First stereoselective total synthesis of pectinolide C and total synthesis of pectinolide A

Article abstract of DOI:10.1016/j.tetlet.2012.12.039

The first stereoselective synthesis of pectinolide C and synthesis of pectinolide A, from easily accessible 1-hexyne and d-mannitol are reported in a convergent manner. The salient features include acetylenic addition to the chiral aldehyde and Still-Genn

Full text of DOI:10.1016/j.tetlet.2012.12.039

Tetrahedron Letters 54 (2013) 1097–1099
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First stereoselective total synthesis of pectinolide C and total synthesis of
pectinolide A
⇑
Gowravaram Sabitha , Sukant Kishore Das, Praveen AnkiReddy, J. S. Yadav
Natural Product Chemistry Division, CSIR–Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first stereoselective synthesis of pectinolide C and synthesis of pectinolide A, from easily accessible 1-
Received 26 October 2012
Revised 10 December 2012
Accepted 12 December 2012
Available online 20 December 2012
hexyne and
D-mannitol are reported in a convergent manner. The salient features include acetylenic addi-
tion to the chiral aldehyde and Still–Gennari olefination.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pectinolides
d-Lactones
Chelation-controlled
Still–Gennari
First synthesis
In recent times, naturally occurring 6-membered lactones have
attracted significant interest among synthetic chemists and biolo-
gists due to their interesting biological activities. Pectinolides A–C
(Fig. 1 and 1–3)1 are such examples, isolated from the Mexican
shrub Hyptis pectinata (Lamiaceae), which was used as a remedy
in the treatment of fevers, skin diseases, gastric disturbances,2 rhi-
nopharyngitis, and lung congestion.3 In addition, pectinolides were
Herein, we report the first stereoselective total synthesis of pec-
tinolide C and total synthesis of pectinolide A by a convergent
strategy which relies on acetylenic addition onto a chiral aldehyde,
and cis-Wittig olefination as the key steps.
Retrosynthetic analysis (Scheme 1) reveals that target pectino-
lides 3 and 1 can be obtained from syn, anti-isomer 4, which was
accessible from acetylenic compound 5 and aldehyde 6 by an addi-
tion reaction. Alkyne 5 and aldehyde 6 in turn could be obtained
found to exhibit significant cytotoxic activity (ED50 <4 lg/ml)
against a variety of tumor cell lines as well as antibacterial activity
against the Gram-positive bacteria. On the basis of spectral, chirop-
tical, and chemical evidence, the absolute stereochemistry of pec-
tinolide A was established as 6S-[(3S-acetyloxy)-1Z-heptenyl]-5S-
(acetyloxy)-5,6-dihydro-2H-pyran-2-one. Mosher ester derivatives
were used with pectinolide B (2) for confirmation of the 30-(S)
absolute stereochemistry on the side chain chiral center of pectino-
lides A–C. The structures of pectinolides B (2) and C (3) were deter-
mined as the monodeacetylated forms of 1 by comparison of their
spectral data and chemical correlation with the prototype com-
pound. Staphylococcus aureus and Bacillus subtilis were sensitive
from readily available 1-hexyne 7 and D-mannitol, respectively.
The synthesis of MOM-protected propargylic alcohol 5 com-
menced from 1-hexyne 7 (Scheme 2) by converting it into propar-
gylic alcohol 8. Thus, we proceeded to couple the in situ metalated
hexyne (obtained by treating 7 with ethyl magnesium bromide)
with formaldehyde to afford 8 with 75% yield. Compound 8 was
converted into chiral propargylic alcohol 9 in four steps as reported
earlier.4k MOM protection of the resulting secondary alcohol in
compound 9 afforded fragment 5 in 85% yield.4l
The aldehyde 6 is a known compound which was synthesized
from the commercially available
D-mannitol 10 according to the re-
to pectinolide A (1) in the concentration range of 6.25–12.5 lg/
ported procedure in 85% yield.6
ml. Our continued interest on the synthesis of bio-active lactones,4
prompted us to undertake the synthesis of these molecules. While
our work on the synthesis of 1 and 3 was in progress, one synthesis
of pectinlolide A has appeared,5 whereas, there is no report on the
synthesis of pectinolide C.
