A convenient approach to total synthesis of synargentolide-B from l-ascorbic acid and d-ribose

Article abstract of DOI:10.1016/j.tetlet.2014.03.133

A convenient and practical approach for the total synthesis of naturally occurring lactone synargentolide-B has been accomplished in 14 steps from the commercially available l-ascorbic acid and d-ribose involving Bestmann-Ohira reaction, zinc mediated all

Full text of DOI:10.1016/j.tetlet.2014.03.133

Tetrahedron Letters 55 (2014) 3087–3089
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A convenient approach to total synthesis of synargentolide-B from
L-ascorbic acid and D-ribose
⇑
Saidulu Konda, K. Bhaskar, Lingaiah Nagarapu, Dattatray M. Akkewar
Organic Chemistry Division-II (CPC), Indian Institute of Chemical Technology (CSIR), Tarnaka, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and practical approach for the total synthesis of naturally occurring lactone synargentolide-
Received 19 February 2014
Revised 27 March 2014
Accepted 29 March 2014
Available online 5 April 2014
B has been accomplished in 14 steps from the commercially available L-ascorbic acid and D-ribose involv-
ing Bestmann–Ohira reaction, zinc mediated allylation, ring closing-metathesis, and cross-metathesis
reactions. The highlight of our strategy describes a one-pot reaction involving stereoselective addition
of allylzinc reagent and selective reduction of terminal alkyne to obtain the key advanced intermediates.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Bestmann–Ohira reaction
Zinc allylation
Ring closing-metathesis
Cross-metathesis
The
a
,b-unsaturated d-lactone moiety is a ubiquitous motif
addition of an allylzinc reagent as well as controlled reduction of
a terminal alkyne for an advanced intermediate, starting from
abundantly available L-ascorbic acid and D-ribose in 14 steps.
As shown retrosynthetically in Scheme 1, synthesis of synargen-
tolide-B could be accomplished with two different olefins, 15 and
exocyclic olefin 9. The exocyclic olefin would be started from the
present in a large number of natural products displaying a wide
range of potent biological activities. It has been shown that the
unsaturated moiety plays an essential role in the biological activ-
ity, due to its potential to act as a Michael acceptor in the presence
of protein functional groups.1 The synthetic and natural products
possessing
a
,b-unsaturated d-lactone moiety gained attention of
TBS-protected D-ribose (5), that would be subjected to Best-
researchers due to their cytotoxic and anti-tumor properties.2 In
addition they inhibit HIV protease,3 induce apoptosis4 and have
proven to be anti-leukemic5 along with having many other immu-
nosuppressive properties.6
mann–Ohira reaction to furnish the triple bond compound 6,
which would be followed by zinc allylation to give 7, which would
be further reacted with acryloyl chloride and RCM cyclization for
the key intermediate 9. The other key intermediate olefin 15 was
The
a
,b-unsaturated d-lactone of synargentolide-B (1), was iso-
obtained from L-ascorbic acid by a standard carbohydrate chemis-
lated in 1998 by Rivett’s group from Syncolostemon argenteus, a
South African genus.7 In 2013 Prasad et al.8a attained its total syn-
thesis making use of WittigꢀHorner and RCM reactions as the key
steps and also established its absolute stereochemistry. Sabitha et
try procedure to obtain epoxide (10), which was regioselectively
opened with LiAlH4 to furnish an alcohol compound (11). The alco-
hol was benzoylated and acetonide was deprotected and the ob-
tained diol compound was converted to the olefinic diol followed
by acylation to give 15.
al.8b, also reported its total synthesis from
D-mannitol and D-ribose
using a tandem ring-closing/cross-metathesis (RCM/CM) and the
second-generation Hoveyda–Grubbs catalyst.
Based on the above mentioned plan, synthesis of synargento-
lide-B (1) was initiated from commercially available
(Scheme 3) and -ribose (Scheme 2). The primary hydroxyl group
of 2,3-O-isopropylidine- -ribose was protected as silyl ether by
L-ascorbic acid
As continuation of our research program directed toward the
total synthesis of bioactive molecules from cheap and readily avail-
able starting materials,9 we have developed an efficient strategy
utilizing Bestmann–Ohira, zinc allylation, ring-closing metathesis
(RCM), and cross-metathesis (CM) reactions, for the convergent
stereoselective synthesis of synargentolide-B (1). Our approach to
the synthesis of synargentolide-B is based on stereoselective
D
D
tert-butyldimethylsilyl chloride (TBDMSCl) and imidazole to give
the known hemiacetal 510 in 90% yield. A solution of hemiacetal
5 in dry methanol was subjected to undergo Bestmann–Ohira
reaction11 with gradual addition of dimethyl (1-diazo-2-oxopro-
pyl)phosphonate and K2CO3 at 55 °C, 8 h leading to acetylenic
moiety in a 65% yield. The free hydroxyl moiety of 6 was subse-
quently subjected to oxidation with sodiumperiodate to give corre-
sponding aldehyde, followed by allylation using activated zinc
⇑
Corresponding author. Tel.: +91 40 27191440/09; fax: +91 40 27193382.
