A stereoselective approach for the total synthesis of (5R,7R,9R)-7,9-dihydroxy-5-decanolide#

Article abstract of DOI:10.1016/j.tetlet.2018.06.010

A stereoselective approach for the total synthesis of lactone (5R,7R,9R)-7,9-dihydroxy-5-decanolide is described. The sequence of synthetic reactions involves a Keck asymmetric allylation, diastereoselective iodo-carbonate cyclization, regioselective ring

Full text of DOI:10.1016/j.tetlet.2018.06.010

Accepted Manuscript
A stereoselective approach for the total synthesis of (5R,7R,9R)-7,9-dihy-
droxy-5-decanolide
Gembali Manikanta, Palakodety Radha Krishna
PII:
S0040-4039(18)30739-1
https://doi.org/10.1016/j.tetlet.2018.06.010
TETL 50048
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 May 2018
31 May 2018
3 June 2018
Please cite this article as: Manikanta, G., Radha Krishna, P., A stereoselective approach for the total synthesis of
(5R,7R,9R)-7,9-dihydroxy-5-decanolide, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.06.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
A stereoselective approach for the total
synthesis of (5R,7R,9R)-7,9-dihydroxy-5-
decanolide
Leave this area blank for abstract info.
Gembali Manikanta and Palakodety Radha Krishna*

1
Tetrahedron Letters
journal homepage: www.els evier.com
A stereoselective approach for the total synthesis of (5R,7R,9R)-7,9-dihydroxy-5-
decanolide
Gembali Manikanta and Palakodety Radha Krishna*
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division
CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A stereoselective approach for the total synthesis of lactone (5R,7R,9R)-7,9-dihydroxy-5-
decanolide is described. The sequence of synthetic reactions involves a Keck asymmetric
allylation, diastereoselective iodo-carbonate cyclization, regioselective ring-opening reaction,
oxidative lactonization.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis,
Lactones,
Bartlett–Smith halocyclization,
Oxidative lactonization.
Introduction
commercially available 1, 5 Pentanediol by a sequential
traditional steps.
ꢀ-Lactone is a common structural motif among many classes
of natural products, some of which exhibit striking biological
properties.1 Recently Yoshihito Shiono and co-workers isolated
ꢀ-lactone containing polyketide natural product (5R,7R,9R)-7,9-
dihydroxy-5-decanolide 1 from rice cultures of Cylindrocarpon
sp. SY-39 along with another compound (4E,6R,9R)-6,9-
dihydroxydec-4-enoic acid (2).2 The biological activity of
compound 1 has not been fully evaluated, compound 2 exhibited
moderate antimicrobial activity against Staphylococcus aureus
NBRC 13276 and Aspergillus clavatus F 318a at a concentration
of 50 µg per disk.2 As part of our research program targeting on
the synthesis of lactone containing natural products, earlier we
reported total synthesis of some lactone containing molecules.3 In
continuation, herein we describe the stereoselective approach to
the total synthesis of (5R,7R,9R)-7,9-dihydroxy-5-decanolide.2
O
O
OH OH
OH OH OH
OBn OH
O
HO
BnO
4
3
1
OH
BnO
1,5 Pentanediol
5
Scheme 1: Retrosynthetic analysis of compound 1
Accordingly, the synthesis of 1 commencing from the
monoprotected 1,5-pentanediol 64 is shown in Scheme 2. The
primary alcohol function in 6 oxidized under Swern conditions to
give the aldehyde, which was immediately subjected to the Keck
asymmetric allylation with (S)-BINOL, 4 Å MS, Ti(OiPr)4,
allyltributylstannane, CH2Cl2, -78 C to -20 C, to afford homo
allylic alcohol 5 in 80% yield (two steps) and 96% ee. All the
spectral data of alcohol 5 matched with the reported values of an
enantiomer but the optical rotation had the opposite sign.5 The
newly formed hydroxy group in 5 was protected with benzyl
bromide in the presence of sodium hydride in THF to afford the
dibenzyl compound 7 in 87% yield. The one-pot oxidative
cleavage of the terminal double bond in 7 with OsO4-NaIO4 and
2,6-lutidine in dioxane-water (3:1)6 afforded the desired
o
o
O
O
OH
OH
O
OH OH
OH
1
2
The envisaged retrosynthetic strategy for compound 1 is
delineated in Scheme 1. A linear synthetic strategy was invoked
wherein compound 1 was accessed from oxidative lactonization
of corresponding acid obtained from 3, that might be prepared by
regioselective ring-opening of epoxide 4 followed by dibenzyl
deprotection. The epoxy alcohol 4 might in turn be obtained from
chiral homo allylic alcohol 5, that could be prepared from
aldehyde,
which
was
immediately
treated
with
allyltrimethylsilane in the presence of titanium tetrachloride in
CH2Cl2 at –78 °C according to Reetz’s protocol7 to give the anti
1,3-homoallylic alcohol 8 stereoselectively in 73% yield (two
steps). All the spectral data of this compound matched with our
earlier data.4

