Secondary compounds in the catalytic hydrogenation of enone and allylic alcohol prostaglandin intermediates: Isolation, characterization, and X-ray crystallography

Article abstract of DOI:10.1039/c9nj01186b

The discovery of the intraocular pressure reduction of 13,14-hydrogenated prostaglandins, among which Latanoprost is the most used drug in glaucoma treatment, has stimulated researchers to improve the synthesis of prostaglandins and their structural analo

Full text of DOI:10.1039/c9nj01186b

View Article Online
View Journal
NJC
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: C. I. Tanase, F. G.
Cocu, C. Draghici, A. Hanganu, L. Pintilie, M. Maganu, C. V.A. MUNTEANU and S. Sova, New J. Chem.,
2019, DOI: 10.1039/C9NJ01186B.
This is an Accepted Manuscript, which has been through the
Volume 40 Number
1 January 2016 Pages 1–846
Royal Society of Chemistry peer review process and has been
accepted for publication.
NJC
Accepted Manuscripts are published online shortly after
New Journal of Chemistry
www.rsc.org/njc
A journal for new directions in chemistry
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
rsc.li/njc

Please do not adjust margins
Page 1 of 18
New Journal of Chemistry
1
2
3
4
View Article Online
DOI: 10.1039/C9NJ01186B
New Journal of Chemistry
5
6
7
8
9
ARTICLE
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
could be useful not only for researchers in the field, but also for organic
chemists who encounter secondary products in this type of hydrogenations.
1. Introduction
Received 00th January 20xx,
Accepted 00th January 20xx
Hydrogenation of a double bond has been known for a long time as a
method in organic chemistry for building an aliphatic C (sp3)-C(sp3)
single bond. The hydrogenation of the double bond of an allylic
alcohol is usually accompanied by secondary reactions, like des-
oxygenation of the hydroxyl. In the synthesis of prostaglandin
analogues, this reaction was extensively used after the discovery of
the intraocular pressure reduction effect of Latanoprost [1], a 17-
phenyl-13,14 dihydro trinor PGF2α isopropyl ester, and its large
applications in the treatment of glaucoma. In the synthesis of
Latanoprost, the hydrogenation of the double bond was realized on
the key intermediate Ia, with the -side chain built (Scheme 1),
protected as p-phenylbenzoate (PPB) at the 5-secondary alcohol. The
hydrogenation was realized at atmospheric pressure of H2 on 10%
Pd/C (catalyst†) as catalyst (25% / substrate), in ethanol (in the
presence of 1M NaOH, 100 % [2]) giving the 13,14-dihydro-
intermediate IIa. Latanoprost was then obtained by the deprotection
of the ester group, followed by the next steps for building the α-side
chain of the PGF2α analogue, and the final isopropyl esterification.
The benzoate intermediate Ib was also hydrogenated in the presence
of 1M NaOH, but at 4-5 atm of H2 (5-8 h, 96%) [3], with Et3N as
base, in THF as solvent (2h, 100% on crude product (CP)) [4] or
without base (methanol, 1.5 h, 85%) [5]. 5% Pt/C was also used as
catalyst (THF as solvent, Et3N as base, 0.34 atm H2) [6] (Scheme 1):
DOI: 10.1039/x0xx00000x
www.rsc.org/
Secondary Compounds in the Catalytic
Hydrogenation of Enone and Allylic Alcohol
Prostaglandin Intermediates: Isolation,
Characterization, X-Ray Crystallography.
Constantin I. Tănase,a*Florea Cocu,a Constantin Drăghici,b
Anamaria Hanganu,b Lucia Pintilie,a Maria Maganu,b Cristian
V. A. Munteanuc and Sergiu Shovad
The discovery of the intraocular pressure reduction of 13,14-hydrogenated
prostaglandins, from which Latanoprost is the most used drug in the
glaucoma treatment, stimulated the researchers to improve its synthesis and
that of structural analogues. We studied the hydrogenation of the 13,14-
double bond of unsaturated allylic and ketone -lactone prostaglandin
intermediates
with
a
17-phenyl
or
16-(3-chloro-
or
3-
O
O
trifluoromethyl)phenoxy radical in -side chain); these intermediates,
without α-side chain, are the last in the Corey prostaglandin sequence that
could be chemo-selectively hydrogenated. The influence of the protection of
the hydroxyl(s) on the yield and the formation of the secondary compounds
in the hydrogenation was also studied. 33 Hydrogenation reactions were
made. 13 Secondary compounds were also isolated and fully characterized,
including by X-ray crystallography for two compounds, to understand the
hydrogenation reactions. The reduction by a factor of ten of quantity of the
noble palladium catalyst needed has been also obtained. The amount of
catalyst, solvent, reaction time in hydrogenations were also described. The
data for such compounds were not found in the literature and our results
HO
O
O
Steps
COOCH(CH3
)
2
11
5
5
15
15
15
OH
OR
OH
OR
OH
OH
Latanoprost
Ia, R = PPB
Ib, R = Bz
Ic, R = H
IIa, R = PPB
IIb, R = Bz
IIc, R = H
Scheme 1. Hydrogenation of the key intermediate I to II as a step
for synthesis of Latanoprost
The unprotected intermediate Ic was also hydrogenated as follows:
at atm pressure H2 (Pd/C in MeOH, 83%) [7], with NaOH as base on
5-10% Pd/C catalyst (10% based on substrate, AcOEt or EtOH, 72-
78%) [3,8], or Raney Ni catalyst (EtOH, 68%) [8], in the presence of
sodium nitrite (in EtOH-water, 33:1, (5% catalyst† / substrate), 1.5
atm H2 for 5h, 94.8-98.4% yield given on CP) (Scheme 1) [9,10]. A
hydrogenation Ic was also realized with potassium formate and 20%
Pd/C as catalyst in ethanol-water (1 h), with a combined yield with
the next DIBAL reduction of the -lactone to -lactol of 79.2-89.9 %
[11]. Some patents mentioned that during the hydrogenation of Ic,
a. National Institute for Chemical-Pharmaceutical Research and Development, 112
Vitan Av., 031299, Bucharest-3, Romania
b. Organic Chemistry Center “C.D.Nenitescu”, 202 B Splaiul Independentei, 060023
Bucharest, Romania
c. Romanian Academy-Institute of Biochemistry (IBAR), 296 Spl. Independenţei,
060031, Bucharest, Romania
d. Institute of Macromolecular Chemistry “Petru Poni”, 700478 Iasi, Romania
Electronic Supplementary Information (ESI) available: [1H-NMR and 13C-NMR copy
spectra for compounds: IIc to IIh, 2a-2c, 3a-3c, 1b-1, 2a-1, 2b-1, 5-7, 9a- 9d, 12a,
12b, 13a, 15, 15+16, 11b-1, 11a-1, 10a-2, 11a-2, crystallography data in Table 1S
for compounds 9 and (-)-3c. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
NJC., 2019, 00,
| 1
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 2 of 18
ARTICLE
New Journal of Chemistry
1
2
3
4
5
6
7
8
9
secondary products were obtained in more than 30% yield, mainly In the series of the corresponding 16-phenoxy (un)substituted
View Article Online
15 desoxy compound, without giving their full characterizations intermediates, only a few hydrogenations were done in the search
DOI: 10.1039/C9NJ01186B
[12].
to achieve similar intraocular pressure reduction effect in the
For diminish the secondary reactions in the hydrogenation of Ia-Ic, corresponding prostaglandin analogues as that of Latanoprost. For
some patents used both hydroxyl groups protected, like 5-PPB-15- example, Va was reduced in methanol (2 atm H2, 1.5 h, 100 %) with
TBDMS [TBDMS = tertbutyldimethylsilyl] (5 % (w/w) catalyst†
/
catalyst† (4.2% catalyst† / substrate) [15], and Vb was reduced in
substrate, toluene, 5.8 atm H2, overnight, 87.4% on the 98.2% AcOEt ((10% catalyst† / substrate, 2.7 atm H2, 1 h, 100 %) (Scheme
purity of the hydrogenated product) [13a], 5-PPB-15-THP in AcOEt
3) (See ref. [15], and also enzyme reduction, [19]).
(10.2 atm H2, 3h, with 20 % (w/w) catalyst† / substrate), 89%) (15-
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
epi isomer was also hydrogenated with 40 % (w/w) catalyst†
/
O
O
substrate)) [13b] or 5,15-bis-THP ( 38% catalyst† / substrate, THF,
atm pressure, 4 h, 97%) [12].
O
O
A second strategy was to first hydrogenate the double bond of
enones III to the keto derivative IV (Scheme 2), followed by the
selective reduction of the ketone to 15α-OH intermediate at the
next step, though this last reaction was generally less selective; for
example, IIIb was hydrogenated at atm pressure H2 (40.6 %
catalyst† / IIIb) in THF (86% on CP) [14]. No data are presented in
the literature for other compounds of type III, with R = H, Bz, THP,
TBDMS, etc.
5
5
15
15
O
O
OR
OR
OH
OH
X
X
Va, R = H, X = CF3
Vb, R = Bz, X = Cl
VIa, R = H, X = CF3
VIb, R = Bz, X = Cl
Scheme 3. Hydrogenation of 3-trifluoromethylphenoxy or 3-
O
O
chlorophenoxy allylic alcohols prostaglandin intermediates
O
O
From the data presented above, there are two steps in the
sequences of prostaglandin synthesis at which hydrogenation can
be selectively done and both ways were used to obtain diol IX from
enone VII (see Scheme 4): a) at the key enone intermediate VII
(hydrogenation to the ketone X, followed by the stereoselective
reduction of the ketone to diol IX) or b) at the key allylic alcohol
intermediate VIII (previously obtained from enone VII by
stereoselective reduction) to obtain diol IX. As an observation, the
stereoselective reduction of enone VII to the allylic alcohol VIII is
easier than the similar reduction of the ketone X to the diol IX. The
hydrogenation is introduced as a supplementary step in the usual
sequence for synthesis of prostaglandins:
5
5
15
O
15
O
OR
OR
IIIa, R = H
IIIb, R = PPB
IIIc, R = Bz
IVa, R = H
IVb, R = PPB
IVc, R = Bz
Scheme 2. Hydrogenation of enones III to ketones IV.
Other modified enones were also hydrogenated, as follows: 5-PPB
enones with natural IIIe or 16-F substituted -side chain IIIf (Fig.1)
[16], compound Id (a 16-cyclohexyl derivative of Ic, see Figure 1)
with a catalytic amount of 5%Pd/C (0.77% / substrate, AcOEt, 2-2.7
atm H2, 3h, 100%) [17], or even a more complex enone like 15-keto-
16-difluoro PGF2α benzyl ester used in the final stage of the
synthesis of Lubiprostone (0.77% 5%Pd/C / substrate, AcOEt, 2-2.7
atm H2, 3h, 100%) [17,18]. A promising enzymatic reduction of
enone IIIc was also realized in a one-pot three reactions to IIc (82%
yield) with P. anomala yeast, which acted as esterase, enoate-
reductase and keto-reductase [19].
O
O
O
O
H2
a)
R
R
OH
O
OH
O
O
O
X
VII
Selective reduction
of enone
Selective reduction
of ketone
HO
O
O
Steps
H2
COOR'
b)
R
R
R
OH
OH
OH
OH
OH
13,14-Dihydro PGF2
Analogues
IX
VIII
O
O
Scheme 4. The hydrogenation sequences to obtain the key allylic
alcohol intermediate IX from enone VII.
O
O
R'
The hydrogenations of prostaglandin enones with catalysts
supported on different mesoporous supports [20] were studied
mainly for the selective reduction of the ketone group to the allylic
alcohol. None were applied to production level and are not
discussed in the paper.
5
5
15
O
15
C4H9
OR
OH
OH
IIIe, R = PPB, R' = H
III f, R = PPB, R' = F
Id
Figure 1. Other enone and allylic prostaglandin intermediates
In the hydrogenations described above:
hydrogenated at the 13,14-double bond.
1) the yields are high and in those reactions with smaller yields
there is no identification of the potential secondary compounds.
Resul B. et al. mentioned in some patents [12] that the unprotected
compound Ic gave nearly 30% deoxygenation of the 15-hydroxyl
2 | NJC., 2019
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 18
New Journal of Chemistry
Please do not adjust margins
New Journal of Chemistry
ARTICLE
1
2
3
4
5
6
7
8
9
O
O
O
group, concomitant with the hydrogenation of the 13,14-double
View Article Online
DOIO: 10.1039/C9NJ01186B
O
bond; the author mentioned that this secondary reaction was
suppressed by the protection of both hydroxyl groups as THP and
subsequent hydrogenation (97% yield on crude product) [12].
2) the hydrogenation of unprotected diol Ic in the presence of
NaNO2 [9.10] improved the yield to 94-98% with no mention of the
formation of 15-desoxy secondary compound.
O
+
5
15
OH
OR
OR
OH
OH
Ic, R = H
IIc, R = H
IId
Scheme 5. Hydrogenation of compound Ic at 20 atm H2 in methanol
on catalyst† for 2h.
3) generally, the protection of the hydroxyl groups of diols I or
enones III increased the yield, without formation of secondary
compounds.
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
However, the 15-desoxy-13,14-hydrogenated by-product IId was
obtained in a smaller yield of 9.0% then the 30% yield specified in
the literature [12] and characterized; a fraction of ~ 3% contained
another lower polar secondary compound, but it was not isolated in
pure form to be analyzed. It is worth mentioning that the formation
of IId was observed even in the hydrogenation with only a smaller
quantity of 5.3 mg catalyst† (1.75 % / Ic) and at 3 atm H2.
4) the amount of used catalyst† was usually 10% (wt./wt.) based
on the substrate. In a lot of other examples, considerably larger
amounts of catalyst were used, from 20% [13b]-25% [2] to 38%
[12], 40% [13b] and 40.6% [14].
5) the influence of the solvent was not mentioned or clearly
explained.
In the present paper, we first studied the hydrogenation of the
(un)protected intermediate Ic, used in the synthesis of Latanoprost.
Then we extended the experiments to m-phenoxy-substituted
analogues of type V or to α,β-unsaturated ketone intermediates of
type III. In these reactions we wanted to identify the secondary
compounds encountered during the hydrogenation of the
prostaglandin key intermediates of types I, III and V. The second
goal of the paper was to study the hydrogenation of the double
bond of the intermediates of types I, III and V with a reduced
amount of catalyst† (near 1% / substrate).
We then found that the 5,15-bis-THP protection of Ic prevented the
formation of the secondary by-products in hydrogenation and IIg
was obtained as the only compound (99 % on CP) on a batch of 0.4
mol Ic (Scheme 6), as it was mentioned by Resul [12]. We then
protected the 5,15-hydroxyl groups of intermediate Ic as TBDMS
ether and the hydrogenation was performed also in nearly 99 %
yield (in ethyl acetate-methanol or toluene-methanol, and NaHCO3
as base to neutralize the HCl present in the catalyst, at 20 atm H2
for 2h) (Scheme 6). The advantage of this protecting group over THP
or other ether groups obtained from ethyl-vinyl ether, iso-butyl-
vinyl ether, is that the hydrogenated compound IIg is easily
crystallized (hexane-ethyl acetate, as thin needles, mp 79.7-80.2 ˚C,
>83 % crystalized), to obtain the purest compound; at this step, all
other protected compounds II were obtained as an oil. In the
literature, IIg was obtained by the hydrogenation of Ig (as a mixture
with 15-epi- isomer) over Pt/C catalyst, and crystallized from
methanol-water [21], from the hydrogenated II (R1 = TBDMS, R2 =
H) [22] or from IIc [3] by silylation. We got the same results with the
5,15-bis-benzoate intermediate Ii, the hydrogenated compound IIi
being obtained in 98.9% yield as oil. Hydrogenation of mono 5-
benzoate protected compound Ie with 2 % catalyst† / substrate
(MeOH, 3 atm H2 for 3 h) gave 66.0 % IIe, 16.5 % 15-desoxy
compound IId-1 and another (lower polar) secondary compound
not isolated in pure form, in a yield close to the one mentioned by
Resul. By the hydrogenation in the presence of NaHCO3 to
neutralize the acid present in the catalyst and for half time (90 min),
the yield of IIe increased to 91.5%. In these last conditions, the 15-
epimer IIf was obtained in 91%. In conclusion, the protection of the
5,15-hydroxyl groups increased the chemo-selectivity of
hydrogenation, and as a consequence, the yield of the reaction
increased to ~99%; for monobenzoates Ie and If, the neutralization
of the acid present in the catalyst and the reduction of the time for
hydrogenation increased the yield to 91%; it is to be mentioned
that the hydrogenation was done with ~2% catalyst† / substrate.
The 15-desoxy secondary compound IId-1 was isolated and
characterized after hydrolyzation to IId.
2. Results and discussion
In this paper we tried to find some insight into the problems
encountered in the hydrogenation of the prostaglandin
intermediates of allylic diol or α,β-unsaturated ketone types. We
organized section 2 in the following subsections:
1. Hydrogenation of allylic alcohol or enone prostaglandin
intermediates over catalyst† (in a ratio of 10% or greater /
substrate):
1.1. Hydrogenation of (un)protected diols used in the
synthesis of Latanoprost,
1.2. Hydrogenation
intermediates,
of
16-(m-substituted)phenoxy
1.3. Hydrogenation of enone intermediates,
2. Hydrogenations with a reduced amount of catalyst† to 1-3% /
substrate
3. Analysis of the compounds
3.1. NMR and IR Spectroscopic analysis
3.2. X-Ray crystallography of the secondary compounds 9b
and (-)-3c.
1. Hydrogenation of allylic alcohol or enone prostaglandin
intermediates over 10% Pd/C (in a ratio of 10% or greater /
substrate),
1.1. Hydrogenation of (un)protected diols used in the
synthesis of Latanoprost
We began with the hydrogenation of the diol intermediate Ic used
for obtaining Latanoprost. The allylic alcohol Ic (1 mmol) was
hydrogenated with a 10% quantity of catalyst (30 mg catalyst†)
based on substrate, in methanol at 20 atm. H2 for 2 h. The crude
product was purified by low pressure chromatography (LPC) and we
obtained the 13,14-hydrogenated compound IIc in 88.0% yield
(Scheme 5), in a greater yield then the 70% mentioned by Resul B.
in a different experiment [12], the yield being of course influenced
by pressure, solvent used, and reaction time.
This journal is © The Royal Society of Chemistry 20xx
NJC., 2019| 3
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 4 of 18
ARTICLE
New Journal of Chemistry
1
2
3
4
5
6
7
8
9
O
O
O
O
obtaining the corresponding 13,14-dihydro-phenoxy-prostaglandin
View Article Online
O
O
analogues for their preliminary screening. Using a smaller quantity
DOI: 10.1039/C9NJ01186B
H2 / 10%Pd/C
of catalyst, compounds 2a and 3a were obtained in 75.5% yield,
respectively 16.9% yield. For 2a, this was close to the reported 70%
yield for the phenyl analogue IIc [15]. In the hydrogenation of 1b
with 3-(trifluoromethyl) phenoxy, 2b was obtained in 78% yield
together with only 9.5% 3b. 15-Desoxy by-products 3a, 3b and 3c
were obtained pure, as an oil ((-)-3c also as white crystals), by low
pressure chromatography (LPC) purification of the crude
hydrogenation mixture of compounds 2 and 3, and characterized,
no physico-chemical data having been presented in the literature.
From these experiments it resulted that in all cases, the 15-desoxy
by-products 3a, 3b and 3c were formed in the hydrogenations and
the yields of the 13,14-hydrogenated compounds 2a, 2b and 2c
were high, but a little smaller than those mentioned in the
literature (100% in refs [15]).
