Total synthesis of (3R,5R) and (3R,5S)-sonnerlactones

Article abstract of DOI:10.1016/j.tetlet.2016.03.030

In this Letter, an enantioselective synthesis of (3R,5R)-sonnerlactone and (3R,5S)-sonnerlactone have been described. Stereochemistry at C-5 position was fixed using a suitable proline catalyzed reaction during the synthesis of aliphatic segment. To accom

Full text of DOI:10.1016/j.tetlet.2016.03.030

Accepted Manuscript
Total synthesis of (3R,5R) and (3R,5S)-sonnerlactones
Chakrapani Sanaboina, Sridhar Chidara, Samaresh Jana, Laxminarayana
Eppakayala
PII:
S0040-4039(16)30252-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.030
TETL 47418
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 November 2015
8 March 2016
9 March 2016
Please cite this article as: Sanaboina, C., Chidara, S., Jana, S., Eppakayala, L., Total synthesis of (3R,5R) and (3R,
5S)-sonnerlactones, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.030
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1
Tetrahedron Letters
Tetrahedron Letters
Total synthesis of (3R,5R) and (3R,5S)-sonnerlactones
Chakrapani Sanaboinaa,b , Sridhar Chidarab, Samaresh Janac, and Laxminarayana Eppakayalad
a Akshaj Moleculor Research Private Limited, Nacharam, Hyderabad-500076, Telangana, India
bDepartment of Chemistry, JNT University, Hyderabad-500082, Telangana, India
c Department of Chemistry, School of Applied Sciences, KIIT University, Bhubaneswar-751024, Odisha, India
dDepartment of Physics and Chemistry, Mahatma Gandhi Institute of Technology, Gandipet, Hyderabad-500075, Telangana, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this paper, an enantioselcetive synthesis of (3R,5R)-sonnerlactone and (3R, 5S)-sonnerlactone
have been described. Stereochemistry at C-5 position was fixed using a suitable proline
catalysed reaction during the synthesis of aliphatic segment. To accomplish this target,
Mitsunobu reaction for inversion of a stereocenter and ring-closing metathesis (RCM) for
macrocyclic ring formations have been applied as key transformations.
Available online
Keywords:
Sonnerlactone
2015 Elsevier Ltd. All rights reserved.
Total synthesis
Enantioselective
Mitsunobu inversion
Ring-closing metathesis
In 2010, Song et al reported1 the isolation and structure
elucidation of two medicinally important compounds, named as
sonnerlactones. Two sonnerlactones known as (3R,5R)-
sonnerlactone (1) and (3R,5S)-sonnerlactone (2) (Figure 1) were
isolated from the extraction of marine derived fungus Zh6-B1-
which was found in the bark of Sonneratia apetala in Zhu Hai,
Guangdong, China.1 During the study of biological activities of
these two compounds, interestingly it has been observed that
sonnerlactones inhibit the growth of KV/MDR cell line up to
certain extent.1 It is also well known that benzanulated
macrocyclic lactones are usually important in medicinal
chemistry for exhibiting antibacterial, antifungal and anticancer
Retrosynthetic analysis of the targets has been depicted in
Scheme 1. Target molecule could be obtained from bis-olefin
compound 3 applying RCM protocol. The olefin compound 3 can
be achieved from aromatic carboxylic acid 4 and alcohol 5
following an esterification reaction. Compound 4 could be
synthesized
from
the
commercially available
3,5-
dihydroxybenzoic acid (6). Similarly, compound 5 could be
easily accessed from L-ethyl lactate (7). So, it might be possible
to segregate the molecule into two segments-aromatic segment 4
and aliphatic segment 5 as shown in Scheme 1.
