First total synthesis of neurotrophic diacetylene tetrol (-)-petrosiol D

Article abstract of DOI:10.1016/j.tetlet.2013.09.058

The first total synthesis of the natural product (-)-petrosiol D has been achieved in a linear fashion. Sharpless asymmetric epoxidation, base induced elimination reaction for the formation of chiral propargyl alcohol and Cadiot-Chodkiewicz coupling react

Full text of DOI:10.1016/j.tetlet.2013.09.058

Tetrahedron Letters 54 (2013) 6370–6372
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Tetrahedron Letters
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First total synthesis of neurotrophic diacetylene tetrol (ꢀ)-petrosiol D
⇑
A. Sathish Reddy, P. Srihari
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of the natural product (ꢀ)-petrosiol D has been achieved in a linear fashion.
Sharpless asymmetric epoxidation, base induced elimination reaction for the formation of chiral
propargyl alcohol and Cadiot–Chodkiewicz coupling reaction are the key steps utilized for the synthesis.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 14 August 2013
Revised 12 September 2013
Accepted 14 September 2013
Available online 21 September 2013
Keywords:
Cadiot–Chodkiewicz coupling
Bromo acetylene
Neurite
Outgrowth
Polyol
Acetonide
Dialkyne compounds with hydroxyl functionality display a
wide spectrum of structural diversities and a broad array of biolog-
1
ical properties. Recent investigations by Ojika et al., towards
identification of small molecules displaying NGF-like properties
lead to the isolation of five novel diyne polyols namely petrosiols
A–E (Fig. 1) from the extract library of marine organism (Okinawan
marine sponge) using PC12 cells.2 Interestingly, all of these com-
pounds (petrosiols A–D) induced neurite outgrowth in approxi-
mately 40% of PC12 cells and also displayed a dose-dependent
inhibitory effect on PDF-induced DNA synthesis with an IC50 value
M, respectively.2 The absolute struc-
,3
of 0.73, 0.71, 0.72 and 0.69
l
ture of petrosiols A–E was elucidated based on spectroscopic
analyses. The impressive biological property of these novel diacet-
ylene tetrols has attracted us to take up the total synthesis of these
natural products for their availability towards further biological
screening.
Figure 1. Structures of petrosiols A–E 1–5 and oploxyne A and B 6 and 7.
Recently, we have accomplished the total synthesis of similar
first known diyne tetrols namely oploxynes A and B (Fig. 1) and
found that these compounds display cytotoxicity towards
the first total synthesis of natural product petrosiol D starting from
the readily available (+)-diethyl L-tartrate.
4
neuroblastoma and prostate cancer cell lines. Our own interest
in identification of small molecules for CNS activity while working
towards the total synthesis of potent natural product paecilomycin
A has resulted in identification of analogues with new scaffold
Retrosynthetically, we envisaged the target compound 2 to be
synthesized by Cadiot–Chodkiewicz coupling of PMB protected
bromo propargyl alcohol 8 with free terminal alkyne 9 (Scheme 1).
Compound 9 can be synthesized from the corresponding chiral
epoxy alcohol 10 after its conversion to chiral epoxy chloride
followed by a base induced elimination reaction. The chiral
epoxide can be obtained from allyl alcohol 11 which in turn can
be synthesized in three steps from alcohol 13. Compound 13 can
be synthesized through a Wittig reaction of the aldehyde obtained
from alcohol 14 which in turn could be prepared from 15 in one
5
towards neurotrophic property. In continuation of our efforts to-
6
wards the total synthesis of biologically active natural products
5
with an emphasis for CNS related therapeutics, we herein report
⇑
Corresponding author. Tel.: +91 4027191815; fax: +91 4027160512.
E-mail address: srihari@iict.res.in (P. Srihari).
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.058

