Total synthesis of (+)-diospongin A

Article abstract of DOI:10.1016/j.tet.2020.131625

Enantioselective total synthesis of 2,4,6-trisubstituted pyran natural product diospongin A is accomplished from benzaldehyde in 5 steps. Key reaction in the synthesis is the addition of a silyl enol ether derived from vinylogous aryl methyl ketone to chiral β-alkoxy aldehyde and subsequent oxa-Michael addition.

Full text of DOI:10.1016/j.tet.2020.131625

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Total Synthesis of (+)-Diospongin A
Kannan Vaithegi, Kavirayani R. Prasad
PII:
S0040-4020(20)30832-2
https://doi.org/10.1016/j.tet.2020.131625
TET 131625
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 August 2020
Revised Date: 16 September 2020
Accepted Date: 26 September 2020
Please cite this article as: Vaithegi K, Prasad KR, Total Synthesis of (+)-Diospongin A, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131625.
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Graphical Abstract
Total Synthesis of (+)-Diospongin A
Kannan Vaithegi and Kavirayani R. Prasad*

1
Tetrahedron
journal homepage: www.elsevier.com
Total Synthesis of (+)-Diospongin A
Kannan Vaithegi and Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, INDIA
FAX: +0091-80-23600529; E-mail: prasad@iisc.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Enantioselective total synthesis of 2,4,6-trisubstituted pyran natural product diospongin A is
accomplished from benzaldehyde in 5 steps using a direct addition of vinylogous aryl methyl
ketone to chiral β-alkoxy aldehyde and subsequent oxa-Michael addition.
.
Available online
Keywords:
diospongin A
natural products
Total synthesis
vinylogous Mukaiyama aldol reaction
oxy-Michael addition
1. Introduction
which can in situ undergo the oxa-Michael addition yielding the
product diospongin A 1 in a single step process (Scheme 1).
Substituted pyrans are ubiquitous structural units present in a
number of natural products displaying various bio-activities.
Diospongin A and B (figure 1) are two simple 2,4,6-tri
substituted pyran natural products isolated from the rhizhomes of
Dioscorea spongiosa possessing potent anti-oesteoporotic
activity.1 Number of groups reported the total synthesis of both
diospongins majority relying on oxa-Michael addition for the
construction of the pyran ring while Prins cylization and
intramolecular carbonylative arylation were also utilized to
construct the pyran framework.2(a-u) While this manuscript was
under preparation Mohapatra’s group reported the synthesis of
diospongin A using a Mukaiyama reaction on a functionalized
lactol.2x
OH
OH
O
Ph
OH
Ph
O
Ph
Diospongin A (ent-1)
O
Ph
3
O
Me
O
H
benzaldehyde
Ph
OTBS
Ph
4
5
OH
O
OH
O
Scheme 1. Retrosynthesis for ent-diospongin A (ent-1).
O
O
2. Results and Discussion
With this proposal, the synthetic sequence commenced with the
preparation of the required β-alkoxy aldehyde
4 from
Diospongin A 1
Diospongin B 2
benzaldehyde involving the Nagao acetate aldol reaction3 and
subsequent conversion of the aldol product 7 to the aldehyde 4.
Mukaiyama aldol reaction of the aldehyde 4 with silylenol ether
9 (obtained from the unsaturated ketone 5) afforded the mono
silyloxy protected diol 10 in 71% yield, as an inseparable mixture
of diastereomers (77:23) and the diol 3 in 14% yield (79:21) as
an inseparable diastereomeric mixture, 1,3-trans diol being the
major diastereomer in both cases. Formation of the major 1,3-
trans diastereomer in the addition of 9 to 4 can be rationalized
based on the model proposed by Evans5 for similar reactions.
Reaction of the alcohol 10 with either camphorsulphonic acid or
Figure 1: Structure of (−)-diospongin A 1 and B 2.
Interestingly, most of the syntheses either relied on the oxa-
Michael addition reaction or on Wacker type oxidation to install
the required carbonyl group in the natural product, while a direct
addition of the vinylogous aryl methyl ketone to the chiral
aldehyde and subsequent oxa-Michael addition was never
investigated. We reasoned that such stereocontrolled direct
addition of unsaturated ketone 5 to the aldehyde 4, leads to the
formation of the 1,3-diol 3 possessing the unsaturated ketone

2
Tetrahedron
with TFA underwent smooth deprotection of the TES group
followed by oxa-Michael reaction2a,4 affording diospongin A
(ent-1) in 18% yield and 5-epi-diospongin A (ent-1a) in 66%
yield. Mitsunobu inversion of ent-1a afforded ent-diospongin A
(ent-1) in 67% yield (Scheme 2).
Table 1: Reaction conditions for vinylogous Mukaiyama aldol
reaction of siloxy aldehyeds (4a-4c) with silyloxydienes (9a-
9c).a
Entry
R1
R2
Time (1a:1)b
1a
1
yieldc
yieldc
1
2
-TMS
4a
-TBS
4b
-TES 4 -TMS 9
-TIPS
4c
-TMS 9 0.5 h 90:10
61%
3%
-TMS 9
1 h
2 h
87:13
48%
6%
3
4
76:24
64:36
36%
27%
8%
14%
-TMS 9 12 h
5
6
7
-TBS
4b
-TES 4
-TBS
9a
-TES
9b
-TIPS
9c
2 h
1 h
84:16
76:24
57:43
36%
40%
26%
6%
8%
-TIPS
4c
12 h
13%
aCondition: reaction was performed at −78 °C for 10 min and
then slowly warmed to room temperature and stirred at room
temperature for the time specified in table.
bRatio of the products 1a:1 (was determined by crude H NMR
1
spectroscopy). cIsolated yield.
