The stereoselective total synthesis of (3R,5R)-sonnerlactone and (3R,5S)-sonnerlactone

Article abstract of DOI:10.1016/j.tetlet.2012.09.032

The stereoselective synthesis of (3R,5R)-sonnerlactone (1) and (3R,5S)-sonnerlactone (2) has been accomplished starting from l-aspartic acid. Our strategy involves asymmetric allylation, Alder-Rickert reaction and Mitsunobu macrolactonization as the key steps.

Full text of DOI:10.1016/j.tetlet.2012.09.032

Tetrahedron Letters 53 (2012) 6380–6382
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Tetrahedron Letters
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The stereoselective total synthesis of (3R,5R)-sonnerlactone and
(3R,5S)-sonnerlactone
⇑
J. S. Yadav , K. Shiva Shankar, A. Srinivas Reddy, B. V. Subba Reddy
Natural Product Chemistry, CSIR–Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 July 2012
Revised 6 September 2012
Accepted 8 September 2012
Available online 17 September 2012
The stereoselective synthesis of (3R,5R)-sonnerlactone (1) and (3R,5S)-sonnerlactone (2) has been accom-
plished starting from
L-aspartic acid. Our strategy involves asymmetric allylation, Alder–Rickert reaction
and Mitsunobu macrolactonization as the key steps.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Sonnerlactones
Antiproliferative
Asymmetric allylation
Alder–Rickert reaction
Mitsunobu macrolactonization
Naturally occurring benzannulated macrolactones were
isolated from various species of fungi.1 Generally, most of these
lactones are known to display potent biological activities such as
antibacterial, antifungal and anticancer behaviour.1–3 In particular,
the 10-membered macrolides such as sonnerlactones,4 herbaru-
mins,5 xestodecalactones6 and stagonolides7 have received signifi-
cant attention due to their interesting biological properties.
(3R,5R)-sonnerlactone (1) and (3R,5S)-sonnerlactone (2) were iso-
lated from the mangrove endophytic fungus Zh6-B1 from the
South China Sea (Fig. 1).4 They are known to exhibit cytotoxic
activity against the human oral floor carcinoma cells and multi-
from the terminal epoxide 5, which is accessible easily from com-
mercially available
The synthesis of target molecules (1) and (2) began from the
commercially available -aspartic acid. Accordingly, -aspartic acid
L-aspartic acid.
L
L
was converted into (S)-2-Bromo 1,4-Butane diel 4 using a known
procedure reported in the literature.9 Protection of a hydroxyl
group of 4 using BnBr in the presence of NaH in THF afforded the
benzyl ether 5 in 90% yield. Reductive opening of epoxide 5 with
LAH afforded the secondary alcohol in 89% yield, which was then
protected as its MOM ether 6 using MOMCl in the presence of DI-
PEA in dichloromethane. Debenzylation of compound 6 with 10%
Pd/C under hydrogen atmosphere in methanol gave the primary
alcohol in 90% yield. Oxidation of the primary alcohol with Dess-
Martin periodinane gave the aldehyde 7 in 85% yield which was
then subjected to asymmetric allylboration with (+)-Ipc2BCl/allyl-
magnesium bromide to afford the homoallyl alcohol 8a in 68%
yield as a major diastereomer (96% de).10 The homoallylic alcohol
was utilized for the synthesis of both target molecules (1) and
(2). The homoallyl alcohol 8a was subjected to Mitsunobu’s proto-
col11 for the inversion of secondary hydroxyl group to produce the
compound 8b in 83% overall yield with (de 9:1 measured by HPLC)
which is a precursor for the synthesis of (3R,5S)-sonnerlactone (2).
The protection of secondary hydroxyl group of 8a with BnBr in
the presence of NaH in THF afforded the benzyl ether 9a in 90%
yield. Hydroboration of 9a using BH3–DMS in THF gave the primary
alcohol 10a12 in 80% yield. Tosylation of hydroxyl group of 10a fol-
lowed by treatment with lithium acetylide–ethylenediamine com-
plex gave the terminal alkyne 11a in 82% yield over two steps.13
Further treatment of alkyne 11a with n-BuLi followed by addition
drug resistant cell lines. As
a result, the total synthesis of
sonnerlactones has been reported recently.8
In this article, we wish to report a concise and efficient
approach for the synthesis of both (3R,5R)-sonnerlactone (1) and
(3R,5S)-sonnerlactone (2). Our synthetic approach involves the
asymmetric allylation, Alder–Rickert reaction and Mitsunobu mac-
rolactonization as the key steps.