We then used the 5,15-bis acetate compound 4, considering that
this protected compound could give only the hydrogenated product
5 (Scheme 8). Its hydrogenation (3.38 g, 8 mmol) with 300 mg
catalyst† (in 150 mL ethyl acetate at 3 atm H2 for 1.5 h) did not
finish (but in TLC only one hydrogenated compound was observed)
and the compound remained in the autoclave overnight, without
stirring. We changed the idea to obtain only one compound, 5.
Therefore, a supplementary quantity of catalyst† (120 mg) was
added and the mixture was stirred for 2h at 3 atm H2. We wanted
to see to what extent the secondary byproducts were formed in the
hydrogenation, and then to isolate and characterize them; in the
literature, there is little or no data about these secondary
compounds and their characterization. Indeed, the TLC showed the
formation of two other secondary compounds, besides the major
compound 5. The crude product was purified by LPC; the major
product and the two secondary compounds were obtained pure
and their structure was established by 1H-, 13C- and 2D NMR
spectroscopy. The major more polar 13,14-hydrogenated product 5
was isolated in 73.0% yield; the smaller polar compound, isolated in
15.7 % yield, was the 13,14-hydrogenated-15-desoxy compound 6;
the one with the smallest polarity was compound 7, isolated in
11.4% yield, and formed by breaking the link between the aliphatic
part of the side chain and the oxygen of the m-chloro-phenoxy
group (Scheme 8). It is very interesting that the aromatic chlorine
atoms of compounds 5 and 6 were not dehydrohalogenated, as it
could be seen in the NMR by the presence of the four protons and 6
different carbon atoms of the aromatic fragment. By
transesterification (MeONa/MeOH), the bis-acetate compound gave
the hydrogenated diol 2a, in 94.1% yield, with the same
characteristics as those of the compound obtained by the
hydrogenation of the allylic alcohol intermediate 1.
5
5
15
15
OR1
OR1
OR2
Ig, R1 = R2
OR2
OR
OH
IIg, R1 = R2 = THP
IIh, R1 = R2 = TBDMS
IIi, R1 = R2 = Bz
Ic, R = H
=
THP
Ih, R1 = R2 = TBDMS
Ii, R1 = R2 = Bz
IIe, R1 = Bz, R2 = H
II f, R1 = Bz, OR2 = 15-OH
IId-1, OR2 = H
H2 / 10%Pd/C
Ie, R = Bz
I f, R = Bz
15-OH
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
Scheme 6. Hydrogenation of 5- or 5,15,-OH protected groups of
compound Ic.
1.2.
Hydrogenation
of
16-(m-substituted)phenoxy
intermediates
After these findings on 16-phenyl diol intermediates I, we studied
the hydrogenation of 16-(3-substituted phenoxy) allylic alcohol
intermediates 1, in order to obtain the corresponding 13,14-
hydrogenated intermediates 2 (Scheme 7) to be used in the
synthesis of 16-aryloxy analogues of Latanoprost (The next steps to
the final prostaglandin analogues are well established and we do
not describe them here). In the literature, a few patents described
the synthesis of 13,14-hydrogenated 3-trifluoromethyl- and 3-
chloro-phenoxy analogues of type 2, the hydrogenation being done
on the unprotected diol 1b [15] or on the 5-benzoate protected diol
Vb (100% yield), (Scheme 3) [15]. We started with the racemic diol
1a (2 g) which contained also the 15-epi-isomer (Scheme 7), and
hydrogenated it at 2 atm H2 for 2h, in methanol (300 mg catalyst†,
15%w/w). We discovered two compounds, 2c and 3c, both formed
by the dehydrohalogenation of the chlorine linked to the phenoxy
group, instead of the 2a desired compound:
O
O
O
H2/10%Pd/C
MeOH or EtOAc
O
O
O
+
O
O
O
OH
OH
O
OH
O
OH
1a, R = Cl
1b, R = CF3
1c, R = H
OH
2a, R = Cl
R
R
R
3a, R = Cl
3b, R = CF3
3c, R = H
2b, R = CF3
2c, R = H
TBDMSCl,
Im, DMAP
THF
H2/10%Pd/C
EtOAc
O
O
O
O
OTBDMS
OTBDMS
OTBDMS
1a-1, R = Cl
1b-1, R = CF3
OTBDMS
2a-1, R = Cl
2b-1, R = CF3
R
R
Scheme 7. Hydrogenation of the allylic alcohols 1a and 1b to the
key intermediates 2a, 2b and 2c, or the corresponding TBDMS-
protected compounds 1a-1 and 1b-1 to 2a-1 and 2b-1.
O
O
O
O
O
O
+
O
O
The phenoxy compound 2c was obtained in 44.3 % yield. From the
15-desoxy-hydrogenated compound 3c, a pure fraction was isolated
in 23.3% yield, as an oil. A better yield (76.6 %) of pure enantiomer
(-)-2c was obtained with a 4.2 % Pd/C catalyst ((-)-3c was also
isolated). In this case, both compounds were by-products of the
hydrogenation reaction and their structure was easily proved in 1H-
and 13C-NMR by the appearance of the five protons and four carbon
types characteristic for the phenoxy group, instead of the signals for
3-chloro-phenoxy fragment; (-)-3c was also characterized by X-ray
crystallography (See 3.2). It is worth mentioning that the phenoxy
analogue 2c could be obtained in this way in moderate yield from
1a, especially in small quantities, an important aspect for its use in
O2CCH3
O2CCH3
O2CCH3
O
O2CCH3
6
4
7
Cl
Cl
O
+
O
O
MeONa/MeOH
O
O
O2CCH3
OH
O2CCH3
OH
Cl
Cl
5
2a
Scheme 8. Hydrogenation of 5,15-bis-acetate protected diol
compound 4.
1.3. Hydrogenation of enone intermediates
4 | NJC., 2019
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 18
New Journal of Chemistry
Please do not adjust margins
New Journal of Chemistry
ARTICLE
1
2
3
4
5
6
7
8
9
The hydrogenation of the enone type intermediates was also appearance of the signals for semiketal 13a (OH, δ 6.00, δ C15, 96.1
studied. The hydrogenation of enone 8a in the same conditions ppm). The pure (-)-12a was stable in the freezer (-1V5iew˚CA)rtficolerOonvliener
DOI: 10.1039/C9NJ01186B
[16.7 % catalyst†/ 8a, methanol, 3 atm H2 for 1.5 h] as for 1a to 2c + one month.
3c, gave the intramolecular six-atom cyclized ketal compound 9c, The hydrogenation of δ-lactone-enone intermediate 14 in the usual
formed by the chemo-selective hydrogenation of the double bond, conditions (9.6% catalyst† / 14, NaHCO3, 3 atm H2, 45 min), gave 15
followed by the also chemo-selective reaction of the ketone with as the only product observed in TLC (isolated pure in 88.1% yield)
the 11-hydroxyl and methanol, catalyzed by the trace HCl present in (Scheme 10). With an increased quantity of catalyst (13.3% / 14,
the catalyst† (Scheme 9); in the reaction, the chlorine atom was also NaHCO3, atm pressure of H2, 4 h) an unseparable mixture of 15 and
dehydrohalogenated as previously described. A similar cyclized 16 was obtained in a ratio of 60: 40, as estimated by NMR, in a
compound 9a is presented in the literature as obtainable by the combined 78% yield. An increased quantity of catalyst favored the
treatment of 12 (X = O, Y = Cl) with methanol in the presence of dehydrochlorination, and as a consequence, a decrease in the
H2SO4 as acid catalyst [23]. Compound 12 is postulated to be in chemo-selectivity like in the similar previous examples.
equilibrium with the hydroxyl-ketal 13a, which is shifted toward the
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
O
O
O
methoxy-ketal 9a by acid catalysis with methanol.
O
O
O
+
Cl
Cl
Cl
Cl
Cl
O
O
O
O
O
O
O
15
O
O
16
14
O
O
O
X
X
X
Scheme 10. Hydrogenation of δ-lactone-enone intermediate 14.
OH
O2CR
O
O2CR
O
O
O
O
12a, X = O, Y= Cl
12b, X = CH2, Y=H
11a-1, R = C6H5
11a-2, R = CH3
11b-1, R = C6H5
Y
10a-1, R = C6H5
10a-2, R = CH3
Y
Y
O
O
Hydrogenation of the 5-protected enones 10a-1, 10b-1 and 10a-2
with a reduced quantity of catalyst† / substrate (1.13% 10a-1, 2.5%
10b-1, 5% and 1% 10a-2) gave compounds 11 straightforward, in
yields greater than 90% (Scheme 9) (>88% 11a-1, quant% 11b-1,
97.7 % and 94.7% 11a-2) with the predicted chemo-selectivity.
Hence, the hydrogenation of enones 8 in methanol and ethanol
lead to the crystallized alkoxy-ketals 9 in high yields, in isopropanol
or in a non-alcoholic solvent like ethyl acetate to the awaited
compounds 12 (the same is for enone 14), and of 5-hydroxy
protected enones 10 to the compounds 11, all cases with
remarkable chemo-selectivity. The hydrogenation of α,β-
unsaturated ketones proceeded faster than that of the diol type
intermediates. With an increased quantity of catalyst† (~16%) and
reaction time, a dehydrochlorination of the m-substituted chlorine
was also observed.
O
O
O
O
X
O
OH
O
O
O
X
X
X
8a, X = O, Y = Cl
8b, X = CH2, Y = H
Y
O
OH
MeOH/H+
O
Y
Y
Y
13a
9a, X = O, Y = Cl
9b, X = CH2, Y = H
9c, X = O, Y = H
9d, X = O, Y = Cl
Scheme 9. Catalytic hydrogenation of the prostaglandin enone
intermediates 8 and 9.
With a reduced quantity of catalyst† (3.3% / 8a) and reduced
hydrogenation time to 15 min, 9a was the only compound formed
in the reaction, in 94.4% yield, with similar characteristics as
presented in refs [23]. By changing the solvent, ethanol instead of
methanol, the corresponding ethoxy-ketal 9d was obtained in
90.4% yield. In the case of 8b, with a benzyl fragment instead of the
previous m-chlorophenoxy fragment, the same type of
intramolecular ketal compound 9b was obtained after 25 min, in
92.6% yield. All compounds 8 were chemo-selectively hydrogenated
to the double bond, followed by an also chemo-selective reaction of
the ketone with the secondary 5- hydroxyl and the solvent (MeOH
or EtOH) with closing a six-atom alkoxy-ketal; 9a-9d were obtained
in yields greater than 90%, which is very interesting, since they are
all byproducts instead of the awaited 12a-12b hydrogenated
compounds. Their structure was established by NMR and confirmed
by X-ray crystallography for compound 9b (see X-ray
crystallography).
In the hydrogenation conditions of the diol and α,β-ketone
prostaglandin intermediates,
a
great
number of secondary
compounds were obtained and each by-product was isolated and
fully characterized, including by X-ray crystallography for two of
them. The data for such compounds were not found in the
literature and our results could be useful for researchers in the
prostaglandin field and more generally for organic chemistry, where
secondary compounds could result in the hydrogenation of allylic
alcohols or enones.
The formation of the secondary compounds should be taken as a
challenge, not as
a tragedy. They must be isolated and
characterized, the mechanism by which they appeared must be
understood, and then the reaction conditions must be optimized in
order to minimize or to prevent their formation.
By changing the solvent from a primary alcohol (like methanol or
ethanol) to a secondary alcohol, like iso-propanol, 12a was obtained
as the only compound from 8a, the internal cyclization of ketone to
the corresponding iso-propoxy-ketal being sterically hindered. In a
non-alcohol solvent like ethyl acetate, 12a and 12b were also
obtained in high yield (~94 %) as singular compounds from 8a and
respectively from 8b. It is evidenced that for enones 8, the solvent
influenced the course of the hydrogenations towards either the
internal ketals 9 or the ketone compounds 12. It is to be mentioned
that the crude compound 12a was partially cyclized to 13a in time
at rt, and isolated in 16.2% after LPC purification. This is easy to put
2. Hydrogenations of diol and enone-intermediates with a
reduced amount of 10% Pd/C catalyst (1-3 % based on the
substrate), in an environmentally friendly manner.
The hydrogenations of the diol or enone type prostaglandin
intermediates are usually performed with a catalyst† / substrate
ratio of 10% or greater which was observed to be associated
(among other things) with the formation of secondary compounds,
and so with a decrease in the selectivity of the reaction. Only in a
few patents a reduced amount of catalyst† was used [17,18].
1
in evidence in H-NMR and 13C-NMR by the disappearance of the
We observed in our preliminary experiments that the amount of
catalyst† / substrate could be reduced to nearly 1-2% and the
signals for ketone 12a (OH, δ 3.38, C15, δ 205.46 ppm) and the
This journal is © The Royal Society of Chemistry 20xx
NJC., 2019| 5
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 6 of 18
ARTICLE
New Journal of Chemistry
1
2
3
4
5
6
7
8
9
hydrogenation of the compounds Ie and If, presented above, was
realized with ~2% catalyst† /substrate in near 91% yield (Table 1,
entries 11-12). Then we extended the hydrogenation with a
reduced amount of catalyst to all types of diol and enone
intermediates used above; the results are presented in Table 1:
One can observe from Table 1 that the yields of the hydrogenated
prostaglandin intermediates, diols and enones, with a reduced
amount of catalyst† were very close to those obtained with a 10%
(w/w) catalyst† / substrate ratio (entries 1-6). Enones 10b-1, 10a-1,
10a-2 and 14 were also hydrogenated in high yields (entries 7-10)
with a reduced amount of catalyst†.
View Article Online
DOI: 10.1039/C9NJ01186B
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
Table 1. Hydrogenation of diol and enone prostaglandin intermediates with a reduced amount of catalyst†
Starting
compd /
exp. no
1a
Substrate
catalyst†
amount
(mg)
catalyst†/
substrate
ratio
Solvent
(mL)
H2
(atm)
Time
h or min
Conditions1 with
Product
>10% catalyst†
(g or
mmol
mg)
4.5 g
13.28
70
1.56 %
EtOAc
(150)
3
45 min
2a, 3.58 g
(79.2 %)
Press.atm.
75.5% 2a,
16.9% 3a
3.1
Ic
3.2
8a
3.3
8a
3.4
8a
3.5
8b
3.6
10b-1
3.7
10a-1
3.8
10a-2
3.9
14
3.10
Ie
1.1.5
If
1.1.6
302 mg
2 g
1
5.94
5.94
11.88
6
5.3
20
1.75 %
1 %
MeOH
(50)
3
3
3
3
3
6
3
3
3
3
3
2 h
IIc, 267 mg
(88.5 %)
12a, 1.88 g,
93.5 %
12a, 1.86 g,
92.4 %
9a, 4.18 g,
95.5 %
12b, 1.69 g
(93.2 %)
(-)-10b-2,
quant.
11a-1, 1.17g
crist (88%)
11a-2, 2.53 g
(94.7%)
15, 2.84 g
(94.7 %)
20 atm, 2 h
88.0% IIc, 9% IId
3 atm2, 50 min
94.8% (-)-12a
3 atm, 20 min
94.5 % (±)-12a
3 atm, 15 min
94.4%
3 atm3, 50 min
94.8% 12b
-
EtOAc
(150)
i-PrOH
(150)
MeOH
(150)
i-PrOH
(150)
THF
(150)
EtOAc
(150)
EtOAc
(150)
EtOAc
(150)
MeOH
(50)5
60 min
75 min4
50 min
75 min4
2 g
40
2 %
4 g
40
1 %
1.6 g
10 g
40
2.2 %
2.5 %
1.13 %
1 %3
1 %
24.7
3
250
15
TLC
monitoring
135 min
1.33 g
2.59 g
3 g
-
6.8
8.4
1
27
135 min
50 min
90 min
90 min
3 atm3, 30 min
97.7% 11a-2
30
-
0.406
6.34 g
8.5
150
2.1%
2.4%
IIe, 372 mg
(91.5%)
IIf, 5.77 g
(91%)
-
-
15.6
MeOH
(150)
1Hydrogenation with 10% catalyst†/ substrate, where no other ratio is specified. 2Hydrogenation with 5.3% catalyst†/ substrate;
3Hydrogenation with 5% catalyst†/ substrate, 4Not optimized; < 20% enone remains after 40 min reaction, 5with 100 mg NaHCO3 for Ie and
200 mg NaHCO3 for If. In all cases, the NMR analysis of the crude product established the end of hydrogenation.
6 | NJC., 2019
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 18
New Journal of Chemistry
Please do not adjust margins
New Journal of Chemistry
ARTICLE
1
2
3
4
5
6
7
8
9
We observed a slight increase of the yield of 2a (from 75.5% to protected compound to appear as a mixture of two compounds. For
View Article Online
79.2%) in the case of diol 1a, and a decrease in the quantity of the the two protecting groups, as for the chromatographically pure
DOI: 10.1039/C9NJ01186B
15-desoxy byproduct IId (from 9% to 4.4%) in the case of diol Ic.
compound IIg, there is a mixture of 4 compounds. This is clearly
Generally, a little longer hydrogenation time is necessary to finish observed in 13C-NMR spectra (See SI 1.1.3.), where four signals
the reaction, but this is not a problem. These findings show that the appear for a specified carbon atom. This is more evident for the
reduction of the amount of catalyst† comes with beneficial effects, following carbon atoms: C3a (43.02, 42.90, 42.51, 42.43), C4 (53.32,
besides the reduction of the price of the noble catalyst used. The 53.01, 52.13, 51.69), C15 (76.38, 76.33, 76.05, 75.98), for example.
1
formation of the secondary compounds is suppressed in the case of In the H-NMR spectra of IIg, only multiplet signals appear for each
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
the protected prostaglandin intermediates in the hydrogenation proton. We also confirmed the chemical structures of two of the
with a catalyst† / substrate ratio of 10% (w/w) or greater, but the byproducts, 9b and (-)-3c, by X-ray crystallography, in addition to
use of a reduced amount of catalyst is still desirable and possible the NMR data.
(see entry 7). In conclusion, the reduction of the amount of The IR Spectra in ATR present accurately the vibration bands of the
catalyst† could be applied to other allylic or α,β-unsaturated functional groups of each molecule. The vibration band for the
compounds, an aspect interesting for organic chemists, for the lactone group of 2a appears at 1719 cm-1, probably due to an
economical (aspect) and cleaner hydrogenation (with reduced intramolecular hydrogen bond with 15-OH in the crystal. In CHCl3,
byproducts).
the polarity of the solvent does not favour the hydrogen bond and
this band moves to 1756 cm-1, a correct value for the lactone group.
3. Analysis of the compounds
3.2 X-Ray crystallography of the secondary compound
9b and (-)-3c
3.1 NMR and IR Spectroscopic analysis
According to X-ray crystallography the crystal belongs to
a
In the hydrogenation of all prostaglandin intermediates, the
difference between the Rf’s of the starting compounds and Rf’s of
the hydrogenated products in TLC are too small to precisely indicate
the end of the reaction. The spots of the starting compounds
developed shortly after spraying with 15% H2SO4 in methanol and
heating at 110˚C, but the spots of the corresponding hydrogenated
products (and of the byproducts also) appeared with difficulty after
a prolonged time of heating the plate. Under these conditions, the
end of the hydrogenation was determined with accuracy by the
NMR analysis of the reaction mixture, which confirmed the
disappearance of the alkene protons. For pure products, 1H-, 13C-
and 2D-NMR analysis are indispensable for determining their
correct chemical structure. The same is true for the byproducts
resulted in those hydrogenations where they appear. The 13C-NMR
spectra of 15-desoxy byproducts show the disappearance of the
C15-OH atoms from δ (ppm): 71.25 (IIc), 77.53 (2a), 69.92 (2b),
68.47 (2c) and the appearance of the methylene C15 carbon atom at
δ (ppm): 31.22 (IId), 29.06 (in DMSO) (3a), 32.83 (3b), 29.31 (3c).
