A convergent approach for the total synthesis of (-)-synrotolide diacetate

Article abstract of DOI:10.1016/j.tetlet.2007.07.172

A simple carbohydrate based convergent approach towards the total synthesis of (-)-synrotolide diacetate is described employing a Sharpless asymmetric epoxidation, a Grignard assisted lactol opening with a terminal alkyne and a Wittig reaction using the H

Full text of DOI:10.1016/j.tetlet.2007.07.172

Tetrahedron Letters 48 (2007) 6977–6981
A convergent approach for the total synthesis
of (ꢀ)-synrotolide diacetate
P. Srihari,* B. Prem Kumar, K. Subbarayudu and J. S. Yadav
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 15 May 2007; revised 17 July 2007; accepted 25 July 2007
Available online 31 July 2007
Abstract—A simple carbohydrate based convergent approach towards the total synthesis of (ꢀ)-synrotolide diacetate is described
employing a Sharpless asymmetric epoxidation, a Grignard assisted lactol opening with a terminal alkyne and a Wittig reaction
using the Horner–Emmons reagent as the key steps.
Ó 2007 Elsevier Ltd. All rights reserved.
Several natural products possessing a,b-unsaturated lac-
tone rings display major pharmacologically relevant
properties.1 Recently, lactones such as anamarine 1,2
hyptolide 2,3 spicigerolide 3,4 synargentolide 45 and
synrotolide 56 were isolated from species of Hyptis,
Syncolostemon and related genera of the family Lamia-
ceae (Fig. 1). These compounds contain a polyoxygen-
ated chain connected to an unsaturated d-lactone ring
and were found to display excellent cytotoxicity against
human tumor cells, as well as antifungal and antimicro-
bial activity.7 These excellent bioactivities have encour-
aged us to take up the synthesis of synrotolide and its
diacetate derivative. So far, and to the best of our
knowledge, there is only one report on the synthesis of
a derivative of this natural product.8
In continuation of our research on the synthesis of lac-
tone-containing natural products,9 we herein disclose
our strategy towards the synthesis of synrotolide and
its diacetate derivative following a convergent approach
utilizing Sharpless asymmetric epoxidation, a Grignard
assisted lactol opening with a terminal alkyne and a ster-
eoselective Wittig reaction using the Horner–Emmons
reagent, as key steps. Retrosynthetic analysis of synroto-
lide 5 revealed an intermediate 6, which can be synthe-
sized via a convergent approach utilizing two key
OAc OAc
OAc OAc
OAc OAc
O
O
O
O
O
O
OAc OAc
OAc OAc
Spicigerolide 3
OAc
Anamarine 1
Hyptolide 2
OAc
OH OAc
O
O
O
O
OAc OAc
OAc OH
Synrotolide 5
Synargentolide 4
Figure 1.
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40 27160512; e-mail: srihari@iict.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.172

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P. Srihari et al. / Tetrahedron Letters 48 (2007) 6977–6981
fragments 7 and 8. These two fragments in turn could be
obtained from readily available D-(ꢀ)-ribose and 3-
butyn-1-ol (Scheme 1).
The key fragment 7 was synthesized from readily avail-
able D-(ꢀ)-ribose, by isopropylination with acetone,
2,2-dimethoxypropane and concd H2SO4 to give 10.10
synrotolide 5
OH
OH
O
H3C
OTBDMS
OH
H3C
+
OPMB
OPMB
8
O
O
O
O
OTBDMS
CH3
CH3
H3C
H3C
7
6
O
CH2OH
PMBO
HO
O
OH
9
HO
HO
OH
D-(-)-ribose
3-butyn-1-ol
Scheme 1.
CH3
OH
O
O
OH
OH
O
HO
H3C
H3C
HO
CH3MgBr, Et2O
0 oC to r.t, 3 h
2,2-DMP, acetone
conc.H2SO4, 0 oC
30 min, 80%
OH
O
75%
O
O
HO
OH
10
11
OH
D-(-)-ribose
H3C
CH3
O
H3C
OH
7
NaIO4, THF:H2O (9:1)
0 oC to r.t
2 h, 80%
O
O
CH3
H3C
Scheme 2.
EtMgBr, (CH2O)n
NaH, PMB-Br
THF, 0 oC, 3 h
HO
OPMB
OH
OPMB
THF, r.t, 2 h
93%
10
11
O
90%
D-(-)-DET, Ti(OiPr)4
LAH, THF
CH2OH
CH2OH
O oC to reflux
2 h, 80%
PMBO
12
DCM, TBHP, -20 oC
6 h, 80%
PMBO
PMBO
9
OH
O
8 eq. Li in liq. NH3
TPP, CCl4
CH2Cl
PMBO
reflux, 2 h, 95%
THF, -30 oC, 3 h, 70%
13
14
OTBDMS
TBDMSCl, imidazole
DCM, r.t, 2 h, 90%
PMBO
8
Scheme 3.