The retrosynthetic analysis of the target molecules (1) and (2) is
depicted in Scheme 1. The aromatic moieties 13a and 13b were
proposed to be obtained via the Alder–Rickert reaction between
1,4-cyclohexadiene 16 and alkyne esters 12a and 12b respectively.
The alkyne esters 12a and 12b could be prepared from compounds
8a and 8b respectively using Brown’s allylation and Mitsunobu
inversion. The compounds 8a and 8b could in turn be obtained
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.032

J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 6380–6382
6381
OH
O
OH
O
NH2 O
Br
O
a, b
c
HO
OBn
HO
O
O
OH
OH
O
5
3
4
HO
HO
OH
OH
1
L-Aspartic acid
2
Figure 1. (3R,5R)-Sonnerlactone and (3R,5S)-sonnerlactone.
OMOM
MOMO
O
h
d, e
f,g
OBn
H
6
7
OH
O
OMe
R1
R1
R2
MOMO
R2
CO2Me
R2 R1
MOMO
O
OMOM
k
j
R2
HO
MeO
1
2
R1
9a
9b
8a R1= OH,R2= H
R = OBn,R = H
13a R1 = OBn; R2 = H
13b
i
1
2
R1 = OH, R2 = H (3R,5R)-
Sonnerlactone (1)
8b
1
2
R = H, R = OBn
R
1 = H; R2 = OBn
R = H, R = OH
R1 = H, R2 = OH (3R,5S)-
Sonnerlactone (2)
R1
R2
R1
R2
MOMO
MOMO
O
l, m
n
OH
MeO
OMe
R1
R2
OMOM
O
1
2
10a
R = OBn,R = H
+
1
2
11a
R = OBn,R = H
10b R1= H, R2= OBn
11b R1= H, R2= OBn
12a R1 = OBn; R2 = H
12b R1 = H; R2 = OBn
16
O
R1
R2
MOMO
O
1
2
12a
R2
R = OBn,R = H
NH2
O
MOMO
R1
12b R1= H, R2= OBn
O
HO
OH
OBn
O
Scheme 2. Reagents and conditions: (a) NaNO2, H2SO4, KBr, H2O, 0 °C, 4 h, 91%. (b)
BH3–Me2S, THF, ꢀ30 °C to rt, 18 h, 97%. (c) NaH, BnBr, dry THF, r.t, 6 h, 90%. (d) LAH,
THF, 0 °C, 90%. (e) MOMCl, DIPEA, CH2Cl2, 0 °C to r.t, 4 h, 98%. (f) H2, 10% Pd/C,
MeOH, r.t, 12 h, 95%. (g) DMP, DCM, 1 h. (h) (+)Ipc2BCl, allylMgBr, dry Et2O, ꢀ90 °C,
5 h, 68% over 2 steps; (i) DEAD, Ph3P, p-nitrobenzoic acid, THF, r.t, 1 h then K2CO3,
MeOH, r.t, 1 h, 83%. (j) NaH, BnBr, dry THF, r.t, 8 h, 90%. (k) BH3–DMS, THF 0 °C 8 h
then H2O2, aq NaOH, r.t, 4 h 80%. (l) TsCl, TEA, CH2Cl2. 0 °C to r.t, 3 h, 98%. (m)
HC„CLi, ethylenediamine complex, DMSO, r.t, 6 h, 85%. (n) ClCO2Me, n-BuLi, THF,
ꢀ78 °C, 1 h, 80%.
5
1 = OH, R2 = H
1 = H, R2 = OH
8a
8b
R
R
L-Aspartic acid
Scheme 1. Retrosynthetic analysis of (3R,5R)-sonnerlactone (1) and (3R,5S)-
sonnerlactone (2).
O
MeO
OMe
R1
a
R2
MOMO
O
+
12a R1= OBn, R2= H
12b R1= H, R2= OBn
16
OMe
OMe
CO2Me
CO2H
R1
OMOM
R2
R1
OH
R2
b
MeO
MeO
14a R1= OBn, R2= H
14b R1= H, R2= OBn
13a R1= OBn, R2= H
13b R1= H, R2= OBn
O
OMe
OH
O
O
c
d
O
R1
R1
MeO
HO
R2
R2
15a R1= OBn, R2= H
15b R1= H, R2= OBn
1 R1= OH, R2= H
2 R1= H, R2= OH
Scheme 3. Reagents and conditions: (a) N,N-dimethylaniline, 180 °C, sealed tube, 48 h, 60%. (b) 10 N NaOH, methanol, 110 °C, 8 h, then 6 N HCl 0 °C to r.t, 3 h, 80%. (c) DEAD,
Ph3P, toluene, 0 °C to r.t, 6 h 70% (d) BBr3, CH2Cl2, ꢀ78 °C to r.t. 80%.
of methyl chloroformate gave the acetylenic ester 12a in 85% yield
(Scheme 2).14
Similarly, compound 12b was prepared from 8b following the
above sequence of reactions.