The same is observed in the 1N-NMR spectra, namely the
disappearance of H-C15-OH at δ (ppm): 3.61 (IIc), 3.99 (2a), 4.06-
3.96 (2b), 3.80-3.68 (2c), and appearance of δ (ppm): 1.65-1.57
(IId), 1.78-1.60 (3a), 1.81 (3b), 1.78 ((-)-3c), in the field of ppm for
the methylene protons linked to C15 carbon atoms (See SI 1.2.). The
hydrogenation of enones 8a and 8b in methanol and ethanol gave
byproducts 9a-9b, by a sequence of two chemo-selective reactions:
hydrogenation of the double bond followed by acid catalyzed
internal closing of a six-atom ring of a ketal structure through
addition of the 5-OH and methanol or ethanol to the 15-ketone.
The formation of the cyclic ketal is evidenced especially in the 13C-
NMR spectra were the signals for the ketone group at δ (ppm):
205.50 (12a) or 209.91 (12b) disappeared and the new signals
appeared at δ (ppm): 99.09 (9a), 100.60 (9b), 98.88 (9c), 99.08 (9d)
for a ketal C15 carbon atom, and of course, the appearance of the
carbon for the methoxy or ethoxy group, δ (ppm): 48.15 (9a), 47.15
(9b), 45.57 (9c), 55.86 and 15.41 for ethyl group of 9d (See SI 1.3.1-
1.3.4.). All other signals confirmed the chemical structure of each
product and byproduct.
monoclinic system and crystallizes in the P21 space group, with one
molecular species as the crystallographic asymmetrical entity in the
unit cell, as shown in Figure 2. The values of the bond lengths and
angles are summarized in Table1S.
Figure 2. X-ray molecular structure of compound 9b, with atom
labeling and thermal ellipsoids at 50% probability. The angles and
torsion angles around the ketal group (deg.): C7-C6-O3 =113.1(2), C6-
O3-C10 = 111.8(2), O3-C10-O4 = 110.8(2), C9-C10-O4 = 104.4(2), C9-C10-
C12 = 113.0(3), O4-C10-C12 = 112.7(2), C11-O4-C10 = 115.9(2); C10-O3-
C6-C7 = 59.6(3), C6-O3-C10-O4 =61.9(3), C6-O3-C10-C9 = -54.2(3), C6-O3-
C10-C12 = -176.7(2), C11-O4-C10-O3 = 55.2(3), O3-C10-C12-C13 = -
175.8(3), C8-C9-C10-O3 = 51.5(4), C11-O4-C10-C9 = 175.((2), C9-C10-C12-
C13 = 62.5(4), O4-C10-C12-C13 = -55.6(4), C9-C10-C12-C13 = 62.5(4), C11-
O4-C10-C12 = -61.1(3)
The neutral molecules in the crystal are associated due to the C-H---
 interactions of 2.886 to form supramolecular chains, as shown in
Figure 3. The further analysis of the crystal packing indicates the
presence of a discrete parallel packed 1D architecture running along
the b-axis.
Tetrahydropyranyl (THP) is a good chemically stable protecting
group in base conditions, but the interpretation of the 1H-, 13C- and
2D-NMR spectra for the compounds protected in this way becomes
very difficult. The THP group has a chiral C1 atom which makes the
This journal is © The Royal Society of Chemistry 20xx
NJC., 2019| 7
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 8 of 18
ARTICLE
New Journal of Chemistry
1
2
3
4
View Article Online
DOI: 10.1039/C9NJ01186B
5
6
7
8
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
Figure 3. A view of the supramolecular chain in the crystal structure
of 9b.
The result of the X-ray diffraction study for (-)-3c is shown in figure
4. The compound crystallizes in the P21212 space group of the
orthorhombic system without co-crystallized solvent molecules. The
values of the bond lengths and angles are summarized in Table1S.
The crystal packing essentially results from the parallel packing of
the supramolecular chains (Figure 5) formed by the hydrogen
bonding between adjacent molecules where the hydroxyl group
acts as donor while the oxygen atom of the heterocycle as acceptor
of proton.
Figure 5. 1D H-bonded supramolecular architecture in the crystal
structure of (-)-3c. H-bond parameters: O2-H---O3[O2-H 0.82 Å, H---
O3 2.072 Å, O2---O3(-0.5 + x, 1.5 - y, 2 - z) 2.863(5) Å, O2HO3
163.0].
4. Experimental
Melting points (uncorrected) were determined in open capillary on
an OptiMelt melting point apparatus. The progress of the reaction
was monitored by TLC on silica gel 60 or 60F254 plates (Merck)
eluted with the solvent systems: I ethyl acetate-hexane-acetic acid
(5:4:0.1), II (benzene-ethyl acetate-methanol-80% formic acid,
20:80:3:2), III (ethyl acetate-hexane-acetic acid, 5:1:0.1), IV
(toluene-ethyl acetate, 1:1), V (ethyl acetate-methanol-acetic acid,
90:13:1), VI (benzene-acetone, 1:1), VII (heptane-ethyl acetate).
Spots developed in UV, 2,4-dinitrophenylhydrazine reagent or with
15% H2SO4 in MeOH (heating at 110˚C, 10 min). IR spectra were
recorded on FT-IR-100 Perkin Elmer spectrometer, in solid phase by
ATR and frequencies were expressed in cm-1, with the following
abbreviations: w = weak, m = medium, s = strong, v = very, br =
broad. MS were recorded on a 1200 L/MS/MS triple-quadrupole
Varian with ESI interface, fragments, obtained by collision with Ar
are given in parenthesis. 1H-NMR and 13C-NMR spectra are recorded
on Varian Gemini 300 BB spectrometer (300 MHz for 1H and 75 MHz
for 13C), or Bruker Avance III 500 MHz spectrometer (500 MHz for
1H and 125 MHz for 13C), spectrometer chemical shifts are given in
ppm relative to TMS as internal standard. Complementary spectra:
2D-NMR and decoupling were done for the correct assignment of
NMR signals. The numbering of the atoms in the compounds is
presented in Schemes. 10% Pd / C has been bought from Merck,
solvents were of pure grade.
Figure 4. X-ray molecular structure of compound (-)-3c, with atom
labeling and thermal ellipsoids at 50% probability. Selected bond
angles and torsion angles around the cyclopentane fragment (deg.):
C10-C11-C15 = 112.9(5), C16-C15-C11 = 115.3(5), C16-C15-C14 =
103.1(4), C13-C14-C15 = 106.7(4), O3-C14-C13 = 110.3(5), O3-C14-
C15 = 106.5(4), C14-C13-C12 = 104.7(5), O2-C12-C13 = 112.0(5),
C13-C12-C11 = 103.5(5), O2-C12-C11 = 106.2(5); C10-C11-C15-C16 =
148.6(5), C10-C11-C15-C14 = -98.4(5), C13-C14- C15-C11 = 1.5(6),
C13-C14- C15-C16 = 122.8(5), O3-C14-C15-C11 = -116.4(5), O3-C14-
C15-C16 = 4.9(6), C12-C13-C14-C15 = -24.9(6), C12-C13-C14-O3 =
90.5(5), O2-C12-C13-C14 = -75.1(5), C11-C12-C13-C14 = 38.9(6),
C10-C11-C12-C13 = 84.1(6), C10-C11-C12-O2 = -157.8(5).
X-Ray crystallographic measurements were carried out with an
Oxford-Diffraction XCALIBUR E CCD diffractometer equipped with
graphite-monochromated Mo-Kα radiation. Single crystals were
positioned at 40 mm from the detector and 716 and 194 frames
were measured each for 5 and 15 s over 1° scan width for 9b and (-
)-3c, respectively. The unit cell determination and data integration
were carried out using the CrysAlis package of Oxford Diffraction
[24]. The structure was solved by direct methods using Olex2 [25]
and refined by full-matrix least-squares on F² with SHELXL-97 [26].
8 | NJC., 2019
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 18
New Journal of Chemistry
Please do not adjust margins
New Journal of Chemistry
ARTICLE
1
2
3
4
5
6
7
8
9
Atomic displacements for non-hydrogen atoms were refined using Largest diff. peak
an anisotropic model. All H atoms attached to carbon were and hole/e·Å-3
introduced in idealized positions (dCH = 0.96 Å) using the riding
0.13/-0.19
0.20/-0.16
View Article Online
DOI: 10.1039/C9NJ01186B
model with their isotropic displacement parameters fixed at 120%
of the riding atom. Hydrogen atoms for OH and NH groups have
been placed by Fourier Difference and refined accounting for
hydrogen bonds parameters. In the absence of significant
anomalous scattering, the absolute configuration of the structure
could not be reliably determined. As a result, Friedel pairs were
merged and any references to the Flack parameter were removed.
The molecular plots were obtained using the Olex2 program. The
crystallographic data and refinement details are quoted in Tables 2,
while bond lengths are summarised in Tables 1S. Crystallographic
data have been deposited at the Cambridge Crystallographic Data
Centre as Supplementary Publication No. CCDC – 1561067 (for 9b)
and -. 1883073 (for (-)-3c). Copies of the data can be obtained free
of charge from CCDC (12 Union Road, Cambridge CB2 1EZ, UK; Tel.:
2 2
2 2
a R1 = Fo - Fc/Fo, b wR2 = {[w (Fo2 - Fc ) ] /[w(Fo ) ]}1/2. c GOF
2 2
= {[w(Fo2 - Fc ) ] /(n – p)}1/2, where n is the number of reflections
and p is the total number of parameters refined.
1. Hydrogenation of allylic alcohol or enone prostaglandin
intermediates over 10% Pd/C catalyst (in ratio equal or greater
than 10% w/w based on substrate)
1.1. Hydrogenation of (un)protected diols used in the synthesis of
Latanoprost
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
1.1.1. Hydrogenation of the diol Ic
Ic (1 mmol, 302 mg) with catalyst† (30 mg) in methanol (50 mL) was
hydrogenated at 20 atm H2 for 2 h, monitoring the end of reaction
by TLC (I, Rf IIc = 0.12, Rf IId = 0.44). The catalyst was filtered, washed
with methanol, the solvent distilled under reduced pressure and the
crude product was purified by LPC (ethyl acetate-heptane, 1:1),
resulting 27 mg (~9%) of secondary compound (3aR,4R,5R,6aS)-5-
hydroxy-4-(5-phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2-
one, as an oil, IId, [α]D = -19.0 ˚(0.685% in THF), IR: 3440brm, 2927s,
2855m, 1757vs, 1495w, 1453w, 1363w, 1307w, 1176m, 1073m,
1032m, 747m, 699m, IR: 3438brm, 2927s, 2855m, 1453w, 1362w,
1308w, 1175s, 1073m, 1032m, 971w, 747w, 699m, 1H-NMR-300
MHz (CDCl3, δ ppm, J Hz): 7.28 (tl, 2H, H-m, 7.9), 7.18 (brt, 1H, H-p,
7.9), 7.16 (dl, 2H, H-o, 7.9), 4.96 (dd, 1H, H-6a, 1.6, 7.0), 4.01 (dt,
1H, H-5, 4.4, 4.6), 2.80 (dd, 1H, H-3, 11.2, 18.8), 2.60 (t, 2H, H-17,
7.6), 2.54 (m, 1H, H-3a), 2.51 (dd, 1H, H-3, 2.8, 18.8), 2.22 (dt, 1H,
H-6, 5.7, 14.9), 2.04 (brd, 1H, H-6, 14.9), 1.83 (m, 1H, H-4), 1.66-1.57
(m, 2H, H-15), 1.40-1.31 (m, 5H, 2H-13, 2H-14,1H-16), 1.14 (m, 1H,
H-16), 13C-NMR-75 MHz (CDCl3, δ ppm): 177.87 (C-2), 142.50 (C-
1Ar), 128.32, 128.21 (4CH, C-o, C-m), 125.61 (C-p), 84.28 (C-6a),
77.56 (C-5), 54.28 (C-4), 42.96 (C-3a), 40.42 (C-6), 36.79 (C-3), 36.22
(C-17), 33.03 (C-16), 31.22 (C-15), 29.29 (C-14), 27.53 (C-13), (ESI
1.1.2),
+
44 1223 336 408; fax: +44 1223 336 033; e-mail:
deposit@ccdc.cam.ac.uk; www:http://ccdc.cam.ac.uk).
Table 2. Crystallographic data, details of data collection and
structure refinement parameters.
9b
C19H24O4
(-)-3c
C17H22O4
Chemical formula
M/g mol-1
Temp./K
316.38
160
290.34
293
Crystal system
monoclinic
orthorhombic
P21212
Space group
P21
a/Å
7.4702(4)
7.6481(17)
30.186(4)
6.7702(6)
90
b/Å
c/Å
α/°
/°
8.3687(4)
13.8595(7)
90
and 268 mg (88.0%) of compound (3aR,4R,5R,6aS)-5-hydroxy-4-(5-
phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2-one, IIc, as an oil,
[α]D = -32.6 ˚(1 % in THF), IR: 3389brs, 2931s, 2859m, 1747vs,
1453m, 1415w, 1363w, 1179s, 1074m, 1030s, 969w, 748w, 700m,
1H-NMR-300 MHz (CDCl3, δ ppm, J Hz): 7.28 (t, 2H, H-m, 8.0), 7.30-
7.17 (m, 3H, 2H-o, 1H-p), 4.93 (dt, 1H, H-6a, 2.0, 6.8), 3.98 (q, 1H, H-
5, 5.1), 3.61 (m, 1H, H-15), 2.78 (dd, 1H, H-3, 11.0, 18.3), 2.71 (dt,
1H, H-17, 8.2, 14.8), 2.65 (m, 1H, H-17), 2.49 (m, 1H, H-3a), 2.49 (d,
1H, H-3, 18.3), 2.28 (dt, 1H, H-6, 6.1, 14.0), 2.02 (brd, 1H, H-6, 14.0),
1.82-1.72 (m, 3H, H-4, 2H-16), 1.57-1.47 (m, 3H, H-13, 2H-14), 1.25
(m, 1H, H-13), 13C-NMR-75 MHz (CDCl3, δ ppm): 177.89 (C-2),
141.86 (C-1’), 128.43, 128.36 (2C-o, 2C-m), 125.89 (C-p), 84.02 (C-
6a), 77.35 (C-5), 71.25 (C-15), 53.86 (C-4), 43.12 (C-3a), 40.34 (C-6),
39.06 (C-16), 35.99 (C-3), 35.17 (C-14), 32.00 (C-17), 28.91 (C-13),
(See ref. 1, 5 and ESI 1.1.1.), MS 304.38 calcd. for C18H24O4 [M+1]+:
103.173(5)
90
90
γ/°
90
V/Å3
843.64(7)
1563.0(4)
Z
2
4
Dc/g cm-3
1.245
1.234
/mm-1
Crystal size/mm3
0.086
0.45 × 0.3 × 0.15
0.087
0.2 × 0.15 × 0.05
o
θmin, θ max
/
5.6 to 50.05
6077
5.398 to 50.04
4747
th.
305.1747, found 305.17583 [287.16 (C18H23O3), 269.15
Reflections
collected
(C18H21O2), 91.05 (C7H7), 105.07 (C8H9)].
Independent
reflections
2976 [Rint
0.0319]
=
2747 [Rint = 0.0348]
1.1.2. Hydrogenation of Ih
The crude Ih obtained from Ic (0.34 mol) was hydrogenated in
toluene (810 mL) and methanol (250 mL), in the presence of
NaHCO3 (3 g) over catalyst† (10 g, 5.5% /th wt Ih) at 20 atm H2 for 2
h. TLC and NMR showed the complete hydrogenation of the 13,14-
double bond. The catalyst was filtered, the filtrate washed with sat.
soln. NaHCO3 (100 mL), water (500 mL), dried (Na2SO4) and
concentrated under reduced pressure [Autoclave and aqueous
Data/restraints/p 2976/1/209
arameters
R1a [(I > 2(I)]
wR2b (all data)
2747/0/191
0.0439
0.0950
0.0804
0.1731
GOFc
1.039
1.102
This journal is © The Royal Society of Chemistry 20xx
NJC., 2019| 9
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 10 of 18
ARTICLE
New Journal of Chemistry
1
2
3
4
5
6
7
8
9
(m, 4H, H-o), 7.47-7.14 (3m, 11H, 3H-p, 2H-o, 6H-m),V5ie.w24Ar-t5ic.l1e7On(lmine,
2H, H-6a, H-5), 5.04 (m, 1H, H-15), 2.87 (dDd,O1I:H10, .H10-339,/1C09.N4J,011188.16)B,
2.74-2.59 (m, 3H, 2H-17, H-3a), 2.47 (dd, 1H, H-3, 2.4, 18.1), 2.35-
2.32 (m, 3H, 2H-6, H-14), 2.14-1.97 (m, 4H, H-4, H-14, 2H-16), 1.55-
1.40 (m, 2H, H-13), 13C-NMR-75 MHz (CDCl3, δ ppm): 177.78 (C-2),
166.27, 165.95 (2CO-Bz), 141.19 (Cq-Ph), 133.57, 133.22 (2-C-p, Bz),
130.17, 130.09 (2C-q-Bz), 129.57, 129.43, 128.46, 128.31, 128.26,
128.20 (C-o, C-m Ph and Bz), 125.90 (C-p Ph), 84.30 (C-6a), 77.33 (C-
5), 73.75 (C-15), 52.36 (C-4), 43.39 (C-3a), 37.70 (C-16), 36.14 (C-6),
35.90 (C-3), 32.25 (C-14), 31.68 (C-17), 29.03 (C-13) (See ESI 1.1.5.).
phases were washed with toluene (2  1L) and unified with the
product), resulting 214
g (99% crude) of compound IIh,
(3aR,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((R)-3-((tert-
butyldimethylsilyl)oxy)-5-phenylpentyl)hexahydro-2H-
cyclopenta[b]furan-2-one, as an oil which crystallized at rt (150.4 g,
83%) from hexane-ethyl acetate, mp 79.7-80.2 ˚C, [α]D = -25.1 ˚(in
THF), IR: 2953s, 2927vs, 2887m, 2856vs, 1752vs, 1472w, 1457w,
1386w, 1360w, 1246m, 1186m, 1127m, 1085w, 1062m, 1030m,
969m, 833vs, 771vs, 1H-NMR-300 MHz (CDCl3, δ ppm, J Hz): 7.28 (t,
2H, H-m, 8.1), 7.21-7.16 (m, 3H, 2H-o, H-p), 4.96 (tl, 1H, H-6a, 5.7),
3.95 (q, 1H, H-5, 4.0), 3.70 (qv, 1H, H-15, 5.5), 2.80 (dd, 1H, H-3,
11.7, 18.8), 2.70-2.48 (m, 3H, H-3a, 2H-17), 2.51 (d, 1H, H-3, 18.8),
2.13 (dt, 1H, H-6, 5.7, 14.4), 2.00 (brd, 1H, H-6, 14.4), 1.82-1.65 (m,
3H, H-4, 2H-16), 1.55-1.48 (m, 2H, H-14), 1.39 (m, 1H, H-13), 1.15
(m, 1H, H-13), 0.91, 0.87 (2s, 18H, CH3C), 0.07, 0.05, 0.04 (3s, 12H,
CH3Si), 13C-NMR-75 MHz (CDCl3, δ ppm): 177.46 (C-2), 142.40 (Cq-
Ar), 128.38, 128.26 (4C, C-o, C-m), 125.78 (C-p), 84.05 (C-6a), 77.94
(C-5), 71.61 (C-15), 52.24 (C-4), 42.74 (C-3a), 40.60 (C-6), 38.88 (C-
16), 36.25 (C-3), 35.08 (C-14), 31.70 (C-17), 28.64 (C-13), 25.87,
25.70 (CH3C), 18.10, 17.91 (CH3C), -4.34, -4.36, -4.69, -4.98 (CH3Si),
(See ESI 1.1.4.) MS 532.90, C30H52O4Si2, calcd for [M+1]+: th
533.34769, found 533.34863 [131.09 (C6H15OSi), 91.05 (C7H7),
105.07 (C8H9), 117.07 (C9H9), 143.09 (C11H11)]. The mother liquors
from crystallization contain a slightly impure IIh.
