Total syntheses of (±)-cis- and (±)-trans-neocnidilides

Article abstract of DOI:10.1016/j.tetlet.2014.06.007

Total syntheses of two antimicrobial natural products (±)-cis- neocnidilide and (±)-trans-neocnidilide starting from a readily preparable cyclohexa[b]-fused 5-oxabicyclo[2.1.1]hexane derivative are presented. The diastereomeric tetrahydrofuran tricarboxylate epimers obtained from a BF₃·OEt₂ promoted Grob-type fragmentation of the oxa-bicycle derivative were converted into title natural products by employing pyridinium dichromate/acetic anhydride mediated bis-oxidative cleavage reaction.

Full text of DOI:10.1016/j.tetlet.2014.06.007

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total syntheses of ( )-cis- and ( )-trans-neocnidilides
Surendra H. Mahadevegowda b, Faiz Ahmed Khan a,
⇑
a Department of Chemistry, Indian Institute of Technology Hyderabad, Ordnance Factory Estate, Yeddumailaram 502205, India
b Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Total syntheses of two antimicrobial natural products ( )-cis-neocnidilide and ( )-trans-neocnidilide
starting from a readily preparable cyclohexa[b]-fused 5-oxabicyclo[2.1.1]hexane derivative are pre-
sented. The diastereomeric tetrahydrofuran tricarboxylate epimers obtained from a BF3ÁOEt2 promoted
Grob-type fragmentation of the oxa-bicycle derivative were converted into title natural products by
employing pyridinium dichromate/acetic anhydride mediated bis-oxidative cleavage reaction.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 14 May 2014
Revised 3 June 2014
Accepted 3 June 2014
Available online xxxx
Keywords:
Antimicrobial
Phthalides
Total synthesis
Grob-type fragmentation
Bis-oxidative cleavage
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
Phthalides are the components of taxonomic groups of the plant
family Apiaceae.1 The stereo isomers cis- and trans-neocnidilides (1
and 2) are the tetrahydro derivatives of phthalides. The compounds
1 and 2 are present in Apium graveolens L. including their structural
analogues. Isolation and structure confirmation of 2 were reported
by Mitauhashi et al. in 1964.2 Later, Fischer et al.3 have isolated and
reported cis-neocnidilide (1) from A. graveolens L., and spectro-
scopic data comparison with previously isolated phthalides
showed that the structure is similar to previously reported isocnid-
ilide. Some naturally occurring 3-butyltetrahydrophthalides are
represented in Figure 1. Literature survey for biological features
of these natural products revealed that the compound 2 inhibits
the growth and toxin production of mycotoxin-producing fungi.4
As additional factors for biological activity profile of 2, (À)-trans-
neocnidilide and its racemic mixture showed inhibiting activity
against microorganisms Aspergillus niger, Cochliobolus miyabeanus,
H
4
7
H
H
H
3
5
6
3a
O
1
O
O
7a
O
O
O
1
trans-neocnidilide (2) cnidilide (3)
)
cis-neocnidilide(
OH
O
HO
HO
O
OH
H
(CH2)3CH3
(CH2)3CH3
O
O
O
O
HO
HO
O
OH
OH
O
celephthalide C (6)
senkyunolideJ (5)
senkyunolideN (4)
Figure 1. Some naturally occurring 3-butyltetrahydrophthalides.
and Pyricularia oryzae at the range of 50 lg/disk to 300 lg/disk
concentration.4 In continuation of hunt for new bioactive com-
pounds in natural resources, Nair and co-worker5a isolated 2 from
A. graveolens along with two other hydroxyl tetrahydrophthalides,
and biological assay for 2 displayed noteworthy mosquitocidal,
nematicidal, and antifungal activities compared to other two addi-
tionally isolated phthalides, which are having conjugation to lac-
tone carbonyl at the ring junction. Moreover, during last decade,
Miyazawa and co-workers5b have isolated trans-neocnidilide (2)
from Cynoglossum officinale including three other butyl phthalides.