E-mail address: dattatray.akkewar@gmail.com (D.M. Akkewar).
http://dx.doi.org/10.1016/j.tetlet.2014.03.133
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3088
S. Konda et al. / Tetrahedron Letters 55 (2014) 3087–3089
O
O
O
O
OAc
a
c
b
d
f
O
O
O
O
O
L-Ascorbic acid
+
OH
O
OAc
OAc
Synargentolide B
OH
O
OAc
9
cross-metathesis
RCM
10
15
11
OH
O
OH
O
HO
O
O
OH
O
OBz
OBz
O
12
13
15
O
7
10
OAc
OH
Zinc allylation
e
OAc
O
OH
OH
OH
14
L-Ascorbic acid
O
6
Scheme 3. Reagents and conditions: (a) Refs. 13,14; (b) LiAlH4, THF, reflux, 3 h, 85%;
(c) benzoyl chloride, Et3N, DMAP, DCM, rt, 3 h, 95%; (d) PTSA, MeOH, rt 2 h, 86%; (e)
(i) NalO4, MeOH/H2O, rt, 2 h, (ii) vinyl magnesium bromide, THF, ꢀ20 °C to rt, 5 h,
58% (over all two steps); (f) Ac2O, pyridine, DCM, rt, 4 h, 92%.
Bestmann-Ohira
reaction
D-Ribose
Scheme 1. Retrosynthetic analysis of synargentolide B.
O
O
PCy3
O
O
O
OH
OH
N
N
OH
Mes
Mes
Ph
TBSO
HO
Cl
Cl
b
OH
a
OAc
OH O
Cl
Cl
Ru
Ru
O
O
c
O
O
Ph
PCy3
PCy3
OAc
OH
6
5
4
1
2
3
O
OH
O
OH
O
Figure 1. Synargentolide B, Grubb’s I and II generation compounds.
O
O
O
O
7
O
OAc
OH O
OAc
O
O
a
b
9+15
O
O
O
O
O
e
d
OAc
OH
OAc
O
16
1
O
8
9
Scheme 4. Reagents and conditions: (a) Grubb’s second generation, DCM, reflux,
6 h, 67%; (b) PTSA, MeOH, reflux, 12 h, 78%.
Scheme 2. Reagents and conditions: (a) TBDMSCI, DMF, rt, 1 h, 90%; (b) Bestmaan–
Ohira reaction, reflux, 8 h, 65%; (c) Zn, allyl bromide, THF-DMF, 0 °C to rt, 4 h, 85%;
(d) acryl chloride, Et3N, DMAP, rt, 0.5 h, 91%; (e) Grubb’s first generation (5 mol %)
DCM, reflux, 3 h, 89%.
coupling of both the fragments, diacetate olefin 15 and exocyclic
olefin 9 via an olefin cross-metathesis reaction by using Grubb’s
second generation17 G-II catalyst 3 (Fig. 1) to give acetonide pro-
tected synargentolide-B (16), which was subsequently treated with
PTSA in MeOH at 65 °C to afford synargentolide-B (1). The spectro-
scopic data18 were in agreement with the recently synthesized
structure of synargentolide-B.8a,8b This method is regarded as the
best procedure from the view point of the number of steps (14)
and the overall yield (21%).
metal to facilitate the reduction of triple bond to double bond12 for
the formation of 7 in a single step, with a good yield and better ste-
reoselectivity with diastereomeric ratio 80:20. Acryloylation of 7
with acryloyl chloride furnished the acrylate 8 in 91% yield, which
was then subjected to ring-closing metathesis in the presence of
the first generation Grubbs’ catalyst (2. in Fig. 1) in DCM at reflux
conditions to produce 6-membered lactone8b as a single product 9
in 89% yield.
3,4-O-Isopropylidene-
acid according to Abushanab’s method.13 The epoxide 10 can be
obtained from 3,4-O-isopropylidene- -threitol by the procedure al-
L
-threitol was derived from
L
-ascorbic
In conclusion, a convergent, stereoselective synthesis of synarg-
entolide-B has been achieved from the commercially available,
L-ascorbic acid and D-ribose via a short and (14 steps) high yielding
L
ready known in the literature.14 The regioselective opening of the
epoxide with Lithium aluminum hydride in dry THF at 0–60 °C
provided a secondary alcohol 11 in 85% yield, The secondary alco-
hol was benzoylated under standard conditions (BzCl, Et3N, DMAP,
DCM) to give 12 in 90% yield, which on acetonide deprotection
with para toluene sulfonic acid (PTSA) in MeOH afforded diol 13.
