Continuous Pd-Catalyzed Carbonylative Cyclization Using Iron Pentacarbonyl as a CO Source

Article abstract of DOI:10.1021/acs.joc.9b02453

This work discloses a continuous flow carbonylation reaction using iron pentacarbonyl as source of CO. The described transformation using this surrogate was designed for use in commonly accessible flow equipment. Optimized conditions were applied to a sca

Full text of DOI:10.1021/acs.joc.9b02453

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Featured Article
Continuous Pd-Catalyzed Carbonylative Cyclization
Using Iron Pentacarbonyl as a CO Source
Pavol Lopatka, Martin Markovic, Peter Koos, Steven V Ley, and Tibor Gracza
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02453 • Publication Date (Web): 24 Oct 2019
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Page 1 of 15
The Journal of Organic Chemistry
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Continuous Pd-Catalyzed Carbonylative Cyclization Using Iron
Pentacarbonyl as a CO Source
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Pavol Lopatka,† Martin Markovič,† Peter Koóš,†§* Steven V. Ley‡ and Tibor Gracza†
†Department of Organic Chemistry, Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of
Technology, Radlinského 9, SK-812 37 Bratislava, Slovakia
‡Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
§Georganics Ltd., Koreničova 1, SK-811 03 Bratislava, Slovakia
Email: peter.koos@stuba.sk
ABSTRACT: This work discloses a continuous flow carbonylation reaction using iron pentacarbonyl as source of CO. The described
transformation using this surrogate was designed for use in commonly accessible flow equipment. Optimized conditions were applied
to a scalable synthesis of the natural compound isolated from perianal glandular pheromone secretion of the African civet cat. In
addition, a flow Pd-catalyzed carbonylation of aryl halides was successfully reported.
PG
INTRODUCTION
O
R
X
H
OH
Pd(II)
-catalyst
n
O
CO
additives
solvent
(g)
Domino reaction processes in organic chemistry have become
popular strategies in synthesis laboratories. The growing
interest in the preparation of structurally complex and
biologically active compounds has led to an expanding effort in
the development and use of these approaches.1 Since its
discovery, the domino palladium catalyzed carbonylative
process cyclization has been proven as a robust and
stereoselective transformation for the synthesis of various
bicyclic lactones.2 Moreover, its chemical tolerance to many
functional groups has been demonstrated in various complex
natural product syntheses (Scheme 1).3 Despite the benefits of
this domino transformation, there are certain drawbacks that
inhibit its common application. One of the main objections
being the use of toxic carbon monoxide gas, which is not
detectable by human senses. While many modifications of the
reaction conditions for this cyclization have appeared over the
last years,4 new approaches are always beneficial, especially
one using surrogates for CO gas. For comparison, several
methods have been developed to carry out normal carbonylation
reactions of aryl halides5 without the direct use of gaseous CO.6
For example, using metal carbonyls7 also or several other CO
surrogates8. Some of these methods have been also transferred
to flow reactors.
X
n
R
X
X
= O, PG = H
= N, PG = Boc, Z
PG
OH
H
O
AcO
Me
O
H
O
O
Me
N
O
H
O
HO
O
HO
O
Me
H
Erythroskyrine
Protulactone A
H
O
O
Me
O
O
O
O
H
HO
H
Pyrenolide D
Plakortone B
O
Me
O
TPSO
O
Me
OH
OH
Me
O
O
Me
H
H
H
O
H
H
H
O
H
O
HO
O
Me
O
O
H
O
Me
Me
O
O
O
O
H
H
Me Me
O
FGH-ring system of
micrandilactone A
Schindilactone A
Pallambins C and D
Indeed continuous-flow methodology has become an important
concept of contemporary chemistry for a more sustainable
reaction processing. It also facilitates the development of
synthetic routes requiring the safe handling of toxic agents and
minimizing excess waste.9 Recent attention has focused on
carbonylation reactions of aryl/alkene halides utilizing the
benefits arising from the use of flow techniques. To date,
several types of the continuous flow for Pd-catalyzed
carbonylation have been reported (Figure 1).
Scheme 1. Pd(II)-Catalyzed Carbonylative Cyclization
Generally, there are two main methods for the introduction of
carbon monoxide into the reaction stream depending on which
type of flow equipment is used. In 2011, we have developed the
flow-approach for carbonylation of aryl and alkenyl iodides
employing a tube-in-tube reactor with porous gas-permeable
Teflon AF-2400 membrane (Figure 1, I.a).10 More commonly
used methods for precise feeding of CO into a reaction stream
employs an in-line mass flow controller (Figure 1, I.b).11
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previous work:
PdCl2(CH3CN)2 (0.1 equiv)
Fe(CO)5 (0.25 equiv)
HO
OH
O
O
- 67% yield
- heterogenous
mixture
I. CO (g) supplied from pressurized cylinder
a) Tube-in-tube reactor
II. CO generated in/ex situ
1
2
HO
a) CO generated ex situ
Cu(OAc)2 (4 equiv)
LiCl (4 equiv)
AcOH, 60 °C
15 min
O
OH
Reactants
CO
2
1
waste
3
air vent
CO
(g)
CO surrogate
4
5
6
7
8
9
reactor
rxn
stream
rxn
stream
Usually, this batch transformation of unsaturated triol 1 under
optimized reaction conditions employs 0.25 equiv of liquid
Fe(CO)5 which corresponds to 1.25 equiv of CO. However, the
reaction cycle necessitates the use of 4 equiv of Cu(OAc)2 and
4 equiv of LiCl as a reoxidation system for PdCl2(CH3CN)2
catalyst. Nevertheless, the reaction mixture results in a
heterogenous mixture in acetic acid. Full conversion of
substrate within 15 minutes is indicated by a color change of the
reaction mixture from green to pale brown.15d Direct use of these
conditions to flow system was not possible due to the
insolubility of reagents. Adjustment of the reaction components
was, however, necessary. We began the optimization of flow
reaction with Pd-catalyzed oxycarbonylation of pent-4-en-
1,2,3-triol 1. Triol 1 was selected as a model substrate for the
initial study due to its moderate reactivity compared to other
previously used unsaturated alcohols. Firstly, the reoxidation
system had to be altered to form a soluble complex in acetic
acid. Thus, changing the ratio of Cu(II) and Li(I) salts from 1:1
to 1:2 resulted in the formation of 0.25 M green and
homogenous solution at room temperature in acetic acid. We
could now focus on further optimization of flow reaction
conditions (Table 1).16
reactor
b) Mass flow controller
b) Direct use of CO surrogate
rxn
stream
rxn
reactor
stream
reactor
CO
MFC
(g)
CO
surrogate
this work:
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Direct use of Fe(CO)5 as a CO surrogate
Carbonylation of arylhalides
OH
CO from Fe(CO)5
HX
R
Pd(0), additives
NuH
O
X
X
Ar
Pd(II), additives
Ar
Nu
reactor
R
Flow
O
transformation
O
Fe(CO)5
only syn
Figure 1. Carbonylations in Microflow Systems
In both cases, the carbon monoxide gas is supplied from a
pressurized cylinder. In addition, there are a few continuous-
flow transformations utilizing CO surrogates. Hydrolysis of
oxalyl chloride using an aqueous NaOH solution leads to in situ
generation of carbon monoxide, which can then be passed
through tube-in-tube reactor to enrich a reaction stream.12
Similar specialized reactors equipped with a CO gas permeable
PTFE inner tube have also been successfully tested in Pd-
catalyzed carbonylation using formic acid as an alternative CO
source (Figure 1, II.a).13 Alcázar, De Borggraeve et al.14 also
described continuous-flow transformation using 2,4,6-
trichlorophenyl formate as a CO surrogate method (Figure 1,
II.b). The limitation of this CO surrogate is the formation of the
corresponding trichlorophenol esters, which requires an
additional processing step for modification.
Table 1. Optimization of Flow Reaction Conditions
1
and Fe(CO)5 (0.25 equiv)
in AcOH
injection
coil
AcOH
A
BPR
Reactor
coil
Filtration
Mixer
10 psi
100 psi
BPR
HPLC
Pumps
T-piece
Magnetic
Stirrer
Omnifit
column
RESULTS AND DISCUSSION
X mL
60 °C
B
BPR
optional
optional
In the course of a program directed towards CO gas-free
carbonylation,15 we have developed a new protocol for Pd-
catalyzed carbonylation reactions based on the use of iron
pentacarbonyl.15c-d The use of this CO source accelerates the
carbonylative cyclization compared to the reaction using
gaseous CO. Moreover, presented reaction conditions facilitate
exclusively the formation of desired products, while
competitive bicyclization of substrate without CO insertion can
occur in the reaction using gaseous CO.15e However, this
transformation has its limitations in upscaling. The instant
release of gaseous CO after the addition of Fe(CO)5 to reaction
mixture causes over-pressure in the reaction flask. In situ
generation of carbonyl species from Fe(CO)5 directly in the
reaction mixture offers excellent opportunities for carrying out
this reaction in a continuous mode. Here we report a flow
update of homogenous Pd-catalyzed carbonylation reaction
using iron pentacarbonyl as a CO surrogate.
10 psi
HO
AcOH
O
O
PdCl2(CH3CN)2 (0.1 equiv)
CuCl2 and LiOAc
in AcOH
O
crude product
2
reactor
(mL)
rxn time filter.
(min)
reox.
scale
/Mb)
flow rate
A/B
(mL/min)
mixer / yield
entry systema (mmol
(%)
(equiv)
1c
2
4
3
0.3/0.4 0.08/0.55
0.4/0.6 0.08/0.55
0.5/0.7 0.08/0.55
0.4/0.6 0.08/0.55
6/10
6/10
- / -
- / -
-
33
55
32
47
56
58
56
59
63
3
2.5
3
6/10
- / -
4d
6/10
- / -
5e,f
6e,f
7e,f
8g
3
1.8/0.6
0.1/0.7
8/10
+ / -
+ / -
+ / -
+ / +
+ / +
+ / +
3
1.8/0.6 0.07/0.47
2.2/0.6 0.11/0.75
8/15
3
26/30
26/15
26/15
26/15
3
2.2/0.6
1.9/0.5
1.9/0.5
0.22/1.5
0.22/1.5
0.22/1.5
Firstly, we investigated the conditions used for common batch
Pd-catalyzed cyclocarbonylation of (amino)alkenols. (Scheme
2).
9g
3.5
10g,h
3.5
aX equiv of reoxidation system corresponds to X equiv of CuCl2
and 2X equiv of LiOAc (0.25 M solution of CuCl2 in AcOH).
bConcentration of substrate in AcOH. cProblems with the isolation
of product due to the large amount of salts. dReaction performed at
40 oC. eFinal BPR was excluded. fSegmented flow was observed. g
Scheme 2. Batch Pd(II)-Catalyzed Cyclocarbonylation of
pent-4-en-1,2,3-triol 1
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The Journal of Organic Chemistry
h
O
OH OH
BPR (15 psi) at the end of flow system was used. 0.3 equiv of
Fe(CO)5 was used.
R
O
6719
1
2
3
4
5
6
7
8
8
39
54
R
O
15
()- , R=C6H13
16
()- , R=C6H13
For these experiments a two reaction stream reactor set-up was
devised. The reagents were loaded into the injection coils and
pumped through a T-piece directly to 1/8-inch HPLC-tube
reactor using Knauer Azura HPLC pumps. In some cases,
mixer17 and filtration units were incorporated into the flow
system. Optimization reactions were conducted by altering the
temperature, the size of the reactor to adjust reaction times and
the amount of reoxidant/Fe(CO)5. The results show that the best
conditions for flow reaction were using 3.5 equiv of CuCl2, 7.0
equiv of LiOAc, 0.3 equiv of Fe(CO)5 and 0.1 equiv of Pd(II)
catalyst (Table 1, entry 10) (0.3 equiv of Fe(CO)5 corresponds
to 1.5 theoretical amount of CO).
O
OH OH
R
O
9
7520
R
O
17
()- , R=C4H9
()-18, R=C4H9
O
OH OH
Ph
O
46 (exo)
15 (endo)
10
N.A.
Ph
O
()-
19
()-
OH OH
20
HO
O
9
O
11
12
61
88
N.A.
8020
OH
O
10
11
12
13
14
15
16
17
18
19
20
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22
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60
21
D-xylo/D-lyxo-
22
D-ido/D-galacto-
(40/60)
(60/40)
O
OH
O
OH
23
()-
24
()-
The optimal flow system involved HPLC column with frit as a
filtration unit to avoid blocking of final back-pressure regulator
(BPR) with solid18 and an in-line mixer for better agitation of
two input streams. The reaction time was 15 min at 1.72
mL/min combined flow (26 mL reactor) and the product 1 was
isolated after MPLC purification in 63% yield similarly to batch
experiment.
With this optimized flow setup, we examined the Pd-catalyzed
carbonylation of different alkenols and aminoalkenols (Table
2). Unsaturated alcohols as substrates were available from our
and prepared by identical preparative
procedures (see Experimental section).
previous study15d,
19-21
Table 2. Continuous Flow Pd(II)-Catalyzed Carbonylation
of Alkenols and Aminoalkenols using Fe(CO)5
By applying the optimized conditions, non-complex lactones 2,
4, 6, 8, 10 and 20 were isolated after the MPLC purification in
similar yields compared to batch experiments (Table 2, entries
1-5 and 10). We also prepared the Hagen´s gland lactones 12
and 14 in 62 and 77% yield, respectively (Table 2, entries 6 and
7).19,20 Substrate 21 was transformed using the flow chemistry
system into lactone 22 that had been previously used in the
formal synthesis of pyrenolide D (61% yield, Table 2, entry
11).3a To prove the versatility and effectiveness of this flow
transformation, longer run experiments were investigated using
substrates 7 and 23. The flow system was adjusted for direct
pumping of the reagent solutions via Azura HPLC pumps. Also,
substrates and Fe(CO)5 were pumped separately to the system.