The larvicidal activity test for 2 against Drosophila melanogaster
shows LC50 value 9.90 lmol/mL, and structure–activity relation-
ship confirms that the presence of conjugation with lactone car-
bonyl moiety plays a crucial role for larvicidal activity. Also, the
acute adulticidal activity test report for 2 shows 97% mortality at
a concentration of 50.0 lg/adult with LD50 value 10.82 lg/adult.
Notably, the difficulty in isolation of pure 1 is the demerit for eval-
uating more biological activity for cis-neocnidilide.3
The literature survey revealed that very few synthetic routes
have been reported for the synthesis of structurally simple 3-buty-
ltetrahydrophthalides 1 and 2.6 In the synthesis of (À)-cis-neocnid-
ilide reported by Tanaka et al.,7 it has been demonstrated that, the
⇑
Corresponding author. Tel.: +91 40 23016084.
E-mail address: faiz@iith.ac.in (F.A. Khan).
http://dx.doi.org/10.1016/j.tetlet.2014.06.007
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mahadevegowda, S. H.; Khan, F. A. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.007

2
S. H. Mahadevegowda, F. A. Khan / Tetrahedron Letters xxx (2014) xxx–xxx
OH
severe steric hindrance between the butyl chain and the olefinic
proton in the most preferable exo transition state of intra molecu-
lar Diels–Alder reaction of triene ester would diminish the forma-
tion of 3–3a cis adduct. Eventually, the variance in position of butyl
chain of triene ester afforded 1:1.4 ratio of 3–3a cis and 3–3a trans
adduct, and then minor isomer was utilized to accomplish the
synthesis of 1 via reduction of non-conjugated double bond and
recreation of conjugated unsaturation to lactone. Moreover,
McClure strategy8 for the total synthesis of both 1 and 2 from dihy-
drofuran involves utilization of phosphonates, which are obtained
via their previously reported condensation reaction involving pen-
tacovalent oxaphosphoranes and carbonyl compounds. However,
this synthesis requires construction of cyclohexene fused lactone
system and late stage Barton deoxygenation was employed to
complete the total synthesis of 1 and 2. Therefore, we sought an
alternative strategy for the synthesis of both natural products.
Grob-fragmentations9 and ring cleavage reactions are generally
efficient, these have been utilized as key reactions in numerous
natural products’ synthesis and construction of organic frame
works.10,11 Recently, we have reported12 a BF3ÁOEt2-mediated
Grob-type fragmentation reaction of compound 7. It provides tet-
rahydrofuran tricarboxylates 8a,b (ratio 8a:8b = 3:1) in near quan-
titative yield. The cyclohexa[b]-fused 5-oxabicyclo[2.1.1]hexane 7
could be prepared in gram-scale quantities from commercial avail-
able 1,2,3,4-tetrachloro-5,5-dimethoxycyclopenta-1,3-diene and
cyclohexene (three steps, overall yield 80%).13,14 The ready avail-
ability of 7 inspired us to utilize it for the synthesis of 1 and 2
employing Grob-type fragmentation12 and bis-oxidative cleavage
reactions as key steps as represented in Scheme 1.15–17
Octahydroisobenzofuran methanols 10a and 10b were prepared
starting from chromatographically well separable THF derivatives
8a and 8b, respectively. The transformation of 8a–10a is depicted
in Scheme 3, it involves conversion of THF tricarboxylate 8a to cor-
responding triol 9a by reduction with LiAlH4 in refluxing THF (74%
yield). When the compound 9a was subjected for acetonide protec-
tion, it afforded the required THF alcohol 10a along with a less
polar mixed acetal (confirmed by 1H NMR),16 which was selectively
deprotected by treatment with pyridinium p-toluenesulfonate in
MeOH at 0 °C for 50 min to afford alcohol 10a with an overall yield
of 90% (from two steps). At this stage, we turned our attention to
demonstrate the feasibility of our proposed pathway for the syn-
thesis of 1 and 2 via bis-oxidative cleavage reaction. The alcohol
10a was protected as TBDPS ether and subsequent acetonide
deprotection with PPTS (10 mol %) in MeOH at 50 °C afforded
dimethanol THF 11a with 84% yield (from two steps) as depicted
in Scheme 3. The similar experimental procedures were adopted
for preparation of 11b from 8b as detailed in Scheme 4. Then, expo-
sure of THFs 11a and 11b to bis-oxidative cleavage with PDC/Ac2O
gave lactones 11c and 11d, respectively, in moderate yields (54%)
as represented in Scheme 2.