As evident from table-1, reaction of the trimethylsiloxy aldehyde
4a with the trimethylsilyl enol ether 9 afforded the products ent-
1a and ent-1 in 90:10 ratio and the major product ent-1a was
isolated in 61% yield. No improvement in the ratio towards the
formation of required ent-diospongin (ent-1) was observed when
the trimethylsilyl group in 4 was replaced with other bulky silyl
groups such as tert-butyldimethylsilyl or triethylsilyl groups
(entries 2-4). It is observed that the less bulky trimethylsiloxy
aldehyde 4a offered better diastereoselectivity in the reaction for
the formation of ent-1a. The reaction of 9 with TIPS protected
aldehyde 4c afforded the product in 3:2 diastereomeric ratio,
while the reaction of the triisopropylsilyloxy aldehyde 4c with
the triisopropylsilyloxy diene 9c furnished the products ent-1a
and ent-1 in 57:43 ratio. These experimental observations (table
1) suggest that the steric bulk in the β-substituent of the aldehyde
plays a crucial role in the outcome of the diastereoselectivity of
the vinylogous Mukaiyama aldol reaction.
Scheme 2. Total synthesis of (+)-diospongin A (ent-1).
Formation of the 2,6 cis-tetrahydropyrans (ent-1a and ent-1) can
be explained on the basis of the proposal of Fuwa et al.6 and also
by the recent theoretical and experimental observations of oxa-
Michael addition reactions on structurally similar substrates
containing unsaturated thioesters (instead of unsaturated ketones)
using trifluoroacetic acid reported by Clarke’s group.2w
In an effort to improve the diastereomeric ratio of the product
diospongins (1a and 1) as well as to decrease the number of steps
in the synthesis, structurally diverse silyl enol ethers 9a-c were
treated with the siloxy aldehyde with varied silyl substitutions
(4a-c). The intermediate products 10 and 3 were treated with
CSA in one pot to afford directly (+)-diospongin A (ent-1) and its
5-epimer (ent-1a) (Scheme 3).
3. Conclusions
In conclusion, synthesis of (+)-diospongin A (ent-1) is
accomplished from β-siloxy aldehyde 4a involving a single pot
operation of vinylogous Mukaiyama aldol reaction,
silyldeprotection and oxa-Michael addition reactions. The total
synthesis involves 5 linear steps, starting from commercially
available benzaldehyde with 25% overall yield.
4. Experimental section
General Procedures: Column chromatography was performed
on silica gel, Acme grade 100-200 mesh. TLC plates were
visualized either with UV, in an iodine chamber, or with
phosphomolybdic acid spray, unless noted otherwise. Unless
stated otherwise, all reagents were purchased from commercial
sources and used without additional purification. THF was
freshly distilled over Na-benzophenone ketyl. Melting points
Scheme 3. One pot vinylogous Mukaiyama aldol reaction/silyl
deprotection/oxa Michael addition.
1
were uncorrected. Unless stated otherwise, H NMR and 13C
NMR spectra were recorded on 400 MHz machine in CDCl3 as
solvent with TMS as reference unless otherwise indicated. Unless
stated otherwise, all the reactions were performed under inert
atmosphere. All the specific rotations were determined at 24 °C.

3
Preparation
of
(R)-3-hydroxy-1-((S)-4-isopropyl-2-
Procedure
B:
Preparation
of
(R)-3-phenyl-3-
thioxothiazolidin-3-yl)-3-phenylpropan-1-one (7): To a pre-
cooled (−15 °C) solution of 6 (0.4 g, 2 mmol) in freshly distilled
dry CH2Cl2 (8 mL) was added diisopropylethylamine (0.45 mL,
2.6 mmol) under inert atmosphere. TiCl4 (0.24 mL, 2.2 mmol)
was introduced into the reaction mixture and the resulting dark
brown solution was stirred for 30 min at −15 °C. The reaction
mixture was cooled to −78 °C and a solution of benzaldehyde
(0.2 mL, 2.1 mmol) in CH2Cl2 (4 mL) was added dropwise and
was stirred at −78 °C. After completion of the reaction (~30
min), it was quenched by addition of saturated NH4Cl solution
(10 mL). The reaction mixture was extracted with CH2Cl2 (2 x 10
mL). The combined organic layers were washed with brine (10
mL) and dried over anhydrous Na2SO4. Evaporation of the
solvent followed by silica gel column chromatography of the
resultant residue with petroleum ether/EtOAc (8:2) as eluent
furnished 7 (0.47 g, 77%) as yellow colour oil and 7a (0.036 g,
((triethylsilyl)oxy)propanal (4): To a solution of the compound
8 (0.28 g, 0.6 mmol) in CH2Cl2 (7 mL) was added DIBAL-H (1.3
mL, 1.3 mmol) at −78 °C and was stirred at the same temperature
for 10 min. After the reaction was complete (TLC), it as
quenched by addition of aqueous saturated solution of sodium
potassium tartrate (10 mL) and allowed to stir at room
temperature for 1 h. The reaction mixture was then extracted with
EtOAc (2 × 20 mL) and the combined organic extract was
washed with brine (10 mL), dried over anhydrous Na2SO4.
Evaporation of the solvent gave the crude residue which on
purification using silica gel column chromatography, petroleum
ether/EtOAc (9:1) as eluent afforded the aldehyde 4 (0.13 g,
75%) as a colourless oil; [α]24 +74.4 (c 2.2, CHCl3); IR (neat)
D
2954, 2877, 2724, 1721, 1666 cm-1; 1H NMR (400 MHz, CDCl3)
δ 9.78 (t, J = 2.4 Hz, 1H), 7.37-7.22 (m, 5H), 5.22 (dd, J = 8.0,
4.4 Hz, 1H), 2.87 (ddd, J = 15.6, 8.0, 2.4 Hz, 1H), 2.64 (ddd, J =
15.6, 4.0, 2.0 Hz, 1H), 0.86 (t, J = 8.0 Hz, 9H), 0.53 (ddd, J =
15.2, 7.6, 2.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) 201.4,
143.8, 128.4 (2C), 127.6, 125.6 (2C), 70.5, 53.9, 6.6 (3C), 4.7
(3C); HRMS for C15H24O2Si+Na calcd 287.1443; found
287.1445.