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
1.1.5. Hydrogenation of Ie
a) Ie (10.98 g, 27.0 mmol), catalyst† (220 mg, 2 % / Ie), methanol
(150 mL), 3 atm H2 for 3 h; TLC (I, Rf Ie = 0.48, Rf IIe = 0.38, Rf IId-1
=
0.62, Rf SP Rf superior = 0.83); LPC (ethyl acetate-hexane, 1:1) gave 7.52
g (66.03%) IIe, (3aR,4R,5R,6aS)-4-((R)-3-hydroxy-5-phenylpentyl)-2-
oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate as an oil, [α]D =
-80.6 ˚ (1% in THF), IR: 3486brm, 2934m, 2860w, 1766s, 1712vs,
1452w, 1315w, 1272vs, 1176m, 1109m, 1069m, 1045m, 1026m,
909w, 711s, 1H-NMR-300 MHz (CDCl3, δ ppm, J Hz): 7.99 (d, 2H, H-o,
Bz, 7.6), 7.53 (t, 1H, H-p, Bz, 7.6), 7.42 (t, 2H, H-m, Bz, 7.6), 7.29-
7.14 (m, 5H, H-p, 2H-o, 2H-m, Ph), 5.24 (m, 1H, H-5), 5.03 (t, H-6a,
5.9), 3.62 (m, 1H, H-15), 2.86 (dd, 1H, H-3, 10.6, 18.4), 2.79 (t , 1H,
H-17, 7.0), 2.70-2.59 (m, 2H, H-17, H-3a), 2.47 (brd, 1H, H-3, 18.4),
2.34 (dt, 1H, H-6, 5.5, 15.7), 2.28 (brd, 1H, H-6, 15.7), 2.11 (m, 1H,
H-4), 1.77 (brq, 2H, H-16, 7.0), 1.64-1.52 (m, 3H, 2H-14, H-13), 1.36
(m, 1H, H-13), 13C-NMR-75 MHz (CDCl3, δ ppm): 176.98 (C-2),
165.75 (CO-Bz), 141.71 (Cq-Ph, Bz), 133.02 (C-p, Bz), 128.30 (Cq-Ph),
129.38, 128.25, 128.11, (C-o, C-m Ph and Bz), 125.64 (C-p Ph), 84.36
(C-6a), 80.06 (C-5), 70.38 (C-15), 52.36 (C-4), 43.16 (C-3a), 38.81 (C-
16), 37.43 (C-6), 36.01 (C-3), 34.82 (C-14), 31.71 (C-17), 29.08 (C-13)
(See refs [6] and ESI 1.1.6.), MS 408.49, C25H28O5, calcd for [M+1]+:
th 409.20095, found 409.20022 [299.1 (C18H19O4), 91.05 (C7H7)].
1.75 g (16.5 %) of pure compound, (3aR,4R,5R,6aS)-2-oxo-4-(5-
phenylpentyl)hexahydro-2H-cyclopenta[b]furan-5-yl benzoate IId-1
and ~1.2 g of impure compound with lower polarity were obtained.
A fraction of 15-desoxy compound IId-1 (200 mg) was hydrolyzed to
IId (10 mL anh. methanol, 10 mL 0.1% MeONa in MeOH for 3 h; LPC
of crude compound gave a pure fraction of 120 mg IIc as an oil) with
IR and NMR spectra similar with those of compound IIc.
Hydrogenation of Ih in THF proceeded similarly.
1.1.3. Hydrogenation of Ig
The crude Ig obtained from Ic 0.40 mol) was hydrogenated as in the
previous example: toluene (950 mL), methanol (300 mL), NaHCO3
(3.5 g), catalyst† (11.8 g, 6.2 % /th wt Ig), 20 atm H2 for 2 h at 45 ˚C,
resulting 189.5 g (~ 99 % based on Ic) of crude compound IIg,
(3aR,4R,5R,6aS)-4-((3R)-5-phenyl-3-((tetrahydro-2H-pyran-2-
yl)oxy)pentyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)hexahydro-2H-
cyclopenta[b]furan-2-one as an oil, Rf = 0.13 (I), Rf = 0.58 (VII), [α]D =
-40.4 ˚(1% in THF), IR: 2938vs, 2865m, 1769vs, 1463w, 1351w,
1200m, 1174m,1131m, 1116m, 1074s, 1022m, 989w, 700w, 1H-
NMR-300 MHz (CDCl3, δ ppm, J Hz): 7.27 (m, 2H, H-m), 7.21-7.16
(m, 3H, 2H-o, 1H-p), 4.98 (m, 1H, H-6a), 4.69-4.56 (m, 2H, H-1-THP),
4.08 (m, 0.5H-5), 3.96-3.78 (m, 2.5H, 0.5H-5, 2H-5-THP), 3.67 (m,
1H, H-15), 3.54-3.43 (m, 2H-5-THP), 2.83-2.48 (m, 5H, H-3a, 2H-3,
2H-17), 2.20 (m, 1H, H-6, 15.3), 2.01 (m, 1H, H-4, from HETCOR),
2.00-1.45 (m, 19H, H-6, 2H-14, 2H-16, 4H-2-THP, 4H-3THP, 4H-4-
THP), 1.34-1.22 (m, 2H- H-13), 13C-NMR-75 MHz (CDCl3, δ ppm):
177.69, 177.49, 177.39, 177.18 (C-2), 142.42, 142.11 (C-1’), 128.38,
128.35, 128.29, 128.22 (C-o, C-m), 125.82, 125.71 (C-p), 98.83,
98.65, 97.67, 95.68 (C-1-THP), 84.08, 84.03 (C-6a), 82.88, 82.70,
79.78, 79.64 (C-5), 76.38, 76.33, 76.05, 75.98 (C-15), 63.60, 63.49,
62.51, 62.42 (C-5-THP), 53.32, 53.01, 52.13, 51.69 (C-4), 43.02,
42.90, 42.51, 42.43 (C-3a), 39.01, 38.94, 36.64, 36.58 (C-6), 36.11,
36.04 (C-16), 35.67, 35.62, 35.53, 35.49 (C-3), 33.03, 32.89, 31.75,
31.62 (C-2THP), 31.91, 31.62 (C-17), 31.42, 30.71 (C-14), 28.87,
28.68, 28.57, 28.36 (C-13), 25.41 (C-4THP), 20.47, 19.98, 19.37,
18.87 (-3THP) (See ESI 1.1.3.).
The lower polarity secondary compound was not re-purified and
characterized.
b) The hydrogenation of compound Ie (1 mmol, 406.5 mg) with 8.5
mg catalyst (2.1%) for only 90 min in the presence of NaHCO3 (100
mg), gave 372 mg of IIe in 91.5% yield.
1.1.6. Hydrogenation of 15-epi-compound If
If (6.34 g, ~15.6 mmol) (with mp 89.4-90.5 ˚C, [α]D = -87.7 ˚ (1% in
THF)), catalyst† (150 mg, 2.4 % / If), methanol (150 mL), 3 atm H2
for 90 min. TLC (II, Rf If = 0.71, Rf IIf = 0.63). Observation: After only 90
min of hydrogenation, the secondary compounds were formed only
in small amounts. LPC (ethyl acetate-hexane, 1:1) gave 5.77 g
(91.0%) of pure compound IIf, (3aR,4R,5R,6aS)-4-((S)-3-hydroxy-5-
phenylpentyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl
benzoate as an oil, [α]D = -78.5 ˚ (1% in THF), IR: 3450brw, 2936m,
2860w, 17655, 1711vs, 1452w, 1272vs, 1176m, 1097m, 1070m,
1.1.4. Hydrogenation of Ii
Ii (8.42 g, 16.5 mmol), ethyl acetate (120 mL), catalyst† (1 g), 20
atm. H2 for 2h, followed by another 1 g catalyst, [total: 2 g, 2.38 % /
Ii] 2 atm. H2, 2h, TLC (silica gel, II, Rf Ii = 0.72, Rf IIi = 0.75); 8.33 g (98.9
1
1026m, 908m, 728m, 711s, H-NMR-500 MHz (CDCl3, δ ppm, J Hz):
7.99 (d, 2H, H-o, Bz, 7.8), 7.53 (t, 1H, H-p, Bz, 7.8), 7.41 (t, 2H, H-m,
Bz, 7.8), 7.29-7.15 (m, 5H, H-p, 2H-o, 2H-m, Ph), 5.22 (dt, 1H, H-5,
2.5, 5.0), 5.03 (t, H-6a, 5.7), 3.59 (m, 1H, H-15), 2.87 (dd, 1H, H-3,
10.7, 18.3), 2.77 (dt, 1H, H-17, 6.6, 13.8), 2.68-2.62 (m, 2H, H-17, H-
3a), 2.45 (dd, 1H, H-3, 2.6, 18.3), 2.35 (dt, 1H, H-6, 5.6, 15.8), 2.29
%)
(R)-1-((3aR,4R,5R,6aS)-5-(benzoyloxy)-2-oxohexahydro-2H-
cyclopenta[b]furan-4-yl)-5-phenylpentan-3-yl benzoate IIi were
obtained as an oil, 1H-NMR-300 MHz (CDCl3, δ ppm, J Hz): 8.05-7.97
10 | NJC., 2019
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 11 of 18
New Journal of Chemistry
Please do not adjust margins
New Journal of Chemistry
ARTICLE
1
2
3
4
5
6
7
8
9
(brd, 1H, H-6, 15.8), 2.09 (m, 1H, H-4), 1.76 (dt, 2H, H-16, 6.6, 8.0), 1584m, 1492m, 1473w, 1248s, 1162vs, 1074m, 1048m, 1018m,
1.62-1.45 (m, 4H, 2H-14, 2H-13), 13C-NMR-125 MHz (CDCl3, δ ppm): 764m, 1H-NMR-300 MHz (CDCl , δ ppm, J Hz): 7.28 (d,V2ieHw,AHrt-icmle,O7n.l5in)e,
DOI: 10.1039/C9NJ01186B
3
176.95 (C-2), 165.86 (CO-Bz), 141.69 (Cq-Ph, Bz), 133.09 (C-p, Bz), 6.93 (t, 1H, H-p, 7.5), 6.89 (d, 2H, 2H-o, 7.5), 4.97 (dt, 1H, H-6a, 2.1,
129.37, 128.30, 128.19, 128.14, (C-o, C-m Ph and Bz), 125.64 (C-p 6.9), 4.04 (q, 1H, H-5, 4.5), 3.96 (t, 2H, H-16, 6.2), 2.82 (dd, 1H, H-3,
Ph), 84.43 (C-6a), 80.28 (C-5), 70.50 (C-15), 52.62 (C-4), 43.05 (C- 11.1, 18.8), 2.56 (m, 1H, H-3a), 2.53 (dd, 1H, H-3, 2.9, 18.8), 2.26
3a), 38.93 (C-16), 37.46 (C-6), 36.09 (C-3), 34.97 (C-14), 31.75 (C- (dt, 1H, H-6, 6.0, 15.0), 2.05 (brd, 1H, H-6, 15.0), 1.87 (m, 1H, H-4),
17), 29.27 (C-13) (See ESI 1.1.7.).
0.42 (~6.9 %)
1.78 (dt, 2H, 2H-15, 6.3, 7.4), 1.60-1.50 (m, 2H, H-14), 1.44 (m, 1H,
g
of
(3aR,4R,5R,6aS)-2-oxo-4-(5- H-13), 1.26 (m, 1H, H-13), 13C-NMR-75MHz (CDCl3, δ ppm): 177.64
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
phenylpentyl)hexahydro-2H-cyclopenta[b]furan-5-yl benzoate, IId- (C-2), 158.87 (Cq-Ar), 129.43 (2C-m), 120.63 (C-p), 114.40 (2C-o),
1, similar with the compound obtained above, and 0.47 g of impure 84.10 (C-6a), 77.57 (C-5), 67.35 (C-16), 54.22 (C-4), 43.05 (C-3a),
lower polarity compound (not identified).
40.55 (C-6), 36.17 (C-3), 32.83 (C-13), 29.31 (C-15), 24.27 (C-14) (See
ESI 1.2.1.3.), MS 290.35, C17H22O4, calcd for [M+1]+ th. 533.34769,
diol found 533.34863 [131.09 (C6H15OSi), 91.05 (C7H7), 105.07 (C8H9),
117.07 (C9H9), 143.09 (C11H11)], X ray crystallography for (-)-3c.
1.2.
Hydrogenation
of
16-(m-substituted)phenoxy
intermediates
1.2.1. Hydrogenation of compound 1 (with 15-epi isomer) in
methanol
1.2.2. Hydrogenation of 1a with a smaller quantity of catalyst
(±)-1a (9.01 g, 26.6 mmol), catalyst† (0.9 g, 10 % / 1a), ethyl acetate
a) with 10% Pd/C (catalyst†) in amount of 15% w/w based on
substrate: (±)- Compound 1a with 15-epi-1a (2.0 g, 5.9 mmol),
methanol (100 mL), catalyst† catalyst (300 mg, 15 % / 1a), 3 atm of
H2 for 2 h. TLC (III, Rf 2c = 0.24, Rf 3c = 0.64, Rf 3c = 0.54). The catalyst
was filtered, the filtrate was concentrated on a rotavapor and the
crude product was purified by LPC (eluent: ethyl acetate-toluene,
1:1), resulting a pure fraction of 0.8 g (44.3%) of compound 2c as an
oil, which, after crystallization from anh. ethyl ether-anh. petroleum
ether (bp 40-67 ˚C), gave 410 mg crystals, mp 104-110 ˚C, 1H-NMR-
300 MHz (DMSO-d6, δ ppm, J Hz): 7.28 (dd, 2H, H-m, 7.0, 8.0), 6.93
(d, 2H, H-o, 7.0), 6.91 (m, 1H, H-p), 4.89 (dt, 1H, H-6a, 2.6, 7.0), 3.82
(d, 2H, H-16, 5.5), 3.80-3.68 (m, 2H, H-5, H-15), 2.80 (ddd, 1H, H-3,
2.2, 10.5, 17.9), 2.46 (m, 1H, H-3a), 2.34 (ddd, 1H, H-3, 3.0, 4.5,
17.9), 2.17 (ddd, 1H, H-6, 5.8, 6.7, 14.4), 1.73 (ddd, 1H, H-6, 2.7, 5.1,
14.4), 1.66-1.17 (m, 5H, H-4, 2H-13, 2H-14), 13C-NMR-75 MHz
(CDCl3, δ ppm): 177.33 (CO, C-2), 158.70 (Cq-Ar), 129.46 (C-m),
120.44 (C-p), 114.47 (2C-o), 83.44 (C-6a), 76.04, 75.94 (C-5), 72.09,
72.04 (C-16), 68.47 (C-15), 53.42, 53.29 (C-4), 42.22, 42.07 (C-3a),
40.06 (C-6), 35.64, 35.58 (C-14), 31.71, 31.61 (C-3), 28.34 (C-13)
(See ESI 1.2.1.1.),
(200 mL), H2 (atm. pressure); TLC (IV, Rf 2a = 0.13, Rf 3a = 0.26, Rf PS
0.46); LPC (toluene-ethyl acetate 2:1); 6.84 (75.5%)
(3aα,4β,5α,6aα)-4-((β)-4-(3-chlorophenoxy)-3-hydroxybutyl)-5-
=
g
hydroxyhexahydro-2H-cyclopenta[b]furan-2-one, 2a were obtained,
mp 107.6-109.6 ˚C, IR-in ATR: 3439s, 2915w, 1719vs, 1595m,
1575w, 1485m, 1371m, 1250m, 1225s, 1065w, 1047s, 1020s, 910s,
762m, IR in CHCl3: 3424brs, 2934s, 2867m, 1756vs, 1592s, 1480m,
1457w, 1428w, 1364w, 1288w, 1231m, 1187m, 1073w, 1037m, 1H-
NMR-300 MHz (CDCl3, δ ppm, J Hz)15: 7.21 (t, 1H, H-5’, 8.1), 6.96
(ddd, 1H, H-4’, 1.0, 2.1, 8.1), 6.91 (t, 1H, H-2’, 2.1), 6.79 (ddd, 1H, H-
6’, 1.0, 2.1, 8.1), 4.96 (dt, 1H, H-6a, 2.4, 6.8), 4.05 (dt, 1H, H-5, 4.8,
5.0), 3.99 (m, 1H, H-15), 3.93 (dd, 1H, H-16, 3.1, 9.2), 3.82 (dd, 1H,
H-16, 7.3, 9.2), 2.83 (dd, 1H, H-3, 10.8, 18.5), 2.55 (dd, 1H, H-3, 2.6,
18.5), 2.54 (m, 1H, H-3a), 2.32 (m, 2H, OH) deuterable with TFA,
2.34 (m, dt with TFA, 1H, H-6, 6.8, 15.6), 2.05 (m, 1H, H-6), 1.94 (m,
1H, H-4), 1.69-1.62 (m, 3H, H-13, H-14), 1.40 (t, 1H, H-14, 6.6), 13C-
NMR-75MHz (CDCl3, δ ppm): 177.46 (C-2), 159.15 (Cq-Ar), 134.96
(C-3’), 130.35 (C-5’), 121.46 (C-4’), 114.97 (C-2’), 113.04 (C-6’),
83.81 (C-6a), 77.53 (C-15), 72.33 (C-16), 69.94 (C-5), 53.81 (C-4),
43.28 (C-3a), 40.62 (C-6), 35.94 (C-3), 30.84 (C-13), 28.86 (C-14) (See
ESI 1.2.2.1.), MS 340.80 calcd. for C17H21ClO5 [M+1]+: th. 341.11503,
found 341.11465 [141.00 (C7H6ClO), 303.08 (C17H16O3Cl), 243.06
(C15H12ClO), 167.01 (C9H8OCl), 117.07 (C9H9)].
and 1.46 g (16.9%) (3aα,4β,5α,6aα)-4-(4-(3-chlorophenoxy)butyl)-5-
hydroxyhexahydro-2H-cyclopenta[b]furan-2-one, 3a, 91.7-92.0 ˚C,
IR: 3430s, 2943m, 2854w, 1735vs, 1584s, 1483w, 1466m, 1366w,
1306s, 1258s, 1201brm, 1073w, 1048w, 1023m, 979w, 865w,
805w, 1H-NMR-300 MHz (DMSO-d6, δ ppm, J Hz): 7.26 (t, 1H, H-5’,
8.1), 6.97 (t, 1H, H-2’, 2.1), 6.94 (ddd, 1H, H-4’, 1.0, 2.1, 8.1), 6.87
(ddd, 1H, H-6’,1.0, 2.1, 8.1), 4.87 (dt, 1H, H-6a, 2.6, 7.2), 3.96 (t, 2H,
H-16, 6.5), 3.75 (dt, 1H, H-5, 5.4, 11.1) +THF, 2.80 (dd, 1H, H-3, 10.5,
18.0), 2.45 (m, 1H, H-3a), 2.32 (ddd, 1H, H-3, 3.0, 7.7, 18.0), 2.19
(dt, 1H, H-6, 4.5, 15.2), 1.78-1.60 (m, 4H, H-4, H-6, 2H-15), 1.45 (m,
2H, H-14), 1.29 (m, 2H, H-13), 13C-NMR-75MHz (DMSO-d6, δ ppm):
177.02 (C-2), 159.36 (C-1’-Ar), 134.45 (C-3’), 130.55 (C-5’), 120.05
(C-4’), 114.11 (C-2’), 113.29 (C-6’), 83.09 (C-6a), 75.64 (C-5 ), 67.49
(C-16), 52.87 (C-4), 41.78 (C-3a), 40.05 (C-6) in DMSO, 35.27 (C-3),
31.71 (C-13), 29.06 (C-15), 23.32 (C-14) (See ESI 1.2.2.2.), elem.
analysis, calctd for C17H21ClO4, th Cl: 10.91 %, found: 10.85 %, MS
324.80 calcd. for C17H21ClO4 [M+1]+: th. 325.12011, found
325.11998 [307.11 (C17H20ClO3), 197.12 (C11H17O3), 179.11
(C11H15O2), 161.10 (C11H13O), 141.01 (C7H6OCl)].