A. Sathish Reddy, P. Srihari / Tetrahedron Letters 54 (2013) 6370–6372
6371
step by hydrogenation reaction. Compound 15 can be easily
synthesized from 16 via an oxidation followed by the Wittig reac-
tion. Alcohol 16 in turn was easily accessible from commercially
yield 10 in 80% yield. The chiral epoxy alcohol 10 was then treated
with triphenylphosphine (TPP) and imidazole in CCl to yield the
corresponding epoxy chloride 19. Treatment of the chiral epoxy
4
1
0
1
1
available raw material (+)-diethyl
L-tartrate in three steps.
chloride with excess n-BuLi (6 equiv)
provided the chiral
Although petrosiol A and D have similar structure with the only
difference in carbon chain length, we initially focused on the
synthesis of petrosiol D as the raw materials required were readily
available in our laboratory. Accordingly, the synthesis began with
propargyl alcohol 9 (Scheme 2), the key alkyne fragment with all
the chiral centres fixed for the total synthesis of petrosiol D.
Our initial attempts to directly couple the key fragment 9 with
propargyl alcohol or hydroxyl protected propargyl alcohol under
Cadiot–Chodkiewicz conditions ended up in the undesired dimer
by-product along with the recovery of 9. With these unsuccessful
results, we proceeded for coupling reaction of compound 9 with
brominated propargyl alcohol 20. Accordingly, propargyl alcohol
was protected as the corresponding PMB ether and then treated
the readily available alcohol 16 synthesized from L-(+)-diethyl tar-
trate in three steps with an overall yield of 81% following well
known literature procedures.7 The alcohol was oxidized using
IBX and then subjected to a Wittig reaction with 7-benzyloxy-1-
heptyl-triphenylphosphonium iodide in the presence of n-BuLi to
yield the corresponding olefin 15. Since we had to reduce the dou-
ble bond, we proceeded further with 15 by exposing it to Pd/C to
result in one pot olefin reduction and debenzylation providing
alcohol 14. Alcohol 14 was oxidized to aldehyde and subjected to
Wittig reaction with n-decyltriphenylphosphoniumbromide in
the presence of n-BuLi to give cis-Wittig product 17 exclusively
in 75% yield. Compound 17 was exposed to TBAF to desilylate
the silyl ether and the resulted alcohol 13 was oxidized with
3
with NBS in the presence of AgNO to yield the brominated product
4
20 following earlier known procedures. With the two fragments
20 and 9 in hand, we proceeded for the coupling reaction of 9 with
1
2
20 under Cadiot–Chodkiewicz coupling conditions to yield the
precursor 21 for petrosiol D. Finally, the protecting groups in 21
(isopropylidene moiety and PMB moiety) were unmasked using
trifluoroacetic acid (TFA) to yield the target natural product petro-
siol D (Scheme 3). The geometry of the olefin moiety Z configura-
tion was conformed based on the coupling constant value of one
8
IBX to furnish the aldehyde which was further subjected to 2C-
1
3
1
13
Wittig reaction with (carbethoxymethylene)triphenylphosphorane
of the olefinic protons (J = 10.7 Hz). The H NMR and C NMR
to yield
a
,b-unsaturated ester 18. Chemoselective reduction of
were is good agreement with that of the reported natural prod-
1
4
25
D
ester functionality with DIBAL-H provided allyl alcohol 11 that
uct. The optical rotation was found to be ½
aꢁ
= ꢀ3.67 (c 0.3,
was subjected to sharpless asymmetric epoxidation9 reaction to
MeOH), lit. ½
2
aꢁ
29
D
= ꢀ4.4 (c 0.18, MeOH).
Scheme 1. Retrosynthesis for petrosiol D 2.
Scheme 2. Synthesis of alkyne 9.