6%) as yellow colour solid; Major diastereomer 7: [α]24
D
+353.5 (c 1.1, CHCl3), [lit3 [α]24 +386.7 (c 1.0, CHCl3)]; IR
D
(neat) 3419, 2921, 1694, 1514, 1161 cm-1; H NMR (400 MHz,
1
CDCl3) δ 7.43-7.25 (m, 5H), 5.27 (dd, J = 9.2, 2.8 Hz, 1H), 5.13
(t, J = 7.2 Hz, 1H), 3.79 (dd, J = 17.2, 2.4 Hz, 1H), 3.59 (dd, J =
17.2, 9.2 Hz, 1H), 3.48 (dd, J = 11.6, 8 Hz, 1H), 3.02 (d, J = 11.6
Hz, 1H), 2.37 (sext, J = 6.8 Hz, 1H), 1.06 (d, J = 6.8 Hz, 3H),
0.99 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.0,
172.6, 142.4, 128.5 (2C), 127.7, 125.8 (2C), 71.5, 70.2, 46.8,
30.8, 30.7, 19.1, 17.8; HRMS for C15H19NO2S2+Na calcd
332.0755; found 332.0765.
Preparation of (R)-1-((S)-4-isopropyl-2-thioxothiazolidin-3-
yl)-3-phenyl-3-((trimethylsilyl)oxy)propan-1-one (8a): TMS-
ether 8a was prepared from the alcohol 7 (0.09 g, 0.32 mmol)
with diisopropylethylamine (0.08 mL, 0.5 mmol) in presence of
trimethylsilyltriflate (0.06 mL, 0.36 mmol) using the procedure A
described above in (0.09 g, 81%) as a yellow oil; [α]24D +350.7 (c
1
1.0, CHCl3); IR (neat) 2960, 2736, 1697, 1598, 1460 cm-1; H
Minor diastereomer 7a: (S)-3-hydroxy-1-((S)-4-isopropyl-2-
thioxothiazolidin-3-yl)-3-phenylpropan-1-one: M.P: 86–90 °C,
[lit.3 M.P: 88–95 °C]; [α]24 +271.7 (c 1.1, CHCl3), [lit3 [α]24
NMR (400 MHz, CDCl3) δ 7.39-7.21 (m, 5H), 5.32 (dd, J = 9.2,
3.2 Hz, 1H), 5.04 (t, J = 7.2 Hz, 1H), 3.86 (dd, J = 16.4, 9.2 Hz,
1H), 3.49 (dd, J = 11.6, 8.0 Hz, 1H), 3.30 (dd, J = 16.4, 3.2 Hz,
1H), 3.02 (d, J = 11.2 Hz, 1H), 2.35 (sext, J = 6.8 Hz, 1H), 1.03
(d, J = 6.8 Hz, 3H), 0.96 (d, J = 7.2 Hz, 3H), 0.02 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 202.7, 171.1, 143.9, 128.3 (2C),
127.4, 126.0 (2C), 71.7 (2C), 48.4, 30.9, 30.8, 19.1, 17.7, 0.1
(3C); HRMS for C18H27NO2SiS2+Na calcd 404.1150; found
404.1151.
D
D
+279.2 (c 1.0, CHCl3)].; IR (KBr) 3423, 2962, 1689, 1493, 1159
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.45-7.20 (m, 5H), 5.21-5.11
(m, 2H), 3.83 (dd, J = 17.2, 9.6 Hz, 1H), 3.59 (dd, J = 17.2, 3.2
Hz, 1H), 3.48 (dd, J = 11.6, 8.0 Hz, 1H), 3.02 (d, J = 11.2 Hz,
1H), 2.36 (sext, J = 6.8 Hz, 1H), 1.06 (d, J = 6.8 Hz, 3H), 0.98
(d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.0, 172.9,
142.4, 128.5 (2C), 127.7, 125.9 (2C), 71.4, 70.7, 46.7, 30.7, 30.6,
19.0, 17.7; HRMS for C15H19NO2S2+Na calcd 332.0755; found
332.0757.
Preparation of (R)-3-phenyl-3-((trimethylsilyl)oxy)propanal
4a: aldehyde 4a was prepared from silyl ether 8a (0.09 g,
0.24mmol) in presence of DIBAL-H (0.5 mL, 0.49 mmol) using
the procedure B described above in (0.051 g, 98%) as a colorless
Procedure A: Preparation of (R)-1-((S)-4-isopropyl-2-
thioxothiazolidin-3-yl)-3-phenyl-3-((triethylsilyl)oxy)propan-
1-one (8): To a pre-cooled (−20 °C) solution of 7 (0.35 g, 1.1
mmol) in CH2Cl2 (10 mL) were added diisopropylamine (0.3 mL,
1.7 mmol) and triethylsilyltriflate (0.28 mL, 1.2 mmol). The
reaction mixture was allowed to stir at −20 °C for 0.5 h. After
completion of the reaction (TLC) it was quenched by addition of
water (10 mL) and the reaction mixture was extracted with
EtOAc (2 × 10 mL). The organic layer was washed with brine
(20 mL) dried over anhydrous Na2SO4 and the solvent was
evaporated under reduced pressure to give a crude residue, which
on purification by silica gel column chromatography petroleum
ether/EtOAc (9:1) as eluent furnished the compound 8 (0.35 g,
oil. [α]24 +88.4 (c 0.45, CHCl3); IR (neat) 2960, 2872, 2723,
D
1
1724, 1494 cm-1; H NMR (400 MHz, CDCl3) δ 9.78 (t, J = 2.0
Hz, 1H), 7.37-7.24 (m, 5H), 5.22 (dd, J = 8.4, 4.0 Hz, 1H), 2.88
(ddd, J = 16.0, 8.8, 2.8 Hz, 1H), 2.63 (ddd, J = 16.0, 4.0, 1.6 Hz,
1H), 0.04 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 201.3, 143.6,
128.5 (2C), 127.6, 125.6 (2C), 70.3, 53.8, −0.01 (3C). HRMS for
C12H18O2Si+Na calcd 245.0974; found 245.0977.