By a similar re-purification of the impure fractions (eluent: ethyl
acetate-toluene, 1:3), a pure fraction of 3c (0.4 g, 23.3 %) was
obtained as an oil, 1H-NMR-300 MHz (DMSO-d6, δ ppm, J Hz): 7.30-
7.25 (m, 2H, H-m), 6.93-6.89 (m, 3H, 2H-o, H-p), 4.88 (dt, 1H, H-6a,
2.9, 7.3), 4.78 (brs, OH), 3.94 (t, 2H, H-16, 6.6), 3.75 (q, 1H, H-5, 5.8),
2.80 (dd, 1H, H-3, 10.5, 18.0), 2.45 (m, 1H, H-3a), 2.34 (dd, 1H, H-3,
3.0, 18.0), 2.17 (ddd, 1H, H-6, 5.8, 6.8, 14.3), 1.76-1.60 (m, 4H, H-4,
H-6, 2H-15), 1.50-1.22 (m, 4H, 2H-13, 2H-14), 13C-NMR-75MHz
(DMSO-d6, δ ppm): 177.30 (C-2), 158.63 (Cq-Ar), 129.45 (2C-m),
120.34 (C-p), 114.37 (2C-o), 83.36 (C-6a), 75.91, 75.82 (C-5), 67.15
(C-16), 53.14 (C-4), 42.05 (C-3a), one C in DMSO = 40.05 (C-6), 35.55
(C-3), 32.03 (C-13), 28.95 (C-15), 23.69 (C-14) (See ESI 1.2.1.2.); the
impure fractions of both compounds were no further purified.
b) By hydrogenation of (-)-1 (7.74 g, 22.8 mmol) in 250 mL methanol
with a fresh catalyst obtained from 3.6 g 7% PdCl2/C (4.2% Pd/C, 30
atm, 1.5 h), after LPC (toluene-ethyl acetate, 2:1) purification of the
crude product, a fraction of 5.93 g (76.3 %) of pure (3aR,4R,5R,6aS)-
5-hydroxy-4-((R)-3-hydroxy-4-phenoxybutyl)hexahydro-2H-
cyclopenta[b]furan-2-one (-)-2c was obtained as an oil (a fraction
was crystallized from EtOH-Et2O, mp 119-122 ˚C, [α]D = -18.6 ˚ (1%
in THF)) and pure fraction of 1.30 g (19.6 %) of secondary
compound
(3aR,4R,5R,6aS)-5-hydroxy-4-(4-
phenoxybutyl)hexahydro-2H-cyclopenta[b]furan-2-one, (-)-3c, as an
oil, which crystalized from ethyl acetate-hexane, mp 65.6-67.1 ˚C,
[α]D = - 31.2 ˚ (1% in THF), IR: 3526vs, a broad shoulder for water in
the crystal, 3470-3200m, 2971w, 2935s, 2856m, 1771vs, 1598m,
1.2.3. Hydrogenation of 1b
This journal is © The Royal Society of Chemistry 20xx
NJC., 2019| 11
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 12 of 18
ARTICLE
New Journal of Chemistry
1
2
3
4
5
6
7
8
9
1b (1 mmol, 372 mg) with mp 115.4-117.0 ˚C, catalyst† (37.2 mg, 10 114.79 (C-2’), 112.89 (C-6’), 83.20 (C-6a), 77.79 (C-5), 71.31 (C-15),
View Article Online
% / 1b), methanol (50 mL), hydrogenated at 20 atm H2 for 2 h. LPC 63.70 (C-16), 56.68 (C-4), 42.25 (C-3a), 40.70 (C-6), 34.82 (C-3),
DOI: 10.1039/C9NJ01186B
(ethyl acetate-heptane, 1:1), gave 34.1 mg (9.5 %) of secondary 15- 25.80, 25.71 (CH3C), 18.30, 17.99 (CH3C), -4.62, -4.65, -4.69, -4.87
desoxy-compound
(trifluoromethyl)phenoxy)butyl)hexahydro-2H-cyclopenta[b]furan-
(3aR,4R,5R,6aS)-5-hydroxy-4-(4-(3- (CH3Si), MS 567.3, C29H47ClO5Si2, [M+1]+: th. 567.27233, found
567.2773.
2-one 3b as an oil, [α]D = -28.1 ˚(1 % in THF), IR: 3443brw, 3075m, 1a-1 (0.5 mmol, 266 mg) was hydrogenated in EtOAc (30 mL),
2867w, 1761s, 1591w, 1493w, 1452m, 1326vs, 1295w, 1237w, catalyst† (27 mg), 20 atm H2 for 40 min. TLC shows only one
1
1162s, 1119vs, 1097m, 1064s, 1031s, 790w, 698w, 698w, H-NMR- compound formed in the hydrogenation. LPC (hexane-ethyl acetate,
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
300 MHz (CDCl3, δ ppm, J Hz): 7.38 (m, 1H, H-5’, 8.1), 7.19 (d, 1H, H- 9:1) gave a pure fraction of 246.8 mg (92.8%) 2a-1, (3aα,4β,5α,6aα)-
4’, 81), 7.10 (s, 1H, H-2’), 7.05 (d, 1H, H-6’, 8.1), 4.97 (t, 1H, H-6a, 5-((tert-butyldimethylsilyl)oxy)-4-((β)-3-((tert-
6.3), 4.05 (q, 1H, H-5, 4.6), 3.99 (t, 2H, H-16, 6.1), 2.83 (dd, 1H, H-3, butyldimethylsilyl)oxy)-4-(3-chlorophenoxy)butyl)hexahydro-2H-
11.0, 18.5), 2.57 (m, 1H, H-3a), 2.53 (dd, 1H, H-3, 2.8, 18.5), 2.27 cyclopenta[b]furan-2-one, as an oil which crystallized in time, mp
(dt, 1H, H-6, 6.0, 15.0), 2.07 (brd, 1H, H-6, 15.0), 1.88 (m, 1H, H-4), 67.5-71.5 ˚C, (68.5-72.0 ˚C, Hexane), IR: 2952s, 2929vs, 2857s,
1.81 (cv, 2H, H-15, 7.0), 1.61-1.51 (m, 2H, H-14), 1.46 (m, 1H, H-13), 1752s, 1597w, 1485w, 1468w, 1252s, 1180m, 1126m, 1101m,
1.30 (m, 1H, H-13), 13C-NMR-75MHz (CDCl3, δ ppm): 177.64 (C-2), 1067w, 1019m, 973m, 832s, 774s, 1H-NMR-300 MHz (CDCl3, δ ppm,
159.01, (C-1’), 131.24 (q, C-3’, JC-F = 32.3Hz), 129.94 (C-5’), 123.94 J Hz): 7.19 (t, 1H, H-5’, 8.1), 6.93 (brd, 1H, H-4’, 8.1), 6.86 (brt, 1H,
(q, CF3, JC-F = 270.75), 117.94 (C-6’), 117.28 (q, C-2’, JC-F =3Hz), H-2’, 2.1), 6.76 (dd, 1H, H-6’, 2.1, 8.1), 4.96 (dt, 1H, H-6a, 2.2, 7.0),
111.09 (q, C-4’, JC-F =3Hz), 84.11 (C-6a), 77.59 (C-5), 67.77 (C-16), 4.02-3.94 (m, 2H, H-15, H-5), 3.83 (dd, 1H, H-16, 6.0, 9.2), 3.77 (dd,
54.19 (C-4), 43.04 (C-3a), 40.56 (C-6), 36.17 (C-3), 32.83 (C-15), 1H, H-16, 5.3, 9.2), 2.82 (dd, 1H, H-3, 11.8, 19.0), 2.55 (m, 1H, H-3a),
29.19 (C-13), 24.25 (C-14) (See ESI 1.2.3.2.),
and 292 mg (78.0%) of pure (3aR,4R,5R,6aS)-5-hydroxy-4-((R)-3- 1H, H-6, 14.4), 1.83 (m, 1H, H-4), 1.68-1.32 (m, 4H, 2H-13, 2H-14),
hydroxy-4-(3-(trifluoromethyl)phenoxy)butyl)hexahydro-2H-
0.89, 0.87 (2s, 15H, CH3C), 0.10, 0.08, 0.05 (3s, 12H, CH3Si), 13C-
2.51 (dd, 1H, H-3, 3.1, 19.0), 2.15 (dt, 1H, H-6, 5.8, 14.4), 1.99 (brd,
cyclopenta[b]furan-2-one, 2b (+ 35 mg impure compound 2b) as an NMR-125MHz (CDCl3, δ ppm): 177.33 (C-2), 159.38 (Cq-Ar), 134.88
oil, [α]D = -23.1 ˚(1% in THF), IR: 3400brm, 2935m, 1750s, 1592w, (C-3’), 130.25 (C-5’), 121.02 (C-4’), 114.68 (C-2’), 112.92 (C-6’),
1493w, 1450m, 1327vs, 1295m, 1237m, 1162s, 1118vs, 1097m, 83.90 (C-6a), 77.74 (C-5), 71.91 (C-16), 70.47 (C-15), 55.01 (C-4),
1
1065s, 1032s, 891w, 791w, 697w, H-NMR-300 MHz (CDCl3, δ ppm, 42.70 (C-3a), 40.62 (C-6), 36.17 (C-3), 32.65 (C-13), 28.36 (C-14),
J Hz)15: 7.40 (t, 1H, H-5’, 8.1), 7.23 (d, 1H, H-4’, 8.1), 7.13 (s, 1H, H- 25.82, 25.68 (CH3C), 18.12, 17.89 (CH3C), -4.22, -4.67, -4.71, -4.98
2’), 7.08 (d, 1H, H-6’, 8.1), 4.96 (t, 1H, H-6a, 6.8), 4.06-3.96 (m, 3H, (CH3Si) (See ESI 1.2.4.), MS 569.32, C29H49ClO5Si2, calcd for [M+1]+:
H-5, H-15, H-16), 3.90 (d, 1H, H-16, 8.5), 2.82 (dd, 1H, H-3, 10.8, th 569.28798, found 569.2883 [226.07 (C12H15O2Cl), 212.06
18.5), 2.57-2.51 (m, 2H, H-3, H-3a), 2.42 (brs, OH), 2.32 (dt, 1H, H-6, (C11H13O2Cl), 244.09 (C12H17O3Cl)].
6.1, 15.1), 2.05 (m, 1H, H-6), 1.88 (m, 1H, H-4), 1.71-1.58 (m, 3H, H-
13, 2H-14), 1.41 (m, 1H, H-13), 13C-NMR-125MHz (CDCl3, δ ppm): 1.2.5. Hydrogenation of bis-TBDMS-protected diol 1b-1.
177.60 (C-2), 158.54 (Cq-Ar), 131.69 (q, C-3’, JC-F = 32.3Hz), 130.11 Diol 1b (30 mmol, 11.17 g) was protected as 5,11-bis TBDMS-ether
(C-5’), 123.84 (q, CF3, JC-F = 270.8), 118.00 (C-6’), 117.96 (q, C-2’, JC-F with TBDMSCl (120 mmol, 18.1 g), imidazole (180 mmol, 12.3 g),
=3Hz), 111.30 (q, C-4’, JC-F =3Hz), 83.88 (C-6a), 77.49 (CH, C-5), DMAP (1.5 g) in THF (100 mL) overnight at rt, then for 2 h at 50 ˚C.
72.25 (C-16), 69.92 (C-15), 53.76 (C-4), 43.25 (C-3a), 40.54 (C-6), TLC (I, Rf 1a = 0.13, Rf 1a-1 = 0.80). The crude product was purified by
35.96 (C-3), 30.86 (C-13), 28.85 (C-14) (See ESI 1.2.3.1.), MS 374.35, LPC (Hexane-ethyl acetate, 9:1), obtaining 16.84 g (93.4.0%) of pure
C18H21F3O5, calcd. for [M+1]+: th. 375.14139, found 375.14227 1b-1,
(3aR,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((R,E)-3-
[357.1 (C18H20F3O4), 355.1 (C18H21F2O5), 337.1 (C18H19F2O4), 131.09 ((tert-butyldimethylsilyl)oxy)-4-(3-(trifluoromethyl)phenoxy)but-1-
(C10H11), 117.1 (C9H9), 105.1 (C8H9), 91.1 (C7H7), 93.1 (C7H9), 107.1 en-1-yl)hexahydro-2H-cyclopenta[b]furan-2-one, mp 91.3-92.1˚C,
(C8H11).
(lit21 91-93˚C) [α]D = -32.4˚(1% in THF), IR: 2953m, 2930s, 2888w,
2857m, 1772vs, 1449m, 1329s, 1252m, 1166s, 1125vs, 1094m,
1065m, 1039m, 832vs, 774vs, 1H-NMR-300 MHz (CDCl3, δ ppm, J
1.2.4. Hydrogenation of the bis-TBDMS-protected diol 1a-1.
Diol 1a (1.5 mmol, 508 mg) was protected as 5,11-bis TBDMS-ether Hz)21: 7.38 (t, 1H, H-5’, 8.1), 7.21 (d, 1H, H-4’, 8.1), 7.07 (s, 1H, H-2’),
with TBDMSCl (6 mmol, 910 mg), imidazole (8 mmol, 545 mg), 7.04 (d, 1H, H-6’, 8.1), 5.63 (m, 2H, H-13, H-14), 4.94 (dt, 1H, H-6a,
DMAP (50 mg) in THF (5 mL) overnight at rt, then for 2 h at 50 ˚C. 2.4, 7.0), 4.51 (dt, 1H, H-15, 2.7, 5.7), 3.99 (q, 1H, H-5, 5.8), 3.86 (d,
TLC (I, Rf 1a = 0.13, Rf 1a-1 = 0.80). The crude product was purified by 2H, H-16, 5.9), 2.75 (dd, 1H, H-3, 10.0, 17.6), 2.63 (~ddt, 1H, H-3a,
LPC (Hexane-ethyl acetate, 9:1), obtaining 675 mg (92.0%) of pure 2.1, 7.1, 10.0), 2.47 (dd, 1H, H-3, 2.1, 17.6), 2.46 (m, 1H, H-4), 2.30
1a-1,
((tert-butyldimethylsilyl)oxy)-4-(3-chlorophenoxy)but-1-en-1-
yl)hexahydro-2H-cyclopenta[b]furan-2-one, as a powder. A fraction (CDCl3, δ ppm): 177.81 (C-2), 158.84 (Cq-Ar), 132.28 (q, C-3’, JC-F
(3aα,4β,5α,6aα)-5-((tert-butyldimethylsilyl)oxy)-4-((R,E)-3- (dt, 1H, H-6, 6.4, 14.8), 1.98 (ddd, 1H, H-6, 2.3, 5.6, 14.8), 0.90, 0.87
(2s, 15H, CH3C), 0.08, 0.05, 0.04 (3s, 12H, CH3Si), 13C-NMR-75MHz
=
was crystalized from hexane-ethyl acetate, mp 95-99.8 ˚C, IR: 32.3Hz), 131.64, 131.21 (C-13, C-14), 129.98 (C-5’), 123.92 (q, CF3,
2931vs, 2885m, 2858s, 1753vs, 1595m, , 1474m, 1250s, 1124s, JC-F = 270.8), 118.08 (C-6’), 117.53 (q, C-2’, JC-F =3.7Hz), 111.05 (q, C-
1090m, 1038sm, 972m, 833vs, 774vs, 671m, 1H-NMR-300 MHz 4’, JC-F =3.7Hz), 83.06 (C-6a), 77.73 (CH, C-5), 72.44 (C-16), 71.09 (C-
(CDCl3, δ ppm, J Hz): 7.17 (t, 1H, H-5’, 8.1), 6.92 (brd, 1H, H-4’, 81), 15), 56.68 (C-4), 42.25 (C-3a), 40.66 (C-6), 34.72 (C-3), 25.77, 25.68
6.84 (t, 1H, H-2’, 2.1), 6.74 (dd, 1H, H-6’, 2.1, 8.1), 5.64-5.55 (m, 2H, (CH3C), 18.29, 17.97 (CH3C), -4.65, -4.68, -4.91 (CH3Si) (See ESI
H-13, H-14), 4.94 (dt, 1H, H-6a, 2.1, 6.9), 4.475 (m, 1H, H-15), 3.99 1.2.5.1.), MS 600.86, C30H47F3O5Si2, [M+1]+: th. 601.29869, found
(q, 1H, H-5, 5.6), 3.80 (d, 2H, H-16, 5.9), 2.74 (dd, 1H, H-3, 10.1, 601.2999.
17.6), 2.62 (m, 1H, H-3a), 2.45 (m, 1H, H-4), 2.47 (dd, 1H, H-3, 2.0,
1b-1 (0.5 mmol, 300.4 mg) was hydrogenated in EtOAc (30 mL),
catalyst† (27 mg), 20 atm H2 for 40 min. TLC shows only one
compound formed in the hydrogenation. LPC (hexane-ethyl acetate,
17.6), 2.27 (dt, 1H, H-6, 6.9, 14.6), 1.96 (ddd, 1H, H-6, 2.1, 5.2, 14.6),
13C-NMR-75MHz (CDCl3, δ ppm): 177.00 (C-2), 159.39 (C-1’), 134.81
(C-3’), 131.62, 131.08 (C-13, C-14), 130.24 (C-5’), 120.95 (C-4’),
12 | NJC., 2019
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 13 of 18
New Journal of Chemistry
Please do not adjust margins
New Journal of Chemistry
ARTICLE
1
2
3
4
5
6
7
8
9
9:1) gave a pure fraction of 290 mg (96.5 %) 2b-1, (3aR,4R,5R,6aS)- ppm): 176.85 (C-2), 170.54 (CH3CO), 159.69 (C-1’), 134.89 (C-3’),
5-((tert-butyldimethylsilyl)oxy)-4-((R)-3-((tert-
butyldimethylsilyl)oxy)-4-(3-
(trifluoromethyl)phenoxy)butyl)hexahydro-2H-cyclopenta[b]furan-
130.27 (C-5’), 120.88 (C-4’), 114.80 (C-2’), 113.05 (CV-6ie’w),A8rti4cl.e1O5nl(iCne-
DOI: 10.1039/C9NJ01186B
6a), 79.71 (C-5), 67.70 (C-16), 52.28 (C-4), 43.22 (C-3a), 37.71 (C-6),
36.29 (C-3), 32.99 (C-15), 29.10 (C-13), 24.20 (C-14), 21.22 (CH3CO)
2-one, as an oil, [α]D = -31.6 ˚(1% in THF), IR: 2951s, 2932s, 2892m, (See ESI 1.2.6.2.).