P. Srihari et al. / Tetrahedron Letters 48 (2007) 6977–6981
6979
Compound 10 on Grignard reaction with excess methyl-
magnesium iodide gave triol 11 exclusively,11 which on
oxidative cleavage with NaIO4 yielded lactol 7 (Scheme
2) in 80% yield.
imidazole to afford tert-butyldimethylsilyl ether 8
(Scheme 3).
With the two intermediates 7 and 8 in hand, we pro-
ceeded to couple the in situ metalated acetylene (ob-
tained by treating 8 with ethyl magnesium bromide)
with lactol 7 to afford the functionalized intermediate
6.14 Diol 6 was protected as diacetate 15 with acetic
anhydride and then the triple bond was partially
reduced to the cis olefin 16 using Lindlar’s catalyst.15
PMB deprotection was achieved using DDQ to give
compound 17. However, we observed 10–15% isomeri-
zation of 17 to 17a (trans isomer) during this reaction,
and the isomers were easily separable by column chro-
matography. Alcohol 17, on oxidation with Dess Martin
periodinane in DCM, afforded aldehyde 18 which was
subjected to a Wittig reaction with ethyl(diphenylphos-
phono)acetate16 to yield the Z-unsaturated ester 19,
exclusively. At this stage, the stereochemistry of com-
pound 19, particularly at C8–C9, was determined by
The other key intermediate 8 was synthesized starting
from 3-butyn-1-ol. Accordingly, the alcohol was pro-
tected as the para-methoxybenzyl ether 10 with NaH
and para-methoxybenzyl bromide. Next, the free acety-
lene was treated with EtMgBr to generate the carbanion
and was quenched with paraformaldehyde to afford
propargyl alcohol 11. Alcohol 11 was reduced with
LiAlH4 in THF to give allyl alcohol 12, Sharpless epox-
idation12 of which with D-(ꢀ)-DET and TBHP afforded
the epoxy alcohol 9. The primary alcohol was converted
to chloride 13 with triphenylphosphine and CCl4 under
reflux and then treated with excess lithium in liq. ammo-
nia to give acetylenic alcohol 14 as reported earlier by
our group for the preparation of chiral propargyl alco-
hols.13 The alcohol was protected with TBDMSCl and
O
H3C
OH
OH
OH
O
O
O
OTBDMS
7
CH3
H3C
H3C
EtMgBr
OAc
OPMB
OPMB
+
THF, r.t, 3 h, 50%
O
OTBDMS
6
CH3
OAc
H C
3
OTBDMS
OPMB
OAc
OAc
H3C
H3C
OPMB
Ac2O, pyridine
0 oC to r.t,
2 h, 80%
Pd/BaSO4
O
O
O
O
quinoline,
15 min, 90%
OTBDMS
OTBDMS
CH3
16
CH3
H3C
15
OAc
H3C
OAc
DDQ
DCM: H2O (8:1)
2 h, 82%
H3C
17a (trans isomer)
OH
+
O
O
CH3
H3C
(85:15)
17
OTBDMS
OAc
OTBDMS
CHO
OAc
OAc
OAc
ethyl(diphenylphosphono)-
acetate
DMP, DCM
H3C
17
H3C
CO2Et
NaH, -78 oC-r.t,
2 h, 60%
r.t, 30 min, 90%
O
O
O
O
CH3
18
19
CH3
H3C
H3C
OAc
OAc
OAc
OAc
OH
OH
CO2Et
OH
O
O
+
PTSA
MeOH, r.t
H3C
H3C
O
O
+
H C
3
O
O
O
O
HO
OH
CH3
CH3
H3C
22
25%
H3C
20
21
25%
10%
19 (10%)
+
Scheme 4.

