R,5S,E)-3-Methyl-8-(m-tolyl)oct-7-ene-1,3,5-triol 4d
Prepared according to general procedure B using SmI2 (6.00 mL, 0.60 mmol,
0.1 M in THF), (E)-6-oxo-1-(m-tolyl)hept-1-en-4-yl 2-bromoacetate 2d (25.4
mg, 0.075 mmol) and H2O (0.27 mL, 15 mmol) to give the title compound
as a colourless oil (18.2 mg, 0.068 mmol, 92%). 1H NMR (400 MHz, CDCl3) δ
1.34 (s, 3 H, CH3), 1.50 – 1.56 (m, 1 H, CquatCHaHbCH), 1.73 (tq, J = 5.7, 3.6,
3.0 Hz, 2 H, CquatCH2CH2OH), 1.86 – 1.92 (m, 1 H, CquatCHaHbCH), 2.34 (s, 3 H,
ArCH3), 2.40 (td, J = 7.2, 1.4 Hz, 2 H, CH2CH=CH), 3.21 (s, 1 H, OH), 3.42 (s, 1
H, OH), 3.91 (t, J = 5.6 Hz, 2 H, CH2OH), 4.20 (dtd, J = 11.1, 6.2, 2.0 Hz, 1 H,
CH), 4.36 (s, 1 H, OH), 6.20 (dt, J = 15.9, 7.3 Hz, 1 H, CH=CHAr), 6.45 (dt, J =
15.9, 1.4 Hz, 1 H, CH=CHAr), 7.01 – 7.06 (m, 1 H, ArCH), 7.14 – 7.23 (m, 3 H,
ArCH). 13C NMR (101 MHz, CDCl3) δ 21.5 (ArCH3), 26.4 (CH3), 42.2
(CH2CH=CH), 43.7 (CquatCH2CH2OH), 45.7 (CquatCH2CH), 59.7 (CH2OH), 69.0
(CH), 74.5 (Cquat), 123.4 (ArCH), 125.5 (CH=CHAr), 127.0 (ArCH), 128.3
(ArCH), 128.6 (ArCH), 133.6 (CH=CHAr), 137.2 (ArC), 138.2 (ArC) ppm. IR
νmax (neat/cm−1): 3343, 2924, 2245, 1603, 1429, 1377, 1117, 1053, 966, 908,
857, 774, 732, 693, 648. HRMS calcd for C16H24O3Na [M + Na]+: 287.1618,
found 287.1605.
rac-(3R,5S,E)-3-Isobutyl-8-phenyloct-7-ene-1,3,5-triol 4g
Prepared according to general procedure B using SmI2 (5.50 mL, 0.55 mmol,
0.1 M in THF), (E)-8-methyl-6-oxo-1-phenylnon-1-en-4-yl 2-bromoacetate
2g (25.3 mg, 0.07 mmol) and H2O (0.25 mL, 13.8 mmol) to give the title
compound as a colourless oil (14.3 mg, 0.05 mmol, 70%). 1H NMR (400
MHz, CDCl3) δ 0.94 (d, J = 6.4 Hz, 3 H, CH3), 0.98 (d, J = 6.4 Hz, 3 H, CH3)
1.52 – 1.64 (m, 3 H, (CH3)2CH, 1 H from CquatCH2CH2OH, 1 H from
CquatCH2CH), 1.65 – 1.73 (m, 2 H, (CH3)2CHCH2), 1.80 – 1.99 (m, 2 H, 1 H
from CquatCH2CH2OH, 1 H from CquatCH2CH), 2.40 (ddt, J = 7.2, 5.8, 1.4 Hz, 2
H, CH2CH=CH), 3.27 (d, J = 9.9 Hz, 1 H, OH), 3.44 (s, 1 H, OH), 3.80 – 4.01 (m,
2 H, CH2OH), 4.18 (dt, J = 11.9, 6.4 Hz, 1 H, CH), 4.32 (s, 1 H, OH), 6.21 (dt, J
= 15.9, 7.4 Hz, 1 H, CH=CHAr), 6.48 (d, J = 15.8 Hz, 1 H, CH=CHAr), 7.19 –
7.25 (m, 1 H, ArCH), 7.30 (dd, J = 8.4, 6.7 Hz, 2 H, ArCH), 7.34 – 7.38 (m, 2 H,
ArCH) ppm. 13C NMR (101 MHz, CDCl3) δ 24.5 (CH3), 24.6 (CH3), 25.1
((CH3)2CHCH2), 40.7 (CquatCH2CH2OH), 42.3 (CH2CH=CH), 43.9 (CquatCH2CH),
47.9 ((CH3)2CH), 59.7 (CH2OH), 68.8 (CH), 77.0 (Cquat), 125.7 (CH=CHAr),
126.3 (ArCH), 127.5 (ArCH), 128.7 (ArCH), 133.6 (CH=CHAr), 137.2 (ArC). IR
νmax (neat/cm−1): 3335, 2953, 2247, 1431, 1081, 966, 907, 727, 693, 647.