OH
O
H
H
H
PDC/Ac2O
DMF, rt, 1 h
O
O
R2
R2
H
R1
R1
R1= CH2OTBDPS, R2 = H, 11c, 54%
R1= H, R2 = CH2OTBDPS, 11d, 54%
R1= CH2OTBDPS, R2 = H, 11a
R1= H, R2 = CH2OT BDPS, 11b
Scheme 2. Demonstration of bis-oxidative cleavage for THF diols 11a and 11b.
afford the required product. To overcome this difficulty, we con-
verted alcohol 10a to corresponding aldehyde by Parikh–Doering
oxidation employing Hünig’s base (iPr2NEt)19 which afforded alde-
hyde 12a in 81% yield without any epimerization despite being ste-
rically congested. Then, aldehyde 12a was subjected to Wittig
olefination using triphenyl(propyl)phosphonium bromide and n-
BuLi to obtain olefin 13a (Z/E = 100:0) in 74% yield.20 Further, the
hydrogenation of olefin 13a using H2, Pd-C gave complex mixture
due to double bond isomerization.21 Afterward, exposure of 13a
to hydrogenation using Adam’s catalyst (PtO2)22 delivered com-
pound 14a in 90% yield, with little amount of olefin isomerized
product (confirmed by 1H NMR). The acetonide deprotection of
14a with 10% HCl in MeOH afforded 15a in 99% yield which upon
bis-oxidative cleavage delivered 16a in 62% yield (Scheme 3).
On the other hand, having sufficient amount of minor octa-
hydroisobenzofuran derivative 8b, we proceeded to synthesize lac-
tone 16b similar to 16a as depicted in Scheme 4. In this part, the
triol 9b was obtained in 80% yield (40 h) followed by mono alcohol
10b after acetonide protection. Then, alcohol 10b was oxidized to
corresponding aldehyde 12b with 80% yield under similar oxida-
tion condition as 12a. Further, when Wittig olefination was carried
out for the compound 12b, Z/E mixture of olefin 13b resulted in
94:06 ratio with 72% yield. Then, on treatment of Z and E mixture
of alkene 13b with H2/cat. PtO2, no isomerized product was
observed and delivered the compound 14b in 94% yield. The diol
15b obtained after removal of the acetonide group of 14b was sub-
jected to bis-oxidative cleavage with PDC/Ac2O to afford lactone
16b in 64% yield.
After successfully synthesizing lactones 16a and 16b, we
focused our attention for creating the conjugated unsaturation in
a
regioselective manner via a-bromination and elimination
sequence. From the literature,23 we believe that bromination of
lactone could be accomplished directly in the presence of LDA
without converting lactone into acid sensitive silyl ketene.7 Then,
the exposure of compounds 16a and 16b to molecular bromine
in the presence of LDA in THF at À78 °C yielded diastereomerically
pure
a-bromo lactones 17a and 17b, respectively, in moderate
yields along with substantial recovery of starting materials as
depicted in Scheme 5. When we subjected compound 17a for
dehydrobromination with DBU in refluxing toluene, incomplete
consumption of starting material was observed. Then treatment
of 17a with DBU (3.0 equiv) in xylene at 140 °C afforded ( )-cis-
neocnidilide (1) and 18a24 in ratio 9:1. Due to isomerization of
conjugated double bond of 1, trace amount of ( )-cnidilide 3 (con-
firmed by 1H NMR and IR spectra) was also observed. On the other
hand, elimination of 17b with DBU (2.0 equiv) in toluene yielded
( )-trans-neocnidilide (2) and 18a with 72% yield (2:18a = 17:03).