1
2858m, 1772vs, 1494m, 1328s, 1250m, 1167s, 1124vs, 1094s, 7: H-NMR-300 MHz (CDCl3, δ ppm, J Hz): 4.96 (ddd, 1H, H-6a, 1.9,
1063m, 1039m, 833vs, 775s, 1H-NMR-300 MHz (CDCl3, δ ppm, J Hz): 5.9, 7.4), 4.88 (dt, 1H, H-5, 3.2, 5.1), 2.81 (dd, 1H, H-3, 10.7, 18.1),
7.39 (t, 1H, H-5’, 8.1), 7.22 (d, 1H, H-4’, 8.1), 7.09 (s, 1H, H-2’), 7.05 2.59 (m, 1H, H-3a), 2.40 (dd, 1H, H-3, 2.8, 18.1), 2.31 (dd, 1H, H-6,
(d, 1H, H-6’, 8.1), 4.97 (brt, 1H, H-6a, 6.5), 4.03-3.95 (m, 2H, H-15, 5.5, 15.7), 2.13 (m, 1H, H-6), 1.95 (s, 3H, CH3), 1.90 (m, 1H, H-4),
H-5), 3.88 (dd, 1H, H-16, 5.3, 9.2), 3.83 (dd, 1H, H-16, 5.5, 9.2), 2.81 1.30-1.15 (m, 6H, 2H-13, 2H-14, 2H-15), 0.83 (t, 3H, H-16, 6.8), 13C-
(dd, 1H, H-3, 11.6, 18.8), 2.56 (m, 1H, H-3a), 2.51 (dd, 1H, H-3, 3.3, NMR (CDCl3, δ ppm): 176.94 (C-2), 170.45 (CH3CO), 84.16 (C-6a),
18.8), 2.17 (dt, 1H, H-6, 6.2, 14.7), 2.00 (brd, 1H, H-6, 14.7), 1.84 (m, 79.79 (C-5), 52.22 (C-4), 43.13 (C-3a), 37.61 (C-6), 36.22 (C-3), 32.90
1H, H-4), 1.67-1.58 (m, 2H, H-14), 1.49 (m, 1H, H-13), 1.28 (m, 1H, (C-14), 29.63 (C-13), 22.58 (C-15), 21.12 (CH3CO), 13.86 (C-16) (See
H-13), 0.90, 0.87 (2s, 15H, CH3C), 0.11, 0.09, 0.07, 0.05 (4s, 12H, ESI 1.2.6.3.).
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
CH3Si), 13C-NMR-75MHz (CDCl3, δ ppm): 177.31 (C-2), 158.77 (Cq-
Ar), 131.87 (q, C-3’, JC-F = 32.3Hz), 130.02 (C-5’), 123.91 (q, CF3, JC-F 1.2.7. Hydrolysis of the acetate groups of compound 5
= 270.8), 117.64 (C-6’), 117.60 (q, C-2’, JC-F =3.7Hz), 110.94 (q, C-4’, 5 (1.67 g, 3.93 mmol) was dissolved in methanol (50 mL), anh.
JC-F =3.7Hz), 83.85 (C-6a), 77.73 (C-5), 71.95 (C-16), 70.45 (C-15), K2CO3 (0.5 g) was added and the mixture was stirred overnight. TLC
54.98 (C-4), 42.69 (C-3a), 40.63 (C-6), 36.14 (C-3), 32.66 (C-14), (III, Rf 5 = 0.77, Rf 2a = 0.28) showed the end of the reaction. The
28.34 (C-13), 25.81, 25.67 (CH3C), 18.12, 17.88 (CH3C), -4.24, -4.66, - solvent was distilled under reduced pressure, the residue was taken
4.69, -5.00 (CH3Si) (See ESI 1.2.5.2.), MS 602.87, C30H49F3O5Si2, in water (15 mL) and ethyl acetate (30 mL), phases separated
[M+1]+: th. 603.31434, found 609.34434 [305.12 (C18H16OF3), (aqueous phase was extracted with 30 mL ethyl acetate), unified
327.16 (C18H22O2F3)].
phases were washed with brine (20 mL), dried (MgSO4),
concentrated and purified by LPC (ethyl acetate-hexane, 1:1),
resulting 1.26 g (94.1%) of pure 2a as an oil, with the same spectral
data (IR, 1H- and 13C-NMR) as mentioned in 1.2.2.).
1.2.6. Hydrogenation of compound 4.
(±)-(β,E)-4-((3aα,4β,5α,6aα)-5-acetoxy-2-oxohexahydro-2H-
cyclopenta[b]furan-4-yl)-1-(3-chlorophenoxy)but-3-en-2-yl acetate
4 (3.38 g, 8 mmol) with catalyst† (300 mg) in 150 mL ethyl acetate
was hydrogenated at 3 atm H2 for 1.5 h. TLC showed only one
product, but the reaction had not ended. During the next day,
another 120 mg catalyst were added and hydrogenated for 2 h at 3
atm H2. TLC showed that three compounds were formed in the
reaction, and the crude product was purified by LPC (eluent,
toluene-ethyl acetate, 2:1), resulting 220 mg (11.4%)
(3aα,4β,5α,6aα)-4-butyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-
yl acetate, 7 as an oil, 460 mg (15.7%) (3aα,4β,5α,6aα)-4-(4-(3-
chlorophenoxy)butyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl
acetate 6 as an oil and 2.48 g (5.84 mmol, 73.0%) 5 (±)-(β)-4-
((3aα,4β,5α,6aα)-5-acetoxy-2-oxohexahydro-2H-
1.3. Hydrogenation of enone intermediates
1.3.1. Hydrogenation of 8a with greater amount of catalyst (16.7%
catalyst / substrate)
Enone compound (±)-8a (1.22 g, 3.56 mmol), methanol (100 mL),
catalyst† (200 mg, 16.67 % / 8a), 3 atm H2 for 1.5 h. TLC (IV, Rf 8a
=
0.39, Rf 9c = 0.76). After filtration, concentration of the filtrate and
crystallization of the crude product from ethyl acetate-hexane, 0.92
g
(81.2 %) of crystallized compound (3aα,3bβ,6R,7aα,8aα)-6-
methoxy-6-(phenoxymethyl)octahydrofuro[3',2':3,4]cyclopenta[1,2-
b]pyran-2(3H)-one, 9c were obtained as prisms, mp 165-168 ˚C, 1H-
NMR-300 MHz (DMSO-d6, δ ppm, J Hz): 7.28 (dd, 2H, H-m, 7.2, 8.8),
6.82-6.92 (m, 3H, 2H-o, H-p), 4.87 (dt, 1H, H-6a, 4.1, 7.1), 4.06 (d,
1H, H-16, 10.3), 3.78 (d, 1H, H-16, 10.3), 3.53 (dt, 1H, H-11, 7.2,
11.1), 3.15 (s, 3H, CH3), 2.74 (dd, 1H, H-3, 9.2, 18.1), 2.39 (dd, 1H, H-
3, 1.5, 18.1), 2.46-2.26 (m, 2H, H-6, H-3a), 1.97 (m, 1H, H-14, 12.7),
1.82 (m, 1H, H-13), 1.62 (dd, 1H, H-14, 4.2, 12.7), 1.59-1.45 (m, 2H,
H-6, H-13), 1.26 (dq, 1H, H-4, 3.5, 11.1), 13C-NMR-75 MHz (DMSO-
d6, δ ppm): 176.72 (C-2), 158.32 (C-1’), 129.49 (C-m), 120.84 (C-p),
114.59 (C-o), 98.88 (C-15), 80.84 (C-6a), 72.66 (C-5), 68.38 (C-16),
47.57 (CH3O), 46.10 (C-4), 39.44 (C-3a) in DMSO, 36.16 (C-6), 32.03
(C-3 or C-14), 31.43 (C-14 or C-3), 22.40 (C-13) (See ESI 1.3.1.).
cyclopenta[b]furan-4-yl)-1-(3-chlorophenoxy)butan-2-yl acetate, as
an oil.
5: 1H-NMR-300 MHz (CDCl3, δ ppm, J Hz): 7.21 (t, 1H, H-5’, 8.1),
6.96 (dd, 1H, H-4’, 2.2, 8.1), 6.90 (t, 1H, H-2’, 2.2), 6.79 (dd, 1H, H-6’,
2.2, 8.1), 5.14 (m, 1H, H-15), 5.03 (dt, 1H, H-6a, 2.1, 6.3), 4.95 (m,
1H, H-5), 4.02 (dd, 1H, H-16, 5.0, 10.9), 3.98 (dd, 1H, H-16, 4.8,
10.9), 2.89 (dd, 1H, H-3, 10.6, 18.1), 2.64 (m, 1H, H-3a), 2.46 (dd,
1H, H-3, 2.6, 18.1), 2.29 (dd, 1H, H-6, 5.4, 15.8), 2.21 (m, 1H, H-6),
2.09, 2.03 (2s, 6H, CH3), 2.10 (m, 1H, H-4), 1.85-1.77 (m, 2H, H-14),
1.49-1.25 (m, 2H, H-13), 13C-NMR (CDCl3, δ ppm): 176.54 (C-2),
170.59, 170.42 (CH3CO), 159.09 (Cq-Ar), 134.96 (C-3’), 130.31 (C-5’), 1.3.2. Hydrogenation of 8a with reduced amount of catalyst (3-4 %
121.47 (C-4’), 115.02 (C-2’), 113.00 (C-6’), 83.94 (C-6a), 79.43, 79.38 catalyst / substrate) and shorter reaction time
(C-5), 71.49, 71.40 (C-15), 68.72, 68.62 (C-16), 52.23, 52.07 (C-4), (±)-8a (3 g, 8.9 mmol), catalyst† (100 mg, 3.33 % / 8a), methanol
43.28, 43.21 (C-3a), 37.59 (C-6), 36.18 (C-3), 28.91, 28.85, 28.81 (C- (140 mL), 3 atm H2 for 15 min. TLC (I, Rf 8a = 0.22, Rf 9a = 0.62). The
13, C-14), 21.13, 21.05 (CH3CO) (See ESI 1.2.6.1.),
crude product crystalized from ethyl acetate-hexane, resulting
2.474 (78.8%) (±)-(3aα,3bβ,6R,7aα,8aα)-6-((3-
chlorophenoxy)methyl)-6-
methoxyoctahydrofuro[3',2':3,4]cyclopenta[1,2-b]pyran-2(3H)-one,
9a, mp 198.2-199.4 ˚C (benzene), mp 200.2-201.0 ˚C (ethyl acetate,
then benzene) [another 0.49 g of pure compound were obtained by
LPC purification of the product which had remained in mother
liquors; total 94.4%], IR: 2946w, 2873w, 1757vs, 1596m, 1474s,
1436w, 1356w, 1287w, 1223m, 1168s, 1120s, 1093w, 1077m,
g
6: 1H-NMR-300 MHz (CDCl3, δ ppm, J Hz): 7.22 (t, 1H, H-5’, 8.1), 6.95
(ddd, 1H, H-4’, 0.9, 2.1, 8.1), 6.90 (t, 1H, H-2’, 2.1), 6.80 (dd, 1H, H-
6’, 2.2, 8.1), 5.06 (ddd, 1H, H-6a, 1.9, 5.8, 7.0), 4.99 (dt, 1H, H-5, 3.2,
5.2), 3.97 (t, 2H, H-16, 6.2), 2.91 (dd, 1H, H-3, 10.6, 18.1), 2.68 (m,
1H, H-3a), 2.49 (dd, 1H, H-3, 2.6, 18.1), 2.31 (dd, 1H, H-6, 5.6, 15.7),
2.24 (m, 1H, H-6), 2.05 (s, 3H, CH3), 2.04 (m, 1H, H-4), 1.81 (dt, 2H,
H-15, 6.2, 14.4), 1.62-1.28 (m, 4H, 2H-14, 2H-13), 13C-NMR (CDCl3, δ
This journal is © The Royal Society of Chemistry 20xx
NJC., 2019| 13
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 14 of 18
ARTICLE
New Journal of Chemistry
1
2
3
4
5
6
7
8
9
1
13
1062m, 1041m, 1023s, 986m, 941w, 880m, 762m, 678m, H-NMR- 4.2, 12.6), 1.38 (dq, 1H, H-4, 3.1, 11.1), 1.20 (t, 3H, VCieHw3,Ar7ti.c1le),OnliCne-
500 MHz (CDCl3, δ ppm, J Hz): 7.20 (t, 1H, H-5’, 8.2), 6.96-6.93 (m, NMR-75 MHz (CDCl , δ ppm): 176.54 (C-2), 159.26 (C-1’), 134.86 (C-
DOI: 10.1039/C9NJ01186B
3
2H, H-2’, H-4’), 6.82 (dd, 1H, H-6’, 1.8, 8.2), 4.90 (dt, 1H, H-6a, 4.3, 3’), 130.24 (C-5’), 121.31 (C-4’), 115.09 (C-2’), 113.04 (C-6’), 99.08
7.2), 4.06 (d, 1H, H-16, 9.9), 3.75 (d, 1H, H-16, 9.9), 3.60 (dt, 1H, H- (C-15), 81.21 (C-6a), 73.20 (C-5), 69.66 (C-16), 55.86 (CH2CH3), 46.66
5, 7.2, 11.2), 3.26 (s, 3H, CH3), 2.71 (dd, 1H, H-3, 9.2, 18.2), 2.55 (dt, (C-4), 40.15 (C-3a), 36.50 (C-6), 32.58 (C-3), 32.18 (C-14), 22.83 (C-
1H, H-6, 7.2, 13.3), 2.42 (dd, H, H-3 1.0, 18.2), 2.33 (m, 1H, H-3a), 13), 15.41 (CH3) (See ESI 1.3.4.), MS 366.84 calcd. for C19H23ClO5
2.15 (m, 1H, H-14), 1.86 (m, 1H, H-13), 1.83 (dd, 1H, H-6, 4.3, 13.3), [M+1]+: th. 367.13068, found 367.13088 [303.08 (C17H16ClO3),
1.69-1.56 (m, 2H, H-13, H-14), 1.39 (dq, 1H, H-4, 3.3, 11.2), 13C- 275.08 (C16H16ClO2), 105.07 (C8H9), 163.08 (C10H11O2), 147.08
NMR-125 MHz (CDCl3, δ ppm): 176.48 (C-2), 159.24 (C-1’), 134.91 (C10H11O)].
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
(C-3’), 130.26 (C-5’), 121.40 (C-4’), 115.12 (C-2’), 113.06 (C-6’),
99.09 (C-15), 81.16 (C-6a), 73.05 (C-5), 68.95 (C-16), 48.15 (CH3O), 1.3.5. Hydrogenation of 8a in ethyl acetate at atmosphere
46.58 (C-4), 40.17 (C-3a), 36.47 (C-6), 32.57 (C-3), 32.02 (C-14), pressure of hydrogen
22.82 (C-13) (See ESI 1.3.2.), MS 352.81 calcd. for C18H21ClO5 [M+1]+: a) (±)-8a (14.15 g, 42 mmol), catalyst† (2 g, 14.2 % / 8a), ethyl
th. 353.11503, found 353.1154 [105.07 (C8H9), 325.12 (C17H22ClO4), acetate (200 mL) H2 (atm. pressure), TLC (IV, Rf in = 0.27, Rf 12a = 0.33,
303.08 (C17H16ClO3)].
Rf
= 0.74). The catalyst was filtered off, the filtrate was
13a
concentrated and the crude product was purified by LPC (benzene-
ethyl acetate, 2:1), after a time at rt, resulting 2.3 g (16.2 %)
1.3.3. Hydrogenation of 8b in methanol
8b (3.024 g, 10 mmol), catalyst† (120 mg, ~4 % / 8b), methanol (140 cyclized
semiketal
(3aα,3bβ,6R,7aα,8aα)-6-((3-
mL), 3 atm H2 for 25 min. TLC (I, Rf 8b = 0.22, Rf 9a = 0.54). The crude chlorophenoxy)methyl)-6-
product was crystalized from ethyl acetate-hexane, resulting 2.316 hydroxyoctahydrofuro[3',2':3,4]cyclopenta[1,2-b]pyran-2(3H)-one
g (73.2 %) [another 0.614 g of pure compound were obtained by 13a, H-NMR-300 MHz (DMSO-d6, δ ppm, J Hz): 7.29 (t, 1H, H-5’,
LPC purification of the product which had remained in mother 8.2), 7.02 (t, 1H, H-2’, 2.2), 6.99 (ddd, 1H, H-4’, 0.9, 2.2, 8.2), 6.92
liquors; total 2.93 g, 92.6 %], (3aR,3bR,6R,7aR,8aS)-6-methoxy-6- (ddd, 1H, H-6’, 0.9, 2.2, 8.2), 6.00 (s, 1H, OH), 4.87 (dt, 1H, H-6a, 4.4,
1
phenethyloctahydrofuro[3',2':3,4]cyclopenta[1,2-b]pyran-2(3H)-
7.3), 3.84 (s, 2H, H-16), 3.81 (dt, 1H, H-5, 7.2, 11.3), 2.74 (dd, 1H, H-
one, 9b, mp 163.2-166.7 ⁰C, [α]D = 8.64 ⁰ (1% in THF), IR: 2939s, 3, 10.2, 17.9), 2.49-2.20 (m, 4H, H-3a, H-3, 2H-14), 1.70-1.12 (m, 5H,
2862w, 1757vs, 1709m, 1452m, 1201m, 1159s, 1114s, 1080m, H-4, 2H-6, 2H-13), 13C-NMR-75 MHz (DMSO-d6, δ ppm): 176.79 (C-
1043m, 1024s, 984m, 943m, 882m, 765m, 704m, 1H-NMR-500 MHz 2), 159.58 (C-1’), 133.67 (C-3’), 130.83 (C-5’), 120.63 (C-4’), 114.78
(CDCl3, δ ppm, J Hz): 7.26 (t, 2H, H-m, 7.5), 7.17 (d, 2H, H-o, 7.5), (C-2’), 113.75 (C-6’), 96.12 (C-15), 81.05 (C-6a), 73.99 (C-16), 72.39
7.16 (m, 1H, H-p), 4.85 (dt, 1H, H-6a, 4.4, 7.2), 3.50 (dt, 1H, H-5, (C-5), 46.48 (C-4), 40.21 (C-3a), 36.33 (C-6), 32.08 (C-3), 30.90 (C-
7.2, 11.1), 3.18 (s, 3H, CH3), 2.68 (dd, 1H, H-3, 9.1, 18.1), 2.63 (m, 14), 22.38 (C-13) (See ESI 1.3.5.2.),
2H, H-17), 2.50 (dt, 1H, H-6, 7.2, 13.3), 2.37 (brd, 1H, H-3, 18.1), and 11.78 g (82.8 %) (3aα,3bβ,6R,7aα,8aα)-4-(4-(3-chlorophenoxy)-
2.26 (m, 1H, H-3a), 2.01 (dt, 1H, H-16, 5.3, 11.6), 1.93 (dt, 1H, H-14, 3-oxobutyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one 12a,
3.4, 12.4), 1.84 (m, 1H, H-16, 6.2, 11.6), 1.80 (m, 1H, H-13), 1.79 (m, mp 110-114 ˚C, 1H-NMR-300 MHz (DMSO-d6, δ ppm, J Hz): 7.29 (t,
1H, H-16), 1.77 (dt, 1H, H-6, 4.4, 13.3), 1.58 (dq 1H, H-14, 3.5, 12.4), 1H, H-5’, 8.4), 7.02-6.98 (m, 2H, H-2’, H-4’), 6.88 (ddd, 1H, H-6’, 1.0,
1.50 (dt, 1H, H-13, 4.4, 13.0), 1.29 (dq, 1H, H-4, 3.3, 11.5), 13C-NMR- 2.4, 8.4), 4.88 (s, 2H, H-16), 4.86 (dt, 1H, H-6a, 3.0, 7.1), 3.74 (cv,
125 MHz (CDCl3, δ ppm): 176.50 (C2), 141.57 (Cq Ar), 128.21 (CH, C- 1H, H-5, 5.6), 3.38 (OH is in water) [4.88 for DMSO without water],
m), 127.97 (C-o), 125.68 (C-p), 100.60 (C-15), 81.22 (C-6a), 79.90 (C- 2.78 (dd, 1H, H-3, 10.2, 17.9), 2.60 (t, 2H, H-14, 7.3), 2.43 (m, 1H, H-
5), 47.15 (CH3O), 46.32 (C-4), 39.99 (C-3a), 37.31 (C-16), 36.41 (C-6), 3a), 2.33 (dd, 1H, H-3, 2.7, 17.9), 2.23 (dt, 1H, H-6, 6.8, 14.3), 1.69
32.45, 32.40 (C-3, C-14), 29.73 (C-17), 22.92 (C-13) (See ESI 1.3.3.), (ddd, 1H, H-6, 3.0, 6.0, 14.3), 1.61-1.42 (m, 3H, H-4, 2H-13), 13C-
MS 316.39 calcd. for C19H24O4 [M+1]+: th. 317.17474, found NMR-75 MHz (DMSO-d6, δ ppm): 205.46 (C-15), 177.05 (C-2),
317.17425 [239.14 (C13H19O4), 267.14 (C18H19O2), 105.07 (C8H9), 158.78 (C-1’), 133.65 (C-3’), 130.76 (C-5’), 120.86 (C-4’), 114.56 (C-
225.12 (C16H17O)].