Figure 1. Structures of sonnerlactones (1) and (2).
activities.2-4 Interesting structural features and promishing
biological properties of macrolactones have drawn much
attention of organic chemists to synthesize in an efficient
manner.5 In this context, we wish to disclose a simple and
enantioselective strategy for the synthesis of (3R,5R)-
sonnerlactone (1) and (3R,5S)-sonnerlactone (2). In our approach,
two important reactions called Mitsunobu inversion which has
been applied to reverse a stereocenter and ring-closing metathesis
(RCM) for macrocyclic ring formation have been utilized.
Scheme 1. Retrosynthetic analysis of sonnerlactones
———
 Corresponding author. Tel.: +91-674-272-5113; fax: +91-674-272-5113; e-mail: samareshfch@kiit.ac.in, samarpdp@yahoo.com.

2
Tetrahedron Letters
Keeping these facts in mind, first we decided to synthesize
(3R,5R)-sonnerlactone and the strategy is depicted in scheme 3.
As per our requirement for both the targets, aromatic segment 4
was found to be a common intermediate. So, we focused on this
part and to complete the synthesis of the segment, a known
protocol has been adopted which is presented in Scheme 2.
was subjected to hydrogenation reaction using Pd-C to afford the
macrocyclic lactone 17 in 91% yields. Interestingly, under the
conditions, benzyl group was also deprotected to obtain the
alcohol 17. Finally, deprotection of methyl groups from phenolic
hydroxyl functionality, was achieved by treating compound 17
with BBr3 to afford (3R,5R)-sonnerlactone (1) in 82% yield.13
The spectral and analytical data of our synthetic compound are in
good agreement with the reported values.1,5 Thus we have
completed the enantioselective synthesis14 of (3R, 5R)-
sonnerlactone (1) in 9 linear steps with 6.8% overall yields..
Scheme 2. Synthesis of segment 4; reagents and conditions: (a)
SOCl2, reflux, 2.5 h, then Et2NH, CH2Cl2, rt, 12 h, 70%; (b) t-
BuLi (1.1 equiv.), THF, −78 °C, 15 min, then DMF, rt, 16 h,
70%; (c) PPh3, CH3I, t-BuOK,, THF, 0 °C to rt, 6 h, 65%; (d)
NaOH, 0.5 N, MeOH, rt, 18 h, 94%.
Amide 13 was prepared from aromatic carboxylic acid 6 via
corresponding acid chloride followed by treatment with diethyl
amine.9 Ortho-lithiation chemistry using t-butyl lithium has been
adopted on 13 to generate carbanion and subsequent trapping of
the carbanion with DMF produced aromatic aldehyde 14 in good
yield.10 Wittig reaction was performed on aldehyde 14 to afford
styrene derivative 15 in moderate yield. Finally, the diethyl
amine group was removed from compound 15 using NaOH at
ambient temperature to obtain the desired aromatic segment 4 in
94% yields.
Scheme 3: Synthesis of 1; reagents and conditions: (a) (i)
(COCl)2, DMSO, Et3N, CH2Cl2, −78 °C, 2 h; (ii) PhNO, D-
proline, CH3CN, −20 °C, 24 h then NaBH4, MeOH, 0 °C; (iii)
10% Pd/C, H2, EtOAc, 12 h, 72% overall; (b) PhCH(OMe)2,
CH2Cl2, PTSA (cat.), rt, 6 h, 81%; (c) DIBAL-H, CH2Cl2, 0 °C
to rt, 2 h, 78%; (d) (i) PPh3, imidazole, I2, THF, 0 °Crt, 1 h; (ii)
vinylmagnesium bromide, CuI, dry THF, −40 °C, 5 h, 48% over
two steps; (e) DDQ, CH2Cl2:H2O (15:1), 0 °C, 1 h, 88%; (f) 4,
DEAD, Ph3P, toluene, 0 °C to rt, 12 h, 68%; (g) Grubbs’ second
generation catalyst, CH2Cl2, reflux, 12 h, 72%; (h) Pd/C, H2,
EtOAc, rt., 2 h, 91%; (i) BBr3, CH2Cl2, −78 °C to rt, 1.5 h, 82%.
