Novel iodine catalyzed diastereoselective synthesis of trans-2,6- disubstituted tetrahydro-2H-pyrans: Synthesis of C1-C13 fragment of bistramide-A

Article abstract of DOI:10.1016/j.tetlet.2013.08.085

A new method for the stereoselective synthesis of trans 2.6-disubstituted tetrahydro-2H-pyrans has been developed involving iodine catalyzed allylation of tetrahydro-2H-pyranol with excellent trans selectivity. The method was also applied toward the construction of C1-C13 fragment of bistramide-A in 11 steps with 21.4% overall yield.

Full text of DOI:10.1016/j.tetlet.2013.08.085

Tetrahedron Letters 54 (2013) 5879–5882
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Tetrahedron Letters
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Novel iodine catalyzed diastereoselective synthesis
of trans-2,6-disubstituted tetrahydro-2H-pyrans: synthesis
of C1–C13 fragment of bistramide-A
⇑
Jhillu Singh Yadav , Eppa Gyanchander, Anand Kumar Mishra, Peddapuram Adithya, Saibal Das
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for the stereoselective synthesis of trans 2.6-disubstituted tetrahydro-2H-pyrans has been
developed involving iodine catalyzed allylation of tetrahydro-2H-pyranol with excellent trans selectivity.
The method was also applied toward the construction of C1–C13 fragment of bistramide-A in 11 steps
with 21.4% overall yield.
Received 19 June 2013
Revised 19 August 2013
Accepted 22 August 2013
Available online 30 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydropyrans
Iodine catalyzed allylation
Non Evans aldol
Isomerization
Bistramide A
Tetrahydropyrans (THP) containing natural products are widely
present in nature and show pronounced biological activities.1 In
particular, 2,6-disubstituted tetrahydro-2H-pyran ring moieties
are found in several of them, namely Phorboxazole A&B,2 Leucasc-
androlide A,3 Apicularen A,4 Aspergillide B,5 etc., having significant
properties and importance (Fig. 1). As a result, construction of the
THP ring is always in demand and till date several approaches6
have been reported that involves activation of glycals with differ-
ent Lewis acid,7 Petasis–Ferrier rearrangement,8 Hetero Diels–Al-
der cycloaddition,9 epoxide opening,10 oxa-conjugate addition,11
Prins reaction,12 tandem cross metathesis/iodocyclization,13 intra-
molecular silyl modified Sakurai reaction,14 and Maitland–Japp
reaction.15
Initially, we investigated compound 3 which upon iodine cata-
lyzed cyclization furnished C-allylated tetrahydro-2H-pyran 13 in
88% yields. To our notice, 1H NMR and 13C NMR spectrum revealed
formation of only one isomer. Further investigation under chiral
HPLC showed a slight existence of other diastereomers in 9:1 ratio,
better compared to the earlier report of 7:3 ratio.17 The NOE inves-
tigation supported the 2,6-trans relationship in the desired com-
pound (Fig. 2). Further the investigation was extended to
different tetrahydro-2H-pyrans for wider applicability and affor-
ded the corresponding C-allylated product in better yields and ra-
tio (Table 1).
We began our investigation after attention was drawn on one of
our earlier reports, where formation of 2,6-disubstituted-3,4-dihy-
R
H
N
2 R1
dropyrans was demonstrated from d-hydroxy
a,b-unsaturated
O
O
OH
O
O
aldehydes catalyzed by molecular iodine.16 The existence of the
double bond in these moieties was found to be of limitation toward
the synthesis of certain natural products with saturated DHP core,
wherein reduction reactions are unavoidable in the later stage. To
support the fact, herein, we prepared such a particular skeleton of
substituted tetrahydro-2H-pyranol and subjected it to C-allylation
conditions (Scheme 1).
O
N
O
O
Me
OH
O
Apicularen A
OMe
O
O
Me
Me
OMe
N
Br
O
H
OH
Me OH
Phorboxazole A (R1=OH, R2=H)
Phorboxazole B (R1=H, R2=OH)
⇑
Corresponding author. Tel.: +91 40 2719 3737; fax: +91 40 2716 0512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
Figure 1. Selective examples of THP containing natural products.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.085

5880
J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 5879–5882
O
O
O
R
OH
R
H
N
O
R
I2
R
O
N
H
O
4
13
Si
H
H
H
O
R
DCM,
0°C to r.t.
R
R
OH
O
H
R
R = H, alkyl, OBn
OH
Scheme 1. General reaction of C-allylation of tetrahydro-2H-pyranol.
