Facile green synthesis of 16-dehydropregnenolone acetate (16-DPA) from diosgenin

Article abstract of DOI:10.1080/00397911.2015.1121280

Chromium- and MnO₂-free green synthesis of industrially important steroidal drug intermediate 16-dehydropregnenolone acetate (16-DPA) starting from diosgenin is reported. The reaction sequence involves three steps: acetolysis followed by acetylation, oxidation, and hydrolysis. In the first step, Ac₂O was used both as reagent and solvent in combination with a Lewis acid (AlCl₃), which led to considerable reduction of high temperature and pressure requirements of earlier processes. The oxidation step was made catalytic with the use of KMnO₄(5 mol%) in the presence of co-oxidant NaIO₄, leading to less waste generation (of chromium, MnO₂, etc.). Minimization of the temperature, pressure, time consumption, and use of nontoxic solvents makes the process very handy and simple.

Full text of DOI:10.1080/00397911.2015.1121280

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Facile green synthesis of 16-dehydropregnenolone
acetate (16-DPA) from diosgenin
Diganta Baruah, Ram Nath Das & Dilip Konwar
To cite this article: Diganta Baruah, Ram Nath Das & Dilip Konwar (2016) Facile green
synthesis of 16-dehydropregnenolone acetate (16-DPA) from diosgenin, Synthetic
Communications, 46:1, 79-84, DOI: 10.1080/00397911.2015.1121280
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1121280
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Date: 21 January 2016, At: 03:07

SYNTHETIC COMMUNICATIONS
016, VOL. 46, NO. 1, 79–84
2
http://dx.doi.org/10.1080/00397911.2015.1121280
Facile green synthesis of 16-dehydropregnenolone acetate
(16-DPA) from diosgenin
Diganta Baruah, Ram Nath Das, and Dilip Konwar
Synthetic Organic Chemistry Division, CSIR, Northeast Institute of Science and Technology, Jorhat,
Assam, India
ABSTRACT
Chromium- and MnO
ARTICLE HISTORY
Received 9 October 2015
2
-free green synthesis of industrially important
steroidal drug intermediate 16-dehydropregnenolone acetate (16-
DPA) starting from diosgenin is reported. The reaction sequence
involves three steps: acetolysis followed by acetylation, oxidation, and
KEYWORDS
16-DPA; diosgenin; green
synthesis
hydrolysis. In the first step, Ac
2
O was used both as reagent and solvent
), which led to considerable
in combination with a Lewis acid (AlCl
3
reduction of high temperature and pressure requirements of earlier
processes. The oxidation step was made catalytic with the use of
KMnO
4
(5 mol%) in the presence of co-oxidant NaIO
4
, leading to less
waste generation (of chromium, MnO
2
, etc.). Minimization of the
temperature, pressure, time consumption, and use of nontoxic
solvents makes the process very handy and simple.
GRAPHICAL ABSTRACT
Introduction
Steroids are widely used drugs in the modern pharmaceutical industry. In spite of contro-
versy about their side effects, the global markets of steroidal drugs and intermediates
are worth more than a billion dollars. 16-Dehydropregnenolone acetate (16-DPA) 3 is
widely used as central intermediate or building block for the synthesis of a large number
of steroidal drugs including anabolic steroids, corticosteroids, sex hormones, and contra-
[
1,2]
ceptives.
Usually, 16-DPA (3β-acetoxy-pregna-5,16-dien-20-one) 3 is prepared from
either of the two naturally occurring steroidal sapogenins, namely diosgenin (22-iso-5-spir-
[
2–11]
ostane-3β-ol) 1 and solasodine ((3β,22α,25 R)-spirosol-5-en-3-ol) 2.
These com-
pounds are extracted from Dioscorea floribunda and Solanum Khasianum tuber berries,
CONTACT Dilip Knowar
dkonwar@yahoo.co.uk
Synthetic Organic Chemistry Division, CSIR, Northeast Institute of
Science and Technology, Jorhat 785006, Assam, India.
Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
©
2016 Taylor & Francis