Aliphatic segment 5 was derived from L-ethyl lactate (7) and the
synthetic outline is presented in Scheme 3. L-Ethyl lactate was
converted to alcohol 8 in good yield following a reported
synthetic route.8 Alcohol 8 was transformed into diol 9 in three
steps. At the first step, primary alcohol 8 was converted to its
corresponding aldehyde under Swern oxidation conditions. In
second step, the aldehyde was subjected to -aminooxylation
reaction9 catalyzed by D-proline followed by reduction afforded
the aminated alcohol. Finally, reductive hydrogenation of the
amino alcohol provided chiral diol 9 in overall 72% yields. Diol
9 was treated with (dimethoxymethyl)benzene and catalytic
amount of p-toluene sulphonic acid (PTSA) at room temperature
to obtain desired protected alcohol 10 in 81% yields. Selective
deprotection of alcohol functionality in compound 10 was
performed using DIBAL-H at low temperature to afford
compound 11 in 78% yields. Later, alcohol group of compound
11 was converted to its corresponding iodo group by treatment
with triphenyl phophine and iodine. This iodo compound was
subjected to reaction with vinyl magnesium bromide to get the
olefin 12 in good yield.10 In next step, p-methoxy benzyl (PMB)
group has been removed from compound 12 using DDQ to afford
the desired segment 5 in 88% yield.
After successful completion of construction of the target 1,
synthesis of the other isomer-(3R, 5S)-sonnerlactone(2)- was
decided to complete to verify the generality of our strategy. The
strategy has been represented in scheme 4. Basic structural
difference between compound 1 and 2 is at the stereochemistry of
C-5 centre. So, for this target, synthesis of the aliphatic segment
5a (Scheme 4) was the crucial. Thus, compound 8 was converted
to 9a in 77% yields using L-proline as the controlling agent for
introduction of OH group. Next, following the similar strategy as
described in scheme 3, compound 5a was synthesized in good
yield. Compound 5a and 4 were subjected to react together under
Mitsunobu conditions to achieve 3a in 71% yield. Compound 3a,
on exposure to Grubbs’ second generation catalyst produced
compound 16a in 68% yields. Then hydrogenation reaction of
16a afforded the desired product in 84% yields. Finally,
demethoxylation was carried out using BBr3 to obtain (3R, 5S)-
sonnerlactone in 76% yield. The analytical data of our
synthesized product are well agreement with the reported value.5
Thus, the synthesis of compound 2 was accomplished in an
enantioselective way with 7.6% overall yields.
At the final stage of our strategy, aliphatic and aromatic segments
were assembled together following esterification reaction and
ring-closing metathesis to achieve the core structure of the
molecule. Firstly, aromatic acid 4 and the alcohol 5 were reacted
in presence of triphenyl phosphine and diethyl azodicarboxylate
(DEAD) at low temperature to obtain bis-olefin compound 3 in
moderate yields.11 Exposure of 3 on Grubbs’ second generation
catalyst12 in CH2Cl2 furnished the desired olefin 16. Olefin 16

3
Tetrahedron Letters
Seliga, C. J.; Pierson, E. E.; Pierson, L. S.; VanEtten, H. D.; Gunatilaka,
A. A. L. J. Antibiot. 2004, 57, 341.
5. (a) Thirupathi, B.; Gundapaneni, R. R.; Mohapatra, D. K. Synlett 2011,
2667; (b) Yadav, J. S.; Shiva Shankar, K.; Reddy, A. S.; Subba Reddy,
B. V. Tetrahedron Lett. 2012, 53, 6380.
6. Kamila, S.; Mukherjee, C.; Mondal, S. S.; De, A. Tetrahedron 2003, 59,
1339.