The oxidative cleavage with NaIO4 led to the aldehyde, which
was vinylated under Grignard reaction conditions. Vinylation was
accompanied by ester cleavage and the resultant olefinic diol 14
was obtained.15 The diol was acetylated with Ac2O in the presence
of pyridine to give 92% of the olefinic fragment 15.16
route (21% overall yield). The prominent steps involved in the one-
pot transformation involved are stereoselective addition of an allyl-
zinc reagent as well as controlled reduction of a terminal alkyne in
the presence of active zinc, construction of exocyclic olefin unit by
RCM, and coupling of two fragments via olefin cross-metathesis
reaction.
Acknowledgments
The authors thank the Director IICT, Head, Organic Chemistry
Division-II, IICT for their support, and gratefully acknowledge
DST-SERB/EMEQ-078/2013 for financial assist. S. Konda and B.K.
thank CSIR, New Delhi for award of research fellowship.
With the key intermediates 9 and 15 in hand, we focused on the
synthesis of synargentolide-B (Scheme 4). It was achieved by the

S. Konda et al. / Tetrahedron Letters 55 (2014) 3087–3089
3089
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D. C. J.; Saibaba, R.; Panzica, R. P. J. Org. Chem. 1988, 53, 2598.
14. Sharma, G. V. M.; Cherukupalli, Govardhan R. Tetrahedron: Asymmetry 2006, 17,
1081–1088.
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16. Marco-Centelles, J.; de Opazo, E. J. Org. Chem. 2000, 65, 5416–5419.
17. Sabitha, G.; Gopal, P.; Nagendra, R. C.; Yadav, J. S. Tetrahedron Lett. 2009, 50,
6298–6302.
References and notes
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18. Spectral data for selected compounds: (R)-1-((4R,5R)-5-ethynyl-2, 2-dimethyl-1,
3-dioxolan-4-yl) ethane-1, 2-diol (6) ½a D27
ꢁ
+7.39 (c = 0.55 DCM) [lit.11 a 2D7
½ ꢁ
+7.24 (c 0.55, DCM)]. IR (KBr) m .
max = 3289, 2920, 1212, 1064 cmꢀ1 1H NMR
(300 MHz, CDCl3): d 4.7 (dd, J = 4.72, 2.13, 1.98 Hz, 1H); 4.14 (d, J = 5.17,
1.52 Hz, 1H); 3.89 (m, 1H); 3.68–3.81 (m, J = 5.18, 3.18 Hz, 2H); 2.57 (d,
J = 2.13 Hz, 1H); 1.51 (s, 3H); 1.43 (s, 3H). 13C NMR (75 MHz, CDCl3): 110.80,
81.87, 81.48, 74.67, 71.46, 66.50, 63.1, 26.7, 25.85 ppm.
(R)-1-((4R,5R)-2, 2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)but-3-en-1-ol (7).
+131 (c = 1.0, MeOH) [lit.,8b
+135 (c 1.0, MeOH)];. IR (KBr) max = 3477,
3080, 2987, 2931, 1728, 1643, 1372, 1215, 1170, 1057, 921, 876 cmꢀ1 1H NMR
(300 MHz, CDCl3): 5.86 (m, 2H); 5.44 (d, J = 17.09 Hz, 1H); 5.27 (d,
½ ꢁ
a 2D7
½
a 2D7
ꢁ
m
.
d
J = 10.22 Hz, 1H); 5.15 (m, 2H); 4.47 (t, J = 7.82, Hz, 1H); 3.88 (m, 1H); 3.75
(dd, J = 7.93, 4.42 Hz, 1H); 2.24 (m, , 2H); 1.45 (s, 3H); 1.43 (s, 3H). 13C NMR
(75 MHz, CDCl3): 136.37, 134.05, 118.61, 118.27, 108.99, 82.51, 78.25, 70.26,
37.97, 26.93, 26.93 ppm. MS (ESI): m/z = 199 [M+H]+. HRMS: calcd for C11H19O3
[M+H]+: 199.1255: found: 199.1250.
(R)-6-((4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-5,6-dihydro-2H-pyran-2-
one (9): ½a 2D7
ꢁ
+3.9 (c = 1.1, MeOH) [lit.,8b
½
a 2D7
ꢁ
+3.7 (c 1.1, MeOH)]. IR (KBr)
1H NMR
d 6.92 (ddd, J = 10.10, 7.10, 2.91 Hz, 1H); 6.04 (dt,
m
max = 2925, 2855, 1746, 1599, 1488, 1239, 1105, 1026 cmꢀ1
.