2
Tetrahedron Letters
Surprisingly, the 1H and 13C NMR spectroscopic data of
OH
c
b
a
1,5 Pentanediol
BnO
OH
BnO
synthetic compound 1 are not in consistent with the reported data
of natural product.2 Thorough examination of the H NMR data
1
6
5
of the synthetic compound 1 revealed contrasting chemical shift
differences of key hydrogens when compared to the natural
product. Remarkably the hydrogens attached to the stereogenic
centres H9 and H7 appeared upfield in the synthetic product
(Table 1). Moreover, some minor differences between other
hydrogens and several carbon chemical shifts were also found
(Table 1).
OBn OBoc
OBn OH
OBn
d
e
BnO
BnO
BnO
7
8
9
OBn OH OH
OBn OH
O
g
f
BnO
BnO
10
4
Scheme
2
;
. Reagents and conditions: (a) Ref. 4 (b) (i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 1 h (ii) S-BINOL,
Ti(OiPr4), allyltributyltin, CH2Cl2, -78 oC, 80% (over two steps); (c) BnBr, NaH, THF, 0o
C
to r.t., 87%; (d) (i)
To corroborate the structure assigned of the synthetic
product further, we resorted to chemical correlation method. The
diacetate of compound is already known in the literature.10
Hence, compound 1 was converted into its diacetate under
OsO4, NaIO4, 2,6-lutidine, 1, 4-dioxane:water (3:1), r.t.; (ii) TiCl4, allyltrimethylsilane, CH2Cl2, –78 °C, 1 h, 73%
(over two steps); e) (Boc)2O, DMAP, CH2Cl2, r.t., 5 h, 88%; (f) NIS, CH3CN, -40 to 0 °C, 10 h; (ii) K2CO3, CH3OH,
0 °C to r.t., 2 h, 73 %, (over two steps); (g) LiAlH4, THF, r.t., 2h, 88%.
Next, Boc protection of allylic alcohol 8 with di-tert-butyl
dicarbonate in the presence of DMAP gave the homoallylic tert-
butyl carbonate 9 in 88% yield. Compound 9 was subjected to the
Bartlett-Smith iodo-carbonate cyclization8 with NIS in CH3CN to
furnish the cyclic carbonate derivative, which on treatment with
K2CO3 in CH3OH delivered the desired syn-epoxy alcohol 4 in
73% yield (two steps). Regioselective reductive opening of
epoxide 4 using LiAlH4 in THF furnished syn-1,3-diol 10 in 88%
yield.
1
standard conditions to obtain 12 (80%). The H and 13C NMR
spectra and other physical data of our synthetic compound 12
was in complete agreement with literature data.10 The
comparative chemical analysis of compound 12 with literature
data confirmed the absolute stereochemistry of synthetic 12 as
(5R,7R,9R) and since 12 was obtained from 1, extending the
argument we thus established the structure of synthetic
compound 1 as (5R,7R,9R)-7,9-dihydroxy-5-decanolide and is
constitutionally correct. It is therefore likely that the spectral
discrepancies are due to stereochemical misassignments of the
natural product.
The relative stereochemistry of the 1,3-diol system in 10 was
determined by Rychnovsky’s analogy.9 Thus, treatment of diol
10 with 2,2-DMP in the presence of PPTS in CH2Cl2 at room
temperature gave the syn-acetonide 11 (86% yield). The 13C
NMR of 11 showed signals assigned to the acetonide methyl
group at δ = 19.9 and 30.3 ppm and quaternary carbon resonated
at 98.3 ppm in accordance with Rychnovsky’s9 model for a 1,3-
syn relationship between the acetonide-attached carbons. Thus the
relative stereochemistry of the newly created stereogenic center
was unequivocally assigned as syn to the existing one and the
absolute stereochemistry of the newly created stereogenic carbon
could be assigned as 'R'.
O
O
Ac2O, Et3N
O
OH OH
O
OAc OAc
DMAP, CH2Cl2
r.t., 80%
12
1
In summary, we accomplished the linear, stereocontrolled
total synthesis of (5R,7R,9R)-7,9-dihydroxy-5-decanolide.1 The
key features of the synthesis include asymmetric Keck allylation,
Bartlett-Smith iodocyclization, regioselective ring opening of
epoxide and oxidative lactonization. The differences in the
spectral data between synthetic 1 and natural product strongly
suggested a structural misassignment during the isolation of
(5R,7R,9R)-7,9-dihydroxy-5-decanolide and a structural revision
is thus warranted.
OBn OH OH
OBn
O
O
2,2-DMP, PPTS
BnO
BnO
CH2Cl2, 0 °C - r.t.
3 h, 86%
10
11
In the next stage debenzylation of compound 10 under H2
and 10% Pd-C in CH3OH for 3 h at room temperature gave the
tetrol 3 (86% yield) which was lactonized in a single step by
selective oxidation of the primary alcohol to its corresponding
acid with TEMPO and [bis(acetoxy)iodo]benzene in CH2Cl2, H2O
(3:1) followed by cyclization to afford the target molecule 1 in
75% yield.
Acknowledgements
One of the authors (G. M) is thankful to the UGC, New Delhi
for financial support in the form of fellowship.
IICT/Pubs/2018/158.
O
OH OH OH
OBn OH OH
a
b
O
OH OH
References
HO
BnO
10
3
1
1. (a) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G.
K. J. Org. Chem. 1990, 55, 4912-4915. b) Drewes, S. E.;
Sehlapelo, B. M.; Horn, M. M.; Scott-Shaw, R.; Sandor, O.
Phytochemistry. 1995, 38, 1427-1430.
Scheme 3: Reagents and conditions : (a) H2, 10% Pd-C, CH3OH, r.t., 3h, 86%; (b)TEMPO, BIAB, CH2Cl2:H2O (3:1),
r.t., 1 h, 75%.
1
Table 1. H and 13C data of natural product and synthetic
compound.
_______________________________________________________
2. Yoshidaa, S.; Suzukia, T.; Furunob, H.; Aboshia, T.; Murayamaa,
T.; Kosekia, T.; Shiono, Y. Nat. Prod. Research. 2018, 32, 60–64.
Position
Natural product
Synthetic product (1)
δ
13C NMR 1H NMR
δ
13C NMR 1H NMR
3. (a) Radha Krishna, P.; Ramana Reddy, V. V. Tetrahedron Lett.
2005, 46, 3905-3907. (b) Radha Krishna, P.; Srinivas Reddy, P.
Tetrahedron. 2007, 63, 3995-3999. (c) Radha Krishna, P.;
Srinivas, R. Tetrahedron Lett. 2007, 48, 2013-2015. (d) Radha
Krishna, P.; Srinivas, R. Tetrahedron: Asymm. 2007, 18, 2197-
2200. (e) Radha Krishna, P.; Srinivas, P. Tetrahedron Lett. 2010,
51, 2295-2296. (d) Radha Krishna, P.; Rajesh, N.; Ramesh, k.
Synthesis. 2014, 46, 307-312. (e) Dayaker, G.; Radha Krishna, P.
Helv. Chem. Acta. 2014, 97, 868-880. (f) Manikanta, G.; Raju, G.;
Radha Krishna, P. RSC Adv. 2015, 5, 7964-7969. (g) Manikanta,
1
177.2
172.3
2,4,6,8
28.1, 34.7 1.79-1.82 m 25.0, 30.2 1.60-1.82 m
43.3, 36.5
1.86-1.93 m 47.7, 45.4 1.86, 1.97 m
2.12-2.20 m
2.40-2.45 m 29.2
3
7
9
5
10
28.8
67.7
67.1
78.9
24.1
2.44, 2.54m
4.33 m
4.49 m
4.87 m
1.37 d
3.99 m
4.04 m
4.90 quin
1.32 d
67.5
67.2
77.6
19.2