7. Brimble, M. A.; Flowers, C. L.; Hutchinson, J. K.; Robinson, J. E.;
Sidford, M. Tetrahedron 2005, 61, 10036
8. See supporting information for detail experimental procedures.
Reagents and conditions: (a) Ag2O, PMBBr, CH2Cl2, reflux, 12 h. (b)
i) DIBAL-H, CH2Cl2, 0 oC to rt, 2 h; ii) Ph3P=CHCO2Me, benzene,
reflux, 2 h, 57% over two steps; (c) LAH, THF, 0 oC to rt, 2 h, 60%.
9. (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett.
2003, 44, 8293; (b) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M.
Angew. Chem. Int. Ed. 2004, 43, 1112.
Scheme 4: Synthesis of 2; reagents and conditions: (a) (i)
(COCl)2, DMSO, Et3N, CH2Cl2, −78 °C, 2 h; (ii) PhNO, L-
proline, CH3CN, −20 °C, 24 h then NaBH4, MeOH, 0 °C; (iii)
10% Pd/C, H2, EtOAc, 12 h, 77% overall; (b) PhCH(OMe)2,
CH2Cl2, PTSA (cat.), rt, 6 h, 86%; (c) DIBAL-H, CH2Cl2, 0 °C
to rt, 2 h, 74%; (d) (i) PPh3, imidazole, I2, THF, 0 °Crt, 1 h; (ii)
vinylmagnesium bromide, CuI, dry THF, −40 °C, 5 h, 50% over
two steps; (e) DDQ, CH2Cl2:H2O (15:1), 0 °C, 1 h, 83%; (f) 4,
DEAD, Ph3P, toluene, 0 °C to rt, 12 h, 71%; (g) Grubbs’ second
generation catalyst, CH2Cl2, reflux, 12 h, 68%; (h) Pd/C, H2,
EtOAc, rt., 2 h, 84%; (i) BBr3, CH2Cl2, −78 °C to rt, 1.5 h, 76%.
10. Nunomoto, S.; Kawakami, Y.; Yamashita, Y. J. Org. Chem. 1983, 48,
1912.
11. (a) Mitsunobu, O. Synthesis 1981, 1, 1; (b) Swamy, K. C.; Kumar, N. N.;
Balaraman, E.; Kumar, K. V. Chemical Reviews 2009, 109, 2551.
12. (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953; (b) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 1013.
13. Synthesis of (3R,5R)-sonnerlactone (1): To a solution of lactone 17 (60
mg, 0.16 mmol) in dry CH2Cl2 (0.5 mL), boron tribromide (3.15 mL, 1 M
in CH2Cl2, 3.2 mmol) was added dropwise under nitrogen atmosphere at
−78 °C. The resulting dark brown solution was allowed to stir at room
temperature for 1 h. After complete conversion (monitored by TLC), the
mixture was again cooled to −78 °C and quenched with methanol (1 mL).
The brown mixture was concentrated in vacuum to get a crude material
which was purified by column chromatography (60-120 silica gel, ethyl
In conclusion, total synthesis of (3R,5R)-sonnerlactone (1) and
(3R,5S)-sonnerlactone (2) have been accomplished in 6.8% and
7.6% overall yields respectively starting from commercially
available materials. In our approach, crucial aliphatic segments
were synthesized in an efficient manner using a proline catalysed
-aminooxylation reaction of aldehyde. Macrocyclic core of the
target molecule with suitable stereochemistry has been accessed
through Mitsunobu reaction and ring-closing metathesis (RCM)
protocol.