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P. Srihari et al. / Tetrahedron Letters 48 (2007) 6977–6981
OTBDMS
OAc
OAc
OAc
OAc
PPTS
CO2Et
OH
TBAF, THF
3 h, 90%
H3C
CO2Et
H3C
benzene,
6 h, 60%
O
O
O
O
CH3
H3C
19
CH3
20
H3C
OAc
OAc
pTSA or
OH
OH
PPTS or
CSA or
amberlyst or
acetic acid or
10%HCl
O
O
H3C
H3C
21
+
O
O
O
O
CH3
OH OH
H3C
21
22
(40% yield)
Scheme 5.
OAc OAc
OH
OH
Ac2O, pyridine
DCM, 0 oC to r.t
6 h, 75%
O
O
O
O
OAc OAc
OH
OH
23
22
Scheme 6.
studying NOSEY and COSY spectra. Also the coupling
constant values confirmed the geometry of the product.
We envisioned that PTSA could be used to obtain (ꢀ)-
synrotolide from 19 in a one-pot reaction via a three-
step sequence (TBDMS deprotection, lactonization
and acetonide deprotection) (Scheme 4). However, this
reaction was time sensitive and always resulted in either
the TBDMS deprotected alcohol 20 or lactone 21 with
the acetonide moiety intact or lactone tetrol 22 but with
no yield of the expected synrotolide 5.
Acknowledgements
B.P.K. thanks CSIR, New Delhi for financial assistance.
Subbarayudu thanks UGC, New Delhi for financial
assistance.
References and notes
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A prolonged reaction time increased the yield of 22 with
a simultaneous decrease in the yields of 20 and 21 but
without any success in the formation of 5. Other acids
such as PPTS, CSA, amberlyst and acetic acid also gave
mixtures of 20, 21 and 22. Alternatively, compound 19,
on treatment with TBAF afforded 20 in 90% yield,
which was subjected to cyclization with PPTS in benzene
to afford lactone 21. Attempts to deprotect the acetonide
group with PTSA, PPTS, CSA, amberlyst, acetic acid,
10% HCl, CuCl2Æ2H2O and FeCl3 resulted in either
recovery of starting material, formation of tetrol 22 or
decomposition of the starting material after prolonged
reaction times (Scheme 5).
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Yadav, J. S. Synthesis 2006, 4041–4045; (b) Yadav, J. S.;
Vishweshwar Rao, K.; Sridhar Reddy, M.; Prasad, A. R.
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After several unsuccessful attempts to obtain the natural
product (ꢀ)-synrotolide from 21, we decided to synthe-
size the diacetate derivative 23, of synrotolide. Thus, te-
trol 22 was protected as its tetraacetate 23 using acetic
anhydride in pyridine. The spectral properties were found
to be similar to those reported earlier (Scheme 6).8,17,18
In conclusion, a carbohydrate based convergent method
for the synthesis of (ꢀ)-synrotolide diacetate has been
described. The application of this strategy for the total
synthesis of the natural product, (ꢀ)-synrotolide is
under investigation.