Both 1H and 13C NMR data of synthesized natural products 1 and
2 are having close agreement with literature reported data (for
detail see S57 and S58 in Supporting information).25
After demonstrating the bis-oxidative cleavage reaction for THF
alcohols 11a and 11b, we committed to achieve the synthesis of 1
and 2, then our attention was drawn to convert the free hydroxy-
methyl group of 10a to nbutyl chain. Initially, our effort for direct
conversion18 of alcohol 10a to alkyl chain by converting it into tri-
flate and treatment with npropyl magnesium bromide failed to
OH
MeO OMe
OH
MeO2C
CO2Me
H
H
O
H
H
1
2
and
O
via bis-oxidative
cleavage
In an effort to enhance the overall yields, we turned our atten-
via Grob-type
fragmentation
R2
R1
7
tion to synthesize
a-hydroxy lactones 19a and 19b. Our results on
R1
=
nBu, R2 = H, 15a
the synthesis of 1 and 2 via
from lactones 16a and 16b are depicted in Scheme 5. The treat-
a
-hydroxylation and elimination route
R1 = H, R2
=
nBu, 15b
Scheme 1. Retrosynthetic analysis of 1 and 2 from 7.
ment of 16a and 16b with molecular oxygen using LDA/HMPA in
Please cite this article in press as: Mahadevegowda, S. H.; Khan, F. A. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.007

S. H. Mahadevegowda, F. A. Khan / Tetrahedron Letters xxx (2014) xxx–xxx
3
Me
Me
Me
O
Me
O
OH
i) PPTS (30 mol%)
2,2-DMP:Acetone(2:5)
rt, 1 h
O
O
CO2Me
CO2Me
O
OH
H
H
H
H
H
H
H
LiAlH4, THF,
DMSO, Py:SO3 (1:1)
O
O
O
ii) PPTS, MeOH
iPr2NEt, CH2Cl2,
0 oC, 3 h, 81%
reflux, 60 h
74%
oC 50 min
90%
H
0
CO2Me
CHO
OH
12a
10a
OH
9a
Br
PPh ,
8a
(from 2 steps)
i) 1H-Imidazole,
n-BuLi
3
10a
TBDPSCl,CH2Cl2,
0 oC to rt, 2 h
THF, -10 oC to rt,
3 h, 74%
ii) PPTS (10 mol%),
MeOH, 50 oC, 9 h
(84% from 2 steps)
11a
Me
O
Me
O
Me
Me
OH
O
OH
O
O
O
H
H
H
H
H2, PtO2
PDC/Ac2O
10% HCl
O
O
O
DMF,
rt, 1.5 h,
62%
EtOAc, rt, 4 h,
90%
MeOH, rt
2 h, 99%
H
H
H
H
Z:E = 100:0
16a
15a
14a
13a
Scheme 3. Synthesis of lactone 16a from 8a.
Me
Me
Me
O
Me
O
OH
O
O
i) PPTS (30 mol%)
2,2-DMP:Acetone(2:5)
rt, 1 h
OH
CO2Me
H
H
H
H
H
H
H
CO2Me LiAlH4, THF
DMSO, Py:SO3 (1:1),
O
O
O
O
iPr2NEt, CH2Cl2,
ii) PPTS, MeOH
0 oC 50 min
92%
reflux, 40 h
80%
H
CHO
CO2Me
0 oC, 3 h, 80%
12b
OH
10b
OH
Br
PPh ,
9b
8b
i) 1H-Imidazole,
(from 2 steps)
10b
11b
n-BuLi
THF, -10 oC to rt,
3 h, 72%
3
TBDPSCl,CH2Cl2,
0
oC to rt, 2 h
ii) PPTS (10 mol%),
MeOH, 50 oC, 9 h
(83% from 2 steps)
Me
Me
O
Me
Me
OH
O
H
OH
O
O
O
H
H
H
H
H
H2, PtO2
10% HCl
PDC/Ac2O
O
O
O
O
DMF,
rt, 1.5 h,
64%
MeOH, rt
2 h, 99%
EtOAc, rt, 5 h,
94%
H
H
16b
Z:E = 94:06
14b
15b
13b
Scheme 4. Synthesis of lactone 16b from 8b.