8
0
D. BARUAH, R. N. DAS, AND D. KONWAR
respectively.[5,6][The conversion of diosgenin 1 to 16-DPA 3 was first reported by Marker
2–12]
and coworkers,
who discovered that the spiroketal ring system of diosgenin 1 and
solasodine 2 could be opened by heating up the compounds with acetic anhydride in
xylene solvent at 220 °C for 14 h at 5 bar pressure. The resultant pseudodiosgenin diacetate
(
3β,26-diacetoxyfurosta-5,20(22)-diene, PDA) 4 were then oxidized with K Cr O to pro-
2
2 7
duce diosone (a keto ester) 5, which on acid hydrolysis gave 16- DPA.
Later, many other processes were also reported. In most of the reported procedures, the
[
5–12]
acetolysis þ acetylation step is carried out either using elevated temperature
or using
acid catalysts such as HCl, p-TsOH, CH COCl, or crotonic acid to avoid the required elev-
3
[
11–16]
ated pressure.
chloride were found to be superior.
pseudodiosgenin diacetate 4 to diosone 5 is usually carried out using highly toxic CrO ,
Among the catalysts, pyridine / acetyl chloride or pyridinium hydro-
[
14,15]
On the other hand, oxidation of
3
[
17]
[18,19]
K Cr O ,
excess amount of KMnO ,
etc. Obviously, the process produces huge
2
2
7
4
quantity of nonreusable MnO or chromic acid, which makes the workup procedure more
2
tedious. Also the problems associated with the waste disposal often arise. Several other
[
11–15,20–23]
workers had also reported
the synthesis of 16-DPA and related compounds from
different sapogenins, but the overall yields were only poor to moderate. Therefore, devel-
opment of a better and handy procedure for the synthesis of 16-DPA, 3 can be considered
as highly useful.
In this communication, we report a chromium- and MnO -free, efficient, and improved
2
method for the synthesis of 16 DPA 3 from diosgenin 1, eliminating the disadvantages of
other reported procedures: (i) involvement of high temperature and pressure, (ii) require-
ment of toxic reagents in excess, (iii) production of hazardous waste, and (iv) requirement
of a long reaction time.
Results and discussion
To develop an improved process, we first studied the acetolysis þ acetylation of diosgenin 1
using different Lewis acids and conditions (Table 1). Studies on various Lewis acids, such as
ZnCl , FeCl , AlCl , InCl , NiCl , and Cu (OAc) , showed that AlCl is the most effective
2
3
3
3
2
2
3
Lewis acid for this transformation with 98% yield of PDA (entry 3, Table 1). Use of AlCl3
significantly shortened the reaction time as well as lowered the reaction temperature
(
entry 3, Table 1). The reaction could be the best carried out using a catalytic amount
of anhydrous AlCl in the presence of an excess of freshly distilled acetic anhydride
3
(
Scheme 1) that serves also as a solvent. The reaction was complete within 3 h by heating
Figure 1. Structure of 16-DPA and its starting materials.

SYNTHETIC COMMUNICATIONS
81
Table 1. Optimization of the Lewis acids for the synthesis of PDA 4 from diosgenin 1.
No.
Lewis acids
Time (h)
Temperature (°C)
Yield (%)
1
2
3
4
5
6
ZnCl
2
6
6
3
6
8
8
160
140
140
160
180
180
45
60
98
40
10
40
FeCl
3
AlCl
3
InCl
3
NiCl
2
Cu(OAc)
2
at 140 °C under atmospheric pressure. After workup in ice-cold water, pseudodiosgenin
diacetate 4 could be obtained in up to 98% yield. No side products such as monoacetylated
or elimination products were observed.
The oxidation of PDA 4 to diosone 5 was carried out using KMnO as oxidizing agent
4
[
24]
(
Scheme 1). To avoid the requirement of stoichiometric or excess oxidizing agent, it was
decided to use a co-oxidant. Subsequently, co-oxidants including NaIO , NaBrO , NaIO ,
4
3
3
and NaClO were screened (entries 1–11, Table 2). In the presence of NaIO , 5 mol%
4
4
KMnO was sufficient to complete the conversion (entries 2 and 3, Table 2). The optimized
4
conditions (entry 4, Table 2) for oxidation of PDA to diosone are 1 mmol PDA, 0.05 mmol
KMnO , 0.05 mmol NaIO , CH Cl /H O (1:1) solvent, and 3 h at room temperature.
4
4
2
2
2
Enhancing the reaction time did not improve the product yield at all (entry 5, Table 2).
Lowering the KMnO loading from 0.05 mmol to 0.03 mmol instantaneously decreased
4
the yield to 60% (entry 6, Table 2). Different solvents such as MeOH and THF neither
enhanced the product yield nor increased the reaction rate (entries 7 and 8, Table 2).
The optimized reactions were carried out using tetra ethyl ammonium bromide as a
phase-transfer catalyst (PTC). The oxidizing system could be recycled up to 4 times, reduc-
ing excessive waste generation. Finally, diosone 5 was hydrolyzed using CH COOH to get
3
1
6-DPA 3. The structure of 16-DPA 3 was confirmed by mixed melting-point determi-
nation and comparison of its FT-IR, NMR, and mass spectral data with an authentic
sample.
Scheme 1. Synthesis of 16-DPA from diosgenin.