Figure 3. Bistramide A.
O
S
TiCl4, i-Pr2NEt
H
N
BnO
BnO
O
S
H
H
H
O
DCM, -20°C
90%
21
23
BnO
2
6
Ph
22
OH
O
S
OH OH
Figure 2. Characteristic NOE of compound 13.
N
NaBH4, MeOH
rt, 88%
S
BnO
O
24
Ph
BAIB, TEMPO
Ph3P=CHCO2Et
Table 1
OH
O
Mg, MeOH
Iodine-catalyzed stereoselective synthesis of trans-2,6-disubstituted-2H-pyrans31
BnO
rt, 3hr,
86%
Benzene, 1hr
85% over two steps
OH
Entry
Substrate
Producta
Time
(h)
Yieldb
(%)
Ratioc
(de)
25
O
OTBDPS
O
OTBDPS
O
OH
BnO
O
1
2
3
0.5
0.5
0.5
88
85
88
99:1
—
26
1
11
Scheme 2. Synthesis of intermediate 26.
OH
O
8
O
8
2
12
OBn
O
OBn
O
mide-A, (Fig. 3) which is a marine metabolite isolated from Lissocl-
inum Bistratum in 1988 by Verbist and co-workers.18a Bistramide B,
C, D, and K were reported by 199418b and these classes of com-
pounds showed significant cytotoxicity, neurotoxicity, and plays
an important role in cell cycle regulation, differentiation, and
OH
9:1
3
13
OBn
OBn
O
OH
O
2
2
4
5
6
0.5
85
85
90
9:1
9:1
9:1
apoptotis.18c–e Bistramide A displayed IC50 of 0.03–0.32
lg/mL for
4
14
OBn
OBn
the P388/DOX, B16, HT29, and NSCLC-N6 cell lines,18f inhibits
Na+ conductance18g,h and is selective toward the activation of a sin-
gle protein kinase C (PKC) isotype-d.18i These promising biological
activities of bistramide A have manifested it as a potential candi-
date for anticancer therapy.
OH
O
O
3
3
0.25
1.0
15
16
5
OPMB
OPMB
OH
O
O
2
2
The first synthesis was achieved by Kozmin and co-workers19a–c
followed by Crimmins et.al.,19d Panek and co-workers20 and our
group.21a Structure validation and its synthesis were reported by
Peter Wipf et al.21b,c and recently Goekjian and co-workers21d dem-
onstrated its synthesis and 36(Z) isomers. A few research groups
have also reported the construction of tetrahydropyran (THP)
core22 in particular.
6
OBn
OBn
O
O
OH
2
2
7
1.0
86
9:1
7
17
OTBS
OTBS
OBn
OBn
OH
O
O
8
0.5
0.5
0.5
88
91
87
99:1
99:1
—
The synthesis of the THP unit 30 commenced with an asymmet-
ric aldol addition23,25 reaction of thiazolidinethione propionate to
the benzyloxypropanal 21 using TiCl4 and DIPEA as the base. This
led to a non Evans syn aldol product 23 in 90% isolated yield.
Reductive cleavage of the chiral auxiliary using NaBH4,24 afforded
diol 2425 in 88% yield. This diol on selective oxidation in the pres-
ence of bis(acetoxy)iodobenzene (BAIB) and 2,2,6,6-tetramethylpi-
peridine-N-oxide (TEMPO), followed by exposure of the crude
b-hydroxy aldehyde to ethoxycarbonylmethylene triphenylphos-
8
18
OBn
OBn
O
OH
O
2
6
2
6
9
9
19
20
O
OH
O
10
10
The products were characterized by1H NMR, IR, and mass spectrometry.
Yield refers to pure products after chromatography.
Determined by HPLC analysis on a mobile phase discovery C8 250 ꢀ 4.6 mm, 5
a
b
c
phorane furnished d-hydroxy-
a
,b-unsaturated ester 2521a,26 in
,b-unsat-
85% overall yield for the two steps. The double bond of
a
l
urated ester was reduced with Mg27 in methanol to yield the ester
26 in 86% yield (Scheme 2). DIBAL-H reduction of saturated ester
afforded the key intermediate lactol 4 in 82% yield.
column.