Next, the Diels–Alder reaction between alkyne 12a and 1,4-
cyclohexadiene 1615,16 in a sealed tube at 180 °C with a catalytic
quantity of N,N-dimethylaniline afford the aromatic precursor
13a in 60% yield.14

6382
J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 6380–6382
compound 13b (237 mg, 60%); ½a D20
ꢁ
+ 19.6 (c 0.5, CHCl3); 1H NMR (CDCl3,
Treatment of ester 13a with sodium hydroxide in methanol at
300 MHz): d 7.35–7.31 (5H, m), 6.34–6.31 (2H, m), 4.66–4.50 (3H, m), 4.44–
4.37 (1H, m), 3.92–3.84 (4H, m), 3.82 (3H, s), 3.80 (3H, s), 3.78 (3H, s), 3.70–
3.60 (1H, m), 3.34 (3H, s), 2.57 (2H, t, J = 6.7 Hz), 1.68–1.57 (6H, m), 1.18 (3H, d,
J = 6.0 Hz); 13C NMR (CDCl3, 75 MHz): d 168.6, 161.2, 157.8, 142.3, 138.6, 128.2,
127.7, 127.5, 116.1, 105.5, 96.1, 95.3, 75.4, 70.8, 70.7, 55.7, 55.2, 52.0, 42.7,
110 °C for 8 h followed by deprotection of MOM ether with 6 N
HCl gave the seco acid 14a.17 The seco acid was then subjected
to Mitsunobu macrocyclization using triphenylphosphine and
diethyl azodicarboxylate to yield the macrolactone 15a.18 Finally,
the deprotection of both methyl and benzyl ethers using BBr3 in
dichloromethane gave the (3R,5R)-sonnerlactone (1) in 80% yield
(Scheme 3).17 The analytical data of the synthetic (3R,5R)-
sonnerlactone (1) were in agreement with the data reported in
the literature.4
Similarly, (3R,5S)-sonnerlactone (2) was achieved from 12b
following the above sequence of reactions. The analytical data of
(3R,5S)-sonnerlactone (2) were indistinguishable with the data
reported in the literature.4,19
41.3, 33.9, 33.6, 26.2, 21.3. IR (neat)
1266, 1099, 920, 829, 741, 699, 609 cmꢀ1
C26H36O7Na[M+Na]: 483.23563, found: 483.23532
2-((4R,6S)-4-(Benzyloxy)-6-hydroxyheptyl)-4,6-dimethoxybenzoate (14a):
tmax: 3503, 2942, 1726, 1602, 1458, 1377,
;
HRMS (ESI) calculated for
A
solution of hydroxy ester 13a (100 mg, 0.22 mmol) in
a
10% solution of
sodium hydroxide (2 mL) in methanol (2 mL) was heated at 110 °C for 8 h.
After cooling, the mixture was diluted with water (20 mL) and Et2O (20 mL).
After careful acidification with dil. HCl, the organic layer was separated and the
aqueous phase was extracted with Et2O (2 ꢂ 30 mL). The aqueous layers were
further extracted with Et2O (3 ꢂ 50 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification
by column chromatography on silica gel (n-hexanes/EtOAc, 7:3) afforded the
seco acid 14a (69.9 mg, 80%) as a colorless oil. ½a D20
ꢁ
= ꢀ8.1 (c 1.4, CHCl3); 1H
In summary, we have demonstrated an efficient synthetic route
for the total synthesis of (3R,5R)-sonnerlactone and (3R,5S)-
sonnerlactone in a highly stereoselective manner. The key steps
involved in this synthesis are asymmetric allylation, Alder–Rickert
reaction and Mitsunobu macrolactonization.