Preparation of (R)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-
isopropyl-2-thioxothiazolidin-3-yl)-3-phenylpropan-1-one
(8b): TBS-ether 8b was prepared from the alcohol 7 (0.106 g,
0.25 mmol) with diisopropylethylamine (0.08 mL, 0.5 mmol) in
presence of tertiarybutyldimethylsilyltriflate (0.08 mL, 0.35
mmol) using the procedure A described above in (0.106 g, 77%)
73%) as a yellow oil; [α]24 +280.9 (c 1.1, CHCl3); IR (neat)
D
2959, 2854, 1697, 1252, 1151 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.38-7.21 (m, 5H), 5.31 (dd, J = 8.8, 3.6 Hz, 1H), 5.02 (t, J =
6.8 Hz, 1H), 3.96 (dd, J = 16.4, 8.8 Hz, 1H), 3.47 (dd, J = 11.6,
8.0 Hz, 1H), 3.21 (dd, J = 16.4, 3.6 Hz, 1H), 3.02 (d, J = 11.6 Hz,
1H), 2.34 (sextet, J = 13.6, 6.8 Hz, 1H), 1.02 (d, J = 6.8 Hz, 3H),
0.94 (d, J = 7.2 Hz, 3H), 0.84 (t, J = 8.0 Hz, 9H), 0.56-0.44 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 202.8, 171.2, 144.1, 128.2
(2C), 127.5, 126.1 (2C), 71.8, 71.7, 48.5, 30.9, 30.8, 19.1, 17.8,
6.7 (3C), 4.7 (3C). HRMS for C21H33NO2SiS2+Na calcd
446.1620; found 446.1620.
as a yellow oil. [α]24 +318.3 (c 2.3, CHCl3); IR (neat) 2927,
D
1
2855, 2314, 1695, 1582 cm-1; H NMR (400 MHz, CDCl3) δ
7.38-7.20 (m, 5H), 5.29 (dd, J = 9.2, 3.6 Hz, 1H), 5.01 (t, J = 6.8
Hz, 1H), 3.99 (dd, J = 16.4, 9.2 Hz, 1H), 3.47 (dd, J = 11.2, 8.0
Hz, 1H), 3.16 (dd, J = 16.4, 3.6 Hz, 1H), 3.02 (d, J = 11.2 Hz,
1H), 2.35 (sext, J = 6.8 Hz, 1H), 1.03 (d, J = 6.4 Hz, 3H), 0.95
(d, J = 7.2 Hz, 3H), 0.83 (s, 9H), 0.03 (s, 3H), −0.18 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 202.8, 171.3, 144.0, 128.2 (2C),

4
Tetrahedron
127.5, 126.2 (2C), 72.1, 71.7, 48.4, 31.0, 30.8, 25.7 (3C), 19.1,
procedure C above in 0.09 g (crude) and the crude product was
used to next step without purification.
18.0, 17.8, −4.7, −5.1; HRMS for C21H33NO2SiS2+Na calcd
446.1620; found 446.1625.
(Z)-triethyl((1-phenylbuta-1,3-dien-1-yl)oxy)silane (9b): TES
enol ether 9b was synthesised from enone 5 (0.05 g, 0.34 mmol)
with diisopropylethylamine (0.15 mL, 0.86 mmol), in the
presence of TESOTf (0.1 mL, 0.38 mmol) following procedure C
above in 0.09 g (crude) and the crude product was used to next
step without purification.
Preparation
of
(R)-3-((tert-butyldimethylsilyl)oxy)-3-
phenylpropanal (4b): aldehyde 4b was prepared from silyl ether
8b (0.106 g, 0.25 mmol) in presence of DIBAL-H (0.53 mL,
0.53 mmol) using the procedure B described above 4b in (0.06 g,
91%) as a colourless oil. [α]24D +70.9 (c 1.0, CHCl ), [lit.7 [α]24
D
3
+70.0 (c 1.0, CHCl3)]; IR (neat) 3432, 2856, 2718, 1727, 1644
1
cm-1; H NMR (400 MHz, CDCl3) δ 9.79 (t, J = 2.4 Hz, 1H),
(Z)-triisopropyl((1-phenylbuta-1,3-dien-1-yl)oxy)silane (9c):
TIPS enol ether 9c was synthesised from enone 5 (0.05 g, 0.34
mmol) with diisopropylethylamine (0.15 mL, 0.86 mmol) in the
presence of TIPSOTf (0.1 mL, 0.38 mmol) following procedure
C above 0.11 g (crude) and the crude product was used to next
step without purification.
7.34-7.22 (m, 5H), 5.21 (dd, J = 8.0, 4.0 Hz, 1H), 2.85 (ddd, J =
15.6, 8.0, 2.4 Hz, 1H), 2.63 (ddd, J = 16.0, 4.0, 2.0 Hz, 1H), 0.87
(s, 9H), 0.04 (s, 3H) −0.14 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 201.3, 143.7, 128.4 (2C), 127.6, 125.7 (2C), 70.7, 54.0, 25.7
(3C), 18.1, −4.7, −5.2; HRMS for C15H24O2Si+Na calcd
287.1443; found 287.1443.
Preparation
of
(7R,E)-5-hydroxy-1,7-diphenyl-7-
Preparation of (R)-1-((S)-4-isopropyl-2-thioxothiazolidin-3-
((triethylsilyl)oxy)hept-2-en-1-one (10): To a stirred solution of
the aldehyde 4 (0.105 g, 0.4 mmol) and silyl enol ether 9 (0.104
g, 0.48 mmol) in CH2Cl2 (8 mL) at −78 °C, was added BF3·OEt2
(0.04 mL, 0,4 mmol) dropwise. After stirring at −78 °C for 10
min. the reaction was quenched by the addition of water (10 mL)
and extracted with CH2Cl2 (2 × 5 mL). The combined organic
layers were washed with brine (5 mL) and dried over anhydrous
Na2SO4. Silica gel column chromatography of the residue
obtained after evaporation of the solvent, using petroleum
ether:EtOAc (9:1) as eluent gave the diastereomeric silyl alcohol
10 (0.166 g, 71%) as a colourless oil and diol 3 (10 mg, 14%) as
yl)-3-phenyl-3-((triisopropylsilyl)oxy)propan-1-one
(8c):
TIPS-ether 8c was prepared from the alcohol 7 (0.11 g, 0.37
mmol) with diisopropylethylamine (0.08 mL, 0.5 mmol) in
presence of triisopropylsilyltriflate (0.11 mL, 0.41 mmol) using
the procedure A described above in (0.14 g, 81%) as a yellow oil.