O
O
O
OAc
OH
O
O
2
OAc
O
4
3'
6
1'
OH
OAc
OAc
Pectinolide B
Pectinolide C
Pectinolide A
3
2
1
⇑
Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail addresses: gowravaramsr@yahoo.com, sabitha@iict.res.in (G. Sabitha).
Figure 1. Structure of pectinolides A–C.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.039

1098
G. Sabitha et al. / Tetrahedron Letters 54 (2013) 1097–1099
O
OMOM
OMOM
OMOM
OBn
OH
2,6-lutidine,
OBn
O
OAc
OBn
TBSOTf, CH2Cl2,
0 °C, 1 h, 92%
OTBS
syn, anti-4
OR
13
4
OH
R = H; Pectinolide C (3)
R = Ac; Pectinolide A (1)
OMOM
OMOM
(1) NMO, OsO4, acetone/H2O
(2) NaIO4, THF/H2O
LiOH, THF, MeOH,
H2O, 1 h
OHC
CO2Me
OBn
OTBS
+
OBn
5
6
(3) (F3CCH2O)2POCH2COOMe
PTSA, Toluene, RT,
15 h, 80%
NaH, THF, 0 °C to -78 °C, 1 h,
85%,over 3 steps
14
D-mannitol (10)
O
O
1-hexyne
7
OH
OBn
OH
H2, Lindlar,s cat.
Scheme 1. Retrosynthesis of pectinolides C and A.
EtOAc, 20 min, 90%
OBn
O
15
16
O
EtMgBr, THF,
OH
(CH2O)n, 0 °C, 75%
O
7
8
O
OAc
TiCl4, CH2Cl2, 0 °C
15 min, 80%
Et3N, Ac2O, DMAP
OR
(1) Ref 4k
(2) Ref 4l
CH2Cl2, 0 °C to
RT, 1 h, 90%
OBn
9
R= H
17
5 R= MOM
O
O
O
Scheme 2. Synthesis of MOM-protected propargylic alcohol 5.
OAc
Et3N, Ac2O, DMAP
O
OAc
With the two intermediates 5 and 6 in hand, we proceeded to
couple in situ metalated alkyne (obtained by treating 5 with ethyl
CH2Cl2, 0 °C to
RT, 1 h, 90%
OAc
OH
magnesium bromide) with aldehyde
6
in the presence of
Pectinolide-A (1)
3
Pectinolide-C (
)
MgBr2ꢀEt2O at ꢁ78 °C to furnish the syn, anti-isomer 4 in 70% yield
with high diastereomeric excess (de = >97%) analyzed by chiral
HPLC.7 Formation of major diastereomeric alcohol can be explained
on the basis of chelation-controlled (Anti Felkin-Anh model) addi-
tion of Grignard nucleophile to the aldehyde leading to the single
stereoisomer syn, anti-4.
Acylation of compound 4 with acryloyl chloride in the presence
of NEt3 in CH2Cl2 gave acrylate ester 11. Unfortunately, several at-
tempts for the ring-closing metathesis of diene 11 using Grubbs’
second-generation ruthenium catalyst (Ru-II) were not successful,
resulting in 10% yield of the required lactone 12 (Scheme 3).
Because of low yields in the RCM reaction, the terminal olefin in
compound 4 needs to be cleaved and Still–Gennari reaction should
be performed. The free hydroxyl group in 4 is thus protected as TBS
ether using TBSOTf and 2,6-lutidine to provide 13. The latter was
Scheme 4. Synthesis of pectinolides C (3) and A (1).
then converted into the corresponding aldehyde by dihydroxyla-
tion of the terminal double bond, oxidative cleavage of the result-
ing 1,2-diol followed by modified Still–Gennari olefination with
(F3CCH2O)2POCH2COOMe) in THF to afford cis-olefinic ester 14.
Since attempts to cyclize TBS-protected ester 14 to the lactone
15 failed under several conditions, we decided to hydrolyze the es-
ter group. Ester 14 was thus converted into the corresponding acid
by hydrolysis using 0.5 N aq LiOH in THF/MeOH (2:1), which with-
out further purification, directly treated with PTSA in toluene at
room temperature to form lactone 15 in a one-pot reaction via a
three-step sequence (TBDMS deprotection, lactonization, and
MOM deprotection) (85%, over two steps). Next, the triple bond
was partially reduced to the cis-olefin 16 using Lindlar’s catalyst
and then free hydroxyl group was acetylated with acetic anhydride
to furnish 17.
OMOM
OBn
EtMgBr, THF, MgBr2.O(Et)2
+
oC
CH2Cl2, -78 , 2 h, 70%, de 97%
OHC
5
6
Finally global debenzylation (TiCl4/CH2Cl2/0 °C/15 min) gave
the target pectinolide C (3) {½a D25
ꢂ
+72.4 (c = 0.5, MeOH), lit. ½a D25
ꢂ
+80.99 (c = 0.76, MeOH)} (80%), whose spectroscopic data were
identical to that of the natural product. Further, in a separate
experiment, 3 was acetylated by using acetic anhydride/Et3N to af-
OMOM
OMOM
OBn
O
Acryl chloride,
OBn
Et3N
ford pectinolide A (1) {½a D25
ꢂ
+191.3 (c = 0.5, MeOH), lit. ½a D25
ꢂ
+202.0
CH2Cl2, 0
O
OH
oC, 1 h, 80%
11
4
syn, anti-
(c = 0.15, MeOH)} in 90% yield (Scheme 4). The physical and spec-
troscopic data of our synthetic sample 1 were identical to those of
the reported natural and synthetic products.
OMOM
G-II catalyst, Toluene
reflux, 6 h, 10%
OBn
O
We have accomplished the total synthesis of 3 and 1 starting
from relatively cheap and commercially available D-mannitol and
1-hexyne by means of a versatile strategy utilizing acetylenic addi-
tion to the chiral aldehyde and Still–Gennari olefination.
O
12
Mg
BnO
O
Acknowledgments
M
Nu
S
H
S.K.D. thanks UGC and A.P.R. thanks CSIR, New Delhi for the
award of fellowships.
Scheme 3. Synthesis of lactone 12.

G. Sabitha et al. / Tetrahedron Letters 54 (2013) 1097–1099
1099
7. The diastereomeric excess of the product was determined using a Shimadzu
high-performance liquid-chromatography (HPLC) system equipped with a chiral
HPLC column (Chiralcel OD) and a UV detector at an absorbance of 225 nm.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.12.
039.
ATLANTIS DC18 150 ꢃ 4.6 mm, 5
l (column) and a solvent system of acetonitrile
and 0.1% formic acid at a flow rate of 1.0 ml/min were used. tR: 15.9 and
17.2 min.
Spectral data for selected compounds:
(3S,4S,7S)-3-(benzyloxy)-7-(methoxymethoxy)undec-1-en-5-yn-4-ol (4):
½ ꢂ :
a 2D5
ꢁ19.4 (c = 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.39–7.29 (m, 5H), 5.97–
5.75 (m, 1H), 5.46–5.35 (m, 2H), 4.92 (dd, J = 6.8, 4.5 Hz, 1H), 4.68 (d, J = 11.3 Hz,
2H), 4.56 (d, J = 6.8 Hz, 1H), 4.43 (d, J = 11.3 Hz, 1H), 4.39–4.32 (m, 1H), 3.96–
3.83 (m, 1H), 3.36 (s, 3H), 1.82–1.62 (m, 2H), 1.48–1.27 (m, 4H), 0.91 (t,
J = 7.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 134.0, 133.7, 128.4, 127.8, 127.7,
120.5, 94.0, 84.9, 83.2, 82.2, 70.8, 70.4, 65.1, 55.5, 35.2, 27.3, 22.3, 13.9; IR (neat)
3444, 2933, 2871, 1457, 1096, 1033, 738, 698 cmꢁ1; ESI HRMS m/z calcd for
References and notes
1. Pereda-Miranda, R.; Hernández, L.; Villavicencio, M. J.; Novelo, M.; Ibarra, M.;
Chai, H.; Pezzuto, J. M. J. Nat. Prod. 1993, 56, 583–593.
2. Mattinez, M. Las Plantas Medicinales de Mexico; Mexico: Editorial Botas, 1989. p
508.
3. Malan, K.; Pelissier, Y.; Marion, C.; Blaise, A.; Blessiere, J. Planta Med. 1988, 54,
531–532.
4. (a) Sabitha, G.; Bhaskar, V.; Reddy, S. S. S.; Yadav, J. S. Tetrahedron 2008, 64,
10207–10213; (b) Sabitha, G.; Bhaskar, V.; Reddy, S. S. S.; Yadav, J. S. Synthesis
2009, 3285; (c) Sabitha, G.; Gopal, P.; Reddy, C. N.; Yadav, J. S. Tetrahedron Lett.
2009, 46, 6298–6302; (d) Sabitha, G.; Gopal, P.; Reddy, C. N.; Yadav, J. S. Synthesis
2009, 3301; (e) Sabitha, G.; Fatima, N.; Gopal, P.; Reddy, C. N.; Yadav, J. S.
Tetrahedron: Asymmetry 2009, 20, 184–191; (f) Sabitha, G.; Prasad, M. N.;
Shankaraiah, K.; Yadav, J. S. Synthesis 2010, 1171–1175; (g) Sabitha, G.; Reddy, S.
S. S.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 6259–6261; (h) Sabitha, G.; Reddy, S.
S. S.; Yadav, J. S. Tetrahedron Lett. 2011, 52, 2407–2409; (i) Sabitha, G.; Reddy, C.
N.; Raju, A.; Yadav, J. S. Tetrahedron: Asymmetry 2011, 22, 493–498; (j) Sabitha,
G.; Rao, A. S.; Yadav, J. S. Tetrahedron: Asymmetry 2011, 22, 866–871; (k) Sabitha,
G.; Reddy, D. V.; Reddy, S. S. S.; Yadav, J. S.; Ganesh, C. K.; Sujitha, P. RSC Advances
2012, 2, 7241–7247; (l) José-Luis, A.; Villorbina, G.; Camps, F. J. Org. Chem. 2004,
69, 7108–7113.
C
20H28O4Na [M+Na]+ 355.18798, found 355.18971.
(S,Z)-1-((2S,3S)-3-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)hept-1-en-3-yl
acetate (3): ½a 2D5
ꢂ
+72.4 (c = 0.5, MeOH); 1H NMR (CDCl3, 300 MHz): d 7.01 (dd,
J = 9.8, 5.3 Hz, 1H), 6.15 (d, J = 9.8 Hz, 1H), 5.78–5.64 (m, 2H), 5.51 (ddd, J = 9.8,
7.5, 6.0 Hz, 1H), 5.30 (dd, J = 6.0, 2.3 Hz, 1H), 4.15 (dd, J = 5.3, 2.3 Hz, 1H), 2.05 (s,
3H), 1.72–1.56 (m, 4H), 1.39–1.30 (m, 2H), 0.91 (t, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d 171.0, 162.7, 144.2, 134.1, 125.5, 122.8, 77.8, 70.9, 63.1, 34.2,
27.1, 22.4, 21.1, 13.9; IR (neat) 3443, 2928, 1725, 1245, 1039 cmꢁ1; ESI HRMS m/
z calcd for C14H20O5Na [M+Na]+ 291.12029, found 291.12109.
(S,Z)-1-((2S,3S)-3-acetoxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)hept-1-en-3-yl
acetate (1): ½a 2D5
ꢂ
+191.3 (c = 0.5, MeOH); 1H NMR (CDCl3, 300 MHz): d 6.96 (dd,
J = 9.6, 5.6 Hz, 1H), 6.24 (d, J = 9.8 Hz, 1H), 5.73 (dd, J = 11.1, 8.3 Hz, 1H), 5.62 (dd,
J = 10.7, 8.3 Hz, 1H), 5.59 (dd, J = 7.9, 2.8 Hz, 1H), 5.35 (ddd, J = 13.5, 7.1, 6.6 Hz,
1H), 5.17 (dd, J = 5.7, 2.8 Hz, 1H), 2.09 (s, 3H), 2.04 (s, 3H), 1.78-1.52 (m, 2H),
1.36–1.12 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 170.2,
169.8, 162.0, 139.9, 133.1, 126.2, 125.1, 75.0, 69.4, 64.2, 34.0, 27.2, 22.4, 21.0,
20.4, 13.8; IR (neat) 2925, 2856, 1739, 1373, 1225, 1029, 771 cmꢁ1; ESI HRMS m/
z calcd for C16H22O6Na [M+Na]+ 333.13086, found 333.13196.
5. Yadav, J. S.; Mandal, S. S. Tetrahedron Lett. 2011, 52, 5747–5749.
6. Kamal, A.; Reddy, P. V.; Prabhakar, S. Tetrahedron: Asymmetry 2009, 20, 1120–
1124.