(600 MHz, CDCl3):
J = 10.10, 2.91 1H); 5.95 (ddd, J = 16.99, 10.99, 5.99 Hz, 1H); 5.45 (d,
J = 16.99 Hz, 1H); 5.29 (d, J = 9.99 Hz, 1H); 4.46 (quin, J = 6,99 Hz, 2H); 3.92
(t, J = 6.98 Hz, 1H); 2.55 (m, 2H); 1.44 (s, 3H); 1.43 (s, 3H). 13C NMR (75 MHz,
CDCl3): 162.8, 144.7, 135.09, 121.13, 118.33, 109.89, 80.55, 79.85, 77.88, 27.75,
26.8, 25.64 ppm. MS (ESI): m/z = 225 [M+H]+. HRMS: calcd for C12H16O4Na
[M+Na]+: 247.0935: found: 247.0940.
7. Collett, L. A.; Davies-Coleman, M. T.; Rivett, D. E. A. Phytochemistry 1998, 48,
651–656.
(2S,3R)-pent-4-ene-2,3-diyl diacetate (15): ½a D27
ꢁ
ꢀ9.6(c = 0.9, MeOH) [lit.,8b a 2D7
½ ꢁ
8. (a) Prasad, K. R.; Phaneendra, G. J. Org. Chem. 2013, 78, 3313–3322; (b) Sabitha,
G.; Shankaraiah, K.; Yadav, J. S. Eur. J. Org. Chem. 2013, 4870–4878.
9. (a) Nagarapu, L.; Paparaju, P.; Satyander, A.; Bantu, R. Tetrahedron Lett. 2011, 52,
7075–7078; (b) Bantu, R.; Mereyala, H. B.; Nagarapu, L.; Kantevari, S. Tetrahedron
Lett. 2011, 52, 4854–4856; (c) Nagarapu, L.; Mallepalli, R.; Yeramanchi, L.; Bantu,
R. Tetrahedron Lett. 2011, 52, 3401–3404; (d) Nagarapu, L.; Mallepalli, R.; Nikil
Kumar, U.; Paparaju, P.; Bantu, R.; Yeramanchi, L. Tetrahedron Lett. 2012, 53,
1699–1700; (e) Nagarapu, L.; Gaikward, H. K.; Bantu, R.; Manikonda, S. R. Eur. J.
Med. Chem. 2011, 46, 2152–2156; (f) Nagarapu, L.; Karnakanti, S.; Bantu, R.
Tetrahedron 2012, 68, 5829–5832.
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Biomol. Chem. 2011, 9, 7372–7383.
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Vedavati G. Org. Biomol. Chem. 2008, 6, 2587–2595.
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ꢀ10.5 (c 0.8, MeOH)]. IR (KBr)
mmax 2925, 1739, 1598, 1482, 1372, 1242, 1113,
751 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.78 (m, 1H); 5.38–5.26 (m, 3H); 5.08
.
(m, 1H); 2.10 (s, 3H); 2.05 (s, 3H); 1.21 (d, J = 6.60 Hz, 3H). 13C NMR (75 MHz,
CDCl3): 170.26, 169.90, 131.87, 119.24, 75.51, 70.39, 21.05, 20.96, 14.83 ppm.
MS (ESI): m/z = 209 [M+Na]+.
Synargentolide-B (1)
DCM)]. IR (KBr) max = 3326, 2934, 2862, 1728, 1489, 1366, 1222, 1110,
1037, 770 cmꢀ1 1H NMR (500 MHz, CDCl3):
6.95 (ddd, J = 9.78, 5.27,
½
a 2D7
ꢁ
+27.1 (c = 0.2, DCM) [lit.,8a
½ ꢁ +26.3 (c = 0.2,
a 2D7
m
.
d
3.28 Hz, 1H); 6.03 (dt, J = 9.78, 1.50 Hz, 1H); 5.89 (dd, J = 15.81, 5.27 Hz,
1H); 5.81 (dd, J = 15.81, 6.77 Hz, 1H); 5.33 (dd, J = 6.40, 3.76 Hz, 1H);
5.07 (dq, J = 6.40, 3.76 Hz, 1H); 4.52 (m, 1H); 4.48 (m, 1H); 3.71 (dd,
J = 6.81, 2.67 Hz, 1H); 2.58 (m, 2H); 2.09 (s, 3H); 2.05 (s, 3H); 1.21 (d,
J = 6.40 Hz, 3H). 13C NMR (75 MHz, CDCl3): 170.45, 170.29, 163.73,
145.80, 134.17, 126.66, 120.93, 76.83, 74.97, 74.26, 70.50, 69.50, 25.52,
21.13, 21.09, 15.08 ppm. MS (ESI): m/z = 365 [M+Na]+. HRMS: calcd for
C
16H22O8Na [M+Na]+: 365.1212: found: 365.1208.