A higher amount of LiOAc (10.5 equiv) in these experiments
was used to prevent precipitation of the reoxidation salt in the
stock solution. Following 193 min long experiment using
substrate 7 provided product 8 (2.66 g) in 83% yield.22
Similarly, a large scale synthesis of the natural compound
isolated from perianal glandular pheromone secretion of the
African civet cat. (1.52 g) using this system was accomplished.
The product (±)-syn-24 was isolated after 172 min long run in
53% yield (Figure 2).
Substrate
(1.9 mmol)
Fe(CO)5 (0.3 equiv)
AcOH
0.22 mL/min
3.9 mL
BPR
Reactor
coil
10 psi
Mixer
Filtration
Omnifit
column
Magnetic
Stirrer
26 mL
60 °C
15 psi
BPR
10 psi
AcOH
26.8 mL
1.5 mL/min
Crude
PdCl2(CH3CN)2 (0.1 equiv)
LiOAc (7 equiv)
product
CuCl2 (3.5 equiv)
yield (%)
entry
substrate
product
flow
batchlit.
6715d
HO
OH
O
HO
1
2
O
O
63
O
OH
1
2
HO
OH
65 (4a, R=Boc)
50 (4b, R=Cbz)
62 (4c, R=Ts)
7415d
2715d
6415d
O
RHN
N
R
OH
OH
PdCl2(CH3CN)2 (0.1 equiv)
LiOAc (10.5 equiv)
CuCl2 (3.5 equiv, 0.25 M)
3
4
OH
O
O
3
4
5
82
83
8015d
7215d
in AcOH
HO
HO
O
1.5
23
()-
5
6
()-
()-
mL/min
(1 equiv, 0.98 M)
in AcOH
O
OH
O
BPR
10 psi
Mixer
O
Reactor
coil
7
()-
8
()-
10 psi
0.11
mL/min
Filtration
O
OH
71 (10a, R=Boc)
77 (10b, R=Cbz)
81 (10c, R=Ts)
9515d
884b
904b
O
RHN
N
R
Magnetic
Stirrer
Omnifit
column
9
()-
10
()-
0.11
mL/min
26 mL
60 °C
15 psi
O
OH OH
BPR
R
O
6
7
62
77
6719
7520
R
10 psi
O
Fe(CO)5
O
11
()- , R=C6H13
()-12, R=C6H13
COOH
(0.3 equiv, 0.29 M)
in AcOH
O
OH OH
R
O
24
()-syn- : 1.52 g (53%)
()-anti- : 0.79 g (30%)
R
O
24
13
()- , R=C4H9
14
()- , R=C4H9
Figure 2. Large scale flow synthesis of natural compound (±)-syn-
24
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The above results suggest the protocol may be applied to Pd-
technique (4000-400 cm-1). High resolution mass spectra
1
2
3
4
5
6
7
8
catalyzed carbonylative couplings of aryl halides. The
conditions for Pd-catalyzed aminocarbonylation of p-
iodoanisole are based on our previously reported study23 and
applied in flow carbonylation using Fe(CO)5 as a CO surrogate
(Figure 3). This transformation after few optimization
experiments readily provided expected product in 64% yield.
(HRMS) were recorded on an OrbitrapVelos mass spectrometer
(Thermo Scientific, Waltham, MA, USA; Bremen, Germany)
with a heated electrospray ionization (HESI) source. The mass
spectrometer was operated with full scan (50–2000 amu) in
positive or negative FT mode (at a resolution of 100,000). The
sample was dissolved in methanol and infused via syringe pump
at a rate of 5 mL/min. The heated capillary was maintained at
275 °C with a source heater temperature of 50 °C and the sheath,
auxiliary and sweep gases were at 10, 5 and 0 units,
respectively. Source voltage was set to 3.5 kV.
1,4-dioxane
0.25
mL/min
p-Iodoanisole (1 mmol)
9
Benzylamine (1.3 equiv)
3 eq. of CO
generated from
Fe(CO)5
Et3N (1.3 equiv)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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60
2 mL
General procedure for flow carbonylation reactions
DMF
10 psi
0.5
mL/min
BPR
4 mL
2 mL
General method 1: Injection coil A (3.9 mL, PTFE tubing, 1/8”
o.d., 1/16” i.d.) was loaded with a solution of substrate (1.90
mmol, 1 equiv) and Fe(CO)5 (75 μL, 0.57 mmol, 0.3 equiv) in
glacial AcOH. Injection coil B (26.8 mL, PTFE tubing, 1/8”
o.d., 1/16” i.d.) was loaded with a solution of CuCl2 (0.89 g,
6.64 mmol, 3.5 equiv), LiOAc (0.88 g, 13.27 mmol, 7 equiv)
and PdCl2(CH3CN)2 (0.05 g, 0.19 mmol, 0.1 equiv) in glacial
AcOH. These reaction mixtures were pumped using HPLC
pumps (Knauer Azura 4.1S with 10 mL pump head) at 0.22
mL/min and 1.5 mL/min flowrate and mixed at a T-piece.
Mixing of both streams was performed by installed magnetic
mixer. Subsequently, combined reaction solutions were
directed to a reactor (25.7 mL, PTFE tubing, 1/8” o.d., 1/16”
i.d) heated in 60 °C water bath. The installation of backpressure
regulators (2 × 10 psi) in front of the T-piece was used to ensure
unidirectional flow through the heating coil (reactor). On
exiting the heating coils, the product flow stream was directed
through a glass Omnifit column (15 mm i.d. × 100 mm length)
with filter to remove any solids. A backpressure regulator (15
psi) was placed immediately after the glass Omnifit column to
prevent out-gassing of the dissolved CO from the solvent
mixture. The product stream was then collected into a round
bottom flask. The reaction mixture was then concentrated in
vacuo and the residue was purified by MPLC.
10 psi
Reactor
coil
O
250 psi
BPR
1,4-dioxane
N
Ph
0.25
mL/min
BPR
H
10 psi
MeO
28 mL
110 °C
64%
Pd(OAc)2 (0.05 equiv)
Xantphos (0.1 equiv)
Figure 3. Preliminary flow chemistry setup for
aminocarbonylation reactions of aryl iodides.
CONCLUSION
In summary, we have demonstrated the compatibility of iron
pentacarbonyl as a CO surrogate for carbonylation reactions in
a
flow reactor. We have shown the Pd-catalyzed
cyclocarbonylation reactions of unsaturated alcohols and
aminoalcohols using Fe(CO)5 in a continuous microflow
system. The robust process proceeds in readily constructed
tube-reactor providing lactones in good yields comparable with
batch experiments. The ability to scale-up these reactions in
flow in a contained environment, is an advantage in providing
access to these useful lactonic building block precursors.
EXPERIMENTAL SECTION
General information
General method 2: A solution of substrate (0.98 M in AcOH,
stream A) and the solution of Fe(CO)5 (0.29 M in AcOH, stream
B) were pumped using HPLC pumps (Knauer Azura 4.1S with
10 mL pump head) at 0.11 mL/min flowrate and mixed together
in T-piece. The combined streams were united with a third
solvent stream C (solution of CuCl2 (0.25 M), LiOAc (0.74 M)
and PdCl2(CH3CN)2 (0.007 M) in AcOH, 1.5 mL/min, pumped
by HPLC pump Knauer Azura 4.1S with 10 mL pump head) via
a second T-piece. Mixing of streams was performed by installed
magnetic mixer. Subsequently, the combined reaction solutions
were directed to a reactor (25.7 mL, PTFE tubing, 1/8” o.d.,
1/16” i.d.) heated in 60 °C water bath. The installation of
backpressure regulators (3 × 10 psi) in front of the T-piece was
used to ensure unidirectional flow through the heating coils
(reactor). On exiting the heating coil (reactor), the product flow
stream was directed through a glass Omnifit column (15 mm
i.d. × 100 mm length) with filter to remove any solids. A
backpressure regulator (15 psi) was placed immediately after
the glass Omnifit column to prevent out-gassing of the
dissolved CO from the solvent mixture. The product stream was
then collected into a round bottom flask. The reaction mixture
was then concentrated in vacuo and the crude product was
purified by MPLC.
Commercial materials which were obtained from Sigma-
Aldrich, Acros Organics, Alfa Aesar or Fisher Scientific were
used without further purification. Reactions were monitored
using TLC on silica gel. Compound purification was affected
by flash chromatography. All solvents were distilled before use.
Hexanes refer to the fraction boiling at 60-65 oC. Flash column
liquid chromatography (FLC) was performed on silica gel
Kieselgel 60 (15-40 m, 230-400 mesh) and analytical thin-
layer chromatography (TLC) was performed on aluminium
plates pre-coated with either 0.2 mm (DC-Alufolien, Merck) or
0.25 mm silica gel 60 F254 (ALUGRAM® SIL G/UV254,
Macherey-Nagel). Analyzed compounds were visualized by
UV fluorescence and by dipping the plates in an aqueous H2SO4
solution of cerium sulphate/ammonium molybdate followed by
charring with a heat gun. Melting points were obtained using a
1
Boecius apparatus and are uncorrected. H and 13C NMR
spectra were recorded on either 300 (75) MHz MercuryPlus or
600 (151) MHz Unity Inova spectrometers from Varian.
Chemical shifts () are quoted in ppm and are referenced to the
tetramethylsilane (TMS), CDCl3 or DMSO-d6 as internal
standard. FTIR spectra were obtained on a Nicolet 5700
spectrometer (Thermo Electron) equipped with a Smart Orbit
(diamond crystal ATR) accessory, using the reflectance
ACS Paragon Plus Environment

Page 5 of 15
The Journal of Organic Chemistry
General method 3: A solution of substrate (0.98 M in AcOH, prepared according to general method 1 from aminodiol 3b (477
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stream A) and the solution of Fe(CO)5 (0.25 M in AcOH, stream
B) were pumped using HPLC pumps (Knauer Azura 4.1S with
10 mL pump head) at 0.32 mL/min flowrate and mixed together
in T-piece. The combined streams were united with a third
stream C (solution of CuCl2 (0.25 M), LiOAc (0.51M) and
PdCl2(CH3CN)2 (0.007 M) in AcOH, 4.36 mL/min, pumped by
HPLC pump Knauer Azura 4.1S with 10 mL pump head) via a
second T-piece. Mixing of streams was performed by installed
magnetic mixer. Subsequently, the combined reaction solutions
were directed to a reactor (15 mL, PTFE tubing, 1/8” o.d., 1/16”
i.d.) heated in 80 °C water sonication bath. The installation of
backpressure regulators (3 × 45 psi) in front of the T-piece was
used to ensure unidirectional flow through the heating coils
(reactor). On exiting the heating coil (reactor), the product flow
stream was directed through a glass Omnifit column (15 mm
i.d. × 100 mm length) with filter to remove any solids. A
backpressure regulator (45 psi) was placed immediately after
the glass Omnifit column to prevent out-gassing of the
dissolved CO from the solvent mixture. The product stream was
then collected into a round bottom flask. The reaction mixture
was then concentrated in vacuo and the crude product was
purified by MPLC.
mg, 1.90 mmol). The purification of crude product by MPLC
(hexanes/EtOAc: 100/0 to 40/60 then isocratic hexanes/EtOAc:
40/60) provided desired lactone 4b (263 mg, 50%, orange
solid). All physical and spectral data were in good agreement
with the literature.26 Rf = 0.20 (hexanes/EtOAc, 2:3); mp 107.1-
107.6 °C, lit.27 mp 108-109 °C; [α]20 -66.8 (c 1.69, CHCl3); IR
(ATR) νmax 3446, 1776, 1690, 1417, 1096 cm-1; 1H NMR (300
MHz, CDCl3, mixture of rotamers) δH 7.40-7.30 (m, 5H, HAr),
5.18-5.07 (m, 2H, PhCH2), 4.92 (dd, J = 5.7, 4.4 Hz, 1H, H-1),
4.56-4.46 (m, 1H, H-5), 4.40-4.34 (m, 1H, H-8), 3.91-3.85 (m,
1H, H-7a), 3.44-3.30 (m, 1H, H-7b), 3.08 (br s, 1H, OH), 2.93-
2.67 (m, 2H, H-4) ppm; 13C{1H} NMR (75 MHz, CDCl3,
mixture of rotamers) δC 175.6, 175.3, 154.6, 154.1, 136.1,
128.8, 128.7, 128.5, 128.4, 128.2, 82.4, 81.8, 70.6, 69.9, 67.8,
67.6, 56.4, 55.9, 50.5, 50.0, 36.7, 36.0 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for:C14H16NO5: 278.1029, Found: 278.1023,
[M+Na]+ Calcd. for C14H15NNaO5: 300.0848, Found: 300.0844.
(1S,5R,8R)-8-Hydroxy-6-tosyl-2-oxa-6-
azabicyclo[3.3.0]octan-3-one (4c). The title compound was
prepared according to general method 1 from aminodiol 3c (515
mg, 1.90 mmol). The purification of crude product by MPLC
(hexanes/EtOAc: 100/0 to 60/40 then isocratic hexanes/EtOAc:
60/40) provided desired lactone 4c (350 mg, 62%, white solid).