acetate/hexane = 2:3) to obtain compound 1 (39 mg, 82%) as a white
25
solid. Mp: 145–147 oC (lit.4 mp 146–147 oC). []D
= + 8.3 (c 0.9,
EtOH), (lit.1 []D = +9.0 (c 1, EtOH); IR (neat): 3504, 3423, 3179,
2941, 1657, 1609, 1458, 1391, 1318, 1264, 1207, 1165, 830, 764 cm–¹;
1H NMR (acetone–d6, 500 MHz) δ 11.03 (br s, 1H), 9.30 (br s, 1H), 6.29
(d, 1H, J = 2.3 Hz), 6.24 (d, 1H, J = 2.3 Hz), 5.01–4.93 (m, 1H), 3.88–
3.82 (m, 1H), 3.23 (dt, 1H, J = 13.4, 7.2 Hz), 2.57 (ddd, 1H, J = 13.4,
8.2, 6.0 Hz), 2.10– 2.06 (m, 1H), 2.03–2.01 (m, 2H), 1.82–1.76 (m, 1H),
1.57–1.51 (m, 1H), 1.42 (3H, d, J = 6.2 Hz), 1.35–1.26 (m, 1H); 13C
NMR (acetone–d6, 75 MHz,) δ 171.8, 163.4, 163.1, 149.4, 111.8, 106.2,
25
Acknowledgments
CS thanks JNTU for constant encouragement during this
research program. SJ acknowledges the financial support of DST,
Govt. of India (Ref No: SB/FT/CS-049/2013). SJ is also grateful
to KIIT University for providing basic research facility.
101.7, 73.2, 71.9, 45.8, 37.5, 37.0, 27.0, 21.5; HRMS (ESI) calculated for
C14H18O5 [M + H]+: 267.1227, found: 267.1221.
14. For examples of enantioselective reactions see: (a) Dong, K.; Li, Y.;
Wang, Z.; Ding, K. Angew. Chem. Int. Ed. 2013, 52, 14191; (b) Zhang,
P.; Han, Z.; Wang, Z.; Ding, K..Angew. Chem. Int. Ed. 2013, 52, 11054;
(c) Dong, K.; Wang, Z.; Ding, K. J. Am. Chem. Soc. 2012, 134, 12474;
(d) Guo, S.; Liu, J.; Ma, D. Angew. Chem. Int. Ed. 2015, 54, 1298; (e)
Yang, X.; Fu, B.; Yu, B. J. Am. Chem. Soc. 2011, 133, 12433; (f) You
Yang, Yao Li and Biao Yu, J. Am. Chem. Soc. 2009, 131, 12076; (g)
Zhang, X.; Zhou, Y.; Zuo, J.; Yu, B. Nat. Commun. 2015, 6, 5879; (h) Li,
J.; Yu, B. Angew. Chem. Int. Ed. 2015, 54, 6618; (h) Nie, S.; Li, W.; Yu,
B. J. Am. Chem. Soc. 2014, 136, 4157; (i) Xiong, H.; Xu, H.; Liao, S.;
Xie, Z.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851; (k) Xu, H.; Qu, J-
P.; Liao, S.; Xiong, S.;Tang, Y. Angew. Chem. Int. Ed. 2013, 52, 4004;
(l) Ye, K. Y.; He, H.; Liu, W. B.; Dai, L. X.; Helmchen, G.; You, S. L.
J. Am. Chem. Soc. 2011, 133, 19006.
References and notes
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Supplementary Material
Supplementary material associated with this article is
available
online
at
4. (a) He, J.; Wijeratne, E. M. K.; Bashyal, B. P.; Zhan, J.; Seliga, C. J.;
Liu, M. X.; Pierson, E. E.; Pierson, L. S.; VanEtten, H. D.; Gunatilaka,
A. A. L. J. Nat. Prod. 1985, 67, 2004; (b) Zhan, J., E.; Wijeratne, M. K.;

Graphical Abstract
Total synthesis of (3R, 5R)-sonnerlactone and
(3R, 5S)-sonnerlactone
Chakrapani Sanaboina, Sridhar Chidara, Samaresh Jana and Laxminarayana Eppakayala

4
Tetrahedron Letters
Highlights
.
(3R,5R) and (3R,5S)-Sonnerlactone: isolated from the marine derived fungus Zh6-B1.
. These compounds inhibit the growth of KV/MDR cell line up to certain extent.
. These lactones exhibit antibacterial, antifungal and anticancer activities.
. Structural features and important medicinal activity, increased the importance to make these.
. Mitsunobu Reaction and RCM protocol have been applied to construct the core.