2’), 113.61 (C-6’), 82.91 (C-6a), 75.75 (C-5), 71.87 (C-16), 52.11 (C-
4), 41.93 (C-3a), 40.18 (C-6) in DMSO, 36.11 (C-3), 35.10 (C-14),
25.30 (C-13).
1.3.4. Hydrogenation of 8a in ethanol
(±)-8a (3 g, 8.9 mmol), catalyst† (100 mg, 3.33 % / 8a), ethanol (140
mL), 3 atm H2 for 25 min. TLC (I, Rf 8a = 0.22, Rf 9a = 0.72) showed the
presence of a single product. The crude product crystalized from
ethyl acetate-hexane, resulting 1.85 g (56.6 %) (another 1.1 g of
pure compound were obtained by LPC purification of the product
present in mother liquors; total 90.4 %), 9d, (3aα,3bβ,6R,7aα,8aα)-
6-((3-chlorophenoxy)methyl)-6-
b) (-)-8a (717 mg, 3 mmol), catalyst† (38 mg, 5.3 % / 8a), ethyl
acetate (50 mL), NaHCO3 (50 mg), 3 atm H2 for 50 min, TLC (I, Rf in
0.31, Rf = 0.31). LPC (ethyl acetate-hexane, 1:1) gave a pure
fraction of 678 mg (94.0 %) of pure compound
(3aR,3bR,6R,7aR,8aS)-6-((3-chlorophenoxy)methyl)-6-
=
12a
hydroxyoctahydrofuro[3',2':3,4]cyclopenta[1,2-b]pyran-2(3H)-one (-
)-12a as an oil, [α]D = -12.9 ˚ (1% in THF), IR: 3480m, 2962w, 2912m,
2884w, 1753vs, 1719s, 1589s, 1470m,1308w, 1290m, 1231m,
1180s, 1074m, 1027s, 951w, 892w, 849w, 758m, 678w, 1H-NMR-
300 MHz (DMSO-d6, δ ppm, J Hz): 7.29 (t, 1H, H-5’, 8.4), 7.01-6.99
(m, 2H, H-2’, H-4’), 6.88 (ddd, 1H, H-6’, 0.9, 2.4, 8.4), 4.88 (s, 2H, H-
16), 4.85 (t, 1H, H-6a, 6.7), 3.74 (cv, 1H, H-5, 5.9), 2.78 (dd, 1H, H-3,
10.2, 17.9), 2.60 (t, 2H, H-14, 7.2), 2.45 (m, 1H, H-3a), 2.34 (dd, 1H,
H-3, 2.8, 17.9), 2.24 (dt, 1H, H-6, 6.7, 14.3), 1.69 (ddd, 1H, H-6, 2.9,
5.9, 14.3), 1.62-1.42 (m, 3H, H-4, 2H-13), 13C-NMR-75 MHz (DMSO-
d6, δ ppm): 205.50 (C-15), 177.16 (C-2), 158.79 (C-1’), 133.67 (C-3’),
130.81 (C-5’), 120.85 (C-4’), 114.52 (C-2’), 113.64 (C-6’), 82.97 (C-
6a), 75.82 (C-5), 71.81 (C-16), 52.13 (C-4), 41.94 (C-3a), 40.20 (C-6),
ethoxyoctahydrofuro[3',2':3,4]cyclopenta[1,2-b]pyran-2(3H)-one,
mp 123.5-126.9˚C (ethyl acetate-hexane), IR: 2970m, 2928m,
2885w, 2863w, 1771vs, 1595m, 1576w, 1487w, 1465w, 1274w,
1256s, 1221w, 1205w, 1175s, 1119m, 1072w, 1043m, 1025s, 982s,
1
886m, 870m, 765w, H-NMR-300 MHz (CDCl3, δ ppm, J Hz): 7.20 (t,
1H, H-5’, 8.1), 6.95 (brd, 1H, H-4’, 8.1), 6.93 (brs, 1H, H-2’), 6.82
(brd, 1H, H-6’, 8.2), 4.90 (dt, 1H, H-6a, 4.3, 7.1), 4.04 (d, 1H, H-16,
9.8), 3.77 (d, 1H, H-16, 9.8), 3.60 (dt, 1H, H-5, 7.3, 11.0), 3.54 (q, 2H,
CH2CH3, 7.1), 2.72 (dd, 1H, H-3, 9.1, 18.2), 2.54 (dt, 1H, H-6, 7.2,
13.3), 2.42 (d, H, H-3 18.2), 2.34 (m, 1H, H-3a), 2.16 (m, 1H, H-14),
1.89-1.78 (m, 2H, H-6, H-13), 1.67 (m, 1H, H-14), 1.59 (dt, 1H, H-13,
14 | NJC., 2019
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 15 of 18
New Journal of Chemistry
Please do not adjust margins
New Journal of Chemistry
ARTICLE
1
2
3
4
5
6
7
8
9
36.12 (C-3), 35.15 (C-14), 25.30 (C-13) (See ESI 1.3.5.1.), MS 338.78, were obtained as an oil: IR:2958w, 1729vs, 1593s, 1479s, 1432m,
C17H19ClO5, calcd for [M+1]+: th 339.09938, found 339.09987 1365m, 1286w, 1230m, 1188m, 1161s, 1075w, 1032sV,ie8w85Arwtic,le8O5n8liwne,
DOI: 10.1039/C9NJ01186B
1
[137.06 (C8H9O2), 107.05 (C7H7O), 321.09 (C17H18O4Cl), 125.09 756m, 681m, H-NMR-300 MHz (CDCl3, δ ppm, J Hz) etalon CHCl3:
(C7H9O2)].
7.31 (t, 2H, H-m, 7.6), 7.23 (t, 1H, H-5’’, 8.1), 7.01 (7, 1H, H-p, 7.6),
7.00 (d, 1H, H-4’’, 8.1), 6.90 (s, 1H, H-2’’), 6.89 (d, 2H, H-o, 7.6), 6.78
(d, 1H, H-6’’, 8.1), 4.69 (s, 1H, H-1), 4.56 (s, 2H, H-16), 4.23 (m, 1H,
/ 8a), H-6), 2.94 (dd, 1H, H-7, 6.1, 15.5), 2.85-2.72 (m, 4H, 2H-2’, 2H-4),
1.3.6. Hydrogenation of 8a in isopropanol
(±)-8a (1.53 g, 4.52 mmol), catalyst† (153 mg, 10%
isopropanol (150 mL), 3 atm H2 for 20 min. TLC (I, Rf
= 0.31) 2.67 (d, 1H, H-5, 4.9), 2.47 (d, 1H, H-7, 15.5), 2.22 (m, 1H, H-8, 5.7),
12a
showed the presence of a single product. The solvent was distilled 1.98-1.80 (m, 2H, H-1’), 13C-NMR-75 MHz (CDCl3, δ ppm): 207.2 (C-
under reduced pressure, the product was crystallized from 15Ph), 206.11 (C-15), 168.28, 168.22 (C-3), 158.18 (C-1’’), 157.50 (C-
benzene, resulting 1.27 g (63.2%) (±)-12a, mp 110-114 ˚C. By LPC 1Ph), 135.17 (C-3’’), 130.55 (C-5’’), 129.77 (C-m), 122.14 (C-4’’),
purification of the mother liquors, another 0.63 g of pure product 121.90 (C-p), 115.11 (C-2’’), 114.38 (C-o), 112.73 (C-6’’), 84.04 (C-1),
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
were obtained (total yield 94.5 %).
72.15 (C-16), 59.28 (C-6), 47.21 (C-8), 45.60 (C-5), 44.07 (C-7), 40.70
(C-14), 36.60 (C-4), 22.59 (C-13) (See ESI 1.3.7.2.); italic for signals of
15, MS for 16: 322.78, C17H19ClO4, [M+1]+: th. 323.10446, found
323.10444 [107.05 (C7H7O), 131.05 (C9H7O), 209.09 (C15H13O)].
1.3.7. Hydrogenation of 8b in ethyl acetate
The hydrogenation of (-)-8b (3 mmol, 907 mg) was performed as
for (-)-8a, example 2.5, with 45 mg catalyst† (5% / (-)-8b)),
resulting 866 mg (94.8%) (3aR,4R,5R,6aS)-5-hydroxy-4-(3-oxo-5-
phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2-one, 12b as an
oil, [α]D = -30.7 ˚ (1% in THF), IR: 3456brm, 2933m, 1760vs, 1707vs,
1496w, 1453w, 1413w, 1369m, 1175s, 1074m, 1033m, 909m, 727s,
2. Hydrogenations with a reduced amount of 10% Pd/C catalyst
(1-3 % based on the substrate)
2.1. Hydrogenation of 1a:
1a (4.5 g, 13.28 mmol), ethyl acetate (150 mL), catalyst† (70 mg,
1.56 % / 1a), 3 atm H2 for 50 min. By crystallization of the crude
product from benzene, 1.95 g (43.3 %) 2a were obtained. From
mother liquors, by LPC (eluent: toluene-methanol, 9:1), another
1.63 g of pure 2a (total yield: 79.2 %) were obtained.
1
609m, H-NMR- 500 MHz (CDCl3, δ ppm, J Hz): 7.27 (m, 2H, 2H-m,
7.2), 7.18 (t, 1H, H-p, 7.2), 7.17 (d, 2H, H-o, 7.2), 4.89 (dt, 1H, H-6a,
2.4, 7.0), 3.89 (q, 1H, H-5, 5.5), 3.10 (brs, OH), 2.88 (t, 2H, H-17, 7.4),
2.74 (m, 1H, H-3, 18.0), 2.73 (m, 1H, H-3), 2.73 (dt, 2H, H-16, 10.7,
7.4), 2.48 (t, 2H, H-14, 7.2), 2.44-2.38 (m, 2H, H-3, H-3a), 2.28 (dt,
1H, H-6, 6.3, 15.0), 1.97 (ddd, 1H, H-6, 2.4, 5.5, 15.0), 1.69 (qv, 1H,
H-4, 6.1), 1.55 (q, 2H, H-13, 7.2), 13C-NMR-75 MHz (CDCl3, δ ppm):
209.77 (CO, C-15), 177.15 (C-2), 140.83 (C-1’), 128.51, 128.36 (2C-o,
2C-m), 126.20 (C-p), 83.27 (C-6a), 77.16 (C-5), 52.83 (C-4), 44.27 (C-
16), 42.92 (C-3a), 40.64, 40.58 (C-6, C-14), 35.49 (C-3), 29.78 (C-
17), 25.78 (C-13) (See ESI 1.3.6.), MS 302.37, C18H22O4, calcd for
[M+1]+: th 303.15909, found 303.15947 [105.07 (C8H9), 285.1
(C18H21O3), 133.06 (C9H9O), 141.0 (C7H9O3)].
2.2. Hydrogenation of Ic
Ic (1 mmol, 302 mg), catalyst† (5.3 mg, 1.75 %/ Ic), methanol (50
mL), 3 atm H2 for 2 h; LPC (ethyl acetate-heptane, 1:1), resulting
13.2 mg IId and 267 mg (88.5 %) of pure compound IIc as an oil, IR:
3396brs, 2934s, 2862m, 1749vs, 1456m, 1417w, 1365w, 1179s,
1076m, 1032s, 971w, 899w, 750w, 702m, 1H-NMR-300 MHz (CDCl3,
δ ppm, J Hz): 7.28 (br t, 2H, H-o, 8.0), 7.22-7.17 (m, 3H, 2H-m, 1H-p),
4.93 (dt, 1H, H-6a, 1.9, 6.8), 3.98 (q, 1H, H-5, 5.1), 3.61 (m, 1H, H-
15), 2.78 (dd, 1H, H-3, 11.0, 18.3), 2.73 (dt, 1H, H-17, 8.1, 14.4), 2.63
(m, 1H, H-17), 2.50 (m, 1H, H-3a), 2.50 (d, 1H, H-3, 18.3), 2.28 (dt,
1H, H-6, 6.2, 15.0), 2.01 (brd, 1H, H-6, 15.0), 1.83-1.73 (m, 3H, H-4,
2H-16), 1.57-1.45 (m, 3H, H-13, 2H-14), 1.27 (m, 1H, H-13), 13C-
NMR-75 MHz (CDCl3, δ ppm): 177.82 (C-2), 141.84 (C-1’), 128.43,
128.35 (2C-o, 2C-m), 125.89 (C-p), 83.99 (C-6a), 77.37 (C-5), 71.26
(C-15), 53.86 (C-4), 43.14 (C-3a), 40.37 (C-6), 39.05 (C-16), 35.98
(C-3), 35.16 (C-14), 32.00 (C-17), 28.90 (C-13).
1.3.8. Hydrogenation of enone 14
a) 9.6 % catalyst / substrate, 3 atm H2 for 45 min: ent-14 (1.044 g,
2.94 mmol), catalyst† (100 mg, 9.6 % / ent-14), NaHCO3 (200 mg),
ethyl acetate (100 mL), 3 atm H2 for 45 min, TLC [IV, Rf 14 = Rf 15
0.78, (15 is yellow 14 orange) and turns black harder in oven]. By
LPC (ethyl acetate-hexane, 1:1), a pure fraction of 920 mg (88.1 %)
=
of
(1R,5R,6R,8R)-6-chloro-8-(4-(3-chlorophenoxy)-3-oxobutyl)-2-
oxabicyclo[3.2.1]octan-3-one 15 was obtained as an oil, [α]D = 38.3
˚(1% in THF), IR:2927w, 1728vs, 1593s, 1478s, 1430m, 1364m,
1285w, 1230m, 1184m, 1161s, 1073m, 1031s, 885w, 857w, 771w,
680w, 1H-NMR-300 MHz (CDCl3, δ ppm, J Hz): 7.24 (t, 1H, H-5’’,
821), 7.00 (d, 1H, H-4’’, 8.2), 6.91 (brs, 1H, H-2’’), 6.78 (dd, 1H, H-
6’’,1.9, 8.2), 4.70 (s, 1H, H-1), 4.56 (s, 2H, H-16), 4.25 (dd, 1H, H-6,
4.4, 8.0), 2.96 (dd, 1H, H-7, 8.0, 16.5), 2.77-2.62 (m, 5H, H-5, 2H-4,
2H-14), 2.46 (dt, 1H, H-7, 4.3, 16.5), 2.23 (t, 1H, H-8, 7.7), 1.95 (q,
2H, H-13, 7.4), 13C-NMR-75 MHz (CDCl3, δ ppm): 206.15 (C-15),
168.15 (C-3), 158.22 (C-1’’), 135.25 (C-3’’), 130.59 (C-5’’), 122.21 (C-
4’’), 115.15 (C-2’’), 112.73 (C-6’’), 84.03 (C-1), 72.81 (C-16), 59.30 (C-
6), 47.28 (C-8), 45.68 (C-5), 44.12 (C-7), 40.75 (C-14), 36.65 (C-4),
22.64 (C-13) (See ESI 1.3.7.1.), MS 357.23, C17H18Cl2O4, [M+1]+: th.
2.3. Hydrogenation of 8a in ethyl acetate
8a (2.0 g, 5.94 mmol), ethyl acetate (150 mL), catalyst† (20 mg, 1 %
/ 8a), 3 atm. H2, 60 min; by crystallization from benzene, 1.26 g
(62.6 %) 12a were obtained, mp 110-114 ˚C. From mother liquors, a
pure fraction of 0.62 g 12a was also obtained (total yield 93.5 %).
2.4. Hydrogenation of 8a in isopropanol
(±)-8a (2.0 g, 5.94 mmol), isopropanol (150 mL), catalyst† (40 mg, 2
% /8a), 3 atm. H2, 75 min; by crystallization from benzene, 1.27 g
(63.1 %) (±)-12a were obtained. From mother liquors, a pure
fraction of 0.59 g 12a was also obtained (total yield 92.4%).
357.06549, found 357.06592 [165.01 (C9H6OCl), 243.06 (C15H12OCl), 2.5. Hydrogenation of 8a in methanol
191.07 (C11H11O3)].
Intermediate (±)-8a (4.0 g, 11.88 mmol), methanol (150 mL),
b) 13.3 % catalyst / substrate, atm. pressure H2, 4 h: 14 (391 mg, catalyst† (40 mg, 1 % / 8a), 3 atm. H2, 50 min; by crystallization from
1.22 mmol), catalyst† (52 mg, 13.3 % / 14), ethyl acetate (20 mL), methanol, 3.0 g (71.6 %) (±)-9a were obtained, mp 192-196 ˚C.
NaHCO3 (90 mg), atm pressure H2 for 4 h, TLC (I, Rf 14 = 0.53, Rf 15
=
From mother liquors, by LPC (eluent, benzene-acetone, 9:1), 1.18 g
0.55). LPC (eluent: ethyl acetate-hexane, 1:1). 325 mg of a product (±)-9a were obtained (total yield 95.5 %).
containing ~ 60% 15 and ~ 40% 16 (Y = H), according with NMR,
This journal is © The Royal Society of Chemistry 20xx
NJC., 2019| 15
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 16 of 18
ARTICLE
New Journal of Chemistry
1
2
3
4
5
6
7
8
9
2.6. Hydrogenation of 8b in isopropanol
100 MHz (CDCl3, δ ppm): 205.93 (CO, C-15), 176.51 (CV-2ie)w, 1Ar6ti6cl.e0O2n(liCne6
8b (1.8 g, 6 mmol), isopropanol (150 mL), catalyst† (40 mg, 2.2 % / H5CO), 158.25 (C-1’), 135.06 (C-3’), 133.3D6O(I:C1-0p.)1,03193/0C.94N4J0(1C1-856’)B,
8b), 3 atm. H2, 75 min; LPC (hexane-ethyl acetate, 2:1) gave 1.69 g 129.57 (C-o), 129.41 (Cq, Bz), 128.52 (C-m), 121.99 (C-4’), 115.11 (C-
(93.2 %) of pure (-)-12b, as an oil.
2’), 112.78 (C-6’), 84.17 (C-6a), 79.62 (C-5), 72.71 (C-16), 52.02 (C-
4), 43.83 (C-3a), 37.58 (C-6), 36.67 (C-3), 36.08 (C-14), 26.02 (C-13)
(See ESI 2.8.), MS 442.89, C24H23ClO6, calcd for [M+1]+: th
443.12559, found 443.12622 [415.2 (C23H24ClO6), 321.09
(C17H18ClO4), 105.03 (C7H5O), 121.08 (C7H5O2)].