All physical and spectral data were in good agreement with the
literature.15d Rf = 0.20 (hexanes/EtOAc, 2:3); mp 141.9-142.4,
lit.15d mp 140-141 °C; IR (ATR) νmax 3419, 1757, 1341, 1160,
537 cm-1; 1H NMR (300 MHz, CDCl3) δH 7.71 (d, J = 8.1 Hz,
2H, HAr), 7.36 (d, J = 8.1 Hz, 2H, HAr), 4.80 (dd, J = 6.5, 4.5
Hz, 1H, H-1), 4.40 (td, J = 6.5, 4.2 Hz, 1H, H-5), 4.08 (td, J =
6.3, 4.5 Hz, 1H, H-8), 3.58 (dd, J = 11.3, 6.3 Hz, 1H, H-7a), 3.36
(dd, J = 11.3, 6.3 Hz, 1H, H-7b), 2.92-2.87 (m, 2H, H-4), 2.45
(s, 3H, CH3) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 174.6,
144.7, 134.5, 130.3, 127.4, 81.7, 70.4, 57.6, 52.1, 36.9, 21.7
ppm; HRMS (ESI): m/z [M+H]+ Calcd. for:C13H16NO5S:
298.0749, Found: 298.0745, [M+Na]+ Calcd. for
C13H15NNaO5S: 320.0569, Found: 320.0564.
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(1R,5R,8R)-8-Hydroxy-2,6-dioxabicyclo[3.3.0]octan-3-one
(2). The title compound was prepared according to general
method 1 from triol 1 (224 mg, 1.90 mmol). The purification of
crude product by MPLC (hexanes/EtOAc: 100/0 to 40/60 then
isocratic hexanes/EtOAc: 40/60) provided desired lactone 2
(172 mg, 63%, white solid). All physical and spectral data were
in good agreement with the literature.24 Rf
= 0.20
(hexanes/EtOAc, 2:3); mp 76.5-77.0 °C, lit. 25 mp 77.0-79.0 °C;
[α]20 +87.8 (c 1.10, CHCl3); IR (ATR) νmax 3363, 1763, 1144,
1041, 588 cm-1; 1H NMR (300 MHz, CD3OD) δH 4.98 (t, J = 4.9
Hz, 1H, H-1), 4.76 (ddd, J = 6.7, 4.9, 1.5 Hz, 1H, H-5), 4.42
(ddd, J = 6.9, 6.0, 4.9 Hz, 1H, H-8), 3.93 (dd, J = 9.0, 6.0 Hz,
1H, H-7a), 3.67 (dd, J = 9.0, 6.9 Hz, 1H, H-7b), 2.92 (dd, J =
18.6, 6.7 Hz, 1H, H-4a), 2.58 (dd, J = 18.6, 1.5 Hz, 1H, H-4b)
ppm; 13C{1H} NMR (75 MHz, CD3OD) δc 178.3, 84.7, 78.4,
72.6, 71.9, 37.4 ppm; HRMS (ESI): m/z [M+H]+ Calcd.
for:C6H9O4: 145.0501, Found: 145.0496, [M+Na]+ Calcd. for
C6H8NaO4: 167.0320, Found: 167.0315.
rac-7,7-Dimethyl-2,6-dioxabicyclo[3.3.0]octane-3-one ((±)-
8). The title compound was prepared according to general
method 1 from diol (±)-7 (247 mg, 1.90 mmol). The purification
of crude product by MPLC (hexanes/EtOAc: 100/0 to 60/40
then isocratic hexanes/EtOAc: 60/40) provided desired lactone
(±)-8 (245 mg, 83%, colorless oil). According to general
method 2 in 193 min. long run 2.656 g (83%) of (±)-8 was
obtained. According to general method 3 in 180 min. long run
7.014 g (80%) of (±)-8 was obtained.All physical and spectral
data were in good agreement with the literature.15d Rf = 0.20
(hexanes/EtOAc, 3:2); IR (ATR) νmax 2973, 1170, 1154, 1065,
(1S,5R,8R)-8-Hydroxy-6-tert-butyloxycarbonyl-2-oxa-6-
azabicyclo[3.3.0]octan-3-one (4a). The title compound was
prepared according to general method 1 from aminodiol 3a (412
mg, 1.90 mmol). The purification of crude product by MPLC
(hexanes/EtOAc: 100/0 to 50/50 then isocratic hexanes/EtOAc:
50/50) provided desired lactone 4a (300 mg, 65%, white solid).
All physical and spectral data were in good agreement with the
literature.15d Rf = 0.20 (hexanes/EtOAc, 1:1); mp 128.1-128.4
1
904 cm-1; H NMR (300 MHz, CDCl3) δH 5.05 (ddd, J = 5.9,
4.7, 2.1 Hz, 1H, H-5), 4.73 (td, J = 4.7, 1.7 Hz, 1H, H-1), 2.75
(dd, J = 18.3, 4.7 Hz, 1H, H-8a), 2.67 (dd, J = 18.3, 1.7 Hz, 1H,
H-8b), 2.20 (dd, J = 14.5, 2.1 Hz, 1H, H-4a), 2.13 (dd, J = 14.5,
5.9 Hz, 1H, H-4b), 1.34 (s, 3H, CH3), 1.26 (s, 3H, CH3) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 175.9, 86.1, 83.2, 77.5,
45.0, 37.3, 29.3, 28.7 ppm; HRMS (ESI): m/z [M+H]+ Calcd.
for:C8H13O3: 157.08647, Found: 157.08598, [M+Na]+ Calcd.
for C8H12NaO3: 179.06841, Found: 179.06795.
rac-2,6-Dioxabicyclo[3.3.0]octane-3-one ((±)-6). The title
compound was prepared according to general method 1 from
diol (±)5 (194 mg, 1.90 mmol). The purification of crude
product by MPLC (hexanes/EtOAc: 100/0 to 50/50 then
isocratic hexanes/EtOAc: 50/50) provided desired lactone (±)-
6 (199 mg, 82%, colorless oil). All physical and spectral data
°C; [α]20 -80.7 (c 0.48, CHCl3); IR (ATR) νmax 3367, 2980,
1774, 1670, 1403 cm-1; 1H NMR (300 MHz, CDCl3, mixture of
rotamers) δH 4.96-4.92 (m, 1H, H-1), 4.51-4.38 (m, 2H, H-5 and
H-8), 3.90-3.80 (m, 1H, H-7a), 3.37-3.20 (m, 1H, H-7b), 2.84-
2.70 (m, 2H, H-4), 2.41 (br s, 1H, OH), 1.46 (s, 9H, C(CH3)3)
ppm; 13C{1H} NMR (75 MHz, CDCl3, mixture of rotamers) δC
175.7, 175.4, 153.9, 153.3, 82.5, 81.9, 80.9, 70.6, 69.9, 55.9,
50.1, 49.9, 36.7, 36.1, 28.8 ppm; HRMS (ESI): m/z [M+H]+
Calcd. for:C11H18NO5: 244.1185, Found: 244.1179, [M+Na]+
Calcd. for C11H17NNaO5: 266.1004, Found: 266.0999, [M+K]+
Calcd. for C11H17KNO5: 282.0744, Found: 282.0738.
(1S,5R,8R)-6-Benzyloxycarbonyl-8-hydroxy-2-oxa-6-
azabicyclo[3.3.0]octan-3-one (4b). The title compound was
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 15
were in good agreement with the literature.28 Rf = 0.20
1H, H-7a), 3.53-3.42 (m, 1H, H-7b), 2.96 (dd, J = 18.7, 1.3 Hz,
1
2
3
4
5
6
7
8
(hexanes/EtOAc, 1:1); IR (ATR) νmax 1766, 1181, 1066, 1026,
828 cm-1; 1H NMR (300 MHz, CDCl3) δH 5.15-5.07 (m, 1H, H-
1), 4.69 (ddd, J = 5.8, 4.5, 0.7 Hz, 1H, H-5), 4.01-3.88 (m, 2H,
H-7), 2.77 (dd, J = 18.7, 5.8 Hz, 1H, H-4a), 2.66 (dd, J = 18.7,
0.7 Hz, 1H, H-4b), 2.37-2.26 (m, 1H, H-8a), 2.27-2.07 (m, 1H,
H-8b) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 175.9, 84.4,
78.2, 67.1, 36.4, 33.2 ppm; HRMS (ESI): m/z [M+H]+ Calcd.
for:C6H9O3: 129.0552, Found: 129.0546, [M+Na]+ Calcd. for
C6H8NaO3: 151.0371, Found: 151.0366.
1H, H-4a), 2.84 (dd, J = 18.7, 6.6 Hz, 1H, H-4b), 2.45 (s, 3H,
CH3), 2.25-2.13 (m, 1H, H-8a), 1.83-1.68 (m, 1H, H-8b) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 174.9, 144.4, 134.9, 130.0,
127.3, 83.5, 60.1, 47.0, 36.8, 31.3, 21.7 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for:C13H16NO4S: 282.0800, Found: 282.0795,
[M+Na]+ Calcd. for C13H15NNaO4S: 304.0620, Found:
304.0614, [M+K]+ Calcd. for C13H15KNO4S: 320.0359, Found:
320.0353.
D-ido/D-galacto-7-methyl-8-hydroxy-2,6-
9
rac-6-(tert-Butyloxycarbonyl)-2-oxa-6-
dioxabicyclo[3.3.0]octan-3-one (22). The title compounds were
prepared according to general method 1 from mixture of
(2R,3S,4S)-hex-5-ene-2,3,4-triol and (2R,3S,4R)-hex-5-ene-
2,3,4-triol (ratio 40:60) (251 mg, 1.90 mmol). The purification
of crude product by MPLC (hexanes/EtOAc: 100/0 to 40/60
then isocratic hexanes/EtOAc: 40/60) provided desired lactones
D-ido/D-galacto (22) as inseparable mixture (183 mg, 61%,
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azabicyclo[3.3.0]octan-3-one ((±)-10a). The title compound
was prepared according to general method 1 from amino
alcohol (±)-9a (382 mg, 1.90 mmol). The purification of crude
product by MPLC (hexanes/EtOAc: 100/0 to 60/40 then
isocratic hexanes/EtOAc: 60/40) provided desired lactone (±)-
10a (306 mg, 71%, white solid). All physical and spectral data
were in good agreement with the literature.29 Rf = 0.20
(hexanes/EtOAc, 3:2); mp 108.3-108.7, lit.29 mp 109-110 °C;
IR (ATR) νmax 1768, 1681, 1409, 1163, 770 cm-1; 1H NMR (300
MHz, CDCl3, mixture of rotamers) δH 5.05 (br s, 1H, H-1), 4.49-
4.39 (m, 1H, H-5), 3.82-3.65 (m, 1H, H-7a), 3.35 (td, J = 11.1,
6.1 Hz, 1H, H-7b), 2.90-2.67 (m, 2H, H-4), 2.29 (dd, J = 14.2,
6.1 Hz, 1H, H-8a), 2.09-1.96 (m, 1H, H-8b) 1.46 (s, 9H,
C(CH3)3) ppm; 13C{1H} NMR (75 MHz, CDCl3, mixture of
rotamers) δC 176.0, 175.6, 153.9, 153.3, 84.3, 83.3, 80.7, 58.0,
44.4, 44.1, 36.8, 36.0, 30.8, 30.3, 28.6. ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for:C11H18NO4: 228.1236, Found: 228.1230,
[M+Na]+ Calcd. for C11H17NNaO4: 250.1055, Found: 250.1050,
[M+K]+ Calcd. for C11H17KNO4: 266.0795, Found: 266.0789.
rac-6-Benzyloxycarbonyl-2-oxa-6-azabicyclo[3.3.0]octan-
3-one ((±)-10b)The title compound was prepared according to
general method 1 from amino alcohol (±)-9b (446 mg, 1.90
mmol). The purification of crude product by MPLC
(hexanes/EtOAc: 100/0 to 50/50 then isocratic hexanes/EtOAc:
50/50) provided desired lactone (±)-10b (381 mg, 77%, pale
yellow solid). All physical and spectral data were in good
agreement with the literature.30 Rf = 0.20 (hexanes/EtOAc, 1:1);
mp 99.0-99.5, lit.30 mp 100-101 °C; IR (ATR) νmax 1762, 1697,
1419, 1111, 734 cm-1; 1H NMR (300 MHz, CDCl3, mixture of
rotamers) δH 7.40-7.30 (m, 5H, HAr), 5.19-5.08 (m, 3H, H-1,
PhCH2), 4.54-4.45 (m, 1H, H-5), 3.91-3.76 (m, 1H, H-7a), 3.43
(td, J = 11.1, 6.2 Hz, 1H, H-7b), 2.94-2.69 (m, 2H, H-4), 2.32
(dd, J = 14.1, 6.2 Hz, 1H, H-8a), 2.11-1.98 (m, 1H, H-8b) ppm;
13C{1H} NMR (75 MHz, CDCl3, mixture of rotamers) δC 175.6,
175.2, 154.4, 154.0, 136.3, 128.8, 128.7, 128.5, 128.3, 128.3,
128.2, 84.1, 83.1, 67.6, 67.4, 58.5, 57.9, 44.7, 44.3, 36.7, 35.8,
30.8, 30.4. ppm; HRMS (ESI): m/z [M+H]+ Calcd.
for:C14H16NO4: 262.1079, Found: 262.1074, [M+Na]+ Calcd.
for C14H15NNaO4: 284.0899, Found: 284.0893, [M+K]+ Calcd.
for C14H15KNO4: 300.0638, Found: 300.0633.