[α]24D +216.3 (c 1.08, CHCl3); IR (neat) 2937, 2864, 1696, 1587,
1
1461 cm-1; H NMR (400 MHz, CDCl3) δ 7.39 (J = 7.2 Hz, 2H),
7.30 (t, J = 7.2 Hz, 2H), 7.27-7.19 (m, 1H), 5.40 (dd, J = 7.2, 5.2
Hz, 1H), 4.98 (t, J = 7.2 Hz, 1H), 4.03 (dd, J = 16.8, 7.6 Hz,
1H), 3.46 – 3.35 (m, 2H), 2.98 (d, J = 11.2 Hz, 1H), 2.23 (sext, J
= 6.8 Hz, 1H), 1.05 – 0.85 (m, 27H); 13C NMR (100 MHz,
CDCl3) δ 202.7, 171.3, 144.2, 128.1 (2C), 127.5, 126.5 (2C),
72.1, 71.7, 48.9, 30.7, 30.6, 19.0, 18.0 (3C), 17.9 (3C), 17.6, 12.4
(3C); HRMS for C24H39NO2SiS2+Na calcd 488.2089; found
488.2083.
a colourless oil. Alcohol 10: [α]24 +44.0 (c 0.55, CHCl3); IR
D
1
(neat) 3440, 2954, 2876, 1669, 1549 cm-1; H NMR (400 MHz,
CDCl3) δ 7.93-7.85 (m, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.44 (t, J =
7.6 Hz, 2H), 7.37-7.22 (m, 5H), 7.10-6.83 (m, 2H), 5.13 (dd, J =
5.2, 4.0 Hz, 0.75H), 4.91 (dd, J = 10.0, 4.0 Hz, 0.22H), 4.10-4.03
(m, 0.24H), 4.02-3.95 (m, 0.75H), 3.90 (s, 0.21H), 3.57 (s,
0.72H), 2.55-2.32 (m, 2H), 1.99-1.72 (m, 2H), 0.96-0.81 (m, 9H),
Preparation
of
(R)-3-phenyl-3-
((triisopropylsilyl)oxy)propanal (4c): Aldehyde 4c was
prepared from silyl ether 8c (0.14 g, 0.3 mmol) in presence of
DIBAL-H (0.6 mL, 0.6 mmol) using the procedure B described
0.65-0.42 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 190.6maj
190.4min, 145.7maj, 145.4min, 144.3min, 143.7maj, 137.7(maj+min)
,
,
above in (0.08 g, 88%) as a colourless oil. [α]24 +59.8 (c 2.35,
132.61min, 132.56maj, 128.5 (2C)(maj+min), 128.43 (2C)min, 128.41
D
CHCl3); IR (neat) 2957, 2893, 2721, 1722, 1500 cm-1; H NMR
1
(2C)maj, 128.3 (2C)min, 128.2 (2C)maj, 128.0min, 127.9maj, 127.7min
127.2maj, 125.9 (2C)min, 125.6 (2C)maj, 76.4min, 73.3maj, 70.4min
,
,
(400 MHz, CDCl3) δ 9.77 (t, J = 2.4 Hz, 1H), 7.40-7.21 (m 5 H),
5.31 (t, J = 6.0 Hz, 1H), 2.86 (ddd, J = 15.6, 6.0, 2.4 Hz, 1H),
2.76 (ddd, J = 15.6, 5.6, 2.4 Hz, 1H), 1.11 – 0.93 (m, 21H); 13C
NMR (100 MHz, CDCl3) δ 201.3, 143.9, 128.4 (2C), 127.6,
125.8 (2C), 71.0, 54.2, 17.9 (3C), 17.8 (3C), 12.2.(3C); HRMS
for C18H30O2Si+Na calcd 329.1913; found 329.1913.
67.0maj, 45.4(maj+min), 40.9(maj+min), 6.7 (3C)maj, 6.5 (3C)min, 4.7
(3C)min, 4.6 (3C)maj; HRMS for C25H34O3Si+Na calcd 433.2175;
found 433.2178.
Diol: (7R,E)-5,7-dihydroxy-1,7-diphenylhept-2-en-1-one (3):
[α]24 +10.5 (c 0.25, CHCl3); IR (neat) 3409, 2923, 1665, 1618
D
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 0.4H),
Procedure
C:
(Z)-trimethyl((1-phenylbuta-1,3-dien-1-
7.90 (d, J = 7.2 Hz, 1.6H), 7.55 (t, J = 7.2 Hz, 1H), 7.45 (t, J =
7.6 Hz, 1H), 7.38-7.20 (m, 5.3H), 7.09-6.90 (m, 1.7H), 5.12-5.03
(m, 0.74H), 4.94 (dd, J = 10.0, 2.8 Hz, 0.2H), 4.22-3.98 (m, 1H),
3.46 (dd, J = 16.0, 5.6 Hz, 0.2 H), 3.25-3.13 (m, 1.2H), 2.58-2.45
(m, 1.6H), 2.25-2.17 (m, 0.4H), 1.96-1.90 (m, 1.6H); 13C NMR
yl)oxy)silane (9): To a pre-cooled solution of (E)-1-phenylbut-2-
en-1-one 5 (0.1 g, 0.67 mmol) in CH2Cl2 (7 mL), were added
diisopropylethylamine (0.3 mL, 1.7 mmol) followed by
trimethylsilyltriflate (0.14 mL, 0.75 mmol) dropwise at −10 °C.