NMR (300 CDCl3, MHz): d 7.35–7.27 (5H, m), 6.44–6.38 (2H, m), 4.66–4.44 (2H,
m), 3.96–3.91 (4H, m), 3.84 (3H, s), 3.78–3.69 (1H, m), 2.98–2.79 (2H, m), 1.84–
1.53 (6H, m), 1.17 (3H, d, J = 5.9 Hz); 13C NMR (CDCl3, 50 MHz): d 169.2, 161.8,
158.7, 145.4, 138.2, 128.4, 128.3, 127.9, 127.6, 107.1, 96.4, 96.3, 76.5, 71.3,
64.9, 55.3, 41.4, 34.4, 32.9, 27.1, 23.5. IR (neat) tmax: 3500, 2938, 1711, 1599,
1457, 1324, 1206, 1093, 938, 833, 769, 697, 604 cmꢀ1. HRMS(ESI) calculated
for C23H30O6Na[M+Na]: 425.19373, found 425.19346.
(3R,5R)-5-(Benzyloxy)-10,12-dimethoxy-3-methyl-3,4,5,6,7,8-hexahydro-1H-
benzo[c]oxecin-1-one (15a): Triphenylphosphine (74 mg, 0.273 mmol,
2.3 equiv) was added to a cooled solution (0 °C) of seco acid 14a (50 mg,
0.124 mmol, 1 equiv) in dry toluene (40 mL) under a nitrogen atmosphere. To
this mixture, a solution of diethyl azodicarboxylate (0.043 mL, 40% in toluene,
0.273 mmol, 2.2 equiv) was added dropwise over 5 h with a syringe pump. The
resulting mixture was then allowed to stir at room temperature overnight.
Removal of the solvent followed by purification on silica gel column
chromatography (petroleum ether/ethyl acetate, 9:1) afforded the lactone
Acknowledgement
K.S.S. and A.S.R. thank the CSIR, New Delhi, India for the award
of fellowships.
References and notes
15a (33.4 mg, 70%) as a colorless oil. ½a D20
ꢁ
+ 2.3 (c 1.7, CHCl3); 1H NMR (CDCl3,
1. (a) Edrada, R. A.; Heubes, M.; Brauers, G.; Wray, V.; Berg, A.; Grafe, U.;
Wohlfarth, M.; Muhlbacher, J.; Schaumann, K.; Sudarsono, K.; Bringmann, G.;
Proksch, P. J. Nat. Prod. 2002, 65, 1598; (b) Lai, S.; Shizuri, Y.; Yamamura, S.;
Kawai, K.; Furukawa, H. Bull. Chem. Soc. Jpn. 1991, 1048, 64; (c) Sponga, F.;
Cavaletti, L.; Lazzarini, A.; Borghi, A.; Ciciliato, I.; Losi, D.; Marinelli, F. J.
Biotechnol. 1999, 70, 65; (d) Huang, Z.; Cai, X.; Shao, C.; She, Z.; Xia, X.; Chen, Y.;
Yang, J.; Zhou, S.; Lin, Y. Phytochem. 2008, 69, 1604.
2. (a) Musgrave, O. C. J. Chem. Soc. 1956, 4301; (b) Lai, S.; Shizuri, Y.; Yamamura,
S.; Kawai, K.; Terada, Y.; Furukuwa, H. Tetrahedron Lett. 1989, 30, 2241; (c)
Robeson, D. J.; Strobel, G. A.; Strange, R. N. J. Nat. Prod. 1985, 48, 139; (d)
Ghisalberti, E. L.; Rowland, C. Y. J. Nat. Prod. 1993, 56, 2175.
3. (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, 2004, 67; (b) Zhan, J.; Wijeratne, E. M. K.; Seliga, C. J.; Pierson, E. E.;
Pierson, L. S.; VanEtten, H. D.; Gunatilaka, A. A. L. J. Antibiot. 2004, 57, 341.
4. Li, K. K.; Lu, Y. J.; Song, X. H.; She, Z. G.; Wu, X. W.; An, L. K.; Ye, C. X.; Lin, Y. C.
Bioorg. Med. Chem. Lett. 2010, 20, 3326.