1
ratio: 60:40 from H NMR, white solid). All physical and
spectral data of D-ido 22 were in good agreement with the
literature.32 Rf = 0.20 (hexanes/EtOAc, 2:3); mp 136.8-137.3,
lit.32 mp 138-140 °C; IR (ATR) νmax 3344, 1767, 1138, 1040,
822 cm-1; D-ido (22): 1H NMR (300 MHz, CDCl3) δH 4.98 (dd,
J = 10.6, 4.9 Hz, 1H, H-1), 4.95-4.89 (m, 1H, H-5), 4.25-4.22
(m, 1H, H-8), 4.14 (qd, J = 6.3, 2.8 Hz, 1H, H-7), 2.81-2.58 (m,
2H, H-4), 2.01 (s, 1H, OH), 1.30 (t, J = 6.3 Hz, 3H, CH3) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 175.8, 88.1, 76.3, 76.0,
1
75.5, 36.0, 13.1 ppm; D-galacto (22): H NMR (300 MHz,
CDCl3) δH 4.95-4.89 (m, 1H, H-1), 4.59 (td, J = 6.1, 3.1 Hz, 1H,
H-5), 4.28-4.25 (m, 1H, H-8), 3.95 (qd, J = 6.3, 4.2 Hz, 1H, H-
7), 2.81-2.58 (m, 2H, H-4), 2.01 (s, 1H, OH), 1.30 (t, J = 6.3
Hz, 3H, CH3) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 175.4,
83.5, 79.0, 75.8, 72.1, 36.2, 14.0 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for:C7H11O4: 159.0657, Found: 159.0653,
[M+Na]+ Calcd. for C7H10NaO4: 181.0477, Found: 181.0472.
rac-(1R,5R,7S)-7-Phenyl-2,6-dioxabicyclo[3.3.0]octane-3-
one
((±)-exo-20)
and
rac-(1R,5R,7R)-7-Phenyl-2,6-
dioxabicyclo[3.3.0]octane-3-one ((±)-endo-20). The title
compounds were prepared according to general method 1 from
diol (±)-19 (338 mg, 1.90 mmol). The purification of crude
product by MPLC (hexanes/EtOAc: 100/0 to 75/25 then
isocratic hexanes/EtOAc: 75/25) provided desired lactones (±)-
exo-20 (178 mg, 46%, orange oil) and (±)-endo-20 (58 mg,
15%, orange oil). All physical and spectral data of (±)-exo-20
were in good agreement with the literature.33 (±)-exo-20: Rf =
0.20 (hexanes/EtOAc, 7:3); IR (ATR) νmax 1774, 1171, 1059,
1
944, 754 cm-1; H NMR (300 MHz, CDCl3) δH 7.41-7.27 (m,
5H, HAr), 5.24 (t, J = 4.8 Hz, 1H, H-1), 5.13 (dd, J = 10.6, 4.8
Hz, 1H, H-7), 5.05 (ddd, J = 5.8, 4.8, 1.6 Hz, 1H, H-5), 2.91-
2.79 (m, 2H, H-4), 2.71 (dd, J = 14.2. 4.8 Hz, 1H, H-8a), 2.10-
1.98 (m, 1H, H-8b) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC
176.0, 140.0, 128.8, 128.2, 125.9, 85.0, 79.8, 78.4, 41.7, 36.8
ppm; HRMS (ESI): m/z [M+H]+ Calcd. for:C12H13O3: 205.0865,
Found: 205.0858, [M+Na]+ Calcd. for C12H12NaO3: 227.0684,
Found: 227.0678, [M+K]+ Calcd. for C12H12KO3: 243.0424,
Found: 243.0417; (±)-endo-20: Rf = 0.20 (hexanes/EtOAc, 7:3);
IR (ATR) νmax 1775, 1194, 1029, 754, 581 cm-1; 1H NMR (300
MHz, CDCl3) δH 7.41-7.27 (m, 5H, HAr), 5.14 (ddd, J = 7.0, 4.6,
2.4 Hz, 1H, H-1), 4.97 (dd, J = 8.3, 7.6 Hz, 1H, H-7), 4.69 (td,
J = 4.6, 1.6 Hz, 1H, H-5), 2.93-2.82 (m, 2H, H-4), 2.82-2.74 (m,
1H, H-8a), 2.26 (ddd, J = 14.5, 8.3, 2.4 Hz, 1H, H-8b) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 175.4, 140.1, 128.8, 128.3,
126.2, 84.7, 81.8, 79.0, 41.1, 36.3 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for:C12H13O3: 205.0865, Found: 205.0859,
rac-6-Tosyl-2-oxa-6-azabicyclo[3.3.0]octan-3-one
((±)-
10c). The title compound was prepared according to general
method 1 from amino alcohol (±)-9c (485 mg, 1.90 mmol). The
purification of crude product by MPLC (hexanes/EtOAc: 100/0
to 50/50 then isocratic hexanes/EtOAc: 50/50) provided desired
lactone (±)-10c (433 mg, 81%, white solid). All physical and
spectral data were in good agreement with the literature.31 Rf =
0.20 (hexanes/EtOAc, 1:1); mp 131.9-132.5, lit.31 mp 133-134
1
°C; IR (ATR) νmax 1773, 1335, 1156, 973, 573 cm-1; H NMR
(300 MHz, CDCl3) δH 7.75-7.68 (m, 2H, HAr), 7.35 (dd, J = 8.6,
0.7 Hz, 2H, HAr), 4.96 (td, J = 5.4, 1.4 Hz, 1H, H-1), 4.37 (ddd,
J = 6.6, 5.4, 1.3 Hz, 1H, H-5), 3.58 (ddd, J = 11.3, 8.6, 2.7 Hz,
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The Journal of Organic Chemistry
[M+Na]+ Calcd. for C12H12NaO3: 227.0684, Found: 227.0679,
to 75/25 then isocratic hexanes/EtOAc: 75/25) provided desired
[M+K]+ Calcd. for C12H12KO3: 243.0424, Found: 243.0419.
rac-(1R,5R,7R)-7-nHexyl-2,6-dioxabicyclo[3.3.0]octane-3-
one ((±)-12). The title compound was prepared according to
general method 1 from diol (±)-11 (354 mg, 1.90 mmol). The
purification of crude product by MPLC (hexanes/EtOAc: 100/0
to 80/20 then isocratic hexanes/EtOAc: 80/20) provided desired
lactone (±)-12 (250 mg, 62%, pale yellow oil). All physical and
spectral data were in good agreement with the literature.19 Rf=
0.20 (hexanes/EtOAc, 4:1); IR (ATR) νmax 2927, 1777, 1170,
1059, 831 cm-1; 1H NMR (300 MHz, CDCl3) δH 5.11 (t, J = 4.8
Hz, 1H, H-1), 4.84-4.78 (m, 1H, H-5), 4.12-4.01 (m, 1H, H-7),
2.76 (dd, J = 18.8, 6.3 Hz, 1H, H-4a), 2.64 (d, J = 18.8 Hz, 1H,
H-4b), 2.37 (ddd, J = 13.9, 4.8, 0.6 Hz, 1H, H-8a), 1.66 (ddd, J
= 13.9, 10.4, 5.0 Hz, 1H, H-8b), 1.60-1.38 (m, 2 H,
CH2(CH2)4CH3), 1.38-1.19 (m, 8 H, CH2(CH2)4CH3), 0.88 (t, J
= 7.0 Hz, 3H, CH3) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC
176.2, 85.1, 78.4, 77.5, 39.0, 36.8, 34.8, 31.9, 29.4, 26.1, 22.7,
14.2 ppm; HRMS (ESI): m/z [M+H]+ Calcd. for:C12H21O3:
213.1491, Found: 213.1485, [M+Na]+ Calcd. for C12H20NaO3:
235.1310, Found: 235.1305.
lactone (±)-18 (189 mg, 54%, pale yellow oil). All physical and
spectral data were in good agreement with the literature.19 Rf =
0.20 (hexanes/EtOAc, 4:1); IR (ATR) νmax 2932, 1774, 1152,
1067, 898 cm-1; 1H NMR (300 MHz, CDCl3) δH 5.01 (ddd, J =
6.9, 4.4, 2.2 Hz, 1H, H-1), 4.54-4.46 (m, 1H, H-5), 3.99-3.87
(m, 1H, H-7), 2.72 (d, J = 3.4 Hz, 2H, H-4), 2.48-2.36 (m, 1H,
H-8a), 1.87 (ddd, J = 14.3, 7.9, 2.2 Hz, 1H, H-8b), 1.73-1.45 (m,
2H, CH2(CH2)2CH3), 1.45-1.19 (m, 4H, CH2(CH2)2CH3), 0.89
(t, J = 7.0 Hz, 3H, CH3) ppm; 13C{1H} NMR (75 MHz, CDCl3)
δC 175.7, 84.8, 80.5, 78.4, 38.4, 36.5, 35.3, 28.3, 22.7, 14.1 ppm;
HRMS (ESI): m/z [M+H]+ Calcd. for:C10H17O3: 185.1178,
Found: 185.1172, [M+Na]+ Calcd. for C10H16NaO3: 207.0997,
Found: 207.0992.
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(6-Methyltetrahydro-2H-pyran-2-yl) acetic acid ((±)-24).
The title compounds were prepared according to general
method 1 from alcohol (±)-23 (217 mg, 1.90 mmol. After
evaporation of acetic acid the residue was dissolved in EtOAc
(50 mL) and solution of HCl was added (w = 0.12, 25 mL). The
organic phase was separated, and the aqueous phase was
extracted with EtOAc (9x50 mL). The combined organic phases
were dried over Na2SO4, filtered and concentrated in vacuo. The
purification of crude product by MPLC (hexanes/EtOAc: 100/0
to 50/50 then isocratic hexanes/EtOAc: 50/50) provided desired
acids (±)-syn-24 (198, 66%, white solid) and (±)-anti-24 (66,
22%, colourless oil). According to general method 2 in 172 min.
long run 1.52 g (53%) of (±)-syn-24 and 0.79 g (30%) of (±)-
anti-24 were obtained. All physical and spectral data were in
good agreement with the literature.34 (±)-syn-24: Rf = 0.20
(hexanes/EtOAc, 1:1); mp 56.3-56.7 °C, lit.35 mp 54-55 °C; IR
(ATR) νmax 2941, 1707, 1226, 1076, 937 cm-1 1H NMR (300
MHz, CDCl3) δH 3.83-3.71 (m, 1H, H-6), 3.63-3.49 (m, 1H, H-
2), 2.57 (dd, J = 16.0, 7.2 Hz, 1H, Ha from CH2CO), 2.51 (dd, J
= 16.0, 5.3 Hz, 1H, Hb from CH2CO), 1.91-1.78 (m, 1H, H-3a),
1.64 (tdd, J = 5.9, 4.5, 2.7 Hz, 2H, H-3b and H-5b), 1.59-1.46
(m, 1H, H-5a), 1.37-1.23 (m, 2H, H-4), 1.21 (d, J = 6.2 Hz, 3H,
CH3) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 175.3, 74.7,
74.1, 41.4, 32.9, 30.9, 23.3, 22.1 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for:C8H15O3: 159.1021, Found: 159.1017,
[M+Na]+ Calcd. for C8H14NaO3: 181.0841, Found: 181.0836,
[M+K]+ Calcd. for C8H14KO3: 197.0580, Found: 197.0573; (±)-
anti-24: Rf = 0.15 (hexanes/EtOAc, 1:1); IR (ATR) νmax 2920,
rac-(1R,5R,7S)-7-nHexyl-2,6-dioxabicyclo[3.3.0]octane-3-
one ((±)-16). The title compound was prepared according to
general method 1 from diol (±)-15 (354 mg, 1.90 mmol). The
purification of crude product by MPLC (hexanes/EtOAc: 100/0
to 80/20 then isocratic hexanes/EtOAc: 80/20) provided desired
lactone (±)-16 (157 mg, 39%, pale yellow oil). All physical and
spectral data were in good agreement with the literature.19 Rf =
0.20 (hexanes/EtOAc, 4:1); IR (ATR) νmax 2928, 1775, 1152,
1066, 893 cm-1; 1H NMR (300 MHz, CDCl3) δH 5.00 (ddd, J =
6.9, 4.5, 2.3 Hz, 1H, H-1), 4.53-4.43 (m, 1H, H-5), 3.97-3.86
(m, 1H, H-7), 2.73-2.66 (m, 2H, H-4), 2.41 (dt, J = 14.2, 6.9 Hz,
1H, H-8a), 1.86 (ddd, J = 14.2, 7.9, 2.3 Hz, 1H, H-8b), 1.73-1.43
(m, 2H, CH2(CH2)4CH3), 1.43-1.12 (m, 8H, CH2(CH2)4CH3),
0.86 (t, J = 7.0 Hz, 3H, CH3) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δC 175.6, 84.8, 80.5, 78.3, 38.4, 36.5, 35.6, 31.8, 29.3,
26.1, 22.7, 14.2 ppm; HRMS (ESI): m/z [M+H]+ Calcd.
for:C12H21O3: 213.1491, Found: 213.1485, [M+Na]+ Calcd. for
C12H20NaO3: 235.1310, Found: 235.1304, [M+K]+ Calcd. for
C12H20KO3: 251.1050, Found: 251.1043.