8
2
D. BARUAH, R. N. DAS, AND D. KONWAR
Table 2. Optimization of the reaction condition for the oxidation of PDA 4 to diosone 5.
Entry
PDA/oxidant/co-oxidant ratio (mmol)
Solvent
Time (h)
Yield (%)
1
2
3
4
PDA/KMnO
PDA/KMnO
PDA/KMnO
4
4
4
/NaIO
/NaIO
/NaIO
4
4
4
¼ 1:1:1
CH
2
2
O
Cl
2
5
5
55
45
75
75
75
60
55
50
62
59
65
¼ 1:1:0.05
¼ 1:1:0.05
H
CH
CH
2
Cl
Cl
2
/H
2
O ¼ 1:1
3
PDA/KMnO
4
/NaIO
4
¼ 1:0.05:0.05
2
2
/H
2
O ¼ 1:1
3
5
PDA/KMnO
PDA/KMnO
PDA/KMnO
PDA/KMnO
PDA/KMnO
PDA/KMnO
PDA/KMnO
4
4
4
4
4
4
4
/NaIO
/NaIO
/NaIO
/NaIO
/NaIO
4
4
4
4
3
¼ 1:0.05:0.05
¼ 1:0.03:0.05
¼ 1:0.05:0.05
¼ 1:0.05:0.05
¼ 1:0.05:0.05
CH
CH
2
Cl
Cl
2
/H
/H
2
O ¼ 1:1
O ¼ 1:1
5
6
7
8
9
2
2
2
4
MeOH/H
THF/H
2
O ¼ 1:1
3
2
O ¼ 1:1
3
CH
CH
CH
2
2
2
2
Cl /H
2
Cl /H
2
Cl /H
2
O ¼ 1:1
2
O ¼ 1:1
2
O ¼ 1:1
6
1
1
0
1
/NaBrO
/NaCIO
3
¼ 1:0.05:0.05
¼ 1:0.05:0.05
10
10
4
Conclusion
In summary, a practical and efficient chromium- and MnO -free green method for the
2
preparation of 16-DPA is described starting from diosgenin. The process holds several
advantages over the other conventional methods (Table 3). During the synthesis of PDA
from diosgenin, the temperature and pressure requirements could be decreased drastically.
Also the oxidation step was made catalytic, thus eliminating the accumulation of hazardous
by-products (chromium, MnO , etc.). The operations in the process are useful in terms of
2
yields, time, and generation of less toxic materials to the environment. Note that the cata-
lyst used in the oxidation process is reusable. Because of the inherent simplicity, it is
expected that the process can easily be exploited for industrial productions.
Experimental
Melting points are uncorrected. Reactions were monitored using thin-layer chromato-
graphy (TLC) on silica gel GF254. NMR spectra were recorded on Avance DPX 300-
MHz FT-NMR spectrometer. Chemical shifts are expressed in δ units relative to
Table 3. Comparison of the developed method with the earlier reported methods.
Chemical steps
Conventional methods
Present method
1
. Acetolysis þ acetylation of diosgenin
to PDA
a. Reagent used
b. Temperature
c. Pressure
d. Reaction time
e Yield
f. Solvent
g. Apparatus
a. Acetic anhydride
a. Acetic anhydride with AlCl
b. 140 °C
c. Normal pressure
d. 3 h
e. 95–98%
f. Acetic anhydride
3
b. 200 °C
c. 5 bar
d. 14 h
e. 80–90%
f. Xylene
g. Autoclave or high-pressure instrument g. Ordinary round-bottomed flask
2. Oxidation of PDA to diosone
a. Reagent used
b. Molar ratio of reagents
c. Temperature
d. Reaction time
e. Yield
2
a. K Cr
2 7
O /CrO
3
4 4
a. KMnO with co-oxidant NaIO
b. PDA : oxidizing agent (1:1.5 or more) b. PDA : oxidizing agent (1:0.05: 0.05)
c. 0–25 °C
d. 4–5 h
c. 25 °C
d. 3 h
e. 75%
e. 60–70%
f. Solvent
g. Side products
f. CH
Cl
2 2
2 2
f. CH Cl and water (1:1)
g. Toxicchromic acid, MnO
quantity
2
, etc., in large g. Very little MnO
products
2
is formed as side
h. Catalyst recyclability
i. Co-oxidant
h. Cannot be recycled
i. No co-oxidant used
h. Can be recycled
i. Co-oxidant used