500 MHz): d 7.35–7.27 (5H, m), 6.25 (2H, dd, J = 3.7, 2.2 Hz), 5.39–5.27 (1H, m),
4.61–4.40 (2H, m), 3.81 (3H, s), 3.79 (3H, s), 3.56–3.47 (1H, m), 2.48–2.41 (2H,
m), 1.97 (2H, dd, J = 2.2, 12.0 Hz), 1.83–1.62 (4H, m), 1.38 (3H, d, J = 6.0 Hz); 13
C
NMR (CDCl3, 75 MHz): d 168.0, 161.3, 157.1, 142.8, 138.5, 128.3, 127.7, 127.5,
114.0, 106.2, 96.3, 77.1, 71.8, 71.2, 55.8, 55.3, 41.5, 33.9, 31.9, 27.5, 20.9. IR
(neat) t .
max: 3449, 2924, 1720, 1604, 1460, 1326, 1206, 1085, 830, 764 cmꢀ1
HRMS (ESI) calculated for C23H28O5Na[M+Na]: 407.18311, found: 407.18290.
(3R,5S)-5-(Benzyloxy)-10,12-dimethoxy-3-methyl-3,4,5,6,7,8-hexahydro-1H-
benzo[c]oxecin-1-one (15b): ½ ꢁ
a 2D0 + 6.2 (c 0.45, CHCl3); 1H NMR (CDCl3,
500 MHz): d 7.38–7.27 (5H, m), 6.30 (2H, dd, J = 3.9, 2.1 Hz), 5.40–5.29 (1H,
m), 4.63–4.44 (2H, m), 3.80–3.78 (6H, m), 3.63-3.52 (1H, m), 2.70 (2H, t,
J = 7.5 Hz), 1.97 (2H, dd, J = 3.0 Hz, 11.3 Hz), 1.76–1.58 (4H, m), 1.39 (3H, d,
J = 6.0 Hz); 13C NMR (CDCl3,75 MHz,): d 168.0, 161.2, 157.7, 142.2, 139.8, 128.3,
127.7, 127.5, 113.6, 106.1, 96.2, 77.1, 71.8, 71.1, 55.7, 55.3, 41.4, 33.8, 31.8,
27.4, 20.9. HRMS (ESI) calculated for C23H28O5Na[M+Na]: 407.18311; found
407.18285.
(3R,5R)-Sonnerlactone (1): Boron tribromide (1.56 mL, 1 M in CH2Cl2,
1.56 mmol, 20 equiv) was added dropwise to a cooled solution (ꢀ78 °C) of
lactone 15 (30 mg, 0.08 mmol, 1 equiv) in dry CH2Cl2 (0.5 mL) under nitrogen
atmosphere. The resulting dark brown solution was allowed to stir at room
temperature over 1 h. After complete conversion, the mixture was again cooled
to ꢀ78 °C and quenched with methanol (1 mL). The brown mixture was
allowed to stir at room temperature and concentrated in vacuo. Purification of
the residue by column chromatography (n-hexane/EtOAc, 6:4 gave the
sonnerlactone (1) (18.3 mg, 80%) as a white solid. mp 144–146 °C (lit.4 mp
5. Hanessian, S.; Ugolini, A.; Dube, D.; Glamyan, A. Can. J. Chem. 1984, 62, 2146.
6. (a) Petrier, C.; Luche, J.-L. J. Org. Chem. 1985, 50, 910; (b) Luche, J.-L.; Einhorn, C.
J. Organomet. Chem. 1987, 322, 177; (c) Sharma, G. V. M.; Kumar, R. K.
Tetrahedron: Asymmetry 2004, 15, 2323; (d) Barth, M.; Bellamy, F. D.; Renaut, P.;
Samreth, S.; Chuber, F. Tetrahedron 1990, 46, 6731; (e) Ishikawa, T.; Ikeda, S.;
Ibe, M.; Saito, S. Tetrahedron 1998, 54, 5869.
7. Krishna, P. R.; Srinivas, R. Tetrahedron: Asymmetry 2008, 19, 1153.
8. Thirupathi, B.; Gundapaneni, R. R.; Mohapatra, D. K. Synlett 2011, 2667.
9. Tan, N. P. H.; Donner, C. D. Tetrahedron 2009, 65, 4007.
10. (a) Ramachandran, P. V.; Chen, G. M.; Brown, H. C. Tetrahedron Lett. 1997, 38,
2417; (b) Bercedo, P. A.; Falomir, E.; Murga, J.; Carda, M.; Marco, J. A. Eur. J. Org.
Chem. 2008, 4015.
11. Yadav, J. S.; Mandal, S. S.; Reddy, J. S. S.; Srihari, P. Tetrahedron 2011, 67, 4620.
12. Yadav, J. S.; Jayaprakash, S.; Gangadhar, Y. Tetrahedron: Asymmetry 2005, 16,
2722.