rac-(1R,5R,7R)-7-nButyl-2,6-dioxabicyclo[3.3.0]octane-3-
one ((±)-14). The title compound was prepared according to
general method 1 from diol (±)-13 (300 mg, 1.90 mmol). The
purification of crude product by MPLC (hexanes/EtOAc: 100/0
to 75/25 then isocratic hexanes/EtOAc: 75/25) provided desired
lactone (±)-14 (269 mg, 77%, pale yellow oil). All physical and
spectral data were in good agreement with the literature.19 Rf =
0.20 (hexanes/EtOAc, 4:1); IR (ATR) νmax 2931, 1774, 1175,
1059, 832 cm-1; 1H NMR (300 MHz, CDCl3) δH 5.11 (t, J = 4.9
Hz, 1H, H-1), 4.84-4.77 (m, 1H, H-5), 4.12-4.00 (m, 1H, H-7),
2.76 (dd, J = 18.8, 6.4 Hz, 1H, H-4a), 2.63 (d, J = 18.8 Hz, 1H,
H-4b), 2.37 (dd, J = 13.9, 4.7 Hz, 1H, H-8a), 1.66 (dd, J = 13.9,
10.4, 4.9 Hz, 1H, H-4b), 1.60-1.43 (m, 2H, CH2(CH2)2CH3),
1.43-1.17 (m, 4H, CH2(CH2)2CH3), 0.90 (t, J = 7.0 Hz, 3H, CH3)
ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 176.2, 85.1, 78.4,
77.5, 39.0, 36.8, 34.5, 28.3, 22.8, 14.1 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for:C10H17O3: 185.1178, Found: 185.1172,
[M+Na]+ Calcd. for C10H16NaO3: 207.0997, Found: 207.0992,
[M+K]+ Calcd. for C10H16KO3: 223.0737, Found: 223.0730.
rac-(1R,5R,7S)-7-nButyl-2,6-dioxabicyclo[3.3.0]octane-3-
one ((±)-18). The title compound was prepared according to
general method 1 from diol (±)-17 (300 mg, 1.90 mmol). The
purification of crude product by MPLC (hexanes/EtOAc: 100/0
1
1705, 1440, 1086, 902 cm-1; H NMR (300 MHz, CDCl3) δH
4.24 (ddd, J = 12.3, 8.0, 4.7 Hz, 1H, H-2), 4.08-3.95 (m, 1H, H-
6), 2.69 (dd, J = 15.3, 8.0 Hz, 1H, Ha from CH2CO), 2.46 (dd, J
= 15.3, 4.7 Hz, 1H, Hb from CH2CO), 1.78-1.60 (m, 4H, H-5
and H-3), 1.44-1.28 (m, 2H, H-4), 1.21 (d, J = 6.5 Hz, 3H, CH3)
ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 175.8, 68.2, 67.7,
39.0, 31.0, 29.8, 19.2, 18.1 ppm; HRMS (ESI): m/z [M+H]+
Calcd. for:C8H15O3: 159.1021, Found: 159.1019, [M+Na]+
Calcd. for C8H14NaO3: 181.0841, Found: 181.0837, [M+K]+
Calcd. for C8H14KO3: 197.0580, Found: 197.0576.
Synthesis of starting materials
(S)-1-((R)-Oxiran-2-yl)prop-2-en-1-ol (26). To a suspension
of crushed molecular sieves (9.80 g, 4Å) in anhydrous CH2Cl2
(383 mL) was added dropwise the solution of L-(+)-DET (8.0
mL, 46.55 mmol, 0.24 equiv) in anhydrous CH2Cl2 (11.5 mL)
at -25 °C followed by a solution of Ti(OiPr)4 (11.5 mL, 38.79
mmol, 0.2 equiv) in anhydrous CH2Cl2 (11.5 mL). After 30 min.
t
of stirring at same temperature the solution of BuOOH (23.3
mL, 13.3 M in anhydrous CH2Cl2, 310.36 mmol, 1.6 equiv) was
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Page 8 of 15
added dropwise and mixture was left to stir for another 15 min. overnight. After concentration in vacuo, the residue was
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Then the solution of divinylcarbinol 25 (16.32 g, 193.97 mmol,
1 equiv) in anhydrous CH2Cl2 (6 mL) was added and resulting
mixture was stirred at -25 °C for 10 days. Subsequently,
solution of tartaric acid (25 g, 168.76 mmol, 0.87 equiv) in
water (63 mL) was added and the biphasic mixture was left to
warm to room temperature under vigorous stirring. After
filtering of insoluble particles, the organic phase was separated,
and aqueous one was extracted with CH2Cl2 (3x100 mL). The
combined organic extracts were dried over Na2SO4, filtered and
concentrated in vacuo. Distillation of the residue (23 mbar, 60-
75 °C) provided desired epoxide 26 (9.90 g, colorless oil) in
51% yield. All physical and spectral data were in good
agreement with the literature.36 Rf = 0.30 (hexanes/EtOAc,
purified by MPLC (hexanes/EtOAc: 100/0 to 50/50 then
isocratic hexanes/EtOAc: 50/50) providing desired product 3a
(1.76 g, white solid) in 71% yield. All physical and spectral data
were in good agreement with the literature.15d Rf = 0.20
(hexanes/EtOAc, 1:1); mp 71.2-71.7 °C; [α]20 -14.9 (c 2.20,
1
MeOH); IR (ATR) νmax 3296, 1677, 1549, 1073, 669 cm-1; H
NMR (300 MHz, CDCl3) δH 5.92 (ddd, J = 17.1, 10.5, 6.0 Hz,
1H, H-4), 5.36 (dt, J = 17.1, 1.4 Hz, 1H, H-5a), 5.26 (dt, J =
10.5, 1.4 Hz, 1H, H-5b), 5.12 (t, J = 5.7, 1H, NH), 4.04 (br s,
1H, H-3), 3.60 (br s, 1H, H-2), 3.48 (br s, 1H, OH), 3.41-3.23
(m, 2H, H-1), 3.07 (br s, 1H, OH), 1.43 (s, 9H, CH(CH3)3) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 157.8, 136.8, 117.5, 80.3,
74.0, 73.9, 42.4, 28.5 ppm; HRMS (ESI): m/z [M+H]+ Calcd.
for:C10H20NO4: 218.1392, Found: 218.1387, [M+Na]+ Calcd.
for C10H19NNaO4: 240.1212, Found: 240.1206, [M+K]+ Calcd.
for C10H19KNO4: 256.0951, Found: 256.0945.
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13:7); [α]20 +58.1 (c 1.70, CHCl3); IR (ATR) νmax 3406, 1251,
930, 885, 466 cm-1; 1H NMR (300 MHz, CDCl3) δH 5.85 (ddd,
J = 17.1, 10.5, 6.2 Hz, 1H, H-4), 5.39 (dt, J = 17.1, 1.3 Hz, 1H,
H-5a), 5.26 (dt, J = 10.5, 1.3 Hz, 1H, H-5b), 4.38-4.29 (m, 1H,
H-3), 3.09 (ddd, J = 6.0, 3.9, 2.9 Hz, 1H, H-2), 2.80 (dd, J = 5.0,
2.9 Hz, 1H, H-1a), 2.75 (dd, J = 5.0, 3.9 Hz, 1H, H-1b), 2.06 (s,
1H, OH) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 135.6,
117.8, 70.3, 54.0, 43.6 ppm; HRMS (ESI): m/z [M+H]+ Calcd.
for:C5H9O2: 101.0603, Found: 101.0597, [M+Na]+ Calcd. for
C5H8NaO2: 123.0422, Found: 123.0416.
Benzyl (2R,3S)-2,3-dihydroxypent-4-enylcarbamate (3b). To
a solution of amino alcohol 27 (1.24 g, 9.48 mmol, 1 equiv) and
NaHCO3 (1.83 g, 21.81 mmol, 2.3 equiv) in H2O (20 mL) was
added dropwise CbzCl (2.3 mL, 14.23 mmol, 1.5 equiv) at 0 °C.
The resulting mixture was stirred at same temperature for 5h.
Reaction mixture was then extracted with CHCl3 (2x15 mL),
the combined organic extracts were dried over Na2SO4, filtered
and concentrated in vacuo. Crystallization of the crude material
from the mixture hexanes/EtOAc = 1/2 provided protected
aminodiol 3b (1.17 g, white solid) in 62% yield. All physical
and spectral data were in good agreement with the literature.38
Rf = 0.15 (hexanes/EtOAc, 1:1); mp 93.8-94.0 °C, lit.38 mp
(2R,3S)-Pent-4-ene-1,2,3-triol (1). Epoxide 26 (10.15 g,
101.38 mmol, 1 equiv) was dissolved in the solution of AcOH
(2 mL, 35.48 mmol, 0.35 equiv) in water (338 mL). This
mixture was stirred overnight at 60 °C and then concentrated in
vacuo. The crude product (11.18 g, 93%, colorless oil) was used
without further purification. All physical and spectral data were
93 °C; [α]20 +1.1 (c 1.52, MeOH); IR (ATR) νmax 3318, 1688,
in good agreement with the literature.36 Rf
= 0.15
1541, 1003, 696 cm-1; 1H NMR (300 MHz, CDCl3) δH 7.43-7.27
(m, 5H, HAr), 5.91 (ddd, J = 17.2, 10.5, 6.4 Hz, 1H, H-4), 5.36
(dt, J = 17.2, 1.4 Hz, 1H, H-5a), 5.31-5.25 (m, 1H, H-5b), 5.24
(s, 1H, NH), 5.12 (s, 2H, PhCH2), 4.11-4.02 (m, 1H, H-3), 3.65
(dd, J = 9.5, 5.0 Hz, 1H, H-2), 3.50-3.31 (m, 2H, H-1), 2.95 (s,
1H, OH), 2.65 (s, 1H, OH) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δC 158.0, 136.6, 136.3, 128.7, 128.4, 128.3, 117.9, 74.1,
73.5, 67.3, 42.7 ppm; HRMS (ESI): m/z [M+H]+ Calcd.
for:C13H18NO4: 252.1236, Found: 252.1230, [M+Na]+ Calcd.
for C13H17NNaO4: 274.1055, Found: 274.1049, [M+K]+ Calcd.
for C13H17KNO4: 290.0795, Found: 290.0788.
(CH2Cl2/MeOH, 17:3); [α]20 -25.8 (c 1.35, MeOH); IR (ATR)
1
νmax 3316, 1423, 1026, 992, 468 cm-1; H NMR (300 MHz,
CD3OD) δH 6.01 (ddd, J =17.2, 10.5, 6.5 Hz, 1H, H-4), 5.32
(ddd, J = 17.2, 1.9, 1.4 Hz, 1H, H-5a), 5.21 (ddd, J = 10.5, 1.9,
1.4 Hz, 1H, H-5b), 4.07 (ddd, J = 6.5, 2.7, 1.4 Hz, 1H, H-3),
3.73-3.64 (m, 1H, H-2), 3.63-3.53 (m, 2H, H-1) ppm; 13C{1H}
NMR (75 MHz, CD3OD) δC 139.1, 116.4, 76.0, 74.9, 64.4 ppm;
HRMS (ESI): m/z [M+Na]+ Calcd. for C5H10NaO3: 141.0528,
Found: 141.0523.
(2R,3S)-1-Aminopent-4-ene-2,3-diol (27). A mixture of
epoxide 26 (1.4 g, 13.98 mmol, 1 equiv) and ammonia (15 mL,
25% wt in water) was stirred overnight at room temperature and
then concentrated in vacuo. The crude product (1.64 g, 82%,
colorless oil) was used without further purification. All physical
and spectral data were in good agreement with the literature.37
N-((2R,3S)-2,3-Dihydroxypent-4-enyl)-4-
methylbenzenesulfonamide (3c). To a solution of amino alcohol
27 (3.66 g, 31.2 mmol, 1 equiv) in pyridine (18.3 mL) was
added TsCl (5.96 g, 31.24 mmol, 1 equiv) at 0 °C. The mixture
was left to warm to room temperature and stirred for next 18 h.
Pyridine was concentrated in vacuo; the residue was suspended
in EtOAc (20 mL) and filtered through short pad of silica gel.
Pad was then washed using EtOAc (100 mL) and filtrate was
concentrated in vacuo. The crude product was purified by
MPLC (hexanes/EtOAc: 100/0 to 30/70 then isocratic
hexanes/EtOAc: 30/70) providing desired product 3c (5.92 g,
70%, white solid). All physical and spectral data were in good
agreement with the literature.27 Rf = 0.20 (hexanes/EtOAc, 3:7);
Rf = 0.10 (CH2Cl2/MeOH, 17:3); [α]20 -36.0 (c 0.71, CHCl3); IR
1
(ATR) νmax 3084, 1645, 1570, 991, 928 cm-1; H NMR (300
MHz, CD3OD) δH 5.97 (ddd, J =17.3, 10.5, 6.1 Hz, 1H, H-4),
5.30 (ddd, J = 17.3, 1.9, 1.5 Hz, 1H, H-5a), 5.18 (ddd, J = 10.5,
1.9, 1.3 Hz, 1H, H-5b), 3.97 (dddd, J = 6.1, 5.9, 1.5, 1.3 Hz, 1H,
H-3), 3.44 (ddd, J = 7.9, 5.9, 3.5 Hz, 1H, H-2), 2.81 (dd, J =
13.2, 3.5 Hz, 1H, H-1a), 2.64 (dd, J = 13.2, 7.9 Hz, 1H, H-1b)
ppm; 13C{1H} NMR (75 MHz, CD3OD) δC 139.4, 116.4, 76.2,
76.0, 44.7 ppm; HRMS (ESI): m/z [M+H]+ Calcd.
for:C5H12NO2: 118.0868, Found: 118.0865.
tert-Butyl (2R,3S)-2,3-dihydroxypent-4-enylcarbamate (3a).