P. Srihari et al. / Tetrahedron Letters 48 (2007) 6977–6981
6981
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2H), 5.22–5.35 (m, 1H), 4.94 (p, 1H, J = 6.2 Hz), 4.66–
4.79 (m, 1H), 4.04–4.23 (m, 4H), 2.73–3.03 (m, 2H), 2.04
(s, 3H), 2.00 (s, 3H), 1.34 (s, 3H), 1.28 (s, 3H), 1.23 (t, 3H,
J = 7.4 Hz), 1.26 (d, 3H, J = 6.2 Hz), 0.85 (s, 9H), 0.08 (s,
3H), 0.01 (s, 3H). 13C NMR (75 MHz, CDCl3): d 170.34,
169.67, 166.33, 146.38, 139.57, 123.82, 121.21, 108.88,
78.43, 77.69, 69.08, 68.17, 67.60, 59.86, 38.12, 27.06, 25.94,
25.32, 21.55, 21.07, 18.19, 16.94, 14.45, ꢀ4.38, ꢀ4.99.
20
LCMS: m/z 542 (M+). ½aꢁD +14.0 (c 0.04 CHCl3). HRMS
for C27H46O9NaSi: Calcd 565.2815; found, 565.2808.
Compound 22: white solid; mp 175–177 °C. 1H NMR
(200 MHz, DMSO-d6): d 7.01–7.16 (m, 1H), 5.99 (d, 1H,
J = 10.6 Hz), 5.58–5.78 (m, 2H), 5.23–5.43 (m, 1H), 5.01
(d, 1H, J = 4.8 Hz), 4.87 (d, 1H, J = 4.8 Hz), 4.42–4.58
(m, 3H), 3.75–3.92 (m, 1H), 3.09–3.22 (m, 1H), 2.34–2.58
(m, 3H), 1.04 (d, 3H, J = 6.4 Hz). 13C NMR (75 MHz,
DMSO-d6): d 163.57, 147.16, 133.70, 127.75, 120.13, 74.78,
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alcohol would be exclusively anti and proceeded further
with the synthesis. The stereochemistry of the newly
generated center was studied later by NMR techniques.
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20
74.72, 73.93, 67.78, 67.24, 29.16, 17.10. ½aꢁD ꢀ26.0 (c 0.5
MeOH). LCMS: m/z 257 (M+H). HRMS for C12H17O6:
Calcd 257.1033; found, 257.1025. Compound 23: colorless
1
solid, mp 98–100 °C. H NMR (300 MHz, CDCl3): d 6.89
(ddd, 1H, J = 9.7, 5.3, 3.0 Hz), 6.03–6.10 (m, 1H), 5.77–
5.89 (m, 2H), 5.41–5.46 (m, 1H), 5.30 (dd, 1H, J = 7.9,
3.5 Hz), 5.21 (ddd, 1H, J = 7.7, 3.4, 1.3 Hz), 4.89–5.06 (m,
2H), 2.34–2.55 (m, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 2.06 (s,
3H), 2.01 (s, 3H), 1.22 (d, 3H, J = 6.6 Hz). 13C NMR
(50 MHz, CDCl3): d 170.00, 169.93, 169.90, 169.88,
163.66, 144.67, 132.85, 126.34, 121.79, 72.26, 72.14,
71.11, 71.06, 71.02, 68.87, 29.58, 21.28, 21.15, 21.07,
20
18. Spectroscopic data of 19: Colorless liquid; IR (neat) 3426,
2986, 2932, 2857, 1742, 1645, 1465, 1372, 1174, 1058, 941,
14.35. ½aꢁD ꢀ10.7 (c 0.05 CHCl3). LCMS: m/z 426 (M+).
HRMS for C20H26O10Na: Calcd 449.1421; found,
449.1423.
1
836, 778 cmꢀ1. H NMR (200 MHz, CDCl3): d 6.28–6.43
(m, 1H), 5.81 (dt, 1H, J = 1.5, 11.7 Hz), 5.49–5.71 (m,