SYNTHETIC COMMUNICATIONS
83
tetramethylsilane (TMS) signal as internal reference. IR spectra were recorded using KBr
pellets using a FTIR system 2000 Perkin-Elmer spectrometer. Mass spectra were recorded
on Esquire 3000 mass spectrometer.
Synthesis of PDA 4
AlCl (67 mg, 0.5 mmol) was added to Ac O (20 mL, freshly distilled) in a round-bottomed
3
2
flask fitted with a CaCl guard tube (drying tube). The mixture was stirred for 15 min at
2
room temperature and then diosgenin 1 (414 mg, 1 mmol) was added. The reaction mix-
ture was refluxed at 140 °C for 3 h. The progress of the reaction was monitored by TLC.
After completion, the reaction mixture was slowly poured into ice water (100 mL) with vig-
orous stirring. The mixture was kept at room temperature for 5 h, when the solid mass was
separated. Filtration of precipitated solid and recrystallization from MeOH produced the
[
13,18,19]
product (488 mg, 98%) as white solid. Mp 98 °C (lit.
98–100 °C); IR (CHCl3):
3
À 1
1
1
736 (broad), 1373, 1250, 1025 cm ; H NMR (300 MHz, CDCl ): δ 0.81(s, 3H), 0.97
(
d, 3H, J ¼ 6.3 Hz), 1.2 (s, 3H), 1.7 (s, 3H), 2.1(bs, 6H, acetate protons), 3.9 (d, 2H, J ¼ 4.5
Hz), 4.80–4.45 (m, 2H), 5.62–5.31 (m, 1H); mass (m/z, 100%): 498 (Mþ).
Synthesis of 16-DPA 3
Pseudodiosgenin diacetate (PDA) 4 (498 mg, 1 mmol) and NaIO (10.7 mg, 0.05 mmol)
4
were dissolved in CH Cl (20 mL) and H O (15 mL). To this mixture a solution of KMnO
4
2
2
2
(
10 mg, 0.05 mmol) in water (5 mL) was added dropwise for a period of 10 min followed by
triethyl benzyl ammonium chloride (TEBA, 5 mg, 2.2 mol%) at pH 4. The reaction mixture
was stirred vigorously for a period of 3 h at room temperature. The progress of the reaction
was monitored by TLC. After completion, the reaction mixture was diluted by addition of
CH Cl (50 mL) and passed through a pad of celite (5 g). The organic solvent was separated
2
2
and dried under reduced pressure to get diosone 5 as a gummy material. Without further
purification, the crude product was treated with CH COOH (20 mL) and refluxed for 4 h at
3
1
10 °C. After completion, the reaction mixture was poured in ice water and extracted
with CH Cl . Separation of the organic layer, washing with 5% NaHCO , drying over
2
2
3
anhydrous Na SO , and evaporation of the solvent gave the solid product, which on recrys-
tallization produced 16-DPA 3 as a white solid (267 mg, 75% w.r.t. PDA). Mp 172 °C
2
4
[
13,18,19]
À 1 1
(
lit.
169–175 °C); IR (CHCl ): 1731, 1661, 1373, 1248, 1137, 1037, 943 cm ; H
3
NMR (300 MHz, CDCl ): δ 1.0 (s, 3H), 1.2 (s, 3H), 2.0 (s, 3H), 2.2 (s, 3H), 4.5 (m, 1H),
3
5
.31 (m, 1H), 6.65 (m, 1H); mass (m/z, 100%): 356 (Mþ).
Acknowledgments
The authors acknowledge the director, CSIR–NEIST, Jorhat, Assam, and Pallab Pahari for their kind
help.
Funding
The authors are also thankful to the Council of Scientific and Industrial Research, New Delhi, India,
for funding NWP Projects CSC-0125 and MLP-3000/03.

8
4
D. BARUAH, R. N. DAS, AND D. KONWAR
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