To a solution of amino alcohol 27 (1.33 g, 11.35 mmol, 1 equiv)
in MeOH (26.4 mL) was added Et3N (8.9 mL, 63.58 mmol, 5.6
equiv) and the mixture was left to stir for 10 min. Subsequently,
Boc2O (3.15 g, 14.42 mmol, 1.27 equiv) was added portion wise
and the resulting mixture was stirred at room temperature
mp 93.0-93.4 °C, lit.27 mp 67-70 °C; [α]20 +8,8 (c 0.80; CHCl3);
IR (ATR) νmax 3430, 3127, 1305, 1153, 544 cm-1; 1H NMR (300
MHz, CDCl3) δH 7.77-7.69 (m, 2H, HAr), 7.30 (dd, J = 8.5, 0.6
Hz, 2H, HAr), 5.82 (ddd, J = 17.2, 10.5, 6.1 Hz, 1H, H-4), 5.50-
5.37 (m, 1H, NH), 5.32 (dt, J = 17.2, 1.4 Hz, 1H, H-5a), 5.22
(dt, J = 10.5, 1.4 Hz, 1H, H-5b), 4.21 (ddt, J = 6.1, 4.9, 1.4 Hz,
1H, H-3), 3.70 (ddd, J = 7.0, 4.9, 3.5 Hz, 1H, H-2), 3.12 (ddd,
J = 13.3, 7.0, 3.5 Hz, 1H, H-1a), 3.07-2.95 (m, 1H, H-1b), 2.83
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The Journal of Organic Chemistry
(s, 2H, OH), 2.42 (s, 3H, CH3) ppm; 13C{1H} NMR (75 MHz,
1H, H-5a), 5.14 (d, J = 10.4 Hz, 1H, H-5b), 4.41 (dt, J = 11.5,
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CDCl3) δC 143.8, 136.6, 136.1, 129.9, 127.2, 117.9, 74.3, 72.4,
44.5, 21.7 ppm; HRMS (ESI): m/z [M+H]+ Calcd.
for:C12H18NO4S: 272.0957, Found: 272.0951, [M+Na]+ Calcd.
for C12H17NNaO4S: 294.0776, Found: 294.0770, [M+K]+
Calcd. for C12H17KNO4S: 310.0515, Found: 310.0509.
5.7 Hz, 1H, H-3), 3.95-3.75 (m, 2H, H-1), 2.50 (s, 2H, OH),
1.91-1.66 (m, 2H, H-2) ppm; 13C{1H} NMR (75 MHz, CDCl3)
δC 140.7, 114.8, 72.9, 61.2, 38.3 ppm; HRMS (ESI): m/z
[M+Na]+ Calcd. for:C5H10NaO2: 125.0579, Found: 125.0573.
2-Methylhex-5-ene-2,4-diol ((±)-7). To a solution of ethyl
ester 28 (17.75 g, 123.12 mmol, 1 equiv) in anhydrous CH2Cl2
(205 mL) was added imidazole (16.76 g, 246.24 mmol, 2 equiv)
and TBSCl (23.20 g, 153.90 mmol, 1.25 equiv) at 0 °C. The
mixture was left to warm to room temperature and stirred until
full conversion was observed (overnight)., After washing with
deionized water (3x80 mL), organic phase was dried over
Na2SO4, filtered and concentrated in vacuo. The crude product
(quantitative yield) was used without further purification. To
the solution of crude ethyl 3-tert-butyldimethylsilyloxy)pent-4-
enoate (29) (14.31 g, 55.37 mmol, 1 equiv) in anhydrous THF
(222 mL) was added dropwise solution of MeMgBr (46.2 mL,
3 M in Et2O, 138.43 mmol, 2.5 equiv) at -78 °C. The resulting
mixture was stirred for 30 min at this temperature and then left
to warm to room temperature (90 min). The reaction was
quenched with saturated solution of NH4Cl (150 ml) and diluted
with Et2O (240 mL). Organic phase was separated, and aqueous
phase was extracted with Et2O (3x240 mL). Combined organic
phases were dried over Na2SO4, filtered and concentrated in
vacuo. The crude product (4-(tert-butyldimethylsilyloxy)-2-
methylhex-5-en-2-ol (30), quantitative yield) was dissolved in
MeOH (300 mL) and DOWEX marathon H+ form (30.60 g) was
added. This suspension was left to stir at room temperature until
full conversion was observed (overnight). Filtration of
DOWEX residues was followed by concentration in vacuo. The
crude product was purified by MPLC using gradient
(hexanes/EtOAc: 100/0 to 65/35 then isocratic hexanes/EtOAc:
65/35) providing desired product (±)-7 (6.16 g, 87% over 3
steps, colorless oil). All physical and spectral data were in good
agreement with the literature.41 Rf = 0.20 (hexanes/EtOAc, 7:3);
IR (ATR) νmax 3330, 1381, 1150, 910, 526 cm-1; 1H NMR (300
MHz, CDCl3) δH 5.84 (ddd, J = 17.2, 10.4, 5.9 Hz, 1H, H-5),
5.23 (dt, J = 17.2, 1.4 Hz, 1H, H-6a), 5.07 (dt, J = 10.4, 1.5 Hz,
1H, H-6b), 4.49 (dddt, J = 10.8, 5.9, 2.6, 1.4 Hz, 1H, H-4), 3.42
(s, 2H, OH), 1.71 (dd, J = 14.6, 10.8 Hz, 1H, H-3a), 1.55 (dd, J
= 14.6, 2.6 Hz, 1H, H-3b), 1.32 (s, 3H, H-1), 1.25 (s, 3H, CH3)
ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 141.1, 114.3, 71.7,
71.0, 47.7, 31.9, 27.8 ppm; HRMS (ESI): m/z [M+Na]+ Calcd.
for C7H14NaO2: 153.0892, Found: 153.0887.
Ethyl 3-hydroxypent-4-enoate (28). To a solution of
LiHMDS (41.78 g, 249.70 mmol, 1.1 equiv) in anhydrous THF
(400 mL) was added dropwise anhydrous EtOAc (22.3 mL,
227.00 mmol, 1 equiv) at -78 °C. The reaction mixture was
stirred for 20 min at same temperature. Subsequently, a solution
of freshly distilled acrolein (22.8 mL, 340.50 mmol, 1.5 equiv)
in anhydrous THF (100 mL) was added dropwise over period
of 30 min. The resulting mixture was stirred for 1 h at -78 °C,
then it was left to warm to 0 °C and quenched by addition of
saturated aqueous solution of NH4Cl (300 mL). After
concentration under vacuum to the 1/5 of previous volume Et2O
(400 mL) was added. Organic phase was separated, and aqueous
phase was extracted with Et2O (3x200 mL). The combined
organic extracts were dried over Na2SO4, filtered and
concentrated in vacuo. Distillation of a residue (4 mbar, 75-76
°C) provided desired hydroxyketone 28 (26.01 g, 79%,
colorless oil). All physical and spectral data were in good
agreement with the literature.39 Rf = 0.30 (hexanes/EtOAc, 7:3);
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IR (ATR) νmax 3292, 1446, 962, 634, 546 cm-1; H NMR (300
MHz, CDCl3) δH 5.88 (ddd, J = 17.2, 10.5, 5.5 Hz, 1H, H-4),
5.31 (dt, J = 17.2, 1.3 Hz, 1H, H-5a), 5.15 (dt, J = 10.5, 1.3 Hz,
1H, H-5b), 4.58-4.48 (m, 1H, H-3), 4.17 (q, J = 7.1 Hz, 2H,
CH2CH3), 2.99 (s, 1H, OH), 2.58 (dd, J = 16.2, 4.4 Hz, 1H, H-
2a), 2.50 (dd, J = 16.2, 8.0 Hz, 1H, H-2b), 1.27 (t, J = 7.1 Hz,
3H, CH2CH3) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 172.4,
138.9, 115.5, 69.1, 60.9, 41.3, 14.3 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. For C7H13O3: 145.0859, Found: 145.0858,
[M+Na]+ Calcd. for C7H12NaO3: 167.0678, Found: 167.0678.
Pent-4-ene-1,3-diol ((±)-5). To a solution of ethyl ester 28
(3.42 g, 23.69 mmol, 1 equiv) in anhydrous CH2Cl2 (40 mL)
was added imidazole (3.23 g, 47.38 mmol, 2 equiv) and TBSCl
(4.46 g, 29.61 mmol, 1.25 equiv) at 0 °C. The mixture was left
to stir at room temperature for 15h. Subsequently, the resulting
suspension was washed with deionized water (3x15 mL).
Organic phase was dried over Na2SO4, filtered and concentrated
in vacuo. The crude product was dissolved in anhydrous THF
(93 mL) and a solution of DiBAl-H (53.4 mL, 1 M in CH2Cl2,
53.40 mmol, 2.3 equiv) was added dropwise at 0 °C. Resulting
mixture was left to warm to 15 °C over a period of 1 hour and
then cooled to 0 °C again. Subsequently, saturated solution of
Rochelle salt (20 mL) was added and this emulsion was stirred
for 5 h at room temperature. Organic phase was separated, and
aqueous phase was extracted with Et2O (3x90 mL). Combined
organic phases were dried over Na2SO4, filtered and
concentrated in vacuo. The crude product (3-(tert-
butyldimethylsilyloxy)pent-4-en-1-ol) (31) was dissolved in
MeOH (75 mL) and DOWEX marathon H+ form (13.5 g) was
added. This suspension was left to stir at room temperature until
full conversion was observed (overnight). Filtration of
DOWEX residues was followed by concentration in vacuo. The
crude product was purified by MPLC using gradient
(hexanes/EtOAc: 100/0 to 35/65 then isocratic hexanes/EtOAc:
35/65) providing desired product (±)-5 (1.45 g, 60% over 3
steps, colorless oil). All physical and spectral data were in good
agreement with the literature.40 Rf = 0.20 (hexanes/EtOAc, 3:7);
IR (ATR) νmax 3317, 1422, 1049, 922, 663 cm-1; 1H NMR (300
MHz, CDCl3) δH 6.00-5.83 (m, 1H, H-4), 5.28 (d, J = 17.2 Hz,
i
3-Hydroxypent-4-enenitrile (32). To a solution of Pr2NH
(23.48 mL, 214.36 mmol, 1.6 equiv) in anhydrous THF (268
mL) was added dropwise solution of nBuLi (126 mL, 1.6 M in
hexanes, 201.0 mmol, 1.6 equiv) at -78 °C. The mixture was left
to stir for 30 min and then solution of acetonitrile (7 mL, 133.98
mmol, 1 equiv) in anhydrous THF (67 mL) was added dropwise
at the same temperature. After stirring over period 1 hour at -78
°C, solution of acrolein (10.8 mL, 160.77 mmol, 1.2 equiv) in
anhydrous THF (54 mL) was added dropwise and resulting
mixture was stirred for 2.5 h. The reaction mixture was
quenched with saturated solution of NH4Cl (150 mL) and
diluted with Et2O (200 mL). Subsequently, organic phase was
separated, and aqueous phase was extracted with Et2O (3x300
mL). The combined organic extracts were dried over Na2SO4,
filtered and concentrated in vacuo. Distillation of a residue (6-
7 mbar, 80-83 °C) provided desired nitrile 32 (9.7 g, 74%, pale
yellow oil). All physical and spectral data were in good
agreement with the literature.42 Rf = 0.60 (hexanes/EtOAc, 1:1);
IR (ATR) νmax 3417, 1415, 1053, 932, 491 cm-1; 1H NMR (300
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The Journal of Organic Chemistry
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MHz, CDCl3) δH 5.92 (ddd, J = 17.1, 10.4, 5.9 Hz, 1H, H-4), (hexanes/EtOAc: 100/0 to 50/50 then isocratic hexanes/EtOAc:
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5.47-5.36 (m, 1H, H-5a), 5.33-5.27 (m, 1H, H-5b), 4.52-4.41 (m,
1H, H-3), 2.64 (dd, J = 15.8, 4.8 Hz, 1H, H-2a), 2.57 (dd, J =
15.8, 5.4 Hz, 1H, H-2b), 2.30 (s, 1H, OH) ppm; 13C{1H} NMR
(75 MHz, CDCl3) δC 137.4, 117.6, 117.4, 68.6, 26.1 ppm;
HRMS (ESI): m/z [M+H]+ Calcd. for:C5H8NO: 98.0606,
Found: 98.0599, [M+Na]+ Calcd. for C5H7NNaO: 120.0425,
Found: 120.0418.
50/50) provided desired product (±)-9b (0.94 g, 50%, colorless
oil). All physical and spectral data were in good agreement with
the literature.45 Rf = 0.20 (hexanes/EtOAc, 1:1); IR (ATR) νmax
3325, 1692, 1518, 1257, 695 cm-1; 1H NMR (300 MHz, CDCl3)
δH 7.39-7.28 (m, 5H, HAr), 5.88 (ddd, J = 17.1, 10.5, 5.8 Hz, 1H,
H-4), 5.25 (dt, J = 17.1, 1.4 Hz, 1H, H-5a), 5.12 (dt, J = 10.5,
1.4 Hz, 1H, H-5b), 5.12-5.07 (m, 3H, NH and Ph-CH2), 4.21
(dddd, J = 8.7, 5.8, 2.9, 1.4 Hz, 1H, H-3), 3.59-3.40 (m, 1H, H-
1a), 3.33-3.19 (m, 1H, H-1b), 2.13 (s, 1H, OH), 1.83-1.57 (m,
2H, H-2) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 157.1,
140.5, 136.6, 128.7, 128.3, 128.2, 114.8, 70.8, 66.9, 37.9, 37.0
ppm; HRMS (ESI): m/z [M+H]+ Calcd. for:C13H18NO3:
236.1287, Found: 236.1281, [M+Na]+ Calcd. for C13H17NNaO3:
258.1106, Found: 258.1100, [M+K]+ Calcd. for C13H17KNO3:
274.0846, Found: 274.0840.