The reaction mixture was stirred at −10 °C for 0.5 h. After
completion of the reaction (TLC) it was quenched by addition of
water (10 mL) and the mixture was extracted with petroleum
ether (2 × 10 mL). The combined organic layer was washed with
brine (20 mL) dried over anhydrous Na2SO4 and the solvent was
evaporated under reduced pressure to give a crude product 9,
which was used to next step without any purification. Same
procedure was utilised to synthesize other silyl enol ethers with
the corresponding triflates.
(100 MHz, CDCl3) δ 190.7(maj+min), 145.4(maj+min), 144.2(maj+min)
137.6(maj+min), 132.9(maj+min), 128.59 (2C)maj+min, 128.57 (2C)min
,
,
128.54 (2C)(maj+min)
,
128.50 (2C)maj, 128.3(maj+min), 127.5maj
,
125.9min 125.6 (2C)min
,
,
125.5 (2C)maj
,
74.6min
,
71.5maj
,
67.7(maj+min), 44.5(maj+min), 40.8(maj+min); HRMS for C19H20O3+Na
calcd 319.1310; found 319.1315.
Preparation of 2-((2S,4S,6R)-4-hydroxy-6-phenyltetrahydro-
2H-pyran-2-yl)-1-phenylethan-1-one (5-epi-diospongin
A
(1a): A solution of the enone 10 (0.085 g, 0.21 mmol) in
methanol (4 mL) was cooled to 0 °C, and camphor sulphonic acid
(48 mg, 0.21 mmol) was added at the same temperature. The
reaction mixture was then slowly warmed to room temperature
(Z)-tert-butyldimethyl((1-phenylbuta-1,3-dien-1-yl)oxy)silane
(9a): TBS enol ether 9a was synthesised from enone 5 (0.05g,
0.34 mmol) with diisopropylethylamine (0.15 mL, 0.86 mmol),
in the presence of TBSOTf (0.1 mL, 0.38 mmol) following

5
and stirred for 1 h. After completion of the reaction (TLC), the
solvent was removed under reduced pressure, to give the crude
residue, which was diluted with saturated NaHCO3 solution and
extracted with EtOAc (2 × 20 mL) and the combined organic
extracts was washed with brine (10 mL), dried over anhydrous
Na2SO4. Evaporation of the solvent gave the crude residue which
on purification through silica gel column chromatography,
petroleum ether/EtOAc (7:3) as eluent gave the 5-epi-diospongin
epimer (yields and ratios of ent-1 and ent-1a are listed in table-
1).
Preparation of 5-epi-diospongin A and diospongin A from 4a:
Using a general procedure D aldehyde 4a (25 mg, 0.11 mmol),
silyl enol ether 9 (37 mg, 0.17 mmol), BF3ꢀOEt2 (0.012 mL, 0.1
mmol) and CSA (52 mg, 0.22 mmol) afforded 5-epidiospongin A
(ent-1a) (20 mg, 61%) and diospongin A (ent-1) (1 mg, 3%).
(ent-1a) (40 mg, 66%) as a colourless oil; [α]24 +14.7 (c 1.1,
D
CHCl3), [lit.2g enantiomer [α]24 −11.6 (c 0.54, CHCl3)]; IR
Preparation of 5-epi-diospongin A and diospongin A from 4b:
Using a general procedure D aldehyde 4b (30 mg, 0.1 mmol),
silyl enol ether 9 (37 mg, 0.17 mmol), BF3ꢀOEt2 (0.012 mL, 0.1
mmol) and CSA (52 mg, 0.22 mmol) afforded 5-epidiospongin A
(ent-1a) (16 mg, 48%) and diospongin A (ent-1) (2 mg, 6%).
D
1
(neat) 3415, 2922, 2856, 1679, 1588 cm-1; H NMR (400 MHz,
CDCl3) δ 7.98 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.46
(t, J = 8.0 Hz, 2H), 7.35-7.21 (m, 5H), 4.44 (d, J = 10.4 Hz, 1H),
4.25-4.15 (m, 1H), 4.05 (sept, J = 10.0 Hz 1H), 3.48 (dd, J =
16.4, 6.0 Hz, 1H), 3.10 (dd, J = 16.4, 6.4 Hz, 1H), 2.23 (dd, J =
12.8, 3.6 Hz, 2H), 1.64 (brs, 1H), 1.51 (q, J = 11.6 Hz, 1H), 1.37
(q, J = 11.6 Hz, 1H; 13C NMR (100 MHz, CDCl3) δ 198.0, 141.7,
137.2, 133.2, 128.6 (2C), 128.3 (2C), 128.3 (2C), 127.5, 125.7
(2C), 77.5, 72.5, 68.2, 44.8, 42.5, 40.9; HRMS for C19H20O3+Na
calcd 319.1310; found 319.1312.
Preparation of 5-epi-diospongin A and diospongin A from 4:
Using a general procedure D aldehyde 4 (30 mg, 0.1 mmol), silyl
enol ether 9 (37 mg, 0.17 mmol), BF3ꢀOEt2 (0.012 mL, 0.1 mmol)
and CSA (52 mg, 0.22 mmol) afforded 5-epidiospongin A (ent-
1a) (12 mg, 36%) and diospongin A (ent-1) (3 mg, 6%).