13. Ito, H.; Inoue, T.; Iguchi, K. Org. Lett. 2008, 10, 3873.
14. Yadav, J. S.; Sreenivas, M.; Reddy, A. S.; Reddy, B. V. S. J. Org. Chem. 2010, 75,
8307.
15. (a) Birch, A. J. J. Chem. Soc. 1944, 430; (b) Birch, A. J.; Subba Rao, G. S. R. Adv.
Organomet. Chem. 1972, 8, 1.
16. (a) Birch, A. J.; Mani, N. S.; Subba Rao, G. S. R. J. Chem. Soc., Perkin Trans. 1 1990,
1423; (b) Kanakum, C. C.; Mani, N. S.; Ramanathan, H.; Subba Rao, G. S. R. J.
Chem. Soc., Perkin Trans. 1 1989, 1907.
146–147 °C). ½a 2D0
ꢁ
+ 9.4 (c 0.6, EtOH), (lit.4
11.03 (1H, br s), 9.30 (1H, br s), 6.29 (1H, d,
½ ꢁ
a 2D0 + 9.0 (c 1, EtOH); 1H NMR
(acetone–d6, 500 MHz):
d
J = 2.1 Hz), 6.24 (1H, d, J = 2.1 Hz), 5.01–4.93 (1H, m), 3.88–3.82 (1H, m), 3.72
(1H, s), 3.23 (1H, dt, J = 13.4, 7.2 Hz), 2.57 (1H, ddd, J = 13.4, 8.2, 6.0 Hz), 2.10–
2.06 (1H, m), 2.03–2.01 (2H, m), 1.82–1.76 (1H, m), 1.57–1.51 (1H, m), 1.44
(3H, d, J = 6.2 Hz), 1.35–1.26 (1H, m). 13C NMR (acetone–d6, 75 MHz,): d 171.8,
163.4, 163.1, 149.4, 111.8, 106.2, 101.7, 73.2, 71.9, 45.8, 37.5, 37.0, 27.0, 21.5. IR
(neat) tmax: 3504, 3423, 3179, 2941, 1657, 1609, 1458, 1391, 1318, 1264, 1207,
1165, 830, 764 cmꢀ1. HRMS (ESI) calculated for C14H18O5[M+H]: 267.1227;
found: 267.1221.
(3R,5S)-Sonnerlactone (2): The above procedure was adopted for the synthesis
of (3R,5R)-sonnerlactone (2) The target molecule (2) was obtained as a white
solid after column chromatography using n-hexanes in EtOAc (6:4)as eluent.
mp 157–159 °C (lit.4 mp 159–160 °C); ½a 2D0
ꢁ
+ 60 (c 0.5, EtOH), (lit.4 a 2D0
½ ꢁ + 64 (c
1, EtOH); 1H NMR (acetone–d6, 500 MHz): d 11.56 (1H, br s), 9.30 (1H, br s),
6.28 (1H, d, J = 2.2 Hz), 6.23 (1H, d, J = 2.2 Hz), 5.44–5.32 (1H, m), 4.26–4.15
(1H, m), 3.38 (1H, ddd, J = 2.6, 4.3, 3.9 Hz), 2.44–2.32 (1H, m), 2.18–2.10 (1H,
m), 1.89–1.74 (3H, m), 1.50–1.41 (1H, m), 1.43 (3H, d, J = 6.4 Hz), 1.31 (1H, m);
13C NMR (75 MHz, acetone –d6): d 172.6, 167.5, 164.4, 150.6, 113.0, 106.2,
102.8, 71.4, 67.9, 43.8, 38.1, 37.2, 29.5, 21.2. HRMS (ESI) calculated for
17. Napolitano, C.; McArdle, P.; Murphy, P. V. J. Org. Chem. 2010, 75, 7404.
18. Navickas, V.; Maier, M. E. Tetrahedron 2010, 66, 94.
19. Methyl-2-((4S,6S)-4-(benzyloxy)-6-(methoxymethoxy)heptyl-4,6-
dimethoxybenzoate (13b):
A mixture of acetylenic ester 12b (300 mg,
0.346 mmol), diene 16 (362 mg, 2.58 mmol) and N,N-dimethyl aniline
(catalytic) was heated in a sealed tube at 180 °C for 48 h. Up-on completion,
as indicated by TLC, the mixture was purified by silica gel column
chromatography using n-hexane-ethyl acetate (9:1) as eluent to give the title
C
14H18O5[M+H]: 267.1227, found: 267.1230.