5-Aminopent-1-en-3-ol (33). To a solution of nitrile 32 (9 g,
92.67 mmol, 1 equiv) in anhydrous THF (185 mL) was portion-
wise added LAH (5.56 g, 146.42 mmol, 1.58 equiv) at 0 °C. The
reaction was left to warm to room temperature and stirred until
full conversion was observed (overnight). Subsequently
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Na2SO4 10 H2O (179 g, 556.04 mmol, 6 equiv) and celite (60
g) were added and this suspension was diluted with CH2Cl2 (200
mL). After next 2 h of stirring, solids were filtered and washed
with CH2Cl2 (200 mL). The filtrate was dried over Na2SO4,
filtered and concentrated in vacuo. Distillation of crude product
(13 mbar, 90 °C) provided desired amino alcohol 33 (2.53 g,
27%, yellow oil). All physical and spectral data were in good
agreement with the literature.43 Rf = 0.10 (EtOAc). IR (ATR)
N-(3-Hydroxypent-4-enyl)-4-methylbenzenesulfonamide
((±)-9c). To a solution of amino alcohol 33 (0.81 g, 8.01 mmol,
1 equiv) in pyridine (16 mL) was added TsCl (1.53 g, 8.01
mmol, 1 equiv) at 0 °C. The mixture was stirred at room
temperature for 3h and pyridine was removed in vacuo.
Obtained residue was purified by MPLC (isocratic
CH2Cl2/MeOH: 99/1) providing desired product (±)-9c (1.14 g,
56%, white solid). All physical and spectral data were in good
agreement with the literature.44 Rf = 0.20 (hexanes/EtOAc, 4:6);
mp 70.2-70.8 °C, lit.44 mp 70.0-71.5 °C; IR (ATR) νmax 3274,
1
νmax 3358, 2933, 1425, 917, 671 cm-1; H NMR (300 MHz,
CDCl3) δH 5.87 (ddd, J = 17.1, 10.4, 5.2 Hz, 1H, H-2), 5.27 (dt,
J = 17.1, 1.6 Hz, 1H, H-1a), 5.08 (dt, J = 10.4, 1.6 Hz, 1H, H-
1b), 4.35 (dddd, J = 7.0, 5.2, 3.7, 1.6 Hz, 1H, H-3), 3.09 (ddd, J
= 12.2, 6.1, 4.0 Hz, 1H, H-5a), 2.95-2.83 (m, 1H, H-5b), 2.57 (s,
3H, NH2 and OH), 1.70 (ddt, J = 13.9, 6.1, 4.0 Hz, 1H, H-4a),
1.62-1.47 (m, 1H, H-4b) ppm; 13C{1H} NMR (75 MHz, CDCl3)
δC 141.3, 113.9, 73.8, 40.3, 37.7 ppm; HRMS (ESI): m/z
[M+H]+ Calcd. for:C5H12NO: 102.0919, Found: 102.0913,
[M+Na]+ Calcd. for C5H11NNaO: 124.0738, Found: 124.0734.
tert-Butyl 3-hydroxypent-4-enylcarbamate ((±)-9a). To
a solution of amino alcohol 33 (0.80 g, 7.91 mmol, 1 equiv) in
CH2Cl2 (40 mL) was added dropwise solution of Boc2O (2.21
g, 10.12 mmol, 1.28 equiv) and Et3N (1.32 mL, 9.49 mmol, 1.2
equiv) in CH2Cl2 (20 mL) at 0 °C. After stirring for 15h at room
temperature was resulting mixture concentrated in vacuo.
Residue was purified by MPLC (hexanes/EtOAc: 100/0 to
65/35 then isocratic hexanes/EtOAc: 65/35) providing desired
product (±)-9a (1.37 g, 86%, colorless oil). All physical and
spectral data were in good agreement with the literature.44 Rf =
0.20 (hexanes/EtOAc, 13:7); IR (ATR) νmax 3367, 2978, 1681,
1166, 990 cm-1; 1H NMR (300 MHz, CDCl3) δH 5.89 (ddd, J =
17.2, 10.5, 5.5 Hz, 1H, H-4), 5.26 (dt, J = 17.2, 1.5 Hz, 1H, H-
5a), 5.10 (dt, J = 10.5, 1.5 Hz, 1H, H-5b), 4.86 (s, 1H, NH), 4.18
(ddd, J = 10.0, 5.5, 1.5 Hz, 1H, H-3), 3.52-3.31 (m, 1H, H-1a),
3.22-3.08 (m, 1H, H-1b), 2.93 (s, 1H, OH), 1.79-1.53 (m, 2H,
H-2), 1.44 (s, 9H, C(CH3)3) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δC 157.0, 140.6, 114.5, 79.7, 70.3, 37.5, 37.3, 28.5 ppm;
HRMS (ESI): m/z [M+H]+ Calcd. for:C10H20NO3: 202.1443,
Found: 202.1439, [M+Na]+ Calcd. for C10H19NNaO3: 224.1263,
Found: 224.1258, [M+K]+ Calcd. for C10H19KNO3: 240.1002,
Found: 240.0997.
1
1425, 1319, 1154, 549 cm-1; H NMR (300 MHz, CDCl3) δH
7.74 (d, J = 8.2 Hz, 2H, HAr), 7.30 (d, J = 8.2 Hz, 2H, HAr), 5.79
(ddd, J = 17.1, 10.6, 5.8 Hz, 1H, H-4), 5.24 (s, 1H, NH), 5.18
(dt, J = 17.1, 1.2 Hz, 1H, H-5a), 5.08 (dt, J = 10.6, 1.2 Hz, 1H,
H-5b), 4.27-4.20 (m, 1H, H-3), 3.18-3.10 (m, 1H, H-1a), 3.03
(td, J = 12.3, 5.2 Hz, 1H, H-1b), 2.42 (s, 3H, CH3), 2.07 (s, 1H,
OH), 1.73 (dddd, J = 16.9, 8.0, 5.2, 4.1 Hz, 1H, H-2a), 1.66-1.58
(m, 1H, H-2b) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 143.5,
140.1, 137.1, 129.8, 127.3, 115.3, 71.9, 40.7, 35.6, 21.7 ppm;
HRMS (ESI): m/z [M+H]+ Calcd. for:C12H18NO3S: 256.1007,
Found: 256.1001, [M+Na]+ Calcd. for C12H17NNaO3S:
278.0827, Found: 278.0822, [M+K]+ Calcd. for C12H17KNO3S:
294.0566, Found: 294.0560.
i
3-Hydroxyundec-1-en-5-one (34). To a solution of Pr2NH
(4.9 mL, 44.77 mmol, 1.4 equiv) in anhydrous THF (65 mL)
n
was added dropwise solution of BuLi (26 mL, 1.6 M in
hexanes, 41.57 mmol, 1.3 equiv) at -78 °C. The mixture was left
to stir for 30 min and then solution of octan-2-one (5 mL,
31.98 mmol, 1 equiv) in anhydrous THF (16 mL) was added
dropwise at the same temperature. After stirring over period of
1 h at -78 °C, solution of acrolein (2.4 mL, 35.18 mmol, 1.1
equiv) in anhydrous THF (12 mL) was added dropwise and
resulting mixture was stirred for 2.5 h. The reaction was
quenched with saturated solution of NH4Cl (50 mL) and diluted
with Et2O (50 mL). Subsequently, organic phase was separated,
and aqueous phase was extracted with Et2O (3x100 mL). The
combined organic extracts were dried over Na2SO4, filtered and
concentrated in vacuo. Purification of crude product by MPLC
(isocratic hexanes/EtOAc: 90/10) provided hydroxyketone 34
(2.78 g, 49%, colorless oil). All physical and spectral data were
Benzyl 3-hydroxypent-4-enylcarbamate ((±)-9b). To
a solution of amino alcohol 33 (0.81 g, 8.03 mmol, 1 equiv) and
Et3N (1.4 mL, 10.04 mmol, 1.25 equiv) in anhydrous THF (50
mL) was added dropwise CbzCl (1.38 g, 9.61 mmol, 1.2 equiv)
at -15 °C. The reaction mixture was left to stir at room
temperature for 15h. Subsequently, the saturated solution of
NaCl was added (50 mL), organic phase was separated, and
aqueous phase was extracted with Et2O (3x50 mL). Combined
organic extracts were dried over Na2SO4, filtered and
concentrated in vacuo. Purification of residuum by MPLC
in good agreement with the literature.19 Rf
= 0.25
(hexanes/EtOAc, 4:1); IR (ATR) νmax 2928, 1705, 1376, 990,
525 cm-1; 1H NMR (300 MHz, CDCl3) δH 5.86 (ddd, J = 17.1,
10.5, 5.5 Hz, 1H, H-2), 5.29 (dt, J = 17.1, 1.4 Hz, 1H, H-1a),
5.13 (dt, J = 10.5, 1.4 Hz, 1H, H-1b), 4.59-4.55 (m, 1H, H-3),
2.66 (dd, J = 17.4, 3.9 Hz, 1H, H-4a), 2.62 (dd, J = 17.4, 8.2 Hz,
1H, H-4b), 2.43 (t, J = 7.4 Hz, 2H, H-6), 1.62-1.52 (m, 2H, H-
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The Journal of Organic Chemistry
7), 1.36-1.22 (m, 6H, H-8, H-9 and H-10) 0.88 (t, J = 7.0 Hz, CDCl3) δH 5.89 (ddd, J = 17.2, 10.4, 5.9 Hz, 1H, H-2), 5.26 (dt,
3H, CH3) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC 211.7,
139.2, 115.1, 68.8, 48.7, 43.9, 31.7, 29.0, 23.7, 22.6, 14.2 ppm;
HRMS (ESI): m/z [M+H]+ Calcd. for:C11H21O2: 185.1542,
Found: 185.1535, [M+Na]+ Calcd. for C11H20NaO2: 207.1361,
Found: 207.1355.
J = 17.2, 1.4 Hz, 1H, H-1a), 5.10 (dt, J = 10.4, 1.4 Hz, 1H, H-
1b), 4.43-4.33 (m, 1H, H-3), 3.95-3.82 (m, 1H, H-5), 2.44 (s,
2H, OH), 1.72-1.19 (m, 12 H, H-4, H-6, H-7, H-8, H-9 and H-
10), 0.88 (t, J = 6.8 Hz, 3H, CH3) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δC 140.9, 114.6, 74.0, 72.7, 42.2, 38.3, 32.0, 29.4, 25.5,
22.7, 14.2 ppm; HRMS (ESI): m/z [M+H]+ Calcd. for:C11H23O2:
187.1698, Found: 187.1691, [M+Na]+ Calcd. for C11H22NaO2:
209.1518, Found: 209.1513; (±)-15: Rf = 0.15 (hexanes/EtOAc,
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3-Hydroxynon-1-en-5-one (35). To a solution of iPr2NH (4.9
mL, 44.77 mmol, 1.4 equiv) in anhydrous THF (65 mL) was
n
added dropwise solution of BuLi (26 mL, 1.6 in hexanes,
M
1
41.57 mmol, 1.3 equiv) at -78 °C. The mixture was left to stir
for 30 min and then solution of hexan-2-one (3.9 mL, 31.98
mmol, 1 equiv) in anhydrous THF (16 mL) was added dropwise
at the same temperature. After stirring over period of 1 h at -78
°C, solution of acrolein (2.4 mL, 35.18 mmol, 1.1 equiv) in
anhydrous THF (12 mL) was added dropwise and resulting
mixture was stirred for 1h. The reaction was quenched with
saturated solution of NH4Cl (50 mL) and diluted with Et2O (50
mL). Subsequently, organic phase was separated, and aqueous
phase was extracted with Et2O (3x100 mL). The combined
organic extracts were dried over Na2SO4, filtered and
concentrated in vacuo. Purification of crude product by MPLC
(isocratic hexanes/EtOAc: 90/10) provided hydroxyketone 35
(2.06 g, 41%, colorless oil). All physical and spectral data were
4:1); IR (ATR) νmax 3392, 2928, 1712, 1176, 1055 cm-1; H
9
NMR (300 MHz, CDCl3) δH 5.94 (ddd, J = 17.2, 10.5, 5.4 Hz,
1H, H-2), 5.30 (dt, J = 17.2, 1.5 Hz, 1H, H-1a), 5.15 (dt, J =
10.5, 1.5 Hz, 1H, H-1b), 4.52-4.43 (m, 1H, H-3), 4.00-3.88 (m,
1H, H-5), 2.07 (s, 2H, OH), 1.81-1.61 (m, 12H, H-4, H-6, H-7,
H-8, H-9 and H-10), 0.88 (t, J = 6.8 Hz, 3H, CH3) ppm; 13C{1H}
NMR (75 MHz, CDCl3) δC 140.9, 114.5, 70.9, 69.5, 42.3, 37.8,
32.0, 29.4, 25.7, 22.8, 14.2 ppm; HRMS (ESI): m/z [M+H]+
Calcd. for:C11H23O2: 187.1698, Found: 187.1692, [M+Na]+
Calcd. for C11H22NaO2: 209.1518, Found: 209.1511.