6
372
A. Sathish Reddy, P. Srihari / Tetrahedron Letters 54 (2013) 6370–6372
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6.
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Srihari, P. Eur. J. Org. Chem. 2011, 6690–6697; (c) Srihari, P.; Mahankali, B.;
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1925; (e) Sabitha, G.; Reddy, Ch. S.; Srihari, P.; Yadav, J. S. Synthesis 2003, 2699–
2
704.
Scheme 3. Total synthesis of petrosiol D.
7
8
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1
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Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem. 1995, 60,
In conclusion, a facile total synthesis of petrosiol D starting from
commercially available (+)-diethyl -tartrate has been achieved.
The natural product was synthesized with an overall yield of
L
7272–7276; (c) DeMunari, S.; Frigerio, M.; Santagos-tino, M. J. Org. Chem. 1996,
61, 9272–9279.
9
.
Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J.
Am. Chem. Soc. 1987, 109, 5765.
5
1
.3% in 14 steps in linear approach starting from alcohol 16 and
7 steps with 4.2% from (+)-diethyl -tartrate using base induced
L
1
0. Lee, J. B.; Downie, I. M. Tetrahedron 1967, 25, 359–363.
11. (a) Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron Lett. 1990, 31,
495–4496; (b) Takano, S.; Samizu, K.; Sugihara, T.; Ogasawara, K. J. Chem. Soc.,
elimination reaction of chiral epoxy halides to get chiral propargyl
alcohol and late stage Cadiot–Chodkiewicz coupling reaction as the
key steps. Synthesis of other petrosiols is currently under progress
in our laboratory.
4
Chem. Commun. 1989, 1344–1345.
1
1
1
2. Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. G., Ed.; Marcel
Dekker: New York, 1969; pp 597–647.
3. The coupling constant was calculated after performing proton decoupling
studies. See Supplementary data.
Acknowledgments
25
D
4. Spectroscopic data for selected products 9: ½
aꢁ
= ꢀ4.67 (c 0.6, CHCl
3
). IR [NEAT]:
ꢀ
1 1
3
448, 2925, 2854, 1733, 1461, 1375, 1248, 1167, 1054, 722, 658 cm
.
HNMR
The authors thank CSIR, New Delhi for financial support as part
of XII Five Year plan programme under title ORIGIN (CSC-0108).
A.S.R. thanks CSIR, New Delhi for financial assistance in the form
of fellowship.
(300 MHz, CDCl
3
): d 5.40–5.32 (m, 2H), 4.33 (dd, J = 4.3, 1.7 Hz, 1H), 4.00–3.93
(
m, 1H), 3.75 (dd, J = 7.5, 4.9 Hz, 1H), 2.52 (d, J = 2.1 Hz, 1H), 2.08–1.95 (m, 4H),
1.72–1.51 (m, 2H), 1.44 (s, 3H), 1.41 (s, 3H), 1.38–1.20 (m, 24H), 0.88 (t,
13
J = 7.0 Hz, 3H) ppm. C NMR (75 MHz, CDCl
77.5, 74.3, 62.6, 33.6, 32.6, 31.9, 29.7(2C), 29.6, 29.5, 29.4, 29.3, 29.2, 29.0, 28.9,
3
): d 129.9, 129.7, 109.4, 83.2, 81.6,
+
2
7.5, 27.2, 27.0, 25.9, 22.7, 14.1 ppm. MS (ESI): m/z 430 [M+Na] . Compound 21
25
½a
ꢁ
= ꢀ2.00 (c 0.25, CHCl
3
). IR [NEAT]: 3447, 2925, 2854, 1741, 1612, 1513,
D
ꢀ
1 1
Supplementary data
1461, 1374, 1249, 821, 770, 512 cm
3
. H NMR (300 MHz, CDCl ): d 7.28–7.24
(
m, 2H), 6.91–6.86 (m, 2H), 5.39–5.32 (m, 2H), 4.52 (s, 2H), 4.41 (d, J = 3.4 Hz,
1
2
H), 4.20 (s, 2H), 3.99–3.89 (m, 1H), 3.81 (s, 3H), 3.75 (dd, J = 7.7, 4.5 Hz, 1H),
Supplementary data (experimental procedures and analytical
data for all the new compounds) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.09.058.
.05–1.93 (m, 4H), 1.73–1.50 (m, 2H), 1.44 (s, 3H), 1.41 (s, 3H), 1.40–1.20 (m,
+
24H), 0.88 (t, J = 7.0 Hz, 3H) ppm. MS(ESI): m/z 604 [M+Na] Compound 2:
.
2
5
29
D
½
a
ꢁ
= ꢀ3.67 (c 0.3, MeOH), lit ½
a
ꢁ
= ꢀ4.40 (c 0.18, MeOH). IR [NEAT]: 3382,
D
ꢀ1 1
2
924, 2583, 1734, 1508, 1460, 1246, 1117, 1034, 771, 696, 540 cm
): d 5.32–5.26 (m, 2H), 4.48 (d, J = 5.9 Hz, 1H), 4.27 (s, 2H),
.75–3.71 (m, 1H), 3.47 (dd, J = 6.6 Hz, 1H), 2.08–1.80 (m, 4H), 1.60–1.07 (m,
. H NMR
(
3
300 MHz, CDCl
3
13
References and notes
26H), 0.81 (t, J = 6.9 Hz, 3H) ppm. C NMR (75 MHz, CDCl
3
): d 130.0, 129.8,
7
2
C
8.1, 77.2, 75.7, 71.3, 70.5, 69.5, 64.9, 51.4, 34.2, 32.6, 31.9, 29.7–28.9(9C), 27.2,
+
5.6, 22.7, 14.1 ppm. MS(ESI): m/z 439 [M+NH
Na 443.31318, found 443.31297.
4
] . HRMS(ESI) m/z calculated for
1
.
(a) Bu’Lock, J. D. Prog. Org. Chem. 1964, 6, 86–134; (b) Kobaisy, M.; Abramowski,
Z.; Lermer, L.; Saxena, G.; Hancock, R. E. W.; Towers, G. H. N. J. Nat. Prod. 1997,
26
44 4
H O
60, 1210–1213; (c) Bernart, M. W.; Cardellina, J. H.; Balaschak, M. S.; Alexander,