2.7. Hydrogenation of 10b-1
10b-1 (10 g, 24.7 mmol), THF (150 mL), 5% Pd/C (0.5 g, equivalent
to 0.25 g catalyst†, 2.5% catalyst / 10b-1), 6 atm H2 until the
reaction ended in TLC (ethyl acetate-methanol, 90:13, Rf 10b-1 = 0.42,
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
Rf
= 0.36). The crude product was crystallized from ethyl
2.9. Hydrogenation of the intermediate 10a-2 in ethyl acetate
Synthesis of 31-Ac 10a-2 (R = CH3): (±)-8a (6.8 g, 20 mmol), pyridine
(30 mL), acetic anhydride (3 mL), stirred overnight. TLC (I, Rf
0.35, Rf 10a-2 = 0.61); the reaction mixture was processed as above,
the crude product was purified by LPC (eluent: benzene) resulting a
11b-1
acetate-hexane, as needle, giving in almost quantitative yield
(3aR,4R,5R,6aS)-2-oxo-4-(3-oxo-5-phenylpentyl)hexahydro-2H-
cyclopenta[b]furan-5-yl benzoate, 11b-1, mp 77.2-77.8 ˚C, [α]D = -
87.1 ˚(1% in THF), IR: 3025w, 2992w, 2951w, 1750s, 1706vs, 1601w,
1495w1449w, 1359w, 1316w, 1276s, 1111m, 1064m, 1043m,
=
8a
pure fraction of 7.3
g (96.5%) (3aα,4β,5α,6aα)-4-((E)-4-(3-
1
1027m, 999m, 710m: H-NMR- 500 MHz (CDCl3, δ ppm, J Hz): 7.97
chlorophenoxy)-3-oxobut-1-en-1-yl)-2-oxohexahydro-2H-
1
(d, 2H, H-oBz, 7.7), 7.56 (t, 1H, H-pBz, 7.7), 7.44 (t, 2H, H-mBz, 7.7),
7.26 (t, 2H, 2H-m, 7.2), 7.17 (t, 1H, H-p, 7.2), 7.16 (t, 2H, H-o, 7.2),
5.16 (dt, 1H, H-5, 2.6, 5.4), 5.07 (t, 1H, H-6a, 6.5), 2.90-2.84 (m, 2H,
H-17), 2.87 (dd, 1H, H-3, 10.7, 18.1), 2.75 (brt, 2H, H-16, 7.4), 2.63
(m, 1H, H-3a), 2.56 (t, 2H, H-14, 7.21), 2.45 (dd, 1H, H-3, 3.3, 18.1),
2.41 (dt, 1H, H-6, 6.5, 15.9), 2.32 (brd, 1H, H-3, 15.9), 2.06 (m, 1H,
H-4), 1.70 (cv, 1H, H-13, 6.9), 1.61 (cv, 1H, H-13, 6.9), 13C-NMR-75
MHz (CDCl3, δ ppm): 208.91 (CO, C-15), 176.63 (C-2), 165.97 (COO),
140.80 (C-1’), 133.31 (C-oBz), 129.56 (C-pBz), 128.52, 128.46,
128.28 (2C-o, 2C-m, 2C-m-Bz), 126.13 (C-p), 84.29 (C-6a), 79.736 (C-
5), 52.27 (C-4), 44.30 (C-16), 43.72 (C-3a), 40.52, (C-14), 37.58 (C-6),
36.14 (C-3), 29.69 (C-17), 26.67 (C-13) (See ESI 2.7.), MS 406.47,
C25H26O5, calcd for [M+1]+: th 407.1853, found 407.18628 [105.07
cyclopenta[b]furan-5-yl acetate, 10a-2, as an oil, H-NMR-300 MHz
(CDCl3, δ ppm, J Hz): 7.23 (t, 1H, H-5’, 8.1), 7.00 (ddd, 1H, H-4’, 0.9,
2.0, 8.1), 6.90 (t, 1H, H-2’, 2.0), 6.78 (ddd, 1H, H-6’, 0.9, 2.0, 8.1),
6.84 (dd, 1H, H-13, 7.9, 15.7), 6.51 (dd, 1H, H-14, 1.1, 15.7), 5.05 (m,
1H, H-6a, 5.3), 5.01 (td, 1H, H-5, 2.1, 6.6), 4.68 (s, 2H, H-16), 2.90-
2.70 (m, 3H, H-3, H-3a, H-4), 2.50 (dt, 1H, H-6, 6.6, 15.3), 2.40 (m,
1H, H-3), 2.15 (ddd, 1H, H-6, 2.1, 5.3, 15.3), 2.02 (s, 3H, CH3), 13C-
NMR-75 MHz (CDCl3, δ ppm): 194.47 (C-15), 175.46 (C-2), 170.12
(CO-Ac), 158.37 (C-1’), 145.43 (C-13), 135.17 (C-3’), 130.48 (C-5’),
126.43 (C-14), 122.13 (C-4’), 115.25 (C-2’), 112.97 (C-6’), 82.66 (C-
6a), 77.71 (C-5), 72.26 (C-16), 53.81 (C-4), 42.48 (C-3a), 37.70 (C-6),
34.65 (C-3), 20.79 (CH3CO) (See ESI 2.9.1.).
(C8H9), 299.13 (C18H19O4), 161.1 (C11H13O), 159.08 (C11H11O), 145.06 Hydrogenation of (±)-10a-2 in ethyl acetate: (±)10a-2 (2.59 g, 6.8
(C10H9O)].
mmol), catalyst† (130 mg, 5 % / 10a-2), ethyl acetate (150 mL), 3
atm H2 for 30 min; TLC (I, Rf 10a-2 = 0.61, Rf 11a-2 = 0.52; VI, Rf 11a-2
0.28) showed only one product; 2.53 g (97.7 %) (3aα,4β,5α,6aα)-4-
(4-(3-chlorophenoxy)-3-oxobutyl)-2-oxohexahydro-2H-
=
2.8. Hydrogenation of compound 10a-1.
Synthesis of 10a-1: (±)-8a (6.8 g, 20 mmol) was dissolved in pyridine
(30 mL), the solution was cooled on an ice-bath, 96% benzoyl
chloride (2.9 mL, 24 mmol) was added dropwise and stirred
overnight. TLC (I, Rf in = 0.35, Rf fin = 0.51) showed the end of the
reaction, the reaction mixture was poured under stirring on
crashed-ice for 1 h, the product was extracted with ethyl acetate
cyclopenta[b]furan-5-yl acetate (±)-11a-2 were obtained as an oil,
1
after work-up of the reaction mixture), H-NMR-300 MHz (CDCl3, δ
ppm, J Hz): 7.22 (t, 1H, H-5’, 8.2), 7.00 (dd, 1H, H-4’, 1.9, 8.2), 6.90
(t, 1H, H-2’, 1.9), 6.78 (dd, 1H, H-6’, 2.2, 8.2), 5.03 (dt, 1H, H-6a, 1.6,
6.4), 4.90 (dt, 1H, H-5, 3.0, 5.4), 4.57 (s, 2H, H-16), 2.87 (dd, 1H, H-3,
10.6, 18.2), 2.80-2.69 (m, 2H, H-14), 2.63 (m, 1H, H-3a), 2.45 (d, 1H,
H-3, 18.2), 2.01 (s, 3H, CH3CO), 2.32 (dt, 1H, H-6, 5.7, 15.7), 2.20 (m,
1H, H-6), 2.01 (s, 3H, CH3), 1.98 (m, 1H, H-4), 1.80-1.58 (m, 3H, H-
14, 2H-13), 13C-NMR-75 MHz (CDCl3, δ ppm): 205.95 (C-15), 176.36
(C-2), 170.46 (CO-Ac), 158.37 (C-1’), 135.23 (C-3’), 130.54 (C-5’),
122.16 (C-4’), 115.17 (C-2’), 112.89 (C-6’), 83.85 (C-6a), 79.14 (C-5),
72.84 (C-16), 51.73 (C-4), 43.56 (C-3a), 37.65 (C-6), 37.49 (C-14),
36.60 (C-3), 36.06 (C-13), 21.06 (CH3CO) (See ESI 2.9.2.).
(2100 mL) the unified organic phases were washed with sat son.
NaHCO3, (100 mL) brine (100 mL), dried (Na2SO4) and concentrated
under reduced pressure. The crude product was purified by LPC
(eluent: benzene) resulting a pure fraction of 8.3 g (94.1%) as an oil.
Hydrogenation of the intermediate 10a-1 in ethyl acetate:
Intermediate 10a-1 (1.33 g, 3.01 mmol), ethyl acetate (150 mL),
catalyst† (15 mg, 1.13 % / 10a-1), 3 atm. H2, 135 min, TLC (I, Rf 10a-1
=
In the same conditions, with only 27 mg catalyst† (1 % / 10a-2), and
135 min hydrogenation time, the yield of 94.7% (2.45 g) of (±)-11a-
2.
0.51, Rf 11a-1 = 0.51). By crystallization from ethanol, 1.17 g (88.0 %)
(3aα,4β,5α,6aα)-4-(4-(3-chlorophenoxy)-3-oxobutyl)-2-
oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (±)-11a-1 were
obtained, mp 92-94 ˚C (from ethyl acetate-hexane, mp 97.8-99.3
˚C), IR: 2944w, 2927w, 2861w, 1764s, 1723vs, 1595m, 1483m,
1429m, 1313m, 1271s, 1251s, 1171s, 1109m, 1071m, 1045m,
2.10. Hydrogenation of 14 in ethyl acetate
(±)-14 (3.0 g, 8.4 mmole), ethyl acetate (150 mL), catalyst† (30 mg, 1
% / 14), 3 atm. H2, 50 min, TLC (IV, Rf 14 = 0.34, Rf 15 = 0.37). By
crystallization from methanol, 2.72 g (90.7 %) (±)-15 were obtained,
mp 95-96 ˚C, with the same IR and NMR presented at 2.7. From
mother liquors, 0.12 g (±)-15 were obtained (total yield: 94.7 %).
1
1027m, 913m, 895m, 780m, 709s, 682m, H-NMR-500 MHz (CDCl3,
δ ppm, J Hz): 7.98 (d, 2H, H-o, 7.4), 7.55 (t, 1H, H-p, 7.4), 7.42 (t, 2H,
H-m, 7.4), 7.18 (t, 1H, H-5’, 8.1), 6.96 (brd, 1H, H-4’, 8.1), 6.84 (brt,
1H, H-2’, 1.8), 6.73 (dd, 1H, H-6’, 1.8, 8.1), 5.19 (dt, 1H, H-5, 3.1,
5.7), 5.09 (t, 1H, H-6a, 6.1), 4.56 (s, 2H, H-16), 2.90 (dd, 1H, H-3,
10.4, 18.3), 2.83-2.78 (m, 2H, H-14), 2.67 (m, 1H, H-3a), 2.49 (d, 1H,
H-3, 18.3), 2.45 (dt, 1H, H-6, 5.9, 14.7), 2.33 (brd, 1H, H-6, 14.7),
2.12 (m, 1H, H-4), 1.80 (m, 1H, H-13), 1.67 (m, 1H, H-13), 13C-NMR-
Conclusions
The hydrogenation of the 13,14-double bond of allylic alcohol
and enone intermediates from the synthesis of 17-phenyl- or
16 | NJC., 2019
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 17 of 18
New Journal of Chemistry
Please do not adjust margins
New Journal of Chemistry
ARTICLE
1
2
3
4
5
6
7
8
9
7
8
9
C.-H. Yao, C.-M. Yang, H.-H. Chao, G.-VRie.w ALrteicele,OnUlinSe
2009/0259066 A1/ May 15, 2009.
16-(3-substituted-phenoxzy)-prostaglandins was studied. In
the reaction, the allylic alcohols gave, besides the main 13,14
hydrogenated compounds, the 15-desoxy-13,14 hydrogenated
byproducts in a large quantity which increases with the
amount of catalyst, the hydrogen pressure, and the reaction
time. The m-chloro-phenoxy intermediate 1a was also
dehydrohalogenated to the phenoxy-compound 2c under
these forced reaction conditions. The protection of the 5,15-
hydroxyl groups as THP, TBDMS, benzoate, increased the yield
of the 13,14-hydrogenated-17-phenyl compound IIg-IIh to
nearly 100%. Hydrogenation of enone intermediates 8 in ethyl
acetate, isopropanol, tetrahydrofuran gave the chemo-
selectively desired 13,14-hydrogenated ketone compounds 12.
In the case of the m-chloro-phenoxy compound, 12a is
transformed in time into the cyclized semi-ketal 13a. In
methanol and ethanol, the hydrogenated ketone is
transformed almost quantitatively in an acid catalyzed (by
traces of HCl in the catalyst) reaction to the six-atom cyclized
ketals with methoxy and ethoxy groups in two consecutive
chemo-selective reactions (13,14-hydrogenation, followed by
intramolecular addition of 5-OH, concomitant with the alcohol
from the solvent, to the 15-ketone). A dehydrohalogenated
cyclized ketal 9c was also obtained from 8a, when increased
amount of the catalyst, pressure of hydrogen and reaction
time were used. Generally, the hydrogenation of enones was
easier than that of allylic alcohols intermediates. In the
reactions described above, we also studied the effect of using
a more economically amount of Pd/C catalyst smaller than
10% / substrate (1-2%), and we found that the hydrogenations
were also realized near the high yields obtained with 10 %
S.-Y. Wei, Y.-C. Yeh, EP 1810967 B1DO/ I:J1a0n.1.01398/,C92N0J0061;18U6BS
8030514 B2/ Oct. 4, 2011.
A. K. Greenwood, D. McHattle, D. G. Thompson, D. Clissold,
US7498458 B2/March 3, 2009.
10 M. C. Dart, H. B. Henbest, J. Chem. Soc. 1960, 3564.
11 M. Albert, A. Berger, D. De Souza, K. Knepper, H. Sturm, US
8,481,758 B2/ July 9, 2013.
12 a) B. Resul, EP 0495069 B1/ August 08, 1990; b) B. Resul, US
5359095/ Oct. 25, 1994; c) B. Resul, RO 109332 B1/ August
08, 1991.
13 a) A. Gutman, G. Nisnevich, M. Etinger, I. Zaltzman, L.
Yudovich, B. Pertsikov, B. Tishin, US7166730 B2/ Jan. 23,
2007; US 2005/0209337 A1/ Sept. 22, 2005; b) A. Gutman, G.
Nisnevich, M. Etinger, I. Zaltzman, L. Yudovich, B. Pertsikov,
US 6927300 B2/ August 9, 2005.
14 J. W. Stjernschantz, B. Resul, US 5,296,504/ May 22, 1994;
US 5578618Nov. 26, 1996; US 2003/0181493A1/ Sept. 25,
2003.
15 a) P. G. Klimko, B. E. Bishop, V. E. Sallee, P. W. Zinke, US
5889052 / May 30, 1999, US 6,723,748 B2/ April 20, 2004; b)
T. R. Dean, J. A. May, V. L. Sallee, L. Desantis Jr, US
2002/0111381/ August 15, 2002.
16 R. Ueno, R. Ueno, T. Oda US 5770759 / June 23, 1998.
17 R. E. Conrow, P. W. Zinke, P. G. Klimko, R. D. Selliah, US
6,344,581 B1/ Febr. 5, 2002.
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
18 D. Alberico, J. Clayton, B. I. Gorin, J. Oudenes, US
2013/0072695 A1/ March 21, 2013.
19 M. L. Contente, P. Zambelli, S. Galafassi, L. Tamborini, A.
Pinto, P. Pinto, F. Molinari, D. Romano, J. Mol. Catalysis B:
Enzymatic, 2015, 114, 7; cited in H. S. Toogood, N. S.
Scrutton, ACS Catal. 2018, 8, 3532.
catalyst amount
/ substrate. A great number (13) of 20 F. Cocu, S. Coman, C. Tanase, D. Macovei, V. I. Parvulescu, in
H. U. Blaser, A. Baiker and R. Prins (Eds.), Stud. Surf. Sci.
Catal. Vol 108, Elsevier, Amsterdam, 1997, 207; b) S. M.
Coman, V. I. Parvulescu, Current Pharmaceutical Design,
Thematic issue: “Challenging organic syntheses and
pharmacological applications of natural products and their
derivatives”, 2015, 21 (38), 5558 and references cited.
21 G. Chambournier, A. Kornilov, H. M. Mahmoud, I. Vesely, S.
D. Barrett, WO 2011/046569/ April 21, 2011.
byproducts formed in the above hydrogenation reactions were
isolated and fully characterized, in addition to the main 13,14-
hydrogenated compounds; compounds 9b and (-)-3c were also
characterized by X-ray crystallography. We have not been able
to find the data for such compounds anywhere in the
literature therefore we believe our work could be useful not
only for researchers in the prostaglandin field, but also for
organic chemists, where hydrogenation of allylic alcohols or
enones may be accompanied by secondary compounds.
22 B. Giancarlo, A. D’Alfonso, L. Feliciani, A. Porta, G. Vidari,
Zanon,i US 2012016136 A1/ Jan.19, 2012.
23 S. Schwartz, G. Weber, H.-J. Palme, M. Wentzke, J. Chem.
Soc. Perkin Trans I, 1990, 751.
24 CrysAlis CCD and CrysAlis RED, version 1.171.36.32;
OxfordDiffractionLtd.: Yarnton, Oxfordshire, UK, 2003.
25 O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard,
H. Puschmann, J. Appl. Cryst. 2009, 42, 339.
Conflicts of interest
There are no conflicts to declare.
26 G. M. Sheldrich, SHELXS, Acta Cryst. A, 2008, 64, 112.
Acknowledgements
Notes and references
Note: Partially results were presented: C. I. Tănase, F. Cocu,
C. Drăghici, A. Hanganu, L. Pintilie, M. Maganu, C. V. A.
Munteanu, S. Shova, The XXXVth National Conference of
Chemistry, 2-5 Oct. 2018, Caciulata, Romania.
1
B. B. Resul, J. J. Stjernschanz, K. K. No, C. C. Liljebris, G. C.
Selen, M. M. Astin, M. M. Karlson, L. Z. I. Bito, J. Med. Chem.
1993, 36, 243.
2
3
M. C. Dart, H. B. Henbest, Nature 1959, 183, 817.
N. R. Karusala, B. Chavhan, M. K. Potla, R. Jerabaj, V. Gosula,
P. R. Burma, D. Datta, WO 2010/109476 A2/Jan.18,2010.
N. Murata, A. Aramata, US7642370/Jan. 05, 2010
R.-T. Suen, Y.-L. Liu, US 7,282,596 B2/Oct. 16, 2007.
K. E. Henegar, US6,689,901/ Oct. 10, 2004; US 2005/0038123
A1/February 17, 2005.
4
5
6
This journal is © The Royal Society of Chemistry 20xx
NJC., 2019| 17
Please do not adjust margins

New Journal of Chemistry
Page 18 of 18
View Article Online
DOI: 10.1039/C9NJ01186B
1
2
3
4
5
Hydrogenation of the double bond in -side chain of prostaglandin intermediates: conditions to increase the
yield and minimize the formation of secondary compounds
6
7
8
O
O
O
O
9
H2/10%Pd/C
Solvent
O
O
O
O
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
5
5
5
5
15
15
15
Y
X
X
X
R2
OR
O
15
R2
R1
R1
OR
OR
X
Y
Y
Y
R3
O
15-desoxy-byproducts
R = H, PG;
R1 = OH, OPG, H; R2 = H, OH, OPG
(semi)ketal byproducts
R3 = H, CH3 or C2H5
R1, R2 = O
X = O, CH2; Y = H, Cl, CF3
Secondary compounds
33 Hydrogenation examples
13 Hydrogenation byproducts