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53
54
55
56
57
58
59
60
rac-syn-Non-1-ene-3,5-diol ((±)-13) and rac-anti-Non-1-
ene-3,5-diol ((±)-17). Procedure A: To a suspension of NaBH4
(0.42 g, 11.20 mmol, 2.5 equiv) in benzene (27 mL) was added
dropwise solution of hydroxyketone 35 (0.70 g, 4.48 mmol, 1
equiv) in benzene (27 mL) at room temperature. After stirring
for 21h a solution of HCl (2 M, 80 mL) and EtOAc (80 mL)
were added. Organic phase was separated, and aqueous phase
was extracted with EtOAc (3x80 mL). Combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by MPLC (isocratic
hexanes/EtOAc: 80/20) providing diols (±)-13 (0.18 g, 25%,
pale yellow oil) and (±)-17 (0.26 g, 37%, pale yellow oil). All
physical and spectral data were in good agreement with the
literature.19 Procedure B: To a suspension of NaBH(OAc)3
(4.75 g, 22.40 mmol, 5 equiv) in benzene (27 mL) was added
dropwise solution of hydroxyketone 35 (0.70 g, 4.48 mmol, 1
equiv) in benzene (27 mL) at room temperature. After 18h of
stirring a solution of HCl (2 M, 23 mL) and EtOAc (80 mL)
were added. Organic phase was separated, and aqueous phase
was extracted with EtOAc (3x80 mL). Combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by MPLC (isocratic
hexanes/EtOAc: 80/20) providing diols (±)-13 (0.13 g, 18%,
pale yellow oil) and (±)-17 (0.38 g, 54%, pale yellow oil). All
physical and spectral data were in good agreement with the
literature.19 (±)-13: Rf = 0.15 (hexanes/EtOAc, 4:1); IR (ATR)
in good agreement with the literature.19 Rf
= 0.25
(hexanes/EtOAc, 4:1); IR (ATR) νmax 3421, 2933, 1704, 1379,
991 cm-1; 1H NMR (300 MHz, CDCl3) δH 5.86 (ddd, J = 17.2,
10.5, 5.4 Hz, 1H, H-2), 5.29 (dt, J = 17.2, 1.4 Hz, 1H, H-1a),
5.13 (dt, J = 10.5, 1.4 Hz, 1H, H-1b), 4.61-4.53 (m, 1H, H-3),
2.66 (dd, J = 17.4, 3.9 Hz, 1H, H-4a), 2.62 (dd, J = 17.4, 8.2 Hz,
1H, H-4b), 2.44 (t, J = 7.5 Hz, 2H, H-6), 1.60-1.52 (m, 2H, H-
7), 1.37-1.26 (m, 2H, H-8), 0.91 (t, J = 7.4 Hz, 3H, CH3) ppm;
13C{1H} NMR (75 MHz, CDCl3) δC 211.7, 139.2, 115.1, 68.8,
48.7, 43.6, 25.8, 22.4, 14.0 ppm; HRMS (ESI): m/z [M+H]+
Calcd. for:C9H17O2: 157.1229, Found: 157.1222, [M+Na]+
Calcd. for C9H16NaO2: 179.1048, Found: 179.1044, [M+K]+
Calcd. for C9H16KO2: 195.0787, Found: 195.0783.
rac-syn-Undec-1-ene-3,5-diol ((±)-11) and rac-anti-Undec-
1-ene-3,5-diol ((±)-15). Procedure A: To a suspension of
NaBH4 (0.57 g, 14.92 mmol, 2.5 equiv) in benzene (36 mL) was
added dropwise solution of hydroxyketone 34 (1.10 g, 5.97
mmol, 1 equiv) in benzene (36 mL) at room temperature. After
21 h of stirring a solution of HCl (2 M, 130 mL) and EtOAc
(100 mL) were added. Organic phase was separated, and
aqueous phase was extracted with EtOAc (5x100 mL).
Combined organic phases were dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by
MPLC (isocratic hexanes/EtOAc: 80/20) providing diols (±)-11
(0.29 g, 26%, colorless oil) and (±)-15 (0.43g, 39%, colorless
oil). All physical and spectral data were in good agreement with
the literature.19 Procedure B: To a suspension of NaBH(OAc)3
(6.33 g, 29.85 mmol, 5 equiv) in benzene (36 mL) was added
dropwise solution of hydroxyketone 34 (1.10 g, 5.97 mmol, 1
equiv) in benzene (36 mL) at room temperature. After 18h of
stirring a solution of HCl (2 M, 30 mL) and EtOAc (100 mL)
were added. Organic phase was separated, and aqueous phase
was extracted with EtOAc (3x100 mL). Combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by MPLC (isocratic
hexanes/EtOAc: 80/20) providing diols (±)-11 (0.19 g, 17%,
colorless oil) and (±)-15 (0,58 g, 52%, colorless oil). All
physical and spectral data were in good agreement with the
literature.19 (±)-11: Rf = 0.15 (hexanes/EtOAc, 4:1); IR (ATR)
1
νmax 3346, 2931, 1711, 1422, 990 cm-1; H NMR (300 MHz,
CDCl3) δH 5.89 (ddd, J = 17.2, 10.4, 5.9 Hz, 1H, H-2), 5.26 (dt,
J = 17.2, 1.4 Hz, 1H, H-1a), 5.10 (dt, J = 10.4, 1.4 Hz, 1H, H-
1b), 4.43-4.33 (m, 1H, H-3), 3.95-3.83 (m, 1H, H-5), 2.60 (s,
2H, OH), 1.75-1.20 (m, 8H, H-4, H-6, H-7 and H-8), 0.91 (t, J
= 7.0, 3H, CH3) ppm; 13C{1H} NMR (75 MHz, CDCl3) δC
140.9, 114.6, 74.0, 72.7, 43.2, 38.0, 27.7, 22.8, 14.2 ppm;
HRMS (ESI): m/z [M+Na]+ Calcd. for C9H18NaO2: 181.1205,
Found: 181.1200; (±)-17: Rf = 0.15 (hexanes/EtOAc, 4:1); IR
1
(ATR) νmax 3347, 2931, 1421, 1042, 921 cm-1; H NMR (300
MHz, CDCl3) δH 5.94 (ddd, J = 17.2, 10.5, 5.4 Hz, 1H, H-2),
5.30 (dt, J = 17.2, 1.5 Hz, 1H, H-1a), 5.15 (dt, J = 10.5, 1.5 Hz,
1H, H-1b), 4.54-4.43 (m, 1H, H-3), 3.99-3.89 (m, 1H, H-5), 2.36
(s, 2H, OH), 1.80-1.62 (m, 2H, H-4) 1.61-1.17 (m, 6H, H-6, H-7
and H-8), 5.15 (t, J = 7.0 Hz, 3H, CH3) ppm; 13C{1H} NMR (75
MHz, CDCl3) δC 140.9, 114.5, 70.9, 69.5, 42.3, 37.5, 28.0, 22.8,
14.2 ppm; HRMS (ESI): m/z [M+Na]+ Calcd. for C9H18NaO2:
181.1205, Found: 181.1200.
1
νmax 3346, 2927, 1712, 1457, 989 cm-1; H NMR (300 MHz,
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The Journal of Organic Chemistry
Page 12 of 15
3-Hydroxy-1-phenylpent-4-en-1-one (36). To a solution of
Hept-6-en-2-ol ((±)-23). To a suspension of Mg (12.6 g,
iPr2NH (7.3 mL, 66.58 mmol, 1.6 equiv) in anhydrous THF (83
518.50 mmol, 1.4 equiv) in anhydrous THF (296 mL) were
added dropwise 1,2-dibromoethane (6.96 g, 37.04 mmol, 0.1
equiv) and then 4-bromobut-1-ene (37.6 mL, 370.36 mmol, 1
equiv). The resulting mixture was left to stir for 2 h and then it
was added dropwise at -78 °C to the suspension of propylene
oxide (20.7 mL, 296.29 mmol, 0.8 equiv) and CuI (5.64 g, 29.6
mmol, 0.08 equiv) in anhydrous THF (158 mL). After stirring
over a period of 1.5 h at -78 °C, the reaction mixture was left to
warm to room temperature and stirred at this temperature for 1
h. Subsequently, the reaction was quenched with NH4Cl (400
mL), the organic phase was separated, and the aqueous phase
was extracted with Et2O (3x400 mL). Combined organic phases
were dried over Na2SO4, filtered and concentrated in vacuo.
Distillation of a crude product (17-20 mbar, 65-70 °C) afforded
alcohol (±)-23 (24.33 g, 72%, colorless oil). All physical and
spectral data were in good agreement with the literature.47 Rf =
0.20 (hexanes/EtOAc, 4:1); IR (ATR) νmax 3332, 2930, 1120,
1
2
3
4
5
6
7
8
n
mL) was added dropwise solution of BuLi (39 mL, 1.6 in
M
hexanes, 62.42 mmol, 1.5 equiv) at -78 °C. The mixture was left
to stir for 30 min and then solution of acetophenone (4.9 mL,
41.62 mol, 1 equiv) in anhydrous THF (21 mL) was added
dropwise at the same temperature. After stirring over period of
1 h at -78 °C, solution of acrolein (3.3 mL, 49.94 mmol,
1.2 equiv) in anhydrous THF (17 mL) was added dropwise and
resulting mixture was stirred for 1 h. The reaction was quenched
with saturated solution of NH4Cl (50 mL) and diluted with Et2O
(50 mL). Subsequently, organic phase was separated, and
aqueous phase was extracted with Et2O (3x100 mL). The
combined organic extracts were dried over Na2SO4, filtered and
concentrated in vacuo. Purification of crude product by MPLC
(isocratic hexanes/EtOAc: 85/15) provided hydroxyketone 36
(3.54 g, 48%, pale yellow oil). Rf = 0.15 (hexanes/EtOAc, 17:3);
IR (ATR) νmax 3433, 1675, 1211, 753, 687 cm-1; 1H NMR (300
MHz, CDCl3) δH 7.97 (ddd, J = 7.1, 3.1, 1.7 Hz, 2H, HAr), 7.64-
7.56 (m, 1H, HAr), 7.52-7.44 (m, 2H, HAr), 5.98 (ddd, J = 17.2,
10.5, 5.6 Hz, 1H, H-4), 5.37 (dt, J = 17.2, 1.5 Hz, 1H, H-5a),
5.19 (dt, J = 10.5, 1.5 Hz, 1H, H-5b), 4.47 (dddt, J = 7.8, 5.6,
3.8, 1.5 Hz, 1H, H-3), 3.24 (dd, J = 16.5, 3.8 Hz, 1H, H-2a), 3.17
(dd, J = 16.5, 7.8 Hz, 1H, H-2b) ppm; 13C{1H} NMR (75 MHz,
CDCl3) δC 200.2, 139.2, 136.8, 133.7, 128.8, 128.3, 115.3, 68.9,
45.0 ppm; HRMS (ESI): m/z [M+H]+ Calcd. for:C11H13O2:
177.0916, Found: 177.0910, [M+Na]+ Calcd. for C11H12NaO2:
199.0735, Found: 199.0729, [M+K]+ Calcd. for C11H12KO2:
215.0474, Found: 215.0468.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
908, 639 cm-1; H NMR (300 MHz, CDCl3) δH 5.80 (ddt, J =
16.9, 10.2, 6.7 Hz, 1H, H-6), 5.06-4.91 (m, 2H, H-7), 3.86-3.73
(m, 1H, H-2), 2.16-1.98 (m, 2H, H-5), 1.65-1.34 (m, 4H, H-3
and H-4), 1.18 (d, J = 6.2 Hz, 3H, CH3) ppm; 13C{1H} NMR
(75 MHz, CDCl3) δC 138.8, 114.7, 68.2, 38.9, 33.8, 25.2, 23.7
ppm; HRMS (ESI): m/z [M+H]+ Calcd. for:C7H15O: 115.1123,
Found: 115.1117.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
1-Phenylpent-4-ene-1,3-diol ((±)-19). To a solution of
hydroxyketone 36 (1.04 g, 5.87 mmol, 1 equiv) in anhydrous
EtOH (29 mL) was added in small portions NaBH4 (0.66 g,
17.33 mmol, 2.95 equiv) at 0 °C and the mixture was left to stir
at this temperature for 1 h. Subsequently, solution of HCl (2 M,
45 mL) was added, resulting mixture was stirred 5 min at room
temperature and then EtOH was removed in vacuo. The residue
was dissolved in EtOAc (50 mL), organic phase was separated,
and the aqueous phase was extracted with EtOAc (2x50 mL).
Combined organic phases were dried over Na2SO4, filtered and
concentrated in vacuo. Purification of crude product by MPLC
(hexanes/EtOAc: 100/0 to 70/30 then isocratic hexanes/EtOAc:
70/30) provided inseparable mixture of diols (±)-19 (0.85 g,
Optimization of reaction conditions; 1H, 13C, and NMR spectra of
all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: peter.koos@stuba.sk
ACKNOWLEDGMENT
We thank Slovak Grant Agencies (APVV-14-0147 and VEGA No.
1/0552/18).
1
83%, colorless oil, syn/anti = 53/47 based on H NMR). All
physical and spectral data were in good agreement with the
1
literature.46 (±)-syn-19: Rf = 0.20 (hexanes/EtOAc, 7:3); H
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217.0631, Found: 217.0624.
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The Journal of Organic Chemistry
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XH OH
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