HRMS calcd for C18H28O3Na [M + Na]+: 315.1931, found 315.1915.
rac-(3R,5S,E)-8-(2-Chlorophenyl)-3-methyloct-7-ene-1,3,5-triol 4e
Prepared according to general procedure B using SmI2 (6.00 mL, 0.60 mmol,
0.1 M in THF), (E)-1-(2-chlorophenyl)-6-oxohept-1-en-4-yl 2-bromoacetate
2e (26.9 mg, 0.075 mmol) and H2O (0.27 mL, 15 mmol) to give the title
1
compound as a colourless oil (18.9 mg, 0.066 mmol, 88%). H NMR (500
MHz, CDCl3) δ 1.35 (d, J = 2.0 Hz, 3 H, CH3), 1.51 – 1.56 (m, 1 H,
CquatCHaHbCH), 1.70 – 1.80 (m, 2 H, CquatCH2CH2OH), 1.84 – 1.91 (m, 1 H,
CquatCHaHbCH), 2.39 – 2.50 (m, 2 H, CH2CH=CH), 3.18 (s, 1 H, OH), 3.64 (s, 1
H, OH), 3.92 (t, J = 5.9 Hz, 2 H, CH2OH), 4.23 (dt, J = 11.9, 6.3 Hz, 1 H, CH),
4.38 (s, 1 H, OH), 6.15 – 6.26 (m, 1 H, CH=CHAr), 6.85 (d, J = 15.8 Hz, 1 H,
CH=CHAr), 7.16 (t, J = 7.7 Hz, 1 H, ArCH), 7.21 (t, J = 7.5 Hz, 1 H, ArCH), 7.33
(d, J = 7.9 Hz, 1 H, ArCH), 7.52 (d, J = 7.7 Hz, 1 H, ArCH) ppm. 13C NMR (126
MHz, CDCl3) δ 26.4 (CH3), 42.2 (CH2CH=CH), 43.7 (CquatCH2CH2OH), 45.7
(CquatCH2CH), 59.7 (CH2OH), 68.9 (CH), 74.6 (Cquat), 126.9 (ArCH), 126.9
(ArCH), 128.5 (ArCH), 129.0 (CH=CHAr), 129.5 (ArCH), 129.8 (CH=CHAr),
132.8 (ArC), 135.4 (ArC) ppm. IR νmax (neat/cm−1): 3345, 2928, 1648, 1469,
1439, 1377, 1115, 1055, 1033, 967, 908, 857, 750, 695. HRMS calcd for
C15H21O3ClNa [M + Na]+: 307.1071, found 307.1058.
rac-(4R,6S)-6-Cinnamyl-4-hydroxy-4-methyltetrahydro-2H-pyran-
2-one 3a
To a solution of SmI2 (0.95 mL, 0.095 mmol, 0.1 M in THF), under N2, at -
78 °C, (E)-6-oxo-1-phenylhept-1-en-4-yl 2-bromoacetate bromoacetate 2a
(12.4 mg, 0.038 mmol) in THF (0.5 mL) was added dropwise and the
mixture stirred for 30 min. After that time, the reaction was allowed to
slowly warm to room temperature before being quenched with air,
followed by a saturated aqueous solution of Rochelle’s salt (5 mL). The
aqueous layer was extracted with Et2O (3 × 5 mL) and the combined
5
This article is protected by copyright. All rights reserved.

10.1002/hlca.201900227
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concentrated in vacuo and purified by column chromatography eluting
with EtOAc/hexane (50:50), to give title compound as a colourless oil (9.32
mg, 0.038 mmol, quantitative). 1H NMR (500 MHz, CDCl3) δ 1.38 (s, 3 H,
CH3), 1.49 (s, 1 H, OH), 1.63 – 1.96 (m, 2 H, CH2CHCH2CH=CHAr), 2.44 – 2.69
(m, 4 H, CH2C(O), CH2CH=CHAr), 4.82 (dtd, J = 11.9, 6.0, 3.0 Hz, 1 H, CH),
6.23 (dt, J = 15.8, 7.3 Hz, 1 H, CH=CHAr), 6.50 (d, J = 15.8 Hz, 1 H, CH=CHAr),
7.21 – 7.25 (m, 1 H, ArCH), 7.31 (dd, J = 8.5, 6.8 Hz, 2 H, ArCH), 7.36 (d, J =
7.4 Hz, 2 H, ArCH) ppm. 13C NMR (126 MHz, CDCl3) δ 30.5 (CH3), 38.9
(CH2CH=CHAr), 41.1 (CH2CHCH2CH=CHAr), 44.3 (CH2C(O)), 68.6 (Cquat), 76.5
(CH), 124.0 (CH=CHAr), 126.3 (ArCH), 127.6 (ArCH), 128.7 (ArCH), 133.9
(CH=CHAr), 137.1 (ArC), 170.4 (C(O))ppm. IR νmax (neat/cm−1): 3431, 2925,
2854, 1741, 1449, 1379, 1256, 1130, 1029, 969, 934, 817, 747, 695. HRMS
calcd for C15H17O3 [M - H]-: 245.1183, found 245.1185.
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Supplementary Material
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/MS-number.
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M. Szostak, M. Spain, D. J. Procter, 'Electron Transfer Reduction of
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Acknowledgements
This work was supported by an Established Career Fellowship to D. J. P.
(EP/M005062/1), and CONACyT, México (PhD Scholarship to M.H.G.-C. No.
510789).
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Author Contribution Statement
M.H.G.-C. and D.J.P. conceived the study and co-wrote the manuscript.
M.H.G-C. designed and performed experiments.
M. Szostak, M. Spain, A. J. Eberhart, D. J. Procter, 'Highly Chemoselective
Reduction of Amides (Primary, Secondary, Tertiary) to Alcohols using
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10.1002/hlca.201900227
Helvetica Chimica Acta
HELVETICA
Entry for the Table of Contents
O
OH
OH OH
1. BrCH2C(O)Br
2. SmI2–H2O
R
Ar
O H
Ar
R
61-94% yield
single diastereoisomer
n Reformatsky cyclization n lactone reduction n cascade reaction
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Procter’s diastereoselective hydroxyethylation of beta-hydroxyketones, mediated by SmI2–H2O, for the construction of 1,3,5-triols.
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