O
O
O
O
O
H
H
Br
LDA, Br2
i) DBU, xylene, reflux
O
O
O
+
or ii) DBU, toluene, reflux
THF, -78 o
C
R2
R2
R2
R2
R1
H
H
R1
R1
R1
R1
=
nBu, R2 = H, 16a
R1
=
nBu, R2 = H, 17a, yield 37% (bsmr = 78%)
R1 nBu, R2 = H, 18a
=
R1
nBu, R2 = H,
1
=
R1 = H, R2
=
nBu, 16b
n
R1 = H, R2
=
Bu,
, yield 39% (bsmr = 80%)
R1 = H, R2 nBu, 2
17a
=
17b
R1 = H, R2 nBu, 18a
=
17b
i)
ii)
1 and 18a
(9:1), yield 60%
2 and 18a
(17:03), yield 72%
O
O
H
H
OH
H
i) and iii) or
ii) and iii)
LDA, HMPA
10 h
O
O
1 and 18a or 2 and 18a
O2, THF, -78 o
C
R2
19b
R2
i) Et3N,
MsCl, DMAP
cat. CH2Cl2
iii) DBU,
toluene,
reflux
19a
R1
R1
ii) SOCl2, Py,
CH2Cl2
iii) DBU,
toluene,
reflux
R1
=
nBu, R2 = H, 19a, yield 72%
nBu, 19b, yield 70%
R1
=
nBu, R2 = H,
16a
R1 = H, R2
=
R1 = H, R2
=
nBu, 16b
2
18a
and
(0:1)
1 and 18a (41% over
(2:1)
(38% over 2 steps)
2 steps)
Scheme 5. Completion of total synthesis of ( )-cis-neocnidilide (1) and ( )-trans-neocnidilide (2) from 16a and 16b, respectively.
THF afforded 19a and 19b in 72% and 70% yields, respectively.26
Further, alcohol 19a was converted into methanesulfonate, and
the mesylate was subjected to elimination with DBU in refluxing
toluene to afford 1 and 18a in 2:1 ratio in 38% yield (over two
steps). In view of the fact that, elimination of mesylate derivative
of alcohol 19a gave moderate regioselectivity and lower yield, we
Please cite this article in press as: Mahadevegowda, S. H.; Khan, F. A. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.007

4
S. H. Mahadevegowda, F. A. Khan / Tetrahedron Letters xxx (2014) xxx–xxx
Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2002, 124, 6542; (c)
Thornton, P. D.; Burnell, D. J. Org. Lett. 2006, 8, 3195; (d) Xu, C.; Liu, Z.; Wang,
H.; Zhang, B.; Xiang, Z.; Hao, X.; Wang, D. Z. Org. Lett. 2011, 13, 1812.
11. For ring cleavage and their applications for synthesis of natural products and
organic frame works see: (a) Lange, G. L.; Merica, A.; Chimanikire, M.
Tetrahedron Lett. 1997, 38, 6371; (b) Deak, H. L.; Stokes, S. S.; Snapper, M. L.
J. Am. Chem. Soc. 2001, 123, 5152; (c) Hansson, T.; Wickberg, B. J. Org. Chem.
1992, 57, 5370; (d) White, J. D.; Li, Y.; Kim, J.; Terinek, M. Org. Lett. 2013, 15,
882; (e) Rao, G. H. M.; Khan, F. A. J. Org. Chem. 2013, 78, 11092.
12. For our recent report of Grob-type fragmentation of oxa-bridged derivatives
and for the preparation of 8a and 8b (3:1) from 7 see: Mahadevegowda, S. H.;
Khan, F. A. Tetrahedron 2013, 69, 8494.
13. The detail for preparation of compound 7 can be found in: (a) Khan, F. A.; Dash,
J.; Sudheer, Ch.; Sahu, N.; Parasuraman, K. J. Org. Chem. 2005, 70, 7565. and
references therein; (b) The commercially available reagents 1,2,3,4-
tetrachloro-5,5-dimethoxycyclopenta-1,3-diene (5.0 g) and cyclohexene
(2.5 mL) are converted into oxa-bridged derivative 7 (4.76 g) in three steps
with overall yield of 80%.
14. For our previous applications of oxa-bridged compound 7 see: (a) Khan, F. A.;
Parasuraman, K. Chem. Commun. 2009, 2399; (b) Khan, F. A.; Parasuraman, K.;
Donnio, B. Tetrahedron 2010, 66, 8745.
15. Tojo, G.; Fernández, M. Oxidation of Alcohols to Aldehydes and Ketones: A
Guide to Current Common Practice. In Basic Reactions in Organic Synthesis; Tojo,
G., Ed.; Springer: New York, 2006; pp 1–95. Chapter 1.
16. Mahadevegowda, S. H.; Khan, F. A. Tetrahedron Lett. 2014, 55, 2266.
17. Cr(VI) mediated oxidative cleavage reaction of b-hydroxy ethers to lactones
have been used in the synthesis of some natural products see: (a) Taber, D. F.;
Song, Y. J. Org. Chem. 1997, 62, 6603; (b) Huang, H.; Panek, J. S. Org. Lett. 2003, 5,
1991; (c) Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2006, 47,
4995; (d) Reddy, M. S.; Narender, M.; Rao, K. R. Tetrahedron 2007, 63, 11011; (e)
Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2005, 46, 2133.
18. (a) Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett. 1989, 30, 1281; (b) Yang,
C.; Bao, Y.-H.; Liang, P.; Ye, J.-L.; Wang, A.-E.; Huang, P.-Q. Tetrahedron 2011, 67,
6281.
further attempted dehydration of alcohol 19b, intended to enhance
the selectivity in formation of unsaturation. Compound 19b was
treated with SOCl2 and pyridine in CH2Cl2 and the resulting prod-
uct was then reacted with DBU (2.0 equiv) in refluxing toluene
(2 h). This afforded 18a with complete reversal in regioselectivity
(2:18a = 0:1).
In conclusion, we have accomplished the total synthesis of ( )-
cis-neocnidilide and ( )-trans-neocnidilide from an oxa-bridged
compound 7 using C-C sigma bond cleavage reactions. The chro-
matographically well separable THFs 8a and 8b were utilized inde-
pendently for the synthesis of 1 and 2. The synthesis has been
achieved with key reactions involving transformation of aldehyde
to alkyl chain using Wittig olefination followed by hydrogenation
and pyridinium dichromate/acetic anhydride mediated bis-oxida-
tive cleavage. Additionally, regioselective creation of conjugated
double bond was demonstrated both via
lactones.
a-bromo and a-hydroxy
Acknowledgments
F.A.K. gratefully acknowledges CSIR for financial support. S.H.M.
thanks CSIR, India for research fellowship.
Supplementary data
Supplementary data (experimental procedures, spectroscopic
data, copies of 1H, 13C spectra for all reported compounds and DEPT
135, APT spectra for selected compounds) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2014.06.007.
19. Mertz, E.; Tinsley, J. M.; Roush, W. R. J. Org. Chem. 2005, 70, 8035.
20. (a) Du, Y.; Liu, J.; Linhardt, R. J. J. Org. Chem. 2006, 71, 1251; (b) Ringstrand, B.;
Oltmanns, M.; Batt, J. A.; Jankowiak, A.; Denicola, R. P.; Kaszynski, P. Beilstein J.
Org. Chem. 2011, 7, 386.
21. Hon, Y.-S.; Chen, H.-F.; Kao, C.-Y.; Luo, C.-Z. Tetrahedron 2010, 66, 8468.
22. Wasserman, H. H.; Rusiecki, V. Tetrahedron Lett. 1988, 29, 4977.
23. Guo, Y.; Fan, L.; Wang, J.; Yang, C.; Qu, H.; Xu, H. Tetrahedron 2013, 69, 774.
24. Miura, M.; Okuro, K.; Hattori, A.; Nomura, M. J. Chem. Soc., Perkin Trans. 1 1989,
73.
References and notes
25. ( )-cis-Neocnidilide (1): Rf = 0.3 (5% EtOAc in hexane, silica gel TLC), colorless
liquid; 1H NMR (400 MHz, CDCl3): d 6.84 (q, 1H, J = 3.3 Hz), 4.65 (td, 1H, J = 8.9,
3.2 Hz), 3.02–3.09 (m, 1H), 2.30–2.37 (m, 1H), 2.14–2.26 (m, 1H), 1.87–1.98 (m,
2H), 1.42–1.60 (m, 2H), 1.25–1.39 (m, 6H), 0.90 (t, 3H, J = 7.1 Hz); 13C NMR
(100 MHz, CDCl3): d 170.2, 136.2, 129.6, 81.8, 39.7, 31.5, 27.5, 25.1, 22.6, 22.5,
21.2, 13.9; IR mmax (neat): 2927, 2856, 1757, 1683, 1454, 1224, 1184, 1093,
1027 cmÀ1; HRMS (ESI): m/z calcd for C12H18NaO2 [M+Na]+ 217.1204, found
217.1191.
1. For review on phthalides see: Beck, J. J.; Chou, S.-C. J. Nat. Prod. 2007, 70, 891.
2. Mitauhashi, H.; Muramatau, T. Tetrahedron 1964, 20, 1971.
3. Fischer, F. C.; Gijbels, J. M. Planta Med. 1987, 53, 77.
4. Suzuki, H.; Tanaka, A.; Yamashita, K. Agric. Biol. Chem. 1987, 51, 3369.
5. (a) Momin, R. A.; Nair, M. G. J. Agric. Food Chem. 2001, 49, 142; (b) Tsukamoto,
T.; Ishikawa, Y.; Miyazawa, M. J. Agric. Food Chem. 2005, 53, 5549.
6. (a) Cocker, W.; Sainsbury, D. M. Chem. Commun. 1965, 479; (b) Cocker, W.;
McMurry, T. B. H.; Sainsbury, D. M. J. Chem. Soc. 1966, 1152; (c) Beak, P.; Kempf,
D. J.; Wilson, K. D. J. Am. Chem. Soc. 1985, 107, 4745; (d) Jiao, X.-Z.; Xie, P.; Zu, L.-
S.; Liang, X.-T. J. Asian Nat. Prod. Res. 2003, 5, 165; (e) Oguro, D.; Watanabe, H.
Tetrahedron 2011, 67, 777.
7. Tanaka, A.; Suzuki, H.; Yamashita, K. Agric. Biol. Chem. 1989, 53, 2253.
8. McClure, C. K.; Jung, K.-Y. J. Org. Chem. 1991, 56, 2326.
9. (a) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6, 1; (b) Prantz,
K.; Mulzer, J. Chem. Rev. 2010, 110, 3741.
( )-trans-Neocnidilide (2): Rf = 0.3 (5% EtOAc in hexane, silica gel TLC),
colorless liquid; 1H NMR (400 MHz, CDCl3): d 6.78 (q, 1H, J = 3.4 Hz), 3.97
(ddd, 1H, J = 8.8, 7.6, 5.1 Hz), 2.45–2.54 (m, 1H), 2.30–2.39 (m, 1H), 2.13–2.24
(m, 1H), 2.03–2.09 (m, 1H), 1.91–1.96 (m, 1H), 1.70–1.81 (m, 2H), 1.47–1.55
(m, 2H), 1.32–1.45 (m, 3H), 1.12–1.25 (m, 1H), 0.92 (t, 3H, J = 7.1 Hz); 13C NMR
(100 MHz, CDCl3): d 170.2, 135.2, 131.1, 85.3, 43.1, 34.3, 27.5, 25.4, 25.0, 22.5,
20.7, 13.9; IR mmax (neat): 2929, 2859, 1758, 1682, 1455, 1326, 1248, 1224,
1182, 1085 cmÀ1. HRMS (ESI): m/z calcd for C12H18NaO2 [M+Na]+ 217.1204,
found 217.1192.
10. For selected references of Grob-fragmentation reactions have been utilized for
the total synthesis of natural products and construction of organic frame works
see: (a) Dong, J.-Q.; Wong, H. N. C. Angew. Chem., Int. Ed. 2009, 48, 2351; (b)
26. Khan, F. A.; Czerwonka, R.; Zimmer, R.; Reissig, H.-U. Synlett 1997, 995.
Please cite this article in press as: Mahadevegowda, S. H.; Khan, F. A. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.007