3
G.; Nagaraju, T.; Radha Krishna, P. Synthesis 2016, 48, 4213-
4220.
4. Raju, G.; Anitha, K.; Radha Krishna, P. Synlett 2015, 26, 937-941.
5. (a) Tony, K. A.; Dabideen, D.; Li. J.; Díaz-Hernández, M. D.;
Jiménez-Barbero, J.; Mootoo, D. R. J. Org. Chem. 2009, 74, 7774-
7780. (b) Yadav, J.S.; Swapnil, N.; Venkatesh, M.; Prasad, A.R.
Tetrahedron Lett. 2014, 55, 1164-1167.
6. Yu,W.; Mei,Y.; Kang, Y.; Hua, Z.; Jin, Z.; Org. Lett. 2004, 6,
3217-3219.
7. (a) Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983, 105, 4833-
4835. (b) Reetz, M. T.; Kesseler, K.; Jung, A. Tetrahedron Lett.
1984, 25, 729-732. (c) Keck, G. E.; Murry, J. A. J. Org. Chem.
1991, 56, 6606-6611.
8. Barrlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.;
Jernstedt, K. K. J. Org. Chem. 1982, 47, 4013-4018.
9. (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990,
31, 945-948; (b) Evans, D. A.; Rieger, D. L.; Gage, J. R.
Tetrahedron Lett. 1990, 31, 7099-7103; (c) Rychnovsky, S. D.;
Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511-3515.
10. Yamauchi, S.; Nishimura, H.; Nishiwaki, H. Biosci. Biotechnol.
Biochem. 2015, 79, 16-24.
11. For spectral data and experimental procedures, please see
Supporting Information.

4
Tetrahedron Letters
HIGHLIGHTS
•
•
•
ꢀ-Lactone natural product
Keck asymmetric allylation
Iodo-carbonate cyclization