(+)-diospongin
A:
2-((2S,4R,6R)-4-hydroxy-6-
Preparation of 5-epi-diospongin A and diospongin A from 4c:
Using a general procedure D aldehyde 4c (38 mg, 0.12 mmol),
silyl enol ether 9 (34 mg, 0.15 mmol), BF3ꢀOEt2 (0.012 mL, 0.1
mmol) and CSA (58 mg, 0.22 mmol) afforded 5-epidiospongin A
(ent-1a) (10 mg, 27%) and diospongin A (ent-1) (5 mg, 14%).
phenyltetrahydro-2H-pyran-2-yl)-1-phenylethan-1-one (ent-
1): (11 mg, 18%) as a white solid. M.P: 97-101 °C, [lit.2m M.P:
98-100 °C]; [α]24 +20.8 (c 1.6, CHCl3), [lit.2m [α]24 +19.2 (c
D
D
1.0, CHCl3)]; IR (neat) 3411, 2917, 2884, 1678, 1593,1054 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 2H), 7.56 (t, J
= 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.32-7.20 (m, 5H), 4.93
(d, J = 10.8 Hz, 1H), 4.70-4.60 (m, 1H), 4.39-4.33 (m, 1H), 3.42
(dd, J = 16.0, 5.6 Hz, 1H), 3.07 (dd, J = 16.0, 7.2 Hz, 1H), 1.96
(d, J = 13.2 Hz, 2H), 1.80-1.63 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 198.3, 142.7, 137.3, 133.1, 128.5 (2C), 128.3 (2C),
128.2 (2C), 127.2, 125.8 (2C), 73.8, 69.0, 64.7, 45.1, 40.0, 38.5;
HRMS for C19H20O3+Na calcd 319.1310; found 319.1310.
Preparation of 5-epi-diospongin A and diospongin A from 4b:
Using a general procedure D aldehyde 4b (30 mg, 0.11 mmol),
silyl enol ether 9a (44 mg, 0.17 mmol), BF3ꢀOEt2 (0.012 mL, 0.1
mmol) and CSA (53 mg, 0.22 mmol) afforded 5-epidiospongin A
(ent-1a) (12 mg, 36%) and diospongin A (ent-1) (2 mg, 6%).
Preparation of 5-epi-diospongin A and diospongin A from 4:
Using a general procedure D aldehyde 4 (20 mg, 0.08 mmol),
silyl enol ether 9b (35 mg, 0.11 mmol), BF3ꢀOEt2 (0.008 mL,
0.08 mmol) and CSA (35 mg, 0.15 mmol) afforded 5-
epidiospongin A (ent-1a) (10 mg, 40%) and diospongin A (ent-1)
(2 mg, 8%).
Preparation of 2-((2S,4S,6R)-4-hydroxy-6-phenyltetrahydro-
2H-pyran-2-yl)-1-phenylethan-1-one (ent-1a) and diospongin
A (ent-1) from 3: To a pre-cooled (0 °C) solution of the diol 3
(0.016 g, 0.05 mmol) in dichloromethane (2 mL), TFA (0.04 mL,
0.54 mmol) was added at the same temperature. After stirring at 0
°C for 10 min. the reaction mixture was quenched by the addition
of saturated NaHCO3 solution (10 mL) and extracted with
CH2Cl2 (2 × 5 mL). The combined organic layer was washed
with brine (5 mL) and dried over anhydrous Na2SO4. Silica gel
column chromatography of the residue obtained after evaporation
of the solvent, using petroleum ether:EtOAc (7:3) as eluent
furnished 4-epi-diospongin (ent-1a) (11 mg, 69%) as a colourless
oil and diospongin A (ent-1) (3 mg, 19%) as a white solid. Both
physical and spectral properties of (ent-1a) and (ent-1) were
identical with that obtained from 10 with the previous step
synthesis.
Preparation of 5-epi-diospongin A and diospongin A from 4c:
Using a general procedure D aldehyde 4c (40 mg, 0.13 mmol),
silyl enol ether 9c (59 mg, 0.19 mmol), BF3ꢀOEt2 (0.01 mL, 0.13
mmol) and CSA (61 mg, 0.26 mmol) afforded 5-epidiospongin A
(ent-1a) (10 mg, 26%) and diospongin A (ent-1) (5 mg, 13%).
Preparation of 2-((2S,4R,6R)-4-hydroxy-6-phenyltetrahydro-
2H-pyran-2-yl)-1-phenylethan-1-one (diospongin A, ent-1):
To a pre cooled (0 °C) solution of triphenylphosphine (138 mg,
0.53 mmol), DIAD (0.1 mL, 0.53 mmol) in toluene (4 mL) was
added a solution of ent-1a (52 mg, 0.18 mmol) in toluene (2 mL)
was added and stirred for 10 min at the same temperature. p-
Nitrobenzoic acid (88 mg, 0.53 mmol) was added at once to the
reaction mixture and it was stirred at room temperature for 1 h.
After completion of the reaction (monitored by TLC) most of the
solvent was evaporated under vacuum and the residue thus
obtained was purified by silica gel column chromatography using
petroleum ether: EtOAc (9:1) as eluent furnish the corresponding
p-Nitro benzoate (80 mg) as colourless oil, which was proceeded
to next step without further purification.
To a stirred solution of the p-Nitrobenzoate (obtained above) in
ethanol was added K2CO3 (74 mg, 0.53 mmol) and was stirred
for 2 h at room temperature. After completion of the reaction
(monitored by TLC) the solvent was evaporated off, under
vacuum and the residue thus obtained was diluted with water (10
mL) and extracted with EtOAc (2 x 10 mL). The combined
General procedure for Mukaiyama aldol reaction and
subsequent oxa Michael addition (procedure D): To a pre-
cooled solution of aldehyde (4a-4c) (1 eq) and silyl enol ether
(9a-9c) (1.3 eq-1.5 eq) in CH2Cl2 (8 mL) at −78 °C, was added
BF3·OEt2 (1 eq) dropwise. After stirring at −78 °C for 10 min.
was added camphor sulphonicacid (2 eq in 1 mL of MeOH) in
dropwise and then slowly warmed to at room temperature, stir for
1 h to 12 h. After completion of the reaction (indicated by TLC),
the mixture was quenched with saturated NaHCO3 solution (10
mL) and extracted with CH2Cl2 (2 × 5 mL). The combined
organic layers were washed with brine (5 mL) and dried over
anhydrous Na2SO4. Silica gel column chromatography of the
residue obtained after evaporation of the solvent, using petroleum
ether:EtOAc (7:3) as eluent gave (+)-diospongin A and its 5-

6
Tetrahedron
R.; Reddy, G. B.; Srikanth, B. Tetrahedron: Asymmetry 2011, 22,
1725. (p) Karlubikova, O.; Babjak, M.; Gracza, T. Tetrahedron
2011, 67, 4980. (q) Ho, T.; Tang, B.; Ma, G.; Xu, P. J. Chin.