The possible reaction mechanism may involve activation of
oxocarbenium ion by the trimethyl silyl group followed by attack
of allyl group from anti direction with respect to sixth position
bearing group favored by stereoelectronic factors.16
After this encouraging result, we focused toward its application
for the synthesis of a C1–C13 tetrahydropyran core unit of bistra-
The lactol 4 was then subjected to the newly developed meth-
odology to furnish the desired C-allylated cyclized product 1421c
in 9:1 ratio with 85% isolated yield (Table 1). Then, ozonolysis of
terminal alkene with ozone afforded the corresponding intermedi-
ate aldehyde, which was directly subjected to an allylation under
Barbier conditions28 to furnish alcohol 28 in 86% overall yield.

J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 5879–5882
5881
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Si
BnO
27
DIBAL-H,
O
OH
I2, DCM, 0°C
26
DCM, -78°C,
15min, 82%
30min, 85%
4
BnO
BnO
O
O
O3, DCM, -78°C
OH
Allyl bromide,
Zn, THF, rt
28
14
86%
TiCl4, DCM
0°C, 0.5hr
BnO
O
COCl2, DMSO
O
DCM, TEA, -78°C
75%
82%
29
HO
O
O
30
C1-C13 Fragment of Bistramide A
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of enone using TiCl4 in methylene chloride gave the enone alcohol
3031 (Scheme 3). The pyran intermediate was found identical in all
respect to that reported by Crimmins et al.,19d and our group.21a
In conclusion, a new method for the stereoselective synthesis of
trans-2,6-disubstituted tetrahydro-2H-pyrans has been developed
with excellent trans selectivity and the approach has been success-
fully applied in the construction of C1–C13 fragment of bistramide-
A in 11 steps with 21.4% overall yield. Further, applications and
extensions of the methodology are currently ongoing in our labora-
tory and will be reported in due course.
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Acknowledgments
E.G.C. and A.K.M. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi for research fellowships. The authors
thank the Council of Scientific and Industrial Research (CSIR)-
New Delhi for financial support through the ORIGIN programme
under 12th five year plan, J.C. Bose and CSIR Bhatnagar Fellowship.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
08.085.
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31. General procedure for iodo cyclization: Iodine (10 mol %) was added to a stirred
solution of lactol (1.0 mmol) and allyltrimethyl silane (1.5 mmol) in DCM
(5 mL) at 0 °C and allowed to come to room temperature. After completion of
the reaction (as indicated by TLC; 30–60 min), the reaction mixture was
quenched with saturated solution of NaHCO3 (3–5 mL) and washed with
saturated hypo solution. The reaction mixture was extracted with DCM
(2 ꢀ 5 mL), combined organic layer was dried over anhydrous Na2SO4, and
concentrated under reduced pressure to give a pale yellow oil, which was
purified by silica gel column chromatography using 4–8% ethyl acetate/hexane
as eluent to obtain 84–94% of isolated yield of the 2-allyl cyclized product.
(2R,6R)-6-Allyltetrahydro-2H-pyran-2-yl)methoxy)(tert-butyl)dipheny-lsilane
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5882
J. S. Yadav et al. / Tetrahedron Letters 54 (2013) 5879–5882
(11): ½a 2D5
ꢁ
ꢂ53.0 (c 0.5, CHCl3); IR (KBr, neat): 3072, 3051, 2956, 2932, 2859,
2930, 2857, 1722, 1641, 1454, 1361, 1273, 1254, 1219, 1177, 1104. 1006, 913,
836, 773, 711, 698 cmꢂ1 1H NMR (CDCl3, 300 MHz): d 7.36–7.29 (m, 5H), 5.87–
1590, 1462, 1428, 1390, 1251, 1164, 1111, 1086, 1035, 902, 840, 772, 741, 703,
;
612 cmꢂ1
;
1H NMR (CDCl3, 300 MHz): d 7.70–47.64 (m, 4H), 7.44–7.34 (m, 6H),
5.70 (m, 1H), 5.11–5.01 (m, 2H), 4.49 (m, 2H), 4.06–3.95 (m, 1H), 3.89–3.80 (m,
1H), 3.62–3.49 (m, 2H), 2.64–2.52 (m, 1H), 2.43.2.29 (m, 1H), 2.01–1.90 (m,
1H), 1.87–1.76 (m, 1H), 1.71–1.59 (m, 2H), 1.36–1.25 (m, 1H), 0.89 (s, 9H), 0.05
(S, 6H) ppm; 13C NMR (CDCl3, 75 MHz): d 135.2, 129.5, 128.3, 127.7, 127.5,
116.6, 73.1, 70.6, 66.9, 66.4, 64.9, 40.5, 37.9, 37.1, 35.6, 25.9, 18.3, ꢂ4.7 ppm;
ESI-HRMS: calcd for C23H38O3 [M+H]+: 391.2663, found 391.2696, HPLC ratio
90.2:9.8.
5.87–5.71 (m, 1H), 5.10–4.97 (m, 2H), 3.90–3.64 (m, 3H), 2.40 (quin, 1H,
J = 6.99, 13.84 Hz), 2.15 (quin, 1H, J = 6.74, 13.83 Hz), 1,621.56 (m, 6H),
1.03–1.07 (m, 9H) ppm; 13C NMR (CDCl3, 75 MHz): d 135.6, 135.3, 129.5,
127.5, 116.4, 71.7, 71.4, 65.0, 38.0, 29.3, 26.8, 26.7, 19.2, 18.2 ppm; ESI-
HRMS: calcd for C25H34O2Si [M+Na]+: 417.2220, found: 417.2190. HPLC ratio
99.3:0.7.
(2S,3S,6R)-6-Allyl-2-(2-(benzyloxy)ethyl)-3-methyltetrahydro-2H-pyran
ꢂ38.66 (c 1.5, CHCl3); IR (KBr, neat): 3071, 3031, 2929, 2857, 1642,
1495, 1454, 1367, 1204, 1170, 1096, 997, 911, 698, 611 cmꢂ1 1H NMR (CDCl3,
(14):
(E)-1-((2R,5S,6S)-6-(2-Hydroxyethyl)-5-methyltetrahydro-2H-pyran-2-yl)pent-3-
½
a 2D5
ꢁ
en-2-one (30): ½a D25
ꢁ
: ꢂ29.5 (c 0.7, CHCl3); IR (KBr, neat): 3448, 2926, 2874,
;
2856, 1670, 1632, 1442, 1380, 1291, 1201, 1165, 1086, 1057, 970, 911 cmꢂ1 1H
;
300 MHz): d 7.38–7.27 (m, 5H), 5.81–5.72 (m, 1H), 5.06–4.96 (m, 2H), 4.49–
4.55 (m, 2H), 3.94–3.88 (m, 1H), 3.62–3.48 (m, 3H), 2.24 (quin,1H, J = 6.93,
13.86 Hz), 2.11 (quin, 1H, J = 7.92, 13.86 Hz), 2.05–1.96 (m, 1H) 1.92–1.82
NMR (CDCl3, 300 MHz): d 6.92–6.84 (dq, 1H, J = 7.0, 16.0 Hz), 6.15 (dd, 1H,
J = 7.0, 16.0 Hz), 4.20–4.14 (m, 1H), 3.92 (dt, 1H, J = 2.0, 16.0 Hz), 3.75 (t, 2H,
J = 6.0 Hz), 2.86 (dd, 1H, J = 8.0, 16.0 Hz), 2.52 (dd, 1H, J = 4.0, 16.0 Hz), 2.01–
1.93 (m, 1H), 1.90 (d, 3H, J = 2.0, 7.0 Hz), 1.88–1.82 (m, 1H,) 1.78–1.72 (m, 1H),
1.67–1.59 (m, 1H), 1.57–1.40 (m, 2H), 1.37–1.25 (m, 2H), 0.84 (d, 3H,
J = 6.99 Hz) ppm.13C NMR (CDCl3, 75 MHz): d 198.7, 143.5, 132.1, 75.4, 66.0,
60.7, 45.5, 32.9, 30.1, 28.5, 26.5, 18.3, 16.3 ppm; ESI-HRMS calcd for [M+Na]+
249.1461 found 249.1458.
(m,1H), 1.68–1.56 (m, 3H),1.41–1.24 (m, 2H), 0.80 (d, 3H, J = 6.93Hz) ppm. 13
C
NMR (CDCl3, 75 MHz): d 138.5, 135.4, 128.3, 127.7, 127.5, 116.3, 73.7, 73.2,
68.6, 67.5, 40.1, 33.0, 30.4, 26.7, 25.7, 16.8 ppm; ESI-HRMS: calcd for C18H26O2
[M+Na]+: 297.1825, found: 297.1851, HPLC ratio 90.5:9.5.
((2S,4S,6S)-2-Allyl-6-(2-(benzyloxy)ethyl)tetrahydro-2H-pyran-4-yloxy)(tert-
butyl)dimethylsilane (17): ½a D25
ꢁ
+24.64 (c 1.4, CHCl3); IR (KBr, neat): 3070, 3031,