Chem. Soc. 2012, 59, 455. (r) Yao, H.; Ren, J.; Tong, R. Chem.
Comm. 2013, 49, 193. (s) Stefan, E.; Nalin, A. P.; Taylor, R. E.
Tetrahedron, 2013, 69, 7706. (t) Meruva, S. B.; Mekala, R.;
Raghunadh, A.; Raghavendra Rao, K. R.; Dahanukar, V. H.;
Pratap, T. V.; Kumar, U. K. S.; Dubey, P. K. Tetrahedron Lett.
2014, 55, 4739. (u) Zuniga, A.; Perez, M.; Gandara, Z.; Fall, A.;
Gomez, G.; Fall, Y. Arkivoc, 2015, 7, 195. (v) Merad, J.; Borker,
P.; Yenda, T. B.; Roux, C.; Pons, J.; Parrain, J.; Chuzel, O.;
Bressy, C. Org. Lett, 2015, 17, 2118. (w) Ermanis, K.; Hsiao, Y.;
Kaya, U.; Jeuken, A.; Clarke, P. L. Chem. Sci., 2017, 8, 482. (x)
Bharath, Y.; Choudhury, U. M.; Sadhana, N.; Mohapatra, D. K.
Org. Biomol. Chem. 2019, 17, 9169.
organic layer was washed with brine (10 mL) and dried over
anhydrous Na2SO4. Evaporation of solvent gave the crude residue
which was purified by silica gel column chromatography using
petroleum ether: EtOAc (6:4) as eluent furnished (ent-1) (35 mg,
67%) as a white solid.
Acknowledgments
K.V. thanks the University Grants commission (UGC), New
Delhi for a research fellowship..
Supplementary Material
3. Hodge, M. B.; Olivo, H. F. Tetrahedron 2004, 60, 9397. We have
isolated the acetate aldol products major diastereomer 7 and minor
diastereomer 7a in 77% and 6% yield, respectively. Hodge and
Olivo isolated the major product 7 in 69% yield. However, no
mention about the isolation of the minor isomer was recorded.
4. Acid catalysed oxa-Michael addition of the α,β-unsaturated
ketones for the synthesis of tetrahydropyran unit see : (a) Ơ Brien,
M.; Taylor, N. H.; Thomas, E. J. Tetrahedron Lett. 2002, 43,
5491. (b) Reddy, C. R.; Rao, N. N. Tetrahedron Lett. 2010, 51,
5840. (c) Liu, J.; Yang, J. H.; Ko, C.; Hsung, R. P. Tetrahedron
Lett. 2006, 47, 6121.
5. (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am.
Chem. Soc. 1996, 118, 4322. (b) A review on Mukaiyama Aldol
Reaction in Total Synthesis: Kan, S. B. J.; Ng, K. K. H.; Paterson,
I. Angew. Chem., Int. Ed. 2013, 52, 9097.
6. (a) Fuwa, H.; Noto, K.; Sasaki, M. Org Lett. 2011, 13, 1820. (b)
Fuwa, H.; Ichinokawa, N.; Noto, K.; Sasaki, M. J. Org. Chem.
2012, 77, 2588. For recent detailed study on the formation of 2,6-
disubstituted THP ring by oxa-Michael reaction see: Csokas, D.;
Ho, A. X. Y.; Ramabhadran, R. O.; Bates, R. W. Org. Biomol.
Chem. 2019, 17, 6293.
1H NMR and 13C NMR spectra for all the new compounds
synthesized are provided.
References and notes
1. Jun, Y.; Kyoji, K.; Yasuhiro, T.; Quan, L. T.; Tatsuro, M.;
Yingjie, C.; Shigetoshi, K. Planta Medica, 2004 , 70, 54.
2. Total synthesis of diospongin A see: (a) Chandrasekhar, S.;
Shyamsunder, T.; Prakash, S. J.; Prabhakar, A.; Jagadeesh, B.
Tetrahedron: Lett 2006, 47, 47. (b) Bressy, C.; Allais, F.; Cossy,
J. Synlett 2006, 20, 3455. (c) Sawant, K. B.; Jennings, M. P. J.
Org. Chem. 2006, 71, 7911. (d) Yadav, J. S.; Padmavani, B.;
Reddy, B. V. S.; Venugopal, C.; Rao, A. B. Synlett, 2007, 2045.
(e) Bates, W. R.; Song, P.; Tetrahedron 2007, 63, 4497. (f) Hiebel,
M.; Pelotier, B.; Piva, O. Tetrahedron 2007, 63, 7874. (g) Kawai,
N.; Hande, S. M.; Uenishi, J. Tetrahedron 2007, 63, 9049. (h)
Wang, H.; Shuhler, B. J.; Xian, M. Synlett 2008, 2651. (i) Sabitha,
G.; Padmaja, P.; Yadav, J. S. Helv. Chim. Acta, 2008, 91, 2235. (j)
Kumaraswamy, G.; Ramakrishna, G.; Naresh, P.; Jagadeesh, B.;
Sridhar, B. J. Org. Chem. 2009, 74, 8468. (k) Lee, K.; Kim, H.;
Hong, J. Org. Lett, 2009, 11, 5202. (l) More, D. J. Synthesis 2010,
14, 2419. (m) Anada, M.; Washio, T.; Watanabe, Y.; Takada, K.;
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Synlett 2012, 23, 2129.

Highlights
•
•
Short one-pot reaction conditions for the synthesis of diospongin A
Involves the vinylogous Mukaiyama Aldol reaction, Silyl deprotection and Oxa-Michael
reaction in one-pot.
•
25% overall yield from benzaldehyde

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: